DOCSLIB.ORG

Copper and Nickel Catalysis for Alkynylation Reactions

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Copper and Nickel Catalysis for Alkynylation Reactions Université de Montréal Copper and Nickel Catalysis for Alkynylation Reactions par Jeffrey Santandrea Département de chimie Faculté des arts et des sciences Thèse présentée à la Faculté des études supérieures et postdoctorales en vue de l’obtention du grade de Philosophiæ Doctor (Ph.D.) en chimie Avril 2018 © Jeffrey Santandrea, 2018 Résumé Les alcynes sont reconnus comme étant des groupements fonctionnels polyvalents pouvant participer à de multiples transformations chimiques. Conséquemment, le développement de nouvelles méthodologies efficaces et chimiosélectives pour permettre la formation d’alcynes internes substitués par des atomes de carbone ou par des hétéroatomes est intéressant. La thèse suivante décrit ainsi le développement de nouveaux systèmes catalytiques à base de cuivre et de nickel pour effectuer des réactions d’alcynylation. Les travaux présentés au Chapitre 3 décrivent le premier couplage croisé de type Sonogashira catalysé par le cuivre menant à la formation de macrocycles à partir de précurseurs linéaires non-biaisés conformationnellement. Le couplage croisé macrocyclique de type Sonogashira a exploité un système catalytique CuCl/phen/Cs2CO3 pour générer 17 macrocycles de différentes tailles de cycle (10 à 25 chaînons) et différents groupements fonctionnels avec des rendements compris entre 38 et 83 %. De plus, la méthode a été réalisée à une concentration relativement élevée (24 mM) sans recourir à des techniques d'addition lente. Les conditions réactionnelles optimisées ont aussi été appliquées à la synthèse du (S)-zéaralane, un produit biologiquement actif. Les travaux présentés au Chapitre 6 décrivent la première synthèse de thioalcynes arylés par le biais de la catalyse photorédox et de la catalyse au nickel. Le couplage C(sp)-S a été réalisé entre des thiols et des bromoalcynes aromatiques en utilisant un système catalytique 4CzIPN/NiCl2•glyme/pyridine sous irradiation de la lumière visible à température ambiante. Ainsi, des thioalcynes dérivés de plusieurs thiols et d'alcynes aromatiques électroniquement et stériquement variés ont été obtenus avec de bons rendements (50-96 %) en utilisant un photoréacteur impliquant lumière visible en flux continu. La méthodologie a également été appliquée à la synthèse d'un macrocycle, un exemple rare de macrocyclisation photochimique en flux continu. La procédure photochimique bi-catalytique représente aussi le premier exemple de macrocyclisation exploitant la double catalyse photorédox/nickel. Les travaux présentés au Chapitre 7 décrivent la première méthode générale pour accéder à toutes les classes de thioalcynes, y compris les thioalcynes comportant des substituants aryle, i alkyle, silyle et des hétéroatomes, par le biais de la catalyse au cuivre. Le système catalytique Cu(MeCN)4PF6/dtbbpy/2,6-lutidine a donné accès à des thioalcynes avec des rendements élevés en dix minutes, tout en étant hautement reproductible, même à grande échelle. De plus, la méthodologie a efficacement mené à la synthèse d’un alcyne di(thio-substitué), un exemple rare d'alcyne orné de deux hétéroatomes comme substituants. Mots-clés : catalyse au cuivre, catalyse au nickel, catalyse photorédox, macrocyclisation, réaction de Sonogashira, thioalcynes, chimie en flux continu ii Abstract Alkynes are recognized as versatile building blocks for chemical synthesis as they can participate in an array of transformations. Consequently, expanding the toolbox of efficient and chemoselective methodologies to access internal carbon- and heteroatom-substituted alkynes is of interest. The following thesis describes the development of new copper- and nickel-based catalytic systems to perform alkynylation reactions. The research presented in Chapter 3 describes the first report of a copper-catalyzed Sonogashira-type cross-coupling toward the formation of macrocycles from conformationally unbiased linear precursors. The macrocyclic Sonogashira-type cross-coupling exploited a CuCl/phen/Cs2CO3 catalytic system to generate 17 macrocycles with various ring sizes (10- to 25-membered rings) and functional groups in yields ranging between 38-83 %. Also, the method could be performed at relatively high concentrations (24 mM) without the need for slow addition techniques. The optimized reaction conditions were additionally applied toward the synthesis of a biologically active natural product, (S)-zearalane. The research presented in Chapter 6 describes the first report of a photoredox/nickel dual-catalytic synthesis of aryl- and heteroaryl-substituted alkynyl sulfides. The C(sp)-S bond- forming coupling was achieved between thiols and aromatic bromoalkynes using a 4CzIPN/NiCl2•glyme/pyridine catalytic system under visible-light irradiation at room temperature. Alkynyl sulfides bearing a wide range of electronically and sterically diverse aromatic alkynes and thiols were obtained in good to excellent yields (50-96 %) using an in- house designed visible-light photoreactor in continuous flow. The methodology was also applied toward the synthesis of a macrocycle, a rare example of a photochemical macrocyclization performed in continuous flow. The photochemical dual-catalytic procedure represented the first example of a macrocyclization exploiting photoredox/nickel dual-catalysis. The research presented in Chapter 7 describes the first general method to access all classes of alkynyl sulfides through copper catalysis, including aryl-, alkyl-, silyl-, and heteroatom-substituted alkynyl sulfides. The Cu(MeCN)4PF6/dtbbpy/2,6-lutidine catalyst system gave access to alkynyl sulfides in high yields under ten minutes, and was