A microwave-assisted deconjugative esterification of α,β- unsaturated carboxylic acids through α,β-unsaturated ketene intermediates

Article abstract of DOI:10.1246/cl.2012.68

A facile synthetic approach to β,γ-unsaturated esters by deconjugative esterification of α,β-unsaturated carboxylic acids with alcohols in the presence of 1,3-dicyclohexylcarbodiimide (DCC), Me ₃N·HCl, and Me₂NEt is described. The on

Full text of DOI:10.1246/cl.2012.68

doi:10.1246/cl.2012.68
68
Published on the web December 30, 2011
A Microwave-assisted Deconjugative Esterification of ¡,¢-Unsaturated Carboxylic Acids
through ¡,¢-Unsaturated Ketene Intermediates
Shigeki Sano,* Takashi Ichikawa, Michiyasu Nakao, and Yoshimitsu Nagao
Graduate School of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770-8505
(Received September 26, 2011; CL-110781; E-mail: ssano@ph.tokushima-u.ac.jp)
A facile synthetic approach to ¢,£-unsaturated esters by
After a preliminary investigation of the effect of a tertiary
amine on deconjugative esterification, we found a combination
of excess amounts of Me3N¢HCl and Me2NEt, instead of a
catalytic amount of Et3N, to be efficient (Table 1, Entries 1-3).10
Thus, DCC and Me3N¢HCl were added to carboxylic acid 1 in
CH2Cl2, then the treatment with Me2NEt and i-PrOH afforded a
mixture of ¢,£-unsaturated ester 2a and ¡,¢-unsaturated ester 3a
with a 2a:3a ratio of 97:3, and in 85% yield. In the reaction with
t-BuOH, the yield was found to be somewhat lower (57%), but
the corresponding ¢,£-unsaturated ester 2b was obtained as the
sole product (2b:3b = 100:0). On the other hand, 2c and 3c were
obtained with a low regioselectivity (2c:3c = 42:58) in the
reaction with MeOH. Under similar conditions, the deconjuga-
tive esterification of carboxylic acid 4 with i-PrOH and t-BuOH
gave 7a and 7b as major products, respectively (Table 2, Entries
1 and 2).
deconjugative esterification of ¡,¢-unsaturated carboxylic acids
with alcohols in the presence of 1,3-dicyclohexylcarbodiimide
(DCC), Me3N¢HCl, and Me2NEt is described. The one-pot
synthesis was effectively improved under microwave irradiation.
¢,£-Unsaturated esters are among the most important
building blocks in organic chemistry.1 Therefore, considerable
efforts have been made to develop an efficient method for
synthesizing ¢,£-unsaturated esters. The deconjugation of ¡,¢-
unsaturated compounds, such as photochemical deconjugation,2
alkylative deconjugation,3 and anionic deconjugation,4 repre-
sents one of the most useful strategies. Nevertheless, only a few
reports have been published on deconjugative esterification5 and
amidation6 of ¡,¢-unsaturated carboxylic acids. As part of our
work in this area, we have already developed deconjugative
esterification and amidation of 2-cyclohexylideneacetic acids,
such as 1 through ¢,£-unsaturated acyl pyridinium intermediates
in the presence of a catalytic amount of 4-(pyrrolidin-1-yl)-
pyridine (PPY) as depicted in Scheme 1.7 The following
describes an outcome of our efforts to synthesize ¢,£-unsat-
urated esters by a microwave-assisted deconjugative esterifica-
tion of ¡,¢-unsaturated carboxylic acids through ¡,¢-unsaturat-
ed ketene intermediates.
To improve the reaction yields and shorten the reaction
times, several experiments were conducted by elevating the
reaction temperature. This revealed that carboxylic acid 1 gave
Table 1. Deconjugative esterification of ¡,¢-unsaturated carbox-
ylic acids 1
The formation of ketenes from acid chlorides and tertiary
amines is an ordinary reaction. However, there have been only a
few reports on the preparation of ¡,¢-unsaturated ketenes by
dehydrochlorination of the corresponding acid chlorides.8 On
the other hand, Olah et al. reported the synthesis of stable
dialkyl ketenes involving intramolecular dehydration of the
corresponding carboxylic acids with 1,3-dicyclohexylcarbodi-
imide (DCC) in the presence of catalytic amounts of Et3N.9
Thus, we first applied our synthetic method to the deconjugative
esterification of 2-cyclohexylideneacetic acid 1 with an equi-
molar amount of DCC in the presence of a catalytic amount of
Et3N in Et2O or CH2Cl2, followed by treatment with excess
amounts of i-PrOH. However, ¢,£-unsaturated ester 2a was not
obtained at all.
Entry
R
Conditionsa Yield/%b
2:3c
1
2
3
4
5
6
7
8
9
i-Pr
t-Bu
Me
i-Pr
t-Bu
Me
Et
A
A
A
B
B
B
B
B
B
C
Be
85
57
81
86
79
91
86
86
91
35
26
97:3 (2a:3a)
100:0 (2b:3b)
42:58 (2c:3c)
98:2 (2a:3a)
98:2 (2b:3b)
78:22 (2c:3c)
94:6 (2d:3d)
94:6 (2e:3e)
69:31 (2f:3f)d
34:66 (2a:3a)
98:2 (2a:3a)
TMSCH2CH2
CF3CH2
10 i-Pr
11 i-Pr
aA: 50 °C, 12-21 h, 1/Me2NEt/ROH (1:7.5:5); B: MW (90 °C),
10 min, 1/Me2NEt/ROH (1:3:1.5); C: MW (90 °C), 10 min,
1/Me2NEt/ROH (1:0:1.5). bIsolated yields. cDetermined by
1H NMR (400 MHz, benzene-d6) analysis of the crude esters.
dThe ratios of 2f:3f were varied from 66:34 to 73:27 on repeated
Scheme 1. Deconjugative esterification of 2-cyclohexylideneace-
tic acid 1 through an acyl pyridinium intermediate.
e
run. Me3N¢HCl was not added.
Chem. Lett. 2012, 41, 68-69
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

