PHOTOCHEMICAL ISOMERIZATION AND STEREOSELECTIVE THERMAL CYCLOADDITION REACTIONS OF CONJUGATED NITRONES

Olga Katkova

A Thesis

Submitted to the Graduate College of Bowling Green State University in partial fulfillment of requirements for the degree of

MASTER OF SCIENCE

December 2005

Committee:

Thomas Kinstle, Advisor

Felix Castellano

David Newman

ii

ABSTRACT

Thomas Kinstle, Advisor

Nitrones have been known for some time as quite versatile intermediates in organic

synthesis. They have been employed for stereoselective formation of synthetically useful

isoxazolidines by their 1,3-dipolar cycloaddition reactions with alkenes. We have further

investigated the behavior of some non-conjugated and conjugated nitrones in cycloaddition

reactions. Several α-conjugated nitrones were synthesized and characterized. New reactions with

electron-rich butylvinylethers were studied. All the synthesized nitrones were shown to undergo

1,3 dipolar cycloaddition with formation of 4- and 5-substituted isoxazolidines. We successfully

synthesized a trans-chelating tridentate ligand (R,R)-4,6-dibenzofurandiyl-2,2’-bis(4-

phenyloxazoline) (DBFOX/Ph) and converted it to the cationic aqua complex

Ni(ClO4)2*PhDBFOX. This complex was previously described by Kanemasa47 as the most

selective chiral catalyst for the normal electron-demand 1,3-dipolar cycloaddition reaction

between nitrones and alkenes. We studied the effect of this catalyst on reactivity of α−phenyl-N-

benzylnitrone and α-styryl-N-benzylnitrone.

A separate study of the photolysis of these non-conjugated and conjugated nitrones

proved the formation of oxaziridines. The structure of these 3-membered ring nitrone isomers

was established by NMR analysis. Oxidation of oxaziridines with peroxides was briefly

investigated.

iii

This work is dedicated to my family, close friends and everyone who supported me and

believed in my capabilities. I am eternally grateful.

iv

ACKNOWLEDGMENTS

Before introducing the findings of my research, I would like to express my gratitude and

appreciation to Bowling Green State University for the priceless opportunity to pursue my

Master's degree in the United States of America. The experience I have gained for the two years I

have spent at the University while communicating with bright, knowledgeable and professional

people was helpful and incomparable to any other experiences. I would like to express my

sincere thanks to the members of the faculty and staff at Bowling Green State University for their

encouragement and especially their friendship. I am grateful to my committee members Dr. Felix

Castellano and Dr. David Newman. I appreciate the assistance of Dr. J. Romanowicz in

acquiring spectroscopic data. I am thankful to all my colleagues and friends for their

encouragement and help during my research work. Special thanks goes to Grigori Karpov.

Especially, I would also like to thank Dr. Thomas Kinstle for his wisdom and patience

while being my academic advisor for those two years and for helping in writing this thesis.

Thank you for leading me to the understanding of the importance and depth of Chemistry as a

practical and hard science.

v

TABLE OF CONTENTS Page

INTRODUCTION………………………………………………………………………………1

Synthetic methods for producing nitrones………………………………………………………2

Properties of nitrones……………………………………………………………………………4

Reactions of nitrones……………………………………………………………………………6

1. 1,3-Dipolar cycloaddition reactions……………………………………...………………..6

1.1 Frontier Molecular Orbital interactions………………………………...…………………7

1.2 The Selectivities of 1,3-dipolar cycloaddition reactions……………..……….…………10

1.2.1 Stereoselectivity………………………………...……………………………………11

1.2.2 Regioselectivity…………...………………………………………………………….13

1.3 Chiral Lewis acid catalyst………………………………………………………...….14

2. Photolysis of nitrones………………………………………………………………...18

RESULT AND DISCUSSION……………………………………...…………………………...22

1. Synthesis of nitrone………………………………………………………………………22

2. Photochemical reactions…………………...…………………………………………….27

3. Oxidation reactions of oxiziridines………………………………………………………31

4. 1,3-Cycloaddition reactions…………………...…………………………………………33

CONCLUSIONS…………………………………………...……………………………………43

SUGGESTION FOR FUTURE RESEARCH…………………………………………………...44

EXPERIMENTAL……………………………………………………………………………….45

General procedures………………………………………………………………………………45

Synthetic procedures……………………………………………………………………………..45

Preparation of N-phenylhydroxylamine(20)………………………………………...…...45

vi

Preparation of α-styryl-N-phenylnitrone(21)…………………………………...……….46

Preparation of 2-methyl-2-nitropropane(22)……………………………………………..46

Preparation of N-t-butylhydroxylamine(23)………………………………..……………47

Preparation of α-styryl-N-t-butylnitrone(24)…………………………………………….48

Preparation of N, N-dibenzylhydroxyamine(25)……………………………...…………49

Preparation of α-phenyl-N-benzylnitrone.(26) Method A………………………………49

Preparation of N-Benzylidenzylamine N-oxide.(26) Method B…………………………49

Preparation of N-Benzylhydroxylamine hydrochloride(29)…………….……………….50

Preparation of α-styryl-N-benzylnitrone(29)…………………………………………….50

Preparation of dibenzofuran-4,6-dicarboxylic acid(51)………………………………….50

Preparation of dibenzofuran-4,6-dicarbonyl chloride(52)…………………………...…..51

Preparation of (R,R)- dibenzofuran-4,6-dicarboxylic acid

bis (2-hydroxy-1-phenyl) amide(53)……………………………………………..52

Preparation of (R,R)-4,6-dibenzofurandiyl-2,2’-bis(4-phenyloxazoline),

DBFOX/Ph(54)…………………………………………………………...……...53

Reaction of α-phenyl-N-benzylnitrone with butylvinylether……………………………53

Reaction of α-styryl-N-benzylnitrone with butylvinylether……………………………..54

Reaction of α-styryl-N-t-butylnitrone with butylvinylether……………………...……...54

Reaction of α-styryl-N-phenylnitrone with butylvinylether……………………………..54

Reaction of α-phenyl-N-benzylnitrone with trans-β-nitrostyrene……………………….54

Reaction of α-styryl-N-benzylnitrone with trans-β-nitrostyrene……………………...…55

Preparation of the Aqua Complex of DBFOX/Ph-Nickel (II) perchlorate……...……….55

Nitrone cycloaddition reaction catalyzed by the aqua complex of

vii

DBFOX/Ph-Nickel (II) perchlorate…………………………..………………….55

Photolysis of α-styryl-N-phenylnitrone………………………………………………….55

Photolysis of α-styryl-N-t-butylnitrone………………………………...………………..56

Photolysis of α-phenyl-N-benzylnitrone………………………………...………………56

Photolysis of α-styryl-N-benzylnitrone………………………………………………….56

REFERENCES…………………………………………………………………………………..57

APPENDIX………………………………………………………………………………………61

viii

LIST OF SCHEMES

Scheme Page

1 The FMO energies between the dipole and dipolarophile…………………………….8

2 The normal electron-demand 1,3-dipolar cycloaddition reaction……………………..9

3 The inverse electron-demand 1,3-dipolar cycloaddtion reaction…………………….10

4 The endo and exo interactions………………………………………………………..12

5 Reaction of nitrones with 1,2-disubstituted alkenes…………………………………14

6 Complexes between DBFOX/Ph and Ni(ClO4)2*6H2O……………………………..17

7 Thermal racemization of chiral oxaziridines proceeds through a high barrier

to nitrogen inversion………………………………………………………………...19

8 Synthesis of α-styryl-N-phenylnitrone (21)…………………………………………23

9 Synthesis of α-styryl-N-t-butylnitrone (24)………………………………………….23

10 Synthesis of α-phenyl-N-benzylnitrone (26). Method A………………………….…24

11 Synthesis of α-phenyl-N-benzylnitrone (26). Method B…………………………….25

12 Synthesis of α-styryl-N-benzylnitrone (29)………………………………………….26

13 Two mechanisms of the formation of amides by N-O cleavage …………………….29

14 Photolysis of α-styryl-N-phenylnitrone (21)………………………………………...30

15 Photolysis of α-styryl-N-t-butylnitrone (24)………………………………………...30

16 Photolysis of α-styryl-N-benylnitrone (29)………………………………………….31

17 Photolysis of α−phenyl-N-benzylnitrone (26)……………………………………….31

18 Decomposition of the N-oxide structure……………………………………………..32

19 Thermal 1,3-cycloaddition reactions with butylvinylether…………………………..34

20 Thermal 1,3-cycloaddition reactions with trans-β-nitrostyrene……………………..37

ix

21 Synthesis (R,R)-4,6-Dibenzofuranyl 2, 2’- bis (4-phenyloxazoline)oxazoline

(DBFOX/Ph)-a novel tridentate ligand………………………………………………40

1

INTRODUCTION

The name “nitrone” is an abbreviation which was suggested by Pfeiffer1 in 1916 for

compounds containing the functional group (1). The name emphasizes their similarity with

ketones. Nitrones2,3 are quite versatile intermediates in organic synthesis and are employed, for

instance, in stereoselective formation of synthetically useful isoxazolidines by their 1,3-dipolar

cycloaddition with alkenes.4-6

C NR

O

1

The general terms, aldonitrones and ketonitrones, have been employed occasionally.

Aldonitrones contain a proton on the α-carbon atom, RCH=N(O)R”, while in ketonitrones the α-

carbon is fully substituted with alkyl and/or aryl groups, RR’C=N(O)R”. Usually for cyclic

nitrones the names are in accordance with the parent heterocyclic structure.

Nitrones exhibit geometric isomerism because of the double bond in the nitrone group.

One example of geometric isomerism in aldonitrones is illustrated with α-phenyl-N-t-

butylnitrones. The cis (E) form of this nitrone is formed first when t-butyl-3-phenyloxaziridine

was treated with boron trifluoride. Complete isomerization to the more stable trans (Z) form

occurs within 24 hours in benzene solution.7

HC N

O

C(CH3)(C6H5)

BF3 HC

C6H5

NO

C(CH3)3

HC

C6H5

NC(CH3)3

O

cis trans

Ultraviolet spectral studies indicate that aldonitrones exist in the stable trans (Z) form,

and this has been confirmed by nuclear magnetic resonance and infrared studies.8

2

R3C

R2

NR1

O

R3C

R2

NR1

O

R3C N

R1

OR2

3 2 4

The three resonance structures 2-4 may be written for nitrones. All of these azomethine

N-oxide groups are dipolar in character and the typical nitrone reactions depend on this dipolar

state. The polarization of the azomethine N-oxide group is moderated by the inductive or

mesomeric effect of the substituents R1, R2 and R3. Electron withdrawing groups in either R2 or

R3 decrease the electron density on the carbon atom and its electrophilic properties are enhanced.

Synthetic methods for producing nitrones

1. From N-monosubstituted hydroxylamines.

The most popular method is the condensation of aldehydes or ketones with N-

monosubstituted hydroxylamines.9

C O N R

OH

H

C

OH

N R

OH

-H2OC N R

O

+

However, this method often fails when applied to the preparation of non-conjugated cyclic

nitrones and ketonitrones having bulky alkyl groups.

2. By oxidation of secondary amines or N,N-disubstituted hydroxylamines.

Direct oxidation of secondary amines to the corresponding nitrones has also been studied

during the last several years and was found to be a useful method for the preparation of nitrones.

Several effective metal catalysts 10-13 and oxidizing agents14-16 were subsequently developed for

these direct oxidation reactions.

3

The oxidation of N,N-disubstituted hydroxylamines, where at least one of the carbons

attached to the nitrogen carries a hydrogen atom,17-19 can be used to produce nitrones. Yellow

mercuric oxide has been used successfully as the oxidizing agent.

R3

C

H

NR2

R1

OH

R3

R2

N R1

O

oxidation

Although this method is particularly useful for the preparation of labile nitrones due to its mild

reaction conditions, there remains a need to develop new and more efficient oxidants other than

the toxic mercuric compound in order to establish this as a useful method for the preparation of

nitrones.

3. From oximes.

The alkylation of oximes was a well developed method as early as 1938.20 Since

alkylation may occur on either oxygen or nitrogen, this method has a disadvantage in that the

reaction products are mixtures of oxime ethers and nitrones. A small effect was noted21 with the

use of different leaving groups. Electron-withdrawing groups in p,p’-disubstituted benzophenone

oxime salts distinctly promoted the formation of nitrones, while electron-donating substituents

favored oxime ether formation.

NOH RX NOR N R

O

HX+ + +

Interestingly, the geometry of the oxime affects the atom selectivity in the subsequent

nitrone forming reaction. Anti-aryloxime anions 5 afford nitrones 6, whereas syn-aryloxime

anions 7 favour the formation of the oxime ethers 8.22

4

Anti-

H

PhN

O RX

Ph

HN

O

R

5 6

Syn-

Ph

HN

O RXH

PhN

OR

7 8

4. From oxaziridines.

In general, the preparation of oxaziridines is based either on the photochemical

isomerization of nitrones or by the reaction between imines and hydroperoxides. The latter

reaction was employed to synthesize a variety of 3-aryloxaziridine derivatives, but 2,3-

diaryloxaziridines could not be synthesized in this fashion. In the next step, smooth thermal

rearrangement of 3-phenyloxaziridines derivatives to the corresponding nitrones has been

reported by various workers.23-24

C6H5 C

R

NR'H2O2 R

CC6H5

NR'

O∆ R

CC6H5

N

O

R'

Properties of nitrones

Nitrones may be either liquid or solid, and due to their polar character can be somewhat

soluble in water unless hydrophobic substituents such as aryl groups are present.

