IJCB 55B(7) 833-853.pdf

Indian Journal of Chemistry

Vol. 55B, July 2016, pp. 833-853

Advances in Contemporary Research

Advanced synthetic and pharmacological aspects of 1,3-oxazoles and

benzoxazoles

Ambreen Ghani*, Erum A Hussain, Zubi Sadiq & Narjis Naz

Department of Chemistry, Lahore College for Women University, Lahore 54000, Pakistan

E-mail: [email protected]; [email protected]

Received 9 December 2014; accepted (revised) 31 March 2016

Broad bio-spectrum of 1,3-oxazole and benzoxazole has created an attractive platform for synthetic chemists to introduce

structural modification in its nucleus by straight forward access to new approaches. Owing to its fascinating features and

interesting pharmacological activities, many researchers have proved that oxazole is an active agent in treating different

diseases. Based on this fact, this article outlines intramolecular and two component intermolecular cyclization to oxazoles and

benzoxazoles. The theme is well documented in this review article covering the era from 2007 till present. Moreover,

bioactivity and mechanistic insights are provided with different synthetic approaches, encompassing various pathways.

Keywords: Benzoxazole, bisoxazole, oxazole, synthesis, bioactivity

Oxazole, a heterocyclic scaffold is believed to occur

in various structurally complex biologically active

natural products. Several oxazole possessing

compounds have been isolated from plants and marine

natural origins such as Martefragin A and Almazol D

(Figure 1) isolated from Martensia fragiles1

and red

algae2 respectively. These naturally occurring

molecules demonstrate the versatile synthetic,

medicinal and industrial applications of oxazoles. The

diversified oxazole analogues with multi-directional

potential stands out in modern organic chemistry and

provides the sharp sword that combat future

challenges related to medicinal and synthetic aspects.

Considerable attention has been made in

formulating high yield synthetic approaches from

simpler chemical catalog. Generally, this widespread

highly substituted building block is attained from

intramolecular cyclocondensation reactions using

dehydrating agents or by intermolecular cyclization

through -substituted ketones as intermediates3-10

.

Nevertheless, direct eco-friendly metal catalyzed

approaches have also been extensively used that

overcome the limitations of multi-step processes11-14

.

The amazing pharmacological profile of oxazole

includes antibiotic, anti-inflammatory, hyperglycemic,

antiproliferative, antihistaminic, antiparasitics and

anti-tuberculosis activities15-17

. For instance, the use of

drug containing oxazole is oxaprozin having non-

steroidal anti-inflammatory activity. Owing to its

privileged importance, a lot of work has been done on

synthesis and medicinal features of oxazoles18

.

To the best of our knowledge, previous reviews19

on oxazole focused on specific aspects of its synthesis

were published during 2008 to 2014. We hereby wish

to describe synthetic routes involving metal catalyzed,

metal free, microwave assisted and different

multicomponent domino approaches adopted for

oxazoles. Metal catalyzed procedures have been

studied by emphasizing their specificity, while their

promising mechanistic insight has also been provided.

Metal free transformations for oxazoles, contribute a

great deal in organic synthesis. Microwave

technology being highly preferred method of heating

provides better possibilities in chemical synthesis.

While MCR approach offer a clear direction with

atom economy, ecofriendly simplified steps and

effective use of resources for 1,3-oxazoles.

In the preceding sections a brief description of

numerous synthetic strategies and pharmacological

implications of 1,3-oxazole hetrocycles is presented in

order to provide an idea for future directions on this

potential molecule.

NH

O

O

N

N

RO

NH

O

NOOC

NH

Figure 1 Oxazoles from natural sources

INDIAN J. CHEM., SEC B, JULY 2016

834

Intramolecular Cyclization

Amide based oxazoles

Benzo[d]oxazole 2 was successfully synthesized from

intramolecular O-arylation of haloanilides 1 using feasible

protocols20

. This direct approach was environmentally

benign and highly cost effective due to open choice in

copper salt and simple diamine derivatives, Scheme I.

The copper catalyzed oxidative cyclization of

enamides furnished 2,5-disubstituted oxazoles in two

steps from alkyne and simple amide precursors21

. An

interesting synthesis of 2-phenyl-4,5-substituted

oxazoles in a couple of steps involving copper mediated

intramolecular cyclization of substituted -(methylthio)

enamides was reported. Two steps copper promoted

cyclization of -(methylthio)enamides generated

from 4-[(methylthio)hetro(aryl)methylene]-2-phenyl-

5-oxazolones afforded functionalized 2-phenyl-4,5-

substituted oxazoles. Texamine and uguenenazole,

two natural, 2, 5-diaryloxazoles were furnished

through hydrolysis and decarboxylation of 2,5-

diaryloxazole-4-carboxylates. Furthermore, oxazole-

4-carboxamides derived from serine to trisubstituted

4,2-bisoxazoles was elaborated via diethylaminosulfur

trifluoride/1,8-diazabicyclo[5.4.0] undec-7-ene

(DAST/DBU) facilitated through cyclodehydration-

dehydrohalogenation arrangement22

.

Nucleophilic ring opening of 4-[(methylthio)

hetro(aryl)methylene]-2-phenyl-5-oxazolone was obtained

by alkyl/aryl grignard reagents, amino acid esters,

amines and alkoxides, so different functionalities like

ester, acyl, N-substituted carboxamide were

introduced at C-4 of oxazole. Regioselective

functionalized molecules of 2-arylbenzoxazoles were

prepared by copper-mediated intramolecular oxidative

coupling of benzanilides23

.

Fabrication of alkyl, aryl, hetero aryl and vinyl

substituted oxazoles by copper catalyzed oxidative

cyclization of enamides through functionalization of

vinylic C-H bond was obtained by Cheung24

.

More recently, Panda revealed a proficient one pot

annulation of enamides to 2,5 and 2,4,5-substituted

oxazoles through NBS/Me2S catalysed reaction in

mild base. The scope of this method has been

thoroughly explored including both electron donating

and withdrawing groups25

. An efficient, simple and

ligand-free preparation of substituted benzoxazoles,

benzimidazoles, 2-aminobenzothiazoles and 2-amino

benzimidazoles were carried out from o-bromoaryl

derivatives via intramoleculer cyclization through

recoverable copper (II) oxide nanoparticles26

.

A direct approach to 2-substituted 5-oxazole

carbaldehydes was achieved by palladium (II) salt

catalyzed intramolecular heterocyclization of alkyl,

aryl and heteroaryl propargylamides27

.

N-Propargylamides also produced 2,5-disubstituted

oxazoles with aryl iodides by same catalyst through

in situ cyclization of coupling product28

.

