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Sodium Acyloxyborohydride as New Reducing Agents. I.
Reduction of Carboxamides to the corresponding Amines

N. Umino, T. lwakuma & N. ltoh
Tetrahedron Letters 763-766 (1976)

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Table I
Reduction of Carboxamides
and Carbamates with
Sodium Acyloxyborohydrides
Carboxamide
Solvent
Ratioc
Time
Yieldd
dioxane
5
4.5 h
71.0%
THF
10
2 h
92.5%
THF
10a
3 h
85.8%a
THF
10
3 h
82.0%
dioxane
5
20 h
27.0%
dioxane
5
4 h
76.2%
dioxane
5
2 h
82.5%
dioxane
10
17 h
35.1%
dioxane
10b
4.5 h
42.7%b
dioxane
5
1 h
88.1%
dioxane
5
1.5 h
89.5%
diglyme
5
1 h
83.8%
dioxane
5
20 h
20.1%
dioxane
10
5.5 h
60.0%
dioxane
10
5 h
28.0%
dioxane
10b
5 h
64.0%b
dioxane
4
5 h
65.7%
dioxane
5
2 h
82.0%
  1. PhCOOH was used as carboxylic acid.
  2. CF3COOH was used as carboxylic acid.
  3. Molar ratio of reducing agent to carboxamide.
  4. Yield calculated on isolated amine hydrochloride.

A number of methods from carboxamides to the corresponding amines have been reported: lithium aluminium hydride, diborane1a, lithium trimethoxy aluminium hydride1b, aluminum hydride1c, sodium borohydride-pyridine1d, sodium borohydride-aluminium chloride1e, lithium cyanoborohydride1f, sodium borohydride-triethyloxonium fluoroborate1g, etc.1h-i.

In 1960, Brown and Rao2 suggested that in diglyme sodium borohydride and propionic acid most probably react as follows:

CH3CH2COOH + NaBH4 → CH3CH2OOBH3Na + H2

Afterwards, Marshall and Johnson3 have reported the hydroboration of 1-hexene with sodium borohydride and acetic acid in tetrahydrofuran. However, little attention4 has been paid to the reducing ability of such sodium acyloxyborohydride. Recently Gribble et al.5 reported on the alkylation of amines with sodium borohydride in neat carboxylic acid, but N-acetyl indoline was recovered in 67% yield with sodium borohydride in neat acetic acid.

Now, we present a new convenient procedure for reduction of carboxamides to the corresponding amines, which is operationally simple, highly selective and efficient. Thus primary and secondary amides were found to be reduced quite easily by sodium acyloxyborohydrides prepared from an equivalent mole sodium borohydride and carboxylic acids in tetrahydrofuran or dioxane, while tertiary amides gave only poor results. For the latter, however, trifLuoroacetic acid was proved to be a satisfactory substitute of acetic acid; e.g. N-acetylindoline was converted to N-ethylindoline with sodium trifluoroacetoxyborohydride in 64% yield in refluxing dioxane for 5 hours, but only 28% yield with sodium acetoxyborohydride. Carbamates were also smoothly reduced to the corresponding amines. The results are summarized in Table 1.

We believe that main reactive species in these reactions are not free diborane by reasons which follow.

  1. Tertiary amides are not appreciably reduced with sodium borohydride and acetic acid.
  2. The externally generated gases in the reaction of sodium borohydride and carboxylic acid (AcOH or CF3COOH) in diglyme at 120°C do not reduce N-(4-methoxyphenethyl)- 3-(3-methoxyphenyl) propionamide in tetrahydrofuran nor do they make pyridine borate in tetrahydrofuran.
  3. The analogously generated gases from the isolated powders6 which can reduce various amides to the corresponding amines in high yield, do not reduce N-(4-methoxyphenethyl)- 3-(3-methoxyphenyl)-propionamide.

Experimental

The following procedure for the reduction of benzamide is representative.

To a stirred suspension of sodium borohydride (1.89g, 50 mmol) and benzamide (1.21g, 10 mmol) in dioxane (20ml) was added acetic acid (3.0g, 50 mmol) in dioxane (10ml) over a period of 10 minutes at 10 and the resulting mixture was stirred under reflux for 2 hours. The reaction mixture was concentrated to dryness in vacuo, excess reagent was decomposed with water and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The chloroform layer was treated with dry hydrogen chloride, evaporated in vacuo and the residue was crystallized from methanol-ether to give benzylamine hydrochloride (1.09g, 76.2%).

Further applications of these versatile reagents are currently explored in our laboratory, and the results will be published in due course.


References

  1.  
    1. H. C. Brown and P. Heim, J. Am. Chem. Soc., 86, 3566 (1964)
    2. H. C. Brown and P. M. Weissman, J. Am. Chem. Soc., 87, 5614 (1965)
    3. H. C. Brown and N. M. Yoon, J. Am. Chem. Soc., 88, 1464 (1966)
    4. Y. Kikugawa, S. lkegame and S. Yamada, Chem. Pharm. Bull. Japan, 17, 98 (1969)
    5. H. C. Brown and B. C. Subba Rao, J. Am. Chem. Soc., 78, 2582 (1956)
    6. R. F. Borch and H. D. Durst, J. Am. Chem. Soc., 91, 3996 (1969)
    7. R. F. Borch, Tetrahedron Letters, 61 (1968)
    8. NaBH4-transition metal salt.
      T. Satoh, S. Suzuki, Y. Suzuki, Y. Miyaji and Z. Imai, Tetrahedron Letters, 4555 (1969)
    9. C. Viel, Ann. Chim., 8, 515 (1963), reported that N-methylphenylacetamide
      was reduced to N-methylphenethylamine with NaBH4 in methanol in 77%.
  2. H. C. Brown and B. C. Subba Rao, J. Am. Chem. Soc., 82, 681 (1960)
  3. J. A. Marshall and W. S. Johnson, J. Org. Chem., 28, 595 (1963)
  4. G. W. Gribble and D. C. Ferguson, J. Chem. Soc. Chem. Commun., 535 (1975)
  5. G. W. Gribble, P. D. Lord, S. E. Dietz, J. T. Eaton and J. L. Johnson, J. Am. Chem. Soc., 96, 7812 (1974)
  6. T. Reetz, J. Am. Chem. Soc., 82, 5039 (1960) reported the isolation of NaBH3OAc from NaBH4-AcOH-THF.