Amide Reduction General Overview
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
The reduction of amides to amines accounts for ~5% of the amine construction in the pharma industry. Given the ubiquitous nature of carboxylic acids/esters/acid chlorides and amine synthons, this would undoubtedly be higher if safer and greener methodology were available for amide reduction. Most imides can be reduced to amines with the reagents used for amide reduction. The greenest methods available have lowest utility – see later. The need to use high energy reactive reductants represents the strength of the amide bond and a thermodynamically unfavourable transformation. Typically most process groups would look to replace an amide bond reduction in a synthetic sequence.
Balanced Chemical Equation
Typical reagents used are:
Metal hydrides – usually Al based
Borane and derivatives
There are few reports of biocatalytic reduction of amides to amines
Green Criteria for amide reduction
- Reagents should be selected to minimise safety issues. Large molar excesses of reagents should be avoided if possible
- Catalytic transformations are preferred over stoichiometric hydride reagents. If metal catalysed, base metals preferred over precious group metals.
- Process has no major safety issues and the generation of hazardous waste is minimised and controlled. Many reagents will generate hydrogen / and or other flammable gases.
- In situ generation of borane/ borane complexes removes the requirement to transport and store cylinders of boranes
- Solvents should be chosen to minimise any potential safety and environmental impact—see later.
General literature reviews on amide reduction
www.organic-chemistry.org/ reduction of amides
VenPure® NaBH4 for Amide/Lactam Reductions
Org. Process Res. Dev. 2012, 16 1156-1184 Large-Scale Carbonyl Reductions in the Pharmaceutical Industry
The Chemistry of Amides; Zabicky, J., Ed.Interscience Publishers: New York, 1970; pp 795-801.
Chem. Reviews 2014, 114, 5477-5510 - Review of Methods for the Catalytic Hydrogenation of Carboxamides
Use of NaBH4 including amide reduction and in situ borane generation
Angew. Chem. Int. Ed. 2011, 50, 6004-6011 Selective Reduction of Carboxylic Acid Derivatives by Catalytic Hydrosilylation