DOCSLIB.ORG

Arynes in Synthesis; New Reaction and Precursor Development

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Arynes in Synthesis; New Reaction and Precursor Development ARYNES IN SYNTHESIS; NEW REACTION AND PRECURSOR DEVELOPMENT A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Engineering and Physical Sciences 2014 By Donald McAusland School of Chemistry 2 Contents Abstract 11 Declaration 12 Copyright 13 Acknowledgements 14 1 Introduction 15 1.1 Generationofbenzyne ............................ 17 1.2 Reactionsofbenzyne............................. 19 1.2.1 Pericyclicreactions. 19 1.2.2 Nucleophilicadditiontoarynes . 21 1.2.3 Transition-metal-catalysed reactions . 26 1.3 Selectivitywithsubstitutedarynes . ..... 28 1.4 (Trimethylsilyl)phenyl triflates and related aryne precursors . 32 1.4.1 ortho-Lithiation ........................... 33 1.4.2 [4+2]Cycloaddition . 34 1.4.3 Oxidative para-triflation of acetanilides . 34 1.4.4 Commerciallyavailableprecursors . 35 1.4.5 Precursors for the synthesis of polyaromatic structures...... 35 1.4.6 Other functionalised Kobayashi precursors . ..... 37 1.4.7 Relatedaryneprecursors. 39 1.5 Arynesinsynthesis.............................. 41 1.5.1 Indolesyntheses ........................... 42 2 The Benzyne Fischer Indole Reaction 46 2.1 Introduction.................................. 46 2.1.1 Buchwaldmodification. 47 Contents 3 2.1.2 The arylation of hydrazones with benzyne . 52 2.2 Application of aryne electrophiles to the Fischer indole synthesis . 52 2.2.1 Aryne reactions of other hydrazones . 55 2.2.2 BenzyneFischerindolescope . 58 2.2.3 Substitutedarynes . 60 2.2.4 Miscellaneoustosylhydrazones. 66 2.3 Conclusions .................................. 67 3 Synthesis and Applications of New Aryne Precursors 68 3.1 Introduction.................................. 68 3.1.1 Palladium cross-coupling chemistry . 68 3.1.2 TheSuzukireaction ......................... 69 3.1.3 Organoboronreagents . 71 3.1.4 Chemoselectivity in Suzuki couplings . 74 3.2 Aims...................................... 78 3.3 Optimisation ................................. 79 3.3.1 distal-Bromoaryneprecursor . 80 3.3.2 ortho-Bromoaryneprecursor . 82 3.3.3 Controlreactions ........................... 86 3.4 ScopeoftheselectiveSuzukicoupling . 88 3.4.1 Alternativecouplingreagents . 90 3.5 Reactions of substituted aryne precursors . ...... 92 3.5.1 ortho-Nucleophilicgroups . 93 3.5.2 Reactivityatanitrilegroup. 94 3.5.3 Metalcatalysed[2+2+2]reactions . 97 3.6 Furtherattemptsandleads . 101 3.6.1 Benzyne–furanreactions . 101 3.6.2 Further reactions on the 2′-ring................... 102 3.6.3 Sonogashiracoupling. 102 3.6.4 Boryl-substituted aryne precursors . 104 3.6.5 More highly functionalised aryne precursors . 105 3.6.6 Conclusions .............................. 105 4 Benzyne σ-Insertions 106 4.1 Introduction.................................. 106 4.2 Aryneynamideinsertions . 109 4.2.1 Insertions with oxazolidinone–acetylene . 109 4 Contents 4.2.2 Insertions with N -ethynyl sulfonamides . 111 4.3 Conclusionsandfurtherwork . 114 5 Conclusions 116 6 Experimental 118 6.1 ThebenzyneFischerindolereaction . 119 6.1.1 Hydrazoneprecursorsyntheses . 119 6.1.2 Arylationofprotectedhydrazones . 123 6.1.3 N -Tosylindolesynthesis. 124 6.2 Biphenyl aryne precursors via palladium-mediated cross-coupling . 129 6.2.1 Startingmaterialsynthesis . 129 6.2.2 Biphenylsynthesis . 131 6.2.3 Reactions with substituted biphenyl aryne precursors....... 139 6.3 Benzyne σ-insertionreactions . 141 6.3.1 Ynamidesynthesis . 141 6.3.2 Insertionreactionproducts . 144 References 146 Appendices 157 Listofabbreviations ................................ 157 Crystallographicdata ............................... 159 Word Count: 57947 5 List of Tables 2.1 Benzyne-mediated N -arylation and Fischer cyclisation. 