DOCSLIB.ORG

1,2,4-Triazine-Accelerated Azide-Alkyne Cycloaddition and Synthesis of Metalloenzyme Inhibitors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
1,2,4-Triazine-Accelerated Azide-Alkyne Cycloaddition and Synthesis of Metalloenzyme Inhibitors University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 5-2013 1,2,4-Triazine-Accelerated Azide-Alkyne Cycloaddition and Synthesis of Metalloenzyme Inhibitors Belinda Shea Lady [email protected] Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Organic Chemistry Commons Recommended Citation Lady, Belinda Shea, "1,2,4-Triazine-Accelerated Azide-Alkyne Cycloaddition and Synthesis of Metalloenzyme Inhibitors. " PhD diss., University of Tennessee, 2013. https://trace.tennessee.edu/utk_graddiss/1750 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Belinda Shea Lady entitled "1,2,4-Triazine- Accelerated Azide-Alkyne Cycloaddition and Synthesis of Metalloenzyme Inhibitors." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the equirr ements for the degree of Doctor of Philosophy, with a major in Chemistry. Shane Foister, Major Professor We have read this dissertation and recommend its acceptance: Michael D. Best, Jimmy W. Mays, Thomas A. Zawodzinski Accepted for the Council: Carolyn R. Hodges Vice Provost and Dean of the Graduate School (Original signatures are on file with official studentecor r ds.) 1,2,4-Triazine-Accelerated Azide-Alkyne Cycloaddition and Synthesis of Metalloenzyme Inhibitors A Dissertation Presented for the Doctor of Philosophy Degree The University of Tennessee, Knoxville Belinda Shea Lady May 2013 Copyright © 2013 Belinda Shea Lady All rights reserved. ii To those who have challenged, supported, and motivated me. iii Acknowledgements First, I would like to thank my parents for instilling in me the value of an education (although they probably didn’t think I would spend the past 22 years in school!) and for all their love, support, and encouragement along the long path. To my sister, thanks for serving as my competition, feeding my desire to be as smart as you, and for always wanting to know what I’m working on. To my brothers, thanks for your support and making me tough. My journey here would not have been possible without all the guidance and lessons learned throughout my high school and college career. Thanks to my math and science teachers along the way who sparked my interest in science in general. I must acknowledge Dr. Darwin Dahl and Dr. Les Pesterfield for without their teaching I may never have become a chemistry major. I would like to thank my committee members for their time and participation on my committee. I am privileged to have a distinguished committee, so thank you Dr. Michael Best, Dr. Jimmy Mays, and Dr. Thomas Zawodzinski. Also, thanks to my advisor, Prof. Shane Foister for giving me the basis to become an independent researcher. Although not on my committee, I would also like to acknowledge Dr. Craig Barnes. Thanks for advice and assistance and for allowing me to take part in the redevelopment of the general chemistry undergraduate program over the past year. To the chemistry department at UTK, thank you for the financial support during my time here. Thank you to everyone in the front office, business office, electronics shop, and general chemistry stockroom that help make things run smoother on a day-to-day basis. Last but not least, I would like to thank the former members of the Foister group that I was privileged to work with. Dave and Jeremiah, you may have scared me a little in my first year, but thanks for showing me all the shortcuts to take and telling funny stories. Thanks Rachel for all the late night studying, food runs, and random walks / naps in front of Ayres Hall. To the undergraduates that I have mentored in the lab, thanks for helping me to realize how much I enjoy teaching. Kelly, Britta, Matt, Kent, and Jillian, I hope that all your hard work and efforts reward you. Very special thanks to Ashleigh Prince and Ashesh Belapure. I was fortunate to work with both of you for the past five years. Despite some of the not so fortunate events that have occurred, I am glad that our paths have crossed. You both have been excellent labmates and friends. Words cannot express the gratitude I have for all the advice you have given me over the years and for keeping me calm and focused. Also, I am very appreciative of you both for your editing of this dissertation. In addition, thanks to Amber for always lending an ear, giving me encouragement along the way, and helping me see my passion for teaching. iv Abstract The work of this dissertation describes the design and