Synthesis of biheteroaryls via 2-methyl quinoline C(sp^(3))-H functionalization under metal-free conditions

An acetic acid-promoted C(sp^(3))-H functionalization of 2-methyl quinoline,enaminoesters and elemental sulfur for the synthesis of 3,4,5-trisubstituted isothiazoles under metal-free conditions has been developed.This approach provides viable access to various 5-(quinolin-2-yl)isothiazoles in moderate to good yields with good functional group tolerance.Moreover,the success of the gram-scale reaction gives this reaction a great potential application.

α-C(sp^(3))-H Arylation of Cyclic Carbonyl Compounds

α-C(sp^(3))-H arylation is an important type of C-H functionalization.Various biologically significant natural products,chemi-cal intermediates,and drugs have been effectively prepared via C-H functionalization.Cyclic carbonyl compounds comprise of cyclic ketones,enones,lactones,and lactams.Theα-C(sp^(3))-H arylation of these compounds have been exhibited high efficiency in forming C(sp^(3))-C(sp^(2))bonds,played a crucial role in organic synthesis,and attracted majority of interests from organic and medicinal communities.This review focused on the most significant advances including methods,mechanism,and applications in total synthesis of natural products in the field ofα-C(sp^(3))-H arylations of cyclic carbonyl compounds in recent years.

Electricity-driven enantioselective cross-dehydrogenative coupling of two C(sp^(3))-H bonds enabled by organocatalysis

An efficient and scalable electrochemical asymmetric protocol with metal-free catalysts and even without additional oxidants for the cross-dehydrogenative coupling reaction(CDC)of two C(sp^(3))-H bonds is reported.A series of aldehydes including natural products and various substrates containing C(sp^(3))-H bonds including xanthenes,acridines,cycloheptatrienes and even diarylmethane have been shown to undergo asymmetric CDC to afford a series of carbon-carbon bond coupling products with up to 94%yield and 98%ee.Mechanistic studies such as radical clock experiment suggest that the reaction proceeds via nucleophilic attack by enamine under electrochemical conditions.

Electro-reductive carboxylation of acyclic C(sp^(3))–C(sp^(3))bonds in aromatic hydrocarbons with CO_(2)

Despite the recent advances in the selective functionalization of C–C bonds in specific substrates,cleavage and functionalization of C–C bonds in acyclic substrates,such as ethane derivatives,remains challenging.In contrast to the well-developed functionalization of one carbon fragment after C–C bond cleavage,herein,we report a novel electro-reductive carboxylation of C(sp^(3))–C(sp^(3))bond in multi-aryl ethanes with carbon dioxide(CO_(2))by utilizing both carbon fragments.Thus,this reaction exhibits an atom-,step-economic approach for the synthesis of carboxylic acids,fulfilling principal aspirations of organic synthesis.Moreover,this method features mild reaction conditions,broad substrate scope,and good functional group tolerance.Symmetric and asymmetric substrates bearing primary,secondary,or tertiary C(sp^(3))–C(sp^(3))bonds are all amenable to this strategy,enabling one or two structurally different carboxylic acids to be facilely constructed at the same time.Mechanistic investigations indicate that carbanions might be the key intermediates in this reaction,which could be captured by CO_(2)efficiently.

Rhodium-catalyzed enantioselective in situ C(sp^(3))-H heteroarylation by a desymmetrization approach

A rhodium-catalyzed desymmetrization reaction for enantioselective methyl C-H arylation is achieved by utilizing an in situ arylating reagent via nucleophilic cyclization of o-aminoaryl alkyne.The reaction results in chiral indoles containing all-carbon quaternary stereocenters under atmospheric conditions,with a wide range of substrates exhibiting good enantioselectivity(44 examples).Mechnism and DFT studies show that the stereocontrol is reasonably achieved through the collaborative control of a large silicon substituted chiral ligand and C-H···π,LP···πinteractions between aryl rings of the carboxylate group and the substrate.Control experiments demonstrate that Rh-aryl bond formation via in situ nucleophilic cyclization is more critical for reaction efficiency than via C-H activation of the nucleophilic cyclization byproduct.

Efficient Photolytic Halogenation and Oxidation of Unactivated Alkyl sp^(3) C—H Bonds with Iodine(III)

A metal-free,green,and sustainable functionalization of unactivated alkyl sp^(3) C—H bonds is reported using iodine(III)as a feasible dehydrogenation agent under visible light or KBr,and alkyl chlorides,bromides,alcohols,and ketones could be constructed by addition of different coupling reagents.Cheap and safe iodobenzene diacetate was used to form a radical to activate the alkyl sp^(3) C—H bond in a highly efficient manner,which can construct different alkylation products by adding corresponding coupling reagents.

