Synthetic Strategy and Therapeutic Utility of Oxygen and Nitrogen Containing Heterocyclic Compounds

Review Article
Journal homepage: http://www.ijpsl.com
ISSN:2277-4564
L. Joseph et al /International Journal of Pharmaceutical Sciences Letters 2014 Vol. 4 (4)| 417-431
Synthetic Strategy and Therapeutic Utility of Oxygen and Nitrogen Containing
Heterocyclic Compounds
Lincy Joseph*, Mathew George and Surekha SR
Pushpagiry College of Pharmacy,Thiruvalla,Kerala-689101
ABSTRACT
The oxygen and nitrogen containing heterocyclic compounds are very important in there synthetic aspect because
of their enormous pharmacological applications. Several new reagents, substrates and methods are being developed
every year to facilitate their synthesis. This review is an effort to sum up the methods recently utilized for the synthesis
of this important group of heterocyclic compounds.
Introduction
Heterocyclic's are an important class of compounds,
making up more than half of all known organic compounds.
In fact two thirds of organic compounds are
heterocyclic compounds. A cyclic organic compound
containing all carbon atoms in ring formation is referred
to as a carboxylic compound. If at least one atom
other than carbon forms a part of the ring system then it
is designated as a heterocyclic compound [1]. Nitrogen,
oxygen and sulfur are the most common hetero atoms.
Besides the vast distribution of heterocyclic in natural
products, they are also the major components of biological
molecules such as DNA and RNA. DNA is
without doubt the most important macromolecule of
life. Nucleotides, the building blocks of our genes are
derivatives of pyrimidine and purine ring structures.
Chlorophyll and heme, the oxygen carriers in plants
and animals respectively are derivatives of large porphyrin
rings.
Heterocyclic's are present in a wide variety of drugs,
most vitamins, many natural products, biomolecules,
and biologically active compounds, including antitumor,
antibiotic, anti-inflammatory, antidepressant, antimalarial,
anti-HIV, antimicrobial, antibacterial, antifungal,
antiviral, antidiabetic, herbicidal, fungicidal, and
insecticidal agents. Also, they have been frequently
found as a key structural unit in synthetic pharmaceuticals
and agrochemicals. Some of these compounds exhibit
a significant solvatochromic, photochromic, and
bio chemi-luminescence properties. Most of the heterocycles
possess important applications in materials science
such as dyestuff, fluorescent sensor, brightening
agents, information storage, plastics, and analytical
reagents. We can classify the oxygen and Nitrogen
Key words: Oxazoles, Oxaziridine, isoxazole, oxadiazole,
morpholine
Received 27 May 2014; accepted 25 June 2014;
*Corresponding Author: Ms. Lincy Joseph
Pushpagiry College of Pharmacy,Thiruvalla,Kerala-
689101
Email: mathewlincg@yahoo.com
Copyright ©2011 Published by IJPSL. All rights reserved
containing heterocycles as shown in Table1.
Table 1. Classification of oxygen and nitrogen containing
heterocyclic compounds
Heteroatom Saturated Structure
Oxygen &
Nitrogen
Oxygen &
Nitrogen
Oxygen &
Nitrogen
Two nitrogen
& one
Oxygen
Oxygen &
Nitrogen
Oxaziridine
Oxazole
Isoxazole
Oxadiazole
Morpholine
O
OXAZIRIDINE
Oxaziridine
An Oxaziridine is an organic molecule that features the
smallest three membered heterocycle containing oxygen,
nitrogen, and carbon. Oxaziridines have been discovered
in 1956 1 . Oxaziridine derivatives are commonly used as
reagents in organic chemistry for a variety of oxidations,
including alpha hydroxylation of enolates, epoxidation
and aziridination of olefins, and other heteroatom transfer
reactions. Oxaziridines are also synthetically useful as
intermediates that undergo rearrangement to amides, as
well as participate in [3+2] cycloadditions with various
heterocumulenes to form substituted five remembered
heterocycles. Chiral oxaziridine derivatives have also
been developed in order to affect asymmetric oxygen
transfer to prochiral enolates, as well as other substrates.
Some oxaziridines also have the interesting property of a
high barrier to inversion of the nitrogen, allowing for the
possibility of chirality at the nitrogen atom.
