University of New Hampshire University of New Hampshire Scholars' Repository Doctoral Dissertations Student Scholarship Spring 1970 PART I ASYMMETRIC REDUCTION OF KETONES WITH THE GRIGNARD REAGENT FROM R-1-BROMO-2-PHENYLETHANE-1,1,2-DEUTERIUM(3) PART II ELECTROPHILICALLYASSISTED NUCLEOPHILIC OPENING OF OPTICALLY ACTIVE STYRENE-OXIDE JOSEPH EDWARD TOMASZEWSKI Follow this and additional works at: https://scholars.unh.edu/dissertation Recommended Citation TOMASZEWSKI, JOSEPH EDWARD, "PART I ASYMMETRIC REDUCTION OF KETONES WITH THE GRIGNARD REAGENT FROM R-1-BROMO-2-PHENYLETHANE-1,1,2-DEUTERIUM(3) PART II ELECTROPHILICALLYASSISTED NUCLEOPHILIC OPENING OF OPTICALLY ACTIVE STYRENE-OXIDE" (1970). Doctoral Dissertations. 925. https://scholars.unh.edu/dissertation/925 This Dissertation is brought to you for free and open access by the Student Scholarship at University of New Hampshire Scholars' Repository. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of University of New Hampshire Scholars' Repository. For more information, please contact [email protected]. PART I. ASYMMETRIC REDUCTION OF KETONES WITH THE GRIGNARD REAGENT FROM R-1 -BROMO- 2 -PHENYLETHANE-1,1,2-d s PART II. ELECTROPHILICALLY ASSISTED NUCLEOPHILIC OPENING OF OPTICALLY ACTIVE STYRENE OXIDE by JOSEPH EDWARD TOMASZEWSKI B. S., University of Scranton, 1965 A THESIS Submitted to the University of New Hampshire In Partial Fulfillment of The Requirements for the Degree of Doctor of Philosophy Graduate School Department of Chemistry March, 1970 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. This thesis has been examined and approved. ?s D. Morrison, Research Director rbciate Professor of Chemistry Rob'er't E . Lyle Professor of Chemistry Associate Professor of Chemistry (], Charles V. Berney Assistant Professor of Chemistry Richard H. skutt Associate Professor of Electrical Engineering 'Tntnd % m o Date Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGEMENTS I would like to thank Dr. James D. Morrison for his invaluable assistance as a research director and friend throughout the years of my studies at the University and especially for his comments during the preparation of this thesis. I would also like to thank Dr. Robert E. Lyle for his comments as the second reader of this thesis and for the use of his gas chromatographic equipment. Special thanks are due to Dr. Harry S. Mosher and Jim Dale of Stanford University for carrying out the NMR analysis of the Grignard reduction products; to my wife- Mary, who persevered through the typing of this thesis to make it a work of art; and also to Bill Walton who allowed the typing to be easier than it might have been. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS LIST OF TABLES ..................................... vii LIST OF FIGURES ................................... ix ABSTRACT ........................................... x*i PART I. ASYMMETRIC REDUCTION OF KETONES WITH THE GRIGNARD REAGENT FROM R-1-BROMO-2-PHENYLETHANE-1,1,2-d3 INTRODUCTION................................... 1 Statement of the P r o b l e m ...................... 9 RESULTS AND DISCUSSION ............................ 10 The Preparation of the Grignard Reagent .... 10 Reactions of the Grignard Reagent ............. 18 EXPERIMENTAL....................................... 39 A n a l y s e s ....................................... 39 Gas-Liquid Phase Chromatography............. 39 Infra-Red....................................... 39 Mass Spectra ................................... 39 Melting Points ................................ 40 NMR ............................................. 40 Optical Rotations .............................. 40 G e n e r a l ......................................... 40 Phenyl -t-Butyl Ketone (36J 42 Phenyl Trifluoromethyl Ketone (38) 42 S-(+)-Methyl Mandelate (18) ................... 43 S-(+)-Methyl-O-Mesyl Mandelate (23) ........... 44 R-(+)-2-Phenylethanol-l,1,2-ds (22) ........... 44 R-l-Bromo-2-Phenylethane-l,l,2~dj (24) .... 45 iv Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Solvolysis to Remove l-Bromo~l-Phenylethane . 46 Grignard Reagent from R-l-Bromo-2-Pheny1- ethane-1,1,2-ds (25) 46 S-(+)“l-Phenylethane-l,2,2-d3 (3j4) ........... 47 Reactions of the Grignard Reagent ............. 47 Phenyl -t-Butyl K e t o n e ..................... 47 Phenyl Trifluoromethyl Ketone . * ......... 48 BIBLIOGRAPHY ....................................... 50 APPENDIXES......................................... 54 I. Determination of Deuterium Content by Mass Spectroscopy ........................ 