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Organocatalysis & Metal Free Reduction

Mechanism + Description

A variant on metal catalysed hydrosilyation in which Hantzsch esters and silanes are used as reductants. Prior activation of the sec or tert amide as the imidoyl triflate is required. More reactive catalysts like boronic acids do not require pre-activation of the amide.

General comments

A number of reductants will reduce activated secondary and tertiary amides – historically as imidoyl triflates, but later work, especially using boronic acids as catalysts with PMHS, TMDS and PhSiH3 will reduce inactivated primary, sec and tert amides. Generally mild conditions and good functional group tolerance, but poor atom economy especially if excess high Mwt silanes / stoichiometric Hantzsch esters are needed as reductants.

Atom Efficiency

  1. Tf2O/ Hantzsch esters
    By-products: 2 eq TfO- (149 g/mol) + 2 eq HEH (253 g/mol) = 804 g by-products/mol amide
  2. Tf2O/Et3SiH/ Hantzsch esters
    By-products: 2 eq TfO- (149 g/mol) + 1 eq 2-Fpyr (97 g/mol) + 1 eq Et3Si  (115 g/mol) + 1 eq HEH (253 g/mol)  = 763 g by-products/mol amide

Generally better atom efficiency is obtained with boronic acid catalysts and silanes avoiding triflic anhydride which is highly corrosive and the by-product trific acid is a persistent environmental pollutant.

Key references

Chem. Commun., 2014, 50, 9349-9352 Efficient metal-free hydrosilylation of tertiary,secondary and primary amides to amines

Angew. Chem. Int. Ed. 2013, 52, 11577 –11580 Selective Reduction of Amides to Amines by Boronic Acid Catalyzed

J.Am. Chem. Soc. 2010, 132, 12817-12819. Controlled and Chemoselective Reduction of Secondary Amides

Org. Chem. Front., 2015, 2, 150-158 Simple, versatile, and chemoselective reduction of secondary amides and lactams to amines with the Tf2O–NaBH4 or Cp2ZrHCl–NaBH4 system

Synlett 2010, 12, 1829-1832 Amide Activation by Tf2O: Reduction of Amides to Amines by NaBH4 under Mild Conditions

Sample Reaction: (up to 1g substrate)

J.Am. Chem. Soc. 2010, 132, 12817-12819.

J. Am. Chem. Soc. 2008, 130, 18-19.