Abstract
Generation of tosyl azide 12 in acetonitrile in flow under water-free conditions using an azide resin and its use in diazo transfer to a series of aryl acetates are described. Successful telescoping with a rhodium acetate-catalyzed O–H insertion has been achieved, thereby transforming the aryl acetate 8 to α-hydroxy ester 10, a key intermediate in the synthesis of clopidogrel 11, without requiring isolation or handling of either tosyl azide 12 or α-aryl-α-diazoacetate 9, or indeed having significant amounts of either present at any point. Significantly, the solution of α-diazo ester 9 was sufficiently clean to progress directly to the rhodium acetate-catalyzed step without any detrimental impact on the efficiency of the O–H insertion. In addition, the rhodium acetate-catalyzed O–H insertion process is cleaner in flow than under traditional batch conditions. Use of the azide resin offers clear safety advantages and, in addition, this approach complements earlier protocols for the generation of tosyl azide 12 in flow; this protocol is especially useful with less acidic substrates.
Highlights
While the utility and versatility of α-diazocarbonyl compounds in synthetic chemistry are clearly evident, in many instances enabling transformations which are not effected using other methodologies, progression of this powerful, elegant, and efficient chemistry to use at scale has been impacted by safety challenges associated with these compounds, and more with their precursors.[1−5] there have been some notable advances in this area including the generation of diazomethane at scale[6] and N−H insertion in the Merck synthesis of thienamycin.[7]Developments in continuous flow processing offer an excellent approach to addressing the challenges associated with use of hazardous materials.[8]
During the course of this work we discovered that our previously reported approach for in-line synthesis of sulfonyl azides using aqueous sodium azide was not compatible with the aryl acetate precursor, and, a new approach was developed utilizing an azide resin as described thereby expanding the sulfonyl azide in flow protocols
Building on our previous reports,[22−25] formation of methyl 2diazo-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 4)
Summary
While the utility and versatility of α-diazocarbonyl compounds in synthetic chemistry are clearly evident, in many instances enabling transformations which are not effected using other methodologies, progression of this powerful, elegant, and efficient chemistry to use at scale has been impacted by safety challenges associated with these compounds, and more with their precursors (including, for example, diazoalkanes, sulfonyl azides).[1−5] there have been some notable advances in this area including the generation of diazomethane at scale[6] and N−H insertion in the Merck synthesis of thienamycin.[7]Developments in continuous flow processing offer an excellent approach to addressing the challenges associated with use of hazardous materials.[8]. While the utility and versatility of α-diazocarbonyl compounds in synthetic chemistry are clearly evident, in many instances enabling transformations which are not effected using other methodologies, progression of this powerful, elegant, and efficient chemistry to use at scale has been impacted by safety challenges associated with these compounds, and more with their precursors (including, for example, diazoalkanes, sulfonyl azides).[1−5] there have been some notable advances in this area including the generation of diazomethane at scale[6] and N−H insertion in the Merck synthesis of thienamycin.[7]. 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
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