Article
Chemistry, Organic
Ya-Ting Wen, Xiang-Tao Kong, Hong-Chao Liu, Cui-Tian Wang, Wan-Xu Wei, Bin Wang, Xue-Yuan Liu, Yong-Min Liang
Summary: An innovative 1,5-HAT cascade strategy has been proposed for nickel-catalyzed distal arylation via cross-electrophile coupling. It selectively activates the remote C(sp(3))-H bond through specific migration and uses Ar-I as the available electrophile for constructing the C(sp(3))-C(sp(2)) bond. The method shows broad applicability for benzylic and aliphatic N-fluorocarboxamides with yields up to 80%. Control experiments suggest that this reaction may be initiated by a radical process.
Article
Chemistry, Organic
Shan-Shan Li, Yu-Shi Jiang, Xue-Ling Luo, Cheng-Xue Pan, Peng-Ju Xia
Summary: Diverse gamma-imino alkenes with excellent stereoselectivity were synthesized through a vinyl radical-mediated 1,5-hydrogen atom transfer strategy under visible-light induced metal-free photochemical conditions. Oxime ester-based bifunctional reagents provided nucleophilic alkyl radicals for radical addition reactions with electron-deficient alkynes and long-lived steady-state imine radicals for trapping alkyl radicals following the intramolecular 1,5-hydrogen migration of unstable olefin radicals.
Article
Chemistry, Multidisciplinary
Weonjeong Kim, Jangwoo Koo, Hong Geun Lee
Summary: A unique functionalization strategy for a benzylic C(sp(3))-H bond has been developed based on the facile oxidation event of indole substrates. The method utilizes mild conditions and exhibits a wide substrate scope for both substituted indoles and C(sp(2))-based reaction counterparts. Competitive hydrogen atom transfer processes, commonly seen in conventional methods, are not involved in the product formation process of this developed strategy.
Article
Chemistry, Organic
Jiayuan Wang, Youwan Ye, Tongzhi Sang, Chenxing Zhou, Xiazhen Bao, Yong Yuan, Congde Huo
Summary: A general C(sp3)-H/C(sp3)-H dehydrogenative coupling strategy for the preparation of various natural or unnatural amino acids from readily available glycine derivatives and hydrocarbons is reported, which involves a combination of SET and HAT process.
Article
Chemistry, Physical
Bryan C. Figula, Ting-An Chen, Jeffery A. Bertke, Timothy H. Warren
Summary: In this study, a radical relay C-H methylation method using a beta-diketiminate copper catalyst was developed, enabling the methylation of unactivated C(sp(3))-H bonds. By utilizing the bench-stable DABAL-Me-3 as a reagent, methylation of various substrates with both activated and unactivated C(sp(3))-H bonds was achieved with minimal overmethylation. Mechanistic studies suggested the involvement of a copper(II) methyl intermediate that reacts with methyl radicals and radicals R-center dot to form R-Me bonds.
Article
Chemistry, Organic
Alisha Rani Tripathy, Amit Kumar, A. Rizwana Rahmathulla, Avishek Kumar Jha, Veera Reddy Yatham
Summary: A metal-free cross-coupling protocol between unactivated alkyl iodides and terminal alkynyl bromides has been developed, utilizing visible light as the promoter. This reaction employs an organic photocatalyst and commercially available tri-n-butylamine as a reductant, allowing for the coupling of various unactivated iodoalkanes with different functional groups and terminal alkynyl bromides to form substituted alkynes under mild reaction conditions.
Article
Chemistry, Multidisciplinary
Sun Dongbang, Abigail G. Doyle
Summary: In this article, a novel Ni/photoredox methodology for C(sp3)-C(sp3) cross-coupling reaction between aziridines and activated aliphatic alcohols is reported. Different activation modes are employed for each coupling partner, leading to cross-selectivity in the bond forming reaction.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Chao Li, Ran Ding, Heng-Yi Guo, Shuang Xia, Lei Shu, Pei-Long Wang, Hongji Li
Summary: In this study, we report a rare catalyst-free electrochemical cross-coupling reaction that can forge various types of chemical bonds at room temperature. The study also reveals the dual role of organotrifluoroborates as both coupling partner and electrolyte in the C-H functionalization reaction.
