ISOQUINOLINES
This is a part ofthe thirty-eighth volume in the series
THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS
THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS A
SERIES OF MONOGRAPHS
EDWARD C. TAYLOR, Editor ARNOLD WEISSBERGER, Founding Editor
ISOQLJINOLINES Part 3
Edited by
Gary M. Coppola and Herbert F. Schuster
AN INTERSCIENCE@PUBLICATION
JOHN WILEY & SONS, INC.
-
NEW YORK * CHICHESTER * BRISBANE * TORONTO SINGAPORE
This text is printed on acid-free paper. Copyright 3;: 1995 by John Wiley & Sons. Inc. All rights reserved. Published simultaneously in Canada. Reproduction or translation of any part of this work beyond that permitted by Section 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or furthei information should be addressed to the Permissions Department, John Wiley & Sons, Inc.. 605 Third Avenue, New York, NY 10 f 58-0012. Library of Congress Cataloging in Publication Data:
Isoquinolines. (The chemistry of heterocyolic compounds, 0069-31M: V. 38.) Pt. 2 edited by F.G. Kathawala. Gary M.Coppola, Herbert F. Schuster; pt. 3 edited by Gary M.Coppola and Herbert F. Schuster. "An Interscience-publication." Includes bibliographical references and indexes. 1. Isoquinoline. 2. Isoquinolines. I. Grethe. Guenter. QD401.183 54T.596 80-1 1510 ISBN 0-471-37481-4 (v. I ) ISBN 0-471-62855-7 (v. 3)
10987654321
To Clare and Perer -G. M. C. To my wife, Maro:
my daughter; Kristianu; my son. SteJan
-H. F. S.
Contributors
Hiroshi Hara Faculty of Pharmaceutical Sciences Science University of Tokyo Shinjuku-ku, Tokyo, Japan Osarnu Hoshino Faculty of Pharmaceutical Sciences Science University of Tokyo Shinjuku-ku, Tokyo, Japan F. G. Kathawala Sandoz Research Institute East Hanover, New Jersey
Herbert F. Schuster Sandoz Research Institute East Hanover, New Jersey Bunsuke Urnezawa Faculty of Pharmaceutical Sciences Science University of Tokyo Shinjuku-ku, Tokyo, Japan
The Chemistry of Heterocyclic Compounds Introduction to the Series The chemistry of heterocyclic compounds constitutes one of the broadest and most complex branches of chemistry. The diversity of synthetic methods utilized in this field, coupled with the immense physiological and industrial significance of heterocycles, combine to make the general heterocyclic arena of central importance to organic chemistry. The Chemistry of Heterocyclic Compounds, published since 1950 under the initial editorship of Arnold Weissberger, and later, until Dr. Weissberger’s death in 1984, under our joint editorship, has attempted to make the extraordinarily complex and diverse field of heterocyclic chemistry as organized and readily accessible as possible. Each volume has dealt with syntheses, reactions, properties, structure, physical chemistry, and utility of compounds belonging to a specific ring system or class (e.g., pyridines, thiophenes, pyrimidines, threemembered ring systems).This series has become the basic reference collection for information on heterocyclic compounds. Many broader aspects of heterocyclic chemistry are recognized as disciplines of general significance which impinge on almost all aspects of modem organic and medicinal chemistry, and for this reason we initiated several years ago a parallel series entitled General Heterocyclic Chemistry, which treated such topics as nuclear magnetic resonance, mass spectra, and photochemistry of heterocyclic compounds, the utility of heterocyclic compounds in organic synthesis, and the synthesis of heterocyclic compounds by means of 1,3-dipolar cycloaddition reactions. These volumes are of interest to all organic and medicinal chemists, as well as to those whose particular concern is heterocyclic chemistry. It has become increasingly clear that this arbitrary distinction created as many problems as it solved, and we have therefore elected to discontinue the more recently initiated series General Heterocyclic Chemistry and to publish all forthcoming volumes in the general area of heterocyclic chemistry in The Chemistry of Heterocyclic Compounds series. EDWARD C. TAYLOR Department of Chemistry Princeton Uniuersiry Princeton, New Jersey
ix
Preface
The isoquinoline skeleton is found in a wide variety of natural and pharmaceutically interesting compounds. Because the field of isoquinolines is so large, four volumes were planned for the presentation of this material. However, unforeseen circumstances and author delays forced a reorganization of the orginally proposed chapters that were outlined in Isoquinolines: Part One. This final volume of the Isoquinoline series examines the chemistry surrounding two classes of isoquinolines, those containing basic functionalitiesin the side chain and those possessing hydroxyl or thiol substituents. The authors have kindly updated their original manuscripts, and we thank them for their efforts. It is our hope that this volume will serve as a useful reference to those actively involved in isoquinolineresearch and to those whose interests will lead them into the rich field of isoquinolines.
GARY M. COPPOLA HERBERT F. SCHUSTER East Hanorer. New Jersey July 1994
xi
Contents
I.
ISOQUINOLINES BEARING BASIC SIDE CHAINS H.F. SCHUSTERAND F.G. KATHAWALA
II. ISOQUINOLINES AND THEIR HYDROGENATED
1
DERIVATIVES 0. HOSHIYO, H.H A R4~~ , R. U W L A I V A
225
INDEX
545
ISOQUINOLINES
This is a part of the thirty-eighth volume in the series
THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS
Chemistry of Heterocyclic Compounds, Volume38 Edited by Gary M. Coppola, Herbert F. Schuster Copyright 0 1995 by John Wiley & Sons, Ltd.
Isoquinolines Bearing Basic Side Chains H.F. Schuster and F. Kathawala I. Introduction 11. Isoquinolines Having Basic-Containing Substituents at C1 A. l-(Aminoalkyl)isoquinolines B. l-(Aminoalkoxy)is~uinolines C. Isoquinolines Containing Aminophenyl Substituents 1. 1-Anilinoisoquinolines (n = 0) 2. I-(Aminobenzyl)isoquinolines(n= 1) 3. 1-(Aminophenethyl)isoquinolines( n = 2) D. Isoquinolines Bearing Basic Heterocyclic Substituents at Cl I. Five-Membered Heterocycles 2. Six-Membered Heterocycles Isoquinolines a. Substituted I -(Pyridyl)isoquinolines b. Substituted I-(Piperidyl)isoquinolines c. Conclusion E. Bis-isoquinolines F. Emetine 111. Isoquinolines Having Basic-Containing Substituents at C2 A. 2-(Aminoalkyl)isoquinolines
B. Substituted 2-(Aminophenyl)isoquinolines C. 2-Heterocyclic Substituted Isoquinolines IV. Isoquinolines Having Basic-Containing Substituents at C3 V. Isoquinolines Containing Basic Substituents at C4 VI. Miscellaneous Isoquinolines Having Basic Substituents References
1
2 2 27 35 36 53 65 70 70 14
14
88 89 89 114 133 133
161
I 69
183 204 212 214
1. INTRODUCTION This chapter discusses the preparation and reactions of side-chain isoquinoline and hydrogenated isoquinoline compounds bearing basic-containing functionalities not directly attached to the isoquinoline nucleus (see Chapter 111 by I. W. Mathison and W. E. Solomons in Isoquinolines. Part Two, F. G. Kathawala, G. M. Coppola, and H. F. Schuster, eds., John Wiley & Sons, New York, 1990). The pharmacological importance of many of these compounds has been the motivation for the syntheses of the numerous variations found in this class of compounds. 1
Isoquinolines Bearing Basic Side Chains
2
11. ISOQUINOLINES HAVING BASIC-CONTAINING SUBSTITUENTS AT C1
A. l-(Aminoalkyl)isoquinoliaes The search for isoquinolines possessing biological activity has provided a variety of synthesis for 1-(aminoalkyl)isquinolines,which have also been further elaborated into more complex heterocyclic systems. A general method for the preparation of unsubstituted aminoalkylisoquinolines involves the reduction of an appropriate nitrile to an amine. The reaction of l-methyl-3,4-dihydroisoquinoline(1) with acrylonitrile followed by the lithium aluminum hydride reduction of 2 furnishes a modest yield of l-(4-aminobutyl)3,4-dihydroisoquinoline(3)' (Equation 1).
qN-qN-'
N Q
CH 2 CH 2 CH2 CN
CHI 1
~ H ~ ( c H ~ ) ~ N H ~
2
3
(1) l-(Alkylha1ide)isoquinolines can undergo an SN2 reaction with amines to furnish unsubstituted or substituted 1-(aminoalky1)isoquinolines.The reaction of l-(chloromethyl)-3,4-dihydroisoquinoline(6), easily prepared in two steps from the appropriately substituted phenethylamine 4, with monosubstituted amines provides 1-(substituted aminomethyl)-3,4-dihydroisoquinolines (7), which can be catalytically reduced to their corresponding 1,2,3,4-tetrahydroisoquinolines 8'-* (Scheme 1).
8
7
Scbemcl
11. Isoquinolines Having Basic-Containing Substituents at C1
3
Derivatives of 8 were converted into a variety of substituted imidazoC5,la]isoquinoIines 9 and pyrazino[2,1-~]isquinoIines 14 by Archer and his Sterling group4-* (Scheme 2).
R'
8
9
I
10
R' 11
I
14
R'
An alternative pathway that has been extensively employed for the preparation of 1-(aminoaIkyl)isoquinolinesinvolves the use of acyl phenethylamines 15 wherein the nitrogen atom of the basic side chain is suitably protected with either a succinoyl or phthaIoy1 group. Subjecting 15 to the BischlerNapieralski cyclization reaction affords 16 which can be hydrolyzed to 17.
4
Isoquinolines Bearing Basic Side Chains
Catalytic reduction of 17 leads to the 1.2,3,4-tetrahydroisoquinoline 1810.19.22,24.3 1.40.41.43 (&heme 3).
POCI, or
PPA
0
0
15
16 OH
In their attempt at preparing aza-steroids having hypotensive properties, Burchhalter et al." have reacted 1-(2-aminoethyl)-1,2,3,4-tetrahydroisoquinolines 19 with the iminoether 20 to produce 21 (Equation 2).
R
dHNH ~ ~ z C H 2 mC O z *C t
O-SOC
CHjO
CI
-
19
R=H b R=OCH,
8
Shiotani and M i t s u h a ~ h i ~ ~refluxed * ~ ~ * ~ ~@-(m-methoxypheny1)-Nphthalimidoacetyl alanine methyl ester (22) for 2 hr with phosphorous oxychloride and phosphorous pentoxide to afford 1-phthalimidomethyl-3-carboethoxy6-methoxy-3,4-dihydroisoquinoline(23) which on catalytic reduction with hydrogen over platinum oxide yields the corresponding 1,2,3,4-tetrahydroisoquin-
11. Isoquinolines Having Basic-Containing Substituents at C1
5
oline 24. Treatment of 24 with hydrazine hydrate generates 8-methoxy-1,2,5,6tetrahydro-l,5-iminobenz[dlazocino-4(3H)-one (25) in excellent yield (Scheme 4).
23
22
H ‘
“
3
\ 0
y
p
y
H
25
The double cyclization of 26 provides in reasonable yield 4-phenyl-9,10dimethoxy-6,7-dihydro-2tl-pyrimido[4,3-uJisoquinoline (28)24(Equation 3). PZ 01
CHCI,
26
ij
-
cHJo CHJO
H NCPh
II
27
0
cH’Olq.. CH3O
6
Isoquinolines Bearing Basic Side Chains
Either 4,Sdimethoxy- or 5,6-dimethoxy-l-phthalirnidomethyl-1,2,3,4-tetrahydroisoquinoline 29a or 29b reacts with p-methylbenzenesulfonyl chloride in pyridine to provide 30 which on refluxing with hydrazine hydrate yields 31. Heating 31 with 37% aqueous formaldehyde for 2 hr resulted in the ring closure at C7 to furnish the 2,3,7,8,9,9a-hexahydro-lH-benzo[d,e][ 1,7]naphthyridines 3% and 32bZ2(Scheme 5). R py rid, n e
0
0
2!3 a R=4,SdiMeO b R=5,6diMe0
1
32
N I H ~' HzO
31
scbeme 5
The Reissert compound 33 on basic hydrolysis affords isoquinoline- 1carboxamide (34)which can be reduced with hydrogen over platinum oxide to the 1,2,3,4-tetrahydroisoquinoline35. Subsequent reduction with lithium alumi(Scheme 6). num hydride provides XZ5
35
36 seb#nc6
11. lsoquinolines Having Basic-Containing Substituents at Cl
7
The reduction of the Reissert compound 37 with “Basler” nickel catalyst at 90‘C and 70 atm pressure for 24 hr affords 38 which under acidic hydrolysis yields X3*(Equation 4).
Catalytic reduction of I-cyanoisoquinoline (39) leads to 1-(aminomethy1)isoquinoline(40)which after acylation with an appropriate acid chloride can be cyclized with phosphorous oxychloride to the imidazoC5,fa]isoquinoline (41) in very good yield4’ (Equation 5).
0
II
I RCCl
CN
40
NH2
41
(5)
A series of 1-(a-aminoalky1benzyl)isoquinolines44 were prepared in reasonable yields by the benzylic oxidation of 1-benzylisoquinoline 42 with selenium 6). dioxide followed by a reductive ~ x i m a t i o n(Equation ~~
Because of the medicinal interest in papavarine-like compounds, a large number of aminoalcohols 46 were prepared by reacting papaveraldine 45 with the appropriate Grignard reagents containing a variety of amino functionality12 (Equation 7).
8
Isoquinolines Bearing Basic Side Chains CH30 CH30
go -
CH30
OCH3
45
46
a R = N(CH& b R = morpholino c R = piperidyl
Isoquinoline analogs 48 of the antihistamine Decapryn were prepared by reacting either methylphenyl(14soquinolyl)carbinol (47a) or diphenyl(1isoquinoly1)carbinol (4%) with b-dimethylaminoethyl chloride and sodium in toluene at 60°C followed by refluxing for 15 hrJ5(Equation 8).
dH
I . CICH,CH,N(CH,), Naltol uenc/t4J°C
2. 1 1 0 ~ C l l S h
47
48
a R=CH3 b R=CIHs
I
(9)
1. H,O'
2. NaBH,
I
H
CHzCHCH2N' C ~ H P
I
OH 51
11. Isoquinolines Having Basic-Containing Substituents at C1
9
The acidic character of the methyl group of 1-methylisoquinoline (49) was exploited by Meyer et a1.j’ for the preparation of a-[(t-buty1amino)methyl-1isoquinoline]ethanol (51). Treating 49 with n-butyllithium and reacting the lithio derivative with t-butylacetonitrile affords 1-[2-amino-3-(~butylamino)propenyl]isoquinoline (50) which after hydrolysis and reduction with sodium borohydride provides the amino alcohol 51 (Equation 9). The synthesis of potential antitumor agents such as 5-(N-ethyl-Nalky1amino)- (53), 5-(N-monoalkylamino)- (54), and 5-(N-alkylacetamido)-lformylisoquinoline thiosemicarbazone (55) from 49 is depicted in Scheme 7.” R, I . B,H6
2. sco, 3. H,NNHCNHl I1
____,
i?
CCH3
49
@ \
R,
CH,
tH3
52
I . SCO
A
2. H,NNCNH,
II
S
,CHzCH2
N I
0 N
,H
10
Isoquinolines Bearing Basic Side Chains
The isoquinoline alkaloid amphibine I (%), isolated from crude alkaline extracts of Ziziphus arnphibid5, possesses chiral centers at C1 and C9 and a third due to the presence of natural (S)-valine.
CHjO
H
CHqO CHqO 2 NaBH,CN
0
0
n
58
0
1
I . HCHOIHCOOH 2. N ~ H I
- 2. H 2 I Pd - c
3. Separation of isomers
59 56 Scbeme 8
11. Isoquinolines Having Basic-Containing Substituents at C1
11
In order to correctly assign the absolute configuration of 56, a total synthesis was undertaken. The condensation of N-phthaloyl-L-alaninewith 3,4dimethoxyphenethylamine affords 57. A Bischler-Napieralski ring closure followed by reduction to the 1,2,3,4-tetrahydroisoquinoline58 occurs with total racemization of the alanine. Considerable racemization could be avoided when a rapid reduction and work up was employed immediately after ring closure. Alkylation and deprotection of 58 affords 59, which after acylation with (S)-Cbzvalylglycine and separation of the resulting mixture yielded 56. By varying the chirality of the amino acids used, all possible diastereomers were prepared and characterized. From this information it was determined that 56 possesses the Cl-(S),C9-(R),syn absolute c~nfiguration~~ (Scheme 8). TABLE 1. BIOLOGICAL ACTIVITY Structure
R
l
q
N
Biological Activity
, NN
Rd.
CNS (central nervous system)
67
CNS depressant, sedative, and
4.V
Antibacterial
22
An tispasmodic
16
tranquilizer
I
R'
anticonvulsant
I
R'
I
P'
12
Isoquinolines Bearing Basic Side Chains
TABLE 1. (Continued) Structure
Biological Activity
Ref.
29
H
Antihistaminic
35
8-Adrenergic blocker
30
Antipasmodic hypotensive. antipsychotic, analgesic, anticonvulsant
12
Antifertility
11.32
CHzfHCHZN'
CH30 C
H
3
0
CH2CHZN 7
' k2 R'
OCH3 OCH3
CH3
13
11. Isoquinolines Having Basic-Containing Substituents at C1 TABLE 1 . (Continued) Structure
Biological Activity
R'
HN(CH z ) n N
/
Ref.
Antimalarial
20.34
Antitussive, antifibrillatory
23
Iontotropic
42
Coronary circulatory activity
37
Sedative, tranquilizcr. hyptmsivc, and cardiovascular
3
\
RZ
R'
HN(CH 2 )n N
/
\
RZ
CHiO
CH2--N /N-R3
W 32
TABLE 2. 1-(AMIN0METHYL)ISOQUINOLINES
n
5
%
0'
X
z n
X
X
14
x x x
N
r,
r,
u"
u"
I
x
I
z
X
x
2"
I
I
X
X
2
0
0
0
Ym
1s
0
' I rn
Rl
3-CH3
H
R'
H
H
TABLE 2. (Continued)
R3
31 225-228 1N6°4
CZOHZ
31
Ref.
230-232
MP ("C)
C21H13N604
Formula
R’ -NH, -NHCH2C6H5 --O(CHz),N(CHdz --O(CHdzN(CH3)z --(CH,),N(CH,),
R
6,7 diMeO 6.7-diMe0 H H
6.7diMeO
3.4-diMe0
C6H5
OH
R3
3.4diMeO 3.4diMeO H H
H H CH3
X
TABLE 3. l-(AMINOBENZYL)ISOQUlNOLlNES
C25H32N205
C26H28N20
c21 H24N20
C.?7H2BN204
C20H22N204
Formula
(CH3I) 127-130
104-106
165-167 126-127 ( H a ) 226-228 99-99.7 ( H a ) 197.6-198.4
MP CC)
12
12 12 35 35
Ref.
R’
-(CHI)
-(CH,),N
-(CH,)3N
-NH, -NH, -NH2
6,7-diMe0
6.7-diMe0
5.7-diMe0 6,7-diMe0 5,7-diOEt
3
3
\p
3N
/7
-(CH,),NCH,
6’7-diMe0
6,7diMe0
R
TABLE 3. (Continued)
H H H
OH
OH
OH
OH
2.3-diMe0 H H
3.4-diMe0
3.4-diMe0
3.4-diMe0
3.4-diMe0
CZOH,*N2O2
I B H 1BNZ04
C20H22N204
C27H34N20S
CZ*H,,N,O,
C27H34N204
C27H36N203
120-150 155-160(d~) 130 (dec)
109-1 10 (CHSI) 135-136
154-155
(CHJ) 158
129- 130 (CH3I) 144-145
93-94 (CHSI) 115-1 16
44 44 44
I2
I2
12
12
11. Isoquinolines Having Basic-Containing Substituents at C1
19
TABLE 4. I-(AMINOALKYL)-3,4-DlHYDROlSOQUlNOLlNES
R'
~-
R'
R2
6-OMe 6.7-diOMe
H H
H
3-Me 3-COzEt -C
Formula
--CH,CH,NH, -CH,CH,NH,
ClzH16N20 Ci3Hi,NzOz
3
H zCH2 N
233 (dcc) 277 (dW (diHCl) 146-147
Ref. 10
1424
CzOHz8N,O, (dipicrate) 172
17 23
H
H
--CH,CH,N(Et),
Cl5H2,N2
H
H
-CH2CH2N(Et),
C16Hz,N,
H 6.7diOMe 6-OMe 6-OMe 6-CHj 6.7-diOMe 7x1 6.7-Methylenedioxy
H H H 3-Me 4-Me H H H
CH3 --CH,CH,N(Me), --CH,CH,N(Me), --CH,CH,N(Me), ---CH ,CH2N(Me), -CH ,CH ,"Me), --CH,CH,N(Et), -CH,CH,N(Et), --CH,CH,N(Et),
6,7-diOMe
H
I
MP ("C)
(diHC1) 232-235.(dec) (diHI) 223-250 (fumarate ) 172
23
(fumarate) 160-162 (diHCI) 170 (diHCI) 124- 126 104-106 (dipicrate) 137-139 (diHI) 255 (diHCl) 206-207 184-186 (diH1) > 160
23 49 48.49 49 49 23 23 23
131.8-137.6
3
f
00 I-"
5
x-
u'
r" z I
I
N
w
n
X
2 u
X
X
X
X
X
X
ez X
X
X
x
-d
N
-
H
H
6,7-diM&
6.7-Mcthylenedioxy 8-OMe
CH3
Ms 1
1
1
Ts
H
6,7diMe0
I
5,MiMeO
H
Ts
H
6-OMe 6,7-diMe0 6,7-diMe0
3 3 I
H
6,7-diMe0
I
H
H
6.7-diMe0
CH,C,H,
H
H
6.7-diMe0
I
H
H
6.7-diMe0
H
H H
H
6.7-diMe0
2
H
6.7-diMe0
CH3
H
6.7-diMe0
I
H
CHj
-NH,
N
-NHz
-NHz
-NH,
-NH,
-NH, -NHz -NH,
-NHCHC
-
-NHC,H,
--NHC,H,
C
H 2 CH j
e
l
233 277 145-150/0.03 mm (diHC1) 265 sulfate-2H20 274-275 178-180 (HCI) 235-238 138-139 (HCI) 255-256 158-160 ( H a ) 250 183
(diHBr) 267
(diHCI) 193-196
102-106 (diHCI) 212-214
79.5-82.5 (HCI) 186-192
78-79
(diHCI) 202-230
28
22
22
22
10 10 43 19
9
9
8
8
n
8
8
Do
N
N 00
c( 00
N 00
N 00
N 00
3 T
P
2
* m
c
2
? !
i ' x
I
I-
ro
$
8
EII
O+
X
z
z
I
3
I
3
i V
u
r"
d
I:
2
X
u X
3:
X
2:
Do
N 00
N P
N
N X
N m
z
N Do
8
N
z
N
9 u I II z
I
I
k$ X
c1
I
z
I
I
X
23
I
X
m 12
m
s
VI
P) m
I
09 m P) m
A
E
s u
2u
X
X
X
5
z
X
7 0 12
*24
u
W
3
Q 2
0
u, X u E
5 2 d 0
-Lo -N
-N
H
H
H
6,7-diM&
6.7-Methy lmdioxy
47diOH
\p
n
n \p
-N
n \p n
R'
H
R'
6,7-diOH
R
2
2
2
1
n
+
C,,H22N20, 2HBr
CI6H22NIO3-2HCI
C,,H,,N,03.2HCI-H2Q
CIIHZONIOJ -2HBr
Formula
TABLE 6. IdALKY LHETEROCYCLE)-I,2.3.4-TETRAHY DROISOQUINOLINES
283-284 (dw)
259 (dcc)
25&252 (dtc)
278 (dec)
Mp or Bp ("C)
so
Ref.
OI
N
H H H
6,7-diOH
6,7-diOH
6,7-diOH
H
6,7,8-ttiOH
H
CH,
6.7diOH
6.7-diOH
R'
R
TABLE 6. (Continued)
n
W0
n
W0
n
\p
A
42
2
2
3
2
2
n
-
n2 LN
--NIC,H
-"W0
-N
-N
--N
R'
C,,H,,N,02 -2HBr
CI,H,,N,0,-2HBr
C16HZ4NJOZ-2HBr
Cl,H,,N,0,-2HBr.
CI$H22N104* 2HBr
C,bH22N,O,*ZWBr
Formula
260-262 (dec)
224-226 (dec)
262-263 (dec)
260-261 (dec)
266 (dec)
286 (dec)
Mp or Bp {"C)
Ref.
11. Isoquinolines Having Basic-Containing Substituents at C1
27
B. l-(Aminoalkoxy)isoquinolines Because of their potential use as therapeutic agents, l-(aminoa1koxy)isoquinolines have received considerable attention. The synthesis of these compounds employs an aromatic nucleophibc substitution reaction of a labile C1 functionality, such as a chloride. Easily generated from the corresponding isoquinoline 60, the 1-chloro 61 undergoes facile substitution with substituted aminoalkoxy sodium salts to afford 62, which have interesting local anaesthetic a~tivity~’-’~’ 61-64 (Equation 10). R
W
R
‘
R
-
v
R’
\
0
CI
60
/
NaOICHzlnR’R’
R’
/N
R 62
q
61
(10)
/R’
O(CHz)n N \
R?
Modifications of 62 in which an afkyl ether occupies C4 can be prepared in the same manner by starting from the 4-keto derivative 63.These types of structural changes were carried out for the purpose of enhancing the local anaesthetic activitys9 (Equation 11). 0
ORZ
I . POCI,
R
W
0R
‘
2. KzCO, RzX
Cl 63
64
b(CH2h NR3R4 65
28
Isoquinolines Bearing Basic Side Chains
The displacement of the chloride with the hydroxymethyloxazolidines 67 provides 68. The hydrolysis of 68 with aqueous acid affords the 2-hydroxy derivative 69, which acts as an adrenaline antagonist in guinea pigs6' (Equation 12). R'
66
68
& H ~ C H C HN ~HR~
I
OH
68
In an effort to develop a nonsteroidal antifertility agent based on the finding that racemic l-phenyl-2-phenethyl-l,~3,4-tetrahydroisoquinolinehydrochloride is active as a female antifertility agent in the rat, a series of analogs in which the 1-phenyl was replaced with a I-phenolic group wherein the 4'-hydroxy functionality is alkylated with a variety of alkylamines were prepared. The starting compound 70 can be prepared either from the Pictet-Spengler reaction or the Bischler-Napieralski reaction depending on the degree of electron enrichment provided by the substituents. Acylation and diborane reduction provides the 2-N-alkylisoquinolines 71, which is demethylated with hydrobromic acid and then alkylated with a variety of chloroalkylamines to afford 72'* (Scheme 9). Treating 73 with hydrogen sulfide in pyridine generates 74, which readily reacts in an SN2fashion with chloroalkylamines to provide the aminoalkylthio derivatives 7!P9 (Equation 13).
@ , -@ N
\
/N
pyridine H1S
OH 73
SH 74
CI(CH2hNR2RJ,
@ \
/ N
(13)
S(CHZ)~NR* R3 75
11. Isoquinolines Having Basic-Containing Substituents at C1
kH2CH2NRZR3 72
29
Isoquinolines Bearing Basic Side Chains
30
A variety of antitussive and defibrillatory agents 77 were prepared by reacting 76 with an assortment of aminoalkylarniness6 (Equation 14). R'
HN(CH~),NR'R'
R
q
N
-
R
q
R'-N(CH?X,
SCH3
n
76
(14)
N NR2R3
TABLE 7. l-(AMINOALKOXY)ISOQUrNOLI"S
R
R'
RZ
Molecular Formula
H
C13H16N20
C2H5
C13H16N20
CH3
Cl'H18N2O
C2H5
I5
20NZ0
C2H5
C15H20N20
CZH5
C16H2ZN202
CH3 n-C3H7
C16H22N20
CH3
c I ,H 22N20 C17H22N20
C2H5
C17H24N20
C2H5
Cl7H22N2O2
n-C,H9
C17H24N20
iso-C,H9
C17H24N20
C2H5
C,8H24N20
n-C5H1
1
C18H26N20
C6H5
C19H20N20
C2H5
C19H2.9N20
n-C6H
I3
H CH2C6H5 C2H5
n-C,H9
C19H28N20 C19H28N20
C2oH2zNzO CzoHz2NzO hydrochloride C20H2BN20
Fp (Flash point) or Bp ("C)
133-134 (2 mm) 177-178 (0.5 mm) 132-134 (I mm) 158- 164 (4 mm) 153-156 (2 mm) 169-172 (0.3 mm) 153-154 (1-2 mm) 150-152 (2 mm) 175-178 (1 mm) 154-157 (1 mm) 170-172 (0.3 mm) 155-157 (3 IUIII) 140-141 175-178 162-164 198-200 172-175 175-176 172-173 188-189 154-155
(0.4 mm) ( 1 mm) (1 IUIII)
(1 mm) (2 mm) (0.4mm) (2 mm) (0.4 IUIII)
189-191 (1 mm)
Ref. 6263 52.61 52.61 52.6 I 52.61 52.6 1 62,63 62.63 62,63 6263 52,61 52-54, 61-63 52.61 62,63 5261 516 1 52.6 1 52.61 62,63 52.61 62,63 52,61
11. Isoquinolines Having Basic-Containing Substituents at C1
31
TABLE 7. (Conrinued)
Molecular Formula
R’
R
R’
C2H5
-CH-(CHI)
CZH, n-C4H,
n-C,HP n-C3H,
C*H5 C,H,
H
CH 3
CH3
I
I
II-C~HP n-C,H,
5261
188-190 (2 mm) 177-178 (2 mm)
52.61 52,61
207-208 (0.3 mm) 220-225 (0.5 mm)
5x61 52,61
C22H32N20
186- 189 (0.4 mm)
52.6 1
C24H36N20
201-203 (0.4 mm)
5261
Fp or Bp (“C)
Ref.
cZl
H32N,0
C21H32N.70
-cH246H4~cH2)2-
CZZHZ4N20
3,4-Dimethoxy- CzzH,,N203 benzyl CH3
CH3
-CH-CH
Z-CH-CH
I
I
C2H5
Ref.
176-1 77 (0.4 mm)
C2oHzLlNzO
J-CH-
Fp (Flash point) or Bp (”C)
(CH3)2 2-C-
I
C6HlJ
I
‘ZH5
-CH-(CH,)-
TABLE 8. I-(AMINOALKOXY)ISOQUlNOLINES
R
X
Formula
Isoquinolines Bearing Basic Side Chains
32
TABLE 8. (Continued) R CzH5
Formula
X
--O--CH,-CH2--CH,-N(Et)2
-0-LH
A-CH31Hz
n-C,H,
- 0 0 - C H 3
I
I CH 2-CH- CH 2
166- 169 (4 mm)
52,61
C19H24N20
177-178 (1 mm)
52,61
154-156 (0.3mm) 168-170 (0.3mm)
5261 5861
C20H30N20
177-179 (0.5 mm)
52,61
cZ 1 H24N20
179-180 (0.05 mm)
55
c, ,H,*N20
189-190 (0.4m)
57,61
cl I H30N20
174-176 (1mm)
57,61
ClPHlBN20 C,9HZ9N3
H
-0-C
I
H- CHz-N( El),
Ref.
C18H26N2O
CHZ-CHCZHS
Fp or Bp (“C)
C6H5
CHZ--CH-CHz n-C,H,
-0-CH
I I
I I
N-Me
CH*--CH-CHz
n-C4H,
I
-O
n-C,H,
- O G - C , H ,
Cl ,H3oN,O
199-201 (1.0 mm)
57,61
n-C,H,
-O-CH-(CH~)~-N(E~)Z
C22H34N20
170-172 (1.Omm)
57,61
C21H30N20
237-240 (0.5 mm)
57.61
I
CH3 n-C,H,
- O ~ N - C H z C s H r
11. Isoquinolines Having Basic-Containing Substituents at C1
33
TABLE 9. SUBSTITUTED-1-(B-DIMETHYLAMINOETHOXY)ISOOUINOLINES5~*61
R H H H C2H5
CH3 C2H5
R’ Br H H H H H H n-C3H, H n-C4H9 C6H 5
R2
R3
NHZ H NHCCH 3
II
H H (33% OCH, H H H OCH3 H H
C13H 1 5BrN20
TN30
c1
C15H20N203 C15H21N30
CI,H2ON2O2
146-148 (1 mm) 169-171 (0.3mm) 181-182 (1 m) 187-188 (0.5mm) 159-161 (1 m)
C17HZ3N302
0
174- 175 (3mm) 167-169 ( I mm) 145-147 (0.3D) 156-160 (1m) 228-229 (5 mm)
CH3 H n-C4HP H H
CH3 H H H H
BP (“(3
Formula
H H
H NH2 H
H H H H H
R4
TABLE 10. SUBSTITUTED-I-(3-AMINO-2-HYDROXY-PROPOXY)ISOQUINOLINOLINES60
!’
I O-cn ,-cn-
I
H
N-R
OH
R1
R
R2
Formula
FP
7-Br
C16H21BrN202
183-186
H
C16H21N304
193-195
H
hydrogen maleate
hydrogen maleate c,7H24NZO2 bisfumarate
215-216
C17H24N20Z
118-120
5-CH3
C17H24N202
116-1 18
7-CH3
C18H26N202
202-204
dCH3
7-WH313
H
bisrumarate bisfumarate bisfumarate
C2oH,oNz02 naphthalene 1,Sdisulfoonate C12H26N202
naphthalene 1,Sdisulphonate
210-213 230-232
34
Isoquinolines Bearing Basic Side Chains TABLE 11. 4-ALKOXY-I-(3-AMINOETHOXY OR 3-AMINO-THIOETHYLF ISOQUINOLINES
R
R'
R'
X
H
CH,
0
H
Et
H
Fp("C)
Ref.
C,6H22N202
180
59
0
C16H22N202
133
59
Et
0
C,7HZ4N202
109
59
H
Et
0
C,7H24N20Z
144
59
n-Bu
Me
0
C18H26N202
n-Bu
Et
0
C18H26N202
140
59
n-Bu
Et
0
CIPH26Nt02
138
59
Et
n-Bu
0
hydrochloride CZlH,,N,OZ hydrochloride
131
59
H
Et
S
C16H2 I
196
8'
H
Et
S
190
59
H
n-Bu
S
138
8.
H
n-Bu
S
128
8'
'For related compounds, see Ref. 8.
Formula hydrochloride hydrochloride hydrochloride hydrochloride
59
hydrochloride hydrochloride
"doS
hydrochloride CI,H,,N,OS hydrochloride C,,H,,N,OS hydrochloride Cl@H,.N,OS hydrochloride
11. Isoquinolines Having Basic-Containing Substituents at C1
35
TABLE 12. SUBSTITUTED ing l-{p-[2-(1-PYRROLIDINYL)ETHOX~ PHENY L}-1,2,3,4-TETRAHYDROISOQUINOLINES'B
R'q R'
3
N-RZ , R3=p-C6H4-O-CHzCH2-N
R'
Formula
R2
H
CHZ--CHZ---C,H,
H
CH 2C H-C
WH,
CHZCH,C,H,
OCH,
CHLCH-C~HS
I
6
CH'
HS
FP ("C) 81-113
C29H34N20
dih ydrochloride
91-145
C30H16N20
dihydrochloride
220-225
C30H16N20Z
dihydrochloride
I CH3
51-59
c 1 1H,,N2OZ dih ydrochloride
TABLE 13. SUBSTITUTED 1-(3-AMINOETHYLAMINO)IsOQUINOLINES AND 3,4-DIHYDROISOQUINOLINES56
I
H N-C H,CH 2-N.
Type B = 3,4Dihydro
Type A
Type A o r B
R
A B
H H
/R' R'
R'
Formula cl 'HZ
Et
1
FP ("C)
3
Cl,HZ,N, dihydrochloride
233
C. Isoquinolines Containing Arninophenyl Substituents
Isoquinolines 78 as well as their reduced forms wherein the C1 basiccontaining substituent is a phenyl group bearing the amino functionality will be discussed in this section. Various useful applications as well as biological activities will be stressed.
36
Isoquinolines Bearing Basic Side Chains R'
78 (n=O. I.or2)
1 . 1-Anilinoisoquinolines (n =0 ) The syntheses of 1-anilinoisoquinolines have been realized from several alternative directions. The most commonly employed method involves the reaction of an appropriately substituted phenethylamine with a nitrobenzoyl chloride followed by a Bischler-Napieralski cyclization and nitro group reduction. Both I+-aminopheny1)- and l-@-aminophenyl)-l,2,3,4-tetrahydroisoquinolines 79rr and 79b were prepared in this (Equation 15).
I. b
CH,O CH O
m
N
H
+
2. POCl,
3. Z d H *
a
In order to develop antimalarial agents, Radionov and Y a ~ o r s k a y a ~ * * ~ ~ prepared ortho-, m a - , and para-aminophenyl analogs SO, which underwent a substitution reaction with 3-chlOrO-1-diethylaminopropane to afford 81 (Equation 16).
bNH2
11. Isoquinolines Having Basic-Containing Substituents at C1
37
M o r i m ~ t ohas ~ ~ prepared l-(p-aminophenyl)-3-methyl-6,7-dimethoxyisoquinoline (84) by the reaction of 3-(3',4-dimethoxyphenyl)-3-methoxy-2aminopropane (82) with p-nitrobenzoyl chloride (83) followed by a Bischler-Napieralski cyclization and nitro group reduction (Equation 17). The corresponding 1,2,3,4-tetrahydroisoquinolines were prepared by the catalytic reduction of 84. A variety of these derivatives were ~ r e p a r e d . ~ '
Q COCl
NO 2
82
83
I. A 2 . POCI,
3. reduction
Q
Ott and Hardtmann have exploited four separate routes for the successful preparation of 1-(2-amino4substituted pheny1~1,2,3,4tetrahydroisooqoquinolines 89.78The first route has already been described and involves the reaction of a phenethylamine with a variety of nitrobenzoyl chlorides to afford an amide that after functional group manipulations provides 86. The second method involves the condensation of a phenethylamine with isatoic anhydride 87 to form the amide 88. Subsequent protection of the free amine, cyclization, and deprotection yields 89. The third route takes advantage of the electron-withdrawingcapacity of the X group to facilitate an Ullmann exchange of the 2-chloro substituent in 90 by ammonia or a primary amine in the presence of copper. Sodium borohydride reduction then provides 89. Finally, the reaction of B-phenethyl chloride with an appropriately substituted benzonitrile in the presence of tin tetrachloride proceeds through a nitrilium salt to afford 90, which has already been used for the preparation of 89 (Scheme 10). Ott and Hardtmann have used 89 derivatives for the syntheis of a wide variety of tetrahydro[2,1-d][1,4]-benzodiazepines in order to study their neuropharof 89 with ethyl bromoacetate macologic a ~ t i v i t i e s . ~ ~ - ~ *The * ' ~reaction -~~ affords 91 in good yields when X is electron-withdrawing enough to decrease the nucleophilicity of the anilino group. This same reaction proceeds on the 2nitrophenyl derivative and involves a last step The cyclization of 91 under either basic or acidic conditions yields 92" (Equation 18). i t should be emphasized that 1,2,3,4tetrahydroisoquinolines bearing a C1 substituent are racemic and that chiral derivatives can be obtained through
38
Isoquinolines Bearing Basic Side Chains
8B
89
1
2 POCl,
cI
NH2R
cu
2 NaBH,
89
resolution. The reduction of 93 with sodium borohydride followed by separation of the enantiomers with D-(+)-and L-( -)-tartaric acids provides the diastereomers 94 and 95, each of which has been used to prepare chiral products. One of the two possible forms is represented by 9174(Scheme 11).
39
11. lsoquinolines Having Basic-Containing Substituents at C1
92
I . NaBH,
NHCHs 2 .
resolution
9J
94
1
95
I . BrCH,CO,Ei
l.OH-IH,O
20oOc
NHCH3
%
97
scheme 11
40
Isoquinolines Bearing Basic Side Chains
The reaction of 86 with 8-chloroacetonitrile provides 98, which, when converted to the imino ether 99, reacts with ammonia to yield the amino derivative 10073*75*89 (Equation 19).
(19)
100
The acid-catalyzed reaction of anthranilonitrile(101)with 1-phenyl-2-methyl2-propanol(lO2) in xylene at 85 "Caffords 1-(2-aminophenyl)-3,3dimethyl-3,4. dihydrgisoquinoline (103), which can be catalytically reduced to -1We1 (Equation 20).
bNHZ CN
+
101
103
11. Isoquinolines Having Basic-Containing Substituents at C1
41
Bishop and Tuckers7 treated 1-(2-aminophenyl)-6,7-dimethoxy-3,4dihydroisoquinoline (105) with glyoxylic acid to produce the Schiff base 106. Subsequent reduction resulted in a cyclization to 107. When this is cleaved with acid and recyclized with either formic or acetic acids, the 8,9-dihydro-l3bHisoquinolino[2,l-c]quinazolines 108a and 108b are produced (Scheme 12). Because many of these quinazolines exhibited a wide range of biological activity, Ott" has prepared a number of 6-amino-substituted derivatives. The reaction of 109 with carbon disulfide in pyridine followed by an alkylation with methyl iodide affords 6-thiomethyl-8,9-dihydro-13bH-isoqunolino[2,1clquinazoline (110). Displacement of the thiomethyl group with an appropriate amine is accomplished by heating either with or without solvent at 140-160°C for 2-40 hr (Equation 21). Resolution of the racemates of 109 with tartaric acid provides chiral routes to 111 derivatives7'. A convenient route to the synthesis of 1-(4-aminophenyl)isoquinoline(113) involves the addition of the organolithium compound 112, formed by a halogen-metal exchange with 4-bromoaniline, to isoquinoline in ether8' (Equation 22). The mutagenic fungal alkaloid necatorone (118) has been prepared in a six-step synthesis starting from 2-(3,4dimethoxyphenyl)ethylamine (114) and 2-nitro-5-methoxybenzoylchloride (11s)'' (Scheme 13).
cH30wN 0
II
aNH2 HCCOOH
CH,O
CH30
&N=cHcmH
106
106
R
-
I . H,O' 2. RCOOH
108
101
a R=H
b R=CH,
scbrme 12
Rv
Isoquinolines Bearing Basic Side Chains
42
R%
NHz
R’
1.
Me
N
~ ~ ~ ~ y r ’ d ’ n e
R‘
RY”l
109
/
110
R ~ R ~ N H
N
R’
111
Q Br
NHZ
I. lsoquinolinc 2. lo1
n.BuLi cthei
112
NH 1W
*
r u 0 c
X
0
i 0
z
+
43
&
H
H
3,ediMe 3-Me 3-Me
H H
H
H
3-Me
H
H
RZ
H
R'
H
R
4-NH2 4-NH2 3-NHz 4-NHa 2-NH2 3-NHz
CNH,
CNH,
4-NH2
X
TABLE 14. SUBSTITUTED-l-(AMINOPHENYL)ISOQUINOLINES
Formula
191-192 (CH3I) 206 130 (dipicrate) 171" (acetate) 152 112-1 13 (CHJ) 262 (CH,I) 247 (CH3I) 247 (CH,I) 247 (CH,I) 294 147- 148 175-176
Mp or Bp ('C)
71 71
85 85 85 85
86
88
86
87
Ref.
80
5 N
5 G
i
5 X
X
X
n
2 X X X
Y *
X I X X
CH,CN
CHZC
H
H
H
H
H
H
n
n
6,7-diMe0
H
‘kH
/
OEf
H
3,34iM e
H
H H H
R2
H
H
H
R’
H
H
H
$ R
R3 R4 Formula
TABLE 16. SUBSTITUTED 142-AMINOPHENYL)-1,2,3,4-TETRAHYDROiSOQUINOLINES
162 157-160 122- 124
(2HCl) 276-278 (dw)
125- 127
107 128-130 192 188-190 I 12- 1 14 (maleate) 192-194
Mp or Bp (“C)
64 78 78
73
73
69,7478 73.78 78 89 81
Rd.
W OI
H
s
z d z N
a5
d ??
z,
3
f
I
X
X
u
B
b N
2
Yi
3:
2
z
2
r r 2 1 2 x u
2
r
d
d I 2 2
3
0,
0
x
8 u, X
U
i V n
z?
X
x
2
Y m
Ym
x
8
3
K 5 C
x Z r r x x r
r
4
r-
d
$
49
Isoquinolines Bearing Basic Side Chains
50
TABLE 17. SUBSTITUTED I-(2-AMINOPHENY L)-2-CARBOXYMETHYL-I,2,3,4TETRAHY DROISOQUINOLINES7a.
R H H H H H
H
H H H H H H 6.7-diMc0 6,7-diMc0 H H H
RL H H H H H H H H H H H H H H 4-CH3 4,ediCH 4,4diCH3
RZ
R3
R4
Formula
Mp or Bp (“C) -95-130 Oil 163-165
Is0
210 98-100 125 (dec) 83-84 115-122 119-120
155 81-83 Oil Amorphous 111-113 111-113 212-21 6
11. Isoquinolines Having Basic-Containing Substituents at C1
51
TABLE 18. SUBSTITUTED 1-(3-AMINOPHENYL)-l,2+3.4-TETRAHYDROISOQUlNOLINES
o\
NHR
R
R'
Rz
H 6.7diMeO
H 3-CH,
H CH,
6,7-Methyl- 3-CH3 enedioxy
CH,
6.7-Methyl- 3-CH, enedioxy
CH,
R'
Formula
M p or Bp ("C)
Ref.
H H
CI,HI,Nz Cl9Hz4NZOz
69 70
H
Cl,HzoNzO
127-180 120-121 AC (106- 108) 221-223 ( H a ) 264-265 133- 135
71
-02 S
Cz4Hz,N,S04
e NH2
71
TABLE 19. SUBSTITUTED I-(4-AMINOPHENYL)-I,2,3ATETRAHYDROISOQUlNOLlNES
R
R'
R
RZ
R3
q
j
'R
R
2
Formula
H H H 6,7-diMe0 3-CH3 CH3
H H
H H
C,,HI,Nz C,9Hz4NzOz
6.7-Methyl- 3-CH3 CH, enedioxy
H
H
6.7-Methylenedioxy 3-CH,
CH3
6,7diMe0 H
H
0 6.7diMe0
H
It
CH3C-
- 0 , S e N H z
Mp ("C)
Ref. 68 70
C 1,HzoNzO
132-133 173-174 (MeCI) 244-245 AC 185-185 135- I36
Cz,Hz,N,S04
208-209
71
71
H
H
C1,HZoNZOZ
151-153
67
CH,
CH,
Cz I Hz6NzO3
136-137
91
lsoquinolines Bearing Basic Side Chains
52
TABLE 20. i,4-DIHYDRO-3(2H)-ISOQUINOLIN~83
NH
*
TABLE 21. 1-[4-(ACYLAMINO)PHENYL)-l,CDIHYDRO-~2H). ISOQUINOLINES~~
R1 H H H CH, CH3 CH3 E,H,
R’
n
H
Formula C18H19N302
H
3
Cl9H2IN3O2
H CH3 H CH3 H
4
C’OHZ3N3O2 C21H25N302 C21H25N302
C22H27N302 C.73H7.9N302
MP or BP CC) 204-205 183- 184 (maleate) 204-205 142-144 151- 152 89-91 107-108 150-151
11. Isoquinolines Having Basic-Containing Substituents at C1
2.
53
I - (Aminobenzyl)isoquinolines ( n = I )
As intermediates for the syntheses of a wide variety of aporphine-like substrates, this class of isoquinolines has been extensively researched. There are a number of useful synthetic routes developed to provide considerableflexibility into the kind of substitution patterns associated with the aromatic ring. The commonly employed Bischler-Napieralski cyclization reaction of the easily prepared amides 119 affords 1-(2-nitrobenzyl)-3,4-dihydroisoquinolines 120. Subsequent alkylation and sodium borohydride reduction provides the corresponding N-alkyl-l,2,3,4-tetrahydroisoquinolines121. The nitro functionality is conveniently reduced to the amine 122 with zinc and a strong mineral acid, usually hydrochloric acid9' (Scheme 14). Other successful reduction methods including catalytic reduction with platinum oxide,102*104-109 Adam's catalyst,"' or palladium on charcoal"' have also been employed.
6)
R'
119
R7R rcduct i o n
c----
Alkylation of the Reissert compound 123 with appropriately substituted o-nitrobenzyl chlorides followed by a basic hydrolysis provides 124, which is (Equation 23). easily converted in three steps and in high yields to 12514'*142
Isoquinolines Bearing Basic Side Chains
54
R NaH 2 KOH
CN 123
.
7
I . R'X 2. KBH,
3. Hz/Pd-C
R
124
The condensation of substituted o-nitrotoluenes 127 with an isoquniolinium iodide 126 under basic conditions affords the corresponding 1,2,3,4-tetrahydroisoquinolines 128, which can be reduced to the desired amino derivatives 122103,134- 136.1 5881 5 9 (Equation 24).
8
&
R'
R'
122 (R = CH,)
128
(24) Direct nitration of 1-benzj.isoquinoline ( 9) with nitric acid has been reported to provide a 66% yield of 1-(4-aminobenzyl)isoquinoline 130142 after reduction of the intermediate NO2 derivative (Equation 25).
.
qN I . HNO,
2 reduction (66%)
129
(25)
130
11. Isoquinolines Having Basic-Containing Substituents at C1
55
The ability of 1-chloroisoquinoline (131)to undergo nucleophilic substitution reactions has been exploited for an unusual synthesis of I-(2-aminobenzy1)isoquinoline (135).The reaction of 131 with the anion of o-bromophenylacetonitrile (132)provides 133,which is hydrolyzed and decarboxylated under acidic conditions to provide 134. Treatment of I34 with cuprous bromide and ammonium hydroxide affords 135142(Equation 26).
134
133
The classical Pschorr synthesis of aporphine alkaloids 137 consists of the copper-catalyzed decomposition of the corresponding diazonium salt derived from 2-aminobenzylisoquinolines'' * I 16,140 (Equation 27). R
m. -
M
R?
136
_.
I
NPNO./H*
R
, NR'
137
In this way such aporphine alkaloids as dlepidicentrine (l38)IJ2, dl-domesticine (139)"' and dl-tuduramine (l4O)'O' were successfully prepared.
Meop c:!p
56
Isoquinolines Bearing Basic Side Chains
Me0
H3
H3
0 L
HO L
O
138
O
140
139
An interesting synthesis employs the Pschorr reaction for the preparation of
+
( )-(S)- 1,2,3,1O-tetramethoxy-9-hydroxyaporphine (141), which then undergoes an Ullmann coupling reaction with ( +)-(S)-6'-bromolaudanosine (142)
for the preparation of the potential antitumor alkaloid adiantifoline (143) is illustrated in Equation 28loo.
+
CH30 CH,O
bH 141
142
I
Ulmann
143
In some cases where copper fails to catalyze the Pschorr ring closure, zincg9or cuprous chlorideg6 have been successfully employed for these ring closures.
11. Isoquinolines Having Basic-Containing Substituents at C1
57
The Pschorr cyclization of 144 afforded a mixture of products among which the indenoisoquinoline 145 was isolated in 30% yield. Treatment of 145 with acid affords a near-quantitative yield of the 1-oxoaporphine 146. This unusual cyclization into the 8a position of the isoquinoline instead of the common angular cyclization into the 4a position is believed to be due to the aromatic planarity of the molecule which prevents the 4a attack for steric reason^^^.^^' (Equation 29).
144
/
145
146
While the Pschorr cyclization provides access to a diversity of aporphines, the Mannich reaction allows the cyclization at the isoquinoline nitrogen to provide aminoprotoberberines. The reaction of substituted 1-(3-arninobenzyl)-6,7dimethoxy-1,2,3,4-tetrahydroisoquinoline 147 with 36% formaldehyde in ethanol results in a para cyclization to yield 148'" (Equation 30).
NH 2 147
liH* 148
Isoquinolines Bearing Basic Side Chains
58
Depending on the substitution present in the aminobenzyl portion of the molecule, mixtures of products are common when both the ortho and para positions are available for the cyclization' 19. The unusual spiro-product racemic glaziovine (152) is prepared from 1-(4aminobenzyl)-7-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline (149)by a kind of push-pull mechanism' 26* 66 (Scheme 15).
'
NCH?
I . NaCIO,
2. K t R u O
150
149
151
152 scheme 15
Isoquinoline derivatives 155, prepared by the reaction of appropriately substituted phenethylamines 153 with the correspanding aldehydes 154, were studied for their muscle-relaxant' 5 1 and antispasmotic' 5 2 properties (Equation 31). XCHzCHO
NHR~
RO
+
(j) R'
153
IS4 [ X = Oor S J
-
RO
11. Isoquinolines Having Basic-Containing Substituents at C1
59
TABLE 22. I-(AMIN0BENZYL)ISOQUlNOLlNES R
R
R‘
X
Q
N
Formula
H
H
2-NHZ
C16H14NZ
H H
4-CH3O 4,5-diCH30
2-NH, 2-NH,
CI’H16N20 C,,H,,N,O,
6.7-diCH30 6-Me0.7-Ac0
4.5-diCH30 4.5-diMeO H
2-NH2 2-NH, 3-NH2
C,,H,,N,04 C,,H,,N,O, Ci,Hi,Nz
H
H
4NHz
CI~HI~NZ
H
Properties (“C)
Ref.
69-70 (HCI) 265-270 (dw) (picrate) 174-174.5 102-103 90-91
142
136-138 79-81 199-202 (pinate) 203-204 (dec) (diAc) 233-234 (HCI) 284-285 (dw) 118-119 (HCI) 212 (Ac) 156.5 (bisulfate) 112-114
165 165 97 41 I42
142
8
5-OEt
S-CI
6-OMc, 7-OH
H
H
5-OMe H
4-OMe
6-OMe 7-OH
6,7-diMc0
H H H H H
H H
6-C1 5-CI dc1 6-CH3 4-CH3 &CF,
6-F
H
H
H
R’
H
R R’
Formula
-R’
TABLE 23. 1-(2-AMINOBENZYL)-1,2,3,~TETRAHYDROISOQUINOLINES
(2HCI)248-250 (2HCI)257-258 (2HCI)272-273 (2HCl) 2MT262 (2HC1) 245-247 (2HC1) 252-255 (2HC1) 228.5-231 (2HC1) 268-269 (2HCl) 256-259 (2HCI) 235-236 (2HC1) 185-187 (2HCI) 228-230 (HCI) 256-257 (k) 257-258 (dx) 188-190 (dx) (2HCl)210-212 (dec) (2HCI) 215-217 118-1 19 (2HCl) (210-212)
Properties (“C)
134,136 161
134
161 161 161 160 163 I 26 136
161
109
141 161 161 161 161 161 161
Ref.
L
n
X
6,7-diMeO
6.7diMeO
6-OMe 7-C,HSCH20, 6-OMe ’I-C,H,CH,O 6.7diMe0
H
CHIC6HS
6,7diMe0
6-C,H,CH,O, 7-OMe 6,7-Methylenedioxy
CH,CH3
6,7diMe0
R‘
4C6HsCH2O 5-OMe 4,5-Methylencdioxy 4,5-diMe0
4-OCH, 5-C,H,CHzO 4-C6H,CH,0 5-OCH,
117 114 99 92 129 193-194 (dipicrate) 154-157 (dec) (HZO) 62-72 (dec) (H10)75-79 (dm) (picrate) 193-194
107 150
163 160 108 I55
94
164
121
143
114-ltS
138-140
(picrate) 178-181 151-151.5 (diHCI) 220-222 (dw)
H 4,s-Meth yleneddioxy
(Ha) 213-215
Syrup Syrup
209-110
114 168 170 170
(picrate) 201 (dec) (diHC1) 188-189 233.5-235 (dec) 117.5-119.5 (picrate) 118-1 19
164 121 104
Ref.
Properties (“C)
174-175 (EtI) 207 (dec) (diHC1) I78 (dec) 120 112-114
Formula
4-OMe, 5-OEt
4,SdiMeO 4,S-diMcO 4,s-Methylendioxy 4,5-diMe0 4.5-diMe0
3,4diMe0
4.5-diMeO
5,6diMe0 5,6-diMc0 6,SdiMeO 6,7-diMe0 6,7diMc0 6-OMe, 7-OEt S46,7-tAMt0
R’ 3.4-diMeO
(Continued)
6.7diMc0
R
TABLE 23.
P,
W
CH3 CH,
7-C6HsCH,O 6-OMe 7-C6H,CH,O 6-C6H&HzO. 7-OMe CC6HsCH,0, 7-OMe 6.7-Methylenedioxy 8-OCH3
CH,
C~HSCH~ CHI
CH,C,H,
6-OMe, 7-C6H,CH,0 6-OMe
6.7diMc0
5.6.7-triMe0
7-OH
6-C,HSCH20 7-OMe 6-OCH3
6.7-diMe0
6 . 7 4 Me0
0
OCHJ
OCH,
H
H 4-OCH3 S-C,H,CH,O 3-CbH SCH 2 0 4-OMe 4.5-Methylenediox y 3.4-diMe0
dOMe 5-CeH SCH 2 4-OCH,
4-OMe
3-C,H,CH*O 4-OMc 3-OCH, 4-C6H,CH ?O 4.5-diMeO
I20 125 I24 Oil Syrup (HCI) 249-250 (dm)
(Ac)149-151 (Bz)123-140
127.156
I57 I39
I35
100
134. 136
I 20
I14
130
(picrate) 177- 178
99-100 (picrate) 143-145
170- 172
117-118
glass
Oil (picrate) 166-40 (dec) (picrate) 207
64
Isoquinolines Bearing Basic Side Chains
RWNRI H2N3‘
TABLE 24. 1-(3-AMINOBENZYL)-1,2,3,4TETRAHYDROISOQUINOLINES
R*
R 6.7-diMe0 6,7-diMe0 6.7-Methylcnedioxy 6.7-diMe0 6.7-diMe0
R1 H H H CH,
H
R2
Formula
Properties (“C)
Ref.
H 4-OMe 4,5-diMe0 COCH, 4,SdiMeO
C,,H,,N,O, Cl9Hz4N20, Cl9HZ2N2O4 CzoH,,N20, C,,HZ,N,O4
144-146 Oil (picrate) 221-230 (diHCl) 220 157-159 (dec)
118 118 119 101 119
TABLE 25. 1-(4AMINOBENZYL)-1,2,3,CTETRAHY DROlSOQUINOLINES
R
R’
RZ
Formula
Properties (“C)
Rd. 126 l38 126 125
6-OCH37-OH 6.7-diMe0
CH3 CH3
H H
C,,H,,N2O, CI9Hz,N,O,
6.7-Methylcnedioxy 8-OMe 5,6,7-lriMeO 6,7.8-triMe0
CH,
H
C19H*,N,Oj
188-190 (dm) (diHCI) 268 (diHCI) 218-221 106-107
CH3 CH3
H H
C,oH2,N,03 C,oH,,N,O,
(diHCl) 253 118-220
123 123
6.7-Mcthylenedioxy 8-OCH3
CH,
2-NHCC6H5
C26H,,N,O,
177-178
124
0
II
11. Isoquinolines Having Basic-Containing Substituents at C1
65
3. I - (Arninophenethyl)isoquinolines ( n = 2 ) The reaction of I-methylisoquinoline with aromatic aldehydes in the presence of a Lewis acid such as zinc ~hloride'~'or acetic anhydride172provides pamino-substituted styrylisoquinolines 156a-c (Equation 32).
-7:;-7
A very interesting variation toward the synthesis of 156 derivatives involves the reaction of 1-methyl-3-phenyl-5,6,7,8-tetrahydroisochromyliumperchlorate (157) with aromatic aldehydes under acidic conditions to afford 158, which when treated with ammonium hydroxide provides 159'73(Equation 33).
6 AcOH R
CH3 157
R
R
l58
199 R =--N(CH,)2
(33)
66
Isoquinolines Bearing Basic Side Chains
Facile catalytic reduction of the styryl olefin of 159 affords the corresponding phenethylisoquinolines. Direct synthesis of the aminophenethyl derivatives can also be achieved. The reaction of 4,5-dimethyl-2-nitrophenylpropionicacid (160) with any desired phenethylamine followed by Bischler-Napieralski ring closure, and subsequent alkylation and reduction provides the 1,2,3,4-tetrahydroisoquinolines161 74 (Equation 34).
cH’oX32H
I.
3. CH,I 4. ZnlHCl
RO
160
CH,O
)@rNH2 bCH3 161
a R=CH, b R = CHzCbH5
(34)
The direct nitration of the corresponding 1-(3,4dimethoxyphenethy1)-2methyl-l,2,3,4-tetrahydroisoquinoline 162 followed by reduction of the nitro group yielding the amino derivatives 161 is another effective route exploited for the preparation of these compounds’74 (Equation 35).
162
Diazotization of either 161s or 161b followed by decomposition of the resulting diazonium salt affords demethoxy-0-methylanhydrocymbine163174 (Equation 36).
67
11. Isoquinolines Having Basic-Containing Substituents at C1
NCHl
CH 1
I
CH
NINO,IH'
2 4
W
P
RO
N
C
H
0
6CHz
161 a o r b
The photo-Pschorr cyclization of the diazonium salt of 1-(2'-amino-3",4,5"trimethoxyphenethyl)-7-hydroxyd-methoxy-2-methyl1,2,3,4-tetrahydroisoquinoline (164) provides kreysigine (165) and 0-methylandrocymbine (166)'" (Equation 37).
y +
CH30
CH3O C H 3 0
H3
CH30 166
''
Kametani and coworkers' have prepared both the Cmethoxy- (16th) and the 4-benzyloxy- (168b) 1,2,3,4-tetrahydroisoquinolinesand found that the Pschorr reaction of these derivatives provides the spiro [indan- 1.1'-isoquinolines] 169 (Equation 38).
68
Isoquinolines Bearing Basic Side Chains
‘H30q CHzOH
3. PCI, C H
RO
167 I R=CH,
b R=CH,C,H,
CH3 C H 30~~~~ 0
2. 1 . Malonic MnO, Acid
,
O
p
N
i
CH,O
H2N
5. POCI, 6. NaBH, 7. CHJ
ch30 OR
/
\
OCH3
169
,.
6
CH O CH3O
(39)
32 rHCI cdrton 4 HCOOH
NMe,
q
N
HCHO
C
H
3
NMc 2
69
11. Isoquinolincs Having Basic-Containing Substituents at C1
Brossi and coworkers' 77 have prepared 1-(4'-dimethylaminophenethy1)-6,7dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(172) from l-methy1-3,4-
dihydroisoquinoline (170). Treatment of 170 with acetic anhydride followed by an acidic ring opening hydrolysis affords 171. Condensation of 171 with p-dimethylaminobenzaldehydefollowed by acidic cyclization and finally reduction and N-alkylation yields 172 (Equation 39). TABLE 26. I-(2-AMINOPHENETHYL-l,2,3&TETRAHYDROISOQUINOLINES
R
R'
RZ
Formula
Properties ("C)
Ref.
6.7-diMeO 6-Me0.7-OH 6.7-diMeO 6-Mc0, 7-OCHzCbH, 47diMeO
CH, CH, CH, CH3
4.5-diMeO 3.4,5-triMeO 3.4.5-triMeO 4.5-diMe0
CzzH,oNzO4 C,,H,oN,O, Cz,H,2Nz0, C2eH,4NzO4
(2HCI) 197-198 (dw) Syrup Syrup 2HCI 230 (dw)
174,178 175 178 174,178
CH,
4-OCH,C6H, 3.5-OCH3
C,,H,6NL0,
Syrup
178
TABLE 27. I-(4-AMINOPHENETHYL-L,2,3,4TETRAHYDROISOQUINOLINES
R 6,7diMeO 6-Me0.70H 1,7diMeO
R'
RL
R'
CH3 CH, CH3
H H H
H H CH3
~~
Formula C10H26N202 C1!3HZ4N202
C,2H,,NzOz
Properties ("C)
Ref.
-
143 174
132-1 33" (2HCI) 163-165"
177
70
Isoquinolines Bearing Basic Side Chains D. Isoquinoliws Bearing Basic Heterocyclic Substituents at C1
Isoquinolines substituted at C1 with a variety of heterocyclic derivatives possessing basic properties have received considerable attention and synthetic effort as a result of their diverse biological applications. Numerous chemical strategems have been developed and employed for the preparation of a large variety of such compounds. This section will discuss those synthetic methods that provide considerable flexibility in substituents as well as heterocycles for the preparation of both isoquinolines and their reduced forms.
1. Five-Membered Heterocycles In order to have an aromatic character, pyrroles must involve the lone pair of electrons on the nitrogen atom with the four olefinic electrons. While the pyrroles are very weak bases, their corresponding reduced forms behave as secondary amines and have considerable basicity. The Bischler-Napieralski reaction is one of the most useful methods available for the synthesis of an unlimited variety of C 1 heterocyclic-substituted isoquinolines. Cyclization of amide 174, prepared by reacting a substituted phenethylamine with an appropriately substituted pyrrole 173, affords the dihydroisoquinolines 175, which are easily aromatized in the presence of palladium at elevated temperatures to 176181*189 (Scheme 16).
173
.$rR' 4
176
R2
Sdteme 16
H&R' 4 175
R2
71
11. Isoquinolines Having Basic-Containing Substituents at C1
The condensation of N-substituted-pyrroles with isoquinolines in the presence of acyl halides at 25-50°C in a ratio of 3:4 affords 1-(2-pyrro1)-1,2dihydroisoquinolines 177 and the (2,5-di-isoquinoline)pyrrole 178 in 50-70% yield. These can be separated by fractional crystallization from ether or by preparative thin-layer c h r ~ m a t o g r a p h y ' ~(Equation ~ . ' ~ ~ 40). R
178
The use of Reissert compound to prepare a large variety of 142pyrroly1)isoquinolines has been extensively studied by McEwen and coworkers.'81.'86-189,196The acid catalyzed reaction of 179 with 1,l-diphenyleth196 (Equation 41). ylene affords 180LB9*
180
Mechanistic s t ~ d i e s ' ~ ' suggest . ' ~ ~ that the 1,l-diphenylethylene undergoes a 1,3-dipolar cycloaddition with the meso-ionic intermediate 181,which provides 182.Subsequent aryl migration reestablishes the aromaticity. Both 182 and 180 can be isolated, and it has been demonstrated that 182 rearranges under acidic conditions to 180189(Equation 42). P J P h
.
(42) 179
181
Ph 182
72
Isoquinolines Bearing Basic Side Chains
Product structure was confirmed by use of the Bischler-Napieralski synthesis of these compound^.'^^*^^^ The acid-catalyzed reaction of 179 with acrylonitrile provides 241-isoquinolyl)-3-cyano-5-phenylpyrrole(183) in moderate yields' E2 (Equation 43).
I . CH,=HCN
179
' H
2. base
183
Nucleophilic aromatic substitution of a labile C1 halide of isoquinoline 184 with imidazoles 185 under basic conditions provides isoquinolines 186 which are of interest as hypolipidemic and hypoglycemic agentsLE5(Equation 44).
R4yyR2 H
R'
I
186
The Friedel-Crafts acylation of electron-rich allylic aryl compounds 187 with 2-thiophenoecarboxylic acid (188) followed by a cyclization with ammonia affords 1-(2-thienyl)isoquinolines 1891E3'(Equation 45).
RYC
b acmH CH,CH=CH,
I . POCI,
+
R
181
2 NH,
188
-
lb
(45)
Reactive methylene containing compounds such as hippuric acid undergo a base-catalyzed nucleophilic addition to 190 to provide 191179*182 (Equation 46).
11. Isoquinolines Having Basic-Containing Substituents at C1
'
T
N
NaOAc
'
V
**.floe
H
C6HS 190
191
73
3
(46)
"'( 4
Bischler-Napieralski cyclization of amide 192 followed by a lithium aluminum hydride reduction of the 2-pyrrolidinone 193 and chromatographic separation of the resulting diastereomeric mixture provides a good yield of 194, which serves as an intermediate for the synthesis of a z a ~ t e r o i d s (Equation '~~ 47).
-
CH30
PPA
(67%)
1%
CH,O
b12S-heterocycle
1%
Heterocycle
N-N
N-N 199 ---((S>CHl
200
4s)
(48)
74
Isoquinolines Bearing Basic Side Chains
A series of heterocyclic isoquinolines prepared for their interest as smoothmuscle relaxants and vasodilators involves the Pictet-Spengler cyclization reaction of acetals 1% with substituted phenethylamines 1% to afford the 1heterocyclic-l,2,3,4-tetrahydroisoquinolines197-201 19’ (Equation 48).
2. Six-Membered Heterocyclic Isoquinolines a. Substituted 1-(Pyridy1)isoquinolines Because of their interest as substrates for some biochemical studies involving catecholamine metabolizing enzymes as well as their potential therapeutic applicability, l-(pyridyl)isoquinolines and their corresponding reduced forms have received extensive synthetic efforts. The Bischler-Napieralski r e a ~ t i o n ’ ~’*244*247 ~ . ’ ~ can be used to prepare a large variety of 3,4dihydro- and 1,2,3,4-tetrahydroisoquinolineshaving C1 heteroaryl substituents. The condensation of a substituted phenethylamine 202 with pyridyl esters 203 affords the amide 204, which undergoes Lewis-acidcatalyzed ring closure to 205. The reduction of 205 with either or heterogeneous catazinc and acetic acid,” sodium borohydride,”’ lysis20’*20’*241 provides 1,2,3,4-tetrahydroisoquinolines206. Dehydrogenation using palladium on charcoal at elevated temperatures yields the fully aromatized isoquinolines 207 (Scheme 17).
’
-”’
75
11. lsoquinolines Having Basic-Containing Substituents at Cl
203
202
204
i
Birchlcr-Nnpierrlrki
r e d uclion
206
\
R
e
R
/ oxidation
2kn
Scheme 17
2
76
Isoquinolines Bearing Basic Side Chains
TABLE 28. SUBSTITUTED l-(PYRROLYL)ISoQUINOLINES
~~~~~
Nature of C Atom of Pyrrole Ring Attachment
R’
R’
H H H
H H
3,4,5-Triphenyl 3.3.5-Triphenyl 3-Cyano-5-phcnyl
2 2 2
H H
H H
2 2
H
H
5-Phenyl 3-Carboxy-5-phenylCsulfonyl 3-Carboxamido5-phenyI-Csulfonyl 3-Carboxyamindo5-phenyl 3-Carboxy-5-phenyl 3-Carbethoxy-5-phenyl 3-M~thyl-5-ph~11yl CNitroso-5-phenyl CDiazo-3-nitro5-phenyl 3,3,5-Triphenyl 3-pAnisyl-4,S-diphenyl 3-pAnisyl-3.5-diphmyI 4-Carbethoxy-3,Sdiphenyl 3.5-Diphenyl
H
H
H H H H H
H H H H H
H H H H
H H
H
H
R’
Formula
Fp(“C)
Ref. 180,187 196 181
C20H16N206S
262.5-263.5 194- 194.5 275-276 221.5-222 140-141 > 360
181 181
2
CZ0H19N306S
260 (dec)
181
2
CIOH, $N,O
283-284
181
2 2 2 2 2
264-265 149-150 169- 170 161
181 181 181 181 181
2 2 2
196-198 212-21 3 204.5-205.8
187 189 189
2 2
169- 170 226-228
189 186
C’IH2ZN’ c,I HZ’N 2 CZOHI’N’ hydrochloride C19H14NZ
disodium saltH,o sodium salt2HZO
190-193
77
11. Isoquinolines Having Basic-Containing Substituents at C1 TABLE 29. SUBSTITUTED I-(PYRROLYL)-3.4DIHYDROAND 1.2.3,CTETRAHY DROISOQUINOLINES
&R3 N
I
I
R’
R2
Type A
R’
R’
H H H H
H H H H
Type B
Point of Attachment Pyrrole Ring
R’ 5-Phenyl 3.4.5-Triphenyl 3-p-Anisyl-4,S-diphenyl LS-Diphenyl
Type A or B
2 2 2 2
A A A A
Formula CI9Hl6Nz C,,Hz,N, C,zH2,NzO Cz,Hz,Nz
Fp(“C)
Ref.
113-114 229.5-230 195-197 214-216
181 189 189 186
TABLE 30. SUBSTITUTED l-(PYRROLYLt.I,2-DIHYDROISOQUINOLINES “QN-R4
~~
Nature of C Atom of R’
R’
R’
R4
H H H H H
H H Phenyl Phcnyl H
H H H 2.5-Dimethyl 23-Dimethyl
Benzoyl Furoyl Benzoyl Benzoyl Benzoyl
Pyrrole Ring Attachment 2 2 2 3 3
Formula
Fp (“C)
Cl,H,,N*O 136 C , ~ H , ~ N ~ 125-126 O~ C,,Hp,NZ 149-150 C2,Hz,N,O 242-243 C*’Hl,N’O -
Ref. 179 179 179 179,180 180
qR
78
Isoquinolines Bearing Basic Side Chains
TABLE 31. SUBSTITUTED-l-(1-IMIDAZOLYL)ISOQUINOLINES185
R
R1
RZ
R3 H
R4
CI
C6H5
CH3
H
CI
C6H,
C6HS
CI CI H
H H Cyclohexyl
H H H
Me
Me
C6H5
C6H5
H
H
H
Cyclohexyl
H
C,H5
H
H
n-Bu
H
H
H
H
n-Bu
H
C6H5
H
Formula
FP (“C)
167-168 hydrochloride 231-232 C Z ~ H I ~ N ~ C I 192-194 oxalate C14H1ZN3C1 164-165 C24H16N3C1 195-196 C18H19N3 92-93 hydrochloride 228-229 C.74H23N3 169- 170 dihydrochloride 192-194 C16H,’lN3 206-207 hydrochloride C22H21N3 166-167
C19H14N3C1
11. Isoquinolines Having Basic-Containing Substituents at C1
79
TABLE 32. SUBSTITUTED 141-IMIDAZOLYL) ISOQUINOLINES R'
R
R'
H
R2 H CH,
R3
H
R4 H H
H
H
H
H
H
H
H
Et
c1
H
H
H
C6H 5
H
H
H
H
C6H$
c1
H
H
H
H Et
FP ("C) ~
H
H
Formula C1.9Hn N, C1,Hl SN, hydrochloride C1BH13N3 oxalate C14H13N3
hydrochloride
C,4H12N3C1 phosphate c l g H 1 3N3
oxalate
C18H12N3C1
oxalate
167-168 243-244 220 (dec) 85-86 224-225 115 148-149 141-142 189-190 189 181-182
TABLE 33. SUBSTITUTED I-(Q)ISOQUINOLINE'
Q
R' H
R'
Q
H
Formula
C1!3H1SN30
132-133
179
207-208
190
I
C6HS
H
Isoquinolines Bearing Basic Side Chains
80
TABLE 33. (Continued) Q
R2
R1 H
H
6.7di-OMe
H
6,7di-OMe
H
6,7di-OMe
H
Fp("C) Ref.
73.4-73.3
o-(
N
)-CHz-
CZlH,IN,O,
195
C16H18NZ03
191
methiodide: C1,Hz1N2031
T~CH,
H
197
0- N
Methiodide: C1,H2,NZO,I
0
H3 6.7-di-OMe
Formula
b+
191
C16H18N203
CH3
methiodide: C, ,H,,N,O,I
CH 3
6.7-di-OMe
3-Me
Q-dilTerent heterocycles.
A ws
N
C16H 16N202S
hydrochloride picrate
153-155 203-205
183a
11. Isoquinolines Having Basic-Containing Substituents at Cl
81
TABLE 34. SUBSTlTUTED 1-(Q)-I,2-DIHYDROISOQUINOLINES'94
R'
R'
X
R'
Formula
FP K)
TABLE 35. SUBSTITUTED I-(Q)-12$,4-TETRAHYDROlSOQUINOLlNES
Q R'
H
R'
RJ
Q
3-Me CH,
I
Ac
H
6,7di-OMe
3-Me Ac
Formula
Cz,Hz4N30
a5
6.7-diOEt
R4
Fp ("C) Ref.
130-135
192
82
Isoquinolines Bearing Basic Side Chains
TABLE 36. SUBSTITUTED l-(THIOMETHYL-(Q) OR-l-(OXYMETHYL-(Q)-1,2.3,4TETRAHY DROISOQUINOLINES
CH,-X-Q
R'
X
(X = 0 or S)
Q
FP ("C)
Formula
6,7-di-OH
S
2-Pyrimidiny l
6,7di-OH
S
>Me- 1,3,4-thiadiazol-2yl
6.7-di-OH
S
5-Me-4H-1,24-triazol-3yl
'1
0
CPyridyl
c l SH1BNZ03
250-255 (dec)
0
1,2,5-Thiadiazol-3-yI
C12H1303N3S2
252 (dec)
S
1,3,4-ThiadiazoI-2yl
C14H1S0ZN3S HCI H 2 0
-
C13H1S02N3S
-
204-205 (dw) 199-201 ( d a )
2HC1-fH20
6,7di-OH 6.7-di-OH 6.74-OH
2HCL*$HZO HCI
6,7-di-OH
S
1-Me-1H-tetrazol-5-yl
6,7di-OH 6,7-diOCH2 6,7-diOCH3
S S
2-Benzo-Thiazoly l 1-Me-lH-tetrazol-5-yl 1-Me-1H-tetrazol-5-yl
S
,N160ZN&S
CHI.O.5 H,O
'1
ZH I 3OZN3S2
HCI
CI ZHI 502N,S HCIHZO c l 7H1S02N2SZ
CZ6H.290ZNSS C14H190ZNSS
224-225
234 (dec) 215-216 (dw) 170- 172 106-108 96-99
The Pictet-Spender reaction has also been successfully employed for the preparation of derivatives of 208, which have been examined for their potential CNS a ~ t i v i t y . ~ The ~ ' reaction - ~ ~ ~ of ~ norepinephrine ~ ~ ~ hydrochlorides 208awith pyridoxals 209d or its corresponding phosphate 209e affords derivatives 210 in modest yields (Equation 49).
a R=H
b R=OH c R=OCHj
d R'=H e R'=OPO,H 210
(49)
11. Isoquinolines Having Basic-Containing Substituents at C1
83
3,3-Disubstituted-3,4-dihydroisoquinolines 214 were successfully prepared by the reaction of pyridylnitriles 213 with P-phenethanols 211 under Graf-Ritter conditions (concentrated sulfuric or perchloric acids). Lewis acids such as boron trifluoride etherate, tin tetrachloride, or aluminum chloride may also be effectively used, but polyphosphoric acid or aromatic or aliphatic sulfonic acids are useful for this reaction. Yields involving pyridylnitriles are reasonable, varying from 40 to 80%.204-206Mechanistically this reaction proceeds through a dialkylbenzyl carbonium ion 212 that undergoes nucleophilic nitrile addition and subsequent Pictet-Spengler ring closure 214206(Equation 50).
212
211
214
(50)
The Graf-Ritter ring-opening reaction of phenylcyclopropanes 215 provides carbonium ion 216 or 217. Each undergoes nucleophilic addition and ring closure with 213 to provide an almost equal mixture of 218 and 219207.208 (Equation 51).
@AR2 R'
R
216
218
217
219
(51)
Isoquinolines Bearing Basic Side Chains
84
Olefins such as 220 in which a tertiary carbonium intermediate can be generated under strongly acidic conditions react similarly with pyridylnitriles to (Equation 52). provide a variety of 3,4-dihydroisoquinolines219z09*210
The alkylation of Reissert compounds 221 at Cl with 2-chloromethyl-6methylpyridine (222) followed by rearomatization with base affords 223 in good yields.zz4~zz6 In this manner, N-oxides such as 224 can be directly preparedzz5 (Equation 53).
