Article
Chemistry, Multidisciplinary
Amit Kumar Simlandy, Turki M. Alturaifi, Johny M. Nguyen, Lucas J. Oxtoby, Quynh Nguyen Wong, Jason S. Chen, Peng Liu, Keary M. Engle
Summary: We report a transient directing group (TDG) strategy for site-selective palladium-catalyzed reductive Heck-type hydroalkenylation and hydroalkynylation of alkenylaldehydes using alkenyl and alkynyl bromides. This strategy allows for the construction of a stereocenter at the delta-position with respect to the aldehyde. Computational studies reveal the beneficial roles of rigid TDGs, such as L-tert-leucine, in promoting TDG binding and inducing high levels of enantioselectivity in alkene insertion.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Joseph A. Kaplan, Adena Issaian, Martin Stang, David Gorial, Suzanne A. Blum
Summary: A metal-free regio- and stereocontrolled group-transfer route to synthesize trisubstituted alkenes is described, where electrophilic heterocyclization followed by ring-opening group transfer is employed. The mechanistic pathway likely involves zwitterionic intermediates rather than haloborated ones, leading to predictable regio- and stereochemistry in the final acyclic alkene product with up to four modifiable substituents. Downstream functionalization reactions demonstrate the versatility of the resulting alkenes with predictable regio- and stereochemistry.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Multidisciplinary
Zhonglin Liu, Lucas J. Oxtoby, Juntao Sun, Zi-Qi Li, Nana Kim, Geraint H. M. Davies, Keary M. Engle
Summary: The site-selective palladium-catalyzed three-component coupling of unactivated alkenyl carbonyl compounds, aryl- or alkenylboronic acids, and N-fluorobenzenesulfonimide is described in this study. Regioselectivity is enhanced by tuning the steric environment on the bidentate directing auxiliary, facilitating challenging C(sp(3))-F reductive elimination from a Pd-IV intermediate to afford 1,2-carbofluorination products in moderate to good yields.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Organic
Ge Zhang, Meng-Yao Li, Wen-Bo Ye, Zhi-Tao He, Chen-Guo Feng, Guo-Qiang Lin
Summary: A new palladium-catalyzed alkyl C-H borylation with bromide as a traceless directing group has been described, allowing for the convenient access to alkyl boronates bearing a beta-allcarbon quaternary stereocenter. The protocol demonstrates broad substrate scope, excellent site selectivity, and good functional group tolerance.
Article
Chemistry, Organic
Shuai Mao, Bo Yuan, Xinyu Wang, Yahao Zhao, Lu Wang, Xue-Yan Yang, Yi-Ming Chen, San-Qi Zhang, Pengfei Li
Summary: This study presents a regioselective ortho,ortho'-diborylation of aromatic triazenes catalyzed by [Ir(OMe)(cod)](2) in near-quantitative yields without an additional ligand. The synthesized products can undergo a variety of transformations, providing a short entry to densely functionalized arenes.
Article
Chemistry, Organic
Kang Liu, Shengnan Jin, Qiuling Song
Summary: An efficient method for synthesizing tetrasubstituted alkenylboronates is presented, involving a cascade borylation/B-N elimination of propargyl amines and B(2)pin(2). A series of tetrasubstituted alkenylboronates were easily obtained with high yields using this strategy. Furthermore, various derivatizations of the tetrasubstituted alkenylboronates were also successfully achieved.
ORGANIC CHEMISTRY FRONTIERS
(2023)
Article
Chemistry, Multidisciplinary
Supriya Rej, Naoto Chatani
Summary: Organoboron reagents play a crucial role in synthetic organic chemistry, and current selective borylation strategies rely heavily on transition-metal catalysts. However, this study introduces a transition-metal-free approach for selective C-H borylation of electron-deficient benzaldehyde derivatives, demonstrating effectiveness even in the presence of external impurities.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Multidisciplinary
Yifan Wang, Yuanyuan Ping, Wangqing Kong
Summary: A cooperative Pd/Cu-catalyzed three-component cross-coupling reaction of alkynes, B 2 Pin 2 and alkenetethered aryl halides is reported. This reaction proceeds under mild conditions and shows broad substrate scope, providing a variety of heterocycles containing tetrasubstituted alkenylboronate moieties in synthetically useful yields with excellent chemoselectivity and regioselectivity. An enantioselective cascade cyclization/cross-coupling process has also been developed for the synthesis of enantiomerically enriched oxindole bearing a tetrasubstituted alkenylboronate moiety.
