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Highly Chemoselective Reduction of Amides (Primary, Secondary, Tertiary) to Alcohols using SmI2/Amine/H2O under Mild Conditions

Michal Szostak*, Malcolm Spain , Andrew J. Eberhart and David J. Procter*

*School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom, Email:,

M. Szostak, M. Spain, A. J. Eberhard, D. J. Procter, J. Am. Chem. Soc., 2014, 136, 2268-2271.

DOI: 10.1021/ja412578t

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A highly chemoselective direct reduction of primary, secondary, and tertiary amides to alcohols in high yields in presence of SmI2/amine/H2O proceeds via C-N bond cleavage in a carbinolamine intermediate and shows excellent functional group tolerance. The expected C-O cleavage products are not formed under the reaction conditions. Notably, the method provides direct access to acyl-type radicals from unactivated amides under mild conditions.

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General procedure for the reduction of amides

An oven-dried vial equipped with a stir bar was charged with an amide substrate (neat), placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. Samarium(II) iodide (THF solution, typically 8 equiv) was added followed by Et3N (typically, 72 equiv) and H2O (typically, 72 equiv) with vigorous stirring, which resulted in the formation of a characteristic dark brown color of the SmI2-Et3N-H2O complex, and the reaction mixture was stirred for the indicated time. In some cases, a solution of amide substrate (1.0 equiv, stock solution in THF, 1.0 mL) was added to the preformed samarium(II) iodide/amine/H2O complex, and the reaction mixture was stirred for the indicated time. The excess of Sm(II) was oxidized by bubbling air through the reaction mixture, and the reaction mixture was diluted with CH2Cl2 (30 mL) and NaOH (1 N, 10 mL). The aqueous layer was extracted with CH2Cl2 (3 x 30 mL), the organic layers were combined, dried over Na2SO4, filtered, and concentrated. The sample was analyzed by 1H NMR (CDCl3, 400 or 500 MHz) and GC-MS to obtain selectivity, conversion and yield using internal standard and comparison with authentic samples. Unless stated otherwise, the crude product was purified by chromatography on silica gel. Routinely, LC/MS analysis was used as a complementary method of analysis to confirm the product distribution. In all examples reported in the manuscript the observed C-N/C-O cleavage selectivity was >95:5. Note that reactions involving samarium(II) can typically be followed by visual observation of the color changes of the respective reaction mixtures. In the case of Sm(II)/amine/H2O complexes, the color changes from SmII (dark brown) to SmIII (dark to light green: oxidized, solvated; then white and yellow: fully oxidized, characteristic of SmI2X).

Pentafluorophenyl Esters: Highly Chemoselective Ketyl Precursors for the Synthesis of α,α-Dideuterio Alcohols Using SmI2 and D2O as a Deuterium Source

H. Li, Y. Hou, C. Liu, Z. Lai, L. Ning, R. Szostak, M. Szostak, J. An, Org. Lett., 2020, 22, 1249-1253.

Electron Transfer Reduction of Nitriles Using SmI2-Et3N-H2O: Synthetic Utility and Mechanism

M. Szostak, B. Sautier, M. Spain, D. J. Procter, Org. Lett., 2014, 16, 1092-1095.

Key Words

reduction of amides, samarium diiodide

ID: J48-Y2014