69
Table 2. Deconjugative esterification of ¡,¢-unsaturated carbox-
ylic acids 4-6
Scheme 2. Deconjugative esterification of 2-cyclohexylideneace-
tic acid 1 through an ¡,¢-unsaturated ketene intermediate.
carboxylic acids 1, 4, and 5 in an efficient microwave-assisted
deconjugative esterification. Efforts toward the deconjugative
esterification of optically active 2-cyclohexylideneacetic acids
with an axis of chirality through an unsaturated ketene
intermediate are ongoing in our laboratories, and the results of
these investigations will be reported in due course.
Entry R1
R2
R
Yield/%b
7-9:(E)-10-12c
1a
2a
3a
4
H
H
H
H
H
H
H
H
H
i-Pr
t-Bu
Me
i-Pr
t-Bu
72
48
72
74
73
79
64
16
7
91:9 [7a:(E)-10a]
100:0 [7b:(E)-10b]
18:82 [7c:(E)-10c]
94:6 [7a:(E)-10a]
99:1 [7b:(E)-10b]
86:14 [8a:(E)-11a]
100:0 [8b:(E)-11b]
99:1 [9a:(E)-12a]
100:0 [9b:(E)-12b]
This work was supported in part by a Grant for the Regional
Innovation Cluster Program (Global Type) promoted by MEXT.
5
H
6
H
Me i-Pr
Me t-Bu
H
H
7
H
References and Notes
8
9
Me
Me
i-Pr
t-Bu
1
T. Berkenbusch, R. Brückner, Tetrahedron 1998, 54, 11471; P. B. Kisanga,
J. G. Verkade, J. Org. Chem. 2002, 67, 426; A. E. Wroblewski, V. Bansal,
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1513.
a50 °C, 18 h, (E)-4/Me2NEt/ROH (1:7.5:5). bIsolated yields.
cDetermined by 1H NMR (400 MHz, benzene-d6) analysis of the
crude esters.
2
2a with high regioselectivity at 90 °C for only 10 min utilizing
a Biotage Initiatorμ microwave synthesizer (Table 1, Entries
4-9).11 In addition, it was proven that microwave irradiation
could reduce the amounts of the reagents, Me2NEt and
i-PrOH. On the other hand, low yields were observed in the
absence of Me3N¢HCl or Me2NEt (Table 1, Entries 10 and 11).
To investigate the scope and limitations of this procedure,
¡,¢-unsaturated carboxylic acids (E)-4-6 were subjected to
microwave-assisted deconjugative esterification. The results are
shown in Table 2. These reactions also gave the corresponding
¢,£-unsaturated esters 7a-7c, 8a and 8b (E/Z = 45:55-50:50)
as major products, except for carboxylic acids (E)-6 (Table 2,
Entries 8 and 9). In the case of (E)-6, steric hindrance may
reduce the yields of (E)-9a and -9b. In addition, the deconju-
gative esterification of (Z)-6 with i-PrOH and t-BuOH afforded
(E)-9a and -9b with 9:12 ratios of 100:0, and in 19% and 7%
yields, respectively. On the other hand, (Z)-4 gave 7a and 7b
(E/Z = 50:50) with 7:(E)-10 ratios of 96:4 and 100:0, and in
78% and 72% yields under the same reaction conditions.
As a mechanism, we propose an initial formation of O-
