Metal Catalyzed Cascade Reactions

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19 Topics in Organometallic Chemistry

Editorial Board: J. M. Brown · P. H. Dixneuf · A. Fürstner · L. S. Hegedus P. Hofmann · P. Knochel · G. van Koten · S. Murai · M. Reetz

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Metal Catalyzed Cascade Reactions Volume Editor: Thomas J. J. Müller

With contributions by C. Aubert · G. Balme · D. Bouyssi · C. Bruneau · S. Dérien P. H. Dixneuf · L. Fensterbank · V. Gandon · M. Malacria A. de Meijere · N. Monteiro · T. J. J. Müller · E. Negishi N. T. Patil · J. Pérez-Castells · G. Wang · Y. Yamamoto P. von Zezschwitz · G. Zhu

123

The series Topics in Organometallic Chemistry presents critical overviews of research results in organometallic chemistry. As our understanding of organometallic structure, properties and mechanisms increases, new ways are opened for the design of organometallic compounds and reactions tailored to the needs of such diverse areas as organic synthesis, medical research, biology and materials science. Thus the scope of coverage includes a broad range of topics of pure and applied organometallic chemistry, where new breakthroughs are being achieved that are of signiﬁcance to a larger scientiﬁc audience. The individual volumes of Topics in Organometallic Chemistry are thematic. Review articles are generally invited by the volume editors. In references Topics in Organometallic Chemistry is abbreviated Top Organomet Chem and is cited as a journal. Springer WWW home page: springer.com Visit the TOMC content at springerlink.com

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Prof. Alois Fürstner Max-Planck-Institut für Kohlenforschung Kaiser-Wilhelm-Platz 1 45470 Mülheim an der Ruhr, Germany [email protected]

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Prof. Gerard van Koten Department of Metal-Mediated Synthesis Debye Research Institute Utrecht University Padualaan 8 3584 CA Utrecht, The Netherlands [email protected]

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Preface

Nature accomplishes many syntheses–even those of complex molecules–by sequences of elementary steps. In the last few decades, the blueprint of catalyzed cascade reactions has found fertile soil through the advent of transition metal catalysis in laboratories. Scrutinizing catalytic cycles and mechanistic insight has paved the way for designing new sequential transformations catalyzed by transition metal complexes in a consecutive or domino fashion. In particular, transition metal-catalyzed sequences considerably enhance structural complexity by multiple iterations of organometallic elementary steps. All this has fundamentally revolutionized synthetic strategies and conceptual thinking. This monograph is not intended to provide a comprehensive treatment of all transition metal-catalyzed cascade reactions, but rather gives an impression of the highly dynamic nature and the potency of concepts in a rapidly developing ﬁeld. Although many transition metal complexes have been found to efﬁciently catalyze cascade and sequential reactions, palladium complexes are clearly privileged and of paramount importance. However, further transition element complexes are increasingly entering the stage with peculiar reactivity and stunning new sequences are being discovered. With breathtaking speed, unusual structural frameworks and scaffolds are being generated by cascade reactions. Based upon fundamental mechanistic insight into elementary steps, such as the insertion of unsaturated functionality, the voyage into the ﬁeld of transition metal-catalyzed cascade reactions commences with an illustration of cyclization via carbopalladation and acylpalladation by E. Negishi, G. Wang and G. Zhu. In a treatment of sequences consisting of Heck and pericyclic reactions, P. von Zezschwitz and A. de Meijere present an array of domino and consecutive transformations. The chemistry of π-allyl palladium chemistry has reached maturity and is well suited for the development of cascade reactions as presented by N. T. Patil and Y. Yamamoto. From the perspective of cross-coupling reactions, the required organometallic coupling partner can also be generated by Michael-type additions that pave the way to transition metal-promoted cyclizative transformations as discussed by G. Balme, D. Bouyssi and N. Monteiro. Killing two or more birds with one stone is the ¨ller, where one source or precursor of pallamotif presented by T. J. J. Mu

VIII

Preface

dium complexes is operative in multiple processes in a sequential or consecutive fashion. Cascade reactions implementing the Pauson–Khand reaction, the ideal type of a metal-catalyzed multicomponent reaction, are covered by J. P´erez-Castells. Besides carbopalladation, metal-catalyzed cycloisomerizations are excellent entries into sequences generating complex polycyclic molecules from acyclic precursors, as highlighted by C. Aubert, L. Fensterbank, V. Gandon and M. Malacria. Finally, ruthenium catalysis stands at the entrance to a new and rich ﬁeld of cascade and sequential catalytic transformations that are introduced by C. Bruneau, S. D´erien, P. H. Dixneuf. This volume introduces researchers, teachers and students, both experts and novices, to an exciting ﬁeld of innovative methodology. I am most grateful to the team of distinguished experts who have contributed by writing a chapter and we dedicate this volume to all pioneers and pathﬁnders of cascade reactions and future adventurers and scouts ready to explore yet unknown ﬁelds and to ﬁnd new routes to complex structures by transition metal-catalyzed cascades. Heidelberg, February 2006

¨ller Thomas J. J. Mu

Contents

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation E. Negishi · G. Wang · G. Zhu . . . . . . . . . . . . . . . . . . . . . . .

1

Domino Heck-Pericyclic Reactions P. von Zezschwitz · A. de Meijere . . . . . . . . . . . . . . . . . . . . .

49

Palladium Catalyzed Cascade Reactions Involving π-Allyl Palladium Chemistry N. T. Patil · Y. Yamamoto . . . . . . . . . . . . . . . . . . . . . . . . . .

91

The Virtue of Michael-Type Addition Processes in the Design of Transition Metal-Promoted Cyclizative Cascade Reactions G. Balme · D. Bouyssi · N. Monteiro . . . . . . . . . . . . . . . . . . . 115 Sequentially Palladium-Catalyzed Processes T. J. J. Müller . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Cascade Reactions Involving Pauson–Khand and Related Processes J. Pérez-Castells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 Complex Polycyclic Molecules from Acyclic Precursors via Transition Metal-Catalyzed Cascade Reactions C. Aubert · L. Fensterbank · V. Gandon · M. Malacria . . . . . . . . . . 259 Cascade and Sequential Catalytic Transformations Initiated by Ruthenium Catalysts C. Bruneau · S. Dérien · P. H. Dixneuf . . . . . . . . . . . . . . . . . . 295 Author Index Volumes 1–19 . . . . . . . . . . . . . . . . . . . . . . . . 327 Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337

Top Organomet Chem (2006) 19: 1–48 DOI 10.1007/3418_013 © Springer-Verlag Berlin Heidelberg 2006 Published online: 4 May 2006

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation Ei-ichi Negishi (u) · Guangwei Wang · Gangguo Zhu H.C. Brown Laboratory of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907-2084, USA [email protected] 1

Introduction and General Discussion . . . . . . . . . . . . . . . . . . . . .

Palladium-Catalyzed Cyclization via Carbopalladation . . . . . . . . . Cyclization via Single Carbopalladation . . . . . . . . . . . . . . . . . . Cyclic Heck Reactions, Noteworthy Variations . . . . . . . . . . . . . . Cyclic Carbopalladation Terminated by Processes Other than β-Dehydropalladation . . . . . . . . . . . . . . . . . . . . . 2.2 Cyclization via Double and Multiple Carbopalladation Reactions . . . . 2.2.1 “Zipper”-Mode Cascade Cyclization via Carbopalladation . . . . . . . . 2.2.2 “Dumbbell”-Mode and Related Circular Cascade Cyclization Processes via Carbopalladation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3 Spiro-Mode and Linear-Fused-Mode Cascade Cyclization Processes via Carbopalladation . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

. . . . . .

11 12 12

. . . . . .

17 26 26

. .

27

. .

31

Palladium-Catalyzed Cyclization via Acylpalladation . . . . . . . . . . . . Cyclization via Single Acylpalladation . . . . . . . . . . . . . . . . . . . . . Double or Multiple Carbopalladative Cyclization Reactions Involving One or More Cyclic Acylpalladation Processes . . . . . . . . . . . . . . . .

32 33 39

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

41

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

43

2 2.1 2.1.1 2.1.2

3 3.1 3.2 4

Abstract Over the past two decades, cyclic carbopalladation and related cyclic acylpalladation of alkenes, allenes, alkynes, and related π complexes including the cyclic Heck reaction have been developed into new and attractive synthetic methods. This chapter mainly discusses catalytic cyclization reactions via cyclic carbopalladation and cyclic acylpalladation, which may not be classiﬁed under the cyclic Heck reaction. Keywords Acylpalladation · Cascade Carbopalladation · Cyclic Acylpalladation · Cyclic Carbopalladation

1 Introduction and General Discussion Alkenes and alkynes represent some of the most reactive classes of functional groups toward Pd. They are generally more reactive than various

2

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carbonyl functionalities including ketones, esters, amides and even aldehydes [1]. Their presence also makes otherwise relatively unreactive functional groups, such as halogens, in their vicinity much more reactive. Thus, alkenyl, alkynyl, allyl, propargyl, as well as aryl and benzyl halides and related electrophiles are generally more reactive than the corresponding ordinary alkyl halides toward Pd. Those interactions mentioned above lead to π-complexation and oxidative addition, representing two of the several most widely employed routes to organopalladium derivatives along with transmetallation with Pd, hydropalladation, and heteropalladation deﬁned as addition of Pd – X bonds to π-bonds, where X is any element other than C or H [2]. Organopalladium derivatives obtained by any of the methods indicated above can undergo carbometallation which may be deﬁned as a process of addition, generally syn-addition, of a C – Pd bond to alkenes and alkynes (Schemes 1 and 2). The regiochemistry of carbometallation can be affected by mutually competing factors and is therefore often somewhat unpredictable.

Scheme 1

Scheme 2

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

3

Carbopalladation itself is a process that is only stoichiometric in Pd (Schemes 1 and 2). It must therefore be combined with some processes for regeneration of Pd to devise catalytic cycles. In the Heck reaction [3–5], which undoubtedly is currently the most widely used synthetic reaction involving carbopalladation, the critical carbopalladation process is followed by β-dehydropalladation for regeneration of Pd(0)Ln as a catalyst (Eq. 1 in Scheme 3). It is instructive to note that the original version of the reaction [6] was only stoichiometric, because the required organopalladium intermediate, RPd(II)Ln X, was generated by non-redox transmetallation (Eq. 2 in Scheme 3). So, a Pd(0)-to-Pd(II) oxidative process was missing for completion of a catalytic cycle. These two reactions vividly indicate the signiﬁcance of correctly choosing and linking appropriate microsteps to come up with synthetically useful catalytic cycles. Another prototypical catalytic process proceeding via carbopalladation is the Maitlis alkyne cyclotrimerization to give benzene derivatives [7, 8], the discovery of which predates that of the Heck reaction. Although its mechanistic details are somewhat unclear, the process most likely involves one halopalladation, two carbopalladations, and one dechloropalladation (Scheme 4). As attractive as this reaction might appear, it is important to note that the reaction generally lacks control over regiochemistry and alkyne “pair”-selectivity in cases where two or three different unsymmetrically substituted alkynes are to be incorporated into benzene derivatives. Consequently, its synthetic application is practically limited to the synthesis of symmetric benzene derivatives perhaps of materials chemical interest. This indeed is a very serious and important consideration in the development of methods for the synthesis of organic compounds of biological and medicinal interest, which is the main topic of this chapter.

Scheme 3

Scheme 4

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Currently, there seems to be a widespread tendency to call many reactions proceeding via carbopalladation the Heck reaction. However, this practice is clearly incorrect, since the scope of carbopalladation is signiﬁcantly wider than that of the Heck reaction. The alkyne carbopalladation reaction shown in Scheme 4, which is not accompanied by β-dehydropalladation may not be viewed as an example of the Heck reaction. In fact, this chapter focuses its attention on various carbopalladation reactions that may not be considered as examples of the Heck reaction. Although some of such processes are combined with the Heck reaction in many cases. Since both starting organometals and products in carbopalladation are organopalladium derivatives (Schemes 1 and 2), the process of carbopalladation can, in principle, repeat itself as exempliﬁed in the reaction shown in Scheme 4. Thus, unless intercepted by some C – Pd bond cleaving process, this “living” process will stay alive, and no catalytic process will result. In both Heck and Maitlis reactions, the carbopalladation steps are spontaneously followed by β-dehydropalladation and dechloropalladation, respectively. In cases where no such process occurs spontaneously, some processes must be deliberately devised usually through addition of appropriate reagents. In addition to dehydropalladation and dechloropalladation shown in Schemes 3 and 4 as well as in Eqs. 1 and 2 in Scheme 5, several other reactions used for this purpose are exemplied with prototypical cases of catalytic cyclic carbopalladation shown in Scheme 5 [9–19]. Patterns of cyclic carbopalladation. As discussed above, the fundamentally stoichiometric and “living” nature of carbopalladation imposes various difﬁculties to be overcome. Carbopalladation can, in principle, be either a single-stage process or double- or multiple-stage processes. Doubleand multiple-stage carbopalladation reactions have often been called either “domino” or “cascade” carbopalladation reactions. In some cases, two-stage carbopalladation reactions have also been called “tandem” carbopalladation reactions. None of these three words is a chemical term, and choice between them is a matter of taste. In this chapter, the term “cascade” will be used for both double- and multiple-stage carbopalladation processes. As discussed in conjunction with the intermolecular cascade carbopalladation reaction shown in Scheme 4, it has been very difﬁcult to satisfactorily control both “queuing” or “pair”-selectivity and regioselectivity of intermolecular cascade carbopalladation processes. Consequently, essentially all of the cascade carbopalladation reactions discussed here are at least partially intramolecular. The currently known cyclic cascade carbopalladation processes can be classiﬁed into a few to several types shown in Scheme 6. At this point, it is appropriate to point out that not all cyclization reactions of organopalladation with π-bonds involve syn-addition of the C – Pd bonds to carbon–carbon π-bonds. Some processes have been shown to involve anti-addition, as exempliﬁed in Scheme 7. This reaction is believed to proceed via π-complexation, nucleophilic attack from the side opposite to Pd,

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

5

Scheme 5

and reductive elimination [22]. No additional discussion of this type of cyclization reactions will be presented in this chapter. The readers are referred to a recent review of this subject [23].

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Scheme 6

Cyclic acylpalladation. Another major subtopic of carbopalladation is acylpalladation. In the mid-1960s, two seemingly independent papers were published by J. Tsuji [24] and P.R. Hughes [25, 26]. The former reported a perfectly alternating copolymerization of norbornadiene with CO (Scheme 8), while the latter described two related Pd-catalyzed carbonylation cyclizations shown in Scheme 9.

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

7

Scheme 7

Scheme 8

Scheme 9

Although the Pd-catalyzed alkene-CO copolymerization reaction must involve a series of acylpalladation reactions, it is outside the scope of this chapter. And, the readers are referred to recent reviews and pertinent references cited therein [27–29]. As such, the cyclic carbonylation reactions of dienes were of limited synthetic utility because of difﬁculties in controlling regiochemistry and other aspects of importance in ﬁne chemicals synthesis. Whatever the reasons might have been, little had been reported further until the 1980s. Development of cyclic acylpalladation of halodienes and haloarylalkenes during the 1983–1985 period [10, 30] (Scheme 10) proved to be a breakthrough triggering many subsequent investigations both by the authors’ group and by others including W. Oppolzer, R. Grigg, and K. Yamamoto. The two discrete cyclic acypalladation reactions shown in Eqs. 1 and 2 of Scheme 10 have been conveniently termed Type I and Type II cyclic acyl-

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Scheme 10

palladation reactions and abbreviated as Type I Ac-Pd and Type II Ac-Pd, respectively. In addition to these processes, yet another process involving trapping of acylpalladium intermediates by enolates generated in situ by cyclic acylpalladation was discovered in 1990 [31] and termed Type III cyclic acylpalladation abbreviated as Type III Ac-Pd (Eq. 3 in Scheme 10). Although no cyclic acylpalladation was involved, trapping of acylpalladation derivatives by enolates had already been discovered in 1986 [32]. Thus, an attempted cyclic acylpalladation of an iodoketone intermediate was aborted by trapping of the acylpalladium intermediate by an enolate generated under the reaction conditions (Eq. 1 in Scheme 11). A few years later, a similar trapping of acylpalladium species by enolates was shown to serve as a process of termination of the alkene-CO copolymerization [33] (Eq. 2 in Scheme 11). Later systematic investigations [34–36] have established that trapping of acylpalladium derivatives with enolates can occur both intramolecularly [34, 35] (Scheme 11) and intermolecularly [31, 36, 37] (Scheme 12) and that intramolecular trapping can be achieved either with O-enolates or with C-enolates depending on the tether length [34, 35] (Eqs. 3–5 in Scheme 11).

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

9

Scheme 11

Scheme 12

The currently available data indicate that seven or eight discrete processes including Type I–III Ac-Pd reactions can take place under carbonylative conditions. In many cases, non-carbonylative cyclic carbopalladation has been observed even in the pressure of CO. A summary of all of these observed processes is presented in Scheme 13 as a “guide map”. It is clearly not practical to discuss in detail all of the reactions to be covered in this chapter. Fortunately, most of the reactions reported before

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Scheme 13

2000 have been discussed in detail in reviews and book chapters, as summarized below. In this chapter, only some noteworthy highlights from earlier investigations and important recent results will be presented in the following sections. In addition to a couple of reviews focused on results obtained in the authors’ group [38, 39], a comprehensive book on organopalladium chemistry for organic synthesis [40] contains two dozens or so chapters on cyclic carbopalladation and cyclic acylpalladation. Thus, its Part IV (p1123–1659) on carbopalladation contains reviews of cyclic carbopalladation on the synthe-

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

11

sis of carbocycles [41], heterocycles [42], asymmetric cyclization [43], nonHeck-type cyclic carbopalladation of alkenes [44], cyclic carbopalladation of alkynes terminated by trapping with nucleophilic regents [45], by trapping with electrophiles [46], cyclic cascade carbopalladation terminated with alkenes [47], with nucleophiles [48], by carbonylative reaction [49], cyclic allylpalladation [50], alkynylpalladation [51], arene analogs of the cyclic Heck reaction [52], cyclic carbopalladation of allenes [53], conjugated dienes [54], conjugated enynes and diynes [55], Pd-catalyzed cyclic alkylzincation [56], and synthesis of natural products via cyclic carbopalladation [57]. And, Part VI contains reviews on cyclic acylpalladation [58], its arene analogs [59], and synthesis of natural products via cyclic acylpalladation [60]. Additionally, those chapters pertaining to polymerization by acylpalladation [29], trapping to acylpalladium derivatives with enolates [37], intermolecular acylpalladation [61], and formation and reactions of ketones generated via acylpalladium derivatives [62] discuss topics related to this chapter.

2 Palladium-Catalyzed Cyclization via Carbopalladation Although the catalytic version of the Heck reaction, as deﬁned by Eq. 1 of Scheme 3, was discovered as early as the 1971–1972 period by Mizoroki [4] and Heck [5], it was not until the mid-1980s that examples of its cyclic version shown at the top of Scheme 5 [9, 10] were reported. In fact, no example of the cyclic Heck reaction appears to be described in a comprehensive survey of the Heck reaction published in 1982 [3]. In the Heck reaction, acyclic or cyclic, the organopalladium intermediates generated via carbopalladation are short-lived owing to the ensuing β-dehydropalladation. In cases where such organopalladium intermediates generated as above should prove to be “living” or long-lived, their further transformations to give organic products must be induced by some processes other than β-dehydropalladation, leading to various Pd-catalyzed organic synthetic reactions that cannot be represented by Eq. 1 of Scheme 3. Despite its inherent limitations as a method of synthesis of ﬁne chemicals, the Maitlis alkyne cyclooligomerization [7, 8] (Scheme 4) is a prototypical example of “non-Heck” cyclic carbopalladation reactions. Another seminal example is the process shown as the item 6 of Scheme 5 reported by Heck himself [18, 19]. In this case, the initially formed Heck alkene substitution product must isomerize to a stable and “living” π-allylpalladium species that must be decomposed by an external reagent, namely piperidine in this example. As the cyclic Heck reactions as deﬁned above are extensively discussed elsewhere in one or more chapters in this compilation, they are not further discussed in this chapter, even though those cascade reactions that involve the use of the Heck reaction as a cascade-terminating device, e.g., those shown

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Scheme 6, represent important exceptions. After all, the main attention in these cases is focused on the “living” and cascading process providing a previously unrecognized synthetic tool for constructing carbon skeletons. 2.1 Cyclization via Single Carbopalladation All examples shown in Scheme 5 except one shown as past of the item 1 involve just one carbopalladation step. They can be classiﬁed according to the π-compound types. As detailed below, allenes, i.e., 1,2-dienes, conjugated dienes, i.e., 1,3-dienes, and higher dienes display reaction characteristics that are different from monoenes. In this connection, it is instructive to note that β-dehydropalladation, critically important for the production of organic products by the Heck reaction, requires a syn-coplanar arrangement of the H – C – C – Pd moiety. Thus, any factors inhibiting this syn-coplanar arrangement can, in principle, lead to “non-Heck” carbopalladation processes. Such factors include (a) simple absence of a β-hydrogen, (b) conformational constraint due to cyclic structures, (c) conﬁgurational constraint due to trans geometry, (d) opportunity for the formation of π-allylpalladium and cyclopropylcarbinylpalladium derivatives and so on. Another useful notion of general and fundamental signiﬁcance is that various organopalladium processes including hydropalladation, halopalladation, and even carbopalladation producing cyclopropylcarbinylpalladiums can be readily reversible. A myriad of seemingly mysterious processes may be readily understood with a good grasp of these fundamental properties and characteristics of organopalladium derivatives. 2.1.1 Cyclic Heck Reactions, Noteworthy Variations Although this chapter focuses its attention on cyclic carbopalladation reactions other than the cyclic Heck reaction, it might be useful to discuss here the following variants of the cyclic Heck reaction. For the vast topic of the cyclic Heck reaction including those variants discussed below, the reader are referred to the following chapters of the Handbook of Organopalladium Chemistry for Organic Synthesis [40]. • • • • •

Synthesis of Carbocycles (Chap. IV. 2.2.1) [41] Synthesis of Heterocycles (Chap. IV. 2.2.2) [42] Asymmetric Heck Reaction (Chap. IV. 2.3) [43] Arene Analogs of the Heck Reaction (Chap. IV. 6.1) [52] Synthesis of Natural Products via Carbopalladation (Chap. IV. 8) [57]

(i) Apparent endo-mode cyclic Heck reaction. The reactions shown in Scheme 14 might appear to be ordinary examples of the cyclic Heck reaction.

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

13

Scheme 14

However, both the endo-mode cyclization and the mysterious geometry of the exo-cyclic C = C bond, which go counter to simple-minded expectations, led to clariﬁcation of a circuitous mechanistic route shown in Scheme 15 [63]. This mechanism has provided plausible explanations for a number of other cases [64, 65], as can be seen later in this chapter. (ii) Cyclic Heck reaction accompanied by cyclopropanation and cyclobutanation. It is readily anticipated that, in cases where the cyclopropylcarbinylpalladium species shown in Scheme 15 can undergo β-dehydropalladation rather than decarbopalladation to undergo ring expansion, cyclopropylalkenes can be obtained as the products. The example shown in Eq. 1 of Scheme 16 [11] appears to be the ﬁrst such example observed in cyclic carbopalladation reactions, although formation of cyclopropanes via homoallylpalladium derivatives was reported earlier for the reaction shown in Scheme 17 [66]. A number of the synthesis of cyclopropane derivatives [67–70] as well as reverse conversion of cyclopropanes into alkenes via cyclopropylcarbinyl-to-homoallyl rearrangement [44] and homologous cyclobutanation [71] (Scheme 18) have also been reported over the past 15 or so years. (iii) Asymmetric cyclic Heck reactions. In most cases, the Heck reaction proceeds, as shown in Eq. 1 of Scheme 3 with no generation of new asymmetric carbon atoms. In cases where β-dehydropalladation is forced to take place with an allylic H atom in the reacting alkenes; however, a new asym-

Scheme 15

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Scheme 16

Scheme 17

Scheme 18

metric carbon center generated via carbopalladation is retained. Under the inﬂuence of either external or internal chiral sources, asymmetric Heck reactions can then be observed (Scheme 19). Alternatively, desymmetrization of prochiral dienes may also be exploited to achieve asymmetric synthesis even in cases where an alkenyl carbon-bound H atom participates in β-dehydropalladation. Seminal contributions to the development of asymmetric cyclic Heck reaction were made in 1989 by Overman [72] and Shibasaki [73]. These and other groups have since developed the reaction as a useful tool for asymmetric synthesis of complex natural products as indicated by representative examples shown in Schemes 20 [74–76] and 21 [77–79]. For further details, the readers are referred to recent reviews [43, 57].

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

15

Scheme 19

Scheme 20

Scheme 21

Scheme 22

Although mechanistic details are not very clear, a recently reported Pd-catalyzed asymmetric ene reaction may proceed via hydropalladationinitiated asymmetric Heck reaction [80] (Scheme 22).

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Scheme 23

(iv) Cyclic carbopalladation of allenes. Although the cyclic carbopalladation–dehydropalladation tandem reaction of allenes shown in Scheme 23 [81, 82] is no more than another variation of the cyclic Heck reaction, it has proved to be one of as yet a very limited number of cyclization reactions that can be satisfactorily applicable to the synthesis of common (5- through 7-membered), medium (8- through 12- or 13-membered), and large (> 12- or 13-membered) rings. Comparably structured allenes and alkenes display striking differences in the ease of cyclization reﬂected by the product yields. The differences must at least in part be due to the more rigid allene moiety relative to the isolated C = C bond. Another noteworthy aspect of the reaction is that the initially formed organopalladium product before dehydropalladation is an allylpalladium derivative, which is signiﬁcantly more stable and longer-living than organopalladium derivatives generated in more usual Heck reactions. The allylpalladium derivatives can be further transformed under the same reaction conditions into various “non-Heck” products [81, 82], as discussed later in detail. (v) Formation of allylpalladium derivatives and conjugated dienes in other cyclic carbopalladation reactions. In any carbopalladation reactions of alkenylpalladium derivatives with alkenes, the initial carbopalladation products are homoallylpalladium derivatives. Their cyclopropanation was discussed in Sect. (i) and (ii) (Schemes 15 and 16). Although very signiﬁcant in the cyclic carbopalladation chemistry, it, nevertheless, is not the most commonly observable process for homoallylpalladium derivatives. In cases

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

17

Scheme 24

where they contain a hydrogen atom that is both allylic to C = C bond and β to Pd, a facile regioisomerization via dehydropalladation–rehydropalladation to generate more stable allylpalladium derivatives can take place. The dichotomy observable with homoallylpalladium derivatives is, in fact, a generally observable phenomenon, as summarized in Scheme 24, except with the shorter and shortest allylpalladium derivatives which do not process the cyclization option. Of course, the cyclization path represents the very subject of this chapter. On the other hand, much less attention has been paid to the through-bond palladotropy to generate π-allylpalladium derivatives. One signiﬁcant consequence of the formation of allylpalladium derivatives is that it represents an “escape” from the Heck reaction manifold permitting a wide variety of “non-Heck” processes via carbopalladation, which is the focal point of the rest of this chapter. 2.1.2 Cyclic Carbopalladation Terminated by Processes Other than β-Dehydropalladation (i) Generation and classiﬁcation of thermally stable and “living” organopalladium derivatives. Organopalladium derivatives generated via carbopalladation can be classiﬁed into several categories according to their thermal and chemical stabilities. (a) Allylpalladium derivatives. The initial products of carbopalladation of alkenes are alkylpalladium derivatives (Eq. 1 in Scheme 1). If they contain a Csp3 – H bond that is β to Pd and can be syn-coplanar with the adjacent Csp3 – Pd bond, they can readily undergo β-dehydropalladation. Otherwise, they can be stable. Although the regiochemistry of carbopalladation of alkenes is capricious and somewhat unpredictable, carbopalladation of 1,1-disubstituted alkenes generally produce “neopentyl-type” alkylpalladium derivatives that are generally stable and “living” (Eq. 1 in Scheme 25). Any other factors preventing the syn-coplanar arrangement of the H – C – C – Pd moiety can also stabilize alkylpalladium derivatives, though it is not practical to discuss all available factors at this point. (b) Alkenyl-, aryl-, and alkynylpalladium derivatives. These organopalladium derivatives are generally relatively stable and long-lived. Thus, alkenyl-

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Scheme 25

palladium derivatives generated via carbopalladation of alkynes or, for that matter via any route, may generally be considered to be stable and “living” even in cases where there is a Csp2 -bound β-H atom (Eq. 2 in Scheme 25). Evidently, β-dehydropalladation of alkenylpalladium derivatives to give alkynes and HPdLn must be energetically unfavorable. (c) Allyl-, Propargyl-, and benzylpalladium derivatives. π-Allylpalladium derivatives (Scheme 24 and Eqs. 3–5 in Scheme 25) are chemically reactive but thermally stable. Thus, they are fundamentally capable of undergoing all types of reactions listed in Scheme 5. (d) Acylpalladium derivatives and palladium enolates or α-palladocarbonyl derivatives. These compounds are chemically reactive and labile. They can readily be decomposed by treatment with either acids or bases, whereas other types of organopalladium compounds are much more resistant to them. For example, water and alcohols do not decompose the categories (a) and (b) organopalladium compounds. The high chemical lability of acylpalladium derivatives makes carbonylative trapping of organopalladium derivatives a useful synthetic tool, as detailed later. (ii) Conversion of organopalladium derivatives via cross-coupling. Conversion of “living” organopalladium derivatives generated via cyclic carbopalladation can be achieved by their reactions with added organometals present in the reaction mixtures [14, 15, 83] (Entry 3 in Scheme 5). In these seminal studies, however, little or no mention was made to the competition between the desired cross-coupling after cyclic carbopalladation and that be-

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19

fore cyclization (Scheme 26). Nor was any trend among different metal countercations discussed. A systematic investigation summarized in Scheme 27 clearly indicated the following. Firstly, highly reactive organozincs tend to favor cross-coupling before cyclization. Secondly, organometals containing metals of moderate electronegativity, such as Zr, Al as well as Sn and B, may lead to the cyclic carbopalladation–cross-coupling tandem proceeding in high yields. The superior ability of alkynyltins to defer Pd-catalyzed alkynylation until after completion of the competing cyclic carbopalladation has been exploited in the synthesis of neocarzinostatin model compounds [85–87] (Scheme 28). The cyclic carbopalladation–cross-coupling tandem reaction has been extensively developed over the past several years. Despite earlier favorable ﬁndings with Al and Zr [84], these metals are still scarcely used. On the other hand, organometals containing Sn and B have been widely used, and favorable results have been obtained for the formation of ﬁve-membered carbocycles and heterocycles containing N and O from halodienes [88] (Eqs. 1 and 2 in Scheme 29), haloenynes [89–92] (Eqs. 3–5 in Scheme 29), haloarylalkynes [94, 95] (Eqs. 6 and 7 in Scheme 29), and allenene derivatives [93, 96] (Eqs. 8 and 9 in Scheme 29). (iii) Hydrogenolysis of organopalladium derivatives. Hydrogenolysis of organopalladium derivatives can be achieved with various hydride sources. As exempliﬁed in Scheme 5 (Entry 5), formic acid and its derivatives have been commonly used as hydride sources [95, 97]. In a recent comparative study, however, Et3 SiH was shown to be generally superior to HCO2 NH4 as a hydride source in the reactions shown in Scheme 30 [98]. (iv) Trapping of π-allylpalladium and other organopalladium derivatives with “soft” carbon nucleophiles. π-Allylpalladium derivatives generated by the reactions shown in Schemes 24 and 25 can be subjected to various reactions that π-allylpalladium derivatives can undergo. The Tsuji–Trost reaction [99–105] is a representative carbon–carbon bond-forming reaction of π-allylpalladium derivatives, and it has indeed been used for converting cyclic carbopalladation products to organic products, as exempliﬁed by the results shown in Scheme 31. The potential scope of the tandem process consisting of cyclic carbopalladation to give π-allylpalladium derivatives and

Scheme 26

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Scheme 27

Scheme 28

their trapping with “soft” carbon nucleophiles should be considerable, and it appears to deserve further systematic investigations.

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

Scheme 29

21

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Scheme 30

Scheme 31

Although no cyclic carbopalladation is involved, the synthetic potential of the tandem process shown in Scheme 32 [106] consisting of conjugated diene carbopalladation and trapping of the resulted π-allylpalladium derivatives with enolates appears to be very high. (v) Trapping of π-allylpalladium and other organopalladium derivatives with N, O, and other heteroatom nucleophiles. The prototypical example of trapping of the product of cyclic carbopalladation with piperidine [18, 19] (Entry 6 in Scheme 5) must involve a nucleophilic attack of a π-allylpalladium derivatives by piperidine. This and many other related reactions can also be exploited to further expand the scope of cyclic carbopalladation, as indicated by the results shown in Scheme 33 [81, 82]. Very interesting and potentially useful tandem processes shown in Scheme 34 [107–109] involve the conjugated diene cyclodimerization shown in Eq. 2 in Scheme 2 followed by trapping of the resultant π-allypalladium derivatives with an amine or alcohol. In this chapter, the vast and important

Scheme 32

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

23

Scheme 33

topics of Pd-catalyzed cyclodimerization is not discussed further. The readers are referred to a recent review [54]. (vi) Trapping of cyclic carbopalladation products via carbonylation with CO. One of the novel and synthetically attractive methods of trapping cyclic carbopalladation products is based on unexpected and initially disappointing results observed by the authors’ group (Entry 7 in Scheme 5) in an attempt to achieve cyclic acylpalladation with incoporation of CO into the desired cyclic ketone [11]. This reaction was soon recognized as a useful means of trapping the products of cyclic carbopalladation without incorporation of CO into the ring moieties [11, 49] (Scheme 35). The available data permit the following tentative generalization as a useful guide to be further scrutinized (Table 1) [67, 110, 111]. In short, common ﬁve- and six-membered rings can be prepared by cyclic carbopalladation even in the presence of CO. Although there is one example of the synthesis of a seven-membered ring, the scope of the synthesis of medium and large rings would be limited due to slower cyclization rates vis-à-vis premature esteriﬁcation.

Scheme 34 Table 1 Effect of ring size ont he competition between cyclic carbopalladation and cyclic acylpalladation in the presence of CO Ring size

Substrate

Cyclic carbopalladation Cyclic acylpalladation

4 vs. 5 5 vs. 6

Alkenes and alkynes Alkenes Alkynes Alkenes and alkynes

not observed can be competitive favored favored

6 vs. 7

favored can be dominant not observed not observed

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Scheme 35

Some notable examples of the use of carbonylative termination of cyclic carbopalladation are shown in Schemes 36–39. Despite an earlier failure to achieve cyclic carbopalladation–carbonylative termination in competition with the cyclic Heck reaction [67] (Eq. 3 in Scheme 35), a series of investigations by Aggarwal [117–119] has provided useful solutions to this problem. In cases where the substrates contain a heteroatom group, such as O or NTs, the cyclic Heck reaction can be suppressed [117] (Eq. 1 in Scheme 37). This reaction has been applied to an asymmetric synthesis of avenaciolide [119] (Eq. 2 in Scheme 37). A more general solution to avoiding the cyclic Heck reaction is not to use a base, e.g., Et3 N, and promote rehydropalladation to reserve β-elimination through the

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

Scheme 36

Scheme 37

Scheme 38

Scheme 39

25

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use of HOAc [118] (Eq. 3 in Scheme 37). Though only stoichiometric, a proximal heteroatom effect to promote carbonylative esteriﬁcation by suppressing β-dehydropalladation was also reported recently [120] (Scheme 38). A spectacular example of application of the cyclic carbopalladation– carbonylative esteriﬁcation tandem process is the synthesis of a possible intermediate for the synthesis of perophoramidine [121] (Scheme 39). 2.2 Cyclization via Double and Multiple Carbopalladation Reactions In Sect. 2.1 various sequential or “tandem” combinations of cyclic carbopalladation and trapping of the “living” carbopalladation products are discussed with the goal of devising Pd-catalyzed synthesis of cyclic organic compounds. The great majority of examples presented above involve just one carbopalladation or acylpalladation process. Since carbopalladation itself is intrinsically repeatable, oligomerization and polymerization via carbopalladation can be exploited for the synthesis of mono-, oligo-, and even polycyclic compounds via cascading carbopalladation processes. Competitive formation of acyclic and partially cyclic polymers and any kind of premature termination, such as β-dehydropalladation must, of course, be avoided, even though any cyclic carbopalladation cascades must eventually be terminated in a preprogrammed manner to produce the desired cyclic compounds. As indicated in Scheme 25, carbopalladation of alkynes is intrinsically “living” and is therefore well-suited for developing cascade cyclization processes exempliﬁed by the Maitlis Pd-catalyzed alkyne cyclotrimerization to give benzene derivatives (Scheme 4). In this chapter, however, strong emphasis is placed on those processes that are designed to produce unsymmetrically structured cyclic compounds and/or those lacking homodimeric and homooligomeric fragments. As indicated in Scheme 6, alkynes are well-suited for the “zipper”-mode and “dumbbell”-mode cascades, the latter of which can be extended to “circular” cascades. Although some other modes of cyclizations are conceivable, the two mentioned above appear to be the two representative ones involving syn-carbopalladation. 2.2.1 “Zipper”-Mode Cascade Cyclization via Carbopalladation The propagation steps of the “zipper”-mode cascade cyclization are by deﬁnition all-intramolecular processes. Some prototypical examples of the “zipper”-mode cascade cyclic carbopalladation producing two to ﬁve fused rings in one step are summarized in Scheme 40 [11, 113–116, 122]. One of the major attractive features of this synthetic methodology is the ease of retrosynthetic analysis, which involves ﬁnding a linear line of dissection indicated in bro-

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

27

Scheme 40

Scheme 41

ken lines in Scheme 38. One very promising application of the “zipper”-mode cascade cyclization is the preparation of a potential key intermediate for the synthesis of nagilactone F [49] (Scheme 41). 2.2.2 “Dumbbell”-Mode and Related Circular Cascade Cyclization Processes via Carbopalladation Synthesis of benzene, cyclohexadiene, along with other related six-membered rings via circular trimerization of three C ≡ C and/or C = C bonds has long attracted attention of the synthetic chemists. In most cases, it is thermo-

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dynamically very favorable. From the viewpoint of ﬁne chemicals synthesis where symmetrical and/or repeating substitution patterns are to be avoided in the great majority of cases, π-bond-pairing selectivity (“pair”-selectivity or copuloselectivity) and regioselectivity are two factors of paramount importance. Therefore, only those processes that may be judged to be useful for “pair”-selective and regioselective synthesis of cyclic compounds will be discussed below. For example, although very attractive and useful for the synthesis of a limited number of benzene derivatives of perhaps materials chemical interest, the Maitlis cyclotrimerization of alkynes (Scheme 4) fails to offer a “pair”-relative and regioselective route to benzene derivatives. It may well be that even today there is no catalytic and all-intermolecular cyclotrimerization of three different alkynes with excellent control of regiochemistry, even though a stoichiometric Zr-mediated “one-pot” synthesis of benzene derivatives with ﬁve different substituents and one H from three different unsymmetrically substituted alkynes has recently been reported [123]. (i) Benzene and fulvene derivatives. Aside from the all-intermolecular cascade carbometallation process discussed above, various all-intramolecular (Type I) and partially intramolecular (Type II) circular cascade processes are conceivable (Scheme 42). All-intramolecular (Type I) processes in most cases would proceed via “dumbbell”-mode cascade cyclization, which can be very satisfactory as shown in Scheme 43 [124, 125]. Selective synthesis of benzene derivatives via partially intramolecular cyclic carbopalladation is considerably more complex than the corresponding all-intramolecular processes. As it is generally difﬁcult to specify the cascadeinitiation point in the Type IIa cyclization process, it would generally be the least selective path. A priori, the most favorable might be the intra–inter cascade cyclization process (Type IIb), since both the point of initiation and the queuing order between the two alkynes is sharply differentiated by the fact that one is intramolecular, while the other is intermolecular. Still, in-

Scheme 42

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29

Scheme 43

corporation of unsymmetrically substituted monoynes is a challenging task. The following regioselectivity patterns observed in alkyne carbopalladation (Eqs. 1 and 2 in Scheme 44) can be exploited in achieving highly regioselective (> 92–98%) incorporation of monoynes (Scheme 44) [126]. In many other cases, however, formation of regioisomeric mixtures would result. In a related study with terminal alkynes [127], a mechanistic path involving the formation of conjugated dienynes and their electrocyclic transformation to give benzene derivatives was proposed. This mechanism is applicable only to those cases where terminal alkynes are used. Furthermore, one reaction with DC ≡ Cn Hex run under the conditions indicated in Scheme 44 produced the desired product retaining D to the extent of 75–85% in the position expected from the mechanism involving a sequential intra–inter cascade carbopalladation [126] (Eq. 5 in Scheme 44).

Scheme 44

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There are at least two issues to be addressed regarding the Type IIc circular cascade process shown in Scheme 42. One is the regioselectivity in the initial intermolecular carbopalladation. Since it is not very difﬁcult to differentiate the two terminal positions of α,ω-diynes, this is not a serious problem in most cases. A more serious problem is the exclusive formation of fulvene derivatives observed in a couple of cases [124] (Scheme 45). It is not very clear what the scope of the fulvene formation is and whether the course of the reaction could be altered to give benzene derivatives. Many other related but alternative routes to benzene derivatives are conceivable. One inter–intra cascade carbopalladation route which is potentially highly selective is shown in Eq. 1 of Scheme 46 [11]. Another proceeds via cyclic allenylpalladation of alkynes followed by cross-coupling with PhB(OH)2 [127] (Eq. 2 of Scheme 46). Yet another related process is the synthesis of naphthalene derivatives shown in Eq. 3 of Scheme 46 [128]. If the regioselectivity problem could be overcome, it would provide an attractive route to naphthalenes. (ii) Cyclohexadienes. Substitution of one of the alkynes in the circular cascade reactions shown in Scheme 42 is expected to produce cyclohexadienes. However, even all-intramolecular cyclization reactions of halodienynes have been shown to be very capricious and both substrate and reagent dependent, as demonstrated in Scheme 47 [129, 130].

Scheme 45

Scheme 46

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

31

Scheme 47

Since this topic is discussed in detail elsewhere in this monograph, no further discussion is intended here. 2.2.3 Spiro-Mode and Linear-Fused-Mode Cascade Cyclization Processes via Carbopalladation Both spiro-mode and linear-fused-mode cascade cyclization processes via carbopalladation were introduced in 1988 [20, 21, 131]. In addition to the

Scheme 48

Scheme 49

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seminal examples shown in Scheme 6, some representative examples [20, 21, 133–137] of the spiro-mode cascade cyclization via carbopalladation including its application to the synthesis of scopadulcic acid B [136, 137] are presented in Scheme 48. Representative examples of the linear-fused-mode cascade cyclization shown in Scheme 49 also suggest that its potential synthetic utility is considerable.

3 Palladium-Catalyzed Cyclization via Acylpalladation As described in Sect. 1, a couple of versions of the cyclic acylpalladation reactions of ω-alkenyl halides and related electrophiles were discovered by the authors’ group during the 1983–1985 period [10, 30]. Subsequent extensive and systematic investigations have led to Scheme 13 showing several competitive carbonylative processes including three types of cyclic acylpalladation processes (Type I–III Ac-Pd Processes) along with carbonylative polymerization, premature and noncyclic carbonylative reactions, and ketene generation and their cycloaddition reactions. Furthermore, it has also been found that, even in the presence of CO, non-carbonylative cyclic carbopalladation can be competitive or even dominant [11]. This ﬁnding has, in turn, led to the development of non-carbonylative cyclization reactions terminated by carbonylative trapping [113–116]. In short, formation of acylpalladation species is known to be highly reversible, and competition among carbonylative and non-carbonylative processes is governed by a number of reaction parameters. One generalization of considerable predictive value is that summarized in Table 1 (Sect. 2.1.2). As is well-known, formation of ﬁve- and six-membered rings is considerably more favorable than that of either four- or sevenmembered rings somewhat irrespective of their structural details. Thus, carbonylative formation of ﬁve-membered rings is strongly favored over that of non-carbonylative four-membered rings from the same starting compounds [113, 114, 116]. On the other hand, non-carbonylative six-membered ring formation is strongly favored over carbonylative seven-membered ring formation. A more subtle, tentative, and yet seemingly reliable generalization also indicated in Table 1 is that non-carbonylative ﬁve-membered ring formation from alkynes is strongly favored over the potentially competitive carbonylative six-membered ring formation. Consequently, six-membered α,β-unsaturated ketones have not been readily accessible via carbonylative cyclic acylpalladation of alkynes, although the corresponding cyclic acylpalladation of similarly structured alkenes can be very favorable, as exempliﬁed in Eq. 2 of Scheme 10 [10]. Today, it seems reasonable to state that the initially highly capricious cyclic acylpalladation processes in the presence of CO may be advantageously exploited to complement and supplement the non-

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

33

carbonylative cyclic carbopalladation proceees discussed in Sect. 2 through judicious planning. Taken together, the non-carbonylative carbopalladation discussed above and acylpalladation processes discussed in this section provide a very promising methodology for the synthesis of a wide range of carbocycles and heterocycles, even through the scope of acylpalladation is predicted to be essentially limited to the synthesis of ﬁve- and six-membered rings, as discussed above. 3.1 Cyclization via Single Acylpalladation (i) Type I cyclic acylpalladation (Type I Ac-Pd). Several of the earliest examples of the Type I Ac-Pd reactions are shown in Eq. 1 of Scheme 10 and Eq. 1 of Scheme 50 [30, 67, 139]. These reactions were run with the stoichiometric amounts of Pd catalysts, and a few attempts to observe catalytic processes were not successful. However, later studies using o-iodostyrene and o-iodoallylbenzene [110, 111] have indicated that these substrates undergo the Type I Ac-Pd reaction under catalytic conditions. It does appear that even those reactions shown in Eq. 1 of Scheme 50 could be carried out under catalytic conditions. In general, the Type I Ac-Pd reactions of ω-vinylated substrates represent some of the most capricious and least favorable cases. In addition to the difﬁculties described above, the Type III Ac-Pd process involving the trapping of acylpalladation derivatives with internal enolates (Eq. 4) [67] and ketene–alkene bicyclization (Eq. 5) [67] can also be dominant processes. Clearly, further investigations are desirable. In this context, a recent investigation of this reaction has led to the discovery of a variant of Type I Ac-Pd reaction most probably via hydrolysis of palladium enolates. A related hydrolysis of palladium enolates had previously been reported [141]. The Type I Ac-Pd reactions of internal alkene-containing organic halides are generally more favorable and predictable (Scheme 52) [67, 110, 111]. In cases where the alkenyl group is stereodeﬁned, the Type I Ac-Pd reaction is not stereospeciﬁc but stereoselective, favoring the E isomer. A number of variations of the Type I Ac-Pd reactions are conceivable. The reaction shown in Scheme 53 involves endo-mode cyclization producing naphthoquinones [32]. It should be reminded that conversion of o-iodostyrenes into indenones (Scheme 50) and indanones (Scheme 51) also involves endo-mode cyclic acylpalladation. In general, cyclic carbopalladation including acylpalldation can proceed both in exo-mode and in endomode. In some cases, the regiochemistry of cyclic carbopalladation is mechanistically deﬁned in a rigid manner, as shown in Scheme 15. In other cases, the regiochemistry of cyclic carbopalladation appears to be more loosely deﬁned, as suggested by the formation of either of the two possible regioisomers, i.e., exo or endo. Formation of E and Z stereoisomeric mixtures also

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Scheme 50

Scheme 51

suggest that these conjugated enone-producing reactions are mechanistically loose or ﬂexible. (ii) Type II cyclic acylpalladation (Type II Ac-Pd). In the Type I cyclic acylpalladation process, the termination step involves β-dehydropalladation. In this sense, the Type I Ac-Pd procees resembles the cyclic Heck reaction. The Type II Ac-Pd process reported in 1985 [10] provided some of the earliest ex-

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

35

Scheme 52

Scheme 53

amples of the trapping of cyclic organopalladium intermediates with external nucleophiles, i.e., MeOH, along with the amine synthesis shown in Entry 6 of Scheme 5 [18, 19]. It is important to note that trapping of acylpalladium species with any nucleophiles can take place either before or after cyclization (Scheme 54). Thus, the desired trapping process must be slower than the desired cyclic acylpalladation to avoid premature trapping of acylpalladium species before cyclization. At the same time, it must be faster than any other cyclization product-depleting side reactions including dimeric, oligomeric, and polymeric acylpalladation. Since these product-depleting acylpalladation processes are intermolecular, they are expected to be slower by a few to several orders of magnitude than favorable processes of cyclic acylpalladation, which is practically limited to ﬁve- and six-membered ketone formation.

Scheme 54

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Despite the seemingly narrow window given to the Type II Ac-Pd process, it has proved to be a very useful synthetic reaction as indicated by the results shown in Scheme 55. In fact, one of the major side reactions is the Type I Ac-Pd process that can be dominant in cases where the reacting alkene is dior trisubstituted. In cases where the reacting alkene is a terminal vinyl group; however, the Type II Ac-Pd process is generally much more predictable, dependable, and satisfactory. Moreover, a variety of alcohols and many other nucleophiles may be considered for successful trapping of the cyclic acylpalladaium derivatives. Although still very limited, the Type II Ac-Pd process has also been applied to the synthesis of heterocycles including some medicinally interesting compounds, such as a core model of martinellines [142, 143] (Scheme 56). The scope of the Type II Ac-Pd process has been signiﬁcantly expanded by the development of those employing ω-alkenyl allyl halides and related electrophiles. Initially formed β,γ -unsaturated ketones must isomerize to give the α,β-unsaturated ketones. Since the α,β-unsaturated ketones thus obtained are the same as those obtainable from the corresponding alkenyl halides, the two

Scheme 55

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

37

Scheme 56

processes offer two synthetic options for the same class of compounds [144] (Scheme 57). Nucleophilic trapping agents used in the Type II Ac-Pd process are not limited to MeOH and other alcohols. A wide range of heteroatom and carbon nucleophiles may be used as in the cases of the Type II cyclic carbopalladation processes terminated by various nucleophilic reagents (Sect. 2.1.2). A couple of reactions shown in Scheme 58 [145] provide additional examples of heterocycles synthesis via Type II Ac-Pd process terminated by cross-coupling. (iii) Type III cyclic acylpalladation (Type III Ac-Pd) and GenerationCycloaddition of Ketenes. Trapping of acylpalladium derivatives with internal enolates was reported as early as 1986 [32], as described in Sect. 1 (Schemes 11 and 12). It was later accidentally discovered that the Type I Ac-Pd process could be diverted to produce γ -alkylidenebutyrolactones via trapping of the second acylpalladium derivatives generated after the cyclic acylpalladation with the enolate ions generated by deprotonation of the initially formed acylpalladium derivatives. Since it is an intramolecular process,

Scheme 57

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Scheme 58

it could be very favorable, as exempliﬁed by Eq. 3 in Scheme 10 [31] and Eq. 4 in Scheme 50 [67]. Even some of the Type II Ac-Pd processes may proceed in some cases via Type III Ac-Pd processes. Yet another process that does not involve cyclic acylpalladation is the formation and [2 + 2]cycloaddition of ketenes generated via β-dehydropalladation of acylpalladium species. Since this ketene cycloaddition reaction has often occurred in competition with the Type III Ac-Pd process, these two reactions are discussed together in this section. A series of Pd-catalyzed carbonylation reactions of o-chloromethylallyl benzenes have provided the following interesting set of results [146] (Scheme 59). As expected, the Type II Ac-Pd process was the only cyclic acylpalladation process observed with the parent o-chloromethyl allylbenzene in the presence of MeOH (4 equiv.), but the predominant process was premature esteriﬁcation (Eq. 1). In the absence of MeOH or any other added trapping agent, the Type III Ac-Pd cyclization product was obtained in high yield (Eq. 2). No Type I Ac-Pd product or other products was formed in a signiﬁcant yield. The presence of a substituted allyl group in the starting compounds tends to competitively give [2 + 2] ketene cycloaddition products and Type III Ac-Pd cyclization products. With β,γ -disubstituted allyl groups present in the starting compounds, the [2 + 2] ketene cycloaddition can be the dominant path (Scheme 59). All of the examples of trapping of acylpalladium species with enolates discussed above as part of the Type III Ac-Pd process involve trapping with O-enolates. As discussed earlier, however, acylpalladium derivatives can also be trapped with C-enolates (Eqs. 4 and 5 in Scheme 11), and this trapping with C-enolates has since been exploited for terminating acyclic carbopalladation process [135] (Scheme 48). However, this process does not appear to have been used for terminating cyclic acylpalladation processes. (iv) Cyclic acylpalladation of alkynes. All cyclic acylpalladation reactions discussed above in this section are those of alkenes. Many earlier attempts to observe cyclic acylpalladation reactions of alkynes failed. These failures have, in turn, led to a tentative conclusion that, for some unknown reasons, acylpalladation of alkynes must be an intrinsically unfavorable process. This

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

39

Scheme 59

conclusion has since been proven to be incorrect. The current notion, which hopefully is correct, is that there is nothing intrinsically unfavorable about acylpalladation of alkynes, but that the ready reversibility of CO insertion and the availability of kinetically more favorable non-carbonylative cyclic carbopalladation processes must be competitively overshadowing acylpalladation of alkynes. This notion has been strongly supported by the results shown in Scheme 60 [113, 114]. In these cases, the cyclic acylpalladation of alkynes to give ﬁve-membered ketones can favorably compete with the noncarbonylative cyclic carbopalladation to produce four-membered rings. These reactions appear to represent the ﬁrst two examples of cyclic alkyne acylpalladation reactions. A closely analogous Pd-catalyzed carbonylative bicylization of 2-(propargyl)allyl phosphates reported recently [147] can readily be explained in terms of a Type III Ac-Pd mechanism shown in Scheme 61, even though the authors of this paper additionally proposed an alternate ketene-alkyne bicyclization mechanism also shown in Scheme 61. 3.2 Double or Multiple Carbopalladative Cyclization Reactions Involving One or More Cyclic Acylpalladation Processes (i) Allylpalladation–Acylpalladation Cascades. Applications of the Types I and II cyclic acylpalladation processes to trapping the products of cyclic allylpalladation by W. Oppolzer [148, 149] and K. Yamamoto [150] led

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Scheme 60

Scheme 61

to the development of the cyclic allypalladation–acylpalladation cascades (Scheme 61). ω-Vinyl-substituted allyl acetates mainly underwent a tandem process consisting of monocyclization via allylpalladation followed by carbonylative esteriﬁcation, since the cyclic allylpalladation produced predominantly trans-disubstituted ﬁve-membered rings (Eqs. 1 and 2). On the other hand, ω-ethynylallyl acetates gave bicyclic products obtained via allylpalladation–acylpalladation–carbonylative esteriﬁcation cascade in good yields (Eq. 3) [148, 149]. A later study by Heathcock described a related allylpalladation-Type I Ac-Pd bicyclization process (Eq. 4) [151]. These allylpalladation–acylpalladation cascade bicyclization reactions have been applied mainly by Oppolzer to the synthesis of various natural products including (±)-pentalenolactone E methyl ester [152], 3-isorauniticine [153], (±)-coriolin [154], and (±)-hirsutene [155]. Their application to the syntheses of [5.5.5.5]fenestrane derivatives by Keese [156, 157] (Scheme 63) is also noteworthy.

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

41

Scheme 62

Scheme 63

(ii) Cyclic acylpalladation cascades. Two groups led by E. Negishi [158] and K. Yamamoto [159] reported prototypical examples of double and triple cyclic acylpalladation cascades (Schemes 64 and 65). In the reaction shown in Scheme 65, a double cyclic acylpalladation cascade was set up by a double cyclic allylpalladation cascade to achieve tetracyclization of an acyclic starting compound. As attractive as these reactions are, further development is clearly desirable.

