PHOTOCHEMICAL ISOMERIZATION AND STEREOSELECTIVE THERMAL CYCLOADDITION REACTIONS OF CONJUGATED NITRONES Olga Katkova A Thesis Submitted to the Graduate College of Bowling Green State University in partial fulfillment of requirements for the degree of MASTER OF SCIENCE December 2005 Committee: Thomas Kinstle, Advisor Felix Castellano David Newman ii ABSTRACT Thomas Kinstle, Advisor Nitrones have been known for some time as quite versatile intermediates in organic synthesis. They have been employed for stereoselective formation of synthetically useful isoxazolidines by their 1,3-dipolar cycloaddition reactions with alkenes. We have further investigated the behavior of some non-conjugated and conjugated nitrones in cycloaddition reactions. Several α-conjugated nitrones were synthesized and characterized. New reactions with electron-rich butylvinylethers were studied. All the synthesized nitrones were shown to undergo 1,3 dipolar cycloaddition with formation of 4- and 5-substituted isoxazolidines. We successfully synthesized a trans-chelating tridentate ligand (R,R)-4,6-dibenzofurandiyl-2,2’-bis(4- phenyloxazoline) (DBFOX/Ph) and converted it to the cationic aqua complex 47 Ni(ClO4)2*PhDBFOX. This complex was previously described by Kanemasa as the most selective chiral catalyst for the normal electron-demand 1,3-dipolar cycloaddition reaction between nitrones and alkenes. We studied the effect of this catalyst on reactivity of α−phenyl-N- benzylnitrone and α-styryl-N-benzylnitrone. A separate study of the photolysis of these non-conjugated and conjugated nitrones proved the formation of oxaziridines. The structure of these 3-membered ring nitrone isomers was established by NMR analysis. Oxidation of oxaziridines with peroxides was briefly investigated. iii This work is dedicated to my family, close friends and everyone who supported me and believed in my capabilities. I am eternally grateful. iv ACKNOWLEDGMENTS Before introducing the findings of my research, I would like to express my gratitude and appreciation to Bowling Green State University for the priceless opportunity to pursue my Master's degree in the United States of America. The experience I have gained for the two years I have spent at the University while communicating with bright, knowledgeable and professional people was helpful and incomparable to any other experiences. I would like to express my sincere thanks to the members of the faculty and staff at Bowling Green State University for their encouragement and especially their friendship. I am grateful to my committee members Dr. Felix Castellano and Dr. David Newman. I appreciate the assistance of Dr. J. Romanowicz in acquiring spectroscopic data. I am thankful to all my colleagues and friends for their encouragement and help during my research work. Special thanks goes to Grigori Karpov. Especially, I would also like to thank Dr. Thomas Kinstle for his wisdom and patience while being my academic advisor for those two years and for helping in writing this thesis. Thank you for leading me to the understanding of the importance and depth of Chemistry as a practical and hard science. v TABLE OF CONTENTS Page INTRODUCTION………………………………………………………………………………1 Synthetic methods for producing nitrones………………………………………………………2 Properties of nitrones……………………………………………………………………………4 Reactions of nitrones……………………………………………………………………………6 1. 1,3-Dipolar cycloaddition reactions……………………………………...………………..6 1.1 Frontier Molecular Orbital interactions………………………………...…………………7 1.2 The Selectivities of 1,3-dipolar cycloaddition reactions……………..……….…………10 1.2.1 Stereoselectivity………………………………...……………………………………11 1.2.2 Regioselectivity…………...………………………………………………………….13 1.3 Chiral Lewis acid catalyst………………………………………………………...….14 2. Photolysis of nitrones………………………………………………………………...18 RESULT AND DISCUSSION……………………………………...…………………………...22 1. Synthesis of nitrone………………………………………………………………………22 2. Photochemical reactions…………………...…………………………………………….27 3. Oxidation reactions of oxiziridines………………………………………………………31 4. 1,3-Cycloaddition reactions…………………...…………………………………………33 CONCLUSIONS…………………………………………...……………………………………43 SUGGESTION FOR FUTURE RESEARCH…………………………………………………...44 EXPERIMENTAL……………………………………………………………………………….45 General procedures………………………………………………………………………………45 Synthetic procedures……………………………………………………………………………..45 Preparation of N-phenylhydroxylamine(20)………………………………………...…...45 vi Preparation of α-styryl-N-phenylnitrone(21)…………………………………...……….46 Preparation of 2-methyl-2-nitropropane(22)……………………………………………..46 Preparation of N-t-butylhydroxylamine(23)………………………………..……………47 Preparation of α-styryl-N-t-butylnitrone(24)…………………………………………….48 Preparation of N, N-dibenzylhydroxyamine(25)……………………………...…………49 Preparation of α-phenyl-N-benzylnitrone.