Construction Of Quinazoline Derivatives Via C-H Bond Functionalization

With the concern about environmental impact, transition-metal catalyzed C-H bond activation and subsequent C-X (X= C, N, O) bond formation via cross-dehydrogenative-coupling (CDC) reactions has been a fascinating hot topic in organic synthesis. The strategy of inert C-H bond functionalization is more atom-economical, step-economical and environmentally friendly without pre-functionalization of the substrates or undesired byproducts. Despite the major advances achieved in transition-metal catalyzed C-H bond activation, the cost effectiveness as well as the presence of heavy transition metal impurities in the final products is a major problem regarding their practical applicability, especially in preparing pharmaceutical agents. Thus, the alternative metal-free direct C-H functionalization is highly desirable. In recent years, methodologies for the amination of primary benzylic C-H bonds in toluene derivates are relatively scarce. Notable examples included transition-metal catalyzed, iodide salt catalyzed and hypervalent iodine mediated benzylic C-H amination via C-H/N-H bond cross-coupling, and the nitrogen sources were limited to sulphonamide, carboxamide and azole derivatives. Besides, there are few examples of the introduction of methylarenes or methylhetarenes to construct nitrogen-containing heterocycles via C-N bond formations.Quinazoline derivatives, as important nitrogen heterocycle molecules, have drawn much attention over the past few years for their various biological activities, especially anticancer. Several tinib-type drugs, such as lapatinib, gefitinib, and erlotinib with a quinazoline core, have been successfully discovered for cancer treatment. Considering the importance of its bioactive derivatives, transition-metal-free synthetic methodologies are highly attractive.In this thesis, we mainly focus our attention on the development of mild, efficient and green approaches for the synthesis of quinazolines via benzylic C-H amination in metal-free cascade reactions. Besides, we also study the reactivity of quinazoline and develop an approach to expand the structure diversity via metal-free C(sp2)-H bond functionalization.This thesis includes the following four parts:Part 1. Metal-free oxidative synthesis of quinazolinones via dual animation of sp3 C-H bondsWe developed a direct approach for the synthesis of quinazolinones from 2-amino benzamides and methylarenes. The transformation could be carried out via DTBP mediated domino reactions in which dual oxidative C-N couplings were involved, and quite different from the previous heterocycle construction reactions starting from methylarenes or methylhetarenes, transition metals were not essential. In addition, the commonly used solvents, such as DMSO, DMF or DMA, were also effective in the similar annulation reactions via C(sp3)-S or C(sp3)-N bond cleavage and C-N bond formation.Part 2. KI-catalyzed three-component synthesis of 2-aryl quinazolines via animation of benzylic C-H bonds of methylarenesWe developed a novel, three-component approach for the synthesis of 2-aryl quinazolines under metal-free conditions. NH4OAc as cheap nitrogen source and sp3 carbon in commercially available methylarene as Cl source were introduced as the additional nitrogen and carbon atom of the quinazolines, respectively. This is the first example of methylarenes applied in multicomponent processes for the synthesis of heterocycles.Part 3. Bu4NI-catalyzed selective dual amination of sp3 C-H bonds:oxidative domino synthesis of imidazo[1,5-c]quinazolines on a gram-scaleA facile and efficient approach to the synthesis of imidazo[1,5-c]quinazolines was developed via a cascade reaction following sp3 C-H functionalization under metal-free conditions. Moreover, the reaction showed a broad scope of substrates including the common commercially available benzylamines and α-amino acids. The reaction offered the products in high yields even on a gram-scale. The new protocol serves not only as a method to construct a new class of imidazo-N-heterocycles but also as a rare example of benzylic primary C-H oxidative amination with primary amines.Part 4. KO/Bu-mediated stereoselective addition of quinazolines to alkynes under mild conditionsA facile alkenylation of quinazolines with unactivated terminal alkynes has been achieved in the presence of KO/Bu without the aid of any transition metal catalysts. The reaction is carried out under very mild conditions within a very short time and shows a high stereoselectivity. The present protocol provides a novel tool to prepare bioactive quinazoline derivatives, extended quinazoline structure diversity and laid a good foundation on the potential bioactivite derivatives.