DOCSLIB.ORG

1. Reduction of Tertiary Benzamides to Benzaldehydes by an in Situ–Generated Schwartz Reagent

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
1. Reduction of Tertiary Benzamides to Benzaldehydes by an in Situ–Generated Schwartz Reagent 1. Reduction of Tertiary Benzamides to Benzaldehydes by an in situ–Generated Schwartz Reagent (Cp2Zr(H)Cl); Formal Synthesis of Lysergic Acid 2. Ru-Catalyzed Amide-Directed Aryl C-H, C-N and C-O Bond Functionalizations: C-B Formation, C-C Suzuki Cross Coupling and Hydrodemethoxylation by Yigang Zhao A thesis submitted to the Department of Chemistry In conformity with the requirements for the degree of Doctor of Philosophy Queen’s University Kingston, Ontario, Canada December, 2010 Copyright ©Yigang Zhao, 2010 ABSTRACT Chapter 2 of the thesis describes a highly efficient in situ method for the reduction of amides to aldehydes and aryl O-carbamates to phenols and other transformations involving hydrozirconations. The method, as a three-component-type reaction, involves in situ generation of the Schwartz reagent (Cp2Zr(H)Cl) from Cp2ZrCl2 and the reductant, LiAlH(O-t-Bu)3, and immediate reaction with a substrate. Substrates include aliphatic and aromatic tertiary amides which are reduced to aldehydes, aryl O-carbamates which are reduced to phenols, and alkynes which undergo other transformations via hydrozirconation. Compared to prior methods, this method has advantage in that reagents are inexpensive and stable, reaction times are short, and reaction temperatures are generally conveniently at room temperature. The use of the in situ method described herein instead of the requirement for the synthesis of the commercially available Schwartz reagent is estimated to provide more than 50% reduction in cost. Chapter 3 of the thesis describes the discovery and development of efficient and regioselective Ru-catalyzed amide-directed C-H, C-N, C-O activation/C-C bond forming reactions, ester-directed C-O activation/C-C bond forming reaction, and amide-directed C-O activation/hydrodemethoxylation reactions under a simple RuH2(CO)(PPh3)3/toluene catalytic system. Of these, the amide-directed C-H activation/cross coupling reaction proceeds well but uniquely on furan 3-amide substrates while the ester-directed C-O activation is effective on the 2- MeO-1-naphthoic acid methyl ester. On the other hand, the amide-directed C-N and C-O activation/coupling reactions are broadly applicable on benzamides and naphthamides. All of these achievements of directed C-H, C-N, C-O activation/coupling reactions complement and may supercede the DoM (directed ortho metalation)-cross coupling strategy, and establish the catalytic base-free DoM-cross coupling process at non-cryogenic temperature as a convenient, ii economical and green alternative. The new catalytic amide-directed ortho-hydrodemethoxylation reaction has potential value in links to aromatic electrophilic substitution and DoM chemistries. Furthermore, a new borylation reaction via Ru-catalyzed amide-directed C-H activation/C-B bond forming process is also reported herein. iii ACKNOWLEDGEMENTS First and foremost, I would like to thank Professor Victor Snieckus for providing me the opportunity to be a part of the incredible and unique group where, learning and practising chemistry under his constant guidance and encouragement, I have been achieving my dream to be a good synthetic chemist. His kindness, enthusiasm and patience are not only limited to research, but they are also much beneficial to my life. Many thanks to Prof. Whitney and Prof. Jessop, committee members of my graduate research, for reviewing my progresses during these years. Special appreciations to Dr. Sauriol and Dr. Jiaxi Wang for the helpful discussions on NMR and MS analysis. Many thanks also