synthesis of 1,2,4-triazine ligands and other N-containing heterocycles and their use in the copper-catalyzed azide-alkyne cycloaddition (CuAAC). A variety of ligands were synthesized to probe the steric and electronic demands required for use in the CuAAC reaction. Substituents on the 1,2,4- triazine were systematically altered and the core 1,2,4-triazine modified to determine the most active ligand. Additional experiments explored the variability in the reaction conditions, such as solvent choice, use of reducing agents, and optimal stoichiometry. Under optimum conditions 5,6-diphenyl-3-(2-pyridyl)-1,2,4-triazine and copper (II) tetrafluoroborate in the presence of triethylamine was found to be an effective accelerant producing 97% of the desired 1,2,3-triaozle in 1 hour. A broad substrate scope was conducted with an assortment of azides and alkynes. The use of 1,2,4-triazine-accelerated CuAAC was applied to the synthesis of solid- supported catalysts on both polystyrene and silica. Immobilized catalysts provide advantages over their soluble counterparts in that they can be recycled and can prevent metal contamination of 1,2,3-triazole products. Results indicated that 1,2,4-triazines appended to solid supports were more effective when compared to 1,2,3-triazole control catalysts. In addition, less metal leaching occurred with triazine supports as compared to triazole controls. The optimal ligand from the homogeneous screening was then used in the synthesis of a library of small molecules containing 1,2,3-triazoles and/or 1,2,4-triazoles. Upon synthesis, compounds were screened for activity against various histone deacetylase (HDAC) enzymes for both activity and selectivity. Although successfully synthesized, the molecules did not prove to be active against the selected metalloenzyme. v Table of Contents Chapter 1. Azide-Alkyne Cycloaddition and 1,2,3-Triazoles .................................... 1 1.1. Click Chemistry .................................................................................................. 2 1.2. 1,2,3-Triazoles as Pharmacophores .................................................................. 4 1.3. Azide-Alkyne Cycloadditions .............................................................................. 7 1.4. Copper-Catalyzed Azide-Alkyne Cycloaddition .................................................. 9 1.5. Ligand-Accelerated CuACC (Homogeneous & Heterogeneous Applications) . 11 1.6. Mechanistic Considerations ............................................................................. 16 1.7. 1,2,4-Triazines as Ligands ............................................................................... 18 1.8. Scope of this Work ........................................................................................... 20 Chapter 2. Design & Synthesis of 1,2,4-Triazine Ligands ...................................... 22 2.1. Background & Significance .............................................................................. 23 2.2. Synthetic Strategies for 1,2,4-Triazine Synthesis ............................................. 25 2.3. Ring Closure Reactions ................................................................................... 27 2.3.1. Synthesis of 3-substituted-5,6-diphenyl-1,2,4-triazine ............................... 27 2.3.2. Synthesis of 3-pyridyl-5,6-disubstituted-1,2,4-triazines ............................. 31 2.4. Substituent Modifications ................................................................................. 37 2.5. Ring Transformations ....................................................................................... 39 2.6. Conclusions...................................................................................................... 41 2.7. Experimental .................................................................................................... 42 Chapter 3. Catalytic Activity of 1,2,4-Triazine Ligands ........................................... 67 3.1. Background & Significance .............................................................................. 68 3.2. Optimization of Reaction Conditions for 1,2,4-Triazine Accelerated CuAAC ... 68 3.3. Substrate Scope ............................................................................................... 72 3.4. Ligand Scope ................................................................................................... 74 3.5. Mechanistic Considerations ............................................................................. 77 3.6. Other Catalytic Applications ............................................................................
