Article
Chemistry, Multidisciplinary
Felipe Verdugo, Ricardo Rodino, Martin Calvelo, Jose Luis Mascarenas, Fernando Lopez
Summary: The reactivity of carbonyl-tethered alkylidenecyclopropanes (ACPs) can be directed towards tandem cycloisomerization/cross-coupling processes by using Pd-0 catalysts with phosphorus-based monodentate ligands. This allows for the synthesis of a wide variety of highly functionalized cyclic alcohols and amines through the formation of key pi-allyl oxapalladacyclic intermediates which are trapped with external nucleophilic partners.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Applied
Sara Payamifar, Foad Kazemi, Babak Kaboudin
Summary: This study introduced a convenient nickel-catalyzed protocol for the Suzuki-Miyaura coupling reaction using a simple mixture of Ni(II) and unfunctionalized beta-cyclodextrin in water. The environmentally friendly and cost-efficient method allows the synthesis of biaryls from arylboronic acids and various aryl halides. The catalyst can be recycled for multiple runs with only a small decrease in catalytic activity.
APPLIED ORGANOMETALLIC CHEMISTRY
(2021)
Article
Chemistry, Organic
Wei Chen, Wanzhi Chen, Miaochang Liu, Huayue Wu
Summary: The palladium-catalyzed Suzuki-Miyaura cross-couplings of nitroarenes and heteroarylboronate esters has been developed, leading to the synthesis of various heterobiaryl compounds. The practicality of this approach is demonstrated through the synthesis of druglike molecules.
Article
Chemistry, Organic
Dmitry A. A. Dulov, Tatiana V. V. Magdesieva
Summary: It has been demonstrated that inexpensive and readily available N,N'-diaryldihydrophenazines can effectively replace Ir(III)- and Ru(II)-based photocatalysts in the dual photoredox/Ni(II)C-N coupling of aryl halides with a wide range of anilines, as shown by 32 examples. This efficient and operationally simple approach to diarylamines can be scaled up using a flow apparatus.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Organic
Baojian Xiong, Jinyu Zhang, Ting Wang, Xuemei Zhang, Gui-juan Cheng, Zhong Lian
Summary: In this study, a palladium-catalyzed multicomponent cross-electrophile coupling utilizing sulfur dioxide without metal-reductant was developed. Both aryl-alkyl and alkyl-alkyl sulfones were successfully synthesized. The protocol demonstrated mild reaction conditions, broad substrate scope, good functional group tolerance, and excellent regioselectivity. Preliminary mechanistic studies indicated the involvement of two Pd catalytic cycles, and SO2 exclusively coupled with aryl iodides rather than allylic acetates, which were consistent with DFT studies.
ORGANIC CHEMISTRY FRONTIERS
(2023)
Article
Chemistry, Multidisciplinary
Hui Wang, Wangyujing Han, Adam Noble, Varinder K. Aggarwal
Summary: This study reports a nickel/photoredox-catalyzed site-selective mono-deboronative arylation of 1,2-bis-boronic esters, which allows for selective coupling of the more sterically hindered secondary/tertiary positions. This is achieved by utilizing a 1,2-boron shift of primary β-boryl radicals to the thermodynamically favored secondary/tertiary radicals for arylation. The mild conditions of this method are suitable for a wide range of aryl halides, resulting in good yields and high regioselectivity. Additionally, this method allows for stereodivergent coupling of cyclic cis-1,2-bis-boronic esters to give trans-substituted products.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Organic
Kento Asai, Masahiro Miura, Koji Hirano
Summary: A palladium-catalyzed cross-coupling reaction between diarylmethanol derivatives and diborylmethane has been developed, delivering the corresponding homobenzylic boronates in good yields.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Guangwu Sun, Herui Liu, Xiu Wang, Wenbo Zhang, Wenjun Miao, Qinyu Luo, Bing Gao, Jinbo Hu
Summary: In this manuscript, a novel palladium-catalyzed coupling reaction between gem-difluoroalkenes and aryl boronic acids is reported, which yields bioactive indane-type ketones with an all-carbon alpha-quaternary center. The mechanism involves a water-induced defluorination and cross-coupling cascade pathway, supported by characterization and stoichiometric reactions of the key intermediates RCF2PdII. The use of vinyl difluoromethylene motif as an in situ carbonyl precursor is unprecedented in transition-metal-catalyzed coupling reactions, and it is expected to spark broad interest in ketone synthesis, fluoroalkene functionalization, and design of new synthetic protocols based on the unique reactivity of difluoroalkyl palladium(II) species.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Zhenzhu Hu, Yuhang Wang, Peng Ma, Xiaqian Wu, Jianhui Wang
Summary: This study reports the synthesis of a variety of 10-arylbenzo[h]quinolines through catalytic cross-coupling reactions. The optimized reaction conditions involve the use of ethyl benzo[h]quinoline-10-carboxylate and arylboronic acids.
