Enantioselective synthesis of allenecarboxylates from phenyl acetates through C-C bond forming reactions

Article abstract of DOI:10.1016/S0957-4166(01)00114-8

A variety of optically active 4,4-disubstituted allenecarboxylic acid methyl esters were prepared from simple α,α-disubstituted phenyl acetate through base treatment of the esters to generate ketenes, followed by successive Horner-Wadsworth-Emmons reaction. The transformation was further developed as a one-pot procedure with satisfactory yields and high enantioselectivity.

Full text of DOI:10.1016/S0957-4166(01)00114-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 669–675
Enantioselective synthesis of allenecarboxylates from phenyl
acetates through CꢀC bond forming reactions
Jiro Yamazaki, Toshiyuki Watanabe and Kiyoshi Tanaka*
School of Pharmaceutical Sciences, University of Shizuoka, Yada 52-1, Shizuoka 422-8526, Japan
Received 5 February 2001; accepted 2 March 2001
Abstract—A variety of optically active 4,4-disubstituted allenecarboxylic acid methyl esters were prepared from simple a,a-disub-
stituted phenyl acetate through base treatment of the esters to generate ketenes, followed by successive Horner–Wadsworth–
Emmons reaction. The transformation was further developed as a one-pot procedure with satisfactory yields and high
enantioselectivity. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
In this study, re-examination of ester candidates which
allow in situ generation of the ketene species for the
successive HWE reactions to allenic compounds, was
carried out. We report herein an improved one-pot
procedure for highly enantioselective preparation of
optically active allenecarboxylates from phenyl esters.
Allenecarboxylates bearing different substituents at the
4-position possess axial chirality; hence, together with
their versatile reactivity,1 these derivatives are interest-
ing building blocks for many asymmetric transforma-
tions. By appropriate synthetic manipulation
transcription to central chirality is possible.
Most of the preceding preparative methods for opti-
cally active allenic compounds are based on the iso-
merisation of propargylic derivatives bearing
a
stereogenic centre.2 Thus, except for two examples,3
producing allenecarboxylates with e.e.s of up to 23%,
little was known about direct transformation through
CꢀC bond forming reactions of ketenes4 before a new
one-flask procedure was described by us.5 In our
method 2,6-di-tert-butyl-4-methylphenyl (BHT) esters6
were used as precursors for labile ketene species. This
procedure, however, involved difficulties such as low
yields in the preparation of the starting materials prob-
ably due to the bulkiness of the BHT group and the
limited availability of bases for both the subsequent
generation of ketenes and appropriate anions for the
Horner–Wadsworth–Emmons (HWE) reactions. Thus,
n-BuLi was found to be the sole effective base for in
situ generation of ketenes whilst KHMDS was found to
be essential for the generation of reactive HWE
reagents.
2. Results and discussion
After a systematic examination of several aromatic
esters, (phenyl, 4-nitrophenyl, pentafluorophenyl, 2,6-
dimethylphenyl, a- and b-naphthyl esters—the alkox-
ides of which were expected to have good leaving
ability under the reaction conditions), phenyl esters
were found to give satisfactory results in the presence of
a ZnCl2 additive (Scheme 1).
To confirm the effectiveness of phenyl esters, such as 4,
as precursors of ketenes, a competitive experiment was
carried out between the corresponding methyl ester 5
with Still’s reagent using lithium 2,2,6,6-tetra-
methylpiperidide (LiTMP) as a base (Scheme 2). Clear
chemoselectivity was observed in this reaction, where
together with formation of the allenic product, the
methyl ester
quantitatively.
5
was recovered unreacted nearly
* Corresponding author. Fax: +81 54 264-5745; e-mail: tanakaki@
u-shizuoka-ken.ac.jp
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00114-8

670
J. Yamazaki et al. / Tetrahedron: Asymmetry 12 (2001) 669–675
Scheme 1.
Scheme 2.
Scheme 3. (a) Phenol, DCC, DMAP, CH2Cl2, rt; (b) LDA, RX (R=Me, Et, iPr, cycl-Hex, Bn), HMPA THF, −78°C; (c)
Ph3PCH2OCH3Cl, PhLi, Et2O, −78°C to rt; (d) 98% HCO2H, H2O, rt; (e) Jones reagent, acetone, 0°C; (f) H2, 5% Rh/Al2O3,
t-BuOH, rt; (g) BBr3, CH2Cl2, rt.

J. Yamazaki et al. / Tetrahedron: Asymmetry 12 (2001) 669–675
671
Scheme 4.
Table 1. Formation of optically active methyl allenecarboxylates from phenyl acetates
Entry
Phenyl esters
R1
HWE reagent
Allenecarboxylates
Compound
R2
Compound
% E.e.a (config.)