1. Spectral properties.

5

The ultraviolet spectra of many nitrones have been reported 25. All the nitrones show

strong absorption between 238 and 251 nm, which must be due to electronic transitions in the

nitrone group.

In the infrared spectrum, a strong absorption in the 1600 cm-1 region is characteristic of

all nitrones, but the exact position of this band varies with substitution on the nitrone. Another

intense absorption is observed at around 1183 cm-1, and this band is attributed to the vibration of

the N+-O- functional group.

The nuclear magnetic resonance spectra of the nitrones have also illustrated that they

generally exist in the more stable Z-conformations.

2. Isomerism.

The double bond in the nitrone group of acyclic compounds can exist as geometrical

isomers and cyclic nitrones are constrained to be syn by the ring structure. However, since

resonance imparts a considerable amount of single-bond character to the system one might

expect a fairly easy isomerization between the syn- and anti-forms, which is observed. Most

nitrones have the more stable anti-configurations.26 As expected on the basis of the available

data27, the conjugated aldonitrone (Table 1) is representative of those compounds containing the

simple 1-azabutadiene N-oxide system. It possesses E geometry of the carbon –carbon double

bond and an s-E conformation of the two double bonds. This was confirmed by proton NMR,

which did not show a ‘through-space’ nitrone deshielding effect on the ortho protons of the

phenyl ring attached to the carbon-carbon double bond in the s-Z conformation, as observed in

the case of common C-aryl nitrones.28Additionally, the nitrone carbon resonance showed a

conjugation between these two bonds, which requires planarity of the system. The nitrone carbon

signal was shifted upfield by approximately 8 ppm compared with a simple non-conjugated

6

aldonitrone group such as a α-cyclohexyl-N-phenylnitrone (δ C1-143.3 ppm).27 This

corresponded well with the effect caused by an aryl substituent on the aldonitrone carbon.

N

H

H

O

H

11

10

9

8 3 2

14

5

6

7

Carbon δ 1J(CH) 2J(CH) 3J(CH) C-1 135.8 178.7d 8.3d - C-2 118.8 162.1d 8.3(H-1)4.3(H-3) - C-3 139.6 153.8d 4.3d 3.3t(H-9) C-4 147.1 - 5.0d 7.4t C-5 121.1 160.5d 4.1d 7.3d C-6 129.1 160.5d 4.2d - C-7 129.6 160.5d 4.2d 7.3t C-8 135.8 - 2.8t 7.9t C-9 128.8 160.5d 2.8t 7.9d C-10 128.6 160.5d 2.8t - C-11 127.2 160.5d 2.8t 7.9t

Table 1. Carbon resonance (ppm) and coupling constants (Hz) for α-styryl-N-phenylnitrone 9.27

Reactions of nitrones

1. 1,3-Dipolar Cycloaddition Reactions.

1,3- Dipolar cycloaddition reactions offer one of the most versatile synthetic routes to

heterocyclic five-membered rings in organic chemistry.29 Concerted cycloaddition reactions are

also among the most powerful tools for the stereospecific creation of new chiral centers in

organic molecules. Nitrones are well-known to behave as 1,3-dipoles in thermal cycloaddition

7

reactions. These cycloadditions of nitrones to substituted olefins 10, often called dipolarophile,

lead to formation of isoxazolidines 11, and as such it provides a novel and facile method for the

synthesis of certain heterocyclic compounds.

R3

CR2

NR1

O

+R5

CR4

CR6

R7 O

N

R1

R4

R5

R6

R3

R2

R7

2 10 11

The addition of a reagent where R2=R3 and R4=R5=R6=R7 would guarantee a

stereochemically pure isoxazolidine. In all other cases a number of stereoisomeric isoxazolidines

may form due to the fact that up to three asymmetric centers are being created. With

unsymmetrically substituted olefinic dipolarophiles, two additional orientations are also possible.

Although cycloaddition to an isolated double bond occurs, conjugation of the dipolarophiles with

another group enhances the polarizability of the double bond and markedly increases the rate of

cycloaddition.

1.1. Frontier Molecular Orbital Interactions.

The transition state of the concerted 1,3-dipolar cycloaddition reaction is controlled by

the frontier molecular orbitals (FMO) of the substrates. Based on the relative FMO energies

between the dipole and the dipolarophile, these 1,3-dipolar cycloaddition reactions have been

classified into 3 types by Sustman (Scheme 1).37 Reactions of type I are typical for azomethine

ylides and carbonyl ylides and is the case where the HOMOdipole interacts with the

LUMOdipolarophile.The reactions of nitrones are normally classified as type II reactions when the

similarity of the dipole and dipolarophile FMO energies permits both HOMO-LUMO

8

interactions to be important. In type III reactions the FMO interactions are dominated by the

LUMOdipole and the HOMOdipolarophile For example, reactions of nitrile oxides are better classified

as borderline to the type III than to the type II because nitrile oxides have relatively low LUMO

energies of -11 to -10 eV.The catalytic control of reaction is based on the relative FMO energies

of the reagents. To be able to control the stereochemistry of a reaction with a sub-stoichiometric

amount of a ligand-metal catalyst it is desirable that large reaction rate increases are obtained

because then the reaction only takes place in the sphere of the metal and the chiral ligand. The

relative energies of the FMO of one of the substrates is changed with catalytic enhancement of

the reaction rate when using chiral Lewis acid complexes.38 As a matter of principle, such

activation can be applied to the 1,3- dipolar cycloaddition of nitrones with alkenes in two

different ways.

HOMO

LUMO

dipole dipolarophile dipole dipolarophile dipole dipolarophile

type I type II type III

Energy

Scheme 1. The FMO energies between the dipole and dipolarophile.

For example, the reaction between a nitrone and an electron-deficient alkene such as an

α,β−unsaturated carbonyl compound is mainly controlled by the interaction between

9

HOMOnitrone-LUMOalkene (Scheme 2). In the presense of a strong electron acceptor such as a

Lewis acid (LA) catalyst coordination of the enone to the Lewis acid diminishes the energy of

the FMOalkene. As a consequence of the decreased energy gap between the interacting FMO’s, the

reaction rate increases substantially. The “inverse electron-demand” is the other catalytic

approach to the 1,3-dipolar cycloaddition reactions in which the nitrone undergoes addition to an

electron-rich alkene such as a vinyl ether (Scheme 3). In this case the FMO’s alkene has higher

energies than the FMOnitrone and the reacting orbitals will be LUMOnitrone-HOMOalkene. The

nitrone can coordinate to the Lewis acid catalyst which decreases the LUMOnitrone energy. The

decreased energy gap between the two FMOs responsible for the dominating interaction leads to

an enhanced rate of the 1,3-dipolar cycloaddition reactions involving nitrones.

Alkene nitrone alkene-LA-complex

HOMO

N

OR

OOELA

LUMO

Scheme 2. The normal electron-demand 1,3-dipolar cycloaddition reaction

10

Nitrone alkene nitrone-LA complex

HOMO

OR2

N

OR1

N

OR1

E

LUMO

LA

Scheme 3. The inverse electron-demand 1,3-dipolar cycloaddtion reaction

1.2. The selectivities of 1,3- Dipolar Cycloaddition Reactions.

The application of 1,3-dipolar cycloaddition reactions in natural product synthesis is

heavily dependent upon an understanding of the regiochemistry and stereochemistry of the

reaction. Although nitrones are only one member of an extensive series of 1,3-dipoles, they can

be considered of special interest, because they are readily available simple derivatives of

carbonyl compounds. Dipolar cycloaddition reactions can be considered as concerted but

asynchronous [4π + 2π] suprafacial processes and the reactions allow creation of up to three

contiguous carbon stereocentres in a single step. It is generally accepted that most 1,3- dipolar

cycloadditions are single-step four centered, concerted reactions, in which the two new δ-bonds

are formed simultaneously although not necessary at equal rates.30

11

N

O R1

R3N

C

O

+

C

R2

R1

R4

R2

C

R4

R3

A two step reaction involving a spin-paired diradical intermediate has been postulated31 but not

generally accepted. A third alternative is a two step reaction involving a zwitterionic

intermediate and such a mechanism cannot be rejected totally for additions involving highly

polarized dipolarophiles.

1.2.1. Stereoselectivity.

Two pairs of regioisomeric and diastereoisomeric products can result in any nitrone-

alkene cycloaddition. These arise from the nitrone and alkene approaching each other in either of

two regiochemical senses, and in either an endo- or exo-fashion.32

R1

R2N

R

O

R3

RN

R2

R1

R3

O

RN

R2

R1

R3

O

RN

R2

R1

R3

O

RN

R2

R1

R3

O

+

endo approach

exo approach

Therefore, much effort has focused on the development of regioselective and

stereoselective inter- and intramolecular nitrone-alkene cycloaddition reactions. The

nomenclature endo and exo is well known from the Diels-Alder reaction.33 The endo isomer

12

arises from the reaction in which the nitrogen atom of the dipole points in the same direction as

the substituent of the alkene. However, the endo transition state in the Diels-Alder reaction is

stabilized by secondary π-orbital interactions and the actual interaction of the N-nitrone pz-

orbital with a vicinal pz-orbital on the alkene, and thus the stabilization, is small.34 The endo/exo

selectivity in the 1,3- dipolar cycloaddition reaction is therefore primarily controlled by the

structure of the substrates or by the presence of catalyst. It should be noticed that for reactions in

which the nitrone can undergo Z/E-interconversion, the endo/exo assignment of the products is

misleading and therefore cis or trans should be used instead.

X+ N

O

endo

X

+N

O

exo

N

O

N

O

X X

Scheme 4. The endo and exo interactions.

13

1.2.2. Regioselectivity.

The regioselectivity is controlled by both steric and electronic effects.35 However, the

steric effect may be overruled by strong electronics effects.29 The 5-substituted isomer of the

cycloaddition reaction results where electron-rich or electron-neutral alkenes react with nitrones.

The reaction is primarily controlled by the lowest unoccupied molecular orbital (LUMO)dipole

and the highest occupied molecular orbital (HOMO)dipolarophile interaction. The nitrone and alkene

combine in a regioselective manner to give the 5-isoxazolidine because the LUMOdipole has the

largest coefficient at the carbon atom and the HOMOalkene has the largest coefficient at the

terminal carbon atom. This is obviously supported by steric factors. For alkenes with an electron-

withdrawing group (EWG) the reaction is primarily controlled by the HOMOdipole-

LUMOdipolarophile interaction. In this case the HOMOdipole has the largest coefficient at the oxygen

atom, whereas the LUMOdipolarophile has the largest coefficient at the terminal carbon atom. This

situation favors to form the 4-isomers, but since steric effect factors oppose this, a mixture of

regioisomers is often obtained.36 However, the steric factor is eliminated in the reaction of

nitrones with 1,2- disubstituted alkenes bearing an electron- withdrawing group and leading to

the frontier molecular orbitals (FMO) controlled regioselectivity of the reaction with the 4-EWG-

substituted isomer as the sole product (Scheme 5).

NO

R1

R2

N

O

N

OR2

R1 R1 R2

++

14

EDG

HOMO

EWG

HOMO

N

O

EWG

N

O EDGLUMO

LUMO

Scheme 5. Reaction of nitrones with 1,2-disubstituted alkenes.36

1.3 Chiral Lewis acid catalyst.

Most of the molecules in the world are chiral and a wide range of biological and physical

functions are generated by accurate molecular recognition which requires strict matching of

chirality.39 The development of efficient chiral catalysts for enantioselective synthesis has

become one of the most intense, dynamic and rapidly growing areas of organic chemical

research.40

Development of new methods for the preparation of enantiomerically pure compounds is

an important goal for synthesis. Many 1,3-cycloaddition reactions can be catalyzed by Lewis

acids in organic solvents.

Based on numerous reports on successful Lewis acid-catalyzed stereocontrol of Diels-

Alder reactions, 41 similar Lewis acid catalysis should be expected in dipolar cycloaddition

reactions. However, a serious problem is that 1,3- dipoles act as much stronger bases than dienes.

And also the strong binding of nitrones to the catalyst has provided a tendency for dipoles to

form inactive dipole/Lewis acid complexes. This oligomeric aggregation often influences the

catalytic activity. To overcome this difficulty, new types of Lewis acids which have a chelate

15

ligand structure have been developed. Cis-chelating ligands have been used quite often to modify

the chirality of the Lewis acid catalyst. However, in cis-complexes, the metallic center tends to

be exposed to other ligand molecules, so that the formation of the oligomer usually occurs

easily.42 To avoid this aggregate formation, the trans-chelating ligand seems to be more

favorable. Neutral ligands such as bisoxazoline types, can be used for this because of the

following reasons: a decrease of the Lewis acidity of the metallic center is made possible by

coordination of three anionic ligands to a metallic center and the combination of neutral

tridentate ligands with noncoordinating anionic ligands will produce a cationic complex which

may maintain a high catalytic activity. Also the trans-chelating structure of two oxazoline

moieties, in the case when these two heterocyclic rings are coplanar, shows an attractive chiral

space around the metallic center. Finally, aggregation is disfavored because the metal included in

the above model complex is located in the middle of the chiral structure and is surrounded by the

chiral ligands.43

While various kinds of Lewis acid-promoted reactions have been developed, and some of

them have even been applied in industry, they have are limited by the fact that they must be

carried out under strictly anhydrous conditions. Thus, the presence of even a small amount of

water stops the reaction. Since most Lewis acids immediately react with water rather than the

substrate and therefore decompose, the application of Lewis acids has been restricted in organic

synthesis.

