Practical Stereoselective Synthesis of (2E)- and (2Z)-4-Cycloalkylidenebut-2-enoic Acids

Article abstract of DOI:10.1081/SCC-120028360

Stereoselective synthesis of α,β-unsaturated esters 7 and 8 was achieved through Horner-Wadsworth-Emmons reaction of β,β -disubstituted α,β-unsaturated aldehydes. Thus, aldehydes 6 undergo olefination with phosphonate carbanion generated from triethyl phosphonoacetate 3 and lithium hydroxide or butyl lithium/DMPU to give (E)-α,β -unsaturated esters 7 with excellent selectivity. The treatment of 6 with the new Horner-Emmons reagents, ethyl(diphenylphosphono)acetate 4a and ethyl (di-o-tolyl-phosphono) acetate 4b in the presence of benzyltrimethyl ammonium hydroxide (Triton B) afforded (Z)-α,β-unsaturated esters 8 with 73-89% selectivity. The esters 7 and 8 were converted to (2E)- and (2Z)-4-cycloalkylidenebut-2-enoic acids 9 and 10, respectively.

Full text of DOI:10.1081/SCC-120028360

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 5, pp. 871–888, 2004
Practical Stereoselective Synthesis of (2E)-
and (2Z)-4-Cycloalkylidenebut-2-enoic
Acids
*
Stoyan K. Karagiozov and Frank S. Abbott
Division of Biomolecular and Pharmaceutical Chemistry, Faculty of
Pharmaceutical Sciences, University of British Columbia, Vancouver,
B.C., Canada
ABSTRACT
Stereoselective synthesis of a,b-unsaturated esters 7 and 8 was achieved
through Horner–Wadsworth–Emmons reaction of b,b-disubstituted
a,b-unsaturated aldehydes. Thus, aldehydes 6 undergo olefination with
phosphonate carbanion generated from triethyl phosphonoacetate 3 and
lithium hydroxide or butyl lithium/DMPU to give (E)-a,b-unsaturated
esters 7 with excellent selectivity. The treatment of 6 with the new
Horner–Emmons reagents, ethyl(diphenylphosphono)acetate 4a and
ethyl (di-o-tolyl-phosphono) acetate 4b in the presence of benzyltri-
methyl ammonium hydroxide (Triton B) afforded (Z)-a,b-unsaturated
*
Correspondence: Frank S. Abbott, Division of Biomolecular and Pharmaceutical
Chemistry, Faculty of Pharmaceutical Sciences, University of British Columbia,
Vancouver V6T 1Z3, B.C., Canada; Fax: þ(604) 822-3035; E-mail: fabbott@
interchange.ubc.ca.
871
DOI: 10.1081/SCC-120028360
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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esters 8 with 73–89% selectivity. The esters 7 and 8 were converted to
(2E)- and (2Z)-4-cycloalkylidenebut-2-enoic acids 9 and 10, respectively.
Key Words: Wittig reactions; Phosphonate carbanions; Stereoselective
synthesis; a,b-Unsaturated esters; Carboxylic acids.
Synthesis of carbon–carbon double bonds with a high degree of
selectivity is of great interest in synthetic organic chemistry and is of
significant value in preparing olefins that exhibit biological properties that are
strongly dependent upon stereochemistry. The Wittig reaction and its
modification, the base-promoted Horner–Wadsworth–Emmons olefination of
aldehydes and ketones with phosphonate carbanions, is a widely employed
approach to the synthesis of a,b-unsaturated esters.[1] In view of our interest in
the design of selected substituted (2E)- and (2Z)-4-substituted but-2-enoic
acids that could represent a new class of antiepileptic candidates, our strategy
was based on the coupling of the b,b-disubstituted a,b-unsaturated aldehydes
6 and the generated phosphonate carbanions under specific conditions that
provide high E- and Z-stereoselectivity (Sch. 1). The starting compounds 6
were obtained by olefination of ketones 1 with diethyl cyanomethyl
phosphonate 2 carried out in ether or DMF to provide nitriles 5.[2a] Further
reduction with DIBALH carried out in pentane or ether, gave known
aldehydes 6a–c[2b] (Sch. 1). Reduction of nitrile 5d, performed in pentane or
ether afforded aldehyde 6d in 47% and 56% yield, respectively, when purified
by flash chromatography. Attempts to isolate 6d by vacuum distillation
resulted in the formation of a mixture of 6d and 6e due to isomerization. The
1H NMR spectrum of the distilled mixture indicated that the ratio of products
formed was approximately 1 : 1. Aldehyde 6d exhibited two doublets at
d ¼ 9.96 and 5.84 due to CHO and CH55C protons, respectively. The
presence of two triplets at d ¼ 9.46 (CHO) and 5.29 (CH55C) for one proton
each were assigned for the enal 6e. Further purification by chromatotron
chromatography afforded pure 6d (Sch. 2).
Initially the stereoselective conversion of aldehydes 6 to (E)-a,b-
.
unsaturated esters 7 was performed under LiOH H2O-promoted Horner–
Wadsworth–Emmons conditions with triethyl phosphonoacetate 3.[3,4] When
.
aldehydes 6 were allowed to react with 3 in the presence of LiOH H2O
(1.1 equiv)[4] for 2.5–16 hr the target (E)-a,b-unsaturated esters 7 were
obtained mainly as a single product with high (E)-selectivity (93–98%) in
38–64% yields (entries 2, 5, 8, and 11, Table 1) and only a small amount of the
corresponding Z-esters 8 were isolated. The yields were slightly increased to
41–66% when the reaction time was reduced to 2.5 hr (entries 4, 7, 10) except
for 7a where the yield was increased from 38% to 65% (entry 1). These results

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873
Scheme 1. Synthesis of (2E)- and (2Z)-4-cycloalkylidenebut-2-enoic acids.
confirmed that despite an excess of base the competing ester hydrolysis
occurred at a very slow rate.[3] An alternative method was applied as reagent 3
was treated with BuLi (1.8 equiv) and DMPU (3.6 equiv) in THF at 08C,
Scheme 2. Reduction of nitrile 5d with DIBALH.