Various rhodium catalysts for cyclodehydration

and carbene N-H insertion were used successfully to

achieve regioselective sulfones, phosphonates and

carboxylates of oxazoles and thiazoles29

. The

-silylalkyl benzoxazoles 6a and oxazoles 6b were

prepared from silyldiazoketones 3 via silylketenes 4

which subsequently combined with amino malonate

and amino phenols followed by cyclocondensation to

give desired products (Scheme II)30

.

Greatly regioselective migration of the sulfonyl

group lead to functionalized oxazoles 8a and 8b by

virtue of silver (I) promoted [3,3] rearrangement of

N-sulfonyl propargylamide 7 (Scheme III)31

.

Silver promoted cyclization of amides and

-bromoketones in microwave was determined by

Bailey. The scope of the reaction was extended to

both the variety of silver catalyst and amide substrates

to produce highly functionalized 2,4 and 2,4,5

substituted oxazoles32

.

Atom-economic approach was adopted to have a

group of functionalized 2,5-disubstituted oxazoles 10

from propargylic amides 9 catalyzed by gold to

alkylidene oxazolines, followed by autoxidation to

hydroperoxides (Scheme IV)33

.

Various important oxazoles from enamides by

phenyliodinediacetate mediated intramolecular

cyclization were achieved. The extensive substrate

choice and metal free oxidative carbon-oxygen bond

formation was the main characteristics of this method34

.

A transition metal free protocol to present

quinoline, pyridine and coumarin annulated oxazoles

(Figure 2) using Cs2CO3 through intramolecular

nucleophilic cyclization of o-bromoamides to

fabricate C-O bond for oxazoles was exposed35

.

A catalyst free domino strategy was adopted to

assemble 2-acyloxazoles from arylacetylenes, methyl

ketones, or arylethenes via successive iodination/

NH

OX

R' N

O

R

R'

R

[Cu], H2O, 120

1 2

NR2R2N

Scheme I

GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES

835

Kornblum oxidation/cyclization36

. 2,5-Disubstituted

oxazole-4-carboxylate 12 was synthesized from

methyl esters of N-acyl--halodehydroamino butyric

acid 11 in 2% DBU-acetonitrile, for investigating

photophysical properties (Scheme V). All the

derivatives showed moderate solvent sensitivity and

high florescence quantum yield which proved it as

good florescent probs37

.

Hernandez et al.38,15

utilized convergent synthetic

strategy via intramolecular Hantzsch macrocyclization

for preparation of 2,4-concatenated oxazoles

(Figure 3). Two oxazole rings were united

simultaneously from oxazole containing peptides

using DAST under mild alkaline conditions followed

by oxidation with DBU/CCl4.

Miyake et al. (2010) revised the structure of

Almazole D by constructing this molecule through

Robinson-Gabriel synthesis utilizing -oxotryptophan

and -oxotryptamine methyl ester with chiral

ketoamides leading to target molecule. This revision

was justified on the basis of NMR and optical activity

of synthetic and natural Almazole D2.

Synthesis and comparative studies of oxazoles and

benzothiazole derivatives were carried out and

explored the later more effective than oxazoles

against all microorganisms. Oxazoles were prepared

via dehydration of hippuric acid 13 to give azalactone

14, which on alkylation and dehydration resulted in

16 (Scheme VI). Antimicrobial benzothiazole

derivatives were furnished by a multistep sequence

involving diazotization, alkylation, halogenation and

condensation39

.

Kandemir et al.40

developed 5-(7-indolyl) oxazole

and 2,5-di(7-indolyl) oxazoles from 7-formylindole

O

OR2

R1 N

Ts

R2

O

N

O

R1

Ts

OR2

O

R2

AgBF4

Et3N

N

O

R1

R2

AgBF4

8b

7

8a

Scheme III

R

N2

SiR3

O

R SiR3

OC

SiR3

NH

O

R

OH

O

NR3Si

R

Rh2(oct)4

PPh3, DEADEtO2C NH3Cl

CO2Et

SiR3

NH

O

CO2Et

CO2Et

R

CO2Et

OEtO

NR3Si

R

34

5a

6a5b6b

NEt3

PPh3, I2

NEt3

NEt3

O-NH2-C6H6OH

Scheme II

N

OEtN

O

N

OO

OCl

N N

OMe

Br

Figure 2 Cesium catalyzed oxazoles

R NH

OO

N

COOH

R

Au1

9 10

O2

Scheme IV

R

HN

O

CO2CH3

Br/I

N

O

CO2CH3

R

DBU, ACN

11 12

Scheme V


836

17, its carbonyl protection with trimethylsilylnitrile

trailed the oxidation reduction sequence to afford 18

and 19, respectively (Scheme VII). The combination

of 19 with different acylating agents produced 20a

and 20b after phosphorylation.

An extremely modest process for di- and

tri-substituted oxazoles under metal free conditions

via bromination and debromination of N-acylated

amino acid was developed41

. The methyl esters of

N-acyldehydroaminobutyric acid and N-acyldehydro-

phenylalanines gave the corresponding substituted

oxazoles in high to moderate yields while under the

same conditions, N-acyldehydroalanines failed to give

the corresponding oxazoles42

. Synthesis of

trisubstituted oxazoles 22a and symmetrical

bisoxazoles 22b was achieved through cyclization of

corresponding diamides of N-acyl amino acid

derivatives followed by oxidation with

trifluoromethanesulfonic anhydride (Scheme VIII)43

.

A robust approach to synthesize substituted

esters of oxazoles, thiazoles, imidazoles and diethyl

pyrazine 2,5-dicarboxylates was reported. The two

step methodology involving the C-formylation and

cyclization of glycine ethyl ester hydrochloride

using Lawessons reagent with triphenyl phosphene

resulted in targeted thiazoles and oxazoles

respectively44

.

Sperry et al. have analyzed Diazonamide A

(Figure 4) natural product by retrosynthetic strategy.

Adopting a multistep approach, they proposed a

biomimetic route to hetrocyclic core. A viable route

involving the oxidative biomimetic cyclization by

DDQ for tri and tetra peptides of tyrosine, valine,

tryptamine and tryptophane, resulted in the direct

synthesis of indole bisoxazole core of Diazonamide A45

.

A library of highly effective anti-tuberculosis

oxazole and oxazoline templates were derived from

threonine or serine in a three step process. In vitro and

ON

ON

HN

NH

O

HNO

NO

O

N

ON

O

Ph

Val

allo-Ile

N

O

ON

N

O

HO NH

O

HN

O

NH

O

N O

Ph

Ile

Leu

NH

OHN

O

O

NH NH

O

HO

O

NN

ON

O

Val

Ala

Ile

Figure 3 2,4-Concatenated oxazoles

NH

O

MeO MeO

O

N

O

Me

HN

OMeO

O

O

N

OMe

Me

POCl3

COOH

1615

1413

AlCl3

O

N

CH3

Cl O

O

Scheme VI


837

in vivo screening proved competency of oxazoles over

oxazolines (Scheme IX)18

.

