Taming tosyl azide: the development of a scalable continuous diazo transfer process

Abstract

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.

An Immobilized‐Dirhodium Hollow‐Fiber Flow Reactor for Scalable and Sustainable C−H Functionalization in Continuous Flow

“…First, the metal carbenes are created by using relatively reactive and unstable diazo compounds, which are potentially explosive and highly toxic. Thus, such reactive compounds are ideally not stored in large quantities on site, and just‐in‐time syntheses are preferred . The price of the soluble dirhodium catalysts (Rh 2 L 4 , L=ligand) is another barrier for industrial applications.…”

An Immobilized‐Dirhodium Hollow‐Fiber Flow Reactor for Scalable and Sustainable C−H Functionalization in Continuous Flow

“…Thus,such reactive compounds are ideally not stored in large quantities on site,a nd just-in-time syntheses are preferred. [17][18][19][20][21][22][23][24][25][26][27] Thep rice of the soluble dirhodium catalysts (Rh 2 L 4 ,L= ligand) is another barrier for industrial applications.R hodium is av ery expensive noble metal and the cost for the synthesis of these ligands for the catalysts also cannot be ignored. To recycle the homogenous dirhodium catalysts, additional separation steps are required and the catalytic activities are often not maintained after recovery and recycle.…”

Exploiting the Continuous in situ Generation of Mesyl Azide for Use in a Telescoped Process

“…A continuous process for formation and use of tosyl azide 1 in situ has previously been developed within the group (Scheme ) . This process involves combining a stream of aqueous sodium azide with a stream of tosyl chloride 2 in acetonitrile at ambient temperature leading to rapid generation of tosyl azide 1 .…”

“…The use of azides, diazo compounds and even diazonium salts in flow is well documented . Following several studies involving diazo transfer in flow that directly utilized sulfonyl azides, we recently reported a scalable continuous diazo transfer process where tosyl azide was generated and used in situ, overcoming the challenges of employing this hazardous reagent on large scales . A similar approach has since been employed by Monbaliu as part of a strategy for continuous synthesis of Ritalin .…”