Pioneering work by Bosnich and co-workers reported in 1992 has described a new type

of transition-metal Lewis acid catalyst. Some aqua complexes of titanium44 and ruthenium45 salts

show high catalytic activity and also are water-tolerant and highly air-stable. This suggests that

the aqua ligands can be rapidly replaced with dienophiles even in the presence of additional

16

water. Use of enantiopure titanium catalysts with aqua ligands, like some anhydrous titanium and

zirconium complexes, has achieved reasonable enantioselectivities.46

In 1998 Kanemasa published a new structure of dibenzofuranyl 2, 2’- bis-oxazoline

(DBFOX) and described it as an excellent ligand for a variety of Lewis acids.47 Cationic aqua

complexes which show a high catalytic activity can be prepared by combination of (R, R)-4,6-

dibenzofurandiyl-2,2’-bis(4-phenyloxazoline) (DBFOX/Ph) with a diversity of metal(II)

perchlorates such as magnesium, nickel, iron, cobalt, copper and zinc ions. After many

experiments, Kanemasa’s group concluded that a Ni(ClO4)2*PhDBFOX complex 12 is the most

selective chiral catalyst for the normal electron-demand 1,3-dipolar cycloaddition reaction

between nitrones and alkenes primarily because of the importance of enantioselectivity.48

Application of 1-10 mol% of this catalyst showed in general very high enantioselectivities of up

to 99% ee.

O

O N N O

Ph Ph

Ni(H2O)3

(ClO4)2

12

This complex can be simply prepared by stirring equamolar amounts of DBFOX/Ph ligand and

nickel(II) perchlorate hexahydrate Ni(ClO4)2*6H2O in dichloroethane for a few hours.

Interestingly, the perchlorate salt is totally insoluble in dichloroethane, but dissolves in the

17

presence of DBFOX/Ph ligand. Accordingly, this chiral catalyst is easy to prepare and

inexpensive, and moreover can be stored in air for months without loss of catalytic activity.48

R, R-DBFOX/Ph + NiBr2+ 2 AgClO4 ANHYDROUS COMPLEX

R, R-DBFOX/Ph*Ni(ClO4)2

AQUA COMPLEXR, R-DBFOX/Ph +Ni(ClO4)2*6H2O

Water from air

R, R-DBFOX/Ph*Ni(ClO4)2*3H2O

HYDROXO COMPLEX

-HClO4

R,R-DBFOX/Ph*Ni(OH)ClO4*2H2O

Scheme 6. Complexes between DBFOX/Ph and Ni(ClO4)2*6H2O

In some cases the aqua complexes are even more active than anhydrous complexes.

Alcohols, acids and amines do not seriously affect the catalytic activity as much as

enantioselectivity.

The role of MS 4A in the nitrone cycloaddition reactions catalyzed by the R, R-

DBFOX/Ph transition metal complexes is important for diastereo- and enantioselectivities.49 The

reaction of 3-crotonoyl-2-oxazolidinone 13 with N-benzylidenemethylamine N-oxide 14

produces 3,4-trans- isoxazolidines 15 with great endoselectivity (endo:exo=99:1) and

enantioselectivity for 3S, 4R, 5S enantiomer (>99% ee).48 In the absence of MS 4A in this

reaction the endo- and enantioselectivity are both lowered. The role of MS 4A can not be

described in detail yet, but when anhydrous magnesium sulfate replaced the MS 4A in the

nickel(II) complex-catalyzed reaction, equally excellent selectivities were achieved.49 In this case

MS 4A was indicated as a dehydrating agent. However, Jorgensen’s group was the first to

observe a dramatic effect of MS 4A in the Lewis acid-catalyzed nitrone cycloadditions.50 They

18

noted that the chemical yield in this reaction did not change with the absence of MS 4A but the

endoselectivity was lowered (endo:exo, from 92:8 to 65:35) and the enantioselectivity almost

disappeared ( 79 to 2% ee). 50

O N

O

Me

O

Ph N

Me

O

O N-Me

Me Ph

CO-OX

O N-Me

Me Ph

CHO-OX

+and/or

Cat12, MS 4A

rt, CH2Cl2

1314

3,4-trans-15 3,4-cis-15

Absolute confuguration isnot assigned

endo exo

2. Photolysis of nitrones.

The discovery of oxaziridines was reported in 1956 49. Oxaziridines have been widely

investigated principally for two reasons. The presence of an inherently weak N-O bond in a

strained ring promised a group of compounds of unusually high reactivity. Moreover, this system

with ring strain and an atom with unshared electron pairs attached to nitrogen seem to be

required to observe stereochemical isomerism at nitrogen. Irradiation of nitrones was found to

lead to the isomeric oxaziridines 16 and amines 17.52

R1

HN

O

R2

R1

N

O

H

R2

R1 NHR2

O

2 16 17

The stereochemistry of the oxaziridine ring has been of interest in several investigations

due to the chirality of the nitrogen atom and the appreciable barrier to its inversion. This barrier

to inversion was determined to be 25-32 kcal/mol for N-alkyl oxaziridines.50 The transition state

19

for thermal epimerization was shown to have increased ring strain and therefore the large barrier

to nitrogen inversion was observed (Scheme 7).53 Oxiziridines have also been shown to be

epimerized photochemically through a nitrone intermediate.54

N

O

Ph

PhMe

Ph

N

O

Ph

Ph

Me

Ph

N

O

Ph

PhPh

Me

G =31.9 kcal/mol

Scheme 7. Thermal racemization of chiral oxaziridines proceeds through a high barrier to

nitrogen inversion.

The inversion barrier becomes smaller when the N-substituent of oxaziridines posseses π-

conjugation or hyperconjugation. Both N-aryl and N-acyl oxaziridines have inversion barriers

close to 20 kcal/mol55 because of their π-conjugation.

The ultraviolet absorption of various ring-substituted α-N-diphenylnitrones was studied

by Wheeler and Gore57 in 1956. They found distinct regions for nitrone absorptions. The E1

absorptions, at approximately 230 nm, were assigned to the electronic transitions in the

individual benzene nuclei. The E2 absorptions, around 280 nm, were assigned the electronic

transitions of the nitrone group in conjugation with one phenyl group. The K bands, at

approximately 320 nm, were considered to be due in each case to the molecule as a whole for the

nitrone system in conjugation with both phenyl groups.

Later Kamlet and Kaplan58 tried to reproduce these results. They even took special

precautions and used some specially purified compounds, however they were unable to observe

these signals. The well-known sensitivity of nitrones to irradiation lead these authors to suppose

that the difference could be due to photochemical reactions. Moreover, they were able to

20

demonstrate that that was indeed the case. After 1 minute exposure to bright sunlight the

absorptions at 314 nm of a solution of C-N-diphenylnitrone disappeared. However, keeping the

solution in the dark for several days did not change the absorbance in the least. Also, the

behavior of other C-N-diphenylnitrones was the same. The entire disappearance of the K-band

on irradiation showed that the conjugation between the two phenyl groups was destroyed and the

double bond of the nitrone system was completely removed. Since this process happened so

rapidly, during 1 minute, Kamlet and Kaplan58 rejected the possibility of dimerization or

polymerization reactions. They also pointed out that it could not be due to cis-trans

isomerizations of the nitrones, because this process would affect the K bands only slightly and

could not have accounted for their complete disappearance. They suggested the formation of the

isomeric oxaziridines 18 as a more rational possibility.

R

CH

O

N

R'

18

Krohnke59, concurrently with Kamlet and Kaplan, proposed the oxaziridine system 18 as

a possible unstable intermediate in the rearrangement of C-benzoylnitrone to an amide. To

confirm the oxaziridine form, Splitter and Calvin60 compared the products of irradiation of

nitrones containing an N-alkyl group, which yields stable oxaziridines, with oxaziridines

prepared by peracetic acid oxidation of imines. They developed a convenient method to

determinate the amount of oxaziridine in a mixture and thus the degree of photoisomerization by

the reaction with iodide ion. Since the oxygen atom in oxaziridines is very reactive in acid

media, iodide ions are readily oxidized to iodine. Iodine concentrations can be determined by

titration.

21

R2

C

R3

N

O

R1

2H+

C

R3

N R1

R2

2 I- + I2 + H2O +

19

This ability to function as an oxidizing agent has lead to the development and commercial

availability of oxaziridines as chiral oxidation reagents. Emmons61 reported the effect of

substituents on the stability of oxaziridines 19. When the nitrogen substituent R1, was a tertiary

alkyl group the compounds were usually very stable and could be distilled without

decomposition. When R1, R2 and R3 substituents were all alkyl groups, the oxaziridines, as

products of irradiation, were thermally stable. When R1 and only one of R2 and R3were alkyl

groups the oxaziridines were reasonably unstable and showed slow decomposition even at room

temperature. When both R2 and R3 substituents were hydrogen atoms, the compounds were even

less stable. If either R2or R3 was an aromatic group the oxiziridines were very unstable and only

if R1 was a tertiary alkyl group could the oxaziridines be isolated. Very unstable oxaziridines

were produced as well when the N-substituent was aromatic.

Many oxaziridines are unstable even at room temperature and are easily and

spontaneously rearranged or decomposed. The driving force for bond cleavage in the oxaziridine

was proposed to be relief of ring strain which is present in all three membered rings. The nature

of substituents not only influences stability but also controls which bond is cleaved. The

instability of the N-aryl-substituted oxaziridine was more likely due to the phenyl group acting as

electron withdrawing group rather than as an electron source. The oxaziridines with an electron

withdrawing C-substituent undergoes only N-O bond cleavage. In the presence of electron-

releasing C-substituents, the instability of the C-O bond is increased, causing up to 20% cleavage

of this bond.62

22

RESULTS AND DISCUSSION

Although there is considerable literature dealing with the chemistry of nitrones, some of

the nitrones which are described in my M.S. research are not found in chemical search programs.

The general problems undertaken for my M.S. research was to improve the synthesis of non-

conjugated and conjugated nitrones, to study photochemical reactions of nitrones and to

determine the products of their rearrangements, and to probe these classes of nitrones both

physically and chemically to determine whether or not conjugated nitrones deviate in behavior

from simpler nitrones in any basic manner. Nitrones are well-known to behave as 1,3-dipoles in

thermal cycloaddition reactions. These cycloadditions of nitrones to substituted olefins lead to

formation of isoxazolidines, and as such it provides a novel and facile method the synthesis of

certain heterocyclic compounds. The factors which determine regioselectivity and

stereoselectivity in these cycloadditions have been discussed earlier in this thesis. We were

particularly interested in developing new methodologies synthetic models for enantioselective

syntheses and, specifically, the use of chiral catalyst for accomplishing these goals. One such

compound has been described by Kanemasa47 in 1998 as an excellent ligand for a variety of

Lewis acids. It is a metal ion complex (a Lewis acid) of enantiopure dibenzofuranyl 2, 2’- bis-

oxazoline (DBFOX). This catalyst has been applied to a nitrone cycloaddition reaction using N-

benzylidenmethylamine N-oxide 14. The results of our studies in these areas are presented and

described in the sections of this thesis.

1. Synthesis of nitrones.

α-Styryl-N-phenylnitrone, 21, was obtained by the most popular method of nitrone

synthesis, the condensation of aldehydes with N-monosubstituted hydroxylamines. This method

often fails when applied to the preparation of non-conjugated cyclic nitrones. However, in our

23

particular reaction, the nitrone 21 prepared using hydroxylamine 20 was isolated in 47% yield.

The higher crude yield was lowered due to inefficient recrystallization from hot ethanol.

NO2

N OH

H

C6H5C6H5

N

O

C6H5

2120

ba

a) Zn, NH4Cl, H2O b) trans-cinnamaldehyde, CH3CH2OH

Scheme 8. Synthesis of α-styryl-N-phenylnitrone 21.

The same method was also applied for synthesis of α-styryl-N-t-butylnitrone 24 using N-

t-butylhydroxylamine 23 prepared by reduction of 2-methyl-2-nitropropane 22. The reaction

mixture was purified by column chromatography and afforded the nitrone as a light yellow

crystalline solid in 74% yield.

CH3

H3C

CH3

NH2

CH3

H3C

CH3

NO2

CH3

H3C

CH3

N

OH

H

N

O

C(CH3)3

C6H5

a b c

22 23 24

a) KMnO4, H2O b) Alfoil+HgCl2+H2O, ether/water c) trans-cinnamaldehyde,

CH3CH2OH

Scheme 9. Synthesis of α-styryl-N-t-butylnitrone 24.

Our first approach to the synthesis of α-phenyl-N-benzylnitrone 26 was patterned after

research described in the BGSU M.S. thesis of Upali Weerasooriya.65 This reaction sequence

employed the use of toxic mercuric oxide for the preparation of nitrones by oxidation of N,N-

24

disubstituted hydroxylamines 25. However, preparation of the starting hydroxylamines is

generally very tedious.

OH

NH H

2 C6H5CH2Cl

OH

NC6H5H2C CH2C6H5 C6H5

HC N

O

CH2C6H5

+a b

2625

a) CH3OH/H2O, NaCO3 b) HgO(yellow), CHCl3

Scheme 10. Synthesis of α-phenyl-N-benzylnitrone 26. Method A.

