A new condensation reaction for the synthesis of carboxylic esters from nearly equimolar amounts of carboxylic acids and alcohols using 2-methyl-6-nitrobenzoic anhydride

Article abstract of DOI:10.1246/cl.2002.286

Various carboxylic esters were obtained in excellent yields with high chemoselectivities from nearly equimolar amounts of carboxylic acids and alcohols using 2-methyl-6-nitrobenzoic anhydride with triethylamine in the presence of a catalytic amount of 4-(

Full text of DOI:10.1246/cl.2002.286

286
Chemistry Letters 2002
A New Condensation Reaction for the Synthesis of Carboxylic Esters from Nearly Equimolar
Amounts of Carboxylic Acids and Alcohols Using 2-Methyl-6-nitrobenzoic Anhydride
Isamu Shiina,ꢀ Ryoutarou Ibuka, and Mari Kubota
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601
(Received November 22, 2001; CL-011181)
Various carboxylic esters were obtained in excellent yields
with high chemoselectivities from nearly equimolar amounts of
carboxylic acids and alcohols using 2-methyl-6-nitrobenzoic
anhydride with triethylamine inthe presence ofa catalytic amount
of 4-(dimethylamino)pyridine.
(DMAP) and it requires stepwise operation, namely, carboxylic
acids are treated with 2,4,6-trichlorobenzoyl chloride and
triethylamine at first to generate the corresponding mixed
anhydrides. After filtration of the mixture under inert gas to
remove triethylammonium chloride formed, the filtrate contain-
ing mixed anhydrides is secondly used for the acylation of
alcohols with an excess amount of DMAP (usually, 2 molar
amounts).
Synthesis of carboxylic esters is one of the most fundamental
and important process for producing natural and unnatural useful
compounds in organic chemistry. In order to perform high
yielding esterification with equimolar reactions of carboxylic
acids and alcohols under mild conditions, coupling reactions
between activated derivatives of carboxylic acids and alcohols
have been employed.1
Therefore, we planned to develop more simple and effective
esterification using carboxylic anhydrides instead of using acid
chlorides in the presence of a catalytic amount of basic promoter.
In the first place, the reaction of 1.1 molar amounts of 3-
phenylpropanoic acid with 1.0 molar amount of 3-phenylpropan-
ol was examined in the presence of 1.1 molar amounts of 4-
substituted benzoic anhydride, 1.1 molar amounts of triethyl-
amine and 10 mol% of DMAP (Scheme 1, Table 1). When
benzoic anhydride was used as a dehydrating reagent, 3-
phenylpropyl 3-phenylpropanoate was obtained in 69% yield
along with a small amount of 3-phenylpropyl benzoate, the
undesirable carboxylic ester (Entry 1). Though the desired
carboxylic ester was obtained with higher chemoselectivity by
using 4-methoxybenzoic anhydride, the reaction proceeded very
slowly (Entry 2). It was proven that electron withdrawing groups
increase the reactivities of benzoic anhydrides and the desired
carboxylic ester was obtained in good yields within shorter time
(Entry 3), however, the chemoselectivities were rather low
compared to the result using benzoic anhydride. Then, we tried to
introduce substituents on the 2-and 6-positions of the aromatic
ring of benzoic anhydride to give hindrance near the carboxyl
group. Methyl or methoxy group existing on 2-and 6-positions
increases the chemoselectivity, however, the reaction proceeded
sluggishly (Entries 4 and 5). 2,4,6-Trichlorobenzoic anhydride
In 1992, we developed a unique method for the preparation of
carboxylic esters starting from silyl carboxylates and alkyl silyl
ethers via active intermediary mixed anhydrides prepared in situ
from silyl carboxylates with 4-(trifluoromethyl)benzoic anhy-
dride by using a catalytic amount of Lewis acid such as Sn(OTf)2
or TiCl2(ClO4)2.2 Further, in 1994, we extended this method to
the reaction between nearly equimolar amounts of free carboxylic
acids and alcohols by varying the combination of Lewis acids.3
The corresponding carboxylic esters or lactones are obtained in
high yields by treating nearly equimolar amounts of free
carboxylic acids and alcohols or !-hydroxycarboxylic acids
with substituted benzoic anhydrides possessing electron with-
drawing group(s) in the presence of catalytic amounts of
TiCl2(OTf)2 and chlorotrimethylsilane. Yamamoto et al. found
in 1995 that Sc(OTf)3 is an effective Lewis acid for the promotion
of this reaction and that the desired carboxylic esters including
medium sized lactones were produced in high yields.4 Our group
achieved the total synthesis of cephalosporolide D, a natural
product consisting of a distinctive 8-membered ring lactone, by
the dehydrating cyclization reaction of the seco acid using 4-
(trifluoromethyl)benzoic anhydride in the presence of a catalytic
amount of Hf(OTf)4 in 1998.5
Although other effective esterification reactions using acidic
catalysts were recently reported,6 it is also required to develop
efficient reactions which proceed under basic conditions since
acid-sensitive protective groups such as acetals or silyl ethers are
sometimes needed in the total synthesis of complex molecules.
