Divergent Reactions of Coumarin- and 7-Azacoumarin-3-Carboxylic Acids with Azomethine Ylides: Spirocyclization and Ring Expansion

Abstract

A series of new spiro-fused polycyclic systems has been synthesized via cascade reactions of 7-azacoumarin-3-carboxylic acid and coumarin-3-carboxylic acid derivatives with azomethine ylides generated in situ from L-proline or sarcosine and various carbonyl components (ninhydrin, aceanthrenequinone, isatin, and substituted isatins). For the conventional cycloaddition products (derived from isatin with L-proline or sarcosine), the cascade reactions contain a 1,3-dipolar cycloaddition with a decarboxylation step, affording a single detectable diastereomer in each case. For those products for which single-crystal X-ray structures were obtained, the crystals belong to centrosymmetric space groups, so the compounds are racemic. The reaction of 7-azacoumarin-3-carboxylic acids with the ylides derived from L-proline and ninhydrin or aceanthrenequinone provides the first example of a pyrrolidine-to-piperidine ring expansion (5→6); this transformation is currently demonstrated only for a limited set of substrates and should be regarded as a proof-of-concept rather than a general method. Transformation differs mechanistically from the conventional cycloaddition–decarboxylation; the proposed mechanism is presented as a working hypothesis. The effect of the solvent on the structure of the final products of reaction of 7-azacoumarin-3-carboxylic acid with ylides based on sarcosine and isatins is shown: in methanol, ring-opened esters are formed, whereas in acetonitrile the coumarin fragment is retained. The structures of all products were established by comprehensive NMR spectroscopy, IR, and mass spectrometry. Single-crystal X-ray diffraction was performed for representative compounds 6a, 10, 12a, 17a, and 20a. The synthesized compounds were evaluated for their in vitro cytotoxic activity against M-HeLa, HuTu80, and A549 tumour cell lines, as well as against the normal Wi-38 fibroblast line. For compounds 10 and 17d, the IC50 values against M-HeLa cells were numerically similar to those of the reference drug 5-fluorouracil, while compound 6b gave an IC50 against HuTu80 cells numerically similar to that of 5-fluorouracil. Compound 10 gave a numerically lower IC50 value than 5-fluorouracil against A549 lung carcinoma cells. These results should be regarded as a preliminary cell-viability screening rather than evidence of therapeutic potential; the spirocyclic scaffolds provide a starting point for further structure–activity investigation.