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Reductive amination reagent selection
Reductive amination reagent selection
Reductive amination reaction.
Reductive amination is a reaction between a carbonyl and an amine. Initially, an imine is formed, that upon the action of a reducing agent (usually a borohydride) yields a substituted amine (Afanasyev et al., 2019). Different combinations of solvents and reducing agents have been screened, and sodium triacetoxyborohydride (STAB) in ethyl acetate appears to be an effective combination for aldehyde reactants (McGonagle et al., 2013). The ACS Green Chemistry Institute Pharmaceutical Roundtable reagent guide for reductive amination elaborates on the greenness, scalability, and utility (scope) of applicable reducing agents. STAB is considered to have wide utility and scalability. Sodium borohydride (NaBH4) is considered to be greener but lacking the wide utility of other boron-based reducing agents. Only hydrogen, catalysed by platinum or palladium, is judged to meet the criteria of a green, scalable reducing agent with wide utility.
Venn Diagram of reductive amination reducing agents.
The complementary reagent guide developed by GSK concurs that hydrogen is a valid reducing agent for green chemistry but enzymatic catalysis is preferred (Adams et al., 2013). The scope of biocatalysis is limited to certain reactants which is reflected by the position of biocatalysts in the ACS Green Chemistry Institute Venn diagram. Sodium cyanoborohydride (NaBH3CN) has the poorest score largely due to its toxicity. Although the GSK reagent table gives an insight into the greenness and consequences of using a given reducing agent, there is a presumption that each reagent is suitable. The ACS Venn diagram of reducing agents highlights possible shortcomings regarding the scalability and utility of potential reagents but with less detail about any hazards or possible environmental impacts.
Reductive amination reagent guide.
References
References
Reductive amination in the synthesis of pharmaceuticals: Afanasyev, O.I., Kuchuk, E., Usanov, D.L. and Chusov, D., Chem. Rev. 2019, 119, 11857-11911.
Development of a solvent selection guide for aldehyde-based direct reductive amination processes: McGonagle, F.I., MacMillan, D.S., Murray, J., Sneddon, H.F., Jamieson, C. and Watson, A.J.B., Green Chem. 2013, 15, 1159-1165.
Development of GSK’s reagent guides – embedding sustainability into reagent selection: Adams, J.P., Alder, C.M., Andrews, I., Bullion, A.M., Campbell-Crawford, M., Darcy, M.G., Hayler, J.D., Henderson, R.K., A. Oare, C.A., Pendrak, I., Redman, A.M., Shuster, L.E., Sneddon, H.F., and Walker, M.D., Green Chem. 2013, 15, 1542-1549.
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