to Krista Voigt and Annette Keyes for their helps on my graduate study management. Next, I would like to thank everyone who I work with over these years in my dear Snieckus group. We share friendship each other and leave many good memories with us. Graduate students: Xiongwei, Kevin, Chris, Justin, Sunny, Eric, Todd, Manlio, Tom, Katie, Zhongdong, Wei; Postdocs: Thomas, Till, Robert, Marc, Heiko, Barbel, Oleg, Toni, Jianxin, John, Tim, Jignesh, Emilie, Cedric, Matt; Visiting professors and scholars: Simon, Wole, Alcides, Haji, Xueling. Finally, I thank my wife, Haixia, for her endless encouragement and understanding, and my son and daughter, Ryan and Eva, for their bright smiles. I owe everything to them for making this all possible. iv STATEMENT OF ORIGINALITY I (Yigang Zhao) hereby certify that all of the work described within this thesis is the original work of the author under the supervision of Prof. V. Snieckus. Any published (or unpublished) ideas and/or techniques from the work of others are fully acknowledged in accordance with the standard referencing practices. Yigang Zhao December, 2010 v To Haixia, Ryan and Eva vi TABLE OF CONTENTS ABSTRACT ii ACKNOWLEDGEMENTS iv STATEMENT OF ORIGINALITY v DEDICATION vi TABLE OF CONTENTS vii LIST OF FIGURES xi LIST OF TABLES xii ABBREVIATIONS xvi Chapter 1. Introduction to the Directed ortho Metalation (DoM) 1.1 History 1 1.2 Directed ortho Metalation Groups (DMGs) 2 1.3 Mechanism of DoM 4 1.4 Utility of DoM Chemistry 6 1.4.1 Utility of the DoM Reaction 6 1.4.2 Utility of the Directed remote Metalation (DreM) Reaction 7 1.4.3 The Combined DoM–Transition Metal-catalyzed Cross Coupling Reaction 8 1.5 Limitations 9 vii Chapter 2. Reduction of Tertiary Benzamides to Benzaldehydes by an in situ- Generated Schwartz Reagent (Cp2Zr(H)Cl); Formal Synthesis of Lysergic Acid 2.1 Introduction 11 2.1.1 Reduction of Tertiary Amides 11 2.1.2 Schwartz Reagent and Georg’s Discovery 17 2.2 Research Goals 22 2.2.1 The Schwartz Reagent and DoM-Derived Benzamides 22 2.2.2 Amide Reduction by the in situ–Generated Schwartz Reagent 23 2.3 Results and Discussion 24 2.3.1 Reduction of DoM–Derived Benzamides by the Schwartz Reagent 24 2.3.2 In situ–Generation of Schwartz Reagent and Use 32 2.3.2.1 Amide Reduction by the in situ–Generated Schwartz Reagent 32 2.3.2.2 Reductive Cleavage of Aromatic O-Carbamates to Phenols by the 43 in situ–Generated Schwartz Reagent 2.3.2.3 Other Application of the in situ–Generated Schwartz Reagent 46 2.3.3 Attempts on Catalytic Reduction of Tertiary Amides to Aldehydes by the 47 Schwartz Reagent 2.4 Conclusions 49 2.5 Utility of the in situ–Generated Schwartz Reagent Methodology 49 2.6 Future Work 50 viii 2.7 Formal Synthesis of Lysergic Acid: Application of the DoM Strategy and Amide 51 to Aldehyde Reduction by the Schwartz Reagent 2.7.1 Results and Discussion 53 2.7.2 Conclusion and Future Work 56 2.8 Experimental Section 57 Chapter 3. Ru-Catalyzed Amide-Directed Aryl C-H, C-N and C-O Bond Functionalizations: C-B Formation, C-C Cross Coupling and Hydrodemethoxylation 3.1 Introduction 107 3.1.1 Directed ortho C-H Bond Activation and Aryl-Aryl Cross Coupling 109 3.1.1.1 Arylation with Aryl Halides 113 3.1.1.2 Arylation with Organometallic Reagents 121 3.1.2 C-O Bond Activation and Cross Coupling 132 3.1.3 C-N Bond Activation and Cross Coupling 137 3.2 Research Goals 139 3.3 Results and Discussion 142 3.3.1 C-H Activation and C-C Bond Formation 142 3.3.2 C-N Activation and C-C Bond Formation 151 3.3.3 C-O Activation and C-C Bond Formation 165 3.3.3.1 C-O Activation of Benzamides and C-C Bond Formation 165 3.3.3.2 C-O Activation of Naphthamides and C-C Bond Formation 181 3.3.3.3 Ester-Directed C-O Activation and C-C Bond Formation 193 ix 3.3.4 Proposed Mechanism for Ru-Catalyzed Amide- and