During research on Telomestatin, Charalambidou

prepared 2,4 linked bis and tris oxazoles from

protected serine derivatives through various steps46

.

An archive of thiazoles and oxazoles with structural

variation at 2 and 5 positions was obtained by reacting

-amido--ketoesters, an intermediate from dual

acylation of a protected glycine, with Lawessons

reagent or dehydration, respectively47

. One pot

17

NH

OH

MeO

OMe R1

R2NH

ONC

MeO

OMe R1

R2

NH

O

MeO

OMe R1

R2

NH2

NH

MeO

OMe R1

R2

N

O

NH

OCl3C

MeO

OMe R1

R2MeO

OMe R1

R2

HN

R2

R1OMe

MeO

N

O

TMSCN

DDQ, dioxane

H2, Pd/C (CH3CO)2O

POCl3

Et3N, MeCN

20a

19

18

POCl3

20b

Scheme VII

MeO

O

NH

PhO OMe

O

N

O

OMeMeO

O

Ph

Tf2O, Et3N

21a 22a

O

(CH2)nHN

O

Ph

MeOHN

O

Ph

OMe

O

O

N(CH2)n

Ph

MeO O

N

Ph

OMe21b

22b

Tf2O, Et3N

Scheme VIII

O

NH

NH

ClN

O

ClN

O

HN

OHN

HOO

G H

F

E

D

BA

C

Figure 4 Diazonamide A


838

protocol was established and compared with two step

method to fabricate 5-oxazolacetonitriles and

5-oxazolacetates 27. The reaction sequence comprised

of cyclodehydration of N-acylamino acids 26 via

diisopropylcarbodiimide (DIC) followed by Wittig

olefination to achieve 5-oxazolacetate (Scheme X)48

.

A facile synthesis of 5-(3-indolyl) oxazoles was

carried out by converting N-protected 3-acetyl-1-

benzenesulfonyl indole 28 to hydroxyl (tosyloxy)

iodobenzene followed by amination of acyl group to

afford 29. Finally, the cyclodehydration by p-toluene

sulfonic acid and deprotection of 29 subsequently

resulted in target molecule 30 (Scheme XI)49

.

Compound 30 was also synthesized by using

[hydroxy(2,4-dinitrobenzenesulfonyloxy) iodo]benzene

and found advantageous due to easy handling,

circumventing toxic metal and better yield50

. Treatment

of different catalytic systems like idosobenzene-

trifloromethane sulfonic acid and idosobenzene-

bistrifloromethane sulfonyl imide to link various nitriles

with mono and dicarbonyl compounds furnished highly

substituted oxazoles in a single step3. Vinyl sulfonamide

based regioselective synthesis was presented for oxazole

analogues with out ring oxidation51

.

Microwave mediated novel (hydroxymethyl)oxa

and thiazole analogues from 3-oxetanone along with

complete computational and synthetic analysis were

explored52

. Oxazoles from oximes

One step dirhodium (II) acetate promoted synthetic

strategy for 4-styryl-5-methoxy oxazoles was trailed

from oximes and styryl diazoacetate with diverse

functionalities53

(Scheme XII).

23

OH

O

R1

R2

NH

O

R1

R2

OBn

O

OH

Oxalyl chloride

L-serine-OBn, DIPEA

DAST

24

N

O OBn

O

R2

R1DBU, BrCCl3 25

Scheme IX

R1 NH

O

R2

COOHO

NR1 R2

COOEt

Ph3P=CHCOOEt, DIC

2726

Scheme X

N

O

SO2C6H5

N

O

SO2C6H5

HN

R

O

N

H

O

N R

C6H5I(OH)OTs

HMTA

RCOCl

PTSA

NaOH, EtOH-H2O

302928

Scheme XI

Ph CO2Me

N2

Ar

NHO

Rh2(OAc)4N

O

Ar

PhOMe

31 32 33

Scheme XII


839

Twenty new derivatives of 2,4,5-tri-substituted

oxazoles 36 were constructed under optimal microwave

irradiation through N,O-acylation and cyclodehydration

of oximes swiftly. In vitro anti-proliferative evaluation

of all new compounds against PC-3 (human prostate

cancer) and A431 (human epidermoid carcinoma)

revealed maximum potential (Scheme XIII)16

.

The 1,3 disubstituted oxazoles were designed and

synthesized for in vivo anti-hyperglycemic, lipid

lowering and in vitro anti-diabetic screening by PTP-

1B assay54

. Multistep synthesis of a series of 2-aryl-

naphthol[1,2-d] oxazole analogues 41 was executed

and evaluated for cholesterol, triglyceride, lipid lowering

activity and protein tyrosine phosphatase-IB inhibition

potential. In vivo antidiabetic evaluation of new oxazoles

showed its promising activity (Scheme XIV)55

.

The 2-substituted benzoxazoles were prepared

and evaluated against various microbial strains and

showed broad spectrum of activity. The

comparative QSAR studies of new compounds were

also accomplished to test growth inhibitory

activity56

. Heterocyclic multi-substituted oxazoles

were obtained from various aldehydes and

evaluated for in vitro antimicrobial activity57

.

Hydrazones 42 from substituted formyl chromones

were treated with alcoholic potash to yield

1-(3,4-diflorophenyl-4-substituted-2-hydroxybenzoyl-

1H-pyrazoles 43. The oxime formation was

continued to Beckman rearrangement to produce

fluorine containing pyrazolyl benzooxazoles 44

exposing most promising antimicrobial activity,

(Scheme XV)58

.

OMe

OMe

MeO

O

OMe

OMe

MeO

N

SR1

OH

O

NR2

SR1

MeO OMe

OMe

Br2, R1SH, Et3N

NH2OH.HCl

3435 36

O

N

CH3

Scheme XIII

OH OH

COOH

OH

O

HO

OH

NOCOCH3

AcO

O

N

OR

NH2OH.HCl

Ac2O

C5H5N

37

39

4041

38

BF3

Scheme XIV

O

N

O

R3

R2

R1

NH

F

F

OH

O

R3

R2

R1

N

N

F

F

N

N

F

FO

N

R1

R2

R3

KOH, HCl

POCl3

42

44

43

NH2OH.HCl

Scheme XV


840

Oxazoles from intramolecular cyclization of amines

Conversion of N-benzyl bis aryloxime ethers 45 to

2-arylbenzoxazoles 46 via copper (II) mediated

cascade of C-H functionality and C-N/C-O bond

formation under oxygen free conditions was reported

(Scheme XVI)59,60

.

A proficient silver promoted one step method for

2,4-disubstituted and 2,4,5-trisubstituted oxazoles was

established61

. Intramolecular iron-catalyzed O-arylation

of 2-haloanilines in presence of 2,2,6,6-tetramethyl-

3,5-heptanedione furnished benzoxazole derivatives

successfully62

.

