Abstract
We report an organophotocatalytic, N–CH3-selective oxidation of trialkylamines in continuous flow. Based on the 9,10-dicyanoanthracene (DCA) core, a new catalyst (DCAS) was designed with solubilizing groups for flow processing. This allowed O2 to be harnessed as a sustainable oxidant for late-stage photocatalytic N–CH3 oxidations of complex natural products and active pharmaceutical ingredients bearing functional groups not tolerated by previous methods. The organophotocatalytic gas–liquid flow process affords cleaner reactions than in batch mode, in short residence times of 13.5 min and productivities of up to 0.65 g per day. Spectroscopic and computational mechanistic studies showed that catalyst derivatization not only enhanced solubility of the new catalyst compared to poorly-soluble DCA, but profoundly diverted the photocatalytic mechanism from singlet electron transfer (SET) reductive quenching with amines toward energy transfer (EnT) with O2.
Highlights
A quintessential theme in medicinal chemistry is probing structure activity relationships
Inspired by intermediates reported in the synthesis of a water-soluble DCA analogue,[39] we began our catalyst synthesis (Fig. 3)
At 7–8 bar, doubling the concentration to 48 mM or using a residence time as short as RT 1⁄4 6.8 min negatively impacted the yield of 2b, but we found that yield (61%) was preserved at RT 1⁄4 13.5 min
Summary
A quintessential theme in medicinal chemistry is probing structure activity relationships. Using 1a (12 mM) as our substrate and 5 mol% of DCAS at rt, a maximum yield of 25% for 2a (with 4 : 1 of 2a : 3a selectivity) was obtained under recycling conditions (90 min) no matter whether dry air, O2, or (1 : 1) N2/O2 were used (entry 2).
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