R
q
N
bCH
223
0p
(53)
CN 221
base
224
The hydrochloric acid-catalyzed condensation of the Reissert compound 225 with 4-vinylpyridine provides a moderate yield of 2-(l-isoquinolyl)-5(panisy1)pyrrole (226). On the other hand, the condensation of the lithium base of 225 with vinylpyridine affords a-(epyridyl)-~-(l-isoquinolyl)-pmethoxypropiophenone (227) that has been cyclized to 2-(4pyridyl)-3-(panisy1)pyrrolo[2,1-a]isoquinoline (228) with concentrated hydrochloric acidzJ0 (Scheme 18).
11. Isoquinolines Having Basic-Containing Substituents at C1
85
I
/HCI
( 42
B)
kH, 226
227
OCH3
J (59%)
HCI
Ring closure of 1 -( fi-hydroxyethyl)-2-methyl- 1,2,3,4-tetrahydroisoquinolines 229 provides the interesting azetidinium salt 230. This readily undergoes nucleophilic ring opening with the sodium salt of mercaptopyridine-N-oxide to afford the 1-[fi-(Zpyridyl-N-oxide)mercaptoethyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline (231). which can be reduced to 232, In this way a variety of such derivatives can be preparedzJ8(Equation 54).
Isoquinolines Bearing Basic Side Chains
86
R%3:Ts0-
AH2CH*SQ
231
uo
t
I
p-TSCI
' W N C H .
i
0
' m N C H 3
CH~CH~OH 229
232
(54)
Lewis-acid-catalyzed nucleophilic addition of phenethylamines to 3-pyridylnitrile affords the amidine 233, which undergoes the Bischler-Napieralski ring closure to 2M2 (Equation 55). ch'
I
233
234
A similar reaction involving the Cpyridyl oxime 235 with B-phenethyl alcohols in the presence of concentrated sulfuric acid provides 2-hydroxy-l-(4pyridy1)isoquinoiines 236, which have interest as antiphlogistics and antipyretics216(Equation 56).
11. lsoquinolines Having Basic-Containing Substituents at CI
6
87
OH
I
R
(y%z
+
23s
236
Catalyzed by such Lewis acids as acetic acidZZ8or zinc chloride,227 1methylisoquinolines 237 react with pyridyl aldehydes at elevated temperatures Subsequent catalytic to afford 1-( l-isoquinolyl)-2-(pyridyl)ethylenes 238.227-229 reduction affords the corresponding ethyl derivatives 239227(Equation 57).
238
239
(57) Direct aromatic nucleophilic substitution of the labile 1-bromine of 240 with 3-hydroxypyridine provides (3-pyridyl)-l-isoquinolyl ether (241) in good yield'" (Equation 58).
Br 240
241
Isoquinolines Bearing Basic Side Chains
88
b. Substituted l-(Piperidyl)isoquinolines Three different approaches to the synthesis of 1-(piperidy1)isoquinolineshave been reported. The first involves the catalytic reduction of the pyridyl ring system of the corresponding l-(pyridyl)-l,2,3,6tetrahydroisoquinolines242. This hydrogenation is usually carried out with plantinum oxide or rhodium on carbon with temperatures ranging from 20 to 100°C and pressures from 600 to lo00 1b203,215*233*246 (Equation 59). R
q
N
-
H
Pt02/H2
or
R
~
L
4
(CH2)n
(CH2)n
(59)
H
242
203
(n=O, l,or2)
The second synthetic method exploits a nucleophilic displacement of the labile C1 halogen with a desired piperidine such as 245242(Equation 60).
R
i
q
f
+
X
p
244
245
‘2R2
I
8 3
246
The third approach utilizes the Bischler-Napieralski reaction to cyclize the amides 247 into derivatives 248243-245.247.248 (Equation 61). Bischlcr -Napieralski
R
W
N
O
3
H
IY R3 247
2
R3
248
11. Isoquinolines Having Basic-Containing Substituents at C1
89
One application of the methods described above for the synthesis of C1 heterocyclic-bearing isoquinolines is illustrated in the preparation of 1,4-dissubstituted piperidines 251 synthesized for their potential antiamebic and anticancer activities250(Equation 62). R
.I
I
I.CO,E I
249
Y I
I 2. POCl,
3. NaBH,
250
h
a R =CH,C6H5 b R=CH,
c. Conclusion The specific examples provided in these sections have developed several approaches to the syntheses of a large variety of isoquinolines bearing basic heterocyclic substituents at C1. One can easily extend these methods for the syntheses of desired functionalized heterocyclic derivatives. The basic principles for the construction of Cl-substituted isoquinolines allows tremendous flexibility, a feature that is particularly attractive to those searching for biologically active molecules.
E Bis-isoquinolines Bis-isoquinolines 254 constitute that class of compounds in which two appropriately substituted isoquinolines are either directly bonded to each other or appear together in a common parent molecule. The synthesis of many of these diverse compounds invokes the numerous methods previously discussed for the preparation of isoquinolines. Many of these derivatives have been prepared for their potential pharmacological activities and several have been sought as alternatives to emetine (to be discussed in the following section). No discussion of bis-benzylisoquinoline alkaloids will be included here, and the reader is referred to several excellent review^*^^-^'^.
90
Isoquinolines Bearing Basic Side Chains
TABLE 37. SUBSTITUTED 1-(PIPERIDYL-Q)rSOQUINOLlNES
I
R
~~
Q
Z
R'
R2
Formula
Fp("C)
0 0
&Piperidyl 4-Pipexidyl-N-methyl
H H
3-Et 3-Et
C,,H2,NzO C,,H2,NZO
0
3-Piperidyl-N-methyl
H
3-nBu
C,,H2,Nz0
0
4-Piperidyl-N-meth yl
H
3-n Bu
C,,H,,N,O
0
4-Piperidyl-N-propy l
H
3-n Bu
C2,H,oN20
0
4-Piperidyl-1,3,6-trimethyl H
3-n Bu
C2,H,,,N,0
0
4-Piperidy l-N-benzoyl
H
3-n BU
C2,H2,N2Oz Hydrochloride
0 II C-CHzCHz
CPiperidyl
H
H
C17H2oN2O*H20 113-114 dipicrate 161
bp 184-185 (4 mm) bp 170-171 (0.4 mm) bp 168-170 (1 mm) bp 199-201 (1 mm) bp 174-176 (1 mm) 203-204
Ref. 242 242 242 242 242 242 242 243
11. Isoquinolines Having Basic-Containing Substituents a t C1
91
TABLE 38. SUBSTITUTED I-( PIPERIDYL-Q)-3,4-DIHYDROISOQLJINOLINES
k Q
CH,CH2 CHZ-CH, CH,CH,
N-Benzyl-2-oxod-Et4-piperidyl 3-Me-2-oxo-S-piperid yl N-(3,4-Dirnethoxyphenethyl)3-pi~~ridyl N-Decyl-3-piperidyl
CHZCH, CH,CH,
6.7-diOMe 6.7-diOMe 6.7-diOMe 6.7-diOMe
H
None None
R'
2
N-[j9-(3,4Dimethxoy-
phen y l)et hyl]-4piperidyl N-(j9-PhenylethyltepiperdyI N-[8-(3,4-Dirnethoxyphenyl)ethyl]-4piperidyl N-(j9-Phenylethyl)-4-piperidyl N-[/.?-(3,CDimethoxyphenyl)ethyl]-4piperidyl
6.7-diOMe H 6.7-diOMe H 6,7-diOMe
Rd.
Formula
Fp("C)
C,,H3,N,03 dipicrolonate C,,H,,N,O, CZaH,,NZO, dihydrochloride CzgH4,N,O, dihydrochloride CZ,H,,Nz dihydrobromide CZ6H34N204
Brown syrup 213-215 165.5-166.5 Shrank at 111-113; mp 167-180 155-162
244
93-94 (dw)
248
125-126
248
C23HzBNz C,,H3,NZO4 dihydrobromide C,,H,,N, Cz8H,,N,O4
235-240 (10-7
248
130-134
248
145-150(10-4) 94-95
248 248
245 245 245
CHzCOEt H H H
2-Piperidyl
2-Piperidyl
2-Piperidyl
2-Piperidyl 3-Pipcridyl CPiperidyl 3-Piperidyl CPiperidyl
None
None
CHZ CH, CHZ CH2 CHZ
H H
II
0
C-OCH,
I1
0
C-CH3
11
0
None
H H
A
CPiperidyl 2-Piperidyl
2
None None
Q
6.7di-OH 6.7diOH 6,740H 6,7diOCH3 6.7diOCH3
6.7-diOMe
6.7-diOMe
6.7diOMe 6.7diOMe
R’ Formula
Cl,Hz2NzO~~2HBr C,,Hz2Nz0,-2HCI .IHzO C,,H22N202*2HCI Cl,H,,N20, e2HCI C,7H26Nz0z-2HC1
CzoH36N204.2HBz
C,aHz6N,03
C,6H,4N202 dihydrochloride Cl,Hz4Nz0, dihydrochloride
TABLE 39. SUBSTITUTED l-(PIPERIDYL-Q)-I,2,3,CTETRAHYDROlSOQUINOLINE!j
275 (dec) 238-241 223-225 (dw) 244 258-260
218-220
141-142
225-228 98-99 257-259
FP (“C)
203 233,246 233,246 233,246 233
203
203
203
215 203
Ref.
z C2H5
CZH, C2H5
N-[/J-(3.4-Dimcthoxyphenyl)ethyl]4
PI-[ /J-(3,4-Dimethoxyphenyl)ethyl)-4-
N-[/J-(3,4-Dimethoxyphcnyl)ethyl)-4-
None
CH,CH,
CHl
piperidyl
piperidyl
piperidyl
piperidyl
H
CH,CH,
IV-[8(3,4-Dimethyoxyphenyl)ethylJ4-
CH,CH,
piperidyl H-(j-Phenylethyl)4piperidyl
N-[B-(3,4-Dimethoxyphenyl~elhyl~-4-
6,7-diOMe
6.7-diOMe
6,74iOMe
H 6,7-diOMe
6.7-diOMe
H
CHI
H
H
H
CHZ
6.7-diOMe
piperidyl N-[/3(3,4-Dimethoxyphenyl~thyl)-3methyl4piperidyl N-(/J-Phenylethyl)-4-piperidyI
H
H 6.7-diOMe
H
6.7-diOMe H
H
6,7-diOMe
None
H H
H
H
H N-(/J-Phenylethyl)-3-carbocthoxy4piperidyl) H N-[ /3-(3,4-DimethoxyphenyIethyl)-4H
N-(/J-Phenylcthyl)-3-Mt-$.piperidyl
2-Piperidyl H-Mcthyl-4-piperidyl H-Methyl-4-piperid yl N-( /?-Phenylethyl~4-piperidyl
None None None
CHI CHl None
CH 1
255-260 mm) 256-262 (lo-' mm) 242.4 (dec)
82
225-230
220-225 mm) 198-m
76-78
2W261 246-248 183-185 195-205 (lo-* mm) 225-230 ( I O - ~ , ~ ) 215-225(10 3, 94-96
248
248
248
248
248
248
248
248
248 248 248
247 248
233 247
P
2-Pyridyl-N-oxide 3-Pyridyl
CHZ
CHZCHZ
CHZ-CH, CHZ
CHZ
I
I1
I1 I1
I1 3-Pyridyl
4Pyridyl 2-Pyridyl
&Me-Zpyridyl
CH2
I
&Me-2-pyridyl
Z
CHZ
Q
I
Type
6,7-diOMe
6,7-diOMe 6.7-diOMe
-
-
__
6.7-diOMe
-
-
6,7diOMe
6,740Me
6,7-diOMe
R'
C-C 6H5
II
0
C-CbH,
II
0
Me
B
Formula
233
115-116 207 (dec) 232 (dec)
C,,H,,N,O, C, ,Hi ,N,O, dihydrmhloride C, 7H1BN20z
231,232. 234 232,234 233
225
224
224
Ref.
88,89 198-200
169- 17 1
165
Oil
FP ("C)
C,,H,,NIO,
,
CzSHzN30,
C,,H,,N,O,
C,,H,,N,O,
Type I1
CN
CN
H
A
Type I
TABLE 40. SUBSTITUTED l-(PYRIDYL-Q)DIHYDROISOQUINOLINES
xx
44; m m
m
r?
N N N
95
n
H H
n H 6,MiOMe Me Me Me Me
3-Pyridyl
CPyridyl
3-Pyridyl
2-Pyridyl-N-oxide
4-Pyridyl-N-oxide 2-Pyridyl CPyridyl
CH=CH
CH=CH
CH=CH
CHICH2
CH2CH, CH,CH--OH CH2CHOH
6.7diOMe 6.7-diOMe 6,7-diOMe
6.7diOMe
H
CHI CH-CH
H
H
6.7diOMe
2-Pyridyl-N-oxide 2-Pyridyl
'tHZ0
C,,HZ4N2O3dihydrochloride CIPHz4N3O3dihydrochloride
C19H24N203
dih ydrochloride * EtOH
C39H24N203
Ci 8H 16N20, dihydrochloride *tH,O
dih ydrochloride
C#6H12N2
C16H12N2 dih ydrochloride
CI 6H 12N2 dihydrochloride
c1 T H 16N203
C19H22N2010C12
2-methyldiperchlorate
C18H18N202
H
6.7-diOMe
6-Me-2-pyridyl
picrate
C14H,0N20
H
H
3-Pyridyl
0
-
TABLE 42. SUBSTITUTED 1-(PYRIDYL-Q)ISOQUINOLINES
110-135 (dec) 118-135 156.5-1 57.5 229-233 195-200
230 2 10-2 I2 164-165 237-238 122- 124 210 121-123 275 245-250
40.5-42 195.5-916 1I5
235
235 236
235
228,229
226
226, 227 226
224 225
224
223
0
' C - where pyridyl ring is attached
CH=CH
3-Pyridyt
QPyridyl 4-Pyridyl-hr-oxide 2-Pyridyl
CHICHIS CH,CH,S
CHZ
2-Pyrid y l-W-oxide
CHZCHZS
2-Pyridyl 3-Pyridyl 4Pyridyl 2-Pyridyl
H
6.7diOMe
H
Me
H
3-Me
6.7-diOMe 6.7diOMe 6,7-0--CHz
6.7diOMe
Mt Me
6.7diOH 6,7diOH 6.7diOH 6.7-diOMe
H H H Me
-- -0--
-
C,,H,,NzO
dipicrate
C,9HI,NZOZ dihydrochloride .H,O
C,,H,,N,O, dipicrate dihydrochloride H,O
C,9H24N203S
C,QH,,NZOZS
Ip H 24N203S
dihydrochloride * EtOH
dihydrochloride * EtOH
C19H24NZ02S
C , ,H,6N202 dihydrobromide C, sH,,N102 dihydrobromide CI,H l b N 2 0dihydrochloride 2
230
230
IfS-l%l
195-196 116-117
239
230
180-185
193- 194
228,229
238 238 24 I
238
21 3 213 21 3,237 238
bp 215 ( I mm) 175 205 233-235
156.5- 157.5
95-06.5
110- I35
118-135
160 (dec)
155-157
189- 190
x x
X X
$ 2
8g
x x
2 X
s s u2 us
gg
x x
x x
x x
x x
x x EE
o,o, x x
0 0
u u
o,o, x x u u
u u
0 0
Y X
o u
X
3u 8
X
0
o=wI
x x
x x
x s
I 0=u
x x
x x
x x
X
X
X
x o
X
X
1:
2 0
o x
33 X
X
8 W
W
98
8
H H H
741
H
Et
Et
Et
Me
Me
Me
Me Me Me
R’
Me Et Et CH,--C,H,
H
H
Me Et
Me Et
Me
Me Et
Me
H
Me H
H H H H
H
H H H
H
H
H
6,740H
6,7diOMe
R3
R’
R1
n
H H
H H
H H H H
H
H
R‘
H H H
H H
H H H H
H
H
R’
H H H
H H
H
H
N H
H
H
R6
R?
H H H
H H
H H H H
H
H
R’
TABLE 44.SUBSTITUTED I-(CPYRIDY L)-l,L3.4-TETRAHYDROISOQUlNOLlNES
Me
Me Me
H H
H
H H H
H
A
.-.
dihydrochloride
C19H?.4N2
CLIHION‘ C,BH”N’
dichydrochloride
C17HZON2 Cl.H2lCIN,
C22H22N2
C,.H,,N’
ClbHIBNZ C17H20N2
dihydrochloride
CI,HI,N,O,
hydrochlonde hydrobromide
C14Ht4N202
Formula
-
69-72 89-91
210 (dec) 19
226-227 121
173-174 96-98 88-89 89-9 I
-
235-240 268 (dec)
-”
FP (“C)
_ _
Ref.
204,209 204,209 204,209 204,209
204.209 204,209
m , 2 0 9
215 204.209 204.20
214 213
__
Et
Et
Me
Et
H
H
H
H
H
H
H
Me
Me
H
R’
R”
H
R’
R1
R’
H
H
H
R5
H
H
H
R6
R’
H
H
H
R7
L“
0
%-H
0
%-H
0
A
R6
C,,H,zNzO
C,,Hz,NzO
C,,H,,N,O
Formula
R4yJR’
RZ
TABLE 45. SUBSTITUTED 1-(4-PYRIDYL)-l,2,3,4-TETRAHYDROISOQUINOLINES
110-112
114-115
157
FP W)
204-209
204,209
2 0 4 m
Ref
H H
Me Et
Me
H
H H 7-CH3 H-CH, H
Me Et
Me
Me
H
H
Me Me Me Me Et
Me
Me
H
H
H H
Me
Me
H
H
Me
Me
H
H
H H H H
H
H
H H H H
H
H
H
H
H
H
H
H
H H H
H
H
H
H
H
H
H H
H H H
H
H
H
H
OH OH OH OH OH
CN-€9
llH
0
CNH2
II
0
C-CH,,
II
0
CI9HZ3N3O
C17H19N30
CIgHZONzO
181-182
180-180.5
202-204
204-209
20-209
204-209
H
H
H
H
H
H H H H
H
H
H
6,7di0H 6,7diOMe 6,7-diOMe 6-Me
6-a
H
H H H H
Me
H
H
H
Me Me
H
R3
-~
H H
H
R2
R1
-
ME
H
H
H
H
H H
Me
Me
M C
H
It”
Me
H
H
H H H H
H
H H
H
R4
H
H
H
H H H H
H
H H
H
R’
H
H
H
H H H H
H
Me
H
H
R6
RS
H
H
H
H H H H
H
H H
H
R’
H H
H
A
H
H
H
H H Me H
0 ‘L-H
R‘
\ N
/
C14H14N2
Formula
FP (’C)
83-84 bp 180-181 (1 mm) 187
79-80 bp 186 89 (2 mm)
bp 89-91 bp 173-174 (2 mm)
2HBr: 273-75
120-122 HCI 222
makatc: 177 -178 112-144 2HCI: 227
98-99
dipicrate: 196-197
155- 159
Rliyf;
TABLE 46. SUBSTITUTED 1-(3-PYR I D Y L t I2,3,4*TETRAHYDROISOQU[NOL[N~
21 1 21 1 21 1 21 1 216
201 21 1
213 201.2 13
204-209
204-209
204-209
221.21 2
Ref.
w
r3
H Me
H
H
H
H
H
6.7diOMe 6,7-diOMe 6.7-diOMe
H
H
H
6.7diOMe
H
H
Me
Mc
H
n
H
H
n
H
H
H H H H
H
H
H
Me
Me
H
H
n
H H H
H H H
H
R5
R4
Er
H
H
El Et Me
R"
Et
H
Me
Er
Et
H
H
RJ
RZ
H
H
- H
R'
H H H H
H
H
W
H H H
R6
H
H H H
H
H
H
H H H
R'
R'
C-H H
COOCH, CHZCOOEI OH
Ac
H
'>-
0
\\
0
A
R?
Formula
TABLE 47. SUBSTITUTED 142-PYRl~YL)-1,2,3.4-TETRAHYDROlSOQUlNOLlNES
101
2HBr. H20: 155-1 57 153
110-132
81-82 HC1:252-253 HBr: 249-250 150- 15 1
104-106
107
135-140 (0.1 mm) ZHCI: 1968
121 HCI:204
FP ("C)
216
203 203 203
203
210
210 204-2 10
204-210
204-210
Ref.
7-a
7-cI
%Me
H H
H
H
H H H
H H H
Me
H H
H
H H
H
H
H H H
H
H
H H
H H H H H H H H
H
H
H H
H H H H H H H H
H H
H
H H H H H
H
H H H
R2
H H H H H H H H
H
H
H
H
TABLE 48. SUBSTITUTED l-(4-PYRIDYL)-3,4-DIHYDROISOQUINOLINES~a4~ 210
2HCI: 198-200 65-67 2HCI : 236-238 91.5-92 110-1 12 63-64 110-1 12 91-92 2HCI: 235-240
60-61
171-172 95-96
H
H
H
H
H
H H €4
6-CI
6-OMe
6.7-diOMe
H
7-a
H
H
H
6-Me
H
H
H
H H
H
H
H H
H
H
H
H
H
H
H
H
R5
H
H
H H
R4
R3’
Me Me +CHz)d-Me Me
H
H
H
H
R’
R2
R’
H H H
H
H
H
H
H
R6
H H H
H
H
H
H
H
R’
R?
C16H16Nz C1,HlBNZ Cl,HIICIN,
C16HlbNLQI
C1,HI*NZO
CI,H,ICIN2
CIJH14Nz
C,,HI2N2
Formula
TABLE 49. SUBSTITUTED 143-PYRIDYL)-3,4-DIHYDROISOQUINOLINES
95-97 2HCI: 182-184 2HCI :228-230
122-123
dipicrate 186-187 bp 1 mm. 185-188
98-99 bp 1 m% 183-185
161-163 dipicrate: 192 bp 2 m m 179-184 HCl: 233-4 bp lmm, 170-173
FP K)
2w-210
204-210 204-210
21 1
21 I
21 1
21 I
21 I
Ref.
5 N
% u X
X X X X X
X
X X X X X
X
x z r r e
S
X
0
X
u s x x x
u 3 v r“ 2s: u u
X 0
X
2
106
X
x s u s x
11. Isoquinolines Having Basic-Containing Substituents at C1
107
TABLE 51. SUBSTITUTED I-(2-PYRlDYL)-3,4-ISOQUINOLINES199~z00
R’ H H H H H
H H
Rz H H
C H H H H H
R3
R4
R5
R6
R’
H H , H H CH, CH, CH,
H H H H H CH, H
H H H H H H H
H H
H H CH3 H CH3 H H
H CH,
H H CH3
Formula
FP (“C)
Picrate (“0
74.5-75.3 75.6-76.3 165“/0.35mm
167.2-168 177- 177.6 156- 156.5 161-161.5 1 70- 170.5 170- 171 162-162.5
55.5-55.8
7I .5-72 142/0.15mm 75-15.6
The Ullmann reaction of I-bromoisoquinoline (253)in the presence of copper powder at 200 “Cprovides a poor yield of l,l’-bis-isoquinoline (254), which gives a negative ferroin r e a ~ t i o n ~ (Equation ~ ~ ’ ~ ~ ’63).
Bischler-Napieralski cyclization of the two corresponding amides in 256, prepared by the reaction of homoveratrylamine (255) with diethyl oxalate at 160- 170 “C, affords 6,6’,7,7’-tetramethoxy-3,3’,4,4‘-tetrahydroI,l’-bisisoquinoline (257)254(Equation 64).
Isoquinolines Bearing Basic Side Chains
108
0
0
II If
ErOC-COEI
cC HH3 03 0 m N H 2
160-1 70'
CH30
w 256
1
POCI,
CHJO
Alternatively, 257 can be prepared from the reaction of I-carboethoxy-6,7dihydroisoquinoline (258)with 255 followed by the Bischler-Napieralski cyclization of 259 to provide 25725*(Equation 65).
The reduction of bis(tripheny1phosphine)nickel(I1) bromide with zinc in the presence of tetraethylammonium iodide produces a reactive nickel catalyst that effects the coupling of I-chloroisoquinoline (260)to afford in 37% yield 2!%255 (Equation 66). Bridging is easily introduced by a Bischler-Napieralski cyclization of the appropriate diamide. Thus, the cyclization of malondi-fl-phenethylamide(261) affords 1,1'-methylene-bis(3,4ihydroisoquinoline) (262) which can be reduced to the bis-l,2,3,4-tetrahydroisoquinoline 263256(Equation 67).
11. Isoquinolines Having Basic-Containing Substituents at C1
W N
NiBr ,(PPh,),
Zn/THF Et,NI
254
CH 2
I
toluene
261
109
262
The alkylation of the Reissert compound 37 with 2-dimethylaminoethyl chloride followed by the alkaline hydrolysis provides in addition to the major product 264 the minor product 1.241'-isoquinoly1)ehtane(265)257(Equation 68).
37
264
Generally, the alkylation reaction of Reissert compound 37 with a variety of bifunctional halides allows for the preparation of a large number of interestingly functionalized bis-isoquinolines 266a-d258(Equation 69). The Bischler-Napieralski cyclization of diamide 267 with phosphorous pentoxide in refluxing xylene affords N,N-bis-(3,4-dihydro-l-isoquinolylmethyl)-~phenethylamine (268)259(Equation 70). The reaction of 269 with primary amines results in the double alkylation of the m i n e to provide a large variety of tertiary amines 270259-261 (Equation 71).
110
Isoquinolines Bearing Basic Side Chains
2.67
268
VCH’ = WCH3 kH2Cl
269
CH 2
I
N-R
I
CHz
I
no
11. lsoquinolines Having Basic-Containing Substituents at C1
111
The double Bischler-Napieralski cyclization of 271 followed by a catalytic reduction provides racemic 272 which failed to exhibit amoebicidal activity226 (Equation 72).
271
1 . P:OI
1
2. [ H I
(72)
m In an effort to improve on the fibrinolytic activity of 273, Buchanan and
coworker^^^^.^^^ have developed two methods for the preparation of the N-
monosubstituted derivatives 276 and 278. Monoprotection of 273 affords 274 in moderate yields. Direct alkylation followed by deprotection provides 276, whereas acylation of 274 followed by a subsequent deprotection and amide reduction yields the homologated 278 (Scheme 19). Alternatively, a synthetic route involving sequential derivatization of each individual isoquinoline was developed to prepare 281, which is readily converted to either 276 or 278 (Equation 73). Bis-isoquinolines 283 bearing a variety of aromatic bridges can also be readily prepared by way of the double Bischler-Napieralski ~yclization’~’ (Equation 74). N-Acylisoquinolinium salts 284 react with pyrroles to afford 2,5-bis(2-acyl1,2-dihydorisoquinolyl)pyrroles285 in good yields266(Equation 75). The reaction of piperazine with 269 in the presence of potassium carbonate 1’)methylpiperazine(286) results in the formation of 1,4-di-(3’-methylisoquinolylin rather poor yields267(Equation 76).
w
& 8 -)$ d
c
h N
c
h N
X
X
-2-
0,
w
0,
u
X
X
W
x
0, X
0, X
V
0
0,
0, X
V
c
h
u
X
z V
0, X u
s u
P N
0,
0, = u
.2
3 N
0, X u
0, X u
w-3 N
0,
0, X u
u X
0, X
0, r
u
u
112
w
11. lsoquinolines Having Basic-Containing Substituents at C1 0 I.
c H 3 0 p N H 2 CH3O
II
0
II
CIC(CH2),COMc
2. 4. 3. B [Hi POCI3 aN,
113
cH30 CH3O
(CHz),
279
I
COzMe 280
mi BircMer-Na pierilrk I
.aH A I
282
0 ;
25-WoC
X284
AI
(74)
283
HNa
(75)
285
qcH3 qcH3 ‘H Isoquinolines Bearing Basic Side Chains
114
H
iNI
L NJ K,CO, H
n
CHzCI
CH*----NWN-cHz
269
F. Emetine Emetine (ma),the principal alkaloid of ipecac obtained from the ground roots of Uragoga ipecucuanha (Brot.)Baill. Rubiaceae, is a potent a n t i a m e b i ~ ~ ~ ~ . CH30
CH3O
H 287
a R=H b R=Ac
The total synthesis of emetine as well as the synthesis of related compounds A.R. Battersby represents the efforts of three groups: the Glaxo and coworkers2s4and A. Brossi and coworkers at Hoffmann-LaRoche.2s6-2ss Published works of groups that do not take into consideration the stereochemistry of synthesized intermediates related to emetine are not reviewed in this s e c t i ~ n .l .~ ~ ~ - ~ ~ Establishing the correct absolute configuration at C1 of the isoquinoline nucleus of emetine involved a series of Hoffman degradative steps of Nacetylemetine (28713) that resulted in the isolation of the chiral acetic acid 288. This acid was shown to have the same negative rotation as the acid derived from the synthesized chiral ester 289 (Equation 77).
CH~O’
-
A
2a8
11. Jsoquinolines Having Basic-Containing Substituents at C1
115
TABLE 52. BIS-ISOQUINOLINES
R
Q
H H
-CH- CHZCHZ-
CHj -CHzN
n /N-CH2-
Formula
MP("C)
Ref.
C,PH,,Nz CZ0Hl6N2
(Dipicrate) 228-229 bp 160-163/ 1 mm (picrate) 159-161
274 251
CZ6HZON,
160-162 (4 picrate) 210-21 1 (4HCI) 216-217
256
Isoquinolines Bearing Basic Side Chains
116
TABLE 53. N,N-BIs(l-ISOQUINOLYL-3-METHY L)ALKYLAMINES
CH2-N-
I
R
R
ck, MP (“C)
Formula
C6H 11
c6H5cH2-
C~H~CHZCHZCeHsHZCH-
I
Rd
(2HCl) 228-231 (2HCl) 272-273 (2HC1) 176 (2HCI) 102
261 261 261 26 I
118-1 19
275
130-13 1
275
146-147
275
188- 189
275
181
260
123-124
260
198
260
200-202
260
CH,
11. Isoquinolines Having Basic-Containing Substituents at C1
117
TABLE 54. I,l'-BIS(3,4-DIHYDROISOQUINOLINES)
R' R'
R2
Formula
H
H
C,,H,,NZ
5.6-diMe0
H
C,,H20N20z
5,6-diMe0 5.6diMeO
S'b'-Methyienedioxy S'b'diMeO
Cz,H10N104 C,,HZIN204
MP ("C) 76" dipicrate 144-146 (monopicrate)220-221 (2HCI) I 1 7 (dipicrate) 225 (Ha) 197-199 (dipicrate) 159-161 CHJ 139-140
Ref. 254 254 254 254
Isoquinolines Bearing Basic Side Chains
118
TABLE 55. BIS(3,4-DIHYDROISOQUINOLINES)SEPARATED BY 2
R
q
Q
/N
R2
R'
R2
Q.
Formula
MP VC)
274
H 5,ddiMeO
Ref.
5',6'-diMe0
5,GdiMeO
-43-
265 265
265
5,6diMe0
5,GdiMeO
5',6'-diMeO
5.6-diMeO
5',6'-diMeO
265
-0-
265
5,dMethylenedioxy
265
5.6-diMe0
5,6'-diMeO
-CH2CHCH2-
5,6-diM@
Et 5',6'-diMc0 CH2-CHCH2-
I
I
a 2 a 2 C H 3
CZ7H34N204 (2HBr) 168-170 (2CH3I) 175-176
262
CIBH3gN204
262
125.5-126.5 (2HCl) 185-187 (dec) (2HBr) 184-185 (dec) (2CH3I) 156-158
11. lsoquinolines Having Basic-Containing Substituents at C1
119
TABLE 56. Sly 1.2-DIHYDROISOQUINOLINES)
R'
RZ
Q
Formula
Mp("C)
Ref.
C,,H,,N,O,
197-198
276
C,,H,,N,O,
170-171
274
n N W
3
I
I
QQ B 2
eW
h
h
aa
120
aa
ow
11. Isoquinolines Having Basic-Containing Substituents at C1
TABLE 58. C H3
121
OCH 3
N.
R' ''R
R'
R'
R3
H CH3 H
H H H
CH3
CH3
C'H, CZH, n-C3H7CZH,
Cz7H3,N,0, CZBHSaNzO, C,,H3aNz0, C29HMN20,
CH3 CH,
H CH3
tK3H7 n-C3H7
CZQH'0Nz04 C3,H,zN,O,
Formula
MP ("C)
(Dioxalate) 185-187" (2HI) 212-214 (dioxalate) 181-183 (2HI) 240-241 (2HBr) 265-266 ( d e ) (2813215-216 (2HI) 235-237 (dm)
Ref. 262 262 262 262 262 262
Correlating the absolute configuration of 288 with the amine 291 derived from (+)-calycotomine (290), whose absolute configuration was clearly establ i ~ h e dconfirmed , ~ ~ ~ the geometry of 287) (Equation 78).
2w
Brossi and coworkers prepared ( +)-Zdehydroemetine (293) from the Bischler-Napieralski cyclization of the benzo[a]quinolizine 292 followed by a reduction and resolution of the racemic mixture with tartaric acidz8" (Equation 79). Catalytic reduction of 292 affords a separable mixture of diastereomeric benzo[a]quinolines from which 294 is cyclized under Bischler-Napieralski conditions to 2%. Catalytic reduction provides dl-emetine (Equation 80). Chapman and coworkers284provided an elegant total synthesis of emetine in which the key step of the synthesis involved the condensation of acetone dicarboxylic acid with 3,4-dihydro-6,7dimethoxyisoquinoline(296)to provide the two diastereomeric ketones 297 and 2!M. By the appropriate choice of reaction conditions it was possible to obtain 298 in 60% yield (Equation 81).
Isoquinolines Bearing Basic Side Chains
122
I . POCl3 2. NaBH,
CH30
3. resolution
CH3O
$H
2
HmOCH3
3
292
292
I.
H2
2. Sepsrruon
CZHS CH2
1
295
11. Isoquinolines Having Basic-Containing Substituents at C1
123
Hh Hot,
OCH,
297
+
?kXocH OCH 3
Alternatively,292the reaction of the pseudobase 299 with the keto acid 300 provided a separable mixture of the diastereomeric ketones 301 and 302 which after debenzylation afforded 297 and 298 (Equation 82). By means of a series of synthetic transformations, 301 is used to prepare racemic isoemetine while 302 provides racemic emetine292*293 (Scheme 20).
124
Isoquinolines Bearing Basic Side Chains CH30 CH3O HO
299
~H~CCH,COOH
II
0
11. Isoquinolines Having Basic-Containing Substituents at C1
tI =0
303
3a2
I . LiINH, 2.HS-SH 3. RaNi
304
305
scheme 20
125
126
Isoquinolines Bearing Basic Side Chains
TABLE 59A. BISISOQUINOLINES RELATED TO EMETINE-LIKE COMPOUNDS AND EMETINE TOTAL SYNTHESIS
R
R
Nm0c
I
I
CH2
OCH,
R
Formula
Fp("C)
13 1-4 36 105-110
A
J-j
295
295
H3
P
B
190-196 173.5-175
Ref.
C27H33N204
hydroiodide* H,O
295 193-195
Racemate A: C27H36N204
dihydroiodide Racemate B dihydroiodide
247-249 210-220
295
127
11. lsoquinolines Having Basic-Containing Substituents at C1 TABLE 59B. BIS-ISOQUINOLINES FOR TOTAL SYNTHESIS OF EMETINEzs4*2 9 ' . 2 9 3
Series A
Series B (leads to f emetine)
R'
R
Series
Formula
A
H
H
B
H
H
A A B
-COCH3 --COCH,CHZCH, -COCH,CH2CH3
-COCH3 --COCH,CH,CH, -COCH2CH2CH,
C33H44N207 C33H,4N207
-CH,--C,H5
C32H38N205
4H2--C6H5
C32H38N205
A
H
B
H
C25H32N205
dihydrochloride C25H32N205
sulfate. 3 H 2 0 C19H36N207
dihydrochloride * 2 H 2 0 dihydrobromide
FP VC) 143-144 204-205 144-145 140-142 (dec)
20-202 173.5-175 161.5- 163 150-152 152- 155
-CH,CH,COCH,
-CH,CH,COCH,
A H ZCH ZCOCH,
xHaCH2COCH3
4 H J C HSCOCHj
A
B
A
B --CHIC6HS
XH2CbHj
-CH,CeH,
--CH,CA
B
4H2C6H5
R'
--CHzC,H,
R
Series A
A
series
TABLE S9C.
-
dihydrochloride * 5H,O
C36H44N206
dihydrmhloride H,O
C3bHUN206
dihydrobromide C,,H,N,O, dihydrochloride 2H,O CjjHUN20, hydrochloride
C39H1&N205
di hydrochloride dihydrobromide
C,9H*,N,O,
Formula
132-134 (dK)
162- 165 (dm)
120-124
188-191
113-115 134-136 143-145 130-131 156- 157 105-107
FP ("C)
Series B
280.282,284.292,293
280,282,284,292,293
280,282,284,292,293
280,282,284,292,293
284,292,293
284,292,293
Ref.
11. Isoquinolines Having Basic-Containing Substituents at C1
129
TABLE 59D.
Series A
R
Scries
Series B
Formula
FP CC)
Ref.
186 199-200 156- I57
280,282,284, 292,293 280,282,284, 292,293 280,282,284, 292,293 280,282,284, 292,293 280,282,284, 292,293 280,282,284, 292,293
dihydrochloride.3Hz0
192-193
perchlorate
238-240
A
--CHZC6H5
C36HUNZ06
B
4HZC6HS
C36H44N206
dihydrochloride * 2H,O
-
dihydrochloride H,O
148-149 198 178-179 187-189
8
c
-cOCH,
XHICH, -CHICHI 4HiCHA
XH,CH,COCH,
4H2C6H5
--CH2C6H5
--CH2C6H5
--CH2C6H5
H
H
B
A
B
A
B
A
B
4H,CH,
-COCH,
-COCH,
--COCH3
--CH,CH,COCH,
A
series
R'
Series A
R
TABLE 59E.
-
HZo
hydrochloride
C19H38N204
dih ydroiodide C36H,,N,O, dihydrobromide* 2 H Z 0 C36H44N204 hydrogen oxalate.5H20 CIPHJ(INIO4 hydrochloride
C36H42N205
dihydroicdide- H,O CJ6H,,N,O5 *0.5H20 di hydrochloride
C3IH6lNZ06
dihydroiodide H,O
C33H42N206'
Formula
230-232
140-145 80-84 220-225
204-206
148-149 173-176 132-134 174-1 75
190
131-132 168 (dec) 126-128
FP ("C)
Series B
280,282,284,292.293,296
280,282,284,292,293 280,282,284,292,293,296
280,282,284,292,293
280,282,284,292,293 280,282,284,292,293 280,282,284.292.293 280,282,284,292,293
280,282, 284,292,293
280,282,284,292,293
Ref.
11. Isoquinoiines Having Basic-Containing Substituents at C1
131
TABLE 59F.
Series A
R
R’
Series A‘ A or A’ or A’ or A’
- - C H ~ C ~ H S --COCH,
A
-CH,C,H, --CH,-C,H,
-COCH, --COCH,
A’ A2
--CH,CsH,
--COCHj
A’
Formula
FP (“C)
Ref.
CS6HUN205 dihydrochloride C36H44NzOs ’ HzO
107-109 206-208 160-161 185-186
280,282,284, 292,293
C36H44N203
-
C36H44N205
dihydrobromide 3 5H,O
207-210
280,282,214, 292,293 280,282,214, 292.293
TABLE 59G.
Series A Series B B
R’
R
CHZC~H, -CH,C,H,
Series B Formula
Fp(“C)
--COCH, Et
C,~H~~NZO,O.SHZO
Akiisocmetine H
Et
C29H40N204
H
Et
Bfcrnetinc
Ref.
~~
C,6H46N204
* 3HZ0
dihydrobrornide dihydrochloride 2 H z 0 C29H40N2O4 dihydrobrornide- 3H20
142-144 211-213
284,292,291 284,292,297
254-256
284,292,291
228-232
284,292,291
Isoquinolines Bearing Basic Side Chains
132 TABLE 59H. H3CO H3C0
IIIIlEt
R’
R’ Series B
Series A
Series
R1
A B A A A
A
R’
Formula
FP VC)
OCH, OCH,
OCH3 OCH3
CZ~H~BNZO~
161-163 122-224
288,287 287,288
OH OCH3 OCH, OGH7
OCH3
117-120 194-195 102-104 201-203
288 288 288 288
~~
OH
C29H38N204
dihydrochloride.4fHz0 CZ~H~J‘JZO~ C2BH36N204
OCJ+, OCH3
C35H42N204 C35H42N204
Ref.
TABLE 60. SUBSTITUED l-(AMINOALKYL)lSQUINOLINES, USED FOR STEREOCHEMICAL ASSIGNMENT IN EMETINE SERIES’”’
Series A
Series B
FP (“C)
R
Formula
A A A
--CON HNH 2 -NHCOOCH,C6Hs -NH2
C14HZ1N305S
A B
-NHCH,C6Hs -NHCHIC,Hs
C20H26N204S
218-219 Gum
C20H26N204S
176-177
series
C21H26N206S
C13H20N204S
picrate
71-72
Gum Gum
Ill. Jsoquinolines Having Basic-Containing Substituents at C2
133
111. ISOQUINOLINES HAVING BASIC-CONTAINING SUBSTITUENTS AT C2 With a pK, = 5.14, isoquinolines can undergo SN2reactions with a variety of functionalized organohalides to provide isoquinolinium salts. The reduction of isoquinoline to either 1.2-dihydro- or 1,2,3,4-tetrahydroisoquinolineaffords a completely basic secondary amine that can be easily substituted to provide tertiary amines of these isoquinolines. In this section useful representative reactions involving various isoquinolines will be illustrated, with tables providing a full range of the kinds of products prepared.
A. 2-(Aminoalkyl)isoquinolines Heating variously substituted isoquinolines 306 with o-aminoalkylhalides in either dry d i ~ x a n e * ~or ~ -a ~~ ~e t' o n i t r i l e ~ for ~ ~ several - ~ ~ ' hours affords good yields of the corresponding isoquinolinium salts 307 (Equation 83). The reduction of these salts can provide both 1,2dihydro- and 1,2,3.4tetrahydroisoquinolines.
307
306
The reduction of either N-(2-aminoethyl)isoquinolinium bromide hydrobromide (308~)or N-(3-aminopropyl)isoquinolinium bromide hydrobromide (308b) with lithium aluminium hydride leads directly to 1,2,3,4,5,10,10uhexahydroimidazo[ 1,2-b]isoquinoline (309rr) or 2,3,4,6,11,1 lu-hexahydro-lkfpyrimido[1,2-b)isoquinoline (309b)302 (Equation 84).
a n=2
b n=3
a (83%) b (53%)
The metal hydride reduction of a tertiary amine such as 2-(3dimethylaminopropy1)isoquinolinium chloride hydrochloride (310) provides the
134
Isoquinolines Bearing Basic Side Chains
1,2-dihydro derivative 311, which has been used to successfully prepare 4aminoalkyl-3~,4,5,9b-tetrahydroisoxazole[5,4-c]isoquinolines 312 (Equation 85). These have been useful as tranquilizers and CNS depressant^.'^^
310
311
1
312
The extraction of thoroughly basic aqueous solution of 308b provides in 95% yield the 1,3,4,11b-tetrahydro-2H-pyrimido[2,I-al]isoquinoline (314). The corresponding 1,3,4,6,7,1 lb-hexahydro analog is prepared in 68% yield by treating N-(3-aminopropyl)-l,2,3,4-tetrahydroisoquinoline(313) first with a solution of mercuric acetate and then aqueous potassium hydroxide 303 (Equation 86).
vl
w
c
3 3
4Br
H
H
H
3 4
3
I
3-Me
H
H
H
H
H
H
5-NH1
H
H
H
H 6
3
H
H 2
3 2
2
n
H H H
R2
H 6-OCzH,
H
R'
Y
305 (dec)
199-201
Br
140
Br
CI
299,301
222-225 3r
299,301
362
299.301
36 1
230
Br
299,H)I
299,301 226-221
..~
299.301
Br
ct
218-219
Br
303 303 300
281-283 207- 209 232-235
299,30 I
Ref.
Fp ('C)
231-132
Formula
Br
Br
Bt
Br
X
R1
TABLE 51. SUBSTITUTED 2-(AMINOALKY L)lSOQUINOLINl UM SALTS
0
8. z
zz
I
136
111. lsoquinolines Having Basic-Containing Substituents at C2
137
TABLE 62. SUBSTITUTED 2-(AMINOALKYL)-3,4-DIHYDROISOQUINOLINlUM SALTS
R*
A
R'
R2 n Y
X
H
H
2 NH,
Br
H 6,7-Methylenedioxy-8-OMe 6.7-diMc0 6.7-Methylenedioxy-8-OMe 6,7-diMe0
H H H H H
3 2 2 3 4
NH, NH, NH, NH, NH,
Br Br Br Br Br
Formula C,,H,,BrN, hydrobromide C,,H,,BrN2-HBr C,,H,,BrN,O, * HBr C,,HI9BrN2O2*HBr-H,O C,,H,,BrN,O, HBr C,,H,,BrN,O,.HBr
-
FP C'C)
Ref.
159 245 192 209 189 193 199
298.303 303 303 298,303 298,303 298,303
Generally the cyclization under strongly basic conditions of the N - ( w
aminoalky1)isoquinolinium salts 315 has provided either 1,2,3,5,6,106hexahydroimidazo[2.1 -a]isoquinolines 316 or 1,3,4,6,7,11b-hexahydro-2Hpyrimido[Z,I-al]isoquinolines 317298(Equation 87).
317
(87)
Variously substituted 1,2,3,4-tetrahydroisoquinoIines318 bearing a wide variety of basic side chains at the 2 position have received extensive synthetic interest because of their medicinal value. The direct nucieophilic displacement of o - h a l o a l k y l a m i n e ~cleanly ~ ~ ~ ~ ~ affords ~~ 320. Alternatively 318 can be first reacted with w-chloroalkanols, then converted with thionyl chloride to the chlorides 319, which when treated with a primary or secondary amine, yields 320. When 318 is reacted with a-chloroacetyl chloride, 321 is obtained. This
Isoquinolines Bearing Basic Side Chains
138
undergoes a nucleophilic substitution reaction with amines to provide substituted glycinamides 322. These compouinds have been found to possess CNS a ~ t i v i t y ~(Scheme ~ ~ ' ~ ~21). '
X(CH I ) n NR'R'
acetone or EtOH
R'
R'
318
3m
HNR'R'
,
R q 2 i NCHZNR3R4
n- BvOH
R' 321
0
R'
scbeme 21
322
N-(Aminoalky1)-1,2,3,4-tetrahydro-2-isoquinoline carboxamides 325 are useful as antiarrhythmic and bactericidal agents. These can be prepared by the reaction of 318 with either a suitably substituted o-chloroalkylcyanate or phosgene to provide either 323 or 324,respectively. When 323 is subsequently treated with an amine, the chloride is displaced in an SN2fashion to afford 325. Mternatively, 324 can be converted in two steps to 325308*309 (Scheme 22). A number of potent antihypertensive agents (327)have been prepared from the reaction of 1,2,3,4-tetrahydroisoquinolinewith a variety of acetylenic amines 326310*322 (Equation 88). Modifications of these structures are illustrated in the conversion of Npropargyl-l,2,3,4-tetrahydroisoquinoline328 to the acetylenic amine 329 which is then oxidized with mercuric oxide to the ketone 330. Following treatment
rg
w
e
2
H
2
2
2
H
H
H
H
2 3 3 2 2 2
67-Methylenedioxy, 8-OMe 6,7diMe0 7-NOZ 7-NHz
H
2
2 2 3 2
n
H H H 6,7-Methylcnedioxy, 8-OMe 6.7-diMc0
R
H -NNHCH
Y
ZCH, N(CH 3
) ~
*
dimaleate
C ,5 H z , N 3 0* dimaleate
C,,H,,N,
Formula
TABLE 63. SUBSTITUTED 24AMINOALKY L)-1,2,3,4-TETRAHY DROlSOQUlNOLlNE
1 61
1w1.2, mm)
133
148
236-237 232 221 -223 192
222
21 1
223-224
229 243
262
154
FP ('C)
365
363
363
363 298 298 364 364 363
323
298
298 363 298 298
Ref.
xm
m v) v)
B
X
N
140
hl
v)
m IA
0, m
0
m
x
0
v) v)
rn
- rN m rin
rI
5
3
5
2,
5 0
a u-
u-
T
2
N Qo
Li
T
a5
T 141
H
H
H
R
TABLE 63. (Continued)
2
1
n
-C
C-CH
*-
Y
3
N
C,,H,,NI -2CH,Br
Formula
366
366 157-160
310
Ref.
187-193
224-225 (dm)
FP ("C)
W 0.
-
6.7-diOMe 6-OMe. 7-OEt 6,7.8-tri(OMe) 6.7-diOEt 6.7.8-triOMe 6.7-diOMe 6,7diOEt 6.7diOEi 6.7,8-triOE! 5.6,7-UiOEt 6,7diOEt 6,7-diOEt 6.7.8-triOE t 6,7diOEt
R'
3.4diOMe 3-OMe, 4 0 E t 3,4.5-triOMe 3.4-diOEt 3,4.$-triOMe 3.4 diOMe 3,ediOEt 3.4- di 0Et 3,4,5-triOE1 2,3.4-tnOEt 3,4-diOEt 3,4-diOEt 3.4,S-triOEt 3.4-diOEt
R2
Wh
--N( E t), - -N(CH,)-CH,-- C6H,(3,4diOMe) -N(CH,)CH,CHzC,H,(3,4-diOMe) -N(nBu), - -N(CH,)CH,CH,C,H,(3,4 diOEt)
-
-N(CHzCH,)z --N(CH,CH,), -N(CH,CH,), .-N(CHZCH,), N(nBu), - -N(CH,) CHzCH,C,H, N(CH,)CHZC~J --N(nBu), -
Y
" q - C H 2 - C H
Formula
C2,,H41N204 dihydrrxhloride C28HllN106 dihydrochloride C3,H4,NZ0, dihydtachloride dihydrtrhloride C,,H,,N,O, CI3H,,N2O, dihydrochloride dihydrochloride C,,H,,N,O, C3,H,,N,0, dihydrochloride C3,H s 4 N z 0 6dihydrochloride C,,H,,N206 dih ydrochloride C,,H,,NzO, dihydrochloride C,,H ,N,O, dihydrochloride C,,H,,N,O, dihydrochloride C,,H,,N,O, dihydrochloride
C,,H 38N204dihydrochloride
!--Y
TABLE 64. SU BSTlTUTED 2-(ALKY LAMlN0)- I -BENZYL-1.2,3,4-TETRAHY DROISOQUlNOLl N ES
200 (dec) 211-213 140.5- 142 210 (dec) 136-138 224-225.5 180- 183.5 132-134 180.5- 183 180- I82 180-183 235-236 132-134 199-201.5
FP (T)
304.305 304.305 304.305 304.305 3M. 305 3M.305 H)4,305 304,305 304,305 304.305 3oS, 305 304.305 3oS, 305 304,305
Ref.
Isoquinolines karing Basic Side Chains
144
323
318
I
ClCCl
-
R2
Rb I . HNaIkyICI
2. HN R'R'
HNR'R'
R2
'
q
N
R'
K%kylNR4R5
0
325
324
R 6 = H or alkyl sfbeme 22
I BICH~C~CCH,NR'R~
W
!
H
326
2 CH,Br
NCH2CsCCH,NR'R2 2CH,Br
with bromomethane, the reaction of 330 with sodium acetylide in liquid ammonia affords the diquaternary salts (331),which are antihypertensiveagents in nonhuman mammals and sedatives in humans 311*322 (Scheme 23). The quest to find potent antihypertensive agents having oral activity has provided a variety of 1,2,3,4-tetrahydroisoquinolines.The reaction of 1,2,3,4tetrahydroisoquinoline with 0-methylpseudourea or S-methylpseudothiourea sulfate in water generates, after treatment with hydrogen bromide, 1,2,3,4tetrahydroisoquinoiie-2tarboxamidine hydrobromide 332.312*313*321 As powerful bases, these guanidines are completely ionized in serum and are prevented by the blood-brain barrier from entering the central nervous system. Introduction of an N-hydroxyl group provides N-hydroxyguanidines that are > lo3 times less basic than their carboxamidine analogs. Treating 1,2,3,4tetrahydroisoquinoline with an excess of cyanogen bromide in the presence of
6of
ZOI- I01
O N H 3
r r rr s z
N-Zi-IYH3-
C H
H aMIO!P-LP
Q--ZH3-0L'9
139-140
126-129
149-150
142-143
2-Br
2x1
4-F
QCI
6.7-diOMe
6.7-diOMe
6,7-diOMc
6.7-diOMe
309 112-1 13
309
309
309
309
309 309 309 309 309
Ref.
Fp ("C)
H
4-F 2-Br
Formula
106-107 128-129 136-137 142-145 109-110
Y
2.6-diCI 4-CI
H
R2
CH 3 6.7-diOMe 6.7-diOMe 6,7-diOMc 6,7-diOMe 6.7-diOMt
4
6,7-0-CH-S
R'
TABLE 65. (Continued)
w
0, L, z-u
!
T
u
I
2
u, T u
I
$
N
147
T
Y4 X u
I
E"0 G
a
r?
u
d L
un X
X
V
I
X
X
5
0
2d
148
111. lsoquinolines Having Basic-Containing Substituents at C2
NCH.CECH 328
I
NaNH:
NCH 2C=C(CH2
D m
)2
149
NMe
329
I
HgOIH,SO,
sodium acetate in methanol affords good yields of the cyanamide 333, which when reacted with hydroxylamine furnishes 334. Enhanced pharmacologic activity supporting the original premise that reduced basicity would result in an altered physiologic distribution was ~ b s e r v e d . ~ ' ~ . ~ ' By modifying the location of the guanidine moiety to the terminal position, a new class of guanidine derivatives is obtained which block the hypertensive effect of amphetamines or similar sympathomimetic drugs effecting the stimulating properties of amphetamine analogs. Thus, 1,2,3,4-tetrahydroisoquinoline is converted to 24 1,2,3,4-tetrahydroisoquinoline1 -yl)ethylamine (335), which when treated with S-methylpseudothiourea affords 2-[2-( 1,2,3,4-tetrahydroisoquinoline)]ethylguanidine sulfate (336).3'6- 31 '. Biguanidines 337, prepared by reacting dicyandiamine with 1,2,3,4-tetrahydroisoquinolineat 142 "C, were reported to act as oral antidiabetic (Scheme 24). Gastric ulcer therapies have led researchers to discover that the 1,2,3,4tetrahydroisoquinoline moiety is an interesting alternative to the imidazole ring present in most synthetic decarboxylase inhibitors. The condensation of N42chloroethyl)-l,2,3,4-tetrahydroisoquinoline(338) with sodium diethyl chloromalonate followed by acidic hydrolysis and subsequent treatment with hydrazine affords d,I-y-N-(1,2,3,4-tetrahydroisoquinolyl)-c acid (339). Alternatively, the condensation of 338 with sodium a-methylacetoacetate in xylene followed by treatment with sodium azide and concentrated sulfuric acid provides an azide that when hydrolyzed under acidic conditions provides the racemic acid 340323.324 (Equation 89).
'
Isoquinolines Bearing Basic Side Chains
150
332
333
334
/ dicyandramoe 14T c
L
NH
331
I . ClCHlCN 2 . LIAIH,
COIEt
I
1. Na-CCI
I
C0,EI
2. HCI
3. NHlNH2
339
338 2. NrN>IH,SO, 3. HCI
340
NH
111. Isoquinolines Having Basic-Containing Substituents at C2
151
TABLE 66. INTERMEDIATES FOR SYNTHESIS OF 1.2.3.4-TETRAHYDROISO-
QUINOLINE-2-CARBOXAMIDINES
R’
R2
A
Formula
Fp(”C)
Ref.
H
H
-C
,SCZH~ *NH.HBr
C,,H, ,N,S * HBr
157-160
321
6.7-diOMe
CH,
-C,
4
C13H18N202S
138-140
321
6-OH,7-OCH,
CH,
-C,
C,,H,,N,O,S.HBr
157-159
321
6.7-diOCH3
H
-C,
C,,H,,N,O,S*HBr
142-144
321
6,7-diOCH3
CH,
-Cs
C,,H,,N,O,S-HBr
-
32 1
NH 2
4NH.HBr SCzH: +NH.HBr SC2Hs NH-HBr SCzHj
152
Isoquinolines Bearing Basic Side Chains
TABLE 67A. SUBSTITUTED 1,2,3,4-TETRAHYDROISOQUINOLINE-2-CARBOXAMIDINES
R1
R2
R3
67-diOMe
H
H
H
6.7-diOMe
H
6.7-diOMe
H
&OH, 7-OMe
CH3 -CH2-CH2-0
6,7-diOMe
H
-CH2CH2-N
-CHz-CH
2-
\p
C18H28N403
hydrobromide
hydrobromide
C19N23N302
hydrobromide
-CH2CH2-0
c2 IH27N204
hydrobromide
C22H29N304
hydrobromide
154-156
321
147-49
321
160-62
321
188-190
321
147-50
321
213-215
321
210-211
321
-CH2-CH2
6,7-diOMe
CH, -CH2CH2-O
C22H29N304
hydrobromide
111. lsoquinolines Having Basic-Containing Substitoents at C2
153
TABLE 67B.
-
Rgp+:-&NH
“H-R3
R’ R’ H
R2
H
R3 H
or
R’
R’
Formula
H
CIOH13N3 H2C03
hydrochloride nitrate hydrobromide monosulfate 6,7-diOMe
H
H
H
H
0
Cl,H17N,O, monosulfate
Fp(”C)
Ref.
60-63 179-181 146-148 175-176 274-276 261-262
312,313 312,313 312,313 312,313 312,313 312,313 312.313
m
353
Isoquinolines Bearing Basic Side Chains
154
TABLE 68. SUBSTITUTED 3,4-DIHY DRO-2(1H)ISOQUINOLINE CARBOXAMIDOXIM ES
R’ H 6.7diOH 5-OH 5-CH3 &Me 7-Me 8-Me H H 6.7diOH 5NHAc H H H H
H
5-CH3 &Me 7-Me 8-Me
H
H 6.7diOMe 6.7diOMe
Formula
R2
H H H H H
H
H I-CH, 3-CH3 I-CH,
H
1--C2H, 3-CZHS 1,I di(CH,) 3.3-di(CH3) 4,4diCH, 1-CH,
1-CH, 1-CH, I-CH, 1,3,3-triMe 1,4,4-triMe I-Me 3-Me
C,,H 13N30p-toluenesulfonate C,,H,,N,O, hydrochloride CloHI3N302 hydrochloride cl 1H1,N30
C , lHl,N,O hydrochloride 1‘
lH1sNJ0
C11H1,N30 1 ‘
lHllN30
cl
I
1S N 3 0
CllH,,N,03 hydrochloride C12Hl,N,O, C, ,HI ,NjO hydrochloride Cl *H ,N,O hydrochloride C12Hl T N 3 0 C12Hl
7N30
C12H17N30
C,,H I ,N,O hydrochloride C12H17N30 C12H17N30
Cl,H17N,0 hydrochloride C13H19N30 1 ‘
9N30
c13H19N303
C, ,H 19N,0, hydrochloride
FP (“C) 144-145 198-200 212-21 3 142-144 152-154 141-145 145-149 170- 172 I 20- 122 195-197 164-166 183-184 135-142 161-162 122-123 117-1 19 193-194 156-1 58 151-1 54 210-21 3 161-1 63 134- 135 149- I50 178-181
Ref. 314,315 314,315 314,315 314,315 314,315 314,315 314.315 314,315 314,315 314,315 314,315 314,315 314,315 314,315 314.315 314,315 314,315 314,315 314,315 314,315 314,315 314,315 314,315 314,315
111. Isoquinolines Having Basic-Containing Substituents at C2
155
TABLE 69. SUBSTITUTED 2-(GUANIDINOALKYL)-l,2,3,4-TETRAHYDROISOQUINOLINES ' m - C H * - ( C H 2 ) , , n
R'
-Y
Formula
Y
Fp("C)
Ref. ~
H
I
-NH--C(
H H H H Ring totally reduced H
1
-NH-C( = St-NHCH, -NH--C( = S)--NHCH, -NH--C(=StNHEt -NH--C( =S)NH(cyclohexyl) -NH--C( = NH)NH,
2 2 2 I
=NH)--NH,
C12HtllN4
disulfate*~H,O c I ,H IPN3S ',,HZ
INSS
C15H23N3S
C,,H,,N,S 12
~~
204-207
3 l6,3I7
316,317 316.317 180-181 316,317 135.5-136 316,317 195-199 318
-
84-85
TABLE 70. 2-(BIGUANID)-l,2,3,4-TETRAHYDROISOQUlNOLINES
Formula
Y
--C( =NH)--NH--C( -C( =NHF-NH-C(
= NH)NH,
=NH)NHCH,
C,,H,,N, hydrochloride C,2H,,N, hydrochloride
Ref.
FP ("C)
226-228 196-198
319,320 319,320
TABLE 71.
Y
-S-C( -S <(
=S)-NHCH, = S)NHC,H,
Formula C,,H,,N,S, hydrochloride CIBH,,N2S, hydrochloride
FP W)
Ref.
216-217 135
369 369
Isoquinolines Bearing Basic Side Chains
156
TABLE 72. SUBSTITUTED 2-(AMINOALKYL-ACYL)-IJ,3,4-TETRAHYDROISOQUINOLINES
R H 3-Me 3-Me
Y
-
FP CC)
Formula
n
--CH,-NH--(CH2)6-N(CH3)2 CH,-NH--CH(CH3~H,--C6H,
C,,H,,N,O
-
370
C20H33N30 Cz,Hz&O
190-193 (1.1 mm) 210 (0.5mm)
307 307
TABLE 73. SUBSTITUTED 2-(AMINOPROPIONYL)-l,2,3,CTETRAHYDROISOQUINOLINES308
R
Y
6.7-diOMe
-N(CHZCH~)Z
6.7diOMe
n
Ref.
Formula
-"W0
n
FP CC)
C14H3ZN203
methiodide
106-107 165-1 68
C24H30NZ04
222-224
6.7-diOMe
-NwN-CH3128-129
6-OMe, 7-OH
-N[CH(CH,),],
6,7-diOMe
-NwN-c hydrochloride
6,7diOMe
-N>c
6.7diOMe
-N>CH2C6H5
C2$H33N303
C26H36N103
n
6HS
?
C30H35N303
158-160
H3 IH38N203
92-93
C ~ Z H ~ O N ~ O127-128 ~
111. Isoquinolines Having Basic-Containing Substituents at C2
157
TABLE 74. SUBSTITUTED 2-(AMINOALKYL)OCTAHYDROISOQUINOLINES."
R
n
H
I
H H
O O
Y
Formula
-NHz
CIIHZONZ hydrochloride CI~H2ONZO CIZHZZNZ dihydrochloride
- C ( C H 3 ) = NOH --CH(CH3)-NHz
1
H
1
-N
n n N-CHzCHzOH W
160-161 ( 2 0 1 ~ n ) 126- 128
Oil
oxalatc
67-68 (0.05 IN^) 220-223 85-87 (0.01m) 125- 126
cZ 1H 3 I N3
274
C17H31N30
161-162
C14H26NZ
H
FP ("C)
dihydrochloride
TABLE 75. SUBSTITUTED 2-(AMINOALKY L)DECAHYDROISOQUINOLlNIUM SALTS
~~
R
Formula
Fp("C)
Ref.
Br -N-(C3Hj),IBr0
CI6H3,Br,N2
228-230
312
Br
C18H36Br2NZ
218-220 196-199
372
-
373
n
X-
H
2
H
2
Y
0
- ( /8 3 ] B r o
H 3c Anisyloxy
2
Br
0
-N(CH,)j]BrO
C,,H,,BrZN, (stereoisomer) Cz,H,2BrzN202
Isoquinolines Bearing Basic Side Chains
158
TABLE 76. SUBSTITUTED 24AMINOALKYL AMINO). 1,2,3,4TETRAHYDROISOQUINOLINES363
Y
NCH,), N(CZH5)2
.3 n
NWo
Formula CI 3Hz I N3 dimethiodide dihydrochloride C15H25N3
dimethiodide C,5H,,N, dimaleate dihydrochloride C,5H*,N30 dimethiodide dimaleate
FP ("C) I91 201
190 200 207 190 133
The ability to generate a carbanion adjacent to a properly activated nitrogen would allow for the a-alkylation of amines. Easily prepared 325 N-formamidines of 1,2,3,4-tetrahydroisoquinoline341 metalate with sec-butyllithium to afford the dipole-stabilized carbanion 342 which undergoes alkylation with a variety of electrophiles to provide after hydrolysis or reduction 343. Repeating this procedure allows for geminal alkylation at C1 to yield isoquinolines 344325 (Equation 90). Metallation of formamidines containing a chiral amine moiety provides a carbon-lithium bond in which the topography of the lithiated species determines the approach vector of electrophiles, thereby creating enantioselectively a chiral carbon-carbon bond.327-3f9 The chiral auxiliary, tert-butylether or valine dimethylamin~formamidine~~~ (M), reacts with 172,3,4,5,6,7,8-octahydroisoquinoline (345) to generate 347 which has been effectively used for the preparation of the two (+)-morphinans 349 and 350, respectively330 (Scheme 25). Similarly were prepared from 351 the aporphine alkaloid (S)-( + ) - o ~ o t e i n e ~ ~ ~ (352) and (S)-benzoquin~lizine~~~ (353) (Equation 91). Preparation of the chiral dibenzo[a, g] quinolizidine 355, which has been utilized in the total synthesis of ( --metine (356), constitutes a formal total synthesis of 356333(Scheme 26). The reaction of 6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline(357) with N bispad-N-N-dimethylforamamidine(358) provides 359, which has been utilized in the preparation of the morphine-like (-)-salutaridine (360)having 85% ee334 (Equation 92).
159
111. Isoquinolines Having Basic-Containing Substituents at C2
E
343
-Ra! [ ] 2. H i O t
'
Mc2N-VR
q
N
,
1
toluene
Li-NR
NR
341
342
t
a R=rBu(89%) b R = C6Hll(95%)
/" Me0
OMe 352 (93'Koee)
to 351
,
\
I . El 2. RLi 3. E,
4 . LiAlH.
160
Isoquinolines Bearing Basic Side Chains
346'
L
toluene
3 45
CHjN
350
161
111. lsoquinolines Having Basic-Containing Substituents at C2 I . r-BuLi 2. 3-McOC,H,CH ,CI
3. SHINHI (97 R)
t ’0
I
OCH 3
351
(R= 6.7 -OCH?)
354
cH3 I . NaINH,
.
2. AeOH NaBH ,CN 3. CH>O
4. Swcrn oaidalion
CH30
0 355
356
(99% ee) SekmeM
B. Substituted 2-(Amiaopbenyl)isoquinlines As a potential antineoplastic agent, l-{p-[bis(2-chloroethyl)amino]benzyl} isoquinolinium p-toluenesulfonate (362) is prepared by the reaction of isoquinoline with pbis(2-chloroethyl)amino]benzyl alcohol (361) in the presence of p-toluenesulfonyl chloride335(Equation 93). The reaction of 6-methylisatoic anhydride (363) with 6,7-dimethoxy-1,2,3,4tetrahydroiosquinoline (357) under basic conditions affords 364, which is reduced with lithium aluminum hydride (LAH) to N-(2-amino-S-rnethylbenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiosquinoline (365), a compound possessing minor tranquilizer properties336(Equation 94).
162
Isoquinolines Bearing Basic Side Chains
I
pTs0
CHZOH
362
361
357
/
LiAl H4
cC H 330 0 m N C H 2 @ c H 3 N H ~
366
The alkylation of 1,2,3,4-tetrahydroiosquinoline with methyl 2-chloropropionate heated with potassium carbonate in a sealed tube provides 366,which after aminolysis with aniline and lithium aluminum hydride reduction affords 2-(a-methyl-~-aminophenethyl)-1~3,4-tetrahydroisoquinoline (367), which has potential local anesthetic activityJ3' (Equation 95). l-Methyl-3,4,-dihydroisoquinoline(368)reacts smoothly with 2-chloro-Nphenylbenzamide to provide after treatment with potassium iodide the quaternary iodide 369,which is reduced first with sodium borohydride and then with lithium aluminum hydride to yield 370, a compound possessing antiprotozoal activity3'* (Equation 96). Under basic conditions, substituted isoquinolines 371 react with p-nitrostyrene epoxide (372) at the less hindered carbon to afford 373, which can be
111. Isoquinolines Having Basic-Containing Substituents at C2
163
CHI
I
CICHC0,Me
m
N
H
N-CHC02Me
K~COI
3m
369
(96)
reduced catalytically to 374. Depending on the nature of the substituents, these compounds have been useful as sedatives, hypotensives, analgetics, and 97). a n t i t u s s i v e ~(Equation ~~~
[
373 X=NOZ
371
IHI
34
X=NHZ
(97)
Isoquinoline Bearing Basic Side Chains
164
The alkylation of 1-phenyl-6,7,-disubstituted-1,2,3,4-tetrahydroisoquinolines 375 with 1,3-dibromopropaneso as to allow only one bromo group to react with the secondary amino group of 375 affords in good yields 376, which can be reacted with different anilino derivatives to provide either 377a or 377). These compounds have been found to be potential t u b e r c u l ~ s t a t (Equation s~~~ 98).
0 377a R’= 3 C 2H5(68%) 37?b R = 3,4diMe(70%)
377
Ethyl 2-(2-aminobenzyl)- or 2-(2-aminophenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate(379) or (380)were utilized as key intermediates for the synthesis of the interesting tetracyclic compounds 381 which depending on the nature of the substituents were examined as potential sedatives, analgesics, tranquilizers, diuretics, and hypoten~ives’~~ (Equation 99).
m
R’
COzEt
R2
mz
R1 2. RaNi or
P i 0 ,I
378
*
CO2Et
RZ
H
R&NH2
381
R3
(99)
111. Isoquinolines Having Basic-Containing Substituents at C2 TABLE 77. ISOQUINOLINIUM SALTS WITH AMINOPHENYL GROUP IN 2 POSITION
165
QI QI
L
H
H
CH, CH, N(C0Et) CH2 CH(0H)
CH, CH(0H)
CH,CH(OH) CH, CH(0H)
H 6.7-U-CHIO
6.7-diOMe
6,740Me CH,CH(OH) 6.7,s-triOMe QNH, 3-NH2
4-NH,
I-Me H
1-CH,
I-CH3
CH, CH, NH
H
1-CH,
CHzCONH
H H
R2
l-CbH5
CHzCH[OCH2CH,N(CHzCH,),]H H
~~
C O W , H, C O W , H, COOC2H5 l-C,H,
H H
H
H
P-OCH2 CH, W H , CHdI
H
2-Amino-S- Me H H 2-NH2 2NH,, 4-CI 2NHz H
R1
CH,CH,
CH, CH(NH,)-CH,
Y
H
H
6.7diOMe H H H H H H
R1
R3
-~
dihydrochlonde
O3 c 2 0 HZ6 N2 0 4
cZO H26 ‘2
hydrochloride
c19 H24 N2, O3
N, 0 3 dihydrochloride
c,, H,,
H20 NZ.o
hydrochloride CI8 Hz2 MZ, hydrochlonde C,lHZ,NZO
clB
H34 N Z
dihydrochloride
cZY
cZ9 H34 N.2°
dihydrochloride * 25H,O
dihydrochloride * 5C2H,0H
c Z 4 H Z 6 HZ
c 1 9
clB
CIN2O4S Hzz N, 0, c,, H2, N, dihydrochloride * 25H20
c J B H20 H2°4S
-
C,Y H24 N, 0, CIS H2o N2O Cl8 H22 N,
-
Formula
TABLE 78. SUBSTITUTED 1,2,3,4-TETRAHYDROISOQUINOLINES WITH AMINOPHENYL GROUP IN 2 POSITION
239-240
121-122
180 164-165 220
-
235-237
184- 187
97-143
2 10.5-2 18.5
231-239
2 10.5-21 8.5
84-85
101 218(1 mm) 142- 149 147-148
-
FP (“C)
339
339
339
339
338
338
338
314
314
374
336 337 337 34 1 341 341 374
Ref.
Ill. Isoquinolines Having Basic-Containing Substituents at C2
I67
TABLE 79. SUBSTITUTED 3-(AMINOPHENYL)-l,2-DIOXO-1,2,3,4-TETRAHYDROISOQUINOLINES
Re
&
R
-
2
HO R ’
R
R2
R’
Br
pBr--€,H4 C6H5
Fp (“C)
Formula
N(CH3),
C23H,, BrN203
203-204
N(CH3)2
c24 H7.2 N 2 0 3
146
c 2 5 H14 N 2
O.3
165 153
‘29
NZ
110
CH3 OCH3
C6H5
N(CHdz
CzhHzzN204
C2H5
C6H5
N(CH3)2
H
C6Hr-’%H,
N(CH3)2
R‘w
Ref. 375 376 374 375 375
TABLE 80. Z-(PIPERAZINYLALKYL) ISOQUINOLIN-1,3-DIONES”’
0
R’ R’
R2 CI
0
R3
N-(CH2),
R4 H
-N
A
WN-R’
n
c23 HZ6 C1N3
hydrochloride
H
H
H
H
F
H
FP CC)
Formula
OZ
C23HZ6C1N302
hydrochloride
228
H26 C1N3 O2 dih ydrochloride
135
c23
c23 H26 FN3 O2
dih ydrochloride
H
H
H
H
231-232
c,?J H27 N3 O2
dihydrochloride ‘23
HZ8 N4°2
dihydrochloride H
H
H
H
c24 H,?9 N 3 O2
H
3-Me
c24 H29 N3
c24 H26 F3 N 3 O2
hydrochloride hydrochloride
OZ
hydrochloride
200-203 193-205 (dm) 176- 178
230 235-238 1%
Isoquinolines Bearing Basic Side Chains
168 TABLE 80. (Continued)
Rl H
H
FP W)
R3
R4
n
C6H4(2Me)
H
2
c24 H29 N 3 O2
2
c24 H29 N 3
R2
Formula hydrochloride
247
O3 hydrochloride
215-218
H
043%
C6HS
H
H
H
C6H4(2)CH3)
H
2
Cz4 Hm N3 0
H
H
C6H4(mH3)
H
2
cZ4
H
H
&Me-2-Pyridyl
H
3
c24 H30 N4 O2
wH3
2-Pyridyl
H
3 3
H H
H
C&(XF,)
H
H
H
C6H3(2,6diMe)
H
2 2
H
H
C6H4(2Et)
H
H
H
C6H4(20Me)
H
3
C6H4(20Me)
H
2
H
C6H3(3,4-diOMe)
H
2
H
O(3.b
CMe-2-Pyrodyl
H
3
OCH, OCH,
OCH3 OCH,
C,H4(20Me) C6H4(20Me)
H
2 3
H H
H
3
dihydrochloride H Z 9 N3
O3
dihydrochloride hydrochloride c24 H30 N4
O3
dihydrochloride c2S H28 F3 N3 O2
hydrochloride CZ5H31N302
hydrochloride c25 H31 N3 0 2 dihydrochloride c*5H31 N3 0 3 hydrochloride C25H31N304
dihydrochloride C25H31N304
dihydrochloride
2 15-21 7
228 88(d%C) 193-196 215-220 230 (d YoC) 188-192 235-237 211-213 158
c25 H32 N4
O.3
c26 H33 N3
OS
172-1 76 264-265
hydrochloride
198-Nx)
dihydrochloride
cz, H3, N, 0,
111. Isoquinolines Having Basic-Containing Substituents at C2
169
TABLE 81. SUBSTITUTED 24ETHYLAMINOALKYL)-I.3-ISOQUINOLINDIONES377
~~
R’
R2
R’
Formula
n
H
H
3.4-diOMe
C23H28N204
H
OCH,
4-OMe
C23H7.BN204
H
a
3.4-diOMe
H
H
3,4-diOMe
C24H30N204
H
OCH,
3.4-diOMe
C24H30N205
H
OCH,
2Me, 3,4-diOCH3
1
H
OCH,
3,UiOMe
2
H
SCH,.
3.4-diOMe
cZ$
H
OCH,
3.4.5-triOM~
C26H34N206
w H 3
OCH,
3.4-diOMe
C26H34N206
(33%
OCH,
2-Me, 3,UiOMc
C2’1H36NZ06
hydrochloride
Cz4 Hz, ClNz 0
hydrochloride
175- 176 4
hydrochloride
hydrochloride C,, H,, N, 0, hydrochloride CZIH32NtOI hydrochloride H32 NZ
~~~
148-151
hydrochloride
2
FP W)
O4S
hydrochloride hydrochloride hydrochloride
hydrochloride
222-226 162- 165 263-265 138-140 191- 193 133-135 157-159 98-101 167-168
C. %HeterocyclicSubstituted Isoquiaolines
The syntheses of 2-heterocyclic substituted isoquinolines generally involves the nucleophilic displacement of an appropriately substituted heterocyclic halide with the basic nitrogen of an appropriately substituted isoquinoline. Isoquinoline and o-bromopicoline (382) react in boiling benzene to give a red solid quaternary bromide 383, which when brominated and subsequently treated with pyridine provides 5-bromopyridino[ 1”: 2”-3:4]isoquinolino [2’: 1 :2)glyoxalinium bromide monohydrate (384)342(Equation 100).
170
Isoquinolines Bearing Basic Side Chains
382 C6Hb
383
The reaction of 1,2,3,4-tetrahydroisoquinolinewith 2-chloromethylpyridine (385) in cold acetonitrile affords 2-(2-pyridylmethyl)-1,2,3,4-tetrahydroisoquinoline (386),which can be cyclized to the quaternary spiro salt 387 by boiling 386 with I J - d i b r ~ m o e t h a n e (Equation ~~~ 101)
The Michael addition of isoquinolines to an appropriately substituted vinyl pyridine 388 is a very effective method for the preparation of the 242pyridylethyl) derivative 389.343-346. These compounds have been examined for as well as fungicidal activity344(Equation 102). hypertensive
R
388
The reaction of variously substituted 1,2,3,4-tetrahydr0-2-isoquinoline ethanols 390 with nicotinoyl chloride hydrochloride in methyl propionate provides 2-(2-nicotinoyloxyethyl)-l,2,3,4-tetrahydrois~uinolines 391, which have been found useful as peripheral vasodilator^^^' (Equation 103).
171
111. lsoquinolines Having Basic-Containing Substituents at C2
390
Ether derivatives 393 which are potent vasodilators and blood-pressurereducing (antihypertensive; i.e., hypotensive) agents, can be conveniently prepared by the reaction of substituted 2-(/3-chloroethyl)-l,2,3,4tetrahydroisoquinolines 392 with 3-pyridol under basic conditionsJ4* (Equation 104).
Ra)/-VC' @
OH
'
r
n
N
-
4
SOH
toluene
392
393
(104)
Morpholine adds in a Michael-like fashion to 5-ethyl-2-vinylpyridine 388 (R=ethyl) to provide S-ethyl-2-(P-rnorpholinoethyl)pyridine394. Catalytic re-
duction of 394 with platinum oxide in acetic acid followed by N-alkylation of the basic nitrogen with formaldehyde affords a suitable intermediate for a nucleophilic substitution reaction with substituted 1,2,3,4tetrahydroisoquinolines to yield 5-ethyl- 1-methyl-2-[ B-( I ,2,3,4-tetrahydroisoquinoline)ethyl]piperdine (3%). The bis-quaternary salts of 395 have been investigated for their antihypertensive properties 3 4 5 * 3 5 4 (Equation 105).
