Sustainable and Continuous Reduction of Amides

Sustainable and Continuous Reduction of Amides

Kathryn Rix, Geoff Kelsall, Mimi Hii, Klaus Hellgardt

Amines are important organic intermediates for the chemical industry; used in the production of agrochemicals, dyes, pharmaceuticals, surfactants and plastics. Amines constitute important core structures of many biologically active molecules, and are particularly prevalent in central nervous system (CNS) drugs, which make up the largest sector of pharmaceuticals sold worldwide.

The reduction of amides to amines can be effected electrochemically by a route summarised below:

Cathode:                    R-CONH₂ + 4H⁺ + 4e^{-    reduction}    R-CH₂NH₂ + H₂O         (1.0)

Nafion membrane:   H⁺ (anolyte)                                 H⁺ (catholyte)                 (1.1)

Anode:                       2H₂O                            ^oxidation      O₂ + 4H⁺ + 4e^-                        (1.2)

Overall reaction:       R-CONH₂ + H₂O                          R-CH₂NH₂ + O₂             (1.3)

An electrochemical flow-cell reactor has been constructed using boron doped diamond cathodes (BDD) to reduce a range of amides, demonstrating chemo-selectivity, stereo-selectivity and product selectivity by forming the corresponding amine.

For example, maleimide was selectively reduced to succinimide rather than to the corresponding amine, demonstrating chemoselectivity. This was developed further to show that the cyclic double bond can be preferentially reduced over an allyl group.

A conversion of >99% and a current efficiency of 96% were achieved. After neutralisation and extraction, ¹H NMR indicated that the cyclic double bond had been reduced while the allyl group remained intact (Figure 1). As the cyclic double bond is more electron deficient, the addition of two electrons and two protons is more favourable than addition to the allyl group.

Figure 1: Electrochemical reduction of N-allylmaleimide

In this presentation we will discuss further examples of the facile continuous electrochemical reduction of amides, avoiding the use of hydride agents.