DOCSLIB.ORG

New Methods for the Synthesis of Functionalised Arenes

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
New Methods for the Synthesis of Functionalised Arenes New Methods for the Synthesis of Functionalised Arenes A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Science and Engineering Danielle L. Bunting School of Chemistry Faculty of Science & Engineering 2018 2 Contents List of abbreviations5 Abstract . 10 Declaration . 11 Copyright statement . 11 Acknowledgements . 12 1 Ruthenium catalysed C{H activation 13 1.1 Introduction . 13 1.1.1 Background: C{H activation . 13 1.1.2 ortho-Functionalisation . 14 1.1.3 meta-Functionalisation . 34 1.2 Investigations into meta-functionalisation . 48 1.2.1 Aims and objectives . 48 1.2.2 Results and discussion . 48 1.2.3 Conclusions . 65 1.3 Ruthenium catalysed ortho-halogenation . 67 1.3.1 Aims and objectives . 67 1.3.2 Results and discussion . 67 1.3.3 Conclusions and future work . 96 1.4 Tandem N,C-diarylation of pyrazole . 99 1.4.1 Background: Diaryliodonium salts . 99 1.4.2 Aims and objectives . 112 1.4.3 Results and discussion . 113 1.4.4 Conclusions and future work . 131 2 Arynes for the synthesis of substituted arenes 133 2.1 Introduction . 133 2.2 Hexadehydro-Diels{Alder (HDDA) reaction . 137 2.2.1 Background: HDDA . 137 2.2.2 Aims and objectives . 143 2.2.3 Results and discussion . 144 2.2.4 Conclusions . 151 2.3 Benzyne Truce{Smiles rearrangement . 154 2.3.1 Background . 154 2.3.2 Aims and objectives . 163 2.3.3 Results and discussion . 164 2.3.4 Conclusions and future work . 182 3 3 Experimental 184 3.1 General . 184 3.2 meta-Functionalisation experimental . 186 3.3 ICl experimental . 190 3.3.1 General procedures . 190 3.3.2 Preparation of starting materials . 191 3.3.3 ortho-Halogenation products . 198 3.3.4 Kinetic isotope experiments . 214 3.4 Tandem N,C-diarylation of pyrazole experimental . 221 3.4.1 Preparation of iodonium salts . 221 3.4.2 N{H/C{H arylation of pyrazoles . 226 3.4.3 Screening of other heterocycles . 232 3.5 HHDDA experimental . 237 3.6 Benzyne{Smiles experimental . 244 3.6.1 Synthesis of starting materials . 244 3.6.2 Screening of conditions . 258 Bibliography 267 4 List of abbreviations δ Chemical shift (in ppm) 1,10-phen 1,10-Phenanthroline 1,2-DCE 1,2-Dichloroethane A˚ Angstr¨om˚ µL microlitre(s) J NMR coupling constant k Rate constant k rel Relative rate of reaction mCPBA meta-Chloroperoxybenzoic acid o-DCB 1,2-Dichlorobenzene AdCO2H 1-Adamantanecarboxylic acid AIBN Azobisisobutyronitrile APCI Atmospheric Pressure Chemical Ionisation app. apparent aq. Aqueous Ar Aryl ATRA Atom transfer radical addition BHT 2,6-Di-tert-butyl-4-methylphenol BNDHP 1,1'-Binaphthyl-2,2'-diylhydrogen phosphate Boc tert-Butyloxycarbonyl bpy 2,2'-Bipyridyl br Broad calcd Calculated cat. Catalyst/catalytic cm centimetre(s) cm−1 wavenumbers CMD Concerted metallation deprotonation COD 1,5-Cyclooctadiene Conc. Concentration 5 Cp* Pentamethyl cyclopentadiene d doublet DABCO 1,4-Diazabicyclo[2.2.2]octane dap 2,9-Bis(4-methoxyphenyl)-1,10-phenanthroline DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane dF-ppy 2-(2,4-Difluorophenyl)pyridine DFT Density functional theory DG Directing group DIPA Diisopropylamine DIPEA N,N -Diisopropylethylamine DMEDA N,N '-Dimethylethane-1,2-diamine DMF N,N -Dimethylformamide DMSO Dimethylsulfoxide DPPB Butane-1,3-diylbis(diphenylphosphine) DPPE Ethane-1,2-diylbis(diphenylphosphine) dppf 1,1'-Ferrocenediyl-bis(diphenylphosphine) DPPH Di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium DPPP Propane-1,3-diylbis(diphenylphosphine) DTBP Di-tert-butyl peroxide dtbpy 4,4'-Di-tert-butyl-2,2'-dipyridyl e− Electron EAS Electrophilic aromatic substitution EI Electron Ionisation Eosin Y 2-(2,4,5,7-Tetrabromo-6-oxido-3-oxo-3H -xanthen-9-yl)benzoate eq. Equivalents ESI Electrospray Ionisation EWG Electron withdrawing group Fluorescein 3',6'-Dihydroxyspiro[isobenzofuran-1(3H ),9'-[9H ]xanthen]-3-one g gram(s) Galvinoxyl 2,6-Di-tert-butyl-α-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1- ylidene)-p-tolyloxy, free