Exploiting Continuous Processing for Challenging Diazo Transfer and Telescoped Copper-Catalyzed Asymmetric Transformations

Abstract

Generation and use of triflyl azide in flow enables efficient synthesis of a range of α-diazocarbonyl compounds, including α-diazoketones, α-diazoamides, and an α-diazosulfonyl ester, via both Regitz-type diazo transfer and deacylative/debenzoylative diazo-transfer processes with excellent yields and offers versatility in the solvent employed, in addition to addressing the hazards associated with handling of this highly reactive sulfonyl azide. Telescoping the generation of triflyl azide and diazo-transfer process with highly enantioselective copper-mediated intramolecular aromatic addition and C–H insertion processes demonstrates that the reaction stream containing the α-diazocarbonyl compound can be obtained in sufficient purity to pass directly over the immobilized copper bis(oxazoline) catalyst without detrimentally impacting the catalyst enantioselectivity.

Generation of Tosyl Azide in Continuous Flow Using an Azide Resin, and Telescoping with Diazo Transfer and Rhodium Acetate-Catalyzed O–H Insertion

“…Building on our previous reports, − formation of methyl 2-diazo-2-chlorophenylacetate ( 9 ) was envisaged through telescoped generation of tosyl azide 12 in aqueous acetonitrile followed by diazo transfer in continuous flow, with subsequent incorporation of rhodium-mediated O–H insertion to form 10 (Scheme ). At the outset, the key challenge was to establish if the diazo transfer could be telescoped with a rhodium-mediated insertion into water, without isolation of the α-aryl-α-diazoacetate 9 .…”

“… 4 , 5 While modified sulfonyl azides have been developed with improved safety profiles, none of these fully resolve the concerns in effecting diazo transfer at scale using a preprepared sulfonyl azide. 4 , 5 , 26 − 31 In recent years, our team has developed a number of protocols for in situ generation of sulfonyl azides followed by diazo transfer, 22 together with telescoping with downstream reactions, including thermal Wolff rearrangement and ketene trapping, 23 copper catalyzed C–H insertion and aromatic additions, 24 and rhodium-mediated S–H insertion. 25 In parallel with our work on the synthesis and use of sulfonyl azides in flow, Krasavin has described in situ generation and use of sulfonyl azides as “sulfonyl azide-free” aqueous phase diazo transfer, under traditional batch conditions.…”

“…The exploitation of α-diazocarbonyl chemistry has been a key beneficiary of advances in continuous processing. − ,− Continuous methodologies for the generation of diazomethane have been reported, including the use of tube-in-tube reactors . Furthermore, generation and use of sulfonyl azides in continuous flow has been demonstrated, obviating the requirement to isolate and handle these potential hazardous reagents. ,− While the Regitz diazo transfer from sulfonyl azides is a remarkably efficient and generally applicable process working with a wide variety of acceptors, the hazards associated with use and handling of sulfonyl azides are well documented. , While modified sulfonyl azides have been developed with improved safety profiles, none of these fully resolve the concerns in effecting diazo transfer at scale using a preprepared sulfonyl azide. ,,− In recent years, our team has developed a number of protocols for in situ generation of sulfonyl azides followed by diazo transfer, together with telescoping with downstream reactions, including thermal Wolff rearrangement and ketene trapping, copper catalyzed C–H insertion and aromatic additions, and rhodium-mediated S–H insertion . In parallel with our work on the synthesis and use of sulfonyl azides in flow, Krasavin has described in situ generation and use of sulfonyl azides as “sulfonyl azide-free” aqueous phase diazo transfer, under traditional batch conditions …”

Synthesis of Diazo Compounds by Using NaN3 and Inexpensive SO2F2

“…Meanwhile, diazo compounds will receive more and more applications in industry with the progress of continuous flow technology. [9] In view of the unique value of diazo compounds in organic synthesis, chemists have developed a variety of approaches to synthesize them. [10a] In brief, these methods include diazo transfer reaction of active methylene compounds, oxidation of hydrazones, diazotization of primary aliphatic amines, reactions of sulfonylhydrazones and N-alkyl-N-nitrososulfonamides with bases, and electrophilic substitution of diazomethyl compounds.…”

“…The chemistry of diazo compounds has attracted long‐standing interests to organic chemists. Meanwhile, diazo compounds will receive more and more applications in industry with the progress of continuous flow technology [9] …”