Erlenmeyer Azlactones

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

ISSN: 2166-0174
Florida, USA
Journal homepage: www.ModernScientificPress.com/Journals/IJOrgChem.aspx
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: a_el_m11@yahoo.com; elmekabaty@mans.edu.eg; Tel: (+2010)03677361.
Article history: Received 22 February 2013, Received in revised form 19 March 2013, Accepted 27
2013, 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, antimicrobial, 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 3,4diaryloxazolones 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
Copyright 2013 by Modern Scientific Press Company, Florida, USA
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.
R\
O
H2C
COOH
NHCOR
Ac2O
AcONa
R\-CHO
H
C
R
1a-s
Table 1: Synthesis of 4-(alkylidene or arylidene)-2-oxazolin-5-one derivatives (1a-s).

Comp. No. 1
CH3
R'
Ref.
Cl
[13-15]
CH3
Cl
CH3
MeO
CH3
No2
[14,16,17]

e
42
CH3
Cl
[14,16]
f
CH3
(H3C)2N
Cl
CH3
[18]
MeO
MeO
MeO
O
CH3
Ph
Ph
H3CO
Ph
Me
Ph
Cl
Ph
H3 C
[19]
[15, 20-22]
C
H
C
H
MeO
Ph
MeO
[17]
o
Ph
N
H
Ph
[23,24]
Ph
[25]
MeO
Ph
[26]
MeO
OMe
MeO
O
Ph
Me
C O
[27-30]
MeO
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].
O
CH2COOH
HN
Ph
CHO
Ph
NHCOPh
Ph
HN
N
Ph
Ph
When phthalic anhydride was condensed with hippuric acid, 2-phenyl-4-phthalyl-2-oxazolin-5one (3) was obtained [35].
Ph
O
O
O
O +
CH2COOH
NHCOPh
Condensation of cinnamoylglycine with acetic anhydride and sodium acetate gave a low yield
of 2-styryl-4-(-hydroxyethylidene)-2-oxazolin-5-one (4) [36].
OH
H3C
CH2COOH
+
NHCOCH=CHPh
2(CH3CO)2O
CH=CHPh
4
Polyconjugated carbazolyl-oxazolones (6) [37] were synthesized starting from 9-methyl-9H-3carbazolecarbaldehyde (5) as follow:
44
O
CHO
c
a,b
N
N
H
N
CH 3
CH3
5
NO2
d,e
CHO
a =CH 3Cl
b =POCl3, DMF
c =2-(4nitrophenylcarboxamido)acetic acid, Ac 2O
d =1-ethoxyethyne, Cp2ZrHCl, AgClO4
e =HCl
N
CH3
d,e
c
O
CHO
CH3
CH3
O
n
NO2
N
CH3
NO2
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 +
(H3C)2N
O
H2N
C
HOOC
PPh3 Cl +
CCl4
CH2
NaNO2 / HCl
NH
NaOH
N(CH3)2
H2
C
HOOC
CCl3
N(CH3)2
+
H
N
N(CH3)2
+
PPh3 Cl
-Ph3PO
O
C
O
H2
C
H
N
7
COO Na
H
N
H2
C
PPh3

(H3C)2N
45
(H3C)2N
N
N
N
Et3N
RCHO
C
H
O
8a-d
a: R= C6H5
b: R= 4-ClC6H5
c: R= C4H3O
d: 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-2one 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].
OH
CHO
+ PhCONHCH2COOH
X
COOH
Base
Ac2O
X
N
COOH
Ph
13
Base
X= H, Cl, Br
OH
O
N
X
14
O
Ph
N
COOH
Ph
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
EtO
O
C
H
N
CH2COOH
Ac2O / CH(C2H5O)3
EtOAc
16
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
O
O
CHO
N
O
Me
O
H2C
CH2
Ph
Me
COOH
CH2
NHCOPh
Ac2O / K2CO3
Me
COOMe
Me
COOMe
24
23
Reaction of acylglycines with 4-hydroxybenzaldehyde arenesulfonate esters (25) in presence of