388
'.W R
3% H
/
2. I .C PH t O, O IIHl
172
Isoquinolines Bearing Basic Side Chains
When 1-(l-piperidyl)-l-[a~l,2,3,4-tetrahydro-2-isoquinolyl)benzylJacetone (3%) is treated in benzene with four equivalents (4 eq) of methylmagnesium iodide, the a,B-diamino tertiary carbinol 2-methyl4phenyl-3-(1 -piperidyl)-4(1,2,3,4-tetrahydro-2-isoquinolyl)-2-butanol (397) is obtained in 14% yield349 (Equation 106).
Substituted 6-aminomethylguanamines 398, prepared for their possible filaricidal activity, can be prepared in two steps by the reaction of 337 first with ethyl chloroacetate under basic conditions and second with a suitably substituted arnine3s073s1(Equation 107). 0
II
I . CICHICOEt NaOCH,
2. HNR'R'
NH
337
NH
NH 2
Isoquinolinium pyrimidine salts 400 have been prepared by treating 2-alkyl4-amino-5-(brornoethyl)pyrirnidine (399) with isoquinoline in a c e t ~ n i t r i l e ~ ~ ~ (Equation 108).
Under basic conditions a-acetyl-y-butyrolactone 401 reacts with 332 to afford
241,2,3,Q-tetrahydroisoquinolino)-4-methyl-5-(2-hydroxyethyl)py~midine (402),
which when treated with phosphorous oxychloride undergoes a dehydrative ring closure to S,ddihydrofuro[2,3-d]pyrimidine (403)3s3 (Equation 109).
111. lsoquinolines Having Basic-Containing Substituents at C2
173
WNYNH* G
o
401
NIOEI
NH
332
/
402
4a3
(109)
A series of substituted 2-(2-piperidinoethyl)-1,2,3,4-tetrahydroisoquinolines 405 were prepared from the reaction of 2-(2-~hloroethyl)pipeeridine404 with substituted 1,2,3,4-tetrahydroisoquinolines in the presence of magnesium
oxide3ss. These were examined for various pharmacologic activities356 (Equation 110).
W .' 'a!" MgO 404
A
' m N 3 4M
(1 10)
Refluxing 1,2,3,4-tetrahydroisoquinolinehydrochloride with paraformaldehyde in acetone containing absolute ethanol affords in 59% yield 4-(1,2,3,4 tetrahydroisoquinoline)-2-butanone hydrochloride (406).The photochemical bromination of 406 generates the a-bromo derivative 407, which undergoes a cyclization with thiourea in an acidic aqueous solution to afford 2-amino-4-[2(1,2,3,4-tetrahydroisoquinolino)ethyl]thiazole (Equation 1 I 1). Because of their promising activity against certain cancers, a variety of quaternary ammonium salts 410 were prepared by reacting substituted isoquine ~ ~ ~ 1 12). olines with 2-amino-4-(chloroethyI)thiazole(409)in p ~ r i d i n (Equation Refluxing 41 1 with substituted 1,2,3,4-tetrahydroisoquinolinein benzene affords in 52-84% yields 3-phenyl-5-[~-(substituted-1,2,3,4-tetrahydro-2isoquinolyl]-l,2,4-oxadiazolehydrochlorides (412), which were useful agents as analgesics, antiphlogistics, antispasmodics, and local anaesthetics359 (Equation 113).
174
lsoquinolines Bearing Basic Side Chains
406
I
HB r 407
f HCH O), acetone
409
411
R' 4u
111. Isoquinolines Having Basic-Containing Substituents at C2
175
Isocarbostyril(413) reacts with methyl vinyl ketone under basic conditions to provide 2-(3-oxobutyI)-2(1H)-isoquinolone (414) in 72% yield. Treatment of 414 with ammonium carbonate and sodium cyanide in 50% ethanol affords the hydantoin 415 which can be ring-opened to racemic 2-amino-2-methyl-4-(1oxo-2(2H)-isoquinolyi)butyricacid (416) with barium hydroxide360(Scheme 27).
413
414
416
415
Scbeme 27 TABLE 82. 3-PHENYL-5-~-(I,2.3,4-TETRAHYDRO-2-ISOQUINOLY L)ETHY L3- 1.2.4-OXADIAZOLE HYDROCHLORIDES359
R
R1
H H H H H OCH3 OCH,
H CH3 CH3CH, C,H, H H CH3
R’ H H H H CH3 H H
Formula
MP CC)
C21H23N30
207 178 I56
C22H2SN30
140
C,9H
C20H21N30
C20H21N30 c2 I H23N,03
C22H2.5N303
175 196 184
L
8
t-
t
x
a z
2
z
ri
n)
ri
ri
X
X
X
I
X
X
176
3
VI v, m
VI
m
E E
m
v,
m
-
xN
L
b
I-
8
Y
t, T
6
A
N
5
2, L,
N
X
N
N
N
I
2
T
X
T
T
N
I77
w
' I ) lr)
m
cE
::
P
r!
I
r-
vlm
Q) N
- N
G X
N
X
178
ri
N
m
X
3:
X
X
X
X
zm
4 m
?
m
0.
01
m 01
2
-
a. c/
N
X
X
X
r
179
Isoquinolines Bearing Basic Side Chains
180
TABLE 84. HETEROSUBSTITUTED N-I,2,3&TETRAHYDROISOQUINOLINOAMINOMETHYLGUANAMINES'so
Hetero
I
0
0
Formula
Mp or Bp ("C)
155-157
I
A -"W0
A
159-160
171-172
-"WN -co Et
137-139
-"wN-
152- 153
A
A
-NWN-' /N
A
m
137- 139
166-168
126-1 27
111. Isoquinolines Having Basic-Containing Substituents at C2
181
TABLE 85.
R
R'
Ref.
H
288
378
3CH,
247
378
3CH,
253
318
H
256
378
244-245 (dec)
358
H
H
Herero
Formula
Mp or Bp ("C)
n
C,3H,2N,CI
343 342
~~
~
t t 9z L Z 'H93'H30-L "H30-9 O N H 3 t t 82 t2 Ol3!PL'9 O N H 3 t t sz t z WW!PL'9 O N H 3 9 t S Z CZ @NUl-8'L69 O N H 3 t t 92 CZ 013!P-L'9 O N H 3 t t 92 C2 gaW!PL'9 O N H 3 t t 9 2 CC WW!P-L'9 O N H 3 t t 9 2 C2 OaW!PL9 O N H 3 sO ?Nt 2 H zz 3 OW!JI-8'L'9 5 t tz rz WWPl-8'L'9 O N H 3 5 t tz I 2 OWIPL'9 O N H 3 5 t 5 z zz WW!PL'9 O N H 3 0t NtzH L Z 3 0tN C Z H"3 t t
0tN ZZH"3
t
tOtN2ZH
I
z3
t
O t NE l H 0 23 tOtNOZHOz3
t t 81 0 N HoZ3
rO*N02"023
t t 02 0 2 O N H 3 f t oz 02 O N H 3 O 5 N L I H 6 13 t
OW!PL'9 OaN!W?'L'9 OaW!PL'9 WW!PL'9 Xxo!paualbqlaW-L'g OW!P-L'9 OaW!PL'9 OWIP-L '9 OaW!PL'9
gaW!PL'9
gaM!PLP
WM!P-L'9 OWL ' O W 9 WUO-L '01W9 gaW!Jl-L'9'S WW!P-LL 013!P-L'9 Jd!OL ' O W 9
C ~ ~ 2 ~ 'ow-9 3 Z ~ 3 0 OW!P8'L OW!PL'9 @WUl-8'L'9 OaWyUl-L'9'S
gaW-L 'Ow9 OaN-L WN!P8'L OaW!W'S gaW!PL'9 HO-8 'O%I-L ~xo!pua~bqlq.q-~'9
H0-9 ' W W - L
H O L '01W-9 OaW-L
20n-1
IV. Isoquinolines Having Basic-Containing Substituents at C3
183
TABLE 87. BIS-I-CYANO-(I.2,3,4-TETRAHYDROISOQUINOLINES)38'
IV. ISOQUINOLINES HAVING BASIC-CONTAINING SUBSTITUENTS AT C3 A variety of 3-(aminoalkyl)- and 3-(aminoaryl)isoquinolines have been synthesized either as a part of a general synthetic effort or as a specific goal toward the discovery of biologically interesting compounds. Ethylenediamine derivatives 418 with potential antiarrhythmicantifibrillatory activity have been prepared from the reaction of ethyl 1,2,3,4tetrahydroisoquinoline-3-carboxylate(417) with a wide assortment of substituted e t h y l e n e d i a m i n e ~ ~ '(Equation ~ - ~ ~ ~ 114).
417
418
(1 14)
Primary amines react with ethyl 2-benzyl-l,2,3,4-tetrahydroisoquinoline-3carboxylates 419 to provide the amides 420, which when reduced with lithium aluminium hydride afforded substituted 1,2,3,4-tetrahydro-3-aminomethylisoquinolines 421. Depending on the nature of the substituents, these have been used as antiarrhythmic agentsje5 as well as agents for treating mental depresion^'^ (Equation 115).
Isoquinolincs Bearing Basic Side Chains
184
R
w
N
H
R
‘
TABLE 88. SUBSTITUTED 1,2,3,4TETRAHYDROISOQUINOLINE-3-CARBOXAMIDES(408)382*314
0
R
RL
R’
Formula
BP (“C)
H H H
CH3 H CZH,
CH, iC,H, CZH,
C,,HzI N 3 0 C,,H,,N,O C,,HZ,N,O
192- 195/0.1 Torr 198-200/0.5 Tom 205-210/0.I TOIT
The carefully regulated reduction of methyl 2-methyl-3,4-dihydrocarbostyril3-carboxylate (422) with lithium aluminum hydride provides 3-hydroxymethyl2-methyl-3,4-dihydroarbostyril (423), 3-hydroxymethyl-2-methyl-1,2,3,4tetrahydroisoquinoline (424) and 8-aza-6-oxa-8-methyl-3,4-dihydrobicycloC3.2. lloctane (425), all of which can be separately isolated. Further treatment of either 423 or 425 with lithium aluminum hydride yields only 424 which is converted in three steps to 3-(2-aminoethyl)-2-methyl-1,2,3,4tetrahydroisoquinoline (427). Alternatively 423 can first be converted to the chloride 426, which is transformed in three steps to 427387(Scheme 28). Ethyl isoquinoline-3-carboxylate(429), prepared from 1,2,3,4-tetrahydro-3isoquinoline carboxylic acid (428), undergoes a Claisen reaction with ethyl 341’benzoyl-4‘-piperidy1)propionate(430) to afford after hydrolysis and decarboxyl-
IV. Isoquinolines Having Basic-Containing Substituents at C3
185
TABLE 89. SUBSTITUTED 1,2,3.+TETRAHY DROISOQUINOLINE-3-AMINOMETHYL DERIVATIVES385.386
Formula
R'
R H
H
H 6.7-diMc0
CH3 H
H H
iC,H,
C17H26N2
Mp or Bp (%) 155/1.0 Torr 51-52 (2HBr) 204-206 150/0.1 Torr
213-214/0.1 Torr (2HCI) 180-182 (2HCI.)HzO) 148-150 71.5-73
C6H5
22210.25 Torr
--CH
H
-
225/0.1 Torr
2C6H 5
2a O) 0
239m.85 Torr (2HC1) 160-162 (dec)
ation 2-(4-piperidylethyl)-3-isoquinolylketone (431). Treatment of 431 with sodium hypobromite followed by a cyclization reaction with sodium ethoxide generates the 3-isoquinolyl 2-quinuclidyl ketone 432, which was tested for antimalarial p o t e n t i a l i t i e ~ ~(Scheme " ~ . ~ ~ ~29). The condensation of 429 with piperidine provides 3-piperidinocarbonylisoquinoline (433), which on reduction with lithium aluminum hydride yields 3piperidinomethylisoquinoline (434)390*393 (Equation 1 16). 3-Isoquinolinecarboxaldehyde(435) is easily converted to 3-cyanoisoquinoline (436),'91 which has been used as a common intermediate for the synthesis of either 3-(4-substitutedthiaole)isoquinolines437391or 3-isoquinolinecarboximidic acid hydrazide (438), which can be further reacted with vicinyl diketones to provide the triazines 439, 440,441392(Scheme 30). l-Chloro-3-chloromethyl-4-methylsubstitutedisoquinolines 442 contain two reactive chloride moieties that have been exploited for the preparation of antitussive isoquinoline derivative^.^^^-'^^ Using only a two-to three-fold excess of a primary amine heated for 4-6 hr at 140°C results in the nucleophilic
186
Isoquinolines Bearing Basic Side Chains
423
422
425
424
I SOCI,
2.
c,n,
I PBr, 3 RaNi
429
428
4
CH,CH,CO,Et
KOE I
O ~ C . H 5
430
43 2
431
Se&m29
IV. lsoquinolines Having Basic-Containing Substituents at C3
COzEt
187
N
H
dphenyloaidc
433
429
434 TABLE 90. 3-HETEROCYCLICCARBONYL ISOQUINOLINES
~~
R
-.3 A
-NwN-
Formula CI,H,,NzO
C,SH,,N,O
-
~~~
Mp or Bp ("C) 210-215/3-4 Torr
Ref.
94-95 (picrate) 174-175
390
140/0.001 TOKT
393
388,389
-CH2CH*CNH
C,,HzoNzO
93-94
388,389
substitution of the chloromethyl chloride to provide 443, which under reductive conditions is converted to 444. Using a large excess of a primary amine and allowing the reaction to undergo complete halide substitution yields 445 (Scheme 31).
Isoquinolints Bearing Basic Side Chains
188
I . HONH,’HCI, 2. Ac,O
43s
pcN NH,
HIS RCOCHzX
I
437
(R = H,CH,,or C ~ H S ) NH,NH,
ethand
438
A number of aliphatic and alicyciic mono- and diamino derivatives 448 of 1-substituted-3-bromomethyl-3-methyl-3,4-dihydroisoquinoline 447 were prepared by reacting methallylbenzene (446) with the appropriate nitrile in the presence of aluminum chloride and brominejg’ (also known as the Ritter reaction) (Equation 117).
189
IV. Isoquinolines Having Basic-Containing Substituents at C3 TABLE 91. 3-HETEROCYCLIC ISOQUINOLINES
R’
R
Formula
H
MP CC)
Ref.
CiiHnNiS
116-117
39 1
CI3HloN2Spicrate
150-151 184.5-185
391
173.5- 174 191.5- 192
391
C, BH ,N,S picrate
H
CinHiiN2
151.5-152
39 1
H
C22H14N6
221-222
392
H
C24H16N4
198-199
392
344-352
392
176-177
392
H
H
qND N
’
C16H1,N3
190
Isoquinolines Bearing Basic Side Chains
TABLE 9 I . (Continued)
R
R'
Formula ~~
MP ("C)
Ref.
H
C19H12N4
235-236
392
H
C15H10N4
278-279
392
H
C22H15N3
189-190
392
C17H16N2
Oil
394
1 53- 154
394
C6H5
C,H,
C20H14N2
(HCI)
IV. Isoquinolines Having Basic-Containing Substituents at C3
443
191
445
444
RCN
AICI, Br,
u
446
447
R=CHIC,H, b R=CH, c R=C6H, 8
/WN" NR'R*
R 448
(1 17)
Isoquinolines Bearing Basic Side Chains
192
TABLE 92. 1 -CHLORO-3-METHY LA M I N 0 4 M ETH Y L (ISOQUINOLINES)(434)396
~~
~
R
R
Formula
Mp or Bp (“C) 159-160
n
65-66
-NWo
79-80
5
106-108
N
A
NwN-cH3
173- 175
67- 59
n NWN-coZEr -N
W
-OH
O
H
127- 128
110-1 12
02 I
n O W N -
z
901-WI
V
WI-SPI
O? N?Z H 613
n
-
13-L
'ON-S
HO wN 2
*ON5
CN-
O w N -
O ?N nzH 1 23
H
PSZ-ZSZ
PLI -ZL I 26-06
OC N 5 2 H 613
? s cc 22 O N H 3
l3
H
H
n -
H
I 11-601 -
H 13H
zOs N scHrz3
n H
HO-NwN
n
13H
8EZ 111-011 6EZ
sN I f H12 3
fH3-NWN-
ENCN-
13H. rNszH613 c
111
N 6z Hi t 3
H H
H
Isoquinolines Bearing Basic Side Chains
194
The reactive methylene at C3 of 4-hydroxyisoquinoline (449)was subjected to the Mannich reaction for the preparation of either 3-(aminoalkyl)-4hydroxyisoquinoline 450 or 451 398399 (Equation 118).
449
450
TABLE 94. 1-SUBSTITUTED-3-METHYL-3-METHYLAMINOSUBSTITUTED-
3,4-DIHYDROISOQUINOLINES (438)397
R C6H5CH2
C6HSCH2
C6H&H2
R2
-NMe2
n
-NWo
-.3
C6H5CH2
C6H5CH2
--HN-OH
Formula
MP ec,
C20H24N2* 2HBr
225-227
C22H26N20. 2HBr
231-232
C2,H2,N2 * 2HBr
212.5-213.5
CZ2HZ6N2 *2HBr
195-197
C20H26N20
Oil
1V. lsoquinolines Having Basic-Containing Substituents a t C3
195
TABLE 94.(Continued)
R
R'
OH
n
-N
W0
-.3
Formula C, 5H3 N, 3H Br
239.5-240
CZ5H3,N,O-3HBr
228-230
C,,H,,N,
231
*
2HBr
C,,H,,N,O
C,,H,,N,
C,,H,,Nz C,,H,,N, dipicrate
8 0 "
MP C'C)
2HBr
-2HBr * H 2 0
- 2HBr - 3HBr
238 (dcc)
232-233 186- 187 119- 122
Oil
C14H22N20 C,,H,,N,
219.5-220
- 3HBr
207-209 114-1 I9
' y N ( E r ) 2
, ,,N 3 0 3HBr
C ,H
*
185-195
OH
Ph
NMe,
A "WO
164-166 and 212-214 (dec) C,,H,,N,
-2HBr
241-242
250-255 (dw) C,,H,,N,~ 2HBr
C26H3SN3
tripicrate
152-155 and 208-210 (dm)
Oil 197.5-199
Isoquinolines Bearing Basic Side Chains
196 TABLE 94. (Continued)
R
R’
Formula
C,,H,,N,
g-N(Et),
*
3HBr
131-136 (dw)
The preparation of 3-@-dimethylaminostyryl)isoquinoline methyl iodide (453) and isoquinoline 3-aldehyde-p-dimethylamjnoanilmethyl iodide (454) utilizes the reactive character of the 3-methyl substituent in 3-methylisoquinoline methyl iodide (452)400(Equation 119)
$/
’ N ‘
453
452 dine
NO
I
I‘ 454
The ring expansion of substituted 3-hydroxy-1-0x0-2-isoindolineacetic acid ethyl ester 456 was utilized for the preparation of a number of substituted 3-(2-irnidazoline-2-yl)isoquinoline-l(2H)-ones 458, which were examined for their CNS depressant activity4” (Scheme 32).
197
IV. Isoquinolines Having Basic-ContainingSubstituents at C3
FHzcozE‘
R%l
R%oH
Npiperidinc HI.HCI
NCHZCOZ Et
R
R’ 455
456
&heme 32
451
The exploitation of the tetrahydroberberine 459 as a starting material allows for the preparation of the CNS agent 3-(2-diethylaminoethyl)-4,5methylenedioxyphenyl)-7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoIine (460)402 (Equation 120).
& do O
CHJO
3. 2I N E ai ,ONHH CNBr
CHjO
CH3O
1
CHzCHZNEtz
CH30 459
460
(120)
Compounds structurally related to 2.2’-bipyridyl have high antimycoplasmal activity. The synthesis of a series of 3-(2-pyridyl)isoquinolines 463 with ortho substituents in its 2,2’-bipyridyl moiety proceeds from 2-phenylacetylpyridine 461. Bischler-Napieralski cyclization of the amide 462 and deprotection with triphenylphosphine in dimethylformamide provides 463. It was found that alkyl
198
Isoquinolines Bearing Basic Side Chains
substituents have an enhanced activity over the unsubstituted series, which may be due to variations in lipophilic, steric and electronic properties of these s u b s t i t u e n t ~(Equation ~ ~ ~ * ~ ~121). ~
@2'.. ZnIRCOOH NHzoH
3 . CH,I
46 1
&IO 7 N H
1 WCI,
CHI
R
2.p7 462
R
463
Treating the 3-chloroisoquinolines 464 with an assortment of primary or secondary arnines in refluxing toluene yields the isoquinoline-4carboxaldehydes 465 which then can be reduced to the alcohols 466.Converting these alcohols to the corresponding methyl chlorides with phosphorous pentachloride followed by treatment with primary or secondary amines provides the CNS derivatives 467405(Equation 122).
466
@
R'
467
IV. lsoquinolines Having Basic-Containing Substituents at C3 TABLE 95. I-SUBSTITUTED PHENYL-3-DIMETHYLAMINOALKY L-3,4-DIHYDRO-SUBSTITUTED ISOQUINOLINES*04
R H H 7-CI 7-F 7-CI 7-CH3 H 5-c1
H H H H H H H
R' H 2-F 2- F H H H
n
1 1
1
ClBH*ONZ C1aH19FNz C1aHiBCIFN2 CIBH19FN2
1
C18HlSCINZ
H
2
Cl9H22N2
4- F
2
C19H2,FNZ
C19H22N2
H
C19H21C1N2
4-a
&Me0 4-CH, 4-NOI
H
2-F
MP ("C)
Formula
CX9H21aN2
2
CZoH2,N20
2 3
C2,H2lN,O2 CzoH24N2
C20H23N2
C20H23FNZ
68
(Oxalate) 200 (2HCI) 150 98 100
90 (2HCI-H20)228 (2HCI) 200 (2HCI*H20)194 (2HCI) 210 (ZHCI) 200 (2HCI-H20)220 (2HCI) 185 (Dioxalate) 163 (Dioxalate) 138
199
Isoquinoiines Bearing Basic Side Chains
200
TABLE 96. 1-SUBSTITUTED PHENYL-3-AMINOSUBSTITUTEDISOQUINOLINE4 CARBOXALDEHYDES (4SS)405
R3
R'
R4
MP W )
Formula
n
-"wNH
H
H
147-148 ( H a ) 218
n
-NwNCH n
Z4-diCl
H
166-168 (HCI) 231
4-CI
H
182- 184 (HCI) 230
-NwN-cH n
H
6.7-diMeO
158-160 ( H a ) 214
H
6-CI
Oil (HCl) 212
H
H
( H a ) 270
H
H
(2HCI) >270
4-Cl
H
( H a ) 210
NwN-cH3 -N
n W0
H -NCHzCH,N
A
\p
CzH5 / H -NCHzCHzN,
C2H5
Oil
mi
IV. lsoquinolines Having Basic-Containing Substituents at C3 TABLE 96. (Continued)
a
I
-NCH
3 2
Formula
CH 3
/
CH 2 N,
'R
R3
R' H
H
CH i
A
-NwNcH3 A
H
6-CI
2-F
H
-2CH3
H
C20H23N30
C21H7. t a N 3 0
MP K) Oil (HCI) 195 185-187
( H a ) 240
-NwN-CH3 A
-"WN A
C22H23N30
166-168
H
H
C28HZ7N30
(Ha) 188
H
H
C22H2SN30
73-14
-NwN-CH-c6H5 /C2HS H -NCHZCH2 N, CzHs
143-146 (HCI) 235
Isoquinolines Bearing Basic Side Chains
202
TABLE 97. I-SUBSTITUTED PHENYL-3-AMINOSUBSTiTUTED ISOQUINOLINE4METHY L ALCOHOLS (456)*05
R'
R*
R3
Formula
MP ("C)
H
H
179- 181
2.4-diCI
H
109-116 ( H a ) 238
n
4C1
H
169- I72 (HCI) 238
n
H
6.7-diMe0
164-170 (HCI) 230
A
H
6-CI
202-205 (HCl) 254
A
H
2-F
140-430 (HCI) 229
H
H
102-104
H
H
109-110
CPyridyl
H
210-215
-"wN-
-NwN-cH
-NwN-cH -NwN-cH3 A
-NWN-c4 N -HCH2
C2HS
/
CH2N
\
CzHS
n
-NwN-cH
203
IV. Isoquinolines Having Basic-Containing Substituents at C3 TABLE 98. I-SUBSTITUTED PHENY L-3-AMINO-SUBSTITUTED.CSUBSTITUTED AMINOMETHY LISOQUINOLINES (457)405
R'
RZ
-NHCbH, A -NWNCHr
A
-"wNH n
-"wN'
n
CHI
-HNC H CH 2C H N/\ 2
2
R'
H
H
C2sH,,N,
Oil (dimakate) 167
H
H
C,,H,,N,
Oil (3HC1) 166
H
H
C ~ ~ H ~ S N 74-76 , (trimaleate) 158
2-F
H
C2,H3,FN,
H
6-CI
CZ6H3,C1N, Oil (trimaleate) 173
2-CH,
H
C27H37N5
Formula
CHI
H --NCH:CH?CH2N
/CHI \
CHI
H -NCH
-NWN-cH'
/CHI
,CH CH N
\
H -NCH,CH?CHzN
-NWN-cH'
MP C'C)
95-96 (trimaleate) 143
CHI
H /CH' A - N C H I C H I C H ~ N\ -NWN-cH ' CHI
n
R'
/CHI
\
CH3
Oil (trioxalate) 145
204
Isoquinolincs Bearing Basic Side Chains
V. ISOQUINOLINES CONTAINING BASIC SUBSTITUENTS AT C4 Isoquinolines bearing basic substituents in the C4 position are usually prepared from the appropriately substituted uncyclized precursors. Cyclization results in the introduction into the C4 position of the desired chemical moiety, which lends itself to a variety of functional-group manipulations for the purpose of creating the desired heterocyclic variant. Heating ethyl 3-amino-2-(3,4-dimethoxyphenyl)propionate(468)with formaldehyde and formic acid affords a good yield of 4-ethoxycarbonyl-6,7dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(469).Reduction of 469 with lithium aluminum hydride followed by heating with thionyl chloride yields the chloride hydrochloride 470, which can be heated with a variety of amines to provide 4-(substituted-aminomethyl)-2-alkyl-1,2,3,4-tetrahydroisoquinolines 471. Depending on the substitution, these derivatives have found use as analgesic, antiinflammatory, and gastric-juice-secretion-stimulating agents406 (Scheme 33). 4-(Benzylaminomethyl~I,2,3,4-tetrahydroisoquinoline(478) is the key intermediate in the synthesis of the azabenzomorphan 4-benzyl-3,4,5,6-tetrahydrolH-2,6-methanobenzo[e][ 1,3]diazocine (479). The first synthesis involves C02Et
CO2Et
I
I
ri,:
ri2
468
469
1
H2NR4R5
_R"H
R' &R !3
I . LIAIH, 2. SOCI,
R 1 J $ ! N R 3
R2
R2
471
470
R 1 = R 2 = O C H 3 or H ; R ' = C H ,
CHzCl
V. lsoquinolines Containing Basic Substitucnts at C4
205
heating a mixture of isoquinoline-4-carboxylicacid (472) with benzylamine at 160 “C, followed by treatment with phosphorous oxychloride to generate in good yield 4-benzylcarbamoylisoquinoline(473). Catalytic reduction of 473 followed by a metal hydride reduction of the amide affords 478. The second synthesis involves the benzoylation of 4-aminomethylisoquinoline (474), derived from 476, to provide 475, which is sequentially reduced to 478. Finally, the reduction4” of 4-cyanoisoquinoline (476) followed by a reductive amination of the resulting amine with benzaldehyde yields 478. When a mixture of 478, paraformaldehydeand benzene is refluxed for 40 min, a good yield of 479 is obtained4” (Scheme 34).
COOH
I
472
473
0
CHzNHz
I
0
\
I . PiOz/Hz 2. LLAIH,
HI1 CHzNCCbH5
I
w
C,H,CCI
474
H
CH~NCH~C~HS
I
2 LiAIH,
475
478
dN 476
479
Isoquinolines Bearing Basic Side Chains
206
Heating 480 with N,N-dimethylaniline in the presence of copper powder at 180-200°C affords a mixture of products from which 481 can be isolated. Subsequent decarboxylation and Bischler-Napieralski cyclization with phosphorous oxychloride yields l-phenyl-3,4dihydro-4-(dimethylaminophenyl)-6,7dimethoxyisoquinoline (48Z)408 (Equation 123).
' N '
CH3O cu 2. pyrrdine
480
CH30
@
481 POCI,,
Q cH30)Ql$ ' N '
J
I
CH30
482
As series of novel 3-amino-4-substituted aryl isoquinolines 485 and 3-amino4-substituted benzylisoquinolines 486 were prepared and evaluated for CNS depressant a c t i ~ i t y . ~The ~ ~ alkylation *~'~ of a-cyano-o-tolunitrile (483) with nitrophenyl halides or nitrobenzyl halides in the presence of potassium hydroxide in pyridine followed by a cyclization and rearomatkition yields 485 or 486 (Equation 124). Isoquinolines, such as 487, undergo alkylation at C4 with a variety of alkylaminoalkyl halides to provide 1,2,3,4-tetrahydro-3-isoquinolines488, which have been found useful as antispasmodic agents. Their quaternary salts are also valuable as germicides and disinfectants4' (Equation 125).
'
V. Isoquinolines Containing Basic Substituents at C4
LdN
483
207
eN
b
QNH2
R = NO:
R
x
485
I . base
2. RX
FN
484
X
487 n
488
R', R2
Formula
Mp or Bp ("C)
CZ,H,,NzO
(HZSO.) 241-242 (CH,I) 229-230
Cz2Hz,NzO,
136.5-138
CZ,H,,N,O ClzHz,NzO
Bp 187-199/0.03 Ton Bp 216-221/2.5 Torr
u
n \p
2
-N
2 2
Me CZH,
Isoquinolines Bearing Basic Side Chains
208
TABLE 99. 3-AMINO-e(AMINO-SUBSTITUTED ARY L)ISOQUINOLINES'09~410
x X
Y
n
H H H H Br H Br H
4-NHz 4-NHAc 4-NHEt 2-NHZ CNHZ 2-NH2 4-NH2 4NHt
0
MP ("C)
Formula
153-154.5 235-237 141-143 142- 143
0 0 0
175 (dec) 135.5- 137 > 170 (dec)
0 1 1 1
153-155
Basic substituted 1,4-dihydro-2H-isoquinolinederivatives 491 exhibiting anticonvulsant activity were prepared by the cyclization of either 489 or 490 with an appropriate aldehyde followed by an arninolysi~~'~ (Equation 126).
R4&(7 R3qx I . RCHO/P20, PPA
R4
RI
R*
R
489 ( X = C N ) 490 (X=COOH)
HOy
C
HO OH 492
0
O
NnOCl H
(126)
R'
"-")$ 49 1
H HO
O
HO
0 OH 493
T
u 494
HO OH 495
(127)
V. Isoquinolines Containing Basic Substituents at C4
209
Macrostomine (501), the main alkaloid of Papauer macrosromum Boiss et Huet,*14 contains a pyrrolidine ring at the C4 position of the isoquinoline The nucleus. A model for the biosynthesis of such alkaloids was de~eloped.4'~ oxidative decarboxylation of 1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid 492 with sodium hypochlorite provided 493, which on condensation with N-methyl-A'-pyrrolidinium acetate (494) and subsequent aerial oxidation yielded 44 1-methyl-2-pyrrolidinyl)isoquinoline4% (Equation 127). A complete synthesis of macrostomine (501) has been developed in which both sides of the isoquinoline nucleus are attached by high-yield carbon-carbon bond formation with lithiated n i t r ~ s a m i n e s . The ~ ~ ~ 4-hydroxy-1,2,3,4tetrahydroisoquinoline 496, obtained in 63% overall yield from the Pomeranz-Fritsch reaction of veratryl aldehyde with a-aminoacetaldehyde acetal, is quantitatively nitrosated with sodium nitrite, doubly deprotonated, alkylated with 3,4-methylenedioxybenzyl bromide, and in situ denitrosated to provide, in 80% yield, a diastereomeric mixture of alcohols 497. N-Benzoylation followed by sodium hypochlorite oxidation affords the ketone 498, which adds lithionitrosopyrrolidine to give in 62% yield a diastereomeric mixture of 499. Denitrosation with Raney nickel provides 500, which after some nontrivial manipulations affords 501 (Scheme 35).
TABLE 100. I-ARYL4SlJBSTITUTEDl.4-DIHYDRO-2H-ISOQUINOLINES41z
X
R
X C6H5
H
H H H H H H H 6.7-diOMe C6H5 CNOzC6H4 6.7-diOMe 6,7-diOMe CPyridyl QNHZC6H4 6.7-diOMe C6H5
2ClC6H4 4diC1C6H3 4-N02C6H4 4-diC1C6H3 CCHSC6Ha 4-NHZCeH4
R' H H H H H H H H H H H H
-
R2
-CH?CH?N
3
Formula
MP CC)
CzIHZ4NzO
(HCI) 224-227 (HCI) 176-179 (HCI) 100-103 150-152 138- 139 133-137 113-115 245-248 169 212-21 3 171-173 (HCI) 183
210
Isoquinolines Bearing Basic Side Chains
I NaNO,
CH30
3
496 4 denitrosation
0 497 (80%)
I C6H,COCIIEt,N 2 NaOCl
CH30 CH,O
498
il
several steps
H C c30*NH 3 0
501
Sebcme 35
V. lsoquinolines Containing Basic Substituents at C4
21 1
TABLE 101. 1-(4-CH LOR0 PH E N Y L)-4&DISUBSTITUTED 1,4-D1HY DRO-2HISOQUINOLINES4*z
R
R
R2
R’
H
Q
Formula
MP (“c) 251-255
H
(HCI) 165-166
H
(HCI) 148-150
3
H
-CH>CH>N
H
-CHlCH2N
H H H H
-CH,CH,CH,N (Me), -CH,CH,CH,N (Me), -CHzCHzN (CZH,) --CH,CH,CHzN (Me),
H
-CH
3
2 CH 2-N
3
(HCI) 240-242
(HCl) 172-175 157-158 156-1 59 120 170-172 138-143
H
193- 196
H H H H 7-diOMe
112-114 227-229 (HCI) 202-205 119-122
212
Isoquinolines Bearing Basic Side Chains
TABLE 101. (Continued)
R
R2
R'
A
H
H
&
Cz 1Hz,NzCIO,
-cH2CHzNWo A
H
H
Formula
-CH ZCH 2 N-N-CH
0 HI1
CH 2 CH 2 NC4
3
C,,H,,N,CIO
MP ("c) 239-245 (Oxalatc)
201-250
NT TTTT \ NY Hi
CH2 CH 2NC4
502
L POCI,
A
/-
504
RaNi
503
-
505
I PdlC 2HCI.
506
VI. Miscelkdneous Isoquinolines Having Basic Substituents
213
VI. MISCELLANEOUS ISOQUINOLINES HAVING BASIC SUBSTITUENTS Substitution of the 5, 6, 7, or 8 positions of isoquinolines with basic heteroatomic moities has been realized through diverse synthetic routes. Heating 1,3-bis(2-benzamidoethyl)benzene (502) with phosphorous oxychloride at 120- 130 "C for 4 hr affords 1-phenyl-6-(2-benzamidoethyl)-3,4-dihydroisoquinoline (503) without formation of the corresponding C8 isomer. Refluxing 503 with concentrated hydrochloric acid provides the free amine 504. Reduction with Raney nickel in ethanol yields 505, while further oxidation with palladium/charcoal and subsequent debenzylation generates S4" (Scheme 36). The Mannich reaction of 5-hydroxyisoquinoline (507) with 3-azabicyclo[3.2.2]nonane (508)in 37% aqueous formaldehyde yields 5-hydroxy-6-(3azabicycloC3.2.2Jnonanemethy1)isoquinoline (W),a compound examined for its potential antibacterial properties4'* (Equation 128).
507
508
The Mannich reaction of 7-hydroxyisoquinoline (510) with piperidine in formaldehyde and methanol generated 7-hydroxy-8-(1-piperdylmethyl)isoquinoline (511)419(Equation 129). H
HO 510
HCHO MeOH
HO
511
214
Isoquinolines Bearing Basic Side Chains
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Chemistry of Heterocyclic Compounds, Volume38 Edited by Gary M. Coppola, Herbert F. Schuster Copyright 0 1995 by John Wiley & Sons, Ltd.
Isoquinolinols and Their Hydrogenated Derivatives Osamu Hosbino, Hiroshi Ham, and Bunsuke Umezawa*
1. lsoquinolinols and Their Derivalives
A. Isoquinolinols and Their Ethers 1. Preparation a. By Ring Closure b. By Dehydrogenation c. By 0-Dealkylation d. By Substitution e. By 0-Alkylation and 0-Arylation f. By Miscellaneous Reaclions g. By 0-Acylation 2. Reactions a. The Reissert Reaction b. Reduction c. Oxidation d. Electrophilic Substitution e. Nucleophilic Substitution f. Miscellaneous Reactions 3. Properties a. General b. Clsoquinolinol c. 4.8-isoquinolinediol d. Dissociation Constants and Ultraviolet Absorption Bands of lsoquinolinols B. Quaternary Salts of Isoquinolinols and Their Derivatives 1. Preparation a. By Reaction with Alkyl Halides, Dimethyl Sulfate, and Alkyl pToluenesulfonata b. By Anion Exchange c. By Oxidation d. By 0-Dealkylation e. By 0-Alkylation and 0.N-Dialkylation f. By Miscellaneous Reactions
'Deceased May 24. 1988.
225
229 229 229 229 233 234 234 238 240 24 1 242 242 243 244 244 247 248 248 248 249 250 25 I 25 I 251 25 I 252 252 255 255 255
226
Isoquinolinois and Their Hydrogenated Derivatives
2 Reactions a. Reduction b. Oxidation c. Nucleophilic Substitution d. N-Dealkylation e. Miscellaneous Reactions 3. Properties a. pK, Values 11. Dihydroisoquinolinols and Their Derivatives A. 3,QDihydroisoquinolinolsand Their Ethers 1. Preparation a. By Ring Closure b. By Dehydrogenation (Oxidation) c. By 0-Dealkylation d. By Miscellaneous Reactions 2. Reactions a. Reduction b. Oxidation c. Nucleophilic Substitution d. Miscellaneous Reactions B. Quaternary Salts of 3,4-Dihydroisoquinolinolsand Their Derivatives 1. Preparation a. By Reaction with Alkyl Halides and Sulfonates b. By Anion Exchange c. By Ring Closure d. By Oxidation e. By 0-Dealkylation f. By Miscellaneous Reactions 2. Reactions a. Nucleophilic Substitution b. Cleavage of C=N+ Bond c. Reduction d. Oxidation Including the Cannizzaro Reaction e. N-Dealkylation 1. Miscellaneous Reactions C. l,2-,1.4, and 7,8-Dihydroisoquinolinolsand Their Ethers 1. Preparation a. By Ring Closure b. By Miscellaneous Reactions 2. Reactions a. Substitution b. Reduction D. 1,2-Dihydro-2-(p-tosyl)isoquinolinols and Their Ethers 1. Preparation a. By Ring Closure 2. Reactions a. Oxidation 111. Phenol Betaines A. Preparation 1. By Oxidation 2. By Base B. Reactions 1. 1.3-Dipolar Cycloaddition 2. Reduction 3. Cleavage of Dimeric Phenol Betaine
258 258 260 261 264 265 265 265 266 266 266 266 267 268 269 270 270 210 271 272 274 274 274 274 274 275 277 277 280 280
284 285 285 287 287 287 287 287 287 289 289 289 290 290 290 290 290 290 290 290 290 293 293
294 294
Isoquinolinols and Their Hydrogenated Derivatives IV. Tetrahydroisoquinolinolsand Their Derivatives A. I,2,3,4-Tetrahydroisoquinolinols and Their Ethers and Esters 1. Preparation a. By Ring Closure b. By Reduction c. By 0-Dealkylation d. By 0-Alkylation and 0-Arylation e. By Miscellaneous Reactions 2. Reactions a. N-Alkylation and N-Arylation b. Oxidation c. C-Alkylation B. 2-Acyl (Aroylk and 2-Arene (Alkane)sulfonyl-l2.3,4-tetrahydroisoquinolinols and Their Ethers 1. Preparation a. By Ring Closure b. By the Schotten-Baurnann Type Reactions c. By 0-Alkylation d. By Miscellaneous Reactions 2. Reactions a. Reduction b. Oxidation c. Condensation d. Nucleophilic Substitution C. 5,6,7,8-Tetrahydroisquinolinols and Their Ethers 1. Preparation a. By Reduction b. By Substitution 2. Reactions V. Octahydro- and Decahydroisoquinolinols A. Preparation I. By Ring Closure 2. By Reduction B. Reactions I . N-Alkylation 2. Oxidation VI. lsoquinolinethiols and Their Hydrogenated Derivatives A. lsoquinolinethiols and Their Ethers I . Preparation a. By Ring Closure b. By Substitution c. By S-Alkylation d. By 0-Alkylation and 0-Acylation 2. Reactions a. Reduction b. Substitution c. Miscellaneous Reactions B. I-Methylthioisoquinoliniurn Iodide I . Preparation a. By Methyl Iodide C. 3,4-Dihydroisoquinolinethiols and Their Ethers 1. Preparation a. By Ring Closure b. By Alkylation
221
295 295 295 295 297 300 301 302 304 305 305 306 307 307 307 308 309 309 310 310 310 31 I 312 312 312 312 313 313 314 314 314 314 317 317 318 318 318 318 318 318 319 320 320 320 32I 321 323 323 323 324 324 324 324
228
VII. VIII.
IX.
X. XI.
Isoquinolinols and Their Hydrogenated Derivatives 2. Reactions a. Nucleophilic Substitution D. 1,2-Dihydro-2-(ptosyI)isoquinolines I. Preparation a. By Ring Closure b. By Miscellaneous Reactions E. 1,2,3,4-Tetrahydro-2-sulfenyl-and 1,~3,4-Tetrahydro-2-sulfonylisoquinolines 1. Preparation a. By Sulfenylation b. By Ring Closure 2. Reactions F. Sulfoxides and Sulfones in Isoquinolines 1. Preparation a. By Oxidation 2. Reactions a. Nucleophilic Substitution Natural Products Pharmacology A. Quaternary Salts of Isoquinolinols and Their Esters B. Quaternary Salts of Alkoxyisoquinolines C. I-Alkoxy- and I-Aryloxyisoquinohes Carrying Basic Functions D. Alkoxy-3,4dihydroi~0quinolinesand Their Quaternary Salts and Their Ethers E. 1,2,3,~Tetrahydroisoquinolinols Analysis and Spectroscopy A. Analysis 1. Polarographic Analysis 2. Fluorirnetric Analysis 3. Chromatographic Analysis a. Paper Chromatography b. Thin-Layer Chromatography c. Gas-Liquid Chromatography d. High-Performance Liquid Chromatography B. Spectroscopy I. Mass Spectrometry 2. Infrared Spectroscopy 3. Ultraviolet Spectroscopy 4. Nuclear Magnetic Resonance Spectroscopy Tables of Isoquinolinols and Their Hydrogenated Derivatives Tabks of Isoquinolinethiols and Their Hydrogenated Derivatives References
324 324 325 325 325 325 326 326 326 327 328 329 329 329 329 329 330 331 33 1 332 333 334 336 339 339 339 339 340 340 341 341 341 341 341 347 360 372 400 504 514
1. lsoquinolinols and Their Derivatives
229
I. ISOQUINOLINOLS AND THEIR DERIVATIVES A.
lsoquinolinols and Their Ethers
I.
Preparation
a. By Ring Closure The Pomeranz-Fritsch reaction of the Schiff bases, derived from benzaldehydes and aminoacetals, is performed by use of acidic reagents such as concentrated sulfuric 73-82% sulfuric phosphoryl chloride/polyphosphoric acid,".' polyphosphoric acid,' boron trifluoride/trichloroacetic,14 trifluor~acetic'~ anhydride, and chlorosulfonic acidl6*" to give the following compounds: 7-2*4*6*'8 and 7 - m e t h o ~ y - 8 - ' ~isoquinolinols; ~'~ and 7-methoxy-,1.3.4.7.8.17.19 7-eth0xy-,'*~ 7-butoxy-,15 6,7-1nethylenedioxy-,~*~ 6,7-dimetho~y-,'~*~~~~~-'~ 7,8-methylenedioxy-,9 and 7,8-dirnetho~y-~*'~-'~ isoquinolines. Another type of Schifl base (I), derived from a benzylamine and glyoxal hemiacetal, also goes into the reaction with 76% sulfuric acid affording 7methoxyisoquinoline (2).3
'
'
2
1 srbcme I
The direction of cyclization is generally to the para position of an activating group. However, cyclization ortho to a hydroxyl group is observed giving a low yield of 5-isoq~inolinol.~ A further exceptional cyclization occurs meta to a methoxyl group leading to 6,8-dimethoxyisoquinoline.20 The secondary amine derived from Schiff base of the common type undergoes cyclization to initially form the 1,2-dihydroisoquinoline,(see this Chapter, Section 1I.C.1.a) which is so unstable in the acidic conditions (concentrated sulfuric acid or 6N hydrochloric acid) that oxidation or disproportionation an isoquinotakes place concomitantly, yielding 6-methoxy-7-isoq~inolinol,~~ line dimer, and 1,2,3,4-tetrahydro-6-methoxy-7-isoquinolinol.2 6,7-Dimethoxy i ~ o q u i n o l i n e ~is~ the * ~ 'sole product when the same cyclization is conducted in the presence of an oxidant, arsenic acid.
230
Isoquinolinols and Their Hydrogenated Derivatives CH3 0
752 HISOL 0’
CH30
- r.t. -~
-
C H 3 0 ~ ~ N 0 c z H 25 ) conc.
HC1
or conc. HISOL
CH30
CH,O
arsenic acid
looo
CH3O
Scheme 2
Sulfonamides of similar secondary amines undergo a Pomeranz-Fritsch reaction and successive elimination of p-toluenesulfinic acid when heated with 6N hydrochloric acid in dioxane or treated with potassium tert-butoxide in tert5,8-dimethbutanol yielding 7-methoxy-8-isoquinolinol,245,7-dimetho~y-.~~ OXY-,5 ~ ,~6 , 7 - t r i m e t h o ~ y , ~6,7,8-trimetho~y-,~~ ~-~~ 7 - m e t h o ~ y - , ’ ~7,8-dim.~~-~~ 5 , 7 - d i b e n ~ y l o x y - , ~ 7,8-di~-~~ e t h o ~ y - , ~8-benzylo~y-7-methoxy-,~~~~’-~~ ~.~~ isoquinolines. b e n z y l ~ x y - , and ~ ~ *6-methoxy-7-(8’-isoquinolyloxy)34 ~~
1
bN HC1 dioxane b
1,2-Dihydro-2-(p-tosyl)isoquinolines[see Section 1I.D.La), the initial products of the reaction, are isolable by quenching at proper stages. As another modification of the Pomeranz-Fritsch reaction a Schiff base reacts with ethyl chloroformate followed by trimethyl phosphite to give the intermediate carbamate phosphites (3), which are treated with titanium tetra-
1. lsoquinolinols and Their Derivatives
23 1
TiCL CHClj
scheme 4
chloride in boiling methylene chloride to form isoquinolines. Thus, 6-, 7-, and 8methoxy-, 6,7-dimethoxy-, and 6.7-methylenedio~yisoquinolines~~ are obtained. 6-Methoxy-7-isoquinolinol is also produced without any protection of the phenolic hydroxyl group.” The modified Pictet-Gams variation of the Bischler-Napieralski reaction (5)36from Nmakes it possible to prepare 6-benzyloxy-7-methoxyisoquinoline [2-(3‘-benzyloxy-4’-methoxyphenyl)-2-methoxyethyl]formamidine (4).
POCl,
toluene A
CH3O
3
4 sfhelw 5
The Cope reaction is applied to cotarnine oxime (6), phenylhydrazone, semicarbazone, t hiosemicarbazone, and benzoylhydrazone. Thus, on refluxing, with 46-50% potassium hydroxide in the presence of potassium cyanide, they are transformed to 8-methoxy-6,7-methylenedioxyisoquinoline(7).37*38
{Ip CHZNOH
6
CaHsOH KOH-KCN
A
scheme 6
-r
(OWN 0
CH30
7
Isoquinolinols and Their Hydrogenated Derivatives
232
By similar treatment of symmetric cotamazine (8). compound (9) or (lo), 8methoxy-6,7-methylenedioxyisoquinoline(7) and norcotarnine (11)38 are produced.
7
CH3b 50% KOH aq.
0
CH3O
0
KCN n-CcHeOH Ha0
*
+
h
CH3b
11
scbeme 7
Cyclopalladated imines (12) give rise to 7- and 6,7-dimetho~yisoquinolin~.~~ In this case, no 6- or 8-methoxyisoquinoline is formed.
12
1. lsoquinolinols and Their Derivatives
233
b. By Dehydrogenation 3,4-Dihydroisoquinolyl ethers and 3,4-dihydroisoquinolinolsundergo dehydrogenation with 5%40.41 and 1 * 4 2 * 4 3 palladium on carbon, palladium b l a ~ k , 33% ~ ~ .palladium ~ ~ asbe~tos,~'or Raney nickel and napthalene.46*47 Similarly, with 10-30% palladium on arbo on^^*^^.^^-^^ or Raney nickel and na~hthalene,~ dehydrogenation of 1,2,3,4-tetrahydroisoquinolinesis achieved. A 1-(2'-picolyl)-3,4-dihydroisoquinolylether is dehydrogenated when heated with palladium on carbon in a sealed tube." Thus, the following isoquinolines are yielded: 6-metho~y-7-~ and 7-meth0xy-8-~~isoquiniolinols; 5,6-dimethoxy-,4O 5,6,7-trimetho~y-,~~ 5,8-dimetho~y-,~'6-rnetho~y-?~*~' 6,7-di6,8-dimetho~y-,~~ and 7,8methoxy-,lO*' 1-45.47 6,7-methylenedio~y-,~~~~~ d i m e t h ~ x y isoquinolines. -~~ l q 4
CH30
10% Pd-C, Pd-black. or Raney Ni-naphthalene
-
CH3O
Dehydrogenation of 1,2,3,4-tetrahydro-4-isoqunionolinol(l3) with palladium black proceeds to yield 4-isoquinolinol (14),53 whereas a rlhydroxyl group in most 1,2,3,4-tetrahydroisoquinolylethers tends to be removed when dehydrogenated with palladium on carbon. Thus, 5,6,7-trimetho~y-'~ and 7,8-dimethO X Y - isoquinolines ~ ~ are produced. Dehydrogenation with gaseous formaldehyde in a dried protein layer of 1,2,3,4-tetrahydro-4,6,7-isoquinolinetriol yields 3,4-dihydro-4,6,7isoquinolinetriol, which is dehydrated to 6,7-isoqunilinediol with warm dilute hydrochloric acid55 (see Section IX.A.2). OH
-
OH
Pd-black
13 CH3 OH CH3O cH30&NH
102 Pd-C
p-cymene
0
14
C H . ; S N CH,O
234
Isoquinolinols and Their Hydrogenated Derivatives
1,2,3,4-Tetrahydro-7,8-dimethoxy-4-isoquinolinol(15) undergoes dehydrogenation with N-bromosuccinimide to presumably furnish 3,4-dihydro-7,8dirnethoxy-4-isoquinolino1,which is readily transformed to 7,8-dimethoxyisoquinoline (16)56on treatment with 6N hydrochloric acid. In contrast, dehydrogenation of 6,7-dimethoxy-2,3-dihydro-4( 1 H)-isoquinolinone (17) with 5% palladium on carbon yields 6,7-dimethoxy-4-isoquinolinol ( 18).s7
CH3Oe CH3
N
15
H
1.
N-bromosuccinimide
2.
6N HC1
CHCl,
CH3O CH3O
16
-
cH301&H
5X Pd-C
CH30
toluene A
17
18 scheme 11
Oxidative or photochemical dehydrogenation of 1,2,3,4-tetrahydroisoquinoline and its derivatives with 5% potassium permanganate in acetone4’ or ultraviolet irradiations8 gives 7,8- or 6,7-dimethoxyisoquinoline. c. By 0-Dealkylation 0-Demethylation of phenolic methoxyl groups is accomplished by heating with 48% hydrobromic a ~ i d ~ ~or *57% ~ ’ hydroiodic20 * ~ ~ acid. 6-Isoquinolare produced in this way. 44pino148.59 and 6,8-isoq~inolinediol~~*~ Tosy1oxy)isoquinoline(19) is converted to 4-isoquinolinol( 14)60*6’through the agency of 38% sulfuric acid or caustic alkali. An unusual 0-demethylation is known. Specifically, heating 4-methoxyisoquinoline (20) with sodium methoxide in methanol leads to 4-isoquinolinol (14)62 as its sodium salt.
’
d. By Substitution
Electron-withdrawing groups at the 1 position of isoquinolines greatly en1-~b -r ~~ ~m o - , ~ ~ hance the electrophilic reactivity of the site. Thus, l - ~ h l o r o - , ~ 1-nitro-,78 l - ~ u l f i n y l - and , ~ ~ l - s ~ l f o n y i -isoquinolines ~ ~ ~ ~ ~ react with sodium or potassium alkoxides to produce 1- a l l y l ~ x y - ,l~ ~- m e t h o ~ y - , ~ ~ * ~ ~ * l - e t h o ~ y - , ~l -~i s.o~p~r ~ p o x y - , 1-(2’-dimethyIaminoetho~y)-,~~*~~ ~~ 1-[2’(di-nbuty1amino)ethoxy]-,63*6s*661-(3’-pyridyIo~y)-,~ 1-( 3’-quinoIylo~y)-,~ 6,7dimethoxy-l-(2’-dimethylaminoethoxy)-,64 6,7-dimethoxy-l-(4-N-methyl-
'""mN -
1. Isoquinolinois and Their Derivatives
235
48% HBr
n
19
202 alkali
OH
14 n
20
OA r
Ar=
-@
"2'
ZH 5
Q
Scheme 13
piperidyl~xy)-,~~ 1,4-diethox~-,~~ and 1 -(2'-dialkylaminoethoxy)-4-alkoxy-7 isoquinolines and l-(3'-alkylamino-2'-hydroxypropoxy)isoquinolyl ether^.'^ The fact that 1 -chloroisoquinoline is less reactive than 1-bromoisoquinoline is well reflected in their reaction with phenols. Consequently, reaction of the
236
Isoquinolinols and Their Hydrogenated Derivatives
former" requires Ullmann reaction conditions (cuprous oxide and potassium carbonate), whereas the latter" does not. Since 3-chloroisoquinoline is envisaged as a vinylog of 1-chloroisoquinoline, it enters into reaction with sodium methoxide or ethoxide to yield 3-rneth0xy-'~ or 3-eth0xy-,'~ isoquinoline. Analogously, 3-(4-carbethoxyphenoxy)isoquinoline8'is produced. In this case, however, cupric oxide is needed as a catalyst.
Scheme 14
On the contrary, 4-bromo- and 5-bromo- or 5-iodo-isoquinolines exhibit significantly reduced reactivity compared to benzene analogs toward nucleophilic attack by sodium alkoxide, hydroxide, or phenoxide. The presence of catalysts such as copper,8s cupric copper bronze-cupric sulfate,86 azoxybenzene, nitrobenzene, dinitrobiphenyl, and l,l-diphenylethylene62is indispensable to ensure the reaction. This method has been used to produce 4-isoquinolinol (14),864-methoxy (20)-.6' and 4- and 5-(0-methoxyphenoxy)-~~ isoquinolines. An unusual reaction of 1-bromoisoquinoline with quinoline 1-oxide is reported to give 1-(3'-quinolyloxy)isoquinoline.82'B7~88 Alkali fusion of isoquinolinesulfonic acids proceeds normally. In this way, 5-,6790-98 7-,94 and 8-59*90isoquinolinols are obtained. 4,8-isoq~inolinedioI,~~ 5-Aminoisoquinoline is transformed to 5-isoquinolinol by three routes: diazotization followed by hydrolysis with hydrochloric acid92.99or with concentrated sulfuric acid,"' hydrolysis with concentrated hydrochloric acid in a , ~ ~ the sealed tubeg2 or 85% phosphoric acid at an elevated t e m p e r a t ~ r eand Bucherer reaction with 20% sodium bisulfitelO1(see Section I.A.2.e). 5,8-Isoq~inolinediol''~is accessible by nitrosation of either 5- or 8-isoquinolinol followed by reduction of the nitroso function with iron and concentrated hydrochloric acid. Alternatively, oxidation of 5-amino-8- or 8-amino-5-
237
1. Isoquinolinols and Their Derivatives OCH3
NaOCHt CuCla
in a sealed tube b
20
@N
Br
scheme 15
OH
mN
1. NaNOL, d i l . HC1 2. Felconc. H C l
HO
OH
A
5 or 8
Scbeme 16
isoquinolinol with ferric chloride produces these compounds via the p-quinone rnonoxime or rnonoirnine. A chloro group at the 1 and 3 positions is reducible to hydrogen by catalytic or with reduction with palladium on carbon and potassium Raney nickel and sodium e t h ~ x i d e ' ~or ' triethylamine106 or by heating
cH30wN 10% Pd-CIHa
CH3O
CH
CI
KOH, &OH or
NaH.*HzO,
30w OCH,
c H 3 0 m CH3O
b
5% Pd-C/Hz KOH-CzH,OH
A
Scbeme 17
cH30QQ OCH3
238
Isoquinolinols and Their Hydrogenated Derivatives
with hydrazine hydrate.47 An iodo group at the 5 position is hydrogenolyzed with Raney nicke1.lo7 Thus, 8-isoquin0linol~~~ and l - p h e n ~ x y - , '3,6-di~~ methoxy-,lo4 3,7-dirnetho~y-,'~~ 4-ethoxy-,'06 6,7dimetho~y-,4'*'~~ 6,8-dimethoxy-," and 7,8-dirnetho~y-"~isoquinolines are obtained. 3-Acetoxyisoquinoline (22)'08 is derived from 3-aminosioquinoline (21) on reaction with isoamyl nitrite in acetic acid. I-CSHIIONO CHsCOaH
OCOCH
c
22
21 Scbme 18
e. By 0-Alkylation and 0-Arylation 0-Alkylation of 1(2H)-isoquinolinoneis accomplished with alkyl halides with to lead to l-methoxythe aid of a silver saltlog or potassium Io9 or l-[3"(l"-morpholinyl)propoxy]-1'0~''1 isoquinoline. The silver salt (23) enters into reaction with a-acetylbromoglucose (a-ABG) by boiling for a short time in anhydrous toluene giving 1-/?-(tetraacetylglucosyloxy)isoquinoline (25),'12 which is convertible to the a-anomer on prolonged treatment with mercuric bromide. 1-Ethoxyisoquinoline(24)behaves similarly, although its reactivity is much lower than that of the silver salt (23).Thus, the fl-anomer
W N-
/ 0-ABC
toluene
OAg
25
reflux. 10 min
no solvent,
50". 2 days
24 sfbeme 19
28 H
R-COCH,
OR HgBr, toluene
A
1.
Isoquinolinols and Their Derivatives
239
(25) is produced in 2 days by fusion of the two components under pressure, while the z-anomer (26) requires 4 days of heating in toluene.'13 Similarly, 0-
allyllation of 3(2H)-isoquinolinone with ally1 bromide is performed in the presence of silver arb on ate.'^ AgaCO,
W
H
O
W O C H 1 ( H a C H z
CH2=CHCH.Br DUF r.t.
Scheme 20
0-Alkylation of isoquinolinols in general is effected with diazomethl9 or phenyltriane,2 1.54.97.114- 1 18 an alkyl bromide or iodide and base,50*92*1 methylammonium methoxide120.'21 to yield 3-methoxy-,' l 6 4-methoxy-,' l 8 5 - m e t h o ~ y - , ~l 4~ "5-eth0xy-,~' 7-[Z-(carbomethoxy) ethoxy-,' 7-carbethoxymethoxy-.' l 9 6,7-dimetho~y-,~'.' l7 8-rnethoxy-," 5*1203121 8-benzyloxy-7m e t h o ~ y - and . ~ ~ 4,5,6,7-tetrametho~y-~~ isoquinolines.
Scheme 21
0-Silylation occurs also with N-trimethylsilyltrifluoroacetamide to give 5- or 8-trimethylsilyloxyisoquinoline.1z2 The Ullmann reactionlZ3 with aryl bromides under forced conditions or reaction with diaryliodonium bromides' 23 is used for 0-arylation. Thus
scheme 22
240
Isoquinolinols and Their Hydrogenated Derivatives
5-(7'-isoquinolyloxy)-, S-(p-formy1phenoxy)-, 5-(ptolyIoxy)-, 5-(p-methoxy)-, 7-(m-formylphenoxy)-, 7-(p-formylphenoxy)-, 'I-(ptolyloxy)-, 7-(p-hydroxy6-methoxy-7-(p-tolyloxy)-, and 6-methoxy-7-(pmethy1phenoxy)-, methoxyphenoxy)-isoquinolines'23 are produced.
f. By Miscellaneous Reactions Both alkali of papaveraldine (27) and lithium aluminum hydride treatment 12' of 1 1-benzoyl-1,2,5,6-tetrahydro-2,6-imino-8,9-dimethoxy-3benzazocin-4-(3H)-one (28)are reported to produce 6,7-dimethoxyisoquinoline.
cH30wN CH3O
t7 CH 3O cH30@@
28
Isoquinoline, on treatment successively with lithium aluminum hydride and oxygen, is transformed to 4-isoquinolinol (14).'
W N
1. LiAlH,, e t h e r
2. 01, CHC1,
-
mN OH
+
other products
14
On thermolysis of methoxyazabullvalene (29), 1- and 3-methoxyisoq ~ i n o l i n e s ' ~30~ as * ' well as azabicyclo C4.2.21 decatetraene (30)are produced. Hydrogenolytic debenzylation of 2-benzyl-4-hydroxyisoquinolinium chlorides over 10% palladium on carbon proceeds well to yield the isoquin~Iinols.'~'-''~
I. Isoquinolinols and Their Derivatives
Q
+
/
@Q
4
24 1
+
OCH,
woc
ao
20
Boiling a 1 -(2'-benzothiazolyl)-1,2,3,4-tetrahydro-6,7-dihydroisoquinoline-3carboxylic acid with 2N hydrochloric acid causes fission accompanied by partial dehydrogenation to produce 6,7-isoquinolinediol and 3,4-dihydro-6,7isoquinolinediol.' '' The formation of isoquinolines by acid treatment of 1,3-diazabiphenylene (31)'34 or by hetero-Diels- Alder reaction of disilylated iminoether (32)'35 with p-quinone is reported to give 1,3-dimethoxy-'34 or 3,5,8-tria~toxy-"~ isoquinoline.
[&CF3C0.H
CH30H r.t.
cH30Q@
31
(CH, ),C(CH,),SiO (CH,)
YCH2 1.
kH ,C(CH,),Si 0
2.
'0' cR3co@
(CH.CO)IO CHJCOIH A
OCti,
0COCH-j OCOCH,
Isoquinoline 2-oxide reacts with p-tosyl c h l ~ r i d e ' ~ ~to* yield ' ~ ~ 4-(ptosyloxy)isoquinoline, while reaction with acetic anhydride' 37 followed by hydrolysis yields 4-isoquinolinol(l4) and 1(2H)-isoquinolinone.Similarly, reaction of isoquinoline 2-oxide with ethyl benzoylacetate and acetic anhydride gives 4-acetoxyisoquinoline'3* and a 1 -alkylated isoquinoline. g.
By 0-Acylation
3-Acetoxyisoquinoline (22)'08.' 39 is derived from 3(2H)-isoquinolinone on acylation with acetic anhydride in 1N sodium hydroxide or boiling acetic
Isoquinolinols and Their Hydrogenated Derivatives
242
OCOCH,
(CH3CO)rO 1N NaOH
hN- WN OCOC6H!j
C.HsCOC1
OCOC6H,
OH
Scheme 27
anhydride, respectively. Similarly, 8 - b e n z o y l o ~ y -5,8-dibenzoyIo~y-'~~ ~~ isoquinolines are produced.
2. Reactions a. The Reissert Reaction Reaction of isoquinolyl ethers with benzoyl chloride and potassium cyanide10~11~25~L6~29~30-32.54.'40~' or aroyl chlorides such as p-methoxybenzoyl and cinnamoyl chloride and liquid hydrogen cyanide" gives rise to socalled Reissert compounds. 2-Furoy1, 2-thien0y1,'~' or p - t o ~ y l chloride '~~ and ethyl chioroformate' s3 also react. Additionally, isoquinolinols are liable to be 0-benzoylated under these reaction conditions. 5 4
CH30
CH3O CN
p- CH ~ O C ~COCl HQ
CH30
+
OH
Scheme 28
I. lsoquinolinols and Their Derivatives
243
b. Reduction Catalytic hydrogenation' O0 of 4-(p-tosyloxy)isoquinoline (19) over palladium on carbon causes detosyloxylation, while reduction of 4-isoquinolinol(l4) over Adams catalyst yields 5,6,7,8-tetrahydro-4-isoquinolinol.'00
-
OSOzCbH4CH3-
P
20% Pd-C/H.
&N
CaH,OH
19 Scheme 29
A high-pressure hydrogenation [3000 psi (lblin.')] of 5-isoquinilinol over in the presence of sodium hydroxide in ethanol9* is known to Raney nickel (W7) give 2-ethyl-decahydro-5-isoquinolinol(33).
OH
OH C,H,OH, Raney N i /NaOH Ha
A.
c
mN
33 Scheme 30
Hydrogenation of the pyridine moiety of 5-isoquinolinol and 5-methoxyisoquinoline takes place on treatment with formic acid and triethylamine at and 2-formyl-1,2,3,4reflux to give 2-formyl- 1,2,3,4-tetrahydro-5-isoquinolinol tetrahydro-5-methoxyisoquinoline,97 respectively. Similarly, reaction of 6benzyloxy-7-methoxyisoquinolinewith carbon monooxide and water in the presence of rhodium carbonyl complex gives 2-formyl- 1,2,3,4-tetrahydro-6benzyloxy-7-methoxyisoquinoline.'5 5 * 1 5 6 OR
OR
Scbeme 31
244
Isoquinolinols and Their Hydrogenated Derivatives c. Oxidation
Permanganate oxidation160 of 6,7-dimethoxyisoquinolineaffords a mixture consisting of 4,5-dimethoxypthaIic acid and pyridine-3,4-dicarboxylicacid. CH 2
/
+
' O a C o COOH o H CH :io
,HOOC OC@?
KMnO.
c H 3 - 0 m N CH3O 30% H a O a
cH30@@Nv CHJO Scheme 32
Alternatively, oxidation of isoquinolyl ether, with 30% hydrogen peroxide 5-Hydroxyisoquinoline-2-oxideis produced yields their from 5-acetoxyisoquinoline by similar oxidation.98 Treatment of 7-isoquinolinol with oxygen in the presence of cupric acetate and a secondary amine, such as piperidine or morpholine, gives rise to 3,5-dipiperidino- or 3,5dimorpholino7,8-i~oquinolinedione.'~~ Treatment of 5,8-dimethoxyisoquinolinewith cerium ammonium nitrate in aqueous acetonitrile in the presence of 1-0xidopyridinedicarboxylic acid gives rise to isoquinoline-5,8-dione.'59
HO
or norpholine
0 X=cH,
or 0
scheme 33
d. Electrophilic Substitution Nitration of 4isoquinolinol (14)160*'61or 4-(p-tosyloxy)isoquinoline(19)I6O occurs at the 3 position. This fact coincides well with the prediction (see Section
I. lsoquinolinols and Their Derivatives
245
I.A.3.b) that the electron density at that position is highest in the protonated 4isoquinolinol. However, s ~ l f o n a t i o noccurs ~ ~ heteronuclearly at the 8 position. Sulfonation at the 3 position'62 is realized only when the base is heated with sodium sulfite in the presence of manganese dioxide. Another heteronuclear substitution is experienced in the case of nitration of l-ethoxyis~quinoline,~~~ the 5 position being nitrated. Analogously, 6-methoxyisoquinoline gives 5-nitroAction of phosphoryl ~hloride'~on 4-iso6-metho~yisoquinoline.~~~~~~~ quinolinol (14) under pressure results in the formation of 4-chloroisoquinoline.
OR
QH KNO..
conc.H,SO,
50-60"
scheme 34
14
in a sealed tube b
246
Isoquinolinols and Their Hydrogenated Derivatives
As 4-, 5-, and 8-isoquinolinols are likely to be viewed as heterocyclic analogs of a-naphthol, coupling of 4-isoquinolinol (14) with 1 eq of an aryldiazonium chloride occurs at the 3 position, whereas with 2eq of the reagent, reaction occurs at both 3 and I positions."' The same is true for the Mannich reaction166.167 of isoquinolinol.
KNO,,
conc. HaSO.
@N OC2H5
0 ~ 2 ~ 5 scheme 36
&
N=NAr
&
14
N=NAr
scbeme 37
R2NH (1 eq.)
OH
30% CHiO
OH
OH RnNH ( 2 eq.)
30% CH.0
1. lsoquinolinols and Their Derivatives
241
Likewise, 6- and 7-isoquinolinols are regarded as congeners of fi-naphthol. Thus nitration'" and the Mannich r e a ~ t i o n ~of' ' 7-isoquinolinol ~~ take place exclusively at the 8 position. Nitration of 7-methoxyisoqunoline proceeds similarly, leading to 7-metho~y-8-nitroisoquinoline.~~~ However, nitration of 5isoquinilinol with a mixture of concentrated nitric acid and 36% hydrochloric acid produces 6,7-dich1oroisoquino1in-5,8-dione.'
30% C H I O
HO
Scheme 39
e. Nucleophilic Substitution The I position in the isoquinoline nucleus is solely susceptible to nucleophilic attack. In reality, amination'" of 4-ethoxyisoquinoline by potassium amide is shown as the case. Analogously. boiling I methoxyisoquinoline with hydroxylamine hydrochloride in isopropanol containing sodium isopropoxide yields I(2hl)-isoquinoline oxime.' l 2
NH2
SH'S0.H
150-160"
OH 5.6.7. o r 8
W N
"2 scheme 40
248
Isoquinolinols and Their Hydrogenated Derivatives
The Bucherer reaction, however, of 5-9s or 8-" and 6-17'or 7-s9isoquinolin-
01s parallels that of a- and B-naphthols. Reaction of 6,7-dimethoxyisoquinoline
with allyltrimethyltin in the presence of 2,4-pentadienoyl chloride is reported to yield l-allyl-3,4-dihydro-2-(2,4-pentadienoyl)-6,7-dimethoxyisoquinoline.174
f.
Miscellaneous Reactions
Ether cleavage of both l - e t h o ~ yand - ~ ~1-(3'-pyridylo~y)-~' isoquinoline with 48% or constant-boiling hydrobromic acid yields 1(2H)-isoquinolinone. Another type of ether cleavage, in which 3,4-dihydro-l(2H)-isoquinolinoneand a benzene derivative instead of a phenol are produced, is achieved by use of hydrogenolysis with 20% palladium on carbon." Hydrolysis of 2-acetoxyisoquinoline108.17s with 2N sodium hydroxide produces 3(2H)-isoquinolinone. Heating 1-methoxyisoquinoline in the presence of a catalyst causes oxygen-tonitrogen alkylmigration leading to 2-methyl-l(2H)-isoq~inolinone.'~~ Heating 1- and 3-alIyloxyisoquinolines under pressure causes a Claisen rearrangement to yield the usual product^.'^
moCocH3 2N NaOH
%heme 41
3. Properties a. General As for 4-isoquinolinol(l4) and 4,8-isoquinolinediol, the chemical reactivity of the nucleus is estimated in terms of rate constants of deuterium exchange reactions. In particular, a molecular orbital calculation on the former base is correlated to the chemical reactivity with considerable success. Calculations on
1. Isoquinolinols and Their Derivatives
249
heats of atomization by semiempirical self-consistent field-molecular orbital (SCF-MO) method is applied to the prototropic tautomerism of all isoquinolinols indicating that 1- and 3-isoquinolinols exist mainly as isoquinolines, whereas others as the enol forms.'77 b. 4Isoquinolinol A deuterium labeling experiment whereby rate constants of Cisoquinolinol (14) in 94% sulfuric acid-d2"' are calculated with the aid of nuclear magnetic
resonance (NMR) spectroscopy reveals that the ease of exchange follows the order C-3 >C-5 > C-8 > C-6 and that no exchange is observed at the 1 and 7 positions. The calculation is based on the fact that a given NMR peak disappears progressively on heating the isoquinolinol in the medium at 145"C. The standard peaks, that is, peaks at room temperature, are reported as 6: 12.6 (HN+), 8.95 (d, 5 = 8 Hz, C-1), 8.30 (m,C-5 and C-8), 8.14 (m, C-6)*, 7.99 (m, C-7)*, and 7.95 (s, C-3); the starred assignment, however, might well be reversed. the 1 position By an analogous experiment in IN sodium hydr~xide-d,'~**''~ is deuterated but the 3 position is deuterated so much faster (> 100-fold) than the former.
94% DaSO.
1 4 5 ' , 15 min
14
/ D$$$D
hr
45 hr
D
D Scheme 42
NMR peaks in the medium are recorded as 6: 8.36 (s, C-I), 8.31 (complex, C-8), 7.82 (s, C-3), 7.87 (complex, C-5), 7.63 (complex, C-'), 7.55 (complex, C-6).
250
Isoquinolinols and Their Hydrogenated Derivatives OH
OH
OH 1N NaOD
-
145". 5 min
220 rnin
D
I4 scheme 43
It is notable that hitherto known electrophilic substitution reactions such as bromination,"O iodination,"' diazo coupling,16' and the Mannich reaction 167 as well as deuterium labeling take place most preferentially at the 3 position of 4-isoquinolinol(l4). Obvious reaction entities in these neutral (14), and anionic reactions are classified into three species: cationic (M), (36),depending on the reaction media employed. Furthermore, in neutraI medium, 70% of the isoquinolinol is believed to exist in a dipolar form (35) on the basis of tautomerization constant (K,[NH form]/[OH form] = 2.39)177,'82 measured by ultraviolet spectroscopic means; the constant is 3.76 in another report. 83
cationic Corm
34
neutral form
d i p o l a r form
35
14 %beme 44
b a s i c form
36
Thus, a calculation performed on the four possible forms by use of the highest molecular orbital (HMO) r n e t h ~ d ~ ~ ~ . approximately '~~.'~' parallels the chemical data displaying that n-electron density is in the decreasing order of C-3 > C-1 >C-8,7,6,5 in all cases and higher in basic than in acidic medium. A NMRlE4study also confirms the point. c. 4,8-1soquinolinediol Similarly, a deuterium labeling experiment of 4,8-isoquinolinediol in 1N sodium hydroxide-d indicates that the benzene ring possesses a somewhat enhanced reactivity that the pyridine ring; the deuterium exchange rate constants are in the order of K 7 > K3>KS>K1.179*180 This is consistent with the common belief that pyridine relative to benzene is inactive toward electrophiles. The deuterium content at the 1 position of the isoquinolinediol amounts up to 90% on 52-hr heating in the medium.
1. Isoquinolinols and Their Derivatives
@& I N NaOD
1 4 5 ' , 10 min
OH
13-52 hr
D OH
D
D
D
25 1
OH
I
<20 min
OH
Scbome 45
d. Dissociation Constants and Ultraviolet Absorption Bands of lsoquinolinols A pair of pK, values of five isoquinolinols are available as shown in the following parentheses. The first value represent pK,, ,which is given by titration in an acidic medium and the second, pK,, in a basic medium; 4-isoquinolinol (14) (4.80, 8.68)IE6and 5- (5.40, 8.45), 6- (5.85, 9.15, 7- (5.70, 8.88), and 8- (5.66, 8.40) i s o q u i n ~ l i n o l s . Factually, '~~ two prominent features are revealed: (1). the pK,,, value of 4-isoquinolinol (14), is Comparable to that (4.86) of 3-hydroxypyridine; and (2). the largest pK,, value of 6-isoquinolinol suggests that the isoquinolinol is mostly present as a p-quinonoid structure in the medium. Wavelength values calculated for three R - K* adsorptions ('La, 'Lb, and 'Bb) by use of HMOLs6or SCF-MO"' are consistent with those ~ b s e r v e d . ' ~ ~ * ' ~ ~ Since the calculated values for 6-isoquinolinol deviate considerably from those for the enol form, which is a heterocyclic analog of P-napthol and a tautomeric constant measured UV spectroscopically (see Section I.A.3.b) is 1.92, the preceding suggestion for the predominant presence of a pquinonoid form in the isoquinoline is further
B. Quaternary Salts of Isoquinolinols and Their Derivatives
I . Preparation a. By Reaction with Alkyl Halides, Dimethyl Sulfate, and Alkyl p-Toluenesulfonates Isoquinolinols and their ethers are generally converted to the quaternary by the action of a]ky] haljdes,3.4.9.36.42.56.83.97.1 14.120.189-203 aikyl
252
Isoquinolinols and Their Hydrogenated Derivatives
'
p-toluenesulfonates~6~200~204~20s or 2,4-dinitrophenyl chloride.' 5 * 1'6*206 Similarly, 2-methoxyisoquinolinium salts are derived from isoquinoline 2-oxide l o or methyl p-toluenes~lfonate.'~~ with methyl iodide,'07 dimethyl
c10;
b. By Anion Exchange Anion exchange is widely applicable. Thus, chloride or bromide is transwhile chloride is formed to iodide by use of potassium iodide,56*'94.'96,'99.2LL converted to triiodide using potassium triiodide.2'2 Silver chloride2" or perchloratezo7is a useful reagent for the conversion of iodide to chloride or perchlorate. An anion exchanger ((21- type)36*213*214 is also adequate to yield chloride from iodide or picrate. 2-Methoxyisoquinolinium methylsulfate is convertible with 70% perchloric acidzo9 to its perchlorate. Anion exchange by way of pseudocyanide is possible. Thus, the chloride (37)is transformed to the perchlorate (38)on successive addition of potassium cyanide and perchloric acid.215
sebemo 47
37
38
c. By Oxidation
'
Narcotine (39)hydrogen triiodide, on boiling with water,' is reported to give 8-methoxy-2-methyl-6,7-methylenedioxyisoquinolinium triiodide. However, a reliable method to improve the reaction is to make use of an oxidant.
I. Isoquinolinols and Their Derivatives
253
Thus, oxidation with i ~ d i n e ~ l yields ~ * ~ ”the isoquinolinium iodide and its 5iodo derivative, while oxidation with mercuric acetate in the absence2I9 or the presence213 of ethylenediarninetetraacetic acid gives isoquinolinium salts. (Scheme 49). i
%WN.
58
CH3
0
I
OCH3
Similarly, hydrastine (a), on oxidation with iodinez1 or mercuric acetate,’13 yields 2-rnethyI-6,7-rnethylenedioxyisoquinoliniumsalt (Scheme 50).