Ester-Directed C-H, 197 C-N, C-O Activation/Cross Coupling Reactions 3.3.5 C-O Activation and Reduction (Hydrodemethoxylation) 198 3.3.6 C-H Activation and C-B Bond Formation 206 3.3.7 Ru-Catalyzed Hydrodehalogenation of Aryl C-Cl, C-Br and C-I Bonds 211 3.4 Conclusions 213 3.5 Utility of Products 215 3.6 Future Work and Outlook 215 3.7 Experimental Section 217 References 339 x LIST OF FIGURES Fig. 1.1 DMG Hierarchy 4 Fig. 2.1 in situ Processes 24 Fig. 2.2 Comparison of the Georg and in situ Schwartz Reduction Methods 39 Fig. 2.3 Lysergic Acid 51 xi LIST OF TABLES Table 1.1 Common Directed Metalation Groups (DMGs) 3 Table 1.2 Common DoM–Cross Coupling Combination Reactions 9 Table 2.1 The Ease of Reduction of Functional Groups with LAH in Ether 12 Table 2.2 Functional Group Compatibility in the Schwarz Reduction of Substituted 25 Benzamides 2.1a-2.13a Table 2.3 Schwartz Reduction of DoM-Derived Benzamides and Naphthamides 28 2.14a-2.24a Table 2.4 Amide Substituent Effects on the Facility of Benzamide Reduction by the 30 Schwartz Reagent Table 2.5 Reductive Cleavage of Indole and Benzimidazole N-Amides 2.29a-2.34a 31 Using the Schwartz Reagent Table 2.6 Screening Reductants for the in situ Schwartz Reduction of 4- 34 Bromobenzamide 2.12a Table 2.7 Comparison of Solvents for the in situ Schwartz Reduction of 4- 34 Bromobenzamide 2.12a Table 2.8 Comparison of Solvents in the Direct Reduction Reported by Georg 35 Table 2.9 Reduction of N,N-Diethyl Amides via the in situ Schwartz Method 37 Table 2.10 Reduction of Differentially N,N-Disubstituted Tertiary Amides via in situ 40 Schwartz Method Table 2.11 Reductive Cleavage of Aryl O-Carbamates to Phenols via the in situ 45 Schwartz Method xii Table 2.12 Regio-and Stereo-Selective Conversion of Alkynes to E-Iodoalkenes via in 47 situ Schwartz Reagent Method Table 3.1 Bond Dissociation Energies of Phenyl Compounds 108 Table 3.2 Screening for Amide-Directed C-H Activation 144 Table 3.3 Amide-Directed C-H Activation and C-C Cross Coupling of N,N-Diethyl 147 Furan-3-carboxamide Table 3.4 C-N Activation/C-C Cross Coupling of the Three Isomeric Dimethylamino 153 Benzamides 3.61-3.63 Table 3.5 Screening Boron Reagents for Cross Coupling of 2-Me2N-N,N-diethyl 154
Load more

Recommended publications
  • United States Patent (19) 11 Patent Number: 6,057,352 Brown Et Al
    US006057352A United States Patent (19) 11 Patent Number: 6,057,352 Brown et al. (45) Date of Patent: May 2, 2000 54 FUNGICIDAL CYCLIC AMIDES WO 96/17851 6/1996 WIPO ............................... CO7F 7/08 WO 96/26.191 8/1996 WIPO ... ... CO7D 249/12 75 Inventors: Richard James Brown, Newark, Del.: WO 96/36633 11/1996 WIPO ... ... CO7D 405/04 Deborah Ann Frasier, Martinez, Calif.; WO96/36229 11/1996 WIPO ... ... A01N 43/653 Michael Henry Howard, Jr., WO 97/02255 1/1997 WIPO m CO7D 261/12 Rockland; Gerard Michael Koether, OTHER PUBLICATIONS Bear, both of Del. Zvilichovsky, G., J. Heterocyclic Chem., 24,465–470, 1987. 73 Assignee: E. I. du Pont de Nemours and Zvilichovsky, G. et al., J. Heterocyclic Chem., 25, Company, Wilmington, Del. 1307-1310, 1988. Davis, M. et al., Australian J. Chem., 30(8), 1815-1818, 21 Appl. No.: 08/952,380 1977. 22 PCT Filed: May 8, 1996 Primary Examiner Mukund J. Shah 86 PCT No.: PCT/US96/06534 Assistant Examiner Deepak R. Rao S371 Date: Nov. 13, 1997 57 ABSTRACT S 102(e) Date: Nov. 13, 1997 Compounds of Formula (I), 87 PCT Pub. No.: WO96/36616 (I) PCT Pub. Date: Nov. 21, 1996 1.Y. Nz Related U.S. Application Data x - W 63 Continuation-in-part of application No. 08/442,433, May NY 17, 1995, abandoned. A-N 60 Provisional application No. 60/004,183, Sep. 22, 1995. Ye 51) Int. Cl." ...................... C07D 249/12; CO7D 233/30; AO1N 43/74; AO1N 43/56 and their N-oxides and agriculturally Suitable Salts are 52 U.S.
