The reduction of azides to amines w zinc/amoniumCl
(Rated as: excellent)
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.
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.
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.
Reduction of oximes with zinc/ammonium formate
(Rated as: excellent)
See also: Post 351892 (foxy2: "Reduction of nitro groups w. Zinc/Ammonium formate", Chemistry Discourse)
Journal of Chemical Research, Synopses, 2003, 6, 332-334
No DOI found
K. Abiraj and D. Channe Gowda
Department of Studies in Chemistry, University of Mysore, Mysore-570 006, India
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.
Keywords: oximes, catalytic transfer hydrogenation, zinc dust, ammonium formate, amines
The conversion of carbonyl derivatives to amines via oximes is a useful transformation in the synthesis of numerous organic compounds and also during the synthesis of compounds which are key intermediates in biosynthesis of many pharmacological important substances. Numerous new reagents have been developed for the reduction of oximes to amines.1-8 Though some of these are widely used, still they have limitations based on chemoselectivity and economic considerations.
The heterogeneous catalytic transfer hydrogenation method has proved more effective for reduction of organic compounds than traditional hydrogenation or other methods of reduction, as it involves mild reaction conditions, easy work-up and a high degree of selectivity. 9-12 Earlier reports reveal that catalytic transfer hydrogenation of oximes to amines had been achieved with systems like ammonium formate/10% Pd/C, 13 cyclohexene/10% Pd/C, 14 but these systems require reaction times as long as 5-10 hours at reflux, expensive catalysts and also offer very low yields. Moreover, stringent precautions must be taken while employing palladium on carbon because of its flammable nature in presence of air.
In this communication, we report a rapid, selective and simple reduction of oximes to corresponding primary amines using low cost zinc dust and ammonium formate or ammonium chloride at reflux temperature as depicted in Scheme 1. Various other functionalities like halogens, -OH, -OCH3, -COOH, -CN, >C=C< and -CH3 are tolerated. Further, we observed that in the case of nitro oximes, the nitro group on the aryl residue underwent reduction to the amine function at room temperature with this system, whereas the oxime function undergoes reduction only at reflux temperature to yield the corresponding diamine.
Scheme 1 R1, R2 = H, alkyl, phenyl or substituted phenyl group
The reduction of oximes in the presence of zinc dust and ammonium formate was completed within two to five minutes. The course of reaction was monitored by TLC and IR spectra. The work-up and isolation of the products were easy. Thus, the oximes reduced (a few examples are listed in Table 1) by this system were obtained in good yields (90-95%). The products were characterised by comparison of their boiling points or melting points, TLC and IR spectra with authentic samples. Further characterisation of the products was done by converting them to known derivatives and also by elementary analysis. The disappearance of strong absorption bands between 1690 and 1640 cm-1 due to C=N stretching and between 3650 and 3500cm-1 due to O - H stretching and appearance of two strong absorption bands between 3500 and 3300 cm-1 of -NH2 group clearly show that the oximes were reduced to the corresponding primary amines.
The use of ammonium chloride for the reduction of nitro compounds to amines15 provoked us to investigate the reduction reaction by replacing ammonium formate by ammonium chloride, which performs the conversion of oximes to amines at a slow rate. The complete conversion requires at least 2-3 hours at reflux temperature. This may be due to the fact that the solubility of ammonium chloride is very poor compared to ammonium formate and also in the case of ammonium formate, formate ion also provides hydride ion for the reduction.
Studies were also carried out to determine the optimum conditions for reduction. An excess of 2-4 equivalents of HCOONH4 was found to be ideal. The rate of transfer hydrogenation decreased substantially when only one equivalent of hydrogen donor was used. On the other hand, a large excess of HCOONH4 produced only a marginal increase in the rate of reaction compared to that observed when 2-4 equivalents were used. A large excess of catalyst improved the rate of transfer hydrogenation. We observed the optimal ratio of catalyst to substrate to be 2:1. Larger amounts of catalyst resulted in only minor improvement. However, the rate of transfer hydrogenation was significantly slower when a smaller amount of catalyst was used. A control experiment was carried out using oximes with ammonium formate or ammonium chloride, but without zinc dust, and the starting material was recovered in almost quantitatively. This clearly indicates that zinc catalyses the reaction. In anticipating metal/alcohol reduction, experiments were performed in absence of hydrogen donor by refluxing substrate with methanol and zinc dust for 4-5 hours. Even after a longer period the starting material was isolated in quantitative yield, which clearly indicates the requirement of ammonium formate or ammonium chloride for the reduction. Here methanol serves as a solvent.
In conclusion, the reduction of oximes can be accomplished in a short time with zinc dust instead of expensive catalyst like palladium. 13,14 The yields are virtually quantitative and analytically pure. This zinc-catalysed procedure provides a very efficient, selective, inexpensive, rapid and is a general methodology for reduction of oximes to amines. Further investigations of other useful applications related to cleavage
of peptides from resin support in solid phase peptide synthesis are in progress.
The oximes were either commercially available or prepared from the corresponding carbonyl compound by standard methods. In cases where the oxime was obtained as an E/Z-mixture, no attempts were made to separate such mixtures.
