Advanced Organic Reactions (Lecture notes)
Carmelo J. Rizzo Associate Professor of Chemistry, Vanderbilt University Nas...
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Advanced Organic Reactions (Lecture notes)
Carmelo J. Rizzo Associate Professor of Chemistry, Vanderbilt University Nashville, Tennessee, USA
Source: http://www.vanderbilt.edu/AnS/Chemistry/Rizzo/chem223/chem223.htm
SELECTIVITY SELECTIVITY Science 1983, 219, 245 Chemoselectivity preferential reactivity of one functional group (FG) over another - Chemoselective reduction of C=C over C=O: H2, Pd/C
O
O
- Chemoselective reduction of C=O over C=C: O
OH
NaBH4
O
O
+
NaBH4, CeCl3
OH only
- Epoxidation: MCPBA
+ OH
OH
O
O (2 : 1)
VO(acac)2, tBuOOH OH
OH
O
exclusively
Regioselectivity - Hydration of C=C: 1) B2H6 2) H2O2, NaOH
OH
R
R
OH R 1) Hg(OAc)2, H2O 2) NaBH4
- Friedel-Crafts Reaction: O RCOCl, AlCl3
R
+
R O
O SiMe3
RCOCl, AlCl3
R
OH
1
SELECTIVITY - Diels-Alder Reaction: R
R
O
O
R
+
+ O major O
R
minor O
R
+
+
R
O minor
major O
O
+ O
H
OAc
O
O
H
OAc
O
O
OAc
O
O
OAc
OAc
Raney Ni, H2
+ O
H
SPh
O
O
H
O
O
SPh
H
O
Change in mechanism: SPh PhSH, H+ R
R
R
SPh
PhSH, (PhCO2)2
Stereochemistry: Relative stereochemistry: Stereochemical relationship between two or more stereogenic centers within a molecule
H
H
HO cholesterol
H enantiomers same relative stereochemistry
H OH
syn: on the same side ( cis) anti: on the opposite side (trans) - differences in relative stereochemistry lead to diastereomers. Diastereomers= stereoisomers which are not mirror images; usually have different physical properties
2
SELECTIVITY Absolute Stereochemistry: Absolute stereochemical assignment of each stereocenter (R vs S) Cahn-Ingold-Prelog Convention (sequence rules) - differences in absolute stereochemistry (of all stereocenters within the molecule) leads to enantiomers. - Reactions can "create" stereocenters O Ph
MeMgBr
HO
H
Ph
MeMgBr
CH3 H
H 3C
OH
Ph
H
O
enantiomers (racemic product)
Ph H HO
CH3
Ph
H
MeMgBr
Diastereomeric transition states- not necessarily equal in energy Me
Me
Me
N
O
Ph
Zn
O
CH3 CH3 Zn
Me N
O
O CH3 CH3
H
Zn
H 3C
H
Zn Ph
H 3C
HO Ph
CH3
HO
CH3
H
H
Ph
Diastereoselectivity CH3MgBr Ph
CH3
Ph
CHO
HO
+
CH3
Ph
H
H OH anti
syn
Diastereomers
Cram Model (Cram's Rule): empirical O O M S
R
O
S
M
H 3C Nu
H
CH3MgBr
CH3MgBr
L R
L
favored
H Ph
3
SELECTIVITY
4
Felkin-Ahn Model S O
O M L
R
L
Nu
Nu
M R
S
disfavored
favored
Chelation Control Mode M OR O
O R S
M
HO
OR
CH3MgBr
CH3MgBr
M
S
favored
Nu
M
R
S
OR
R
HO TBSO
O
TBSO
MgBr
relative stereochemical control
H O
H O
OBn
OBn
Stereospecific Stereochemictry of the product is related to the reactant in a mechanistically defined manner; no other stereochemical outcome is mechanistically possible. i.e.; SN2 reaction- inversion of configuration is required Br2
H
H 3C
Br
Br2
H
meso
H CH3
Br
CH3 Br
+
H CH3
Br
CH3 H
Br H
CH3 Br
enantiomers (racemic)
Stereoselective When more than one stereochemical outcome is possible, but one is formed in excess (even if that excess is 100:0). CH3
H2, Pd/C
H H α-pinene O
only isomer O
O
H
H
O
H
+
CH3 H not observed O
O
LDA, CH3I N
O S
N
O
+
S
N
O S
(96 : 4) Diasteromers
Diastereoselective Enantiospecific
OXIDATIONS Oxidations Carey & Sundberg: Chapter 12 problems: 1a,c,e,g,n,o,q; 2a,b,c,f,g,j,k; 5; 9 a,c,d,e,f,l,m,n; 13 Smith: Chapter 3 March: Chapter 19 I. Metal Based Reagents 1. Chromium Reagents 2. Manganese Rgts. 3. Silver 4. Ruthenium 5. other metals II Non-Metal Based Reagents 1. Activated DMSO 2. Peroxides and Peracids 3. Oxygen/ ozone 4. others III. Epoxidations Metal Based Reagents Chromium Reagents - Cr(VI) based - exact stucture depends on solvent and pH - Mechanism: formation of chromate ester intermediate Westheimer et al. Chem Rev. 1949, 45, 419 JACS 1951, 73, 65. HO R2CH-OH
HCrO4
-
R R
H+
Cr
C O
O-
R
O-
O
R
+ HCrO3- +
H+
H + H2O
Jones Reagent (H 2CrO4, H2Cr2O7, K2Cr2O7) J. Chem. Soc. 1946 39 Org. Syn. Col. Vol. V, 1973, 310. - CrO3 + H2O → H2CrO4 (aqueous solution) K2Cr2O7 + K2SO4 - Cr(VI) → Cr(III) (black)
(green)
- 2°- alcohols are oxidized to ketones R2CH-OH
Jones reagent
R
acetone
R
O
- saturated 1° alcohols are oxidized to carboxylic acids. Jones reagent RCH2-OH
acetone
O R
hydration H
HO OH
Jones reagent
R
acetone
H
O R
OH
- Acidic media!! Not a good method for H+ sensitive groups and compounds
5
OXIDATIONS 1) Jones, acetone
SePh OH
6
SePh CO 2CH 3
2) CH2N2
Me 3Si
Me 3Si JACS 1982, 104, 5558
H17C 8
H17C 8
O
O
O
OH Jones acetone
O
O
O
JACS 1975, 97, 2870
O
Collins Oxidation (CrO3•2pyridine) TL 1969, 3363 - CrO3 (anhydrous) + pyridine (anhydrous) → CrO 3•2pyridine↓ - 1° and 2° alcohols are oxidized to aldehydes and ketones in non-aqueous solution (CH 2Cl2) without over-oxidation - Collins reagent can be prepared and isolated or generated in situ. Isolation of the reagent often leads to improved yields. - Useful for the oxidation of H+ sensitive cmpds. - not particularly basic or acidic - must use a large excess of the rgt.
CrO3•(C 5H5N)2 OH ArO
H
CH 2Cl 2
O
O ArO
O
JACS 1969, 91, 44318.
O O
CrO3 catalyzed (1-2 mol % oxidation with NaIO6 (2.5 equiv) as the reozidant in wet aceteonitrile. oxidized primary alcohols to carboxylic acids. Tetrahedron Lett. 1998, 39, 5323. Pyridinium Chlorochromate (PCC, Corey-Suggs Oxidation) TL 1975 2647 Synthesis 1982, 245 (review) CrO3 + 6M HCl + pyridine → pyH+CrO3 Cl- ↓ - Reagent can be used in close to stoichiometric amounts w/ substrate - PCC is slighly acidic but can be buffered w/ NaOAc PCC, CH 2Cl 2 OHC HO
JACS 1977, 99, 3864. O
O O
PCC, CH 2Cl 2 OH
O
CHO TL, 1975, 2647
OXIDATIONS - Oxidative Rearrangements Me
OH Me
PCC, CH 2Cl 2
JOC 1977, 42, 682 O
Me
Me PCC, CH 2Cl 2
JOC 1976, 41, 380
OH
O
- Oxidation of Active Methylene Groups PCC, CH 2Cl 2 O
O
O
JOC 1984, 49, 1647
PCC, CH 2Cl 2 O
O O
- PCC/Pyrazole PCC/ 3,5-Dimethylpyrazole JOC 1984, 49, 550. NH
NH
N
N
- selective oxidation of allylic alcohols OH OH PCC, CH 2Cl 2 H
3,5-dimethyl pyrazole
H
HO
H O
H (87%)
Pyridinium Dichromate (PDC, Corey-Schmidt Oxidation) TL 1979, 399 - Na2Cr2O7•2H2O + HCl + pyridine → (C5H5N)2CrO7 ↓ PDC
PDC CHO
CH 2Cl 2
OH
DMF
1° alcohol
-allylic alcohols are oxidized to α,β-unsaturated aldehydes
CO 2H
7
OXIDATIONS - Supported Reagents Comprehensive Organic Synthesis 1991, 7, 839. PCC on alumina : Synthesis 1980, 223. - improved yields due to simplified work-up. PCC on polyvinylpyridine : JOC, 1978, 43, 2618. CH 2 CH cross-link N
CH 2 CH
R2CH-OH
R2C=O
CH 2 CH
CrO3, HCl N
N Cr(III)
N Cr(VI)O3 •HCl
8
partially spent reagent
to remove Cr(III) 1) HCl wash 2) KOH wash 3) H2O wash
CrO3/Et2O/CH2Cl2/Celite Synthesis 1979, 815. - CrO3 in non-aqueous media does not oxidized alcohols - CrO3 in 1:3 Et2O/CH2Cl2/celite will oxidized alcohols to ketone and aldehydes C 8H17
C 8H17 CrO3 Et2O/CH 2Cl 2/celite (69%)
HO
Synthesis 1979, 815
O
H2CrO7 on Silica - 10% CrO3 to SiO2 - 2-3g H2CrO3/SiO2 to mole of R-OH - ether is the solvent of choice Manganese Reagents Potassium Permanganate KMnO4/18-Crown-6 JACS 1972 94, 4024.
(purple benzene)
O O
O K+
O
MnO 4O
O
- 1° alcohols and aldehydes are oxidized to carboxylic acids - 1:1 dicyclohexyl-18-C-6 and KMnO4 in benzene at 25°C gives a clear purple solution as high as 0.06M in KMnO4. O JACS 1972, 94, 4024 CO 2H CHO Synthesis 1984, 43 CL 1979, 443 CHO
OXIDATIONS
9
Sodium Permanganate TL 1981, 1655 - heterogeneous reaction in benzene - 1° alcohols are oxidized to acids - 2° alcohols are oxidized to ketones - multiple bonds are not oxidized Barium Permanganate (BaMnO4) TL 1978, 839. - Oxidation if 1° and 2° alcohols to aldehydes and ketones- No over oxidation - Multiple bonds are not oxidized - similar in reactivity to MnO2 Barium Manganate BCSJ 1983, 56, 914 Manganese Dioxide Review: Synthesis 1976, 65, 133 - Selective oxidation of α,β-unsatutrated (allylic, benzylic, acetylenic) alcohols. - Activity of MnO2 depends on method of preparation and choice of solvent - cis & trans allylic alcohols are oxidized at the same rate without isomerization of the double bond. OH
OH
HO
HO MnO 2, CHCl3
J. Chem. Soc. 1953, 2189 JACS 1955, 77, 4145.
(62%) O
HO
- oxidation of 1° allylic alcohols to α,β-unsaturated esters OH
MnO2, ROH, NaCN CO 2R
OH
CO 2Me
JACS1968, 90, 5616. 5618
MnO 2, Hexanes MeOH, NaCN
Manganese (III) Acetate α-hydroxylation of enones Synthesis 1990, 1119 TL 1984 25, 5839 O
O Mn(OAc)3, AcOH
AcO
Ruthenium Reagents Ruthenium Tetroxide - effective for the conversion of 1° alcohols to RCO2H and 2° alcohols to ketones - oxidizes multiple bonds and 1,2-diols.
OXIDATIONS Ph
OH O
H
O JOC 1981, 46, 3936
RuO4, NaIO4
OH CH 3
CO 2H
Ph
CCl 4, H2O, CH3CN
OH Ph
RuO4, NaIO4
10
Ph
CCl 4, H2O, CH3CN
CO 2H
H
96% ee
CH 3
94%ee
HO RuO2, NaIO4
O TL 1970, 4003
CCl 4, H2O
O
O
O
O
Tetra-n-propylammonium Perruthenate (TPAP, nPr4N+ RuO4-) Aldrichimica Acta 1990, 23, 13. Synthesis 1994, 639 - mild oxidation of alcohols to ketones and aldehydes without over oxidation OH
O TPAP MeO 2C
MeO 2C
OSiMe 2tBu
OSiMe 2tBu
O N+ -O Me
TL 1989, 30, 433
(Ph3P)4RuO2Cl3 RuO2(bipy)Cl2 - oxidizes a wide range of 1°- and 2°-alcohols to aldehydes and ketones without oxidation of multiple bonds. OH
CHO CHO OH
JCS P1 1984, 681.
H
H
Ba[Ru(OH)2O3] -oxidizes only the most reactive alcohols (benzylic and allylic) (Ph3P)3RuCl2 + Me3SiO-OSiMe3 - oxidation of benzylic and allylic alcohols TL 1983, 24, 2185. Silver Reagents Ag2CO3 ( Fetizon Oxidation) also Ag2CO3/celite - oxidation of only the most reactive hydroxyl O OH
Synthesis 1979, 401 O
Ag 2CO 3
O
OH
OH O
O
OH
O
OH
Ag 2CO 3, C 6H6
O O O
JACS 1981, 103, 1864. mechanism: TL 1972, 4445.
OXIDATIONS - Oxidation of 2° alcohol over a 1° alcohol OH
OH
Ag2CO3, Celite
OH
JCS,CC 1969, 1102
(80%)
O
Silver Oxide (AgO2) - mild oxidation of aldehyde to carboxylic acids AgO 2, NaOH RCHO
CHO
RCO 2H CO 2H
AgO 2
JACS 1982, 104, 5557 Ph Ph
Prevost Reaction Ag(PhCO2)2, I2 Ag(PhCO 2)2, I2
AcO
OAc
AcOH
AcO
Ag(PhCO 2)2, I2
OH
AcOH, H 2O
Other Metal Based Oxidations Osmium Tetroxide OsO 4 review: Chem. Rev. 1980, 80, 187. -cis hydroxylation of olefins old mechanism: O
OH
Os O O
OH
O
OsO 4, NMO
osmate ester intermediate
cis stereochemistry
- use of R 3N-O as a reoxidant TL 1976, 1973. OsO 4, NMO
O O
O
OH
O
OH
OH OH
TL 1983, 24, 2943, 3947 Stereoselectivity:
OsO 4 R3
R2 RO
H
R4
OsO 4, NMO
HO H R2 HO R3 RO H R4
11
OXIDATIONS - new mechanism: reaction is accelerated in the presences of an 3° amine R1
R1
O
O O
R2
Os O
O
[2+2]
R3N
R1 R2
O Os
O
12
O
Os O
O
O
R2
O NR3
[O] [3+2]
OsO2
R1 O O
R2
O
[O] hydrolysis
R1
Os O
R2
+
O
HO
OH
OsO4
- Oxidative cleavage of olefins to carboxylic acids. JOC 1956, 21, 478. - Oxidative cleavage of olefins to ketones & aldehydes. OH CHO CHO
OH OsO 4, NMO
O
O
NaIO4
OH
O
H2O
O O
O
O
O
O
OAc
O
OAc
OAc
JACS 1984, 105, 6755.
Substrate directed hydroxylations: -by hydroxyl groups
Chem. Rev. 1993, 93, 1307 HO
OsO4, pyridine
O
HO
HO O
HO
+
O
HO HO
HO 3:1 HO
OsO4, pyridine
O
HO O
TMSO TMSO
HO
CH3
HO
CH3 OH
OsO4, Et2O
HO OH
CH3
CH3
+
OH CH3
(86 : 14)
- by amides AcO
AcO OH
MeS
OsO4
MeS OH
HN
O OAc
CH3 OH
HN
O OAc
OXIDATIONS - by sulfoxides ••
••
OMe
O
OsO4
S
OMe OH
O S
OH 1) OsO4 2) Ac2O
S HN
OAc
(2 : 1)
••
••
O
13
O S
O
AcO
O
HN
(20 : 1)
- by sulfoximines O Ph S
O Ph S
OH
MeN
MeN
OsO4, R3NO
O
OH ∆
OH
OH OH
OH CH3 Raney nickel H 3C
OH OH OH CH3
- By nitro groups PhO2S
PhO2S
1) OsO4
N NHR
N
+
2) acetone, H
N NHR
N O2N
O2N
N N
N
O
N
O N
N HO
HO
NHR
N
NHR
N
N N
N
O
N
O
- OsO4 bis-hydroxylation favors electon rich C=C. OsO4 X
OH OH
X
+ OH OH
X= OH = OMe = OAc = NHSO2R
- Ligand effect:
80 : 20 98 : 2 99 : 1 60 : 40
OsO4 OH
K3Fe(CN)6, K2CO3 MeSO2NH2, tBuOH/H2O
OH OH
OsO4 (no ligand) Quinuclidine DHQD-PHAL
X
4:1 9:1 > 49 : 1
+
X
(directing effect ?) (directing effect ?)
OH OH
OH
OXIDATIONS Chem. Rev. 1994, 94, 2483.
Sharpless Asymmetric Dihydroxylation (AD) - Ligand pair are really diastereomers!!
14
dihydroquinidine ester
N "HO
Ar
OH"
H
H R3
OR'
R2
R3 OH
0.2-0.4% OsO4
R2
R1
acetone, H 2O, MNO
80-95 % yield 20-80 % ee
OH
R1 H OR' "HO
Ar
OH"
MeO Ar =
N
dihydroquinine ester
N R'= p-chlorobenzoyl
Mechanism of AD: L HO
OH
O O H 2O
O
O
Os
O
O O O
First Cycle (high enantioselectivity)
O
Os
O O
Second Cycle (low enantioselectivity)
[O]
[O]
O O
Os
O
O
L
Os O
L
O O
O O
Os
O
O O
O R 3N
HO
OH H 2O, L
- K3Fe(CN)6 as a reoxidant gives higher ee's- eliminates second cycle TL 1990, 31, 2999. - Sulfonamide effect: addition of MeSO2NH2 enhances hydrolysis of Os(VI) glycolate (accelerates reaction) - New phthalazine (PHAL) ligand's give higher ee's N
Et Et O
H
Et
N
N N
N N
O
H
O
H
OMe
MeO
O
H
MeO N
OMe
N N
N (DHQ)2-PHAL
(DHQD)2-PHAL JOC 1992, 57, 2768.
Et
N N
OXIDATIONS
15
- Other second generation ligands N
Et Et O
H MeO
Et N
Ph O
N
N
H
N
OMe
Ph
N
N O
H
O
OMe
N
N
PYR
IND
Proposed catalyst structure: O
H
O O
Os
N
MeO
N
Os
"Bystander quinoline (side wall)
Asymmetric Binding Cleft
O
N H
H
N
N
O
N
N
N
O
Phthalazine Floor
OMe
OMe
OMe O
Corey Model: JACS 1996, 118, 319 Enzyme like binding pocket; [3+2] addition of OsO4 to olefin.
N
O O
Os O N O
O
N
H
N N O
O
N
DHQL
Rs
RM
RL
H
DHQ
RL large and flat, i.e Aromatics work particularly well
OXIDATIONS Olefin
Preferred Ligand
ee's
PYR, PHAL
30 - 97 %
PHAL
70 - 97 %
IND
20 - 80 %
PHAL
90 - 99.8 %
PHAL
90 - 99 %
PHAL, PYR + MeSO2NH2
20 - 97 %
R1 R2 R1
R1 R2
R2
R1
R2 R3
R1 H R2
R3
R1 R4
"AD-mixes" commercially available pre-mix solutions of Os, ligand and reoxidant AD-mix α (DHQ)2PHAL, K 3Fe(CN)6, K2CO3, K2OsO4 (0.4 MOL % Os to C=C) AD-mix β (DHQD)2PHAL, K 3Fe(CN)6, K2CO3, K2OsO4 O HO O Campthothecin
N N O OMe N
OMe
OMe AD (DHQD)2PYR
O
N
N
O
94 % ee
O O
OH OH
OH
- Kinetic resolution (not as good as Sharpless asymmetric epoxidation) H Ph tBu
Ph H tBu
H Ph
H Ph
AD mix α 30% conversion
Ph H
OH OH tBu
tBu
olefins with axial dissymmetry
H
Ph
+
OH OH
+
tBu (4 : 1)
tBu enriched
16
OXIDATIONS 17 Asymmetric Aminohydroxylation TL 1998, 39, 2507; ACIEE 1996, 25, 2818, 2813, preparation of α-aminoalcohols from olefin. Syn addition as with the dihydroxylation regiochemistry can be a problem O Ph
O
N Na
CO2Me
Ph
O
OH
Cl Ph
O
NH
+ CO2Me
Ph
K2OsO6H4 (cat) Ligand
CO2Me
Ph N
OH
O
Ph
O
Ligand= PHAL AQN
4:1 1:4
Molybdenum Reagents MoOPH [MoO5•pyridine (HMPA)] JOC 1978, 43, 188. - α-hydroxylation of ketone, ester and lactone enolates. O
OR'
R
O
+
Mo O L
R
O
H R
R
Pd(OAc) 2, CH 3CN, 80° C
HO
H R
O
H R
- CO 2
O
O Pd
-
TL 1984, 25, 2791 Tetrahedron 1987, 43, 3903
O
OH
2
HO
CO
H OH JACS 1989, 111, 8039.
Pd2(DBA) 3•CHCl 3, CH 3CN, 80° C
OH
O
R
R
Pd(0) O
H
H
(Tsuji Oxidation)
O
O 2 CO
OH
R' OH
L
Palladium Reagents Pd(0) catalyzed Dehydrogenation (oxidation) of Allyl Carbonates Tetrahedron 1986, 42, 4361 R
O
THF, -78°C
O
H
O
O
Oxidation of silylenol ethers and enol carbonates to enones O
OTMS
Pd(OAc) 2, CH 3CN
O
O O
OTIPS Ph
O
Pd(OAc) 2, CH 3CN
(NH 4)2Ce(NO 3)6 DMF, 0°C
O
O Ph
TL 1995, 36, 3985
R
Oppenauer Oxidation
OXIDATIONS Organic reactions 1951, 6, 207
Synthesis 1994, 1007 OiPr +O Al
R1R2CHOH (CH3)2C=O
OiPr
OiPr +O Al O OiPr
H R1
R2
O R1
18
+ Al(OiPr)3 R2
Nickel Peroxide Chem Rev. 1975, 75, 491 Thallium Nitrate (TNN, Tl(NO 3)3•3H2O Pure Appl. Chem. 1875, 43, 463. Lead Tetraacetrate Pb(OAc)4 Oxidations in Organic Chemistry (D), 1982, pp 1-145. Non-Metal Based Reagents Activated DMSO Review: Synthesis 1981, 165; 1990, 857. Me
Me S+
S+
+ E
O-
Me
E
O
Organic Reactions 1990, 39, 297
Nu:
Nu
S
Me
Me
+
+ E-O Me
E= (CF3CO)2O, SOCl2, (COCl)2, Cl2, (CH3CO)2O, TsCl, MeCl, SO3/pyridine, F 3CSO2H, PO5, H3PO4, Br2 Nu:= R-OH, Ph-OH, R-NH2, RC=NOH, enols Swern Oxidation - trifluoroacetic anhydride can be used as the activating agent for DMSO O Me
Me
(COCl) 2
S + O-
CH 2Cl 2, -78°C
Me
R2CH-OH Me Me
Me
-CO, -CO 2
Cl -
Me S + Cl Me
O
R R
S+ O
Cl
S+ O
Et3N:
Me
R
S
+
O
Me
R
H B:
O Cl
O
DMSO, (COCl) 2 OH
Moffatt Oxidation (DMSO/DCC)
O
JACS 1965, 87, 5661, 5670.
Me
C 6H11
S + O-
CF 3CO 2H, Pyridine
Me + C 6H11 N C
TL 1988, 29, 49.
CH 2Cl 2, Et3N
N C 6H11
OH CO 2Me O
Me
NH S
+
O C
R2CH-OH
Me
R O
H
R B:
C 6H11 CHO DCC/ DMSO CO 2Me
CF 3CO 2H, Pyridine
JACS 1978, 100, 5565
O
S
SO3/Pyridine
S+ O
N
Me
R R
Me
S
JACS 1967, 89, 5505. CO 2Me HO
H
CONH 2 H
HO
OH
OH
CO 2Me H
SO 3, pyridine, DMSO, CH 2Cl 2
CONH 2 H HO
O
JACS 1989, 111, 8039.
OXIDATIONS Corey-Kim Oxidation
(DMS/NCS)
19
JACS 1972, 94, 7586. O
Me
Me S:
+
S + Cl
N Cl
Me
Me O N-Chlorosuccinimide (NCS)
Acc. Chem. Res. 1980, 13, 419
••
••
••
O O
singlet
"ene" reaction
H O
Tetrahedron 1981, 37, 1825
hν
•• •• •O O • •• •• triplet
••
Oxygen & Ozone Singlet Oxygen
Ph3P:
H
O
O
O
OH Tetrahedron 1981, 1825
1) O2, hν, Ph2CO 2) reduction
Ozone
HO
Comprehensive Organic Synthesis 1991, 7, 541 O
O 3, CH 2Cl 2
O
O
-78°C
O
Ph3P:
O O
NaBH 4
+
O
O
H Jones
OH
RCOOH
Other Oxidations Mukaiyama Oxidation
BCSJ 1977, 50, 2773 O R
PrMgBr CH OH
R
N
R
N
N
N R
O
CH O MgBr
O
R
THF
R
OH Cl MeO
CH 3
O
O
NH
O O SEt SEt MeO
N
Cl
O N N
N
O
MeO
CH 3
OHC O
NH
OEt
O tBuMgBr, THF (70%)
SEt SEt MeO JACS 1979, 101, 7104
OEt
OXIDATIONS
20
O
OH
tBuMgBr, THF O N
N
N
N O
O
O
Dess-Martin Periodinane JOC 1983, 48, 4155. - oxidation conducted in CHCl3, CH3CN or CH2Cl2 - excellent reagent for hindered alcohols - very mild
JACS 1992, 113, 7277.
OAc
OAc
AcO
••
I
O
OAc
R
R2CH-OH
I O
+
+ 2 AcOH
O
R O
O
HO
Dess-Martin
O JOC 1991, 56, 6264
(99%) RO
RO
Chlorite Ion -oxidation of α,β-unsaturated aldehydes to α,β−unsaturated acids. Tetrahedron 1981, 37, 2091 NaClO 2, NaH2PO 4 OBn
- HClO2 OBn
OBn OH H
tBuOH, H 2O
CHO
CO 2H
-O-Cl-O
Selenium Dioxide - Similar to singlet oxygen (allylic oxidation) 1) SeO2 2) NaBH 4
OAc
OAc OH
Phenyl Selenium Chloride O
OLi PhSeCl
O SePh
H2O 2
Ph Se O-
THF
O - PhSeOH
H
- PhS-SPh will do similar chemistry however a sulfoxide elimination is less facile than a selenoxide elinimation. Peroxides & Peracids - R3N: → R3N-O - sulfides → sulfoxides → sulfones -Baeyer-Villiger Oxidation- oxidation of ketones to esters and lactones via oxygen insertion Organic Reactions 1993, 43, 251 Comprehensive Organic Synthesis 1991, vol 7, 671.
OXIDATIONS
21
m-Chloroperbenzoic Acid, Peracetic Acid, Hydrogen peroxide O
O
H O
O 2N
O
O
O
H
O R1
R2
O O
HO
O
NO 2
Cl
R1
H
Ar
O
C R2 O
R1
O
+
R2
ArCO2H
Ar
O O
- Concerted R-migration and O-O bond breaking. No loss of stereochemistry - Migratory aptitude roughly follows the ability of the group to stabilize positive charge: 3° > 2° > benzyl = phenyl > 1° >> methyl JACS 1971, 93, 1491 O
O mCPBA
O
HO
O CO2H
O
CHO O
HO
O
O
CO2H
HO
OH PGE1
O O CH3
O
mCPBA
Tetrahedron Lett. 1977, 2173 Tetrahedron Lett. 1978, 1385
CH3
(80 %) CH3
CH3
Oxone (postassium peroxymonosulfate)
Tetrahedron 1997, 54, 401
oxone
RCHO
RCOOH
acetone (aq)
Oxaziridines reviews: Tetrahedron 1989, 45, 5703; Chem. Rev. 1992, 92, 919 O N C R
R3 R2
- hydroxylation of enolates O R
O
Base
R
R'
O
_ R R'
O O
PhSO2 O R
Ph
N
R
R'
+ PhSO2N=CHPh
HO Ph O
_ R'
O
R' _ NSO2Ph
R
+ PhSO2N=CHPh Ph
R' NHSO2Ph
By-product supresed by using bulkier oxaziradine such as camphor oxaziradine
OXIDATIONS
22
Asymmetric hydroxylations O
O NaN(SiMe3)2, THF
MeO 2C
HO Tetrahedron 1991, 47, 173
MeO 2C OMe
OMe N Ar
MeO
O
SO 2 O MeO
KN(SiMe3)2
CO2Me
(67% ee) O
O
OH CO2Me
OH
O OH OH
N SO2 O
MeO
MeO
MeO
O
OH
OH
(>95% ee)
- hydroxylation of organometallics R-Li or R-Mg → R-OH
JACS 1979, 101, 1044
- Asymmetric oxidation of sulfides to chiral sulfoxides. JACS 1987, 109, 3370. Synlett, 1990, 643. Remote Oxidation (functionalization) Barton Reaction
Comprehensive Organic Synthesis 1991, 7, 39.
