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they have long been superseded by the more reactive Grignard reagents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, op...
