Chapter 1

Introduction to 1,3-dipolar cycloaddition reaction

Chapter - 1

1

1.1 Brief Description of Cycloaddition Reaction

Cycloaddition reaction is a process in which two or more π electron

system combines to form a stable cyclic molecule. During which, sigma

bonds are formed between the terminal π systems and no fragments are

lost. A concerted mechanism requires a single transition state and no

intermediate, which lies on the reaction path between reactant and

adducts. The two important cycloaddition reactions by concerted

mechanism are

(a) Diels-Alder Reaction: This reaction is addition of conjugated diene to

alkene, commonly called as dienophile, to give a six membered ring

system. This reaction is classified as (4+2) cycloaddition reaction1

because diene component provides 4 π electrons and dienophile provides

2π electrons to form a six membered adduct.

Z Z Z

The reaction is easy and rapid.2 In the terminology of the symmetry

classification, the Diels- Alder reaction is a (π4S+π2S) cycloaddition

because, the classification consider

i) The number of electrons in each participating unit.

ii) The nature of orbital undergoing change either π or σ

iii) Stereochemical mode either Syn (supra) or anti (antra) addition

with respect to both diene and dienophile.

Most dienophile are in the form,

C C Z C C ZZIor

Where Z, Z' are CHO, COR, COOH, COOR, COCl, COAr, CN, NO2, Ar, CH2OH, CH2NH2, CH2COOH, Cl, Br. F

Beside carbon-carbon multiple bonds other double bond and triple

bond compounds can be dienophile, giving rise to heterocyclic

compounds. Among these are O=N, -C=O, and -C≡N, -N=C-, -N=N-

compounds.3 The term 1,3 dipole arose because such compounds can be

Chapter - 1

2

described in terms of dipolar resonance contributor in valence bond

theory (VBT) as follows.

ab

c ab

c

(b) 1,3- dipolar cycloaddition (DC) reaction: The (3+2) 1,3-dipoar

cycloaddition is a reaction where two organic compounds, a dienophile, 1

and a 1,3 dipole (or ylide) 2, combine to form a five membered heterocycle

3 (Figure 1.1). The reaction is related to the Diels- Alder reaction where a

diene and a dienophile, cycloaddition reaction can furnish very complex

heterocycles, containing multiple stereogenic centres. Therefore this

reaction is used for the preparation of molecules of fundamental

importantance for both academia and industry.

The history of 1,3-dipoles goes back to Crutius, who in 1883

discovered diazoacetic ester.4 Five years later his younger colleague

Buchner studied the reaction of diazoacetic ester with α, β- unsaturated

esters and described first 1,3 DC reaction.5 In 1893 he suggested that the

product of the reaction of methyl diazoacetate and methyl acrylate was a

1-pyrazoline and the isolated 2-pyrazole was formed after rearrangement

of the 1-pyrazole.6 Five years later nitrones and nitriloxide were

discovered by the Beckmann, Warner and Buss respectively.7,8 The Diels-

Alder were found in 1928,9 and synthetic values of this reaction soon

became obvious. The chemistry of 1,3 dipolar cycloaddition reaction has

thus evolved for more than 100 years, and a variety of different 1,3

dipoles have been discovered.10 However, only a few dipoles have found

general application in synthesis during the first seventy years after

discovery of diazoacetic ester. Two well known exception are ozone and

diazo compounds.11,12 The general application of 1,3 dipole in organic

chemistry was established by the systematic studies by Huisgen in the

1960s.13 At the same time the new concept of conservation orbital

symmetry, developed by Woodward and Hoffman, appeared.14,15 There

work was a milestone for the understanding the mechanism of concerted

cycloaddition reactions. On the basis of the concept by Woodward and

Chapter - 1

3

Hoffmann, Houk et al., have further contributed to our present

understanding and ability to predict relative reactivity and region

selectivity of 1,3 DC reactions.16,17

cb

aa

bc

Figure 1.1

1.2. Nature of the dipole

A 1,3-dipole is defined as an a-b-c structure that undergoes 1,3-DC

reactions and is portrayed by a dipolar structure as outlined in Figure

1.1. Basically, 1,3-dipoles can be divided into two different types: the

allyl anion type and the propargyl/allenyl anion type. The allyl anion type

is characterized by four electrons in three parallel Pz orbitals-

perpendicular to the plane of the dipole and that the 1,3- dipole is bent.