(26) Method A………………………………49 Preparation of N-Benzylidenzylamine N-oxide.(26) Method B…………………………49 Preparation of N-Benzylhydroxylamine hydrochloride(29)…………….……………….50 Preparation of α-styryl-N-benzylnitrone(29)…………………………………………….50 Preparation of dibenzofuran-4,6-dicarboxylic acid(51)………………………………….50 Preparation of dibenzofuran-4,6-dicarbonyl chloride(52)…………………………...…..51 Preparation of (R,R)- dibenzofuran-4,6-dicarboxylic acid bis (2-hydroxy-1-phenyl) amide(53)……………………………………………..52 Preparation of (R,R)-4,6-dibenzofurandiyl-2,2’-bis(4-phenyloxazoline), DBFOX/Ph(54)…………………………………………………………...……...53 Reaction of α-phenyl-N-benzylnitrone with butylvinylether……………………………53 Reaction of α-styryl-N-benzylnitrone with butylvinylether……………………………..54 Reaction of α-styryl-N-t-butylnitrone with butylvinylether……………………...……...54 Reaction of α-styryl-N-phenylnitrone with butylvinylether……………………………..54 Reaction of α-phenyl-N-benzylnitrone with trans-β-nitrostyrene……………………….54 Reaction of α-styryl-N-benzylnitrone with trans-β-nitrostyrene……………………...…55 Preparation of the Aqua Complex of DBFOX/Ph-Nickel (II) perchlorate……...……….55 Nitrone cycloaddition reaction catalyzed by the aqua complex of vii DBFOX/Ph-Nickel (II) perchlorate…………………………..………………….55 Photolysis of α-styryl-N-phenylnitrone………………………………………………….55 Photolysis of α-styryl-N-t-butylnitrone………………………………...………………..56 Photolysis of α-phenyl-N-benzylnitrone………………………………...………………56 Photolysis of α-styryl-N-benzylnitrone………………………………………………….56 REFERENCES…………………………………………………………………………………..57 APPENDIX………………………………………………………………………………………61 viii LIST OF SCHEMES Scheme Page 1 The FMO energies between the dipole and dipolarophile…………………………….8 2 The normal electron-demand 1,3-dipolar cycloaddition reaction……………………..9 3 The inverse electron-demand 1,3-dipolar cycloaddtion reaction…………………….10 4 The endo and exo interactions………………………………………………………..12 5 Reaction of nitrones with 1,2-disubstituted alkenes…………………………………14 6 Complexes between DBFOX/Ph and Ni(ClO4)2*6H2O……………………………..17 7 Thermal racemization of chiral oxaziridines proceeds through a high barrier to nitrogen inversion………………………………………………………………...19 8 Synthesis of α-styryl-N-phenylnitrone (21)…………………………………………23 9 Synthesis of α-styryl-N-t-butylnitrone (24)………………………………………….23 10 Synthesis of α-phenyl-N-benzylnitrone (26). Method A………………………….…24 11 Synthesis of α-phenyl-N-benzylnitrone (26). Method B…………………………….25 12 Synthesis of α-styryl-N-benzylnitrone (29)………………………………………….26 13 Two mechanisms of the formation of amides by N-O cleavage …………………….29 14 Photolysis of α-styryl-N-phenylnitrone (21)………………………………………...30 15 Photolysis of α-styryl-N-t-butylnitrone (24)………………………………………...30 16 Photolysis of α-styryl-N-benylnitrone (29)………………………………………….31 17 Photolysis of α−phenyl-N-benzylnitrone (26)……………………………………….31 18 Decomposition of the N-oxide structure……………………………………………..32 19 Thermal 1,3-cycloaddition reactions with butylvinylether…………………………..34 20 Thermal 1,3-cycloaddition reactions with trans-β-nitrostyrene……………………..37 ix 21 Synthesis (R,R)-4,6-Dibenzofuranyl 2, 2’- bis (4-phenyloxazoline)oxazoline (DBFOX/Ph)-a novel tridentate ligand………………………………………………40 1 INTRODUCTION The name “nitrone” is an abbreviation which was suggested by Pfeiffer1 in 1916 for compounds containing the functional group (1). The name emphasizes their similarity with ketones. Nitrones2,3 are quite versatile intermediates in organic synthesis and are employed, for instance, in stereoselective formation of synthetically useful isoxazolidines by their 1,3-dipolar cycloaddition with alkenes.4-6 R CN O 1 The general terms, aldonitrones and ketonitrones, have been employed occasionally. Aldonitrones contain a proton on the α-carbon atom, RCH=N(O)R”, while in ketonitrones the α- carbon is fully substituted with alkyl and/or aryl groups, RR’C=N(O)R”. Usually for cyclic nitrones the names are in accordance with the parent heterocyclic structure. Nitrones exhibit geometric isomerism because of the double bond in the nitrone group. One example of geometric isomerism in aldonitrones is illustrated with α-phenyl-N-t- butylnitrones. The cis (E) form of this nitrone is formed first when t-butyl-3-phenyloxaziridine was treated with boron trifluoride. Complete isomerization to the more stable trans (Z) form occurs within 24 hours in benzene solution.7 O BF3 H O H C(CH3)3 (C6H5) HC N C(CH3) C N C N C6H5 C(CH3)3 C6H5 O cis trans Ultraviolet spectral studies indicate that aldonitrones exist in the stable trans (Z) form, and this has been confirmed by nuclear magnetic resonance and infrared studies.8 2 R3 R1 R3 R1 R3 R1 C N C N CN R2 O R O O 2 R2 3 2 4 The three resonance structures 2-4 may be written for nitrones. All of these azomethine N-oxide groups are dipolar in character and the typical nitrone