Recently, Long’s group developed a novel solvent and oxidant-switchable divergent synthesis of multisubstituted quinazolines and benzimidazoles via metal-free oxidative sp3 C-H and N-H functionalization, with chemoselectivity controlled simply by the solvent polarity or oxidant system. This work has been published this June on the ACS journal of Organic Letters 2014, 16, 2822-2825 (Among The Most Read Articles List of June). This work was supported by the National Natural Science Foundation of China. 

Quinazoline and benzimidazole are two important privileged scaffolds widely present in numerous drugs and bioactive compounds with a broad and potent spectrum of pharmcological activities, such as antitumor, antibacterial, anticonvulsant, and antidiabetic activities. Although there are various well-established methods to prepare quinazolines and benzimidazoles, most of the synthetic routes require special starting materials, multi-step procedures and harsh reaction conditions, severely impeding the biological studies and therapeutic applications of these privileged structures.

Quinazoline and benzimidazole are two important privileged scaffolds widely present in numerous drugs and bioactive compounds with a broad and potent spectrum of pharmcological activities, such as antitumor, antibacterial, anticonvulsant, and antidiabetic activities. Although there are various well-established methods to prepare quinazolines and benzimidazoles, most of the synthetic routes require special starting materials, multi-step procedures and harsh reaction conditions, severely impeding the biological studies and therapeutic applications of these privileged structures.

Starting from the rationally designed N-alkyl-N'-arylamidine precursor, the hypervalent iodine(III)-promoted direct C(sp3)-C(sp2) and C(sp2)-N coupling afforded a broad range of multi-substituted quinazolines and benzimidazoles in good to excellent yields in toluene and acetonitrile, respectively. An optimized oxidation system of potassium persulfate in combination with catalytic TEMPO realized a metal-free straightforward synthesis of multisubstituted quinazolines in polar solvents in excellent yields and wide substrate scopes. The common N-phenylcarboxamidine precursor was readily prepared from easily accessible aniline, alkyl/benzylamine and carboxylic acid, ensuring a broad substrate availability scope. This is the first example to achieve the chemoselectivity between oxidative sp3C-H/sp2C-H and N-H/sp2C-H coupling simply by the choice of solvent or oxidant. No metal or base or other additives were needed.

Privileged scaffold-based structurally diverse drug-like libraries usually generate diverse biological activities, thus leading to the discovery of new structure and new mechanism lead compounds. Prof. Long’s group is focused on the commonly existent heterocycles such as quinolone-carboxylic acid, quinazoline, benzimidazole, benzofuran, and naphthyridine, and  develop highly efficient and green synthetic methodologies to construct these privileged scaffolds, via metal-free oxidative C-H functionalization (Chem. Comm. 2013, 49, 5313-5315; J. Org. Chem. 2014, 79, 4727-4734; Org. Lett. 2014, 16, 2822-2825). By using the synthetic protocols, structurally diverse focused libraries were established, delivering new structure multiple tyrosine kinase inhibitors (J. Med. Chem. 2012, 55, 9492-9509), novel PTP1B inhibitors targeting inactive conformation  (J. Am. Chem. Soc. 2008, 130, 17075-17084; Bioorg. Med. Chem. 2014, 22, 3670-3683), integrase-LEDGF/p75 interaction inhibitors (Bioorg. Med. Chem. 2013, 21, 5963-5972), and HCV NS5B small molecule inhibitors targeting allosteric site (Acta Chim. Sinica 2014, 72, 906-913, cover paper).