Search

Herein, we report an efficient synthetic method for polysubstituted pentafulvenes via palladium-catalyzed deacetylative [2+2+1] annulation of enones with alkynes.

We report herein the synthesis of 1,3-enynes via palladium-catalyzed cross-coupling between enone derivatives and alkynylsilanes. The employment of an appropriate pyridine-oxazoline ligand is the key to the C-C cleavage and the high

Spiroindoles are key scaffolds in a large number of natural products, pharmaceuticals, and agrochemicals. Selective C–H activation has emerged as a powerful synthetic approach to streamline the synthesis of substituted spiroindoles. To date, various 2- and 3-indolyl-tethered aza-spiro-centers have been successfully achieved via C–H activation. However, introduction of spiro-containing systems onto the benzenoid core of indole still remains challenging. Herein, a method of Rh(III)-catalyzed selective C7-H activation/cyclization of indole with maleimide to afford novel spiroindole derivatives is reported, which incorporate both succinimide and spirocycle into indole unit. Gram-scale synthesis demonstrates the utility of this protocol, further modification via click chemistry offered a novel scaffold as a versatile spiro linker.

We report herein a copper-mediated ortho-C-H amination of anilines using oxalamide as the directing group and DMF as the amination reagent. This protocol tolerates various functional groups and shows good heterocyclic compatibility. Late-stage dimethylamination of drugs demonstrated the synthetic practicality of the protocol. Mechanistic experiments indicate that a radical pathway may be involved in the reaction.

The transition-metal-catalyzed decarboxylation of aryl carboxylic acids has drawn significant attention as an efficient and practical tool for the synthesis of substituted arenes. However, the decarboxylative construction of polysubstituted arenes with different contiguous substituents has not been widely reported. Herein, we describe a novel decarbonylative Catellani reaction via palladium-catalyzed, norbornene (NBE)-mediated polyfunctionalization of aromatic thioesters, which serve as readily available carboxylic acid derivatives. A variety of alkenyl, alkyl, aryl, and sulfur moieties could be conveniently introduced into the ipso-positions of the aromatic thioesters. By combining carboxyl-directed C-H functionalization and the classical Catellani reaction, our protocol allows for the construction of 1,2,3-trisubstituted and 1,2,3,4-tetrasubstituted arenes from simple aromatic acids. Furthermore, the late-stage functionalization of a series of drug molecules highlights the potential utility of the reaction.

We report herein a palladium-catalyzed diarylative dearomatization of indole by employing thioester and arylboronic acid as the aryl electrophiles. The reaction involved a decarbonylation/migratory insertion/terminal Suzuki coupling procedure. Substrates bearing various functional groups are well tolerated in the reaction, affording the diarylated indoline skeletons in moderate to good yields.

Herein, we report an efficient palladium-catalyzed silylation of aryl and alkenyl ketones via C-C bond cleavage and C-Si bond formation. This protocol features high efficiency and broad substrate scope. Further applications in the late-stage diversification of biologically important molecules demonstrate the synthetic utility of this method.

Mizoroki-Heck reaction of unstrained aryl ketone with acrylate/styrene is accomplished via palladium-catalyzed ligand-promoted C-C bond cleavage. Various (hetero)aryl ketones are compatible in the reaction, affording the alkene product in good to excellent yields. Further applications in the late-stage olefination of some drugs, natural products, and fragrance-derived aryl ketones demonstrate the synthetic utility of this protocol. By employing ketone as both the directing group and the leaving group, 1,2-bifunctionalization is achieved via sequential ortho-C-H alkylation/ipso-Heck olefination.

Conversion of the numerous aryl ketones into aryl electrophiles via Ar–C(O) cleavage remains a challenging yet highly desirable transformation in Sonogashira-type coupling. Herein, we report a pall...

C3-Arylation of indoles with aryl ketones is accomplished via palladium-catalyzed ligand-promoted Ar-C(O) cleavage and subsequent C-H arylation of indole. Various (hetero)aryl ketones are compatible in this reaction, affording the corresponding 3-arylindoles in moderate to good yields. Further introduction of an indole moiety into the natural products desoxyestrone and evodiamine demonstrate the synthetic utility of this protocol.

A copper-catalyzed oxalamide-directed ortho-C-H amination of anilines has been developed by using 1 atm of air as the sole oxidant. The protocol shows excellent functional group tolerance, and some heterocyclic amines including indole, benzothiophene, benzothiazole, quinoline, isoquinoline, and quinoxaline could be compatible in the reaction. The late-stage diversification of medicinal drugs demonstrates the synthetic utility of this protocol.

