ejbps, 2015, Volume 2, Issue 3, 964-987.

Janmajoy et al.

Review Article

SJIF Impact Factor 2.062

ISSN 2349-8870
European
Journal of Biomedical
and Pharmaceutical Sciences
European
Journal
of Biomedical
Volume: 2
AND
Issue: 3
964-987
Pharmaceutical sciences
Year: 2015

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A REVIEW ON OXAZOLONE, IT S METHOD OF SYNTHESIS AND

BIOLOGICAL ACTIVITY
Niraj Sharma, Janmajoy Banerjee*, Nomi Shrestha and Deepak Chaudhury
Department of Pharmacy Sunsari Technical College, Dharan, Nepal.
Article Received on 24/04/2015

Article Revised on 18/05/2015

Article Accepted on 11/06/2015

ABSTRACT
*Correspondence for
Author
Janmajoy Banerjee

Oxazolones are five membered heterocyclic entity containing oxygen

and Nitrogen. It is important synthons for the synthesis of various

Department of Pharmacy

biologically active compounds and is an important pharmcophore of

Sunsari Technical College,

synthesized drugs. Oxazolone is being synthesized in many ways since

Dharan, Nepal.

1883. It shows marked pharmacological activity such as: antimicrobial,

anifungal, anti-diabetic, anti-cancer, and anti-inflammatory. In present

article we review the mechanism of oxazolone formation, its chemistry, diversity oriented
synthesis of oxazolone, various method of synthesis and pharmacological activity of
synthesized compound along with SAR.
KEYWORDS: Erlenmeyer-Plochl reaction, FriedelCrafts reaction, Contact allergen,
anti-angiogenic.
INTRODUCTION
In the field of Medicinal chemistry, the family of heterocyclic compounds containing
Nitrogen, sulphur and oxygen as hetero atoms in five and six membered ring structure plays
an important role. Oxazolone are one of those five membered heterocyclic compounds which
are in three isomeric forms, one according to the location of the carbonyl group and two
according to the location of double bond containing.[1, 2]

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5-(4H)-oxazolone
Oxazolones are important intermediate for the synthesis of several compounds such as amino
alcohols, amides[1], amino acids[2,3], dyes[3,4], heterocyclic precursors, biological active
compounds as well as biosensors coupling and photosensitive composition devices for
proteins.[2] Oxazolone is crucial for the manufacturing of various biologically active drugs. 6-Naltrexol is the major active metabolite of naltrexone, a potent -opioid receptor antagonist
used in the treatment of alcohol dependence and opioid abuse. Chemical structure of the
carbonate codrug, CB-NTXOL-BUPOH, consisting of 6--naltrexol covalently linked by
carbonate ester linkage to modified form of hydroxybupropion (bupropion with oxazolone). [5]
Posizolid is an oxazolidinone antibiotic effective against phase 2 Tuberculosis is under
investigation[6], Deflazacort, contains oxazolone scaffold derived from prednisone, has antiinflammatory and immunosuppressive effects[7], ZHD-0501, is a metabolite of staurosporine
(STA) analog with an oxazolone scaffold which inhibit the proliferation of several human
and murine cancer cell lines.[8] Jadomycin B, an antifungal antibiotic with a unique 8Hbenz[b]oxazolo[3,2-]phenanthridine pentacyclic skeleton produced by the bacterium
Streptomyces venezuelae ISP 5230.[9] Phenacyl oxazolone involves the intramolecular DielsAlder reaction, resulting in the synthesis of anti-cancer drug, pancratistatin[10], a naturally
occurring Amaryllidaceae alkaloid exhibits potent apoptotic activity against a large panel of
cancer cells.[11]

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Fig: Some drugs which contains oxazolone scaffold

Oxazolone is important synthons in synthesizing various drugs, oxazolone scaffold shows
various biological activity such as, anti-microbial[12,13], anti-diabetic[14], anti-viral[15], antifungal[16], anti-cancer[17], cardioprotective
obesity,

anti-depressant[20],

[18]

, contact allergen

anti-HIV[21],

[19]

, anti-inflammatory, anti-

anti-angiogenic[22],

anti-convulsant[23,24],

sedative[15,25], Tyrosinase inhibitor,[25, 26] fungicide and herbicide.[26]

