Stereoselective synthesis of Z-α-aryl-α,β-unsaturated esters

Article abstract of DOI:10.1021/jo060586t

An efficient method for the stereoselective synthesis of (Z)-α-arylacrylates is described. Treatment of α-hydroxyesters with triflic anhydride and pyridine at 0 °C followed by warming to room temperature afforded the corresponding (Z)-α-aryl-α,β- unsatura

Full text of DOI:10.1021/jo060586t

selectivity.9 Perhaps the most serious disadvantage to this
method is the difficulty of accessing the required phosphono-
carboxylate precursors with substituents in the R-position.10 In
connection with our work aimed at the synthesis of a (Z)-1,2-
diarylacrylate intermediate for a drug discovery program, we
too observed diminished Z-selectivity in the Still-Gennari
reaction, particularly in large-scale (10-20 g) reactions, prompt-
ing us to explore alternate approaches. One of the approaches
we examined was the possibility of stereoselective dehydration
of an R-hydroxy ester. Herein we report our results, which show
that carefully controlled dehydration of R-aryl-R-hydroxyesters
can proceed with remarkable Z-selectivity, efficiently providing
the desired Z-R-arylacrylates.
Stereoselective Synthesis of
Z-r-Aryl-r,â-unsaturated Esters
Neelakandha S. Mani,* Christopher M. Mapes, Jiejun Wu,
Xiaohu Deng, and Todd K. Jones
Department of Drug DiscoVery, Johnson & Johnson
Pharmaceutical Research and DeVelopment, L.L.C.,
3210 Merryfield Row, San Diego, California 92121
nmani@prdus.jnj.com
ReceiVed March 16, 2006
Aldol condensation and subsequent dehydration of a â-hy-
droxy ester is a classical method for the synthesis of R,â-
unsaturated acid derivatives.11 High stereoselectivities were
observed in the E2 elimination of erythro-aldols to form
E-acrylates. However, in the case of corresponding threo-aldols,
a clean E2 elimination to form Z-acrylates remains elusive.12
Stereoselective dehydration of an R-aryl-R-hydroxy ester (eq
1) was devised based on the hypothesis that the aryl group being
larger than the ester group, a trans E2 elimination should give
the desired Z-acrylate, as suggested by the corresponding
Newman projection (eq 2).
An efficient method for the stereoselective synthesis of (Z)-
R-arylacrylates is described. Treatment of R-hydroxyesters
with triflic anhydride and pyridine at 0 °C followed by
warming to room temperature afforded the corresponding
(Z)-R-aryl-R,â-unsaturated esters in very good yields and
excellent stereoselectivity.
Stereoselective synthesis of Z-R,â-unsaturated acid derivatives
remains one of the enduring, classic problems in organic
synthesis. The Corey-Winter1 olefination of 1,2-diols, carbo-
diimide-assisted syn elimination of erythro-aldols,2 Peterson
olefination,3 Wittig reaction,4 and Z-selective modifications of
the Horner-Wadsworth-Emmons reaction developed by Sey-
den-Penne et al.,5 Breuer and Bannet,6 Still and Gennari,7 and
Ando8 are some of the notable solutions developed over the
years to address the problem of controlling olefin geometry.
Among these methods, the Still-Gennari protocol has clearly
emerged as the method of choice in most applications. However,
even this method is not without some limitations, particularly
in the synthesis of R,â-disubstituted acrylate derivatives, wherein
Marshall et al. and others have observed diminished Z-
Disubstituted R-hydroxy esters are easily prepared either by
addition of a Grignard reagent to an R-keto ester13 or more
efficiently by the alkylation of an R-hydroxyester.14
Initial attempts at dehydration according to conventional
methods were disappointing. In this regard, heating the hydroxy-
ester 1 with acetic anhydride in the presence of catalytic amounts
of sodium acetate15 favored formation of the E-isomer. Treat-
ment with methanesulfonyl chloride and triethylamine gave
(1) (a) Corey, E. J.; Winter, R. A. E. J. Am. Chem. Soc. 1963, 85, 2677-
2678. (b) King, J. L.; Posner, B. A.; Mak, K. T.; Yang, N. C. Tetrahedron
Lett. 1987, 28, 3919-3922.
