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 -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

phenyloxazoline)

trans-chelating
(DBFOX/Ph)

tridentate
and

ligand

converted

(R,R)-4,6-dibenzofurandiyl-2,2-bis(4it

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 phenyl-Nbenzylnitrone and -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
INTRODUCTION1
Synthetic methods for producing nitrones2
Properties of nitrones4
Reactions of nitrones6
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 nitrone22
2. Photochemical reactions....27
3. Oxidation reactions of oxiziridines31
4. 1,3-Cycloaddition reactions...33
CONCLUSIONS...43
SUGGESTION FOR FUTURE RESEARCH...44
EXPERIMENTAL.45
General procedures45
Synthetic procedures..45
Preparation of N-phenylhydroxylamine(20)......45

vi
Preparation of -styryl-N-phenylnitrone(21)....46
Preparation of 2-methyl-2-nitropropane(22)..46
Preparation of N-t-butylhydroxylamine(23)..47
Preparation of -styryl-N-t-butylnitrone(24).48
Preparation of N, N-dibenzylhydroxyamine(25)...49
Preparation of -phenyl-N-benzylnitrone.(26) Method A49
Preparation of N-Benzylidenzylamine N-oxide.(26) Method B49
Preparation of N-Benzylhydroxylamine hydrochloride(29)..50
Preparation of -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 -phenyl-N-benzylnitrone with butylvinylether53
Reaction of -styryl-N-benzylnitrone with butylvinylether..54
Reaction of -styryl-N-t-butylnitrone with butylvinylether......54
Reaction of -styryl-N-phenylnitrone with butylvinylether..54
Reaction of -phenyl-N-benzylnitrone with trans--nitrostyrene.54
Reaction of -styryl-N-benzylnitrone with trans--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 -styryl-N-phenylnitrone.55
Photolysis of -styryl-N-t-butylnitrone.....56
Photolysis of -phenyl-N-benzylnitrone...56
Photolysis of -styryl-N-benzylnitrone.56
REFERENCES..57
APPENDIX61

viii
LIST OF SCHEMES
Scheme

Page

The FMO energies between the dipole and dipolarophile.8

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

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

The endo and exo interactions..12

Reaction of nitrones with 1,2-disubstituted alkenes14

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

Thermal racemization of chiral oxaziridines proceeds through a high barrier

to nitrogen inversion...19

Synthesis of -styryl-N-phenylnitrone (21)23

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

10

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

11

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

12

Synthesis of -styryl-N-benzylnitrone (29).26

13

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

14

Photolysis of -styryl-N-phenylnitrone (21)...30

15

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

16

Photolysis of -styryl-N-benylnitrone (29).31

17

Photolysis of 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--nitrostyrene..37

ix
21

Synthesis

(R,R)-4,6-Dibenzofuranyl

2,

2-

bis

(4-phenyloxazoline)oxazoline

(DBFOX/Ph)-a novel tridentate ligand40

1
INTRODUCTION
The name nitrone is an abbreviation which was suggested by Pfeiffer1 in 1916 for
compounds containing the functional group (1). The name emphasizes their similarity with
ketones. Nitrones2,3 are quite versatile intermediates in organic synthesis and are employed, for
instance, in stereoselective formation of synthetically useful isoxazolidines by their 1,3-dipolar
cycloaddition with alkenes.4-6

R
C

N
O
1

The general terms, aldonitrones and ketonitrones, have been employed occasionally.
Aldonitrones contain a proton on the -carbon atom, RCH=N(O)R, while in ketonitrones the carbon is fully substituted with alkyl and/or aryl groups, RRC=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 -phenyl-N-tbutylnitrones. The cis (E) form of this nitrone is formed first when t-butyl-3-phenyloxaziridine
was treated with boron trifluoride. Complete isomerization to the more stable trans (Z) form
occurs within 24 hours in benzene solution.7
O
(C6H5)

HC

BF3
N

H
C

C(CH3)

C6H5

C(CH3)3

H
C

C(CH3)3

C6H5

cis

N
O

trans

Ultraviolet spectral studies indicate that aldonitrones exist in the stable trans (Z) form,
and this has been confirmed by nuclear magnetic resonance and infrared studies.8

2
R3

R1
C

R3

R2

R1
C

R2

R1

R3
C

N
O

R2

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 Nmonosubstituted hydroxylamines.9
H
C

O + N

-H2O

OH OH

OH

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
these direct oxidation reactions.