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Table 1. Horner–Wadsworth–Emmons reaction of R1R2C55CHCHO 6 with
(EtO)2P(O)CH2COOEt 3 in THF.
Entry
6
R1R2
Base
Reaction conditions
Yield 7 (%) (E/Z)
.
1
2
a
a
a
b
b
b
c
–(CH2)4– LiOH H2O
r.t., 2.5 hr
r.t., 16 hr
65
38
50
66
64
71
41
40
64
58
48
70
98 : 2
98 : 2
.99
.
–(CH2)4– LiOH H2O
3
–(CH2)4– BuLi, DMPU 2788C to 08C, 3.5 hr
.
4
–(CH2)5– LiOH H2O
r.t., 2.5 hr
r.t., 16 hr
93 : 7
93 : 7
97 : 3
96 : 4
96 : 4
98 : 2
96 : 4
96 : 4
98 : 2
.
–(CH2)5– LiOH H2O
5
6
–(CH2)5– BuLi, DMPU 2788C to 08C, 3.5 hr
.
7
–(CH2)6– LiOH H2O
r.t., 2.5 hr
r.t., 16 hr
.
–(CH2)6– LiOH H2O
8
c
9
c
–(CH2)6– BuLi, DMPU 2788C to 08C, 3.5 hr
.
10
11
12
d
d
d
–(CH2)7– LiOH H2O
r.t., 2.5 hr
r.t., 16 hr
.
–(CH2)7– LiOH H2O
–(CH2)7– BuLi, DMPU 2788C to 08C, 3.5 hr
followed by 6 at 2788C and warming to 08C over 1.5 hr to give esters 7 with
E-stereoselectivity (97–99%) in 50–71% yields (entries 3, 6, 9, and 12,
Table 1). Finally, esters 7 were cleanly hydrolyzed under basic conditions[5] to
(E)-acids 9 in 60–89% yield. (E)-acids 9 were converted to sodium salts 11
with NaOH in MeOH. The stereochemistry of the 2,3 double bond in 7–11
was determined on the basis of the coupling constants of vinyl proton signals
1
in the H NMR spectra.
The next focus was on the stereoselective synthesis of (2Z)-4-cyclo-
alkylidenebut-2-enoates 8. Since Wittig and other related reactions such as
Horner–Emmons modification preferentially give the more stable (E)-
unsaturated isomers, we reviewed the latest findings devoted to the construc-
tion of (Z)-a,b-unsaturated esters.[6,7] The Horner–Wadsworth–Emmons
olefination was performed on aldehydes 6 with ethyl (diphenylphos-
phono)acetate 4a and ethyl (di-o-tolylphosphono) acetate 4b, respectively,
in the presence of benzyltrimethylammonium hydroxide (40% in MeOH)
(triton B) as a base in THF. When 6a,b were treated with 4a at 2788C for 1 hr
followed by warming to 08C over 3 hr the olefination occurred smoothly to
give the corresponding (2Z)-4-cycloalkylidenebut-2-enoates 8a and 8b with
(Z)-selectivity (73% and 75%) (entries 1 and 3, Table 2). Slightly improved
Z-selectivity (78% and 79%) was obtained with 6c and 6d as partners in the
reaction (entries 5, 8). Subsequently, we further studied the reaction with ethyl
(di-o-tolylphosphono)acetate 4b in an attempt to improve the (Z)-selectivity
and yields. When 4b was treated with triton B at 2788C for 15 min, stirred
for 30 min, followed by 6 for 20 min and warming to 08C over 6 hr, the

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875
Table 2. Horner–Wadsworth–Emmons reaction of R1R2C55CHCHO 6 with (o-R-
Ar)2P(O)CH2CO2Et 4 in THF in the presence of triton B.
Entry
1
6
a
R1R2
4
a
R
H
Reaction conditions
Yield 8 (%) (Z/E)
–(CH2)4–
2788C to 2508C 1 hr,
2508C to 2208C 1 hr
2208C to 08C 1 hr
47
73 : 27
2
3
a
–(CH2)4–
–(CH2)5–
b
a
Me
H
788C to 2258C 1.5 hr
258C to 08C 1.5 hr
2788C to 2508C 1 hr
2508C to 2208C 1 hr
2208C to 08C 1 hr
56
61
79 : 21
75 : 25
b
4
5
b
c
–(CH2)5–
–(CH2)6–
b
a
Me
H
788C to 2258C 1.5 hr
258C to 08C 1.5 hr
2788C to 2508C 1 hr
2508C to 2208C 1 hr
2208C to 08C 1 hr
67
45
82 : 18
78 : 22
6
7
c
c
–(CH2)6–
–(CH2)6–
b
b
Me 2788C to 2258C 1.5 hr
2258C to 08C 1.5 hr
Me 2788C 30 min
2788C to 2358C 2.5 hr
2358C to 2158C 1 hr
2158C to 08C 2 hr
76
84
89 : 11
89 : 11
8
d
–(CH2)7–
a
H
2788C to 2508C 1 hr
2508C to 2208C 1 hr
2208C to 08C 1 hr
38
79 : 21
9
d
d
–(CH2)7–
–(CH2)7–
b
b
Me 2788C to 2258C 1.5 hr
2258C to 08C 1.5 hr
Me 2788C 30 min
2788C to 2358C 2.5 hr
2358C to 2158C 1 hr
2158C to 08C 2 hr
66
82
85 : 15
85 : 15
10
(Z)-selectivity was improved to 79–89% and the (2Z)-4-cycloalkylidenebut-
2-enoates 8a–d were obtained in 56–82% yield (entries 2, 4, 6, 10). The
results indicated that the (Z)-selectivity and yield increased with increasing the
size of the cycloalkyl substituent at the b,b-position of the a,b-unsaturated
aldehydes 6. The results are summarized in Table 2.
The Z/E ratios of all Horner–Wadsworth–Emmons products 8/7 were
1
determined by integrating the vinyl proton signals in the 300 MHz H NMR
spectra of a mixed sample of both isomers purified by chromatotron and/or by
analysis of the pure (E)- and (Z)-isomers isolated by further chromatography
purification. The chromatography did not affect the Z/E ratio of the isomers.