Load more

Recommended publications
  • Synthesis and Characterization of Oligothiophene - Based Fully Π-Conjugated Macrocycles
    Synthesis and Characterization of Oligothiophene - based Fully π-Conjugated Macrocycles Dissertation zur Erlangung des Doktorgrades Dr. rer. nat. der Fakultät der Naturwissenschaften der Universität Ulm vorgelegt von Gerda Laura Fuhrmann aus Neustadt (Baia Mare) Rumänien Ulm, 2006 Amtierender Dekan: Prof. Dr. Klaus-Dieter Spindler 1. Gutachter: Prof. Dr. Peter Bäuerle 2. Gutachter: Prof. Dr. Volkhard Austel Tag der Promotionsprüfung: 15.03.2006 This thesis was elaborated and written between November 1999 and February 2006 at the department of Organic Chemistry II, University of Ulm, Germany. für meine Eltern “The chemist does a mysterious thing when he wants to make a molecule. He sees that it has got a ring, so he mixes this and that, and he takes it, and he fiddles around. And at the end of a difficult process, he usually does succeed in synthesizing what he wants.” There’s a Plenty of Room at the Bottom - R. Feynman Ich möchte mich an dieser Stelle bei all denjenigen bedanken, die mich in den zurückliegenden Jahren begleitet und unterstützt haben und damit zum Gelingen dieser Arbeit beigetragen haben. Mein besonderer Dank gilt: - Herrn Prof. Dr. Peter Bäuerle für die stete Unterstützung und Förderung bei der wissenschaftlichen Gestaltung dieser Arbeit, für sein Interesse und persönliches Engagement, sowie für die mir gewähren Freiräume bei der Bearbeitung des Themas - Frau Dr. Pinar Kilickiran für ihre moralische und inspirative Unterstützung, für ihre unermüdliche Hilfe, für die Durchsicht und sprachliche Überarbeitung des Manuskripts und für vieles mehr - Herrn Prof. Dr. V. Austel für die stets anregende wissenschaftliche Diskussionen und seine Bereitschaft diese Arbeit zu begutachten - Herrn Dr.
    [Show full text]
  • New Methodologies for the Synthesis Of
    NEW METHODOLOGIES FOR THE SYNTHESIS OF ORGANOPHOSPHORUS COMPOUNDS by MONIKA I. ANTCZAK Master of Science, 2002 Wroclaw University of Technology Wroclaw, Poland Submitted to the Graduate Faculty of the College of Science and Engineering Texas Christian University in partial fulfillment of the requirements for the degree of Doctor of Philosophy December 2008 NEW METHODOLOGIESFOR THE SYNTHESISOF ORGANOPHOSPHORUSCOMPOLNDS by MonikaI. Antczak Dissertationapproved: Maior Professor f Scienceand Engineering Copyright by Monika I. Antczak 2008 ACKNOWLEDGMENTS I wish to acknowledge Prof. Jean-Luc Montchamp for the constant interest in the progress of my work over the past five years. I also wish to thank him for his advice and intense discussions, which helped me in expanding my knowledge and understanding of organic chemistry, and in guiding me in my educational progress at Texas Christian University. His patience and support helped me overcome some difficult situation and successfully completing my Ph.D. program. I express my gratitude to my colleagues and friends, Jennifer Tellez, Dr. Laëtitia Coudray, Yamina Belabassi and Dr. Clemence Queffelec for their help, guidance and support. I also would like to thank Dr. Onofrio Annunziata, Dr. Waldek Zerda and Dr. Dale Huckaby for their guidance and interesting discussions during these years. I wish to thank: Monika Wieligor and Dr. Mauricio Quiroz for their friendship and constant support. Finally, I wish to thank my parents for their unconditional love and support. The Chemistry Department at Texas Christian University, the National Science Foundation (CHE-0242898), the National Institute of General Medical Sciences/NIH (R01 GM067610), and the Robert A. Welch Foundation (P-1666) are gratefully acknowledged for the financial support of this research.
    [Show full text]
  • 1,3,5-Triazine As Core for the Preparation of Dendrons
    The Free Internet Journal Paper for Organic Chemistry Archive for Arkivoc 2020, part iii, 0-0 Organic Chemistry to be inserted by editorial office 1,3,5-Triazine as core for the preparation of dendrons Rotimi Sheyi,a Anamika Sharma,a,b Ashish Kumar,a,b Ayman El-Faham,c,d Beatriz G. de la Torre,b,* and Fernando Albericioa,c,e,f* aPeptide Science Laboratory, School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa bKwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa cDepartment of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia dDepartment of Chemistry, Faculty of Science, Alexandria University, PO Box 426, Alexandria 21321, Egypt eInstitute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain fCIBER-BBN (Networking Centre on Bioengineering, Biomaterials and Nanomedicine) and Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain *Corresponding authors. email: [email protected]; [email protected] Received mm-dd-yyyy Accepted mm-dd-yyyy Published on line mm-dd-yyyy Dates to be inserted by editorial office Abstract A unique property of 2,4,6-trichloro-1,3,5-triazine (TCT) is its ability to undergoes a nucleophilic aromatic substitution reaction (SNAr) under temperature-controlled conditions. Using a convenient and biologically friendly protocol, mono-substituted s-triazines were treated with excess nucleophiles to obtain tri-substituted triazines in 1 + 2 mode (one nucleophile as the first substitution followed by another nucleophile for the other two positions).
