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Synthetic Approaches to Heterocyclic Bicyclo[2.1.0]Pentanes

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Synthetic Approaches to Heterocyclic Bicyclo[2.1.0]Pentanes SYNTHETIC APPROACHES TO HETEROCYCLIC BICYCLO[2.1.0]PENTANES Rabah N. Alsulami A THESIS Submitted to the Graduate College of Bowling Green State University in partial fulfillment of The requirements for the degree of MASTER OF SCIENCE August 2011 Committee: Thomas H. Kinstle (Advisor) Marshall Wilson Alexander N. Tarnovsky ABSTRACT Thomas H. Kinstle, Advisor Bicyclic systems such as bicyclo[2.1.0]pentanes and 5-oxabicyclo[2.1.0]pentanes are known to display a variety of unique chemical properties associated with their high strain energy. To the best of our knowledge, there were no reports regarding synthesis and investigation of 5- azabicyclo[2.1.0]pentanes. Therefore, the initial goal of this research was synthesis of 5-azabicyclo[2.1.0]pentane and investigation of its chemical properties. The cycloaddition reaction of azides (58, 59, 61) to olefins (54, 55) with further elimination of nitrogen was chosen as a synthetic method in order to obtain the compounds of interest. Starting olefins (3,3-dimethyl-1-cyclobutene-1-carboxylic acid (54) and methyl 3,3-dimethyl-1-cyclobutene-1-carboxylate (55) and azides phenyl azide (58), p- toluenesulfonyl azide (59), and picryl azide (61) were successfully synthesized and characterized by NMR spectroscopy and GCMS spectrometry. The addition reaction between azides and olefins was performed under various conditions, such as different solvents and temperature; however, according to NMR spectroscopy and GCMS spectrometry, olefins (54, 55) do not undergo cycloaddition reaction with azides (58, 59, 61). In order to investigate that behavior, cycloaddition reactions of more reactive olefins (66, 68) with azides (58, 59, 61) were performed under a variety of conditions. The reaction of endo-bicycloheptene-2,3-dicarboxylic anhydride (68) with phenyl azide (58) in toluene at 80 0C resulted in successful formation of triazoline. Additionally, triazoline was formed in the reaction between norbornene (66) and picryl azide (61) in chloroform at room temperature. ACKNOWLEDGMENTS In this acknowledgement I would like to express my gratitude to all those people who helped me during this period. I thank my advisor, Dr. Thomas H. Kinstle, for giving me the opportunity and the challenge to study of organic chemistry. Thanks to Dr. Wilson and Dr. Tarnovsky for patiently waiting on my draft and being on my committee. Special thanks to my husband Nawaf, my family, and my friend Valentina, for without their love, support, encouragement, none of this would have been possible. TABLE OF CONTENTS Page INTRODUCTION ……………………………………………………………………….......... 1 1.1. Strained Monocyclic Systems ………………………………………………..….… 1 1.1.1 Cyclopropanes …….………………………………………………..….….... 1 1.1.2 Cyclobutenes ……………………..……………………………….………… 2 1.1.3 Heterocycles ……………………………………………………..………….. 2 1.2 Highly Strained Carbobicyclic Systems ……………………………………………. 3 1.3 Bicyclic Systems Containing Oxygen Heteroatom…………………………………. 5 1.4 Aziridines …………………………………………….…………………………….. 9 RESULTS AND DISCUSSION ………………..………….……..………………….……… 15 2.1 Synthesis of Requisite Cyclobutenes ……………………...…………………….….. 15 2.2 Cycloaddition of Azides to Form Triazolines …………………….………………… 18 2.3 Azide Cycloaddition to Norbornenes …………………..……………….…….…….. 22 EXPERIMENTAL SECTION …………………………………………………………...…… 23 3.1 General ……………………………………………………………………….……… 23 3.2 Synthesis of 1-(2-methylprop-1-enyl) piperidine …………………..…..…………… 23 3.3 Synthesis of 3,3-dimethyl-1-cyclobutene-1-carboxylic acid ………….…..………… 23 3.4 Synthesis of nitrosomethyl urea …………………………………………..………… 24 3.5 Synthesis of diazomethane ………………………………………………..……...…. 25 3.6 Synthesis of methyl 3,3-dimethyl-1-cyclobutene-1-carboxylate ……….……..….… 25 3.7 Synthesis of phenyl azide ………………………………………………….…….…. 25 3.8 Synthesis p-toluenesulfonylazide …………………………………………..……..… 25 3.9 Synthesis of o-nitrophenylazide ………………………………………………… 26 3.10 Synthesis of picryl azide ……………………………………………………..… 26 3.11 Synthesis of compound (49) general procedure for preparation of triazoline …. 27 3.12 Picryl azide addition to norbornene ……………………………………….…… 27 3.13 Phenyl azide addition to endo-bicycloheptene -2, 3-dicarboxylic anhydride… 27 4-REFERENCES……………………………………………………………………. 28 5- FUTURE WORK………………………………………………………………… 29 LIST OF SCHEMES Page 1.1 Scheme 1. Structures of small strained rings and their strain energy ……… 1 1.2 Scheme 2. Rates of solvolysis reaction …………………………………….. 4 1.3 Scheme 3.Thermal decomposition of bicyclo [2.1.0] pentane ………….…... 5 1.4 Scheme 4. Reaction of cyclohexane epoxide using acid catalysis ………..... 5 1.5 Scheme 5. Thermolysis of exo-bicyclo [3.2.0]hept-6-ene oxide …………... 6 1.6 Scheme 6. Pyrolysis of 5-oxabicyclic[2.1.0]pentanes …………………….... 