Reduction of azides to amines or amides with zinc and ammonium chloride as reducing agent

Article abstract of DOI:10.1081/SCC-120014032

Alkyl azides and acyl azides were reduced to the corresponding amines and amides with zinc and ammonium chloride as reducing agent under mild conditions in good to excellent yield.

Full text of DOI:10.1081/SCC-120014032

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REDUCTION OF AZIDES TO AMINES OR AMIDES WITH
ZINC AND AMMONIUM CHLORIDE AS REDUCING AGENT
Wenqing Lin a , Xiaomei Zhang a , Ze He a , Yi Jin a , Liuzhu Gong a & Aiqiao Mi b
a Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu, 610041, China
b Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu, 610041, China
Version of record first published: 16 Aug 2006.
To cite this article: Wenqing Lin, Xiaomei Zhang, Ze He, Yi Jin, Liuzhu Gong & Aiqiao Mi (2002): REDUCTION OF AZIDES TO
AMINES OR AMIDES WITH ZINC AND AMMONIUM CHLORIDE AS REDUCING AGENT, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 32:21, 3279-3284
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 21, pp. 3279–3284, 2002
REDUCTION OF AZIDES TO AMINES OR
AMIDES WITH ZINC AND AMMONIUM
CHLORIDE AS REDUCING AGENT
Wenqing Lin, Xiaomei Zhang, Ze He, Yi Jin,
*
Liuzhu Gong, and Aiqiao Mi
Union Laboratory of Asymmetric Synthesis,
Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, 610041, Chengdu, China
ABSTRACT
Alkyl azides and acyl azides were reduced to the correspond-
ing amines and amides with zinc and ammonium chloride as
reducing agent under mild conditions in good to excellent
yield.
It is widely known that most of primary amines are biologically active
compounds or the important building blocks for the syntheses of biologi-
cally active compounds, such as aminobenzlactam 1,[1] aminobenzlactam 2,[2]
and L-homophenylalanine 3,[1a,3] and so on. The reduction of azides to amines
is of considerable importance for the introduction of primary amino group
in organic synthesis because of the easy preparation of azide by regio and
*Corresponding author. Fax: 86-28-5223978; E-mail: ulas@china.com
3279
DOI: 10.1081/SCC-120014032
Copyright & 2002 by Marcel Dekker, Inc.
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3280
LIN ET AL.
stereo controlled procedure.[4] Many common reagents for this purpose
have been developed,[5] but some of them suffer from poor selectivity[4] or
using some environmentally unfriendly chemicals.[6] The use of zinc and
ammonium chloride has been well established in organic synthesis for the
reduction of nitro group,[7] however, little attention has been focused on
the reduction of azido group.[8] Herein, we will describe a facile method for
the reduction of azides to amines or amides in good to excellent yield using
zinc and ammonium chloride as reducing agent under mild condition.
Aminobenzlactam 1, a key intermediate for the synthesis of many
biologically active compounds,[1] such as thromboxane synthase inhibitors,
and benazepril hydrochloride, can be prepared by reduction of the
corresponding azide 4. Initially, we tried to reduce 4 via hydrogenation
over 10% and 5% palladium on carbon at room temperature under 1, 5
and 10 atmospheric hydrogen, a general method for the reduction of
azides,[4] but the yields were always below 54% due to the incomplete
conversion (Table 1, Entry 1). Hydrogen transfer reduction was tested for
this transformation with ammonium formate as hydrogen donor,[9] in the
presence of 10% palladium on carbon, but the reaction could not proceed
completely, either, and only 43% yield was isolated (Table 1, Entry 2).
Using 5% palladium on aluminum as catalyst and ammonium formate as
hydrogen donor, resulted in more than 65% yield (Table 1, Entry 3).
The combination of sodium borohydride and cobalt chloride, which was
very efficient for the reduction of azides,[5b] was also employed to reduce 4,
but low yield of 45% was obtained (Table 1, Entry 4). The treatment of

