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endo1

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The reduction of azides to amines w zinc/amoniumCl
« on: January 18, 2003, 03:48:00 AM »
Reduction of Azides to Amines or Amides with Zinc and Ammonium Chloride as Reducing Agent
Synthetic Communications 32(21), 3279 (2002)

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 1,1a,1b,1c,1d aminobenzlactam 2,2a,2b and l-homophenylalanine 3,1a,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 procedure.4 Many common reagents for this purpose have been developed,5a,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 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,1a 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 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 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 
--------------------------------------------------------------------------------

 
Entry Reducing Agent Temperature Time Isolated Yield (%)
1 H2-10%Pd/C rt 8–24 h1* <54
2 HCO2NH4-10%Pd/C rt 24 h 43
3 HCO2NH4-5%Pd/Al rt 24 h 65
4 NaBH4/CoCl2  6H2O rt 24 h 45
5 Fe/NH4Cl reflux 1 h 73
6 Zn/NH4Cl reflux 10 min 90

--------------------------------------------------------------------------------

1  *The hydrogenation of 4 to 1 were carried out under 1, 5, 10 atmospheric 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. 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).


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


***Shows various azides converted to their corosponding amines all high yields mostly 90%+ some at rt for 120 min and some at reflux for 10-30 min



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.
 
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.

  
References

1a  Watthey J.W.H., Stanton J.L., Desai M., Babiarz J.E., Finn B.M., J. Med. Chem., 28 (1985) 1511.
1b  Ksander G.M., Erion M., Ruan A.M., Diefenbacher C.G., El-chehabi L., Cote D., Levens N., J. Med. Chem., 37 (1994) 1823.
1c  Parsons W.H., Davidson J.L., Taub D., Aster S.D., Thorsett E.T., Patchett A.A., Biochem. Biophys. Res. Commun., 117 (1983) 108.
1d  Boyer S.K., Pfund R.A., Portmann R.E., Sedelmeier G.H., Wetter H.F., Helv. Chim. Acta, 71 (1988) 337.

2a  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 (1994) 897.  Aminoenzlactam 2 is an Important Precursor for Growth Hormone Secretagogue such as L-692429.
2b  Shieh W.-C., Carlson J.A., Zaunius G.M., J. Org. Chem., 62 (1997) 8271.

3a  Watthey J.W.H., Chappaqua N.Y., U.S. Patent 4473575, 1984; Chem. Abstr., 102 (1985) 113326.   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..
3b  Attwood M.R., Hassall C.H., Kröhn A., Lawton G., Redshaw S., J. Chem. Soc., Perkin Trans. 1, (1986) 1011.

4  Scriven E.F.V., Turnbull K., Chem. Rev., 88 (1988) 351.

5a  Bosch I., Costa A.M., Martín M., Urpí F., Vllarrasa J., Org. Lett., 2 (2000) 397.  references cited therein; For the reduction methods of azides reported in the last several years.
5b  Fringuelli F., Pizzo F., Vaccaro L., Synthesis, (2000) 646.  references cited therein.

6a  Maiti S.N., Singh M.P., Micetich R.G., Tetrahedron Lett., 27 (1986) 1423.
6b  Kirk D.N., Wilson M.A., Chem. Commun., (1970) 64.
6c  Kondo T., Nakai H., Goto T., Tetrahedron, 29 (1973) 1801.
6d  Mungall W.S., Greene G.L., Heavner G.A., Letsinger R.L., J. Org. Chem., 40 (1975) 1659.
6e  Vaultier M., Knouzi N., Carrie R., Tetrahedron Lett., 24 (1983) 763.
6f  Adachi T., Yamada Y., Inoue I., Synthesis, (1977) 45.

7  Bartra B., Romea P., Urpí F., Vilarrasa J., Tetrahedron, 46 (1990) 587.

8  Boruah A., Baruah M., Prajapati D., Sandhu J.S., Synlett, (1997) 1253.  For the reduction of azides to amines with Zn/NiCl2.