0-
0‘
OCH3 HVDRASTINE
CH3
1.
1.
2.
MIS
CHO
reflux
I‘
OCH,
40
Catalytic oxygenation of corypalline with platinum blackzo1 is of interest, giving a mixture consisting of the isoquinolinium and 3,4dihydroisoquinolinium salts and dimers. (Scheme 51).
254
Isoquinolinols and Their Hydrogenated Derivatives
+ CHHO ' O
W
N
c1-
Pt-black/O.
. CH3
0.34 NaHCO,
HO
+
CH3 c1-
DIMERS
Scbeme 51
Whereas oxidation of 2-benzyl-2,3-dihydro-4(1H)-isoquinolinones with acetate 13 1.1 32.220.22 1 yields 2-benzyl-4-hydroxyisoquinoliniumsalts, 3-ethoxycarbonyl-2,3-dihydro-4(1 H)-isoquinoline is oxidized to 4-hydroxy-2methylisoquinolinium salts by use of brominezz2or cupnc chloride.222 2-Alkyl-l,2,3,4-tetrahydro-4-isoquinolinolsare converted to 2-alkylisoquinolinium salts on oxidation with N-bromosu~cinimide~~ or potassium ferricyanideZz3followed by subsequent dehydration.
c1-
1. K,Fe(CN). 10N NaOH
L
2. 1N HCl
c1-
c1-
CH3
Scheme 52
6-Methoxy-, 7-methoxy-, and 8-methoxy-6,7-methylenedioxyisoquinolinium salts2' are formed as by-products on heating the respective 1-benzyl-Zmethyl12-dihydroisoquinolines with O.5N hydrochloric acid.
I. lsoquinolinols and Their Derivatives
255
d. By 0-Dealkylation
6-Methoxy-2-methylisoquinolin~um iodide undergoes smooth O-demethylation with 48% hydrobromic acid’” to lead to 6-hydroxy-tmethylisoquinolinium bromide. 48% t i B r
A
C” 3
I-
-
H
o
W
N
: CH3
B r-
e. By 0-Alkylation and 0,N-Dialkylation 0-Alkylation of 6-hydroxy-Zmethylisoquinolinum bromide in acetonitrile is effected by use of a variety of alkyl halides or alkyl p-toluenesulfonates in the presence of soidum carbonate.”’ Both quaternization and 0-alkylation of isoquinolinols occur on treatment with dimethyl sulfate and sodium hydroxide‘” or alkyl iodide and sodium alkoxide.’2 0 * 2 5 4
r4a1C0.
C.HsCHIBr. CHICN.
A
c 7 H 7 0 m N :
Br-
CH3
BrScheme 54
’
f. By Miscellaneous Reactions
* (Section I.B.l .c) of 2-alkyl-3,4-dihydro-4-hydroxyisoquinolinium salts with hot 6N hydrochloric acid proceeds readily to give 2alkylisoquinolinium salts. OH
1. 6N HC1. CIHSOH
CH30 a N ’ C H 3
Br-
CH30
Scheme 55
CH 3
I-
Isoquinolinols and Their Hydrogenated Derivatives
256
Hydrolysis of 2-benzyl-3carbethoxy4hydroxy-6,7dimethoxyis0quinolinium chloride with 2N sodium hydroxide in ethanol followed by boiling in concentrated hydrochloric acid causes facile decarboxylation to yield 2-benzyl-4hydroxy-6,7-dimethoxyisoquinoliniumchloride.131,1 3 2 Heating of a-methylpapaverinol (41)with methyl iodide under pressure,226 boiling of papaveraldine methosalt (42) with potassium hydroxide in or warming of 1,2-dihydro-2-methylpapaverinol(43) in 2% acetic acidzz8causes fission to produce 6,7-dimethoxyisoquinoliniumsalt, which results also from 1,2-dihydro-2-methyl-1-[2’-(6‘-methylpicolyl)]isoquinoline (44) on treatment with 0.1N hydrochloric acid, 0.1N acetic acid, acetic acid in ether, or even with methanol in ether.229
“ CH30 ’
W
#2
CH3-$-OH
OCH3
UCH3 3
X2x CH.COIH & /
x-
=
I-, c1-, c1oa
cH30w /
CH3O
N
”CH 3
43
cH
\
CHSCOIH
ch30
OCH3 OCH3
Sebeme 56
A mixture consisting of 1,5,7,8-tetrahydroxy-tetrahydro-3-methylbenzazepin2-one (45) and 1-carboxy-4,6,7-trihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (a), which is formed by the phenol cyclization of an N-methyl-N-(Bhydroxyphenethy1)amineand glyoxylic acid, on boiling with thionyl chloride, yields 6,7dihydroxy-2-methylisoquinoliniumchloride.z30 N-~-(3’-Indolyl)ethyl]isoquinolinium salts (47) (1 96) are produced when 2-phenacylisoquinolinium bromides react with trimethylskatylammonium
257
1. Isoquinolinols and Their Derivatives
HO
c1-
Br-
CH3
1. KOH-CHIOH r.t.
2. CHrCOiH
w
c
H
2+ N; CH3 )3
H
47
H scheme 58
methylsulfate or iodide in the presence of methanolic potassium hydroxide followed by neutralization with acetic acid. Reaction of 1,2-dihydroisoquinolineand a phenylglyoxal with concentrated hydrochloric acid and subsequent boiling in aqueous hydrochloric acid produces an N-phenacylisoquinoliniumsalts.” * Aziridine derivatives, formed on photolysis of indenone and phenyl aides, upon further irradiation in the presence of cis-dichloroethylene produce 4-hydroxy-2-phenylisoquinolinium~hloride.’~
’
258
Isoquinolinols and Their Hydrogenated Derivatives
scheme 59
1. C.H.N.
n- hexane 2. hw benzene
NC6H5
I
0 cis-1.2-dichloroethylene
hw
OH
c1-
2. Reactions a. Reduction Hydrogenation of isoquinolinium salts to 2-alkyl-l,2,3,4tetrahydroisoquinolines is achieved by use of tin and hydrochloric a~id,’~.’~’ zinc and diluted sulfuric acid,233 Adams catalyst,36~97~’95.2z4~z34-236 palladium on carbon,’ * or-more conveniently-sodium borohyd~de.36.42.97,1Z0.123,199,2 15.225.228.237-239
Lithium aluminum hydride reductiod6 of an isoquinolinium salt, however, results in partial reduction and the formation of 1,2-dihydroisoquinoline. Reduction of 2-benzyl-4-(p-tosyloxy)isoquinoliniumbromide with sodium borohydrideZJgor sodium cyanobor~hydride’~~ in pyridine produces either 2benzyl-1,2,3,4-tetrahydro-4-oxoisoquinolineand 2-benzyl-l,2,3,4tetrahydro-4isoquinolinol or the former product alone.
259
1. lsoquinolinols and Their Derivatives NaBH,
cCH3O H 3 0 m N +w
5
50% MeOH
CH 30
C2H5
c1-
CH
‘-b LiAlH.
THF
CH30W N ’
0
CH3O
H3
OCH
Scheme 61
When refluxed with formic acid and triethylamine,” 5-hydroxy- and 5methoxy-2-methyiisoquinoliniumiodides are reduced to 1,2,3,4-tetrahydroisoquinolines (see Section I.A.2.b). 2-Ethyl-5-hydroxyisoquinoliniumhydroxide is completely reduced to the decahydro-5-isoquinolinol(49) on hydrogenation with Adams catalyst under pressure in an acidic r n e d i ~ m , ~whereas ~ ~ . ~ ~the ’ bromide (48) forms the ether (50) shown in Scheme 62.L34.235
Scheme 62
260
Isoquinolinols and Their Hydrogenated Derivatives
In contrast, 5-hydroxy-2-methylisoquinoliniumtosylate is reduced to a mix(2 : 1) ture consisting of the cis,cis- and trans,trans-decahydro-5-isoqu~nolinols [(51):(52)J by use of A d a m catalyst under forced condition^.'^^
scheme 63
On the contrary, 10% palladium on carbon in the presence of hydrochloric acid is not so powerful as to induce nuclear hydrogenation. Thus, the nitro group of an isoquinolinium salt is selectively reduced to an amino
scheme 64
b. Oxidation
An isoquinolinium methylsulfate undergoes fission of the pyridinium ring on oxidation with potassium permanganate in aqueous potassium hydroxide’” to produce a 6-methyicarbamylphenylglyoxylicacid. Oxidation of 2-methylisoquinolinium salts with potassium ferri~yanide’~~*’~’ in the presence of alkali produces 2-methyl-l(2H)-isoquinolinones,the rational intermediate being pseudobases.
KCN-Ha0 or
CH3O
NazCOs-H1O
NO2 R=CN, OH Scheme 65
NO2
1. lsoquinolinols and Their Derivatives
26 1
c. Nucleophilic Substitution Unlike 3,4-dihydroisoquinoliniumsalts [see Section II.B.2.a). 6,7-dimethoxy2-methylisoquinolinium salt produces no pseudobase at pH 13. To render the carbon-nitrogen double bond sufficiently reactive to enter into the reaction, a strong electron-withdrawinggroup such as 2,4-dinitrophenyl instead of methyl must be attached at the nitrogen atom. Thus, 2-(2'.4'-dinitrophenyl)isoquinolinium salts react with potassium cyanide' l 5 or aqueous bases, including diluted ammonium hydroxide,' 2 6 sodium carbonate,' and sodium hydrogen carbonate' to yield pseudocyanides or pseudobases. In particular, when 2-(2',4'-dinitrophenyl)isoquinolinium chloride is treated with sodium carbonate or ammonium hydroxide, a mixture consisting of the pseudobase (53) and the open-chain aminoaldehyde (54) is produced. The formation of the latter is ascribable to the strong electron-withdrawing effect of 2,4-dinitrophenyl group. With sodium or potassium hydroxide the dimeric compound (55) is produced.2432-(2',4'-Dinitrophenyl)isoquinolinium chloride (56)reacts with a methoxystyrene in the presence of base to give a Diels-Aldertype adduct (57).244
''
''
CH3O cH30@@Ar
Pseudobase formation, however, is experienced by adopting drastic conditions. Thus, 2-phenethylisoquinolinium salts, when boiled with 40% sodium hydroxide:*24' undergo the pseudobase formation followed by disproportionation to give first 2-phenethyl- 1(2H)-isoquinolinones and 1,Zdihydro-2phenethylisoquinolines, both of which are cyclized to 10-oxotetrahydroprotoberberines and tetrahydroprotoberberines with hydrochloric acid.
262
lsoquinolinols and Their Hydrogenated Derivatives
ch30 & m ‘ArN *r+ CaCO,
56
CHIOH 40°
p
3
57 CH3O OCH3 Scheme 67
-:?
2. I . 40% HCI. NaOH, r.t. A
OCH,
+
OCH,
OCH3
scbeme 68
A 2-(2’,4‘-dinitrophenyl)isoquinolinium chloride reacts with phenyl- or p brom~phenyl-hydrazine~~~ to yield the benzimidazoC2,l-a]isoquinoline (58). The essential feature of this reaction is nucleophilic attack of the hydroxylamino group generated in situ on the 1 position. The same condensed heterocycle is also produced when a 2-(2’,4‘-dinitropheny1)isoquinoliniumchloride is boiled in water with copper tetraammonium sulfate.240 Formally, isoquinolinium salts are liable and react with Grignard re1,2-dihydroisoquinolines.Their a g e n t ~ ~ ~at *the* 1~position, ~ ~ - producing ~ ~ ~ instability, of which in part however, prohibits their actual isolation’2 with the
I. Isoquinolinols and Their Derivatives
263
58 Scheme 69
exception of two examples. One is the reaction of 0-methyltarconine iodide (59) with phenylmagnesium bromide,z4s giving the 1,2-dihydroisoquinoline (a), the successful isolation of which is probably due to homoconjugation in the product, and the other the reaction of the 4-hydroxyisoquinolinium chloride (61) with methylmagnesium iodidezz' yielding not a 1 ,tdihydroisoquinoline but the I ,2,3,4-tetrahydro-4-oxoisoquinoline (62).
CHsHgI ether
61
c1-
C7H7
62
CH3
Scheme 70
Although unsubstituted isoquinolinium iodides enter into reaction with nitrotoluenes in the presence of sodium alkoxides to yield 1,2-dihydroisoquinolines, 7-methoxy-2-methylisoquinoliniumiodide does not react even with
264
Isoquinolinols and Their Hydrogenated Derivatives
2 , 4 d i n i t r o t o l ~ e n e This . ~ ~ ~fact is explained in terms of an unfavorable assistance of the methoxyl group to the generation of a carbonium ion at the 1 position. d. N-Dealkylation
A reliable method for N-debenzylation of a 2-benzylisoquinolinium salt is hydrogenolysis with 10% palladium on carbon.' 3 1 Alternately, 2-methyl- and 2(2',4'-dinitropheny1)isoquinolinium salts are Ndemethylated and N-dearylated by heating with concentrated hydrochloric acid under pressure2 l 6 and with '~~ aniline, p-toluidine, or p i p e ~ i d i n e , " ~ . respectively.
cow. HCl
CH30
b i n a s e a l e d tube
c1-
'
0
W CH30
N
7
Scbeme 71
+ ANr@ H-N02
CH3O p i p e r f d i n e , C.H.OH
O2N or
Ar = C,H,
p-CH,C,H, 02N' Scbeme 72
265
1. Isoquinolinols and Their Derivatives
e. Miscellaneous Reactions Bromination’ of 0-methyltarconine chloride with bromine takes place at the 5 position. is accessible An o-quinonoid compound, 2-methyl-3(2H)-isoquinolinone(a), on treatmente3 of 3-methoxy-2-methylisoquinolinium iodide with 1N sodium hydroxide (63).
Br
63
1
64 Sebtmt 73
Heating 2-methoxyisoquinolinium perchlorate with phenyl sulfinate gives isoquinoline 2-oxide, while heating with piperidine produces a mixture of the oxide and i s o q ~ i n o l i n e . ~ ~ ~
I piperidine
c10;
I
W N
‘0
3. Properties a. pK, Values halides are measThe pK, values of several hydroxy-2-methylisoquinolini~m
red'^^-^^^ as described in the following parentheses: 4(4.93)-,5(6.90)-, q6.02)-,
7(7.09)-, and 8(5.8 l)-hydroxy-2-methylisoquinoliniumchlorides and 5-hydroxy-
266
lsoquinolinols and Their Hydrogenated Derivatives
2-methylisoquinolinium idodide (6.78). It is noteworthy that the smallest value of 4-hydroxy-2-methylisoquinoliniumchloride is almost equal to that of 4isoquinolinol (see Section 1.A.3.d) and that the smaller values of 6- and 8hydroxy-Zmethylisoquinolinium chlorides are reminiscent of stabilization due to the full conjugation of the anionic charge at their phenolic oxygen atoms with their quaternary nitrogen.
11. DIHYDROISOQUINOLINOL!3 AND THEIR DERIVATIVES A.
3,4-Dihydroisoguinolinolsand Their Ethers
I.
Preparalion
a. By Ring Closure 3,4-Dihydroisoquinolyl ethers are formed by the Bischler-Napieralski reaction on phenethylamides using phosphoryl chloride,l0.' 1.36.40.47.232,250-274 phosphorous p e n t a c h l ~ r i d e , ~phosphoryl ~ ~ - ~ ~ ~ chloride and phosphorus p e n t a ~ h l o r i d e , ' ~phosphorus ~ p e n t o ~ i d e : ~ * ~ or ~ ~ polyphosphoric ~~~-~~~ acidzE2in an anhydrous solvent such as toluene, benzene, acetonitrile, and chloroform. The following compounds are prepared in this way: 3,4isoquinolinols dihydr0-6-methoxy-5-~~~ and 3,4-dihydr0-6-methoxy-7-~~~*~~~ 3,4-dihydr0-5,6-dimethoxy~~*~~~*~~~ 3,4-dihydr0-5,8-dimethoxy-$~ and 5-ethoxy-3,4-dihydr0-6-methoxy-,~~~.~~~ 6-ethoxy-3.4-dihydr0-8-methoxy-,~~~ 3,4dihydr0-6-rnethoxy-,~~~*~~~ 6-ethoxy-3,4-dihydr0-,~~~ 3,4-dihydro6,7-methylenedioxy-,44.2 50.2 56.2S7.2 76- 2 78.2 8 3 3,4-dihydro-6,7-dimethoxy-,lo.
1 1,42.44.47.259,260.266,269.275.280.282
~ e ~ ~ o x y ~ ~ , ~ ~ ~ y ~ r ~ m e ~ ~ o x y ~ , 2
6-ethoxy-3,4dihydr0-7-rnethoxy-,~~~7-benzyloxy-3,4-dihydr0-6-methoxy-~~~*~~~ 3,4-dihydr0-6,8-dimethoxy-,~~~ 6-benzyloxy-3,4-dihydr0-7-methoxy-,~~ 3,4-dihydr0-6,7,8-trimethoxy-,'~~3,4-dihydro-8-methoxy-6,7-methylenedioxy2so~2s1 (norcotarnine) (ll)-, 7-benzyloxy-3,4-dihydr0-6,8-dimethoxy-,~~~ 6-benzyloxy-3,4-dihydr0-7,8dimethoxy-,~~~*~~~*~~~*~~ 8-benzyloxy-3,4dihydro-6,7dimetho~y-,~~ and ~ . ~3,4-dihydr0-6,7-dimethoxy-8-phenoxy-~~' ~~.~~~ isoquinolines. The para position, whenever it is unoccupied with an alkoxyl group, is always the site of cyclization. When ring closure is possible in two directions, some regioselectivity is (65)cyclizes possible. Thus, 5-methoxy-3,4-methylenedioxyphenethylformamide regiospecifically ortho to the methoxyl group yielding norcotarnine (ll).250*2s1 In the case of 3-benzyloxy-4,5dimethoxyphenethylformamide(66),the 8-bemyloxy regioisomer (67) is somewhat preferred to the 6-benzyloxy (68);262.26s the former is separable as its ~ a l i c y l a t e . ~ ~ ~ Sometimes d e b e n z y l a t i ~ ntakes ~ ~ ~place * ~ ~in~the reaction of 4-benzyloxy-3methoxypheneth ylformamide.
11. Dihydroisoquinolinols and Their Derivatives
c H 3 0 v N H C H 0
POCl,
c
H
3
0
a
267
N
Scheme 75
Heating cotarnone (69)with ammonia in the presence of potassium hydroxide under pressure gives rise to a Cope-type cyclization producing norcotarnine (1 1).2844.285
b. By Dehydrogenation (Oxidation) Oxidation of 1,2,3,4-tetrahydroisoquinolinesto 3,4-dihydroisoquinolinesis ~~*~~~~~~~ realized with the aid of sodium h y p o ~ h l o r i t e , ~N-bromosuccinimide,56*288s289 Fremy's 5% potassium ~ e r r n a n g a n a t e ~or ~ ' ruthenium chloride-phosphine complex, and t e r t - b ~ t y l p e r o x i d e . Selected ~~~ examples are 3,4-dihydr0-5,7-dimethoxy-,~~'3,4-dihydro-6,7-dirnetho~y-,~~~*~~~ 3,4-dihydro-6,8-dimeth o ~ y - , ~ ~ ' 6-benzyloxy-3,4-di hydro-7-met h ~ x y - , ~ ~ ' 8-benzyloxy-3,4-dih y d r 0 - 6 , 7 - d i r n e t h o x y - , ~3~,4~ d~ihydro-8-methoxy-6,7~~~*~~~ m e t h y l e n e d i ~ x y - , ~3,4dihydr0-7,8-dimethoxy-,~~~-~~~ ~~.~~' and 3,4-dihydro-8methox y-' 2o isoquinolines and 3.4-dihydro-7,8-dimethoxy-4-isoquinolinol.56 3,4-Dihydro-6,7-dimethoxyisoquinolineis produced on electrolysis of Nnorarmepavinetg3 or its oxidation with p e r o x i d a s e ~ Alternately, .~~~ it is pro-
Isoquinolinols and Their Hydrogenated Derivatives
268
N-bromosuccinimide CHC1..
CH30 dCH3O N
r.t.
ch30 CHJO
H Scbeme 77
duced on oxidation of tetrahydropapaverine (70) and its N-benzoyl derivative’96*297with manganese dioxide and diluted sulfuric acid.29s in Photolysis of 1,2,3,4-tetrahydro-6,7-dimethoxy-2~p-tosyl)isoquinolineZ98 the presence of sodium carbonate or N-nitrosotetrahydropapaverineand in the presence of concentrated hydrochloric acid299causes elimination of p-toluenesulfinic acid or a benzyl group leading to a 3,4dihydroisoquinoline.
-
CH3O
b 02
d i l . H,SO,
OCH3 hV, 80% CzHsOH-HzO Na2C0,
cCH30 H 3 0 m N . SO~C~H~CH~-P
CH30
-
c
ch30H
3
0
a
N
Scheme 78
c. By 0-Dealkylation Whereas 0-demethylation occurs by use of concentrated hydrochloric concentrated hydrobromic acid,263*267*300 and aluminum chloride or 0-debenzylation is easily effected by 20% hydrochloric Thus, the following compounds are produced: 3,4-dihydr0-6-’~~and 3,4dihydr0-6,8-dimethoxy-7-’~~ isoquinolinols, and 3,4-dihydr0-6,7-~’’ and 3,4dihydr0-7,8’~~isoquinolinediols. 62% HBr
HO 20% HC1
HO
sdmae 79
11. Dihydroisoquinolinols and Their Derivatives
269
Partial demethylation of 3,4-dihydro-6,7-dimethoxyisoquinolinewith concentrated hydrobromic acid produces 3,4-dihydro-6-methoxy-7-isoquinolino1’00 as a major product. Much success, however, is attained by use of 6 2oh 267 under strictly and 48%267*J0’.302 hydrobromic or 20% hydrochloric controlled conditions. The following compounds are produced in this way: 3,4-dihydr0-6-methoxy-5-,~~’ 3,4-dihydr0-8-methoxy-5-,~~~ 3,4-dihydro-53,4-dihydr0-8-methoxy-6-,~~’ 3,4methoxy-7,2673,4-dihydr0-7-methoxy-6-,~~~ isoquinolinols. dihydr0-6-methoxy-7-,”~ and 3,4-dihydr07-methoxy-8~~~ One factor to bring about the reaction is obviously stenc in origin. Thus, 3,4dihydro-6,8-dimethoxy-7-isoquinolino1264results from 3,4-dihydro-6,7,8trimethoxyisoquinoline by use of concentrated hydrochloric acid, aluminum trichloride, or aluminurn tribromide.
48% HBr
CH30b
“”@3 CH 3O
CH36
A
N
cow.
HO
HCl
or AlCl,
or AlBr,.
CSz
=
HO CH30
d. By Miscellaneous Reactions Two pentacyclic compounds (71) and (72) undergo fragmentation with hot 3-5N hydrochloric acid to produce 3,4-dihydro-6,7-dimethoxyisoq u i n ~ l i n e .From ~ ~ ~ the ~ ~ ~former, ~ 2-(~-cinnamoylethyl)3,4-dihydro-6,7dimethoxyisoquinoliniumchloride (73)303is also obtained as counterpart in the reaction. Analogous fragmentation occurs as a side reaction when an ethyl 20x0-1 1bH-benzo[a]quinolizidine-3-carboxylate is treated with hot 10% hydrochloric a ~ i d . ’ ~ ~ . ’Retrogression ’~ (retro-Michael and retroaldol) of 2-0x0hydrobenzo[~)quinolizidine and its derivatives takes place in boiling acetic acid or aqueous barium hydroxideJo6 to yield a dihydroisoquinolyl ether and a methyl vinyl ketoneJo7(see Section ILA.2.c). Reaction of 3,4-dihydro-1(2H)-isoquinolinones (74) with triethyloxoniurn tetrafluoroborate yields 1-ethoxy-3,4-dihydroisoquinoline(75).’08 A glycol-cleavage of a 1,2,3,4-tetrahydro-l-(a-hydroxybenzy1)isoquinoline (76) with periodic acid is known to give a 3,4-dihydroi~oquinoline.~~~ 3,4-Dihydro-6,7-isoquinolinediol is formed on refluxing 1-@‘-benzothiazoIyl) 1,2,3,4-tetrahydrod,7-dihydroxyisoquinoline-3-carboxylicacid with 2N hydrochloric acid”’ (see Section l.A.l.f). U-Methylation of the diol yields 3,4-
dihydro-6,7-dimethoxyisoquinoline.
Isoquinolinols and Their Hydrogenated Derivatives
270
5 N HC1
A
RxCH3,
C2H5
72
cH303H CH3O
HIO.
1N H,SO.
76
Scheme 82
2. Reactions a. Reduction See Section IV.A.1.b. b. Oxidation
Oxidation of a 3,4-dihydroisoquinolylether with potassium pemanganate2" yields a phthalic acid.
11. Dihydroisoquinolinols and Their Derivatives
27 1
c. Nucleophilic Substitution The carbon at the 1 position of 3,4-dihydroisoquinolinesis susceptible to nucleophilic attack, if properly activated by a residing positive charge on the nitrogen of the carbon to nitrogen double bond (see Section I.B.2.c) or by modifying the double bond to an imino ether [see Section I.A.2.e). Carbethoxy, cyano,309-3'2m a l ~ n y l , ~and ~ ~benzoy13" -~'~ acetic acids react with a 3,4-dihydroisoquinolyl ether leading to l-alkyl-1,2,3,4-tetrahydroisoquinolines. The six-membered hydrogen-bonded species (77) involving both the reactant and the reagent is believed to be an active intermediate whereby activation of the carbon and creation of an intramolecular nucleophile are secured simultaneously.
..H m .0CH30 c3N.
77
OH
x
CH " m CH30
N
.
.
o\ 78
" 0
F' cc13
scheme 84
The similar intermediate (78) must be responsible for the formation of the 1trichloromethyl-l,2,3-4-tetrahydroisoquinoline (79) when the dihydroisoquinolyl ether reacts with trichloroacetic On reaction of the dihydroisoquinolyl ether with formalin and active methylene compounds such as dialkyi malonates, alkyl cyanoacetates, cyanoacetamide, ethyl benzoylacetate, mal~nodinitrile,~"and acet~acetamide,~'~ the benzo[a]quinolizidine (80) is obtained. Apparently, two kinds of the Mannich reaction are involved. The same ring system is constructed on reaction of the dihydroisoquinolyl ether with methyl vinyl ketone in the presence of 3N sodium hydroxide3" or on boiling of its hydrochloride with paraformaldehyde and N,N-dialkylacetoa~etamides.~ ' In the former the Michael and aldol reactions are responsible for the formation; in the latter, the Mannich and aldol reactions. Numerous reactions of 3,4-dihydroisoquinolyl ethers with acyclic or cyclic x,B-unsaturated ketones, esters and lactones under acidic conditions give benzo[a]quinolizidine derivatives.319-330 The reaction with lithiated methyl or methylene compounds proceeds to give dibenzo[a,e]quinolizidines, which are
212
Isoquinolinols and Their Hydrogenated Derivatives
C1 ICCOSH
7g
CCI,
Scheme 85
%heme 86
obtained by a thermal reaction with l-cyanobenzocyclobutene.331-334 Similarly, reaction with malonic acid or its monoester gives l-carboxy- or 1carboalkoxy-methyl-1,2,3,4-tetrahydroisoq~inoIine.~~~*~~~ N - A ~ y l a t i o n ’ ~ ’ -is~also ~ ~ a means to activate the carbon at the 1 position and nucleophilic attack on the imino ether308is a matter of simplicity. Representative examples of these reactions are depicted in the following schemes. d. Miscellaneous Reactions B r ~ m i n a t i o no ’f~norcotarnine ~ (11) takes place at the 5 position as expected. Nitration of 3,4-dihydro-6-methoxy-7-isoquinolinolproduces 8-nitro-3,4di hydroisoquin~linol.~~~ On reaction of the 3,4-dihydroisoquinolylether (81) with aluminum amalgam in moist ether the dimer, 1,l-bis-tetrahydroisoquinolyl(82). is produced.
11. Dihydroisoquinolinols and Their Derivatives CHjCO
165’ In a 6sealed C H rube 3
-
273
::::q?J
cH30mN -
(CH2) 2CH(OH) CH3
0
CH3O
N.H.-HaO CaH,OH
N& OC2 H5
NHNH,
!+heme 88
84
274
Isoquinolinols and Their Hydrogenated Derivatives
A 3,4-dihydroisoquinolylether yields the Reissert compound (83)(see Section I.A.2.a) when treated with benzoyl chloride and potassium ~yanide.’~’ -343
83 scheme 90
Reaction of a 3,4dihydroisoquinolyl ether with an acid chloride in dichloromethane in the presence of aqueous sodium hydrogen carbonate is also known to produce 2-aminoethylbenzaldehyde derivative^.^^*^^^
B. Quaternary Salts of 3,4Dihydroisoquinolinolsand Their Derivatives
I . Prepurution a. By Reaction with Alkyl Halides and Sulfonates Quaternization of the parent compounds is performed by a routine method with alkyl halidesZ53.255.258,259.261.264-266.268.269,274.280,286,289,296.297, 313.314*321346-365 or dimethyl A pseudobase is converted to an iodide on treatment with methyi b. By Anion Exchange
~ ~iodide369 ~ ~ is ~useful ~ for ~ the~ anion ~ ~ Silver ~ h l o r i d oresodium exchange (iodide to chloride or vice versa). While a bromide is transformed to a picrate on mere treatment with picric acid,346a chloride in hydrochloric acid is transformed to a hydrogen bichromate on contact with potassium bichromate.370Hydrotetrafluoroboric acid is also used for the anion exchange (iodide to tetrafluoroborate).’ c. By Ring Closure
2-Alkyl-3,4-dihydroisoquinolinium salts are prepared directly from phenethyl-alkylformamides by the Bischler-Napieralski cyclization with use or thionyl of phosphoryl chl0ride,2~1.346*372*373 phosphorus pento~ide,2~’ ~hloride.~~~*”~ 1. SOC1,.
CHO
benzene,
A
under reduced pressure
*me
91
CH30
c1-
CH3
~
~
11. Dihydroisoquinolinols and Their Derivatives
275
d. By Oxidation
Phthalide isoquinoline alkaloids such as narcotine (39)219*332*376-384 and aldlumidine or capnoidine (84)3a5undergo oxidative degradation with manganese dioxide and diluted sulfuric a ~ i d , ~ ’ ~ . ~chromic ’’ acid and diluted hydrochloric acid,2* barium ~ermanganate,”~or warm diluted nitric a ~ i d ~ ~ ~ . to~ yield ~ ’cotarnine . ~ ~ salts ~ (85). . ~ Cotarnine ~ ~ . (86) ~ ~is pro~ . ~ ~ ~ duced when narcotine (39) is oxidized with the last oxidant and successively treated with potassium or sodium h y d r o ~ i d e . ~ ~ ~ * ~ ~ ~ . ~ ~ ~ ~
3
NARCOTINE
@&
(WLCH
/
OH
CH3O
COTARNINE
86
0 J 0 A D L U M I D I N E or C A P N O I D I N E *me
Hydrastinine
salts
(87)
are
92
similarly
obtained
from
hydrastine
(40)381*382*386-3a8 and adlumine (88).389 Heating of hydrastine (40)with chloroplatinic acid in concentrated hydro-
chloric acid also causes fission to yield hydrastinine c h l o r ~ p i a t i n a t e . ~ ~ ~ The oxidative degradation is of general character. Thus, 1-benzy1-1,2,3,4tetrahydroisoquinolinolyl ether^,^^^*^^^-^^^ including laudanosine (89),393*394 undergo oxidative debenzylation by use of manganese dioxide and diluted sulfuric a ~ i d ~ ~ or~ mercuric - ~ ~acetate.394 ~ * ~ ~ ’ * ~ ~ ~ The same type of reaction is realized by use of electrolytic or biomimetic and oxidation of oxidation. For example electrolysis of armepavine armepavine (!XI) and N-methylcoclaurine with p e r o x i d a ~ e . In ~ ~addition, ~*~~~
276
Isoquinolinols and Their Hydrogenated Derivatives
CH3
Xscheme 93
cH30z&!kcH3 CH3O
X-
or peroxidase/HaO,
OH scbeme 94
the pseudocyanide (91) is oxidized with iodine to a 3,4-dihydroisoquinolinium triiodide, which when treated with sulfurous acid yields the iodide (92).370 Oxidation of 2-alkyl- or taryl-l,2,3,4-tetrahydroisoquinolinols and their ethers to 3,4-dihydroisoquinolinium salts is performed with iodine,233,368.369.379.J9L-402 mercuric amtate,220.399-404 N-bromosuccinim-
11. Dihydroisoquinolinols and Their Derivatives
N-bromosucclnlmide
CHCl3
CH3O
&N-
CH
277
-
CH30&NkH3
B r-
sebeme 95
ide," 1.288.405*406 sodium h y p o ~ h l o r i t e ,potassium ~ ~ ~ * ~ ~dichromate ~ and sulfuric a~id,4*~" chromic acid and sulfuric acid408 or oxygen and platinum black. O e. By 0-Dealkylation 0-Deaikylation of 3,4-dihydroisoquinoliniumslats is of some synthetic utility. Thus, demethylation is effected by heating with hydrobromic aluminum chloride,409 or hydrochloric acidq1' under pressure. By use of concentrated hydrochloric acid4' debenzylation takes place selectively with no damage to the methoxyl group in the molecule. Demethylation is possible with the aid of aluminum chloride409or phospho' rus penta~hloride.~' conc. HC1
A
145- 150"
CH3d
CH3O ' O
HO
X-
f. By Miscellaneous Reactions
m
N
: CH3
CH3
Certain types of benzo[u]quinolizidines (e.g., '' A ' undergo a retroMannich reaction to yield 3,4-dihydroisoquinolinium salts when boiled in ethanolic hydrogen chloride.31
Isoquinolinols and Their Hydrogenated Derivatives
278
80 scheme 97
A fragmentation reaction, that is, elimination of the substituent at the 1 position of 1,2disubstituted 1,2,3,4-tetrahydroisoquinolyl ethers including psedo~yanides,"~*~'~ and 1-anilino (93),416*417 1and l-ethoxy4*5*416*418 congeners nitromethyl,4'2 l-(dicarbetho~y)methy1-,~*~ ~ ~ ~ *hydro~~~,~~~.~ takes place on treatment with h y d r o ~ h l o r i ~ , 5*416 ~ ~ ~or bromic,39f .4 6-4 18 hydroiodic,370 pic.ic,393.4 14 or c h l o r ~ a u r i cacid methyl iodidetE9to give 3,4-dihydroisoquinolinium salts. Similarly, a pseudosulfide and a peroxide derived from cotarine (86), on respective treatment with hydrogen sulfide and peroxide produce cotarnine chloride, iodide, or chloroplatinate419 when treated with hydrogen chloride in benzene, methyl iodide, or chloroplatinic acid. Cotarnine itself reacts with methyl iodide to yield cotarnine iodide and cotarnine methine methiodide (94).420
04
scbemc 98
In the case where an eliminating oxygen function is bound to the molecule, a protonic acid is ineffective to bring about the reaction. Consequently, a 3,4,6,7tetrahydro-2H,ll bH-[ 1,3]-oxazino[2,3-~]isoquinoline (95) is cleaved with acetyl or benzoyl chloride353yielding 3,4dihydroisoquinolinium salts. In contrast, protonic acids are still applicable to the reaction when a nitrogen function is the eliminating group. Thus, the 1,3-diphenyl-2-oxo-l,2,3,5,6,lObhexahydroirnidazo[2,l-~)isoquinoline (96) or the 1,2,3,4,6,7-hexahydro-11bHpyrimidoC2,l -aJisoquinoline (W)undergoes fragmentation with 0.1N hydro-
11.
Dihjdroisoquinolinols and Their Derivatives RCOCl
ether or benzene ref lux
CH 30
-
279
cCHH303 0 ~ N t ( C t 1 2 ) ,OCOR
c1-
05
C6H5
0.1N HC1
abs. C.H,OH
Scheme loo
chloric acid4” or with hydrogen chloride in ethanol4” to yield a 3,4-dihydroisoquinolinium chloride. The hydrochloride of 3,4-dihydroisoquinolylethers and a$-unsaturated carbony1 compounds enter into the Michael reaction to give 3,4-dihydroisoquinolinium ~ h l o r i d e s . ~ * ~ ~ * ~ ~ - ~ ~ ~ Reduction of the isoquinolyl ether with diborane yields the 3,4dihydroisoquinoline- bordne adduct (98),426which is a potential precursor to a 1,2,3,4-tetrahydroisoquinoline(see Section 1V.A.I .e).
BH>-THF 2-3”
-
CH ’ 0 CH30
~
98 Scherne 101
N
~
&
3
Isoquinolinolsand Their Hydrogenated Derivatives
280
Sodium in liquid ammonia in the presence of ethanol cleaves the methylenedioxy group of cotarnine chloride with concomitant removal of one hydroxyl group to produce 3,4-dihydro-6-hydroxy-7-methoxyisoquinolinium salt.369
Heating of 3,4-dihydro-l -diphenylhydroxymethylisoquinolineZZ6with methyl iodide under pressure and an undetailed treatment of a l-benzyl-3,4-dihydro-2rnethylisoquinolinium salt203yield 3,4-dihydro-2-methylisoquinolinium salts.
2. Reactions a. Nucleophilic Substitution Since the electrophilic character of the carbon at the 1 position of 3,4-dihydroisoquinolinium salts is greatly reinforced by the positive charge on the nitrogen, pseudocyanides (e.g., 99) and pseudobases (e.g., 88 or 100)
are
readily
produced
on
treatment
of
the
salts with
potassium sodium
C y a n ~ ~ e 2 8 4 , 2 8 0 , 2 9 7 , 3 O 3 , 3 l 7 . 3 4 6 . 3 S 3 , 3 6 4 , 3 6 8 , 3 9 3 . 3 9 7 , 4 O S . 4 O 9 , 4 l ~ , 4 2 7 - 4 3 Oand
or potassium hydroxide212.254.3 10.3 13.~14,368.37S.307.391-393.397.407.408,412.416. 420*43 -433 or t~iethylamine,'~respectively. Cotarnine chloride is transformed to a pseudosulfide or hydr~sulfide.~'
cH30qN 1 CH3O
I
NaOH-Ha0
Scheme 103
The phenomenon that the pseudobase (101) turns yellow in polar solvents is due to the appearance of the quaternary ammonium species (102). Thus, the establishment of an between the carbinolamine (101) and the
28 1
11. Dihydroisoquinolinols and Their Derivatives
quaternary ammonium hydroxide (102) is widely accepted mainly on the basis of ~ ~ ~ -the ~ * 'measurement of electrical the ultraviolet s p e c t r o s c ~ p i c ~ ~ ~ -and cond~ctivity.*~~**~~ The former method also confirms that the pseudosalts derived from a pseudobase by the action of sodium hydrogen sulfide or sulfurous acid change into the true salts on dissolution in water.441Likewise, a pseudocyanide that is by no means e l e c t r o l y t i ~turns ~ ~ ~partly * ~ ~ to ~ a true cyanide on dissolution in
The polarographically active form442-444of cotarnine (86) and related substances is believed to be the ammonium cation even in strongly alkaline solution. A quantitative analysis of narcotine (39) in poppy capsules, opium, and its pharmaceutical preparations involves preoxidation of the alkaloid to cotarnine (86)and its polarographic estimation.445 Cotarnine chloride in slightly acidic to neutral aqueous solutions is extractable with various solvents;446isoamyl alcohol, l,Zdichloroethane, benzene or chloroform, and ether at pH 6.0-7.5, 5.5-6.5, 5.0-6.5, and 5.0-6.0, respectively. Moreover, the chloride in aqueous solutions, on reaction with diazosulfanilic acid, is photometrically determinable down to 50 pg.446 Polarography of the ~ h l o r i d e ' ~ *has . ~ also ~ ~ been determined. Hydrastine (40)when exposed to ultraviolet light for a short time is oxidized to hydroastinine (101). which displays blue fluoroescence"' by UV light. The whole operation is conveniently conducted on a filter paper. In a formal sense, the salt is regarded as a cyclic Mannich component. Thus, on the activated carbon, attack at the 1 position of various nucleophiles, including the Grignard reagents,1 20.2 20.248.262.2 6 5 . 2 86.40 2 -404.406.449 - 4 5 1 active methyls,147.356.357.359.366.368.397.4 12.414.452-464 and active methylene,274.289.317.323.465 organomelithium ~ o m p o ~ n d s , ~ ~ani~ , ~ ~ ~ . line:' 6*4 and r e s o r ~ i n o l .Reformatsky-type ~~~ reactionz89s32 1,469-47 or electroreductive a l k y l a t i ~ -n4 7~4~of~ alkoxy-3,4-dihydroisoquinoliniumsalts is also known. Intramolecular reactions of this type take place more readily. Thus, the Michael reaction of a 3,4-dihydroisoquinolyl ether hydrochloride with methyl vinyl ketone421first forms the 3,4-dihydroisoquinolinium salt (103) as an active intermediate, which then undergoes cyclization on treatment with sodium carbonate to yield the 1 1bH-benzo[a]quinolizidine (104).
'
Isoquinolinols and Their Hydrogenated Derivatives
282
CH,MgI
<
W
N
. CH3 CH3
Scheme 105
resorcfnol. KOH, C.H,OH
cCH30 H 3 0 a N : c H 3
r.t.
::;:Q 0
I-
cH30w&c6~5 cH30 OH
aniline. KOH-H.0
CH3O
CH30
X-
Scheme 107
“CdH5 NHC6H5
11. Dihydroisoquinolinols and Their Derivatives
283
cH30mN< CH30
CH3
Zn, C H L N 1.c..
ti,
I-
OCK,
OCH3
J
C2H502C
scheme 108
CH.COCH=CH,
CH3O c H 3 0 m N ;
C1-
h
3
c H 3 0 a N t CH3O
103
CH3
0
c1-
I
5% aq.Na.CO,
scheme 109
Many studies are directed toward similar cyclizations, where nucleophiles are carbanions,271~303~3"~4'z~4z3~425~476~47' including an activated benzene,479a t r i m e t h y l ~ i l y l b e n z e n e , ~a~l~k.o~ ~' ~i d e s , ~ ' ~an+ en01;~~ ~'~ and a secondary amine.303Thermolysis of a 3,4-dihydroisoquinolyl ether with benzocyclobutenyl derivative^^^^*^^^-^^' produces protoberberines. Since it is highly probable that the 2-benzocyclobutenyl-3,4dihydroisoquinolinium bromide (105) formed first is converted to the salt (106) involving o-quinodimethane moiety, the reaction as a whole constitutes a variation of the Diels-Alder reaction.
284
Isoquinolinols and Their Hydrogenated Derivatives
2-Alkoxycarbonyl- or 2-cyanomethyl-3,4dihydroisoquinoliniumsalts react with diethyl maleate or fumarate4" or an imine36s*482 to produce a 1,3-dipolar cycloadduct . b. Cleavage of C=N
+
Bond
3,4-Dihydorisoquinoliniumsalts are cleaved to 2-aminoehtylbenzaldehyde derivatives on treatment with benzoyl ~ h I o r i d e ~or~ ethyl ~ * ~chloro~ ~ * ~ ~ ~ formate4" in the presence of sodium hydroxide or with hydroxylamine hydr~chloride.~'~
c1-
I f . Dihydroisoquinolinols and Their Derivatives
285
In a similar fashion, 2-vinylbenzaldehydes are produced with dimethyl sulfate and sodium hydroxide4*5 . 4 9 1 as a result of the Hoffmann elimination, which occurs concurrently. The cleavage is greatly facilitated by the introduction of an electron-withdrawing group at the nitrogen. Thus, the molecular compound (107) possessing 3,4-dihydro-2-(2',4-dinitrophenyl)isoquinoliniummoiety is cleaved with
scbeme 112
c. Reduction
2-Alkyl-3,4-dihydroisoquinolinium salts are reduced to 2-alkyl-1,2,3,4tetrahydroisoquinolines by the action of metallic (zinc and mineral a ~ i d , ' ~ ' amalgamated * ~ ~ ~ * ~zinc/calcium ~ ~ and the acids,401 tin and hydrochloric acid,255347 or sodium/liquid ammonia and ammonium catalytic (Adams catalyst20'.255*303 or palladium or c a r b ~ n , ~ ~or~ metal .~'~) hydride (lithium aluminum h ~ d r i d e ~or~ more ' conveniently sodium borohydride226.232.26 1.264.268.269.294.354.358.372.400.493).This also allows the introduction of one deuterium atom to the 1 position by use of sodium borode~teride.'~~ NaBH,
CH30 X-
CH3
CHsOH
C"3
Scbeme 113
d. Oxidation Including the Cannizzarro Reaction The 3,4-dihydroisoquinolinium salts are convertible to 3,4-dihydro- 1 (2H)~*~~~*~~~ isoquinolinones on oxidation with potassium p e r ~ n a n g a n a t e ~or~ ferric
Isoquinolinols and Their Hydrogenated Derivatives
286
cyanide266*357*494*495 in the presence of potassium or sodium hydroxide; the possible intermediates are pseudobases. Tandem reaction with the Bischler-Napieralski r e a ~ t i o n makes ~ ~ ~ .it ~ ~ ~ possible to prepare the 3,4,5,6-tetrahydro-9,1O-dehydrodibenzo pyridocolinium ether. salt (108) starting from a 3,4-dihydro-2-phenethylisoquinolyl K,Fe(CN).
HO X-
10% KOH aq.
CH3
HO
2 . POC1.
CH3
&iH3
1. K.Fe(CN).
CH3O
0
CH30 CH30
OCH 3
OCH 1
108 Scheme 114
On the other hand, heating the salts with caustic alkali causes a Cannizzarro of the pseudobase yielding 3,4-dihydro-l(2H)isoquinolinones and 1,2,3,4-tetrahydroisoquinolines. While a tetrdmethylene bis-salt undergoes a Cannizzarro reaction interEvidently, molecularly, di- and trimethylene analogs do so intramole~ularly.4~~ reaCtion295.347,368.393,407
0 10% NaOH aq. n-b
c
scheme 115
0
+
OCH3
11. Dihydroisoquinolinols and Their Derivatives
287
a steric requirement for hydride shift within the molecule is fulfilled in the later case. Effectiveness of alkalies for the reaction is shown to follow the order of calcium hydroxide > barium hydroxide >sodium hydroxide > potassium hydroxide on the basis of the determination of rates.430 e. N-DeaIkylation N-Dealkylation of 3,4-dihydro-Z-methylisoquinolinium methylsulfates occur with 7.5% potassium hydroxide,252although the results are unreliable.
f. Miscellaneous Reactions Hydrolysis of the acetoxyl group in the side chain of a 3,4-dihydroisoquinolinium iodide with hydrochloric acid followed by chlorination with thionyl chloride399proceeds normally.
CH3O
Scheme 116
Reaction of a 3,4-dihydroisoquinolinium salt with diazomethane produces an aziridinium salt, which is reductively cleaved with Raney nikel (W2) to give a ben~azepine.~'~ C.
1,2-, l,4, and 7,&Dihydroisoquinolino~ and Their Ethers
1.
Preparation
a. By Ring Closure The Schiff base generated from a benzaldehyde and diethyl aminoacetal, when reduced to the secondary amine, and cyclized with concentrated hydrochloric acid, produces dihydroisoq~inolines."~~ However, 1,2-dihydroisoquinolinols and their ethers undergo further reactions21*199*496-498 because of general instability (see Section 1.A.I .a). b. By Miscellaneous Reactions Reaction of 1,4-dihydro-3(2H)-isoquinolinonewith triethyloxonium tetrafluoroborate yields 3-ethoxy-1,4-dihydroisoquinoline (1W).499*500
lsoquinolinols and Their Hydrogenated Derivatives
288
cone. HCI
I
Scheme 117
109
Scheme 118
Ketalization of 7,8-dihydro-6(5H)-isoquinolinone (110) with ethyleneglycol in the presence of excess p-toluenesulfonic acid gives 7,8-dihydro-6-(/Ihydroxyethoxy) isoquinoline (1 1 as a by-product. The dihydroiso1)5013502
p" P-CH,C.H.SOsH benzene A
+
110
Scheme 119
N& '
11. Dihydroisoquinolinols and Their Derivatives
289
quinoline usually forms a methiodide, which is also obtained on quaternization with methyl iodide of 7,8-dihydro-6(5H)-isoquinolinoneethylene acetal (1 12) although not mainly.501~502
2. Reactions a. Substitution Aldehydes can be coupled to the 4 position of 1,2-dihydroisoquinoline,which is a typical cyclic enamine."j Thus, a 1,2-dihydroisoquinolyl ether reacts with 89 yielding a 4-benzyl- or phenacylb e n ~ a l d e h y d e or ~ ~phenylglyoxal,' ~*~~~ isoquinoline. 3-Ethoxy- 1,4-dihydroisoquinoline (109) is comparable to the 1 -ethoxy-3,4dihydro analog in its reactivity (see Section II.A.2.c). Thus, the former undergoes nucleophilic substitution with c y ~ l o p r o p y l a m i n eor ~ ~p-diethylarnino~ ethylamine.500
benzaldehyde
c HO H 3 C1- 0 m conc. H C 1 . A ! H HO 2
m" OCzHs
c1-
cyclopropylamine i-CaH70H. A
scheme 120
b. Reduction Sodium borohydride reductions01~s02 of 7,8-dihydro-6-(p-hydroxyethoxy)isoquinolinium methiodide yields octahydro-2-methyl-6(5H)-isoquinolinone ethylene acetal.
290
Isoquinolinols and Their Hydrogenated Derivatives
D. 1,2-Dihydro-%(ptosyl)isoquinolinols and Their Ethers
1 . Prepuration a. By Ring Closure Stability of 1,2-dihydroisoquinolinesis greatly enhanced by fixing the lonepair electrons of the nitrogen atom. As a result, a Pomeranz-Fritsch reaction of N-benzyl-N-tosylaminoacetaldehyde dimethyl acetals with 6N hydrochloric acid in boiling dioxane under nitrogen yields, 1,2-dihydr0-7-rneth-,’~~’~ 1,2-dihydr0-8,7-dimethoxy-,’~ 1,2-dihydr0-5,6,7-trimethoxy-,~~ 1,2dihyro6,7,8-trimetho~y-,’~ 1,2-dihydr0-6,7-methylenedioxy-,’~1,2-dihydro-7,8-dimeth~xy-.’~ 1,2-dihydr0-6,7-dimethoxy-,’~ 1,2-dihydro-7,8-dimetho~y-,~~ 8-benzyloxy-1,2-dihydro-7-methoxy,’4~’7*’9 and 7,8-diben~yloxy~’*~’ 24ptosyl)isoquinolines, which are spectroscopically well characterized (see Section I.A.1.a). Among others, the last six are sufficiently stable to allow recrystallization.
2. Reac I ions a. Oxidation The title compounds are readily oxidized to isoquinolines (see Section LA. 1.a).
111. PHENOL BETAINES A.
I.
Preparation
By Oxidation
Narcotoline (113), on oxidation with mercuric acetate in the presence of the disodium salt of ethylenediamine tetraacetate, yields a phenol betaine, tarconine (114).’14
2. By Base Tarconine (I 14) is also formed by heating 0-methyltarconine hydroxide (derived from its chloride on treatment with silver oxide) withSo4or without barium hydroxide216. A phenol betaine, cotarnoline (1IS), is produced when narcotoline (113)243*506*507 narcotolinediol (116), narcotolic acid (117), and narcotosoline (118)’14 are treated with ammonia or when 115 is hydrolyzed with 0.01N
Ill. Phenol Betaines
I
sot"*-,
g0
U
113
dCH 3
Hg(OCOCH,)
I
EDTA (disodlum s a l t ) 1% CH,CO.H
<w+ 29 1
'CH3
0-
114
CHaOH
NHs-H.0,
4
& r n 0N : c " 3
115 scheme 122
( ' y ' HC HOH 3
'OH
116 R 5 C H 2 0 H 117 R = CO,H
sodium hydroxide.214The structure of the phenol betaine is deduced by the fact that no reaction occurs with diazomethane or nitromeconine and that the values of its pK, (13.0) and p K , (9.15)closely resemble those (>13 and 9.58) of tarconine (114), apparently differing from those (- and 3.42) of O-methyltarconine hydro~ide.''~ 4-Hydroxy-2-[(E)-p-chlorocinnamoyl]isoquinolinium chloride also produces a phenol betaine,203 when treated with triethylamine. Treatment of 4-hydroxy-2-methylisoquinolinium iodide (119) with Amberlite IRA-401 gives rise to another phenol betaine, 2-methyl-4-oxidoisoquinolinium ( 1 2 0 ) . ~ ~ * The third phenol betaine is derived from 3,4-dihydro-6,7-dihydroxy-2methylisoquinolinium chloride with a calculated quantity of sodium hydroxide, excess sodium carbonate, or
292
Isoquinolinols and Their Hydrogenated Derivatives
&+ N Y H3
Amberlfte IRA-401 Ha0
CH3
I-
118
140 scheme 124
scheme 125
Since methylation of the phenol betaine with methyl iodide or benzylation with benzyl iodide411 takes place mainly at the 6 position, the structure is most probably 7-hydroxy-2-methyl-6-oxidoisoquinolinium, On oral administration of 1-(a-diazo)methylhydrocotarnines (121-I=), 3,4dihydro-7,8-dimethoxy-2-methyl-6-oxidoisoquinolinium (124), along with cotarnoline (115), is excreted as a major metabolite in the urine of male Wistar ratS.509,510
115
Scheme 126
I l l . Phenol Betaines
293
Moreover, treatment of a 3,4-dihydro-7-hydroxy-2-methylisoquinolinium salt with ammonium hydroxide410or potassium carbonate4’ * leads to the dimeric phenol betaine (125). HO
cH30
conc. SH.OH
HO
0 N.
c H i i W N < c H 3
CH3
c1-
125
c1Sebeme 127
B. Reactions 1. 1.3-Dipolar Cycloaddition 2-Methyl-4-oxidoisoquinolinium (120) enters into a 1,3dipolar cycloaddition r ea~t ion”~ with acrylonitrile and methyl acrylate yielding the endo-cycloadduct (126) or a mixture consisting of the exo- and endo- cycloadducts (127 and l a ) , respectively. CHl*CHCN
/---
THF, reflux
120
THF. r e f l u x
CN
128
294
Isoquinolinols and Their Hydrogenated Derivatives
Similarly, 4-hydroxy-2-(2’,4-dinitrophenyl)isoquinoliniumchloride leads to the regioisomeric cycloadducts [(129:130)] (1 : l), when boiled with phenylacetylene in acetonitrile in the presence of triethylamine.206 Other dipolarophiles that can be employed in these reactions are dimethyl acetylenedicarboxylate, diethyl azodicarboxylate, N-phenylmaleinimide, styrene, and acrylonitrile.
149
+ ITS ISOMER
130
Scheme 129
2. Reduction Cotarnoline (115) is reduced to the 1,2,3,4-tetrahydroisoquino~ine (131) by use of sodium amalgam and water.*I4
115
131
3. Cleavage of Dimeric Phenol Betaine The dimeric phenol betaine (132) is severed to its components when treated with an equivalent amount of hydroiodic acid408or methyl i~dide.~’’
IV. Tetrahydroisoquinolinols and Their Derivatives
295
I-
+
Scheme 131
IV. TETRAHYDROISOQUINOLINOLSAND THEIR DERIVATIVES A. 1,2,3,4Tetrahydroisoquinolinolsand Thew Ethers and Esters
I.
Preparation
a. By Ring Closure The Pictet-Spengler reaction allows easy access to these systems and uses methyla15' -521 and formalin as one carbon unit and generally aqueous hydrochloric acid of varying concentrations. The following compounds and 1,2,3,4tetraare prepared in this way: 1,2,3,4-tetrahydrod-metho~y-~~~ hydr0-6,8-dirnethoxy-~~~ 7-isoquinolinols; 1,2,3,4-tetrahydro-6,7-dimethoxy8-isoquinolinol(anhalamine~ 133);52 1,2,3,4-tetrahydro-6,7-isoquinolinedio1;519*5241,2,3,4-tetrahydro-4,6,7-isoquinolinetri0~;~~~~~~~~~~~ 1,2,3,4-tetrahydr0-4,8,7-isoquinolinetriol;~ and 1,2,3,4-tetrahydr0-5,6-dimethoxy-,~~~ Set hox y- 1,2,3,4-tetrahydr0-6-methoxy-,~ 1,2,3,4-tetrahydr0-6-methoxy-,~ 26* 528 - 530 -6-ethoxy-1,2,3,4-tetrahydr0-,~~~ 1,2,3,4-tetrahydro-6,7-methoxylenedioxy-,5 1 1 - 513.526.51 3 - 533 1,2,3,4-tetrahydro-6,7-dimethoxy-,5'7.5zo~526~53~~ 534-538 7-ethoxy-l,2,3,4-tetrahydro-6-methoxy-,s27 7-benzyloxy-l,2,3,4 tetrahydr0-6-methoxy-,~~'1,2,3,4-tetrahydr0-6,7,8-trimethoxy-,~~* and 6ethoxy-l,2,3,4-tetrahydro-7-metho~y-~~~ isoquinolines. A t times addition of acid is unnecessary. Consequently, heating of 4-alkoxy-3hydroxyphenethylamine hydrochlorides with formalin is enough to ensure the 542 and 7-ethoxy-1,2,3,4reaction leading to 1,2,3,4-tetrahydr0-7-methoxy-~~Ot e t r a h y d r ~ - ~ 6-isoquinolinols. ~'.~~~ Moreover, 3,4-dihydroxyphenethylamine
'
i
296
Isoquinolinols and Their Hydrogenated Derivatives
hydrobromide enters into reaction with formalin in ethanol at room temperature and, after a prolonged time, yields 1,2,3,4-tetrahydro-6,7i s o q ~ i n o l i n e d i o l7-3H-( . ~ ~ ~ +)-Norepinephrine reacts with formalin at pH 6 (1M A sodium acetate buffer) yielding 1,2,3,4-tetrahydro-4.,6,7-isoquinolinetriol.544 condensing agent is not necessarily required. Thus, 3,4-dimethoxy- and 3,4dihydroxy-phenethylaminesreact with 40% formalin at an elevated temperature or with gaseous formaldehyde yielding 1,2,3,4-tetrahydro-6,7dimethoxyis~quinoline~' and 1,2,3,4-tetrahydro-6,7-dihydroxyisoquinoline,sz4 respectively. Preferential cyclization occurs at the para position to an activating 0-function and the directing power of methoxyl group is likely to be stronger than that of h y d r o ~ y l , ~although ~' not conclusive. Whereas the benzyloxy group is deben~ y l a t e d ~ ' ~in. ~ the' ~reaction, ethoxycarbonyloxy remains intact.523
133 scbrme 132
A phenethylamine with an a-hydroxyl group is converted to the tetrahydroisoquinoline with no loss of the group. Thus, 1,2,3,4-tetrahydro-4,6,7isoquinolinetriols'8~szo~5zs~s4s~s46 is obtained along with a trace of the regioisomeric 4,7,8-tri01.~'~ Contrary to the general directing effect, two e ~ a m p l e s ~ ' ~where -~*~ the cyclization takes place at the meta position to an 0-function are reported, for l 6 and 1,2,3,4-tetrahydr0-7-~~~ isexample, 1,2,3,4-tetrahydro-5-metho~y-4-~'~*~ oquinolinols (134 and 135).
134
sebcme 133
IV. Tetrahydroisoquinolinols and Their Derivatives
297
A logical intermediate in the Pomeranz-Fritsch reaction, a 1,2,3,4tetrahydro-rtisoquinolinol,is virtually isolable by use of 6 N hydrochloric acid at room temperature or below. The following compounds are prepared in this way; 1,2,3,4-tetrahydr0-5,6,7-trirnethoxy-,’~1,2,3,4-tetrahydro-5,7,8-trimethO X Y - , ’ ~ ~ 1,2,3,4-tetrahydr0-5-methoxy-7,8-methylenedioxy-,~~~ 1,2,3,4-tetrahydro-6,7-rnethylenedio~y-,’~~~~~~ 1,2,3,4-tetrahydr0-6,7dimethoxy-,~~*~~~ and 1,2,3,4-tetrahydr0-7,8-dimethoxy-~~*~~*’~~ 4-isoquinolinols; 1,2,3,4tetrahydr0-7-methoxy-4,6-,~~~ 1,2,3,4-tetrahydro-6-methoxy-4,7-,s4s~550 and 1,2,3,4-tetrahydro-7-methoxy-4,8-54s-isoquinolinediols, and 1,2,3,4-tetrahydroand 1,2,3,4-tetrahydro-4,7,8iso4,5,8-,s48 1,2,3,4-tetrahydro-4,6,7,s46~sso*ss1 quinolinetriols. Hydrogenolysis of the tetrahydro-4-isoquinolinolsover 5- 10% palladium on carbon yields tetrahydroisoquinolines. For example 1,2,3,4-tetrahydro-7and 1,2,3,4m e t h o ~ y - 6 - , ~ ’ *1,2,3,4-tetrahydro-6-methoxy-7-,21*400~498 ~~~ tetrahydro-7-methoxy-8-z1~400~498 isoquinolinols and 1,2,3,4-tetrahydro-5,6,7t r i m e t h o ~ y - , ” * ~1,2,3,4-tetrahydr0-6,7-dimethoxy-,~’ ~~ 1,2,3,4-tetrahydro-7isoquinolines are m e t h ~ x y - , ~ ’ . and ~ ~ ’ 1,2,3,4-tetrahydr0-7,8-dimetho~y-~~ produced. Application of the Mannich reaction to the synthesis of 1,2,3,4-tetrahydro-78-isoquinolinolsis of synmethoxysS3and 1,2,3,4-tetrahydr0-6,7-dirnethoxy-’~~ thetic value. For instance, a mixture consisting of guiacol, formalin, and dimethylaminoacetal is first treated with 6N hydrochloric acid to effect the cyclization and subsequently subjected to direct hydrogenolysis over 5% palladium carbon, to produce the desired product.
HO
+ CHZO + NHzCHzCH(OCH,),
’.
6N”C1
2 . 5% Pd-C/Ha
,s c HO H
3
0
m
N
~
scheme 134
b. By Reduction
3,4-Dihydroisoquinolines are readily hydrogenated to the tetrahydoisoquinolines by catalytic (palladium on carbonz53or Adams c a t a l y ~ t , ’ ~ ’ ~metallic ~~~), (tin and concentrated hydrochloric a ~ i d ~of sodium ~ * ~amalgams32), ~ ~ , ~or ~ ~ reduction. Thus, the following compounds sodium borohydridez63~300~ss5*ss6 are produced: 1,2,3,4-tetrahydr0-6.’~~ 1,2,3,4-tetrahydr0-8-methoxy-6-,~~~ 1,2,3,4-tetrahydr0-5-methoxy-7-,~~~ 1,2,3,4,-tetrahydr0-6-methoxy-7-,~~~ and 1,2,3,4-tetrahydr0-7-methoxy-8-~~~ isoquinolinols and 1,2,3,4-tetrahydro-6,71,2,3,4-tetrahydro-6.7-methylenedio~y-,~~~~~~~~~~~ 7-ethoxydimetho~y-,~ ~.~~~ 1,2,3,4-tetrahydro-6-methoxy-,253 8-benzyloxy-l,2,3,4-tetrahydro-6,7-dimethO X Y - , ~ ’ ~ 1,2,3,4-tetrahydro-8-methoxyd,7-methylenedioxy-,z84and 6benzyloxy- 1,2,3,4-tetrahydr0-7,8-dimet hoxy 56 isoquinolines.
’
Isoquinolinols and Their Hydrogenated Derivatives
298
Since hydrogenation is nucleophlic in nature, hydrogen first adds to the pyridine ring of isoquinoline. Likewise, isoquinolines carrying electron-donating group(s) in the benzene ring are hydrogenated to the tetrahydroisoquinolines by catalytic (usually under pressure: palladium on carbonzfi7 or Adams 5s9) or metallic (tin and hydrochloric a ~ i d , ' ~ * ~ ' zinc * ' ' and hydrochloric acid,7 sodium and absolute ethanol? or sodium in liquid ammonia and methano1114)reduction.
O 'm N iBr@!Ni
C1-
NaBHL H.0,
C.C.
PtO,/H,(50
psi)
CaH,OH, r.t.
RO
WNH RO
R-H,
CH3 Scbcme 135
Thus, the following compounds are prepared: 1,2,3,4-tetrahydr0-5-,97.~~*~~~ 1,2,3,4-tetrahydr0-7-,"~ and 1,2,3,4-tetrahydro-8-l2'isoquinolinols and 1,2,3,4tetrahydr0-5-methoxy-."~ 1,2,3,4-tetrahydr0-6-methoxy-,~~~ 1,2,3,4tetrahydr0-6,7-dimethoxy-,'~~~~ 1,2,3,4-tetrahydr0-6,8-,~"~ 1,2,3,4-tetrahydro-71,2,3,4-tetrahydr0-8-rnethoxy-,~~~ and 1,2,3,4-tetrahydro-8methoxy-$3' metho~y-6,7-methylenedioxy-~~ isoquinolines. Chemical behavior of the hydroxyl or carbonyl group at the 4 position toward the catalytic hydrogenation over palladium on carbon is dependent on the reaction conditions. Whereas the hydroxyl group readily undergoes hydrogenolysis over 5% palladium on carbon in hydrochloric acid,s48 the 2-benzyl-2,3-dihydro-4(1 H)isoquinolinone (136) is reduced to a 1,2,3,4-tetrahydro-4-isoquinolinol over 5-10% Pd-C/H,
CHICO zH
CH3O
136 5% Pd-C/H,
CHJO
6N HCl. r.t.
Sebeme 136
CH3Od
N
H
HowNH
CH3O
IV. Tetrahydroisoquinolinols and Their Derivatives
299
5- 10% palladium on carbon in acetic Similarly, the propionate group at the 4 position undergoes no hydrogenolysis under the latter conditions.1
32.1 33
2-Benzyl-2,3-dihydro-6-hydroxy-7-met hoxy-4(1H)-isoquinolinone ethylenethioacetal undergoes both desulfurization and debenzylation to lead to 1,2,3,4tetrahydro-7-methoxy-6-isoquinolinol 32 when hydrogenated over Raney nickel. As is well known, palladium on carbon is an effective catalyst for Ndebenzylation. Accordingly, a 2-benzyl-1,2,3,4-tetrahydro-4-propionoyloxyisoquinolyl ether is hydrogenated over the catalyst in acetic acid to yield a 1,2,3,4tetrahydro-4-propionoyloxyisoquinolyl ether132-133or by high-pressure (33-80 atm) hydrogenation of 2-benzyl-tetrahydroisoquinolines'33*560- 562 over 10% palladium on carbon.
CH 3O
HO
w,
10% P d - C A i 2 . A
under pressure
scheme 137
- PNH CH3O
1,2,3,4-Tetrahydro-7,8-dimethoxy-4-isoquino~in0l~~~~~~~ is produced from the 2,3-dihydro-2-(p-tosyI)-4(lH)-isoquinolinone(137) on reduction with sodium bis(2-methoxyethoxy)aluminum hydride. Reductive hydrolysis of 2sulfonyltetrahydroisoquinolylether with the same reagent is also known to give 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline, s65 The lactam carbonyl group of 3,4-dihydro- 1(2H)-isoquinolinones is reducible to a methylene group by use of sodium and absolute ethanol256 or lithium aluminum hydride.37.364,386,557 The following compounds are produced in and 1,2,3,4this way: 1,2,3,4-tetrahydro-6,7-dimethoxy-8-isoquinolinol264 1,2,3,4-tetrahydro-7-meth ~ x y -5,7~ 1,2,3,4tetrahydro-6-met h ~ x y - ,'~ OH
137 LiAlH,
dioxane
CH3O
0
60"
scheme 138
=, CH3b
300
Isoquinolinols and Their Hydrogenated Derivatives
tetrahydr0-8-methoxy-,~~~ 1,2,3,4-tetrahydr0-6,7-methylenedioxy-,~~~ 1,2,3,4tetrahydro-6,7-methylenedioxy-8-methoxy-,37 and 8-benzyloxy-l,2,3,4tetrahydr0-6,7-dimethoxy-~~~ isoquinolines. Optically active (-)-2-acetyl1,2,3,4-tetrahydro-4-isoquinolinol is formed from 2-acetyl-1,2,3,4-tetrahydro-4isoquinolinone by reduction with chiral bis(2,2’-naphthyloxyethoxy)aluminum h~dride.’~~ Although details are unknown, the treatment of 8-methoxyisoquinoline hydrochloride with sodium methoxide in methanol gives rise to 1,2,3,4tetrahydro-8-methox yisoquinoline. 2o c. By 0-Dealkylation 0-Dealkylation is achieved with concentrated hydrochloric acid under or by 36%s68 and 48%s19vs67 hydro20% hydrochloric 1,2,3,4-tetrahydr0-7-,”~ and bromic acid. Thus, 1,2,3,4-tetrahydr0-6-,~~~~~~~ 1,2,3,4-tetrahydro-8isoquinolinols and 1,2,3,4-tetrahydro-5,6-, 1,2,3,4tetrahydr0-6,7-,~26*567 1,l -dideuterio-1,2,3,4-tetrahydr0-6,7-,~’~and 1,2,3,4tetrahydr0-7,8-’~~.’~~ isoquinolinediols are prepared.
s c k
t39
Partial 0-demethylation is performed by 20% hydrochloric529 or 36% hydrobromicS6*acid under strictly controlled conditions and the fact that the steric factor (see Section 1I.A.l.c) plays in the reaction a decisive role is well reflected in the following transformations. The reaction of 1,2,3,4-tetrahydro6,7,8-trimethoxyisoquinolinol(anhalinine) (138) with 20% hydrochloric acid (139),569while yields mainly 1,2,3,4-tetrahydro-6,8-dimethoxy-7-isoquinolinoI
cH30mH 202 t l C l
A
CH30
CH36
138
CH30@!H
CH30
20%A ttclH N m ”
CHO IW HO N,
CH30
36% HBr 115’
*
“ “ HO
,:”
139
HO CH30QQH
HO
133
IV. Tetrahydroisoquinolinols and Their Derivatives
301
that of both the latter and 1,2,3,4-tetrahydro-6,7-dimethoxy-8-isoquinolinol proceeds smoothly to yield 1,2,3,4-tetrahydro-6-methoxy-7,8isoquinolinediol ( In accordance with the generality, 1,2,3,4tetrahydro7-metho~y-8-isoquinolinol~~~ is largely produced when 1,2,3,4-tetrahydro-7,8dimethoxyisoquinoline reacts with 36% hydrobromic acid. Hydrogenolytic 0-debenzylation with palladium on carbon is of some synthetic utility and 1,2,3,4-tetrahydr0-7,8-dimethoxy-6-~~~ and 1,2,3,4-tetrahydro6 , 7 - d i m e t h o ~ y - 8 - isoquinolinols ~ ~ ~ * ~ ~ ~ are prepared in this manner. (133)
O W N H
CH3O
Pd/Ha
F
CH30
CH30 Scbemc 141
d. By 0-Alkylation and 0-Arylation O-Methylation of the phenolic tetrahydroisoquinolinols with diazomethane proceeds normally, and 1,2,3,4-tetrahydr0-5-methoxy-,9~ and 1,2,3,4tetrahydro-6,7,8-trimetho~y-~~~~~~~ isoquinolines are produced. undergoes selecInterestingly, 1,2,3,4-tetrahydro-6-methoxy-7-isoquinolinol tive 0-acylation with 3,4,5-trimethoxybenzoic acid in polyphosphoric acid to produce 1,2,3,4-tetrahydro-6-methoxy-7-(3',4,5'-trimethoxybenzoyloxy)isoquinoline. 52 C HHO3 0 @ 3 N H
ArCOaH PPA, h
Ar
=
@:lHC CH30
Scbeme 142
A mixture consisting of 6-methoxy-7 and 7-methoxy-6-isoquinolinols (0.62 : is formed on methylation of 1,2,3,4tetrahydro-6,7-isoquinolinediol with catechol 0-methyltransferase. Likewise, 1,2,3,4-tetrahydro-4,6,7-isoquinolinetriolundergoes selective 0methylation to lead to 1,2,3,4-tetrahydro-6-methoxy-4,7-isoquinolinediol544 when incubated with brain or liver homogenate. Biologically, the 6-0-methyl and 7-0-methyl isomers are distributed in the three brain regions (striaturn, hypothalamus, and hippocampus) of the rat in a ratio of about 55:45.'"
302
Isoquinolinols and Their Hydrogenated Derivatives
e. By Miscellaneous Reactions
1,2,3,4-Tetrahydro-5-isoquinolinol9 7 * 5 5 7 and 1,2,3,4-tetrahydro-Smeth-
OX^-,^^*''^ and 6-benzyloxy-1,2,3,4-tetrahydro-7-methoxy-,’ ”*’ 5 6 isoquinolines
are produced on hydrolysis of their 2-formyl, 2-acetyl, or 2-carbethoxy derivatives with 3N and concentrated hydrochloric acids or sodium hydroxide.
conc. HCl
b
N
Y
H
O
ref lux
*
Scheme 143
N-Oxides of 1,2,3,4-tetrahydro-2-phenethylisoquinolines7’ and N-fl-( 1,2,3,4tetrahydroisoquinoly1)propionic acidS7l and its ethyl e ~ t e r ’ ~ ’ . undergo ’~~ a Cope rearrangement yielding 1,2,3,4-tetrahydro-2-hydroxyisoquinoline.’71 - 573 In the case of the latter two, aqueous sodium hydroxide is necessary to bring about the reaction. Formation of the 2-hydroxyisoquinoline is also confirmed when 1,2,3,4-tetrahydroisoquinolinereacts with acetone and 1.5% hydroperoxide.572Additional evidence concerning the structure is ofTered by oxidation of the tetrahydroisoquinoline to a cyclic nitrone (see Section IVA.2.b). The borohydride adduct of 3,4-dihydro-6,7-dimethoxyisoquinoline(see Section 1I.B.1.f) is transformed to 1,2,3,4-tetrahydr0-6,7-dimethoxyisoq u i n ~ l i n ewhen ~ ~ ~boiled with concentrated hydrochloric acid in ethanol. conc. HC1 CIHSOH,
reflux
*
H I 3=’NH
CH3O
scheme 144
A methoxyl group flanked by two others in the benzene moiety of the tetrahydroisoquinolines is displaced by hydrogen on treatment with sodium in liquid ammonia. Thus, 1,2,3,4-tetrahydro-5,7- and 6,8-dimethoxyisoquinoli n e P 7 are yielded from 1,2,3,4-tetrahydro-5,6,7-and 1,2,3,4-tetrahydro-6,7,8trimethoxyisoquinolines, respectively.
Na/liq.NH,
CH30 cH30&NH
CH3O
Meme 145
1V. Tetrahydroisoquinolinols and Their Derivatives
303
Catalytic hydrogenation of the tetrahydroisoquinolines containing nitrogen substituents at the 1 Dosition over palladium on carbon in hydrochloric acid 1,2,3,4-tetrahydr0-6,7-dimethoxy-~~~ and 1,2,3,4-tetrahydro-6,7yields methylenedioxy-8-methoxy-405 isoquinolines.
cH30mv
CH30 102 Pd-CIH.
80% CHJOH
conc. HC1
c H 3 0 ~ N ~ ~ C H 2 ~ 2 C O C H ~ CH30
OCH3 schemc 146
The formers74 is also produced on photolysis of 1,2,3,4-tetrahydro-6,7dimethoxy-Z(p-tosy1)isoquinoline in the presence of sodium borohydnde and sodium carbonate.
Scheme 147
1,2,3,4-Tetrahydro-4-isoquinolinols3*s7s is produced on reductive cyclization of 2-(r-hydroxy-/?-nitroethyl)benzaldehydelactol with Adams catalyst. Deprotection of a 7-ethoxycarbonyloxy-1,2,3,4-tetrahydrois~uinoline with sodium hydroxide produces 1,2,3,4-tetrahydro-6,8-dimethoxy-7isoq~inolinol.'~~ Interestingly, bicyclic phenethylamine (141) reacts with N-methylmaleimide to give 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.s76 ( +)-2-Benzoyl- 1,2,3,4tetrahydro-4-isoquinolinol is shown to be produced by an enzymatic reaction of 2-benzoyl- 1,2,3,4-tetrahydroisoq~inoline.~~'
304
cH30m
Isoquinolinols and Their Hydrogenated Derivatives
6 W H 3
CH3O
+
0
_______c Ha0 50'
CH3O
2. Reactions Being a typical secondary amine, 1,2,3,4-tetrahydroisoquinolines undergo Nalkylation, N-nitrosation," ' 3 3 * 5 7 8 N-cyanat ion,' 78 N-formamidation,' 79*'80 and the M a n n i ~ h ~-m3 ~ ~ .or ' ~ the ~ M i ~ h a e 1 ~ reaction ~ ~ * ~without ~ ~ - ~ ~ ~ difficulty. Sn/HCl
N <="O
NaNO.,
d i l . HC1
Scheme 149
The 2-nitroso group is displaced by hydrogen on reduction with tin and hydrochloric acid.' 12313
IV. Tetrahydroisoquinolinols and Their Derivatives a.
305
N-Alkylation and N-Arylation
N-Alkylation with alkyl halidess57~s78-s92 needs a base, while that with alkyl iodidess6’ does not. As in the conventional order of reactivity alkyl bromidess6*52z*577 lie in between. Methyl dimethyl sulfate,529or formalin and a reducing agent such as Raney nickel,286 sodium borohydride,406*594-59s and formic acids30.s36is used for N-methylation. Norhydrastinine hydrochloride is N-methylated when heated with excess f o ~ m a l i n N.~~~ Alkylation with 4-hydroxybenzyl alcohol under heating is possible, and proceeds through an intermediate quinone methide.596 Tetrahydroisoquinolylaminoquinazolines,597 which possess antihypertensive activity, are produced by N-arylation of the tetrahydroisoquinolines with a 4amino-2-chloroquinazoline.
iH
*
Scheme 151
Anhalamine (133)(see Section VII) is alkylated at both the oxygen and nitrogen atoms giving a 2,2-diethyl-1,2,3,4-tetrahydroisoquinoliniumsalt when treated with dimethyl sulfate and sodium h y d r o ~ i d eor~ ethyl ~ ~ *iodide ~ ~ ~and (138) is also quaternized by the former resodium e t h ~ x i d e . ’Anhalinine ~~ agent.s39 With diazomethane, anhalamine (133)undergoes both 0-methylation and N,0-dimethylation in the ratio of 3 4: 1 .406
-
Scbeme 152
b. Oxidation
over zinc dust gives rise to Distillation of 1,2,3,4-tetrahydro-7-isoquinolinol isoquinoline. 599 Oxidation of 1,2,3,4-tetrahydro-2-hydroxyisoquinoline57z with mercuric oxide and electrooxidative dimerization of a phenolic 1,2,3,4-tetrahydroisoquinolino1600-601yield the cyclic nitrone (142) and the C--C dimer,143 respectively.
Isoquinolinols and Their Hydrogenated Derivatives
306
OH
HgO acetone-Hs0
c
r.t.