4 Conclusion A couple of prototypical examples of the cyclic version of the Heck reaction, deﬁned as a process consisting of alkene carbopalladation followed by β-elimination, were reported during the 1984–1985 period [9, 10]. Almost concurrently, seminal examples of both the “non-Heck” cyclic carbopallation reactions [10, 30] were reported during the 1983–1985 period. Thus, with due respect paid to earlier discoveries of alkyne cyclooligomerization via cascade carbopalladation [7, 8] as well as copolymerization [24] and cocyclization [25,

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Scheme 64

Scheme 65

26] of CO with alkenes and dienes, respectively, via a acyclpalladation, which intrinsically lack control over “pair”-selectivity, regioselectivity, and/or degree of polymerization, it may be stated that the carbopalladation-based cyclization methodology of both Heck and “non-Heck” types, was founded during the 1983–1985 period. Those involving single cyclic carbopalladation are discussed in Sect. 2.1. Collectively, these cyclic acylpalladation reactions

Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation

43

have provided a novel cyclization methodology of wide synthetic applicability and have indeed been widely used. Another epoch-making advance was made during the 1988–1989 period. In dealing with “living” carbopalladation of alkynes and 1,1-disubstituted ethylenes that are incapable of undergoing facile β-dehydropalladation and hence the Heck reaction, a few research groups realized that the “living” nature of these carbopalladation reactions could be exploited to develop cascade carbopalladation processes (Sect. 2.2). These cascade reactions and those involving acylpalladation cascades discussed in Sect. 3.2 have collectively provided new and attractive opportunities for the synthesis of oligocyclic compounds to be further developed and exploited by the synthetic chemists. A systematic investigation of cyclic acylpalladation of haloenes, haloynes, and related electrophiles conducted since 1983 [30] has led to the development of three types of cyclic acylpalladation processes (Types I–III AcPd) and Pd-catalyzed carbonylation-induced ketene [2 + 2] cycloaddition (Sect. 3.1). Collectively, these cyclic acylpalladation and related reactions have provided a number of new and attractive routes to cyclic compounds. Signiﬁcantly, they nicely complement and supplement the non-carbonylative cyclic carbopalladation reactions. Thus, they have become integral and indispensable parts of the carbopalladation-based cyclization methodology.

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Top Organomet Chem (2006) 19: 49–89 DOI 10.1007/3418_009 © Springer-Verlag Berlin Heidelberg 2006 Published online: 7 April 2006

Domino Heck-Pericyclic Reactions Paultheo von Zezschwitz · Armin de Meijere (u) Institut für Organische und Biomolekulare Chemie der Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany [email protected] 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Sequential Heck–Diels–Alder Reactions . . . . . . . . . . . . . . . . . . Intermolecular Cross-Coupling Reactions Followed by Intermolecular Cycloadditions . . . . . . . . . . . . . . . . . . . . . 2.1.1 Stepwise Versus Domino Reactions—the Problem of Chemoselectivity . 2.1.2 All-Intermolecular Domino Processes Involving Bicyclopropylidene . . 2.1.3 Intermolecular Heck Reactions of Allenes . . . . . . . . . . . . . . . . . 2.2 Intramolecular Cross Couplings with Subsequent Intermolecular Diels–Alder Reactions . . . . . . . . . 2.3 All-Intramolecular Heck–Diels–Alder Sequences . . . . . . . . . . . . .

50

. .

52

. . . .

. . . .

52 52 55 58

. . . .

60 65

3

Heck Reactions Followed by 1,3-Dipolar Cycloadditions . . . . . . . . . .

68

4 4.1 4.2

. . . . . . . . . . . . . . . .

71 71

4.3

Cross Couplings with Ensuing 6π-Electrocyclizations . . . . Intermolecular Coupling Reactions . . . . . . . . . . . . . . Cascade Reactions Involving Intra- and Intermolecular Carbon–Carbon Bond Formations All-Intramolecular Processes . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

75 80

5

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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2 2.1

Abstract Palladium-catalyzed cross-coupling reactions and cycloadditions as well as electrocyclic transformations can efﬁciently be combined in one-pot sequences to build up complex molecular skeletons from simple precursors. The intermolecular Heck reaction of alkenyl halides with alkenes leads to 1,3-butadienes prone to undergo subsequent Diels–Alder reactions. Frequently, special precautions have to be taken in order to avoid a domino reaction in which the alkene acts as both coupling partner and dienophile if a cycloaddition with a different alkene is desired. This can comprise a careful adjustment of the reaction conditions or the use of bicyclopropylidene (37) or allenes which are highly reactive in Heck reactions but poor dienophiles. Another domino transformation consists of an intramolecular cross coupling followed by either an inter- or intramolecular [4 + 2] cycloaddition. These processes typically occur with complete chemoselectivity and formation of two or even three new rings, respectively. When combining cross-coupling cascades with 1,3-dipolar cycloadditions, interesting heterocyclic compounds can be obtained, however, only a few of such domino reactions have been realized. Finally, the preparation of 1,3,5-hexatrienes is achieved by a variety of palladium-catalyzed transformations and these compounds can smoothly undergo 6π-electrocyclizations to give various oligocyclic skeletons.

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Keywords 1,3-Dipolar cycloadditions · 6π-Electrocyclizations · Cross coupling · Diels–Alder reactions · Palladium catalysis Abbreviations BBEDA N,N-bis(benzylidene)ethylenediamine BHT 2,6-di-tert-butyl-4-methylphenol BSA N,O-bis(trimethylsilyl)acetamide dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone dppe 1,2-bis(diphenylphosphanyl)ethane EWG electron-withdrawing group MOM methoxymethyl Nf nonaﬂuorobutanesulfonyl NMP N-methylpyrrolidone PMB p-methoxybenzyl TBDMS tert-butyldimethylsilyl Tf triﬂuoromethanesulfonyl TFP tris(2-furyl)phosphine TMS trimethylsilyl

1 Introduction Palladium-catalyzed cross-coupling reactions are among the most versatile processes for carbon–carbon bond formation. A vast range of such methods is known which usually feature a high tolerance of many functional groups [1]. This especially holds true for the palladium-catalyzed cross coupling of an aryl or alkenyl halide with an alkene, today generally known as the Heck reaction [2–6]. After being ﬁrst executed with stoichiometric amounts of palladium and later on catalytically by Heck et al. [7, 8] and independently also by Mizoroki et al. [9] this transformation has subsequently been elaborated to an effective tool in organic synthesis, however, in the 1970s mainly being used for singular bond-forming events. Starting in the mid 1980s the interest in this reaction signiﬁcantly broadened as shown by an ever increasing number of publications on its scope and on its mechanism. This trend was mainly triggered by the observation that the Heck reaction can bring about more than one newly formed carbon–carbon bond, but can be applied in multiple cross-couplings, e.g. iterative reactions on oligohaloarenes as well as oligohaloalkenes or domino reactions. The latter may involve either sequential multifold Heck-type reaction steps or Heck-type couplings followed by related palladium-catalyzed processes (for a classiﬁcation of sequential reactions see: [10–12]). The starting point for such consecutive reactions is typically the σ -(β-alkenyl)- or σ -(β-aryl)alkylpalladium halide

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complex 5 which is formed by oxidative addition of the respective halide 2 to the catalytically active 14-electron palladium(0) complex 1 with subsequent coordination and syn-carbopalladation of the alkene 4 (Scheme 1) (for detailed investigations on the mechanism see: [13, 14]). While the standard Heck reaction then proceeds through an internal rotation and subsequent syn-β-dehydropalladation, additional reactions can arise if the β-hydride elimination is prevented or at least slowed down. This occurs after carbopalladation of a 1,1-disubstituted alkene, when the palladium rests in a neopentyl position, or after syn-carbopalladation of an alkyne, when syn-βdehydropalladation to form an alkyne is impossible and elimination to form an allene is energetically unfavorable. Subsequent processes might include additional carbopalladations of alkenes leading to intermediates of type 9, reactions with added nucleophiles—so-called “reductive Heck reactions” with hydride as a nucleophile—cross couplings with organometallic reagents, e.g. Stille-type reactions with stannanes, or carbonylative couplings, e.g. the formation of methyl esters 12 by subsequent trapping with CO and methanol. However, one has to keep in mind that the σ -alkenyl- or σ -arylpalladium halide 3 can compete with complex 5 in these consecutive reactions. Therefore, a thorough ﬁne-tuning of the reaction conditions is frequently necessary to ensure the formation of the desired products. Nevertheless, various types of such cascade reactions have been realized, especially towards the syntheses of cyclic and oligocyclic skeletons [15–17].

Scheme 1 Mechanism of the Heck reaction and possible consecutive transformations

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Another gain in diversity is achieved by the combination of these cross couplings with uncatalyzed reactions. Because of their oligounsaturated character, the coupling products are obviously well suited for subsequent pericyclic reactions leading to additional cyclizations. These atom-efﬁcient processes are especially attractive since they typically proceed with high chemo-, regio- and stereoselectivity [18]. This review is intended to cover Heck reactions and related palladium-catalyzed processes followed by Diels–Alder reactions, 1,3-dipolar cycloadditions or 6π-electrocyclizations.

2 Sequential Heck–Diels–Alder Reactions 2.1 Intermolecular Cross-Coupling Reactions Followed by Intermolecular Cycloadditions 2.1.1 Stepwise Versus Domino Reactions—the Problem of Chemoselectivity The Heck coupling of vinylic halides and alkenes leading to 1,3-butadiene moieties is an evident route to starting materials for [4 + 2] cycloadditions. However, since the cross-coupling reaction usually requires elevated reaction temperatures—typically in the range of 60 to 100 ◦ C depending on the substrates—a problem of chemoselectivity can occur if the alkene not only functions as a coupling partner but also as a dienophile. Frequently, the alkene is used in excess, which enhances this difﬁculty as seen in an early example by Heck et al. [19]. On attempted cross-coupling reactions of vinyl iodide (13) with methyl acrylate (14) at 100 ◦ C the desired butadiene completely underwent a subsequent endo-diastereoselective cycloaddition to form the

Scheme 2 Early examples of domino Heck–Diels–Alder reactions [19]

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cyclohexenedicarboxylate 15 along with the cyclohexenedicarboxylate 16 as the result of a base-catalyzed double bond migration in 15. A related cascade reaction was observed upon the coupling of 2-bromopropene (17) with styrene (18) which, in the presence of dimethyl maleate (19), occurred with high chemoselectivity in such a way, that only styrene acted as a coupling alkene and the maleate as a dienophile. Two diastereomeric 3-phenylcyclohex-4-ene-1,2-dicarboxylates were thus obtained with 20 being formed by the usual endo attack. The relative conﬁguration of the second diastereomer 21 was not assigned and it remains unclear whether it was formed by an exo-cycloaddition of dimethyl maleate or by cycloaddition of dimethyl fumarate formed by the frequently observed (Z)(E)-isomerization of dimethyl maleate [20, 21]. While this reaction is an example for a rational utilization of the different properties of alkenes 18 and 19, Reissig et al. recently reported on similar problems in Heck reactions of methyl acrylate (14) with alkenyl nonaﬂates [22–24], which are very reactive substrates for these cross couplings [25]. Upon reaction of the highly substituted nonaﬂate 22a with 14 for 18 h, the product 23a was isolated in 75% yield, which could be transformed in a consecutive [4 + 2] cycloaddition of N-phenylmaleimide with an endo “top-side” attack (Scheme 3). When the Heck coupling was left to run for 48 h, a sequential reaction with methyl acrylate took place leading to a mixture of 23a (20%) and 25a (42%). In the analogous transformation of the related substrate 22b the subsequent Diels– Alder reaction could not be avoided at all at 70 ◦ C so that a mixture of 23b (17%) and 25b (10%) was formed. Only at room temperature with K2 CO3 as a solid base and nBu4 NCl as a phase transfer catalyst, i.e. under the so-called

Scheme 3 Stepwise versus domino cross-coupling-cycloaddition reactions on 8-oxabicyclo[3.2.1]octa-2,6-dienes [22]

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“Jeffery conditions” [26, 27], could 23b be obtained as the sole product, but only in a slightly improved yield of 25%. These examples demonstrate that a selective Heck–Diels–Alder sequence with two different alkenes is only possible either in a stepwise manner, if an alkene reacts much faster in the Heck reaction than in the subsequent cycloaddition so that the 1,3-diene can be isolated, or as a real cascade reaction if one alkene is more reactive and thus selectively reacts as a coupling partner, whereas the other one is a better dienophile. Both concepts have been used by Kollar et al. for the annelation of cyclohexene rings onto the steroidal skeleton 26 (Scheme 4) [28–30]. At 60 ◦ C the cycloaddition was sufﬁciently suppressed so that the Heck coupling product 29 could be isolated and subsequently subjected to Diels–Alder reactions with different dienophiles. For a domino reaction with both methyl acrylate and dimethyl fumarate (28) present in the reaction mixture, the conditions had to be precisely adjusted so that the mixed products 31 and 32 were formed predominantly along with only small amounts of the products of a twofold reaction of either 27 (R = CO2 Me) or 28 with 26. These conditions also proved suitable for a cascade reaction of 26 involving allyl alcohol 27 (R = CH2 OH) or allyl acetate 27 (R = CH2 OAc) and dimethyl fumarate (28).

Scheme 4 Inter-intermolecular cascade reactions on a steroidal substrate [28, 29]

The same authors also presented a completely selective three-component cascade reaction but of a slightly different type. By reacting 26 with a vinylstannane 27 (R = SnBu3 ) in the presence of methyl acrylate or diethyl maleate, a sequential Stille-type [31] cross-coupling-Diels–Alder reaction took place, which only gave the desired products [30]. Since the Stille coupling proceeds without a base present, the dienophile does not participate in a Heck reaction, but only in a [4 + 2] cycloaddition with the initially formed electron-rich diene. This same strategy, yet performed in two separate steps, was applied towards the assembly of the B-ring in a steroid skeleton. The functionalized cyclohexenol triﬂate 33 was efﬁciently coupled with the bicyclic stannane 34

Domino Heck-Pericyclic Reactions

55

to furnish the tricyclic conjugated diene 35 which underwent [4 + 2] cycloadditions with dienophiles like (E)-but-2-enedinitrile or N-methylmaleimide (Scheme 5) [32, 33].

Scheme 5 Assembly of the steroid skeleton by a sequential reaction [32]

Drawn from these examples it is apparent that controlling the chemoselectivity in inter-intermolecular Heck–Diels–Alder reactions of two different alkenes can be tedious if the alkenes show comparable reactivities. Nevertheless, the stepwise approach was realized in several other cases. In a synthesis of a derivative of cephalostatin 1 containing a central benzene instead of the pyrazine ring, Winterfeldt et al. linked two steroidal systems by a Heck coupling and subsequently performed high pressure Diels–Alder reactions of the conjugated diene with electron-deﬁcient alkynes [34]. Another example, reported by Hayashi et al., involves a selective Heck reaction of a bromoglucal with ethylene or acrylic acid derivatives followed by cycloadditions with maleic anhydride or N-phenylmaleimide [35]. 2.1.2 All-Intermolecular Domino Processes Involving Bicyclopropylidene Although it is a tetrasubstituted alkene, bicyclopropylidene (37) has proved to be exceptionally reactive in Heck couplings [36]. As such, it is more rapidly carbopalladated than even methyl acrylate—presumably due to its high lying HOMO, leading to a high nucleophilicity, which facilitates the attack of the electrophilic organopalladium species. Accordingly, it is well suited for chemoselective domino Heck–Diels–Alder reactions. Indeed 37, when treated with iodoethene (13) and dimethyl maleate (19) in the presence of a palladium precatalyst at 70 ◦ C, furnished the spirocyclopropanated octahydronaphthaline derivative 38 in 49% yield (Scheme 6) [37–41], and no direct coupling product of iodoethene and dimethyl maleate was observed. The ﬁrst formed carbopalladation intermediate 39, which contains a cyclopropylpalladium as well as a cyclopropylcarbinylpalladium iodide moiety, under-

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Scheme 6 A cascade reaction consisting of a Heck coupling and a transmissive Diels– Alder reaction [37, 38]

goes a rapid cyclopropylcarbinyl to homoallyl rearrangement, and the latter intermediate 40, by β-hydride elimination, furnishes the cross-conjugated triene 41. This compound, which can be isolated when no dienophile is present from the beginning, then undergoes a so-called transmissive cycloaddition [42, 43] or essentially a domino Diels–Alder reaction in which the diene for the second step is formed in the ﬁrst cycloaddition. This new multicomponent cascade reaction can also be performed with a large variety of aryl halides, most favorably iodides (Scheme 7). The yields in this coupling-cycloaddition sequence are particularly high with the parent

Scheme 7 The combinatorial potential of a new multicomponent reaction involving bicyclopropylidene (37) [39–41]

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57

iodobenzene applying the Jeffery protocol for Heck reactions, and working with as little solvent as possible. Under these conditions, the sequence can occur multiple times on an oligohaloarene, e.g. 1,4-diiodobenzene, which reacts cleanly to furnish 46 as a single diastereomer in up to 83% yield. Accordingly, 1,3,5-triiodo- and 1,2,4,5-tetraiodobenzene undergo this sequential reaction three and four times, respectively. In the latter transformation, which overall is a nine-component reaction, 12 new carbon–carbon bonds are formed, and yet 47 is obtained in 47% yield. The combinatorial potential of this reaction has been demonstrated with the preparation of a library of more than 180 different compounds on a synthesizing robot, and the coupling has also been performed with aryl iodides bound to a solid phase, employing the triazene linker methodology of Bräse et al. [44–46]. Hetero atoms can be brought in with the dienophile as well as with the iodoarene, and the combinatorial diversity can be further increased by the use of substituted bicyclopropylidene derivatives. The utility of bicyclopropylidene (37) in multicomponent reactions is greatly enhanced by the fact that in the presence of tris(2-furyl)phosphine (TFP) instead of triphenylphosphine, the carbopalladation with an arylpalladium halide does not lead to an alkylidenecyclopropane of type 41, but to a σ -allyl-/π-allylpalladium complex 53/54 which can quite efﬁciently be trapped with various nucleophiles (Scheme 8). The formal rearrangement

Scheme 8 Yet another cascade reaction involving bicyclopropylidene (37) [47–49]

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of the homoallyl- 52 to the σ -allylpalladium intermediate 53 most probably proceeds by β-hydride elimination and immediately ensuing hydridopalladation in the initially formed hydrido(alkene)palladium iodide intermediate with the reverse regioselectivity to yield 53. Nitrogen, oxygen as well as carbon nucleophiles have successfully been employed in such combinations with cross couplings of aryl iodides to 37 to yield allyl substitution products of type 50 (R = Ar) [47, 48]. This domino reaction, when performed with vinyl iodide, leads to substituted reactive dienes which can undergo [4 + 2] cycloadditions yielding functionally substituted spiro[2.5]octene derivatives 51. This constitutes an overall four-component reaction in a one-pot, yet two-step operation. The cascade reactions can be performed with a wealth of dienophiles and alkenyl iodides, e.g. with cyclohexenyl iodide and N-phenyltriazolinedione, to give 51d or with functionalized iodides 55 and 56, which, after cross coupling and in these cases intramolecular trapping of the allylpalladium intermediate, furnished tricycles 57 and 58, respectively [49]. It is obvious that the dienophile cannot be present in the reaction mixture from the beginning, as it generally also is a good Michael acceptor and as such would compete for the nucleophile. 2.1.3 Intermolecular Heck Reactions of Allenes Allenes are another interesting type of substrate for domino Heck–Diels– Alder reactions, since they are rapidly carbopalladated—preferably placing the organic residue at the central sp-hybridized carbon atom—yet are rather unreactive as dienophiles. These properties were exploited by Grigg et al. in elegant cascade reactions of alkylallenes with aryl iodides and dienophiles. Carbopalladation of dimethylallene (59) leads to a σ -allyl-/π-allylpalladium complex 62/63, which undergoes dehydropalladation to 1,3-dienes 64, and these are eventually trapped by a dienophile (Scheme 9) [50, 51]. A large variety of electron-rich and -deﬁcient aryl and heteroaryl iodides as well as alkenyl iodides can be employed, the latter furnishing, for example, the product 61a with N-methylmaleimide (60). Upon reaction of n-octylallene or vinylidenecyclohexane with thienyl or phenyl iodide, respectively, the products 65 and 66 were formed as mixtures of diastereomers with the main component (shown) resulting from an endo attack in the cycloaddition. Interestingly, maleic anhydride gave the desired product 67 as a single diastereomer. The same authors also reported on palladium-catalyzed domino cyclization-anion capture reactions employing allene (69) as a relay switch (Scheme 10) [52]. Such a reaction of the alkynyl-tethered aryl iodide 68 starts with an oxidative addition to the catalytic metal species, and is followed by an intramolecular carbopalladation of the triple bond. An intermolecular car-

Domino Heck-Pericyclic Reactions

59

Scheme 9 Three-component reactions involving alkylallenes [50, 51]

bopalladation of allene (69) then takes place leading to an allylpalladium intermediate which is ﬁnally trapped by a secondary amine. With variation of the composition and length of the tether linking the aryl and the alkynyl moiety, interesting oligocyclic systems were obtained, yet a subsequent cycloaddition of N-phenyltriazolinedione onto the exocyclic diene unit in 70 was only performed for a single example.

Scheme 10 A cyclization-anion capture cascade with ensuing [4 + 2] cycloaddition [52]

Cyclopropyl-substituted allenes open the door to yet another reaction mode. When treated with aryl iodides in the presence of a typical Heckcatalyst system and a dienophile, cyclohexene derivatives 77 were obtained (Scheme 11) [53, 54]. Thus, the initially formed arylpalladium iodide carbopalladates 72 to form a σ -allylpalladium intermediate 73. It swiftly undergoes the cyclopropylcarbinyl to homoallyl rearrangement yielding the homoallylpalladium species 74 which ﬁnally suffers β-hydride elimination. The thus formed 2-aryl-1,3,5-hexatrienes 75 are prone to undergo polymerization, but can be efﬁciently trapped by an appropriate dienophile at the least steri-

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Scheme 11 Cyclopropylallenes as precursors for 2-aryl-1,3,5-hexatrienes and their subsequent [4 + 2] cycloadditions [53, 54]

cally encumbered diene moiety. The fact that the [4 + 2] cycloadditions with dimethyl maleate and dimethyl fumarate do not occur with complete diastereoselectivity, but yield both diastereomers trans,trans-77 and cis,trans-77 in ratios ranging from 2.1 : 1 to 5.7 : 1, has been taken to indicate that these Diels–Alder reactions proceed stepwise via the well-stabilized zwitterionic intermediates 76. This new three-component reaction is quite versatile in terms of the applied aryl halides 48, allenes 72, and dienophiles. 2.2 Intramolecular Cross Couplings with Subsequent Intermolecular Diels–Alder Reactions Another way to ensure complete chemoselectivity in domino Heck–Diels– Alder reactions is to tether the alkenyl halide with the alkene designated to be the coupling partner. Thus, the cross-coupling reaction proceeds intramolecularly, which is kinetically favored over intermolecular transformations by at least a factor of 105 . Additionally, these processes involve cyclizing carbopalladations and therefore usually result in products of higher complexity than all-intermolecular cascades. Cross couplings leading to the formation of 1,2-dialkylidenecycloalkanes are especially attractive since these products contain a ﬁxed s-cis-butadiene moiety, and thus are predisposed for facile cycloadditions proceeding with the release of steric strain. This concept has been realized in a number of examples employing different types of palladium-catalyzed cross-coupling reactions (Scheme 12), however, some of them are limited to the formation of ﬁve-membered rings (n = 5). If at all, larger rings are usually formed in lower yields, because other competing transformations lead to the formation of side products.

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Scheme 12 Various palladium-catalyzed transformations of open-chain precursors leading to 1,2-dialkylidenecycloalkanes 83 [55, 57–60, 62–75]

Grigg et al. showed the feasibility of this methodology employing Heck reactions of 2-bromo-α,ω-dienes 78 (n = 5, 6) [55]. In these transformations, quaternary ammonium chlorides as additives had a beneﬁcial effect in that the carbopalladation occurred faster and with higher selectivity for a 5-exo-trig cyclization to 83 (n = 5), whereas signiﬁcant amounts of 3-alkylidenecyclohexene derivatives were obtained without their presence as a consequence of 6-endo-trig cyclizations (conditions A.1) (later on, it was shown that such 6-endo-trig cyclizations can actually occur by a sequence of 5-exo-trig cyclization, cyclopropanation and cyclopropylcarbinyl to homoallyl rearrangement: see [56]). While initially the [4 + 2] cycloadditions were only performed after isolation of the dienes 83 in a separate second operation, the sequence was later slightly modiﬁed (conditions A.2), and carried out as a domino reaction which gives consistently better overall yields [57–60]. With dienophiles like tetracyanoethene or p-benzoquinone, which are also strong oxidants, the sequence has to be performed in a two-step, yet one-pot procedure by adding the dienophile after completion of the intramolecular Heck reaction. This method was further developed to conveniently access heteroanalogous bicyclo[4.3.0]- and bicyclo[4.4.0]alk-1(6)-ene derivatives 86 from appropriate acyclic 2-bromo-1,ω-dienes 85 and dienophiles (Scheme 13). Early examples of such carbobicycles frequently were derived from 2-bromo-α,ωdienes containing a gem-diester group as in 85i to proﬁt from both an efﬁcient preparation of the acyclic precursors from malonates and the Thorpe–Ingold effect in the cyclization step [61]. However, gem-disubstitution in the tether is not a prerequisite for the cyclization to occur efﬁciently as is evident for many of the heterobicycles and the all-carbon bicyclic system 86g. Cyclopropenecarboxylates and cyclopropylideneacetates have been applied as dienophiles

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Scheme 13 Intra-intermolecular domino Heck–Diels–Alder reactions [57–60]

in such domino reactions to lead to cyclopropane-annelated 86j and spirocyclopropanated bicycles 86k, respectively. A second method for the preparation of 1,2-dialkylidenecycloalkanes 83 starts from 2-bromoenynes 79 and comprises a hydride ion capture by an initially formed σ -alkenylpalladium species (a reductive Heck reaction) [62]. Good results were obtained for the preparation of ﬁve-membered rings, but the yields seriously dropped when going to the next higher homologues with n = 6, and no sequences including subsequent [4 + 2] cycloadditions have been reported to date. Grigg et al. also introduced another Heck-type reaction. 2,6-Dibromohepta-1,6-dienes 80 cyclize to the same products 83 (n = 5) as do 2-bromo1,6-dienes 78 (n = 5) when treated with the usual precatalyst mixture, yet containing a stoichiometric amount of triphenylphosphine [63, 64]. In this case, palladium dibromide rather than hydridopalladium bromide is eliminated in the ﬁnal step of the cross-coupling reaction, and the palladium(II) salt is reduced by the phosphine to regenerate the reactive palladium(0) species. Completely selective exo-trig cyclizations occur in these examples, however, the respective cyclohexane derivatives with n = 6 are formed in poor yields. Additionally, it is sometimes difﬁcult to separate the product from the phosphine oxide after aqueous work-up. This latter difﬁculty was circum-

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vented by Moreno-Manas et al. by using a polymer-bound triarylphosphine in an application of this method towards the synthesis of bicyclic α-amino acids. A cascade of twofold allylation of ethyl nitroacetate (87) and reductive intramolecular cross coupling led to the dimethylenecyclopentane 90 which was isolated just by ﬁltration of the solids and then subjected to a Diels–Alder reaction with maleimide (Scheme 14) [65].

Scheme 14 A domino of twofold palladium-catalyzed allylation and reductive intramolecular cross-coupling reaction with subsequent cycloaddition [65]

Yet another palladium-catalyzed transformation leading to 1,2-dialkylidenecycloalkanes was established by Trost et al. when investigating a catalytic Alder-ene reaction (path D in Scheme 12). They showed that two different catalyst systems are capable of cycloisomerizing enynes 92 to either cyclic 1,4-dienes 96—the products of regular Alder-ene reactions— or the 1,3-dienes 95 (Scheme 15) [66–68]. Starting from palladium acetate, the reaction presumably occurs by coordination of both unsaturated moieties (intermediate 93) and subsequent cycloisomerization to the ring-

Scheme 15 Mechanisms of the palladium-catalyzed cycloisomerization of acyclic 1,nenynes (n = 6, 7) [66–68]

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annelated palladacyclopentene 94. Dehydropalladation involving either Hb or Ha and reductive elimination then furnishes products 95 or 96, respectively. This mechanism involves Pd(II) and Pd(IV) species and N,Nbis(benzylidene)ethylenediamine (BBEDA) turned out to be a superior ligand most likely due to its ability to efﬁciently stabilize the intermediate 94. The second methodology utilizes a palladium(0) precatalyst to which a carboxylic acid, mostly acetic acid, is added oxidatively. A regioselective hydridopalladation of the triple bond then leads to a species of type 97 which undergoes an intramolecular carbopalladation to form 98. Dehydropalladation and release of either diene 95 or 96 ﬁnally completes the catalytic cycle. In the cases of enynes 92 with an internal alkene moiety the regioselectivity of the dehydropalladation in 94 and 98 mainly depends on the nature of the external allylic carbon atom. If this is a primary or a secondary, alkylsubstituted atom, formation of 1,4-dienes occurs, since only Ha can easily adopt a synperiplanar orientation relative to the palladium, and be involved in β-dehydropalladation. In contrast, if this carbon is either tertiary or bears an electron-withdrawing group (EWG), elimination of Ha is disfavored for steric or electronic reasons. Hb is now eliminated since the C – Hb bond is weaker than the C – Ha bond due to the allylic character of the former. This method has the advantage of being most atom-economical and tolerant to a wide variety of functional groups. However, it is more or less limited to the construction of ﬁve-membered rings. Cyclohexane derivatives have been obtained this way, but the yields were always lower than for the cyclopentene derivatives. Five-membered heterocycles, starting from acyclic precursors with either an oxygen or a nitrogen in the tether between the double and the triple bond, are well accessible [66–68]. In combination with a subsequent Diels–Alder reaction, an equally atom-economical transformation, various oligocyclic products can be obtained, and this sequence does not have to be performed in two steps [68–72], but can also be executed as a cascade reaction with the dienophile present in the reaction mixture from the beginning [57, 73]. In this context, an allylic hydroxy group can exert a strong inﬂuence on the overall selectivity as shown in the case of enyne 99 (Scheme 16) [69]. It controls the regioselectivity of the dehydropalladation in the cycloisomerization leading to the 1,3-diene 100 as the sole product, and in addition effects the formation of just one diastereomer in subsequent [4 + 2] cycloadditions with N-phenylmaleimide and methyl acrylate, respectively. Quite remarkably, the facial selectivity is completely changed upon going from maleimide to acrylate, and in the latter case complete ortho-type regioselectivity is also observed, which leads to subsequent lactone formation yielding the tricycle 102. This methodology has been used as the key step in the total synthesis of the natural products (–)-Sterepolide (107) [70, 71] and (–)-Merulidial (108) [72] starting from the highly functionalized enyne 103. Finally, reductive cycloisomerizations of 1,6- and 1,7-diynes 82 provide access to 1,2-dialkylidenecycloalkanes 83 by a palladium-catalyzed reaction

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Scheme 16 Synthesis of tricyclic systems by cycloisomerization of enynes and subsequent Diels–Alder reaction [69–72]

with triethylsilane as the hydride source (Scheme 12) [74, 75]. It is applicable to diynes with both internal and terminal triple bonds, however, this transformation has so far not been combined with a cycloaddition. 2.3 All-Intramolecular Heck–Diels–Alder Sequences When both, the palladium-catalyzed cross-coupling and the [4 + 2] cycloaddition can proceed intramolecularly, a maximum of chemo-, regio- and diastereoselectivity is achieved, and the sequence leads to the closure of at least three rings. Trost et al. demonstrated a number of examples for this sequence employing cycloisomerizations of enynes in the ﬁrst step, and in this context also encountered yet another structural factor exerting inﬂuence on the regioselectivity of the dehydropalladation [67–69]. Substrates 109 were expected to lead to 1,4,ω-trienes, since the allylic Ca is a secondary carbon atom bearing an alkyl substituent (vide supra). However, with a twoor three-carbon chain tethering the terminal alkene moieties (n = 1, 2),

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Scheme 17 All-intramolecular domino cycloisomerization-Diels–Alder reactions [67–69]

1,3,ω-trienes 111 were formed almost exclusively while the next higher homologue (n = 3) gave a 1 : 1-mixture of 111 and the respective 1,4,9-triene (Scheme 17). Obviously, a remote coordination of the palladium to the double bond in the intermediates 110 (n = 1, 2) can hold the system in an orientation which disfavors dehydropalladation involving Ha or Hb by a large dihedral angle between the C – Pd and the C – Ha,b bonds. With a threecarbon tether, the triene 111 (n = 2) can be isolated, when the reaction is carried out at low temperature, whereas at 110 ◦ C an intramolecular [4 + 2] cycloaddition immediately ensues furnishing tricycle 112. With an acyclic precursor 113 set up to yield a [5.6.6]-tricycle, an allylic hydroxy group is necessary in order to achieve selective formation of the triene 114. This compound is less prone to undergo a subsequent Diels–Alder reaction and requires a temperature of 172 ◦ C with the presence of the stabilizers 2,6di-tert-butyl-4-methylphenol (BHT) and N,O-bis(trimethylsilyl)acetamide (BSA), the latter one giving rise to a concomitant silylation of the hydroxy group. Anyhow, the product 115 is obtained as a single diastereomer. Even enediynes can successfully be employed as substrates, if the two alkyne moieties exhibit different reactivities towards hydridopalladation (for a study on the reactivity of different alkynes in related transformations see [76]). In compound 116, the terminal triple bond reacts preferentially leading

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67

to dienyne 117, and a 6 : 1 mixture of two diastereomeric tricycles 118 (main isomer shown) is formed in the subsequent intramolecular cycloaddition. While the syntheses of the acyclic precursors in the examples above each require a couple of steps, symmetrical dienynes with a central triple bond and heteroatoms in the tethers are more easily accessible. They can yield heterotricyclic compounds by the same reaction mode, for example, the diaza- and dioxatricycles 121 are obtained starting from dienynes 119 (Scheme 18) [73]. Yields were best (90%) with N-tosyl linkers, with N-Boc groups the reaction was slower (41% yield), and with N-benzyl linkers only decomposition occurred. This may be due to coordination and blocking of the catalyst by the more Lewis-basic amines. The cis- and trans-diastereomers of 121 were formed in a ratio of 1.8 : 1, and this ratio did not change in other solvents, at different temperatures, with other catalyst precursors or under high pressure (10 kbar). In view of the apparent inﬂuence of the tether, the unsymmetrical oxazaprecursor 122 gave a 7 : 3 mixture of tricycles 123 and 124. Obviously, the hydridopalladation of the triple bond occurred with some regioselectivity such that intramolecular carbopalladation of the allylamine predominated. It is noteworthy that in these cases the intramolecular Diels–Alder reactions of the intermediate trienes 120 already occur under the employed conditions, i.e. at 80 ◦ C.

Scheme 18 Assembly of heterocycles by domino cycloisomerization Diels–Alder reactions [73]

Starting from suitably substituted 2-bromotrideca-1,11-diene-6-ynes, an all-intramolecular domino Heck–Diels–Alder reaction can occur which features the formation of even four rings. When (E/Z)-125 is treated with

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Scheme 19 An all-intramolecular domino Heck-cycloaddition reaction leading to a tetracycle [77]

a palladium catalyst at 80 ◦ C, intermediate 126 was formed by two consecutive Heck-type cyclizations and subsequent β-dehydropalladation only from the terminal methyl group to give cis/trans-127 (Scheme 19) [77]. At 130 ◦ C with potassium carbonate as a base, trans-127 underwent an intramolecular Diels–Alder reaction to give the tetracycle 128, while cis-127 remained unchanged.

3 Heck Reactions Followed by 1,3-Dipolar Cycloadditions Palladium-catalyzed cross-coupling reactions followed by 1,3-dipolar cycloadditions are potentially very useful combinations since the latter transformation can occur with a large variety of 1,3-dipoles, leading to heterocycles which are either interesting themselves or can be transformed to compounds bearing interesting functionalities [78]. It is therefore surprising that only a few examples of such cascades have been reported so far. Grigg et al. started from iodophenol 129 which, after oxidative addition to the palladium catalyst, carbonylation with CO, carbopalladation of 1,1-dimethylallene (59) and intramolecular nucleophilic attack of the phenolic hydroxy group furnished the chroman-4-one 131 with complete regioselectivity [79]. This sequential reaction is highly versatile since it tolerates a number of different substituents both on the allene and on the aromatic ring and can also be employed towards the synthesis of quinol-4-ones starting from N-tosyl-oiodoanilines. These products were used for subsequent Michael additions, yet if their synthesis is performed in the presence of a suitable 1,3-dipole

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69

like the aldonitrone 130, isoxazolidines of type 132 are obtained by an ensuing 1,3-dipolar cycloaddition [80]. This sequence can also be performed with azomethine ylides as 1,3-dipoles which can be generated in situ from imines like 133 with a Ag2 O/DBU catalytic system, but the two diastereomers 134 and 135 were obtained as a 1 : 1 mixture. Better selectivities were achieved when carrying out the sequence in a two-step procedure with isolation of the chroman-4-ones.

Scheme 20 Synthesis of chroman-4-ones and their subsequent cycloadditions [79, 80]

A different domino reaction yet involving rather similar steps, i.e. carbopalladation of an allene and nucleophilic attack of a phenol, was elaborated by the same group and leads to isoxazolidines 138 after intramolecular cycloaddition in the intermediates 137 [81] (Scheme 21). This transformation was performed with several aryl and hetaryl iodides 48 and gave the highest yields with electron-rich aryl iodides while only traces of products were obtained starting from electron-deﬁcient aryl iodides.

Scheme 21 Access to tricyclic isoxazolidines by an inter-intramolecular cross-couplingcycloaddition cascade [81]

Another example features a Heck-type 5-exo-trig cyclization of the aryl iodide 139 occurring at room temperature in dichloromethane (Scheme 22) [82]. Azomethine ylides originating from imines 133 were used to trap the Heck product 140 in a subsequent 1,3-dipolar cycloaddition. The diastereomeric products 141 and 142 both derive from an endo attack of

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Scheme 22 Preparation of spiro oxindoles in a domino reaction [82]

the 1,3-dipole, yet the dipole must have been oriented in a syn- or anticonformation, respectively. While in the previous examples the cross-coupling reactions are used to assemble dipolarophiles, in a fourth type developed by Grigg et al. the dipoles 144 are generated in a cyclizing carbopalladation-anion capture reaction (Scheme 23) [83, 84] (for the ﬁrst examples of cyclizing carbopalladations of allenes see: [85, 86]). With dimethyl acetylenedicarboxylate as a dipolarophile, cycloadditions could only be performed on isolated 144 to give triazoles 145. In contrast, norbornadiene as the dipolarophile did not interfere with the cross coupling, thus paving the way for a domino reaction. However, the primary cycloaddition product 146 immediately underwent a retro Diels–Alder reaction forming cyclopentadiene and the triazoles 147.

Scheme 23 Cascade reactions yielding triazoles by a sequence of cross coupling, azide capture and 1,3-dipolar cycloaddition [83, 84]

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4 Cross Couplings with Ensuing 6π-Electrocyclizations 4.1 Intermolecular Coupling Reactions 6π-Electrocyclizations of 1,3,5-hexatrienes occur in a stereoselective manner under the inﬂuence of heat or light to give cyclohexa-1,3-dienes [18]. The starting materials can efﬁciently be prepared by transition metal-catalyzed cross-coupling reactions and in several examples an independently generated dienyl halide has been coupled with an alkene under palladium catalysis (a different approach not really within the concept of this article consists of palladium-catalyzed cross coupling of enol triﬂates with propargyl alcohols and subsequent domino carbomagnesiation of the triple bond by vinylmagnesium chloride and 6π-electrocyclization of the thus obtained 1,3,5-hexatrienes: see [87]). Gilchrist et al. applied this concept toward the assembly of the C-ring in the steroidal skeleton employing the butadienyl bromide 148 which in turn was obtained from 2-bromo-3,4-dihydronaphthalene1-carbaldehyde by a Peterson methylenation (Scheme 24) [88, 89]. Compound 148 was lithiated and transformed into the respective bromozinc intermediate which underwent a Negishi-type cross-coupling reaction [91] with the cycloalkenyl iodide 150a. At 156 ◦ C in reﬂuxing bromobenzene, a cyclization of the thus formed hexatriene 151a occurred, however unexpectedly the tetracycle 152 was produced, most probably via intermediate formation of the hexatriene 153 by a 1,7-H shift. This sigmatropic rearrangement must have to do with the carbonyl moiety in 151a, as the respective alcohol 154 which was formed by cross coupling of 149 with the bromozinc intermedi-

Scheme 24 Assembly of the steroid skeleton by cross coupling and 6π-electrocyclization [88–90]

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ate from silyl ether 150b and subsequent desilylation, cyclized to the desired steroidal skeleton, yet under concomitant acid-catalyzed double bond migration to give 155 [90]. A series of other iodides was also transformed in this cross-coupling-6π-electrocyclization cascade [88–90], and even pyridine derivatives could be obtained when applying this method on 1-bromo-3,4dihydronaphthalene-2-carbaldehyde N,N-dimethylhydrazone [92]. A related access to pyridine derivatives was reported by Yoon et al. performing a domino Heck-reaction-6π-electrocyclization–elimination sequence on uracil 156 which furnished pyrido[2,3-d]pyrimidines 158 in high yields (Scheme 25) [93]. When using dimethyl fumarate, the diester 158e was obtained along with reasonable amounts of a decarboxylated product, and with tert-butyl vinyl ether a mixture of regioisomers was formed with the 5-substituted isomer 158d predominating.

Scheme 25 A domino Heck-reaction-6π-electrocyclization–elimination sequence [93]

Twofold Heck reactions of 1,2-dibromocycloalkenes with suitable alkenes provide an even shorter route to 1,3,5-hexatrienes. These compounds are especially suited for subsequent 6π-electrocyclizations since the central double bond is part of a ring system and thus (Z)-conﬁgured, as in the examples above. This strategy was initially used for a highly efﬁcient assembly of symmetrically substituted dibenzoannelated [2.2]paracyclophanedienes of type 161 applying a fourfold cross coupling of 1,2,9,10tetrabromo[2.2]paracyclophanediene (159) with monosubstituted alkenes followed by two independent thermal 6π-electrocyclizations and aromatizations (Scheme 26) [94, 95]. With the use of styrene in the Heck reaction, the interesting 161 with eight mutually perpendicular biphenyl units was obtained. While good yields in the multifold Heck reactions on the tetrabromide 159 were only achieved under Jeffery conditions with a solid base in the presence of a quaternary ammonium salt, classical Heck conditions using a tertiary amine proved to be superior in the case of simple

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Scheme 26 Dibenzo[2.2]paracyclophanedienes by fourfold Heck reactions followed by two independent 6π-electrocyclizations [94, 95]

1,2-dibromocycloalkenes 162-n (Scheme 27) [96–98]. (E,Z,E)-1,3,5-Hexatrienes 163-n with two identical electron-withdrawing groups (e.g. CO2 R, Ph) in the 1,6-positions were thus obtained, and the corresponding diiodides 162-n furnished the SiMe3 -substituted hexatrienes when applying a modiﬁed protocol. These s-trans,s-trans-oriented hexatrienes required elevated temperatures (≥ 150 ◦ C) to undergo 6π-electrocyclizations to ring-annelated cis-disubstituted cyclohexadienes 164-n. Hexatrienes 163-n can also be utilized to prepare enantiopure bicyclic β-amino acids [99], strained 11-oxabicyclo[4.4.1]undeca-1,5-dienes [100] as well as functionalized cyclodecenones and -undecenones [101]. Upon attempted photochemical 6π-electrocyclizations of hexatrienes 163a-5,6, a fast equilibration of the (E, Z, E)- and their (E, Z, Z)-diastereomers 165-5,6 occurred [98]. Even

Scheme 27 Twofold Heck reactions of 1,2-dihalocycloalkenes and subsequent further transformations of the products [96–98]

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though the photochemical conrotatory 6π-electrocyclizations could not be brought about, the trans-disubstituted cyclohexadienes 166-n could be obtained by thermal cyclization of the isolated (E, Z, Z)-hexatrienes 165-n. Moreover, the hexatriene 163a-6 with a central cyclohexene moiety, upon extended irradiation, yielded the cyclohexane-annelated 8-oxabicyclo[3.2.1]octa-2,6-diene 167. This unprecedented intramolecular formal hetero-Diels– Alder reaction of an ester carbonyl group with a diene unit probably proceeds as a radical reaction of the triplet excited state. The preparation of unsymmetrically terminally disubstituted 1,3,5-hexatrienes by twofold Heck coupling of 162-n with two different alkenes cannot be achieved, since the second coupling step turned out to be signiﬁcantly faster than the ﬁrst one [96]. Sufﬁcient differentiation could not be brought about with a triﬂate and a bromide leaving group as in 168. How-

Scheme 28 Chemoselective Stille-Heck coupling sequences of 2-bromocyclohexenyl triﬂates [102–104]

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75

ever, this substrate proved to undergo completely chemoselective Stille cross couplings with various alkenylstannanes at the triﬂate position, and this could be succeeded by a Heck reaction at the remaining bromide [102–104]. In several cases this sequence has been carried out as a one-pot operation, for example, towards triene 169 as a versatile intermediate (Scheme 28). The thermal 6π-electrocyclization of 169 and subsequent treatment of the product with HCl yields the ring-annelated cyclohexenone 170. The overall result of this sequence from cyclohexanone, the precursor of 168, is a cyclohexenone annelation complementing the well-known Robinson annelation. Direct hydrolysis of the methoxyhexatriene 169 yields the dienylketone 171, the enolate of which undergoes an intramolecular Michael addition to yield (91% overall) the cyclopentenone-annelated product 172. In an approach to the steroid skeleton, the 4-substituted bromotriﬂate 173 representing the A-ring was coupled to the bicyclo[4.3.0]nonenylstannane 34 (the CD-ring fragment) with a catalyst cocktail containing triphenylarsine and copper(I) iodide, to give bromodiene 174 in very good yield [103, 104]. Under optimized conditions at 105 ◦ C with the thermally relatively stable palladacycle as a catalyst, 174 was then coupled with tert-butyl acrylate leading to the hexatriene 175 which, upon heating at 215 ◦ C, underwent 6π-electrocyclization with complete rotaselectivity, albeit the expected product 176 was accompanied by its isomer 177 arising from a subsequent 1,5-H shift. These steroidal products have the favorable feature of bearing a versatile substituent at C-7. 4.2 Cascade Reactions Involving Intra- and Intermolecular Carbon–Carbon Bond Formations Towards the synthesis of 1,3,5-hexatrienes by an inter-intramolecular reaction mode, Trost et al. treated alkenyl bromides with enyne 178 under palladium catalysis (Scheme 29) [105]. Even though a methoxycarbonylsubstituted double bond is rather reactive towards carbopalladation, its reactivity is surpassed by that of a triple bond. Thus, selective formation of the hexatrienes 179 takes place, and the latter immediately undergo a diastereoselective, i.e. rotaselective 6π-electrocyclization yielding bicycles 180. This complete diastereoselectivity must be due to steric and stereoelectronic effects exerted by the silyloxy group at C-5 in 178, since substrates lacking this group furnished mixtures of diastereomers (for an explanation of these effects in related transformations see: [106]). The method was extended to other 1,6-enynes, for example, substrates with a trimethylsilyl group instead of the ester moiety, and also 1,7-enynes. However, it is less efﬁcient for compounds with terminal triple bonds, since formal 6-endo-trig instead of 5-exo-trig cyclization predominates, and this, for example, leads to the selective formation of the 3-propenylidenecyclohexene 182 from the enyne 181 [107].

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Scheme 29 Inter-intramolecular cross couplings yielding 1,3,5-hexatrienes [105, 107]

The very ﬁrst assembly of 1,3,5-hexatrienes, yet by an intra-intermolecular sequence of cross couplings, was realized by Parsons et al. [108]. In the palladium-catalyzed reactions of 2-bromo-1-ene-6-ynes 183 with methyl acrylate, a selective formation of the respective hexatriene took place which subsequently underwent electrocyclization followed by aromatization to ﬁnally provide ring-annelated arenes 184 (similar compounds have been prepared using cyclizing cascade carbopalladation reactions not involving a pericyclic reaction: see [109]) (Scheme 30). Interestingly, in these examples the second, thus intermolecular carbopalladation only occurs on methyl acrylate and not on the triple bond of a second molecule of 183. However, good yields were only reported in the case of the carbocyclic derivative [X = C(CO2 Me)2 ]. Using the phenyl-substituted bromoenyne 185 and employ-

Scheme 30 Preparation of ring-annelated arenes [108] and cyclohexadienes [110] by intraintermolecular cross couplings with subsequent 6π-electrocyclizations

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ing electron-rich alkenes at lower temperature de Meijere et al. later were able to suppress the aromatization and obtain the ring-annelated cyclohexadienes 186 [110]. When employing bicyclopropylidene (37) in the intra-intermolecular cascade coupling with 2-bromoenynes 187 containing bulky substituents R on the alkyne terminus, cross-conjugated tetraenes 188 were obtained in good yields (Scheme 31) [111]. Their formation again stems from the rapidly occurring cyclopropylcarbinyl to homoallyl rearrangement which frequently enriches the chemistry involving this unique substrate (cf. Schemes 6–8). NMR evidence corroborates that these molecules adopt an almost 90◦ dihedral angle between the two diene moieties. When carried out at elevated temperature (110 ◦ C in DMF), the reaction proceeds with a subsequent 6πelectrocyclization to yield the spiro[cyclopropane-1,4 -bicyclo[4.3.0]nona1(6),2-dienes] 189 (up to 71%). With a cyclohexenyl substituent at the triple bond terminus of 187 (R = cyclohexenyl), this sequence is extended in that the initially formed cross-conjugated pentaene 190 undergoes two consecu-

Scheme 31 Intra-intermolecular cross-coupling-6π-electrocyclization sequences incorporating bicyclopropylidene (37) [111]

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tive electrocyclizations, leading to the pentacyclic product 192, albeit in a moderate yield of only 31%. The same palladium-catalyzed domino cyclization-anion capture sequence involving carbopalladation of allene (69), which was employed by Grigg et al. for the synthesis of diene 70 (Scheme 10) can yield 1,3,5-hexatriene 194, when starting from 2-bromo-1-ene-6-yne 193 instead of the aryl iodide 68 (Scheme 32) [52]. Under the conditions of its formation, 194 immediately undergoes thermal 6π-electrocyclization to give the bicyclic product 195.

Scheme 32 A cyclization-anion capture cascade with ensuing 6π-electrocyclization [52]

While such 5-exo-dig cyclizations are favored according to the Baldwin rules and thus easily achievable, the related 4-exo-dig cyclizations are disfavored. Nevertheless, they can take place in a palladium-catalyzed cascade reaction as shown by Suffert et al. [112, 113]. Bromoenynes 196b,c, in the presence of a palladium(0) species, underwent intramolecular carbopalladation followed by a Stille-type cross coupling with tri-n-butylvinylstannane to yield intermediate 1,3,5-hexatrienes 199 (Scheme 33) which undergo 6πelectrocyclization furnishing tricycles 197. The outcome of the reaction strongly depends on the structure of the starting material. A good yield of the tricyclic product was only achieved in the case of the seven-membered ring starting material 196c. The lower homologues either gave only a moderate yield of the desired product 197b (n = 6) or only the monocyclic product 198a (n = 5) of a direct Stille coupling without preceding 4-exo-dig cyclization.

Scheme 33 A domino cross coupling-6π-electrocyclization reaction featuring a 4-exo-dig cyclization [112, 113]

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This is most probably due to the severe increase in steric strain upon going from 196a to the tricyclic 197a with a four-, a ﬁve- and a six-membered ring. In addition, best results were obtained from starting materials like 196 featuring an anti-diol moiety while both syn-diols as well as substrates with only one hydroxy group were less suitable. Finally, the terminal silyl group turned out to be essential for the 6π-electrocyclization to occur, since the domino reaction ceased at the stage of the hexatriene of type 199 when starting from a derivative of type 196 with a methyl group on the triple bond terminus. Another interesting domino cross-coupling-6π-electrocyclization sequence has recently been reported by Zhang et al. [114]. Propargylic carbonates 200 with a tethered additional alkyne moiety undergo oxidative addition to suitable palladium(0) species with concomitant release of carbon dioxide leading to the allenylpalladium intermediates 201 (Scheme 34). Subsequently, intramolecular carbopalladation and Suzuki-type cross coupling with added phenylboronic acid takes place to form 203. The 6π-electrocyclization of these compounds requires annihilation of the aromatic system in the phenyl group, yet the phenylvinylallenes 203 readily cyclized under the employed conditions to yield the ring-annelated naphthalene derivatives 205 via intermediates 204. In one case, the intermediate 204 could even be isolated. This sequence could be extended to various aryl- and heteroarylboronic acids as well as with diyne starting materials containing additional substituents, providing an elegant access to numerous naphthalene, benzofuran, and benzothiophene derivatives.

