Scale-up of Azide Chemistry: A Case Study

Abstract

We report research and development conducted to enable the safe implementation of a highly enantioselective palladium-catalyzed desymmetrization of a meso−bis-ester using trimethylsilylazide (TMSN 3 ) as the nucleophile. This work is used as a case example to discuss safe practices when considering the use of azide reagents or intermediates, with a focus on the thermodynamic and quantitative analysis of the hazards associated with hydrazoic acid (HN 3 ).

9.03 Organic Synthesis in Small Scale Continuous Flow: Flow Chemistry

“…Furthermore, the available concentration of HN 3 should in fact be significantly higher than that in a sealed microwave vessel, where a large amount of this volatile reagent can be expected to be in the gas phase. 40 For flow processing (Figure 9), the nitrile solution was pumped into the mixer (M, T-piece), joining the azide solution at a differential flow rate providing approximately 2.5 mol l À1 excess of azide. The resulting stream was passed through the Sulfinert reactor coil (approximately 10 ml heated volume) at 220 1C at a system pressure of 3.6 MPa.…”

Gold‐Catalyzed Synthesis of Tetrazoles from Alkynes by CC Bond Cleavage

“…We first studied the reaction of the aryl alkynes 1 a – c with TMSN 3 [ 16 ] and complex A under stoichiometric conditions. Surprisingly, the reaction gave 5-methyl-1-aryl-1 H -tetrazole–gold(I) complexes ( 9 a – c ) as crystalline white solids, whose structures were determined by X-ray diffraction (Scheme 4 ).…”

Allylic azides: synthesis, reactivity, and the Winstein rearrangement

“…These reagents have been used on large scales. [38][39][40][41][42][43][44] However, improper use has resulted in explosions. 45 Reactions involving nucleophilic azides (e.g.…”