An Effective Use of Benzoic Anhydride and Its Derivatives for the Synthesis of Carboxylic Esters and Lactones: A Powerful and Convenient Mixed Anhydride Method Promoted by Basic Catalysts

Article abstract of DOI:10.1021/jo030367x

Various carboxylic esters are obtained at room temperature in excellent yields with high chemoselectivities from nearly equimolar amounts of carboxylic acids and alcohols using 2-methyl-6-nitrobenzoic anhydride with triethylamine by the promotion of a basic catalyst such as 4-(dimethylamino)pyridine. A variety of lactones are also prepared in high yields at room temperature from the corresponding ω-hydroxycarboxylic acids with use of 2-methyl-6-nitrobenzoic anhydride in the presence of 4-(dimethylamino)pyridine. A similar reaction occurs with triethylamine when using a catalytic amount of 4-(dimethylamino)pyridine 1-oxide as an effective promoter for the intramolecular condensation reaction. These methods are successfully applied to the synthesis of erythro-aleuritic acid lactone and an eight-membered-ring lactone moiety of octalactins A and B. The efficiency of the cyclizations is compared to those of other reported lactonizations.

Full text of DOI:10.1021/jo030367x

An Effective Use of Ben zoic An h yd r id e a n d Its Der iva tives for th e
Syn th esis of Ca r boxylic Ester s a n d La cton es:
A P ow er fu l a n d Con ven ien t Mixed An h yd r id e Meth od P r om oted
by Ba sic Ca ta lysts
Isamu Shiina,* Mari Kubota, Hiromi Oshiumi, and Minako Hashizume
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science,
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, J apan
shiina@ch.kagu.sut.ac.jp
Received December 3, 2003
Various carboxylic esters are obtained at room temperature in excellent yields with high
chemoselectivities from nearly equimolar amounts of carboxylic acids and alcohols using 2-methyl-
6-nitrobenzoic anhydride with triethylamine by the promotion of a basic catalyst such as
4-(dimethylamino)pyridine. A variety of lactones are also prepared in high yields at room
temperature from the corresponding ω-hydroxycarboxylic acids with use of 2-methyl-6-nitrobenzoic
anhydride in the presence of 4-(dimethylamino)pyridine. A similar reaction occurs with triethylamine
when using a catalytic amount of 4-(dimethylamino)pyridine 1-oxide as an effective promoter for
the intramolecular condensation reaction. These methods are successfully applied to the synthesis
of erythro-aleuritic acid lactone and an eight-membered-ring lactone moiety of octalactins A and
B. The efficiency of the cyclizations is compared to those of other reported lactonizations.
In tr od u ction
lactones in the presence of triethylamine and 4-(di-
methylamino)pyridine (DMAP) was established by
Yamaguchi et al. using 2,4,6-trichlorobenzoyl chloride as
a bulky acid moiety of the intermediary mixed anhy-
dride.4 This method was conventionally carried out by
using an excess amount of bases and it requires a
stepwise operation, namely, carboxylic acids are first
treated with 2,4,6-trichlorobenzoyl chloride and triethyl-
amine to generate the corresponding mixed anhydrides,
then after filtration of the mixture under inert gas to
remove the formed triethylammonium chloride, the
filtrate containing the mixed anhydrides is next used for
the acylation of alcohols with an excess amount of DMAP.
On the other hand, we reported an efficient method
for the preparation of carboxylic esters from free car-
boxylic acids and alcohols using substituted benzoic
anhydrides by the promotion of Lewis acids.5 In the
course of our studies utilizing benzoic anhydrides as
condensation reagents,6 it was anticipated that the
following successive reactions would also lead to the
formation of carboxylic esters starting from nearly equimo-
The synthesis of carboxylic esters is one of the most
fundamental and important processes for producing
natural and unnatural useful compounds in organic
chemistry. To perform high-yielding esterifications with
equimolar reactions of carboxylic acids and alcohols
under mild conditions, the coupling reactions between
activated derivatives of carboxylic acids and alcohols have
been employed.1
Although several effective esterification reactions with
acidic catalysts were recently reported,2 it was 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 for the total synthesis of complex molecules.
It is well-known that Mukaiyama et al. developed
1-alkyl-2-halopyridinium salts which function as useful
reagents for the preparation of carboxylic esters coexist-
ing with tertiary amines.3 Furthermore, a convenient
method for the preparation of carboxylic esters and
(1) Mulzer, J . Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 6, pp 323-
380.
(4) (a) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. J pn. 1979, 52, 1989-1993. See also: (b) Hikota,
M.; Tone, H.; Horita, K.; Yonemitsu, O. Tetrahedron 1990, 46, 4613-
4628.
(2) (a) Otera, J .; Dan-oh, N.; Nozaki, H. J . Org. Chem. 1991, 56,
5307-5311. (b) Izumi, J .; Shiina, I.; Mukaiyama, T. Chem. Lett. 1995,
141-142. (c) Ishihara, K.; Ohara, S.; Yamamoto, H. Science 2000, 290,
1140-1142. (d) Wakasugi, K.; Misaki, T.; Yamada, K.; Tanabe, Y.
Tetrahedron Lett. 2000, 41, 5249-5252. (e) Manabe, K.; Sun, X.-M.;
Kobayashi, S. J . Am. Chem. Soc. 2001, 123, 10101-10102.
(3) (a) Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K. Chem. Lett.
1975, 1045-1048. (b) Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett.
1976, 49-50. (c) Saigo, K.; Usui, M.; Kikuchi, K.; Shimada, E.;
Mukaiyama, T. Bull. Chem. Soc. J pn. 1977, 50, 1863-1866. (d)
Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1979, 18, 707-721.
(5) (a) Shiina, I.; Miyoshi, S.; Miyashita, M.; Mukaiyama, T. Chem.