Scheme 34 acid [114]

Cascade reaction of propargyl methyl carbonates with phenylboronic

Lately, Balme et al. reported on a new and completely different reaction mode leading to ring-annelated cyclohexadienes similar to those obtained from inter-intramolecular Heck reactions with subsequent 6πelectrocyclizations (cf. Scheme 29). The method employs conjugated enynes with a tethered stabilized enolate as a nucleophilic carbon center, generated

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Scheme 35 Yet another access to ring-annelated cyclohexadienes involving cyclization by intramolecular nucleophilic attack on a palladium-coordinated triple bond [115]

by deprotonation of the cyanoacetate moieties in the starting materials 206 with strong bases, for example, KH (Scheme 35) [115]. In the same ﬂask, a palladium(0) catalyst is in-situ formed from a palladium(II) salt and BuLi and undergoes oxidative addition of an alkenyl bromide or triﬂate to give an electrophilic palladium(II) species which coordinates and activates the triple bond in 206 towards nucleophilic attack. This via 210 leads to cyclization furnishing dialkenylpalladium intermediates 211 which ﬁnally suffer reductive elimination to give hexatrienes 208. At room temperature in THF the transformation ceases at this stage, while in reﬂuxing toluene a subsequent 6π-electrocyclization occurs to give the ring-annelated cyclohexadienes 209. 4.3 All-Intramolecular Processes Cascade reactions of 2-bromodienynes involving two intramolecular carbopalladations with subsequent 6π-electrocyclizations are especially attractive since they provide tricyclic skeletons from acyclic precursors in a single step. The oxabromodienyne precursor 212a was set up to give the [6.6.5]tricyclic skeleton 215a. When treated with a typical Heck palladium catalyst cocktail in the presence of silver carbonate in order to prevent double bond migrations in the intermediate 214 (Scheme 36), 212a indeed gave 215a along with 10% of the tetracycle 217a [116, 117]. With potassium carbonate as a base, the cross-conjugated triene 216a was obtained along with 5% of

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Scheme 36 Tri- and tetracyclizations of 2-bromodienynes [116, 117]

the tetracyclic propellane 217a, formed as a single diastereomer. Subsequent work showed that the tetracycle 217b arising from 213b by a sequence of 5-exo-trig-, 3-exo-trig-cyclization and β-dehydropalladation can be obtained as the sole product from the acyclic precursor 212b with a substituent R = H preventing β-dehydropalladation at the intermediate stage 213. Yet another reaction mode showed up with bromodienyne 218. The expected tetracycle 219 was isolated along with the tricycle 220, which is formed from an intermediate of type 213 by 3-exo-trig-carbopalladation of the tetrasubstituted double bond (similar tail-biting processes have also been observed by other authors: see [118, 119]). Obviously, the outcome of the overall reaction is strongly controlled by the reaction conditions and the tether lengths in the precursors. These important features initiated an extensive study of the scope and limitations of such reaction cascades with respect to various substitution patterns, ring sizes and heteroatoms in the tethers between the unsaturated moieties (for a review see [120]). Thus, the tetracycles 222ab with an attached cyclohexane ring were obtained in excellent yields by completely diastereoselective conversions of 221a,b (Scheme 37) [121]. Heterotricyclic compounds, such as the diaza-, dioxa- and oxazatricycles 224a–c were obtained in 55–80% yield when using the palladacycle shown in Scheme 28 as a precatalyst [122]. The yield of crude 224a was actually much better, and higher yields can often be obtained by carefully avoiding losses during puriﬁcation. With a phenyl substituent at the terminating unit, the 6π-electrocyclization yielded a single

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Scheme 37 Preparation of [5.6.5]-tricyclic skeletons by cascade reactions on 2-bromodienynes [121–123]

diastereomer 226 [123]. As in the case of hexatrienes 179 (cf. Scheme 29) one of the two possible disrotatory cyclization modes is apparently favored due to steric interactions exerted by the methoxy substituent. In all these cases, the 6π-electrocyclization proceeds under the conditions of the Heck reaction and thus at remarkably low temperatures (60–100 ◦ C). In order to evaluate the scope concerning achievable ring sizes, precursors with different tether lengths between the bromoene starter unit, the alkyne relay and the alkene terminator were prepared and subjected to the conditions of this cascade reaction. In the case of precursors 227a–c leading to [n.6.5]-tricycles 228a–c, the time required to form 228b was signiﬁcantly longer, and the yield of 228b (actually isolated as a 2 : 1 mixture with the corresponding aromatic compound) was 20% lower (Scheme 38), whereas the [8.6.5]-tricycle 228c was not formed at all. Attempts to assemble tricycles with six-membered B- and C-rings led to tetracycles of type 230 with cyclopropane moieties bridging the A- and B-rings just like the ones mentioned above (see Scheme 36) [124, 125]. The reasons for this anomalous reaction mode most likely relate to different conformations of the key intermediates of type 213 or 214. Thus, a retarded β-dehydropalladation or a retarded electrocyclization giving the eliminated hydridopalladium halide an opportunity to rehydropalladate the 1,3,5-hexatriene could favor a σ -alkylpalladium

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Scheme 38 Variation of the tether lengths in precursors for palladium-catalyzed tricyclizations [124, 125]

intermediate of type 213 to undergo a 5-exo-trig- and subsequent 3-exo-trigcyclization to yield a tetracycle 230 after β-dehydropalladation. Apparently, there is no rule without an exception, as certain substituents on acyclic bromodienynes set up for such tetracyclizations can cause the sequential reaction to proceed in an unprecedented direction. Thus, the bromodienyne 232a yielded the novel tetracyclic system 231 as proved by an X-ray crystal structure analysis, while the bromodienyne 232b with a terminal phenyl group sequentially cyclized to give the pentacycle 233 rather than a phenyl-substituted skeleton of type 230. Bromodienynes designed to lead to tricycles with a seven-membered C-ring, combined with a ﬁve- or six-membered A-ring only underwent polymerization. Altogether, this sequence of all-intramolecular palladium-catalyzed 1,3,5-hexatriene formation with subsequent 6π-electrocyclization works particularly well as long as ﬁvemembered rings are formed in both Heck-type cyclization steps. The overall yields are not as good, when one of the Heck-type cyclizations leads to a sixmembered ring, especially when this is the second cyclization step. Other tricycles are formed only in moderate yields ([7.6.5]) or as minor products ([6.6.6] and [5.6.7]). Yet another access to such [5.6.5]- and [6.6.5]-tricyclic skeletons is viable employing palladium-catalyzed cycloisomerizations of enediynes. Starting

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Scheme 39 Tricyclizations by palladium-catalyzed cycloisomerizations followed by 6πelectrocyclizations [126, 127]

from substrates 234, Trost et al. obtained tricycles 236 as single diastereomers in high yields, as again the 6π-electrocyclizations occurred with complete rotaselectivity (Scheme 39) [126, 127]. As can be seen from the transformations of enediynes 237, this method is applicable for substrates bearing diverse substituents on the terminal unsaturated moieties. In all but one case these substituents ended up in a cis-relationship with respect to each other as shown in structures 238, due to the disrotatory ring closure, however, in the case of 237b the trans-conﬁgured product 239b was isolated. This stereochemistry may result from a facile epimerization of the kinetically favored cis-isomer 238b to the thermodynamically more stable trans-isomer due to the relatively high acidity of the proton adjacent to the ester moiety. It should be noted that in the case of substrate 237d the acetoxy group exerts the same effect as described above (cf. Scheme 15), directing the ﬁnal β-dehydropalladation towards formation of the 1,3,5-hexatriene of type 235 instead of a potential 1,3,6-hexatriene. The complete chemoselectivity of these transformations has led to the presumption that the initial hydridopalladation which can occur on either the terminal or the internal triple bond of the enediynes is reversible. Thus, only the former hydridopalladation eventually proceeds to a subsequent second cycloisomerization. This even holds true for compound 240a lacking geminal substitution in the tether linking the alkyne moieties. Elongation of this tether by one carbon, however, led

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to a mixture of products 241b and 242b, since both the geminal substitution and the tether length now favor cycloisomerization of the enyne moiety towards 242. Nevertheless, [6.6.5]-tricycles can selectively be formed, for example, when removing the geminal substitution from the enyne tether as in enediyne 240c. Following the course of such a transformation by NMR spectroscopy proved the proposed mechanism involving formation of 1,3,5-hexatrienes of type 235 with subsequent 6π-electrocyclizations, since the signals of such an intermediate were observed during the transformation of 240c. A different cyclization mode must therefore emerge in transformations of substrates 243 leading to tricycles 244 with an anomalous position of the double bonds (Scheme 40). Moreover, the intermediacy of a 1,3,5-hexatriene can be excluded in the case of precursor 243c due to the methyl group preventing the required ﬁnal β-dehydropalladation. These transformations most likely occur by intramolecular Diels–Alder reactions of the monocycles 245 furnishing the π-allylpalladium intermediates 246. The preference for tricycles 244 then derives from the preference for deprotonation at the most C,H-acidic position, i.e. adjacent to the ester group.

Scheme 40 A different cyclization mode in cascade reactions of enediynes [126]

5 Conclusion The Heck reaction, which initially appeared to be just an interesting new C – C-bond forming process to access alkenylarenes and conjugated dienes, has emerged as an extremely versatile tool for the synthesis of complex organic molecules. Heck reactions, especially when performed in a multifold manner and/or combined with pericyclic reactions in sequential or dominotype processes can lead to an impressive increase in molecular complexity in a single or just a few operations. Thus, starting from readily available

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acyclic precursors, oligocycles can efﬁciently be obtained, frequently with high chemo-, regio-, and diastereoselectivity. According to the examples presented here, the reaction mode for a given substrate can be predicted in most cases. Yet, there is ample room for more unexpected routes to other oligocyclic skeletons. This fact ensures that research on these types of transformations is far from being complete, and therefore the future will undoubtedly bring a continuing growth, and advancement of this chemistry. This will trigger an ever increasing use of the Heck reaction in natural product synthesis as well as in industrial processes. Acknowledgements The work of our group in Göttingen presented here, including the fruitful collaboration with Philip J. Parsons (now at the University of Sussex, Brighton, UK) has been supported by the Deutsche Forschungsgemeinschaft, the ARC Program administered jointly by the German Academic Exchange Service and the British Council, the Volkswagen-Foundation, the Alexander-von-Humboldt-Stiftung, the Fonds der Chemischen Industrie, the Studienstiftung des Deutschen Volkes, the European Community as well as Bayer, BASF, Degussa, Aventis, Hüls AG and Chemetall GmbH (chemicals). The authors are grateful to Dr. Burkhard Knieriem for his careful reading of the manuscript.

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23. Lyapkalo IM, Högermeier J, Reissig HU (2004) Tetrahedron 60:7721 24. Lyapkalo IM, Webel M, Reissig HU (2002) Eur J Org Chem 3646 25. Voigt K, von Zezschwitz P, Rosauer K, Lansky A, Adams A, Reiser O, de Meijere A (1998) Eur J Org Chem, p 1521 26. Jeffery T (1985) Tetrahedron Lett 26:2667 27. Jeffery T (1996) Tetrahedron 52:10113 28. Jeges G, Skoda-Földes R, Kollár L, Horváth J, Tuba Z (1998) Tetrahedron 54:6767 29. Skoda-Földes R, Bodnár M, Kollár L, Horváth J, Tuba Z (1998) Steroids 63:93 30. Skoda-Földes R, Jeges G, Kollár L, Horváth J, Tuba Z (1996) Tetrahedron Lett 37:2085 31. Mitchell TN (2004) Organotin Reagents in Cross-Coupling Reactions. In: de Meijere A, Diederich F (eds) Metal-Catalyzed Cross-Coupling Reactions. Wiley, Weinheim, p 125 32. Sünnemann HW (2006) Dissertation, Universität Göttingen, Germany 33. For an assembly of the steroid skeleton from an acyclic precursor by a sequence of cyclizing carbopalladations see: Zhang Y, Wu G, Agnel G, Negishi E (1990) J Am Chem Soc 112:8590 34. Flessner T, Ludwig V, Siebeneicher H, Winterfeldt E (2002) Synthesis, p 1373 35. Hayashi M, Tsukada K, Kawabata H, Lamberth C (1999) Tetrahedron 55:12287 36. Preparation of 37: de Meijere A, Kozhushkov SI, Späth T (2000) Org Synth 78:142 37. Bräse S, de Meijere A (1995) Angew Chem 107:2741 38. Bräse S, de Meijere A (1995) Angew Chem Int Ed Engl 34:2545 39. de Meijere A, Nüske H, Es-Sayed M, Labahn T, Schroen M, Bräse S (1999) Angew Chem 111:3881 40. de Meijere A, Nüske H, Es-Sayed M, Labahn T, Schroen M, Bräse S (1999) Angew Chem Int Ed 38:3669 41. Nüske H, Bräse S, Kozhushkov SI, Noltemeyer M, Es-Sayed M, de Meijere A (2002) Chem Eur J 8:2350 42. Tsuge O, Wada E, Kanemasa S (1983) Chem Lett, p 239 43. Tsuge O, Wada E, Kanemasa S (1983) Chem Lett, p 1525 44. Bräse S, Schroen M (1999) Angew Chem 111:1139 45. Bräse S, Schroen M (1999) Angew Chem Int Ed 38:1071 46. Bräse S, Dahmen S (2000) Chem Eur J 6:1899 47. Nüske H, Noltemeyer M, de Meijere A (2001) Angew Chem 113:3509 48. Nüske H, Noltemeyer M, de Meijere A (2001) Angew Chem Int Ed 40:3411 49. Yücel B, Arve L, de Meijere A (2005) Tetrahedron 61:11355 50. Grigg R, Brown S, Sridharan V, Uttley MD (1998) Tetrahedron Lett 39:3247 51. Brown S, Grigg R, Hinsley J, Korn S, Sridharan V, Uttley MD (2001) Tetrahedron 57:10347 52. Grigg R, Savic V, Sridharan V, Terrier C (2002) Tetrahedron 58:8613 53. Knoke M, de Meijere A (2005) Eur J Org Chem, p 2259 54. Knoke M, de Meijere A (2003) Synlett, p 195 55. Grigg R, Stevenson P, Worakun T (1988) Tetrahedron 44:2033 56. Owczarczyk Z, Lamaty F, Vawter EJ, Negishi E (1992) J Am Chem Soc 114:10091 57. Meyer FE, Ang KH, Steinig AG, de Meijere A (1994) Synlett, p 191 58. Ang KH, Bräse S, Steinig AG, Meyer FE, Llebaria A, Voigt K, de Meijere A (1996) Tetrahedron 52:11503 59. Bhat L, Steinig AG, Appelbe R, de Meijere A (2001) Eur J Org Chem, p 1673 60. Körbe S, de Meijere A, Labahn T (2002) Helv Chim Acta 85:3161 61. Kaneti J, Kirby AJ, Koedjikov AH, Pojarlieff IG (2004) Org Biomol Chem, p 1098 62. Burns B, Grigg R, Sridharan V, Worakun T (1988) Tetrahedron Lett 29:4325

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P. von Zezschwitz · A. de Meijere Grigg R, Stevenson P, Worakun T (1985) Chem Commun, p 971 Grigg R, Stevenson P, Worakun T (1988) Tetrahedron 44:2049 Moreno-Manas M, Pleixats R, Roglans A (1995) Liebigs Ann Chem, p 1807 Trost BM (1990) Acc Chem Res 23:34 Trost BM, Tanoury GJ, Lautens M, Chan C, MacPherson DT (1994) J Am Chem Soc 116:4255 Trost BM, Romero DL, Rise F (1994) J Am Chem Soc 116:4268 Trost BM, Lee DC (1989) J Org Chem 54:2271 Sünnemann HW (2006) Dissertation, Universität Göttingen, Germany Trost BM, Hipskind PA, Chung JYL, Chan C (1989) Angew Chem 101:1559 Trost BM, Hipskind PA, Chung JYL, Chan C (1989) Angew Chem Int Ed Engl 28:1502 Trost BM, Hipskind PA (1992) Tetrahedron Lett 33:4541 van Boxtel LJ, Körbe S, Noltemeyer M, de Meijere A (2001) Eur J Org Chem, p 2283 Trost BM, Lee DC (1988) J Am Chem Soc 110:7255 Trost BM, Fleitz FJ, Watkins WJ (1996) J Am Chem Soc 118:5146 Negishi E, Ay M, Sugihara T (1993) Tetrahedron 49:5471 Henniges H, Meyer FE, Schick U, Funke F, Parsons PJ, de Meijere A (1996) Tetrahedron 52:11545 Padwa A (1984) 1,3-Dipolar Cycloaddition Chemistry. Wiley, New York Grigg R, Liu A, Shaw D, Suganthan S, Woodall DE, Yoganathan G (2000) Tetrahedron Lett 41:7125 Grigg R, Liu A, Shaw D, Suganthan S, Washington ML, Woodall DE, Yoganathan G (2000) Tetrahedron Lett 41:7129 Aftab T, Grigg R, Ladlow M, Sridharan V, Thornton-Pett M (2002) Chem Commun, p 1754 Grigg R, Millington EL, Thornton-Pett M (2002) Tetrahedron Lett 43:2605 Gardiner M, Grigg R, Sridharan V, Vicker N (1998) Tetrahedron Lett 39:435 Gardiner M, Grigg R, Kordes M, Sridharan V, Vicker N (2001) Tetrahedron 57:7729 Ma S, Negishi E (1994) J Org Chem 59:4730 Ma S, Negishi E (1995) J Am Chem Soc 117:6345 Tessier PE, Nguyen N, Clay MD, Fallis AG (2005) Org Lett 7:767 Gilchrist TL, Summersell RJ (1987) Tetrahedron Lett 28:1469 Gilchrist TL, Summersell RJ (1988) Perkin Trans 1, p 2595 Gilchrist TL, Summersell RJ (1988) Perkin Trans 1, p 2603 Negishi E, Zeng X, Tan Z, Qian M, Hu Q, Huang Z (2004) Palladium- or NickelCatalyzed Cross-Coupling with Organometals Containing Zinc, Aluminum, and Zirconium: The Negishi Coupling. In: de Meijere A, Diederich F (eds) Metal-Catalyzed Cross-Coupling Reactions. Wiley, Weinheim, p 815 Gilchrist TL, Healy MAM (1993) Tetrahedron 49:2543 Rho KY, Kim JH, Kim SH, Yoon CM (1998) Heterocycles 48:2521 Reiser O, Reichow S, de Meijere A (1987) Angew Chem 99:1285, Angew Chem Int Ed Engl 26:1277 Reiser O, König B, Meerholz K, Heinze J, Wellauer T, Gerson F, Frim R, Rabinovitz M, de Meijere A (1993) J Am Chem Soc 115:3511 Lansky A, Reiser O, de Meijere A (1990) Synlett, p 405 Voigt K, von Zezschwitz P, Rosauer K, Lansky A, Adams A, Reiser O, de Meijere A (1998) Eur J Org Chem, p 1521 von Essen R, von Zezschwitz P, Vidovic D, de Meijere A (2004) Chem Eur J 10:4341 Voigt K, Lansky A, Noltemeyer M, de Meijere A (1996) Liebigs Ann Chem, p 899

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100. von Zezschwitz P, Voigt K, Lansky A, Noltemeyer M, de Meijere A (1999) J Org Chem 64:3806 101. von Zezschwitz P, Voigt K, Noltemeyer M, de Meijere A (2000) Synthesis, p 1327 102. von Zezschwitz P, Petry F, de Meijere A (2001) Chem Eur J 7:4035 103. Sünnemann HW, de Meijere A (2004) Angew Chem 116:913 104. Sünnemann HW, de Meijere A (2004) Angew Chem Int Ed 43:895 105. Trost BM, Pfrengle W, Urabe H, Dumas J (1992) J Am Chem Soc 114:1923 106. Trost BM, Shi Y (1993) J Am Chem Soc 115:12491 107. Trost BM, Dumas J (1993) Tetrahedron Lett 34:19 108. Parsons PJ, Steﬁnovic M, Willis P, Meyer FE (1992) Synlett, p 864 109. Negishi E, Harring LS, Owczarczyk Z, Mohamud MM, Ay M (1992) Tetrahedron Lett 33:3253 110. Henniges H, Meyer FE, Schick U, Funke F, Parsons PJ, de Meijere A (1996) Tetrahedron 52:11545 111. Schelper M, de Meijere A (2005) Eur J Org Chem, p 582 112. Salem B, Klotz P, Suffert J (2004) Synthesis, p 298 113. Salem B, Klotz P, Suffert J (2003) Org Lett 5:845 114. Wang F, Tong X, Cheng J, Zhang Z (2004) Chem Eur J 10:5338 115. Lomberget T, Bouyssi D, Balme G (2005) Synthesis, p 311 116. Meyer FE, Parsons PJ, de Meijere A (1991) J Org Chem 56:6487 117. Henniges H, Meyer FE, Schick U, Funke F, Parsons PJ, de Meijere A (1996) Tetrahedron 52:11545 118. Zang Y, Negishi E (1989) J Am Chem Soc 111:3454 119. Oh CH, Kang JH, Rhim CY, Kim JH (1998) Chem Lett, p 375 120. de Meijere A, von Zezschwitz P, Bräse S (2005) Acc Chem Res 38:413 121. Meyer FE, Brandenburg J, Parsons PJ, de Meijere A (1992) Chem Commun, p 390 122. Verhoeven LJ (2000) Dissertation, Universität Göttingen, Germany 123. Meyer FE, Henniges H, de Meijere A (1992) Tetrahedron Lett 33:8039 124. Schweizer S, Song ZZ, Meyer FE, Parsons PJ, de Meijere A (1999) Angew Chem 111:1550 125. Schweizer S, Song ZZ, Meyer FE, Parsons PJ, de Meijere A (1999) Angew Chem Int Ed 38:1452 126. Trost BM, Shi Y (1993) J Am Chem Soc 115:12491 127. Trost BM, Shi Y (1992) J Am Chem Soc 114:791

Top Organomet Chem (2006) 19: 91–113 DOI 10.1007/3418_014 © Springer-Verlag Berlin Heidelberg 2006 Published online: 7 April 2006

Palladium Catalyzed Cascade Reactions Involving π-Allyl Palladium Chemistry Nitin T. Patil · Yoshinori Yamamoto (u) Department of Chemistry, Graduate School of Science, Tohoku University, 980-8578 Sendai, Japan [email protected] 1

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Reactions Involving π-Allyl Palladium Complex Bis-functionalization of Activated Oleﬁns . . . . Cycloaddition Reactions . . . . . . . . . . . . . Synthesis of Heterocycles . . . . . . . . . . . . . Miscellaneous Reactions . . . . . . . . . . . . .

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Abstract Palladium-catalyzed cascade reactions have gained steadily increasing importance over the last decade. The important factor in these reactions is the catalytic generation of π-allyl palladium intermediates which further undergo a variety of reactions. π-Allyl palladium complexes can be easily formed by the treatment of allylic substrates with Pd(0). A π-allyl palladium complexes on treatment with allylic metal species produce bis π-allyl palladium complex. In this review, the palladium catalyzed cascade reactions involving π-allyl palladium chemistry is described. The ﬁrst part deals with catalytic reactions involving π-allyl palladium complexes as an intermediate, while the second part features catalytic reactions involving bis π-allyl palladium complex as an intermediate. Keywords Cascade reaction · Palladium · π-Allyl palladium complex · Bis π-allyl palladium complex · Synthetic strategies · Heterocycles

Abbreviations Ac acetyl Ar aryl dba dibenzylideneacetone dppf 1,1 -bis(diphenylphosphino)ferrocene dppp 1,3-bis(diphenylphosphino)propane dppe 1,2-bis(diphenylphosphino)ethane

92 ee TBAB THF TMS Ts rt

N.T. Patil · Y. Yamamoto enantiomer excess tetrabutylammonium bromide tetrahydrofuran trimethylsilyl tosyl room temperature

1 Introduction Transition metal-catalyzed reactions have gained a steadily increasing importance in the last decade. One method for increasing the efﬁciency of such reactions is to carry out multiple transformations in a one-pot without isolating any of the intermediates. Such reactions are known as cascade or tandem or domino reactions. If the reaction system contains more than one substrate it may called as multi-component reaction. The cascade process involves sequential reactions with several steps of two or more different reaction types. Such processes in which a single event triggers the conversion of starting material to a product that becomes the substrate for another reaction, resulting in a cascade of transformations, are highly desirable. These processes are desirable not only for their elegance, but also for their efﬁciency in increasing complexity and selectivity in product formation. In some cases these processes offer a wide range of possibilities for the efﬁcient construction of highly complex molecules in a single procedural step, frequently with enhanced regio-, diastereo-, and even enantioselectivity for the overall transformation. This is the reason why cascade reactions are becoming more popular nowadays [1–8]. Among all transition metals, palladium is considered to be the most versatile element in organic synthesis. One of the most useful applications of palladium in organic chemistry is a consequence of the fact that an η3 or π-allyl palladium species is easily formed in several different ways from various organic substrates that contain at least one double bond (Scheme 1). The reaction requires an allylic leaving group in the form of an allylic ester or ether (including cyclic ethers like epoxides and higher oxacyclic systems) as well as an electron-deﬁcient cyclopropane ring. In addition the π-allyl palladium species can be easily substituted by a number of carbon and heteroatom nucleophiles (Tsuji–Trost type reaction) [9–11] (Scheme 2, Structure 1). Recent study showed that π-allyl palladium species can also be generated from enynes [12, 13], and propargylic substrates [14–22]. Therefore π-allyl palladium chemistry has been recognized as a powerful tool in organic synthesis as can be judged by a number of publications appeared in the literature from various research groups [23–26].

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Scheme 1

It is very well known that π-allyl palladium complex 1, which is a key intermediate for the Tsuji–Trost type allylation, has an electrophilic character and reacts with nucleophiles to afford the corresponding allylation products. We discovered that bis π-allyl palladium complex 2 is nucleophilic and reacts with electophiles such as aldehydes [27] and imines [28–32] (Scheme 2, Structure 2). We have also shown that bis π-allyl palladium complex 2 can act as an amphiphilic catalytic allylating agent; it reacts with both nucleophilic and electrophilic carbons at once to produce double allylation products [33]. These complexes incorporate two allyl moieties that can bind with different hapticity to palladium (Scheme 3). The different complexes may interconvert by ligand coordination. The complexes 2a, 2b and 2c are called as η3 ,η3 bisallypalladium complex (also called bis-π-allylpalladium complex), η1 ,η3 bis(allyl)palladium complex, η1 ,η1 -bis(allyl)palladium complex, respectively. Bis π-allyl palladium complex 2 can easily be generated by reaction of monoallylpalladium complex 1 and allylmetal species 3 (Scheme 4) [33–36]. Because of the unique catalytic activities of the bis π-allyl palladium complex 2, a number of interesting cascade reactions appeared in the literature. The subject of the present chapter is to review some recent synthetic and mechanistic aspects of the interesting palladium catalyzed cascade reactions which in-

Scheme 2

Scheme 3

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Scheme 4

volves π-allyl palladium complex 1 and bis π-allyl palladium complex 2, as an intermediate.

2 Reactions Involving π-Allyl Palladium Complex 2.1 Bis-functionalization of Activated Olefins We recently reported a tandem procedure for the alkoxyallylation of activated oleﬁns with allylic carbonate in the presence of a palladium catalyst under neutral condition [37]. Ethylidenemalononitriles 4 underwent the facile alkoxyallylation with allylic carbonates 5 in the presence of catalytic amounts of Pd(PPh3 )4 (5 mol %) to give the corresponding alkoxyallylated products 6 in high yields. The procedure involves the Michael addition followed by Tsuji–Trost allylation cascade. Only aryl substituted and t-butyl substituted oleﬁns were proved good substrates for this reaction, however, in the case of n-pentyl substituted oleﬁn the desired product formation did not take place. A plausible mechanism for this reaction is shown in Scheme 5. Oxidative addition of allylic carbonates 5 to Pd(0) most probably gives the cationic π-allyl palladium complexes 7 and then the resulting alkoxide anion reacts with the oleﬁns 4 to give the π-allyl palladium complexes 8. Reductive elimination from 8 gives the products 6 along with the regeneration of palladium

Scheme 5

Palladium Catalyzed Cascade Reactions

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Scheme 6

Scheme 7

Scheme 8

(0). It should be noted that by external addition of other alcohols (R2 OH) to the reaction mixture, – OR2 group was introduced at β-position of 4 instead of OR1 group. Thus when 4a and 5a was treated with allyl alcohol 9 (10 equiv) under the standard conditions, the corresponding allyloxy-allylation product 6a was obtained in 84% yield (Scheme 6). A similar observation was reported by Hauske et al. [38]. The three component aminoallylation reaction of the activated oleﬁns 4 was also reported by us (Scheme 7) [39]. The palladium catalyzed reaction between phthalimid 10, oleﬁns 4 and allyl chloride 11 proceeded well in the presence of Cs2 CO3 to give the corresponding aminoallylation products 12 in high yields. Likewise, cyanoallylation of activated oleﬁns was also reported (Scheme 8) [40]. In both cases only aryl substituded and t-butyl substituded oleﬁns are proved good substrates. The mechanism of these reactions is presumably similar to that of hydroalkoxylation reaction (see Scheme 5). 2.2 Cycloaddition Reactions The palladium catalyzed cycloaddition of the activated oleﬁns 4 with the allylic carbonates having a hydroxy group at the terminus of the carbon chain 15 gave the corresponding cyclic ethers 16 (Scheme 9) [41]. This two component coupling process proceeds through [3 + 2] cycloaddition reaction. The method is suitable for synthesizing ﬁve and six membered cyclic ethers, however, lesser yields were noticed for the formation of seven membered cyclic ethers. Generally, the diastereoselectivities of the products were in the range of ca. 60–70/40–30. It should be noted that with the Trost ligand and Hayashi

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Scheme 9

ligand, good to high ee’s were achieved in the cycloaddition. The oxidative insertion of Pd(0) to the allylic carbonates 15 produces the π-allylpalladium complex 17, and then isopropyl alcohol would be removed through the in situ alkoxy exchange reaction to produce another π-allylpalladium complex 18. This alkoxy exchange process is very similar to that observed in the external three-component alkoxyallylation which was discussed in Scheme 6. The Michael addition of the oxygen nucleophile of 18 to 4 gives the C – O bond forming intermediate 19, which undergoes the intramolecular attack of the nucleophilic carbon to the π-allylpalladium complex resulting in the formation of the cyclic ethers 16. The palladium-catalyzed [3 + 2] cycloaddition of vinylic oxirane 20a [42] and aziridine 20b [39] with the activated oleﬁn 4a for the formation of ﬁve membered cyclic ether 21a and pyrrolidine derivative 21b has also been reported in our laboratories. The mechanistic issue is very much similar to that discussed in Scheme 9. Pd(0) catalyst added oxidatively to 20 to produce the π-allylpalladium complex 22. The Michael addition of a hetero nucleophile in 22 to the activated oleﬁn 4a gives 23 which undergoes intramolecular nucleophilic attack on the inner π-allylic carbon atom to give the cyclized products 21 and Pd(0) species is generated (Scheme 10). Similarly, the palladium-catalyzed [3 + 2] cycloaddition of vinylic oxirane 20a with the N-tosylimines 24 is also known (Scheme 11) [43]. Intermolecular cycloaddition of vinyl epoxides and aziridines with the heterocumulenes such as isocyanates, carbodiimides and isothiocyanates is also known [44, 45]. Alper et al. reported the regio- and enatioselective formation of the thiaolidine, oxathiolane, and dithiolane derivatives by the palladium-catalyzed cyclization reaction of 2-vinylthiirane with heterocumulenes [46]. Recently, we reported an entirely new and efﬁcient formal [3 + 2] cycloaddition based on the hydrocarbonation reaction of allenes. The palladiumcatalyzed reaction of the activated oleﬁns 4 with allenes 26, bearing an acti-

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Scheme 10

Scheme 11

vated methine at the carbon chain terminus, gave the cyclopentanes 27 with good to excellent yields (Scheme 12) [47]. Turning towards the mechanistic issue, the palladium(0) produced in situ would add oxidatively to an acidic C – H bond of 26 to give the hydridopalladium(II) intermediate 28. This complex 28 undergoes the carbopalladation reaction with 4 to lead to another hydridopalladium species 29. Intramolecular hydropalladation of 29 gives the π-allylpalladium complex 30. Reductive elimination of Pd(0) from 30 gives the carbocycles 27. We reported that the palladium catalyzed hetero [3 + 2] cycloaddition of the alkylidenecyclopropanes 31 with the aldehydes 32 gave the 3-methylenetetrahydrofurans 33 in good yields (Scheme 13) [48]. The reaction initiated by oxidative addition of palladium(0) to a distal bond of the alkylidene-

Scheme 12

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N.T. Patil · Y. Yamamoto

Scheme 13

cyclopropanes 31 which leads to the formation of the palladacyclobutane complexes 34. The allylpalladium addition reaction of 34 to 32 may proceed further to give the π-allylpalladium complexes 35. Reductive elimination of palladium(0) from 35 then gives the [3 + 2] cycloadducts 33. We also demonstrated that the palladium catalyzed reaction of the alkylidenecyclopropanes 31 with the imines 24 gave the 3-methylenepyrrolidines 36 in good to excellent yields (Scheme 14) [49]. An interesting extension of this chemistry has been achieved for the synthesis of 5-azaindolizine derivatives. The palladium-catalyzed formal [3 + 2] cycloaddition reaction of the alkylidenecyclopropanes 31 with the 1,2-diazine 37 gave the corresponding 5-azaindolizine derivatives 38 in good yields (Scheme 15) [50]. Since the palladacyclobutane intermediate 34 is a sort of σ allylmetal species, the α-allylation of allylpalladium reagent at the three position of pyridazine 37 would occur to form the π-allylpalladium complex 39. Reductive elimination gives 2-methylenetetrahydroindolizine species 40. Subsequent isomerization and dehydrogenation would give the 2-alkyl-5azaindolizines 38. We reported that the palladium-catalyzed three-component coupling reaction of the activated alkynes 41, allyl methyl carbonate 5b, and trimethylsilyl azide 42 gave the 2-allyl-1,2,3-triazoles 43. The reaction proceeds via the [3 + 2] cycloaddition of π-allylpalladium azide 44 to the alkynes 41, followed by the formation of (η3 -allyl)(η5 -triazoyl)-palladium 45 (Scheme 16) [51]. However, this method was limited only for activated alkynes. Synthesis of the triazoles 47 from the nonactivated terminal alkynes 46 was achieved by the three-

Scheme 14

Palladium Catalyzed Cascade Reactions

99

Scheme 15

Scheme 16

component coupling reaction with allyl methyl carbonate 5b and trimethylsilyl azide 42 using a Pd(0)–Cu(I) bimetallic catalyst (Scheme 17) [52, 53]. In the absence of Cu(I), the desired product was not afforded at all. The reaction proceeds through [3 + 2] cycloaddition between the copper acetylides 48, in which copper acts as an activating group of the alkynes 46, and the azide palladium complex 44 to form the (η3 -allyl)(η5 -triazoyl)palladium intermediate

Scheme 17

100

N.T. Patil · Y. Yamamoto

49. Subsequent reductive elimination of Pd(0) from 49 and protonolysis of the C – Cu bond give 47. Fully substituted triazoles were synthesized via the four-component coupling reaction of the unactivated silylacetylenes 50, two equivalents of allyl carbonates 5b, and trimethylsilyl azide 42 in the presence of a Pd(0)–Cu(I) bimetallic catalyst (Scheme 18) [54]. Various trisubstituted 1,2,3-triazoles were obtained in good yields. The reaction most probably proceeds through the formation of alkynylcopper species 52, which on cross-coupling reaction with the π-allylpalladium complex 53 gives the products 51. The selective synthesis of the 2-allyltetrazoles 55 by the three-component coupling reaction of the cyano compounds 54, allyl methyl carbonate 5b, and trimethylsilyl azide 42 was accomplished in the presence of Pd2 (dba)3 .CHCl3 and P(2-furyl)3 (Scheme 19) [55, 56]. Most probably, the formation of (η3 allyl)(η5 -tetrazoyl)-palladium complex 56 took place through [3 + 2] dipolar cycloaddition of π-allylpalladium azide 44 with the nitrile 54. The complex 56 thus formed would undergo reductive elimination to form the products 55.

Scheme 18

Scheme 19

Palladium Catalyzed Cascade Reactions

101

2.3 Synthesis of Heterocycles A one-pot procedure for the palladium-catalyzed allylation/cyclization of o-alkynyltriﬂuoroacetanilides 57a [57] and o-alkynylphenols 57b [58] was developed by Cacchi et al. (Scheme 20). This method provides a valuable tool for the synthesis of 2-substituted-3-allylindoles 58a and 2-substituted3-allylbenzofurans 58b. It was reported that reaction proceeded through the formation of X-allyl derivatives, which form π-allylpalladium species 59. A subsequent rearrangement of 59 would then lead to the π-allylpalladium species 60. Intramolecular nucleophilic attack of the hetero atom across the activated carbon-carbon triple bond in 60, followed by reductive elimination of Pd(0) gives the products 58. A similar reaction was reported by Balme et al. [59]. Recently, we reported the three-component synthesis of the N-cyanoindoles 62 (Scheme 21) [60]. The reaction takes place between 2-alkynylisocyanobenzenes 61, allyl methyl carbonate 5b and trimethylsilylazide 42 in the presence of catalytic [Pd2 (dba)3 ], with tris(2-furyl)phosphine as ligand, at 100 ◦ C in THF. Good yields were generally obtained independently of the substitution pattern on the aryl ring. As described in mechanism ﬁrstly Pd(0) reacts with allyl methyl carbonate 5b and TMSN3 42 to give π-allylpalladium azide 44; CO2 and TMSOMe would be generated at this stage. The insertion of the isocyanide 61 between the Pd – N3 bond in π-allylpalladium azide 44 then gives the π-allylpalladium intermediate 63. Elimination of N2 followed by the 1,2-migration of π-allylpalladium moiety from the carbon atom to the α-nitrogen atom in 63 gives the palladium-carbodiimide complex 64. It should be noted that the conversion from 63 to 64 is a π-allylpalladium mimic of the Curtius rearrangement. The palladium-carbodiimide complexes 64 could be in equilibrium with the palladium-cyanamide complexes 65. Finally,

Scheme 20

102

N.T. Patil · Y. Yamamoto

Scheme 21

the N-cyanoindoles 62 are formed via the insertion of the alkyne moiety into the Pd – N bond of this intermediate 65 followed by the reductive elimination of Pd(0). We reported a novel synthetic route to cyanamides via palladiumcatalyzed three component coupling of the isocyanides 61, allyl carbonates 5, and trimethylsilyl azide 42 [60, 61]. Lu and Xie have reported a three-component coupling for the synthesis of α-alkylidene-γ -lactams 69 (Scheme 22) [62]. Treatment of N-(2,4dienyl)alkynamide 66 with an aryl iodide 67 affords a σ -vinylpalladium intermediate 70 through regioselective insertion of the active ArPdX species into the triple bond. Subsequent intramolecular carbopalladation of the diene affords π-allylpalladium complex 71, which undergoes nucleophilic attack by amines 68 at the less hindered terminus to afford the product 69. Ma and co-workers [63] have developed a tandem procedure for the synthesis of pyrrolidine derivatives based on the three component coupling of

Scheme 22

Palladium Catalyzed Cascade Reactions

103

Scheme 23

δ-allenic malonate 26a, aryl halide 72 and N-tosylimines 24 (Scheme 23). The reaction takes place in boiling MeCN in the presence of 5 mol % Pd(PPh3 )4 and 10 mol % TBAB, with a variety of organic halides, including phenyl bromide, as well as phenyl triﬂate participating as coupling partners. Most probably, the reaction proceeds through the π-allylpalladium complexes 74 and 75. 2.4 Miscellaneous Reactions The reaction of furans 77 with alkylidenecyclopropanes 76 proceeded smoothly in the presence of palladium catalysts, producing the corresponding α-allylated products 78 in good to high yields (Scheme 24) [64]. Later we showed that not only furans but also another heteroaromatics such as, thiophenes, thiazoles, and pyrroles underwent allylation under this condition [65]. Plausible mechanisms for the hydrofurylation reaction are shown in Scheme 25. The oxidative addition of palladium (0) to the carbon–hydrogen bond of furan 77 would lead to the hydride palladium complex 79 (path A). Hydropalladation of a double bond of 76 followed by the distal bond cleavage of the cyclopropane ring would afford the π-allylpalladium intermediate 82. Reductive elimination of palladium(0) from 82 gives the products 78. Another possibility is that Pd(0) inserts to a distal bond of 76 forming palladacyclobutane 34. Since 34 is a sort of σ -allylpalladium species, the pallada-ene reaction with 77 may take place as shown in 81, giving the π-allylpalladium species 82.

Scheme 24

104

N.T. Patil · Y. Yamamoto

Scheme 25

A novel synthetic method for the cyclic carbonates 85 was reported by Ihara et al. (Scheme 26) [66–68]. The reaction of 4-methoxycarbonyloxy2-butyn-1-ol 83 with phenols 84 in the presence of Pd2 (dba)3 .CHCl3 and dppe gave 85 in good yields. Firstly, the generation of the allenylpalladium 86 would take place which is then attacked by ArOH 84 to produce the π-allylpalladium complex 87, which undergoes insertion of CO2 to give 85. Thus, recyclable use of CO2 molecule is possible in this reaction. The same author described palladium-catalyzed cascade ring rearrangement of four-membered ring systems containing various propargylic components. The reactions of the cyclobutanols 88, that have a propargylic carbonate moiety, with phenols 84 as nucleophiles produced phenoxy attached exoalkylidene cyclopentanones 89 in high yields [69, 70]. A plausible mechanism for the reaction is shown in Scheme 27. The palladium catalyst initially promotes decarboxylation of the substrate 88, leading to allenylpalladium species 90, which is regarded as a π-propargylpalladium intermediate 91. The complex 91 undergoes nucleophilic attack by a nucleophiles 84 to form the π-allylpalladium

Scheme 26

Palladium Catalyzed Cascade Reactions

105

Scheme 27

Scheme 28

intermediate 92. Finally, ring expansion reaction of 92 gives the substituted cyclopentanones exo-89, which further isomerises to endo-89 under the same reaction conditions. The stereoselective synthesis of α-disubstituded cyclopentanones by palladium-catalyzed rearrangement of allenylcyclobutanols with aryl halides was also reported by the same authors [71]. Tietze et al. reported the conceptually new domino process involving a combination of Tsuji–Trost and Heck reaction (Scheme 28) [72]. This reaction represents a powerful and ﬂexible tool for the synthesis of substituted tetrahydroanthracenes. This method allows efﬁcient access to tetrahydroanthracene derivatives 94 in up to 89% isolated yield in a one-pot process starting from the diketone 93.

3 Reactions Involving Bis π-Allyl Palladium Complex 3.1 Reactions of Activated C – C and C – N Bonds The palladium-catalyzed reaction of 1 : 1 mixture of allyl chloride 11 and allyl stannane 3a with alkylidene malonitriles e.g., 4a resulted into the doubleallylated product 95 (Scheme 29) [33]. The mechanism of this reaction is

106

N.T. Patil · Y. Yamamoto

Scheme 29

particularly interesting and involves the in situ generation of bis π-allyl palladium complex. The ﬁrst step of the reaction is the oxidative addition of palladium(0) catalyst to allyl chloride to give mono-allylpalladium chloride complex. This complex undergoes transmetallation with 3a providing bis π-allyl palladium intermediate 2, which reacts with the activated oleﬁn 4a to give the π-allyl palladium intermediate 96. Subsequent reductive-coupling from 96 gives the corresponding product 95 with the regeneration of palladium(0) species. Not only C – C activated unsaturated compounds but also activated C – N unsaturated compounds such as imines underwent the amphiphilic bis allylation reaction [73]. We also achieved the tandem bis allylation of p-toluenesulfonyl isocyanate 97 by three-component coupling reaction with allyl chlorides and allyl stannane to form the diene 98 (Scheme 30) [73]. Sjabo and coworkers also reported similar reaction [74]. The bis-allylation reaction can also be performed by using functionalized allyl chloride precursors together with hexamethylditin (instead of allyl stannanes) [75]. The reaction of the activated oleﬁns 4 with allyl acetoacetate 99 in the presence of catalytic amounts of Pd(PPh3 )4 (5 mol %) in THF at room temperature gave the corresponding β-acetonated α-allylated double addition products 100 regioselectively in good yields (Scheme 31) [76]. A proposed mechanism for this three-component coupling reaction involves the oxa-πallyl-π-allylpalladium intermediate 102. At the beginning, oxidative addition of Pd(0) to allyl acetoacetate 99 would afford the π-allylpalladium β-keto carboxylate 101, which would undergo decarboxylation to produce the oxaπ-allyl-π-allylpalladium intermediate 102 (a synthetic analogue of 2). The activated oleﬁns 4 react with this intermediate 102 to give the corresponding π-allylpalladium complexes 103. The reductive elimination of Pd(0) from 103 gives the desired double addition products 100.

Scheme 30

Palladium Catalyzed Cascade Reactions

107

Scheme 31

Scheme 32

We reported that the palladium-catalyzed reaction of arynes with bis-πallyl palladium complex afforded 1,2-diallylated derivatives of benzene in good yields (Scheme 32) [77]. The reaction of 104 with allyltributylstannane 3a and allyl chloride 11 in acetonitrile in the presence of 2.5 mol % Pd2 (dba)3 .CHCl3 /dppf catalyst at 40 ◦ C for 12 h afforded 1,2-diallyl benzene 105 in 76% yield. The generation of benzyne 106 takes place presumably ﬁrst from 104 under the conditions of the palladium catalysis, which reacts with the complex 2 in a manner similar to the diallylation of activated oleﬁns (refer Scheme 29). 3.2 Synthesis of Heterocycles A novel procedure for the tandem nucleophilic allylation–alkoxyallylation of alkynylaldehydes is also known [78]. The reaction of the alkynylaldehydes 108 with allyltributylstannane 3a and allyl chloride 11 proceeded in the presence of catalytic amounts of the allylpalladium chloride dimer at room temperature in THF to give the corresponding bisallylated 5-exo-dig cyclic ethers 109a along with 6-endo-dig cyclic ethers 109b. A mechanistic rationale which accounts for the tandem nucleophilic allylation–alkoxyallylation of alkynylaldehydes is shown in Scheme 33. The in situ generated bis-πallylpalladium complex reacts with 108 in a nucleophilic manner to give the π-allylpalladium intermediate 110. The anti-attack of the alkoxy anion to

108

N.T. Patil · Y. Yamamoto

Scheme 33

the alkyne through path a or path b as shown in 111 would then afford the 5-exo-dig products 109a or 6-endodig products 109b, respectively. The selectivity of 5-exo and 6-endo cyclization was dependent on the functional groups present on the alkyne. It was found that the alkynylaldehydes having an electron-withdrawing group at the R gave the 5-exo products exclusively or very predominantly, while those having an electron-donating group at the R afforded the 6-endo products in an increased yield or predominantly. Later we extended this approach for the synthesis of 1,2-dihydroisoquinolines 113 from o-alkynylarylimines 112 (Scheme 34) [79]. It should be noted that 5-exodig cyclized product was not obtained and that Cu(OAc)2 as an additive was necessary for the reaction to occure. We have reported on a tandem procedure for the synthesis of 3-allyl-N(alkoxycarbonyl)indoles 115 via the reaction of 2-(alkynyl)phenylisocyanates 114 and allyl carbonates 5 in the presence of Pd(PPh3 )4 (1 mol %) and CuCl (4 mol %) bimetallic catalyst [80]. A proposed mechanism is shown in Scheme 35. Initially, the insertion of the isocyanates 114 into the complex 7, formed by the reaction of 5 with Pd(0), would form the π-allylpalladium intermediates 117. This intermediate, with Pd – N bonding, could be in equilibrium with the Pd – O bonded intermediates 118, which should more probably be represented as the bis-π-allylpalladium analogue 119. Insertion of the alkyne then occurs to form the indoles 115 and the Pd(0) species is regenerated. It should be emphasized that no carboamination takes place at all in the absence of CuCl; the product 116 was obtained.

Scheme 34

Palladium Catalyzed Cascade Reactions

109

Scheme 35

Scheme 36

The reaction of the allylic halides 120 having an aldehyde 120a or an imine 120b moiety in the molecule with allyltributylstannane 3a proceeded smoothly in the presence of Pd2 (dba)3 .CHCl3 (5 mol %) giving the corresponding heterocycles 121a and 121b, respectively [81] (Scheme 36). Turning to the mechanistic point, oxidative addition of palladium(0) to 120 would give the π-allylpalladium chloride complex 122 and then transmetalation of 122 with allyltributylstannane 3a gives the bis-π-allylpalladium complex 123. A hetero atom in the complex 123 coordinates to the palladium in an intramolecular manner to form the π-allyl-σ -allylpalladium 124 wherein the σ -allyl group on the palladium is transferred to give 125. The anti-attack of the alkoxy anion to the π-allyl group on the palladium 125 affords 119 and palladium(0) is regenerated. 3.3 Miscellaneous Reactions A novel method for the palladium-catalyzed tandem allylative dearomatization is also reported by us [82]. The reaction of benzylic chlorides 126 with

110

N.T. Patil · Y. Yamamoto

Scheme 37

Scheme 38

allyltributylstannane 3a in the presence of Pd2 (dba)3 .CHCl3 (5 mol %) and PPh3 (40 mol %) in acetone at room temperature gives the corresponding allylative dearomatization products 127 in high yields (Scheme 37). The mechanism of the reaction is particularly interesting. Benzyl chloride 126 reacts with Pd(0) to produce the π-allylpalladium intermediate 128. Allyltributylstannane reacts with 128 to produce a bis-π-allylpalladium intermediate 129 upon ligand exchange. The dearomatization product is obtained through reductive elimination of Pd(0) from the intermediate 130. The palladium-catalyzed reaction of allyl chloride 11 with the benzyne precursor 104 to produces phenanthrene derivatives 131 is also known [83]. A plausible mechanism for this intermolecular benzyne–benzyne–alkene insertion reaction is shown in Scheme 38. Initially π-allyl palladium chloride 1a is formed from Pd(0) and 11. Benzyne 106, which is generated from the reaction of CsF and 104, inserted into 1a to afford the aryl palladium intermediate 132. A second benzyne insertion into 132 produce 133 and subsequent carbopalladation to the alkene afford the cyclized intermediate 134. β-Hydride elimination from 134 followed by isomerization gave 9methylphenanthrene 131.

Palladium Catalyzed Cascade Reactions

111

4 Perspective Palladium-catalyzed cascade reactions involving π-allyl palladium chemistry provide a powerful tool to organic synthetic chemists. The discovery that the π-allyl palladium complexes 1 and 2 possess ability to interact with both nucleophilic and electrophilic organic moieties in an inter- and intramolecular manner through cascading processes is certainly a breakthrough in organometallic and organic chemistry. These new methodologies offer straightforward routes to a wide range of polyfunctionalized heterocyclic compounds that may not be easily obtainable by other means. The most important factor in these reactions is that they proceed under mild and neutral conditions. As demonstrated in this review, important contributions to this area may be achieved through applications of highly selective palladium catalysed processes to the assembly of properly designed easily available building blocks. It is expected that further combinations of fundamental Pd catalyzed carbon–carbon and carbon–heteroatom bond-forming processes will be investigated toward this goal in the near future. The authors believe that future development of the palladium catalyzed cascade reactions will certainly involve new regio-, stereo-, and enatioselective processes.

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Poli G, Giambastiani G, Heumann A (2000) Tetrahedron 56:5959 Heumann A, Reglier M (1996) Tetrahedron 52:9289 Meijere AD, Brase S (1999) J Organomet Chem 576:88 Tietze LF (1996) Chem Rev 96:115 Balme G, Bossharth E, Monteiro N (2003) Eur J Org Chem 4101 Ramon DJ, Yus M (2005) Angew Chem Int Ed 44:1602 Tejedor D, Gonzalez-Cruz D, Santos-Exposito A, Marrero-Tellado JJ, Armas PD, Garcia-Tellado F (2005) Chem Eur J 11:3502 Meijere AD, Zezschwitz PV, Brase S (2005) Acc Chem Res 38:413 Tsuji J (2000) Transition Metal Reagents and Catalysts, chap 4. Wiley, New York Trost BM, Van Vranken DL (1996) Chem Rev 96:395 Johannsen M, Jorgensen KA (1998) Chem Rev 98:1689 Gevorgyan V, Kadowaki C, Salter MM, Kadota I, Saito S, Yamamoto Y (1997) Tetrahedron Lett 53:9097 Radhakrishnan U, Al-Masum M, Yamamoto Y (1998) Tetrahedron Lett 39:1037 Minami I, Yuhara M, Watanabe H, Tsuji J (1987) J Organomet Chem 334:225 Tsuji J, Mandai T (1995) Angew Chem Int Ed Engl 34:2589 Kozawa Y, Mori M (2002) Tetrahedron Lett 43:1499 Yoshida M, Nemoto H, Ihara M (1999) Tetrahedron Lett 40:8583 Fournier-Nguefack C, Lhoste P, Sinou D (1996) Synlett 553 Kozawa Y, Mori M (2003) J Org Chem 68:8068 Labrosse J-R, Lhoste P, Sinou D (1999) Tetrahedron Lett 40:9025

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Damez C, Labrosse J-R, Lhoste P, Sinou D (2003) Tetrahedron Lett 44:557 Labrosse J-R, Lhoste P, Sinou D (2000) Org Lett 2:527 Szabo KJ (2004) Chem Eur J 10:5268 Trost BM, Crawley ML (2003) Chem Rev 103:2921 Trost BM (2004) J Org Chem 69:5813 Heumann A, Reglier M (1995) Tetrahedron 51:975 Nakamura H, Iwama H, Yamamoto Y (1996) J Am Chem Soc 118:6641 Bao M, Nakamura H, Yamamoto Y (2000) Tetrahedron Lett 41:131 Nakamura H, Nakamura K, Yamamoto Y (1998) J Am Chem Soc 120:4242 Nakamura K, Nakamura H, Yamamoto Y (1999) J Org Chem 64:2614 Fernandes RA, Yamamoto Y (2003) J Org Chem 69:735 Fernandes RA, Stimac A, Yamamoto Y (2003) J Am Chem Soc 125:14133 Nakamura H, Shim J-G, Yamamoto Y (1997) J Am Chem Soc 119:8113 Henc B, Jolly PW, Salz R, Wilke G, Benn R, Hoffman EG, Mynott R, Schroth G, Seevolgel K, Sekutowski JC, Kruger C (1980) J Organomet Chem 191:425 Goliaszewski A, Schwartz J (1984) J Am Chem Soc 106:5028 Goliaszewski A, Schwartz J (1985) Tetrahedron 41:5779 Nakamura H, Sekido M, Ito M, Yamamoto Y (1998) J Am Chem Soc 120:6838 Xie RL, Hauske JR (2000) Tetrahedron Lett 41:10167 Aoyagi K, Nakamura H, Yamamoto Y (2002) J Org Chem 67:5977 Nakamura H, Shibata H, Yamamoto Y (2000) Tetrahedron Lett 41:2911 Sekido M, Aoyagi K, Nakamura H, Kabuto C, Yamamoto Y (2001) J Org Chem 66:7142 Shim J-G, Yamamoto Y (1998) J Org Chem 63:3067 Shim J-G, Yamamoto Y (1999) Tetrahedron Lett 40:1053 El AB, Alper H (1999) In: Murahashi S-I, Davies SG (eds) Transition Metal Catalysed Reaction. Blackwell, Oxford, p 261 Courillon C, Thorimbert S, Malacria M (2000) In: Negishi E (ed) Handbook of Organopalladium Chemistry for Organic Synthesis. Wiley, New York, p 1795 Larksarp C, Sellier O, Alper H (2001) J Org Chem 66:3502 Meguro M, Yamamoto Y (1999) J Org Chem 64:694 Nakamura I, Oh BH, Saito S, Yamamoto Y (2001) Angew Chem Int Ed 40:1298 Oh BH, Nakamura I, Saito S, Yamamoto Y (2001) Tetrahedron Lett 42:6203 Siriwardana AI, Nakamura I, Yamamoto Y (2004) J Org Chem 69:3202 Kamijo S, Jin T, Huo Z, Yamamoto Y (2002) Tetrahedron Lett 43:9707 Kamijo S, Jin T, Huo Z, Yamamoto Y (2003) J Am Chem Soc 125:7786 Kamijo S, Jin T, Huo Z, Yamamoto Y (2004) J Org Chem 69:2386 Kamijo S, Jin T, Yamamoto Y (2004) Tetrahedron Lett 45:689 Kamijo S, Jin T, Yamamoto Y (2002) J Org Chem 67:7413 Gyoung YS, Shim JG, Yamamoto Y (2000) Tetrahedron Lett 41:4193 Cacchi S, Fabrizi G, Pace P (1998) J Org Chem 63:1001 Cacchi S, Fabrizi G, Moro L (1998) Synlett 7:741 Monteiro N, Balme G (1998) Synlett 746 Kamijo S, Yamamoto Y (2002) J Am Chem Soc 124:11940 Kamijo S, Jin T, Yamamoto Y (2001) J Am Chem Soc 123:9453 Xie X, Lu X (1999) Tetrahedron Lett 40:8415 Ma S, Jiao N (2002) Angew Chem Int Ed 41:4737 Nakamura I, Saito S, Yamamoto Y (2000) J Am Chem Soc 122:2661 Nakamura I, Siriwardana AI, Saito S, Yamamoto Y (2002) J Org Chem 67:3445 Yoshida M, Ihara M (2001) Angew Chem Int Ed 40:616 Yoshida M, Fujita M, Ihara M (2003) Org Lett 3:3325

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Top Organomet Chem (2006) 19: 115–148 DOI 10.1007/3418_007 © Springer-Verlag Berlin Heidelberg 2006 Published online: 7 April 2006

The Virtue of Michael-Type Addition Processes in the Design of Transition Metal-Promoted Cyclizative Cascade Reactions Geneviève Balme (u) · Didier Bouyssi · Nuno Monteiro Laboratoire de Chimie Organique, CNRS UMR 5181, Université Claude Bernard Lyon 1, 43 Bd du 11 novembre 1918, 69622 Villeurbanne Cedex, France [email protected] 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

116

2 2.1

Cycloaddition Reactions Based on Zwitterionic π-AllylPd Complexes . . . Pd-Catalyzed Ring Expansion Reactions of Vinylcyclopropanes and Related Heterocyclic Systems . . . . . . . . . . . . . . . . . . . . . . . Cycloaddition Reactions Involving Pd-TMM Equivalents as 1,3-Dipoles . .

117

2.2 3

117 122

Sequential Michael Addition/Metal-Promoted Nucleophile Addition to Unactivated C – C π-Bonds . . . . . . . . . . . . . . . . . . . . . . . . . Sequential Reactions Resulting in Monofunctionalization of the Carbon–Carbon Multiple Bonds . . . . . . . . . . . . . . . . . . . . Sequential Reactions Resulting in Difunctionalization of the Unsaturation .

126 131

Tandem Conjugate Addition/Metal-Catalyzed Intramolecular Coupling Reaction . . . . . . . . . . . . . . . . . . . . . . .

137

Metal-Catalyzed Tandem Conjugate Addition/Electrophilic Trapping Reactions . . . . . . . . . . . . . . . . . .

138

Reactions Involving a Coupling Reaction and Terminated by a Michael Addition . . . . . . . . . . . . . . . . . . . .