Iodine promoted cyclization of commercial aromatic

aldehydes yielded disubstituted oxazoles63

. Dess-Martin

periodinane mediated cyclization of phenolic azomethines

47 to obtain pure 48 (Scheme XVII) was experimented64

.

Two distinctive routes to achieve 2-substituted

benzoxazoles or 3-substituted benzisoxazoles from

o-hydroxyaryl N-H ketimines via N-chloro imine

intermediate were presented. The key reaction was

NaOCl facilitated Beckmann-type readjustment of

imine to benzoxazole and N-O bond formation to

benzisoxazole65

. Potent arylpiperazinylalkylamines

substituted oxazoles were synthesized by convergent

synthetic process and biologically tested against 1G

(Gav 3.1)T-type calcium channel66

. O-Acylations of

ester functionalities followed by Wittig reactions

furnished trisubstituted oxazoles chemoselectively67

.

Perner et al.68

put forward many innovative mono and

di-substituted-2-arylamino oxazole derivatives by two

methods given below. These novel compounds were

transient receptor potential vanilloid 1 antagonists

(Scheme XVIII).

Two component intermolecular cyclization

Oxazoles established from amides

A facile synthesis of oxazolyl methylacetate

derivatives 54a was demonstrated via oxidative

cycloisomerization of propargylamide 53 by

phenyliodine (III) diacetate or hexafluoroisopropanol

as oxidants69

. Oxazoles with unsaturated side chains

54b were also described by the same researcher. They

exploit oxypalladation induced cycloisomerisation of

propargyl amides with allyl ethyl carbonates by

Pd2(dba)3, IPr.HCl.Cy3P and Cs2CO3 in methyl nitrile

as catalytic systems with the subsequent reductive

elimination with variable yields (Scheme XIX)70

.

An elegant transformation of acyl cyanides 55 into

oxazoles 56 through dipolar cycloaddition of

diazomalonic esters was described (Scheme XX). These

ON

ArRCu(OTf)2, O2

O

NR

Ar

45 46

Scheme XVI

N

OH

Ar

R DMP

N

OArR

47 48

Scheme XVII

CF3

Br

O

CF3

O

N

HN

Ar

CF3

O

NCF3

O

H

Method A

Method B

52a

52b

4950

51

PPh3, 1,4-dioxane

TosCH(R4)NC, K2CO3

N CSAr

Scheme XVIII

53

Ph

HN

O

N

O ORPh

54a

N

OPh

Pd2(dba)3

54b

EtO2CO

PIDA

Scheme XIX

CN

O

NO

OCH3H3CO2C

O55 56

N2C(CO2CH3)2

Rh2(OAc)4

Scheme XX


841

multicomponent condensations readily provide complex

heterocyclic scaffolds with outstanding applications71

.

Substituted amide 57 was irradiated with different

haloketones 58 in presence of AgSbF6 in microwave.

Bromo and iodo acetophenones gave excellent yield

of oxazoles 59, while -chloro and -mesylate keto

derivatives provided low yield and no reaction

respectively (Scheme XXI)72

.

The stereoselective production of alkylidene

oxazoles, oxazoles, and 1,3-oxazines from N-propargyl

carboxamides by utilizing gold (I) or (III) catalysts and

various alkynes as reactants was accomplished73

.

Acetylenic amides cyclization via ZnI2 and FeCl3

fabricated 2-oxazoline and 2-oxazoles in high

yields74

. A unique and effective combination of

ultrasonic radiation and deep eutectic solvents for

oxazoles synthesis was pioneered. The phenacyl

bromide and phenyl urea precursors joined

sonochemically, proved cutting edge in terms of

reaction time, yield and energy consumption as

compared to conventional methods75

.

Catalyst free synthesis of oxazole analogues from

cyclization of -haloketone with urea in presence of

reusable non-ionic liquid PEG 400 was reported76

.

Three step synthesis of novel oxazoles Schiff bases

and antimicrobial activities were executed. The steps

involved formation of 2,4 disubstituted oxazole 62

from aromatic aldehyde and hippuric acid 60 that was

transformed to hydrazone leading to target molecule 62

using various aromatic aldehydes (Scheme XXII)77

.

Intermolecular bond between enamines and

different carboxylic acids, together with N-protected

amino acids by using iodosobenzene as an oxidant

was established. Thus functionalized -acyloxy

enamines were transformed into oxazole through

cyclodehydration by conventional method78

.

Bastug et al. explored benzooxazole, benzothiazole

and benzimidazole derivatives by combining

o-substituted anilines with esters79

. 2-Acetyl benzofuran

63 was selected to form various derivatives of

benzofuran oxazole 64 via bromo acetyl benzofuran.

Targeted compounds were also evaluated for

antibacterial activity (Scheme XXIII)80

.

Treatment of substituted primary amides 65 with

2,3-dibromopropene under the influence of Cs2CO3 furnished a variety of 2-aryl-5-alkyl substituted

oxazoles 66a in single step (Scheme XXIV)81

. The

variety of oxazoles 66b was depicted by tandem one

pot cycloisomerisation of propargylic alcohols with

amides 65 using p-toluenesulfonic acid monohydrate82

.

R1 NH2

O

R3

O

Br

R2

N

OR2

R1

R3W, 90, 2-3 h

595857

AgSbF6

Scheme XXI

HN

OO

R

OH

ON

R2

R1

O

R O

N

R2

R1

N RN

R4

R3

(CH3CO)2O

ArCHO

NH2NH2

60 61

62

ArCHO

Scheme XXII

O O O O

N NH2

NH2CONH26463

Br2

Scheme XXIII

R NH2

O

Br

Br

Cs2CO3N

OR

65

66a

Ar

HO R'

PTSAN

OR

66b

Ar

R'

Scheme XXIV


842

Stokes et al. established the synthesis and structure

activity relationship (SAR) of oxazoles benzamides.

The oxazole benzamide chemotype (Figure 5) was

prepared through different routes with various

substitutions and studied for antibacterial effects as

FtsZ inhibitor. Among all the compounds,

5-halosubstituted derivatives proved potent against

the mutant encoding the FtsZ G 196A amino acid.

Besides this, the improvement in pharmacokinetic

properties by considering the importance of

substitution pattern to pseudo benzylic position of

oxazoles, were also studied83

.

Conventional and microwave assisted routes for 4-

(3-indolyl)oxazole series were compared (Figure 6).

Among all the new oxazole motifs, three compounds

showed promising cytotoxic activity due to the

presence of benzyl group at indole nitrogen and

-fluoro phenyl at C-2 of oxazole ring84

.

Fused oxazoles with antimicrobial screening were

prepared through microwave assisted reaction of

4-phenyl piperidine 4,6-dione with -bromoketones.

Although this protocol furnished oxazoles in excellent

yield but the reaction scope is limited to bromoaceto

phenone and -bromoacetothiophenone85

.