Palladium-catalyzed highly meta-selective C H iodination of phenylacetic acid, benzylphosphonate and benzylsulfonate scaffolds with molecular I2 is developed using a pyridine-type template. The practical ester linkages enable the directing template easily installed and readily removed. The substrate scope is broad, and alkyl, methoxyl, trifluomethyl, and halo substituents are compatible with this reaction. Further transformations of ibuprofen iodide intermediates by Pd-catalyzed C C and C–heteroatom bond formation illustrate the broad utility of this method.

Here, we report O-methyl S-aryl thiocarbonates as a versatile esterification reagent for palladium-catalyzed methoxycarbonylation of arylboronic acid in the presence of copper(I) thiophene-2-carboxylate (CuTC). The reaction condition is mild, and a variety of substituents including sensitive -Cl, -Br, and free -NH2 could be tolerated. Further applications in the late-stage esterification of some pharmaceutical drugs demonstrate the broad utility of this method.

Copper mediated C(sp2)–H amination and hydroxylation of arylphosphinic acid are accomplished by adopting phosphinamide as the directing group. This method is distinguished by its wide substrate scope and excellent functional group tolerance, thus allowing for the rapid preparation of organophosphorus compounds in organic synthesis.

We report herein a copper-mediated

Herein, we report the arylation, alkylation, and alkenylation of aryl ketones via a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. The use of the pyridine-oxazoline ligand is the key to the cleavage of the unstrained C-C bond. The late-stage arylation of aryl ketones derived from drugs and natural products demonstrated the synthetic utility of this protocol.

C3-Arylation of indoles with aryl ketones is accomplished

Herein, we have developed a strategy of sequential C-H activations of indole to construct novel 2-alkynyl aza-spiro[4,5]indole scaffolds, which incorporated both alkyne and spiro-units into indole. Gram-scale synthesis and a one-pot, three-step synthesis demonstrated the utility of this protocol. Hybrid conjugates with an oseltamivir derivative further offered a powerful tool for the construction of a versatile spiroindole-containing library via click chemistry.

Herein, we report the palladium-catalyzed asymmetric acyl-carbamoylation of an alkene by employing thioesters as the acyl electrophiles and t-BuNC as the carbamoyl reagent, affording an α-quaternary chiral cycloketone in synthetically useful yields with excellent enantioselectivity. The reaction proceeded via asymmetric 1,2-migratory insertions of acyl-Pd into alkenes and subsequent migratory insertion of isocyanides into C(sp3)-PdII. The product could be diversified to some valuable skeletons with retention of enantiopurity, demonstrating the synthetic utility of this protocol.

A rhodium(III)-catalyzed domino annulation of simple olefins with diazo oxindoles to give spirooxindole pyrrolone products is described. This reaction can be formally viewed as the result of an anomalous tandem C-H activation, carbene insertion, Lossen rearrangement, and a nucleophilic addition process. The potential utility of this reaction was further demonstrated by the late-stage diversification of drug molecules.

Palladium-catalyzed meta-selective C-H deuteration of a series of substrates, including phenylacetic acids, hydrocinnamic acid, benzylphosphonate, benzylsulfonate, and benzyl and phenyl ethyl alcohol ester, is developed by using a pyridine-based directing template. The template is installed into the substrate through a practical ester linkage. Under mild reaction conditions, a variety of phenylacetic acids containing alkyl, methoxyl, and halo substituents are compatible in the reaction, resulting in high levels of D-incorporation at the meta position.

We report herein the Pd-catalyzed oxazoline-directed C-H olefination of the N-arylindole skeleton, affording two diastereomers of axially chiral olefin-oxazoline ligands in a one-step procedure. Modifications at the 3- and 3'-positions were facilely achieved via electrophilic substitution of the indole fragment and subsequent oxazoline-directed C-H amidation or olefination of the arene fragment.