highly reproducible even on large scale. Furthermore, the methodology efficiently led to a bis(thio- iii substituted)alkyne, a rare example of an alkyne functional group adorned with two heteroatom substituents. Keywords : copper catalysis, nickel catalysis, photoredox catalysis, macrocyclization, Sonogashira reaction, alkynyl sulfides, continuous flow chemistry iv Table of Contents Résumé ......................................................................................................................................... i Abstract ...................................................................................................................................... iii Table of Contents ........................................................................................................................ v List of Tables ............................................................................................................................. ix List of Figures ............................................................................................................................. x List of Schemes ......................................................................................................................... xii List of Abbreviations ................................................................................................................ xv Acknowledgments ................................................................................................................... xxii 1. Introduction to Macrocycles .................................................................................................. 1 1.1 Importance and Applications of Macrocycles ................................................................................. 1 1.1.1 Medicinal Chemistry ................................................................................................................ 2 1.1.2 Aroma Chemistry ..................................................................................................................... 4 1.1.3 Supramolecular Chemistry ....................................................................................................... 5 1.2 Synthetic Challenges in Macrocyclization Reactions ...................................................................... 7 1.2.1 Kinetic Aspects ......................................................................................................................... 7 1.2.2 Reactive Conformation ........................................................................................................... 10 1.3 Employing Catalysis for Macrocycle Synthesis ............................................................................ 12 1.3.1 Ring-Closing Metathesis ........................................................................................................ 12 1.3.2 Copper-Catalyzed Azide-Alkyne Cycloaddition .................................................................... 14 1.4 Conclusions.................................................................................................................................... 15 1.5 Bibliography .................................................................................................................................. 16 2. Introduction to the Sonogashira Reaction ............................................................................ 19 2.1 Discovery and Evolution of C(sp2)-C(sp) Couplings .................................................................... 19 2.2 Applications Toward Macrocyclization ......................................................................................... 23 2.2.1 Synthesis of Macrocyclic Natural Products ............................................................................ 23 2.2.2 Synthesis of Macrocyclic Nonnatural Products ...................................................................... 25 2.3 Development of
Load more

Recommended publications
  • Cubane and Triptycene As Scaffolds in the Synthesis of Porphyrin Arrays
    Cubane and Triptycene as Scaffolds in the Synthesis of Porphyrin Arrays Submitted by Gemma M. Locke B.A. (Mod.) Medicinal Chemistry Trinity College Dublin, Ireland A thesis submitted to the University of Dublin, Trinity College for the degree of Doctor of Philosophy Under the Supervision of Prof. Dr. Mathias O. Senge University of Dublin, Trinity College September 2020 Declaration I declare that this thesis has not been submitted as an exercise for a degree at this or any other university and it is entirely my own work. I agree to deposit this thesis in the University’s open access institutional repository or allow the Library to do so on my behalf, subject to Irish Copyright Legislation and Trinity College Library conditions of use and acknowledgement. I consent to the examiner retaining a copy of the thesis beyond the examining period, should they so wish. Furthermore, unpublished and/or published work of others, is duly acknowledged in the text wherever included. Signed: ____________________________________________ March 2020 Trinity College Dublin ii Summary The primary aim of this research was to synthesise multichromophoric arrays that are linked through rigid isolating units with the capacity to arrange the chromophores in a linear and fixed orientation. The electronically isolated multichromophoric systems could then ultimately be tested in electron transfer studies for their applicability as photosynthesis mimics. Initially, 1,4-diethynylcubane was employed as the rigid isolating scaffold and one to two porphyrins were reacted with it in order to obtain the coupled product(s). Pd-catalysed Sonogashira cross-coupling reactions were used to try and achieve these bisporphyrin complexes.
