No 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 micro flow system consisting of micromixers and microtube reactors provides an effective method for the introduction of two electrophiles onto p-, m-, and o-dibromobenzenes. The Br-Li exchange reaction of p-dibromobenzene with nBuLi can be conducted by using the micro flow system at 20 degrees C, although much lower temperatures (< -48 degrees C) are needed for a batch reaction. The resulting p-bromophenyllithium was allowed to react with an electrophile in the micro flow system at 20 degrees C. The p-substituted bromobenzene thus obtained was subjected to a second Br-Li exchange reaction followed by reaction with a second electrophile at 20 degrees C in one flow. A similar transformation can be carried out with m-dibromobenzene by using the micro flow system. However, the Br-Li exchange reaction of o-dibromobenzene followed by reaction with an electrophile should be conducted at -78 degrees C to avoid benzyne formation. The second Br-Li exchange reaction followed by reaction with an electrophile can be carried out at 0 degrees C. By using the present method, a variety of p-, m-, and o-disubstituted benzenes were synthesized in one flow at much higher temperatures than are required for conventional batch reactions.

A flow chemistry process for the synthesis of a key boronic acid starting material was developed utilizing flow flash chemistry that allowed formation and subsequent productive reaction of an unstable organolithium intermediate. Rapid scale-up from Discovery Chemistry and process optimization to kilogram-scale production was achieved using a short residence time (0.25 s) and noncryogenic temperature (0 °C), without the need to increase the number of reactors. A comparison of the flow process with a Miyaura borylation process suggested some potential benefit in the overall process operating efficiency from avoiding the use of Pd and genotoxic boron reagents.

Halogen compounds Q 0090Generation and Reactions of o-Bromophenyllithium Without Benzyne Formation Using a Microreactor. -A new method is presented to study conversions with highly unstable intermediates. In situ generated o-bromophenyllithium is treated in a new microreactor system with various electrophiles at -78°C to avoid decomposition. In all cases, the corresponding ortho-substituted bromobenzene derivatives are formed. The procedure is also applicable to the sequential reaction with two electrophiles which is performed in a microsytem consisting of four micromixers and four microtubes. The first Br-Li exchange must also be performed at -78°C whereby, the second one can be performed at 0°C since the aryllithium intermediate is more stable than o-bromophenyllithium. -(USUTANI, H.; TOMIDA, Y.; NAGAKI, A.; OKAMOTO, H.; NOKAMI, T.; YOSHIDA*, J.-I.; J.