Lett. 1994, 515-518. (b) Shiina, I.; Mukaiyama, T. Chem. Lett. 1994,
677-680. (c) Shiina, I.; Fukuda, Y.; Ishii, T.; Fujisawa, H.; Mukaiyama,
T. Chem. Lett. 1998, 831-832. (d) Shiina, I.; Fujisawa, H.; Ishii, T.;
Fukuda, Y. Heterocycles 2000, 52, 1105-1123. (e) Shiina, I. Tetrahe-
dron 2004, 60, 1587-1599. See also: (f) Ishihara, K.; Kubota, M.;
Kurihara, H.; Yamamoto, H. J . Am. Chem. Soc. 1995, 117, 4413-4414,
6639 (correction). (g) Ishihara, K.; Kubota, M.; Kurihara, H.; Yama-
moto, H. J . Org. Chem. 1996, 61, 4560-4567. (h) Ishihara, K.; Kubota,
M.; Yamamoto, H. Synlett 1996, 265-266.
10.1021/jo030367x CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/10/2004
1822
J . Org. Chem. 2004, 69, 1822-1830

Synthesis of Carboxylic Esters and Lactones
TABLE 1. Effect of 3- or 4-Su bstitu ted Ben zoic
An h yd r id es
F IGURE 1. Synthesis of carboxylic esters with benzoic
anhydrides.
lar amounts of carboxylic acids and alcohols via the active
intermediary mixed anhydrides in the presence of basic
catalysts instead of acidic catalysts: that is (1) the initial
formation of the mixed anhydride from the corresponding
carboxylic acid with benzoic anhydride and (2) the
chemoselective alcoholysis of the initially formed mixed
anhydride to form the desired carboxylic ester (Figure
1). We would now like to report a new and powerful
method for the synthesis of carboxylic esters and lactones
using substituted benzoic anhydrides as dehydrating
reagents in the presence of basic catalysts.7
entry
Xn
time/h
yielda/%
1/2b
1
2
3
4
5
6
7
8
9
H
8
1
20
1
1
1
1
1
1
70
1
69
82
62
67
67
74
75
77
70
36
59
100/1
38/1
170/1
32/1
36/1
13/1
17/1
46/1
19/1
4/1
4-Me
4-MeO
3-Cl
4-Cl
4-NO2
4-CN
3-CF3
4-CF3
4-CF3
3,5-(CF3)2
10c
11
Resu lts a n d Discu ssion
6/1
a
b
Isolated yield of 1. Determined by 1H NMR with a crude
Ester ifica tion Rea ction via Mixed An h yd r id es
w ith Ben zoic An h yd r id es. The reaction of 1.1 M
amounts of 3-phenylpropanoic acid with a 1.0 M amount
of 3-phenylpropanol was initially examined in the pres-
ence of 1.1 M amounts of 3- or 4-substituted benzoic
anhydride, 1.1 M amounts of triethylamine, and 10 mol
% of DMAP (Table 1). When benzoic or 4-methylbenzoic
anhydride was used as the dehydrating reagent, 3-phen-
ylpropyl 3-phenylpropanoate was obtained in 69% or 82%
yield along with a small amount of 3-phenylpropyl
benzoate, an undesirable carboxylic ester (entry 1 or 2).
Though the desired carboxylic ester was obtained with
higher chemoselectivity using 4-methoxybenzoic anhy-
dride, the reaction proceeded very slowly (entry 3). It was
proven that electron-withdrawing groups increase the
reactivities of the benzoic anhydrides and the desired
carboxylic ester was obtained in good yields within a
shorter time period; however, the chemoselectivities were
rather low compared to the result with benzoic anhydride
(entries 4-9 and 11).
We then tried to introduce substituents on the 2- and/
or 6-position(s) of the aromatic ring of the benzoic
anhydride to provide a hindrance near the carboxyl group
(Table 2). A methyl or methoxy group existing on the 2-
and/or 6-position(s) increases the chemoselectivity; how-
ever, the reaction sluggishly proceeded (entries 1-6).
Although the reaction with benzoic anhydrides possessing
electron-withdrawing groups rapidly proceeded, the
chemoselectivities were not satisfactory (entries 7-9).
mixture. c The reaction was carried out in the absence of DMAP.
TABLE 2. Effect of 2- a n d /or 6-Su bstitu ted Ben zoic
An h yd r id es
entry
Xn
2-Me
time/h
yielda/%
1/2b
1
2
24
24
70
18
18
16
1
85
85
56
75
82
87
75
72
77
67
100/1
>200/1
>200/1
>200/1
>200/1
80/1
2-MeO
3
4
5
6
2,4,6-Me3
2,4-(MeO)2
2,6-(MeO)2
2-MeO-4-Cl
2-Cl
7
10/1
8
2,6-Cl2
1
30/1
9
2,4,6-Cl3
2-Me-6-NO2
1
27/1
10
1
>200/1
a
b
Isolated yield of 1. Determined by 1H NMR with a crude
mixture.
2,4,6-Trichlorobenzoic anhydride, which might afford the
same mixed anhydride in the Yamaguchi protocol, gave
a somewhat lower selectivity as shown in entry 9. On
the other hand, we found that 2-methyl-6-nitrobenzoic
anhydride (MNBA) was a quite effective dehydrating
reagent for producing the carboxylic ester with high
chemoselectivity in the presence of a catalytic amount
of DMAP (entry 10).7a
The yield of the desired carboxylic ester increased to
over 80% when MNBA was used as the condensation
reagent with an excess amount of triethylamine, since
the reaction rapidly proceeds under the influence of
(6) (a) Mukaiyama, T.; Shiina, I.; Miyashita, M. Chem. Lett. 1992,
625-628. (b) Miyashita, M.; Shiina, I.; Miyoshi, S.; Mukaiyama, T.