Yamaguchi et al. developed an effective mixed anhydride method
for the synthesis of carboxylic esters from carboxylic acids and
alcohols using 2,4,6-trichlorobenzoyl chloride.7 In this reaction,
carboxylic acids are transformed to the corresponding mixed
anhydrides by the reaction with 2,4,6-trichlorobenzoyl chloride
and triethylamine, followed by the second reaction of the mixed
anhydrides with alcohols to give the desired carboxylic esters.
However, Yamaguchi method was conventionally carried
out using an excess amount of 4-(dimethylamino)pyridine
Scheme 1. Synthesis of carboxylic esters using benzoic anhydrides.
Table 1. Yields of esters A and ratios of esters A to esters B
Entry
Xn
Time/h
Yield of A/%
A/B
1
2
3
4
5
6
7
H
4-MeO
4-CF3
2,4,6-Me3
2,6-(MeO)2
2,4,6-Cl3
2-Me-6-NO2
8
20
1
70
18
1
69
62
70
56
82
77
67
100/1
170/1
19/1
>200/1
>200/1
27/1
1
>200/1
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
287
which might afford the same mixed anhydride in the Yamaguchi
protocol gave lower selectivity as shown in Entry 6. On the other
hand, we found that 2-methyl-6-nitrobenzoic anhydride was a
quite effective dehydrating reagent for producing the carboxylic
ester with high chemoselectivity in the presence of a catalytic
amount of DMAP (Entry 7).
were obtained in good to high yields under the mild reaction
conditions (Entries 9–14).
Further, we compared our results with those obtained
according to Yamaguchi procedure using 2,4,6-trichlorobenzoyl
chloride.7a These data are presented in the right column of
Table 2. We observed the formation of considerable amounts of
the undesired alkyl 2,4,6-trichlorobenzoates (C) in many cases
(Entries 1 (6%), 2 (9%), 3 (29%), 8 (10%), 9 (6%), 11 (12%), 12
(4%) and 13 (8%)), though our method gave almost perfect
chemoselectivities except Entry 13 (2%). It is noted that
maximum yield of the desired ester A is limited to ca. 70% by
Yamaguchi method in Entry 3 since the reaction proceeded
without high chemoselectivity.
One of features of the present protocol using 2-methyl-6-
nitrobenzoic anhydride is the quite simple procedure for the
synthesis of a variety of carboxylic esters, that is, only mixing
carboxylic acids, 2-methyl-6-nitrobenzoic anhydride, triethyl-
amine, a catalytic amount of DMAP and alcohols at room
temperature gave the desired compounds in excellent yields with
high purity.
Several examples of carboxylic esters obtained by the present
method under the optimized conditions (standard ratio; 1.0 mol.
of R1OH; 1.2 mol. of R2COOH; 1.2 mol. of 2-methyl-6-
nitrobenzoic anhydride; 2.2 mol. of triethylamine and 10 mol%
of DMAP, in dichloromethane at rt) are listed in Table 2.8
Including benzyl and allyl alcohols, primary aliphatic alcohols
were successfully employed and the corresponding carboxylic
esters were obtained in excellent yields with complete chemo-
selectivities (Entries 1–3). The reaction of secondary aliphatic
alcohols also gavethe desired carboxylic esters inhigh yields with
perfect selectivities (Entries 4–6). It is noteworthy that acid
sensitive alcohols could be converted to the desired esters in high
yields without forming undesirable by-products (Entries 7 and 8).
This protocol is also applicable to other carboxylic acids such as
cyclohexane carboxylic, (E)-cinnamic and benzoic acids, and
various aliphatic, ꢀ; ꢁ-unsaturated and aromatic carboxylic esters
The authors dedicate this paper to Professor Teruaki
Mukaiyama on the celebration of his 75th birthday.
Table 2. Yield of various carboxylic esters using 2-methyl-6-nitro-
benzoic anhydride and a catalytic amount of DMAP
References and Notes
1
Yield of A/%
[A/B]
R1
R2
J. Mulzer, ‘‘Comprehensive Organic Synthesis,’’ ed. by B. M. Trost and
I. Fleming, Pergamon Press, Oxford (1991), Vol. 6, p 323.
Entry
[A/Cd]c
95
(90)c
2
a) T. Mukaiyama, I. Shiina, andM. Miyashita, Chem. Lett., 1992, 625;b)
M. Miyashita, I. Shiina, S. Miyoshi, and T. Mukaiyama, Bull. Chem.
Soc. Jpn., 66, 1516(1993). Seealso, T. Mukaiyama, M. Miyashita, andI.
Shiina, Chem. Lett., 1992, 1747; T. Mukaiyama, J. Izumi, M. Miyashita,
and I. Shiina, Chem. Lett., 1993, 907; M. Miyashita, I. Shiina, and T.
