Author Topic: Raney Nickel CTH Reduction of Nitro/Nitrile Groups  (Read 6702 times)

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Raney Nickel CTH Reduction of Nitro/Nitrile Groups
« on: September 05, 2002, 07:03:00 PM »
Application of hydrazinium monoformate as new hydrogen donor with Raney nickel: a facile reduction of nitro and nitrile moieties
Tetrahedron, Volume 58, Issue 11, 11 March 2002, Pages 2211-2213
Shankare Gowda and D. Channe Gowda

The nitro groups in aliphatic and aromatic nitrocompounds also containing reducible substituents such as ethene, acid, phenol, halogen, ester etc., are rapidly reduced at room temperature to corresponding amines by employing hydrazinium monoformate, a new hydrogen donor, in the presence of Raney nickel. It was observed that the nitrile function also undergoes reduction to methylamine (-CH2-NH2). Hydrazinium monoformate is a more effective donor than hydrazine or formic acid and reduction of nitro and nitrile groups occurs without hydrogenolysis in the presence of low cost Raney nickel, compared to expensive metals like palladium, platinum or ruthenium. The reduction is reasonably fast, clean and high yielding.

In this communication, we wish to report a rapid and simple reduction of aliphatic and aromatic nitrocompounds, and nitriles to the corresponding amino derivatives by using Raney nickel and hydrazinium monoformate, a new hydrogen donor, at room temperature (Scheme 1). This new system reduced with ease a wide variety of nitro and nitrile compounds directly to the corresponding amines and many functional groups are tolerated. Hydrazinium monoformate is soluble in solvents like methanol, ethanol, tetrahydrofuran, dimethylformamide and glycols. But with solvents like dichloromethane, chloroform, benzene, etc., it forms a biphasic system and in this system, the reactions are rather slow. This system cannot be employed with ketonic and nitrile solvents, as it forms hydrazones with former and reduces the latter.

Our main intention was to reduce nitrocompounds selectively to the corresponding amines. But surprisingly, we observed that this system reduced nitriles to methylamines, unlike the reduction of a nitrile group to methyl group, using 10% Pd-C/HCOONH4.{33 and 34} In the case of nitro nitriles, the two moieties are reduced to an amino group and a methylamine group, respectively. This system is not helpful to directly obtain an amino carbonyl compound, due to the formation of a hydrazone derivative with the donor. However, the nitro hydrazones are reduced to the corresponding amino hydrazines by this system. Further, hydrazinium monoformate/Raney nickel system is more effective than either triethylammonium formate/5% Pd-C {35} or cyclohexene/10% Pd-C {36} or hydrazine hydrate/Fe(III) {37} and equally compatible with the systems like HCOONH4/10% Pd-C,{1} HCOONH4/5% Pt-C{11} and HCOONH4/Raney Ni.{12} Though ammonium formate is extensively used in the field of catalytic transfer hydrogenation, it is sparingly soluble in solvents such as methanol; but hydrazinium monoformate is freely soluble in `methanol-like' solvents. Therefore, this system may find its own application in the field of catalytic transfer hydrogenation.

The reduction of nitro aromatic compounds in the presence of Raney nickel and hydrazinium monoformate was complete within 2-10 min. The course of reaction was monitored by thin layer chromatography (t.l.c.) and IR spectra. The work-up and isolation of the products were easy. Thus, all the compounds reduced (Table 1) by this system were obtained in good yields (90-95%). All the products were characterized by comparison of their t.l.c., IR spectra and melting points with authentic samples. A control experiment was carried out using nitrocompounds with hydrazinium monoformate but without Raney nickel, does not yield the desired product. The t.l.c. and IR spectra could not detect any intermediates such as nitroso or hydroxylamine in the reaction mixture after the completion of reaction. Since the reaction is so fast (2 min), the detection of intermediates is not possible. In order to test the selectivity, the reduction was attempted with p-dichlorobenzene, p-chloro-m-cresol, -naphthol, cinnamic acid, acetanilide, benzoic acid, anisole, phenyl acetate, etc., at laboratory temperature. However, the reaction failed to give any reduced product. Further, it was observed that hydrazinium monoformate is a more effective donor than either hydrazine or formic acid in the presence of Raney nickel. The reduction was completed within 2-6 min with the present system. The methods reported earlier for the reduction of nitro arenes to amino arenes by using Raney nickel and hydrazine requires longer reaction time as long as 2-10 h at reflux temperature{24, 26, 28 and 29} and Raney nickel/formic acid system needs 20-30 min for the completion of reduction.{12} Furthermore, both the systems are unable to reduce nitrile function. Thus, the reduction of nitrocompounds and nitriles can be accomplished with Raney nickel instead of expensive platinum, palladium etc., without effecting the reduction of any reducible or hydrogenolysable substituents except the nitrile group. The yields are virtually quantitative and the compounds obtained are analytically pure. The obvious advantages of the proposed method over previous methods are: (i) selective reduction of nitro and nitrile compounds, in the presence of other reducible or hydrogenolysable groups, (ii) easy to operate, (iii) rapid reduction, (iv) high yields of substituted amines, (v) avoidance of strong acid media, (vi) no requirement for pressure apparatus and (vii) inexpensive. This procedure will therefore be of general use, especially in the cases where rapid, mild and selective reduction is required. Further investigations of other useful applications related to the deblocking of protecting groups in peptide synthesis are in progress.

