In pharmaceutical research and development, N-Boc deprotection (deBoc) ranks among the top three most frequently-encountered reactions. Compared to either homogeneously-catalyzed reactions operated in batch mode or thermal (non-catalytic) conditions, conducting N-Boc deprotection with a heterogeneous catalyst in a continuous flow reactor has several potential advantages, including enhanced efficiency and productivity due to elimination of separation requirements, compatibility with more benign solvents, and lower operating temperatures. In this study, the use of solid Brønsted acids to catalyze the N-Boc deprotection reaction under continuous flow conditions was explored. The microporous strongly acidic zeolite H-Beta affords &gt;90 % yields of a variety aromatic and aliphatic amines within minutes at 140 °C using THF as the solvent, without additional isolation workup. The same catalyst is ineffective in batch conditions, in part due to the much lower reaction temperature of refluxing THF. A throughput of ca. 14 mmol.h-1.g-1 was sustained for 48 h in the flow process. Interestingly, the active sites are not the strongly Brønsted acidic protons associated with Al substitution (AlOHSi) in the zeolite framework, since Na+-exchanged Beta is also an effective catalyst. The strong acid sites are poisoned rapidly by the amine product under reaction conditions. Instead, weaker Brønsted acid sites that are unaffected by Na+-exchange are believed to be the active sites.

Continuous flow N-Boc deprotection of amines using solid acid catalysts

2019 Fall National Meeting

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