A Novel Approach to Functionalization of Aryl Azides through the Generation and Reaction of Organolithium Species Bearing Masked Azides in Flow Microreactors.

A novel straightforward method for aryl azides having functional groups based on generation and reactions of aryllithiums bearing a triazene group from polybromoarenes using flow microreactor systems was achieved. The present approach will serve as a powerful method in organolithium chemistry and open a new possibility in the synthesis of polyfunctional organic azides.

Generation of hazardous methyl azide and its application to synthesis of a key-intermediate of picarbutrazox, a new potent pesticide in flow.

Generation and reactions of methyl azide (MeN3) were successfully performed by using a flow reactor system, demonstrating that the flow method serves as a safe method for handling hazardous explosive methyl azide. The reaction of NaN3 and Me2SO4 in a flow reactor gave a MeN3 solution, which was used for Huisgen reaction with benzoyl cyanide in a flow reactor after minimal washing. The resulting 1-methyl-5-benzoyltetrazole serves as a key intermediate of picarbutrazox (IX), a new potent pesticide.

Three-component coupling based on flash chemistry. Carbolithiation of benzyne with functionalized aryllithiums followed by reactions with electrophiles.

A flow microreactor method for three-component coupling of benzyne was developed based on flash chemistry. o-Bromophenyllithium generated from 1-bromo-2-iodobenzene and a functionalized aryllithium generated from the corresponding aryl halide were mixed at -70 °C. In the subsequent reactor o-bromophenyllithium is decomposed to generate benzyne without affecting the functionalized aryllithium at -30 °C, and carbolithiation of benzyne with the aryllithium took place spontaneously. The resulting functionalized biaryllithium was reacted with an electrophile in the subsequent reactor to give the corresponding three-component coupling product. The precise optimization of reaction conditions using the temperature-residence time mapping is responsible for the success of the present transformation. The present method has been successfully applied to the synthesis of boscalid.

Reactions of organolithiums with dialkyl oxalates. A flow microreactor approach to synthesis of functionalized α-keto esters.

Reactions of functionalized aryllithiums with dialkyl oxalates were achieved using a flow microreactor to obtain α-keto esters with high selectivity by virtue of fast 1 : 1 micromixing.