142
cH3 cH30mNH HO
electrolysis
HO
0.1N HC1
g r a p h i t e anode
!+ 0.78 V)
143 Scbeme 153
One equivalent mole of periodic acid is consumed by 1,2,3,4-tetrahydro-4isoquinolinol (144), which involves a system equivalent to g I y c 0 1 . ~ ~ ~ Oxidation of 1,2,3,4-tetrahydroisoquinolylether with 36% hydrogen peroxide in the presence of sodium tungstate affords alkoxy-3,4-dihydroisoquinoline 2-0xide.~~~
144
c. C-Alkylation Heating in a mixture of concentrated hydrochloric acid and ethanol 1,2,3,4tetrahydro-6,7-dimethoxy-4-isoquinolino1504 with benzaldehyde produces a 4benzylisoquinoline and the d i n ~ e r . ' ~ ~
IV. Tetrahydroisoquinolinolsand Their Derivatives
307
cH30
CH30
CeHsCHO
NH2 C1- 0 cone. HC1. C,HsOH+ CH30 H c 3 m
+
CH3O cH30@@4
145
B. 2-Acyl(Aroyl)-
and 2-Arene(alkane)sulfonyl-l,2,3,4tetrabydroisoquinolinols a d Tbeir Ethers
1. Preparation a. By Ring Closure The Pictet-Spengler reaction of an N-benzoylphenethylamine with chloromethyl methyl ether in acetic acid is an attractive method to produce the 2benzoyl-1,2,3,4-tetrahydroisoquinolylether ( 146).603In particular, the reaction proceeds fairly well in solvents such as acetone and tetrah~drofuran.~'~ A modified Pictet-Spengler reaction of N-phenethylamides with methanesulfonic acid in the presence of acetic anhydride produces a 2-sulfonyl-1,2,3,4tetrah ydroisoquinoline. "' Cyclization of an N-mesyl- or N-( p-tosy1)-N-phenethylaminoacetylchloride (see Section VI.E.1.b) with aluminum chloride at -70°C gives a 1,2,3,4tetrahydr0-2-rnesyl-~'~or 1,2,3,4-tetrahydro-2-(p - t o ~ y l ) isoquinolyl -~~~ ether.
Isoquinolinols and Their Hydrogenated Derivatives
308
146
SOZCH3
CH3O
- cH3m
AlC1,. CHzClz -70”
“SO
CH3
toc I
2 CH3
scheme 156
b. By Schotten-Baumann Type Reactions Tetrahydroisoquinolyl ethers smoothly undergo N-acetylation with acetic anhydride alone or in the presence of pyridine98*534*606 or N-benzoylation with 3-nitrobenzoyl chloride in aqueous potassium hydroxide to give N-acylated in the case of the tetrahydroisoquinolinols i s o q ~ i n o l i n e . However, ~~~ selective N-acetylation or N-benzoylation in the presence of a phenolic hydroxyl group is a matter of concern. For example, the Schotten-Baumann benzoylof anhalamine (133) with 3-nitrobenzoyl chloride gives rise to a ation523*539*607 mixture of N-benzoyl- and N,O-dibenzoyl-anhalamine,although the latter is transformed to the former on standing with excess ethanolic sodium hydroxide.s39 The problem is chiefly solved by taking advantage of the fact that esters are more sensitive to alkaline hydrolysis than amides. Thus, selective N-
CH CH3O 30rnN.c0Ar
c H CH30
3
HO
0
w
N
~
133 CH3O A r = m-N02C6H4 1. CH,COCl.
c HO H 3 0 m N H
(C.H.),N.
2. 10% KOH eq.
HO CHCl,
A
scbeme 157
“COAr
c HHO3 0 ~ N , ( O I H 3
IV. Tetrahydroisoquinolinols and Their Derivatives
309
acetylation is accomplished by N,O-diacetylation with acetyl chloride in the presence of triethylamine and subsequent hydrolysis with 10% potassium hydroxide601 or by use of acetic anhydride and methanol.558 Analogously, selective N-benzoylation with 3,4,5-trimethoxybenzoyl chloride is effected by heating the isoquinoline in a mixture of sodium ethoxide and water.522 -t
ArCOCl NaOCIH.
c HO H 3 0 m N i 2 c1-
HiO.
cH3 HO
A
Ar = 3.4.5-(CH30I3C6H2
(CHoC0)zO
CHBOH
hO
-
HOa N Y O C H 3
scheme 158
Other combinations of reagents for N-acetylation and N-benzoylation are a disubstituted acetyl chloride and N-ethylpiperidine,584substituted acetyl chlorides and pyridine,608*609a phenylpropionyl chloride and triethylamine,610 and nitrobenzoyl chloride and potassium hydroxide or 8% sodium hydroxide. 5 1 2.5 1 3,539 N-Sulfonation is performed by use of arenesulfonyl chlorides611 in the presence of pyridine12'p612-614or 10% sodium hydroxide.'" c. By 0-Alkylation As usual, phenolic 2-acetyl-l,2,3,4-tetrahydroisoquinolinols are 0-alkylated by use of methyl iodide and sodium e t h ~ x i d e dimethyl ,~~ sulfate and sodium methoxide in methanol,s39 or benzyl chloride and potassium carbonate in dimethylf~rmamide.~~~ 06HaCHIC1
c HHO3 0 m N . c H 0
KoC03. DMF
c H C7"7O
3
0
w
N
y
~
2,3-Epoxypropoxylation is also performed by use of epichlorohydrin in the presence of base.656*667 d. By Miscellaneous Reactions N-Formylation of tetrahydroisoquinolines is performed with formic acid and or f ~ r m a m i d e 5.616 .~~~,~~ triethyIamine97*402
~
310
Isoquinoiinols and Their Hydrogenated Derivatives
Acetic anhydride (see Section 1V.B.l.b) and isatoic anhydrideP’ are used for N-acetylation and N-benzoylation. Similarly, a 6-methoxy-tetrahydrosioquinoline hydrochloride undergoes N-sulfonylation with carylsulfate in the presence of potassium carbonate and hydroxide to yield the potassium sulfonylsulfate (147).61 8+61
147 Scbeme 161
2-Cyano-l,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline reacts with hydrogen sulfide in the presence of pyridine and triethylamine to yield 2-(1‘,2’,3’,4tetrahydro-6,7’dimethoxyisoquinolyl)thio~arbamide.~’~
2. Reactions a. Reduction
Lithium aluminum hydride reduction of a 2-formyl-1,2,3,4- rahydroisoquinolyl ether leads to a 2-methyl d e r i ~ a t i v e . The ~ ~ ’ reaction also works well ~ ~ ~ * ~ ~ ~ ~ ethers. ~ ~ ~ ~ ~ for 2-ben~oyl-~’and 2 - a ~ y 1 -1,2,3,4-tetrahydroisoquinolyl
’
LUlH.
CH30 W N \ C H O OC7H7
THF
CH3O
Scbeme 162
Reductive removal of an N-p-tosyl group is accomplished with sodium bis(2methoxyethoxy)aluminum h ~ d r i d e ’ ~ ’ or - ~ by ~ ~photolysis in the presence of sodium b ~ r o h y d r i d e ~(see ’ ~ Section 1I.A.l.b). b. Oxidation Electron-oxidative dimerization of phenolic 2-acetyl-l,2,3,4tetrahydroisoquinolinols occurs ortho or para to the hydroxyl group.6o1
IV. Tetrahydroisoquinolinols and Their Derivatives
CH3O
w
c
3
o
g MC0CH3
(c,H, ) .N+cI(I.CI{,CS-HzO
N-COCH3
ONa
H
31 1
''
(0.16-0.21')
Graphite Anode
CH3G
OH
COC H 3
Scheme 163
Oxidation of a 1,2,3,4-tetrahydroisoquinolylether and its 2-acetyl derivative with chromic acid in 33% sulfuric acid yields the phthalonimide c H 3 0 m N . CH3O C0CH3
1 33% HaSO..
ch30 cH30&
CH
CH3O m
0
146 N
H Scheme 164
c. Condensation Although mechanistically uncertain, a 2-aroyl-l,2,3,4-tetrahydroisoquinolyl ether is reported to react with methyl opianate in the presence of concentrated sulfuric acid to give the condensed product (149).5"-513 "C0
JQ * rJ0
conc. HISO.
CHO
0ch3
srheme 165
312
Isoquinolinols and Their Hydrogenated Derivatives
d. Nucleophilic Substitution The exchange of a methoxyl group to an ethoxyl group at the benzylic 4 position is documented when a 2-benzoyl-l,2,3,4-tetrahydro-4-rnethoxyisoquinolyl ether is boiled in ethanol.603
C. 5,6,7,8-Tetrahydroisoquinolinols and Tbeir Ethers 1 , Preparation
a. By Reduction Catalytic hydrogenation of isoquinolines bearing an electron-donating group or Raney nickel under at the 1 or 4 position over Adams catalyst60~6'~69*100*'18 gives rise to the following compounds: 5,6,7,8-tetrahydro-4pressure' isoquinolinols8*61~100*118 and 5,5,7,8-tetrahydro-4-methoxyisoquinoline.1'8 The mode of the reaction is consistent with the general rule (see Section 1V.A. 1.b). Diazotization followed by reduction with hypophosphorous acid of 4aminol-ethoxy-5,6,7,8-tetrahydroisoquinolineyields l-ethoxy-5,6,7,8-tetrahydroisoquinoline.6*
2 . HsPOa
Scheme 167
iV. Tetrahydroisoquinolinolsand Their Derivatives
313
b. By Substitution Decomposition of the diazonium salt from 4-amino-5,6,7,8tetrahydroisoquinoline with cupric sulfate leads to 5,6,7,8-tetrahydro-4isoquinolinol,6r' which, when methylated with diazomethane, yields the 4-methoxytetrahydroisoquinoline."* 0-Tosylation of the tetrahydro-4isoquinolinol proceeds normally with tosyl chloride and pyridine.61
1. NaNOI, HISO,
aq.
scheme 168
4-Cyano-3-methoxy- and 4-cyano-3-ethoxy-5,6,7,8-tetrahydroisoquinolines react with phosphoryl chloride to produce 3-methoxy- and 3-ethoxy-5,6,7,8tetrahydroisoquinolines.622 Reaction of 4,4-ethylenedioxy- or 4-benzyloxy-lcyclohexenylpyrrolidines with 1,2,44riazabenzene is shown to give 7,7-ethylenedioxy- or 7-benzyloxy-5,6,7,8-tetrahydroisoquinoline~.~~~
2. Reacfions Ether cleavage of 1-ethoxy-5,6,7,8-tetrahydroisoquinolineb2 ' with 48% hydrobromic acid yields 5,6,7,8-tetrahydro- 1(2H)-isoquinolinone. Detosylation takes place on catalytic hydrogenation of 5,6,7,8-tetrahydro-4(p-tosy1)isoquinoline over Adams catalyst in the presence of concentrated hydrochloric acid.61
sdnme 169
314
Isoquinolinols and Their Hydrogenated Derivatives
V. OCTAHYDRO- AND DECAHYDROISOQUINOLINOLS A.
Preparation
1. By Ring Closure The Pictet-Spender type cyclization of I-cyclohexenyl and I,4-cyclohexadienyl a-ethylamines with formalin and 5N hydrochloric acid gives rise to 4a-isoquinolinols, red e ~ a h y d r o -and ~ ~1,2,3,4,4a,5,8,8a-o~tahydro-~~~.~~’ ~,~~~ spectively.
Scbeme 170
2. By Reduction Decahydro-4,’ and decahydr0-7-~isoquinolinols are produced by exhaustive catalytic hydrogenation under drastic conditions of the respective isoquinolinols, for example, Raney at a high pressure (150-160 kg/cm2)and an elevated temperature or Adams catalyst234*235*628 at a low pressure (50psi or 2.8 kg/cm2) in acetic acid containing concentrated sulfuric acid. The resulting decahydroisoquinolinolspossess cis-fused rings with the exception where a mixture of a trans isomer and cis is produced by Adams catalyst.628
Scheme 171
Four possible stereoisomers [cis,cis (150); cispans (151); trans,cis (152); trans,trans (153)] of decahydro-4-isoquinolinol are known. The former two’ 18.629 are produced on hydrogenation of 4-isoquinolinol over Raney nickel or of 5,6,7,8-tetrahydro-4-isoquinolinolover Adams catalyst and on lithium
V. Octahydro- and Decahydroisoquinolinols
315
PtOa/Hz CH,C02tl
150 CH3C02
LiAlH,
..
0
ether
151
Scheme 172
LiAIH, TttF
*
d
N
H
152
LiAlH, THF
153 Scheme 173
aluminum hydride reduction of cis-4-acetoxy-3,4,4a,5,6,7,8,8a-octahydro-1 (2H)-isoquinolinone.The latter two are formed630on lithium aluminum hydride reduction of the respective rrans-4-acetoxy-3,4,4a,5,6,7,8,8a-octahydro-l(2H)isoquinolinones The stereochemistry of these isomers is discussed in terms of hydrogen bonding, the presence of which is estimated by the measurements of pK,, values and infrared spectroscopy.Since pK; values of the &,cis (150) and cis,trans (151) isomers are 9.68 and 10.20, respectively, the latter is clearly hydrogen-bonded intramolecularly. As a result, these isomers exist in a nonsteroid conformation.'"? Ratios of the hydrogen bonded molecules in the cis,cis and cispans isomers are infrared-spectroscopically determined at 16% and 44%, respectively, suggesting that 84% of the former isomer exist in a nonsteroid conformation. As to the latter, an intrinsic steric repulsion between the axial hydrogen at
Isoquinolinols and Their Hydrogenated Derivatives
316
the 8 position and the hydrogen or the lone-pair electrons of the nitrogen in the steroid conformation probably shifts the equilibrium toward the other nonsteroid conformation accompanied by inversion at the nitrogen. While the pK.. value of the trans,& isomer (152) is approximately 10.54, that of the ttans,trans isomer (153) is 9.66. Infrared spectroscopy of the former isomer6" indicates that the hydrogen-bonded molecules amount to 74%. Thus, the proposed conformational equilibrium6'' of these isomers is illustrated in Scheme 174.
+
26 %
H
152 Scheme 174
2-Acetyldecahydr0-5-~"and 2-acetyldecahydr0-7-~~'isoquinolinols are produced on high-pressure hydrogenation of 2-acetyl-I,2,3,4-tetrahydroisoquinols over Raney nickel (W7) in the presence or absence of sodium hydroxide.
Raney N i / H I NaOH. CIHSOH
A
-62
"COCH,
Scheme 175
2-Acetyldecahydr0-4a-~*~ or 2-benzoyIdecahydro-4-' l 8 isoquinolinol is produced by acetylation of the respective decahydroisoquinolinols with acetic
V. Octahydro- and Decahydroisoquinolinols
317
anhydride and pyridine or benzoylation with benzoyl chloride and 10% sodium hydroxide. N,O-Dibenzoylation also occurs in the latter reaction. Reduction of cis-octahydro- or cis-2-benzoyloctahydro-6(5H)-isoquinolinone with lithium aluminum hydride or with sodium borohydride yields a diastereomeric mixture of cis-decahydro- or cis-2-benzoyldecahydro-6isoquinolinol. Mesylation and subsequent treatment with Meerwein reagent and aqueous sodium carbonate, transform a mixture of the 2benzoyldecahydro-6-isoquinolinols to that of cis-decahydro-6-mesyloxyisoquinoline~.~~* Incubation of Sporotrichum exile Q M -1250 under anaerobic conditions in the presence of racemic cis-2-benzoyl- 1,2,3,4,4a,7,8,8a-octahydro-6(5H)isoquinolinone (154) causes a chiral hydrogenation of the keto group leading to a mixture consisting of 4a(S),8a(R)-2-benzoyldecahydro-6-isoquinolinol (155)6 and 4a(R ),8a(S)-2-benzo yldeca h yd ro-6-isoq uinolinone ( I S ) , both of which are of 70% optical purity. Interestingly, 4a(S),8a(R)-2-benzoyldecahydro6-isoquinolinone of 70% optical purity is transformed to the 4a(S),8a(R)decahydroisoquinolinol (155) of 90% optical purity on similar treatment.
sporot r ichum
r
155
L
154
156 Scheme 176
B. Reactions 1. N-Alkylation N-Ethylation or N-methylation * l8 of cis,cis-decahydro-4-isoquinolinolis performed with ethyl bromide or 37% formalin and 88% formic acid. 1,2,3,4,4a,5,8,8a-Octahydro-4a-isoquinolinol can also be N-methylated with the latter reagent.627 An unusual N-ethylation takes place with ethanol (see Section I.A.2.b). N-Carbomoylation is also effected by reaction with an isocyanate.625
318
Isoquinolinols and Their Hydrogenated Derivatives
seheme 177
2. Oxidution Jones oxidation of cis-2-acetyldecahydro-5-isoquinolinolyields trans1,2,3,4,4a,7,8,8a-octahydr0-5(6H)-isoquinolinone.~~ Similar oxidation is performed with chromic acid in acetic acidSS*or 2% chromic anhydride in 95% acetic
VI.
ISOQUINOLINETHIOLS AND THEIR HYDROGENATED DERIVATIVES A.
Isoquinolinethiols and Their Ethers
I. Prepurution a. By Ring Closure
m-Methylthiobenzylaminoacetal or its N-p-tosylamide can be used in the Pomeranz-Fritsch reaction. In this way,634 5- and 7-methylthio-l,2,3,4tetrahydro-4isoquinolinolsand 5-and 7-methylthioisoquinolines are produced. With m-methylthiophenethylamine and its formamide the Pictet-Spengler reaction or the Bischler-Napieralski reaction proceeds smoothly634 to give 6-methylthio-l,2,3,4-tetrahydro-or 6-methylthio-3,4-dihydroisoquinoline, respectively. b. By Substitution 1 -Chloroisoquinoline, on treatment with sodium tert-butylmercaptide in ethanol or tetrahydrofuran, gives 1-(t-butylthio)is~quinoline.~~~ Similarly, 4bromoisoquinoline reacts with sodium phenylmercaptide in methanol or diUnder the latter methylformamide to yield 4-phenylthioisoq~inoline.~~~*~~~ condition^^^' 4-methylthio-, 4-ethylthio-, and 4-isopropylthioisoquinolinesare produced. Addition of sodium methoxide is known to vastly improve the reaction with respect to both velocity and yield. 2,3,5,6-Tetrahydrothiazolo[2,3-a]isoquinolinium perchlorate reacts with sodium phenylmercaptide or ethylmercaptide in dimethylformamide to give 3,4-dihydro-l-[2-(phenylthio)ethylthio]- or 1-[2-(ethylthio)ethylthio)i~oquinoline.~~~
VI. lsoquinolinethiols and Their Hydrogenated Derivatives
3 19
Bis (4'-ethoxy-!'-isoquinolyl)sulfide(157)72 is produced when l-chloro-4ethoxyisoquinoline reacts with thiourea or with sodium 4-ethoxy-lisoquinolylsulfide.
SNa Scheme 178
1-Methylsulfonyl- or 1 -nitro-isoquinoline reacts with thiophenoi to give 1phenylthioi~oquinoline~~~~~ even in the absence of a base. obviously as a result of the strongly electron-withdrawing effect of the substituent (see Section LA. 1 .d).
C.H,SH,
or C.H,SNa,
-
A 170'
NO2
SC6H5
Scheme 179
c. By S-Alkylation Alkylation of a 1-71.72.639-645 or 3-646 mercapto group of isoquinolines is performed with alkyl halides mostly in the presence of a base, such as sodium ethoxide 641.642 and caustic alkali. b39*640 Similarly, benzoylation of 3(2H)thioisoquinolinone proceeds with ease.646 C.H,COCH*Br SaOC I H
,
c
SH
SCH,COC,H, %beme 180
The S,Z-type reaction of r-acetobromoglucose with 1-mercaptoisoquinoline lakes place to give 1 -~-acetylglucosylthioisoquinoline.639
320
Isoquinolinols and Their Hydrogenated Derivatives
d. By 0-Alkylation and 0-Acylation Alkylation of l-methylthio-3(4H)-isoquinolinone with alkyl halides in the presence of 8% sodium hydroxide or 2a-thiohomophthalimide with diazomethane yields 3-alkoxy-l-methylthioisoquinolines.647On the other hand, the isoquinolinone, when treated with acetic anhydride and 5% potassium hydroxide, is transformed to 3-acetoxy-1-methylthio- or l-ethylthio-is~quinoline.~~~ CHaNn
OCOCHj
t
(CHaCO)10
SCH3 CHa I 8% NaOH aq.
A
5% KOH aq.
SCH3
SCH3
Scbeme 181
2. Reactions a. Reduction Borohydride reduction of 1-alkylthioisoquinoline in an acidic (pH 3-4, maintained by addition of jxrchloric acid) or a basic medium produces l(2H)isoquinolinone and its thio analog besides the unchanged i s ~ q u i n o l i n e In .~~~ contrast, 12-dihydro- 1-methylthioisoquinoline(158) 649 is mainly formed on NaBH.
I +
158 Scbeme 182
V1. Isoquinolinethiols and Their Hydrogenated Derivatives
321
lithium aluminum hydride reduction of 1 methylthioisoquinoline and its perchlorate. However, the same reduction of 1-allylthioisoquinoline and its perchlorate leads to 1 (2H)-thioisoquinolinone. 1 -@-Hydroxyethy1)thioisoquinoline reacts similarly.649 b. Substitution Amination of 4-methylthioisoquinoline at the 1 position is performed by use of potassium amide in liquid ammonia 650 or methanolic ammonia 645 (see Section I.A.2.e).
@;
l i qKNH . NH1 a
NH2 Scheme I83
Reaction with carbethoxyguanidine produces, 9,1O-dimethoxy-2-amino-6,7dihydro-4H-1,3,5-triazino[2,1 -~]isoquinolin-4-one.~*~
c. Miscellaneous Reactions
Reaction of 1-cyanomethylthioisoquinolinewith benzoyl chloride leads to the sydnon (159), which is cleaved to yield 1-carboxymethylthioisoquinolinewhen A similar sydnon is produced with treated with 10% hydrochloric acetyl chloride.640 C .H, COCl benzene '3
SCH2CN
159
The perchlorate of N-(1'-isoquinoly1thio)methyIsuccinimide(160) undergoes condensation with a mixture consisting of polyphosphoric acid and phosphoryl chloride to produce the thiadiazino[2,3-a]isoquinolin-4-ium perchlorate
(161).644
322
Isoquinolinols and Their Hydrogenated Derivatives
Rearrangements peculiar to the sulfur atom are known. First, 142oxocyclohexy1thio)isoquinoIine undergoes sulfur extrusion to lead to 1-(2oxocyclohexy1)isoquinoline when heated in dirnethylf~rmamide.~~~ Second, treatment of a /?-glucosylthioisoquinoline(162) with mercuric bromide exclusively gives sulfur to nitrogen glucose migration639yielding the 2-(/3-glucosyl1(2H)-thioisoquinolinone(163) instead of anomerization, which is the prevalent change when a /3-glucosyloxy counterpart is treated similarly.
4-
R&;p
R;&p I
RO
H OR
164
R-COCH,
HgBr,, toluene
RO
H
OR
163
0.2M NaOCH,-CH.OH
OH
R = COCH,
VI. Isoquinolinethiols and Their Hydrogenated Derivatives
323
Alkaline hydrolysis (sodium methoxide in methanol or aqueous sodium carbonate) of an acetate6’’ or an ester72in the side chain of l-alkylthioisoquinolines does not influence the rest of the molecule. However, boiling 3-methoxy1-methylthioisoquinoline in concentrated hydrochloric acid results in the formation of h ~ m o p h t h a l i m i d e . ~ ~ ~
conc. HC1
A
SCH,
0
B. 1-MethylthioisoquinoliniumIodide I. Preparation a. By Methyl Iodide 1-Methylthioisoquinoline forms the methiodide (164) devoid of quaternization at the sulfur atom on treatment with methyl iodide,6S1probably because the nucleophilicity of the nitrogen considerably increases with the participation of the lone-pair electrons of the sulfur.
W N -WN: methanol Cfree H s I acetone
I-
A
CH3
SCH3
SCH3
164
Isoquinolinols and Their Hydrogenated Derivatives
324
C. 3,4-Dihydroisoquinolinethiolsand Their Ethers 1, Preparation a. By Ring Closure Heating of phenethyl chlorides and alkyl or aryl thiocyanates with or without a nonaqueous solvent such as nitrobenzene, carbon disulfide, and odichlorobenzene causes cyclization to produce 1-alkylthio- or l-arylthio-3.4-
dihydroisoq~inolines.~~~ CH,O
@2
CHSSCN
A
CH30
CH3OP
N
(
6
1. (CHs)sO+BP; 2. 5N NaOH
-
&N' CH3O
SCH3
, CH&lr, A CH 30 8CH3
While these cyclizations are also effected with stannic another variation consists of refluxing phenethyl isothiocyanates with trialkyloxonium tetrafluoroborate in d i ~ h l o r o m e t h a n e . ~ ~ ~ b. By Alkylation
1(2H)-Thioisoquinolinones are readily methylated on sulfur by use of methyl iodide or dimethyl sulfate to yield 3,4-dihydro-l -methylthioisoquinoline~.~~~*~~~
2. Reactions a. Nucleophilic Substitution The carbon at the 1 position of l-alkylthio-3,4-dihydroisoquinolinesis susceptible to nucleophilic attack (see Section II.A.2.c). Thus, primary am-
VI. Isoquinolinethiolsand Their Hydrogenated Derivatives
325
ines,65j.656 dim e t h ~ l a m i n e ,thio~emicarbazide,~~~ ~~~ g l y ~ i n e , 6amino ~~ es6 5 3 and f ~ r m y l - ~and ~ ' ethoxycarbonylhydrat e r ~ diethylaminoacetal, , ~ ~ ~ zine6s6 react at the 1 position. Condensed heterocycles are formed in the case of the last two amines.
CH CH30
W N
C1-
NHaCHzCH(0CaHs). DHF, 135"
SCH,
- cH3
-
CH 30
N
Scheme 192
D. 1,2-Dihydro-2-(ptosyl)isoquinofines I. Preparation a. By Ring Closure The synthetic route to 1,2-dihydro-2-(p-tosyl)isoquinolylethers is described elswhere (see Section 1I.D.l.a). 1,2-Dihydro-2-(p-tosyl)isoquinoline (166) is formed when N-[Z-(/?-hydroxyethyl)benzyl J-p-toluenesulfonamide (165) is oxidized with dicyclohexylcarbodiimide and dimethyl sulfoxide or with chromium trioxide in pyridine.
165
166 sfheme 193
b. By Miscellaneous Reactions lsoquinoline reacts with sodium hydride and p-tosyl chloride in the presence of hexamethylphosphortriamide to yield 1,2-dihydro-4-(p-toluenesuIfenyl)-2-(ptosy1)isoquinoline (167)? The initial formation of p-toluenesulfinyl chloride
326
Isoquinolinols and Their Hydrogenated Derivatives
and of a sodium salt of 1,2-dihydroisoquinoline due to sodium hydride, which functions as a reducing agent, is deemed to be responsible for the reaction. Whereas desulfurization of the dihydroisoquinoline (167) with Raney nickel (slightly more active than W2) yields 1,2-dihydro-2-(p-tosyl)isoquinoline (166),6s8deoxygenation with Raney nickel (W2) and oxidation with m-chloroperbenzoic acid of the former result in the formation of l,Zdihydro-4-@toluenethi0)-2-(p-tosyl)-~~~ and 1,2-dihydr0-2,4-bis(-tosyl)-~~* isoquinolines (168 and 169), respectively.
scheme 194
E. 1,2,3,4-Tetrahydro-2-sulfenyl- and 1,2,3,4-Tetrahydro2-sulfonylisoquinolines 1. Preparation a. By Sulfenylation
1,2,3,4-Tetrahydroisoquinolinereacts with 2,4-dinitrobenzenesulfenylchlor659 ide to yield 1,2,3,4-tetrahydro-2~2’,4’-dinitrophenyl)thioisoquinoline.
VJ. Isoquinolinethiols and Their Hydrogenated Derivatives
327
Sheme 1%
b. By Ring Closure
Two methods for the preparation of 2-arenesulfonyl-l,2,3,4-tetrahydroisoquinolines by cyclization have been established. One is based on the reaction of heating an N-phenethyl-N-(p-tosy1)glycine(170) with phosphorus pentoxide in xylene 660 or polyphosphoric acid. 605-614 The acid chloride (171) and the anilide (172) of the sulfonylglycine also undergo the cyclization with aluminum ~ h l o r i d e , ~borontrifluoride ~~*~~' etherate,605 and phosphoryl chloride or hydtated phosphoryl chloride,42 respectively.
170
AlCl.,
171
COC 1
so 2C6H5
CHIC12
-70"
S0ZC6H5
The other method makes use of the reaction with arenesulfonamides of 048bromoethy1)benzyl bromide (173) in the presence of potassium carbonate, 663 A
Isoquinolinols and Their Hydrogenated Derivatives
328
double cyclization leading to the 2-[p-( 1',2',3',4-tetrahydroisoquinol-2'yl)benzenesulfonyl]-l,2,3,4-tetrahydroisoquinoline (174)663 occurs when the bromide (173) reacts with 0.5 eq of p-aminobenzenesulfonamide. A series of reactions, mesylation of N-[2-(~-hydroxyethyl)benzyl)-p-toluenesulfonamide followed by cyclition with sodium hydride in dimethylformamide 664 consistutes a variant of the latter method.
/ 173
P-NH,C.H.SO.NH,
(1 eq.)
2@NH
reflux
*
L p-NHIC.H.SOINH2
(0.5 eq.)
K,CO,, C,HtOH reflux
174
2. Reactions Both hydrolysis of 2-(p-acetamidobenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline with concentrated hydrochloric acid in ethanol 612*663 and reduction of 2-(p-nitrobenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline with zinc and ammonium chloride6" yield 2-(p-aminobenzenesulfonyl)tetrahydroisoquinoline.
VI. Isoquinoiinethiols and Their Hydrogenated Derivatives conc.HC1.
or d i l . H C l .
SOzC6H4NHCOCH3-P
329
CIH,OH
reflux
F. Sulfoxides and Sulfones in Isoquinolines
I. Preparation a. By Oxidation Oxidation of 1-methylthio- and 1-phenylthio-isoquinolineswith potassium permanganate in acetic acid 74*80leads to sulfones, l-methanes~lfonyl-,~~*~~ and l-benzene~ulfonyl-~~ isoquinolines, whereas with m-chloroperbenzoic acid, 1-methylthioisoquinolineaffords the sulfoxide at 20 0C.79
-
SO2CH3
scn3 o-CIC.HsCOdl
2. Reactions a. Nucleophilic Substitution Since the 1-sulfonylgroup greatly reinforces the reactivity of the carbon at the
1 position toward nucleophiles, 1-methanesulfonylisoquinolineenters into reac-
tion with hydrazine, aniline, Grignard reagents, and a variety of active methyls
330
Isoquinolinols and Their Hydrogenated Derivatives
and methylenes such as acetone, acetonitrile, and so onEowithout difficulty. One drawback of the reaction, however, is the formation of 1(2H)-isoquinolinone, which apparently is produced by the action of the liberated sulfinic acid on the starting isoquinoline.
-@ (CH,)ICO. NaNH.
benzene, reflux
+ CH2COCH3
W!H 0
sckme 202
VI1. NATURAL PRODUCTS 6,7,8-Trioxygenated tetrahydroisoqunolines are the members of Anhaloniurn alkaloids, and the structures of anhalamine (133)607*665 - 672 and anhalinine 1*673were elucidated in the beginning of nineteenth century; (139)666*667*6699.67 the former is 1,2,3,4-tetrahydro-6,7-dimethoxy-&isoquinolinol, while the latter 1,2,3,4-tetrahydro-6,7,8-trimethoxyisoquinoline.Recently, gas-liquid chrom a t o g r a p h ~ and ~ ~ its ~ .combined ~~~ use with mass or tandem mass ~ p e c t r o m e t r y ~ made ’ ~ . ~ it ~ ~possible to establish the structures of minor consituents. Thus, 6 , 7 - d i r n e t h o ~ y - , 4 ~7,8-dimetho~y-,4’*~~~ .~~~ 5 6 7isoquinolines; 3,4-dihydro-6,7t r i r n e t h o ~ y - ,and ~ ~ ~5,6,7,8-tetrametho~y-~~~ 3,4-dihydro-5,6,7d i m e t h o ~ y - , 4 ~ , ~ ~3,4-dihydro-7,8-dirnethoxy-,41.6’5 ’.~~~ isoquinolines; 1,2,3,4trimetho~y-,6~’ and 3,4-dihydr0-5,6,7,8-tetramethoxy-~~’ tetrahydr0-6-methoxy~~*~~~ (l~ngimammatine)-,~’~.~~~ 1,2,3,4-tetrahydro-71,2,3,4m e t h o ~ y(~~ e~b~e r i d i n e ) - , 1,2,3,4-tetrahydro-5,6-dimethoxy-,678 ~~~ tetrahydr0-6,7-dimethoxy~~*~~’*~~~ (heliamine)-,677.6’8 1,2,3,4-tetrahydro-6,8dirnetho~y-,6’~1,2,3,4-tetrahydr0-7,8dimethoxy~’*~~~ (lemaire~cereine)-,~~~ 1,2,3,4-tetrahydr0-5,6,7-trimethoxy~~~( n ~ r t e h u a n i n e ) - , ~ ~and ~ 1,2,3,4tetrahydr0-5,6,7,8-tetrarnethoxy-~~’ isoquinolines; and 1,2,3,4-tetrahydro-7,89
,
VIII. Pharmacology
33 1
dimethoxy-6-isoquinolinol( i s ~ a n h a l a m i n e ) ~ and ~ ” ~ ~three ~ 2-acyl-1,2,3,4tetrahydroisoquinolines, 2-acetyl- and 2-formyl-1,2,3,4-tetrtahydro-6,7dimethoxy-8-isoquinolinols,670~67z~674 and 2-formyl-l,2,3,4-tetrahydro-6,7,8trimethoxyisoquinoline670~67z*674 were identified as constituting this class of alkaloid. The presence of 1,2.3,4-tetrahydr0-6,7-isoquinolinediolin the rat brain is shown by use of gas-liquid chromatography combined with mass spectrom e t r ~l 9, ~in which the tetrahydroisoquinolinediol:dopamine ratio is about 1 : 100. Moreover, two betaine-type alkaloids, 3,4-dihydro-6,7-dimethoxy-8oxidoisoquinolinium ( 175)680and its 2-methyl analog (176),680in addition to a trace of anhalamine ( 1 3 3 p 0 were isolated from Lophophora williamsii var. casspitosa. Recently, 3,4-dihydro-6-methoxy-2-methyI-7-oxidoisoquinolinium (pycnarrhine)681*682 and 3,4-dihydro-7-methoxy-2-methyl-8-oxidoisoquinolinium ( i ~ o p y c n a r r h i n e )were ~ ~ ~ isolated from Corydalis stricta and Poponia pisocarpa, respectively.
0-
175 176
R-H R=CH,
Scheme 203
VIII. PHARMACOLOGY A.
Quaternary Salts of lsoquinolinols and Their Esters
An inhibition of acetylcholinesterase in electric eels (Electrophorus electricus) is observed by use of the fresh electric organ on mono- and diquaternary salts of 5-isoquinolino1z00 and its m e ~ y l - , ~diethylph~sphonyl-,’~~ ’~ and dimethyl~ a r b a m y lesters. - ~ ~ ~Furthermore, an inhibition of human plasma cholinesterase is observed with 2-ethyl-5-hydroxyisoquinoliniumbromide (47) and its acetate,686which also possess cardiovascular in anesthetized dogs. The . ~ ~ ~ toxicities of the former same is true for 5-isoquinolinol h y d r o ~ h l o r i d eAcute are also presented. Quaternary salts of 5-, 7- or 8-isoquinolinol with cepham derivatives were prepared for antibacterial activity.1z2*688
lsoquinolinols and Their Hydrogenated Derivatives
332
R-CH,,
X - = I-
R = C2H5, X- = Br" OR2
'
OR
R' = C2H5, R2 COCH,, R = CH3, R2 =S02CH3,
X- = Br-
R' = CH, R' = CH,,
X- = picrate X- = I -
R~ = PO(OC2H5)2, R2 = CON(CH3)2,
x-
=I-
OR
)(- = p i c r a t e
B. Quaternary Salts of Alkoxyisoquinolines 2-n-Amyl-6,7-dimethoxyisoquinolinium bromide (177)'69 possesses bloodpressure-lowering, spasmodic, and local anesthetic activity, while alkyl halides (59,178-184) of 0-methyltarconine (7)19*exhibit toxicity comparable to nicotine in mice. On the other hand, paralyzing and curarizing effects are observed for 2,2'decamethylene-bis(6,7-dimethoxyisoquinolinium)diiodide (185),'90*19' The ED,, of which is 1.8 mg in a mouse.
H
VIIJ. Pharmacology
cCH30
333
( 0O W N : , *r-n-Cs"l
1
CH,O
177
59 178 178 180 181 182 188 184
X' R = CH3,
X - = I'
R = C2HS,
X-=Br-
R = n-C3H7,
X- = B r -
R = n-C,H,
X- = B r -
R = n-C5Hll,
X- = B r -
R = i-CsHIl,
X'
R = n-C6HI3,
X' = Br'
R=C7H7,
X-=CI-
=
Br-
6-Isopropoxy-2-methylisoquinoliniumiodide (186)"' possesses antidiabetic activity equal to phenformin [N-(2-phenethyl)imidodicarbonimidic diamide] and is an effective agent for hypoglycemia in rats and dogs.
185
5-[3'-(5'-Tetrazoyl)propoxy]isoquinoline (not the quaternary salt) is reported
to act as a throboxane A, synthetase inhibitor.689
C. I-Alkoxy- and l-Aryloxyisoquinolines Carrying Basic Functions This class of compounds are claimed to have promising pharmaceutical activities. Thus, 143'4 1"-morphorinyl)propoxy]-' l o and 6.7-dimethoxy-l-(l'-
Isoquinolinols and Their Hydrogenated Derivatives
334
methyl4‘-piperidylo~y)-~~ isoquinolines (187 and 188) are local anesthetics, while 1-(3’-pyridyloxy)-and 1-(3’-quinolyloxy)isoquinolines(189 and are tranquilizers and bactericidies.
180
O Q
190
o w
D. Alkoxy-3,4-dikydroiui~linesand Their Quaternary Salts At an early stage, 3,4-dihydro-6,7-dimethoxyisoquinolinehydrochloride295 has been shown to have very little effect on an isolated uterus or on the heartbeat and is lethal in a small dose. Later, it was confirmed that the hydrochloride has a positive tail reaction and has no effect on HeLa and Ehrlich carcinoma, and causes tremor.690
cH30a CH30
c1-
The effect of raising blood pressure and of paralysis is observed with hydrastinine chloride (87, X- = Cl-).691 Both the chloride692and cotarnine chloride (75, X- =C1-)692 have no antitussive effect against dogs and guinea pigs. Lodal, 3,4-dihydro-6,7-dimethoxy-2-methylisoquinolinium known as an a~tringent,~~’ like cotarnine, has a contracting action on an isolated uterus and is a pure short-acting pressor.
335
VIII. Pharmacology
A systematic study of these types of compounds (191-1%)350 indicates that pressor activity is dependent on the length of the alkyl chain and a gradual change from pure pressor to pure depressor with the lengthening of the carbon chain is noted, specifically, shortening of the alkyls bis to methyl enhances the pressor activity, while lengthening up to n- or iso-amyl results in the manifestation of depressor activity. 2,2'-(Decamethylene)-bis(3,4-dihydroisoquinolinium) diiodide acts as neuronuclear blocking agent.9642-Alkyl-3,4-dihydro6,7-dihydroxyisoquinolinium chlorides350exhibit circulatory effects in dogs, and the pressor-depressor relationship as to the length of the alkyls is similarly observed with the chlorides, which stimulate the rabbit and guinea pig uteri.
CH 30
c1-
c H 3 0 m N : R CH30
CH3
c1-
191 194 193 194 195 196
R-C~HS R = n-C3H7 RI i - C 3 H 7 R = n-C,H, R = n-C5Hl R - i-C5H11
sekme 210
Hypotensive activity, an acute toxicity in anesthetized dogs, and no ganglion blocking effect are observed with the unsymmetric bis-quaternary bromide
'
""'m+
(197).69
CH3O
HO
"-(
B r-
c1-
CH2 1
3i( CH3) 3 Br-
197
scheme 211
6,7-Diethoxy-3,4-dihydro-2-methylisoquinolinium chloride350 has a longlasting depressor effect on dogs, and some 6-alkoxy-2-alkyl-3,4-dihydroisoquinolinium chlorides350 are shown to be of either a biphasic depressor-pressor action or purely a depressor.
336
Isoquinolinols and Their Hydrogenated Derivatives
c1R' = CH3, R1 =CH3, R
1
=
n-C,H,,
R2 = CH3 RZaC2H5 R2 = C2H5
scheme 212
E. 1,2,3,4Tetrahydroisoquinolinolsand Their Ethers Since 1,2,3,4-tetrahydroisoquinolinols are regarded as a cyclic equivalent of epinephrine analogs, much concern is posed on the physiological properties of the former. An epinephrine vasomotor reversal in dogs and pressor activity are observed with 1,2,3,4-tetrahydro-6-isoquinolinoland 1,2,3,4-tetrahydro-5,6isoquinolinediol hydrochloride^,^^^^^^^ the toxicity of is also discussed. R
R = H , OH scbeme 213
1,2,3,4-Tetrahydr0-5,8-isoquinolinediolis known to lower blood pressure and transiently increase pulse rate in spontaneously hypertensive and deoxycortisane acetate (D0CA)-salt-hypertensiverats.50gInvestigation of metabolites of 1,2,3,4-tetrahydro-4-isoquinolinolor its 2-carbamidyl derivative in the brain has also been A formal cyclic epinephrine lacking an a-hydroxyl group is 1,2,3,4tetrahydro6,7-isoquinolinediol (198), which is endowed with some notable actions. The base causes hypothermia7" by releasing catecholamines from central adrenergic nerve terminals and functions as false adrenergic neurotransmitt e r ~ . ' ~ ' . 'It~ ~ is also reported to affect brain membrane receptors,703acts as a inhibits of monoamine stimulant of locomotor activity in ~ x i d a s e , ~- ' ~l 1 and reduces the intensity of tremors produced by subcutaneous
VIII. Pharmacology
337
harmane” or epileptogenic and behavioral change induction effects.713The base has also been investigated as a dopamine metabolite by the brain.519*699*714-The hydrochloride (199) has been shown to have a direct z-adrenergic action567as measured by contraction of the nictitating membrane of spinally anesthetized cats, epinephrine vasomotor reversals67in dogs, and a pressor activity696in dogs and cats. Toxicity of the hydrochloride69s is also documented. Moreover, a sympathomimetic activity has been confirmed with the hydrobromide (200)7’7by use of pithed rats. The hydrobromide (201)(ED,,: 7.4 x 10-’M) shows inhibitory effect on the accumulation of ’H-dopamine by rat brain An accumulation of ’I+labeled norepinephrine by cardiac sympathetic nerve in mice pretreated with reserpine (10 mg/kg, injected intraperitoneally) is 12.7%. Similar administration of the hydrobromide (200)(10 mg/kg, injected intravenously) improves the accumulation up to 38.2%.719The most potent analog, 1,2,3,4-tetrahydro-4,6,7isoquinolinetriol hydrochloride (u)l),720 however, possesses a-adrenergic activity at a dose approximately lo00 times greater than that of ( - )-epinephrine in anesthetized dogs. In contrast, a related analog, 1,2,3,4-tetrahydro-4,7,8isoquinolinetriol hydro~hloride,’~~ has practically no such an activity. The hydrobromide (200) (6 x 10-’M) elicits small random twitches of the rat hypogastric nerve-vas deferens preparation, while (202)(6 x lO-’M) shows no response during a 30-min incubation period.721
HomNH
HO
HO ‘ O W N ; ,
186
20 1
X-
188 x- = c1400 X - = B r -
202
OH
Scheme 214
Effects of 1.2,3,4-tetrahydro-4,6,7-isoquinolinetriol on endogeneous catecholamine have been i n ~ e s t i g a t e d . ’ ~ ~ * ~ ~ ~ ~ ~ ’ ~ hydrochloride^^^^.^^^ of 6-ethoxy- and 6,7-diethoxy-l,2,3,4tetrahydro isoquinolines, 5-ethoxy-l,2,3,4-tetrahydro-6-methoxy-,7-ethoxy-1,2,3,4-tetrahydro-6-methoxy-, and 6-ethox y- 1,2,3,4-tetrahydro-7-methoxy-isoquinolines and 1,2,3,4-tetrahydro-6-methoxyand 1,2,3,4-tetrahydr0-5,6-dimethoxyisoquinolines possess epinephrine vasomotor reversal activity in dogs
338
Isoquinolinols and Their Hydrogenated Derivatives
and decreased pressor activity. Toxicity of the hydrochloride698has also been studied. Both 3- and Caryloxy- 1,2,3,4-tetrahydroisoquinolines and their salts 1,2,3,4have been shown to have analgesic or anticonvulsant Tetrahydr0-6-methoxy,~~~*~’~ 1,2,3,4-tetrahydr0-7-methoxy-,’~’*~~ 3.727 or 1,2,3,4-tetrahydro-6,7-dimetho~y-~~~~’’~ isoquinoline and its derivatives have been investigated pharmacologically or as metabolites in the brain. The intrastriatal injection of the hydrobromide (200) and the hydrochlorides of 1,2,3,4-tetrahydro-6,7-methylenedioxy-and 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinolines in guinea pigs causes weak development of abnormal involuntary movements (dyskinesias).
RomN;I OR
cH30&i2 c1-
c1-
R-CH3,
C2H5
R - C H 3 , C2H5
R’oQQ2
R20
c1-
1
CH3,
R2
R -CZH,,
2
R
=
1
R1
=
=
C2H5
R =CHj
C2H5, R2
CzH5
Epinephrine vasomotor reversal in dogs is observed for 1,2,3,4-tetrahydro6,7-dimethoxyisoquinolinehydro~hIoride,6~~ which is positive in regard to tail reaction and tremor and negative anti-HeLa and anti-Ehrli~h.~~’ The same is true for 1,2,3,4-tetrahydro-6,7-methylenedioxyisoquinoline hydrochioride.690*732 On the other hand, 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride733 is reported to inhibit the growth of sarcoma 45 in rats by 60-79%. Toxicity of 1,2,3,4-tetrahydro-6,7- or 1,2,3,4-tetrahydro-7,8methylenedioxyisoquinoline hydrochloride698has been reported.
Scheme 216
I X . Analysis and Spectroscopy
339
1,2,3.4-Tetrahydro-5,8-dimethoxyisoquinoline(SK&F 72223) is reported to 7 3 6 and its sulfonimide possess a weak z-adrenoreceptor antagonist has been tested on antagonism of partially purified SRS-A-induced constractions of isolated guinea pig ileum.737 a cactus alkaloid, has little activity The hydrochloride of anhalamine (133),262 as anticonvulsants, tranquilizers, or muscle relaxants, and possesses no significant hallucinogenic action.
IX. ANALYSIS AND SPECTROSCOPY A.
Aaalysis
I . Polarogruphic Analysis See Section II.B.2.a.
2. Fluorimetric Analysis When exposed to gaseous formaldehyde in a dried protein layer under warming, phenolic phenethylamines, including dopamine, norepinephrine, and epinephrine, first produce 1,2,3,4-tetrahydroisoquinolinols,which undergo partial dehydrogenation to give fluorescent 3,4-dihydroisoquinolinols;3,4-dihydr0-6-isoquinolino1~~~ at (pH 6-8, F,,, 510 nm, Em,, 385 nm), 3,4-dihydro-6,7-isoquinolinedio15 2 4 * 5 " 3 5 * 7 38*739 (at pH 6.5-7, F,,, 480 nm, Em,, 400-405 nm;55 at pH 6-10, F,,, 480 nrn740), 3,4-dihydro-4,6,7isoq~inolinetriol~~~~~~~ (F,,, 480 nm, Em,, 280, 320, 410 nmS5),and its metho salts55.552 or carboxymethyl salts.'39 Since the 6,7-diol displays no fluorescence
HOO
m
N
H
-
CH.0 in a d r i e d protein h
OH-
HO Scheme 217
340
Isoquinolinols and Their Hydrogenated Derivatives
at pH 1-5, the phenomenon is in all probability is ascribable to a p-quinonoid structure. 5 3 7*740 Similarly, hydrochlorides of 1,2,3,4-tetrahydro-6,7-dimethoxy-and 1,2,3,4tetrahydro-6,7-dimethoxy-2-methylisoquinolines yield fluorescent 3,4-dihydro6,7-dimethoxyisoquinoline (F,,, 470 nm, Em,, 240, 305, 355 nm) and its metho salt,55s respectively. Thus, the fluorimetric analysis constitutes a potentially useful technique for histochemical identification of primary or secondary cathecolamines in central and peripheral adrenergic nerves.55.555~739 The accumulation of dopamine, norepinephrine, or 1,2,3,4-tetrahydro-6,7isoquinolinediol in the sympathetic nerves of the iris of the rat has been studied by this te~hnique.’~’On the other hand, the 6-01 fluoresces on treatment with hydrogen chloride gas (F,,, 420 nm, Em,, 360 nm).263 Although another possible technique for the analysis of catecholamines and phenethylamine involves a sequence of reactions with formalin and with potassium ferricyanide, only the latter amine is detectable as the metho salt of 6isoquinolinol (at pH > 7, F,, 450 nm, Em,, 370 nm), the presumed fluorescent entity of which is a phenol betaine, 2-methyl-6-oxoisoquinolinium.223 t-Methoxyisoquinoline in 95% ethanol also displays fluorescence (Fmaa 347 nm, Em,, 321.5 nm).742
OH 3. HC1-He0
c1-
CH3
scheme 218
3. Chromatographic Analysis a. Paper Chromatography
’
3,4-Dihydr0-6,7-isoquinolinediol,~ ’3’ 3.4-di hydro-6,7-dimethoxyisoquinoline, and hydr~chloride’~~ and alkyl iodides743of 3,4-dihydroisoquinolyl ethers can be chromatographically analyzed on paper. In a systematic R , values of the alkyl iodides show no linear correlation with number of carbon atoms in the alkyl group but increase with that of the solvent (butanol, 1pentanol, etc.) saturated with water.
IX. Analysis a n d Spectroscopy
341
b. Thin-Layer Chromatography Determination of 1,2,3,4-tettahydro- and 3,4-dihydr0-6-isoquinolinols~~~ (= (see Section IX.A.2), anhalamine (133) and anhalinine (138)668*67’*672 Section VII), and 1,2,3,4-tetrahydro-6,7-isoquinolinedio1606~744 on thin-layer plates is documented. Dopamine hydrochloride yields the diol on incubation with rat brain homogenate in the presence of 5-methyltetrahydrofolicacid.606 Retardation factor (Rf) values728of hydrochlorides of 6,7-dimethoxyisoquinoline and its hydrogenated bases or 1,2,3,4-tetrahydro-7-methoxy-6i s o q u i n ~ l i n o are l ~ ~recorded. ~ c. Gas-Liquid Chromatography Gas-liquid chromatography has been used for the detection of peyote663 and a n h a l ~ n i u m alkaloids ~~~ (see Section VII), 1,2,3,4-tetrahydro-6,7isoquinolinediolas an in vitro metabolite597(see Section IX.A.3.b), and tetrahydroisoquinoline alkaloids formed in the nervous tissues by the condensation of norephinephrine with alcohol metabolite^.^^^*^^^ d. High-Performance Liquid Chromatography This type of chromatography is useful for determination of alkaloids. Conare rapidly detersequently, hydrochlorides and tetrahydroi~oquinolinols~~~ mined by use of ion-pairing reverse chromatography in conjuction with electrochemical detection. Retention time (Rt) values of 6,7-dimethoxyisoquinolineand its hydrogenated bases have been determined.728
B. Spectroscopy 1.
Mass Spectrometry
Mass spectrometry of isoquinolinols, isoquinolinethiols, and their hydrogenated derivatives has not been studied systematically. This restricts its application only to detect molecular ions. Gas-liquid chromatography-mass spectrometry was discussed elsewhere (see Section VII).
h,
Cl- * 1.5H20
c1-
II-
1I11-
' Doubly char@ ions with m/z.
m/z (Relative Intensity)
188(M')b(l kO),173(M' -15)(14+7), 159(Mi-29){6&1). 156(5+2), 142(100*0) M2(M 'y( 1 20). l87(M '- I5)(9rl: 3). 170(4f 3h 159(M -43)( I 2 rl: 2). 142(100+01, I88lM 'T(l1 k I). 173(M - 15)(35k 3), 159IM - 29)(65f8), 156(69* 7), 142(92f 1I) 202(Mt)b(16+2), 187(M'-l5)(18kl), 170(22*3), 159(M+-43)(84* 12). 142(100~0) 202(M ?(2 & 1 ) , I 73{M - 29)(100 f 0). 156(88f9) 216(MtT(2f), 173(M+-43)(100*0), 170(46* 11) B 5 t M ' + 1)(7).2M(M t)(C,~H140z)b(10), l89{100).188(62) 326(M++1)(44). 325(Mt)(C,,H,,NO,)b(55X 320(M'- 15)(24),319(M+-1 -15) 122). 279(Mt - l5-31)(21), 204(21). 190(100~188(23), 176(8.8), 147 (5.9),162'(8), 161SC(60),155'(3), 154'(3)
145(M+p(89), 118(17). 1 17(loo), 1 16(1I), 104(28),103(1l), %(SO), 89(42) 159(M'P(94), 158(100),130(53),129(63), 116(26), 102(29), 89(M), 63(26) 217(Mf)"(72),202(lOO) 217(M+)'(62), 202(100) 272(M'Y(100),271(Mt -1)(16),245(7).244(17), 243(17), 128(9), 116(10), lOl(12) 251(M'Pt100), 252(M'+ 1)(17),250(15).234(8),222(18),145(37),129(17), 116 (19),106(22),101(14),89(119),79(24),77(14) 189(M')"(100), 174(Mi - 15)(14),147(70) 189(M'P(i00), 174(M'- IS)( 15). 146(M -43) 174(M' - 15),158(29),145(44), 129(38), 116(22),103(19), 95(45),89(10).75(10). 63(9),51(6) 207(82), 206(97),191(31),178(100), 163(25) 203(tCQ), 188(47),160(2),158(75),130(2),102(31)
The alkyl isoquinolinium ions without associated iodide.
' Parent peaks.
2-C,H,,6-CH,O, 2-C3H7,6-CH,O 2-CZH3.7-CHJO 2-C3H7,7-CH,O 2-C2HS36,7-(OCH20) 2+C3H7,6.7-(OCH10) 2-CH3, 6,7-(CH@), 2-CH3. 6.7-(CH30)z, 8-(p-HOCHZC,H,)
(b) Quaternary Salts of Alkoxyisoquimlines
7,8-(CH,O), 6,7-(OCHzO), 8-CH30
3-HO 3-CH3O 4-(CH 3),Si0 5-(CH3)3Si0 5-(7-isoquinolyloxy) ~~PHW H~C~H ~O )
+
(a) Isoquinolinols and Alkoxyisoquinolines
+
Anion
+
Substituent
+
TABLE 1. ISOQUINOLINES
+
762 762 762 762 762 762 763 763
292 41 41 510 510
760 83 76 1 76 I I23 I23
Ref.
~~~-~
pcaks without hydrochloride. Metastable ions. Parent peaks. AIkyl isoquinolinium ions without associated anions.
' Parent
(b) 5,6-DihydroisoquinolInc 5P75a1HO),
1-
2-CH,,7,8-(CH30), 2-CHa. 7-CH3O. 8-C,H,0
I-
I-
CI -
2-CH5,6,8-(CH,O),
(a)
3.4-Dihydroisoquinolinesand Their Quaternary Salts 5,6-(CH,O)2 H C1
Salf or Anion
r( r(
28 1
191(M 'P(l00). 190[14, 189.01(rnt)b], 176(79, l62.I8(1n*)~J. 16118, I47.28(m*)*], 149(8), 146(9),133(1I) ZOS(M')"(100). 190[26, 176.10(m*)b],177[11, 158.52(m*)b]. l76( 13). 162148. 148,27(m*).b138.1 3(m*)b] 191(M * 100). 176fM - 1S){SS). 164(61. 134(10) I9 1 (M 100L 176(27). 163(8) 297(M 'r(20). 284(4), 206(12), 167(10),120(15),91(100) I94(7), 193(M')d(60),192(M' - 1)(66). 191(6), 190(12), 177 ( 1 6). 151(12). I50(CqH,o02 )(100) W ( M - lY(23). 19L(M - 1 - 15)(l I). I l4( 16). 71(14), 69(!4). 59( 18). 58(27), 57(27), 55( 17). 43( IOO), 42( 1 I), 41 ( I 6) 191(M+-CH31)(]OD), 142(52), 127(57),77(23) 282(M+Y(2),230(7). 229(5). 218(24), 192(25), 191(1W), 190W).189(m*).b167(17), 143(3), 129.4(m8y 307(Mfr(31), 147(43),75(45). 73(100)
761
400
290
764
765 750
764
292
272
Ref.
mi: (Relative Intensity)
+
Subslituenf
+
TABLE 2. DIHYDROISOQUINOLINES
+
+
' Relative intensity is not described.
4-Oxido-2-(p-anisyl)isoquinolinium 6-Oxido-3,4-dihydro-7,8-dimethoxy2-methyliquinolinium &Oxido-3,edihydro-6,7-rnethylene dioxy-2-methylisoquinolinium (cotarnoline]
COxido-2-phenylisquinoliniurn 4-Oxido-2-(p-nitropheny1)isoquinoliniurn
Structure
TABLE 3. PHENOL BETAINES (Relative Intensity)
22i(lCO), 220(40), 193(26), 192(14), 165(19) 256(100),238(33), 220(12), 208(10), 192(27) 251 (71).250(29), 223(23), 222(13),2oS(IOO~ 221(36). 206(100), 192(4), 190(23), 180(5), 178(18) 211.'206(100) 205(100), 176(10), 164(81), 147(16)
m/z
767 510
510
766 766
766
Ref.
Salt
2-(CH,),CCO.6,7-IOCH~O~ 6.71CH30)zb 2*C,H5CO, 6,7-(CH,0)2 2-(CH,),CCO. 5.7-(CA30)2‘ 6974CH30)Z
2-CHjCO,4-HO 2-(CH313Si,4-(CH, ),SiO 4.6-(HO), 4,WHO)z 6.7-(HO)zb 4.6.7-(HO), 4.6.84HO), 4.7,8-(HO)3 6-HO. 7-CH3O 2-C2H,C0. 6-C2H,CO,,7-CH30 4-HO. 5,84CH,O), 2-CH3CO. 4-HO, 5,8-(CH,O), 4-HO, 484C,H,01, I-CHjO, 2-CeHSCHICO 7-CH30
HCIe HCI’ HCI
HCI‘
HCI
HCI HCI HCI
HCI HCI
m/z (Relative Intensity)
179(M’r(70). 178(67),163(24),lH)(100), 135(35),107(31),91(9) 471(9). 352(7). 32W1). 309(26), 308(33),297(14),296(100),277(7). 264(5), 253(6), 205(6) 209(M+)?d I%O(K@) 251(M+),’*d 190(100) 361(M’)”(4),360(2),341(4),332(7),270(tO),269(5),lS1(8),91(100) 281.45(M r(0.5) 163(M*):.d l34( 100) 163(M+p(60), 162(331, l35(17), 134(100), 119(8), I04(8),91(17) 261(M’r(100). 246.204.176,161, 148,57 194(M’ + 1)(28),193(M+r(100), 265(M +)(32),236(100) 277(Mtr(100),262,220, 192,177,176,164,57 193(M+y(90),l92(57). 178(9), 165(17),164(100), 149/34), 121(16) 193(M+)”(61.5),192(60), 176(11.5). 165(18), 164(100), 149(17). 121(19) 193(Mt)”(63),192(59), 176(14), 165(19.5), 164(100), 149(19),121(20)
331(2Mt +1)(4),330(2Mt)(5), 166(M++1)(90). 165(M‘r(100), 164(Mt -1)(19), 181(M’)”(13),164(67),162(75). 152(58), 151(65), 136(100) 181(M’)’(25), 180(9). 162(13),lSZ(l(M).123(48) 181(M+)”(19),164(42),162(77), 152(82),151(100),136(50)
173(86),148(9),IM(1001, 119(75),91(43) 203(46).202(45), 192I80).177(100).147(19),73(86) 165(M’)”(17),164(5), 146(39), 136(95),135(66),I07(100).77(60) 1651M*Y(23),164(4). 146(41),136(100), 135(96), 107(69),77(88)
(a) 1.2,3.4-7etrahydroisoquinoIinolsand Their Derivatives
Substituent
TABLE 4. TETRAHY DROISOQUINOLINES
+
773 52 I 52 1
745 745 771 77 I 768 788 771 773 757 769 772 757
525.769
768 768 769 769 768
566
566
Ref.
HCI' HCI' HCIh
7MCH 3 0 1 2 5d,74CH,O), 5,6,7&(CH 30)4 2-(p-tosyl) 221,206,192,178, 164, 150, 137, 121, I09,91,77,65,53 222,207, 193, 179,165. 151, 138, 122. 110,92,78,66, 53
193(M+)"(IOD), 192(46), 164(82), 178(14), 149(45), 121(11) 223(M+P(80),222(48), 194(65), 192(100), 179(39), 156(58) 267(M'Y(90), 266(96),236(100),224(96).209(93), 181(17) 287(M *f(9.8), 286(9), 223(0.6),222(3), 155(3.5), 139(0.9),132(100),131I33.1)
m/r (Relative Intensity)
Parent peaks without hydrochloride. Measured by field desorption mass spectrometry. Parent peaks. Relative intensities are not described. Measurement by chemical ionization mass spectrometry gives m j i 164 (M + H)+. Natural product. Measurement by chemical ionization mass spectrometry gives m/r 244 (h4+ HI'. Measurement by chemical ionization mass spectromctry gives miz 268 (M + H)'.
(b) 5.6.7.8-Tetrahydroisoquinolines 1.34C2H50),d 1,3-(C2H50),, 4-Dd
Salt
Substituent
TABLE 4. ( C o n r i n d )
622 622
773 773 773 775
Ref.
1X. Analysis and Spectroscopy
347
2. Infrared Spectroscopy Assignment of the carbon-nitrogen or the carbon-quaternary nitrogen double bond of isoquinolines and 3,4-dihydroisoquinolinesor their quaternary salts in spectroscopy is uncertain because of the complex vibrational interaction between the carbon-carbon and the carbon-nitrogen or the carbon-quaternary nitrogen double bond. In addition, no characteristic absorption bands are available in the case of 1,2,3,4-tetrahydroisoquinolines. TABLE 5. ISOQUINOLINOLS AND THEIR DERIVATIVES Substituent
Anion
(a) lsoquinolinols and Their Derivatives 4-HO HCI 8-HO 5-HO 4-CH3C0, 6-HO 7-HO 4-HO, 7-CH3O 6.8iHO)z 637iHO)z 3-CH,O 3-CZH50 3-n-C3H,O 3-i-C3H,0 3-n-CaHqO 4-Ce H $0 CCH,SO,O 4-C,H,SOZ0 4-CsH$OzO qp-losyloxy) I-CHJSO,. QCH3SOZO 5-(7-isoquinolyloxy) 6,74CH30)2
HCI
HCI HCI
HCI HCI
Sample Handling K Br KBr K Br KBr K Br K Br KBr KBr KBr. Nujol Film Film-CHCI CHCI, CHCl, CHCI, CHCI, CHCI, Film KBr KBr K Br KBr K Br K Br K Br Nujol Nujol Nujol Film Film
,
v (an-')
Ref.
1620, I580 1626,1582 1645, 1615, 1595 1621. 1557 1623, 1588 1625,1585 1625,1614 1628,1589 1620, 1600 1625, 1575, 1545 1630 1632,1595 1640.1600 1150 I170 I160 I160 1635, 1625. 1220 1335, 1178 1370,1172 1370, I 1 9 0 1372,1190 1368,1288,1150,1132
137 776 131 776 776 137 776 776 131 20 426 83 116 777 777 777 777 778 576 576 576 576 576 123 300 351 20 56
1580
1632, 1614,1570 1644 1635,1575 1630.1590, 1565 3250,2060 3000.2400.2100. 1620.I460,l I65
30
719
348
Isoquinolinols and Their Hydrogenated Derivatives
TABLE 5. (Continued) Substit uen t
Anion
Sample Handling
v
7 N C7 H7 0 ) ~ 6,7-(CH30),, 8-CTH70
HCI HCI
Film KBr
I625 1655, I595
30 286
1647 1660,1611 2940,1590,1385, 1165 3275 3400,1605 Moo,2960,1630,1610 1630,1610,1570 1630,1600,1560
I21 83 239 780 78 I 93 352 56
(b) Quaternary Salts of lsoquinolinols and Their Derivatives 2-CH3.8-HO 1K Br 2-CH3, 3-CHsO INujol 2-C7H,,4-@-tOsylOxy) BrKBr 2-NH2.7-CH30 CH3SO; KBr 2-C7H,, 5,7-(C7H-@), Br- -C,H,OH' Nujol 2-CH3,6.7-(CH3O), IK Br 2-(3-lndolylethyl),6,7-(CH30), Br KBr 2-(3,4-Methyleaedioxyphenethyl), INujol 7,84CH30)2 2-(3.4-Dimethoxyphenethyl), 7.84CH@)2 2-CH3,6,7-(OCH,O), 8-HqCH 3 0 )
(an
I)
Ref.
I-
Nujol
1635.1610, 1570
56
CI -
K Br
16401630,1600
214
TABLE 6. DIHYDROISOQUINOLINOLS AND THEIR DERIVATIVES Substituent
Salt or Anion
Sample Handling
v
KBr CHCI, KBr K Br Nujol CHCI, KBr Nujol KBr KBr KBr CHCI, KBr
1635 1625 1599,1510 1625,1580,1490 1624 1630,1605.1580 1632,1614,1570 1644 1630 1800,1650 I629 1625,1605,1580 1645
(an-')
Ref. 266 264
300 290 351 292 300 351 782 782 355 764 765
IX. Analysis and Spectroscopy
349
TABLE 6. (Continued) Substituent
Salt o r Anion
Sample Handling
(b) Quaternary Salts of 3.4-Dihydroisoquinolinolsand Their Derivatives CHCI, 2-H,6,7-(CH30)2,8-0-0 -b 2-CH3,6-0-,7,84CH30), -' Nujol 2-CH3.6,74CH30),. 8 - 0 2-CH3.6-CH30.7-HO CI b KBr HSO; 2-CH3.4-H0,6,74CH30), BrKBr 2-CH3.6,7-(OCH20) CIKBr 2-BH3.6.74CH3O)Z KBr 2-CH3.6,74CH,O)2 INujol 2-HO(CH2)2,6.7-(CH30), BrKBr 2-HO(CH2)3.6,74CH,O), BrKBr BrKBr 2-C2H,OOC, 6,7-(CH3 0 ) 2 BrKBr ~-CH,COZ(CH~),.~,~~CH~O)Z CIKBr 244-N0,C,H,CH2) 6,74CH,O), BrCHCI, 242-CzH ,O,CC,H,CH2 ). 6.74CH3O)Z Br CHCI,
Y
(cm- ')
Ref.
1695 1610 1645-1595 1655 164O,l6l0,1580 1660.1600,1575 1672 I646 1659 1647 1645 1661 2900,1740,1620 1656 1643,1606 1650.1610
680 510 680 20 1 783 783 432 426 351 353 353 353 365,784 353 360 360
1655, 1570 1660,1582.1498 1665,1605,1580 1661,1618 1655,1600 1655
476 290 403 785 286 286
2-
674CH3O)z 2-CH3,6,74CH30)2 2-CH3.7-CH30. E-CTHTO 2-CH3,6,7-(OCH,O), 8-CH30 2-CH3,6,74CH3O),. 8-C7H,O 2-C7H7,6.7-(CH30)2.8-C7H70 Phenol betaina. No description. Borane complex.
CI ICIO;
CIBrBr-
KBr KBr KBr CHCI, KBr KBr
Salt
(a) 1,2,3,4-Tetrahydroisoquinolinolsand Their Ethers nci 4-HO HCI 5-HO 2-CH3OOC, 5-HO 2-CH3OOC. S-CH,OOCO 6-HO 7-HO 8-HO 2-C7H,OOC, &HO,7-CHaO 2-C,H,OOC, 6-CH3O. 7-HO 4HO,6,8-(CH,O), HCI I-CH,O, 2-C,H,CH,CO HCI +CH30 2-CH3OOC. S-CH,O 6-CH30 7-CHJO HCl 8*CH,O 2-(CH,),CCO. 6,7-(0CH,O) 24CH3)3CCO7&7-(CH30), 6-CH30, 7-~-D-Glucopyranosyloxy 2-C7H,00C, 6-CH30, 7-/?-DGlucopyranosyloxy
Substituent
K Br Film Fitrn Film KBr Film K Br KBr KBr KBr
-
-0
Film K Br KBr K Br KBr KBr
-a
KBr KBr
Sample Handling
TABLE 7. TETRAHYDROISOQUINOLINOLS AND THEIR ETHERS
(m-')
3290,2950,2786 3326,2980,2853. 1601 3326.1674 3005,2957.1765,1705, I469 3290,3120,2945.2845,2735,2670,1580 3340,2996,2860,2705,2680,2500,1618,1517 3225,3119,3036,2926,2824,2654,1597 3 m , 1480 3420,1700 3375,1610, I160 1650,1450 3289,2950,2786 3036,2984,1701, 1589, 3300.3040,2960,2870.1612 1504 3350,309S.2974,2875,1617,1567 2910,2830,2784l. ISM, 1240 3268,3038,2934.1603,1588 2980,2%40,1630,1480 2980,2950,1615.1515 3400,3250,2900,2700-2400,1680,1610 3350,1700, ,1690
V
788 786 557 557 557 773 557 757 757 787 787
768
786 557 557 557 557 557 557 787 787
Ref.
W
z!
No description
(b) 5.6.7.8-Tetrahydroiosoquinolinols and Their Ethers 5-HO I-CZHSO, 3-CHaO 1,34CzH,O),
5,6.7.H-(CH,O),
7,WCHaO)Z 5,6,7-(CH rO), 5-CH,0,7,8-(0CH,O) 5,7.8-(CH JO)3
2-C,H ,OOC, 6-Tetra-0-acetyl-p-Dglucopyranosyloxy. 7-CH ,O
2-C7H,OOC, h-P-n-Glucopyrdnouylony. 7-CH 3 0
HCI HCI
HCI HCI
HCI
nci 0
Nujol Nujol Nujol
K Br
K Br K Br
....
K Br K Br
CHCI, K Br
79 1 622 622
773 773 547 547 173 79 I 772
3035,2720,2600, 1580. 1495 2920.2770.1585,1480,1 I 15 2770-2470 2770-2470 2900,2750, 1610. 1510 2950,2780.2720.25M. 1470, t420 2830.2540. 1415 . 1 3 6 0
3210 1605. I570 1610,1580
7x7 787
7H7 717
7H7
1695 1720. 1710. 1260-1205
3250-3500.1610 3320, 1705. 1680
K Br
6-/~-D-Glucopyranouyloxy.7-CH,O
K Br
1720. 1710.1695,12RO-1205
K Br
awtyI-8-D-glucopyranosylaxy
2-C,H700C. 6-CH30. 7-Tetra-O-
352
Isoquinolinols and Their Hydrogenated Derivatives
TABLE 8. ISOQUINOLINETHIOLS AND THEIR DERIVATIVES Substituent
Salt
(a) Isoquinolinethiols and Their Derivatives I-HS I-CHaS I-CHZ =CHCHz I-CH,SOz I-CzH,SOz I-C,H,SOz I-@-Tosyl) 3-CH3SOZ 3-CzH,SOz 3-(p-T0~yl) 4-CzH,S0 C@-Tosyl)
Sample Handling
v(cm-')
Ref.
KBr CHCI, KBr Neat K Br KBr K Br KBr K Br KBr KBr CHCI, CHCI3
1630 1627 I551 1642 1300, 1138 1295,l I24 1305,1140 1290,1138 1290.1 I25 1290.1132 1308,l I48 1130 1320.1140
792 792 792 641 576 576 576 576 576 576 576 793 777
1620 3230,1630 1620 3300,1627,1100 1680 1120-1040 3250 3350.1 120-I020
794 794 794 794 795 795 795 795
CHCI, CHCI, CHCI, CHCI, CHCI, CHCI, CHCI, CHCI,
1350,1160 1350, I160 1350,1170 l350,1150 l350,1170 1350, 1I70 1360.1 I70 1340,l I35
7% 7% 796 796 796 796 796 797
CHCI, CHCI,
1360,1160 134O.1140
796 797
(b) Alkylthio-3,4-dihydroisoquinolinesand Their Derivatives I-CH,S
I -CzH I-CHz=CHCHz 1-(2-Cyclohexenylrhio)
HS03F HBF, HBr HCIO, H Br HCIO,
Film Nujol Film Nujol CHCI, CHCI, CHCI, CHCI,
(c) Sulfonamides of 1.2,3,4-TetrahydroisoquinoIine and Its Ether
2-CH3SOZ ~~PNO&.H~SOZ) 24pTosyl) 2-(d-Camphorsulfonyl) 2-(pTosyl),6-CH30 2-(pTosyl),8-CH30 2-@-Tosyl),6,7-(OCHzO) 2-[CH,OOC(CHz)zSOZ], 6.74CH3O)z 24pTosylh 6974CH3O)z 2-(3',4'-CI,C,H,CHzSO~), 6.74CH3O)z
5-HO
4-HO
3-HO
(a) Isoquinolinols and Their Ethers
Substit uen t
HCI
salt or Anion
.
E 95%E pH 6.92 O . i N HCI-M 0.01N HCI-M Conc. HClO, 0.I MHCIO, pH 7.0 0.01 N NaOH-M 0.1 NaOH-M
E E M
E E
pH 6.74 IN KQH IP E
E 25%E IN HCI
E
E
E
-
Solvent
TABLE 9. ISOQUINOLINOLS AND THElR DERIVATIVES
4o(y
I^__--
248(4.27Lb334(3.85)b 248(4.28), M(3.81)
223(4.60).233(s)(4.5 I 345(3.26) 234(2.25), 295I3.67)-320I3.73). 330(3.76) 230(4.2I), 295(3.60), 330(3.69) 234(4.21), 295(3.63), 318(3.68). 330(3.71) 230(4-24),294(3.65), 315(3.67),329(3.72) 209(4.66),230(4.22). 295(3.54),319(3.62), 331(3.65) 209(4.53), 232(s)(4.05), 261 (s)(3.62),330(3.59). 355(3.71) 222(s)(4.49).229(4.53),284(3.45), 295(3.43). 331(s)(3.86), 342U.93) 240(s or infl.) (3.94).3Mts or infl.) (3.63). 359(3.88) 223(4.091. 248(4.09). 323(3)(3.75),345(3.83) 233(4.40), 286(3.51), 298(3.52), 33 1-332(3.88)*342-243(3.87) 218(4.77),265(3.58), 272(3.64), 283(3.56). 308(3.44), 321 (3.54) 218(4.75), ZM(3.68). 273(3.72), 284(3.58), 308(3.46),321 (3.55) 260(s)(3.703' 273(3.76)? 283(3.65).bm(3.55): 32006 I 265(3.70)? 274(3.76)? 284(3.65)! 308(3.5)! 322(3.60? 2 l8(4.8 I), 265(3.70), 274(3.74),285(3.62). Ms(3.5 I), 322(3.61) 234(4.45),303(3.65), 328(3.70) 235(4.49), 302(3.72). 326(3.72) 235(4.41lb286(3.63): 326(3.65? 230(4.36), 296(3.55). 330(3.64).4oo(s or infl.)(2.13) 251(4.47), 318(3.63),3.67(3.70) 248(4.45Xb3 12(3.45Lb360(3.65p 446' 359'
L: (nm)(log E )
800 189,798
800 801 801 801
800 I82 189
I82 799 131 576 576 loo 160 576 189 183,798
76 I 798 183 53 76 I 799 799 799
Ref.
(Continued)
8-HO
7-HO
6-HO
Substituent
TABLE 9.
na
Salt or Anion
IP
O.iN NaOH-M
0.1NHCI-M
pH 7.03
IF
__a
M E
E 95%E P -_ pH 7.29 0.01N HCI 0.1N HCI-M 0.01N NaOH 0.1N NaOH-M
M M
pH 7.50 0.1N HCI-M 0.1N NaOH-M
CH
183 800 76 1 183 800 189,798 800 189,798 189 183,798 762 107 183,798 189 189 107
189,798 761 183 183 189,798 189.798 802 189,798
229(4.65), 266(3.62), 286(3.65),300(3.63) 228(4.78), 290(3.77) 225(4.41),280(3.33), 319(2.84) 229(4.64) 263(4.24). 353(3.91) 228(4.55), 247(4.51).321(3.84) 241(4.46),253(4.40),276(s)(3.20), 308(3.87). 332(3.65) 224(4.55), 260(3.59), 268(3.59), 273(3.42), 333(3.58) 224(4.55). 260(3.59). 268(3.59),273(3.42). 301(s)(3.3 I), 333(3.54) 225(4.72),259(3.74), 338(3.54) 265(3.74): 332(3.48),’ 345(3.53y 224(4.74), 257(3.77), 267(3.78), 338(3.56) 221(4.69), 257(3.82),338(3.49), W(2.04) 235(4.70): 272(3.65Lb 344(s)(3.52); 360(3.54)b 241(4.64), 278(3.65). 3 18(s) (3,16).362(3.63) 236(4.60Lb 282(3.91): 366(3.53? 238(4.64), 282(3.85), 289(3.88), 360(3.51) 233(4.47X M(3.57). 334(3.79) 233(4.45), 333t3.61). 380(3.27) ZZ(4.49). 334(3.39) 233(4-38).294(5)(3.48),332(3.72) 247(s or infl.)(4.19), 328(3.64). 430(3.43) 245(4.47), 3 10I3.39). 378(3.72) 247(4.281,328(3.66),370(3.78) 244(4.31), 310(3.36), 335(s)(3.301 379(3.55)
M
-*
Ref.
Solvent
v,
v,
7-CH30
4-CbH SO WH,O
3-CH30
I-CH3O
(b) Alkoxyisoquinolines
4-HO, 7-CHsO
HCL
HCI
E
M
M
IP 0.1N HCI
E 0.lN HCI-M 0.lH NaOH-M
M
0 . l N HCI-M 0.1N NaOH-M
E
Abs0.E
E
pH 0.2
pH 6.0
1P E E
E
E
E
IP
237.W.72). 255(3.73), 300(3.68),3 lO(3.67). 36512.56)
233(4.31), 261 (QI3.27).285(s)(3.49), BFj(3.531,316f3.72) 243(4.36), 279(s)(3.0),306(3.19), 368(3.77) 288I3.41). 300(3.40), 320(3.40) 258(3.81), 352(3.54), 362(3.56)
(3.32), 309(3.52). 320(3.50) 220(4.60), 227(s)(4.56),234(s)(4.36).225(3.59), 264 (3.57). 274(3.43). 304(5)(3.46), 3 18(3.71). 330(3.69) 224f4.9I), 265(3.67). 337(3.68} 339(3.56) 208(3.26), 274(2.97), 284(2.86), 31 lJ(2.61). 323.5(2.60) 230(4.49),247(4.45).31 t(3.76) 231(4.65),266(3.40). 280(3.49), tW(3.50) 256(3.763.264(3.73). 326(3.46),337(3.43) 225(4.70),257(3.74), 264(3.71). 327(3.52),339(3.59) 241 (4.58). 268(3.58), 275(3.61), 354(3.46) 233(4.67). 255(3.69),263(3.66), 326(3.32), 337(3.33)
262(s ar infl.}(3.651,270(3.78). 281 (3.71), 29H(s)
239(4.46),291 (3.36).298(3.36).335(3.20). 334I3.39) 239t4.46). 265(3.6).278(3.65).287(s)(3.62),3 I7(3.52),329f3.53) 239(4.63). 268(3.67),280(3.621,291(3.57),315(3.45),327(3.46) 253(4.68), 3I7(3.89).340- 341 (3.81) 248(4.53). 287(3.77).298(3.74),330(3.74).343(3.77) 24W4.42). 3233.491
235(4.55). 253(4.26), 261 (4.23).281-282(3.60), 291 (3.54). 347 -348(3.74),358 --359(3.72)
803
I21 104 104
121
a3 I 16.798 77x I 89,798 189.798 17 24 189,798 I89.798 802
74,798
74,798
20
54
24 1 39 139 131
131
(Continued)
Substituent
TABLE 9.
