Novel deconjugative esterification of 2-cyclohexylideneacetic acids through 4-(pyrrolidin-1-yl)pyridine-catalyzed carbodiimide couplings

Article abstract of DOI:10.1246/cl.2006.1286

4-(Pyrrolidin-1-yl)pyridine-catalyzed deconjugative esterification of 2-cyclohexylideneacetic acids afforded isopropyl 2-(cyclohex-1-enyl)acetate by employing 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride as a coupling reagent. On the other

Full text of DOI:10.1246/cl.2006.1286

1286
Chemistry Letters Vol.35, No.11 (2006)
Novel Deconjugative Esterification of 2-Cyclohexylideneacetic Acids
through 4-(Pyrrolidin-1-yl)pyridine-catalyzed Carbodiimide Couplings
Shigeki Sano,Ã Etsuko Harada, Tomohiro Azetsu, Takashi Ichikawa,
Michiyasu Nakao, and Yoshimitsu Nagao
Graduate School of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770-8505
(Received September 4, 2006; CL-061009; E-mail: ssano@ph.tokushima-u.ac.jp)
Table 1. Deconjugative esterification of 2-cyclohexylideneace-
tic acids 1–3
4-(Pyrrolidin-1-yl)pyridine-catalyzed deconjugative esteri-
fication of 2-cyclohexylideneacetic acids afforded isopropyl 2-
(cyclohex-1-enyl)acetate by employing 1-ethyl-3-(3-dimethyl-
aminopropyl)carbodiimide hydrochloride as a coupling reagent.
On the other hand, 4-(pyrrolidin-1-yl)pyridine-catalyzed esterifi-
cation with 1,3-dicyclohexylcarbodiimide was not accompanied
by deconjugation and gave isopropyl 2-cyclohexylideneacetate.
R2OH
(5 mol equiv.)
R1
Conditions
CH2Cl2
1 h
CH2Cl2
rt, 4−6 h
R1
CO2H
1−3
R1
+
CO2R2
CO2R2
α,β-Unsaturated esters 5
β
,
γ
-Unsaturated esters 4
ꢀ,ꢁ-Unsaturated esters are of interest as synthetic building
blocks in organic chemistry and medicinal chemistry. There
are numerous deconjugative reactions of ꢂ,ꢀ-unsaturated esters,
such as photochemical deconjugation,1 alkylative deconjuga-
tion,2 and anionic deconjugation.3 However, conventional ester-
ification of carboxylic acids with alcohols utilizing carbodiimide
reagents has received little attention as a deconjugative
reaction.4 Here, we describe the 4-(pyrrolidin-1-yl)pyridine
(PPY)5-catalyzed deconjugative esterification of 2-cyclohexyli-
deneacetic acids 1–3 achieved by employing 1-ethyl-3-(3-di-
Entry R1
R2 Conditionsa Yield/%b
4:5c
1
2
Ph i-Pr
Ph Me
A
A
A
A
A
A
B
74
83
73
5
79
79
59
36
53
79
70
79
96:4 (4a:5a)
62:38 (4b:5b)
62:38 (4c:5c)
97:3 (4d:5d)
92:8 (4e:5e)
93:7 (4f:5f)
12:88 (4a:5a)
24:76 (4a:5a)
93:7 (4a:5a)
4:96 (4a:5a)
11:89 (4e:5e)
7:93 (4f:5f)
3
Ph
Et
4
5
6
7
8
9
10
11
Ph t-Bu
Me i-Pr
t-Bu i-Pr
Ph i-Pr
Ph i-Pr
Ph i-Pr
Ph i-Pr
Me i-Pr
6
C
.
methylaminopropyl)carbodiimide hydrochloride (EDC HCl)
as a coupling reagent.
Bd
D
D
D
We have found that an esterification of 2-(4-phenylcyclo-
hexylidene)acetic acid (1) and i-PrOH through PPY-catalyzed
.