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Further basic hydrolysis of 8 under mild conditions afforded the corresponding
(2Z)-4-cycloalkylidenebut-2-enoic acids 10 in excellent yields. The selected
(Z)-acids 10c,d were converted to the corresponding sodium salts 12c,d by
treatment with NaOH in MeOH.
In summary, we reported the synthesis of (2E)- and (2Z)-4-cycloalkyl-
idenebut-2-enoic acids that could represent a new class of antiepileptic
candidates. We have demonstrated synthetic routes for the preparation of
a,b-unsaturated esters with high (E)- and (Z)-stereoselectivity from
b,b-disubstituted a,b-unsaturated aldehydes under the base-promoted
Horner–Wadsworth–Emmons reaction utilizing a broad range of conditions.
The LiOH-promoted Horner–Wadsworth–Emmons reaction with triethyl
phosphonomethylacetate gave the corresponding (2E)-2,4-pentadienoates in
93–97% stereoselectivity and with moderate yields. Using BuLi/DMPU and
an excess of phosphonate anion increased the yields while retaining the high
E-selectivity. We have also extended the utilization of newer (Z)-selective
Horner–Wadsworth–Emmons reagents recently discovered by Ando and co-
workers such as ethyl (diphenylphosphono)acetate 4a and ethyl (di-o-
tolylphosphono)acetates 4b for the preparation of (2Z)-4-cycloalkylidenebut-
2-enoates, which were obtained in 73–89% (Z)-selectivity and with moderate
to good yields. The methodologies employed could afford the preparation of
building blocks with a variety of synthetic applications requiring conjugated
double bonds with defined stereochemistry.
EXPERIMENTAL
All air and/or water sensitive reactions were performed in flasks flame
dried under a positive flow of argon and conducted under Ar with, freshly
distilled anhydrous solvents using standard syringe/cannula/septa techniques.
THF and Et2O were distilled from sodium/benzophenone. CH2Cl2 and
pentane were dried over CaH2 and distilled. The starting materials were
1
synthesized as described in the literature with some modifications. H NMR
spectra were recorded on Bruker spectrometers Avance AV-300 (300 MHz),
Avance AV-400 (400 MHz), Bruker AC-200 (200 MHz) and Bruker WH-400
(400 MHz) using the indicated solvents. Chemical shifts are expressed in ppm
with TMS as internal standard. Data are reported as follows: chemical shift
multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, br ¼ broad,
m ¼ multiplet), integration, coupling constants (Hz). 13C NMR spectra were
recorded on AV-300 (75 MHz) with complete proton decoupling. Chemical
shifts are reported in ppm from TMS with the solvent as internal reference. IR
spectra were obtained on a Perkin–Elmer 1600 FT instrument. Elemental
analyses were performed on a Carlo Erba model 1106 CHN elemental

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877
analyzer, melting points were recorded on a Fisher–Johns apparatus and are
uncorrected. LC-MS was recorded on a Fisons VG Quattro (Altrincham UK)
tandem spectrometer with Hewlett Packard (Avondale PA) 1090II liquid
chromatograph. HRMS were recorded on Kratos MS 50, MS-80 or Concept II
HQ mass spectrometers. Analytical TLC was performed using silica gel 60
F254 precoated plates Merck, 0.25 mm thickness with a fluorescent indicator.
Visualization was accomplished with one or more of the following: UV light
(254 nm), KMnO4/5%NaOH/K2CO3/H2O (1 : 4 : 6.5 : 100) solution and heat
as a developing agent. Flash column chromatography was performed on
Merck silica gel 60 (0.040–0.063 mm) using the indicated solvents.
Chromatotron chromatography was performed on a 7924T Chromatotron,
Harrison on silica gel, 60 PF-254 (with calcium sulfate), TLC grade 7749, E.
Merck. Solvents were evaporated under reduced pressure using a Buchi rotary
evaporator connected to a water aspirator. Chemicals were purchased from
Acros, Aldrich, BDH, Fluka, and TCI and were used without further
purification.
Cyclooctylideneacetonitrile (5d); Typical Procedure
To a stirred suspension of sodium hydride (1.48 g, 37.0 mmol, 60% in
mineral oil) in anhyd DMF (50 mL) under argon at 08C was added dropwise a
solution of diethyl cyanomethylphosphonate 2 (6.7 g, 37.0 mmol) in DMF
(15 mL) over 20 min. The stirring was continued for 60 min and cyclooctanone
1d (4.24 g, 33.6 mmol) in DMF (15 mL) was added over 15 min and the
reaction mixture allowed to warm to r.t. overnight. The reaction was quenched
with H2O (300 mL), extracted with Et2O (5 Â 50 mL), washed with H2O
(100 mL) and brine (100 mL), respectively, and dried over MgSO4. The Et2O
was evaporated under reduced pressure and the residue was purified by
vacuum distillation to give 5d as a colorless liquid (4.31 g, 86%); bp 67–
698C/0.55 Torr (Lit.[2a] column chromatography); 1H NMR (300 MHz,
CDCl3): d ¼ 5.12 (br s, 1H), 2.51 (t, J ¼ 6.2 Hz, 2H), 2.29 (t, J ¼ 6.4 Hz, 2H),
1.81–1.66 (m, 4H), 1.53–1.39 (m, 6H); 13C NMR (75 MHz, CDCl3):
d ¼ 173.28, 117.17, 94.74, 36.30, 33.13, 27.05, 26.91, 26.67, 26.26, 25.19;
anal. calcd for C10H15N (149.23): C 80.48; H 10.13; N 9.38; found: C 80.57; H
10.26; N 9.22; IR (film): v ¼ 2213 cm21
.
Cyclopentylideneacetonitrile (5a)
Yield: (89%); colorless liquid purified by distillation at bp 72–748C/
10 Torr (Lit.[2a,b] bp 83–848C/12 Torr).

