DOCSLIB.ORG

C(Sp3)−H AMINATION REACTIONS UNDER FIRST ROW TRANSITION METAL CATALYSIS

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
C(Sp3)−H AMINATION REACTIONS UNDER FIRST ROW TRANSITION METAL CATALYSIS C(sp3)−H AMINATION REACTIONS UNDER FIRST ROW TRANSITION METAL CATALYSIS BY SHAUNA MARIE PARADINE DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate College of the University of Illinois at Urbana-Champaign, 2015 Urbana, Illinois Doctoral Committee: Professor M. Christina White, Chair Professor Scott E. Denmark Professor Wilfred A. van der Donk Professor John A. Katzenellenbogen C(sp3)—H AMINATIONS UNDER FIRST ROW TRANSITION METAL CATALYSIS Shauna M. Paradine University of Illinois at Urbana-Champaign Research Advisor: Prof. M. Christina White February 2015 ABSTRACT Nitrogen functionality is ubiquitous in biologically active molecules, from naturally occurring alkaloids and peptides to synthetic pharmaceuticals. However, due to its promiscuous reactivity, nitrogen can be challenging to incorporate into molecules and carry through synthetic sequences. Traditional methods to introduce nitrogen (e.g. Mannich, reductive amination) often rely on pre-existing functionality and require additional transformations such as oxidation state changes and/or protecting group maniuplations. C—H amination represents a powerful alternative synthetic strategy. This approach involves the direct functionalization of highly robust sp3 C—H bonds, which allows for the introduction of nitrogen functionality at late stages in synthetic sequences, both obviating the requirement for lengthy functional group manipulation strategies and enabling rapid access to a diversity of structures. Although small molecule iron and manganese catalysts were first explored for metallonitrene-mediated C—H amination reactions, the majority of synthetic advances in the field have been with noble metal dirhodium carboxylate catalysts. These catalysts are highly reactive and have collectively displayed the ability to efficiently aminate benzylic, ethereal, and aliphatic C—H bonds. However, they are poorly chemoselective in the presence of π- functionality such as olefins and alkynes, and direct addition to these π-bonds is often competitive with desired C—H amination reactivity. It is likely that rhodium’s concerted asynchronous C—H insertion mechanism, which favors functionalization at more electron-rich ii sites, is responsible for this lack of chemoselectivity. Conversely, first row transition metal catalysts like iron and manganese are thought to react through a stepwise homolytic C—H abstraction/rebound mechanism. We hypothesized that this different mechanism would lead to orthogonal reactivity under first row transition metal catalysis, including the ability to functionalize allylic C—H bonds with high chemoselectivity. In addition, iron and manganese are highly abundant and non-toxic base metals that have been relatively unexplored. The first chapter of this dissertation describes the development of the first synthetically useful C—H amination method under iron catalysis. This reaction, which employs the bulk commodity complex [FeIIIPc], confirms our initial hypothesis, displaying excellent chemoselectivity (generally >20:1 ins./azir.) for allylic C—H amination over a range of olefin classes and exhibiting site-selectivity trends that are orthogonal to those observed under rhodium catalysis. In addition, this bulky, electrophilic catalyst is able to differentiate between allylic C— H bonds in polyolefinic substrates on the basis of their electronic and steric nature. Mechanistic studies support a stepwise mechanism involving discrete electrophilic intermediates. In seeking to expand the scope of this C—H amination methodology, we were struck by a clear divergence in the literature between reactivity and selectivity. Existing catalysts for C(sp3)—H amination, including our [FeIIIPc] catalyst, are either highly reactive or highly selective, but not both. We sought to exploit the exquisite chemoselectivity of first row transition metals in order to develop a small molecule C—H amination catalyst that was truly general. The second chapter of this dissertation describes the discovery and development of [Mn(tBuPc)], a novel manganese catalyst that for the first time is able to effectively functionalize all types of sp3 C—H bonds with preparative product yields (>50%) even for very strong 2° and 1° aliphatic C— H bonds, while maintaining excellent chemoselectivity for C—H amination (>20:1) in the iii presence of readily oxidizable π-bonds. We conduct mechanistic studies to investigate the often drastic reactivity differences between [Mn(tBuPc)] and our previous [FeIIIPc], finding subtle changes in the C—H cleavage step that suggest attenuated radical behavior with manganese relative to iron. The generality of this method and versatility of the oxathiazinane C—H amination product lend it well for application to the diversification of topologically and functionally complex bioactive molecules. This is demonstrated for picrotoxinin and isosteviol derivatives, which maintain (or magnify) the reactivity and