We report the development and demonstration
of a continuous-flow
process for the safe formation, extraction, and drying of aryldiazoacetate 2, which enables direct use in a fed-batch dirhodium-catalyzed
enantioselective cyclopropanation reaction to provide cyclopropane 4. Designing this process with safety as a primary objective,
we identified the appropriate arylsulfonyl hydrazone starting material
and organic soluble base to facilitate a Bamford–Stevens diazo-generating
flow process at 30 °C, well below the thermal onset temperature
(T
onset = 57 °C), while also minimizing
accumulation of the highly energetic diazo intermediate (ΔH
D = −729 J/g). The Bamford–Stevens
reaction byproducts are efficiently removed via a continuous aqueous
extraction utilizing a liquid–liquid hydrophobic membrane separator.
Continuous molecular sieve drying of the organic layer was demonstrated
to maintain water levels <100 ppm in the final aryldiazoacetate
solution, thereby ensuring acceptable reactivity, selectivity, and
purity in the water sensitive cyclopropanation reaction. The full
process was successfully executed on a 100 g scale, setting the foundation
for the wider application of this and related chemistries on a kilogram
scale.
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