Improved Horner-Wadsworth-Emmons preparation of α-methyl- or α-ethyl-α, β-unsaturated esters from aldehydes

Article abstract of DOI:10.1081/SCC-100000184

The E-isomer selectivity of the Horner-Wadsworth-Emmons olefination of aldehydes to form α-methyl- or a-ethyl-α,β-unsaturated esters has been improved by using lithium tert-butoxide as the base, triethyl-2-phosphonopropionate or triethyl-2-phosphonobutyrate as the phosphonate, an aldehyde, and hexane as the reaction solvent. Greater E-isomer selectivity was observed in the formation of α-methyl-α,β-unsaturated esters than α-ethyl-α,β-unsaturated esters. These compounds are useful intermediates for the synthesis of insect pheromones and natural products.

Full text of DOI:10.1081/SCC-100000184

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IMPROVED HORNER-WADSWORTH-EMMONS
PREPARATION OF α-METHYL- OR α-ETHYL-α,β-
UNSATURATED ESTERS FROM ALDEHYDES
Richard J. Petroski a & David Weisleder a
a National Center for Agricultural Utilization Research , 1USDA, REE, Agricultural
Research Service, Bioactive Agents Research Unit and Analytical Support Unit, 1815 N.
University Street, Peoria, IL, 61604, U.S.A.
Published online: 09 Nov 2006.
To cite this article: Richard J. Petroski & David Weisleder (2001) IMPROVED HORNER-WADSWORTH-EMMONS PREPARATION
OF α-METHYL- OR α-ETHYL-α,β-UNSATURATED ESTERS FROM ALDEHYDES, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 31:1, 89-95, DOI: 10.1081/SCC-100000184
To link to this article: http://dx.doi.org/10.1081/SCC-100000184
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SYNTHETIC COMMUNICATIONS, 31(1), 89–95 (2001)
IMPROVED
HORNER-WADSWORTH-EMMONS
PREPARATION OF α-METHYL- OR
α-ETHYL-α,β-UNSATURATED ESTERS
FROM ALDEHYDES
Richard J. Petroski∗ and David Weisleder
1USDA, REE, Agricultural Research Service, National
Center for Agricultural Utilization Research, Bioactive
Agents Research Unit and Analytical Support Unit, 1815 N.
University Street, Peoria, IL 61604
ABSTRACT
The E-isomer selectivity of the Horner-Wadsworth-Emmons
olefination of aldehydes to form α-methyl- or α-ethyl-α,β-
unsaturated esters has been improved by using lithium tert-butoxide
as the base, triethyl-2-phosphonopropionate or triethyl-2-phospho-
nobutyrate as the phosphonate, an aldehyde, and hexane as the re-
action solvent. Greater E-isomer selectivity was observed in the
formation of α-methyl-α,β-unsaturated esters than α-ethyl-α,β-
unsaturated esters. These compounds are useful intermediates for
the synthesis of insect pheromones and natural products.
∗ Author to whom correspondence should be addressed; fax (309) 681-6693; e-mail:
petrosrj@mail.ncaur.usda.gov.
1 Names are necessary to report factually on available data; however, the USDA neither
guarantees nor warrants the standard of the product, and the use of the name by USDA
implies no approval of the product to the exclusion of others that may also be suitable.
89
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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PETROSKI AND WEISLEDER
Scheme 1.
Insect pheromones are currently used as pest management tools. Aggrega-
tion pheromones have been identified for nine species of sap beetles, belonging
to the genus Carpophilus (1). The pheromones are composed of alkyl-branched,
conjugated triene or tetraene hydrocarbons having all E-double-bond configu-
ration (1). A project was undertaken to improve the synthetic pathway leading
to the sap beetle pheromones (2). Robust reactions using mild conditions were
sought.
The pheromones have been prepared using Horner-Wadsworth-Emmons
(HWE) reactions to build up the carbon chain (2). High yields, and E-isomer
double-bond configuration, were critical to our efforts.
HWE reactions resulting in the formation of α-methyl- or α-ethyl-α,β-
unsaturated esters from aldehydes do not always yield acceptable E-isomer se-
lectivity because alkyl substitution on the 2-position of the phosphonate (e.g.,
triethyl-2-phosphonobutyrate vs triethyl-2-phosphonoacetate) has been linked to
increased Z-isomer formation in the reaction products (3).
In this paper, we report facile conversion of aldehydes to α-methyl- or
α-methyl-α,β-unsaturated esters with high E-isomer selectivity using lithium
tert-butoxide as the base and hexane as the reaction solvent (Scheme). These
compounds can serve as useful synthetic intermediates (1,2).
RESULTS AND DISCUSSION
Mild HWE reaction conditions for the formation of mainly E-isomer α,β-
unsaturatedestersfromaldehydesutilizingeitherbariumhydroxide(4,5)orlithium
hydroxide (4) as the base and 1,4-dioxane or THF as the reaction solvent have been
developed, but our attempts to prepare α-branched-α,β-unsaturated esters using
these conditions resulted in the formation of little or none of the desired product
when either triethyl-2-phosphonopropionate (TEPP) or triethyl-2-phosphonobuty-
rate (TEPB) was substituted for triethyl-2-phosphonoacetate (TEPA).
The results of our synthetic study (Table 1) show that the reaction conditions
afford high yields (86–98%) of the desired products. The reactions are facilitated
by the fact that lithium tert-butoxide is commercially available as a 1.0 M solution
in hexane (Aldrich Chemical Co., St. Louis, MO). Longer reaction times (4 h) are
required when triethyl-2-phosphonobutyrate (TEPB) is used to prepare α-ethyl-
branched-α,β-unsaturated esters. The workup is straightforward.