140

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

145

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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3.1 3.2 4

5

6

7

125

Abstract Cascade reactions involving a transition metal-promoted step and a Michaeltype addition process have emerged as a powerful tool to construct cyclic and polycyclic structures. In this review, recent advances in this ﬁeld are presented. The ﬁrst part is related to cycloaddition reactions based on zwitterionic π-allylPd complexes. The second part deals with Michael initiated metal-catalyzed cyclofunctionalization reactions of unactivated C – C π-bonds. Parts three and four feature reactions where an initial Michael addition reaction is followed by either a coupling reaction or an electrophilic trapping. Part ﬁve is devoted to Michael terminated reactions. Keywords Cyclization · Heterocycles · Michael addition · Tandem reactions · Transition metal catalysis

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Abbreviations BINAP 2,2 -bis(diphenylphosphino)-1,1 -binaphtyl COD cyclooctadiene dba dibenzylidene acetone DCM dichloromethane DME dimethoxyethane DMF dimethylformamide DMSO dimethylsulfoxide dppb 1,4-bis(diphenylphosphino)butane dppe 1,2-bis(diphenylphosphino)ethane dppp 1,3-bis(diphenylphosphino)propane EWG electron-withdrawing group L ligand MCP methylene cyclopropane MS 3˚ A molecular sieves 3 ˚ A Nu nucleophile THF tetrahydrofuran TMM trimethylene methane

1 Introduction The conjugate addition of carbo- and heteronucleophiles to electron-deﬁcient oleﬁns (Michael-type addition) is an extremely important reaction in organic chemistry which plays a pivotal role in a myriad of sequential bondforming processes. For instance, anionic 1,4-adducts generated in an initial intermolecular addition step may subsequently ring close when appropriate functionalities are present in either reactant. The term MIRC (Michael initiated ring closure) was introduced by Little in 1980 to deﬁne this valuable class of transformations [1, 2]. The applicability of these anionic reaction sequences to the rapid construction of elaborate cyclic systems in a single, atom economical operation is now well recognized and has been the subject of numerous accounts [3–7]. In recent years, some very imaginative transition metal-catalyzed cascade processes have also integrated Michael-type addition reactions as key steps in the catalytic pathways. The purpose of this review is to illustrate the importance of Michael-type addition reactions in the design of efﬁcient cyclization processes by means of transition metal catalysis. The review will not only focus on Michael initiated processes but will also discuss Michael terminated sequences where the metal is employed to build up a nucleophile-containing activated oleﬁn that will undergo intramolecular conjugate addition. Some recent and innovative reactions involving addition of metal complexes to electron-deﬁcient oleﬁns in Michael fashion will also be included herein.

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2 Cycloaddition Reactions Based on Zwitterionic π-AllylPd Complexes One of the most important classes of Michael initiated ring closure processes in the construction of carbo- and heterocycles are stepwise cycloaddition reactions where a metal induces dipolar behavior in otherwise unreactive organic compounds to be reacted with activated oleﬁns. In this area, Pd-assisted cycloaddition reactions which involve zwitterionic π-allylPd complexes of type I (linear type), II, or III (Pd-Trimethylenemethane (TMM) type and analogs) as reactive dipole partners are popular methods that provide highly functionalized, saturated ring systems often with high stereocontrol and atom economy (Scheme 1). Discovered in the early 1980s, they have been extensively covered in the review literature [8–16]. As will be highlighted in the following examples, the most interesting feature of this strategy lies in the possibility of generating the dipole component in situ under mild, neutral conditions by simple exposure of a properly designed allylic substrate to a suitable palladium catalyst (for an updated, general review of Pd-catalyzed cyclizations of allylic compounds, see [17]).

Scheme 1

2.1 Pd-Catalyzed Ring Expansion Reactions of Vinylcyclopropanes and Related Heterocyclic Systems Zwitterionic π-allylPd complexes of type I may be obtained either from acyclic precursors (1)—usually allylic carbonates having a pronucleophile

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Scheme 2

at the terminus of the carbon chain—or from vinylic cyclic compounds (2) which incorporate the pronucleophile (Scheme 2). In his pioneering work, Tsuji reported on cycloaddition reactions of carbonucleophilic π-allylPd dipole 3 with various α,β-unsaturated esters and ketones [18]. It was shown that the outcome of the reaction could differ depending on the mode of formation of the dipole, i.e., from allylic carbonate 1 or from vinyl cyclopropane 2. While Pd-catalyzed ring-opening of 2 in the presence of methyl acrylate provided selective formation of the desired cycloaddition product 5, reaction of 1 under identical conditions furnished acyclic diene 6 along with substantial amounts of cyclopropane 2 (Scheme 3). In the latter case, intermediate 4 most probably undergoes protonation through methine hydrogen abstraction from 1 and subsequently evolves through β-elimination of palladium hydride. Nevertheless, cycloaddition reactions involving carbonate precursor 1 remained possible with oleﬁns having two electron-withdrawing groups. Although such a limitation in cycloaddition reactions of allylic carbonates should only concern those bear-

Scheme 3

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ing carbon pronucleophiles, ring expansion reactions of vinylic cyclic compounds are still more appealing because they maximize atom economy. Since Tsuji’s report in 1985, Pd-catalyzed ring expansion reactions of vinyl cyclopropanes with activated oleﬁns have remained unexploited. We may, however, mention the reaction of chiral (β-sulﬁnyl)vinylcyclopropane (Ss)-7 with acrylonitrile which has been reported to provide optically active cyclopentane (3R, 4R, Ss)-8 (Scheme 4) [19]. More attention has been devoted to the development of Pd-catalyzed ring expansion reactions of heterocyclic systems such as vinyloxiranes [20, 21] and oxetanes (9a), vinylaziridines, azetidines, and pyrrolidines (9b), as well as vinylthiiranes (9c) to provide ﬁve- to seven-membered ring heterocycles (Scheme 5). However, virtually all this research has involved heterocumulenes (10) as dipolarophiles which include carbon dioxide, isocyanates, isothiocyanates, carbodiimide, ketenes, and keteneimines [22, 23] (for enantioselective versions, see [24]). Therefore, in most cases, ring closure proceeds via heteronucleophilic attack on the allyl-Pd complex. However, it was reported that reaction of keteneimine 12 with 2-vinylazetidine 13 affords the tetrahydropiperidine derivative 14 regio- and stereoselectively in the presence of catalytic Pd(OAc)2 /PPh3 , the cyclization step occurring at the carbon terminus of the heterocumulene [25]. Remarkably, regioselective ring closure at the nitrogen terminus had previously been observed in the reaction of 12 with 2-vinylthiirane 15 to furnish 1,3-thiazolidine 16 (Scheme 6) [26]. Aside from reactions involving heterocumulenes, processes involving simple activated oleﬁns as dipolarophile partners have been only scarcely investigated. The popular 2-vinyloxiranes [27] as well as N-tosyl-2-vinylaziridine 20 [28] have been shown to react with Michael acceptors having neces-

Scheme 4

Scheme 5

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Scheme 6

sarily two electron-withdrawing groups at the α-position to give the corresponding tetrahydrofurans 21 and pyrrolidines 22, respectively, in high yields but poor 1,3-diastereoselectivities. Acrylonitrile-derived oleﬁns 17 have been shown to be the most reactive but the reaction also accommodated those of the Meldrum type (18) as well as disulfonyl-substituted oleﬁn 19 (Scheme 7). Allylic carbonates 23 having a pendant hydroxy group have also been exploited to access analogous cyclic ethers of various sizes (24) [29]. Remarkably, as Scheme 8 illustrates, a trans preference was observed in tetrahydrofurans (24a) whereas a cis preference occurred in tetrahydropyrans (24c). The selectivities have been rationalized on the basis of favored transition states 25 and 26 which both minimize steric interactions (Scheme 9). Oxepane 24c was also synthesized from allylic carbonate 23c but required a higher reaction

Scheme 7

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Scheme 8

Scheme 9

temperature (100 ◦ C instead of 20 ◦ C for smaller rings) and was isolated in poor yield with low diastereoselectivity. It is worth mentioning that best degrees of diastereoselectivities (> 99% cis) were achieved in pyran derivatives obtained from Michael acceptors of the Meldrum type (18). Enantioselective cycloadditions of allylic carbonates 23a,b have also been examined with chiral phosphine ligands which led to reasonably high ee’s up

Scheme 10

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to 92%. For instance, diphenylsulfonyl-tetrahydrofuran 27 was obtained in 87% ee in the presence of Trost ligand 28 (Scheme 10). 2.2 Cycloaddition Reactions Involving Pd-TMM Equivalents as 1,3-Dipoles In the last two decades, [3 + 2]-cycloaddition reactions involving TMM-Pd zwitterionic intermediates as 1,3-dipoles have emerged as a powerful method for methylenecyclopentane construction. A great deal of work has been done in this area with regards to mechanistic and synthetic aspects, which have been discussed in depth in several reviews [8–10, 13–16]. Different methods to generate TMM-Pd species have been investigated (Scheme 11). Electronwithdrawing group-substituted allylic carbonates 29 were proposed by Tsuji in 1985 [30] as precursors of TMM-Pd complexes of type II according to a similar strategy as for the above-discussed linear dipoles (type I). Additionally, two methods have been considered to generate TMM-Pd intermediates of type III. Introduced by Trost in the early 1980s [8], the most popular of them exploits the propensity of silylmethylallyl acetate precursors (30) to undergo concomitant ionization of the allylic acetate and subsequent desilylation when exposed to a palladium catalyst. Although recent investigations on a TMM-Pd cycloaddition reaction involving such reactive zwitterionic dipoles clearly point to a concerted mechanism [31], a stepwise mode of cyclization remains generally admitted based on stereochemical evidence. It was observed that E-oleﬁns give the trans-isomer exclusively whereas Zoleﬁns give a mixture of trans- and cis-isomers. Pd-(or Ni)-induced cleavage of methylene cyclopropanes (MCP) (31) has also been suggested to form TMM metal complexes. However, on the basis of recent mechanistic studies it is now generally accepted that metal-catalyzed MCP-based [3 + 2] cycload-

Scheme 11

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ditions, as pioneered by Binger [32], do not involve zwitterionic intermediates of type Ic although the actual nature of the reaction mechanism is still much debated [33]. Reactions involving MCP derivatives as synthetic TMM equivalents are therefore not directly relevant to the topic of this review (for a general review of this topic see [34]). Amongst the aforementioned [3 + 2] cycloadditions, those involving 2-(sulfonylmethyl)allylcarbonates (29, EWG = SO2 Ar) as TMM-Pd precursors offer an interesting synthetic advantage in that they provide cyclopentane adducts retaining the allylic sulfone moiety which may be used for further chemical transformations [30, 35]. Surprisingly, the method has remained rather undeveloped while challenging, metal-free anionic variations of the process have emerged based on the reactivity of allylbromides 32 as TMM equivalents [36]. We may underline, however, the catalytic asymmetric 1,3-dipolar cycloaddition of ethyl 2-(phenylsulfonylmethyl)allylcarbonate (29a) with methyl vinyl ketone using the chiral Pd-ferrocenylphosphine catalyst 34, as reported by Ito and Hayashi [37]. The reaction yields transand cis-methylenecyclopentanes 33a,b in 75 and 78% ee’s, respectively (Scheme 12). On the other hand, Pd(0)-catalyzed reactions of silylmethylallyl acetates or carbonates have been extensively studied with regards to chemo-, regio-, and stereoselectivities. Many inter- and intramolecular variations of the process have been investigated which have paved the way for numerous applications in total synthesis [16]. An interesting feature of the process is the dynamic behavior of TMM-Pd complexes which has been demonstrated in studies involving diversely substituted TMM precursors. Indeed, regioisomeric complexes IIIa and IIIb, obtainable from acetates 30a and 30b, respectively, have been shown to equilibrate in favor of the thermodynamically more stable IIIb bearing the carbanion charge on the most substituted carbon atom. As equilibration occurs generally faster than trapping with the double bond, reactions give predominantly cyclopentanes 35b irrespective of the starting

Scheme 12

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Scheme 13

material 30a or 30b (Scheme 13) [38, 39]. Equilibration toward complexes IIIb is even more favored when R is an electron-withdrawing group capable of stabilizing the allyl carbanion as in TMM-Pd complexes of type II. This has been elegantly applied to cyclization reactions of carbonyl-substituted TMM-complexes. For instance, as illustrated in Scheme 14, equilibration of TMM-complexes 36a,b in favor of 36b allowed the intramolecular production of the tricyclic ring systems 37–38 [40, 41]. The regioselectivity in reactions of TMM-Pd complexes incorporated into a 5- or 6-membered ring has also been investigated recently [42]. Asymmetric cycloadditions of TMM-Pd complexes of type III have been achieved based essentially on the use of chiral oleﬁns, including vinylsulfoxides [43], γ -alkoxy-α,β-unsaturated sulfones [44], sugar-derived acrylates [45], lactones [46], and lactams [47]. For instance, chiral naphtoxy-

Scheme 14

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Scheme 15

butenolide 39 added to 2-(trimethylsilylmethyl)allylic acetate to yield 40 with complete control of diastereofacial selectivity (Scheme 15). The cycloadduct was then elaborated further toward (+)-Brefeldin A [46]. Besides the common oleﬁnic dipolarophiles, other unsaturated systems have been evaluated in cycloaddition reactions of zwitterionic TMM-Pd complexes, including polyenes and acetylenes. While acyclic electron-poor dienes generally gave mixtures of ﬁve- and seven-membered rings [48], a limited number of selective [3 + 4] and [3 + 6] cycloaddition reactions have been achieved with cyclic polyenic substrates as illustrated by formation of cycloadducts 41 and 42 from pyrone [49] and tropone [50], respectively (Scheme 16). On the other hand, activated alkynes have failed to produce the corresponding cyclopentene derivatives [51].

Scheme 16

3 Sequential Michael Addition/Metal-Promoted Nucleophile Addition to Unactivated C – C π-Bonds While the addition of stabilized carbanions to activated unsaturated systems (Michael addition) remains one of the most popular methods for the for-

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mation of carbon–carbon bonds [1–7], much less is known concerning the addition of stabilized carbon nucleophiles to less reactive unactivated alkenyl or alkynyl groups. In these latter approaches, the development of new transition metal-catalyzed cyclization processes has received special attention. Various combinations of these two powerful synthetic methods (including hetero-Michael addition) that allow the rapid preparation of a variety of carbo- and heterocycles have been recently reported. This section will discuss important achievements made in this area. 3.1 Sequential Reactions Resulting in Monofunctionalization of the Carbon–Carbon Multiple Bonds An interesting sequence based on an intermolecular Michael addition and a subsequent transition metal-catalyzed carbocyclization was recently explored. Much of the development of this strategy relies on recent studies related to the intramolecular carbometalation reaction of stabilized carbanions bearing an unactivated alkynyl group. Several transition metal complexes such as Cu [52], Pd [53], Ti [54], Zn [55], Co [56] and Sn [57] have been reported to catalyze this reaction (Scheme 17). In particular, the copper-promoted cycloisomerization of unsaturated alkynes bearing a stabilized nucleophile was found to be a general method that allows the cyclization of a variety of δ-acetylenic-stabilized carbanions by using catalytic amounts of base and copper [52]. This copper-catalyzed reaction was applied to disubstituted alkynes such as 43 and converted to the (Z)-isomer 44 as a single product (Scheme 18). This result further supports

Scheme 17

Scheme 18

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a mechanism in which the nucleophile and the copper species add in a trans fashion across the unsaturated bond. A combination of this intramolecular cupration with an initial intermolecular Michael addition provided the key step for several naturally occurring iridoid monoterpenes such as mitsugashiwalactone which has attractive physiological action on the Felidea, and rotundial, a natural mosquito repellent recently isolated from the leaves of Vitex rotundiforia [52]. This one-pot two-step procedure consisted of the reaction of a malonic enolate (prepared from dimethylmalonate and potassium tert-butoxide) to the unsaturated ester 45 leading to the intermediate enolate 46. In this strategy, the malonate unit serves as the nucleophile in both processes, ﬁrstly as Michael addition initiator and secondly as the nucleophile involved in the ring closure. The addition of catalytic amounts of copper iodide allowed the cyclization process to take place (Scheme 19). The conjugate addition of various propargyl alcohols [57] or propargyl amines [58] to gem-diactivated oleﬁns such as 47 can be used in tandem with the intramolecular carbocupration reaction (Scheme 20). This sequential

Scheme 19

Scheme 20

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hetero-Michael addition/carbocyclization process is initiated by only catalytic amounts of both base and catalyst and provides a new convenient access to structurally diverse tetrahydrofuran or pyrrolidine derivatives. The tandem oxa-Michael addition/carbocyclization reaction was further developed into a solution-phase combinatorial protocol for the generation of a representative library of highly substituted tetrahydrofurans. The reaction is promoted by catalytic amounts of copper iodide that is removed at the end of the reaction by simple ﬁltration affording the substituted tetrahydrofurans in high yield and purity [59]. A palladium-mediated carbocyclization may also be involved in this Michael initiated tandem reaction. This one-pot procedure was developed in our laboratory to efﬁciently prepare a number of highly functionalized 3-methylenetetrahydrofurans as potential precursors of tetrasubstituted tetrahydrofuran lignans, a class of natural products widely distributed in nature and exhibiting interesting biological activities [60]. In this case, the intermolecular conjugate addition of a propargyl alcohol to a Michael acceptor is followed by attack of the resulting enolate onto the triple bond activated by coordination to a palladium hydride species. The latter is formed in situ from insertion of the palladium into the C – H bond of a terminal acetylene [61]. An application of this methodology to the synthesis of several tetrahydrofuran lignan derivatives having trypanocidal activity was further reported by Kato and co-workers [62]. This sequential palladium-mediated Michael

Scheme 21

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addition–carbocyclization protocol has been chosen for this synthesis due to its efﬁciency, convergence and mild reaction conditions as well as for the ready availability of the starting materials. The methylenetetrahydrofuran derivative 50 was easily prepared in good yield from hindered substrates such as 48 and 49. Further manipulations allowed the preparation of several tetrasubstituted 2,5-dihydrofuran lignans and the highest activity was observed for compound 51 in which IC50 was 1.5 µM (Scheme 21). The palladium-mediated oxa-conjugate addition/carbocyclization reaction was also examined with arylidene or alkylidene β-ketosulfones such as 52 (Scheme 22). In this case, the ability of the arylsulfonyl group to act as a leaving group generates the carbenoid palladium complex 53 which is then attacked by the oxygen of the adjacent ketone. A subsequent 6πelectrocyclization process produces the furo[3,4-c]furan derivatives 54 and regenerates the catalyst [63]. This interesting cascade reaction permits the formation of two carbon–oxygen bonds, one carbon–carbon bond and two rings in a single process. A similar metal-catalyzed tandem conjugate addition/cyclization between propargyl alcohol and benzylidene malonate derivatives leading to 3-methylene tetrahydrofurans was further reported by Nakamura [64]. The reaction was carried out at room temperature, under solvent free conditions, using 20 mol % of the Zn(OTf)2 /Et3 N catalyst system, and in the presence of a large excess of propargyl alcohol (5 equiv). The catalytic coupling reaction is supposed to start with the conjugate addition of a zinc alkoxide to the Michael acceptor. This is followed by an intramolecular addition of the resulting zinc enolate of the active methine compound to the triple bond. Protonolysis of the resulting alkenylzinc intermediate 55 by the excess of alcohol furnishes the tetrahydrofuran product 56 and regenerates the zinc alkoxide (Scheme 23). It is worth mentioning that in this reaction, addition of the zinc enolate to the alkyne bond proceeded in a completely cis-selective man-

Scheme 22

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Scheme 23

ner that is in sharp contrast to the E-stereochemistry of the above-discussed copper or palladium-mediated carbocyclization reactions. The scope of the Cu-catalyzed cycloaddition between propargylamines and electron-deﬁcient oleﬁns in the presence of catalytic amounts of a copper salt was subsequently expanded to a one-pot, three-component coupling strategy involving phenols as third components [65]. In this case, reactive Michael acceptors such as ethyl 2-aryl- or alkylsulfonyl cinnamates 57 are involved in the process. This sequence leading to 3(4)-phenoxymethyl pyrrolidines 60 and their isomeric pyrrolidines 61 comprises of the relay process of

Scheme 24

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two metal-catalyzed reactions: (1) the Cu-catalyzed tandem aza-Michael addition/carbocyclization reaction giving access to heterocyclic allyl sulfones 58 and (2) the subsequent removal of the arylsulfonyl group by palladiumcatalyzed displacement with various phenolic derivatives 59 (Scheme 24). This Michael initiated sequence exploits the dual reactivity of the sulfone moiety which can be used as a stabilizing carbanion in the cyclization step and as a leaving group in the nucleophilic displacement. The scope of this methodology has been extended to nitrooleﬁns so as to permit the synthesis of highly substituted pyrrolines. 3.2 Sequential Reactions Resulting in Difunctionalization of the Unsaturation Another interesting tandem Michael initiated sequence was developed in our laboratory by combining the conjugate addition of unsaturated alkoxides to alkylidene malonates with a palladium-mediated coupling reaction with an organic halide. In this cyclization reaction, an organopalladium species acts as the electrophilic partner of the cyclization. This reaction results in the trans addition of the organopalladium species and of the nucleophile across the unsaturation, and therefore, in overall difunctionalization of the unsaturated substrates [66, 67]. Pioneering experiments were performed on allylic alcohols [68] (Scheme 25). It is noteworthy that although several strategies have been successfully employed for the intramolecular cyclization of stabilized carbanions bearing an unactivated alkynyl group, only a few examples have been reported on the similar carbocyclization onto a less reactive unactivated double bond [56, 69]. A limitation of this palladium-mediated three-component reaction was the necessity of using slow addition techniques to introduce the allylic alkoxide partner in order to avoid undesirable competitive reactions. The reaction

Scheme 25

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proceeded well in DMSO at 50 ◦ C in the presence of 5 mol % Pd/dppe and best results were obtained with potassium allylic alkoxides using KH as base. A large variety of aryl iodides can be used for the coupling reaction and gives access to highly functionalized tetrahydrofurans 62. This three-component reaction has, however, been found to have limited versatility since this reaction was restricted to simple allylic alcohol. This synthetic methodology was further extended to propynyl alcohols [70]. This Michael initiated sequence produced a new class of stereodeﬁned arylidene-(or alkenylidene)tetrahydrofurans 63 in high yields (Scheme 26). In this case, due to higher reactivity of these unsaturated alcohols, it was possible to introduce all components simultaneously at the start of the reaction with no side reaction occurring. The efﬁciency of this palladium-mediated three-component reaction has been shown to be strongly inﬂuenced by the nature of the catalyst and, in this regard, a palladium complex generated in situ by reduction of dichlorobis(triphenylphosphine)palladium(II) (PdCl2 (PPh3 )2 ) with n-butyllithium was found to be particularly effective. In marked contrast with what was observed with allylic alcohols, a wider range of propargyl alcohols (secondary, tertiary and disubstituted) can be involved in this multicomponent reaction and each of the three components can be varied. This palladium-mediated Michael addition/cyclization sequence also proceeded nicely with propargylamines [71] as nucleophilic partners. This method was effective for the preparation of a number of diversely functionalized (Z)-4-benzylidene (and alkenylidene) pyrrolidines that were obtained under conditions similar to those developed for their propynyl alcohols analogs, the sodium amides giving, however, better results than the corresponding lithium salts. This sequential aza-Michael conjugate addition/carbopalladation/reductive elimination sequence can be carried twice with 1,4-diodobenzene. This latter transformation effects the formation of four C – C bonds, two C – N bonds and two rings in a single operation giving the single diastereomer 64 in 54% yield (Scheme 27). This type of Michael initiated sequence was also successfully applied to allylic amines [72]. This mul-

Scheme 26

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Scheme 27

ticomponent reaction leading to functionalized 4-substituted pyrrolidines does not have the drawbacks mentioned earlier for their corresponding allylic alcohols (see Scheme 25) since a range of readily available propargyl amines, unsaturated halides or triﬂates, and activated oleﬁns can be reacted without using slow addition techniques. On the basis of this palladium-mediated Michael addition cyclization process, a novel two-step synthetic entry into functionalized furan derivatives 67 has also been devised (Scheme 28). Substitution of benzylidene (or alkylidene) malonates for their ethoxymethylene analog (65) as activating oleﬁns gave rise to the formation of the corresponding 2-ethoxy-4-arylidene tetrahydrofurans 66. An in situ addition of potassium tert-butoxide induced a decarboxylative elimination reaction which was followed by an isomerization of the exocyclic double bond. The entire process successively involved a conjugate addition, a palladium-catalyzed cyclization-coupling reaction, a base-induced eliminative decarboxylation, and ﬁnally, a double bond isomerization [73]. A formal synthesis of the lignan antitumor burseran (69) employing this process as a key step illustrated the potential utility of this concept for the preparation of some natural products of the 3,4-benzyltetrahydrofuran lignans family. The 4-benzylfuran-3-carboxylate 67a prepared in a single step from three readily available starting materials was transformed into the known 4-benzyltetrahydrofuran-3-carboxaldehyde 68 [74] by the following three steps: reduction of the ester into the corresponding alcohol, hydrogenation and oxidation. On the basis of this palladium-mediated three-component coupling reaction, Morimoto and co-workers developed a methodology for the synthesis of two novel modiﬁed furanoeremophilane-type sesquiterpenes isolated from Trichilia cuneata, the 13-hydroxy-14-nordehydrocacalohastine 72 and 13-acetoxy-14-nordehydrocacalohastine 73 [75]. These two natural products showed inhibitory activities for membrane lipid peroxidation in mitochon-

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Scheme 28

dria and microsomes. Palladium-mediated tandem 1,4-addition/cyclization/ coupling reaction between three readily available components, 2-iodotoluene, 1-penten-4-yn-3-ol and diethyl ethoxymethylenemalonate followed by a treatment of the resulted methylene tetrahydrofuran with potassium tert-butoxide gave the desired trisubstituted furan 70 which was utilized as a key intermediate for the construction of the naphtofuran 71. Further elaboration gave the two natural products, alcohol 72 and acetate 73 in good yields (Scheme 29). A convergent, high yielding and practical synthesis of dibenzylbutyrolactone lignans 76 exploiting this three-component coupling strategy was further developed in our laboratory [76]. This new access to these natural products is based on the one-pot Lewis acid Yb(OTf)3 -catalyzed ring-opening/cyclization reaction of the readily available 2-methoxy-4benzyltetrahydrofuran derivatives 74 leading to γ -butyrolactones 75 as a key step. These functionalized lactones were further transformed in the expected natural lignans 76 in a one-pot alkylation/decarbalkoxylation method. By

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Scheme 29

Scheme 30

simply changing the reaction conditions, it was possible, from the same substrates 74 to obtain selectively functionalized cyclopropanic compounds 77 (Scheme 30). A related one-pot three component coupling reaction leading to allylidene tetrahydrofuran derivatives 80 and which combines a conjugate addition of a propargyl alcohol with an activated oleﬁn and an in situ palladiumcatalyzed carbopalladation–cyclization in the presence of a large excess of allyl chloride has been recently developed by Lu and Liu (Scheme 31) [77]. The cyclization process is here initiated by addition of a catalytic amount of Pd(OAc)2 and in marked contrast with the above-discussed reactions, a catalytic cycle involving divalent palladium proceeds in the reaction. In this process, the ester enolate formed in the Michael addition undergoes

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Scheme 31

a nucleophilic attack onto the alkyne coordinated with Pd(II) salt. A subsequent insertion of allyl chloride into the carbone–palladium bond of the resulting vinylpalladium 78 gave intermediate 79. This is followed by a β-Cl elimination in the presence of an excess of lithium chloride to give the desired tetrahydrofuran and regenerate the Pd(II) catalyst. It is noteworthy that the halide ion plays an important role in this process in inhibiting the classical β-H elimination in 79. Apart from the different hetero-Michael initiated metal-mediated cyclization processes giving access to a variety of functionalized heterocycles, a conceptually related approach involving a tandem conjugate addition/carbocyclization/functionalization of a copper-zinc mixed organometallic has been recently developed by Normant and Chemla [78]. This new method allows the diastereoselective formation of substituted pyrrolidines in a three-component one-pot sequence. Thus, addition of 81 prepared from PhLi and a mixture of ZnBr2 and CuCN in diethyl ether with the readily available Michael acceptor 82, led to 3,4-disubstituted 3-methoxycarbonylpyrrolidines 84 with good to excellent stereochemical control depending on the nature of the substituent introduced during the conjugate addition reaction. The diastereoselectivity was totally controlled by using aryl or vinylic organometallic reagents whereas a moderate selectivity was observed with an alkyl organometallic reagent. The transition state model 83 shown in Scheme 32 was proposed to explain the predominant formation (or the exclusive formation) of one diastereoisomer. The diastereo-

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Scheme 32

selectivity of this reaction involving copper-zinc reagents was attributed to a chelation of a zinc species with the nitrogen and the sp2 oxygen atoms of the ester moiety. The pyrrolidinylmethylzinc reagents derived from the carbocyclization of zinc enolates were further functionalized with various electrophiles such as iodine or allyl bromide. In this last case, three carbon–carbon bonds, and one ring were formed in a single operation.

4 Tandem Conjugate Addition/Metal-Catalyzed Intramolecular Coupling Reaction An interesting method of ring formation involving a palladium-catalyzed displacement of halide from aromatic substrates by stabilized enolates has also been developed [79]. The ﬁrst procedure based on this strategy was developed by Ciufolini and co-workers in 1987 to access benzofused, ﬁve- or six-membered rings in moderate to good yields [80]. On the basis of these ﬁndings, a combination of this intramolecular crosscoupling with an initial intermolecular Michael addition was reported by Singer in order to afford cyanobenzofulvene acetal 85 which was an intermediate of the synthesis of a benzazepine [81]. Thus, Michael addition of 2-halophenylacetonitrile derivatives of 86 to ethoxy acrylate performed in the presence of a large excess of base leads to the corresponding conjugated allylic anion 87. The crucial issue in this process is the oxidative addition of the palladium to the electron-rich arene. This problem was solved

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Scheme 33

by a judicious choice of the phosphine ligand and best results were obtained with electron-rich dialkylphosphines such as triclohexylphosphine or tri-tert-butylphosphine. Finally, the palladium-catalyzed arylation α to ester function occurred efﬁciently leading to indene 88. To avoid isolation of the latter a further transformation was conducted in the presence of ethylene glycol, in acidic medium, to give the more stable crystalline cyanobenzofulvene 85 (Scheme 33).

5 Metal-Catalyzed Tandem Conjugate Addition/Electrophilic Trapping Reactions Several elegant methodologies involving addition of organometallic reagents to a conjugate acceptor followed by an intramolecular cyclization with a range of electrophilic partners were recently reported in the literature. Reactions involving organocopper reagents have been largely reviewed and will not be presented herein [5, 7]. In this area, Krische and co-workers have developed a family of catalytic transformations based on the use of enones as latent enolates. Nucleophilic activation of the enone is induced via carbometallation, nucleophilic organocatalysis or hydrometallation. The following examples illustrate some aspects of these new catalytic conjugate addition/electrophilic trapping reactions. Krische has reported an unprecedented rhodium-catalyzed tandem conjugate addition/aldol cyclization initiated by a ﬁrst addition of a boronic acid. The participation of boronic acids in this methodology greatly enhances its synthetic potential owing to their large availability [82]. This catalytic

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tandem conjugate addition/aldol cyclization reaction is restricted to methyl ketones as the electrophilic aldol partner. Indeed, in such intramolecular processes, the generation of the enolate must take place in the presence of the appendant electrophile partner. Therefore, this tandem reaction cannot be developed with substrates bearing a pendant aldehyde moiety. This is due to the tendency of arylboronic acids to react with aldehyde in the presence of Rh-catalyst before the cyclization takes place. Rhodium-catalyzed addition of boronic acids to enone moiety 89 led to a rhodium-enolate 90 which can be trapped by addition to the adjacent carbonyl function giving functionalized cyclopentanes or cyclohexanes 91. An important feature of this methodology is that this process allows the creation of three contiguous stereocenters with a high level of stereoselectivity. An asymmetric version of this reaction has also been realized with a chiral ligand (BINAP) giving excellent enantiomeric excesses (77 to 95%) (Scheme 34). On the basis of this concept the same group has developed a similar strategy using a copper-catalyzed addition of organozinc reagents to enones, followed by trapping of the resulting zinc-enolate by ketones, esters or nitriles as terminal electrophiles (Scheme 35) [83]. Furthermore, following an analogous methodology, combining the Morita– Baylis–Hillman reaction and the Trost–Tsuji reaction, Krische and co-workers have obtained allyl-substituted cyclopentenones 94 [84]. Reaction was initiated by Michael addition of tributyl phosphine to an enone moiety 92, generating a latent enolate 93 which reacts intramolecularly with a π-allylPd complex as the electrophile partner. A ﬁnal β-elimination step of tributylphosphine, favored by the presence of the methoxide ion, delivered the substituted cyclopentenones 94 (Scheme 36).

Scheme 34

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Scheme 35

Scheme 36

Apart from this work, Krische has also developed Co- and Rh-catalyzed 1,4-reduction-aldol cyclizations where a hydrido-metal species adds to an enone moiety before aldol cyclization [85, 86].

6 Reactions Involving a Coupling Reaction and Terminated by a Michael Addition Another type of metal-catalyzed cascade reaction using a Michael addition step was the use of this latter in the terminating step of the reaction in order to trap an initial intermediate created by a metal-catalyzed step. This particularly useful strategy was developed by several groups allowing the creation of polyfunctionalized structures.

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Scheme 37

Thus, a domino-Heck–Michael reaction has been reported by Yamada and co-workers [87]. This transformation allowed the formation of three contiguous cycles in one single operation. The mechanism involves ﬁrst a Heck alkenylation of the iodide 95 which after a β-hydride elimination step leads to intermediate 96 which undergoes attack of the α-nitro group carbanion to produce the tricyclic compound 97 (Scheme 37). An original transformation has also been developed by Furstner as a key step in the total synthesis of the antitumor agent TMC-69-6H 98, a saturated analog of a 2-pyridone derivative isolated from the culture broth of the fungus Chrysosporium sp, TC1068. This analog exhibits a remarkable efﬁcacy against P388 murine leukaemia and B16 melanoma in nude mice and even a better stability than that of the natural product [88, 89]. This reaction involves attack of the enol at the carbon atom site of 4-hydroxypyridone 99 onto the π-allylpalladium complex generated from 6-acetoxy-6H-pyran-3-one 100. A spontaneous Michael addition of the phenol follows the ﬁrst addition leading to pyridone derivative 101 with an excellent enantiomeric excess. This one-pot reaction demonstrated two novelties; (1) the ﬁrst C-arylation of 6acetoxy-6H-pyran-3-one 100 so far limited to oxygen nucleophiles and (2) the preferential reaction with allylic substrates at the enol site of 2-pyridone rather than at the N-position in the presence of a palladium catalyst. Total synthesis of compound 98 has been further completed in seven steps (Scheme 38) [90]. A three-component palladium-catalyzed cascade process has been employed by Grigg and co-workers for the one step preparation of 3-substituted isoindolin-1-ones 103 [91]. This cascade reaction involves Pd-catalyzed carbonylation of aryl iodide 102 and subsequent trapping of the acyl palladium species by an amino derivative. The resulting amide undergoes an intramolecular Michael addition leading to the bicyclic systems 103 isolated in moderate to good yields (Scheme 39). In a similar manner, Grigg and co-workers have demonstrated that a combination of 102, allene and a nucleophile (YH2 ) affords hetero- or carbocycles in the presence of palladium(0) [92]. Presumably, insertion of aryl iodide to allene gives a π-allyl intermediate 103, intercepted by a nucleophile (YH2 ), the latter being trapped by addition onto the Michael acceptor to furnish hetero- or carbocycles 105 (Scheme 40).

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Scheme 38

Scheme 39

An alternative pathway for the above reactions has also been proposed by the authors, involving ﬁrst a Michael addition of the nucleophile, followed by a subsequent interception of the palladium intermediate species. Nevertheless, the authors opinion is in favor of the ﬁrst mechanism as proved, in a control experiment, by no isolation of Michael adduct when benzylamine was used as the sole reagent and in the absence of carbon monoxide. In the case of allene, when malonitrile was used as the nucleophile (YH2 ) and the reaction stopped before completion, a mixture of intermediate 104 and ﬁnal product was isolated giving an evidence for the proposed mechanism. A domino palladium(II)-mediated rearrangement/oxidative cyclization of β-aminocyclopropanols has been reported by Brandi and co-workers lead-

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Scheme 40

ing to 2,3-dihydro-1H-pyridin-4-ones 107. The analogous tetrahydropyrid4-ones 109 could also be obtained selectively when the couple Pd(OAc)2 / Cu(OAc)2 was used [93] (Scheme 41). The ﬁrst step of this reaction is the known ring cleavage of the cyclopropanol 106 under Pd(II) catalysis [94]. Next, the authors suggest either a Wacker-type process for the Pd(II)-catalyzed reaction leading to 2,3-dihydro-1H-pyridin-4-ones 107 after a β-hydride elimination step, or

Scheme 41

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a process where the palladium salt acts as Lewis acid to favor nitrogen attack giving rise to an oxo-π-allyl-palladium(II) complex 108 which gives the enaminone 107 by HPdX elimination. The formation of saturated pyridones 109 can be explained by the presence of copper acetate which can easily catalyze the aza-Michael addition. Desmaele and co-workers have developed a sequence involving attack onto a π-allylPd complex followed by an intramolecular Michael addition leading to functionalized cyclohexane derivatives [95]. This useful transformation was used as a key step in the total synthesis of racemic dihydroerythramine 110, a biologically active compound of the Erythrina alkaloids family [96] (Scheme 42). The mechanism involves addition of an α-nitro group carbanion issued from 111 to a π-allylPd complex generated from allylic acetate 112. This latter intermediate can further undergo ring closure through intramolecular Michael addition delivering substituted cyclohexane 113 which has been transformed into dihydroerythramine in several steps. A following article has demonstrated the generality of this reaction using various active methylene compounds as nucleophilic partners [97] (Scheme 43). Concerning the mechanism of this sequential reaction, the

Scheme 42

Scheme 43

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Michael addition–alkylation pathway has to be considered because simple methylene active compounds such as dimethyl malonate or methylcyanoacetate were found to be good Michael donors with β-substituted unsaturated esters such as 5-phenyl-2-pentenoate in the reaction conditions. However, when the reaction was quenched before completion, a substantial amount of product resulting from attack onto the π-allylPd complex was isolated, bringing an evidence for the alkylation/Michael addition pathway. Apart from reactions where Michael addition terminated the process, Gabriele and co-workers have developed a useful and expedient palladiumcatalyzed synthesis of 4-aminofuran-2-one 113 starting from three simple starting components, a propargyl alcohol, a dialkyl amine and carbon monoxide [98] (Scheme 44). Propargyl alcohol was ﬁrst monoaminocarbonylated leading to 4-hydroxy2-ynamide 111. This ﬁrst stage is followed in situ by conjugate addition of dialkylamine to the triple bond of the ynamide to yield 112 which gives spontaneously an intramolecular lactonization to afford the furanone 113. Similarly, lactams have been prepared using propargyl amines [99].

Scheme 44

7 Conclusion Over the last twenty years, the tandem process involving transition metalpromoted cyclization reactions initiated or determined by a Michael addition has attracted an increasing interest in organic chemistry. The diversity of examples discussed in this work demonstrates the high potential of these tandem reactions for the efﬁcient one-pot synthesis of complex structures with limiting catalysts and remarkable atom economy. It is expected that the development of further useful new sequences founded on this concept will be developed in the near future.

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89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99.

Top Organomet Chem (2006) 19: 149–205 DOI 10.1007/3418_012 © Springer-Verlag Berlin Heidelberg 2006 Published online: 6 May 2006

Sequentially Palladium-Catalyzed Processes Thomas J. J. Müller Organisch-Chemisches Institut der Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany [email protected] 1

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Sequences Initiated by Heck Reaction . . . . . . . . . . . . . . . . . . . . . Irreversible Oleﬁn Insertion as Initial Step . . . . . . . . . . . . . . . . . . Intermediate Reversible Vinylation as Initial Step . . . . . . . . . . . . . .

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Sequences Initiated by Allylic Substitution . . . . . . . . . . . . . . . . . .

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Sequences Initiated by Amination . . . . . . . . . . . . . . . . . . . . . . .

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Sequences Initiated by Sonogashira Coupling . . . . . . . . . . . . . . . .

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Sequences Initiated by Metallation . . . . . . . . . . . . . . . . . . . . . .

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Sequences Initiated by CH Activation . . . . . . . . . . . . . . . . . . . . .

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Sequences Initiated by Cycloisomerization . . . . . . . . . . . . . . . . . .

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Sequences Initiated by Miscellaneous Processes . . . . . . . . . . . . . . .

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Abstract Sequentially palladium-catalyzed reactions consist of combinations of identical, related, or signiﬁcantly different palladium-catalyzed processes that occur in a sequential or consecutive fashion in the same reaction vessel without addition of further amounts of catalyst to the reaction media. This novel type of cascade reaction can be elaborated into both domino and multicomponent processes and represents a signiﬁcant contribution to the highly topical ﬁeld of diversity-oriented synthesis. Keywords Allylic substitution · CH activation · Cross-coupling · Cycloisomerization · Domino reactions · Metallation · Multicomponent reactions · Palladium catalysis Abbreviations Ac Acetyl AcO Acetyloxy Ar Aryl BINAP 2,2 -Bis(diphenyl)phosphano)-1,1 -binaphthyl

150 Boc Bn Bu cat Cbz dba DMA DMF DME dppe dppf dppm EWG Et Hal L Me NMP Nu Oct Ph Pr PTSA R TBAB TBAF THF THP TBDMS Tol Ts TMS

T.J.J. Müller tert-Butyloxycarbonyl Benzyl Butyl Catalyst Carbonyloxybenzyl Dibenzylideneacetone N,N-Dimethylacetamide N,N-Dimethylformamide 1,2-Dimethoxyethane 1,2-Bis(diphenylphosphanyl)ethane 1,1 -Bis(diphenylphosphano)ferrocene Bis(diphenylphosphanyl)methane Electron-withdrawing group Ethyl Halogen Ligand Methyl N-Methylpyrrolidone Nucleophile Octyl Phenyl Propyl p-Toluenesulfonic acid Organic substituent Tetra-n-butylammonium bromide Tetra-n-butylammonium ﬂuoride Tetrahydrofuran Tetrahydropyranyl tert-Butyldimethylsilyl Tolyl p-Tolylsulfonyl Trimethylsilyl

1 Introduction Nowadays, total synthesis of a complex natural product can hardly be imagined and realized without using the tremendously developed toolbox of organometallic transition metal complexes. The advent of transition metal catalysis in organic chemistry has fundamentally revolutionized synthetic strategies and conceptual thinking. In particular, transition metal-catalyzed reaction sequences that considerably enhance structural complexity by multiple iterations of organometallic elementary steps have become known as domino, tandem, or cascade reactions. For a recent review with a suggestion for a taxonomy of domino, tandem, and cascade metal catalyzed reactions see [1]. Although the synonymous use of the latter terms hampers a homo-

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geneous treatment and discussion, in the past decade these peculiar types of one-pot transformations, which inevitably increase the structural complexity of simple starting materials, have stimulated a rapid development in a steadily expanding ﬁeld [2–15]. Cascade reactions catalyzed by transition metals can be divided into two large categories: 1. Domino reactions that involve multiple iterations of the same elementary step [2k – m] 2. Reaction sequences that involve two or more fundamentally different reactions (for recent examples see [16–24]) The former category of metal-catalyzed domino reactions is characterized by transition metal specimens, generated by an organometallic elementary step, which are regenerated in multiple insertion events and yield, after an elimination step, the organic product of enhanced complexity. Predominantly, unimolecular reactions that proceed in an intramolecular fashion have been brought to a high level (e.g., in cyclic carbopalladation; for reviews see [25, 26]), starting from linear polyunsaturated substrates and giving rise to complex polycyclic structures. However, the latter type of metal-catalyzed cascade reactions turns out to be even more challenging since issues of selectivity and efﬁciency are crucially dependent on the particular catalyst structure. This type can either be performed in a parallel or sequential fashion [16, 21]. Whereas parallel catalysis is signiﬁcantly more difﬁcult to develop, sequential catalysis offers the possibility of altering reaction conditions and additives from step to step in the sense of bi- or multicatalytic one-pot processes, assisted tandem catalysis, or auto tandem catalysis [1]. Therefore, a demanding goal is the development of one-catalyst multireaction sequences that set the stage for new reactions in diversity-oriented syntheses of complex molecular structures (for reviews on diversity-oriented syntheses see [27–33]). For successfully performing sequentially catalyzed processes two major criteria have to be fulﬁlled: (1) the initial catalyzed process has to generate or retain a functional group suitably reactive for a subsequent transformation and (2) a catalyst or catalyst precursor has to be present in the reaction medium. This review is restricted only to sequences where initial and subsequent steps are catalyzed by palladium complexes. Furthermore, neither Pd-catalyzed unimolecular, parallel, nor multicomponent domino reactions will be treated in this overview. Reactions where identical functionalities are transformed by the same Pd-catalyzed step, i.e., multiple Pd-catalyzed reactions, will also not be covered. Hence, only those processes are within the scope of this review where an initially introduced Pd catalyst or precursor catalyzes related or signiﬁcantly different reactions and where the sequence offers advantages over the stepwise conducted transformation. With respect

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to Fogg’s and de Santos’ classiﬁcation of Pd-catalyzed one-pot processes [1] auto and assisted tandem catalysis will be discussed. The categories of sequentially Pd-catalyzed processes in this chapter are based upon the initial process. These are Heck reactions, allylic substitutions, aminations, Sonogashira couplings, metallations, CH activations, cycloisomerizations and miscellaneous processes.

2 Sequences Initiated by Heck Reaction Palladium-catalyzed vinylations of aryl halides are generally referred to as the Heck reaction (for reviews on the Heck reaction see [34–40]), a versatile process that can be performed inter- and intramolecularly [41]. In the Heck reaction the carbon–carbon single bond forming step is an insertion of an alkene into the aryl-Pd bond, i.e., a carbopalladation, giving rise to an alkyl-Pd species. If this insertion is terminated by β-hydride elimination the expected vinylation product is the outcome of the classical Heck reaction. Likewise, reversible insertion of a highly strained oleﬁn where the β-hydride elimination is suppressed leads to an entry to multiple Pd-catalyzed bond forming processes. 2.1 Irreversible Olefin Insertion as Initial Step Palladium on activated carbon has turned out to be a highly versatile, simple heterogeneous catalyst for one-pot multistep syntheses. Recently, Djakovitch and coworkers [42] have demonstrated that low catalyst loadings of Pd on activated carbon efﬁciently catalyze the Heck reaction of bromo benzene and styrene giving rise to E-stilbene (1) (92%), Z-stilbene (1%), and 1,1-diphenylethene (7%). If the Heck products are not isolated but an atmosphere of 20 bar of hydrogen is imposed onto the reaction vessel the sequence furnishes 1,2-diphenylethane (2) in 93% yield (Scheme 1). Upon exploitation of the gradual reactivity differences of carbon–iodine and carbon–bromine bonds in oxidative addition, a Heck–Suzuki sequence

Scheme 1 Sequential Heck–hydrogenation reaction [42]

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Scheme 2 Sequential Heck–Suzuki reaction [42]

with Pd on activated carbon was also presented where p-bromo-iodo benzene was ﬁrst selectively vinylated with styrene to furnish p-bromo stilbene, which was subsequently reacted with phenyl boronic acid in the presence of sodium carbonate to give the 4-phenyl stilbene (3) in 86% yield (Scheme 2). Besides addressing additional halide functionality that can be elaborated into Heck–cross-coupling sequences, vinyl organometallics such as vinyl silanes or boranes are suitable bifunctional reaction partners. Appending a catalyst-directing 2-pyridyl group on silicon made it possible to overcome the otherwise difﬁcult Heck reaction of vinylsilanes [43–49]. The silyl group on the other hand implements a starting point for a subsequent Hiyama coupling (for reviews see [50–53]). Interestingly, Heck vinylation and Hiyama coupling can be conducted in a sequential fashion, as shown by Yoshida and coworkers [48], where ﬁrst vinyl(2-pyridyl)silane (4) and ethyl p-iodo benzoate (5) are coupled and subsequent addition of TBAF and p-iodo acetophenone (6) furnishes the trisubstituted alkene 7 in 71% yield (Scheme 3). In this Heck–Hiyama sequence the vinyl silane 4 acts as a platform that can be regioselectively coupled with 5 to give the 2-aryl ethenyl(2pyridyl)silane 8. The addition of ﬂuoride activates the silyl group towards a Hiyama coupling of 8 giving rise to the formation of 7. Upon inverse addition of the aryl iodides 6 and 5, the regioisomer of 7 can be obtained in 79% yield. This diversity-oriented methodology is well suited to the rapid synthesis of extended π-conjugated systems containing the 1,2-arylethene or stilbene scaffold, an important motif in functional conjugated materials [54–62]. Interestingly, the concept of sequentially combining two Heck reactions and a cross-coupling reaction within the same vessel failed with vinyl silanes. However, applying another vinyl organometallic as a template proved to be successful. Starting with vinyl pinacolyl boronate (9) Yoshida and coworkers [63] have reacted two equivalents of (hetero)aryl halide in toluene at 80 ◦ C in the presence of bis[tris(tbutyl)]phosphane palladium(0) and diisopropylamine to give the double Heck arylation product 10, a boronate, which was not isolated (Scheme 4). Simply adding 1.1 equivalents of a second (hetero)aryl halide, sodium hydroxide, and water concluded the sequence by a Suzuki cross-coupling and gave rise to the formation of 1,1,2tri(hetero)arylethenes 11 in moderate to good yields. For a solid-phase synthesis of indolecarboxylates 14 a sequence of a Heck reaction and an intramolecular N-arylation was recently devised by Kondo

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Scheme 3 Sequential Heck–Hiyama reaction [48]

Scheme 4 Sequential multiple Heck–Heck–Suzuki reactions [63]

and coworkers [64] (Scheme 5). This one-pot indole synthesis commences with the vinylation of 1,2-dibromo benzene (13) with immobilized Cbzprotected 2-amino acrylate 12 [65] (REM, regenerable Michael resin) to provide the immobilized dehydrobromophenylalaninate 15, an intermediate that sets the stage for an intramolecular Pd-catalyzed N-arylation upon addition of sodium methoxide in a methanol/THF mixture to give the indole 14 in 78% yield. Finally, the Heck reaction can be conducted as an intramolecular process where the β-hydride elimination after the cyclizing alkene insertion is hampered, resulting in a highly reactive alkyl Pd species. Kim and Ahn [66] have introduced a sequential Heck–cyclization–Suzuki coupling that provides an

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Scheme 5 Sequential Heck–amination reaction on solid support [64]

efﬁcient synthetic access to 4-methylene-3 arylmethylpyrrolidines 17, which are not readily available by other routes (Scheme 6). However, studies on the scope of this sequence revealed that the substrate has to be an N-tosyl sulfonamide and that certain boronic acids are not transmetallated but rather give rise to the formation of the pyrrole 21 or a pyridine derivative 22 (Scheme 7). The peculiar outcome as a carbopalladation–Suzuki sequence is rationalized by coordinative stabilization of the insertion intermediate 18 by the sulfonyl oxygen atom, as represented in structure 19, now suppressing the usual β-hydride elimination. If the transmetallation is rapid the Suzuki pathway is entered leading to product 17. However, if the transmetallation is slow, as for furyl or ferrocenyl boronic acid, either β-hydride elimination or a subsequent cyclic carbopalladation occurs. The former leads to the formation of the diene 20 that is isomerized to the pyrrole 21. The latter furnishes the cyclopropylmethyl Pd species 23, which rearranges with concomitant ring expansion to furnish piperidyl-Pd intermediate 24 that suffers a β-hydride elimination to give the methylene tetrahydro pyridine 22.

Scheme 6 Intramolecular Heck–intermolecular Suzuki sequences [66]

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Scheme 7 Mechanistic road map for intramolecular Heck reactions

2.2 Intermediate Reversible Vinylation as Initial Step As indicated in the previous example, carbopalladation does not necessarily culminate in β-hydride elimination as the expected outcome of reactions under Heck conditions. In those cases where the initial carbopalladation can be reversed at a later stage in the sequence fascinating options for catalytic processes may evolve. In particular, Catellani (for an overview see [67]) has established that norbornene, a strained oleﬁn, which is reversibly introduced and eliminated, might efﬁciently serve as a relay to open new pathways for Pd-mediated processes. Indeed, most of the processes were explored and conducted both in a stoichiometric and in a catalytic fashion. As an illustration, vinylarenes 25 that are selectively substituted in both their ortho positions with different alkyl groups are virtually obtained by the three-component reaction of an ortho-substituted aryl iodide, an alkyl halide, and a terminal oleﬁn (Scheme 8) [68]. The observed byproduct 26 arises from

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reductive elimination of an intermediate, which rationalizes that norbornene plays a vital role in this unusual sequence of Pd-mediated elementary steps. As an overall consequence, not only Pd complexes but also norbornene serve as catalysts. Furthermore, the sequential ortho-alkylation–vinylation of iodo benzene as a substrate even leads to ortho, ortho double alkylated vinyl arenes 27, representatives of 1,2,3-trisubstituted arenes that are not easily accessible by conventional methods (Scheme 9). A mechanistic rationale commences with the oxidative addition of iodo benzene to a Pd(0) complex furnishing a phenyl-Pd species that readily inserts norbornene to furnish an alkyl Pd-intermediate 28 that undergoes basemediated CH activation of the ortho position of the phenyl ring (Scheme 10). The palladacycle 29 is either prone to reductive elimination, furnishing the minor by-product 26, or to an oxidative addition of an alkyl iodide, giving rise to an octahedral Pd(IV) species 30. Reductive elimination places the alkyl substituent in the ortho position and another CH activation furnishes the palladacycle 31. Again, an octahedral Pd(IV) intermediate 32 is obtained after an oxidative addition of an alkyl iodide. As before, reductive elimination occurs and gives an alkyl-Pd intermediate 33 that sets the stage for a β-elimination and expulsion of norbornene. Now, the resulting ortho, ortho double alkylated aryl Pd intermediate 34 reacts with the terminal oleﬁn and ﬁnally concludes the sequence with a Heck vinylation to give the ﬁnal product 27.

Scheme 8 Heck sequences catalyzed by Pd complexes and norbornene [68]

Scheme 9 Sequential multiple ortho-alkylation–vinylation of iodo benzene

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Scheme 10 Mechanistic rationale of multiple ortho-alkylation–vinylation sequences [67]

Based upon this principle, aryl Pd species like 34 can also terminate in a transmetallation with boronic acids (i.e., in a Suzuki coupling) where the biphenyl 35 was obtained in 90% yield (Scheme 11) and the terphenyl derivative 36 was isolated in 93% yield (Scheme 12) [69]. Additionally, ortho-isopropyl substituted iodo benzene is efﬁciently coupled with internal alkynes such as tolane as a relay to furnish the substituted phenanthrene derivative 37 in excellent yield (Scheme 13) [70]. Some mechanistic insight was also obtained from sequences where norbornene was ﬁnally incorporated in the product. In particular, if an internal

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Scheme 11 Sequential multiple ortho-alkylation–Suzuki coupling of iodo benzene [69]

Scheme 12 Sequential multiple ortho-coupling–Suzuki coupling [69]

Scheme 13 Sequential ortho-coupling–alkyne insertion [70]

alkyne like tolane was added, the reaction course changed towards insertion of the alkyne and norbornene with subsequent CH activation of one of the tolane phenyl groups to give, after reductive elimination, the polycyclic product 38 in 87% yield (Scheme 14). Based upon the mechanistic scenario of Pd-norbornene-catalyzed orthoalkylation sequences, Ferraccioli et al. (for a recent review see [71]) have

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Scheme 14 Sequential multiple insertion–ortho-coupling [70]

just recently reported exiting new syntheses of carbo- and heterocyclic frameworks. Hence, Ferraccioli and Catellani have disclosed syntheses of 1-substituted 1,2,3,4-tetrahydroisoquinolines 40a and 2,3,4,5-tetrahydro-1H2-benzazepines 40b from o-iodoalkylbenzene, N-Cbz-bromoalkylamine and an electron-poor oleﬁn through a one-pot sequence involving ortho-alkylation, alkenylation, and intramolecular aza-Michael reaction (Scheme 15) [72]. The intermediacy of the uncyclized ortho-alkylation species 39 was supported as a consequence of incomplete cyclization and isolation of 39b.

Scheme 15 Sequential ortho-alkylation–vinylation–Michael addition [72]

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Furthermore, 6-phenanthridinones 41 and their heterocyclic analogs 42–46 could be obtained in modest to excellent yields via a sequence of Pd-catalyzed aryl–aryl and N-aryl coupling from iodoarenes, orthosubstituted by electron-releasing substituents and amides of o-bromoareneand heteroarenecarboxylic acids (Scheme 16) [73]. Likewise, Lautens and coworkers have demonstrated the strength of the concept of sequential alkylation–alkenylation by application to the synthesis of fused aromatic rings. Hence, in the presence of 10% of Pd acetate, 20% of tri-2-furylphosphane, two equivalents of norbornene, and two equivalents of cesium carbonate, bromoenoates and related derivatives, ortho-substituted aryl iodides react in boiling acetonitrile in the sense of a Pd-catalyzed orthoalkylation–intramolecular Heck reaction to furnish fused aromatic carbocycles 47–53 in moderate to excellent yields (Scheme 17) [74]. Additionally, benzoannelated cycloheptanes 54 were obtained in good yields (Scheme 18). It was also possible to extend the methodology to disubstituted or benzoannelated iodo arenes as substrates, giving rise to the formation of various functionalized annelated cyclohexanes and cyclohexanes 55–61 (Scheme 19). If Z-conﬁgured trisubstituted bromoenoates are used as substrates, the exclusive formation of the nonconjugated cyclized enoate 62 is observed in 64%, whereas the corresponding E-isomer gives rise to a mixture of 62 and 63 in 40 and 27%, respectively (Scheme 20). Similarly, Lautens and coworkers could readily expand this concept to the synthesis of 2-substituted-4-benzoxepines and 2,5-disubstituted-4benzoxepines [75], and in an intermolecular–intramolecular bisalkylation– alkenylation sequence to the syntheses of oxacycles such 2,3-dihydro-

Scheme 16 Sequential aryl–aryl-N-aryl coupling [73]

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Scheme 17 Synthesis of alkylidene tetrahydronaphthalins by sequential ortho-alkylation– vinylation [74]

Scheme 18 Cycloheptane annulation by sequential ortho-alkylation–vinylation [74]

benzofurans 64, chromans 65, and 2,3,4,5-tetrahydro-benzo[b]oxepines 66 (Scheme 21) [76].