Article
Chemistry, Multidisciplinary
Zhenzhu Hu, Yuhang Wang, Peng Ma, Xiaqian Wu, Jianhui Wang
Summary: In this study, various substituted 10-phenyl[h]quinolines were synthesized through the cross-coupling reaction of ethyl benzo[h]quinoline-10-carboxylate with arylboronic acids.
Article
Chemistry, Organic
Chenpeng Gao, Christopher A. Wilhelmsen, James P. Morken
Summary: Palladium-catalyzed conjunctive cross-coupling can be achieved using chiral phosphine-oxazoline based ligand structures. This reaction specifically works on Grignard-based boron ate complexes and does not require halide-scavenging additives used in other catalyst systems.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Organic
Chenpeng Gao, Christopher A. Wilhelmsen, James P. Morken
Summary: Palladium-catalyzed conjunctive cross-coupling can be achieved using chiral phosphine-oxazoline ligand structures. Notably, the reaction can be performed on Grignard-based boron ate complexes without the need for halide scavenging additives required by other catalyst systems.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Organic
Dejiang Zhang, Zhi Xu, Ting Tang, Liyuan Le, Cairong Wang, Nobuaki Kambe, Renhua Qiu
Summary: In this study, a general method for the synthesis of unsymmetric diarylmethanes from (hetero)aryl methylhalides and Sb-aryl stibines is described. The protocol has a broad substrate scope and good functional group tolerance. Gram-scale synthesis of drug molecules and their derivatives was efficiently achieved using this method.
Article
Chemistry, Physical
Yanhui Wang, Xiaotian Qi, Qiao Ma, Peng Liu, Gavin Chit Tsui
Summary: The diastereoselective synthesis of densely functionalized tetrasubstituted (E)-monofluoroalkenes via Pd(0)-catalyzed base-free Suzuki-Miyaura crosscouplings offers a significant method for producing pharmaceutically relevant compounds. Computational studies support the reaction design, revealing an intriguing mechanism of C-F bond activation leading to complete control of stereoselectivity. This method does not require extraneous base assistance, making it a powerful tool for stereocontrolled synthesis of monofluoroalkenes.
Article
Chemistry, Organic
Xiaoshen Ma, Charles S. Yeung
Summary: Our study focused on achieving C(sp(2))-C(sp(3)) coupling reactions using 2,2-difluorobicyclo[1.1.1]pentane (BCP-F-2) building blocks. Through comparison of reactivities between BCP and BCP-F-2 analogues, we found that the Barluenga coupling reaction showed promising results, expanding the potential applications of BCP-F-2 in organic chemistry and medicinal chemistry.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Stavros K. Kariofillis, Shutian Jiang, Andrzej M. Zuranski, Shivaani S. Gandhi, Jesus I. Martinez Alvarado, Abigail G. Doyle
Summary: In this study, a Ni/photoredox-catalyzed (deutero)methylation and alkylation of aryl halides was developed using benzaldehyde di(alkyl) acetals as alcohol-derived radical sources. Data science techniques were applied to categorize a diverse collection of aryl bromides and compare them with previous methods, leading to quantitative analysis of reactivity trends and potential functional group incompatibility.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Review
Chemistry, Multidisciplinary
Agustin Millet, Paul T. Cesana, Kassandra Sedillo, Matthew J. Bird, Gabriela S. Schlau-Cohen, Abigail G. Doyle, David W. C. MacMillan, Gregory D. Scholes
Summary: Photoredox catalysis allows for milder, cheaper, and more environmentally friendly chemical reactions. The BioLEC Energy Frontier Research Center aims to utilize bioinspired schemes to promote the application of photoredox catalysis in chemical manufacturing, reducing energy consumption and emissions. This review highlights the major advances made by the Center, emphasizing the impact of interdisciplinary collaboration on the field's progress.