H
N
O
N
OXAZOLE
O
N
ISOXAZOLE
O
N
N
OXADIAZOLE
HN
O
MORPHOLINE

L. Joseph et al /International Journal of Pharmaceutical Sciences Letters 2014 Vol. 4 (4)| 417-431
Chemistry of Oxaziridine
SCHEME 1
Widmer.J. Keller-Schierlein, W.Helv,et al Oxidized
imines with per acids and carbonyl compounds with
amine to synthesize Oxaziridines.
R
N
R 2 R 3 R 4 CO 3 H
R 1 ,R 2 ,R 3 =Alkyl,aryl
N
O
R 2
R 3 R 2
R 3
A
SCHEME 2
HO
H 3 C
O
CH 3
O
RCl+NaOH (Phase
Transfer catalysis)
O
O
O
CH 3
H 2 O 2 (30%.acq)
R-CO-NH 2
eg;acetamide,benzamide
* asymetric carbon atom
O
R 2
R 1 -NHX
R 3 X==Cl,OSO 3 H,
N R 1
B
H 3 C
O
O
O
OH
O
*
NH
+ H 2 O
R 1 =H,CH 3
X=Cl,OSO 3 H
SCHEME 2
Perfluorinated oxaziridines may be synthesized by
subjecting perfluorinated imines to perfluoromethy l
fluorocarbonyl peroxide and a metal fluoride to act as an
HF scavenger
H 3 C
O
O
O
p- TsOH (cat/toluene)
dist.water azeotropically
in to a Dean-Stark Tube.
O
N
O
R 1
N
F
R 2
CF 3 OO(O)F
C S F
R 1
N
O
F
R 2
H 3 C
O
O
ethyl carbitol
b.p 202 0 C
1 eq.
OH + 1/3
O
O
O
s-Trioxane
m.p 62 0 C
0.4 eq.
+ H 2 O
+
O
H 3 C CH 3
acetone
b.p 520C
1.5 eq.
R 1 =i-C 3 F 7 ,n-C 3 F 7 ,n-C 4 F 9
R 2 =CF 3 ,C 2 F5,n-C 3 F 7
p-Ts OH( cat)
reflux
N-Acyloxaziridines
Schulz, Becker and Rieche proposed practical schemes
which involve the addition of primary amine to an olefin
undergoing ozonolysis produce a β aminohydroperoxide
which is an unstable intermediate .dehydration of this
intermediate closes the three atom ring to yield the
oxaziridine.
The second scheme proposed is the modification of this
reaction in which hydrogen peroxide and a primary amide
add to a ketone carbonyl group with a subsequent dehydration
of the hydroperoxide amide intermediate to the N-
Acyloxaziridines.
H 3 C
H 3 C
O
O
O
H2O2 (30% (1 eq.))
+ R-CO-NH 2 (1 eq.)
O
O
O CH 3
O
OH
O
+ H 2 O
O R
+ H 2 O
NH
CH 3
SCHEME.1
H 3 C
O
O
Ethyl carbitol
B.P.202 0 C
OH
SOCl 2
CH 2 Cl 2
O
H 3 C O
Cl
1-Chloro3,6-dioxo-octane=RCl
H 3 C
O
p-TsOHcat/toluene
dist.H 2 O,azeotropically
in to a Dean Stark tube.
O
O
O
N
CH 3
O
R
+ H 2 O
R = alkyl /aryl group.eg; acetamide,benzamide..
418

L. Joseph et al /International Journal of Pharmaceutical Sciences Letters 2014 Vol. 4 (4)| 417-431
Pharmacological Activity of Oxaziridines
The cytotoxicity of oxaziridines photo generated after
irradiation of chlordiazepoxide (CDZ) and its metabolites
was investigated in vitro by a MTT assay on P388 leukemia
and B16 melanoma cell lines and compared with that
of the anticancer drug, melphalen. It was found that for
the longer time-exposure experiment, oxaziridines had
the same cytotoxicity as melphalen and this toxicity was
higher when oxaziridines were photo generated in the
presence of cells. In conclusion, oxaziridines generated
after CDZ, demoxepam, and desmethylchlordiazepoxide
ultraviolet irradiation exhibited cytotoxicity activity
against cancer cell lines. A possibility of CDZ use within
the context of photodynamic therapy as a treatment for
small, superficial tumors should not be excluded, because
oxaziridines can be generated locally by skin-tumor local
irradiation after CDZ topical administration. Oxaziridine
is also used in impregnated silica nanoparticles for removal
of sulfur mustard from wastewater.
