Direct Functionalization Of Unactive C(Sp~3)-H Bond In Cyclic Ethers And Cycloalkanes

Transition metal-catalyzed C-H activation has recently emerged as the most powerful and straightforward tool for the functionalization of organic molecules. Although many efforts have focused on the direct sp C-H activation in the past two decades, much less research has been devoted to the activation of more inert spj C-H bonds, which is more challenging owing to their low reactivity and the lack of a coordination site for the transition-metal catalyst. This project mainly focused on the studies of cheap metal or metal-free catalyzed C-H bond functionalization of cyclic ethers and cycloalkanes to construct C-X (X=C, O, S) bonds. The contents were listed as below:1. Iron-catalyzed cross-dehydrogenative coupling esterification of unactive C(sp3)-H Bonds with carboxylic acids for the synthesis of a-acyloxy ethers.An efficient procedure for the Fe(acac)3-catalyzed direct esterification of unactivated C(sp3)-H bonds with DTBP as an oxidant has been developed. This is a novel method for the construction of C-O bonds using iron as catalyst via CDC reaction. Furthermore, this reaction provides a useful strategy for synthesis of substituted a-acyloxy ethers. Various carboxylic acids and several symmetric and asymmetric ethers could be well tolerated in this catalytic system with moderate to excellent chemical yields and completely controlled regioselectivities. The intermolecular competing kinetic isotope effect (KIE) experiment was also carried out, which indicates C(sp3)-H bond cleavage may be the rate-determining step of this CDC reaction.2. Cu-catalyzed dehydrogenation-olefination and esterification of the C(sp3)-H bonds of cycloalkanes with aromatic aldehydes.This work describes the first example of Cu-catalyzed dehydrogenation-olefination and esterification of C(sp3)-H bond of cycloalkanes with aromatic aldehydes in the presence of TBHP as oxidant. This reaction involves four formal C-H bond activations. An appreciable range of aromatic aldehydes can be used in this reaction with cycloalkanes allowing a direct preparation of the corresponding cycloallyl esters in 18-53% yields. The intermolecular competing kinetic isotope effect (KIE) experiment was also carried out, which indicates C(sp3)-H bond cleavage may be the rate-determining step of this reaction. Based on the extensive experimental data, we propose a double circulation mechanism, which includes dehydrogenation-olefination of cycloalkanes followed by a cross dehydrogenative coupling reaction.3. DTBP-promoted oxidative C(sp3)-H bond thiolation of cycloalkanes with disulfides.A concise thiolation of C(sp3)-H bond of cycloalkanes with diaryl disulfides in the presence of oxidant of DTBP has been developed. This reaction without using any of metal catalyst, tolerates varieties of disulfides and cycloalkanes substrates, giving good to excellent chemical yields, which provides a useful approach to cycloalkyl aryl sulfides from unactivated cycloalkanes.4. Metal-free oxidative C(sp3)-H bond functionalization of alkanes and conjugate addition to chromones.2-Alkyl chromanone skeleton is an important type of heterocycles found in a number of bioactive natural products and pharmaceutical molecules, which show a wide range of biological activities including anticancer, antitumor, antibacterial, antioxidant and antimicrobial properties. We have developed an unprecedented directed oxidative sp3 C-H functionalization and subsequent conjugate addition reaction using DTBP as the oxidant without use of any metal catalyst. Different substituted chromones and various simple alkanes could be tolerated, affording 2-alkylchromanones in moderate to good yields. This method not only provided a simple and atom-economic route for the syntheses of 2-alkylchromanones but also represented a new strategy for selective functionalization of simple alkanes. The intermolecular competing kinetic isotope effect (KIE) experiment was also carried out, which indicates C(sp3)-H bond cleavage may be the rate-determining step of this reaction.5. Metal-free oxidative C(sp3)-H bond functionalization of alkanes and alkylation-initiated radical 1,2-aryl migration in α,α-diaryl allylic alcohols.We have developed an unprecedented DTBP-promoted radical alkylation reaction of α,α-diaryl allylic alcohols with simple alkanes under metal free conditions. It involves new C(Ar)-C(sp3) and C(sp3)-C(sp3) bond formation in one step via C(sp3)-H bond functionalization and 1,2-aryl migration cascade process. It tolerates a wide range of simple alkane substrates to react with symmetrical and unsymmetrical α,α-diaryl allylic alcohols for direct preparation of α-ary1-β-alkylated carbonyl ketones in moderate to excellent yields. Notably, preferential migration of the more electron-poor or the less steric hindrance aryl groups was observed in this reaction of substrates bearing different aryl groups. This method not only enriched the content of radical ("neophyl") rearrangement, but also represented a new strategy for selective functionalization of simple alkanes.