58 2.2 N -Arylation and Fischer cyclisation with substituted arynes. ...... 61 3.1 Control reactions for Suzuki coupling of 216 and phenyl boronic acid . 87 3.2 Suzuki coupling of boronic acids and 216.................. 89 3.3 Suzuki coupling of boronic acid precursors with 216............ 91 4.1 Conditions for C–N insertion with 311 ................... 113 A1 Crystal data and structure refinement for 283. .............. 159 A2 Atomic coordinates and equivalent isotropic displacement parameters for 283 ...................................... 160 A3 Bond lengths and angles for 306....................... 167 A4 Anisotropic displacement parameters for 283................ 184 A5 Hydrogen coordinates and isotropic displacement parameters for 283. 191 A6 Torsion angles for 283............................. 197 A7 Crystal data and structure refinement for 306. .............. 205 A8 Atomic coordinates and equivalent isotropic displacement parameters for 306 ...................................... 206 A9 Bond lengths and angles for 306....................... 207 A10 Anisotropic displacement parameters for 306................ 208 A11 Hydrogen coordinates and isotropic displacement parameters for 306. 208 A12 Torsion angles for 306............................. 209 6 List of Figures 1.1 Representationsofbenzyne. 15 1.2 Benzyne–transition metal complexation. ...... 26 1.3 Selectivity in nucleophilic addition to an aryne. ......... 29 1.4 Commercially availble ortho-(trimethylsilyl)aryl triflates . 36 1.5 Larger polycyclic ortho-(trimethylsilyl)aryl triflates. 36 1.6 Alkoxy-substituted Kobayashi aryne precursors. ........ 39 1.7 Alternative fluoride activated aryne precursors. ......... 40 2.1 Indole-containing compounds. 46 2.2 Buchwald–Hartwig catalytic cycle for a 2° amine. ....... 48 2.3 Arylationofprotectedhydrazones. 56 2.4 Three possible isomers of 168 and 169. .................. 62 2.5 Two of the three possible isomers of phenylindole 170........... 63 3.1 The catalytic cycle of the Suzuki reaction. ...... 70 3.2 Prominent organoboron cross-coupling reagents. ........ 73 3.3 Halo-aryneprecursors. 80 3.4 Initial screen of conditions for coupling 220 and PhB(OH)2 ....... 81 3.5 Screen of bases for coupling 216 and PhB(OH)2 .............. 83 3.6 Screen of solvent for coupling 216 and PhB(OH)2 ............. 84 3.7 Optimised Suzuki coupling conditions. ..... 85 3.8 Potassium trifluoroborate salts attempted. ....... 92 3.9 1H NMR spectra for purification of 275 .................. 96 3.10 X-ray crystal structure of triphenylene 283................. 99 3.11 Triphenylenes synthesised by P˜ena et al. .................. 101 4.1 The molecular structure of 306 with displacement ellipsoids at the 50 % probabilitylevel. ............................... 111 4.2 Possible substrates for further aryne–ynamide insertion reactions. 114 7 List of Schemes 1.1 Early 14C labelling experiment to demonstrate the existence of benzyne. 15 1.2 Routes to generate benzyne from stable precursors. ........ 17 1.3 Reactionsofaryneprecursors.. 18 1.4 Diels–Alderreactionwithfuran. 19 1.5 [3+2] cycloaddition with diazoalkanes. ...... 19 1.6 Enamine–benzynereactions.. 20 1.7 Enereactionofaryneswithalkynes. 20 1.8 Nucleophilicadditiontobenzyne. 21 1.9 Arylation reactions under mild conditions. ....... 22 1.10 Three-component couplings with electrophilic CO2............. 22 1.11 Self-quenching three-component couplings. ....... 23 1.12 N–C(sp2)aryneinsertion. .......................... 24 1.13 Organolithium–aryne C–CN insertion . 24 1.14 σ-Insertionreactionsatnitrile. 25 1.15 Addition of C(sp) nucleophiles to benzyne. ....... 25 1.16 Palladium-catalysed triphenylene synthesis. ......... 27 1.17 Benzyne–alkyne [2+2+2] cycloaddition. ...... 27 1.18 Palladium-catalysed Sn–C(sp) benzyne insertion. ......... 27 1.19 C(sp)–Br bond fission in aryne reactions. ..... 