Oxazoles from amines

Cano86

et al. developed 2,5-disubstituted oxazoles

in reasonable to excellent yields by reacting acyl

azides with 1-alkynes in the presence of

BrCu(NCMe)] BF4. Copper catalysed87

mild oxidative

cyclization yielded polysubstituted oxazole

derivatives 68. Liu further extended this work using

chalcones as substrate to provide 2,5-diaryl oxazoles.

The scope of substrate for this reaction was relatively

wide but the hetroaryl attached with carbonyl group

produced correspondingly low yields while chalcone

having -methyl substituent limited the scope of this

reaction88

.

Few aromatic analogues, 69 were also prepared by

using readily available starting materials 67 in one-pot

operation under temperate domino oxidative

cyclization, mediated by t-BuO2H/I2 (Scheme XXV)89

.

Amidation of vinyl halides promoted by copper,

following I2 mediated cyclization leads to various

substituted oxazoles and polyazols90

. Another

application of microwave mediated synthesis was

experimented in one pot domino acylation of 2-

bromoanilines from acyl chloride in Cs2CO3, 1,10-

phenanthroline, and copper iodide to afford

benzoxazoles 72 (Scheme XXVI)91

.

Some novel 2-alkyl-5-aryl-substituted oxazoles were

prepared by iodine catalyzed reaction of aryl methyl

ketones, -keto esters or styrenes with -amino acids

through decarboxylative domino reaction92

.

Palladium catalyzed three components coupling of

2-amino phenols, aryl halides, and t-butyl isocyanide

in presence of Cs2CO3-toluene system afforded a

range of benzoxazoles93

.

The synthesis of trisubstituted oxazoles through

cascade formation of CN and CO bonds via Pd and

Cu mediated oxidative cyclization provides a suitable

process for the rapid synthesis of a range of 2,4,5-

trisubstituted oxazoles in good yield94

.

F

H2N

O

F

OO

N

R1

R2

Figure 5 Oxazole benzamide chemotype

NR

O

N R1

NCH3

O

N

NH

N O

N

Cl

Cl

Figure 6 Oxazoles with promising bioactivity

Ar' NH2

R1 R2

O O

Cu(OAc)2.H2O, I2N

O

R1

Ar'

R2

O

68

Ar

t-BuOOH, I2N

O

Ar

Ar'

67

69

Scheme XXV


843

Investigations on two and three steps synthesis of

tri substituted oxazoles were done. In two step one-

pot procedure, in situ generated propargyl amides

were catalyzed by gold to propargyl amines while in

three step reaction the acid chlorides produced in situ

were reacted with propargyl amine preceding the

AuCl3 to afford a variety of target moieties95

.

With reusable o-benzenedisulfonimide catalyst, the

reaction among 2-amino-thiophenol, 2-aminophenol,

o-phenylenediamine with various o-esters or

aldehydes provided benzo fused azoles96

. Two step

alkali promoted cyclization of N-sulfonyl

propargylamides via 1,4-sulfonyl migration efficiently

gave 5-sulfonylmethyl oxazoles involving allenes as

the key intermediates97

. A catalyst free approach for

benzothiazole and benzoxazole 75 was adopted by

using 2-acylpyridazine-3(2H)-ones 74 as acyl source

and 2-amino benzene thiole 2-amino phenol 73

(Scheme XXVII)98

.

The 5-nitrobenzoxazloes were obtained efficiently

under solvent free conditions. For this different

benzoyl chlorides were reacted with 2-fluoro-5-

nitroaniline in presence of potassium carbonate at

130 C via nucleophilic acyl substitution

99.

One-pot amidation-coupling-cycloisomerization

was initiated from amidation of propargylamine 77,

followed by cross-coupling with acid chloride

to afford substituted oxazol-5-ylethanones 79

(Scheme XXVIII)100

.

The preparation of new N-(4-phenylthiazol-2-yl)-

substituted benzo[d]thiazole-, thiazolo[4,5-b] pyridine-,

thiazolo[5,4-b]pyridine- and benzo[d]oxazole-2-

carboximidamides, motivated by aquatic topsentines

and nortopsentines was reported. Different

aminopyridines aminophenols and o-halogenated

anilines were condensed with 4,5-dichloro-1,2,3-

dithiazolium chloride providing the corresponding

aryliminodithiazoles as intermediate. Then copper

mediated cyclization of aryliminodithiazoles gave

thiazolo[4,5-b]- and thiazolo [5,4-b]-pyridines

benzo[d]oxazoles, benzo[d]thiazoles carbonitriles

which were further treated with substituted

4-phenylthiazol-2-amines to provide twenty seven

novel polyaromatic carboximidamides in good

yields101

.

Three-components one-pot preparation of aryl-

substituted 5-(3-indolyl) oxazoles (Figure 7) was

based on microwave induced MCR approach,

involving Sonogashira coupling, cycloisomerization

and ultimate Fischer indole synthesis102

.

R-COCl

H2N

Br N

OR'

15 min

CuI, Cs2CO3R'

R'

7270 71

Scheme XXVI

R Cl

O

N

O

ArO

R

H2N

CuI

PTSA.H2O7876

79

PdCl2(PPh3)2

Ar Cl

O

77

Scheme XXVIII

N

O Z

N

O Z

N

O ZOO

N

OOO

Z

O

HN O Ph

OR

O

nZ =

Figure 7 Aryl substituted oxazoles

NH2

OHN

N

Cl

Cl

O

O Ph

N

OPh

7374

75

Scheme XXVII


844

A domino oxidative cyclization process to

assemble 2,5-disubstituted oxazole derivatives was

demonstrated in metal and peroxide free, I2 promoted

conditions103

. This dual sp3 C-H functionalization

approach was explored by using series of aryl methyl

ketone and a group of various benzyl amines having

phenyl iodide and phenyl glyoxal as intermediates. A

one pot synthesis of 2,4,5-trisubstituted oxazoles by

tandem reaction of a vinyl imino phosphorane with

acyl chlorides was also explored104

.

Economical formation of 2-substituted oxazoles

and 2-imidazolines was provided by using

multicomponent approach among amines, ketones or

aldehydes and esters or -acidic isocyano amides105

.

3-Oxazoline-4-carboxylates were oxidized to

oxazole-4-carboxylates and derivatized to 4-keto-

oxazole analogues utilizing grignard reagents106

. A

new anti-inflammatory benzoxazole was formulated

by condensation of aromatic aldehydes with

methyl-2-(2-aminothiazol-5-ylamino)benzo[d]oxazole-

5- carboxylate (Figure 8) by Ampati et al.17

Fabrication of chiral 2-(substituted-hydroxyl)-3-

(benzo[d]oxazol-5-yl) propanoic acid (Figure 9)

analogues was achieved by structural modification in

3-(4-hydroxyphenyl) propanoic acid skeleton107

.