NOCl, CH2Cl2 pyridine OH
hν O
NO
- NO •
O •
OH
H
•
•NO
JACS 1975, 97, 430 OH
OH
NO
N
N ketone oxidation state
HO
C5H11
perhydrohistricotoxin
Epoxidations Peroxides & Peracids - olefins → epoxides Tetrahedron 1976, 32, 2855 - α,β-unsaturated ketones, aldehydes and ester → α,β-epoxy- ketones, aldehydes and esters (under basic conditions). O
(CH 2)n
tBuOOH triton B, C6H6
O
O (CH 2)n
JACS 1958, 80, 3845
OXIDATIONS O CO 2Me
CO 2Me mCPBA, NaHPO3
TL 1988, 23, 2793 O
O
H
H O
O
Henbest Epoxidation- epoxidation directed by a polar group OH
OH
OH mCPBA
+
O
OAc
O
10:1 diastereoselection OH
OAc mCPBA
+
O
O
1:4 diastereoselection O Ph
O NH
Ph
NH "highly selective"
mCPBA O
Ar O H H
O proposed transition state: -OH directs the epoxidation
O
O H
- for acyclic systems, the Henbest epoxidation is often less selective Rubottom Oxidation:
JOC 1978, 43, 1588
O
OTMS LDA, TMSCl
TMSO mCPBA
O
H2O
O OH
Sharpless Epoxidation tBuOOH w/ VO(acac)2, Mo(CO)6 or Ti(OR) 4 Reviews: Comprehensive Organic Synthesis 1991, vol 7, 389-438 Asymmetric Synthesis 1985, vol. 15, 247-308 Synthesis, 1986, 89. Org. React. 1996, 48, 1-299. Aldrichimica Acta 1979, 12, 63 review on transition mediated epoxidations: Chem. Rev. 1989, 89, 431. - Regioselective epoxidation of allylic and homo-allylic alcohols - will not epoxidize isolated double bonds - epoxidation occurs stereoselectively w/ respect to the alcohol.
23
OXIDATIONS - Catalysts: VO(acac)2; Mo(CO)6; Ti(OiPr)4 - Oxidant: tBuOOH; PhC(CH3)2OOH
VO(acac)2 tBuOOH
OH
OH
O
OH
OH
(CH2)n
O
(CH2)n
ring size 5 6 7 8 9
VO(acac)2 >99% >99 >99 97 91
MoO2(acac)2 -98 95 42 3
mCPBA 84 95 61 <1 <1
Acyclic Systems: L
M
1,3-interaction
O
R3 A1,2-strain
tBu
O O
R1 R3
L
Rc
Rt
R1
Rt
R2
Rc
O
O M
R2
L
A1,3-strain
Major influences: A1,2-Strain between Rg and R1 A1,3 -strain between R2 and Rc 1,3-interactions between L and R1
O L
(Rg and R2) (R1 and Rc) (L and R2)
VO(acac)2, tBuOOH O OH
+
O
OH
OH
(4 : 1)
tBu
CH3
H
O
L M
H H L
O
O
M
L O
O
L
tBu
O
H 3C H
H H
24
OXIDATIONS VO(acac)2, tBuOOH O OH
+
O
OH
OH
(19 : 1)
tBu L H 3C H
H
H 3C
O
H
M L
H O
O
O
H 3C
H
O
M
L
L
H
O
tBu
CH3 SiMe3
SiMe3
VO(acac)2, tBuOOH
O OH
SiMe3
+ OH
O
OH
(> 99 : 1)
- Careful conformational analysis of acyclic systems is needed. Homoallylic Systems L L O
O OH
V
OtBu
O
OH
dominent stereocontrol element
Titanium Catalyst structure: RO2C OR Ti
CO2R O
O
O
RO
O
OR O
Ti
OR OR
O OR CO2R O
OR Ti
CO2R O
O
O
RO
O
OR O CO2R
Ti O
RO Ti O
O
CO2R O
CO2R O
O
tBu OR
Disfavored
O O
tBu OR
Ti
O
Favored
O CO2R
25
OXIDATIONS
26
Asymmetric Epoxidation tBuOOH, Ti(OiPr), (+) or (-) Diethyl Tartrate, 3Å molecular sieves Empirical Rule R1
(+)- DET epoxidation from the bottom (-)- DET epoxidation from the top
R2
R3
OH
Catalytic system: addition of molecular sieves to "soak" up any water with 3A sieves, 5-10 mol % catalyst is used. Preparation of Allylic Alcohols: R
CO2R'
[(CH3)2CHCH2]2AlH
Na (MeOCH2CH2O)2AlH2
R
(DIBAL)
OH
(REDAL)
R CHO
R C C CH2OH R CO2R'
R
[(CH3)2CHCH2]2AlH
H2, Lindlar's Catalyst
OH
"In situ" derivatization of water soluble epoxy-alcohol (-)-DIPT
O
OH
(R)-glycidol OH
water soluble O (+)-DIPT
O
O OH
OH
(S)-glycidol O O S
NO2
organic soluble
O
Alkoxide opening of epoxy-alcohol product reduced by use of Ti(OtBu)4 and catalytic conditions OO R
OH
O OH OH
from Ti(OiPr)4
R
Stoicheometric vs Catalytic epoxidation: (+)-DET Ti(OiPr)4 tBuOOH
O
OH
stoicheometric: catalytic (6-7 mol %) in situ deriv. with PNB
OH
85% ee 47% yield >95% ee 78% yield 92 % ee >98 %ee after 1 recrystallization (+)-DET Ti(OiPr)4 tBuOOH
R
R
OH
yields: 50 - 100 % ee: > 95%
O
OH
OXIDATIONS Ring Opening of Epoxy-Alcohols OH
REDAL R O
AE R
OH
OH 1,3-Diol
R
OH
DIBAL
R
OH OH 1,2-Diol
Two dimensional amplification OH
OH
OH
(+)-DIPT, Ti(OiPr)4, tBuOOH, 3A sieves
+
(90 % ee) O OH
O
OH
95 : 5
major major
O
O
minor minor
major
minor
95 : 5
95 : 5
OH
OH
O
O
OH
90 % (>99.5 % ee)
OH O
O
OH
meso 9.75%
(+)-DIPT, Ti(OiPr)4, tBuOOH, 3A sieves
OH
R
+
R
OR Ti
CO2R O
O
O
RO
O
O tBu
OR
H
Ti O
O R
CO2R O
OH
0.25 %
Kinetic Resolution of Allylic Alcohols OH
OH
O CO2R
OH
27
OXIDATIONS R3
R4
R3
kinetic resolution -20 °C, 0.5 - 6 days OH
R2
R4
R4 O
+
OH
R2
R1
R3 R2
R1
OH
R1
40 - 50 % yield > 99 % ee
40 - 50 % yield high ee
Reiterative Approach to the Synthesis of Carbohydrate OR OR
OR
(+)-DET, Ti(OiPr)4, tBuOOH, 3A sieves
DIBAL
(MeO)2P(O)CH2CO2Me NaH
CHO
OH
CO2Me OR
OR
HOO OH
PhS
OR OH
OR OH
acetone, H+
O
mCPBA, Ac2O
O
-
HO
Pummerer
O SPh
SPh
PhS-
O O
O
O
DIBAL OAc
CHO
OR
OR
OR
O
O
O
CHO
HO
H
HO
H
HO
H
HO
SPh
O
CHO
H CH2OH L-glucose
Jacobsen Aysmmetric Epoxidation JACS 1990, 112, 2801; JACS 1991, 113, 7063; JOC 1991, 56, 2296. - Reaction works best for cis C=C conjugated to an aromatic ring H
H
H N
N
H N
NaOCl
Mn
Mn O
O Cl O tBu
O
O
tBu
tBu
O
N
5 mol % Cat. ,NaOCl, H2O, CH2Cl2
tBu
O (98% ee)
O
86% ee O
Methyltrioxoruthenium (MTO) Ru(VII) Sharpless et al. JACS 1997, 117, 7863, 11536. Ph
0.5 mol % MTO Ru (VII), pyridine, CH2Cl2 1.5 eq. 30% H2O2 (aq.)
Ph O
28
OXIDATIONS Oxaziridines - Asymmetric epoxidation of olefins
29
Tetrahedron 1989 45 5703 CH3
Ph
O2 O N S N
*
(Murray's Reagent)
C6F5
*
Ph
Dioxiranes
*
Reviews: Chem. Rev. 1989, 89, 1187; ACR 1989, 27, 205 Org. Syn. 1996, 74, 91 O
KHSO 5
O
"oxone"
O
- epoxidation of olefins O
OTBS TBSO TBSO
-
OTBS
O
O
O
TBSO TBSO
CH 2Cl 2, acetone (100%)
JOC 1990, 55, 2411 O
Asymmetric epoxidation JACS 1996, 118, 491. oxidation of sulfides to sulfoxides and sulfones oxidation of amines to amine-N-oxides oxidation of aldehydes to carboxylic acids hydroxylation of enolates 1) LDA 2) Cp 2TiCl2 3)
O
OH H
O
JOC 1994, 59, 2358
O
O
- bis-trifluoromethyldioxirane, much more reactive JACS 1991, 113, 2205. F3C
O
F3C
O
- oxidation of alcohols to carbonyl compounds. 1° alcohols give a mixture of aldehydes and carboxylic acids. - Insertion into 3° C-H bonds to give R3C-OH DCC-H2O2
JOC 1998, 63, 2564 R R N C N R
H2O2, MeOH
H
N R
N C
H O
O
O
O
R R
+ H
N R
C
N R
H
REDUCTIONS Carey & Sundberg Chapter 5 problems: 1a,b,c,d,f,h,j; 2; 3a-g, n,o; 4b,j,k,l; 9; 11; Smith: Chapter 4 March: Chapter 19
30
Reductions 1. Hydrogenation 2. Boron Reagents 3. Aluminium Reagents 4. Tin Hydrides 5. Silanes 6. Dissolving Metal Reductions Hydrogenations Heterogeneous Catalytic Hydrogenation Transition metals absorbed onto a solid support metal: Pd, Pt, Ni, Rh support: Carbon, alumina, silica solvent: EtOH, EtOAc, Et2O, hexanes, etc. -
Reduction of olefins & acetylenes to saturated hydrocarbons. Sensitive to steric effects and choice of solvent Polar functional groups, i.e. hydroxyls, can sometimes direct the delivery of H2. Cis addition of H2. R1
R1
R2
R2
H
H2, Pd/C R1
H
R2
R1 R2
- Catalyst can be "poisoned" - Directed heterogeneous hydrogenation O
O
H
H2, Pd/C O
O
OH
MeO
O
OH
MeO H2, Pd/C
H
O
O
CO2Me
MeO
O
CO2M2 (86 : 14)
MeO
Lindlar Catalyst ( Pd/ BaSO4/ quinoline)- partially poisoned to reduce activity; will only reduce the most reactive functional groups. acetylenes + H2, Pd/BaSO4/ quinoline → cis olefins Acid Chlorides + H2, Pd/BaSO4 → Aldehydes
R
SiMe 3
(Lindlar Reduction) (Rosemund Reduction) Org. Rxn. 1948, 4, 362
H2, Pd/BaSO4, Quinoline
SiMe 3 TL 1976, 1539 R O
O H2, Pd/BaSO4, pyridine CO 2Me
CO 2Me
JOC 1982, 47, 4254
REDUCTIONS HO
OH
H2, Lindlar Catalyst CH 2Cl 2: MeOH: Quinoline (90:9.5:0.5)
8π e-
JACS 1982, 104, 5555 6π edisrotatory
conrotatory
HO
OH
HO
H H HO
OH
H
OH
Ease of Reduction: (taken from H.O. House Modern Synthetic Reactions, 2nd edition) R COCl
R CHO
R NO 2
R NH 2
R
R'
R
R CH 2-OH
R CHO R CH CH
R CH 2 CH 2 R'
R'
O R
HO H R'
Ar
R'
R
O
R
R'
Ar
CH 3
+
HO R
R CH 2 NH 2
R C N
O R CH 2-OH R
+
HO R'
OR' O R'
R
R
N
CH 2
R' N R'
R'
requires high temperature & pressure
R CO 2- Na+
no reaction
Raney Nickel Desulfuriztion , Reviews: Org. Rxn. 1962, 12, 356; Chem. Rev. 1962, 62, 347. R
R S
R
Raney Nickel
R
H
R
H
(CH 2)n
O R S
31
REDUCTIONS O O
O
O O
HO
32
O
HO Raney Nickel JOC 1987, 52, 3346
EtOH (74%)
H
S
H
S
Homogeneous Catalytic Hydrogenation - catalyst is soluble in the reaction medium - catalyst not "poisoned" by sulfur - very sensitive to steric effects - terminal olefins faster than internal; cis olefins faster than trans R
R
>
>
R
R
R
R
>
R
R
R
>
R
R
>>
R
R R
- (Ph3P)3RhCl (Wilkinson's Catalyst); [R3P Ir(COD)py]+ PF6- (Crabtree's Catalyst) (Ph3P)3RhCl, H2
OH
OH
JOC 1992, 57, 2767
C 6H6 (92%)
Directed Hydrogenation Review: Angew. Chem. Int. Ed. Engl. 1987, 26 , 190 - Diasterocontrolled hydrogenation of allylic alcohols directed by the -OH group -
+
O K
O- K+
PPh3 O PPh3 Rh H H
(Ph3P)3RhCl, H2
H MeO
MeO
Ph Ph P Rh+ P Ph Ph Brown's Catalyst
BF4-
Ir +
P(C 6H11)3 N
PF6 -
(Crabtree's Ctalyst) JACS 1983, 105 , 1072
Regioselective Hydrogenation- allylic and homoallylic alcohols are hydrogenated faster than isolated double bonds MeO2C OH
MeO2C OH
REDUCTIONS
33
mechanism: L
+ M
H2
+ M
L
L
L
+
OH
L
S
M
L
S
O H
lose
H H
H2 (oxidative addition)
reductive elimination OH migratory insertion
HO H L
M L
+
H H
M
L
S
L
O H
Diastereoselective Hydrogenation: since -OH directs the H2, there is a possibility for control of stereochemistry - sensitive to: H2 pressure catalyst conc. substrate conc. solvent. Regioselective Hydrogenation- allylic and homoallylic alcohols are hydrogenated faster than isolated double bonds HO "Ir" (20 mol %)
HO
O
O
H
Brown's Catalyst OH
JACS 1984, 106, 3866
H2 (640 psi), CH2Cl 2
H
OMe
OMe
Me
(24 : 1)
OH
OMe H Me
OMe Brown's Catalyst H2 (1000 psi)
O
TL 1987, 28 , 3659
O OH
OH
Selectivity is often higher with lower catalyst concentration: OH
OH
OH
20 mol % Catalyst
2.5 mol % Catalyst
50 : 1
150 : 1
33 : 1
52 : 1
OH
REDUCTIONS
34
Olefin Isomerization: CH3 (3 : 1) OH
OH olefin isomerization
O
OH
major product
- Conducting the hydrogenation at high H 2 pressures supresses olefin isomerization and often gives higher diastereoselectivity. Other Lewis basic groups can direct the hydrogenation. (Ir seems to be superior to Rh for these cases) OMe
CO2Me
OMe Ir
CO2Me
+
Ir+
99 : 1
O
O
CO2H
Ir+ 7 : 1 Rh+ 1 : 1
O
O
N
O
O
N
O
130 : 1
1:1
Acyclic Examples Rh+ (2 mol %)
OH
Me CH 3 JCSCC 1982, 348
H2 (15 psi)
Me
L L M
OH
(97:3)
H O OH
H H
Ph H 3C
H H L
CH3 Ph
M L
Ph
anti
H
H
O H
32 : 1
CO2H
> 99 : 1
O
> 99 : 1
Rh+
OH
1,2-strain Ph
syn
REDUCTIONS L L R3 H OH R3
35
H O
M
R2 R1
OH
favored R3
H
syn
R1 R2
R1 R2 R3 H L
H
R1 R2
M
OH
disfavored R3
1,2-strain
R1 R2
O H
L
anti
- Supression of olefin isomerization is critical for acyclic stereocontrol ! L L
OH R2
H O
M
OH R2 H
R1
CH3 R1
CH3
R2
H
R1
anti
R2
olefin isomerization OH R2
OH
L L
R1
H O
M
R2
H H
R1 R2
CH2R2 R1
H
- Rh+ catalyst is more selective than Ir + for acyclic stereoselection. Acyclic homoallylic systems: HO R1
R3 R2
relative stereochemistry is critical
A E R2
A O H
M R3
1,3-strain R3
L L
E 1,2-strain R2
O H
L M
L
syn
REDUCTIONS Rh+
OH
(20 mol %)
36
OH
H2 (15 psi) OBz
OBz
TBSO
32 : 1
TBSO
Tetrahedron Lett. 1985, 26, 6005 Rh+ (20 mol %)
OH
OH
H2 (15 psi) OBz
OBz
TBSO
8:1
TBSO
Asymmetric Homogeneous Hydrogenation - Chiral ligands for homogeneous hydrogenation of olefins and ketones H O
P OMe
MeO
PPh2 PPh2
O
P
H DIOP
PPh2
PPh2
PPh2
PPh2
PPh2
PPh2
R= -CH3 PROPHOS = -Ph PHENPHOS = -C6H11 CYCPHOS
CHIRAPHOS
DBPP
DIPAMP Ph2P
PPh2 PPh2
X
PPh2
CO2tBu BPPM
PPh2
CO 2H
Ph HN
PPPFA
PPh2
P
BINAP
DIPHEMP Rh (I) L*, H2
CO 2H
Ph HN
Ph
(95% ee)
O CO 2Me
Ph O CO 2H
NHAc O
NH 2
HO O
OH L-DOPA
DIOP DIPAMP PPPFA BINAP NORPHOS BPPM
85% ee 96% ee 93% ee 100% ee 95% ee 91% ee
PPh2 PPh2
PPh2
PPh2
DUPHOS
Fe
N
X= CH2 DPCP X= N-R PYRPHOS
CAMPHOS
P
PPh2 PPh2
PPh2 PPh2 NORPHOS
NMe2
ACR 1983, 16, 106.
REDUCTIONS 37 General Mechanism: J. Halpern Science 1982, 217, 401 Asymmetric Synthesis 1985, vol 5, 41. CO2Me
Ph S
P
Rh
P
Ph
NHAc
S
P
Rh
NH O
P
(fast equilibrium)
CO2Me CH3
rate limiting
CO2Me
Ph
H2 (slow)
NHAc Ph P
H Rh
P
O
S
Ph
H CO2Me NH
S
P
(fast)
P
CO2Me H NH
Rh O
CH3 CH3
Detailed Mechanism: P
*
P
MeO2C
+ S
Ph
CO2Me NHAc
NH
P
*
S Rh
Ph
Rh P
P
Ph CH3
O
CO2Me
HN
H 3C
P
O
major complex
minor complex
H2 (slow) MeO2C H H P
* P
H2 (slow)
NH
NH
Ph
Rh
CH3
O
H 3C
Rh
*
S
H
CH3
NH
Ph
H N
H 3C O
P P * S
CO2Me
P
H
Rh O
CH3 O
CO2Me H
Ph
S
P
*
Rh
CO2Me Ph
(R) Minor product
HN MeO2C
O S
P
Rh
*
H P
Ph
MeO2C Ph
H N
CH3 O
(S) Major product
REDUCTIONS
+
MeO2C H
NH
H
Ph
Rh P P
Free Energy
*
NH
38
CH3
O
+
CO2Me H H
Ph
+
CO2Me
HN
Rh O
P P *
P
Ph H 3C
H 3C
Rh
*
P
O minor complex
MeO2C
*
Ph
Rh P
+
NH
P
CH3
O major complex
Reaction Coordinate
Ph Ph O O P Ru O P O Ph Ph
ACR 1990, 23, 345.
BINAP
O O
(BINAP)RuAc2, H2 (100 atm)
O
O
O R
O
O
50 °C, CH2Cl 2
(BINAP)RuAc2, H2 (100 atm)
R O
50 °C, CH2Cl 2
(95 - 98 % ee)
(94 % ee)
CO 2H
Ru(AcO)2(BINAP), H2 (135 atm), MeOH (97% ee)
MeO
CO 2H 97 % ee
MeO (S)-naproxen
MeO MeO
MeO (BINAP)RuAc2, H2 (4 atm)
NAc
MeO
MeO NAc
NH
MeO
OMe
OMe (95 - 100 % ee)
OMe
OMe
OMe
OMe Tetrahydropapaverine
Directed Asymmetric Hydrogenation (BINAP)Ru (II), H2 OH
CHO
OH
(96 - 99 % ee)
OH
OH
HO J. Am. Chem. Soc. 1987, 109, 1596 O Vitamin E
REDUCTIONS
39
Kinetic Resolution by Directed Hydrogenation
CF 3SO 3-
Rh+
MeO Ph P
P Ph
CO 2Me
MeO 2C
H2 (15 psi), L*Rh+
Et Ph OMe
CO 2Me
MeO 2C
0 °C (~60% conversion)
R
R=
OMe
R
> 96 % ee 82 % 93 %
Hydrogenation of Carbonyls 1,3-diketones: O R1
O
O
R1
OH
H2
O
H
OH
OH R2
R2 R1
O
H O H
syn
anti Ru2Cl 4(BINAP) Et3N, H2 (100 atm)
MeO 2C
99 : 1 16 : 1 (90 % ee) 32 : 1 49 : 1
R1
R2
R1
R2
Directed Reduction
M
O
R1
anti : syn=
OH
R1
O R2
OH
syn
anti
H O
M
OH
R2
-CH3 -CH2CH3 -iPr -CH2CH3
R2
R2
+ R1
R2=
OH
R1
OH
R2
-CH3 -CH3 -CH2CH3 -CH2CH3
O R2
Ru (II) H2 (700 psi)
O
R1
O
R1
R2
O
R1=
OH
O
OH JACS 1988, 110 , 6210
MeO 2C
(98% ee)
Decarbonylations O
(Ph3P)3RhCl
O
(Ph3P)3RhCl
R H R
H
- CO
R Cl R
Cl
- CO
REDUCTIONS
40
OHC
(Ph3P)3RhCl Fe
Fe
Fe
PhCH 3, ∆
JOC 1990, 55, 3688
Fe
Diimide HN=NH Review: Organic Reactions 1991, 40J. Chem. Ed. 1965, 254 - Only reduces double bonds - Syn addition of H 2 - will selectivley reduce the more strained double bond - Unstable reagent which is generated in situ K+O2C-N=N-CO2K+ + AcOH → H-N=N-H H2N-NH2 + Cu2+ + H2O2 → H-N=N-H HN=NH ACIEE 1965, 271 (76%) O
O +-
CO 2MeK
O 2C N N CO 2- K+
CO 2Me
AcOH, MeOH (95%)
NO 2
JACS 1986, 108 , 5908
NO 2
O HN HN
hν (254 nm)
S
NH NH
+ COS + CO
O O
S
O
N N H H
TL 1993, 34, 4137
hν, 16 hr (96%)
Metal Hydrides Review on Metal Hydride Selectivity:
Chem Soc Rev. 1976, 5 , 23 Comprehensive Organic Synthesis 1991, vol 8, 1. Boron Hydrides Review: Chem. Rev. 1986, 86 , 763. NaBH4 reduces ketones and aldehydes LiBH4 reduces ketones, aldehydes, esters and epoxides. THF soluble LiBH4/TMSCl stronger reducing agent. ACIEE 1989, 28, 218. Zn(BH4)2 reduces ketones and aldehydes R4N BH4 organic soluble (CH2Cl2) borohydrides. Synth Commun. 1990, 20, 907 LiEt3BH reduces ketones, aldehydes, esters, epoxides and R-X Li s-Bu3BH reduces ketones, aldehydes, esters and epoxides (hindered borohydride) Na(CN)NH3 reduces iminium ions, ketones and aldehydes Na(AcO)3BH reduces ketones and aldehydes (less reactive) NaBH2S3 reduces ketones and aldehydes
REDUCTIONS
41
Sodium Borohydride NaBH4 - reduces aldehydes and ketones to alcohols - does not react with acids, esters, lactones, epoxides or nitriles. - Additives can increase reactivity. Sodium Cyanoborohydride Na (CN)BH3 Reviews: Synthesis 1975, 136; OPPI 1979, 11 , 201 - less reactive than NaBH4 - used in reductive aminations (Borch Reduction) Na(CN)BH3 reduces iminium ions much more quickly than ketones or aldehydes R"-2NH, MeOH, AcO - NH4+ , pH~ 8
R O
R
R'
O CHO
R
N R' JACS 1971, 93 , 2897
R"-2NH, MeOH, AcO- NH4+
N H
Na(CN)BH3
N
R'
R'
R
R
R H
Na(CN)BH3
N+
N
- Related to Eschweiler-Clark Reaction H2CO, HCO 2H R NH 2
R
or
N H
Me
H2CO, H2/Pd
- Reduction of tosylhydrazones gives saturated hydrocarbon O H
H
1) TsNHNH 2, H+ 2) Na(CN)BH3
TL 1978, 1991
(90%)
H
HO
H
HO 1) TsNHNH 2, H+ 2) Na(CN)BH3
O
(100%)
JOC 1977, 42 , 3157
- migration of the olefin occurs w/ α,β-unsaturated ketones O JACS 1978, 100 , 7352 (75%)
- Epoxide opening O OH
NaBH3CN, BF3•OEt2, THF
OH HO
JOC 1994, 59, 4004
NaBH2S3
REDUCTIONS Synthesis 1972, 526 Can. J. Chem. 1970, 48 , 735.
Lalancette Reduction
42
NaBH4/ NiCl 2 Chem. Pharm. Bull. 1981, 29 , 1159; Chem. Ber. 1984, 117 , 856. Ar-NO2 → Ar-NH2 Ar-NO → Ar- NH2 R2C=N-OH → R2CH-NH2 NaBH4 / TiCl 4 Synthesis 1980, 695. R-COOH → R-CH2-OH R-COOR' → R-CH2-OH R-CN → R-CH2-NH2 R-CONH2 → R-CH2-NH2 R2C=N-OH → R2CH-NH2 R-SO2-R' → R-S-R' NaBH4 / CeCl 3 Luche Reduction reduced α,β-unsaturated ketones in a 1,2-fashion OH NaBH 4/ CeCl3
R R
NaBH 4
R
R
O
OH
O
R
+
R R
R
R R
R
H
R JCSCC 1978, 601 JACS 1978, 100 , 2226
O
OH CO 2Me
NaBH 4/ CeCl3
C 5H11
CO 2Me
MeOH
C 5H11
OH
OH
- selective reduction of ketones in the presence of aldehydes. OH
O CO 2Me
CO 2Me
NaBH 4/ CeCl3 EtOH, H2O CHO
CHO O CeCl 3 H2O
1) NaBH 4, CeCl3 2) work-up
R
JACS 1979, 101 , 5848
OH OH O
OH
CHO NaBH 4/ CeCl3 EtOH, H2O (78%)
CHO
REDUCTIONS Zinc Borohydride Zn(BH4)2 Synlett 1993, 885. ZnCl2 (ether) + NaBH 4 → Zn(BH4)2 - Ether solution of Zn(BH4)2 is neutral- good for base sensitive compounds - Chelation contol model Zn RO
O R1
H
O
OR
OH
H B H
H
R2
OR
R1 R2
H
R1 R2
Zn(BH4)2, Et2O, 0°C
OH
OH OH
O H
H-
Me
TL 1983, 24 , 2653, 2657, 2661 O
O Zn
R
Na + (AcO)3BH , Me4N + (AcO)3BH Review: OPPI 1985, 17 , 317 - used in Borch reductive amination TL 1990, 31 , 5595; Synlett 1990, 537 - selective reduction of aldehydes in the presence of ketones O
Bu4N (AcO) 3BH C 6H6, ↑↓
O OH
CHO (77%)
TL 1983, 24 , 4287 AcO O
Bu4N (AcO) 3BH C 6H6, ↑↓
CHO
Ph
H O
OAc B OH
O Ph
Ph
OH
-hydroxyl-directed reduction of ketones TL 1983, 24 , 273; TL 1984, 25 , 5449 OH
O
Me
O
OH Ph
N Me
Me
OH
Me4N (AcO) 3BH, CH 3CN, AcOH, −40°C
Me
O
Ph
N Me
O
O
Me O
O
TL 1986, 27 , 5939 JACS 1988, 110 , 3560
(98:2) OAc
H O R
B
O
OAc
OAc
H R
R
H
OAc
H O
R
minor
major
OH
B
O
O Na+ BH(OAc)3
OH
OH
50 : 1
43
REDUCTIONS OH
O
O
OH
Na+ BH(OAc)3
OH
O CO2R
CO2R
OH
Na+ BH(OAc)3
44
OH
OH CO2R
HO OBn
BnO
OBn
BnO
Me
MeO
OBn
O
OBn
Me4N (AcO) 3BH, CH 3CN, AcOH, −40°C
O
Me MeO
Me
O
MeO
O
O Me
Me
OH
O
N
OH
O
Me O
O HO
OH
OH
Me FK-506
OH OH
TL 1989, 30 , 1037
(Ph3P)2Cu BH4 reduction of acid chlorides to aldehydes reduction of alkyl and aryl azides to amines
JOC 1989, 45, 3449 J. Chem. Res. (S) 1981, 17
R4N BH4 organic soluble borohydride (CH2Cl2) R4N= BnEt3N or Bu4N Heterocylces 1980, 14, 1437, 1441 reduction of amides to amines reduction of nitriles to amines BnEt3N BH4 / Me 3SiCl reduction of carbolxylic acids to alcohols LiBH4/ Me 3SiCl
Synth. Commun. 1990, 20, 907
ACIEE 1989, 28, 218.
