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DeNEALE, Richard Jay, 1942- A STUDY ON THE CONFIGURATION AND HYDROLYSIS OF SOME OXAZOLIDINES DERIVED FROM THE EPHEDRINES.

The Ohio State University, Ph.D., 1973 Health Sciences, pharmacy

University Microfilms, A XEROX Company , Ann Arbor, Michigan

THIS DISSERTATION HAS BEEN MICROFILMED EXACTLY AS RECEIVED. A STUDY ON THE CONFIGURATION AND HYDROLYSIS OF SOIVIE OXAZOLIDINES DERIVED FROM THE EPHEDRINES

DISSERATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University

By Richard Jay DeNeale, B.S. *****

The Ohio State University 1973

Reading Committee Louis Mals£ei_s Approved By Jules B, LaPidus Robert_E_î_ Notari__ Lester Mitscher Ai^isey Department of Pharmacy ACKNOWLEDGMENTS

I would like to express my gratitude toward the many friends, colleagues, and acquaintances who have generously contributed their criticira, support, and encouragement during my tenure at Ohio State, Especially, I am grateful for the efforts of my adviser, Dr, Louis Malspeis, in providing his concern for and interest in his students, I am appreciative of the financial support given me by the National Institutes of Health in the form of a Medicinal Chemistry Trainee Grant (GMl9^9-03) under which most of the present work was accomplished. Finally, and most important, I cannot acknowledge adequately in any manner the self- sacrificing efforts of my wife. Leanna, in bringing the efforts of the past years to fruition.

ii VITA

September 20, 1942...... Born - Washington, D. C.

1967 ...... B.S. in Pharmacy, The University of Maryland, Baltimore, Maryland

1967-1969 ...... Teaching Assistant, College of Pharmacy, The Ohio State University, Columbus, Ohio

1969 -1973» ...... NSF-NIH Trainee, College of Pharmacy, The Ohio State University, Columbus, Ohio

FIELDS OF STUDY Major Fieldj Pharmaceutical Chemistry Studies in Organic Chemistry. Professors Harold Shechter, Paul Gassman, and Derek Horton Studies in Pharmaceutics. Professors Louis Malspeis, Robert Notari, and Theodore Sokoloski Studies in Separation Techniques. Professor Raymond Doskotch Studies in Biopharmaceutics. Professors Robert Notari and Richard Reuning Studies in Surface Chemistry. Professor Quentin Van Winkle Studies in Chemical Kinetics. Professor Frank Verhoek Studies in Chemical Thermodynamics. Professor George MacWood Studies in Radioisotopes. Professor Louis Malspeis Studies in Statistics. Professor Russell Skavaril ill TABLE OF CONTENTS

Page

ACKNOWLEDGMENTS...... ü VITA...... iii LIST OF TABLES...... vii LIST OF FIGURES...... % LIST OF COMPOUNDS...... xiii INTRODUCTION AND STATEMENT OF PROBLEM...... 1 Chapter I. BACKGROUND...... '...... 5 II. EXPERIMENTALPROCEDURES ...... 15 A. Synthetic Procedures...... 15 1. Reagents 2. Instrumentation 3. Methods of Synthesis 4. Isolation of Intermediate in the Hydrolysis of 2-Styryl-3, 4-dimethyl-3-phenyloxazolidines 5. Identification of Products of Hydrolysis B. Reaction of Oxazolidines with Grignard Reagents and Hofmann Degradation of the Resulting Tertiary Amino Alcohols...... 39 1. Reagents 2. Instrumentation 3. Procedures C. Kinetic Procedures...... 41 1. Reagents 2. Instrumentation 3. Methods of Analysis a. General Procedures b. Preparation of Buffers

iv c. Preparation of Stock Solutions d. Preparation of Solutions of Hydrogen Chloride e. Preparation of Solutions of Sodium Hydroxide D, Measurement of Equilibrium Values for Ring Closure.,...... 50 III. RESULTS AND DISCUSSION...... 52 A. Synthesis of Oxazolidines from (-)-Ephedrine and (t)-Pseudoephedrine $2 B. Synthesis of Oxazolidines from (x)-Norephedrine and (+)-Norpseudoephedrine...... 54 C. Stereochemical Aspects of Ring Closure...... 6o 1. Evidence from Proton Magnetic Resonance Spectral Data and Infrared Spectral Data 2. Evidence from Reaction of Grignard Reagents with Oxazolidines and Subsequent Hofmann Degradation 3. Evidence from X-ray Diffraction Analysis 4. Proposed Mechanism of Ring Formation D. Attempt to Measure Equilibrium Values for Ring Closure of the Styryl- oxazolidines...... 93 E. Some Spectral Characteristics of Hydrolysis Intermediates from 2-Styryl-3»4-dimethyl-5-phenyl- oxazolidines (II and XII) and 2,5-Diphenyl-3f4-dimethyloxazolidines (I and XI) and of Styrylidene-N- methyl-N-[2-(erythro-1-hydroxy-1- phenyl)propyl] ammonium perchlorate (XXXIV)..... 93 F. Kinetics of the Hydrolysis of Some Oxazolidines Derived from the Ephedrines and of Some Intermediates and Analogues ..... 99 1. Methods of Assay 2. Kinetics of the Hydrolysis of 2-Styryl-3,4-dimethyl-5- phenyloxazolidines a. Methodology b. Kinetics in Acidic Solutions c. Kinetic Characterization of Solvent Participation in Ring Opening of the Oxazolidines in Acidic Solutions d. Kinetics in Buffer Solutions, pH 3.0 - 7.0 e. Rate Dependency on Temperature - Concentrated Acid Solutions f. Kinetics in Alkaline Solutions g. Solvent Kinetic Isotope Effects in Alkaline Solutions h. Rate Dependency on Temperature - Alkaline Solutions i. Stopped-flow Measurements of the Hydrolysis Reaction in Alkaline Solution 3. Some Oxazolidines from (-)-Ephedrine and Aliphatic Carbonyl Compounds 4. Kinetics of the Hydrolysis of 2,^-Diphenyl-3,4-dimethyloxazolidines 5. Comparative Kinetic Characteristics Defining the Hydrolysis of the 2-Styryl- 3,4-dimethyl-5-phenyloxazolidines 6. Comparative Kinetic Characteristics of Ring Opening of the 2-Styryl-3,4- dimethyl-5-phenyloxazolidines 7. Comparative Kinetic Characteristics of the Hydrolysis of the Intermediates from 2-Styryl-3,4-dimethyl-5- phenyloxazolidines from 6 M HCl to pH 7 SUfmARY. . ., 190 REFERENCES, 193

Vi LIST OF TABLES

Table Page

1. Selected IR and PMR (6) Spectral Properties for Condensation Products of (Î)-Norephedrine and (+)-Norpseudoephedrine with '/arious Carbonyl Compounds in Chloroform-d 56 2. Infrared Bands Between 2700 and 2800 c m . 65 3. Selected PMR ((5 ) Chemical Shifts for Oxazolidines from the Ephedrines and Norephedrines in Chloroform-d 69 4. Mollecular Ellipticities at Selected Wavelengths for the Ephedrines and Selected Analogous Compounds in Methanolic Solutions 83

5 . Absolute Configurations of the Ephedrines and Selected Analogous Compounds 84 6. Torsion Angles for 2-p-Bromophenyl-3»4- dimethyl-5-phenyloxazolidines 86

7. Bond Angles for 2-p-Bromophenyl-3,4- dimethyl-5-phenyloxazolidines 87 8. Proton Magnetic Resonance Spectral Data of 2-Styryl-3.4-dimethyl-5-phenyl- oxazolidines and 2,5-Diphenyl-3,4-dimethyl- oxazolidines in Trifluoroacetic Acid 95

9. Selected Circular Dichroisra Spectral Properties of Some Oxazolidines and Their Hydrolytic Products 98

vii 10, Selected Ultraviolet Spectral Properties of Some Oxazolidines and Their Hydrolytic Products 100 11, Rate Constants for the Hydrolysis of 2-Styryl- 3.4-dimethyl-^-phenyloxazolidines (II and XII) in 6.35 M HCl at 30° 103 12, Rate Constants for the Hydrolysis of 2-Styiyl- 3.4-dimethyl-5-phenyloxazolidines (II and XII) in pH 6,00 Phosphate Buffer 0,05 M at 30° 103

1 3 , Rate Constants for the Hydrolysis of 2-Styryl- 3.4-dimethyl-5-phenyloxazolidines (II and XII) in Hydrochloric AcidSolutions at 30° 104 14, Rate Constants for the Hydrolysis of Styrylidene-N-methyl-N-[2-(1-phenyl)propylJ- ammonium Perchlorate (XXXV) in Hydrochloric Acid Solutions at 30° 111 15* Rates of Ring Opening of 2-Styryl-3,4-dimethyl- 5-phenyloxazolidines (II and XII) in Hydrochloric Acid Solutions at 15° 112

1 6 , Rate Constants for Ring Opening of erythro-2- Styryl-3,4-dimethyl-5-phenyloxazolidine (II) in Aqueous Solutions of HCl - LiCl at 30° 118

17, Rate Constants for Ring Opening of the 2-Styryl- 3»4-dimethyl-5-phenyloxazolidines (II and XII) in DCl and HCl Solutions at 17° 119 18, Rate Constants for Hydrolysis of 2-Styryl-3»4- diraethyl-5-phenyloxazolidines (II and XII) at 30° in Buffer Solutions of pH 3*0 to 7,0 121

1 9* Rate Constants for Hydrolysis of 2-Styryl-3,4- dimethyl-5-phenyloxazolidines (II and XII) at 30° 126

viii 20. Activation Parameters for Hydrolysis of 2-Styryl-3,^-diraethyl-5-phenyloxazolidines (II and XII) in 6.35 M HCl 129 21. Rate Constants for the Hydrolysis of the 2-Styryl-3,4-dimethyl-5-phenyloxazolidines (II and XII) at 17° 13^ 22. Fraction of the 2-Styryl-3,4-dimethyl-5- phenyloxazolidines (II and XII) present as Immonium Ion in Various Buffers at Zero Time at 17° 142

23. Rate Constants for the Hydrolysis of 2-Styryl- 3 f4-dimethyl-5-phenyloxazolidines (II and XII) in Alkaline Solutions at 17° 150 24. Solvent Kinetic Isotope Effect for Ring Opening of the 2-Styryl-3,4-dimethyl-5""phenyloxazolidines (II and XII) in Alkaline Solutions Containing 1^ Dioxane at 17° 153

2 5 . Activation Parameters for Hydrolysis of 2-Styryl- 3i4-dimethyl-5“Phenyloxazolidines (II and XII) in 0.1 M NaOH Containing 1^ Dioxane 158

26 . Stopped-flow Measurements of Compounds XXXIV and XXXV in 98^ Dioxane - 2# 0.1 M NaOH 159

27. Hydrolysis of Some Oxazolidines from (-)-Ephedrine and Aliphatic Carbonyl Compounds Using Circular Dichroism Measurements at 25° I60 28. Rate Constants for the Hydrolysis of 2,5- Diphenyl-3»4-dimethyloxazolidines (I and XI) in Various Buffers Containing 1^ Dioxane at 30° 162

29. Rate Constants for Ring Opening of 2-Styryl- oxazolidines in 5.64 M HCl at 17° I69

ix LIST OF FIGURES

Figure l'âge

1, Plots of log vs.time for the ring opening of erythro-2-styryl-3,4-dimethyl- 5“phenyloxazolidine at 50 ° made at various times after stock solution preparation 48 2, Spectrum of erythro-2-styryl-3,4-dimethyl- 5-phenyloxazolidine in (a) dioxane, (b) pH 3 citrate buffer at maximum intermediate concentration, (c) pH 3 citrate buffer showing decomposition of intermediate and formation of aldehyde, and (d) final product of the reaction 102 3, Plots of absorbances extrapolated to zero time vs. concentration of the 2-styryl- oxazolidines in 6.35 M HCl at 30° 107 4, Plots of absorbances extrapolated to zero time vs. concentration of the 2-styryl- oxazolidines in pH 6,0 phosphate buffer, 0.05 M at 30°. Plot of absorbance vs. concentration of cinnamaldéhyde in the same medium at 30° 109 5, Plots of log vs. log a^ for ring opening of the 2-styryloxazolidines in hydrochloric acid solutions at 15 ° 115

X 6 . Plots of log vs. for ring opening of the 2-styryloxazolidines in hydrochloric acid solutions at 1^° 117

7. Plots of rate constants for the hydrolysis of 2-styryl-3 ,4-dimethyl-^-phenyloxazolidines at pH 4 and pH 5 as a function of acetate buffer concentration at 30°i 1^ dioxane. Reactions monitored at 33^ nm 123

8. Plots of rate constants for the hydrolysis of 2-styryl-3 ,4-dimethyl-5-phenyloxazolidines at pH 6 and pH 7 as a function of phosphate buffer concentration at 30^, 1% dioxane. Reactions monitored at 33^ nm 125 9. Plots of log vs. pH for the 2-styryl- 3 14-dimethyl-5-phenyloxazolidines from 6 M HCl to pH 7 at 30° 128 10. Plots of log k^^g vs. 1/ï for ring opening of erythro-2-styryl-3.4-dimethyl-5-phenyl- oxazolidine in 6.35 M HCl 131 11. Plots of log k^^g y^. 1/T for ring opening of threo-2-styryl-3,4-dimethyl-5-phenyl- oxazolidine in 6.35 M HCl I33 12. Plots of rate constants for the hydrolysis of 2-styryl-3 ,4-dimethyl-5 -phenyloxazolidines at pH 7I 7,3, and 8 as a function of phosphate buffer concentration at 17°, 1^ dioxane. Reactions monitored at 33^ nm 137

x i 13t Plots of rate constants for the hydrolysis of 2-styryl-3 ,^-dimethyl-5 -phenyloxa2;olidines at pH 9 and 10 as a function of borate buffer concentration at 1?^, 1% dioxane. Reactions monitored at 33^ nm 139 14. Plots of log vs, pH for the 2-styryl- 3.4-dimethyl-5-phenyloxazolidines from pH 5 to pH 10 at 17° 141

15 . Hydrolysis of erythro-2-styryl-3,4-dimethyl- 5-phenyloxazolidine in pH 9 borate buffer* 0.0 0 5 M, 60% dioxane, 25° 144

16 . Hydrolysis of erythro-2-styryl-3.4-dimethyl- 5-phenyloxazolidine in pH 9 borate buffer, 0.0 0 5 M, 20^ dioxane, 25° 146

17. Hydrolysis of erythro-2-styryl-3i4-dimethyl- 5-phenyloxazolidine in pH 9 borate buffer, 0 .0 0 5 Mf 1^ dioxane, 25° 148 18. Plots of OH" activity vs. log k^^^ for the 2-styryl-3,4-dimethyl-5-phenyloxazolidines in aqueous sodium hydroxide solutions at 17°, 1% dioxane 152

19. Plots of log k^^g vs, l/ï for erythro-2- styryl-3,4-dimethyl-5-phenyloxazolidine in 0.1 M NaOH, 1% dioxane 155

20. Plot of log k^^g vs. l/T for threo-2-3tyr.vl- 3.4-dimethyl-5-phenyloxazolidine in 0.1 M NaOH, dioxane 157

xii LIST OF COMPOUNDS

Number Compound Page I erythro-2,5-Diphenyl-3 > 4- dimethyloxazolidine 19 II erythro-2-Styryl-3•4-dimethyl- 5-phenyloxazolidine 19 III erythro-2-o-Hydroxyphenyl-3.4- dimethyl-5-phenyloxazolidine 20 IV erythro-2-p-Bromophenyl-3.4- dimethyl-5-phenyloxazolidine 20 V erythro-2-p-Methoxyphenyl-3•4- dimethyl-5-phenyloxazolidine 20 VI erythro-2-Spirocyclohexyl-3.4- dimethyl-5-phenyloxazolidine 21 VII erythro-2-Benzyl-3•4-dimethyl- 5-phenyloxazolidine 21 VIII erythro-2,2,3,4-Tetramethyl-5- phenyloxazolidine 21 IX erythro-2.3.4-Trimethyl-5- phenyloxazolidine 22 X erythro-3.4-Dimethyl-5- phenyloxazolidine 22 XI threo-2,5-Dipheavl-3i4-dimethyl- oxazolidine 22 XII threo-2-St.vryl- 3.4-dime thvl- 5- phenyloxazolidine 23 XIII threo-2-o-Hydroxyphenyl-3.4- diraethyl-5-phenyloxazolidine 23 XIV threo-2-p-Bromophenyl-3,4- dimethyl-5-phenyloxazolidine 23 xiii XV threo-2-p-Methoxyphenyl-3 f 4- diraethyl-5-phenyloxazolidine 24

XVI threo-2-Spirocyclohexyl-314- dimethyl-5-phenyloxazolidine 24 XVII threo-2,2,3» 4-Tetramethyl-S- phenyloxazolidine 24 XVIII threo-2,3 » 4-Triinethyl-5- phenyloxazolidine 25 XIX threo-3,4-Dimethyl-5-phenyl- oxazolidine 25 XX erythro-2,3.4-Trimethyl-5- phenyloxazolidine 25 XXI erythro-2,4-Dimethyl-5-phenyl- oxazolidine 26 XXII erythro-4-Methyl-5-phenyl- oxazolidine 26 XXIII erythro-2,5-Diphenyl-4-methyl- oxazolidine 26 XXIV threo-2,2,4-Trimethyl-5-phenyl- oxazolidine 27 XXV threo-2,4-Dimethyl-5-phenvl- oxazolidine 27 XXVI thre0-4-Methyl-5-phenyl­ oxazolidine 27 XXVII threo-2,5-Diphenvl-4-methyl- oxazolidine 28 XXVIII 2,5-Diphenyl-3-raethyloxazolidine 28 XXIX erythro-2.4.5-Triphenvl-3-raethvl- oxazolidine 30 XXX erythro-2-Styryl-3-methyl-4,5- diphenyloxazolidine 31

xiv XXXI 2-Styryl-3,4-dimethyloxazolidine 32

XXXII Styrylidene-N- [2-(erythro-1-phenyl- 1-hydroxy)propyl] amine 33 XXXIII Styrylidene-N-f 2-(threo-l-phenyl- 1-hydroxy)propyl] amine 33 XXXIV Styrylidene-N-methyl-N-[2-(erythro- 1-phenyl-1-hydroxy)propyl] - ammonium perchlorate 33

XXXV Styrylidene-N-methyl-N-[2-(1-phenyl) propyl] ammonium perchlorate 34 XXXVI erythro-2-Stvryl-3.3.4-trimethvl-5- phenyloxazolidinium iodide 35

XV INTRODUCTION AND STATEMENT OF PROBLEM

Pro-drugs are derivatives of pharmacologically active molecules which are converted in-vivo to the biologically active parent compound. The conversion of the pro-drug to the parent compound in the body may proceed enzymatically, non-enzymatically, or by both of these processes. There ere numerous objectives for the preparation of pro-drugs. In certain instances, it is desired to prepare a derivative whose rate of absorption from the gastro­ intestinal tract is more rapid than that of the parent drug. In others, it is desired to detain a compound with a longer duration of action them that of the parent. The pro-drug may be prepared in order to decrease the amount of the drug which is bound to food components or to provide a compound whose taste is less objectionable than that of the parent, The objective may be to prepare a derivative which is less readily degraded in the dosage form or in the stomach than is the parent drug. Another is the preparation of a derivative which is less rapidly metabolized or excreted than the drug itself. To date, various types of derivatives have been studied as potential pro-drugs. The large majority of the

1 2 compounds studied are inorganic esters or aliphatic and aromatic esters of drugs. No study has yet been made of the potential use of oxazolidines as pro-drugs. 1,3-Oxazolidines are five-membered heterocyclic organic compounds having the following structure and num­ bering systemI

4 C-N

Such compounds are formed by condensation of a beta-amino alcohol and a carbonyl compound. Aldehydes condense readily with amino alcohols containing primary and secondary amino groups ; ketones are usually less reactive, especially towards secondary amino groups. In the case of "nor-" oxazolidines, a tautomeric Schiff base form exists in equilibrium with the ring structure *

c ' " O H I 'c I C ' - N ^ ^ N = C H Hence, oxazolidines obtained from beta-amino alcohols having a primary amino group are not obtained in pure form, but as

a mixture with the Schiff base (I-3 0 ). With amino alcohols having a substituent on the nitrogen no such equilibrium exists, and the product is pure oxazolidine

In order to study oxazolidines as pro-drug candidates, the parent drugs must be vicinal amino alcohols. Secondary amino alcohols are preferred since the pro-drug is exclusively oxazolidine. The candidates selected for the present study are (-)-ophedrine and (+)-pseudoephedrine. The use of oxazolidines as pro-drugs for ephedrine and other sympathomimetic amines has an inherent liability in that oxazolidines are labile to hydrolysis, especially in the presence of acids. One must obtain a derivative which is sufficiently stable to provide therapeutic blood levels of the active form for the desired time interval (depending on the route of administration), but not so stable that little or none of the active form is released. If such an approach to prolonging the biological half-life of the amino alcohol is to be further investigated, definite characteri­ zation of the mechanism(s) of hydrolysis must be first established. The objectives of the present work are to prepare various oxazolidines of (-)-ephedrine and (+)-pseudo­ ephedrine, to establish the structures of these compounds. 4 and to study the kinetics of the hydrolytic decomposition of these compounds in solution with the purpose of ascertaining whether these oxazolidines may be potential pro-drug candidates. I. BACKGROUND

The first reported preparation of oxazolidines is by Knorr, et al., (31,32) who prepared the compounds by refluxing vic-amino alcohols and carbonyl compounds in ether with potassium carbonate as the catalyst, Oxazolidines derived from aromatic aldehydes or ketones often form spontaneously upon mixing of the reagents. Acetone has been used as a reactant-solvent. Water has been used, especially in cases involving formaldehyde as the carbonyl component

(30), Alcohol has been used as solvent or cosolvent v/ith benzene or ether in condensations (33-36), The most frequently encountered method of preparation involves sol­ vents forming azeotropes with water, especially benzene, toluene, and the xylenes (7,9,10,1^-16, 30,37-39), Catalysts used have included iodine (1,7,30), anhydrous sodium sulfate (4o), perchloric acid (4l), acetic acid

(1,7,30), and other dehydrating agents. More recently Linde molecular sieves have been used as dehydrating agents for oxazolidine synthesis (20), Other methods of forming oxazolidines include cyclo- addition reactions involving 2-acyl aziridines and aldehydes (42), epoxides and azomethines (43), aziridines and ketenes • 6 (44), high pressure reactions of aliphatic beta-amino alcohols with ethylene (45)» and addition of aldehyde bisulfites to amino alcohols (46), Some of the more important reactions of oxazolidines include hydrolysis, polymerization (4?), reduction, N-substitution, and reaction with Grignard reagents as summarized by Bergmann (48) in his review of oxazolidines, Schmidt (49) in 1914, first prepared oxazolidines from the ephedrines by condensing benzaldehyde with (-)-ephedrine and with (+)-pseudoephedrine.

0 7 However, he erroneously reported the products to be diastereoisomeric 1,4-diphenyl-2-methylamino-4-hydroxy- butene-1, from "oxidative decomposition".

9 V /H H O -C -C -C = C

Stuart (50 ) showed that these oxazolidines were formed by a loss of one water molecule, and that the optical rotations differed from those of the reactants, Davies (25) reported an inertness of these products to phenylisocyanate, ethereal méthylmagnésium iodide, and dilute permanganate solution, which indicated the absence of hydroxy and imino groups and the presence of a saturated compound. The inertness to ethereal méthylmagnésium iodide is not correct as documented by Bergmann (48) in his review. In the case of condensation of an unsymmetric aldehyde or ketone with a beta-amino alcohol, an asymmetric center is created upon ring closure (8 ,33).

: Ç - 0 . R

''R' ' ' R 8 The absolute configurations of (-)-ephedrine and (+)-pseudoephedrine are as follows; (51-53)»

H H" I “ Ephedrine

C Ho

(+)-Pseudoephedrine ^ P ^ ' N H CH,

Thus, for each of these compounds there exists the possibility of two diastereoisomeric oxazolidines formed on condensation with an unsymmetrical carbonyl compound. Before proceeding with a kinetic study, it is necessary to know whether one or two compounds result when the oxazolidines of (-)-ephedrine and (+)-pseudoephedrine are prepared from aldehydes or asymmetric ketones. If two compounds are formed, the diastereoisomers should be separated. The formation of oxazolidines ( 5^ and other heterocyclic compounds (55 ) from the ephedrines indicated 9 different stable conformations of each diastereoisomeric amino alcohol. Hyne (56) suggested preferred conformations among the various rotaraers of the ephedrines from PMR data. The dihedral angle between the nitrogen and oxygen was given as

30 to for pseudoephedrine and 80 to 90^ for ephedrine. This difference was postulated as a result of stronger internal hydrogen bonding in the case of the pseudoephedrine.