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Cyclohexylideneacetonitrile (5b)
Yield: (91%); colorless liquid purified by distillation at bp 56–588C/
2 Torr (Lit.[2a,b] bp 86–888C/10 Torr).
Cycloheptylideneacetonitrile (5c)
Yield (92%); colorless liquid purified by distillation at bp 62–648C/
0.8 Torr or flash column chromatography (Lit.[2a,b] bp 94–958C/6 Torr or
column chromatography).
Cyclooctylideneacetaldehyde (6d); Typical Procedure
To a solution of 5d (2.1 g, 14.07 mmol) in anhyd Et2O (35 mL) at 2608C
was added in one portion DIBALH (28.14 mL, 1.0 M in hexanes,
28.14 mmol). The stirring was continued for 30 min at 2608C and for 5 hr
at 08C. Then ethyl formate (1.14 mL, 14.07 mmol) was added dropwise over
10 min. After stirring for 60 min the reaction mixture was treated with sat. aq
NH4Cl (28.2 mL) over 20 min. The resulting mixture was warmed to r.t. over
60 min followed by 1 M H2SO4 (56.5 mL) over 15 min. The organic layer was
separated and the aq phase was extracted with Et2O (5 Â 75 mL). The
combined organic phases were washed with 5% NaHCO3 (2 Â 100 mL) and
brine (100 mL) respectively, dried over MgSO4, filtered and concentrated
under reduced pressure. The residue was purified by chromatotron chroma-
tography (silica gel, 100 g, hexanes/ether 5/1 v/v) to afford pure 6d (1.19 g,
56%) as a colorless liquid. Attempts to purify the crude product 6d by vacuum
distillation gave s colorless mixture (536 mg, 25%); bp 668C/0.5 Torr of an
1 : 1 ratio approximately of 6d and its isomer cyclooct-1-en-1-ylacetaldehyde
6e. Further purification on chromatotron (CH2Cl2) provided pure 6d: 1H NMR
(300 MHz, CDCl3): d ¼ 9.96 (d, J ¼ 8.2 Hz, 1H), 5.84 (d, J ¼ 8.2 Hz, 1H),
2.68 (t, J ¼ 6.2 Hz, 2H), 2.33 (t, J ¼ 6.2 Hz, 2H), 1.81–1.69 (m, 4H), 1.53–
1.38 (m, 6H); 13C NMR (75 MHz, CDCl3): d ¼ 190.73, 172.47, 127.43, 38.35,
29.64, 29.53, 27.36, 26.12, 25.21 (2 Â CH2); anal. calcd for C10H16O (152.2):
C 80.90; H 10.59; found: C 80.92; H 10.57.
Cyclooct-1-en-1-ylacetaldehyde (6e)
1H NMR (200 MHz, CDCl3): d ¼ 9.66 (t, 1H), 5.54 (t, 1H), 3.0 (d, 2H),
2.09 (br d, 4H), 1.42 (br d, 8H).

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Cyclopentylideneacetaldehyde (6a)
Yield: 2.38 g (52%); flash column chromatography (silica gel, hexanes/
Et2O 4 : 1); pale yellow liquid (Lit.[2b,d]).
Cyclohexylideneacetaldehyde (6b)
Yield: 3.61 g (58%); colorless liquid purified by distillation at bp 448C/
1 Torr; (Lit.[2b–d] bp 52–548C/2 Torr).
Cycloheptylideneacetaldehyde (6c)
Yield: 5.09 g (89%); pale yellow liquid; flash column chromatography
(silica gel, hexanes/Et2O 4 : 1) (Lit.[2b,c] column chromatography).
Ethyl (2E)-4-Cycloalkylidenebut-2-enoates (7)
General Procedure A
.
A suspension of LiOH H2O (2.2 mmol) in anhyd THF (4 mL) was treated
at r.t. with 3 (2.2 mmol) followed by aldehyde 6 (2 mmol) and stirred over 2.5
or 16 hr. Then the resulting mixture was filtered through a plug of silica gel
eluting with ether (25 mL). The filtrate was concentrated in vacuo and the
residue was purified by chromatotron chromatography (2 mm silica gel plate,
hexanes/Et2O 100 : 1.5) to afford esters 7 as colorless liquids in 93–99%
(E)-stereoselectivity.
General Procedure B
To a solution of triethyl phosphonoacetate 3 (30.06 mmol) in anhyd THF
(36 mL) under argon at 08C was added DMPU (7.58 mL) over 10 min and
BuLi (21.8 mL, 1.6 M in hexanes, 34.88 mmol) over 20 min and the stirring
was continued for 20 min. Then cooled to 2788C and a solution of aldehyde 6
(17.0 mmol) in THF (36 mL) was added dropwise over 1.5 hr, stirred for 1 hr
and the reaction mixture was allowed to warm to 08C over 1.5 hr. The reaction
was quenched with sat. aq NH4Cl solution (70 mL), extracted with EtOAc
(4 Â 75 mL) and the combined organic layers were washed successively with
H2O (2 Â 100 mL) and brine (100 mL), dried (MgSO4) and then concentrated
under reduced pressure. The resulting crude product was purified by flash

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Karagiozov and Abbott
column chromatography on silica gel (hexanes/Et2O 18 : 1) to yield (E)-7 and
(Z)-8. The Rf for (Z)-8 was found to be higher than (E)-7.
Ethyl (2E)-4-Cyclopentylidenebut-2-enoate (7a)
Procedure A
Yield: 7a (235 mg, 65%), 8a (5.8 mg, ,2%) reaction time 2.5 hr; 7a
(136 mg, 38%), 8a (2 mg, ,1%) reaction time 16 hr.
Procedure B
1
Yield: 7a (1.53 g, 50%) and 8a (15 mg, ,1%); H NMR (300 MHz,
CDCl3): d ¼ 7.35 (dd, J ¼ 15.2, 11.6 Hz, 1H), 6.0 (d, J ¼ 11.6 Hz, 1H), 5.62
(d, J ¼ 15.2 Hz, 1H), 4.11 (q, J ¼ 7.1 Hz, 2H), 2.41 (t, J ¼ 7.1 Hz, 2H), 2.31
(t, J ¼ 7.1 Hz, 2H), 1.68–1.57 (m, 4H), 1.24 (t, J ¼ 7.2 Hz, 3H); 13C (75 MHz,
CDCl3): d ¼ 167.59, 158.91, 142.33, 119.01, 117.59, 59.93, 34.66, 30.03,
26.09, 25.84, 14.23; IR v ¼ (film): 1718 cm21; LC/MS: m/z (%) ¼ 181
[(M þ H)þ, 100], 173 (3), 163 (8), 153 (15); HRMS (EI): m/z calcd for
C11H16O2 180.11504; found 180.11503.
Ethyl (2E)-4-Cyclohexylidenebut-2-enoate (7b)
Procedure A
Yield: 7b (255 mg, 66%), 8b (19%, 5%), reaction time 2.5 hr; 7b (247 mg,
64%), 8b (18%, 5%), reaction time 16 hr.
Procedure B
Yield: 7b (2.34 g, 71%) and 8b (66 mg, 2%); 1H NMR (300 MHz,
CDCl3): d ¼ 7.55 (dd, J ¼ 15.0, 12.0 Hz, 1H), 5.89 (d, J ¼ 11.9 Hz, 1H), 5.74
(d, J ¼ 15.0 Hz, 1H), 4.15 (q, J ¼ 7.2 Hz, 2H), 2.41–2.29 (m, 2H), 2.21–2.11
(m, 2H), 1.58–1.54 (m, 6H), 1.24 (t, J ¼ 7.2 Hz, 3H); 13C (75 MHz, CDCl3):
d ¼ 167.64, 154.15, 140.23, 120.45, 118.74, 59.98, 37.66, 29.74, 28.45, 27.84,
26.45, 14.27; IR (film): v ¼ 1713 cm21; LC/MS: m/z (%) ¼ 195 [(M þ H)þ,
88], 149 (100), 131 (4), 121 (7); HRMS (EI): m/z calcd for C12H18O2
194.13068; found 194.13086.