History
In 1883 at first time, Plo chl synthesized oxazolone by condensation of benzaldehyde with
hippuric acid in presence of acetic anhydride.[27, 28] Further in 1893, first correct structure of
oxazolone was established by Friedrich Gustav Carl Emil Erlenmeyer, by reacting
benzaldehyde with N-acetylglycine in the presence of acetic anhydride and sodium acetate
and the reaction was proceeds by Perkins condensation followed by initial cyclisation of Nacetylglycine yielding Erlenmeyer azlactones. [29, 30]

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General method of synthesis and chemistry

In literature numbers of methods are reported for the synthesis of oxazolone but the general
method of synthesis of oxazolones is by Erlenmeyer azlactone synthesis.[27,29,30] The
compound is synthesized by intramolecular condensation of glycine moiety in presence of
dehydrating agent such as acetic anhydride and carbodiimides.[27, 31] The general mechanism
of oxazolone formation is depicted in scheme 1.[32] For better yield, different types of
catalysts such as Zinc oxide[13,24], Antimony pentafluoride[33], Dodecatungstophosphoric acid,
Samarium catalysts and Ruthenium chloride[2], and under solvent condition such as
chloroform, methanol and ethanol, DMF[34], has been reported. New attempts are being
carried out for the synthesis and better yield of oxazolone derivatives.

Types of Reaction
Oxazolone when substituted at C-2 and C-4 position shows various activities.[24] In literature
it was suggested that an extension of conjugation through an aliphatic double bond present at
C-4 position of oxazolone moiety and a pshenyl ring present at C-2 or bears a cinnamoyl
residue at C-4 of oxazolone moiety play a pivotal role in tyrosinase inhibitory activity.[25]
Deprotonation of -carbon in oxazolone ring shown in scheme 2, leads to a conjugated
structure in which the negative charge is practically delocalized over the entire oxazolone
ring, providing enhanced gas-phase stability.[32] The acidic nature of the proton(s) found at
the C-4 position (pKa # 9)[6] of the oxazolone moiety allows for the easy formation of an
oxazole enolate, which can react with a range of electrophiles. Alternatively, the use of Lewis
acids with the oxazolones results in the formation of either the 1, 3-dipole (also known as a

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munchnone) or the reactive ketene intermediate, each yielding the possibility of synthesizing
novel heterocyclic compounds via cycloaddition reactions (scheme 2). The nucleophilic
attack at the carbonyl group of the ring system oxazolone ring can be opened readily to form
various types amino acids.[27]
Ring opening of Oxazolone
It has been reported that the ring opening of 2-phenyl-5(4H)-oxazolone using either water or
simple alcohols as nucleophile and the reaction was catalyzed by enzyme. This reaction leads
to formation of corresponding ester. The ring opening of oxazolone depends upon the
substitution at C-2, C-4 position and the nucleophilic alcohol.[35] The rate of ring opening of
oxazolone decreases with increase in electron donating species as a substituent of the phenyl
ring at C-2 position.[1]

The most important reaction in the chemistry of oxazolones is the nucleophilic opening of the
heterocyclic ring, hydrolysis and alcoholysis of oxazolone giving the respective amino acids
and esters, which are used to prepare a variety of new synthetic amino acids.[36]

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The oxazolone ring contains numerous reactive sites and is used in diversity oriented
synthesis which is illustrated in scheme 4. This section of review describe the recent
development of using oxazolone ring as key intermediate for synthesizing important ring
structure and the mechanism of their formation. [27]
1. Amino acid
Oxazolone has proven as key intermediate for synthesizing amino acid derivatives. The
mechanism by which amino acid formation are: preparation of enantiomerically pure
nonquaternary amino acids is the dynamic kinetic resolution of oxazolones

[37]

, nucleophilic

ring opening of quaternary substituted oxazolone moiety leads to quaternary substituted

amino acid as described in Steglich reaction[38], arylation and alkylation of oxazolone at C-4
position results in novel amino acid[39,40], intermolecular ene reaction at C-4 position results
in formation of amino acid.[41]
2. Oxazole
The great variety of oxazole moiety is found in biologically active molecule. Many route of
synthesizing oxazole through oxazolone are already developed; one-pot Friedel

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Crafts/RobinsonGabriel synthesis results in highly substituted oxazole, 2-acylamino ketones

can be prepared from oxazolones via a FriedelCrafts reaction.[42]
3. -Lactams
- Lactams moiety shows Anti-bacterial activity. The -lactam moiety is synthesized via the
reaction of imines with oxazolones, as demonstrated by Huisgen and Funke

[43]

