Metabolism Mimicry: An Electrosynthetic Method for the Selective Deethylation of Tertiary Benzamides

Abstract

The electrosynthetic deethylation of tertiary amides, commonly encountered moieties in pharmaceuticals and agrochemicals, is an analogue of the function of cytochrome P450 enzymes, a major oxidant metabolic pathway for xenobiotics. The ability to tractably synthesise, in a late‐stage manner, drug metabolites from the parent drug is currently unsolved. We report the first study, mechanistic rationale, and synthetic scope of an undivided controlled current electrosynthetic method that selectively mono deethylates tertiary amides without over‐reaction. An optimisation survey found that changing the electron input from controlled voltage to controlled current conditions led to deethylation rather than the expected dehydrogenative coupling. The scope and limitations of the method were interrogated with 14 examples with the parent benzamide reaction optimised (86 % yield) and the scalable production of the major human metabolite of the insect repellent DEET was achieved from the parent molecule in one step.

Electrically Driven N(sp2)–C(sp2/3) Bond Cleavage of Sulfonamides

“…This is a markedly different reactivity to the related amide bond containing systems that stop further C−N bond scission after monodealkylation is accomplished. 9 Furthermore, the reaction proceeds in flow using the commercially available Ammonite8 electroflow reactor. 55 In comparison to the batch process, a significant lowering of electrolyte loading was possible due to the 500 μm interelectrode gap (5.0 mM LiClO 4 ).…”

The preparation and applications of amides using electrosynthesis

“…55,56 Finally, the use of Shono-type oxidation has even been extended to the selective deethylation of tertiary amides (a common pharmaceutical moiety) in a metabolism-mimicking protocol, as reported by Bal and co-workers in 2019. 57 The N-dealkylation of drug molecules is a common metabolism pathway facilitated by cytochrome P450. This work, carried out in an undivided cell and shown in Scheme 36, demonstrates the potential for late-stage synthesis of drug metabolites directly from the parent drug using electrosynthesis, saving a great deal of intellectual and practical effort if the same metabolites were to be synthesised independently.…”

“…It was proposed that the reduction of MeOH and H + ions was taking place at the cathode in this reaction. 57…”

Electrochemical Formation of Cinnamaldehyde by the Electrolyte System N,N‐Diisopropylethylamine and 1,1,1,3,3,3‐Hexafluoropropan‐2‐ol

“…m-Fluorobenzaldehyde led to 7 in 47 % yield. The other halogen groups gave the corresponding products in low yields (8)(9)(10)(11)(12). This can be attributed to the cleavage of the halogen by cathodic reduction since benzaldehyde was detected.…”

“…Given that the oxidation potential of DIPEA (+ 0.8 V vs. Ag/AgCl) is the lowest in this reaction media ( Figure S1), it is reasonable to suppose that two electrons oxidation occurs and that the corresponding iminium cation species are generated. [10] Moreover, the addition of water is required (Table 1, entry 2), which suggests that hydrolysis can take place, [11] generating acetaldehyde and N,N-diisopropylamine. To support this claim, the reaction was carried out with 18 O-labeled water (Scheme 3a).…”