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Ethyl (2E)-4-Cycloheptylidenebut-2-enoate (7c)
Procedure A
881
Yield: 7b (169 mg, 41%), 12b (13 mg, 3%), reaction time 2.5 hr; 7b
(165 mg, 40%), 8b (4 mg, 1%), reaction time 16 hr.
Procedure B
1
Yield: 7c (2.27 g, 64%) and 8c (31 mg, ,1%); H NMR (300 MHz,
CDCl3): d ¼ 7.56 (dd, J ¼ 14.8, 11.8 Hz, 1H), 5.96 (d, J ¼ 11.7 Hz, 1H), 5.79
(d, J ¼ 15.1 Hz, 1H), 4.18 (q, J ¼ 7.1 Hz, 2H), 2.51 (t, J ¼ 5.4 Hz, 2H), 2.33
(t, J ¼ 5.5 Hz, 2H), 1.69–1.61 (m, 3H), 1.50–1.41 (m, 5H), 1.27
(t, J ¼ 7.1 Hz, 3H); 13C (75 MHz, CDCl3): d ¼ 167.72), 156.00, 140.73,
123.55, 118.65, 60.04, 38.50, 30.73, 29.57, 28.88, 27.22, 27.08, 14.33; IR
(film): v ¼ 1713 cm21; anal. calcd for C13H20O2 (208.3): C 74.96; H 9.67;
found: C 75.40; H 9.72.
Ethyl (2E)-4-Cyclooctylidenebut-2-enoate (7d)
Procedure A
Yield: 7d (258 mg, 58%) and 8d (12 mg, ,3%), reaction time 2.5 hr; 7d
(214 mg, 48%) and 8d (8 mg, ,2%), reaction time 16 hr.
Procedure B
Yield 7d (2.64 g, 70%) and 8b (54 mg, 2%); 1H NMR (300 MHz, CDCl3):
d ¼ 7.56 (dd, J ¼ 15.1, 11.8 Hz, 1H), 5.96 (d, J ¼ 11.8 Hz, 1H), 5.69
(d, J ¼ 15.1 Hz, 1H), 4.16 (q, J ¼ 7.2 Hz, 2H), 2.41 (t, J ¼ 6.2 Hz, 2H), 2.25
(t, J ¼ 6.2 Hz, 2H), 1.69–1.64 (m, 4H), 1.48–1.39 (m, 6H), 1.25
(t, J ¼ 7.1 Hz, 3H); 13C (75 MHz, CDCl3): d ¼ 167.67, 157.14, 140.68,
123.57, 118.25, 59.94, 38.08, 29.76, 28.37, 27.37, 26.21, 25.78, 25.46, 14.28;
IR (film): v ¼ 1713 cm21; LC/MS: m/z (%) ¼ 223 [(M þ H)þ, 100], 177
(30), 159 (4), 149 (43), 135 (8); HRMS (EI): m/z calcd for C14H22O2
222.16190; found 222.16198.

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General Procedure for the Preparation of Ethyl (2Z)-4-
Cycloalkylidenebut-2-enoates (8a–d)
To a solution of 4a/4b (1 mmol) in THF (3 mL) at 2788C under argon
was added dropwise triton B (benzyltriethylammonium hydroxide 40% in
MeOH) (0.54 mL, 1.35 mmol) over 15 min. After 30 min, a solution of
aldehyde 6 (1.1 mmol) in THF (1 mL) was added dropwise for 20 min and the
resulting mixture was gradually warmed to 08C (see Table 2). The reaction
was quenched with sat. aq NH4Cl (10 mL) extracted with EtOAc (4 Â 5 mL)
and the combined organic layers were washed successively with H2O
(2 Â 5 mL) and brine (5 mL), dried (MgSO4) and then concentrated in vacuo.
The crude residue was purified on chromatotron (silica gel, hexanes followed
by hexanes/Et2O 100 : 1.5) to yield a mixture of (Z/E) products 8/7 deter-
mined by 1H HMR analysis. Further separation of the mixture afforded
analytical samples of 8 and 7, respectively, as colorless liquids.
Ethyl (2Z)-4-Cyclopentylidenebut-2-enoate (8a)
From 4a: Yield: 8a (85 mg, 47%) and 7a (30 mg, 17%); from 4b: Yield:
8a (101 mg, 56%) and 7a (27 mg, 15%); 1H NMR (300 MHz, CDCl3):
d ¼ 7.21 (d, J ¼ 12.0 Hz, 1H), 6.65 (t, J ¼ 11.6 Hz, 1H), 5.44 (d, J ¼ 11.5 Hz,
1H), 4.09 (q, J ¼ 7.2 Hz, 2H), 2.36 (t, J ¼ 6.4 Hz, 4H), 1.67–1.56 (m, 4H), 1.2
(t, J ¼ 7.2 Hz, 3H); 13C (75 MHz, CDCl3): d ¼ 166.76, 159.39, 141.97,
117.67, 113.69, 59.61, 34.80, 29.29, 25.97, 25.75, 14.22; IR (film):
n ¼ 1713 cm21; LC/MS: m/z (%) ¼ 181 [(M þ H)þ, 100], 173 (3), 163 (1);
HRMS (EI): m/z calcd for C11H16O2 180.11503; found 180.11504.
Ethyl (2Z)-4-Cyclohexylidenebut-2-enoate (8b)
From 4a: Yield: 8b (118 mg, 61%) and 7b (39 mg, 20%); from 4b: Yield:
8b (130 mg, 67%) and 7b (29 mg, 15%); 1H NMR (300 MHz, CDCl3):
d ¼ 7.08 (d, J ¼ 11.9 Hz, 1H), 6.84 (t, J ¼ 11.7 Hz, 1H), 5.47 (d, J ¼ 11.4 Hz,
1H), 4.09 (q, J ¼ 7.1 Hz, 2H), 2.27 (br t, 2H), 2.18 (br t, J ¼ 5.8 Hz, 2H),
1.51–1.49 (m, 6H), 1.19 (t, J ¼ 7.1 Hz, 3H); 13C (75 MHz, CDCl3):
d ¼ 166.84, 154.48, 139.69, 118.65, 114.89, 59.71, 37.97, 28.94, 28.43, 27.85,
26.54, 14.22; IR (film): n ¼ 1713 cm21; LC/MS: m/z (%) ¼ 195 [(M þ H)þ,
100), 193 (4), 163 (2), 131 (2), 121 (3); HRMS (EI): m/z calcd for C12H18O2
194.13096; found 194.13068.