    [Show full text]
  • Chem 314 Preorganic Evaluation
    Organic Reaction Guide Beauchamp 1 Chem 316 / Beauchamp Reactions Review Sheet Name SN2 Reactions - special features: biomolecular kinetics Rate = kSN2[RX][Nu ], single step concerted reaction, E2 is a competing reaction o o o o relative order of reactivity: CH3X > 1 RX > 2 RX >> 3 RX (based on steric hinderance, no SN2 at 3 RX) allylic & benzylic RX are very reactive, adjacent pi bonds help stabilize transition state and lower TS energy (Ea) o complete substitution at Cα (3 RX) or Cβ (neopentyl pattern) almost completely inhibits SN2 reactions vinyl & phenyl are very unreactive, bonds are stronger and poor backside approach leaving group ability: OTs = I > Br > Cl in neutral or basic conditions (just like E2, SN1 adn E1), and neutral molecule leaving groups are good from protonated, cationic intermediates in acid conditions, + + + + -OH2 , -ORH , -OR2 , -NR3 , etc. we will consider all anions, ammonia, amines, thiols and sulfides to be strong nucleophiles (favors SN2 and E2 reactions) in our course some electron pair donors are mainly nucleophiles (sulfur, azide, cyanide, carboxylates) and - + + - + - some are mainly bases (t-BuO K , Na H2N , Na H ) polar, aprotic solvents work best for SN2 reactions because nucleophiles are relatively unencombered for electron doantion (dimethyl sulofoxide = DMSO, dimethylformamide = DMF, acetonitrile = AN, acetone, etc.) in our course some electron pair donors are mainly nucleophiles (sulfur, azide, cyanide, carboxylates) and we will consider neutral solvent molecules such as water, alcohols and acids to be weak nucleophiles (favors SN1 and E1) stereoselectivity: 100% inversion of configuration from backside atack regioselectivity: reacts at carbon with leaving group, completely unambiguous chemoselectivity: N/A The following list is designed to emphasize SN2 reactions.
    [Show full text]
  • Role of Organolithium Aggregates and Mixed Aggregates in Organolithium Mechanisms Hans J
    Review pubs.acs.org/CR Role of Organolithium Aggregates and Mixed Aggregates in Organolithium Mechanisms Hans J. Reich* Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, United States 3.3. Metalation Reactions 7148 3.3.1. Fluorene and Triphenylmethane 7148 3.3.2. Allylic and Benzylic Metalations 7149 3.3.3. Dipole-Stabilized Metalations 7150 3.3.4. Silane Metalation 7150 3.3.5. Acetylene Metalations 7150 3.3.6. Aromatic Ortho-Metalations 7151 3.3.7. Solvent Metalations 7153 3.3.8. Miscellaneous Metalations 7153 3.4. Alkene Addition (Carbolithiation) 7154 3.4.1. (Cyclopropylmethyl)lithium 7155 3.4.2. Addition to Aromatic Rings 7155 3.4.3. Addition to 1,1-Diphenylethylene 7155 CONTENTS 3.4.4. Addition to Ethylene 7156 1. Introduction 7130 3.4.5. Polyene Addition 7156 2. Structures of Organolithium Reagents 7131 3.5. Additions to Carbonyl Compounds 7156 2.1. Types of Solid-State Structures 7132 3.5.1. Ketones 7156 2.1.1. Hexamers and Higher Aggregates 7132 3.5.2. Enones 7158 2.1.2. Tetramers 7132 3.5.3. Aldehydes 7159 2.1.3. Trimers 7133 3.5.4. Aldol Condensation 7160 2.1.4. Dimers 7134 3.5.5. Carboxylic Esters 7161 2.1.5. Monomers 7135 3.5.6. Carboxylic Amides 7162 2.1.6. Substrate Complexes 7135 3.5.7. Imines 7163 2.2. Solution Structures of Organolithium Re- 3.5.8. Nitriles 7163 agents 7136 3.6. Elimination Reactions 7164 2.2.1. Colligative Properties 7136 3.7. Li/Br, Li/I, and Li/Sn Exchange 7164 2.2.2.