10-13

and oxidizing agents14-16 were subsequently developed for

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
R2

R1
N

R3

oxidation

OH

N
R2

R1

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

R+

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
AntiH

RX

Ph

Ph

Syn-

Ph

RX

OR

Ph
7

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 2,3diaryloxaziridines 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
R
C6H5

NR'

H2O2

R
C

NR'

C6H5

R
C

R'

C6H5
O

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 -cyclohexyl-N-phenylnitrone ( C1-143.3 ppm).27 This
corresponded well with the effect caused by an aryl substituent on the aldonitrone carbon.
11
8

10

H
O

N
H

1
5
7
6

Carbon
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
C-9
C-10
C-11

135.8
118.8
139.6
147.1
121.1
129.1
129.6
135.8
128.8
128.6
127.2

J(CH)
178.7d
162.1d
153.8d
160.5d
160.5d
160.5d
160.5d
160.5d
160.5d

J(CH)
8.3d
8.3(H-1)4.3(H-3)
4.3d
5.0d
4.1d
4.2d
4.2d
2.8t
2.8t
2.8t
2.8t

J(CH)
3.3t(H-9)
7.4t
7.3d
7.3t
7.9t
7.9d
7.9t

Table 1. Carbon resonance (ppm) and coupling constants (Hz) for -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
R3

R5

R1
C

R2

R6
C

R1

R2

R4

R7

R4

R5

R7

R6

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.
Energy
dipole

dipolarophile

dipole

dipolarophile

dipole

dipolarophile

LUMO

HOMO

type I

type II

type III

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
,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 FMOs, 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 FMOs

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

O
R

LA

O
N

LUMO

HOMO

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

10
Nitrone

alkene

nitrone-LA complex

E
R1

O
N

OR2

R1

LA

LUMO

HOMO

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 [4 + 2] 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 -bonds
are formed simultaneously although not necessary at equal rates.30

11

C
N

R4

R4

R3

R3

R2

R1

R1

O
R2

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 nitronealkene 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
endo approach

R2

R2

R
N

R1
O

R2

R
N
O

N
R1

R3

+
R1
R3

exo approach

R2

R
N

R3
R1

R2

R3

R
N
O

R3

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 -orbital interactions and the actual interaction of the N-nitrone pzorbital 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.
O

O
X

+
exo

endo

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 electronwithdrawing group (EWG) the reaction is primarily controlled by the HOMOdipoleLUMOdipolarophile 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-EWGsubstituted isomer as the sole product (Scheme 5).
O

R2

R2

O
N

+
R1

R1

R1

R2

14
LUMO

HOMO
O
EDG

HOMO

EDG

LUMO
O
N
EWG
EWG

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 DielsAlder 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)-4,6dibenzofurandiyl-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, Kanemasas 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.

(ClO4)2
O

Ni

(H2O)3

Ph

Ph

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
Water from air

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

AQUA COMPLEX
R, R-DBFOX/Ph*Ni(ClO4)2*3H2O
-HClO4
HYDROXO COMPLEX
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, RDBFOX/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, Jorgensens 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
O

Me Ph

+
O

13

Cat12, MS 4A O
Me

N-Me

N-Me

and/or

rt, CH2Cl2
Me

Ph Me

Ph

14

CO-OX

3,4-trans-15
endo

CHO-OX

3,4-cis-15
exo
Absolute confuguration is
not assigned

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

R1

NHR2

R1

O
N

N
H

H
R2

R2

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
Ph
N

Me
N

Me

Ph

O
Ph

Ph

Ph

Ph

Me

Ph

Ph

Ph

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 conjugation or hyperconjugation. Both N-aryl and N-acyl oxaziridines have inversion barriers
close to 20 kcal/mol55 because of their -conjugation.
The ultraviolet absorption of various ring-substituted -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.
O

C
H

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
O

R2

2 I-

R2

2H+
N

I2 + H2O +

R1

R3

R3

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 electronreleasing 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 nonconjugated 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- bisoxazoline (DBFOX). This catalyst has been applied to a nitrone cycloaddition reaction using Nbenzylidenmethylamine 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.
-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.
O
NO2

a
N

OH

C6H5
C6H5

20

C6H5

21

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

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

The same method was also applied for synthesis of -styryl-N-t-butylnitrone 24 using Nt-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.
O
CH3

CH3

CH3

a
H3
C

NH2

H3C

CH3

NO2

H3C

CH3

22

a) KMnO4,

OH

H2O

b)

Alfoil+HgCl2+H2O,

N
CH3

C(CH3)3

H C6H5

23

ether/water

24

c)

trans-cinnamaldehyde,

CH3CH2OH
Scheme 9. Synthesis of -styryl-N-t-butylnitrone 24.

