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

Protecting-group-free synthesis has received significant recent research interest in the context of ideal synthesis and green sustainable chemistry. In general, organolithium species react with ketones very rapidly, and therefore ketone carbonyl groups should be protected before an organolithium reaction, if they are not involved in the desired transformation. If organolithium chemistry could be free from such a limitation, its power would be greatly enhanced. Here we show that a flow microreactor enables such protecting-group-free organolithium reactions by greatly reducing the residence time (0.003 s or less). Aryllithium species bearing ketone carbonyl groups are generated by iodine-lithium exchange reactions of the corresponding aryl iodides with mesityllithium and are reacted with various electrophiles using a flow-microreactor system. The present method has been successfully applied to the formal synthesis of Pauciflorol F.