CHINESE CHEMICAL LETTERS
(2023)
Article
Chemistry, Organic
Cancan Feng, Luqing Tang, Fan Yang, Yangjie Wu
Summary: In this study, we reported a copper-catalyzed carbonyl-assisted hydroboration of terminal aliphatic alkenes with Markovnikov regioselectivity, using readily available and stable B(2)Pin(2) as the boron source. The reaction showed smooth progress with exclusive Markovnikov regioselectivity, providing easy access to a range of branched secondary alkyl boronic esters in moderate to excellent yields. The solvent was demonstrated to be the source of hydrogen, as confirmed by the deuterium experiments.
ORGANIC CHEMISTRY FRONTIERS
(2023)
Article
Chemistry, Physical
Helen A. Clement, Mohamad Estaitie, You-Ri Kim, Dennis G. Hall, Claude Y. Legault
Summary: The study provides insights into the mechanism of a palladium-catalyzed enantioselective borylative migration reaction, revealing a Miyaura-type borylation followed by an alkene isomerization pathway involving an electrophilic cationic palladium species.
Article
Chemistry, Multidisciplinary
Uttam Dutta, Gaurav Prakash, Kirti Devi, Kongkona Borah, Xinglong Zhang, Debabrata Maiti
Summary: A method for directing group-assisted para-selective C-H alkynylation using Rh catalyst has been reported. The para-selectivity was achieved with the assistance of a cyano-based directing template, and remained unaltered regardless of the steric and electronic influence of the substituents. The study provides insights into the mechanistic intricacies and shows potential applications for post-synthetic modification.
Article
Chemistry, Multidisciplinary
Uttam Dutta, Gaurav Prakash, Kirti Devi, Kongkona Borah, Xinglong Zhang, Debabrata Maiti
Summary: In this study, the first report on the rhodium-catalyzed para-selective C-H alkynylation is presented, and its mechanistic insights are obtained from experimental and computational studies. The para-selectivity is achieved with the assistance of a cyano-based directing template, which remains unchanged regardless of the steric and electronic influence of the substituents.
Article
Chemistry, Multidisciplinary
Saqib A. Iqbal, Marina Uzelac, Ismat Nawaz, Zhongxing Wang, T. Harri Jones, Kang Yuan, Clement R. P. Millet, Gary S. Nichol, Ghayoor Abbas Chotana, Michael J. Ingleson
Summary: Amide directed C-H borylation using BBr3 can generate borenium cations which can be reduced to amines. This method allows for one-pot electrophilic borylation-reduction process to synthesize ortho borylated compounds and B,N-polycyclic aromatic hydrocarbons. It is a valuable addition to the metal-free borylation toolbox.
Article
Chemistry, Organic
Jian-Shu Wang, Lingyun Yao, Jun Ying, Xiaoling Luo, Xiao-Feng Wu
Summary: A palladium-catalyzed regioselective cyclocarbonylation of N-(2-pyridyl)sulfonyl (N-SO2Py)-2-iodoanilines with allenes has been developed, achieving up to 95% yield of various 3-methylene-2,3-dihydroquinolin-4(1H)-ones. Control experiments and DFT calculations were conducted to understand the reaction details and propose a possible reaction mechanism.