Chemical yield (%)b
1
2
3
4
5
6c
7
8
9
7
8
4
4
4
4
9
10
13
H
Ph
Ph
Ph
Ph
Ph
Ph
i-Pr
Cycl-Hex
(S)-2
(S)-2
(S)-1
(S)-2
(S)-3
(S)-2
(S)-2
(S)-2
(S)-2
–
18
6
6
6
–
–
31
48
57
57
61
69
71
39
CH3
C2H5
C2H5
C2H5
C2H5
Ph
77 (aR)
23 (aR)
88 (aR)
55 (aR)
87 (aR)
88 (aS)
83 (aS)
89 (aR)
6
19
20
21
Ph
10
11
12
13
11
14
17
16
PhCH2
C2H5
CH3
Ph
(S)-2
(S)-2
(S)-2
(S)-2
22
23
24
–
89 (aR)
78 (aR)
32 (aR)
–
55
43
21
–
Cycl-Hex
PhCH2
Cycl-Hex
i-Pr
a Determined by HPLC analysis on chiral column CHIRALPAK AS or AD.
b Isolated yield based on the consumed starting material.
c The reaction was carried out at −78 to −45°C for 2 h.
Using the phenyl ester as a substrate and an achiral
trimethylphosphonoacetate as a HWE reagent, several
bases adaptable to allene formation, such as amides
and n-BuLi, were next examined. From this, LDA was
also found to be a satisfactory base for this transforma-
tion. Among the homochiral HWE reagents7 used, (S)-
2 gave the best result in accord with the BHT esters
previously reported. Several derivatives of phenyl
acetates were prepared (Scheme 3).
−78 to −45°C without any significant effect on either
the yield or the enantioselectivity of the reaction (entry
6).
E.e.s were determined by HPLC analysis on a chiral
stationary phase and the absolute configuration of the
products was assigned by comparison with specific
rotation data in the literature and measurement of the
CD spectra. The stereostructures of the products were
in good agreement with the mechanistic consideration
previously described with the same HWE reagents.5c
Contrary to the a,a-disubstituted phenyl acetate, the
a-monosubstituted phenyl ester is not a suitable
starting material for this transformation (entry 1),
probably due to instability of the intermediate ketene
species.
Both the rate and enantioselectivity of the reactions
were then examined using the optimised (S)-2/LDA
system (Scheme 4).
Thus, starting from a variety of the a,a-disubstituted
phenyl acetates, the corresponding methyl allenecar-
boxylates were obtained in moderate to good yields,
and these results are tabulated (Table 1). Generally, the
same yields and levels of enantioselectivity as the previ-
ous BHT procedure were obtained, and in some cases
improved selectivity was observed. The best e.e. of 89%
was observed in the reaction of the benzyl and phenyl
substituted derivative (entry 10).
Since LDA could be used for the generation of both
anions, a one-pot procedure, in which all the substrates,
reagents and additives were simultaneously added, was
attempted. Using this protocol, allenecarboxylates were
obtained in comparable yields with the procedure
described above. The induction of enantioselectivity
significantly in the one-pot reaction was found to be
heavily dependent on the reaction temperature. Thus, a
reaction carried out at −40°C for 2 hours afforded near
racemic mixtures (with up to 3% e.e.), but a much
higher e.e. was observed at −78 to −45°C over 2 hours
(Scheme 5).
For comparison, Table 1 also includes results of the
reactions with (S)-1 and (S)-3 (entries 3 and 5).
Moderately good e.e.s were achieved even where the
difference in size between R1 and R2 was small (entries
7 and 8). The reaction time could be shortened to 2 h at

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J. Yamazaki et al. / Tetrahedron: Asymmetry 12 (2001) 669–675
Scheme 5.
3. Conclusion
1.86–2.29 (m, 1H), 2.15–2.29 (m, 1H), 3.70 (t, 1H,
J=7.6 Hz), 6.96–7.43 (m, 10H).
In conclusion, we have developed a convenient and
efficient one-flask procedure for the preparation of
optically active allenecarboxylate from simple and read-
ily available phenyl esters. This protocol is not only
practical but also complementary to the previously
reported BHT method, and therefore might lead to
more extensive usage of allenecarboxylates as chiral
synthons.
4.2.2. Benzeneacetic acid phenyl ester 7. In the same way
as above, benzeneacetic acid phenyl ester (4.7 g, 100%)
was obtained from phenyl acetic acid (3.0 g, 22.0 mmol)
and phenol (2.5 g, 26.6 mmol). Benzeneacetic acid
phenyl ester 7: pale yellow oil; 1H NMR (CDCl3) l 3.86
(s, 2H), 7.04–7.39 (m, 10H).