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AZIDE REDUCTION WITH ZINC AND AMMONIUM CHLORIDE
3281
Table 1. Reduction of Azide 4 to Amine 1 with Various Reducing
Agents
Reducing
Agent
Isolated
Yield (%)
Entry
Temperature
Time
1
2
3
4
5
6
H2-10%Pd/C
rt
rt
rt
rt
reflux
reflux
8–24 h*
24 h
24 h
24 h
1 h
<54
43
65
45
73
90
HCO2NH4-10%Pd/C
HCO2NH4-5%Pd/Al
NaBH4/CoCl2 ꢀ 6H2O
Fe/NH4Cl
Zn/NH4Cl
10 min
*The hydrogenation of 4 to 1 were carried out under 1, 5, 10 atmos-
pheric hydrogen in EtOH and THF.
ferrum and ammonium chloride with 4 led to much higher yield of 73%
(Table 1, Entry 5).[10] However the conversion was still not complete even if
the reaction was prolonged.
Considering zinc is more reactive than ferrum, we proposed that the
combination of zinc and ammonium chloride was probably more efficient
for the reduction of azides than that of ferrum and ammonium chloride. As
we expected, the azide 4 was reduced to amine completely in a short time to
provide 90% isolated yield (Table 1, Entry 6). The co-solvents of ethyl
acetate and water, ethyl alcohol and water as well as ethyl acetate, ethanol
and water were suitable for the reaction, which could be selected based on
the solubility of azides.
To extend the scope of the reducing reagent of zinc and ammonium
chloride for the reduction of other azides, a variety of azides prepared
according to the literature[4,11] were tested for this transformation
(Table 2). All of azides were reduced completely with zinc and ammonium
chloride at refluxing or room temperature to readily give the corresponding
amines or amides in good to excellent yields. Moreover, this new reduction
system of zinc and ammonium chlorides could tolerate some functional
groups which were easily destroyed during hydrogenation, such as C¼C
bond, benzyl, and so on, thus the azides bearing such groups were reduced
in high yields (Entries 2 and 4). The reductions of Aroyl azide, arylsulphonyl
azides were performed at room temperature to afford the corresponding
amides smoothly in over 94% yields (Entries 5 and 6). Aryl azide was
also reduced in excellent yield (98%, Entry 7). For the reduction of the
optically active azide, no racemization was observed (Entry 8).

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3282
LIN ET AL.
Table 2. Reduction of Azides to Amines or Amides with Zn/NH4Cl in EtOH/H2O
(3 : 1)
Time Yield
Temperature (min) (%)
Entry
1
Azides
Product
reflux
10
98
2
3
reflux
reflux
10
10
87
96
4
5
reflux
rt
10
86
94
120
6
rt
120
95
7
8
reflux
reflux
30
10
98
87
*Yield of isolated product.
In summary, using zinc and ammonium chloride to reduce a broad
spectrum of azides to amines or amides in good to excellent yields was first
presented, which might provide a facile alternative for the reduction of
azides to amines and amides under a mild condition.

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AZIDE REDUCTION WITH ZINC AND AMMONIUM CHLORIDE
EXPERIMENT
3283
Typical Experiment Procedure for the Reduction of Azides to
Amines and Amides with Zinc and Ammonium Chloride
To the solution of azides (0.03 mol) and ammonium chloride
(0.07 mol) in ethyl alcohol (80 mL) and water (27 mL), zinc powder
(0.04 mol) was added, the mixture was stirred vigorously at room
temperature or at refluxing. After the reaction is over (monitored by
TLC), ethyl acetate (200 mL) and aqueous ammonia (10 mL) was added.
The mixture was filtered, and the filtrate was washed with brine, dried over
anhydrous sodium sulfate. After removal of solvent under reduced pressure,
the residue was purified by a flash chromatography or recrystallization to
give the corresponding amines or amides.
ACKNOWLEDGMENT
We are extremely grateful to the National Natural Science Foundation
of China for funding this research (No. 29790124).
REFERENCES
1. Watthey, J.W.H.; Stanton, J.L.; Desai, M.; Babiarz, J.E.; Finn, B.M.
J. Med. Chem. 1985, 28, 1511; (b) Ksander, G.M.; Erion, M.; Ruan,
A.M.; Diefenbacher, C.G.; El-chehabi, L.; Cote, D.; Levens, N. J. Med.
Chem. 1994, 37, 1823; (c) Parsons, W.H.; Davidson, J.L.; Taub, D.;
Aster, S.D.; Thorsett, E.T.; Patchett, A.A. Biochem. Biophys. Res.
Commun. 1983, 117, 108; (d) Boyer, S.K.; Pfund, R.A.; Portmann,
R.E.; Sedelmeier, G.H.; Wetter, H.F. Helv. Chim. Acta 1988, 71, 337.
2. Aminoenzlactam 2 is an Important Precursor for Growth Hormone
Secretagogue such as L-692429, see (a) Schoen, W.R.; Pisano, J.M.;
Prendergast, K.; Wyvratt, Jr. M.J.; Fisher, M.H.; Cheng, K.; Chan,
W.W.-S.; Butler, B.; Smith, R.G.; Ball, R.G. J. Med. Chem. 1994, 37,
897; (b) Shieh, W.-C.; Carlson, J.A.; Zaunius, G.M. J. Org. Chem. 1997,
62, 8271.
3. L-Homophenylalanine 3 can be used as a key intermediate for the
synthesis of most of angiotensin converting enzyme inhibitors, such as
benazepril, enalapril, quinapril, ramipril, etc. see (a) Watthey, J.W.H.;
Chappaqua, N.Y. U.S. Patent 4473575, 1984; Chem. Abstr.