(2) (a) Corey, E. J.; Anderson, N. H.; Carlson, R. M.; Paust, J.; Vedejs,
E.; Vlattas, I.; Winter, R. E. K. J. Am. Chem. Soc. 1968, 90, 3245-3247.
(b) Corey, E. J.; Letavic, M. A. J. Am. Chem. Soc. 1995, 117, 9616-9617.
(3) Colvin, E. W. Silicon in Organic Synthesis; Butterworth: London,
1981.
(9) (a) Marshall, J. A.; DeHoff, B. S.; Cleary, D. G. J. Org. Chem. 1986,
51, 1735-1741. (b) Hammond, G. B.; Cox, M. B.; Weimer, D. F. J. Org.
Chem. 1990, 55, 128-132.
(10) Patois, C.; Savignac, P.; About-Jaudet, E.; Collignon, N. Organic
Synthesis; John Wiley & Sons: New York, 1996; Collect. Vol. IX, pp 88-
91.
(11) (a) Zimmerman, H. E.; Ahramjian, L. J. Am. Chem. Soc. 1959, 81,
2086-2091. (b) Feuillet, F. J. P.; Robinson, D. E. J.; Bull, S. D. J. Chem.
Soc., Chem. Commun. 2003, 2184-2185.
(4) Kishi, Y.; Schmid, G.; Fukuyama, T.; Akasaka, K. J. Am. Chem.
Soc. 1979, 101, 259-260.
(12) Sai, H.; Ohmizu, H. Tetrahedron Lett. 1999, 40, 5019-5022.
(13) Pardo, S. N.; Ghosh, S.; Solomon, R. G. Tetrahedron Lett. 1981,
22, 1885-1888.
(5) (a) Deschamps, B.; Lefebvre, G.; Seyden-Penne, J. Tetrahedron 1972,
28, 4209-4222. (b) Deschamps, B.; Lampin, J. P.; Mathey, F.; Seyden-
Penne, J. Tetrahedron Lett. 1977, 1137-1138.
(14) Ciochetto, L. J.; Bergbreiter, D. E.; Newcomb, M. J. Org. Chem.
1977, 42, 2948-2950.
(6) Breuer, E.; Bannet, D. M. Tetrahedron Lett. 1977, 1141-1142.
(7) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
(8) Ando, K. J. Org. Chem. 1998, 63, 8411-8416.
(15) Marathe, K. G.; Byrne, M. J.; Vidwans, R. N. Tetrahedron 1966,
22, 1789-1795.
10.1021/jo060586t CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/23/2006
J. Org. Chem. 2006, 71, 5039-5042
5039

SCHEME 1. Stereoselective Dehydration
SCHEME 3. Mechanism of Dehydration
only trace amounts of elimination product. In contrast, clean
elimination according to our method was achieved by treating
a cold (0 °C) solution of the R-hydroxyester in dichloromethane
(∼0.2 M) with triflic anhydride and pyridine. After warming
to room temperature and an aqueous workup, the Z-acrylate was
obtained in very good yields and excellent stereoselectivity
(Scheme 1).
DMAP also gave clean elimination product. Strong tertiary
amine bases, triethylamine, and Hu¨nig’s base also gave the
Z-acrylate, but the reactions were messy and incomplete. Other
strong organic bases such as DBU, N-methylpiperidine, quino-
line, and 2,6-lutidine or inorganic bases such as sodium acetylide
and K2CO3 gave only trace amounts of the elimination product.
When a mixture of Et3N (5 eq) and pyridine (0.1 eq) was used,
it gave lower yields and diminished stereoselectivity. Nonpolar
solvents, such as toluene and dichloromethane, gave very good
results. In polar solvents, such as acetonitrile and DMF, and in
ethereal solvents, such as THF, diethyl ether, and DME, very
little or no reaction was observed.