Alkyl Borohydrides Selectrides M + HB 3
M + = Li (L-selectride) K (K-selectride)
LS-selectride
Li + HB
3
- hindered reducing agent increased selectivity based on steric considerations CO 2H
O
CO 2H
OH
L-selectride THF
JACS 1971, 93, 1491 R
R HO
HO OH
OH
REDUCTIONS
45
- selective 1,4-reductions of α,β-unsaturated carbonyl cmpds. JOC 1975, 40 , 146; JOC 1976, 41 , 2194 O
O K-selectride, THF (99%)
- 1,4-reduction generates an enolate which can be subsequently alkylated. O
O a) K-selectride, THF b)
Br
K+ HBPh3 Syn. Comm. 1988, 18 , 89. - even greater 1,4-selectivity Li + HBEt3 (Super Hydride) - very reactive hydride source - reduces ketones, aldehydes, esters, epoxides and C-X (alkyl halides and sulfonates) O
HO
Li Et3BH, THF
HO
HCA 1983, 66 , 760
HO
H
H HO
HO
CH 3
OH
HO
1) TsCl, pyridine 2) Li Et3BH, THF
HCA 1988, 71 , 872
HO H
H
Boranes Hydroboration H2O 2, NaOH
B 2H6 B
R
R'
R
B 2H6
R' B
R
B 2H6
H
HO H
H H3O +
H
R
B
H2O 2, NaOH
R
R'
H
H
R-CH 2CHO
H
- BH3 reduces carboxylic acids to 1° alcohols in the presence of esters, nitro and cyano groups. - BH3 reduces amides to amines HO 2C
BH 3•SMe 2 O
O
THF
HO O
O
- Boranes also reduce ketones and aldehydes to the corresponding alcohols.
REDUCTIONS Hindered Boranes Disiamyl Borane (Sia2BH)
B H
Thexyl Borane
B H
H B 9-BNN
=
B H
B H O
Catecholborane
BH O BH
BH Pinylborane 2
2
B
B H
Alpine Borane
BCl
BCl IPC 2BCl (DIP-Cl)
2
2 B H
Borolane
Ph Oxazaborolidine
N B H
Ph O
Asymmetric Reduction of Unsymmetrical Ketones Using Chiral Boron Reagents Review: Synthesis 1992, 605. Alpine Borane Midland Reduction JACS 1979, 111 , 2352; JACS 1980, 112 , 867 review: Chem. Rev. 1989, 89 , 1553. O
alpine-borane THF, 0°C
OH Tetrahedron 1984, 40 , 1371 (94% ee)
46
REDUCTIONS B H
B =
9-BBN
B B
α-pinene
9-BBN
B H
Mechanism:
OH O
RL
Rs
RL
Rs
- works best for aryl- and acetylenic ketones - because of steric hindrance, alpine-borane is fairly unreactive Chloro Diisopinylcamphenylborane (DIP-Cl, Ipc2BCl) H.C. Brown Review: ACR 1992, 25 , 16. Aldrichimica Acta 1994, 27 (2), 43 BCl
2
- Cl increases the Lewis acidity of boron making it a more reactive reagent - saturated ketones are reduced to chiral alcohols with varying degrees of ee. O
OH
I
CO2tBu
Ipc2B-Cl, THF
I
CO2tBu JOC 1992, 57, 7044
PrO
PrO OMe
(90 % ee)
OMe
Borolane (Masamune's Reagent) JACS 1986, 108 , 7404; JACS 1985, 107, 4549 B H B O
OH
H MeSO 3H, pentane
(80% ee)
Asymmetric Hydroboration: a)
B H
b) H2O 2, NaOH
OH (99.5% ee)
(99.5% ee)
47
REDUCTIONS Oxazaborolidine (Corey) JACS 1987, 109 , 7925; TL 1990, 31, 611l ; TL 1992, 33 , 4141 Ph
Ph
O
N B
Ph
N B H
Ph O
+ BH3
CH 3 Catalytic
O
OH R
R
> 90 % ee OH
O
92 % ee
O
OH
I
86 % ee
I O
OH 93 % ee
Ph Ph O
O N B Me
OH
BH 3•THF, -0°C
TL 1988, 29 , 6409 (90% ee) CF 3
O
OH Cl
O Cl
• HCl N H
CH 3
94 % ee Fluoxetine (Prozac)
O
O
O
O 90 : 10
BzO
BzO
O
Aluminium Hydrides 1. LiAlH 4 2. AlH3 3. Li (tBuO)3AlH 4. (iBu)2AlH DIBAL-H 5. Na (MeOCH2CH2O)2AlH2
REDAL
OH
48
REDUCTIONS 49 Chem. Rev. 1986, 86, 763 Org. Rxn. 1951, 6, 469.
Lithium Aluminium Hydride LiAlH4 (LAH) - very powerful reducing agent - used as a suspension in ether or THF - Reduces carbonyl, carboxylic acids and esters to alcohols - Reduces nitrile, amides and aryl nitro groups to amines - opens epoxides - reduces C-X bonds to C-H - reduces acetylenic alcohols trans-allylic alcohols LAH
OH
R
OH
R
H2N
LAH, THF
N H
NH 2
H2N
(62%)
NH 2
N H
NH 2 Lindlar/ H2 H2N O
N H HO
CO 2Me
OH LAH, THF, ↑↓ TL 1988, 29 , 2793.
(100%) O
O
H O
H O
BINAL-H (Noyori) - Chiral aluminium hydride for the asymmetric reduction of prochiral ketones
OH OH
1) LiAlH4 2) ROH
H
O
Li +
Al O
OR
R= Me, Et, CF 3CH 2-
BINOL
BINAL-H
O O
O
BINAL-H,THF
Tetrahedron 1990, 46 , 4809
-100 to -78°C HO
(94% ee)
Intermediate for 3-Component Coupling Strategy to Prostaglandins I O
Li+ O CO 2Me
RO
Li+ RCu
RO OTBS
O
OTBS O CO 2H
CO 2Me
HO RO
OTBS
OH PGE 2
REDUCTIONS Alane
50
AlH3 LiAlH 4 + AlCl3 → AlH3 - superior to LAH for the 1,2-reduction of α,β-unsaturated carbonyls to allylic alcohols OMe Ph
1) AlH3, ether, 0°C 2) H3O +
O
O
HO
O Me
O JACS 1989, 111 , 6649
Me
O
OH
O
Diisobutyl Aluminium Hydride
DIBAL or DIBAL-H Al H
- Reduces ketones and aldehydes to alcohols - reduces lactones to hemi-acetals O
Al
O
OH CHO
work up
DIBAL O (CH 2)n
O
OH
O
(CH 2)n
(CH 2)n
(CH 2)n lactol
(stable complex)
- reduces esters to alcohols - under carefully controlled reactions conditions, will partially reduce an ester to an aldehyde Al
O DIBAL
R CO 2Me
if complex is unstable
R C OMe
fast
R CHO
R CH 2 OH
H if complex is stable R CHO O O
O
OBn O
DIBAL, CH 2Cl 2
O
HO OH
HO
HO
H
O
HO
OBn O
OBn
OH
OBn
OH JACS 1990, 112 , 9648 OBn
OBn DIBAL, CH 2Cl 2
CO 2iPr
iPrO2C
OHC
OBn O R
OBn O
TMS-Cl, Et3N OH
CHO
CH2Cl2
R
O
DiBAl-H OSiMe3
CH2Cl2, -78°C
TL 1998, 39, 909 R
H
Reduction of O-Methyl hydroxamic acids O R
O
R'-M R'
R
O OMe N Me
TL 1981, 22 , 3815
DIBAL or LAH R
H
REDUCTIONS
51
Sodium Bis(2-Methoxyethoxy)Aluminium Hydride REDAL Organic Reactions 1988, 36, 249 Organic Reactions 1985, 36, 1. MeO MeO
Na+
H
O
Al
O
H
- "Chelation" directed opening fo allylic epoxides OH O
REDAL R
OH
DIBAL-H
R
R
OH
Ph
1,2-diol OH
REDAL
O
OH
Ph
TL 1982, 23 , 2719
OH
1,3-diol Sharpless epoxidation
OH
OH
DME
LiAlH4 AlH3
OH
OH
+
OH
O
JOC 1988, 53 , 4081
Ph
2 : 98 95 : 5 OH
O
OH
BnO
+
OH
BnO
OH
BnO
OH REDAL DIBAL
O
OH Me HO
OH
O O Me
OH
OH
150 : 1 1 : 13
OH
OH
Me
OH
HO
O
OH
Me
Amphotericin B HO
O NH 2
Me
Me O
Me O
OH
Me OH
O
O O
sugar
sugar
Me Erythromycin A
Li+ (tBuO)3AlH
Lithium Tri(t-Butoxy)aluminium Hydride - hindered aluminium hydride, will only react with the most reactive FG's O R
Li(tBuO)3AlH Cl
R
H
Me
Cl
O
N+ R-CO 2H
O
Me
H
R
pyridine, -30°C
O H
Me N+ Me
O
Li(tBuO)3AlH CuI (cat), -78°C
R
TL 1983, 24 , 1543 H
Meerwein-Ponndorf-Verley Reduction: opposite of Oppenauer oxidation Synthesis 1994, 1007 Organic Reactions 1944, 2, 178 O H
O H Al(O-Pr)3, iPrOH
O
O O AcHN
O
O AcHN
OH
REDUCTIONS
52
Asymmetric M-P-V Reduction Bn
Ph
X
O
Ph
N O
Sm
X
O
OH
I
JACS 1993, 115, 9800
iPrOH, THF X= H, Cl, OMe yield: 83-100 % 96% ee
Dissolving Metal Reductions Birch Reductions reduction of aromatic rings Organic Reactions 1976, 23, 1. Tetrahedron 1986, 42, 6354. Comprehensice Organic Synthesis 1991, vol. 8, 107. - Li, Na or K metal in liquid ammonia H H
H H M, NH3
_• •
R
R
R
R
H
H H
- position of the double bond in the final product is dependent of the nature of the substituent R
R
R R= EWG
R= ERG
- ketones and nitro groups are also reduced but esters and nitrile are not. - α,β-unsaturated carbonyl cmpds are reduced in a 1,4-fashion to give an enolate which can be subsequently used to trap electrophiles Me HO
Me Me
O O
K, NH3, MeOH, -78°C
Me HO
O
JOC 1991, 56 , 6255 O
(92%)
O
Me Me OH
Me
Me O O
O O
a) Li, NH3, tBuOH b) CH 2O
JOC 1984, 59 , 3685
O
O HO
Other Metals - Mg Mg, MeOH X
X
X- CN, CO2R, CONR'2
H
H Mg, MeOH
EtO2C
(98%)
TL 1987, 28 , 5287 EtO2C
- Zn reduction of α-halocarbonyls O
O Br
Zn, PhH, DMSO, MeI
Me
JACS 1967, 89, 5727
REDUCTIONS Cl R
Zn
O
X
Y
Zn, AcOH
R
R'
X= Cl, Br, I Y= X, OH
R
R-OH O
CH
53
CH R'
"Copper Hydrides" LAH or DIBAL-H + MeCu → "CuH" - selective 1,4-reduction of α,β-unsaturated ketones (even hindered enones) O
O 1) MeCu, DIBAL, HMPA, THF, -50°C 2) MeLi 3)
JOC 1987,52 , 439
Br
O
O MeCu, DIBAL, HMPA THF, -50°C
H
H
JOC 1986,51 , 537
(85%)
O
H
H
O H
[(Ph3P)CuH]6 Stryker Reagent JACS 1988, 110 , 291 ; TL 1988, 29 , 3749 - 1,4-reduction of α,β-unsaturated ketones and esters; saturated ketones are not reduced - halides and sulfonates are not reduced - 1,4-reduction gives an intermediate enolate which can be trapped with electrophiles. O
Br
O [(Ph3P)CuH] 6, THF
TL 1990, 31 , 3237
Silyl Hydrides - Hydrosilylation Et3SiH + (Ph3P)3RhCl (cat) - selective 1,4-reduction of enones, 1,2-reduction of saturated ketones to alchohols. O
Et3SiH, (Ph3P)3RhCl (cat)
O SiEt3
H3O +
O TL 1972, 5085 J. Organomet. Chem. 1975, 94 , 449
O O O
iPr3SiH, Et2O Si O 2
Pt 2
OSi(iPr)3 O JOC 1994, 59, 2287 O
(87%)
- Buchwald Reduction JACS 1991, 113 , 5093 - catalytic reagent prepared from Cp2TiCl2 + nBuLi and stoichometric (Et)3SiH in THF will reduce ester, ketones and aldehydes to alcohols under very mild conditions. - α,b− unsaturated esters are reduced to allylic alcohols - free hydroxyl groups, aliphatic halides and epoxides are not reduced
REDUCTIONS
54
Clemmensen Reduction
Organic Reactions 1975, 22, 401 Comprehensive Organic Synthesis 1991, vol 8, 307. - reduction of ketones to saturated hydrocarbons Zn(Hg), HCl
H
O
Wolff-Kishner Reduction
H
Organic Reactions 1948, 4, 378 Comprehensive Organic Synthesis 1991, vol. 8, 327.
- reduction of ketones to saturated hydrocarbons H2N-NH2, KOH
H
O
H
Radical Deoxygenation Review: Tetrahedron 1983, 39 , 2609 Chem. Rev. 1989, 89, 1413. Comprehensive Organic Synthesis 1991, vol. 8, 811 Tetrahedron 1992, 48, 2529 W. B. Motherwell, D. Crich Free Radical Chain Reactions in Organic Synthesis (Academic Press: 1992) - free radical reduction of halide, thio ethers, xanthates, thionocarbanates by a radical chain mechanism. nBu3Sn-H, AIBN Ph-CH3 ↑↓
R3C-H
R3C-X S X= -Cl, -Br, -I, -SPh,
S
S Ph , O
O
Barton-McCombie Reduction JCS P1 1975, 1574 R3C-X → R3C-H
N N CN
SMe , O
CN AIBN
N
N
X= -OC(=S)-SMe, -OC(=S)-Im, -OC(=S)Ph O
O O
O HO
NaH, imidazole, THF, CS2, MeI
O
O
O
O
O
O
O
nBu3SnH, AIBN PhCH3, reflux
O
O
O
O
(85%) O
SMe S Xanthate R
R
Cl a) Ph
nBu3SnH, AIBN PhCH3, reflux
NMe2 , THF +
S
b) H2S, pyridine HO
(73%) Ph
(90%)
R
O Thionobenzoates
S Ph
O O O HO AcHN OBn
N
N
N (CH2Cl)2 59%
Ph N N
N
O O O O AcHN OBn S
Thiocarbonyl Imidazolides
nBu3SnH, AIBN PhCH3, reflux (57%)
Ph
O O AcHN
O OBn
REDUCTIONS - Cyclic Thionocarbonates: deoxygenation of 1,2- and 1,3-diols to alcohols
55
S OH
N
O
HO MeO MeO
S
N
O O MeO
N
N
HO
O
JCS P1 1977, 1718
MeO
(61%)
MeO
OMe
nBu3SnH, AIBN PhCH3, reflux
O
MeO
OMe
OMe
- Thionocarbonate Modification (Robbins) JACS 1981, 103 , 932; JACS 1983, 105 , 4059. iPr iPr
O
O
Si
PhOC(S)Cl, pyridine, DMAP
B
iPr iPr
O
nBu3SnH, AIBN PhCH3, reflux
B
O
O
> 90%
Si O iPr iPr
O Si
OH
iPr iPr
O
B
O
O
(58-78%)
Si O iPr iPr
O Si Si O iPr iPr
OPh S
S OAr O O
O CH3
nBu3SnH, AIBN, PhCH3
O O
O
Tetrahedron 1991, 47, 8969
O
88-91%
O
O O
O Best method for deoxygenation of primary alcohols
Ar= 2,4,6-trichlorophenyl, 4-fluorophenyl
- N-Phenyl Thionocarbamates iPr iPr
O
O
Si
U
PhNCS NaH, THF S
O Si O iPr iPr
Tetrahedron 1994, 34, 10193. iPr iPr
O
U
Si O iPr iPr
NHPh
(TMS)3SiH, AIBN PhH, reflux S
O
(78%)
O
O Si
O
(93%)
iPr iPr
O
O
Si
U
O Si O iPr iPr
NHPh
Thiocarbamates
- Methyl oxylates OAc
O
OAc
O MeO2CCOCl THF
OC
nBu3SnH, AIBN PhCH3, reflux
OC O
HO CO2Me
CO2Me MeO2C
O
OAc
O OC CO2Me
Methyl Oxylate Esters
- Water Soluble Tin Hydride: [MeO(CH2)2O(CH2)3]3SnH / 4,4'-Azo(bis-4-cyanovaleric acid) TL 1990, 31 , 2957 - Silyl Hydride Radical Reducing Agents - replacement for nBu3SnH (Me3Si)3SiH Chem Rev. 1995, 95, 1229. JOC 1991, 56 , 678; JOC 1988, 53 , 3641; JACS 1987, 109 , 5267 Ph2SiH2 / Et3B / Air TL 1990, 31 , 4681; TL 1991, 32 , 2569 - hypophosphorous acid as radical chain carrier JOC 1993, 58, 6838
REDUCTIONS - Photosensitized electron transfer deoxygenation of m-trifluoromethylbenzoates JACS 1986, 108, 3115, JOC 1996, 61, 6092, JOC 1997, 62, 8257 iPr iPr
O
O
Si
U N-methylcarbazole, hν, iPrOH, H2O
O Si O iPr iPr
O
iPr iPr
(85%)
O Si O
CF3
O
U
O
Si O iPr iPr
Dissolving Metal : JACS 1972, 94, 5098 O OH
O
nBuLi, (Me2N)2P(O)Cl
O
P(NMe2)2 Li, EtNH2, THF, tBuOH
O O
H
CH3 O
O
H
O
Radical Decarboxylation: Barton esters Aldrichimica Acta 1987, 20 (2), 35 S
hn or ∆
N S
R
N
nBu3SnH, ∆
O
O
R
- CO2
Radical Deamination Comprehensive Organic Synthesis 1991, vol. 8, 811 Reduction of Nitroalkanes
JOC 1998, 63, 5296 NO2 Bu3SnH, PhSiH3
O O
initiator, PhCH3 (reflux) (75%)
O O
R H
H
56
PROTECTING GROUPS Carey & Sundberg Chapter 13.1 problems # 1; 2; 3a, b, c ; Smith: Chapter 7
57
Protecting Groups T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis (2nd edition) J. Wiley & Sons, 1991. P. J. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994 1. 2 3. 4.
Hydroxyl groups Ketones and aldehydes Amines Carboxylic Acids - Protect functional groups which may be incompatible with a set of reaction conditions - 2 step process- must be efficient - Selectivity a. selective protection b. selective deprotection
Hydroxyl Protecting Groups Ethers Methyl ethers R-OH → R-OMe Formation: Cleavage: -
difficult to remove except for on phenols
CH2N2, silica or HBF4 NaH, MeI, THF AlBr3, EtSH PhSe Ph2P Me3SiI OMe
O
OH
O AlBr3, EtSH
TL 1987, 28 , 3659 O
O OBz
Methoxymethyl ether MOM R-OH → R-OCH2OMe
OBz
stable to base and mild acid
Formation: - MeOCH2Cl, NaH, THF - MeOCH2Cl, CH2Cl2, iPr2EtN Cleavage - Me2BBr2 TL 1983, 24 , 3969
PROTECTING GROUPS Methoxyethoxymethyl ethers (MEM) R-OH → R-OCH2OCH2CH2OMe
stable to base and mild acid
Formation: - MeOCH2CH2OCH2Cl, NaH, THF - MeOCH2CH2OCH2Cl, CH2Cl2, iPr2EtN Cleavage - Lewis acids such as ZnBr2, TiCl4, Me2BBr2
TL 1976, 809
S B Cl
MEM-O
HO
S
C5H11
O-Si(Ph)2tBu
O
C5H11
TL 1983, 24 , 3965, 3969 O
O-Si(Ph)2tBu
- can also be cleaved in the presence of THP ethers Methyl Thiomethyl Ethers (MTM) R-OH → R-OCH2SMe
Stable to base and mild acid
Formation: - MeSCH2Cl, NaH, THF Cleavage: - HgCl2, CH3CN/H2O - AgNO3, THF, H2O, base Benzyloxymethyl Ethers (BOM) R-OH → R-OCH2OCH2Ph
Stable to acid and base
Formation: - PhOCH2CH2Cl, CH2Cl2, iPr2EtN Cleavage: - H2/ PtO2 - Na/ NH3, EtOH Tetrahydropyranyl Ether
R-OH
(THP)
O H
+
, PhH
Formation Cleavage:
R
O
O
Stable to base, acid labile
- DHP (dihydropyran), pTSA, PhH - AcOH, THF, H2O - Amberlyst H-15, MeOH
Ethoxyethyl ethers (EE) JACS 1979, 101 , 7104; JACS 1974, 96 , 4745. R-OH
O H+
R
Benzyl Ethers (R-OBn) R-OH → R-OCH2Ph Formation: Cleavage:
O
O
(R-OEE)
base stable, acid labile
stable to acid and base
- KH, THF, PhCH2Cl - PhCH2OC(=NH)CCl3, F3CSO3H - H2 / PtO2 - Li / NH3
JCS P1 1985, 2247
58
PROTECTING GROUPS 2-Napthylmethyl Ethers (NAP) JOC 1998, 63, 4172 formation: 2-chloromethylnapthalene, KH cleavage: hydrogenolysis OH
O
ONAP
BnO
OH
H2, Pd/C
-
OH
BnO
(86%)
p- Methoxybenzyl Ethers (PMB) Formation: - KH, THF, p-MeOPhCH2Cl - p-MeOPhCH2OC(=NH)CCl3, F3CSO3H Cleavage:
O
59
TL 1988, 29 , 4139
H2 / PtO2 Li / NH3 DDQ Ce(NH4)2(NO3)6 (CAN) e-
o-Nitrobenzyl ethers Review: Synthesis 1980, 1; Organic Photochemistry, 1987, 9 , 225 O 2N
NaH, THF R-OH Cl
R
O
NO 2
Cleavage:
- photolysis at 320 nm NO 2
HO HO HO
O
HO hν, 320 nm, pyrex, H2O
O
HO HO
OH
O
OH JOC 1972, 37 , 2281, 2282.
OH
p-Nitrobenzyl Ether TL 1990, 31 , 389 -selective removal with DDQ, hydrogenolysis or elctrochemically 9-Phenylxanthyl- (pixyl, px)
TL 1998, 39, 1653
Formation:
Ph
Ph
Cl
OR
pyridine
ROH
+ O
Removal:
Ph
O Ph
OR
OH
hν (300 nm)
ROH O
CH3CN,H 2O
+ O
Trityl Ethers -CPh3 = Tr R-OH → R-OCPh3 - selective for 1° alcohols - removed with mild acid; base stable formation: - Ph3C-Cl, pyridine, DMAP - Ph3C + BF4Cleavage: - mild acid
PROTECTING GROUPS
60
Methoxytrityl Ethers JACS 1962, 84 , 430 - methoxy group(s) make it easier to remove R1 (p-Methoxyphenyl)diphenylmethyl ether 4'-methoxytrityl MMTr-OR R2
Di-(p-methoxyphenyl)phenylmethyl ether 4',4'-dimethoxytrityl DMTr-OR
C O R
Tri-(p-methoxyphenyl)methyl ether 4',4',4'-trimethoxytrityl TMTr-OR R3
Tr-OR < MMTr-OR < DMTr-OR << TMTr-OR O
O
HN R O
HN
O
80% AcOH (aq)
N
O
HO
O
20°C
N
O
HO OH
HO OH R = Tr 48 hr. R= MMTr 2 hr. R= DMTr 15 min. R= TMTr 1 min.
(too labile to be useful)
Oligonucleotide Synthesis (phosphoramidite method - Lessinger) Review: Tetrahedron 1992, 48 , 2223 S I L I C A
S I L I C A
OH OH OH
S I L I C A
O Si (CH 2)3 NH 2
O O
DMTrO O
O
DMTrO
O
B O
Cl 3CCOOH S
O
B' O
P
O
CN
O
CN
O
DMTrO
O
O
Base
O
B
O
P
-
O
B
O
coupling S DMTrO
O
O HO
B'
O
S
B'
O
O
O I2, H2O
Si (CH 2)3 N C (CH 2)2 C OH H
HO
B'
N (iPr)2
O
B
Si (CH 2)3 N C (CH 2)2 C O H O
O
O P
O
O
B'
O
O
O
S I L I C A DMTrO
O
P
OO-
Cl 3CCOOH
O
B
O
P O
B O
O S
O
Repeat Cycle
OO
S
O
PROTECTING GROUPS Silyl Ethers Synthesis 1985, 817 Synthesis 1993, 11 Synthesis 1996, 1031 R-OH → R-O-SiR3 formation: - R3Si-Cl, pyridine, DMAP - R3Si-Cl, CH2Cl2 (DMF, CH3CN), imidazole, DMAP - R3Si-OTf, iPr2EtN, CH2Cl2
61
Trimethylsilyl ethers Me3Si-OR TMS-OR - very acid and water labile - useful for transiant protection Triethylsilyl ethers Et3Si-OR TES-OR - considerably more stable that TMS - can be selectively removed in the presence of more robust silyl ethers with with F - or mild acid O OH
H2O/ACOH/THF (3:5:11), 15 hr
TESO OTBS
O
(97%)
Liebigs Ann. Chem. 1986, 1281 OTBS
Triisopropylsilyl ethers iPr3Si-OR TIPS-OR - more stabile to hydrolysis than TMS Phenyldimethylsilyl ethers J. Org. Chem. 1987, 52 , 165 t-Butyldimethylsilyl Ether tBuMe 2Si-OR TBS-OR TBDMS-OR JACS 1972, 94 , 6190 - Stable to base and mild acid - under controlled condition is selective for 1° alcohols t-butyldimethylsilyl triflate tBuMe 2Si-OTf TL 1981, 22 , 3455 - very reactive silylating reagent, will silylate 2° alcohols cleavage: - acid - F- (HF, nBu4NF, CsF, KF) TBSO HO CO2Me
HF, CH3CN
CO2Me
(70%) O
OTBS
O
HO
JCS Perkin Trans. 1 1981, 2055
t-Butyldiphenylsilyl Ether tBuPh2Si-OR TBDPS-OR ∑-OR - stable to acid and base - selective for 1° alcohols - Me3Si- and iPr 3Si groups can be selectively removed in the presence of TBS or TBDPS groups. - TBS can be selectively removed in the presence of TBDPS by acid hydrolysis. TL 1989, 30 , 19
PROTECTING GROUPS cleavage - F- Fluoride sources: -
nBu 4NF (basic reagent) HF / H2O /CH3CN HF•pyridine SiF4. CH2Cl2
TL 1979, 3981. Synthesis 1986, 453 TL 1992, 33 , 2289
Me O Si
OH
tBu Me
JOC 1981, 46 ,1506 TL 1989, 30 , 19.