The resonance structures in which the three centers have an electron

octet, and two structure in which a or c has an electron sextet, can be

drawn. The central atom b can be nitrogen, oxygen, or sulfur (Figure

1.2(A)). The propargyl anion type has an extra π orbital located in the

plane orthogonal to the allenyl anion type molecular orbital (MO), and the

former orbital is therefore not directly involved in the resonance

structures and reactions of the dipole. The propagyl/allenyl anion type is

linear and the central atom b is limited to nitrogen (Figure 1.2B). The

three sextet resonance structures that also can be drawn are omitted in

Figure 1.2. The 1,3-dipoles are occasionally presented as hypervalent

structures (Figure 1.2C). The classification and presentation of the

parent 1,3-dipole is depicted in Table 1.1.10

Chapter - 1

4

ab

c ab

c

a b c a b c

ab

c ab

c

(A) Allyl anion type

(B) Propargyl/allenyl anion type

(C) Hypervalent representations

ab

c a b c

Octet -Structure

Sextet-structure

Figure 1.2

Chapter - 1

5

Table 1.1. Classification of the parent 1,3- dipoles

C N

O

C N N

C N N

N N N

O N O

Nitrones

Azomethine Imines

Azomethine Ylides

Azimines

Azoxy CompoundsN N O

Nitro compounds

C O C

C O O

N O N

O O O

Carbonyl Imines

NitrosoxidesN O O

Ozone

C O N

Carbonyl Ylide

Carbonyl Oxides

Nitrosoimines

Allyl anion type

Nitrogen in the middle Oxygen in the middle

Propagyl/allenyl anion type

C N O

Nitrilium Betaines

Nitrile Oxides

Nitrile Imines

Nitrile Yildes

N N C

N N N

N N O

Diazoalkanes

Azides

Nitrous Oxide

Diazonium Betaines

C N N

C N C

1.3. Nature of the Dipolarophile

The dipolarophile in a 1,3-dipolar cycloaddition is a reactive alkene

moiety containing 2π electrons. Thus, depending on which dipole that is

present, α β-unsaturated aldehydes, ketones, and esters, allylic alcohols,

allylic halides, vinylic ethers and alkynes are examples of dipolarophiles

that react readily. It must be noted that, other 2π- moieties such as

carbonyls and imines also can undergo cycloaddition with dipoles. The

alkene moiety can be mono-, di-, tri- or even tetrasubstituted (only

monosubstituted ones are shown here). However, mostly due to steric

Chapter - 1

6

factors, tri and tetra substituted ones often display very low reactivity in

reactions with dipoles.

It must be pointed out that dipolarophiles (Figure 1.3) incorporating

two conjugated double bonds such as dipolarophile 4 can exist in two

different main confirmations, s-cis and s-trans respectively, where as the

s-cis/s-trans descriptor refers to the single bond connecting the two

double bonds. Such s-cis/s-trans isomerism can have a major impact on

the outcome of an asymmetric 1,3-dipolar cycloaddition reaction.

R1

OR1

O

Br OMeR1

1 1 2 3 4

R1 = H, Me, or OMe X= OH or halogen

Figure 1.3. Examples of dipolarophile in 1,3-dipolar cycloaddition reactions

1.4. Synthesis and Reaction of Nitrones

The chemistry of nitrones and their cycloaddition reaction with

unsaturated substrate has attracted considerable attention both from the

point of synthetic and biological studies. The nitrone cycloadducts are

attractive intermediates for the synthesis of several classes of biologically

active compounds and natural products.18,19,20 Cycloaddition of nitrones

to unsaturated substrate constitute the best procedure for the

construction of 5-membered isoxazolidines ring system with regio and

steriochemical control. The presence of nitrogen atom within

isoxazolidines ring has made this heterocyclic moiety especially attractive

for the synthesis of the β-lactum.21,22 The key step of this approach

involves a reductive cleavage of the isoxazolidines ring to give a γ-amino

alcohol, which undergoes subsequent cyclisation with neighbouring

methoxy carbonyl group to form a lactum ring.