12 t-Bu i-Pr
EDC HCl coupling in CH2Cl2 at room temperature afforded
a
.
ꢀ,ꢁ-unsaturated ester 4a with a 4a:5a ratio of 96:4, and in
74% yield (Table 1, Entry 1).7 The tendency toward deconjuga-
tion in the esterification seemed to depend on the bulkiness of
alcohols. The esterification of carboxylic acid 1 with MeOH
and EtOH resulted in a low regioselectivity (4:5 = 62:38)
(Table 1, Entries 2 and 3). In the reaction with t-BuOH, the
regioselective esterification suffered from low yield (Table 1,
Entry 4). Under similar conditions, carboxylic acids 2 and 3
afforded ꢀ,ꢁ-unsaturated esters 4e and 4f with high regioselec-
tivities (Table 1, Entries 5 and 6). On the other hand, when 1,3-
dicyclohexylcarbodiimide (DCC)8 or EDC was used instead of
A: rt, 1–3/PPY/EDC HCl (1:0.3:1.5), B: rt, 1/PPY/DCC
(1:0.3:1.5), C: rt, 1/PPY/EDC (1:0.3:1.5), D: 0 ꢀC, 1–3/
PPY/DCC (1:1.5:1.5). bIsolated yields. cDetermined by
1H NMR analysis of the crude esters. Trimethylamine hy-
drochloride (1.5 mol equiv.) was added.
d
tive esterification. The amidation of carboxylic acid 1 with
BnNH2 and PhNH2 afforded ꢀ,ꢁ-unsaturated amides 6a and
6b with modest regioselectivity (Table 2, Entries 1 and 2). On
the other hand, treatment of 1 and 4-nitroaniline (4-NO2C6H4-
.
NH2) with PPY and EDC HCl in CH2Cl2 at room temperature
afforded ꢀ,ꢁ-unsaturated amide 6c as the sole product
(Table 2, Entry 3). The regioselectivity in the amidation of
carboxylic acid 1 seemed to vary depending on the pKaH value
of each amine (BnNH2: 9.34, PhNH2: 4.87, 4-NO2C6H4NH2:
1.02).9 The amidation of 1 and BnNH2 or PhNH2 without
employing PPY afforded ꢂ,ꢀ-unsaturated amides 7a and 7b,
though in low yields. It is worth noting that these reactions
were not accompanied by any deconjugation (Table 2, Entries
4 and 5).
In conclusion, we demonstrated a novel deconjugative
esterification of 2-cyclohexylideneacetic acids 1–3 catalyzed
by PPY employing EDC HCl as a coupling reagent. Although
the mechanism underlying this reaction is not clear at this stage,
the reaction probably involves the equilibrium between the
active PPY-intermediates, ꢀ,ꢁ-unsaturated acyl pyridinium
and ꢂ,ꢀ-unsaturated acyl pyridinium, as shown in Scheme 1.
.
EDC HCl, ꢂ,ꢀ-unsaturated ester 5a was obtained as the major
product (4a:5a = 12:88 or 24:76) (Table 1, Entries 7 and 8).
This suggested the significance of a tertiary amine hydrochloride
.
moiety of EDC HCl for deconjugative esterification. Hence, tri-
methylamine hydrochloride was added to the PPY-catalyzed re-
action utilizing DCC as a coupling reagent to alter the regiose-
lectivity. The major product of this was ꢀ,ꢁ-unsaturated ester
4a (4a:5a = 93:7) (Table 1, Entry 9). Ordinary PPY-catalyzed
esterification of carboxylic acids 1–3 and i-PrOH with DCC,
which was not accompanied by deconjugation, were carried
out within a range of 4:5 ratios of 11:89–4:96 (Table 1, Entries
10–12). The 4:5 ratios were determined by 1H NMR analysis
(400 MHz, C6D6).
.