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Table 1. Preparation of α-branched-α,β-unsaturated Esters from Aldehydesa
Isolated
E/Z
Entry
1
Structure
Phosphonate
TEPP
Product
Time (h) Yield (%)b Ratio
1
93
140
25
2
3
TEPB
TEPP
4
1
95
86
8.6
4
5
TEPB
TEPP
4
1
90
98
1.7
44
6
TEPB
4
92
8.0
aReaction conditions: phosphonate (20 m moles), Li OtBu (20 m moles), aldehyde (13.3 m
moles), hexane (60 mL), 25◦C.
bKugelrohr distillation.
Double-bond configurations were assigned by NMR spectroscopy. Brouwer
and Stothers reported that the olefinic protons of E- and Z-methyl-2-methyl-2-
butenoate were found at δ 6.745 and δ 5.978, respectively (7). The E-isomer
olefinic proton is downfield when compared to the Z-isomer olefinic proton. We
prepared ethyl-2-ethyl-2-hexenoate as a mixture of E- and Z-isomers in a ratio of
1.7 to 1.0 (Entry 4, Table 1). The olefinic protons of E-ethyl-2-ethyl-2-hexenoate
and Z-ethyl-2-ethyl-2-hexenoate were found at δ 6.91 and δ 5.72, respectively, in
the integrated ratio of 1.7 to 1.0. The olefinic protons at the 3-position of all the
compounds encountered in our study were observed at a chemical shift of at least δ
6.91, which partially justifies our assignment of the E-double-bond configuration
for the major isomer produced by synthesis.
Further confirmation of our assigned double-bond geometry was acquired
with the use of nOe difference NMR spectra. When the protons of the 2-methyl or
2-methylene (of ethyl branch) were irradiated, very small nOe’s for the olefinic
proton at the 3-position were observed. The very small nOe’s obtained by NMR
analysis confirm the E-configuration. If the olefinic proton was cis to the irradi-
ated methyl or methylene protons, then an easily noticeable nOe effect would be
expected.
The minor isomer of all compounds was assigned the Z double-bond con-
figuration on the basis of nearly identical mass spectra to the major product
isomer and earlier GC retention times. In the case of ethyl-2-ethyl-2-hexenoate
(entry 4, Table 1), we could determine the double-bond configuration for both
isomers directly by NMR analysis because both isomers were abundant in the
NMR sample.