    [Show full text]
  • Stereoselective Preparation and Stereochemical Behaviour of Organozinc and Organolithium Reagents
    Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München Stereoselective Preparation and Stereochemical Behaviour of Organozinc and Organolithium Reagents Stephanie Seel aus Köln 2012 Erklärung Diese Dissertation wurde im Sinne von § 7 der Promotionsordnung vom 28. November 2011 von Herrn Prof. Dr. Paul Knochel betreut. Eidesstattliche Versicherung Diese Dissertation wurde eigenständig und ohne unerlaubte Hilfe erarbeitet. München, am 05. November 2012 …..…………………………………… Stephanie Seel Dissertation eingereicht am: 06. November 2012 1. Gutachter: Prof. Dr. Paul Knochel 2. Gutachter: Prof. Dr. Konstantin Karaghiosoff Mündliche Prüfung am: 01. Februar 2013 This work was carried out from November 2009 to November 2012 under the guidance of Prof. Dr. Paul Knochel at the Department Chemie und Pharmazie of the Ludwig- Maximilians-Universität, Munich. First, I would like to thank Prof. Dr. Paul Knochel for giving me the opportunity to do my Ph.D. in his group, for his generous support and guidance in the course of my scientific research. I am also very grateful to Prof. Dr. Konstantin Karaghiosoff for agreeing to be the second reviewer of this thesis as well as Prof. Dr. Hendrik Zipse, Prof. Dr. Heinz Langhals, Prof. Dr. Klaus Theodor Wanner and Prof. Dr. Manfred Heuschmann for their interest shown in this manuscript by accepting to be referees. I really would like to thank Tobias Thaler and Andreas Steib for the careful correction of this manuscript. I thank all past and present co-workers I have met in the Knochel group for their kindness and their help. Special thanks to my actual and former lab mates Dr.
    [Show full text]
  • TDC Part I Paper I, Group B Inorganic Chemistry Department of Chemistry L.S COLLEGE MUZAFFARPUR B. R. A. BIHAR UNIVERSITY Dr. Pr
    TDC Part I Paper I, Group B Inorganic Chemistry Department of Chemistry L.S COLLEGE MUZAFFARPUR B. R. A. BIHAR UNIVERSITY Dr. Priyanka TOPIC:- ORGANOLITHIUM REAGENT Organolithium reagent Organolithium reagents are organometallic compounds that contain carbon – lithium bonds. They are important reagents in organic synthesis, and are frequently used to transfer the organic group or the lithium atom to the substrates in synthetic steps, through nucleophilic addition or simple deprotonation Organolithium reagents are used in industry as an initiator for anionic polymerization, which leads to the production of various elastomers. They have also been applied in asymmetric synthesis in the pharmaceutical industry. Due to the large difference in electronegativity between the carbon atom and the lithium atom, the C-Li bond is highly ionic. This extremely polar nature of the C- Li bond makes organolithium reagents good nucleophiles and strong bases.These reagents are highly reactive, sometimespyrophoric, and should be handled with extreme caution. chemists found that in comparison with Grignard reagents, organolithium reagents can often perform the same reactions with increased rates and higher yields, such as in the case of metalation. Since then, organolithium reagents have surpassed Grignard reagents in usage. Structure: Although simple alkyllithium species are often represented as monomer RLi, they exist as aggregates (oligomers) or polymers. Their structures depend on the nature of organic substituent and the presence of other ligands. Nature of carbon-lithium bond A simplistic look at the large difference in electronegativity suggests the C-Li bond to be highly ionic.[ Certain organolithium compounds possess properties such as solubility in nonpolar solvents that complicate the issue.