acetic anhydride and sodium acetate afforded 2-aryl-4-[4-(arylsulfonyloxy) phenylmethinyl]-4,5dihydro-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].
O
H2 C
HN
COOEt
Cl
O
C
O
C
OEt
Et3N
H2 C
COOH
NHCOAr2
Ar2
Ar1
Ac2O / AcONa
OH
-EtOH -CO2
CH
Ar1-CHO
(25)
Ar2
Ar1-CHO
(25)
Ar2
Ar1
H
C
Ar2
a, Ar1= C6H5SO3C6H4b, Ar1= 4-CH3C6H4SO3C6H4c, Ar1= 3,4-(CH3)2C6H3SO3C6H4d, Ar1= 4-CH3C6H4SO3-3-MeOC6H3e, Ar1= C6H5SO3C6H4-
: Ar 2= C6H526
: Ar 2= C6H5: Ar2= C6H5: Ar2= C6H5: Ar 2= C6H5SO2NHC6H4-
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
C6H5-CH2-CH-COOH
NHCOCH2Cl
Ac2O
H2
C
CH2Cl
C6H5
H2
C
C6H5
CH2
H
C
CH3
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].
EtO
CH
Ac2O
CH3-CH2OCH2-CH-COOH
NHCOCHPh
Cl
Pyridine
CH2Ph
27
2.3. Miscellaneous Methods

Reaction of 4-acetamido-5-phenyl-3-isothiazolidinone-1,1-dioxide (28) with acetic anhydridepyridine mixture gave the corresponding 4-benzylidene-2-methyl-2-oxazolin-5-one (1) [50].
NHCOCH3
Ph
Ph
CH
N
Ac2O
O2S
C5H5N
N
H
CH3
28
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].
Ar\
H2C
COOH
NHCOAr
Ac2O
Ar\N=N-Cl
H
N
AcONa
Ar
\
29
a, Ar= C6H5
: Ar = 4-OHC6H5
b, Ar= 4-ClC6H5 : Ar\= 4-OHC6H5
c, Ar= 4-CH3C6H5 : Ar\= 4-OHC6H5
The acid catalyzed rearrangement of 3-benzamido-1,4-diphenyl-2-azetidinone (30) gave 4benzylidene-2-phenyl-2-oxazolin-5-one (1) [54].
NHPh
O
Ph
NH
Ph
Ph
CH
Ph
N
O
Ph
30
-PhNH2
H
O
CH
Ph
N
O
O
1
Ph
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.
PhH2C
O
Ph-CH2-CH
+ CH3COOH
Ph
NH
CO
Ph-CH2-CH
AcOH
COPh
OCOCH3
NH
COOH 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].
O
COOH
COOH
O
OCOCH3
OCOCH3
N
AcOH
H3COCO
CH3
OH / H2O
HO
H3COCO
1
32
31
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].
CH
H2N
+
N
SO2NHR1
Ph
H
C
R
N
SO2NHR1
CH3
Ph
R1=
35
N
N
CH3
CH3
R= 4-ClC6H4-, 2-NO2C6H4-
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].
HC
OCH2CH3
N
O
H2N
36
Ethanol
H
N
HC
N
O
R= CH3, SH
37
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].
CN
NC
DAMN / EtOH
r.t.
EtO
N
H
NH2
O
Ph
39
O
ROH /
Ph
CN
36
DAMN / ROH
NC
COOR
N
H
NH2
NHCOPh
38
R= Methyl, Ethyl, Propyl, Pentyl
It was stated by many investigators that anthranilic acid reacts with 2-phenyl-4-arylmethylene2-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-2imidazolin-5-ones (41) [67,81,82].
Ar
H
C
Ar
H
C
NH3
O
Ph
1
NH
Ph
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].