To avoid the sometimes difficult preparation of hydroxylamines and the use of toxic

mercuric compounds, Murahashi and co-workers63 in 1990 reported a convenient safe method

for nitrone synthesis. Oxidation of secondary amines by sodium tungstate catalyzed with

hydrogen peroxide provided nitrones in a single step in good to excellent yields. The activity of

various oxidants were examined by this research group.63 They have reported, for example,

oxidation of dibutylamine with 70% aqueous tert-butyl hydroperoxide in the presence of metal

complexes such as Na2WO4*2H2O, SeO2, MoO2(acac)2 and VO(acac)2 (acac=acetylacetonate)

gave the corresponding nitrone in low yield. Next, oxidation using tert-butyl hydroperoxide in

dry benzene in the presence of catalysts, such as those mentioned above, gave no nitrones.

Oxidation with cumene hydroperoxide or m-chloroperbenzoic acid gave many products. The

reaction did not proceed when NiO4 was used as an oxidant. Finally, hydrogen peroxide was

found to be the best oxidant. They examined the catalytic activity of various metal complexes for

use in the oxidation of dibutylamine with 30% aqueous hydrogen peroxide in methanol.

Na2WO4*2H2O gave the best yield of α-propyl-N-butylnitrone. The effect of solvent was also

tested for the oxidation of dibutylamine with hydrogen peroxide in the presence of

25

Na2WO4*2H2O. Methanol gave the best result for that reaction although water, dioxane,

acetonitrile and acetone could be applied with good results. The oxidation did not proceed in

dimethylformamide or dimethyl sulfoxide because of the decomposition of hydrogen peroxide

under the reaction conditions.63 We successfully applied this convenient method for our

synthesis. In our case, we replaced dibutylamine with dibenzylamine 27. Αccordingly, crystals

of α-phenyl-N-benzylnitrone were obtained in 92% yield even after recrystallization from

petroleum ether/dichloromethane, which is much better then the 72% in the two step synthesis of

Method A.

C6H5

H2C

NH

H2C

C6H5 CH3OHC6H5

HC N

O

CH2C6H5

26

30% H2O2, 5 mol %Na2WO4*2H2O

27

Scheme 11. Synthesis of α-phenyl-N-benzylnitrone 26. Method B.

α-Styryl-N-benzylnitrone 29 required the availability of N-benzylhydroxylamine.

Reduction of α−nitrotoluene is not useful, since the nitrotoluene is so difficult to obtain. Instead,

we employed nitrone 26, readily available in quantity as described above, as a source of 28.

Hydrolysis of 26 using aqueous hydrochloric acid provided benzaldehyde and the desired 28. At

first, we had some problems with recrystallization from hot ethanol but after several attempts,

crystals were obtained, in small quantity. We tried some other recrystallization solvent systems

and finally ethylacetate was used successfully. Melting point and NMR spectra of N-

benzylhydroxylamine chloride 28, obtained in 90% yield, showed it to be pure. The final

product, as α-styryl-N-benzylnitrone 29, was carried out by the condensation of

cinnamoaldehyde with 28. To neutralize the hydrochloride, sodium bicarbonate was added to the

26

reaction mixture and this mixture was stirred thoroughly until the evolution of carbon dioxide

stopped. Recrystallization from hot ethanol was not successful and the previous ethylacetate

system was tested for this reaction. Slightly yellow crystals of 29 were obtained but only in 30%

yield, in spite of the fact that this process was repeated numerous times.

C6H5

HC N

O

CH2C6H5

OH

N

C6H5H2C H

C6H5

O

HNaHCO3

CH3CH2OH

OH

N

C6H5H2C H

C6H5

N

O

CH2C6H5

* HCl +

28 29

26

* HCl

28

CH3CH2OH, 10%HCl

Scheme 12. Synthesis of α-styryl-N-benzylnitrone 29.

To summarize, four different nitrones were synthesized and described in my M.S. research work,

these nitrones was successfully applied to the photoisomerization reactions and 1,3-cycloaddition

reactions as described below.

C6H5

N

O

C6H5

N

O

C(CH3)3

C6H5

C6H5

HC N

O

CH2C6H5

C6H5

N

O

CH2C6H5

α-styryl-N-benzylnitrone 29α-phenyl-N-benzylnitrone 26

α-styryl-N-t-butylnitrone 24α-stryl-N-phenylnitrone 21

27

2. Photoisomerization reactions.

Photochemical rearrangement of several conjugated nitrones, namely α-styryl-N-

phenylnitrone, α-styryl-N-t-butylnitrone and α-phenyl-N-benzylnitrone, were studied. The

sensitivity of nitrones to light has been known for many years.64 The irradiation of nitrones with

light of correct wavelength produces oxaziridines.7 The kind of substituents in the molecule has a

major influence on the stability of the oxaziridines. 7, 62 Oxaziridines are generally stable when

α- and N-substituents are both alkyl groups (see introduction part of this thesis). Interestingly,

when even one of the α-substituents or the N-substituents is an aromatic group the oxaziridine is

generally unstable. However, when the N-substituent is a tertiary alkyl group the oxaziridine can

be isolated.62 A comprehensive study of the irradiation products of a number of nitrones where

the substituents were varied from primary alkyl and tertiary alkyl groups to aryl groups

containing a range of electron-releasing or electron withdrawing groups, helped Splitter and co-

workers to obtain interesting information and a general understanding of the stability and

rearrangement tendencies of oxaziridines.62

R1

HN

O

R2

R1

N

O

H

R2

hvRearrangment or decompositionproduct

In general, N-aryl substituents destabilize the N-O bond, whereas N-alkyl substituents

stabilize the N-O bond. Electron releasing α-substituents decrease the stability of the C-O bond

and electron withdrawing substituents increase the stability of the C-O bond. Summarily, the

cleavage of the C-O bond of oxaziridines leads to nitrone when an alkyl group is substituted on

the nitrogen atom. In the other hand, cleavage of the N-O bond leads to formation of amides.

28

R1

N

O

R2

R3

R1

R2N

O

R3

R1

R2N

O

R3

For example, irradiation with ultraviolet light at a wavelength of 350 nm at the room temperature

of α-phenyl-N-benzylnitrone 26 gave N-benzylbenzamide 30. This product was formed by N-O

bond cleavage and hydrogen rearrangement of the intermediate oxaziridine.

C6H5

C

H

N

O

CH2C6H5

O

C NCH2C6H5

H

C6H5

C6H5 C

O

N

CH2C6H5

H

26 30

Formation of amides by N-O bond cleavage with subsequent migration of one of the α-

substituents can be considered to occur according to either an ionic mechanism 1 or a concerted

mechanism 2.62 The free radical mechanism was discounted by Splitter and Calvin60 for the

simple reason that in the oxaziridines electron-releasing groups opposed bond cleavage and

electron withdrawing groups facilitated bond cleavage. This is a completely opposite effect to

that found in reactions which are generally accepted as occurring via a free radical mechanism.

An ionic mechanism is the most favorable for these rearrangements.

Mechanism 1

H C

O

N

R2

R1

H

C

R2

O

N R1 C N

OR2

H R1

R2

C

H

O

N R1 R2-CO-NHR1

29

Mechanism 2

C N

OR2

H R1

C N

OR2

H R1

+H+

H C

O

N R1

R2 C

O

N R1

H C

O

N

R2

R1

R2 C

O

N

H

R1

+ R2+

Scheme 13. Two mechanisms of the formation of amides by N-O cleavage.

The driving force for the N-O and C-O bond cleavage of the oxaziridines is considered to

be relief of strain imposed on the system by the three membered ring. In this case, we can

assume that the weakest bond will cleave because the strain can be assumed to be evenly

distributed over the ring.

Kinstle and Weerasooriya65 reported that the products of irradiation of the α-styryl-N-

phenylnitrone with ultraviolet light are cinnamaldehyde, azobenzene and azoxybenzene. They

proposed that the oxaziridine intermediate was unstable and these products were formed by

decomposition. In our study we photolysed a solution in deuterated dichloromethane of α-styryl-

N-phenylnitrone 21 at a wavelength of 350 nm. We observed three absorption bands E1, E2 and

K at λ max 208, 261, 352 nm respectively. The corresponding values found in the literature for α,

N-diphenylnitrone60 for E1, E2 and K are 230, 280 and 320 nm. The shifting of the K-band and

the higher E max value for 21 could be due to the extra conjugation present in the α-styryl-N-

phenylnitrone 21. As a first experiment, α-styryl-N-phenylnitrone was irradiated for 30 minutes.

During this time the solution’ color changed from bright yellow to only slightly yellow and the

UV spectrum showed growth of the 261 nm and 352 nm absorptions. When the solvent was

removed, orange oil remained. Studies of the NMR spectrum of this reaction product proved the

30

presence of cinnamaldehyde 31 as a main photolysis product along with unreacted nitrone and

formation of α−styryl-N-phenyloxaziridine 32 (Scheme 14). In a subsequent reaction, irradiation

of 21 for a shorter time (18 min), α−styryl-N-phenyloxaziridine was the main product as shown

by NMR analysis. Storage for 30 min at 360C did not result in change in the NMR spectrum.

Ph

HC CH

C N

Ph

O

H

Ph

HC C

C

O

H

H Ph

C

C N

O

PhH

H

+

hv

21 31 32δ 6.7

δ 9.7

δ 4.5

δ 6.1

δ 7.95

Hδ 7.05

Scheme 14. Photolysis of α-styryl-N-phenylnitrone (21).

Irradiation of α-styryl-N-t-butylnitrone 24 for 15 minutes in deuterated dichloromethane

solution showed the formation of α-styryl-N-t-butyloxaziridine 33. Chemical analysis and

spectral data were used to prove the structure of oxaziridine 33.

Ph

HC CH

HC N

tBu

O

Ph

C N

O

t-BuH

H

H

hv

15 min

δ 1.14

24 33

δ 4.50

δ 6.94

δ 5.95

Scheme 15. Photolysis of α-styryl-N-t-butylnitrone (24).

Irradiation of α-styryl-N-benzylnitrone 29 proceeded smoothly in 15 minutes to produce

the stable α-styryl-N-benzyloxiziridine 34. The NMR spectrum of this compound showed an

interesting doublet of doublets for the diastereotopic N-benzyl protons. The nitrogen atom in the

oxaziridine structure undergoes inversion only very slowly (or not at all), unlike the nitrogen in

the starting nitrone in which the N-benzyl protons appear as a singlet at δ 4.9.

31

Ph

HC CH

C N

CH2C6H5

O

H

Ph

HC C

C N

O

CH2H

H

C6H5

hv

δ 3.87δ 4.3

δ 5.929 34

Scheme 16. Photolysis of α-styryl-N-benylnitrone (29).

Irradiation of α-phenyl-N-benzylnitrone 26 for 15 minutes produced the α-phenyl-N-

benzyloxiziridine 35 as a main product of the photochemical reaction. Chemical analysis and

spectral data proved the formation of oxiziridines.

Ph

HC N

O

CH2C6H5Ph

C N

O

CH2H C6H5hv

δ 4.05δ 4.7

26 35

Scheme 17. Photolysis of α−phenyl-N-benzylnitrone (26)

The fact that we saw the formation of oxaziridines in the phenyl case is very important.

The oxaziridines which were obtained during photochemical reactions were unstable and it was

not easy to study their properties.

3. Oxidation reactions of oxaziridines.

With these oxaziridines in hand, we carried out a brief study of their oxidation with the

goal of identifying an N-oxide structure generalized by 36.

N

O

CH

RR' N

O

CH

R

O

R'36

oxidation

32

The structure similar to this nitrogen, i.e. with 2 carbon and 2 oxygen single bonds, was not

identified by searching the literature using Sci-Finder. In the event, oxidation of the oxaziridine

35 was first studied using m-chloroperbenzoic acid (MCPBA). After mixing equimolar quantities

of the two reagents and stirring for 15-60 minutes at different temperature (20-350C), the

reaction mixture showed the presence of benzaldehyde, along with unreacted oxaziridine, m-

chlorobenzoic acid and some other products. The source of benzaldehyde was of interest.

Decomposition of the desired N-oxide structure, according to the (Scheme 18) would form

benzaldehyde as well as a nitroso compound.

N

O

CO

CH2Ph

H

Ph

O

Ph H

O

N

CH2C6H5

dimer

35

Scheme 18. Decomposition of the N-oxide structure.

Nitroso compounds are known to dimerize to azoxy and azodioxides. We could find no evidence

for either the monomeric or dimeric form of the nitrosocompounds. It is also known that a

nitroso compound can be colored due to radicals formed by its reaction with O2.

We next investigated the oxidation of α-styryl-N-t-butyloxaziridine 33 with either

peroxycarboxylic acid or hydrogen peroxide oxidants. We again observed the formation of

cinnamaldehyde, as well as blue coloration of the reaction mixture. However, we could find no

real mass spectral or NMR evidence for the presence of nitrosoisobutane or its dimer, in spite of

the availability of a commercial sample of the dimer for comparison.

In summary, it is clear that the oxidation of oxaziridines does not produce an N-oxide

product efficiently, it at all. Further work must be done to allow a firm conclusion to be drawn,

33

including the oxidation of some cyclic secondary hydroxylamine ethers such as 37 which do not

have an easy strain driven decomposition pathway available to them.

R

N

R

OCH3

R

N

R

O

OCH3

?

37

4. 1,3-Cycloaddition reactions.