selectivity trends observed with the corresponding simple substructural units. iv ACKNOWLEDGEMENTS I am wholly indebted to my Ph.D. advisor, Prof. M. Christina White. Christina has been doing something truly special with her research program, and it’s an honor to be a part of that. She offered me exactly what I was looking for in graduate school: the opportunity to engage in exploratory and transformative research. She has challenged me and supported me throughout my time in graduate school, pushing me to be able to reach high and far. Her talent for pursuing and finding solutions for the most interesting and challenging problems in organic synthetic methodology is exquisite, and her vision, optimism, energy, and passion for the field are infectious. I expect to carry that tremendous influence with me throughout my own career. I would like to thank my thesis committee members, Prof. Wilfred van der Donk, Prof. Scott Denmark, and Prof. Thomas Rauchfuss. I’ve learned much from their broad expertise and deep knowledge of the field. Their insight, helpful suggestions and constructive criticisms have been instrumental in aiding my growth as a chemist and independent researcher. In addition, I am grateful to Prof. John Katzenellenbogen (Dr. K) for serving as a committee member for my final defense. I have an immense amount of respect for his intelligence, creativity, and the excellent example he sets as a senior member of the chemical community. These past several years I’ve had the immense pleasure of working with the best group of people out there. I’m thankful to all White group members, past and present, who have made our lab such a fulfilling and humbling environment in which to work. They have guided me, challenged me, grown with me, laughed with me, and pushed me much farther than I could have gone on my own. I’m especially grateful to Prof. Jared Delcamp and Dr. Dustin Covell, who had different research styles, but who both helped me as I began my graduate career and taught me how to be an effective chemist. The talent of my classmates, Dr. Iulia Strambeanu and Dr. Paul v Gormisky, has humbled me and I’m glad to have shared all the ups and downs of grad school with them. Dr. Jennifer Howell’s broad expertise, organization and rigor, creativity, and honesty have been invaluable to me. Over the last year, I’ve had the wonderful fortune to work directly with Jennifer Griffin, Aaron Petronico, and Jinpeng Zhao. There’s nothing more satisfying than sharing in the growth of research that I care so much about, and I’ve learned so much from their knowledge and fresh insight. They have elevated this C—H amination method to something that is truly special, and I’m excited to see what amazing things they accomplish in the coming years. Shannon Miller has set an impossibly high standard in my mind for undergraduate researchers – her incredible talent, quick mind, and strong work ethic will take her far in her future career, and it’s been a pleasure to work with her. As they say, life is a journey and not a destination, and there have been many people along the way who have collectively led me to this point in my career. I’m grateful to my teachers at the Kalamazoo Area Mathematics & Science Center (KAMSC), who awakened the scientist in me by showing me how big, fascinating, fun, challenging, messy, and thriving science is. I will always appreciate their knowledge, creativity, and all-consuming love of science. The chemistry department at Albion College was another collection of highly intelligent and zealous individuals. Prof. Vanessa McCaffrey, Prof. Cliff Harris, Prof. Craig Bieler, Prof. Amy Beilstein Bethune, Prof. David Green, Prof. Dan Steffenson, Prof. Lisa Lewis, and Prof. Chris Rohlman all contributed to deepening my conviction to pursue a career in chemistry research through their infectious passion and love for the field. And of course I am forever grateful to my undergraduate research advisor, Prof. Andrew French, who was as energetic and passionate as any. He introduced me to research as college freshman, and through my four years he went out of his way to create learning and research opportunities for me both at Albion and vi abroad. He was instrumental in laying the foundation that has made it possible for me to reach out and find success at a high level in the field. I wouldn’t be where I am today if I weren’t blessed with such a wonderful family. I come from a long line of strong women who worked hard, took risks, and challenged what society expected of them. My humble family history, from my parents to my grandparents and beyond, is one of dreaming big, overcoming obstacles and having a passion both for learning and for life. My parents, especially, have been the best role models I could ask for. They’ve lovingly supported me from the very beginning of my “scientific career” as a highly inquisitive four year old, never forcing me in any direction but always encouraging me to continually challenge myself and grow in every way. They raised my sisters and me with the earnest belief that we could accomplish anything if we were willing to work hard enough for it.
