Nitrogen-rich heterocyclic compounds have had a profound impact on human health, as 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, the development of practical and selective C–H functionalization methods that do not rely upon prefunctionalized starting materials is an underdeveloped area.1–9 Paradoxically, the innate properties of heterocycles that make them so desirable for biological applications render them challenging substrates for direct chemical functionalization, such as limited solubility, functional group incompatibilities, and reagent/catalyst deactivation. Herein we report that zinc sulfinate salts9 can be used to transfer alkyl radicals to heterocycles, allowing for a mild, direct and operationally simple formation of medicinally relevant C–C bonds while reacting in an orthogonal fashion to other innate C–H functionalization methods (Minisci, borono-Minisci, electrophilic aromatic substitution, transition metal-mediated C–H insertion, C–H deprotonation).2–7,9 A toolkit of these reagents was prepared and reacted across a wide range of heterocycles (natural products, drugs, building blocks) without recourse to protecting group chemistry, and can even be employed in a tandem fashion in a single pot in the presence of water and air.

Radical addition processes can be ideally suited for the direct functionalization of heteroaromatic bases, yet these processes are only sparsely used due to the perception of poor or unreliable control of regiochemistry. A systematic investigation of factors affecting the regiochemistry of radical functionalization of heterocycles using alkylsulfinate salts revealed that certain types of substituents exert consistent and additive effects on the regioselectivity of substitution. This allowed us to establish guidelines for predicting regioselectivity on complex π-deficient heteroarenes, including pyridines, pyrimidines, pyridazines and pyrazines. Since the relative contribution from opposing directing factors was dependent on solvent and pH, it was sometimes possible to tune the regiochemistry to a desired result by modifying reaction conditions. This methodology was applied to the direct, regioselective introduction of isopropyl groups into complex, biologically active molecules, such as diflufenican (44) and nevirapine (45).

Metal-catalysed C-H bond functionalisation has had a significant impact on how chemists make molecules. Translating the methodological developments to their use in the assembly of complex natural products is an important challenge for the continued advancement of chemical synthesis. In this tutorial review, we describe selected recent examples of how the metal-catalysed C-H bond functionalisation has been able to positively affect the synthesis of natural products.

Supporting Information Experimental procedures and data 1 H and 13 C NMR spectra General Experimental 1 H NMR spectra were recorded on a Bruker DPX 400 spectrometer in deuterochloroform (CDCl 3 ), unless stated otherwise, operating at 400 MHz. 13 C NMR spectra were recorded on a Bruker DPX 400 spectrometer operating at 100 MHz. Chemical shifts (δ) are quoted relative to residual solvent (CHCl 3 , δ = 7.26 ppm for 1 H and δ = 77.0 for 13 C of CDCl 3 ) and coupling constants (J) are corrected and quoted to the nearest 0.1 Hz. The following abbreviation are used to indicate the multiplicity of the signals: s = singlet; d = doublet; t = triplet; q = quartet; qn = quintet; m = multiplet; br = broad; app = apparent; and associated combinations, e.g. dd = doublet of doublets. The temperature of the acquisition of the NMR spectra was 298 ± 3K. DEPT135 and 2dimensional experiments (COSY, HMBC and HMQC) were used to support assignments where appropriate but are not included. High resolution mass spectra (HRMS) were measured on a Micromass Q-TOF spectrometer using EI (electron impact) or ES (electrospray ionisation) techniques at the Department of Chemistry, University of Cambridge or at the EPSRC Mass Spectrometry Service at the University of Swansea. Infared (IR) spectra were recorded on a Perkin Elmer 1FT-IR Spectrometer fitted with an ATR sampling accessory as neat films, either through direct application or deposited in CHCl 3 . Optical rotations were measured in CHCl 3 on a Perkin Elmer 343 Polarimeter; [α] D values are reported in 10 -1 degrees cm 2 g -1 at 589 nm. Chiral HPLC analysis was performed on HP Agilent 1100 apparatus. Melting points (m.p.) were recorded using a Reichert hot stage apparatus and are reported uncorrected. All anhydrous solvents were solvents were dried by standard techniques and freshly distilled before use. Diethyl ether and tetrahydrofuran were distilled from lithium aluminium hydride; acetonitrile, dichloromethane and toluene from calcium hydride; and triethylamine from potassium hydroxide. N, N-dimethylformamide and dimethyl sulfoxide were purchased in anhydrous form. All flash chromatography was carried out using dry packed Merck 9385 Kieselgel 60 silica gel. Reactions monitored by thin layer chromatography (t.l.c.) were carried out on Kieselgel 60 PF 254 (Merck) 0.2 mm plates.All reagents were purified by standard procedures or used as obtained from commercial sources.Reactions were carried out using oven dried glassware and under an atmosphere of nitrogen unless otherwise stated.

A sequential CH functionalization strategy for the synthesis of the marine alkaloid dictyodendrin B is reported. Our synthesis begins from commercially available 4-bromoindole and involves six direct functionalizations around the heteroarene core as part of a gram-scale strategy towards the natural product.