    [Show full text]
  • S-Triazine: a Privileged Structure for Drug Discovery and Bioconjugation
    molecules Review s-Triazine: A Privileged Structure for Drug Discovery and Bioconjugation Anamika Sharma 1,2 , Rotimi Sheyi 1, Beatriz G. de la Torre 1,2 , Ayman El-Faham 3,4,* and Fernando Albericio 1,3,5,6,* 1 Peptide Science Laboratory, School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa; [email protected] (A.S.); [email protected] (R.S.); [email protected] (B.G.d.l.T.) 2 KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa 3 Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia 4 Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 12321, Egypt 5 Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain 6 CIBER-BBN (Networking Centre on Bioengineering, Biomaterials and Nanomedicine) and Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain * Correspondence: [email protected] (A.E.-F.); [email protected] (F.A.) Abstract: This review provides an overview of the broad applicability of s-triazine. Our many years working with this intriguing moiety allow us to discuss its wide activity spectrum (inhibition against MAO-A and -B, anticancer/antiproliferative and antimicrobial activity, antibacterial activity against MDR clinical isolates, antileishmanial agent, and use as drug nano delivery system). Most Citation: Sharma, A.; Sheyi, R.; of the compounds addressed in our studies and those performed by other groups contain only de la Torre, B.G.; El-Faham, A.; N-substitution.
    [Show full text]
  • A Conceptual Design of Fluorous Surfactants Based on a Heterocyclic Core, Put Into Practice Through Synthesis of Fluorous 1,2,3-Triazoles Roger W
    Chiang Mai J. Sci. 2009; 36(2) 247 Chiang Mai J. Sci. 2009; 36(2) : 247-257 www.science.cmu.ac.th/journal-science/josci.html Invited Paper A Conceptual Design of Fluorous Surfactants Based on a Heterocyclic Core, Put into Practice Through Synthesis of Fluorous 1,2,3-Triazoles Roger W. Read* and Xiao Bei Wang School of Chemistry, The University of New South Wales, UNSW Sydney NSW 2052, Australia. *Author for correspondence; e-mail: [email protected] ABSTRACT The concept of a design of fluorous surfactants based on a heterocyclic core molecule is introduced and illustrated through the synthesis of polyfluoroalkyl-substituted 1,2,3-triazoles. A two step, one-pot process is described in which a small range of perfluoroalkylethyl azides is prepared in situ and made to undergo Huisgen 1,3-dipolar cycloaddition with terminal alkynes. Measurement of the changes in surface tension of the library of fluorous triazoles at different concentrations in m-xylene reveals unusual behaviour in molecules with a secondary, C8 alkyl substituent. Keywords: organic synthesis, heterocycles, fluorous chemistry, surfactants, click chemistry, polyfluoroalkyl-1,2,3-triazoles. 1. INTRODUCTION Fluorous surfactants have been studied might have applications in the design of new widely, not least for their interest in drug delivery systems and, through self- combination with perfluorocarbons, as assembly, unique molecular devices. emergency blood replacements.[1] Highly Considerable literature exists in the area of fluorinated amphiphiles and colloid systems fluorous block polymers with localised are chemically stable and can carry high crystalline segments and fluorous liposomes concentrations of oxygen and carbon dioxide, and vesicles for drug delivery, but, with a few and therefore have many applications in the exceptions [8-11], most fluorous components biomedical field [2,3].