    [Show full text]
  • A New Method for Synthesis of Aziridine 2-Phosphonates and Their Biological Activities
    A NEW METHOD FOR SYNTHESIS OF AZIRIDINE 2-PHOSPHONATES AND THEIR BIOLOGICAL ACTIVITIES A THESIS SUBMITTED TO THE GRADUATE SCHOOL OF NATURAL AND APPLIED SCIENCES OF MIDDLE EAST TECHNICAL UNIVERSITY BY HAKAN BAB İZ IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN CHEMISTRY SEPTEMBER 2010 Approval of the thesis: A NEW METHOD FOR SYNTHESIS OF AZIRIDINE 2-PHOSPHONATES AND THEIR BIOLOGICAL ACTIVITIES submitted by HAKAN BAB İZ in partial fulfillment of the requirements for the degree of Master of Science in Chemistry Department, Middle East Technical University by, Prof. Dr. Canan Özgen _____________________ Dean, Graduate School of Natural and Applied Sciences Prof. Dr. İlker Özkan _____________________ Head of Department, Chemistry Prof. Dr. Özdemir Do ğan ______________________ Supervisor, Chemistry Dept., METU Examining Committee Members: Prof. Dr. Ayhan S. Demir ______________________ Chemistry Dept., METU Prof. Dr. Özdemir Do ğan ______________________ Chemistry Dept., METU Prof. Dr. Cihangir Tanyeli ______________________ Chemistry Dept., METU Prof. Dr. Metin Zora ______________________ Chemistry Dept., METU Assoc. Prof. Dr. Adnan Bulut ______________________ Chemistry Dept., Kırıkkale Üniv. Date: 17.09.2010 I hereby declare that all information in this document has been obtained and presented in accordance with academic rules and ethical conduct. I also declare that, as required by these rules and conduct, I have fully cited and referenced all material and results that are not original to this work. Name, Last name : Hakan Babiz Signature : iii ABSTRACT SYNTHESIS OF AZIRIDINE 2-PHOSPHONATES AND THEIR BIOLOGICAL ACTIVITIES Babiz, Hakan M.S., Department of Chemistry Supervisor: Prof. Dr. Özdemir Do ğan September 2010, 74 pages A systematic study was carried out for the synthesis of aziridine 2-phosphonates by using two methods.
    [Show full text]
  • Transannular Interactions in Medium-Ring Carbocycles: Theoretical and Experimental Investigations
    Transannular interactions in medium-ring carbocycles: Theoretical and experimental investigations Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften im Fachbereich Chemie der Universität Duisburg-Essen vorgelegt von Parveen Choudhary Mohr Chandigarh, India 2006 This work was carried out between January 2004 and July 2006 at the Fachbereich Chemie, Universität Duisburg-Essen, Germany. The systems discussed in chapter 7 (section 7.2) and 10 (section 10.2) have been studied using Gamess under supervision of Prof. Dr. Harjinder Singh, Dr. Tej Vir Singh and Dr. Paloth Venugopalan at Panjab University, Chandigarh, India. Ph.D. Advisor: Prof. Dr. Paul Rademacher Referee: Prof. Dr. Dr. h.c. Reiner Sustmann Date of the oral examination and defense of the Ph.D. thesis: 25-10-2006 For Andreas and my family Acknowledgments During my research work I have been accompanied and supported by many people directly or indirectly. Today, I am very pleased to express my gratitude to all of them. First and foremost I would like to express my sincere gratitude and thanks to my advisor Prof. Dr. Paul Rademacher at the Universität Duisburg-Essen for his valuable advice, guidance and constant encouragements throughout this research work. His editorial advice was essential to the completion of this dissertation and has given me insights on the workings of scientific research in general. Moreover, I am especially thankful to him for providing me the opportunity to work at Universität Duisbürg- Essen and carry out this research work. Special thanks are due to Prof. Dr. Dr. h. c. Reiner Sustmann for providing generous support and opportunity to attend and discuss my research work in his research group seminars.