4.2.3. General procedure for the synthesis of alkylated
esters: a-methyl-benzeneacetic acid phenyl ester 8. To a
stirred solution of LDA (60 mL, 0.3 M in THF) was
added dropwise a solution of benzeneacetic acid phenyl
ester (1.9 g, 9.0 mmol) in THF (20 mL) at −78°C and
the mixture was stirred for a further 30 min at the same
temperature. Methyl iodide (5.6 mL, 90.0 mmol) and
HMPA (15.6 mL, 90.0 mmol) were added and the
mixture stirred for 18 h at the same temperature. The
mixture was quenched by addition of 2N HCl and
extracted with AcOEt. The extract was washed with
brine, water and then dried. Concentration of the
extract gave a residue, which was subjected to column
chromatography on silica gel with AcOEt:hexane (1:20)
as solvent system, to afford a-methyl-benzeneacetic
4. Experimental
4.1. General
Melting points are uncorrected. Nuclear magnetic reso-
nance (NMR) spectra were taken at 200 or 270 MHz in
CDCl3 with chemical shifts being reported as l ppm
from tetramethylsilane as an internal standard and
couplings are expressed in hertz. Infrared (IR) spectra
were measured in CHCl3 solution. Analytical and
preparative HPLC was carried out using Shimadzu
LC-10AT (Daicel chiral columns) and JAI LC-908
(direct connection of 1H and 2H columns) with hex-
ane–iso-propanol and chloroform solvent systems,
respectively. THF was distilled from sodium benzophe-
none ketyl and dichloromethane was distilled from
calcium hydride. Unless otherwise noted, all reactions
were run under an argon atmosphere. All extractive
organic solutions were dried over anhydrous MgSO4.
Column chromatography was carried out with silica
gel 60 (spherical, 150–325 mesh), and silica gel 60
F254 plates (Merck) were used for preparative TLC
(pTLC).
1
acid phenyl ester 8 as a pale yellow oil (1.9 g, 93%); H
NMR (CDCl3) l 1.62 (d, 3H, J=7.3 Hz), 3.97 (q, 1H,
J=7.3 Hz), 6.97–7.42 (m, 10H).
4.2.4. a-iso-Propyl-benzeneacetic acid phenyl ester 9.
Using the same procedure for the preparation of 8,
a-iso-propyl-benzeneacetic acid phenyl ester 9 (514 mg,
22%) was obtained from benzeneacetic acid phenyl
ester (1.9 g, 9.0 mmol) and iso-propyl iodide (7.8 mL,
45.0 mmol). a-Isopropyl-benzeneacetic acid phenyl
1
ester 9: pale yellow oil; H NMR (CDCl3) l 0.79 (d,
3H, J=6.6 Hz), 1.19 (d, 3H, J=6.6 Hz), 2.42–2.51 (m,
1H), 3.39 (d, 1H, J=10.6 Hz), 6.97–7.43 (m, 10H); IR
(CHCl3) 3030, 2964, 2874, 1751, 1595, 1493, 1211, 1196,
1161, 1142 and 1111 cm−1; MS (m/z) 255 (M++H);
HRMS (m/z) calcd for C17H19O2 (M++H) 255.1385,
found: 255.1383.
4.2. Preparation of derivatives of phenyl acetate
4.2.1. a-Ethyl-benzeneacetic acid phenyl ester 4. To a
stirred solution of 2-phenylbutanoic acid (5.00 g, 30.5
mmol), DCC (6.92 g, 33.6 mmol), DMAP (745 mg, 6.1
mmol) in CH2Cl2 (40 mL) was added a solution of
phenol (36.6 mmol) in CH2Cl2 (10 mL). The mixture
was stirred for a further 18 h at room temperature. The
mixture was concentrated under reduced pressure, dis-
solved in AcOEt and filtered through a Celite pad. The
filtrate was evaporated and subjected to column chro-
matography on silica gel (AcOEt:hexane=1:9) to give
a-ethyl-benzeneacetic acid phenyl ester (6.81 g, 93%).
a-Ethyl-benzeneacetic acid phenyl ester 4: colourless
oil; 1H NMR (CDCl3) l 1.00 (t, 3H, J=7.3 Hz),
4.2.5. a-Phenyl-cyclohexaneacetic acid phenyl ester 10.
Using the same procedure for the preparation of 8,
a-phenyl-cyclohexaneacetic acid phenyl ester (1.2 g,
45%) was obtained from alkylation with cyclohexyl
iodide (11.6 mL, 90.0 mmol). a-Phenyl-cyclohex-
aneacetic acid phenyl ester 10: pale yellow oil; 1H NMR
(CDCl3) l 0.81–2.16 (m, 11H), 3.46 (d, 1H, J=10.6
Hz), 6.97–7.43 (m, 10H); IR (CHCl3) 3032, 2932, 2854,
1750, 1595, 1493, 1211, 1196, 1161, 1142 and 1117
cm−1; MS (m/z) 295 (M++H); HRMS (m/z) calcd for
C20H23O2 (M++H) 295.1698, found: 295.1700.

