Competition between charge and orbital control governs the divergent reactivity of hydrazines toward donor–acceptor cyclopropanes

Competition between charge and orbital control governs the divergent reactivity of hydrazines toward donor–acceptor cyclopropanes Научная публикация

Журнал

Organic Chemistry Frontiers
ISSN: 2052-4110 , E-ISSN: 2052-4129

Вых. Данные

Год: 2026, DOI: 10.1039/d6qo01409g

Авторы

Anisovich Kanstantsin V. ¹ , Gaiazov Ernal R. ¹ , Chabuka Beauty K. ² , Boichenko Maksim A. ¹ , Lebedev Danila S. ^3,1 , Tarasenko Elena A. ¹ , Plodukhin Andrey Yu. ¹ , Zhokhov Sergey S. ¹ , Ratmanova Nina K. ¹ , Andreev Ivan A. ¹ , Trushkov Igor V. ⁴ , Alabugin Igor V. ² , Ivanova Olga A. ¹

Организации

1	M. V. Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory 1-3, Moscow 119991, Russian Federation
2	Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306-4390, USA
3	HSE University, Moscow 101000, Russian Federation
4	N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky pr. 47, Moscow 119991, Russian Federation

A reagent-controlled, chemodivergent approach to hexahydropyridazin-3-ones and 1-aminopyrrolidin-2-ones has been developed via Lewis acid-promoted ring-opening/ring-closure reactions of donor–acceptor cyclopropanes with unsymmetrically substituted hydrazines. The method enables efficient, single-step access to two classes of biologically relevant azaheterocycles in good yields under mild conditions. The reaction outcome is dictated by the nature of the hydrazine substituent: arylhydrazines bearing electron-rich or neutral groups selectively form six-membered products via internal nitrogen attack, whereas electron-withdrawing aryl substituents, acyl hydrazines, and carbazates favor five-membered ring formation through terminal nitrogen reactivity. Both pathways proceed through a domino sequence involving nucleophilic ring opening followed by in situ Lewis acid-induced cyclization, providing a modular platform for the synthesis of structurally diverse nitrogen heterocycles. Mechanistic studies reveal that the observed selectivity arises from a competition between charge control and frontier orbital control in ambident hydrazines. While charge distribution favors the attack by the terminal nitrogen, the higher-energy lone pair on the internal nitrogen governs reactivity in arylhydrazines, leading to an inverse α-effect. This interplay, supported by stereochemical probes, NBO analysis, and computations, provides a predictive framework for the ambident reactivity of hydrazines in reactions with activated cyclopropanes.

Anisovich K.V. , Gaiazov E.R. , Chabuka B.K. , Boichenko M.A. , Lebedev D.S. , Tarasenko E.A. , Plodukhin A.Y. , Zhokhov S.S. , Ratmanova N.K. , Andreev I.A. , Trushkov I.V. , Alabugin I.V. , Ivanova O.A.
Competition between charge and orbital control governs the divergent reactivity of hydrazines toward donor–acceptor cyclopropanes
Organic Chemistry Frontiers. 2026. DOI: 10.1039/d6qo01409g

Поступила в редакцию:	29 сент. 2026 г.
Принята к публикации:	31 окт. 2026 г.

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