HCI
HCIO,
Salt or Anion
E
M
W E
E M E E M
E E E
E
2N HCI-E
M E E E ME D 1M HCI
E E
Solvent
246(4.61). 285(3.87),325(3.79), 338(3.83)
244(4.11), 318(3.71), 341(3.76), 234(4.49), 278(3.40), 289(3.33), 313(3.22), 327(3.33) 268(4.55), 310(3.61), 322(3.69) 23614.79). 275(3.55), 287(3.50), 310(3.42), 323(3.45) 235(4.81), 265(3.65),270(~)(3.62),285.5(~)(3.51),310(3.41), 323(3.46) 235(3.68),265(3.56), 275(s)(3.56), 2%0(infl.)(3.54),31 1 (3.53), 324(3.54) 312(3.78) 242(4.30), 262(s)(3.7 I), 273(3.62). 309(3.45),322(3.52) 228(s)(4.30), 248(4.78), m(3.94) 252(4.87), 310(4.12) 238t4.71) 306(3.72), 319(3.691 206(4.25), 236(4.73), 265(3.69), 312(3.46), 324(3.50) 236(4.63), 276(3.65), 284(3.68), 329(3.45), 347(3.55) 236(4.33), 252(4.35), 29O(s)(3.493 360(3.28) 234(4.69), 277(3.66),286(3.59), WS(3.65) aZ(3.48). 290(3.43), 336(3.45), 342(3.46) 240(4.73),320(3.72)335(s)(3.66) 240(4.70),279(3.46), 290(3.37), 323(3.34), 334(3.35) 243’ 218(4.03), 255(4.04), 336(4.16) 239(4.99), 286(3.79). 323(3.61), 334(3.49) 235(4.92), 284(3.81)
L G (m) (log €1
54
34
802 24
510
24
104 54
24
56
20 36 24
43
803
803
43
292
w>
24 24 17 24
Rd
2-C,H7, 4-HO. 6.7-(CH30), 2-CH 1, 6.7-(OCH20), 8-HO
2-Y, 8-HO 2-C7H7,4-HO, 7-CH,O
2-Y, 5-HO 2-CH3.6-HO 2-CH3.7-HO
,so;
CI-
aaa-
III-
11CI-
c1-' CI -
CH
CHjSO;
I-
1-
of Isoquinolinols 2-CH3.4-HO CI 2-C,H,,4-HO a2-(pNOzC,H,), 4-HO cl2-(pCH30C,H,), 4-HO c12-CH3. 5-HO a-
(c) Quaternary Salts
M
IP
O.IN KOH
IP
.
0.1N HCI-M 0.IN NaOH-M -
IP
pH 10
pH 10 pH 10 0.1N HCI-M 0.1N NaOH-M
-a
E pH 10 0.IN HCI-M 0.1N NaOH-M Conc. HCIO, pH 7.0
E E
pH 8.5
ZSS(3.W). 320(s or infl.)(3.56),364(3.98) 227(4.32), 243(4.31).258(4.28), 338(4.53) 247(3.89), 283(4.21), 352(4.01) 235(4.70), 293(4.27), 339(4.19) 233(4.23), 269(4.32).349(3.79),408(3.57) 255(4.51), 322(3.46), 368(3.66) 245(s)(4.22).274(4.26).362(3.871.430(3.52) 446c 401 254(4.38) 230(4.54),267(4.36), 358I4.09) 261(4.70),298(3.91X 408I3.47) 217(4.48), 243(4.71). 280(3.72), 3.67(3.54) 217(4.39), 265(4.641 MS(3.86). 424(3.38) 257(4.30), 334(3.69).q 3 . 1 6 ) 2m4.48). 314(3.30),38 I(3.72) 217(4.48), 250I4.31)/315(3.22), 378(3.68) 263(4.21), 347(3.59).460(3.69) 254(4.40) 239-240(4.61), 262-263I4.34). 284-286(3.76), 364-365(3.72) 231-232(4.58), 278(4.22),308-3W43.47). 378(3.96) 256(4.74), 323[4.08), M(3.94) 264( 1.99); 314(0,3L' 365(0.2y
189 122 131 131 131 214
39 189
183
189
1 89
183
801 122 183
8q1
189 189
183 231 231 231 183
w VI w
~
Salt or Anion
M
I-
1-
CIOi
Cl0;
CI0;
ao;
1-
I-
i-
E
I
-
M
M M M
E 0.03M HCI-E 1M HCI
iP
c1-
I-
M M
E
W
Solvent
ao; c10;
I-
(d) Quaternary Salts of AlkoxyisoquinoEnese CI0;
-
Substiluent
TABLE 9. (Continued)
258(4.74), 285(3.763,318(4.11)
272(s)(3.45),280(3.47), 334(3.60) 270(3.63), 278(3.58). 360(3.84) 231(4.51), 251 (4.49),315(3.97) 244(4.69),277(3.68),358(3.45) 249(4.44), 280(3.32),W(3.22). 341(3.77) 253(4.91), 3 lO(3.95) 220(4.45),254(4.77), 314(4.01) 310(3.97) 227(4.47), 25 1(4.74), 310(3.97) 25414.87). 314t4.12) 255(4.76), 314(4.03) 254(4.74), 3 I4(4.02) 256(4.82), 3 16(4.I 1) 280(4.29), 310(4.20)
L.,: (nm) (1% E)
36
8W 803 433 803 805 238 238 238 199
215 215 121
207 83
Ref.
u l
*
w
CI -
2-CHp 6.7-(OCH,Q), 8-CHsO
KOH-E
M E
E
E
E
. ..I
-1
262( 1.96): 3 16(0.6).b357(0.3?
258(4.49),2874s) (3.74)
255(4.59).290f3.70). 385(3.60) 258(4.56),293(3.83)
The solvent is not described. Wavelengths (h)and molecular extinction coefficients (c) are obtained from figures in the original literaturc. ' Mulecuhr extinction coefficients (E) are not described. ' E- values. ' Since the spectral data of 6.7-methylenedioxy- and 8-methoxy-6,7-methylenedioxy-2-methylisoquinolinium salts (Rel. 213) are obtained on the maction mixtures. no tabulation is attempted. f Wavenumben ( l / h3370, l / h 3150) are described. Wavenumber ( l / h3380) is described.
II'
1-
7.84CH,0I2
II-
6-C,H-,O, 7-CHsO 2-CH3, 7,8-(CH,O), 3.4-IOCHzOfCeH &CHz)2. 7.84CI-130), 3.4-(CH,OI,C,H,(CHz)z.
217
214 217
56
803 56
360
Isoquinolinols and Their Hydrogenated Derivatives
3. Ultraviolet Spectroscopy For simplicity and clarity, the spectroscopic data randomly scattered in the cited literature are tabulated according to the following principles. All of the largest molecular extinction coefficients ( E ) are converted to the logarithmic values (log E). 2. Abbreviations used here are as follows: E, ethanol; M. methanol; W, water; IP, isopropanol; C, chloroform; D, dioxane; CH, cyclohexane; ME, methoxyethane; s, shoulder; infl., inflexion. 3. The original data presented as figures are as far as possible described in terms of absorption maxima (Amx) and log E on the reviwers’ own responsibility or indicated in the form of a reference number. 1.
The relationship between the spectra and the molecular orbital method has been described briefly elsewhere (see Section I.A.3.d).
2
w
7-Ha. K H j O
7-HO,S-CH,O
GHO, 8-CH30
HCI, H l r HCI, HBr HCI, HBr H k
HCI, HBr H a H3r HCI, HBr HBr
HBr H k HBr H 3r
HBr
HBr
HCI
(a) 3, QDihydroisoquinolinols' 5-HO, 6-CHJO
5-HO, 8-CH,O GHQ,7-CH10
Salt or Anion
Substituent
E
0.01N HCI-E 0.01N NaOH-E
E
0.01 N HCI-E 0.01N NaOH-E
E E
0.01 N HCI-E 0.01 N NaOH-E E 0.01 N HCI-E 0.01N NaOH-E
E
0.01 N HCI-E 0.01N NaOH-E E 0.01 N HCI-E 0.01 N NaOH E E 0.1N KOH
E E E
Solvent
TABLE 10. DIHYDROISOQUINOLINOLS AND THEIR DERIVATIVES
213(4.22), 243(3.75). 275(infl.)(3.57),324(4.06) 23 l(3.90). 263(3.85). 342(3.64) 269(3.98), 316(3.58). 402(4.32) 248(4.19), 307(3.96). 362(3.92) 245(4.126), 332(4.14) 248(4.18), 397(3.%), 362(3.96) 249(4.19), 307(3.97), 361(3.%) 246(4.18), 333(4.16) 238(3.98), 320(infl.) (4.02). 351 (4.18). 380(3.80) 223(4.26). 261(3.62). 303(3.80). 385(3.08) 237(4.37),273(3.69), 350(3.38) 238(4.36). 270(3.823,310(3.82) 247(4.27), 303(4.00). 360(3.90) 245I4.48). 278(s) (3.74),347(3.73) 246(4.32). 302(4.06). 360(3.%) 246{4.32), 303(4.06), 358(3.96) 245(4.56), 275(s) (3.88), MS(3.84) 217(4.13), 235(infl.)(3.90).307(4.09), 398(3.53) 224(3.98), 270(3.94). 310(3.57), W(4.32) 245(4.21), 305(3.95), 353(4.02) 245(4.08).331(4.26) 246(4.17), 305(3.91), 355(4.00) 24514.20). 304(3.94), 354(4.02) 245(4.1 I), 332(4.26) 213(4.10), 240(3.85), 312(4.14). 410(3.48)
L, (nm) (log el
300 300 267 300 300 300 300 300 300 267
3w 300 300 267 267 267 300 300 300 300
300
267 267 300 300
Ref.
5,64CH,O),
a-
CI-
3H3
HQ
Ha
na
HCI HCI
Ha
HCI HCI HCI
(c) Alkoxy-3,4dihydroisoquinolines
2-CH,, 7-HO, 6-CHJO
@) Quaternary Salts 3,4-DihydroisoquinolinoIs
TABLE 10. (Continued)
E
E
90% E E
0.01N NaOH-E 0.1M NaOH-E
Ha-E
0.011%’HCI-E
E E E
1M HCI 1 M HCI IN HCI
E
0.1 M NaOH-E
E HCI-E
HCI-E O.1M NaOH-E
E
NHj-M 210(4.19),238(3.76),279(s)(3.74),327(4.13) 2 15(4.18),262(4.14) 223(4.20), 306(3.91), 385(3.23) 215(4.26). 235(s)(3.93),298(4.08),408(3.78) 225(s) (4.16). 263(3.98). 333(3.72) 215(4.10), 240(Infl.)(3.73). 298(3.90),W(3.56) 248(4.26), 305(3.76), 363(3.88) 248(4.24), 305(3.793,363(3.88) 248(4.27), 303(3.80),362(3.88) 225(s) (4.15), 276(3.98), 325I3.89) 230(4.39), 278(3.85), 310(3.85) 230(3.64), 278(3.58), 309(3.57) 226(4.36), 273(3.88), 306(3.84) 243(4.29), 301(3.97), 350(3.96) 244(4.25), 306(4.00), 355(3.93) 225(4.46), 269(3.93), 306(3.86) 230(4.21), 272(3.98), 303(3.91) 242(4.31), 290(s)(3.91), 299(3.98). 332(4.01) 245(4.15), 308(3.88), 360(3.80) 237(4.07), 245(405), 308(3.84), 360(3.70) 310: 36ob
251(4.24). 312(4.00),370(3.86) 265,b 325*
300 300 807 300 807 426 810 352 270
808 803 809 272 352 29 2
267
807
807 807 267 807
806 750
NiiOH-E E 0.01N HCI-E 0.01N NaOH-E
HCI
HCI HBr H Br HBr H Br
HCI
HCI
HCI
W
nci
0.1N HCI 0.1N KOH
IP
HCI IM HCI IN H C I
1M
HCI-E
IM H C I
E
E IM HCI
0.1 M NaOW-E
HCI-E
0.1M HCI-M
M
E
HCI-E E
NaOH-E
HCI-E
E
NaOH-E E
HCI
HCI
HCI
1 M HCI-W
1M HCI
HCI 244(4.26), 306(4.00). 356(3.%) 244(4.25), 306(4.00), 355(3.93) 230: 270: 310) 230(4.34). 277(3.79), 308(3.73) 243(4.23). 302(3.94). 352(3.9 1 ) 246I4.45). 308(1.44), 361(4.09) 237(4.25), 301(3.95). 3333.94) 223(4.42). 269(3.90), 305(3.83) 23 1(4.40), 269(3.90), 308(3.78) 246(4.34), 307(3.%), 353(3.88) 230(4.41). 278(3.86). 308(3.76) 223(4.20), 306(3.91). 385(3.23) 210(4.14), 237(4.16), 3M(inA.) (4.07). WS(4.14) 209(4.29), 232(4.42). 280(3.91), 313(3.85) 227(4.42). 262(3.92), 320(3.34) 218(s) (4.17). 23f(s)(4.10),297(4.04), 375(3.41) 237 (4.06). 293(3.98), 374(3.34) 224(4.38), 260(3.87), 322(3.32) 224(4.23), 268(3.67), 298(3.83). 380(3.04) 237(4.06), 293i3.98). 374(3.34) 234 (4.271 ZSS(3.85). 3 12(3.79) 246(3.921 307(3.671353(3.6 1) 237(4.06). 293(3.98). 374(3.34) 252(4.09), 330(4.14), 370(3.61) 252(4.09), 330(4.14). 370(s), (3.61) 252(4.08), 330I4.12) 216(4.15). 252(4.10). 318(4.15) 241(4.16). 330(4.15) 24q4.15). 323(4.13) 232(4.32), 279(3.96) 36 290 290 807 807 267 803 782 782 807 807 803 812 809 286 286 286
807 247
270 270 270
81 1 803 2m 810 300 307 300 300
Subtituent
TABLE 10. (Continued)
Salt or Anion
1M HCI INHCI
E E
NaOH-E W
-t
E 1M HCI
E
NaOH-E
W E
0.1M NaOH-E IM HCI 0.03M H a - E HCI-E 0.1MNaOH-E
HCI-E
0.03M H a - E
-
W
-c
Solvent
355 784 814 815
245.7(4.33), 309.2(4.07), 359.6I4.04) 2I2(3.90), 253(3.93), 320(3.78), 380(3.75) 210(3.71), 285(2.85) 247(4.28), 311(4.04), 364(4.02) 249(4.26), 310(4.05), 363(4.02)
353
270
401
m3
35 1
810 810 270
807 803 432 807 807 217
807
433
2w
210(s)(4.37),247t4.31). 308(4.MA 360(4.06) 282(3.60) 310; 36ob 248(4.33), 308(4.05), 360(4.05) 244(4.35), 308(4.03), 358(4.00) 247(4.47), 310(4.13), 361(4.09)
-
250(4.25), 306(3.84), 371(3.98) 365I3.95) 244(4.25), 306(4.00), 355t3.95) 234(3.66), 293(3.67) 250(4.27), M7(3.81). 365(3.94) 358(4.03) 244(4.35), 308(4.03), 358(4.00) 222(4.26), 285(3.54)
272 813 36h
247.5(4.06),304.8(3.85). 366.7(3.94)
Ref.
216(4.52),331(4.32)
Lx(nm) (lot3 €1
248(4.4), 314(4.21), 379(4.22) 247(4.54), 311(4.33), 367(4.31) 24J3(4.64), 310(4.4), 364(4.41) 246(4.56). W(4.31). 361 (4.28) 246(4.60), M7(4.34), 359(4.32)
2Br2Br-
W W W
W
W
2Br
2Br2Br
282(3.75)
NaOH-E
1-
313(4.08),350(4.37),365(4.05)
2W3.92) 250(4.39.314(4.12).368(4.09)
2w
310) 3 W 250(4.30),312(4.08). 365(4.08) 282(3.62) 209(4.20). 254(4.19). 317(3.891. 373t3.115) 248(4.34), 3I2(4.07), 367(4.07) 310: 36ob 248(4.34),312(4.08), 3.67(4.08) 284(3.94)
E
M
NaOH-E NaOH-E NaOH-E
E
E
M E
NaOH-E
E
E
I-
1Br-
I'
1-
II-
1-
Br-
1I' 1-
815 817 817 817 81s
810
810
360
8 10 270 816
2 70 810
816
360
270 810 810
E
1.-
rp O.1H HC1
BrBr-
2-C7HT,6,7-(CH30)1,8-C,H,O
IP 0.1N HCI
-c
BrBr-
W W 0.03M HCI-E 1 M HCI HCI-E 0.lM NaOH-E 7.8 x 10-4N KOH O X N NaOH 025N KOH-E
E
E
0.03M HCI-E I M HCI 0.1 M NaOH-E IP
M HCI-E
c1-’
c1-
a-
-4 CI -
-4
CI CI -4
CI -
c10; CI CI -
1-4
1
-1
E
HCI-E NaOH-E
Solvent
2-CH3,6,7-(CH,O),, 8-C7H7O
2-CH3,7-CH,O, 8-CTHTO 2-CH,,6,7-(OCH,O). 8-CH3O
2-CH3, 7,8-(CH30),
CICI CI -
2-@-C,H,OC,H,CH,). 7-C,H,0
6-CH30,
Salt or Anion
Substituent
TABLE 10. (Continued)
25O(4.37), 3 I 3(4.08 ), 365(4.05) 250(4.37), 313(4.07), 365(4.03) 282(3.75) 218(4.06), 297(3.77), 375(3.03) 219(4.43), 244(s)(4.03),300(4.03),380(3.38) 380(3.38) 2 19(4.43), 244(4.03). 300(4.03) 223(4.32), 254(3.43), 287(3.43) 239(4.12), 301(4.07), 379(3.43) 254(0.65),f 334(0.89) 255(4),”338(8)s 254.8(4.14), 332.6(4.24) 251(0.74),’ 331(0.87)f 338(4.16) 252(3.98), 334(4.08), 375(s)(3.56) 252(3.98), 334(4.08), 3751s) (3.56) 219(4.22), 2301s) (3.86), 287(3.28) 283(0.15)f 279(0.14),’ 325(0.08),’ 377I0.03)’ 249(0.33),’ 337(0.39)’ 255(4.09). 335(4.23) 248(4.17). 333(4.19), 26W) (3.89) 247(4.19),326(4.16) 248(4.1 I), 341(4.31) 246(4.12). 335(4.28)
270 270 270 290 807 433 803 807 402,403 43 1 808 813 43 I 433 803 807 807 43 I 43 I 43 1 401 286 286 286 286
Ref.
'
W
Since the spectral data of 3.4-dihydro-disoquinolinol (Ref. 263) and 3,4-dihydrcc6,7-isoquInolinol(Ref. 5 5 ) in the reaction mixtures are presented as figures, no tabulation is atiempted. Molecular extension coefiients (E) are not described. The solvent is not described. Anions are not described. ' The spectrum measured with an old instrument is presented as figure. Wavelengths (I)and E values are obtained from figures in the original literature. Values described in the original literature.
226I4.64).295I4.39) 225(4.56),295I3.97) 230; 289 229(4.40).313(3.73) 232(4.25),293I3.95) 227: 291' 228: 2Mb 229,b 2 w
24 24 24 24 24 24 24 24
368
Isoquinolinols and Their Hydrogenated Derivatives
TABLE 11. PHENOL BETAINES structure
2-Methyl4oxidoisoquinolinium 2-Methyl-6,7-methylenedioxy-8oxidoisoquinolinium 3,4-Dihydro-6,7-dimethoxy-8oxidoisoquinolinium
Solvent -e
680
1% HCI-E
28ob 276' 336: 422' 335.5' 290: 346' 219,' 268.6 395'
M
232: 257,' 352: 428'
510
345.5: 4 w
680 680
C D E
C D E
0.1N NaOH-E
' Molecular extention coefficients
Ref. 1028 214
1% HCI-E
' The solvent is not described.
(nm) (log E )
367' 285( 1.8r
M
0.1N NaOH-E 3,4-Dihydro-7,8-dimethoxy-2-methyl- M
6-oxidoisoquinolinium 3,4-Dihydro-6,7-met hylenedioxy-2methyl-8-oxidoisoquinolinium (cotarnoline) 3,4-Dihydro-6.7-dimethoxy-2-methyl8-oxidoisoquinolinium
,A
340?448' 341(4.26), 425(3.90) 337b 340; 4206
( E ) are not described. Wavelengths (1)and E values are obtained from figure in the original literature.
680
680 680 680 510
680 55 1 55 1
3
(a)
HCI
0.1N KOH
0.1N
IP
0
1,2.3.4,-Te~rahydroisoqunolinols and Their Derivatives 8-HO IP HCI IP HCt O.1N KOH 4-OH. 7-CH3O HCI 1P 5.HO. 7-CH,O E E HBt HBr 6-HO, 8-CH30 E 7-HO. S-CH3O H Br E 7-HO, 6-CH3O E 0.01N HCI-E 0.01 N NaOH-E HCt E HCl 0.01N HCI-E 0.01N NaOH-E HCI 7-HO, 8-CH30 Hcl Ha 0.1N KOH 8-HO. 7-CH3O HCI E HCI 0.1 N KOH 2-CHO, 8-HO,7-CH,O rp 0.1N KOH 6-HO 7,8-(CH30), IP 0.1N HCI 0.1N KOH HBr IP HBr 0.1N HCI HBr 0.1N KOH
TABLE 12. TETRAHYDROISOQUINOLINOLS AND THEIR DERIVATIVES
220(s)(3.88). 274(3.26), 281 (3.26) 216(3.84), 275f3.38). 281 (3.37) 242(3.96),288(3.53) 227(4.01), 277-278(3.24). 284(3.22) 225(infl.)(4.03), 280(infl.) (3.32). 286(3.33) 227(inff.)(3.96). 280(infl.)(3.40). 286(3.41) 224I3.891, 281(3.32) 225(3.89),282(3.43) 223(s)(3.85), 284(3.59) 224(3.83), 283.5(3.59) 243.5(3.94), m(3.76) 225(3.75). 285(3.60) 225(3.83), 285(3.60) 245I3.88). 302(3.71) 28 1-283I3.3 1) 239-240(3.911,295-296(3.48) 230(s)(3.76), 280(3.34) 245(3.87). 290(3.63) 2306) (3,83), 280(3.36) 240(3.86),292(3.65) 23U(s)(3.90), 273(s) (3.20). 282(3.26) 233(s)(3.92), 273(s)(3.11). 279(3.15) 240(9)(3.89), 295(3.56) 23W) (3.90),275(s)(3.18), 281(3.20) 225(s)(3.90),27S(s) (3.14). 279(3.15) 24O{s] (3.89),295(3.56) 227(s) (3.98). 272(2.90), 280(s) (2.84) 225(s)(3.92), 270(2.88), 280(s) (2.70) 240(s)(3.90),285(3.38)
568 561 403 403 262 262 262 262 262 262 286 286 286
568
300 568
Mo
3M)
300 300
300
562 562 267 267
510
121 121 121
(b) 5.6,7,8-Tetrahydroisoquinolinol 4-HO
The solvent is not described. Molecular extinction coefficients ( E ) are not described
HCI
5$,7,84CH10),
HCI HCf HCI HCI
HCI
IP
W
0.1N HCI 01N KOH
IP
M
W
W
E
W
E
W
IP
HCI
IP
E
a
10% HCI
E
E -
HCI H a
HCI
-a
HCI
E
0.1N HCI O.1N KOH
M IP
Solvents
nci
HCI HCI HCI
Salt
HCI HCI HCI HC1
Substituent
TABLE 12. (Continued) (nm) (log 4
233(3.44), 282-283i3.81)
270(2.93),340(1.98) 227(s)(3.98),272(2.93),280(s) (2.83) 222(s)(3.93), 270(2.88), BO(2.72) 240(s)(3.91). 284(3.39) 290(2.95) 284(3.31) 206(4.59), 227(infl.)(3.85), 271(2.96), 280 (infl.) (2.86) 283b 271(3.14) 271(3.17) 28ob 281,' 2 8 9 225-226(3.94), 280(3.42),287(3.40) 200(4.4), 214(3.83,280(3.4),288(3.4) 2 18(3.87),272(3.24), 278(3.26) 226(3.94),283(3.40) 203I4.5). 220U.83, 284(3.6),288(s) (3.6) 226(3.82),276(s)(3.23), 282(3.25) 201(4.5),223(s) (3.9), 278(3.4),286(3.4), 293(s) (3.3) 203(4.4), 223(s) (3.7), 281 (3.2), 290(s)(3.0) 240: 279: 284b 225(s) (4.1 I),2591s)(2.83),265(s)(2.93), 275 (3.04). 2800.05) 280(3.08) 280(3.21) 205I4.0). 223(s)(3.5),282(2.9),292(s)(2.8)
,L
131
267 773 131 773 773 510 286 286 286 773
122
819 286 286 286 54 568 569 525 114 1 I4 525 7 131 173
Ref.
2
W
salt
HCIO,
HCIO,
HC10,
HCIO,
CH
E
E
E E
E pH 1.0 pn 9.4
E
E
E pH -3.2 pH 6.0
95% E E
pH 9.0 95% E
pH -2.0 pH 6.0
E pH -3.6
Sol ven I
' Molecular extinction coefficients ( E ) are not dexribed.
14CH2=CHCH,S) 1+2-Cyclohexenylthio)
(b) Alkylthio-3,4-dihydroi~oquinolines
3-CH3SQ, 3-C,H,SO, 3-C,H,S02
I -CH,SO,
1 -(2-Oxocyclohexylthio)
1 -HO(CHz)zS
l-CH,S
I-CH,SO2.4-CH,SO,
(a) lsoquinolinethiols and Their Derivatives
Substitucnt
TABLE 13. ISOQUlNOLlNETHlOLS AND THEIR DERIVATIVES
28V 240." 275'
2234.553. 28 1 (3.54). 292(3.53). 3 14( 3.5 I ), 3264 3.57) 225(4.46),23q4.44). 2W(s)(3.81), 278(4.02). 28Q3.94). 348(3.9%), 361(3.98) 237(4.571.279(3.58 ).305(s)(3.32). 34S-34q 3.78) 222(4.63), 26f(s)( 3.49). 277(3.55), 287(sH3.481, 315(sW3.5111.325(3.65) 245(~)(3.82). 2W3.75). 296(3.79), 330(3.79), 3*5)(3.76) 226,' 2 4 5 q ~ )2747s). , 283.' 294,' 310-3W (broad hump) 237'(s), 286'(s).297.' 325,'336" 21Y4.74b 245(sH3.88), 2Wsn3.73). 278(3.76),297(3.78). 324(sM 3.73),334(3.74) 234," 284,' 3 W . 3.70" 243(4.63). 283(s or infl.)(3.22).293(3.27), 308(3.13), 3533.61 1 227(4.58),281(3.4S), 32q3.63) 223(4.53). 277(3.53), 312(sM3.51),32q3.57) 22q4.493. 267(sH3.48), 27q3.521, 32y3.54) 225(4.39),275(3.47),323(3.45) 233(4.19),2534.42). 285(3.84), 373(3.53) 24644.34L 269(s)(3.89),28q3.97). 290(3.91), 342(3.25) 225(4.86). 272(3.60), 303(3.32). 3W3.25). 317I3.43) 226(4.55), 272 (3.37). 303(3.09), 309(3.02), 317I3.20) 222(4.31), 24oI4.27), 265@)(3.66),305(3.15), 310(3.06), 31q3.23)
A,,.* (nm)(loed
795 795
643 74.820 74,820 576 576 576 684,820 684,820 576 576 576
641 78
6114.820 641
79.820 79.820
576 684,820
Ref.
372
Isoquinolinols and Their Hydrogenated Derivatives
4. Nuclear Magnetic Resonance Spectroscopy To be useful for the reader, the table of the ‘H-NMR spectroscopic data originally reported in a variety of ways is listed according to the following principles. However, the tables of I3C-NMR spectroscopic data are excluded because of few l i t e r a t ~ r e . ” ~-~7 5~5 ~citations. * 1. All chemical shifts are given in b values. Values originally in 7 are converted
to those of b. 2. A part of the assignment of chemical shifts, to which the original authors make no remarks, is added when it is self-evident. Most of the chemical shifts including signal shapes, however, are tabulated as given by the original authors. 3. Abbreviations used here are as follows: s, singlet; bs, broad singlet; b, broad; d, doublet; dd, double doublet; t, triplet; asym. t, asymmetric triplet; rough t, rough triplet; q, quartet; AB, AB quartet; bq, broad quartet; AA BB, A A BB system; ABXm, ABX multiplet; m, multiplet; bm, broad multiplet; c, complex; Wt, half-band width; TFA, trifluoroacetic acid; AcOH-d4, tetradeuterioacetic acid; DMSO-d,, hexadeuteriodimethylsulfoxide; DMSO, dimethylsulfoxide.
W
4
W
Salt
l-CH,O, N-oxide I-CZHSO
HCI
AcOHd, CM3 AcOH-d,-CDCI,
8-HO, 7-CHJO
CW3 cM313
DMSO-d6
DMSO-d6 1N NaOD
CDCI,
CDCls
CDCl,
AcOH-d4
AcOH-d,
CDc4
CXI,
CDCI,
cm3
Solvent
8-C6H,C02
(a) Isoquinolinols and Their Ethers CCH,SO,O 4-C2H,S0,0
Substituent
TABLE 14. ISOQUINOLINIOLS AND THElR DERIVATIVES
2.34(s,3H,OZCCH3),6.04(~,ZH,OCH,0)."6.99. 7.13,7.22(~,3H,4-,5,8-H), 8.74(~,1H. I-H) 1.35(s,3H,O,CCH3). 3.98(&6H,2xOCH,), 7.02,7.17, 7.28(~,3H,4-,S-,8-H). 8.854%1 H. 1-H) 4.01,4.03(~.6H.2xOCH,), 7.52(5,1H), 7.qs,lH), 8.16(S, I-H,l-H), 8.79(~,I H , E H ) 3.98,4.05(~,6H,2xOCHJ, 7.53,7.78,8.03,9.12(~,4H,8-,5-,3-,I-H) 6.60(dd,lH,J=l.8,7.5 H~,7-fl),7.21ym,lHJ=0.8,8.5,1.8Hz,S-H), 7.42(q,lH,J=8.5,7.5Hs6-H), 7.57(~,1H,3-H),8.61(d,lH,J=O.S Hz,I-H) 6.88b(q,2H,J= 2 k5-.7-H),8.05,' 8.3SC(q,2H,J= 6 HG 4.3-H), 9.40(~,1H,l-H) 8.0yd.J = 6.5 H2.3-H) 7.08(~,4-H),7.9Ys.3-H)
8.6yd,lH,3-H),9.7y~,lH,l-H)
3.26(~,3H,CH,), 7.40-8.14(m411). 8.4S(b~.3-H),9.10(bs, I-H) 1.62(t,3H.CH3), 3.48(q,2H,0CH1). 7.48-8.24(m,4H), 8.51(s.3-H), 9. Iqs, I-H) 7.28-8,M(m,9H), 8. l q r 3 - H 9.13s 1 -H) 2.44(s,3H.ArCH3), 7.20-8.30(m.9H), 9.17(bs.I-H) 7.30,7.54(q,2H,J=2.5,8H~S-or~-H),7.94(1,1H,J=8Hz6-H), 8.lYd,IH,J=6HZ,4-H),8.SO(d,lH,J=6 Hz,~-H),~.~~(s.IH,I-H) 7.4-7.9(m.7H,arom. H),ca-8.36(m.2H,arom.H'). 8.84(d.lH.J=6 k t ~ 3 - H ) . 9.53s. 1H.I-H) 4.05(s, 3H. OCH,), 7.Hl(rn. 4H. arom. H), 9.66(s, IH, I-H) 3.97(s,0CH3), 7.37(m,4-.5-,6-H), R.M(d,J = 5 Hs3-H), 9.53(1H) 3.95(s,3H,ArOCH3),4.07(+3H,7-OCH3), 7-8.4(rn.7H,arorn. H),
6 Wpm)
822 823
20
190
131
82 1
139
I39
so
24
so
50
50
576 516
576
5'16
R d.
2
W
~-wC~H~O 3-i-C3H,0 3-n-C4H,0 4-CH30 4-CH30, N-oxide CCZHSO 5-(7-lsoquinolyloxy) 7-CH30
3-CHjO
Substi tuent
TABLE 14. (Conrinued)
~
Salt
CDCI,
CDCI,
CDCI,
CDCl, CDCI, CDCI, CDCI,
CDCI, CDCI, CDCI, CCI,
cm,
CDCI,
CDClJ
Solvent 4.03(S90CH,), 6.98(~,4H),8.95(~, I-H) 4.OYs,OCH3),7.OD(s,lH),7.2-8.qm,4H, 8.8(s,lH) 3.90(s.3H.0CH3),6.78(s,IH), 7.36(m,4H), 8.7(s,lH) 6.9qs.4-H), 8.88(~,I-H) 4.O3(s,3H,OCW3),7.00Is,IH,4-H), 7.68,7.88(d,2H, J = 8 H~,5-,8-)1).8.9Ys,lH,I-H) 7.l(~,4-H),8.854s.l-H) I-H) 6.69(~,4-H),8.w~ 6.95(~,4-H),~ . Wl-H) S, 6.94(~,4-H).8.88(~,I-HI 6.9ys,4-H), 8.88(~,I-H) 7.00(~,4-H),8.96(~,1-H) 4.Ol(s.3H), 7.40-8.10(m5H), 8.22-9.3qbr, IH) 7.7(d.J=2 HL 3-H).8.3S(d.J=2 Hz. I-H) 8.q43-H). 8.81(~,1-H) 7.24-8.06(88), 8.6q2H). 9.1qlH). 9.40(1H) 3.95(s,0CH3).7.5qrn,5-.6-,8-H), 7.53(d,J =6 Hz,QH1, 8.4yd.J = 6 H&3-H),9 . m 1-H) 1.28(t,3H.J=7 Hz),4.3flIq,2H,J=7 Hz),4.77(s,2H), 7.2qd.lH.J = 3 Hz), 7.4ydd.lH.J = 3.9 Hz), 7 . q d . l H . J = 6 Hz), 7.80(d,1H.J = 9 Hz), 8.47(d,I H,J = 6 Hz). 9.18(s, 1H) 22o(t,2H,J=7 Hz),3.63(~,3H),4.q1,2H,J=7Hz), 7.20(d, 1H,J = 3 Hz), 7.43dd. I H,J = 3,9 Hz), 7.62(d,l H,J =6 Hz), 7.78(d, IH,d,J =9 Hz), 8.Wd. 1H.J = 6 Hz). 9.154,lH) 1.2-2.3(m,lOH), 3.9(m,2H), 3.65(s,3H), 7.15(d,IH), 7.401d,lH,J=3.9 Hz),7.60(d,lH.J=6 Hz), 7.8qd,IH, J = 9 Hz).8.45(d,IH,J=6 Hz), 9.2qs.IH)
119
1 I9
119
822 777 823 777 777 717 62 822 823 123 24
83 116 I30 777 824
Ref.
____
HCI
CDCI,
HCIO,
TFA
CDCI,
CDCI,
CDCI,
CDCI,
CDCI,
CDCI,
9.77( b,1H,1-H)
49
24
20
I5
749
43
815
43
24
7.46(d,IH.J=6HzQH),8.38(d,lH,J=6 H2.3-H), 9.02(s,IH, I-H), 3.97(~,2x OCH,). 6.98(~,8*H).7.14(~,5-H),7,45(d.J= 6 Hq4-H), 8.4qd.J=6 Hz.3-H), 9.02(1-H) 3.97(~.2~OCH3).6.97.7.12(~,5-.8-H).7.42.8.30(d,J=5.8 H%4-,3-H), 8.95(~.I-H) 3.99.4.02(s,6H,2xOCH3),7.06.7.1~arom. H).7.54.8.15 (d,2HJ=6 H2,4-,3-H). 8 . 9 4 IH.1-H) ~~ 4.00,4.04(2~OCH3).7.55,7.6Y5-,&H),8.10.8.27(d.J=6 H&4,3-H), 9.2qs. 1-H) 3.80(&3H,OCH3), 5.O2(s,2H.OCH2C,H,), 6.76.6.9qs.2H. 5 - 3 - or 8-3-H), 7.00-7.28(m.6H,arom.H],8.07(d,lH.J=6 Hz.3-H), 8.66(s,IH,I-H) 0.95-2.1 [m,7H. (CH,)z,CH3],4.15(s- 3H,0CH3), 4.20-4.35 (t,2H.0CHz), 7.35--8.4~arom.H),9.6#s,IH,I-H) 6.5D"(q,2H.J=2 H~.5-,7-H17.39.' 8.3Y(d,2H,J=6 Hz, 4.3-H). 9.44(~.1H,I-H) 3.92,4.00(s,2xOCH3). 7.40(~,5-,6-H17.44(d.J=7Hz,4H), 8.3qd.127 H2,3-H).9.5qI-H) 4.24,4.36(~,6H.2 x OCH,), 8.16,8.38(bs,4H,3-,4,5-,6-H),
CDCI,
M
779
24
~.~~(S.~H~~OCH~),~.O~(S.~H,S-H).~.I~(~.IH,~-H).
3.94,3.96(~.2x OCH3). 6.63dJ = 3 Hz,6-H), 6.8qd.J = 3 HKS-H), 7.91(d.J=6 Hs4-H), 8.4qdJ-6 H~.3-H),9.14((I-H) 4.0(6H),7.1(1H),7.311H),8.4(2H19.4(1H) 5.16(s.4H.2xOCH,C,H,).6.82,6.88(d,2H,J=2.5 Hz.6-.8-H). 7.2--7.6(m.IOH.2 x C,H,).7.95.11.40(AB.ZH.J=6 Hz.4.3-H),9.07(s,lH,I-H) 3.92,3.94(~.2x OCH,). 6.68(d,J = 6 Hz.~-H),6.8qd,J = 6 Hz, 6-H), 7.90(d.J=6 H~.4-HJ.8.54(d,J=6 H~,3-H).9.54( I-H) 6.05(s.OCH,O). 7.02(s.&H1.7.12(~,5-H),7.43(d.J = 7 Hz, 4-H), 1(.32(d.J=7 HZ,3-H), 8.94(1-H) 6.l4(s.2H,OCH2O). 7.08.7.15(arom. H), 7.53.8.18(d.ZH.J = 6 Hz4-,3-HJ, 8.92(~,I I f . I -H)
CDC13
CDCI,
CDCI,
CDCI,
DMSO-d, CDCI,
BH 3
HCI
CDCI,
Salt
~~
CDCI,
CDCI,
CDCI, cDC1,
CDCI,
AcOHd,
CDCI,
CDCl,
TFA
Solvent
DSOi
AcOD
SO%DZSO,-
(b) Quaternary Salts of Isoquinolinols and Their Ethers 2-CH3, I-DO DSO; IO%D2SO,AcOD
Substituent
TABLE 14. (Continued)
4.18(N'CH,), 7.81(4-H), 7.88(3-H),8.58(8-H)
4.00(NiCH,), 7.45(4-H),7.75(3-H), 8.538-HI
8.45(d,J=5 Hz3-H) 9.131-H) 3.95,3.96,4.10(~.3x OCH,), 6.82(~,5-H],7.41145 = 6 H&4-H) 8.37(d,J = 6 H&3-H),9.34(1-H) 3.93,4.05,4.18(~,9H.3x OCH,),6.98, 7.10, 7,24(~,3H,5-,5'-,8'-H), 7.38-7.68(m,2H,4-,4-H), 8.20-8.59(m2H, 3-,3'-H), 8.83,9.29(~,2H,1-, 1'-H) 3.9qs,3H,OCH,). 3.98(~6H,2x OCH3).4.038,3H,OCH,), 7.02(~,1H,8-H), 7.97,8.68(~,2H.3-,I-H)
827
827
54
34
24
24
4.00,4-05(~,3~OCH3),7.07(~,8-H),7.84(d,J=5H~,4-H),
8.43(d, 1H.J = 6 Hr3-H). 9.1qs.lH. 1-H)
821 54
30
50
29
24
828
46
3.98,4.01,4.03(s,9H,3xOCH3),7.17(s,1H~7.4~~1H),8.77(s,lH) 3.97,3.99,4.03(~.9H,3x OCH,), 7.07(~, 1H,8-H),7.85(d91H,J~6 Hs4-H),
4.2,4.3(sV6H,2x OCH,), 8.1(b~,2H,5-,6-H),8.4(k2H33-,4-H), 9.8(d,IH,J=7 H r l - H ) 1.47(t,3H.J = 7 HrCHzCH,), 3.94(~,3H,OCHa),4.24(qJH, J = 7 H&OCH,CH,), 7.24-7.%(m,3H,arom.H), 8.28(diKused d,lH, 5 = 7 Hs3-H),9.38(bs,IH,I-H) 3.8S(s,0CH3),5.82(s,0CHIAr), 7.38(m,4-,5-,6-H),7.40(m,C6H,), 8.38(d,J = 6 Hz,~-H),~.S(I-H) 3.88(OCH3), 5.19(OCH2Ar).7.15-7.6(8H.arorn. H),8.38(d,J= 6 Hz, 3-H), 9.y I-H) 3.87(s,3H,0CH3),5.28(s,2H,0CHzAr),6.43(d, lH,arom.H), 7.00-7.44(m,8H,arom.H). 9.37(s.lH,l-H) 5.23(~,4H,2x OCH&H,X 7.1-7.6 (m,13HX 8.31(d,J=6 Hz,~-H), 9.41(~,1H,I-H)
Rd.
-I
4
W
2-C7H 7,4-HO, 6.7-(CH3O), 2-CH3,6.74HO),
2-Y, 8-HO
CD,OD D&CD,OD
CDCI,-TTFA
1-
ao;
TFA
a-
a-
CD3OD CDCI,
DMSO-d,
DMSO-d,
CH,SO; Br-:C,H,OH
CI -
DMSO-d,
DMSO-d,
2-CH 3. h-HO
Pictate
DMSO-d,
CD,OD
CH ,so,
2-Y, 5-HO
2-CH3, 5-HO
DMSO-db
CD,OD CD3OD CD,OD
Br
a-
CI -
CI -
3.3(q,2HX 3.7ysq3H),s.I(d,lH). 5.5(q,2H), 5.6Yq.lH), 6.7(~,1H),7.lys.2H), 7.531, lH), 7.8(d,2H), 8.3d.lHh 9.l(d,lH),9.5(d,lH), 10.09(s,IH) 4.03,4.1qs,bH,2 x OCH 3). 5.93(~,2H,N'CHlAr). 7.3-7.8(~.7H.C,H,, 5-,8-H), 8.35,9.5(~,2H,2-.3-H) 4.37,(~,3H,N+CH,j,7.73, 7.8Ys.2H.5-.8-H),8.23.8.53(ddJ=7HZ. 4-3-H), 9.86(~,1H.1-H) 3.90(s,3H,OCH3), 7.4-8.3(m.SH.3-,4-. arom. H), 9.28(s,lH,I-H) 1.21(1,H,J =7 HzCH,CH,OH), 3.70(q,2HJ= 7 H&CH,CH,OH), 5.21(~,4H.2 x OCH,C,H,), ~.~~(S.~H,N+CH,C,H,), 7.0-7.9(m, 17H). 8.33,8.73(AB,2H,J-7 H14-,3-H), 10.97(s,lH,I-H) 4.27,4.30(~,6H,2x OCH,), 4.57(q3H.NiCH,), 7.60(s,lH,5-H), 7.7ys,lH,8-H), 8.22(b~,2H,3-,4-H),9.30(9.1H,l-H) 4.07,4.12(~,2x OCH,),4.43(s,N+CH,), 7.64,7.71(~,5-,8-H),8.20, 8.3YABq.J = 7 H&2-.3-H), 9.38(~,1-H) 4.10,4.1~2xOCH3).4.47(N+CH,),7.&, 7.74(5-,8-H),8.23, 8.3yJ-6.8 H&4-,3-H),9.3q1-H)
9.7q1H3 I-H)
6.7(s,IH). 7.2(s,2H),7.6(t,lH). 7.83d,2H), 8.5Yd.IH). 9.1yd. lH), t0.09(s,lH) 4.40(N+CHJ),8.52QH.arom. af picratc), 7.5-8.5(5H.nrom.H),
3.3~q.2H),3.7~s.3H),5.1(ld,lH),5.5(q,2H),5.6~q,IH),
7.7(5H,C,H,),8.0-8.7(5H,3-.5-,6,7-,8-H), 9.3 lH, 1-H) 7.2-7.8(4H,C,H,). 8.0-8.7(5H,3-,5-,6-,7-,8-H), 9.3IH, 1-HI 3.97(3H,OCH3). 7.1 -7.7(4H.C,HA), 7.9-8.7(5H.3-,5-,6-.7;8-H), 9.q lH.1-H) 2.46(s,3H,ArCH3), 6.17(s,2H, N'CH,C,H,), 7.30-8.90(m. I3H.arom.H). 8.98(~, 1H,3-H), 10.72(~,lH,I-H) 3.66(OCH3).4.40(N'CH3), 7.33(dd,8-H),7.67(m,ZH,6-.7-H), 8.29, 8.35(d,l=6.8 HZ..4-,3-H),9.61(S.l-H)
805
43
804
433
780 781
230
131
I22
230
I22
210
710
23 1 23 I 23 1
QI
w 4
salt
&tho protons
CDIOD
TFA
I-
Cl-: 1.5 H,O
TFA
Solvent
I-
of benzoyloxy group. Measured at the center of an AB system. Part of an AB system. ' The spoctral data (Ref. 127) are presented as figure. Aromatic protons of a phenethyl group.
a
2-CH3, 6,74CH3O)Z3 8+-HOCHlC,H,0)
2-E3,4-(CH,O),C,H,COCH,I, 6.74CH30)Z 2-[3,e(OCH,O)C,H,(CH*),]. 7,8-CH,0),
~-CL~-(CH~~)~C~H~CH CIZ- ] . 674CH3O)Z
Substitucnt
TABLE 14. (Continued)
3.3Yt.2H,N +CH,CH,Ar), 4.20(s,6H,2 x OCH,), 5.qt,2H,N+CH2CH,Ar), 5.95(s.2H,0CH20),6.5,6.8(m,3H,arom. He).8.08(s,2H,5-,6-H), 8.25(~,2H,3-,4-H), 9.2S(s,IH, I-H) 3.76,4.17(7-,4-OCH,), 4.41(N*CH,). 4.57(28), 6.97, 7.33d.4H. J = 8 Hz),7.67(S-H),8.29(d,lH,J=6 Hq4-H). 8.44(qd,IH,J=2,6 l 4 ~ 3 - H ) . 9.44(bs,I-H)
3.82.3.94,4.08,4.15(s, IZH, 4 x OCH,, 6.10(s, 2H, NtCHzAr), 6.92-7.58(m.4H.arom H), 7.98(s, lH, arom. H), 8.14, 8.48(ABq.2H,J=7.5 Hz, 4.3-H), 10.72(s,lH,l-H) 7.25(s,2H,N +CH,Ar), 8.9(bs,2H,3-,4-H), 9.25(s IH,I-H)
8 (PPm)
763
56
199
826
Ref.
\o
4
W
Salt or Anion
DMSO-d, DZO DMSO-db CDCI, DMSO-d, DMSO,-db
CDCI,
H Br
HBr
HBr
HCI
Hcl
HCI
6.7-(HO),
7,8iHO), 6 C H ,O, N-oxide
5.7-(CH30),
5.84CH3O)Z
5-C2H,0, 6-CH30
D2O
CDCI, CDCI,
DMSO-d,
DMSO-d,
DMSO-d,
DMSO-d,
Solvent
8-HO, 7-CHJO
HCI
HBr
7-HO, 5-CHJO
7-HO, 6-CH30
H Br
HCI
b-HO, 8-CHJO
5-HO. 8-CHJO
5-HO. 6-CH,O
(a) 3,4-Dihydroisoquinolinulsand Their Ethers
Substituent
TABLE 15. DIHYDROISOQUINOLINES AND THEIR DERIVATIVES Ref.
3.03. 3.86(4H.4-,3-H), 4.00(3H,OCH,). 7.15,7.53(2H,7-,8-H). 267 8-931 H.1 -HL9.M 1H.OH) 2.50.3.60(4H,4-,3-H). 3.80(3H,OCH,). 6.86,6.90(2H.6-,7-H), 267 8.43 1H, I-H) 3.03,3.R0(4H,4~,3~H),3.92(3H,OCH~).6.49(2H,5-.7~~), 8.8Q1H.1-H). 267 1 i.B(2H,OH.N+H) 21q2H.4-H). 3.8q 3M,OCH3). 3.85(2H.3-H), 6.89.6.9S(2H.b.,I(-H 1, 267 9.16( IH.1-H), I0.1(2H,OH.N+H) 3.93(sa3H.0CH3). 6.69,6.90(~,2H,5-.8-H) 266 3.93(OCH,).6.67,6.88(arom. H).8.21(t,IH,J=2.3 HzI-H) 336 2.30(1.2H,4-H), 3.16(s,3H,OCH3). 3.19(t,2H,>H).6.14.6.27 300 (S.ZH.~-.&H). 7.8%~,IH, I-H) 2.95, 3.85(3H,4-,3-H), 3.89(3H,OCH,).6.80,7.34(2H,5-,6-H), 267 9.0 I( 1H . I-H) 300 222(t.ZH.4-H), 3.131t.2H.3-H). 5.93, 6.28(s,2H.arom. H), 7.79( S, 1H,1-H ) 2.93. 3.83(4H,4-,3-H), 6.66.7.79(2H,5-,6-H).9.01H,I-H) 67 I 3.12(t, 1 H , J = 7 Hz),,3.82(~,3H).4.OY1.2H,J=7 Ht),6.80(4 IH, 729 J = 2 Hz),6.82(dd,IH.J=2,8 Hz), 7.12(d,lH.J=8 H~).7.77(s,lH) 267 2.93,3.88(4H,4-,3-H), 3.85,3.88(6H,2 x OCHA), 7.03,7.19(2H.&,S-H), 9.1S( 1H, I-H) 2.94,3.86(4H.4,3-H), 3.78,386(6H,2 x OCHII. 7.10,7.S2(2H,C, 267 7-H), ,8.W( IH, I -H) 1.38(t.3H,I=7 H&CH3). 2.74(t,2H,J=2H HGQH). I47 3 . 7 q t d , m , ~=a,z HG 3-14),3 . 8 9 ( s . 3 ~ , 0 ~ ~ , ~ 4.02(qV2H,J= 7 Hit,OCH,), 6.80,7.03(AB,2H, J = S Hgar0rn.H). 8.24(t,IH,J=2 H s l - H )
(PPm)
CDCI,
CDCI,
DMSO-d,
CDCl,
DMSO-I,
2-CH3 7-HO, K H 3 O
c1D20
(b) Quaternary Salts of 3,4Dihydroisoquinolinolr and Their Ethers
6-CqHT0, 7,8-(CH,O)z
HCI
HC)
CDCI,
CDCI,
6CH30,7-C7H,O
cm3
CDCI,
Solvent
CDCI,
Salt or Anion
6,74CH30),, N-oxide
Substbuent
TABLE 15. (Continued)
6.8qs,IH,arom.
H),7.37(~,5H,C,H,),8.17(s,lH,I-H)
3.W%3H,N+CH3),3.78(s,3H,0CH3),6.74,6.89(%2H,arom.H), 8.5O(S, lH, I-H)
2.61(1,2H.J=8 Hz,~-H),3.70(m2N.J=2,8 H2.3-H), 4.88(s,3H,0CH3), 5.1O(s,2H,OCH2Ar),6.65. 6.79(~,2H,8-,5-H),8.1 1(t, 1H J = 2 HG I-H) 3.03,3.81(4H,4-,3-H), 3.97(6H,2 x OCH,), 6.65(2H,5-,7-H), 8.78( IH, I-H) 2.54(P,4H.J=8 H2,3-,4H), 3.89,3.93(~,6H,7-,8-OCH,), 6.90(~,2H,5;6-H).8.7(bS, 1-H) 3.05,3.91(4H,4-,3-H), 3.91,4.00(68.2~OCH,),7.17, 7.56(2H,5-,6-H), 9.i2(1H, 1-H) 2.58-3.Wm,4H.4-,3-H). 3.87.3.!W(s,6H,2 x OCH,). 5.1Ys 2H.0CH2ArX 6.48(s, 1H . 5-H), 7.40(m, SH,C,H,), E.Sl(t,lH,J =2.5 Hz, 1-H) 260-3.7qm,4H,4-,3-H), 3.87,3.9S(~,6H,2 x OCH,), 5.15(s,2H, OCH,Arh 7.4i(m,5H,C6H,), 8.58,(1,IHJ =2.5 H a I-H)
3.7’(2H,3-H), 82(t,lHJ=2 Hal-H), 2.63(bq,2H,J = 8 Hz). 3.74(m,2H).3.87(s,6H), 6.65(s,lHX 678(s,IHX 8.2qbs.lH) 3.13(1,2Hb=8 Hz),3.90,3.93(~,6H),4.08(l,ZH, J = 8 Hz). 6.70,6.80,7.70(~.3H) 2.63(1,2H.J =8 Hz.4-H). 3.71(rn,2H,3-H), 3.87(s,3H,OCH,), 5.11(q2H, OCH,ArX 6.68(s,lH,amm. H).
6 (PPm)
20 1
265
265
671
189
267
355
270
729
292
503
Rel.
Bc -
Br-
D20
I-
CD,OD
CDCI,
cm3
3.16(t,2ZHJ=7.5 H~4-l-l).3.8-4.0(rn.2H.3-H), 3.88,3.94.3.96. 4.Ws, 12H,4 x OCH,), 5.4&2H,N +CH,Ar). 6.94-7.34(m.4H.arorn. H), 7.74(s,lH,arorn. Ff), 10.46(s.1H,!-HJ 3.0-4.qm,4H,4-,3-Hb 3.8Ysq6H,2x OCH,), 3.86, 3.93(s.6H,2 xOCH,), 5.10(s,2H,NSCH,Ar), 7.03,7.08, 7.43(s.3H,arorn. H).9.01(s. lH,I-H) 3.20(t.J=7.5 H e e H ) , 3.8-4.0(m.3-H), 3.77,3.82(~,6H,2xOCH,). 3.8qa6H.2 x OCH,).5.4ys.N +CHzAr),6.ms.5-H). 6.95-7.2qm. arom.H), 7.69(s,8-H), lO.I~s,I-H)
to.oys,IH.l-H)
CDCI,
1-
CDCl, CDCI,
TFA
c1-
362
826
8 26
826
830 360
275
2.88.3.2qt,J=8 H2,4-.3-H), 3.76(~.3H,N'CH3), 3.88. 3.96(~.6H, 2xOCH3),7.OB(s,1H.arom. H),8.72(s,IH.arorn. H) 3.91,4.00(2 x OCH,). 6.83. 7.7qarom. H),lO.l3$s,l-H) 3.21 (bm,4H.4;3-Hb 3.90,3.99(~,6H.2Y OCH,), 5.78(s.2H.CH,ArX 6.88(s, 1 H,S-H), 7.62-83 (m, SH.arom. H), 10.25(s, 1 H,1-H1 3.0-3.7(m,4H.4-.3-H), 3.88- 3.95(s,6H.2 x OCH,). 5.38 (&2H,N CH,Arh 5.9Ys2H.0CtlzO), 6.7-7.2(m.4H,arorn. H), 7.68(s,IH,arorn. H),
TFA
c1-
8.0S(brs. I-H)
1.!wt,3H,J = 7 HsCH,), 3.10-3.55(m,4H.4-,3-H). 272 3.74s.3H.N +CH,), 4.WS.3H.OCH3b 4.03(q,2H.J = 7 HIOCHZ), 7.28,7.69(A3.2H,J=8 Hz.ar0rn.H). 9.17(bs.lH,I-H) 3.29. 3.89(tL4H,J= 7 Hq4-,3-H), 3.80 s,3H,N 'CH,). 433 6.17(~.2H,OCH,0), 6.94(~,lH,S-H), 7.14(~,IH,B-HI, 8.52L~,Iff.!-H) 3.37,4.W1,4H,J=7 Hq4-,3-H). 3.87(~,38,N'CH,I4.07,4.12(s6H, 433 2 x OCH,), 7 . I q s I H.5-H). 7.43[5,1H,&H). 8.7%~.IH. I-H) 2.56,3.6!(t,J =7.8 H54-,3-H), 3.80(2 x OCH,),6.51,6.73(~,5-,8-H). 43
DMSO-d,
1-
Suhtit uent
Table IS. (Conrinued)
CDCl, CDCI, CW,
3r-
%I-
1-
I-
CI-
I-
CD,OD
CD,OD
CDCi,
Br-
%r-
CD,OD
Solvent
a-
8r-
Salt or Anion
830
360
826
362
Rd.
-
830 6.82,7.45(~,2H,5-,8-H),9 . 8 % ~I-H) 3.40,4.031n,4H,C,3-H), 393(~.3H,N+CH3), 400 4.03(~,3H.OCH3),6.94.7.73 (~,2H,5-,8-H), S.2qs,2ff,0CH2Ar), 7.40(m,SH,C 6Hs), 8.78(s, Iff, I-H) 3.05,3.8qt,4N.J = 8 Hz4-.3-H), 5.07,5.18(s,4ff.2x OCH,Ar), 364 5.39(s,2H,N+CHz,Ar),6.90,7.78(~,2H.arom.H), 7.0-7.7(111,15H, 3 xC ~ H , ) ,10.31(~,lff,l-H) 3.0-3.20(111,2H,4-H), 3.92,3.95@,6H,2 x OCH3), 3.6-4.l(m,2H,3-H), 764 6.60(b6.2H,5-,7-H), $.92(bs,lH, I-H) 433 3.27,4.10(1,4H,J=7 H2,4-,3-H), 3.w~,3H.N+CH3),4.00, 4.20(~,6H.2x OCH,), 7.14,7.32(d,2H,J=8.5 HsS-,6-H), 9.12(~,1H,I-H) 3.39(te,4H,J=8 Hz),3.86(~,3H,N+CH3),3.95,4.I0(&6H,7-, 290 8-OCH3). 7.15, 7.52(d.lH,J=& HZ,S-,CHX9.27(bs,IH,I-H)
4.05,4.10,4.20(3xOCH3),6.18(s,2H.N+CHzCO),
3.20(tJ=7.5 Hs4-H), 3.8-4.0(rn,3-H).3.92,3.9@,2 x OCH3), 5.46(s,N+CH2Ar.).5.9qs,%HzO), 6.75(4J=8.5 HGarom. H), 6.82(s,S-H], 7.0-7.2(m,arorn. H), 10.24(s,lH) 2.9-3.S(m,4H,4-,3-H), 3.81,3.83, 3.85, 3.95(s,12H,4 x OCH,), 5.Ws,2H,N+CH2Ar), 6.8-7.2(rn,4H,arom. H), 7 4 s , I H , arorn.H), 9.01(s,IH,l-H) 1.37(t33H,J= 7 Hz,CH,CH~),3.28(bm4H,4-,3-H), 3.94(d.6H,2 x OCH,), 4.36(q.2H,J= 7 H G O C H ~CH~) , 5.70(s,2H,CH2Ar),6.99-8.0(rn,6H,arom. H) 4.00(6H,2 x OCH,), 6.41,6.83~,2H,5-.8-H),lO.OO(s.1-H)
6 (PPd
00
W
6,7-(OCH,O)
(c) Alkoxy- 1.2-dihydro-2-(p-losyl)isoquinolines 7-CH 3 0
c1o;
CDCI,
CDCI,
CDCI,
CDCI,
DMSO-I,
D,o
TFA
CDClj
DMSO-I,
-
2.38(~,ArCH,),3.76($OCH,), 4.56( I-H), 5.82(d.J = 7 Ha 4-H), 6.78(d.J = 7 Hz.3-H). 6.80(m,5-,6-H), 7.28, 7 . 7 3 6 5 = 8 Hrarom. H ) 2.45(s.ArCH,), 4.231-HA 5.95(s,0CH20). 6.47{d,J= 7 H2.4-H), 6.69(~,5*,8-H), 6.83(d,J = 7 HZ.3-H), 7.35.7.75 ( d J - 8 Hz,arom. H) 2.37(s.ArCH,). 3.72(~,2x OCH,). 4.60(1-H). 6.11(d,J=8 Hg 4-H), 6.61IS,6*,7-H8),6.7Yd.J = 8 Hz3-H), 7.27, 7.7qd.J = 8 Hz,arom. H ) 2.31(s,ArCH3), 3.76(s.2 x OCH,), 4.52( I-H), 5.77(d,J=8 H r 4-H), 6.49(5-H). 6.56(8-H),6,68(d,J=8 HZ.3-H), 7.24. 7.72(d,J = 8 H i a r o m . H )
-
3.07.(t.2H.J=8 H14-H). 3.76(s.3H,N+CH3), 3.93~,3H.oCH,), 3.9'(t.ZH.J=8 Hr3-H), 5.22(~,2H,OCHzAr). 7.13. 7.47(AB 2W.J = 8 Hr,5-,6-H), 7.43(~,5H,C,H,) 3.16,3.98( t,4H,4-,3-H). 3.8qs. 3H, N 'CH J), 3.89(OCH,). 7.28(6.5-,6-H), 5.30(OCH,Ar), 7.35(C,H 5), 8.73 I-H) 3.I8,3.95(~,4H.J = 7 Hr4-.3-H), 3.75(s,3H,N*CHS). 4.27is.38. OCH,), 6.12(s,2H,OCH,O), 6.58(~,1N.5-H),8.72(~,1H.t.H) 3.88(3H.N 'CH,). 3.97,4.10,4.18(~,9H,3x OCH,], 7 . 0 w 1 H,5-H). 9.09(~.1H, I-H) 3.08(t,ZH,4-H),- 3.80(rn,2H,3-H), 3.80. 3.98(s.6#.2 x OCH,), 5.33(m.4H.OCH,Ar.NfCH,A~), 7.1 I(s.IH.5-H), -7.SQ111.10tf. 2 x C ~ H , ) , ~ . ~ I ( S . I H , I - H )
24
24
24
24
286
406
433
4M)
403
z CDCI, CJXI,
5,6.74CH,O),
6,7,84CH,O),
'
a
Half of an A2X, triplet. further spilitting (J=2 Hz) into six lines. Closely overtapping triplet. Closely overlapping poorly diffused triplet. Patially hidden by the N+CH3and OCH, signals. ' In the original literature these assignments are described as 5 and 8 positions
CDCI
7&(C,H,O)2
,
CDCI,
CDC13
7-CH30, 8-C,H,O
~
Solvent CDCI,
~~~
!&It or Anion
7,8-(CH3011
~~
Substituent
TABLE 15. (Continued)
2.32(s,ArCH,). 3.7qs.2 xOCH,), 4.62(1-H), 5.72(d.J=8 Hz, 4-H). 6.61(~,5-,6-H),6.62(d,J=8 Hs3-H), 7.20.7.66(d J = 8 Hzarom. H) 2.29(s,ArCH3),3.76(qOCH3),4.37( I-H).4.90(s,0CH2Ar), 5.61(d,J = 8 HzCH), 6.55(m,3-,5-,6-H,arom.H), 7.36(m,arom. H) 2.29(qArCH3),3.76(s,0CH1,),4.37( I-H), 4.90(s,0CH2Ar), H), 5.61(d,J = 8 H~3-H).6.40-6.71(3H.arom. 7.07-7.63(9H,arom. H) 2.35(st3H.ArCH,h 4.50(~,2H,I-H), 4.95, 5.05(~,4H2x OCH,Ar). 5.7qd. 1H,J = 7.9 Hz,Q-HX 6.57,6.74(AB,2H,J = 8.5 Hz,S;~-H), 6.624d,IH,J=7.9 Hz3-H), 7.15(AB,2H,J=8.3 Hz,.arom. Hh7.30. 7.33(s.IOH,C6H,). 7.6qAB,2H,J=8.3 Hzarom. H) 2.39(rArCH3),3.72(m), 3.83(s,3 x OCH,), 4.5ql-H), 6.09(d,J = 6 Hz4-H). 6.33(~,8-H),6.67(d,J=6 Hz,3-H), 7.22,7.69(d,J = 8 HLarom. H) 244(s,ArCH,), 3.85(m,3 x OCH& 4.33(1-H) 6.69(d,J=6 WLCH), 6.80(~,S-H), 7.06(d.J=6 Hs3-HA 7.36,7.70(d,J = 8 Hzarom. H)
6 (PPm)
24
24
30
29
24
24
Ref.
W
v,
~~
' Overlapped with a proton at 8 position.
8-oxidoiscquIndinIum
3,4-Dihydro-6.7-dimethoxy-2-methyl-
6-oxidoisoquinoliniurn 3,4-Di hydro-6,7-methylenedioxyS-oxidoisoquinolinium (cotarnoline) 3,4-Dihydro-6,7dimethoxy8-oxidoisoquinolinium
3,4-Dihydro-7,8dimethoxy-2-methyl-
2-Methyl-6-oxidoisoquinolinium
Struaure
TABLE 16. PHENOL BETAINES
DMSO
DMSO
ACCIOW-~~
DMSO-Ib-TFA Acetone-d,
DMSO-I6
Solvent -
6( P W ) ~
~~
3.92(N'CH,). 6.32(dgJ=2Hz, 5-H),6.77(q.J=9 Hz. 7-H), 7.13(d, J = 7 HG 4-H). 7 . W ( d , 3-H), 7.62(d, 8-H). 8.50(1-H) 4.d0(N'CH3), 9.67(1H, I-H) 2.80(1,4.H), 3.40(N*CH,), 3.55(t, 3-H), 3.76. 3.92(7-.8-OCH,), 5.85(1-H). 7.80(5-H) 2.82(t. 4-H), 3.49(N+CH,), 3.60(t, 3-H), 5.67(OCH20), 5.72(1-H), 8.20(5-H) 2.75(m,4ff), 3.82(3H), 3,88(s. 3 H ) . 6.20(s, I f f ) , 8.33(bs, 1H) 2.85(m, 4H), 3.4% 3H). 3.60(s, 3H),3.824%3H), 6 1O(s. 1H).8.40(1 H)
~
680
680
510
230 510
230
Ref.
o\
00
W
Salt Solvent
DMSO-d,
DMW, DMSOd6
D M Sod6 DMSO-d, DMSO-d,
HCI
HCI
HBr
HCI
HCI HBr
640
7-HO
CDCI,
2-CH,OzC, 5-CH,COz
CDCI,
W l S DMSOd,
l-Dz, 3-D,, 4-HO 5-HO
2-CH,OzC, 5-HO
CDCI,
4-HO
HCI
CCI,
2-HO
(a) 1,2,3,4-Tetrahydmisoquinolinolsand Their Derivatives
Substituent
6( P P 4 2.94(b~,4H, 3-,4-H), 3.94(b~,2H, 1-H), 6.99(b, 4H, 5-,6-,7-,8-H). 7.67(b, 1 H,OH) 2,47(bs. 2H. 3-H), 3.7(b~,4H, I-H. NH, OH), 4.43(t. 1H,4-H), 7.16(m, 4H. arorn. HI 2.7(bs, 2H,OH, NH),4.52(s, 1H,4-H), 6.95-7.5(m, 4H) 2.79(t, 2H.4-H), 3.27(t, ?H.3-H), 4.11(~.2H, I-H), 6.59(d, IH, J = 7 Hz, 6-H), 6.80(d, lH, J ~ 7 . Hz, 5 8-H). 7.00(t, IH, 7-H). 9.71(bs, OH, N'H,) 2.94(t,J=5.9 H z , ~ - H )3.85(t. , J = 6 Hz, 3-H), 3.91(s,OCH,), 4.63(s, I-H), 6.73-7.18(m, arom. H, OH) 2.73(t, J-5.9 Hr4-H), 3.68(t,J=6.1 Hz, 3-H), 3.73. 3.88, 4.63(s. 1-H), 6.87-7.27(rn, arorn. H) 3.24(t, 2H,3-H), 4.06(~,2H, 1-H), 6.60(bs. IH, S-H), 2.89(t, 2H,4-H), 6.64ldd. 1H,J=2.5,8Hz,7-H),6.97(d,tH,J=8Hz,8-H), 9.48(s, 1H.OI-l).9.67(b,N+HL) 2.89(t, 4-H), 3.24(t, 3-H) 2.92(t, J=6.5 Hz, 4-H), 3.33(t, J z 5 . 8 Hz, 3-H), 4.15(~,1-H), 6.61 (s, 5-H), 6.69(d, J = 1.95 Hz, 7-H), 7.02(d, J = 8.3 HZ 8-H), 9.44(0H, N+Hz) 2.87(1,2H, 4-H). 3.25(t, 2H.3-H), 4.10(~,2H, 1-H), 6.60(b~.lH, 8-H), 6.68(dd, lH, J=2.5,8 Hz, 6-H), 6.96(d, 1 H , J = 8 Hz, 5-H), 9.61(b, OH, N+H,) 2.87(t, 4-H), 3.25(t, 3-H) 2.88(t,J=5.48 Hz, 4H), 3.33(t.J=5.37 Hz, 3-H), 4.18(~,l-H), 6.61(~,8-H). 6.70(d,l=8.31 Hz, 6-H), 7.00(d, J-8.31 Hz, 5-Hh 9.42-9.18(OH, N+tI,)
TABLE 17. TETRAHYDROISOQUINOLINES AND THEIR DERIVATIVES
789 757
121
789 757
121
757
757
831 I21
786
571
Ref.
0 21
W
DMSO-d6
HBr
H Br
5-HO. 7-CHJW
6-HO. S-CH,O
HCI
D*O
HCI
DMSO-d,
CDCI,
D,O
HCI
7-HO. 6-CH,O
2-CH0, 7-HO. MHaO
DMSO-dh
DMSO-I,
DMSO-dh
2-CHO, 7-HO, 5-CH3O.
7-HO, 5-CHSO
HBr
DMSO-dh
H Br
2-CH0, 6-HO, S-CHJO
CDCI, DMSO-I,
HCI
2-CH 3CO. 7-CH 3C0, 8-HO
DMSO-I,
CDCI,
2-CHJCO. 7-HO 2.18(COCH,), 4.54, 4.68(~.2H, I-H). 6.76(8-H), 8.72. 7.01(d, 1 H, arom. H) 2.16(s, 3H. NCOCH,), 2.28(s. 3H,OCOCH,), 4.59. 4.70(s, 2H. I-H) 2.94(m. 2H. 4-H). 3.27(m. 2H. 3-H). 4.00(s, 2H. I-H), 6.72(d, I H , J = 7 HL 7-H). 6.7R(d. 1 H. J = 7.5 Hz, 5-HI, 7.M(1. 1H.6-H). 9.72(b. N'H,). 9.96(b,OH) 2.94(1, J = 6 . 3 H z 4 - H ) , 3.34(1.J=5.6Hz9 3-H). 4.05(~,I-H). 6+66(d.J-7.8 HZ 7-H), 6.75(d. J =8.4 Hz, S-H), 7.08(t, J ~ 7 . H8 L 6-H), 9.13(bs. NH), 9.87(bs. OH) 2.82(1.2H, J = 6 HG 4-H). 3.45(1. 2H, I =6 HL 3-H), 3.67(~,3H. OCHJ), 4.16(~,2H. 1-H), 6.25td. I H , 5 = 2 Hz. 6-H), 6.36(d. I H , J = 2 Hz.8-H). 9.03(s,ZH. N'H,), 9.65(~.IH,OH) 2.87, 3.30(4H. 4-,3-H). 3.76(3H. OCH,)), 3.98(2H, I-HI. 6.23, 6.33(2ff. S.7-H). 9.25(3H. OH, N'H,) 2*73,3.60(4H. 4-. 3-H). 3.75(3H. OCHJ, 4.21(2H. I-HI. 6.17, 6.27(2H, 5-,7-H), 8.13. 8.20(1H.NCHO). 9.23(1H.OH) 2.68, 3.29(4H,4-,3-H), 3.71(3H,0CH3),4.11(2H, I-H), 6.18, 6.33(2H, 6-.8-H), 9.27(3H, OH, N'H,) 2.50, 3.57(4H. 4-.3-H), 3.70(3H, OCH,). 4.41(2H, I-H), 6.17, 6.24(2H,6-.8-H). 8.12, 8.16(IH,NCHO), 9.26(1H,OH) 3.3, 3.6(48,4-,3-H), 3.94(3H, OCH,), 4.25(2H, I-H), 6.99, 7.06(2H, 5-,8-H) 3.10(t, 2H. 4-H), 3.57(t, 2H, 3-H), 3.88(~,3H, OCH,), 4.30(s. 2H. I-H). 6.72. 6.87(s. 2H.worn. fl) 2.78(t. 2H,4-H), 3.5-3.8(rn. 2H. 3-H), 3.8% 3H, OCI-I,), 4.42, 4.56(2H, I-H). 6.18(1H,OH), 6.60, 6.66(2H, 5-,8-H), 8.16, 8.20(1H, NCHO) 2.83(t. 2 H , J = 6 Hz.4-H). 3.21(t, 2H, J = 6 HC 3-H), 3.74(s, 3H.OCH3),4.09(s. 2H, I-H), 6.71, 5.82(AB, 2H. J = 8 . 5 Hz, 5-,6-H), 9.30-10.10(b, 3H. OH, N*H,)
568
400
300
400
267
267
267
267
562
757
121
77 I
771
00
00
W
4.S*(HO)2, 7-CH3O 4,6+(HO)2.7-CH,O 4,7-(Ho),, 6-CH30
7,8-(HO)*
GHO, 7,8-(CH30)2
CHO, 6,7-(OCH,O) CHO,7,8-(CH30),
4HO,5,8-(CH30)2 2-CHaCO. &HO, 5,8-(CH30)2
Substituent
TABLE 17. (Continued)
HCI
HCI HC1
Ha
HCI
HCI
Mt
DZO
DMSO-d,
CDCI,
CDCI, CDCI,
DMSGd,
CDCI3-TFA CDCI,
DMSO-d,
Solvent
561
L52(t, 2H,J=5.5Hg4-H), 280(t,2H,J=5.5&3-H), 3.67(~.5H. I-H, OCH,), 5.2(b, 2H. OH, NH), 6.38, 6.63(AB, 2H. J = 8 HC S.6-H) 3.04, 3.47(t, 4H, 4-,3-H), 3.86(~,3H. OCH,), 4.28(~,2H, I-H), 6.78, 6.98(d, 2H, 5-.6-H) 6.7, 4.8(d, J=8.5 Hz, 5-,6-H) 2.6-2.85(rn, 2H, CH), 3.4-3.8(m, 2H,3-H), 3.79(s, 3H, OCH3), 4.44, 4.58(2H, 1-H), 5.85(bs, IH,OH). 6.5-6.7(m, 2H. 5-,6-H), 8.12, 8.19(1H, NCHO) 2.82Irough t, 2 H , J = 6 Hz,4-H), 3.63, 3.78(1,2H,I=6 Hz, 3-H), 3.88(~,3H,OCH3). 4.55. 4.68(~,2H. 1-H). 5.72(~,lH, OH), 6.7ob(AB. 2H,5-,6-H), 8.22, 8.28(s, lH, NHCO) 3.70, 3.78(s, 6H, 2xOCH3), 4 . W . lH,4-H),6.68(~,2H,arom. H) I.I5(COCH,), 3.78, 3.83(~.6H, ZXOCH~), 4.95(bt, lH,&H). 6.70(bs, 2H, arorn. H) 3.3-3.7(q, 3-H), 4.8-5.l(asyrn. t,4-H),4.2-4.4(9, I-H) .2.98(m,2H. 3-H), 3.24(bs, 3H,2xOCH3), 3.8-4.6(m, 2H, 4-H, NH), 6.89, 7.12(d, 2 H , J = 8 Hz, 5-,6-H) -2.68(m 2H, 4-H), -3.07(m. 2H. 3-H), 3.80, 3.85(s. 6H, 2xOCH3). -3.90(rn,2H, I-H), 6.42(s, lH, 5-H) 2.92, 3.22(AABB’. 4H. 5 = 6 HZ, C,3-H), 4.07(~,2H, 1-H), 6.51, 6.75(AB, 2H,J=8.5 Hz, 5*,4H) 3.3-3.7(q, 3-H), 4.8-5.l(asym. 1, 4-H),4.3b(AB, I- 13 Hg 1-H) 3.3-3.7(t, 3-H), 4.8-5.l(asym. t, 4-H),4.2-4.4(~,I-H) 2.50(t, 2H, 3-H), 3.93% 3H, OCHI), 4.33(~,2H, 1-H), 5.05(1,2H, 4-H, OH), 6.75, 7.10(s, arom. H)
548 548 548
%a
262
49
548
832 832
403
400
399
400
Rd.