Mukaiyama, Chem. Lett., 1993, 1053; M. Miyashita, I. Shiina, and T.
Mukaiyama, Bull. Chem. Soc. Jpn., 67, 210 (1994); I. Shiina, M.
Miyashita, M. Nagai, and T. Mukaiyama, Heterocycles, 40, 141 (1995).
I. Shiina, S. Miyoshi, M. Miyashita, and T. Mukaiyama, Chem. Lett.,
1994, 515; I. Shiina and T. Mukaiyama, Chem. Lett., 1994, 677.
K. Ishihara, M. Kubota, H. Kurihara, and H. Yamamoto, J. Am. Chem.
Soc., 117, 4413&6639(1995);K. Ishihara, M. Kubota, H. Kurihara, and
H. Yamamoto, J. Org. Chem., 61, 4560 (1996).
1
2
Bn
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
c-C6H11
[>200/1] [15/1]
92
(85)c
[>200/1] [10/1]
CH2 ¼ CHCH2
Ph(CH2)3
94
[>200/1]
95
(58)c
[2/1]
(92)c
3
4
Ph(CH2)2CHCH3
Menthyl
3
4
[>200/1] [152/1]
90
(88)c
[>200/1] [>200/1]
83
(86)c
[>200/1] [70/1]
94a (51)c,e
[>200/1] [>200/1]
5
6
5ꢀ-Cholestan-3ꢁ-yl
C9H19C(CH3)2
THPO(CH2)5
Ph(CH2)3
5
6
I. Shiina, Y. Fukuda, T. Ishii, H. Fujisawa, and T. Mukaiyama, Chem.
Lett., 1998, 831; I. Shiina, H. Fujisawa, T. Ishii, and Y. Fukuda,
Heterocycles, 52, 1105 (2000).
J. Otera, N. Dan-oh, and H. Nozaki, J. Org. Chem., 56, 5307 (1991); K.
Ishihara, S. Ohara, and H. Yamamoto, Science, 290, 1140 (2000); K.
Wakasugi, T. Misaki, K. Yamada, and Y. Tanabe, Tetrahedron Lett., 41,
5249 (2000); K. Manabe, X.-M. Sun, and S. Kobayashi, J. Am. Chem.
Soc., 123, 10101 (2001).
7
98
[>200/1]
96
[143/1]
quant.b
(62)c
[6/1]
(89)c
[14/1]
(97)c
8
9
7
8
a) J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, and M. Yamaguchi, Bull.
Chem. Soc. Jpn., 52, 1989 (1979). See also, B. Hartmann, A. M.
´
Kanazawa, J.-P. Depres, and A. E. Greene, Tetrahedron Lett., 32, 5077
(1991).
10
11
12
13
14
Ph(CH2)2CHCH3
Ph(CH2)3
c-C6H11
[>200/1] [187/1]
98
[187/1]
95
(82)c
[7/1]
(87)c
(E)-PhCH¼CH
A typical experimental procedure is described for the reaction of 3-
phenylpropanoic acid with 4-phenyl-2-butanol; to a solution of
triethylamine (66.1 mg, 0.65 mmol) in dichloromethane (1.5 mL) were
added DMAP (2.5 mg, 0.020 mmol), 2-methyl-6-nitrobenzoic an-
hydride9 (82.9 mg, 0.24 mmol) and 3-phenylpropanoic acid (36.3 mg,
0.24 mmol). After havingbeen stirredfor 10 min, asolutionof 4-phenyl-
2-butanol (30.1 mg, 0.20 mmol) in dichloromethane (2.0 mL) was
added. The reaction mixture was stirred for 20 h at room temperature
and then saturated aqueous ammonium chloride was added. Usual work
up and purification of the mixture by TLC on silica gel afforded 53.9 mg
(95%) of 1-methyl-3-phenylpropyl 3-phenylpropanoate.
Ph(CH2)2CHCH3 (E)-PhCH¼CH
[>200/1] [22/1]
92
[42/1]
88b
(85)c
[11/1]
(98)c
Ph(CH2)3
Ph
Ph
Ph(CH2)2CHCH3
[>200/1] [>200/1]
a3 equiv of carboxylic acid, 3 equiv of 2-methyl-6-nitrobenzoic
anhydride and 5 equiv of triethylamine were used. b1.3 equiv of
carboxylic acid and 1.3 equiv of 2-methyl-6-nitrobenzoic anhydride
were used. cthe data obtained by Yamaguchi protocol according to
the procedure in Ref. 7a. dThe undersired 2,4,6-trichlorobenzoates
(C) of the corresponding alcohols. e38% of 2-methylundecan-2-ol
was recovered.
9
2-Methyl-6-nitrobenzoic anhydride was prepared from 2-methyl-6-
nitrobenzoic acid and 2-methyl-6-nitrobenzoyl chloride with pyridine
according to the procedure for the preparation of 4-trifluoromethylben-
zoic anhydride. See Ref. 2b.