A copper-catalyzed oxalamide-directed

The coupling of aromatic electrophiles (aryl halides, aryl ethers, aryl acids, aryl nitriles etc.) with nucleophiles is a core methodology for the synthesis of aryl compounds. Transformations of aryl ketones in an analogous manner via carbon-carbon bond activation could greatly expand the toolbox for the synthesis of aryl compounds due to the abundance of aryl ketones. An exploratory study of this approach is typically based on carbon-carbon cleavage triggered by ring-strain release and chelation assistance, and the products are also limited to a specific structural motif. Here we report a ligand-promoted β-carbon elimination strategy to activate the carbon-carbon bonds, which results in a range of transformations of aryl ketones, leading to useful aryl borates, and also to biaryls, aryl nitriles, and aryl alkenes. The use of a pyridine-oxazoline ligand is crucial for this catalytic transformation. A gram-scale borylation reaction of an aryl ketone via a simple one-pot operation is reported. The potential utility of this strategy is also demonstrated by the late-stage diversification of drug molecules probenecid, adapalene, and desoxyestrone, the fragrance tonalid as well as the natural product apocynin.

Here, we report

Copper mediated C(sp2)-H amination and hydroxylation of arylphosphinic acid are accomplished by adopting phosphinamide as the directing group. This method is distinguished by its wide substrate scope and excellent functional group tolerance, thus allowing for the rapid preparation of organophosphorus compounds in organic synthesis.

The first copper-mediated diastereoselective C–H thiolation of ferrocenes has been developed. A chiral oxazoline directing group with tert-butyl substituent is essential to the high diastereoselectivity ratio and the suppression of overreaction of monothiolated products. This reaction tolerated various functional groups on arylthiols, implying its potential application in N,S-bidentate planar chiral ligands.

Here we report an efficient Cu(i)-mediated C–H amination reaction with oximes as amino donors to introduce NH2 groups directly., Here we report an efficient Cu(i)-mediated C–H amination reaction with oximes as amino donors to introduce NH2 groups directly. Various strongly coordinating heterocycles including quinoline, pyrimidine, pyrazine, pyrazole and triazole were tolerated well. The potential utility was further demonstrated in a late-stage modification of telmisartan (an antagonist for the angiotensin II receptor).

Although chelation-assisted C–H olefination has been intensely investigated, Pd(II)-catalyzed C–H olefination reactions are largely restricted to acrylates and styrenes. Here we report a quinoline-derived ligand that enables the Pd(II)-catalyzed olefination of the C(sp2)–H bond with simple aliphatic alkenes using a weakly coordinating monodentate amide auxiliary. Oxygen is used as the terminal oxidant with catalytic copper as the co-oxidant. A variety of functional groups in the aliphatic alkenes are tolerated. Upon hydrogenation, the ortho-alkylated product can be accessed. The utility of this reaction is also demonstrated by the late-stage diversification of drug molecules.

Here we report an aerobic Pd(0) catalyzed C2-H functionalization of indoles and pyrroles with tethered N-methoxylamide as the directing group. A Pd(0)-initiated mechanism overcomes the directing or poisoning effect from a wide range of heterocycles including pyridine, pyrimidine, and thiazole. The imidazo[1,5-a]indole products are transformed to bioactive analogs after one-step manipulations, demonstrating the potential utility of this reaction in drug discovery.

We report herein a copper-mediated ortho C H primary amination of anilines by using cheap and commercially available benzophenone imine as the amination reagent. The protocol show good functional group tolerance and heterocyclic compatibility. Late-stage diversification of drugs demonstrate the synthetic utility of this protocol.

One long-standing issue in directed C-H functionalization is that either nitrogen or sulfur atoms present in heterocyclic substrates may bind preferentially to a transition-metal catalyst rather than to the desired directing group. This competitive binding has largely hindered the application of C-H functionalization in late-stage heterocycle drug discovery. Reported here is the use of an oxazoline-based directing group capable of overriding the poisoning effect of a wide range of heterocycle substrates. The potential use of this directing group in pharmaceutical drug discovery is illustrated by diversification of Telmisartan (an antagonist for the angiotensin II receptor) through copper-mediated C-H amination, hydroxylation, thiolation, arylation, and trifluoromethylation.

The use of a weakly coordinating monodentate directing group for copper-mediated ortho-hydroxylation and amination reactions allows for the identification of an external oxazoline ligand as a promoter.

Cu-mediated C-H thioetherification of arenes with ethylene sulfide has been developed using a readily removable directing group. The reaction proceeded at room temperature, and a variety of sensitive functional groups including chloro, bromo, and vinyl were well tolerated. The thiolated products could be converted to the seven-membered benzoxathiepinones derivatives by a sequence of hydrolysis-lactonization reactions.

One formidable challenge in sp2 C–H activation is how to achieve high para selectivity on electron-deficient arenes because such site selectivity is disfavored by the electronic bias induced by the electron-withdrawing groups. The first highly selective para-C–H acetoxylation of various benzoic acids using a nitrile-based template was realized. Removal of the template leads to para-hydroxylated benzoic acids, which are versatile intermediates for a wide range of synthetically useful transformations.