28 1.20 ortho-Biphenylarynereactions. 28 1.21 Reactions with ortho-phenyl Kobayashi aryne precursor. 29 1.22 Fluoride induced selectivity in ortho-(trimethylsilyl)arynes. 30 1.23 Boryl group controlled selectivity. ....... 31 1.24 ortho-Selective addition to (triethylsilyl)benzyne. 32 1.25 Other effects that may influence regiomeric outcome of aryne reactions. 32 1.26 (Trimethylsilyl)phenyl triflate synthesis from ortho-halophenols. 33 1.27 Aryne precursors via ortho-lithiation..................... 34 8 List of Schemes 1.28 Preparation on substituted aryne precursors by a [4+2] cycloaddition– decarboxylationapproach . 35 1.29 Oxidative para-triflationofacetanilides. 35 1.30 Introduction of ortho-difunctionality via cobalt-catalysed cycloaddition. 37 1.31 Diaryne precursors for acene and helicene extension. .......... 37 1.32 Aryne precursor with pendant furan. 38 1.33 Aryne precursors for intramolecular [4+2] reactions. ........... 38 1.34 Tethered acetylene precursors for benzofuran syntheses. ......... 39 1.35 Nonafluorobutanesulfonyl fluoride-induced aryne formation. 40 1.36 Arynesbyanionrelayroute.. 41 1.37 (-)-Curvularin synthesis from polysubstituted benzyne........... 41 1.38 Indolyne indolactam V synthesis. 42 1.39 Intramolecular cyclisation indole aryne syntheses. ............ 42 1.40 Aziridine–aryne indole synthesis. ...... 43 1.41 Jamart-Grégoire and Kudzma indole syntheses. ...... 43 1.42 Benzyne–titanocene indole synthesis. ....... 44 1.43 4-Substituted indoles by cyclisation/trapping. .......... 44 1.44 2-azidoacrylate benzyne indole synthesis. ........ 44 1.45 Benzyne Bischler–Möhlau indole synthesis. ........ 45 1.46 Benzynecarbazolesyntheses. 45 2.1 The Fischer indole reaction from an N -phenylhydrazone. 47 2.2 Traditional and C–N routes to arylhydrazones. ...... 48 2.3 Buchwald’s palladium catalysed synthesis of arylhydrazones and sub- sequent transformation into indoles. 49 2.4 C–N bond forming cross-couplings with hydrazines. ....... 50 2.5 Fischer indole syntheses
Load more

Recommended publications
  • Download Answer
    Question #72514, Chemistry / Organic Chemistry Explain the electrocyclic and sigmatropic reaction in detail. Answer: In organic chemistry, an electrocyclic reaction is a type of pericyclic rearrangement where the net result is one pi bond being converted into one sigma bond or vice versa. The Diels-Alder reaction is a common example. The especially interesting thing about this reaction is its stereochemistry. When performing an electrocyclic reaction, it is often desirable to predict the cis/trans geometry of the reaction's product. The first step in this process is to determine whether a reaction proceeds through conrotation or disrotation. Reactions can be either photochemical or thermal and their mexanisms are different. Mechanism of thermal reactions: Correlation diagrams, which connect the molecular orbitals of the reactant to those of the product having the same symmetry, can then be constructed for the two processes. Mechanism of photochemical reactions: If the ring opening of 3,4-dimethylcyclobutene were carried out under photochemical conditions the resulting electrocyclization would be occur via a disrotatory mode instead of a conrotatory mode as can be seen by the correlation diagram for the allowed excited state ring opening reaction. A sigmatropic reaction in organic chemistry is a pericyclic reaction wherein the net result is one σ-bond is changed to another σ-bond in an uncatalyzed intramolecular process. The most well-known of the sigmatropic rearrangements are the [3,3] Cope rearrangement, Claisen rearrangement, Carroll rearrangement [3,3] sigmatropic shifts are well studied sigmatropic rearrangements. The Woodward– Hoffman rules predict that these six electron reactions would proceed suprafacially, via a Huckel topology transition state.
