5696
D. H. Kang et al. / Tetrahedron Letters 47 (2006) 5693–5696
Br3CCO2Et (2 equiv),
PPh3 (2 equiv)
O
O
tBuNH2 (1 equiv)
N
Et3N (3 equiv), rt, 1 h
OH
CH2Cl2, rt, 3 h
H
98%
Scheme 1.
summarized in Table 2. The reaction of aromatic car-
boxylic acids with electron-donating groups such as p-
tert-butylbenzoic acid and p-methoxybenzoic acid at
room temperature afforded the corresponding amide in
91% and 90% yield, respectively (entries 1 and 2). The
reaction also proceeded efficiently with a slightly deacti-
vated aromatic carboxylic acid such as p-chlorobenzoic
acid (entry 3). However, the yields of amide decreased
with aromatic carboxylic acids that have electron-with-
drawing groups, indicating that the key step for the pro-
cess is the reaction of carboxylic acid with the
phosphonium bromide intermediate (entries 4–6). Het-
eroaromatic carboxylic acids such as furan-2-carboxylic
acid and thiophene-2-carboxylic acid produced amides
in high yields (entries 7 and 8). a,b-Unsaturated carbox-
ylic acids were not good substrates under the reaction
conditions and afforded poor yields of amide (entries
10 and 11), although a moderate yield of amide was ob-
tained with trans-cinnamic acid (entry 9). Aliphatic car-
boxylic acids were also found to be less reactive than
aromatic carboxylic acids under the reaction conditions
(entry 12).
of Br3CCO2Et (650 mg, 2.0 mmol) and PPh3
(524 mg, 2.0 mmol) in CH2Cl2 (2 mL). The mixture
was stirred at room temperature for 3 h. Et3N
(0.42 mL, 3.0 mmol) and cyclohexylamine (0.12 mL,
1.0 mmol) were added subsequently, and after stirring
for 1 h at room temperature, the mixture was diluted
with CH2Cl2, washed with water and dried over anhy-
drous MgSO4. After evaporation, the residue was
purified by column chromatography on silica gel elut-
ing with hexane:EtOAc (8:2) to give N-cyclohexyl
benzamide (204 mg, 90%): mp 148–149 °C (lit.6
147 °C); IR (KBr) 3315, 2936, 2852, 1627, 1535,
1489, 1446, 1330 cmÀ1 1H NMR (CDCl3) d 1.12–
;
2.03 (m, 10H), 3.88–4.02 (m, 1H), 6.03 (br, 1H),
7.24–7.75 (m, 5H); MS m/z (relative intensity) 203
(M+, 51), 122 (77), 105 (100), 77 (42).
Acknowledgments
This work was supported by Joint Research Project
under the KOSEF-NRCT cooperative program (F01-
2004-000-10252-0) and CBMH.
We next investigated the generality of our process by
varying the structure of amines at the second step. The
results are summarized in Table 3. The reaction of
p-methoxybenzoic acid with secondary amines under
the reaction conditions afforded high yields of the corre-
sponding amides (entries 1–4). And the amides were ob-
tained in high yields when weakly nucleophilic amines
such as aniline, 1-naphthylamine, and 1,2,3,4-tetrahy-
droquinoline were used as nucleophiles (entries 5–7).
Moreover, the reaction with sterically hindered amines
was also achieved. When the reaction was performed
References and notes
1. (a) The Chemistry of Acyl Halides; Patai, S., Ed.; Inter-
science: New York, 1972; (b) Larock, R. C. Comprehensive
Organic Transformations; VCH: New York, 1989.
2. Benz, G. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 6, pp
381–418.
3. (a) Villeneuve, G. B.; Chan, T. H. Tetrahedron Lett. 1997,
38, 6489; (b) Azumaya, I.; Okamoto, T.; Imabeppu, F.;
Takayanagi, H. Tetrahedron 2003, 59, 2325.
t
with BuNH2, a high yield of the amide was obtained
(entry 8).
4. (a) Coulson, E. A. J. Chem. Soc. 1934, 1406; (b) Burton, T.
M.; Degering, E. F. J. Am. Chem. Soc. 1940, 62, 227; (c)
Devos, A.; Remion, J.; Frisque-Hesbain, A.-M.; Colens,
A.; Ghosez, L. J. Chem. Soc., Chem. Commun. 1979, 1180;
(d) Aizpurua, J. M.; Palomo, C. Synthesis 1982, 684; (e)
Bains, S.; Green, J.; Tan, L. C.; Pagni, R. M.; Kabalka, G.
W. Tetrahedron Lett. 1992, 33, 7475; (f) Fryeyen, P.
Phosphorus, Sulfur Silicon Relat. Elem. 1995, 102, 253; (g)
Matveeva, E. D.; Podrugina, T. A.; Sandakova, N. G.;
Zefirov, N. S. Russ. J. Org. Chem. 2004, 40, 1469.
5. (a) Jang, D. O.; Park, D. J.; Kim, J. Terahedron Lett. 1999,
We also carried out the reaction of sterically hindered
carboxylic acid, pivalic acid, with sterically hindered
amine, BuNH2, under the present conditions to give
t
98% yield of the corresponding amide (Scheme 1).
In conclusion, we developed a method of preparing acid
bromides from carboxylic acids with readily available
Br3CCO2Et and PPh3 under mild and neutral condi-
tions. The present process is not only easy to perform
but also has other advantages such as neutral reaction
conditions and low toxicity of the reagents.
´
40, 5323; (b) Girard, C.; Tranchant, I.; Niore, P.-A.;
´ ´
Herscovici, J. Synlett 2000, 1577; (c) Vago, I.; Greiner, I.
Tetrahedron Lett. 2002, 43, 6039.
6. Cannon, G. W.; Grebber, K. K.; Hsu, Y. J. Org. Chem.
1953, 18, 516.
A typical experimental procedure is as follows: Benz-
oic acid (122 mg, 1.0 mmol) was added to a mixture