Review
Chemistry, Organic
C. M. A. Afsina, Thaipparambil Aneeja, Mohan Neetha, Gopinathan Anilkumar
Summary: Copper-catalyzed organic reactions have attracted widespread attention due to the abundance and affordability of copper, as well as its low toxicity, eco-friendliness, sustainable nature, and versatility as a catalyst. These reactions are primarily used for the synthesis of biologically important nitrogen heterocycles, amines, amides, imines, and alkynes.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Chemistry, Organic
Xiao-De An, Da-Ying Shao, Bin Qiu, Jian Xiao
Summary: An unprecedented cross-dehydrogenative coupling reaction of two C(sp(3))-H bonds to form ninemembered rings via hydride transfer has been developed. This methodology offers atom and step economy, metal-free and redox-neutral conditions, and water as the byproduct, making it applicable even with decomposed aldehydes.
Article
Chemistry, Organic
Xiao-De An, Da-Ying Shao, Bin Qiu, Jian Xiao
Summary: An unprecedented hydride transfer-triggered cross-dehydrogenative coupling of two C(sp(3))-H bonds to target nine membered rings has been developed. Salient features of this methodology include atom and step economy and metal-free and redox-neutral conditions, with water as the byproduct and proceeding well even with decomposed aldehydes.
Article
Chemistry, Multidisciplinary
Zi-Xuan Wang, Bi-Jie Li
Summary: This study reports an amide-directed, regiodivergent, and enantioselective hydroalkynylation reaction. The regioselectivity can be tuned by choosing appropriate ligands, leading to the formation of products with acyclic tertiary or quaternary stereocenters beta to an amide. Furthermore, an asymmetric conjugated alkynylation reaction was achieved through a sequence of alkene isomerization and regioselective hydroalkynylation.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Organic
Cui-Lian Zeng, Hao Wang, Di Gao, Zhen Zhang, Dong Ji, Wei He, Cheng-Kou Liu, Zhao Yang, Zheng Fang, Kai Guo
Summary: This study presents a green and gentle Minisci-type reaction method, in which the cross-dehydrogenative coupling of heteroarenes with aliphatic C(sp(3))-H bonds is achieved under visible-light irradiation. This method does not require oxidants or transition metal catalysts, and only the catalytic equivalent of CF3SO2Na and room temperature are needed to ensure an efficient reaction.
Review
Chemistry, Multidisciplinary
Jianbin Li, Chia-Yu Huang, Chao-Jun Li
Summary: This review summarises recently developed strategies for achieving C-C cross-couplings between an inert aliphatic C-H bond and another C-H bond through different C(sp3)-H functionalisation tactics.
TRENDS IN CHEMISTRY
(2022)
Article
Chemistry, Organic
Lijun You, Wei Yuan, Chuan He
Summary: This study successfully developed an iridium-catalyzed reaction for the synthesis of arylbenzyl bis(silanes), featuring high selectivity and the ability to generate multifunctional organosilanes in good yields from readily available starting materials.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Chemistry, Organic
Wei Wei, Xiaodan Zhao
Summary: The carbon-carbon bond-forming cross-dehydrogenative coupling reaction using organoselenium catalysis involving a high-valent para-methoxyphenyl selenium species has been developed. This method enables the synthesis of alpha,alpha-disubstituted alpha-amino acid derivatives with excellent regioselectivities through vinyl or allylic C-H functionalization. The generality of this method has been demonstrated by the cross-coupling of an alkene with an oxindole and the direct functionalization of electron-rich arenes with azlactones.
