Session: Flow Chemistry & Continuous Processes:

Alfa-haloketones are versatile starting materials for alkylation and various heterocyclization reactions. Haloketones derived from protected aminoacids stand out as precursors for functional azoles, which oftentimes are limited accessible via other synthetic routes. However, storage and transportation of alfa-haloketones require low temperatures and inert conditions, which, on average, is insufficient to keep these compounds from decomposition. In practice, this means that the safest way for usage alfa-haloketones as synthetic intermediates is their fresh preparation if necessary. It is noteworthy, that preparation of alfa-haloketones from diazoketones is a common laboratory protocol, which does not demand specialized equipment or special safety precautions. For the time being, only a few diazocarbonyl compounds, for example, diazoacetic ether, found their way to laboratories as safe stock reagents. In this regard, we have performed purity control for Boc-protected amino-alfa-diazocarbonyl compounds after prolonged storage times (up to 12 months) as dry powders at ambient temperature and found no signs of decomposition overtime for these samples. This gives grounds to view boc-protected amino-alfa-diazoketones as stable starting materials for respective alfa-haloketones synthesis.
Preparation of both, haloketones of diazo-precursors demands use of diazomethane, consequently possessing specialized equipment for its safe handling, especially when it comes up to synthesis in scale. Continuous flow generation of diazomethane has proven to be safe and scalable (up to 0.45 mol per hour) approach. Herein we report continuous flow diazomethane generation followed by its in-flow acylation with the formation of respective boc-protected amino-alfa-diazoketones in multi-hundred gram scale. Further study of this type of diazocarboniles showed that they could be purified via common liquid column chromatography on silica gel without decomposition. We have also conducted thermal stability check and found onset temperatures of decomposition at around 150 ^oC, which clearly indicates safe handling at ambient temperatures. The scope of the transformation is shown on 28 examples; the compounds were prepared with 70 – 90% preparative yields with >95% purity.

Viacheslav Pendiukh

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