    [Show full text]
  • The Use of Arynes in Organic Synthesis
    Dedicated to all those too lazy to visit a library Tetrahedron 59 (2003) 701–730 Tetrahedron report number 629 The use of arynes in organic synthesis He´le`ne Pellissier* and Maurice Santelli Laboratoire de Synthe`se Organique UMR no. 6009, Faculte´ des Sciences de Saint-Je´roˆme, Avenue Esc. Normandie-Niemen, 13397 Marseille, Cedex 20, France Received 27 November 2002 Contents 1. Introduction 701 2. Structure and reactivity 701 3. Generation of arynes 702 4. Pericyclic reactions of arynes 704 4.1. Diels–Alder cycloadditions 704 4.1.1. With cyclic heterodienes 704 4.1.2. With acyclic heterodienes 707 4.1.2.1. Intermolecular cycloadditions 707 4.1.2.2. Intramolecular cycloadditions 709 4.1.3. With other dienes 709 4.2. [2þ2] Cycloadditions 711 4.3. 1,3-Dipolar cycloadditions 712 4.4. 1,4-Dipolar cycloadditions 715 4.5. Ene reactions 715 5. Nucleophilic additions to arynes 717 5.1. Addition of nitrogen nucleophiles 717 5.2. Addition of carbon nucleophiles 718 5.2.1. Lithioacetonitrile derivatives as carbon nucleophiles 718 5.2.2. Lithioenolates as carbon nucleophiles 722 6. Transition metal-catalysed reactions of arynes 723 7. Conclusions 727 1. Introduction arynes. The importance of arynes for the synthesis of natural products particularly alkaloids is well illustrated. The This review is an update of aryne chemistry and covers the term ‘arynes’ will be used to refer both to derivatives literature from 1990–2002 since early work has already of 1,2-dehydrobenzene (benzyne) and their heterocyclic been reviewed extensively.1 The preceding review covered analogues (heteroarynes).
    [Show full text]
  • R. B. Woodward Precipitation of Barium in the Copper-Tin Group Of
    HETEROCYCLES, Vol. 7, No. 1. 1977 R. B. Woodward Precipitation of barium in the copper-tin group of qualitative analysis. W.J.Hal1 and RBW, -Ind. Eng. Chem., Anal. Ed., 6, 478 (1934). A new pressure regulator for vacuum distillation. R.L.Emerson and RBW, g.,2, 347 (1937). The Staling of coffee. II. S.C.Prescott, R.L.Emerson, RBW, and R. Heggie, Food Re- --search, 2, 165 (1937). Pyrolysis of organomagnesium compounds. I. A new agent for the reduction of bemophenone. D.B.Clapp, and RBW, 1. ---Am. Chem. Soc., -60, 1019 (1938). The direct introduction of the angular methyl group. RBW, Ibid., 62, 1208 (1940). Experiments on the synthesis of oestrone. I. 2-(8-phenylethy1)-furans as components in the diene synthesis. RBW, Ibid., 62, 1478 (1940). The formation of Reissert's compounds in non-aqueous media. RBW, Ibid., 62, 1626 (1940). A new optically active reagent for carbonyl compounds. The resolution of -dl-camphor. RBW, T. P. Kohman, and G. C. Harris, Ibid., 63, lu) (1941). The isolation and properties of 1, 1-dineopentylethylene, a component of triisobutylene. P.D.Bartlett, G.L. Fraser, and RBW, x.,3, 495 (1941). Structure and absorption spectra of a,p-unsaturated ketones. RBW, Ibid., 3, 1123 (1941). 5 Structure and absorption spectra. II. 3-Acetoxy-A -(6)-~cholestene-7-carboxylicacid. RBW, and A.F.Clifiord, -Ibid., -63, 2727 (1941). The structure of cantharidine and the synthesis of desoxycantharidine. RLW, and R.B. Loftfield, Ibid., 3, 3167 (1941). -t-Butyllithium. P.D.Bardett, C .G.Swain, and RBW, --Ibid., 63, 3229 (1941).