The 1,3-dipolar cycloaddition of many simple nitrones with a variety of dipolarophiles

have been studied and results were reported by several chemists.3, 5, 8 The application of 1,3-

dipolar cycloaddition reactions in natural product synthesis is heavily dependent upon an

understanding of the regiochemistry and stereochemistry of the reaction. Houk and co-workers

used frontier molecular orbital calculations to explain the regionselectivity of the cycloaddition

reactions.66 Simple nitrones with various electron rich (see scheme 19) dipolarophiles give the 5-

substituted regioisomer, while reaction with highly electron-deficient dipolarophiles give largely

the 4-substituted isomer (see scheme 5).66

In order to understand any effect of extended conjugation of the open-chain conjugated

nitrones, we have studied cycloaddition of some α−styryl nitrones. Electron rich dipolarophiles

should66 undergo cycloaddition with nitrones to give 5-substituted isoxazolidines, but there have

been only a few examples reported in this area of chemistry. DeShong and Dicken67 reported the

cycloaddition reactions of ethylvinyl ether with C-phenyl-N-methylnitrone and C-methyl-N-

ethylnitrone at elevated pressure and temperature produced a mixture of cis and trans isomers of

the 5-alkoxy-isoxazolidine. We have synthesized and studied the 1,3-cycloaddition reactions of

nitrones (21, 24, 26, 29) with several dipolarophiles. The first series of reactions was carried out

with the electron rich dipolarophile butylvinylether 38 (Scheme 19).

34

Ph

HC N

CH2C6H5

O

O

Ph

HC CH

C N

CH2C6H5

O

H

Ph

HC CH

C N

Ph

O

H

Ph

HC CH

HC N

tBu

O

N

O

O-Bu

PhPh

N

O

O-Bu

tBuPh

N

O

O-Bu

CH2PhPh

N

O

O-Bu

CH2PhPh

24

21

29

26

+ EDG

+ EDG

+ EDG

+ EDG

39

40

41

42

benzene

85-1000C, 24-39 hr

benzene1000C, 25-62 hr

benzene

1200C, 25-64 hr

benzene

850C, 42hr

EDG=butylvinylether38

Scheme 19. Thermal 1,3-cycloaddition reactions with butylvinylether.

All reactions were monitored by TLC. The reaction of α-styryl-N-benzylnitrone 29 with

butylvinylether 38, even after 62 hours at 1000C, still showed the presence of starting materials.

The same incomplete reaction was found with α−styryl-N-t-butylnitrone 24 after 64 hours. The

reaction of α-styryl-N-phenylnitrone 21 with butylvinylether 38 was carried out for 42 hours at

850C. GCMS analysis identified the formation of product 41 by its molecular ion m/z 323.

35

Column chromatography with a (2:1) solvent system hexane/ethylacetate did not lead to clear

separate ion of products, but a major and minor stereoisomer could be identified by their NMR

spectrum of 41.

The reaction of α-phenyl-N-benzylnitrone 26 with butylvinylether 38 was carried out

during 48 hours at 1000C and then checked by GCMS analysis which showed the presence of a

molecular ion m/z 311 for the product 39 and also the presence of starting materials. NMR

analysis showed a very incomplete formation of product, so we extended the reaction time to 60

hours. The NMR spectrum for this sample showed the same mixture. Finally, we decided to

increase the temperature of the reaction to 1300C and to double the concentration of

butylvinylether 38. An NMR spectrum after 21 hours showed that starting nitrone 26 was still

present in the reaction mixture. The reaction was continued for another 20 hours and column

chromatography allowed separation of pure N-benzyl 3-phenyl-5-n-butyloxy oxazolidine 39 as a

pure compound. COSY NMR analysis helped to assign the protons as follows: 1H NMR (300

MHz, CDCl3) δ 0.91 (t, 3H, J=7.5 Hz), 1.37 (s, 1H, J=7.5 Hz), 1.55 (m, 1H), 2.29 (ddd, 1H,

J=3.0, 9.3, 13.2 Hz), 2.85 (ddd, 1H, J=6.3, 8.1, 13.2 Hz), 3.38 (dt, 1H, J=6.6, 9.6 Hz), 3.69

(complex, 3H), 4.0 (d, 1H, J=14.7 Hz), 5.12 (dd, 1H, J=6.3, 3.0 Hz), 7.14-7.37 (m, 8H), 7.46 (dd,

2H).

36

N

O

O

H2C

CH2

H2C

H3C

H

H

H

H

H

CH2

H

δ 0.91

δ 1.37

δ 1.55

δ 3.38

δ 5.12

δ 4.0

aromatic δ 7.14−7.37

δ 2.85

δ 2.29

δ 3.6

δ 7.46

39

Joucla and Hamelin reported that nitrostyrene reacts with C,N-diphenylnitrone to give an

85:15 mixture of the 3,4-trans- and 3,4-cis-4-nitroisoxazolidines 43 and 44.68

C

Ph

H

H

NO2

NR O

Ph

O

N

Ph

HPh

R

NO2H

H

O

N

Ph

HPh

H

NO2H

R

(a) R= Ph(b) R=-COPh

43 44

C-Benzoyl, N-phenylnitrone (R=COPh) reacted stereospecifically to give only trans-4-

nitroisoxazolidine.

In our hands trans-β-nitrostyrene 45 reacts with conjugated nitrone 29 rapidly to give 4-

substituted nitroisoxazolidines. We performed a comparison study with the non-conjugated

nitrone 26.

37

Ph

N

CH2C6H5

O

H H

Ph

NO2

H

Ph

C N

CH2C6H5

O

H

H

H

H

Ph

NO2

H

O

N

O2N Ph

Ph

CH2C6H5

O

N

O2N Ph

C

CH2C6H5

CPh

H

H

29

26

+

+

45

45

46

47

benzene

1100C, 10hr

benzene

1100C, 10hr

Scheme 20. Thermal 1,3-cycloaddition reactions with trans-β-nitrostyrene.

The reactions were monitored with time by TLC and GCMS analysis. The reaction with α-

phenyl-N-benzylnitrone 26, was checked first after 10 hours at 1100C. GCMS analysis did not

show a peak with m/e 360, the molecular weight of the expected N-benzyl-4-nitro-3-phenyl-5-

phenyloxaziridine 46. There were two peaks which correspond to the two starting materials

nitrone 26 and trans-β-nitrostyrene 45 (M/z: 211 and 149, respectively). However, MALDI

analysis proved the presence of the product 46. In this case, we propose that the product 46 of the

reaction decomposed during GCMS analysis. DIP mass spectral analysis shows a peak with m/z

360. The same reaction with a prolonged time of 25 hours showed the same results, which means

that the reaction was complete in 10 hours. Column chromatography with hexane/ethylacetate

(7:1) system allowed the separation of the reaction mixture into a pure major component and a

mixture of minor isomers. The major isomer was assigned the all trans structure 46, based on the

coupling constants J4,5=4.2 Hz and J3,4=6.6 Hz. The minor isomers are tentatively assigned the

structures 46’’ and an N-stereoisomer 46’. Interestingly, the geminal H-H coupling constant for

38

this other compound 46’ is only 7.2 Hz compared to 13.8 Hz for all the other N-benzylnitrone

adducts.

N

O

CH2Ph

Ph

H4

H5O2N

H3

PhN

O

CH2Ph

Ph

H4

H5O2N

H3

Ph

46, 46' 46''

The reaction of α-styryl-N-benzylnitrone 29 with trans-β-nitrostyrene 45 was complete

after 10 hours at 1100C. DIP analysis proved the presence of molecular ion m/z 386 for the

adduct N-benzyl-4-nitro-5-phenyl-3-styryloxaziridine 47. The NMR spectrum of the crude

reaction mixture indicated the presence of a mixture of product adducts. Column

chromatography with dichloromethane/hexane (2:1) allowed separation of a mixture of isomeric

product adducts. The preponderant product was the all trans isomer 48. Evidence for this

structure was obtained from the proton NMR of a pure sample. The coupling constants for the

ring protons were J3,4=6.3 Hz and J4,5=4.5 Hz. One of the two compounds present in another

chromatography fraction was the 3,4-cis-4,5-trans stereoisomer 49. Here the ring proton coupling

constants were measured to be J3,4=8.4 Hz and J4,5=5.7 Hz. The third stereoisomer present in a

quantity equal to that of 49, is most probably an isomer differing in its nitrogen stereochemistry

from that of 48, which will be designated as 48’. There is NMR evidence for the non-inversion

of the nitrogen of the oxazolidine ring, since the benzylic protons are clearly diastereotopic (d of

d, J=13.8 Hz) and do not interchange or average at temperatures several degrees above room

temperature. The specific N-stereochemistry for 48 and 48’ is not clear, and final assignment of

structure is therefore not possible.

39

Ph

H

H

N

O

CH2Ph

Ph

H4

H5O2N

H3

N

O

CH2Ph

Ph

H4

H5O2N

H3Ph

H

H

d, J=4.5

d of d J=6.3, 8.7d of d J=8.7, 15.9

d, J=15.9d of d J=4.5,6.3

48, 48'

d, J=5.7

d of d J=3.6, 8.4

d of d J=5.7, 8.4

49Because development of new methods for the preparation of enantiomerically pure compounds is

an important goal for synthesis, recently our purpose was to investigate the stereocontrol for our

thermal 1,3-cycloadditon reactions. Enantioselective nitrone cycloaddition reactions have been

reported that utilize chiral reactants and these compounds use this asymmetry to induce

stereoselectivity in the bond forming cycloaddition step. Many cycloaddition reactions can be

accelerated by Lewis acid catalysts, indicative of dipolarity in the transition state for these

nominally “concerted” reactions. The combination of a Lewis acid catalyst and enentioselectivity

can be approached by using a chiral Lewis acid catalyst in these nitrone cycloaddition reactions.

Some initial results in this area have appeared in the literature.

Kanemasa47 reported, in 1998, the synthesis of dibenzofurandiyl 2, 2’- bis-oxazolines

(DBFOX’s) and described them as excellent ligands for a variety of Lewis acids. Cationic aqua

complexes that show a high catalytic activity can be prepared by the combination of chiral (R,

R)-4,6- dibenzofurandiyl-2,2’-bis(4-phenyloxazoline) (DBFOX/Ph) with a variety of metal(II)

perchlorates such as magnesium, nickel, iron, cobalt, copper and zinc ions. They tested these

various complexes as cycloaddition catalysts. They concluded that the most selective chiral

catalyst for the normal electron-demand 1,3-dipolar cycloaddition reaction between nitrones and

alkenes was Ni(ClO4)2*PhDBFOX complex.48 First, my challenge was to synthesize this ligand.

The synthesis was carried out in several steps as shown in Scheme 21.

40

All intermediates were purified by recrystallization and checked with NMR analysis.

O

O

CO2H CO2H

O

ClO ClO

O

NHO OHN

HO OHPh Ph

O

NHO OHN

HO OHPh Ph

O

CO2H CO2H

O

O N N O

Ph Ph

O

ClO ClO

1. s-BuLi, TMEDA

Et2O, 250C, 24hr

2. CO2(g), -780C

3. H2O

SOCl2, CHCl3

680 C, 3hr

(R)-phenylglycinol

Et3N, CHCl3250 C, 24 hr

2,3 eq DAST

CH2Cl2

-200 C, 18 hr

50 51

52

53

54

A.

B.

C.

D.

51

52

53

Scheme 21. (R,R)-4,6-Dibenzofuranyl 2, 2’- bis (4-phenyloxazoline)oxazoline (DBFOX/Ph)-a

novel tridentate ligand.

41

All glassware were dried at 1400C for at least 2 hr and cooled under argon where appropriate

before use in the reactions. Solvents were distilled from the appropriate drying agent and were

used immediately. In step A the beige-colored lithiated reaction mixture turned white upon

introduction of gaseous carbon dioxide at -780C. After 1 hour of stirring, the reaction mixture

was warmed to 250C over 4 hours still under a constant CO2 stream. We observed that at -250C

the reaction mixture changed color again, from white to red-brown. After filtration and drying

under vacuum there was obtained 2.82g (92% yield) of dibenzofuran-4,6-dicarboxylic acid 51.

For step B, it was important not to use too much chloroform during the filtration process because

the product is somewhat soluble. After drying in a vacuum desiccator for 15-20 hr the

dibenzofuran-4,6-dicarbonyl chloride was obtained 52 as a white powder (1.75 g, 77 % yield).

For step C, we used of a heat gun to heat the addition funnel to completely dissolve the (R)-(-)-2-

phenylglycinol. It was hard to avoid formation of a thick gel-like slurry while adding the mixture

of the (R)-(-)-2-phenylglycinol and triethylamine in chloroform. Addition of more chloroform

was necessary to keep the reaction mixture stirring. (R, R)-dibenzofuran-4,6-bicarboxylic acid

bis(2-hydroxy-1-phenylethyl) amide 53 was obtained after purification by different methods

(2.39g, 81% combined yield). Previous workers48 used an electrical refrigeration bath to

maintain the reaction mixture temperature at -200C during 18 hours. In our case we used

methanol/water/dry ice mixture to maintain this temperature. The material formed in step D was

chromatographed using silica gel (3:1, ethylacetate/hexane) to yield 0.85 g (92% yield) of

product. NMR analysis proved that (R,R)-4,6-Dibenzofurandiyl-2,2’-bis(4-phenyloxazoline),

DBFOX/Ph 54 was the pure product obtained.