acylurea 13, which leads to ¡,¢-unsaturated ketene intermediate
14 as shown in Scheme 2. ¢,£-Unsaturated ester 2 should be
obtained by the esterification of unsaturated ketene 14 with
alcohols. Direct esterification of O-acylurea 13 may afford ¡,¢-
unsaturated ester 3 as minor products. Although the detailed
reaction mechanism remains obscure, free Me3N, which might
be furnished by HCl exchange with Me2NEt during the reaction,
seems to be important in the deprotonation of one of the £-
protons.
3
4
For recent papers, see: K. E. Murphy, A. H. Hoveyda, J. Am. Chem. Soc.
2003, 125, 4690; M. C. Jones, S. P. Marsden, D. M. M. Subtil, Org. Lett.
2006, 8, 5509.
For recent papers, see: M. Iguchi, K. Tomioka, Org. Lett. 2002, 4, 4329;
S. K. Guha, A. Shibayama, D. Abe, Y. Ukaji, K. Inomata, Chem. Lett.
2003, 32, 778; F. Bargiggia, O. Piva, Tetrahedron: Asymmetry 2003, 14,
1819; S. K. Guha, A. Shibayama, D. Abe, M. Sakaguchi, Y. Ukaji, K.
Inomata, Bull. Chem. Soc. Jpn. 2004, 77, 2147; M. Yamazaki, S. K. Guha,
Y. Ukaji, K. Inomata, Bull. Chem. Soc. Jpn. 2008, 81, 740.
G. Lange, M. E. Savard, T. Viswanatha, G. I. Dmitrienko, Tetrahedron Lett.
1985, 26, 1791; G. Cardillo, A. De Simone, A. Mingardi, C. Tomasini,
Synlett 1995, 1131.
5
6
7
8
V. Theodorou, M. Gogou, M. Philippidou, V. Ragoussis, G.
Paraskevopoulos, K. Skobridis, Tetrahedron 2011, 67, 5630.
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Lett. 2006, 35, 1286.
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340.
9
G. A. Olah, A.-h. Wu, O. Farooq, Synthesis 1989, 568.
10 Effects of
a combination of reagents, such as Me3N¢HCl/Me2NEt,
Me3N¢HCl/Et3N, Me3N¢HCl/i-Pr2NEt, Me3N¢HCl/DBU, Me3N¢HCl/
TMG, Et3N¢HCl/Me2NEt, Et3N¢HCl/Et3N, etc., were investigated.
11 A typical procedure was as follows. To a solution of 2-(4-phenylcyclohex-
ylidene)acetic acid (1) (65 mg, 0.30 mmol) in anhydrous CH2Cl2 (0.75 mL)
in a Biotage vial of 0.5-2.0 mL were added DCC (93 mg, 0.45 mmol) and
Me3N¢HCl (43 mg, 0.45 mmol). The mixture was stirred at room temper-
ature for 1 h, and then Me2NEt (97 ¯L, 0.90 mmol) and i-PrOH (34 ¯L,
0.45 mmol) were added to the solution. The vial was sealed and then
irradiated at 90 °C for 10 min. The reaction mixture was then filtered and
concentrated in vacuo. The oily residue (2a:3a = 98:2) was purified by
silica gel (Kanto Chemical 60N) column chromatography [n-hexane-
AcOEt (40:1)] to afford the mixture of 2a and 3a (67 mg, 86% yield) as a
colorless oil.
In conclusion, we have presented a method for obtaining
¢,£-unsaturated esters 2, 7, and 8 from ¡,¢-unsaturated
Chem. Lett. 2012, 41, 68-69
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/