    [Show full text]
  • Mechanistic Studies Into the Reactions of Diazonium And
    MECHANISTIC STUDIES INTO THE REACTIONS OF DIAZONIUM AND RELATED COMPOUNDS by CHARLES DOUGLAS MURRAY, B.Sc. Thesis presented for the degree of DOCTOR of PHILOSOPHY University of Edinburgh September 1974 GLBY TO MY PARENTS Douglas William and Isabella Seaton McKenzie Murray • • AND MY BROTHER • • William Graeme Murray I declare that this thesis is my own composition, that the work of which it is a record has been carried.out by myself, and that it has not been submitted in any previcis application for a Higher Degree. The thesis describes results of research carried out • in the Department of Chemistry, University of Edinburgh under the supervision of Professor J. I. G. Cadogan since the 1st October, • 1971, the date of my admission as a research student. The following is a statement of postgraduate courses attended during the last three years: Summer School in Mass Spectrometry, University of Sheffield, 26-30 March 1972; - Recent Developments in the Theory of Concerted Processes, Dr. A. J. Bellamy (five lectures); Organometallic Processes in Organic Chemistry, Professor P. L. Pauson (five lectures); Industrial Research and Development, Dr. B. Gravenor (five lectures); E. U. Chemistry Department Seminars (twenty-five periods). • ACKNOWLEDGEMENTS I should like to express my gratitude to Professor J. I. G. Cadogan for suggesting the topic of research and to Professor Cadogan and Dr. J. T. Sharp for their guidance and encouragement in all aspects of this work. I would also like to record my thanks and appreciation to various other members of Edinburgh University Chemistry Department: to Dr. R. M.Paton for advice and assistance related to e.
    [Show full text]
  • Robert Burns Woodward 1917–1979
    NATIONAL ACADEMY OF SCIENCES ROBERT BURNS WOODWARD 1917–1979 A Biographical Memoir by ELKAN BLOUT Any opinions expressed in this memoir are those of the author and do not necessarily reflect the views of the National Academy of Sciences. Biographical Memoirs, VOLUME 80 PUBLISHED 2001 BY THE NATIONAL ACADEMY PRESS WASHINGTON, D.C. ROBERT BURNS WOODWARD April 10, 1917–July 8, 1979 BY ELKAN BLOUT OBERT BURNS WOODWARD was the preeminent organic chemist Rof the twentieth century. This opinion is shared by his colleagues, students, and by other distinguished chemists. Bob Woodward was born in Boston, Massachusetts, and was an only child. His father died when Bob was less than two years old, and his mother had to work hard to support her son. His early education was in the Quincy, Massachusetts, public schools. During this period he was allowed to skip three years, thus enabling him to finish grammar and high schools in nine years. In 1933 at the age of 16, Bob Woodward enrolled in the Massachusetts Institute of Technology to study chemistry, although he also had interests at that time in mathematics, literature, and architecture. His unusual talents were soon apparent to the MIT faculty, and his needs for individual study and intensive effort were met and encouraged. Bob did not disappoint his MIT teachers. He received his B.S. degree in 1936 and completed his doctorate in the spring of 1937, at which time he was only 20 years of age. Immediately following his graduation Bob taught summer school at the University of Illinois, but then returned to Harvard’s Department of Chemistry to start a productive period with an assistantship under Professor E.
    [Show full text]
  • Pericyclic Reactions Notes
    - 1 - PERICYCLIC REACTIONS NOTES Pericyclic reactions cannot be treated adequately by “curly-arrow” formalisms and a knowledge of molecular orbital theory is crucial to their understanding. They are reactions in which “all first order changes in bonding relationships takes place in concert on a closed curve” (Woodward & Hoffmann). More simply, the term “pericyclic” covers all concerted reactions involving a cyclic flow of electrons through a single transition state. Pericyclic reactions can be predicted and controlled to a great degree, which makes them very useful in synthesis. There are broadly four classes of pericyclic reaction: Sigmatropic – These are unimolecular isomerisations, and involve the movement of a σ-bond from one position to another. An illustration would be the first step of the Claisen Rearrangement: Note the nomenclature of this reaction, being described as a [i,j] shift. For example, this following is a [1,7] shift: Electrocyclic – These are unimolecular. They are characterised by ring opening or closing with a σ- bond forming at one end. Ring closing is more common, since this is formation of a σ-bond at the expense of a π-bond, but ring strain can lead to opening. Two examples are: Cycloaddition – This is the largest class of pericyclic reaction. It is characterised by two fragments coming together to form two new σ-bonds in a ring. Some examples are Diels-Alder and Ozonolysis reactions, which are described below. Chelotropic reactions are a specific type of cycloaddition, where the two bonds are made or broken at the same atom. The classic example of this is carbene addition to a double bond.