    [Show full text]
  • Sonogashira Coupling Reaction in Water Using a Polymer-Supported Terpyridine–Palladium Complex Under Aerobic Conditions
    Trans. Mat. Res. Soc. Japan 40[2] 103-106 (2015) Sonogashira Coupling Reaction in Water Using a Polymer-Supported Terpyridine–Palladium Complex under Aerobic Conditions Toshimasa Suzuka,* Mika Adachi, and Kazuhito Ogihara Department of Chemistry, Biology and Marine Science, University of the Ryukyus, Nishihara Okinawa 903-0213, Japan Fax: 81-098-895-8531, e-mail: [email protected] The palladium-catalyzed coupling reaction between an aryl halide and a terminal alkyne, the so-called Sonogashira coupling reaction, was found to occur in water under copper-free conditions using an amphiphilic polystyrene–poly(ethylene glycol) (PS-PEG) resin-supported palladium–terpyridine complex, giving the corresponding aryl-substituted alkyne in high yield. The PS-PEG resin-supported palladium–terpyridine catalyst was recovered simply by filtering the product mixture under air and could be reused three times with only slightly decreased catalytic activity after each use. Key words: Sonogashira, palladium, terpyridine, water, cross-coupling 1. INTRODUCTION organic solvent or metal-contaminated wastes are The palladium-catalyzed coupling reaction produced; and (2) the presence of oxygen and between an aryl halide and a terminal alkyne, the moisture do not negatively affect the reaction. so-called Sonogashira reaction [1], is recognized These benefits therefore allow the Sonogashira as being the most successful method for forming coupling reaction to be performed meeting the an sp2 carbon–sp3 carbon bond. Since its requirements of “green chemistry”. discovery by Sonogashira and co-workers in 1975, a vast amount of research has been performed cat 1. ( 5mol% Pd) into its synthetic applications and on improving X + R1 R1 the reaction efficiency [2].
    [Show full text]
  • Synthetic Routes Towards Thiazolo[1,3,5]Triazines (Review)1
    HETEROCYCLES, Vol. , No. , , pp. -. © The Japan Institute of Heterocyclic Chemistry Received, , Accepted, , Published online, . COM-06- (Please do not delete.) SYNTHETIC ROUTES TOWARDS THIAZOLO[1,3,5]TRIAZINES (REVIEW)1 Anton V. Dolzhenko School of Pharmacy, Curtin University of Technology, GPO Box U1987, Perth, Western Australia 6845, Australia, E-mails: [email protected]; [email protected] Abstract – The present review summarizes information on the synthetic approaches to thiazolo[3,2-a][1,3,5]triazines and polyfused systems bearing this heterocyclic core since the first report on this structure in 1887. The methods allowing access to the heterocyclic systems comprising isomeric thiazolo[3,4-a][1,3,5]triazine scaffold are also included in the review. Data concerning potential applications of the thiazolo[1,3,5]triazines, particularly as biologically active agents are discussed. Dedicated to Professor Viktor E. Kolla with my best wishes on the occasion of his 85th birthday CONTENTS 1. INTRODUCTION 2. SYNTHESIS OF THIAZOLO[3,2-a][1,3,5]TRIAZINES AND THEIR POLYFUSED ANALOGUES 2.1. Synthesis of thiazolo[3,2-a][1,3,5]triazines by annelation of the 1,3,5-triazine ring onto a thiazole scaffold. 2.1.1. Synthesis of thiazolo[3,2-a][1,3,5]triazines using Mannich condensation. 2.1.2. Synthesis of thiazolo[3,2-a][1,3,5]triazines using multicomponent reactions of thiazole derivatives with heterocumulenes. 2.1.3. Synthesis of thiazolo[3,2-a][1,3,5]triazines using other multicomponent reactions of 2-aminothiazoles and their derivatives. 2.1.4. Synthesis of thiazolo[3,2-a][1,3,5]triazines via reactions of 2-aminothiazoles with C-N-C triatomic synthons.
