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
INDIAN J. CHEM., SEC B, JULY 2016
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
GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES
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
INDIAN J. CHEM., SEC B, JULY 2016
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
GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES
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
INDIAN J. CHEM., SEC B, JULY 2016
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
GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES
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
INDIAN J. CHEM., SEC B, JULY 2016
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
GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES
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
INDIAN J. CHEM., SEC B, JULY 2016
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
GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES
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
INDIAN J. CHEM., SEC B, JULY 2016
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
GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES
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
INDIAN J. CHEM., SEC B, JULY 2016
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
GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES
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
INDIAN J. CHEM., SEC B, JULY 2016
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
GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES
851
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