Our first approach to the synthesis of -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
N
H

+
H

OH

a
2 C6H5CH2Cl

b
HC

N
C6H5H2C

CH2C6H5

25

C6H5

CH2C6H5

26

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

Scheme 10. Synthesis of -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 -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. ccordingly, crystals
of -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.
H2
C
C6H5

H2
C
N
H

30% H2O2, 5 mol %Na2WO4*2H2O

C6H5

CH3OH

27

HC

C6H5

CH2C6H5

26

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

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

Reduction of 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 Nbenzylhydroxylamine chloride 28, obtained in 90% yield, showed it to be pure. The final
product, as -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.
O
HC

OH

CH3CH2OH, 10%HCl

C6H5

CH2C6H5

* HCl
H

C6H5H2C

28

26
O

OH
N

* HCl +

CH3CH2OH
NaHCO3

C6H5H2C

C6H5

28

H
CH2C6H5

C6H5

29

Scheme 12. Synthesis of -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.
O

N
C6H5

-stryl-N-phenylnitrone 21

C6H5

C(CH3)3
C6H5

-styryl-N-t-butylnitrone 24
O

O
HC
C6H5

CH2C6H5

CH2C6H5

-phenyl-N-benzylnitrone 26

C6H5

-styryl-N-benzylnitrone 29

27
2. Photoisomerization reactions.
Photochemical rearrangement of several conjugated nitrones, namely -styryl-Nphenylnitrone, -styryl-N-t-butylnitrone and -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

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

when even one of the -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 coworkers to obtain interesting information and a general understanding of the stability and
rearrangement tendencies of oxaziridines.62
1

R
O

hv

Rearrangment or decomposition
product

N
H

H
2

R2

In general, N-aryl substituents destabilize the N-O bond, whereas N-alkyl substituents
stabilize the N-O bond. Electron releasing -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

R1

R2

R3

R2
3

R3

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

O
C

C6H5

C6H5
H

CH2C6H5

26

CH2C6H5

30

N
CH2C6H5

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

R2

H
C

N
R1 R2

R1

N
1

R2

R H

R1

R2-CO-NHR1

29
Mechanism 2
O

R1

H
2

R2

R1

R1

N
1

+ R2+
O

R2

R
O
N

R1

R2

+H+

H
N
R1

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 -styryl-Nphenylnitrone 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 -styrylN-phenylnitrone 21 at a wavelength of 350 nm. We observed three absorption bands E1, E2 and
K at max 208, 261, 352 nm respectively. The corresponding values found in the literature for ,
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 -styryl-N-

phenylnitrone 21. As a first experiment, -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 styryl-N-phenyloxaziridine 32 (Scheme 14). In a subsequent reaction, irradiation
of 21 for a shorter time (18 min), 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.
7.95
H

Ph
C

HC

hv

9.7

7.05

Ph
C

H
HC

CH

Ph

4.5

Ph

21

+
H

Ph

6.7

31

O
H

32

6.1

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

Irradiation of -styryl-N-t-butylnitrone 24 for 15 minutes in deuterated dichloromethane
solution showed the formation of -styryl-N-t-butyloxaziridine 33. Chemical analysis and
spectral data were used to prove the structure of oxaziridine 33.
tBu
HC
HC

hv
O

CH

15 min

6.94

4.50

1.14

t-Bu
C

H
O

Ph

24

Ph

33

5.95

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

Irradiation of -styryl-N-benzylnitrone 29 proceeded smoothly in 15 minutes to produce
the stable -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 4.9.

31

3.87

4.3
H
C
HC

hv

HC

CH

29

Ph

CH2

CH2C6H5

N
O

Ph

C6H5

34

5.9

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

Irradiation of -phenyl-N-benzylnitrone 26 for 15 minutes produced the -phenyl-Nbenzyloxiziridine 35 as a main product of the photochemical reaction. Chemical analysis and
spectral data proved the formation of oxiziridines.