Nitrones represent a well known and thoroughly investigated class

of 1,3-dipoles and used as an excellent spin trapping agent.23 Nitrogen

are one of the members of the series of 1,3-dipoles. They can be

considered of spiral interest, because they play role in the synthesis of

Chapter - 1

7

alkaloids and other natural compounds. Nitrones are compounds

containing the group as follows

NO

The name nitrone is derived from nitrogen ketone in order to

indicate a chemical relationship between nitrones and carbonyl

compounds. The nitrogen group bears a marked resemblance to the

carbonyl group in facilitating the removal of proton from an adjacent

carbon under basic condition. The oxidation of methyl group, adjacent to

the carbonyl group by means of selenium dioxide, the addition of

organometallic reagents, the addition of hydrocyanic acid and reduction

by complex metal hydrides.

The nomenclature employed by Chemical Abstract in recent years as

follows:

NH

O

It is named as α, N-diphenylnitrone. In old literature it was called as N-

phenyl “ether” of benzaldoxime.

Nitrones exhibit geometric isomerism because of the double bond in the

nitrone group.

NR2

R1R3

ON

R2

R1

R3

O

transCis

The existence of geometric isomerism was first demonstrated in

1918 for α-Phenyl- α-(p-tolyl)-N-methylnitrone.24 The configurations of

the isomers were established by dipole moment studies. For the cis form

the dipole moments range between 5.6-6.3 D and the trans form between

0.9-1.7 D. The cis form convert easily into the trans from by heating. The

resonance structure of nitrone may be written as follows,

Chapter - 1

8

N

R2

R1R3

N

R2

R1R3

O O

Due to this resonance structure, it shows versatile reactivity with various

reagents.

Synthesis of Nitrones

Nitrones are easily accessible and material can be synthesized by

various methods. The most general preparation involves the

condensation of N-monosubstituted hydroxylamines with carbonyl

compounds and the oxidation of N,N-substituted amines.25,26,27

(a) Condensation of N-monosubstituted Hydroxylamine with carbonyl

compounds

R NHOH OR1

R2

NR

R2O

RH2O

The reaction proceeds smoothly and with high yield when R is an

alkyl or aryl group and if R1 and R2 are of small size. Where R1 and R2 are

bulky groups the reaction does not proceed.28 N-phenylhydroxylamines

are treated with variety of aldehyde and ketones to from N-phenyl nitrone

and N-phenylhydroxylamine and formaldehyde which in-situ undergoes

an intermolecular 1,3-addition followed by the loss of hydrogen and the

formation of dinitrone.29

N CH2Ph

O

NH2CPh

OH

HC N Ph

O

N CH

Ph CH

N Ph

O O

Ring substituted N-phenylhydroxylamines when treated with

benzaldehyde nitrones were isolated in good yield. From N-

methylhydroxylamine and cyclopentanone nitrone could be isolated. This

nitrone is very hygroscopic, which instantly hydrolysed by water and

decomposed by ethanol.

O

N CH3

Chapter - 1

9

Nitrones have also been prepared by in-situ generation of the

hydroxylamine in the presence of a carbonyl compound. The α, N-

diphenylnitrone is obtained by the reaction of nitrobenzene,

benzaldehyde and zinc dust in a mixture of water, ethanol and acetic acid.

(b) N-Alkylation of oximes: Alkylation of oximes were reviewed in

1938.30 The disadvantage of this method is that reaction products are

mixture of oxime ethers and nitrones. Since alkylation may occur on

either oxygen or nitrogen. Electron withdrawing groups in p-substituted

benzophenone oxime salts markedly promoted the formation of nitrones.

