Chemistry › Organic Chemistry

Catalytic C–H Functionalization Methods

Works Count: 54307

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Description

This cluster of papers focuses on the transition-metal-catalyzed functionalization of carbon-hydrogen (C–H) bonds, enabling the formation of carbon-carbon bonds, arylation, and synthesis of heterocycles. The research also explores applications in drug synthesis and oxidative coupling reactions.

Keywords

Transition Metal Catalysis; C–H Activation; Carbon–Carbon Bond Formation; Arylation; Heterocycles; Drug Synthesis; Oxidative Coupling; Directed C–H Functionalization; Metal-Catalyzed Reactions; Biaryl Molecules

Transition metal-catalyzed C–H bond functionalizations by the use of diverse directing groups

2015-01-01

Zhengkai Chen , Binjie Wang , Jitan Zhang +3 more

In this review, a summary of transition metal-catalyzed C–H activation by utilizing the functionalities as directing groups is presented. In this review, a summary of transition metal-catalyzed C–H activation by utilizing the functionalities as directing groups is presented.

The medicinal chemist's toolbox for late stage functionalization of drug-like molecules

2015-10-28

Tim Cernak , Kevin D. Dykstra , Sriram Tyagarajan +2 more

The advent of modern C-H functionalization chemistries has enabled medicinal chemists to consider a synthetic strategy, late stage functionalization (LSF), which utilizes the C-H bonds of drug leads as points … The advent of modern C-H functionalization chemistries has enabled medicinal chemists to consider a synthetic strategy, late stage functionalization (LSF), which utilizes the C-H bonds of drug leads as points of diversification for generating new analogs. LSF approaches offer the promise of rapid exploration of structure activity relationships (SAR), the generation of oxidized metabolites, the blocking of metabolic hot spots and the preparation of biological probes. This review details a toolbox of intermolecular C-H functionalization chemistries with proven applicability to drug-like molecules, classified by regioselectivity patterns, and gives guidance on how to systematically develop LSF strategies using these patterns and other considerations. In addition, a number of examples illustrate how LSF approaches have been used to impact actual drug discovery and chemical biology efforts.

Ru-, Rh-, and Pd-Catalyzed C−C Bond Formation Involving C−H Activation and Addition on Unsaturated Substrates: Reactions and Mechanistic Aspects

2002-04-04

Vincent Ritleng , Claude B. Sirlin , Michel Pfeffer

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTRu-, Rh-, and Pd-Catalyzed C−C Bond Formation Involving C−H Activation and Addition on Unsaturated Substrates: Reactions and Mechanistic AspectsVincent Ritleng, Claude Sirlin, and Michel PfefferView Author Information … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTRu-, Rh-, and Pd-Catalyzed C−C Bond Formation Involving C−H Activation and Addition on Unsaturated Substrates: Reactions and Mechanistic AspectsVincent Ritleng, Claude Sirlin, and Michel PfefferView Author Information Laboratoire de Synthèses Métallo-Induites, UMR CNRS 7513 Université Louis Pasteur, 4, rue Blaise Pascal 67070 Strasbourg, France Cite this: Chem. Rev. 2002, 102, 5, 1731–1770Publication Date (Web):April 4, 2002Publication History Received13 October 2001Published online4 April 2002Published inissue 1 May 2002https://pubs.acs.org/doi/10.1021/cr0104330https://doi.org/10.1021/cr0104330research-articleACS PublicationsCopyright © 2002 American Chemical SocietyRequest reuse permissionsArticle Views23427Altmetric-Citations1854LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Addition reactions,Aromatic compounds,Catalysts,Hydrocarbons,Ligands Get e-Alerts

Palladium-catalyzed vinylic hydrogen substitution reactions with aryl, benzyl, and styryl halides

1972-07-01

Richard F. Heck , J. P. Nolley

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPalladium-catalyzed vinylic hydrogen substitution reactions with aryl, benzyl, and styryl halidesR. F. Heck and J. P. Nolley Jr.Cite this: J. Org. Chem. 1972, 37, 14, 2320–2322Publication Date … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPalladium-catalyzed vinylic hydrogen substitution reactions with aryl, benzyl, and styryl halidesR. F. Heck and J. P. Nolley Jr.Cite this: J. Org. Chem. 1972, 37, 14, 2320–2322Publication Date (Print):July 1, 1972Publication History Published online1 May 2002Published inissue 1 July 1972https://pubs.acs.org/doi/10.1021/jo00979a024https://doi.org/10.1021/jo00979a024research-articleACS PublicationsRequest reuse permissionsArticle Views21610Altmetric-Citations1907LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

C−H Activation for the Construction of C−B Bonds

2009-12-22

Ibraheem A. I. Mkhalid , Jonathan H. Barnard , Todd B. Marder +2 more

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTC−H Activation for the Construction of C−B BondsIbraheem A. I. Mkhalid†‡, Jonathan H. Barnard†, Todd B. Marder*†, Jaclyn M. Murphy§¶, and John F. Hartwig*¶View Author Information Durham … ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTC−H Activation for the Construction of C−B BondsIbraheem A. I. Mkhalid†‡, Jonathan H. Barnard†, Todd B. Marder*†, Jaclyn M. Murphy§¶, and John F. Hartwig*¶View Author Information Durham University, Department of Chemistry, South Road, Durham, DH1 3LE, United Kingdom; Department of Chemistry, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 61821; and the University of Illinois, Department of Chemistry, A410 Chemical Life, Science Lab, 600 S. Matthews Avenue, Urbana, Illinois 61801* To whom correspondence should be addressed.†Durham University.‡King Abdulaziz University.§Yale University.¶The University of Illinois.Cite this: Chem. Rev. 2010, 110, 2, 890–931Publication Date (Web):December 22, 2009Publication History Received25 May 2009Published online22 December 2009Published inissue 10 February 2010https://pubs.acs.org/doi/10.1021/cr900206phttps://doi.org/10.1021/cr900206preview-articleACS PublicationsCopyright © 2009 American Chemical SocietyRequest reuse permissionsArticle Views51432Altmetric-Citations2399LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Aromatic compounds,Borylation,Catalysts,Hydrocarbons,Organic compounds Get e-Alerts

Transition metal-catalyzed C–H activation reactions: diastereoselectivity and enantioselectivity

2009-01-01

Ramesh Giri , Bing‐Feng Shi , Keary M. Engle +2 more

This critical review discusses historical and contemporary research in the field of transition metal-catalyzed carbon–hydrogen (C–H) bond activation through the lens of stereoselectivity. Research concerning both diastereoselectivity and enantioselectivity in … This critical review discusses historical and contemporary research in the field of transition metal-catalyzed carbon–hydrogen (C–H) bond activation through the lens of stereoselectivity. Research concerning both diastereoselectivity and enantioselectivity in C–H activation processes is examined, and the application of concepts in this area for the development of novel carbon–carbon and carbon–heteroatom bond-forming reactions is described. Throughout this review, an emphasis is placed on reactions that are (or may soon become) relevant in the realm of organic synthesis (221 references).

Cross-Dehydrogenative Coupling (CDC): Exploring C−C Bond Formations beyond Functional Group Transformations

2008-12-16

Chao‐Jun Li

Synthetic chemists aspire both to develop novel chemical reactions and to improve reaction conditions to maximize resource efficiency, energy efficiency, product selectivity, operational simplicity, and environmental health and safety. Carbon-carbon … Synthetic chemists aspire both to develop novel chemical reactions and to improve reaction conditions to maximize resource efficiency, energy efficiency, product selectivity, operational simplicity, and environmental health and safety. Carbon-carbon bond formation is a central part of many chemical syntheses, and innovations in these types of reactions will profoundly improve overall synthetic efficiency. This Account describes our work over the past several years to form carbon-carbon bonds directly from two different C-H bonds under oxidative conditions, cross-dehydrogenative coupling (CDC). We have focused most of our efforts on carbon-carbon bonds formed via the functionalization of sp(3) C-H bonds with other C-H bonds. In the presence of simple and cheap catalysts such as copper and iron salts and oxidants such as hydrogen peroxide, dioxygen, tert-butylhydroperoxide, and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), we can directly functionalize various sp(3) C-H bonds by other C-H bonds without requiring preactivation. We demonstrate (1) reaction of alpha-C-H bonds of nitrogen in amines, (2) reaction of alpha-C-H bonds of oxygen in ethers, (3) reaction of allylic and benzylic C-H bonds, and (4) reaction of alkane C-H bonds. These CDC reactions can tolerate a variety of functional groups, and some can occur under aqueous conditions. Depending on the specific transformation, we propose the in situ generation of different intermediates. These methods provide an alternative to the separate steps of prefunctionalization and defunctionalization that have traditionally been part of synthetic design. As a result, these methods will increase synthetic efficiencies at the most fundamental level. On an intellectual level, the development of C-C bond formations based on the reaction of only C-H bonds (possibly in water) challenges us to rethink some of the most fundamental concepts and theories regarding chemical reactivities. A successful reaction requires the conventionally and theoretically less reactive C-H bonds to react selectively in the presence of a variety of functional groups. With further investigation, we expect that C-C bond formations based on cross-dehydrogenative coupling will have a positive economic and ecological impact on the next generation of chemical syntheses.

C–H bond activation enables the rapid construction and late-stage diversification of functional molecules

2013-04-23

Joanna Wencel‐Delord , Frank Glorius

Highly Regioselective Arylation of sp3 C−H Bonds Catalyzed by Palladium Acetate

2005-08-31

V. G. Zaitsev , Dmitry Shabashov , Olafs Daugulis

A new palladium-catalyzed arylation process based on C−H activation has been developed. The utilization of pyridine-containing directing groups allows the β-arylation of carboxylic acid derivatives and γ-arylation of amine derivatives. … A new palladium-catalyzed arylation process based on C−H activation has been developed. The utilization of pyridine-containing directing groups allows the β-arylation of carboxylic acid derivatives and γ-arylation of amine derivatives. Both primary and secondary sp3 C−H bonds, as well as sp2 C−H bonds, are reactive.

Palladium- and Copper-Catalyzed Arylation of Carbon−Hydrogen Bonds

2009-06-24

Olafs Daugulis , Hien‐Quang Do , Dmitry Shabashov

The transition-metal-catalyzed functionalization of C−H bonds is a powerful method for generating carbon−carbon bonds. Although significant advances to this field have been reported during the past decade, many challenges remain. … The transition-metal-catalyzed functionalization of C−H bonds is a powerful method for generating carbon−carbon bonds. Although significant advances to this field have been reported during the past decade, many challenges remain. First, most of the methods are substrate-specific and thus cannot be generalized. Second, conversions of unactivated (i.e., not benzylic or α to heteroatom) sp3 C−H bonds to C−C bonds are rare, with most examples limited to t-butyl groups, a conversion that is inherently simple because there are no β-hydrogens that can be eliminated. Finally, the palladium, rhodium, and ruthenium catalysts routinely used for the conversion of C−H bonds to C−C bonds are expensive. Catalytically active metals that are cheaper and less exotic (e.g., copper, iron, and manganese) are rarely used. This Account describes our attempts to provide solutions to these three problems. We have developed a general method for directing-group-containing arene arylation by aryl iodides. Using palladium acetate as the catalyst, we arylated anilides, benzamides, benzoic acids, benzylamines, and 2-substituted pyridine derivatives under nearly identical conditions. We have also developed a method for the palladium-catalyzed auxiliary-assisted arylation of unactivated sp3 C−H bonds. This procedure allows for the β-arylation of carboxylic acid derivatives and the γ-arylation of amine derivatives. Furthermore, copper catalysis can be used to mediate the arylation of acidic arene C−H bonds (i.e., those with pKa values <35 in DMSO). Using a copper iodide catalyst in combination with a base and a phenanthroline ligand, we successfully arylated electron-rich and electron-deficient heterocycles and electron-poor arenes possessing at least two electron-withdrawing groups. The reaction exhibits unusual regioselectivity: arylation occurs at the most hindered position. This copper-catalyzed method supplements the well-known C−H activation/borylation methodology, in which functionalization usually occurs at the least hindered position. We also describe preliminary investigations to determine the mechanisms of these transformations. We anticipate that other transition metals, including iron, nickel, cobalt, and silver, will also be able to facilitate deprotonation/arylation reaction sequences.

