Continuous Process to Safely Manufacture an Aryldiazoacetate and Its Direct Use in a Dirhodium-Catalyzed Enantioselective Cyclopropanation

Abstract

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.

Diastereoselective Synthesis of Cyclopropanes from Carbon Pronucleophiles and Alkenes

“…While indisputably effective, the modularity of these methods is limited by the requisite synthesis of unique carbene precursors to deliver each distinct substituent. Furthermore, hazardous diazo compounds are commonly required, which further complicates broad implementation due to safety concerns [41–57] . Despite these varied approaches to prepare cyclopropanes, development of new approaches is an area of contemporary interest [58–63] .…”

“…Furthermore, hazardous diazo compounds are commonly required, which further complicates broad implementation due to safety concerns. [41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] Despite these varied approaches to prepare cyclopropanes, development of new approaches is an area of contemporary interest. [58][59][60][61][62][63] Overall, a modular annulative cyclopropane synthesis that couples two abundant building blocks has remained elusive and is poised to substantially impact synthetic chemistry.…”

Photosensitized O 2 enables intermolecular alkene cyclopropanation by active methylene compounds

“…Among the limited methods available for intermolecular cyclopropanation ( 8 ), the most preferred and reliable is carbene insertion into alkenes ( 9 – 11 ). This method is profoundly dependent on reactive carbene and metal-carbenoid intermediates [[M]=CR 2 ], in particular the donor-acceptor Rh-carbenoids ( 9 , 10 , 12 ) derived from highly energetic diazoalkanes, which require stringent precautions for handling ( 13 , 14 ). The metal-carbenoids are typically generated from diazomethane (CH 2 N 2 ), TMSCHN 2 , PhCHN 2 , and α-diazocarbonyl compounds by decomposition in reaction with transition-metal [M] catalysts ( 8 , 15 , 16 ), and more recently under photoredox ( 17 , 18 ) and engineered enzymatic ( 19 – 22 ) conditions.…”

Rapid and Safe Continuous‐Flow Simmons‐Smith Cyclopropanation using a Zn/Cu Couple Column

“…However, this process was conducted in a batch manner. In subsequent years, Charette [12] and Lathrop [13] devised a scalable and safer approach for the continuous-flow production of diazo compounds, eliminating the need for a metal cartridge. Despite their efforts, no significant advancements were made in the cyclopropanation reaction, and the requirement for batch conditions remained unchanged.…”