radical GCMS Gas Chromatography Mass Spectrometry 6 h hour(s) HDDA Hexadehydro-Diels{Alder HHDDA Hetero-Hexadehydro-Diels{Alder HMDS Bis(trimethylsilyl)amine Hz Hertz IR Infra-Red kcal/mol kilocalories per mole KIE Kinetic isotope effect L Ligand LDA Lithium diisopropylamide LED Light emitting diode LG Leaving group LR Low resolution M Molecular mass (in mass spectrometry) M mol dm−3 m medium (IR absorbance) m multiplet (NMR peak) m.p. Melting point mA milliamp Mes Mesityl mg milligram(s) MHz megahertz MIDA N -Methyliminodiacetic acid min minute(s) mL millilitre(s) MLCT Metal to Ligand Charge Transfer mmol millimole(s) mol% molar percentage MPAA Mono-protected amino acid MS Mass Spectrometry MS Molecular sieves MW Microwave NBE Norbornene 7 NBS N -Bromosuccinimide NCS N -Chlorosuccinimide NIS N -Iodosuccinimide nm nanometre(s) NMP N -Methyl-2-pyrrolidone NMR Nuclear Magnetic Resonance NR No reaction Nu Nucleophile PE Petroleum ether pin Pinacolato Piv Pivaloyl PMP para-Methoxyphenyl ppm parts per million PPTS pyridinium p-toluenesulfonate ppy 2-Phenylpyridine PRC Photoredox Catalyst psi Pound per square inch PTFE Poly(tetrafluoroethylene) q quartet quant. Quantitative yield RDS Rate determining step rt Room temperature s second(s) s singlet (NMR peak) s strong (IR absorbance) sat. saturated sept septet SET Single electron transfer SM Starting material soln. solution t triplet t1=2 Half life TBA-OAc Tetra-n-butylammonium acetate 8 TBAF Tetra-n-butylammonium fluoride TBAT Tetra-n-butylammonium difluorotriphenylsilicate TBATB Tetra-n-butylammonium tribromide TBHP tert-Butyl hydroperoxide temp Temperature TEMPO (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl Tf Triflyl TFA Trifluoroacetic acid THF Tetrahydrofuran THP 2-Tetrahydropyranyl TLC Thin Layer Chromatography TM Transition metal TMEDA N,N,N ',N '-Tetramethylethylenediamine Ts Tosyl UPLC Ultra Performance Liquid Chromatography UV Ultraviolet Val Valine vis Visible w weak w/u Work-up w/w weight/weight Xyl 3,5-(Dimethyl)phenyl 9 Abstract The University of Manchester Danielle L. Bunting School of Chemistry Doctor of Philosophy 2018 New methods for the synthesis of functionalised arenes Arenes are a cornerstone of organic chemistry, and new methods for their functionali- sation, whether with improved efficiency, or for the synthesis of novel, highly function- alised skeletons remain crucial. The methods available for achieving such transforma- tions are diverse. This thesis is comprised of two chapters, one investigating the use of ruthenium catalysis for directed C{H functionalisation of arenes possessing a strongly coordinating directing group. The second concerns the use of arynes for the construction of highly functionalised pyridines (via a hexadehydro-Diels{Alder (HDDA) reaction) and ortho- hydroxy biaryls (via a tandem benzyne-Truce{Smiles rearrangement). Ruthenium catalysis has successfully been used to introduce a number of functional groups by C{H activation. Combined with halocarbons, it could be used to introduce novel functionalities such as tetrasubstituted alkenes, or a formyl group in the meta- position of phenylpyridine. Pleasingly, the use of iodine monochloride as a halogenating agent allowed catalyst dependent ortho-halogenation of phenylpyridine substrates. Use of Ru3(CO)12 catalysis resulted in selective iodination, whereas RuCl2(PPh3)3 enabled chlorination. The substrate scope, as well as the reasons behind this intriguing change in selectivity were investigated. Ruthenium catalysis has also been used to achieve a one-pot tandem N,C-arylation of pyrazoles, using both aryl components of diaryliodonium salts, avoiding the waste of one equivalent of aryl iodide. Effective for both symmetrical and unsymmetrical di- aryliodoniums in good yields, this could also be extended to the use of styrylphenyliodo- niums for synthesis of trisubstituted alkenes. The use of arynes also provides a powerful method for the synthesis of functionalised arynes. Attempts to achieve a pyridyne synthesis and subsequent trapping in a HDDA cascade were