Comprehensive structure activity relationship and

antimicrobial activity of this molecule was also

explored.

A direct method for the synthesis of 2,4-

disubstituted oxazoles 82 was presented by

condensing aldehydes 80 with serine 81 via

oxazolidine intermediate. Mild conditions were

required for this method as it did not require

intermediate purification due to the use of aldehydes

as a starting material rather than the methods using

carboxylic acids as reactant (Scheme XXIX)108

.

Effect of substituents on yield and reaction

conditions were explored by environmentally benign

protocol for oxidation of 2-oxazolines-4-carboxamides/

carboxylates to corresponding oxazoles 84. The same

methodology was also employed to synthesize a key

intermediate for SC 9 the phosphatase inhibitor

(CDC25) as anticancer agent (Scheme XXX)109

.

Highly proficient fragment-assembling approach

for oxazoles starting from aryl acetaldehydes and

amines was explained110

. A variety of 2,4-

disubstituted naphth[2,1-d]-oxazol-5-ols 86 were

prepared from 3-substituted-2-amino1,4-

naphthoquinones 85 and substituted aldehydes in

presence of HBr whereas H2SO4 produced 1,4-

naphthaquinone, other than oxazole. Ring opening of

oxazole to N-acyl-2-amino-1,4-naphthoquinone was

also experimented through cerium (IV) ammonium

nitrate and bistrifloroacetoxy iodobenzene mediated

oxidation (Scheme XXXI)111

.

Fabrication of 2-arylnaphtho[2,3-d]oxazole-4,9-

dione derivatives by the action of benzoyl chloride

analogs with 2-amino-3-bromo-1,4-naphthoquinone

was demonstrated and evaluated for anticancer

activity on human prostate cells112

.

R H

O

H2N CO2Me

HO

N

OR

CO2Me

BrCCl3, DBU

80

MgSO4

81 82

Scheme XXIX

O

NNH

N

S N Ar

H3CO2C

Figure 8 Methyl-2-(2-(4-(dimethylamino) benzylideneamino)

thiazol-5-ylamino) benzo[d] oxazole-5-carboxylate

N

O

O

N

COOR2R1O

Figure 9 Representative structure for substituted chiral oxazole

RCOOH, RCN/R1CHOHO

NH2

COOR2

R3O

NR3

R1

COOR28384

O

Scheme XXX

85 86

O

NH2

R1

O

R2CHO, HBrR1

OH

ON

R2

Scheme XXXI


845

The efficient preparation of substituted

anthraquinones and ring fusion into anthra[2,3-

d]oxazole-2-thione-5,10-dione derivatives was

described, and all the compounds were subjected for

cytotoxicity against PC-3 cancer cell lines113

. A

variety of aliphatic and hetroaromatic carboxylic

acids were reacted with 2-amino phenol and 2-amino

thiophenol in microwave, to accomplish 2-substituted

benzoxazoles 5 and benzothiazoles 6 with Lawessons

reagent as effective promoter114

.

Oxazoles from cyanide

Two step palladium mediated route for 2,5-

disubstituted oxazoles115

and single step iodoarene

catalyzed pathway for substituted aryl oxazoles from

alkyl aryl ketones in trifluoromethanesulfonic acid

was accounted116

. Moreover, new series of 2,4,5-

trisubstituted oxazoles by using versatile aryl alkyl

ketones, iodoarene and m-chloroperbenzoic acid was

also established117

.

Gold catalyzed highly regioselective process was

adopted for 2,4,5-(hetero)aryl substituted oxazoles

from unsymmetrical internal alkynes via

intermolecular cyclization118

. A novel synthetic

approach initiating from indole proceeded through

iodization, N-protection, Sonogashira coupling and

intermolecular alkyne oxidation steps generated -

oxacarbine which after gold catalysis yielded

5-(3-indolyl) oxazoles119

.

[2+2+1] Annulation of nitrile and terminal alkyne

yielded 2,5-disubstituted oxazoles. This procedure

involved an intermolecular cyclization of gold

carbene, generated from oxidation of alkyne and

nitrile (Scheme XXXII)120

.

Nickel catalyzed cross-coupling of organo-zinc

reagents with 2-methylthio-oxazoles furnished 2 and

2,5-disubstituted oxazoles121

. This method was

improved by one pot synthesis of chemoselective 2,5-

disubstituted unsymmetrical oxazoles and complementary

to existing cyclodehydration approaches.

A reaction of 1-aryl-2-nitroethanone or 2-

nitrophenols with suitable orthoesters 90 as coupling

reagent in presence of indium afforded oxazoles 91b

and benzoxazoles 92a, correspondingly. The

mechanism involved one pot reduction-prompted

intermolecular hetrocyclization of nitroso anion with

immediate neighboring group (Scheme XXXIII)122

.

The scope of metal free decarboxylative cyclization

of 2-bromoacetophenone and a variety of -amino

acids to polysubstituted oxazoles was investigated and

explored t-butyl hydroperoxide as the best oxidant for

this reaction123

. A facile synthetic application for anti-

inflammatory drug was presented by assembling 2,4-

disubstituted and 2,4,5-trisubstituted oxazoles 94 via

metal free [2+2+1] annulation of nitriles 92, alkynes

93 and oxygen regioselectively (Scheme XXXIV)124

.

One pot Van Leusen oxazole approach by

consuming various aldehydes, tosylmethyl isocyanide

36 and aliphatic halides in ionic liquids led to 4,5-

disubstituted oxazoles 38 (Scheme XXXV)125

.

Oxazole and pyrrole 3-arylsulfonyl/3-carbethoxy

D- and L-2-deoxyribosides were synthesized via

TosMIC addition/cyclization126

. The association of

oxone and iodoarene to elaborate metal free one pot

synthesis of 2-alkyl, 5-aryl- and 2,4-disubstituted-5-

aryl-oxazoles was investigated by reaction of aryl and

alkyl ketones with alkyl nitrile127

. An efficient one pot

route (Scheme XXXVI) was accessed for

2,5-disubstituted oxazoles 98. The reaction proceeded

via in situ isocyanides generation from cyanide salts,

triethyl benzyl ammonium chloride128

.

R NCR'

N

OR

R'Ph3PAuNTf

Oxidant

89

87 88

Scheme XXXII

NO2

OH

R1

N

ORR1

Ph

NO2

O

Ph

N

OR

MeO R

OMeMeO91a

91b

90

In

Scheme XXXIII

R1

R2N

R3N

O

R2

R3R1

92 93 94

PhIO

Scheme XXXIV

SOT CN N

O

R'

RR'CHO

RX, K2CO3

95

96

Scheme XXXV


846

Convergent multistep synthesis of 2,4-linked

trioxazoles 103 was proposed from oxazole ester 101

via cyclisation to oxazolone intermediate

(Scheme XXXVII). Over three steps the oxazolones

were transformed to bisoxazol 102 which after

Niegishi cross coupling with mono oxazole furnished

trioxazole fragment129

.

