Erlenmeyer Azlactones

Copyright 2013 by Modern Scientific Press Company, Florida, USA

International Journal of Modern Organic Chemistry, 2013, 2(1): 40-66International Journal of Modern Organic Chemistry

Journal homepage: www.ModernScientificPress.com/Journals/IJOrgChem.aspx

ISSN: 2166-0174Florida, USA

Review

Erlenmeyer Azlactones: Synthesis, Reactions and Biological Activity

Ahmed El-Mekabaty

Department of Chemistry, Faculty of Science, Mansoura University, ET-35516 Mansoura-Egypt

E-Mail: [email protected]; [email protected]; Tel: (+2010)03677361.

Article history: Received 22 February 2013, Received in revised form 19 March 2013, Accepted 272013, Published 1 April 2013.

Abstract: This review summarizes results from the literature concerning on synthetic

approaches and chemical properties of title compounds as well as their chemical reactions

since the azlactone chemistry began in 1893 by Friedrich Gustav Carl Emil Erlenmeyer1 to

date are reported. These compounds are important intermediates for the synthesis of a

variety of otherwise difficult to obtain synthetically useful and novel heterocyclic systems.

The most eye catching features of these structures are their greatest utility resides in

pharmaceuticals (analgesic, antibacterial, antifungal, antagonists, anti-inflammatory, anti-

microbial, anti-diabetic).

Keywords: Oxazolone; imidazolone; reactions, heterocycles, antimicrobial activity.

1. Introduction

The Erlenmeyer reaction was first described in 1893 by Friedrich Gustav Carl Emil

Erlenmeyer1 who condensed benzaldehyde with N-acetyl glycine in the presence of acetic anhydride

and sodium acetate. The reaction goes via a Perkin condensation following the initial cyclization of the

N-acetylglycine yielding the so-called Erlenmeyer azlactones.

Erlenmeyer azlactones have been used in a wide variety of reactions as precursors for

biologically active peptides, herbicides, fungicides, and as drugs, pesticides and agrochemical

intermediates. Oxazol-5-ones inhibit the activity of tyrosinase enzyme with a maximum inhibition by

the derivative which bears a cinnamoyl residue at C-4 of oxazolone moiety. Some prepared 3,4-

diaryloxazolones showed inhibition of cyclooxygenase-2 (COX-2), in vivo anti-inflammatory and

excellent activities of arthritis and hyperalgesia [1-5]. Several imidazolidine derivatives are proved as

Int. J. Modern Org. Chem. 2013, 2(1): 40-66


41

insecticides such as imidazolidin-2-one and imidaclopride; herbicides as imazamethabenz-methyl and

oxadiargyl and fungicides as iprodione that controlled the brown patch (Rhizoctonia solani) [6]. Great

fungitoxic effect was exhibited by imidazole derivatives that posse an electron-attracting moiety

substituted on the imine nitrogen atom [7-9]. Also, oxazolone and imidazolone derivatives are used as

antioxidant and anticorrosive additives for lubricant oils [10-12].

2. Synthesis

The various methods that have been used for the preparation of 2-oxazolin-5-one derivatives

are discussed as follows.

2.1. Erlenmeyer Synthesis

In this process, the interaction between carbonyl compounds (aldehydes and ketones) and

acylglycines or aroylglycines in the presence of acetic anhydride containing sodium acetate gives the

corresponding 4-(alkylidene or arylidene)-2-oxazolin-5-one derivatives (1a-s) as shown in Table 1.

The reaction proceeds via the formation of 2-(alkyl or aryl)-5-oxazolones which undergo Perkin

condensation with aromatic aldehydes to give the corresponding alkylidene or arylidene oxazolones.

H2C COOH

NHCOR

Ac2OAcONa

R\-CHOON

O

R

HCR\

1a-s

ON

O

R

Table 1: Synthesis of 4-(alkylidene or arylidene)-2-oxazolin-5-one derivatives (1a-s).