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Efficient catalytic addition of aromatic carbon-hydrogen bonds to olefins

1993-12-01

Shinji Murai , Fumitoshi Kakiuchi , Shinya Sekine +4 more

Palladium(II)-Catalyzed Alkene Functionalization via Nucleopalladation: Stereochemical Pathways and Enantioselective Catalytic Applications

2011-03-23

Richard I. McDonald , Guosheng Liu , Shannon S. Stahl

ADVERTISEMENT RETURN TO ISSUEPREVReviewPalladium(II)-Catalyzed Alkene Functionalization via Nucleopalladation: Stereochemical Pathways and Enantioselective Catalytic ApplicationsRichard I. McDonald, Guosheng Liu†, and Shannon S. Stahl*View Author Information Department of Chemistry, University of Wisconsin—Madison, … ADVERTISEMENT RETURN TO ISSUEPREVReviewPalladium(II)-Catalyzed Alkene Functionalization via Nucleopalladation: Stereochemical Pathways and Enantioselective Catalytic ApplicationsRichard I. McDonald, Guosheng Liu†, and Shannon S. Stahl*View Author Information Department of Chemistry, University of Wisconsin—Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States*E-mail: [email protected]Cite this: Chem. Rev. 2011, 111, 4, 2981–3019Publication Date (Web):March 23, 2011Publication History Received1 November 2010Published online23 March 2011Published inissue 13 April 2011https://doi.org/10.1021/cr100371yCopyright © 2011 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views25023Altmetric-Citations1029LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (7 MB) Get e-AlertsSUBJECTS:Catalysts,Cyclization,Hydrocarbons,Ligands,Palladium Get e-Alerts

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Understanding and exploiting C–H bond activation

2002-05-01

Jay A. Labinger , John E. Bercaw

Decarboxylative coupling reactions: a modern strategy for C–C-bond formation

2011-01-01

Nuria Rodríguez , Lukas J. Gooßen

This critical review examines transition metal-catalyzed decarboxylative couplings that have emerged within recent years as a powerful strategy to form carbon–carbon or carbon–heteroatom bonds starting from carboxylic acids. In these … This critical review examines transition metal-catalyzed decarboxylative couplings that have emerged within recent years as a powerful strategy to form carbon–carbon or carbon–heteroatom bonds starting from carboxylic acids. In these reactions, C–C bonds to carboxylate groups are cleaved, and in their place, new carbon–carbon bonds are formed. Decarboxylative cross-couplings constitute advantageous alternatives to traditional cross-coupling or addition reactions involving preformed organometallic reagents. Decarboxylative reaction variants are also known for Heck reactions, direct arylation processes, and carbon–heteroatom bond forming reactions.

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Synthesis and Functionalization of Indoles Through Palladium-catalyzed Reactions

2005-07-01

Sandro Cacchi , Giancarlo Fabrizi

ADVERTISEMENT RETURN TO ISSUEPREVArticleSynthesis and Functionalization of Indoles Through Palladium-catalyzed Reactions†Sandro Cacchi and Giancarlo FabriziView Author Information Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli … ADVERTISEMENT RETURN TO ISSUEPREVArticleSynthesis and Functionalization of Indoles Through Palladium-catalyzed Reactions†Sandro Cacchi and Giancarlo FabriziView Author Information Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi "La Sapienza", P.le A. Moro 5, 00185 Roma, Italy Cite this: Chem. Rev. 2005, 105, 7, 2873–2920Publication Date (Web):July 13, 2005Publication History Received4 March 2005Published online13 July 2005Published inissue 1 July 2005https://pubs.acs.org/doi/10.1021/cr040639bhttps://doi.org/10.1021/cr040639bresearch-articleACS PublicationsCopyright © 2005 American Chemical SocietyRequest reuse permissionsArticle Views18607Altmetric-Citations1643LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Cyclization,Hydrocarbons,Indoles,Palladium,Reaction products Get e-Alerts

Towards mild metal-catalyzed C–H bond activation

2011-01-01

Joanna Wencel‐Delord , Thomas Dröge , Fan Liu +1 more

Functionalizing traditionally inert carbon–hydrogen bonds represents a powerful transformation in organic synthesis, providing new entries to valuable structural motifs and improving the overall synthetic efficiency. C–H bond activation, however, often … Functionalizing traditionally inert carbon–hydrogen bonds represents a powerful transformation in organic synthesis, providing new entries to valuable structural motifs and improving the overall synthetic efficiency. C–H bond activation, however, often necessitates harsh reaction conditions that result in functional group incompatibilities and limited substrate scope. An understanding of the reaction mechanism and rational design of experimental conditions have led to significant improvement in both selectivity and applicability. This critical review summarizes and discusses endeavours towards the development of mild C–H activation methods and wishes to trigger more research towards this goal. In addition, we examine select examples in complex natural product synthesis to demonstrate the synthetic utility of mild C–H functionalization (84 references).

Rhodium Catalyzed Chelation-Assisted C–H Bond Functionalization Reactions

2011-12-08

Denise A. Colby , Andy S. Tsai , Robert G. Bergman +1 more

Over the last several decades, researchers have achieved remarkable progress in the field of organometallic chemistry. The development of metal-catalyzed cross-coupling reactions represents a paradigm shift in chemical synthesis, and … Over the last several decades, researchers have achieved remarkable progress in the field of organometallic chemistry. The development of metal-catalyzed cross-coupling reactions represents a paradigm shift in chemical synthesis, and today synthetic chemists can readily access carbon–carbon and carbon–heteroatom bonds from a vast array of starting compounds. Although we cannot understate the importance of these methods, the required prefunctionalization to carry out these reactions adds cost and reduces the availability of the starting reagents.The use of C–H bond activation in lieu of prefunctionalization has presented a tantalizing alternative to classical cross-coupling reactions. Researchers have met the challenges of selectivity and reactivity associated with the development of C–H bond functionalization reactions with an explosion of creative advances in substrate and catalyst design. Literature reports on selectivity based on steric effects, acidity, and electronic and directing group effects are now numerous.Our group has developed an array of C–H bond functionalization reactions that take advantage of a chelating directing group, and this Account surveys our progress in this area. The use of chelation control in C–H bond functionalization offers several advantages with respect to substrate scope and application to total synthesis. The predictability and decreased dependence on the inherent stereoelectronics of the substrate generally result in selective and high yielding transformations with broad applicability. The nature of the chelating moiety can be chosen to serve as a functional handle in subsequent elaborations.Our work began with the use of Rh(I) catalysts in intramolecular aromatic C–H annulations, which we further developed to include enantioselective transformations. The application of this chemistry to the simple olefinic C–H bonds found in α,β-unsaturated imines allowed access to highly substituted olefins, pyridines, and piperidines. We observed complementary reactivity with Rh(III) catalysts and developed an oxidative coupling with unactivated alkenes. Further studies on the Rh(III) catalysts led us to develop methods for the coupling of C–H bonds to polarized π bonds such as those in imines and isocyanates. In several cases the methods that we have developed for chelation-controlled C–H bond functionalization have been applied to the total synthesis of complex molecules such as natural products, highlighting the utility of these methods in organic synthesis.

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Transition‐Metal‐Catalyzed Direct Arylation of (Hetero)Arenes by CH Bond Cleavage

2009-12-08

Lutz Ackermann , R. Vicente , Anant R. Kapdi

The area of transition-metal-catalyzed direct arylation through cleavage of C-H bonds has undergone rapid development in recent years, and is becoming an increasingly viable alternative to traditional cross-coupling reactions with … The area of transition-metal-catalyzed direct arylation through cleavage of C-H bonds has undergone rapid development in recent years, and is becoming an increasingly viable alternative to traditional cross-coupling reactions with organometallic reagents. In particular, palladium and ruthenium catalysts have been described that enable the direct arylation of (hetero)arenes with challenging coupling partners--including electrophilic aryl chlorides and tosylates as well as simple arenes in cross-dehydrogenative arylations. Furthermore, less expensive copper, iron, and nickel complexes were recently shown to be effective for economically attractive direct arylations.

Catalytic Functionalization of Arenes and Alkanes via C−H Bond Activation

2001-05-18

Chengguo Jia , Tsugio Kitamura , Yuzo Fujiwara

Several novel synthetic reactions of arenes and alkanes discovered and investigated in our laboratory are summarized here. These include olefin arylation, hydroarylation of alkynes, hydroxylation of arenes, carboxylation of arenes … Several novel synthetic reactions of arenes and alkanes discovered and investigated in our laboratory are summarized here. These include olefin arylation, hydroarylation of alkynes, hydroxylation of arenes, carboxylation of arenes and alkanes, and aminomethylation and acetoxylation of alkanes. Most of these reactions are catalyzed by highly electrophilic transition metal cationic species generated in situ in an acid medium, involving electrophilic metalation of C-H bonds of arenes and alkanes which lead to the formation of aryl-metal and alkyl-metal sigma-complexes.

Rhodium-Catalyzed C−C Bond Formation via Heteroatom-Directed C−H Bond Activation

2009-05-13

Denise A. Colby , Robert G. Bergman , Jonathan A. Ellman

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTRhodium-Catalyzed C−C Bond Formation via Heteroatom-Directed C−H Bond ActivationDenise A. Colby, Robert G. Bergman*, and Jonathan A. Ellman*View Author Information Department of Chemistry, University of California, and … ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTRhodium-Catalyzed C−C Bond Formation via Heteroatom-Directed C−H Bond ActivationDenise A. Colby, Robert G. Bergman*, and Jonathan A. Ellman*View Author Information Department of Chemistry, University of California, and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California, 94720* E-mail: [email protected] and [email protected]Cite this: Chem. Rev. 2010, 110, 2, 624–655Publication Date (Web):May 13, 2009Publication History Received7 January 2009Published online13 May 2009Published inissue 10 February 2010https://pubs.acs.org/doi/10.1021/cr900005nhttps://doi.org/10.1021/cr900005nreview-articleACS PublicationsCopyright © 2009 American Chemical SocietyRequest reuse permissionsArticle Views44444Altmetric-Citations3479LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Alcohols,Arylation,Catalysts,Hydrocarbons,Post-translational modification Get e-Alerts

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Beyond Directing Groups: Transition‐Metal‐Catalyzed CH Activation of Simple Arenes

2012-09-20

Nadine Kuhl , Matthew N. Hopkinson , Joanna Wencel‐Delord +1 more

The use of coordinating moieties as directing groups for the functionalization of aromatic C-H bonds has become an established tool to enhance reactivity and induce regioselectivity. Nevertheless, with regard to … The use of coordinating moieties as directing groups for the functionalization of aromatic C-H bonds has become an established tool to enhance reactivity and induce regioselectivity. Nevertheless, with regard to the synthetic applicability of C-H activation, there is a growing interest in transformations in which the directing group can be fully abandoned, thus allowing the direct functionalization of simple benzene derivatives. However, this approach requires the disclosure of new strategies to achieve reactivity and to control selectivity. In this review, recent advances in the emerging field of non-chelate-assisted C-H activation are discussed, highlighting some of the most intriguing and inspiring examples of induction of reactivity and selectivity.

