Shine light on your chemistry! Irradiating 3-(4-methoxyphenyl)-3-(trifluoromethyl)-3H-diazirine in the presence of equimolar solutions of phenol and tyrosine derivatives leads to Friedel-Crafts alkylations (see scheme), which suggests a strategy for the development of "cleaner" diazirines for chemical biology.

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The first photoreactive derivative of the cytotoxic marine natural product psammaplin A (1) has been synthesized by appending 1‐azi‐2,2,2‐trifluoroethyl moieties at both benzene rings. Photopsammaplin 8 exhibited anticancer activity in vitro with a geomean IC50 value of 1.4 μM in a panel of 42 human cancer cell lines. Particularly sensitive cell lines were found among bladder, lung, mammary, and prostate cancer as well as melanoma (MEXF 276), with IC50 values ≤ 0.6 μM. In a COMPARE analysis, diazirine‐functionalized photopsammaplin exhibited a very similar cytotoxicity profile to that of the natural product 1. Furthermore, photopsammaplin 8 was found to be a potent HDAC inhibitor (IC50 35 nM) and can be considered as a suitable candidate for photoaffinity labeling, which may assist in the identification of new targets of psammaplin A. Irradiation experiments with a model diazirine‐functionalized α‐hydroxy iminoester in dichloromethane in the presence or absence of acetic acid and methanol revealed the stability of the oxime unit and confirmed that reactions took place solely at the carbene center. The isolation of triplet and singlet photoproducts is consistent with DFT calculations [B3LYP 6‐311G (2d,2p)] showing that, in polar solvents, the triplet‐singlet gap is very small.

The synthesis, thermal stability, and photoreactivity of trifluoromethyl diazirines installed at the heterocyclic section of N‐methylindole, N‐methylbenzimidazole, and at N‐methylimidazole were investigated. N‐Tosyl‐3‐diazirinylindole and N‐methyl‐2‐diazirinylbenzimidazole proved to be thermally stable, whereas the corresponding 2‐diazirinylindole was not. The least stable was 2‐diazirinylimidazole, which underwent rapid decomposition. Quenching with ethanol indicated that the corresponding carbene was formed. Decomposition is rationalized by exothermic coarctate ring‐opening of the carbene. Quantum mechanical calculations [B3LYP/6‐311G(2d,2p)] predict singlet ground states of all carbenes. Accordingly, Friedel–Crafts alkylation products were formed on irradiation (350 nm, Rayonet) of the N‐methylbenzimidazole‐based diazirine in the presence of phenol.

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