NOHR1

RR2 X NOR2

R1

RN

R

R1

R3

O

HX+ ++

While, electron–donating substituent favoured oxime ether formation. A

pronounced steric effect was observed by comparing the reaction between

benzophenone oxime sodium salt with methyl bromide or benzyl bromide,

the small size of the alkylating agent favouring nitrone formation, the

large size favoring oxime ether formation.

(c) Reaction of Aromatic nitroso compounds with active methylene

compounds:

Aromatic nitroso compounds react readily with compounds such as

2,4,6-trinitrotoulene or 9-methylacridine, containing a sufficiently

activated methyl group. The reaction products often are mixture of anils

and nitrones.31-33 The reaction is normally catalyzed by small amounts of

base such as pyridine, piperidine and sodium carbonate. The following

sequences of steps have been proposed for the reaction (Scheme 1.1).

Chapter - 1

10

Ph CH3 Ph CH2

Ph1 NO2Ph C

HN Ph1

O

CH2

PhN

OH

Ph1

Ph CH N Ph1 + H2OPh CH N Ph1

O

Ph N N Ph1

O

H2O

Scheme 1.1

The methyl group in mononitrotoulene apparently were not

sufficiently acidic, since a reaction was not observed with either

nitrosobenzene or p-nitroso-N,N-dimethylaniline. On the other hand, 2,4-

dinitrotoulene when refluxed with piperidine as catalyst, yield anil as sole

product, but the use of potassium hydroxide as the catalyst produces the

nitrone exclusively.34

(d) N-oxidation of imines (Schiff’s bases): Imines or Schiff’s bases give

initially oxazaridines, which under controlled condition thermally

rearrange to nitrones.35

Ph C N R1

R

H2O2Ph C N R1

R

O

PhC N R1

R

O

(e) From Diazo compounds: This reaction was described previously,

which involves the introduction of diazo compounds into a solution of an

aromatic nitroso compounds leading to the formation of nitrone.

Ph NO Ph2CN2 Ph N CPh2 N2+ +

O

Reaction of nitrones

(a) With alkenes: The 1,3-cycloaddition of a nitrone with alkene leads to

the formation of a five membered heterocyclic ring.

C N

O

C C ON

Chapter - 1

11

Unconjugated alkenes appear to react considerably slower than

conjugated unsaturated systems. Intra molecular addition of the in-situ

generated nitrone group was also reported in case of N-methyl-N-(-5-

hexynyl)hydroxylamine which upon treatment with mercuricoxide yields

an isoxazolidines derivative, presumably through a nitrone intermediate.

H3C NOH

(CH2)4CH CH2

HgO

NO

ONCH3

Intramolecular 1,3-cycloaddition was also observed for

cycloalkenes. 4-cyclopentene carboxaldedyde when treated with N-

methylhydroxylamine, isoxazolidines derivative was obtained, but

intramolecular addition was not observed with 3-cyclo

hexenecarboxaldehyde. Styrene and α, N-diphenylnitrone yields two

isomeric adducts, presumably diastereoisomers.36

CHO C2H5 NHOH CH

N C2H5

O

CH3 NHOH

ON

CHO

(b) With Benzyne: Benzyne forms stable adducts with simple nitrones,37

but those derived from heteroaromatic N-oxide can not be detected

and are postulated to undergo rearrangement to phenolic derivatives.

Ph CH

N CH3

O

NO

Ph

(c) With Phosporanes: Methylene, benzidine and

isopropylidinetriphenylphosphoranes give oxazophospholidines on

reaction with nitrones.38 So intersection of heteroatom helps a lot

synthetic chemistry.

Chapter - 1

12

C N

OP (Ph)3 P

ON

PhPh

(d) With Isocyanate: The cycloaddition of isocyanate to nitrone is apex

identification.

C N

ON

NO

Ph N C O

Ph

O

(e) Addition of organometallic reagents: Grignard reagents are added to

aldonitrones in a 1,3-fashion, but the reaction with ketonitrones leads to

imines.39

.