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Scheme 19 Yet an extension of the scope of sequential ortho-alkylation–vinylations [74]

Scheme 20 Effect of alkene substitution in sequential ortho-alkylation–vinylations [74]

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Scheme 21 2,3-Dihydrobenzofurans, chromans, and 2,3,4,5-tetrahydro-benzo[b]oxepines by sequential ortho-alkylation–vinylations [75, 76]

3 Sequences Initiated by Allylic Substitution Allylic substitutions are among the most frequently used Pd-catalyzed CC-bond forming processes in organic synthesis (for reviews see [77–79]). Since tetrahedral carbon centers are formed, high levels of enantioselectivity can be obtained if chiral Pd catalysts are applied. On the other hand allylic substitutions are well suited for establishing sequentially catalyzed processes, either if both allylic positions can subsequently be reacted or if the shifted oleﬁn moiety can set the stage for further Pd-catalyzed bond forming processes. In this sense Organ and coworkers [80] have developed intriguing syntheses of polysubstituted oleﬁns based upon consecutive intermolecular reactions such as allylic and allylic–vinylic halide coupling sequences. Therefore, 1-acetoxy-4-chloro but-2-ene can be readily submitted as a template for Pdcatalyzed allylic substitutions with two different carbon or nitrogen nucleophiles, leading to unsymmetrically substituted butene derivatives 66–70 in good yields (Scheme 22). Mechanistically, the chloro substituent is replaced

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Scheme 22 Unsymmetrical double allylic substitution sequences [80]

ﬁrst giving rise to the formation of the vinyl acetate derivative 65. Compared to the stepwise protocol, the sequential reaction always gives higher yields. If 2,3-dibromo propene is used as an allylic substrate the substitution product 71 can be either isolated or, after addition of additives and adjustment of the reaction conditions, 71 can readily react in cross-coupling reactions with alkynes (Sonogashira coupling), stannanes (Stille coupling), or boronic acids and boronates (Suzuki coupling) to provide the sequential allylic substitution– cross-coupling products 72–78 in moderate to good yields (Scheme 23). Equally, a 1.5 : 1 mixture of cis- and trans-1,3-dibromo propene reacts with sodium dimethyl methylmalonate to furnish the vinyl bromo derivative 79 in excellent yield, which in turn is transformed in a one-pot fashion to a 1.5 : 1 mixture of enyne 80 or the corresponding Suzuki products 81 and 82 (Scheme 24). Interestingly, ((E)-3-bromo-propenyl)-tributylstannane furnishes the vinyl stannane 83 upon allylic substitution that instantaneously is subjected to the conditions of a Stille coupling with iodo benzene to give the sequence’s product 84 in 68% yield (Scheme 25). Sequential allylic substitutions have also been used in an intermolecular– intramolecular fashion with 1,4-diacetoxy cis-2-butene 85 as a module, as shown by Hayashi and coworkers [81], to deliver morpholines 86 and piperazines with enantioselectivities up to 61% ee if a chiral chelating bisphosphane such as BINAP is applied as a ligand (Scheme 26).

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Scheme 23 Sequential allylic substitution–cross-coupling [80]

Mechanistically, the twofold allylic substitution with amino alcohols commences with the intermolecular nucleophilic attack of the amino group to the π-allyl-Pd-species 87 and concludes with the enantiogenic intramolecular attack of the hydroxy group to the newly generated π-allyl-Pd-complex 88 to furnish 86 (Scheme 27). As both E and Z 1,4-diacetoxy-cis-2-butene give the same levels of enantioselectivity of the product 86, it can be assumed that the enantiodiscriminating and rate-determining step is the slow intramolecular allylic substitution with the weaker nucleophilic oxygen. Furthermore, the rapid interconversion of syn- and anti-isomers on the stage of the allyl-Pd precursors supports this rationale. Intramolecular allylic substitutions in an exo-fashion are perfectly appropriate for cyclizations with concomitant generation of a vinyl group that sets the stage for a Heck vinylations. Poli and his group [82] have recently presented a sequence where methylene active malonamide esters with an al-

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Scheme 24 Sequential allylic substitution–Sonogashira and Suzuki coupling [80]

Scheme 25 Sequential allylic substitution–Stille coupling [80]

Scheme 26 Sequential enantioselective inter- and intramolecular allylic substitution [81]

lylic acetate side chain and aryl bromides undergo, in the presence of the Hermann–Beller catalyst 89, a pyrrolidone formation via allylic substitution and subsequent Heck vinylation to give substituted pyrrolidones in moderate to good yields (Scheme 28).

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Scheme 27 Mechanistic pathway of sequential inter- and intramolecular allylic substitutions

Scheme 28 tion [82]

Sequential intramolecular allylic substitution–intermolecular Heck reac-

The Heck reaction may also proceed in an intramolecular fashion if the aryl halide is covalently bound to the allyl substrate. In this case the sequential allylic substitution–Heck-cyclization with Pd acetate as a catalyst takes place very smoothly as an unimolecular process and furnishes the polycondensed pyrrolidones 91 in excellent yields (Scheme 29). An intriguing showcase for polycyclizations based upon hetero-domino reactions is outlined in Scheme 30, where the catalyst 89 gives rise to the formation of a mixture of indolone skeletons 92–94 with a preference for the generation of tetracycle 94 as a result of an intramolecular allylic substitution–Heck sequence. Palladium-catalyzed allyl rearrangements can be considered special cases of allyl substitutions that occur intramolecularly. Hence, via the forma-

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Scheme 29 Sequential intramolecular allylic substitution–Heck reaction [82]

Scheme 30 Polycycles by sequential intramolecular allylic substitution–Heck reaction [82]

tion of π-allyl-Pd complexes, the allyl rearrangement can also set the stage for a consecutive Pd-catalyzed sequential process. Itami and Yoshida [83] have recently described a Pd-catalyzed one-pot rearrangement/arylation of 2-allyloxypyridine by applying a catalyst/base combination of Pd[P(tBu)3 ]2 /Ag2 CO3 to give N-allylaryl 2-pyridones 95 in good to excellent yields (Scheme 31). Among the several Pd catalysts PdCl2 (PhCN)2 , PdCl2 , Pd(PPh3 )4 , and Pd(Pt Bu3 )2 have been found to be effective for the rearrangement whereas Pd(OAc)2 has proven to be a less suitable system. A Pd(0)-catalyzed Claisen rearrangement with a subsequent intramolecular Heck vinylation has been demonstrated by Watson and coworkers [84]. Upon treatment with Pd(PPh3 )4 the allyl vinyl ether undergoes a Pd(0)catalyzed 1,3 oxygen to carbon allyl shift to afford an α-allyl ketone that

Scheme 31 Sequential allyl rearrangement–arylation [83]

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Scheme 32 Sequential Claisen rearrangement–intramolecular Heck reaction [84]

Scheme 33 Sequential homobimetallic deprotection–heterocyclization [85]

undergoes a subsequent intramolecular Heck arylation to give the spiro indane 96 (Scheme 32). On the other hand, an allyl ether can also be considered a protected alcohol that is liberated by Pd(0)-catalyzed allylation for further catalytic transformation. As an excellent example for sequential homobimetallic catalysis, Gabriele and coworkers [85] just recently disclosed a Pd(0)-catalyzed deprotection-Pd(II)-catalyzed heterocyclization of allyloxyaryl propargylic alcohols 97 to provide benzofurans 98 in excellent yields (Scheme 33). Mechanistically, this homobimetallic catalytic process can be described and rationalized as a Pd(0)-catalyzed deprotection of the phenyl allylether 97 furnishing phenolate 99 that now can enter the second Pd(II)-catalyzed cycle (Scheme 34). The destiny of the π-allyl-Pd complex is a carbonyl insertion to furnish, after nucleophilic displacement with methanol, but-3-enoic acid methyl ester and hydroiodic acid. The phenolate 99 cyclizes to give a vinylPd species that inserts carbon monoxide followed by the attack of methanol.

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Scheme 34 Mechanistic rationale of the sequential homobimetallic deprotection–heterocyclization

Finally, the allyl alcohol ester is hydrometallated with a concomitant loss of water. Protonation with hydroiodic acid liberates the benzofuran 98 and Pd(II) iodide to begin a new catalytic cycle.

4 Sequences Initiated by Amination Palladium-catalyzed carbon–nitrogen bond formation (for reviews see [86– 91]) has been considerably developed in the past decade and, due to the omnipresence of nitrogen-containing compounds in natural products such as alkaloids or non-natural functional targets such as electron-rich π-systems,

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sequences initiated by Pd-catalyzed amination have aroused special attention. One of the ﬁrst examples of sequential multifold Pd-catalyzed aminations was presented by Marder and coworkers [92] who were synthesizing unsymmetrical triarylamines for photonic applications. The sequential coupling of aniline derivatives with 4,4 -dibromo biphenyl and aryl bromides in the presence of Pd2 dba3 , with dppf as a ligand and sodium tert.-butoxide as a base, gives rise to the formation of tetrasubstituted benzidines 100 in modest to excellent yields (Scheme 35). These are useful as hole transport components in organic light-emitting diodes with a variety of band gaps, band offsets, and glass transition temperatures. In the sense of an intermolecular amination with heterocyclic amidine derivatives, such as amino azines and diazines, and 2-chloro-3-iodopyridines followed by an intramolecular amination, Maes and coworkers [93] have established a facile synthesis of dipyrido[1,2-a : 3 ,2 -d]imidazole and its benzoand aza-analogs 101–106 (Scheme 36). The chemo- and regioselective heterocyclization can mechanistically be rationalized by the gradually decreasing difference in reactivity between the carbon–iodine and the carbon–chlorine bond. In the presence of a catalyst system of [Pd2 dba3 ] and proazaphosphatrane (107) Verkade and Nandakumar [94, 95] have achieved a doubleamination–intermolecular Heck reaction sequence in a one-pot fashion with 4-amino styrene and various aryl halides to furnish the triarylated products 108 in moderate to excellent yields (Scheme 37). Here, the order of coupling can be nicely illustrated upon varying the stoichiometry of the aryl halide and the reaction conditions. The amination proceeds faster and at lower temperatures than the Heck reaction, as shown by symmetrical N,N-diarylation at 60 ◦ C followed by the Heck vinylations of a second aryl halide at 110 ◦ C to give the amino stilbene derivatives 109 (Scheme 38). Even unsymmetrically substituted arylated amino stilbenes 110 can be readily synthesized by reaction of one equivalent of an aryl halide in

Scheme 35 Sequential unsymmetrical multiple aminations [92]

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Scheme 36 Sequential inter–intramolecular amination [93]

Scheme 37 Sequential multiple amination–Heck reaction [94, 95]

Scheme 38 Sequential unsymmetrical multiple amination–Heck reaction [94, 95]

a monoamination at 60 ◦ C, followed by the addition of two equivalents of another aryl halide to undergo amination and Heck reaction at 110 ◦ C (Scheme 39).

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Scheme 39 Yet another mode of sequential unsymmetrical amination–Heck reactions [94, 95]

Just recently, Stauffer and Steinbeiser [96] have presented an intermolecular consecutive aryl amination–Suzuki coupling sequence where, in the presence of potassium orthophosphate as a weak base and Pd[P(tert.-Bu)3 ]2 as a catalyst system, the morpholino-biaryl derivative 111 was obtained in moderate yield (Scheme 40). Yet, intramolecular sequences are often more viable than bimolecular processes. Therefore, the combination of Pd-catalyzed aminations with subsequent cyclization opens new perspectives in heterocycle synthesis. Lately, Willis and coworkers [97, 98] have developed a cascade N-annulation route to 1-functionalized indoles. Amine, aniline, amide, carbamate, and sulfonamide functional groups can efﬁciently be introduced as coupling partners if 2-(2-bromo-phenyl)-cyclohex-1-enyl triﬂate 112 is reacted in the presence of [Pd2 dba3 ] and dpephos or xantphos as ligands to give a variety of tetrahydrocarbazoles 113 in moderate to excellent yields (Scheme 41). The scope of the aryl bromide moiety and the enol triﬂate fragment has revealed that this sequential amination is relatively broad and leads to various substituted and annelated indole derivatives 114–122 in good to excellent yields (Scheme 42). Another intriguing option for sequential annulations is the combination of amination and CH activation. Here, Bedford and Cazin [99] have introduced a novel catalytic one-pot synthesis of carbazoles 123 via a consecutive amination–CH activation process of ortho-chloro anilines and aryl bromides (Scheme 43). Since the diarylamine intermediate is a chloroarene, the pres-

Scheme 40 Sequential amination–Suzuki coupling [96]

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Scheme 41 Tetrahydrocarbazole synthesis by sequential inter–intramolecular amination [97, 98]

Scheme 42 Indole syntheses by sequential inter–intramolecular amination [97, 98]

ence of P(tert.-Bu)3 as a ligand warrants a rapid oxidative addition for the concluding cyclization via CH activation. Also, the pyridazino-fused ring system 124 containing an indole core can be readily synthesized upon using a Pd(OAc)2 -BINAP catalyst system for the amination–CH activation sequence, as recently demonstrated by Mátyus and coworkers [100, 101] (Scheme 44).

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Scheme 43 Carbazole synthesis by sequential amination–CH activation [99]

Scheme 44 Yet another sequential amination–CH activation [100, 101]

Furthermore, Pd-catalyzed aminations can be sequentially coupled with alkene insertion and amination. Wolfe and Lira [102] have established a transformation involving two different sequential metal-catalyzed reactions that lead to N-aryl-2-benzylindolines 125 in moderate to excellent yields upon formation of two C – N bonds and one C – C bond in a one-pot process (Scheme 45). Interestingly, the selective installation of two different aryl groups in this sequence can be accomplished by in situ modiﬁcation of the Pd catalyst system Pd-126 upon addition of the chelating ligand dpephos prior to addition of the second aryl bromide (Scheme 46). The selectively substituted indoline derivatives 127 were isolated in good to excellent yields.

Scheme 45 Sequential insertion–amination [102]

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Scheme 46 Sequential intramolecular amination–insertion–intermolecular amination [102]

Scheme 47 Mechanistic rationale of sequential intramolecular amination–insertion– intermolecular aminations [102]

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Mechanistically, the latter sequence rationalizes as follows (Scheme 47). The Pd-catalyzed arylamination with the bulky monodentate phosphane stops at the stage of the N-aryl allyl benzene 128. Upon addition of the chelating ligand dpephos, a subsequent cycle is opened that commences with the oxidative addition of the aryl bromide to the Pd-dpephos chelate. After the complexation of 128 to the Pd complex, the insertion of the alkene takes place to furnish an alkyl aryl Pd species that, due to the chelating dpephos, undergoes reductive elimination rather than β-hydride elimination to furnish the product 127. Likewise, the same principle underlies the N-arylation-carboamination sequences as a stereoselective synthesis of N-aryl-2-benzyl pyrrolidines 129 presented by Wolfe and coworkers [103] (Scheme 48). The pyrrolidine derivatives 129 were obtained with modest to excellent yields and good to excellent levels of diastereoselectivity (2,5-disubstituted 1-aryl pyrrolidines: syn/anti > 20 : 1; 2,3-disubstituted 1-aryl pyrrolidines: syn/anti 9 : 1 to > 20 : 1). Using the bulky N-heterocyclic carbene 130 as a ligand for Pd(0) complexes Schneider and coworkers [104] have recently reported a novel synthetic strategy to ﬁve-, six- and seven-membered N-arylated heterocycles 131–135 via sequential Pd-catalyzed intra- and intermolecular arylamination reactions (Scheme 49). Finally, ortho-(2,2-dibromovinyl)-aniline or -acetanilide can successfully be applied in a sequential cyclizing amination–cross coupling reaction with diethyl phosphonate to furnish the indolyl phosphonic ester 136 or the N-acetyl 2-aryl indole 137 as recently shown by Bisseret and coworkers [105] (Scheme 50). This sequence can be also performed with corresponding phenol derivatives furnishing benzofurans. For the N-acetyl 2-aryl indole 137 it can be shown that the Suzuki coupling occurs prior to the intramolecular amination as a consequence of the gradual difference in reactivity between transand cis-carbon–bromine bonds.

Scheme 48 Pyrrolidines by sequential intramolecular amination–insertion–intermolecular amination [103]

Sequentially Palladium-Catalyzed Processes

Scheme 49 Sequential intramolecular amination–intermolecular amination [104]

Scheme 50 Sequential cross-coupling–intramolecular amination [104]

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5 Sequences Initiated by Sonogashira Coupling The Sonogashira coupling (for lead reviews on Sonogashira couplings see [106–108]) is a bimetallic, catalytic alkyne-to-alkyne transformation and has found considerable application in the synthesis of complex molecules, carbon-rich scaffolds, and organic materials. The most straightforward Pd source for Sonogashira alkynylation is Pd on activated carbon. Therefore, this system is also well suited for the generation of sequences. As pointed out before, for sequences initiated by Heck reactions, Djakovitch and coworkers [42] have demonstrated that Pd on carbon can be applied for coupling ortho-iodo aniline and phenylacetylene with concomitant cyclization to give the indole derivative 138 in good yield (Scheme 51). Independently, Pal and coworkers [109] have shown that this approach can be performed in water as a solvent and that it is also fairly general for the synthesis of 2-substituted sulfonated indoles 139 (Scheme 52). With homogenous catalysts such as Pd(PPh3 )2 Cl2 or Pd(PPh3 )4 the most sequential catalyses using the Sonogashira reaction as initial step have been performed. Among the classic examples is the coupling–cyclization of alkynes with Z-β-bromo acrylic acid derivatives invented by Negishi and Kotora [110] as a sequential access to the γ -alkylidenebutenolide 140 in excellent yield (Scheme 53). The constitutional isomeric α-pyranone 141 is only formed in 4% yield.

Scheme 51 Sequential Sonogashira coupling–amine addition [42]

Scheme 52 Indoles by sequential Sonogashira coupling–amine addition [109]

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Scheme 53 Butenolides by sequential Sonogashira coupling–cyclization [110]

Nice applications of this sequential method are the concise syntheses of rubrolide diacetates A, C, D, and E (142) (Z/E ratios of > 50 : 1) (Scheme 54) that were converted into the rubrolides (R = H) by saponiﬁcation of the acetates with methanolic K2 CO3 in MeOH/THF (1 : 1). Following the same principle Fiandanese and coworkers [111] have developed an efﬁcient stereoselective approach to silylated polyunsaturated γ -alkylidene butenolides 143–145 starting from Z-3-iodo-propenoic acid (Scheme 55). In addition, Fiandanese and coworkers [112] have applied this methodology to concise syntheses of dihydroxerulin (146) and xerulin (147) that are potent inhibitors of the biosynthesis of cholesterol (Scheme 56). Furthermore, Z-3-bromo-propenoates 148 are suitable substrates for Sonogashira–[4 + 2]-cycloadditions to furnish 6H-dibenzo[b,d]pyran-6-ones 149 in moderate to excellent yields as shown by Yamamoto and

Scheme 54 Rubrolide diacetates

Scheme 55 Polyunsaturated γ -alkylidene butenolides by sequential Sonogashira coupling– cyclization [111] (newly formed bonds drawn in bold lines)

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Scheme 56 Syntheses of dihydroxerulin (146) and xerulin (147) [112]

Kawasaki [113] (Scheme 57). The enyne intermediate 150, which is formed by Sonogashira coupling, undergoes a thermal benzannulation in the sense of a [4 + 2]-cycloaddition followed by rearrangement to the aromatic system. However, starting with 2-iodo-phenyl Z-3-bromo-acrylate (151) and butadiynes two subsequent Sonogashira coupling reactions and a benzannulation give rise to the formation of the diynes 152 in moderate yields (Scheme 58). Indeed, the gradual differences in reactivity between an oleﬁnic carbon– bromine bond and an aromatic carbon–iodine bond in the acrylate 151 can be

Scheme 57 Sequential Sonogashira coupling–[4 + 2]-cycloaddition [113]

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Scheme 58 Sequential twofold Sonogashira coupling–[4 + 2]-cycloaddition [113]

exploited by sequentially performing a Sonogashira coupling with a terminal alkyne to furnish the enyne iodide 153. This is reacted in a one-pot fashion with 1,3-decadiyne to give the enetriyne 154 that undergoes the benzannulation; the alkynes 155 are obtained in moderate yields (Scheme 59). A completely different mode of applying the Sonogashira coupling for sequential catalysis can be envisioned by introduction of further steps that are not catalyzed by transition metals. Here, Müller and coworkers [114] have just recently demonstrated that acid chlorides 156 and terminal propargyl THP ethers 157 after Sonogashira coupling can be transformed in a one-pot fashion into iodo furans 158 in moderate to good yields (Scheme 60).

Scheme 59 Mechanistic rationale of sequential twofold Sonogashira coupling–[4 + 2]cycloadditions [113]

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Scheme 60 3-Iodo furans by sequential Sonogashira coupling–addition–cyclocondensation [114]

This sequence can be rationalized by acid-catalyzed transacetalization of the initially formed ynone 159 to give the propargyl alcohol 160 (Scheme 61). Then, the acid-mediated Michael addition of iodide to the ynone moiety gives rise to the formation of the Z-conﬁgured enone 161 which, in turn, cyclocondenses to furnish the iodo furans 158. Based upon this one-pot synthesis of iodo furans 158 a sequential Sonogashira–cyclization–Suzuki sequence was developed where the coupling of 156 and 157 followed by deprotection, Michael addition and addition of boronic acid and sodium carbonate leads to the formation of 2,3,5trisubstituted furans 162 in moderate to good yields (Scheme 62). Another option for Sonogashira coupling as an initiator of sequential catalysis is the coupling isomerization reaction (CIR) of electron-deﬁcient halide and 1-aryl propargyl alcohols giving rise to the formation of chalcones [115, 116]. Based upon the CIR of electron-deﬁcient halides 163 and 1-(p-bromo phenyl) propyn-1-ol (164) Müller and Braun [117] presented a consecutive

Scheme 61 Mechanistic rationale of sequential Sonogashira coupling–addition–cyclocondensations

Scheme 62 Sequential Sonogashira coupling–addition–cyclocondensation–Suzuki coupling [114]

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Scheme 63 Sequential coupling–isomerization–Sonogashira coupling [117]

CIR–Sonogashira sequence that allows a rapid construction of more complex frameworks in a one-pot reaction and in good yields (Scheme 63). If the alkyne in the second step is a 1-aryl propargyl alcohol the product is a bischalcone as a consequence of a CIR–CIR sequence. Furthermore, it is also possible to perform CIR–Heck and CIR–Suzuki sequences if alkenes or boronates and potassium carbonate are added after completion of the initial CIR step. Here again, the gradual differences in reactivity in the oxidative addition between an electron-deﬁcient and an electro-neutral carbon– bromine bond can be readily exploited for selective cross-coupling, ﬁrst to furnish an aryl propargyl alcohol that is slowly isomerized upon base catalysis to give the bromo chalcone for further cross-coupling.

6 Sequences Initiated by Metallation Many organometallic compounds that have main group metal–hydrogen or metal–metal bonds undergo 1,2-hydrometallation or 1,2-dimetallation of alkynes. Pd complexes are good catalysts for these processes [118]. Since the resulting products contain one or two reactive carbon–metal bonds they are well suited for further transformations, particularly in a sequential fashion. A particularly nice application of the hydrostannylation is the Stille coupling (for reviews on the Stille coupling see [119–123]) that becomes catalytic in tin, as introduced by Maleczka and coworkers [124, 125]. Terminal alkynes and organobromides can be coupled in the presence of catalytic amounts of tributyltinchloride and Pd(II) and Pd(0) catalysts and stoichiometric amounts of PMHS (polymethylhydrosiloxane) to give the alkene derivatives 166–173 in good to excellent yields (Scheme 64). Mechanistically, this sequence can be rationalized as an interdigitating hydrostannylation–Stille coupling–tin recycling process (Scheme 65). The Pd(0)-catalyzed hydrostannylation of the terminal alkyne with tributyltinhydride furnishes the vinyl stannane, which is transmetallated to the

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Scheme 64 Sequential hydrostannylation–Stille coupling that is catalytic in tin [124, 125] (bonds formed by Stille coupling are drawn in bold lines)

organo-Pd species arising from the oxidative addition of the organobromide, and concludes the cross-coupling via reductive elimination. However, the Bu3 SnBr liberated in the transmetallation step is transformed into a stannoxide derivative that in turn is reduced by PMHS, simultaneously regenerating the tributyltinhydride, which can start a new hydrostannylation. Hexamethylditin is a suitable reagent for Pd-catalyzed metallation of arylhalides to furnish aryltin compounds that in turn can react in Stille couplings with aryl halides to form biaryl derivatives. Hitchcock and coworkers [126] have shown that 2-pyridyl triﬂate and (hetero)aryl bromides can be coupled to 2-(hetero)aryl pyridines 174 in moderate to good yields (Scheme 66). The underlying principle of this heterocoupling of two aryl (pseudo)halides is the selective stannylation of the triﬂate that is undergoing a faster oxidative addition to the Pd(0) complex than the bromide. Similarly, Mori and coworkers [127] have demonstrated that stannanylsilanes such as Bu3 SnSiMe3 can be applied for the intramolecular coupling of vinyl triﬂates with a tethered vinyl bromide, as in compound 175, to give cyclic dienes 176–181 (Scheme 67). The tentative mechanism suggests that the Pd-catalyzed metallation regioselectively substitutes triﬂate by tin (Scheme 68). Then, the intramolecular cross-coupling takes over to conclude the sequence with a reductive elimination resulting in the cyclization product 176. Furthermore, Kang and coworkers [128, 129] have developed a sequential silastannylation–allyl addition reaction upon reacting allenyl aldehydes

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Scheme 65 Mechanistic rationale of sequential hydrostannylation–Stille coupling with tin recycling

Scheme 66 Sequential stannylation–Stille coupling [126]

with trimethyl(tributylstannyl)silane, in the presence of (π-allyl)2 Pd2 Cl2 as a Pd catalyst, to furnish diastereoselectively trimethylsilyl ethenyl cyclopentanols and cyclohexanols and their heterocyclic derivatives 182 in good yields (Scheme 69). The syn-diastereoselectivity can be rationalized by assuming an

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Scheme 67 Sequential stannylation–intramolecular Stille coupling [127] (bonds formed by Stille coupling are drawn in bold lines)

Scheme 68 coupling

Mechanistic rationale of the sequential stannylation–intramolecular Stille

equilibrium for the chelating intermediates that reduces steric strain by placing the less-demanding carbonyl group in a pseudo-equatorial orientation (Scheme 70). Queiroz and coworkers [130] have devised a sequential Pd-catalyzed borylation–Suzuki coupling as the key step to thienocarbazole precursors. This one-pot processes begins with a Pd-catalyzed borylation using pinacolborane and a bromo benzothiophene derivative and concludes with the add-

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Scheme 69 Sequential silastannylation–intramolecular allyl addition [128, 129]

Scheme 70 Intermediates rationalizing the observed syn-diastereoselectivity

Scheme 71 Sequential borylation–Suzuki coupling [130]

ition of ortho-bromo nitrobenzenes and aqueous barium hydroxide to start the Suzuki step furnishing the nitroaryl-substituted benzothiophenes 183 in good to excellent yields (Scheme 71). Finally, as shown by Kabalka and Yao [131] bis(pinacolato)diboron can be applied in a sequential Pd-catalyzed Miyaura borylation and Suzuki coupling to a (bromomethylene)cyclobutane furnishing an efﬁcient synthesis of the (dicyclobutylidene)-ethane derivative 184, whereas the presumed boronate intermediate 185 was only obtained in trace amounts (Scheme 72).

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Scheme 72 Sequential borylation–Suzuki homocoupling [131]

7 Sequences Initiated by CH Activation The activation of sp2 - or sp-hybridized CH bonds (for reviews on metalmediated CH bond activation in catalytic processes see [132–137]) generating an organopalladium species suitable for subsequent transformation is the key step for sequences initiated by CH activation. Recently, Larock and coworkers [138] have introduced a 1,4-Pd migration via CH activation followed by arylation as an elegant synthetic entry to fused polycycles 186–190 (Scheme 73). This intriguing intramolecular sequence begins with an oxidative addition of the carbon–iodine bond to the Pd(0) species followed by a 1,4-Pd migration to the adjacent aryl ring via a CH activation–reductive elimination step. Then, the base-mediated CH activation results in a biaryl-Pd species that undergoes a reductive elimination to furnish the expected annulation products. For clarity, the initially generated CH bonds and the newly formed CC bonds are highlighted as bold lines in Scheme 73. Likewise, the alkynyl 3-(2-iodophenyl) indole 191 is transformed under similar conditions into the 6,7-dihydro-5H-4b-aza-benzo[a]aceanthrylene 192 in good yield (Scheme 74). The Sonogashira coupling can be considered a special case of catalytic alkyne activation. Interestingly, it is also possible to conduct alkyne activation under oxidative conditions in the presence of Pd catalysts without oxidative dimerization. Here, Costa and coworkers [139] have developed a Pd-catalyzed sequential carboxylation–alkoxycarbonylation of acetylenic amines in the presence of oxygen to give mixtures of Z- and E-conﬁgured 2-oxo-oxazolidin5-ylidene]-acetic acid methyl ester 193 and 194 in good to excellent yields (Scheme 75). The mechanism can be rationalized as follows (Scheme 76). Palladium iodide triggers the carbonylation of the propargyl amine to give an η2 -alkynyl carbamate-Pd-iodide complex that inserts the triple bond to give a syn-vinyl-

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Scheme 73 Sequential 1,4-migration–CH activation–arylation [138] (bonds formed by CH activation and arylation are drawn in bold lines)

Scheme 74 Sequential 1,4-migration–insertion–CH activation–arylation [138] (bonds formed by CH activation and arylation are drawn in bold lines)

Pd species. This intermediate undergoes carbonylation, methoxy substitution, and reductive elimination to furnish the Z-conﬁgured derivative 193. The resulting Pd(0)-species is reoxidized by oxygen in the presence of iodide ions. On the other hand, the presence of potassium iodide can also equilibrate the η2 -alkynyl carbamate-Pd-iodide complex to the η2 -alkynyl carbamatePd-diiodide complex, which, in turn, causes an anti-attack of the carbamate at the PdI2 -complexed alkyne. Therefore, an anti-vinyl-Pd species results, which ultimately and accordingly leads to the E-conﬁgured derivative 194. Without carbon monoxide the vinyl-Pd-species suffer a hydro-demetallation.

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Scheme 75 Sequential carboxylation–alkoxycarbonylation [139]

Scheme 76 Mechanistic rationale of the regiochemistry in sequential carboxylation– alkoxycarbonylations

Recently, Gabriele and coworkers [140] presented an expedient synthesis of 4-dialkylamino-5H-furan-2-ones 195 by a one-pot sequential process (Scheme 77). Based upon the oxidative aminocarbonylation of terminal alkynes [141], a conjugate addition of the amine to the ynoylamide leads to the stereoselective formation of an E-conﬁgured 2-amino 3-hydroxy enamide that lactonizes to furnish the dialkylamino-5H-furan-2-one 195 (Scheme 78).

Scheme 77 Intramolecular sequential alkoxycarbonylation [140]

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Scheme 78 Mechanistic rationale of intramolecular sequential alkoxycarbonylations

8 Sequences Initiated by Cycloisomerization Cycloisomerizations of enynes catalyzed by Pd complexes address fundamental issues of atom-economy and have become valuable tools in synthetic organic chemistry (for leading reviews on Pd-catalyzed cycloisomerizations see [142–146]). Of the two mechanistic pathways, i.e., via palladacyclization or via hydropalladation–cyclic carbopalladation, the latter seems to be more suitable for the development of sequentially catalyzed processes. Considering cycloisomerizations via the hydropalladation–cyclic carbopalladation route the catalytic reaction can terminate by β-hydride elimination giving rise to the formation of dienes and derivatives thereof (Scheme 79). Alternatively, the alkyl-Pd species formed in the cyclic carbopalladation can be susceptible to subsequent transmetallation with organometallic substrates. Then, a reductive elimination could conclude this second Pd-mediated step releasing the Pd(0) species for a new catalytic cycle. Using this principle, Kibayashi and coworkers [147] have introduced a sequential cyclic carbopalladation–Stille vinylation of enyne compounds. Upon treating the enyne 196 and vinyl tributylstannane with catalytic amounts of Pd2 (dba)3 · CHCl3 in the presence of AcOH the allyl-substituted methylene cyclopentane 197 was formed in 53% yield (Scheme 80). The subsequent cross-coupling occurs with complete suppression of β-H-elimination and the Alder-ene product 198 was not detected. Likewise, this sequence was extended to heteroatom-linked enynes and further vinyl tin compounds to provide the heterocyclic analogs 199 in moderate to excellent yields (Scheme 81). Furthermore, the choice of enyne substrates can lead to cyclized products that contain other functionalities than dienes. Very recently, Müller and Kressierer [148] have shown that yne allyl alcohols 200 can be rapidly cycloisomerized by a Pd2 dba3 -N-acetyl phenyl alanine catalyst system to furnish heterocyclic enals 202 in excellent yields (Scheme 82). The intermediate product of the enyne cycloisomerization in this case is the enol 201, which rapidly tautomerizes to the aldehyde 202. However, this intriguing catalyst system is capable of performing a subsequent reductive amination in the same pot and under the same conditions if secondary amines are added and if an atmosphere of hydrogen is introduced. Therefore, alkyne allyl alcohols 200 are readily transformed in moderate to good yields into β-amino ethyl alkylidene tetrahydrofurans 203

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Scheme 79 Mechanistic pathways in cyclic carbopalladations with Pd – H species

Scheme 80 Sequential cyclic carbopalladation–Stille coupling [147]

Scheme 81 Scope in sequential cyclic carbopalladation–Stille coupling [147]

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Scheme 82 Cycloisomerization of alkynyl allyl alcohols to cyclic enals [148]

Scheme 83 Sequential cycloisomerization–reductive amination [148]

or β-amino ethyl alkylidene pyrrolidines 204 in the sense of a Pd-catalyzed cycloisomerization–reductive amination sequence with remarkable chemoselectivity (Scheme 83).

9 Sequences Initiated by Miscellaneous Processes Finally, there are also sequences that are unique and represent the ﬁrst examples of further modes of entries using Pd-catalyzed elementary processes. Inevitably, here lies a vast potential for this highly developing topical ﬁeld. As already discussed for cross-coupling initiated sequential reactions, organometallic specimens are a prerequisite for entering this pathway. Ketone and ester enolates have also been explored in cross-coupling methodologies as favorable coupling partners for carbon–carbon bond formation in the sense of an enolate arylation [149–151]. Therefore, a unique example by Wills and coworkers [152] shows that the reaction of the in situ-generated enolate of pinacolone with the TBDMS-protected 3-(o-bromophenyl)allylic alcohol (205) in the presence of a Pd(0)-dppf catalyst system furnishes a 1-vinyl1H-isochromene 207 as a result of a cross-coupling–intramolecular allylation sequence (Scheme 84). It is reasonable to assume that the coupling product 206 sets the stage as a substrate for the generation of a π-allyl species that reacts intramolecularly with the ketone enolate moiety and terminates the cyclization sequence. A comparable yield of 207 (54%) is achieved if the

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Scheme 84 Sequential enolate coupling–allylation [152]

more bulky TBDPS ether is chosen for protection of the allyl alcohol. Using o Tol P as a ligand for Pd gives similar yields of 207 (61%), whereas the ap3 plication of t Bu3 P not only drastically reduces the yield of 207 (27%) but also gives rise to the formation of several side products. Acetophenone and propiophenone can also be well applied in the sequence, but furnish signiﬁcantly lower yields of the cyclization products (28 and 36%, respectively). In a related case, Maier and coworker [153] have recently also demonstrated that vinylogous enolates can enter into a cross-coupling step. However, the ﬁnal products of Pd-catalyzed reactions of the hexahydro naphthalenone and aryl bromides or iodides in the presence of cesium carbonate and tetraalkylammonium bromide in DMF at room temperature are 7-aryltetralones 208 (Scheme 85). This process can be readily interpreted as a Pd-catalyzed γ -selective arylation of the thermodynamic enone enolate with a concomitant dehydrogenation–aromatization of the initial crosscoupling product. Pd-catalyzed alkyne dimerizations to conjugated enynes have been introduced by Trost [154, 155] as an atom-economical way of forming carbon– carbon bonds, taking advantage of the different electronic nature of the participating coupling partners. With well-designed substrates this peculiar electronic situation also sets the stage for a subsequent Pd-catalyzed intramolecular nucleophilic addition to the triple bond of the initial enyne product. Trost and Frontier [156] have disclosed a sequentially Pd-catalyzed alkyne dimerization–intramolecular nucleophilic addition giving rise to complex functionalized oxygen heterocycles. Upon reacting the hydroxy

Scheme 85 Sequential γ -arylation–aromatization [153]

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alkynoate 209 and 1-heptyne, in the presence of Pd acetate and TDMPP (tris-(2,6-dimethoxyphenyl)phosphane) as a ligand, a 20 : 1 mixture of the dihyropyran 211 and the dihydropyranone 212 was obtained in 61% yield (Scheme 86). The sequence presumably proceeds through the alkyne dimerization product 210, which preferentially cyclizes in a 6-endo-dig fashion to furnish the dihyropyran 211. For secondary hydroxy alkynoates 213 the cyclization occurs by nucleophilic addition to the alkyne, however, the ratio of dihyropyran 214 to dihyrofuran 215 formation strongly depends on the nature of the terminal alkyne coupling partner (Scheme 87). A highly chemo- and regioselective [2 + 2 + 2] sequential cycloaddition of alkynes and 1,3-butadiynes catalyzed by Pd(0) complexes as an elegant de novo synthesis of tetrasubstituted benzenes 216 (Scheme 88) and pen-

Scheme 86 Sequential alkyne dimerization–intramolecular nucleophilic addition [156]

Scheme 87 6-Endo-dig vs. 5-exo-dig cyclization in sequential alkyne dimerization– cyclizations [156]

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Scheme 88 Tetrasubstituted benzenes by sequential cycloaddition of alkynes [157]

Scheme 89 Pentasubstituted benzenes by sequential cycloaddition of alkynes [157]

tasubstituted benzenes 217 (Scheme 89) was developed by Gevorgyan and coworkers [157]. Mechanistically, this unusual multicomponent trimerization can be rationalized as a sequence of a Pd-catalyzed alkyne dimerization [154, 155] giving rise to the regioselective formation of the enyne 218, which undergoes subsequent Pd-catalyzed [4 + 2]-benzannulation [158, 159] with a butadiyne as an enynophile to furnish the benzene 216 via an allenyl-Pd species 219 (Scheme 90). Upon submitting an electron-deﬁcient alkyne together with a terminal alkyne in equimolar amounts to the sequence, the unsymmetrical alkyne dimerization gives a trisubstituted enyne to set the stage for the formation of pentasubstituted benzene derivatives 217. Rawal and Thadani [160] have taken advantage of alkynes as excellent insertion partners in Pd(II)-catalyzed allylations. Interestingly, the Pd(II) species present in the medium after alkyne insertion into allyl chlorides or bromides can serve for a sequential Wacker–Tsuji oxidation upon introduction of CuCl, oxygen, and water to the reaction medium to give γ -halo β,γ -enones 220 in good yields (Scheme 91). If phenylacetylene is used as an alkyne 1-phenyl-pent-2-ene-1,4-dione can be isolated in 77% yield as the result of a subsequent oxidative hydration of the γ -halo β,γ -enone 220.

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Scheme 90 Mechanistic rationale of sequential cycloaddition of alkynes [158, 159]

Scheme 91 Sequential halo allylation–Wacker oxidation [160]

Furthermore, the presence of a Pd catalyst in the medium and the generation of an allylated halo alkene can be readily exploited for a subsequent Sonogashira coupling to give the dienynes 221 in good yields as a consequence of a halo-allylation–Sonogashira sequence (Scheme 92).

Scheme 92 Sequential halo allylation–Sonogashira coupling [160]

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Scheme 93 Sequential dimerization–cyclization of alkynones [161]

Finally, Ling and coworkers [161] have presented an intriguing Pdcatalyzed dimerization–cyclization sequence of alkynones 222 to furnish 3,3 -bifurans 223 with good to high selectivity with respect to the furans 224 in good yields (Scheme 93).

Scheme 94 Mechanistic rationale of sequential dimerization–cyclization of alkynones [161]

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201

This unusual cyclizing dimerization occurs in THF in the presence of PdCl2 (PPh3 )2 and triethylamine at room temperature. While other Pd catalysts under similar conditions lead to 2,5-disubstituted furans by rearrangement, this distinguishing property of PdCl2 (PPh3 )2 has been attributed to the involvement of hydridopalladium halide. Therefore, the regioselective formation of 3,3 -bifurans 223 can be rationalized as follows (Scheme 94): First the ammonium halide formed in the conversion of PdCl2 (PPh3 )2 into the Pd(0) species undergoes an oxidative addition to give a hydridopalladium halide. This intermediate now inserts the alkynone 222 to furnish a vinyl-Pd species that either isomerizes to a regioisomeric vinyl-Pd intermediate or undergoes a β-hydride elimination to liberate an allenone. The allenone can be cyclized in the presence of Pd(II) complexes to give the furan 224 or it reacts with the regioisomeric vinyl-Pd to furnish an allyl-Pd species that contains all atoms of a formal dimer of the initial alkynone. Upon cyclization, an alkyl-Pd intermediate is generated that eliminates a β-hydrogen to form the ﬁrst furan ring. Finally, the second Pd-catalyzed cyclization releases the 3,3 -bifuran 223 and completes the sequence.

10 Conclusion Palladium-catalyzed reactions have always played a paramount role in the invention of new reactions and methodologies. The most fundamental crosscoupling, vinylation, and allylation processes have reached maturity both in academia and industry, as demonstrated by numerous applications in total syntheses of natural and non-natural products as well as in the ﬁeld of organic materials. However, sequential and consecutive reactions catalyzed within the same reaction vessel without further addition of catalyst have become a new spin-off within the past ten years. The examples shown here in this brief overview are just the beginning of a new chapter in Pd catalysis. Most characteristic for Pd-catalyzed processes is the high degree of functional group tolerance, which bears the seed for yet unexplored new combinations of elementary and still unknown sequentially Pd-catalyzed processes. Furthermore, the option to conduct these peculiar types of cascade reactions either in sequential or consecutive fashion opens the door for both multicomponent and domino reactions to tackle the demanding challenge of diversity-oriented syntheses. Sequentially Pd-catalyzed processes have been serendipitous as well as designed. All this indicates a plethora of opportunities for inventing and discovering new methodologies in the near future.

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Top Organomet Chem (2006) 19: 207–257 DOI 10.1007/3418_008 © Springer-Verlag Berlin Heidelberg 2006 Published online: 12 April 2006

Cascade Reactions Involving Pauson–Khand and Related Processes Javier Pérez-Castells Dpt. Chemistry, Fac. Farmacia, Universidad San Pablo CEU., Boadilla del Monte, 28668 Madrid, Spain [email protected] 1 1.1 1.2 1.3 1.4

Introduction. What is the Pauson–Khand Reaction, Its Origin and an Outline of the General State of the Art Scope and Limitations . . . . . . . . . . . . . . . . . . . . Reaction Pathway and Promotion . . . . . . . . . . . . . Catalytic PKR . . . . . . . . . . . . . . . . . . . . . . . . Asymmetric PKR . . . . . . . . . . . . . . . . . . . . . .

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Cascade Synthesis of Enynes/Pauson–Khand RCM-PKR . . . . . . . . . . . . . . . . . . . Nicholas-PKR . . . . . . . . . . . . . . . . . Allylic Alkylations . . . . . . . . . . . . . . . Aminocarbonylation . . . . . . . . . . . . . Other Pre-PKR Processes . . . . . . . . . . .

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Reactions Occurring after the Pauson–Khand Process . Traceless Tethers . . . . . . . . . . . . . . . . . . . . . . . Reductive PKR . . . . . . . . . . . . . . . . . . . . . . . . Isomerizations and Migration of Double Bonds . . . . . Other Post-PK Reactions (Hydrogenolysis, Oxidation, Michael, Retro-Diels–Alder)

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Abstract The Pauson–Khand [2 + 2 + 1] cycloaddition is one of the best ways to construct a cyclopentenone. It implies the formation of three new bonds and one or two cycles in the intermolecular or intramolecular versions, respectively. Furthermore some groups have enhanced the synthetic power of this transformation by combining the PKR with other processes. In addition, some unexpected results imply that successive events have occurred, usually after the cycloaddition process. This review aims to point out the most recent advances in cascade reactions in which the Pauson–Khand and PK-type

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reactions are involved. The non-specialist reader will have an introduction section to outline the state of the art of this chemistry. This will involve, the reaction mechanism, the most useful reaction conditions, the scope of the inter- and intramolecular PKR and the development of asymmetric and catalytic versions. Keywords Catalysis · Cycloaddition · Cyclopentenones · Pauson–Khand reaction · Transition metal complexes

Abbreviations BINAP 2,2 -Bis(diphenylphosphino)-1,1 -binaphthyl BSA Bis(trimethylsilyl)acetamide BOC tert-Butoxycarbonyl cod Ciclooctadiene dba Dibenzylidenacetone DCM Dichloromethane DME Dimethoxietane DMF N,N-Dimethylformamide dppe Bis(diphenylphosphino)ethane dppp Bis(diphenylphosphino)propane DSAC Dry state adsorption conditions EWG Electronic withdrawing group NMO 4-Methylmorpholine N-oxide PKR Pauson–Khand reaction RCM Ring-closing metathesis SDS Dodecyl sulfate, sodium salt TBS terc-Butyldimethylsilyl TFA Triﬂuoroacetic acid TIPS Triisopropylsilyl TMANO Trimethylamine N-oxide TolilBINAP 2,2 -Bis(di-p-tolylphosphino)-1,1 -binaphthyl TON Turnover number TPPTS Triphenylphosphine-3,3 ,3 -trisulfonic acid trisodium salt

1 Introduction. What is the Pauson–Khand Reaction, Its Origin and an Outline of the General State of the Art The Pauson–Khand reaction (PKR) is among the most powerful transformations in terms of molecular complexity increment [1]. Only a few of other reactions like the Diels–Alder, or the cyclotrimerization of alkynes can compete with the PKR, which consists formally of a [2 + 2 + 1] cycloaddition in which a triple bond, a double bond and carbon monoxide form a cyclopentenone [2–12]. This constitutes one of the best ways to construct cyclopentenones, which upon further transformations can be converted into structures present in numerous natural products (Scheme 1).

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Scheme 1 The PKR: an inter- or intramolecular [2 + 2 + 1] cyclization

Scheme 2 Heterobimetallic complexes mediate the PKR

This reaction was ﬁrst reported in the early 1970s as an unexpected result in search for the synthesis of new organometallic cobalt complexes [13–18]. Dicobalt octacarbonyl was the only cluster used in its beginnings, although now, many cobalt species and other metal complexes are able to mediate or catalyze this reaction. Thus, the stoichiometric reaction has been performed with Zr, Ni, Fe, Ti, W and Mo derivatives. In addition, heterobimetallic Co – W and Co – Mo complexes (1), are suitable precursors for the PKR and impart a high degree of selectivity in the process giving exclusively endo adducts 2 (Scheme 2) [19, 20]. The catalytic version is actually carried out with Co, Ti, Ru, Ir, and Rh complexes being the latter the more promising ones in terms of scope and efﬁciency [21]. 1.1 Scope and Limitations PKRs can be performed inter- or intramolecularly. The latter reactions, although developed later, avoid regioselective problems and work with more types of double bonds. The ﬁrst intramolecular PKR was reported by Schore and allows the formation of 5,5- and 5,6-fused bicycles, and more recently even some 5,7-bicycles. In general, good conversions are achieved only with gem-disubstituted enynes (Scheme 3) [22–24]. With the exception of propynoic acid derivatives, all alkynes undergo the reaction. On the other hand, generally, only strained oleﬁns react efﬁciently in the intermolecular PKR whereas electron deﬁcient alkenes give the reaction only in limited examples. With respect to regioselectivity, the bulkier substituent of the alkyne is placed adjacent to the carbonyl in the cyclopentenone product. Unsymmetrical oleﬁns usually give mixtures of regioisomers

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Scheme 3 The scope of the intramolecular PKR with regard to ring size

(Scheme 4) [25]. Substitution at the double bond is restricted as disubstituted oleﬁns usually fail to react. The idea that alkenes possessing electron-withdrawing groups are not adequate substrates for Pauson–Khand reactions has in recent years turned out not to be precise. Carretero has reported several examples involving electrondeﬁcient alkenes 3), such as α,β-unsaturated ketones, esters, nitriles, sulfoxides and sulfones. In these reactions they reach good yields of PK products (4) and isolate small amounts of dienes 5, that come from a β-elimination competitive reaction (Scheme 5) [26, 27]. In terms of functional group compatibility, ethers, alcohols, tertiary amines, acetals, esters, amides and heterocycles are compatible with the Pauson–Khand reaction. In the intramolecular version, relatively few carbon skeletons undergo the cyclization. Most intramolecular PKRs use systems derived from hept-1-en-6-yne (6) or propargyl allyl ethers (7) or amines (8). Other interesting and more recent substrates are enynes connected through aromatic rings like 9–11, which have allowed us and other groups to obtain aromatic polycycles (Fig. 1) [28–31].

Scheme 4 Regioselectivity in the intermolecular PKR

Scheme 5 PKR with electron deﬁcient alkenes

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Fig. 1 Some aliphatic and aromatic substrates used for intermolecular PKR

In addition, allenes can act as the oleﬁnic part of the reaction [32]. Allenynes like 12 may react with both double bonds. Brummond established the substitution patterns for the reaction with either the external or the internal bond of the allenic fragment, that give products with different ring sizes (13– 14) [33]. This group has applied these studies to the synthesis of hydroxymethylfulvalene (17), a potent anticancer agent related with illudines, a natural sesquiterpene family. The key step was the synthesis of 16 from 15 with a PKR mediated by molybdenum carbonyl (Scheme 6) [34, 35]. In addition they have developed an asymmetric version of the reaction. They have transferred efﬁciently chirality from a non-racemic allene to an α-alkylidene and an α-silylidene cyclopentenone in a molybdenum mediated reaction [36–38]. The synthesis of medium-sized rings is very interesting and has been an important limitation for the intramolecular PKR. It is only possible if certain

Scheme 6 The allenic PKR: a Study on the substitution patterns that make either double bond react; b Application in synthesis of an illudine derivative

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structural features allow the increase in the population of the reactive conformation. This has happened with several aromatic substrates [28–31, 39]. On the other hand, the intramolecular allenic PKR has allowed the efﬁcient synthesis of seven membered rings. Mukai has synthesized bicyclo[5.3.0]decenones (19) from allenynes 18, using several rhodium catalysts. The process tolerates hydroxy and silyloxy groups and generally reaches good yields (Scheme 7) [40, 41]. Exocyclic oleﬁn fragments are among the few disubstituted double bonds that react efﬁciently in PKRs. Several examples have appeared in the literature and include methylenecyclohexanes (20), methylenecyclopropanes (21) and methylenepyranes (22) [42, 43]. Cyclopropyl tethered methylenecyclopropanes can give the expected PK products or rearranged hydroindenones in which neither of the two carbon atoms of the alkyne form part of the cyclopentenone ring in the ﬁnal product [42]. Other substrates like enamines (23) and ynamines (24) undergo readily this reaction (Fig. 2) [44–47].

Scheme 7 The allenic PKR allows the synthesis of medium sized rings

Fig. 2 Some recently introduced substrates: Exocyclic alkenes, ynamides and enamines

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1.2 Reaction Pathway and Promotion Mechanistically, the pathway proposed by Magnus is generally accepted as it explains most experimental results (Scheme 8) [48, 49]. The main problem with the demonstration of this mechanism is that beyond the cobalthexacarbonylalkyne complex (A), it is difﬁcult to detect further intermediates. Starting from the initial complex A, the ﬁrst step would be the loss of one CO in a dissociative manner. This step, which is strongly endothermic, is the rate-determining step and, consequently, acceleration of the process usually involves the use of promoters that act at this point, labilizing one of the CO ligands [50]. Pericàs has isolated sulfur-ligated decarbonylated type B intermediates that support the dissociative mechanism [51]. Then, the oleﬁn coordinates with the cobalt (C) and is inserted into a Co – C bond forming cobaltacycle E which recovers one CO to give F. This is the other important stage in the reaction course as it determines its stereochemical outcome. DFT calculations show the importance of facilitating CO dissociation but point out that the energy of the second step is also important and this is the reason why strained oleﬁns react so well [51]. In this second step, the strain of cyclic oleﬁns is liberated, favoring the process [52]. Several other theoretical stud-

Scheme 8 The commonly accepted reaction pathway for the PKR of acetylene and ethylene. Energy proﬁle for the important stages of the mechanism

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ies support this mechanism while it explains the regio- and stereochemical results of numerous examples. Thus, Nakamura [53] and Milet and Gimbert [54] have performed high-level theoretical calculations on the cobaltacycle formation step, showing that the insertion of the oleﬁn is the critical stereo- and regiochemical-determining step of the PKR. Continuing with the reaction pathway, from complex F, insertion of CO follows giving G, and a subsequent complex reorganization forms H. Finally a reductive elimination leads to the cyclopentenone I. Several reports show different ways to accelerate the reaction. These are important for the aims of this chapter as sometimes they lead to unexpected results that involve cascade reactions occurring after the PKR. For instance, the ﬁrst important ﬁnding on the promotion of the PKR was by Smit and Caple, who effected the reaction with the reagents adsorbed in several solid supports (Dry State Adsorption Conditions, DSAC) observing reduced products and other unexpected results in many cases (vide infra) [55]. Actually, promotion of the PKR usually involves the use of chemical additives. Amine N-oxides [56, 57] act oxidizing one CO ligand, which is transformed into CO2 , thus forming a vacant in the cobalt cluster. Other possibilities include addition of sulﬁdes and sulfoxides [58] or cyclohexylamine [59, 60]. These additives probably act helping the displacement of a CO ligand and stabilizing reaction intermediates. We have shown the positive effect of molecular sieves in both the catalytic and the stoichiometric version of the reaction. These zeolites probably retain CO molecules, increasing conversions even with non favorable substrates, such as substituted oleﬁns [61, 62]. Other ways of labilizing CO ligands consist of irradiating the complex with ultraviolet light [63], ultrasounds [64] or microwaves [65, 66]. The latter conditions seem to shorten reaction times remarkably, though results are not spectacular with respect to conversions. 1.3 Catalytic PKR With the focus on green chemistry, it is actually impossible to think on an industrial chemical reaction, which involves transition metal complexes, that is not efﬁciently catalytic. The chemical industry demands atom economical reactions, that is, those in which substrates are transformed into products with the only aid of catalytic amounts of the rest of reactants. Although really catalytic PKR appeared only in the mid-1990s, developments from recent years allow us to be moderately enthusiastic. The literature gives a good deal of catalytic protocols that use different cobalt and other metal complexes. Still, a lack of scope is generally observed in these reports. In addition there are few examples of intermolecular reactions performed in catalytic conditions [21]. The ﬁrst important advances in the development of a catalytic PKR were by the groups of Livinghouse [67, 68] and Krafft [69, 70] who reported reaction

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conditions using only 1 atmosphere of CO. Soon afterwards other groups observed that addition of certain ligands enhanced the efﬁciency of the process. Thus, the addition of phosphines and phosphites may avoid the formation of inactive cobalt species, stabilizing intermediate active clusters [71, 72]. When adding chiral phosphines such as BINAP to the reaction of 25, 26 was formed with good enantiomeric excesses and moderate chemical yields. Substitution patterns in the skeleton of the substrate affect dramatically the stereochemical outcome of the reaction and, in general, they need high catalyst loadings (Scheme 9) [73, 74]. Chiral phosphites, used by Buchwald, reached good ee values only in certain substrates [75]. Modiﬁed carbonylcobalt complexes can catalyze the PKR. One or more CO can be substituted by phosphines, and these can be immobilized in resins thus giving anchored cobalt complexes (27), that were able to catalyze the reaction of 28 giving 29 with good yield and minor amounts of 30 (Scheme 10) [76]. Other cobalt metal clusters like Co4 (CO)12 [77] or methylidynetricobalt nonacarbonyl [78] have exhibited high reactivity in the catalytic PKR. With regard to PK-type reactions, Buchwald studied titanium species as efﬁcient catalysts in the PKR and in PK-like reactions with cyanides. Following preliminary results with [Cp2 Ti(PMe3 )2 ] and [Cp2 TiCl2 ] [79–81], they reported a more practical procedure which improved the TON using commercial titanocene dicarbonyl (33) [82, 83]. This complex is able to catalyze the

Scheme 9 Formation of chiral catalysts in situ by addition of chiral phosphines

Scheme 10 PKR with anchored cobalt complex catalysis

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reaction of different 1,6 and 1,7-enynes (31) with excellent functional group tolerance and under low CO pressure, but fails to react with sterically hindered oleﬁns and alkynes. In an enantioselective version of this methodology, Buchwald has used chiral titanocenes like 34 to effect the PKR. These catalysts have reached good chemical yields of 32 with moderate enantiomeric excesses (72–96%) [84–86]. This group has prepared recently a series of aryloxide complexes (35) that are able to promote cyclisations with some sterically hindered enynes (Scheme 11) [87]. A couple of reports used [Ru3 (CO)12 ] as catalyst. Both studies, by Murai [88] and Mitsudo [89], used enynes bearing disubstituted alkynes and needed severe reaction conditions with high CO pressures. Rhodium complexes are effective catalysts for the PKR and are receiving much attention. In addition to the studies by Narasaka with [RhCl (CO)2 ]2 [90], Jeong has introduced several species as new catalysts. Some of these rhodium complexes need activation with AgOTf. The reaction works well with non-terminal alkynes (36) and the scope and efﬁciency is dependent on the catalyst used. In the case of chiral species, a careful choice of conditions, including CO pressure, activation, solvent and ligands, is essential to obtain 37 with high enantioselectivity (Scheme 12) [91].