Controlling Site Selectivity in Palladium-Catalyzed C–H Bond Functionalization

2012-05-03

Sharon R. Neufeldt , Melanie S. Sanford

Effective methodology to functionalize C–H bonds requires overcoming the key challenge of differentiating among the multitude of C–H bonds that are present in complex organic molecules. This Account focuses on … Effective methodology to functionalize C–H bonds requires overcoming the key challenge of differentiating among the multitude of C–H bonds that are present in complex organic molecules. This Account focuses on our work over the past decade toward the development of site-selective Pd-catalyzed C–H functionalization reactions using the following approaches: substrate-based control over selectivity through the use of directing groups (approach 1), substrate control through the use of electronically activated substrates (approach 2), or catalyst-based control (approach 3). In our extensive exploration of the first approach, a number of selectivity trends have emerged for both sp2 and sp3 C–H functionalization reactions that hold true for a variety of transformations involving diverse directing groups. Functionalizations tend to occur at the less-hindered sp2 C–H bond ortho to a directing group, at primary sp3 C–H bonds that are β to a directing group, and, when multiple directing groups are present, at C–H sites proximal to the most basic directing group. Using approach 2, which exploits electronic biases within a substrate, our group has achieved C-2-selective arylation of indoles and pyrroles using diaryliodonium oxidants. The selectivity of these transformations is altered when the C-2 site of the heterocycle is blocked, leading to C–C bond formation at the C-3 position. While approach 3 (catalyst-based control) is still in its early stages of exploration, we have obtained exciting results demonstrating that site selectivity can be tuned by modifying the structure of the supporting ligands on the Pd catalyst. For example, by modulating the structure of N–N bidentate ligands, we have achieved exquisite levels of selectivity for arylation at the α site of naphthalene. Similarly, we have demonstrated that both the rate and site selectivity of arene acetoxylation depend on the ratio of pyridine (ligand) to Pd. Lastly, by switching the ligand on Pd from an acetate to a carbonate, we have reversed the site selectivity of a 1,3-dimethoxybenzene/benzo[h]quinoline coupling. In combination with a growing number of reports in the literature, these studies highlight a frontier of catalyst-based control of site-selectivity in the development of new C–H bond functionalization methodology.

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Recent developments in natural product synthesis using metal-catalysed C–H bond functionalisation

2011-01-01

Lindsay McMurray , Fionn O’Hara , Matthew J. Gaunt

Metal-catalysed C–H bond functionalisation has had a significant impact on how chemists make molecules. Translating the methodological developments to their use in the assembly of complex natural products is an … Metal-catalysed C–H bond functionalisation has had a significant impact on how chemists make molecules. Translating the methodological developments to their use in the assembly of complex natural products is an important challenge for the continued advancement of chemical synthesis. In this tutorial review, we describe selected recent examples of how the metal-catalysed C–H bond functionalisation has been able to positively affect the synthesis of natural products.

Palladium-Catalyzed Ligand-Directed C−H Functionalization Reactions

2010-01-15

Thomas W. Lyons , Melanie S. Sanford

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTPalladium-Catalyzed Ligand-Directed C−H Functionalization ReactionsThomas W. Lyons and Melanie S. Sanford*View Author Information Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109* … ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTPalladium-Catalyzed Ligand-Directed C−H Functionalization ReactionsThomas W. Lyons and Melanie S. Sanford*View Author Information Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109* To whom correspondence should be addressed. E-mail: [email protected]Cite this: Chem. Rev. 2010, 110, 2, 1147–1169Publication Date (Web):January 15, 2010Publication History Received8 May 2009Published online15 January 2010Published inissue 10 February 2010https://pubs.acs.org/doi/10.1021/cr900184ehttps://doi.org/10.1021/cr900184ereview-articleACS PublicationsCopyright © 2010 American Chemical SocietyRequest reuse permissionsArticle Views81864Altmetric-Citations5606LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Chemical reactions,Functionalization,Halogenation,Palladium,Reagents Get e-Alerts

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Weak Coordination as a Powerful Means for Developing Broadly Useful C–H Functionalization Reactions

2011-12-14

Keary M. Engle , Tian‐Sheng Mei , Masayuki Wasa +1 more

Reactions that convert carbon–hydrogen (C–H) bonds into carbon–carbon (C–C) or carbon–heteroatom (C–Y) bonds are attractive tools for organic chemists, potentially expediting the synthesis of target molecules through new disconnections in … Reactions that convert carbon–hydrogen (C–H) bonds into carbon–carbon (C–C) or carbon–heteroatom (C–Y) bonds are attractive tools for organic chemists, potentially expediting the synthesis of target molecules through new disconnections in retrosynthetic analysis. Despite extensive inorganic and organometallic study of the insertion of homogeneous metal species into unactivated C–H bonds, practical applications of this technology in organic chemistry are still rare. Only in the past decade have metal-catalyzed C–H functionalization reactions become more widely utilized in organic synthesis.Research in the area of homogeneous transition metal–catalyzed C–H functionalization can be broadly grouped into two subfields. They reflect different approaches and goals and thus have different challenges and opportunities. One approach involves reactions of completely unfunctionalized aromatic and aliphatic hydrocarbons, which we refer to as "first functionalization". Here the substrates are nonpolar and hydrophobic and thus interact very weakly with polar metal species. To overcome this weak affinity and drive metal-mediated C–H cleavage, chemists often use hydrocarbon substrates in large excess (for example, as solvent). Because highly reactive metal species are needed in first functionalization, controlling the chemoselectivity to avoid overfunctionalization is often difficult. Additionally, because both substrates and products are comparatively low-value chemicals, developing cost-effective catalysts with exceptionally high turnover numbers that are competitive with alternatives (including heterogeneous catalysts) is challenging. Although an exciting field, first functionalization is beyond the scope of this Account.The second subfield of C–H functionalization involves substrates containing one or more pre-existing functional groups, termed "further functionalization". One advantage of this approach is that the existing functional group (or groups) can be used to chelate the metal catalyst and position it for selective C–H cleavage. Precoordination can overcome the paraffin nature of C–H bonds by increasing the effective concentration of the substrate so that it need not be used as solvent. From a synthetic perspective, it is desirable to use a functional group that is an intrinsic part of the substrate so that extra steps for installation and removal of an external directing group can be avoided. In this way, dramatic increases in molecular complexity can be accomplished in a single stroke through stereo- and site-selective introduction of a new functional group. Although reactivity is a major challenge (as with first functionalization), the philosophy in further functionalization differs; the major challenge is developing reactions that work with predictable selectivity in intricately functionalized contexts on commonly occurring structural motifs.In this Account, we focus on an emergent theme within the further functionalization literature: the use of commonly occurring functional groups to direct C–H cleavage through weak coordination. We discuss our motivation for studying Pd-catalyzed C–H functionalization assisted by weakly coordinating functional groups and chronicle our endeavors to bring reactions of this type to fruition. Through this approach, we have developed reactions with a diverse range of substrates and coupling partners, with the broad scope likely stemming from the high reactivity of the cyclopalladated intermediates, which are held together through weak interactions.

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Recent advances in the transition metal-catalyzed twofold oxidative C–H bond activation strategy for C–C and C–N bond formation

2011-01-01

Seung Hwan Cho , Ji Young Kim , Jaesung Kwak +1 more

The direct functionalization of heterocyclic compounds has emerged as one of the most important topics in the field of metal-catalyzed C–H bond activation due to the fact that products are … The direct functionalization of heterocyclic compounds has emerged as one of the most important topics in the field of metal-catalyzed C–H bond activation due to the fact that products are an important synthetic motif in organic synthesis, the pharmaceutical industry, and materials science. This critical review covers the recent progresses on the regioselective dehydrogenative direct coupling reaction of heteroarenes, including arylation, olefination, alkynylation, and amination/amidation mainly utilizing transition metal catalysts (113 references).

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Catalytic Functionalization of C(sp2)H and C(sp3)H Bonds by Using Bidentate Directing Groups

2013-09-17

Guy Rouquet , Naoto Chatani

C-H bonds are ubiquitous in organic compounds. It would, therefore, appear that direct functionalization of substrates by activation of C-H bonds would eliminate the multiple steps and limitations associated with … C-H bonds are ubiquitous in organic compounds. It would, therefore, appear that direct functionalization of substrates by activation of C-H bonds would eliminate the multiple steps and limitations associated with the preparation of functionalized starting materials. Regioselectivity is an important issue because organic molecules can contain a wide variety of C-H bonds. The use of a directing group can largely overcome the issue of regiocontrol by allowing the catalyst to come into proximity with the targeted C-H bonds. A wide variety of functional groups have been evaluated for use as directing groups in the transformation of C-H bonds. In 2005, Daugulis reported the arylation of unactivated C(sp(3))-H bonds by using 8-aminoquinoline and picolinamide as bidentate directing groups, with Pd(OAc)2 as the catalyst. Encouraged by these promising results, a number of transformations of C-H bonds have since been developed by using systems based on bidentate directing groups. In this Review, recent advances in this area are discussed.

CH Bond Functionalization: Emerging Synthetic Tools for Natural Products and Pharmaceuticals

2012-08-06

Junichiro Yamaguchi , Atsushi Yamaguchi , Kenichiro Itami

Abstract The direct functionalization of CH bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon–carbon and carbon–heteroatom bonds. This Review provides … Abstract The direct functionalization of CH bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon–carbon and carbon–heteroatom bonds. This Review provides an overview of CH bond functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets.

Hydroamination: Direct Addition of Amines to Alkenes and Alkynes

2008-08-26

Thomas E. Müller , Kai C. Hultzsch , Miguel Yus +2 more

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTHydroamination: Direct Addition of Amines to Alkenes and AlkynesThomas E. Müller*†, Kai C. Hultzsch*‡§, Miguel Yus∥§, Francisco Foubelo∥§, and Mizuki Tada⊥§View Author Information CAT Catalytic Center, ITMC, … ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTHydroamination: Direct Addition of Amines to Alkenes and AlkynesThomas E. Müller*†, Kai C. Hultzsch*‡§, Miguel Yus∥§, Francisco Foubelo∥§, and Mizuki Tada⊥§View Author Information CAT Catalytic Center, ITMC, RWTH Aachen, Worringerweg 1, 52074 Aachen, Germany, Department of Chemistry and Chemical Biology, Rutgers University, 610 Taylor Road, Piscataway, NJ 08854-8087, Departamento de Química Orgánica, Universidad de Alicante, E-03080 Alicante, Spain, and Department of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan* To whom correspondence should be addressed. Phone: +49 241 80 28594. Fax: +49 241 80 22593. E-mail: [email protected]†RWTH Aachen.‡Rutgers University.∥Universidad de Alicante.⊥The University of Tokyo.§E-mail addresses: [email protected]; [email protected]; [email protected]; [email protected].Cite this: Chem. Rev. 2008, 108, 9, 3795–3892Publication Date (Web):August 26, 2008Publication History Received22 January 2008Published online26 August 2008Published inissue 10 September 2008https://pubs.acs.org/doi/10.1021/cr0306788https://doi.org/10.1021/cr0306788review-articleACS PublicationsCopyright © 2008 American Chemical SocietyRequest reuse permissionsArticle Views40285Altmetric-Citations1817LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Amines,Catalysts,Cyclization,Hydrocarbons,Organic reactions Get e-Alerts

C–C, C–O and C–N bond formation via rhodium(iii)-catalyzed oxidative C–H activation

2012-01-01

Guoyong Song , Fen Wang , Xingwei Li

Rhodium(III)-catalyzed direct functionalization of C-H bonds under oxidative conditions leading to C-C, C-N, and C-O bond formation is reviewed. Various arene substrates bearing nitrogen and oxygen directing groups are covered … Rhodium(III)-catalyzed direct functionalization of C-H bonds under oxidative conditions leading to C-C, C-N, and C-O bond formation is reviewed. Various arene substrates bearing nitrogen and oxygen directing groups are covered in their coupling with unsaturated partners such as alkenes and alkynes. The facile construction of C-E (E = C, N, S, or O) bonds makes Rh(III) catalysis an attractive step-economic approach to value-added molecules from readily available starting materials. Comparisons and contrasts between rhodium(III) and palladium(II)-catalyzed oxidative coupling are made. The remarkable diversity of structures accessible is demonstrated with various recent examples, with a proposed mechanism for each transformation being briefly summarized (critical review, 138 references).