Ar\
HNN
52
CONH2
O
N
O
Ar
29
NH3
CH3OH
Ar\-NH-N=C
COOCH3
NHCOAr
Ar\
Ar
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-1,3thiazole, 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 antihypertensive action [86-89]. So, the reaction of 4-benzylidene-2-methyl oxazol-5-one (1a) with Nacylhydrazones of 3,5-di(tert-butyl)-4-hydroxybenzaldehyde in acetic acid afforded 2-imidazolin-5ones (48) in high yield [90].

t-Bu
Ph CH
N
O
53
Me
t-Bu
1a
N
R=
t-Bu
C N R
H
HO
Ph CH
SCH2CONH , N
N
R
OH
t-Bu
48
CONH
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].
OH
O
AcO
O
-H2O
ArCHO
Ar
Ar
N
Ph
Ph
O
Ph
1
Ph
reduction OH
Ar
CO2
NH3
49
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.
N
CH2CH(NH2)COOH
HC
N
Ph
N
H
H
N
CH
PhCONHC
H2C
CONH
C
H
COOH
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].
HC
H2 N
Ar
Ar
O
N
Ph
COOR1
H
N
R
Ph
COOR1
N
H
O
51
OH
Ar
O
H
N
Ph
COOH
N
H
O
52
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].
NH2-CH(R1)..............-NH-CH(R2)-CO-XH
NH-CH(R1).........-NH-CH(R2)-CO-XH
HC
HC
OC2H5
N
Naphthyl
Naphthyl
EtOH
53
17
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].
Ar
H
C
Ar
H
C
N
H
Ph
PhNHNH2
N
N
Ph
Ph
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-5ones (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.
ArHNN
CONHNH2
O
NH2NH2
N
ArNH-N=C
CONHNH2
NHCOPh
N
Ar
Ph
Ph
29
59
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-2furohydrazidimide (64) in dioxane afforded 7-benzylidene-5-methyl-2-(5-nitro-2-furyl)-7H-imidazo(3,4-b)(1,2,4)triazole (65) [110].
CH
N
CH
O
O
Me
NH2
H2N N C
64
N
O
NO2
N
Me
N N
NO2
65
3.2.6. With diamines

Many investigators [111-114] stated that fussion of 4-arylmethylene-2-phenyl-2-oxazolin-5ones with o-phenylenediamine at 140C in the presence of fused sodium acetate gave (oaminophenyl)-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].
H
C
Me
O
+
N
NH2
O
NH2
Ph
CH3COOH
NH
NH
+
N
C
H2
73
Me
Ph
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]
CH2N2
Ar
CH
Ar-CH=C
COOCH3
CH3OH
NHCOPh
O
Ph
78
O
Ar
CH2N2
dioxan
Ph
79
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
CH3
H 3C
H
C
H3C
CH2N2
Ph
1a
Ph
80
On the other hand, reaction of 4-arylmethylene-2-phenyl-2-oxazolin-5-ones with 1,3diphenylnitrilimine at room temperature afforded spiro-pyrazolines (81) [126].
Ar
H
C
C6H5
C6H5
N
N
Ph
Ph
Ar
C6H5
N
C6H5
81
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-4arylmethylene-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].
Ph
CH
t-Bu
N
OH
N
R
48
t-Bu
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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Erlenmeyer Azlactones

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

International Journal of Modern Organic Chemistry

Erlenmeyer Azlactones: Synthesis, Reactions and Biological Activity

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

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

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

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

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

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

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

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

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

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

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

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

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

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

2.2. Bergmann Synthesis

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2.3. Miscellaneous Methods

Coupling of aroylglycines with the appropriate aryldiazonium salts in acetic anhydride

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

3.2. Reaction with Amines

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

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

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

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

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R= Methyl, Ethyl, Propyl, Pentyl

3.2.2. With ammonia

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

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3.2.3. With heterocyclic amines

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3.2.4. With amino acids

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

Copyright 2013 by Modern Scientific Press Company, Florida, USA

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

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

3.2.5. With hydrazines

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

Copyright 2013 by Modern Scientific Press Company, Florida, USA

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

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

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

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

Copyright 2013 by Modern Scientific Press Company, Florida, USA

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

3.2.6. With diamines

Copyright 2013 by Modern Scientific Press Company, Florida, USA

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