    [Show full text]
  • Organometallic Compounds - Reagents with Carbon-Metal Bonds 14.1: Organometallic Nomenclature (Please Read)
    Chapter 14: Organometallic Compounds - Reagents with carbon-metal bonds 14.1: Organometallic Nomenclature (please read) H H C C - + H3CH2CH2CH2C-Li (H3C)2Cu Li H MgBr Butyllithium vinylmagnesium bromide Dimethylcopper lithium 14.2: Carbon-Metal Bonds in Organometallic Compounds C X C MgX - + !+ !- ! ! _ C X C MgX C Alkyl halides: Carbanions: nucleophile electrophiles react with electrophile 302 Alkyl halides will react with some metals (M0) in ether or THF to form organometallic reagents 14.3: Preparation of Organolithium Compounds Organolithium Compounds 2 Li(0) R-X R-Li + LiX diethyl ether - + ! ! _ very strong bases C Li C very strong nucleophiles organolithium reagents are most commonly used as very strong bases and in reactions with carbonyl compounds M(0) H O R-X R-M 2 R-H + M-OH 303 1 14.4: Preparation of Organomagnesium Compounds: Grignard Reagents Mg(0) R-X R-MgX (Grignard reagent) THF R-X can be an alkyl, vinyl, or aryl halide (chloride, bromide, or iodide) Solvent: diethyl ether (Et2O) or tetrahydrofuran (THF) H CH C CH CH 3 2 O 2 3 O diethyl ether (Et2O) tetrahydrofuran (THF) Alcoholic solvents and water are incompatible with Grignard reagents and organolithium reagents. Reactivity of the alkyl halide: -I > -Br > -Cl >> -F alkyl halides > vinyl or aryl halides 304 The solvent or alkyl halides can not contain functional groups that are electrophilic or acidic. These are incompatible with the formation of the organomagnesium or organolithium reagent. Grignard reagents will deprotonate alcohols 0 _ Mg + H3O HO Br HO MgBr O H HO H _ BrMg Other incompatible groups: -CO2H, -OH, -SH, NH2, CONHR (amides) Reactive functional groups: aldehydes, ketones, esters, amides, halides, -NO2, -SO2R, nitriles 305 2 14.5: Organolithium and Organomagnesium Compounds as Brønsted Bases - Grignard reagents (M = MgX) and organolithium reagents (M = Li) are very strong bases.
    [Show full text]
  • Organometallic Chemistry
    ORGANOMETALLIC CHEMISTRY 1 Organometallic Chemistry (Prelude) What is Organometallic Chemistry? Organometallic chemistry refers to reactions that use the classes of compounds (R-M) that contain a covalent bond between carbon and a metal. They are prepared either by direct reaction of the metal with an organic compound (metallation) or by replacement of a metal in an organometallic compound with another metal (transmetallation). 12:44 PM 2 Organometallic Chemistry Why Go Organometallic Chemistry What is so special about the Organometallic approach to organic synthesis? Classical organic syntheses that proceed by the SN2 pathway require a strong nucleophile attacking an electrophilic site to be effective. Such reactions are of limited scope. For instance, the formation of biaryl systems via the classical substitution reaction is difficult to achieve. 12:44 PM 3 Organometallic Chemistry Applications Organometallic chemistry offers a way out of this dilemma. Through special organometallic reactions, a variety of carbon-carbon bonds can be formed and even biaryl systems can be readily synthesized. This possibility has expanded the scope of their use in organic synthesis since bonds that were hitherto difficult to form through the classical syntheses can almost now be routinely formed. Organometallic chemistry can make possible the synthesis of 12:44 PM pharmacologically relevant natural products containing biaryl units. 4 Organomagnesium or Grignard Reagents R-Mg-X The use of organometallic reagents in organic synthesis began around 1899 when Victor Grignard discovered that alkyl halides reacted with magnesium metal in diethylether to give homogenous solutions. The Grignard reagents proved to be very reactive carbanion nucelophiles and strong bases capable of abstracting highly acidic protons attached to heteroatoms such as O, N and S, and have remained very useful synthetic reagents ever since.