Load more

Recommended publications
  • 6 Synthesis of N-Alkyl Amino Acids Luigi Aurelio and Andrew B
    j245 6 Synthesis of N-Alkyl Amino Acids Luigi Aurelio and Andrew B. Hughes 6.1 Introduction Among the numerous reactions of nonribosomal peptide synthesis, N-methylation of amino acids is one of the common motifs. Consequently, the chemical research community interested in peptide synthesis and peptide modification has generated a sizeable body of literature focused on the synthesis of N-methyl amino acids (NMA). That literature is summarized herein. Alkyl groups substituted on to nitrogen larger than methyl are exceedingly rare among natural products. However, medicinal chemistry programs and peptide drug development projects are not limited to N-methylation. While being a much smaller body of research, there is a range of methods for the N-alkylation of amino acids and those reports are also covered in this chapter. The literature on N-alkyl, primarily N-methyl amino acids comes about due to the useful properties that the N-methyl group confers on peptides. N-Methylation increases lipophilicity, which has the effect of increasing solubility in nonaqueous solvents and improving membrane permeability. On balance this makes peptides more bioavailable and makes them better therapeutic candidates. One potential disadvantage is the methyl group removes the possibility of hydro- gen bonding and so binding events may be discouraged. It is notable though that the N-methyl group does not fundamentally alter the identity of the amino acid. Some medicinal chemists have taken advantage of this fact to deliberately discourage binding of certain peptides that can still participate in the general or partial chemistry of a peptide. A series of recent papers relating to Alzheimers disease by Doig et al.
    [Show full text]
  • A General N-Alkylation Platform Via Copper Metallaphotoredox and Silyl Radical Activation of Alkyl Halides
    ll Article A general N-alkylation platform via copper metallaphotoredox and silyl radical activation of alkyl halides Nathan W. Dow, Albert Cabre´, David W.C. MacMillan [email protected] Highlights General, room temperature N- alkylation via copper metallaphotoredox catalysis Broad reactivity across diverse alkyl bromides, N-heterocycles, and pharmaceuticals Convenient approach to N- cyclopropylation using easily handled bromocyclopropane Readily extended to functionalization of unactivated secondary alkyl chlorides Traditional substitution reactions between nitrogen nucleophiles and alkyl halides feature well-established, substrate-dependent limitations and competing reaction pathways under thermally induced conditions. Herein, we report that a metallaphotoredox approach, utilizing a halogen abstraction-radical capture (HARC) mechanism, provides a valuable alternative to conventional N-alkylation. This visible-light-induced, copper-catalyzed protocol is successful for coupling >10 classes of N-nucleophiles with diverse primary, secondary, or tertiary alkyl bromides. Moreover, this open-shell platform alleviates outstanding N-alkylation challenges regarding regioselectivity, direct cyclopropylation, and secondary alkyl chloride functionalization. Dow et al., Chem 7,1–16 July 8, 2021 ª 2021 Elsevier Inc. https://doi.org/10.1016/j.chempr.2021.05.005 Please cite this article in press as: Dow et al., A general N-alkylation platform via copper metallaphotoredox and silyl radical activation of alkyl halides, Chem (2021), https://doi.org/10.1016/j.chempr.2021.05.005
    [Show full text]
  • Rational Design of Selective Metal Catalysts for Alcohol Amination with Ammonia
    Rational design of selective metal catalysts for alcohol amination with ammonia Tao Wang,a Javier Ibañez,b,d Kang Wang,b Lin Fang,b Maarten Sabbe,c Carine Michel,a Sébastien Paul,d Marc Pera-Titus,b,* Philippe Sautet e,f,* a) Univ Lyon, ENS de Lyon, CNRS UMR 5182, Université Claude Bernard Lyon 1, Laboratoire de Chimie, F69342, Lyon, France. b) Eco-Efficient Products and Processes Laboratory (E2P2L), UMI 3464 CNRS – Solvay, 3966 Jin Du Road, Xin Zhuang Ind. Zone, 201108 Shanghai, China. c) Department of Chemical Engineering, Ghent University, Technologiepark 914, 9052, Zwijnaarde, Belgium. d) Univ. Lille, Univ. Artois, CNRS, Centrale Lille, ENSCL, UMR 8181 – UCCS – Unité de Catalyse et Chimie du Solide, Lille, F-59000, France e) Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA 90095, United States f) Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, United States Abstract: The lack of selectivity for the direct amination of alcohols with ammonia, a modern and clean route for the synthesis of primary amines, is an unsolved challenge. Here, we combine first-principles calculations, scaling relations, kinetic simulations and catalysis experiments to unveil the key factors governing the activity and selectivity of metal catalysts for this reaction. We show that the loss of selectivity towards primary amines is linked to a surface-mediated C-N bond coupling between two N-containing intermediates: CH3NH and CH2NH. The barrier for this step is low enough to compete with the main surface hydrogenation reactions and can be used as a descriptor for selectivity.
