Practical and innate carbon-hydrogen functionalization of heterocycles

Abstract

Nitrogen-rich heterocyclic compounds have had a profound effect on human health because these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and pathophysiological conditions. Advances in transition-metal-mediated cross-coupling have simplified the synthesis of such molecules; however, C-H functionalization of medicinally important heterocycles that does not rely on pre-functionalized starting materials is an underdeveloped area. Unfortunately, the innate properties of heterocycles that make them so desirable for biological applications--such as aqueous solubility and their ability to act as ligands--render them challenging substrates for direct chemical functionalization. Here we report that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild (moderate temperature, 50 °C or less), direct and operationally simple formation of medicinally relevant C-C bonds while reacting in a complementary fashion to other innate C-H functionalization methods (Minisci, borono-Minisci, electrophilic aromatic substitution, transition-metal-mediated C-H insertion and C-H deprotonation). We prepared a toolkit of these reagents and studied their reactivity across a wide range of heterocycles (natural products, drugs and building blocks) without recourse to protecting-group chemistry. The reagents can even be used in tandem fashion in a single pot in the presence of water and air.

Figure 1. Development of a reagent toolkit for an innate C–H functionalization of heterocycles

A modular set of zinc sulfinate salts were identified as being highly desirable for the installation of medicinally relevant moieties (Fig. 1C): zinc trifluoromethanesulfinate (TFMS; A), zinc difluoromethanesulfinate (DFMS; B), zinc trifluoroethanesulfinate (TFES; C), zinc monofluoromethanesulfinate (MFMS; D), zinc isopropylsulfinate (IPS; E), and zinc triethyleneglycolsulfinate (TEGS; F). The fluoroalkyl and alkyl groups that we wish to introduce hold privileged positions in drug discovery and are described in detail below.

Figure 2. Chemoselectivity, rapid diversity and complexity generation, and practical utility

Cy = cyclohexyl. ^a % conversion as observed by GC-MS analysis. ^b 6% yield of the C5-cyclohexyl isomer was also obtained.