6 bpml
2
W
CDCI,
DMSO-d6
DMSO-d,
CDCI,
5-CHjO
HCI
CDCI,
4CH30
I-CH,O, 2-(C6H,CHzCO)
(b) Alkoxy-I,2,3,4-tctrahydroisoquinolinesand Their Derivatives
3.B. 3.29(s, 3H, OCH,). 25-4.0(m,4H,4-,3-H), 5.82, 6.55(s.0.71/0.29H, I-H), 7.32(m.9H. arom.H) 2.95(& 2H. 3-H). 3.75[~,6H. 1-H, OCH,, NH (exchangeable with D,O)], 4.44(1, IH, QH), 7.15(m, 4H. arom. H) 2.07(~, NH), 2.63(t, J 5.86 Hz,4-H), 3.10(t.J = 5.86 Hz., 3-H). 3.79(OCH3). 3.95(s. IH), 6.61(d, I = 7.92 H g atom. H), 6.65(d, J = 8.3 Hz,arom. H). 7.08(t, J = 7.71 Hz, 7-H) 2.81(t, 2H.4-H), 3.25(t. 2H, 3-H), 4.14(~,2H, I-H), 3.76(~,3H,OCH3),6.76(d,lH,J-8H~CH),6.84(d,lH, J = 8 HG 8-H), 7.18(t, IH, 7-H), 9.86(d, W , N'H,) 2.59, 3.60(4H, 4-,3-H), 3.76(3H, OCHJ, 4.52(2)1, 1-H), 6.50-6.90. 7.03(38.6-.7-,8-H), 8.14,8.19(1H,NCHO) 2.66(t, J = 5.9 Hz, 4-H), 3.57(t. 6.1 Hz,3-H), 3.63, 3.70(2 x OCH,), 4.46(s.I-H), 6.43-7.12(m, arom. H)
2.88, 3,25(111,4H, 4.3-H), 3.77(~.3H. OCHS).4.00(~.2H.1-H), 6.32(~.1H.5-H). 8.53. 8.88(b,2H. 2xOH). 9.H)(b,2H, N'HZ) 3.3-3.7(q. 3-H), rl.l-S.l(asym. 1.4-H), 4.3*(AB. J = 13 Hz, I-H) 3.3-3.8(mr, 2H.3-H), 4.3(s, 2H. I-H). 4.9{rnd,4-H), 6.7,6.95(~.2H. S.8-H) 3.60(t, 2H. 3-H), 4.33(~,ZH, I-H), S.OO(t, IH,&H). 6.78. 7.00(s. 2H.arom. H) 3.55(m. 2H), 4.26(s. 2H), 4.95(t. IH, J = 3 Hz), 6.68, 6.91(s, 2H)
757
267
121
757
786
788
525
550
546
US
545
s
0
2*CH&O. 7-CH 3 8-CH30
7-CHaO
6-CH 3
Substituent
0
TABLE 17. (Continued)
HCI
HCI
HCI
salt
CXl,
CDCI,
CDCI,
DMSO-db
CWI,
cm,
CDCI,
DMSO-db
CDCI,
Solvent
7%
121
757
Rd
77 I 833
173
121
~.~~(s,NH~,~.~~(~,J=~.SHZ,CH),~.O~(~,J=S.~H~ 757 3-H), 3.75(OCHJ, 3.90(5, I-H), 6.61(d, J = 8.1 Hz, 7-H), 6.67(d,J=7.2 WZ,5-H), 7.07(t,J=7.8 Hz,6-H)
2.90(1, 2H. 4-H), 3.24(t. 2H, 3-H), 3.69(~,3H. OCH3), 6.77(d, IH,J=Z.SHz.S-H), 6.78(dd, 1H,J=2.5, 9 Hz, 6-H), 7.07(d, lH, J = 9 HL 5-H), 9.84{d.2H,N+H2) 3.0, 3.5(1,4H, 4.3-H), 3.8(s, 3H,OCH,), 6.8(unresolved t, 6H), 6.9(d,IH,J=2.6H~,8-H),7.2(d,IH,J=8.6HZ,5-H) 2.07(s. 3H, NCOCH,). 3.68(s, 3H, OCHJ 1.58(s, IH), 2.75, 3.OD(d.4H.J=5 Hz),3.73(s. 3H), 3,90(9,2H). 6.61(m. 2H), 7.031~ IH)
6.67(dd,lH,J=3,9H~.7-H),6.92(d,lH,J=9H~,8-H).7.27. 7.67(AB, 4H. J =8 Hz, arom. H) 2.40(~,NH),2.68(t,J=5.8 Hz,4-H), 3.07(t,J=5.8 Hz, 3-H), 757 3.75(0CH3), 3.88(~,1-HI, 6.94(6J = 7.8 Hz, 5-H) 3.65(~,3H,OCH,), 4.55(~,2H,1-H) 77 1
1.64(S, NH), 2.75(1 J ~ 6 . H 2 s 4-H), 3.03(t. J = 5 Hz,3-H), 3.73(OCH3), 3.88(bs, l-H), 6.57(h 5-H), 6.68(d, J=7.7 Hz, &H), 6.86(d.I = 7.7 H& 8-H) 2.96(t. 2H,4H),3.24(1.2H, 3-H). 3.70(~,3H, OCH,), 4.0!3(~,2H, 1-H), 6 . 7 3 h lH, 5-H), 6.77(dd,J=2.5. 9 Hz. 7-Hh 7.09(d. IH,J =9 HG 8-H), 9.84(b,2H, N'HZ) 2.41(~,3H. ArCH,). 2.87(1,5=6 Hz, 4-H), 3.32It. 2H. J = 6 Hz, 3-H), 3.73(s, 3H. OCH,), 4.16(s, 2H, 1-H), 6.55(d, I f f , 5-H),
6 bpm)
2-CHO,5-CH,O, 74 1-Phcnyltetrazolyl-5-oxy) 2-[(CH,),CCO]. 6,7-(OCH,O)
2-CHO, 8-CH30
HCI
HCI
HCI
CD,OD
D,O
CDCI,
CDCI,
DMSO-d,
DMSO-d,
CDCI,
CDCI,
CDCI,
DMSO-rlh
DMSO-J, 2.96(1, ZH, 4-HI. 3.24(t, 2H. 3-H). 3.78(~,3H. OCH,). 4.00(~,2H. I-H), 6.77(d. IH. J = 3 HZ 7-H), 6,84(d. I H , J = 8 HLS-H). 7.21(t. IH,6-H), 9.85(b. 2H, N'H,) 2.95. 3.6W4H. 4-,3-H). 3.79(3H. OC'H,). 4.40(2ff, I-H)% 6.60-6.91. 7.15(3H, 5-,6-.7-H). 8.1 I . 1.20(111, NCHO) 1 . 2 8 [ ~9H. C(CH,),]. 2.80(bt. 2H. 4-H), 3.8(s, 3H. OCH,), 3.5-4.0(m. 2II. 3-H). 4.65(s, 2H. 1-H), 6.5 -7.4(m. 3H. arom. H) 2.811. ZH. 4-H). 3 . 7 ( ~5H. , OCH,, I-H), 4.6(bs, 2H. 3-H), 6.5-7.3(m, 3H, worn. €4). 7.4{s. 5H,C,H,) 2.41(~,3H, ArCH,), 2.89, 3.32(1. 4H. 5 = 6 Hr,4-,3-H), 3.76(~.3H. OC'H,). 4.16(~.2H. I-H). 6.63(d. 2H. 1 = 9 Hz.5-,7-H). 7.07(t,lH.J=9Hz.6-H). 7.27. 7 . 7 1 ( d , 4 H . J = 8 H ~ a r o m .H) 1.331s. 9H. C(CH,),J. 2.83(bt* 2H. 4-H), 3.73s. 3H. OCH,). 3.5 4.0(m. 2H.3-H), 4.67(bs, ZH,I-H), 6.5-7.2(rn, 3H. arorn. H). 7.37(s. 4H, C6H4) 2.8(1,2H. J - 6 Hz 4-H). 3.73(s, 3H, OCH,), 3.5-4.0(m. 2H. 3-H), 4.6S(bs 2H, 1-H), 6.5-7.7(m. IZH, arom. H) 2.85, 3.32(4H,4-.3-H), 3.76, 3.81(~,6H. 2 xOCH,). 4.15(2H. 1-H). 6.40, 6.48(2H, 6-.8-H), 9.62{2H, "HI) 2.66. 3.65(4H. 4-,3-H). 3.75(3H, OCH,], 4.54(2H, 1 -H), 6.95, 7.05(2H, 6-,8-H), 7.50-8.00(5H, C,H,), 8.16. 8.21(IH, NCHO) 1 C(CH,),]. 2.76. 3.78(t. 5 = 6 Hz. 4-.3-H), 4.63(s, 1-H) 5.88(s, OCH,O), 6.56(s, arom. H) 4.15(s, 2H, I-H), 6.52, 6.47(~,2H, 5-,8-H) Z.IO(NH), 3.77(2 x OCH,),6.47, 6.63(s, arom. H) 3.0(1,2H, +H), 3.5(t, 2H, 3-H), 3.8(~.6H,2 x OCH,), 4.3(s 2H, I-H), 6.0, 6.8(s, 2H. arom. H) 3.80(s, 6H. 2 x OCH,), 4.27(5,2H. I-Hj. 6.78. 6.80(s, 2H, arorn. H) 521
796 712 773
757
26 7
267
833
833
796
833
x33
267
121
2-CH SCO, 6,7-(CH 3 0 ) 2 2-C,H,O,C, 6,7*(CH,O),
Substitucnt
TABLE 17. (Continued)
Salt
CDCI,
CDCI,
CDCI,
CDCI, CDC1,
Solvent
-
2.93, 3.68(t, 4-,3-H), 4.38(1-H), 6.66, 6.67(5-,8-H), 7.37(CH-N), 7.66, 8.14(AB, arom. H) 1.99, 2.03(~12H,4 x COCHJ, 2.75, 3.7C(t, 4H, 4.3-H). 3.78(s, 3H, WHd, 4.24(m,2H, sugar CH,), 4.55(s, 2H, 1-H), 4.85-5.35(m, 4H. sugar CH), 5.18(s, 2H, OCH,C6H,), 6.68, 6.90(~,2H, S-,8-H), 7.38(~,5H. C,HJ 3.43. 3.85(4H, 43-H), 4.08, 4.10(2 x OCHJ, 4.47(2H, 1-H), 6.75(231, S.7-H) 3.0, 3.4(n 4H, 4-,3-H), 3.8, 3.9(5 6H, 2 x OCH,), 4 . 4 ( ~ , 2 HI-H), , 7.l(~,ZH, 5-,6-H)
4.469 4.55[~,lH( 3 : 2r,I-H)] 1.37(1, CH,), 3.90(~,2 x OCHj), 4.62(~,2H, I-H), 6.63, 6.67(s, arom. H) 3.83(2 X OCH,), 4.62(bS, CHZCCI,). 4.73(~,I-H), 6.57.6.60(s, arom.H) 1.30[s, C(CH3)J, 2.78(1, J -8 Hz,4-H), 3.76-3.88(m, 2 x OCH,, 3-H), 4.66(s, I-H). 6.58(s, ZH,arom. H) 1.20(t, CH,), 2.62-3.05(m, 4H, 4-H, CH,CO). 3.26(t, 2H, SCH,), 3.53(t,3-H), 3.80(~,6H. 2 x OCH,), 4.36(~,1-HI, 6.51, 6.57(~,5-J-H) 287, 3.59(t,4,3-H), 4.36(~,I-H). 6.71, 6.72(~,5-,8-H), 7.61. 8.M(AB. arom. H) 2.72(4 4-W 3 W t . 3-H). 3.83(6H, 2 x OCH,), 4.13(~,ZH, SCH,), 4.26(s, 1-H).6.42-6.57(5-,8-H). 7.00-7.67(m, arom. H) 4.18( 1 -H), 6.51, 6.55(5-J-H)
6 (PPm)
773
267
787
835
7%
565
835
565
757
772
834 772
Ref.
2-CHO. 7-CHl0, 8-( 1-Phenyl-tetrazolyl-5-oxy)
HCI
HCI
HCI
HCI
TFA
HCI
J
CDCI,
J
TFA
HCI
CDCl
CDCI
HCI
DMSO-d6
CDCI, 2.6-2.9(m,2H,4-H), 3.4-3.8(m.ZH,J-H). 3.M. 3.86(3H.0CH3). 4.26, 4.60(2H, I-H), 5.07(2H, OCH,Ar), 6.80(2H, 5-.6-H), 7.34(5H.C6H,), 7.96, 8.13(1H. NCHO) 2.03, 2.08(s. 12H,4xC0CH3), 2.75, 3.71(1,4H,4-,3-H), 3.78(s. 3 H , OCH,), 4.2S(m, 2H.sugar CH,). 4.6(s, 2H, I-H). 5.20(s 2H. C,H,CH,O), 5.35(m,4H. sugar CH). 6.64. 6.90(~.2H, 5-,8-H), 7.40(~,SH,C*H,) 2.90, 3.73(4H. 4-.3-H), 3.90(3H, OCH,), 4.45(2H, 1-H). 7.00, 7.15(2H, S.7-H). 7.60-8.03{5H, C6H5),8.24, 8.34(IH, NCHO) 3.85, 3.88(~,3 x OCHJ). 2.97(t, 2H, 4H), 3.5(1,2H, 3-H), 4.3(~.2H, I-H), 6.7(~,IH. 8-H) 3.10(1. ZH, J = 6 HG 4-H), 3.55-3.85(111, 2H. 3-H). 3.92(~,3H. OCH,), 4.48(bt, ZH, I = 5 HG 1-H). 5.99(s, 2H, OCH,O). 6.66(s. IH, 6-H), 7.66(bs, N'H,) 3.07(t,2H.J=6Hz,4-H). 3.5&3.80(m.2H.3-H), 3.93(s. 3H, OCH,), 3.9(s. 3 H , OCH,),3.96(46H, 2 x OCH,), 4.58(b1,2H,J=5 HG I-H), 6.70(~,1H. 6-H), 7.65(bs, 2H. N'H,) 2.53-2.65, 289-3.02(m, 4H, 4-,3-H), 3.70, 3.78(~.12H. 4 Y OCHS), 3.80(bs,2H. I-H) 2.92-3.12. 3.35-3.4S(m. 4H. 4.3-H). 3.75. 3.78, 3.81. 3.84(S, 12H. 4 x OCH,).4.16(b~,2H, I-H), 9.82(bs, 2H, NH,HCI) 3.2(mV4H.4-,3-H),3.83, 3.86, 3.88, 3.9(s, 12H, 4 xOCH,), 4.2(bs. 2H, I-H) 3.64.21m: 2H. 3-H), 4.35-5.1(m, ZH, I-H), 5.2(s, OH), 5.1-5.8(m:' 1H,4H), 7.35(s, ZH,5-,6-H) 3.5l(m, 2H), 4.33(ABq, 2H). 4.99(t, IH, J = 3 Hz),6.95(s, 2H)
525
546
773
790
790
547
547
773
267
787
400
'
H Br
Salt
~~
D2O
DMSad,
solvent
CDCI,
'
Measured at the center of an AB system. AB Part of an ABX system. X Part of an ABX system. ' Coalesces to a single line at 80°C.
' J Values are not described in the original literature (Ref. 267).
&%
CDCI,
1-C2HS0,3-CH30
1J-(C,H
CDCls
5-HO
(c) 5.6.7.8-Tetrahydroisoqurnolinols and Their Ethers
6,7-(HO),
8-HO. 6,7-(CH,O),
Substituent
TABLE 17. (Continued)
~~
2.0(m,4H, 2 x CHI), 2.7(m, ZH, CHI), 4.7(m, IH, 5-H), 6.1 (s. I H, OH), 7.4(d, IH, J = 5 Hq 4-H), 8.2 (m. 2H,1-,3-H) 1.34(t, 3H, I = 7 HG CHjCH,), 1.5-1.87, 2.3-2.74(111,8H), 3.75(~,3H. OCH,), 4.34(q. 2H, 5 = 7 HG CHICH,), 5.94(s, 1H) 1.28, 1.32(t,6H.J=7 Hz,2xCHZCHa). 1.76-1.9, 2.35-2.7(rn, 8H), 4.22,4.3(q, 4H, 5 = 7 Hz, 2 xCH,CH,), 5.89(s,lH)
2.86(m, 4H, 4-,3-H), 3.75/3.66[(5/3)s, (I-H, 2 x OCH,)],
S.OO(b, 2H. OH, NH), 6.21(s, IH, 5-H) 3.09(m2H), 3.60(m,2H), 4.90,6.84(m, 2H)
2.55,
-- -
d(PP4
622
622
79 I
543
286
Ref.
IX. Analysis and Spectroscopy
395
TABLE 18. DECAHY DROlSOQUINOLINOLS Structure ( f)-4,4a-cis-4a.&-1rons-Decahydro-
Solvent
CDCI, 4-isoquinolinol (kt4,4a-rr(ms-448a-rra~-Decahydro- CDCI, 4isoquinolinol ( )-4,4a-cis-4a,8a-cis-DecahydroCDCI, 4-isoquinolinol ( f)-4,4a-rrans-4a,&-cis-DecahydroCDC1, Cisoquinolinol
6 (ppm)
Ref.
3.53 (b, 1H. W/2= 6 Hz,4-H)
630
3.33 (b. lH, W/2= 22 Hz, 4-H)
630
3.68 (b, IH, W / 2 = 17 Hz.4-H)
118
3.61 (b, I f f , W / 2 = 14 H z , ~ - H )
118
Anion Solvent
CDCI,
I-CH,&HCH,S
I-[(E)-CHjCH=CHSJ
CDCI, CKI3
DCI-D,O
l-CIH,S 1-CzH,SO,
I-CHpCHS
I-CH3S02
1-CH,SO
CDCI, DCI-D,O or DzSO,-DzO CDCI, CDCI,
CDCI3 DCI-DZO CDCI,
I-CH3S
I-CICHZS
CDCl,
I-CH,SOz, CCH,SO,O
8 (PPm)
3.55(CH3), 7.92(4-8), 7.95(5-,6-.7-H), 8.58(3-H), 9.09(8-H) 3.43(s, 3 H , CW,), 7.40-7.9O(m, 4H, arorn. H), 8.32(d, 1 H , J = 6 Hr3-H), 8.84(m, lH, 8-H) 3.92(CH,), 8.6(5-,6;7-H), 9.1(3-&H), 9.2(8-H) 5.17-5.46(m,2H. vinylic H),6.83(d, IH, vinylic H). 7.45-9.00(m, 6H.arom. H) 7.18(4 l H , J = d H t 4 - H ) , 8.20(d, 1H.J=6H2.3-H) 1.52(t, 3H,5=8 %CH,CH,). 3.78(q,2H. J = 8 Hz,CH,CH,), 7.44-8.24(rn, 4H, arorn. H). 8.51(d, IH,J=~Hz,~-H),~.O~(~,IH,~-H) 4.02(d, 2H. J ='I HI, CH,), 4.95-5.75(ABXm 3H, CH-CH,), 7.21(d, lH, J = 6 Hr4-H), 8.21(d, lH, J = 6 H&3-H), 7.3-7.7, 8.0-8.15jrn, 4H,arom. H) 1.85(dd. 3H, J = 1.5.6 H z C H X H C H &, 5.72-6.06(rn, lH,vinylic H), 7.17(d, IH, J = 6 & vinylic H), 7.33-8.27(m, 6H, arom. H)
3.35(~,3H .OSOICHJ, 3.51(~,3H, SOZCH,), 7.5&8.40(111, 3H), 8.56(s,3-H), 9.02(m,8-H) 2.75(CH,), 7.45(4-H), 7.?5(5-,6.7-H), 8.34(8-H). 8.47{3-H) 2.93(CHj), 7.78(4-H), 8.00(5-,&-.7-,8-H). 8.05(3-H) 5.38(s, ZH, SCH,CI), 7.27-7.72(m, 4H). 7.85-8.07(m, 1H). 8.27(d, 1H , J = 6 Hz,3-H) 2.99(CHj), 7.5-7.8(5;6,7-H), 8.65(3H), 8.80(S-H) 3.33(CH3), 8.92(3-H), 8.3-8.5(5-,&,7-,8-H), 8.79(4-H)
(a) Alkylthioisoquinolinesand 1-Methylsulfinyl- and CUkyl(aryl)sulfonyl-isoquinolines
Substitucnts
TABLE 19. ISOQUINOLINETHIOLS AND THEIR DERIVATIVES
83?
641
576
793
74 751
576
74
79
19
74 835
74
576
Rel.
CWI, DCCI,
CDCI,
1- ( PTOSYI)
3-CH sS0,
3-CZH5SOZ
1-DS, 2-CH3
DSOi DSO;
(b) Quaternary Salts of Isoquinoline-l(2H)-thione
cDc1,
I-CeH $0,
50% DZSO4-AcOD
10% DZSO4-AcOD
DMSO-db
DMSO-d,
CDCI,
CDCI,
1-(2-Oxocyclohexylthio)
4.64(N+CH3). <8.0(8-H), 8.12(4-H), 8.56(3-H) 4.90(N+CH3). <8.0(8-H), 8.48(4-H), 8.82(3-H)
0.75(t, 3H). 1.0-1.8(m,4H). 3.20(t. 2H), 6.98(d, IH), 7.1-7.5(m. 3H). 7.7-8.0(m. IH). 8.13(d. IH) 1.39-1.78(m,4H,CH,CHZ), 2.25-2.50 (m, 4H. CH,COCH,). 4.75-5.1S(m, IH, COCHS), 7.40-8.90(m. 6H. arom. H) 7.35-8.26(m, 9H, arom. H). 8.40(d. 1 H, 3-H). 9.l4(m 1H. 8-H) 2.43(s. 3H,ArCHs), 7.19-8.l6(m, IIH, arom. H), 9.22(11~I H, 8-H) 3.22(s, 3 H . CH,),7.58-8.10(m, 4H, arom. H). 8.40(~,lH,4*H), 9.21(~,IH, 1-H) 1.32(1,3H, CH2CHJ. 3.48(q, 2H. CHICHJ. 7.67-8.28(m, 4H.arom. H), 8.56(s, IH. &H), 9.35(s, 1H. 1 4 ) 2.40(3,3H, ArCH,), 7.20-8.22(m, 8H, arom. H). 8.69(~.I H , 4-H), 9.26(~,1H, 1-H) 2.64(~,3H,SCH,). 8.43(~,IH, 3-H), 9 . 1 6 ( ~I H , 1-H) 8.50(~,3-H), 9.00(5. I-H) 1.26(1,3H,J = 7 HZ,CHICH~), 3.08(q, 2H, J = 7 HqCH,CHl), 8.56(~, 1H. 3-H). 9.22(~,1H, I-H) 9.36(~,1-H) 9.04(~,3-H), 1.25[d, 6H,5 = 7 HsCH(CH3)J. 3.47C~cp..IH,CH(CHj)J, 8.70(~1H. 3-H). 9.33(~,1H. I-H) 7.25(~,5H,C,H,), 8.67(~,1H. 3-H),9.43(~,IH,I-H) 2.40(s, 3 H , ArCH,), 7.24, 7.84(d, 4H, J - 8 H z arom. H), 7.50-8.60(m 411.5-,6-,7-,8-H). 9.20(~,IH, 3-H), 9.30(~,I H,f -H)
827 827
637 777
793 637
637 793 637
576
576
576
516
576
643
838
2i
W
1-(Cyclohex-2-enylthio)
I-CH3CH =CHS
I-CHZ =CHCH,S
l-C,H,S
I -CH, =CHS
l-CH3S
Subatituents
CDcl
-13
HCIO,
1-, J
CDCI,
CDCI,
DMSOd,
CCI,
DMSO-d,
DMSOd,
El,
DMSO-d,
Solvent
HBr
H Br
HBF,
HSO,F
salt
2.40(s, 3H, SCH,), 2.54(t, 2H. J = 7 Hz,4-H), 3.7q1, 2H. J = 7 Hz, 3-H), 6.95-7.4Qm, 3H. S-,b,f-H), 7.55-7.75(m, 1H. 8-€4) 2.39(~,3H, SCH,), 2.63(t, 2H, J = 7 Hz. 4-H), 3.71(t, 2H, J = 7 Hz,3-H), 7.00-7.43m. 3H. 5-,6-,7-H). 7.45-7.71(m, lH, 8-H) 2.88(~,38, SCH,), 3.13(t, 2H, J = 7 Hz, 4-H), 3.90(t, 2H, J = 7 Hz. 3-H), 7.40-7.90(m, 5-.6-,7-H), 7,90-8.2qm, IH, 8-H), 9.30(bs, IH, N'H) 2.95. 3.qt. 4H, 4-,3-H), 3.60-3.77(m, 2H, vinylic H), 4.31(t, IH, vinylic HA 6.75-7.60(m, 4H, arom. H) 1.Iqt. 3H, J s 7 . 5 H r SCH,CH,), 2.28(t, 2H, J = 7 Hz,&HI, 2.88(q. 2H, J=7.5 HZ. SCHZCH,), 3.47(t. 2H. J = 7 Hz,3-H). 6.70-7.2qm. 3H, 5-,6-,7-H). 7.30-7.60(m, IH, 8-H) 1.330, 3H, J = 7 . 5 H .z SCHZCH,), 2.68(t, 2H, 5 x 7 Hz, 4-HX 3.01(q. 2H, J=7.5 Hz, SCHZCH,), 3.71(1, 2H. J = 7 Hz, 3-H), 7.00-7.50(~1, 5-.6-,7-H). 7.50-7.75(m, IH, 8-H) 1 3 3 1 , 3H, J = 7 Hz, SCHICHI), 3.12(t, 2H. J=7.5 Hz, 4H), 3.41(q, 2H, J = 7 HZ SCH,CH3), 3.97(1, 2H, J =7.5 H& 3-H), 7.30-7,80(m, 5-.6-,7-H), 7.80-8.05(m, lH, 8-H) 2 4 4 2H, J = 7 Hz,4H), 3.3-4.03m, 4H, 3-H, allylic CH,), 4.5-6.25(rn, 3H. vrnylic H),6.7-7.9(m 4H, arom. H) 3.W. 2H, J = 7 Hz, 4-H), 3.9-4.25tm. 2H, 3-H), 4.45(d, 2H, allylic CHI), 5.25-6.qm. 3 H . vinylic H), 7.3-8.1 (m, 4H, arom. H),12.25-13.qbs. 1H. N'H, exchangeable with D,O) 1.85(dd, 3H, J = 1.5, 7 Hz, CH =CHCH,), 5.72-7.21(m, 2H. vinylic H), 7.33-8.27(m, 6H, arom. H) I.4-2.4[1~ 6H, (CH,),], 3.4t. 2H. J = 7 Hz, 4-H), 4 . 3 1 2H. ~ 3-H), 4.25-4.7(rn, lH, =CH).5.4-5.6(m, IH, SCH=), 5.8-6.06(m, IH, =CH) 1.5-27Cm 6 H , (CHJJ, 3.2(t, 2H, J = 7 Hz, 4-H), 4.1(t, 2H, 5 = 7 Hz,3-H), 4.7(m, lH, SCH-), 4.4-4.6, 4.7-5.qm, 2H, CH=CH), 7.3-8.75(m, 4H. arorn. H), 103(bs, lH, N'Y exchangeable with D,O) 1.6-2.6[m. 6H,(CHzhJ, 3.131, 2H, 5 = 7 Hq 4-H) 3.9-4.2ym, I f f , SCH=), 5.5-6.25+n, 2H, CH=CH). 7.25-8.qm, 4H, arom. H), I0.45(bs, iff, N'H, exchangeable with D,O)
TABLE 20. ALKYLTHIO-3.4-DIHYDROlSO~U~NOLINES AND THEIR DERIVATIVES
795
795
795
751
795
795
794
794
794
75 1
794
794
194
I X . Analysis and Spectroscopy
399
TABLE 21. SULFONYL DERIVATIVES OF 1,2,3,4TETRAHY DROISOQUINOLINE Substituent
Solvent
6 (PPm)
Ref.
2-CH3SOz
CDCI,
4.44(~,2H,I-H)
7%
2-(pN0,C6H,S02) 2-(p-T0syl) 2-d-Camphorsulfonyl
CDCI, CDCI, CDCI,
4.33s 2H. I-H) 4.26(~,2H. I-H)
7% 7%
4.M(s, 2H. I-H)
796
4-Isoquinolinol and ( - )-cis-(7S,8R)-7,8-dihydro-7,8-isoquinolinediol are produced by enzymatic reaction (Pseudomonas purida) of i s ~ q u i n o l i n e . ~ ~ ~ There are three reports of alkylation of tetrahydroisoquinolines at the 1 position; the first involves a diastereoselective alkylation, where lithiation of 1,2,3,4-tetrahydro-2-pivaloylisoquinolinewith t-butyllithium followed by reaction with an aldehyde in the presence of magnesium bromide gives rise to 1aklylated tetrahydrois~quinoline.’~~ In a similar sense N-Boc-1,2,3,4tetrahydroisoquinoline, can also be alkylated in the 1 position using t-butyllithium/TMEDA as the base.855 The Boc group can then be easily removed with trifluoroacetic acid. Enantioselective alkylation can be accomplished with a valine chiral auxiliary on nitrogen.758 Useful reviews on natural products of simple isoquinoline alkaloids appear elsewhere.7 5 5 * 7 5 9
H
HO CH3C0,
R'
HO
H
H
R1
H
H H
TABLE 22. 1SOQUINOLlNOLS
R3
H
H H
'R
H
H H
R'
R3
R2
H
H H
R6
Salts with
-
221-221.5 (dec) 222-223 (dw) 223 223-224 223-225 (d=p 223-225 224' 225 (dec) 228b 228-229.5' 223 (dec)
-
85-86
-
M P or BP ("c)
X. TABLES OF ISOQUINOLINOLS AND THEIR HYDROGENATED DERIVATIVES
I36 53 136 128 182 61,62,84.89,118 160- 162,166 167,177-181, 183-188.206, 306,760,761, 778,785,798, 799,840-842, l07C 1072
839
I75 70 60 86 la839 137
108
760
Ref.
8 -
w
H
H
H
H H
H
CbHsCH,SO, prosyloxy
CbHSSo3
CH,SO, C2HSS0,
HQ
H H
H H
H H
H
H H H
H
H H
H
H
H
H H
H
H
H
H
H
H
Picric acid
HCI
ficric acid
Pictic acid Picric acid Picric acid p-Tosyl chloride
HCl Picric acid
230 (dec)
-
139-140 1 80 215-220 225-228 228-230 230
-
109-109.5 109-1 10 91-92 159-160 105-106 92.5-93.5 87-89 92b 92-93
108-109
107-109
202-203 54-55 55-55.5 135-139/1mrn
243-244
242 (dec)
238 (dec) 240 (dec)
207-208
131,132
98 96 102 93,95,99 91,101
100
100
137 797,844 128 845 128 137 576 576 576 576 846 136 60,100 61,160,239
137
138
100
86
53 137
60*100
i3
P
H H H
H H
H
H
H
R'
R'
TABLE 22. (Continued)
cn,co,
R'
H
R*
ti
H H
H
U'
H
H
H
n
R6
-
Picric acid
HCI HCI HZSO, HzPtC16:2H20' HzPtCI6:7H,O' Picric acid
HC1
Salts with
90 -
255-257 (dm) 59-60 99-100 150-155/0.3 m m
-'
279-280 (&c) > 300 (dec)'
-
207 207-208
-
23 1-233
Mp or Bp ('C)
90
1073 197
98 6 98 98 684
6 3,91,92,94.97, 107,114,122, 123,154.17 I , 177.183.185189,195,204. 2052 10.224. 225,234,235, 557,756,76 1, 785,798,800, 801,847-854, 856-858, 1073,1074 92 131 687 92 92
Rd.
2n oz n
2
2
I
X
I
2
0
2
I
2
X
X
I
I
X
I
I
I
z
I
T
I
403
H
H
H
H
n
H
H
H
H
HO
H
4 "
H
HO
H H
H
H
H
H
H
H
H
R'
H
R'
TABLE 22. (Continued)
R3
H 0-CHI-0
H
CHJO
HO
H H
H
R4
CHSO
CH30
HO
C,HgO
H CH,O
H
R'
pCEI,OC,H*CO, H
HO
H
H
C6HSCOI H
HO
R'
HCI
Picric acid Ficric acid
Picric acid Styphnic acid
HCI HCI
Picric acid
H*Ptfl,
HCI
HCI
HCI
Salts with
218-220 220-225 M4-206 270-272'
-
249-250 159-163 181-1 83 183-184
252-254
-
182-183
279-280 206 179 l8&181.5
285 76-77
I
-
244
240-242
-
MP or BP ("c)
139
50
24
50
14 13
50
59 50 866.867 131-133 15 35 868 21 201,503 21 21 24
90
177,183, 185-189,236, 785,798,858. 861,863,1075 107 59 236
Ref.
H HO
H H
H
H
H H
H
HO
CH,C02
CHjO H HO C,H,CO, H H
H
H H H H H H
H
H H HO HO
H
CH,O CH,O
CH,O CH,O CH,O CH,O
0-CHI-0
0-CHa-0
' Browned BI 215'C. ' Labelled with tnO. ' Sublimed at lsO°C/9 x lo-' mm and measured in a sealed tube. ' Blackened at 20°C. ' Water of crystallization. The salt contains two bases. Dried at 50-60 'C. ' Darkened at > 260 "C.
CH,COl
ti H H H H
H H HO
H
H
H
NaO CH,CO, HO NaO CH,CO, H
H
CHSO CH,O H H H HO H
CH,O CH,O CH,O CH,O
CHIC02
HO
HO C.SH5COI H
HO
HO H
H H H H
H
H
HBr:H,O'
HCI
HCI HCI
HCI
:H,O'
-
220 (dec) 253-257 (dw) 250 (dec)
162- 163 -
-L
-
96-98.5 243-245 242-244 (dec) 264-265 196-197 (dw) 116-117
-
..
> 360 134- I36
51 135
m
54 89,l 79.1 80 I02 102 55.117 51
232
I39 I39 I39 I39 I 39 821 220 57 131,133
n-CdH90
CH, =CHCH20
i-C3H70
C2H50
C2H50
CH,O
CH,O
R
TABLE 23. ALKOXYISOQUINOLINES A. I-ALKOXYISOQUINOLINESAND THEIR DERIVATIVES
R
Picric acid
Picric acid
Picric acid
N-wxide HsCIz Picric acid Picric acid Picric acid Picric acid
Salh with
-
-
156 156-1 57 12813 rnm 170 102-104/1.5 mrn
156 160-162 161-162 163.5-165.5 (dw] 1 69 170- 17 1 102-102.5/3.5 mm 7210.3 mm -
s4ss
Il6-119/8-9mm 119p rnm 135-136/21 rnm 138-14/25 rnm 240 -
Mp or Bp ("C)
80 74,79 69 76 113,163,823, 838,869 69 838 69 69 73 213
70
109 129,130 78
822
70 742 68 74 109 129,130,172 176,754,798,822
Ref.
3-Quinol yloxy
2-H ydroxy-3-neopentylaminopropoxy 2-H ydroxy-H 1',I 'dimethylpropyny1amino)propony
2-Hydroxy-3-(2-methyl-3'-butylarnino)propoxy 3-Cydopentylamino-2-hydroxypropoxy
'.
3-( 1'-Morphoriny1)propoxy 2- Hydroxy-3-( I I'-dimethyl-2-propenylamino)propoxy 2-Hydroxy-3-( l',l'-dimethyl-2'-propynylamino)propoxy
2-Hydroxy-3-isopropylaminopropoxy 3-Cyclopropylamino-2-hydrox ypropoxy 2-H ydroxy-3-isobut ylaminopropoxy 3-t-3ut ytamino-2-hydroxypropoxy 2-nydr~wy-3-(2-hydroxy-I '.I '-dimethylethylaminu~propoxy
HCI
Fumaric acid
Picric acid
Fumaric acid Furnaric acid Maleic acid Maleic acid Maleic acid
Maleic acid Furnaric acid Maleic acid Maleic acid Naphthalene-l.5disulfonic acid
Picric acid
75
6355.66 75 75 75
.-
172- 173/2 m m 121-123
77.87.88 81 75
82
110.1 1 I 75 75 75 75 75 75 77.87.88
75
75 75
81 75 75
105
63.65 77.82 77.82 870
282-284' 98 148-1496
-
I 7 6 1 71b 176- 177' 178- l 8 P 115-117' 151- 153" 75-76
195-196/2 mrn
178- 180" 180' 168- 171
166-167" -b
._.
133- 134/2 mrn 40.5-42 195.5 - 196 68-69 69
3-(2’-Phenethyl)-2-phenyl-5-oxazolidinylmethoxy 3-[ 2‘-(p-Chlorophenyl)ethyl)]-2-phcnyl-5~x~lidinylmethoxy 3-[2’-(p-Tolyl)ethyl)]-2-phenyl-5-oxazolidInylmethoxy 3-~2’~3’.4-Dimethoxyphenyl)ethyl]-2-phenyl-5-oxazolidinylmethoxy 34 1‘-Adamantyl)-2-phenyI-5-oxazolidinylmet hoxy
D-a-Tetraacetylglucosyl 3-( I’,I’-Dimethyl-2’-propenyl)-2-phenyl-5-oxazolidinylmethoxy 34 1‘.I ‘-Dimethyl-2’-propynyl)-2-phenyl-S-oxazolidinylmethoxy 34 I ‘.I ’-Dimethyl-3’-butyny~)-2-phenyl-5-0x~lidinylmethoxy 3-Cyclopentyl-2-phenyl-5-oxazolidin~Imet hoxy 3-Neopent yl-2-phcnyl-5-oxazolidinylrnet hoxy 34 ]’,I ‘-Dimethylpropyl)-2-phenyl-5-mazolidinylmethoxy 3-( 1’. I‘-Diethyl-2’-propyny1)-2-phenyl-5-oxazolidinylmethoxy 34 I’-Methylcyclohexyl)-2-phenyl-59xazolidinylmethoxy 3-D-N-Methylmorphinyloxy
2-Hydroxy-3-[2’~3’,4‘-dimethoxy-phenyl)xy ZHydroxy-34I ‘-adamanty1amino)propolry 3-lsopropyl-2-phenyl-5-oxazolidinylme~ hoxy 3-Cyclopropyl-2-phenyl-5-oxazolidinylmethoxy 3-lsobutyl-2-phenyl-5-oxazolidinylmethoxy 3-(2’-Hydroxy-I ’,1 ’-dimethylethyl)-2-pheny~-5-oxazolidinylmethoxy D-fi-Tetraacetylglucosyl
R
TABLE 23. (Continued) Fumaric acid Maleic acid
Salts with
104-107 -_
132- 134 134- 135
-
168-169 166-167*
M P or BP(aC) i5
75
75
15
75
75
81
75 75
15
15
IS
75
75
75
75 75 75 75 75 113 112 112,113
Ref.
III- m I-Ip
t
0
X
c n
f
J,
E
E E
E
2
O
H
0-CH,OC, H 4 0 PCH,W*H40 p-CHOC,H40 7-Isoquinolyloxy
H
H
H
C,H,O PCH JC6H40
(CH,),SiO
C2H50
CH,O
H
R'
H H H H
H
e HH
H H H
H H H
R2 H
(Continued)
H
R'
TABLE 23B.
Picric acid HCI Picric acid
Picric acid
Ficric acid
Picric acid
HCI HCI HCI
Picric acid
Salts with
21 5-2 I6 192-195 %/o.15 mm' 206 207-210 205-206 152-153
.-
130-140/0.06 m d 223 120/5mm
122/1 mm 170 191-194 186-187 164-167 66-67
Mp or Bp ("C)
97,115.856.872 I14 92 122 149 864 I23 85 85 123 123 I23
I14
823,869 106 87 1 871 871 778 85 85
106
Ref.
m
00 Q
I Q -
0
I Q -
0
PQ
0
PQ
2
0
m
N Q
f
X
I
I
I
X
X
I
r
I
2
I
2
41 1
P
N
c
H
CHJO
R'
CH,O
H
R2
H
H
H
H
8'
R'
TABLE 23C. 6-,7-, or 8-ALKOXYISOQUINOLINES AND THEIR DERIVATIVES
Picric acid Picric acid Picric acid
HCl
Salts with
48 48-48.5 49 49-49.5
167
.-
214-216 216 223 225
132-135/5 m m -
Mp or Bp ("C) 859
24
26 4,802
19
874
48 202
46
48.115,164,165,189, 202,245,762798, 872,873 859 46 35
Ref.
H H
HCI H,P1C16 H 2 P1CI6 H ,504 HzCrz07 Oxalic acid Tartaric acid Picric acid F’icric acid Picric acid Picric acid Picric acid Picric acid Picric acid
202
-
245b 24rb(dec)
-
223
-
202-204 7-9 182-183/27mrn 199150 m m
I98 IW-MO (dec)
193-194 193-195 194-195 194- 196
-.
180-182
-
4 1.4
1
2,3 4 4 4
1 4
14 4
7
35
8 3.4 24
1
4 4 7 4
1
762,780.798.875
4 4
22I 235-236 ( ~ c c ) ’ 235-236b
I__
14 8 14 17 1,802 4 39,170,189.245.559,
49-50 I I1/3 m m 118-120/7mm 146-14715 m m 182-186/34mm 194-195/50mm
0
0
' E 'C
s,X.s.s"
x x z z x x x x
20, 2 2
u u
x x
X
x x
X
H
H
H
H
H H CH,O H H H
CHAO H H
RS
H CH,O H H H H CH,O H H H
H
H
H H H H
H
H
H
H
H
H
n
H
H
H
R4
H
R'
R'
R'
H H H
H
CH,O H H
R'
H H 2-H ydroxy-3-isopropylaminopropoxy H 3-r-Butylamino-2-h ydroxy propox y H 3-t-But ylamino-2-hydroxy propox y H 3-Isopropyl-2-phenyl-5-oxazolidinylmethoxy H 3-lsopropyl-2-phenyl-5-oxazolidinylmetho~y H 3-Isopropyl-2-phenyl-5-oxazolidinylmethoxy H 3-t-Butyl-2-phenyl-5-oxazolidinylmethoxy H 3-r-Butyl-2-phenyl-5-oxazolidinylmethoxy H
2-Hydroxy-3-isopropylilminopropoxy 2-H ydraxy-3-isopropylaminopropxy
R'
R4
TABLE 23D. lJ(4.5.6. or 7)-DIALKoXYISOC)UlNOLlNES AND THEIR DERlVATlVES
CH,O
n
H H CH,O
cn,o
H
cn,o
H
H
H
H
H
H H H H
H
H
Rh
Maleic acid
Mdeic acid
Maleic acid
HBr
HBr
HCI
HCI
HCI HCI
Salts wilh
__
-
-
134- I46 190-192"
158.-160' 95-97 144-146'
144
I33 43
56
I75 I42 180 109 148- 150
56
55
Mp or Bp ("C)
75 75 75 75 75 75 75
75
71 71 75 75
t34 72 72 71 71 71 71 71 71 71
ReC.
"WR'
R2
H
H
CH,O
CH3O
CH,O
C,H,O
R'
CH,O
CH,O
H
H
H
H
H
C,H,O
H
CH,O
H
H
H
H
CH,O
H
H
H
H CH,O
RS
R'
R'
CH,O
H
CH,O
R3
R4
R2
HCI HCI
Picric acid Picric acid
HCI Picric acid
Picric acid
Salts with
217-218 Id=) 219-220 Id=)
-
2 10 (dec) 210-212 113-li5
192-193 227 57-58 58 -
-_
211 75-76
-
40
8 0 / W 3 TorP
58
80/10- Tomn
78
Mp or Bp ("C)
TABLE 23E. 3.6(7)- or 5,6(7 or S)-DIALKOXYISOQUINOLINESAND THEIR DERIVATIVES
30
30
40 803 40 24 779,876,871 779 24 24 40 159 40 24 30-32 78I
104 104 I04 104
Ref.
21
e
CH,O
0-CHZ-0
R'
CH,O
R=
H
n
R'
HCI HlPtCI, HZPtCl6 Picric acid Picric acid Picric acid Picric acid Picric acid
Salts with
R'
66 88 89 88-90 91 90-91
250 (dec) 243 (dcc)' r26Sb 204-206 206 235 (dec) 240-241' -
-
.-
I 18 119-120 I22 122- I23 124 127-128 170/1 mm 214-216/50mm
Mp or Bp ("C)
TABLE 23F. 6.7-, 63-, or 7.8-DIALKOXYISOQUINOLlNESAND THEIR DERIVATIVES
52 2 44 4 I17 IS 3s 579 878 24.26
2 24
4
4
44 44 43.143,146.762.825.877
z4
25
52 24 35
Ref,
R'
R2
TABLE 23F. (Continued 1
R'
HQ
HCI HCI:3H,O' HCI HCI HCI
Salts with
208-210 (dK) 216-218 (dec) 219 220 221 (corr)
336
-
93-94.5 94.5 80-100/0.01 mm' 130- 150/0.2 m m 13210.5 m m 132/0.05 m m 140-150/0.1 mmf 152- I58/0.8-0.9 m m 160/1 mm 198-200/10 mrn
93-94
91-92 92-93 92 93 (corr.)
Mp or Bp ("C)
15 22 47 837 45 23
1078
10 44 I92 3,16,36,39,41,58,133, l4O,145,147,151, 155- 1 57,174,194, 196,352,368,426,497, 6'75,752,803,825,826, 872,873,875,877, 880-885,882,1077,
45
I5
22.44,4 7 1 26 125 126 43 42
23
126 17,879 43,192
Ref.
B9 3
I N
r
419
X
x
x
z
X
R'
R2
TABLE 23F. (Continued)
H
H
H
H
H
H
H
H H
H
H H
R3
HCI
HCI
Picric acid
HCI
HCI
HCI
HCI
HCI
191
87
115/0.01 m m 206
112
89 13Spl.05m m 21 1 96 195 89 138/0,01m m 209 127-128 250 (dec)
225
111
66 145/0.01m m I58
-
-
192-195 73 169 150-153
Picric acid
HCI
Mp or Bp ("C)
Salts with
749,887
15
15 15 15
15
36
36
15 IS IS 15 15 IS I5
15
IS
1s
15
IS
15
34
123 15 I5 749
Ref.
H
H
n
H
H H
CiH4
CH,O CH,O
0-CH 2 -0 CH,O CH30
ClHl0
CJ,O
C,H,O
CH30 CH,O
H H CH,O
H
Picric acid Picric acid
HCIO4 Picric acid Picric acid Picric acid Picric acid Picric acid
Picric acid
HCI HCI HCI
172- 175 189-191 70-71
-
205-216 55-60 185- 188 188
197- I93 200-201 204 -
166- 167
-
(I 34/0.5 mrn) 140/1mnl
107-309~.15m m I2%/0.5mm
90
124-125 125- 126 loO/al mm' 230 (dec)
121
68 186 205 200
30
24,29 50
29 59 28 24,27,144,150,890, 1079
888 3,5,9,12,24,41,49.56, 141.l42675.877.888 56 24,26 103 14 5 828
13
9 14
51 20 20 51 51
15
IS
15 IS
H H
H H
2-Hydroxy-3H isopropylarninopropoxy 3-I~0~0pyl-2-ph~yl-S-H oxazolidinylmet hoxy CHAO H CH30 CH,O
H CH,O
H
CH30
CH,O
H
H
CH,O
H
H
CH,O
CH30
CH,O
R’
H
R‘
H
H
H
I-M~thyl-4-pi~ridyl0~y H
(CH,)zN(CHM
H
R’
H
RZ
H
R’
H H
H
CH30 CH,O CH30
H
H
H
H
CH,O
CH,O
CH,O
CH,O
R6
TABLE 23G. TRI- OR TETRAALKOXYISOQUINOLINES AND THEIR DERIVATIVES R‘ R’
It’
HCI Picric acid Picric acid Picric acid
Picric acid
Salts with
180-181 180-182
179
179- I80
-
100/10- Torte 166-167 160/0.5mm
114
98-100
181-182/1 mm 200-201‘ -
Mp or Bp (‘C)
25 24 26
54
821 888 24,25,54.132, 148,675,877, 888,891
104 104
75
67 75
64 64
Rd.
&
w
N
H
' '
H
H
CH30
Labeled with a deuterium at I position. Bath temperature. Sublimation. In vacuum. Water of crystallization.
' Isolated as hydrogen fumarate.
' Isolated as monopicrate.
* The salt contains two bases.
' Isolated as hydrogen maltate.
H
H
H H
H
H
H
H
H H
H H
H H
CH,O
CH,O
H
H
CH,O H
CHJO
CH,O
CH,O CH,O
CH,O
CH,O
CH,O
CH,O
CH ,O
H 0-CHI-0
CHaO
H
C,H,O
CH,O
CH,O CH,O
HCI
Picric acid
H,PtCI, Picnc acid
HCI HCI:fH,O
HCI
HCI
-
148-150
96
179- 180
I65/0.5mm
228
b
192 224
141- 143 142-144 143-144
I59
54 54 675
216 216 37 888 24,888 24 3
I99
37
no2
38 38 37.38 510
R'
HO HO pTosyloxy pTosyloxy pTosyIoxy
HO
HO
HO
HO
HO
R2
TABLE 24. QUATERNARY SALTS OF ISOQUINOLINOLS A. 4- OR 5-ISOQUINOLINOLS AND THEIR DERIVATIVES
R'
H
H
H
H
H H
H H
H
H
R'
R2
X-
aa-
Br-
CI1-:1/2i-I*@
CI-
CI -
c1-
a-
CI 3rBr1IPicrate Picrate Picrate CI -
~-~
185
253 222 213-215 191-192 151 (dcc] 170-173 184-185
208 185-186
224-23V 233 144-145 (dec) 222-226 224-228' 227
-
MP.( 'C)
60
239 100
100
203
206
231 231
203
841,991 222 222 222 23 1
508
222 222
183
Ref.
H
HO HO
HO
H
H
HO
H
I-:2H,0b pTosylate Br OH -:2H,0b C1-:2H20b
Br-
Cr CH,SO; CH,SO; CH3SO; CH$O; pTosylate pTosylate OH-:2H,0b OHBr-:2H2@ Br-
NO;
IIII-
I-
a-
CI-
OHCI CI-:3/2H,Ob
117J
110
212-213
275
-
200 209.4-210.6
7w
I72 100 (dxr 140 270-275 (dec) 280 ( d a y 184-187 -
234-235 235-237 239 239 (dx) 246-247
-
1M(daC) 256-258 259 259-251 (dx)
92 92
1074
92 205
686,687
234235
96 204 92 234.235 92
801
92
90
97 189 92.200 90 225 92 92 210
90 I83
92 90 92
CZH,
2-(3',4',5'-Trimethoxybe1uoyloxy)ethyl 2-(3',4,5'-Trimet hoxybenzoyloxy)propyI 3-(3'.4'.5'-Trimet hoxybenzoy1oxy)propyI
H H H
H
H
H
H H
H
6-(3',4',5'-Trimethoxy bemoy1oxy)hexyl
too-
H
(Continued)
2-(3',4,5'-Trimethoxy benzoy1oxy)ethyl
R'
TABLE 24A. R'
HO
no
HO
%3
Br -
BrCI -
Br-
Picrate BrBrBr-
I-
1'"
BrIBr -
228
1353
203 212 212-213
-
-
195 I95
195
684 685 197 686 687 686 195
122
i95 195 195
-4
N P
CH 3
CH,
R'
HO HO HO
H H
H
R'
H
HO
R'
R4
H
H H
H
H
R4
TABLE 248. 6-, 7-, OR 8-ISOQUINOLINOLS AND THEIR DERIVATIVES
ICI-
r-
I-
CI-
Picratc
BrITartrate
a-
OHC1-:H 'Ob CI - :H,Ob
X-
-
273-274
__
21 8-220
225
2 16-2 I9 202-204 185 (dcc)
-
I26 208
90
122
183 189 18,237 237 874
230 230
m2
202
230 223 230 183
s 0
s
X
X
X
2
z
CI
Q
V
P V
0
428
X. Tables of Isoquinolinols and Their Hydrogenated Derivatives
429
TABLE 24C. ALKOXYISOQUINOLINOLS AND ISOQUINOLINEDIOLS
R’
RZ
R’
R4
R’
HO
H
CH,O
H
H
CH,O
HO
H
H CH,O
CH,O CH,O
HO H
H
HO H
HO
0-CHZ-0
HO
H
0-CHZ-0
H
CH,O
CH,O
HO
H
HO
HO
H
X-
CI -
c1a-
IICI CI CI CI CI CI-:H,Ob HS04:3H,0b SO:- :6H,0b
so:-
Picrate CI ICI -
’ In an evacuated capillary tube.
’ Water of crystallization.
‘ The salt contains two bases.
‘ Decomposition starts at -270°C. ’
The anhydrous product decomposes at 160°C. The anhydrous product melts at 202°C after drying at 1 0 0 - 1 10°C. Over a range starting at 135°C. Dried at 72% in vacuum. Dried at I20 ”C and the anhydrous product is hygroscopic.
MP ( “C)
Ref.
251-253
131,132 133
-
I
217-218 196-197 229-234 23a-239 . ~
-
241-243 (dec) -1
174- 175 188 (dec) 270-275
201 201
13J4 221 131,I 32 133 214 216 504 216 216 216 214 232 232 230
CH,O
R'
CHJO CH,O
H
H
H
R3
R'
CHSO H
H
R2
R'
TABLE 25. QUATERNARY SALTS OF ALKOXYISOQUINOLINES A. QUATERNARY SALTS OF 3-, 4, OR 5-ALKOXYISOQUINOLINES
H
H H
H
R*
a0;
BrBrI-
200-203 227-228 170-173
173-175 (dec)
130-131 (deer
171-173
I-
CI -
139-140 154-155 -
._
104
101-102
MP ('C)
CH,SO; p-Tosylate Picrate
c10; c10; ao;
X-
83 196 196 196 196 196
209 207 892 208 209 209 I081
Ref.
M
30 OI
-u I
9 2,
3u
T
X
b
X
TI:
T
I
X I
I
43 1
R' R1
H
H
H
H H
H
H
H
H H
H
H H H H H
H
H
H H H
H
H H H H
H
H H H
I-
H
H
CI -:CH,OHd BrBrC1-:3/2H,(Y BrBrIBr-:HzW HSO; :H# IIBrBr1-
a-:3/2H,(r
Br-
Cr0,-
X-
'R
R'
TABLE 25B. QUATERNAY SALTS OF 6-,7-. OR 8-ALKOXYISOQUINOLINES
80-83 208-210 182-186 188-189 130-133 63 160-161.5 125-127 115-116 238-240 (da) 121-123
21 1
133- 134 155-158
57
232-234 210-211 140-142
MP ('C)
245 202 202 762 762 202 202 202
202 245
115 202 202 202
202 215 202 202
Ref.
H
CH,O
H H H CH,O
H
H H
H
H
H
H
H H H
H
H H H
H H
H
H
H H H
H H
H
H
n
I(30;
Br-:H,(Y pTosyla te Br-:H20‘ Br-:H,CT BrBrBrI1II-
Br-:H,O‘
CI-:H,OC
H
CI-:H,CT
Br -:H2@ Picrate BrBrBrBr-:H,@ ICI -
1-
1-
H H H H
H
H H H
H
H H
H
188-189
-
137 129 233-235 149-152 173- I76 194-196 207 (dcc) 112-1 1 s 206-208 125- 128 64-65 83-85 83-85 77 144- 146 178-180 105-107 210-213 223-225 165-169 189-191 195-196 196197 196-198
215
4 3 249,894
8 21 1
202 202 202 202 202 202 202
202 202
202 202
202 202 202 202 202 202 202 m2 202
R'
TABLE 25B. (Continued)
H H
H
R2
H H H
CH,O
H
H
CHaO CH,O CH,O CH,O
R4
R3
I-
11IIICI -
c10;
Br1-
IBr -
I-
X-
175-210
I22
-
120
4
4 I23 120.12 I 120 115
4 762 762 895 245 245 245
Ref.
21G215 193- 194 122- 123 219-222 231 -232 204-209.5 196
.....
178- 179 178.5-179.5 114-1 17 -
MP ("C)
X. Tables of Isoquinolinols and Their Hydrogenated Derivatives
435
TABLE 25C. QUATERNARY SALTS OF DI- OR TRIALKOXYISOQUINOLINE R?
RJ
R'
R'
R'
R4
X-
BrBrBrBr-:CzH,OH C1-:3/2Hz0 I-:2HzO
2,4-(N02)zC,H, C7H7
C7H7O C,H70
CH'O H
H CiHiO
CH3 CH3
CH30 CHJO
CH30 CH'O
p-HOCH2C,H,0 p-IHgCH&,HdO
Mp("C)
115-120 102-110 196 240
TABLE 25D. QUATERNAY SALTS OF 6.7-METHYLENEDlOXY ISOQUINOLINE
R
X-
MP ("C)
Ref.
113 119
244 __ b
169- I70 230-232 138-141
4 119,241 I19 119 1 I9 1 I9 213 762 762 244,890
Ref. 895 246,896 78 1 78 1 763 763
436
Isoquinolinols and Their Hydrogenated Derivatives
TABLE 25E. QUATERNARY SALTS OF 6,7-DIMETHOXYISOQUINOLINE
xMP ("c)
X-
R CI CI 111-
II1-
I-
11-
CIO; c10;
na: -
185.5- 186.5 182 223-224 (dw) 234 (dec) 236-237 237 (dec) 238 (dec) 253-254 -256 (dec) (corr.) 295-298
HSO; CHaSO; Picrate Picrate
-b 257-259 202-203 209 221-223
a0;
228-230 244-245
-
clo;
aBrBr -
Picrate
c1-
c1CI Br-
aBr-:H,O
CIO;
c1Br I-
195- I96 160-165 123-125
254 154-155 109-112 115-1 17 168 177-187 114' 204-205
-
Ref. 804 228,897 42 41 226 24 1 191 43 21 23 247,433,803, 894 805 229 221 227 227 241 226 898 238 238 464 198 88I 881 240 126 240,243 244 826 899 238 227 368 368
X. Tables of Isoquinolinols and Their Hydrogenated Derivatives
437
TABLE 25E. (Conrinued) R
~,-WCH~O)ZC~HJCHZ 3NCH ,O)zC6H,CHz
1;
3,YCH,OhCJ+KHz),
CI BrI-
Br1-
I-
2-(3’-Indolyl)cthyl 2-(3’-lndolyl)ethyl
BrBr-:fCH,OH’ I-
I-
C~HSCOCH~ 3,4-(CH,O)zC,H,COCHz
MP (“C)
X-
Picrate BrI-
159-160 137-138 203-204 -
-
209-210 (dm) 210-21 1 215-218 (dm)’ 219(dec) 246-247 (dm) 247-248 (dm) 180
121- 122.5
189-190
Ref. 368 397 397 36 245 36 56 352 194 194 I96 194 1% 199
P
w
W
R’
R2 R3
R4
R4
T A B L E 25F. QUATERNARY SALTS OF 6.7; OR 7.8-DIALKOXYISOQUINOLINES
X-
198-200 181-182 162- 163 164-165 182.5-184
166-1 70 (d=)L 175- 178 174-176 178 182-183 (dK)
208-210 206-207 250
MP (“C)
56 56 50 901
56
12 14 141 13,14 49 803 9
900
9
123
36
Ref.
X. Tables of lsoquinolinols and Their Hydrogenated Derivatives TABLE 2%. QUATERNARY SALTS OF 8-METHOXY-6.7METHY LENEDlOXYlSOQUlNOLlNE
R
XOH C1- :3/2HzO' III1; 1; 1; 1; a04 SCNHgCl; HgCl; HgIi AuCI; AuCI;
ptc1:PtcI: BiBr;
-
M P ("C)
205-208 (dm) -
192 205
I51 - 1 52 160
161 67-70 234-236 __
225
I51
-
220-22Sb -. b
BiI;
SbBr; SbBr; SbI; HSO; Picraie Br Br Br Br Br Br CI -
I 80 225-227 200 195-198 214-215 190
225-227 218-220
Ref. 2 12,2I 6,504 218 212,214,216 504 233 37 198,212,2 16 2 17,248 212 216 218 212 215 212 218 212 212 218 212 218 2 12,216 212 212 212 212 212 233 213.218 198 198
198 198 198 198 198
439
440
Isoquinolinols and Their Hydrogenated Derivatives
TABLE 25H. BIS-QUATERNARY SALTS OF ISOQUINOLINOLS AND THEIR DERIVATIVES
R R'z&N+
xR'
R2
2
HO CH,SO, CH,SO, (CHdzNCOz (CH&NCOz
H H H H H
CHZOCH, CHZOCH, (CH2)IO CH2OCH2 (CH,), (n=3-7) (n=8) (n=9)
%bR R'
'Z'
X'
MP ec,
X-
(n = 10)
II-
237 219
Picrate
I18
IBrBr Br-
221
-
121-125
__
NO;
HSO;
-
c10; (CH&NC02 (CzH,0)2PO2
H H
(CHz)m(n=ll-16) CHZOCH,
H
CH,O (CH,),o
-
257-258
200 684 684 685 1073 1073 1073 1073 1073 1073 1073 1073 1073 197
(C$AB HOZCCOOBrPicrate
-
II-
208-210 (dm) 191 190
-
TABLE 251. BIS-QUATERNARY SALTS OF BISISOQUINOLYL ETHERS
I-
Ref.
123
X. Tables of Isoquinolinols and Their Hydrogenated Derivatives TABLE 25J. TRIS-QUATERNARYSALTS OF 4-METHOXYISOQUINOLINE
MP ("C)
X-
aa
225 (dec)
Ref.
192,193
Decomposed on attempted recrystallization.
' The salt contains two bases. Water of crystallization. ' Methanol of crystallization. f
No description.
Softened at 109°C.
' Sintered at 21 1 "C.
The salt decomposes at 166-170°C when heated slowly, but when inserted into a preheated bath at 170"C.it does not decompose until 193°C.
441
S X
x x
X Z T
x x
0,
0
X X X U
x x
x x x
T X
X X X
XI
0
0
0 0
x x
x x
x x
f
d
N
w
A
m
L 442
x x
m N I-. I N N
E
m
s
r 0
I S
x x
PP 0, X
x u
0 0 X
T T E
00
P
zzs
x
0
I
r x 0
0
I I
X X X
I
r r
x x
S
x
X I
I
X
443
H
H
H
H
H
n
H
C , W
R'
RZ
H H
H
H
R'
CH,O
H
R'
H
H
R5
H
H
R6 Salts with
-
156-168
-
I I 1-1 12/10 m m 129-131/16 m m 100-110/0.1 Torr I 55/16 mm -
Mp or Bp ( "C)
TABLE 27. ALKOXY-3.4-DIHYDROISOQUINOLINES A. 1-, 6,OR 8-ALKOXY- A N D 1,4(6)- OR 5,6(7 OR 8)-DIALKOXY-3,4DIHYDROISOQUINOLINES A N D THEIR DERIVATIVES
308
909
324,909
258
254 829,843,872, 912-9 15 916 917
263
910,911
905
Ret
H
H
H H
H
H
H
H
H H H
H
H
CH,O
H H H H CH,O CH30
H H CH,O
H
CH,O H H
H
H H
H
H
H
H
H CH,O H
H H H
CH,O
H H CH,O
H H H
H CH,O
H
HCI Picric acid
HCI HCI HCIO, Picric acid Picric acid HCI HCI
HCI
HCI HCI
267
I60
185-187
-
225-227
203'
293
267
40
460 267
272 267
40 185 186-188
236,833 120,236 308 308 252807 28 1 803
-
-
193'
-
175- 175.5
-
904 322
446
Isoquinolinols and Their Hydrogenated Derivatives TABLE 27B. 3.4-DIHYDRO-6.7-METHYLENEDIOXYISOQUINOLINE A N D ITS DERIVATIVES
0 MP (“C)
Salts with
Ref.
257,276-278 44 44 44 250.256,283,291, 346.36 1,392,532, 554,909,913.91 8-924 276,808.809 321,803.9O9,925 44 276 218 276
90-91 92-94 95-86 170/1mmb
192
HCI
HCI
-~
Picric acid Picric acid Picricacid
H2PtCI,
230-232’ 237-238 238 240 (dec)’
TABLE 27C. 3.4-DIHYDRO-6.7-METHYLENEDIOXY-ISOQUINOLINE A N D ITS DERIVATIVES CH c 3H0 3 Salts with
0
m
MP ( “C)
39-40 53-54.5 132/0.4mm 132/0.6m m 146-14812 m m 150/0.01Tomb lSO/O.STOK 150-156/2-3mm 155-160/1 m m 159-160/1 m m 159-16111 m m 169-170/9mm 205-208/24m m
N Ref.
268,269 417 268,269 42 351 292 555 259 44 358 260 41 297
X. Tables of Isoquinolinols and Their Hydrogenated Derivatives
447
TABLE 27C. (Conrinued)
MP ( 'C)
Salts with -
Ref. 11,19,41,43,45,54.55,117.174J63,273,275,282, 287-289,291-297,300,302-305,307,3 10-3 17, 3 19-324323-339.34 1-345,349,354,360-363,365, 366,4 1 7.429,452,464.468,469,476,477,483-489, 491,492,494,503,555,675,745,750,752,753,784,807, 8 10,826,829,843,880,902-904,907,909,913,918-920, 922-924,926-959,1083 677 677
HCI HCl HCI HCI HCI
194-196 195-196 201-205 (dec) 208 (dec) -
HCI:3HZO' HCI:3H20' HCI:3H20c HCl:3:H20'
72-75 75-76' 72-75
81 1
HCI:3;H,Or
-
HBr HBr H Br HBr
186- 188 196- 198 230 231
412 288 307 300 301 743 165 917 582
-
-
HI
-
HCIO,
194-196 185-187
HZSO, Naphthalene-2sulfonic acid BH3 BH 3 Picric acid Picric acid Picric acid Picric acid Picric acid Picric acid Picric acid Rcric acid Picric acid Picric acid
174- 1 7 9
144.5-145.5 199-200 201-202 20 1-203 201-206 202-203 203 204-206 206-208 207-208 __
35 I
297 275,295,303.3 1 5 3 18,319,321,354,423,425, 478,492,690,728,732,803,8 10,925,961,962 297 305 424,425
426 926 260 351 44 298 47 42 280 297 10 303
Isoquinolinols and Their Hydrogenated Derivatives
448
TABLE 27D. 3,CDIHYDRODIALKOXY- OR TRIALKOXYISOQUINOLINES AND THEIR DERIVATIVES
R4 R'
R2
R3
R*
R' Salts with
H
Mp or Bp ("C) 84-85 86-87
279 253
202 (dec) 202 (dec)' 206
253 253 219 32 1 270 300 355 255 347,354,359,468, 908,923,959 300 354,355,459 764 807 764 267 219 280,347 318 279 782 312,184,835,909. 963,964 782 312 322904,909,922, 925,965 318 341,852,966 300 36
-
H H
HCI HXRCI, Picric acid HCI
CH,O HCI H HCI Picric acid H
H
191-191.5
~-
58-60
HCI
H H
-.
95-96 91-98 101-101.5 183 -
HCI HCI
Ref.
-
20 1-203 m3-204 12 -
-
195 46-47 -
HCI HCI HCI
223-224 250
HCI
-
HCI HCl HCI HCI Oxalic acid Picric acid
103-104 105 192-193
__
-
184 (dec) 188- 189
-
347
300
967 366 36 364
X. Tables of Isoquinolinols and Their Hydrogenated Derivatives
449
TABLE 27D. [Conrinued) R'
H
R2
H 0-CHZ-0 CH,O
H
R3
R*
CH,O
CH j 0
CH,O
H H
Salts with
HCI HCI
143-145 _.
-
HBF,
CH,O
GCHZ-0
M p or Bp ("C)
175-177 89-90 9 1-92 _.
H
CH,O
CH,O
H
CH,O CH,O
CH ,O CH,O
H
H H H
HCI HCI H Br HI H,PtCI, Picric acid Picric acid
182-183 (dec) -4
HCI HCI 2HzO' HCIO, Salicylic acid
152- 153 140-142 167-1 69 122- 123
CH,O
CH,O
CH,O
CH,O
CH,O
181-182 182- 184 91-92 215-217 138-140/0.5 m m
-
44-46 120- 122/0.I m m
C2H50
C2H50
187
__ HCI HCIO, Picric acid
148-150 142-144 172- 174
Ref.
41,290,675,807 267 803 308 308,968 969 38 284 285,423427,429. 492,803,807 284,809,8 12 250 288 250 219 284 250,251 191 306 191 264,274,354 26 1 262,265.27 1,286. 290,970 286 265 265 27 1 264 191 191 232,262,265,27 1 265 265 232
Isoquinolinols and Their Hydrogenated Derivatives
450
TABLE 27E. 3,CDIHYDROTRIALKOXY- OR TETRAALKOXYISOQUINOLINES AND THEIR DERlVATIVES
R'
N* 2R R'
R4 R'
R'
R3
R4
CH30 C,H,O
CH,O CH,O
CH30 CH,O
H
CH,O
CH,O
CH,O
H
CH,O
Salts with
HCI
Acetone/ether. Bath temperature. ' In an evacuated capillary tube. ' The salt contains two bases. Water of crystallization. I Decomposed at 198-201 "C. Double melting points are observed at 170-171 "C and 174-175°C.
MP ("C)
Rd.
-
765 765 675
114
-
o, X u
X
s X
2 0
u
45 1
-t: -8
E
9 s m
v)
ZI
L
s o
v x x
z
02 x x x
452
2
e
W
,
'
HO HO HO HO H
H H HO
HO
H
HO If0 HO
HO
H
HO
HO
HO
H
H
H H H H H
HO
HO
HO HO HO HO HQ
HO
HO
HO HO HO HO HO
SO;-.:
CI 1CI IBr -
CI ICI I-
I
CI -
~
2H2W
CI CF,COO
Water of crystallization. Sintered from 140°C. Sintered from I55 "C. Dried at 100°C. A methoxyl group and a hydroxyl group are located at 6 or 7 and 7 or 6 positions, respectively. The salt contains two bases.
j3-(3',4-Dihydroxyphenyl)ethyl H CHJOO' HO CHICOOH HO CH, H
H
H
n-C,H,
I-C,H,
H
i-C,H,
n-C,H,
CH,COOCHICOOH CHJOCO C,H,OCO --
265-270 (dcc)'
175- 176
203 (corr.) -
173.5 (corr.) -
190.5 (corr.)
-
-
2325 (corr.)
-
741 409
739
372
350 350 350 350 3% 350 350 350
3M
350
975
232 (corr.)
739,913 74 1 974
CH3 H H H
H
H
H CH30 CH30
CH30
H
2-Chlorobenzyl
CH30
H
H
R’
R’
R’
CH30 H H
H H
H
H
H
H
R4
I
1II1-
aa-
1; CI CI III-
1;
i-
r-
a-
X-
CI -
R‘
TABLE 29. QUATERNARY SALTS OF ALKOXY-3,4-DIHYDROISOQUINOLINES A. QUATERNARY SALTS OF 6- OR 8- ALKOXY- AND 5.6-DIALKOXY-3,4DIHYDROtSOQUINOLINES
174-175 165
182-182.5
64 (soft) (corr.) 76 (flow)(corr.) -
82 (dec) 82 (dcc) 156- I58 (dtc) 150 (corr.)’
199 (dcc)
137 (c0rr.P
350 254 254 218,350 254 254 917 350 258,350 258 258 350 350 258.350 120,236 252 272
912
-
-
Ref.
m p rc)
X. Tables of lsoquinolinols and Their Hydrogenated Derivatives
455
TABLE 29B. QUATERNARY SALTS OF 3,4-DIHYDR0-6,7-METHYLENEDlOXYlSOQUJNOLINE
CH,SO; CI CI CI -
aI1-
II-
I1; 1;
-
232-237 233-234 234 238
-
132-134
-
-
HSO;
216 216 (dec)
HSO; HSO; CH,SOi Cr,O+Cr,O:Cr,O:-
cr,o;
HCr,O;
pta: PtcI: Picrate Picrate Picrate Picrate
ClH 5SO;
-
-
117-119 1 74b 175b.' l7Sb
-b
175 (dec) 247 (dec)b __ b
172-173 173 175
-
-
CI -
222 195-197 I75 215
CI BrPicrate CIO;
187-188 230 184-185 186-188
IHPtCI, Picrate Br-
2,3-Methylenedioxy-6(trimethylsilylmethyl~ phenylmethyl
210 212 212 (dec)
c10;
c10;
2,4-(NOz)zC,H, 3.4-Methylenedioxyphenylmethyl
.__
-.
976 375 398,691,977 370 282,374,392,401, 41 1,432,433,437, 450,692,803,813 921 379,977 277,392 356 I91,278,357,367. 398,467,471,978, 979 413 398 387 392 691 370 408 278,392 4 407 691 387 370 4 370,386,387 25 1 388,392,401,414 278 386 392 392 251 251,392 392 470,471 492 340 346 361
456
Isoquinolinols and Their Hydrogenated Derivatives
TABLE 29C. QUATERNARY SALTS OF 3,4-DIHYDRO-6,7-DIMETHOXYISOQUINOLlNE
CHjO
CH3O
X-
R
H CH3
R
CH3SO;
TsO CI CI- 34H20’
clCI -
acl-
MP (“C)
-
61-62 61-62 (corr.) 186 (dec) (c0rr.Y 186 188 (corr.)’
-
OH -
-
CHJSO;
-
CH,SOi
Br Br BrBr1-
II-
II-
1-
IIII1-
1-
I-
1-
I-
2H,O‘
157
87-90‘ 195 (c0rr.Y 212 87-90 (corr.) 18C182 187-I93 189-196 198-200 194 (dec) 191 (dec) 199 199 (dec) 199-201 201 (dec) 201-202 202
203-205 (dw) 218
-
X-
-
BF;
-
ao;
AuCI;
185-187 169 (corr.)
Ref.
783,976
901
291 393 315 375.693 350 217,280, 295-2974 10, 438,810,926 980 366 473 291 393 783 393 459 275 275 955 226 43 555
401
351 47 259 280 288 268,269 23,147,270,289,321. 349,350,363,371, 456,458,467, 471-473,475,493, 743,752,774,803. 901,921,950,953. 976,978,919, 981-983 299,395,474 807,898,984 371 938,985 393
X. Tables of Isoquinolinols and Their Hydrogenated Derivatives TABLE 29C. (Conrinued)
NHACHA N+H,(CH,), .Br NH,COCH, n-C3H,
Picrate Picrate Picrate Cl- : 2H,0d CI CI BrIIAuCI; Picrate BrBrBrBrBr- : H,O' CI CI- :2H,O CI Br11-
Picrate I(CH,), Ally1 3.3-Ethylenediox ypropyl
i-C,H, C,H@CO CH,OCOCH, C,H,OCOCH,
169 169-170 (corr.) 170 91-92 (corr.) * 190 (dec) (COIT.). 192 (dec) (corr.) 188-189 186.5 .-
138-139 (corr.) 139-140 (COIT.) 170-171 171
-
226 189 225 (dec) 78-79 (corr.) 177 (dec) (corr.)" 182-183 158 -
148-149 (COIT.)'
1-
-
BrBr-
-
c1-
IICF,COOBrBrBrBrIBrCI-:H,O' Br-:H,O' BrBrBrCI CI II-
161-163
183 (dec) (corr.) 201 (Pas) ._
-
170-172
-
138-139
-
148-149 I92 188 199
205 (dec) I96
-
147-150 169 (dec) (corr.). 152
-
375 393 389,401 295 295 350 463 348 350,743,981 295 295 480 353 273 429 429 429 295 350 288 348 350,981 295 471 830 369 350 348 350,743 975 472 471,481 472 784 939 353 422 429 429 434 986 353 350 348 350,743,981
451
Isoquinolinols and Their Hydrogenated Derivatives
458
TABLE 29C.
(Cunrinued)
R
n-C5H1
MP
X-
1
ICI - :2H,O' CI- :2HzO' CI CI CI I1CI 1-
II-
a-
-
142-143 148-149 197-198 143 (corr.) I23 165 (dec) (corr.)' 134.5 .-
__
I
CI-:H,O" CI -
a-
CI -
189-190 ( d e ) 193-194 (dec) I89 -
BrBrBrBrBr-
181- 183 191 191-192 192-195 ( d e ) 198-200 -
BrBr-
aa-
C,H,CO o-FC,H,CH,
IPicrate CI CI CI- :+H,O' a-:tH,@ Cl-:+H,O' CI-:iH,O' CI- :H20' :H,O' CI - :fH,@
a-
pCIC,H,CHz 2,4-CI,C,jH3CH 2
113-1 I5
-
HSO; CI CI a-:fH,O'
__
157-159 (dec) 80- 120 196-198 (dec) 2049 24lY 225s 2@ 165s 24oL 196-197 194- I96 227-229 182-184 183-184 138'
Ref. 47 1 424,425 423 423 303 350 348 350 350 348 350 47 I 412,478 365 365 412,814.81 5 425 424,425 405 405 492 412 917 452 268,269 309 310.31 3,314 269,362,364. 466,470,471 270,8 10 309 492 917 269.358 358 269,358 358 269.358 358 268,269 917 917 917 268,269 269
X. Tables of Isoquinolinols and Their Hydrogenated Derivatives
459
TABLE 29C. (Conrinued)
R
c1-
3,4-CI,C,H,CH, p-N0,C6H4CH, p-N0,C6H4C0 2.3-Methylenedioxyphenylmethyl 3,QMet hylenedioxyphenylmethyl /?-Acetyl-pisobutylethyl 2,3-Dimethoxyphenylmethyl
BrCI BrCI CI BrBr-
199-202 215' 208-209 187-189 195-197 202-205 200
c111;
CI -
c1-
.-
52-56 123-127 153-154 153-154' __
I1; BrBr - :fH,O' BrBrI-
184-185 160 187-188 187- 188' 186- 188 192-193
Br-
CI Br-
165 154-155 192 196-199 202-203 (dw) 193-195 (dm) 181-183 (dw) -
CI- :H,@
179- 180 189-190
CI Br-
Br-
BrI-
o-CH,C,H,CH, PCHIC~H~CHZ 2-BrCH2C,H4CH2 C~HSCO(CH,)~ C6HlCH =CHCO(CH,), ~-Acctyl-~-benzylethyl 2,2,4,4-Tetraethoxycarbonylbutyl C,H, NHCOCH (C,H,) 3,4,5-TrirnethoxyphenyImethylphenylmethyl
190-192 90-110 164-166
-
ao;
p-CH30C6H4COCH2 pBK~H~COCHI 6-Ethyl-3.4-methylenedioxyphenylmethyl 0-C, H sOCOC6H4CH 1 /3-(3',4'-Dimethoxyphenyi)ethyl
1 W
1-
CI CI CI -
8-(3',4'-Met hy1eneioxyphenyl)ethyl
1W -
CI -
BrBr-
3,QDimethoxyphenylmethyl
MP ("C)
X-
a-
a-
._
c1-
-
CI CI CI -
136137 I72 187-189 (dw) -
ao;
Ref.
269 453 269 360 492 826 362 269 270,810,816 324,325 826 362 826 368 368 397 826 268 269 354 826 397 397 950 349,494 830 830 816 360.489 372 349,494,950 479 495 372 917 917 473 353 303 412 317 42 1 917 985
460
Isoquinolinols and Their Hydrogenated Derivatives
TABLE 29C. (Continued)
R
MP (“C)
X-
6-(Brornomethyl)-3,4-methylenedioxyphenylernthyl 6-(Bromomethyl)-3,4imethoxyphenylmethyl 6-(Trirncthylsilyl)-3,4-dirnethoxyphenylmethyl
X-
Br-
ao;
._
176- 178
X-
__
CI -
-
Ref. 810 472 361 982
476
0 CH,O
c H 3%.CH
c1- :4H@
137
416
C ~ H S OOCzH5 CF3SO;
a-
468.959 303
m
w
VI
I?
N
.r
VI-
IZI?
X
X
I
i
u
461
T
Z
I
%; h)
6-(Trimethylsilylmethyl)-3,4dimethoxyphenylmethyl CH,
~-(3',4'-Dimethoxyphenyl)ethyl 3.43-Trimcthoxyphenylmethyl P C ~ H ~ ~ ~ H ~ C H Z
R'
TABLE 29D. (Continued)
CH30
H
H CH30
CH,O
CH,O CZHSO
H
CH,O
H
H H H
ClHlO
CiHiO ClHlO CiH70
R3
CH,O
CH,O CH,O CH30
R2
R4
1-
a-
II-
a-
CI - :2H,0d Br- :H,Od BrIAuCI; Picrate Br -
c1-
180 (dec)(corr.)" -
-
95 100 164 131-132 155-156 190-191 187'-189,
__
-
145-146 176-178
CI CI IX-
170-172
-
MP ("C)
Br-:H20d
a-
X-
347 350 350
280 280
39 1 391 39 1 764 39 1 39 1 417
354 354 270 354 354 810 373
Ref.
