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Ketone Reduction

The inclusion of an article in this document does not give any indication of safety or operability. Anyone wishing to use any reaction or reagent must consult and follow their internal chemical safety and hazard procedures and local laws regarding handling chemicals

General Overview

Ketone reduction is a common transformation, with the resultant alcohol products often being converted on to other functional groups. Occasionally, deoxygenation to the resulting methylene product is the desired reaction. A wide range of reductants have been used – ketones being within the reduction potential of most reductants.

  • Dissolving metals (no longer widely used)
  • Catalytic hydrogenation (homogenous and heterogeneous metals)
  • Aluminium and boron hydrides (chiral and achiral transformations)
  • Biocatalytic reduction (normally chiral)

The choice of methodology for ketone reduction often reflects the need for selectivity and/or ease of operation on scale. Generally, ketones can be selectively reduced in the presence of other functional groups. Enantioselective reduction of ketones to chiral alcohols is also a common transformation. The chiral alcohol products might be target products, or further converted to chiral ethers, thiols, thioethers, amines, etc. Typical reagents utilized are chiral boranes (stoichiometric and catalytic), biocatalytic reduction using ketone reductase/alcohol dehydrogenase enzymes, and catalytic hydrogenation with chiral metal complexes, either using transfer hydrogenation or H2 gas.

General literature reviews on ketone reduction

Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J. Asymmetric synthesis of active pharmaceutical ingredients. Chem. Rev. 2006, 106, 2734-2793.

Magano, J.; Dunetz, J. R. Large-Scale Carbonyl Reductions in the Pharmaceutical Industry. Org. Proc. Res. Dev. 2012, 16, 1156−1184.

Shende, V. S.; Singh, P.; Bhanage, P. Recent trends in organocatalyzed asymmetric reduction of prochiral ketones. Catal. Sci. Technol., 2018, 8, 955-969.

Murray, B. A. Reactions of Aldehydes and Ketones and their Derivatives. Organic Reaction Mechanisms (2016), 1-70.

Brown, H. C.; Ramachandran, P. V. Asymmetric reduction with chiral organoboranes based on .alpha.-pinene.  Acc. Chem. Res.  1992, 25, 16-24.

Midland, M. M. Asymmetric reductions with organoborane reagents. Chem. Rev. 1989, 89, 1553-1561.

Riley, D. L.; Neyt, N. C. Approaches for Performing Reductions under Continuous-Flow Conditions. Synthesis 2018, 50, 2707-2720.

Cho, B. T. Recent development and improvement for boron hydride-based catalytic asymmetric reduction of unsymmetrical ketones. Chem. Soc. Rev., 2009, 38, 443-452.

Yoshimura, M.; Tanaka, S.; Kitamura, M. Recent topics in catalytic asymmetric hydrogenation of ketones. Tetrahedron Letts. 2014, 55, 3635–3640.

Foubelo, F.; Najera, C.; Yus, M. Catalytic asymmetric transfer hydrogenation of ketones: recent advances. Tetrahedron: Asymm. 2015, 26, 769-790.

Baiker, A. Crucial aspects in the design of chirally modified noble metal catalysts for asymmetric hydrogenation of activated ketones. Chem. Soc. Rev., 2015, 44, 7449-7464.

Adams, J. P.; Alder, C. M.; Andrews, I.; Bullion, A. M.; Campbell-Crawford, M.; Darcy, M. G.; Hayler, J. D.; Henderson, R. K.; Oare, C. A.; Pendrak, I.; Redman, A. M.; Shuster, L. E.; Sneddon, H. F.; Walker, M. D. Development of GSK’s reagent guides – embedding sustainability into reagent selection. Green Chem., 2013, 15, 1542-1549

Further web-based resources

www.commonorganicchemistry.com/Rxn_Pages/Ketone_to_Alcohol/Ketone_to_Alcohol_Index.htm

www.organic-chemistry.org/synthesis/O1H/reductioncarbonylcompounds.shtm

Green Criteria for Ketone Reduction

  1. Large molar excesses of reagents should be avoided if possible.
  2. Solvents with CMR properties/alerts should be avoided.
  3. Reductants with lower mass intensity should be used if possible and stoichiometry optimized to utilise all available hydrides.
  4. Highly reactive/flammable reagents should be avoided if possible, e.g., BH3, LiAlH4, LiBH4, etc.
  5. Catalytic methods are preferred.
  6. Consideration needs to be given to safe operating procedures and to avoiding forming hazardous mixtures with solvents with known incompatibility to specific reductants like NaBH4, BH3 complexes, LiAlH4, etc. The process has no major safety issues and the generation of hazardous waste is minimized and controlled.
  7. Large molar excesses of hydride reductants should be avoided if possible.
  8. Any excess reagents should be safely destroyed at the end of the reaction. Most hydride reagents will generate H2 on quenching, however borane-based hydrides can produce boric acid on quenching—this material is a suspect mutagen.
  9. Base metals are preferred to PGM for catalytic reactions.