54 II. Chemical Shifts of the Diastereomeric MTPA Esters of Phenyl'--£-butylcarbinol (37) and Phenyltrifluoromethylcarbinol(39) . 57 PART II. ELECTROPHILICALLY ASSISTED NUCLEOPHILIC OPENING OF OPTICALLY ACTIVE STYRENE OXIDE INTRODUCTION....................................... 61 Synthesis of Optically Active Styrene Oxide . 61 The Reaction of Epoxides with Mixed Hydride R e a g e n t s ..................... 65 Reaction of Epoxides with Borane ............. 78 The Reaction of Epoxides with Grignard Reagents and R a M g ....................................... 84 Statement of the P r o b l e m ..................... 92 RESULTS AND DISCUSSION ............................ 94 The Preparation of Optically Active Styrene O x i d e ........................................... 94 The Reaction of R-(+)-Styrene Oxide with Alane R e a g e n t s ....................................... 97 The Reaction of R-(+)-Styrene Oxide with the B2D6/BF3*OEt2 Reagent .......................... 105 The Reaction of R-(+)-Styrene Oxide with DiethyImagnesium/Magnesiurn Bromide Dioxanate....................................... 110 EXPERIMENTAL.................................... 114 v Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. G e n e r a l ......................................... 114 R-(-)-Methyl Mandelate (64) ................... 115 R-(-)-l-Phenyl-l,2-Ethanediol ( 2 ) ............. 115 R- (-) -2-Brosyloxy-l-Phenylethanol (65^) .... 115 R-(+)-Styrene Oxide (4) ....................... 116 Reactions of R-(+)-Styrene O x i d e ............. 117 Reaction with AlDs/EtaO Reagent ........... 117 Reaction with AlDa/THF Reagent ............. 118 Reaction with B2D 6/BF3*0Et2 Reagent .... 119 Reaction with Die thylmagnes ium/Magnes i urn Bromide*Dioxanate .......................... 120 S-(-)-Styrene Oxide (S-_4)..................... 122 BIBLIOGRAPHY....................................... 123 vi Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF TABLES PART I. ASYMMETRIC REDUCTION OP KETONES WITH THE GRIGNARD REAGENT FROM R-l-BROMO-2-PHENYLETHANE-l,1,2-d3 Table Page 1. Asymmetric Reduction of Alkvl Phenyl Ketones by Grignard Reagents ...................... 4 2. Deuterium Analysis of R-(+)-2-Phenylethanol- 1,1,2-dj (22) and R~l--Bromo-2- Phenylethane-l/l,2-d3 (24) by Mass Spectroscopy .............................. 17 3. Rotations of R-(+)-2-Phenylethanol-l,1,2-dj (22) and S-(+)-1-Phenylethane-l,2,2-dj ( 3 4 ) ....................................... 21 4. Reduction Products from the Reaction of the Grignard Reagent 25 with Phenyl £-Butyl and Phenyl Trifluoromethyl Ketones .... 22 5. NMR Analysis of the MTPA Esters of Phenyl- -t-butylcarbinol (37) and Phenyltrifluoro- methylcarbinol (39) 27 6 . Calculated Free Energy Differences Between the Competing Modes of Reduction for Phenyl £~Butyl (36) and Phenyl Trif luoro­ methyl Ketones ( 3 8 ) ..................... 32 PART II. ELECTROPHILICALLY ASSISTED NUCLEOPHILIC OPENING OF OPTICALLY ACTIVE STYRENE OXIDE 1. Reduction of Styrene Oxide with "Mixed Hydride" Reagents ........................ 67 2. Reduction of Epoxides with "Mixed Hydride" R e a g e n t s .................................. 67 3. Reduction of 3-Methylcyclohexene Oxide with Hydride Reagents .......................... 69 4. Reduction of Epoxides with Alane/THF Reagent and LiAlHi*................................ 74 vii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table Page 5. Reaction of Epoxides with B3H6/BF3»0Et2 R e a g e n t .................................. 84 6. Results of the Reduction of R-(+)-Styrene Oxide with the AlDs/EtjO Reagent ..... 98 7. Results of the Reduction of R-(+)-Styrene Oxide with the AID3/THF Reagent . 99 8. Results of the Reaction of R-(+)-Styrene Oxide with the B2D6/BF3«0Et2 Reagent . 106 9. Results of the Reaction of R-(+)-Styrene Oxide with Et2Mg/MgBr2 *Dioxanate . Ill viii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OP FIGURES PART I. ASYMMETRIC REDUCTION OF KETONES WITH THE GRIGNARD REAGENT FROM R-1-BROMO-2-PHENYLETHANE-l,1,2-d3 Figure Page 1. Reduction and Addition Reactions of Carbonyl Compounds with Grignard Reagents ................................ 1 2. Whitmore Mechanism for Grignard Reductions .............................. 2 3. Competing Transition States in the Asymmetric Reduction Reaction ........... 4 4. Preparation of the Grignard Reagent 25 . 13 5. Green Scheme for the Preparation of S- (-) - 2-Phenylethanol-2-d ...................... 14 6. DePuy Scheme for the Preparation of Optically Active 2-Phenylethanol-2-d