Article
Chemistry, Multidisciplinary
Mo Chen, Austin M. Ventura, Soumik Das, Ammar F. Ibrahim, Paul M. Zimmerman, John Montgomery
Summary: Current methodologies for metal-catalyzed cross-couplings require the installation of reactive functional groups on both reaction partners in advance. In contrast, C-H functionalization approaches show potential in simplifying the substrates required; however, challenges such as low reactivity and similar reactivity of different C-H bonds add complexity. This study describes an oxidative cross dehydrogenative coupling of α-amino C(sp(3))-H bonds and aldehydes to produce ketone derivatives using an unusual reaction medium that simultaneously utilizes di-tert-butyl peroxide as an oxidant and zinc metal as a reductant. The method has a broad substrate scope and offers an attractive approach for accessing α-amino ketones through the formal acylation of C-H bonds adjacent to nitrogen in N-heterocycles. Experimental investigation and computational modeling provide evidence for a mechanistic pathway involving cross-selective nickel-mediated cross-coupling of α-amino radicals and acyl radicals.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Organic
Pete Delgado, Raoul J. Glass, Gina Geraci, Rohit Duvadie, Dyuti Majumdar, Richard Robinson, Imran Elmaarouf, Malte Mikus, Kian L. Tan
Summary: Facilitating photoredox coupling reactions in process-friendly green solvents was achieved by the successful application of a dual Ir/Ni catalyst system with enhanced solubility properties. This presentation highlights the benefits of altering the solubility properties of the ligands used in the Ir/Ni dual catalyst.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
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, 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, Physical
Shaofang Zhou, Kang Lv, Rui Fu, Changlei Zhu, Xiaoguang Bao
Summary: The study demonstrates the successful construction of aliphatic C-N bonds via nickel/photoredox dual catalysis, utilizing single electron transfer and photocatalyst-induced mechanisms. Synergistic experimental and computational studies propose a reaction pathway involving oxidative quenching of the photocatalyst and a potential Ni-catalyzed cycle for C(sp(3))-N bond formation.
Article
Chemistry, Organic
Qi-Chao Gan, Zi-Qi Song, Chen-Ho Tung, Li-Zhu Wu
Summary: This paper reports the first example of C(sp)-H/Si-H cross-coupling by photocatalysis. A series of alkynylsilanes are prepared in good to excellent yields using cheap and readily available starting materials and visible-light irradiation of CuCl and alkynes with silane. The potential of this transformation in practical organic synthesis of alkynylsilane intermediates is shown through large scale reactions with flow chemistry and late-stage functionalization of natural products.
Article
Chemistry, Multidisciplinary
Dawson J. Konowalchuk, Dennis G. Hall
Summary: In this study, a divergent synthetic strategy was developed to transform an optically enriched scaffold into a variety of derivatives with different substitution patterns through desymmetrization and cross-coupling reactions. This method exhibits high yields and enantioselectivity, and can be applied to the synthesis of valuable tetra-C-substituted cyclobutane products.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Applied
Lilian Geniller, Marc Taillefer, Florian Jaroschik, Alexis Prieto
Summary: The Ni-photoredox catalyzed desulfurative cross-coupling reaction enables the synthesis of various unsymmetrical diarylmethane molecules under mild reaction conditions, providing new transformations of abundant, naturally occurring thiols.
ADVANCED SYNTHESIS & CATALYSIS
(2022)
Article
Chemistry, Organic
Qi Zhu, En Zhao, Yajing Shen, Zupeng Chen, Weiwei Fang
Summary: An easy to prepare nickel-coordinated mesoporous graphitic carbon nitride (Ni-mpg-CN) was used as a heterogeneous photocatalyst to efficiently catalyze the photocatalytic C-N cross-coupling of (hetero)aryl bromides and aliphatic amines, yielding the desired monoaminated products in good yields. Furthermore, the synthesis of the pharmaceutical tetracaine was successfully achieved, highlighting its practical applicability.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Chemistry, Organic
James T. Brewster II, Samuel D. Randall, John Kowalski, Cole Cruz, Richard Shoemaker, Eugene Tarlton, Ronald J. Hinklin
Summary: Photoredox-transition metal dual catalysis is an important platform for constructing sp3-rich chemical matter, which is significant for medicinal chemistry programs. By cross-coupling commercially available or easily prepared compounds, novel saturated heterocyclic scaffolds can be obtained, providing opportunities for diversification.
