Optimization of the thiol-ene reaction for the preparation of methyl 3-((3,3,3-trifluoropropyl)thio)propanoate (4), a key intermediate in the synthesis of sap-feeding insecticide tyclopyrazoflor (1), will be described. The major challenge with the radical thiol-ene chemistry was getting selectivity between the linear and branched products. Reducing the radical initiation temperature was found to be the key variable in controlling selectivity. Due to high cost and storage challenges associated with the use of room temperature diazo initiator 2,2'-azobis(4-methoxy-2.4-dimethyl valeronitrile) (V-70), a two component initiator system consisting of benzoyl peroxide and N,N-dimethylaniline was developed, allowing for radical initiation at temperatures as low as -15 °C. Application of semi-batch operation gave 90:1 selectivity favoring the linear product. The overall yield and selectivity of the radical thiol-ene reaction was improved from 78% yield, 11:1 selectivity, with azobisisobutyronitrile (AIBN) in batch mode to 91% yield, 90:1 selectivity, with the two component system in semi-batch mode further eliminating the need for a fractional distillation purification step.

Scalable synthesis of methyl 3-((3,3,3-trifluoropropyl)thio)propanoate via thiol-ene chemistry

2019 Fall National Meeting

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