Portoghese (5 7 ) reported essentially similar conclusions from a PMR investigation of (-)-ephedrine and (+)-pseudo­ ephedrine interpreting his results in terms of percentage relative population of the three pure staggered conformations of the two isomers. Fischer and Schiene (41 ) noted that the measured equilibrium constants of cycloaddition of the ephedrines and other 1,2-amino alcohols in dioxeine show a greater extent of cyclization in the cases of the threo diastereoisomer provided free rotation is allowed between and Cg of the amino alcohols. The values of the equilibrium constants for the cyclization of the ephedrines with acetone decrease with increasing temperature from 20 to 40°. Simultaneously, the differences between the equilibrium constants decrease with increasing temperature. The rate of cyclization of ephedrine with acetone in acetone solution is approximately tenfold slower than the rate of cyclization of pseudoephedrine, the threo isomer. 10 under the same conditions.

Pfanz and Kirohner (58 ) in a study of the hydrolysis of oxazolidines from the ephedrines and formaldehyde monitored the reaction in sulfuric acid by recovering the formaldehyde by steam distillation of aliquots of the reaction mixture taken at various time intervals. They reported a faster rate of hydrolysis for the oxazolidine from (-)-ephedrine and formaldehyde, which was interpreted in terms of non-bonded interactions' between the methyl and phenyl. Cleary (5 9 ) suggested that they may have measured extent rather than rate of hydrolysis.

Konvisser (60 ) noted that erythro oxazolidinium methiodide salts hydrolyze in alkali under severe conditions to a greater extent than do threo isomers. A mechanism of the hydrolysis of oxazolidines derived from the ephedrine was reported by Sakai, et al., ( 61) in

1963 , in a study concerned with the combination of the major components of Ephedra, Chinese cinnamon, and Japanese apricot seeds. The authors were able to note a two-step decomposition of oxazolidines formed from (-)-ephedrine and cinnamaldéhyde. The first step was ring opening which they hypothesized occurred by N-C bond breaking to form a cationic Schiff base. Their evidence included data from ultraviolet spectrophotometry, (MeOH) = 336 nmi in SIX 6 = 32,500 , and the presence of a C*=N stretch in the infrared (Nujol) at I660 cm.“^. Ring opening was then 11 followed by aldehyde formation.

Cleary in 1964, (6 2 ) studied the acid hydrolysis of oxazolidines derived from the ephedrines and para- substituted benzaldehydes. Rates of aldehyde formation were significantly greater for the threo isomers than for the erythro isomers. From pH 1 to 4 Cleary reported that the rate of aldehyde formation decreased linearly with for 2,5-diphenyl-3*4-dimethyloxazolidines. Cleary obtained a linear correlation of Hammett’s values with log at pH 2,03 (0.01 N HCl) with

P = +0 ,2 6 for the erythro isomers and p = +0.49 for the threo isomers. The mechanism of hydrolysis which he proposed is that of C-N cleavage to form a carbonium ion which then reacts with the solvent to form a hemiacetal intermediate. The rate determining step was considered to be dehydration of the hemiacetal. Internal general acid catalysis of the hemiacetal cleavage was proposed. The conformation required for the catalysis imposes the restriction that the protonated nitrogen and alcohol oxygen be eclipsed resulting in a steric interaction between the phenyl and methyl in the erythro isomer. This, Cleary proposed, is the source of the lower observed rata of hydrolysis of the erythro isomers than the threo isomers. 12

H CH) CH)

4 H'^-H C Hj — . c^H ^Vh C h,

0

In 1 9 68 , Fife and Hagopian (63 ) reported a study on the solvent participation in the hydrolysis of 2-para- substituted phenyl-3-ethyloxazolidines. In acidic media they found general base catalysis by formate and acetate ions. The authors were able to characterize an intermediate having a cationic Schiff base character by its intense ultraviolet absorption maximum in acid. The ultraviolet absorption was nearly identical to that of a synthesized benzylideneethanolamine in acid. The hydrolytic rate 13 constants from the benzylideneethanolamines compared favorably to those of the N-ethyloxazolidines in acid solutions. The overall hydrolysis in acid they noted consisted in a relatively fast ring opening step followed by a slower hydrolytic step to yield the aldehyde, Hammett plots yielded p = +1.6 for the ring opening in 3*57 N HCl and p"^ = +0.5 for the subsequent hydrolysis. In the region pH 1 to 3 ring opening was pH independent and from pH 2 to 4 intermediate hydrolysis was pH independent. The authors noted that ring opening via 0-0 bond breaking to yield a carbinolamine intermediate by nucleophilic attack of water on the protonated oxazolidine is unlikely since ring opening is accelerated by

substitution of a methyl for a proton in 2-phenyl-2-methyl- 3-ethyloxazolidine. Steric and inductive effects of the methyl should retard a nucleophilic attack at the Cg carbon. At high pH no sign of intermediate was obtained. Formation of aldehyde was subject to a general acid catalysis by imidazole buffer from pH 7 to 8, and a decrease in the rate of hydrolysis with increasing pH was noted in this region. Above pH 10 the rate of hydrolysis (aldehyde formation) was pH independent. A Hammett plot yielded P = -1.1 in 0.01 N NaOH. They observed in their study of the hydrolysis of

2-phenyl-3-ethyloxazolidine that for ring opening in acid 14 solution w plots (plots of log k versus water activity) were curved, which they considered as characteristic of reactions involving several water molecules in the trans­ ition state. For decomposition of the intermediate of the same oxazolidine a linear plot was obtained with w = +7 .1 , Entropies of activation of -13*9 e.u. and -15.5 e.u. v/ere obtained in 2.37 M HCl and 5»74 N HCl, respectively for 2-phonyl-3-ethyloxazolidine ring opening and -8 .9 e.u. and -9.6 e.u. for intermediate hydrolysis. This they asserted v/as more nearly in accord with solvent participation than with a unimolecular reaction. They also noted a solvent kinetic isotope effect of ^H c/^D 0 “ 2.65 for 2-p-methoxyphenyl-3-ethyloxazolidine for intermediate formation at pH 2 and pH 4. The authors proposed a mechanism of ring opening in acidic media based on (1) a solvent kinetic isotope effect of k^ q/^d 0 = 2.65; (2) the presence of general catalysisi (3) negative salt effects; and (4) negative entropies of activation. , , , ,

/ H II. EXPERIMENTAL PROCEDURES

A. Synthetic Procedures

1. Reagents

The ephedrine used in this study was obtained either as the free base or the hydrochloride salt from the S. B, Penick Company and from the Inland Alkaloid Company, The free base was prepared from the salt by treating a concentrated aqueous solution of the salt with sodium hydroxide pellets, extracting into benzene or ether, remov­ ing the solvent, and vacuum distilling the residue. The pseudoephedrine was obtained either as the free base from Cane's Chemical Works or as the hydrochloride salt from Burroughs-V/ellcome. The free base was prepared from the salt as above except that vacuum distillation was not required. Phenylpropanolamine ((±)-norephedrine) both as the free base and the hydrochloride salt was obtained from the Nepara Chemical Company, (+)-Norpseudoephedrine sulfate and (+)-methamphetamine hydrochloride were obtained from K & K Laboratories, (+)-Alanine was obtained from Difco Company. Benzaldehyde, N, P,, was obtained from Matheson,

15 16 Coleman, and Bell Company, purified by vacuum distillation, and kept under refrigeration. Cinnamaldéhyde was obtained from MCB and treated in the same manner as benzaldehyde. Salicylaldéhyde was obtained from the Aldrich Chemical Company, and kept under refrigeration, Anisaldehyde was obtained from the Eastman Kodak Company, and kept under refrigeration, p-Bromobenzaldehydo was obtained from Aldrich and kept in the freezer, A aqueous solution of methylamine was obtained from Aldrich and used without further purification, Phenylacetone and acetophenone were obtained from MCB and used without further purification. Acetone and benzil were obtained from J, T, Baker Chemical Company, Acetaldehyde was obtained from MCB and kept under refrigeration. Formaldehyde 37^ aqueous solution v/as obtained from Mallincrodt Chemical Works, Cyclohexanone was obtained from Eastman Distillation Chemicals and used without further purification, (+)-Mandelie and (-)-mandelic acids were obtained from Aldrich and used without further purification. Potassium benzyl penicillin v/as obtained from Pfizer,

Formamide was obtained from Fisher, Perchloric acid 70fo was obtained from G, Frederick Smith Chemical Company, Potassium bromide and 3- (trimethylsilyl)-propane sulfonic acid sodium salt were obtained from E, Merck A, G, Reagent grade solvents were obtained from J, T, Baker Company, Solvents for proton magnetic resonance (PMR) use in 17 characterizing the synthesized compounds included tetramethylsilane, DMSO-d^, CDCl^s and trifluoroacetic acid (îFA) from Mallincrodt, Spectral quality methanol was obtained from Eastman Organics. Spectral quality chloroform was obtained from J. T. Baker. Raney nickel alloy was obtained from the W. Grace Company. Lithium aluminum hydride and sodium borohydride were obtained from Ventron Corporation. Linde molecular

sieves types 3A and 5A as I/I6 " pellets were obtained from Union Carbide Company and from Ventron,

2. Instrumentation ‘

Instruments used in the synthetic studies included1 a Beckman DU spectrophotometer, a Cary 15 spectrophotometer, a Gilford 240 spectrophotometer, a Jasco spectropolarimeter, a Perkin-Elmer grating infrared spectrophotometer model 257, and a Varian 60 megacycle nuclear magnetic resonance spectrometer A-60 A,

3» Methods of Synthesis

General Method A - A solution of 3*3 g» (0.02 mole) of

(-)-ephedrine or (+)-pseudoephedrine and 0 ,0 2 mole of the appropriate aldehyde or ketone in 75 ml, benzene was placed in a 250 ml. round bottom flask attached to a reflux condenser with a Dean-Stark trap. The contents were 18 refluxed until no further water collected in the trap (about 4 hours). Generally more than the theoretical amount of water was collected due to water in the solvent and atmospheric moisture. The solvent was removed in a flash evaporator and the residue allowed to crystallize. The product was recrystallized from ether or benzene.

General Method B - A solution of 3*3 &• (0.02 mole) of (_)-ephedrine or (+)-pseudoephedrine and 0.02 mole of the appropriate aldehyde or ketone in 75 ml. benzene v/as placed in a 250 ml. Erlenmeyer flask and sufficient 3A or 5A molecular sieves added to cover the benzene. The mixture was allowed to stand overnight at room temperature, the sieves removed by filtration, and the solvent evaporated in vacuo. The resultant solid was recrystallized from ether or benzene.

General Method 0 - A solution of 3.3 g* (0.02 mole) of (-)-ephedrine or (+)-pseudoephedrine and 0.02 mole of the appropriate aldehyde or ketone in 150 ml. benzene was placed in a 500 ml. round bottom flask, and sufficient 3A or 5A molecular sieves added to cover the benzene. The flask was fitted to a reflux condenser and the contents refluxed overnight. The sieves were removed by filtration, the solvent evaporated in vacuo, and the resultant solid recrystallized from ether or benzene.

General Method D - A solution of 4.54 g. (O.O3 mole) of 19 (±)-norephedrine or (+)-norpseudoephedrine and 0 .0 3 mole of

the appropriate aldehyde in a mixture of 90 ml, ether and

10 ml, methanol was allowed to stand for 5 minutes at room temperature. The solvent was evaporated in vacuo and the resultant liquid residue vacuum distilled,

erythro-2,5-Diphenyl-3t^-dimethyloxazolidine (I) - (-)-Ephedrine and benzaldehyde were reacted to form I by method A: yield 920; mp 74-75°j ir (GHCl^) 1055, 1120, 1133, 1158, 1173 cm."^ (0-C-N), 2852, 2807, 2795, 2752 cra,"^

(Bohlmann bands); nmr (CDCl^) 6 0,78(d,3H,J = 6 , 6 H z ) , 2.20(s,3

h), 2,99(m,lH), 4,72(s ,1H), 5,17(d,lH,J = 8 H z ) , Anal,^ Calcd, for C^^H^^NOi C. 80,60; H, 7.55; N, 5.53. Found; C, 80,73; H, 7,62; N, 5.57. The compound was also prepared by refluxing in absolute alcohol; yield 900; all the above characteristics were the same,

erythro-2-Styryl-3.4-dimethyl-5-phenyloxazolidine (II) - (-)-Ephedrine and cinnamaldéhyde were reacted to form II by method A; yield 930; mp 90-91°; ir (KBr) 1075, 1115, 1128, 1157, 1189 cra,"^ (0-C-N), 2850, 2800, 2745, 2721 cm,“^ (Bohlmann bands); nmr (CDCl^) 6 0,69(d,3H,J=6,5Hz), 2,27 (s,3H), 2,91(m,lH), 4,29(d,lH,J=7Hz), 5.11(d,IH,J=8Hz), Anal, Calcd, for C^^H^j^NO; C, 81,68; H, 7,58; N, 5,01, Found; C, 81,60; H, 7.55; N, 5.06,

^ Analyses were performed by Scandinavian Microanalysis, Herlev, Denmark; and by ICff// Laboratories, Garden City, MI 20 erythro-2~o->HydroxyT>hen,vl~ 3. ^-dimethyl- S-pheavIoxazolidine (III) - (-)-Ephedrine and salicylaldéhyde were reacted to

fonn III by method A* yield 9W<>1 mp 117,5-118.5°; ir (Nujol) 1058, 1109, 1139, 1153, 1189 cm.“^ (0-C-N), 2840, 2770, 2711

cm.“^ (Bohlmann bands); nmr (CDCl^) 6 0,82(d,3H,J=6,5Hz), 2.38(s,3H), 3.07(m,lH), 4.91(8,IH), 5.25(d,lH,J=8.5Hz). Anal. Calcd. for 73.80; H, 7.11; N, 5.20. Found* C, 75.59; H, 7.10; N, 5.2?.

erythro-2-p-Bromophenvl-3 » 4-dimethyl-6-phenyloxazolidine (IV) - (-)-Ephedrine and p-broraobenzaldehyde were reacted to form IV by method B* yield 88^; mp 92°; ir (CHCl^) 1052, 1095, 1129, 1155, 1180 cm.“^ (0-C-N), 2822, 2783, 2720 cm.“^ (Bohlmann bands); nmr (GDCl^) 6 0.77(d,3H,J=6.0Hz), 2 .1 7(3 ,3 H), 2.96(m,lH), 4.66(s,lH), 5.l4(d,lH,J=8.5Hz). Anal. Calcd. for C^^H^gNOBri C, 61.46; H, 5.46; N, 4.21, Found* C, 61.44; H, 5.41; N, 4.21. erythro-2-p-Methoxyphenvl-3.4-dimethyl-5-phenyloxazolidine (V) - (-)-Ephedrine and anisaldehyde were reacted to form V by method B* yield 83^; mp 82-83°; ir (CHCl^) 1059, 1115, 1140, 1175 , 1189 cra.”^ (0-C-N), 2850, 2802, 2750, 2726 cm.“^ (Bohlmann bands); nmr (CDCl^) Ô 0,77(d,3H,J = 6 H z ) , 2,17(s,3H), 2.96(ra,lH), 4.66(s,lH), 5.l4(d,lH,J=8.5Hz). Anal. Calcd. for CjgHg^NOg* C, 76 .2 9; H, 7.4 7 ; N, 4.94. Found*

C, 76 .3 2 ; H, 7.40; N, 4.93. 21 erythro-2~Spirocvclohexyl-3t ^-dimethvl~5-phenvloxazolidine

( V I ) - (-)-Ephedrine and cyclohexsunone were reacted to form

V I by method Ci yield 89^j mp 73-7^*^J ir (CHGl^) 1072, 1093, 1125, 1151, 1193 cm."^ (0-C-N)j nmr (CDC1_) 6 0.61(d, 3H,J=6.3Hz), 2.27(s,3H), 3.24(m,lH), 5.05(d,lH,J=7.7Hz). Anal. Calcd. for C^^Hg^NO: C, 78.22; H, 9.45; N, 5.71. Pound : C, 78.22; H, 9.42; N, 5.58. erythro-2-Benzyl-2,3,4-trimethyl-5-phenyloxazolidine (VII) -

(-)-Ephedrine 4.96 g. (O.03O mole) and phenylacetone 4.70 g.

(0.0 3 5 mole) were added together in a 1000 ml. round bottom flask and heated to 150° for 12 hours. Upon cooling, crystals appeared in the mixture. A nuclear magnetic resonance spectrum of the crude product v/as made in CDCl^i 6 0.51(d,6H,J=6.3Hz), 0.60(d,3H,J=6.3Hz), 1.08(s,6H), 1.35(s,3H), 2 .3 1 (s,9H), 4.97(d,2H,J=7.6Hz), 5.03(d,IH,J=7. 6 Hz). Recrystallization twice from ether yielded purified product : yield 6 l^; mp 105-106°; ir (CHCl^) 1064, I098, 1130, 1181 cm."^ (0-C-N); nmr (CDCl^) 6 O.5 1 (d,3H,J=6.3Hz), 1.35(s,3H), 2.3Ks,3H), 5.03(d,lH,J=7.6Hz). Anal. Calcd. for C^^Hg^NOi C, 81.10; H, 8.24; N, 4.98. Pound: C, 80.97;

H, 8.17; N, 4 .97. erythro-2,2,3,4-Tetramethyl-5-phenyloxazolidine ( V I I I ) -

(-)-Ephedrine and acetone were reacted to form V I I I by method C, using acetone as a solvent: yield 88^; bp 53-55°

(0.6 mm.); mp 39-40° lit. (64) 26-34°; ir (CHC1_) lu86 , 1121, 22 1134, 1153, 1172 cm.”^ (0-C-N)j nmr (CDCl^) 6 0.60(d,3H,J=

6.3Hz), 1.18(s,3H), 1.48(s,3H), 2.22(s,3H), 3 .1 3 (m,lH),

5.01(d,lH,J=8.0Hz). Anal. Calcd. for C, ?6,06t

H, 9.33; N, 6.82. Pound, C, 75.97; H, 9.45; N, 6 .6 9 . erythro-2,3»4-Trimethyl-5~phenyloxazolidine (IX) - (-)-Ephedrine and acetaldehyde were reacted to form IX by method B, yield 85^; bp 64° (1 mm.); ir (CHCl^) 1074, 1107,

1144, 1178 cm."^ (0-C-N), 2858, 28l6, 2788, 2733 cm.”^

(Bohlmann bands); nmr (CDCl^) 6 0.67(d,3H,J=6 .6 Hz), l,47(d, 3H,J=5.2Hz), 2.23(s,3H), 2.?6(m,lH), 3.94(q,lH,J=5.2Hz), 4.99(d,lH,J=8Hz). Anal. Calcd. for C^gH^yNO: C, 75.33;

H, 8 .9 6 ; N, 7 .32. Found, ' C, 75.58; H, 8.63; N, 7.56. erythro-3.4-Dimethyl-5~phenyloxazolidine (X) - (-)-Ephedrine and 37^ formaldehyde solution v/ere reacted to form X by method B, yield 93^; bp 63 ° (1 mm.); ir (CHCl^) 1064, 1099,

1139, 1152 , 1178 cm."^ (0-C-N), 2861, 2800, 2728 cm.~^ (Bohlmann bands); nmr (CDCl^) (5 0.66(d,3H,J=6.5Hz), 2.36(s, 3H), 2.88(m,lH), 4.06(d,lH,J=-3.1Hz), 4.85(d,IH,J=-3.2Hz), 5.10(d,lH,J=7Hz). Anal. Calcd. for C^^H^^^NO, C, 74.54;

H, 8.53; N, 7 .9 0. Found, C, 74.33; H, 8.53; N, 7.98. threo-2,5-Diphenyl-3.4-dimethyloxazolidine (XI) - (+)-Pseudoephedrine and benzaldehyde were reacted to form XI by method A, yield 95% l mp 67 °; ir (CHCl^) 1082, 1128,

1147, 1163 , 1192 cm."^ (0-C-N), 2857, 2810, 2730 cm.“^

(Bohlmann bands); nmr (CDCl^) 6 1,23(d,3H,J=6,0Hz), 2.22(s, 23 3H), 2.56(m,lH), ^,78(d,lH,J=8.5Hz), 4,96(s,lH). Anal.

Calcd. for G, 80.60j H, 7.55» N, 5.53. Found, 0, 80.37» H, 7.49» N, 5.44. threo~2~St.vryl-3.4-dimethyl-5--phenyloxazolidine (XII) - (+)-Pseudoephedrine and cinnamaldéhyde were reacted to form XII by method A, yield 94^; mp 78-78.5^» ir (KBr) 1068,

1114, 1140, 1166, 1183 cra.-^ (0-C-N), 2845, 2802, 2783,

2725 cm.”^ (Bohlmann bands); nmr (CDCl^) Ô l.l8(d,3H,J=6Hz),

2 .3 0 (s,3H), 2.42(m,lH), 4.58(d,lH,J=7Hz), 4.66(d,lH,J=8.5Hz). Anal. Calcd. for G^oHg^NO: C, 81.68; H, 7.58» N, 5.01.

Found, C, 81.60; H, 7.60; N, 5 .32. threo-2-o-Hydroxyphenyl-3,4-dimethyl-5-phenyloxazolidine (XIII) - (+)-Pseudoephedrine and salicylaldéhyde were reacted to form XIII by method A, yield 95^» mp 78°; ir

(CHCl^) 1065 , 1115 , 1130, 1160 , 1191 cra.“^ (0-C-N), 2860,

2816 , 2748 cm.”^ (Bohlmann bands); nmr (CDCl^) Ô 1.29(d,3H,

J=6.2Hz), 2.39(s,3H), 2.65(m,lH), 4.80(d,IH,J=8.7Hz), 5.16(s,1H). Anal. Calcd, for C^^H^^NO^, C, 75.70» H, 7.11» N, 5.20. Found, C, 75.66; H, 7.20; N, 5.28. threo-2-p-Bromophenyl-3.4-dimethyl-5-phenyloxazolidine (XIV) - (+)-Pseudoephedrine and p-broraobenzaldehyde were reacted to form XIV by method C, yield 52^» mp 71-72°; -1 ir (CHCl^) 1075 , 1114, 1148, II78, 1195 cm.”-^ (0-C-N),

2822, 2791, 2730 cm.“^ (Bohlmann bands); nmr (CDCl^) Ô 1.21 (d,3H,J=6.0Hz), 2.l8(s,3H), 2.56(m,lH), 4.74(d,lH,J=8.5Hz), 24 4.92 (s, IH). Anal. Calcd. for C^^ipH^gNOBr i C, 6l ,46; H, 5.46; N, 4.21. Found* C, 61.44; H, 5.41; N, 4.21. threo-2-n-Methoxyohenyl-3,4-dimethyl-5-phenvloxazolidine

(X V ) - (+)-Pseudoephedrine and anisaldehyde were reacted to form XV by method Ci yield 8l^; mp 71-72°; ir (GHCl^) 1082, 1113, 1147, 1175, 1186 cm.“^ (0-C-N), 2850, 2805, 2726 cm.~^ (Bohlmann bands); nmr (CDCl^) 6 1.19(d,3H,J=6Hz), 2.15(s,3H), 2.50(m,lH), 4.74(d,lH,J=8.5Hz), 4.90(s,lH). Anal. Calcd. for C^gHg^NOg: C, 76.29; H, 7.47; N, 4.94. Found* C, 76.16; H, 7.51; N, 4.94. threo-2-Spirocyclohexyl-3,4-dimethyl-5-phenyloxazolidine

(XVI) - (+)-Pseudoephedrine and cyclohexanone were reacted to form X V I by method C* yield 91^; mp 75-76°; ir (CHCl^)

1076, 1093, 1121, 1146, 1196 cm.“^ (0-C-N); nmr (CDCl^) 6 1 .0 7 (d,3H,J=6Hz), 2.3Ks,3H), 2.65(m,lH), 4.45(d,lH,J= 8.5Hz). Anal. Calcd. for C^^H^^NO* C, 78.32; H, 9.45;

N, 5 .7 1. Found* C, 78.54; H, 9.43; N, 5.43. threo-2,2,3 .4-Tetramethyl-5-phenyloxazolidine ( X V I I ) -

(+)-Pseudoephedrine and acetone were reacted to form XVII by method C, using acetone as a solvent* yield 83^; bp 65 ° (1 mm.); ir (CHCl^) 1082, 1127, 1140, 1153, 1178 cm.“^ (0-C-N); nmr (CDCl^) 6 1.06(d,3H,J=6Hz), 1.30(s,3H),

I.4l(s,3H), 2.24(s,3H), 2.52(m,lH), 4.45(d,IH,J = 8 . 6 H z ) . Anal. Calcd. for C^^H^^NO* C, 76.05; H, 9.33; N, 6.82. Found* C, 76.07; H, 9.13; N, 6.95. 25 threo-2,3.4-Trimethyl-5~phenyloxazolidine (XVIII) - (+)-Pseudoephedrine and acetaldehyde were reacted to form XVIII by method Bi yield 68^; bp 57° (1 mm.); ir (GHGl^) 1078, 1107, 1147, 1180 cm."^ (0-C-N), 2858, 2817, 2790,

2736 cm.”^ (Bohlmann bands)1 nmr (GDGl^) Ô 1»15(d,3H,J = 6 H z ) , 1.39(d,3H,J=5.3Hz), 2.25(m,lH), 2.27(s,3H), 4.25(q,lH,J=5.0

H z ) , 4,54(d,lH, J=8,2Hz) • Anal. Galcd. for G, 75.33; H, 8.96; N, 7.32. Pound: G, 75.14; H, 8.80;

N, 7.39. threo-3.4-Dimethyl-5-phenvloxazolidine (XIX) - (+)-Pseudoephedrine and 37^ formaldehyde solution were reacted to form XIX by method Bi yield 94^; bp 5 6 .6 °

(1 mm.); ir (GHCl^) IO6 6 , I105 , 1142, II5 2 , 1182 cm.“^

(0-G-N), 2862, 2800, 2730 cm.“^ (Bohlmann bands); nmr (GDCl^) 6 l.l7(d,3H,J=6Hz), 2.36(s,3H), 2.45(m,lH), 4.29 (d,lH,J=-3.4Hz), 4.51(d,lH,J=8.1Hz), 4.75(d,lH,J=-3.4Hz).