, Cremonesi

and coworkers also described formation of -lactam utilizing bicyclic munchnones with
imines under basic conditions and as described yield of trans -lactam is increased when
imines contains electron donating species. [44]
5. Pyrroles
Pyrroles moiety is assessed from 1,3-dipolar cycloaddition using oxazolones

[45]

cycloaddition is promoted when the oxazolone is in its munchnone form, pyrroles are also
synthesized by reacting munchnones with alkynes through decarboxylative cycloaddition
[46]

, pyrroles have been synthesized from munchnones through their reaction with alkyne

equivalents

[47]

, Weak nucleophiles, incapable of nucleophilic attack at the carbon atom in

position 4 of the oxazolone ring, bring about cleavage of the ring at position 2 leads to
formation of pyrrole derivatives. [48]
6. Imidazole
Imidazole moiety has been synthesized by reacting oxazolones with appropriate nitriles or
with nitrile equivalents. Huisgen and coworkers[49], Consonni and coworkers[50], Bilodeau
and Cunningham[51] synthesized imadazole from Oxazolone moiety.
7. Pyrrolines
The pyrrolines moieties are generated by Gotthardt, Huisgen, and Schaefer involved D2pyrroline formation through the cycloaddition reaction of oxazolones with alkenes[52],
Maryanoff and coworkers utilized oxazolone in the diastereoselective preparation of a D1pyrroline.[53]
8. Imidazolines
Imidazolines with four point diversity can be diastereoselectively produced via a silicon
mediated 1,3-dipolar cycloaddition of oxazolones with imines. [54]

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SYNTHESIS
The general method of synthesis of oxazolone is Erlenmeyer reaction.[27,29,30] In literature, it is
reported that the conventional synthesis is modified for better yield:
Tandel C. R. et al. reported the synthesis of 4-Benzylidene-2- phenyloxazol-5(4H)-one from
starting material 4-substituted benzoic acid, on addition of thionyl chloride and glycine, 4subtituted benzoyl glycine was synthesized and further addition of appropriate aldehyde,
acetic anhydride and sodium acetate results in formation of desired oxazolone derivatives.[7]

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Mariappan G. et al. synthesized 4-arylidine 2-[4-methoxy phenyl] oxazol-5-one derivatives

firstly, the starting material 4-methoxy benzoyl glycine was prepared by the reaction of
glycine and 4-methoxy benzoyl chloride in the presence of sodium hydroxide. It was then
reacted with substituted aromatic and hetero aldehyde in presence of acetic anhydride and
glacial acetic acid to obtain oxazolones. [14]

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Jat R. L. et al. reported that the derivatives of 4-Benzylidene-2- phenyloxazol-5(4H)-one by

refluxing the mixture of substituted benzaldehyde, hippuric acid, acetic anhydride and
anhydrous sodium acetate after completion of reaction the mixture was cooled and ethanol
was added slowly and left overnight. The crude product was washed with water and methanol
and recrystallized with ethanol.[17]

Mekabaty El-A, reported Coupling of aroylglycines with the appropriate aryldiazonium salts
in acetic anhydride containing freshly fused sodium acetate at 0C gave 2-aryl-4-arylazo-2oxazoline-5-ones.[29]

Islam M.A, reported the compound 2-Aryl-4-phthalidyliden-l,3-oxazolin-5-one was

synthesized when pthalic anhydride is condensed with hippuric acid. [55]

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Mekabaty El-A, reported the (1,3-diphenyl-4-pyrazolin)-4-methylene-2-oxazolin-5-one is

synthesized from treatment of 2,3-dihydro-1,3-diphenyl-1H-pyrazole-4-carbaldehyde with
hippuric acid.[29]

Scheme 10: synthesis if (1,3-diphenyl-4-pyrazolin)-4-methylene-2-oxazolin-5-one from

hippuric acid
Gulsiye Ozturk et al, reported the synthesis of 2-Aryl-4-[4-(1,4,7,10-tetraoxa-13azacyclopentadecyl)-benzylidene]-5-oxazolone derivatives were prepared by the cyclization
of 4-(1,4,7,10-tetraoxa-13-azacyclopentadecyl) benzaldehyde with aroyl glycine derivatives
in the presence of acetic anhydride.[56]

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Tikdari M. Ahmad et al. reported the Synthesis of Unsaturated 2-Phenyl-5(4H)-oxazolone

derivatives was carried out by microwave irradiation of mixture of appropriate aldehyde or
ketone, hippuric acid, acetic anhydride and the appropriate catalyst under solvent free
condition. The yield and rate of reaction were high.[31]

