Generation and reaction of cyano-substituted aryllithium compounds using microreactors

Abstract

We developed a microflow method for the generation and reactions of aryllithiums bearing a cyano group, including o-lithiobenzonitrile, m-lithiobenzonitrile and p-lithiobenzonitrile. The method was effective at much higher temperatures than are required for conventional macrobatch reactions, by virtue of rapid mixing, short residence time, and efficient temperature control. In addition, reactions of o-lithiobenzonitrile with carbonyl compounds followed by trapping of the resulting lithium alkoxides with electrophiles were achieved in an integrated microflow system.

A flow-microreactor approach to protecting-group-free synthesis using organolithium compounds

“…2b, see also Supplementary Table S1). However, acceptable yields were not obtained even at the minimum limit of the residence time of our current system (0.01 s), although this residence time was successful for the generation of alkoxycarbonyl- 44 , nitro- 45 and cyano-substituted 46 aryllithiums. Aryllithium 2 bearing a ketone carbonyl group decomposed very rapidly, the major by-product being dimeric compound 4.…”

Homocoupling of aryl halides in flow: Space integration of lithiation and FeCl3 promoted homocoupling

“…Such intermediates can be rapidly generated and transferred to another location to be used in a subsequent reaction before they decompose. We have already reported the generation and reactions of unstable aryllithium species such as o -bromophenyllithiums, and aryllithiums bearing alkoxycarbonyl, cyano, nitro, and ketone carbonyl groups [86–87 93,95–96 98], which are difficult to use in conventional macro batch reactors. As shown in Table 1, reactions of aryllithiums bearing cyano and nitro groups proceeded successfully to give the corresponding homocoupling products, where in contrast it is very difficult to achieve such reactions using conventional batch reactors.…”

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

“…41 Then, the boronate was subjected to a Suzuki reaction using a monolithic palladium catalyst, which in turn, restricted the achievable flow rate. Reactor size could not be increased in this case; consequently, the high volumetric throughput boronate forming and the much slower flowing coupling sections of the system were connected by splitting the flow evenly to multiple streams by an elaborate flow distributor.…”