Unravelling the mechanism of cobalt-catalysed remote C-H nitration of 8-aminoquinolinamides and expansion of substrate scope towards 1-naphthylpicolinamide.

Melody Chu,Christopher J Whiteoak,Alex Hamilton,Oriol Planas,Anna Company,Xavi Ribas

doi:10.1039/c9sc05076k

Abstract

Previously, an unexpected Co-catalysed remote C-H nitration of 8-aminoquinolinamide compounds was developed. This report provided a novel reactivity for Co which was assumed to proceed through the mechanistic pathway already known for analogous Cu-catalysed remote couplings of the same substrates. In order to shed light into this intriguing, and previously unobserved reactivity for Co, a thorough computational study has now been performed, which has allowed for a full understanding of the operative mechanism. This study demonstrates that the Co-catalysed remote coupling does not occur through the previously proposed Single Electron Transfer (SET) mechanism, but actually operates through a high-spin induced remote radical coupling mechanism, through a key intermediate with significant proportion of spin density at the 5- and 7-positions of the aminoquinoline ring. Additionally, new experimental data provides expansion of the synthetic utility of the original nitration procedure towards 1-naphthylpicolinamide which unexpectedly appears to operate via a subtly different mechanism despite having a similar chelate environment.

Highlights

The controlled and selective functionalisation of C–H bonds is currently a topic which is attracting a signi cant amount of interest from the chemical community.[1]
Relative free energies for ligand exchange (Table 1) identi ed Co(OAc)[2] as the most thermodynamically stable Co species. This compound was used as the basis for the active catalyst species for the remainder of the reaction mechanism. It should be noted at this point that the observed bene t of using Co(NO3)[2] over Co(OAc)[2] in the Scheme 1 (a) Cu-catalysed remote chlorination reported by Stahl. (b) First Co-catalysed remote nitration reported by Whiteoak and Ribas. (c) Co-catalysed remote perfluoroalkylation reported by Niu and Song. (d) Co-catalysed remote sulfonylation reported by Xia
Due to the potential for different spin states to be involved in the mechanism, which pose a signi cant challenge for Density Functional Theory (DFT) based methods, the recently implemented open shell DLPNO-CCSD(T) method was utilised.[18,19]

Summary

Introduction

Several rst-row transition metals have been shown to provide reactivities amenable for application in C–H functionalisation protocols. One novel approach to the functionalisation of 8-aminoquinolinamides has been the remote (non-proximate) C–H bond chlorination catalysed by Cu at the C7 position, which was originally reported by Stahl/Ertem and co-workers in 2013 (Scheme 1a).[11] Non-proximate C–H bond functionalisation, moving beyond directing group based protocols, is a major challenge in synthetic chemistry with only a limited, but increasing, number of approaches currently available.[12] This initial work by Stahl/Ertem and co-workers demonstrated the rst example of a metal-catalysed remote C–H functionalisation of 8-aminoquinolinamides and Density Functional Theory (DFT) calculations were employed to elucidate the mechanism, which was found to be based on a key Single Electron Transfer (SET) step. We describe our ndings and demonstrate that the protocol can be successfully transferred to the remote nitration of 1-naphthylpicolinamide analogues which replace the aminoquinolinamide chelate environment with a picolinamide, further expanding the applicability of the previously discovered protocol

Results and discussion

Conclusions

For an overview of mechanisms of C–H bond activation see