As a safe alternative to diazomethane, trimethylsilyldiazomethane (TMSCHN2) is a versatile, widely-used synthetic reagent. Trimethylsilyldiazomethane can either be commercially obtained or can be prepared from TMSCH2MgCl and diphenyl phosphoryl azide. Although this synthetic approach provides access to TMSCHN2 in good yields on large scale, disadvantages to this approach include both long reaction times and extensive product purification. Furthermore, these heterogenous reaction conditions are incompatible with continuous flow synthesis. Designing a new synthesis of TMSCHN2 is challenging, considering the limited number of available starting materials. Our synthetic strategy employs TMSCH2NH2 as a TMSCHN2 precursor. We envisioned that diazotization of TMSCH2NH2 could achieve access to TMSCHN2 via a continuous flow process. We first developed a protocol to produce TMSCH2NH2 in a cost-effective manner. Condensation of TMSCH2Cl with NH4OH afforded TMSCH2NH2 with a daily production of 500 mmol via continuous flow synthesis. The diazotization of TMSCH2NH2 proved challenging as TMSCHN2 is 10,000 times more nucleophilic compared to other diazo reagents such as ethyldiazoacetate. After a careful optimization, the diazotization of TMSCH2NH2 was successfully achieved in batch using propyldinitrite in 2-MeTHF for 20 min. Under these reaction conditions in continuous-flow synthesis, TMSCHN2 was produced as a 0.65 M solution in 2-MeTHF (2.4 mol.d-1). Additionally, other silylated diazomethane reagents were accessible via the optimized continuous-flow conditions. The synthetic utility of trimethylsilyldiazomethane and its related diazo analogues was then demonstrated. For example, a user-friendly one-pot diazotization/esterification continuous-flow procedure employing TMSCHN2 was developed to afford esters from carboxylic acids. Pyrazole synthesis was also possible by adding TMSCHN2 to alkynes, via a [3+2] cycloaddition. Finally, using TMSCHN2 as an isolated solution in 2-MeTHF, both Colvin rearrangement and transition metal-catalyzed methylenation of aldehydes were achieved. This poster presentation will present details of both the synthesis and the use of TMSCHN2 and its related diazo analogues.

Synthesis of silylated diazo reagents via continuous flow synthesis

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.