An Introductory Overview of C–H Bond Activation/ Functionalization Chemistry with Focus on Catalytic C(sp3)–H Bond Borylation

Ronald Reyes,Masaya Sawamura

doi:10.26534/kimika.v32i1.70-109

Abstract

The direct and selective functionalization of C–H bonds provides novel disconnections and innovative strategies to streamline the synthesis of molecules with diverse complexities. However, despite the significant advances in the elaboration of techniques for C–H activation, the utilization of unactivated C(sp3)–H bonds remains challenging. In particular, asymmetric transformation of C(sp3)–H bonds is underdeveloped owing to the lack of catalytic systems that can competently discriminate among ubiquitous C–H bonds in organic molecules. This short review aims to outline the challenges and strategies for the catalytic functionalization of C(sp3)–H bonds giving a general and non-exhaustive explanatory approach. Current strategies on the basis of the substrates and reaction mechanisms are summarized in Section 1. Examples of enantioselective C–H bond transformations are then given in Section 2. Finally, in Section 3, an outline of current methodologies towards the direct borylation of C(sp3)–H bonds is described to showcase the importance of developing techniques for catalytic C–H bond chemistry. While we try to cover all excellent reports available in the literature on this topic, any omissions are unintentional, taking note of the most representative examples available.

Highlights

Transformative synthetic methodologies have evolved from the traditional approach of functional group interconversion to the direct activation and functionalization of strong C–H bonds via transition metal catalysis, Figure 1 (Corey and Cheng, 1989; Hudlicky and Reed, 2007; Corey and Kürti, 2010)
An Introductory Overview of C–H Bond Activation/Functionalization Chemistry... 71 utilization of C(sp2)–H bonds has matured into a successful field with the development of methodologies that circumvent challenges such as selectivity given the many possible chemical environments for these transformations (Arndtsen et al, 1995; Yamaguchi et al, 2012; Gutekunst and Baran, 2011; Davies and Morton, 2016)
Overcoming the challenge of siteselectivity due to the ubiquitous nature of C–H bonds is at the forefront of C–H bond activation chemistry

Summary

Me O Me O

(R,R)-L3 up to 25% ee up to 26% ee Figure 50. Rh- and Ir-catalyzed C(sp3)–H borylation of using homogeneous phosphoramidite ligands. In the transition state leading to the major enantiomer product, the L*-Ir(Bpin) forms a narrow chiral reaction pocket where the alkylpyridine substrate is accommodated not just by the Ir–N coordination and by the assembly of weak attractive interactions contributing to the overall stabilization of the transition state (Figure 51) These crucial secondary interactions include -stacking, CH– and C–H···O noncovalent bonding between the substrate and the catalyst. Sawamura and co-workers reported their findings that a rhodium catalyst system with the identical chiral phosphite ligand (R,R)-L* enabled a highly enantioselective borylation of N-adjacent C(sp3)–H bonds (Figure 52) allowing the direct asymmetric synthesis of -aminoboronates for a range of substrate classes including 2-(N-alkylamino)heteroaryls and N-alkanoyl or aroyl-based secondary or tertiary amides (Reyes et al, 2020). O β R X 1.0 equiv pinB–Bpin, 0.30 mmol [Ir(OMe)(cod)]2, 1.5 mol% (R,R)-L*, 3.0 mol%

Me OH

OUTLOOK AND FUTURE PERSPECTIVE

Findings

Encyclopedia of Reagents for