Kanemasa and co-workers successfully applied Ni(ClO4)2*DBFOX/Ph 12 as a chiral

catalyst for the 1,3-cycloadditon reaction using non-conjugated nitrone 55. The reaction of 3-

42

crotonoyl-2-oxazolidinone 56 with N-benzylidenemethylamine N-oxide 55 produced 3,4-trans-

isoxazolidines 57 with great endoselectivity (endo:exo=98:2) and enantioselectivity for 3S, 4R,

5S enantiomer (>99% ee).47

Ph N

Me

O

O N

O

Me

ONMeO

C

Me Ph

ON

O

+(R, R)-(12) 10 mol%

4 A MS, 250C, CH2Cl255 56 57

O Before we tried to apply this method to our 1,3-cycloaddition reaction, the cationic aqua

complex Ni(ClO4)2*PhDBFOX was simply prepared from a trans-chelating tridentate ligand

(R,R)-4,6-dibenzofurandiyl-2,2’-bis(4-phenyloxazoline) (DBFOX/Ph) 54 and Ni(ClO4)2*6H2O

in dichloroethane by stirring at the room temperature for 3 hours. Then we tried to repeat our

previous reaction of α-phenyl-N-benzylnitrone 26 with trans-β-nitrostyrene 45 (Scheme 20) but

using our newly prepared cationic aqua complex Ni(ClO4)2*PhDBFOX. MS 4A, trans-β-

nitrostyrene and nitrone 26 were added to a stirred solution of the chiral Ni-complex in this

order. The reaction was performed under the same conditions and monitored by TLC.

Eventually, the reaction was carried out for 6 hours at room temperature, plus 10 hours at 750C

and additional 6 hours at 1100C. We did not observe any evidence for the formation of N-benzyl-

4-nitro-3-phenyl-5-phenyloxaziridine 46. We then repeated this reaction for 5 hours at 1450C and

unfortunately, there was still no evidence for a cycloadduct.

43

CONCLUSIONS

Several non-conjugated and α-conjugated nitrones were synthesized and characterized.

Before we started work with my M.S. research, a search for information in Sci-Finder and

Beilstein did not show any references about α-conjugated nitrones such as α-styryl-N-

phenylnitrone, α-styryl-N-t-butylnitrone and α-styryl-N-benzylnitrone. We have synthesized

them and studied their characteristics. Photolysis of these nitrones lead to the formation of

oxaziridines. We also briefly tried to apply the oxidation reactions on these oxaziridines. All

nitrones underwent the new 1,3-cycloaddition reactions with electron-rich butylvinylether and

showed the formation of 4-and 5-substituted isoxazolidines with other dipolarophiles. The trans-

chelating tridentate ligand(R,R)-4,6-dibenzofurandiyl-2,2’-bis(4-phenyloxazoline) (DBFOX/Ph)

was successfully synthesized. The cationic aqua complex Ni(ClO4)2*PhDBFOX was applied as a

chiral catalyst for 1,3-cycloaddition reactions.

This project has produced interesting results, which give new interest for future

investigation in this field of chemistry.

44

SUGGESTIONS FOR FUTURE RESEARCH

The chemistry of α-styryl substituted nitrones has been developed to some extent.

However, the chemistry of these conjugated nitrones is still largely unknown. The suggestions

for future work are to continue the development of convenient syntheses of these nitrones, to

improve and study mechanistically their photoisomerization reactions and to study the stability

and synthetic utility of the resulting oxaziridines. Still open is the question of possible oxidation

of oxaziridine with formation of N-oxide. In my M.S. work we successfully synthesisized the

trans-chelating tridentate ligand (R,R)-4,6-dibenzofurandiyl-2,2’-bis(4-phenyloxazoline)

(DBFOX/Ph) 54 and preparated from it a cationic aqua complex Ni(ClO4)2*PhDBFOX, which

was reported by Kanemasa47 to be a very selective chiral catalyst for the normal electron-demand

1,3-dipolar cycloaddition reaction between nitrones and alkenes. Future work should develop

applications of this complex or related complexes for synthetic diversity studies of nitrones.

45

EXPERIMENTAL General procedure

The melting points of compounds were determined using a Mel-Temp apparatus and

temperatures are reported in degrees Celsius. Nuclear magnetic resonance spectra (NMR) were

obtained in deuterated solvents using a Bruker Avance 300 NMR at 300 MHz or a Varian Unity

Plus NMR spectrometer at 400 MHz. Chemical shifts are reported in ppm (parts per million)

field in relation to the internal standard tetramethylsilane (TMS) as 0 ppm. Multiplicity of signals

is abbreviated as follows: (s) singlet, (d) doublet, (t) triplet, (q) quartet and (m) multiplet. IR

spectra were recorded using a Thermo Nicolet IR 200 spectrophotometer. The mass spectra were

obtained using a Shimadzu QP5050A/GC-17A instrument or Hewlett Packard 5987A. Column

chromatography was carried out with Merck Silica gel powder (60-200 Mesh size) using

appropriate solvents. All thin layer chromatograms were obtained using pre-coated Baker-flex

silica gel plates (IB-F). Air sensitive reactions were carried out under Ar or N atmosphere.

Synthetic Procedures

Preparation of N-phenylhydroxylamine (20). Ammonium chloride (25 g, 470 mmol)

and nitrobenzene (50 g, 470 mmol) were added to 800 mL water in a three-necked round-

bottomed flask. This yellow mixture was stirred with a mechanical stirrer for 60 min, then during

a period of 30 min zinc powder (53g, 830 mmol) was slowly added. The temperature of the

yellow/grey reaction mixture increased to 54 0C. Stirring was continued for 15 min after which

time the reaction was complete as indicated by a lowering of the temperature of the reaction

mixture. Stirring was continued for 15 min, then the solution was suction filtered while still hot

to remove zinc oxide. The solids were washed with 100 mL of hot water. The combined aqueous

46

portions were saturated with NaCl salt and cooled to 0 0C. The crystalline N-

phenylhydroxylamine which precipitated from the solution was removed by suction filtration.

These crystals after being dried in a vacuum desiccator overnight amounted to 17.41 g (34%

yield). Mp 80-82 0C. (lit.60 81-82 0C). 1H NMR (CDCl3): δ 6.5 (2H, br, NHOH), 7.02 (3H, m),

7.30 (2H, m).

Preparation of α-styryl-N-phenylnitrone (21). In a 125 mL Erlenmeyer flask 6g (55

mmol) of N-phenylhydroxylamine and 11 mL of absolute ethanol were stirred and warmed to 50

0C. An additional 5 mL of absolute ethanol was added slowly to completely dissolve the N-

phenylhydroxylamine. To this solution 7.2g (55 mmol) of trans-cinnamaldehyde was added.

After the initial evolution of heat had subsided the reaction mixture was kept overnight at room

temperature in the dark. The crude nitrone product was filtered from the brown colored solution

and recrystallized from hot absolute ethanol. The yellow crystals obtained after filtering and

vacuum drying weighed 5.5g (47% yield). Mp 152-154 0C. 1H NMR (CDCl3): δ 7.17 (d, 1H,

J=15.9 Hz), 7.33- 7.41 (m, 3H), 7.44-7.48 (m, 3H), 7.57 (dd, 2H, J=1.8, 7.8 Hz), 7.62 (d, 1H,

J=9.6Hz),7.75(m,2H),7.86(dd,1H,J=0.6,9.6Hz).13CNMR(CDCl3):δ 77.6, 77.0, 77.2, 77.4, 119.0,

121.3, 127.4, 128.9, 129.0, 129.4, 129.9, 136.0, 136.4, 140.1, 147.3.

Preparation of 2-methyl-2-nitropropane (22). In 1-L three-necked flask fitted with a

reflux condenser, a mechanical stirrer and a thermometer was added a well-stirred suspension of

potassium permanganate (65g, 410 mmol) in 300 mL of water. Then during 10 min t-butylamine

(10g, 137 mmol) was added dropwise and with stirring. When the addition was complete, the

reaction mixture was heated to 55 0C over a period of approximately 2 h, and maintained at 550

C with continuous stirring for 3 h. The dropping funnel and reflux condenser were replaced by a

stopper and a still head fitted for steam distillation and the product was steam distilled from the

47

reaction mixture. The distillate was transferred to a separatory funnel and 50g of sodium chloride

was added and dissolved. The organic layer was separated from the more dense water layer,

diluted with 50 mL of ether, and washed successively with 10 mL portions of aqueous 2M

hydrochloric acid and 10 mL of water. After the etheral solution had been dried over anhydrous

magnesium sulfate, the solution was fractionally distilled at atmospheric pressure to remove the

ether. The residual crude product amounted to 11.1g (78% yield) and was sufficiently pure for

use in the next step. M/z: 57(100), 41(67), 39(31).

Preparation of N-t-butylhydroxylamine (23). Aluminum foil (3g) was cut into strips

and each strip was rolled into a cylinder about 1 cm in diameter. Each of the aluminum foil

cylinders was amalgamated by immersing it in a solution of 0.96g (3.6 mmol) mercury (II)

chloride in 48 mL of water for 15-20 sec. Each amalgamated cylinder was then rinsed

successively in ethanol and in ether and added to a mixture of ether (180 mL) and water (1.8 mL)

contained in a 500 mL three-necked flask fitted with a dropping funnel, a mechanical stirrer, and

a large efficient reflux condenser. The reaction mixture was stirred vigorously and 2-methyl-2

nitropropane (6g, 58 mmol) was added dropwise at such a rate that the ether refluxed briskly. A

vigorous reaction occurred and cooling with an ice bath was necessary. After addition of the

nitro compound was complete, the reaction was stopped and the gelatinous precipitate was

allowed to settle. The colorless supernatant was decanted through glass wool and washed with

100 mL of aqueous 2M sodium hydroxide. The precipitate in the reaction flask was washed with

two 100 mL portions of ether and these washings were dried over anhydrous sodium sulfate and

concentrated under reduced pressure with a rotary evaporator. The residual white crystalline

solid was dried under reduced pressure at room temperature to give 2.37g (48% yield) of crude

48

N-t-butylhydroxylamine. Mp 60-62 0C. (lit.61 64-65 0C). M/z: 89 (4) [M+], 74 (63) [M+-15], 57

(60), 41 (100).

Preparation of α-styryl-N-t-butylnitrone (24). In a 125 ml Erlenmeyer flask t-

butylhydroxylamine (2.37g, 26.6 mmol) was dissolved in 15.8 mL of absolute ethanol and the

solution was warmed to 50 0C. Trans-cinnamaldehyde (3.46g, 26.6 mmol) was added to this

solution. The reaction mixture was heated to 50 0C for 15 minutes and kept overnight in the dark

at room temperature. The light yellow semi-solid obtained after removing solvent with rotary

evaporator was purified by column chromatography on silica gel using first ethyl acetate/hexane

(ca. 1.25:1) and then ethyl acetate/hexane (ca. 2:1) as solvents. Removal of the solvent under

reduced pressure afforded the nitrone 3.9g, (74% yield) as a light yellow crystalline solid. 1H

NMR (CDCl3): δ 1.55 (s, 9H), 7.0 (d, 1H, J=15.9 Hz), 7.27-7.37 (m, 3H), 7.43 (d, 1H, J=9.6 Hz),

7.49-7.57(m, 3H). 13C NMR(CDCl3):δ 28.1, 69.3, 76.6, 77.0, 77.5, 119.5, 127.2, 128.8, 128.9,

132.1, 136.4, 137.9.

Preparation of N, N-dibenzylhydroxylamine (25). In a 500 ml three-necked, round

bottomed flask hydroxylamine hydrochloride (10.5g, 150 mmol), benzylchloride (36g, 300

mmol) and sodium carbonate (22.5g) were mixed in 50 mL of water-250 mL of ethanol mixture

for 6 h. Then the solution was then heated to 78-85 0C. Ethanol was distilled off, more water was

added and the crude dibenzylhydroxylamine precipitated. The solution was filtered and 24.8g

(78% yield) of product was obtained. After recrystallization twice from hot ethanol large white

crystals were isolated. Small crystals of tribenzylamine impurity were removed by washing with

ether. The product was again recrystallized from ethanol. Mp 122-124 0C. (lit.72 1230C). 1H NMR

(CDCl3): δ 3.76 (s, 4H), 7.2-7.3 (m, 10H).

49

Preparation of α-phenyl-N-benzylnitrone (26). Method A. In a 100 ml one-necked,

round bottomed flask N,N-dibenzylhydroxylamine (2g, 10 mmol) in 18 mL of chloroform and

yellow mercuric oxide (2.4g, 10 mmol) were mixed thoroughly at room temperature. The

hydroxylamine was gradually oxidized to the nitrone and the reaction was complete after 12 h.

The reaction mixture was filtered and chloroform was removed to obtain the crude nitrone 1.49g,

(71% yield) which was recrystallized from absolute ethanol at 0 0C. Mp 82-84 0C, (lit.63 80-82

0C). 1H NMR (CDCl3): δ 5.35 (s, 2H), 7.34-7.54 (m, 9H), 8.15-8.25 (m, 2H). 13C NMR (CDCl3):

δ 72.2, 128.1, 128.4, 128.9, 129.1, 131.2, 131.4, 132.7, 133.9. Mass spectrum (EI, 70 eV): 211

(M+, 4.7), 91 (base peak). Calcd for C14H13NO: 211.26.

Preparation of N-benzylidenebenzylamine N-oxide (α-phenyl-N-benzylnitrone) (26).

Method B. In a 250 mL side-armed flask equipped with a magnetic stirring bar were placed

dibenzylamine (5g, 25 mmol), Na2WO4*2H2O (0.512g, 1.5 mmol), and 77.5 mL of methanol. To

the stirred solution was added 30% aqueous hydrogen peroxide (13.18 g) dropwise with ice

cooling. After the addition was complete, the reaction mixture was stirred at room temperature

for 4 h. Methanol was removed under reduced pressure. To the residue were added 380 mL of

dichloromethane and 155 mL of saturated aqueous sodium chloride solution. The organic layer

was separated, washed with 155 mL of saturated aqueous sodium chloride, and dried over

anhydrous sodium sulfate. Removal of the solvent gave 4.95g, (92% yield) of nitrone as crystals.