Comp. No. 1 R R' Ref.

a CH3

[13-15]b CH3

Cl

Cl

c CH3 MeO[14,16,17]

d CH3 No2



42

e CH3 Cl[14,16]

f CH3 (H3C)2N

g CH3 MeO

MeO

Cl

[18]

h CH3MeO

OC

O

H3C[19]

i Ph

[15, 20-22]

j Ph H3CO

k Ph Me

l Ph Cl

m Ph CH CH

n PhMeO

MeO

[17]

o PhNH

p Ph O [23,24]

q Ph S [25]

r Ph

MeO

MeO

OMe

[26]

s Ph

MeO

O

MeO

C

O

Me [27-30]

Some of the above derivatives have been also prepared using acetic anhydride and alumina as a

mild base [31, 32], or calcium acetate under microwave irradiation [33], giving oxazolone (1).



43

Treatment of 2,3-dihydro-1,3-diphenyl-1H-pyrazole-4-carbaldehyde with hippuric acid

afforded the corresponding (1,3-diphenyl-4-pyrazolin)-4-methylene-2-oxazolin-5-one (2) [34].

CH2COOH

NHCOPh+

2

NHN

Ph

CHOPh

NHN

Ph

Ph

N

O

O

Ph

When phthalic anhydride was condensed with hippuric acid, 2-phenyl-4-phthalyl-2-oxazolin-5-

one (3) was obtained [35].

O CH2COOH

NHCOPh+

3

O

O

N

O PhOO

O

Condensation of cinnamoylglycine with acetic anhydride and sodium acetate gave a low yield

of 2-styryl-4-(-hydroxyethylidene)-2-oxazolin-5-one (4) [36].

CH2COOH

NHCOCH=CHPh2(CH3CO)2O+

4

ON

O

CH=CHPh

CH3C

OH

Polyconjugated carbazolyl-oxazolones (6) [37] were synthesized starting from 9-methyl-9H-3-

carbazolecarbaldehyde (5) as follow:



44

ON

NO2

NNH

CH3

CHO

N

CH3

O

5

a,b c

a =CH3Clb =POCl3, DMFc =2-(4nitrophenylcarboxamido)acetic acid, Ac2Od =1-ethoxyethyne, Cp2ZrHCl, AgClO4e =HCl

d,e

N

CH3

CHO

ON

NO2

N

CH3

O

N

CH3

CHO

ON

NO2

N

CH3

O

n

c d,e

c

6

Condensation of sodium 2-[4-{2-[4-(dimethylamino)phenyl]-1-diazenyl}benzoylamino]acetate

(7) with aromatic aldehydes in the presence of Ph3P/CCl4 reagent afforded 4-arylidene-5(4H)-

oxazolone azo dyes (8a-d) [38].

PPh3 + CCl4 PPh3 Cl + CCl3

H2N C NH

O

CH2HOOC

NaNO2 / HCl

N(CH3)2

(H3C)2N N N

C OHN

H2CHOOC

NaOH

N N N(CH3)2

CHN

O

H2C COO Na

PPh3 Cl+

N N N(CH3)2

CHN

O

H2C C

O

O PPh3

7

-Ph3PO+



45

(H3C)2N N

N

N O

O

Et3N

RCHO

(H3C)2N N

N

N O

OCHR

8a-d

a: R= C6H5b: R= 4-ClC6H5c: R= C4H3Od: R = 3-O2NC6H4

Cycloalkanones (9) were heated with DMF/DMA giving the intermediate -enaminoketones

(10) which reacted with hippuric acid in the presence of acetic anhydride to give a mixture of pyran-2-

one derivatives (11) and oxazolone derivatives (12) [39].

The reaction of N-benzoylglycine with o-formyl benzoic acids (13) in presence of acetic

anhydride and piperidine as a catalyst afforded 3,5\-dioxo-2\-phenyl-1,3-dihydrospiro[indene-2,4\-

[1,3]oxazol]-1-ylacetates (14) [40].

X

CHO

COOH

+ PhCONHCH2COOHBase

Ac2O

X COOHN

O

O

Ph

OH

Base

X COOHN

O

O

Ph

OH

X

O

O

O

N

O

O

Ph

13

14

X= H, Cl, Br

Reaction of 1-naphthoyl-glycine (16) with acetic anhydride and triethylorthoformate in ethyl

acetate under reflux afforded 4-ethoxymethylene-2-[1]-naphthyl-5(4H) -oxazolone (17) [41].