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Synthesis of (2E)- and (2Z)-4-Cycloalkylidenebut-2-enoic Acids
Ethyl (2Z)-4-Cycloheptylidenebut-2-enoate (8c)
883
From 4a: Yield: 8c (93 mg, 45%) and 7c (27 mg, 13%); from 4b: Yield: 8c
1
(159 mg, 76%) and 7c (20 mg, 10%); H NMR (300 MHz, CDCl3): d ¼ 7.16
(d, J ¼ 11.9 Hz, 1H), 6.87 (t, J ¼ 11.7 Hz, 1H), 5.53 (d, J ¼ 11.4 Hz, 1H),
4.16 (q, J ¼ 7.2 Hz, 2H), 2.47 (t, J ¼ 5.4 Hz, 2H), 2.39 (t, J ¼ 5.7 Hz, 2H),
1.62–1.55 (m, 4H), 1.51–1.46 (m, 4H), 1.27 (t, J ¼ 7.2 Hz, 3H); 13C
(75 MHz, CDCl3): d ¼ 166.87, 157.62, 140.19, 121.71, 114.61, 59.57, 38.69,
30.0, 29.58, 28.71, 28.21, 27.1, 14.24; IR (film): n ¼ 1713 cm21; anal. calcd
for C13H20O2 (208.3): C 74.96; H 9.68; found: C 75.00; H 9.64.
Ethyl (2Z)-4-Cyclooctylidenebut-2-enoate (8d)
From 4a: Yield: 8d (85 mg, 38%) and 7d (22 mg, 10%); from 4b: Yield:
8d (182 mg, 82%) and 7d (33 mg, 14%); 1H NMR (300 MHz, CDCl3):
d ¼ 7.21 (d, J ¼ 12.1 Hz, 1H), 6.87 (t, J ¼ 11.7 Hz, 1H), 5.51 (d, J ¼ 11.4 Hz,
1H), 4.14 (q, J ¼ 7.1 Hz, 2H), 2.38 (t, J ¼ 6.1 Hz, 2H), 2.32 (t, J ¼ 6.2 Hz,
2H), 1.70–1.66 (m, 4H), 1.49–1.44 (m, 6H), 1.25 (t, J ¼ 7.2 Hz, 3H);
13C (75 MHz, CDCl3): d ¼ 166.87, 157.62, 140.35, 121.85, 114.11, 59.59,
38.52, 29.09, 28.72, 27.53, 26.16, 25.51 (2 Â CH2), 14.28; IR (film):
n ¼ 1713 cm21; LC/MS: m/z (%) ¼ 223 [(M þ H)þ, 80], 177 (69), 149 (8),
149 (100), 159 (4), 135 (14); HRMS (EI): m/z calcd for C14H22O2 222.16204;
found 222.16198.
General Procedure for Preparation of (2E)-
4-Cycloalkylidenebut-2-enoic Acids (9a–d) and
(2Z)-4-Cycloalkylidenebut-2-enoic Acids (10a–d)
A mixture of esters (E)-7 or (Z)-8 (0.44 mmol) and NaOH (1.2 g,
30 mmol) in H2O/MeOH (7.8/3.9 mL) was gently refluxed for 45 min.
After cooling the reaction mixture was diluted with brine (5 mL) and
extracted with Et2O (2 Â 10 mL). The aqueous layer was acidified with 10%
HCl until pH 1 was attained, extracted with EtOAc (5 Â 6 mL), and the
combined extracts washed with brine (5 mL), dried (MgSO4) and con-
centrated in vacuo. Chromatotron chromatography (silica gel, hexanes/
EtOAc 90 : 10) afforded pure acids (E)-9 or (Z)-10 respectively as a white
solid.