Furniss S. Brain et al. reported that 4-Benzylidene-2-Methyloxazol-5-one is synthesized by

warm a mixture of acetylglycine, benzaldehyde, anhydrous sodium acetate and acetic
anhydride in water bath, boil the resulting solution for 1 hour, cool and left overnight in
refrigerator the resulting soild is wash with cold water and recrystallized from carbon
tetrachloride or ethyl-acetate light petroleum.[57]

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Fareed Ghulam et al. synthesized a series of 4-(arylmethylidene)-2-phenyl/methyl-5(4H)

oxazolone derivatives by condensation of aldehydes with N-benzoyl/N-acetyl glycine in the
presence acetic anhydride and zinc oxide as a catalyst at room temperature in ethanol. [58]

Patil G.S. reported the synthesis of 4-(4- Benzylidene)-2-phenyl-5-(4H) oxazolone by

hippuric acid, benzaldehyde and acetic anhydride in presence of basic ionic liquid 1-n-butyl3-Methylimidazoliumhydroxide [bmIm]OH as a catalyst at a room temprature under solvent
free condition.[59]

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Mazurkiewicz R. et al. described simple and effective method for synthesizing 4phosphoranylidene-5(4H)-oxazolones from N-acylglycine.

The method consists in the

transformation of N-acylated glycine into the corresponding 5(4H)-oxazolone followed by

the phosphorylation of this compound in situ with dibromotriphenylphosphorane or
dibromotributylphosphorane in the presence of triethylamine.[60]

Roiban D. G. et al. synthesized Unsaturated 4,4-bis-[5(4H)-oxazolones] by heating the

mixture of Benzene-1,2-dicarboxaldehyde, N-benzoylglycine, anhydrous sodium acetate and
acetic anhydride, the precipitate was washed with ethanol and recrystallized with same
solvent.[61]

Sandhu and his group reported an efficient method for the azlactonisation via
cyclodehydration using zeolite under microwave irradiation forms 4,5-Dihydrooxazol-5-ones
(2-oxazolin-5-ones).[62]

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Clarke,

H.

European Journal of Biomedical and Pharmaceutical Sciences

synthesized

2-styryl-4-(-hydroxyethylidene)-2-oxazolin-5-one

by

Condensation of cinnamoylglycine with acetic anhydride and sodium acetate but the yield of
final product is low.[63]

Bergmann and Stern reported 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.[64]

Scheme 20: Synthesis of oxazolone from amino acids

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Koczan G et al.

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synthesized 4-ethoxymethylene-2-[1]-naphthyl-5(4H) -oxazolone by

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

acetate under reflux condition.[65]

Scheme 21: Synthesis of 4-ethoxymethylene-2-[1]-naphthyl-5(4H) oxazolone from 1napthoylglycin

Bird C. W. et.al., demonstrated the acid catalyzed rearrangement of 3-benzamido-1,4diphenyl-2-azetidinone gave 4-benzylidene-2-phenyl-2-oxazolin-5-one.[66]

Scheme 22: Synthesis of 4-benzylidene-2-phenyl-2-oxazolin-5-one from -lactam

derivative
PHARMACOLOGICAL ACTIVITY
Oxazolone shows various pharmacological activities. Those activities are affected by
substitution on C-2 and C-4 position.[1,

24]

Some of the synthesized derivatives, their

pharmacological and general physical activity is summarized below.

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1. Anti-diabetic activity[14]
Structure

Chemical name

Physical activity

4-[3-Methoxybenzylidene]-2-(4methoxy-phenyl)
oxazol-5-one

Color: Pale yellow

powder
M.P(0C): 158-160
Yield %: 71

Note: Among all synthesized compound, the electron donating species at meta position of
benzyl group shows better anti-diabetic activity whereas ortho or para substituted benzyl
group shows decrease in activity. Either the unsubstituted benzyl oxazolone moiety shows
marked Anti-diabetic activity.
2. Anti-cancer activity[17]
Structure

Chemical name

Physical activity

4-(mM.P(0C): 144Hydroxybenzylidene)145
2-phenyloxazol-5(4H)Yield %: 77%
one

Note: Substitution of Benzyl group with 3-OH, 3-OCH3, 4-F shows good anticancer activity
than substitution by Cl, -NO2, and N(CH3)2 at different position.
3. Anti-bacterial activity[13]
Structure

Chemical name

Physical activity

4-(4-flurobenzylidene)M.P.(0C): 1692-phenyloxazol-5(4H)170 Yield %: 98

one
Out of synthesized compound, 4-CH3, 3-Cl, 4-Cl and 4-F substitution at benzyl group exhibit
significant anti-bacterial activity against Bacillus subtilis and Escherichia coli.