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3284
LIN ET AL.
1985, 102, 113326; (b) Attwood, M.R.; Hassall, C.H.; Krohn, A.;
Lawton, G.; Redshaw, S. J. Chem. Soc., Perkin Trans. 1 1986, 1011.
4. Scriven, E.F.V.; Turnbull, K. Chem. Rev. 1988, 88, 351.
5. For the reduction methods of azides reported in the last several years,
see (a) Bosch, I.; Costa, A.M.; Martın, M.; Urpı, F.; Vllarrasa, J.
Org. Lett. 2000, 2, 397 and references cited therein; (b) Fringuelli, F.;
Pizzo, F.; Vaccaro, L. Synthesis 2000, 646 and references cited therein.
6. (a) Maiti, S.N.; Singh, M.P.; Micetich, R.G. Tetrahedron Lett. 1986,
27, 1423; (b) Kirk, D.N.; Wilson, M.A. Chem. Commun. 1970, 64; (c)
Kondo, T.; Nakai, H.; Goto, T. Tetrahedron 1973, 29, 1801; (d)
Mungall, W.S.; Greene, G.L.; Heavner, G.A.; Letsinger, R.L. J. Org.
Chem. 1975, 40, 1659; (e) Vaultier, M.; Knouzi, N.; Carrie, R.
Tetrahedron Lett. 1983, 24, 763; (f) Adachi, T.; Yamada, Y.; Inoue, I.
Synthesis 1977, 45.
7. Bartra, B.; Romea, P.; Urpı, F.; Vilarrasa, J. Tetrahedron 1990, 46, 587.
8. For the reduction of azides to amines with Zn/NiCl2, see Boruah, A.;
Baruah, M.; Prajapati, D.; Sandhu, J.S. Synlett 1997, 1253.
9. Gartiser, T.; Selve, C.; Delpuech, J.J. Tetrahedron Lett. 1983, 24, 1609.
10. Cho, S.-D.; Choi, W.-Y.; Lee, S.-G.; Yoon, Y.-J.; Shin, S.C.
Tetrahedron Lett. 1996, 37, 7059.
11. (a) Reeves, W.P.; Bahr, M.L. Synthesis 1976, 823; (b) Suzuki, H.;
Kawaguchi, T.; Takaoka, K. Bull. Chem. Soc. Jpn. 1986, 59, 665; (c)
Hollywood, F.; Nay, B.; Scriven, E.F.V.; Suschitzky, H.; Khan, Z.U.
J. Chem. Soc., Perkin Trans. 1 1982, 421; (d) Suzuki, T.; Tanaka, S.;
Yamada, I.; Koashi, Y.; Yamada, K.; Chida, N. Org. Lett. 2000, 2,
1137; (e) Hoffman, R.V.; Kim, H.-O. Tetrahedron 1992, 48, 3007.
Received in the Netherlands October 20, 2001