Reduction of Nitriles and Amides to Amines with Tetrabutylammonium Borohydride In Dichloromethane

T. Wakamatsu, H. Inaki, A. Ogawa, M. Watanabe, Y. Ban
Heterocycles 14(10), 1437-1440 (1980)

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Abstract

The reduction of nitriles and amides to the corresponding amines with tetra-n-butylammonium borohydride in dichloromethane has been reported, in which the other functional groups such as ester, nitro, and halogen attached to the aromatic ring are not affected.

The reduction of nitriles and amides to the amines is a very important, but not so easy organic transformation. The improved methods for the reduction of nitriles1 and amides2 with complex metal hydrides have been so far reported. We wish herein to describe another convenient and efficient method for the reduction of nitriles and amides to the amines with tetra-n-butylammonium borohydride3-6 in refluxing dichloromethane, in which the chemospecificity of tetra-n-butylammonium borohydride toward organic cyano and amide compounds was observed. The other functional groups of the ester, nitro, and halogen attached to the aromatic ring are not affected (Table 1, entry No. 6, 7, and Table 2 entry No. 10).

Table 1
Reduction of nitriles with n-Bu4BH4

No.
Starting Material
Amine HCl
Yield
1
benzonitrile
71%
2
phenylacetonitrile
72%
3
p-tolunitrile
87%
4
α-cyanonaphthalene
68%
5
diphenylacetonitrile
80%
6
p-nitrophenylacetonitrile
53%
7
p-chlorophenylacetonitrile
64%

Table 2
Reduction of amides with n-Bu4BH4

No.
Starting Material
Amine HCl
Yield
1
PhCONH2
70% (8%)
2
PhCONHCH2CH3
75% (7%)
3
PhCON(CH2CH3)2
51% (31%)
4
PhNHCOCH3
74% (1%)
5
PhNHCOPh
70% (14%)
6
PhN(CH3)COCH3
53% (15%)
7
Ph(CH-)2CONH2
55% (16%)
8
Ph(CH2)2NHCOCH3
58% (12%)
9
Ph(CH2)2N(CH2CH3)COCH3
50% (29%)
10
4-(COOEt)-PhNHCOCH3
77%

Numbers in parenthesis are yields
of recovered carboxamides.

The feature of this method is shown by the fact that the above reducing agent is readily soluble in dichloromethane which is a powerful solvent for many organic compounds in contrast with ether as a widespread solvent for alkali metal hydrides. The results are summarized in Table 1 and 2.

Experimental

The typical procedure is described in the following:

  1. Reduction of p-tolunitrile with tetra-n-butylammonium borohydride to p-tolubenzylamine:
    To a solution of 298mg (2.55mmol) of p-tolunitrile in 15ml of dichloromethane was added 1.969g (7.65mmol) of tetra-n-butylammonium borohydride. The mixture was vigorously refluxed with stirring for 10h. After removal of the solvent, a solution of 10% hydrochloric acid (15ml) was added to the residue and then refluxed for 1h. An acidic solution was neutralized with solid sodium hydroxide followed by extraction with ether. Evaporation of the solvent dried over anhydrous magnesium sulfate gave the crude amine, which was taken up in dichloromethane and dry hydrogen chloride was bubbled into this solution to afford 320mg (87%) of p-tolubenzylamine hydrochloride, mp 224-226°C (lit.7 mp 234-235°C).
  2. Reduction of acetanilide with tetra-n-butylammonium borohydride to N-ethyl-aniline:
    To a solution of 543mg (4.01mmol) of acetanilide in 15ml of dichloromethane was added 3.11g (12.1 mmol) of tetra-n-butylammonium borohydride. The whole mixture was vigorously refluxed with stirring for 10h. A similar work-up as described above afforded 470mg (74%) of N-ethylaniline hydrochloride, mp 175-177°C (lit.8 mp 173-175°C).

References

  1. N. Umino, T. Iwakuma, and N. Itoh, Tetrahedron Letters 2875 (1976) and references cited therein.
  2.  
    1. N. Umino, T. Iwakuma, and N. Itoh, Tetrahedron Letters 763 (1976) and references cited therein;
    2. Y. Tsuda, T. Sano, and H. Watanabe, Synthesis 652 (1977)
    3. M. E. Kuehne and P. J. Shannon, J. Org. Chem. 42, 2082 (1977)
    4. A. Basha and A. Rahman, Experientia 33, 101 (1977)
  3. A. Brandström, U. Junggren, and B. Lamm, Tetrahedron Letters 3137 (1972)
  4. D. J. Raber and W. C. Guida, Synthesis 808 (1974)
  5. D. J. Raber and W. C. Guida, J. Org. Chem. 41, 690 (1976)
  6. R. O. Hutchins and D. Kandasamy, J. Am. Chem. Soc. 95, 6131 (1973)
  7. T. Ueda, J. Pharm. Soc., Japan 58, 156 (1938)
  8. R. Mozingo, C. Spenser, and K. Folkers, J. Am. Chem. Soc. 66, 1859 (1944)