D. H. Cho, D. O. Jang / Tetrahedron Letters 45 (2004) 2285–2287
2287
a
Table 2. Preparation of dipeptides from a-amino acids
Acknowledgements
b
Entry Acyl halide
Peptide
Time (h) Yield (%)
This work was supported by Center for Bioactive
Molecular Hybrids at Yonsei University.
1
2
3
4
5
Fmoc-Ala-Cl
Fmoc-Phg-Cl
Fmoc-D-Phg-Cl
Leu-OMe
Phe-OMe
Phe-OMe
Leu-OMe
Pro-OMe
6
10
9
81
85
88
85
75
Fmoc-Phe-Cl
Fmoc-Pro-Cl
9
12
References and notes
a
All the products were reported previously in the literature.
Isolated yields.
b
1
2
. Benz, G. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 6, pp 381–
4
18.
. Villeneuve, G. B.; Chan, T. H. Tetrahedron Lett. 1997, 38,
489.
In summary, we have demonstrated a novel and facile
method for the synthesis of amides by using indium
metal as a promoter under mild and neutral reaction
conditions. The reaction was used for the preparation of
peptides with no epimerization and deblocking pro-
tecting groups detected during the reaction. The
advantages of the present method include high yields of
products, simple experimental procedure, nontoxicity of
the reagent, no need for dry solvent and no pretreatment
of metal promoter.
6
3. (a) Haver, A. C.; Smith, D. D. Tetrahedron Lett. 1993, 34,
2239; (b) Miyazawa, T.; Otomatsu, T.; Yamada, T.;
Kuwata, S. Tetrahedron Lett. 1984, 25, 771; (c) Gamet, J.
P.; Jacquier, R.; Verducci, J. Tetrahedron 1984, 40, 1995;
(
d) Arendt, A.; Kolodziejczyk, A. M.; Sokolowska, T.
Tetrahedron Lett. 1978, 19, 2711; (e) Zimmerman, J. E.;
Anderson, G. W. J. Am. Chem. Soc. 1967, 89, 7151.
4
. For examples for the synthesis of amides from acyl
chlorides, see: (a) V ꢀa g oꢀ , I.; Greiner, I. Tetrahedron Lett.
2
002, 43, 6039; (b) Girard, C.; Tranchant, I.; Nior ꢀe , P.-A.;
Herscovici, J. Synlett 2000, 1577; (c) Jang, D. O.; Park,
D. J.; Kim, J. Tetrahedron Lett. 1999, 40, 5323.
General procedure for preparation of amides (repre-
sentive example): To a mixture of Fmoc-Ala-Cl (93 mg,
0
.28 mmol) and In (32 mg, 0.28 mmol) in CH CN (1 mL)
3
5. (a) Chen, F. M. S.; Stainauer, R.; Benoiton, N. L. J. Org.
Chem. 1983, 48, 2939; (b) Bodanszky, M.; Bodanszky, A. J.
Chem. Soc., Chem. Commun. 1967, 591; (c) Bodanszky, M.;
Conklin, L. J. Chem. Soc., Chem. Commun. 1967, 773.
was added a solution of Leu-OMe (41 mg, 0.28 mmol) in
CH
mixture was stirred for 6 h (monitored by TLC), filtered
through a sintered glass packed with Celite. The solu-
tion was washed with water and dried over anhydrous
MgSO
product, which was purified with flash column chro-
matography on silica gel (CH Cl /MeOH, 12:1) to fur-
nish the peptide Fmoc-Ala-Leu-OMe (100 mg, 81%),
which is in full agreement with physical and spectral
data of authentic sample. Fmoc-Ala-Leu-OMe: mp 123–
3
CN (1 mL) under stirring at 20 °C. The reaction
6
. (a) Minemo, T.; Choi, S.-R.; Avery, M. A. Synlett 2002,
83; (b) Ranu, B. C.; Samanta, S.; Das, A. Tetrahedron
8
Lett. 2002, 43, 5993; (c) Chauhan, K. K.; Frost, C. G. J.
Chem. Soc., Perkin Trans. 1 2000, 2015; (d) Ranu, B. C.
Eur. J. Org. Chem. 2000, 2343; (e) Li, C.-J.; Chan, T.-H.
Tetrahedron 1999, 55, 11149; (f) Li, C.-J. Tetrahedron 1996,
52, 5643; (g) Cintas, P. Synlett 1995, 1087; (h) Li,
C.-J. Chem. Rev. 1993, 93, 2023.
4
. Evaporation of the solvent produced the crude
2
2
7. Jang, D. O.; Cho, D. H. Synlett 2002, 631.
8a
25
D
8a
8
. For examples for the synthesis of amides using activated
zinc, see: (a) Gopi, H. N.; Suresh Babu, V. V. Tetrahedron
Lett. 1998, 39, 9769; (b) Meshram, H. M.; Reddy, G. S.;
Reddy, M. M.; Yadav, J. S. Tetrahedron Lett. 1998, 39,
1
26 °C (lit. 125–127 °C); ½a )25.2° (c 1, CHCl
3
) (lit.
2
5
1
½
a )28.6° (c 1, CHCl
3 3
); H NMR (CDCl ) d 0.91 (s,
D
6
2
H), 1.41 (d, J ¼ 2:3 Hz, 3H), 1.54 (m, 1H), 1.64 (m,
H), 3.72 (s, 3H), 4.22 (t, J ¼ 2:4 Hz, 1H), 4.29 (t,
4
103.
. (a) Ishihara, K.; Kubota, M.; Yamamoto, H. Synlett 1996,
65; (b) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamam-
J ¼ 2:2 Hz, 1H), 4.40 (d, J ¼ 2:3 Hz, 2H), 4.61 (q,
9
J ¼ 1:6 Hz, 1H), 5.43 (br, 1H), 6.38 (br, 1H), 7.27–7.79
2
13
(
3
m, 8H); C NMR (CDCl ) d 18.8, 22.1, 23.0, 25.1,
oto, H. J. Am. Chem. Soc. 1995, 117, 4413; (c) Cardillo, G.;
Simone, A. D.; Mingardi, A.; Tomasini, C. Synlett 1995,
1131.
4
1
1.8, 47.4, 51.1, 52.5, 67.4, 120.2, 125.3, 127.3, 128.0,
41.5, 144.0, 156.1, 172.2, 173.3.