4.05

4.7
O

hv
HC

Ph

CH2

Ph

CH2C6H5

C6H5

N
O

35

26
Scheme 17. Photolysis of 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.
O

O
H

oxidation
C

O
C

R'
R

36

R'

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, mchlorobenzoic 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.
O

O
O

H
N

C
Ph

35

N
CH2Ph

Ph

dimer

H
CH2C6H5

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 -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

OCH3

R
N
R

37

OCH3

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 5substituted 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 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-Nethylnitrone 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
O-Bu

EDG=butylvinylether

O
CH2C6H5

HC

+ EDG

Ph

38
O

benzene
85-1000C, 24-39 hr
Ph

26

HC

CH2C6H5

+ EDG

1000C, 25-62 hr

CH

Ph

29

Ph
C

+ EDG

CH2Ph

40

benzene
850C, 42hr

CH

Ph

21

Ph

O-Bu

HC

benzene

Ph

CH2Ph

O-Bu

H
C

39

Ph

41
O-Bu

tBu
HC
HC
Ph

+ EDG
O

CH

benzene

1200C, 25-64 hr
Ph

42

tBu

24

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

All reactions were monitored by TLC. The reaction of -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 styryl-N-t-butylnitrone 24 after 64 hours. The
reaction of -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 -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) 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
3.38

1.37
0.91 H C
3

H2
C

H2
C

1.55 H2

H 5.12

2.85 H
2.29H

O
N

3.6 H

CH2 4.0

H
H 7.46

aromatic 7.147.37
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
Ph

H
C

Ph
H

NO2

Ph

H
NO2

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

NO2
O

O
N

H
Ph

Ph

43

Ph

44

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

In our hands trans--nitrostyrene 45 reacts with conjugated nitrone 29 rapidly to give 4substituted nitroisoxazolidines. We performed a comparison study with the non-conjugated
nitrone 26.

37
CH2C6H5
H

CH2C6H5

NO2

110 C, 10hr

Ph

45

CH2C6H5
C

29

46

O2N

benzene

Ph
CH2C6H5

NO2

O
Ph

26

Ph

benzene

N
Ph

Ph

Ph

45

110 C, 10hr
H
O2N

47

Ph

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

The reactions were monitored with time by TLC and GCMS analysis. The reaction with 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-5phenyloxaziridine 46. There were two peaks which correspond to the two starting materials
nitrone 26 and trans--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.
Ph

Ph
H5

O2N

H5

O2N

O
H4

O
H4

Ph
H3

CH2Ph

46, 46'

Ph
H3

CH2Ph

46''

The reaction of -styryl-N-benzylnitrone 29 with trans--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

Ph
H5

O2N

d of d J=4.5,6.3
H4
d, J=15.9 H
Ph

d, J=4.5

H3

H4

CH2Ph

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

Ph

d, J=5.7

d of d J=5.7, 8.4

H5

O2N

H3

CH2Ph

d of d J=3.6, 8.4

48, 48'
49
Because 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
(DBFOXs) 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.
1. s-BuLi, TMEDA
Et2O, 250C, 24hr

A.

2. CO2(g), -780C

3. H2O

50

51
CO2H

B.

CO2H

SOCl2, CHCl3
680 C, 3hr

52

51
CO2H

CO2H

C.

Cl

Cl

HN

(R)-phenylglycinol
Et3N, CHCl3
250 C, 24 hr

53
O

Cl

Cl

NH

52
HO

Ph

Ph

OH

2,3 eq DAST

D.
O

-200 C, 18 hr

53
O

NH

CH2Cl2
HN

54

O
O

HO

Ph

Ph

OH

Ph

Ph

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)-(-)-2phenylglycinol. 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-transisoxazolidines 57 with great endoselectivity (endo:exo=98:2) and enantioselectivity for 3S, 4R,
5S enantiomer (>99% ee).47
O

O
Me
Ph

Me
O

Me

Ph

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

4 A MS, 250C, CH2Cl2

55

NMe

CON

56
O

57

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 -phenyl-N-benzylnitrone 26 with trans--nitrostyrene 45 (Scheme 20) but
using our newly prepared cationic aqua complex Ni(ClO4)2*PhDBFOX. MS 4A, trans-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-benzyl4-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 -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 -conjugated nitrones such as -styryl-Nphenylnitrone, -styryl-N-t-butylnitrone and -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 transchelating 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 -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 roundbottomed 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

C. 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): 6.5 (2H, br, NHOH), 7.02 (3H, m),
7.30 (2H, m).
Preparation of -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
0

C. 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): 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): 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 -styryl-N-t-butylnitrone (24). In a 125 ml Erlenmeyer flask tbutylhydroxylamine (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): 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): 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): 3.76 (s, 4H), 7.2-7.3 (m, 10H).