Article
Chemistry, Multidisciplinary
Geunho Choi, Geun Seok Lee, Beomsoon Park, Dongwook Kim, Soon Hyeok Hong
Summary: A mild and operationally simple C(sp(3))-H trifluoromethylation method has been developed for unactivated alkanes using a bench-stable Cu-III complex as the initiator of the visible-light photoinduced reaction, as well as a source of trifluoromethyl radicals and trifluoromethyl anions for functionalization. The methylene-selective reaction mechanism involves radical-polar crossover and ionic coupling between the reactive carbocation intermediate and the anionic CF3 source, enabling efficient C-CF3 bond formation. This method can be applied for late-stage trifluoromethylation of natural products and bioactive molecules.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Organic
Canlin Zou, Hongting Wu, Jiangtao He, Yunfei Hu, Weijie Deng, Xinling Li, Jinhui Hu, Yibiao Li, Yubing Huang
Summary: An efficient anodic C(sp(3))-H acyloxylation protocol has been developed, which enables the direct oxidation of indolin-3-ones to obtain various C2-acyloxy indolin-3-ones without the need for metal catalysts and external oxidants. The practicality of this protocol has been demonstrated through the effective application of several medical drugs and gram-scale experiments.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Organic
Sandeep Patel, Arijit Chakraborty, Indranil Chatterjee
Summary: The single-electron-transfer-mediated desulfonative radical-cross-coupling reaction can be triggered by the photoexcitation of 4-alkyl-1,4-dihydropyridines in the presence of a base. This method allows for the construction of C(sp(3))-C(sp(3)) bonds without the need for any metal or photocatalyst. The reaction exhibits good functional group compatibility and a broad scope.
Article
Chemistry, Multidisciplinary
Yang Gao, Benxiang Zhang, Jiayan He, Phil S. Baran
Summary: The first examples of enantioselective doubly decarboxylative cross coupling are reported. Malonate half amides are successfully coupled to primary carboxylic acids via formation of redox-active esters under Ni-electrocatalytic conditions using a new chiral ligand based on PyBox. The reaction demonstrates a broad scope, tolerates various functional groups, and shows high enantioselectivity. The potential utility of this enantioselective radical-radical reductive cross coupling for synthesis simplification is demonstrated through several case studies.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Physical
Lingjuan Zhang, Lijuan Ma, Jincong Yuan, Xian-Ming Zhang, Zhiyong Tang
Summary: This study explores the construction of C(sp3)-C(sp3) and C(sp3)-O bonds through the oxidation of beta-carbonyl C(sp3)-H bonds by photo-generated holes. The tandem radical-radical cross-coupling, hydrogen atom transfer, and radical-radical cross-coupling reactions enable an effective difunctionalization of C(sp3)-H bonds.
APPLIED CATALYSIS B-ENVIRONMENTAL
(2023)
Article
Chemistry, Organic
Ya-Nan Ding, Ning Li, Yan-Chong Huang, Yang An, Yong-Min Liang
Summary: In this study, a practical and highly efficient method for visible-light-induced copper-catalyzed N-aminoquinoline-directed asymmetric C(sp(3))-C(sp(3))-H glycosylation was reported. Additionally, C-glycopeptides were synthesized through the glycosylation of nondeoxysugars with amino acids. This research provides a new approach for the synthesis of C-glycopeptides and C-glycoamino acids.
Article
Chemistry, Physical
Rong-Hua Wang, Jiang-Fei Li, Yue Li, Shao-Long Qi, Tao Zhang, Yu-Xin Luan, Mengchun Ye
Summary: A selective C(sp(3))-H cleavage of N-formyl enamides without modifying the backbone to synthesize 2-pyridones in good yields was reported in this study. The use of a bifunctional phosphine oxide ligand-bridging Ni-Al bimetallic catalyst played a key role in the reaction.
Review
Chemistry, Multidisciplinary
Spencer D. Dreher, Shane W. Krska
Summary: The concept of informer libraries provides a standardized set of substrates for evaluating synthetic methods, improving reaction conditions, and expanding the scope of applications. It also enables comparison of different methods for complex synthesis and identifies opportunities for further development. The combination of informer libraries and nano-scale reaction screening allows for parallel evaluation of numerous synthetic methods, facilitating predictive reactivity modeling.
ACCOUNTS OF CHEMICAL RESEARCH
(2021)
Article
Chemistry, Multidisciplinary
Si-Jie Chen, Dung L. Golden, Shane W. Krska, Shannon S. Stahl
Summary: This study presents a copper-catalyzed method for site-selective cross-coupling of pyrazoles and other N-H heterocycles with substrates bearing (hetero)benzylic C-H bonds. The strategy achieves excellent N-site selectivity controlled by co-catalytic additives, allowing broad scope for complex molecule synthesis and medicinal chemistry application.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Organic
Ryan P. King, Shane W. Krska, Stephen L. Buchwald
Summary: Palladium oxidative addition complexes (OACs) have emerged as useful tools for challenging bond connections, but each complex can only be formed with one dative ligand at a time. A ligand exchange protocol has been developed to prepare a series of OACs with various ancillary ligands from a common complex, which have been further applied to cross-coupling transformations.
Article
Chemistry, Organic
Ryan P. King, Shane W. Krska, Stephen L. Buchwald
Summary: The utilization of isolated Palladium Oxidative Addition Complexes (OACs) has been crucial for Pd-catalyzed and Pd-mediated cross-coupling reactions. However, the instability of their precursor complexes has limited their widespread utility. By using Campora's palladacycle as a stable precursor, a series of biarylphosphine ligated OACs were prepared, including those with pharmaceutical-derived aryl halides, showing relevance to bioconjugation research.