Article
Chemistry, Organic
Ruixin Liu, Xiaojuan Liu, Tanyu Cheng, Yaofeng Chen
Summary: Alkynylsilanes are important organic compounds that can be synthesized through dehydrogenative coupling of hydrosilanes with terminal alkynes, and the use of organocalcium complexes in organic synthesis has been gaining increasing attention.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Zi-Chao Wang, Jia-Wen Zhang, Ming Joo Koh, Shi-Liang Shi
Summary: In this study, a highly selective carbonickelation of light alkenes was reported, enabling efficient synthesis of diverse compounds through addition reactions with various reagents. The use of bulky N-heterocyclic carbene ligands played a crucial role in the reaction. This strategy provides a rare, modular platform for upgrading feedstock alkenes and is expected to find broad applications in medicinal chemistry and industrial processes.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Cristian Cavedon, Sebastian Gisbertz, Susanne Reischauer, Sarah Vogl, Eric Sperlich, John H. Burke, Rachel F. Wallick, Stefanie Schrottke, Wei-Hsin Hsu, Lucia Anghileri, Yannik Pfeifer, Noah Richter, Christian Teutloff, Henrike Mueller-Werkmeister, Dario Cambie, Peter H. Seeberger, Josh Vura-Weis, Renske M. van der Veen, Arne Thomas, Bartholomaus Pieber
Summary: We demonstrate visible-light-mediated carbon-heteroatom cross-coupling reactions using a photoactive Ni(II) precatalyst. The activation of this precatalyst involves an initial intraligand charge transfer event triggered by visible light irradiation. Additionally, a porous, recyclable organic polymer for heterogeneous nickel catalysis of cross-coupling reactions is obtained through ligand polymerization.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Organic
Fang Wang, Qianting Zhou, Xinying Zhang, Xuesen Fan
Summary: A novel and efficient alpha-C(sp(3))-H alkenylation of cyclic amines with maleimides was presented, featuring readily available and structurally diverse substrates, a green and economical catalyst, a unique reaction pathway, mild reaction conditions, high efficiency, and excellent atom economy. This new reaction enriches the application of Fe(III)-catalyzed C(sp(3))-H activation and functionalization.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Chemistry, Organic
Aditya Paul, Arunava Sengupta, Somnath Yadav
Summary: The visible light-triggered regioselective synthesis of 2-sulfonamidoindoles and other 2-sulfonamido heteroarenes is achieved through an oxidative cross-dehydrogenative coupling reaction. The reaction is catalyzed by eosin-Y and a nitrogen-centered radical is generated, followed by regioselective addition to the heteroarene. The methodology is straightforward and allows for the synthesis of a wide range of compounds.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Babasaheb Sopan Gore, Jeh-Jeng Wang
Summary: Here, we report a photoinduced energy-transfer catalysis reaction of tethered conjugated dienes, enabling the synthesis of bridged cyclopropanes. This single-step reaction efficiently generates complex tricyclic compounds with multiple stereocenters from readily accessible starting materials. The reaction demonstrates a broad substrate scope, atom-economy, excellent selectivity, and satisfactory yield, including facile scale-up synthesis and synthetic transformation. An in-depth mechanistic study reveals that the reaction proceeds via an energy-transfer pathway.
CHEMICAL COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Xin Zhang, Shuo Tong, Jieping Zhu, Mei-Xiang Wang
Summary: Under the catalysis of PdBr2 and a chiral phosphoramidite ligand, mono (2-bromoaroyl)-substituted calix[4]arene derivatives with upper-rim underwent an easy enantioselective desymmetrization reaction, yielding 9H-fluorene-embedded inherently chiral calixarenes with good yields and excellent enantioselectivities. The transannular dehydrogenative arene-arene coupling reaction most likely proceeded through oxidative addition of the C-aryl-Br bond to a ligated palladium catalyst, followed by a sequence of enantioselective 1,5-palladium migration and intramolecular C-H arylation. This new family of inherently chiral calixarenes has unique chiroptical properties due to their highly rigid structure induced by the 9H-fluorene segment.
