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.

光催化甲苯衍生物、环烷烃与无机亚磺酸盐的位点选择性C(sp^(3))-H砜基化

烃类是最基础的有机分子之一,具有品种丰富、来源广泛、价格低廉等优势,其多样性、选择性转化一直备受合成化学家关注.然而,这些化合物中通常存在多个键能高、极性低、相互间差异性小的C(sp^(3))-H键,因此,实现高效、选择性C-H官能化极具挑战性.近年来,可见光催化广泛应用于有机合成中,与氢转移催化相结合所发展的可见光氢转移光催化策略在C(sp^(3))-H官能化反应中展现了较大的潜力,特别是为化学、位点、立体选择性等问题的解决带来了新机遇.尽管如此,能在激发态有效切断烷烃、环烷烃等中未活化的C(sp^(3))-H键,被用于直接氢转移光催化的催化剂种类很少,主要局限于十钨酸盐、芳香酮衍生物等,因此,发展新型氢转移光催化剂和新反应具有重要意义.近期人们发现,一种共轭多元醌分子(5,7,12,14-并五苯四酮,PT)具有较好的光物理性质、电化学性能及溶解性,可被用作直接氢转移光催化剂.为了深入研究其催化活性及在惰性烃类化合物转化中的应用,本文利用PT与铜盐协同作用,开发了一种高效、高选择性的C(sp^(3))-H砜基化反应,以无机亚磺酸盐作为砜基化试剂,将一系列甲苯衍生物、环烷烃、药物类似物等转化为具有潜在生物活性和重要合成应用的砜类产物.该反应条件温和、操作简单,不需要使用贵金属催化剂和配体,反应原料均已商品化且价格较便宜.通过自由基淬灭与捕获、自由基钟、控制实验、荧光淬灭等机理实验,证明了反应的自由基历程和铜介导的金属有机过程.X射线光电子能谱证明过程中伴随着零价铜的产生,反应仅需要1.2当量的二价铜盐作为氧化剂,为多样性C‒H官能化反应提出了新的策略和路径.此外,该方法还成功应用于药物类似物的后期官能化,展现了良好的官能团兼容性和位点选择性,进一步证明了其应用价值.综上所述,本文以一种商品化的共轭多元醌作为直接氢转移光催化剂,铜盐为氧化剂,无机亚磺酸盐为砜基化试剂,开发了一种经济低毒、温和易操作的甲苯衍生物、环烷烃C(sp^(3))-H官能化新方法,为砜类化合物的合成与开发利用提供了高效、高选择性的途径,也为药物分子后期官能化提供了有效的手段.

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.

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.

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.

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.

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.

新型C3-含硅基取代手性脯氨酸型催化剂的高效构筑

为将C-H活化策略应用于手性有机催化剂的开发,选择以L-脯氨酸为原料、C(sp^(3))-H硅烷化反应为关键步骤,设计合成了两种新型的C3-三甲基硅基取代的手性脯氨酸催化剂,并将其分别应用于对硝基苯甲醛与丙酮的分子间不对称aldol反应和亚胺与β-甲基丁醛的分子间不对称Mannich反应,均可以良好对映选择性实现目标产物的合成.该策略有效丰富了脯氨酸结构的修饰手段,为新型含硅小分子催化剂的开发提供了新方法.

Radical Mechanism of IrⅢ/NiⅡ Metallaphotoredox-Catalyzed C(sp^(3))-H Functionalization Triggered by Proton-Coupled Electron Transfer:Theoretical Insight

Photoredox catalysis can be induced to activate organic substrates or to modulate the oxidation state of transition-metal catalysts via unique singleelectron transfer processes,so as to achieve challenging C(sp^(3))-H functionalization under mild conditions.However,the specific reaction mechanism and relevant electron transfer process still need to be clarified.Here,a highly regioselective Ir^(Ⅲ)/Ni^(Ⅱ)-metallaphotoredox-catalyzed hydroalkylation of asymmetrical internal alkyne with an etherα-hetero C(sp^(3))-H bond has been investigated by density functional theory(DFT)calculations.A novel radical mechanism was predicted to merge oxidative quenching(Ir^(Ⅲ)-*Ir^(Ⅲ)-Ir^(Ⅳ)-Ir^(Ⅲ))and nickel catalytic cycles(NiⅡ-NiⅢ-NiI-NiⅢ-NiⅡ)for this C(sp^(3))-H functionalization to construct C(sp^(3))-C(sp^(2))bonds.It consists of seven major steps:the single-electron transfer involved in the photoredox cycle for generating active Ni(Ⅰ)-chloride complexes,proton-coupled electron transfer process to provide α-carbon-centered tetrahydrofuran(THF)radicals,radical capture by Ni(Ⅱ),reductive elimination to obtain 2-chlorotetrahydrofuran,alkyne oxidative hydrometallation,innersphere electron transfer,and σ-bond metathesis to yield the desired alkyne hydroalkylation product.Importantly,both the thermodynamic performance for redox potentials and the kinetic exploration for energy barriers and electron-transfer rates have also been evaluated for the corresponding electron transfer processes.In addition,the steric effects play a major role in determining the regioselectivity of alkyne oxidative hydrometallation.

无金属条件下芳基酮与二甲亚砜的α-C(sp^(3))-H亚甲基化反应合成γ-酮亚砜

芳基酮通过C(sp^(3))-H键官能化与二甲亚砜发生直接的α-C(sp^(3))-H亚甲基化反应生成γ-酮亚砜,该方法适用于各种芳基酮.此外,二甲基亚砜(DMSO)在反应中不仅用作溶剂,而且用作含硫单元.这种转化的实际价值在于γ-酮亚砜的高效和稳健的一锅合成法,并在初步实验的基础上,提出了一种可能的反应机理.

Nano palladium catalyzed C(sp^(3))-H bonds arylation by a transient directing strategy

Reported herein is the first example of heterogeneous palladium catalyzed C(sp^(3))-H bonds arylation by a transient-ligand-directed strategy.Using supported palladium(metallic state) na nopariticles as catalyst,a wide range of aryl iodides undergo the coupling with various o-methylbenzaldehyde derivatives to assemble a library of highly selective and functionalized o-benzylbenzaldehydes.The stability of the catalyst was easily recovered four runs without significant loss of activity.The XPS analysis of the catalyst before and after reaction indicated that the reaction might be carried out by a catalytic cycle starting with Pd~0.

Unactivated C(sp^(3))–H functionalization via vinyl cations

Direct functionalization of inert C(sp^(3))–H bonds is a topic of immense contemporary interest and exceptional value in organic synthesis.The recent research has established a novel and practical protocol which features the engagement of vinyl cation species to functionalize C(sp^(3))–H bonds.The discussion of the topic is arranged by the strategies to generate the reactive intermediates,including ionization of vinyl triflates,addition of electrophiles to alkynes,tandem cyclization of enynes or diynes,and decomposition ofβ-hydroxy-α-diazo ketones.This review closes with a personal perspective on the dynamic research area of unactivated C(sp^(3))–H functionalization via vinyl cations.Hopefully,it will provide timely illumination and beneficial guidance for organic chemists who are interested in this area.Meanwhile continued development of the field is strongly anticipated in the future.