AcOH / THF/ H2O Ph O Si tBu
O Si
Me
Ph tBu Ph
Ph Me tBu Si
62
Me tBu
O
Si
Me
OTHP
O OH
PPTS / EtOH
JACS 1984, 106 , 3748
Esters R-OH → R-O2CR' Formation: - "activated acid", base, solvent, (DMAP) Activated Acids Chem. Soc. Rev. 1983, 12, 129 Angew. Chem. Int. Ed. Engl. 1978, 17, 569. RCO2H → "activated acid" → carboxylic acid derivative (ester, amide, etc.) Acid Chlorides O
O O
O
N
N
+ N
R R
OH
R
R
N
Cl
+ N
N acyl pyridinium ion (more reactive)
1. SOCl2 2. PCl5 3. (COCl)2 Anhydrides O
O
P2O 5
2 R
OH
R
O O
R
Activating Agents: Carbonyl Diimidazole O
O O R
OH
N
+ N
R
N N
N
N Acyl Imidazole
NH +
CO
+
N
PROTECTING GROUPS
63
Dicyclohexylcarbodiimide C 6H11
O
NH
O R
+
OH
R
N C N
O
O
Nu:
O C N
R
+C 6H11 Nu
N H
N H
C 6H11
C 6H11
Ketene formation is a common side reaction- scambling of chiral centers C 6H11
O
NH
R
R
O C N
H
C O
"ketene"
C 6H11
Hydroxybenzotriazole (HOBT) - reduces ketene formation C 6H11
O R
O
N
NH
+
O C
N
N
N
O N
R
N
N
OH
C 6H11
N-Hydroxysuccinimide (NHS) O
C 6H11
O R
O
O
NH
HO
+
O C
N R
N
O N
O
C 6H11
O
2,2'-Dipyridyl Disulfide (Aldrithiol, Corey Reagent) Aldrichimica Acta 1971, 4 , 33 O R
OH
O
Ph3P:
+ N
S S
R
N
+ S
+
N
N
Ph3P=O
SH
Mukaiyama's Reagent (2-Chloro-1-methyl pyridinium Iodide or 2-Fluoro-1methyl pyridinium p-toulenesulfonate) Aldrichimica Acta 1987, 20 , 54 Chem. Lett. 1975, 1045; 1159; 1976, 49; 1977, 575 O
+ R
OH
F
+ N Me
O
TsO R
O
+ N
I-
Me
Acetates R-OH → R-O2CCH3 - stable to acid and mild base - not compatable with strong base or strong nucleophiles such as organometallic reagents Formation: - acetic anhydride, pyridine - acetyl chloride, pyridine
PROTECTING GROUPS Cleavage:
-
K2CO3, MeOH, reflux KCN, EtOH, reflux NH3, MeOH LiOH, THF, H2O enzymatic hydrolysis (Lipase) OAc
64
Org. Rxns. 1989, 37, 1. OAc
Porcine Pancreatic Lipase
TL 1988, 30 , 6189
OAc
OH
(96% ee)
Chloroacetates - can be selectively cleaved with Zn dust or thiourea. O Me
O OR
O
HO
AcO Me OAc O
Cl
Me
O OR
Cl
H2NNHCOSH
O
AcO Me
O
JCS CC 1987, 1026 O
OAc O
HO
Cl
O
O
OH
O
Trifluoroacetates Formation: - with trifluoroacetic anhydride or trifluoroacetyl chloride Cleavage: - K2CO3, MeOH Pivaloate (t-butyl ester) - Fairly selective for primary alcohols Formation: - tbutylacetyl chloride or t-butylacetic anhydride Cleavage: - removed with mild base Benzoate (Bz) - more stable to hydrolysis than acetates. Formation: - benzoyl chloride, benzoic anhydride, benzoyl cyanide (TL 1971, 185) , benzoyl tetrazole (TL 1997, 38, 8811) Cleavage: - mild base - KCN, MeOH, reflux 1,2 and 1,3- Diols
Synthesis 1981, 501
Chem. Rev. 1974, 74, 581
R2 O
OH R1
R
OH
Isopropylidenes
R3 H+ , -H2O
R2
R3
O
O
R
R1
(acetonides) H+
OH R
R1 OH
acetone or OMe MeO OMe or
Me
Me
O
O
R
R1
- in competition between 1,2- and 1,3-diols, 1,2-acetonide formation is usually favored - cleaved with mild aqueous acid
PROTECTING GROUPS
65
Cycloalkylidene Ketals - Cyclopentylidene are slightly easier to cleave than acetonides - Cyclohexylidenes are slightly harder to cleave than acetonides O
(CH 2)n -or-
OH
OMe
MeO
(CH 2)n
(CH 2)n
R1
R
O H+ , -H2O
OH
O
R
R1
Benzylidene Acetals PhCHO -orPhCH(OMe)2
OH R1
R
Ph O
O
+
H , -H2O
OH
R
R1
- in competition between 1,2- and 1,3-diols, 1,3-benzylidene formation for is usually favored - benzylidenes can be removed by acid hydrolysis or hydrogenolysis - benzylidene are usually hydrogenolyzed more slowly than benzyl ethers or olefins. p-Methoxybenzylidenes - hydrolyzed about 10X faster than regular benzylidenes - Can be oxidatively removed with Ce(NH 4)2(NO3)6 (CAN) OMe
OBn BnO
O
MeO
BnO
OH
(95%)
O
O
OBn
Ce(NH 4)2(NO3)6 CH 3CN, H2O
MeO
O
OH
Other Reactions of Benzylidenes - Reaction with NBS (Hanessian Reaction) H O
Ph O O HO
NBS, CCl 4
O
Br Ph
HO OMe
O HO
Org. Syn. 1987, 65, 243
O HO OMe
- if benzylidene of a 1° alcohol, then 1° bromide - Reductive Cleavage Ph O
Na(CN)BH3, TiCl4,CH 3CN
O
OH MeO 2C
MeO 2C O
MeO
CO 2Me
O O
Ph O
CO 2Me
Synthesis 1988, 373.
OBn O
TMS-CN BF3•OEt2
OH Tetrahedron 1985, 41, 3867
MeO
O
O H
Ph CN
PROTECTING GROUPS Ph O
O
BnO
OH
DIBAL-H TL 1988, 29 , 4085 O
O
OMe
OMe
Carbonates O
OH R1
R
(Im)2CO
O
OH
O
R
R1
- stable to acid; removed with base - more difficult to hydrolyze than esters Di-t-Butylsilylene (DTBS) TL 1981, 22 , 4999 - used for 1,3- and 1,4-diols; 1,2-diols are rapidly hydrolyzed - cleaved with fluoride (HF, CH 3CN -or- Bu4NF -or- HF•pyridine) - will not fuctionalize a 3°-alcohol OH
(t-Bu)2SiCl 2, Et3N CH 3CN, HOBT
O
tBu Si
O
OH
1,3-(1,1,3,3)-tetraisopropyldisiloxanylidene (TIPDS) - specific for 1,3- and 1,4-diols - cleaved with fluoride or TMS-I
tBu
TL 1988, 29 , 1561
O
O HN
HN HO
O
N
iPr2Si(Cl)-O-Si(Cl)iPr2 pyridine
O
O Si
O
N
O
O Si
HO OH
O OH
Ketones and Aldehydes - ketones and aldehydes are protected as cyclic and acyclic ketals and acetals - Stable to base; removed with H3O+ R
O
MeOH, H+
R1
R
R1 (CH 2OH)2, H+ PhH, -H2O -or(CH2OSiMe 3)2, TMS-OTf, CH2Cl 2 CH 2(CH 2OH)2, H+ , PhH, -H2O
OMe OMe
R
O TL 1980, 21 , 1357
R1 O 1,3-dioxolanes R O R1 O 1,3-dioxanes
66
PROTECTING GROUPS
67
Cleavage rate of substituted 1,3-dioxanes: Chem. Rev. 1967, 67 , 427. R O
R O
R O
> R1 O
>> R1 O
R1 O
- Ketal formation of α,β-unsaturated carbonyls are usually slower than for the saturated case. O
O O
CH 2(CH 2OH)2, H+ , PhH, -H2O
O
O
Fluoride cleavable ketal: O
O LiBF4
O
O
(88%) O
Me3Si
TL 1997, 38, 1873
O O
Base cleavable ketal: HO
O
SO2Ph
SO2Ph
DBU, CH2Cl 2
OH R1
R2
O pTSA, C6H6
R1
O
TL 1998, 39, 2401
O R1
R2
R2
Carboxylic Acids Tetrahedron 1980, 36, 2409. Tetrahedron 1993, 49, 3691 Nucelophilic Ester Cleavage: Organic Reactions 1976, 24, 187. Esters Alkyl Esters formation: - Fisher esterification (RCOOH +R'OH + H+) - Acid Chloride + R-OH, pyridine - t-butyl esters: isobutylene and acid - methyl esters: diazomethane Cleavage: - LiOH, THF, H2O - enzymatic hydrolysis Org. Rxns. 1989, 37, 1. - t-butyl esters are cleaved with aqueous acid - Bu 2SnO, PhH, reflux (TL 1991, 32, 4239) OH MeO 2C
CO 2Me
O R
Pig Liver Esterase pH 6.8 buffer
Bu2SnO, PhH, ↑↓ OR'
OH MeO 2C
CO 2H
O R
OH
TL 1991, 32, 4239
R= Me, Et, tBu
9-Fluorenylmethyl Esters (Fm) TL 1983, 24 , 281 - cleaved with mild base (Et2NH, piperidine) DCC RCO 2H
+ O
OH R
O
PROTECTING GROUPS 2-Trimethylsilyl)ethoxymethyl Ester (SEM) HCA 1977, 60 , 2711. - Cleaved with Bu 4NF in DMF DCC RCO 2H
HO
+
O
R
SiMe 3
O
O
SiMe 3
O
- Cleaved with MgBr2•OEt2 TL 1991, 32, 3099. 2-(Trimethylsilyl)ethyl Esters JACS 1984, 106 , 3030 - cleaved with Fluoride ion DCC RCO 2H
HO
+
R
O
SiMe 3
SiMe 3 O
Haloesters
- cleaved with Zn(0) dust or electrochemically DCC RCO 2H
HO
+
CCl 3
R
O
CCl 3
O
Benzyl Esters RCO2H + PhCH2OH → RCO2Bn Formation: Cleavage: -
DCC Acid chloride and benzyl alcohol Hydrogenolysis Na, NH3
Diphenylmethyl Esters DCC RCO 2H
HO
+
R
O
CHPh 2
CHPh 2 O
Cleavage:
- mild H3O+ - H2, Pd/C - BF3•OEt2
o-Nitrobenzyl Esters - selective removed by photolysis Orthoesters Synthesis 1974, 153 TL 1983, 24 , 5571
Chem. Soc. Rev. 1987, 75
O RCOCl
O
BF 3•OEt2
+ R OH
- Stable to base; cleaved with mild acid
O R
O O
O O
68
PROTECTING GROUPS
69
Amines Carbamates 9-Fluorenylmethyl Carbamate (Fmoc) Acc. Chem. Res. 1987, 20 , 401 - Cleaved with mild base such as piperidine, morpholine or dicyclohexylamine NaHCO 3 H2O, dioxane
+
R2NH
O
O Cl
O
R2N
O
2,2,2-Trichloroethyl Carbamate O
O Cl 3C
O
R2NH, pyridine Cl 3C
Cl
O
N
R
R
- Cleaved with zinc dust or electrochemically. O N
O
CCl 3
S
Te Te S
TL 1986, 27 , 4687
NaBH 4
EtO2C
NH EtO2C
S
S
2-Trimethylsilylethyl Carbamate (Teoc) - cleaved with fluoride ion. O
O Me 3Si
O
O +
O N
Me 3Si
R2NH
O
N
R R
O SiMe 3 OH Cl
O
MeO
OTBS
O N
Cl Bu4NF, THF
O CH 3
H N
MeO
O CH 3
(100%)
H O SEt
H O SEt
OEt
OEt
SEt
SEt JACS 1979, 101 7104
t-Butyl Carbamate
(BOC) O
O O
R2NH
Cleavage:
tBuO
O
OtBu R2N
OtBu
- with strong protic acid (3M HCl, CF3COOH) - TMS-I O B Cl
Allyl Carbamate
(Alloc)
O
TL 1985, 26 , 1411 TL 1986, 27 , 3753
PROTECTING GROUPS O O
R2NH
O O
O O R2N
O
- removed with Pd(0) and a reducing agent (Bu3SnH, Et 3SiH, HCO2H) O HN
1) Pd(OAc) 2, Et3N, Et3SiH 2) H3O +
O CO 2Me
Benzyl Carbanate
NH 2 TL 1986, 27 , 3753
CO 2Me
(Cbz) O BnO
O
Cl
R2NH
Cleavage:
-
R2N
O
Ph
Hydrogenolysis PdCl 2, Et3SiH TMS-I BBr3 hν (254 nm) Na/ NH3
m-Nitrophenyl Carbamate JOC 1974, 39 , 192 NO 2
O R2N
O
- removed by photolysis Amides Formamides - removed with strong acid R2NH
+
O
HCO 2Et R2N
H
Acetamides - removed with strong acid R2NH
+
O
Ac2O R2N
Trifluoroacetamides Cleavage: - base (K2CO3, MeOH, reflux) - NH3, MeOH R2NH
Sulfonamides p-Toluenesulfonyl
+
O
(CF3CO) 2O R2N
(Ts) R2NH
pTsCl, pyridine R2N
CH 3
SO 2
CF 3
70
PROTECTING GROUPS Cleavage:
Ts
- Strong acid - sodium Naphthalide - Na(Hg)
N
N
Na(Hg), MeOH Na2HPO 4
Ts
H
N
N
H JOC 1989, 54 , 2992
(65%) N
N
Ts
H
Trifluoromethanesulfonyl Tf
Tf N
N
N
NH
Na, NH3
HN
JOC 1992, 33, 5505 NH
N
HN
Tf
Tf
Trimethylsilylethanesulfonamide (SES) TL 1986, 54 , 2990; JOC 1988, 53, 4143 - removed with CsF, DMF, 95°C SO 2Cl
Me 3Si
R2NH
Et3N, DMF
R2N O
SiMe 3
S O
tert-Butylsulfonyl (Bus) JOC 1997, 62, 8604
R-NH2
tBuSOCl, Et3N, CH2Cl2
mCPBA -orRuCl3, NaIO4
O R 2N
S
tBu
R2N SO2tBu
CF3SO3H, CH2Cl2, anisole
R-NH2
71
C-C BOND FORMATION
72
Carbon- Carbon Bond Formation 1. Alkylation of enolates, enamines and hydrazones C&S: Chapt. 1, 2.1, 2.2 problems Ch 1: 1; 2; 3, 7; 8a-d; 9; 14 Ch. 2: 1; 2; 4) Smith: Chapt. 9 2. Alkylation of heteroatom stabilized anions C&S :Chapt. 2.4 - 2.6) 3. Umpolung Smith: Chapt. 8.6 4. Organometallic Reagents C&S: Chapt. 7, 8, 9 problems ch 7: 1; 2; 3, 6; 13 Ch. 8: 1; 2 Smith: Chapt. 8 5. Sigmatropic Rearrangements . C&S Chapt. 6.5, 6.6, 6.7 # 1e,f,h,op Smith Chapt. 11.12, 11.13 Enolates Comprehensive Organic Synthesis 1991, vol. 2, 99. - α-deprotonation of a ketone, aldehyde or ester by treatment with a strong nonnucleophillic base. - carbonyl group stabilizes the resulting negative charge. O H H
O-
O
B:
H -
R H
H
R
H
R H
- Base is chosen so as to favor enolate formation. Acidity of C-H bond must be greater (lower pKa value) than that of the conjugate acid of the base (C&S table 1.1, pg 3) O H 3C O H 3C
CH3
pKa = 20
unfavorable enolate concentration
MeO- pKa = 15 tBuO- pKa = 19
more favorable enolate concentration
O CH2
OEt
pKa = 10
- Common bases: NaH, EtONa, tBuOK, NaNH2, LiNiPr2, M N(SiMe3)2, Na CH2S(O)CH3 Enolate Formation: - H+ Catalyzed (thermodynamic) O
OH H+
- Base induced (thermodynamic or kinetic) O
:B
O-
+
B:H
H
Regioselective Enolate Formation Tetrahedron 1976, 32, 2979. - Kinetic enolate- deprotonation of the most accessable proton (relative rates of deprotonation). Reaction done under essentially irreversible conditions. O - Li+
O LDA, THF, -78°C
C-C BOND FORMATION typical conditions: strong hindered (non-nucleophilic) base such as LDA R2NH pKa= ~30
73
Li
N
Ester Enolates- Esters are susceptible to substitution by the base, even LDA can be problematic. Use very hindered non-nucleophillic base (Li isopropylcyclohexyl amide) O
O OR'
LDA, THF, -78°C N
E+
R
R
O
O- Li+ N Li
OR'
R
OR'
THF, -78°C
R
- Thermodynamic Enolate- Reversible deprotonation to give the most stable enolate: more highly substituted C=C of the enol form O - K+
O - K+
O tBuO- K+,
tBuOH
kinetic
thermodynamic
typical conditions: RO- M+ in ROH , protic solvent allows reversible enolate formation. Enolate in small concentration (pKa of ROH= 15-18 range) - note: the kinetic and thermodynamic enolate in some cases may be the same - for α,β-unsaturated ketones O
thermodynamic site
kinetic site
Trapping of Kinetic Enolates - enol acetates 1) NaH, DME 2) Ac2O
Ph O
Ph
+
Ph O
O
kinetic
O
isolatable separate & purify
CH3Li, THF
Regiochemically pure enolates
O
CH3Li, THF
Ph
Ph O- Li+
O- Li+
- silyl enolethers
Synthesis 1977, 91. 1) LDA 2) Me3SiCl
Ph O
C-C BOND FORMATION Acc. Chem. Res. 1985, 18, 181.
Ph
+
Ph OTMS
OTMS
kinetic
isolatable separate & purify CH3Li, THF -orBu4NF -or- TiCl4 Ph
Ph
Geometrically pure enolates
CH3Li, THF
O- M+
O- M+
- tetraalkylammonium enolates- "naked" enolates - TMS silyl enol ethers are labile: can also use Et3Si-, iPr3Si- etc. - Silyl enol ether formation with R 3SiCl+ Et3N gives thermodyanamic silyl enol ether - From Enones 1) MeLi 2) E+
1) Li, NH3 2) TMS-Cl O
O
TMSO
OSiMe3
H
H
E
O
OSiMe3
TMS-Cl, Et3N
TMS-OTf Et3N
O
OSiMe3 Li, NH3, tBuOH TMS-Cl
- From conjugate (1,4-) additions O
O- Li+
O E+
(CH3)2CuLi
E
Trap or use directly
- From reduction of α-halo carbonyls O Br
Zn or Mg
O- M+
Alkylation of Enolates (condensation of enolates with alkyl halides and epoxides) Comprehensive Organic Synthesis 1991, vol. 3, 1. 1° alkyl halides, allylic and benzylic halides work well 2° alkyl halides can be troublesome 3° alkyl halides don't work
74
C-C BOND FORMATION O
75
O a) LDA, THF, -78°C b) MeI
Me
- Rate of alkylation is increased in more polar solvents (or addition of additive) O (Me2N)3P
R NMe2 R= H DMF R-CH3 DMA
HMPA
O
O
O
S
H 3C
O
CH3N
CH3
CH3N
NMe2 NCH3 Me2N
DMSO
TMEDA
Mechanism of Enolate Alkylation: SN2 reaction, inversion of electrophile stereochemistry X C
180 ° M+ -O
Alkylation of 4-t-butylcyclohexanone: O
O R
E R
equitorial anchor
E H
H
A
E tBu
favored
A
Chair
tBu
R
R
B
O
O- M+ H O
E tBu
B
Twist Boat
R E
on cyclohexanone enolates, the electrophile approaches from an "axial" trajectory. This approach leads directly into a chair-like product. "Equitorial apprach leads to a higher energy twist-boat conformation. Alkylation of α,β-unsaturated carbonyls O- M+ R1 O
R2 Kinetic
R1
E
O R1
H
R2 E
H
R2 H
H
O- M+ R1
O R2
H
E
R1
R2 H
Thermodynamic
E
C-C BOND FORMATION
76
Stork-Danheiser Enone Transposition: - overall γ-alkylation of an α,β-unsaturated ketone O
O
LDA PhCH2OCH2Cl
HO CH3 CH3Li
PhO
OMe
H3O
PhO
CH3
+
PhO
OMe
OMe
O J. Org. Chem. 1995, 60, 7837.
Chiral enolates- Chiral auxilaries. D.A. Evans JACS 1982, 104 , 1737; Aldrichimica Acta 1982,15 , 23. Asymmetric Synthesis 1984, 3, 1. - N-Acyl oxazolidinones O
O R
H 2N
OH
Me
Ph
O
N Me
Ph
norephedrine
O
O
H 2N
R
OH
O
N
valinol O
O R
R
LDA, THF
O
N
O
O N
O LiOH, H2O, THF
O
R
OH
Et-I Me
Ph O
O R
N
O
Complimentary Methods for enantiospecific alkylations
Me Ph major product (96:4) O O LDA, THF
R
N
O LiOH, H2O, THF
O
R
OH
Et-I
Diastereoselectivity: 92 - 98 % for most alkyl halides
major product (96:4)
Enolate Oxidation Chem. Rev. 1992, 92, 919. R
O
O
O N
O
NaN(SiMe3)2, THF, -78°C
R
N
N
(88 - 98 % de)
SO2Ph O
LDA, THF
R
O tBuO
O
OH
O Ph
O
Boc N
N
OtBu O
O N
N HN Boc
O
1) HO2) CH2N2 3) TFA 4) Raney Ni
(94 - 98 % de)
O R
OMe NH2
C-C BOND FORMATION O R
Bu
Bu
O
B
N
O
Bu2BOTf, Et3N
O
O N
N
O
N
1) LiOH 2) H2, Pd/C
O
O R
N3
R
D- amino acids
O
O N
R
KN(SiMe3)2, THF
O
OH NH2
Ph
O
O
Ph
Ph
O
O
N3-
Br
Ph
R
O
O
NBS R
R
77
O N
O
N3
SO2N3
Ph
Ph
Oppolzer Camphor based auxillaries Tetrahedron, 1987, 43, 1969. diastereoselectivities on the order of 50 : 1 SO2Ph N O
R
Ar Ar
N O
R
O SO2Ph O
R N
O SO2N(C6H11)2
O
S O2
R H O
H
LDA, NBS
Et2Cu•BF3
O
O SO2N(C6H11)2
O
H
O Br
O SO2N(C6H11)2
HO
O SO2N(C6H11)2
Asymmetric Acetate Aldol O
S
O N
O
TIPSO
H
1) Br
Sn(OTf)2, CH2Cl 2, R3N, -40°C 2) TIPS-OTf, pyridine 3) NH3
O
Br
NH2
J. Am. Chem. Soc. 1998, 120, 591 J. Org. Chem. 1986, 51, 2391
85 %, 19:1 de
Chiral lithium amide basess CH3 MeO CO2Et OMe
Ph
N Li THF, -78°C (CH3)2C=O
CH3
OMe MeO
O OMe O
NH2 O
(72% ee)
C-C BOND FORMATION H N
O
Ph N
H
But O
N Li
Li N (97 % ee)
THF, HMPA TMSCl
tBu
OTMS
Ph
N
tBu
N Me
Lewis Acid Mediated Alkylation of Silyl Enolethers- SN1 like alkylations OTMS
O
tBu-Cl, TiCl4, CH2Cl2, -40°C
CH3
(79%) SPh
OTMS R
note: alkylation with a 3° alkyl halide
C(CH3)3
O
Cl
SPh
ACIEE1978, 17, 48 TL 1979, 1427
O Raney Ni
R
R
(95 %)
TiCl4, CH2Cl2, -40°C (78%)
Enamines Gilbert Stork Tetrahedron 1982, 38, 1975, 3363. - Advantages: mono-alkylation, usually gives product from kinetic enolization O
O
N
N
"Thermodynamic"
"Kinetic"
O O N H
can not become coplanar
O
O
•• N
+ N
R-I
R
H2O
O E
H+, (-H2O) enamine
-Chiral enamines O
N
Imines
E
Isoelectronic with ketones Me O
Ph N
Li
OMe
N LDA, THF, -20°C
Ph
1) E 2) H3O+
O E
E = -CH3, -Et, Pr, PhCH2-, allylee 87 - 99 %
78
Hydrazones
C-C BOND FORMATION isoelectronic with ketones Comprehensive Organic Synthesis 1991, 2, 503 O
N
N
N
Me2N-NH2
-N
N
LDA, THF
79
N
-
+
H , (-H2O)
N
E+
N
O
hydrolysis E
E
- Hydrazone anions are more reactive than the corresponding ketone or aldehyde enolate. - Drawback: can be difficult to hydrolyze. - Chiral hydrazones for asymmetric alkylations (RAMP/SAMP hydrazones- D. Enders "Asymmetric Synthesis" vol 3, chapt 4, Academic Press; 1983) OMe
MeO
N
N
H 2N
SAMP
RAMP
N
LDA
OMe
N
N
NH2
O
O3
OMe
N
H I
OTBS
(95 % de)
TBSO
TBSO
N
1) LDA 2) Ts-CH3, THF -95 - -20 °C OMe 3) MeI, 2N HCl
N
O CH3 (100 % ee)
Me O Li R1 E (C,C)
MeO
••
N N
R2
H
R1
N N
R2
Z (C,N)
H E
E
Aldol Condensation
Comprehensive Organic Synthesis 1991, 2, 133, 181. O
H
R
a) LDA, THF, -78°C b R'CHO
O
β-hydroxyl aldehyde (aldol)
OH
H
R' R
- The effects of the counterion on the reactivity of the enolates can be important Reactivity Li+ < Na+ < K+ < R4N+ addition of crown ethers
C-C BOND FORMATION - The aldol reaction is an equilibrium which can be "driven" to completion. M
O- M+
O +
R
RCHO
O
H
R'
O
work-up
OH
H
R'
80
R' R
R
In the case of hindered enolates, the equillibrium favors reactants. Mg2+ and Zn2+ counterions will stabilize the intermediate β-alkoxycarbonyl and push the equillibrium towards products. (JACS 1973, 95, 3310) O
O- M+
OH
PhCHO, THF
M= Li M= MgBr
Ph
16% yield 93% yield
- Dehydration of the intermediate β-alkoxy- or β-hydroxy ketone can also serve to drive the reaction to the right. O
O
O
tBuO- Na +, tBuOH O
JACS 1979, 101 , 1330 O
H O
H O
Enolate Geometry - two possible enolate geometries O - Li+
O - Li+
O LDA, THF, -78°C
H
+ H Z - enolate
E - enolate
- enolate geometry plays a major role in stereoselection. OM
Z -enolate R
R2
1
O
R3CHO R
R
OM R
H
1
3
erythro (syn)
R2
H
E -enolate
OH
1
O
R3CHO R
OH
1
R
R2
R
3
threo (anti)
2
- Zimmerman-Traxler Transition State : Ivanov condensation JACS 1957, 79 , 1920. +
O -
Ph
H
+
MgBr - +
PHCHCO2 MgBr
Br
H O Ph
O Mg
Ph H
"pericyclic" T.S.
