Oxidative Ring Contraction of Cyclobutenes: General Approach to Cyclopropylketones including Mechanistic Insights

Abstract

An original oxidative ring contraction of easily accessible cyclobutene derivatives for the selective formation of cyclopropylketones (CPKs) under atmospheric conditions is reported. Comprehensive mechanistic studies are proposed to support this novel, yet unusual, rearrangement. Insights into the mechanism ultimately led to simplification and generalization of the ring contraction of cyclobutenes using mCPBA as an oxidant. This unique and functional group tolerant transformation proceeds under mild conditions at room temperature, providing access to a new library of polyfunctionalized motifs. With CPKs being attractive and privileged pharmacophores, the elaboration of such a simple and straightforward strategy represents a highly valuable tool for drug discovery and medicinal chemistry. Additionally, the described method was employed to generate a pool of bioactive substances and key precursors in a minimum number of steps.

Uncommon Four‐Membered Building Blocks – Cyclobutenes, Azetines and Thietes

“…We therefore adapted the conditions to force this rearrangement, employing m CPBA as the oxidant (Scheme 26). [73] …”

Bromomethyl Silicate: A Robust Methylene Transfer Reagent for Radical‐Polar Crossover Cyclopropanation of Alkenes

“…Regardless of the electron‐donating or ‐withdrawing characters of the substituents on the aromatic ring, no contamination of the undesired noncyclized Giese‐type addition product was observed. [12a] Furthermore, the protocol was extended to the access of cyclopropylketones which can be found in a number of bioactive substances by exalting crucial hydrophobic interactions In addition to the efficient formation of 5f from 2‐phenyl‐1‐buten‐3‐one, 2‐methoxyphenyl‐substituted methyl vinyl ketone was nicely cyclopropanated to cyclopropylketone 5g in 66 % yield. Moreover, the cyclopropanation was also suitable for 2‐aryl‐1‐buten‐3‐one containing halogens on aryl group, producing 5h – j in 63–65 % yields.…”

Gold-Catalyzed Synthesis of Small Rings

“…The synthesis of cyclopropanes has been traditionally approached by methodologies such as the Simmons–Smith reaction (through metal carbenoids) − or the Johnson–Corey–Chaykovsky reaction (also developed for the assembly of epoxides or aziridines) − or via metal carbenes through decomposition of diazo compounds (Scheme B). − Some alternative methods for the synthesis of cyclopropanes involve the use of different types of ylides, − free dihalocarbenes, direct cyclizations, , ring contractions, − radical pathways, − or the Kulinkovich reaction, − among others. − …”