Organozinc Reagents: Highly Efficient Scalable Continuous Conversion in Various Concentrations and Reaction Types

Abstract

Organometallic reagents play a crucial role in today’s synthetic chemistry. They are used in the production of active pharmaceutical ingredients (APIs), fragrances, and agrochemicals, among other things, as they are instrumental and invaluable to form new carbon–carbon bonds. In addition to the widely used organolithium and organomagnesium compounds, better known as Grignard reagents, organozinc compounds are predestined coupling partners in C–C bond formation. Even though organozinc compounds are among the oldest organometallic compounds, they have long been superseded by the more reactive Grignard reagents (RMgX) and lithium organyls (RLi). The low reactivity of organozinc compounds in combination with a high sensitivity to oxygen and moisture lead to difficult handling and problematic storage. Their usefulness for C–C bond formation was therefore underestimated for a long time but has experienced a renaissance in recent decades. In a previous publication, the scalable continuous synthesis of organozinc compounds in different concentrations and solvents was demonstrated. The organozinc compounds were produced in both laboratory and pilot scale with good to very good yields and the formation of highly concentrated organozinc compounds was also confirmed. To build on this work, the continuous conversion of organozinc compounds is described below. Two different reaction types were investigated: the noncatalyzed Saytzeff reaction and the palladium-catalyzed Negishi cross-coupling reaction. The former was carried out in both a two-step and a one-pot approach. The reactive allylzinc bromide was chosen as the organometallic reagent, which was reacted with various aldehydes and ketones to yield secondary or tertiary homoallyl alcohols. In the Saytzeff reaction, residence times of 2.0 min were sufficient to achieve complete conversion of the carbonyl compound and isolated yields of 66–98%. The conversion of the carbonyl compound was monitored using an online process IR spectrometer with flow cell. In the case of the Negishi coupling, a fixed-bed reactor filled with Pd catalyst was used. The syntheses investigated were focused on the reaction of benzylzinc bromide with various functionalized organic halides. The Negishi coupling provided complete to near complete conversion of the electrophilic substrate with isolated yields of 72–92% at residence times of 23–32 s. Both the Saytzeff and Negishi reactions were extended to include the conversion of highly concentrated 2.0 M organozinc compounds. The former delivered yields of 83% and 92%, the latter 72% and 79%. The Saytzeff conversion was additionally transferred to pilot scale to demonstrate the ease of scalability. The synthesis of two selected compounds was successfully transferred to pilot scale, where a liquid throughput of 13 L/h was achieved. The main objective of this work was to establish various catalyzed and noncatalyzed conversions of organozinc reagents, particularly at high organozinc reagent concentrations to enable fast and safe process intensification, optimization and scalability to industrially relevant throughputs.