Direct conversion of azides to carbamates and sulfonamides using Fe/NH4Cl: Effect of sonication

Article abstract of DOI:10.1016/S0040-4039(00)01373-3

A simple, direct and effective conversion of azides to carbamates and sulfonamides is achieved using Fe/NH₄Cl in methanol. The influence of sonication and direct application in solution phase combinatorial chemistry are also studied by developing a 6x4 matrix library. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01373-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7969–7972
Direct conversion of azides to carbamates and sulfonamides
using Fe/NH4Cl: effect of sonication†
S. Chandrasekhar* and Ch. Narsihmulu
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 26 June 2000; accepted 10 August 2000
Abstract
A simple, direct and effective conversion of azides to carbamates and sulfonamides is achieved using
Fe/NH4Cl in methanol. The influence of sonication and direct application in solution phase combinatorial
chemistry are also studied by developing a 6×4 matrix library. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: azides; carbamates; sulfonamides; sonication; combinatorial chemistry; iron.
Introduction of amino groups via reduction of an azido functionality1 is carried out rather
routinely in organic synthesis. Among the most common methods used for this transformation
are hydride reagents,2 catalytic hydrogenation3 and metal acid reduction.4 There are, however,
very limited protocols available for direct conversion of azides to protected amines5, which
include PdꢀC,6 20% Degussa Pd(OH)2/Et3SiH,7 n-Bu3P,8 Me3P,9,10 in combination with (Boc)2O
or alkylchloroformate. All these procedures suffer from their own disadvantages, for example,
catalytic hydrogenation is not favored for substrates which contain the NꢀCbz group or
unsaturation, whereas phosphorus reagents are not recommended for aromatic azides and also
result in unwanted byproducts.
Our own interest in the total synthesis of biologically significant molecules containing the
amino11 moiety in general demanded development of newer methodologies for the introduction
of an amino group. Herein, we disclose our findings where Fe in combination with NH4Cl and
MeOH under the influence of sonication reduced azides to amines, which were insitu trapped
with electrophiles viz., ClCOOEt, CbzCl, (Boc)2O, TsCl and PhSO2Cl (Scheme 1). The versatil-
ity of this methodology was further demonstrated by directly converting azides to carbamates
and sulfonamides in a combinatorial fashion (6×4 matrix) in a single operation in a sonicator for
the first time. Sonication12 has proved its efficiency in rate enhancement as well as yield
* Corresponding author. Tel: +91 40 7170512; fax: 7173387; e-mail: srivaric@iict.ap.nic.in
†
IICT Communication No. 4556
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01373-3

7970
Scheme 1.
improvement and has a distinct advantage over microwave irradiation, which performs a similar
function through rapid heating and which may not be desirable in some cases where the
substrates are thermally labile. The efficiency of sonication may be attributed to chemical
activation through cavitation. Initially benzyl azide (entry 1, Table 1) was subjected to reduction
Table 1

7971
Table 2
with Fe/NH4Cl in the presence of ethylchloroformate and MeOH as solvent to observe
formation of N-carbethoxybenzylamine in 60% yield after refluxing for 12 h. Interestingly,
however, when the same experiment was carried out in a sonicator,13 the product was obtained
in 90% yield within 15 min. Encouraged by this finding, other azido substrates (Table 1) were
subjected to both conventional heating as well as sonication at 25°C and comparative time taken
versus yield were recorded. In all the cases studied, without exception, all substrates behaved
exceedingly well under the influence of sonication. For instance, p-chloroazidobenzene (entry 4),
2-azidoketones (entries 5,6), which contain hydride labile groups, yielded the corresponding
carbamates in excellent yields. Similarly, hydrogenation sensitive substrates (entries 10 and 11)
also yielded required carbamates without affecting the benzyl ether group, olefinic and acetylenic
functionalities.
To further demonstrate the usefulness of the above methodology, the experiment was carried
out in a combinatorial fashion (6×4 matrix). Various azides (Table 2, y-axis) were taken in 24
test tubes and were treated with CbzCl, (Boc)2O, TsCl and PhSO2Cl (x-axis) in the presence of
Fe/NH4Cl and MeOH as solvent under sonication. After 1 h all the reactions were worked up
by filtering and the products were obtained in excellent yields and high purity (>90%) after
column chromatography.14
In conclusion, sonication has been utilized for efficient conversion of azides to amino
derivatives in one pot using FeꢀNH4Cl. Also, its utility is further demonstrated by synthesizing
a combinatorial library for the first time in a sonicator.

7972
Acknowledgements
One of us (C.N.) thanks CSIR (New Delhi) for financial support.
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