ACCOUNTS OF CHEMICAL RESEARCH
(2022)
Article
Chemistry, Multidisciplinary
Stephen Ting, Wendy L. Williams, Abigail G. Doyle
Summary: This study reports the synthesis of a well-defined nickel complex that undergoes oxidative addition with aryl halides, characterized by solution-phase speciation and a redox equilibrium. This has significant implications for organometallic studies of nickel catalysis.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
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
Jose Antonio Garrido Torres, Sii Hong Lau, Pranay Anchuri, Jason M. Stevens, Abigail G. Doyle, Jose E. Tabora, Jun Li, Alina Borovika, Ryan P. Adams
Summary: We developed an open-source experimental design platform based on Bayesian optimization algorithm for multiimentation (HTE) and virtual screening data sets. The platform optimized the reaction yield and enantioselectivity in a short time period, surpassing human-driven optimization. To make it more accessible to nonexperts, a graphical user interface with features like real-time condition modification and data visualization was developed.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Samuel H. Newman-Stonebraker, Jason Y. Wang, Philip D. Jeffrey, Abigail G. Doyle
Summary: This study analyzes the structure-reactivity relationships of Buchwald-type phosphines in Ni-catalyzed cross-coupling reactions, providing guidance for further exploration of this ligand class in organonickel chemistry and the development of new Ni-catalyzed cross-coupling methodologies.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Andrzej M. Zuranski, Shivaani S. Gandhi, Abigail G. Doyle
Summary: The application of machine learning techniques to high-throughput experimentation datasets has been increasingly popular. However, modeling the interaction effects between reaction components using machine learning algorithms is still a challenge. To address this, we propose a two-part statistical modeling approach that combines classical analysis of variance and regression analysis using chemistry-informed features. By applying this approach to a previously published dataset, we achieve a significant improvement in performance compared to a random forest model. Additionally, this approach can facilitate the generation of new mechanistic hypotheses and deepen the understanding of chemical reactivity.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Isabelle Nathalie-Marie Leibler, Shivaani S. Gandhi, Makeda A. Tekle-Smith, Abigail G. Doyle
Summary: This Perspective article provides an overview of the progress and current limitations of nucleophilic fluorination methodologies. Despite the challenges, researchers have been actively studying and developing this transformation to gain a better understanding of its mechanism, create user-friendly fluorination reagents, and contribute to the invention of synthetic methods for radiofluorination. The article discusses studies from the Doyle group and others in the field, highlighting developments in fluoride reagent development and the mechanistic implications of reagent identity. It also outlines the inaccessible chemical space and future directions for filling the existing gaps in synthetic technologies.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Tianhua Tang, Avijit Hazra, Daniel S. Min, Wendy L. Williams, Eli Jones, Abigail G. Doyle, Matthew S. Sigman
Summary: In this study, the oxidative addition process of Ni(I) with aryl iodides was investigated using electroanalytical and statistical modeling techniques. Essential electronic and steric factors influencing the addition rate were identified through multivariate linear regression models based on over 200 experimental rate measurements. The mechanisms of oxidative addition were classified into three-center concerted or halogen-atom abstraction pathways based on the ligand type. A global heat map of predicted oxidative addition rates was created, which was shown to be applicable in understanding the reaction outcome in a Ni-catalyzed coupling reaction through a case study.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Physical
Julia E. Borowski, Samuel H. Newman-Stonebraker, Abigail G. Doyle
Summary: A comparison study of mono- and bisphosphine ligands in Ni-catalyzed Suzuki-Miyaura cross-coupling reactions revealed that monophosphines exhibit higher reactivity, particularly with electronically deactivated and sterically hindered substrates. Mechanistic experiments showed that monoligated (P1Ni) species accelerate the organometallic steps of the catalytic cycle, while bisligated (P2Ni) species prevent off-cycle reactions and catalyst poisoning by heterocyclic motifs. These findings provide guidelines for ligand selection against challenging substrates and future ligand design tailored to the mechanistic demands of Ni-catalyzed cross-coupling reactions.
