University of Huddersfield Repository Qamar, Muhammad Ilyas Synthesis and Reactions of Cyclopropenones Original Citation Qamar, Muhammad Ilyas (2011) Synthesis and Reactions of Cyclopropenones. Doctoral thesis, University of Huddersfield. This version is available at http://eprints.hud.ac.uk/id/eprint/12304/ The University Repository is a digital collection of the research output of the University, available on Open Access. Copyright and Moral Rights for the items on this site are retained by the individual author and/or other copyright owners. 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For more information, including our policy and submission procedure, please contact the Repository Team at: [email protected]. http://eprints.hud.ac.uk/ Synthesis & Reactions of Cyclopropenones Muhammad Ilyas Qamar A Thesis Submitted to the University of Huddersfield in Partial Fulfilment of the Requirements for the Degree of Doctor of Philosophy University of Huddersfield Department of Chemical & Biological Sciences September 2011 I would like to dedicate this thesis to my mother and father, for their constant love, support and encouragement, they have made many sacrifices, faced many hardships and worked countless hours so that I could have a better life. Without them none of this would be possible. I Contents Contents 1 INTRODUCTION ......................................................................................................... 1 1.1 CYCLOPROPENONES ..................................................................................................... 1 1.2 REACTIONS OF CYCLOPROPENONES .......................................................................... 12 1.2.1 Reaction at the ketone double bond ...................................................................... 12 1.2.2 Reactions across carbon-carbon double bond ...................................................... 13 1.2.3 Reactions with imines: formation of pyrroles ...................................................... 15 1.2.4 Synthesis of six-membered rings .......................................................................... 21 1.2.5 Miscellaneous ....................................................................................................... 24 1.3 PROLOGUE TO THESIS DISCUSSION ............................................................................ 26 2 DISCUSSION ............................................................................................................. 31 2.1 SYNTHESIS OF PYRROLIZIDINES ................................................................................ 32 2.1.1 Synthesis of 5-ethylthio-2,3-diphenyl-1-azabicyclo[3.3.0]oct-2-en-4-one .......... 32 2.1.2 Attempted synthesis of 5-ethoxy-2,3-diphenyl-1-azabicyclo[3.3.0]- oct-2-en-4-one ...................................................................................................... 36 2.1.3 Synthesis of 5-methylthio-2,3-diphenyl-1-azabicyclo[3.3.0]oct-2- en-4-one ................................................................................................................ 37 2.1.4 Synthesis of 5-methoxy-2,3-diphenyl-1-azabicyclo[3.3.0]oct-2-en-4-one .......... 39 2.1.5 Synthesis of 5-methyl-2,3-diphenyl-1-azabicyclo[3.3.0]oct-2-en-4-one ............. 44 2.1.6 Synthesis of 5-methylthio-2,3-diphenyl-8-methyl-1-azabicyclo-[3.3.0]- oct-2-en-4-one ...................................................................................................... 45 2.1.7 Synthesis of 5-methylthio-2,3-diphenyl-8-ethylcarboxylate-1-aza- bicyclo[3.3.0]oct-2-en-4-one ................................................................................ 49 2.1.8 Synthesis of 5-methylthio-2,3-diphenyl-8-(4-methylbenzenesulfonate)- 1-azabicyclo[3.3.0]oct-2-en-4-one ....................................................................... 52 2.1.9 Attempted synthesis of 5-methylthio-2,3-diphenyl-8-hydroxymethyl-1- azabicyclo[3.3.0]oct-2-en-4-one ........................................................................... 54 2.2 REACTIVITY OF PYRROLIZIDINES .............................................................................. 55 2.2.1 Reactivity of 5-methylthio-2,3-diphenyl-1-azabicyclo[3.3.0]-oct-2- en-4-one ................................................................................................................ 55 2.2.2 Reactivity of 5-methoxy-2,3-diphenyl-1-azabicyclo[3.3.0]oct-2-en-4-one ......... 62 2.2.3 Synthesis of 5-hydroxy-2,3-diphenyl-1-azabicyclo[3.3.0]oct-2-en-4-one ........... 