9  Gartiser T., Selve C., Delpuech J.J., Tetrahedron Lett., 24 (1983) 1609.

10  Cho S.-D., Choi W.-Y., Lee S.-G., Yoon Y.-J., Shin S.C., Tetrahedron Lett., 37 (1996) 7059.

11a  Reeves W.P., Bahr M.L., Synthesis, (1976) 823.
11b  Suzuki H., Kawaguchi T., Takaoka K., Bull. Chem. Soc. Jpn., 59 (1986) 665.
11c  Hollywood F., Nay B., Scriven E.F.V., Suschitzky H., Khan Z.U., J. Chem. Soc., Perkin Trans. 1, (1982) 421.
11d  Suzuki T., Tanaka S., Yamada I., Koashi Y., Yamada K., Chida N., Org. Lett., 2 (2000) 1137.
11e  Hoffman R.V., Kim H.-O., Tetrahedron, 48 (1992) 3007.

armageddon

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table?
« Reply #1 on: June 07, 2004, 05:27:00 PM »
Hi Lego!

This for sure is one of the most facile reduction methods I know - cheap reagents, no huge excess of ammonium formate being used (like with CTHs)..

But where did the nice table go?  :(  I remember it was readable time ago, but now it's html code seems a bit messed up!?

Perhaps you could re-edit it (with the help of a mod) or just scan the original article and upload it to the hive?

I (and surely MANY other bees) would grrrreatly appreciate it!!

Greetz A


Rhodium

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now available in HTML
« Reply #2 on: June 07, 2004, 08:53:00 PM »
The above two articles are now available in HTML at my page:

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

Synthetic Communications 32(21), 3279 (2002)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/azide2amine.zn-nh4cl.html)

Abstract
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.
____ ___ __ _

Zinc/ammonium formate: a new facile system for the rapid and selective reduction of oximes to amines
K. Abiraj and D. Channe Gowda

Journal of Chemical Research (Synopses) 6, 332-334 (2003)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/oxime2amine.zn-af.html)

Abstract
Various oximes, both aldoximes and ketoximes, are selectively reduced to corresponding amines employing low cost zinc dust and ammonium formate despite presence of other functional groups such as halogens, -OH, -OCH3, -COOH, -CN, >C=C< and -CH3.


Kinetic

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Azides to amines with Zn/NiCl2 in THF
« Reply #3 on: June 12, 2004, 01:41:00 AM »
This is reference 8 from endo1's post above. The excess of reagents, along with the use of anhydrous THF, is probably overkill. The above, more recent, reduction system uses only a slight excess of zinc, and is tolerant of water.


The Effective Chemoselective Reduction of Azides to Primary Amines
Anima Boruah, Mukulesh Baruah, Dipak Prajapati and Jagir S. Sandhu*
Synlett
, 1997, 1253-1254

Abstract

Reduction of azides to amines or amides occurs in excellent yields upon treatment with a novel reduction system consisting of Zn-NiCl2*6H2O-THF


Kinetic

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More azide references
« Reply #4 on: June 13, 2004, 04:23:00 PM »
Although the experimental from reference 5b in endo1's post is archived at

Synthesis and Reduction of Azides

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/azide.rxns.html), the full paper demonstrates the excellent selectivity of the method:

Cobalt(II) Chloride-Catalyzed Chemoselective Sodium Borohydride Reduction of Azides in Water
Francesco Fringuelli, Ferdinando Pizzo,* Luigi Vaccaro
Synthesis
, 2000 (5), 646-650

Abstract
Reduction of azides to amines and amides was carried out with NaBH4/CoCl2•6H2O in sole water at 25°C under catalytic heterogeneous conditions. A broad spectrum of azides was reduced in a short time, chemoselectively in high yield and purity.




This is reference 10, the reduction of azides with Fe/NH4Cl:

Chemoselective Reduction of Highly-functionalized Azidopyridazines to Corresponding Aminopyridazines Using Fe/NH4Cl in Organic Solvent-Water Two-phase Solution
Su-Dong Cho, Woo-Yong Choi, Sang-Gyeong Lee, Yong-Jin Yoon*, and Sung Chul Shin*
Tetrahedron Letters
, 37 (39), 7059-7060, 1996

Abstract
Highly functionalized azidopyridazines can be reduced chemoselectively to the corresponding amines in excellent yields.