46

CHN

O

16

CH2COOH

Ac2O / CH(C2H5O)3

EtOAc

ON

OEtO

17

2-Aryl-4-[4-(1,4,7,10-tetraoxa-13-azacyclopentadecyl)-benzylidene]-5-oxazolone derivatives

(19) [42] were prepared by the cyclization of 4-(1,4,7,10-tetraoxa-13-azacyclopentadecyl)

benzaldehyde (18) with aroyl glycine derivatives in the presence of acetic anhydride.

The reaction of indole-3-carboxaldehyde (21) with (3-phenyl-propionylamino)-acetic acid (20)

in presence of acetic anhydride and calcium acetate afforded the oxazolone derivative (22) [43].

Condensation of 16-formyllambertianic acid methyl ester (23) with hippuric acid in the

presence of acetic anhydride and potassium carbonate gave labdanoid oxazol-5(4H)-one (24) in a low

yield [44].



47

Me

COOMeMe

CH2

O

CHO

Me

COOMeMe

CH2

O

N

O

O

Ph

H2C COOH

NHCOPhAc2O / K2CO3

23 24

Reaction of acylglycines with 4-hydroxybenzaldehyde arenesulfonate esters (25) in presence of

acetic anhydride and sodium acetate afforded 2-aryl-4-[4-(arylsulfonyloxy) phenylmethinyl]-4,5-

dihydro-5-oxo-1,3-oxazoles (26). The same products were obtained by allowing acylglycines to react

with ethyl chloroformate in the presence of triethylamine followed by the reaction with (25) [45-48].

H2C COOH

NHCOAr2

ON

O

Ar2

CHAr1

OH

ON

O

Ar2

HCAr1

Cl C

O

OEtEt3N

H2C C

HN

O

O COOEt

CO

Ar2

-CO2

ON

O

Ar2

Ar1-CHO(25)

Ac2O / AcONa

26a, Ar1= C6H5SO3C6H4- : Ar2= C6H5-b, Ar1= 4-CH3C6H4SO3C6H4- : Ar2= C6H5-c, Ar1= 3,4-(CH3)2C6H3SO3C6H4- : Ar2= C6H5-d, Ar1= 4-CH3C6H4SO3-3-MeOC6H3- : Ar2= C6H5-e, Ar1= C6H5SO3C6H4- : Ar2= C6H5SO2NHC6H4-

Ar1-CHO(25)

-EtOH

2.2. Bergmann Synthesis

Bergmann and Stern [49] stated that oxazolones can be prepared by the action of acetic

anhydride on certain -(-haloacyl)-amino acids. Thus, refluxing N-chloroacetyl phenylalanine with

acetic anhydride gave 4-benzylidene-2-methyl-2-oxazolin-5-one.

C6H5-CH2-CH-COOHON

CH2Cl

H2CC6H5

ON

O

CH2

H2CC6H5

ON

O

CH3

HCC6H5O

NHCOCH2Cl

Ac2O



48

Similarly, 2-benzyl-4-ethoxymethylene-2-oxazolin-5-one (27) was obtained by treatment of N-

(-chlorophenylacetyl)-o-ethylserine with acetic anhydride in pyridine [36].

ON

O

CH2Ph

CHEtO

Ac2O

Pyridine

27

CH3-CH2OCH2-CH-COOHNHCOCHPh

Cl

2.3. Miscellaneous Methods

Reaction of 4-acetamido-5-phenyl-3-isothiazolidinone-1,1-dioxide (28) with acetic anhydride-

pyridine mixture gave the corresponding 4-benzylidene-2-methyl-2-oxazolin-5-one (1) [50].

NH

O2S

NHCOCH3

O

Ph

Ac2O

C5H5NO

N

CH

CH3O

Ph

128

Coupling of aroylglycines with the appropriate aryldiazonium salts in acetic anhydride

containing freshly fused sodium acetate at 0 C gave 2-aryl-4-arylazo-2-oxazoline-5-ones (29) [51-53].

H2C COOH

NHCOAr+ Ar\N=N-Cl

Ac2O

AcONa ON

O

Ar

NHNAr\

29a, Ar= C6H5 : Ar\= 4-OHC6H5b, Ar= 4-ClC6H5 : Ar\= 4-OHC6H5c, Ar= 4-CH3C6H5 : Ar\= 4-OHC6H5

The acid catalyzed rearrangement of 3-benzamido-1,4-diphenyl-2-azetidinone (30) gave 4-

benzylidene-2-phenyl-2-oxazolin-5-one (1) [54].