The effectiveness of pyridine and DMAP toward dehydration
piqued our curiosity about the actual mechanism of dehydration,
that is, whether base-induced elimination of a triflate intermedi-
ate occurred by an E2 pathway or through the formation of an
acylcarbenium ion by an E1 pathway. Although formation of
species having positively charged carbon attached to strongly
electron-withdrawing groups are expected to be highly unfavor-
able, electron-withdrawing groups such as cyano, acyl, and
alkynyl substituents have indeed been shown to stabilize the
carbenium ion through resonance. Thus, Gassman et al.16 and
Olah et al.17 have shown that the surprising stability of cyano-
substituted carbocations arose from the mesomeric acylnitrenium
ions. In the case of R-acylcarbenium ions, Morize and Begue18
have postulated that mesomeric stabilization can occur through
an overlap with the lone pair p orbital of the oxygen or the pi
orbital of the carbonyl group. Solvolytic studies by Richard et
al.19 have shown that the lifetime of R-carboxyethyl-4-meth-
oxybenzylcarbocation is indeed 14-fold longer than that for the
unsubstituted carbocation. To test these possibilities, a number
of NMR time course experiments were carried out using 1 as
the substrate.
of the elimination product from the starting material. The triflate
intermediate 3 was not observable in the NMR time scale,
indicating that it may be highly reactive. Interestingly, formation
of small amounts (∼20%) of a polar product, which did not
undergo further elimination, was observed in this experiment.
Isolation of this side product by thin-layer chromatography,
followed by NMR and mass spectral analysis, revealed it to be
the pyridinium triflate 4 (Scheme 2).
The pyridinium salt 4 was quite stable at room temperature.
Treating 4 with various bases, such as triethylamine, DBU, or
pyridine, to induce elimination were unsuccessful, and heating
4 in pyridine led to decomposition. Solution and vapor-phase
elimination of alkylpyridinium salts to form alkenes has been
reported,20 however, from the above experiments it is clear that
this pathway does not operate to form alkenes in our experi-
ments. Next, in a similar experiment we used only triflic
anhydride without any added pyridine. This experiment also
showed slow conversion of the starting alcohol to the alkene, a
clear indication that the elimination possibly takes place through
an acylcarbenium ion. In a third time-course experiment, we
used triflic acid to see if protonation can lead to the carbocation,
with water as a leaving group. In this case, stereoselective
elimination to form the Z-alkene was also observed, strongly
suggesting an acylcarbenium ion intermediate 5 (Scheme 3).
To examine the scope of this reaction, a diverse set of R-aryl-
R-hydroxy esters (Table 1) was subjected to dehydration
conditions. Although use of triflic acid as the dehydrating agent
did result in elimination to form the alkene in our NMR
experiments, in large-scale experiments, diminished yields and
isomerizations were observed in many instances. Dehydration
using triflic anhydride and pyridine, however, gave a cleaner
reaction profile and only very small amounts (1-2%) of the
pyridine adduct 4 were observed. Triflic anhydride-pyridine
was thus chosen as the preferred reagent system for the
preparation of alkenes. Excellent Z selectivity was observed,
typically Z/E > 40/1 in most cases. Particularly striking was
the good Z-selectivity observed even in cases with sterically
less-demanding, â-carbon substituents such as methyl, vinyl,
and alkynyl groups (entries 4, 7, and 8). The stereochemistry
1
In the first experiment, a solution of 1 in CD2Cl2 taken up in
an NMR tube was cooled to 0 °C, and triflic anhydride and
pyridine-d5 were added. The NMR tube was then transferred
to the NMR instrument, and a time-course experiment was
started immediately, while allowing the reaction to warm to
room temperature. This experiment indicated slow formation
of the olefins obtained was easily ascertained, mostly by H
NMR spectroscopy, based on the considerable downfield shift
of the olefinic proton in the case of E-acrylates. Typically, the
olefinic proton of Z-acrylates appears at δ 6-6.5 ppm, and for
the corresponding E-isomers, the olefinic proton appears at δ
7-8 ppm.
1
SCHEME 2. Study of Dehydration by H NMR
5040 J. Org. Chem., Vol. 71, No. 13, 2006

TABLE 1. Stereoselective Dehydration of r-Hydroxyesters
toward large-scale synthesis of pharmaceutical target molecules
from our laboratories will be reported in due course.