    [Show full text]
  • Mechanism of Reaction of Carbon Monoxide with Phenyllithium'
    lReprintedfrom the Journalof the AmericanChemical Society, 95,8118 (1973).] Copyright 1973by the American Chemical Societyand reprinted by permissionof the copyright owner. Mechanism of Reaction of Carbon Monoxide with Phenyllithium' Larry S. Trzupek, Terry L. Newirth,2 Edward G. Kelly, Norma Ethyl Sbarbati,sand George M. Whitesides* Contribution from the Department of Chemistry, MassachusettsInstitute of Technology,Cambridge, Massachusetts 02139. ReceiuedJuly 14, 1973 Abstract: The product mixtures obtained by reaction between phenyllithium and carbon monoxide in diethyl ether, followed by hydrolysis, include benzophenone (1). a,a-diphenylacetophenone(2), benzil (3), a,a-diphenyl- a-hydroxyacetophenone (4), benzpinacot (5), a-hydroxyacetophenone (6), 1,3,3-triphenylpropane-1,2-dione(7), 1,3,3-triphenylpropan-1-one-2,3-diol(8). and benzhydrol (9). Compounds 1, 2, 6,7, and 8 are produced in signifi- cant yields i 3,4,5, and 9 are produced in trace quantities. Spectroscopicstudies establish dilithium benzophenone dianion (18) as the first long-lived intermediate formed in this reaction; qualitative correlations betweenthe basicity of a number of organolithium reagentsand their reactivity toward carbon monoxide suggests,but does not prove, that benzoyllithium is a precursor of 18. Labeling experiments indicate that the products ultimately isolated following hydrolysis of the reaction mixture are derived from at least two pathways which compete for the initially formed 18. One involves combination of l8 with 1 equiv of phenyllithium and 1 equiv of carbon monoxide, followed by elimination of I equiv of lithium oxide. yielding 17, the lithium enolateof 2; a secondinvolves com- bination of 18 with 1 equiv of phenyllithium and 2 equiv of carbon monoxide.
    [Show full text]
  • Writing Reaction Mechanisms in Organic Chemistry by Audrey Miller, Philippa H
    Writing Reaction Mechanisms in Organic Chemistry by Audrey Miller, Philippa H. Solomon · ISBN: 0124967124 · Publisher: Elsevier Science & Technology Books · Pub. Date: November 1999 PREFACE TO THE SECOND EDITION In revising this text for the second edition, a major goal was to make the book more user-friendly for both graduate and undergraduate students. Introductory material has been fleshed out. Headings have been added to make it easier to locate topics. The structures have been redrawn throughout, with added emphasis on the stereochemical aspects of reaction mechanisms. Coverage of some topics such as solvent effects and neighboring group effects has been expanded, and Chapter 6 has been completely reorganized and extensively rewritten. As in the previous edition, the focus of this book is on the how of writing organic mechanisms. For this reason and to keep the book compact and portable, the number of additional examples and problems has been mini­ mized, and no attempt has been made to cover additional topics such as oxidation-reduction and organotransition metal reactions. The skills devel­ oped while working through the material in this book should equip the reader to deal with reactions whose mechanisms have been explored less thoroughly. I am most grateful to the reviewers, who gave so generously of their time and experience in making suggestions for improving this book. Particular thanks go to series editor Jim Whitesell, who cast his eagle eye over the numerous structures and contributed to many stimulating discussions. Thanks also to John DiCesare and Hilton Weiss, and to John Murdzek, who meticu­ lously annotated the entire manuscript both before and after revisions.