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(2E)-4-Cyclopentylidenebut-2-enoic Acid (9a)
Yield: 40 mg (60%); mp 112–1148C; 1H NMR (300 MHz, CDCl3):
d ¼ 7.43 (dd, J ¼ 15.2, 11.6 Hz, 1H), 6.12 (d, J ¼ 11.6 Hz, 1H), 5.67
(d, J ¼ 15.4 Hz, 1H), 2.48 (t, J ¼ 6.9 Hz, 2H), 2.39 (t, J ¼ 7.0 Hz, 2H), 1.79–
1.63 (m, 4H); 13C (75 MHz, CDCl3): d ¼ 171.21, 160.34, 144.21, 120.15,
118.79, 35.61, 30.89, 27.18, 26.94; LC/MS: m/z (%) ¼ 151 [(M 2 H)2,
100], 106 (18), 62 (5); HRMS (EI): m/z calcd for C9H12O2 152.07590; found
152.07570; IR (KBr): n ¼ 1679 cm21
.
(2E)-4-Cyclohexylidenebut-2-enoic Acid (9b)
Yield: 58 mg (80%); mp 132–1348C; 1H NMR (300 MHz, CDCl3):
d ¼ 7.64 (dd, J ¼ 15.0 Hz, 1H), 5.99 (d, J ¼ 11.8 Hz, 1H), 5.75
(d, J ¼ 15.1 Hz, 1H), 2.39 (br s, 2H), 2.26 (br s, 2H), 1.61 (br d, 6H); 13C
(75 MHz, CDCl3): d ¼ 171.11, 155.61, 142.05, 121.57, 119.97, 38.66, 30.65,
29.73, 29.11, 27.59; LC/MS: m/z (%) ¼ 165 [(M 2 H)þ, 100), 131 (7), 113
(25), 69 (15); HRMS (EI): m/z calcd for C10H14O2 166.09938; found
166.09920; IR (KBr): n ¼ 1680 cm21
.
(2E)-4-Cycloheptylidenebut-2-enoic Acid (9c)
Yield: 67 mg (85%); mp 88–898C; 1H NMR (300 MHz, CDCl3):
d ¼ 7.58 (dd, J ¼ 15.1, 11.7 Hz, 1H), 6.02 (d, J ¼ 11.7 Hz, 1H), 5.74
(d, J ¼ 15.1 Hz, 1H), 2.53 (t, J ¼ 5.8 Hz, 2H), 2.32 (t, J ¼ 5.8 Hz, 2H), 1.75
(br d, 4H), 1.51 (br d, 4H); 13C (75 MHz, CDCl3): d ¼ 171.08, 157.31, 142.98,
124.69, 119.83, 39.43, 31.58, 30.72, 29.87, 29.37, 28.40; LC/MS: m/z
(%) ¼ 179 [(M 2 H)2, 100], 135 (11), 131 (5), 113 (25), 62 (8); HRMS (EI):
m/z calcd for C11H16O2 180.11503; found 180.11524; IR (KBr):
n ¼ 1680 cm21
.
(2E)-4-Cyclooctylidenebut-2-enoic Acid (9d)
Yield: 76 mg (89%); mp 114–1168C; 1H NMR (300 MHz, CDCl3):
d ¼ 7.62 (dd, J ¼ 15.1, 11.8 Hz, 1H), 6.07 (d, J ¼ 11.8 Hz, 1H), 5.72
(d, J ¼ 15.1 Hz, 1H), 2.47 (t, J ¼ 6.2 Hz, 2H), 2.32 (t, J ¼ 6.1 Hz, 2H), 1.75
(br d, 4H), 1.51 (br d, 6H); 13C (75 MHz, CDCl3): d ¼ 171.21, 158.63, 142.57,
124.76, 119.39, 39.22, 30.66, 29.75, 28.59, 27.26, 26.69, 26.65; LC/MS: m/z

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Synthesis of (2E)- and (2Z)-4-Cycloalkylidenebut-2-enoic Acids
885
(%) ¼ 193 [(M 2 H)2, 100], 167 (3), 155 (2), 131 (4); HRMS (EI): m/z calcd
for C12H18O2 194.13068; found 194.13064; IR (KBr): n ¼ 1680 cm21
.
(2Z)-4-Cyclopentylidenebut-2-enoic Acid (10a)
Yield: 42 mg (63%); mp 105–1078C; 1H NMR (300 MHz, CDCl3):
d ¼ 7.19 (d, J ¼ 12.0 Hz, 1H), 6.79 (t, J ¼ 11.6 Hz, 1H), 5.49 (d, J ¼ 11.4 Hz,
1H), 2.47–2.39 (m, 4H), 1.79–1.62 (m, 4H); 13C (75 MHz, CDCl3):
d ¼ 170.52, 160.10, 143.33, 119.03, 115.22, 35.74, 30.16, 27.09, 26.87; LC/
MS: m/z (%) ¼ 151 [(M 2 H)2, 100], 141 (4), 113 (48), 59 (6); HRMS (EI):
m/z calcd for C9H12O2 152.08373; found 152.08352; IR (KBr):
n ¼ 1684 cm21
.
(2Z)-4-Cyclohexylidenebut-2-enoic Acid (10b)
Yield: 50 mg (68%); mp 121–1238C; 1H NMR (300 MHz, CDCl3):
d ¼ 7.06 (d, J ¼ 12.1 Hz, 1H), 7.0 (d, J ¼ 11.1 Hz, 1H), 5.53 (d, J ¼ 11.0 Hz,
1H), 2.39 (br t, 2H), 2.34 (br t, 2H), 1.61 (br s, 6H); 13C (75 MHz, CDCl3):
d ¼ 170.34, 155.27, 141.14, 119.96, 116.27, 39.07, 29.84 (2 Â CH2), 29.14,
27.71; LC/MS: m/z (%) ¼ 165 [(M 2 H)2, 41], 131 (4), 113 (100), 69 (50);
HRMS (EI): m/z calcd for C10H14O2 166.09938; found 166.09922; IR (KBr):
n ¼ 1680 cm21
.
(2Z)-4-Cycloheptylidenebut-2-enoic Acid (10c)
Yield: 68 mg (86%); mp 86–888C; 1H NMR (300 MHz, CDCl3):
d ¼ 7.12 (d, J ¼ 11.9 Hz, 1H), 6.94 (t, J ¼ 11.8 Hz, 1H), 5.53 (d, J ¼ 11.4 Hz,
1H), 2.51 (t, J ¼ 5.3 Hz, 2H), 2.39 (t, J ¼ 5.5 Hz, 2H), 1.65–1.64 (m, 4H),
1.54–1.52 (m, 4H); 13C (75 MHz, CDCl3): d ¼ 170.28, 156.97, 141.62,
123.12, 115.99, 39.76, 30.89, 30.76, 29.84, 29.51, 28.34; anal. calcd for
C11H16O2 (180.2): C 73.29; H 8.94; found: C 73.14; H 9.00; IR (KBr):
n ¼ 1684 cm21
.
(2Z)-4-Cyclooctylidenebut-2-enoic Acid (10d)
Yield: 55 mg (64%); mp 110–1128C; 1H NMR (300 MHz, CDCl3):
d ¼ 7.16 (d, J ¼ 12.1 Hz, 1H), 6.97 (t, J ¼ 11.7 Hz, 1H), 5.53 (d, J ¼ 11.4 Hz,
1H), 2.45 (t, J ¼ 6.1 Hz, 2H), 2.33 (t, J ¼ 6.2 Hz, 2H), 1.79–1.68 (m, 4H,

