Studies in Multicyclic Chemistry This thesis is submitted in fulfillment of the requirements for the degree of Doctor of Philosophy by Djamal Sholeh Al Djaidi Supervisor Professor Roger Bishop School of Chemistry The University of New South Wales Sydney, Australia December, 2006 PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: AL DJAIDI First name: DJAMAL Other name/s: SHOLEH Abbreviation for degree as given in the University calendar: PhD School: CHEMISTRY Faculty: SCIENCE Title: STUDIES IN MULTICYCLIC CHEMISTRY Abstract 350 words maximum: (PLEASE TYPE) * A series of investigations has been carried out on multicyclic organic systems. The Ritter Reaction was used to obtain bridged imines containing an azacyclohexene functionality. The crystal structure of the benzene inclusion compound of one of these was determined, and also that of another spontaneously oxidised example. The reactivity of these bridged imines was then investigated using mercaptoacetic acid, and also dimethyl acetylenedicarboxylate (DMAD). The three bridged imines studied were found to react with DMAD in totally different ways and produced most unusual products whose structures were proved using X-ray crystallography. Mechanistic explanations are provided for the formation of these novel and totally unexpected products. * 6-Methylidene-3,3,7,7-tetramethylbicyclo[3.3.1]nonan-2-one was reacted with acetonitrile and sulfuric acid to deliberately combine molecular rearrangement with Ritter Reaction chemistry. Five different products were obtained and the pathway of formation of these products was uncovered. The structures of three of these rearranged substances were confirmed by X-ray methods. * The rare tricyclo[5.3.1.1 3,9]dodecane ring system is known to contain severe skeletal distortions due to the nature of its skeleton. These properties were investigated by means of X-ray determinations at two temperatures. It was found that although the bond lengths were little affected, several of the bond angles were highly anomalous. These had angles far from the ideal tetrahedral value and, in some cases, were close to planar (120 degrees). The molecular motion of the skeleton was also investigated using variable temperature NMR measurements and energy values for the twisting motion involved were determined. * Schroeter and Vossen's Red Salt, first discovered in 1910, was investigated in detail by NMR and X-ray spectroscopy. The detailed structure of this most unusual compound was determined for the first time. * The Red Salt is based on the bicyclo[3.3.0]octane ring system and can be converted into several synthetically useful derivatives, including a tetraester and the 3,7-diketone. The former was shown to exist completely in the enolised tautomeric form (like Meerwein's Ester), and the latter was used as a synthetic entry for making diquinoline substituted analogues of interest in host-guest chemistry. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). …………………………………………………………… ……………………………………..……………… ……….……………………...……. Signature Witness … Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: THIS SHEET IS TO BE GLUED TO THE INSIDE FRONT COVER OF THE THESIS Studies in Multicyclic Chemistry DECLARATION The research presented in this thesis was undertaken in the School of Chemistry at the University of New South Wales, Sydney, Australia under the supervision of Professor Roger Bishop. The work presented in this thesis is, to the best of my knowledge and belief, original. This thesis has not been submitted in part or whole for a degree at any other university. Full acknowledgment has been made where the work of others has been cited or used. Djamal Sholeh Al Djaidi, BSc Pharm, FDA Dip. December, 2006 ii Studies in Multicyclic Chemistry Table of Contents Chapter 1 Introduction 1 1.1 The Ritter Reaction 1 1.1.1 The Classical Ritter Reaction 1 1.1.2 Intramolecular Ritter Reactions 6 1.1.3 Bridged Ritter Reaction Products 9 1.1.4 Inclusion Compounds Formed by Ritter Reaction Products 15 1.2 Addition of DMAD to Bridged Ritter Reaction Products 16 1.3 Ritter Rearrangement Reactions 