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PETROSKI AND WEISLEDER
The E/Z isomeric ratio was higher in the case of α-methyl-α,β-unsaturated
esters (8.6–140 to 1) than for the corresponding α-methyl-α,β-unsaturated
esters (1.7–25 to 1). Our results suggest that the E/Z isomeric ratio is enhanced
when α-α,β-unsaturated aldehydes are used in HWE reactions instead of aliphatic
aldehydes. Very high E/Z isomeric ratios (at least 25 to 1) were observed when
benzaldehyde was used in the reaction.
This is an improved HWE preparation of α-branched-α,β-unsaturated esters
from aldehydes because of higher yields and greater selectivity in terms of E-
double-bond configuration in the reaction products. When compounds 3, 5, and
6 were prepared using n-BuLi as the base and THF as the reaction solvent, the
yields were 83%, 82%, and 87%, respectively, and the E/Z isomeric ratios were
5.9, 38, and 6.0, respectively (Bartelt, personal communication). Our yields were
slightly higher and a greater proportion of the desired E-double-bond isomer was
obtained. Also, it was previously necessary to heat the reaction mixture to THF
reflux temperature when TEPB was used as the phosphonate (2). Preparation of α-
branched-α,β-unsaturated esters from aldehydes using alkoxide bases in alcohols
resulted in lower yields of the desired products (2).
EXPERIMENTAL
General Synthetic Procedure Using
Triethyl-2-phosphonopropionate (TEPP)
TEPP (4.76 g, 20 mmol) was added to 35 mL of hexane. A nitrogen atmo-
sphere was introduced and the mixture was stirred at room temperature. Lithium
tert-butoxide (20 mL of a 1.0 M solution in hexane) was added in one portion via
syringe. The solution became turbid, but no significant heating of the solution was
observed. Afterstirringfor15min, thealdehyde(13.3mmolin5mLofhexane)was
added dropwise over the course of 10 min. The solution clarified as aldehyde was
added, but no heating of the solution was observed. The solution was allowed to stir
for an additional hour before it was transferred to a separatory funnel and washed
with 100 mL of water (4×). The hexane phase, containing the product, was dried
over anhydrous MgSO4. After filtration and rotary evaporation of the solvent, the
product was distilled (Kugelrohr), to afford a colorless liquid. Purity was checked
by gas chromatography (GC) and found to be 94%, 98%, and 95% for products 1,
3, and 5, respectively. Products are composed of both E- and Z-isomers (Table 1).
General Synthetic Procedure Using
Triethyl-2-phosphonobutyrate (TEPB)
TEPB (5.04 g, 20 mmol) was added to 35 mL of hexane. A nitrogen atmo-
sphere was introduced and the mixture was stirred at room temperature. Lithium

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tert-butoxide (20 mL of a 1.0 M solution in hexane) was added in one portion
via syringe. No significant heating of the solution was observed. After stirring for
15 min, the aldehyde (13.3 mmol in 5 mL of hexane) was added dropwise over the
course of 10 min. The solution was allowed to stir for an additional 4 h before it
was transferred to a separatory funnel and washed with 100 mL of water (4×). The
hexane phase, containing the product, was dried over anhydrous MgSO4. After fil-
tration and rotary evaporation of the solvent, the product was distilled (Kugelrohr),
to afford a colorless liquid. Purity was checked by GC and found to be 99%, 99%,
and 98%, for products 2, 4, and 6, respectively. Products are composed of both E-
and Z-isomers (Table 1).
Analysis of Reaction Products
All reactions were monitored by GC using a Hewlett-Packard (HP) 5890
Series II instrument equipped with flame ionization detector, splitless injector, and
an HP 7673 autosampler and interfaced to a HP ChemStation data system. The
oven temperature was programmed from 50◦ to 250◦C at 10◦C/min; the injector
temperature was 250◦C and the detector temperature was 250◦C. A DB-1 capillary
column (15 m × 0.25 mm, 1.0-mm film thickness, J&W Scientific, Folsom, CA)
was used with 1-ml sample injections.
Electron impact mass spectra (70 eV) were obtained with an HP 5970 MSD
instrument, with a DB-1 capillary GC column as described above. Proton NMR
spectra (C6D6) were obtained on a Bruker (Bellerica, MA) Advance 400 spectrom-
eter at 400-MHZ. Chemical shifts are referenced to tetramethylsilane; J is in Hertz.
Standard Bruker software was used to obtain the nuclear Overhauser enhancement
(nOe) difference spectra.
The E/Z-isomeric ratio of all reaction products was calculated by gas chro-
matography/mass spectrometry and the stereochemistry of the major isomer was
confirmed by NMR analysis. The E-isomer of all the products had a greater GC
retention time than the corresponding Z-isomer. Compound names, boiling point
data, MS data, and NMR spectral data (C6D6) follow:
Ethyl-α-methylcinnamate
B.p. 70◦C, 1.1 Torr, MS m/z (% base) 190 (M+, 51), 161 (17), 145 (54),
133 (6), 115 (100), 91 (35), 77 (7), 1H NMR δ 1.07 (3H, t, J = 7.1), 2.11 (3H, br
s), 4.13 (2H, q, J = 7.1), 7.1 (1H, m), 7.1 (2H, m), 7.2 (2H, m), 7.92 (1H, br s).
Ethyl-α-ethylcinnamate
B.p. 69◦C, 1.0 Torr, MS m/z (% base) 204 (M+, 50), 175 (9), 158 (43), 147
(7), 131 (100), 115 (59), 91 (64), 77 (18). 1H NMR δ 1.06 (3H, t, J = 7.1), 1.21

