Improved Synthesis of 1-(Azidomethyl)-3,5-bis-(trifluoromethyl)benzene: Development of Batch and Microflow Azide Processes

Abstract

A batch process was developed to produce 1-(azidomethyl)-3,5-bis-(trifluoromethyl)benzene, 1, in 94% yield by an efficient nucleophilic substitution reaction between 3,5-bis-(trifluoromethyl)benzyl chloride, 4, and sodium azide. Hydrazoic acid (HN3), a toxic volatile compound with explosive properties, can be formed in the reactor headspace during conventional batch processing that requires significant engineering controls. In order to improve the overall safety profile, the process to produce azide 1 was optimized for operation in a microcapillary tube reactor. In addition, azide 1 was prepared in a simple biphasic solvent system using phase-transfer catalysis which results in an overall low e-factor. The product was purified via wiped film evaporation (WFE) technology.

9.03 Organic Synthesis in Small Scale Continuous Flow: Flow Chemistry

“…33 Unfortunately, HN 3 is extremely toxic (comparable to HCN) and owing to the explosive nature and low boiling point (37 1C) of this high-energy material, [34][35][36] procedures involving free HN 3 have not found many practical applications.…”

Hydrazoic Acid and Azides

“…The S N 2 reaction of alkyl halides [93] (chlorides [94] or bromides) or alkyl sulfonates (such as mesylates [95,96], brosylates [97], triflates [98] or tosylates) with sodium azide is generally applicable in the aliphatic series. Dimethylformamide is particularly suitable as solvent.…”

Microfluidics in Planar Microchannels: Synthesis of Chemical Compounds On-Chip

“…Kopach reported (Kopach et al 2009) the development of a continuous flow reactor suitable for the synthesis of azide from the chloride (Fig. 8.23 (2008) demonstrated the efficient synthesis of fluorinated alcohols, aldehydes and carboxylic acids using diethylaminosulphurtrifluoride (DAST) in a PTFE tube reactor (Volume, 16 mL).…”