Palladium(II)‐Catalyzed CH Activation/CC Cross‐Coupling Reactions: Versatility and Practicality

2009-06-25

Xiao Chen , Keary M. Engle , Dong‐Hui Wang +1 more

Abstract Pick your Pd partners : A number of catalytic systems have been developed for palladium‐catalyzed CH activation/CC bond formation. Recent studies concerning the palladium(II)‐catalyzed coupling of CH bonds with … Abstract Pick your Pd partners : A number of catalytic systems have been developed for palladium‐catalyzed CH activation/CC bond formation. Recent studies concerning the palladium(II)‐catalyzed coupling of CH bonds with organometallic reagents through a Pd II /Pd 0 catalytic cycle are discussed (see scheme), and the versatility and practicality of this new mode of catalysis are presented. Unaddressed questions and the potential for development in the field are also addressed. magnified image In the past decade, palladium‐catalyzed CH activation/CC bond‐forming reactions have emerged as promising new catalytic transformations; however, development in this field is still at an early stage compared to the state of the art in cross‐coupling reactions using aryl and alkyl halides. This Review begins with a brief introduction of four extensively investigated modes of catalysis for forming CC bonds from CH bonds: Pd II /Pd 0 , Pd II /Pd IV , Pd 0 /Pd II /Pd IV , and Pd 0 /Pd II catalysis. A more detailed discussion is then directed towards the recent development of palladium(II)‐catalyzed coupling of CH bonds with organometallic reagents through a Pd II /Pd 0 catalytic cycle. Despite the progress made to date, improving the versatility and practicality of this new reaction remains a tremendous challenge.

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The Cross‐Dehydrogenative Coupling of CH Bonds: A Versatile Strategy for CC Bond Formations

2013-11-08

Simon A. Girard , Thomas Knauber , Chao‐Jun Li

Abstract Over the last decade, substantial research has led to the introduction of an impressive number of efficient procedures which allow the selective construction of CC bonds by directly connecting … Abstract Over the last decade, substantial research has led to the introduction of an impressive number of efficient procedures which allow the selective construction of CC bonds by directly connecting two different CH bonds under oxidative conditions. Common to these methodologies is the generation of the reactive intermediates in situ by activation of both CH bonds. This strategy was introduced by the group of Li as cross‐dehydrogenative coupling (CDC) and discloses waste‐minimized synthetic alternatives to classic coupling procedures which rely on the use of prefunctionalized starting materials. This Review highlights the recent progress in the field of cross‐dehydrogenative C C formations and provides a comprehensive overview on existing procedures and employed methodologies.

Cu(II)-Catalyzed Functionalizations of Aryl C−H Bonds Using O2 as an Oxidant

2006-05-01

Xiao Chen , Xueshi Hao , Charles E. Goodhue +1 more

Cu(II)-catalyzed acetoxylation and halogenation of aryl C−H bonds are developed. ortho-Selectivity was observed with a wide range of 2-arylpyridine substrates. Both mono- and difunctionalizations are achieved by tuning the reaction … Cu(II)-catalyzed acetoxylation and halogenation of aryl C−H bonds are developed. ortho-Selectivity was observed with a wide range of 2-arylpyridine substrates. Both mono- and difunctionalizations are achieved by tuning the reaction conditions. Excellent functional group tolerance and use of O2 as a stoichiometric oxidant are significant advantages over our recently developed Pd-catalyzed C−H functionalization reactions. These newly discovered reaction conditions are also applicable for cyanation, amination, etherification, and thioetherification of aryl C−H bonds. Mechanistic investigations are carried out to gain insights into the Cu(II)-catalyzed C−H functionalization reactions.

Recent advances in homogeneous nickel catalysis

2014-05-13

Sarah Z. Tasker , Eric A. Standley , Timothy F. Jamison

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Oxidative Coupling of Aromatic Substrates with Alkynes and Alkenes under Rhodium Catalysis

2010-08-25

Tetsuya Satoh , Masahiro Miura

Aromatic substrates with oxygen- and nitrogen-containing substituents undergo oxidative coupling with alkynes and alkenes under rhodium catalysis through regioselective C-H bond cleavage. Coordination of the substituents to the rhodium center … Aromatic substrates with oxygen- and nitrogen-containing substituents undergo oxidative coupling with alkynes and alkenes under rhodium catalysis through regioselective C-H bond cleavage. Coordination of the substituents to the rhodium center is the key to activate the C-H bonds effectively. Various fused-ring systems can be constructed through these reactions.

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Direct transition metal-catalyzed functionalization of heteroaromatic compounds

2007-01-01

И. В. Серегин , Vladimir Gevorgyan

During the last two decades there has been considerable growth in the development of catalytic reactions capable of activating unreactive C–H bonds. These methods allow for the synthesis of complex … During the last two decades there has been considerable growth in the development of catalytic reactions capable of activating unreactive C–H bonds. These methods allow for the synthesis of complex molecules from easily available and cheaper precursors in a fewer number of steps. Naturally, the development of C–H activation methods for direct functionalization of heterocyclic molecules, invaluable building blocks for pharmaceutical and synthetic chemistry and material science, has received substantial attention as well. This critical review summarizes the progress made in this field until November 2006 (117 references).

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C-H Bond Functionalization in Complex Organic Synthesis

2006-04-06

Kamil Godula , Dalibor Sameš

Direct and selective replacement of carbon-hydrogen bonds with new bonds (such as C-C, C-O, and C-N) represents an important and long-standing goal in chemistry. These transformations have broad potential in … Direct and selective replacement of carbon-hydrogen bonds with new bonds (such as C-C, C-O, and C-N) represents an important and long-standing goal in chemistry. These transformations have broad potential in synthesis because C-H bonds are ubiquitous in organic substances. At the same time, achieving selectivity among many different C-H bonds remains a challenge. Here, we focus on the functionalization of C-H bonds in complex organic substrates catalyzed by transition metal catalysts. We outline the key concepts and approaches aimed at achieving selectivity in complex settings and discuss the impact these reactions have on synthetic planning and strategy in organic synthesis.

C–H functionalization logic in total synthesis

2011-01-01

Will R. Gutekunst , Phil S. Baran

In this critical review, the strategic and economic benefits of C-H functionalization logic will be analyzed through the critical lens of total synthesis. In order to illustrate the dramatically simplifying … In this critical review, the strategic and economic benefits of C-H functionalization logic will be analyzed through the critical lens of total synthesis. In order to illustrate the dramatically simplifying effects this type of logic can potentially have on synthetic planning, we take the reader through a series of case studies in which it has already been successfully applied. In the first section, a chronological look at key historical syntheses will be examined, leading into modern day examples. In the second section, our own experience with applying and executing synthesis with a C-H functionalization "mindset" will be discussed (114 references).

Direct C−H Transformation via Iron Catalysis

2010-11-04

Chang‐Liang Sun , Bi‐Jie Li , Zhang‐Jie Shi

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTDirect C−H Transformation via Iron CatalysisChang-Liang Sun, Bi-Jie Li, and Zhang-Jie Shi*View Author Information Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and … ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTDirect C−H Transformation via Iron CatalysisChang-Liang Sun, Bi-Jie Li, and Zhang-Jie Shi*View Author Information Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering and PKU Green Chemistry Centre and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China*E-mail: [email protected]. Phone/fax: (+86) 10-62760890.Cite this: Chem. Rev. 2011, 111, 3, 1293–1314Publication Date (Web):November 4, 2010Publication History Received30 June 2010Published online4 November 2010Published inissue 9 March 2011https://pubs.acs.org/doi/10.1021/cr100198whttps://doi.org/10.1021/cr100198wreview-articleACS PublicationsCopyright © 2010 American Chemical SocietyRequest reuse permissionsArticle Views34344Altmetric-Citations1856LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Catalysts,Cross coupling reaction,Hydrocarbons,Iron,Oxidation Get e-Alerts

Ruthenium(II)-Catalyzed C–H Bond Activation and Functionalization

2012-08-31

Percia B. Arockiam , Christian Bruneau , Pierre H. Dixneuf

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTRuthenium(II)-Catalyzed C–H Bond Activation and FunctionalizationPercia Beatrice Arockiam, Christian Bruneau*, and Pierre H. Dixneuf*View Author Information Laboratoire Organométalliques, Matériaux et Catalyse, Institut Sciences Chimiques, UMR 6226 CNRS−Université … ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTRuthenium(II)-Catalyzed C–H Bond Activation and FunctionalizationPercia Beatrice Arockiam, Christian Bruneau*, and Pierre H. Dixneuf*View Author Information Laboratoire Organométalliques, Matériaux et Catalyse, Institut Sciences Chimiques, UMR 6226 CNRS−Université de Rennes1, Campus Beaulieu, 35042 Rennes, France*E-mail: [email protected]; [email protected]Cite this: Chem. Rev. 2012, 112, 11, 5879–5918Publication Date (Web):August 31, 2012Publication History Received14 April 2012Published online31 August 2012Published inissue 14 November 2012https://pubs.acs.org/doi/10.1021/cr300153jhttps://doi.org/10.1021/cr300153jreview-articleACS PublicationsCopyright © 2012 American Chemical SocietyRequest reuse permissionsArticle Views41440Altmetric-Citations2535LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Alcohols,Aromatic compounds,Catalysts,Hydrocarbons,Organic reactions Get e-Alerts

Catalytic Dehydrogenative Cross-Coupling: Forming Carbon−Carbon Bonds by Oxidizing Two Carbon−Hydrogen Bonds

2011-03-09

Charles S. Yeung , Vy M. Dong

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTCatalytic Dehydrogenative Cross-Coupling: Forming Carbon−Carbon Bonds by Oxidizing Two Carbon−Hydrogen BondsCharles S. Yeung and Vy M. Dong*View Author Information Department of Chemistry, University of Toronto, 80 St. … ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTCatalytic Dehydrogenative Cross-Coupling: Forming Carbon−Carbon Bonds by Oxidizing Two Carbon−Hydrogen BondsCharles S. Yeung and Vy M. Dong*View Author Information Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6*E-mail: [email protected]Cite this: Chem. Rev. 2011, 111, 3, 1215–1292Publication Date (Web):March 9, 2011Publication History Received24 August 2010Published online9 March 2011Published inissue 9 March 2011https://pubs.acs.org/doi/10.1021/cr100280dhttps://doi.org/10.1021/cr100280dreview-articleACS PublicationsCopyright © 2011 American Chemical SocietyRequest reuse permissionsArticle Views52222Altmetric-Citations3594LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Catalysts,Coupling reactions,Cross coupling reaction,Hydrocarbons,Indoles Get e-Alerts

Carboxylate-Assisted Ruthenium-Catalyzed Alkyne Annulations by C–H/Het–H Bond Functionalizations

2013-02-04

Lutz Ackermann

To improve the atom- and step-economy of organic syntheses, researchers would like to capitalize upon the chemistry of otherwise inert carbon–hydrogen (C–H) bonds. During the past decade, remarkable progress in … To improve the atom- and step-economy of organic syntheses, researchers would like to capitalize upon the chemistry of otherwise inert carbon–hydrogen (C–H) bonds. During the past decade, remarkable progress in organometallic chemistry has set the stage for the development of increasingly viable metal catalysts for C–H bond activation reactions. Among these methods, oxidative C–H bond functionalizations are particularly attractive because they avoid the use of prefunctionalized starting materials. For example, oxidative annulations that involve sequential C–H and heteroatom–H bond cleavages allow for the modular assembly of regioselectively decorated heterocycles. These structures serve as key scaffolds for natural products, functional materials, crop protecting agents, and drugs. While other researchers have devised rhodium or palladium complexes for oxidative alkyne annulations, my laboratory has focused on the application of significantly less expensive, yet highly selective ruthenium complexes.This Account summarizes the evolution of versatile ruthenium(II) complexes for annulations of alkynes via C–H/N–H, C–H/O–H, or C–H/N–O bond cleavages. To achieve selective C–H bond functionalizations, we needed to understand the detailed mechanism of the crucial C–H bond metalation with ruthenium(II) complexes and particularly the importance of carboxylate assistance in this process. As a consequence, our recent efforts have resulted in widely applicable methods for the versatile preparation of differently decorated arenes and heteroarenes, providing access to among others isoquinolones, 2-pyridones, isoquinolines, indoles, pyrroles, or α-pyrones. Most of these reactions used Cu(OAc)2·H2O, which not only acted as the oxidant but also served as the essential source of acetate for the carboxylate-assisted ruthenation manifold. Notably, the ruthenium(II)-catalyzed oxidative annulations also occurred under an ambient atmosphere of air with cocatalytic amounts of Cu(OAc)2·H2O. Moreover, substrates displaying N–O bonds served as "internal oxidants" for the syntheses of isoquinolones and isoquinolines. Detailed experimental mechanistic studies have provided strong support for a catalytic cycle that relies on initial carboxylate-assisted C–H bond ruthenation, followed by coordinative insertion of the alkyne, reductive elimination, and reoxidation of the thus formed ruthenium(0) complex.