Anal. Galcd. for C^^H^^NO: G, 74.54; H, 8.53; N, 7.90. Found: G, 74.38; H, 8.57; N, 8.12. erythro-2.2.4-Trimethyl-5-nhenvloxazolidine (XX) - (±)-Norephedrine and acetone were reacted to form XX by method G, using acetone as solvent: yield 78^; bp 87-88®

(3mm.); ir (GHGl^) IO88, 1118, 1162 c m . ( 0 - C - N ) ; nmr (GDGl^) 6 0.63(d,3H,J=6.8Hz), 1.38(s,3H), 1.59(s,3H), 3.8l(m,lH), 5.0(d,lH,J=7.5Hz). Anal. Galcd. for ^12^17^®* c, 75.35; H, 8.9 6 ; N, 7.32. Found: G, 75.29; H, 8.93; N, 7.32. 26

erythro-2,^~DiTnethyl~5-Phenyloxazolidine (XXI) - (+)-Norephedrine and acetaldehyde were reacted to form XXI

by method Di yield 83^; bp 72-73° (3 mm.); ir (CHCl^) 1092, 1131, 1177 cm.”^ (0-C-N); nmr (GDCl^) 6 0.67(d,3H,J=6.7Hz), 1.52(d,2.3H,J=5.6Hz), 5.15(q.0.3H,J=5.5Hz), 1,37(d,0.7H,J=

5 .6 Hz), 3.57(m,lH), 4.70(q,0.7H,J=5.5Hz), ^.92(d,lH,J=?.5Hz). Anal. Calcd. for C, 74.5^; H, 8.53; N, 7.90.

found: C, 74.34; H, 8 .6 O; N, 7.84.

erythro-4-Methyl-5~phenyloxazolidine (XXII) - (±)-Norephedrine and 37^ formaldehyde solution were reacted to form XXII by method D: .yield 91^1 bp 77° (1 mm.); ir (CHCl^) 1092, 1119, 1174 cm.""^ (0-C-N); nmr (CDCl^) 6 0.73(d, 3H,J=6.8Hz), 3.48(m,lH), 4.46(d,lH,J=6.0Hz), 4.85(d,IH,J=6.0 Hz), 4.88(d,lH,J=5.5Hz). Anal. Calcd. for C^qH^^NOi

C, 73.59; H, 8.03; N, 8 .5 8 . Found: C, 73.51; H, 7.96; N, 8.42.

erythro-2,5-Diphenyl-4-methyloxazolidine (XXIII) - (+)-Norephedrine and benzaldehyde were reacted to form XXIII by method A, using 90^ benzene - 10^ methanol as solvent and

recrystallized from 70% ligroine - 30% benzene: yield 73%; mp 88-89°; ir (CHCl^) 1082, II3 1 , 1177 cm.~^ (0-C-N), l640 cm.’^ (C=N); nmr (CDCl^) 6 0.76(d,0.6H,J=7Hz), 0.77(d,0.3H, J»7Hz), 1.12(d,2.IH,J=6.6Hz), 3.65(m,lH), 5.1(d,0.3H,J=7.4 Hz), 4.84(d,0.7H,J=4.5Hz), 5.6(s,0.2H), 6.05(s,0.1H), 8.24 27 (s,0,7H). Anal. Calcd. for 0, 80.30; H, 7.16; N, 5.85. Found; C, 80.03; H, 7.23; N, 5.82. threo-2. 2 , imethyl«-5~phenyloxazolidine (XXIV) - (+)-Norpseudoephedrine and acetone were reacted to form XXIV by method C, using acetone as solvent; yield bp 83-84° (3 mm.); ir (GHGl^) 1085, 1115, 1170 cm.”^ (0-G-N), nmr (CDGl^) 6 1.17(d,3H,J=6Hz), 1.15(s,6h), 3.15(m,lH), 4.17(d, lH,J=8.7Hz). Anal. Galcd. for 75.35; H, 8.96;

N, 7 .3 2 . Found; G, 75.22; H, 8.88; N. 7.36. threo-2,4-Dimethyl-5-phenyloxazolidine (XXV) - (t)-Norpseudoephedrine and acetaldehyde were reacted to form

XXV by method D; yield 82^; bp 68 -69 ° (3 mm.); ir (CHCl^)

1090, 1125 , 1172 cm.”^ (0-G-N); nmr (GDGl^) (5 1.22(d,1.5H,J= 6Hz), 1.24(d,1.5H,J=6Hz), 1.44(d,l.5H,J=5.5Hz), 1.46(d,1.5H,

J=5.5Hz), 3.10(m,lH), 4.15(d,lH,J=8Hz), 4.89(q,O.5 H,J=5Hz), 4,98(q,0.5H,J=5Hz). Anal. Galcd. for G^^H^^NO; G, 74.54;

H, 8.53; N, 7 .90. Found; G, 74.40; H, 8 .50; N, 7.98. threo-4-Methyl-5-phenyloxazolidine (XXVI) - (+)-Norpseudoephedrine and 37^ formaldehyde solution were reacted to form XXVI by method D; yield 86^; bp 98-99°

(1 mm.); ir (CHCl^) 1089, 1132, II68 cm."^ (0-C-N); nmr (CDCl^) 6 1.25(d,3H,J=6Hz), 3.02(ra,lH), 4.12(d,IH.J=7Hz), 4.70(d,2H,J=0Hz). Anal. Calcd. for C^^H^^NO; G, 73.59;

H, 8.03; N, 8.58. Found; C, 73.40; H, 7.92; N, 8 .3 9. 28 threo-2.5-Dipheavl-»^~methvloxazolidine ( X X V I I ) - (+)-Norpseudoephedrine ajid benzaldehyde were reacted to form X X V I I by method A, using 90% benzene - 10%o methanol as solvent and recrystallized from ?0% ligroine - 30^ benzenei yield 79^; mp 73-74°; ir (CHCl^) 1090, 1133, 1172 cm.~^ (0-C-N), 1643 cm.”^ (C=N); nmr (CDGl^) 1.31(d,2.2H,J=6.5 Hz), 1.15(d,0.8H,J=6.7Hz), 3.36(m,lH), 4.48(d,0.2H,J=6.5Hz), 4.69(d,0.55H,J=6.5Hz), 4.40(d,0.25H,J=8,0Hz), 5.78(s,0.2H), 5.90(s,0.55H), 8.31(s,D.25H). Anal. Calcd. for C^^H^»NO: C, 80.30; H, 7.16; N, 5.85. Found: C, 80.34; H, 7.23; N, 5.72.

2,5-Diphenyl-3-methyloxazo'lidine (XXVIII) - (+)-Halostachine, alpha-(methylamino)methyl-benzyl alcohol, was prepared from (+)-mandelic acid by the method of Lukes, £t al., (65).

(+)-Mandelic acid 1 5 .2 g, and 50 ml. acetone were placed in a 500 ml. round bottom flask in an acetone - dry ice bath for 30 minutes. Concentrated sulfuric acid 10 g. was added dropwise with stirring such that the temperature of the reaction did not exceed -10°. The reaction mixture was then poured into an ice-cold solution of 20 g. NagCO^

(2 3 .4 g. monohydrate) in 180 ml. water. The resulting precipitate was removed by filtration, washed with ice water, and recrystallized from absolute ethanol, mp 73-74°, [lit. (66) 75°] . The resulting (+)-mandelic acetonide 18 g. was 29 dissolved in ?0 ml. methanol. Methylamine gas 10 g. released from a ^Ofo aqueous solution by refluxing was introduced into a tared flask of 70 ml. methanol. The methanolic solutions of the acetonide and methylamine were mixed and placed in a pressure bomb and allowed to stand at room temperature for two days. The reaction mixture was placed in a round bottom flask and the solvent removed in vacuo. The resulting solid was recrystallized from methanol, mp 101-102°, [lit. (65) 102.5-103.5°]. The resulting (+)-alpha-methylamido-benzyl alcohol 8.8 g. was slowly added to a reaction mixture of 6 g. liAlH^^ dispersed in 500 ml. anhydrous tetrahydrofuran in a 1000 ml. round bottom flask, and the contents refluxed overnight. The excess LiAlH^ was decomposed by the method of Micovic and Mihailovic (6?), and the mixture extracted three times with 150 ml. ether. The combined ether extracts were evaporated to dryness jji vacuo and the resulting (+)-halostachine recrystallized from methanol, mp 45-46° (same as lit.). (+)-Halostachine 1.51 g. (0.01 mole) was dissolved in absolute ethanol 100 ml. Benzaldehyde 10.6 g. (0.01 mole) was added and the mixture refluxed for 4 hours. The solvent was removed in the rotary flash evaporator and the residue vacuum distilled to afford a colorless liquid, bp 76 ° (0.6 ram.)i yield 91^; ir (CHCl^)

1075 , 1115 , 1142, 1152 , 1176 cm."^ (0-C-N); nmr (CDCl^) 6 2.22(s,3H), 2.24(s,3H), 4.79(s,lH), 4.90(s,lH). Anal. Calcd. for C^^H^^NOi C, 80.3O; H, 7.16; N, 8 .5 8 . Found* 30 c, 7 9.9 0; H, 6.84; N, 5.9^. erythro-2,4.5-Triphenyl-3~methvloxazolidine (XXIX) -

2-Methylamino-l,2-diphenylethanol was prepared by the method of Wheatley, et al., (6 8 ) and resolved by the method of Young (6 9 ). Benzil 32.5 g. was added to I50 ml. methanol in a pressure bomb together with 225 ml. of a 25 ^ aqueous solution of methylamine, and the bomb maintained in a water bath at 50° overnight. The contents were placed in a round bottom flask and the solvent removed vacuo. The resulting solid was recrystallized from methanol, mp 89-90° (same as lit,). The purified methylimine-ketone 22.3 g. was added to 10 g. activated Raney nickel in 100 ml. methanol and hydrogenated at 51 pounds per square inch. The Raney nickel catalyst was removed by filtration and kept under methanol (or carefully destroyed by addition of small increments of nitric acid). The filtrate was evaporated in vacuo and the resulting solid recrystallized from methanol, mp 136-137°. The hydrochloride salt was formed by passing hydrogen chloride gas through an ether solution of the resulting (+)-erythro-2-methylamino-l,2-diphenvlethanol. The precip­ itate was separated by filtration, washed with ether, and recrystallized from methanol. The hydrochloride salt 15 g. was dissolved in 650 ml. water. A solution of 11.37 g. potassium benzyl penicillin in 41 ml. water was added at once to the solution of the amino alcohol hydrochloride. After standing for an hour, the resulting precipitate was 31 removed by filtration and saved. The pH of the filtrate was adjusted to 9,0 with 10^ sodium hydroxide. The resulting precipitate was rinsed with water and recrystallized from ligroine, mp 129-131° (same as lit,); = + 37° (lit,

O C ^ = + 38,2°), The previous precipitate was rinsed with 4o ml, water and recrystallized from methanol. The resulting penicillinate 7 g, was dissolved in 105 ml, ether and 315 ml, water added. The pH of the solution was adjusted to 1,0 with lOfo hydrochloric acid. The aqueous layer v/as separated and made alkaline to pH 9.0 with 10^ sodium hydroxide. The resulting precipitate was separated by filtration, rinsed with v/ater, and recrystallized from ligroine, mp 131-132° (same as lit, ) ; = - 39° (lit. = - 40,0°), (-)-erythro-2-Methylamino-l,2-diphenylethanol and benzalde­ hyde were reacted by method Ci yield 86^; mp 100-102°; ir (CHCl^) 1072, 1100, 1126 , 1171 cm,"^ (0-C-N), 2840, 2?9 2, 2720 cm,"^ (Bohlmann bands); nmr (CDGl^) (5 2.10(s,3H), 4,09(d,lH,J=8.6Hz), 4,96(s,lH), 5.^1(d,lH,J=8,2Hz), Anal,

Calcd, for 022^ 21^ ^ * G, 83,78; H, 6,71; N, 4,44, Found: C, 83,97: H, 7.00; N, 4 ,3 8 . erythro-2-Styryl-3-methyl-4,5-diphenyloxazolidine (XXX) - (+)-erythro-2-Methylamino-l,2-diphenylethanol and cinnamaldéhyde were reacted to form XXX by method C* yield

91%; mp 170-171°; ir (CHCl^) 1057, 1123, 1135, 1162, II78 cm,"^ (0-C-N), 2850, 2794, 2740, 2717 cm,"^ (Bohlmann bands); nmr (CDCl^) 6 2.20(s,3H), 3.98(d,lH,J=7.8Hz), 4,55(d,IH,J= 32 6.5Hz), 5.32(d,lH,Jï=8,0Hz). Anal. Calcd. for 0, 84.42; H, 6.79; N, 4.10. Pound: 0, 84.76; H, 6.78; N, 3.98.

2-Styr.vl~3.4-dimethyloxazolidine (XXXI) - 2-Methylamino- propanol-1 was prepared by modification of the methods of

Biilman and of Beckett (70). (±)-Alanine 25 g. v/as dissolved in 45 ml. of 97^ formic acid. Acetic anhydride, 30 ml., was cooled to 0° and 15 ml. of 97^ formic acid was added. The mixture was heated to 50 ° for 15 minutes, then cooled immediately to 0°. The alanine solution was then added with stirring. After 5 minutes the mixture was evaporated to dryness in the rotary flash evaporator, and the residue washed repeatedly with ether. The residue v/as recrystallized from warm water, mp 147-148° (same as lit.). Lithium aluminum hydride 12,0 g, (O.3I mole) was dispersed in 300 ml, of anhydrous tetrahydrofuran and N-formyl alanine 2 5 .0 g.

(0 .2 8 mole) was added in small portions with stirring. The mixture was refluxed for 24 hours, then decomposed by the method of Micovic and Mihailovic (67 ). The mixture was extracted three times with 150 ml. ether. The ether extract was evaporated to dryness in the flash evaporator, and the residue vacuum distilled, bp 33-34° (0.6 mm.) [lit. (7 0 )

85 -86 ° (28 m m . ) j . 2-Methylamino-propanol-l and cinnamal­ déhyde were reacted to form XXI by method Ax yield 96 ^; bp 80° (0.6 mm.); ir (CHGl^) IO6 1 , III3 , 1144, II6 5 , 1187 cm.“^ (0-C-N), 2820, 2790, 2740 cm."^ (Bohlmann bands); 33 nmr (CDCl^) Ô 1.10(d,3H,J = 6 H z ) ,, 2.20( s , 3H), 2.58(m,lH), 4.l8(d,lH,J=?Hz). Anal. Calcd. for G^^H^^NOi G, 76.81; H, 8.43; N, 6.89. Found, G, 76,91; H, 8.26; N, 7.00.

Styrylidene-N-.|^2-(erythro-l-phenyl-.l~hydrox.v)-propylj amine

( X X X I I ) - (i)-Norephedrine and cinnamaldéhyde were reacted

to form X X X I I by method G: yield 67 ^; rap 108-109^; ir (GHGl^) 1631 cm."^ (G=N); nmr (GDGl^) 6 1.l4(d,3H,J=6.5Hz), 4.8l(d,lH,J=4.2Hz), 6.85(d,lH,J=3.5Hz). Anal. Galcd, for ^18%9^°‘ 81.47; H, 7.22; N, 5.28, Found, G, 81.40;

H, 7 .1 9; N, 5 .1 9.

Styrylidene-N-^2-(threo-1-phenyl-1-hydroxy)-propyljamine

(XXXIII) - ,(+)-Norpseudoephedrine and cinnamaldéhyde were reacted to form X X X I I I by method G, yield 68 ^; mp 176.5- 177°; ir (GHCl^) 1634 cm.“^ (G=N); nmr (GDGl^) 6 1.10(d,3H,J= 6.4Hz), 3.4(m,lH), 4.65(d,lH,J=7Hz), 6.95(d,lH,J=4Hz). Anal. Galcd. for C^gH^^NO: G, 81.47; H, 7.22; N, 5.28. Found, G, 81.24; H, 7.26; N, 5.18.

Styrylidene-N-methyl-N~ |^2- (erythro-1-pher.yl-1-hydroxy )propylj - ammonium perchlorate (X X X IV ) - The compound was prepared using the general method of Leonard and Paukstelis (71).

(-)-Ephedrine 4.0 g . was dissolved in 150 ml. water and 70?& perchloric acid was added to pH 7.0. Two drops of triethyl- amine were added. The water was removed in the flash evaporator and the solid residue was recrystallized from methanol (mp 128-129°), The resulting ephedrine perchlorate 34 • and cinnamaldéhyde were reacted to form XXXIV by method Ai

yield 87^j mp 168-169^; ir (KBr) I613 cm, ^ (C=N); nmr (TFA) 6 1.71(d,3H,J=7Hz),3.58(s,3H), 4.30(m,lH), 5.27(d,IH,J=6 Hz), 7.75(d,lH,J=5.5Hz). Anal. Calcd. for ClO^j

C, 6 0 .0 8; H, 5.84; N, 3 .6 9 . Founds C, 59.93; H, 5.89;

N, 3 .63 .

Compound X X X IV was also prepared by the method of Sakai, et al. (62). erythro-2-Styryl-3,4-dimethyl-5- phenyloxazolidine (II) 3.0 g. (0.01 mole) was dissolved in

50 ml. ether and 10 ml. of a 10^ aqueous solution of perchloric acid (0,01 mole) was added with stirring. A colorless precipitate immediately separated; the solvent v/as decanted, and the precipitate washed with ether. The

precipitate was recrystallized from hot methanol, rap I70-

172°; ir and nmr identical to that described above. Anal.

Calcd. for CigHggNO'ClO^^ C, 6 O.O8 ; K, 5.84; N, 3 .6 9 . Founds C, 59.85; H, 5.76; N, 3.62.

Styrylidene-N-methyl-M-|2-(1-phenyl)propyljammonium perchlorate (XXXV) - The perchlorate salt of (±)-methamphetamine was prepared in the same manner as above. (±)-Methamphetamine perchlorate and cinnamaldéhyde were reacted to form XXXV by method As yield 89^; rap 166 -167 °; ir (KBr) I610 cm,“^ (C=N); nmr (TFA) (5 1.68(d,3H,J=6.5Hz), 4.31(m,lH). Anal. Calcd.

for Cj^H^gN'ClG^s C, 62.72; H, 6.09; N, 3 .8 5 . Founds

C, 6 2 .76 ; H, 6 .2 3 ; N, 3 .76 . 35 erythro~2-Styryl~3,3t^-trimethyl-5-phenyloxazolidinium iodide (XXXVI) - erythro-2-Styryl-3,4-dimethyl-5-phenyloxazolidine (II) 0.28 g. (0,001 mole) was dissolved in 5 ml. methyl iodide in a 25 ml. Erlenmeyer flask and the reaction mixture was allowed to stand overnight. The solvent was then removed in vacuo, and the solid residue washed repeatedly with anhydrous ether, mp 195-196° d,; ir (KBr) 1188, 1157, 1133» 1100, 1074 cm."l (0-C-N); nmr (DMSO-d^) 1.05(d,3H,J=?Hz), 3.25(s,3H), 3.40(s,3H), 4.59(m,lH), 5.80(d,lH,J=9Hz). Anal. Calcd. for Cg^Hg^NOI: G, 57.01> H, 5.74; N, 3.32. Pound: C, 56,94; H, 5,93; N, 3.25.

Attempted Preparation of Ethylidene-N-methyl-K-^2-(erythro- l-nhenyl-l-hydroxy)propyl ammonium perchlorate - (-)-Ephedrine perchlorate 5.3 g. and acetaldehyde 0,9 g. were dissolved in benzene and refluxed for 12 hours. The solvent was removed iji vacuo and the resulting solid washed with ether. The solid had the same mp, ir (KBr), and nmr (TFA) as that of (-)-ephedrine perchlorate. The use of ether and methanol as solvents also resulted in recovery of starting material.

Attempted Preparation of Benzylidene-N-methyl-N-|^2-(erythro- 1-phenyl-1-hydroxy)propyljammonium perchlorate - (-)-Ephedrine perchlorate 5.3 g. and benzaldehyde 2.1 g. were dissolved in benzene and refluxed for 12 hours. The solvent was removed in vacuo and the resulting solid washed 36 with ether. The solid had the same mp, ir (KBr), and nmr (TFA) as that of (-)-ephedrine perchlorate.

Attempted Preparation of Isonropylidene-N~methyl~N-1^2- (erythro-1-phenyl-1-hydroxy)propvlj ammonium perchlorate - (-)-Ephedrine perchlorate 4 g. was dissolved in acetone 150 ml. Two drops of triethylamine were added and the reaction mixture refluxed overnight. The solvent was removed in vacuo. The resulting crystalline solid was washed in ether, mp 128-129°. The ir (KBr) and nmr (TFA) were identical to that of (-)-ephedrine perchlorate.

Attempted Preparation of erythro-2,5-Diphenyl-2,3,4-trimethyl- oxazolidine - (-)-Ephedrine 3*3 (0.02 mole) and aceto- phenone 2.4 g. (0.02 mole) were added to a 1000 ml. round bottom flask and covered v/ith 5A molecular sieves. The reaction mixture was heated to 150° for 12 hours. The mixture was dissolved in ligroine and filtered. The solvent was removed in vacuo. A nuclear magnetic resonance spectrum was made on the crude residue. The spectrum was that of a physical mixture of (-)-ephedrine and acetophenone.

Attempted Preparation of threo-2,5-Diphenyl-2.3»4-trimethyl- oxazolidine - (+)-Pseudoephedrine 3*3 g« (0.02 mole) and acetophenone 2.4 g. (0.02 mole) were added to a 1000 ml. round bottom flask and covered with 5A molecular sieves. The reaction mixture was heated to 150° for 12 hours. The 37 mixture was dissolved in ligroine and filtered. The solvent was removed iri vacuo. A nuclear magnetic resonance spectrum was made on the crude residue. The spectrum was that of a physical mixture of (+)-pseudoephedrine and acetophenone.

Attempted Preparation of erythro-2,2 , riphenyl-3,4- dimethyloxazolidine - (-)-Ephedrine 3*3 g» (0.02 mole) and benzophenone 3.6 g. (0.02 mole) were added to a 1000 ml. round bottom flask and covered with 5A molecular sieves. The reaction mixture was heated to 150*^ for 12 hours. The mixture was dissolved in ligroine and filtered. The solvent was removed iji vacuo. A nuclear magnetic resonance spectrum was made on the crude residue. The spectrum was that of a physical mixture of (-)-ephedrine and benzophenone.

Attempted Preparation of erythro-2-Styryl-2,3,4-trimethvl-

5-phenyloxazolidine - (-)-Ephedrine 3 .3 g. (0.02 mole) and benzalacetone 2,9 g. were added to a 500 ml. round bottom flask and covered with 5A molecular sieves. The mixture was heated to I50 ® for 12 hours. Ligroine was added to dissolve the product. The sieves were removed by filtration and the filtrate was evaporated rn. vacuo. A nuclear magnetic resonance spectrum was made on the resultant semi-solid residue; (CDCl^) Ô 0.62(d,l.5H,J=6,5Hz), 0.6?(d,1.5H,J= 6.5Hz), 0.83(d,1.5H,J=6.5Hz), 2.26(s,1.5H). 2.32(s,3H), 4.79(d,0.5H,J=4Hz), 5.13(d,lH,J=8Hz). 38 Isolation of Intermediate in the Hydrolysis of 2-Styryl-3,4-dïmethyï-5-nh eny1o xa z o1idine s

To a solution of 5 g- erythro-3,4-dimethyl-3-phenyl- oxazolidine in 100 ml. dioxane v/as added 300 ml. of 5 N HCl, After standing one hour at room temperature, the solvent was removed in vacuo and the residue washed repeatedly with anhydrous ether to remove residual water and HCl. The amorphous solid obtained was pale yellow, mp 178-179°» Introduction of an excess of acid invariably led to some hydrolysis, even though a solid product with a sharp melting point was obtained. When the same procedure was tried v/ith the corresponding threo-oxazolidine, XII, an amorphous semi-solid was obtained which was extremely hygroscopic. All attempts to solidify the product were unsuccessful. Another procedure involved the use of HCl gas dissolved in anhydrous ether. erythro-2-Styryl-3.^-dimethyl-5-phenyl- oxazolidine (II) 300 mg. (0.0011 mole) v/as dissolved in 50 ml. anhydrous ether. A saturated solution of HCl in ether 0,2 ml. (O.001 mole HCl) v/as added and the resulting precipitate was washed three times with anhydrous ether. The product became soft and yellow immediately upon exposure to the atmosphere, and a pronounced odor of cinnamaldéhyde developed. The product was hygroscopic and some hydrolysis products persisted as impurities as indicated by PMR spectra. 39 5. Identification of Products of Hydrolysis

To erythro-2-Styryl-3,4-dimethyl-5-phenyloxazolidine

(II) 5.58 g. (0.02 mole) was added 50 ml. ether plus 300 ml. 1 N HCl in a 1000 ml. round bottom flask. The contents were refluxed for 2^■ hours and extracted v/ith four 50 ml. portions of ether. The ether was removed in the rotary flash evaporator. A portion of the residue was dissolved in spectral chloroform and placed between NaCl plates to run an infrared spectrum. The spectrum v/as identical to one of cinnamaldéhyde. Nuclear magnetic resonance spectrum in CDGl^ also corresponded to cinnamaldéhyde. A portion of the acidic aqueous phase shov/ed a positive Cotton effect at 260 nm. The solvent v/as removed and the residue washed with petroleum ether and recrystallized from methanol, mp 217°. The infrared spectrum (KBr) was identical to (-)-ephedrine hydrochloride as was the nuclear magnetic resonance spectrum in DgO.