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1.58–1.46 (m, 6H); 13C (75 MHz, CDCl3): d ¼ 170.34, 158.25, 141.68,
123.28, 115.60, 39.63, 29.98, 29.80, 28.66, 27.27, 26.74, 26.70; LC/MS: m/z
(%) ¼ 193 [(M 2 H)2, 100], 167 (4), 155 (5), 131 (4), 113 (21); HRMS (EI):
m/z calcd for C12H18O2 194.13068; found 194.13098; IR (KBr):
n ¼ 1684 cm21
.
General Procedure for the Preparation of Sodium
(2E)-4-Cycloalkylidenebut-2-enoates (11a–d) and
Sodium (2Z)-4-Cycloalkylidenebut-2-enoates (12c,d)
To a solution of acid (E)-9 or (Z)-10 (2.4 mmol) in dry MeOH (10 mL)
was added dropwise a solution of NaOH (2.18 mmol) in MeOH (20 mL) at 08C
under argon and the resulting mixture was warmed to r.t. overnight. The
MeOH was concentrated under reduced pressure and the white solid formed
was filtered, washed successfully with Et2O (5 Â 25 mL), and dried in vacuo
to give pure sodium salt ((E)-11)/((Z)-12) as a white solid; mp . 3008C.
Sodium (2E)-4-Cyclopentylidenebut-2-enoate (11a)
1
White solid; yield: 330 mg (87%); mp . 3008C; H NMR (400 MHz,
CD3OD): d ¼ 7.35 (dd, J ¼ 15.2, 11.3 Hz, 1H), 6.03 (d, J ¼ 11.3 Hz, 1H),
5.73 (d, J ¼ 15.1 Hz, 1H), 2.46 (t, J ¼ 6.4 Hz, 2H), 2.36 (t, J ¼ 6.4 Hz, 2H),
1.73–1.63 (m, 4H); HR (-LSIMS): calcd for C9H11O2Na 151.07590
(M 2 Na); found 151.07578.
Sodium (2E)-4-Cyclohexylidenebut-2-enoate (11b)
1
White solid; yield: 369 mg (90%); mp . 3008C; H NMR (200 MHz,
CD3OD): d ¼ 7.40 (dd, J ¼ 15.0, 11.6 Hz, 1H), 6.0 (d, 1H), 5.8
(d, J ¼ 15.1 Hz, 1H), 2.4 (br s, 2H), 2.2 (br s, 2H), 1.6 (br s, 6H); HR
(-LSIMS): calcd for C10H13O2Na 165.09155 (M 2 Na); found 165.09124.
Sodium (2E)-4-Cycloheptylidenebut-2-enoate (11c)
1
White solid; yield: 339 mg (77%); mp . 3008C; H NMR (400 MHz,
CD3OD): d ¼ 7.35 (dd, J ¼ 15.1, 11.5 Hz, 1H), 5.93 (d, J ¼ 11.5 Hz, 1H),
5.78 (d, J ¼ 15.1 Hz, 1H), 2.51 (t, J ¼ 5.8 Hz, 2H), 2.33 (t, J ¼ 5.8 Hz, 2H),

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Synthesis of (2E)- and (2Z)-4-Cycloalkylidenebut-2-enoic Acids
887
1.73–1.63 (m, 4H), 1.57–1.52 (m, 4H); HR (-LSIMS): calcd for C11H15O2Na
179.10720 (M 2 Na); found 179.10689.
Sodium (2E)-4-Cyclooctylidenebut-2-enoate (11d)
1
White solid; yield: 358 mg (76%); mp . 3008C; H NMR (400 MHz,
CD3OD): d ¼ 7.39 (dd, J ¼ 15.1, 11.6 Hz, 1H), 5.97 (d, J ¼ 11.7 Hz, 1H),
5.77 (d, J ¼ 15.1 Hz, 1H), 2.45 (t, J ¼ 6.2 Hz, 2H), 2.28 (t, J ¼ 6.2 Hz, 2H),
1.78–1.71 (m, 4H), 1.66–1.51 (m, 6H); HR (-LSIMS): calcd for C12H17O2Na
193.12285 (M 2 Na); found 193.12268.
Sodium (2Z)-4-Cycloheptylidenebut-2-enoate (12c)
1
White solid; yield: 414 mg (94%); mp . 3008C; H NMR (300 MHz,
CD3OD): d ¼ 6.97 (d, J ¼ 11.8 Hz, 1H), 6.51 (d, J ¼ 11.6 Hz, 1H), 5.65
(d, J ¼ 11.5 Hz, 1H), 2.44 (t, J ¼ 5.9 Hz, 2H), 2.34 (t, J ¼ 6.4 Hz, 2H),
1.63 2 1.59 (m, 4H), 1.56–1.51 (m, 4H).
Sodium (2Z)-4-Cyclooctylidenebut-2-enoate (12d)
Yield: 433 mg (92%); mp . 3008C; 1H NMR (300 MHz, CDCl3):
d ¼ 7.04 (d, J ¼ 12.0 Hz, 1H), 6.56 (d, J ¼ 11.7 Hz, 1H), 5.48 (d, J ¼ 11.5 Hz,
1H), 2.39 (t, J ¼ 6.1 Hz, 2H), 2.29 (t, J ¼ 6.3 Hz, 2H), 1.71 (m, 4H), 1.51 (br s,
6H).
ACKNOWLEDGMENT
We gratefully acknowledge financial support from Abbott Laboratories,
100 Abbott Park Rd., Abbott Park, Illinois, USA.
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Received in the USA August 21, 2003

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