Article
Chemistry, Multidisciplinary
Michael Traxler, Sebastian Gisbertz, Pradip Pachfule, Johannes Schmidt, Jerome Roeser, Susanne Reischauer, Jabor Rabeah, Bartholomaus Pieber, Arne Thomas
Summary: Covalent organic frameworks (COFs) are porous and crystalline polymers constructed through the covalent attachment of small organic building blocks. This study reports the synthesis of a new family of COFs using an acridine linker and benzene-1,3,5-tricarbaldehyde derivatives, and their application as photocatalysts in metallaphotocatalytic C-N cross-coupling reactions, exhibiting high activity and good yields.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Organic
Megan Amy Bryden, Marco Villa, Andrea Fermi, Paola Ceroni, Eli Zysman-Colman
Summary: In this study, the performance of a newly developed photocatalyst, pDTCz-DPmS, was evaluated in a previously documented reaction. The results showed that the catalyst significantly increased the product yield, particularly in the presence of Hantzsch ester (HE). UV-Vis absorption and quenching studies revealed the photosensitization mechanisms of the catalyst.
ASIAN JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Organic
Jack L. Sloane, Anna Beatriz Santos, Eric M. Simmons, Trevor C. Sherwood
Summary: A decarboxylative C(sp(2))-C(sp(3)) cross-coupling reaction using dual nickel/photoredox catalysis enables the synthesis of complex morpholines and other saturated heterocycles, providing access to drug discovery scaffolds. This methodology allows coupling of various (hetero)aryl halides and alpha-heteroatom acids to afford C(sp(2))-C(sp(3)) coupled products in modest to excellent yields, allowing for further derivatization to multivector architectures.
Review
Chemistry, Multidisciplinary
Stavros K. Kariofillis, Abigail G. Doyle
Summary: In recent years, the development of light-driven reactions has made significant advancements in synthetic organic chemistry, particularly in combining photoredox and nickel catalysis for challenging cross-coupling reactions. The question of whether photo-induced activation of the nickel catalyst itself could lead to new approaches to cross-coupling has been explored. By utilizing a visible-light-driven mechanism for chlorine radical formation and conducting mechanistic investigations on organometallic Ni complexes relevant to cross-coupling, the study aims to facilitate new catalyst design and develop novel synthetic methods.
ACCOUNTS OF CHEMICAL RESEARCH
(2021)
Article
Chemistry, Multidisciplinary
Ayan Jati, Suranjana Dam, Shekhar Kumar, Kundan Kumar, Biplab Maji
Summary: Researchers synthesized a pyrene-based two-dimensional C=C linked pi-conjugated COF with Ni(ii)-centers through bipyridine moieties. This COF catalyst exhibited significantly higher efficiencies in diverse photocatalytic C-X cross-coupling reactions compared to homogeneous controls, due to enhanced energy and electron transfer.
Article
Chemistry, Multidisciplinary
Irini Abdiaj, Alberto Fontana, M. Victoria Gomez, Antonio de la Hoz, Jesus Alcazar
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2018)
Article
Chemistry, Applied
Cecilia Bottecchia, Raul Martin, Irini Abdiaj, Ettore Crovini, Jesus Alcazar, Jesus Orduna, Maria Jesus Blesa, Jose R. Carrillo, Pilar Prieto, Timothy Noel
ADVANCED SYNTHESIS & CATALYSIS
(2019)
Article
Chemistry, Organic
Irini Abdiaj, Clemens R. Horn, Jesus Alcazar
JOURNAL OF ORGANIC CHEMISTRY
(2019)
Article
Chemistry, Multidisciplinary
Xiao-Jing Wei, Irini Abdiaj, Carlo Sambiagio, Chenfei Li, Eli Zysman-Colman, Jesus Alcazar, Timothy Noel
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2019)
Article
Chemistry, Organic
Edgar Peris, Raul Porcar, Maria Macia, Jesus Alcazar, Eduardo Garcia-Verdugo, Santiago Luis
BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY
(2020)
Article
Chemistry, Medicinal
Enol Lopez, Maria Lourdes Linares, Jesus Alcazar
FUTURE MEDICINAL CHEMISTRY
(2020)
Article
Chemistry, Applied
Enol Lopez, Carlo van Melis, Raul Martin, Alessia Petti, Antonio de la Hoz, Angel Diaz-Ortiz, Adrian P. Dobbs, Kevin Lam, Jesus Alcazar
Summary: This two-step methodology involves the generation of aminal derivatives through anodic oxidation of carboxylic acids, followed by rapid alkylation of iminium ions under flow conditions using organozinc reagents in the presence of BF3 center dot OEt2. It successfully assembles secondary, tertiary, and quaternary carbon centers and can enhance C(sp(3))-functionalities within a molecular framework, making it relevant to drug discovery.