Experimental Section
General Procedure for the Dehydration of R-Hydroxy Esters
(Entries 1-9). To a solution of the hydroxyl ester (1.0 mmol) in
anhydrous CH2Cl2 (10 mL) cooled to 0 °C using an ice bath was
added triflic anhydride (0.31 g, 1.1 mmol). After 10 min, anhydrous
pyridine (0.4 mL, 5.0 mmol) was added dropwise. The reaction
mixture was stirred for 10-12 h, while allowing the mixture to
slowly warm to room temperature. The reaction was then quenched
by the addition of water (20 mL), and the mixture was transferred
to a separatory funnel. The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (2 × 30 mL). All organic layers
were combined, washed with brine, dried over MgSO4, filtered,
and evaporated under reduced pressure. The crude unsaturated ester
thus obtained was purified by flash column silica gel chromatog-
raphy (eluting with a gradient of 10-25% EtOAc/hexanes).
entry
R1
R2
R3
Me
Me
Me
Me
Me
Me
Me
Z/Ea
yield (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
40/1
20/1
40/1
40/1
40/1
99/1
8/1
88
93
86
90
93
92
91
81
86
2-CH3OC6H4
4-PhC6H4
Me
Me2CH
CO2Me
HCtC
H2CdCH
Ph
3-ClC6H4
Ph
Ph
Me
Me2CH
10/1
70/1
a Z/E ratios were determined by 1H NMR from the integration of the
olefinic protons of Z- and E-isomers.
(Z)-2,3-Diphenylacrylic acid methyl ester (7, Entry 1): color-
less oil; yield 88%; Z/E ) 40/1; IR (film) 2921, 1724, 1433, 1264,
1250, 1211, 1195, 1172, 1037, 1007, 751, 734, 694 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 3.79 (s, 3H), 7.05 (s, 1H), 7.29-7.40 (m,
8H), 7.46-7.47 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 52.3,
126.4, 128.1, 128.3, 128.5, 128.7, 131.5, 134.8, 135.6, 136.8, 170.1;
HRMS (EI) m/z calcd for C16H15O2 [M + H]+, 239.1067; found,
239.1072.
Because the mechanistically derived preference for the
Z-isomer is dependent on the relative size of the R-substituent
and the ester group, a smaller R-substituent should exhibit the
opposite preference, thus leading to the E-isomer. Application
of the dehydration procedure to substrate 8 in which the
R-substituent is methyl (smaller in size than the ethoxycarbonyl)
gave two isomeric products in a 3:1 ratio (Scheme 4). The major
product was the expected E-cinnamate 9 with an E/Z ratio of
40/1. The minor product was the isomeric R-benzyl acrylate
10.21
(Z)-3-(2-Methoxyphenyl)-2-phenylacrylic Acid Methyl Ester
(7, Entry 2): white crystalline solid; yield 93%; Z/E ) 20/1; mp
50-51 °C; IR (film) 2948, 2920, 2839, 1722, 1596, 1578, 1494,
1486, 1462, 1433, 1359, 1308, 1275, 1248, 1207, 1194, 1172, 1111,
1077, 1051, 1025, 1007, 971, 847, 779, 751, 736, 694, 668 cm-1
;
SCHEME 4
1H NMR (CDCl3, 400 MHz) δ 3.73 (s, 3H), 3.84 (s, 3H), 6.89-
6.94 (m, 2H), 7.27 (s, 1H), 7.29-7.33 (m, 3H), 7.35-7.39 (m,
3H), 7.45-7.47 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 51.9,
55.4, 110.5, 120.4, 125.1, 126.8, 128.1, 128.3, 128.5, 128.6, 129.8,
134.7, 137.4; HRMS (EI) m/z calcd for C17H17O3 [M + H]+,
269.1172; found, 269.1180.