B, Reaction of Oxazolidines v/ith Grignard Reagents and Hofmann Degradation of the Resulting; Tertiary Amino Alcohols

1, Reagents

Bromobenzene was obtained from MCB. Methyl iodide and iodine were obtained from J. T. Baker. Magnesium turnings were obtained from Mallincrodt. Silver nitrate and barium hydroxide were obtained from Allied Chemical Company, Nev/ 40 York, and used to prepare silver oxide,

2. Instrumentation

The instruments included in this reaction study were a

Varian A-6 OA nuclear magnetic resonance spectrometer, a Jasco spectropolarimeter, and a Zeiss polarimeter,

3 . Procedures

Magnesium turnings 1.0 g, (0,04 g.-atom) was added to a

250 ml, round bottom flask along with 10 ml. anhydrous ether, A solution of methyl iodide 5*6 g. (0,04 mole) in 30 ml, anhydrous ether was slowly added to form the Grignard reagent. After the reaction ceased, a solution of erythro- 2,5-diphenyl-3,4-dimethyloxazolidine (I) or erythro-2,4,5- triphenyl-3-methyloxazolidine (XXIX) 0,01 mole in 30 ml. anhydrous ether was added slowly with stirring. The mixture was then refluxed for 8 hours. The product from the reaction and excess Grignard reagent were decomposed with water, and the ether layer separated. The solution was dried with 34 molecular sieves overnight. The solvent was removed in the rotary flash evaporator, and the product dissolved in methyl iodide and allowed to stand overnight. The methyl iodide was removed in the rotary flash evaporator, and the methiodide salt was washed with ether several times. For erythro-2.3,4- trimethyl-5-phenyloxazolidine (IX) the Grignard reagent was prepared from bromobenzene and magnesium turnings in the same 41 manner as above except that heating was required to form the Grignard reagent from the less reactive bromobenzene. PMR spectra of the products from the Grignard reaction were run in deuterated chloroform. The procedure used by Neelakantan for the Hofmann degradation of the products from the Grignard reaction was duplicated. The methiodide product 0.004 mole was suspended in 12 ml, water and silver oxide O.85 g, (0,005 mole) v/as added. The mixture was stirred for 24 hours at room temperature. The silver salts were removed by filtration ajcd the aqueous filtrate refluxed for 2 hours. The solution was cooled, acidified, and extracted with ether. The solvent was removed on the rotary flash evaporator and methyl iodide was added to the residue. The resulting methiodide salt was washed repeatedly v/ith ether. The product was characterized by determining its rotation using a Zeiss polarimeter and by circular dichroism,

C. Kinetic Procedures

1 . Reagents

Reagents for buffer preparation included: potassium chloride, lithium chloride, citric acid, tribasic sodium citrate, glacial acetic acid, monobasic sodium phosphate monohydrate, dibasic sodium phosphate, malonic acid, boric acid, imidazole, Q5% phosphoric acid solution, sodium hydroxide, and hydrochloric acid. All reagents were from 42 J, T. Baker except malonic acid from Fisher Scientific and imidazole from Eastman Organics, Solvents for stock solutions were methanol and dioxane from J. T. Baker. Dioxane was purified by the method of Fieser (?2) and stored frozen. Solvents for kinetic isotope effect studies included DgO, 20^ DCl in D^O, and NaOD solutions prepared from metallic sodium and DgO. Trifluoroacetic acid (TFA) from Mallincrodt was used in PIÆR studies of ring opening.

2. Instrumentation

A Varian A-60A nuclear magnetic resonance spectrometer was used to characterize the species obtained in acid hydrolysis of various oxazolidines. Rates of hydrolysis were measured by ultraviolet spectrophotometry at various wavelengths between 245 nm and 336 nm on a Beckman DU spectrophotometer, a Cary 15 spectrophotometer, or a Gilford 240 spectrophotometer, all equipped with a jacketed cell compartment to maintain constant temperature (± 0 .1°) and connected to either a Lauda or Haake constant temperature pump to circulate water through the cell compartment. Rates of hydrolysis were also measured by circular dichroism at 26o nm on a Jasco spectropolarimeter using a jacketed quartz cell. For extremely slow reactions, samples were kept in a constant temperature bath with a Braun Thermomix regulator. Fast reactions were measured on a Durrum-Jasco stopped-flow spectrophotometer at 256 , 290, and 336 nm at ambient ^3 temperature. The pH of buffers was adjusted and checked using a Sargent DR pH meter equipped with a Sargent

S-30072-I5 glass electrode.

3 . Methods of Analysis

a. General Procedures

The general procedure followed for ultraviolet spectrophotometry studies included preparation of a stock solution of the compound being studied usually at 2 x 10“'^ M, adding buffer or other solutions to 1 cm. quartz cells, allowing the solutions to attain thermal equilibrium (ca. -h hour), injecting the stock solution by either a ^ ml. tuberculin syringe or a 50 ul. Hamilton syringe into the cell, and recording the absorbance values with time. The final absorbance values were obtained after ca. 10 half- lives. In cases of extremely slow reactions, the solution was maintained in a 50 ml. volumetric flask in a constant temperature bath, and samples v/ere removed periodically to determine the absorbance. In most cases the dioxane or methanol concentration (from stock solution) was 1 - 1 . which did not effect the measured pH value of the hydrolytic medium. In the stopped-flow studies, the changes in absorbance with time were recorded as an oscilloscope tracing and preserved as a Polaroid print. The time scales varied from 1 msec, per division to 1 sec. per division. Scans were made 44- in triplicate then recorded as a print. The stock solutions in dioxane for kinetic studies using circular dichroism were usually 5 x 10 M, The buffer solution was added to a quartz 1 cm. cell and allowed to equilibrate thermally; then the wavelength was fixed on a value previously determined from ultraviolet studies as an absorption peak of the oxazolidine under investigation (usually 260 nm). The stock solution was introduced into the cell and mixed thoroughly, and the change in rotation recorded as a function of time. In the PMR studies in trifluoroacetic acid 10^ solutions of the selected oxazolidines v/ere used and the spectra recorded at ambient temperature. The reactions were generally slow enough at these concentrations that spectra needed to be made only daily or less frequently,

b. Preparation of Buffers

The ionic strength of buffers was adjusted to 0.15 with KCl, and the pH adjusted with either HCl or NaOH solutions and checked over a two-day period to insure reasonable stability. The pH meter was standardized against pH 4,00 biphthalate standard, pH 6.86 phosphate standard, and pH $.18 borax standard, where applicable (7 3). The following buffers were prepared in total concen­ trations of 0,005 M, 0.01 M, 0,02 M, and 0,05 M: pH 3 citrate, pH 4 acetate, pH 5 acetate, pH 6 phosphate, and ^5 pH 7 phosphate. The following buffers were prepared in total concentrations of 0.01 M, 0.02 M, 0,05 0.08 Mi pH 5 malonate, pH 6 malonate, pH 7 phosphate, pH 9 and pH 10 borate. Phosphate buffer pH 7.5 was prepared in total concentrations of 0.01 M, 0.02 M, 0.04 M, and 0,06 M to maintain constant ionic strengths; likewise, pH 8 phosphate buffer was prepared in total concentrations of 0.01 M, 0,02 M, and 0,05 M only. The formation of the tetraborate ion in the borate buffers is insignificant in concentrations below 0.1 M (7^), Although sympathomimetic amines, such as the ephedrines, are known to complex with boric acid, (75 ) the low concentrations of amino alcohol formed compared to buffer concentration and the low absorptivity of the amino alcohol compared to the aldehyde resulted in no effect on the observed species in the ultraviolet spectrophotometric studies. Imidazole buffers were prepared in the following total concentrations for pH 7,0, pH 7.5, and pH 8.0: 0,2 M, 0,1 M, 0,05 M, 0,02 M, and 0.01 M.

c. Preparation of Stock Solutions

Stock solutions of the styryl oxazolidines were not stable in methanol. This was readily demonstrated by following ring opening of erythro-2-stvrvl-3.4-dimethvl-4- phenyloxazolidine (II) in acid media, A methanol solution of II was prepared, 18 mg,^. Portions of the stock solution 46 were introduced into 3,00 ml, volumes of 2,40 M HCl in quartz ultraviolet cells at various time intervals after preparation. The reaction was followed at 256 nm. Runs commencing no later than 5 minutes after stock solution preparation showed pseudo-first order kinetics; thereafter a biphasic plot was obtained. From Pig, 1 it is shown that the extrapolated initial absorbance of the second, slower phase of the plot, as expressed as percentage of the extrapolated initial absorbance of the first phase, increases with time I 29fo at 5 hours, 40^ at 8 hours, 70% at 25 hours,

80%> at 45 hours, and about 8y% at one week, all at 50°, The decreasing absorbance at 256 nm occurred simultaneously with increasing absorbance at 336 nm. Further studies on the characterization of this reaction were not made. Stock solutions of the styryloxazolidines in purified dioxane were stable for at least three v/eeks. The stock solutions of the isolated immonium ions and of the perchlorate and methiodide analogues were made in methanol and used immediately after preparation,

d. Preparation of Solutions of Hydrogen Chloride

Various quantities of 3?^ hydrochloric acid were added to volumes of distilled water in volumetric flasks to obtain various strengths of the acid. The solutions were titrated three times against 1,00 M NaOH standard from the Ohio State University Laboratory Stores, The following concentrations 47

Figure 1

Plots of log vs, time for the ring opening of erythro-2-Styryl-3,4-dimethyl- 5-phenyloxazolidines in 2.40 M HCl at 50° made at various times after stock solution preparation 48 Age of stock solution: a < 5min. b 1 hour c 8 hou PS -0 .5 ^ ' ® « ^ d 24 hours e 1wee k

8 < I 4- <

Ü O

0 2 4 8 /o 1 2 1 4 1 6 TIME in MINUTES 49 were obtained: 6,35 M, 4,81 M, 2,54 M, 2,40 M, 1,20 M, 1,02 M, and 0,51 M. For further dilutions 1,00 M HCl standard was used and diluted serially to obtain 0,10 M, 0,01 M, 0,001 M, and 0,0001 M, Ionic strength was adjusted with potassium chloride. For kinetic studies, the solution of 20^ DCl in DgO was titrated against standard 1,00 M NaOH solution. The concentration of the DCl solution so determined v/as 5#64 M, The following procedure was used to obtain 5*64 M HCl in H^O:

200 ml, of 2>T/o HCl solution was added to 150 ml, water. The resulting concentration was 6,89 M, The 6,89 M HCl solution was placed in a burette, and 45.13 ml, measured into a standard-taper flask. To .this volume was added 10,0 ml, of water and mixed thoroughly. This solution was then titrated against standard NaOH, The results confirmed 5*64 M as the concentration. For water activity studies, the lithium ion was used to replace the proton in varying amounts, thus changing the hydrogen ion concentration without greatly affecting the water activity of the solutions. The following solutions were prepared: (a) 100 ml, 0.5 M HCl; (b) 50 ml, 0,4 M HCl

+ 50 ml, 0,6 M LiCl = 0.2 M HCl and 0,3 M LiCl; (c) 50 ml,

0,2 M HCl + 50 ml, 0 ,8 M LiCl = 0.1 M HCl and 0,4 M LiCl;

(d) 50 ml, 0.1 M HCl + 50 ml, 0,9 M LiCl = 0,05 M HCl and

0,45 M LiCl; and (e) 50 ml, 0.04 M HCl + 50 ml. O.96 M LiCl = 0,02 M HCl and 0,48 M LiCl, All dilutions of lithium chlor­ ide were made from the same 5*0 M LiCl stock solution as the 50 crystalline LiCl is deliquescent.

e. Preparation of Solutions of Sodium Hydroxide

The following solutions were made and titrated against 1 M HCl standard: 5.0 M NaOH, 3,0 M NaOH, 2.0 M NaOH. Serial dilutions of 1 M NaOH standard were made to yield 0.1 M NaOH and 0.01 M NaOH, A portion of the 0.01 M NaOH was adjusted in ionic strength with KCl to obtain 0.15 and 1.01. In both the 0.01 M NaOH and the 0.01 M HCl solutions having ionic strengths of 1,01 there was a change in pH of

0.03 units due to the added salt. For solvent isotope effects in alkaline solution an NaOD solution v/as prepared’ as follov/s: to 10 ml. of D^O v/as added freshly cut small pieces of metallic sodium. The solution was diluted to 100 ml, with D^O and titrated against standard 1 M HCl in the same manner as for the DCl solutions. The concentration of the solution was 0.0?6 M. A solution of the same concentration of NaOH was prepared by dilution and titration in the same manner as for the HCl solutions.

D. Measurement of Equilibrium Values for Ring Closure

Fischer and Schiene (41) determined the equilibrium constants (± 10^) for ring closure of oxazolidines from ketones and various amino alcohols in dioxane using the Karl Fisher method to measure the water formed upon condensation. The same equilibrium could be determined for the 2-styryl- 51 oxazolidines (II and XII) by measuring the decrease in absorbance of cinnamaldéhyde by the following general procedure. Purified dioxane was dried overnight using 5A molecular sieves. The sieves were removed by filtration, and the following compounds were added to thedioxanei cinnamaldéhyde, 2 x 10" ^ M; (-)-ephedrine or

(+)-pseudoephedrine 1.96 x 10“-^ M; ephedrine perchlorate or pseudoephedrine perchlorate, 4 x 10"^ M, The dioxane solution was placed in a stoppered quartz 1 cm. cell and the change in absorbance monitored at 290 nm. III. RESULTS AND DISCUSSION

A. Synthesis of Oxazolidines from (-)-Ephedrine and '( + ) “Pseudoephedrine

The oxazolidines from (-)-ephedrine and (+)-pseudo- ephedrine were generally obtained by reacting these compounds with aldehydes or ketones under dehydrating conditions. The condensation occurred much more readily with aldehydes than with ketones. The reaction between (-)-ephedrine and formaldehyde occurred immediately even in the presence of water. Similarly, acetaldehyde condensed immediately and was readily purified by simple vacuum dis­ tillation. Acetone, however, condensed with ephedrine only to the extent of about on standing at room temperature as indicated by the integrated PMR spectrum of the reaction mixture. Refluxing with 3A molecular sieves for several hours and vacuum distilling were required to obtain a pure product. The aromatic aldehydes and cinnamaldéhyde proved to readily condense with the ephedrines to yield crystalline products. These results are in accord with the general conclu­ sions made by Bergmann (48 ) in which he noted that ketones condense with secondary amino alcohols with much greater

52 53 difficulty than do aldehydes. An oxazolidine was readily formed on refluxing a benzene solution of benzaldehyde and

2-anilinoethanol (48) whereas no product resulted from the

reaction of any ketone with 2-anilinoethanol under the same

conditions (30)* Our attempts to condense (-)-ephedrine or (+)-pseudo-

ephedrine with acetophenone by heating at 150 ° without

solvent for 12 hours failed to yield an oxazolidine. Benzophenone also did not condense with (-)-ephedrine. The failure of (-)-ephedrine to react with either acetophenone or benzophenone was also observed by Fischer and Schiene (4l) who studied oxazolidine formation from the ephedrines in dioxane at ambient temperature. Hov/ever, Fife and

Hagopian (63 ) obtained 2-phenyl-2-methyl-3-ethyloxazolidine

on refluxing a benzene solution of 2-ethylaminoethanol and acetophenone. Therefore, the ease of oxazolidine formation

depends upon the substituents on the 2-alkylaminoethanol as well as upon the nature of the carbonyl-containing compound. The use of molecular sieves in the condensation reactions proved to be a useful alternate to benzene azeotropic distillation or the heating of reactants without solvent. Reactions in which the yield of product was low on benzene azeotropic distillation gave greatly improved yields by the heating of the reactants in benzene with molecular sieves. A 90^ yield of oxazolidines was obtained when cyclohexanone was reacted with the ephedrines in this 5^ manner. Neelakantan (?6) failed to obtain the desired oxazolidine when he reacted cyclohexanone v/ith (-)-ephedrine using the benzene azeotropic distillation method. Most of the solid oxazolidines prepared in our study were purified by fractional crystallization from ether or benzene. The liquid oxazolidines and several of the solid oxazolidines were purified by vacuum distillation. Early attempts in this work to purify the oxazolidines by means of column adsorption chromatography using alumina, silicic acid, or bentonite were unsuccessful due to hydrolysis of the oxazolidines on these columns. No significant difference in yield of oxazolidine was obtained when (-)-ephedrine or (+)-pseudoephedrine was reacted with a given aldehyde or ketone under a given set of conditions.

B. Synthesis of Oxazolidines from (±)-Norephedrine and ( 4- ) - Nor p s eu do e ph e drine

The products of the condensation of (±)-norephedrine and (+)-norpseudoephedrine with various carbonyl compounds exist as open-chain Schiff bases, oxazolidines, or ring- chain tautomers. The presence of Schiff base tautomers may be determined by the C=N stretch in the infrared spectrum and the deshielding of protons on the sp carbon from 1 to 2 ppm below the chemical shifts observed or anticipated for the analogous proton in the ring tautomer (Table 1). 55

R

Identification of the presence of the open-chain Schiff base and the oxazolidine is readily determined from the PilR spectra of the condensation products from (±)-norephedrine. The coupling constant for the proton doublet at in the ring form is 7-8 Hz, while in the chain form the coupling constant of that proton becomes ^-5 Hz, indicating a change in the dihedral angle between the and protons. The products of the reaction of (±)-norephedrine and acetone (XX) and acetaldehyde (XXI) appear to be in the ring form as the chemical shifts of the Cg and protons are in the region ^-5 ppm downfield from tetramethylsilane. The coupling constants indicate ring closure, and there is an 56 Table 1

Selected IR and PMR (6) Spectral Properties for Condensation Products of (j:)-Norephedrine and (t)-iiorpseudo'ephedrine With Various Carbonyl Compounds in Chloroform-d

Compound IR(cm.~^) Hg

XX (erythro) _$,00(d,lH, J=7.^Hz) XXI (erythro) 4.92(d,lH,J=7.5Hz) 4.?0(q,0.?H,J=5-5Hz) 5.15(q.0.3H,J=5.5Hz) XXII (erythro) 4.88(d,lH,J=5 .5 Hz) 4.46(d,IH,J=6.OHz) 4.85(d,lH,J=6.0Hz) XXIII (erythro) l640 5 .1 (d,0 .3H,J=7.4Hz) 5 .60 (s,0 .2H) 4.84(d,0,7H,J=4.5Hz) 6 .05 (s,0 .1H) 8.24(s,0.7H) XXXII (erythro) I63 I 4.81(d,IH,J=4.2Hz) 6 .85 (d,IH,J=3 .5 Hz) XXIV (threo) 4.17(d,lH,J=8.7Hz) XXV (threo) 4.15(d,lH,J=8Hz ) 4.89(q,0.5H,J=5Hz ) 4.98(q,0.5H,J=5Hz) XXVI (threo) 4.12(d,lH,J=7Hz) 4.70(d,2H,J=OHz) XXVII (threo) 1643 4.48(d,0.55H,J=6.5Hz) 5.78(s,0.55H) 4.69(d,0.2H,J=6.5Hz) 5.90(s,0.2H) 4.40(d,0.25H,J=8.0Hz) 8.3I(s,0.25H) XXXIII (threo) 1634 4.65(d,lH,J=7Hz) 6.95(d,IH,J=4Hz ) 57 absence of C=N stretch in the infrared spectra of these compounds. Although the coupling constant for the product from (±)-norephedrine and formaldehyde (XXII) is low for the

ring form (5 »5 Hz), the chemical shift of the Cg proton and the absence of C=N in the IR support the ring form. Similarly, the IR and PIvlR data for the products of the reaction of (+)-norpseudoephedrine with acetone (XXIV), acetaldehyde (XXV), and formaldehyde (XXVI) indicate that in each instance the product is a noroxazolidine with no Schiff base tautomer detectable. The PMR spectra of the products of acetaldehyde and (t)-norephedrine (XXI) and (+)-norpseudoephedrine (XXV) show in each case two separate quartets for the Cg protons. This is a consequence of the presence of two isomeric ring forms.

H H 58 For the reaction product of benzaldehyde with (+)-norephedrine (XXIII) there is evidence for both ring and Schiff base forms present. Evidence for the ring form includes an doublet at ca. 5«1 ppm having a coupling constant of 7.4 Hz and two isomeric Hg singlets at 5*60 and 6,05 ppm. Evidence for the Schiff base form include the H^ doublet at 4.84 ppm having a coupling constant of 4.5 Hz, an Hg singlet at 8.24 ppm, and the presence of C=N stretch at l640 cm."^. From the relative intensities of the PMR signals it is estimated that the compound exists as a mixture of ca. 70^ Schiff base and ca. 30^ isomeric oxa­ zolidines. The IR and PMR data for the corresponding threo compound (XXVII) in Table shows the presence of ring-chain tautomerism, with the ring form predominating. The ratio of noroxazolidine to Schiff base is 3x1. The product of the reaction of cinnamaldéhyde and (±)-norephedrine (XXXII) appears to exist exclusively in the Schiff base foirm since the doublet has a small coupling constant (4.2 Hz), and the proton is considerably deshielded so that the Hg doublet appears downfield from the Hg doublet (4.29 ppm) for the corresponding N-methyl oxazolidine (II). A strong C=N stretch is seen in the IR spectrum. Similar evidence from the IR and PMR spectra of the threo analog (XXXIII) indicates that this compound is present only as Schiff base. 59 It is of interest that Eergmann (48) observed that the reaction product of ethanolarnine and benzaldehyde is a Schiff base. This result is compared to the present work in which the product of the reaction of

(+)-norephedrine and benzaldehyde is a mixture of 30fo oxazolidines and 70fo Schiff base. Moreover, the reaction product of (+)-norpseudoephedrine and benzaldehyde is a mixture of 75% oxazolidine and 25^ Schiff base. Portoghese

(57) and Hyne (56 ) in their PIvlR studies of solutions of the diastereoisorneric ephedrines noted the greater degree of intramolecular hydrogen bonding in the three isomer. It is evident that similar non-bonding interactions occur in the diastereoisomeric norephedrines. The closer proximity of the amino and hydroxy groups in the three isomer favors oxazolidine over Schiff base formation. The finding that the reaction products of the norephedrines and cinnamaldéhyde (XXXII and XXXIII) are present entirely as Schiff bases is contrasted with the exclusive formation of oxazolidines from these amino alcohols and aliphatic carbonyl compounds. In a study of ring-chain tautomerism in the products of the reaction of substituted benzaldehydes with 2-methyl-2-amino-propanol-l, Paukstelis and Lambing (22 ) found that the Hammett plot of the equilibrium oxazolidine imine exhibited a p value of -0,54 and correlated with CT ^ and not (S . They 60 interpreted this correlation as resulting from a loss of resonance of the aromatic ring with the imino group. Such resonance would increase the electron density at the imine carbon sufficiently to reduce the tendency of ring closure by intramolecular nucleophilic attack of the oxygen. Similar resonance considerations favor Schiff base formation in the products of the reactions of the norephedrines and cinnamaldéhyde. Three general conclusions can be made regarding the tautomerism of the resulting condensation products. First, increased substitution on the carbon atoms of aminoethanol favors oxazolidine formation. Second, with diastereoisomeric vicinal amino alcohols, the threo configurations favor ring formation. Third, Schiff base formation is favored when a system conjugated with the imine results in increased electron density on the imine carbon atom,

C, Stereochemical Aspects of Ring Closure

1. Evidence from Proton Magnetic Resonance Spectral Data and Infrared Spectral Data

The assignment of chemical shift (CDCl^, 6 ) for compounds I, II, IX, XI, XII, and XVIII are as followsi 61

5.17 4 .7 8

. o o ri^ "i:C-R^^0 "C'"'" 1.23 0tbcR__0 ' ' V ' '"c" "4.72 H 1 ,= % 2.56 CH, 2.2 2

XI

CHj 118^’^^ ^^3 '069 2.2 7 2.30 II XII G v "

C H j (*2.25 CH, 2.23 1.15 2.2 7 IX XVIII 62 The basis on which the assignments are made is as follows. The singlet integrating to 3 protons is the N-methylj xhe singlet integrating to one proton is the proton for compounds I and XI, The multiplet integrating to one proton is the proton. The doublet integrating

to one proton and coupled upfield to the Cj^ multiplet is the proton. The doublets of the styryloxazolidines are coupled downfield to the beta-proton of the styryl group. The Cg compounds IX and XVIII are recognized as quartets. The methyls and methyls are differentiated by coupling constants; the methyl has a smaller coupling constant than that of the methyl. In the erythro-oxazolidines. the methyls are shielded to a greater extent by the phenyl than in the

threo isomers. Similarly, the Oj^ protons in the threo- oxazolidines are shielded by the G^ phenyl to a greater extent than in the erythro isomers. From this spectral data, it is determined that of the two possible isomeric oxazolidines from each amino alcohol and an unsymmetric aldehyde only one isomer forms. This is shown by a single signal for the and G^ protons, G^ methyl, and N-methyl, Different configurations at Gg would affect the chemical shift of all the above signals. In the case of unsymmetric ketones, there are tv/o Gg isomers formed. The PMR spectrum of the mixture of isomers 63 resulting from the reaction of phenylacetone and (-)-.ephedrine shows clearly two signals for the protons (overlapping doublets at 4.97 and 5.03 ppm), Cg methyls (1.08 and 1.35 ppm doublets), and methyls

(0,51 and 0.60 ppm doublets). If two Cg isomers were formed on condensation with unsymmetric aldehydes, the deshielding effect of the phenyl on the proton would be significantly different for the tv/o configurations. Of the two possible isomers, A and B, resulting from the reaction of (-)-ephedrine and an aldehyde, the proton at Cg on B should occur downfield from the same proton on A by approximately 0.2 ppm based upon the results observed by Baggett (77) for substituted

1 ,3-dioxolanes.