After recrystallization from petroleum ether/dichloromethane the melting point of nitrone was

81-83 0C. (lit.63 80-82 0C). 1H NMR (CDCl3): δ 5.31 (s, 2H), 7.31-7.51 (m, 9H), 8.17-8.25 (m,

2H). 13C NMR (CDCl3): δ 71.2, 128.4, 128.6, 128.9, 129.1, 130.3, 130.4, 133.2, 134.3. Mass

spectrum (EI, 70 eV): 211 (M+, 4.7), 91 (base peak). Calcd for C14H13NO: 211.26.

50

Preparation of N-Benzylhydroxylamine hydrochloride (28). In a 50 mL one-necked,

round bottomed flask α-phenyl-N-benzylnitrone (1.4g, 6.7 mmol) was dissolved in 14 mL of

ethanol. To this solution 5.6 mL of 10% hydrochloric acid solution was added and stirred for 2 h,

by which time the hydrolysis was complete. Most of the alcohol was then removed under

vacuum and the benzaldehyde formed in the reaction was extracted with ether. The aqueous

solution which contained the benzylhydroxyamine hydrochloride was vacuum dried to remove

water and crystallized from ethylacetate. White benzylhydroxylamine hydrochloride 0.94g, (90%

yield) was obtained. Mp 108-110 0C. (lit. 105-107 0C). 1H NMR (Me2SO-d6): δ 4.3(s, 2H, CH2),

7.42(m, 3 (Me2SO-d6) meta and para aryl H’s), 7.51(m, 2H, ortho aryl H’s), 11.65(br s, 3H, NH2

and OH).

Preparation of α-styryl-N-benzylnitrone (29). In a 100 mL two-necked, round

bottomed flask benzylhydroxylamine chloride (1.5g, 10 mmol) in 25 mL of ethanol and

cinnamaldehyde (1,3g, 10 mmol) were mixed together. To this mixture sodium bicarbonate 3.0g

was added to neutralize the hydrochloride and the mixture was stirred thoroughly until the

evolution of carbon dioxide stopped. This mixture was left in the dark overnight. The alcoholic

solution was then filtered and the filtrate cooled to yield yellowish crystals of the crude nitrone

0.7g, (30% yield). This crude product was then recrystallized from absolute ethanol to give pale

yellow crystals. Mp 124-1260 C. 1H NMR (CDCl3): δ 4.95 (s, 2H), 6.95 (d, 1H), 7.2-7.55 (m,

12H).

Preparation of dibenzofuran-4,6-dicarboxylic acid (51). A 250 mL three-necked,

round bottomed flask was fitted with a magnetic stirbar. Under argon, the flask was charged with

dry, freshly distilled diethyl ether (70 mL), dibenzofuran (2g, 0.012 mmol) and

tetramethylethylenediamine (TMEDA) (5.4 mL). The mixture was cooled to -78 0C using a dry

51

ice/acetone bath and stirred while sec-butyllithium (25.44 mL, 35.62 mmol) was added over 1 h

via syringe. After warming the reaction mixture to 25 0C, the suspension was stirred for 24 h.

The mixture was cooled again to -78 0C under vigorous stirring and gaseous carbon dioxide

(CO2) was introduced into the flask over 1 h through a wide pipette which was submerged below

the surface of the reaction mixture, over 1 h. The beige-colored suspension turned white upon

introduction of carbon dioxide. The reaction mixture was then warmed to 25 0C during 4 h under

a constant CO2 stream. At -25 0C, the white suspension turned red-brown color. After decanting

the supernatant liquid, a brown solid was isolated by filtration using a Buchner funnel. The

yellow supernatant/filtrate comprised TMEDA in diethyl ether, while the remaining solid was

the lithiocarboxylate of diacid. No precaution was taken during filtration to exclude air or

moisture. The residue was washed with 60 mL of diethyl ether and then suspended in 40 mL

water, acidified with aqueous 2N HCl to pH 3, and stirred for 1 h. After filtration, the beige

solids were washed first with 80 mL of water and then with 40 mL of diethyl ether. The solids

after drying under vacuum over phosphorus pentoxide (P2O5) for three days amounted to 2.82g,

(92% yield) of dibenzofuran-4,6-dicarboxylic acid. 1H NMR (300 MHz, DMSO-d6) δ 7.53 (dd,

2H), 8.04 (d, 2 H), 13.30 (bs, 2H), MS (EI) m/z 256 (M+, 15), 181 (15), 69 (100); Calcd for

C14H8O5Na 279.0264.

Preparation of Dibenzofuran-4,6-dicarbonyl chloride (52). A 100 mL, three-necked

flask, equipped with a magnetic stirbar, condenser, thermometer, and addition funnel, was

charged with diacid (2g, 7.8 mmol) and 27.3 mL of chloroform. At 25 0C, thionyl chloride (17.6

mL) and 1 drop of dimethylformamide (DMF) were added, followed by heating the mixture at 68

0C for 3 h. After the initial suspension turned into a yellow solution, the reaction mixture

remained cloudy throughout. The heating source was removed and the diacid chloride

52

precipitated as a white solid. After the reaction mixture was cooled to 25 0C, the solid was

collected via filtration using a Buchner funnel and was washed with chloroform and then dried in

a vacuum desiccator for 15 h to give 1.75 g, (77 % yield) of a white powder. 1H NMR (300

MHz, CDCl3) δ 7.59 (dd, 2H), 8.31 (dd, 2H), 8.33 (dd, 2H), MS (EI) m/z 292 (M+, 40), 257 (40),

169 (20), 119 (20); Calcd for C14H6Cl2O3 291.9694

Preparation of (R,R)- Dibenzofuran-4,6-dicarboxylic acid bis (2-hydroxy-1-phenyl)

amide (53). A 250 mL, three-necked flask, equipped with a large magnetic stirbar, was charged

with diacid chloride (1.75g, 6 mmol) and 47 mL of freshly distilled CHCl3. After cooling the

suspension to 0 0C under argon, a solution of (R)-2-phenylglycinol (1.8g, 13.11 mmol) and

triethylamine (Et3N) (1.85 mL, 13.11 mmol) in 8.75 mL of chloroform was added over 2 h via

an addition funnel. The contents in the addition funnel were carefully warmed to completely

dissolve the (R)-2-phenylglycinol and then were allowed to cool before addition to the reaction

mixture. Additional CHCl3 was added slowly to avoid formation of a thick gel-like slurry which

was too viscous to stir. After the reaction mixture was stirred for 15 h at 25 0C, 35 mL of

chloroform and solid ammonium chloride (1.75 g) were added and the suspension was stirred for

a further 0.5 h. The suspension was filtered and the residue was washed with CHCl3 (3*17.5

mL). The residue was put aside for suspension in tetrahydrofuran (THF). The combined filtrate

and washings were evaporated to dryness under reduced pressure. The resulting residue was

purified by two recrystallizations from ethyl acetate/hexane (ca. 9:1) to give amide 1.8g, (61%

combined yield). The original solid residue obtained from the filtration, was suspended in 70 mL

of THF. The slurry was stirred using a magnetic stirbar for 30 min and then filtered. The THF

extraction of this residue was repeated and the filtrates were combined. Removal of the solvent

under reduced pressure afforded additional amide, which was recrystallized as before 0.59g,

53

(20% yelid). 1H NMR (300 MHz, DMSO-d6) δ 3.66−3.81 (m, 4H, CH2OH), 4.98 (t, 2H,

CH2OH), 5.20 (dd, 2H, CHPh), 7.16-7.27 (m, 6H), 8.00 (dd, 2H), 8.36 (dd, 2H), 8.81 (d, 2H,

PhCHNH), MS (ES) m/z 517 (M+Na+, 40), 495 (M+H, 100), 375 (50), 255 (25). Calcd for

C30H26N2O5Na 517.1739.

Preparation of (R,R)-4,6-Dibenzofurandiyl-2,2’-bis(4-phenyloxazoline), DBFOX/Ph

(54). A 50 mL one-necked flask equipped with a magnetic stirbar was charged with (R,R)-

dibenzofuran-4,6-dicarboxylic acid bis (2-hydroxy-1-phenyl) amide (1.00g, 2 mmol) and 20 mL

of dichloromethane (CH2Cl2). After the suspension was cooled to -20 0C, 0.62 mL of

diethylaminosulfur trifluoride (DAST) was slowly added via syringe. After 14 hr at -20 0C, 1.67

mL of aqueous 4N ammonium hydroxide (NH4OH) was added and the resulting solution was

stirred for 15 min at -20 0C. Subsequently, the cooling bath was removed and 4 mL of water was

added. The yellow aqueous phase was extracted with CH2Cl2 (3*5 ml) and the combined organic

phases were dried over magnesium sulfate (MgSO4) and concentrated under vacuum. The

resulting material which was chromatographed using silica gel (40% EtOAc/hexane) amounted

to 0.85 g, (92% yield) as an off-white foam. This foam could be recrystallized from

EtOAc/hexanes to yield white crystals. 1H NMR (300 MHz, CDCl3) δ 4.38 (br t, 2H), 4.96 (dd,

2H), 5.54 (dd, 2H), 7.23-7.45 (m, 12H), 8.10-8.19 (m, 4H).

Reaction of α-phenyl-N-benzylnitrone with butylvinylether. A solution of α-phenyl-

N-benzylnitrone (0.5g, 2.4 mmol) in 15 mL of benzene and butylvinylether (0.35 g, 3.6 mmol)

was sealed in a high pressure reaction tube. Then the tube was heated at 100 0C for 39 h. After

cooling, the solvent was removed by evaporation under reduced pressure with a rotary

evaporator. Column chromatography leads to obtain the product 39. 1H NMR (300 MHz, CDCl3)

δ 0.91 (t, 3H, J=7.5 Hz), 1.37 (s, 1H, J=7.5 Hz), 1.55 (m, 1H), 2.29 (ddd, 1H, J=3.0, 9.3, 13.2

54

Hz), 2.85 (ddd, 1H, J=6.3, 8.1, 13.2 Hz), 3.38 (dt, 1H, J=6.6, 9.6 Hz), 3.69 (complex, 3H), 4.0 (d,

1H, J=14.7 Hz), 5.12 (dd, 1H, J=6.3, 3.0 Hz), 7.14-7.37 (m, 8H), 7.46 (dd, 2H). (See appendix

13).

Reaction of α-styryl-N-benzylnitrone with butylvinylether. A solution of α-styryl-N-

benzylnitrone (0.1g, 0.42 mmol) in 15 mL of benzene and butylvinylether (0.063 g, 0.6 mmol)

was sealed in a high pressure reaction tube. Then the tube was heated at 100 0C for 62 h. After

cooling, the solvent was removed by evaporation under reduced pressure with a rotary

evaporator.

Reaction of α-styryl-N-t-butylnitrone with butylvinylether. A solution of α-styryl-N-

t-butylnitrone (0.1g, 0.5 mmol) in 15 mL of benzene and butylvinylether (0.074 g, 0.7 mmol)

was sealed in a high pressure reaction tube. Then the tube was heated at 100 0C for 25 h. After

cooling, the solvent was removed by evaporation under reduced pressure with a rotary

evaporator.

Reaction of α-styryl-N-phenylnitrone with butylvinylether. A solution of α-styryl-N-

phenylnitrone (0.1g, 0.45 mmol) in 15 mL of benzene and butylvinylether (0.067 g, 0.67 mmol)

was sealed in a high pressure reaction tube. Then the tube was heated at 85 0C for 24 h. After

cooling, the solvent was removed by evaporation under reduced pressure with a rotary

evaporator. Column chromatography leads to obtain the product 41. (See appendix 12).

Reaction of α-phenyl-N-benzylnitrone with trans-β-nitrostyrene. A solution of α-

phenyl-N-benzylnitrone (0.5g, 2.4 mmol) in 15 mL of toluene and trans-β-nitrostyrene (0.35 g,

2.4 mmol) was a high pressure reaction tube. Then the tube was heated at 110 0C for 10 h. After

cooling, the solvent was removed by evaporation under reduced pressure with a rotary

evaporator. Column chromatography leads to obtain the product 46 1H NMR (300 MHz, CDCl3)

55

δ 4.14 (d, 1H, J=13.8 Hz), δ 3.95 (d, 1H, J=13.8 Hz), 4.63 (d, 1H, J=6.3 Hz), 5.25 (dd, 1H,

J=3.9, 6.6 Hz), 5.68 (d, 1H, J=4.2 Hz), 7.25-7.40 (m, 15H). (See appendices 15-17).

Reaction of α-styryl-N-benzylnitrone with trans-β-nitrostyrene. A solution of α-

styryl-N-benzylnitrone (0.3g, 1.3 mmol) in 15 mL of benzene and trans-β-nitrostyrene (0.19 g,

1.3 mmol) was sealed in a high pressure reaction tube. Then the tube was heated at 110 0C for 25

h. After cooling, the solvent was removed by evaporation under reduced pressure with a rotary

evaporator. Column chromatography leads to obtain the product 40. (See appendices 18-19).

Preparation of the aqua complex of DBFOX/Ph-Nickel (II) perchlorate. A mixture of

(R,R)-4,6-dibenzofurandiyl-2,2’-bis(4-phenyloxazoline) (R,R- DBFOX/Ph, 39 mg, 0.085 mmol)

and Ni(ClO4)*6H2O (31.15 mg, 0.085 mmol) in dichloroethane (5.3 mL) was stirred at room

temperature for 3 h during which time most of the nickel salt was dissolved.