(Z)-3-Biphenyl-4-yl-2-phenylacrylic Acid Methyl Ester (7,
Entry 3): white crystalline solid; yield 86%; Z/E ) 40/1; mp 115-
116 °C; IR (film) 3029, 1724, 1598, 1486, 1434, 1361, 1218, 1198,
In conclusion, we have developed an efficient method for
the synthesis of Z-R-arylacrylates on the basis of the stereose-
lective dehydration of the corresponding R-hydroxyester. Excel-
lent Z-selectivity was observed with a diverse set of R-aryl-R-
hydroxyesters. Our studies coupled with reported investigations
on resonance stabilized carbocations strongly suggest that the
mechanism involves the intermediacy of an acylcarbenium ion,
and the remarkable stereochemical preference likely results from
the larger size of the aryl substituent vis-a`-vis the alkoxy
carbonyl group favoring the Z-isomer. A vast number of
R-arylacrylates and R-heteroarylacrylates have been reported
in the literature,22 and the methodology outlined here should
be suitable to a considerable number of this important class of
compounds. The successful application of this methodology
1
1171, 1004, 892, 836, 763, 695 cm-1; H NMR δ 3.81 (s, 3H),
7.06 (s, 1H), 7.23-7.61 (m, 14H); 13C NMR δ 52.2, 126.3, 126.9,
127.1, 127.5, 128.3, 128.6, 128.7, 128.8, 128.9, 131.0, 134.5, 134.6,
136.8, 140.3, 141.0, 170.1; HRMS (EI) m/z calcd for C22H19O2 [M
+ H]+, 315.1381; found, 315.1371.
(Z)-2-Phenylbut-2-enoic Acid Methyl Ester (7, Entry 4):
colorless oil; yield 90%; Z/E ) 40/1; IR (film) 2950, 1718, 1494,
1434, 1352, 1202, 1114, 1005, 753, 696 cm-1; 1H NMR δ 2.03 (d,
J ) 7.2 Hz, 3H), 3.79 (s, 3H), 6.25 (q, J ) 7.2 Hz, 1H), 7.29 (m,
5H); 13C NMR δ 15.9, 51.5, 127.2, 127.4, 128.1, 135.3, 135.4,
138.1, 168.4; HRMS (EI) m/z calcd for C11H13O2 [M + H]+,
177.0912; found, 177.0905.
(Z)-4-Methyl-2-phenylpent-2-enoic Acid Methyl Ester (7,
Entry 5): colorless oil; yield 93%; Z/E ) 40/1; IR (film) 2952,
1720, 1615, 1495, 1435, 1331, 1200, 1171, 1093, 1028, 990, 868,
812, 775, 699 cm-1; 1H NMR δ 1.08 (d, J ) 6.6 Hz, 6H), 2.95 (m,
1H), 3.79 (s, 3H), 5.95 (d, J ) 10.0 Hz), 7.27 (m, 5H); 13C NMR
δ 22.6, 29.4, 51.6, 127.1, 127.4, 128.2, 132.3, 137.8, 146.4, 168.7;
HRMS (EI) m/z calcd for C13H17O2 [M + H]+, 205.1225; found,
205.1228.
(16) Dixon, D. A.; Charlier, P. A.; Gassman, P. G. J. Am. Chem. Soc.
1980, 102, 3957-3959.
(17) Olah, G. A.; Surya Prakash, G. K.; Arvanghi, M. J. Am. Chem.
Soc. 1980, 102, 6641-6642.
(18) Begue, J.-P.; Morize, M. C. Acc. Chem. Res. 1980, 13, 207-212.
(19) Richard, J. P.; Amyes, T. L.; Stevens, I. W. Tetrahedron Lett. 1991,
32, 4255-4258.
(20) Katritzky, A. R.; Watson, C. H.; Dega-Szafran, Z.; Eyler, J. R. J.
Am. Chem. Soc. 1990, 112, 2479-2484.
(Z)-2-Phenylbut-2-enedioic Acid Dimethyl Ester (7, Entry 6):
pale tan oil; yield 92%; Z/E ) 99/1; IR (neat) 2951, 2836, 1719,
1625, 1577, 1497, 1450, 1434, 1357, 1291, 1197, 1169, 1024, 1003,
(21) The identities of the products were confirmed by comparing with
the reported NMR data for 8 and 9. See ref 8 and Lee, H.-S.; Park, J.-S.;
Kim, B. M.; Gellman, S. H. J. Org. Chem. 2003, 68, 1575-1578.