    [Show full text]
  • Grignard Reagent (Organometallic Halides)
    Chapter 18 Additions to the Carbonyl Groups Nucleophilic substitution (S N2andS2 and SN1) reaction occurs at sp3 hybridized carbons with electronegative leaving groups Why? The carbon is electrophilic! Addition to the carbonyl group also occurs at the carbon of a carbonyl groups which is also electrophilic. Why? 1 Substitution vs . Addition δ+ δ− HO CH substitution HO + H3C Cl 3 + Cl reaction nucleophile electrophile leaving group (Nu:-) (R-L) (Nu-R) (L-) - - O O + OH NR O H Nu=NHR C+ RY RY RY R Y - H2OR Y Nu N Nu u = Y + C = - - H U Y = good leaving group O R - n -Y X 'X sa - H t Nu: 2 O . - CHR' Unsat. OH 1. Nu: O RNu + 2. H RNu RY R'HC Y Nu 2 18.1 General Mechanisms Possible both in basic and acidic conditions ! δ+ δ− HO CH substitution HO + H3C Cl 3 + Cl reaction nucleophile electrophile leaving group (Nu:-) (R-L) (Nu-R) (L-) 3 1. Mechanism under basic condition a. NbtlNu: can be neutral b. If Nu: is a strong base, acidic solvents (H2O, alcohol) must be avoided. Then solvent without acidic proton such as ether is used. Acid is added after the anionic compound is formed (during workup). c. If Nu: is less basic, acidic solvents can be used. d. If Nu: is less nucleophilic, use acidic condition! 4 2. Mechanism for acidic condition TilFtTypical Features a. Stereochemistry is not a concern (no way to determine whether syn or anti addition) b. Equilibrium favors the products or the reactants ⇒ strong Nu:, equilibrium is toward the product ⇒ Structural effect, which will be discussed 5 Electrophilic additions to C=C vs to C=O H E - E regioselective
    [Show full text]
  • PREPARATION and USE of ALKALI METALS (Li and Na) in ALUMINA and SILICA GEL AS REAGENTS in ORGANIC SYNTHESES
    PREPARATION AND USE OF ALKALI METALS (Li AND Na) IN ALUMINA AND SILICA GEL AS REAGENTS IN ORGANIC SYNTHESES By Fatmata Jalloh A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry – Doctor of Philosophy 2017 ABSTRACT PREPARATION AND USE OF ALKALI METALS (Li AND Na) IN ALUMINA AND SILICA GEL AS REAGENTS IN ORGANIC SYNTHESES By Fatmata Jalloh This work describes the development of alkali metals (Li and Na) encapsulated in silica and alumina gel (SG and AG), and their applications in organic syntheses. The methods elucidated involved the thermal incorporation of these metals into the pores of SG and AG, serving as solid- state reagents. The encapsulation method/approach addresses the problems associated with the high reactivity of these metals that limit their synthetic utility in research laboratories, pharmaceutical, and manufacturing industries. These problems include their sensitivity to air and moisture, pyrophoricity, difficulty in handling, non-commercial availability, and instability of some of the organoalkali metals reagents. Herein, we describe the developments to synthesize alkali metal precursor (Li-AG) in solid form that offer safer organolithium reagents. This precursor reduces or eliminates the danger associated with the traditional handling of organolithium reagents stored in flammable organic solvents. The use of Li-AG to prepare and deliver organolithium reagents from organic halides and ethers, as needed especially for those that are commercially not available is put forward. In addition, exploration of additional applications of Na-SG and Na-AG reagents in the demethoxylation of Weinreb amides to secondary amines, and Bouveault-Blanc type reduction of amides to amines are described.
    [Show full text]
  • Lithiation Methods to Fabricate Li2s Cathodes for Future Li-Ion Sulfur Battery
    Lithiation Methods to Fabricate Li2S Cathodes for Future Li-ion Sulfur Battery 将来型 Li-S 二次電池用 Li2S 正極形成のための 電極リチエーション手法 July, 2018 Yunwen WU 呉 蘊雯 Lithiation Methods to Fabricate Li2S Cathodes for Future Li-ion Sulfur Battery 将来型 Li-S 二次電池用 Li2S 正極形成のための 電極リチエーション手法 July, 2018 Waseda University Graduate School of Advanced Science and Engineering Department of Applied Chemistry Research on Applied Electrochemistry Yunwen WU 呉 蘊雯 Principal referee: Prof. Dr. Toshiyuki Momma (Waseda University) Referees: Prof. Dr. Yoshiyuki Sugahara (Waseda University) Prof. Dr. Takayuki Homma (Waseda University) I sincerely appreciate their reviewing this dissertation Contents Chapter 1 General Introduction ................................................................ 1 1.1 Rechargeable Lithium-Sulfur Battery ................................................................... 2 1.2 Challenges of Li-S battery .................................................................................... 5 1.2.1 Dissolution of polysulfide ............................................................................... 5 1.2.2 Formation of Li dendrite ................................................................................. 8 1.2.3 Degradation of Li anode ................................................................................. 9 1.2.4 Other challenges ............................................................................................ 11 1.3 Li2S based cathode .............................................................................................
    [Show full text]