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

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.

Chemo- and regioselective benzylic C(sp3)–H oxidation bridging the gap between hetero- and homogeneous copper catalysis

“…In the past, copper ( Rout et al., 2012 ), iron ( Lu et al., 2017 ), palladium-catalyzed ( Ju et al., 2013 ), or metal-free ( Feng et al., 2012 ) intermolecular acetoxylation of benzylic C‒H bonds have been reported where the reaction proceeds through the formation of a putative metal-carboxylate or acyloxy radical species. The Stahl group and others reported copper-catalyzed intermolecular benzylic C‒H functionalization for the synthesis of pharmacophores from feedstock chemicals ( Chi et al., 2019 ; Hu et al., 2020a ; Liu et al., 2020 ; Vasilopoulos et al., 2017 ; Wang et al., 2019 ). The Ritter group reported a copper (II)-catalyzed synthesis of benzylic alcohols from alkyl arenes employing bis(methanesulfonyl)peroxide as an oxidant followed by hydrolysis ( Tanwar et al., 2019 ).…”

Redox-Neutral Synthesis of α-Iminonitriles, α-Cyanoenamines, and N-Acyl Derivatives from Amides

“…Indeed, although many methods have been developed for the syntheses of α-iminonitriles − ( 1 ) and α-cyanoenamines − ( 2 and 3 ), most of them involve multistep transformations and are limited to a specific class of compounds. To further explore the synthetic potential of imidoyl cyanides ( 1 ), several elegant approaches have been developed during the last two decades. ,− Among them, Zhu’s one-pot oxidative three-component Strecker reaction of aldehydes, amines, and trimethylsilyl cyanide (TMSCN) using o -iodoxybenzoic acid (IBX)/tetra- n -butylammonium bromide (TBAB) combination proved to be the most versatile and efficient approach to imidoyl cyanides 1 (Scheme a) . The method was further improved by replacing IBX with tert -butyl hypochlorite or with Oxone .…”

“…On the other hand, the α-cyanoenamine motifs ( 2 / 3 ), which also possess several reaction sites, have been shown to be useful functional groups in organic synthesis. − It is worth noting that N , N -disubstituted α-cyanoenamines 2 behave very differently from tautomerizable N -monosubstituted α-cyanoenamines 3 , and specific methods are required for the synthesis of each subclass of cyanoenamines 2 / 3 . In this regard, many methods have been developed for the synthesis of N , N -disubstituted α-cyanoenamines 2 . − However, to the best of our knowledge, only two multistep methods have been documented for the synthesis of N -monosubstituted α-cyanoenamines 3 . , The typical protocol consists of converting aldehydes to aldimines, α-chlorination, and cyanation with 2.2 equiv of KCN (Scheme b).…”

Toward Rational Understandings of α-C–H Functionalization: Energetic Studies of Representative Tertiary Amines

“…type compounds, tertiary amines are the most popular due especially to the widespread presence of their structural motif in many natural alkaloids and bioactive molecules (Beatty et al, 2015;Rommelspacher et al, 1985;Shamma, 2012). As a result, numerous oxidative cross-dehydrogenative couplings (CDC) have been developed for functionalization of tertiary amines via a-C-H bond dissociation (Chi et al, 2019;Girard et al, 2014;Szatmá ri et al, 2016;Yoo et al, 2010) (Scheme 1).…”