Scheme 11 Titanocene derivatives as catalysts in PK-type reactions

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Scheme 12 The use of several rhodium complexes for [2 + 2 + 1] cyclizations. The role of AgOTf activation

Although ﬁrst results with iridium complexes were disappointing in terms of conversions with typical substrates, when adding phosphanes yields improved. This observation prompted Shibata to use chiral phosphanes like S-tolylBINAP, reaching high chemical yields and enantioselectivities. Impressively, the ﬁrst example of an asymmetric intermolecular PKR was reported using these conditions. The reaction was not totally regioselective, reaching a mixture of 38 and 39, but ee was 93% (Scheme 13) [92].

Scheme 13 The best (and almost unique) example of an asymmetric catalytic intermolecular PK-type reaction

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1.4 Asymmetric PKR There are several possibilities to induce asymmetry in the PKR, which are summarized in Fig. 3. These are: (1) The chiral substrate approach. This approach involves using chiral precursors that transfer their chirality to the ﬁnal cyclopentenone. This implies the synthesis of chiral substrates, which has generally been made from classic chiral pools. Examples include carbohydrate derivatives like 40 that give 41 with variable yields depending on the substitution pattern. 41 is transformed into cyclopenta[c]pyrane 42, which is the skeleton of iridoids [93]. In another example epichlorhydrin (43) is used to construct chiral enyne 44 which gives cyclopentenone 45 [94] (Scheme 14).

Fig. 3 Inducing asymmetry in the PKR. A wide variety of possibilities

Scheme 14 Two examples of the chiral substrate approach: a carbohydrates as starting materials for the construction of chiral enynes; b epichlorhydrin as source of chirality in assymetric PKRs

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(2) The chiral auxiliary approach. Pericàs’ group has worked with chiral sulfur moieties like 10-methylthioisoborneol, Oppolzer’s camphorsultam or chiral oxazolidinones which gave excellent results in stereocontrol and yields [95–100]. Recently they have reported that chiral alkynylthiols like 46 exhibit excellent diastereoselectivities in both inter- and intramolecular PKR, and have used this approach for the synthesis of 47, an intermediate in the synthesis of (+)-15-nor-pentelenene (48) (Scheme 15) [101, 102]. Carretero used chiral sulfoxides attached at the oleﬁn that are efﬁcient auxiliaries due to the proximity of the chiral sulfur to the reaction centre. Reductive cleavage of the sulfoxide is carried out by treatment with activated zinc [103, 104]. (3) The chiral metal complex approach. We have shown in the previous section several methodologies included in this approach. They go from the addition of chiral ligands to metal species that form in situ chiral aggregates, to the synthesis of complexes including chiral ligands or non-symmetrical heterobimetallic clusters. As an example, Pericàs has recently obtained different chiral complexes (50) using bidentate (P,N) and (P,S) ligands. The most effective result was achieved using a ligand called PuPHOS, which is readily obtained from natural product (+)-pulegone (49). The reaction of these complexes with norbornadiene gave 51 with high yields and ees (Scheme 16) [105].

Scheme 15 Synthesis of (+)-15-nor-pentelenene with a PKR of an enyne bearing a chiral auxiliar

Scheme 16 An example of synthesis and application of chiral metal clusters in assymetric PKRs

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(4) The chiral promoter approach. Chiral promoters, generally natural alkaloid N-oxides, might be able to make a selective decarbonylation of one carbonyl of the cobalt cluster. Nevertheless they gave poor results in terms of ee in all the reports appeared to date [106–109]. We have seen in this ﬁrst section the state of the art in the PKR. In following sections this chapter will deal with those single synthetic steps in which multiple reactions are combined, being one of them a PKR or a PK-type reaction. This will include those processes named domino or cascade reactions in which a substrate suffers at least two transformations in a single step, and also sequential reactions in which additional reagents or changes in the reaction conditions are involved during the process but without isolation or puriﬁcation of the intermediates (what is usually called a one pot procedure). Some of the transformations will be stoichiometrically mediated by one or several metal complexes, others will constitute concurrent tandem catalyzed reactions, that is, reactions that involve two or more catalytic cycles in which the same or different catalysts perform successive transformations. In general the reactions that are added to the PK transformation may occur before the cycloaddition, generally implying the formation of the enyne, or the formation of CO from a decarbonylation reaction, or after the PKR involving a myriad of simple transformations such as reductions, double bond shifts or cleavage of carbon–heteroatom bonds (Fig. 4).

Fig. 4 Summary of main pre- and post-PKR processes

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2 Cascade Synthesis of Enynes/Pauson–Khand Reaction The synthesis of enynes is not always trivial. Some synthetic reactions have functional group compatibility problems, others give poor yields due to instability of the products. Transition metals can be useful in reactions that give enynes which can suffer subsequent PKRs. 2.1 RCM-PKR Our group has used a combined metathesis-PKR for the synthesis of tricyclic compounds in one step. The process starts from pure cobalt complexed dienynes 52. The cobalt cluster acts ﬁrst as a protecting group to avoid undesired enyne metathesis processes. The methodology allows the formation of tricyclic [6.5.5] (53) and [7.5.5] (54) structures including, in some examples, oxygen or nitrogen. Tricycles 53 are obtained in a total stereoselective manner, while compounds 54 are formed as mixtures of two diastereomers (Scheme 17) [110]. In a complementary contribution to this chemistry, Young assembled a [9.5.5] system by sequential metathesis reaction on a diene linked by a cobalt hexacarbonyl complexed alkyne followed by domino Nicholas-PKR which we will comment later [111].

Scheme 17 Tandem RCM-PKR for the synthesis of tricyclic compounds in one step

2.2 Nicholas-PKR Complexation of an alkyne to dicobalthexacarbonyl is a well-known way to stabilize carbocationic charges generated in the carbon α to the alkyne. These carbocations react with different nucleophiles. This process, the Nicholas reaction [112], has been used to generate enynes that undergo, in a domino fashion, a PKR.

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In a very early example, Smit and Caple generated the stabilized cation from a conjugated enyne (55) by electrophilic attack followed by incorporation of a nucleophile to give 56. When they used allyl alcohol as nucleophile they generated an enyne that underwent a PK cyclization giving tricyclic spirocompounds 57 (Scheme 18) [55]. The complementary approach using an unsaturated electrophile did not work as it implied the reaction of an electron deﬁcient double bond. In this case they transformed the ketone into an alcohol by reaction with a Grignard reagent and performed the PKR independently. Some years later the same group succeeded in performing their second approach, that is the PKR of a 1,6-enyne-3-one, prepared via a Nicholas reaction. In that case they used cyclic conjugated enynes which were reacted with an alkanoyl tetraﬂuorborate to give enynes like 58 which, under DSAC conditions, gave the corresponding PK products. Scheme 19 shows two interesting

Scheme 18 Spirocompound synthesis in a one pot procedure using a Nicholas-PKR sequence

Scheme 19 The ﬁrst published PKR of an unsaturated ketone. A combination of several pre- and post-PKR in one synthetic step

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examples of this chemistry. The ﬁrst leads to tetracyclic product 59 and includes a post-PKR elimination of methanol. In the second case the complexed enyne 61 is obtained in situ by means of a HCl elimination in 60 previous to the PKR. The authors expected the formation of the enyne 61, when they found that it was directly transformed into the cyclization products 63 and 64 in the reaction conditions. Thus, after formation of 62, a methanol elimination followed and, in the case of 64, further addition of water to the emerging double bond occurred. A small amount of reduced product 65 was also isolated. This was the ﬁrst example in which a conjugated ketone underwent the PKR [113, 114]. Another one pot Nicholas-PKR strategy was reported by Jeong using amidic nitrogen nucleophiles in the Nicholas step. Thus, a series of tosyl and CBz amides (67) were effectively propargylated using cobalt complexed propargylic alcohols 66 as precursors of the corresponding cations. The Nicholas process was quenched with triethylamine giving 68, and upon addition of a promoter (generally TMANO), PKR followed giving bicyclic enones 69 with moderate to good yields (Scheme 20) [115]. Later on, Schreiber used consecutively these two reactions in the key step for the synthesis of diterpene (+)-epoxydictimene (73), starting from natural (R)-pulegone [116, 117]. This approach was built on their preliminary studies on Lewis acid mediated intermolecular Nicholas reactions [118]. They prepared functionalized enyne 70 bearing a mixed acetal. This compound was transformed into its dicobalt-hexacarbonyl complex and, in the presence of a carefully selected Lewis acid, it formed a stabilized carbocation by release of the more accessible ethyl moiety. This cation reacted intramolecularly with the allylsilane giving the central eight membered ring of the natural product

Scheme 20 Nicholas-PKR for the synthesis of propargyl allyltosylamides and subsequent cyclization

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with the desired conﬁguration at C10 (71). This intermediate is transformed without puriﬁcation into the PK product 72. The conditions that gave better results in terms of yield and diastereoselection at C12 were NMO promotion in dichloromethane (Scheme 21). As commented above, Young has reported one example of a Nicholas/PKR starting from cobalt complex 74, prepared by means of a RCM reaction [111]. The reaction of 74 with allyl alcohol in the presence of BF3 Et2 O gave enyne 75 which cyclized with t-BuSMe promotion to give tricycle 76 (Scheme 22). The stabilization of positive charges adjacent to a cobalt hexacarbonyl complex is the base of a rearrangement of an enol ether complex described by Harrity [119]. They used enolether 77 with a pending alkene, which, when treated with dibutylboron triﬂate, gave cis-complexed enyne 78. The selection of the Lewis acid was essential to avoid an undesired ene/Prins side reaction that formed 79. Complex 78 gave the corresponding PK product 80 under several reaction conditions. Isomeric mixtures of diene 81 were found also in the reaction mixtures. This by-product appears frequently in PKRs and comes from the β-elimination of the metallacyclic intermediate. Best results were achieved using Kerr’s polymer supported sulﬁde resin (Scheme 23) [120].

Scheme 21 Synthesis of natural sesquiterpene (+)-epoxidictimene using a tandem Nicholas-PKR as the key step

Scheme 22 Cyclic alkynes in the PKR. Tandem Nicholas-PKR for a tricycle construction

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Scheme 23 Tandem rearrangement and PKR for the synthesis of polycycles

The most recent contribution in this area is by Shea who prepared tricyclic oxygen containing heterocycles from acyclic enynes 82 using a combination of intramolecular Nicholas and PKRs. They constructed [5.7.5] and [5.8.5] (83–84) systems involving the formation of a complexed cyclic alkyne. They used several PKR conditions that give different yields and diastereoselectivities. Due to the strain of the intermediate, [5.6.5] systems (85) were obtained in poor yields (Scheme 24) [121].

Scheme 24 Tandem intramolecular Nicholas-PKR for the synthesis of tricycles

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Complexation of propargyl aldehydes to cobalt also enhances the reactivity and enantioselectivity of the addition of alkylzinc reagents. This fact was used to create non-racemic enyne-ol 88 reacting the aldehyde 86 with bishomoallylzinc in the presence of a chiral bis-(sulfonamide) and Ti(Oi Pr)4 . The resulting complexed substrate 87 underwent the PKR promoted by TMANO in a one pot fashion (Scheme 25) [122]. In connection with this, an unusual isomerization of the propargyl chiral centre in 89 was observed during a PKR in which 90 was obtained as an only isomer. This result shows the transition formation of positive charges at the propargylic position during the cycloaddition (Scheme 26) [123]. Finally, a Nicholas-type reaction is presumably responsible for an unexpected result reported by Alcaide. During their work devoted to the application of the PKR in the ﬁeld of β-lactams and azetidines they reacted complexed azetidine 91 with TMANO, isolating a mixture of the expected PK product 92 and by-product 93. The formation of 93 is believed to be a consequence of the ionization of the propargylic C – N bond at the cobaltacycle step. The crowded metallacycle formed after the insertion of the oleﬁn (93), would prompt the cleavage of the C – N bond, forming an ionic species (94) that would trap a hydride, possibly from a cobalt hydride giving 95, which then would follow the usual pathway towards the cyclopentenone (Scheme 27) [124].

Scheme 25 One pot asymmetric addition of dialkyl zinc to a cobalt complexed propargyl aldehyde followed by PKR

Scheme 26 Epimerization at the propargylic position during a PKR

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Scheme 27 Unexpected formation of azepine in the PKR of azetidines. Mechanistic hypothesis

2.3 Allylic Alkylations An excellent example of concurrent tandem catalysis involving PK-type reactions is that in which different catalysts perform successively the synthesis of an enyne by means of an allylic alkylation followed by the PKR. Jeong used a combination of [Pd2 (dba)3 (CHCl3 )] with [RhCl(CO)(dppp)]2 to convert derivatives 96 and an allylacetate into the cyclopentenone 98 [125]. It was necessary to perform a detailed investigation of Pd and Rh catalyst precursors, ligands and reaction conditions as the PK step was in principle problematic, and interferences between catalysts had to be avoided. The ratio of the Rh(I)/Pd catalyst was optimized by 2–3 to 1 in order to avoid undesired reactions, reaching high yields of the ﬁnal product. The formation of the intermediate enyne 97 was detected following the reaction by gas chromatography. The reaction is highly dependent on the substrate and while malonyl derivatives and amides reacted smoothly, propargyl alcohols did not react (Scheme 28).

Scheme 28 Tandem action of different catalysts in allylic alkylation-PKR

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Evans used a single catalyst for an allylation-PKR sequence that only required changing the reaction temperature for each step. Thus, they synthesized cyclopentenone 101 from allylic acetate 99 and diethyl propargylmalonate salt in the presence of [RhClCO(dppp)]2 with high yield. When formation of intermediate 100 was complete they just heated the reaction to 80 ◦ C to get 101 (Scheme 29) [126]. Several non-carbonyl cobalt sources used recently show high efﬁciency in the catalysis of the PKR. Chung has reported different reusable catalysts like cobalt supported on mesoporous silica or on charcoal that work under high CO pressures [127]. Most recently they have described milder conditions with the use of colloidal cobalt nanoparticles, which react at lower CO pressures and can be used in aqueous media [128]. The combination of cobalt with other metals like Pd increases the synthetic utility of this methodology. Thus, a concurrent tandem catalysis reaction of 102 and 103 using ﬁrst an homogeneous chiral palladium complex, followed by the action of heterogeneous cobalt/C led to high enantioselective synthesis of PK products 104 (Scheme 30) [129]. More recently this group has prepared a combination of palladium and cobalt nanoparticles immobilized on silica (PCNS) to form bicyclic enones after domino allylic alkylation-PKR [130].

Scheme 29 Tandem rhodium catalyzed allylic alkylation-PKR

Scheme 30 Tandem action of chiral Pd(II) and Co/C catalyst for the asymmetric synthesis of cyclopentenones from propargyl malonate and allylic acetates

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A spectacular application allowed the synthesis of fenestranes by a threestep sequential action of cobalt nanoparticles and a palladium catalyst [131]. The cascade reaction started with a PKR of enyne 105, accomplished by the cobalt catalyst giving 106, followed by the formation of allyl-π 3 palladium complex 107 which reacted with a nucleophile derived from diethyl malonate, to give enyne 108. The ﬁnal step was a second PKR that gave 109 in good yield. They used cobalt nanoparticles as with Co/charcoal the third step did not take place, apparently due to damage in this catalyst after the allylation step (Scheme 31).

Scheme 31 Three-step one pot synthesis of fenestranes from an enyne and an alkyne

2.4 Aminocarbonylation Pericàs group reported an interesting case of a tandem process in which dicobalt hexacarbonyl complexes of haloacetylenes suffered an aminocarbonylation followed by a PKR. They reacted de dicobalt hexacarbonyl complex of 1-chloro-2-phenylacetylene (110) and observed its decomposition into two new species. One of them was apparently a dichloro tetracobalt decacarbonyl complex of 1,4-diphenyl-1,3-butadiyne (111) while the other was assigned to acyl cobalt complex 112 that was able to cyclize with norbornadiene to give 113. On the other hand 112 was trapped with different amines and the resulting complexes (114) were submitted to PKR with norbornadiene. When they used chiral amines, they obtained non-racemic compounds 115 with high yields, whereas when using allylic amines, the corresponding intramolecular PKR afforded bicyclic amides 116 with moderate to good yields (Scheme 32) [132].

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Scheme 32 Tandem aminocarbonylation/PKR of haloacetylenes

2.5 Other Pre-PKR Processes Some double-bond shifts and isomerizations have been observed previous to the PKR. Sometimes 1,6 enynes have reacted partially as 1,7 enynes, or 1,8-enynes have isomerized to 1,7-enynes prior to the PKR [59, 60, 133]. In some intermolecular examples strained alkenes have isomerized totally before the cyclization giving unexpected products. An example, in the synthesis of triquinanes like 120, depicted in Scheme 33, the starting alkene 118 was isomerized to 119 prior to the reaction with 117 [134, 135].

Scheme 33 A pre-PK double bond shift. Synthesis of triquinanes

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Other reactions that may occur before the PK are hydrogenolysis, reductions of the alkyne complex and, when using dienes as the alkene part, a Diels–Alder reaction. When hydrogenolysis is observed in enynamides or enynethers, the resulting products usually do not cyclize, so no PK products are obtained [136]. One interesting case of previous reduction of a cobalthexacarbonyl complex, shown in Scheme 34, implied that in the presence of TFA, part of complex 121 was reduced to alkene 122 which reacted further with other complex molecules to give the PK product 123 [137]. The dienyl PK-type catalytic reaction, introduced recently by Wender’s group, is an interesting variant as it allows low rhodium catalyst loadings and mild conditions both in the intramolecular [138] and the intermolecular version [139]. These authors have optimized the reaction conditions to avoid competitive [4 + 2] cycloadditions that occurred in their preliminary studies. In an early example Pauson described a cascade Diels–Alder-PKR with 1,3-cyclohexadiene and the dicobalt hexacarbonylcomplex of phenylacetylene. The cobalt complex has to be active in the [4 + 2] reaction as this diene does not give Diels–Alder products in similar conditions with usual dienophiles. The resulting adduct 124 undergoes the PKR giving 125–126 mixtures in moderate yield (Scheme 35) [140].

Scheme 34 Partial reduction of the alkyne-cobalt hexacarbonyl complexes under PK conditions in the presence of TFA

Scheme 35 A Diels–Alder-PKR cascade

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3 Previous Decarbonylations as a Source of CO The major drawback in the development of efﬁcient catalytic PK protocols is the use of carbon monoxide. Many groups probably refuse to use this reaction in their synthetic plans in order to avoid the manipulation of such a highly toxic gas. Carbonylation reactions without the use of carbon monoxide would make them more desirable and would lead to further advances in those areas. Once the use of rhodium complexes was introduced in catalytic PKR, two independent groups realized these species were known for effecting decarbonylation reactions in aldehydes, which is a way to synthesize metal carbonyls. Thus, aldehydes could be used as a source of CO for the PKR. This elegant approach begins with decarbonylation of an aldehyde and transfer of the CO to the enyne catalyzed by rhodium, ruthenium or iridium complexes under argon atmosphere (Scheme 36). Morimoto studied several aldehydes and concluded that the best conditions were using two eqs of C6 F5 CHO in xylene, in the presence of [RhCl(cod)]2 (5%) and dppp (11%) at 130 ◦ C under N2 . The conversion of 127 into 128 was high yielding. [IrCl(cod)]2 and Ru3 (CO)12 were able to transfer CO from the aldehyde although in lower efﬁciency (Scheme 37) [141].

Scheme 36 The two catalytic cycles in the decarbonylation-PKR methodology

Scheme 37 PKR with aldehydes as a CO source

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In two recent communications this group has used formaldehyde as the CO source in aqueous media and has introduced chiral ligands in the rhodium complex reaching high yields and enantioselectivities. A hydrophilic phosphine (TPPTS) and a surfactant (SDS) are also added to enable the reaction (Scheme 38) [142, 143]. Shibata reported soon afterwards a solvent-free reaction in which the transferring aldehyde was cinnamaldehyde and the catalyst [Rh(dppp)2 Cl]2 . The authors show there is no free CO in the reaction medium that is used to form the PK product, as they perform reactions of 129 in 13 CO atmosphere observing very little incorporation of 13 C in the ﬁnal product (130 : 131 = 7 : 1). The enantiomeric excess reached when using a chiral ligand is higher with this methodology than when using CO atmosphere in the absence of the aldehyde (Scheme 39) [144, 145]. Following their works on immobilized heterobimetallic nanoparticle catalysts, Chung’s group has synthesized Ru/Co nanoparticles immobilized in charcoal and shown the ability of this system to catalyze a PKR-type reaction in the presence of pyridylmethyl formiate as a CO source. They used these conditions with intra- and intermolecular reactions and showed that the catalyst can be reused without loss of catalytic activity (Scheme 40) [146]. In addition, the same authors showed that α,β-unsaturated aldehydes 132 could act both as CO and alkene source and give the PK products 134 upon reaction with different alkynes (133) (Scheme 41). As part of their study, they performed a cross reaction of cinnamaldehyde and a substituted styrene with phenylacetylene, isolating two PK products coming from both alkenes. This is a proof for a decarbonylative-[2 + 2 + 1] reaction pathway [147].

Scheme 38 Aqueous asymmetric PKR with formaldehyde as CO source

Scheme 39 Cinnamaldehyde as a CO source. Studies on the CO transference from the aldehyde to the cyclopentenone

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Scheme 40 Ru/Co nanoparticles as catalysts for the PKR in the presence of pyridylmethyl formiate

Scheme 41 An oleﬁnic aldehyde as an oleﬁn and CO source

4 Tandem Carbocyclizations Involving [2 + 2 + 1] Reactions Several groups have developed the combination two or more PKR or PK-type reactions in the same reaction step. The multiplication of the synthetic power of this transformation has found immediate application for the synthesis of natural [5.5.5.5] systems called fenestranes. Starting materials have been enediynes that give two [2 + 2 + 1] cycloadditions. The extension of the reaction to triynes has led to interesting tandem processes that may include [2 + 2 + 2] cyclizations. Other cycloadditions like the Diels–Alder have also been combined with the PK. 4.1 Tandem PKRs Keese envisioned the use of a tandem PKR for the synthesis of fenestranes. The second cycloaddition was in principle problematic as it involved an alkene conjugated with a ketone. They were surprised when they observed the direct formation of the tetracyclic unit 136 from the endiyne 135 although with low yield [148]. Further studies from this group led to a mechanistic proposal that explained this result. It was clear from the fact that compound 140 failed to react, that the second PKR had to start from an intermediate metallacycle rather than from the uncomplexed ﬁnal cyclopentenone. Thus, cobalt complex 137 would lead to 138 were both metal clusters would interact giving intermediate 139 which would evolve in the usual way to the ﬁnal product (Scheme 42) [149]. These systems have been obtained later by Chung’s group using cobalt nanoparticles as commented above (Sect. 2.4) [131].

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Scheme 42 Direct synthesis of [5.5.5.5]fenestrenedione via tandem PKR

Cook has developed in recent years a tandem PKR towards the synthesis of pentalenes, that is, linear [5.5.5.5] systems. Their ﬁrst studies used suitable diendiynes 141–143 that gave the corresponding tetracyclic biscyclopentenones. These were described as precursors of dicyclopenta[a, d] (144) and [a, e]pentalenes (145). The same methodology allowed the synthesis of [5.6.6.5] systems (146) where the central decaline system was cis fused (Scheme 43) [150–152]. This group succeeded in tuning up efﬁcient photochemical catalytic conditions for these reactions [153]. As depicted in Scheme 44 some further transformations of the tetracycles such as 148 have allowed the synthesis of tryciclic cyclooctenes (149), present in many sesquiterpenes. For these recent studies they have used catalytic conditions for the PKR of diendiyne 147 mediated by Rh, Ir or Co complexes [154]. Impressive examples of allenic tandem-PKR depicted in Scheme 45 are the last contribution from this group. Dicyclopenta[a, e]pentalenes 152 were obtained from intermediates 151 which were synthesized using a molybdenum hexacarbonyl mediated tandem reaction of diallenediynes 150 as the key step [155–157]. An interesting unexpected product (153) was obtained in some reaction conditions, which included a four-membered ring. The authors showed this ring was not formed by the action of Mo(CO)6 as they observed the formation of cyclobutane 154 by heating the starting allene in the ab-

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Scheme 43 Tandem PKR for the construction of tetracycles

Scheme 44 Tandem PKR in the synthesis of dicyclopenta[a,d]cyclooctenes

sence of catalyst. They concluded that an unusual [2 + 2] thermal cyclization had occurred, which was possible due to the rigid geometry of the starting material. Twofold inter- and intramolecular PKRs have found interesting applications in synthesis of ansa-zirconocenes. An early example illustrated the use of this approach for the synthesis of cyclopentadiene anellated[2,2]paracyclophanes 157–158. The reaction of several paracyclophanedienes (155) with alkynes gave the corresponding twofold cycloaddition products 156, which were transformed into cyclopentadienyl anions orthogonally attached to the bridges of the paracyclophane (Scheme 46) [158].

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Scheme 45 The synthesis of a dicyclopenta[a,e]pentalene via molybdenum-mediated tandem allenic PKR

Scheme 46 Twofold intermolecular PKR for the synthesis of cyclopentadiene anellated [2.2]paracyclophanes

On the other hand, most studies on twofold PKRs deal with the use of acyclic and cyclic diynes for the synthesis of phenyl or alkyl bridged ansazirconocenes such as 161. Scheme 47 shows an example of the reaction of a diendiyne (159) that gives a twofold PKR, forming compound 160 [159, 160]. Gleiter has studied the reaction of diynes with alkenes as an intermediate step in the synthesis of ansa-metallocenes 164. They have reacted acyclic diynes with ethylene [161] and cyclic diynes 162 in supercritical ethylene [162] giving tricyclic diketones 163 in low to moderate yields. The presence of coordinating heteroatoms in the link increased the reaction yields (Scheme 48) [163].

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Scheme 47 Double PKR for the synthesis of bis-cyclopentadienes

Scheme 48 Twofold PKR of cyclic diynes in supercritical ethylene

Scheme 49 Catalytic double PKR followed by a retro-Diels–Alder reaction for the synthesis of ansa-zirconocenes

Lee and Chung reported a different approach that avoided using ethylene for the synthesis of the same type of alkyl bridged ansa-zirconocenes 168. They reacted diyne 165 with norbornadiene giving a tricyclic compound which was functionalized with Me2 CuLi to yield 166. When 166 was heated in a quartz tube at 420 ◦ C, 167 was formed by means of a retro-Diels–Alder reaction followed by double bond isomerization (Scheme 49) [164]. 4.2 Tandem Cycloadditions of Di- and Triynes Cobalt catalyzed double [2 + 2 + 1] cycloaddition reactions of branched triynes 169 have led to novel [5.5.5.6] tetracyclic dienone systems 172, instead of the expected [5.5.5.5] systems 173. These substrates underwent ﬁrst

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a [2 + 2 + 1] cycloaddition of two triple bonds which the authors claim to go through cobaltacycle intermediate 170. This reaction gives cyclopentadienone 171. Due to the steric effect of the TIPS, the subsequent PKR occurred between the unsubstituted double bond an the alkyne in the pending chain, giving the ﬁnal polycycles (Scheme 50) [165]. In previous works this group had observed a competition between the PKR and a [2 + 2 + 2] cyclization in the second reaction step of three triple bonds. Thus, when reacting linear triynes 174 under catalytic, high CO pressure, cobalt mediated PKR conditions, they obtained mixtures of products 175 coming from two [2 + 2 + 1] cycloadditions, and 176 from a [2 + 2 + 1]/ [2 + 2 + 2] tandem reaction. When the triple bonds were ether linked, the latter was the favored reaction, while with substrates lacking oxygen atoms, the iterative PKRs was the major pathway (Scheme 51) [166]. When the reaction was performed intramolecularly between a diyne and an alkyne, the only reaction products were the result of a [2 + 2 + 1]/[2 + 2 + 2] tandem cycloaddition [167, 168].

Scheme 50 Cyclization of triynes to tetracycles catalyzed by cobalt

Scheme 51 Tandem [2 + 2 + 1]/[2 + 2 + 2] cycloaddition of linear triynes

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4.3 Other Cycloadditions in Combination with the PKR Few examples from the literature show the viability of performing a 2 + 2, 4 + 2 or 5 + 1 cycloaddition combined with the PKR. An early contribution by Smit showed a photochemical 2 + 2 cyclization performed on PK product 178 which was obtained by selective reaction of dienyne 177. It is not clear from the work if product 179 is obtained in a one pot fashion or stepwise (Scheme 52) [169]. Chung has used a combined PK/Diels–Alder cascade reaction to synthesize [5.5.5.6] fenestranes and triquinanes. The ﬁrst products (181) were obtained in high yield from diendiynes 180 upon reaction with dicobalt octacarbonyl (5%) under 30 atm of CO at 130 ◦ C. The authors think it is more probable that the Diels–Alder reaction occurs after the PKR instead that the diene reacts ﬁrst with the closer triple bond to form a 1,4-cyclohexadiene that would undergo the PKR (Scheme 53) [170]. This group has used the same reaction conditions with diynes 182 and cyclic dienes like cyclopentadiene to form tetracyclic enone 183 which was transformed into triquinane 184 by means of an oxidative cleavage of the double bond. When phenyl groups at the alkyne terminus were substituted by H or Me they observed a competitive [2 + 2 + 1]/[2 + 2 + 2] process, with the participation of two diyne molecules giving compounds 185 (Scheme 54) [171]. No mechanistic hypothesis appears in this work but the formation of a norbornene derivative by means of the Diels–Alder reaction of cyclopentadiene and the diyne that would react with the other triple bond of the diyne seems attractive in this case.

Scheme 52 Combination of a PKR with a [2 + 2] photochemical cycloaddition

Scheme 53 Tandem [2 + 2 + 1]/[4 + 2] cycloaddition of diendiynes for the one pot synthesis of fenestranes

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Scheme 54 Cycloaddition of diynes with dienes in the synthesis of triquinanes. Tandem [2 + 2 + 1]/[4 + 2] cycloadditions

Scheme 55 Cobalt mediated tandem [5 + 1]/[2 + 2 + 1]-cycloaddition reaction

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Liu has reported recently a new Co2 (CO)8 -mediated tandem [5 + 1]/ [2 + 2 + 1]-cycloaddition reaction that gives tricyclic δ-lactones from cisepoxy enynes 186. This process possibly involves an initial opening of the epoxide in the cobalt hexacarbonyl complex 187 to from the complexed allene 189 via 188. Further coordination of the tethered oleﬁn leads to 190 and further oxidative cyclization gives cobaltacycle 191 which inserts CO leading to the ﬁnal compound 192. When performing the reaction under N2 , 191 suffers a reductive elimination to give cyclobutane 193 (Scheme 55) [172].

5 Reactions Occurring after the Pauson–Khand Process Several reactions can occur after the PKR. We will comment in detail those that have synthetic utility, either because they were planned or because they have been optimized after a ﬁrst unexpected ﬁnding. Those results involving minor by-products or single cases among a series, will be only mentioned. The review on unexpected results in the PKR by Krafft is a good option for obtaining more information on these latter cases [2]. 5.1 Traceless Tethers One group of interesting new substrates recently introduced for the PKR are those possessing traceless tethers. These compounds have the advantage of using the intramolecular version of the PKR, which is not limited to strained oleﬁns and does not have regioselection problems. In a second step, which sometimes occurs in a domino fashion, they give a monocyclic compound upon cleavage of the tether. The ﬁrst tethers contained oxygen, and were cleaved during PKRs performed under DSAC conditions. These results appeared when heating the reactions and led to monocyclic cyclopentenones in moderate yields [173, 174]. Recently this approach has found synthetic utility for the construction of a 3-methylcyclopentenone (195) by means of a PKR and reductive cleavage of compound 194 (Scheme 56) [175]. Pericàs, reported some examples in which a sulfur atom was reductively eliminated after the PKR in a stepwise manner [176]. Several recent reports use silicon as a traceless tether. Pagenkopf has succeeded in obtaining monocyclic cyclopentenones in one step, starting from a vinylsilane tethered to a propargyloxy chain (196). When they used longer tethers, they observed a cycloisomerization of the silane instead of the PK product. The mechanism of the reductive elimination of the silicon tether was investigated by this group. The cleavage starts from a species in which cobalt is still coordinated to the enone (197) and implies the participation of wa-

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ter in the process. When using dry solvents, cleavage of the silicon tether did not occur. Thus, wet acetonitrile was used. Simple deuterium labeling studies showed that the two new enone hydrogens came from the water present in the solvent. The reaction goes trough a cobalt dienolate (198) which suffers several [1, 5]-H sigmatropic rearrangements (199) that explain the incorporation of deuterium from the solvent at different positions of the ﬁnal cyclopentenone (200) (Scheme 57) [177, 178]. In the ﬁeld of PK-type reactions, Itami and Yoshida have recently used ruthenium complexes to expand the scope of the intermolecular PKR. The strategy consists of using oleﬁns 201 bearing a pyridylsilyl group which is readily removed after the reaction. These α or β substituted vinylsilanes are easily obtained from alkynes. The pyridyl group directs the PKR by a possible coordination of the nitrogen with the metal (202–204), which accelerates the process and gives complete regioselectivity. The directing group is eliminated in the reaction, giving rise directly to 4 and/or 5 substituted cyclopentenones 205–206. This avoids the use of ethylene or strained oleﬁns in the intermolecular PKR and is a way to solve the problem of the regioselectivity with unsymmetrical oleﬁns (Scheme 58) [179, 180].

Scheme 56 Ether cleavage combined with a PKR

Scheme 57 The silicon tethered reductive PKR. Mechanistic considerations

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Scheme 58 An expansion of the scope of the intermolecular PKR with the use of a pyridylsilyl group

5.2 Reductive PKR The direct synthesis of cyclopentanones from enynes under PKR conditions has been reported since early times, generally as a side reaction. This is a tandem process in which the cyclopentenone arising from the PKR is reduced. The ﬁrst reports on the formation of reduced products described PKR carried out under severe conditions (high temperatures, DSAC etc.), and the reduced products were obtained along the usual cyclopentenones [181]. This precedents prompted several groups to develop reaction protocols that lead exclusively to the reduced products (the reductive PKR), in order to use them in synthesis. Thus, Becker obtained diazabicyclooctanones like 208 from amines (207) as the only reaction product when they used DSAC conditions under an inert atmosphere. The nitrogen atmosphere was essential as in air they obtained mixtures of the cyclopentanones and the cyclopentenones. This group has used this methodology for the synthesis of azaadamantanes like 209 as part of the structure of certain antagonists (Scheme 59) [182–184]. Addition of TFA to the reaction favors the formation of reduced products. A series of alkynes produced cyclopentanones as the major product when reacted with norbornene, Co2 (CO)8 and TFA. The authors think TFA reacts with the cobalt complex 210, prior to the reductive elimination that gives the ﬁnal product 211 (Scheme 60) [185]. Krafft has studied modiﬁcations of the reaction conditions that can lead to variations in the result of the intramolecular PKR. Thus, they describe re-

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Scheme 59 Reductive DSAC conditions

Scheme 60 The role of TFA in the reductive PKR

action conditions that allow the synthesis of cyclopentanones with certain enynes (212). The best results are obtained with Co4 (CO)12 in alcohols under H2 or N2 . The reduction of the cyclopentenone is though to be mediated by a cobalt hydride generated from residual cobalt species and takes place only with terminal alkynes. The role of the alcohol is to improve the generation of such hydrides. The hydrogen incorporated to 213 comes from the alcohol, as observed from deuterium labeling studies and not from the H2 atmosphere, that, nevertheless, seem to have a favorable effect on yields. Non-terminal alkynes give cyclopentenones 214 in these conditions (Scheme 61) [186]. Recently, a combination of two metals has been used to perform a domino PKR-transfer hydrogenation. After a detailed study on the reaction conditions, the authors described that a mixture of Co2 (CO)8 (1 eq), RuCl2 (PPh3 )3 (0,1 eq) in i Pr – OH and addition of 1 eq of KOH after 2 hours of reaction were the best conditions to obtain almost exclusively the reduced PK product 215 (Scheme 62) [187]. A one-pot PKR-hydrogenation sequence was the key step in a non-racemic synthesis of (–)-dendrobine (222) published recently. Starting from (+)-trans-

Scheme 61 The reductive PKR. Conditions and substrate dependence

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Scheme 62 A reductive PKR carried out by a combination of two metals

verbenol (219), and using a cascade process in which a carbamoyl radical was involved, they prepared a suitable enyne (220). In order to adjust the conditions for the PKR of 220 they prepared compound 216 and submitted it to different reaction conditions with Co2 (CO)8 using NMO as promoter. The authors observed partial hydrogenolysis of the C – N bond when using DCM as solvent, isolating 218 jointly with the PK product 217. In acetonitrile, 218 was not formed. Reaction of 220 in the latter conditions gave an unstable cyclopentenone that was directly hydrogenated affording tricyclic compound 221 in 51% yield from 220 (Scheme 63) [188].

Scheme 63 The synthesis of (–)-dendrobine using a PKR/hydrogenation combination as the key step. Partial hydrogenolysis was observed when optimizing reaction conditions

5.3 Isomerizations and Migration of Double Bonds Migration or isomerizations of double bonds and epimerizations are frequently observed in PKRs. Several groups have studied these processes and believe they take place during the PKR or with participation of the metal

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species present in the reaction. We have reported several unexpected results that involve the shift of the emerging double bond. Thus, in the intramolecular reaction of styrene substrates 223, we obtained the isomerized and more stable product 229, and we proposed the participation of allyl cobalt complexes (225 and 227) arising from the intermediates of the reaction (224, 226, 228). We also isolated 230, an intermediate in the isomerization process (Scheme 64) [28]. Similarly, the reaction of enynoindoles 231 bearing an unprotected hydroxy group led to mixtures of saturated diketones 232, coming from the desilylation and double-bond migration. In addition we obtained oxidized product 233, as a result of the oxidation of the alcohol in the PK adduct (Scheme 65) [189]. Other groups observed double-bond shifts in intermolecular reactions. As an example, in a dimethylamino directed reaction of 234 a partial double bond shift was observed, isolating mixtures of the expected product 235 and the isomer 236 (Scheme 66) [190]. With regard to isomerizations of double bonds, sulﬁnyl enynes gave unexpected results when submitted to PKR. These chiral substrates were thought to give high asymmetric inductions due to the proximity of the chiral sulfur atoms to the reaction centers. Surprisingly, both cis and trans tert-butyl vinyl sulfoxides (237–238) were transformed into the same PK diastereoisomer 239 with high ee and moderate yields (Scheme 67) [103, 104].

Scheme 64 Double bond shift in the PK reaction of styrenes. Mechanistic explanation

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Scheme 65 Unexpected products in the PKR of indole derivatives. Double bond shifts and oxidation post-PK reactions

Scheme 66 A partial double bond shift in an intermolecular directed PKR

Scheme 67 An example of double bond isomerization during a PKR. Both cis and trans isomers gave the same reaction product

5.4 Other Post-PK Reactions (Hydrogenolysis, Oxidation, Michael, Retro-Diels–Alder) Cleavage of C – O, C – N and other C-heteroatom bonds is a frequent side reaction observed in many PKR specially those performed under severe conditions or DSAC conditions. We have shown before how, in the synthesis of dendrobine, this reaction was observed and was strongly dependent on the solvent used. The cleavage of ether links probably happens in most cases after the PKR. It has been observed in bonds included in the link between the alkyne and the alkene and in other tethers. If the cleavage happens prior to the cyclization, the PKR becomes intermolecular and in most cases does not take place. Section 5.1 shows the synthetic utility of programmed post-cleavages in enynes bearing traceless tethers. We will show here other cases in which the hydrogenolysis of carbon–heteroatom bonds is the major or only reaction observed and does not occur in bonds included in the enyne skeleton.

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Vinyl esters and vinylethers were studied as substrates for the intermolecular PKR by Pauson’s group and led to cyclopentenones 240 lacking the ether which was cleaved during the process (Scheme 68) [191]. Recently Gais has described an asymmetric synthesis of fused bicyclic amino acids having a hexahydro-cyclopenta[c]pyridine skeleton (245). The key steps of the synthesis were a highly selective allylation of a N-tertbutylsulfonyl imino ester with bis(allylsulfoximine)titanium complexes and a highly diastereoselective Pauson–Khand cycloaddition. They constructed sulfonimidoyl-substituted γ ,δ-unsaturated α-amino acid esters (241) and introduced a propargyl group at the nitrogen (242). The cyclization of the corresponding cobalt complexes 243 was accompanied by a reductive cleavage of the sulfoximine group of the primary cyclization product. One interesting fact in this reaction was that the removal of the sulfoximine group proceeded with inversion of the conﬁguration at the S-atom giving N-methylphenylsulﬁnamide (244) with > 97% ee (Scheme 69) [192]. The presence of halogens in norbornene-derived systems is a good way to control the regiochemistry of the PKR with alkynes. This has been observed with 7-oxa- and 7-azanorbornenes 246 and 249. Thus, the carbonyl is bonded with the oleﬁnic carbon that bore the halogen, which is eliminated in the pro-

Scheme 68 Ether cleavage in an intermolecular PKR

Scheme 69 Synthesis of bicyclic aminoacids via PKR with removal of a sulfoximine group

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cess (products 247 and 250). The reaction of 246 was not totally regioselective and the minor isomer 248 was detected. In both cases no traces of halogenated products appeared in the reaction mixtures (Scheme 70) [193, 194]. Other post-PKR processes that may happen are oxidation reactions in those cases in which ﬁnal PK products may liberate part of their strain by adding water or epoxidizing the emerging double bond [195, 196]. These results appear under oxidative reaction conditions (using N-oxides as promoters), as in the synthesis of medium sized rings from certain aromatic enynes, where small amounts of epoxides were obtained [28]. There is only one early precedent on coupling of the PKR with a Michaeltype reaction. When performing a catalytic high CO pressurized cobalt mediated reaction of alkynes with excess of oleﬁns bearing EWGs, the authors obtained as the major product cyclopentenone 254, which aroused from a domino PKR-Michael-type reaction. The process was regioselective both with respect to the alkene and the alkyne. The authors do not ascertain weather the Michael reaction occurs on the cobaltacycle 251 forming complex 253 or on the cyclopentenone 252. The use of high CO pressures was essential in this case to avoid the β-hydrogen elimination, the typical competitive side reaction with this type of alkenes that gives 255 (Scheme 71) [197]. Finally, one recent report has succeeded in using a cyclobutadiene surrogate as the oleﬁn partner in an intermolecular PKR. Cyclobutadiene is a very attractive oleﬁn for an intermolecular PKR as it would lead to bicyclic products that cannot be obtained with the intramolecular reaction. Unfortunately it is too unstable to handle. Gibson has used cyclobutene surrogate 256, obtained from cyclooctatetraene and dimethyl acetylenedicarboxylate, as cyclobutene equivalent in catalytic PKR with alkynes. After the cycloaddition, the resulting product 257, that could be isolated, was submitted to thermolysis at high temperature, inducing a retro-Diels–Alder process that gave the bicyclic ketones 258 in high yields (Scheme 72) [198].

Scheme 70 Intermolecular PKR with halonorbornene derivatives. Cleavage of the C – Br bonds

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Scheme 71 Tandem PKR-Michael type reaction

Scheme 72 A cyclobutadiene surrogate for the PKR. Tandem [2 + 2 + 1]/retro Diels–Alder reaction

6 Conclusions Few organic transformations add as much molecular complexity in one step as the Pauson–Khand reaction. This reaction is one of the best examples of how organometallic chemistry is useful in modern organic synthesis, and can serve as a key tool for the synthesis of natural products, in this case those possessing cyclopentane units. The limited scope, low yields and lack of efﬁcient catalytic procedures were serious drawbacks in the past that have been

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overcome in recent years with the special aid of newly developed PK-type reactions. Still, the intermolecular version is quite limited, as unstrained oleﬁns scarcely react, although the use of traceless tethers or directing groups has circumvented this problem in certain cases. On the other hand the wide variety of catalytic protocols available generally give good results only with favorable substrates. This mature state of the art has prompted many groups to step ahead and design combined synthetic processes that increase even more the synthetic power of this reaction. We have organized these results in this chapter. Much of the work commented here has aroused unexpected results. In this sense we encourage researchers to be especially aware of strange results that can turn out to be important ﬁndings. There are many secondary reaction pathways that can appear depending on the substrates or reaction conditions. Other results included herein were planned. In particular multicomponent catalytic reactions are the most promising areas of development of this chemistry. We get closer to biosynthesis when we succeed in making several reactions in one synthetic operation, making different catalyst to work successively inside the same ﬂask, or that the same species catalyses several reactions one after another. In this sense the most exciting future will deal with such tandem catalytic transformations, which meet perfectly the atom economy principle.

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Billington DC, Kerr WJ, Pauson PL, Farnocchi CF (1988) J Organomet Chem 356:213 Blanco-Urgoiti J, Casarrubios L, Pérez-Castells J (1999) Tetrahedron Lett 39:2817 Lakshmi M, Rao N, Periasamy M (1996) Organometallics 15:442 Wender PA, Deschamps NM, Gamber GG (2003) Angew Chem Int Ed Eng 42:1853 Wender PA, Deschamps NM, Williams TJ (2004) Angew Chem Int Ed Eng 43:3076 Khand IU, Pauson PL, Habib MJA (1978) J Chem Res (S)346 Morimoto T, Fuji K, Tsutsumi K, Kakiuchi K (2002) J Am Chem Soc 124:3806 Fuji K, Morimoto T, Tsutsumi K, Kakiuchi K (2003) Angew Chem Int Ed Eng 42:2409 Fuji K, Morimoto T, Tsutsumi K, Kakiuchi K (2004) Tetrahedron Lett 45:9163 Shibata T, Toshida N, Takagi K (2002) Org Lett 4:1619 Shibata T, Toshida N, Takagi K (2002) J Org Chem 67:7446 Park KH, Son SU, Chung YK (2003) Chem Commun 1898 Park KH, Jung IG, Chung YK (2004) Org Lett 6:1183 van der Waals A, Keese R (1992) Chem Commun, p 570 Thommen M, Veretenov AL, Guidetti-Grept R, Keese R (1996) Helv Chim Acta 79:461 van Ornum SG, Cook JM (1996) Tetrahedron Lett 37:7185 van Ornum SG, Cook JM (1997) Tetrahedron Lett 38:3657 Bruendl M, van Ornum SG, Chan T-M, Cook JM (1999) Tetrahedron Lett 40:1113 van Ornum SG, Bruendl M, Cao H, Reddy M, Grubisha DS, Bennett DW, Cook JM (2000) J Org Chem 65:1957 Cao H, Mundla SR, Cook JM (2003) Tetrahedron Lett 44:6165 Cao H, van Ornum SG, Cook JM (2000) Tetrahedron Lett 41:5313 Cao H, Flippen-Anderson J, Cook JM (2003) J Am Chem Soc 125:3230 Cao H, van Ornum SG, Deschamps J, Flippen-Anderson J, Laib F, Cook JM (2005) J Am Chem Soc 127:933 Buchholz H, Reiser O, de Mejiere A (1990) Synlett, p 20 Halterman RL, Ramsey TM, Pailes NA, Khan MA (1995) J Organomet Chem 497:43 Panarello AP, Khinast JG (2003) Tetrahedron Lett 44:4095 Rausch BJ, Gleiter R (2001) Tetrahedron Lett 42:1651 Rausch BJ, Becker H, Gleiter R, Rominger F (2002) Synlett, p 723 Gleiter R, Schulte JH, Werz DB (2004) Eur J Org Chem, p 4077 Lee BY, Kim YH, Won YC, Han JW, Suh WH, Lee IS, Chung YK, Song KH (2002) Organometallics 21:1500 Son US, Yoon YA, Choi DS, Park JH, Kim BM, Chung YK (2001) Org Lett 3:1065 Son US, Paik S-J, Lee SI, Chung YK (2000) J Chem Soc Perkin Trans I 141 Lee SI, Son US, Choi MR, Chung YK, Lee SG (2003) Tetrahedron Lett 44:4705 Son US, Choi DS, Chung YK (2000) Org Lett 2:2097 Smit WA, Buhanjuc SM, Simonyan SO, Shaskov AS, Struchkov YT, Yanovsky AI, Caple R, Gybin AS, Anderson LG, Whiteford JA (1991) Tetrahedron Lett 19:2105 Kim DH, Son SU, Chung YK, Lee S-G (2002) Chem Commun, p 57 Son SU, Park KH, Lee SJ, Kim BM, Chung YK (2003) Synlett, p 1101 Odedra A, Wu C-J, Madhushaw RJ, Wang S-L, Liu R-S (2003) J Am Chem Soc 125:9610 Simonyan SO, Smit WA, Gybin AS, Shaskov AS, Mikaelian GS, Tarasov VA, Ibragimov II, Caple R, Froen DE (1986) Tetrahedron Lett 27:1245 Smit WA, Simonyan SO, Tarasov VA, Mikaelian GS, Gybin AS, Ibragimov II, Caple R, Froen DE, Kreager A (1989) Synthesis, p 472 Muto R, Ogasawara K (2001) Tetrahedron Lett 42:4143 Castro J, Moyano A, Pericás MA, Riera AJ (1998) J Org Chem 63:3346

150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172. 173. 174. 175. 176.

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Top Organomet Chem (2006) 19: 259–294 DOI 10.1007/3418_011 © Springer-Verlag Berlin Heidelberg 2006 Published online: 21 April 2006

Complex Polycyclic Molecules from Acyclic Precursors via Transition Metal-Catalyzed Cascade Reactions Corinne Aubert · Louis Fensterbank · Vincent Gandon · Max Malacria (u) Université Pierre et Marie Curie, Laboratoire de Chimie Organique associé au CNRS Tour 44-54, 2ème étage, CC 229, 4 place Jussieu, 75252 Paris Cedex 05, France [email protected] 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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2 2.1 2.1.1 2.1.2 2.1.3 2.2 2.2.1 2.2.2 2.2.3 2.2.4 2.3 2.3.1 2.3.2 2.3.3

Cascades Involving Non-carbenoid Intermediates . . . . . . . . Formation of Two Rings . . . . . . . . . . . . . . . . . . . . . . . Copper-Catalyzed Intramolecular Kinugasa Reaction . . . . . . . Tandem Hydroformylation/Acetalization . . . . . . . . . . . . . . Domino Allylic Substitution/Carbocyclization . . . . . . . . . . . Formation of Three Rings . . . . . . . . . . . . . . . . . . . . . . [2 + 2 + 2]/[4 + 2] . . . . . . . . . . . . . . . . . . . . . . . . . . . Carbonylative Carbotricyclization . . . . . . . . . . . . . . . . . . Silylcarbotricyclization (SiCaT) . . . . . . . . . . . . . . . . . . . Cascade Cyclizations and Couplings Involving Nickel . . . . . . . Formation of Four Rings . . . . . . . . . . . . . . . . . . . . . . . [2 + 2 + 1]/[2 + 2 + 1], [2 + 2 + 1]/[4 + 2] and [2 + 2 + 1]/[2 + 2 + 2] Alder-ene/[4 + 2]/[4 + 2] . . . . . . . . . . . . . . . . . . . . . . . [2 + 2 + 2]/[4 + 2] and Conia-ene/[2 + 2 + 2]/[4 + 2] . . . . . . . .

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Cascades Relying on Transition Metalo Carbenoid Intermediates . . . . . Precursors Bearing a Carbenoid Function . . . . . . . . . . . . . . . . . . Cascades Involving Non-carbenoid Precursors . . . . . . . . . . . . . . . .

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Abstract This review gives an insight into the growing ﬁeld of transition metal-catalyzed cascades. More particularly, we have focused on the construction of complex molecules from acyclic precursors. Several approaches have been devised. We have not covered palladium-mediated cyclizations, multiple Heck reactions, or ruthenium-catalyzed metathesis reactions because they are discussed in others chapters of this book. This manuscript is composed of two main parts. In the ﬁrst part, we emphasize cascade sequences involving cycloaddition, cycloisomerization, or ene-type reactions. Most of these reaction sequences involve a transition metal-catalyzed step that is either followed by another reaction promoted by the same catalyst or by a purely thermal reaction. A simple change in the temperature of the reaction mixture is often the only technical requirement to go from one step to another. The second part covers the cascades relying on transition metalo carbenoid intermediates, which have recently undergone tremendous

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developments and synthetic applications. The ﬁrst section deals with precursors already incorporating a carbenoid species (mostly diazo derivatives); the second section covers cascades in which an incipient carbenoid species originating from one or two catalytic steps intervenes. Keywords Cascade · Skeletal rearrangement · Cycloisomerization · Cycloaddition · Carbenoid Abbreviations Cp∗ Pentamethylcyclopentadienyl capH2 N-[(S)-3-Mercapto-2-methylpropionyl]-L-proline DMAD Dimethyl acetylenedicarboxylate BPTV N-Benzene-fused-phthalyl-(S)-valine

1 Introduction Since synthetic strategies to highly functionalized polycyclic compounds have become directed increasingly towards both efﬁciency and stereoselectivity, the use of transition metal-mediated cyclizations has grown at an exponential rate. Transition metal catalysis is used to perform, in a selective manner, carbon–carbon and carbon–heteroatom bond forming reactions that would be much more difﬁcult, even impossible, with conventional organic reagents alone. In addition, in some favorable cases, the metal catalysts allow the formation of several bonds in a single step. However, the driving forces of the synthesis of relevant organic compounds such as natural products are not only an increase of selectivity and efﬁciency, but also an absence of waste production and compatibility with our ecological and economical requirements. To meet these criteria, cascade reactions increasingly occupy a central role in the construction of a multitude of diverse molecules. This methodology allows the formation of complex molecules starting from simple substrates in very few steps, sometimes in a one-pot operation. Because of the large number of publications in this area [1–3], it is impossible to present more than a limited set of examples and several very interesting topics have to be excluded, particularly the topics of other chapters of this volume such as those involving Pd-mediated cyclizations and ruthenium-catalyzed metathesis reactions. The objective of this chapter is to present an overview of the synthesis of complex polycyclic molecules starting from acyclic precursors, either in bimolecular or intramolecular fashion. This review is not intended to serve as a comprehensive survey but rather as an account of how alkynes, alkenes, aldehydes and ketones, allenes, and carbon monoxide can take part in cascade reactions to give products with four-, ﬁve-, six-, or seven-membered rings. The ﬁrst part is devoted to the cascades involving non-carbenoid

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intermediates. In all cases we have favored the examples in which the sequences of reactions have been made in a one-pot procedure. The second part covers the cascades relying on transition metalo carbenoid intermediates, which have recently undergone tremendous developments and synthetic applications.