\ H \ CH, CH3

A B 64 Since only one signal is obtained for the Cg proton in the oxazolidines from the ephedrines and each aldehyde studied, it can be reasonably assumed that only one isomer is formed in each instance. As the absolute configurations of the amino alcohols are known (53)» it is of interest to establish the absolute configuration at C^. Infrared spectral evidence is presented to attempt to ansv/er the question of which isomer is formed when an oxazolidine is prepared from an aldehyde and (~)-ephedrine or (+)-pseudoephedrine.

Bohlmann (78) correlated the stereochemistry of quinolizidines with the infrared spectra of these compounds. He found that the infrared spectra of trans­ fused quinolizidines in which the nitrogen lone pair of electrons is trans to at least two axial hydrogens on alpha-carbon atoms exhibit a prominent band between 2700 and 2800 cm,“^ Such bands are absent in the corresponding cis-fused compounds. The correlations are useful in compounds with bridgehead nitrogens or in situations where the lone pair configuration is fixed and the nitrogen substituents are not free to "flip". If the assumption is made that the methyl fixes the N-methyl in a trans position then the correlation might prove helpful. Examination of the oxazolidine ring shows that one proton would then be approximately trans- diaxial to the lone pair. If the Cg proton is also trans 65

Table 2

IR Bands Between 2700 and 2800 cm."^

Compound cm,"^ I 2795, 2752 II 2745, 2721 III 2770, 2711

IV 2783, 2720

V 2750 , 2726

IX 2788, 2733 X . 2728

XI 2730 XII 2783, 2725 XIII 2748 XIV 2791, 2730 XV 2726

XVIII 2790, 2736

XIX 2730

XXIX 2792, 2720

XXX 2794, 2740, 2717

XXXI 2745 , 2725 66 to the lone pair, then Bohlmann bands should be noted in the infrared spectrum, and this would imply an S config­ uration at Cg. If no Bohlmann bands are present, then either the method is not applicable or an R configuration is implied. Examination of the infrared spectral data (Table 2) of various oxazolidines from the ephedrines and aldehydes reveals prominent Bohlmann bands. Moreover, there is an absence of such bands in oxazolidines from ketones (e_.g#, acetone and cyclohexanone) where two trans-diaxial protons on CX-carbons are not possible. Associated with the same stereochemistry is an abnormally large proton magnetic resonance shielding effect on trans-diaxial protons by the N-lone pair. Differences as large as 0.93 ppm have been noted between methylene protons adjacent to N in quinolizidine (79). This phenomenon has been attributed to partial participation of the N lone pair in a (S orbital on the adjacent

0 atom which leads to an increase in the electron density yielding some double bond character at the axial proton with a corresponding increase in shielding. In order to pursue PMR analysis of the configurations of the isomers resulting from the reaction of the ephedrines and aldehydes it is necessary to consider whether the N-methyl configuration is fixed relative to 67 the Cg and protons. It has been shown from the PMR data in comparing the oxazolidines of acetaldehyde and benzaldehyde to the corresponding noroxazolidines that the presence of the N-methyl is required for stereoselective ring closure. However, the presence of a Cj^ substituent is also required as shown by the PMR data from XXVIII, the oxazolidines formed from the reaction of (+)-halostachine and benzaldehyde. The presence of two N-methyl singlets, 2.22(s,3H) and 2.24(s,3H), and two Cg proton singlets, 4.79(s,lH) and 4.90(s,lH) in the PMR spectrum indicates that two isomers are present. Thus, both an N-methyl and a substituent are required for stereoselective ring formation. These observations suggest that in oxazolidines having both an N-methyl and a methyl, the configurations of both methyls are fixed. It is likely that the configuration of the N-methyl is dictated by non-bonding interactions and is trans to the methyl.

''H - 0 CH3 CHj XXVIII 68 When the N-methyl is trans-diaxial to the Cj^ methyl, the nitrogen lone pair is trans-diaxial to the proton. Removal of the methyl on the nitrogen should eliminate the

shielding effect of the lone pair on the Cj^ proton. If a similar loss of shielding is observed for the Gg proton, then the Cg proton in the N-methyl oxazolidine is also trans-diaxial to the lone pair, A comparison of the chemical shifts of the and protons of noroxazolidines with the chemical shifts of the same protons in the corresponding N-methyl oxazolidines should afford evidence for the absolute configuration at Cg in the N-methyl oxazolidines. A large difference in chemical shifts (O.6-1.0 ppm (80) for protons between the noroxazolidines and N-methyl oxazolidines) is indicative of a trans-diaxial relationship for the proton with the nitrogen lone pair in N-methyl oxazolidines. As vicinal protons trans to the lone pair in a five-raerabered ring are probably not exactly trans- diaxial (180°), the resulting shielding by the lone pair is expected to be somewhat reduced. However, the strong shielding of the N-methyl cis to the vicinal protons is expected to compensate for this reduction in shielding. The chemical shifts ( (5 ) of the and protons for the N-methyl and corresponding noroxazolidines of ephedrine and pseudoephedrine is reported in Table 3» The change in chemical shift for the proton in going from an N-methyl oxazolidine to the corresponding 69

Table 3

Dhedrines and Norephedrines in Chloroforra-d

Compound &

VIII (erythro) 3.13 XX (erythro) 3.81 IX (erythro) 2.76 3.94 XXI (erythro) 3.57 4.70 and 5.15 X (erythro) 2.88 4.06 and 4.85 XXII (erythro) 3.48 . 4.46 and 4.85

XVII (threo) 2.52 —— XXIV (threo) 3.15 — — XVIII (threo) 2.25 4.25 XXV (threo) 3.10 4.89 and 4.98 XIX (threo) 2.45 4.29 and 4.75 XXVI (threo) 3.02 4.70(d,2H,J=0H%) I (erythro) 2.99 4.72 XXIII (erythro) 3.65 5.60 and 6.05 XI (threo) 2.56 4.96

XXVII (threo) 3.36 5.78 and 5.90 70 noroxazolidine is of comparable magnitude and direction to the change for the Cg proton suggesting that both protons are trans-diaxial to the nitrogen lone pair in the N-methyl oxazolidines.

The absolute configuration at Cj^ for the oxazolidines derived from both (-)-ephedrine and (t)-pseudoephedrine is S. The configuration of the nitrogen is determined by the methyl. Since the Cg proton is approximately trans- diaxial to the nitrogen lone pair, the absolute configur­ ation at Cg is S,

"H I

CH 3

The difference in chemical shifts of the protons in the oxazolidines from (-)-ephedrine and acetone (VIII) and from (1)-norephedrine and acetone (XX) is 0.68 ppm, the extent of which is indicative of an approximate trans- diaxial relationship between the proton and the nitrogen lone pair, and a cis relationship between the proton and N-methyl in compound VIII, Similarly, a comparable change in chemical shifts is noted for the corresponding threo- 71 oxazolidines, XVII and XXIV. The analogous chemical shifts of oxazolidines from (-)-ephedrine and acetaldehyde (IX) and from (±)-norephedrine and acetaldehyde (XXI) indicate that the configuration of the proton in IX is also approximately trans-disixial to the nitrogen lone pair. The configuration assigned to the Cg proton of compound IX is based upon shielding and deshielding effects reported for substituted 1,3-dioxolanes. Baggett and co-workers ( 77) determined the effects of various Cj^ substituents on the chemical shift of Cg benzylicproton signals in derivatives of 2-phenyl-l,3-dioxolane. M. Anteunis and F. Alderweireldt (82,83) studied the PMR spectra and. conformations of dioxplanes from 1,2-propanediol with acetone and acetaldehyde and from 2,3-butanediol with acetophenone. The generalizations deduced from this data which is useful in comparing similar interactions in oxazolidines, e.g., 2,5-interactions across the oxygen, adjacent 4,3 interactions and geminal interactions, are *

Substituent Effect on Chemical Shift

C^^ phenyl trans Gg proton deshielded 0.22 ppm C^ phenyl cis Cg proton deshielded 0.42 ppm C^ methyl cis C^ methyl shielded by 0.1 ppm

C^ methyl trans C^ methyl shielded by 0.03 ppm C|^ methyl cis C^ proton shielded 0.8 ppm methyl trans C^ proton shielded 0.2 ppm 72 cont. Cg phenyl cis 0^ proton deshielded 0.33 PPm over trans Cg methyl cis C^ proton shielded by 0.08 to 0.2 ppm over trans gem methyl proton deshielded 0.04 ppm gem phenyl methyl deshielded 0.25 ppm

In compound VIII, a Cg methyl cis to a C^ phenyl is expected to be deshielded 0 ,06 -0.1 ppm more than a Cg methyl which is trans to a C^ phenyl and a Cg methyl cis to an N-methyl should be shielded ca. 0.1 ppm more than a Cg methyl trans to an N-methyl. Accordingly, the Cg methyl at 1,18 ppm downfield from TMS is assigned trans to the C^ phenyl (cis to N-methyl) and the Cg methyl at 1.48 ppm is cis to the C^ phenyl (trans to N-methyl), Since the Cg methyl of IX occurs at 1.4? ppm, it is cis to the C^ phenyl and the Cg proton is then trans to the C^ phenyl and trans to the nitrogen lone pair.

f e ç - o K ,

' 5 ^"^3 CH, VIII IX 73 The condensation product from (±)-norephedrine and acetaldehyde (XXI) is a mixture of two isomeric noroxazolidines in a ratio of 3:1, The Cg methyl doublet occurring at 1.52 ppm has a relative intensity 3 times that of the Cg methyl doublet occurring at 1.37 ppm, and the Cg proton quartet at 4.70 ppm has a relative intensity 3 times that of the Cg proton quartet at 5*15 ppm. The Gg methyl doublet at 1.52 ppm is cis to the C^ phenyl and the Cg proton quartet at 4.70 ppm is trans to the C^ phenyl. Therefore, the difference in chemical shifts of the Cg protons of compound IX and of the oxazolidine in XXI having the same Cg configuration is 3*94-4.70 = -0.7& ppm, which is in accord with the trans-diaxial relationship of the Cg proton with the nitrogen lone pair in compound IX. The same arguments based on the dioxolane correlations are developed for the corresponding threo oxazolidines, XVIII and XXV. The chemical shifts of the Cg methyl of the oxazolidine from (+)-pseudoephedrine and acetone (XVII) occur at I.30 and 1.41 ppm. The Cg methyl which is cis to the C^ phenyl is also cis to the N-methyl. The net effect expected is that a Cg methyl cis to a C^ phenyl will be shielded ca. O.05 ppm upfield from a Cg methyl trans to a

C^ phenyl. On this basis the Cg methyl at I.30 ppm is cis to the C^ phenyl and the Cg methyl at 1,41 ppm is trans to the C^ phenyl. The Cg methyl doublet for compound XVIII occurs at 1.39 ppm and is trans to the C^ phenyl. Therefore, 7 4 protons appear for the oxazolidines of (-)-ephedrine and benzaldehyde (I) and (±)-norephedrine and benzaldehyde

(XXIII) (4.72 -5.60 = -0,88 ppm) and for the oxazolidines of (+)-pseudoephedrine and benzaldehyde (XI) and (+)-norpseudoephedrine and benzaldehyde (XXVII) (4,96 -5*90

= -0,94 ppm), Based on the relative intensities of the signals and on the previous arguments of effects on chemical shifts, assignment can be made for XXIII as a mixture of 20^ oxazolidine of C^-S configuration 5.60(s,0,2H) and 10?S oxazolidine of Cg-R configuration 6 .05 (s,0 ,lH) with 70% Schiff base 8,24(s,0,7H) In the Cg-R configuration, the Cg proton i’s cis to the phenyl and deshielded to a greater extent than the same proton in the Gg-S configuration. Similarly, assignment can be made for XXVII as a mixture of 55% oxazolidine of Cg-S configuration 5«90(s, 0.55H) and 20^ oxazolidine of Cg-R configuration 5*78

(s,0,2H) with 25% Schiff base 8,31(s,0.25H) . In the

CH, ^ H I XXIII 15 •the Cg proton quartet in XVIII is cis to the 0^ phenyl and trans to the nitrogen lone pair.

4,70 1 IX CH, H

The condensation product from (+)-norpseudoephedrine and acetaldehyde (XXV) is a mixture of two isomeric noroxazolidines in nearly equal abundance. The chemical shifts of the Cg methyl doublet and Cg proton quartet of the two isomeric noroxazolidines are too close to make an unambiguous assignment relating chemical shifts to config­ uration of the noroxazolidines. However, the difference in chemical shift of the Cg proton in compound XVIII and of either Cg proton in XXV is compatible with an approximate trans-diaxial relationship of the Cg proton in compound XVIII with the nitrogen lone pair. A comparable difference in chemical shifts of the Cg 76 Cg-S configuration the Cg proton is cis to the C^ phenyl and deshielded to a greater extent than the same proton in the Cg-R configuration. It is of interest to note that the product from phenylacetone and (-)-ephedrine is a mixture of oxazolidines in about a 2:1 ratio. Only one isomeç (VII), crystallizes from the reaction mixture, leaving the liquor enriched in the other isomer. The crystalline product is assigned a Cg-S configuration. Attempts to crystallize the other

"CH^0

t n T CH,

Crystal Melt

isomer were not successful. Attempted recrystallization from benzene resulted in reversion of the enriched liquor

( 90% in the Cg-R form) to the initial concentration of about 63% Cg-S isomer and 35fo Cg-R isomer. The Cg-S isomer appears to be the thermodynamically more stable of the two. 77 2, Evidence from Reaction of Grignard Reagents with Oxazolidines and Subsequent Hofmann Degradation

The PMR and IR data presented in the previous section indicate that the absolute configuration at Cg in oxazolidines derived from (-)-ephedrine and from (+)-pseudoephedrine and aldehydes is S. In direct contrast to our conclusions, Neelakantan (76 ) reported an R configuration at Cg in oxazolidines derived from (-)-ephedrine and aromatic aldehydes. He assumed that the specific rotation of substituted benzylamines derived from these oxazolidines by Grignard reaction followed by Hofmann degradation reflected the configuration at Cg for the oxazolidine. The absolute configurations of the substituted benzylamines had been previously correlated with the specific rotations (84). He utilized three procedures in synthesizing the oxazolidinesI (a) reflux in benzene using a Dean-Stark trap; (b) reflux in absolute alcohol; and (c) reaction of amino alcohol, aldehyde, and sodium bisulfite to form an arainoalkane sulfonate, which was then decomposed in alkaline solution to yield an oxazolidine. Since he reported that an R configuration at Cg results regardless of the mode of synthesis, the synthetic procedures for those compounds which were common to both his study and the present study were investigated. The compounds in question are the oxazolidines from (-)-ephedrine and benzaldehyde and from 78 (-)-ephedrine and acetaldehyde. Neelakantan reported a specific rotation of -55^ for an ethanolic solution of the oxazolidine which he obtained from (-)-ephedrine and benzaldehyde. The specific rotation of compound I measured under the same conditions (20°, 1 g./lOO ml.) was -56°. Compound I prepared by his method (b) showed the same PMR spectrum as the compound prepared by our general method A. No mixed melting point depression was observed for the oxazolidines prepared by the two procedures. The molecular ellipticities were also the same (Table 9 )• It appears that the compounds prepared by Neelakantan and in this study are identical. The discrepancy between his conclusion and ours regarding the absolute configuration of the oxazolidines prepared from (-)-ephedrine and aromatic aldehydes prompted us to examine the methods which he employed. erythro-2,5~Diphenyl-3,4-dimethyloxazolidine (I), erythro- 2,^,5-triphenyl-3-methyloxazolidine (XXIX), and erythro- 2,3,^-triraethyl-5-phenyloxazolidine (IX) were each reacted with Grignard reagents and the resulting tertiary amino alcohol subjected to Hofmann degradation. The product of the Grignard reaction of compound I with méthylmagnésium iodide shows the following PMR spectral datai (CDCl^, 6 ) 1.28(d,3H,J=6.5Hz), 2,10(s,3H), 3.83(q,lH,J=6.5Hz). The subsequent Hofmann degradation of this product yielded a product which possesses a negative Cotton effect 79 at 260 nm (as the methiodide salt in v/ater), The product of the Grignard reaction of compound IX with phenylmagnesium "bromide shows the following PMR spectral data: (GDGl^) 6 1,25(d,3H,J=6.5Hz), 1.2?(d,3H,

J=6.5Hz), 2.06(s,3H), 2.08(s ,3H), 3.75(q,lH,J=6.5Hz ), 3.83(q,lH,J=6.5Hz). The subsequent Hofmann degradation of this product yielded a product which is optically inactive. The nature of the Grignard reaction with oxazolidines has been reviewed by Bergmann (48). No work other than that

H H

% R' Mg X lylgX H / -C— C-='R'

,H R "Hr 80 reported by Neelakantan (?6) was found concerning the stereochemistry of this reaction with oxazolidines. Felkin, et al., (85) studied the stereochemistry of epoxide ring opening by allylic organomagnesiura compounds. They found inversion of configuration of the epoxide carbon to occur. Oxazolidines undergo ring fission via C-0 bond breaking when reacted with Grignard reagents. If the reaction proceeds by the same mechanism as that given for epoxide fission, inversion of configuration should occur at C^.

I R

N-C--H R CH 81 The PMR data of the product resulting from the reaction of méthylmagnésium iodide with compound I shows only one configuration present. The subsequent Hofmann degradation to a benzylamine retains the configuration of the product. The negative Cotton effect of the product at 260 nm is indicative of an R configuration for the benzylamine (86).

Neelakantan (76 ) obtained the same optically active amine from this reaction, since the product which he obtained and ours show a specific rotation of +19*8° at the sodium D line. The Grignard reaction of méthylmagnésium iodide v/ith erythro-2,4,6-triphenyl-3-methyloxazolidine (XXIX) and subsequent Hofmann degradation yielded N,N-dimethyl-Cy- phenethylamine having a positive Cotton effect at 260 nm. XXI X

CH 3 (-)-erythro-2-Methylamino-l.2-diphenyl ethanol used in the synthesis of XXIX probably has the same absolute configura­ tion as (+)-ephedrine (NOTE). The resulting benzylamine is the enantiomer of the compound obtained from the Grignard reaction and subsequent Hofmann degradation of I. In these reactions either complete retention or complete inversion of configuration occurs when the oxazolidine reacts with 82 the Grignard reagent,

Neelakantan ( 76 ) stated that acetaldehyde reacts with (-)-ephedrine to yield a mixture of diastereoisomers. He based this conclusion upon the fact that the Grignard reaction of the phenylmagnesium bromide on the oxazolidine from (-)-ephedrine and acetaldehyde followed by Hofmann degradation yields optically inactive N,N-dimethyl-CX~ phenethylamine. In view of the PMR data presented above v/hich established that the reaction of (-)-ephedrine with acetaldehyde is stereoselective, it is evident that racemization occurred during the Grignard reaction. To verify this conclusion v/e examined the PMR spectrum of the product resulting from the reaction of phenylmagnesium bromide with the oxazolidine from (-)-ephedrine and acetaldehyde (IX), The spectrum shows "Cg" methyls at 1,25 and 1,27 ppm, N-methyls at 2.06 and 2,08 ppm, and "Cg" protons at 3»75 and 3,83 ppm. The signals at 1,27, 2,08, and 3,83 ppm correspond to the product from méthylmagnésium iodide and compound I, Thus, racemization does occur in the formation of the Grignard adduct,

Neelakantan ( 76 ) assumed that retention of configuration occurs on reacting the oxazolidines from (-)-ephedrine and aldehydes with Grignard reagents. This assumption is suspect. 83 NOIEI The evidence for assignment of absolute configuration of the erythro-2-methylamino-l, 2-diphenyl ethanols is correlation of molecular ellipticities of compounds of kno\vn configuration with the molecular ellipticities of the (+)-erythro and (-)-erythro epimers. Molecular ellipticities listed below v/ere determined in methanol unless otherwise indicated and at ambient temperature,

Table ^

Molecular Ellinticities at Selected Wavelengths for the Ephedrines and Selected Analogous Compounds in Ivlethanolic Solutions

Compound ^ A nm

(-)-Halostachine + 457 260 (+)-Amphetamine + 142 261

(-)-Ephedrine (dioxane) + 1300 261 (+)-Pseudoephedrine (dioxane) - 360 261 (-)-erythro-2-Methylamino- 1 ,2-diphenyl ethanol - 532 259 (+)-erythro-2-Methylamino- + 472 259 1,2-diphenyl ethanol

^ 3.0 X 10"^ M. 84 Table 5

Absolute Configurations of the Ephedrines and Selected Analogous Compounds Amino Benzyl Alcohol Ref. Compound Carbon Carbon

66 (-)-Halostaohine — R 83 (+)-Amphetamine S 51-53 (-)-Sphedrine S R 51-53 (+)-Pseudoephedrine S S

An S configuration at the amino carbon contributes a positive rotation to molecular ellipticity ((+)-amphetamine) and an R configuration at the benzyl alcohol carbon contributes a positive rotation to the molecular ellipticity ((-)-halostachine). On this basis the (+)-epimer, possessing a positive Cotton effect at ca. 26o nra, is assigned a configuration analogous to (-)-ephedrine and the (-)-epimer is assigned the reverse absolute configuration.