    [Show full text]
  • Catalytic Reductive N-Alkylation of Amines Using Carboxylic Acids
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Repository@Nottingham Catalytic Reductive N-Alkylation of Amines using Carboxylic Acids Keith G. Andrews, Declan M. Summers, Liam J. Donnelly and Ross M. Denton* We report a catalytic reductive alkylation reaction of primary or secondary amines with carboxylic acids. The two-phase process involves silane mediated direct amidation followed by catalytic reduction. Reductive amination between aldehydes and amines (Scheme 1A) constitutes one of the most versatile methods for carbon-nitrogen bond construction and underpins the synthesis of natural products, active pharmaceutical ingredients, agrochemicals and advanced materials.1,2 Despite its importance and prevalence there are several disadvantages associated with the conventional process, including the handling of unstable aldehydes (mostly accessed via stoichiometric oxidation) and selectivity for monoalkylated products. Replacing aldehydes with carboxylic acids, which are far easier to store and handle (Scheme 1B), would open up a powerful complementary approach to reductive N-alkylation with high synthetic utility. However, such reductive amination from the higher oxidation level remains underexplored.3,4 Scheme 1. a) Classical reductive amination reaction. b) This work: catalytic reductive alkylation using carboxylic acids. Indeed, until recently, the only reported reductive amination of higher carboxylic acids was the interesting but non-preparative system investigated by Cole-Hamilton and co-workers.3g
    [Show full text]
  • Nucleophilic Dearomatization of Activated Pyridines
    Review Nucleophilic Dearomatization of Activated Pyridines Giulio Bertuzzi *, Luca Bernardi * and Mariafrancesca Fochi * Department of Industrial Chemistry “Toso Montanari” and INSTM RU Bologna, Alma Mater Studiorum-University of Bologna, Via Risorgimento 4, 40136 Bologna, Italy * Correspondence: [email protected] (G.B.); [email protected] (L.B.); [email protected] (M.F.); Tel.: +39-051-209-3626 (M.F.) Received: 16 November 2018; Accepted: 1 December 2018; Published: 6 December 2018 Abstract: Amongst nitrogen heterocycles of different ring sizes and oxidation statuses, dihydropyridines (DHP) occupy a prominent role due to their synthetic versatility and occurrence in medicinally relevant compounds. One of the most straightforward synthetic approaches to polysubstituted DHP derivatives is provided by nucleophilic dearomatization of readily assembled pyridines. In this article, we collect and summarize nucleophilic dearomatization reactions of - pyridines reported in the literature between 2010 and mid-2018, complementing and updating previous reviews published in the early 2010s dedicated to various aspects of pyridine chemistry. Since functionalization of the pyridine nitrogen, rendering a (transient) pyridinium ion, is usually required to render the pyridine nucleus sufficiently electrophilic to suffer the attack of a nucleophile, the material is organized according to the type of N-functionalization. A variety of nucleophilic species (organometallic reagents, enolates, heteroaromatics, umpoled aldehydes) can be productively engaged in pyridine dearomatization reactions, including catalytic asymmetric implementations, providing useful and efficient synthetic platforms to (enantioenriched) DHPs. Conversely, pyridine nitrogen functionalization can also lead to pyridinium ylides. These dipolar species can undergo a variety of dipolar cycloaddition reactions with electron-poor dipolarophiles, affording polycyclic frameworks and embedding a DHP moiety in their structures.