OMgBr
C-C BOND FORMATION
81
Analysis of Z-enolate stereoselectivity R2 O
R3
O
M
R2
R2 O
R3
M
O
R3
O
M
O
O H
H
R1
H
R1
H
H
R3
R1
H
R1
OH
R2
erythro (syn) favored R2 O
H
R2 O
H
R2
M
O
M R1
R3
O
M
O
R3
R1
R3
R1
OH
R1
H
R3
H
H
O
H
O
R2
threo (anti) disfavored
Analysis of E-enolate stereoselectivity R3
H O
R3
M R
O
3
O R2
H
R1
H
O
O
M
R2
H
H
R2
H
R
OH
R1
R3 R2
threo (anti) favored H
H O
O
R1
H
R1
O
M
O
M
H
H
O
M
O
H
O
2
R1
R3
R2
R2
R3
R3
R1
O
M
O
OH
R1
R1
R3 R2
erthro (syn) disfavored
Analysis of Boat Transition State for Z-Enolates R2 O
R3
O
O
M
R3
H R1
H
R3
R1
H
O
HO O
M
R2
R2 R1
H
Favored Chair
Boat H O
R2 O
O
O
M
H
HO
R1 H R3
R1
Disfavored Chair
R3 R3
R2
staggered
O R2 R1 H Boat: R1-R2 1,3-interaction is gone
M
C-C BOND FORMATION
82
Analysis of Boat Transition State for E-Enolates R3
H O
M
R3
O
O O
HO
R1
R2
R1
H
H R3
O
M
H
R2
R1
R2
Favored Chair
Boat H
H O
O O
M
O
HO
R3
H R1
R2
R3
O
M
H
R2
R1
R3
staggered
R1
R2
Disfavored Chair
Boat: R1-R2 1,3-interaction is gone
Summary of Aldol Transition State Analysis: 1. Enolate geometry (E- or Z-) is an important stereochemical aspect. Z-Enolates usually give a higher degree of stereoselection than E-enolates. 2. Li+, Mg 2+, Al3+= enolates give comparable levels of diastereoselection for kinetic aldol reactions. 3. Steric influences of enolate substituents (R1 & R2) play a dominent role in kinetic diastereoselection. O- M+
O
Path A R2
R1
R1
R3
Path B
H
R2
O- M+
O H
R1
HO
R1
Path A
R2
HO R3 R2
When R1 is the dominent steric influence, then path A proceeds. If R2 is the dominent steric influence then path B proceeds. 4. The Zimmerman-Traxler like transition state model can involve either a chair or boat geometry. Noyori "Open" Transition State for non-Chelation Control Aldols Absence of a binding counterion. Typical counter ions: R4N+, K+/18-C-6, Cp2Zr2+ - Non-chelation aldol reactions proceed via an "open" transition state to give syn aldols regardless of enolate geometry. Z- Enolates: R1
O-
R1 Favored
H H
R3
R2
R3
O-
R1
H R3 O
R2
H
H
R2
HO
R1
Favored R1 O-
O-
R3 R2
Syn Aldol O
H
HO
R3
H H R R2 3 O
O
O
Disfavored H
R3 H R2
O
O R1
H
O-
R1
O-
R1 H
R2 O
Disfavored
R3 R2
Anti Aldol
C-C BOND FORMATION
83
E- Enolate: -
O
-
R1
-
R1
O
O
favored H R3
R3
R2
H
R3
H
R1
-
O
H R3
O
Syn Aldol
R1
R1
O H
R2
HO
R3
H H R3 R2
R1 H
O
O
R3 R2
R2
O favored
disfavored H
R1
H
-
O
HO
H
H R2
O
O -
R1
O
O disfavored
R3 R2
R2
Anti Aldol
NMR Stereochemical Assignment. Coupling constants (J) are a weighted average of various conformations. H
O
O
R1
Syn Aldol JAB = 2 - 6 Hz
HB R3
R2 HA 60 °
60 °
HA H O
O
HB
HB
R3
R2
R2 O
R3
OH
R3 O
R1
R2 R1
HA
HA
H
R1
O
HB
non H-bonded
O
H
OH B
R1
Anti Aldol JAB = 1 - 10 Hz
R3 R2 HA
60 ° HA H O
O
R3
R3
OH
O
R2
R2 O
HB
HA
HB
HB
R1
R2 R1
60 °
HA
H
R1
O
R3
non H-bonded
Boron Enolates:
Comprehensive Organic Synthesis 1991, 2, 239. Organic Reactions 1995, 46, 1; Organic Reactions 1997, 51, 1. OPPI 1994, 26, 3. - Alkali & alkaline earth metal enolates tend to be aggregates- complicates stereoselection models. - Boron enolates are monomeric and homogeneous - B-O and B-C bonds are shorter and stronger than the corresponding Li-O abd Li-C bonds (more covalent character)- therefore tighter more organized transition state. Generation of Boron Enolates: O
R2B-X iPrEtN
OBR2
X= OTf, I R= Bu, 9-BBN
C-C BOND FORMATION R3N:
_
H R1
+ BL2OTf O R2
H
R3N:
OBL2
Z-enolate
OBEt2
_
H
+ BL2OTf O H
R1 R2
R2
R1
R1 R2 E-enolate
O
OBR2
R 3B R OSiMe3
OBR2
R2B-X
+ Me3 Si-X
O
OBR'2
R' 3B N2
R
Hooz Reaction
R'
R
Diastereoselective Aldol Condensation with Boron Enolates O
O
OBEt2
Ph
Ph
Ph pure Z-enolate
R2
R1
OH
R3CHO R1
R3 R2
Z-enolate OBEt2
O R1
R3 R2
R2
generally > 95 : 5 syn : anti
OH
R3CHO
R1
R
100% Syn Aldol
O
OBEt2
OBEt2
RCHO
generally ~ 75 : 25 anti : syn
E-enolate
Asymmetric Aldol Condansations with Chiral AuxilariesD.A. Evans et al. Topics in Stereochemistry, 1982, 13 , 1-115. - Li+ enolates give poor selectivity (1:1) - Boron and tin enolates give much improved selectivity Bu
Bu O Me
B
O N
Bu2BOTf, EtNiPr2 , -78°
O
O - O + N
O
OH RCHO
R
O
O N
Me
> 99:1 erythro O
O
1) Bu2BOTf, EtNiPr2 , -78°
Me N
O
2) RCHO Ph
OH R
O X
Me
O
84
C-C BOND FORMATION L
L B _
O
H +
O
R
L
L B _
O
O
O
N
RCHO
H R
O
B _
O
+
O
R
O
N
L
L
B _
O
O
+
N
L
L
L
L
O
O
B _
O
O
+
+
R
N
N
O
O
O
O
preferred conformation R2 O
O L
H O
B
R3 L
R3 N
H
L
H R3
O
B
N
L
O
O
O
O
Favored O O
R2
Disfavored
O
O
OH
N
O
R3
O
OH
N
R2
R3 R2
Oppolzer Sultam L 2B
O R2
N
O R2
N
S O2
S O2
O S O
N
O
S O2
OH
O
R3CHO R2
R3
N S O2
R2
R3
N
1) LDA 2) Bu3SnCl R3 Sn
OH
O R3CHO R2
85
C-C BOND FORMATION Chiral Boron BOTf
O
OH
StBu
O
Ph
OH StBu
iPrEt2N, PhCHO,-78°C
when large, higher E-enolate selectivity
O
ArO2SN SPh
Ph
StBu
1 : 33 (> 99 % ee)
Ph
Ph
R
+
O
B Br
NSO2Ar
OH
O
Ph
OH SPh
+
Ph
SPh
R
iPrEt2N, PhCHO,-78°C
O
R
> 95 : 5 (> 95 % ee)
• In general, syn aldol products are achievable with high selectivity, anti aldols are more difficult Mukaiyama-Aldol- Silyl Enol Ethers as an enolate precursors. Lewis acid promoted condensation of silyl ketene acetals (ester enolate equiv.) with aldehydes: proceeds via "open" transition state to give anti aldols starting from either E- or Z- enolates. OSiMe3
RCHO, TiCl4, CH2Cl2, -78°C
OH
OH CO2Et
R OEt
+
CO2Et
R
CH3
CH3
R= iPr (anti : syn) = 100 : 0 C6H11 94 : 6 Ph 75 : 25
OSiMe3
RCHO, TiCl4, CH2Cl2, -78°C
OH R
OEt
OH CO2Et
+
CO2Et
R
CH3
CH3
R= iPr (anti : syn) = 52 : 48 C6H11 63 : 37 Ph 67 : 33
Asymmetric Mukiayama Aldol: Ph H 3C
O OSiMe3 NMe2
RCHO, TiCl4, CH2Cl2, -78°C
OH R
O
OH Rc
+
R
O Rc
(90-94% de) syn : anti = 85 : 15 selectivity insenstivie to enolate geometry
86
C-C BOND FORMATION Ph N SO Ph 2 O
O
iPrCHO, TiCl4, CH2Cl2, -78°C
HO 96 % de anti : syn = 93 : 7
Rc
OSitBuMe2
CH3
O
RCHO, TiCl4, CH2Cl2, -78°C
O
87
HO + Syn product
Rc CH3
OSitBuMe2 SO2N(C6H11)2
E-Enolate R= Ph % de= 90 nPr 85 iPr 85
anti : syn = 91 : 19 94 : 6 98 : 2
Z-Enolate R= iPr % de= 87
anti : syn = 97 : 7
Mukaiyama-Johnson Aldol- Lewis acid promoted condensation of silyl enol ethers with acetals: OSiMe3
OH
O TiCl4 or SnCl4
Mukaiyama-Johnson Aldol
R RCHO or RCH(OR')2 CH2Cl2, -78°C
via Ti or Sn enolate
O
O TiCl4, CHCl2, -78 °C
O
O
O HO
O
O O
OTMS
+ Cl4Ti
O+
O
Cl4Ti
O
O
OSiMe3
OTMS Ph
TiCl4, (CH3)2C(OEt)2 (78 %)
O
OEt
Ph
Fluoride promoted alkylation of silyl enol ethers
Acc. Chem. Res. 1985, 18, 181 O
OSiMe3 nBu4NF, THF, MeI
C-C BOND FORMATION
88
Meyer's Oxazolines: O
(ipc)2BOtf iPrEt2N, Et2O
N
1) RCHO 2) 3N H2SO4 3) CH2N2
O
H 3C
CO2Me
OH
(ipc)2B Ester equiv.
R
+
CO2Me
(~ 30%)
N
H 3C
R
OH
R= nPr %ee (anti) = 77 anti : syn = 91 : 9 C6H11 84 95 : 5 tBu 79 94 : 6
Anti-Aldols by Indirect Methods: SePh O PhSe
C6H11
1) (C5H7)2BOTf R3N
1) TBS-Cl 2) DiBAl-H
3) NaIO4 4) CH2N2
O
CO2Me
HO
CH3
O3
R
R
HO
Anti Aldol Product
CHO
OTBS CO2Me
OTBS O 1) LDA, THF, -78 °C 2) RCHO
N
OH
1) HIO6 2) CH2N2
O
N
MeO2C
R CH3
R CH3
Anti Aldol O
MOMO O
O MeO
O
MOMO 1) LDA, THF, -78 °C
N O
R
syn aldol CH3
3) TsCl 4) Ba(CN)BH3
C6H11
HO
chiral auxillary
CO2Me
R
R
2) RCHO
OTBS
1) HF 2) [O]
OTBS
N
N
KBEt3H, Et2O, -78 °C
O
MeO
CH3 CH3
CH3
syn : anti 1 : 99
OMOM
CH3 OMOM
2) RCOCl
HO
O
MOMO Zn(BH4)2
HO
N
CH3
syn : anti 97 : 3
CH3 OMOM
Syn Aldols by Indirect Methods: O O
O N
O
1) LDA, THF, -78 °C
O
O
O
Zn(BH4)2 O
2) RCOCl
O N
R CH3
O
OH
N
R CH3
syn : anti = 100 : 1
C-C BOND FORMATION Aldol Strategy to Erythromycin: O 9
10
8
11
OH
12 13 O 1
O
3
2
1
6
OH
4
Erythromycin seco acid
CO2H
5
15 14
4 7
OH
OH
O
OH
OH
3
OH
2
[O]
[O] syn aldol
Erythromycin aglycone
3
CHO
CO2H
OH
O
syn aldol
OH syn aldol
4
+
CHO
OH 1
CHO
CHO O
+ CO2H
OH syn aldol
CHO
2
+
CHO
O 1 HO2C
O
O
O
O
LDA, CH3CH 2COCl
N
O
O
OH
OH
O
OH
3
5
9
11
13
O
O
O
TiCl4, iPr 2EtN, CH2Cl2 O
N 1
83%, (96:4)
O
N
90% (> 99:1)
O
O
1) 9-BBN, THF 2) Swern oxid.
3
5
73% (85:15)
O O
O
5
O
O
Ph
O CHO
N
Ph
Ph
O
1) Zn(BH3)2 2) (H3C)2C(OMe)2 CSA
OH
CHO Ph
O
N
O
(100%)
Ph
O
OH
O
O
O
Sn(OTf)2, Et3N, CH2Cl2 O
N CH3CH 2CHO
O
O
OH
N 9
11
13
1) Na BH(OAc)3 2) TBS-OTf, 2,6-lutidine 3) AlMe3, (MeO)MeNH•HCl MeO 72% (>99:1)
84% (> 96:4) Ph O
OH
OTBS
11
13
EtMgBr 86%
8
Ph 1) PMBC(NH)CCl3 TfOH 2) (PhMe2Si)2NLi, TMS-Cl 48 %
PMBO TMSO
OTBS
O N CH3
OH
OTBS
89
C-C BOND FORMATION X
L
H3C H Sn H O L O
X O
O
O
X
H
O O
O N
O 3
H3C CH3
O
CHO 7
O
R
H H
anti-syn
+
O O
13
1) Zn(BH3)2 2) DDQ
O
O
OH
O
N
OTBS
O
O
O
OH
PMBO O
3
5
7
9
13
70%
O
O
O
p-MeOC 6H4 O
OTBS
1) LiOOH 2) TBAF
O
N
O
O
O
O
OH
Cl3C6H2COCl iPr2EtN, DMAP
HO 63%
Ph
11
OTBS
1) NaH, CS2, MeI 2) nBu3SnH, AIBN
N
Ph p-MeOC 6H4 O
O
Ph O
95%
O
O L
83% (95:5)
p-MeOC 6H4 O
L
Ti O
J. Am. Chem. Soc. 1990,112, 866
L
H3C CH3
BF3•OEt2, CH 2Cl2, -78 °C
OTBS
11
Ph O
H CH3 CH3
X
CH3 CH3
8
O
Disfavored
O
H3C H
OH
X
PMBO TMSO
5
O
Disfavored
O
O
L
CH3
H
anti-syn
H L CH3 Sn H O O L
O
Ti
CH3 CH3
H CH3 CH3
X
L
R
H
O
L
OH
13
p-MeOC 6H4
(86%
O 9
O 9
10
1) Pd(OH)2, iPrOH 2) PCC 3) 1M HCl, THF
8 11
7
O
12
O
58 %
13
O
4
1
O
OH 5
6 5
13
11
OH
1
3
O
3
2
O
OH
O
Michael Addition - 1,4-addition of an enolate to an α,β-unsaturated carbonyl to give 1,5-dicarbonyl compounds -
O
+
O
O
O M
Ph
R
Ph
R
Organometallic Reagents Grignard reagents: O R-Br
Mg(0)
OH R-MgBr R
THF
O O
OH R-MgBr
THF
R
often a mixture of 1,2- and 1,4-addition
+ R
90
C-C BOND FORMATION
91
O OH R-MgBr
O R-MgBr
1,2-addition
R
THF, CeCl3
O 1,4-addition
CuI,THF, -78C R
Organolithium reagents - usually gives 1,2-addition products - alkyllithium are prepared from lithium metal and the corresponding alkyl halide vinyl or aryl- lithium are prepared by metal-halogen exchange from the corresponding vinyl or aryl- haidide or trialkyl tin with n-butyl, sec-butyl or tbutyllithium. Li(0)
R-Br
R-Li
Et2 O X
Li
nBu-Li
X= Br, I, Bu3Sn
Et2 O
Organocuprates Reviews: Synthesis 1972, 63; Tetrahedron 1984, 40 , 641; Organic Reactions 1972, 19 , 1. - selective 1,4-addition to α,β-unsaturated carbonyls CuI, THF
2 R-Li
R2CuLi O
O R2CuLi
R
- curprate "wastes" one R group- use non transferable ligand _
MeO
MeO
Cu
Li+
Cu R
R-Li
non-transferable ligand Other non transferable ligands _ _ + Bu3P Cu R Li Me2S Cu R Li+
_
_ NC Cu R
Li
+
F3B Cu R
Li+
22Li
Cu R
S
Mixed Higher Order Cuprate B. Lipshutz Tetrahedron 1984, 40 , 5005 Synthesis 1987, 325.
+
CN
Addition to Acetals O R
CH3
n-C6 H13
(n-C6H13)2CuLi
H3C O
Tetrahedron Asymmtetry 1990, 1, 477. O
BF3•OEt 2 R
1) PCC 2 NaOEt OH
LA
O O H
CH3
O O
R
CH3 Nu:
H
CH3
OH Chiral axulliary is destroyed 99 % ee LA
R
n-C6 H13
O H R
O Nu
TL 1984, 25, 3087
C-C BOND FORMATION
92
TMS O
1) TiCl4
O
2) [O] 3) TsOH
JACS 1984, 106, 7588 OH
98 % ee
Stereoselective Addition to Aldehydes - Aldehydes are "prochiral", thus addition of an organometallic reagent to an aldehydes may be stereoselective. - Cram's Rule JACS 1952, 74 , 2748; JACS 1959, 84 , 5828. empirical rule O R
1
*
OH
-
M S
1) "R2 - " 2) "H + "
R1
R
M S
2
L
L
O
OH
M
S
M
R2
L R1
-
R
S
1
L
R
2
- Felkin-Ahn TL 1968, 2199; Nouv. J. Chim. 1977, 1 , 61. based on ab initio calculations of preferred geometry of aldehyde which considers the trajectory of the in coming nucleophile (Dunitz-Burgi trajectory). O L
R2 R
S
vs.
M
R2
-
L
-
S
1
O
M
better
R
1
worse
- Chelation Control Model- "Anti-Cram" selectivity - When L is a group capable of chelating a counterion such as alkoxide groups + M
OH
O R
OR' R1
*
S M
2
R
1
OR' "Anti-Cram" Selectivity
M S
M+ O OR'
HO
R2 M R
1
-
M
S
OR' R2 R1
S
Umpolung - reversal of polarity Aldrichimica Acta 1981, 14, 73; ACIIE 1979, 18, 239. i.e: acyl anion equivalents are carbonyl nucleophiles (carbonyls are usually electophillic) O R
Benzoin Condensation O-
KCN PhCHO Ph
H CN
usually -
R
O +
Comprehensive Organic Synthesis 1991, 1, 541. OH Ph - CN Cyanohydrin anion
PhCHO
HO Ph
OCN
Ph
-O Ph
CN
O
OH Ph
Ph
OH
Ph Benzoin
C-C BOND FORMATION 93 Thiamin pyrophosphate- natures acyl anion equivalent for trans ketolization reactions H
NH2
NH2
_
+ N
N N
H 3C
+
S
N
N
S
OPO3PO3
H 3C
H 3C
N
OPO3PO3
H 3C
Thiamin pyrophosphate CHO H
H 2C
OH
H
+
H
OH
H 2C
OPO3
thiamin-PP
O HO
OH
H 2C
OH
H 2C
+
OPO3
OPO3
glyceraldehyde-3-P (C3 aldose)
D-ribulose-5-P (C5 ketose)
D-ribose-5-P (C5 aldose)
H
OH
H
OH
CHO
O
OH
H
H 2C
OH
H
H
OH
H
OH
H
OH
H 2C
OPO3
sedohepulose-7-P (C7 ketose)
Trimethylsilycyanohydrins O R
TMSO
TMS-CN
CN
R
H
LDA, THF
TMSO
H
CN
acyl anion equivalent
_
R
O
NC OMs OEE
NaHMDS, THF, -60°C
CSA, tBuOH
CN O
Tetrahedron Lett. 1997, 38, 7471
(72%)
OEE
O
O
O
O
O
Dithianes B:, THF S
S
S
R
H
R
O
Hg(II)
R'-I
S -
S
S
R
R'
R
R'
Aldehyde Hydrazones B:
H N
R
N
tBu
R
H
Heteroatom Stabilized Anions Sulfones R
LDA, THF
S O
H
O R
E
E
(Dithiane anion is an example) O
_ Ph
tBu
N
E+
N
Ph R
S O
O
R'
R'
OH
R'
Al(Hg)
R'
R'
OH
R' Ph
R
O
S O
R O
Sulfoxides O
R'
_ Ph R
S O
LDA, THF
Ph R
S O
R'
R'
OH
Raney Ni
R' Ph R
R' R'
S O
R
OH
C-C BOND FORMATION Epoxide Opening
94
Asymmetric Synthesis 1984, 5, 216.
Basic (SN2) Condition
Nu: R
R
Nu
Steric Approach Control O
HO
Acid (SN1-like) Condition R
R
Nu: attachs site that best stabilizes a carbocation
OH
O+ Nu
Nu
H
OH
O
OH
BnO
OH
BnO
+
OH
BnO
TL 1983, 24, 1377
OH Me2CuLi AlMe3
O
6:1 1:5 OH
Me3Al
JACS 1981, 103, 7520
S
S
OH S
_
O
JOC 1974, 3645 S
O S Ph
+
S _
S
O
OH
Ph
(69 %) 1) TBS-Cl 2) MeI, CaCO 3, H+
S
OH
Tetrahedron Lett. 1992, 33, 931
Ph
Cyclic Sulfites and Sulfates (epoxide equivalents)
Synthesis 1992, 1035.
O OH R2
R1
SOCl2, Et3N
O
S O
R1
OH
O
RuCl3, NaIO4
O
S O
O
R1
Nu:
R2
O
R1
R2
R2
sulfate
sulfite O
O
O
S
-
O
S O
H
H2O
R2 Nu
R1
HO
H R2 Nu
R1 H2O
O
O
O S O R1
O R2
Nu:
O S O R1
OH R2 Nu
H
Nu: Nu2
R1
H R Nu1 2
C-C BOND FORMATION CO2Me
O SO2
O
2) TBS-Cl
CH3
OBn
MeO OMe
O SO2
carpenter Bee pheromone
O
CO2Me
O
OMe
OBn
OMe
H N
H3C
OMe NCH3
OMe
1) Ac2O 2) HCl
∆
O
OH
MeO OBn
R2
1) H2, Rh 2) HF
OTBS
1) (CH3)2CuLi
CO2Me
R1
NaH
O
O SO2
CO2Me
CO2Me
R2
R1
MeO2C
MeO meso
OBn
OBn
HO
OBn OMe
MeO
OMe
MeO
NCH3
BnO
NCH3
BnO OAc
Irreversible Payne Rearrangement OH
O OH
O O SO2 OH
Bu 4NF
OTBS O
O
Payne Rearrangement of 2,3-epoxyalcohols Sigmatropic Rearrangements Nomenclature: σ bond that breaks
Asymmetric Synthesis 1984, 3, 503.
1
2 3 R
1
3 R
2
∆
1
2 3 R
1
R
R
H
σ bond that breaks
σ bond that forms
[3,3]-rearrangement
3 4
1
3
2
3 2
Aldrichimica Acta 1983, 16, 60
2
∆
5
4
1 R
H
1
1
[1,5]-Hydogen migration
5
σ bond that forms
3,3-sigmatropic Rearrangements Cope Rearrangemets- requires high temperatures R
∆
R
Organic Reaction 1975, 22, 1
95
C-C BOND FORMATION
96
Chair transition state: CH3
CH3 Z
220 °C
H 3C H
H 3C E
H
E,Z (99.7 %)
Z,Z (0 %)
E,E (0.3 %)
CH3
H HH
H 3C H 3C
CH3
H
CH3 Z
E
H 3C H 3C E
E,Z (0 %)
H 3C
Z
Z,Z (10 %)
E,E (90 %)
"Chirality Transfer" H
Ph R
S CH3
E Ph
CH3
CH3
(87 %) Diastereomers
Ph Ph H 3C
H 3C
Z CH3 R (13 %) H
R E
Ph
R
CH3 R H
E Z
CH3
Ph CH3
Diastereomers Ph Ph
H 3C
H 3C R Z
Z H S CH3
- anion accelerated (oxy-) Cope- proceeds under much milder conditions (lower temperature) JACS 1980, 102 , 774; Tetrahedron 1978, 34, 1877; Organic Reactions 1993, 43, 93; Comprehensive Organic Synthesis 1991, 5, 795. Tetrahedron 1997, 53, 13971.
C-C BOND FORMATION O
OMe
OH
97
KH, DME, 110°C
OMe
KH
OH
O
O-
Ring expansion to medium sized rings OH
O
KH, ∆
9-membered ring
Claisen Rearrangements - allyl vinyl ether to an γ,δ-unsaturated carbonyl Chem. Rev. 1988, 88, 1081.; Organic Reactions 1944, 2, 1.; Comprehnsive Organic Synthesis 1991, 5, 827. ∆ O
O
O
OH
CHO O
220 °C
Hg(OAc)2
JACS 1979, 101 , 1330
O
O
O
H
H
H
O
O
O
Chair Transition State for Claisen E-olefin
R
O
O R
H
X
X
X=H X= OEt, NMe2, etc R
O
1,3-diaxial interaction
X R
E/Z = 90 : 10 E/Z = > 99 : 1
Z-olefin R
X
X
H O
O
new stereogenic centers R old stereogenic center
O O H
X
R X
C-C BOND FORMATION 98 - Chorismate Mutase catalyzed Claisen Rearrangement- 105 rate enhancement over non-enzymatic reaction CO2H
O
CO2H
HO2C
Chorismate mutase
J. Knowles JACS 1987, 109, 5008, 5013
O
CO2H
OH
OH
Chorismate
Prephenate
- Claisen rearrangement usually proceed by a chair-like T.S. HO2C
H HO2C
O
H CO2H
H H
O
Chair T.S
OH
OH
Opposite stereochemistry
H H O
CO2H CO2H
CO2H
H
Boat T.S
H
OH
O CO2H
OH OH
OH
OH +
O
J. Org. Chem. 1976, 41, 3497, 3512 J. Org. Chem. 1978, 43, 3435
O
+
O R
R
O
H
H
O
s CH3
R
O R
H
CH3
H s CH3
O H
CH3 CH3
OH
CH3
OH
O
CH3 H
CH3 CO2R
CH3
OH
CH3
OH
Tocopherol 94 - 99 % ee
hydrophobically accelerated Claisen - JOC 1989, 54, 5849
C-C BOND FORMATION Johnson ortho-ester Claisen: EtO OEt OH
OEt
O
H3C-C(OEt)3
∆
OEt [3.3]
O
O
- EtOH
H+
Ireland ester-enolate Claisen.
Aldrichimica Acta 1993, 26, 17. OTMS
O
LDA, THF TMS-Cl
O
OH [3.3]
O
O
O LDA, THF TMS-Cl
OBn
O
Me CO2H
Me Me
Me
JOC 1983, 48, 5221
OBn
Eschenmoser NMe2
R OH
EtO
OEt
∆
O
O NMe2
NMe2
BF3
R
R
"Chirality Transfer" R
R N
O
N
R
Ph
N
O
aldehyde oxidation state
O
Ph
Ph (86 - 96 % de)
R= Et, Bn, iPr, tBu
[2,3]-Sigmatropic Rearrangement H
Z
Comprehensive Organic Synthesis 1991, 6, 873. H
H
:X Y
X Y:
R
R
R
H X
Y:
R
R1
R H
-Wittig Rearrangement
:X
Y
Organic Reactions 1995, 46, 105 _
base
O
O
SnR3
BuLi
:X Y
R
R1
X Y:
E
HO
_ O
Synthesis 1991, 594.
99
C-C BOND FORMATION TBDPSO
TBDPSO
KH, 18-C-6, Me3SnCH2I
TBDPSO nBuLi
H MeO
H
O
MeO
H
O
MeO
OH
O
O
O SnMe3
TBDPSO
+
O
H MeO
H3C
O
OH
(58%)
(42%)
CH3 Ph _
O
CH3
H3C
CH3
CH3 H
(87 %)
OH
Ph
H
_
O
CH3 Ph
H3C
Sulfoxide Rearrangement R
J. Am. Chem. Soc. 1997, 119, 10935
Li
TBDPSO H
MeO
100
R
S -
O
S
(13 %) OH
Ph
(MeO) 3P HO
O
O
O CO2Et
CO2Et
(MeO) 3P
Ph
S
HO
O-
Ene Reaction Comprehensive Organic Synthesis 1991, 5, 1; Angew. Chem. Int. Ed. Engl. 1984, 23, 876; ; Chem. Rev. 1992, 28, 1021. H
H
- Ene reaction with aldehydes is catalyzed by Lewis Acids (Et2AlCl) R
R
H O H
O H
OH CHO
JOC 1992, 57, 2766
Et2AlCl CH2Cl2 -78°C
Ph O
O
O Ph O
O H
OH
SnCl4
Ph O SnCl4
99.8 % de
O OH + syn isomer
H3C
(94 : 6)
C-C BOND FORMATION O TiCl2 O OH
O H
CO2Me
CO2Me
PhS
+
H
OH
OH
O R
Tetrahedron Lett. 1997, 38, 6513
(97% ee)
+
+
PhS
CO2Me
CO2Me R
syn (90 % ee)
Angew. Chem. Int. Ed. Engl. 1989, 28, 38 CH3
CH3 C6H13
CH3
CO2Me R
(9 : 1)
anti (99 % ee)
- Metallo-ene Reaction
PhS
C6H13
H2O
C6H13
(10 %)
H 3C ClMg
Cl
C6H13
MgCl H 3C
C6H13
H2O H 3C
ClMg
H 3C (> 1%)
intramolecular
BrMg +
(11 : 1)
+
MgBr
BrMg
1)
CH3
1) Mg(0), Et2 ) 2) 60 °C
Li
CHO 2) SOCl2
MgCl MgCl
Cl
CH3
O
CH3 OH
Cl
SOCl2
CH3
CH3 MgCl
O2 H
1) PCC 2) MeLi 3) O3
CH3 CHO
4) KOH 5) H2 6) Ph3 P=CH2
MgCl
H3C
H
H O
1) Mg(0), Et2 ) 2) 60 °C
Capnellene
H
OH
101
C-C BOND FORMATION Synthesis of Phyllanthocin O
A. B. Smith et al. J. Am. Chem. Soc. 1987, 109, 1269. O
O (Me3Si)2 NLi
O
N
Ph
O
O
1) LAH 2) BnBr
N
Br Ph
CH3
CH3
BnO 1) O3 2) H2, Lindlar's
BnO
MeAlCl CHO
BnO
1) MEM-Cl 2) O3
H
BnO
BnO
CH3
O H
OH
CHO OMEM
O
1) 2)
-
O
O
2) H
O
MEMO
3) Swern
O
1) DBU 2) H2, Pd/C
O 3) RuO4
O
O
O O
(CH3 )2S(O)CH 2-
CH O 3
O
BnO
O
O
O
1) LDA, TMSCl 2) BnMe3 NF, MeI
O
O
HO2C
O BnO
O
O BnO
O
+
O
H3O +
O
1) ZnCl2
BnO
CH3
O
CH3 MeO2C
O
O O
Ph
Phyllanthocin
102
C=C BOND FORMATION C=C Bond Formation 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 11.