Oxazole
Oxazole is a heterocyclic organic compound that has a
five-member ring molecular structure,C 3 H 3 ON, containing
three carbon atoms, one oxygen atom and
one nitrogen atom. It is a clear to yellowish liquid with a
pyridine like odor. It is soluble in alcohol and ether and
slightly soluble in water. Oxazoles and its derivatives are
used as building block for biochemicals and pharmaceutical
as well as in other industrial applications such as pesticides,
dyes, fluorescent brightening agents, textile auxiliaries
and plastics. The term of isoxazole is for 1,2-
oxazole.
Oxazoles derivatives have become increasingly important
because of their use as intermediates for the preparation
of new biological materials. The oxazole ring is present
in numerous pharmacologically important compounds,
including those used as antibiotics and antiproliferatives.
The wide range of biological activities of oxazoles
includes anti-inflammatory, analgesic, antibacterial,
antifungal, hypoglycemic, antiproliferative, antituberculosis,
muscle relaxant and HIV inhibitor activity.
In addition, oxazole derivatives are useful synthetic intermediates
and can be used as diversity scaffolds in combinatorial
chemistry and as peptidomimetics. The presence
of a halogen allows these reagents to be used as substrates
in various coupling reactions, including Suzuki-Miyaura
cross-coupling reactions.
SYNTHESIS
SCHEME 1
N.A. Strotman,H. R.Chobanian et al report a complementary
[3] methods for direct arylation of with high regioselectivity
at both C-5 and C-2 have been developed for a
wide range of aryl and heteroaryl bromides, chlorides,
iodides, and triflates. Using task-specific phosphine
ligands, palladium-catalyzed C-5 arylation of oxazoles is
preferred in polar solvents, whereas C-2 arylation is preferred
by nonpolar solvents.
Ar-X
X: Cl,Br,
+
O
N
5 mol - % Pd(OAc) 2
. 1
eq. ligand
3 eq. K 2
CO 3
, . 4 eq . PivOH
DMA, 110 0 C , 16h
SCHEME2
N. A.Strotman, H.R.Chobanian et al [3] in 2010 again
reported a quaternary ammonium hydroxide ion exchange
resin catalyzes the reaction of p-
tolylsulfonylmethyl isocyanide (TosMIC) with aromatic
aldehydes to give 5-aryloxazoles. The base and
the p-tolylsulfinic acid byproduct can be removed by
simple filtration, resulting in oxazoles in high yield and
purity.
Ar
O
+
H
Tos
SCHEME 3
A simple and efficient Cs 2 CO 3 -mediated reaction of
aromatic and unsaturated primary amides with 2,3-
dibromopropene allows the synthesis of 2-aryl-5-alkylsubstituted
oxazoles in a single step good yields.
O
R +
NH 2 H 2 C
B.Wu,J.Wen, et al [4] in 2009 reported an improved
one-pot van Leusen oxazole synthesis using tosylmethyl
isocyanide (TosMIC), aliphatic halides and
various aldehydes in ionic liquids allows the preparation
of 4,5-disubstituted oxazoles in high yields. The
recovered ionic liquids could be reused as solvent for
six runs without significant loss of yields.
F.Besselievre,S.Lebrequier et al in 2009 [5] reported a
method in which Pd (PPh 3 ) 4 efficiently catalyses both
direct arylation and alkenylation of oxazoles. The
method is regio- and stereo specific respect to bromoalkenes
and tolerates a wide range of functional
groups.
Ar
ToS
O
N
NC
+
(TosMIC)
Br
NC
Br
Ar
Amber sep 900 OH
1.85 g / mmol aldehyde
O
DME/MeOH (1:1)
reflux, 8hr
3.3 eq. Cs 2 CO 3
DMSO,110 0 C, 2-3hr
1.5eq,R-X
2eq K 2 CO 3 TOS
R
r.t-12hr
RX=Alkyl-Br,Bn-Cl
allyl-Br
R1X=Ar,vinyl,(1.2 eq)
allyl(2eq)
NC
5 mol - % Pd(PPh 3 ) 4
1.5 - 2 eq . 1.5 - 2 eq .tBuOLi
Br
R
dioxane
120 0 c ,2 -6 hr
N
R
1.2eq -2eq R-CHO
r.t-10hr
Ar
O
N
O
N
R
Ligand
R
R 1
Ar
P
Bu
O
419
N
R: Ar , vinyl
O
R: Ar (1.5 eq . RBr /tBuOLi)
N
vinyl(1.5 eq . RBr /tBuOLi)

L. Joseph et al /International Journal of Pharmaceutical Sciences Letters 2014 Vol. 4 (4)| 417-431
G.C.Senadi, W.P.Hu,J.S.Hsiao et al [6] in 2012 reported a
ZnI 2 and FeCl 3 mediate a direct approach to the selective
and regio controlled synthesis of 2-oxazolines and 2-
oxazoles in very good yields under mild reaction conditions
by cyclization of acetylenic amides. Various functionalities
were well tolerated.