N

PhNH

O Ph

C

O

Ph

H

O

N

PhO

CHPh

NHPh

O

N

PhO

CHPh

30 1

-PhNH2



49

3. Reactions

3.1. Reaction with Acids and Alkalies

Carboxylic acids can undoubtedly cause ring fission of oxazolones even in the absence of

water. Carter and Stevens [55] found that, when 4-benzyl-2-phenyl-2-oxazolin-5-one was heated with

acetic acid afforded benzoylphenylalanine.

O

NPhH2C

O Ph+ CH3COOH

Ph-CH2-CH

CONH

OCOCH3

COPhPh-CH2-CH

COOH

NHAcOH

COPh

The basic hydrolysis of 4-(4\-acetoybenzylidine)-2-methyl-5-oxazolone (1) did not yield the

expected phenylpyruvic acid, but it gives the enol acetate (31).On the other hand, treatment of (1) with

acetic acid afforded enolacetate derivative (32) [56].

N

O

O

CH3

H3COCOH3COCO

COOH

OCOCH3

HO

COOH

AcOH OH / H2O

3132

OCOCH3

1

Phenyl pyruvic acid (33) was obtained through a two steps hydrolysis of oxazolones (1L) with

aqueous sodium hydroxide followed by aqueous hydrochloric acid [57].

3.2. Reaction with Amines

3.2.1. With aliphatic and aromatic amines

The 2-oxazolin-5-one derivatives react readily with primary amines than with secondary

amines via ring opening of oxazolone at C5 to give the corresponding amides [58]. Thus, reaction of

primary aromatic amines with 2-phenyl-4-arylmethylene-2-oxazolin-5-ones (1) leads to ring opening

at C5 to give the arylamides of -carboxamido--arylacrylic acids which recyclise to the corresponding

1,2-diaryl-4-arylmethylene-2-imidazolin-5-ones (34) by heating at 200C under vacuum [59]. It was

stated by many investigators that 2-imidazolin-5-one derivatives (34) were also prepared directly by



50

the reaction of 2-phenyl-4-arylmethylene-2-oxazolin-5-ones with primary aromatic amines in the

presence of acetic acid and sodium acetate [60-66], anhydrous ZnCl2 under fussion [67],

DMF/Me3SiCl [68], or in Pyridine/Zeolite [69-71] under reflux.

Condensation of 2-phenyl-4-arylmethylene-2-oxazolin-5-ones with sulpha drugs at 140C

afforded 2-imidazolin-5-one derivatives (35) [72].

ON

O

Ph

CH

+R H2N SO2NHR1

NN

O

Ph

HC

R

SO2NHR1

35

R= 4-ClC6H4-, 2-NO2C6H4-

R1=N

N

N

NCH3

CH3

ON CH3

, ,

It has been reported that reaction of 4-(ethoxymethylene)-2-phenyl-5-oxazolone (36) with

primary aromatic amines in ethanol gave compounds (37) [73,74].

O

N

HC

O

OCH2CH3

+ H2N R

O

N

HC

O

HN R

Ethanol

R= CH3, SH

37

36



51

On the other hand, reaction of 2-oxazolin-5-one (36) with diaminomaleonitrile (DAMN) under

reflux in alcohol afforded the corresponding propenoates derivatives (38) but at room temperature gave

oxazolone (39) which on heating in alcohol afforded (38) [75,76].

ON

O

Ph

EtO

DAMN / EtOHr.t. ON

O

Ph

NH

CN

NH2

NC

NH

NH2

NC

CN

NHCOPh

COORDAMN / ROH

ROH /

36

38

39

R= Methyl, Ethyl, Propyl, Pentyl

It was stated by many investigators that anthranilic acid reacts with 2-phenyl-4-arylmethylene-

2-oxazolin-5-ones to give the corresponding benzoxazinone derivatives (40) [77-80].