Bull. Chem. Soc. J pn. 1993, 66, 1516-1527. See also: (c) Mukaiyama,
T.; Miyashita, M.; Shiina, I. Chem. Lett. 1992, 1747-1750. (d)
Mukaiyama, T.; Izumi, J .; Miyashita, M.; Shiina, I. Chem. Lett. 1993,
907-910. (e) Miyashita, M.; Shiina, I.; Mukaiyama, T. Chem. Lett.
1993, 1053-1054. (f) Miyashita, M.; Shiina, I.; Mukaiyama, T. Bull.
Chem. Soc. J pn. 1994, 67, 210-215. (g) Shiina, I.; Miyashita, M.;
Nagai, M.; Mukaiyama, T. Heterocycles 1995, 40, 141-148.
(7) Preliminary communications: (a) Shiina, I.; Ibuka, R.; Kubota,
M. Chem. Lett. 2002, 286-287. (b) Shiina, I.; Kubota, M.; Ibuka, R.
Tetrahedron Lett. 2002, 43, 7535-7539. 2-Methyl-6-nitrobenzoic an-
hydride (MNBA) is commercially available from Tokyo Kasei Kogyo
Co., Ltd. (TCI, M1439).
J . Org. Chem, Vol. 69, No. 6, 2004 1823

Shiina et al.
TABLE 3. Effect of Mola r Ra tios of Su bstr a tes a n d
Rea gen ts
for the completion of the esterification (entry 4). An
examination of the catalysts showed that not only het-
eroaromatic compounds such as DMAP and 4-pyrrolidi-
nopyridine (PPY)8 promoted the reaction but also their
N-oxides9 such as 4-(dimethylamino)pyridine 1-oxide
(DMAPO) and 4-pyrrolidinopyridine 1-oxide (PPYO) fa-
cilitated a desirable condensation between the carboxylic
acids and alcohols (entries 5-8). Pyridine, TMEDA,
tributylphosphine, and CsF were ineffective for this
reaction as a catalyst as shown in entries 9-12.
Several examples of carboxylic esters obtained by the
present method under the optimized conditions are listed
in Table 5. Including the benzyl and allyl alcohols,
primary aliphatic alcohols were successfully employed
and the corresponding carboxylic esters were obtained
in excellent yields with complete chemoselectivities (en-
tries 1-3). The reaction of secondary aliphatic alcohols
also gave the desired carboxylic esters in high yields with
perfect selectivities (entries 4-7). It is noteworthy that
acid-sensitive substrates could be converted into the
desired esters in high yields without forming undesirable
byproducts (entries 8 and 9). This protocol is also ap-
plicable to other carboxylic acids including R,R-disubsti-
tuted, R,â-unsaturated, and aromatic carboxylic acids,
and various aliphatic, R,â-unsaturated, and aromatic
carboxylic esters are obtained in good to high yields under
the mild reaction conditions (entries 10-22). Acceptable
chemoselectivities (<1% yield of B) were observed for all
cases except for a few combinations (entries 14-16 and
18). When using (E)-crotonic acid or the fumaric acid
monoethyl ester for the reaction, the corresponding â,γ-
unsaturated carboxylic ester or maleic acid diester was
produced as a byproduct due to the base-promoted double
bond migration or isomerization (entries 18 and 19, or
22).6b,10
entry
X
Y
Z
W
yielda/%
1
2
3
4
5
6
7
1.1
1.1
1.1
1.0
1.0
1.1
1.2
1.0
1.0
1.0
1.0
1.1
1.0
1.0
1.1
1.1
1.1
1.1
1.0
1.2
1.2
1.1
2.2
3.3
2.2
2.2
2.2
2.2
67
87
88
84
81
90
94
a
Isolated yield.
TABLE 4. Effect of Ca ta lysts a n d Ba ses
Furthermore, we compared our results with those
obtained according to the Yamaguchi procedure using
2,4,6-trichlorobenzoyl chloride.4a These data are pre-
sented in the left column of Table 6 and the compared
data obtained by MNBA are shown in the right column.
We observed the formation of significant amounts of the
undesired alkyl 2,4,6-trichlorobenzoates (C) in many
cases (entries 1 (6%), 2 (9%), 3 (29%), 9 (10%), 10 (6%),
12 (2%), 13 (8%), 15 (12%), and 16 (4%)), though our
method gave almost perfect chemoselectivities except for
entry 13 (2% yield of B). It is noted that the maximum
yield of the desired ester 1 is limited to ca. 70% by the
Yamaguchi method in entry 3 since the reaction pro-
ceeded without high chemoselectivity.
entry
catalyst
base
iPr2NEt
time/h
yielda/%
1
2
3
4
5
6
7
8
9
10
11
12
13
DMAP
DMAP
DMAP
DMAP
DMAP
PPY
DMAPO
PPYO
pyridine
TMEDA
nBu3P
CsF
1
1
1
120
1
1
1
1
1
1
94
87
89
91
94
81
86
82
0
5
9
24
1
N-methylpiperidine
TMEDA
MgO
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
1
1
1
none
a
Isolated yield.
One of the features of the present protocol with MNBA
is the quite simple procedure for the synthesis of a variety
of carboxylic esters. The Yamaguchi method usually
DMAP (Table 3). The use of 2.2 M amounts of triethyl-
amine gave the similar result as that of the reaction with
a 3.3 M amount of triethylamine (entries 2 and 3). The
molar ratios of the carboxylic acid, alcohol, and MNBA
were also examined in detail (entries 4-7), and it was
revealed that 1 was obtained in nearly quantitative yield
by employing slightly excessive amounts of the carboxylic
acid and MNBA (entry 7).
Other tertiary amines such as N-ethyldiisopropyl-
amine, N-methylpiperidine, and N,N,N′,N′-tetramethyl-
ethylenediamine (TMEDA) were also effective (Table 4,
entries 1-3), and MgO could function as a solid base
although an extension of the reaction time was required
(8) Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, H. Angew. Chem., Int. Ed.
Engl. 1978, 17, 569-583.