Reduction of oximes to amines, general procedure: To a solution of the substrate (5 mmole) in methanol (10 ml) was added ammonium formate (10-20 mmole) [or ammonium chloride (10-20 mmol)] and zinc dust (10 mmol). The mixture was stirred under reflux. After the completion of the reaction (monitored by TLC), the reaction mixture was filtered through celite. The filtrate was evaporated under vacuum and the residue was taken into chloroform or ether, washed twice with 80% saturated brine solution and finally with water. The organic layer was dried over anhydrous sodium sulphate and evaporation of the organic layer was followed by purification either by preparative TLC, or by column chromatography, to yield the desired product.
Table 1 Transfer hydrogenation of oximes to amines catalysed by commercial zinc dust using ammonium formate or ammonium chloride
a Isolated yields are based on single experiment and the yields were not optimised.
b Low yield is due to low boiling point of the product which was isolated as picrate derivative.
c Isolated as hydrochloride salt.
d Melting point.
e 1l 4-Nitrobenzaldehyde oxime 2l 4-Aminobenzylamine
f 1m Succinaldehyde dioxime 2m 1,4-Diaminobutan
g 1n Cyclohexanone oxime 2n Cyclohexylamine
h 1o 4-Nitrocinnamic acid 2o4-Aminocinnamic acid
1 R.O. Hutchins and M.K. Hutchins, Comprehensive Organic Synthesis Vol. 8; eds. I. Fleming, Pergamon press; Oxford, 1991; pp. 60.
2 A.S. Demir, C. Tanyeli, O. Sesenoglu and S. Demic, Tetrahedron Lett., 1996, 37, 407. 3 Y. Diab, A. Laurent and P. Mison, Tetrahedron Lett., 1974, 17,1605.
4 M.A. Rahman and B. Fraser-Reid, J. Am. Chem. Soc., 1985, 107, 5576.
5 J. March, Advanced Organic Chemistry, 4th edn., A Wiley-Interscience Publication, Singapore, 1992; pp. 1219.
6 M.R. Pitts, J.R. Harrison and C.J. Moody, J. Chem. Soc. Perkin Trans.1, 2001, 955.
7 K.I. Booker-Milburn, I.R. Dunkin, F.C. Kelly, A.I. Khalaf, D.A. Learmonth, G.R. Proctor and D.I.C. Scopes, J. Chem. Soc. Perkin Trans.1, 1997, 3261.
8 F.D. Popp and H.P. Schultz, Chem. Rev., 1962, 62, 19.
9 R.A W. Johnstone, A.H. Wilby and I.D. Entwistle, Chem. Rev. 1985, 129.
10 S. Ram and R.E. Ehrenkaufer, Synthesis, 1988, 91.
11 S. Gowda and D.C. Gowda, Synthesis, 2002, 460.
12 S. Gowda and D.C. Gowda, Tetrahedron, 2002, 58, 2211.
13 G.K. Jnaneshwara, A. Sudalai and V.H. Deshpande, J. Chem. Res. (S), 1998, 160.
14 G. Brieger and T.J. Nestrick, Chem. Rev., 1974, 74, 567.
15 B.K. Banik, M. Suhendra, I. Banik and F.F. Becker, Synth. Commun., 2000, 30, 3745.
16 A.I. Vogel, Text Book of Practical Organic Chemistry; 5th edn., Addison Wesely Longman Limited, UK, 1997.
17 The Merck Index, 11th edn., (ed. S. Budavari), Merck & Co., Inc., USA, 1989.
The candle that burns twice as bright burns half as long
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!!
"..ein Trank von unterschiedlicher Farbe, in ihm ist Heilung für die Menschen."
|now available in HTML|
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) (../rhodium/chemistry /azide2
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) (../rhodium/chemistry /oxime2
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.
The Hive - Clandestine Chemists Without Borders
Azides to amines with Zn/NiCl2 in THF
(Rated as: good read)
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
Reduction of azides to amines or amides occurs in excellent yields upon treatment with a novel reduction system consisting of Zn-NiCl2*6H2O-THF
More azide references
(Rated as: excellent)
Although the experimental from reference 5b in endo1's post is archived at Synthesis and Reduction of Azides (../rhodium/chemistry /azide.
Cobalt(II) Chloride-Catalyzed Chemoselective Sodium Borohydride Reduction of Azides in Water
Francesco Fringuelli, Ferdinando Pizzo,* Luigi Vaccaro
Synthesis, 2000 (5), 646-650
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
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
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 (../rhodium/chemistry /mda.az
Phase Transfer Catalysis; Preparation of Alkyl Azides
W. Preston Reeves, Martin L. Bahr
Synthesis, 1976, 823
Reductions with NaBH4/catalytic CuSO4
(Rated as: good read)
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)
Sodium borohydride/copper (II) sulfate reduces alkyl and aryl azides to primary amines and aroyl azides to amides under mild conditions.
More on borohydride-copper sulfate
(Rated as: good read)
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
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
Azide reductions with SnCl2 or formate CTH
(Rated as: excellent)
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 (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
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
The azides are reduced to amines in very good yields by ''Catalytic Transfer Hydrogenation'' (CTH) using ammonium formate