To expand the utility of α-cleavage at cryogenic temperatures, we investigated the photoreactivity of 2-azido-2-phenyl-1,3-indandione (1). EPR spectroscopy revealed that irradiating 1 in 2-methyltetrahydrofuran (mTHF) matrices forms alkylnitrene 3 2, which has zero-field splitting parameters (D/hc = 1.5837 cm–1; E/hc = 0.0039 cm–1) typical of an alkylnitrene. IR spectroscopy demonstrated that irradiating 1 in argon matrices results in the concurrent formation of 3 2, imine 3, benzocyclobutenedione 4, and benzonitrile 5.

To enhance the versatility of organic azides in organic synthesis, a better understanding of their photochemistry is required. Herein, the photoreactivity of azidoisoxazole 1 was characterized in cryogenic matrices with IR and UV-Vis absorption spectroscopy. The irradiation (λ = 254 nm) of azidoisoxazole 1 in an argon matrix at 13 K and in glassy 2-methyltetrahydrofuran (mTHF) at 77 K yielded nitrosoalkene 3. Density functional theory (DFT) and complete active space self-consistent field (CASSCF) calculations were used to aid the characterization of nitrosoalkene 3 and to support the proposed mechanism for its formation. It is likely that nitrosoalkene 3 is formed from the singlet excited state of azidoisoxazole 1 via a concerted mechanism or from cleavage of an intermediate singlet nitrene that does not undergo efficient intersystem crossing to its triplet configuration.

β-Lapachone is an ortho-naphthoquinone natural product with significant antiproliferative activity but suffers from adverse systemic toxicity. The use of photoremovable protecting groups to covalently inactivate a substrate and then enable controllable release with light in a spatiotemporal manner is an attractive prodrug strategy to limit toxicity. However, visible light-activatable photocages are nearly exclusively enabled by linkages to nucleophilic functional sites such as alcohols, amines, thiols, phosphates, and sulfonates. Herein, we report covalent inactivation of the electrophilic quinone moiety of β-lapachone via a C(sp3)–C(sp3) bond to a coumarin photocage. In contrast to β-lapachone, the designed prodrug remained intact in human whole blood and did not induce methemoglobinemia in the dark. Under light activation, the C–C bond cleaves to release the active quinone, recovering its biological activity when evaluated against the enzyme NQO1 and human cancer cells. Investigations into this report of a C(sp3)–C(sp3) photoinduced bond cleavage suggest a nontraditional, radical-based mechanism of release beginning with an initial charge-transfer excited state. Additionally, caging and release of the isomeric para-quinone, α-lapachone, are demonstrated. As such, we describe a photocaging strategy for the pair of quinones and report a unique light-induced cleavage of a C–C bond. We envision that this photocage strategy can be extended to quinones beyond β- and α-lapachone, thus expanding the chemical toolbox of photocaged compounds.

Intramolecular C–N bond formation is achieved through oxidative cyclization of 1-(3-arylisoquinolin-1-yl)-2-(arylmethylene)hydrazines, 3, in the presence of hypervalent iodine oxidant and dichloromethane at ambient temperature.

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