unsuccessful. However, generation of benzyne from ortho-trimethylsilyl aryl triflate, followed by nucleophilic attack, and subsequent Truce{Smiles rearrange- ment of an aryl sulfonate ester was successful in the synthesis of ortho-functionalised biaryls. Word count: 56627 10 Declaration Work towards Sections 1.2 & 1.3 has been submitted in support of an application for a degree of PhD at this university: Christopher J. Teskey, Strategic use of transition metals for selective C{H bond func- tionalisation. Ph.D. thesis, University of Manchester, 2016. Part of this work (Section 1.4) has been published in a peer reviewed journal: Christopher J. Teskey, Shariar M. A. Sohel, Danielle L. Bunting, Sachin G. Modha and Michael F. Greaney, Domino N-/C-Arylation via In Situ Generation of a Directing Group: Atom-Efficient Arylation Using Diaryliodonium Salts, Angew. Chem. Int. Ed. 2017, 56, 5263{5266. Copyright statement i The author of this thesis (including any appendices and/or schedules to this thesis) owns certain copyright or related rights in it (the \Copyright") and she has given The University of Manchester certain rights to use such Copyright, including for administrative purposes. ii Copies of this thesis, either in full or in extracts and whether in hard or electronic copy, may be made only in accordance with the Copyright, Designs and Patents Act 1988 (as amended) and regulations issued under it or, where appropriate, in accordance with licensing agreements which the University has from time to time. This page must form part of any such copies made. iii The ownership of certain Copyright, patents, designs, trademarks and other intel- lectual property (the \Intellectual Property") and any reproductions of copyright works in the thesis, for example graphs and tables (\Reproductions"), which may be described in this thesis, may not be owned by the author and may be owned by third parties. Such Intellectual Property and Reproductions cannot and must not be made available for use without the prior written permission of the owner(s) of the relevant Intellectual Property and/or Reproductions.
Load more

Recommended publications
  • The Development and Application of Metal-Catalyzed Processes for Organic Synthesis
    The Development and Application of Metal-Catalyzed Processes for Organic Synthesis by Edward J. Hennessy B.A. Chemistry Northwestern University, 2000 Submitted to the Department of Chemistry in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY IN ORGANIC CHEMISTRY at the Massachusetts Institute of Technology June 2005 © 2005 Massachusetts Institute of Technology All Rights Reserved Signature of Author: " - - 1_"' .Da-uirnt of Chemistry May 19, 2005 Certified by: Stephen L. Buchwald Camille Dreyfus Professor of Chemistry Thesis Supervisor Accepted by: Robert W. Field Chairman, Departmental Committee on Graduate Students ARCHIVES: This doctoral thesis has been examined by a committee of the Department of Chemistry as follows: -/ Professor Gregory C. Fu: " Ch Chair Professor Stephen L. Buchwald Thesis Supervisor Professor Timothy M. Swager: , -L i \ O 2 The Development and Application of Metal-Catalyzed Processes for Organic Synthesis by Edward J. Hennessy Submitted to the Department of Chemistry on May 19, 2005 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at the Massachusetts Institute of Technology ABSTRACT Chapter 1. Copper-Catalyzed Arylation of Stabilized Carbanions A mild, general catalytic system for the synthesis of a-aryl malonates has been developed. Aryl iodides bearing a variety of functional groups can be effectively coupled to diethyl malonate in high yields using inexpensive and widely available reagents, making this a superior method to those previously described that employ copper reagents or catalysts. The functional group tolerance of the process developed makes it complementary to analogous palladium-catalyzed couplings. Importantly, a set of mild reaction conditions has been developed that minimize product decomposition, a problem that had not been addressed previously in the literature.