    [Show full text]
  • Reduction of Ketoximes to Amines by Catalytic Transfer Hydrogenation Using Raney Nickel and 2-Propanol As Hydrogen Donor
    University of Tennessee at Chattanooga UTC Scholar Student Research, Creative Works, and Honors Theses Publications 5-2014 Reduction of ketoximes to amines by catalytic transfer hydrogenation using Raney Nickel and 2-propanol as hydrogen donor Katherynne E. Taylor University of Tennessee at Chattanooga Follow this and additional works at: https://scholar.utc.edu/honors-theses Part of the Catalysis and Reaction Engineering Commons, and the Chemistry Commons Recommended Citation Taylor, Katherynne E., "Reduction of ketoximes to amines by catalytic transfer hydrogenation using Raney Nickel and 2-propanol as hydrogen donor" (2014). Honors Theses. This Theses is brought to you for free and open access by the Student Research, Creative Works, and Publications at UTC Scholar. It has been accepted for inclusion in Honors Theses by an authorized administrator of UTC Scholar. For more information, please contact [email protected]. Reduction of Ketoximes to Amines by Catalytic Transfer Hydrogenation Using Raney Nickel® and 2-Propanol! as Hydrogen Donor ! ! By Katherynne E. Taylor ! Departmental Thesis The University of Tennessee at Chattanooga Department of! Chemistry Project Director: Dr. Robert Mebane Examination Date: March 20, 2014 Committee Members: Dr. Jisook Kim Dr. John Lee Dr. Robert Mebane Dr. Abdul! Ofoli ! _________________________________________________________ Project Director _________________________________________________________ Department Examiner _________________________________________________________ Department Examiner _________________________________________________________
    [Show full text]
  • Palladium-Catalyzed Aerobic Oxidative Hydroamination Of
    Letter pubs.acs.org/OrgLett Palladium-Catalyzed Aerobic Oxidative Hydroamination of Vinylarenes Using Anilines: A Wacker-Type Amination Pathway Eunsun Song, Hun Young Kim, and Kyungsoo Oh* Center for Metareceptome Research, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak, Seoul 06974, Republic of Korea *S Supporting Information ABSTRACT: A palladium-catalyzed intermolecular hydroamination of vinylarene derivatives using anilines has been developed for the first time under aerobic conditions, where the regioselective formation of N- arylketimines is accomplished. The current aerobic oxidative hydro- amination pathway of anilines is distinct from that of palladium- catalyzed hydroamination reactions that proceed to give sec-arylethyl- amine and arylethylamine derivatives, identifying a longstanding missing reaction pathway, Wacker-type amination, to N-arylketimines using anilines. The ready availability of both starting materials, vinylarenes and anilines, offers an attractive and facile synthetic route to N-arylketimines in good to excellent yields. mine derivatives continue to be a major source of presence of an acid cocatalyst (Scheme 1, path A).3 In contrast, A innovation in the chemical sciences as they serve as the base-catalyzed Markovnikov hydroaminations of anilines to basic scaffolds for the preparation of fine chemicals, vinylarenes were observed by the groups of Hultzsch4 and pharmaceuticals, and natural products. One of the most direct Doye,5 demonstrating the possibility of complementary synthetic methods to amine derivatives is the intermolecular regiodivergent hydroamination of anilines (Scheme 1, path addition of amines to unsaturated C−C multiple bonds, also B). Nevertheless, the catalytic hydroamination of styrenes with known as hydroamination.1 However, the development of anilines via oxidative addition remains an unsolved problem.