    [Show full text]
  • Use of Isotopes for Studying Reaction Mechanisms 1
    SERIES I ARTICLE Use of Isotopes for Studying Reaction Mechanisms 1. Isotopes as Markers Uday Maitra and J Chandrasekhar Isotopes can be used as markers to keep track of positions of atoms during a chemical transformation. This strategy Uday Maitra and of determining reaction mechanisms is illustrated in the J Chandrasekhar are members of the Organic article with several examples. Chemistry faculty in Indian Institute of Introduction Science at Bangalore. When a reaction is carried out, the primary effort goes towards the identification of the product(s) of the reaction. A more time consuming endeavour, however, is the elucidation of the reaction mechanism. The study of reaction mechanisms is intellectually challenging, and at the same time provides opportunities to excercise greater control over the reaction. For example, a detailed knowledge of the intermediate formed in a reaction would help us optimize reaction conditions to effect higher yields, minimize reaction times, etc. The transformation of a reactant A to product B can in principle take place via a number of pathways. To find experimental evidence for one of these pathways detailed physical studies are needed. The techniques normally used for studying reaction mechanisms include kinetic analysis, trapping of a reactive intermediate, etc. One of the most powerful techniques is the use of isotopes as labels in a reaction. An atom in the reactant is selectively replaced by one of its isotopes. The reaction is carried out as usual, and the location (and/or distribution) of the isotopic label in the product(s) is determined (see Box 1). The probable mechanism can then be inferred.
    [Show full text]
  • Sigmatropic Rearrange- Ment of Allyloxy- and Propargyloxy-Indoles Revealed by Computa- Tion and Experiment Osvaldo Gutierrez,*† Charles E
    Divergent Reactivity in Pd-Catalyzed [3,3]-Sigmatropic Rearrange- ment of Allyloxy- and Propargyloxy-Indoles Revealed by Computa- tion and Experiment Osvaldo Gutierrez,*† Charles E. Hendrick,‡ Marisa C. Kozlowski*‡ ‡*Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Supporting Information Placeholder R1 RO2C FC 1 CO2R R FC R2 2 CO2R O R O [Pd]L* [Pd]L* N N FC H Concerted Pathway H Stepwise Pathway O via via N H Lewis Acid Activation π Acid Activation ABSTRACT: Detailed computational (DFT) studies of the palladium(II)-catalyzed Claisen rearrangement of 2-allyloxy- and propargyloxyin- doles revealed an unexpected divergent mode of reactivity. Subsequent experimental kinetic isotope effects are in accord with the mechanism derived from the computations. The computational results led to the development of Pd(II)-catalyzed [3,3]-sigmatropic rearrangement of 3- aryl substituted 2-propargylindoles. Sigmatropic shifts constitute an essential class of pericyclic reac- Scheme 1. (A) Representative natural products bearing the oxy- tions in organic chemistry.1 Initially discovered by Cope and Hardy indole backbone with a C3–quaternary stereocenter. (B) Enanti- in 1940,2 the thermal [3,3]-sigmatropic rearrangement of 1,5-dienes oselective palladium(II)-catalyzed [3,3]-sigmatropic rearrange- (e.g., Cope rearrangement) is the prototypical reaction of this class ment of 2-allyloxyindoles (top) and 2-propargyloxyindoles (bot- taught in undergraduate organic chemistry courses to showcase con- tom). certed (and stereospecific) s- and π-bond reorganization.3 Seminal work by Overman showed that palladium(II) chloride salts could catalyze the Cope rearrangement. 4 In 2012, Gagné and co-workers reported the first enantioselective variant using a chiral Au(I) cata- lyst.