    [Show full text]
  • Nucleophilic Aromatic Substitution
    NUCLEOPHILIC AROMATIC SUBSTITUTION Ms. Prerana Sanas M.Pharm (Pharmceutical Chemistry) Asst.Professor, NCRD’s Sterling Institute of Pharmacy Nerul Navi Mumbai Nucleophilic aromatic substitution results in the substitution of a halogen X on a benzene ring by a nucleophile (:Nu– ). Aryl halides undergo a limited number of substitution reactions with strong nucleophiles. NAS occurs by two mechanisms i) Bimoleccular displacement (Addition –Elimination) ii) Benzyne Formation( Elimination –Addition) 7/5/2019 Ms.Prerana Sanas 2 Bimolecular displacement (Addition – Elimination) Aryl halides with strong electron-withdrawing groups (such as NO2) on the ortho or para positions react with nucleophiles to afford substitution products. For example, treatment of p-chloronitrobenzene with hydroxide (– OH) affords p-nitrophenol by replacement of Cl by OH. Nucleophilic aromatic substitution occurs with a variety of strong nucleophiles, including – OH, – OR, – NH2, – SR, and in some cases, neutral nucleophiles such as NH3 and RNH2 . 7/5/2019 Ms.Prerana Sanas 3 Mechanism…… The mechanism of these reactions has two steps: Step i) Addition of the nucleophile (:Nu– ) forms a resonance-stabilized carbanion with a new C – Nu bond—three resonance structures can be drawn. • Step [1] is rate-determining since the aromaticity of the benzene ring is lost. In Step ii) loss of the leaving group re-forms the aromatic ring. This step is fast because the aromaticity of the benzene ring is restored. 7/5/2019 Ms.Prerana Sanas 4 Factors affecting Bimolecular displacement Increasing the number of electron-withdrawing groups increases the reactivity of the aryl halide. Electron-withdrawing groups stabilize the intermediate carbanion, and by the Hammond postulate, lower the energy of the transition state that forms it.
    [Show full text]
  • The Total Synthesis of Securinine and Other Methodology Studies
    University of Windsor Scholarship at UWindsor Electronic Theses and Dissertations Theses, Dissertations, and Major Papers 2010 The total synthesis of securinine and other methodology studies Bhartesh Dhudshia University of Windsor Follow this and additional works at: https://scholar.uwindsor.ca/etd Recommended Citation Dhudshia, Bhartesh, "The total synthesis of securinine and other methodology studies" (2010). Electronic Theses and Dissertations. 8275. https://scholar.uwindsor.ca/etd/8275 This online database contains the full-text of PhD dissertations and Masters’ theses of University of Windsor students from 1954 forward. These documents are made available for personal study and research purposes only, in accordance with the Canadian Copyright Act and the Creative Commons license—CC BY-NC-ND (Attribution, Non-Commercial, No Derivative Works). Under this license, works must always be attributed to the copyright holder (original author), cannot be used for any commercial purposes, and may not be altered. Any other use would require the permission of the copyright holder. Students may inquire about withdrawing their dissertation and/or thesis from this database. For additional inquiries, please contact the repository administrator via email ([email protected]) or by telephone at 519-253-3000ext. 3208. The Total Synthesis of Securinine and Other Methodology Studies by Bhartesh Dhudshia A Dissertation Submitted to the Faculty of Graduate Studies through the Department of Chemistry and Biochemistry in Partial Fulfillment of the Requirements
    [Show full text]
  • Organic Synthesis: New Vistas in the Brazilian Landscape