    [Show full text]
  • Reductive Amination of (Alpha) - Amino Acids: Solution - Phase Synthesis Rohini D'souza
    Rochester Institute of Technology RIT Scholar Works Theses Thesis/Dissertation Collections 7-1-2001 Reductive amination of (alpha) - amino acids: Solution - Phase synthesis Rohini D'Souza Follow this and additional works at: http://scholarworks.rit.edu/theses Recommended Citation D'Souza, Rohini, "Reductive amination of (alpha) - amino acids: Solution - Phase synthesis" (2001). Thesis. Rochester Institute of Technology. Accessed from This Thesis is brought to you for free and open access by the Thesis/Dissertation Collections at RIT Scholar Works. It has been accepted for inclusion in Theses by an authorized administrator of RIT Scholar Works. For more information, please contact [email protected]. REDUCTIVE AMINATION OF ex - AMINO ACIDS: SOLUfION - PHASE SYNTHESIS Rohini D'Souza July 2001 A thesis submitted in partial fulfillment of the requirements for the degree of Masters of Science in Chemistry Approved: Kay Tumer Thesis Advisor Terence Morrill Department Head Department of Chemistry Rochester Institute of Technology Rochester, NY 14623-5603 COPYRIGHT RELEASE FORM Reductive Amination of a. - Amino Acids: Solution-Phase Synthesis I, Rohini D'Souza, hereby grant permission to Wallace Memorial Library of the Rochester Institute of Technology, to reproduce my thesis in whole or in part. Any reproduction will not be for commercial use or profit. Date: 07 ·;(5, 2-001 Signature: _ vii TABLE OF CONTENTS LIST OF TABLES Hi LIST OF FIGURES iv LIST OF SCHEMES v LIST OF APPENDICES vi COPYRIGHT RELEASE FORM vii DEDICATION viii ACKNOWLEDGEMENTS
    [Show full text]
  • Nickel-Catalyzed Regio- and Diastereoselective Arylamination of Unactivated Alkenes
    Nickel-Catalyzed Regio- and Diastereoselective Arylamination of Unactivated Alkenes Chao Wang ( [email protected] ) Tianjin Normal University https://orcid.org/0000-0001-6979-8506 Shenghao Wang Tianjin Normal University Lanlan Zhang Tianjin Normal University https://orcid.org/0000-0002-6218-7865 Leipeng Xie Tianjin Normal University Lei Zhao Tianjin Normal University Chun Luo Tianjin Normal University Linping Mu Tianjin Normal University Xiuguang Wang Tianjin Normal University Article Keywords: arylamination, unactivated alkenes Posted Date: March 25th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-346280/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/16 Abstract An intermolecular syn-1,2-arylamination of unactivated alkenes with arylboronic acids and O- benzoylhydroxylamine electrophiles has been developed with Ni(II) catalyst. The cleavable bidentate picolinamide directing group facilitated formation of stabilized 4-, 5- or 6-membered nickelacycles and enabled the difunctionalization of diverse alkenyl amines with high levels of regio-, chemo- and diastereocontrol. This general and practical protocol was compatible with broad substrate scope and high functional group tolerance. The utility of this method was further demonstrated by the site-selective late-stage modication of pharmaceutical agents. Introduction C–C and C–N bonds are two of the most omnipresent bonds in nature, and arylamination of olens represents a powerful and attractive synthetic tool for
    [Show full text]
  • Catalytic Amino Acid Production from Biomass-Derived Intermediates
    Catalytic amino acid production from biomass-derived intermediates Weiping Denga,b,1, Yunzhu Wanga,1, Sui Zhanga, Krishna M. Guptaa, Max J. Hülseya, Hiroyuki Asakurac,d, Lingmei Liue, Yu Hane, Eric M. Karpf, Gregg T. Beckhamf, Paul J. Dysong, Jianwen Jianga, Tsunehiro Tanakac,d, Ye Wangb, and Ning Yana,2 aDepartment of Chemical and Biomolecular Engineering, National University of Singapore, 117585 Singapore; bState Key Laboratory for Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, 361005 Xiamen, China; cDepartment of Molecular Engineering, Graduate School of Engineering, Kyoto University, 615-8510 Kyoto, Japan; dElements Strategy Initiative for Catalysts & Batteries, Kyoto University, 615-8245 Kyoto, Japan; eAdvanced Membranes and Porous Materials Center, Physical Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Saudi Arabia; fNational Bioenergy Center, National Renewable Energy Laboratory, Golden, CO 80401; and gInstitut des Sciences et Ingénierie Chimiques, École Polytechnique Fédérale de Lausanne (EPFL), CH 1015 Lausanne, Switzerland Edited by Alexis T. Bell, University of California, Berkeley, CA, and approved April 10, 2018 (received for review January 6, 2018) Amino acids are the building blocks for protein biosynthesis and find cellulose under hydrothermal conditions (24), whereas barium hy- use in myriad industrial applications including in food for humans, in droxide catalyzes the quantitative conversion of glucose into lactic animal feed, and as precursors for bio-based plastics, among others. acid at room temperature (26). Several other α-hydroxyl acids are However, the development of efficient chemical methods to convert also readily available from lignocellulosic biomass. Cellulose may be abundant and renewable feedstocks into amino acids has been largely converted into glycolic acid via selective oxidation over heteropoly unsuccessful to date.