J. Yamazaki et al. / Tetrahedron: Asymmetry 12 (2001) 669–675
673
4.2.6. 2,3-Diphenylpropanoic acid phenyl ester 11. Using
the same procedure for the preparation of 8, ester 11
(1.9 g, 70%) was formed from benzeneacetic acid
phenyl ester (1.9 g, 9.0 mmol) and benzyl bromide (10.7
mL, 90.0 mmol). 2,3-Diphenylpropanoic acid phenyl
Compound 13 (1.36 g, 95%) was obtained from 1,2,3,4-
tetrahydro-1-naphthalenecarboxylic acid (999 mg, 5.7
mmol) and phenol (643 mg, 6.84 mmol) in the same
way as described above. 1,2,3,4-Tetrahydro-1-naph-
thalenecarboxylic acid phenyl ester 13: colourless oil;
1H NMR (CDCl3) l 1.80–2.37 (m, 4H), 2.75–2.96 (m,
2H), 4.07 (t, 1H, J=5.9 Hz), 7.05–7.39 (m, 9H).
1
ester 11: white crystals; mp 67–70°C; H NMR (CDCl3)
l 3.15 (dd, 1H, J=6.3, 13.9 Hz), 3.51 (dd, 1H, J=9.3,
13.9 Hz), 4.11 (dd, 1H, J=6.3, 9.3 Hz), 6.81–6.84 and
7.14–7.44 (m, 15H); IR (CHCl3) 3032, 1753, 1595, 1493,
1194, 1163 and 1134 cm−1. Anal. calcd for C21H18O2: C,
83.44; H, 5.96. Found: C, 83.42; H, 5.97.
4.2.8. a-Ethyl-cyclohexaneacetic acid phenyl ester 14.
Cyclohexaneacetic acid phenyl ester (4.0 g, 100%) was
obtained from cyclohexaneacetic acid (2.6 mL, 18.1
mmol) and phenol (643 mg, 6.84 mmol) in a similar
way to above. Cyclohexaneacetic acid phenyl ester:
1
4.2.7. 1,2,3,4-Tetrahydro-1-naphthalenecarboxylic acid
colourless oil; H NMR (CDCl3) l 1.02–1.99 (m, 11H),
phenyl ester 13. To
a
stirred suspension of
2.43 (d, 2H, J=7.0 Hz), 7.05–7.40 (m, 5H); IR (CHCl3)
3029, 2928, 2855, 1749, 1595, 1493, 1217, 1213, 1196,
1161 and 1111 cm−1; MS (m/z) 219 (M++H); HRMS
(m/z) calcd for C14H19O2 (M++H) 219.1385, found:
219.1379.
Ph3PCH2OCH3Cl in dry ether (40 mL) was added
n-BuLi (6.0 mL, 1.66 M in hexane) and PhLi (27.0 mL,
0.88 M in ether) at −78°C and the reaction temperature
was allowed to rise to 0°C for 1 h. After re-cooling to
−78°C, a-tetralone (2.92 g, 20.0 mmol) in ether (15 mL)
was added and the reaction mixture was stirred for 2 h
at 0°C. The mixture was poured into ice-cold satd
NH4Cl solution and extracted with AcOEt. The extract
was washed with water, brine, dried and then evapo-
rated to give the residue. Chromatographic separation
on silica gel (AcOEt:hexane=1:45) afforded the crude
enol-methyl ether (3.4 g, 97%). Enol-methyl ether:
Using the same procedure for the preparation of 8, 14
(407 mg, 30%) was obtained from cyclohexaneacetic
acid phenyl ester (1.2 g, 5.5 mmol) and ethyl iodide (4.4
mL, 55.0 mmol). a-Ethyl-cyclohexaneacetic acid phenyl
ester 14: colourless oil; 1H NMR (CDCl3) l 1.03 (t, 3H,
J=7.3 Hz), 1.05–1.91 (m, 13H), 2.32 (q, 1H, J=7.9
Hz), 7.05–7.41 (m, 5H); IR (CHCl3) 2932, 2855, 1748,
1593, 1493, 1209, 1196, 1159 and 1127 cm−1; MS (m/z)
247 (M++H); HRMS (m/z) calcd for C16H23O2 (M++H)
247.1698, found: 247.1698.
1
colourless oil; H NMR (CDCl3) l 1.73–1.83 (m, 2H),
2.51 (t, 2H, J=6.6 Hz), 2.73 (t, 2H, J=6.3 Hz), 3.73 (s,
3H), 6.62 (s, 1H), 7.05–7.37 (m, 4H).
A mixture of the enol ether (3.4 g) and 98% HCO2H
(20 mL) was stirred for 10 h at room temperature. The
reaction mixture was brought to pH 8.2 by addition of
satd aq. NaHCO3 solution and extracted with AcOEt.
