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. 2022 Sep 5;61(36):e202208014.
doi: 10.1002/anie.202208014. Epub 2022 Jul 26.

Dearomative Ring Expansion of Polycyclic Arenes

Paolo Piacentini  1 , Tanner W Bingham  2 , David Sarlah  1   2
Affiliations

Dearomative Ring Expansion of Polycyclic Arenes

Paolo Piacentini et al. Angew Chem Int Ed Engl. .

Abstract

Benzocycloheptenes constitute a common structural motif embedded in many natural products and biologically active compounds. Herein, we report their concise preparation from non-activated polycyclic arenes using a two-step sequence involving dearomative [4+2]-cycloaddition with arenophile in combination with palladium-catalyzed cyclopropanation, followed by cycloreversion-initiated ring expansion. The described strategy provides a working alternative to the Buchner reaction, which is limited to monocyclic arenes. Overall, this methylene-insertion molecular editing approach enables rapid and direct conversion of simple (hetero)arenes into a range of substituted (aza)benzocycloheptatrienes, which can undergo a myriad of downstream functionalizations.

Keywords: Arenophiles; Benzocycloheptatrienes; Buchner Reaction; Dearomatization; Ring Expansion.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
a) Selected examples of benzocycloheptane‐containing bioactive natural products and drug leads. b) Challenges associated with Buchner ring expansion of polycyclic arenes. c) This work: dearomative arenophile‐based ring expansion of polycyclic arenes. TMS=trimethylsilane, SERD=selective estrogen receptor degrader, MTAD=4‐methyl‐1,2,4‐triazoline‐3,5‐dione.
Scheme 2
Scheme 2
Diversification of product 8 a and two‐step methylene 2,3‐insertion into naphthalene (4 a→21). NMO=4‐methylmorpholine N‐oxide, TBHP=tert‐butyl hydroperoxide, Pyr=pyridine, NMP=N‐methyl‐2‐pyrrolidone.
See this image and copyright information in PMC

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