K. Bahrami et al. / Tetrahedron Letters 54 (2013) 5064–5068
5065
Table 1
Condensation of carboxylic acids with different alcohols promoted by TAPCa
O
C
R
COOH
R' OH
+
R
OR'
Entry
R
R0
C6H5CH2–
4-Cl-C6H4CH2–
4-O2N-C6H4CH2–
n-Bu
(C6H5)2CH–
C6H5CH2–
C6H5CH2–
C6H5CH2–
4-O2N-C6H4CH2–
C6H5CH2–
4-MeO-C6H4–
C6H5CH2–
C6H5CH2–
Product
Yieldb (%)
Time (min)
Mp (°C) (Lit mp)
Ref.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
C6H5–
C6H5–
C6H5–
C6H5–
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
92
90
90
83
0
90
90
90
95
90
93
90
85
90
5
5
7
15
40
13
15
30
30
5
Oil (oil)
3b
3c
3d
3e
—
3b
3b
3b
4b
3b
4c
5b
3b
20
59–60 (58–58.5)
89–90 (90–91)
Oil (oil)
C6H5–
—
4-Cl-C6H4–
4-Br-C6H4–
4-O2N-C6H4–
4-O2N-C6H4–
4-MeO-C6H4–
4-MeO-C6H4–
C6H5-CH@CH2–
2-Furyl
Oil (25–26)
50–51 (52–53)
81–82 (82–83)
167–168 (169–171)
Oil (oil)
Oil (oil)
37–39 (38–39)
Oil (oil)
5
10
10
8
CH3–
4-O2N-C6H4CH2–
76–78 (77–79)
a
The products were characterized by comparison of their spectroscopic and physical data with authentic samples synthesized by reported procedures.
Yields refer to pure isolated products.
b
Under these optimized conditions, the generality and scope of
procedures for the synthesis of amide derivatives in terms of oper-
ational simplicity and economic viability.
the procedure was assessed with a panel of carboxylic acids and
the results are summarized in Table 1. The present procedure is
general as a wide range of carboxylic acids including aromatic
and aliphatic examples reacted easily with electronically diverse
benzyl alcohols under mild conditions to afford the desired esters
3a–n11 in 83–95% yields. Aromatic carboxylic acids substituted
with electron-donating groups (Table 1, entry 10) reacted faster
than those with electron-withdrawing groups (Table 1, entries 6–
9). Both electron-rich and electron-poor benzylic alcohols gave
excellent yields of the corresponding esters. This procedure could
also be applied for the conversion of primary aliphatic alcohols into
their corresponding esters (Table 1, entry 4).
These substrates were converted selectively into their corre-
sponding esters without undergoing further transformations of
the functional groups in the products. For example, with cinnamic
acid, no hydrochlorination of the double bond was observed, and
only the corresponding ester was obtained in excellent yield (Ta-
ble 1, entry 12). Furan-2-carboxylic acid was reacted without the
formation of any side products, which are normally observed in
the presence of protic or Lewis acids (Table 1, entry 13).
We also examined acetic acid, as an aliphatic carboxylic acid,
which reacted similar to aromatic acids (Table 1, entry 14).
Nevertheless, this protocol has its limitations. Diphenylmetha-
nol, a secondary alcohol, was resistant to esterification, probably
due to steric effects (Table 1, entry 5). Amides are important as
pharmaceuticals12a as well as agrochemicals.12b The preparation
of amides from their corresponding carboxylic acids is a well-
known transformation in the organic synthesis.13,14 In general,
the formation of carboxamides from carboxylic acids requires acti-
vation of the carboxyl group. Carboxylic acid activation can be
achieved either by conversion into more reactive functional groups
such as acyl halide, anhydride, and acyl azide or by in situ activa-
tion with coupling reagents including N,N0-dicyclohexylcarbodiim-
ide (DCC),15 TiCl4,16 Cl3CCN/Ph3P,17 ArB(OH)2,18 and Lawesson’s
reagent.19
We report here the preparation of amides from carboxylic acids
and amines in the presence of TAPC as an effective promoter,
employing a solvent-free grinding technique (Scheme 2).
Initially, we studied the catalytic efficiency of different amounts
of TAPC in a model reaction using benzoic acid and aniline using
the solvent-free grinding technique. In terms of yields and reaction
time, the best conditions utilized a 1:1:0.5 mol ratio of the carbox-
ylic acid, amine, and TAPC. Moreover, we also found that excess
catalyst did not increase the yield.
Having established optimized reaction conditions, we then suc-
cessfully synthesized a range of amide derivatives 5a–p21 in 85–
98% yields and the results are summarized in Table 2.
Carboxylic acids, with electron-donating or electron-withdraw-
ing groups reacted smoothly to afford the corresponding amides in
excellent yields. Naphthalen-1-carboxylic acid reacted well with 4-
methylaniline to give the corresponding amide in 93% yield (Ta-
ble 2, entry 11). An excellent chemoselectivity was observed for
a,b-unsaturated substrates (Table 2, entries 9 and 10) without
any competitive conjugate addition. Interestingly, the presence of
ether, carboxyl, and thiol groups (Table 2, entries 5–7) did not
interfere with the condensation process.
We also explored a range of amines as substrates for the amide
formation. An aromatic amine and primary aliphatic amine (Ta-
ble 2, entry 15) were successfully converted into an amide. How-
ever, the use of piperidine (Table 2, entry 16), afforded none of
the expected amide, presumably due to steric reasons.
A proposed mechanism for the esterification and amidation
reactions is shown in Scheme 3. Nucleophilic attack of the carbox-
ylic acid (1) on TAPC leads to the intermediate (6). Next, nucleo-
philic attack of the alcohol or amine derivative on this
intermediate produces the corresponding product (3 or 5) and
by-product (7) as a new promoter which reacts with carboxylic
All of these methods have some degree of general applicability
but most are associated with several drawbacks such as expensive
and hazardous reagents, tedious experimental procedures, harsh
reaction conditions, long conversion times, incompatibility with
other functionalities in the molecules, the use of organic solvents,
and difficult work-ups. Hence, there is a need to develop better
O
TAPC
R
COOH
1
R' NH2
4
R
C
5
NHR'
+
grinding, r.t.
R, R' = alkyl, aryl
Scheme 2. The synthesis of various amides.