5mol % Ph 3 PAu NTF
+ NC-R 1 1.3 eq..oxidant
60 0 C ,,3hrs.
R
O
N
R 1
R= alkyl,Ar,vinyl
R 1 = me/iPr,Bn,Ph.
O - +
N
oxidant
R
O
Cl
+
N H 2
CH 3 CH 3
2 eq. NEt 3
2 eq. FeCl
O
3
DCM
DCE
R' r.t.,2 - 12 hr
R NH R'
80 0 c ,3-8 hr
Y.Zheng,X.Li.D.Zhang et al [7] in 2012 proposed that a
broad range of functionalized oxazoles were synthesized
in good yields from enamides via phenyliodine diacetate
(PIDA)-mediated intramolecular cyclization. The oxidative
carbon-oxygen bond formation process is heavymetal-free.
R'
R
O
NH R"
1.3 eq.Phl(OAc) 2
2 eq. BF 3. Et 2 O
DCE
reflux,.5 - 2 hr
X.Liu,R.Cheng, F.Zhao,et al [8] in 2012 reported the use
of iodosobenzene (PhIO) as an oxidant realizes an intermolecular
oxidative C(sp 2 )-O bond formation between
enamines and various carboxylic acids, including N-
protected amino acids. This direct β-acyloxylation of
enamine compounds tolerates a wide range of functional
groups and furnishes various β-acyloxy enamines that can
be conveniently converted to oxazoles via cyclodehydration.
R
O
C.Verrier,T.Martin et al [9] in 2008 proposed a straightforward
route allows the synthesis of 2-(hetero)arylated
and 2,5-di(hetero)arylated oxazoles through regiocontrolled
palladium-catalyzed direct (hetero)arylation of
ethyl oxazole-4-carboxylate with iodo-, bromo-, and
chloro(hetero)aromatics.
EtO 2 C
O
O
N
EWG
R'
NH 2
AcOH
reflux,30 min
W.He,C/.Li et al [10] in 2011 proposed an efficient intermolecular
reaction of gold carbene intermediates generated
via gold-catalyzed alkyne oxidation using nitriles as
both the reacting partner and the reaction solvent offers a
generally efficient synthesis of 2,5-disubstituted oxazoles
with broad substrate scope. The overall reaction is a [2 +
2 + 1] annulation of a terminal alkyne, a nitrile, and an
oxygen atom from an oxidant.
R
N
R
O
R"
R'
+ Ar Cl 5 mol - % Pd(OAc) 2
.1 eq. P(o-tol) 3
2 eq. Cs 2 CO 3
toluene, 110 0 c,18 hr
N
O
R'
CH 3
R : Ar, alkyl,vinyl
R : Ar,Me,COMe, CO 2 Me
R : CO 2 Me,Me,Ar, COph,H
R" : alkyl, Ar
R
N
O
R'
EWG
R : Ar, alkyl, vinyl
R' : Me, Ph
R" : CO 2 Me, CN
EtO 2 C
O
N
Ar
H.Jiang,H.Huang et al in 2010 [11] proposed a facile
one-pot, transition-metal-free process enables the synthesis
of various polysubstituted oxazoles via t-
BuOOH/I 2 -mediated domino oxidative cyclization
from readily available starting materials under mild
conditions.
2.5 eq.
CH 2
H N Ar
+ -
2
H 5 C 6
In a practical and simple synthesis of 2,5-disubstituted
oxazoles via an iodine-catalyzed tandem oxidative cyclization,
a wide range of common commercial aromatic
aldehydes can be used as reaction substrates,
which displayed excellent functional group compatibility.
Ph
added in two portions over 8 hr
1. 5 eq. tBuOOH
1. 2 eq I 2
DMSO 80 0 C, 12 h
N.Yasmin,J.K.Ray et al in 2009 [12] proposed a simple
and efficient Cs 2 CO 3 -mediated reaction of aromatic and
unsaturated primary amides with 2,3-dibromopropene
allows the synthesis of 2-aryl-5-alkyl-substituted oxazoles
in a single step in good yields.