Article
Chemistry, Applied
Matthew J. Goldfogel, Xuelei Guo, Jeishla L. Melendez Matos, John A. Gurak, Matthew Joannou, William B. Moffat, Eric M. Simmons, Steven R. Wisniewski
Summary: Interest in using base metals instead of palladium catalysts led to the development of a 24-reaction screening platform for identifying nickel-catalyzed Suzuki-Miyaura reaction conditions. The addition of methanol was found to greatly improve the reaction performance and allow for the use of organic-soluble amine bases. The screening platform and scale-up workflow were successfully applied to develop a gram-scale synthesis using the antipsychotic perphenazine, highlighting the advantages of this method and nickel catalysis for metal remediation.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2022)
Article
Chemistry, Applied
William P. Gallagher, John R. Coombs, Carlos A. Guerrero, Eric M. Simmons, Francisco Gonzalez-Bobes
Summary: We have developed a six-step synthesis for the tricyclic core 10 of BMS-986251, which involves the installation of a perfluoro isopropyl group through a radical mechanism and a novel diastereoselective annulation to form the pyrrolidine ring. Using this new route, compound 10 was obtained as a single stereoisomer in 499'6 yield after 6 steps and 3 isolations.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2022)
Article
Chemistry, Applied
Daniel S. Treitler, Maxime C. Soumeillant, Eric M. Simmons, Dong Lin, Bahar Inankur, Amanda J. Rogers, Michael Dummeldinger, Sergei Kolotuchin, Collin Chan, Jun Li, Adam Freitag, Federico Lora Gonzalez, Michael J. Smith, Chris Sfouggatakis, Jianji Wang, Tamas Benkovics, Joerg Deerberg, James H. Simpson, Ke Chen, Steven Tymonko
Summary: Deucravacitinib is a deuterated small-molecule TYK2 inhibitor developed for the treatment of autoimmune disorders. The development of a new synthesis route and impurity control allowed for large-scale production of Deucravacitinib for clinical and commercial use.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2022)
Article
Chemistry, Applied
Jason M. Stevens, Eric M. Simmons, Yichen Tan, Alina Borovika, Junying Fan, Robert Forest, Peng Geng, Carlos A. Guerrero, Sha Lou, Dimitri Skliar, Sarah E. Steinhardt, Neil A. Strotman
Summary: This study describes the invention of a commercial route to the Bruton's tyrosine kinase inhibitor branebrutinib (BMS-986195) in four total chemical steps. By utilizing high-throughput experimentation and a first-principles approach, a novel indolization reaction that rapidly generated high synthetic complexity was identified as the centerpiece of the synthesis.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2022)
Article
Chemistry, Organic
Anthony N. Cauley, Antonio Ramirez, Chandan L. Barhate, Andrew F. Donnell, Purnima Khandelwal, Melda Sezen-Edmonds, Trevor C. Sherwood, Jack L. Sloane, Cullen L. Cavallaro, Eric M. Simmons
Summary: By utilizing quinoline as a mild catalytic additive, a broadly applicable method for Ni/photoredox-catalyzed C(sp(2))-C(sp(3)) cross-coupling was developed, which can be used in both batch and flow reactions. The method is effective for both primary benzylic nucleophiles and stabilized/nonstabilized secondary alkyl boronic esters.
Article
Chemistry, Inorganic & Nuclear
Jason M. Stevens, Jun Li, Eric M. Simmons, Steven R. Wisniewski, Stacey DiSomma, Kenneth J. Fraunhoffer, Peng Geng, Bo Hao, Erika W. Jackson
Summary: This study generated a large dataset to investigate the performance of catalysts and ligands in the aryl (pseudo)halide borylation reaction. It found that simple triarylphosphines and mixed aryl-alkyl phosphines performed well. Machine learning models were used to predict the reaction performance of ligands not included in the training set.
Article
Chemistry, Physical
Melissa Cadena, Roberto Silva Villatoro, Jyoti Shah Gupta, Cody Phillips, Jonathan B. Allen, Hadi D. Arman, Daniel J. Wherritt, Nicholas A. Clanton, Alexander L. Ruchelman, Eric M. Simmons, Albert J. DelMonte, John R. Coombs, Doug E. Frantz
Summary: A highly chemoselective Pd-catalyzed O-benzylation reaction has been discovered and developed, and the reaction mechanism has been analyzed in detail. This method allows for selective O-alkylation of 2-quinolinones with various functional groups, providing high yields and good selectivity.
Article
Chemistry, Organic
Cong Bi, James Chadwick, Merrill L. Davies, Albert J. DelMonte, Peng Geng, Andrew W. Glace, Rebecca A. Green, John A. Gurak, Matthew W. Haley, Brian L. He, Bahar Inankur, Christopher R. Jamison, Candice L. Joe, Sergei Kolotuchin, Dong Lin, Sha Lou, Jeffrey Nye, Adrian Ortiz, Geoffrey E. Purdum, Victor W. Rosso, Mansi Shah, Eric M. Simmons, Jason M. Stevens, Neil A. Strotman, Yichen Tan, Ling Zhang
Summary: A new convergent route for the synthesis of NLRP3 agonist BMS-986299 is reported, which involves a key Miyaura borylation and a tandem Suzuki-Miyaura coupling. The synthesis utilizes an iodoimidazole and an o-aminochloroarene as starting materials, leading to the formation of the aminoquinoline core through acid-mediated cyclization. The target compound is obtained through subsequent Boc deprotection and regioselective acylation. This convergent six-step route reduces process mass intensity by 80% compared to the linear enabling synthesis.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Samantha L. Goldschmid, Nicholas Eng Soon Tay, Candice L. Joe, Brendan C. Lainhart, Trevor C. Sherwood, Eric M. Simmons, Melda Sezen-Edmonds, Tomislav Rovis
Summary: Aryl amination plays a crucial role in medicinal, process, and materials chemistry. Blue-light-driven metallaphotoredox catalysis is a valuable tool for C-N cross-coupling, but its limited penetration through reaction media and the formation of unwanted side-products pose challenges for industrial scalability. Using low-energy light, such as deep red or near-infrared, can enhance penetration and suppress unwanted reactions, leading to an enhanced scope of aryl bromides and amine-based nucleophiles.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Physical
Paul O. Peterson, Matthew Joannou, Eric M. Simmons, Steven R. Wisniewski, Junho Kim, Paul J. Chirik
Summary: The synthesis and characterization of phenoxy(imine) iron(II) alkyl precatalysts for C(sp2)-C(sp3) Suzuki-Miyaura cross-coupling reaction is reported. This method utilizes mild alkoxide bases and nonpolar solvents to achieve high efficiency C(sp2)-C(sp3) bond formation with various aryl boronic esters and alkyl bromides. The study also highlights the compatibility of the precatalysts with base-sensitive functionality and the role of boronate intermediates in transmetalation.
