From Isocyanides to Iminonitriles via Silver-mediated Sequential Insertion of C(sp3)-H Bond.

Huiwen Chi,Bingxin Liu,Hao Li,Rongxuan Ye,Bin Xu,Yin-Long Guo,Qitao Tan,Haoyang Wang

doi:10.1016/j.isci.2019.10.057

Abstract

SummaryHeterocycles are prevalent constituents of many marketing drugs and biologically active molecules to meet modern medical challenges. Isocyanide insertion into C(sp3)–H bonds is challenging especially for the construction of quaternary carbon centers. Herein, we describe an efficient strategy for the synthesis of α-iminonitrile substituted isochromans and tetrahydroisoquinolines (THIQs) with quaternary carbon centers through silver-triflate-mediated sequential isocyanide insertion of C(sp3)–H bonds, where isocyanide acts as the crucial “CN” and “imine” sources. The produced α-iminonitriles have extensive applications as valuable synthetic building blocks for pharmacologically interesting heterocycles. This protocol could be further applied for the synthesis of iminonitrile-decorated phenanthridines and azapyrene. Interestingly, a remarkable aggregation-induced emission (AIE) effect was first observed for an iminonitrile-decorated pyrene derivative, which may open a particular area for iminonitrile applications in materials science.

Highlights

Isochromans and tetrahydroisoquinolines (THIQs) are prevalent in many biologically active compounds including marketing drugs (Figure 1A) (Scott and Williams, 2002; Ennis et al, 1998)
The significance of the given chemistry is as follows: (1) the formation of a-iminonitriles was first realized by the synergistically cascade isocyanide insertion via C–H bond activation, where the isocyanide was used as both the crucial ‘‘CN’’ and ‘‘imine’’ sources; (2) it is the first example to construct pharmacologically relevant a-iminonitrile substituted isochromans and THIQs with quaternary carbon centers through direct C(sp3)–H bond isocyanide insertion; (3) a remarkable aggregation-induced emission (AIE) effect was first observed for as-prepared a-iminonitrile substituted pyrene derivative, which may open a particular area for iminonitrile applications in materials science; (4) the a-iminonitrile substituted products are valuable synthetic building blocks for facile access of pharmacologically interesting heterocycles
We have developed a direct synthesis of iminonitrile substituted isochromans and THIQs with quaternary carbon centers through silver-mediated sequential isocyanide insertion of C(sp3)–H bonds

Summary

Introduction

Isochromans and tetrahydroisoquinolines (THIQs) are prevalent in many biologically active compounds including marketing drugs (Figure 1A) (Scott and Williams, 2002; Ennis et al, 1998). The site-selective C1 mono-functionalization of isochromans and THIQs has been extensively studied, which commonly involved the formation of oxonium/iminium ions or a-heteroatom carboncentered radicals initiated by irradiation or treatment with an oxidant (Yoo et al, 2009; Zhou et al, 2017; Bartling et al, 2016; Lin et al, 2017; Muramatsu and Nakano, 2014; Muramatsu et al, 2013; Zhang et al, 2013; Meng et al, 2014). The C1 difunctionalization of isochromans and THIQs is limited in scope and commonly requires multiple steps using active Grignard or organolithium reagents (Figure 1B) (Guo et al, 2017; Li and Coldham, 2014)

Methods

Results

Conclusion