A facile synthesis of trisubstituted oxazoles

through gold catalyzed three component domino

reaction was achieved. The synthetic utility of

reaction was investigated by decarboxylation and 1,2

migration reaction to yield vinyl and allyl substituted

oxazoles (Scheme XXXVIII)130

.

Ugi/Robinson-Gabriel methodology was optimized

to obtain oxazoles 112. Different carboxylic acids 109

and several isonitriles 111 were subjected with

arylglyoxal 110 and 2,4-dimethoxy benzylamine 108

to assemble intermediate N-acyl--amino ketone

(Scheme XXXIX). The subsequent debenzylation and

cyclization of intermediate corresponded to trisubstituted

oxazole analogues in considerable yield131

.

Synthesis, in vivo activity, structure activity

relationship and metabolic profile were described for

a series of triazolopyridine based oxazole132

. Two

strategies to generate potent oxazole derivative of

2-amino thiazole (Figure 10) having high affinity for

phosphoinositide-3-kinase (PI3K gamma) were

adopted. The synthesis executed via aza Wittig

olefination followed by hydrolysis and deprotection.

The second approach comprised of reduction,

coupling with acid and finally dehydration yielded the

target molecules133

.

CN

OEt

O

O

OO

ON

OEtO

O

N N

O

O

ON

N

O

N

O

O

EtO

O

N

OEt

O

ZnCl

DBU NH4OH

(COCl)2

CH2N2

Tf2O

Pd(PPh3)4

99101100 102

103

Scheme XXXVII

N

R

Ph Cl

O

t-Bu NBn NO

Ph

t-Bu

R

104 105 106107

[Au(salen)]PF6

Scheme XXXVIII

OMeMeO

NH2

R1COOH

ArNC

R2O

NO

O R1

O

HN R2

Ar108 109112

111110

H

Scheme XXXIX

R1 BrN

O

R2

R1AgCN, KCN, TEBAC cat.

9798

R2COCl

Scheme XXXVI

N

SNH

O

O

N

R1

Figure 10 Substituted oxazole as phosphoinositide-3-kinase inhibitor


847

Coupling of acyl chloride with isocyanide to obtain

2,5-disubstituted oxazoles, avoiding 4,5-disubstituted

products by the use of Schollkopf conditions was

experimented. This method provides significant base-

induced chemoselectivity in isocyanide chemistry134

.

Zhanga et al.135

put forward elegant synthesis

(Scheme XXXX) and photophysical properties of

diversely substituted oxazole nucleus. This ring was

mainly functionalized with electron accepting

moieties.

Substituted 1,3-oxazole 117 and thiazoles were

prepared from alkyl, aryl, heteroaryl and 4-substituted

aryl amides and thioamides with substituted phenacyl

bromide (Scheme XXXXI). Thiazole and aryl moiety

with 2-alkyl/hetro aryl substitution in relation with

p-bromo/chloro groups contribute significantly towards

bactericidal potential than 1,3-oxazole analogues136

.

Solvent free microwave conditions for oxthiocyanates

condensation with different anilines were elaborated to

prepare 6-substituted-N-arylbenzo[d]oxazol-2-amines137

.

Structure modifications of oxazole nucleus starving

for functionalized oxazoles Several synthetic protocols have been established to

synthesize different oxazole derivatives. Some of these

approaches involved microwave mediated preparation

of oxazole and benzoxazole exhibiting analgesic

activity138

, derivatives of oxazoles with activity against

Cannabinoid receptors139

, Pd/Cu-mediated arylation of

oxazoles with aryl halide140

. Palladium catalyzed

Suzuki cross coupling with C-2 alkylation of

2-iodooxazole regioselectively was also reported141

.

Furthermore, the amination, alkoxylation, Suzuki-

Miyaura and Migita-Stille coupling of 5-bromooxazole142

,

homocoupling of oxazole-4-carboxylates were carried

out to obtain bis 5,5-oxazole-4,4-dicarboxylic oxazole

derivatives143

. Arylation144,145

, alkenylation, alkynylation

of oxazole and benzooxazole moieties with regio and

stereospecificity also resulted in highly functioalized

oxazoles146-149

.

Simultaneously, C-H arylation of oxazole hetrocycles

via aryl bromide150

or iodide151

and carboxylation under

metal free conditions was studied152

. Alternatively,

oxazole analogues are also achieved by the coupling of

2-amino-1,3 oxazoles with chloro hetrocycles under

catalytic conditions153

, two stage polyoxazole formation

involving TBS-iodine exchange and Suzuki Miyaura

coupling154

. The same substrate reacts with secondary

alkyl halides using bis [2-(N,N-dimethyl amino) ethyl

ether to afford coresponding derivatives155

. Amination of

benzooxazoles with different amines was reported via

copper catalyzed oxidation156

, using iodine in aqeous t-

butyl hydroperoxide157

tetra-butyl ammonium iodide in

aqeous hydrogen peroxide and transition metal free

methods158

.

A new series of 4-substituted-2-(2-hydroxyphenyl)

benzoxazoles was constructed by modifying

substituted phenyl oxazoles and also evaluated as

efficient anticancer agents159

. Coupling of oxazoles

with diarylmethyl carbonates in presence of PdCl2

(MeCN)2/PPhCy2 as catalyst fabricated hetroarene

containing triarylmethanes160

.

The exploration of diversified oxazoles towards

synthesis and pharmacological efficacy encompassed

in vitro PPAR agonistic potential and in vivo

hypoglycemic, hypolipidemic, antitubercular,

antibacterial, anti-inflammatory activity, while

glycine substituted oxazoles in conjugation with

hydroxycinnamic acid motifs afforded antioxidant

activity161-165

. Synthesis of benzo[d] oxazole-4,7-

dione derivatives having antifungal activity166

and

phenyl oxazole with in vitro cervical and breast

cancer cells proficiency along with in vivo screening

of zebrafish embryos was unvailed by Dulla et al167

.

In vitro anti-inflammatory action was best shown by

azomethines of aryl oxazoles when diclofenac sodium

was the reference standard168

.

Benzoxazole containing analogues have been

recognized as having high potential for showing

various biological activities like antidepressant,

antimicrobial, analgesic, anti-inflammatory and

anticancer169

. Biaryl substituted oxazoles, imidazoles

and lower molecular weight thiazole carboxamides

were very potent for peripherally sodium channel

blockers170

. Novel oxazole derivatives were developed

to conceal photophysical properties and proved new

derivatives to exihibit more antifungal potential over

CHO

R

O

NHO

O

HCl

R

N

O

O

Zn

113114

115

Scheme XXXX

RCN

Br

O

R'

O

NR R'Silica gel G-sulphuric acid

116

117

Scheme XXXXI


848

antibacterial171

. Cyclocondensation of oxa and thiazol

analogues with thioglycolic acid was carried out to

discover antibacterial potential in comparison with

ampicillin and ciprofloxacin as standards172

.