103
C&S Chapt. 2 # 5,6,8,9,12
Aldol Condensation Wittig Reaction (Smith, Ch. 8.8.A) Peterson Olefination Julia-Lythgoe Olefination Carbonyl Coupling Reactions (McMurry Reaction) (Smith Ch. 13.7.F) Tebbe Reagent Shapiro and Related Reaction β−Elimination and Dehydration From Diols and Epoxides From Acetylenes From Other Alkenes-Transition Metal Catalyzed Cross-Coupling and Olefin Metathesis
Aldol Condensation -Aldol condensation initially give β-hydroxy ketones which under certain conditions readily eliminated to give α,β-unsaturated carbonyls. OMe
OMe LDA, THF, -78°C O O
OMe OR
O
O
O
Tetrahedron 1984, 40, 4741
CHO
-78C → RT
OMe OR
O
Robinson Annulation : Sequential Michael addition/aldol condensation between a ketone enolate and an alkyl vinyl ketone (i.e. MVK) to give a cyclohex-2-en-1one JOC 1984, 49 , 3685 Synthesis 1976, 777. O
O
O
O
O
L-proline
Weiland-Mischeler Ketone (chiral starting material)
Mannich Reaction - α,β-unsaturated carbonyls (α-methylene carbonyls) O
H2C=O, Me2NH•HCl Me
H 2C N + Me
O Cl-
Mannich Reaction
C=C BOND FORMATION
104
Wittig Reaction review: Chem. Rev. 1989, 89, 863. mechanism and stereochemistry: Topic in Stereochemistry 1994, 21, 1 - reaction of phosphonium ylide with aldehydes, ketones and lactols to give olefins R
X
Ph3P
R X
O R1
strong base
+ PPh3
R
-
+ PPh3
R
Ph3P O
PPh3
phosphorane
ylide
+ Ph3P O -
R2
_
- Ph3P=O
R2
R R R1 2
R
R R1 2
R
R1
oxaphosphetane
betaine
- Olefin Geometry O L
S Z- olefin
Ph3P L
S O L
S
E- Olefin
Ph3P S
L
- With "non-stabilized" ylides the Wittig Reaction gives predominantly Z-olefins. Seebach et al JACS -
O
O O L
S
L
S
S
L
L
S
O
+ PPh3
S
- Ph3P=O L L
S S
S
S
S
L
L
Z-olefins
- "Stabilized ylides" give predominantly E-olefins O + Ph3P
L
O PPh3
Ph3P L
S
S
PPh3 +
+ PPh3
L
L
_
L CO2Me
S
S L
CO2Me
C=C BOND FORMATION
105
- Betaine formation is reversible and the reaction becomes under thermodynamic control to give the most stable product. - There is NO evidence for a betaine intermediate. - Vedejs Model: R O
H R
Ph Ph P
Pukered (cis) oxaphosphetane (kinetically favored)
Cis
H Ph
H
R
Ph Ph P
R H
Planar (trans) oxaphosphetane (thermodynamically favored)
Trans
O
Ph
Phosphonate Modification (Horner-Wadsworth-Emmons) (EtO)3P
R X Arbazov Reaction
R
_ R
P(OEt)2
P(OEt)2 O
O
- R is usually restricted to EWG such as CO2H, CO2Me, CN, SO2Ph etc. and the olefin geometry is usually E. - Still Modification
TL 1983, 24, 4405. (CF3CH2O)2P
CO2Me
O
- CF3CH2O- groups make the betaine less stable, giving more Z-olefin. O CHO
Me3Si
(CF3CH2O)2P -
CO2Me Me3Si +
CO2Me
(Me3Si)2N K , THF, 18-C-6
Peterson Olefination
JACS 1988, 110, 2248
Z:E = 25:1
review: Synthesis 1984, 384
Organic Reactions 1990, 38 1. -
O
O
Me3Si
CO2Me
LDA, THF Me3Si
_
CO2Me
R1
R2
R1 Me3Si MeO2C
Silicon can stabilize an α- negative charge O R1
R2
Me3Si MeO2C
- Me3Si-O
R1 R2
H
usually a mixture of E and Z olefins CO2Me
R2
H
C=C BOND FORMATION Julia-Lythgoe Olefination
106
TL 1973, 4833 Tetrahedron 1987, 43, 1027 OH
SO2Ph LDA, THF, -78°C
OTBS
1) MsCl, Et N OTBS 2) Na(Hg),3MeOH
TL 1991, 32, 495
mixture of olefins
CHO
TBSO
R
PhO2S
R
R Tetrahedron Lett. 1993, 34, 7479
O O
H O
O 1) tBuLi, THF, HMPA, -78°C 2) Na(Hg) NaHPO4 THF, MeOH, -40°C
OBz
OSitBuPh2
HO
O
OSitBuPh2
HO
O
HO
O
O
O
OH
OH
OH
Milbemycin α1
OR OTBDPS
O
SmI2, HMPA/THF
O
R= H, Ac
O
SO2Ph
O
O
OBz
+ PhO2S
O O
OTBDPS
Synlett 1994, 859
75 % yield E:Z = 3 : 1
Ramberg-Backlund Rearrangement Br OSiPh2tBu
1) Na2S•Al2O3 2) mCPBA
OSiPh2tBu
O
OSiPh2tBu
S
SOCl2
OSiPh2tBu
O
Br Cl O
OR
S
MeLi, THF
OR
O
O
OR
S
- SO2
OR
OR
O thiiarane dioxide
OR JACS 1992, 114, 7360
Carbonyl Coupling Reactions (McMurry Reaction) Reviews: Chem. Rev. 1989, 89, 1513. - reductive coupling of carbonyls with low valent transition metals, Ti(0) or Ti(II), to give olefins O "low-valent Ti" R1
R2
R1
R1
R2
R2
+
R1
R2
R2
R1
usually a mixture of E and Z olefins
excellent method for the preparation of strained (highly substituted) olefins - Intramolecular coupling gives cyclic olefins
C=C BOND FORMATION
107
CHO "low-valent Ti"
JACS 1984, 106, 723
CHO
OMe
OMe
TiCl4, Zn, pyridine (86 %)
OMe
OHC
Tetrahedron Lett. 1993, 34, 7005 OMe OH OH
O
Tebbe Reagent Cp2Ti(CH2)ClAlMe2 - methylenation of ketones and lactones. The later gives cyclic enol ethers. H2 C Ti AlMe2 Cp Cl Cp
O
O
O
200 °C O
- Cp2TiMe2 will also do the methylenation chemistry JACS 1990, 112, 6393. Shapiro and Related Reactions Organic Reactions 1990, 39, 1 : 1976, 23, 405 - Reaction of a tosylhydrazone with a strong base to give an olefin. NNHTs Et
N
2 eq. nBuLi
_ N
Et
N N
Ts
Et
Et
- N2
_
THF
Me
_
Me
Me
E
_ E+
Me
Et
Me
Bamford-Stevens Reaction- initial conversion of a tosylhydrazone to a diazo intermediate H
H
R1 R2
R3
H
R1 R2
base
R1 R2
R3
NNHTs
N N _
R3 +N _ N
Ts
a: aprotic- decomposition of the diazo intermediate under aprotic conditions gives and olefin through a carbene intermediate. H R1 R2
R3
H
- N2
R1 R2
+N _ N
R1
R3 ••
R3
R2
Carbene
b. protic- decomposition of the diazo intermediate under protic conditions an olefin through a carbonium ion intermediate. H R1 R2
H R3
+N _ N
H+
R1 R2
R3 + N N
H
- N2
H R1 R2
R3 + H
-H
R1
+
R2
R3
C=C BOND FORMATION
108
β- Eliminations Anti Eliminations - elimination of HX from vicinal saturated carbon centers to give a olefin, usually base promoted. - base promoted E2- type elimination proceeds through an anti-periplanar transition state. B:
H R1 R3
R2 R4
R1
R2
R3
R4
X
- typical bases: NaOMe, tBuOK, DBU, DBN, DABCO, etc. N
N
N
N
N N
DBN
DBU
DABCO
- X: -Br, -I, -Cl, -OR, epoxides O
O
O
B:
OH
R
R
O
R
N AlEt2
R'
OH
R
- or TMS-OTf, DBU
"unactivated"
BCSJ 1979, 52, 1705 JACS 1979, 101, 2738
R'
Syn Elimination - often an intramolecular process H R1
R2
R1
R2
X R3
R4
R3
O X=
R4
O
Se
S Ph
Ph
Cope Elimination- elimination of R2NOH from an amine oxide OLI
O
+ Me2N=CH2 I -
O NMe2
THF, -78°C
ON Me2
mCPBA THF
O
O 1) Me2CuLi + 2) Me2N=CH2 CF3CO2-
NMe2
JACS 1977, 99 , 944 Tetrahedron 1977, 35 , 613
O - Me2NOH
C=C BOND FORMATION Selenoxide Elimination
109
Organic Reactions 1993, 44, 1.
O N SePh R'
R
R
Bu3P: O
R'
R
- or NO2
OH
mCPBA
R'
H
SeAr
- ArSeOH
R'
R
JACS 1979, 101, 3704
Se O
SeAr
SeCN
H 3C H3CHN
O H 3C N
H 3C
PhSeO2H, PhH, 60 °C
O N
H3CHN
(82%)
Ph
O H 3C
O
O
JOC 1995, 60, 7224 JCS P1 1985, 1865
N
N
Ph
O
Dehydration of Alcohols - alcohols can be dehydrated with protic acid to give olefins via an E 1 mechanism. - other reactions dehydrate alcohols under milder conditions by first converting them into a better leaving group, i.e. POCl3/ pyridine, P2O5 Martin sulfurane; Ph2S[OCPh(CF3)2]2 JACS, 1972, 94, 4997 dehydration occurs under very mild, neutral conditions, usually gives the most stable olefin OH
MSDA, CH2Cl2
BzO
JACS 1989, 111 , 278
BzO
H
H
Burgess Reagent (inner salt) JOC, 1973, 38, 26 occurs vis a syn elimination _ + MeO2CNSO2NEt3 H R1 R2
_ + MeO2CNSO2NEt3
R3 R4
MeO2C
- N SO2 H O
PhH, reflux
OH
Olefins from Vicinal Diols Corey-Winter Reaction
R1
R2
R4 R3
R1
R4
R2
R3
JACS 1963, 85, 2677; TL 1982, 1979; TL 1978, 737 S
OH R'
Im2C=S
O
O
R
R3P: R
OH
R
R'
R'
C=C BOND FORMATION
110
- vic-diols can be converted to olefins with K2WCl6 JCSCC 1972, 370; JACS 1972, 94, 6538 - This reaction worked best with more highly substituted diols and give predominantly syn elimination. - Low valent titanium; McMurry carbonyl coupling is believed to go through the vic-diol. vic-diols are smoothly converted to the corresponding olefins under these conditions. JOC 1976, 41 , 896 Olefins from Epoxides Ph2P -
O R1 H
HO H
H R2
R2
HO H
MeI
H PPh2
R1
R2
H PPh2Me +
R1
+ PPh2Me
HO R2
-
NC-Se -
O H H
R1
R2 NCO H R1
H
R1
R2
H
H
"inversion " of R groups
H
R1
R1
-Ph2MeP=O
R2
-
H SeCN
OR 2
R1 R1
-
NCOR 2
H
H
R1
R2 H
H
R2
H Se
Se -
NCSe O H
Se
R1
H
H
R2
H
"retention" of R groups
From Acetylenes - Hydrogenation with Lindlar's catalyst gives cis-olefins R
R'
Co2(CO)8
R
H2, Rh
R'
R
Co2(CO)6
R'
Bu3SnH
Tetrahedron Lett. 1998, 39, 2609 H
SnBu3
R
R'
From Other Olefins Sigmatropic Rearrangements - transposition of double bonds Birch Reduction
Tetrahedron 1989, 45, 1579 OMe
OMe
H3O+
O
H
C=C BOND FORMATION
111
Olefin Isomerization- a variety of transition metal (RhCl3•H2O) catalyst will isomerize doubles bonds to more thermodynamically favorable configurations (i.e. more substituted, trans, conjugated) RhCl3•3H2O
JOC 1987, 52 , 2875
EtOH OH
OH
Cl
Cl Ti
JACS 1992 114 , 2276
+
up to 80% ee
Olefin Inversion Tetrahedron 1980, 557 - Conversion of cis to trans olefins - Conversion of trans to cis- olefins R
R'
R
hν, PhSSPh
R' OH
OH
I2, CH2Cl2
CO2Me
HO
C5H11 OH
CO2Me C5H11
OH
OH
JACS, 1984, 107, xxxx
Transition Metal Catralyzed Cross-Coupling Reactions Coupling of Vinyl Phosphonates and Triflates to Organometallic Reagents - vinyl phosphates review: Synthesis 1992, 333. O
OP(OEt)2 Li, NH3, tBuOH
R2CuLi
R
R O
O
O
R2CuLi
(EtO)2PCl
- preparation of enol triflates
Synthesis 1997, 735
O
OTf
LDA, THF, -78°C
kinetic product
Tf2NPh
O
R
OP(OEt)2
O
Tf2O, CH2Cl2
tBu
N
tBu
OTf thermodynamic product
C=C BOND FORMATION - reaction with cuprates.
112
Acc. Chem. Res. 1988, 25, 47
OTf
Ph
TL 1980, 21 , 4313
Ph2 CuLi tBu
tBu
- palladium (0) catlyzed cross-coupling of vinyl or aryl halides or triflates with organostannanes (Stille Reaction) Angew. Chem. Int. Ed. Engl. 1986, 25, 508.; Organic Reactions 1997, 50, 1-652 SnMe3
O
O
1)LDA, Tf2NPh 2) Pd(PPh3)4
O
JOC 1986, 51 , 3405
O
O
OH
OTBS
Bu3Sn I
I Bu Sn 3 O
O
O
OH
J. Am. Chem. Soc. 1998, 120, 3935
OH
HO TBSO Bu3Sn
HO TBSO
(-)-Macrolactin A
I
BOMe TESO CHO 1)
2
MgBr
TESO
O3, NaBH4
TESO
3) TBSCl, imidazole (76%)
CHO
1) Dess-Martin Periodinane 2) Ph3P+CH2I, INaHMDS
(38%)
TBSO
I
TESO
CO2H
SnBu3
(42%)
OH TBSO
3) DIBAL (50%)
Bu3SnCHBr2, CrCl2
PdCl2(MeCN)2 (65%)
TESO
Bu3SnH, AIBN
OH I
OH
TBSO
TESO
OTES
I
TBSO
PdCl2(MeCN)2
TESO
OH b) I2 (83%
OPiv Bu3Sn
1) HF, MeCN 2) Me4NBH(OAc)3
OH
a) nBu3SnH, (Ph3P)2PdCl2
OTES
(77%) OPiv
TBSO
3) Dess-Martin Periodinane (70%)
2) TESOTf, 2,6-lutidine (52%) TESO
1) O3, Me 2S 2) allyl bromide, Zn
I
Bu3Sn CO2H
TESO
CO2H
C=C BOND FORMATION
113
I TESO OH
+
Bu3Sn
Ph3P, DEAD
TESO
CO2H
(50%)
TESO TESO Bu3Sn
OH
I O
1) Pd2(dba)3 iPr2NEt 2) TBAF
O
O HO
(35%)
TESO
O
HO TESO
(-)-Macrolactin A
palladium (0) catalyzed carbonylations- coupling of a vinyl triflate with a organostanane to give α,b-unsaturated ketones. O OTf
Ph
Me3SnPh Pd(0), CO
But
JACS 1994, 106 , 7500
tBu
Nickel (II) Catalyzed Cross-Coupling with Grignard Reagents (Kumada Reaction): Pure Appl. Chem. 1980, 52, 669 Bull Chem. Soc. Jpn. 1976, 49, 1958 R-MgBr (dppp)NiCl2
X
R
R= alkyl, vinyl or aryl
Aryl or vinyl halide or triflate
Br
AcO
OMe
Br Ni
1) N H
OAc
HO Ni
R1
N H
OH
(±)-Neocarazostatin B
Tetrahedron 1998, 54, 4413, Acc. Chem. Res. 1995, 25, 446. +
olefin metathesis R2
catalyst
catalyst (CH 2)n
R1
R2
Ring-Opening Metathesis Polymerization (ROMP) (CH 2)n
catalyst (CH 2)n
Tetrahedron Lett. 1998, 39, 2537, 2947,
(2 equiv), 65 °C 2) LiAlH4 , Et2 O (72%)
Olefin Metathesis
OMe
Br
(CH 2)n
n
Ring-Closing Metathesis (RCM)
C=C BOND FORMATION Metathesis Catalysts: iPr H3C F3C F3C
iPr
(C6H11)3P Cl
N
Ru
O Mo O
F3C F3C
Ph
Ph
Ph
Cl (C6H11)3P
(C6H11)3P Cl Ru Cl (C6H11)3P
CH3
Schrock' s Catalyst
Grubbs' Catalyst
Mechanism: +
R1
R2 [M]
R1
[M]
R1 [M] R1 R2
R2
+
[M]
Ph
114
C≡C BOND FORMATION
115
C≡C Bond Formation 1. 2. 3. 4. 5. 6.
From other acetylenes From carbonyls From olefins From Strained Rings Eschenmosher Fragmentation Allenes
From Other Acetylenes - The proton of terminal acetylenes is acidic (pKa= 25), thus they can be deprotonated to give acetylide anions which can undergo substitution reactions with alkyl halides, carbonyls, epoxides, etc. to give other acetylenes. R R1-X R
_
R
H
R1
O R2
OH
R3
R
R R2 3
M+ O Et2AlCl
OH R
- Since the acetylenic proton is acidic, it often needs to be protected as a trialkylsilyl derivative. It is conveniently deprotected with fluoride ion. R
H
F-
B:, R3SiCl
R
SiR3
R
H
Acetylide anions and organoboranes R1
_
Li+
R3B
_ R1
BR3
Li+
I2
R1
R
JOC 1974, 39 , 731 JACS, 1973, 95 , 3080
Palladium Coupling Reactions: O
O O
Cl iPr3Si
SnBu3
O JACS 1990, 112, 1607
Cl
(Ph3P)4Pd iPr3Si
SiiPr3
C≡C BOND FORMATION
116
OTBS OTBS
CO2Me Br
CO2Me
C5H11
OTBS
OTBS
OTBS
Pd(Ph3P)4, CuI iPr2NH, PhH
TBSO
JACS 1985, 107, 7515
C5H11
OH HO CO2H OH
Copper Coupling- 1,3-diynes +
R1
Cu(OAc)2
R2
R1
Adv. Org. Chem. 1963,4 , 63
R1
Nicholas Reaction - acetylenes as their Co2(CO)8 complex can stabilize an α-positive charge, which can subsequently be trapped with nucleophiles. OR4 R1
(CO)6Co2
Co2(CO)8
OR4
R1
R2
(CO)6Co2 R1
R2
(CO)6Co2
Nu:
R1
oxidative decomplexation
Nu
Nu R1
R2 R3
R2
R3
N
CO2Me
R R3 2
R3
R3
N
Tf2O, CH2Cl2, MeNO2, -10°C
+
CO2Me
N
I2
CO2Me JCSCC 1991, 544
O
TBSO tBu
HO
N
tBu
O
(OC)6Co2
Co2(CO)6
Co2(CO)6-acetylene deocomplexation: JOC 1997, 62, 9380 From Aldehydes and Ketones R'-X RCHO
P3P, CBr4
Br
R Br
2 eq. nBuLi R
_
Li+
ClCO2Et
R
R'
R
CO2Et
R
H
H2O
C≡C BOND FORMATION Br2C OHC
OSitBuPh2
OHC
OSitBuPh2
OSitBuPh2
CBr4, Ph3P
OSitBuPh2
Br2C
a) nBuLi, THF, -78°C b) ClCO2Me
MeO2C
117
OSitBuPh2 OSitBuPh2
MeO2C
JACS 1992, 114 , 7360
- by conversion of ketones to gem-dihalides followed by elimination O
PCl5
R'
R
Cl
Cl
R
Cl
tBuOK
R'
- HCl
R'
R
tBuOK
R
- HCl
R'
- by conversion of ketones to enol phosphates followed by elimination LDA, (EtO)2P(O)Cl
O
O
R'
R
P(O)(OEt)2 LiNH , NH 2 3
R
JOC 1987, 52 , 4885
R'
R'
R
- Insertion reaction of a vinyl carbene (terminal acetylenes) N2
R
C
N2CHP(O)(OMe)2 R'
tBuOK
R
+
-N2 R'
••
O
C
R
R
R'
JOC 1982, 47 , 1837
R'
O Me3Si
_
N2 Synlett 1994, 107
THF, -78°C → RT
Via Elimination Reactions of Vinyl Halides - Treatment of vinyl halides with strong base gives acetylenes. X Base
R'
R
R
R'
- HX
H X= Cl, Br, I, OTf, O3SR, OP(O)R2
Base= LDA; tBuOK; NaNH2, DBU
- Addition of Grignard reagents to 1,1-difluoroethylene yields an acetylide anion which can be subsequently trapped with electrophiles. H2C=CF2
R-MgX
E+
_
R
R
E
TL 1982, 23 , 4325 JOC 1976, 41 , 1487
Strained Rings Topics in Current Chemistry 1983, 109, 189. - Cyclopropenones and cyclobutendiones can be photolyzed or thermolyzed (FVP) to give acetylenes. O
O
O hν (209 nm) 8 °K
C
- CO
O
- CO
JACS 1973, 95 , 6134
C O
Benzyne
C≡C BOND FORMATION 1) 370 °C 2) 12°K
O
118
ACIEE 1988,27 , 398 JACS 1991, 113 , 6943
- CO
R1 R2
FVP
R1
(retro- D-A)
+
R2
CL 1982, 1241
Eschenmoser Fragmentation Ph N
O
Ph
N R
R O
R'
HCA 1972, 55 , 1276
O R'
R'
HN NH2 iPr iPr
O
O
R
Base -orheat
O
tBuOOH, triton B, C6H6
O
JOC 1992, 57, 7052
iPr AcOH, CH2Cl2
Allenes Tetrahedron 1984, 40, 2805 - from dihalocyclopropanes Br
R
R'
Br
R'
R
_
••
R
Br
R'
H
R'
R
H
- From SN2' Reactions Nu:
X
H
Nu
R R'
R
R'
- from sigmatropic rearrangements from propargyl sulfoxides and phosphine oxides. Ph OH
O
R R'
Ph
:P
Ph2PCl, Et3N R
O Ph2P R
R'
R' H
TL 1990, 31 , 2907 JACS 1990, 112 , 7825
FUNCTIONAL GROUP INTERCONVERSIONS
119
Functional Group Interconversions C&S Chapter 3 #1; 2; 4a,b, e; 5a, b, d; 6a,b,c,d; 8 1 2 3 4 5 6 7
sulfonates halides nitriles azides amines esters and lactones amides and lactams
Sulfonate Esters - reaction of an alcohols (1° or 2°) with a sulfonyl chloride R OH
O
R'SO2Cl
R'=
R O S
CH3
mesylate
CF3
triflate
R'
O sulfonate ester
CH3
- sulfonate esters are very good leaving groups. competing side reaction
tosylate
Elimination is often a
Halides - halides are good leaving groups with the order of reactivity in SN2 reactions being I>Br>Cl. Halides are less reactive than sulfonate esters, however elimination as a competing side reaction is also reduced. - sulfonate esters can be converted to halides with the sodium halide in acetone at reflux. Chlorides are also converted to either bromides or iodides in the same fashion (Finkelstein Reaction). O R O S
R'
X-
X= Cl, Br, I
R X
O
R Cl
NaI, acetone reflux
- conversion of hydroxyl groups to halides: R OH
- R-OH to R-Cl - SOCl2 - Ph3P, CCl4 - Ph3P, Cl2 - Ph3P, Cl3CCOCCl3
R
I
Organic Reactions 1983, 29, 1 R X
FUNCTIONAL GROUP INTERCONVERSIONS
- R-OH to R-Br - PBr3, pyridine - Ph3P, CBr4 - Ph3P, Br2 - R-OH to R-I - Ph3P, DEAD, MeI Nitriles - displacement of halides or sulfonates with cyanide anion KCN, 18-C-6 DMSO
R X
R C
N
- dehydration of amides O R
-
R C N
NH2
POCl3, pyridine TsCl, pyridine P2O5 SOCl2
- Reaction of esters and lactones with dimethylaluminium amide TL 1979, 4907 Me
H 3C
Me2AlNH2 O O
OH
JOC 1987, 52, 1309
NC Ar
Ar
- Dehydration of oximes R CHO
N
H2NOH•HCl R
OH P2O5
R C
H
N
- Oxidation of hydrazones O O N NMe2
(97%)
- Reduced to aldehydes with DIBAL. DIBAL
RC≡N
C N
RCHO
Tetrahedron Lett. 1998, 39, 2009
120
FUNCTIONAL GROUP INTERCONVERSIONS
121
Azides - displacement of halides and sulfonates with azide anion LDA, THF NBS
O
O
O
NaN3
O
O
O
SO2N(C6H11)2
SO2N(C6H11)2
Br
SO2N(C6H11)2 N3
O
O
O
TL 1986, 27, 831
HO
SO2N(C6H11)2
NH2
NH2
- activation of the alcohol R OH
+
+ N
+ N
F
Me
N
Me
+
EtO2C N N CO2Et
O
Me
TsO -
R OH
+
R N3 OR
Ph3P, NaN3
+ PPh3
EtO2C
N N _ CO2Et
DEAD
activated alcohol + R O PPh3
R-OH
R N3
+
Ph3P=O
JOC 1993, 58, 5886 HO (PhO)2P(O)-N3 O
N3
O O
DBU, PhCH3
SN2
P(OPh)2 +
+ DBU-H
-
+ N3
(91 %)
O (97.5 % ee)
Ar
(99.6 % ee)
- Photolyzed to aldehydes Amines - Gabriel Synthesis O N - K+
O R
O
- reduction of nitro groups R NO2 H2, Pd/C Al(Hg), H2O NaBH4 LiAlH 4 Zn, Sn or Fe and HCl H2NNH2 sodium dithionite
X
N R
H2NNH2
O
R NH2
R NH2
FUNCTIONAL GROUP INTERCONVERSIONS - reduction of nitriles R C N
R CH2 NH2
H2, PtO 2/C B2H6 NaBH4 LiAlH 4 AlH3 Li, NH3 - reduction of azides R N3 H2, Pd/C B2H6 NaBH4 LiAlH 4 Zn, HCl (RO)3P Ph3P thiols
R NH2
- reduction of oximes (from aldehydes and ketones) N R
OH NH2 R'
R
R'
R'
R
N
H2, Pd/C Raney nickel NaBH4, TiCl4 LiAlH 4 Na(Hg), AcOH - reduction of amides O R
N
R'
R''
R''
H2, Pd/C B2H6 NaBH4, TiCl4 LiBH4 LiAlH 4 AlH3 - Curtius rearrangement O
O NaN3 R
R N O isocyanate
H2O
O
∆ - N2
R
•• N
••
Cl
••
R
•• •• N N N +
nitrene R NH2
122
FUNCTIONAL GROUP INTERCONVERSIONS - reductive aminations of aldehydes and ketones - Borsch Reaction - Eschweiler-Clark Reaction - alkylation of sulfonamides Tf
Tf
N
HN
N
HN
Tf
Tf
K2CO3, DMF 110°C
Tf Br
Br
Tf
N
N
N
N
Tf
NH HN
Na, NH3
TL 1992, 33 , 5505
NH HN
Tf
cyclam
- transaminiation O
Ph
N
PhCH2NH2
Ph
N
NH2
Can. J. Chem. 1970, 48, 570
H3O +
tBuOK
H+
Esters and Lactones - Reaction of alcohols with "activated acids" - Baeyer-Villigar Reaction Organic Reactions 1993, 43, 251 - Pd(0) catalyzed carboylation of enol triflates OTf
CO2R
CO, DMF Pd(0), ROH
TL 1985, 26 , 1109
- Arndt-Eistert Reaction O R
Angew. Chem. Int. Ed. Engl. 1975, 15, 32. O
CH2 N2 Cl
Et2 O
O
hν
N2
R
Wolff Rearrangement
C O H
O
R'OH
R
OR'
ketene
O
O
TsN3, Et3N CO2Me
R
•• CH
R
ROH
R diazo ketone
N2
R
- Diazoalkanes: carbene precursors R-CHO
1) NH2NH2 2) Pb(OAc)4, DMF
R-N2
R3N H 2N R
- Halo Lactonizations
JOC 1995, 60, 4725
TsN3
N
N2
R
R
review: Tetrahedron 1990, 46 , 3321 +
I I
I2-KI CO2H
R
H2O, NaHCO3
O
O H O
O
123
FUNCTIONAL GROUP INTERCONVERSIONS Pd(OAc)2 (5 mol %) CO2H
JOC 1993, 58, 5298
O
DMSO, air (86%)
O
- Selenolactonization PhSe O
H 2O 2
O
PhSeCl, CH2Cl2
O
O
JACS 1985, 107 , 1148
O
OH
- Mitsunobu Reaction
Synthesis 1981 , 1; Organic Reactions, 1991, 42, 335 Mechanism: JACS 1988, 110 , 6487 O DEAD, Ph3P
OH R
O
R''CO2H
R'
R
R''
Inversion of alcohol stereochemistry
R'
Amides and Lactams - reaction of an "activated acid" with amines - Beckman Rearrangement Organic Reactions 1988, 35, 1 O R
N R'
R
OH
PCl5
O
R'
R
NR'
- Schmidt rearrangement O R
O
HN3 R'
H+
R
NR'
- others O OTf
NR2
CO, DMF Pd(0), R2NH
TL 1985, 26 , 1109
OH O
O O
PhCH2NH2
N H
AlMe3 OTHP
Ph
TL 1977, 4171
OTHP
-Weinreb amide Tetrahedron Lett. 1981, 22, 3815 O
DIBAL O R
O
H3CNH(OCH3) •HCl OR'
AlMe3
R
R N
H
OCH3 O
CH3 R1-M
R
R1
124
THREE-MEMBERED RING FORMATION 3 Membered Rings 1.
2.
