Redirection of the Beckmann Rearrangement to Form Pyrrolidino[1,2- a ]benzimidazoles and Application to an Independent Synthetic Route to the Core of Balinatunfib

Q: What does this research mean for the field?

A proximal amine can redirect the Beckmann rearrangement to form benzimidazole products, providing an independent synthetic route to the core structure of TNF inhibitors such as Balinatunfib. Novelty: ClaimNovelty.METHODOLOGICAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Ignacio Rubio; Aurélie Dos Santos; Myriam Benisty; Marie-Pierre Delage; François J. Alvey; Luke J. Alvey

doi:10.1021/acs.joc.6c01086

September 9, 2026The Journal of Organic Chemistry

Redirection of the Beckmann Rearrangement to Form Pyrrolidino[1,2- a ]benzimidazoles and Application to an Independent Synthetic Route to the Core of Balinatunfib

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Key Points

Investigate the redirection of the Beckmann rearrangement using a proximal amine to synthesize pyrrolidino[1,2-a]benzimidazoles and the core of balinatunfib.
Applied amine-promoted Beckmann rearrangement redirection to the oxime of 1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one across seven analogs.
Elaborated two selected benzimidazole intermediates via independent parallel synthetic routes toward the methanobenzobenzoimidazodiazocinone framework.
Proximal amine successfully redirected the Beckmann rearrangement to yield ortho-fused pyrrolidinobenzimidazoles across seven diverse analogs.
Parallel routes successfully accessed the core scaffold of clinical TNF inhibitor candidates balinatunfib and FT2109.

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Implication

Chemical synthesis demonstrates redirected Beckmann rearrangement via proximal amines, indicating an efficient independent route to TNF inhibitor cores.

Abstract

A proximal amine redirects the Beckmann rearrangement to a benzimidazole product. This transformation was repeated on the oxime of 1,2,3,4-Tetrahydro-5H-benzo[b]azepin-5-one where the product benzimidazole is additionally ortho-fused to pyrrolidine. This was exemplified by seven analogs, of which two, in independent parallel routes, were elaborated to (7R,14R/7S,14S)-6,7-Dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one, which is the core structure of competing tumor necrosis factor (TNF) inhibitor clinical candidates Balinatunfib and FT2109.

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Rubio et al. (2026) studied this question.

synapsesocial.com/papers/6aa27ba958559d80afc75146 https://doi.org/10.1021/acs.joc.6c01086

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Redirection of the Beckmann Rearrangement to Form Pyrrolidino[1,2- a ]benzimidazoles and Application to an Independent Synthetic Route to the Core of Balinatunfib

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Redirection of the Beckmann Rearrangement to Form Pyrrolidino[1,2- a ]benzimidazoles and Application to an Independent Synthetic Route to the Core of Balinatunfib

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