(9) (a) Ife, R. J .; Dyke, C. A.; Keeling, D. J .; Meenan, E.; Meeson,
M. L.; Parsons, M. E.; Price, C. A.; Theobald, C. J .; Underwood, A. H.
J . Med. Chem. 1989, 32, 1970-1977. For the modified purification
see: (b) Mukaiyama, S.; Inanaga, J .; Yamaguchi, M. Bull. Chem. Soc.
J pn. 1981, 54, 2221-2222.
(10) Double bond migration: (a) Shoda, S.; Mukaiyama, T. Chem.
Lett. 1980, 391. (b) Shoda, S. Ph.D. Thesis, The University of Tokyo,
Tokyo, J apan, 1980. Z-E isomerization: (c) Hartmann, B.; Kanazawa,
A. M.; Depre´s, J .-P.; Greene, A. E. Tetrahedron Lett. 1991, 32, 5077-
5080. (d) Brocksom, T. J .; Coelho, F.; Depre´s, J .-P.; Greene, A. E.; Freire
de Lima, M. E.; Hamelin, O.; Hartmann, B.; Kanazawa, A. M.; Wang,
Y. J . Am. Chem. Soc. 2002, 124, 15313-15325.
1824 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Carboxylic Esters and Lactones
TABLE 5. Syth esis of Va r iou s Ca r boxylic Ester s w ith MNBA
entry
R1
Ph(CH2)2
R2
R1COOR2
yielda/%
95
92
94
95
92
90
A/Bb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Bn
3
4
1
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
>200/1
>200/1
>200/1
>200/1
>200/1
>200/1
>200/1
>200/1
>200/1
183/1
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
PhCH(OTBS)CH2
c-C6H11
CH2dCHCH2
Ph(CH2)3
Ph(CH2)2CHCH3
c-C6H11
menthyl
5R-cholestan-3â-yl
C9H19C(CH3)2
THPO(CH2)6
Ph(CH2)3
Ph(CH2)3
Ph(CH2)2CHCH3
c-C6H11
Ph(CH2)3
Ph(CH2)2CHCH3
Ph(CH2)3
Ph(CH2)2CHCH3
Ph(CH2)3
Ph(CH2)2CHCH3
Ph(CH2)3
83
94c
98
92
96
143/1
c-C6H11
quant.d
87
>200/1
>200/1
7/1
c-C6H11
tBu
72
72
tBu
73/1
42/1
Ph
Ph
92
88d
>200/1
(E)-MeCHdCH
(E)-MeCHdCH
(E)-PhCHdCH
(E)-PhCHdCH
(E)-EtO2CCHdCH
78 (37/1)e
81 (7/1)f
98
55/1
>200/1
187/1
>200/1
>200/1
Ph(CH2)2CHCH3
Ph(CH2)3
95
90 (37/1)g
a
b
1
Isolated yield of A. Determined by H NMR with a crude mixture. c 3.0 M amounts of carboxylic acid, 3.0 M amounts of MNBA, and
5.0 M amounts of triethylamine were used. 1.3 M amounts of carboxylic acid and 1.3 M amounts of MNBA were used. e Ratio of A to
d
3-phenylpropyl 3-butenoate. f Ratio of A to 1-methyl-3-phenylpropyl 3-butenoate. Ratio of A to ethyl 3-phenylpropyl maleate.
g
requires a stepwise operation, namely, carboxylic acids
are treated with 2,4,6-trichlorobenzoyl chloride and tri-
ethylamine at first to generate the corresponding mixed
anhydrides. After filtration of the mixture under an inert
gas to remove the formed triethylammonium chloride, the
filtrate containing mixed anhydrides is next used for the
esterification of alcohols with an excess amount of DMAP.
On the other hand, by only mixing carboxylic acids,
alcohols, MNBA, triethylamine, and a catalytic amount
of DMAP at room temperature, the desired compounds
are produced in excellent yields with high purity accord-
ing to our new method.
chloride with 2-methyl-6-nitrobenzoic acid in the presence
of triethylamine, and it was found that there is an
equilibrium among the mixed anhydride, MNBA, and
methoxyacetic anhydride (ca. 4:3:3).12 Therefore, it is
postulated that the pyridinium salt (I) is formed by the
reaction of the mixed anhydride (II) or homogeneous
methoxyacetic anhydride with DMAP, and the successive
nucleophilic addition of the alcohol to I gives the desired
carboxylic ester in high yield. On the other hand, the
activated 2-methyl-6-nitrobenzoyl pyridinium salt was
not formed in the above experiment. The byproducts, the
corresponding alkyl 2-methyl-6-nitrobenzoates, were there-
fore hardly produced in the present esterification reaction
due to the stability of the 2-methyl-6-nitrobenzoate anion.
La cton iza tion via Mixed An h yd r id es w ith Ben -
zoic An h yd r id es. The macrocyclic framework is one of
the most basic structures for useful natural and un-
natural organic molecules. Recently, several effective
C-C bond-forming reactions such as transition metal-
promoted coupling and olefin metathesis have been
widely studied for producing cyclic compounds.13,14 How-
ever, macrolactonization is still the most popular
1
The reaction pathway was studied by H NMR with a
mixture of a carboxylic acid and MNBA under the
reaction conditions (Figure 2). The formation of ca. 10
mol % of a reactive key intermediate, the pyridinium salt
of methoxyacetic acid (I), was observed after mixing 1.2
M amounts of methoxyacetic acid, 1.2 M amounts of
MNBA and a 1.0 M amount of triethylamine in the
presence of 10 mol % of DMAP.11 The addition of
3-phenylpropanol to the reaction mixture gave 3-phenyl-
propyl methoxyacetate in 70% yield with perfect chemose-
lectivity. Independently, the mixed anhydride (II) con-
sisting of methoxyacetic acid and 2-methyl-6-nitrobenzoic
acid was generated by the reaction of methoxyacetyl
(12) The ratio was determined by the intensity of 1H NMR signals
at 4.25 and 4.13 ppm (MeO in II and methoxyacetic anhydride).