Carboxylate-Assisted Transition-Metal-Catalyzed C−H Bond Functionalizations: Mechanism and Scope

2011-03-09

Lutz Ackermann

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTCarboxylate-Assisted Transition-Metal-Catalyzed C−H Bond Functionalizations: Mechanism and ScopeLutz Ackermann*View Author Information Institut für Organische und Biomolekulare Chemie, Georg-August-Universität, Tammannstrasse 2, 37077 Göttingen, Germany*Fax: (+49)551-39-6777. E-mail: [email protected]Cite … ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTCarboxylate-Assisted Transition-Metal-Catalyzed C−H Bond Functionalizations: Mechanism and ScopeLutz Ackermann*View Author Information Institut für Organische und Biomolekulare Chemie, Georg-August-Universität, Tammannstrasse 2, 37077 Göttingen, Germany*Fax: (+49)551-39-6777. E-mail: [email protected]Cite this: Chem. Rev. 2011, 111, 3, 1315–1345Publication Date (Web):March 9, 2011Publication History Received2 December 2010Published online9 March 2011Published inissue 9 March 2011https://pubs.acs.org/doi/10.1021/cr100412jhttps://doi.org/10.1021/cr100412jreview-articleACS PublicationsCopyright © 2011 American Chemical SocietyRequest reuse permissionsArticle Views35746Altmetric-Citations3100LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Anions,Functionalization,Hydrocarbons,Metalation,Organic reactions Get e-Alerts

Mild metal-catalyzed C–H activation: examples and concepts

2016-01-01

Tobias Gensch , Matthew N. Hopkinson , Frank Glorius +1 more

C–H Activation reactions that proceed under mild conditions are more attractive for applications in complex molecule synthesis. Mild C–H transformations reported since 2011 are reviewed and the different concepts and … C–H Activation reactions that proceed under mild conditions are more attractive for applications in complex molecule synthesis. Mild C–H transformations reported since 2011 are reviewed and the different concepts and strategies that have enabled their mildness are discussed.

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Palladium-Catalyzed Transformations of Alkyl C–H Bonds

2016-12-02

Jian He , Masayuki Wasa , Kelvin S. L. Chan +2 more

This Review summarizes the advancements in Pd-catalyzed C(sp3)-H activation via various redox manifolds, including Pd(0)/Pd(II), Pd(II)/Pd(IV), and Pd(II)/Pd(0). While few examples have been reported in the activation of alkane C-H … This Review summarizes the advancements in Pd-catalyzed C(sp3)-H activation via various redox manifolds, including Pd(0)/Pd(II), Pd(II)/Pd(IV), and Pd(II)/Pd(0). While few examples have been reported in the activation of alkane C-H bonds, many C(sp3)-H activation/C-C and C-heteroatom bond forming reactions have been developed by the use of directing group strategies to control regioselectivity and build structural patterns for synthetic chemistry. A number of mono- and bidentate ligands have also proven to be effective for accelerating C(sp3)-H activation directed by weakly coordinating auxiliaries, which provides great opportunities to control reactivity and selectivity (including enantioselectivity) in Pd-catalyzed C-H functionalization reactions.

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C–H activation

2007-03-21

Robert G. Bergman

Organic synthesis provides opportunities to transform drug discovery

2018-03-22

David C. Blakemore , Luis C. Misal Castro , Ian Churcher +4 more

A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry

2018-01-01

Carlo Sambiagio , David Schönbauer , Rémi Blieck +7 more

The present review is devoted to summarizing the recent advances (2015-2017) in the field of metal-catalysed group-directed C-H functionalisation. In order to clearly showcase the molecular diversity that can now … The present review is devoted to summarizing the recent advances (2015-2017) in the field of metal-catalysed group-directed C-H functionalisation. In order to clearly showcase the molecular diversity that can now be accessed by means of directed C-H functionalisation, the whole is organized following the directing groups installed on a substrate. Its aim is to be a comprehensive reference work, where a specific directing group can be easily found, together with the transformations which have been carried out with it. Hence, the primary format of this review is schemes accompanied with a concise explanatory text, in which the directing groups are ordered in sections according to their chemical structure. The schemes feature typical substrates used, the products obtained as well as the required reaction conditions. Importantly, each example is commented on with respect to the most important positive features and drawbacks, on aspects such as selectivity, substrate scope, reaction conditions, directing group removal, and greenness. The targeted readership are both experts in the field of C-H functionalisation chemistry (to provide a comprehensive overview of the progress made in the last years) and, even more so, all organic chemists who want to introduce the C-H functionalisation way of thinking for a design of straightforward, efficient and step-economic synthetic routes towards molecules of interest to them. Accordingly, this review should be of particular interest also for scientists from industrial R&D sector. Hence, the overall goal of this review is to promote the application of C-H functionalisation reactions outside the research groups dedicated to method development and establishing it as a valuable reaction archetype in contemporary R&D, comparable to the role cross-coupling reactions play to date.

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3d Transition Metals for C–H Activation

2018-11-27

Parthasarathy Gandeepan , Thomas Müller , Daniel Zell +3 more

C–H activation has surfaced as an increasingly powerful tool for molecular sciences, with notable applications to material sciences, crop protection, drug discovery, and pharmaceutical industries, among others. Despite major advances, … C–H activation has surfaced as an increasingly powerful tool for molecular sciences, with notable applications to material sciences, crop protection, drug discovery, and pharmaceutical industries, among others. Despite major advances, the vast majority of these C–H functionalizations required precious 4d or 5d transition metal catalysts. Given the cost-effective and sustainable nature of earth-abundant first row transition metals, the development of less toxic, inexpensive 3d metal catalysts for C–H activation has gained considerable recent momentum as a significantly more environmentally-benign and economically-attractive alternative. Herein, we provide a comprehensive overview on first row transition metal catalysts for C–H activation until summer 2018.

Cobalt-Catalyzed C–H Annulation of Aryl Sulfonamides and Benzamides with CaC2 as the Acetylene Source

2025-06-25

Aleksandrs Cizikovs , Liene Grigorjeva | Organic Letters

We have developed a cobalt-catalyzed, aminoquinoline-directed C-H/N-H annulation reaction of benzamides and aryl sulfonamides, enabling access to 3,4-unsubstituted isoquinolinone and 3,4-unsubstituted benzothiazine dioxide derivatives. This method employs calcium carbide as … We have developed a cobalt-catalyzed, aminoquinoline-directed C-H/N-H annulation reaction of benzamides and aryl sulfonamides, enabling access to 3,4-unsubstituted isoquinolinone and 3,4-unsubstituted benzothiazine dioxide derivatives. This method employs calcium carbide as an inexpensive, easy-to-handle, and solid acetylene source. The reaction conditions showed a broad functional group tolerance, which allowed the synthesis of various C-H/C-N annulation products in yields of up to 99%.

Blue-Light-Irradiated Copper-Catalyzed Regio-tunable Double C–H/C–H Cross-Coupling Reaction: A Sustainable Approach to Construct C2-Indolyl-1,4-naphthoquinones

2025-06-24

Chhavi Chhavi , Raushan Kumar Jha , Devendra Parganiha +2 more | The Journal of Organic Chemistry

Double C-H functionalization of unfunctionalized arenes is always challenging due to their inherent chemical inertness. Moreover , enhancing step and atom economy in reaction methodology is highly desirable. Herein, a … Double C-H functionalization of unfunctionalized arenes is always challenging due to their inherent chemical inertness. Moreover , enhancing step and atom economy in reaction methodology is highly desirable. Herein, a regio-tunable double C-H/C-H cross-coupling of 1,4-naphthoquinone with indole has been achieved using a Cu(II) catalyst under blue-light irradiation without utilizing any external base, oxidant, or prefunctionalized precursors. Using the presented methodology, an array of high-value-added C2-indolyl-1,4-quinones and C2-pyrrolyl-1,4-naphthoquinones were constructed under ambient reaction conditions. Also, four postsynthetic modifications have been made to the synthesized C2-indolyl-1,4-naphthoquinone. Mechanistic insight from radical trapping, radical scavenging, EPR, and control experiments, well corroborated with DFT studies, suggests that the reaction proceeds by a radical pathway in which 1,4-naphthoquinone forms a highly oxidizing naphthoquinonyl biradical upon blue-light irradiation that further forms an electrophilic naphthoquinone-copper adduct upon interacting with Lewis acid Cu(II). Consequently, electron transfer from electron-rich indole to an oxidizing naphthoquinone-copper adduct leads to a naphthoquinone-copper radical anion adduct and an indolyl radical cation, followed by cross-coupling of both radical ion pairs, affording a 3-(indolyl)-4-oxo-3,4-dihydronaphthalen-1-olate copper adduct by overcoming the barrier energy of +2.08 kcal/mol. This adduct upon oxidation by the excited naphthoquinone enabled C2-indolyl-1,4-naphthoquinone along with the concomitant release of the copper catalyst.

Impact of Induced Fitting and Secondary Noncovalent Interactions on Site-Selective and Enantioselective C–H Functionalization of Arylcyclohexanes

2025-06-24

Duc Ly , Yannick T. Boni , Korkit Korvorapun +4 more | Journal of the American Chemical Society

A major challenge in organic synthesis is the selective functionalization of C-H bonds. As most organic compounds contain multiple C-H bonds with similar properties, distinguishing between them requires precise control. … A major challenge in organic synthesis is the selective functionalization of C-H bonds. As most organic compounds contain multiple C-H bonds with similar properties, distinguishing between them requires precise control. In this study, we show how transition metal catalysts can adopt many of the characteristics associated with enzymes, leading to unprecedented site-selectivity in the C-H functionalization step. The catalysts are dirhodium complexes that adopt a bowl-shaped shape on formation. The flexible microenvironment within the bowl causes an induced fitting to occur as the reagent and substrate approach the catalyst. The key factors controlling the selectivity are noncovalent interactions between the approaching substrate and the catalyst wall, which cause a specific C-H bond in the substrate to be placed close to the metal-bound reagent.

Gold and Bismuth Trimetallic Synergistic Redox Catalysis for Non‐Directed C‐H Arylation with Aryl Bismuth

2025-06-24

Duanyang Liu , Sitian Zhou , Lijun Tian +7 more | Angewandte Chemie International Edition

The influence of substituent effects plays an important role on the efficiency and regioselectivity toward C‐H activation of non‐directed arenes. Here, an unprecedented trimetallic synergistic redox catalysis system has been … The influence of substituent effects plays an important role on the efficiency and regioselectivity toward C‐H activation of non‐directed arenes. Here, an unprecedented trimetallic synergistic redox catalysis system has been developed to achieve a highly efficient and orthogonal C–H arylation of non‐directed arenes with aryl bismuth. Both electron‐rich and ‐deficient aryl bismuth can proceed C‐H arylation readily, thus affording an elegant strategy for the synthesis of challenging electron‐rich and sterically hindered biaryls by means of gold catalysis. Mechanistic studies reveal that Bi(V) species generated in‐situ from Ar‐Bi(III) and NFSI is not only an arylating reagent but also an oxidant to form a critical Au(II)‐Au(II)‐Bi intermediate (detected by HRMS). Interestingly, the binding Bi‐moiety can modulate the electronic and steric environment of gold center through cooperative interactions, thus promoting the intramolecular transmetallation and reductive elimination. In addition, the synthetic robustness of this protocol has been demonstrated by gram‐scale experiments and late‐stage functionalization of complex molecules.

