Redox‐Neutral Coupling between Two C(sp³)−H Bonds Enabled by 1,4‐Palladium Shift for the Synthesis of Fused Heterocycles

Abstract

The intramolecular coupling of two C(sp3)−H bonds to forge a C(sp3)−C(sp3) bond is enabled by 1,4‐Pd shift from a trisubstituted aryl bromide. Contrary to most C(sp3)−C(sp3) cross‐dehydrogenative couplings, this reaction operates under redox‐neutral conditions, with the C−Br bond acting as an internal oxidant. Furthermore, it allows the coupling between two moderately acidic primary or secondary C−H bonds, which are adjacent to an oxygen or nitrogen atom on one side, and benzylic or adjacent to a carbonyl group on the other side. A variety of valuable fused heterocycles were obtained from easily accessible ortho‐bromophenol and aniline precursors. The second C−H bond cleavage was successfully replaced with carbonyl insertion to generate other types of C(sp3)‐C(sp3) bonds.

Large Isotope Effects in Organometallic Chemistry

“…Baudoin and coworkers reported a palladium-catalyzed intramolecular cyclization of 1-bromo-2-methoxy-3-acetyl-5-fluorobenzene to a chromanone product, requiring sp 3 CÀ H bond activations at the methoxy and acetyl groups (Scheme 6f). [125] Scheme 6. CÀ H activation by palladium.…”

Synthesis of Amides and Esters by Palladium(0)‐Catalyzed Carbonylative C(sp3)−H Activation

“…Moreover, intramolecular dearomatizing carbopalladation ( B , R=naphthol) provides spiroannulation products . The alkylpalladium intermediate B was also shown to be a competent intermediate to perform a second intramolecular C(sp 3 )−H activation, thus generating fused heterocycles and cyclopropanes (Scheme d) . In this paper, we show that the trapping of this σ‐alkylpalladium complex by carbon monoxide is feasible, and developed a carbonylative coupling of aryl bromides and amines or alcohols to generate amides and esters containing a β‐quaternary center (Scheme e) .…”

Recent advances in transition metal migration involving reactions

“…In 2019, a novel intramolecular coupling of two C(sp 3 )-H bonds via 1,4-Pd migration from aryl to alkyl was developed by Baudoin and co-workers (Scheme 29). 24 This reaction proceeded under redox-neutral conditions, with the C-Br bond acting as an internal oxidant. Numerous 2,3-dihydrobenzofurans and indolines 164 were prepared in moderate to good yield (Scheme 29a), and a few 6-membered ring products 166 were also achieved as shown in Scheme 29b.…”