Divergent Reactions of Coumarin- and 7-Azacoumarin-3-Carboxylic Acids with Azomethine Ylides: Spirocyclization and Ring Expansion
5 affiliations
- 1Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Science, Arbuzova Str., 8, Kazan 420088, Russia
- 2Laboratory of Engineering Profile “Physical and Chemical Methods of Analysis”, Korkyt Ata Kyzylorda University, Aiteke Bi Street, 29A, Kyzylorda 120014, Kazakhstan
- 3Institute for Radio-Electronics and Telecommunications, Department for Design and Techniques of Electronic Tools Manufacturing, Kazan National Research Technical University Named After A. N. Tupolev-KAI, Karl Marx Str., 10, Kazan 420111, Russia
- 4Institute Of Petroleum, Chemistry And Nanotechnologies, Department of General Organic and Petrochemical Synthesis Technology Named After Prof. G. Kamai, Kazan National Research Technological University, Karl Marx Str., 68, Kazan 420015, Russia
- 5Department of Chemistry and Biochemistry, Florida State University, 102 Varsity Way, Tallahassee, FL 32306-4390, USA
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.
Related
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BibTeX
@article{trifonov2026divergent,
title = {{Divergent Reactions of Coumarin- and 7-Azacoumarin-3-Carboxylic Acids with Azomethine Ylides: Spirocyclization and Ring Expansion}},
author = {Alexey V. Trifonov and Nurbol O. Appazov and Lyudmila K. Kibardina and Almir S. Gazizov and Alexandra D. Voloshina and Anna P. Luybina and Alexey B. Dobrynin and Igor A. Litvinov and Aiym E. Tolegen and Alexander R. Burilov and Michail A. Pudovik and Rakhymzhan A. Turmanov and Nurgali I. Akylbekov and Igor V. Alabugin and Elena A. Chugunova},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219600},
url = {https://www.mdpi.com/1422-0067/27/21/9600},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Divergent Reactions of Coumarin- and 7-Azacoumarin-3-Carboxylic Acids with Azomethine Ylides: Spirocyclization and Ring Expansion
AU - Alexey V. Trifonov
AU - Nurbol O. Appazov
AU - Lyudmila K. Kibardina
AU - Almir S. Gazizov
AU - Alexandra D. Voloshina
AU - Anna P. Luybina
AU - Alexey B. Dobrynin
AU - Igor A. Litvinov
AU - Aiym E. Tolegen
AU - Alexander R. Burilov
AU - Michail A. Pudovik
AU - Rakhymzhan A. Turmanov
AU - Nurgali I. Akylbekov
AU - Igor V. Alabugin
AU - Elena A. Chugunova
PY - 2026
DA - 2026/10/27
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219600
UR - https://www.mdpi.com/1422-0067/27/21/9600
AB - 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.
SN - 1422-0067
ER -