2 Cascades Involving Non-carbenoid Intermediates In this section, we will mainly emphasize cascade sequences where cycloaddition, cycloisomerization or ene-type reactions take part. Most of these reaction sequences involve a transition metal-catalyzed step (mostly cobalt and rhodium), which is either followed by another reaction promoted by the same catalyst or by a purely thermal reaction. A simple change in the temperature of the reaction mixture is often the only technical requirement to go from one step to another. This part will be divided into sections according to the number of rings produced during the cascade reactions. 2.1 Formation of Two Rings 2.1.1 Copper-Catalyzed Intramolecular Kinugasa Reaction On account of their very important biological activity, β-lactams are important synthetic targets [4–9]. Fused polycyclic β-lactam subunits appear in many natural products such as penicillins [4–6] and trinems/tribactams [10–13]. Fu et al. reported that such frameworks can be prepared with high levels of enantioselectivity via the intramolecular Kinugasa reaction [14, 15] of alkyne-nitrone in the presence of a planar chiral Cu/phosphaferroceneoxazoline catalyst [16]. For instance, compound 1 was transformed into tricyclic β-lactam 3 in good stereoselectivity and yielded (88% ee and 74% yield) using 5 mol % of CuBr and 5.5 mol % of complex 2 (Scheme 1). A plausible mechanistic rationale for the Kinugasa reaction is depicted in Scheme 2 [14, 15]. Copper-acetylide A is ﬁrst obtained from the terminal alkyne in the presence of a Cu(I) salt and a base. This intermediate then undergoes a [3 + 2] cycloaddition with the nitrone to give heterocycle B, which rearranges into enolate C. This conjugated system reacts with a proton to afford the product. The possibility of trapping intermediate C with an electrophile in the reaction cascade was investigated. Starting from substrate 1 and allyl iodide, product 4 was obtained in 76% yield and 85% ee (Scheme 3).

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Scheme 1 Enantioselective synthesis of a tricyclic β-lactam

Scheme 2 Postulated mechanism of the Kinugasa reaction

Scheme 3 Cascade Kinugasa reaction/alkylation

In this single cyclization/alkylation cascade, two C – C bonds, one C – N bond, a carbonyl group, a tertiary and a quaternary stereocenter have been generated. 2.1.2 Tandem Hydroformylation/Acetalization Many natural compounds, such as dihydroclerodin [17] or aﬂatoxin B2 [18, 19] contain bicyclic acetal units of type furo[2,3b]furan. The synthesis of perhydrofuro[2,3b]furans and perhydrofuro[2,3b]pyrans was achieved by

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Scheme 4 Rh(I)-catalyzed cascade hydroformylation/acetalization

Scheme 5

Eilbracht et al. by means of rhodium-catalyzed tandem hydroformylation/acetalization of α,ω-alkenediols [20]. It had been previously reported that hydroformylation of alkenol resulted in cyclic hemiacetal [21]. Starting from enediols, the authors paved the way for subsequent acetalization, leading to fused bicyclic compounds in a one-pot cascade. As expected, exclusive formation of cis-fused perhydrofuro[2,3b]furan 6 occurred when applying 60 bar of syngas (CO : H2 = 3 : 1) at 120 ◦ C in dichloromethane to diol 5 in the presence of a [Rh(cod)Cl]2 /PPh3 catalytic system (Scheme 4). Besides, benzoannelated tetrahydrofuro[2,3b]furans such as 8 were also efﬁciently prepared by hydroformylation of o-hydroxy cinnamyl alcohols, using the Rh(acac)(CO)2 /PPh3 catalyst system in 1,4-dioxane (Scheme 5). 2.1.3 Domino Allylic Substitution/Carbocyclization Martin et al. disclosed that [Rh(CO)2 Cl]2 catalyzes highly regio- and stereoselective allylic alkylation using α-substituted sodiomalonates. The new C – C bond was formed at the carbon bearing the leaving group [22]. Owing to the known ability of Rh(I) complexes to catalyze carbocyclizations such as the Pauson–Khand reaction (PKR) [23, 24] or [5 + 2] cycloadditions [25], Martin anticipated that the aforementioned reaction could be the ﬁrst step of

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Scheme 6 Rh(I)-catalyzed cascade alkylation/carbocyclization

a domino sequence involving in situ enyne formation and subsequent carbocyclization [26] (Scheme 6). Using 10 mol % of [Rh(CO)2 Cl]2 and 1 atm of CO, allyl triﬂuoroacetate 10 reacted rapidly at room temperature with the anion of malonate 9. Completion of the subsequent PKR required heating to reﬂux for 12–24 h [27] (Scheme 7). On the other hand, using cyclopropyl-substituted allylic triﬂuoroacetate 12 led to [5 + 2] cycloaddition product 13 after the temperature was raised to 80 ◦ C (Scheme 8). Both procedures are experimentally simple since only a change in temperature is necessary to promote the second step of the sequential reactions. It is noteworthy that this strategy was precedented by the work of Jeong who achieved the one-pot preparation of bicyclopentenones from propargyl malaonates and allylic acetates by a tandem action of two different catalysts [28].

Scheme 7

Scheme 8

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2.2 Formation of Three Rings 2.2.1 [2 + 2 + 2]/[4 + 2] Transition metal-catalyzed [2 + 2 + 2] cocyclization of two molecules of an alkyne with an alkene is a powerful method for forming 1,3-cyclohexadienes [29–31]. These compounds are of course valuable partners for Diels– Alder reactions [32]. Through the right choice of substrates, both [2 + 2 + 2] and [4 + 2] cycloadditions can be performed in a single chemical operation [33]. Indeed, the reaction of electroneutral diyne 14 with electrondeﬁcient maleimide 15 in the presence of 1 mol % of a Ru(I) catalyst exclusively afforded the highly symmetrical 1 : 2 adduct 17 in 74% yield (Scheme 9). It was shown that the role of the catalyst was only to promote the formation of 16, whereas the Diels–Alder step was purely thermal.

Scheme 9 Cascade [2 + 2 + 2]/[4 + 2] cycloaddition reactions

2.2.2 Carbonylative Carbotricyclization 2.2.2.1 [5 + 1]/[2 + 2 + 1] Liu et al. reported the Co2 (CO)8 -mediated coupling of epoxyalkyne, CO, and oleﬁn functionalities, proceeded as tandem [5 + 1]/[2 + 2 + 1] cycloadditions to give tricyclic δ-lactones [34]. As an example, compound 18 was ﬁrst treated with 1.1 equivalents of Co2 (CO)8 at 23 ◦ C under N2 for 2 h in benzene. Heating of the resulting black solution under 50 psi of CO at 80 ◦ C for 24 h gave fused 5,6-dihydropyran-2-one 19 as a sole product in 74% yield (Scheme 10).

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Scheme 10 Cascade [5 + 1]/[2 + 2 + 1] cyclizations

Scheme 11 Postulated mechanism of the Co(0)-mediated cascade [5 + 1]/[2 + 2 + 1] cyclizations

The structure of 19 was unambiguously conﬁrmed by an X-ray diffraction study. A mechanistic rationale is depicted in Scheme 11. After Co2 (CO)6 complexed alkyne A is obtained, a SN 2 attack of the Co2 (CO)6 fragment opens the epoxide moiety to afford intermediate B, which subsequently incorporates CO to give C. The latter rearranges into cobalt-stabilized cyclic allene species D. The net result is a [5 + 1] cyclization that creates the lactone group. Coordination of the tethered oleﬁn leads to oxidative cyclization to give E. Finally, insertion of CO followed by reductive elimination affords the desired product 19. 2.2.2.2 Nicholas Reaction/[2 + 2 + 1] In connection with the aforementioned reaction, Shea et al. reported the synthesis of [5,8,5]- and [5,7,5]-tricyclic oxygen-containing heterocycles via tandem Nicholas [35] and Pauson–Khand [23, 24] reactions of acyclic enynes [36]. A typical Nicholas/[2 + 2 + 1] sequence is depicted in Scheme 12. This method has the advantage of being most atom-economical and tolerant to a wide variety of functional groups. Enyne 22 was reacted with Co2 (CO)8 to afford complex 23 in good yield. Treatment with BF3 · OEt2 enabled the intramolecular nucleophilic substitution of the propargylic ether function by the primary alcohol moiety to give an eight-membered ring in-

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Scheme 12 Cascade Nicholas reaction/[2 + 2 + 1]

termediate 24. Further treatment with N-methylmorpholine N-oxide (NMO) afforded [5,8,5]-tricycle 25 as major isomer (trans conﬁguration) in satisfactory yield. 2.2.2.3 [2 + 2 + 1]/[2 + 2 + 2] Whereas both Pauson–Khand based reactions presented above are intramolecular processes, a bimolecular route to [5,5,6]-tricyclic compounds is also available [37]. Indeed, it was shown that diynes could be reacted with monoalkynes using a catalytic amount of Co2 (CO)8 . In this way, compound 27 and phenylacetylene were converted into tricyclic product 28 in 68% yield (Scheme 13). Although high temperature and pressure of CO were required, compound 28 was obtained as a single regio- and diastereomer.

Scheme 13

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Scheme 14 Plausible mechanism for the cascade of [2 + 2 + 1]/[2 + 2 + 2] cyclizations

This tandem reaction is believed to proceed via Pauson–Khand reaction between the diyne and carbon monoxide to give an intermediate bicyclopentadienone. A carbon–carbon double bond of this intermediate then reacts with two alkyne units via a cobalt-catalyzed [2 + 2 + 2] process leading to a cobalt-1,3cyclohexadiene complex which undergoes subsequent reductive elimination (Scheme 14). The regioselective outcome of this reaction was explained in terms of steric congestion. 2.2.3 Silylcarbotricyclization (SiCaT) Extensively developed by Ojima and coworkers, silylcarbotricyclization (SiCaT) and carbonylative silylcarbocyclization (CO-SiCaC) represent a rapid entry to polycyclic molecules of interest [38]. For instance, the rhodiumcatalyzed intramolecular SiCaT of triyne 29 afforded tricyclic compound 30 in high yield, accompanied by a small amount of cycloadduct 31 [39] (Scheme 15). It is noteworthy that the latter was not obtained without silicon assistance, which means that the reaction is in fact initiated by Si-[Rh] species (Scheme 16). Fused tricyclic benzenes such as 31 are formed exclusively using an exactly stoichiometric amount of silane. On the other hand, two equiv-

Scheme 15

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Scheme 16 Possible mechanism for the SiCaT reaction

alents of silane preferably lead to silylated benzenes such as 30 through a hydrosilylation–carbocyclization–β-hydride elimination cascade. 2.2.4 Cascade Cyclizations and Couplings Involving Nickel Enolates The synthesis of complex polycyclic molecules has been achieved by Montgomery et al. by cascade cyclization processes involving nickel enolates [40]. Up to three cycles could be generated in the intramolecular version of the reaction. Alkynyl enal or enone were ﬁrst converted into their corresponding seven-membered cyclic enolates in the presence of Ni(cod)2 /TMEDA [41]. These species could be trapped by electrophiles such as aldehydes. For example, upon treatment with the nickel catalyst, dialdehyde 32 afforded spirocycle 35 in 49% yield as a single diastereomer (Scheme 17). Compound 33, obtained by chemoselective oxidative cyclization of the enal and the alkyne units is a likely intermediate. Indeed, in the absence of an electrophile, such species have been isolated and characterized by X-ray crystallography [41]. Bis-alkoxide 34 was then formed by diastereoselective

Scheme 17 Cascade cyclic nickel enolate formation/aldolization reaction

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intramolecular aldol addition via an open transition state. Aqueous workup then provided compound 35. 2.3 Formation of Four Rings 2.3.1 [2 + 2 + 1]/[2 + 2 + 1], [2 + 2 + 1]/[4 + 2] and [2 + 2 + 1]/[2 + 2 + 2] Fenestranes are compounds of theoretical interest in which the central carbon atom undergoes severe planarization distortion. Reactions sequences involving double intramolecular Pauson–Khand reactions of ene-diynes, or intramolecular Pauson–Khand of dienynes followed by photochemical [2 + 2] cycloaddition, successfully lead to [5.5.5.5]- or [4.5.5.5]fenestrane, respectively [42]. For instance, compound 37 was obtained from ene-diyne 36 in moderate yield as a single all-cis stereoisomer [43] (Scheme 18). Similarly, Chung et al. described a cobalt-catalyzed route to 5.5.5.6 tetracyclic compounds. Tetracyclic dienones were prepared by double Pauson– Khand reaction of triynes. Interestingly, reactions of triynes such as 38 with CO in the presence of 2.5 mol % of Co2 (CO)8 did not give any [5.5.5.5]fenestrane derivative but a bridged system (39) (Scheme 19). The authors stated that the steric effect of the substituent of the inner triple bond inhibits the reaction path leading to the fenestrane framework. Indeed, intermediate 40, obtained after the ﬁrst Pauson–Khand reaction, displays a congested carbon–carbon double bond on the cyclopentadienone framework. This leads to a regioselective second Pauson–Khand reaction on the less hindered position (Scheme 20).

Scheme 18 Synthesis of a [5.5.5.5] fenestrane via a cascade [2 + 2 + 1]/[2 + 2 + 1] reactions

Scheme 19

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Scheme 20 Regioselective outcome of the cascade [2 + 2 + 1]/[2 + 2 + 1] reactions of triynes

Scheme 21 Synthesis of a [5.5.5.6] fenestrane via a cascade [2 + 2 + 1]/[4 + 2] reactions

Scheme 22 Cascade of [2 + 2 + 1]/[4 + 2] cyclizations

However, in another contribution, Chung and coworkers realized the onepot synthesis of [5.5.5.6]fenestranes 42 via intramolecular cobalt-catalyzed tandem Pauson–Khand/Diels–Alder reactions of dienediynes 41 [44] (Scheme 21). It is also worthy of note that the construction of tetracyclic compounds 44 by cobalt-catalyzed tandem Pauson–Khand/[2 + 2 + 2] cycloaddition reactions of 1,6-diynes 43 was also reported by Chung et al. [45, 46]. It was experimentally shown that the [2 + 2 + 2] cycloaddition reaction occurs after the [2 + 2 + 1] cycloaddition between CO and the substrate (Scheme 22). 2.3.2 Alder-ene/[4 + 2]/[4 + 2] Brummond et al. disclosed that acyclic allenynes could be efﬁciently converted into tetracyclic compounds via consecutive rhodium-catalyzed Alderene and double Diels–Alder cycloaddition reactions [47]. The former reaction transforms alkynyl allenes such as 45 into triene-ynes (46) using rhodium biscarbonyl chloride dimer. Conversion of 46 into a triene such as 47 was achieved using either [Rh(dppe)Cl]2 , AgSbF6, or [Rh(C10 H8 )(cod)]SbF6 . Exposure of these trienes

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Scheme 23 Cascade Alder-ene/[4 + 2]/[4 + 2] cyclizations

to an external dienophile gave the desired tetracycles in good yields. For instance, treatment of cycloadduct 47 with methylvinylketone regioselectively furnished 48 in 75% as a 1 : 1 mixture of diastereomers (Scheme 23). This one-pot procedure is highly chemoselective with the Alder-ene and the ﬁrst Diels–Alder reaction providing a single isomer. Although not diastereoselective, the second Diels–Alder reaction is highly regioselective when unsymmetrical dienophiles are employed. Better diastereoselectivities (up to 5 : 1) were obtained when using symmetrical cyclic dienophiles such as N-methyl maleimide. 2.3.3 [2 + 2 + 2]/[4 + 2] and Conia-ene/[2 + 2 + 2]/[4 + 2] The cobalt(I)-mediated [2 + 2 + 2] cycloaddition of 1,5-diynes with monoalkynes provides access to benzocyclobutene derivatives (Scheme 24). Thermal rearrangement of benzocyclobutenes into o-quinodimethane and subsequent Diels–Alder reaction with an alkene moiety allow the formation of a tricyclic compound. This strategy was applied to the synthesis of the ABC core of steroid and terpene derivatives. One striking example of this strategy was reported by

Scheme 24 Principle of the [2 + 2 + 2]/[4 + 2] cascade via orthoquinodimethane

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Vollhardt et al. The total synthesis of estrone, which is one of the three naturally occurring estrogens and a primary estrogenic component of several pharmaceutical preparations, was achieved in a few chemical operations [48]. Precursor 52 was prepared via consecutive cobalt(I)-mediated

Scheme 25

Scheme 26 Access to the phyllocladane diterpene skeleton through the cascade Coniaene/[2 + 2 + 2]/[4 + 2] reactions

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diyne–monoakyne cooligomerization and a [4 + 2] cycloaddition reaction (Scheme 25). The in situ-generated o-quinodimethane 51 underwent Diels–Alder reaction giving rise to the formation of both B- and C-rings with the correct relative stereochemistry in one step. Racemic estrone was then obtained in two steps in very good yield. A one-pot access to the ABCD-rings of diterpenes has also been described by ourselves [49]. In the following example, the ε-acetylenic-β-ketoester 53 furnished through a diastereoselective onepot sequence [ene type]/[2 + 2 + 2]/[4 + 2] the phyllocladane framework 56 in 42% yield (Scheme 26). It is noteworthy that the methylenecyclopentane 54 was generated in situ via a cobalt-catalyzed Conia-ene type reaction. By a subtle change in the position of the β-ketoester substituent relative to the tether, the sequence could be reversed and allow the formation of the basic skeleton of the kaurane family [50].

3 Cascades Relying on Transition Metalo Carbenoid Intermediates This rather large ﬁeld of applications of cascade reactions has recently undergone tremendous developments and we will focus on this aspect. We will divide this part into two sections. The ﬁrst section will deal with precursors already incorporating a carbenoid species (mostly diazo derivatives); the second section will cover cascades in which an incipient carbenoid species originating from one or two catalytic steps intervenes. 3.1 Precursors Bearing a Carbenoid Function While most of the initial studies have involved the transition metalcatalyzed decomposition of α-carbonyl diazo compounds and have been reviewed [3–51], it appears appropriate to highlight again some milestones of these transformations, since polycyclic structures could be nicely assembled from acyclic precursors in a single step. Two main reactivities of metalo carbenoids derived from α-carbonyl diazo precursors, namely addition to a C – C insaturation (oleﬁn or alkyne) and formation of a ylid (carbonyl or onium), have been the source of fruitful cascades. Both of these are illustrated in Scheme 27 [52]. The two diazo ketone functions present in the same substrate 57 and under the action of the same catalyst react in two distinct ways. The initially formed carbenoid adds to a pending oleﬁn to form a bicyclo[4.1.0] intermediate 58 that subsequently cyclizes to produce a carbonyl ylide 59, that is further trapped intramolecularly in a [3 + 2] cycloaddition. The overall process gives birth to a highly complex pentacyclic structure 60.

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Scheme 27 Dual reactivity of transition metal-catalyzed decomposition of α-carbonyl diazo derivatives

The transient intervention of a carbonyl ylids has culminated in numerous elegant approaches to total syntheses of natural products, such as the synthesis of the tigliane ring system (61–63) by Dauben [53] (Scheme 28). It is worthy of note that this reaction is still the subject of solid and productive interest, as shown by the following recent examples. Chiu has exploited a rhodium carbene-promoted intramolecular formation of a carbonyl ylid – cycloaddition cascade as the key reaction in the synthesis of the nucleus of the cytotoxic diterpenoids pseudolaric acids A and B [54]. Although the diastereoselectivity was preferential for the undesired isomer 64, use of Hashimoto’s chiral rhodium catalyst Rh2 (SBPTV)4 reversed the selectivity in favor of 65 (64 : 65, 1 : 1.4) [55] (Scheme 29). In the same vein, Schmalz has proposed a facile construction of the colchicine skeleton by a rhodium-catalyzed cyclization/cycloaddition cascade [56]. A TMS group has to be introduced on the alkyne moiety of 66 in order to avoid participation of the relatively acidic alkynyl hydrogen atom in undesired proton transfers. The resulting 6,7,7 of 67a and 67b architecture was assembled in a remarkably diastereoselective manner (14 : 1) and in satisfactory yield (Scheme 30).

Scheme 28 Approach to the tigliane polycyclic system

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Scheme 29 Approach to pseudolaric acids

Scheme 30 Approach to colchicine

The game is certainly not over, very recently catalytic enantioselective intermolecular cycloadditions of 2-diazo-3,6-diketoester of type 68 derived carbonyl ylides with alkene dipolarophiles have been developed [57]. Relying on chiral rhodium(II) clusters I and II, Hodgson et al. obtained very high enantioselectivities (up to 92% ee on 69) with norbornene as a trap, as disclosed in Scheme 31. Addition of a rhodium carbenoid to an alkyne leads to a cyclopropene derivative. In an intramolecular context, the fused cyclopropene moiety is unstable and undergoes ring opening to generate a rhodium vinyl carbenoid entity, which can then undergo cyclopropanation or cyclopropenation, carbon hydrogen insertion, and ylide generation. This is illustrated

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Scheme 31 Asymmetric catalysis

Scheme 32 An intermediate vinyl carbene

with the efﬁcient transformation of 70 into 71 [58]. In that case, the vinylcyclopropane intermediate 73 resulting from the intramolecular addition of the carbene 72 on the diene moiety undergoes a Cope rearrangement to produce 71 (Scheme 32). This chemistry has already been nicely and extensively reviewed [3–51] and we will deal below with extensions of this strategy. Based on his previous work describing the catalytic double addition of diazo compounds to alkynes [59], Dixneuf used Cp∗ RuCl(cod) and worked out a simple synthesis of alkenyl bicyclo[3.1.0]hexane derivatives 75 from enyne precursors 74 (Scheme 33). The catalytic cycle starts with the formation of

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Scheme 33 A ruthenium route to bicyclo[3.1.0]hexane derivatives

a Ru = CHR species. It can then couple to alkyne to form ruthenacyclobutene C, which evolves into vinylcarbene 76. [2 + 2] Cycloaddition gives ruthenacyclobutane 77. The novelty in this transformation is the subsequent reductive elimination to give 75a, and not the formation of a diene product. This would be ascribable to the steric hindrance of the C5 Me5 – Ru group. Vinyl carbene intermediates can also be generated from the intermolecular addition of TMS diazomethane onto an alkyne component in the presence of Ni(cod)2 as a catalyst. If a diene moiety is also present, as in 1,6-enyne system 78, reaction of the intermediate nickel carbenoid with this partner gives birth to the fused 5,7-bicyclic system 79 in fair yields (Scheme 34). Several mechanistic scenarios are possible from generic precursor 78, including a metathesis-type sequence to generate a nickelacyclobutane 80, followed by

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Scheme 34 Nickel carbenoid intermediate

reductive elimination and Cope rearrangement, or rearrangement to a nickelacyclooctadiene intermediate 81 and reductive elimination. Another route involving Ni(0) preliminary oxidative addition was also proposed [60]. Further studies will probably elucidate the mechanism of this [4 + 2 + 1] cycloaddition of a diazoalkane, diene, and alkyne. 3.2 Cascades Involving Non-carbenoid Precursors This section focuses on cascades that rely on starting materials with no carbene function. Based on the reaction previously described by McDonald [61], endo-selective catalytic alkynol cycloisomerization, Barluenga has reported a tandem W(CO)5 -catalyzed cycloisomerization reaction [62, 63]. Thus, upon treatment of enynol 82 with 20 mol % of preformed [(THF)W(CO)5 ] or with 10 mol % of [W(CO)6 ] in the presence of Et3 N (2 mol %), good yields of bicyclic adducts 84 and generic structures 86 as single diastereomers were obtained. It has to be noted that in the presence of an excess of Et3 N, the usual cyclic enol ether 83 is obtained from 82. Thus, the originality lies here in the trapping of the tungsten carbenoid 87, which introduces the cyclopropyl function. The process is one of very few examples of a catalytic reaction in

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Scheme 35 Tungsten carbenoid intermediate

which a heteroatom-stabilized Fischer carbene complex is implied. Moreover and gratifyingly, bicyclic adducts could be cleanly opened with HCl in acetone to provide valuable eight-membered carbocycles 88 (Scheme 35). An elegant synthesis of furo[3,4-c] heterocyclic (furans and pyrroles) derivatives has been reported by Balme [64]. The overall reaction is an intriguing interplay of inter- and intramolecular events. After a Michael addition involving an alkoxide or an amide, the resulting anion cyclizes in a 5exo-dig fashion, which is rationalized by a palladium complexation of the triple bond. The palladium species involved is a σ -alkynyl hydride species generated through insertion of the metal into the C – H bond of the terminal acetylene 89, giving birth to intermediate 92. Then, departure of a sulfonyl anion triggers the formation of a palladacarbene that undergoes cyclization with the carbonyl function. Thus, the anions of propargyl alcohol 95 and benzylpropargyl amine 98 could serve as triggers for the process involving α,β-unsaturated ketosulfones as Michael acceptors and leading to interesting heteroatomic platforms 97 and 100 (Scheme 36).

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Scheme 36 Inter- and intramolecular events leading to bicyclic furans and pyrroles

Besides these works with tungsten and palladium, a large amount of data has emerged in the last decade on metal halides, which play the role of π-Lewis acids and promote an electrophilic activation of an alkyne moiety. We will describe in detail these recent and spectacular developments. Thus, these reactions generally start with a metal-promoted electrophilic activation of the alkyne moiety, a process well known for some time with organoplatinum complexes [65]. This reactivity has been exploited in the context of skeletal rearrangements of enynes. One of the ﬁrst reports of these was given by Trost in 1988 [66] with a special palladium catalyst (tetracarbomethoxypalladacyclopentadiene, TCPC, in the presence of tri-o-tolylphosphite 102), a metal very rarely met later. As shown in Scheme 37, a formal metathesis reaction takes place in the transformation of 101 in 103 and 104. However, other studies, notably including 13 C labelling by Trost and coworkers, suggested that these reactions are mechanistically distinct from classical metal carbene-mediated pathways [67, 68]. Further work by Trost established the intervention of metallacarbenoid species [69, 70]. A dimer product (108) was observed in the reaction of 106

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Scheme 37 Enyne skeletal rearrangement

in the presence of the highly electron-deﬁcient palladole catalyst 105. This transformation is the signature of an intermediate of type 107. This chemistry could be rendered useful by playing with other insaturations as the carbene acceptor, and a variety of polycyclic adducts such as 109 could prepared. Parallel to these developments, in 1994, Murai and coworkers found a highly selective skeletal reorganization of 1,6- and 1,7-enynes using [RuCl2 (CO)3 ]2 under an atmosphere of carbon monoxide [71]. Interestingly, this contribution mentions that other metal halides such as [RhCl(CO)2 ], ReCl(CO)5 , [IrCl(CO)3 ]n , PtCl2 , and AuCl3 could give birth to similar skeletal reorganization. Murai also proposed three alternatives for the ﬁrst step of the reaction mechanism that accounts for this reactivity: (i) formation of a classical ruthenacyclopentene via oxidative cyclization, (ii) a vinyl ruthenium complex via chororuthenation, or (iii) based on Dixneuf ’s ﬁndings [72], a slipped, polarized η1 -isomer bearing a positive charge at the β-position via rearrangement of an η2 -alkyne ruthenium complex. Shortly afterwards, two reports established the high reactivity of platinum halide salts. First, Blum

Scheme 38 Intervention of a palladacarbene

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Scheme 39 Formation of cyclopropyl-substituted dihydropyrans

reported a novel PtCl4 -catalyzed rearrangement of allyl propargyl ethers to 3-oxabicyclo[4.1.0]heptenes [73]. This series of reactions (110 → 111) and those of Trost (Scheme 38) also represented the ﬁrst entries in the formation of cyclopropyl moieties relying on skeletal rearrangements [74] (Scheme 39). We shall discuss further this intriguing aspect. Murai introduced platinum dichloride as one of the most versatile catalysts for the promotion of various skeletal rearrangements, a ﬁnding soon conﬁrmed by a myriad of papers describing new uses of this metal halide complex [75]. Therein it was shown that 1,6- or 1,7-enynes could be very efﬁciently transformed into vinylcyclopentenes or -hexenes. Recently, it has also been shown that GaCl3 could also trigger the enyne to 1-vinylcycloalkenes skeletal reorganization in a stereospeciﬁc manner. All this paved the way for numerous synthetic applications and notably for total syntheses [76–78]. Thus, the “low tech” PtCl2 , PtCl4 , or PtBr4 systems, as named by Fürstner, proved superior and more reliable than the Trost’s TCPCTFE system [67], on the cyclooctene substrates of type 112 [79]. These reactions, which could be run on a multigram scale, proved useful for instance for the formal synthesis of streptorubine B (Scheme 40). Similarly, a formal synthesis of roseophilin could be devised, based on a nearly quantitative transformation of an enyne moiety into a bicyclic diene system [80].

Scheme 40 Applications in total synthesis

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Many studies rapidly appeared that were aimed at understanding the mechanism of these processes. Since carbenoids species were suspected to play a crucial role in these processes, Murai examined the behavior of acyclic linear dienyne systems such as 116 and 118 in order to trap any carbenoid intermediate by a pending oleﬁn [81]. A remarkable tetracyclic assembly took place and gave as single diastereomers the unprecedented tetracyclo[6.4.0.0.1,9 02,4 ]-undecane derivatives 117 and 119 (Scheme 41). This transformation proved to be relatively general, as shown by the variation of the starting material 116 and 118 and could take place with different organometallic complexes from group 8 to 10 (ruthenium, rhodium, iridium, and

Scheme 41 One-pot formation of tetracyclic architectures from acyclic precursors

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platinum). Formally, this reaction involves two cyclopropanations as if both carbon atoms of the alkyne moiety acted as carbenes, which results in the formation of four C – C bonds in a single operation. An interesting ﬁnding came from changing the connectivity (1,1 instead of 1,2) of the central oleﬁn on the precursor 120, since the usual diene 122 from the skeletal rearrangement was observed in that case (Scheme 42). The fact that the reactivity pattern was totally different if rhodium was used instead of platinum also shows all the subtlety and complexity of the mechanism of these transformations. More recently, the bis-cyclopropanation reactivity has also been observed to make highly strained cyclopropyl-substituted diquinane frameworks in a completely diastereoselective manner [82] (Scheme 43). It is noteworthy that the formal metathesis product was also observed in these reactions, albeit as a minor product, and that the simple introduction of a methyl group on one ene partner was quite troublesome. Interestingly, when an acetate was present at the propargylic position (126), a completely different behavior was observed, giving birth to a mixture of bicyclic products 127 and 128. π-Electrophilic complexation (130), which can be in equilibrium with zwitterionic complex 129, triggers a 1,2-O-

Scheme 42 Diene versus tetracyclic derivative depending upon the metal complex

Scheme 43 Synthesis of highly strained tetracyclic structures

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acyl migration to give oxonium 131 (Scheme 44). Charge readjustment leads to platina carbene intermediate 132 that mainly undergoes cyclization to the six-membered ring 127. This reactivity, which had some precedent with the seminal work of Rautenstrauch [83], has been the source of numerous recent reports [84–87]. This reaction also gave the opportunity to open an access to various polycyclic derivatives, as illustrated by the transformation of the mixture of diastereomers 133 into tricyclic derivative 134 as a single diastereomer, thanks to a completely stereoconvergent process. An interesting entry into carene 136 and carone derivatives 137 has also been disclosed by Fürstner [88]. 1,5-Enynes have proven to be versatile precursors for the preparation of perfumery agents such as sabina ketone (Scheme 45). Diver has recently reported new entries for the assembly of tetracyclic derivatives [89]. Interestingly, ruthenium metathesis-type catalysts have also given birth to tricyclic derivatives incorporating a cyclopropane from dienynes [90]. Cationic gold-based catalysts have proven to be even more reactive promotors of various reactions resulting from a preliminary electrophilic activation [91]. They also allow the formation of tetracyclic derivatives 140 from acyclic precursors 139 at low temperature and as single diastereomers. In one case, the minor metathesis diene 141 was isolated. Tetracyclic products

Scheme 44 1,2-O-acyl migration

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Scheme 45 Various applications of the 1,2-O-acyl migration

Scheme 46

139a and 139b resemble the natural product myliol and related tetracyclic sesquiterpenes, although the fusion of the dimethylcyclopropane unit occurs with the opposite conﬁguration (Scheme 46).

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Gold(I) or (III) complexes are attracting a lot of attention and allow very interesting transformations [92]. Kozmin has reported a gold-catalyzed assembly of heterobicyclic sytems like 145 that consist of a double cyclization of simple 1,5-enynes of type 144 armed with either oxygen or nitrogen-based nucleophiles [93]. The diastereospeciﬁc course of the reaction is rationalized by either a concerted process from a η2 -gold complex 146, or from a stepwise mechanism involving a nucleophilic opening of the cyclopropyl gold carbene intermediate 147 originating from a 5-endo-dig process. Proton transfer from the resulting intermediate 148 achieves the construction of the bicyclic framework (Scheme 47). An enriched 1,3-diene as in substrates 149 can act as a nucleophile towards an activated alkyne. Iwasawa has reported an elegant synthesis of diquinane frameworks 150 that operates with various metals, out of which rhenium(I) appears to be the best [94]. Minor products 152 presumably result from insertion of a carbenoid entity into the neighboring activated benzylic C – H bond. The same carbenoid species can undergo a 1,2-H shift to give 151 (Scheme 48). The Uemura group has been very creative in the activation of alkynes with a variety of metals: Mo, W, Ru, Rh, Pd, and Pt. 2-Furyl or 2-pyrrolyl

Scheme 47 Double cyclization of 1,5-enynes bearing a nucleophilic center

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Scheme 48 Catalytic diquinane formation

carbenoids can be generated in situ from ene-yne-aldehydes or -ketones systems as well as ene-yne-aldimine precursors [95, 96]. The same group has developed a simple preparation of fused polycyclic compounds through an intramolecular cyclization of a propargyl alcohol onto a pending oleﬁn on precursors 153, to give polycyclic derivatives 154 as a mixture of syn and anti diastereoiomers [97]. An intriguing aspect of this reaction is that the catalyst is a mixture of a ruthenium and a platinum complex, each acting separately and selectively. The thiolate-bridged diruthenium complex ﬁrst promotes propargylic substitution via allenylidene complex 155. The latter evolves via an ene reaction to give a 1,5-enyne system 156 that can cyclize in the presence of PtCl2 in 5-exo-dig manner (Scheme 49).

Scheme 49 Ruthenium- and platinum-catalyzed sequential reactions

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Using the same metal for conducting two distinct steps is a powerful approach. Allenynes partners are highly appealing in the context of organometallic catalysis. One problem though might reside in the tedious synthesis of the precursors. In order to alleviate this problem, we have quite recently reported a dual catalysis by PtCl2 [98]. The ﬁrst catalytic step consists in a 1,3migration of a propargylic acetate group (158) that generates an allenylester intermediate 160. The latter then undergoes a cycloisomerization process giving birth to a dienyl ester 161 that can be cleanly hydrolyzed to a conjugated enone 159 (Scheme 50).

Scheme 50 Dual PtCl2 catalysis

Scheme 51 Biomimetic mercury(II)-catalyzed polycyclization

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Mercury(II) is certainly an obvious choice for an electrophilic activation of an alkyne moiety. Nishizawa has very recently published a catalytic and biomimetic polycyclization leading to tricyclic derivatives 163, from aromatic precursor 162 [99]. After the Friedel&Crafts step that generates 166 and TfOH, protonation of the alkene as in 167 is followed by regeneration of the catalyst (Scheme 51).

4 Conclusions In this review, we have shown the major advances in the growing ﬁeld of cascade chemistry that have led to regio-, chemo-, and stereoselective formation of several new carbon–carbon and carbon–heteroatom bonds in a stepwise economical fashion by using transition metal-catalyzed reactions. These approaches have already allowed very impressive and rapid construction of unnatural and natural polycyclic compounds of very high molecular complexity. These initial achievements should stimulate the synthetic community to pursue further works; notably to develop more efﬁcient and selective strategies that involve new generations of versatile catalysts. Next endeavors will have to focus on green processes as well as asymmetric catalysis.

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Top Organomet Chem (2006) 19: 295–326 DOI 10.1007/3418_010 © Springer-Verlag Berlin Heidelberg 2006 Published online: 7 April 2006

Cascade and Sequential Catalytic Transformations Initiated by Ruthenium Catalysts Christian Bruneau (u) · Sylvie Dérien · Pierre H. Dixneuf Institut de Chimie de Rennes, UMR6509, Université de Rennes-CNRS, Organométalliques et Catalyse, Campus de Beaulieu, 35042 Rennes Cedex, France [email protected] 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Cascade Catalytic Reactions Involving Ruthenium Catalysts . . . . . . . . Cascade Enyne Metathesis . . . . . . . . . . . . . . . . . . . . . . . . . . . Cascade Alkene Metathesis . . . . . . . . . . . . . . . . . . . . . . . . . . .

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3 3.1 3.2 3.3

Sequential Catalytic Transformations Involving Ruthenium Catalysts Only Only One Ruthenium Precursor at the Outset of the Reaction . . . . . . . . Several Ruthenium Precursors at the Outset of the Reaction . . . . . . . . Modiﬁcation of the First Ruthenium Catalyst by External Addition of Reagent after the First Step . . . . . . . . . . . . . ROMP Polymerization/C = C Bond Hydrogenation . . . . . . . . . . . . . . ADMET Polymerization/C = C Bond Hydrogenation . . . . . . . . . . . . . Diblock ROMP/ATRP Polymerization/C = C Bond Hydrogenation . . . . . Ring-Closing Metathesis or Cross-Metathesis/C = C Bond Hydrogenation . Enyne Metathesis/Cyclopropanation . . . . . . . . . . . . . . . . . . . . . . Michael Addition/Ketone Enantioselective Hydrogenation . . . . . . . . . . Enantioselective C – C Bond Formation/Ketone Hydrogenation . . . . . . .

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Abstract Ruthenium holds a prominent position among the efﬁcient transition metals involved in catalytic processes. Molecular ruthenium catalysts are able to perform unique transformations based on a variety of reaction mechanisms. They arise from easy to make complexes with versatile catalytic properties, and are ideal precursors for the performance of successive chemical transformations and catalytic reactions. This review provides examples of catalytic cascade reactions and sequential transformations initiated by ruthenium precursors present from the outset of the reaction and involving a common mechanism, such as in alkene metathesis, or in which the compound formed during the ﬁrst step is used as a substrate for the second ruthenium-catalyzed reaction. Multimetallic sequential catalytic transformations promoted by ruthenium complexes ﬁrst, and then by another metal precursor will also be illustrated. Keywords Cascade catalytic reactions · Ruthenium catalysis · Sequential catalytic reactions

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1 Introduction During the last decade, molecular ruthenium catalysts have attracted increasing interest for organic synthesis due to their ability to perform speciﬁc new reactions with a large panel of applications. Beside individual catalytic transformations, a variety of multi-step catalytic transformations in one pot have appeared. These transformations present practical and economic advantages as far as they are efﬁcient, selective and proceed with atom economy. Ruthenium catalysis has entered this ﬁeld with a variety of cascade and sequential catalytic transformations. In this review, we will focus on cascade and sequential catalytic transformations in which the ﬁrst one is a ruthenium-catalyzed reaction. This will include: (i) Cascade catalytic reactions in which the transformations are performed successively from only one ruthenium catalyst precursor, present from the outset of the reaction, and which involve a common mechanism. These catalytic cascade reactions mainly concern alkene and enyne metathesis transformations. Many ruthenium catalytic transformations involve sequential formation of carbon–carbon and carbon–heteroatom bonds within one catalytic cycle. They have been recently reviewed [1, 2], and will not be presented here. (ii) Sequential catalysis, in which the compound formed during the ﬁrst step is used as a substrate for the second ruthenium-catalyzed reaction. This type of catalytic sequence can take place without changing any reaction parameters, or it can be induced by addition of a reagent which modiﬁes the nature of the ruthenium catalytic species and triggers another catalytic cycle. They will also be reported here, even when the nature of the second catalyst is not proved. (iii) Multimetallic sequential catalysis where the second catalytic transformation is catalyzed by another metal precursor present from the outset of the reaction. It is noteworthy that an illustrative review on tandem catalysis, including some ruthenium-catalyzed transformations, has recently appeared [3], which also proposed a useful deﬁnition rationalization effort.

2 Cascade Catalytic Reactions Involving Ruthenium Catalysts Cascade reactions in which the transformations are performed with a catalytic system offering, along the various successive steps, only one single catalytic process are always attractive but true examples have not been frequently described. This part will present examples of a single mechanism

Cascade and Sequential Catalytic Transformations Initiated by Ruthenium Catalysts 297

promoted by ruthenium catalytic precursors. They essentially concern alkene and enyne metathesis reactions. This topic beneﬁts from the long-term investment in both fundamental science and applications leading to the discovery of the alkene metathesis mechanism involving a metal carbene intermediate by Y. Chauvin in 1971, followed by the preparation of well-deﬁned efﬁcient alkylidene metal catalyst derivatives of molybdenum by R.R. Schrock in 1990, and ruthenium by R.H. Grubbs in 1992. The importance of their contributions in the development of alkene metathesis catalysis has been recognized with the award of the Nobel prize 2005 for chemistry. 2.1 Cascade Enyne Metathesis Ruthenium-alkylidene complexes have been revealed as efﬁcient catalysts in alkene and enyne metathesis reactions for the formation of ring structures including the synthesis of natural products [4–6]. To obtain more complex ring systems, cascade metathesis reactions involving molecules with several unsaturated C – C bonds have been studied. In the ﬁrst example of a cascade metathesis reaction of dienyne, Grubbs and co-workers have shown that if a triple bond is correctly located between two oleﬁnic groups, two successive ring-closing metatheses (RCM) occur in the presence of a catalytic amount of RuCl2 (PCy3 )2 (= CHCH = CPh2 ) and leads to a fused bicyclic compound [7, 8] (Scheme 1). The enyne metathesis generates the ﬁrst ring and an intermediate ruthenium carbene species, which undergoes a second RCM process to produce the fused [n.m.0]bicyclic product (Scheme 2). This strategy is general and allows the construction of a variety of fused rings. Extended to analogous precursors bearing two or more of these oleﬁn metathesis relays such as (dienyl)polyalkynes, this reaction leads to the synthesis of polycyclic molecules [9] (Scheme 3). However, starting from more functionalized substrates, Grubbs catalysts of the ﬁrst generation were not efﬁcient to achieve cascade ring-closing metathesis of dienynes. The development of the second generation ruthenium catalysts, containing a N-heterocyclic ligand, has allowed the use of functionalized oleﬁns such as α,β-unsaturated carbonyl compounds to obtain α,β-unsaturated lactones and enones via cascade RCM reactions [10]

Scheme 1

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Scheme 2

Scheme 3

(Scheme 4). This cascade RCM applied to diene-ynamides leads to fused azabicyclic products with good yields [11], and carbohydrates can be used to synthesize polyoxygenated bicyclic systems that contain seven- and eightmembered rings [12]. Chiral dioxabicyclic systems are selectively formed from 3,4-bisallyloxybut1-yne derivatives under an ethylene atmosphere. A single RCM is performed when a RuCl2 (PCy3 )2 (= CHPh) is employed, while the cascade RCM of dienyne is the major reaction with a second generation Grubbs catalyst (Scheme 5). In this case, the substitution of the allyloxy groups can selectively lead to dioxabicyclo[4.4.0]decane or to dioxabicyclo[5.3.0]decane [13]. Illustrating the high potential of these reactions, cascade ring-closing metathesis of dienynes or trienynes have also provided access to fused 6,8,6-tricarbocyclic systems [14], and to a highly functionalized 5,7,6-tricyclic ring system related to the terpenoid guanacastepene A structure [15].

Scheme 4

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Scheme 5

Recently, a catalytic system consisting of a second generation Grubbs catalyst or an in situ non-carbenic ruthenium complex have allowed a cascade catalytic reaction of cyclopropanation/ring closing metathesis of dienynes containing a malonate or bissulfone moiety. In this reaction, the interaction between the triple bond and one double bond gives a bicyclic product via cyclopropanation, and then the subsequent diene RCM produces the last cyclization step [16] (Scheme 6). Enynes containing a cycloalkene moiety can lead, in the presence of another oleﬁn and a catalytic amount of ruthenium carbene complex, to ringopening and ring-closing metathesis (ROM–RCM) followed by cross metathesis (CM) to produce trienes (Scheme 7). Ethylene [17, 18] or monosubstituted alkenes [18–20] have been used to carry out the CM step (Scheme 8). In this latter case, the presence of either oxygen or nitrogen at the propargylic position seems to have an inﬂuence on the regioselectivity of the incorporation of the CM partner. The extension of this reaction to cyclic enones produces trienes, able to perform intramolecular Diels–Alder cycloaddition reactions giving fused tricyclic products [21].

Scheme 6

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Scheme 7

Scheme 8

Under an atmosphere of ethylene, the ROM–RCM of cycloalken-ynes, when the cycloalkene bears the alkyne moiety at the oleﬁnic C1 position, produce dimeric and/or bicyclic compounds [22] (Scheme 9). The expected bicyclic product with a cyclooctadiene ring is obtained with a low yield, whereas the dimeric macrocycle is the major compound. Enynes without the cycloalkene moiety can also react with electrondeﬁcient alkenes by a cascade ring-closing metathesis-cross metathesis (RCM–CM) process [23] (Scheme 10). The use of Hoveyda’s catalyst is necessary, not to stop the reaction at the RCM step, but to perform the subsequent CM step. Indeed, the organic product arising from the RCM is ﬁrst formed and then reacts with the alkene in the presence of the ruthenium complex to give the CM reaction.

Scheme 9

Cascade and Sequential Catalytic Transformations Initiated by Ruthenium Catalysts 301

Scheme 10

The opposite sequence is described with alkynyl silyloxy-tethered enynes. A cascade CM–RCM reaction proceeds in the presence of a second generation ruthenium carbene to give cyclic siloxanes. The initial CM is directed to occur on the alkyne by employing sterically hindered substituted alkenes tethered to the alkyne via a silyl ether group [24] (Scheme 11). The intermolecular enyne cross metathesis, and consecutive RCM, between a terminal alkyne and 1,5-hexadiene produces cyclohexadienes, by cascade CM–RCM reaction, and trienes, formed during the sole CM step. Studies of various parameters of the reaction conditions did not show any improvement of the ratio of desired cyclohexadiene product [25] (Scheme 12). The reaction with cyclopentene instead of hexadiene as the alkene leads to 2-substituted-1,3-cycloheptadienes [26]. After the ﬁrst cyclopentene ROM, the enyne metathesis is favored rather than ROMP by an appropriate balance between cycloalkene ring strain and reactivity of the alkyne. Diynes are also used to perform intermolecular enyne metathesis. With the objective of producing functionalized hetero- and carbocycles, a cascade diyne-alkene cross metathesis leading to ﬁve-membered cyclic products has recently been proposed [27] (Scheme 13).

Scheme 11

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Scheme 12

Scheme 13

Scheme 14

Norbornene derivatives bearing two alkynes undergo cascade enyne metathesis reactions when treated with a ﬁrst generation ruthenium carbene and ethylene, giving heterocyclic dienes [28]. The ROM of the norbornene moiety initiates the cascade enyne RCM reactions (Scheme 14). When ethylene is replaced by a monosubstituted alkene, a single enyne RCM takes place, after the initial ROM of norbornene. 2.2 Cascade Alkene Metathesis After they demonstrated that an alkyne well located between two oleﬁnic groups acts as a relay for the metathesis catalyst [7], producing bicyclic compounds by enyne metathesis, Grubbs and co-workers have shown that the unsaturation of a cycloalkene could also be used to relay the metathesis catalyst. Indeed, as a typical molecule, a strained cycloalkene located between oleﬁnic side chains, allows cascade alkene metatheses via the ring closing-ring opening-ring closing metathesis (RCM–ROM–RCM) of cyclic alkenes. Cycloalkenes bearing two allyloxy groups [29] (Scheme 15) or α,β-

Cascade and Sequential Catalytic Transformations Initiated by Ruthenium Catalysts 303

Scheme 15

unsaturated carbonyl functions [10] as oleﬁnic side chains, in the presence of a catalytic amount of a ruthenium carbene complex, lead to polycyclic ethers or polycyclic substrates with an unsaturated lactone moiety in good yields. The reactivity of the cycloalkenes depends on strain, thus ring size of the molecules, but good results are obtained with four- to eight-membered rings and with norbornenes as cycloalkenes. Multiple cyclooleﬁnic relays are also suitable substrates to promote cascades of RCM–ROM–RCM reactions [9] (Scheme 16). Thus, N-protected polycyclic amines have been synthesized in moderate to good yields, but an increasing number of cyclopentene relays gave rise to less efﬁcient cascade transformations. This ring rearrangement metathesis (RCM–ROM–RCM) has been extensively reported by Blechert and co-workers for its application in the synthesis of natural products [30–34]. A similar type of cascade reaction has been carried out with cyclic alkenes bearing only one oleﬁnic side chain to obtain substituted heterocycles via ruthenium-catalyzed ring closing-ring opening metathesis (RCM– ROM) reactions. The preparation of enantiomerically pure cis- or trans-α,αdisubstituted piperidines has been achieved in the same yield for the two diastereoisomers [35] (Scheme 17). This reaction has also been used as a key step for the synthesis of natural products [36–39]. The cascade alkene metathesis processes described above result from the combination of ROM and RCM. The cascade alkene metathesis reaction involving ROM, RCM and CM reported in Scheme 18 leads to [n.3.0]bicycles in a stereo-controlled manner [40]. The reaction combines ring opening of

Scheme 16

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Scheme 17

Scheme 18

norbornene, ring-closing metathesis with the terminal double bond and cross metathesis with a second alkene. Different lengths of the norbornene side chain have allowed the synthesis of bicycles with various ring size (n = 0, 1, 2), even relatively strained bicyclooctene derivatives (n = 0). This reaction applied to cascade metathesis of allyl-(2-endo-7-oxanorborn-5-enyl)ethers with allyl acetate as the second alkene stereoselectively affords substituted cisfused bicyclic ethers [20]. The enantioselective synthesis of azabicyclic γ -lactams starting from 2-azanorbornenones after treatment of a catalytic amount of RuCl2 (PCy3 )2 (= CHPh) in the presence of ethylene or allyl acetate proceeds also via ring rearrangement—alkene metathesis (ROM–CM–RCM) [41] (Scheme 19). If n = 0 or 3, no RCM occurs and a cyclic dialkenyl compound is formed by cascade ROM–CM reactions. All the above cascade alkene metathesis reactions are based on the ROM of a cycloalkene moiety. Harrity and co-workers have described the synthesis of functionalized spirocyclic systems by cascade selective oleﬁn ringclosing metathesis reactions from an acyclic tetraalkene. The selectivity for ﬁve-membered ring closure over seven-membered ring closure would be the result of a kinetically favored cyclization process [42] (Scheme 20). The syn-

Scheme 19

Cascade and Sequential Catalytic Transformations Initiated by Ruthenium Catalysts 305

Scheme 20

thesis of angularly fused tricyclic compounds has also been studied through the use of selective cascade RCM reactions of cyclopentane derivatives bearing four acyclic alkenyl side chains [43].