The extract was washed with water, brine and then
dried. Concentration of the extract gave the residue,
which was purified by column chromatography on sil-
ica gel with AcOEt:hexane (1:45) to give crude aldehyde
(2.29 g). Further purification by preparative HPLC
with chloroform yielded pure 1,2,3,4-tetrahydro-1-
naphthalenecarboxaldehyde 12 (1.47 g, 47%). 1,2,3,4-
Tetrahydro-1-naphthalenecarboxaldehyde 12: colour-
4.2.9. a-iso-Propyl-cyclohexaneacetic acid phenyl ester
16. a-iso-Propyl-benzeneacetic acid methyl ester (2.2 g,
100%) was obtained from a-phenylacetic acid methyl
ester (1.5 g, 10.0 mmol) and isopropyl iodide (10.0 mL,
100.0 mmol). a-iso-Propyl-benzeneacetic acid methyl
1
ester: colourless oil; H NMR (CDCl3) l 0.70 (d, 3H,
J=6.6 Hz), 1.03 (d, 3H, J=6.6 Hz), 2.27–2.38 (m, 1H),
3.15 (d, 1H, J=10.5 Hz), 3.65 (s, 3H), 7.26–7.32 (m,
5H).
Catalytic hydrogenation of a-iso-propyl-benzeneacetic
acid methyl ester (960 mg, 5.0 mmol) with 5% Rh/
Al2O3 (455 mg) in t-BuOH (30 mL) was carried out
under atmospheric pressure of hydrogen at room tem-
perature for 50 h. The crude residue was purified by
preparative HPLC to give a-iso-propyl-cyclohex-
aneacetic acid methyl ester 15 (988 mg, 100%). a-iso-
Propyl-cyclohexaneacetic acid methyl ester 15:
1
less oil; H NMR (CDCl3) l 1.75–2.28 (m, 4H), 2.79 (t,
2H, J=6.3 Hz), 3.58–3.61 (m, 1H), 7.17–7.26 (m, 4H),
9.68 (d, 1H, J=2.0 Hz).
To a stirred solution of 12 (300 mg, 1.88 mmol) in
acetone (3 mL) was added dropwise Jones reagent at
0°C until the orange colour of the mixture disappeared
(within 5 min). The mixture was poured into ice-water
and extracted with CH2Cl2. The organic layer was
re-extracted with 5% NaOH solution and the aqueous
phase was washed with AcOEt. The aqueous layer was
acidified by addition of cold HCl solution and then
extracted with CH2Cl2. The organic extract was washed
with brine, dried and then concentrated under reduced
pressure to leave the residue, which was purified by
preparative HPLC to give 1,2,3,4-tetrahydro-1-naph-
thalenecarboxylic acid (288 mg, 85%). 1,2,3,4-Tetra-
1
colourless oil; H NMR (CDCl3) l 0.89 (d, 3H, J=3.0
Hz), 0.92 (d, 3H, J=3.0 Hz), 1.02–1.75 (m, 11H),
1.97–2.04 (m, 2H), 3.65 (s, 3H); IR (CHCl3) 3029, 2932,
2855, 1746, 1595, 1493, 1219, 1211, 1192, 1157 and
1109 cm−1.
A mixture of 15 (1.3 g, 6.6 mmol), CH2Cl2 (40 mL),
BBr3 (20.0 mL, 1.0 M in CH2Cl2) was stirred for 2 h at
room temperature. The mixture was poured into ice-
cold water and extracted with CH2Cl2. The organic
layer was treated with 5% aq. NaOH solution and the
aqueous solution was washed with AcOEt and then
acidified with HCl solution. The aqueous layer was
extracted with CH2Cl2 and washed with water, brine
1
hydro-1-naphthalenecarboxylic acid: white crystal; H
NMR (CDCl3) l 1.75–2.24 (m, 4H), 2.72–2.90 (m, 2H),
3.85 (t, 1H, J=5.6 Hz), 7.13–7.26 (m, 4H).

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J. Yamazaki et al. / Tetrahedron: Asymmetry 12 (2001) 669–675
and then dried. Concentration of the extract left a-iso-
propyl-cyclohexaneacetic acid (560 mg, 46%). a-iso-
4.4. General procedure for the preparation of optically
active methyl allenecarboxylates
1
Propyl-cyclohexaneacetic acid: colourless oil; H NMR
(CDCl3) l 0.95 (d, 3H, J=3.3 Hz), 0.97 (d, 3H, J=3.3
Hz), 1.03–1.76 (m, 11H), 2.00–2.07 (m, 2H). Esterifica-
tion of the acid a-iso-propyl-cyclohexaneacetic acid
(834 mg, 4.5 mmol) with phenol (508 mg, 5.4 mmol)
was carried out to give 16 (1.00 g, 86%). a-iso-Propyl-
cyclohexaneacetic acid phenyl ester 16: colourless oil;
1H NMR (CDCl3) l 1.03 (d, 3H, J=3.0 Hz), 1.06 (d,
3H, J=3.0 Hz), 1.11–1.94 (m, 11H), 2.11–2.19 (m, 1H),
2.28 (t, 1H, J=7.6 Hz), 7.05–7.41 (m, 5H); IR (CHCl3)
3029, 2932, 2855, 1746, 1595, 1493, 1219, 1211, 1192,
1157 and 1109 cm−1; MS (m/z) 261 (M++H); HRMS
(m/z) calcd for C17H25O2 (M++H) 261.1854, found:
261.1852.