Nitrone cycloaddition reaction catalyzed by the aqua complex of DBFOX/Ph-Nickel

(II) perchlorate. To the mixture of the DBFOX/Ph*Ni(ClO4)2*3H2O was added MS 4A (0.6

mg), trans-β-nitrostyrene (0.126 g, 0.85 mmol), α-phenyl, N-benzylnitrone (0.224 g, 1.061

mmol), and the mixture was stirred. The reaction was performed at different temperature and

monitored by TLC. Summarily, the reaction was carried out for 6 hours at room temperature,

plus 10 hours at 750C and additional 6 hours at 1100C.

Photolysis of α-styryl-N-phenylnitrone. A sample of α-styryl-N-phenylnitrone (0.05g,

0.2 mmol) in 100 mL of dichloromethane in 5 tubes was photolysed using uv lamps at a

wavelength of 350 nm at room temperature. Initial nmr spectra and uv spectra were taken before

photolys and the photochemical reaction was followed by nmr spectra and uv spectra. After 10

min of irradiation, the solution had changed color from slightly yellow to colorless. At this time,

a new set of peaks appeared in the nmr spectra and the uv spectra λmax was changed from 288

56

nm to 261 nm. The structure assignment of the product was based mainly on the nmr spectra

which suggested an oxaziridine structure. (See appendix 7).

Photolysis of α-styryl, N-t-butylnitrone. A sample of α-styryl-N-butylnitrone (0.02g,

0.1 mmol) in 100 mL of dichloromethane in 5 tubes was photolysed using uv lamps at a

wavelength of 350 nm at room temperature. Initial nmr spectra and uv spectra were taken before

photolys and the photochemical reaction was followed by nmr spectra and uv spectra. After 15

min of irradiation, the solution had changed color from slightly yellow to colorless. The structure

assignment of the product was based mainly on the nmr spectra which suggested an oxaziridine

structure. (See appendix 9).

Photolysis of α-phenyl-N-benzylnitrone. A sample of α-phenyl-N-benzylnitrone

(0.02g, 0.1 mmol) in 100 mL of dichloromethane in 5 tubes was photolysed using uv lamps at a

wavelength of 350 nm at room temperature. Initial nmr spectra and uv spectra were taken before

photolys and the photochemical reaction was followed by nmr spectra and uv spectra. After 15

min of irradiation, the solution had changed color from slightly yellow to colorless. The structure

assignment of the product was based mainly on the nmr spectra which suggested an oxaziridine

structure. (See appendix 11).

Photolysis of α-styryl-N-benzylnitrone. A sample of α-styryl-N-benzylnitrone (0.02g,

0.1 mmol) in 100 mL of dichloromethane in 5 tubes was photolysed using uv lamps at a

wavelength of 350 nm at room temperature. Initial nmr spectra and uv spectra were taken before

photolys and the photochemical reaction was followed by nmr spectra and uv spectra. After 15

min of irradiation, the solution had changed color from slightly yellow to colorless. The structure

assignment of the product was based mainly on the nmr spectra which suggested an oxaziridine

structure. (See appendix 10).

57

REFERENCES

1. P. Pfeiffer, Annalen, 1916, 72, 412.

2. Hamer, J.; Macaluso, A. Chem. Rev. 1964, 64, 473.

3. Delpierre, G.R.; Lamchen, M. Quart. Rev. 1965, 19, 329.

4. Huisgen, R. Angew. Chem. Int. Ed. Engl., 1963, 2, 565.

5. Black, D.S.C.; Crozier, R. F.; Davis, V.C. Synthesis, 1975, 205.

6. Tufariello, J.J. Acc. Chem. Res., 1979, 12, 396.

7. Emmons, W. D., J. Am. Chem. Soc., 1957, 79, 5739.

8. Hamer, J., and Macaluso, A., Tetrahedron Lett., 1963, No. 6, 381.

9. Sandler, S.R.; Daro, W. In Organic Functional Group Preparations, Second Ed.,

Academic Press, San Diego, 1989, Vol. 3, pp. 351-376.

10. Mitsui, H.; Zenki, S.; Shiota, T.; Murahashi, S. I. J. Chem. Soc., Chem. Commun. 1984,

874.

11. Murahashi, S. I.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe, S. J. Org. Chem. 1990, 55,

874.

12. Murahashi, S. I.; Shiota, T., Imada, Y. Org. Synth. 1991, 70, 265.

13. Yamazaki, S. Bull. Chem. Soc. Jpn. 1997, 70, 877.

14. Zajac, Jr., W. W.; Walters, T. R.; Darcy, M. G. J. Org. Chem. 1988, 53, 5856.

15. Murray, R. W.; Singh, M. J. Org. Chem. 1990, 55, 2954.

16. Cicchi, S.; Corsi, M. J. Org. Chem. 1999, 64, 7243.

17. Fenselau, A. H.; Hamamura, E. H.; Moffatt, J.G.J. Org. Chem. 1988, 53, 5856.

18. Smith, P.A.S.; Gloyer, S.E.J. Org. Chem. 1975, 40, 2508.

58

19. Nojima, M.; Takeuchi, K.; Fukui, E.; Tokura, N.J. Chem. Soc., Perkin. Trans. 1 1976,

2202.

20. Smith, L.I., Chem.Rev., 1938, 23, 193.

21. Renner, G., Z. Chem. Abstr., 1963, 193, 92.

22. P.A.S. Smith and J. E. Robertson, J. Am. Chem. Soc.,1962, 84, 1197

23. Splitter, J. S., and Calvin, M., J. Org. Chem., 1958, 23, 651.

24. Sayigh, A. A. R., and Ulrich, H., J. Org. Chem., 1962, 27, 4662.

25. Hamer, J. and Macaluso, A., Chem. Rev., 1964, 64, 485.

26. Thesing, J. and Sirrenberg, W., Chem. Ber. 1959, 1750.

27. Moskal, Janusz; Milart, Piotr., Magnetic Resonance in Chemistry, 1985, 23(5), 361-6.

28. D.A. Kerr and D. A. Wilson, J. Chem. Soc. C, 1970, 1718.

29. Torssell, K. B. G. Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis;VCH,

Weinheim, 1988.

30. Huisgen, R., J. Org. Chem., 1968, 33, 2291.

31. Firestone, R. A., J. Org. Chem.1968, 33, 2285

32. Kanemasa and O. Tsuge, Heterocycles, 1990, 30, 719.

33. Woodward, R. B., Hoffmann, R. The conservation of orbital symmetry, Verlag Chemie,

Weinheim, 1970.

34. Gothelf, K.V., Hazell, R.G., Jorgensen, K. A., J. Org. Chem.1996, 61, 346.

35. Houk, K. N., Yamaguchi, K. in 1,3-Dipolar Cycloaddition Chemistry, Wiley, New York,

1984, Vol.2, 407.

36. Houk, K.N.,Top. Curr. Chem.1979, 79, 1.

37. Sustmann, R. Pure Appl. Chem. 1974, 40, 569.

59

38. Gothelf, K. V., Jorgensen K. A., Acta Chem. Scand. 1996, 50, 652.

39. Thall, E. J. Chem. Ed., 1996, 3(6), 481.

40. Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. Engl., 1998, 37, 388.

41. Cooper R. and Unger S., J. Org. Chem., 1986, 51, 3942.

42. Kanemasa, S., Oderaotoshi, Y. J. Org. Chem. 1997, 62, 6454-6455.

43. Iserloh, U., Curran, D.P., Kanemasa, S. Tetrahedron Asymmetry 1999, 10, 2417.

44. Odenkirk, W., Bosnich, B, B. J. Chem. Soc., Chem. Commun. 1995, 1181-1182.

45. Odenkirk, W., Rheingold, A. L.; Bosnich, B. J. Am. Chem. Soc. 1992, 114, 6392-6398.

46. Hong, Y.; Kuntz, B. A.; Collins, S. Organometallics 1993, 12, 964-969.

47. Kanemasa, S.; Oderaotoshi, Y.; Sakaguchi, S.; Yamamoto, H.; Tanaka, J.; Wada, E.;

Gurran, D. P. J. Am. Chem. Soc. 1998, 120, 3074.

48. Kanemasa, S.; Oderaotoshi, Y.; Tanaka, J.; Wada, E. J. Am. Chem. Soc. 1998, 120,

12355.

49. Posner, G. H.; Dai, H. Y.; Bull, D. S. ; Lee, J. K; Eydoux, F.; Ishihara, Y.; Welsh, W.;

Pryor, N. J. Org. Chem. 1996, 61, 671-676.

50. Gothelf, K. V.; Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 1998, 63, 5483-5488.

51. Emmons, W. D., J. Am. Chem. Soc. 1956, 78, 6208.

52. Bjorgo, J., Boyd, D. R. J. Chem. Soc., Perkin Trans., 1973, 1575.

53. Forni, A.; Garuti, G.; Moretti, I.; Torre, G.; Andreetti, G. D.; Bocelli, G.; Sagarabotto, P.;

J. Chem. Soc., Perkin Trans. 1978

54. Bjorgo, J.; Boyd, D. R.; Campbell, R. M.; Neill, D. C. J. Chem. Soc., Chem. Commun.

1976, 162.

55. Ono, H.; Splitter, J. S.; Calvin, M. Tetrahedron Lett. 1973, 42, 4107.

60

56. Jennings, W. B.; Watson, S. P.; Tolley, M. S. J. Am. Chem. Soc. 1987, 109, 8099.

57. Wheeler O. H., Gore P. H., J. Am. Chem. Soc., 1956, 78, 3363.

58. Kamlet M. J., Kaplan L. A., J. Org. Chem., 1957, 22, 256.

59. Krohnke F., Ann. Chem., 1957, 604, 203.

60. Splitter J. S., Calvin M., J. Org. Chem., 1958, 23, 651.

61. Emmons W. D., J. Am. Chem. Soc., 1957, 79, 5739.

62. Splitter J. S., Calvin M., J. Org. Chem., 1965, 30, 3427.

63. Murahashi, S., Mitsui H., Shiota T., Tsuda T., Watanabe S. J. Org. Chem. 1990, 55,

1736-1744.

64. Alessandri, L., Chem. Abstr. 1911, 5, 276.

65. Weerasooriya, U., Master Thesis, Bowling Green State University, 1977.

66. Houk, K. N., and Sim, J., J. Am. Chem. Soc. 1973, 95, 5798.

67. DeShong, P. and Dicken, C. M., J. Org. Chem. 1982, 47, 2047.

68. Joucla, M; Hamelin J. and Gree, D., Tetrahedron 1973, 29, 2315.

69. Iserloh, U.; Curran, D. P.; Kanemasa, S. Tetrahedron: Ass. 1999, 10, 2417.

70. Kanamasa, S.; Oderaotoshi, Y.; Wada, E. J. Am. Chem. Soc. 1999, 121, 8675.

71. Emmons W. D., J. Am. Chem. Soc., 1957, 79, 5739, 6522.

72. Wragg, A. W., J. Chem. Soc.,1959, 461.

61

APPENDIX

1. 1H-NMR spectrum of N-benzylhydroxylamine chloride

62

2. 1H-NMR spectrum of α-styryl-N-phenylnitrone 21

63

3. 1H-NMR spectrum of α-styryl-N-t-butylnitrone 24

64

4. 1H-NMR spectrum of α-phenyl-N-benzylnitrone 26

65

5. 1H-NMR spectrum of α-styryl-N-benzylnitrone 29

66

6. 1H-NMR spectrum of (R,R)-4,6-Dibenzofurandiyl-2,2’-bis(4-phenyloxazoline),

DBFOX/Ph

67

7. 1H-NMR spectrum of photolysis of α-styryl-N-phenylnitrone 21 (30 min)

68

8. 1H-NMR spectrum of photolysis of α-styryl-N-phenylnitrone 21 (18 min)

69

9. 1H-NMR spectrum of photolysis of α-styryl-N-t-butylnitrone 24

70

10. 1H-NMR spectrum of photolysis of α-styryl-N-benzylnitrone 29

71

11. 1H-NMR spectrum of photolysis of α-phenyl-N-benzylnitrone 26

72

12. 1H-NMR spectrum for 1,3-cycloaddition reaction of α-styryl-N-phenylnitrone 21 with

Butylvinylether

73

13. 1H-NMR spectrum for 1,3-cycloaddition reaction of α-phenyl-N-benzylnitrone 26 with

Butylvinylether

74

14. COSY 1H-NMR spectrum for 1,3-cycloaddition reaction of α-phenyl-N-benzylnitrone 26

with Butylvinylether

5

10 10’, 7, 4’

46

32

1

5

10’

(10, 10’) 4

6

6’

3 2

1

(3, 4) (3, 4’)

(6, 7)

(6, 7’)

75

15. 1H-NMR spectrum for 1,3-cycloaddition reaction of α-phenyl-N-benzylnitrone 26 with

trans-β-nitrostyrene (fraction 1)

76

16. 1H-NMR spectrum for 1,3-cycloaddition reaction of α-phenyl-N-benzylnitrone 26 with

trans-β-nitrostyrene (fraction 2)

77

17. 1H-NMR spectrum for 1,3-cycloaddition reaction of α-phenyl-N-benzylnitrone 26 with

trans-β-nitrostyrene (fraction 3)

78

18. 1H-NMR spectrum for 1,3-cycloaddition reaction of α-styryl-N-benzylnitrone 29 with

trans-β-nitrostyrene (fraction 1)

79

19. 1H-NMR spectrum for 1,3-cycloaddition reaction of α-styryl-N-benzylnitrone 29 with

trans-β-nitrostyrene (fraction 2)