3 Sequential Catalytic Transformations Involving Ruthenium Catalysts Only 3.1 Only One Ruthenium Precursor at the Outset of the Reaction In this section, we will ﬁrst present sequential catalytic reactions, in which the compound formed during the ﬁrst step is used as the substrate for the second reaction, both catalytic reactions being catalyzed by ruthenium species arising from a unique precursor. The ruthenium-catalyzed Rosenmund– Tishchenko reactions represent one of the ﬁrst examples of such chemical transformations (Scheme 21) [44]. Ru(H)Cl(PPh3 )3 in the presence of 2,4,6-collidine at 55 ◦ C under 1 bar of hydrogen pressure promotes the formation of benzyl benzoate from benzoyl chloride and hydrogen. This transformation involves the intermediate formation of benzaldehyde, which then rapidly reacts with benzoyl chloride to produce the benzoate. The ﬁrst catalytic cycle involves the formation of [Ru(H)COPh] species, delivering benzaldehyde, or directly entering the second catalytic cycle to form a [Ru(COPh)(OCH2 Ph)] intermediate via in-

Scheme 21

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sertion of an aldehyde moiety into a Ru – H bond. Subsequent reductive elimination leads to benzyl benzoate as the ﬁnal product. In the presence of catalytic amounts of 1,10-phenanthroline and Ru3 (CO)12 , methyl and ethyl acrylate were subject to sequential transformations leading to valerolactones (Scheme 22) [45]. The ﬁrst catalytic hydroformylation reaction gives β-formyl esters which react with the starting acrylate via Michael addition. A subsequent hydrogenation of the formyl group provides the alcohol which cyclizes under the experimental conditions. Hydroformylation, Michael addition and hydrogenation are catalyzed by in situ generated ruthenium species. Direct hydrogenation of the acrylate competes with hydroformylation and explains the low yields observed. This example shows the difﬁculty in obtaining sequential noncompeting reactions, when a single metal precursor is used. In the presence of PPh3 instead of phenanthroline, the hydrogenation step does not take place and the linear formyl dimethyl ester is obtained in 18% yield. Several ruthenium complexes, especially ruthenium hydrides or ruthenium complexes able to generate metal hydride species in situ have shown their potential to catalyze carbon–carbon double bond isomerization or allylic activation. This transformation may give rise to the formation of new substrates which can undergo further catalytic transformation such as oleﬁn metathesis, Claisen rearrangement, ... The sequence isomerization/ring-closing metathesis has been observed with wellestablished metathesis catalysts and is illustrated by the formation of macrolactones catalyzed by RuCl2 (= CHPh)(PCy3 )(bis(mesityl)imidazolylidene) in toluene (Scheme 23) [46]. Besides the expected 21-membered lactone, the 20-membered ring formed in 15% yield corresponds to cyclization after iso-

Scheme 22

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Scheme 23

merization of one of the terminal oleﬁnic bonds with elimination of propene rather than ethylene. With the same catalyst precursor, attempts to synthesize seven-membered cyclic enamides via ring closing metathesis of N-protected 5-hexenyl enamines failed, and selectively led to the formation of six-membered cyclic enamides resulting from initial isomerization of the 5-hexenyl into a 4-hexenyl group followed by cyclization [47]. Several examples of sequential isomerization/ring-closing metathesis for the preparation of heterocycles have also been performed by using two successive catalytic reactions catalyzed by two different ruthenium catalysts, but the second catalyst was introduced after completion of the ﬁrst catalytic reaction. The isomerization was usually catalyzed by RuHCl(CO)(PPh3 )3 [48], or RuCl2 (= CHPh)(PCy3 )(bis(mesityl)imidazolylidene) in the presence of trimethylsilyl vinyl ether [49], whereas a classical metathesis catalyst was subsequently introduced for the cyclization [48, 49]. Interestingly, when RuCl2 (= CHPh)(PCy3 )(bis(mesityl)imidazolylidene) was used as the catalyst in dichloromethane under a N2 : H2 (95 : 5) atmosphere, the ring-closing metathesis of allyl homoallyl ethers and tosylamide was performed but a subsequent ruthenium-catalyzed double bond isomerization took place and very little hydrogenation was observed (Scheme 24) [50]. The metathetic transformation of enynes in the presence of ruthenium precursors provide conjugated cycloalkenes, which are reactive under Diels– Alder reaction conditions with dienophiles. Many examples of such thermally activated [2 + 4] cycloadditions have been reported in the literature [51–59], and the beneﬁcial effect of a ruthenium catalyst has been shown when the reaction was performed in one pot without isolation of the diene [60]. In the presence of appropriate ruthenium catalyst precursors, diallyl and allyl homoallyl ethers do not lead to the expected metathesis or cycloisomerization products, but undergo ﬁrst isomerization to form allyl vinyl ethers, and then a Claisen rearrangement which gives unsaturated alde-

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Scheme 24

hydes (Scheme 25). Thus, when the typical metathesis catalyst precursor RuCl2 (= CHPh)(PCy3 )2 is used in the presence of ethyl vinyl ether, the ruthenium hydride RuHCl(CO)(PCy3 )2 expected to be formed upon heating at 110 ◦ C promotes these two successive reactions [61]. We have also shown that the same catalytic sequence took place when the catalytic system was generated in situ from Ru3 (CO)12 , bis(2,6-diisopropyl) phenylimidazolinium chloride and cesium carbonate [62], from (bis(oxazo-

Scheme 25

Cascade and Sequential Catalytic Transformations Initiated by Ruthenium Catalysts 309

line)) and (bisimine)-ruthenium complexes [63], and from the mononuclear complex Ru(methallyl)2 (cyclooctadiene) [64]. It is interesting to mention that the vinylic allyl ether PhCH = CH – OCH2 CH = CH2 together with its Claisen-rearranged aldehyde CH2 = CHCH2 CH (Ph)CHO have been obtained via ruthenium-catalyzed anti-Markovnikov addition of allyl alcohol to phenylacetylene, thus representing another example of sequential transformation initiated by ruthenium catalysis and ending by a Claisen rearrangement [65]. Under much more drastic conditions, at 200 ◦ C RuCl2 (PPh3 )3 promotes the isomerization of diallyl ethers into aldehydes [66], and under 50 bar of

Scheme 26

Scheme 27

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Scheme 28

carbon monoxide a subsequent ruthenium-catalyzed hydroacylation takes place to provide saturated cyclic ketones (Scheme 26) [67]. The selective consecutive cycloisomerization/isomerization of 1,6-dienes to form exocyclic and then endocyclic oleﬁnic compounds is not a common transformation. At 80 ◦ C, with RuCl2 (p-cymene)(N-mesitylmethylbenzimidazole) activated by reaction with diphenylpropynol in the presence of AgOTf as the catalyst, as an attempt to generate allenylidene intermediate, diallyl tosylamide is selectively transformed into 3-methyl-4-methylene-Ntosylpyrrolidine. When this catalytic cycloisomerization is completed, the isomerization into 3,4-dimethyl-N-tosylpyrrolidine starts without external modiﬁcation of the catalytic system (Scheme 27) [68]. The double phosphinylation of propargylic alcohols with diphenylphosphine oxide to form 2,3-bis(diphenylphosphinyl)-1-propenes is catalyzed by a thiolate-bridged diruthenium complex (Scheme 28) [69]. It has been shown that the reaction proceeds via three ruthenium-catalyzed transformations : propargylation of the phosphine oxide, alkyne to allene isomerization, and addition of phosphine oxide to the allene structure. 3.2 Several Ruthenium Precursors at the Outset of the Reaction A straightforward pyrrole synthesis from N,N-diallylamine catalyzed by a catalytic system generated from two ruthenium precursors has been recently reported. RuCl2 (= CHPh)(PCy3 )(bis(mesityl)imidazolinylidene) associated to RuCl3 .xH2 O provides the pyrrole, formally resulting from ring-closing metathesis/dehydrogenation of the transient pyrroline (Scheme 29) [70]. The reaction takes place at 60 ◦ C in 1,2-dichloroethane and is improved by

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Scheme 29

the effect of ultrasonic activation. It is noteworthy that this reaction only proceeds with tertiary amines and does not operate with N-protected diallyl amines such as N-Boc, N-Tosyl, N-acetyl. The coordination of the nitrogen atom to a Lewis acid ruthenium species might be the key for both transformations. It has been shown that the simultaneous use of the metathesis catalyst RuCl2 (PCy3 )(IMes)(= CHPh) and the isomerization catalyst RuClH(CO) (PPh3 )3 promoted the selective ring-closing metathesis of the diene resulting from initial isomerization of congested 1,9-dienes [71]. 3.3 Modification of the First Ruthenium Catalyst by External Addition of Reagent after the First Step 3.3.1 ROMP Polymerization/C = C Bond Hydrogenation The project to produce polyethylene, with regularly displayed functional groups along the chain, was designed by successively promoting the ringopening cyclic oleﬁn polymerization (ROMP) with alkene metathesis catalyst and then the catalytic polymer C = C bond hydrogenation, using the residual metal catalyst for hydrogenation (Scheme 30). The ﬁrst attempt seems to have been promoted by binuclear ruthenium alkene metathesis catalyst for the ROMP of cyclooctene followed by hydrogenation (50 ◦ C, 30 psi H2 ) in the presence of 10 equiv. of triethylamine [72] (Scheme 31). It was motivated by the observed capability of [RuCl2 (arene)]2

Scheme 30

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Scheme 31

Scheme 32

derivative to hydrogenate alkenes [73, 74], and to be the precursor of the binuclear alkene metathesis catalyst on reaction with RuCl2 (= CHR)(PCy3 )2 . Thus, the alkylidene-ruthenium moiety likely promotes the ROMP polymerization and the ruthenium species arising from the addition of amine and displacement of p-cymene catalyzes the hydrogenation. A similar approach was performed using the alkene metathesis catalyst RuCl2 (= CHPh)(PCy3 )2 [76]. It was known that this complex reacts with hydrogen in THF to give ruthenium hydride complexes capable of catalytic alkene hydrogenation [77] (Scheme 32). Thus, the ROMP of cyclooctene was carried out with RuCl2 (= CHPh) (PCy3 )2 in dichloromethane, as alkene metathesis does not take place in THF, and then after dilution with THF catalytic hydrogenation was completed after 24 h at 1000 psi H2 . The addition of NEt3 , by generating a new hydrogenation catalyst, increases hydrogenation activity (85%, 100 psi H2 ). These conditions applied to sequential ROMP of methoxymethyl norbornene derivative and hydrogenation afforded almost monodispersed hydrogenated polynorbonene derivative (Mn = 29 500, PDI = 1.04) [76]. A review has reported the initial tandem ROMP/hydrogenation catalytic reactions [78]. 3.3.2 ADMET Polymerization/C = C Bond Hydrogenation Sequential homogeneous acyclic diene metathesis (ADMET) polymerization and heterogeneous hydrogenation were performed on several types of dienes. It followed the observation that RuCl2 (= CHPh)(PCy3 )2 deposited on silica, by simple addition of silica to a metathesis reaction solution, constituted a hydrogenation catalyst [79]. Thus, the ADMET reaction of 1,9-decadiene in the presence of soluble RuCl2 (= CHPh)(PCy3 )2 catalyst

Cascade and Sequential Catalytic Transformations Initiated by Ruthenium Catalysts 313

Scheme 33

Scheme 34

was performed in the bulk, in the presence of 9-decenylacetate as a chain limiter. The unsaturated formed polymer was mixed with silica and exposed to hydrogen (120 psi H2 , 30 min). Partial hydrogenation took place. Then addition of toluene and further hydrogenation (120 psi H2 , 90 ◦ C, 5 h) led to quantitative formation of the polyethylene as a white solid [79] (Scheme 33). A similar procedure was used for the preparation of functionalized polyethylenes such as that including ester groups as the internal function regularly placed in the chain [79] (Scheme 34). Thus, the ester with two terminal alkene bonds was successively submitted to homogeneous ADMET to give the unsaturated polymer. Then, after addition of silica gel, the product was submitted to hydrogenation. A highly crystalline polymer (Tm = 97 ◦ C) [– CO2 (CH2 )18 –]n was produced (Scheme 34). This strategy also allowed the one pot preparation of polyethylene with regularly placed carbonyl groups, according to the following Scheme 35 [79].

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Scheme 35

3.3.3 Diblock ROMP/ATRP Polymerization/C = C Bond Hydrogenation The ruthenium catalyst RuCl2 (= CHPh)(PCy3 )2 is able to promote both alkene metathesis polymerization (ROMP) and atom transfer polymerization (ATRP) [80, 81]. The bifunctional catalyst A was designed to promote both ROMP of cyclooctadiene (COD) and ATRP of methyl methacrylate (MMA). Thus, catalyst A was employed to perform both polymerizations in one pot leading to diblock polybutadiene/polymethylmethacrylate copolymer (58–82% yield, PDI = 1.5). After polymerization the reaction vessel was exposed to hydrogen (150 psi, 65 ◦ C, 8 h), under conditions for Ru(H2 )(H)Cl(PCy3 )2 to be produced, and the hydrogenation of diblock copolymer could attain 95% [82] (Scheme 36).

Scheme 36

Cascade and Sequential Catalytic Transformations Initiated by Ruthenium Catalysts 315

3.3.4 Ring-Closing Metathesis or Cross-Metathesis/C = C Bond Hydrogenation The ability of ruthenium alkene metathesis catalysts to subsequently generate under hydrogen atmosphere a C = C bond hydrogenation catalyst has been used for the synthesis of saturated macrocycles. The ring-closing metathesis (RCM), that leads to unsaturated macrocycles usually with no stereoselectivity of the formed C = C bond, and subsequent catalytic hydrogenation affords unique cyclic compounds. Thus, (R)-(–)-muscone has been produced from the hydroxydiene precursor in 56% yield, by successive RCM with the ruthenium-alkylidene catalyst RuCl2 (= CHPh)(IMes)(PCy3 ), dehydrogenative oxidation of alcohol, and hydrogenation with a catalyst arising from the parent alkene metathesis catalyst [83] (Scheme 37). The strategic sequential RCM/hydrogenation reactions have been used for the synthesis of (R)-(+)-muscopyridine. The RCM of the protonated pyridine bearing two alkene chains was performed with an indenylidene-ruthenium catalyst that also allows hydrogenation under 50 atm of hydrogen, and muscopyridine was obtained in 57% yield [84] (Scheme 38). Normuscopyridine was similarly prepared in 68% yield [84]. A similar strategy has been used to build robust conformationally restricted cyclic dinucleotides. Thus, dinucleotide with two allyl chains reacts in the presence of ruthenium alkylidene catalyst and leads to the unsaturated cyclic dinucleotide. On addition of hydrogen (1000 psi H2 ) the saturated related dinucleotide was obtained, which appears to be more stable toward nucleophiles than the parent unsaturated one [85] (Scheme 39).

Scheme 37

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Scheme 38

Scheme 39

Scheme 40

A better hydrogenation catalyst was generated by reaction of alkene metathesis ruthenium catalyst, with sodium hydride, after the RCM reaction was performed. In that case, hydrogenation can be performed under 1 bar of H2 at 20 ◦ C [86]. Thus, cyclopentanols can be selectively prepared in one pot by RCM of the parents dienes, followed by addition of NaH and hydrogenation [86] (Scheme 40).

Cascade and Sequential Catalytic Transformations Initiated by Ruthenium Catalysts 317

Scheme 41

An attempt to produce indenols via RCM reaction of the parent dienes, in the presence of RuCl2 (= CHPh)(imidazolinylidene)(PCy3 ) at 80 ◦ C, actually led to the corresponding indenones [87]. Whereas the indenols are obtained at room temperature, it was shown that the alkene metathesis ruthenium catalyst is also responsible for the dehydrogenative oxidation of indenols at 80 ◦ C (Scheme 41). 3.3.5 Enyne Metathesis/Cyclopropanation Enyne metathesis catalyzed by RuCl2 (= CHPh)(PCy3 )2 under ethylene is a very efﬁcient reaction to produce conjugated dienes with one endocyclic C = C bond and an exocyclic vinylic bond. The addition of a diazo com-

Scheme 42

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pound after completion of the metathesis reaction and heating at 75 ◦ C leads to the selective catalytic cyclopropanation of the exocyclic C = C bond with a low cis/trans stereoselectivity [88] (Scheme 42). The catalytic species which is generated in the presence of the diazoester is no longer active in enyne metathesis after the cyclopropanation reaction, which shows that the metathesis ruthenium carbene catalyst has been irreversibly modiﬁed to form a cyclopropanation catalyst. This reaction contrasts with the transformation obtained with the same substrates introduced at the outset of the reaction in the presence of RuClCp∗ (cod), which affords another type of cyclopropane derivative via a vinylation/cyclopropanation tandem reaction [89, 90] (Scheme 42). 3.3.6 Michael Addition/Ketone Enantioselective Hydrogenation The Michael addition of malonates to cyclic enones, catalyzed by chiral Ru(η6 -arene)(p-toluenesulfonyl-1,2-diamine), has been performed to afford the adduct with excellent enantiomeric excess [91, 92]. A related catalyst was designed to perform sequentially the Michael addition to cyclic enone and the enantioselective hydrogenation of the ketone. Thus, the chiral ruthenium catalyst B containing trans hydride and borohydride ligands was able to enantioselectively (96% ee) promote the Michael addition of malonate to cyclohexenone. Further in situ catalytic hydrogenation (400 psi H2 ) was performed and led to excellent diastereoselectivity trans/cis : 30/1 [93] (Scheme 43).

Scheme 43

3.3.7 Enantioselective C – C Bond Formation/Ketone Hydrogenation Optically active polymer containing the BINOL unit, associated with dialkylzinc, was shown to promote the enantioselective alkylation of a variety

Cascade and Sequential Catalytic Transformations Initiated by Ruthenium Catalysts 319

Scheme 44

of aldehydes [94]. On the other hand, Noyori et al. [95] have shown that RuCl2 (BINAP) ((R, R)-1,2-diphenylethylenediamine) catalyzed the enantioselective hydrogenation of ketones. Thus, a polymer containing both BINOL and RuCl2 (BINAP)(DPEN) has been prepared. It was shown to selectively transform in one pot para-acetyl benzaldehyde into optically active diol [96] (Scheme 44). Thus, the catalytic addition of ZnEt2 to the aldehyde function was ﬁrst performed in toluene and then catalytic hydrogenation (150 psi of H2 ) in isopropanol was carried out using the same bifunctional catalyst. These one-pot catalytic reactions lead to 99% yield of optically active diol with ee = 99% for addition of ZnEt2 and de = 86% for hydrogenation [96].

4 Multimetallic Sequential Catalytic Transformations Initiated by Ruthenium Catalysts The combination of ruthenium and palladium catalysis has been illustrated by the performance of the oleﬁn metathesis—Heck coupling sequence [97,

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Scheme 45

98]. The ring-closing metathesis of amides bearing two oleﬁnic arms and a halogenated phenyl group ﬁrst undergoes ruthenium-catalyzed ring-closing metathesis to form a new amide containing a cycloalkene moiety in the neighborhood of the halogenated aromatic ring. This new substrate is a precursor of choice to perform a new cyclization via palladium-catalyzed Heck reaction (Scheme 45). As illustrated in Scheme 45, the two separate reactions provide satisfactory yields, however the introduction of both catalysts at the beginning of the reaction led to slightly lower yields [97]. Taking advantage of the slow hydrogenation of carbon–carbon double bonds at room temperature in the presence of platinum dioxide, it was possible to perform the ruthenium-catalyzed cross coupling reaction of electrondeﬁcient oleﬁns such as conjugated enones and acrylic derivatives with allyl silanes in the presence of PtO2 under hydrogen (Scheme 46) [99]. Prolonged

Scheme 46

Cascade and Sequential Catalytic Transformations Initiated by Ruthenium Catalysts 321

reaction times led to complete hydrogenation of the internal C = C double bond. This one-pot sequential transformation performed in the presence of both a ruthenium carbene precursor and PtO2 shows the compatibility of the two catalysts, and from allylic and homoallylic alcohols it makes possible the synthesis of lactones with acrylic acid, and hemiacetals with acrolein (Scheme 46) [100]. The selective activation of propargylic alcohols by [Cp∗ RuCl(µ2 -SR)2 RuCp∗ Cl] complexes (R = Me, i Pr) in the presence of NH4 BF4 , promotes the nucleophilic substitution of the hydroxy group by various carbon nucleophiles such as ketone, amides and alkenes (Schemes 47–49) [101]. Thus, γ -ketoalkynes are formed from ketones. PtCl2 is able to catalyze the Markovnikov addition of O- and N-nucleophiles to the triple bond of this sub-

Scheme 47

Scheme 48

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Scheme 49

strate to form diketones and ketoimine intermediates which cyclize to form aromatic furans and indoles (Scheme 49) [102]. The one-pot reaction where both the ruthenium and the platinum precatalysts and the initial substrates are present at the outset of the reaction carried out in reﬂuxing acetone, directly leads to the ﬁnal compounds in good yields. PtCl2 is also a catalyst of choice to perform the electrophilic activation of enynes towards the formation of cyclopropane derivatives [103, 104]. The sequence ruthenium-catalyzed C – C bond formation/platinum-catalyzed cycloisomerization has been successfully carried out in one pot at 60 ◦ C to form

Scheme 50

Cascade and Sequential Catalytic Transformations Initiated by Ruthenium Catalysts 323

fused polycyclic compounds. The reaction can be applied to intermolecular reaction from propargylic alcohols with alkenes, but it also makes possible the preparation of polycyclic compounds via intramolecular transformations with high stereocontrol (Scheme 48) [105]. The substitution of propargylic alcohols by amides gives propargylic amides which can be isomerized into allenyl amides and cyclized into oxazoles in the presence of catalytic amounts of gold chloride (Scheme 49). The catalytic transformations can be performed by introduction of all the starting products including the catalysts at the beginning of the reaction, but better yields are obtained when AuCl3 is introduced after completion of the ruthenium-catalyzed reaction [106]. It is worth mentioning the emergence of sequential catalytic processes involving a ruthenium-catalyzed step followed by a catalytic enzymatic transformation. This strategy has been developed by the groups of J.E. Bäckvall, and M.-J. Kim and J. Park especially for the dynamic kinetic resolution of alcohols (Scheme 50) [107–109].

5 Conclusion During the last 15 years, molecular ruthenium catalysts have been at the forefront of innovation in synthesis and materials science. They are now efﬁcient partners in the fantastic action of catalysis in the discovery and development of clean processes with energy and atom economy, avoiding waste and separations. Cascade catalytic reactions are targets in this crusade. There is no doubt that the best examples of cascade ruthenium-catalyzed reactions involving one single mechanism are illustrated by alkene and enyne metathesis, and their numerous applications. In addition, there are already a variety of ruthenium-catalyzed transformations leading to multiple C – C and carbon–heteroatom bond formation, involving in the same catalytic cycle, a variety of metal-catalyzed steps and mechanisms, that have been recently reviewed. As illustrated above sequential catalytic reactions, performed in the same ﬂask, either by modifying the initial ruthenium complex to create a new catalyst, or by introduction of another metal catalyst have been developed with efﬁciency for the production of useful molecules or polymers. We can easily predict that cascade and sequential catalytic reactions will be the subject of important investigations not only by promoting the cooperation of several metal catalysts but also by organizing the tolerance and the cooperative work of metal and organo catalysts, and of metal and enzyme catalysts. This will be possible through a deep understanding of the mechanisms of each catalytic system, so as to organize their mutual tolerance.

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Fürstner A, Leitner A (2003) Angew Chem Int Ed 42:308 Borsting P, Nielsen P (2002) Chem Commun, p 2140 Schmidt B, Pohler M (2003) Org Biomol Chem 1:2512 Van Otterlo WAL, Coyanis EM, Panayides JL, de Konig CB, Fernandes MA (2005) Synlett, p 501 Kim BG, Snapper ML (2005) J Am Chem Soc 127:ASAP Monnier F, Castillo D, Dérien S, Toupet L, Dixneuf PH (2003) Angew Chem Int Ed 42:5474 Eckert M, Monnier F, Shchetnikov GT, Titanyuk ID, Osipov SN, Toupet L, Dérien S, Dixneuf PH (2005) Org Lett 7:3741 Watanabe M, Murata K, Ikariya T (2003) J Am Chem Soc 125:7508 Watanabe M, Ikagawa A, Wang H, Murata K, Ikariya T (2004) J Am Chem Soc 126:11148 Guo R, Morris RH, Song D (2005) J Am Chem Soc 127:516 Huang WS, Hu QS, Pu L (1999) J Org Chem 64:7940 Doucet H, Ohkuma T, Murata K, Yokozawa T, Kozawa M, Katayama E, England AF, Ikariya T, Noyori R (1998) Angew Chem Int Ed Engl 37:1703 Yu HB, Hu QS, Pu L (2000) J Am Chem Soc 122:6500 Grigg R, Sridharan V, York M (1998) Tetrahedron Lett 39:4139 Grigg R, York M (2000) Tetrahedron Lett 41:7255 Cossy J, Bargiggia FC, Bouzbouz S (2002) Tetrahedron Lett 43:6715 Cossy J, Bargiggia FC, Bouzbouz S (2003) Org Lett 5:459 Nishibayashi Y, Milton MD, Inada Y, Yoshikawa M, Wakiji I, Hidai M, Uemura S (2005) Chem Eur J 11:1433 Nishibayashi Y, Yoshikawa M, Inada Y, Milton MD, Hidai M, Uemura S (2003) Angew Chem Int Ed 42:2681 Anorbe L, Dominguez G, Prez-Castells J (2004) Chem Eur J 10:4938 Bruneau C (2005) Angew Chem Int Ed 44:2328 Nishibayashi Y, Yoshikawa M, Inada Y, Hidai M, Uemura S (2004) J Am Chem Soc 126:16066 Milton MD, Inada Y, Nishibayashi Y, Uemura S (2004) Chem Commun, p 2712 Larsson ALE, Persson BA, Bäckvall JE (1997) Angew Chem Int Ed Engl 36:1211 Martin-Matute B, Edin M, Bogar K, Kaynak B, Bäckvall JE (2005) J Am Chem Soc 127:8817 Choi JH, Kim YH, Nam SH, Shin ST, Kim MJ, Park J (2002) Angew Chem Int Ed 41:2373

88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109.

Author Index Volumes 1–19 The volume numbers are printed in italics

Abdel-Magid AF, see Mehrmann SJ (2004) 6: 153–180 Akiyama K, see Mikami M (2005) 14: 279–322 Allardyce CS, Dyson PJ (2006) Medicinal Properties of Organometallic Compounds. 17: 177–210 Alper H, see Grushin VV (1999) 3: 193–225 Anwander R (1999) Principles in Organolanthanide Chemistry. 2: 1–62 Arends IWCE, Kodama T, Sheldon RA (2004) Oxidations Using Ruthenium Catalysts. 11: 277–320 Armentrout PB (1999) Gas-Phase Organometallic Chemistry. 4: 1–45 Aubert C, Fensterbank L, Gandon V, Malacria M (2006) Complex Polycyclic Molecules from Acyclic Precursors via Transition Metal-Catalyzed Cascade Reactions. 19: 259–294 Balme G, Bouyssi D, Monteiro N (2006) The Virtue of Michael-Type Addition Processes in the Design of Transition Metal-Promoted Cyclizative Cascade Reactions. 19: 115–148 Barluenga J, Rodríguez F, Fañanás FJ, Flórez J (2004) Cycloaddition Reaction of Group 6 Fischer Carbene Complexes. 13: 59–121 Basset J-M, see Candy J-P (2005) 16: 151–210 Beak P, Johnson TA, Kim DD, Lim SH (2003) Enantioselective Synthesis by Lithiation Adjacent to Nitrogen and Electrophile Incorporation. 5: 139–176 Beller M, see Jacobi von Wangelin A (2006) 18 Beller M, see Strübing D (2006) 18 Bertus P, see Szymoniak J (2005) 10: 107–132 Bien J, Lane GC, Oberholzer MR (2004) Removal of Metals from Process Streams: Methodologies and Applications. 6: 263–284 Blechert S, Connon SJ (2004) Recent Advances in Alkene Metathesis. 11: 93–124 Böttcher A, see Schmalz HG (2004) 7: 157–180 Bonino F, see Bordiga S (2005) 16: 37–68 Bordiga S, Damin A, Bonino F, Lamberti C (2005) Single Site Catalyst for Partial Oxidation Reaction: TS-1 Case Study. 16: 37–68 Bouyssi D, see Balme G (2006) 19: 115–148 Braga D (1999) Static and Dynamic Structures of Organometallic Molecules and Crystals. 4: 47–68 Breuzard JAJ, Christ-Tommasino ML, Lemaire M (2005) Chiral Ureas and Thiroureas in Asymmetric Catalysis. 15: 231–270 Brüggemann M, see Hoppe D (2003) 5: 61–138 Bruneau C (2004) Ruthenium Vinylidenes and Allenylidenes in Catalysis. 11: 125–153 Bruneau C, Dérien S, Dixneuf PH (2006) Cascade and Sequential Catalytic Transformations Initiated by Ruthenium Catalysts. 19: 295–326

328

Author Index Volumes 1–19

Brutchey RL, see Fujdala KL (2005) 16: 69–115 Butler PA, Kräutler B (2006) Biological Organometallic Chemistry of B12 . 17: 1–55 Candy J-P, Copéret C, Basset J-M (2005) Analogy between Surface and Molecular Organometallic Chemistry. 16: 151–210 Castillón S, see Claver C (2006) 18 Catellani M (2005) Novel Methods of Aromatic Functionalization Using Palladium and Norbornene as a Unique Catalytic System. 14: 21–54 Cavinato G, Toniolo L, Vavasori A (2006) Carbonylation of Ethene in Methanol Catalysed by Cationic Phosphine Complexes of Pd(II): from Polyketones to Monocarbonylated Products. 18 Chatani N (2004) Selective Carbonylations with Ruthenium Catalysts. 11: 173–195 Chatani N, see Kakiuchi F (2004) 11: 45–79 Chaudret B (2005) Synthesis and Surface Reactivity of Organometallic Nanoparticles. 16: 233–259 Chlenov A, see Semmelhack MF (2004) 7: 21–42 Chlenov A, see Semmelhack MF (2004) 7: 43–70 Chinkov M, Marek I (2005) Stereoselective Synthesis of Dienyl Zirconocene Complexes. 10: 133–166 Christ-Tommasino ML, see Breuzard JAJ (2005) 15: 231–270 Chuzel O, Riant O (2005) Sparteine as a Chiral Ligand for Asymmetric Catalysis. 15: 59–92 Claver C, Diéguez M, Pàmies O, Castillón S (2006) Asymmetric Hydroformylation. 18 Clayden J (2003) Enantioselective Synthesis by Lithiation to Generate Planar or Axial Chirality. 5: 251–286 Connon SJ, see Blechert S (2004) 11: 93–124 Copéret C, see Candy J-P (2005) 16: 151–210 Costa M, see Gabriele B (2006) 18 Cummings SA, Tunge JA, Norton JR (2005) Synthesis and Reactivity of Zirconaaziridines. 10: 1–39 Damin A, see Bordiga S (2005) 16: 37–68 Damin A, see Zecchina A (2005) 16: 1–35 Dechy-Cabaret O, see Kalck P (2006) 18 Delaude L, see Noels A (2004) 11: 155–171 Dedieu A (1999) Theoretical Treatment of Organometallic Reaction Mechanisms and Catalysis. 4: 69–107 Delmonte AJ, Dowdy ED, Watson DJ (2004) Development of Transition Metal-Mediated Cyclopropanation Reaction. 6: 97–122 Demonceau A, see Noels A (2004) 11: 155–171 Dérien S, see Bruneau C (2006) 19: 295–326 Derien S, see Dixneuf PH (2004) 11: 1–44 Deubel D, Loschen C, Frenking G (2005) Organometallacycles as Intermediates in OxygenTransfer Reactions. Reality or Fiction? 12: 109–144 Diéguez M, see Claver C (2006) 18 Dixneuf PH, Derien S, Monnier F (2004) Ruthenium-Catalyzed C–C Bond Formation. 11: 1–44 Dixneuf PH, see Bruneau C (2006) 19: 295–326 Dötz KH, Minatti A (2004) Chromium-Templated Benzannulation Reactions. 13: 123–156 Dowdy EC, see Molander G (1999) 2: 119–154

Author Index Volumes 1–19

329

Dowdy ED, see Delmonte AJ (2004) 6: 97–122 Doyle MP (2004) Metal Carbene Reactions from Dirhodium(II) Catalysts. 13: 203–222 Drudis-Solé G, Ujaque G, Maseras F, Lledós A (2005) Enantioselectivity in the Dihydroxylation of Alkenes by Osmium Complexes. 12: 79–107 Dyson PJ, see Allardyce CS (2006) 17: 177–210 Eilbracht P, Schmidt AM (2006) Synthetic Applications of Tandem Reaction Sequences Involving Hydroformylation. 18 Eisen MS, see Lisovskii A (2005) 10: 63–105 Fañanás FJ, see Barluenga (2004) 13: 59–121 Fensterbank L, see Aubert C (2006) 19: 259–294 Flórez J, see Barluenga (2004) 13: 59–121 Fontecave M, Hamelin O, Ménage S (2005) Chiral-at-Metal Complexes as Asymmetric Catalysts. 15: 271–288 Fontecilla-Camps JC, see Volbeda A (2006) 17: 57–82 Fraile JM, García JI, Mayoral JA (2005) Non-covalent Immobilization of Catalysts Based on Chiral Diazaligands. 15: 149–190 Frenking G, see Deubel D (2005) 12: 109–144 Freund H-J, see Risse T (2005) 16: 117–149 Fu GC, see Netherton M (2005) 14: 85–108 Fujdala KL, Brutchey RL, Tilley TD (2005) Tailored Oxide Materials via Thermolytic Molecular Precursor (TMP) Methods. 16: 69–115 Fürstner A (1998) Ruthenium-Catalyzed Metathesis Reactions in Organic Synthesis. 1: 37–72 Gabriele B, Salerno G, Costa M (2006) Oxidative Carbonylations. 18 Gandon V, see Aubert C (2006) 19: 259–294 García JI, see Fraile JM (2005) 15: 149–190 Gates BC (2005) Oxide- and Zeolite-supported “Molecular” Metal Clusters: Synthesis, Structure, Bonding, and Catalytic Properties. 16: 211–231 Gibson SE (née Thomas), Keen SP (1998) Cross-Metathesis. 1: 155–181 Gisdakis P, see Rösch N (1999) 4: 109–163 Görling A, see Rösch N (1999) 4: 109–163 Goldfuss B (2003) Enantioselective Addition of Organolithiums to C=O Groups and Ethers. 5: 12–36 Gossage RA, van Koten G (1999) A General Survey and Recent Advances in the Activation of Unreactive Bonds by Metal Complexes. 3: 1–8 Gotov B, see Schmalz HG (2004) 7: 157–180 Gras E, see Hodgson DM (2003) 5: 217–250 Grepioni F, see Braga D (1999) 4: 47–68 Gröger H, see Shibasaki M (1999) 2: 199–232 Groppo E, see Zecchina A (2005) 16: 1–35 Grushin VV, Alper H (1999) Activation of Otherwise Unreactive C–Cl Bonds. 3: 193–225 Guitian E, Perez D, Pena D (2005) Palladium-Catalyzed Cycloaddition Reactions of Arynes. 14: 109–146 Hamelin O, see Fontecave M (2005) 15: 271–288 Harman D (2004) Dearomatization of Arenes by Dihapto-Coordination. 7: 95–128 Hatano M, see Mikami M (2005) 14: 279–322

330

Author Index Volumes 1–19

Haynes A (2006) Acetic Acid Synthesis by Catalytic Carbonylation of Methanol. 18 He Y, see Nicolaou KC (1998) 1: 73–104 Hegedus LS (2004) Photo-Induced Reactions of Metal Carbenes in organic Synthesis. 13: 157–201 Hermanns J, see Schmidt B (2004) 13: 223–267 Hidai M, Mizobe Y (1999) Activation of the N–N Triple Bond in Molecular Nitrogen: Toward its Chemical Transformation into Organo-Nitrogen Compounds. 3: 227–241 Hirao T, see Moriuchi T (2006) 17: 143–175 Hodgson DM, Stent MAH (2003) Overview of Organolithium-Ligand Combinations and Lithium Amides for Enantioselective Processes. 5: 1–20 Hodgson DM, Tomooka K, Gras E (2003) Enantioselective Synthesis by Lithiation Adjacent to Oxygen and Subsequent Rearrangement. 5: 217–250 Hoppe D, Marr F, Brüggemann M (2003) Enantioselective Synthesis by Lithiation Adjacent to Oxygen and Electrophile Incorporation. 5: 61–138 Hou Z, Wakatsuki Y (1999) Reactions of Ketones with Low-Valent Lanthanides: Isolation and Reactivity of Lanthanide Ketyl and Ketone Dianion Complexes. 2: 233–253 Hoveyda AH (1998) Catalytic Ring-Closing Metathesis and the Development of Enantioselective Processes. 1: 105–132 Huang M, see Wu GG (2004) 6: 1–36 Hughes DL (2004) Applications of Organotitanium Reagents. 6: 37–62 Iguchi M,Yamada K,Tomioka K (2003) Enantioselective Conjugate Addition and 1,2-Addition to C=N of Organolithium Reagents. 5: 37–60 Ito Y, see Murakami M (1999) 3: 97–130 Ito Y, see Suginome M (1999) 3: 131–159 Itoh K, Yamamoto Y (2004) Ruthenium Catalyzed Synthesis of Heterocyclic Compounds. 11: 249–276 Jacobi von Wangelin A, Neumann H, Beller M (2006) Carbonylations of Aldehydes. 18 Jacobsen EN, see Larrow JF (2004) 6: 123–152 Johnson TA, see Break P (2003) 5: 139–176 Jones WD (1999) Activation of C–H Bonds: Stoichiometric Reactions. 3: 9–46 Kagan H, Namy JL (1999) Inﬂuence of Solvents or Additives on the Organic Chemistry Mediated by Diiodosamarium. 2: 155–198 Kakiuchi F, Murai S (1999) Activation of C–H Bonds: Catalytic Reactions. 3: 47–79 Kakiuchi F, Chatani N (2004) Activation of C–H Inert Bonds. 11: 45–79 Kalck P, Urrutigoïty M, Dechy-Cabaret O (2006) Hydroxy- and Alkoxycarbonylations of Alkenes and Alkynes. 18 Kanno K, see Takahashi T (2005) 8: 217–236 Keen SP, see Gibson SE (née Thomas) (1998) 1: 155–181 Kendall C, see Wipf P (2005) 8: 1–25 Kiessling LL, Strong LE (1998) Bioactive Polymers. 1: 199–231 Kim DD, see Beak P (2003) 5: 139–176 King AO, Yasuda N (2004) Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis of Pharmaceuticals. 6: 205–246 King NP, see Nicolaou KC, He Y (1998) 1: 73–104 Kobayashi S (1999) Lanthanide Triﬂate-Catalyzed Carbon–Carbon Bond-Forming Reactions in Organic Synthesis. 2: 63–118

Author Index Volumes 1–19

331

Kobayashi S (1999) Polymer-Supported Rare Earth Catalysts Used in Organic Synthesis. 2: 285–305 Kodama T, see Arends IWCE (2004) 11: 277–320 Kondratenkov M, see Rigby J (2004) 7: 181–204 Koten G van, see Gossage RA (1999) 3: 1–8 Kotora M (2005) Metallocene-Catalyzed Selective Reactions. 8: 57–137 Kräutler B, see Butler PA (2006) 17: 1–55 Kumobayashi H, see Sumi K (2004) 6: 63–96 Kündig EP (2004) Introduction. 7: 1–2 Kündig EP (2004) Synthesis of Transition Metal η6 -Arene Complexes. 7: 3–20 Kündig EP, Pape A (2004) Dearomatization via η6 Complexes. 7: 71–94 Lamberti C, see Bordiga S (2005) 16: 37–68 Lane GC, see Bien J (2004) 6: 263–284 Larock R (2005) Palladium-Catalyzed Annulation of Alkynes. 14: 147–182 Larrow JF, Jacobsen EN (2004) Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 6: 123–152 Lemaire M, see Breuzard JAJ (2005) 15: 231–270 Li CJ,Wang M (2004) Ruthenium Catalyzed Organic Synthesis in Aqueous Media. 11: 321–336 Li Z, see Xi Z (2005) 8: 27–56 Lim SH, see Beak P (2003) 5: 139–176 Lin Y-S, Yamamoto A (1999) Activation of C–O Bonds: Stoichiometric and Catalytic Reactions. 3: 161–192 Lisovskii A, Eisen MS (2005) Octahedral Zirconium Complexes as Polymerization Catalysts. 10: 63–105 Lledós A, see Drudis-Solé G (2005) 12: 79–107 Loschen C, see Deubel D (2005) 12: 109–144 Ma S (2005) Pd-catalyzed Two or Three-component Cyclization of Functionalized Allenes. 14: 183–210 Malacria M, see Aubert C (2006) 19: 259–294 Mangeney P, see Roland S (2005) 15: 191–229 Marciniec B, Pretraszuk C (2004) Synthesis of Silicon Derivatives with Ruthenium Catalysts. 11: 197–248 Marek I, see Chinkov M (2005) 10: 133–166 Marr F, see Hoppe D (2003) 5: 61–138 Maryanoff CA, see Mehrmann SJ (2004) 6: 153–180 Maseras F (1999) Hybrid Quantum Mechanics/Molecular Mechanics Methods in Transition Metal Chemistry. 4: 165–191 Maseras F, see Drudis-Solé G (2005) 12: 79–107 Le Maux P, see Simonneaux G (2006) 17: 83–122 Mayoral JA, see Fraile JM (2005) 15: 149–190 de Meijere A, see von Zezschwitz P (2006) 19: 49–90 Medaer BP, see Mehrmann SJ (2004) 6: 153–180 Mehrmann SJ, Abdel-Magid AF, Maryanoff CA, Medaer BP (2004) Non-Salen Metal-Catalyzed Asymmetric Dihydroxylation and Asymmetric Aminohydroxylation of Alkenes. Practical Applications and Recent Advances. 6: 153–180 De Meijere, see Wu YT (2004) 13: 21–58 Ménage S, see Fontecave M (2005) 15: 271–288

332

Author Index Volumes 1–19

Michalak A, Ziegler T (2005) Late Transition Metal as Homo- and Co-Polymerization Catalysts. 12: 145–186 Mikami M, Hatano M, Akiyama K (2005) Active Pd(II) Complexes as Either Lewis Acid Catalysts or Transition Metal Catalysts. 14: 279–322 Minatti A, Dötz KH (2004) Chromium-Templated Benzannulation Reactions. 13: 123–156 Miura M, Satoh T (2005) Catalytic Processes Involving b-Carbon Elimination. 14: 1–20 Miura M, Satoh T (2005) Arylation Reactions via C–H Bond Cleavage. 14: 55–84 Mizobe Y, see Hidai M (1999) 3: 227–241 Molander G, Dowdy EC (1999) Lanthanide- and Group 3 Metallocene Catalysis in Small Molecule Synthesis. 2: 119–154 Monnier F, see Dixneuf (2004) 11: 1–44 Monteiro N, see Balme G (2006) 19: 115–148 Mori M (1998) Enyne Metathesis. 1: 133–154 Mori M (2005) Synthesis and Reactivity of Zirconium-Silene Complexes. 10: 41–62 Moriuchi T, Hirao T (2006) Ferrocene–Peptide Bioconjugates. 17: 143–175 Morokuma K, see Musaev G (2005) 12: 1–30 Müller TJJ (2006) Sequentially Palladium-Catalyzed Processes. 19: 149–206 Mulzer J, Öhler E (2004) Oleﬁn Metathesis in Natural Product Syntheses. 13: 269–366 Muñiz K (2004) Planar Chiral Arene Chromium (0) Complexes as Ligands for Asymetric Catalysis. 7: 205–223 Murai S, see Kakiuchi F (1999) 3: 47–79 Murakami M, Ito Y (1999) Cleavage of Carbon–Carbon Single Bonds by Transition Metals. 3: 97–130 Musaev G, Morokuma K (2005) Transition Metal Catalyzed s-Bond Activation and Formation Reactions. 12: 1–30 Nakamura I, see Yamamoto Y (2005) 14: 211–240 Nakamura S, see Toru T (2003) 5: 177–216 Nakano K, Nozaki K (2006) Carbonylation of Epoxides. 18 Namy JL, see Kagan H (1999) 2: 155–198 Negishi E, Tan Z (2005) Diastereoselective, Enantioselective, and Regioselective Carboalumination Reactions Catalyzed by Zirconocene Derivatives. 8: 139–176 Negishi E, Wang G, Zhu G (2006) Palladium-Catalyzed Cyclization via Carbopalladation and Acylpalladation. 19: 1–48 Netherton M, Fu GC (2005) Palladium-catalyzed Cross-Coupling Reactions of Unactivated Alkyl Electrophiles with Organometallic Compounds. 14: 85–108 Neumann H, see Jacobi von Wangelin A (2006) 18 Nicolaou KC, King NP, He Y (1998) Ring-Closing Metathesis in the Synthesis of Epothilones and Polyether Natural Products. 1: 73–104 Nishiyama H (2004) Cyclopropanation with Ruthenium Catalysts. 11: 81–92 Noels A, Demonceau A, Delaude L (2004) Ruthenium Promoted Catalysed Radical Processes toward Fine Chemistry. 11: 155–171 Nolan SP, Viciu MS (2005) The Use of N-Heterocyclic Carbenes as Ligands in Palladium Mediated Catalysis. 14: 241–278 Normant JF (2003) Enantioselective Carbolithiations. 5: 287–310 Norton JR, see Cummings SA (2005) 10: 1–39 Nozaki K, see Nakano K (2006) 18 Oberholzer MR, see Bien J (2004) 6: 263–284 Obst D, see Wiese K-D (2006) 18 Öhler E, see Mulzer J (2004) 13: 269–366

Author Index Volumes 1–19

333

Pàmies O, see Claver C (2006) 18 Pape A, see Kündig EP (2004) 7: 71–94 Patil NT, Yamamoto Y (2006) Palladium Catalyzed Cascade Reactions Involving π-Allyl Palladium Chemistry. 19: 91–114 Pawlow JH, see Tindall D, Wagener KB (1998) 1: 183–198 Pena D, see Guitian E (2005) 14: 109–146 Perez D, see Guitian E (2005) 14: 109–146 Pérez-Castells J (2006) Cascade Reactions Involving Pauson–Khand and Related Processes. 19: 207–258 Prashad M (2004) Palladium-Catalyzed Heck Arylations in the Synthesis of Active Pharmaceutical Ingredients. 6: 181–204 Prestipino C, see Zecchina A (2005) 16: 1–35 Pretraszuk C, see Marciniec B (2004) 11: 197–248 Riant O, see Chuzel O (2005) 15: 59–92 Richmond TG (1999) Metal Reagents for Activation and Functionalization of Carbon– Fluorine Bonds. 3: 243–269 Rigby J, Kondratenkov M (2004) Arene Complexes as Catalysts. 7: 181–204 Risse T, Freund H-J (2005) Spectroscopic Characterization of Organometallic Centers on Insulator Single Crystal Surfaces: From Metal Carbonyls to Ziegler–Natta Catalysts. 16: 117–149 Rodríguez F, see Barluenga (2004) 13: 59–121 Roland S, Mangeney P (2005) Chiral Diaminocarbene Complexes, Synthesis and Application in Asymmetric Catalysis. 15: 191–229 Rösch N (1999) A Critical Assessment of Density Functional Theory with Regard to Applications in Organometallic Chemistry. 4: 109–163 Roucoux A (2005) Stabilized Noble Metal Nanoparticles: An Unavoidable Family of Catalysts for Arene Derivative Hydrogenation. 16: 261–279 Sakaki S (2005) Theoretical Studies of C–H s-Bond Activation and Related by TransitionMetal Complexes. 12: 31–78 Salerno G, see Gabriele B (2006) 18 Satoh T, see Miura M (2005) 14: 1–20 Satoh T, see Miura M (2005) 14: 55–84 Savoia D (2005) Progress in the Asymmetric Synthesis of 1,2-Diamines from Azomethine Compounds. 15: 1–58 Schmalz HG, Gotov B, Böttcher A (2004) Natural Product Synthesis. 7: 157–180 Schmidt AM, see Eilbracht P (2006) 18 Schmidt B, Hermanns J (2004) Oleﬁn Metathesis Directed to Organic Synthesis: Principles and Applications. 13: 223–267 Schrock RR (1998) Oleﬁn Metathesis by Well-Deﬁned Complexes of Molybdenum and Tungsten. 1: 1–36 Schulz E (2005) Use of N,N-Coordinating Ligands in Catalytic Asymmetric C–C Bond Formations: Example of Cyclopropanation, Diels–Alder Reaction, Nucleophilic Allylic Substitution. 15: 93–148 Semmelhack MF, Chlenov A (2004) (Arene)Cr(Co)3 Complexes: Arene Lithiation/Reaction with Electrophiles. 7: 21–42 Semmelhack MF, Chlenov A (2004) (Arene)Cr(Co)3 Complexes: Aromatic Nucleophilic Substitution. 7: 43–70

334

Author Index Volumes 1–19

Sen A (1999) Catalytic Activation of Methane and Ethane by Metal Compounds. 3: 81–95 Severin K (2006) Organometallic Receptors for Biologically Interesting Molecules. 17: 123– 142 Sheldon RA, see Arends IWCE (2004) 11: 277–320 Shibasaki M, Gröger H (1999) Chiral Heterobimetallic Lanthanoid Complexes: Highly Efﬁcient Multifunctional Catalysts for the Asymmetric Formation of C–C, C–O and C–P Bonds. 2: 199–232 Simonneaux G, Le Maux P (2006) Carbene Complexes of Heme Proteins and Iron Porphyrin Models. 17: 83–122 Staemmler V (2005) The Cluster Approach for the Adsorption of Small Molecules on Oxide Surfaces. 12: 219–256 Stent MAH, see Hodgson DM (2003) 5: 1–20 Strassner T (2004) Electronic Structure and Reactivity of Metal Carbenes. 13: 1–20 Strong LE, see Kiessling LL (1998) 1: 199–231 Strübing D, Beller M (2006) The Pauson–Khand Reaction. 18 Suginome M, Ito Y (1999) Activation of Si–Si Bonds by Transition-Metal Complexes. 3: 131–159 Sumi K, Kumobayashi H (2004) Rhodium/Ruthenium Applications. 6: 63–96 Suzuki N (2005) Stereospeciﬁc Oleﬁn Polymerization Catalyzed by Metallocene Complexes. 8: 177–215 Szymoniak J, Bertus P (2005) Zirconocene Complexes as New Reagents for the Synthesis of Cyclopropanes. 10: 107–132 Takahashi T, Kanno K (2005) Carbon–Carbon Bond Cleavage Reaction Using Metallocenes. 8: 217–236 Tan Z, see Negishi E (2005) 8: 139–176 Tilley TD, see Fujdala KL (2005) 16: 69–115 Tindall D, Pawlow JH, Wagener KB (1998) Recent Advances in ADMET Chemistry. 1: 183–198 Tobisch S (2005) Co-Oligomerization of 1,3-Butadiene and Ethylene Promoted by Zerovalent ‘Bare’ Nickel Complexes. 12: 187–218 Tomioka K, see Iguchi M (2003) 5: 37–60 Tomooka K, see Hodgson DM (2003) 5: 217–250 Toniolo L, see Cavinato G (2006) 18 Toru T, Nakamura S (2003) Enantioselective Synthesis by Lithiation Adjacent to Sulfur, Selenium or Phosphorus, or without an Adjacent Activating Heteroatom. 5: 177–216 Tunge JA, see Cummings SA (2005) 10: 1–39 Uemura M (2004) (Arene)Cr(Co)3 Complexes: Cyclization, Cycloaddition and Cross Coupling Reactions. 7: 129–156 Ujaque G, see Drudis-Solé G (2005) 12: 79–107 Urrutigoïty M, see Kalck P (2006) 18 Vavasori A, see Cavinato G (2006) 18 Viciu MS, see Nolan SP (2005) 14: 241–278 Volbeda A, Fontecilla-Camps JC (2006) Catalytic Nickel–Iron–Sulfur Clusters: From Minerals to Enzymes. 17: 57–82 Wagener KB, see Tindall D, Pawlow JH (1998) 1: 183–198 Wakatsuki Y, see Hou Z (1999) 2: 233–253 Wang M, see Li CJ (2004) 11: 321–336

Author Index Volumes 1–19

335

Wang G, see Negishi E (2006) 19: 1–48 Watson DJ, see Delmonte AJ (2004) 6: 97–122 Wiese K-D, Obst D (2006) Hydroformylation. 18 Wipf P, Kendall C (2005) Hydrozirconation and Its Applications. 8: 1–25 Wu GG, Huang M (2004) Organolithium in Asymmetric Process. 6: 1–36 Wu YT, de Meijere A (2004) Versatile Chemistry Arising from Unsaturated Metal Carbenes. 13: 21–58 Xi Z, Li Z (2005) Construction of Carbocycles via Zirconacycles and Titanacycles. 8: 27–56 Yamada K, see Iguchi M (2003) 5: 37–60 Yamamoto A, see Lin Y-S (1999) 3: 161–192 Yamamoto Y, Nakamura I (2005) Nucleophilic Attack by Palladium Species. 14: 211–240 Yamamoto Y, see Itoh K (2004) 11: 249–276 Yamamoto Y, see Patil NT (2006) 19: 91–114 Yasuda H (1999) Organo Rare Earth Metal Catalysis for the Living Polymerizations of Polar and Nonpolar Monomers. 2: 255–283 Yasuda N, see King AO (2004) 6: 205–246 Zecchina A, Groppo E, Damin A, Prestipino C (2005) Anatomy of Catalytic Centers in Phillips Ethylene Polymerization Catalyst. 16: 1–35 von Zezschwitz P, de Meijere A (2006) Domino Heck-Pericyclic Reactions. 19: 49–90 Zhu G, see Negishi E (2006) 19: 1–48 Ziegler T, see Michalak A (2005) 12: 145–186

Subject Index

Acetalization, tandem 262 Acylpalladation 1 –, cyclic 1, 6 ADMET polymerization, C=C bond hydrogenation 312 Alder-ene 271 Alkene metathesis 295 Alkylallenes 59 Alkylidene malonitriles 105 Alkylidene metal catalyst derivatives 297 3-Alkylidenecyclohexene 61 Alkylidenecyclopropanes 98 Alkynylaldehydes, allylation–alkoxyallylation 107 o-Alkynylphenols 101 o-Alkynyltriﬂuoroacetanilides 101 Allenes, intermolecular Heck reactions 58 π-Allyl palladium 91, 105 3-Allyl-N-(alkoxycarbonyl)indoles 108 Allyl-(2-endo-7-oxanorborn-5-enyl)ethers 304 Allylic alkylations 227 Allylic substitution 149, 163 AllylPd 117 2-Allyltetrazoles 100 Allyltributylstannane 107 Amination 171 Aminocarbonylation 229 2-Azanorbornenones 304 Azetidines 119 Bicyclopropylidene 49, 56, 57 Bicyclopropylidene, all-intermolecular domino processes 55 BINOL/BINAP 318 3,4-Bisallyloxybut-1-yne 298 Bis π-allyl palladium complex 91 N, N –Bis(benzylidene)ethylenediamine (BBEDA) 64

2,3-Bis(diphenylphosphinyl)-1-propenes 310 Bis-functionalization, activated oleﬁns 94 N,O-Bis(trimethylsilyl)acetamide (BSA) 66 1,3-Butadienes 49 C–C bonds 105 – –, formation, enantioselective 318 – –, –, cascade reactions 75 C–C π-bonds, unactivated, Michael addition/metal-promoted nucleophile addition 125 C–C multiple bonds, monofunctionalization 126 C=C bond hydrogenation 311 C–H activation 149, 190 C–N bonds 105 Carbenoid 260 Carbocyclizations, tandem, [2+2+1] reactions 234 Carbometallation 2 Carbonylative carbotricyclization 265 Carbopalladation 3 –, cyclic 1, 4 Cascade 91, 260 –, non-carbenoid intermediates 261 –, transition metalo carbenoid intermediates 274 Cascade alkene metathesis 302 Cascade carbopalladation 1 Cascade catalytic reactions 295 – – –, ruthenium catalysts 296 Cascade cyclizations, “dumbbell”-mode/circular, carbopalladation 27 – –, nickel couplings 269 – –, spiro-mode/linear-fused-mode, carbopalladation 31

338 – –, “zipper”-mode, carbopalladation 26 Cascade enyne metathesis 297 Catalysis 128 Chemoselectivity, domino reactions 52 Conia-ene 272 Copper acetylides 99 Cross couplings 49, 149 – –, 6π-electrocyclizations 71 – –, intermolecular cycloadditions 52 Cross-metathesis, C=C bond hydrogenation 315 Cyclic acylpalladation 1 Cyclic carbopalladation 1 Cyclization 115, 128 –, multiple carbopalladative 39 –, palladium-catalyzed, acylpalladation 32 –, – –, carbopalladation 11 –, single acylpalladation 33 –, single carbopalladation 12 Cyclization-anion capture cascade 59 Cycloadditions 95, 260 –, 1,3-dipolar 49 –, zwitterionic π-allylPd complexes 117 Cycloalkenes 302 Cycloisomerization 149, 193, 260 Cyclooctadiene 314 Cyclopentanols 316 Cyclopentenones 128 Cyclopropanation 317 – / RCM, dienynes 299 Cyclopropenecarboxylates 61 Cyclopropylallenes, 2-aryl-1,3,5-hexatrienes 60 Cyclopropylcarbinylpalladium iodide 55 Cyclopropylideneacetates 61 Decarbonylations, CO 232 Dechloropalladation 3 1,2-Dialkylidenecycloalkanes 61 Diels–Alder reactions 49 – –, intermolecular, intramolecular cross couplings 60 Difunctionalization, unsaturation 131 Dioxabicyclic systems 298 Dioxabicyclo[5.3.0]decane 299 1,3-Dipoles, cycloaddition, Pd-TMM equivalents 122 2,6-Di-tert-butyl-4-methylphenol (BHT) 66

Subject Index Diynes, tandem cycloadditions 238 Domino allylic substitution/carbocyclization 263 Domino reactions 149 6π-Electrocyclizations 49 Electrophilic trapping reactions 138 Enynes, metathesis 297, 317 –, Pauson–Khand reaction 221 Ethylidenemalononitriles 94 Exoalkylidene cyclopentanones 104 Guanacastepene A 299 Halopalladation 3 Heck reactions 51, 152 – –, cyclic 12 – –, 1,3-dipolar cycloadditions 68 – –, reductive 51 Heck–Diels–Alder, all-intramolecular 65 – – –, domino 52 – – –, sequential 52 Heterocumulenes 96 Heterocycles 91, 115 –, synthesis 95, 107 1,3,5-Hexatrienes 49 Hydroformylation, tandem 262 Hydrogenolysis 248 Indenones 317 Intramolecular coupling reaction, metal-catalyzed 137 Ketone enantioselective hydrogenation 318 Kinugasa reaction, intramolecular, copper-catalyzed 261 Merulidial 64 Metallation 149, 185 Metathesis, enyne 297 4-Methoxycarbonyloxy-2-butyn-1-ol 104 Methyl methacrylate (MMA) 314 Michael addition 115, 248, 318 Michael-initiated ring closure 116 MIRC (Michael initiated ring closure) 116 Molybdenum 297 Multicomponent reactions 149 Multimetallic sequential catalytic transformations 295

Subject Index – – – –, ruthenium catalysts 319 Muscone 315 Muscopyridine 315 Nicholas-PKR 221 Octahydronaphthaline, spirocyclopropanated 55 Oleﬁn insertion, irreversible 152 Oligohaloalkenes/oligohaloarenes 50 Organopalladium 2 8-Oxabicyclo[3.2.1]octa-2,6-dienes 53 Oxepane 120 Oxetanes 119 Palladacyclobutane 98 Palladium catalysis 49, 91, 117, 149 Pauson–Khand reaction (PKR) 128 – – –, enynes 221 – – –, Nicholas-PKR 221 – – –, pre-PKR processes 230 – – –, RCM 221 – – –, reductive 244 – – –, tandem 234 Pd-trimethylenemethane (TMM) 117 Phthalimids 95 Polybutadiene/polymethylmethacrylate 314 Polyethylene 311 Polymethylmethacrylate (PMMA) 314 Propargylic amides 323 Pyrrolidines 119 RCM-PKR 221 Retro-Diels–Alder 248 Ring-closing metathesis (RCM) 221, 315 ROMP polymerization, C=C bond hydrogenation 311

339 – / ATRP polymerization, C=C bond hydrogenation 314 Rosenmund–Tishchenko reactions, ruthenium-catalyzed 305 Ruthenium catalysis 295, 305 Sequential catalytic reactions 295 – – –, ruthenium catalysts 305 Silylcarbotricyclization (SiCaT) 268 Silylmethylallyl acetates 123 Skeletal rearrangement 260 Sonogashira coupling 178 Sterepolide 64 Steroids 54 2-(Sulfonylmethyl)allylcarbonates 123 Tandem conjugate addition 137 – – –, metal-catalyzed 138 Tandem PKRs 234 Tandem reactions 115 Traceless tethers 242 Transition metal catalysis 115, 128 Transition metalo carbenoid intermediates 274 Trimethylenemethane 117 Tris(2-furyl)phosphine 57 Triynes, tandem cycloadditions 238 Tsuji–Trost allylation cascade 94 Valerolactones 306 Vinylation, intermediate reversible 156 Vinylaziridines 119 Vinylcyclopropanes, Pd-catalyzed ring expansion 117 Vinyloxiranes 119 Vinylthiiranes 119 Zwitterionic π-allylPd complexes 117