3.
epoxides a. peracids, hydroperoxides and dioxiranes b. transition metal catalyzed epoxidations c. halohydrins d. Darzen's condensation e. sulfur ylides cyclopropanes a. Simmons-Smith reactions b. diazo compounds c. sulfur ylides d. S N2 displacements aziridines a. nitrenes b. SN2 displacements
Epoxides - peracid, hydroperoxide and dioxirane oxidation of alkenes - transition metal catalyzed epoxidation of alkenes - Sharpless epoxidation - Metal oxo reagents (Jacobsen's reagent) - from halohydrins Br
NBS, H2O
base O
OH bromohydrin
- Darzen's Condensation O _ BrCHCO2Et
B: BrCH2CO2Et
R
R R'
OO
CO2Et
R'
R'
Br
- sulfur ylides Chem. Rev. 1997,97, 2421. O
O Me S + CH2Me Corey
+ Me2SCH2-
Ph S
CH2-
+ _ SPh2
NMe2 Johnson sulfoximine
CO2Et
R
Trost
125
THREE-MEMBERED RING FORMATION
126
- dimethylsulfoxonium methylide and dimethylsulfonium methylide (Corey's reagent) review: Tetrahedron 1987, 43 , 2609. O
O R
-
O
DMSO, NaH R'
O
SMe2
R
R
R'
R'
- cyclopropyldiphenylsulfonium ylide (Trost's reagent) ACR 1974, 7, 85. +
O R
_
O
SPh2
-
O
R'
O
SPh2
R
BF3
R
R'
- sulfoximine ylides (Johnson's reagent) O Ph S CH2NMe2
O R
ZnCu +
R
ACR 1973, 6 , 341
O R
R'
Cyclopropanes - Simmons-Smith Reaction
R'
R'
R'
Org. Reactions 1973, 20, 1. ICH2ZnI
CH2I2
- polar groups (-OH, -NR2- CO2R) can direct the cyclopropanation OH
OH JACS 1979, 101 , 2139
ZnCu, CH2I2
- sulfur ylides O
O
O Me2S CH2-
Ph
Ph
O _ Ph S NMe2
Tetrahedron 1987, 43 , 2609
Ph
Ph
O O
ACR 1973, 6 , 341
THREE-MEMBERED RING FORMATION
127
- diazo alkanes and diazo carbonyls Synthesis 1972, 351; 1985, 569 - cyclopropanation with diazoalkanes; olefin requires at least on electron withdrawing group. N N
CO2Me MeO2C
CH2N2
(MeO)2HC
CO2Me
CO2Me
JACS 1975, 97 , 6075
MeO2C
hν
MeO2C (MeO)2HC
(MeO)2HC
- diazoketones; photochemical or metal catalyzed decomposition of diazoketones to carbenes followed by cyclopropanation of olefins. Org. Rxns. 1979, 26, 361; Tetrahedron 1981, 37, 2407 CuSO4 , ∆
N2
JACS 1970, 92 , 3429 JACS 1969, 91 , 4318
O
O
Rh2(OAc)2
O Ph
O
O
O
Ph Ph
N2
O
JACS 1993, 115, 9468
O
O O
Ph
91 % yield 89 % de
Asymmetric cyclopropanation: Doyle, Chem Rev. 1998, 98, 911 Aldrichimica Acta 1997, 30, 107 O
O CO2Et
CO2Et
TsN3 , Et3N N2 C5H11
C5H11 O
O CO2Et
- SPh
JACS 1977, 99, 1940
CO2Et C5H11
C5H11 SPh
- SN2 Reactions DBU
O O
O Br
O O
O
CO2Et
JACS 1978, 99 , 1940
CO2Et
- Electrophillic Cyclopropanes review: ACR 1979, 12 , 66 in many ways, cyclopropanes react silmilarly to double bonds - homo-1,4-addition CO2R Nu:
CO2R
Nu
CO2R CO2R
ACR 1979,12 , 66
THREE-MEMBERED RING FORMATION Nu:= malonate anion, amines, thiolate anion, enamines, cuprates (usually requires double activation of cyclopropane) Me
H MeO2C
MeO2C
Me2CuLi O
TL 1976, 3875
O
- hydrogenation CO2Me
CH2I2, Zn-Cu
O
ArCO3H, Na2HPO4
CO2Me
CO2Me
H
H
H
O CO2Me
H2, PtO2, AcOH
TL 1982, 23 , 1871
H
- hydrolysis OH
OH
OH CH2I2, Zn-Cu
H , MeOH
MeO
OMe
JACS 1967 89 , 2507
+
O
Aziridines R2 R1
Ts
Cu(acac)2 R3
PhN=ITs
N R2
R1
J. Org. Chem. .1991, 56, 6744 R3
128
FOUR-MEMBERED RING FORMATION 4 Membered Rings 1. 2.
cyclobutanes & cyclobutenes oxatanes
Cyclobutanes - [2+2] cycloadditions - photochemical cycloadditions (2πs +2πs) Acc. Chem. Res. 1968, 1, 50; Synthesis 1970, 287; Acc. Chem. Res. 1971, 4, 41; Organic Photochemistry 1981, 5, 123; Angew. Chem. Int. Ed. Engl. 1982, 21, 820; Acc. Chem. Res. 1982, 15, 135; Organic Photochemistry 1989, 10, 1 Organic Reactions 1993, 44, 297 - for synthetic purposes, cyclic α,β-unsaturated carbonyl are the most useful. intersystem crossing
1
E*
E
3
E*
- symmetry requirements 2πs + 2πs
*
hν
O
O
~ 340 nm
HOMO LUMO
- enones with olefins O
O +
CH2
O
O
O
hν +
CH2
JCSCC 1966, 423
+
(90%)
O
O
O
O
hν
H E.J. Corey JACS 1963, 85 , 362
+
+
H Caryophellene Base
Hot Ground State? O
O
O H2C=CH2
hν
2πs + 2πa thermal cyclization
CH3 N H
H2C=CH2 hν, CH2Cl2 CH3
O
N CH3
isomerization
cis ring-fusion
H
CH3
O Ph
H
H
CH3 O
JACS 1986, 108 , 306
HO CH3
grandisol
129
FOUR-MEMBERED RING FORMATION O
O
O
130
H
H +
JACS 1984 106 , 4038
hν H
H 2:1
- enones with acetylenes O O
hν
O
O
O
JACS 1982 104, 5070
- DeMayo Reaction O
O
O
hν, pyrex
O
O
CO2Me
H
pTSA, MeOH reflux
JACS 1986, 108 , 6425
O O H
O
R
hν
O
R
O
R O
O
MeO2C
H
O
O
70-80 % de
favored
O
O O
controls conformation O
O
hν
H 3C
O
O
CH3
O
H
CH3
O disfavored
TL 1993, 34, 1425
H 3C H 3C
H
- Photochemistry of Ketones (Norrish Type I and II reactions) H
H hν
Norrish I cleavage
O •
•
254, 307 nm Norrish II cleavage HO
Yang reaction
OH •
•
H
H H
O
O• •
H
H 3C
O
O
H
O
CH3 CH3 controls addition
O
H
O
O
H 3C
H
OH +
FOUR-MEMBERED RING FORMATION - filtering photchemical reaction to prevent Norrish reactions quartz 180 nm Vycor 200 nm Pyrex 280 nm Uranium glass 320 nm - Yang Reaction MOMO
MOMO O hν (254 nm)
OH
C6H6 SEMO
CH3
JACS 1987, 109 , 3017
CH3
SEMO
- thermal cycloadditons (2πa + 2πs) - symmetry requirements 2πa + 2πs
O
HOMO
LUMO
- ketenes O
∆
H O
O
H
O Cl
Et3N O
H O Cl
Zn
O
Cl O N2
R
R
hν
O H
- thermal cyclization of ketene with olefins Tetrahedron 1986, 42, 2587; 1981, 37, 2949; Organic Reactions 1994, 45, 159. LUMO of ketene 2πa
pz
py
O HOMO of olefin 2πs
131
FOUR-MEMBERED RING FORMATION Cl
O CH3
Ph
O
Cl
Cl
CH2N2
CH3 O
O
O
Cl CCl3
CH3
Zn-Cu, Et2O
Cl
Ph
H 3C H 3C
N+ 2) H2O
H 3C
Ar
JACS 1987, 109 , 4753
H
O
1)
CH3
R*O
CH3
H 3C
132
N+
JACS 1982, 104, 2920 H
OMe
OMe
-reaction of ketene with enamines H NR2
O
O H
NR2
O
O
NR2
R'
R'
- reaction of ketene with imines to give β-lactams (Staudinger Reaction) R
H N
O H NR O
O O
R
N
+
H
CH2Cl2 -78°C → 0°C
N
Ph O
Bn
N
O
N
Ph
N
Ph
H
O
O
R
O H
O
Bn
R NBn
O (90-96 % de)
- reaction of difluorodihaloethylene with olefins Organic Reactions 1962, 12, 1 F
F2C=CX2 R
F X= F, Cl
X X
R
- reaction of difluorodihaloethylene with acetylenes- biradical mechanism F
F2C=CX2 R
F X= F, Cl
R
X
hydrolysis
O
X R
O
FOUR-MEMBERED RING FORMATION
133
- SN2 Reaction O
O KH, DMSO
JACS 1980, 102 , 1404
OTs
O
_
CN
CN HO
OR
JACS 1974, 96, 5268, 5272
OH
OR
Grandisol
- acyloin reaction
Organic Reactions 1976, 23, 259
CO2Me
OTMS
Na, TMS-Cl
(CH2)n
O
F-
(CH2)n CO2Me
(CH2)n
OTMS
OH
R
CO2Me
R
O
R
CO2Me
R
OH
- benzocyclobutanes
ACIEE 1984, 23, 539; Synthesis 1978, 793 O
O
O
O
O benzocyclobutane
O
o-quinodimethane
- cyclotrimerization of 1,5-diyenes with an acetylenes SiMe3
Me3Si
SiMe3
CpCo(CO)2
Me3Si
- sulfur ylides +
O R
_
SPh2
R'
O BF3
O R
R' R'
R
Oxatanes Organic Photochemistry 1981, 5, 1 - [2+2] cycloaddition (Paterno-Buchi Reaction) O R
R
R' O
R
O
hν
R' hν (254 nm)
R'
O R R'
FOUR-MEMBERED RING FORMATION
O
O
hν
O
Me2C CMe2
O O
134
TL 1975 1001
O
- SN2 reaction O
NBS
OH
JCSCC 1979, 421
SiMe3
SiMe3 Br OH CO2Me
Tf2O, CH2Cl2
CO2Me
O
C5H11
HO
TL 1980,21 , 445
C5H11
OTBS
OH
OH Br
Br CO2Me
HO
(MeO)3P, DEAD
O
CO2Me
O
C5H11
C5H11
O
OH
JACS 1984, 107 , 6372
OH
- sulfur ylides O
O
-
O
O
NTs
H2C_ S Me
S
NTs
O
JACS 1979, 101 , 6135
CH3
β-Lactones R2
R1
LDA, THF SPh
H
BnO
N H
O
R3
CO2H
R1
R2 R1
O BnO
JOC 1991, 56 , 1176
SPh
R4
DEAD, Ph3P
O O
R4
O R3
OH
O
O-
O
R2CuLi
O N H
R2
R3
R4
CO2H
R BnO
NH
JACS 1987, 109 , 4649
O O
1) MgBr2•OEt2 2) KF, H2O, CH3CN
O OBn O
OBn
O
O
+ H
SiMe3
H
96 % de
TL 1995, 36, 4159
BALDWIN'S RULES FOR RING CLOSURE Baldwin's Rules (Suggestions) for Ring Closure JOC 1977, 42 , 3846 JCSCC 1976, 734, 736, 738
135
Approach Vector Analysis - for an SN2 displacement at a tetrahedral center, the approach vector of the entering nucleophile is 180° from the departing leaving group Nu:
Nu
L
Nu
L
:L
- for the addition of a nucleophile to an Sp2 center, the nucleophile approaches perpendicular to the π-system. Nu Nu
Nomenclature 1. indicate ring size being formed 3 membered ring = 3 4 membered ring = 4 etc. 2. indicate geometry of electrophilic atom if Y= Sp3 center; then Tet (tetrahedral) if Y= Sp2 center; then Trig (trigonal) if Y= Sp center; then Dig (digonal) Z Y
X:
3. indicate where displaced electrons end up - if the displaced electron pair ends up out side the ring being formed; then Exo - if the displaced electron pair ends up within the ring being formed; then Endo Z Y
X: Exo
Z
Y
X: Endo
BALDWIN'S RULES FOR RING CLOSURE 136 4. Ring forming reaction is designated as Favored or Disfavored disfavored does not imply the reaction can't or won't occur- it only means the reaction is more difficult than favored reactions. Rules (Suggestions) for Ring Closure - All Exo-Tet reactions are favored
X:
Y
Z
X: Y
X:
Z
X:
Y Z
3-
4-
X:
Y
Y Z
5-
Z
6-
7-
- - - - - - - - - - - - - - - - - - - - - - - - --Favored- - - - - - - - - - - - - - - - - - - - - - - - -
- 5-Endo-Tet and 6-Endo-Tet are disfavored Z
Z
Y
Y X:
X: 5-
6-
- - - - -Disfavored- - - - -
- All Exo-Trig reactions are favored
X:
Y
Z
X: Y
Z
X:
X:
Y Z
3-
4-
5-
X:
Y
Y
Z
Z
6-
7-
- - - - - - - - - - - - - - - - - - - - - - - - --Favored- - - - - - - - - - - - - - - - - - - - - - - - -
- 3-Endo-Trig, 4-Endo-Trig and 5-Endo-Trig are disfavored; 6-Endo-Trig, 7Endo-Trig, etc. are favored
Z
Z X:
Y 3-
Z
X: Y 4-
Z
Y
X: 5-
- - - - - - - - - - - - -Disfavored- - - - - - - - - - - -
X:
Y
X:
Z Y
76- - - - - -Favored- - - - - -
BALDWIN'S RULES FOR RING CLOSURE 137 - 3-Exo-Dig and 4-Exo-Dig are disfavored; 5-Exo-Dig, 6-Exo-Dig, 7-Exo-Dig, etc. are favored
X:
X:
Y
X:
Y
Z
Z
3-
4-
Y
X:
Z
Z
5-
- - - - - -Disfavored- - - - - -
X:
Y
Y Z
6-
7-
- - - - - - - - - - - - -Favored- - - - - - - - - - - -
- All Endo-Dig are favored Z Z X:
Z Y
Y X:
X:
3-
4-
Z
Y
5-
X: 6-
Y
X:
Z Y 7-
- - - - - - - - - - - - - - - - - - - - - - - - - - --Favored- - - - - - - - - - - - - - - - - - - - - - - - - - - - -
EXCEPTION: There are many !!!
(see March p 212-214)
FIVE-MEMBERED RING FORMATION 5 Membered Rings HO
O CO2H
HO
CO2H
HO
OH
OH
PGF2α
PGE2 Me H
Me Me Me Me
Me Me Me Hirsutene
1. 2. 3. 4.
5. 6. 7. 8. 9.
Isocumene
Modhephane
Intramolecular SN2 Reactions Intramolecular Aldol Condensation and Michael Addition Intramolecular Wittig Olefination Ring Expansion and Contraction Reactions a. 3 → 5 b. 4 → 5 c. 6 → 5 1,3-Dipolar additions Nazarov Cyclization Arene-Olefin Photocyclization Radical Cyclizations Others Synthesis 1973, 397; ACIEE 1982, 21 , 480;
Intramolecular SN2 Reaction
5-exo-tet: favored O LDA
O
JCSCC 1973, 233
Br
O
O CO2Me
O CO2Me
Br
CN
CN
OH JACS 1974, 96 , 5268
O
138
FIVE-MEMBERED RING FORMATION O
Cl JACS 1979, 101 , 5081
O RO2C
RO2C
Cl
CO2R
CO2R
O
O NaH, DMSO
JCSCC 1979, 817
TsO
Intramolecular Aldol Condensation 5-exo-trig: favored intramolecular aldol condensation of 1,4-diketones O
O R
R
O R' R' O
O CH3
CH3
O
TL 1982, 29, 2237
CH3 CH3
Br
Br
O
NaOMe, MeOH O
O
CO2Me
JACS 1980, 102 , 4262
CO2Me O
O JOC 1983, 48 , 1217
NaOH O
O
O
Intramolecular Michael Addition 5-exo-tet: favored Organic Reactions 1995, 47, 315-552 O O MeO2C
O
O
JACS 1979, 101 , 7107
139
FIVE-MEMBERED RING FORMATION Tetrahedron 1980, 36, 1717
Intramolecular Wittig Olefination O
O
1) (MeO) 2P(O)CH2 -
O
P(OMe)2
O
2) Collins
O
C5H11
THPO
OTHP
C5H11
THPO
OTHP
CO2H
O
JOC 1981, 46 , 1954
base C5H11
THPO
OTHP
C5H11
HO
OH
Ring Expansion Reactions - 3 → 5: Vinyl Cyclopropane Rearrangement _
O
SPh2
O
Organic Reactions 1985, 33, 247.
O
H
OTMS
O
O
O
H O
H O
TMSO
JACS 1979, 101 , 1328 O
H O
- 4 → 5: Reaction of cyclobutanones with Diazomethane Cl
Me
CH2N2
Me
Me
Cl O
O O Me
Cl
Me
Me
CH2N2
TL 1980, 21 , 3059
O
Cl Cl
Cl
Cl
O
O
Cl
Cl CH3 O
CH3
CH2N2
Cl CH3 O
CH3 JACS 1987,109 , 4752
Ph Ph
140
FIVE-MEMBERED RING FORMATION Ring Contraction Reactions - 6 → 5: Favorskii Reaction
Organic Reactions 1960, 11 , 261 _
O
O Cl
OH
-
O OH CO2H
_
1,3-Dipolar Addition to Olefins 1,3-Dipolar Cycloaddition Chemistry , vol 1 & 2 (A. Padwa ed.) (Wiley, NY 1984); ACIEE 1977, 16 , 10. Chem Rev. 1998, 98, 863. 1,3-Dipole (4π) LUMO
+ _ b c a
4πs + 2πs
- trimethylenemethane (TMM)
Alkene (2π) HOMO
ACIEE 1986, 25 , 1. Synlett 1992, 107.
high temperature
• • TMM
CO2Me
MeO2C
∆, MeCN N
MeO2C H
•
• •
-N2
N
CO2Me CH3
H
•
JACS 1981, 103 , 2744
note: TMM usually reacts poorly w/ electron defficient olefins _ Pd(0) Me3Si
OAc
+ PdLn
O O
Me3Si
H
OAc
O O TL 1986, 27 , 4137
Pd(0), 80°C
MeO2C
CO2Me
Ni(COD)2, 35 °C CO2Me
ACIEE 1985, 24 , 316 TL 1983, 24 , 5847 CO2Me
- α,α'-dihaloketones O OFeLn
O Fe(CO)9
Ar
ACR 1979, 12 , 61
+ Br
Br
Ar
141
FIVE-MEMBERED RING FORMATION ACR 1979, 12 , 396; Organic Reactions, 1988, 36 , 1
- nitrones
O+N
O R1 N
R2
R1
JACS 1964, 86 , 3756
O O
N
N
Me O
N
MeNHOH, EtONa H
O Me
NH
N S
Me
NH
JOC 1984, 49 , 5021
H
H
MeO2C
Bn
OH
Me2N
1) MeI 2) H2, Pd/C
H
H
MeO2C
R3
R2
R3 Nitrone
-
142
Bn N
O-
JACS 1983, 104 , 6460
O S
C 4H 9
C 4H 9
- nitrile oxides O
O
+ O N
N
N O
ArNCO
CO2Et
CO2Et O
O N
O
O
O N
O
O
OTHP
+ _ N O
THPO
N O
OH OTHP
Bu3Sn (80%)
OTHP H2, Raney Ni, H2 O, MeOH, B(OMe)3
(88%)
1) TBS-Cl, DMF, imidazole 2) nBuLi, THF
OH
O O
OH O
HF•pyridine, CH3 CN, pyridine
3) Swern (48%) TBSO
O
(88%)
O
1) PPTS, EtOH, ↑↓ 2) (CH3 )2C(OMe)2 , PPTS
O O
(89%)
OH
Ph
(99%)
N
1) Swern 2) NH2OH•HCl AcONa, MeOH
OTHP
(60%)
OTHP NaOCl, H2 O, CH2 Cl2
CO2Et
1) DHP, PPTS CH2 Cl2, ↑↓ 2) LAH
CH3
H
Ph
JACS 1992, 104 , 4023
CO2Et
OH
Bu 2BOTf, iPr 2EtN, CH2 Cl2, -78°C
OH
O
H2
Cassiol TL 1996, 37, 9292
(73%) O
TBSO O
HO
OH OH
FIVE-MEMBERED RING FORMATION OTBS
OTBS
OTBS LAH
N + O _
TL 1993, 34, 3017
O N
OH
NH2
Arene -Olefin Photocyclization Organic Photochemistry 1989, 10 , 357 - the photochemistry of benzene is dominated by the singlet state 1
*
hν
*
*
hν
OAc OAc
* Me2CuLi
O
O
JACS 1982, 104 , 5805 JCSCC, 1986 247
Me
1) FVP 2) H2, Pd/C
* * hν +
isocume
+
* Tetrahedron 1981,37 , 4445
*
*
*
hν
OMe
OMe
JACS 1981, 103 , 688 OMe cedrane
AcO
hν
AcO
*
*
HO H+
H TL 1982, 23 , 3983 TL 1983, 24 , 5325
143
FIVE-MEMBERED RING FORMATION
144
Intramolecular Photochemical [2+2] "Rule of Five" O
O hν O
O
O
O
JOC 1975, 40 , 2702 JOC 1979, 44 , 1380
hν O
O
Nazarov Cyclization review: Synthesis 1983, 429 - cyclization of allyl vinyl or divinyl ketones
Organic Reaction 1994, 45, 1 O
O H3PO4/HCO2H
O
O H3PO4/HCO2H
- 1,4-hydroxy-acetylenes
HO
H2SO4, MeOH OH
H
O
OH
JOC 1989, 54 , 3449
H OH
- Silicon-Directed Nazarov O
O Tetreahedron 1986, 42 , 2821
FeCl3 SiMe3 Me
- Tin -directed Nazarov
Me
TL 1986, 27 , 5947
Radical Cyclization B. Giese Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds (Pergamon Press; NY) 1986; Bull. Soc. Chim. Fr. 1990, 127 , 675; Tetrahedron 1981, 37 , 3073; Tetrahedron 1987, 43, 3541; Advances in Free Radical Chemistry 1990, 1, 121. Organic Reactions 1996, 48, 301-856. Radical Addition to multiple bonds: 1. Free radical addition is a two stage process involving an addition step followed by an atom transfer step. 2. In general, the preferred regioselectivity of the addition is in a manor to give the most stable radical (thermodynamic control)
FIVE-MEMBERED RING FORMATION Advantages of free radical reactions: 1. non-polar, little or no solvent effect 2. highly reactive- good for hindered or strained sysntems 3. insensitive to acidic protons in the substrates (i.e. hydroxyl groups do not necessarily need to be protected Mechanism of radical chain reactions 1. initiation 2. propagation 3. termination (bad) Formation of carbon centered radicals: tin hydride reduction of alkyl, vinyl and aryl halides, alcohol derivatives: xanthates, thionocarbonate, thiocarbonylimidazolides organosselenium & boron compounds carboxylic acid derivatives (Barton esters) reduction of organomercurials thermolysis of organolead compounds thermolysis or photolysis of azoalkanes. Radical Ring Closure For irreversible ring closure reaction, the kinetic product will predominate. Both the 5-exo-trig and 6-endo trip are favored reactions, with the 6 exo-trig mode producing the most stable radical. However, the 5-exo-trig is about 50 time faster •
• k1,5
•
k1,6
thermodynamically favored
kinetically favored
• •
+
•
100 : 0 •
•
+ •
•
•
100 : 0 •
3-exo-trig vs 4-endo-trig 4-exo-trig vs 5-endo-trig 5-exo-trig vs 6-endo-trig
+ 98:2 • •
•
+
6-exo-trig vs 7-endo-trig
85:15 • •
•
+ 100 : 0
7-exo-trig vs 8-endo-trig
145
FIVE-MEMBERED RING FORMATION •
146
•
and
radicals open up fast and are not synthetically useful; often used as probes for radical reaction
Effects of substituent on the regiochemistry of the 5-hexenyl radical cyclization • •
•
+ 48:1 •
•
•
+ >200:1 • •
•
+ 2:3 • •
•
+ < 1:100
Stereochemistry of 5-hexenyl radical cyclization 1-, or 3-substitued 5-hexenyl radicals give cis disubstituted cyclopentanes 2-, or 4-substituted 5-hexenyl radicals give trans disubstitued cyclopentanes 2 Br
Bu3SnH
H R
•
R
H
R
+
R
65 : 35 prefered transition state R • 3
R
R
Br
R
+
H H
75 : 25
H 4 Br R
H R 1
Bu3SnH Br
+
R
•
R
R •
83 : 17
R
+ H R
73 : 27
R
FIVE-MEMBERED RING FORMATION Br
OH
nBuSnH, AIBN
147
JACS 1983, 105 , 3720 OH CN
CN
Bu3SnH, AIBN CO2Me
JACS 1990, 112, 5601
Br
CO2Me
Br
OH
Si O
H Si O
Bu3SnH
THPO
H
H2O2
THPO
OH
THPO
multiple cyclizations: D. Curran Advances in Free Radical Chemistry 1990, 1, 121. OTBS
O
OAc
1) NaBH4, CeCl3 2) Ac2O, Et3N
1) LDA, THF 2) TBSCl
O
70 °C
O OTBS
PhSe H2O2
O
PhSeCl, CH2Cl2
O
O THPO
O
1) PPTS, EtOH 2) LAH CO2H
I
CuSMe2 Li+
THPO
I
1) Me3Si Li (1.0 equiv) I
3) (CF3SO2)2O pyridine 4) Bu4NI, PhH
2) CsF
Me H
•
Bu3SnH, AIBN PhH, reflux
JACS 1985, 107 , 1148 H H (±)-hirsutene
O O
CH3MgBr, CuBr•SMe2
HO
O
O
1) I2 2) DBU
O
O
O
MgBr
CuBr•SMe2, THF O O
HO
O
1) LAH 2) CH3SO2Cl 3) NaI
CO2Me
1) CH3MgBr (excess)
Li 4) 5) CrO3, H2SO4, H2O Bu3SnH, AIBN PhH, reflux
Br
2) Me3SiBr H H
• H 3C
H
(±)-capnellene Tetrahedron Lett. 1985, 41, 3943
FIVE-MEMBERED RING FORMATION O
O
Me
nBuSnH, AIBN
O
148
O JACS 1986, 108, 1106 Me
Me Me
Br
OH H
CHO
O
JACS 1988, 110 , 5064
O
SmI2, THF
O
O H
radical trapping OEt I
OEt
OEt
O O
nBuSnH, AIBN RO
O
tBuNC
JACS 1986, 108 , 6384
•
RO
CN
RO
can also be trapped with acrylate esters or acrylonitrile. OEt
OEt I O
O
nBuSnH, AIBN
O Me3Si
OEt C5H11
OEt
O SiMe3 C5H11
• RO
RO
RO
1) (S)-BINAL-H 2) HCl, H2O, THF
O
C5H11 RO
1) Wittig 2) deprotect
CHO
RO
CO2H
HO
OH
(+)-PGF2α
O
Paulson-Khand Reaction
Tetrahedron 1985, 41 , 5855; Organic Reactions 1991, 40 , 1. O
O R
R''
R'
R
R
R''
Organometallics 1982, 1 , 1560
+
Co2(CO)6 R'
R'
R''
O JOC 1992, 57 , 5277
Co2(CO)8, NMO O
O
O
O
OTMS
HO
C5H11
C5H11 RO
HO
Brook rearrangement
O
OEt Pd(OAc)2, CH3 CN
O
140°
FIVE-MEMBERED RING FORMATION Ph
Cp2TiCl2, EtMgBr, CO
EtO2C CO2Et
CO2Et
Ph
Ring-Closing Metathesis
CO2Et
Tetrahedron 1998, 54, 4413, Acc. Chem. Res. 1995, 25, 446.
O
O N
O
OH
Bu2BOTf, CH2Cl 2, -78°C
P(C6H11)3 Ph Cl Ru Cl P(C6H11)3
O
O N
O
(97%)
CHO (82 %)
Ph
Ph OH
JOC 1992, 57 , 5803
O
O
O N
LiBH4, THF, MeOH
OH
J. Org. Chem. 1996, 61, 4192
O OH
(78%) Ph
Diazoketones
Tetrahedron 1981, 37 , 2407; Organic Reactions 1979, 26 , 361 O R1
O N2
BF3
R1 TL 1975, 4225
R2
R2
FVP of Acetylenic Ketones O
O
R1 R2
FVP H
R3
R1 R2
O R3
H ••
R1 R2
R3
TL 1986, 27 , 19
149
6-MEMBERED RING FORMATION Six Membered Rings 1. 2. 3. 4. 5.
Diels-Alder Reaction o-Quinodimethanes Intramolecular ene reaction Cation olefin cyclizations Robinson annulation
Diels-Alder Reaction ACIEE 1984, 23 , 876; ACIEE 1977, 16 , 10; Organic Reactions 1984, 32 , 1 W. Carruthers Cycloadditions Reactions in Organic Synthesis (Pergamon Press, Oxford) 1990 - reaction of a 1,3-diene with an olefin to give a cyclohexene. - thermal symmetry allowed pericyclic reaction - diene must reaction is an s-cis conformation - highly stereocontrolled process- geometry of starting material is preserved in the product - possible control of 4 contiguous stereocenters in one step B
B A A
X
B
A
Y
X
Y
Y Y X
+ X
Y X X
+ Y
B A
B
A
B A
- Alder Endo Rule: In order to maximize secondary orbital interactions, the endo TS is favored in the D-A rxn. Tetrahedron 1983, 39, 2095 X X
B
Y Y B A A
A
X Y Y X
B
B A
O O
exo
O
O
minor
O
H H O
H
endo
O
H
O
major
O O O O
Orientation Rules X
X
+
Y
X Y
+ Y
major
minor
150
6-MEMBERED RING FORMATION X
Y
+
X
+
X
151
Y
Y major
minor
- when both the diene and dienophile are "unactivated" the D-A rxn is sluggish - D-A rxns with electron rich dienes and electron defficient dienophiles work the best. Some electron deficient dienophiles are quinones, maleic ahydride, nitroalkenes, α,βunsaturated ketones, esters and nitriles. - D-A rxns with electron deficient dienes and electron rich dienophiles also work well. These are refered to as reverse demand D-A rxns. - D-A rxns are sensitive to steric effects of the dienephiles, particularly at the 1- and 2postions. Steric bulk at the 1-position may prevent approach of the dienophile while steric bulk at the 2-position may prevent the diene from adopting the s-cis conformation. - The D-A rxn is promoted by Lewis acids (TiCl4, BF3 AlCl3, AlEt2Cl, SnCl4,...) - The D-A rxn is promoted by high pressure (1 kbar ~ 14200 psi) Synthesis 1985, 1. O
OMe
OMe
5 Kbar
Me
Me O
+
JACS 1986, 108 , 3040
O O
H
NHBOC 20 kbars, 50°C
H
+
Eu(fod)3
O
OMe
O
NHBOC
H +
O
OMe
NHBOC Synthesis 1986, 928
OMe
- The D-A rxn is usually insenstive to solvent effects, except for water. ACR 1991, 24 , 159 O isooctane +
O
+
krel=1 O endo
H exo 4:1
H2O
JACS 1980, 102 , 7816 TL 1983, 24 , 1901 TL 1984 , 25 , 1239
20 : 1
krel= 700
CO2- Na+ CHO
OHC
CO2H
CO2H
H
H
+ OHC
H2O (70%)
(15%)
JOC 1984, 49 , 5257 JOC 1985, 50 , 1309 Tetrahedron 1986, 42 , 2847
6-MEMBERED RING FORMATION
152
- The mechanism of the D-A rxn is believed to be a one-step, concerted, non-synchronous process. - concerted- bond making and bond breaking processes take place in a single kinetic step (no dip in the transition state) - synchronous- bond making and bond breaking take place at the same time and to the same extent. M.J.S. Dewar JACS 1984, 104 , 203, 209.