OH ,0" I CHj ^ CHj

(+)-2-Methylamino-l,2- (-)-2-Methylamino-l,2- diphenyl ethanol diphenyl ethanol 85 3. Evidence from X-ray Diffraction Analysis

Proof of the absolute configuration at Cg for the phenyl oxazolidines was obtained by x-ray diffraction analysisa The oxazolidines of p-bromobenzaldehyde and the ephedrines (IV and XIV) were prepared and used for x-ray analysis. The results confirmed an S configuration at Cg for both the erythro and threo isomers. The x-ray analysis was done by Dr, Eli Schefter of The State University of New York at Buffalo. Part of his data is listed in Tables 6 and ?• Neelakantan also reported the x-ray diffraction study of erythro-2-p-bromophenyl-3,4-dimethyl-5-phenyloxazolidine. He interpreted his data (8?) as indicating an R configuration at Cg in direct conflict with Schefter. Schefter (88) believes that misallignraent of the positional parameters caused a misinterpretation of the calculated structure and that proper allignment would then support the notion of an S configuration at Cg. In conclusion, the ring stereochemistry of oxazolidines derived from (-)-ephedrine and (+)-pseudoephedrine condensing with asymmetric aldehydes is such that the oxazolidines from the two diastereoisomeric amino alcohols differ from each other only in the configuration at C^. The erythro isomers have an R configuration at C^, and the threo isomers have an S configuration at C^. 86

Table 6

Torsion Angles (°) for

Atoms Erythro- Threo-

C5-01-C2-.N3 -33 25 01-G2-N3-C4 49 -43 C2-N3-C4-C5 -44 44 N3-C4-C5-01 24 -29 C^"*C3**01 ”02 5 2 C6-N3-C2-C8 -70 74 C7-C4-C5-C14 • 26 85 C6-M3-C4-C7 71 -70 01-C2-C8-C9 66 -77 87 Table 7

Bond Angeles (°) For 2-p~Bromophenyl-3i4-dimethyl-S-Vhenyloxazolidines

Atoms Erythro- Threo- Atoms Erythro- Threo-

Br-Cll-ClO 101.8 122.6 08-09-010 121.4 117.4 Br-Cll-C12 118.3 121.4 09-010-011 119.6 123.6 C2-01-C5 106.3 109.3 010-011-012 118.3 115.5 01-C2-N3 103.2 103.7 011-012-013 119.3 122.4 C2-N3-C4 102.2 101.5 012-013-08 121.9 120.0 C2-N3-C6 111.3 113.2 013-08-09 118.0 120.7 N3-C4-C6 101.1 100.9 05-014-015 120.3 121.8 N3-C4-C7 112.2 114.5 05-014-019 124.0 122.0 C4-C5-01 103.2 103.5 015-014-019 115.7 116.2 C4-C5-C14 116.0 115.3 014-015-016 123.9 124.6 01-C5-C14 110.0 103.3 015-016-017 118.1 117.3 C5-C4-C7 116.3 115.1 016-017-018 122.2 120.0 01-02-08 109.6 112.4 017-018-019 116.86 123.4 N3-02-08 115.0 112.7 018-019-014 122.9 118.5 02-08-09 121.5 120.1 02-08-013 120.5 119.0 C16

Plate la

Crystal Structure of erxt2iro-2-£-Bromophenyl-3,^-dimethyl-5-phenyloxazolidine (IV) œ Plate Ib Crystal Structure of threo-2-2-Bromophenyl-3,4-dimethyl-5-phenyloxazolidine (XIV) VOCO 90

I CH,'H XIV

0 V o

H-'" c n % V

It is of interest that the N-methyl in each compound is trans-staggered to the Cj^ methyl. It follows that reaction of these oxazolidines with Grignard reagent involves inversion of configuration at Cg when the Grignard adduct is formed,

4, Proposed Mechanism of Ring Formation

A reasonable mechanism of ring closure may be proposed based on the stereoselectivity noted, Fischer and Schiene (4l) proposed a mechanism based on their studies of the equilibrium of ring closure, which is essentially a dehydration of a carbinolamine to an oxazolidine (Scheme 1), 91

+ \ - o -H c ■OH R

tl,

R

R'ÇH

H- / H— C W R

Scheme 1

Scheme 1 is modified to Scheme 2 in order to account for the stereoselectivity of ring closure. . 92 ’g^C'OH R _ R

c" # % C H > . . - C H , \

tl- i xR ^ 1 . xR _ C Hj^H C

" V F V " H ^ C H, H J Scheme 2

The stereoselective ring closure appears to be determined by the absolute configuration of the carbon atom bearing the methylamino group in the ephedrine isomers. As incipient ring formation occurs, the nonbonded interaction of the methyl of the ring forces the N-methyl to become trans-staggered which in turn determines that the bulky substituent at is trans-staggered to the N-methyl. 93 D, Attempt to Measure Equilibrium Values for Rinp: Closure of the Styryloxazolidines

The study of equilibrium between cinnamaldéhyde and the ephedrines in dioxane solution showed no change in absorbance at 290 nm over a four-day period. Hence, there appears to be no measurable equilibrium for these compounds with the corresponding oxazolidines, (II and XII), These results are surprising in terms of steric factors. Both (-)-ephedrine and (+)-pseudoephedrine have measurable equilibrium constants for condensation v/ith acetone and with butanone (41), The syntheses of the 2-styryloxazolidines involve comparable or even milder conditions than the syntheses of the acetone oxazolidines,

E, Some Spectral Characteristics of Hydrolysis Intermediates from 2-otyryl~3,4-dimethyl-5- phenyloxazolidines (II and XII) and 2,5-Diphenyl- 3,4-dimethyloxazolidines (l and XI) and of Styrylidene-ïl-methyl-H-[2-(erythro-l-hydroxy- TLphenyl )propyl]ammonium perchlorate (XXXIV) '

The irnmonium ion intermediate in the hydrolysis of the

2-styryloxazolidines was prepared by mixing an ether solution of the oxazolidine with an ethereal hydrogen chloride solution. The resulting precipitated irnmonium ion chloride was filtered, repeatedly washed with ether, and dried. The infrared spectra of the intermediates isolated in this way from erythro-2-stvrvl-3.4-dimethvl-5-phenvl- oxazolidine (II) and the corresponding threo-oxazolidine

(XII) show a strong absorbarce at I613 cra,”^ and I6 I5 cm,“^ 94 respectively, which is characteristic of C=N stretch. The PMR spectra of these intermediates in trifluoro- acetic acid (TFA) are identical v/ith the spectra obtained for TFA solutions of the parent oxazolidines (Table 8 ), When the oxazolidine is dissolved in TFA and the PMR spectrum repeatedly determined, it is possible to observe the spectra of the decomposing and forming species. For compound I, the methyl of the protonated oxazolidine (decomposing species) is shielded by the cis phenyl. The chemical shift is 1.25 ppm in TFA. In the forming species, the chemical shift of the corresponding methyl is 1.78, indicating ring opening and loss of shielding from the cis phenyl. The N-methyl in the protonated oxazolidine occurs as a doublet at 3.18 ppm, since it is coupled v/ith the nitrogen proton. In the forming species the N-methyl appears as a singlet at 3«94 ppm indicating loss of the nitrogen proton. Neither hemiacetal nor carbinolamine is present in any significant concentration since in both of these cases the nitrogen would remain protonated in TFA, A similar behavior of the N-methyl multiplicity is noted for compound XI (3,08 doublet for protonated oxazolidineI 3,98 singlet for intermediate), The change in the coupling constant of the proton in I and II indicates that an open chain compound has formed (5«66(7Hz) to 5.31(5«5Hz) I; 5«70(8Hz) to 5«28(5Hz) II). 95 Table 8

Proton Maj^netic Resonance Spectral Data of 2~St.vr.yl~ 3 » 4-dimethyl-5-nheny 1 oxazolidines and 2,5"-Piphenyl~.^j, 4-dimethy3.oxazolidines in Tril'luoroacetio Acid

Compound

I Protonated Oxazolidine 1.25(d,3H,J=?Hz), 3.l8(d,3H,J=5Hz), 4.24(m,lH), 5.66(d,IH,J=?Hz), 5.79(d,IH,J=7Hz). Irnmonium Ion 1.78(d,3H,J= 7Hz), 3.9^(s,3H), 4.79(m,lH), 5.31(d,IH,J=5.5Hz).

II Protonated Oxazolidine 1.19(d,3H,J=6 Hz),

4. l4(m,IH), '5.70(d,lH, J-8Hz), Irnmonium Ion 1.73(d,3H,J=6Hz), 4.51(m,lH), 5.28(d,lH,J=5Hz).

XI Protonated Oxazolidine 1.72(d,3H,J=6,5Hz), 3.08(d,3H,J=5Hz), 3.90(m,lH), 5.45(d,lH,J= 8.5Hz), 5.91(d,IH,J=8Hz). Immonium Ion 1.54(d,3H,J=7Hz), 3.98(s,3H), 5.10(m,lH), 5.00(d,lH,J=8Hz), 7.83(s,1H).

XII Protonated Oxazolidine 1.70(d,3H|J=6,5Hz),

^.65(m,lH), 6,17(d,IH,J = 8 H z ) . Immonium Ion 2.27(d,3H,J=6.5Hz), 4.54(m,lH), 5.l2(d,lH,J=

8 H z ) . 96 The ultraviolet spectra of the styryl intermediates

in dioxane show wide absorbance bands at 336 nra.

Styrylidene-N-raethyl-N- [2- (erythro-l-hydroxy-1-phenyl) propylj ammonium perchlorate (XXXIV) prepared by the general method of Leonard and Paukstelis and by the method of Sakai,

et al., shov/s an ultraviolet absorbance maximum at 336 nm,

€ = 33,000. The similarity of the ultraviolet absorbance maximum of the styryl intermediates and that of compound XXXIV indicates a structural similarity in the chromophore, the =C—C—C— group. Circular dichroism measurements in 2.4 N HCl show that the styryl intermediates from II and XII both exhibit positive Cotton effects at 336 nra. A possible explanation for this behavior might be the fact that the carbon possesses the same absolute configuration in both compounds,

and the proximity of the strong chromophore, ^ n’*’=C-C=C-C^H^, to this carbon exerts a controlling influence on the molecular ellipticity of these compounds. The spectra were too noisy to obtain any quantitative measure of molecular ellipticity for these compounds. Elemental analyses of the styryl intermediates from II and XII were unsatisfactory because of partial hydrolysis. Elemental analysis of XXXIV was satisfactory. It is of interest to note that in contrast to relative ease of formation of immonium ion hydrolytic intermediates of I, II, XI, and XII, the PMR spectra in 20^ DCl/DgO of 97 oxazolidines from the ephedrines and aliphatic carbonyl compounds show no evidence for immonium ion intermediates. Comparison of the spectra of the aliphatic oxazolidines with that of the hydrochloride salt of the amino alcohol and of the carbonyl compound indicated only protonated oxazolidine and the products of hydrolysis were present in measureable quantities under these conditions. Furthermore, the solid product isolated from treatment of aliphatic oxazolidines with ethereal hydrogen chloride solution yielded no absorbance in the infrared (KBr) indicative of C=N stretch. The PMR spectra in DMSO-d^ of the product resulting from treatment of erythro- 3,4-dimethyl-^-phenyloxazolidines with ethereal hydrogen chloride indicate ring form present. Some of the maxima and minima in the circular dichroism (c.d.) spectra of several oxazolidines and related compounds are listed in Table 9» The spectra were obtained at 25° in a Jasco spectropolarimeter. Rotations obtained are generally converted to molecular ellipticity values, [^j , by the ,4 formulas, r , ^ Q c x i r , [^]MW where 100 = pen displacement in cm. x c.d. scale (millideg./cm.) c t= g./liter and 1 a pathlength in cm. 98 Table 9

Selected Circular Dichroism Spectral Properties of Some Oxazolidines and Their Hydrolytic Products

Wavelength Molar Molecular Compound (nm)&Solvent Concentration Ellipticity

I 260 dioxane 3.0 X 10"^ + 180

XI 260 dioxane 1.24 X 10~^ - 680

II 248 dioxane 6.0 X 10"^ - 20,000

XII 248 dioxane 6,0 X 10“'^ + 31,000

VI 260 dioxane 2.4 X 10"^ + 670

XVI 260 dioxane 2.4 X 10"^ 670

IV 268 dioxane 1.0 X 10“^ + 400

IX 261 dioxane 2.38 X 10“^ + 360

(-)-Ephedrine 261 dioxane 2.78 X 10"^ + 1300 (+)-Pseudo- ephedrine 261 dioxane 2.78 X 10"^ - 360 (-)-Ephedrine Hydrochloride 261 methanol 1.5 X 10“^ + 800^ (+)-Pseudo- ephedrine HCl 260 methanol 7.2 X 10"3 220^

L. Mitscher, et al., Canadian Journal of Chemistry, iZ» 1957, (1959), 99 Formation of (-)-ephedrine can be followed by circular dichroism as shown by the data in Table 9 . For example, there is about a fourfold increase in molecular ellipticity in going from compound IX, the oxazolidine of acetaldehyde and (-)-ephedrine, to (-)-ephedrine. The difference in molecular ellipticities between (+)-pseudoephedrine and the oxazolidines from benzaldehyde (XI) and cyclohexanone (XVI) is not as great as the difference between (-)-ephedrine and the corresponding erythro oxazolidines (I and VI), With the exception of the styryloxazolidines, the difference in the molecular ellipticities of the oxazolidine and those of the resulting hydrolysis product, (-)-ephedrine or (+)-pseudoephedrine, is generally too small to obtain quantitative kinetic data,

F, Kinetics of the Hydrolysis of Some Oxazolidines Derived from the Ephedrines and of Some Intermediates and Analogues

1, Methods of Assay

The ultraviolet spectral characteristics of some oxazolidines and related compounds are listed in Table ID, The spectra were determined at ambient temperature in a Cary 15 spectrophotometer. The ultraviolet characteristics of the styryl­ oxazolidines II and XII, the styryl intermediates, and cinnamaldéhyde are such that the three species can be easily differentiated, (-)-Ephedrine is not readily identified by 100

Table 10

Selected Ultraviolet Spectral Properties of Some Oxazolidines and Their Hydrolytic Products

Compound Wavelength (nm) Solvent Molar Cone, €

I 258 dioxane 1.5 X 10“^ 376 XI 258 dioxane 1.0 X 10"^ 373 II 252 dioxane 2,0 X io“-5 22,900

XII 252 dioxane 2,0 X io“-5 20,700 VI dioxane 1.5 X 10“^ 226 XVI 256 dioxane 2,0 X 10“^ 180 (-)-Ephedrine Hydrochloride 258 methanol 2,0 X 10-3 203 Cinnamaldéhyde 290 methanol 2,0 X 10-3 17,000 Acetaldehyde 227 9.6 M HCl 2,0 X 10-3 180 IX 257 9.6 M HCl 2,0 X 10-3 260

this method since its absorptivity is nearly two orders of magnitude lower than that of cinnamaldéhyde (Fig, 2),

2, Kinetics of the Hydrolysis of 2-Styryl- 3.^-dimethyl-5~phenyioxazolidines

a. Methodology

The 2-styryloxazolidines (II and XII) were selected for detailed kinetic studies since the parent compounds, intermediates in the hydrolysis, and hydrolytic products 101

Figure 2

Spectrum of erythro-2-styryl~3i^"dimethyl- 5-phenyloxazolidine in (a) dioxane, (b) pH 3 citrate buffer at maximum intermediate concentration, (c) pH 3 citrate buffer showing decomposition of intermediate and formation of aldehyde, and (d) final product of the reaction (cinnamaldéhyde) ABSORBANCE

Co Os oo

Q_ cr o

Os o > < m Oo - o m z Q. O H %

U) o

Go cr O

Go CD

2 0 1 103 Table 11

Rate Constants for the Hydrolysis of 2~Stvryl~3.4~dimeth.yl~ 5~pbenyloxazc)lidines (II and XIlT in o#35 N HCl at 30

Concentration, M k. m m -1 a erythro threo

2.0 X 10“^ 0.066 0.283

1.0 X 10-5 0.066 0.278

5.0 X 10-^ 0.068 0.278

2,0 X 10-^ 0.067 0.282

Ring opening monitored at 256 nm.

Table 12

Rate Constants for the Hydrolysis of 2-Styryl-3, dimethyl-5~phenyloxazolidines (II and XIIj in pH 6.00 Phosphate Buffer 0.05 W at 30^

Concentration. M -1 a erythro threo

2.0 X 10 -5 0. 0# 0.038

1.0 X 10-5 0.043 0,038 -6 5.0 X 10 0.043 0.038 -6 2.0 X 10 0.043 0.037

a Intermediate hydrolysis monitored at 336 1 0 4 Table 13

Rate Constants for the Hydrolysis of 2~Styryl~3.4-. dimethyl-5~phenyloxazolidines (II and XIIJin Hydrochloric Acid Solutions at 30

Ring Opening Intermediate Hydrolysis HCl. M erythro threo erythro threo 6.35 0.07 0.29 4.0 X 10"^ 5.6 x 10**^ 4.81 0.14 a

2.54 0.34 1.1 X 10"^ 7.5 X lO"-^ 1.20 0.48

1.02 0.58 3.0 X 10"^ 2.2 X 10“^

0.51 0.59

0.10 , 0.72 8.2 X 10"^ 7.8 X 10“^ ( ^ = 0.15 )

0.01 , 0.92 1.1 X 10“^ 1.1 X 10“^ C/ji^o.isr 0.01 0.97 1.2 X 10"^ 1.3 X 10“^ (/^=0.01)

0.01 . 0.75 6.8 X 10”^ 6.3 X 10“^ (a=i-oir ob ob 0.01 , - 1.1 X 10“-^ 1.1 X 10" J (//=o.i5)^ 0.001 3.0 1.5 X 10"^

0 .0001® a e.f 1.02 0.16

^Reaction proceeds rapidly. ^Isolated immonium ion was used. Measured pH after reaction 4.21. Ionic strength adjusted with KOI. ^Product from attempted synthesis of 2-styryl-2,3, 4-trimethyl-5-phenyloxazolidine. Reaction monitored at 336 nra. 105 are readily followed by ultraviolet absorption measurements

(256 nm, oxazolidinesj 336 nm, intermediates; 290 nm, cinnamaldéhyde). Figure 2 shows spectra of the species observed during the hydrolysis. An ultraviolet spectrum of styrylidene-N-methyl-N-[2-(erythro-1-phenyl-1-hydroxy) propyljammonium perchlorate (XXXIV) is identical to that shown for the hydrolysis intermediate. Due to the instability of the oxazolidines and intermediates in aqueous solutions, a Beer's law plot for each of these species requires the use of an inert solvent or procedures involving extrapolation to zero time for a series of different concentrations of these compounds in aqueous solutions. Preliminary experiments demonstrated that the oxazolidines are most stable in concentrated acid solutions, decomposing comparatively slowly to the intermediates. In order to obtain a Beer's law plot for the oxazolidines, solutions of each compound using a range of concentrations

(2,0 X 10”^ M to 2.0 X 10“-^ M) were prepared in 6,35 M HCl and the first-order plots of the composition (log(A^-Aco) vs. time) v/ere extrapolated to zero time. The relationship between the intercept absorbance values and oxazolidine concentrations are shown in Figure 3 . The calculated absorptivities of the oxazolidines (erythro. C = 19,100; threo, 6 = 18,300) determined in this way are significantly less than the values determined using dioxane solutions 106

Figure 3

Plots of absorbances extrapolated to zero time vs. concentration of the 2-styryl­ oxazolidines in 6.35 M HCl at 30° 107 o II

O

ç5 o CL 05 threo L_ € = I 8 ,3 0 0 X (D

U U z < cû 0: O ui cû <

0 2 4 6 8 /O / 2 M /6 / 8 2 0

MOLAR CONC N. x 10 1 0 8

Figure 4

Plots of absorbances extrapolated to zero time vs. concentration of the 2-styryl­ oxazolidines in pH 6,0 phosphate buffer, 0.05 M at 50°. Plot of absorbance vs. concentration of cinnamaldéhyde in the same medium at 50 ° 109

erythro 6 = 35,200 / LU U Z < Dû DU O m Dû <

cinnamaldéhyde C = / 7,00 0

0 2 4 6 8 /O /2 /4 /6 /8 20 MOLAR CONC'N. x 10 1 1 0 (Table 10). Hydrolysis of the oxazolidine to the intermediate in a pH 6,0 phosphate buffer is so rapid that no oxazolidine can be detected immediately following preparation of the solution. A Beer's lav/ plot for the intermediates in pH 6,0 phosphate buffer was determined in a manner similar to that described for the oxazolidines (Fig. 3 )• Figure also shows the relationship betv/een absorbance and concentration of cinnamaldéhyde in the pH 6.0 phosphate buffer.

b. Kinetics in Acidic Solutions

The apparent first-order rate constants for the hydrolysis of the oxazolidine (ring opening) to the intermediate or for the hydrolysis of the intermediate to the aldehyde were determined to be independent of the substrate concentration in the solutions studied. Tables 11 and 12 show the lack of dependence of the rate constants on oxazolidine concentration in 6.35 M HGl and in pH 6.0 phosphate buffer. The rate constants for the hydrolysis of the 2-styryl- oxazolidines (II and XII) in various hydrochloric acid solutions are reported in Table 13. The ring opening reaction was followed at both 256 nra (oxazolidine decomposition) and at 33^ nra (intermediate formation). The subsequent hydrolysis reaction v/as followed at 33^ nm (intermediate decomposition) and at Ill

290 nra (cinnamaldéhyde formation). In each instance, the rate of decomposition of one species equalled the rate of formation of the product in the reaction sequence within a - variation. All kinetic determinations were made in triplicate.

In agreement with Fife (63 ), a negative salt effect was observed for both ring opening and immonium ion hydrolysis. It is of interest to note that an immonium ion (XXXV) which is similar in structure to the intermediates in the hydrolysis of II and XII, lacking only the hydroxy group, is somewhat more stable to hydrolysis in acid (Table 14).

Table 14

Rate Constants for the Hydrolysis of Styrylidine- N-methyl-N-[2-(l-phenyl)propyl] ammonium perchlorate (XXXV) in Hydrochloric Acid Solutions at 30*^

0.01 4 X 10"^ 0.001 4.6 X 10"4 0.0001^ 6.6 X 10"^

^ Measured pH after reaction 4.20. 1 1 2 c. Kinetic Characterization of Solvent Participation in Rin% Opening of the Oxazolidines in Acidic Solutions

The ratio of rates of ring opening to subsequent intermediate hydrolysis range from about 10,000:1 at 6,35 M HCl to about 800:1 at 0.01 M HCl ( // = 0,01). These values allow essentially complete separation of the kinetics of ring opening and kinetics of intermediate hydrolysis. Ring opening of the three isomer proceeds more rapidly than that of the erythro isomer in concentrated hydrochloric acid solutions. In order to compare the rate constants for

Table 15

Rates of Ring Opening of the 2-Styryl-3,4- dimethyl-5-phenyloxazolidines (ll and XII) in HCl Solutions at 15^

erythro three

HCl.M HCl.M -1

6.35 0,00155 5.40 0.156 5.40 0,0077 2,70 1.56 2.82 0.092 1.35 3.3 0.50 0.165 0.67 4.3 0,01 0,283 / 0.05 6.8 113 ring opening of the isomeric styryloxazolidines, the reactions were studied at 15*^» The comparative rate constants are reported in Table 15. The rate constants for ring opening of both isomers markedly decrease as the acid concentration increases. The activity of water is known to decrease with increasing acid concentration in concentrated HCl solutions. A plot of the log of the observed rate constants for ring opening of the tv/o isomers at 15 ° in these concentrated acid solutions vs. the log of the activity of water in these solutions is shown in Figure 5. The slopes, w, are essentially equal for the tv/o isomers (erythro. w = +9.2 ; threo, w = +8.9). The large values of w implicate water molecules in the transition state of ring opening. The fact that the slopes are about equal suggests that the same number of water molecules are involved in the transition state for each isomer. A plot of the log of the rate constants for ring opening of the tv/o isomers at 15° vs. the Hammett acidity function, H^, is shown in Figure 6 . The plots are markedly nonlinear. It is well established that a linear dependence of log k V8, H^ is observed for acid-catalyzed reactions in which the transition state differs from the reactant by a single proton (89). If the transition state differs from the reactant by a proton as well as a solvent molecule, a nonlinear relationship is obtained. The nonlinear 114

Figure 5

Plots of log vs. log for ring opening of the 2-styryloxazolidines in hydrochloric acid solutions at 15 ^ 1 1 5

erythro threo

c Ê

O o

-LOG a 1 1 6

Figure 6

Plots of log k^i3g vs. for ring opening of the 2-styryloxazolidines in hydrochloric acid solutions at 15*^ 1 1 7

I

threo

0

LO _Q O erythro CD O 2

3 2 0

- h : 118 relationship observed for the ring opening of the oxazolidines supports the participation of water molecules in the transition state complex. The radius of the solvated lithium ion approximates that of the solvated proton. The effect of replacing protons with lithium ions is that an approximately constant water activity is maintained while permitting a variation of the acidity of the medium. The rate constants for the hydrolysis of the erythro isomer in various solutions containing both HCl and LiCl concentrations so that the activity of water is approximately constant are reported in Table 16, In the presence of a twenty-fivefold variation

Table 16

Rate Constants for Ring Opening of erythro- 2-Styryï-3,4— dimethyl-5-phenyloxazolidine (II) in Aqueous Solutions of HCl - LiCl at 30^

Solution Composition ^obs

0,50 M HCl 0.52 0.2 M HCl - 0.3 M LiCl 0.52 0.1 M HCl - 0,4 M LiCl 0.55 0.05 M HCl - 0,45 M LiCl 0,56 0,02 M HCl - 0.48 M LiCl 0.62 119 in the concentration of acid, the observed rate constants remain essentially the same. Clearly, the rate of the ring opening reaction in acid solutions depends upon the activity of water in these solutions. The rate constants for ring opening of the isomers in DgO and HgO solutions are shown in Table 1?, The reaction takes place more slov/ly in a DCl/D^O solution having approximately the same acid strength as an HGl/H^O solution. This observation also supports the participation of the solvent in the transition state. The relative rates of ring opening of the erythro isomer in the two solvent systems, ^DCl/^HCl ~ 0*28, is identical with that determined for the

Table 1?