(13) Duncton, M. A. J .; Pattenden, G. J . Chem. Soc., Perkin Trans.
1 1999, 1235-1246 and references cited therein.
(14) Armstrong, S. K. J . Chem. Soc., Perkin Trans. 1 1998, 371-
388 and references cited therein.
(11) The conversion yield of I was determined by the intensity of a
1H NMR signal at 4.18 ppm (MeO in I).
J . Org. Chem, Vol. 69, No. 6, 2004 1825

Shiina et al.
TABLE 6. Exp er im en ta l Resu lts Com p a r ed betw een Tw o Mixed An h yd r id e Meth od s
entry
R1
R2
yielda/% [A/C]b,c
yielda/% [A/B]b,d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph(CH2)2
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
c-C6H11
c-C6H11
Ph
Ph
(E)-PhCHdCH
(E)-PhCHdCH
Bn
90 [15/1]
85 [10/1]
58 [2/1]
92 [152/1]
94 [>200/1]
88 [>200/1]
86 [70/1]
51e [>200/1]
62 [6/1]
89 [14/1]
97 [187/1]
94 [54/1]
85 [11/1]
98 [>200/1]
82 [7/1]
95 [>200/1]
92 [>200/1]
94 [>200/1]
95 [>200/1]
92 [>200/1]
90 [>200/1]
83 [>200/1]
94 [>200/1]
98 [>200/1]
96 [143/1]
quant. [>200/1]
87 [>200/1]
92 [42/1]
88 [>200/1]
98 [187/1]
CH2dCHCH2
Ph(CH2)3
Ph(CH2)2CHCH3
c-C6H11
menthyl
5R-cholestan-3â-yl
C9H19C(CH3)2
THPO(CH2)5
Ph(CH2)3
Ph(CH2)2CHCH3
c-C6H11
Ph(CH2)3
Ph(CH2)2CHCH3
Ph(CH2)3
Ph(CH2)2CHCH3
87 [22/1]
95 [>200/1]
a
b
1
Isolated yield of A. Determined by H NMR with a crude mixture. c The data were obtained by Yamaguchi protocol according to the
procedure in ref 4a. Abstracted from Table 5. e 38% of 2-methylundecan-2-ol was recovered.
d
TABLE 7. Effect of Mola r Ra tios of Rea gen ts
yielda/%
monomer
entry
X
Y
Z
dimer
1
2
3
4
5
6
1.0
1.0
1.0
1.0
1.2
1.2
0.1
0.2
0.3
0.2
0.2
2.4
2.2
2.2
2.2
3.3
2.2
0
65
84
86
82
88
92
6
5
3
6
3
1
a
Isolated yield.
F IGURE 2. Formation of an active intermediate of the
present esterification reaction.
smoothly proceeds at room temperature, therefore, it is
assumed that the MNBA method might be successfully
applied to the intramolecular reaction for producing the
macrocyclic compounds under mild conditions. We would
now like to report a novel and efficient lactonization of
ω-hydroxycarboxylic acids using MNBA, an effective
condensation reagent, by the promotion of DMAP or
DMAPO.7b
First, 15-hydroxypentadecanoic acid is employed as a
model substrate for optimizing the reaction conditions
(see Table 7). When a solution of 15-hydroxypentade-
canoic acid in dichloromethane was slowly added to the
reaction mixture of a 1.0 M amount of MNBA, 2.2 M
amount of triethylamine, and 10 mol % of DMAP in
method for producing cyclic compounds including car-
boxylic ester moieties since there are some effective
methods for constructing the ester linkage.1
In the previous section, we developed a new condensa-
tion reaction for the synthesis of carboxylic esters from
nearly equimolar amounts of carboxylic acids and alco-
hols using MNBA with triethylamine in the presence of
DMAP. This protocol is quite effective and the desired
carboxylic esters are produced in excellent yields with
higher chemoselectivities compared with those obtained
by the Yamaguchi esterification method. The reaction of
nearly equal amounts of carboxylic acids and alcohols
1826 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Carboxylic Esters and Lactones
TABLE 8. Syn th esis of La cton es w ith MNBA a n d DMAP
TABLE 9. Syn th esis of La cton es w ith MNBA w ith Ba sic
Ca ta lysts
yielda/% (ring size)
yielda/% (ring size)
entry
R
n
conc/mM time/h
monomer
dimer
1
H
10
1.0
2.0
1.0
1.0
1.8
1.8
1.8
15
15
15
15
15
12
15
88 (13)
86 (13)
75 (14)
89 (15)
92 (16)
91 (16)
92 (17)
5 (26)
1 (26)
1 (28)
<1 (30)
1 (32)
3 (32)
<1 (34)
entry catalyst
n
conc/mM time/h monomer
dimer
2b
3
C6H13 10
1
2
3
4
DMAP
13
1.8
1.8
1.8
1.4
15
14
13
16
88 (16)
91 (16)
95 (16)
92 (17)
3 (32)
<1 (32)
<1 (32)
1 (34)
H
H
H
H
H
11
12
13
13
14
DMAPO 13
PPYO 13
DMAPO 14
4
5
6c
7
a
Isolated yield.
a
b
Isolated yield. 1.3 M amounts of MNBA and 3.5 M amounts
of DMAP were used. c PPY was used as a base.