Considerable progress has been made in the area of copper-mediated C(sp2)–H functionalization reactions with the assistance of chelating directing groups. Due to the advantages of copper catalysts such as low cost, low toxicity, and unique reactivity compared to precious metals, they have attracted more and more attention in organic synthesis. This review summarizes recent advances in this field according to the classification of directing groups. 1 Introduction 2 The Pyridine Directing Group 2.1 C–N Bond Formation 2.2 C–O Bond Formation 2.3 C–S Bond Formation 2.4 C–C Bond Formation 2.5 C–CN Bond Formation 2.6 C–Halogen Bond Formation 3 Bidentate Directing Groups 3.1 8-Aminoquinoline 3.2 (2-Pyridyl)Sulfonyl and Picolinic Acid 3.3 Amide-Oxazoline Auxiliary 3.4 2-(Pyridin-2-yl)isopropylamine (PIP Amine) 3.5 2-Aminopyridine 1-Oxide 4 Conclusions and Outlook

A quinoline-based ligand effectively promotes the palladium-catalyzed borylation of C(sp(3))-H bonds. Primary β-C(sp(3))-H bonds in carboxylic acid derivatives as well as secondary C(sp(3))-H bonds in a variety of carbocyclic rings, including cyclopropanes, cyclobutanes, cyclopentanes, cyclohexanes, and cycloheptanes, can thus be borylated. This directed borylation method complements existing iridium(I)- and rhodium(I)-catalyzed C-H borylation reactions in terms of scope and operational conditions.

We have developed a copper-mediated C H thiolation of (hetero)arenes by using monodentate amide as weakly coordinating directing group. This protocol features excellent functional group tolerance and shows satisfactory compatibility with various heterocycles, such as indole, pyrrole, imidazole, pyridine, thiophene and quinoline. The robust nature of this protocol renders that it has potential value in the synthetic application.

A palladium-catalyzed fluoroacylation of (hetero)aryl boronic acid with the fluorothioacetates is described at ambient temperature. A variety of aryl, and heteroaryl boronic acids are compatible in the reaction, affording the corresponding fluoroalkyl ketones in moderate to good yields. Further late-stage di-, and trifluoroacylation of drug molecule clofibrate and estrone demonstrated the synthetic practicability of this protocol.2009 Elsevier Ltd. All rights reserved.

In a Pd-catalyzed double C-H activation reaction, a pyridine-type ligand is identified, for the first time, to enable a highly para-selective C-H arylation of monosubstituted arenes. Excellent para-selectivity is achieved with a variety of arenes containing alkyl, methoxyl, and halo substituents.

A new Cu(II)-catalyzed oxidative coupling of arenes with malonates has been developed using an amide-oxazoline directing group. The reaction proceeds via C(sp(2))-H activation and malonate coupling, followed by intramolecular oxidative N-C bond formation. A variety of arenes bearing different substituents are shown to be compatible with this reaction.

In directed C-H activation reactions, any nitrogen or sulphur atoms present in heterocyclic substrates will coordinate strongly with metal catalysts. This coordination, which can lead to catalyst poisoning or C-H functionalization at an undesired position, limits the application of C-H activation reactions in heterocycle-based drug discovery(1-5), in which regard they have attracted much interest from pharmaceutical companies(3-5). Here we report a robust and synthetically useful method that overcomes the complications associated with performing C-H functionalization reactions on heterocycles. Our approach employs a simple N-methoxy amide group, which serves as both a directing group and an anionic ligand that promotes the in situ generation of the reactive PdX2 (X = ArCONOMe) species from a Pd(0) source using air as the sole oxidant. In this way, the PdX2 species is localized near the target C-H bond, avoiding interference from any nitrogen or sulphur atoms present in the heterocyclic substrates. This reaction overrides the conventional positional selectivity patterns observed with substrates containing strongly coordinating heteroatoms, including nitrogen, sulphur and phosphorus. Thus, this operationally simple aerobic reaction demonstrates that it is possible to bypass a fundamental limitation that has long plagued applications of directed C-H activation in medicinal chemistry.

Cu(II)-promoted ortho alkynylation of arenes and heteroarenes with terminal alkynes has been developed to prepare aryl alkynes. A variety of arenes and terminal alkynes bearing different substituents are compatible with this reaction, thus providing an alternative disconnection to Sonogashira coupling.