+
- study of secondary D-isotope effects have indicated a highly symmetrical T.S. D H
D H
k1
D
D
H
H
+
D
JACS 1972, 94 , 1168
D
D D
k2
D
D
D
D
+
Diels Alder Reactions: O
O PhH, reflux
O O
H
MeO2C
H
CHO
MeO2C
CO2H
OAc OMe
HO2C MeO Tetrahedron 1958, 2 , 1
N
N
H H O2CAr
MeO2C reserpine
H
CHO
H
+ NHCO2Bn
OMe
H
O
O trans
trans
H
CHO
BnO2CHN
BnO2CHN
NHCO2Bn
JACS 1978, 100 , 5179 N H pumiliotoxin C
CH3 H
6-MEMBERED RING FORMATION OMe
MeO O
R
+
O
O R
MeO2C
CO2Me
O
MeO2C
R
O MeO2C
PhS
SPh
PhS
SPh MeO
OMe O
O JACS 1986, 108 , 5908
O
Compactin
OMe
OMe R
R
R
+ Me3SiO
ACR 1981, 14 , 400
O
Me3Si-O
Danishefsky's Diene
OMe MeO2C
OH
O
CO2Me
H
O
+
H
Me3SiO
O
O H
Vernolepin
O
Hetero Diels-Alder Reactions - Heterodienophiles OMe CO2Bn N
+
PhH, reflux O
EtO2C
Me3SiO
N
CO2Bn
JACS 1982, 102 , 1428
CO2Et
O CO2Me
Me3SiO
+
HO
N
N H
TsN
Ts
TL 1987, 28 , 813
HO
PhH, 5°C
OH
CO2Me
CH(OMe)2
CH(OMe)2 O +
CH3
N
O CO2Bn
N CH3
OAc AcO
CO2Bn
AcO
OH NAc CH3
TL 1985 27 , 4727
153
6-MEMBERED RING FORMATION
Me
Me
Me
Me
O +
S
Me
O
S
Me
NTs
Me
Me
Me
S Ph
S
S
Ph
Ph
H
Ph
1) MgBr2
O
2) H3O+
OMe Me3SiO
Tetrahedron, 1983, 39 , 1487
S
O
+
TL 1983, 24 , 987
Me
Me
NTs
NHTs
Me
O
H OBn
JACS 1985, 107 , 1256
O OBn
OMe
+
Ar
H
Yb(fod)3
Me
Me3SiO
OMe
OMe
O
Me
HF, Pyridine
O
O
Ar
Me3SiO Me
JACS 1985, 107 , 6647
Me Ar
O Me
Me
O
Me
C3F7
M O
O C3F7
M
O 3
3
M(fod)3
M(hfc)3
- Heterodienes O
H
O
O
+
AcO
OAc
Me
O
PhS OAc
+
OEt
O
O
H O ACIEE 1983, 22 , 887
+ MeO2C
MeO2C
H
EtO
endo:exo 10 : 1
O
H
endo: exo 1:2
Me
MeO2C AcO
HO
H
O
OH
SPh OAc
Me
OH
ACR 1986, 19 , 250
154
6-MEMBERED RING FORMATION
155
OR' N
O
N
O
+
RO
O
O
RO RO
RO
N OR
OR
OR'
OR'
O
O
RO
N
OMe
RO
JACS 1987, 109 , 285
NHAc OR
CO2R'
H JOC 1985, 50 , 2719
∆
AcO
N
N
N
O
O
O
Intramolecular Diels-Alder Reactions - Type I IDA rxns
(IDA)
Fused bicyclc
Bridged Bicyclic
- Generally, for E-dienes, the fused product is observed unless the connecting chain is very long. For Z-dienes, either the fused or bicyclic products are possible. - Type II IDA rxns: gives bridgehead olefin
395°C
JACS 1982, 104 , 5708, 5715 O
O O
O
O
O
185°C EtO2C
EtO2C
JACS 1987, 109 , 447
O EtO2C
CO2Et AcO
NHBz O 155°C
Ph
O
OH ACIEE 1983, 24 , 419
O OH
O
O
H OH BzO AcO Taxol
O
6-MEMBERED RING FORMATION
156
- IDA reactions to give fused 6•5 (hydroindene) and 6•6 (hydronaphthalene) ring systems are usually favorable reactions. R'
R'
R (CH2)n
R
n= 1 or 2
(CH2)n
- Intramolecular D-A rxns that give medium sized rings (7,8,9, 10) are much less favorable. - Intramolecular D-A rxn which form large rings are often favorable reactions with the diene and olefin portions act as if they were seperate molecules H H
O
O
O +
H
H
O
O
O
endo
+
JACS 1980, 102 , 1390
H
O
O
O
O
O
H
O
O
O
O O
exo
6.2 : 6.8 : 1 (77% combined yield)
- Preference for endo or exo transition state depends on the substituition of the diene, dieneophile and connecting chain. - For intramolecular D-A rxns, geometric constraints can now reverse the normal regiochemistry of the addition as compared to the intermolecular rxn. + CO2R'
CO2R'
R
R CO2R'
CO2R'
- for intramolecular D-A reactions, we will use endo and exo to described the disposition of the connecting chain R
R'
R'
R
H (CH2)n
R' H
(CH2)n
R (CH2)n
endo R
R'
R'
R
H (CH2)n
(CH2)n exo
H
6-MEMBERED RING FORMATION
157
- Lewis acids can greatly effect the endo/exo ratio of IDA reactions especially when the olefin portion is E. The effects for Z-olefins is much more subtle MeO2C MeO2C
MeO2C
H
H
+
JACS 1982, 104 , 2269 H
H 75 : 25
150°C
(75% combined yield)
100 : 0
(RO)2AlCl2, rt
CO2Me
(72% combined yield)
MeO2C
MeO2C
H
H
+ H
H 75 : 25
180°C
63 : 37
EtAlCl2, rt
(74% combined yield) (60% combined yield)
- the effect of substituents on the connectinng chain can influence the stereochemical course of the IDA reaction HN O HN
EtAlCl2 O
JOC 1981, 46 , 1509
H
MeO2C
rt
MeO2C
H
R O
R R
R O H
H
Intramolecular Diels-Alder Reactions: CO2Me MeO2C 130°C TBSO
H
TBSO
JOC 1981, 46 , 1506
H
O
O O
150°C
O
TL 1973, 4477
6-MEMBERED RING FORMATION OTBS
OTBS CF3CO2H
H
JACS 1981, 103 , 4948
H H
H O
TBSO
OTBS
CO2Me
H
CO2Me JOC 1982, 47 , 180
EtAlCl2 H
Asymmetric Diels-Alder Reactions - Chiral Auxillaries Chem. Rev. 1992, 92 , 953; Tetrahedron 1987, 43 , 1969 OAc O
OAc O
M O
+
HO
OH
BF3•OEt2, -40°C H
CO2H
HO
H
OH
OAc
OAc
(-)- Shikimic Acid
>98% d.e.
O O
O
TiCl4, 0°C
+
JOC 1983, 48, 1137 JOC 1983, 43, 4441 ACIEE 1985, 24, 1
TL 1984, 25 , 2191
O R*
O
O
(97:3)
X
O
∆ = 4.5 %ee TiCl4= 78% ee iBu2AlCl= 90% ee
CO2R*
O O
CO2R*
O O Ph O
O
O Ph +
O +
OR* O
Ph
Ph
O
JOC 1989, 54 , 2209
OR*
18 : 82 w/ BF3•OEt2
O Ar O
O
Et2AlCl
+ OTMS
d.e > 95%
92 : 8
R*
CH2Cl2, -80°C
Chem Lett. 1989, 2149
O
up to 70% d.e.
O Ph H O Me
O OR* +
Eu(hfc)3 OTMS
Ph O
PhCHO
O
Me
8 : 92
OR* O
Me
JACS 1986, 108, 7060
158
6-MEMBERED RING FORMATION CH3
O Ph O
O R*
SnCl4, -78C
N +
O
O N
O
O S
S O
R
O
R*
PhMgBr
R 97% d.e.
159
R*
N H O S Ph
O
OH N
R
R
JCSCC , 1985 , 1449 TL 1986, 27 , 1853
O O H
(iPrO)2TiCl2, CH2Cl2, 0°C
O
H O SO2 N
Tetrahedron 1987, 43 , 1969
H CO2R*
O TL 1989, 30 , 6963
endo/exo= 86:4 98% de
X EtAlCl2, -78°C
Oppolzer Auxillary O
O Evan's auxillaries
N
R
O
O O
N
R Me
O
Ph
+ O
O
CO2R*
Me2AlCl N
O
CO2R*
endo (major)
endo CO2R*
CO2R*+ exo endo/exo endo A/ endoB k(rel)
O
O
+ O
O
Me2AlCl N
O
2 equiv. Me2AlCl 60:1 20:1 100
_ Me2AlCl2
_ Me2ClAl
exo
1 equiv Me2AlCl 20:1 4:1 1
N
O
Me2AlCl
+ Al O O N
O O
H
N
Al O O
6-MEMBERED RING FORMATION
O
O N
R
O O
OH
R* EtAlCl2, -100°C
Ph
O
O
O
R* N
Ph
R* H
Me2AlCl
H + TL 1984 , 25 , 4071 JACS 1988, 110 , 1238
Me H O
O
JACS 1984, 106, 4261 JACS 1988, 110 , 1238
(R)-(+)-α-terpineol
O O
160
H 15 : 85
O N Me2AlCl
Ph
95 : 5
- Chiral Dienes O OMe O
Ph
O CHO
OHC
OMe
BF3•OEt2, -20°C BF3•OEt2, -78°C
Ph
4:1 94:6
O
O
OH
OMe O
π-stacking arrangement
MeO H
Ph
O
+
O Ph
O OMe
O
H
O
OH
O O
H
approach of dienophile
O only product
- Chiral Catalysts Chem. Rev. 1992, 92 , 1007; Synthesis 1991, 1; OPPI 1994, 26, 129158 OH
CHO
CHO + EtAlCl2, -78°C
JCSCC 1979, 437
72% (ee)
OtBu Me +
Eu(hfc)3, -10°C
O O
TMSO Me
TL 1983, 24 , 3451
PhCHO Ph Me
6-MEMBERED RING FORMATION
161
Ph Ph Ph O O
O
OH OH
Me O
Ph Ph N
+
O
CL 1986, 1967
N
O
(iPrO)2TiCl2
O O O
O
Ph Ph O
O N
Ph O
OH
O
Me O
OH
H
O
Ph Ph
O
70% yield 95% ee
O
(iPrO)2TiCl2 O
N
O
(30 mol % catalyst)
H
Ph O
O OH OH +
OH
O
JACS 1986, 108 , 3510
Ph BH3, -78°C
OAc
OH
O
OAc
(98%)
Ts N Et B Br
O
CHO
O
N H
CHO
+ -78°C
Br
JACS 1992, 114 , 8290
(> 99% ee)
H N O Br
CHO
O N B Bu Ts
+
CHO Br
CH2Cl2, -78 °C, 16 hrs
Br
Br
O
(81%, 99% ee)
OC O
H N
O B O N Ts
OH
HO
approach of diene
CO2H Gibberellic Acid
Br
Br
H
H N OTBS
H 3C H
CHO +
O O
O
1) NaBH4 2) DDQ
OTBS
O O N B H Ts
CH2Cl2, PhCH3 -78 °C, 42 hrs
3) F
O JACS 1994, 116, 3611
-
4) HCl CHO (83%, 97% ee) O
O
OH
HO Cassiol
OH
6-MEMBERED RING FORMATION
162
Ketene Equivalents in the D-A reaction - ketenes undergo thermal [2+2] cycloaddition with dienes to give vinyl cyclobutanones. - 2-chloroacrylonitrile as a ketene equiv. for D-A rxns. AcO
+
Cl
Cl
CN AcO
ortho-Quinodimathanes
CN
KOH, tBuOH 70 °C
R R R
o-quinodimethane
benzocyclobutane
1)
Nature (London) 1994, 367, 630 ACIEE 1995, 34, 2079
Synthesis 1978, 793; Tetrahedron 1987, 43 , 2873 R
O
O
HO
O
OTMS
LiNH2, NH3, THF
MgBr
CuI, TMS-Cl
Me3Si
SiMe3
CpCo(CO)2
I
O
O
O 170 °C Me3Si Me3Si
H
H
H
Me3Si
Me3Si O
1) CF3CO2H, CCl4, -30°C 2) Pb(O2CCF3)4
H H
ACIEE 1984, 23 , 539 JACS 1977, 99 , 5483 JACS 1979, 101 , 215 JACS 1980, 102 , 241
H
HO Estrone
O O HN HN
JACS 1971, 93 , 3836
155 °C H
O
Me N
O
Me N
155 °C
ACIEE 1971, 11 , 1031
O
O
Me O
O
N
Me N
155 °C N
O
N
ACIEE 1971, 11 , 1031 N
OMe
Me
O
OMe Me
N ACIEE 1971, 11 , 1031
180 °C
N
H
Me3Si
Me3Si
NH
H
6-MEMBERED RING FORMATION Photoenolization
Tetrahedron 1976, 22, 405
R O
R •
hν
H
R O•
OH
R MeO2C
OH
CO2Me
CO2Me
H CO2Me
R
R
R O
R O
O
-H2O R
OH O
R
CO2Me O CO2Me O
R
Intramolecular Ene Reactions
R
ACIEE 1984, 23 , 876, Synthesis 1991, 1 H SnCl4 CHO
JOC 1985, 50, 4144
OH
H
JACS 1991, 113 , 2071
Me2AlCl BnO
H
OH
CHO OBn
Binaphthol
Tetrahedron Lett. 1985, 26, 5535
CHO
OH
Me2Zn
90% ee)
Polyene Cyclization +
Terpene Biosynthesis terpenes sesquiterpenes diterpenes steroids
C 10 C 15 C 20 C 30
+
geraniol farnesol geranylgeraniol squalene
- isoprene- basic building block OPP isopentyl-PP
isoprene unit
OPP OPP OPP
geraniol-PP (C10)
Farnesyl-PP (C15)
geranylgeraniol-PP (C20)
squalene (C30)
163
6-MEMBERED RING FORMATION
164
O HO2C
α-Cedrane
Camphor
Abietic Acid
Biosynthesis of camphor:
+ OPP
O +
Biosynthesis of cedrane: OPP
H
+
+
H + +
Stork-Eschenmoser Hypothesis- Olefin Geometry is preserved in the cyclization reaction, i.e. trans olefin leads to a trans fused ring jucntion A. Eschenmoser HCA 1955, 38, 1890; G. Stork JACS 1955, 77, 5068 Me
Me + Me
Me
R H
Me
Me Me
Me
R
H H
H
Biosynthesis of Abietic acid: OPP
OPP
+
OPP
H
+
H
H
H +
H + H H
H H
H
HO2C
H
6-MEMBERED RING FORMATION
165
-Steroid Biosynthesis: H+
H squalene cyclase
squalene epoxidase
squalene
H
+
H
H HO
+O
H HO
H
H
Protosterol
squalene oxide
H
H
+ H H
H
H H
H HO
H HO
H
H
HO
H Lanosterol
Cholesterol
- Polyene cyclization in synthesis ACR 1968, 1, 1; Bioorg. Chem. 1976, 5, 51; Asymmetric Synthesis 1984, 3, 341-409; ACIEE 1976, 15, 9 SnCl4 CH3NO2, 0°C
H
E.E. van Tamelen JACS 1972, 94 , 8229
(8%) H HO
O
H
δ- Amyrin
OH CHO
SnCl4 PhH, rt
JACS 1974, 96 , 3333
H
(38%) MeO
MeO
H
SnCl4 pentane H
(27%) O
O HO CO2Me OPO(OEt)2
O
W.S. Johnson JACS 1974, 96, 3979 H
H
CO2Me
1) Hg(O2CCF3)2 2) NaCl
O ClHg H
JACS 1980, 102 , 7612
6-MEMBERED RING FORMATION Robinson Annulation
166
Synthesis 1976, 777; Tetrahedron 1976, 32, 3. O
acid or base (thermodynamic conditions)
O
O
- unfavorable equillibium for the Michael addition under kinetic conditions O
base (kinetic conditions)
-
O
-O
O
- stabilizing the resulting enolate of the Michael Addition product can shift the equilibrium as in the case of the vinyl silane shown below O Me3Si
Me3Si
-
O
-
O
O
O
base (kinetic conditions)
OR
OR
OR
a) MeLi
Me3SiO
O
H
b) Me3Si
O
O
JACS 1974, 96 , 6181
O H
O O
O
c) MeONa
- Methyl Vinyl Ketone equivalents I +
mCPBA -
O
O
Me3Si
Me3Si
Me3Si
Aldol O
O
O
H+
O O
JACS 1974, 96 , 3862
I +
O O
O -
O
O
O
O
6-MEMBERED RING FORMATION Intramolecular Aldol Condensation of 1,5-Diketones 6-exo-trig; favored process O O
R'
R'
base - H2O R
R
O
- DeMayo reaction to 1,5-diketones O
O
O O
O
H
DIBAL-H
hν
O
O H 3C
Intramolecular Alkylations (SN2 reaction) Radical Cyclizations Acyloin Reaction Birch Reduction
Organic Reactions 1992, 42, 1.
Aromatic Substitution
(Carey & Sundberg, Chapter 11)
Intramolecular Wittig Reaction Sigmatropic Rearrangements
O
167
7-MEMBERED RING FORMATION
168
Medium Sized Rings 7-Membered Rings [4+2] cycloadditions - [4+2] cycloadditions between dienes and allylcations leads to cycloheptadienes review: ACIEE 1984, 23 , 1; ACIEE 1973, 12 , 819 +
+
+
I
+
CF3CO2Ag
ACIEE 1973, 12, 819 ACIEE 1984, 23, 1
-78°C Me
ZnCl2, -30°C
ACIEE 1982, 21, 442
+ +
H
H
F3CCO2 SiMe3
SiMe3
O
O OTMS +
JACS 1982, 104 , 1330
ZnCl2 Br
O
OMe O O
+
O
O
O
+
O
O
O
O O
JACS 1979, 101, 226
O
mCPBA O HO
- Noyori [4+2] cycloaddition of α,α'-dibromoketones and dienes review: ACR 1979, 12 , 61 O R
R Br
Br
Fe2(CO)9 -orZn-Cu
O
OM R
R R
+
R
ACR 1979, 61 Organic Reactions 1983, 29, 163
7-MEMBERED RING FORMATION
O
O
Br
Fe2(CO)9
Br Br
O
Br
Zn
Br O
O
Br
169
O
CO2Me O
N
Br
Br Br
MeO2C
1)
N
JACS 1978, 100 , 1786 Tetrahedron 1985, 41, 5879
Fe2(CO)9 2) Zn
Br
O
O
OMe O O
O
+
O
O
+
O
O
O
O O
O
mCPBA
JACS 1979, 101, 226
O HO
O
O Me
Me Br
Br
1) H2, Pd/C 2) CF3CO3H
O
1) Fe2(CO)9
OH
O O
O
H
O
JACS 1972, 94, 3940 JOC 1976, 41, 2075 H
O
O
O
1) CF3CO3H 2) LDA, MeI
O O
Me
O
Me
CO2H
Me OH JCSCC 1985, 55
O Me OBn
OBn
OH
OH
OBn
O
- [4+2] cycloaddition between pentadienyl cations and olefins +
+
O HO
OH ∆
O
-
O +
O
+
O O
Tetrahedron 1966, 22, 2387 JOC 1987, 52, 759
7-MEMBERED RING FORMATION O
MeO OMe OMe
SnCl4 OMe
O
O
JACS 1977, 99, 8073 JACS 1979, 101, 6767 JACS 1981, 103, 2718
Seven-Membered Rings from Funnctionalization of Tropone Organic Reactions 1997, 49, 331-425 O-
O
O
Cl
R
R
JOC 1988, 53, 4596 JACS 1987, 109, 3147
O
- [6+4] cycloadditions of tropones with dienes [6+4]
O
JACS 1986, 108, 4655 JOC 1986, 51, 2400
150°C
O
(88%)
O
HO HO HO
OH
Ingenol
- [4+2] cycloaddition between tropone and olefins O
O [4+2] 150°C (81%)
Radical Ring Expansion Reactions - one carbon ring expansions O
O CO2Me (CH2)n
n = 1,2,3
NaH, CH2Br2
Br CO2Me
nBu3SnH
CO2Me (CH2)n
(CH2)n
• CO2Me
(CH2)n
(CH2)n O
•O
O
nBu3SnH, AIBN
• CO2Me
O JACS 1987,109, 3493 JACS 1987,109 , 6548 (CH2)n
CO2Me
170
7-MEMBERED RING FORMATION
O
O Bu3SnLi BrCH2SePh
CH3
171
O •
SePh SnBu3
SnBu3 Tetrahedron 1989, 45, 909 Tetrahedron 1991, 47, 6795
O •O +
Bu3Sn•
SnBu3
- more than one carbon expansion O
R
O
X (CH2)n
(CH2)n
SnBu3
Tetrahedron 1989, 45, 909 Tetrahedron 1991, 47, 6795
R
X= I, SePh n= 1,2
Br
Bu3SnH, AIBN, C6H6, reflux
Br
+
JOC 1992, 57, 7163
O
O
Eight-Membered Rings [4+4] Cycloaddition of Dienes
O
review:Tetrahedron 1992, 48 , 5757. Ni(COD)2, Ph3P
MeO2C MeO2C
JACS 1986, 108 , 4678
MeO2C MeO2C
60°C
O
O
O
O
O
O Ni(COD)2, Ph3P
H
60°C
H O Asteriscanolide
Carbonyl Coupling Reactions - Acyloin Reaction CO2Me
O
Na
CO2Me
JACS 1971, 93 , 1673
OH
- McMurry Reaction R
R
CO2Et
Ti (0)
O O
JACS 1988, 110 , 5904
7-MEMBERED RING FORMATION
172
CHO OHC TiCl3, Zn-Cu H
JACS 1986, 108 , 3513
H
Aldol-like Condensations O O
TiCl4
O OTMS
OH
JCSCC 1983, 703
O
SiMe3
SiMe3
(CH2)n
R
Lewis Acid
R O
O
(CH2)n
OMe
O
JACS 1986, 108 , 3516
n= 1,2 Me3Si
Cl SnCl4 OTs O
tBuPh2SiO
Cl
Cl
Me3Si
OTs
O
O
tBuPh2SiO OEt
Laurenyne
TiCl4 O
SiMe3
JACS 1988, 110 , 2248
JOC 1988, 53 , 50 O
Pinocol Rearrangement O
Me3SiO
SnCl4
Me3SiO +
OMe
JACS 1989, 111 , 1514
OMe OMe
H
OMe
Tiffeneu-Demyanov Ring Expansion - one carbon ring expansion for virtually any size ring O
HO 1) Me3SiCN 2) LAH
N2
NH2 HONO
O H
O JOC 1980, 45 , 185
- also see Beckman and Schmidt rearrangements as a one atom ring expansion for the conversion of cyclic ketones to lactams.
7-MEMBERED RING FORMATION
173
DeMayo Reaction O O
O
O
hν
O
O
+ OAc AcO O JCSCC 1984, 1695 O
O
O
O
O
O
hν, pyrex
O
O
CO2Me
H
pTSA, MeOH reflux
JACS 1986, 108 , 6425
O O H
Ring Expansion/Contraction via Sigmatropic Rearrangements - Cope Rearrangement
O
O SMe
TL 1991, 32 , 6969
55°C O
O O
O
- Anion Accelerated Cope KH, 18-C-6 115°C
O
JACS 1989, 111, 8284
OH
O
OCOCH2OH Pleuromutilin
- Claisen Rearrangement O
O O
Tebbe reagent
O
185°C H
TL 1990, 31 , 6799
7-MEMBERED RING FORMATION - Ester Enolate Claisen- 4 carbon ring contractions O 1) LDA, TBS-Cl 2) 110°C
O
CO2H JACS 1982, 104 , 4030 Tetrahedron 1986, 42 , 2831
MOMO
MOMO H O O
1) LDA, TBS-Cl 2) 110°C
JOC 1988, 53 , 4141
H
H CO2TBS
174
Exam 1
page 1 of 5 1.
Give the reagent(s) necessary to carry out the following transformations. The stereochemistry of the products and reactants is as shown. (20 pts)
OH
HO
HO
CO2CH3
OH
OH
O
OH
OH
O
OH
O N
CO2H O
O
O
O
O OH
O
O OH
OH
page 2 of 5 2.
Give the product of the following reactions. The stereochemistry of the reactant is as shown. Give the proper sterochemistry of the major steroisomer of the product. (20 pts) OsO4, MNO
O O
O (CH3)2CuLi tBuMe2SiO
O mCPBA
O
O
1) LDA, THF
Ph
N
O 2)
H 3C
Ph
O
Ph
SO2Ph N
O Ph
H O
OCH3
CH3MgBr
page 3 of 5
3. What are the following reagents used for. Please be specific. (8 pts each) +
Ir
P(C6H11)3 PF6 -
N
PPh2 PPh2
H
H N
N
Bu2BOTf, iPr2NEt
Mn O
O
tBu
4.
O tBu
Give the reagent(s) needed to selectively deprotect the substrate below to the desired product. (16 pts) BnO
O
OSitBuMe2
O BnO
AcO
O
O
OSitBuMe2
BnO
O
OSitBuMe2
OH AcO
O
OH
OH
BnO
O
OH
O OH
OSitBuMe2
O AcO
O
O
O AcO
O
page 4 of 5
5.
Provide the product and all intermediates for the following sequence of reactions. (20 pts) 1) LiAlH4 2) MnO2 3) tBuMe2SiCl, pyridine
O O
4) pCH3C6H3SO2NHNH2 H+, C6H6 (- H2O) 5) NaCNBH3
page 5 of 5
6.
Starting from cyclohexanone, provide a feasible synthesis target shown. Give all reagents and intermediates. (16 pts) O ~ 4 steps
Exam 2
1.
page 1 of 5. Give the product of the following reactions. The stereochemistry of the reactant is as shown. Give the proper sterochemistry of the major stereoisomer of the product. (24 pts)
_ + MeO2CNSO 2NEt3
Me
PhH, ∆
Ph OH
O
Cp2 Ti O
CH2 Al(CH3 )2 Cl
NNHTs a) BuLi (2 equiv) b) CH3I H O O
1) LDA, TMS-Cl 2) ∆
H
OTf
Pd(0), CO, MeOH
O Cl
1) CH2 N2 2) hν, MeOH
2.
page 2 of 5. Give the reagent(s) necessary to carry out the following transformations. The stereochemistry of the products and reactants is as shown. (24 pts)
CHO CO2 Me
O
CO2 Me
O
O
H
O
H H H H
H
H H
O OH
O
O
Ph
O
O H
H
page 3 of 5. 3.
Give the expected product from a thermal and photochemical [2+2] cycloaddition of cycloheptenone with ethylene. Using MO's, clearly show why the photochemical and thermal pathways give different stereochemical outcomes. (12 pts) O
+
4.
page 4 of 5. Provide the product and all intermediates for the following sequence of reactions. (20 pts) 1) cyclopentene, hν O
2) DIBAL
O
4a) (CH3)2CuLi
3) tBuO-K+
O b) Tf2NPh 5) Ph2CuLi
5.
page 5 of 5. Complete the synthesis for the target shown. Give all reagents and intermediates. (20 pts). OH
~5 steps OH
O
O
Exam 3
1.
page 1 of 6. Give the product of the following reactions. The stereochemistry of the reactant is as shown. Give the proper sterochemistry of the major stereoisomer of the product. (20 pts)
CpCo(CO)2 R
R
CHO
NHBn
I2 CO2 H
H H2 , Pd/C O N H
CH3
O
O N
Ph
O
a) Bu2BOTf, Et3N b) PhCHO
2.
page 2 of 6. Give the reagent(s) necessary to carry out the following transformations. The stereochemistry of the products and reactants is as shown. (20 pts)
Ph
Ph CHO
OH
CH3
O
OBn
OBn OBn
OBn
OH
O CO 2H O
OMe
OMe
OMe
O
Me O
O OH
OH
OEt O
OEt I
O
CN
page 3 of 6. 3.
Short Answers. (5 points each, 20 points total) a. Define enantioselective and enantiospecific and give examples of each.
b. What is the Stork-Eschenmoser hypothesis?
page 4 of 6. c. What are Baldwin's Rules (be general, do not give each specific rule)? Be sure to explain what are the basis of the rules and give one example each of a reaction that is favored and disfavored according to Baldwin's rule.
d. Define umpolung and give an example.
page 5 of 6. 4. Provide the product and all intermediates for the following sequence of reactions. (20 pts)
OH
OH
1) (CH3)2 C(OCH3)2 , H+ 2) MnO2 3) (EtO)2P(O)CH2 CO 2Me, base 4) AcOH, THF, H2 O OH 5) tBuSiCl (1 equv), pyridine 6) TsCl, pyridine 7) Bu4NF
5.
page 6 of 6. Complete the synthesis for the target shown. Give all reagents and intermediates. (20 pts). O ~ 6 steps O OBn
O