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PETROSKI AND WEISLEDER
(3H, t, J = 7.4) 2.65 (2H, q, J = 7.4), 4.13 (2H, q, J = 7.1), 7.1 (1H, m), 7.1
(2H, m), 7.3 (2H, m), 7.92 (1H, br s).
Ethyl-2-methyl-2-hexenoate
B.p. 34◦C, 1.2 Torr, MS m/z (% base) 156 (M+, 44), 141 (4), 128 (13),
1
111 (60), 102 (16), 95 (16), 87 (53), 83 (32), 55 (100). H NMR δ 0.78 (3H, t,
J = 7.4), 1.04 (3H, t, J = 7.1), 1.3 (2H, m), 1.87 (3H, br s), 1.9 (2H, m), 4.09
(2H, q, J = 7.1), 6.9 (1H, m).
Ethyl-2-ethyl-2-hexenoate
B.p. 34◦C, 1.0 Torr, MS m/z (% base) 170 (M+, 41), 155 (20), 141 (14),
125 (45), 101 (19), 95 (22), 81 (23), 67 (20), 55 (100). 1H NMR δ 0.79 (3H, t, J =
7.4), 1.04 (3H, t, J = 7.1), 1.11 (3H, t, J = 7.5), 1.3 (2H, m), 1.9 (2H, m), 2.41
(2H, q, J = 7.5), 4.10 (2H, q, J = 7.1), 6.91 (1H, m).
Ethyl-2,4-dimethyl-2,4-heptadienoate
B.p. 48◦C, 1.0 Torr, MS m/z (% base) 182 (M+, 22), 153 (65), 137 (17),
125 (100), 109 (49), 93 (22), 79 (18), 67 (25). 1H NMR δ 0.86 (3H, t, J = 7.5),
1.07 (3H, t, J = 7.1), 1.63 (3H, br s), 1.9 (2H, m), 2.12 (3H, br s), 4.12 (2H, q,
J = 7.1), 5.5 (1H, m), 7.44 (1H, br s).
Ethyl-2-ethyl-4-methyl-2,4-heptadienoate
B.p. 52◦C, 1.0 Torr, MS m/z (% base) 196 (M+, 23), 167 (70), 151 (14),
139 (100), 123 (37), 107 (20), 91 (19), 81 (25), 67 (12). 1H NMR δ 0.86 (3H, t,
J = 7.5), 1.06 (3H, t, J = 7.1), 1.20 (3H, t, J = 7.4), 1.66 (3H, br s), 1.9 (2H,
m), 2.66 (2H, q, J = 7.4), 4.13 (2H, q, J = 7.1), 5.6 (1H, m), 7.4 (1H, m).
ACKNOWLEDGMENTS
We thank Bruce W. Zilkowski for acquiring mass spectral data and
Dr. Robert J. Bartelt for helpful discussions.
REFERENCES
1. Bartelt, R.J. Recent Res. Devel. in Entomol. 1997, 115.
2. Bartelt, R.J.; Weisleder, D.; Plattner, R.D. J. Agric. Food Chem. 1990, 2192.

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3. Johnson, W.A. Ylides and Imines of Phosphorous; John Wiley & Sons, Inc.:
New York, 1993; 326.
4. Sinisterra, J.V.; Mouloungui, Z.; Delmas, M.; Gaset, A. Synthesis 1985, 1097.
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Received in the U.S.A. April 4, 2000

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