Gold and Bismuth Trimetallic Synergistic Redox Catalysis for Non‐Directed C‐H Arylation with Aryl Bismuth

2025-06-24

Duanyang Liu , Sitian Zhou , Lijun Tian +7 more | Angewandte Chemie

Cu-Catalyzed Acylation of Quinoline-N-oxides with gem-Difluorostyrenes via the Tandem Cycloaddition/Elimination/Oxidation Process

2025-06-24

Yang Feng , Yuanyuan Wu , Zengjiang Yue +3 more | The Journal of Organic Chemistry

The copper-catalyzed defluorination and decarbonization cross-coupling reaction between quinoline-N-oxides and gem-difluorostyrenes via key 2-arylmethylquinoline intermediates to access 2-aroylquinolines is described. Versatile 2-aroylquinolines were obtained in up to 83% yield with … The copper-catalyzed defluorination and decarbonization cross-coupling reaction between quinoline-N-oxides and gem-difluorostyrenes via key 2-arylmethylquinoline intermediates to access 2-aroylquinolines is described. Versatile 2-aroylquinolines were obtained in up to 83% yield with exclusive regioselectivity. The detailed reaction mechanism investigation shows that it undergoes a tandem [3 + 2] cycloaddition/elimination of formyl difluoride/oxidation of 2-arylmethylquinolines. This copper-catalyzed transformation proceeds efficiently at 90 °C, eliminating the necessity for exogenous oxidants or hazardous reagents, while maintaining excellent functional group tolerance.

Ligand-Controlled Cobalt-Catalyzed Regioselective Annulation: Divergent Synthesis of Indenols from o-Haloaromatic Ketones and Terminal Alkynes

2025-06-23

Gang Qian , Ran Chen , Tingting Miao +4 more | Organic Letters

The annulation of o-haloaromatic ketones with terminal alkynes to access indenols remains a persistent challenge, with limited successful precedents reported to date. Herein, we disclose a cobalt-catalyzed ligand-controlled strategy for … The annulation of o-haloaromatic ketones with terminal alkynes to access indenols remains a persistent challenge, with limited successful precedents reported to date. Herein, we disclose a cobalt-catalyzed ligand-controlled strategy for the divergent synthesis of indenols. By simple modulation of the ligand, the annulation of o-iodoaromatic ketones with terminal alkynes can be selectively achieved toward either 2- or 3-substituted indenols. This approach features excellent regioselectivity, a broad substrate scope, and late-stage modification.

Branched‐Selective Functionalization of 2‐Alkyl Aziridines through Ni‐Catalyzed Dynamic Kinetic Activation

2025-06-23

Xin Chen , Yang Chen , Yunfei Bai +4 more | Angewandte Chemie

Overriding the inherent substrate‐controlled regioselectivity in aziridine activation holds significant potential. It could enable previously inaccessible disconnections from these readily available, strained heterocycles, facilitating the diverse synthesis of nitrogen‐containing products. … Overriding the inherent substrate‐controlled regioselectivity in aziridine activation holds significant potential. It could enable previously inaccessible disconnections from these readily available, strained heterocycles, facilitating the diverse synthesis of nitrogen‐containing products. In this study, we present a Ni‐catalyzed dynamic kinetic activation of 2‐alkyl (and 2,2‐dialkyl) aziridines, leading to unconventional branched‐selective alkyl Heck‐type coupling with styrenes and reductive defluorinative coupling with trifluoromethyl alkenes. In addition to enabling the functionalization of the N‐adjacent sites of aziridines, this catalyst‐controlled activation strategy triggers an unprecedented reaction framework for aziridines, namely, the remote desaturation via ring‐opening. Notably, detailed mechanistic studies demonstrate the operation of a rare 'self‐terminated' chain‐walking process, offering a flexible method for remote desaturation that generates alkenyl amines with varying chain lengths. Overall, this study provides a modular approach to access a wide range of alkenyl amine derivatives.

Branched‐Selective Functionalization of 2‐Alkyl Aziridines through Ni‐Catalyzed Dynamic Kinetic Activation

2025-06-23

Xin Chen , Yang Chen , Yunfei Bai +4 more | Angewandte Chemie International Edition

Overriding the inherent substrate-controlled regioselectivity in aziridine activation holds significant potential. It could enable previously inaccessible disconnections from these readily available, strained heterocycles, facilitating the diverse synthesis of nitrogen-containing products. … Overriding the inherent substrate-controlled regioselectivity in aziridine activation holds significant potential. It could enable previously inaccessible disconnections from these readily available, strained heterocycles, facilitating the diverse synthesis of nitrogen-containing products. In this study, we present a Ni-catalyzed dynamic kinetic activation of 2-alkyl (and 2,2-dialkyl) aziridines, leading to unconventional branched-selective alkyl Heck-type coupling with styrenes and reductive defluorinative coupling with trifluoromethyl alkenes. In addition to enabling the functionalization of the N-adjacent sites of aziridines, this catalyst-controlled activation strategy triggers an unprecedented reaction framework for aziridines, namely, the remote desaturation via ring-opening. Notably, detailed mechanistic studies demonstrate the operation of a rare 'self-terminated' chain-walking process, offering a flexible method for remote desaturation that generates alkenyl amines with varying chain lengths. Overall, this study provides a modular approach to access a wide range of alkenyl amine derivatives.

Ruthenium-Catalyzed Regiodivergent Methylsilylation via C(sp2)–H Activation

2025-06-23

| Synfacts

Palladium-Catalyzed Synthesis of 2,3-Dialkylindoles from ortho-Alkenylisocyanobenzenes

2025-06-23

| Synfacts

Sustainable Photoinduced Difunctionalization of Olefins

2025-06-23

| Synfacts

Silver-Mediated Dual Oxidation of 1,3-Dicarbonyls for Migration–Annulation

2025-06-23

Ziren Mao , Hongyan Xu , Jingming Zhang +6 more | Organic Letters

A new type of radical cascade reaction has been reported, by which free radicals were generated twice successively through the implementation of dual oxidation on a 1,3-dicarbonyl compound in a … A new type of radical cascade reaction has been reported, by which free radicals were generated twice successively through the implementation of dual oxidation on a 1,3-dicarbonyl compound in a single operation, thereby realizing a conceptually novel alkynyl migration-annulation mode. The reaction involved addition, 1,2-alkynyl migration, and 4-exo-dig/6-endo-trig bicyclization under mild reaction conditions, offering an efficient route to tetrahydrocyclobuta[b]naphthalene in good yields. Control experiments revealed migration products as key intermediates and elucidated the step sequence in these transformations.

Spirocyclization of γ-C(sp3)–H Activated Substituted Amino Acids with Maleimides by Palladium Catalysis

2025-06-23

| Synfacts

Shedding Light on the Precatalytic Mixture of Pd(OAc)2 and Cooperating Bipyridone Ligands for the C─H Functionalization of Arenes

2025-06-23

Francisco Villalba , Sara Martín‐Martín , Ana C. Albéniz | ChemCatChem

Abstract The use of a mixture of a precursor palladium compound and a ligand as precatalyst is a common practice in metal catalyzed organic synthesis. In general, little attention is … Abstract The use of a mixture of a precursor palladium compound and a ligand as precatalyst is a common practice in metal catalyzed organic synthesis. In general, little attention is paid to how these mixtures develop into the active species, but this is crucial for an efficient catalysis. We describe here the complexes that are obtained from Pd(OAc) 2 and PdCl 2 and the chelating bipyridones [2,2′‐ bipyridin]‐6(1 H )‐one (bipy‐6‐OH) and 1,10‐phenanthrolin‐2(1 H )‐one (phen‐2‐OH). This type of ligands plays a cooperating role in the C─H activation step and are useful in many Pd‐catalyzed C─H functionalization reactions. Both monomeric and dimeric complexes were obtained. The catalytic performance observed when using the isolated, well defined Pd‐ligand complexes and the Pd(OAc 2 )/ligand mixtures in a model direct arylation of toluene have been analyzed, as well as the plausible pathway for the generation of Pd(0) active species under catalytic conditions.

Site-Selective C–H Annulation Reaction via Thianthrenium Salts of Arenes

2025-06-23

Bao‐qin Huang , Xinxiang Xu , Bing‐Hao Wu +3 more | The Journal of Organic Chemistry

This work presents a site-selective C-H annulation strategy for dihydrobenzoisoxazole synthesis using readily accessible thianthrenium salts as aryne precursors. The process involves base-mediated generation of reactive aryne intermediates from thianthrenium … This work presents a site-selective C-H annulation strategy for dihydrobenzoisoxazole synthesis using readily accessible thianthrenium salts as aryne precursors. The process involves base-mediated generation of reactive aryne intermediates from thianthrenium salts followed by regioselective [3 + 2] cycloaddition with nitrone 1,3-dipoles, exhibiting excellent functional group tolerance and exceptional regiocontrol. The synthetic utility of this protocol is highlighted by the successful annulation of commercially available drug molecules, providing expedient access to novel scaffolds with potential bioactivity.

Copper(II)‐Catalyzed Regioselective Cascade Reaction of β,γ‐Alkynyl‐α‐Imino Esters with α‐Amino Acid‐Derived Esters

2025-06-23

Guilong Wang , Feiyang Chen , Jian Liao +4 more | Chemistry - An Asian Journal

Abstract A cascade reaction between β,γ‐alkynyl‐α‐imino esters and α‐amino acid‐derived esters has been developed, enabling the efficient synthesis of a series of novel α‐amino acid derivatives featuring oxazolone moieties under … Abstract A cascade reaction between β,γ‐alkynyl‐α‐imino esters and α‐amino acid‐derived esters has been developed, enabling the efficient synthesis of a series of novel α‐amino acid derivatives featuring oxazolone moieties under mild reaction conditions. Control experiments and mechanistic studies were conducted to elucidate the reaction pathway and gain insights into the underlying process.

Transition‐Metal‐Catalyzed C(sp2)‐H Activation and Cyclization with Isocyanates

2025-06-23

Ming‐Xia Pan , Peng Chen , Yijun Jiang | Advanced Synthesis & Catalysis

Nitrogen‐containing heterocyclic compounds represent the core structures of natural products and drugs, and their efficient synthesis is of great significance for the development of medicinal chemistry and functional materials. Isocyanates, … Nitrogen‐containing heterocyclic compounds represent the core structures of natural products and drugs, and their efficient synthesis is of great significance for the development of medicinal chemistry and functional materials. Isocyanates, owing to their high electrophilicity and multifunctionality, have become a universal building block for constructing complex nitrogen‐containing heterocycles. The transition‐metal‐catalyzed cyclization of isocyanates through C(sp 2 )H bond activation to construct heterocyclic frameworks has emerged as an atom‐economical alternative. This review systematically summarizes the research progress of transition‐metal‐catalyzed cyclization of isocyanates through C(sp 2 )‐H activation from 2006 to 2025. It categorizes these advancements according to the substrates involved in the cyclization reaction, providing a concise analysis of substrate scopes, limitations, molecular modifiability, mechanistic studies, and their applications in the precise synthesis of diversely functionalized molecules. Moreover, the main challenges and future opportunities are also succinctly elucidated with the goal of expanding the application range of these reactions.

Pd(II)‐Catalyzed Dehydrogenative Annulation of 2‐Arylimidazo[1,2‐a]pyridines with Maleimides: Regioselectivity Switch and Photophysical Properties

2025-06-23

Hemant Joshi , Krishna Yadav , Suman Mahala +2 more | Chemistry - A European Journal

Herein, we report a palladium(II)-catalyzed dehydrogenative annulation of 2-arylimidazo[1,2-a]pyridines with maleimides, representing the first example of the regioselectivity reversal for this class of substrates. Notably, the transformation proceeds efficiently with … Herein, we report a palladium(II)-catalyzed dehydrogenative annulation of 2-arylimidazo[1,2-a]pyridines with maleimides, representing the first example of the regioselectivity reversal for this class of substrates. Notably, the transformation proceeds efficiently with a low catalyst loading (1.5 mol %). A plausible reaction mechanism is proposed, supported by control experiments and in situ HRMS analysis. Photophysical investigations of the annulated products reveal moderate to high quantum yields, highlighting their potential for optoelectronic applications. Furthermore, these molecules demonstrate promising sensitivity as picric acid-sensing probes.