    [Show full text]
  • Calculations 273 Absolute Asymmetric Synthesis 634, 635 Absolute
    1317 Index A activation enthalpy 23, 39, 188, 195–196, 204, 205, 206, aaptosine 358, 359 217, 339, 341, 345, 370, 393, 398, 411, 412, 443, 444, ab initio Hartree–Fock (HF) calculations 273 452, 453, 462, 465, 500, 697, 728 absolute asymmetric synthesis 634, 635 activation entropy 39, 188, 190, 192–196, 198, 369, 500, absolute electronegativity 37 689, 695, 872 absolute hardness 37–39, 839 activation entropy and reaction mechanism absolute softness 37 – Cope rearrangement 195 absorbance 616 – gas phase – – homolysis and radical combination 192–193 absorption complex 624, 667 – – isomerizations 193–194 absorption on crystalline quartz 44 – neighboring group directing effects 197 acetaldehyde 15, 18, 60, 66, 70, 80, 82, 86, 145, 146, 147, – retro-carbonyl-ene reaction 195–197 195, 197, 223, 514, 551, 619, 683, 686, 697, 732, 797, activation parameters 819, 855, 920, 921, 1168 – Curtin–Hammett principle 190–192 acetamide 62, 66, 82, 89, 619 – temperature effect, two parallel reactions 190 acetic acid 12, 13, 49, 60, 87, 89, 151, 373, 503, 619, 650, acyclic ,-and,-enones 60, 642 699, 800, 808, 900, 1030, 1032–1034, 1050 acyclic alkylaminocarbene 439 acetic anhydride 12, 61, 216, 619, 802, 1033 acyclic diene 55, 468, 633, 1126 acetone 15, 25, 35, 36, 60, 70, 80, 85, 86, 88, 90, 122, acyclic 1,3-dienes 55, 697, 698 143, 146–148, 153, 203, 210, 213, 224, 226, 229–232, acyclic dithiosilylene 448 373, 374, 382, 383, 412, 413, 435, 619, 622, 623, 628, acyclic peroxides 729 633, 637, 638, 641, 656, 662, 669, 671, 682, 685, 686, (1,2)-acyloxy shifts
    [Show full text]
  • A Theoretical Investigation of the Ring Strain Energy, Destabilization Energy, and Heat of Formation of CL-20
    Hindawi Publishing Corporation Advances in Physical Chemistry Volume 2012, Article ID 175146, 7 pages doi:10.1155/2012/175146 Research Article A Theoretical Investigation of the Ring Strain Energy, Destabilization Energy, and Heat of Formation of CL-20 John A. Bumpus Department of Chemistry and Biochemistry, University of Northern Iowa, Cedar Falls, IA 50614, USA Correspondence should be addressed to John A. Bumpus, [email protected] Received 10 April 2012; Accepted 13 August 2012 Academic Editor: Dennis Salahub Copyright © 2012 John A. Bumpus. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The cage compound CL-20 (a.k.a., 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane, HNIW, or 2,4,6,8,10,12-hexanitro- 2,4,6,8,10,12-hexaazatetracyclo[5.5.0.03,11.05,9]dodecane) is a well-studied high-energy-density material (HEDM). The high Δ ◦ Δ ◦ positive gas- ( f Hg ) and solid- ( f Hs ) phase heat of formation values for CL-20 conformers have often been attributed to the strain energy of this cage compound and, by implication, to the conventional ring strain energy (CRSE) inherent in isowurtzitane Δ ◦ which may be viewed as a “parent compound” (although not the synthetic precursor) of CL-20. f Hg values and destabilization energies (DSEs), which include the contribution from CRSE, were determined by computation using a relatively new multilevel ab intio model chemistry. Compared to cubane, isowurtzitane does not have an exceptionally high CRSE.
    [Show full text]
  • From H to F: Strategies in Selective Sp3 C-H Fluorination by STEVEN P
    From H to F: Strategies in Selective sp3 C-H Fluorination BY STEVEN P. BLOOM A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland March, 2015 ABSTRACT The replacement of a single hydrogen atom by fluorine can impart a unique set of chemical and physical properties onto organic molecules, oftentimes modifying their reactivity. In many instances, fluorination improves the metabolic stability of pharmaceuticals, amplifies the electronic properties of polymers, and heightens the efficiency of industrial solvents and surfactants. Despite these and others, fluorination methods have endeavored to become commonplace, a fact consistent with the lack of synthetically mild sources of atomic fluorine. Until recently, fluorination strategies have been predicated upon the use of harsh, unselective, and often destructive sources of fluorine, such as fluorine gas and explosive hypofluorites, limiting their synthetic utility. Over the last 20 years, the advent of bench-top stable N-F reagents have incurred a renaissance in the discovery of regio- and chemoselective methods for the direct incorporation of fluorine atoms into organic molecules. In this Dissertation, the applications of one such N-F compound, 1-chloromethyl-4- fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) is highlighted as a practical reagent for the monofluorination of unactivated sp3 C-H bonds of aliphatic, benzylic, and allylic containing compounds in conjunction with earth-abundant, inexpensive transition metals and commercially available photocatalysts. The use of Selectfluor in the α,α-difluorination of acid chloride derivatives and photocatalyzed ring opening-β-fluorination of cyclopropanols is ii likewise discussed.