including inorganic solid bases, it was proved that
substituted pyridine 1-oxides are quite effective catalysts
for the reaction forming large ring-size lactones with
triethylamine in the presence of MNBA (Table 9). For
example, the desired pentadecan-15-olide and hexadecan-
16-olide were obtained in 91% and 92% yields, respec-
tively, accompanied by only a trace and 1% of the
corresponding dimers when 20 mol % of DMAPO was
employed as a catalyst for the reactions with 2.2 M
amounts of triethylamine at room temperature (entries
2 and 4). PPYO, a derivative of DMAPO, was also proved
to be effective for the macrolactonization, and the desired
pentadecan-15-olide was produced in good yield (95%)
from 15-hydroxypentadecanoic acid at room temperature
(entry 3). As far as we know, the present method is the
first successful example utilizing pyridine 1-oxides for the
effective synthesis of macrolactones.15
Syn th esis of th e P r otected er yth r o-Aleu r itic Acid
La cton e. We further examined the effect of the substit-
uents on the aromatic moiety of the benzoic anhydrides
in our mixed anhydride method for the synthesis of a
functionalized macrocyclic molecule. For this purpose,
seco acid 24 was prepared from erythro-aleuritic acid
(erythro-9,10,16-trihydroxyhexadecanoic acid) by treating
with PhCH(OMe)2 and 10-camphorsulfonic acid (CSA).
In the presence of 2.4 M amounts of DMAP, the macro-
lactonization of 24 was then carried out with use of
dichloromethane for over a 15 h period at room temper-
ature, the corresponding monomeric lactone was obtained
in 65% yield accompanied by 6% diolide and 1% triolide
(entry 1). Though the yield of the desired pentadecan-
15-olide increased to 84% or 86% with 20 or 30 mol % of
DMAP, respectively, under the same reaction conditions,
the ratio of monomer to dimer was not satisfactory as
shown in entry 2 or 3. Furthermore, employing an excess
amount of triethylamine decreased the ratio to some
extent (entry 4). On the other hand, better product
selectivity was observed when a slight excess amount of
MNBA was used (entry 5). We finally used a stoichio-
metric amount of DMAP to MNBA in the absence of
triethylamine, and the desired monomeric lactone was
produced in high yield with an excellent selectivity (entry
6). In this case, DMAP works not only as an activator
for the dehydration condensation but also as a base to
generate the corresponding protonated pyridinium salt.
Table 8 shows the yields of the several macrolactones
synthesized by the present method with MNBA and
DMAP. All reactions were carried out at room temper-
ature by adding a solution of ω-hydroxycarboxylic acids
to a mixture of MNBA and DMAP in dichloromethane.
Each concentration in the table shows the molar amounts
of ω-hydroxycarboxylic acids to the total volume of the
dichloromethane solvent. Although a small amount of
diolide formed in the case of using 12-hydroxydodecanoic
acid as shown in entry 1, from 14- to 17-membered-ring
macrolactones were obtained in high yields and the
undesired dimers were scarcely produced (entries 3-5
and 7). Since the reaction rate was not sufficiently fast
when a secondary ω-hydroxycarboxylic acid was em-
ployed for the reaction, an excess amount of reagents was
required to produce the excellent product selectivity
(entry 2). It is also noted that this reaction could be
performed by the promotion of PPY, a derivative of
DMAP, as shown in entry 6.
(15) An effective phosphorylation was developed in 1985 using these
substituted pyridine 1-oxides as promoters with condensation reagents.
(a) Efimov, V. A.; Chakhmakhcheva, O. G.; Ovchinnikov, Yu. A. Nucleic
Acids Res. 1985, 13, 3651-3666. (b) Efimov, V. A.; Chakhmakhcheva,
O. G. Biochimie 1985, 67, 791-795. (c) Efimov, V. A.; Chakhmakh-
cheva, O. G. Chem. Scr. 1986, 26, 55-58. (d) Efimov, V. A.; Buryakova,
A. A.; Dubey, I. Y.; Polushin, N. N.; Chakhmakhcheva, O. G.;
Ovchinnikov, Yu. A. Nucleic Acids Res. 1986, 14, 6525-6540. (e)
Efimov, V. A.; Buryakova, A. A.; Polushin, N. N.; Dubey, I. Y.;
Chakhmakhcheva, O. G.; Ovchinnikov, Yu. A. Nucleosides Nucleotides
1987, 6, 279-282. See also, (f) Sekine, M. J . Synth. Org. Chem. J pn.
1990, 48, 1038-1039. For the synthesis of arylsulphanilides see: (g)
Savelova, V. A.; Solomoichenko, T. N.; Litvinenko, L. M. Zh. Org. Khim.
1972, 8, 1011-1018. (h) Savelova, V. A.; Belousova, I. A.; Litvinenko,
L. M.; Yakovets, A. A. Dokl. Akad. Nauk SSSR 1984, 274, 1393-1398.
Polymer-supported DMAPO was employed for the synthesis of phenyl
benzoate from phenol with benzoyl chloride. See: (i) Zitsmanis, A.;
Klyavinsh, M.; Skuyinsh, A.; J akobsone, I. React. Polym. 1989, 11,
227-236.
Next, we tried to investigate other activators for the
present reaction to improve the efficiency for producing
the desired compounds with a higher ratio of monomers
to dimers. After screening several basic compounds
J . Org. Chem, Vol. 69, No. 6, 2004 1827

Shiina et al.
TABLE 10. Effect of Su bstitu ted Ben zoic An h yd r id es
for th e Syn th esis of th e P r otected er yth r o-Aleu r itic Acid
La cton e (Stoich iom etr ic)
TABLE 12. Syn th esis of th e P r otected er yth r o-Aleu r itic
Acid La cton e w ith MNBA u n d er Sever a l Con d ition s
yielda/%
yielda/%
entry
reagents
conc time/h monomer dimer
entry
Xn
monomer
dimer
1b
2c
3d
DMAP (2.4 eq.)
DMAP (2.4 eq.)
DMAPO (20 mol %),
Et3N (2.2 eq.)
