Organophotocatalytic N–O Bond Cleavage of Weinreb Amides: Mechanism-Guided Evolution of a PET to ConPET Platform

Abstract

A mild, organophotocatalytic N–O bond cleavage of Weinreb amides is disclosed, thereby expanding the chemistry of this venerable motif beyond acylation. This redox neutral process begins to reconcile the ubiquity of N–O bonds in contemporary synthesis with the disproportionately harsh, stoichiometric conditions that are often required for bond cleavage. The strategy is compatible with the parent alkyl derivatives (N–OMe, N–OAlkyl), thereby complementing tailored O-substituent approaches that require N–OAr groups (Ar = electron-deficient). A broad range of acyclic and cyclic derivatives are disclosed (>40 examples, up to 95%), and the synthetic utility of the method is demonstrated in a range of applications. In the case of cyclic Weinreb amide derivatives, this platform enables ambiphilic amide aldehydes, of varying chain lengths, to be generated in a single transformation. Inspired by Emil Fischer’s seminal 1908 synthesis of aminoacetaldehyde using sodium amalgam, this method provides a milder route to access this important class of materials. Mechanistically guided reaction development demonstrates the involvement of a photoinduced electron transfer (PET) mechanism, and this has been further advanced to a consecutive photoinduced electron transfer (ConPET) manifold: this has significantly expanded the scope of compatible substrates.

A general photocatalytic strategy for nucleophilic amination of primary and secondary benzylic C–H bonds

“…While the NMR experiments described are suggestive that the ground-state PC •is reducing HAT reagent, under the standard reaction conditions, which include constant irradiation with blue LEDs, we cannot necessarily rule out a consecutive photoinduced electron transfer (ConPET) process wherein the photocatalyst radical anion is excited by a second photon to generate the excited-state radical anion *CF3-4-CzIPN •-. [45][46][47][48] Taken together, these results are consistent with the proposed catalytic cycle in Figure 6. The reaction is initiated by an offcycle reductive quenching of *CF3-4-CzIPN to generate its ground-state radical anion, which subsequently reduces the HAT reagent followed by mesolytic fragmentation to generate the active amidyl radical species.…”

Metal–Organic Bichromophore Lowers the Upconversion Excitation Power Threshold and Promotes UV Photoreactions

“…Storing roughly 3.68 eV of excitation energy (Table ), the fluorescent singlet-excited state of 2,5-diphenyloxazole ( 1 * PPO ) is a fairly strong reducing agent with an oxidation potential of −2.2 V vs SCE (Supporting Information Section 10). , Consequently, it seemed attractive to explore whether 1 * PPO , formed via upconversion of visible light, can catalyze chemical reductions that previously required UV irradiation, such as the recently reported reductive N–O bond cleavage reactions of Weinreb amides (Figure a) . The reduction potential of these substrates is tunable through variation of the substituent R in para-position to the protected amide group (Table S7).…”

“…The Paterno−Buchi reaction between two benzaldehydes and furan usually relies on 365 nm (3.40 eV) irradiation, 76 whereas here it was accomplished with 447 nm light (2.77 eV), owing to energy transfer from the upconverted PPO state at 3.68 eV. N−O bond cleavage reactions of three Weinreb amides, normally requiring UV activation, 77 and one thermodynamically demanding C−C coupling reaction were driven by blue light, as a result of the strongly reducing character of the formed PPO singlet-excited state. The proof-of-concept that several different chemical reaction types, some relying on energy transfer and others functioning on the basis photoinduced electron transfer, become accessible after blue-to-UV upconversion represents another key novelty of our study.…”

“…Following this initial elementary process enabled by upconversion, the deprotection of the Weinreb amide is expected to proceed along the same reaction pathway as postulated for direct UV excitation (Scheme S1). 77 Substrate 1 is converted to product 1-P in 71% yield under 447 nm irradiation of 1 mol % Ir Naph as the sensitizer and 10 mol % PPO as the annihilator. Control experiments confirm that both upconversion components (sensitizer, annihilator) and light are indispensable for this reaction (Table S8 and Figures S30−S36), and only a minor background reactivity (17% yield of 1-P) is observed when the annihilator is missing (Supporting Information Section 12.1).…”

Sensitizer-controlled photochemical reactivityviaupconversion of red light

“…1 In these cases, two (or more) photons are required per catalytic turnover, but thermodynamically unusually challenging reactions become accessible as a result of the combined energy input from multiple photons. Most systems investigated in this context operate on the basis of a single photocatalyst, for example involving consecutive photoinduced electron transfer (conPET), 2–10 photoionization processes, 11,12 structural in situ catalyst modifications, 13–15 or light-driven catalyst recovery. 16,17 The combination of a photoredox catalyst with a co-catalyst is less common, 18,19 and combinations of two photoactive catalysts are yet very scarce.…”