3.2.2. With ammonia

Reaction of (1) with ammonia or ammonium acetate in the presence of potassium carbonate or

under microwave irradiation using graphite as a catalyst afforded 2-phenyl-4-arylmethylene-2-

imidazolin-5-ones (41) [67,81,82].

ON

O

Ph

HCAr

NH3NHN

O

Ph

HCAr

1 41

Sawdey has been reported that, treatment of 4-arylazo-2-aryl-2-oxazolin-5-one (29) with

ammonia in methanol affects ring opening followed by cyclization to yield 1,5-diaryl-3-carboxamido-

(1H)-1,2,4-triazoles (42) [83].



52

ON

O

Ar

HNNAr\

NH3CH3OH

Ar\-NH-N=C COOCH3

NHCOAr

N

N

N

CONH2

Ar

Ar\

29 42

3.2.3. With heterocyclic amines

Treatment of 2-phenyl-4-dichloromethylideneoxazole-5(4H)-one (43) with some heterocyclic

amines namely, 2-amino-1,3-thiazole, 2-amino-4-phenyl-1,3-thiazole, 2-amino-4,5-dimethyl-1,3-

thiazole, 2-amino-benzothiazole and 2-amino-6-methylbenzothiazole in the presence of THF and

triethylamine leads to the formation of enamides (44) and (45) via opening of the oxazole ring. Heating

of these enamides with excess morpholine or piperidine in pyridine gave compounds (46) and (47)

respectively [84].

Several authors stated that imidazoline derivatives containing sterically hindered phenols

possess inhibitors of cyclooxygenase and 5-lipoxygenase [85], -adrenoblockers [86,87], and anti-

hypertensive action [86-89]. So, the reaction of 4-benzylidene-2-methyl oxazol-5-one (1a) with N-

acylhydrazones of 3,5-di(tert-butyl)-4-hydroxybenzaldehyde in acetic acid afforded 2-imidazolin-5-

ones (48) in high yield [90].



53

N

O

CHPh

O Me

t-Bu

HO

t-Bu

CH

N R

t-Bu

OH

t-BuN

N

CHPh

OR

SN

SCH2CONH N CONHR =

+

481a

,

3.2.4. With amino acids

Azlactones were find diverse applications in the synthesis of aromatic -amino acids [91-94].

The base catalyzed deprotonation of azlactone and the addition of the resulting anion to aromatic

aldehydes leads to the formation of arylidene derivatives (1) which are subsequently transformed into

the amino acids (49) in basic medium [95].

ON

O

Ph

ON

O

Ph

ON

O

Ph

OH

Ar

ON

O

Ph

Ar

Ar CO2

NH3

AcO -H2O

OHreduction

49

1

ArCHO

N-Benzoyl dehydro-3-(3-pyridyl)alanyltryptophan (50) [96] was obtained by condensation of

2-phenyl-4-(3-pyridyliden)-5(4H)-oxazolone with tryptophan in the presence of triethylamine as the

condensing agent.

O

N

HC

OPh

N

NH

CH2CH(NH2)COOH

PhCONHC

CH

N

CONH CH

H2C

COOH

HN

50

+



54

The unsaturated oxazolone were converted into the corresponding dipeptide by two reaction

sequences. One is to condense oxazolone with the amino acid ester to form (51) which was hydrolyzed

to give (52) [97,98].

O

N

Ph

HC

O

ArH2N COOR1

R

Ph NH

HN COOR1

OAr

O R

Ph NH

HN COOH

OAr

O R

51

52

OH

On the other hand, reaction of 4-ethoxymethylene-2-(1)-naphthyl-5(4H)-oxazolone (17) with

the amino group of peptides gave 2,4-disubstituted oxazolone derivatives (53) and ethylalcohol [99].

O

N

HC

O

OC2H5

Naphthyl

NH2-CH(R1)..............-NH-CH(R2)-CO-XH

+

O

N

HC

ONaphthyl

NH-CH(R1).........-NH-CH(R2)-CO-XH

1753

+ EtOH

3.2.5. With hydrazines

It has been reported that treatment of 4-arylmethylene-2-phenyl-2-oxazolin-5-one with phenyl

hydrazine in acetic acid containing fused sodium acetate gave the corresponding 1,2,4-triazin-6-one

derivatives (54) [60,64,100].