    [Show full text]
  • Three-Component Radical Homo Mannich Reaction ✉ Shuai Shi1, Wenting Qiu1, Pannan Miao1, Ruining Li1, Xianfeng Lin1 & Zhankui Sun 1
    ARTICLE https://doi.org/10.1038/s41467-021-21303-3 OPEN Three-component radical homo Mannich reaction ✉ Shuai Shi1, Wenting Qiu1, Pannan Miao1, Ruining Li1, Xianfeng Lin1 & Zhankui Sun 1 Aliphatic amine, especially tertiary aliphatic amine, is one of the most popular functionalities found in pharmaceutical agents. The Mannich reaction is a classical and widely used transformation for the synthesis of β-amino-carbonyl products. Due to an ionic nature of the mechanism, the Mannich reaction can only use non-enolizable aldehydes as substrates, which significantly limits the further applications of this powerful approach. Here we show, by 1234567890():,; employing a radical process, we are able to utilize enolizable aldehydes as substrates and develop the three-component radical homo Mannich reaction for the streamlined synthesis of γ-amino-carbonyl compounds. The electrophilic radicals are generated from thiols via the desulfurization process facilitated by visible-light, and then add to the electron-rich double bonds of the in-situ formed enamines to provide the products in a single step. The broad scope, mild conditions, high functional group tolerance, and modularity of this metal-free approach for the synthesis of complex tertiary amine scaffolds will likely be of great utility to chemists in both academia and industry. 1 Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., 200240 ✉ Shanghai, China. email: [email protected] NATURE COMMUNICATIONS | (2021) 12:1006 | https://doi.org/10.1038/s41467-021-21303-3 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-21303-3 mines are very important functional groups in medicinal react with the enolizable carbonyl compound (Fig.
    [Show full text]
  • Practical and Regioselective Synthesis of C4-Alkylated Pyridines Jin Choi†, Gabriele Laudadio†, Edouard Godineau††, Phil S
    Practical and Regioselective Synthesis of C4-Alkylated Pyridines Jin Choi†, Gabriele Laudadio†, Edouard Godineau††, Phil S. Baran*† † Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States ††Process Research, Syngenta Crop Protection, Schaffhauserstrasse 101, CH-4332 Stein, Switzerland ABSTRACT: The direct position-selective C–4 alkylation of pyr- group reported a radical-type addition using N-sulfon- idines has been a longstanding challenge in heterocyclic chemistry, amidopyridinium species10 using alkyl bromide donors requiring particularly from pyridine itself. Historically this has been ad- photochemical initiation and super stoichiometric amounts of an 11 dressed using pre-functionalized materials to avoid overalkylation expensive silane [(TMS)3SiH]. While this is an important prece- and mixtures of regioisomers. This study reports the invention of a dent it could not be employed easily on process scale as three steps simple maleate-derived blocking group for pyridines that enables are needed to install the blocking group (1. N-amination using hy- exquisite control for Minisci-type decarboxylative alkylation at C– droxylamine-O-sulfonic acid, 2. tosylation, and 3. methylation with 4 that allows for inexpensive access to these valuable building Meerwein’s salt along with 1 column purification, 1 recrystalliza- blocks. The method is employed on a variety of different pyridines tion). Herein we disclose a highly practical method featuring on a and carboxylic acid alkyl donors, is operationally simple, scalable, new blocking group based on a simple fumarate backbone (6a) en- and is applied to access known structures in a rapid and inexpensive abling classic Minisci decarboxylative alkylations to take place fashion.
    [Show full text]