Organozinc Reagents:\nHighly Efficient Scalable Continuous\nConversion in Various Concentrations and Reaction Types

Organometallic reagents play a crucial role in today’s\nsynthetic\nchemistry. They are used in the production of active pharmaceutical\ningredients (APIs), fragrances, and agrochemicals, among other things,\nas they are instrumental and invaluable to form new carbon–carbon\nbonds. In addition to the widely used organolithium and organomagnesium\ncompounds, better known as Grignard reagents, organozinc compounds\nare predestined coupling partners in C–C bond formation. Even\nthough organozinc compounds are among the oldest organometallic compounds,\nthey have long been superseded by the more reactive Grignard reagents\n(RMgX) and lithium organyls (RLi). The low reactivity of organozinc\ncompounds in combination with a high sensitivity to oxygen and moisture\nlead to difficult handling and problematic storage. Their usefulness\nfor C–C bond formation was therefore underestimated for a long\ntime but has experienced a renaissance in recent decades. In a previous\npublication, the scalable continuous synthesis of organozinc compounds\nin different concentrations and solvents was demonstrated. The organozinc\ncompounds were produced in both laboratory and pilot scale with good\nto very good yields and the formation of highly concentrated organozinc\ncompounds was also confirmed. To build on this work, the continuous\nconversion of organozinc compounds is described below. Two different\nreaction types were investigated: the noncatalyzed Saytzeff reaction\nand the palladium-catalyzed Negishi cross-coupling reaction. The former\nwas carried out in both a two-step and a one-pot approach. The reactive\nallylzinc bromide was chosen as the organometallic reagent, which\nwas reacted with various aldehydes and ketones to yield secondary\nor tertiary homoallyl alcohols. In the Saytzeff reaction, residence\ntimes of 2.0 min were sufficient to achieve complete conversion of\nthe carbonyl compound and isolated yields of 66–98%. The conversion\nof the carbonyl compound was monitored using an online process IR\nspectrometer with flow cell. In the case of the Negishi coupling,\na fixed-bed reactor filled with Pd catalyst was used. The syntheses\ninvestigated were focused on the reaction of benzylzinc bromide with\nvarious functionalized organic halides. The Negishi coupling provided\ncomplete to near complete conversion of the electrophilic substrate\nwith isolated yields of 72–92% at residence times of 23–32\ns. Both the Saytzeff and Negishi reactions were extended to include\nthe conversion of highly concentrated 2.0 M organozinc compounds.\nThe former delivered yields of 83% and 92%, the latter 72% and 79%.\nThe Saytzeff conversion was additionally transferred to pilot scale\nto demonstrate the ease of scalability. The synthesis of two selected\ncompounds was successfully transferred to pilot scale, where a liquid\nthroughput of 13 L/h was achieved. The main objective of this work\nwas to establish various catalyzed and noncatalyzed conversions of\norganozinc reagents, particularly at high organozinc reagent concentrations\nto enable fast and safe process intensification, optimization and\nscalability to industrially relevant throughputs.