R CH

N R1

O

R2 Mg Br NOH

R1R2

R

R C N R2

R1 O

R3 Mg Br NR

R1

R2

(f) Addition of HCN: Generally nitrone form a 1,3-adduct with hydrogen

cyanide. In the presence of base adduct readily lose to yield cyano imine.

R CH

N R1

O

N

OH

R1HCRHCN

CN

N R1CRCN

H2O

1.5 Rearrangements of nitrones

(a) The nitrone-amide rearrangements: This common reaction

observed in nitrones.40 Aldonitrones rearranged to the isomeric amides

by treatment with a variety of reagents e.g. Phosphoruspentachloride,

phosphoroustrichloride, phosphorousoxychloride, sulfurdioxide,

aceticanhydride, acetylchloride and solution of base in ethanol.

(b) The nitrone-Oxime O-Ether rearrangement: The isomerisation may

occur either under the influence of heat or acid. Thus, by heating α, α-

diphenyl-N-diphenylmethylnitrone to 160-200 0C, a quantitative yield of

the O-ether was obtained.41

Chapter - 1

13

Ph CH

N CH3

O

HN CH3CPh

O

PhC N CH

OPh

Ph PhC N O

Ph

PhPh

Ph

(c) Behrend Rearrangement: Ketonitrones may undergo

rearrangements by catalytic influence of base. This rearrangement has

also been observed in the synthesis of nitrone.

PhC N CH2

OPh

Ph PhCH N

PhPh

O

PhC N

OH

PhPh CH2 Br

PhCH N

PhPh

O

1.6 Reduction of Nitrones

Nitrones upon treatment with either lithium alluminium hydride or

sodium borohydride yields the corresponding hydroxylamines, generally

in high yields, presumably by a 1,3-addition mechanism.

C N

O

CH N OHLAH

Deoxygenating of nitrones has been accomplished by zinc, tin, or

iron dust, phosphines, sulfurdioxide, sulfur and catalytic hydrogenation,

N-diphenylnitrone and zinc in aceticacid forms the corresponding anils.

C N

O

C N

1.7 Oxidation of Nitrones

Leadtetraacetate (LTA) oxidizes aldonitrones to (N) O-

acetylhydroximic acids which are used in the synthesis of nucleoside

adduct.