Photoelectrochemical Iron-Catalyzed C(sp^(3))-H Borylation of Alkanes in a Position-Selective Manner

Catalytic C-H borylation is of prime topical importance,since easily available feedstock chemicals can thereby be transformed into valuable transient functional groups in the absence of directing groups.Herein,we disclose an iron-catalyzed C(sp^(3))-H borylation of simple,non-prefunctionalized alkanes,providing access to value-added products in a single step by means of photoelectrochemistry.The power of merging photo-and electrochemistry was mirrored by ample scope and exceedingly mild reaction conditions.Moreover,an outstanding position-selectivity in favor of primary C(sp^(3))-H proved viable within the photoelectrochemical borylation through a chemo-selective anodic overoxidation manifold.The ferro-photoelectrochemistry strategy avoids toxic precious transition metals,enabling C(sp^(3))-H borylations in a site-selective fashion.

氢原子转移介导的C(sp^(3))-H键选择性硼基化

作为一种高度原子经济性和步骤经济性的策略,C(sp^(3))-H键的选择性官能团化一直备受关注.其中硼基化反应以低毒害、高效多样的转化能力,倾注了合成化学家最多的努力.然而,由于C(sp^(3))-H键的惰性,控制C(sp^(3))-H键硼基化的化学选择性和区域选择性是一项重大的挑战.作为一种新兴的方法,利用氢原子转移(HAT)实现C(sp^(3))-H键选择性硼基化相比以往过渡金属催化的过程有着其独特之处.此专题中,我们对最近兴起的各种HAT介导的C(sp^(3))-H键选择性硼基化的方法进行了分析.从分子内和分子间的HAT的角度分类,重点介绍了各种方法不同选择性的来源,并对所涉及的机理进行了具体的讨论.最后,我们整理了目前方法的局限性,并对这一领域的前景进行了展望.

Photocatalyzed site‐selective C(sp^(3))‒H sulfonylation of toluene derivatives and cycloalkanes with inorganic sulfinates

The development of practical methods for the direct and selective C(sp^(3))‒H functionalization of hydrocarbons is an attractive topic in synthetic chemistry.Although the radical‐mediated hydrogen atom transfer(HAT)process has shown considerable potential in such reactions,it still faces fundamental problems associated with reactivity and selectivity.Herein,we report a convenient and economic approach to site‐selective C(sp^(3))‒H sulfonylation via photo‐induced HAT catalysis.Employing a conjugated polycyclic quinone as a direct HAT photocatalyst,commercially available inorganic sulfinates as the sulfonylation source,copper triflate as an inexpensive oxidant,a variety of toluene derivatives and cycloalkanes were converted into biologically and synthetically interesting sulfone products under mild conditions.The mechanistic studies reveal that the reaction sequence involves direct HAT‐induced radical formation and a subsequent copper‐mediated organometallic process for the C‒S bond formation.This method offers an appealing opportunity to furnish high value‐added products from abundant hydrocarbon starting materials and inexpensive reagents.

Recent advances in directα-C(sp^(3))-H bond functionalization of thioethers

Thioether skeletons are widely present in drugs,natural products,functional materials,and life science.In the past decade,the selective C–H functionalization of thioethers has been extensively studied to construct novel thioether derivatives.This mini-review systematically introduces the recent advances in the field of the directα-C(sp^(3))-H functionalization of thioethers.

Radical Functionalization of Remote C(sp^(3))-H Bonds Mediated by Unprotected Alcohols and Amides

Aliphatic alcohols and amides are highly valued,ubiquitous chemicals in synthetic chemistry.Radical-promoted regioselective functionalization of unactivated C(sp^(3))–H bonds offers an atom and step economic manner for direct transformation of aliphatic alcohols and amides,especially structural elaboration of complex natural products and bioactive molecules without de novo synthesis.Despite the rapid growth of hydrogen atom transfer(HAT)processes mediated by O-or N-centered radicals generated from prefunctionalized precursors of alcohols and amides in the past few years,exploration of remote C(sp^(3))–H functionalization via HAT mediated by unprotected alcohols or amides lags behind,due to the difficult homolysis of O–H and N–H bonds with high bond-dissociation energies(BDEs).In this minireview,the recent advances in regioselective C(sp^(3))–H functionalization mediated by unprotected alcohols and amides are summarized.

Nucleophilic Radicals as Hydrogen Atom Abstractors in C(sp3)-H Functionalization Reactions

Hydrogen atom transfer(HAT)is an elementary mechanistic step in organic synthesis.The photoredox-catalyzed HAT has transformed organic synthesis by enabling the activation and subsequent cross-coupling of traditionally inert yet ubiquitous C(sp^(3))-H bonds.