The phenyl ester (0.7 mmol) in THF (2 mL) was treated
with LDA (0.7 mmol) in THF at −78°C for 1 h under
Ar. This was treated with a solution of freshly prepared
ZnCl2 (0.7 M in THF, 1.0 mmol) and the mixture was
stirred for 5 min at the same temperature. The anion of
the HWE reagent (0.7 mmol in 2 mL of THF) was
prepared by treatment of LDA (0.7 mmol) in THF at
−78°C for 1 h under Ar in a separate vessel, and then
transferred to the above solution of ketene. The reac-
tion mixture was stirred initially at −78°C and then
allowed to warm to room temperature over 18 h under
Ar with stirring. The usual work-up and purification of
the residue by pTLC or preparative HPLC afforded
pure allenecarboxylate in the yields shown in Table 1.
4.2.10. 2-Methyl-3-phenylpropanoic acid phenyl ester 17.
Esterification of 3-phenylpropanoic acid (1.5 g, 10.0
mmol) with phenol (1.1 g, 12.0 mmol) was completed as
above and afforded benzenepropanoic acid phenyl ester
(2.3 g, 100%).
4.4.1. (aR)-(−)-4-Phenyl-2,3-hexadienoic acid methyl
ester 63. Yellow oil; [h]D24 −173 (c 1.9, CCl4) (Ref. 3 [h]2D5
−225 (c 5.0, CCl4)); HPLC (Chiralpak AS. 0.5% iso-
1
propanol/hexane), e.e.=88%; H NMR (CDCl3) l 1.18
(t, 3H, J=7.3 Hz), 2.54–2.60 (m, 2H), 3.76 (s, 3H), 5.98
(t, 1H, J=3.3 Hz), 7.26–7.40 (m, 5H).
1
Benzenepropanoic acid phenyl ester: colourless oil; H
NMR (CDCl3) l 2.89 (t, 2H, J=6.9 Hz), 3.08 (t, 2H,
J=6.9 Hz), 6.99–7.39 (m, 5H). Using the same proce-
dure for the preparation of 8, benzenepropanoic acid
phenyl ester (1.36 g, 6.0 mmol) and methyl iodide (3.7
mL, 60.0 mmol) afforded 17 (1.22 g, 84%). 2-Methyl-3-
phenylpropanoic acid phenyl ester 17: pale yellow oil;
1H NMR (CDCl3) l 1.33 (d, 3H, J=6.6 Hz), 2.83 (q,
1H, J=6.9 Hz), 2.94–3.07 (m, 1H), 3.14 (q, 1H, J=7.6
Hz), 6.91–7.37 (m, 5H); IR (CHCl3) 3030, 2936, 1752,
1595, 1493, 1219, 1213, 1194, 1163 and 1144 cm−1; MS
(m/z) 241 (M++H); HRMS (m/z) calcd for C16H17O2
(M++H) 241.1228, found: 241.1234.
4.4.2. (aR)-(−)-4-Phenyl-2,3-pentadienoic acid methyl
ester 183. Yellow oil; [h]D24 −200 (c 1.1, CCl4); HPLC
(Chiralpak AS. 0.5% iso-propanol/hexane), e.e.=77%;
1H NMR (CDCl3) l 2.21 (d, 3H, J=3.0 Hz), 3.75 (s,
3H), 5.91 (q, 1H, J=3.0 Hz), 6.97–7.41 (m, 5H).
4.4.3. (aS)-(+)-5-Methyl-4-phenyl-2,3-hexadienoic acid
methyl ester 19. Yellow oil; [h]2D3 +161 (c 2.3, CHCl3);
HPLC (Chiralpak AS. 0.5% iso-propanol/hexane),
e.e.=88%; 1H NMR (CDCl3) l 1.15–1.19 (dd, 6H,
J=2.3, 6.6 Hz), 2.89–2.95 (m, 1H), 3.75 (s, 3H), 5.93–
5.94 (d, 1H, J=2.6 Hz), 7.26–7.37 (m, 5H). IR (CHCl3)
2965, 1945, 1721, 1449, 1255, and 1148 cm−1; MS (m/z)
216 (M+), 201; HRMS (m/z) calcd for C14H16O2 (M+)
216.1149, found: 216.1137. Anal. calcd for C14H16O2:
C, 77.75; H, 7.45. Found: C, 77.68; H, 7.38%.