7 1.7 Scheme 7. Epoxides thermal ring opening …………………………...……... 8 1.8 Scheme 8 .Disallowed “disrotatory” ring opening ………………………….. 9 1.9 Scheme 9. Naturally occurring aziridines ………………………………..… 10 1.10 Scheme 10. Synthetic aziridines ………………..…………….............. ….10 1.11 Scheme 11.The ring opening reaction of aziridines ………………….…... 11 1.12 Scheme 12. Aziridines thermal ring opening ……………………..……… 12 1.13 Scheme 13. Synthesis of aziridines …………………………………….... 13 1.14 Scheme 14. Singlet and triplet aziridine formation ………..…………….. 14 1.15 Scheme 15. Cycloaddition of azides to alkenes …….……………………. 15 1.16 Scheme 16. Synthesis of compounds 52, 53, 54, and 55 …..………….... 17 1.17 Scheme 17. Proposed synthesis of 5-azabicyclo [2.1.0]pentanes ……… 21 1.18 Scheme 18. Successful synthesis of triazoline cycloadducts …………... 22 1-INTRODUCTION The study of ring strained organic compounds has been a popular area of research since 1885 when the first small ring compound was reported by Aldolf von Baeyer. From simple monocycles such as cyclopropane 1, cyclobutane 2, epoxide 3, aziridine 4 to literally hundreds of examples of bicyclic and polycyclic ring systems have been reported and studied. Of particular relevance to this thesis are bicyclo[2.1.0]pentanes 5 and their heterocyclic analogues: 5-oxa- bicyclo[2.1.0]pentanes 6 and 5-azabicyclo[2.1.0]pentanes 7. While substituted examples of 5 and 6 have been investigated rather thoroughly, to the best of our knowledge there have been no reports in the literature regarding synthesis and properties of 5-azabicyclo[2.1.0]pentanes 7. Therefore, the purpose of our research is to synthesize and compare the chemical properties of 5- azabicyclo [2.1.0]pentanes 7 with the previously reported and studied analogous systems, such as bicyclo[2.1.0]pentanes and 5- oxabicyclo[2.1.0]pentanes. H O N O N R 1 2 3 4 5 6 7 Cyclopropane Epoxide Aziridine Cyclobutane Bicyclo[2.1.0]pentane 5-oxabicyclo[2.1.0]pentane 5-azabicyclo[2.1.0]pentane about 27 K/cal 56 K/cal ? Scheme 1. Structures of small strained rings and their strain energy 1.1 Strained Monocyclic Systems 1.1.1 Cyclopropanes Cyclopropane (1) is a saturated three-membered ring with an endocyclic angle of 600. Therefore, valence angles are significantly distorted and valence bonds exist in a “banana” shape (so called bent bonds). This distortion leads to the high ring strain energy (27 kcal/mol) in cyclopropane,1 which is the highest strain energy in monocyclic rings. Therefore, in 1 cyclopropane the cleavage of a C-C bond proceeds even easier than in ethylene oxide. The C-C bonds in cyclopropane posses a high degree of sp2 character, therefore, it exhibits behavior similar to the double bond in olefins.2 Cyclopropanes undergo electrophilic addition reactions, such as addition of HX (X = Halogen), that obey Markovnikov’s rule and result in ring opened products reaction. Likewise, bromination leads to the formation of 1, 3-dibromopropane 3 and thermolysis at 450-5000 C leads to the formation of propene.4 These ring bond cleavage reactions proceed even easier than those in ethylene oxide. 1.1.2 Cyclobutanes Cyclobutane is a saturated four-membered ring, which possesses high strain energy (26 kcal/mol) similar to cyclopropane again due to its endocyclic angle distortion from 1090 (sp3) to 0 90 . However, unlike cyclopropane cyclobutane is not planar and has an angle between planes of 350.5 As a result of lower strain energy, the ring opening by pyrolysis proceeds at higher temperatures compared to cyclopropane ring opening. Also, cyclobutane shows less reactivity than cyclopropane in addition reactions, such as bromination and hydrogenation. 1.1.3 Heterocycles Ethylene oxide (2), also known as an epoxide or oxirane, is a saturated three-membered oxygen-containing heterocycle with an endocyclic bond angle of 600. Ethylene oxide possesses ring strain energy of about 27 kcal/mol. Ring opening of ethylene oxide occurs under basic or neutral condition, and by acid catalyzed reaction with even weak nucleophiles.6 2 Aziridine (3), also known as ethyleneimine, is a saturated three-membered nitrogen- containing heterocycle. Again, valence angles are significantly distorted and bonds exist in a “banana” shape. This distortion makes the ring strain energy about 27 kcal/mol in this molecule.7 Therefore, easy cleavage of the C-N bond occurs upon nucleophilic attack. Usually, this cleavage proceeds with high stereoselectivity and regioselectivity, which makes this strained ring system a valuable synthetic intermediate. 1.2 Highly Strained Carbobicyclic Systems Bicyclic systems have gained much attention since 1957 due to high ring strain energies (up to 56 kcal/mol) that they posess.8 Therefore, they display greater reactivity and less stability than their monocyclic analogues. It has been shown that cyclopropyl rings are able to stabilize
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