ADVANCED SYNTHESIS & CATALYSIS
(2021)
Article
Multidisciplinary Sciences
Wei Liu, Marissa N. Lavagnino, Colin A. Gould, Jesus Alcazar, David W. C. MacMillan
Summary: The S(H)2 mechanism has been utilized in the synthetic formation of organic molecules to create quaternary sp(3)-carbon centers. The mechanism involves distinguishing between primary and tertiary carbons to form S(H)2 bonds and generating radical classes simultaneously from abundant functional groups using photocatalysis.
Article
Chemistry, Physical
Brenda Pijper, Irini Abdiaj, Daniele Leonori, Jesus Alcazar
Summary: Increasing Fsp(3) in drug molecules is essential in the pharmaceutical industry. This study combines continuous flow chemistry with photochemistry to develop an automated platform for library synthesis using halogen atom transfer reaction. It provides a diverse method to introduce C(sp(3)) into drug molecules and improves productivity and scalability in drug discovery.
Article
Chemistry, Medicinal
Irini Abdiaj, Santiago Canellas, Alejandro Dieguez, Maria Lourdes Linares, Brenda Pijper, Alberto Fontana, Raquel Rodriguez, Andres Trabanco, Eduardo Palao, Jesus Alcazar
Summary: In this study, an end-to-end process for increasing Fsp3 in bioactive molecules was reported, involving synthesis, work-up, purification, and post-purification with minimal human intervention using Negishi coupling. The protocol offers advantages such as automated sequential generation of organozinc reagents from alkyl halides, allowing a diverse range of alkyl groups to be functionalized via Pd-catalyzed Negishi coupling in continuous flow. Additionally, a fully automated liquid-liquid extraction was developed for unattended operations, and mass-triggered preparative HPLC facilitated efficient production of compounds with enriched sp3 character and better drug-like properties.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Christine F. Gelin, Brice Stenne, Heather Coate, Afton Hiscox, Akinola Soyode-Johnson, Jessica L. Wall, Brian Lord, Jeffrey Schoellerman, Kevin J. Coe, Kai Wang, Jesus Alcazar, Christa C. Chrovian, Curt A. Dvorak, Nicholas I. Carruthers, Tatiana Koudriakova, Bartosz Balana, Michael A. Letavic
Summary: Here, a series of substituted 1H-((1,2,3-triazol-4-yl)methoxy)pyrimidines are described as potent GluN2B negative allosteric modulators. Exploration of various heterocycles led to the identification of O-linked pyrimidine analogues with balanced potency and desirable ADME profiles. Compound 31, identified through comprehensive investigation of pyrimidine substitution, demonstrated high GluN2B receptor affinity, improved solubility, and a clean cardiovascular profile.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Organic
Brenda Pijper, Raul Martin, Alberto J. Huertas-Alonso, Maria Lourdes Linares, Enol Lopez, Josep Llaveria, Angel Diaz-Ortiz, Darren J. Dixon, Antonio de la Hoz, Jesus Alcazar
Summary: Here, a new method is presented for the formation of C(sp(3))-C(sp(3)) bonds via the reductive coupling of abundant tertiary amides with organozinc reagents prepared in situ. A multistep fully automated flow protocol enables library synthesis and gram-scale target molecule synthesis starting from bench-stable reagents. The reaction also demonstrates excellent chemoselectivity and functional group tolerance, making it ideal for late-stage diversification of drug-like molecules.
Article
Chemistry, Physical
Brenda Pijper, Jesus Alcazar, Gabriela Oksdath-Mansilla, Fabricio Roman Bisogno
Summary: The article discusses the current state of continuous-flow photochemistry in drug discovery and its future integration with closed-loop artificial intelligence and machine learning approaches.
Article
Chemistry, Physical
Gabriela Oksdath-Mansilla, Fabricio Roman Bisogno, Brenda Pijper, Jesus Alcazar
Summary: This article discusses the importance of utilizing continuous-flow photochemistry as a tool in drug-discovery programs, and examines the next challenges in the field.
Article
Chemistry, Multidisciplinary
Eduardo Palao, Enol Lopez, Ivan Torres-Moya, Antonio de la Hoz, Angel Diaz-Ortiz, Jesus Alcazar
CHEMICAL COMMUNICATIONS
(2020)