    Anais da Academia Brasileira de Ciências (2018) 90(1 Suppl. 1): 895-941 (Annals of the Brazilian Academy of Sciences) Printed version ISSN 0001-3765 / Online version ISSN 1678-2690 http://dx.doi.org/10.1590/0001-3765201820170564 www.scielo.br/aabc | www.fb.com/aabcjournal Organic Synthesis: New Vistas in the Brazilian Landscape RONALDO A. PILLI and FRANCISCO F. DE ASSIS Instituto de Química, UNICAMP, Rua José de Castro, s/n, 13083-970 Campinas, SP, Brazil Manuscript received on September 11, 2017; accepted for publication on December 29, 2017 ABSTRACT In this overview, we present our analysis of the future of organic synthesis in Brazil, a highly innovative and strategic area of research which underpins our social and economical progress. Several different topics (automation, catalysis, green chemistry, scalability, methodological studies and total syntheses) were considered to hold promise for the future advance of chemical sciences in Brazil. In order to put it in perspective, contributions from Brazilian laboratories were selected by the citations received and importance for the field and were benchmarked against some of the most important results disclosed by authors worldwide. The picture that emerged reveals a thriving area of research, with new generations of well-trained and productive chemists engaged particularly in the areas of green chemistry and catalysis. In order to fulfill the promise of delivering more efficient and sustainable processes, an integration of the academic and industrial research agendas is to be expected. On the other hand, academic research in automation of chemical processes, a well established topic of investigation in industrial settings, has just recently began in Brazil and more academic laboratories are lining up to contribute.
    [Show full text]
  • Reactions of Aromatic Compounds Just Like an Alkene, Benzene Has Clouds of  Electrons Above and Below Its Sigma Bond Framework
    Reactions of Aromatic Compounds Just like an alkene, benzene has clouds of electrons above and below its sigma bond framework. Although the electrons are in a stable aromatic system, they are still available for reaction with strong electrophiles. This generates a carbocation which is resonance stabilized (but not aromatic). This cation is called a sigma complex because the electrophile is joined to the benzene ring through a new sigma bond. The sigma complex (also called an arenium ion) is not aromatic since it contains an sp3 carbon (which disrupts the required loop of p orbitals). Ch17 Reactions of Aromatic Compounds (landscape).docx Page1 The loss of aromaticity required to form the sigma complex explains the highly endothermic nature of the first step. (That is why we require strong electrophiles for reaction). The sigma complex wishes to regain its aromaticity, and it may do so by either a reversal of the first step (i.e. regenerate the starting material) or by loss of the proton on the sp3 carbon (leading to a substitution product). When a reaction proceeds this way, it is electrophilic aromatic substitution. There are a wide variety of electrophiles that can be introduced into a benzene ring in this way, and so electrophilic aromatic substitution is a very important method for the synthesis of substituted aromatic compounds. Ch17 Reactions of Aromatic Compounds (landscape).docx Page2 Bromination of Benzene Bromination follows the same general mechanism for the electrophilic aromatic substitution (EAS). Bromine itself is not electrophilic enough to react with benzene. But the addition of a strong Lewis acid (electron pair acceptor), such as FeBr3, catalyses the reaction, and leads to the substitution product.