ORGANIC CHEMISTRY FRONTIERS
(2021)
Article
Chemistry, Multidisciplinary
Mingyu Liu, Juntao Sun, Tugce G. Erbay, Hui-Qi Ni, Raul Martin-Montero, Peng Liu, Keary M. Engle
Summary: This paper describes a palladium(II)-catalyzed C(alkenyl)-H alkenylation reaction enabled by a transient directing group strategy. The reaction takes advantage of reversible condensation between the substrate and a transient directing group to facilitate the coordination of the metal catalyst and subsequent activation of the C(alkenyl)-H bond. The reaction produces 1,3-dienes with high regio- and E/Z-selectivity and enables the synthesis of enantioenriched atropoisomeric 2-aryl-substituted 1,3-dienes that have seldom been studied before. The reaction mechanism and stereoinduction model were elucidated by density functional theory calculations and the alkenyl palladacycles were characterized by X-ray crystallography.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
Tanner C. Jankins, William C. Bell, Yu Zhang, Zi-Yang Qin, Jason S. Chen, Milan Gembicky, Peng Liu, Keary M. Engle
Summary: In this study, a simple W(O) precatalyst W(CO)(6) was found to catalyze the isomerization and carbonylation reactions of alkenes. Through the W(O)/W(II) redox cycle and conformationally flexible directing group, selective functionalization at internal positions was achieved.
Article
Chemistry, Physical
Taeho Kang, Jose Manuel Gonzalez, Zi-Qi Li, Klement Foo, Peter T. W. Cheng, Keary M. Engle
Summary: This study presents a versatile method for accessing differentially substituted 1,3- and 1,4-diamines through nickel-catalyzed three-component 1,2-carboamination of alkenyl amines. The reaction is efficient, regioselective, and compatible with a wide range of coupling partners, all performed at room temperature.
Article
Chemistry, Physical
Yang Gao, Nana Kim, Skyler D. Mendoza, Sima Yazdani, Andre Faria Vieira, Mingyu Liu, Aaron Kendrick, Douglas B. Grotjahn, Guy Bertrand, Rodolphe Jazzar, Keary M. Engle
Summary: Cyclic(alkyl)(amino)carbene (CAAC) ligands were found to affect the regioselectivity of copper-catalyzed carboboration of terminal alkynes, favoring the formation of internal alkenylboron regiosomers through alpha-selective borylcupration. Various carbon electrophiles, including ally! alcohol derivatives and alkyl halides, can participate in the reaction. This method provides a straightforward and selective route to access challenging trisubstituted alkenylboron compounds.
Article
Chemistry, Multidisciplinary
Zhonglin Liu, Lucas J. Oxtoby, Juntao Sun, Zi-Qi Li, Nana Kim, Geraint H. M. Davies, Keary M. Engle
Summary: The site-selective palladium-catalyzed three-component coupling of unactivated alkenyl carbonyl compounds, aryl- or alkenylboronic acids, and N-fluorobenzenesulfonimide is described in this study. Regioselectivity is enhanced by tuning the steric environment on the bidentate directing auxiliary, facilitating challenging C(sp(3))-F reductive elimination from a Pd-IV intermediate to afford 1,2-carbofluorination products in moderate to good yields.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Mingyu Liu, Juntao Sun, Tao Zhang, Yi Ding, Ye-Qiang Han, Raul Martin-Montero, Yu Lan, Bing-Feng Shi, Keary M. Engle
Summary: This article describes a catalytic 1,2-oxyhalogenation method that converts non-conjugated internal alkynes into tetrasubstituted alkenes with high selectivity. The selectivity depends on the formation of a six-membered palladacycle intermediate in the oxypalladation step and the identity of the halide anion.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
Van T. Tran, Nana Kim, Camille Z. Rubel, Xiangyu Wu, Taeho Kang, Tanner C. Jankins, Zi-Qi Li, Matthew V. Joannou, Sloan Ayers, Milan Gembicky, Jake Bailey, Emily J. Sturgell, Brittany B. Sanchez, Jason S. Chen, Song Lin, Martin D. Eastgate, Steven R. Wisniewski, Keary M. Engle
Summary: A flurry of recent research has focused on utilizing nickel catalysis in organic synthesis. This report presents ten different bench-stable, 18-electron, formally zero-valent nickel-olefin complexes that serve as competent pre-catalysts in various reactions. Characterization and analysis shed light on the structure, bonding, and properties of these complexes, while their application in nickel-catalyzed reactions highlights the complementary nature of the different pre-catalysts within this toolkit.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Tao Zhang, Kangbao Zhong, Zhi-Keng Lin, Linbin Niu, Zi-Qi Li, Ruopeng Bai, Keary M. Engle, Yu Lan