Rate Constants for Ring Opening of the 2-Styryl- 3,^~dimethyl~5-phenyloxazol'idines (II and XII) In PCI and HGl Solutions at 17^

HCl.M PCI,M erythro threo 5.64 0.022 0.098

5.64 0.0062 0.028

0,056 0.29 a

0.056 0.060 1.97

^ Reaction proceeds rapidly. 120 threo isomer, = 0.29. The solvent is considered to participate to the same extent in the hydrolytic ring opening of each isomer.

d. Kinetics in Buffer Solutions, pH 3.0 - 7.0

In pH 4.0 - 7.0 solutions, oxazolidine was not detected immediately following solution preparation. An intense absorption due to the immonium ion intermediate was observed which decreased with time as the aldehyde formed. The rate constants for the hydrolysis of the immonium ions from II and XII in various buffer solutions pH 3*0 to pH 7.0 at 30^ are listed in Table 18. Immonium ion hydrolysis is strongly catalyzed by buffer in the acetate and phosphate buffer solutions. In Figure 7 are shown plots of the apparent first-order rate constants vs. the total concentration of acetate for the hydrolysis of the immonium ions from II and XII at pH 4 and pH 5» Catalysis by phosphate buffer at pH 6 and pH 7 is shown in Figure 8 , As the pH increases, the slopes of these plots increase suggesting more effective catalysis by the conjugate base of the buffer. The slopes of these plots were determined by the method of least squares. Extrapolation of these plots to zero buffer concentration eliminates the catalytic effect of the buffer components (Table I9). A log k - pH profile for immonium ion hydrolysis was constructed from the extrapolated intercept 121 Table 18

Rate Constants for the Hydrolysis of 2-Styryl-3,4' dimethyl-5~pbenyloxazolidines (II and XIl) in Buffer Solutions, pH 3.0 to 7.0 at 30°, ^ =0.15

-1

Buffer £H Cone,,M erythro threo

Citrate 3.0 0.005 0.0017 0.0015 0.01 0.0020 0.0016 0.02 0.0024 0.0020

0.05 0.0053 0.0025 Acetate 4.0 0.005 0.0028 0.0025

0.01 0.0032 0.0027 0.02 0.0040 0.0031 0.05 0.0052 0.0038

Acetate 5.0 0.005 0.0065 0.0056

0.01 0.0075 0.0059

0.02 0.0088 0.0073 0.05 0.011 0.0090

Phosphate 6.0 0.005 0.031 0.030

0.01 0.035 0.032

0.02 0.037 0.032 0.05 0.046 0.038 Phosphate 7.0 0.005 0.252 0.222

0.01 0.270 0.229

0.02 0.287 0.234

0.05 0.346 0.279 122

Figure 7

Plots of rate constants for the hydrolysis of 2-styryl-3»^-dimethyl-5-phenyloxazolidines at pH 4 and pH 5 as a function of acetate buffer concentration at 30°, 1% dioxane. Reactions monitored at 33^ nm 123

erythro pH 5

O X threo

c Ë erythro _Q pH 4 o

threo

0.02 0.04 0.0 6 [M] TOTAL ACETATE 124

Figure 8

Plots of rate constants for the hydrolysis of 2-styryl-3f^-diniethyl-5-phenyloxazolidines at pH 6 and pH 7 as a function of phosphate buffer concentration at 30*^, 1% dioxane. Reactions monitored at 33^ nm 125

c Ë e ry thro 10 threo -Q o

O"

.0/ .02 .03 .04 .05 [M] TOTAL PHOSPHATE 126 values (Table 19) and the first-order rate constants for intermediate hydrolysis in acid solutions (Table 13) and is shown in Figure 9 . A short pH-independent region is seen from pH 2 to 3» At values above pH 4 the rate increases markedly v/ith an increase in pH, which is consistent v/ith hydroxide ion catalysis. As the pH decreases below 2, a decrease in rate is observed which suggests that the reaction intermediate which decomposes to form the product is decreased in concentration as the hydronium ion concentration increases.

Table 19

Rate Constants for Hydrolysis of 2-Styryl-3,4- dimethyl-5~phenyloxazoiidines (II and XII) at 30°

. . -1 ^

pH erythro threo

3.00 0.0011 0.0014

4,00 0.0027 0.0024

5.00 0.0064 0.0053

6.00 0.031 0.029 7.00 0.246 0.214

Hydrolysis of the intermediate monitored at both 290 nra and 336 nm. Extrapolated to zero buffer concentration, fJ.= 0.15. 127

Figure 9

Plot of log vs. pH for the 2-styryl- 3,4-dimethyl-5-phenyloxazolidines from 6 M HCl to pH 7 at 30° 128

o X

T -I C E

(j) n o -2 O oÜ X 0

6 S -3 o erythro X threo

o - 4 X

j ------1------1------1------1------1_ ■10 123^567 P H 129 Rate Dependency on Temperature - Concentrated Acid Solutions

Arrhenius plots of the log of the observed rate constants for the ring opening reaction in 6.35 M HCl are shown in Figure 10 for the erythro isomer and in Figure 11 for the threo isomer. Activation parameters were calculated from the plots and the values of A H* and A S* are included in Table 20 . The entropies and enthalpies of activation for ring opening for the isomers are similar. Although the entropies of activation are not as negative as is often associated with reactions involving attack of solvent on protonated substrates, they are more nearly in accord with a reaction involving solvent participation than

Table 20

Activation Parameters for Ring Opening of 2-Styryl-3,4-dimethyl-5-phenyloxazolïdines (II and XII) in 6.36 M HGl

A h ^ A s ^ Compound kcal/mole kcal/mole en.

II 17.1 16.5 -8.3 XII 16.6 16.0 -7.6

^ Estimated error is - 1.0 kcal/mole. ^ Calculated at 30°. Rate constants have the units sec.“^ 130

Figure 10

Plots of log vs. l/T for ring opening of erythro-2-styryl-3.4-dimethyl-5-phenyl- oxazolidine in 6.35 M HCl - LOG kobs ^ ^

CN

O Co X Co

H m Z T)m XI > c mX o 7 ; Co

wH* 132

Figure 11

Plots of log vs, 1/T for ring opening of threo-2~styryl-3,4"diinethyl-5~phenyl- oxazolidine in 6.35 M HCl LOG kobs iTti nV I CD CN tNj rv) o u> X m— 1 2 nTl

c m o 7; Co I Co

U)VjO 134 with a uniraolecular reaction.

f . Kinetics in Alkaline Solutions

Above pH 7 at 30°, the rates of immonium ion hydrolysis proceed too rapidly to obtain reliable kinetic data. To extend the data beyond pH 7, the temperature was decreased.

Table 21

Rate Constants for the Hydrolysis of the 2-Styryl-3,^-dimethyl-$-phenyloxazolidines (II and XÏÏ) at 17^

a, c -1 obs min.

pH erythro threo

5.00 0.0020 0.0017

6,00 0.0052 0.0055 7.00 0.048 0.046 7.50 0.126 0.104

8.00 0.360 0.170

9.00 0.51 0.21

10.00 1.07 0.27 ^

Hydrolysis monitored at 256 , 290, and 336 nm.

Hydrolysis monitored at 256 and 290 nm.

Extrapolated to zero buffer concentration, jJi = 0.I5 , 135 The decrease was from 30° to 17°, Rate constants were determined in buffers from pH 5 to pH 10 (Figs, 12 and 13)» The rate constants for the hydrolysis of the isomers obtained by extrapolation to zero buffer concentration are shown in Table 21, A plot of the log of these extrapolated rate constants vs, pH is shown in Figure 14, The log k - pH rate profile for the isomers is seen to be the same for both isomers in the pH range 5 to 7, At pH values greater than 7, the erythro isomer appears to hydrolyze more rapidly. From pH 5 through pH 7 the kinetics reflect decomposition of immonium ion (335 nm) and simultaneous

formation of cinnamaldéhyde (290 nm) at the same observed rates. At pH 7,5 the erythro isomer (II) maintains this behavior, but the threo isomer (XII) shows oxazolidine absorbing at 254 nm and decomposing at the same rate as the immonium ion and at a rate equal to the formation of aldehyde. Extrapolation of kinetic plots to zero time shows that the immonium ion is decreased in initial absorbance by about 35^. At pH 8,0 and above, the presence of oxazolidine in solutions of both isomers at zero time is observed. The fraction of the oxazolidines present as immonium ion in various buffers at zero time is shown in Table 22. Increasing the dioxane concentration for kinetic runs in effect decreases the hydrogen ion concentration, and, as above, decreases the percentage of immonium ion present. Using pH 9 borate buffer 0,005 M at 1^ dioxane concentration 136

Figure 12

Plots of rate constants for the hydrolysis of 2-styryl-3,4-dimethyl-^-phenyloxazolidines at pH 7, 7.5I and 8 as a function of phosphate buffer concentration at 17°, 1^ dioxane. Reactions monitored at 336 nm 137

° erythro " t h r e e

p H 3

E if) _o o

pH 7, 5 o-

o - X -

■OS .06 TOTAL PHOSPHATE 138

Figure 13

Plots of rate constants for the hydrolysis of 2-styryl-3,4-dimethyl-3-phenyloxazolidines at pH 9 and 10 as a function of borate buffer concentration at 17°, 1^ dioxane. Reactions monitored at 336 nm 139 ° erythro « threo

A3 A2 pH 10 A/; AO .9

T .6 c pH 9 .7 Ë •6 CO JD .5' O .4- pH 10 .3 * = Z L ,2- p H 9 ./•

______L. ______L. 0 .04 .06 .06

[M] TOTAL BORATE 140

Figure 14

Plots of log v^. pH for the 2-styryl- 3,4-dimethyl-5-phenyloxazolidines from pH 5 to pH 10 at 17° -/ LOG kobs min

1 Co rV) O --- %— I -

cn X O

0\

*M "O % X o X O CP CD =T -1 -1 K VO CD <~f- O o

-{=• 142 Table 22

Fraction of the 2-Styrvl-3,4-dimethyl-5- phen.vloxazolidines (II and Xll) present as Immonium Ion in Various Buffers at Zero Time at a Fraction Imrnonium Ion pH Buffer II XII 5.0 malonate 1.0 1.0

6,0 malonate 1.0 1.0 7.0 phosphate 1.0 1.0 7.5 phosphate 1.0 0,65

8,0 phosphate 0.85 0.35 9.0 borate 0.58 0,18

10,0 borate 0.05 0,0

^ Monitored at 256 nm and 336 nm.

(from introduction of stock solution) the immonium ion is present at 58^ of maximum concentration. The same buffer in 6 0^ dioxane yields a measured pH of 11,10, which differs from the actual pH only slightly (90). In this medium no absorbance at 33^ nm is noted (Fig. 15). At 20^ dioxane a small amount of immonium ion is noted (Fig, 16), but much less than is seen in 1^ solutions (Fig, 17). Using compound XXXIV in the same buffer at 60% dioxane concentration, no absorbance at 336 nm is obtained, and the observed rate constants at 256 nm and 290 nm are the same as those from 143

Figure 15

Hydrolysis of erythro-2-styryl~3.4-dimethyl- 5-phenyloxazolidine in pH 9 borate buffer,

0.005 M, 60 ^ dioxane, 25 *^ ABSORBANCE

Cl cr >

en n m CP o Z5 CP c r Q. c r CD Co cg O o d ’ CL n cr (D g (Q3 Cu en en a) CP CD n C o O g 145

Figure 16

Hydrolysis of erythro~2-styryl-3,4-dimethyl- 5-phenyloxazolidine in pH 9 borate buffer,

0.005 M, 20^ dioxane, 25 ° 146 Scans beginning at: a 15 sec. b 60 sec. c 90 sec. d 5 min.

LÜ Uz < CÛ cr O u i CÛ <

260 280 300 320 340 WAVELENGTH (myiil 147

Figure 17

Hydrolysis of erythro-2-styryl-3.4-dimethyl- 5-?phenyloxazolidine in pH 9 borate buffer,

0.005 M, 1% dioxane, 25 ® 148

Scans beginning at: a 10 sec.

ÜJ O z < ÛÛ cr O lO CO <

260 2S0 300 320 340 WAVELENGTH (m//) 14 9 the corresponding oxazolidine (II). Above pH 10, hydrolysis of the isomers in NaOH solutions was studied. The rate constants for the hydrolysis of the isomers in NaOH solutions are reported in Table 23, It is evident that the rate constants are largely insensitive to the NaOH concentration, A plot of the observed rate constants vs. hydroxide ion activity (Fig, 18) clearly shows the very lov/ dependence of the rates of hydrolysis on the hydroxide ion activity. Extrapolation of these plots to zero hydroxide ion activity reveals that there is a very substantial catalysis by v/ater. The extrapolated rate constants for each isomer do not differ greatly from the rate constants determined in pH 10 borate buffer (Table 21 and Fig, 13),

g. Solvent Kinetic Isotope Effects in Alkaline Solutions

Solvent participation in the hydrolysis of the oxazolidines in alkaline solution is apparent from the kinetic data (Table 23), It was anticipated that a significant deuterium isotope effect would be observed in these reactions. The rate constants for ring opening of the isomeric oxazolidines in NaOH/HgO and NaOD/DgO solutions are reported in Table 24, Hydrolysis proceeds much more slowly in the deuterated solvent. The relative rates in the solvent systems, k^^gg and for the two isomers are 150 Table 23

Rate Constants for the Hydrolysis of 2-Styryl-3,4- dimethyl-j-phenyloxazolidines (II and XII) in Alkaline Solution at 17*^

-1

NaOH, M erythro threo 0.01 //= 0.01 1.32 0.30 0.01 jl = 1.01 - 0.37 0.01 // = 0.15 1.32 0.31 0.10 1.44 0.33 0.20 1.55 0.33 0.50 1.90 0.33 1.00 2.7 0.39 5.00 4.2 c 0.10 1.43 ^ 0.33

Solutions contained 1.0^ dioxane. ^ Monitored at 254 nm. ^ Incomplete solubility. ^ Styrylidene-N-methyl-N-[2-(erythro-1-phenyl-1-hydroxy)ythro-l-' propyl ] ammonium perchlorate C XXXIV).' e Immonium ion isolated from XII was used. 151

Figure 18

Plots of OH" activity vs, log for the 2-styryl-3,^-diraethyl-5-phenyloxazolidines in aqueous sodium hydroxide solutions at

17°I 1^ dioxane 152

erythro c/) JQ threo O

0.5

X

. 0 5 .15 153 nearly the same (erythro, 0,6l; threo, 0,64), It would appear that the number of molecules of solvent which are involved in the formation of the transition states for both isomers is the same.

Table 24

Solvent Kinetic Isotope Effect for Rin^^ Opening of the 2-Styryl-3,4~dimethyl~5--phenyloxa2ioiidines (ll"and XII) in Alkaline Solutions Containing 19^ biox'ane at 17*^

-1

Solution Cone, erythro threo

NaOH/HgO 0,076 1.35 0,27 NaOD/DgO 0,076 0,82 0,18

h. Rate Dependency on Temperature - Alkaline Solutions

Arrhenius plots for the hydrolysis of the erythro isomer (II) and the threo isomer (XII) in 0.1 M NaOH are shown in Figures I9 and 20, Activation parameters were calculated from these plots and the values of A H , and As are listed in Table 25 , The A h and As values are approximately the same for both isomers. The 1 5 ^

Figure 19

Plots of log vs. 1/T for erythro-2- styryl-3 » 4-dimethyl-5-phenyloxazolidine in 0.1 M NaOH, 1^ dioxane LOG kobs i^in. '

O

O Co X Co — 1 Co m 2 D m Co > H

o Co

Ca Cn 156

Figure 20

Plot of log vs. l/T for threo-2-styryl- 3»^-dimethyl-5”Phenyloxazolidine in 0,1 M

NaOH, Ifo dioxane LOG kobs min."'

Ôo CN O o Co

X Co m 2 “D Co m > H Co CI %] m

H* Va -O 158 Table 25

Activation Parameters f o r Hydrolysis of 2-Styryl- 3i^~dimethyl-5~Pbenyloxazc)lidines (II and XII) In 0.1 M NaOH Containing Dioxane

E„ A h^ A s^ a , Compound kcal/mole kcal/mole e.u.

II 13.9 13.3 - 19.5 XII 14.6 14.0 - 20.5

^ Estimated error is t 1.0 kcal/mole. ^ Calculated at 17°. Rate constants have the units sec.“^

entropy of activation for the erythro isomer is about the same as that for the threo isomer.

i. Stopped-flow Measurements of the Hydrolysis Reaction in Alkaline Solution

Fast reaction kinetics were utilized to observe the rate of disappearance of perchlorate immonium ion at high pH and to determine whether equilibrium between oxazolidine and immonium ion occurs. The runs were made at ambient temperature using purified dioxane stock solution in one

syringe and 96 ^ dioxane - 4^ 0.1 M NaOH as the hydrolytic medium in the other syringe. The tremendous excess of dioxane was used to reduce the absorbance changes due to the heat of dilution of dioxane. Compounds XXXIV and XXXV were used in this study. Compound XXXIV is capable of 159 existing in equilibrium with a protonated oxazolidine while compound XXXV cannot. The results are summarized in Table 26.

Table 26

Stopped-flow Measurements of Compounds XXXIV and XXXV in 9èfo Dioxane - 2;% O.T M NaOH Mixtures

Compound XXXIV (2^4 and 336 nm) = 1,5 raillisec,^ Compound XXXV (290 and 336 nm) t^ = 600 raillisec,

^ This approaches the instrument's limitj a reaction is shown by absorbance beyond blank runs.

If these results are applicable to oxazolidines, then it appears that ring closure occurs at a much faster rate than intermediate hydrolysis (aldehyde formation) i,e_.,

ki kg A -T B ^ C with k_j > => kg =» > kj^ ^-1

3, Some Oxazolidines from (-)-Ephedrine and Aliphatic Carbonyl Compounds

Unlike the styryl-and phenyl-oxazolidines, the oxazolidines from the aliphatic carbonyl compounds do not possess a chromophore of suitable intensity and separation for use in ultraviolet spectrophotometry. The data in Table 9 indicates that sufficient difference in molecular 160 Table 2?

Hydrolysis of Some Oxazolidines from (_)-Ephedrine and Aliphatic darbonyl Corapounds Using Circular Dichroism Measurements at 25"

a b Compound Wavelength Solution Half-life * 10#

VI 260 nra 60^ methanol 4 hr. W pH 7.5 phosphate buffer 0.02 M

VI 260 nm 0.02 M HCl 9 hr. VIII 260 nm 0.01 M HCl 3 hr. X 259 nm 0.02 M HCl 1 hr.

X 259 nm pH 5 malonate buffer 0.05 M 0

259 nm pH 7.5 phosphate d buffer 0.06 M

^ Concentration 5*0 x 10“^ M. ^ Solutions contain dioxane ® No Further change in rotation after 10 minutes. Reaction was too rapid to be followed with c.d. 161 ellipticities exists between the oxazolidine (e.g., VI or IX) and (-)-ephedrine so that circular dichroism might prove useful as a continuous method for monitoring formation of the amino alcohol. In the case of the threo oxazolidines (e.g., XVI) and (+)-pseudoephedrine, the difference in molecular ellipticities is not as great as in the case of the erythro compounds and it is therefore more difficult to obtain measurable changes in rotation. The spectra were sufficiently noisy and the total change in pen deflection, ca. 3.5 cm., insufficiently large, so that the data is presented in terras of half-lives t 10%, The results are summarized in Table 27.

4. Kinetics of the Hydrolysis of 2.5-Diphenyi-3,4-dimethyloxazolidines

As a comparison to Fife’s study (63 ), selected kinetic runs were made on the phenyloxazolidines of the ephedrines (I and XI), The results are summarized in Table 28, In the case of the phenyloxazolidines from the ephedrines, the rate of ring opening is similar enough to that of subsequent hydrolysis so that the kinetics are not easily separated as in the case of the styryloxazolidines. The intermediates absorb near 280 nm, where the benzaldehyde carbonyl chromophore also absorbs. The main absorption peak of benzaldehyde occurs at ca, 250 nm. Thus, it is not possible to follow either ring opening or immonium ion hydrolysis without interference. 16 2 Table 28

Rate Constants for the Hydrolysis of 2,5"Diphenyl- 3,4-dimethyloxazolidines (I and XI) in Various Buffers Containing I'W Dioxane at 30

Ionic Buffer Cone,,M strength erythro threo

2.0 phosphate 0.005 0.15 0.035 0,135 0,15 0.15 0,047 0,167

3.0 phosphate 0.005 0.15 0,043 0.153 0.15 0.15 0,074 0.26 7.0 phosphate 0.005 0.25 0,099 0,0124 0,20 0,25 0.190 0.021 8.0 phosphate 0,005 0.25 o,o4o - 0.20 0.25 0,062 0.0076

9.0 borate 0.005 0.25 0,034 0.0067

0.20 0.25 0.067 0,0105

10.0 borate 0.005 0.25 0.030 0,0067

0.20 0.25 0.039 0.0075 d HCl 0.01 0.035 ® d HCl 0.01 0.038 ® d,f HCl 0.001 0.042 ®

Ionic strength adjusted witn KCl, Monitored at 245 nm. Concentration 2,0 x 10 -5 M. Concentration of -4 I = 5 ,0 X lO”"^ M. ^Monitored at 280 nm, ^Measured pH after reaction 3.58» 163 Attempts to isolate the intermediate in order to obtain separate kinetics of intermediate hydrolysis have not been successful thus far in that the desired product is extremely hygroscopic and hydrolyzes readily from atmospheric moisture.

5. Comparative Kinetic Characteristics Defining the Hydrolysis of the 2-St.yryl~3.^-dimethyl- 5-phenyloxazolidines

The reaction of the model 2-styryloxazolidines in acidic media has been defined by isolation and identifi­ cation of the final products, isolation of intermediates possessing similar characteristics to synthesized immonium ion perchlorates including the same kinetic behavior (see Tables 13»21| and 23 and Figs. 1,15, and 17 ), and the lack of evidence for other "side" reactions. The ephedrine isolated in the process of identification of the final products of hydrolysis maintained its optical activity. The intermediates isolated accounted for essentially 100 t yfo of the reaction pathway as evidenced by comparison of extrapolated initial absorbances of the oxazolidine with extrapolated initial absorbances of the corresponding isolated immonium ion at equimolar concentrations. The molar absorptivity value for the intermediate, which was obtained using the oxazolidine (II) in pH 6 phosphate buffer (Fig. 4) by extrapolation to zero time, was the same value as obtained using the synthesized 164 immonium ion perchlorate (XXXIV) in the same buffer. If the reaction can be so defined, then information as to a mechanism of the reaction can be sought by monitoring the species known to participate in the reaction. In the case of the 2-styryloxazolidines, the ultraviolet spectra of the oxazolidine, intermediate, and aldehyde are sufficiently separated to allow for monitoring these species by this method. Adherence to Beer's law allows correlation of absorbance with concentration of these species. These particular oxazolidines have the definite advantage of allov/ing monitoring of decomposition of one species and formation of a subsequent, species to give a direct comparison- of the relative rates. Such is not the case in Cleary's study (59) in which he monitored only aldehyde formation.

The linear relationship of log (A.^, - A q q ) and time in hydrolysis of II and XII studies demonstrates pseudo- first order kinetics. In the case of the 2-styryloxazolidines, the intermediates have been characterized as cationic Schiff bases (immonium ions). The evidence for this is sufficient for such an assignment in that the ultraviolet absorption maximum of the compounds is 336 nm, a considerable bathochromic shift from the oxazolidine, which absorbs at

256 nm. The extended conjugation of an immonium ion structure would be similar to that of cinnamaldéhyde. 165 which absorbs at 290 nra, A heraiacetal (from C-N cleavage) would possess a chromophore similar to that of the oxazolidine, A carbinolamine structure as a possible intermediate would not be expected to yield such a shift in the ultraviolet absorption maximum. The equality of the rate constants for intermediate hydrolysis obtained using the 2-styryloxazolidinesf the isolated intermediates, or the synthesized perchlorate immonium ions (XXXIV) also favors immonium ion structure for the intermediates in the hydrolysis of II and XII,

6, Comparative Kinetic Characteristics of Ring Opening of the 2-Styryl-3«4- d ime t hy 1 - 5~phe ny-1 oxazol id ine s^

Fife and Hagopian (63 ) have characterized the hydrol­ ysis of oxazolidines from N-ethylethanolamine and substituted benzaldehydes as consisting of two basic parts 1 (a) ring opening, usually a fast step in acidic media, followed by (b) intermediate hydrolysis, generally rate-determining in acidic media. In concentrated aqueous solutions of strong acid, the rate of ring opening is sufficiently slow for both 2-styryl­ oxazolidines to obtain reliable kinetic data by ultraviolet spectrophotometry. It is noted that the erythro oxazolidine decomposes more slowly than the threo (See Table 13). This behavior was noted by Cleary (59 ) in the hydrolysis of the 2-g-8Ubstituted-phenyl-3,4-dimethyl-5-phenyloxazolidines at 1 6 6

pH 2 ,03. Such behavior precludes a major influence of nonbonded interaction between the phenyl and Cj^ methyl of the oxazolidines. If such an interaction were signi­ ficant in influencing the rate of ring opening, then the erythro isomer, in which the phenyl and methyl have a cis relationship, would be expected to undergo ring opening more rapidly as the strain imposed on the ring by such an interaction would lessen the energy required for bond breaking. The internal acid catalysis suggested by Cleary (62) to explain this difference in rates of ring opening assumed a hemiacetal intermediate, which is not the case for the

2-styryloxazolidines and does not appear to be the case for the 2-phenyloxazolidines either, based on the evidence from

PMR in TFA (Table 8). In contrast to the ring opening reaction of the

2-styryloxazolidines where subsequent hydrolysis of the intermediate is much slower, the 2-phenyloxazolidines undergo ring opening and subsequent hydrolysis at more comparable rates, making the separation 01 the kinetics more difficult, especially as the carbonyl chromophore of the aldehyde and the absorbance maximum of the intermediate nearly coincide. The fact that there exists a measurable difference in rates of aldehyde formation (threo > erythro) for the phenyl compounds (I and XI) up to at least pH 3 results from partially rate-determining ring opening. 167 Evidence for a stable intermediate from the aliphatic oxazolidines has not been obtained as yet. The kinetics followed for these compounds have been the formation of the amino alcohol. From the data in Table 16 the effect of changing the hydrogen ion concentration while maintaining a relatively constant water activity shows that the effect of the proton concentration on ring opening is less than that of water activity. Addition of potassium chloride to 0,01 M HCl results in a reduction of rate of ring opening (the change in pH on addition of the salt is negligible).

