Yamaguchi esterification conditions as a template, new
procedures making use of aromatic anhydrides instead of
the acid chlorides in the presence of Lewis acids have been
reported.7-11 An adapted protocol making use of aromatic
anhydrides and DMAP as coupling agents was also re-
ported.12 In all of these cases, the in situ synthesis of a mixed
aliphatic-aromatic anhydride was assumed.7-12 The Yamagu-
chi esterification involves the reaction of an aliphatic acid
with 2,4,6-trichlorobenzoyl chloride to form the mixed
aliphatic-2,4,6-trichlorobenzoyl anhydride.13 The isolated
mixed anhydride, upon reaction with an alcohol, in the
presence of DMAP, produces the aliphatic ester regioselec-
tively. The mixed anhydrides with sterically hindered
aromatic counterparts were thought to ensure the regiose-
lective synthesis of the corresponding ester. This line of logic
initially was advanced by Yamaguchi and co-workers in their
original publication.13 However, during the selection of the
appropriate acid chloride, Yamaguchi and co-workers as-
sumed that upon the reaction of a carboxylic aliphatic acid
with an aromatic acid chloride the mixed anhydride would
be formed exclusively (Scheme 1). Investigation of the mixed
Table 1. Reaction of Aromatic Acid Chlorides with Water in
the Presence of Triethylamine or Pyridine
entry
acid chloride
benzoyl
product
min (a/b) % (a/b)
1
2
3
4
5
6
7
anhydride
anhydride
anhydride
anhydride
anhydride
acid
20/60
15/60
10/60
120b
5/30
85/97
83/96
78/98
99
78/99
99
p-toluoyl
p-nitrobenzoyl
p-methoxybenzoyl
2-furoyl
2,6-dichlorobenzoylc
18 h
2,4,6-trichlorobenzoylc acid
18 h
99
a The acid chloride was dissolved in pyridine at room temperature, stirred
to allow the formation of the pyridinium complex, and quenched with excess
water. The precipitate was filtered to afford the pure solid product. b Acid
chloride, TEA, and 0.5 equiv of water were dissolved in acetone. When
the reaction was completed, triethylammonium chloride was filtered, and
washed with acetone. Acetone was evaporated to afford the pure product.
c The reaction was performed as described in (b). The residue was partitioned
between water and ethyl acetate. The organic phase was dried and evaporated
to afford the product.
the corresponding carboxylic acids (Table 1, entries 6 and
7). Intially, the acylammonium complex reacts with water
to form the aromatic carboxylate. The unhindered carboxylate
formed in situ must react faster with the acylammonium
complex than water, thus leading to the formation of the
anhydrides. However, in the case of hindered acylammonium
complexes, the hindered acid salt formed in situ does not
react with the remaining acylammonium complex, most
probably due to steric hindrance (Scheme 2).
Scheme 1. Yamaguchi Esterification
Scheme 2. Reaction of Unhindered Acylammonium
Complexes with Water
anhydride formation led us to postulate a different mecha-
nism.
While optimizing the synthesis of several aromatic anhy-
drides, we observed that acyl-pyridinium or triethylammo-
nium salts of 2,6-substituted benzoyl chlorides react differ-
ently compared to unhindered ones.14 The acid chlorides were
chosen from literature examples to compare the advantage
of using equivalent amounts of substrates in acetone. In the
case of unhindered acid chlorides, the data indicate that even
for reactive anhydrides our procedure works well, without
need for extensive purification (Table 1).
To our surprise, upon quenching with excess water, the
unhindered aromatic acid chlorides afforded the correspond-
ing anhydrides instead of the acids (Table 1, entries 1-5).
The 2,6-disubstituted benzoyl chlorides afforded exclusively
These findings prompted us to investigate the reaction of
propionic acid with various aromatic acid chlorides. The acid
chlorides were reacted with 1 equiv of propionic acid in the
presence of triethylamine (Table 2). In the case of the
Yamaguchi acid chloride, the reaction, according to chro-
matographic analysis, proceeded very slowly at room tem-
perature without reaching completion. After 16 h, propionic
anhydride, propionic acid, and 2,4,6-trichlorobenzoic acid
were isolated. There was very little (less than 1%) mixed
anhydride detectable by NMR in the reaction mixture.
However, benzoyl chloride and p-toluoyl chloride gave a
mixture of symmetric aromatic, symmetric aliphatic, and
mixed anhydride in quantitative overall yield (Table 2).
The following reaction pathway was postulated on the
basis of the fact that aliphatic carboxylates are more reactive
than aromatic ones (Scheme 3).
(7) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Am. Chem.
Soc. 1995, 117, 4413.
(8) Ishihara, K.; Kubota, M.; Yamamoto, H. Synlett 1996, 265.
(9) Shiina, I.; Miyoshi, S.; Miyashita, M.; Mukaiyama, T. Chem. Lett.
1994, 515.
(10) Shiina, I.; Mukaiyama, T. Chem. Lett. 1994, 677.
(11) Shiina, I.; Miyashita, M.; Mukaiyama, T. Chem. Lett. 1992, 625.
(12) Shiina, I. Tetrahedron 2004, 60, 1587.
(13) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 7, 1989.
Propionic carboxylate should be more reactive toward the
aliphatic moiety of the mixed anhydride formed by 2,4,6-
(14) Dhimitruka, I.; SantaLucia, J., Jr. Synlett 2004, 335.
48
Org. Lett., Vol. 8, No. 1, 2006