HI is remarkably selective under certain conditions, and can be used to reduce azides to amines:

Simple and facile reduction of azides to amines: synthesis of DNA interactive pyrrolo[2,1-c][1,4]benzodiazepines
Ahmed Kamal,* P. S. M. M. Reddy and D. Rajasekhar Reddy
Tetrahedron Letters
, 43 (2002), 6629–6631

Abstract
The reduction of aromatic azido compounds to the corresponding amines with hydriodic acid has been investigated andfound to result in high yields. This reductive methodology which proceeds under non refluxing condition has been extended for the synthesis of DNA-interactive pyrrolo[2,1-c][1,4] benzodiazepine antibiotics.




Finally, here is a route to make alkyl azides from alkyl halides, similar to the method used by Ritter in

MDA from Bromosafrole Using a PTC and an Azide Intermediate

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/mda.azide.html):

Phase Transfer Catalysis; Preparation of Alkyl Azides
W. Preston Reeves, Martin L. Bahr
Synthesis
, 1976, 823


Kinetic

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Reductions with NaBH4/catalytic CuSO4
« Reply #5 on: June 17, 2004, 08:32:00 PM »
Yet another great article from India, referenced in the CoCl2/NaBH4 reduction of azides posted above:

Facile Reduction of Azides with Sodium Borohydride/Copper (II) Sulfate System
H. Surya Prakash Rao* and P. Siva
Synthetic Communications
, 24(4), 549-555 (1994)

Abstract
Sodium borohydride/copper (II) sulfate reduces alkyl and aryl azides to primary amines and aroyl azides to amides under mild conditions.


Kinetic

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More on borohydride-copper sulfate
« Reply #6 on: June 17, 2004, 10:44:00 PM »
This was a reference from the above paper, which deserves its own post: look what else this system is capable of!

Reduction of Organic Compounds with Sodium Borohydride-Copper Sulfate (II) System
Sung-eun Yoo*, Sang-hee Lee
Synthesis
, 1990, 419-420

Abstract
The reduction of various groups was investigated using sodium borohydride-copper (II) sulfate. Ketones, aliphatic esters, olefins, nitriles and aliphatic and aromatic nitro groups were reduced, but amides, aliphatic and aromatic carboxylic acids were inert. Rate of reaction was different for the various functional groups, allowing selective reductions to be peformed.




Edit: Here's a bonus article, as the CuSO4-NaBH4 system doesn't reduce carboxylic acids or amides to their respective alcohols or amines. For this, and for high-yielding reductions of oximes to amines (for which it is referenced in

Post 54080

(Sonson: "High-yielding synthesis of MDA from MDP2P", Methods Discourse)
), TiCl4-NaBH4 can be used:

Reduction of Some Functinal Groups with Titanium (IV) Chloride/Sodium Borohydride
Shinzo Kano, Yasuyuki Tanaka, Eiichi Sugino, Satoshi Hibino
Synthesis
, 1980, 695-697


Kinetic

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Azide reductions with SnCl2 or formate CTH
« Reply #7 on: June 22, 2004, 12:26:00 AM »
Here are two more high-yielding reductions of azides. The first looks similar to a quote by from Total Synthesis II, posted by psyloxy in

Post 108887 (missing)

(psyloxy: "Re: Sodium Azide route", Novel Discourse)
:


Facile Conversion of Azides to Amines
Samarendra N. Maiti, Maya P. Singh and Ronald G. Micetich
Tetrahedron Letters
, 27(13), 1423-1424, 1986

Summary
A simple method for the reduction of azides to primary amines is described




The second article uses a simple CTH method for the azide to amine reduction:

Reduction D'Azides En Amines Par Le Formiate D'Ammonium Par ''Transfert D'Hydrogene Catalyse'' (CTH)
T. Gartiser, C. Selve* et J.-J. Delpuech
Tetrahedron Letters
, 24(15), 1609-1610, 1983

Summary
The azides are reduced to amines in very good yields by ''Catalytic Transfer Hydrogenation'' (CTH) using ammonium formate