Palladium-Catalyzed Construction of Trisubstituted Oxazoles from Trifluoroalanine Derivatives

2025-06-22

Junrui Wang , Chuangchuang Liu , Wenjie Ju +5 more | Organic Letters

The preparation of trisubstituted oxazole rings, which serve as privileged structural motifs in bioactive molecules and natural products, presents synthetic challenges such as low efficiency and multistep procedures. Herein, we … The preparation of trisubstituted oxazole rings, which serve as privileged structural motifs in bioactive molecules and natural products, presents synthetic challenges such as low efficiency and multistep procedures. Herein, we present a streamlined synthetic strategy enabling the one-step construction of trisubstituted oxazoles through a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. This practical protocol facilitates gram-scale synthesis while also enabling the direct preparation of the bioactive molecule Almazole D, highlighting its synthetic utility and importance.

Copper(I)-Catalyzed Synthesis of 1-Amino-1,3-diene Derivatives through a Formal 1,3-Amino Migration Process

2025-06-22

Junwei Li , Shuangshuang Liu , Tiantian Zhang +2 more | Organic Letters

We present a highly efficient method utilizing a CuBr/DTBP (di-tert-butyl peroxide) catalyst system for the synthesis of 1-amino-1,3-diene derivatives from propargylamines and activated methylene compounds. This transformation efficiently assembles a … We present a highly efficient method utilizing a CuBr/DTBP (di-tert-butyl peroxide) catalyst system for the synthesis of 1-amino-1,3-diene derivatives from propargylamines and activated methylene compounds. This transformation efficiently assembles a wide range of substrates with good functional group tolerance and high atomic efficiency. Mechanistic investigations reveal that this reaction proceeds through a copper-catalyzed C-C bond formation followed by a formal 1,3-amino group migration. Notably, the C-N bond activation facilitated by cross-dehydrogenative coupling is identified as a crucial step that ensures the smooth progression of the reaction.

Dual Activation of Enals and γ‐C(sp3)‐H Bond of p‐Quinols for the Synthesis of Naphthylamines via Cyclization/Dual Aromatization

2025-06-21

Junsheng Zhi , Liping Deng , Weijie Huang +5 more | Chinese Journal of Chemistry

Comprehensive Summary The synthesis of fused arenes from non‐aromatic precursors is useful but challenging. Herein, the synthesis of widely‐used naphthylamines was focused. The three‐component reactions of p ‐quinols, enals and … Comprehensive Summary The synthesis of fused arenes from non‐aromatic precursors is useful but challenging. Herein, the synthesis of widely‐used naphthylamines was focused. The three‐component reactions of p ‐quinols, enals and amines were investigated under the dienamine/iminium‐ based dual organocatalysis. The efficient synthesis of naphthylamines was achieved via a formal [3+3] cyclization of the amines activated p ‐quinols and enals, with the following Bu 4 NOAc/AgNO 3 facilitated dual aromatization. The different reactivity of in‐situ generated dienamine and iminium intermediates resulted in the differentiating catalysis, providing an efficient and practical methodology for the synthesis of fused arenes from non‐aromatic precursors.

Dual Nickel/Photoredox-Catalyzed Stereoselective Allylation for the Synthesis of 1,3-Diols

2025-06-20

Xinyi Zhang , Huailiang Xu , Zhixian Wu +4 more | Synlett

An efficient dual Ni/organophotoredox catalytic system has been developed for the stereoselective allylation of aldehydes with vinyl cyclic carbonates (VCCs). This method enables the construction of 1,3-diols bearing quaternary carbon … An efficient dual Ni/organophotoredox catalytic system has been developed for the stereoselective allylation of aldehydes with vinyl cyclic carbonates (VCCs). This method enables the construction of 1,3-diols bearing quaternary carbon centers under mild conditions (room temperature, visible light irradiation) with excellent yields (up to 89%) and diastereoselectivity (dr >20:1). Key to the success is the synergistic interplay between nickel catalysis and photoredox activation, which facilitates the generation of nucleophilic allyl-Ni intermediates and subsequent C–C bond formation via a Zimmerman–Traxler-type transition state. The protocol employs inexpensive and commercially available catalysts, exhibits broad substrate scope, and demonstrates applicability to late-stage functionalization of pharmaceuticals.

Copper-Catalyzed Highly Efficient and Asymmetric Allylic C–H Oxidation of 3-Aryl-Substituted Terminal Alkenes

2025-06-20

Ying Zhou , Pinhong Chen , Guosheng Liu | Journal of the American Chemical Society

Asymmetric allylic C(sp3)-H oxidation of terminal alkenes provides a streamlined process for accessing allylic alcohols and their derivatives; however, it represents a long-standing challenge in the field for several decades. … Asymmetric allylic C(sp3)-H oxidation of terminal alkenes provides a streamlined process for accessing allylic alcohols and their derivatives; however, it represents a long-standing challenge in the field for several decades. Herein, we disclosed a copper-catalyzed approach for the enantioselective allylic C(sp3)-H oxidation of terminal alkenes, facilitated by introducing a sterically bulky B2Im(C6F5)6 anion. Notably, a wide range of aryl-substituted terminal alkenes were used as limiting reagents, delivering various products with excellent enantioselectivity and regioselectivity (up to 99% ee, >20:1 b/l). Mechanistically, the bulky counteranion was found to be essential for achieving excellent enantioselective control and high catalytic efficiency.

Spatially Tweaked Amide-Directing Group Enables High-Turnover Pd Catalysts for Site-Selective Remote C–H Arylation

2025-06-20

C Sivaraj , Thirumanavelan Gandhi , Debabrata Maiti | ACS Catalysis

None

2025-06-20

Ahlem Rahali , Norman Le Floch , Fatma Allouche +1 more | Comptes Rendus Chimie

In the context of palladium-catalyzed C–H bond arylation, it has been well-established that pyrazoles, with both C4 and C5 available positions, typically result in the formation of mixtures of C4-, … In the context of palladium-catalyzed C–H bond arylation, it has been well-established that pyrazoles, with both C4 and C5 available positions, typically result in the formation of mixtures of C4-, C5-arylated, and also C4, C5-diarylated products. In this study, the reactivity of ethyl 1-methylpyrazole-4-carboxylate in palladium-catalyzed C–H arylation was investigated. The objective was to determine the effectiveness of the presence of an ester substituent at the C4 position of the pyrazole as a blocking group in controlling the regioselectivity of such C–H bond arylations. It was observed that the presence of such an ester substituent acted as a convenient blocking group, thereby enabling the control of regioselectivity in the arylation process at the C5 position of the pyrazole. The reaction exhibits a high degree of tolerance to a wide variety of aryl bromides, including a diverse array of functional groups at the para , meta , and ortho positions of the aryl bromides. Heteroarylation is also possible. In the course of these couplings, no decarboxylation of the pyrazole unit was observed, and the reaction requires only 2 mol% of an air-stable phosphine-free palladium catalyst and KOAc as an inexpensive base. Furthermore, the removal of the pyrazole ester substituent was found to be easy, which demonstrates the potential of such an ester substituent as a removable blocking group.

Dicarbofunctionalization of Alkenes/Alkynes via CAN‐Mediated Cyclization Reactions

2025-06-20

Subramaniapillai Selva Ganesan , Mannan Boopathi | Asian Journal of Organic Chemistry

Abstract Ceric ammonium nitrate (CAN) was utilized to transform readily available terminal alkenes/alkynes to the corresponding chroman‐4‐one/chromenoquinoline analogues. Interestingly, the type of unsaturation on the substrate dictates the course of … Abstract Ceric ammonium nitrate (CAN) was utilized to transform readily available terminal alkenes/alkynes to the corresponding chroman‐4‐one/chromenoquinoline analogues. Interestingly, the type of unsaturation on the substrate dictates the course of the CAN‐mediated cyclization reaction. With alkenes, sequential carbofunctionalization/cyclization cascade facilitated the formation of chroman‐4‐one, whilst for alkyne substrates, sequential condensation with amine followed by cycloaddition yielded the corresponding chromenoquinolines. All the aforementioned transformations were successfully accomplished under one‐pot operation under aerobic conditions. Studies on mechanistic investigation revealed that the reaction followed a radical pathway.

Visible-Light-Induced Aerobic ortho-Selective C–H Hydroxylation of Benzils

2025-06-20

J. F. Lv , Huiying Zeng | The Journal of Organic Chemistry

Herein, we report a visible-light-induced ortho-selective C-H hydroxylation of benzils, which exhibits good functional group tolerance and excellent regioselectivity. This method is scalable, as demonstrated by gram-scale experiments, and is … Herein, we report a visible-light-induced ortho-selective C-H hydroxylation of benzils, which exhibits good functional group tolerance and excellent regioselectivity. This method is scalable, as demonstrated by gram-scale experiments, and is further applied in the synthesis of rotenoids. Control experiments reveal the involvement of singlet oxygen in the reaction mechanism. Moreover, it proceeds via a five-membered ring radical intermediate, with dimethyl sulfoxide serving both as the solvent and reducing agent.

Ni-Catalyzed Regioselective Hydrodimerization of Enamides with Unactivated Alkenes

2025-06-20

Qifa Chen , Qing Yan , Li Cheng +2 more | Synthesis

In this study, we described the Ni-catalyzed cross-hydrodimerization of enamides with unactivated alkenes under SiH/DTBP-mediated ther-moredox conditions that was promoted by catalytic CuBr. The reaction afforded α-branched primary amines/secondary amides … In this study, we described the Ni-catalyzed cross-hydrodimerization of enamides with unactivated alkenes under SiH/DTBP-mediated ther-moredox conditions that was promoted by catalytic CuBr. The reaction afforded α-branched primary amines/secondary amides in good yields and high regioselectivity through the formation of C(sp3)–C(sp3) bond at the N-α-carbons. Excellent functional compatibility was observed across a wide range of sterically congested enamides and alkenes, including allylic branched enamides and 1,1-disubstituted alkenes. The use of chiral BiOx ligand enabled the formation of chiral amides at a high level of enantioselectivity. The present study offers a new entry for expediting the preparation of secondary amides appended to the internal alkyl chains, complementing existing methods in the rapidly growing field of C(sp3)–C(sp3) bond construction via the hydrodimerization of two distinct alkenes.

Direct and Site-Selective C–H Cyanation of (Hetero)arenes by a Nontoxic Cyano Source

2025-06-19

Ao Xu , Songlin Zhang | Organic Letters

Direct C-H cyanation of arenes and heteroarenes is herein reported using a nontoxic cyano source with high regioselectivity. CuI serves as an essential multifunctional catalyst, which promotes the in situ … Direct C-H cyanation of arenes and heteroarenes is herein reported using a nontoxic cyano source with high regioselectivity. CuI serves as an essential multifunctional catalyst, which promotes the in situ generation of Cu-CN and aryl iodides and the subsequent cross-coupling of these two intermediates to yield aryl nitrile products. The new strategy of C-H cyanation, good regioselectivity, and the use of a nontoxic cyano source together represents a significant advancement in cyanation chemistry.