ON

O

Ph

HCAr

PhNHNH2

NH

N

N Ph

PhO

HCAr

54

4-Arylmethylene-2-phenyl-2-oxazolin-5-ones react with hydrazines in alcohol to give the

hydrazides (55) [64,100], which undergoes cyclization by heating under reflux with sodium hydroxide

to give the corresponding 1,2,4-triazin-6-one derivatives (54) [101,102].



55

Microwave irradiation has become an important method in organic synthesis that can be

applied to a wide range of reactions within short reaction times and with high yields. So, 2-oxazolin-5-

ones (56) were irradiated in microwave oven with hydrazine hydrate at 90 W for 10 min. to afford 5-

[(6-bromo-4-oxochromen-3-yl)methylene]-3-phenyl-2,5-dihydro-1H-[1,2,4] triazin-6-ones (57) [103].

On the other hand, reaction of 4-benzylidene-2-phenyloxazol-5-one with hydrazine hydrate in

pyridine afforded N-amino-2-phenyl-4-benzylidene-1,3-diazol-5-one (58) [104].

Reaction of hydrazine hydrate with 4-arylazo-2-oxazolin-5-ones (29) in the presence of basic

reagents yielded 1,5-diaryl-1,2,4-triazole-3-carboxylic acid hydrazides (59) [51] via ring opening

followed by cyclization.

ON

O

Ph

ArHNN

NH2NH2

NHCOPh

CONHNH2

N

N

N

CONHNH2

Ph

Ar

29 59

ArNH-N=C

1-Acyl-3-hydroxy-1H-pyrazoles (61) were obtained in high yields by the reaction of

ethoxymethylene oxazolone (36) with hydrazide derivatives via the intermediate pyrazolone derivative

(60). On the other hand, reaction of (36) with two equivalents of an appropriate hydrazine derivative,



56

the corresponding symmetrically N,N\-disubstituted hydrazines (62) together with the oxazolone (63)

were obtained. [105,106].

The chemotherapeutic properties of drugs belonging to the nitrofuran series offer an alternative

to antibiotics and antimicrobial [107-109]. So, the reaction of 2-oxazolin-5-one with 5-nitro-2-

furohydrazidimide (64) in dioxane afforded 7-benzylidene-5-methyl-2-(5-nitro-2-furyl)-7H-imidazo-

(3,4-b)(1,2,4)triazole (65) [110].

ON

O

Me

CH

ONO2C

NH2NH2N O

NO2N

N NN

Me

CH

6564+

3.2.6. With diamines

Many investigators [111-114] stated that fussion of 4-arylmethylene-2-phenyl-2-oxazolin-5-

ones with o-phenylenediamine at 140C in the presence of fused sodium acetate gave (o-

aminophenyl)-4-arylmethylene-2-phenyl-2-imidazolin-5-ones (66) which on refluxing with acetic acid

containing sodium acetate afforded benzimidazolo-[2,1-e]-imidazoles (67). On the other hand, when

the reaction was carried out with o-phenylenediamine in ethanol, the product (68) was obtained. While

heating in presence of acetic acid and sodium acetate gave the benzimidazole derivatives (69).



57

Treatment of 4-arylmethylene-2-phenyl-2-oxazolin-5-one (26) with 2,3-diaminopyridine in

ethanol containing fused sodium acetate under reflux gave compound (70). Using acetic acid instead of

ethanol yielded 2-[2-[(4-arylsulfonyloxyphenyl)-1-benzoylamino] ethen-1-yl] -3H-imidazo (4,5-b)

pyridine (71). On the other hand, when the reaction was carried out by fusion with a catalytic amount

of fused sodium acetate, 3-amino-2-[4-(4-arylsulfonyloxyphenylmethylene)-5-oxo-2-phenyl

imidazolin-1-yl]pyridines (72) were obtained [47].

Condensation of 4-methylbenzylidene-2-phenyl-2-oxazolin-5-one with 1,8-diaminonaphthalene

in glacial acetic acid at room temperature yielded a mixture of 2-(4-methylbenzyl)-1H-pyrimidine (73)

and 2-phenyl-1H-pyrimidine (74), respectively [115].