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4. Urease inhibition activity[24]

Structure

Chemical name

Physical activity

4(3,5 dibromo,4hydroxybenzylidene)- M.P(0C): 149

2-phenyloxazolYield %: 82
5(4H)-one
Among all synthesized 6 compounds, this compound shows excellent anti-bacterial due to
presence of electron withdrawing substitution at C-4 and phenyl group at C-2 position and
urease inhibitory activity against jack bean urease.
5. Fungicidal activity[26]
Structure

Chemical name

Physical activity

4-benzylidine-2phenyloxazol-5-one

M.P.(0C): 166167
Yield %: 44.1

The synthesized 2-phenyl substituted oxazolone exhibit good activity than substitution by 2methyl group but both of these compound are less toxic than imidozolidine derivatives.
6. Anti-fungal activity[16]
Structure

Chemical name

Physical activity

2-[4-(4-Methylbenzylidene)-5-oxo4,5-dihydrooxazol2-ylmethyl]isoindole-1,3-dione

M.P(0C): 138141
Yield%: 80.91

Total eight derivatives of oxazolone containing 4-substituted benzylidene were synthesized

among those, above compound shows most potent anti-bacterial and anti-fungal activity.
7. Tyrosinase inhibitory activity[25]
Structure

Chemical name
Physical activity
2-Methyl-4-[(E)-3phenyl-2M.P(0C): 105
propenyliden]-1,3Yield %: 80
oxazol5(4H)-one
Study reveals that, substitutions of functional group at C-4 and C-2 positions of oxazolone are
crucial for tyrosinase inhibitory activity and concluded that, extension of conjugation through an
aliphatic double bond present at C-4 position of oxazolone moiety and a phenyl ring present at
C-2 play a crucial role in activity.

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8. Cardioprotective activity[18]
Structure

Chemical name

Physical property

4-(4-(3-(butylamino)-2Color: Brown
hydroxypropylamino)be
crystal
nzylidene)-2Yield %: 80
phenyloxazol-5(4H)-one
Studies shows that, substitution at C-4 by benzylidene and at C-4 by 3-(butylamino amino)2hydroxy propyl amino side chain shows maximum activity as compared to other synthesized
derivatives and concluded that substituted phenyl oxazolone with amino propanol as a side chain
possess good Cardioprotective activity.
9. Contact allergen[19]
Structure

Chemical name

Physical property

4-Ethoxymethylene-2phenyl-2-oxazolin-5one

M.P(0C): 93-97
Physical
State:

Solid

All tested derivative of oxazolone has respiratory allergenic potential.

10. Immunomodulatory activity[67]
Structure

Chemical name

Physical property

4-[(E)-(4Color: Yellow
Nitrophenyl)methylidene
solid
]-2-phenyl-1,3Yield %: 61
oxazol-5(4H)-one
The data presented in the study indicates that C-4 para-nitro substituted exocyclic phenyl
group on oxazolone moiety greatly influences the immunosuppressive activity. The nitro
substitution at para-position contributes in activity, while a methoxy group at the same
position decreases the activity.
11. Anti-inflammatory & Analgesic activity[68]
Structure

Chemical name
Physical property
5-Methyl-3-substituted M.P(0C): 167-168
piperazinomethyl-2Yield %: 82
benzoxazolinones

Among synthesized and tested derivatives, compounds bearing electron-withdrawing

substituents (F, Cl, COCH3) in the ortho/para position of the phenyl nucleus shows promising
analgesic effect than anti-inflammatory effect.

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12. Anti-angiogenic activity[69]

Structure

Chemical name

Physical activity

Bicyclic
tetrahydropyrano[3,2d]oxazolones derivatives

Not reported

The mono- and the disubstituted pyranyl analogues retained anti-angiogenic activity while
modification of the C2 side chain terminus, by introduction of either a methoxy or a
phenyl, did not significantly alter the the activity.
CONCLUSION
The presented review provides general idea regarding the introduction and synthesis of
oxazolone derivatives and its chemistry. The review also provides information about the use
of oxazolone in diversity oriented synthesis and use of those synthesized compounds in
invention of biologically active compounds. The review summarized about some synthesized
derivative of oxazolone, their pharmacological activity and structure activity relationship.
This review may help researcher to get and clarify more on their research.
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