Article
Chemistry, Multidisciplinary
Wendy L. Williams, Neyci E. Gutierrez-Valencia, Abigail G. Doyle
Summary: This paper reports the first branched-selective cross-coupling of 2-alkyl aziridines with aryl iodides using a Ti/Ni dual-catalytic system. The study demonstrates the tolerance towards functional groups and the effect of the steric and electronic profile on reactivity, resulting in predictive reactivity models and insights into the mechanism.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Madeline E. Ruos, R. Garrison Kinney, Oliver T. Ring, Abigail G. Doyle
Summary: We report a visible-light photoredox-catalyzed method that enables nucleophilic amination of primary and secondary benzylic C(sp(3))-H bonds. A novel amidyl radical precursor and organic photocatalyst operate in tandem to transform primary and secondary benzylic C(sp(3))-H bonds into carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar crossover. Furthermore, the resulting carbocations can be intercepted by various N-centered nucleophiles, leading to the formation of pharmaceutically relevant C(sp(3))-N bonds under unified reaction conditions.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
John H. H. Dunlap, Jeffrey G. G. Ethier, Amelia A. A. Putnam-Neeb, Sanjay Iyer, Shao-Xiong Lennon Luo, Haosheng Feng, Jose Antonio Garrido Torres, Abigail G. G. Doyle, Timothy M. M. Swager, Richard A. A. Vaia, Peter Mirau, Christopher A. A. Crouse, Luke A. A. Baldwin
Summary: We implemented a human-in-the-loop approach for multi-objective experimental design using a Bayesian optimization platform (EDBO+) to optimize the synthesis of butylpyridinium bromide under continuous flow conditions. The EDBO+ algorithm simultaneously optimized reaction yield and production rate, generating a well-defined Pareto front. We demonstrated the versatility of EDBO+ by expanding the reaction space mid-campaign. Continuous flow techniques improved control over reaction parameters, offering potential for automated synthesis and scalability. Additionally, we used the open-source module nmrglue for semi-automated NMR spectroscopy analysis and compared results obtained from manual processing methods, providing insight into the effect of data analysis on model predictions. Quaternization of poly(4-vinylpyridine) with bromobutane showcased the application of continuous flow chemistry for synthesizing functional materials.
Article
Chemistry, Multidisciplinary
Mandana Saebi, Bozhao Nan, John E. E. Herr, Jessica Wahlers, Zhichun Guo, Andrzej M. M. Zuranski, Thierry Kogej, Per-Ola Norrby, Abigail G. G. Doyle, Nitesh V. V. Chawla, Olaf Wiest
Summary: The lack of publicly available, large, and unbiased datasets poses a challenge for applying machine learning in synthetic chemistry. While data from electronic lab notebooks (ELNs) can potentially provide less biased large datasets, there is currently a lack of publicly available ELN datasets. This study presents the first real-world dataset from the ELNs of a pharmaceutical company, and explores its relationship with high-throughput experimentation datasets. The study shows that an attributed graph neural network performs well on high-throughput experimentation datasets for yield predictions, but fails to be predictive when trained on the ELN dataset. The implications of using ELN data for training ML-based models for yield predictions are discussed.
Article
Chemistry, Multidisciplinary
Andrzej M. Zuranski, Jason Y. Wang, Benjamin J. Shields, Abigail G. Doyle
Summary: Auto-QChem is an automatic, high-throughput, and end-to-end DFT calculation workflow that computes chemical descriptors for organic molecules. It is tailored towards users without extensive programming experience and has various functionalities and applications.
REACTION CHEMISTRY & ENGINEERING
(2022)