4.3. Competitive experiment between methyl and phenyl
esters
A solution of LiTMP (1.0 mL in THF, 1.06 M) was
added dropwise to the stirred solution of methyl- (5, 60
mg, 0.25 mmol) and phenyl-2-phenylbutanoate 4 (44.5
mg, 0.25 mmol) in THF (2 mL) at −78°C under Ar and
the mixture was stirred for 0.5 h at the same tempera-
ture. To this stirred mixture was added a solution of
bis(2,2,2 - trifluoroethyl)(methoxycarbonylmethyl)phos-
phonate (160 mg, 0.50 mmol) in THF (1.0 mL) and the
resulting mixture was stirred for 20 min at the same
temperature. After addition of a solution of ZnCl2 (1.45
mL, 0.73 M in ether) and stirring for 10 min at the
same temperature, the cooling bath was removed and
the reaction temperature was allowed to rise from
−78°C to room temperature for 4 h with stirring. The
reaction mixture was poured into cold dil. HCl and
extracted with AcOEt. The organic phase was washed
with brine, dried and then evaporated to give the
residual mixture. Separation by pTLC with hex-
ane:AcOEt (15:1) gave allenic product 6 (22.3 mg, 44%)
together with the recovered methyl ester 5 (43.5 mg,
98%) and phenyl ester 4 (23.5 mg, 39%).
4.4.4.
(aS)-(+)-4-Cyclohexyl-4-phenyl-2,3-butadienoic
acid methyl ester 20. White powder; [h]3D1 +102 (c 2.8,
CHCl3); HPLC (Chiralpak AS. 0.5% iso-propanol/hex-
ane), e.e.=83%; 1H NMR (CDCl3) l 1.19–2.04 (m,
10H), 2.51–2.58 (m, 1H), 3.75 (s, 3H), 5.92 (d, 1H,
J=2.3 Hz), 7.26–7.36 (m, 5H). IR (CHCl3) 2927, 1944,
1723, 1449, 1150, 1034, 831, 767 and 695 cm−1; MS
(m/z) 256 (M+), 197; HRMS (m/z) calcd for C17H20O2
(M+) 256.1462, found: 256.1450. Anal. calcd for
C17H20O2: C, 79.65; H, 7.86. Found: C, 79.59; H,
7.95%.
4.4.5.
(aR)-(−)-3-(3,4-Dihydro-1(2H)-naphthalenyl-
idene)-2-propenoic acid methyl ester 213. Yellow oil;
[h]3D1 −110 (c 1.9, CCl4); HPLC (Chiralpak AS. 0.5%
1
iso-propanol/hexane), e.e.=89%; H NMR (CDCl3) l
1.88–2.86 (m, 6H), 3.75 (s, 3H), 5.94 (t, 1H, J=3.0 Hz),
7.06–7.39 (m, 4H).

J. Yamazaki et al. / Tetrahedron: Asymmetry 12 (2001) 669–675
675
4.4.6.
(aR)-(−)-4,5-Diphenyl-2,3-pentadienoic
acid
References
methyl ester 22. Yellow oil; [h]2D4 −155 (c 3.0, CHCl3);
HPLC (Chiralpak AS. 0.5% iso-propanol/hexane),
1. (a) Schuster, H. F.; Coppola, G. M. Allenes in Organic
Synthesis; Wiley: New York, 1984; (b) Jung, M. E. In
Comprehensive Organic Synthesis; Trost, B. M.; Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 4, p. 53; (c)
Zhang, C.; Lu, X. Synlett 1995, 645; (d) March, P.;
Font, J.; Gracia, A.; Qingying, Z. J. Org. Chem. 1995,
60, 1814; (e) Gillmann, T.; Hu¨lsen, T.; Massa, W.;
Wocadlo, S. Synlett 1995, 1257; (f) Naruse, Y.; Kakita,
S.; Tsunekawa, A. ibid. 1995, 711; (g) Trost, B. M.;
Kottirsch, G. J. Am. Chem. Soc. 1990, 112, 2816; (h)
Ishar, M. P. S.; Gandhi, R. P. Tetrahedron 1993, 49,
6729; (i) Tsuboi, S.; Kuroda, H.; Takatsuka, S.;
Fukawa, T.; Sakai, T.; Utaka, M. J. Org. Chem. 1993,
58, 5952; (j) Tanaka, H.; Sumida, S.; Sorajo, K.; Torii,
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2. (a) Tsuji, J.; Sugiura, T.; Minami, I. Tetrahedron Lett.
1986, 27, 731; (b) Sleeman, M. J.; Meehan, G. V. ibid.
1989, 30, 3345; (c) Katsuhira, T.; Harada, T.; Maejima,
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58, 7180; (e) Marshall, J. A.; Wallace, E. M. J. Org.
Chem. 1995, 60, 796; (f) Nishibayashi, Y.; Singh, J. D.;
Fukuzawa, S.; Uemura, S. J. Org. Chem. 1995, 60, 4114;
(g) Naruse, Y.; Watanabe, H.; Ishiyama, Y.; Yoshida, T.
ibid. 1997, 62, 3862.
3. (a) Musierowicz, S.; Wro´blewski, A. E.; Krawczyk, H.