Article
Chemistry, Physical
Shasha Li, Dmitri Pissarnitski, Timothy Nowak, Michael Wleklinski, Shane W. Krska
Summary: An integrated workflow combining high-throughput experimentation and solid-phase peptide synthesis is presented for rapid synthetic method development for peptide diversification. The method allows for the identification of robust coupling conditions and synthesis of diverse peptide libraries in high yields.
Article
Chemistry, Multidisciplinary
Ning Qi, Michael K. Wismer, Donald Conway, Shane W. Krska, Spencer D. Dreher, Shishi Lin
Summary: The development of a high intensity photoreactor allows for high throughput screening of up to 1536 reactions on nanomole scales in parallel, offering increased photon flux for reactions sensitive to light intensity. The reactor's uniform illumination and efficient heat removal enable systematic investigation of parameter interplay on nanomole scale, providing a standardized platform for screening and data gathering. Additionally, the reactor allows for successful reproduction of screening hits at medicinal chemistry relevant scales.
REACTION CHEMISTRY & ENGINEERING
(2022)
Article
Multidisciplinary Sciences
Cesar N. Prieto Kullmer, Jacob A. Kautzky, Shane W. Krska, Timothy Nowak, Spencer D. Dreher, David W. C. MacMillan
Summary: The generality of a reaction is crucial for determining its overall impact and usefulness in synthetic methods. This study developed an additive mapping approach that rapidly expands the utility of synthetic methods and provides mechanistic insight. By validating this approach on a specific reaction, the discovery of a phthalimide ligand additive was made, which overcomes limitations and has important mechanistic implications for nickel-catalyzed cross-couplings.
Editorial Material
Chemistry, Organic
Sriram Tyagarajan, Deodial Guiadeen, Eric Streckfuss, Xiaolei Gao, Alexei V. Buevich, George Doss, Jian Liu, Petr Vachal, Shane W. Krska
Summary: Late-stage functionalization (LSF) allows for rapid exploration of structure-activity relationships (SAR) and improvement of the pharmacokinetic properties of lead molecules.
Article
Chemistry, Physical
Rebecca T. Ruck, Neil A. Strotman, Shane W. Krska
Summary: The Catalysis Laboratory at Merck was established in 2002 with the aim of discovering and developing asymmetric hydrogenation transformations for use in the company's projects. Over the past 20 years, not only has this goal been achieved, but numerous catalytic technologies have also emerged from this group. The successes achieved locally have led to further investments in catalytic manifolds and other enabling technologies in both industry and academia.
Article
Biochemical Research Methods
Wendy Cao, Johnathan C. Maza, Natalia Chernyak, John A. Flygare, Shane W. Krska, F. Dean Toste, Matthew B. Francis
Summary: Cysteines are commonly used as handles to synthesize antibody-drug conjugates, and tyrosinase can be used to attach phenolic cargo to cysteines engineered on antibody surfaces. This method provides more stable linkages and can be used for constructing antibody conjugates with cytotoxic payloads and attaching various cargos.
BIOCONJUGATE CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Dung L. Golden, Chaofeng Zhang, Si-Jie Chen, Aristidis Vasilopoulos, Ilia A. Guzei, Shannon S. Stahl
Summary: Copper-catalyzed radical-relay reactions offer a versatile strategy for selective C-H functionalization; however, excessive C-H substrates are often needed when using peroxide-based oxidants. In this study, a photochemical approach using a Cu/2,2'-biquinoline catalyst was developed to overcome this limitation and achieve benzylic C-H esterification with limited C-H substrate. Mechanistic studies revealed that blue-light irradiation promotes carboxylate-to-copper charge transfer, leading to the activation of peroxide and generation of alkoxyl radical hydrogen-atom-transfer species. This photochemical redox buffering provides a unique strategy to sustain Cu catalyst activity in radical-relay reactions.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Soham Maity, Marco A. Lopez, Desiree M. Bates, Shishi Lin, Shane W. Krska, Shannon S. Stahl
Summary: New synthetic methods utilizing polar reactions have been developed to selectively chlorinate heterobenzylic C-H bonds in alkyl-substituted pyridines and other heterocycles.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Sung-Eun Suh, Leah E. Nkulu, Shishi Lin, Shane W. Krska, Shannon S. Stahl
Summary: This study presents a straightforward C(sp(3))-H isocyanation method for the efficient synthesis of pharmaceutically relevant benzylic ureas, demonstrating high site selectivity and functional group tolerance. The approach utilizes commercially available catalyst components and reagents, allowing for the direct use of isocyanate products in subsequent coupling steps to generate diverse ureas, thus serving as a template for drug discovery through C-H functionalization/cross-coupling.