21 1.4 Tricyclo[5.3.1.13,9]dodecane System Chemistry 30 1.5 Schroeter and Vossen’s Red Salt 35 1.6 Bicyclo[3.3.0]octane-based Diquinolines 38 1.6.1 Inclusion Behaviour of the Dibromo Host 94 43 1.6.2 Inclusion Behaviour of the Dichloro Derivative 97 50 1.6.3 Inclusion Behaviour of the Tetrabromide 95 54 1.6.4 Inclusion Chemistry of the Hexabromide 96 58 1.7 Aims of the Project 64 Chapter 2 Results and Discussion 66 2 Chemistry of Multicyclic Ritter Reactions 66 2.1 The Structure of a Ritter Reaction Product-Benzene Inclusion Compound 66 2.2 The Structure of an Oxidised Ritter Reaction Product 74 Chapter 3 Results and Discussion 80 3 Reaction of Bridged-Ritter Products 80 3.1 Reaction of the Bridged Imines with Mercaptoacetic Acid 80 iii Studies in Multicyclic Chemistry 3.2 Reaction of the Bridged Imines with Dimethyl Acetylenedicarboxylate (DMAD) 83 3.2.1 Reaction of Imine 36a with DMAD 83 3.2.1.1 Mechanism for the Formation of 110 and 112 88 3.2.1.2 Structure of the Inclusion Compound (112).(benzene)0.5 90 3.2.2 Reaction of Imine 100 with DMAD 97 3.2.2.1 Mechanism for Formation of 111 97 3.2.2.2 X-ray Structure of the Orthoester 111 99 3.2.3 Reaction of Imine 101 with DMAD 104 3.2.3.1 Mechanism for Formation of 115 105 3.2.3.2 X-ray Structure of the Lactam 115 106 Chapter 4 Results and Discussion 111 4 A Sequence of Novel Ritter Rearrangement Reactions 111 4.1 Rearrangement of the Unsaturated Ketone 120 111 4.2 3,3,6,6,7-Pentamethylbicyclo[3.3.1]non-7-en-2-one 121 115 4.3 4,4,7,8,8-Pentamethylbicyclo[3.3.1]non-6-en-3-one 122 116 4.4 {7-Anti-hydroxy-3,4,4,8,8-pentamethylbicyclo[3.2.2]non-2-en-1- yl}acetamide monohydrate 123 118 4.5 {3,4,4,8,8-Pentamethyl-2-oxatricyclo[3.3.1.13,7]dec-1- yl}acetamide 124 125 4.6 {4,4,8,8-Tetramethyltricyclo[3.3.1.13,7]decane-1,3- diyl}bis(acetamide) 125 130 Chapter 5 Results and Discussion 137 3,9 5 Tricyclo[5.3.1.1 ]dodecane System Chemistry 137 5.1 Synthetic Studies 137 iv Studies in Multicyclic Chemistry 5.2 X-ray Studies on Tricyclo[5.3.1.13,9]dodecane Derivatives 139 5.2.1 Crystal Structure of the Bis(pyrazolone) 135 139 5.2.2 Crystal structures of compound 83 at 90K and 300K 142 5.3 NMR Studies 149 5.3.1 Tricyclo[5.3.1.13,9]dodecane System Chemistry 149 5.3.2 Dynamic NMR Analysis of Compound 83 161 Chapter 6 Results and Discussion 165 6 The Structure of Schroeter and Vossen’s Red Salt 165 Chapter 7 Results and Discussion 175 7 Further Bicyclo[3.3.0]octane-based Diquinolines 175 7.1 The Stucture of the Tetraester 90 175 7.2 Diquinoline-substituted Bicyclo[3.3.0]octanes 181 Chapter 8 Experimental 185 Chapter 9 References 225 Published Material Related to this Thesis vi v Studies in Multicyclic Chemistry Published Material Related to this Thesis 1. Ritter Reactions. X. Structure of a New Multicyclic Amide—Benzene Inclusion Compound D. Djaidi, R. Bishop, D.C. Craig and M.L. Scudder Journal of Inclusion Phenomena and Molecular Recognition in Chemistry, 1995, 20, 363. (36a).(benzene) ZIPYIG 2. Ritter Reactions. Part 11. The Diverse Reactivity of 5,10-(Azenometheno)-5H- dibenzo[a,d]cyclohepten-11-yl Amides with Dimethyl Acetylenedicarboxylate D. Djaidi, R. Bishop, D.C. Craig and M.L. Scudder Journal of The Chemical Society, Perkin Transactions 1, 1996, 1859. 101 TITKAI (112).(benzene)0.5 TITJIP 111 TITJUB 115 TITJOV 3. Ritter Reactions. XIII. Reactivity of Schiff Bases with Dimethyl Acetylenedicarboxylate and Mercaptoacetic Acid Q. Lin, D. Djaidi, R. Bishop, D.C. Craig and M.L. Scudder Australian Journal of Chemistry, 1998, 51, 799. 4. Ritter Reactions. Part 14. Rearrangement of 3,3,7,7-Tetramethyl-6- methylidenebicyclo[3.3.1]nonan-2-one D. Djaidi, I.S.H. Leung, R. Bishop, D.C. Craig and M.L. Scudder Journal of The Chemical Society, Perkin Transactions 1, 2000, 2037. (123).(H2O) MAYVOX 124 MAYVUD 125 MAYWAK 5. Schroeter and Vossen’s Red Salt Revealed D. Djaidi, R. Bishop, D.C. Craig and M.L. Scudder New Journal of Chemistry, 2002, 26, 614. (89a).(methanol)2 XIZRED Crystallographic data for the X-ray structures listed above were deposited with the Cambridge Crystallographic Data Centre at the time of publication.