Hydrazinium monoformate was prepared by slowly neutralizing equal moles of hydrazine hydrate and 85% formic acid in an ice water bath, with constant stirring. The hydrazinium monoformate solution thus obtained was used as such for reduction. A suspension of an appropriate nitrocompound or nitrile (5 mmol) and Raney nickel (100 mg) in methanol or in any suitable solvent (3 mL) was stirred under nitrogen atmosphere with hydrazinium monoformate (2 mL), at room temperature. The reaction was exothermic and effervescent. After the completion of reaction (monitored by t.l.c.), the reaction mixture was filtered through celite. The organic layer was evaporated and the residue was dissolved in chloroform or dichloromethane or ether was washed with saturated sodium chloride solution to remove excess of hydrazinium monoformate. The organic layer after drying and evaporation gave the desired amino derivative.

In order to get a good yield of volatile aliphatic amines, the reaction was carried out by controlled addition of hydrazinium monoformate, through the top of a condenser circulated with ice water and by immersing the reaction flask in a cold-water bath. After filtration, the whole reaction mixture was neutralized with HCl. The solvent was evaporated under reduced pressure. The residue was lyophilized or subjected to column chromatography. Aliphatic amines were obtained as their hydrochloride salts up to 80% yield.

Table 1. Reduction of nitrocompounds and nitriles using hydrazinium monoformate/nickel
nitro/nitrile; time(min); product; Yield(%)
m-nitrophenol; 2; m-aminophenol; 94

o-nitrotoluene; 3; o-toluidine; 93

p-nitrotoluene; 2; p-toluidine; 94

p-nitroanisole; 2; p-anisidine; 95

m-nitroaniline; 3; m-phenylenediamine; 94

nitromethane; 2; methylamine; 80

nitroethane; 2; ethylamine; 81

1-nitropropane; 2; 1-aminopropane; 84

1-nitrobutane; 3; 1-aminobutane; 75

acetonitrile; 3; ethylamine; 75

propionitrile; 3; n-propylamine; 76

benzonitrile; 5; benzylamine; 80

phenylacetonitrile; 5; 2-phenylethylamine; 80

p-chlorobenzonitrile; 6; p-chlorobenzylamine; 70

m-methoxybenzonitrile; 6; m-methoxybenzylamine; 72
-Isolated yields are based on single a experiment and the yields were not optimised.
-Low boiling compounds were isolated as hydrochloride salt

1. S. Ram and R.E. Ehrenkaufer Tetrahedron Lett. 25 (1984), p. 3415.

11. D.C. Gowda and B. Mahesha Synth. Commun. 30 (2000), p. 3639.

12. D.C. Gowda, A.S.P. Gowda, A.R. Baba and S. Gowda Synth. Commun. 30 (2000), p. 2889.

24. D. Balcom and A. Furst J. Am. Chem. Soc. 75 (1953), p. 4334.

25. R.E. Moore and A. Furst J. Org. Chem. 23 (1958), p. 1504.

26. R.K. Brown and N.A. Nelson J. Am. Chem. Soc. 76(1954), p. 5149.

27. A. Furst and R.E. Moore J. Am. Chem. Soc. 79 (1957), p. 5492.

28. B.E. Leggeter and R.K. Brown Can. J. Chem. 38 (1960), p. 2363.

29. N.R. Ayyanger, A.G. Lugade, P.V. Nikrad and V.K. Sharma Synthesis (1981), p. 640.

33. G. Brieger and T.J. Nestrick Chem. Rev. 74 (1974), p. 67.

34. G.R. Brown and A.J. Foubister Synthesis (1982), p. 1036.

35. N.A. Cortese and R.F. Heck J. Org. Chem. 42 (1977), p. 3491.

36. I.D. Entwistle, R.A.W. Johnstone and T.J. Povall J. Chem. Soc., Perkin Trans. 1 (1975), p. 1300.

37. T. Hirashima and O. Manabe Chem. Lett. (1995), p. 259.

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Great find
« Reply #1 on: September 05, 2002, 09:29:00 PM »
There should be a rating that is better than excellent.

So if I am reading this right, a nitrile can be reduced directly to the amine on site of the molecule with high selectivity in 95% yeilds in ten minutes or less.

And I was excited when I learned I could make methylamine in situ.  This is so much better.  And considering the reagents this synth is feasable for the average chemistry student.

Amazing. 8)


Conclusion /nm./: the place where you got tired of thinking.


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Nitro to Amine Reduction - Formic Acid/Ra-Ni
« Reply #2 on: November 22, 2003, 12:56:00 AM »
Selective Reduction of Nitro Compounds Using Formic Acid and Raney Nickel

Synth. Commun. 30(16), 2889-2895 (2000)


Aliphatic and aromatic nitro compounds were selectively reduced to their corresponding amino derivatives in good yields using formic acid and Raney nickel. This system is found to be compatible with several sensitive functionalities such as halogens, -OH, -OCH3, -CHO, -COCH3, -COC6H5, -COOH, -COOEt, -CONH2, -CN, -CH=CH-COOH, -NHCOCH3. The reduction can be carried out not only with HCOOH but also with HCOONH4.