Chapter - 1

14

PhC N

OH

PhCH

NHLTA

OAc

94%

1.8. Mechanistic considerations: 1,3 –dipolar cycloaddition reaction

Huisgen and coworkers have systematically studied the mechanism of

1,3 dipolarcycloadditions.42-45 The most of 1,3-cycloadditions, the

reaction rate is not markedly influenced by the dielectric constant of the

solvent medium in which the reaction is conducted. The independence of

solvent polarity, the very negative entropies of activation and stereo

specificity and regio specificity point of a highly ordered transition state.46

In most of 1,3-DP reactions, when two isomers are possible as a result of

the use of unsymmetrical reagents, one isomer usually predominates,

often to the exclusion of the other. The principal question that arises

when considering the regio specificity of the 1,3-dipolar additions is

whether the two new σ-bonds formed on addition of the 1,3 dipole to the

dipolarophile are formed simultaneously or one after the other. The

mechanism that as emerged from Huisgen’s group is that of a single step,

four center, ‘no mechanism’ cycloaddition, in which the two new bonds

are both partially formed in the transition state, although not necessarily

to the same extent.47 A symmetry energy correlation diagram reveals that

such a thermal cycloaddition reaction is an allowed process.48 A proposed

alternative mechanism is a two step process involving a spin-paired

diradical intermediate.49

Chapter - 1

15

ab

c a cb

ab

c a cb

a cb

C NAr OHD

D

NO

Ar D

D

Scheme 1.2

eq-1

eq-2

eq-3

On the basis of an extraordinary series of investigation, which led to a

monumental collection of data Huisgen et al., developed a detailed

rationale for a concerted mechanism for the 1,3-dipolar cycloaddition

reaction (Scheme 1.2, eq 1). Firestone considered the 1,3-DC reaction to

proceed via singlet diradical intermediate (Scheme 1.2, eq 2). Both sides

in the debate based their arguments on a series of experimental facts.50

On the basis of the stereo specificity of the 1,3-DC reaction, the dispute

was settled in favour of the concerted mechanism. The 1,3 DC reaction of

benzonitrile oxide with trans-diduterated ethylene gave exclusively the

trans-isoxazoline (Scheme 1.2, eq 3). A diradical intermediate would

allow for a 1800 rotation of the terminal bond and would thus be

expected to yield a mixture of the cis and trans isomers. Huisgen et al.

have later shown that the 1,3-Dc reaction can take place by a stepwise

reaction involving an intermediate and in these cases the stereo

specificity of the reaction may be destroyed.

Stepwise Mechanism

The stereo specificity observed in many 1,3-dipolar cycloaddition is

often considered to be compelling, if not conclusive, evidence for the

concert in these reactions. However, if the rate constant for rotation (kr)

about bond ‘a’ in a diradical intermediate, was much smaller than the

rate constant for cyclisation (kc), high stereo specificity would still be

Chapter - 1

16

observed Scheme 1.3.50 The reported examples of stereo specific 1,3-

dipolar cycloaddition involved di- tri-, or tetra- substituted alkenes.

Barriers to rotation of simple primary, secondary and tertiary alkyl

radicals are only 0-1.2 Kcal mol-1 (1 Kcal =4.18 kJ),51 but more highly

substituted radicals have barriers to rotation estimated to be as high as 4

kcal mol-1.52 The rate ratio of rotation to ring closure is highly dependant

on the degrees of the substitution at the terminal-labelled methylene

rotor offers the highest chance to bring about an intermediate in the

cycloaddition reaction. This was the reason why Houk and Firestone

studied the 1,3-dipolar cycloadditions of 4-nitrobenzonitrile oxide to cis-

and trans-dideuterioethylene (Scheme 1.3; R=D).53 These experiments

establish that the reaction is >98% stereo specific. If a diradical

intermediate were formed, the barrier to rotation barrier about bond ‘a’

would have to be at least, 2.3 kcal mol-1 higher than the barrier to

cyclisation. Since the rotational barrier of bond ‘a’ is that expected for a

normal primary radical (i.e <0.4 kcal mol-1), there can be no barrier to

cyclization. Thus, the most reasonable mechanism for 1,3-dipolar

cycloadditions appears to be a concerted one.

NAr O

R R

ONAr

R R

akc O

NAr

R R

ONAr

R R

a

NAr O

R

R

kc ONAr

R R

Scheme 1.3

An Orbital Symmetry Analysis

Frontier molecular orbital (FMO) Method: The transition state of

concerted 1,3-DC reaction is thus controlled by the frontier molecular

orbitals (FMO) of the substrates. The LUMO dipole can interact with the

HOMOalkene and HOMOdipole can interact with the LUMO alkene. Sustman

has classified 1,3-DC reactions into three types, on the basis of the

Chapter - 1

17

relative FMO energies between the dipole and the alkene (Figure

1.4)46,5457

In Type I, 1,3-DC reactions the dominant FMO interaction is that of the

HOMOdipole with the LUMOalkene as outlined in Figure 1.4. For Type II

1,3-DC reactions the similarity of the dipole and alkene FMO energies

implies that both HOMO-LUMO interactions are important. 1,3-DC

reactions of Type III are the dominated by the interaction between the

LUMOdipole and the HOMOalkene.

1,3-DC reactions of Type I are typical for substrates such as

azomethine ylides and azomethine imines, while reactions of nitrones are

normally classified as Type II. 1,3-DC reactions of nitrile oxides are also

classified as Type II, but they are better classified as borderline to Type

III, since nitrile oxides have relatively low lying HOMO energies.

Examples of Type III interactions are 1,3-DC reactions of ozone and

nitrousoxides. However, introduction of the electron donating or electron

withdrawing substituent on the dipole or the alkene can alter the relative

FMO energies, and therefore the reaction type dramatically.