(22) A SciFinder search revealed more than 1000 stereodefined R-aryl/
heteroarylacrylates cited in the literature.
1
887, 835, 773, 753, 687, 668, 633 cm-1; H NMR (CDCl3, 400
MHz) δ 3.78 (s, 3H), 3.94 (s, 3H), 6.31 (s, 1H), 7.37-7.42 (m,
3H), 7.46-7.48 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 52.0,
J. Org. Chem, Vol. 71, No. 13, 2006 5041

52.7, 116.9, 126.7, 128.9, 130.6, 133.1, 148.9, 165.4, 168.3; HRMS
(EI) m/z calcd for C12H13O4 [M + H]+, 221.0808; found, 221.0812.
(Z)-2-(3-Chlorophenyl)-pent-2-en-4-ynoic Acid Methyl Ester
(7, Entry 7): pale yellow oil; yield 91%; Z/E ) 8/1; IR (film)
3289, 2951, 2100,1725, 1592, 1563, 1475, 1435, 1345, 1207, 1178,
(Z)-2,3-Diphenylacrylic Acid Isopropyl Ester (7, Entry 9):
colorless oil; yield 86%; Z/E ) 70/1; IR (film) 2980, 1715, 1495,
1449, 1373, 1215, 1184, 1103, 1078, 1030, 1001, 985, 914, 858,
1
826, 753, 719, 692, 668, 649 cm-1; H NMR (CDCl3, 400 MHz)
δ 1.18 (d, J ) 6.3 Hz, 6H), 5.19 (septuplet, J ) 6.3 Hz, 1H), 7.02
(s, 1H), 7.27-7.40 (m, 8H), 7.46-7.78 (m, 2H); 13C NMR (CDCl3,
100 MHz) δ 21.4, 68.9, 126.3, 128.1, 128.2, 128.3, 128.6, 130.6,
135.7, 135.8, 136.9, 169.1; HRMS (EI) m/z calcd for C18H19O2 [M
+ H]+, 267.1380; found, 267.1373.
1
1099, 1048, 784, 690, 638 cm-1; H NMR δ 3.48 (d, J ) 2.4 Hz,
1H), 3.88 (s, 3H), 6.17 (d, J ) 2.4 Hz, 1H), 7.26-7.37 (m, 4H);
13C NMR δ 52.3, 79.6, 87.2, 114.6, 125.2, 127.1, 129.1, 129.7,
134.5, 137.0, 144.2, 166.4; HRMS (EI) m/z calcd for C12H10ClO2
[M + H]+, 221.0291; found, 221.0293.
Acknowledgment. We thank professor Scott E. Denmark
and Dr. James P. Edwards for useful discussions.
(Z)-2-Phenylpenta-2,4-dienoic Acid Methyl Ester (7, Entry
8): pale yellow oil; yield 81%; Z/E ) 10/1; IR (film) 2951, 1714,
1484, 1493, 1434, 1345, 1243, 1202, 1171, 1003, 918, 763, 695
Supporting Information Available: Representative experi-
mental procedures, details of NMR time course experiments, and
spectroscopic data for all new compounds are provided. This mater-
ial is available free of charge via the Internet at http://pubs.acs.org.
1
cm-1; H NMR δ 3.83 (s, 3H), 5.43 (dd, J ) 1.4, 10.4 Hz, 1H),
5.52 (ddd, J ) 1.4, 2.1, 16.7 Hz, 1H), 6.66 (d, J ) 11.2 Hz, 1H),
7.01 (m, 1H), 7.29-7.35 (m, 5H); 13C NMR δ 51.8, 123.8, 127.4,
127.9, 128.3,133.5,133.7, 137.1, 137.4, 168.0; HRMS (EI) m/z calcd
for C12H13O2 [M + H]+, 189.0912; found, 189.0910.
JO060586T
5042 J. Org. Chem., Vol. 71, No. 13, 2006