Bridgehead-Functionalized Bicyclo[2.1.1]hexanes – Promising Saturated Isosteres of Monosubstituted Benzene
Тип публікації :
Препринт
Дата випуску :
17 серпня 2026 р.
Автор(и) :
Andriy A. Koblik
Oleksandra V. Shvek
Bohdan V. Vashchenko
Dmytro Lesyk
Petro Borysko
Oleksandr V. Stryzhak
Oleksandr O. Grygorenko
eKNUTSHIR URL :
Журнал :
ChemRxiv
Цитування :
[APA 7] Andriy, A. K., Oleksandra, V. S., Bohdan, V. V., Dmytro, L., Petro, B., Oleksandr, V. S., & Oleksandr, O. G. (2026). Bridgehead-Functionalized Bicyclo[2.1.1]hexanes – Promising Saturated Isosteres of Monosubstituted Benzene. ChemRxiv,. https://doi.org/10.26434/chemrxiv.15007511/v1
[ДСТУ] Bridgehead-Functionalized Bicyclo[2.1.1]hexanes – Promising Saturated Isosteres of Monosubstituted Benzene / A. K. Andriy та ін. ChemRxiv. 2026. DOI: 10.26434/chemrxiv.15007511/v1 (дата звернення: 11.09.2026).
Bicyclo[2.1.1]hexanes (BCHs) are firmly established as saturated surrogates of ortho- and meta-disubstituted benzenes, whereas their bridgehead-monofunctionalized congeners – the direct counterparts of a monosubstituted phenyl ring – have remained largely inaccessible as building blocks. In this work, we have aimed to achieve a scalable entry into such compounds and to experimentally position the BCH core within the physicochemical scale of the bicyclo[m.n.k]alkane series. Two orthogonal routes to the key bridgehead carboxylic acids were developed. The first relied on the six-step sequence from bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, whose key step is a Favorskii ring contraction, giving the parent carboxylic 36% yield on over 100 g scale, with the key intermediates optimized for synthesis on over 600 g scale. Alternatively, a two-step sensitized [2+2] photocycloaddition–oxidative cleavage sequence from myrcene was applied, giving a 5,5-dimethylated analog (32% overall yield, 69 g scale). Divergent elaboration afforded the multigram preparation of 27 building blocks, i.e., amines, alcohols, aldehydes, alkynes, bromides, nitriles, boronates and trifluoroborates, α-amino acids, amides, and the corresponding homologs,19 of which have not been reported to date. LogP and pK a (H) values measured for model benzamides and anilides place BCH between bicyclo[1.1.1]pentane and bicyclo[2.2.2]octane on both scales: the parent BCH benzamide closely reproduces the lipophilicity of N-phenylbenzamide (LogP 2.57 vs. 2.65), while gem-dimethylation and homologation raise LogP by 0.5–0.8 and 0.3–0.7 units, respectively, and homologation restores amine basicity from pKa(H) 9.65 to 10.47–10.54, i.e., to the cyclohexylamine level. We believe that the title compounds will find application in early drug discovery in the near future.
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