6268
J . Org. Chem. 2000, 65, 6268-6269
Ta ble 1. Syn th esis of N,N-Dim eth ylh yd r a zon es fr om
F a cile P r ep a r a tion of Hyd r a zon es by th e
Tr ea tm en t of Azid es w ith Hyd r a zin es
Azid es
Ca ta lyzed by F eCl3‚6H2O
Ian C. Barrett, J onathan D. Langille,† and
Michael A. Kerr*
entry
R1
R2
time (h)
yield (%)a
Department of Chemistry, University of Western Ontario,
London, Ontario N6A 5B7
1
2
3
4
5
6
7
8
9
Ph-
H
H
H
H
H
H
H
CH3
H
8
7
3
100
98
99
91
95
97
98
87
89
93
91
81
p-BrPh-
p-NO2Ph-
p-CH3O2CPh-
p-CH3OPh-
m-CH3OPh-
o-CH3OPh-
Ph-
makerr@julian.uwo.ca
Received May 9, 2000
8
21
15
23
11
17
17
18
34
In tr od u ction
PhCH2-
Recently, we reported that the reduction of aromatic
nitro compounds was effected in high yields by treatment
with N,N-dimethylhydrazine in the presence of catalytic
ferric chloride hexahydrate.1 While unsure of the exact
mechanism of that reduction, we were curious as to
whether this system would be effective in reducing other
nitrogen functional groups, particularly the conversion
of azides to amines, a commonly used and valuable
transformation. To that end we began an investigation
in which a series of simple azides were treated with N,N-
dimethylhydrazine/ferric chloride. Coincident with the
outset of our research, a report by Kamal and co-workers
appeared in which a series of azides, when treated with
virtually the same reagent/catalyst system, produced the
corresponding amines in reasonable yields.2 While ini-
tially disappointed, we soon realized that our initial
results were in stark contrast to those of Kamal.3 Using
benzyl azide as a substrate, we isolated the benzaldehyde
N,N-dimethylhydrazone as the sole product and not
benzylamine as reported. We have found this to be a
10
11
12
trans-PhCHCH-
CH3(CH2)6-
CH3(CH2)5-
H
H
CH3
a
Yields refer to yields of homogeneous compounds isolated from
the reaction mixture and which required no further purification.
as metalation substrates,5 we feel that this transforma-
tion will be of use to the synthetic chemist. The results
of our investigation form the basis of this report.
Resu lts a n d Discu ssion
A variety of azides (each prepared by simple treatment
of the corresponding alkyl halides with sodium azide)
were treated with N,N-dimethylhydrazine and 5-10 mol
% ferric chloride hexahydrate in refluxing acetonitrile.
The results are shown in Table 1.6,7 It is noteworthy that
the products (isolated by extractive workup) yielded the
pure hydrazones which were homogeneous as recovered
and needed no further purification. Note that the yields
are uniformly high and that 1° and 2° benzylic, allylic,
and 1° and 2° aliphatic azides reacted smoothly to give
the corresponding hydrazones.
A variety of solvents (CH3OH, THF, CH2Cl2, and CH3-
CN) were screened; however, none were superior to
acetonitrile in performance. A number of other potential
catalysts (BF3‚Et2O, Yb(OTf)3, Cu(OTf)2, CuCl2, and
TsOH) were ineffective in promoting the reaction, leaving
ferric chloride hexahydrate as the catalyst of choice. The
reaction failed to proceed in the absence of catalyst.
general reaction of azides with a variety of hydrazines
and believe this to be the only report of such a conversions
a net oxidation of the nitrogen-bearing carbon. Given the
synthetic utility of hydrazones as protecting groups4 and
(5) (a) Caine, D. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp 34-35.
(b) Corey, E. J .; Enders, D. Tetrahedron Lett. 1976, 3-6.
(6) Aside from the p-carbomethoxybenzyl hydrazone (Table 1, entry
4), all of the products are known compounds. The identity of the known
products was confirmed by comparison of 1H NMR to the published
data. The identity of all of the products was confirmed by routine
spectroscopic analysis (1H NMR, 13C NMR, and MS). In addition,
several hydrazones (Table 1, entries 1 and 11) were synthesized for
comparison from the aldehydes using known procedures.
(7) For published data on the N,N-dimethylhydrazones in Table 1,
see: (a) (benzaldehyde, cinnamaldehyde, acetophenone) Sharma, S.
D.; Pandhi, S. B. J . Org. Chem. 1990, 55, 2196-2200. (b) (p-
bromobenzaldehyde) Said, S. B.; Skarzewski, J . M.; Mlochowski, J .
Synthesis 1989, 223-224. (c) (p-nitrobenzaldehyde, phenylacetalde-
hyde) Clark, L. F.; O’Sullivan, F.; Hegarty, A. F. J . Chem. Soc., Perkin
Trans. 2 1991, 1649-1652. (d) (p-methoxybenzaldehyde) Smith, R. F.,
Albright, J . A.; Waring, A. M. J . Org. Chem. 1966, 31, 4100-4102. (e)
(m-methoxybenzaldehyde) Hwu, J . R.; Wang, N. Tetrahedron 1988,
44, 4181-4196. (f) (o-methoxybenzaldehyde, octanal) Wiley, R. H.;
Slaymaker, S. C.; Kraus, H. J . Org. Chem. 1957, 22, 204-207. (g) (2-
octanone) Yamashita, M.; Matsumiya, K.; Hiroko, M.; Rikisaku, S. Bull.
Chem. Soc. J pn. 1989, 62, 1668-1670.
* Author to whom correspondence should be addressed. Phone: (519)
661-2111 ext 86354.
† Current address: ANORMED INC., 20353 64th Avenue, Ste 100
Langley, B.C., Canada V2Y 1N5.
(1) Boothroyd, S. R.; Kerr, M. A. Tetrahedron Lett. 1995, 2411-2414.
(2) (a) Kamal, A.; Reddy, B. S. N. Chem. Lett. 1998, 593-594. (b)
Kamal, A.; Reddy, B. S. N.; Reddy, B. S. P. Bioorg. Med. Chem. Lett.
1997, 7, 1825-1828.
(3) There are differences between our optimized reaction conditions
and those of Kamal (acetonitrile rather than methanol as solvent, the
presence of charcoal in their case). However, using the exact conditions
(and substrates) of Kamal, we observed no reduction to the amines.
The substrates remained unchanged for the most part; however, phenyl
azide produced a small amount of aniline along with several other
unidentified products when reacted for prolonged periods. While we
do not dispute the findings of Kamal, we can offer no explanation at
this time for this discrepancy.
(4) Wuts, P. G. M.; Greene, T. W. Protective Groups in Organic
Synthesis; Wiley: New York, 1991.
10.1021/jo000708w CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/18/2000