49
Preparation of -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
0

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

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 (-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): 5.31 (s, 2H), 7.31-7.51 (m, 9H), 8.17-8.25 (m,
2H).

13

C NMR (CDCl3): 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 -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): 4.3(s, 2H, CH2),
7.42(m, 3 (Me2SO-d6) meta and para aryl Hs), 7.51(m, 2H, ortho aryl Hs), 11.65(br s, 3H, NH2
and OH).
Preparation of -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): 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) 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
0

C 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) 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) 3.663.81 (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) 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 -phenyl-N-benzylnitrone with butylvinylether. A solution of -phenylN-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)

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 -styryl-N-benzylnitrone with butylvinylether. A solution of -styryl-Nbenzylnitrone (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 -styryl-N-t-butylnitrone with butylvinylether. A solution of -styryl-Nt-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 -styryl-N-phenylnitrone with butylvinylether. A solution of -styryl-Nphenylnitrone (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 -phenyl-N-benzylnitrone with trans--nitrostyrene. A solution of phenyl-N-benzylnitrone (0.5g, 2.4 mmol) in 15 mL of toluene and trans--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

4.14 (d, 1H, J=13.8 Hz), 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 -styryl-N-benzylnitrone with trans--nitrostyrene. A solution of styryl-N-benzylnitrone (0.3g, 1.3 mmol) in 15 mL of benzene and trans--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--nitrostyrene (0.126 g, 0.85 mmol), -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 -styryl-N-phenylnitrone. A sample of -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 max 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 -styryl, N-t-butylnitrone. A sample of -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 -phenyl-N-benzylnitrone. A sample of -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 -styryl-N-benzylnitrone. A sample of -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
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61
APPENDIX
1.

H-NMR spectrum of N-benzylhydroxylamine chloride

62
2.

H-NMR spectrum of -styryl-N-phenylnitrone 21

63
3.

H-NMR spectrum of -styryl-N-t-butylnitrone 24

64
4.

H-NMR spectrum of -phenyl-N-benzylnitrone 26

65
5.

H-NMR spectrum of -styryl-N-benzylnitrone 29

66
6.

H-NMR

DBFOX/Ph

spectrum

of

(R,R)-4,6-Dibenzofurandiyl-2,2-bis(4-phenyloxazoline),

67
7.

H-NMR spectrum of photolysis of -styryl-N-phenylnitrone 21 (30 min)

68
8.

H-NMR spectrum of photolysis of -styryl-N-phenylnitrone 21 (18 min)

69
9.

H-NMR spectrum of photolysis of -styryl-N-t-butylnitrone 24

70
10. 1H-NMR spectrum of photolysis of -styryl-N-benzylnitrone 29

71
11. 1H-NMR spectrum of photolysis of -phenyl-N-benzylnitrone 26

72
12. 1H-NMR spectrum for 1,3-cycloaddition reaction of -styryl-N-phenylnitrone 21 with
Butylvinylether

73
13. 1H-NMR spectrum for 1,3-cycloaddition reaction of -phenyl-N-benzylnitrone 26 with
Butylvinylether

74
14. COSY 1H-NMR spectrum for 1,3-cycloaddition reaction of -phenyl-N-benzylnitrone 26
with Butylvinylether
1
10

10, 7, 4

5
3
4

2
6

10
(10, 10)
4
6

(6, 7)
(6, 7)

(3, 4)

(3, 4)

3
2
1

75
15. 1H-NMR spectrum for 1,3-cycloaddition reaction of -phenyl-N-benzylnitrone 26 with
trans--nitrostyrene (fraction 1)

76
16. 1H-NMR spectrum for 1,3-cycloaddition reaction of -phenyl-N-benzylnitrone 26 with
trans--nitrostyrene (fraction 2)

77
17. 1H-NMR spectrum for 1,3-cycloaddition reaction of -phenyl-N-benzylnitrone 26 with
trans--nitrostyrene (fraction 3)

78
18. 1H-NMR spectrum for 1,3-cycloaddition reaction of -styryl-N-benzylnitrone 29 with
trans--nitrostyrene (fraction 1)

79
19. 1H-NMR spectrum for 1,3-cycloaddition reaction of -styryl-N-benzylnitrone 29 with
trans--nitrostyrene (fraction 2)