Multipurpose sulfoximine-mediated radicalγ-heteroarylation of unactivated C(sp^(3))–H bonds

A conceptually novel,trifunctional sulfoximine-mediatedγ-functionalization of unactivated C(sp^(3))–H bonds has been achieved.The reaction is initiated by the photo-induced homolytic cleavage of an N–S bond in the absence of photosensitizer,and proceeds sequentially through a cascade of 1,5-hydrogen atom transfer,1,4-functional group migration,desulfoximination and a Minisci reaction.A major feature of this approach is the use of sulfoximine as a traceless directing group.Other positive properties include mild conditions,simple operation,exclusive site-selectivity,high product diversity and the avoidance of additional photosensitizers.The protocol provides a new reaction mode for HAT-induced C(sp^(3))–H functionalization,and allows a much broader chemical space for sulfoximine studies.

C(sp^(3))-H bond functionalization of oximes derivatives via 1,5-hydrogen atom transfer induced by iminyl radical

Oximes derivatives have been vastly used in organic synthesis. In this review, C(sp^(3))-H bond functionalization of oximes derivatives via iminyl radical induced 1,5-hydrogen atom transfer was discussed. According to the different type of products, this review was divided into three parts: (1) C(sp^(3))-H bond functionalization for C-C bond formation. (2) C(sp^(3))-H bond functionalization for C-N bond formation. (3) C(sp^(3))-H bond functionalization for C-S, C-F bond formation.

Alumina-supported heteropoly acid:An efficient catalyst for the synthesis of azaarene substituted 3-hydroxy-2-oxindole derivatives via C(sp^3)-H bond functionalization

A method of C（sp^3）-H bond functionalization of methyl azaarenes catalyzed by alumina-supported heteropoly acid and addition to isatins was developed. This transformation could be used for the synthesis of biologically important 3-hydroxy-2-oxindole derivatives in good to excellent yields and the catalyst could be reused for six times without significant decrease in activity.

电化学促进未活化C(sp^(3))—H官能团化研究进展

有机电合成以无痕电子代替传统的化学氧化剂或还原剂,具有绿色易放大等优势.未活化C(sp^(3))—H键的官能团化可以将目标官能团直接引入分子中进行修饰,避免预官能团化,兼具原子经济性和步骤经济性.随着有机电合成发展的日益成熟,电化学促进未活化C(sp^(3))—H官能团化成为了有机合成的研究热点之一.根据官能团类型对反应进行分类,总结了近年来涉及未活化C(sp^(3))—H官能化的研究成果,重点分析了反应优势、底物特点以及反应机理,最后展望了面临的挑战及未来的发展趋势.

喹啉酮C-3位直接官能团化研究进展

C-3位取代的喹啉酮是一类重要的杂环化合物,在材料和医药等方面具有较为广泛的应用。通过C-H直接官能团化来构建3-喹啉酮衍生物是最为简便和有效的方法,引起了人们极大的关注。近年来,在金属或非金属催化下一系列高效、绿色的合成3-喹啉酮衍生物的方法已经被实现。本文按照不同的官能团化反应类型进行分类,综述了3-喹啉酮衍生物合成的研究进展。

BrΦnsted acid-promoted ‘on-water’ C(sp^3)-H functionalization fot the synthesis of isoindolinone/[1,2,4]triazolo[1,5-a]pyrimidine derivatives targeting the SKP2-CKS1 interaction

The isoindolinone and biaryl scaffolds are prevalent in natural products and drug molecules,which have showed broad and interesting biological activities.The efficient construction of such hybridized molecules and biological evaluation are of great interest to medicinal chemistry community.In this communication,we report an efficient BrΦnsted acid-promoted C(sp^3)-H functionalization approach that enables the rapid construction of biologically important isoindolinone/[1,2,4]triazolo[1,5-a]pyrimidine hybrids from 5-methyl-7-(2,4,6-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine,2-formylbenzoic acid and various anilines.The title compounds were generated in high to excellent yields(up to 96%)regardless of the electronic nature and steric effects of the substituents.In this reaction,an isoindolinone scaffold,one C-C single bond,and two C-N bonds were formed simultaneously with high atom economy.In this work,we have envisioned that the methyl group linked to the electron-deficient Nheterocycles could be used as a new synthetic handle for late-state diversification and may have broad applications in the field of organic and medicinal chemistry.Besides,the title compounds have exhibited promising activity against the SKP2-CKS1 interaction.

C(sp^3)–H bond functionalization of non-cyclic ethers by decarboxylative oxidative coupling with α,β-unsaturated carboxylic acids

A copper-catalyzed decarboxylative oxidative coupling of α,β-unsaturated carboxylic acids with non-cyclic ethers is developed.This method provides a new approach for C(sp^3)–H bond functionalization of non-cyclic ethers. Mechanism study shows the reaction involves a radical process.

Metal-free direct C(sp^(3))-H functionalization of 2-alkylthiobenzoic acid to access 1,3-benzooxathiin-4-one

Metal-free direct α-C(sp^(3))-H intramolecular cyclization of 2-alkylthiobenzoic acid in the presence of Selectfluor is described.This novel strategy provides a facile and efficient method to access important 1,3-benzooxathiin-4-one derivatives with good functional groups tolerance and yields.