LUMO

HOMO

AlkeneDipole Dipole

DipoleAlkene Alkene

Energy

Type I Type II Type III

Figure 1.4. The Classification of 1,3-DC reactions on the basis of the FMOs: Type I; a HOMdipole LUMOalkene interaction Type II; interaction of both HOMOdipole and LUMOalkene Type III; a LUMOdipole-HOMOalkene interactions

Endo and Exo-approch: Depending on the nature of the dipole and

dipolarophile, the 1,3-dipolar cycloaddition reaction is controlled either

by a LUMO (dipolarophile)-HOMO (dipole)- or a LUMO (dipole)-HOMO

(dipolarophile) interaction but in some cases a combination of both

interactions is involved. An example of a LUMO (dipolarophile)-HOMO

Chapter - 1

18

(dipole) controlled reaction is depicted in Scheme 1.4. The approach of

the dipole (eg. 1, Scheme 1.4) to the dipolarophile (eg. 2, Scheme 1.4)

can occur in an endo or exo mode resulting in two diastereomeric

endo/exo cycloadducts, endo-3 and exo-3 respectively. An overview over

both these approach is stabilized by small secondary π-orbital

interactions, contributing to the endo/exo selectivity of the reaction.

However, other factors such as steric ones can have a major influence on

this endo/exo selectivity and can often override this stabilizing effect.

O

R1

B C

A

R3

R2

1

2

R3

R2

R1LUMO

HOMO

O

R1

AC

B

H

R3

HR2

*

A* B

C*

R2 R3

R1

O

Endo-3

R3

R2

R1LUMO

HOMO

O

R1

AC

B

H R3

H

R2

*

A* B

C *R2 R3

R1

O

Exo-3

Scheme 1.4. Example of an endo- and an exo approch of a LUMO(dipolarophile)-HOMO (dipole) controlled reaction. Primary orbital interactions are indicated with double headed arrows and secondary orbitals interactions with dotted lines

Chapter - 1

19

1.9. Scope of the present work

The 1,3-dipolar cycloaddition reactions of nitrones, nitrile oxide

with olefins is highly useful reaction for the construction of five

membered heterocyclic ring. It is attractive to apply this reaction for the

synthesis of biologically interesting isoxazoli(di)nes since these

compounds have drawn attention for their potential synthetic

applications. Currently, there is an immediate need to address the

following problems for the successful treatment of inflammation and

fungal infection disease.

1. Development of effective and less toxic new molecules for the

treatment of fungal infection as well as inflammation.

2. Understanding the mechanism of action on various enzymes as

well as in microbes.

In the direction of finding suitable solution to the above problems,

the candidate has synthesized biologically significant isoxazolidine,

isoxazoline derivatives of imdazolyl, trimethoxyphenyl, and tricyclic

azepines and studied the regio and stereochemistry using 1H, 13C, 2D

NMR experiment. The synthesized isoxazoline derivatives were subjected

to antifungal evaluation, phospholypase inhibition study. It is found that

some novel isoxazolidines shown to be more effective antifungal and PLA2

inhibition agents than standard drugs used in the experiment.

Chapter - 1

20

1.10 References

1. J. Fleming, “Frontier Orbital and Organic Chemical Reactions”

Wiley, New York, 1976.

2. D. St. C. Black, R. F. Crozier and V. C. Davis, Synthesis, 7, 205,

1975.

3. D. M. McQueen. U. S. Patent 2, 426, 894; Chem. Abstr., 41, 7289,

1947.

4. T. Curtius. Ber. Dtsch. Chem. Ges., 16, 2230, 1883.

5. E. Buchner. Ber. Dtsch. Chem. Ges., 21, 2637, 1888.

6. E. Buchner.; M. Fretisch.; A. Papendieck.; H. Witter. Liebigs Ann.

Chem., 273, 214, 1893.

7. E. Beckmann. Ber. Dtsch. Chem. Ges., 23, 3331, 1890.

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