    [Show full text]
  • AROMATIC NUCLEOPHILIC SUBSTITUTION-PART -2 Electrophilic Substitution
    Dr. Tripti Gangwar AROMATIC NUCLEOPHILIC SUBSTITUTION-PART -2 Electrophilic substitution ◦ The aromatic ring acts as a nucleophile, and attacks an added electrophile E+ ◦ An electron-deficient carbocation intermediate is formed (the rate- determining step) which is then deprotonated to restore aromaticity ◦ electron-donating groups on the aromatic ring (such as -OH, -OCH3, and alkyl) make the reaction faster, since they help to stabilize the electron-poor carbocation intermediate ◦ Lewis acids can make electrophiles even more electron-poor (reactive), increasing the reaction rate. For example FeBr3 / Br2 allows bromination to occur at a useful rate on benzene, whereas Br2 by itself is slow). In fact, a substitution reaction does occur! (But, as you may suspect, this isn’t an electrophilic aromatic substitution reaction.) In this substitution reaction the C-Cl bond breaks, and a C-O bond forms on the same carbon. The species that attacks the ring is a nucleophile, not an electrophile The aromatic ring is electron-poor (electrophilic), not electron rich (nucleophilic) The “leaving group” is chlorine, not H+ The position where the nucleophile attacks is determined by where the leaving group is, not by electronic and steric factors (i.e. no mix of ortho– and para- products as with electrophilic aromatic substitution). In short, the roles of the aromatic ring and attacking species are reversed! The attacking species (CH3O–) is the nucleophile, and the ring is the electrophile. Since the nucleophile is the attacking species, this type of reaction has come to be known as nucleophilic aromatic substitution. n nucleophilic aromatic substitution (NAS), all the trends you learned in electrophilic aromatic substitution operate, but in reverse.
    [Show full text]
  • Aryl Halides
    Block 3 Aromatic Hydrocarbons and Halogen Derivatives UNIT14 ARYL HALIDES Structure 14.1 Introduction Electophilic Substitution Reactions Expected Learning Outcomes 14.2 Structure and Reactivity Reactions due to C−X bond 14.5 Reactivity and Relative 14.3 Preparation of Aryl Halides Strength of C−X Bonds in 14.4 Reaction of Aryl Halides Halogen Derivatives Nucleophilic Substitution by 14.6 Summary Addition-Elimination 14.7 Terminal Questions Nucleophilic Substitution via 14.8 Answers Benzene Intermediate 14.1 INTRODUCTION In Unit 13, we have pointed out that there is a difference in the nature of C−X bond of aryl halides and aryl halides. Because of this aryl halides differ from the alkyl halides in their preparation and properties. In this Unit, we will study the unique chemistry of aryl halides. First, we shall take up the structure and reactivity of aryl halides, which is followed by their preparations and properties. At the end of the unit we shall compare the reactivity and relative strength of C−X bond in different type of halogen derivatives. Expected Learning Outcomes After studying this unit, you should be able to: explain why aryl halides are less reactive than alkyl halides, outline the methods of preparation of aryl halides, describe the reactions of aryl halides, and explain the difference in structure and reactivity of alkyl, alkenyl and aryl halides towards nucleophilic substitution reactions. 94 Unit 14 Aryl Halides 14.2 STRUCTURE AND REACTIVITY Before going into the details of the preparations and properties of aryl halides let us take a look at the structure and reactivity of these compounds so that we can understand why their reactions are different from alkyl halides.
    [Show full text]
  • Aromatic Substitution Reactions: an Overview
    Review Article Published: 03 Feb, 2020 SF Journal of Pharmaceutical and Analytical Chemistry Aromatic Substitution Reactions: An Overview Kapoor Y1 and Kumar K1,2* 1School of Pharmaceutical Sciences, Apeejay Stya University, Sohna-Palwal Road, Sohna, Gurgaon, Haryana, India 2School of Pharmacy and Technology Management, SVKM’s NMIMS University, Hyderabad, Telangana, India Abstract The introduction or replacement of substituent’s on aromatic rings by substitution reactions is one of the most fundamental transformations in organic chemistry. On the basis of the reaction mechanism, these substitution reactions can be divided into electrophilic, nucleophilic, radical, and transition metal catalyzed. This article also focuses on electrophilic and nucleophilic substitution mechanisms. Introduction The replacement of an atom, generally hydrogen, or a group attached to the carbon from the benzene ring by another group is known as aromatic substitution. The regioselectivity of these reactions depends upon the nature of the existing substituent and can be ortho, Meta or Para selective. Electrophilic Aromatic Substitution (EAS) reactions are important for synthetic purposes and are also among the most thoroughly studied classes of organic reactions from a mechanistic point of view. A wide variety of electrophiles can effect aromatic substitution. Usually, it is a substitution of some other group for hydrogen that is of interest, but this is not always the case. For example, both silicon and mercury substituent’s can be replaced by electrophiles. The reactivity of a particular electrophile determines which aromatic compounds can be successfully substituted. Despite the wide range of electrophilic species and aromatic ring systems that can undergo substitution, a single broad mechanistic picture encompasses most EAS reactions.
