Heat and shock sensitive tosyl azide was generated and used on demand in a telescoped diazo transfer process. Small quantities of tosyl azide were accessed in a 'one pot' batch procedure using shelf stable, readily available reagents. For large scale diazo transfer reactions tosyl azide was generated and used in a telescoped flow process, to mitigate the risks associated with handling potentially explosive reagents on scale. The in situ formed tosyl azide was used to rapidly perform diazo tranfer to a range of acceptors, including β-ketoesters, β-ketoamides, malonate esters and β-ketosulfones. An effective in-line quench of sulfonyl azides was also developed, whereby a sacrificial acceptor molecule ensured complete consumption of any residual hazardous diazo transfer reagent. The telescoped diazo transfer process with in-line quenching was used to safely prepare over 21 g of an α-diazocarbonyl in >98% purity without any column chromatography.
Abstract:The hazardous diazo transfer reagent mesyl azide has been safely generated and used in situ for continuous diazo transfer as part of an integrated synthetic process with an embedded safety quench. Diazo transfer to -keto esters and a -
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.
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