ON

O

Ph

HCMe

+

N

NH

CH2

Me

NH2

NH2

N

NH

Ph

CH3COOH

73 74

+



58

It was stated that, 2-alkenyl-4,4-dialkyl-5-oxazolones (75) [116,117] are of special interest for

the synthesis of bisazlactones and multiazlactones [118-121] because of their ability to undergo

Michael type addition on the vinyl group. They are also key intermediates for a large number of novel

monomers and polymers. Their ring opening reaction with primary amines and alcohols has been

utilized extensively for the synthesis of acrylamide monomers [116,122,123].

3.2.7. With diazocompounds

4-Arylmethylene-2-phenyl-2-oxazolin-5-ones were converted into methyl--benzoylamino

cinnamates (78) by the action of ethereal diazomethane in methanol. When the reaction was carried out

in dry dioxane, the cyclopropane derivatives (79) were formed [36,124,125]

ON

O

Ph

CHArCOOCH3

NHCOPh

ON

O

Ph

Ar

79

78

CH2N2

CH3OH

CH2N2dioxan

Ar-CH=C

Mustafa et al. [125] reported that treatment of 4-ethylidene-2-phenyl-2-oxazolin-5-one (1a)

with diazomethane leads to the formation of 4-isopropylidene-2-phenyl-2-oxazolin-5-one (80).



59

ON

O

Ph

HCH3C

CH2N2 ON

O

Ph

C

CH3

H3C

1a 80

On the other hand, reaction of 4-arylmethylene-2-phenyl-2-oxazolin-5-ones with 1,3-

diphenylnitrilimine at room temperature afforded spiro-pyrazolines (81) [126].

+

C

N

C6H5

N

C6H5

NN

C6H5

C6H5

Ar

O

N

OPh

81

ON

O

Ph

HCAr

4. Biological Activity

2-Oxazolin-5-ones can be considered as semi acid anhydrides which undergo many of the

reactions of true acid anhydrides but at a slower rate. This special reactivity allows this class of

compounds to be quite useful as serine protease inhibitors, inactivating enzymes such as chymotrypsin

[127], human leucocytes elastase [5-9,128,129], porcine pancreatic elastase, cathepsin G [130] and CIr

serine protease [131]. The chemical stability and potency of the oxazolones can be turned by choosing

substituent which influences the reactivity of the carbonyl by electronic and steric effects.

A variety of 4-(alkoxymethylene)-2-phenyl-5-oxazolone have been designed to inhibit enzymes

such as chymotrypsin [132,133], thrombin [134], cathepsin G [128], HSV-1 protease[135], protac R

[131], human leukocyte proteinase [136], HLE [137] and pancreatic elastase [127]. 2-Phenyl-4-

arylmethylene-2-oxazolin-5-ones act as Cirserine protease inhibitors [131]. Also it converted to the

corresponding imidazolones via interaction with 4-amino-1-phenyl-2,3-dimethylpyrazolin-5-one

(aminoantipyrine), which acts as non-steroidal anti-inflammatory agents [138]. Also, combination of

2-oxazolin-5-ones with 2-aminothiazole, 2-aminobenzothiazole or 2-aminothiadiazole give substituted

imidazolones which act as potent anticonvulsant and enzyme inhibitors [139, 146-147]. On the other

hand, it acts as new class of antimitotic, anticancer agents which inhibit tubulin polymerization [140].

Compounds 35 are used for inhibitors HCMV protease, Chymotrypsin and human leukocyte

elastase as well as cell culture assay results for antiviral activity [2, 3].



60

2-Imidazolin-5-ones 48 are useful for the treatment of viral infections, viral protease inhibitors

and useful for treatment of infection by CMV, HSV-1, HSV-2 [141].

t-Bu

OH

t-BuN

N

CHPh

O

R 48

7-Benzylidene-5-methyl-2-(5-nitro-2-furyl)-7H-imidazo-(3,4-b)(1,2,4)triazole 65 has been

synthesized and tested for inhibitory activity against human leukocyte elastase. It was shown activities

both in vitro toward human sputum elastase and in vivo in a hemorrhagic assay [142-145].

5. Conclusion

The present survey has clearly demonstrated that azlactones may be successfully used to

synthesize a wide variety of heterocycles of academic and pharmaceutical interest. Moreover, in

general, the desired compounds may be obtained in a single step with high yield.

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