64 2.2.4 Attempted synthesis of 5-trifyl-2,3-diphenyl-1-azabicyclo[3.3.0]- oct-2-en-4-one ...................................................................................................... 68 II Contents 2.2.5 Attempted formation of 5-sulfoxy and 5-hydroxy-8-methyl-2,3- diphenyl-1-azabicyclo[3.3.0]oct-2-en-4-one ........................................................ 69 2.2.6 Hydrolysis of 5-methylthio-2,3-diphenyl-8-(4-methylbenzenesulfonate)- 1-azabicyclo[3.3.0]oct-2-en-4-one ....................................................................... 70 2.2.7 Attempted synthesis of 4-butyl-5-ethylthio-2,3-diphenyl-1-azabicyclo- [3.3.0]oct-2-en-4-ol .............................................................................................. 71 2.2.8 Attempted synthesis of 5-ethylthio-2,3-diphenyl-1-azabicyclo-[3.3.0]- oct-2-en-4-ol ......................................................................................................... 71 2.3 SYNTHESIS OF POLYHYDROXYLATED PYRROLIZIDINES ............................................ 72 2.3.1 Synthesis of 2,3-O-isopropylidene-L-erythrose ................................................... 72 2.3.2 Synthesis of (3S,4R)-3,4-isopropylidenedioxypyrroline 1-oxide ......................... 73 2.3.3 Attempted synthesis of 2,3-diphenyl-6,7-isoproylidenedioxy-1-aza- bicyclo[3.3.0]oct-2-en-4-one ................................................................................ 74 2.4 SYNTHESIS OF A HIGHLY SUBSTITUTED , FUNCTIONALISED PYRROLIZIDINE ............ 75 2.4.1 Synthesis of 2-methyl-4-phenyl-5-cyano-1H-pyrroline ....................................... 75 2.4.2 Synthesis of 5-methyl-2,3,7-triphenyl-8-cyano-1-azabicyclo[3.3.0]- oct-2-en-4-one ...................................................................................................... 76 2.5 CYCLOPROPENONES ................................................................................................... 78 2.5.1 Unsubstituted cyclopropenones ............................................................................ 78 2.5.2 Synthesis of dialkylcyclopropenones ................................................................... 83 2.6 ACYCLIC IMINES ......................................................................................................... 88 2.6.1 Synthesis of N-(benzylidene)-tert -butanesulfinamide .......................................... 88 2.6.2 Synthesis of 3-tert -butyl-2-phenyl-1-indenone .................................................... 89 2.6.3 Synthesis of N-(alkylidene)-tert -butanesulfinamides ........................................... 91 2.6.4 Reaction with diphenylcyclopropenone ............................................................... 92 2.7 SYNTHESIS OF INDOLIZIDINES AND PYRROLOAZEPINES ........................................... 93 2.7.1 Indolizidines ......................................................................................................... 93 2.7.2 Pyrroloazepines .................................................................................................... 97 2.8 1,3-DIPOLAR CYCLOADDITIONS ............................................................................... 101 2.8.1 Attempted synthesis of ethyl-5-methylthio-4,1,3-oxadiazobicyclo- [3.3.0]oct-2-ene-2-carboxylate ........................................................................... 101 2.8.2 Synthesis of 4-methoxy-(α-[N-(2-pyrrolidinone)])benzaldoxime ...................... 103 2.8.3 Synthesis of 2-azido-(α-[N-(2-pyrrolidinone)])benzaldoxime ........................... 104 III Contents 2.8.4 Synthesis of 2-[triphenylphosphoranylimino]-α-[N-(2-pyrrolidinone)]- benzaldoxime ...................................................................................................... 105 2.8.5 Synthesis of pyrrolo[1,2-b][1,3]benzodiazin-4-oxime ....................................... 105 2.8.6 Attempted reaction of 2-methylthio-1-pyrroline with a nitrilimine ................... 107 2.9 CONCLUSION & FUTURE WORK .............................................................................. 108 3 EXPERIMENTAL .................................................................................................... 112 3.1 SYNTHESIS OF PYRROLIZIDINES .............................................................................. 112 3.1.1 Synthesis of 5-ethylthio-2,3-diphenyl-1-azabicyclo[3.3.0]oct-2- en-4-one .............................................................................................................. 112 3.1.2 Attempted synthesis of 5-ethoxy-2,3-diphenyl-1-azabicyclo[3.3.0]oct- 2-en-4-one 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