Tetrahedron Lett. 1975, 437; (b) Musierowicz, S.; Wro´b-
lewski, A. E. Tetrahedron 1980, 36, 1375.
4. (a) Gong, L.; McAllister, M. A.; Tidwell, T. T. J. Am.
Chem. Soc. 1991, 113, 6021; (b) Brady, W. T. Tetra-
hedron 1981, 37, 2949; (c) Tamai, Y.; Yoshiwara, H.;
Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc.,
Chem. Commun. 1994, 2281.
5. (a) Tanaka, K.; Otsubo, K.; Fuji, K. Synlett 1995, 933;
(b) Tanaka, K.; Otsubo, K.; Fuji, K. Tetrahedron Lett.
1995, 36, 9513; (c) Tanaka, K.; Otsubo, K.; Fuji, K.
Tetrahedron Lett. 1996, 37, 3735.
1
e.e.=89%; H NMR (CDCl3) l 3.76 (s, 3H), 3.88 (s,
2H), 5.87 (t, 1H, J=2.6 Hz), 7.20–7.41 (m, 10H); IR
(CHCl3) 3029, 2953, 1948, 1717, 1221, 1211 and 1163
cm−1; MS (m/z) 264 (M+); HRMS (m/z) calcd for
C18H16O2 (M+) 264.1150, found: 264.1155.
4.4.7. (aR)-(−)-4-Ethyl-4-cyclohexyl-2,3-butadienoic acid
methyl ester 23. Yellow oil; [h]2D4 −53 (c 1.0, CCl4);
HPLC (Chiralpak AD. 0.5% iso-propanol/hexane),
e.e.=78%; 1H NMR (CDCl3) l 1.02 (t, 3H, J=7.3 Hz),
1.09–1.86 (m, 11H), 2.06–2.14 (m, 2H), 3.72 (s, 3H),
5.63 (q, 1H, J=3.3 Hz); IR (CHCl3) 2932, 2857, 1954,
1709, 1267, 1219 and 1161 cm−1; MS (m/z) 208 (M+);
HRMS (m/z) calcd for C13H20O2 (M+) 208.1463, found:
208.1456.
4.4.8. (aR)-(−)-4-Methyl-5-phenyl-2,3-pentadienoic acid
methyl ester 24. Yellow oil; [h]2D4 −19 (c 0.15, CHCl3);
HPLC (Chiralpak AS. 0.5% iso-propanol/hexane),
e.e.=32%; 1H NMR (CDCl3) l 1.74 (d, 3H, J=2.6
Hz), 3.40 (d, 2H, J=2.0 Hz), 3.74 (s, 3H), 5.52 (q, 1H,
J=2.6 Hz), 7.20–7.34 (m, 5H); IR (CHCl3) 3029, 2926,
1966, 1709, 1269, 1211 and 1163 cm−1; MS (m/z) 202
(M+); HRMS (m/z) calcd for C13H14O2 (M+) 202.0994,
found: 202.0995.
4.5. General procedure for one-pot preparation of
methyl allenecarboxylates
To a stirred solution of the phenyl ester (0.7 mmol), the
HWE reagent (0.7 mmol), and ZnCl2 (0.7 M solution in
THF, 1.0 mmol) in THF (4 mL) was added LDA in
THF (1.4 mmol) at −78°C under Ar. The reaction
mixture was stirred for 2 h. During this period of time,
the reaction temperature was allowed to rise from −78
to −45°C. The reaction mixture was quenched by the
addition of satd NH4Cl solution, and then worked-up
in the usual manner to give the residue, which was
purified by pTLC or preparative HPLC.
6. (a) Seebach, D.; Amstutz, R.; Laube, T.; Schweizer, W.
B.; Dunitz, J. D. J. Am. Chem. Soc. 1985, 107, 5403; (b)
Ha¨ner, R.; Laube, T.; Seebach, D. ibid. 1985, 107, 5396;
(c) Heathcock, C. H.; Pirung, M. C.; Montgomery, S.
H.; Lampe, J. Tetrahedron 1981, 37, 4087; (d) Hattori,
T.; Hayashizaka, N.; Miyano, S. Synthesis 1995, 41.
7. (a) Tanaka, K.; Ohta, Y.; Fuji, K. Tetrahedron Lett.
1993, 34, 4071; (b) Tanaka, K.; Watanabe, T.; Ohta, Y.;
Fuji, K. Tetrahedron Lett. 1997, 38, 8943; (c) Tanaka,
K.; Watanabe, T.; Shimamoto, K.; Sahakitpichan, P.;
Fuji, K. Tetrahedron Lett. 1999, 40, 6599.
Acknowledgements
This work was partially supported by a grant-in-aid
(No. 11470471) from the Ministry of Education, Sci-
ence, Sports, and Culture, Japan. HRMS spectral data
were measured at the Institute for Chemical Research,
Kyoto University.
.