The Quinazoline N-O Directed C-H Bond Functionalizations

Quinazolines are bicyclic compounds which represent privileged scaffolds displaying with a wide range of important biological activities.Therefore,studies on the synthesis of quinazoline and its derivatives have been a hot research topic in the field of organic chemistry.The strategy of assembling building blocks was used to introduce different functional groups into the quinazoline skeletons.Therefore,modification of structural diversitied would be expected to generate a series of novel quinazoline derivatives with optimized biological activities.On the other hand,the N-oxide moiety in aza-heteroarene has been recognized as a powerful and removable directing group for the ortho C–H bond activation.There are many reports related on the C–H-functionalization reactions of heterocyclic N-oxides,including arylation,alkenylation,alkylation,cyanation,amidation,and sulfonylation reactions.Based on the N-O directed C-H activation strategy,we studied herein the introducing ether,cyanoalkyl,naphthol and indole skeletons into the C4 position of quinazoline by free radical initiation or metal catalysis transformations.Several classes of potentially biologically active quinazoline derivatives were produced.The thesis involves the following four segments.1)A novel and efficient protocol for the direct C-4 alkylation of quinazoline-3-oxides with ethers under metal-free conditions was reported.The radical oxidative cross-coupling reaction of sp~3 C-H bond in ethers with the sp~2 C-H bond in quinazoline-3-oxide proceeded smoothly in the presence of t-butyl peroxybenzoate(TBPB),provided the desired products in moderate to good yields.The intermolecular kinetic isotopic experiment confirmed the k_H/k_D for ether C–H was 3.4,indicating that the cleavage of sp~3 C–H bond was involved as the rate-determining step for this transformation.A plausible mechanism for this reaction was proposed.2)It is widely known that nitriles are extremely core structural motifs that are present in numerous natural products,agrochemicals and pharmaceuticals.It's noteworthy that the 1-Cyano-1-methylethyl radical from the thermolysis of Azobisisobutyronitrile(AIBN)has also been used for C–H functionalization,for instance,the construction of?-cyano quaternary carbon centers.An efficient catalyst-,base-,and oxidant-free reaction of quinazoline-3-oxide and AIBN under mild conditions was described.This transformation leads to bi-cyanoalkylation of quinazoline N-oxides in good to excellent yields via a radical mechanism.The reaction exhibits excellent functional group tolerance and substrate compatibility.Azo compound 1,1'-(diazene-1,2-diyl)bis(cyclohexane-1-carbonitrile)can also be added to the quinazoline 3-oxide.3)Indoles are core structural motifs of many natural products and pharmaceuticals.We reported a copper-catalyzed cross-dehydrogenative coupling(CDC)reaction between the Csp~2–H of quinazoline-3-oxide and the Csp~2–H of various indoles for the synthesis of 4-(indole-3-yl)quinazolines using a mild and operationally simple procedure.The reaction exhibits excellent functional group tolerance and substrate compatibility.The coupling reaction occurs selectively at the C4 position of the quinazoline-3-oxides and at the C3 position of the indoles.When2-(p-tolyl)quinazoline-3-oxide was replaced by 2-(p-tolyl)quinazoline,the desired product was unable to be obtained,which indicating that the N-O group is crucial in this transformation.Furthermore,oxygen was found to play crucial roles in this reaction.4)Biaryl atropisomers provide important classes of structures with extensive utility in asymmetric synthesis.Considerable efforts have been devoted on the construction of biaryl(hetero)N-oxides with potential axial chirality.A novel,simple and efficient protocol for the synthesis of 4-(naphthol-1-yl)quinazolines via a cross-dehydrogenative coupling of quinazoline-3-oxides and?-naphthol under an air atmosphere has been successfully developed.A series of biheteroaryl products were obtained in moderate to good yields.