CH,O
CH,O
CH,O CH,O CH,O C7HiO
C7H70
H
H
H
H
CH,O
H
6-Hydroxymethyl-3,4 met hylenedioxyphcnoxy 6-Chloromethyl-3,4methylenedioxyphenoxy 6-Acetoxymcthyl-3,4methylenedioxyphenoxy
C7H7O
H
-.
ICFSSO;
-
._
CI -
__
235 (dec) I-
c10;
c10;
I-
Cl0;
~
-
142-144 176- I77 194-195 165-166 > I 0 0 (dcc) 165-166
-
222-225
135-136 181-182.5 I81 - I83
X-
II-
Br I-
1-
CH,SO; Picrate
ao;
Ic10;
468,959
399
399
374 41 I 314 3% 41 I 41 I 364 764 290 803 807 400 400 402-404 220 399
Isoquinolinols and Their Hydrogenated Derivatives
464
TABLE 29E. QUATERNARY SALTS OF 3.4-DIHYDRO-&METHOXY4,7-METHYLENEDJOXYISOQUINOLINE
R
c1-
X-
CI CI CI- :2H# CI -
Br IIII-
15
I; :H,@ OHXCNNO; HSO;
so:-
H a , AuCI; AuCl; Pta: Ptct: CH,SO; Picrate Picrate Picrate Picrate Phthalate Hydrogen Phthalate:H20' Hydrogen Phthalate
MP ( "C) 190 (dec) 192 197 197 (dec)
Ref.
143-144 102-105 113-1 I5
375 792 818 390,987 29,212,251,283, 369,374,4Oo,401, 409,414,415,419, 427,428,431-433, 436,439,441,446, 441,449,465,490, 692,803,813,988 288 288 284.419 250351 233,248,289,321, 420,471,979 212 396 767 807 449 989 408 409 419 218 390,987 419 219,409 25I 251 390 218,284,401, 987,990 414 987 987
140
987
-
197-198 179 180 184-186
-
142 144
-_
-b
180 136 136-137 212
_.
129-130" 143" 143
X. Tables of Isoquinolinols and Their Hydrogenated Derivatives TABLE 29E. (Conrinued)
R
X-
MP ( "C)
Ref.
I-
163-164
284
Br-
209 (dec)
429
a-
182 (dec) 120-122 169- I70 153 201
429 284 284 353 429
193 (dec) 77
429 284 41 2,424,425 418 416 405 416 405 405 416 284 416 492 424
Br1BrBrBrBrc1BrCI BrBrBr' BrBrBrBrc1c1-
-
178- I80 (dm) 151 184-185 (dec) 232 179- 184 (dec) 188-189 (dm) 164 I62 I58 187-188 208-209
465
CH,O CH,O C,H,O H
H
CHI
R'
CH3 CH3 CH, CA,
Ri R'
CH,O
CHSO
R'
CH,O
0 -CH,-O H CHJO CH,O H CH,O CH,O H CH,O 0 --CH,-O
R3
R2
BrIIX-
XCI-: lfH,O" AuCl; Picrate
XX-
X-
TABLE 29F. QlJATERNARY SALTS OF TRIALKOXY-3.4-DIHYDROISOQUINOLINES
-
185 (dec) 127 (dec) 1W 184 179-180 (dec) -
-
MpI'CI
3w 406,411,979 474
191
406
984 984 984 390 390
Ref.
& 4
C',H,O C,H,O
H
H
C,H7
CH,
CZHSO
H
CH 3
CH30
H
C-H,
CH3O CH,O UH,O CH,O
CHaO CHJO
H
H
H
n
H H
CH,
CH 3
CHI CH,
CIH, 3.4,s-Trimethrrryphenylmerhyl
CH,O
CH,O
CZHSO
CH,O
CHJO CH,O
C,H,O CH,O
CHJO
CH,O
CH,O
CH,O
C2HSO
C,H,O
p-HOC,H C,H,O
C,H@
CH,O
CH3O CH 3O
3 0
1-
Br-
I-
Br-
1-
Br "
Br-
Br -
IOH BrBr-
1-
C1~
203 (dec) 170-172
150-151
145-146.5 147- 148
-
163-164 178- 180.5
155-157 (dw)
191 265 232 262
2 18,262
286
22045 I
265 286
980
264 26 I
191
354
Isoquinolinols and Their Hydrogenated Derivatives
468
TABLE 29G. BIS-QUATERNARY SALTS OF 3.4DIHYDRO-6,7-DIMETHOXYISOQUINOLINE
n
X-
2
BrBrCI BrBr-
3 4 5 6 7
8 10
clBrBrBrBrBrBrBrBrI-
I' Dried at
YBrBrBr Br Br Br Br Br Br Br Br BrBr Br iI-
2H2@ 2H,@
2H,@
MP ("C)
Ref.
197-199 197-199 165 181-182 181-182 1% 232-233 232-233 217 203-204 205-207 210 180-181
815 430 430 817 430 430 817 436 430,817 430 430 430.81 5 430 289 32 1 694
-
168-170 -
100°C.
The salt contains two bases.
' Sintered.
' Water of crystallization. ' In a sealed tube.
Sintered at 146°C. Measured on a Buchi apparatus. Measured on a Kofler hot plate. ' Effervesces at 142°C after drying at 80°C in vacuum. Sintered at 125°C. The anhydrous product melts at 135-138°C after drying at 80°C in vacuum. I Solvent of crystallization. Then solidifies on cooling and melts sharply at 143"C. " Sintered at 130°C. Sintered at 90°C. 1
*
'
X. Tables of Isoquinolinols and Their Hydrogenated Derivatives TABLE 30. 1,4-, 5 . 6 , AND 7,8-DIHYDROISOQUINOLINOLSAND THEIR ETHERS
R
Salts with
MP ("C)
GHsO
HCI
107
Ref. 499.500
R'
R
R
OH
OH
-
Salts with
Mp("C)
Ref.
-
761
~~
R'
R'
HO(CH,)@
H
H
OH
Salts with
MP ("C)
Picric acid
127-128 155.5-156
Ref. 501,502
501.502 756
TABLE 31. QUATERNARY SALTS OF 7.8-DIHYDRO-6(8HYDROXYETHOXY) ISOQUINOLINE
R 2 m N ; R' xR' CH3
R2 HO (CHzhO
X-
Mp("C)
II-
138-139 139-140
Rd. 502 501,502
469
470
Isoquinolinols and Their Hydrogenated Derivatives
TABLE 32. ALKOXY-1,2-DIHYDRO-2-@-TOSY L) ISOQUINOLINES
R'
R4 R'
R2
R'
R4
H
H
CHJO
H
Mp("C)
Ref.
112-113
26 24 24 24 24 24 24 24,29 27,28 33 30 24 24
-
CH,O CH30 H H H H
H H
CH,O
H
O--CH,-0 CH,O CH30 H CH30 H CHAO
__
H CH,O H H CH,O
-
C7H7O
99.5-100.5
144-145 107-108 10 I - 102 _.
H
103-106 104-106
CH,O H
CH,O CH,O
H CH30
CH,O CH30
TABLE 33. PHENOL BETAINES A. PHENOL BETAINES OF ISOQUINOLINOLS
R'
R'
R' R' CH3 C6H5 C1H7
PNOzC6H4 pCH,0C6H4 CH,
R3
R4
0-
H
H
0000-
H H H H MH2
R2
H
R' ~
H H H H -0
Mp("C)
Ref.
53-54
508 7 7 8 9I 766 766 766 766 214 504
~~~
H H H H
H
-
.-
-. H 0238-240 2H20" 244
X Tables of Isoquinolinols and Their Hydrogenated Derivatives
47 1
TABLE 33B. PHENOL BETAINES OF 3,4-DIHYDROISOQUINOLlNOLS
R?
R'
R' R4
R'
R2
R'
R4
CH,O CH30 CH,O
0H CH30 0-
~
CH,O 00O---CHz-O
CH,O CH30 HO (0-) O-(HO)
0H
0-(NaO)
H
NaO(O-)
HO (0-) 0 - ( H O )
159-165
95- 104
HzO" 4HZW 6Hz04 HZO'
H
~~
680 760
222 (dec) (corr.)
-
235 (dec) (corr.)
509,510,912 214,505,506 509,510 680 410 374 410 410 410
TABLE 33C. EXTERNAL PHENOL BETAINES OF 3,4-DIHYDROISOQUINOLlNOLS
R2
R'
R3
R'
CH,O ( O w ) 0-(CH,O)
HO
HO
CH3O (HO) C,H,O
HO (CH30) CH,O (0-1 0-(CH,O) HO C4,O 0-
Water of crystallization.
XCI- H,O' ICI- 34Hz(T 1-
MP ( "C)
Ref. ~~
186-187 (corr.) 410 181-182 (con.) 410 135 (dec) (corr.) 410 196- 198 41 I
w N
X
2
X
X
X
X
X
X
d
ez
2
ez
0 X
X
X
3:
X
472
W
2
CzH5NHC0 (C~H,)ZNCO C,H,NHCO C,H,NHCS H
CHO
CH,CO
CH,OCO C,H,CO
H
H
H H
CHO C,H,CO C,H,CH,CO NH,(NH)C
H H H H
H H H H H
CH,CO
H
H H
HO HO
HO
HO
H
H
H H H H HO
H H H H
H
HO HO HO HO H
HO HO HO HO
HO
H H
H
H H H
H
H H H H H
H H H H
H
H
H
H
H
H
H
H
H
H H H
H H H H
H
HCI HCI HCl
HCI HCI HCI ( + )-Mandelic acid ( - )-Mandelic acid
105.6-106.7 178-180
-
171-172 172- 174
254 257.6-259.7 275-277 171-172 -
-
185 156 273
__
153 264-266
-J
101-102
201-202 203 (dec) 155- 156" 155-1 56b 108b-r 97-98 -
992 52,575 786.993 566 566 566 566 41 5,548,551, 579.786 786 994 786 786 580 669,83 1 786 786 786 786 96 995 96 557 120 96 615 96 97 995 557 995
H H H H H H
:
H H H H H H
R’
CHO CH,CO pCIC,H,CO NH,(NH)C CH3CO H
NHz(NH)C CH,CO CH30C0 CH3CO C,H,CO H
RZ
TABLE 34. (Conrinued)
H H H H H H
H H H H H H
R3
H H H H H H
HO CH,COZ CH,OCO, C,H,CO, C,H,CO, H
R4
HO HO HO HO CH,CO, H
H H H H H HO
RS
H H H H HO
H
H H H H H H
R6
H H H H H H
R’
HCl HCI HBr Picric acid Picric acid
HCI HCI HCI HCI HBr HBr
Salts with
129-1 30 210-220/18 m m 254-255 210.3-211.4 195 (dcc) 198-201
185.5-186 135-136 170 -
-
196.7-197.8
-
190.5 222-224 233
-
128-130 113-115 192-193
-
-
Mp or Bp (“C)
699 995 557 995 995 263 589,874,902, 987,996 121 263 526 789,696-698 557 615,874,997 615,616 a74 874 699 874 874 599 558,592,600,998 121 514,599,789 557 514 599
Ref.
W
E!
& X
0
0, o x T u x
P
X b X
I X I
x
III
x
x x x
x x x
x
1 x 2
x z x
r
2 x 2
% o x
x x
X X X X
0, X u x
X T T X
z
6
0
0
PP
X T 475
0 0 0
%
x
u x x x
x
X T X X
T
H H
H
H
H
H ? i H 9* H H H
H H
R'
R2
CHO H CHO H
H
H
CZHSCO C,H,OCO CH,CO CZFICO
CHO CH3CO
-
TABLE 34. (Conrinued)
H H H
H
H
H CH30 CH30 H
H
H
cn,o
HO H H
HO HO CH3COZ CZFSCO, HO HO
H H H
H H H H H
H
HO HO
R5
H H
R4
H H
R3
HO HO
HO
H
CJ,O H
CH,O
CH,O CH,O CH,O
CH30 CH,O
R6
H
H
CH,O €I
CH,O
H
H
H
H
H
H
H
R'
HBr
HBr
HCI HCI HCl H Br Picric acid
Salts with
-
264-265 196- 198 198-2W' 234-235 167- 169 272-274 158-160 197-199 214-217 216-21 7 220-22 1
-
-
116-118 102-103
-
259-260 260-263 238-240 172.5-174 149-150
MP of BP ('0
503,570,583.596, 597,601,looOA
300
745 541,542 267 267 267 267 267 267 522 491 21
601
548 21.497 616,747,781 615 21,497 615,616 601 616 615.616 787
Ref.
2
H
H
H
H
H H H
HO
H
CH,O
benzoyl
CHO CH,O 3,4,5-Trimethoxy-
CH,CO CH,CO ClF5C0 o-CICH,C,H,CO H CHJO H
H
H
CHO
H
H
H H
B
HO
HO
H HO
H H
H
H
H
H H H
H
H CH,O CH,O
H
H H
H
CH,O
CH,O CH,O CHSO
H H O--CH1-0
CH,O
H
H
H
H
CH,C02
HO
HO
HO
H
H
CH,O
CH,O CH ,o CH,O
CH,O
H
H
H H
CH,O CH ,O H
H
C1F5C01
HO CH ,COl
HO
HC1 Picric acid
HCI HCI HCI
picric acid
HQ HCI HCI HCI HCI HCI Ha HCI HCI HCI HCI
122 187-190 254-256 256-258 266-267 22 1-223 145-147 159-160 176- 179
169
-.
-
-
160-161
177- 179
246-248 280 280-282 28 1-282.5 281 -283 282-283 282-284 283 283-284 283-286 204-206 177- I78
601
522
601
400
21.497
21.497 300
400
21 568 497 561 267 402,404 2 1.50.497 400 402-404 601 601 745 913 832 832 548
400 550
522 3 9 548
P 0,
2 0
o x
X
0,
o x x u
X
u z
o,o,
on X
X X
X
x x u u
u
x x
X
X X
0 X
X X
0 X X
X
X X
X
478
X X
H
H
H H
H
H
H H
H
H
H
H
H H
H
H
CH ,O CH ,O
CH 3O
HO
C,H,O,CO CH ,O
HO
CH,O
CH,O HO
CH,O
CH,O
HCI HC1 HCI HCI HCI HCI
HCI :2H2@
HCI
HCl HCI
Salicylic acid
HCI HCI H Br H Br
.-
256-258' 256-258" 257 257-258 258" 274-275 277-278
185.5 186" 186- I88 187-188" 188-1 89" 189- I9 1"
213-215 214.5-215.5 155-1 57 166- I67
214-216
172-174 173- I75
lo05
556 264,553 523,1006 819 286 262,265,539,607, 666,68471 t 1009,1011,1012
262 265 1003 1003 262,556 556.672 262 262 523 104 569 523 607 665 286 523,1005 666 672, looh 289.406.569. 583.593,598. 667-67 I m. 1004.1007-101 I 523
0
P 00
CHO CHaCO C6H,C0 m-NO,C,H,CO
m-NO,C,H,CO
H H
H H
H
HO H
H H
R2
H H H H
R'
TABLE 34. (Continued)
HO HO
H HO
H
H H H H
R'
CH,O H H
CHJO CH,O
CH,O
H
O-CH,-O CH,O
CR,O
CH,O CH,O CH ,o
CH,O
R5
H
H
H H H
R4
O--CH,--O CH,O
CH,O
CH,O CH,O CH30 CH,O
R6
CH,O
c6H SCo2
HO HO HO HO
R'
234-236 234-236'
HCl:H,Ok HCI:2H2@ H,FtCI,' HIS04' Picric acid Picnc acid Picric acid Picric acid Picric acid Salicyclic acid
138- 139 -
-
167.5" 173- 175 173-175' 175-176 128-129" 129"
-
237-24@ 249-2449.5' 222-223.5
235-237"
MP or BP VC)
Salts with
547
541
539 522 54 996,1013
607 607 607 607,1005 523 1005 523 1006 286 262 670,672,674 670,672,674 607,1005 523 523 539 607,1005 1006
Ref.
H
H
H
H
H
H
H
H
H
H
HO
H
H
HO
H
H
H
H
HO
HO
HO
H
HU
I4
H HO
H
H
HO
HO
H
H
H
)I
HO
260 (dec)
H Br HBr HBr HBr H Br
-r
260-262*
260-262
255-258 262 265
265-267
__
246
219-220 229-232 (dw)
207-209 (dm) 208-210
HCI HCI HCI:H,@ HCI
HCI
HCI HCI HCI HCI HCI
HCI
HCI
537 519 1016 705,7 12,713, 717-7 19,721, 731,738,739
543
586 748,7 68. 1014.1060 768 1014 768,996,I014 1014 768 748 526 696-698 1015 548 5 19,524,570. 609,699-704, 707-716.738, 744,769,902. 999, IOOO, 1016- I022 567 526 55 696-698,704. 706,724,747, 1023,1024
@ @ cj T X
x
ggg
0
x xxx
2 so
2
0 0
u u x
z x x
x x x
225:
0 X
nxnx
X
482
W
P 00
H
H
H
H HO
H
H
+ 8.7"(c = 1.2, C,H,OH).
H
[ZJD
+3.53".
-7.2" (c=0.78. C,H,OH).
The salt contains two btlscs. Sublimed at 140°C in high vacuum. Dried at 100 "C/70mm. After sublimation. Water of crystallization. h c r i b e d in the footnote of the original Literature. Dried at 55 'C in vacuum. " Natural product. In a scaled tube. In vacuum. Labclcd with two deutcriums at I position. ' LabeIed with tritium. * Dried at 64°C in vacuum.
*
'
4R-Isomer.
' 4S-Isomer.
HO
H
H
HO
HO
' [%In- 14.4" ( ~ = 0 . 1 8CZHSOH). .
4R-1mmer.
4S-Ismcr.
H
H
HO
HO
HO
HO
HO
H
HCI
HCI HCI
HC1:+HI@
-
-
168- 172 (dK) 196-198
225-227.5
-
1 W
720
546
748 768 525.996 551
E
e
3
I
= I 3 I I I I I I I I l l 1
uX
X
9 5
2
x
X
3:
v,
P eo
CHO
CHO
CHSCO
cno
p.NO,C,H,CO
CH,CO
O CH30C0
a
H
R'
0 (CHJ,CHNHCH,CHIOHKH1O (CH&CNHCHzCH(OH)CHZO
0
CH,O CHJO CH,O CHSO C02-C,HFH,0 0 CH2C,H,a,O
CH 3
RZ
Ref.
615
615
H €I
H
615,997
615
97,267 557 97 91
114551 1 I4
H
157
-
__
I 15p.05m m
-
97
233 233-234 234.9-236 21 5-216 (dec)
1 I4
I14
114
105-10715 m m 228-230
lo(r126
Mp or Bp ("0
H
HCI HCI HCI HCI Picric acid
f H P
Salts with
H
H
RS
H
H
R'
H
H H H H
H
R3
R'
TABLE 358. ALKOXY-1~,3,4-TETRAHYDROlSOQUlNOtlNESAND THEIR DERIVATIVES
rn
00 P
H
H
R’
H
H H
H
Picric acid
H,PtCl,$
HCI HCI HCI HCI HCI HCI
198 173- 174 (doc)
-
233-234 236 238-239 242.6-244.1 244-2455’
143-34436 mrn -
Maleic acid’ 178- I80
235-240
Ref.
528 40.46,47,530, 535,559.584, 589,590.619, 678,729,859. 872,874,1027 528,529,58I 526 121 557 679 6 18,696-698, 708,726,874 528 528
871
1076
HCI‘
61 5
H
Mp or Bp (“C)
615
Salts with
H
R5
H
R4 H
R3
H
\N--(CH2fzo CH,O
A
(CH3)ZCHNHCHzCH(0H)CHzO (CH,),CNHCH,CH(OH)CH,O
(Continued)
(PF CBH&CH(CH z ) 3 - ~
CH3C0
CH,CO
R’
TABLE 358.
& 4
H
H
H
H
CH,CO
CHO
Cf,CO
CA,CO
H
H
CHO
CbH,CO
H
CH,CO
0
CHI-CHCHZO
H
CHO H
H H H H H
Y
Y
(CH3)aCNHCHZCH(0H)CHlO
(CH,),CNHCW,CH(0H)CH ,O
H
H
H
H
(CH3)ZCHNHCHz- H CH(OH)CH,O
CH,-CHCH,O H \ I 0 (CHA)ICHNHCH,- H CH(0H)CH ,O
\ I
CH,O CH,O CHaO CH,O C,H@
H H H H H
KSO,O(CH,),SO, pTosyl CTHL,CO pFC,H,CO(CH,),CO H
H
H
H
H
H
H
H
H
HCI
HCI
HCI HCI
?4-75
~~
173- 174.5
1Htl21
-
147-148 75-76
-
56.5-58
-
69-70
78-79
-
25 I
135
147-148
874 874
615
615 616
615 616 616
615 616 616
616
615.616 997
619 796 872 590 527 696-698 615,616
R'
H H H H H
H H H
H
H
H
H
H H
TABLE 35B. (Continued)
R2
Y H
Y
Y
Y
Y
Y Y Y Y Y Y Y Y
R3
H H H H H H CH,O
N
H H H H H H
R*
H H H H H H
H
H H
H
H H H H
R'
HCI HCl HCI HCI HCI
HCI
HCI
Salts with
228 228-229 23 1-232 231.5-232 232-233 233 233-234
146/11 mn 184-186/50 MBI
Mp or Bp ("C) 814
21
557 173
874 874 814 814 814 814 814 549 4 21,535,597, 675,618,710, 132,171,773 773 4,549 121 131
814
874
an
814
814
Rd
CI,CHCO CH,CO
H
C6H3SQ2
CIICHCO
CH,CO
H H H
H H
H H H H
H
H H
H
H H
H
H
H H
H
H
H
)I
H
H H
H H
H H
H H
H H H H
H H H H
Y Y Y Y
Y
Y Y
Y
Y Y
Y
Y Y
Y
CZH5 0 (CH,),CN HCHZCH(0H)CHZO
CIH@
CH,O CH,O
cn,o
H
H H H H H H H H H H
H H
H H
H
H H
H H HCI H,PICI,#
H2PtC16’ Picric acid Picric acid
Ha
Ha
135-137 194-195/50 m m 256 218
202 207-208 215-216
235-236
874 a14 874 814 a74 a74 a74 874 a74 874 a74 a74 874 874
615
605 4 4 4 1048
loQs
7 21 997
552 713 4
’
CHO (CH,),CCH,CO C6H,co (CH,),C,H,CO PGHSC6H4CO pTosyl CH,CO
H
CPiColinoyl
8’
H
H
TABLE 35B. (Continued)
R2
H H
R’
Y=
Y H
R4
,CI
CH,-CHCH,O \ / 0
CH,O CH,O CH,O CHJO CH,U CH,O
CH30
H
R5
HCI HCI HCI HCI
Salts with
259.1-261.2 260.5-263 261-262 (dec) 261-262.5 14-16 19-80 133-135 111-113 171-173 136
-
38-39 13-16/65 pm
Mp or Bp (“C)
814 833 833 120,236 551 120,236 a33 121 267 833 833 833 833 1% 991
Ref.
X. Tables of lsoquinolinols and Their Hydrogenated Derivatives
491
TABLE 3SC. I.2,3,4-TETRAHYDRO-6.7-DIMETHOXYISOQUI”LlNE AND ITS DERIVATIVES
R
Salts with
Mp or Bp (“C)
80- I3P 84-85 86 126-121 116-117/1 m m 175/10m m
H
-
HCI HCI HCI HCI HCI H CI HCI HCI HCI HCI HCI HCI HCI HCI HCI HCI HCI HCI
Hf-0, Oxalic acid Oxalic acid Pi& acid
240-242‘ 243 248 248-251 2w. 252 253 254-255 254-256 255 255-256+2 (dec) 255-256 256-251 262 (corr.) 263 264-266 261
-
-
213-215 ( d e ) 214-21 5 197-199
Ref.
23 21 517,585 538 772 587 41,43,58,287,291, 293,303,321,522, 534,535,537,555, 578,586,588,591, 592,591,602, 608-610,675,676. 129,752,169,710, 173,835,855,884,916, 934,970,975,1000, 1019,1028-1041 519 676 773.1042 521 521 173 526 536 930 1029 538 531 426,517,585 23 581 534 16
1 17,287,292,303, 405,574,578,582,588, 617,690,696-698, 705,728,731-733, 960,975.1O44- 1046 287 49 531 565
492
Isoquinolinols and Their Hydrogenated Derivatives
TABLE 35C. (Continued) ~
R
NO CHO CH,CO CICH,CO CI,CHCO CICH(CH,)CO NH2CS C,H50C0
Picric acid Rcric acid Picric acid Rcric acid Picric acid
198-200.5 199-200 202-203 (con.) 2osrns
-
125- 126
-
104-105
-
115-116 122-123 __
171-172 70-72
-
114 129 123- 124 123- 126 85-86 106-106.5 I10 220 172-173 141-143 144-145 110-111 76-78 200/10-2.5 127.5- 129.5
574 538 22 21 303 960,1068
531 155,156,1032 534 834 1043 1043 1043 578 975 712 772 604 757 855 655 603 419 617 565 298 7% 1044
119-120
608,620 610 581 730.1044 609
141.5-143
587
-
X
X
X
T
x z
X
X
X
X
x x
e
0,
5
0,
o_
U
u
X
B 0
X
X
493
u, E vx v
x
H
CHSO
CH,O
H
H H H H
H H
H
H H H
CHJO
H H
1
OCHj
CHiO CH,O
CH,O CHIO CH,U CHiO
H
b'
5-yloxy
n-C,H,O 2-4.1idyl0~y
n-C,H,O i-C,H,O CH2=CHCH20 CH2-CHCH20
H
H
1-Phenyl- IH-tetrazol-
H
CH,O
CHO
'R H
R3
CHJO
H
R2
(CH3)JCNHCH2CH(OH)CH,O CH,O
(Continued)
CHJCO
R'
TABLE 35D.
597
597
597
H
253 656698 597 597
253
1048
737
597
H
Ref.
267 734,735,1047
615
997
-
266-267
1 15-1 32'
-
145-147 258-259 189-190
-
Mp or Bp ("C)
H
HCl HCI
HCI
Salts with
n
H
n
H
CH 3O
H CH30
H
R'
vi n
2 s " '0 * * w ro
"'0
P P X
w w
P I-
moo I-r-
d VI
c
E E oo
0,
h
I S
2
X
2 2 2
I
X
X
I
a X
a X 0
a 2
a X u
a a a aa 2 2 x X I v
u u
O V
X
X
X
T
2
X
2 2 2
V
2
x z
X
V
495
I
T X
vx
CH30
CHI-CHCH20
‘ 0 ’ CICH2CH(OHjCH,0 CH30 (CHJ2CHNHCHZ- CH,O CH(OH)CH,O
ClHSCQ
CH3C0 CHO
b’
CH30
CHZ-CHCHZO
CHO
cn,co
/ ; \
R3
CH~O
R2
CH -CHCH,O
H
H
C,H,OCO
C,H70C0
R’
TABLE 35D.(Continued) R*
R’
HCI HCI HCI HCI HCI HCI HCI
HCI
HCI
HCI
HCI
Salts with
-
291,5l0,522.
-
59 1,597 512 533 532 533 548 526 568,690.73 1,732
616
255-257 274-275 274-276 275 276278 >315
615
110-111
61 5616
-
6768
1.1I-! 12
121-121.5
-
268
-
282 -
615,6316,997
787 597,835 527 696-698 591 527 696-698 615,616
161-162
-
781
Ref.
137-138
MP or BP m
i3
x
x x x
P
989 ddd
0, u X
x u
?L4
z
p u
000, x x u u
X X
x x
x x
P
x u 497
R2
o-CICH,C,H,CO o-CICH,C,H,CO C,H5C0
C,H ,CO H
H H H
H
R'
CH,O C2H50 H
H H
H H H
H
H
H
H
H H H MH2-O
CH ,O
H
CH,O CHjO CH,O CH ,o CH,O
R'
CHSO CH,O H
H
CH,O
H
H H H
R"
C2H50
H H CH,O
R3
R6
R3
CH,O
CHI0 MH,-0
CH,O CHJO CH ,o CH ,O CH ,O
R4
CH 3o
CHIO
CHjO
H H H H H
R1
WBr HBr
HBr
NCI
HCI
HCI HCI HCI Picric acid HCI HCI
HCI
Salts with
238-240 240 240 (dec) 61-63'
-
175-177
230-233 279-284 63 244-245
260 268 268-269 213-215
-
115-1 16 120-122 122-123 132-133 71-72
Mp or Bp ("C)
TABLE 35E. TRIALKOXY-OR TETRAALKOXY-I.2,3,4-TETRAHYDROISOQUiNOLINES AND THEIR DERIVATIVES
666.612,6?3, 1005,1006,
541 284 405 288 31 37 284
541
113 21 261 21
615.678.773 113
913 913 603 603 21 25,594,595.597,
Ref.
H
H
H
H
H
H
H
H
Dimaleate. Natural product. The salts contain two bases.
' Dichloridc.
Syn : mi-geometric isomer ratio is 71 : 29. Sun : anti-geometric isomer ratio is 35 : 65. ' Water of crystallization.
H
CHO C1,CHCO m-N0,C6H,C0 H
H
$p
H H H
CH,O
H
H H H H
' '
CH ,O
CH ,o
204-307 164-165 172-173
HCI HCI
-
188-190
207-209" HCI
HCI HCI
147- 14%
139-140' 139-140 207-208 (dw) 184-185
-
242-243' 24f-251y 248-250
Readily takes up CO, from the air. Dried at 8O"C in vacuum. Sintered at 107°C. Bath temperature. In a sealed tube. Double melting points are observed at 180-190°C and 207-209°C.
CH,O
CH,O
CH ,O
CH30
C7Hl0
CH ,O CH ,O CHjO C,HlO
CH,O
CH,O CH ,O
CH,O CH,O CH,O CH,O
HCI HCI HCI HCI HAuCI, HAuCI, H,PtCI, Picric acid
539 226.286,556 265 286 262,265 265 615,113,790 1042 773 790
1043
670,672614
673,1005 267,406,553. 559.567-569, 593.597.671 1006 539 553 569.666.1014 1006 539 539 539.1006
lsoquinolinols and Their Hydrogenated Derivatives
500
TABLE 36. 5,6,7,8-TETRAHYDROiSOQUINOLINOLS AND THEIR ETHERS R4 R'
d -
H
R'
R'
R2
H
HO
Rs
R4 H
Salts with
H
Mp or Bp("C)
Ref.
192-193 194-196
60,101,621 118
HCI H H
p-Tosyloxy H
H HO
H H
C2Hs0 H
H
H
H
H
CH,O
H
H
H
H H
H
H
CZHSO CH,O C2Hs0 C,H,O
H
H
C,H,O
H H
H H
H H
Picric acid HCI Picric acid
191-192 114 89.5-91 130-132/0.5m m
-
137 104-105/4mm 132-136/11 mm 195-197 156-157
-
51 38
61
131 61 791 791 621 621 118
I18 118 118 423 217 217
X. Tables of Isoquinolinols and Their Hydrogenated Derivatives TABLE 37. OCTAHYDRO- O R DECAHYDROISOQUINOLINOLS AND THEIR DERIVATIVES A. OCTAHYDROISOQUlNOLINOLS
R
H CH,CO
Ref.
Mp or Bp ("C) ~~
85/0.06 Toma -
85p.66Tom'
626 627 626
B. ALKOXYOCTAHYDROISOQUINOLINE
OH
R
Mp or Bp ("C)
Ref.
C*H,
-
1053
501
a
0
m
zz
Q Q Q X
x x
2 x 2
x x
X X 2 Z
x x
x x x x
x x
0 X Z Z T
& &
2 z x
QiQiQiX
6
0 0
5 5u
a
x x 502
u,
O F
Z 2 2 X
E!
v1
H H
H
H
C,H &O H
CHJO
H
.
H
. .....
H
CH,SO, H H H
H H H H
~
H H H
H H HO CH,SO, HO
Z-HO a-HO H H H
H
H HO HO H
H H
H
H
HO
H
H
HO
H
HCI HCI
' 90%
optically pure compound [4a(S),8a(R)].
' Diastereomeric mixlure.
' Stereochemistryof a hydroxyl group at the 4 position is not presented in the original literature.
' Unless otherwise noted, the prefixes a and ) are arbitrary, expressing only thc relative configuration.
Stereochernisiry is not described.
H
H H H
~
H H
H H H H C,H,CO
CH,CO
H
CH,CO
558 624 ti2 5 624 625 624
117" 119-119.5 243" 248-250 (dec) I lo*
98 98 1054 628 628 632,to27 632 632 633 632 8
--
108-1 15/3 mm'
-d
4
-1
._d
258-259 208-209.5 -d
163- 166/0.2-0.25 mmd 189-193/2 mmd -
H
H
CH3CH=CHS
H H H
H
H H H H
H
H H
H
H H
H H
C6HsCOS H
RZ
CNCH,S CHI = CHS HOzCCHzS CH, =CHCH,S
H CH3S
R' R3
H
H H H H
H
H
H
H H
R4
R'
TABLE 38. ISOQUINOLINETHIOLS A. ISOQUINOLINETHIOLS AND THEIR ALKYL (ARYL) THIOETHERS R4 R'
H
H
H H H
H
H H
H H
R'
HCIO,
HCIO,
HCI04
HCIO,
HCIO,
Salts with
107-109 -
95.5 122 98
142-145
128-132/1 m m
641,648,649 641 648,649 751,837
75 I 640
640
641,US, 541
793
649 648 836
82
-
684 74,79,80,646, 649,776,820, 836,1055
Ref. 139 -
Mp or Bp ("C)
XI. TABLES OF ISOQUINOLINETHIOLS AND THEIR HYDROGENATED DERIVATIVES
H H
H
H
H
H
H
H
H
H
H H CH,S
H CH,S H
H
H
H H H H H H
H
H
CH,COCH,S 2-Hydroxypropylthio ICH,j,CS CH,CO(CH )2S C,H,S(CH,),S N-Succinylmcthylthio
CH3S H
H H H
H
H H H H H H
CH,S
H
H H
H
H H
H
H
H
H
H
H
H
H
H H
HCI
HCI
HCIO,
HCIO,
44-47
177- I79 -
214-216 136.-140 156-1 58 143-145 60-62
_.
t 38- 140 197- 199" 66-67
108-109 115-1 I6 144
loo-101
88-92
59-6I)
85-87/0.05 m m I 20- I 2 I 80 101 I72 -. I 73 57.5-59 5n-60
642 642 646 637 650 637 793 637 637 637 636 637 634,637 634,637
644 644 838 HO 78 643 639 641 642 642
641 641 635 642 63X
SO6
Isoquinolinols and Their Hydrogenated Derivatives
qR2
TABLE 38B. ALKYLTHIOISOQUINOLINOLS AND THEIR ETHERS
R'
R'
R'
Mp ("C)
Ref.
CH,COz CH3CO2 H
63 64 258
647 647 72
H CH,O
99.5-101.5
1057 647 647 647 647 72 72 72 71.72 12 71,72
R2
R'
Salts with
57 70 66 95 55 138 143 196(dec) I35 190 I38 138 (dec) I28 128 (dec) 200 (dec)b
C2H50
n-C,H,O C,H,O H H H H H H H
2-Diethyaminopropylthio and Z-diethylamino-I-methylethylthio 1-(4'-Methoxyisoquino1yl)thio 1-(4'-Ethoxyisoquinoly1)thio After sublimation.
H
HCI HCI HCI HCI HCI HCI HCI
71
72 71 72 71
H
205-206
72
H
146
72
A mixture of two isomers.
TABLE 39. 1-METHYLTHIOISOQUINOLINIUMIODIDE MP ("C)
Structuk
Ref. ~ _ _ _
q N + ,CH3 r SCH,
' Dried at 100°C.
134 (dec)
65 1
143-146'
1055
XI. Tables of Isoquinolinethiols and Their Hydrogenated Derivatives TABLE 40. 3.4-DIHYDROlSOQUlNOLlNETHlOLS A. I-ALKY LTHIO-3.4-DIHYDROISOQUlNOLlNES AND THEIR DERIVATIVES
R
Salts with
Mp or Bp (“C)
80-84/0.05m m 82-82fl.05mm 98-100/0.7m m
CHjS
-
HBF, HI Picric acid
188 195-198 136 89-90/0.5m m 89-9510.1 100-102/0.2m m 109-1 11/0.7m m
__
HBF, Picric acid CH, = CHS CH, =CHCH,S
.-
-
HCIO, HBr n-C,H,S
Picric acid HzSO, HCIO, H Br C6H5S
125 130
Picric acid
Picric acid
104-105 129-1 30 120/1m m
117 -
163-164
-
118-120 129-130 79-80 I78 (dec) 83 79 167 I42
Picric acid
I19 168
Ref.
794 794 652 653,655, 656,911, 1058-1060 794 1061
652 652 653 794 654,794 656,657,1059 794 652 75I 795 795 795 652 655 652 638 655 795 795 195 652 652 652 638 652 652 652 652
507
508
Isoquinolinols and Their Hydrogenated Derivatives TABLE 40B. 6-METHY LTHIO-3.4-DIHYDROISOQUINOLINE Structure
Salts with
Oxalic acid
Mp ('C)
Ref.
-
1062 637
147- I5 1'
TABLE 4 K . ALKOXY-1-ALKYLTHIO-3.4-DIHYDROISOQUINOLINES AND THEIR DERIVATIVES
R'
R3
R4
RS
Salts with
Mp or Bp ("C)
CH,O H
H CH,O
H H
HFSO, H BF, HFSO,
106-1 19 208-209.5
R2
H
CH,S CH,S
H
C2H$ CH,S CH,S
H H CH,O
H
CH,O O--CH, 0 H H
H H CH,O
CH,S
H
CH,O
H
CH,O
HI Picric acid
HI C2H8
CH,O
CH,O
H
C2H8
CH ,O
H
H
CH,O
n-C,H,S
CH,O
H
H
CH,O
258-260 57-58 143-144/0.6 m m 155
94-96
HCI HCI HI H
-
HBF, Picric acid Picric acid
Ref. 969 969 969 654 655 652 652 652 653,654. 794 645,10631065
190-192 (dec) 190-192 1%
653 794 655
-
645
142-145/0.25 m m 174- 176 140/0.4 mm 160 38 170-171/1 mm 141
794 794 652 652 652 652 652
XI. Tables of Isoquinolinethiols and Their Hydrogenated Derivatives TABLE JOD. 1.2-DIHYDRO-I-METHYLTHIOISOQUINOLINE Structure
M P (‘C)
Ref.
Hemioxalate.
TABLE 41. I,2-DlHYDRO-2-(pTOSYL)ISOQUINOLINES
R
H
p-CH,C,H,S pCH,C,H,SO P-TOSYI
M P (‘C)
Ref.
121-122 129- I30 142.5 143.5 167- 168
658 658 658 658
509
Isoquinolinols and Their Hydrogenated Derivatives
510
TABLE 42. 1,2,3,4-TETRAHYDROISOQUlNOLINETHlOLS A. 1~3,4-TETRAHYDROISOQUlNOLlNETHlOLS AND THEIR ALKYLTHIOETHERS
R4
R‘
R2
R’
R4
H
H
HS
H
CHSCO H H
H H CH’S
HS H
H HS H
H CH&O H CH3C0 H
H H H H H
CH’S CHIS CF,S CF,S C13CS
H H H H H
CH,CO H H H
H H
a3cs
H CH,S
H
H H H
H
H
Salts with
Mp(”C)
Ref.
HCI
-
1066 1066 1066 1066 1062 634 1066 1066 1066 1066 1066 1066 1066 1066 1066
HCI HCI HCI
HCI Maleic acid
-
230-235 247-248
-
190-191
-
218-220 159-160
-
-
CFSS
CI’CS
1066
1066
TABLE 42B. METHYLTHIO-l,2,3.4-TETRAHYDROISOQUINOLIN40LS
R’
R*
CHSS
H
H
CH,S
Salts with
MP CC)
R d
138-140
634 1062 643 1062
-
I02
-
XI. Tables of lsoquinolinethiols and Their Hydrogenated Derivatives
51 1
TABLE 43. SULFOXIDES AND SULFONES OF ISOQUINOLINES
R'
R'
CH,SO, H CH3SO
H P-TOSYI H
CH,SO, HO H
175- 175.5 179-180 65-66 -
CH,SO,
H
H
152 153-1 54
C,H,SO, C,H,S02
H
H
83-84
H
H
C,H,CH,SO,
H CH3S0,
H H
C,H,SO* CeHsCHzSO, H H
H H
140.5-141.5 142-143 177- 177.5 94-95 78-79
H H H H H
CzH5SO C,HsCH,SOi
182-183
191-193
576 1067 79 820 80 74,576 79,820 576 576 80
576 576 576 576 793 777
Isoquinolinols and Their Hydrogenated Derivatives
512
TABLE 44. SULFOXIDES AND SULFONES OF 1,2,3.4-TETRAHYDROISOQUINOLINES
R4
R' H H
H H
CF,CO
H
CH3CO CF,CO CH,CO CH,CO
H CH3CO H CH3CO CH3CO
R'
R3
H H H H H H H H
CF,SO CF3SOZ CF,SO, FSO, FSO, NHzSOz CISO, CISO, CF,SO CF,SO, CH3S0 CH,SO CH3S0, CH,SO, CI,CSO H H H H H H H
H H H H H
H
H
H H H
H
H H H
H CH3C0 H H H
H H
R4
H H H
H H H
Salts with H CI HCI
Fumaric acid HCl
H
H H H CH,SO CH,S02 CISO, CF3S0 CF,SO,
Ref.
205-206
1066 1066 1066 1066 1066 1047 1066 1066 1066 1066 1066 1066
__
199-200 230-232 99-103
__
H H
H H H
Mp ("C)
108-109 _.
HCI
200-202 -
HCI
258-260 -
__
I _
__
c1,cso
-
CI,CSO,
-
1066 1066 1066 1066 1066 1066 1066 1066 1066 1066
XI. Tables of Isoquinolinethiols and Their Hydrogenated Derivatives TABLE 45. SULFENAMIDES AND SULFONAMIDES OF 1.2.3.4TETRAHYDROISOQUINOLlNE
R 2,4-(NO,),C6H,S CH,SO, C,H,SO,
p-NH,C,H,SO, p-NO,C,H,SOZ p-Tosyl
d-Camphorsulfonyl pCH,CONHC,H,SO, p-( I ,2,3.4-Tet rah ydroisoquinol2-yl)benzenesulfon yl
MP ("C) 157.5-159.5 129- 130 I52 153-1 54 154 155-1 56 174' 177-178 179- 180.5 161 179 138- 141 142 142- I43 143 I45 145- 146 147 -
Ref. 659 7% 660 128 661 605
175-176b 181.5-183 I4 1 - 142'
970 663 613 612 796 613 612 663 61 I 614 42 1,614,662 664 796 775 796 663 612 663
142-144' 149* 153-154' 153-156' 157-1579
663 663 663 663 663
160
With softening at 172 'C. Heated at 100°C in vacuum. An opaque liquid. ' Softened at 140 'C after drying in vacuum for I week. ' Softened at 144 "C(from benzene-cyclohexane). I n vacuum for 3 weeks. Recrystallization from ethanol-acetone. ' Softened at 153 "C (from CCI,).
51 3
514
Isoquinolinols and Their Hydrogenated Derivatives
Acknowledgments The authors are grateful to Dr. Hiroshi Mishima for his valuable suggestion on this manuscript and to Mr. Toshiaki Ishida and Dr. Hiromichi Ogasawara for their help in preparing the manuscript.
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Chemistry of Heterocyclic Compounds, Volume38 Edited by Gary M. Coppola, Herbert F. Schuster Copyright 0 1995 by John Wiley & Sons, Ltd.
Index 3-Acetoxyisoquinoline. 238.24 I 4-Acetoxyisoquinoline. from isoquinoline 2-oxide. 241 5-Acetoxyisoquinoline. oxidation of. 244 3-Acetoxy- I -methylthioisoquinoline.320 a-Acetyl-y-butyrolactone. 172 N-Acylisoquinolium salts. reaction with pyrroles. I 1 I Adams catalyst. 243.259.297.298.3 12.3 14 in reductive cyclization. 303 Adiantifoline. 56 Adlumidine. 275 hydrastinine salts from. 275 Aldol reaction. retro. 269 2-Al kyl-4-ami no-5-(bromoethyl)pyrim id ine. reaction with isoquinoline. 172 I-(Alkylha1ide)isoquinolines.reaction with amines. 2 I-Allyloxyisoquinoline. Claisen rearrangement of. 248 Amberlite IRA-401. 291 I-(Aminoa1koxy)isoquinolines.27 Ida-AminoalkylbenzyI)isoquinolines.7 3-(Aminoalkyl)4hydroxyisoquinoline.194 I-(Aminoal kyl)isoquinolines. 2 2-(Aminoalkyl)isoquinolines. 133 3-(Am inoal ky1)isoqui nolines. I83 N.(Aminoal ky1)- I .2,3.4-tetrahydro-2isoquinoline carboxamide. 138 4-Aminoal ky1-30.4.5.9h-tetra hydroisoxazole~5.4-c~isoquinolines. 124 3-(Aminoaryl)isoquinolines. 1x3 2-(p-Aminohenzenesulfonyl)-l.2.3.4tetrahydroisoquinoline. 328 I -(4-Aminobenzyl)-7-hydroxy-bmethoxy1.2.3.4-retrahydroisoquinoline. 5X
I-(Aminohenzy1)isoquinolines.53 I-(4-Aminohenzyl)isoquinoline.54 I-(4-Aminobutyl~3.4-dih~droisoquinolin~. 2 I-Amino-4-(chloroethyl)thiazoIe. reaction with 1.2.3..btetrahydroisoquinolines. 173 N-(’-Aminoeth~I)isoquinolinium bromide hydrohromide. reduction with lithium aluminum hydride. 133 3-i\minoisoquinoline. diazotiration of. uith i ~ o i ~ nnitrite. ~ q l 138
5-Aminoisoquinoline. diazotization of. 236 5-Amino-8-isoquinolinol. oxidation of. with ferric chloride. 236 8-Amino-5-isoquinolinol. oxidation of, with ferric chloride. 236 N-(2-Amino-S-methyl benzyl)-6.7-dimethoxy1.2.3.4-tetrahydroisoquinoline.161 6-Aminomethylguanamines. 172 I-(Aminomcthyl)isoquinoline.7 4-Aminomet hylisoquinoline. benzoylation of. 205 34 2-Aminomethyl)-2-methyl1.2.3.4tetrahydroisoquinoline. 184 2-Amino-2-methyl-l-( I -oxo-Z(ZH)isoquinoly1)butyric acid. 175
I-(Aminophenethyl)isoquinolines. 65 I-( 2-Aminophenyl)-6.7-dimethoxy1-3,4d i h yd roisoq u i no1i ne. 4 1 I-(2-Aminophenyl)-3.3-dimethyl-3.4dihydroisoquinoline. 40 I -(4-Aminophenyl )isoquinoline. 4 I
2-(Aminophenyl)isoquinolines.I61 N-( 3-Aminopropy1)- I .2.3.4tetrahydroisoquinoline. 134 N-(Aminopropyl)isoquinoliniumbromide hydrobromide. reduction with lithium aluminum hydride. 133 Aminoprotoberberines. 57 3-Amino-4-substituted arylisoquinolines. 206 2-Amino-4-[2-( I .2,3.4-tetra hydroisoquino1ino)ethyljthiazole. 173 Amphibine 1. 10 Anhalamine. 295.330.331 alkylation of. 305 hydrochloride of. 339 Schottcn-Baumann reaction of. 308 thin layer chromatography of. 341 Anhalinine. 300.330 quaternization of. 305 thin laycr chromatography of. 341 I-Anilinoisoquinolines. 36 Anthranilonitrile. acid catalyzed reaction of. 40 Apaverdldine. 240 Armepavine: hiomimetic oxidation of. 275 electrolysis of. 275
ti45
546
Index
Azahicyclo~4.2.2jdecatetraene. 2.10 3-ALabicyclo13.2.2)nonane.2 12 X-ALa-6-oxa-8-methyl-3.4-di hydrohicyclol3.2. Iltxtane. I84 Azastcroids. 4. 73
Brnzamidaro[2.1-alisoquinoline,262
(S)-Benzoquinolizine. 158 Benzolujquinolizidine derivatives. from 3.4-dihydmisoquinolyl ethers. 27 1 Benro[alquinolizine. 121 4-(Brnzylaminomethyl)- 1.2.3.4-tetra hydroisoquinoline. 204 4-Benzylcarhamoylisoquinolinr. synthcsis of. 205 2-Benzyl-2.3-di hydro-q I H)-isoquinolinoncb. oxidation of. 254 7-Benzyloxy-3.4-dihydro-6.8-diniethox~ isoquinolinr. 266 8-Benz y loxy-3.44 ih ydm-6.7-d imet hoxyisoquinoline. 266 7-Benzyloxy-3.44 hydro-6-met hoxyisoquinolinr. 266 6-Benzyloxy-7-mrthoxyisoquinoline. 23 1 8-Benz yloxy-7-mrthoxyisoquinoline. 239 6-Benzyloxy- 1.2.3.4-tetra hydro-7.8dimethoxyisoquinoline. 297 2-Benzyl- 1.2.3.4-tetrahydroisoquinoline-3carboxylates. 183 4-Benzyl-3.4.5.6-tetrahydro- I ti-2.hmethanobenzo[el( I .3ldiazocine. 204 2-Benzyl-l.2.3.4-tetra hydro-4-oxoisoquinoline. 258 Riguanidincs. 149 2.5-Ris(2-acyl- 1.2-dihydroisoquino1yl)pyrroles. 1 1 I 1.3-Bis(2-henzamidorthyl)henrene.reaction with phosphorous oxychloridr. 2 12 p-(Bis(2-chlora.thyl)amino(henzyl alcohol. reaction with isoquinoline. 161 I-{p-~Ris(2-chloroethyl)aminolhenzyl~isoquinolinium p-toluenesulfonatc. 161 Bischltrr-Napieralski reaction. 3. 11. 28. 36. 37. 53.66. 70. 72-74. 86. 88. 107. 100. 1 11. 121. 197.2oh.266.274.3Ix Pictet-Gams variation of. 23 I tandem. 286 N.N-Bis-(3.4-dihydro- I-isoquinolylmethyl)-Bphenethylamine. 100 His-isoquinolines. 89 1.1 '-derivatives. 107
N'-Bispad-N.N-dimethylformamidine. 158 Bis-1.2.3.4-telrahydroisoquinoline. I08 I -Bromoisoquinoline. I07 suhstitution of. 234
4-Bromoisoquinolinr. reaction with sodium phenylmercaptide. 318 (+ )-(.S)-6'-Bromolaudanosine. 56 w-Bromopicoline. I69 5-Bromopyridinoll" :2"-3 :4lisoquinolino12': I :2)glyoxalinium bromide. I69 Bucherer reaction. 236.248 I-(I-Butylthio)isoquinoline. 3 18 I+)-Calycotomine. I21 Cannizzaro reaction. 286 Capnoidins. 275 1-Chloro-3i.hloromethyl4methyl substitutedisoquinolines. 185 2-('-Chloroethyl)piperidine. reaction with I 2.3.4-tetra hydroisoquinolines. I73 N-( 2-Chloroet h yl)- I .2.3.+telrahydroisoquinoline. reaction with sodium dicthyl chloromalonate. 149 2-(PChloroethyl)-1.2.3.4-tetrahydroisoquinoline. reaction with 3-pyridol. 171 I-Chloroisoquinolinr. 55 hydrogenolysis of, 237 reaction with 1-butylmcrcaptide. 3 I X 3-Chloroisoquinoline. I98 substitution of. 236 4-Chloroisoquinoline. from 4-isoquinolinol. 245 I-(Chlorc~methyl)-3.4-Jihydr~~isoquinoline. 2 2-C'hloromethyl-6-niethylpyridine. 84 2-C'hloromethylpyridine. reaction with I .2.3A-tetrahydroisoquinoline. 170 Cope reaction. 23 I rearrangement. 302 Corypalline. catalytic oxygenation oC 253 Cotarine. peroxide derived from. 278 Cotarnazine. 232 Cotarnine. 281.334 chloride: clciivage of. 280 conversion t o hydrosulfide. 280 extraction of. 281 oxime. 23 I polarographic activity of. 281 reaction with methyl iodide. 278 Cotarnoline: formation of. 290 reduction of. 295 urine metabolite. 292 Cotarnone. 267 l - C y ~ ~ n o i s o ~ u i n o lI85 in~. 4-Cyanoisoquinolinc. reduction of. 105 I-Cyanomethylthioisoquinoline.reaction with henzoyl chloride. 321 a-Cyano-rr-tolunitrilr. alkylation of. 206
Index
547
formation ol. 266 0-Dea I h! I u tion. w i t h concs n tra ted H Cl. 3 M ) thsrnio1)sis of. 283 0-Dehenr! lation. h) drogenol! tic. 301 7.X-Dihydro-6(SN)-isoquinolinone. f)ec.ah!dro-5-isoquinolinol. 259 ketalization of. 2x8 Decah!Jroisoquinolin[)ls. 3 I4 X.9-Dihydro- I3hH-isoquinolinol2. I-+ (+)-'-Deh!droenietine. 121 quinamlines. 41 13eh)drogenation. 24 I 1.2-Dihydro-h.7-methylencdioxy-2~pwith .\'-hroniosuccin iniide. 234 tosyl )isoquinolinc. 2YO with palladium hlack. 234 3.4-Dihydro-5-nirrht,xy-7-isoquinolinol. 269 with piillatlium (in carhon. 233 .~.4-DihSdro-h-mcthox)'-S-isoquinolinoI.266 with ptitawiuni perniangiiniite. 234 3.4-Dihydro-h-mrthoxy-7-isoquinolinol. 266 photochemical. 234 nitration of. 26Y Demethoh~-O-nieth)l a n h ~ d r t ~ ) n i h i n e66. ?.4-I~ihydro-7-methoxy-~isoquinolinoI. 269 0-Denieth) lation. 234 3.4-Di hydro-X-methoxy-5-isoquinolinol. 269 Dihenzolu.Klquinoliridine. 158 1.2-Di hydro-2-(p-tosyl)isoquinolinrs. 230 7.X-Dihenr~los~-2-(p-tos~l)isoquinol1ne. 2%) 3.4-Di hydrtrh.7.X-trimethoxyisoquinoline. 6.7-Dic hloroi\oquinolin-5.X-dione. 247 266 Dic!andianiine. reiic~ionnith 1.2..?.4-tetr;i1.2-Di hyJro-Z.h.7-rrimcthoxy-2-(ph! droisoquinol ine. I49 tosy1)isoquinoline. 3 0 Diels-Alder reaction. hetero. 241 1.2-Di hytIro-6.7.X-trimrthoxy-~-(p3-( 2-Dieth! laminoeth! I )-4.5-nieth>lenetosy1)isoquinoline. 290 dioxyphen) I-7.X-Jiniethos! - I .2.3.4-tetra(2.S-Di-iaoquinoline)pyrrole.7 1 h! d roisoq u i noli ne. I 97 6.7-Diiiiethoxy-2.3-dihydro-4(I I { ) ?.J-Dih!Jro-s.h-Jimethos! iwquinoline. 266 isoquinolinone. dehydrogenation of. 3.CDih! dro-6.7-tlimethoa> isoquinoline. I2 I . with palladium o n carhon. 233 266.269 1.3-Dimethox) isoquinoline. 241 from O-nieth!lation rsiiction. 269 3.h-Dinierhox) isoquinoline. 238 from .\'-norarmspa\ ine. 267 3.7-Dinicthox)isoquinoline. 238 paper chromatograph! ol.340 ?.4-Dih~dro-h.X-dimsthos~-7-isoquiiiolinol. 6.7-Dimethox) isoquinoline. 229. 234. 238. 139.240 269 I'roni Pomcranr-Fritsch reaction. 23 I 1.2-Dih!dro-?.X-dinicthos! - 2 - ( p t o s ! I ) i w quinoline. 2W pcrmanganate oxidation of. 244 5.6-Dih!drofuro(2.3-~/lp)riniidinr. 172 reaction with allyltriniethyltin. 248 h.X-Ditiiclhox!,isoclinoline.E Y . 2.18 I .2-Dih)Jroisoquinoline: coupling of a1deh)des to. 28Y 7.X-Dimcthoa!, isoquinolins. 233.234.238 reaction with phen>lgl)oxals. 257 S.h-Dimethox! isoquinolinol. 233 I .4-Di h>dro-'l/-isty uinolincs. S.X-Dimethoxvisoquinolino1.233 anticon\ulsant ctctivit?. 208 h.7-Dimethoxyisoquinolinol. 233 3.J-Dih> dro- I (2H)-isoquinol inones. reaction 6.7-Dimcthox> -4-isoqu inolinol. 234 with trieth! losonium 1etr;iIluorohorate. 6.8-I)imethoxyisoquinolinol. 233 269 7.X-1)iniethosyisoquiiiolinol. 233 3.4-Di h) d ro- I (2H)- isoq u i no1inone. red uct ion 6.7-Dinicthox>- I .2..;.4-tetra hydroisoquiiiolinc: reaction with ,V '-hispad-,V.Nof lacrani group. 2YY ?.4-Dih>droisoquinolines. from 1.2.3.4dinieth~lformamidine.I Z X tctrah!droisoyuinolinrs. 267 reaction with 6-niethqlisatoic anh)dride. ?.4-l)ih!dro-h.7-isoquinolinedi~~l.24 I I61 piper chromatograph) of. 340 2-( 3-Diniet h y lani inopropy l)isoquinoliniu in 3.4-Dihgdroisoquinc)Iiniuni salts: chloride hydrochloride. 133 3-(~~-Dinirthvlsmiiiosh.ryl)isoquinoline 2-alk>l.reduction of. 2x5 0-dealk)lation of. 277 methyl iodide. 196 oxidation of. 2x5 I.CDi-(3'-niethylisoquinolyl-l ')methyl3.4-Dih!droisoquiriolinols. quaternan siilts piperazine. I 1 I of: 274 Diphenyl( I-isoquinoly1)carbinol. X 3 . 4 D i h ~ J r o i s o q u i n o1I ethers: ~ .~.3-Disuhstitutrd-?.4-Jihydroisoquinolines. dehydrogenation 01.233 from pyridylnitriles. 83
Index
548 &Domesticine. 55
Emetine. I14 (-)-enantionier. 158 cll-Epidicentrine. 55 4-Ethoxyca~onyl-6.7-dimethoxy-2-mef hql1.2.3.4-tetrahydroisoquinoline.204 I-Ethoxy-3.4-dihydroisoquinoline. 269 3-Ethoxy- 1.4-dihydroisoquinoline.288.289 ~Ethoxy-3.4-dihydr~~isoquinolinc. 266 I-Ethoxyiscyuinoline. 238 ether cleavage of. 248 nitration of. 245 3-Ethoxyisoquinoline. 236 4-Ethoxyisoquinoline. 238 animation of. 247 5-Ethoxyisoquinoline. 239 7-Ethoxy- 12.3.4-tetrahydro-6-isoquinolinol. 295
Ethyl 2-(2-aminobenzyl)-12.3.4-tetrahydroisoquinoline-3-carhoxylate.164 Ethyl 3-amino-2-(3.4-dimethoxyphenyl)propionate. reaction with formaldehyde. 204 Ethyl 3-( I'-henzoyl-4'-piperdyl)propionate. I84 2-Ethyl-5-hydroxyisoquinoliniumhydroxide. hydrogenation of. 259 Ethyl isoquinoline-3-carboxylate.Claisen reaction of. 184 5-Ethyl- I -methyl-2-Jf3-(1.2.3.4-tetrahydroisoquino1ine)ethyl)piperidine. I7 I S-Ethyl-2-(P-morpholinoethyl)pyridine.I7 I Ethyl I.2.3.4-tetrahydroisoquinoline-3carhoxylate. 183 I -Ethylthioisoquinoline. 320 5-Ethyl-2-vinylpyridine. addition o f morpholine to. 171 Formamidines. metallation of. 158 2-Formyl-1.2.3.4-tetrahydro-5-isoquinolinol. 243 2-Form yl- I .2.3.4-tetrahydro-6-benzyloxy-7methoxyisoquinoline. 243 Friedel-Crafts acylation. 72 Glaziovine. 58 Graf-Ritter conditions. 83 Heliamine. 330 2-Heterocyclic substituted isoquinolines. 169 2.3.7.8.9.9a-Hexahydro- I HhenzoldeJ I I .7 J naph th yridines. 6 I .2,3.4.5.10.10a-Hexa hydroimidazoI12-hlisoquinoline. 133
1.2.2.5.6. IM-Hexahydroimidazo-
[2.lwlisoquinolines. 137 I J.4.6.7. I Ib-Hexahydro-2H-pyrimido12.1wlisoquinoline. 134. 137 2.3.4.6.1 1.1 lo-Hexahydro-l H-pyrimido[ 1.2-hlisoquinoline. 133 Hoffmann elimination. 285 Homoveratrylamine. reaction with diethyl oxalate. 107
Hydrastine: oxidation of. with iodine. 253 oxidation to hydroastinine. 281 Hydrastinine chloroplatinate. 275 7-Hydro-8-( I-pipridylmethy1)isoquinoline. 212 Hydroastinine. from hydrastine. 181 Hydrogenation. 259 exhaustive. 314 high pressure. 316 5-Hydroxy-6(3-azahicyclo(3.2.2]nonamethy1)isoquinoline. 212 I-( B-HydroxyethyI)-2-rnethyl12.3.4tetrahydroisoquinolines. 85 N-Hydroxygua nidines. I 4 4 4-Hydroxyisoquinoline. in the Mannich reaction. 194 S-Hydroxyisoquinolinr. Mannich reaction of. 212 7-Hydroxyisoquinoline. Mannich reaction or. 212 S-H ydroxyisoyuinoline-2-oxide. from 5-acctoxyis~uinoline.244 4-Hydroxy-2-rnethylisoquinolinium iodide. 29 I 3-Hydroxymethyl-2-methyl-3.4dihydrwarhostyril. 184 Hydroxy-2-methylisoquinoliniumhalides. pK, values of. 265 3-Hydroxymethyl-2-methyl-1.2.3.4tetrahydroisoquinoline. 184 3-Hydroxy- I-0x0-2-isoindoline acetic acid ethyl ester. ring expansion of. 196 2-Hydroxy-1-(4-pyridyl)isoquinolines. 86 4-Hydroxy- 1.2.3.4-tetra hydroisoquinoline.
-'OH
Imidazol5. I -a lisoquinoline. 3.7 3-(2-lmidazoline-2-yl)isoquinolineI(2H)ones. 1% Indenoisoquinoline. 57 lsatoic anhydrides. 3 10 Isoanhalamine. 331 Isocarhostyril. reaction with methyl vinyl ketone. 175
Index Isoquinoline: catalytic hydrogenation of. 3 I2 hydrogenation of the pyridine ring. 298 oxidation of. 240 reaction with tosyl chloride. 325 lsoquinoline 3-aldeh~de-p-dimethylanil methyl iodide. 196 Isoquinoline-4-carhoxaldehydes.198 3-lsoquinolinecarboxaldehyde. 185 Isoquinoline- I-carboxamide. 6 3-lsoquinolinecarhoximidicacid hydrazide. reaction with vicinyl diketones. 185 lsoquinoline-4-carboxylicacid. reaction with benzylamine. 205 4.8-lsoquinolinediol. 236 deuterium labeling of. 250 S.X-lsoquinolinediol. 236 6.7-lsoquinolinediol. 24 I Isoquinoline-5.8-dione. 244 1(2H)-Isoquinoline oxime. 248 lsoquinolinium pyrimidine salts. from 2-alkyl-4-amino-S-(bromoethyl)pyrimidine. 172 lsoquinolinium salts: dealkylation of. 264 reaction with Grignard reagents. 263 reduction of. with lithium aluminum hydride. 258 4lsoquinolinol. 233.234 coupling of. 246 deuterium labeling of. 249 from demethylation of 4methoxyisoquinoline. 234 hydrogenation of. 314 from isoquinoline. 240 from isoquinoline ?-oxide. 241 nitration of. 244 reaction with phosphoryl chloride. 245 reduction of. with Adams catalyst. 243 5-lsoquinolinol. 236 from S-aminoisoquinoline. 236 nitration of. 247 nitrosation of. 236 7-lsoquinolinol. 236 Mannich reaction of. 247 nitration of. 247 8-lsoquinolinol. 236.238 nitrosation of. 236 Isoquinolinols. 0-alkylation of. 239 1(2H)-lsoquinolinone. 248 0-alkylation of. 238 3(2H)-lsoqu inoli none. 248 0-allylation of. 239 2 4 I-Isoquinolyl)
[email protected])pyrrole. 84
549
14 I -Isoquinolyl)-3-cyano-5-phenylpyrrole. 72 l 2 - ( 1'-lsoquinolyl)ethane. 109 I -( 1 -Isoquinolyl)-2-(pyridyl)ethylenes. 87 3-lsoquinolyl-2-quinuclidylketone, 185
Jones oxidation. 3 18 Kreysigine. 67 Laudanosine. oxidative debenzylation of. 275 Lemaireocereine. 330 Lithiated nitrosamines. in carbon-carbon bond formation. 209 Lodal. 334 Longimammatine. 330 Macrostomine. 209 Malon-di-p-phenethylamide. cyclization of. I08 Mannich reaction. 57.212.250.297 of 4-hydroxyisoquinoline. 194 of 7-isoquinolinol. 247 of 1.2.3.4-tetrahydroisoquinolines, 304 Mercaptopyridine-N-oxide.85 Methallylbenzene. 188 I-Methanesulfonylisoquinoline.reaction with nucleophiles. 329 Methoxyazabullvalene. thermolysis of. 240 I-Methoxyisoquinoline. 240 fluorescence of. 340 hydrolysis of. 248 methyl migration of. 248 3-Methoxyisoquinoline. 236.239.240 4-Methoxyisoquinoline. 239 5-Methoxyisoquinoline. 239 6-Methoxyisoquinoline: from Pomeranz-Fritsch reaction. 231 nitration of. 245 7-Methoxyisoquinoline: from Pomeranz-Fritsch reaction. 231 nitration of. 247 8-Methoxyisoquinoline. 239 from Pomeranz-Fritsch reaction. 23 1 6Methoxyisoquinolinol. 233 6Methoxy-7-isoquinolinol. 229.233 7-Methoxy-8-isoquinolinol. 230.233
8-Methoxy-6.7-methylenedioxyisoquinoline.
23 1 7-Methoxy-8-nitroisoquinoline. 247 8-Methoxy- 1.2.3,4-tetrahydro- I .5iminobenzldlazocino-rl(3H)-one. 5 24a-Methyl-&aminophenethyl)-1.2.3.4tetrahydroisoquinoline. 162 0-Methylandrocymbine. 67
550
Index
N-Methylcoclaurine. oxidation of. 275 I-Methyl-3.4-dihydroisoquinoline. 2.69. I62
I. I '-Methylene-bis(3.4-dihydroisoquinoline). 108 6.7-Meth ylenedioxyisoquinoline. from Pomeranz-Fritsch reaction. 231 6,7-Methylenedioxyisoquinolinol.233
bMethylisatoic anhydride. 161 I-Methylisoquinoline. 9.87 3-Methylisoquinoline methyl iodide. 196 2-Methyl-I(2H)-isoquinoline.248 2-Methylisoquinolinium salts. oxidation of. with potassium ferricyanide. 260 2-Methyl-3(2H)-isoquinolinonr.265 Methyl l-methyl-3.4-dihydrocarhostyril-3carboxylate. reaction with lithium aluminum hydride. 184 a-Methylpapaverinol. fission of. 256 Methylphenyl(1-isoquinoly1)carbinol. X 2-Methyl-J-phenyl-3-( I -piperdyl)-4-( I .2.3.4tetrahydro-2-isoquinolyl~2-hutanol.172 I-Methyl-3-phenyl-5.6.7.8-tetra hydroisochromylium perchlorate. 65 N-Methyl-AI -pyrrolidinium acetate. 209 4-(I-Methyl-2-py~olidinyl)isoquinoline. 209 S-Methylpseudothiourea. I49 reaction with 12.3.4-tctrahydroisoquinoline. 144
0-Methylpscudourea. reaction with 1.2.3.4tetrahydroisoquinoline. 144 0-Methyltarconine: alkyl halides of. 332 chloride. bromination of. 265 iodide. reaction with phenylmagncsium bromide. 263 6Methylthio-3.4-dihydroisoquinoline.3 1 X I-Methylthio-3(4H)-isoquinoline. alkylation of. 320 4-Methylthioisoquinoline.amination of. 32 I 5-Methylthioisoquinoline. 3 18 7-Methylthioisoquinoline.3 18 bMethylthio- 1.2.3.4-tetra hydroisoquinoline. 318 7-Methylth io- 1.2.3.4-tetra h yd ro-4isoquinolinol. 3 I8 Michael reaction. 279 of isoquinolines. 170 of 1.2.3.4-tetrahydroisoquinolines. 30 retro. 269 (+)-Morphinans. 158 Narcotine. 262 oxidative degradation of. 275 quantitative analysis of. 281
Narcotolic acid. reaction with ammonia. 290 Narco~oline.reaction with ammonia. 2% Narcotolinediol. reaction with ammonia. 2% Nicotinoyl chloride hydrochloride. 170 2-(2-Nicotinoyloxyethyl)-1.2.3.4-terra hydroisoquinolines. 170 8-Nitro-3.4-dihydroisoquinolinol.272 I-Nitroisoquinoline, substitution of. 234 5-Nitro-6-mcthoxyisoquinoline. 245 p-Nitrostyrene epoxide. I62 N-Norarmepavinc. electrolysis of. 267 Norcotarnine. 232 hromination of. 272 formation of. 2h6 from i t Cope-typc cyclization o f cotarnone. 267 Nortehuanine. 330
(S)-( + Mkoteine. I58
1.2.3.4.5.6.7.8-Octahydroisoquinoline. 158 ~tahydroisoquinolinols.3 14 I-Oxoaporphine. 57 2-(3-Oxobutyl)-2( IH)-isoquinolone. 175 2-OxohydrobenzolaIquinolizidine.rctroaldol of. 269 I-Phenoxyisoquinolinc. 23X I-Phenyl~-(2-henzamidoethyl)-3.4-dihydroisoquinoline. 212 I-Phcnyl-3.4-dihydro-4-(dimeihylaminophenyl)-6.7-dimethoxyisoquinoline. 206 4-Phenyl-9. I0-dirnethoxy-6.7-dihydrc-2Hpyrimido[4.3-a]isoquinolinc.5 I-Phenyl-h.7-disubstituted- 12.3.4-tetrahydroisoquinolines. alkylation with l.3dihromopropane. I 6 4 3-Phenyl-5-1~-~suhstituied)-1.2.3.4-tctra hydro2-isoquinolyll- I .2.4-oxidiazole hydrochloride. 173 4-Phenylthioisoquinoline. 3 18 Phosphorous pentachloride. 198 Pictet-Spengler reaction. 28.74.82. 83.295. 314.318 modified. 307 3-Piperidinocarbonylisoquinoline.reduction with lithium aluminum hydride. 185 2-(2-Piperidinoethyl)- 1.2.3.4-tetrahydroisoquinolines. 173
3-Piperidinomethylisoquinoline.185 2-(4-Pi~ridylethyl)-3-isoquinolylketone.
reaction with sodium hypobromite. 185
I-(Piperidyl)isoquinolines. 88 I-( I-Piperidyl)- I-[a-(I .2.3A-tetrahydro-2isoquinolyl)~enzyl]acetone.172
isolation of intermediates. 3 7 mtdilication of. 230 of sulfonamidcs. 230 N-Propargyl- 1.2.3.4-tetra hydroisoquinoline. 138 Protoberberincs. 2x3 Pschorr reaction. 55. 56. 57.67 Pyrazinol2. I w I isoquinolines. 3 3-Pyridol. 17 1 2-(4-Pyridyl)-3-(p-anisyl)pyrrolo I2.t-alisoquinoline. 84 I-(Pyridyl)isoquinolincs.74 3-(-1-PyridqI)isoquinolines.197 (3-Pyridyl p 1-isoquinol yl ether. X7 2-(2-Pyridyl methyl )- 1.2.3.4-let ra h yd roisoquinoline. 170 1-~~-(2-~ridyl-~Y-oxide)mercaptoethyij-2methyl- 1.2.3.4-tetra hydroisoquinoline.
n5
4-Pyridyl onime. 86 I 42-PyrroI)- I .2-di h ydroisoquinolines. 7 I I-(1-Pyrrolyl)isoquinolines.from Reissert compounds. 71 Quarternar) spiro salt. of I .2.3.4-tetrahqdroisoquinolinc. 170 Raney nickel. 137.312.314 dehydrogenation catalyst. 233 Reissen compound. 6. 7.52. 71. 84.274 alkaline hydrolysis of. 109 alkylation of. 109 Reissert reaction. 142 Ritter reaction. 188 )-Salutaridine. 158 Schottrn-Baumann reaction. 308 Spirolindan-I. 1'-isoquinolinesl. 67 Styrylisoquinolines. 65 4-(Substituted-aminomethyl)-2-alkyl1.2.3.4tetrahydroisoquinolines.104 I-Substi?uted-3-hromomerhyl-3-methyl-3.~di h) droisoquinoline. 1x8 ?-(rl-Suhstituted thiarole)isoquinolincs. 185 I-Sulrrnylisoquinoline. 234 I-Sulfonylisoquinolinc. substitution of. 234 (-
Tarconine. 290 from 0-methy Itarconinc hydroxide. 290 1.2.3.4-Terra hydro-3-aminoniethylisoquinolines. 183 Tetrahydroherberine. 197 Tetrahydroll.l-dl1 1.4)-henzodiazepine~.37
202 I .2.3.4-Tetrahydro-6.7-dimethoxyisoquinoline. 302 1.2.3.4-Tetrahydro-7.8~imethoxyisoquinolinc. reaction with 36% HBr. 301 1.23.4-Tetrahydro-6.7-dimet hoxy-4isoquinolinol. 297 1.2.3.4-Tetrahydro-7.8-dimet h o x y 4 isoquinolinol, -197.299 I .2.3.4-Tetrahydro-6.7-dimethoxy-8isoquinolinol. 297.299.300 1.2.3.4-Tetrahydro-7.8-dimethoxy4 isoquinolinol. dehydrogenation of. with N-bromosuccinimide. 234 1.2.3.4-Tetrahydro-6.11-dimethoxy-7isoquinolinol. 295 from anhalinine. 300 1.2.3.4-Tetra hydro-2-hydroxyisoquinoline. oxidation of. with mercuric oxide. 305 1.2.3.4-Tetra hydroisoquinolines: acylation of. with isatoic anhydrides. 310
2-alkyl. 185 1%'-alkylation of. 304 N-Boc derivative. alkylation at the I-position. 399 I-carboxymethyl. 272 from catalytic hydrogenation of. 3.4di hydroisoquinolines. 297 M-cyanation of. 304 dehydrogenation of. photochemical. 234 N-formamidation of. 304 N-formylation of. 309 Mannich reaction of. 304 Michael reaction of. 304 N-nitrosation of. 304 oxidation of. 267 photolysis of. 268 quaternary spiro salt of. 170 N-sulfonation of. 300 4-(1.2.3.4-Tetrahydroisoquinoline)-2-hutanone hydrochloride. 173 I 2.3 &Tetra hyd roisoq ui no1ine-2-a rboxam ide hydrohromide. I44 1.2.3.4-Tetra hydro-3-isoquinoline carboxylic acid. 184 I .2.3.4-Tetrahydroisoquinoline-3-carboxylic acid. oxidative decarhoxylation of. 209 1.2.3.4-Tetra hydro-5.8-isoquinolinediol.hlood pressure lowering of. 336 I .2.3.4-Tetra hydro-6.7-isoquinolinediol. 326 2-124 1.2.3.4-Tetra hydroisoquinoline))ethylguanidine sulfate. 149
552
Index
123.4-Tetrahydroisoquinoline hydrochloride.
reaction with paraformaldehyde. I73 2 4 1.23.4-Tetra hydroisoquinoline- I-ylkthylamine. reaction with S-methylpseudothiourea. 149 1,2,3.4-Tetrahydro-4.6.7-isoquinolinetriol. 2% dehydrogenation of, 233 effects on endogenous catecholamine. 337 1.2.3.4-Tetra hydro-2-isoquinolinothanols. reaction with nicotinoyl chloride hydrochloride. 170 Tetrahydroisoquinolinols.0-methylation of. with diazomethane. 301 1.23.4-Tetrahydroisoquinolinols. 2-acctyl. hydrogenation of. 3 16 I.23.4-Tetrahydro-4-isoquinolinol.303 dehydrogenation of. with palladium black. 233 i.2.3.4-Tetrahydro-5-isoquinoIinol.302 1.2.3.4-Tetrahydro-6-isoquinolinol.300 1.2.3.4-Tetrahydro-7-isoquinolinol.300 5.6.7.8-Tetrahydro-Q-isoquinolinol. 243 2-( I .2.3.4-Tetra hydroisoquinolino)-4-rnethyl5-(2-hydroxyethyl)pyrimidine. 172 d./.y-N-( 12.3.4-Tetra hydroisoquinolyl)-ahydrazinobutyric acid, 149
I .2,3.4-Tetrahydro-S-methoxyisoquinoline. 298 1.2.3.4-Tetrahydro-6-methoxyisoquinoline.
29Y 1.2.3.4-Tetrahydro-7-met hoxyisoquinoline. 298.299 1.2.3.4-Tetra hydro-8-me1hoxyisoquinoline. 298.300 1.2.3.4-Tetrahydro-6rnethoxy-7-isoquinolinol. 229.295 1.2.3.4-Tetrahydro-7-methoxy-6-isoquinolinol. 295 12.3.4-Tetrahydro-7-methoxy-8-isoquinolinol.
297.301 I .2.3.4-Tetrahydro-6.7-me~hylenedioxyisoquinoline. 300 1.2.3.4-Tetra hydro-6.7-methylenedioxy4 isoquinolinol. 297
12.3.4-Tetrahydro-6.7-methylenedioxy-8rnethoxyisoquinoline, 300 1.3.4.1 16-Tetrahydro-2H-pyrimido12.1w]isoquinoline. 134 1.2.3.4-Tetra hydro-6.7.8-trimethoxyisoquinoline. 330 partial demethylation of. 300 I.2.3.4-Tetra hydro-5.6.7-trimethoxy-4isoquinolinol. 297 I.2.3,4-Tetrahydro-S.6.8-trimethoxy-4isoquinolinol. 297 (+ )-(S)-l2.3.4-Tetramethoxy-9hydroxyaporphine. 56 4.S.6.7-Tetrarnethoxyisoquinoline. 239 6.6‘.7.7’-Tetramethoxy-3,3’,4.4‘-tetrahydroI. I’bisisoquinoline. I07 1-(2-ThienyI)isoquinolines.72 1(2H)-Thioisoquinolines.methylation on sulfur. 324 bThiomethyl-8.9-dihydro-I3hHisoquinolino~2.1-c]quinazoline. 41 qp-Tosy1oxy)isoquinoline.hydrogenation or. 243 3.5.8-Triacetoxyisoquinoline.241 Triazines. 185 5.6.7-Trimethoxyisoquinoline.233 5.6.7-Trimethoxyisoquinolinol.233 dl-Tuduramine. 55 Ullmann reaction. 37.56. 107.239 Valine dimethylformamidine. 158 4Vinylpyridine. 84 Weheridine. 330