Summary: In this study, computational evidence is presented to support the role of Zn coordination in accelerating reductive elimination from Ni(II) centers in Ni-catalyzed cross-couplings. The Zn-assisted pathway was found to have lower energy compared with direct reductive elimination from a Sigma-coordinated Ni(II) intermediate. Theoretical calculations reveal a significant Z-type Ni-Zn interaction that enhances reductive elimination.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Amit Kumar Simlandy, Turki M. Alturaifi, Johny M. Nguyen, Lucas J. Oxtoby, Quynh Nguyen Wong, Jason S. Chen, Peng Liu, Keary M. Engle
Summary: We report a transient directing group (TDG) strategy for site-selective palladium-catalyzed reductive Heck-type hydroalkenylation and hydroalkynylation of alkenylaldehydes using alkenyl and alkynyl bromides. This strategy allows for the construction of a stereocenter at the delta-position with respect to the aldehyde. Computational studies reveal the beneficial roles of rigid TDGs, such as L-tert-leucine, in promoting TDG binding and inducing high levels of enantioselectivity in alkene insertion.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Carla Calvo-Tusell, Zhen Liu, Kai Chen, Frances H. Arnold, Marc Garcia-Borras
Summary: We successfully engineered P411 enzymes for enantiodivergent enzymatic carbene N-H insertions through computational modeling and molecular simulations. By introducing a new H-bond anchoring point, we could control the accessible conformations of the lactone-carbene intermediate and direct the reactive carbene for an enantioselective N-nucleophilic attack. With site-saturation mutagenesis and screening, we reversed the stereoselectivity of previously engineered S-selective P411 enzymes. The resulting variant, L5_FL-B3, displayed broad substrate scope, high yields (>99%), high efficiency (up to 12,300 TTN), and good enantiocontrol (up to 7:93 er).
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Hui-Qi Ni, Malkanthi K. Karunananda, Tian Zeng, Shenghua Yang, Zhen Liu, K. N. Houk, Peng Liu, Keary M. Engle
Summary: Multistep organic synthesis allows the conversion of simple chemical feedstocks into more complex products with specific functions. This study introduces a novel approach to organic reactions that can generate multiple valuable products with different carbon skeletons in a single operation. Through a palladium-catalyzed reaction, a single alkene starting material can be converted into two structurally distinct products, demonstrating the potential for simultaneous access to diverse compounds. The findings of this study provide insights into the mechanistic details of this unique catalytic system and establish a new method for small-molecule library synthesis.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
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)
Review
Chemistry, Organic
Taeho Kang, Omar Apolinar, Keary M. Engle
Summary: In this Review, the various strategies, mechanisms, and catalysts that have been applied to achieve enantioinduction in alkene 1,2-DCF are discussed.
SYNTHESIS-STUTTGART
(2023)
Article
Chemistry, Organic
Yilin Cao, Zi-Qi Li, Keary M. Engle
Summary: A nickel-catalyzed heterocycle-directed 1,2-diarylation of alkenes with aryl iodide electrophiles and arylboronic acid neopentyl ester nucleophiles is reported, resulting in a series of 1,2,4-tri(hetero)aryl products under mild conditions. The transformation is enabled by a collection of azaheterocycle directing groups, giving moderate to excellent yields. The preparative utility of the method is demonstrated by a large-scale reaction.
TETRAHEDRON LETTERS
(2023)
Article
Chemistry, Multidisciplinary
Yeongyu Hwang, Steven R. Wisniewski, Keary M. Engle
Summary: This study presents a ligand design approach for nickel-catalyzed three-component carboamidation, which is applicable to the synthesis of alkenyl amine derivatives. With this method, diverse nitrogen functionalities can be installed onto unactivated alkenes, leading to differentially substituted diamines.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