    [Show full text]
  • Advances in Cross-Coupling Reactions
    molecules Editorial Advances in Cross-Coupling Reactions José Pérez Sestelo * and Luis A. Sarandeses * Centro de Investigaciones Científicas Avanzadas (CICA) and Departamento de Química, Universidade da Coruña, E-15071 A Coruña, Spain * Correspondence: [email protected] (J.P.S.); [email protected] (L.A.S.); Tel.: +34-881-012-041 (J.P.S.); +34-881-012-174 (L.A.S.) Received: 28 September 2020; Accepted: 30 September 2020; Published: 1 October 2020 Cross-coupling reactions stand among the most important reactions in chemistry [1,2]. Nowadays, they are a highly valuable synthetic tool used for the preparation of a wide variety of organic compounds, from natural and synthetic bioactive compounds to new organic materials, in all fields of chemistry [3]. Almost 50 years from its discovery, the research in this topic remains active, and important progresses are accomplished every year. For this reason, we believe that a Special Issue on this topic is of general interest for the chemistry community. Advances in cross-coupling reactions have been developed with the aim to expand the synthetic utility of the methodology, through the involvement of new components, reaction conditions, and therefore, novel synthetic applications [4]. Although initially the term “cross-coupling” referred to the reaction of an organometallic reagent with an unsaturated organic halide or pseudohalide under transition metal catalysis, currently the definition is much more general and applies to reactions involving other components, conditions, and more complex synthetic transformations. In addition to the well-known and recognized cross-coupling reactions using organoboron (Suzuki-Miyaura), organotin (Stille), organozinc (Negishi), or organosilicon (Hiyama) nucleophiles, reactions involving other organometallic reagents such as organoindium [5,6], organolithium [7], and Grignard reagents [8] are now useful synthetic alternatives.
    [Show full text]
  • Multimetallic Catalysed Radical Oxidative C(Sp3)–H/C(Sp)–H Cross-Coupling Between Unactivated Alkanes and Terminal Alkynes
    ARTICLE Received 2 Jan 2016 | Accepted 19 Apr 2016 | Published 24 Jun 2016 DOI: 10.1038/ncomms11676 OPEN Multimetallic catalysed radical oxidative C(sp3)–H/C(sp)–H cross-coupling between unactivated alkanes and terminal alkynes Shan Tang1, Pan Wang1, Haoran Li1 & Aiwen Lei1,2 Radical involved transformations are now considered as extremely important processes in modern organic synthetic chemistry. According to the demand by atom-economic and sustainable chemistry, direct C(sp3)–H functionalization through radical oxidative coupling represents an appealing strategy for C–C bond formations. However, the selectivity control of reactive radical intermediates is still a great challenge in these transformations. Here we show a selective radical oxidative C(sp3)–H/C(sp)–H cross-coupling of unactivated alkanes with terminal alkynes by using a combined Cu/Ni/Ag catalytic system. It provides a new way to access substituted alkynes from readily available materials. Preliminary mechanistic studies suggest that this reaction proceeds through a radical process and the C(sp3)–H bond cleavage is the rate-limiting step. This study may have significant implications for controlling selective C–C bond formation of reactive radical intermediates by using multimetallic catalytic systems. 1 College of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS), Wuhan University, Wuhan 430072, China. 2 National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, China. Correspondence and requests for materials should be addressed to A.L. (email: [email protected]). NATURE COMMUNICATIONS | 7:11676 | DOI: 10.1038/ncomms11676 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms11676 ubstituted alkynes are fundamental structural motifs in been developed through normal cross-dehydrogenative numerous natural products, bioactive molecules and coupling33 pathway (Fig.
    [Show full text]
  • Recent Advances in Microwave-Assisted Copper-Catalyzed Cross-Coupling Reactions
    catalysts Review Recent Advances in Microwave-Assisted Copper-Catalyzed Cross-Coupling Reactions Younis Baqi Department of Chemistry, College of Science, Sultan Qaboos University, P.O. Box 36, Muscat 123, Oman; [email protected]; Tel.: +968-2414-1473 Abstract: Cross-coupling reactions furnishing carbon–carbon (C–C) and carbon–heteroatom (C–X) bond is one of the most challenging tasks in organic syntheses. The early developed reaction protocols by Ullmann, Ullman–Goldberg, Cadiot–Chodkiewicz, Castro–Stephens, and Corey–House, utilizing elemental copper or its salts as catalyst have, for decades, attracted and inspired scientists. However, these reactions were suffering from the range of functional groups tolerated as well as severely restricted by the harsh reaction conditions often required high temperatures (150–200 ◦C) for extended reaction time. Enormous efforts have been paid to develop and achieve more sustainable reaction conditions by applying the microwave irradiation. The use of controlled microwave heating dramatically reduces the time required and therefore resulting in increase in the yield as well as the efficiency of the reaction. This review is mainly focuses on the recent advances and applications of copper catalyzed cross-coupling generation of carbon–carbon and carbon–heteroatom bond under microwave technology. Keywords: cross-coupling reaction; Cu catalyst; microwave irradiation; methodology; synthesis 1. Introduction Carbon–carbon (C–C) and carbon–heteroatom (C–X) bond formations through cross- Citation: Baqi, Y. Recent Advances in coupling reactions represents as one of the most useful strategy in the synthetic organic Microwave-Assisted chemistry, hence many procedures and methodologies have been developed and published Copper-Catalyzed Cross-Coupling in the literature.
