Catalyst-Controlled Selective Functionalization of Unactivated C–H Bonds in the Presence of Electronically Activated C–H Bonds

Abstract

A new chiral dirhodium tetracarboxylate catalyst, Rh( S-2-Cl-5-BrTPCP), has been developed for C-H functionalization reactions by means of donor/acceptor carbene intermediates. The dirhodium catalyst contains four ( S)-1-(2-chloro-5-bromophenyl)-2,2-diphenylcyclopropane-1-carboxylate ligands, in which all four 2-chloro-5-bromophenyl groups are on the same face of the catalyst, leading to a structure, which is close to C symmetric. The catalyst induces highly site selective functionalization of remote, unactivated methylene C-H bonds even in the presence of electronically activated benzylic C-H bonds, which are typically favored using earlier established dirhodium catalysts, and the reactions proceed with high levels of diastereo- and enantioselectivity. This C-H functionalization method is applicable to a variety of aryl and heteroaryl derivatives. Furthermore, the potential of this methodology was illustrated by sequential C-H functionalization reactions to access the macrocyclic core of the cylindrocyclophane class of natural products.

Influence of Aryl Substituents on the Alignment of Ligands in the Dirhodium Tetrakis(1,2,2‐Triarylcyclopropane‐ carboxylate) Catalysts

“…Both catalysts are sterically demanding, preferring primary over secondary C−H functionalization at activated C−H bonds, such as allylic, benzylic or alpha to oxygen [13a,b] . Later, Rh 2 ( R ‐3,5‐di( p ‐ t BuC 6 H 4 )TPCP) 4 ( 4 ) [14] and Rh 2 ( S ‐2‐Cl‐5‐BrTPCP) 4 ( 5 ) [15] were developed and both are very significant catalysts because they display a strong preference for the C−H functionalization of the most accessible secondary site in systems with unactivated C−H bonds. Another important member of the Rh 2 (TPCP) 4 catalysts is Rh 2 [ R ‐tris( p ‐ t BuC 6 H 4 )TPCP] 4 ( 6 ) because it has a different selectivity profile and to date, it is the most effective for selective C−H functionalization at the most accessible primary C−H bond of unactivated substrates [16]…”

“…The more elaborate catalyst, Rh 2 ( R ‐3,5‐di( p ‐ t BuC 6 H 4 )TPCP) 4 ( 4 ), with large 3,5‐diarylphenyl group on the C1 aryl, adopts a D 2 ‐symmetric structure in the crystalline form [14] . In contrast, the X‐ray structures of all the catalysts in which the aryl group has an o ‐chloro substituent, such as Rh 2 ( S ‐2‐Cl‐5‐BrTPCP) 4 ( 5 ) adopt a C 4 ‐symmetric structure [15,17] …”

“… X‐ray structures of catalysts 2–5 (C1 aryl in blue, C2 cis aryl in green) from previously published studies [9,14–17] …”

Synthetic Exploration of α‐Diazo γ‐Butyrolactams

“…α-Diazo monocarbonyl compounds have attracted considerable attention due to their high reactivity and wealth of possible synthetic transformations. [1][2][3][4] Today, however, certain such compounds remain poorly explored. In particular, five-membered cyclic diazo monocarbonyl compounds are only sporadically encountered in the literature.…”

Functionalization of Piperidine Derivatives for the Site‐Selective and Stereoselective Synthesis of Positional Analogues of Methylphenidate

“…[10,11] We have been exploring the rhodium-catalyzed reactions of donor/acceptor carbenes for catalyst-controlled CÀH functionalization. [6c,7f] Recently,w eh ave designed catalysts that are capable of selective functionalization of inactivated primary,s econdary, and tertiaryC ÀHb onds, [12] inactivated CÀH bondso ver electronically activated CÀHb onds, [13] and desymmetrization of alkylcyclohexanes. [14] In this project, we describe the applicationo ft hese catalysts to generate methylphenidate analogues with substituents at either C2, C3, or C4 of the piperidine rings startingf rom appropriate piperidine derivatives ( Figure 1).…”