    [Show full text]
  • II.Pericyclic Reactions 7
    M.Sc. Semester-IV Core Course-9 (CC-9) Synthetic Organic Chemistry II.Pericyclic Reactions 7. Claisen Rearrangement, The Nazarov Reaction Dr. Rajeev Ranjan University Department of Chemistry Dr. Shyama Prasad Mukherjee University, Ranchi II Pericyclic Reactions 20 Hrs Molecular orbital symmetry, Frontier orbitals of ethylene, 1,3-butadiene, 1, 3, 5-hexatriene, allyl system, Classification of pericyclic reactions. FMO approach, Woodward-Hoffman correlation diagram method and PMO approach for pericyclic reaction under thermal and photochemical conditions. Electrocyclic reactions: Conrotatary and disrotatary motion, 4n and (4n+2) systems, Cycloaddition reaction: [2+2] and [4+2] cycloaddition reaction, Cycloaddition of ketones, Secondary effects in [4+2] cycloaddition. Stereochemical effects on rate of cycloaddition reaction, Diels-Alder reaction, 1,3-dipolar cycloaddition, Chelotropic reaction, The Nazarov reaction. Sigmotropic rearrangement: Suprafacial and antarafacial shift involving H and carbon-moieties, Peripatetic cyclopropane bridge, Retention and inversion of configuration, [3,3]-, [1,5]-, [2,3]-, [4,5]-, [5,5]-, and [9,9]- Sigmatropic rearrangements, Claisen rearrangements (including Aza-Claisen, Ireland-Claisen), Cope rearrangements (including Oxy-Cope, Aza-Cope), Sommelet-Hauser rearrangements, Group transfer reaction, Ene reaction, Mislow - Evans rearrangement, Walk rearrangement. Coverage: 1.Claisen Rearrangement 2.The Nazarov Reaction 2 Claisen Rearrangement : [3, 3] Sigmatropic Rearrangement How and Why? Claisen rearrangement: A thermal rearrangement of allyl phenyl ethers to form 2- allylphenols. Rainer Ludwig Claisen O OH 1851-1930 200-250°C Allyl phenyl ether 2-Allylphenol Dr. Rajeev Ranjan 3 Claisen Rearrangement : [3, 3] Sigmatropic Rearrangement Mechanism: O O heat Allyl phenyl Transition ether state O OH keto-enol tautomerism H A cyclohexadienone o-Allylphenol intermediate Dr.
    [Show full text]
  • PDF (Appendix 2: the Cope Rearrangement)
    65 APPENDIX TWO The Cope Rearrangement A2.1 The Cope Rearrangement In 1940, Arthur Cope discovered a thermal rearrangement of 1,5-diene 137a to a more conjugated isomeric 1,5-diene (137b, Scheme A2.1.1).1 Cope postulated that his rearrangement was an all-carbon analogue of the Claisen rearrangement,2 and was intramolecular. He speculated that the reaction proceeded through a six-membered transition state. Cope published these hypotheses 25 years before Woodward and Hoffman3 disclosed the first papers on conservation of orbital symmetry, a theory that explained the molecular orbital basis for synchronous Cope rearrangements, calling them [3,3] sigmatropic rearrangements. Scheme A2.1.1 The Cope rearrangement 150–160 °C NC NC Me 4 h Me EtO2C EtO2C Me Me 137a 137b A2.2 Transition State Geometry in Concerted Cope Rearrangements4 Thermal [3,3] sigmatropic rearrangements occur with suprafacial–suprafacial geometries3 through a six-membered cyclic transition state in either a chair or boat conformation. In 1962, Doering and Roth5 determined that in simple cases, the Cope rearrangement proceeded through a chair-like transition state (Scheme A2.2.1). On the basis of product ratios, Doering and Roth estimated that ΔΔG‡ (boat–chair) for meso 66 138a was 5.7 kcal/mol. Subsequent experiments by Hill excluded the twist (helix) arrangement,6 which had not been considered by Doering and Roth. Scheme A2.2.1 Feasible transition states for the Cope rearrangement Me Me Me Me ! Me Me Me Me (99.7% yield) 138b Me Me Me Me ! ! Me Me Me Me Me Me (0.3% yield) 138a 138c Me Me Me Me ! Me Me Me Me 138d While simple Cope rearrangements employ a chair transition state, the boat transition state is used when molecules are geometrically constrained, as is the case with 1,2-divinyl cyclopropanes in which the vinyl groups are nearly elipsed.7 Most 1,2- divinylcyclobutanes also proceed through boat transition states,8,9 but their larger ring size accompanies greater structural flexibility.