Next, we attempted amidation of carboxylic acid 1 with
several amines under conditions similar to those of deconjuga-
Copyright ꢀ 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.11 (2006)
1287
Table 2. Deconjugative amidation of 2-cyclohexylideneacetic
acid 1
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RNH2
Ph
(1 mol equiv.)
Conditions
1389; T. Bach, F. Hofer, J. Org. Chem. 2001, 66, 3427; F.
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CH2Cl2
r.t., 1 h
CH2Cl2
r.t., Time
CO2H
1
Ph
Ph
+
CONHR
CONHR
α,β-Unsaturated amides 7
β
,
γ
-Unsaturated amides 6
Conditionsa Time/h Yield/%b
6:7c
2
3
R. M. Cory, B. M. Ritchie, A. M. Shrier, Tetrahedron Lett.
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Entry
R
1
2
3
4
5
6
Bn
A
A
A
B
B
B
6
71
81
45
18
10
36:64
(6a:7a)
55:45
(6b:7b)
100:0
(6c:7c)
0:100
(6a:7a)
0:100
Ph
4-NO2C6H4
Bn
6
21
6
´
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Activating Agents and Protecting Groups, ed. by A. J.
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188.
Ph
24
24
(6b:7b)
—
4-NO2C6H4
0d
a
.
A: 1/PPY/EDC HCl (1:0.3:1.5), B: 1/EDC HCl (1:1.5).
.
bIsolated yields. cDetermined by 1H NMR analysis of the crude
amides. No reaction.
d
4
5
6
R
R
O
O
N
N
N
N
X
X
β,
γ
-Unsaturated acyl pyridinium
α,β-Unsaturated acyl pyridinium
Scheme 1. Proposed migration of the double bond in acyl
pyridinium intermediates.
7
The typical procedure was as follows. To a solution of
2-(4-phenylcyclohexylidene)acetic acid (1) (100 mg, 0.462
mmol) and PPY (20.5 mg, 0.139 mmol) in anhydrous
The counter anion (XÀ) seems to have a significant influence on
the reactivity of these acyl pyridiniums. For reference’s sake, it
should be noted that Dai et al. reported that ꢀ,ꢁ-unsaturated es-
ter 4c was thermodynamically more stable than ꢂ,ꢀ-unsaturated
ester 5c.10 We are currently investigating the mechanism under-
lying and the extension of this intriguing deconjugative esterifi-
cation.
CH2Cl2 (4 mL) was added EDC HCl (132.9 mg, 0.693
.
mmol) at room temperature. The mixture was stirred at room
temperature for 1 h, and then i-PrOH (176.4 mL, 2.31 mmol)
was added to the solution. After being stirred at room tem-
perature for 6 h under argon, the reaction mixture was treated
with 5% HCl (10 mL) and then extracted with CHCl3
(30 mL Â 3). The extract was dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The oily residue
(4a:5a = 96:4) was purified by silica gel (Kanto Chemical
60N) column chromatography [n-hexane–AcOEt (10:1)] to
afford the mixture of 4a and 5a (88.6 mg, 74% yield) as a
colorless oil.
This work was supported in part by a Grant-in-Aid for
Scientific Research (C) from the Japan Society for the Promotion
of Science. The authors also greatly appreciate a research grant
from the Research Foundation for Pharmaceutical Sciences.
8
9
J. S. Albert, in Handbook of Reagents for Organic Synthesis–
Activating Agents and Protecting Groups, ed. by A. J.
Pearson, W. R. Roush, Wiley, Chichester, 1999, pp. 133–
136.
The dissociation constants of amines (pKaH) are presented as
pKa values for the conjugated acid at 25 ꢀC: D. R. Lide, in
CRC Handbook of Chemistry and Physics, 81st ed., Lenci,
CRC Press, Boca Raton, Florida, 2000, pp. 8/46–8/56.
References and Notes
1
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10 J. Wu, H. Wu, S. Wei, W.-M. Dai, Tetrahedron Lett. 2004,
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Published on the web (Advance View) October 21, 2006; doi:10.1246/cl.2006.1286