DMAPO (20 mol %),
Et3N (2.2 eq.)
i
ii
iii
16
9
16
90
83
90
2
1
2
1
2
3
4
5
6
7
8
9b
H
77
71
29
83
83
76
79
90
87
4
8
6
3
4
3
2
2
3
4-Me
4-MeO
4-Cl
4c
ii
9
79
<1
4-NO2
4-CF3
2,4,6-Cl3
2-Me-6-NO2
2-Me-6-NO2
a
b
Isolated yield. A solution of 24 (0.380 mmol) in dichlo-
romethane (84.6 mL) was slowly added to a solution of reagents
in dichloromethane (135.8 mL). c A solution of 24 (0.360 mmol) in
dichloromethane (180.0 mL) was slowly added to a solution of
a
b
Isolated yield. PPY was used as a base.
d
reagents in dichloromethane (36.0 mL). A solution of 24 (0.360
mmol) in dichloromethane (108.0 mL) was slowly added to a
solution of reagents in dichloromethane (151.0 mL).
TABLE 11. Effect of Su bstitu ted Ben zoic An h yd r id es
for th e Syn th esis of th e P r otected er yth r o-Aleu r itic Acid
La cton e (Ca ta lytic)
TABLE 13. Syn th esis of th e P r otected er yth r o-Aleu r itic
Acid La cton e w ith 2,4,6-Tr ich lor oben zoyl Ch lor id e u n d er
Sever a l Con d ition s
yielda/%
entry
Xn
monomer
dimer
1
2
3
4
5
6
7
8
9b
H
4-Me
4-MeO
4-Cl
4-NO2
4-CF3
2,4,6-Cl3
2-Me-6-NO2
2-Me-6-NO2
60
48
24
62
43
53
64
69
90
8
8
4
<1
2
4
6
6
2
yielda/%
entry
conc
temp/°C
time/h
monomer
dimer
1b
2c
3b
4c
i
ii
i
rt
rt
120
120
16
9
16
9
33
52
43
70
3
5
6
9
a
b
ii
Isolated yield. 20 mol % of DMAPO was used as a catalyst.
Isolated yield. b A solution of MA derived from 24 (0.360 mmol)
in toulene (84.6 mL) was slowly added to a solution of DMAP (2.16
mmol) in toulene (135.8 mL). c A solution of MA derived from 24
(0.360 mmol) in toulene (36.0 mL) was slowly added to a solution
of DMAP (2.16 mmol) in toulene (180.0 mL).
a
several substituted benzoic anhydrides (Table 10). Al-
though 4-methoxybenzoic anhydride afforded a poor
result as shown in entry 3, other anhydrides such as
benzoic or 4-methyl-, 4-chloro-, 4-nitro-, 4-trifluorom-
ethyl-, and 2,4,6-trichlorobenzoic anhydrides gave similar
yields of the desired monomer 25 (71-83%) and dimer
(2-8%) (entry 1 or entries 2 and 4-7). From the point of
view concerning the commercial economy, the use of
cheap benzoic anhydrides is also one of the convenient
ways to produce the desired compounds, for example, a
simple benzoic anhydride could be utilized for the forma-
tion of 25 in relatively good yield (77%).
The best yield of 25 and product selectivity of the
monomer to the dimer was attained again for the
macrolactonization of 24 using MNBA with 2.4 M amounts
of DMAP (entry 8). When PPY was used for the reaction
under the same conditions as entry 8, 25 was also
obtained in 87% yield (entry 9). Facile deprotection of
25 with acetic acid produced the erythro-aleuritic acid
lactone in 93% yield.
1828 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Carboxylic Esters and Lactones
F IGURE 3. Synthesis of the eight-membered-ring lactones with MNBA or dipyridyl disulfide.
Furthermore, the catalytic reaction accelerated by 20
mol % of DMAP was carried out using several substituted
benzoic anhydrides as listed in Table 11. It was found
that the reaction using MNBA with triethylamine and a
catalytic amount of DMAP afforded the best yield of 25
(entry 8) compared to the cases when using other benzoic
anhydrides (entries 1-7). As shown in entry 9, the
DMAPO-promoted cyclization cleanly took place to pro-
duce 25 in 90% yield under the influence of triethylamine.
To compare the efficiency of our new protocols with
other mixed anhydride methods, the macrolactonization
of 24 was further examined. These data are summarized
in Tables 12 and 13. Although the MNBA method
provided excellent results at room temperature under the
optimized conditions as shown in entries 1 and 3 in Table
12 (90% yield), the desired lactone 25 was obtained in
moderate yield with lower product selectivity by the
Yamaguchi protocol at the same temperature (Table 13,
entry 2). The yield increased to 70% when the reaction
was carried out at refluxing temperature in toluene
according to the originally optimized procedure (Table
13, entry 4),4a but the product selectivity is not sufficient
for producing 25 with high purity. These reactions were
carried out again at room temperature under strictly
identified conditions such as the concentrations (i and
ii) of the substrate and reagents (compare entry 1 in
Table 12 with entry 1 in Table 13; entries 2 and 4 in
Table 12 with entry 2 in Table 13). In every case, the
benzoic anhydride method with MNBA gave better yields
in comparison with the reaction using 2,4,6-trichloro-
benzoyl chloride.
ety, and octalactin A exhibits a potent cytotoxic activity
against some tumor cell lines.
Next, the lactonization of a seco-acid 26, a synthetic
intermediate of octalactins, was attempted by the present
mixed anhydride method with use of MNBA in the
presence of DMAP.18 The cyclization reaction of 26 was
efficiently accelerated by MNBA with DMAP to afford
the desired lactone 28 in 84% yield at room temperature,
and the corresponding diolide was not produced (Figure
3). Buszek et al. successfully synthesized an eight-
membered-ring lactone 29 from the corresponding seco-
acid 27, which has the PMBO group instead of the BnO
group at the C3 position of 26 via formation of the
intermediary S-Py ester in refluxed toluene.17a,19 It was
reported that the cyclization of the S-Py ester requires a
long reaction time such as 96 h even in the presence of a
(17) Total syntheses: (a) Buszek, K. R.; Sato, N.; J eong, Y. J . Am.