    [Show full text]
  • Toward a Symphony of Reactivity: Cascades Involving Catalysis and Sigmatropic Rearrangements
    NIH Public Access Author Manuscript Angew Chem Int Ed Engl. Author manuscript; available in PMC 2014 May 22. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Angew Chem Int Ed Engl. 2014 March 3; 53(10): 2556–2591. doi:10.1002/anie.201302572. Toward a Symphony of Reactivity: Cascades Involving Catalysis and Sigmatropic Rearrangements Amanda C. Jones*, Chemistry Department, Wake Forest University Box 7486, Winston Salem, NC 27109 (USA) Jeremy A. May, Department of Chemistry, University of Houston Houston, TX 77204-5003 (USA) Richmond Sarpong, and Department of Chemistry, University of California Berkeley, CA 94720 (USA) Brian M. Stoltz Department of Chemistry and Chemical Engineering, California Institute of Technology MC 101-20, Pasadena CA 91125 (USA) [email protected] Abstract Catalysis and synthesis are intimately linked in modern organic chemistry. The synthesis of complex molecules is an ever evolving area of science. In many regards, the inherent beauty associated with a synthetic sequence can be linked to a certain combination of the creativity with which a sequence is designed and the overall efficiency with which the ultimate process is performed. In synthesis, as in other endeavors, beauty is very much in the eyes of the beholder.[**] It is with this in mind that we will attempt to review an area of synthesis that has fascinated us and that we find extraordinarily beautiful, namely the combination of catalysis and sigmatropic rearrangements in consecutive and cascade sequences. Keywords homogeneous catalysis; sigmatropic reactions; tandem reactions 1. Introduction The development of tandem processes has had a profound impact on organic synthesis and synthetic planning.
    [Show full text]
  • Year 3 Understanding Organic Synthesis Course; Professor Martin Wills Contents of the Course
    Year 3 Understanding Organic Synthesis Course; Professor Martin Wills Contents of the course: Introductory lecture describing the contents of the course. Pericyclic reactions and Woodward-Hoffmann rules for concerted cycloadditions, electrocyclisations and sigmatropic rearrangements. Baldwin's rules and related cycloaddition reactions, including radicals. Stereoelectronic effects: How such effects can be moderated to the advantage of the synthetic chemist. Detailed example of the application of several stereoelectronically controlled reactions. Reading: Clayden et al.; “Organic Chemistry” by Clayden, Greeves, Warren and Wothers, Oxford 2001. R. B. Woodward and R. Hoffmann in Angew. Chem., Int Edn. Engl., 1969, 8, 781. “Organic Reactions and Orbital Symmetry”, T. L Gilchrist and R. Storr, CAP, 1979. Note: Since not all the material is in the handout, it is essential to attend ALL the lectures. Professor M. Wills CH3B0 Understanding Organic Synthesis 1 Introduction: Unexpected results of cyclisation reactions. Pericyclic reactions are; “Any concerted reaction in which bonds are formed or broken in a cyclic transitions state”. i.e. there is a single transition state from start to finish, in contrast to a stepwise reaction. Concerted reaction Multistep reaction Transition state Transition states Energy Energy inter- starting product starting mediate inter- material material mediate product reaction co-ordinate reaction co-ordinate Properties of pericyclic reactions: (a) Little, if any, solvent effect (b) No nucleophiles or electrophiles involved. (c ) Not generally catalysed by Lewis acids. (d) Highly stereospecific. (e) Often photochemically promoted. 2 Examples of pericyclic reactions: 1) Electrocyclisation reactions – Linear conjugated polyene converted onto a cyclic product in one step. The mechanism is not particularly surprising, but the stereochemistry changes depending on whether heat or irradiation (typically UV-light) is used to promote the reaction.
    [Show full text]