Reduction of Acid Chlorides to Aldehydes using Sodium Borohydride and Pyridine

By use of sodium borohydride in N,N-dimethylformamide solution containing a molar excess of pyridine as a borane scavenger, direct conversion of both aliphatic and aromatic acid chlorides to the corresponding aldehydes can be achieved in >70% yield with minimal (5-10%) alcohol formation.

Procedure:

To a solution of 129 mg (3.4 mmoles) of sodium borohydride and 2.0 mL of pyridine in 5.0 mL of DMF and 3.0 mL of anhydrous THF cooled to approximately 0°C (external bath temperature) was added rapidly (<5 seconds) a solution of 4.0 mmoles of an acyl chloride in 2.0 mL of anhydrous THF. This mixture was subsequently stirred at 0°C for 1 minute before 0.50 mL of water was added to the flask to hydrolyze the excess acid chloride. Stirring of this mixture was continued at 0°C for an additional 60 seconds, after which 50 mL of 4:1 (v/v) hexane: solvent ether was quickly introduced into the flask. The globules of pyridine borane which appeared at this point can be separated from the reaction product by rapid filtration of the reaction mixture through a small column of Florisil (25 mL). An additional 25 mL portion of 4:1 (v/v) hexane: solvent ether was used to rinse out the reaction flask and ensure quantitative elution of the desired aldehyde (and any of the corresponding alcohol17) from the Florisil column18. 25 mL of ether was added to the combined filtrate, and this organic phase was washed successively with 15% aqueous NaCl (2x100mL), 1:1 (v/v) 2M aqueous hydrochloric acid:brine (1x100mL), 4:1 (v/v) 1M aqueous NaOH:brine (2x100mL), and saturated brine (100 ml). The organic layer was then dried (MgSO4) and the solvent removed in vacuo.

Reference: Synthetic Communications 12(11), 839-846 (1982)

Other reagents which can be used for partial reduction of acyl chlorides to aldehydes are:

• bis(Triphenylphosphine)cuprous borohydride [Fleet, G.W.J., Fuller, C.J., and Harding, P.J.C.,Tetrahedron Lett., 1437 (1978); Sorrell, T.N. and Spillane, R.J., Tetrahedron Lett., 2473 (1978); Sorrell, T.N. and Pearlman, P.S., J. Org. Chem., 45, 3449 (1980)]
• Lithium tri-tert-butoxyaluminum hydride [Brown, H.C. and Subba Rao, B.C., J. Am. Chem. Soc., 80, 5377 (1958)]
• Complex copper cyanotrihydridoborate salts [Hutchins, R.O. and Markowitz, M., Tetrahedron Lett., 21, 813 (1980)]
• Anionic iron carbonyl complexes [Watanabe, Y., Mitsudo, T., Tanaka, M., Yamamoto, K., Okajima, T., and Takegami, Y., Bull. Chem. Soc. Jpn., 44, 2569 (1971); Cole, T.E. and Pettit, R., Tetrahedron Lett., 781 (1977)]
• Tri-n-butyltin hydride in the presence of tetrakis(triphenylphosphine)palladium(0) [Four, P. and Guibe, F., J. Org. Chem., 46, 4439 (1981)]