Chemodivergent assembly of ortho-functionalized phenols with tunable selectivity via rhodium(III)-catalyzed and solvent-controlled C-H activation

Haiman Zhang,Wei Yi,Kaixin Zhang,Shuang Lin,Hui Gao,Zhi Zhou,Yi Wang

doi:10.1038/s42004-021-00518-x

Abstract

Ortho-functionalized phenols and their derivatives represent prominent structural motifs and building blocks in medicinal and synthetic chemistry. While numerous synthetic approaches exist, the development of atom-/step-economic and practical methods for the chemodivergent assembly of diverse ortho-functionalized phenols based on fixed catalyst/substrates remains challenging. Here, by selectively controlling the reactivities of different sites in methylenecyclopropane core, Rh(III)-catalyzed redox-neutral and tunable C-H functionalizations of N-phenoxyacetamides are realized, providing access to both ortho-functionalized phenols bearing linear dienyl, cyclopropyl or allyl ether groups, and cyclic 3-ethylidene 2,3-dihydrobenzofuran frameworks under mild cross-coupling conditions. These divergent transformations feature broad substrate compatibility, synthetic applications and excellent site-/regio-/chemoselectivity. Experimental and computational mechanistic studies reveal that distinct catalytic modes involving selective β-C/β-H elimination, π-allylation, inter-/intramolecular nucleophilic substitution cascade and β-H’ elimination processes enabled by different solvent-mediated and coupling partner-controlled reaction conditions are crucial for achieving chemodivergence, among which a structurally distinct Rh(V) species derived from a five-membered rhodacycle is proposed as the corresponding active intermediates.

Highlights

Ortho-functionalized phenols and their derivatives represent prominent structural motifs and building blocks in medicinal and synthetic chemistry
A diverse range of synthetic approaches is developed for the efficient assembly of these motifs, among which the transition metal (TM)-catalyzed C–H functionalization represents a powerful and straightforward method toward their construction[5,6,7,8,9]
Methylenecyclopropanes, with the presence of an alkene moiety and the strained cyclopropyl ring, are available building blocks that have been well-explored in diverse reactions including recently disclosed TM-catalyzed C–H functionalization[44,45,46,47,48,49,50,51]

Summary

Introduction

Ortho-functionalized phenols and their derivatives represent prominent structural motifs and building blocks in medicinal and synthetic chemistry. By selectively controlling the reactivities of different sites in methylenecyclopropane core, Rh(III)-catalyzed redox-neutral and tunable C-H functionalizations of N-phenoxyacetamides are realized, providing access to both ortho-functionalized phenols bearing linear dienyl, cyclopropyl or allyl ether groups, and cyclic 3-ethylidene 2,3dihydrobenzofuran frameworks under mild cross-coupling conditions. These divergent transformations feature broad substrate compatibility, synthetic applications and excellent site-/regio-/chemoselectivity. Accessible C–H activation process of N-phenoxy amides mediated by an active Rh(III) catalyst and a putative, highly reactive Rh(V) species[41,42,43] that was enabled by the post-insertion oxidative addition of O–N bond allow for the realization of diversified reactions under mild redox-neutral conditions with broad synthetic versatility (Fig. 1b). L FG active RhV species c this work: tunable couplings of N-phenoxyacetamides with methylenecyclopropanes for the divergent assembly of ortho-functionalized phenol derivatives versatile ODG

Methods

Results

Conclusion