Factors Influencing the Regioselectivity of the Oxidation of Asymmetric Secondary Amines with Singlet Oxygen

Abstract

Aerobic amine oxidation is an attractive and elegant process for the α functionalization of amines. However, there are still several mechanistic uncertainties, particularly the factors governing the regioselectivity of the oxidation of asymmetric secondary amines and the oxidation rates of mixed primary amines. Herein, it is reported that singlet-oxygen-mediated oxidation of 1° and 2° amines is sensitive to the strength of the α-C-H bond and steric factors. Estimation of the relative bond dissociation energy by natural bond order analysis or by means of one-bond C-H coupling constants allowed the regioselectivity of secondary amine oxidations to be explained and predicted. In addition, the findings were utilized to synthesize highly regioselective substrates and perform selective amine cross-couplings to produce imines.

Recent Advances in Aerobic Oxidation of Alcohols and Amines to Imines

“…110 As shown in Figure 1, a good linear relationship between the selectivity and the difference in % s character can be established for unsymmetric secondary amines with less bulky substituents (circle dots). The amines with higher differences in % s character gave better selectivity than those with lesser differences, and the oxidative dehydrogenation was preferred to occur at the less hybridized α-CH side (Scheme 34a).…”

“…97 In addition, primary benzylic amines were also suitable for the reaction. It was revealed that the exposure of both (040) and (110) facets of BiVO 4 played important roles in promoting the spatial separation of photogenerated electrons and holes to enhance the catalytic activity. Considering the steric hindrance around the nitrogen atom, the adsorption of bulky N-tert-butyl derivatives on BiVO 4 was unfavorable, and the substrates, therefore, were likely to be oxidized via a direct oxidative dehydrogenation pathway rather than the formation of aldehyde intermediates.…”

Liquid phase oxidation chemistry in continuous-flow microreactors

“…Recently, the method was extended to allow for the preparation unnatural amino acids 193 and selective crosscondensation of amines. 194 Scheme 18. Continuous-flow aerobic oxidative cyanation of primary and secondary amines using singlet oxygen.…”

A flow reactor setup for photochemistry of biphasic gas/liquid reactions

“…Stimulated by the ground-breaking works of the Seeberger [41–42 47,50–51], Booker-Milburn [52–53], and Noël [34,54–55] groups in recent years, we therefore decided to develop our own home-made flow reactor for photooxidations of organic molecules but also envisaged its general applicability to other challenging processes with the ternary “reagent” combinations liquid/gas/light. With the objective of constructing a robust and versatile flow reactor, we set out to explore and test commercially available parts.…”

“…Under irradiation in the presence of a sensitizer, singlet oxygen can easily be generated from the triplet ground state. Several applications of such photooxidations to chemical synthesis have been reported [71–73], in recent years most effectively under microflow conditions [41–42 50–51 74–75]. …”