Chem. Soc. 1994, 116, 5511-5512. (b) McWilliams, J . C.; Clardy, J . J .
Am. Chem. Soc. 1994, 116, 8378-8379. (c) Buszek, K. R.; Sato, N.;
J eong, Y. Tetrahedron Lett. 2002, 43, 181-184. Formal syntheses: (d)
Buszek K. R.; J eong, Y. Tetrahedron Lett. 1995, 36, 7189-7192. (e)
Kodama, M.; Matsushita, M.; Terada, Y.; Takeuchi, A.; Yoshio, S.;
Fukuyama, Y. Chem. Lett. 1997, 117-118. (f) Inoue, S.; Iwabuchi, Y.;
Irie, H.; Hatakeyama, S. Synlett 1998, 735-736. Partial syntheses:
(g) Andrus, M. B.; Argade, A. B. Tetrahedron Lett. 1996, 37, 5049-
5052. (h) Bach, J .; Garcia, J . Tetrahedron Lett. 1998, 39, 6761-6764.
Other synthetic studies: (i) Bach, J .; Berenguer, R.; Garcia, J .;
Vilarrasa, J . Tetrahedron Lett. 1995, 36, 3425-3428. (j) Hulme, A. N.;
Howells, G. E. Tetrahedron Lett. 1997, 38, 8245-8248. (k) Shimoma,
F.; Kusaka, H.; Wada, K.; Azami, H.; Yasunami, M.; Suzuki, T.;
Hagiwara, H.; Ando, M. J . Org. Chem. 1998, 63, 920-929. (l) Harrison,
J . R.; Holmes, A. B.; Collins, I. Synlett 1999, 972-974. (m) Anderson,
E. A.; Holmes, A. B.; Collins, I. Tetrahedron Lett. 2000, 41, 117-121.
(n) Bluet, G.; Campagne, J .-M. Synlett 2000, 221-222.
(18) Shiina, I.; Oshiumi, H.; Hashizume, M.; Yamai, Y.; Ibuka, R.
Tetrahedron Lett. 2004, 45, 543-547.
Syn th esis of th e Eigh t-Mem ber ed -Rin g La cton e
Moiety of Octa la ctin s A a n d B. Octalactins A and B
were isolated from the marine bacterium Streptomyces
sp. in 1991.16,17 The structure of these compounds in-
cludes an unusual saturated medium-sized lactone moi-
(19) (a) Buszek, K. R.; J eong, Y.; Sato, N.; Still, P. C.; Muino, P. L.;
Ghosh, I. Synth. Commun. 2001, 31, 1781-1791. Original S-Py ester
methods for the synthesis of macrolactones: (b) Corey, E. J .; Nicolaou,
K. C. J . Am. Chem. Soc. 1974, 96, 5614-5616. (c) Gerlach, H.;
Thalmann, A. Helv. Chim. Acta 1974, 57, 2661-2663. (d) Corey, E. J .;
Brunelle, D. J . Tetrahedron Lett. 1976, 17, 3409-3412. See also the
synthesis of unsaturated eight-membered-ring lactones: (e) Nicolaou,
K. C.; McGarry, D. G.; Somers, P. K.; Kim, B. H.; Ogilvie, W. W.;
Yiannikouros, G.; Prasad, C. V. C.; Veale, C. A.; Hark, R. R. J . Am.
Chem. Soc. 1990, 112, 6263-6276.
(16) (a) Tapiolas, D. M.; Roman, M.; Fenical, W.; Stout, T. J .; Clardy,
J . J . Am. Chem. Soc. 1991, 113, 4682-4683. (b) Macrolide Antibiotics,
2nd ed.; Omura, S., Ed.; Academic Press: San Diego, CA, 2002.
J . Org. Chem, Vol. 69, No. 6, 2004 1829

Shiina et al.
silver salt as an accelerator. Therefore, we examined the
S-Py ester method for the cyclization of 26 again under
similar reaction conditions according to the reported
procedure. The desired lactone 28 was also produced in
satisfactory yield after 96 h; however, the macrolacton-
ization sluggishly proceeded in refluxed toluene with the
silver salt catalyst. When the reaction was carried out
at room temperature, the target molecule 28 was not
produced at all. On the other hand, it is noteworthy that
the MNBA method gives the desired lactone in higher
yield at ambient temperature within a shorter time.
Thus, an efficient method for the preparation of the
synthetic precursor of octalactins was established via the
effective construction of the eight-membered-ring lactone
moiety.18
from ω-hydroxycarboxylic acids and MNBA with basic
catalysts was established.20 One of the features of the
present protocol is the very simple procedure for produc-
ing the desired products, that is, the addition of ω-hy-
droxycarboxylic acids to the mixture of MNBA and the
promoters at room temperature affords the desired
macrolactones in excellent yields with high purity. The
utility of the present protocol was also demonstrated by
the syntheses of erythro-aleuritic acid lactone and the
eight-membered-ring lactone moiety of octalactins A and
B.
Ack n ow led gm en t. The author is grateful to Dr.
Ryoutarou Ibuka for his cooperation. This study was
partially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science,
Sports and Culture, J apan.
Con clu sion
An efficient method for the synthesis of various car-
boxylic esters from nearly equimolar amounts of car-
boxylic acids and alcohols with MNBA as the dehydrating
reagent by the promotion of a catalytic amount of DMAP
in the presence of triethylamine was successfully devel-
oped. Furthermore, a convenient and powerful method
for the synthesis of a variety of macrolactones with high
product selectivities via mixed anhydrides generated
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic data. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O030367X
(20) Quite recently, the MNBA method was applied to the synthesis
of patulolide C, a natural macrolactone. Tian, J .; Yamagiwa, N.;
Matsunaga, S.; Shibasaki, M. Org. Lett. 2003, 5, 3021-3024.
1830 J . Org. Chem., Vol. 69, No. 6, 2004