Amido sulfonamido methane linked bisoxazoles,

thiazoles and imidazoles with excellent antimicrobial

and anticancer potential were reported by

Premakumari173

. A group of benzothiazole/benzoxazole-

2,3-dihydrobenzo[b][1,4] dioxine derivatives synthesized

from 2-(piperidine-4-yl)-benzo[d]thiazole/oxazoles

revealed high affinities for the 5-HT1A and 5-HT2A

receptors with striking antidepressant-like activity174

.

Mechanistic perceptions leading to oxazoles Following is the role of accelerating agents and

metal catalysts in the successful execution of oxazole

ring. Efficient procedures have been adopted to

construct and improve the yield of targeted nucleus.

Phenyliodine (III) diacetate (PIDA) is a very famous

oxidant in metal based oxidative addition of nucleophile

to alkyne functionality. Here propargylamide undergoes

oxidative cycloisomerization in the presence of PIDA

to yield derivatives of oxazole acetate (Route 1).

2,4,5-Trisubstituted oxazoles have been prepared

from alkyl aryl ketone very conveniently. Oxone is

responsible for the oxidation of iodoarene to

aryliodonium species that further reacted with ketone

to give corresponding -keto iodonium species. In the

final step nitrile make connection with -keto

iodonium compound to furnish oxazole (Route 2).

Herein, one pot synthesis of benzoxazole has been

reported using intermolecular heterocyclization approach

catalysed by indium (Route 3). Nitro compound was

transformed into aniline molecule via nitroso species that

further reacted to give an imidate intermediate. In next

step, hydroxyl group attacked the neighbouring imidate to

form the ring structure. Aromatization was achieved by

the removal of methanol.

Synthetic methodology starting from primary -

amino acid for oxazole provides a new path to utilize

the benefits of iodine. Decarboxylative cyclization

was put forwarded that was initiated by the attack of

iodine. A molecule of carbondioxide was eliminated

from radical intermediate which further produced an

imine. Subsequent intramolecular type nucleophilic

addition followed by oxidation yielded the required

oxazole moiety (Route 4).

Silver (I) salt catalysts promote an extensive range

of reactions with improved yield. Amide and -

halopyruvate underwent dehydrative cyclization via

Ag+ activated -halo group (pathway A) or activated

carbonyl group (pathway B). By this mechanism,

-halo keto derivatives proved to be very promising

potential building blocks for oxazole synthesis so this

N

O

R

R1

Ar

Ar

O

H

R1H

Ar

OH

H

R1

ArI

R1

Ar

O

HO

N

Ar

R1R

RCN

ArI

ArIOH

2KHSO5 KHSO4 K2SO4

TfOH

2KHSO4 KHSO4 K2SO4

TfO

Route 2 Proposed mechanism showing the role of iodoarene

for oxazole nucleus118

PhI

OAc

HN

R2OR1

N

OR1

R2

I

H

OAc

Ph

OAcOAc

N

OR1

R2

I

OAc

Ph

H

N

OR1

R2

IPh

N

OR1

R2

OAc

AcOH

PhI

AcOH

AcOH

Route 1 PIDA accelerated mechanism of oxazole synthesis67


849

is an extension of substrate scope in the field of

oxazole fabrication (Route 5).

Gold salen complex is involved in different

concentration in catalytic cycle of propargyl amide.

Reaction is initiated by the attractions of activated

N-acyl iminium compound to metal acetylidine

leading to amide formation. Loss of benzyl chloride is

in connection with the synthesis of oxazole because it

OH

NH2

MeO

OMe

OMe

R HOH

NH

OO H

R

OH

NH

O

R

OH

N

O

RNH

HO O

RNH

O OH

RN

OR

H

-H

protontransfer-MeOH

-H

OH

NO2

In/AcOH

Route 3 Indium mediated synthesis of benzoxazole113

Ph

O

NH

Ph COOH

Ph

O

NH

Ph COO

Ph

O

NH

Ph

Ph

O

N

Ph

Ph

OH

N

Ph

Ph

HO

NH

Ph

Ph

O

N

Ph

I 1/2I2

-H+

-CO2

-H+O

H+

-H+

O

Route 4 Plausible mechanism involving iodine for oxazole ring construction114

R1 NH2

O R2X

O

R1 NH2

O

R2X

O

O NH2

R1

R2X

O AgAg

R1O

NH

OHR2

XO

NR1

H

O X

R2

B

O

NR1

R2

O

O

NH2

R1

R2

-H2O

A B

Route 5 Silver mediated oxazole synthesis70


850

preserves the catalytic behavior of gold. Finally,

isomerization is followed by proto-demetallation

resulting in the five membered ring (Route 6).

Deep eutectic solvents offer unique properties

whenever is employed for organic synthesis. This

cutting edge methodology uses choline chloride and

urea that build up attractions for reaction substrates.

This frame work increased the compatibility of

reagents; substituted amide and phenacyl bromide for

each other, hence efficiently furnished novel oxazole

derivatives (Route 7)73

Conclusion

This review focuses on all different synthetic

methodologies for 1,3-oxazole and benzoxazole

nucleus starting from 2007 till now, and also provides

a glimpse on its biological activity. Mainly

intramolecular cyclization of appropriately substituted

amides, amines and oximes furnish this five member

heterocyclic motif. Moreover, intermolecular

approaches and three component reactions are well

known for this scaffold. Our objectives to highlight

different synthetic approaches adopted for oxazole, to

drag researchers for its production on modern aspects

where deep eutectic solvents and sonication energy is

the core of interest. However, mechanistic insights

clearly demonstrate the role of supporting agents like

catalytic metals, etc. Reviewing this material would

be rewarding to explore its untouched

pharmacological activities and turn the focus of

chemists to develop novel versatility on oxazole.

Acknowledgement

Authors are obliged to Higher Education

Commission of Pakistan for financially supporting

this document.

MH+

M+ / H+

O

N

H+/M+O

NH

+H/+M

O

N

H

M+O

N

Cl

N

O

Cl

O

H

NBn

N

O

H

Ph

Ph N O

Cl-

+H

O

N N

O

Au

PF6-

Route 6 Mechanism proposing gold metal activity for the preparation of oxazole121

N

O

O

R1

H

O

NH

R1

-O

RR

O

N

R1

OH

R

O

N

R1

R

-H2O

-HBr

N

H

N

O

H

H

H

N

H

R1

O

H

Br

O

R

H

N

N

H

OH

HN

OHCl

Route 7 Mechanistic perception based on DES role in synthesis of oxazole73


851

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