    [Show full text]
  • Nonconjugated Hydrocarbons As Rigid‐Linear Motifs: Isosteres For
    DOI:10.1002/chem.201804225 Review & Materials Science NonconjugatedHydrocarbons as Rigid-Linear Motifs:Isosteresfor Material Sciences and Bioorganic and Medicinal Chemistry GemmaM.Locke,Stefan S. R. Bernhard, and Mathias O. Senge*[a] DedicatedtoProfessor Philip E. Eaton Chem. Eur.J.2019, 25,4590 –4647 4590 2019 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Review Abstract: Nonconjugated hydrocarbons, likebicyclo[1.1.1]- manner. In this Review article, recent developments and pentane, bicyclo[2.2.2]octane, triptycene, andcubane are a usagesofthese special, rectilinear systems are discussed. unique class of rigid linkers. Due to their similarity in size Furthermore, we focusoncovalently linked, nonconjugated and shape they are useful mimics of classic benzene moie- linear arrangements and discuss the physical and chemical ties in drugs, so-calledbioisosteres.Moreover,they also fulfill properties and differences of individual linkers, as well as an important role in material sciences as linear linkers, in their applicationinmaterial and medicinalsciences. order to arrangevarious functionalities in adefined spatial 1. Introduction cyclo[2.2.2]octane (BCO) and triptycene (Figure 1). In particular, the use of triptycene as amolecular rotor has received much Arranging functionalities in alinear fashion enablesthe altera- interest, propelled by the Nobel prize in chemistry for molecu- tion of the distance between functionalities withoutaffecting lar machines awarded in 2016.[4] the overall geometry of the molecule, and this is of high im- This Reviewaims at identifyingthe origins of rigid-linear-ali- portanceinmedical and materialsciences. This can be achiev- phatichydrocarbons and their use in functional materials, ed with nonconjugated rigid hydrocarbons (NRHs) which share while tying together the chemistry,differences and commonal- three main features for their usage in biological and material ities between thesegroups and outlining the missing compo- sciences:1)they are rigid,that is, all conformational changes nents of those dormantgroups.
    [Show full text]
  • A Polycomponent Metalcatalyzed Aliphatic, Allylic, and Benzylic
    Angewandte Chemie DOI: 10.1002/anie.201203642 Synthetic Methods A Polycomponent Metal-Catalyzed Aliphatic, Allylic, and Benzylic Fluorination** Steven Bloom, Cody Ross Pitts, David Curtin Miller, Nathan Haselton, Maxwell Gargiulo Holl, Ellen Urheim, and Thomas Lectka* The selective incorporation of fluorine into organic molecules 18% yield and in good selectivity [8:1 with respect to 2- has advanced in dramatic ways over the last 30 years.[1] fluoroadamantane (3)]. It should be noted that in the absence Although arene[2] and alkyne[3] fluorination using metal of a metal catalyst, the reaction produced no fluorinated catalysis has received much attention, the corresponding products under the specified reaction conditions. At this methods for metal-catalyzed alkane fluorination remain only point, a number of other copper(I) salts were screened (CuBr, [4] a promising goal [Eq. (1)]. To date, the most notable CuCl, CuClO4), but CuI proved to be the most effective. For example, CuCl afforded only trace amounts of product, whereas CuClO4 resulted in a complex mixture of highly fluorinated adamantane-based products in variable quanti- ties. Our group has shown that reactions employing Selectfluor concomitant with a metal cocatalyst can be accelerated by the addition of a phase-transfer catalyst as a solubilizing agent methods for alkane fluorination[5] involve the use of stoichio- and presumed metal counteranion exchanger.[10] To this end, metric quantities of difficult-to-handle or indiscriminate we added KB(C6F5)4 (10 mol%) to our reaction
    [Show full text]