Article
Chemistry, Applied
Paul J. Chirik, Keary M. Engle, Eric M. Simmons, Steven R. Wisniewski
Summary: Earth-abundant metal (EAM) catalysis has significant impact on the sustainability and cost improvement in the pharmaceutical industry. It replaces precious metals like palladium and utilizes the reactivity of first-row metals to enable more efficient routes to clinical candidates. This article describes the strategy for building these capabilities within the process group, including the development of a reaction screening platform, scalability demonstration, and increasing mechanism understanding.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2023)
Article
Chemistry, Multidisciplinary
L. Reginald Mills, Francesca Di Mare, David Gygi, Heejun Lee, Eric M. Simmons, Junho Kim, Steven R. Wisniewski, Paul J. Chirik
Summary: The relative rates of the cobalt-catalyzed C(sp(2))-C(sp(3)) Suzuki-Miyaura cross-coupling were evaluated, and it was found that smaller N-alkyl substituents on the phenoxyimine ligand accelerated the reaction. This inspired the design of optimal cobalt catalysts with phenoxyoxazoline and phenoxythiazoline ligands. The catalyst lifetime was improved by adding excess KOMe•B(O-iPr)3, which attenuated alkoxide basicity and prevented demetallation of the ligand.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
L. Reginald Mills, David Gygi, Eric M. Simmons, Steven R. Wisniewski, Junho Kim, Paul J. Chirik
Summary: The mechanism of phenoxyimine (FI)-cobalt-catalyzed C(sp(2))-C(sp(3)) Suzuki-Miyaura cross-coupling was studied using kinetic measurements and catalytic and stoichiometric experiments. Dimeric (FI) cobalt(II) bromide complexes were isolated and characterized, and one complex was used as a single-component precatalyst for the cross-coupling reaction. The involvement of boronate intermediates in transmetalation was confirmed by Hammett studies of aryl boronic esters. A cobalt(II)/cobalt(III) catalytic cycle was proposed that proceeds through a boronate-type mechanism.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Inorganic & Nuclear
Roberto Silva Villatoro, Joshua R. Belfield, Hadi D. Arman, Lucas W. Hernandez, Eric M. Simmons, Zachary J. Garlets, Steven R. Wisniewski, John R. Coombs, Doug E. Frantz
Summary: A general method utilizing a dual-base strategy for the Ni-catalyzed Buchwald-Hartwig amination of (hetero)aryl chlorides using anilines and aliphatic amines under homogeneous conditions has been developed. This method is significant as it allows for aminations across a broad scope of substrates using a low catalyst loading (as low as 1.0 mol%) and commercially available compounds.
Article
Chemistry, Physical
Melissa Cadena, Roberto Silva Villatoro, Jyoti Shah Gupta, Cody Phillips, Jonathan B. Allen, Hadi D. Arman, Daniel J. Wherritt, Nicholas A. Clanton, Alexander L. Ruchelman, Eric M. Simmons, Albert J. DelMonte, John R. Coombs, Doug E. Frantz
Summary: We have developed a highly selective Pd-catalyzed O-benzylation reaction and identified the formation of a key intermediate through detailed reaction analysis. This method enables the selective O-alkylation of substituted 2-quinolinones with high efficiency using a minimal amount of Pd catalyst.