    [Show full text]
  • Synthesis of a Poison Frog Bioactive Alkaloids Sara Mazeh
    Synthesis of a poison frog bioactive alkaloids Sara Mazeh To cite this version: Sara Mazeh. Synthesis of a poison frog bioactive alkaloids. Organic chemistry. Université Grenoble Alpes, 2019. English. NNT : 2019GREAV043. tel-02613846 HAL Id: tel-02613846 https://tel.archives-ouvertes.fr/tel-02613846 Submitted on 20 May 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE Pour obtenir le grade de DOCTEUR DE LA COMMUNAUTÉ UNIVERSITÉ GRENOBLE ALPES Spécialité : Chimie organique Arrêté ministériel : 25 mai 2016 Présentée par SARA MAZEH Thèse dirigée par Philippe DELAIR préparée au sein du Laboratoire Département de Pharmaco chimie Moléculaire dans l'École Doctorale Chimie et Sciences du Vivant Synthèse d'alcaloïdes bioactifs issus de batracien Synthesis of a poison frog bioactive alkaloids Thèse soutenue publiquement le 9 décembre 2019, devant le jury composé de : Madame MERCEDES AMAT PROFESSEUR, UNIVERSITE DE BARCELONE - ESPAGNE, Rapporteur Monsieur DAVID AITKEN PROFESSEUR DES UNIVERSITES, UNIVERSITE PARIS-SUD, Rapporteur Monsieur PETER GOEKJIAN PROFESSEUR DES UNIVERSITES, UNIVERSITE LYON 1, Examinateur Madame SANDRINE PY DIRECTRICE DE RECHERCHE, CNRS DELEGATION ALPES, Examinateur Monsieur OLIVIER RENAUDET PROFESSEUR DES UNIVERSITES, UNIVERSITE GRENOBLE ALPES, Président Monsieur PHILIPPE DELAIR MAITRE DE CONFERENCES HDR, UNIVERSITE GRENOBLE ALPES, Directeur de thèse Dedicated to my parents, this simply wouldn’t exist without you.
    [Show full text]
  • Simple, Efficient Catalyst System for the Palladium-Catalyzed Amination of Aryl Chlorides, Bromides, and Triflates
    1158 J. Org. Chem. 2000, 65, 1158-1174 Simple, Efficient Catalyst System for the Palladium-Catalyzed Amination of Aryl Chlorides, Bromides, and Triflates John P. Wolfe,† Hiroshi Tomori, Joseph P. Sadighi,‡ Jingjun Yin, and Stephen L. Buchwald* Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 Received October 29, 1999 Palladium complexes supported by (o-biphenyl)P(t-Bu)2 (3)or(o-biphenyl)PCy2 (4) are efficient catalysts for the catalytic amination of a wide variety of aryl halides and triflates. Use of ligand 3 allows for the room-temperature catalytic amination of many aryl chloride, bromide, and triflate substrates, while ligand 4 is effective for the amination of functionalized substrates or reactions of acyclic secondary amines. The catalysts perform well for a large number of different substrate combinations at 80-110 °C, including chloropyridines and functionalized aryl halides and triflates using 0.5-1.0 mol % Pd; some reactions proceed efficiently at low catalyst levels (0.05 mol % Pd). These ligands are effective for almost all substrate combinations that have been previously reported with various other ligands, and they represent the most generally effective catalyst system reported to date. Ligands 3 and 4 are air-stable, crystalline solids that are commercially available. Their effectiveness is believed to be due to a combination of steric and electronic properties that promote oxidative addition, Pd-N bond formation, and reductive elimination. Owing to the many important applications of aniline derivatives, and the limitations of most methods for their synthesis, a considerable amount of effort has been recently devoted to the development of catalysts that are capable of effecting the cross-coupling of amines with aryl halides and sulfonates.1 However, the proper choice of catalyst (Pd source, ligand choice) is crucial for the success of these reactions.
