This file is a part of the Rhodium site archive. This Aug 2004 static snapshot is hosted by Erowid
as of May 2005 and is not being updated. > > Back to Rhodium Archive Index > >
[] [] [Chemistry Archive]

Reduction of Azides to Amines or Amides
With Zinc and Ammonium Chloride as Reducing Agent

W. Lin, X. Zhang, Z. He, Y. Jin, L. Gong, A. Mi
Synth. Commun. 32(21), 3279-3284 (2002)

HTML by Rhodium


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.

It is widely known that most of primary amines are biologically active compounds or the important building blocks for the syntheses of biologically active compounds, such as aminobenzlactam 11a,1b,1c,1d aminobenzlactam 22a,2b and l-homophenylalanine 31a,3a,3b 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 stereo controlled procedure4. Many common reagents for this purpose have been developed5a,5b but some of them suffer from poor selectivity4 or using some environmentally unfriendly chemicals.6a,6b,6c,6d,6e,6f The use of zinc and ammonium chloride has been well established in organic synthesis for the reduction of nitro group7, however, little attention has been focused on the reduction of azido group8. 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 compounds1a,1b,1c,1d 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 atm. hydrogen, a general method for the reduction of azides4, 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 donor9, 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 azides5b, was also employed to reduce 4, but low yield of 45% was obtained (Table 1, Entry 4). The treatment of 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.

Table 1.
Reduction of Azide 4 to Amine 1
with Various Reducing Agents.

Reducing Agent
8–24 h*
HCO2NH4-10% Pd/C
24 h
HCO2NH4-5% Pd/Al
24 h
NaBH4/CoCl2·6 H2O
24 h
1 h
10 min

* The hydrogenation of 4 to 1 were carried out
under 1, 5, 10 atm. hydrogen in EtOH and THF.

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 literature4,11a,11b,11c,11d,11e 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.

Table 2.
Reduction of Azides to Amines or Amides
with Zn/NH4Cl in EtOH/H2O (3:1)

Shows various azides converted to the
corresponding amines, all with high yields
(mostly 90%+). Reactions performed at
RT for 2h or at reflux for 10-30 min.

Moreover, this new reduction system of zinc and ammonium chlorides could tolerate some functional groups which were easily destroyed during hydrogenation, such as C=C 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).

General Procedure

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.

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.



    1. Watthey J.W.H., Stanton J.L., Desai M., Babiarz J.E., Finn B.M., J. Med. Chem., 28, 1511 (1985)
    2. Ksander G.M., Erion M., Ruan A.M., Diefenbacher C.G., El-chehabi L., Cote D., Levens N., J. Med. Chem., 37, 1823 (1994)
    3. Parsons W.H., Davidson J.L., Taub D., Aster S.D., Thorsett E.T., Patchett A.A., Biochem. Biophys. Res. Commun., 117, 108 (1983)
    4. Boyer S.K., Pfund R.A., Portmann R.E., Sedelmeier G.H., Wetter H.F., Helv. Chim. Acta, 71, 337 (1988)
    1. 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. 37, 897 (1994). Aminobenzlactam 2 is an Important Precursor for Growth Hormone Secretagogue such as L-692429.
    2. Shieh W.-C., Carlson J.A., Zaunius G.M., J. Org. Chem., 62, 8271 (1997)
    1. Watthey J.W.H., Chappaqua N.Y., U.S. Patent 4473575, 1984; Chem. Abstr., 102, 113326 (1985). 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..
    2. Attwood M.R., Hassall C.H., Kröhn A., Lawton G., Redshaw S., J. Chem. Soc., Perkin Trans. 1, 1011 (1986)
  4. Scriven E.F.V., Turnbull K., Chem. Rev., 88 (1988) 351
    1. Bosch I., Costa A.M., Martín M., Urpí F., Vllarrasa J., Org. Lett., 2, 397 (2000) and references cited therein; For the reduction methods of azides reported in the last several years.
    2. Fringuelli F., Pizzo F., Vaccaro L., Synthesis, 646 (2000) and references cited therein.
    1. Maiti S.N., Singh M.P., Micetich R.G., Tetrahedron Lett., 27, 1423 (1986)
    2. Kirk D.N., Wilson M.A., Chem. Commun., 64 (1970)
    3. Kondo T., Nakai H., Goto T., Tetrahedron, 29, 1801 (1973)
    4. Mungall W.S., Greene G.L., Heavner G.A., Letsinger R.L., J. Org. Chem., 40, 1659 (1975)
    5. Vaultier M., Knouzi N., Carrie R., Tetrahedron Lett., 24, 763 (1983)
    6. Adachi T., Yamada Y., Inoue I., Synthesis, 45 (1977)
  7. Bartra B., Romea P., Urpí F., Vilarrasa J., Tetrahedron, 46, 587 (1990)
  8. Boruah A., Baruah M., Prajapati D., Sandhu J.S., Synlett, 1253 (1997). For the reduction of azides to amines with Zn/NiCl2.
  9. Gartiser T., Selve C., Delpuech J.J., Tetrahedron Lett., 24, 1609 (1983)
  10. Cho S.-D., Choi W.-Y., Lee S.-G., Yoon Y.-J., Shin S.C., Tetrahedron Lett., 37, 7059 (1996)
    1. Reeves W.P., Bahr M.L., Synthesis 823 (1976)
    2. Suzuki H., Kawaguchi T., Takaoka K., Bull. Chem. Soc. Jpn., 59, 665 (1986)
    3. Hollywood F., Nay B., Scriven E.F.V., Suschitzky H., Khan Z.U., J. Chem. Soc., Perkin Trans. 1, 421 (1982)
    4. Suzuki T., Tanaka S., Yamada I., Koashi Y., Yamada K., Chida N., Org. Lett., 2, 1137 (2000)
    5. Hoffman R.V., Kim H.-O., Tetrahedron, 48, 3007 (1992)