As Fife and Hagopian .(63 ) offer considerable evidence for solvent, participation in the ring opening step for the oxazolidines from N-ethylethanolamine and p-substituted benzaldehydes, a possible explanation of the difference in rates between the two styryloxazolidines would involve a difference in the extent of solvent participation during ring opening. Such information could be derived from water activity plots, entropies of activation, and solvent kinetic isotope effects. In all of these parameters there exists no significant difference between the erythro and threo isomers. The water activity plots at 15° have the saime w value (+ 9*8, erythrot + 8,9, threo) even though the actual rate of the threo oxazolidine is about 22 times that of the erythro isomer. The entropies of activation in

6.35 M HCl calculated at 30° differ by only 1 e.u,, which 16 8 is insignificant under the experimental conditions. The solvent kinetic isotope effects are virtually the same in

5.6^ M HCl: erythro, c/^h 0 “ 0.28; threo. ~ 0.29. There is sufficient evidence here for solvent participation, but no evidence to explain the difference in rates between the isomers. From the stereochemistry of these oxazolidines, the

only difference between the two is the configuration at C y Hv-q \H

SEtihro In acid media îiîEÊO Since solvent participation appears to be involved as a proton transfer agent (w > 3.3), then transferring a proton from the nitrogen to the oxygen would involve greater steric interaction with the Cg styryl and 0^ phenyl groups in the case of the erythro isomer, (II). The steric influence of the styryl and phenyl groups is considered the main factor in the slower rate of ring opening of the erythro isomer. Hence, one would expect a rate of ring opening in the absence of the phenyl to be 169 nearly the same as that of the threo isomer if not greater. Comparison of the rates of ring opening of the 2-styryl- 3,4-dimethyl-5~phenyloxazolidines (II and XII) with that of 2-styryl-3»4-dimethyloxazolidine (XXXI) is given in Table 29,

Table 29

Rate Constants for Ring Opening of 2-Styryloxazolidines in 5.p4 M HCl at 17°

Ir • -1 Compound obs.™^^' II 0.022 XII 0.098 XXXI 0.035

The conformations of the oxazolidine rings in the threo and erythro isomers are essentially the same as shown by x-ray analysis (88), It appears that the presence of the phenyl ring acts to enhance the rate over the unsubstituted analogue in the case of the threo isomer, and to retard the rate slightly in the case of the erythro isomer. This clearly implicates other than steric effects on the relative rates of ring opening between the isomers. A synthetic note is appropriate here. As the (t)-2-8tyryl-3,4-dimethyloxazolidine is made from (±)-2-methylaminopropanol-l and cinnamaldéhyde, one would expect two isomers. If the stereoselective mechanism of 170 ring closure is operative, then the configuration of fixes the configuration of C^, thus generating two mirror images which have the same kinetic behavior under the conditions of this study. The assumption that the two isomers are epimers is evidenced by the PMR spectral data which indicates only one isomer is present (mirror images in CDCl^ are not distinguishable by PMR),

CH, CH,

The above two structures are mirror images. It appears that the phenyl must influence the nucleophilicity of the oxygen through its effect on solvation and its inductive effect on the electron density at the oxygen. Solvation per se would be expected to reduce somewhat the nucleophilicity of the oxygen, and thus reduce the tendency for proton acceptance. If the Cg and substituents may be regarded as sterically hindering solvation (as well as solvent-assisted proton transfer), then such hindrance would tend to maintain sufficient 171 nucleophilicity at the oxygen for proton transfer. Removal of the phenyl would allow for greater solvation of the oxygen and loss of inductive effect of tne phenyl to yield a reduced nucleophilicity at the oxygen v/hile allowing steric access to solvent-assisted proton transfer. As the hydrogen ion concentration decreases, the rate of ring opening increases. This behavior is in accord with the findings of Fife and Hagopian (63 }, but in contrast to Cleary's results which showed decreasing rate of hydrolysis with decreasing hydrogen ion concentration, kjj q+ = 8,2 x —1 —1 -.1 3 10” liter mole" min.” (62), Repeating Cleary's experiment using compound -I, a definite increase in rate of hydrolysis was obtained with decreasing hydrogen ion concentration, and in using pH 2 and pH 3 phosphate buffers general base catalysis was noted, which Fife and Hagopian also reported (See Table 28), A mechanism of ring opening proposed by Fife and Hagopian for the hydrolysis of 2-phenyl-3-ethyloxazolidines and hydroxide-catalyzed ring opening of the protonated oxazolidine to yield a cationic Schiff base is shown in Scheme 3» 172 H

À

Scheme 3

An alternate mechanism, attack of hydronium ion on the unprotonated oxazolidine, is kinetically equivalent. General acid catalysis might be expected from this mechanism,

C H j

The general base catalysis reported by Fife and

Hagopian ( 63 ) for the ring opening of 2-£-methoxyphenyl-3- ethyloxazolidine in formate and acetate buffer solutions from pH 2 to 4 was proposed as possible general base catalysis of nitrogen de-protonation in a concerted attack 1 7 3 by (Scheme 4).

OCH

Scheme 4

The p value reported' by Fife and Hagopian for ring opening indicates an acceleration of ring opening by electron-v/ithdrawing para substituents on the phenyl group at Cg. Electron withdrawal would favor proton removal from the oxygen but retard proton transfer to the oxygen. The evidence for extensive solvent involvement as a proton transfer agent, significant kinetic isotope effects for the solvent and slower hydrolysis rate for the erythro isomer (greater steric hindrance in a solvent-assisted proton transfer), favors the protonated oxazolidine (Scheme 3) as the reactive species in acidic media. The fact that substitution of a methyl group for the proton at Cg in 2-phenyl-3-ethyloxazolidine accelerates the rate of ring opening in 3*5 M HCl at 30° effectively 1 7 4 eliminates ring opening directly to carbinolamine by hydroxide attack at Cg (63 ). However, substitution of a methyl group for the proton at Cg in erythro-2-styryl-

3 ,4-dimethyl-5-phenyloxazolidine (II) retards the rate of ring opening in 1 M HCl at 30°»

erythro-2-styryl-3,4-dimethyl-5-phenyloxazolidine koba =0-58 min."I erythro-2-styryl-2 ,3.4-trimethyl-9-phenyloxazolidine

kobs = 0-18 min.-^

Data for ring opening of erythro-2-styryl-3.4-dimethvl-

5 -phenyloxazolidine at 30° fits the rate expression

kobs = 1.35 X 10~* a„ + 2.3 x 10 “ OH" from pH 1 and above. Below pH 1 the experimental values decrease slightly faster than predicted from the rate expression. This change might be due to increased difficulty of nitrogen de-protonation in more concentrated solutions of acid. As water is extensively involved in ring opening, its structure and the degree of solvation of the oxazolidine in concentrated acid solution are not reflected in the change of a^. Hence, the rate expression is not sufficient in explaining a situation in which there are probably more parameters than are included in such a simple treatment. But in the pH region where nitrogen de-protonation by 175 solvent assisted proton transfer is facile, the data fits the expression satisfactorily. The expression predicts a rate constant of 23 rain.“^ at pH 4 and 30°, which is too fast to measure by normal spectrophotoraetric methods. The experimental results show that the reaction is complete within 15 seconds at pH 4, Fife and Hagopian (63 ) report the same bahavior for 2-£-methoxyphenyl-3-ethyloxazolidine.

7 . Comparative Kinetic Characteristics of the Hydrolysis of the Intermediates from 2-Styryl- 3,4-diTnethyl-5~phenyioxazolidines from 6 M î-icT to pH 7

Subsequent to ring opening of the styryloxazolidines in acid is a slow decomposition to aldehyde (Table 13). The ratio of the rates of ring opening to subsequent hydrolysis in acid is such that they may be considered as two separate reactions under these conditions. Examination of intermediate hydrolysis shows pseudo- first order kinetics. The rate of intermediate decomposition followed at 336 nm is the same as that of aldehyde formation followed at 290 nm. Although not directly monitored, the ephedrine isolated from the products of hydrolysis is identical to the starting amino alcohol. The rate of intermediate hydrolysis is the same whether an oxazolidine is used, an isolated cation Schiff base hydrochloride, or a synthesized perchlorate immonium ion. The effect of the anion is negligible (Table I3 ), 17 6 Likewise, C-N bond breaking to form a hemiacetal should also proceed if the nitrogen is quaternized»

OH" OH Q / , r " 0 - C

Ring closure must occur immediately when the immonium ion is placed in alkaline solution, followed by a rapid but measurable hydrolysis to aldehyde. The stopped-flow measurements indicate that the rate of hydrolysis of intermediate in alkaline solution i 98fo dioxane - 2^ 0,1 M NaOH) is much slower than the rate of ring closure (Table

2 6 ), if it can be assumed that the rate of hydrolysis of the desoxy analogue (XXXV) reflects the actual rate of immonium ion hydrolysis when the intermediate species is present at very low steady-state concentrations after ring closure to oxazolidine. If the reaction proceeds through the immonium ion, the decomposition of the immonium ion would not be rate- determining as hydroxide ion is expected to catalyze the decomposition of such species. The observed reaction in the hydrolysis of the 2-styryloxazolidines, (II and XII), is ring opening. The observed general acid catalysis (Pig, 13) 1 7 7 R R B'~* H—0~C—N—R BH + 0=C + N—R ^ A

In the case of a strong base, the electron pair on the neutral oxygen does not provide sufficient driving force to expel a strongly basic amine (or amino alcohol) (91). In this hypothesis of rate-determining carbinolamine decomposition, it must be assumed that the ultraviolet spectral characteristics are the same as those of the immonium ion, since no other absorption band except that at 336 nm appears in acidic media. Replacement of the Cg proton on the erythro-2-styryl- 3,4-dimethyl-3-phenyloxazolidine, II, with a methyl yields an oxazolidine which hydrolyzes in pH 7.5 phosphate buffer about twenty times more slowly than the oxazolidine from cinnamaldéhyde at 30*^. The inductive effect of the methyl together with its steric hindrance would retard nucleophilic attack on the immonium ion. The same general behavior is noted for the aliphatic oxazolidines in monitoring formation of (-)-ephedrine by circular dichroism (Table 27). The cyclohexanone oxazolidine hydrolyzes about ten times as slowly as the formaldehyde oxazolidine in dilute hydrochloric acid. 17 8

In contrast to ring opening, the hydrolysis o f the compounds II and XII occurs at nearly the same rate in going from concentrated HCl to pH 7 (Table 13). The reaction site for hydrolysis is probably the carbonium carbon which is well removed from the benzyl alcohol carbon, where the two diastereoisomers differ in configuration. Site for nucleophilic attack

I ■ " f+ V O H

The rate of intermediate hydrolysis increases with decreasing hydrogen ion concentration, and general base catalysis is observed for acetate and phosphate buffers

(Figures 7 and 8), The entropies of activation were sufficiently negative to indicate solvent participation. From the pH rate profile constructed for intermediate hydrolysis, there is a region of near linear dependence of rate on OH” from 2.5 M HCl to 0.1 M HCl, Between pH 2 and 179 pH 4 the rate becomes nearly pH independent, and above pH 5 the rate again approaches a linear dependence on OH", Fife's data on the hydrolysis of 2-phenyl-3-ethyl- oxazolidine also showed similar behavior. In going from 5 M HCl to 0,1 M HCl the rate increased with decreasing hydrogen ion concentration, and an area of pH independence was noted from pH 1 to pH Electron withdrawing substituents accelerated the rate of hydrolysis under these conditions ( p = + 0,5). Water activity plots yielded w s= + 7,1, and negative salt effects were observed. The entropies of activation were - 8,6 e.u, at 2,37 M HCl and - 9.6 e.u. at 5.74 M HCl, The reaction here does not involve oxazolidines but cationic Schiff bases which cannot exist in a de-protonated state. Above pH 2 ring opening even for compound II is complete before the first kinetic measurements are made at 30°. It appears that general base catalysis is observed for the hydrolysis of I and XI in the region pH 2 to 3 with increasing rate as the hydrogen ion concentration decreases (Table 28), The rates of aldehyde formation for these compounds are not equivalent as in the case of the styryl­ oxazolidines, It is likely that this results from the ring opening being partially rate-determining. Earlier works on the hydrolysis of Schiff bases by Cordes and Jencks (92,93 ) and Koehler, et al,, (94) offer 180 some insight as to a possible mechanism of hydrolysis. In the hydrolysis of and _m- substituted benzylidene- 1,1-dimethylethylaraines a pH rate profile, which is quite similar to that of the styryloxazolidine hydrolysis, is noted for some of the Schiff bases. At low pH (0 to 4) a linear dependence of rate on OH” is noted. The authors interpret this as rate-determining decomposition of carbinolamine,

\ ^ /C = N —R + H^O ^ H O - C - N - R

LJ I ,V slow / 0 -Ç —N—R ^---- 0=C » H^NR H

Pronounced substituent effects are noted from the pre­ equilibrium addition of water. From pH ^ to pH 5 (pH independent region) there is a change in the rate-determining step from decomposition of carbinolamine to water attack of the protonated Schiff base. General base catalysis is observed here,

V " " ® OH \ *1 / I / + C=N <-^C-N -C-N + B-H H H ' 181

A kinetically equivalent mechanism is not possible here as OH H HO'^C—N— T——C~~N + A / I \ the Schiff base exists only in protonated form. As the pK values of the Schiff bases are approached,the mechanism changes from water attack to hydroxide ion attack of the protonated Schiff base. This was shown by the linear increase in rate with OH" above pH 7 in the case of benzhy- drylidenemethylammonium ion, which can exist only as a cationic species. General base catalysis is also observed in this case. The immonium ions from II and XII do not show any region of rate-determining decomposition of carbinolamine from water attack as decomposition of the 336 nm species occurs at the same rate as aldehyde formation, even in concentrated acid. The general base catalysis observed would parallel the mechanism proposed by Cordes and Jencks for protonated Schiff bases. "B OH —N—C + -,— -N-C— ^ CHj CM, CH3

H O " 9 -N-C— aA — NH + C I I I / \ CHj CH3 182 Although the rate of hydrolysis in concentrated acid approximately correlates to the decrease in H (or increase in OH") the increase in water activity also fits the data. Substituent effects in Fife’s study in the region of pH 1 to pH 3 are diminished, which favors water attack rather than hydroxide. From pH 4 to pH 7 the mechanism changes from water attack to hydroxide ion attack. The hydrolysis of the intermediate should follow closely the behavior of Schiff bases in acid solution* a change from rate-determining water or hydroxide attack on the immonium ion in alkaline and neutral media to rate- determining carbinolamine decomposition in acidic media. A rate expression involving only water and hydroxide ion fits the data reasonably well from pH 2 and above *

k = 5.2 X 10"-^ + 2.4 X 10 ^ OH"

Possible partial ring closure is eliminated by comparing the behavior of compound XXXV (the desoxy analogue) in 0.01 M, 0.001 M, and 0.0001 M HCl (Table 14). Although the actual rate of intermediate hydrolysis is more than an order of magnitude slower than the rate for the oxazolidine (II), its pattern of rate increase matches that of the oxazolidine. For a hundredfold increase in OH", a twofold increase in rate results. In this region there is obviously no change in water activity. This behavior might indicate a species different from 183 the immonium ion is involved in the kinetics. Assuming that C-0 bond breaking is occurring, a possibility would be a carbinolamine, as suggested from previous studies on Schiff base hydrolysis. The transition to partially rate-determining carbinol­ amine decomposition would occur in the region below pH 2 to allow for a decreasing rate with decreasing pH, if such a mechanism is operative. From Fife's data on intermediate hydrolysis, there appears to be a pH independent region from 1 to 3» In such cases the transition from water or hydroxide attack of the cationic Schiff base to carbinolamine decomposition would occur at a lower pH than the analogous transition for the ephedrine oxazolidines (91*95-98 ). General base catalysis would be expected for rate- determining nucleophilic attack on the immonium ion. For rate-determining carbinolamine decomposition, no effect of added bases or acids would be expected in cases involving the release of strong bases, e.g., ethanolamine. Hence, the general base catalysis observed in the 2-£-methoxyphenyl-3- ethyloxazolidine would be the partially rate-determining nucleophilic attack on the immonium ion, and the general base catalysis observed in the case of the styryl­ oxazolidines from the ephedrines might be interpreted as general base catalysis of that step. 184 Ring opening becomes rate-determining over the range pH 7 .5 to 10 for the styryloxazolidines from the ephedrines. For the phenyloxazolidines from the ephedrines, the change to rate-determining ring opening occurs at lower pH values. This is characterized by the appearance of general acid catalysis and decreasing rate with increasing pH for the phenyloxazolidines from the ephedrines. The decreasing rate with pH would indicate rate-determining water or hydroxide attack on the protonated oxazolidine for the phenyl­ oxazolidines from the ephedrines (I and XI). For the styryloxazolidines, general acid catalysis is noted, but the rate increases slowly with pH. This may be due to the change in rate-determining step occurring well above the pK value for the oxazolidines in the case of the styryl­ oxazolidines, and below or very near the pK value (9 9) for the phenyloxazolidines. An indication of this behavior may be found in the ratio of rates of ring opening to intermediate hydrolysis in the styryl- and phenyl­ oxazolidines. From 6 M HCl to pH 3 the ratio ranges from

10,00011 to 800:1 for the styryloxazolidines from the ephedrines, and from 6 M HCl to 1 M HCl the ratio ranges from ca. 100:1 to 40:1 for the phenyloxazolidines from N-ethylethanolamine, It appears that the extended conjugation of the styryl intermediates gives them additional stability over the corresponding phenyl intermediates. The stability of the styryl intermediates 185 makes their hydrolysis the rate-determining step of the overall reaction over much of the pH rate profile. Since there is no spectral evidence for the immonium ion intermediate in alkaline solution during the hydrolysis of II and XII, it is of interest to attempt to establish evidence for a reasonable mechanism under these conditions. By methylating the nitrogen of compounds II and XII with methyl iodide to form the methiodide salts, one obtains compounds which do not hydrolyze to any appreciable extent in 0.1 M NaOH at 30°.

\

XXXVI CH3 CH3

If the ring opening mechanism were hydroxide ion attack to form a carbinolamine directly, then such méthylation would not hinder the reaction.

OH • 0 ‘ — c- Y OH

CH, 186 It appears that steric hindrance at Cg is more important for stability than conjugation in the immonium ion, assuming that the aliphatic oxazolidines undergo the same mechanism of hydrolysis as the 2-phenyl- and 2-styryl- oxazolidines.

8, Comparative Kinetic Characteristics of the Hydrolysis of the 2-Styryl-3,4-dimethyl-5- phenyloxazolidine in Alkaline Media

Figure 14 shov/s the continuation of the pH rate profile for the 2-styryloxazolidines beyond pH 7 at 17°. To pH 7 the rates of hydrolysis of the two isomers are essentially the same. Above pH 7 the rates of aldehyde formation are significantly different for the two isomers. The erythro isomer hydrolyzes about three times as fast as the three. Continuing to solutions of NaOH (Fig. 18) the rate for aldehyde formation for the threo isomer is pH independent above 12, and nearly so for the erythro isomer. The most outstanding change in the region pH 7.5 to 10 is the appearance of a species in the ultraviolet spectra which absorbs at the same wavelength as the oxazolidine. and has the same spectral pattern as the oxazolidine. The reaction shows increasing sign of oxazolidine and decreasing sign of immonium ion as the pH or dioxane con­ centration is increased.(Figs. 15-17). Rate of hydrolysis of immonium ion equals that of the oxazolidine: e,, when both species exist simultaneously im measurable 1 8 7 quantities, they display the same kinetics of degradation (which also parallels aldehyde formation)• The threo isomer possesses a greater percentage of oxazolidine than the erythro isomer over the pH range 7,5 to 10, which may reflect the greater ease of ring closure in the case of the threo isomer. When the synthesized per­ chlorate immonium ions are used instead of the oxazolidines, the same behavior is obtained. See Table 22 and Figure 16. General base catalysis occurs up to pH 8. In borate buffers at pH 9 and 10 there appears to be slight general acid catalysis (Figures 12 and 13). Fife also noted a change in catalysis from general base to general acid as the pH increased. However, this change over occurs at a lower pH (pH 7 or perhaps lower), and the rate of hydrolysis decreases with increasing pH from pH 7 to 10. Furthermore, substituent effects in sodium hydroxide solutions yield a negative p value (-1.1) indicating that electron withdrawal hinders the reaction, possibly by making C-0 bond breaking more difficult. From the data in Table 28, the rate of hydrolysis of I and XI decrease as the pH increases from 7 to 10. General acid catalysis is indicated in this region for these compounds. As in the case of the styryloxazolidines, the erythro isomer (I) hydrolyzes faster than the threo, (XI), The styryloxazolidines from the ephedrines show increasing pH in this region. 188 would not favor rate-determining immonium ion decomposition. Ring opening and parallel aldehyde formation are also the only reactions observed when the synthesized perchlorate immonium ion is used (XXXIV). The fact that compound II hydrolyzes faster in alkaline media than compound XII might also implicate methyl - phenyl nonbonded interaction during rate-determining ring opening. If the methyl is replaced by a phenyl to obtain compound XXX, excluding electronic effects of the phenyl, the bulkier phenyl group would lead to a greater ring strain and ease of ring opening, if such nonbonded interactions are important in ring opening. The results in pH 9 borate buffer, 30° (3^^ dioxane used because of solubility limitations) preclude any such interaction influencing the rate of hydrolysis. In fact, the addition of the phenyl group retards the reaction (k^^ = 0.68 min."^; ^XXX “ O.O3 min.. - 1 ).\ The fact that the erythro-2-st.vryloxazolidine. (II), hydrolyzes faster than the threo isomer, (XII), would seem to indicate that proton transfer via solvent molecules is not as important in alkaline media as in acidic media. Since proton transfer is no longer important in solutions of sodium hydroxide, and the oxygen of the erythro isomer, (II), is sterically more accessible to protonation either by water or hydronium ion, this isomer hydrolyzes faster than the threo isomer, (XII). Water or hydroxide attack on the 189

protonated species would require removal of the nitrogen proton to effect ring opening to a cationic Schiff base. The gradual increase in rate in increasingly concentrated sodium hydroxide solutions for the erythro isomer is not explained, A pH-independent rate, as in the case of the threo isomer, would be expected. Although hydroxide ion attack is the mechanism of hydrolysis of protonated Schiff bases at high pH, the reaction observed in the hydrolysis of the 2-styryl­ oxazolidines is not immonium ion decomposition, but rather ring opening, A significant mechanism in the hydrolysis of the styryloxazolidines in alkaline solutions appears to be water attack on the oxazolidine, as extrapolation to zero OH" leaves a large residual reaction (Fig, 18), Water involvement in the hydrolysis is indicated by the substantially negative entropies of activation in 0,1 M NaOH. The overall scheme of hydrolysis in alkaline media remains the same as that in acid except for a change in the rate-determining step from decomposition of immonium ion to ring opening. SUMMARY

1. Oxazolidines derived from the ephedrines were synthesized and characterized.

2. Oxazolidines from the norephedrines may exist as oxazolidines, Schiff bases, or mixtures of the two tautoraers. Several factors influencing the equilibrium were discussed,

3. Stereoselective ring closure was deduced from PMR spectral data for oxazolidines from condensation of the ephedrines with aldehydes. Requirements for the stereoselectivity were discussed and a mechanism of ring closure proposed.

4. Absolute configuration of the oxazolidines from the ephedrines was deduced from IR and PMR spectral data and confirmed for oxazolidines from the ephedrines and aromatic aldehydes by x-ray diffraction analysis.

5. Intermediates in the hydrolysis of the 2-styryl-3,4- diraethyl-5-phenyloxazolidines were isolated and characterized. Analogous immonium ion compounds were synthesized.

190 191 6. Some aspects of the hydrolysis of 2-styryl-3,4- dimethyl-5-phenyloxazolidines, 2,5-diphenyl-3»^- diraethyloxazolidines, and some oxazolidines from (-)-ephedrine and various aliphatic carbonyl compounds were characterized by kinetic methods.

7. Mechanisms for the hydrolysis of the 2-styryl-3,4- dimethyl-5-phenyloxazolidines were proposed. 192 Oxazolidines as Pro-Drugs

It is readily apparent that the model compounds studied, the 2-styryl-3,4-dimethyl-5-phenyloxazolidines, are not sufficiently stable for pro-drug use. Furthermore, all such oxazolidines which undergo rapid ring opening to an immonium ion would be unsatisfactory for such use. In acid media, ring opening is essentially irreversible in that the equilibrium lies exclusively in favor of the immonium ion species. Since the immonium ion exists only in protonated form, it cannot be absorbed and is, therefore, not useful as a pro-drug. However, as a sustained-release form it invites further investigation. The oxazolidines from the aliphatic carbonyl compounds and the ephedrines appear to form protonated oxazolidines which are stable in acid solutions and apparently do not readily form immonium ions. This behavior parallels the ring-chain tautomerism exhibited by noroxazolidines in that the aliphatic noroxazolidines exist exclusively in the ring form. If the protonated oxazolidine is stable, then the possibility exists that the pro-drug may be absorbed in the gastro-intestinal tract as the unprotonated oxazolidine as the pH increases. The stability towards hydrolysis of the oxazolidines from the ephedrines and aliphatic carbonyl compounds requires further investigation. REFERENCES

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