    [Show full text]
  • Room-Temperature Copper-Catalyzed Synthesis of Primary Arylamines from Aryl Halides and Aqueous Ammonia
    LETTER 1355 Room-Temperature Copper-Catalyzed Synthesis of Primary Arylamines from Aryl Halides and Aqueous Ammonia SynthesisChuanzhou of Primary Arylamines Tao,*a Weiwei Liu,a Aifeng Lv,b Mingming Sun,a Ying Tian,a Qi Wang,a Jing Zhao*b a School of Chemical Engineering, Huaihai Institute of Technology, Lianyungang 222005, P. R. of China Fax +86(518)85895121; E-mail: [email protected] b State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, P. R. of China Fax +86(25)83592672; E-mail: [email protected] Received 11 February 2010 In the meantime, Fu et al. reported a mild copper-cata- Abstract: Primary arylamines can be prepared via a copper-cata- lyzed cross-coupling between aryl halides and aqueous ammonia lyzed coupling of aryl boronic acids and aqueous ammo- nia (Scheme 1).6 The reaction proceeds at room using K3PO4 as a base and DMF as a solvent at room temperature. temperature without ligands, bases, or other additives, and Key words: copper, catalysis, cross-coupling, room temperature, aqueous ammonia, primary arylamine many functional groups are tolerated under mild condi- tions. However, the cost and availability of the aryl boron- ic acids, particularly the highly functionalized ones, hampers their applications. Usually aryl halides are pre- Primary arylamines are important intermediates in the ferred substrates because these electrophiles tend to be manufacture of agrochemicals, pharmaceuticals, dyes, cheaper and easier to prepare. Thus, we set out to develop pigments, and rubber.1 Their preparation has attracted in- more economical, practical, and efficient protocols for the creasing attention.
    [Show full text]
  • Alkaloids 11
    THÈSE Pour obtenir le grade de DOCTEUR DE L’UNIVERSITÉ DE GRENOBLE Spécialité : CHIMIE ORGANIQUE Arrêté ministériel : 7 août 2006 Présentée par ANUSHREE KAMATH Thèse dirigée par Dr. PHILIPPE DELAIR préparée au sein du DCM-SERCO dans l'École Doctorale Chimie et Sciences du Vivant Contribution à la synthèse totale de l'alcaloïde (-)-205B Thèse soutenue publiquement le 24 Mai, 2011 devant le jury composé de : Prof. Mercedes AMAT Professeur, Universit é de Barcelone, Rapporteur Dr. Bernard DELPECH Directeur de Recherche, Institut de Chimie des Substances Naturelles CNRS, Gif-sur-Yvette, Rapporteur Prof. Yannick VALLÉE Professeur, Départment de Chimie Mol éculaire, Université Joseph Fourier, Grenoble, Examinateur Dr. Philippe DELAIR Maître de Conférence, Départment de Chimie Mol éculaire, Université Joseph Fourier, Grenoble, Directeur de thèse Dr. Andrew E. GREENE Directeur de Recherche, Départment de Chimie Mol éculaire, Université Joseph Fourier, Grenoble, Invité Table of Contents Abbreviations 3 General Introduction 6 I. Introductions to Alkaloids 11 1.1 Introduction: General 12 1.2 Biosynthesis of alkaloids 14 1.3 Ecological role of alkaloids 15 II. Alkaloids from the Amphibian skin 18 2.1 Introduction 19 2.2 Coding System of dendrobatid alkaloids 22 2.3 Structural Classification 23 2.4 Biosynthesis and ecological role 24 2.5 Alkaloid (-)-205B: Isolation and Structure elucidation 27 III. Amphibian Alkaloids: Biological Perspectives 29 3.1 General principles 30 3.2 Nicotinic Acetyl Choline Receptors: Structure and Functions 32 3.3 Alkaloids from the frog skin: Pharmacological activities 35 IV. Reported Syntheses 38 4.1 First total synthesis of the antipode of Alkaloid (-)-205B 39 4.2 A convergent Multi-Component Linchpin coupling strategy for synthesis of (-)-205B 44 V.
    [Show full text]