Mechanistic Studies of Pd-Catalyzed β- and γ-C(sp3)–H Arylations and the Computational Design of Bidentate Pyridone Ligands

2025-06-19

Yue Qiao , Miaomiao Xu , Wei Li +5 more | The Journal of Organic Chemistry

This study outlines a detailed reaction mechanism for the Pd-catalyzed β-C(sp3)-H arylation of free carboxylic acids, which unfolds through three distinct stages: (i) ligand-driven β-C(sp3)-H activation, leading to the formation … This study outlines a detailed reaction mechanism for the Pd-catalyzed β-C(sp3)-H arylation of free carboxylic acids, which unfolds through three distinct stages: (i) ligand-driven β-C(sp3)-H activation, leading to the formation of the five-membered-ring intermediate IM2; (ii) oxidative addition of ArI to Pd of IM2, resulting in the Pd(IV) complex IM4; and (iii) reductive elimination, which produces the desired arylated product and regenerates the active species for the next catalytic cycle. Notably, the oxidative addition step, with a free energy barrier of 28.5 kcal/mol, is identified as the rate-determining step (RDS) of the entire catalysis. EDA-NOCV analysis revealed that the RDS is governed by a combination of intrinsic energy (ΔEint) and preparation energy (ΔEprep). Building on these mechanistic insights, we further explored a series of bidentate pyridone ligands (L2-L12) aimed at lowering the free energy barrier of the RDS. Among them, ligand L9 exhibits exceptional potential in promoting the overall reaction efficiency. Furthermore, L9 possesses computational potential in facilitating remote γ-C(sp3)-H arylations. These findings offer valuable mechanistic insights into both β- and γ-C(sp3)-H arylations, providing a theoretical guide for improving current catalytic systems and advancing the development of new arylation methodologies for free carboxylic acids.

Chiral Transient Directing Groups for Catalytic Asymmetric Intramolecular Alkene Hydroacylation

2025-06-19

Parker B. Staub , Hannah M. Holst , Nitha Nahan Puthalath +1 more | ACS Catalysis

Copper-catalyzed Enantioselective Oxidative Coupling between Benzylic C(sp 3 )‒H Bond and Carboxylic Acids

2025-06-19

Xianming Liu , Li Fu , Li-Yuan Xue +4 more | CCS Chemistry

Solventless Catalytic C–H and C–X Functionalization without Ball Milling

2025-06-18

Carolina Méndez‐Gálvez , Fredrik Barnå , Boris Olsthoorn +3 more | The Journal of Organic Chemistry

A low-cost, operationally simple approach to eight different solventless Rh-, Ru-, Ir-, and Pd-catalyzed C-H and C-X functionalizations, as well as the synthesis of difficult-to-make rhodacyclic complexes, is presented. The … A low-cost, operationally simple approach to eight different solventless Rh-, Ru-, Ir-, and Pd-catalyzed C-H and C-X functionalizations, as well as the synthesis of difficult-to-make rhodacyclic complexes, is presented. The method uses open-air grinding and heating, is reproducible, gives competitive yields compared with automated ball milling protocols, and can be extended to the late-stage modification of various bioactive compounds.

Direct C(sp2)‐H Bond Alkylation of Maleimide via Fe(<scp>III</scp>)‐Catalyzed Hydrogen Atom Transfer Strategy

2025-06-18

Ji‐Yu Wang , Dongwei Huang , Yao Xiao +6 more | Chinese Journal of Chemistry

Comprehensive Summary The direct C(sp 2 )‐H bond alkylation of maleimides using iminophosphorane‐induced Fe(III)‐catalyzed HAT (hydrogen atom transfer) strategy was achieved, and a series of novel alkyl maleimide derivatives were … Comprehensive Summary The direct C(sp 2 )‐H bond alkylation of maleimides using iminophosphorane‐induced Fe(III)‐catalyzed HAT (hydrogen atom transfer) strategy was achieved, and a series of novel alkyl maleimide derivatives were synthesized. The reaction has the characteristics of mild conditions, widespread functional group compatibility and substrates adaptability. The mechanism study shows that it mainly involves MHAT (metal‐catalyzed hydrogen atom transfer), radical conjugate addition, SET (single electron transfer) processes, and theoretical calculations reveal that the critical step is that phosphorus radical intermediate G is converted to phosphorus cationic intermediate I . The research provides a new insight into the direct functionalization of C(sp 2 )‐H to form C(sp 2 )‐C(sp 3 ) bonds via the HAT strategy.

An Oxidative Palladium-Catalyzed Remote meta-Selective Homo-Biaryl Coupling Assisted by Nitrile Directing Templates

2025-06-17

Chinnabattigalla Sreenivasulu , P. Ramesh , Dakoju Ravi Kishore +2 more | Organic Letters

Remote meta-C-H functionalization has emerged as a transformative approach in organic synthesis, allowing for the selective functionalization of inactive meta-C-H bonds. While considerable progress has been made in meta-C-H functionalization … Remote meta-C-H functionalization has emerged as a transformative approach in organic synthesis, allowing for the selective functionalization of inactive meta-C-H bonds. While considerable progress has been made in meta-C-H functionalization strategies, including olefination, cyanation, acetoxylation, and arylation, regioselective meta-C-H homo-biaryl coupling remains unexplored. In this study, we report the first palladium-catalyzed oxidative protocol for regioselective meta-C-H homo-biaryl coupling, targeting substrates such as 3-phenylpropanoic acid, 2-phenylethan-1-ol, phenylacetic acid, and phenylmethanesulfonic acid derivatives. This method significantly enhances the synthetic tool box for the construction of complex biaryl frameworks with exceptional precision. The reaction proceeds efficiently under ambient conditions, with copper trifluoromethanesulfonate identified as a critical additive for driving the process. Furthermore, this strategy has been extended to the synthesis of complex trimeric and diolefination products. The protocol delivered the desired products in good yields with excellent regioselectivity and demonstrated broad applicability across a range of substrates bearing diverse aliphatic and aromatic nitrile-based directing group templates.

Iron Photocatalysis Enabling Decarboxylative Bromination of (Hetero)Aryl Carboxylic Acids

2025-06-17

Xiaoqin Deng , Jian Jin | Organic Letters

A decarboxylative bromination protocol of (hetero)aryl carboxylic acids was achieved via iron photocatalysis. The photocatalytic decarboxylative functionalization of carboxylic acids was mostly limited to alkyl carboxylic acids. While several decarboxylative … A decarboxylative bromination protocol of (hetero)aryl carboxylic acids was achieved via iron photocatalysis. The photocatalytic decarboxylative functionalization of carboxylic acids was mostly limited to alkyl carboxylic acids. While several decarboxylative functionalization reactions of aryl carboxylic acids by copper photocatalysis have been disclosed in the last five years, the iron-catalyzed version is still rare. This work takes one step further to iron catalysis and uses NaBrO3 as both the oxidant and the bromine source, with simple operation and readily available raw materials. A diverse range of (hetero)aryl carboxylic acids can undergo decarboxylative bromination through the iron catalyzed photocatalytic ligand-to-metal charge-transfer (LMCT) process, providing a feasible synthetic approach for multisubstituted bromoarenes.

Catalytic reductive annulation reactions of alkenes using dihaloalkanes

2025-06-16

Sayan Roy , Divya Garg , Christopher Uyeda | Tetrahedron Letters

Enhancing chemical synthesis planning: automated quantum mechanics-based regioselectivity prediction for C–H activation with directing groups

2025-06-16

Julius Seumer , Nicolai Ree , Jan H. Jensen | Beilstein Journal of Organic Chemistry

The mild and selective functionalization of carbon–hydrogen (C–H) bonds remains a pivotal challenge in organic synthesis, crucial for developing complex molecular architectures in pharmaceuticals, polymers, and agrochemicals. Despite advancements in … The mild and selective functionalization of carbon–hydrogen (C–H) bonds remains a pivotal challenge in organic synthesis, crucial for developing complex molecular architectures in pharmaceuticals, polymers, and agrochemicals. Despite advancements in directing group (DG) methodologies and computational approaches, predicting accurate regioselectivity in C–H activation poses significant difficulties due to the diversity and complexity of organic compounds. This study introduces a novel quantum mechanics-based computational workflow tailored for the regioselective prediction of C–H activation in the presence of DGs. Utilizing (semi-empirical) quantum calculations hierarchically, the workflow efficiently predicts outcomes by considering concerted metallation deprotonation mechanisms mediated by common catalysts like Pd(OAc) 2 . Our methodology not only identifies potential activation sites but also addresses the limitations of existing models by including a broader range of directing groups and reaction conditions while maintaining moderate computational cost. Validation against a comprehensive dataset reveals that the workflow achieves high accuracy, significantly surpassing traditional models in both speed and predictive capability. This development promises substantial advancements in the design of new synthetic routes, offering rapid and reliable regioselectivity predictions that are essential for accelerating innovation in materials science and medicinal chemistry.

Direct C4 Halogenation of Isoquinolines via a Boc2O-Mediated Dearomatization Strategy

2025-06-15

Byeung Mun Song , Jiangtao Cai , Dazhong Yuan +3 more | The Journal of Organic Chemistry

A cost-effective method for directly halogenating isoquinolines at the C4 position has been developed through a one-pot sequence involving Boc2O-mediated dearomatization, electrophilic halogenation (X = Cl, Br, I), and acid-promoted … A cost-effective method for directly halogenating isoquinolines at the C4 position has been developed through a one-pot sequence involving Boc2O-mediated dearomatization, electrophilic halogenation (X = Cl, Br, I), and acid-promoted rearomatization. This reaction exhibited high C4 site selectivity, efficiently affording 4-halogenated isoquinolines, and demonstrated good functional group tolerance at C5-C8. In addition, the C-X bond-containing products could serve as versatile synthetic intermediates for further modification of isoquinolines, including Suzuki coupling, Sonogashira coupling, and Stille coupling.

Cobalt-Catalyzed Markovnikov Hydroarylcarbonylation of Unactivated Alkenes via Distal Aryl Migration

2025-06-14

Mengdie Xiao , Wei Li , Donghao Jiang +1 more | CCS Chemistry

Metal-Bound Heteroatom Radicals: Advancing Site-Selective C–H Functionalization

2025-06-14

Jiayuan Li , Tobias Blockhaus , Guosheng Liu | Journal of the American Chemical Society

Selective transformation of C-H bonds represents a frontier research area in synthetic chemistry. While the high reactivity of radicals provides an alternative and efficient pathway for C-H bond functionalization, controlling … Selective transformation of C-H bonds represents a frontier research area in synthetic chemistry. While the high reactivity of radicals provides an alternative and efficient pathway for C-H bond functionalization, controlling their selectivity─particularly in processes such as site-selective hydrogen atom abstraction (HAA)─remains a long-standing and unresolved challenge in radical chemistry, largely due to the lack of effective regulation strategies. This review deliberately avoids a comprehensive discussion of the field's current state or landmark discoveries in C-H functionalization. Instead, by focusing on recent advances in metal-catalyzed, highly site-selective C-H bond transformations, this Perspective elucidates how metal-bound radicals enable precise hydrogen abstraction for targeted functionalization. This emerging paradigm offers innovative strategies for regulating radical behavior, potentially unlocking novel radical-mediated selective transformations─including but not limited to the precise functionalization of C-H bonds.

Rh(III)-Catalyzed [3 + 4] Annulation of 3-Arylisoindolinones with 2-Methylidenetrimethylene Carbonate via C–H Activation to Access Isoindolinone Spirobenzoxepines

2025-06-13

Hai-Shan Jin , Yan Wang , Ru-Jie Zhang +1 more | Organic Letters

A Rh(III)-catalyzed C-H activation/annulation of 3-aryl-3-hydroxyisoindolinones with 2-methylidenetrimethylene carbonate has been developed. This method leads to the synthesis of seven-membered isoindolinone spirobenzoxepines through sequential C-C and C-O bond formations, which … A Rh(III)-catalyzed C-H activation/annulation of 3-aryl-3-hydroxyisoindolinones with 2-methylidenetrimethylene carbonate has been developed. This method leads to the synthesis of seven-membered isoindolinone spirobenzoxepines through sequential C-C and C-O bond formations, which are interesting scaffolds in drug discovery. Its synthetic application has also been demonstrated to highlight the versatility. In addition, this is the first example in which 2-methylidenetrimethylene carbonate serves as a C3O1 synthon to accomplish [3 + 4] annulation in transition-metal-catalyzed C-H activation reactions.