    [Show full text]
  • New Trends in C–C Cross-Coupling Reactions: the Use of Unconventional Conditions
    molecules Review New Trends in C–C Cross-Coupling Reactions: The Use of Unconventional Conditions Marta A. Andrade and Luísa M. D. R. S. Martins * Centro de Química Estrutural and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal; [email protected] * Correspondence: [email protected]; Tel.: +35-121-841-9389 Academic Editor: Giuseppe Cirillo Received: 30 October 2020; Accepted: 20 November 2020; Published: 24 November 2020 Abstract: The ever-growing interest in the cross-coupling reaction and its applications has increased exponentially in the last decade, owing to its efficiency and effectiveness. Transition metal-mediated cross-couplings reactions, such as Suzuki–Miyaura, Sonogashira, Heck, and others, are powerful tools for carbon–carbon bond formations and have become truly fundamental routes in catalysis, among other fields. Various greener strategies have emerged in recent years, given the widespread popularity of these important reactions. The present review comprises literature from 2015 onward covering the implementation of unconventional methodologies in carbon–carbon (C–C) cross-coupling reactions that embodies a variety of strategies, from the use of alternative energy sources to solvent- free and green media protocols. Keywords: cross-coupling reactions; microwave irradiation; ultrasounds; mechanochemistry; solvent-free; water; ionic liquids; deep eutectic solvents; sustainability 1. Introduction Cross-coupling reactions have attracted and inspired researchers in the academia and industry for decades, given its significance as a synthetic tool in modern organic synthesis. The continuous interest in cross-coupling reactions, with more than 40 years of history, has been mostly driven by its valuable contributions and applications in the medicinal and pharmaceutical industries.
    [Show full text]
  • 1-Iodo-1-Pentyne
    MIAMI UNIVERSITY-THE GRADUATE SCHOOL CERTIFICATE FOR APPROVING THE DISSERTATION We hereby approve the Dissertation of Lizhi Zhu Candidate for the Degree: Doctor of Philosophy ________________________________ Robert E. Minto, Director ________________________________ John R. Grunwell, Reader ________________________________ John F. Sebastian, Reader ________________________________ Ann E. Hagerman, Reader ________________________________ Richard E. Lee, Graduate School Representative ABSTRACT INVESTIGATING THE BIOSYNTHESIS OF POLYACETYLENES: SYNTHESIS OF DEUTERATED LINOLEIC ACIDS & MECHANISM STUDIES OF DMDS ADDITION TO 1,4-ENYNES By Lizhi Zhu A wide range of polyacetylenic natural products possess antimicrobial, antitumor, and insecticidal properties. The biosyntheses of these natural products are widely distributed among fungi, algae, marine sponges, and higher plants. As details of the biosyntheses of these intriguing compounds remains scarce, it remains important to develop molecular probes and analytical methods to study polyacetylene secondary metabolism. An effective pathway to prepare selectively deuterium-labeled linoleic acids was developed. By this Pd-catalyzed method, deuterium can be easily introduced into the vinyl position providing deuterolinoleates with very high isotopic purity. This method also provides a general route for the construction of 1,4-diene derivatives with different chain lengths and 1,4-diene locations. Linoleic acid derivatives (12-d, 13-d and 16,16,17,17,18,18,18-d7) were synthesized according to this method. A stereoselective synthesis of methyl (14Z)- and (14E)-dehydrocrepenynate was achieved in five to six steps that employed Pd-catalyzed cross-coupling reactions to construct the double bonds between C14 and C15. Compared with earlier methods, the improved syntheses are more convenient (no spinning band distillations or GLC separation of diastereomers were necessary) and higher Z/E ratios were obtained.
    [Show full text]