LETTER
Direct Synthesis of Acyl Azides from Carboxylic Acids
2073
H
ylic acids afforded higher yields of acyl azides. Carbox-
ylic acids with an electron-releasing group or electron-
withdrawing group were readily converted into acyl
azides in high yields. This method is found to be very
mild, efficient, and general for the transformation of car-
boxylic acids into the corresponding acyl azides without
the Curtius rearrangement.
H
Cl3CCN, PPh3, NaN3
acetone, r.t., 2 h, 86%
N3
OH
FmocHN
FmocHN
O
O
N-Fmoc-L-Ala-N3
H
2,4,6-collidine,
CH2Cl2, r.t., 24 h
82%
OMe
H3N
Cl
Table 2 Formation of Various Acyl Azides from Carboxylic Acidsa
O
Entry Acid
Time
(h)
Yield of azide
(%)
O
H
H
N
OMe
FmocHN
1
2
p-methylbenzoic acid
0.5
0.5
0.5
0.5
0.5
0.5
2.0
0.5
0.5
1.0
2.0
2.0
2.0
2.0
2.0
1.0
2.0
2.0
2.0
94
93
89
97
90
91
82
93
89
89
83
84
86
88
87
83
81
89
87
H
O
p-(dimethylamino)benzoic acid
p-chlorobenzoic acid
p-methoxybenzoic acid
p-nitrobenzoic acid
p-acetylbenzoic acid
salicylic acid
N-Fmoc-Ala-Leu-OMe
3
Scheme 2
4
5
ble to the preparation of dipeptide without deprotection or
rearrangement during the reaction.
6
7
Acknowledgment
8
2-naphthoic acid
This work was supported by the Center for Bioactive Molecular Hy-
brids.
9
nicotinic acid
10
11
12
13
14
15
16
17
18
19
phthalimidoacetic acid
3-phenylpropionic acid
trimethylacetic acid
n-octanoic acid
References and Notes
(1) (a) Lowski, W. In Azides and Nitrenes; Scriven, E. F. V.,
Ed.; Academic: Orlando, 1984, 205–246. (b) Moore, H. W.;
Goldfish, D. M. In The Chemistry of Halides, Pseudo-
Halides and Azides, Vol. 1; Patai, S.; Rappoport, Z., Eds.;
Wiley: Chichester, 1983, 321–368. (c) Patai, S. The
Chemistry of the Azido Group; Wiley Interscience:
Chichester, 1971, 397–405.
(2) (a) Jones, J. The Chemical Synthesis of Peptides; Clarendon
Press: Oxford, 1991. (b) Meienhofer, J. The Peptides, Vol.
1; Academic Press: New York, 1979. (c) Vommina, V.;
Suresh Babu, V. V. S.; Ananda, K.; Vasanthakumar, G.-R.
J. Chem. Soc., Perkin Trans. 1 2000, 4328.
(3) (a) Frøyen, P. Phosphorus, Sulfur Silicon Relat. Elem. 1993,
78, 161. (b) Rawal, V. H.; Zhong, H. I. Tetrahedron Lett.
1994, 35, 4947. (c) Sakai, K.; Anselme, J.-P. J. Org. Chem.
1971, 36, 2387. (d) Van Reijendam, J. W.; Baardman, F.
Synthesis 1973, 413. (e) Prakash, G. K. S.; Iyer, P. S.;
Arvanaghi, M.; Olah, G. A. J. Org. Chem. 1983, 48, 3358.
(f) Pfister, J. R.; Wymann, W. E. Synthesis 1983, 38.
(g) Ongeri, S.; Aitken, D.; Husson, H.-P. Synth. Commun.
2000, 30, 2593.
palmitic acid
adamantane-1-carboxylic acid
trans-cinnamic acid
3,5-difluoro-trans-cinnamic acid
phenoxyacetic acid
phenylacetic acid
a See the typical experimental procedure14 for the reaction conditions.
Spectroscopic data of the products were consistent with those in the
literature.
Next, we applied our present method to the synthesis of
dipeptide (Scheme 2). Treatment of N-Fmoc-L-Ala with
Cl3CCN, Ph3P and NaN3 in acetone gave N-Fmoc-L-Ala-
N3 in 86% yield.15 When treated with L-Leu-OMe in the
presence of 2,4,6-collidine, the acyl azide was readily
converted into the dipeptide, N-Fmoc-Ala-Leu-OMe,16 in
82% yield without indication of deprotection or rear-
rangement.
(4) Lee, J. G.; Kwak, K. H. Tetrahedron Lett. 1992, 33, 3165.
(5) Marinescu, L.; Thinggaard, J.; Thomsen, I.; Bols, M. J. Org.
Chem. 2003, 68, 9453.
(6) Chiyoda, T.; Iida, K.; Takatori, K.; Kajiwara, M. Synlett
2000, 1427.
(7) El-Faham, A.; Abdul-Ghani, M. Org. Prep. Proced. Int.
2003, 35, 369.
(8) Lago, J. M.; Arrieta, A.; Palomo, C. Synth. Commun. 1983,
13, 289.
In summary, we have developed a mild and convenient di-
rect process for the synthesis of acyl azides from carbox-
ylic acids with Cl3CCN, Ph3P and NaN3. The process
shows the generality for the preparation of acyl azides
from various carboxylic acids. The reaction was applica-
(9) Arrieta, A.; Aizpurua, J. M.; Palomo, C. Tetrahedron Lett.
1984, 25, 3365.
(10) (a) Gumaste, V. K.; Bhawal, B. M.; Deshmukh, A. R. A. S.
Tetrahedron Lett. 2002, 43, 1345. (b) Bao, W.; Wang, Q.
J. Chem. Res., Synop. 2003, 700.
Synlett 2008, No. 13, 2072–2074 © Thieme Stuttgart · New York