R
O
O . 3 eq I 2
1. 5 eq. t BuOOH
NH 2 . HCl +
C 6 H 1 eq. NaHCO
H 5
3
DMF, 70 0 C, 10 h
C.W.Cheung, S.L.Buchwald in 2012 [13] reported a
copper(II)-catalyzed oxidative cyclization of enamides
gives oxyzoles via vinylic C-H bond functionalization
at room temperature. Various 2,5-disubstituted oxazoles
bearing aryl, vinyl, alkyl, and heteroaryl substituents
could be synthesized in good yields. This reaction
protocol is complementary to a previously reported
iodine-mediated cyclization of enamides to afford 2,
4,5-trisubstitutedoxazoles.
H 5 C 6
O
NH 2
+
NH
C H 2
O
R
Br
Br
3. 3 eq. Cs 2 CO 3
DMSO, 110 0 C, 2 - 3 h
7. 5 mol - % CuBr 2
15 mol - ethyl nicotinate
1. 2 eq. TBAB, 1. 3 eq K 2
S 2
O 8
MeCN, r.t. , 24 h
H 5 C 6
Y.M.Pan,f.j.Zheng et al in 2009 [14] proposed an efficient
one pot propargylation/cycloisomerisation tandem
process provides a rapid andefficient access to substituted
oxazoles from propargylic alcohols and amides
R
O
N
O
Ph
N
N
O H 5 C 6
C 6 H 5
O
N
420
C 6 H 5
CH 3
R : Ar, vinyl
R
R : Ar, vinyl

L. Joseph et al /International Journal of Pharmaceutical Sciences Letters 2014 Vol. 4 (4)| 417-431
with use of p-toluene sulfonic acid monohydrate (PTSA)
as a bifunctional catalyst.
OH
Ar + NH 2 R 1
R
1.2 eq
O
1 eq PTSA
Toluene
reflux,.0.5-5hrs
R.Martin, A.Cuenca.et al in 2007 [15] proposed a modular
and practical synthesis of highly substituted oxazoles
consists of a sequential copper-catalyzed amidation of
vinyl halides followed by cyclization promoted by iodine.
A wide variety of functionalized oxazoles and polyazoles
can be obtained in a selective manner from simple and
easily accessible precursors.
R
R'
CH 3
+
A series of propargylic amides were transformed to the
corresponding alkylideneoxazolines by a gold (I) catalyst.
A subsequent autoxidation to hydro peroxides bearing the
heteroaromatic oxazoles followed by reduction to the
corresponding alcohols with sodium borohydride enables
a highly efficient, and atom-economic access to a series
of functionalized 2,5-disubstituted oxazoles.
N
+
Ar - O
O
H 2 N
R"
5 mol - % CuI
0. 2 eq MeNH CH 2 CH 2 NHMe
1. 5 eq Cs 2 CO 3
THF, 80 0 C, 3 - 8h
3-Oxazoline-4-carboxylates as easily available synthetic
intermediates can be oxidized to yield oxazole-4-
carboxylates. Furthermore, derivatization of 3-oxazoline-
4-carboxylates with Grignard reagents enables a facile
preparation of 4-keto-oxazole derivatives.
Ar - 2 eq.
C. Wang, J. Zhang, et al in 2010 [16] reported a highly
efficient copper-catalyzed tandem oxidative cyclization
gives poly substituted oxazoles from readily available
starting materials under mild conditions. This is an attractive
alternative method for the synthesis of oxazole derivatives.
Ar - 2 eq.
Cl
Cl
1. 5 eq.
O
Ar'
NH 2 +
R R'
O
O
O
NH 2 +
R R'
5 mol - % Pd(OAc) 2
6 mol - % DPEPhos
5 eq LiOtBu
dioxane 120 0 c, 14 h
J.F.Sanz-Cervera, R. Blasco et al [17] in A small library
of compounds with oxazole and thiazole scaffolds and
structural diversity in both positions 2 and 5 has been
synthesized. Double acylation of a protected glycine af-
R
R'
. 1 eq. Cu(OAc).H 2
O
2 eq. t BuOOH,
1. 2 eq I 2
DMF, r. t., ~ 7h
. 1 eq. Cu(OAc).H 2
O
2 eq. t BuOOH,
1. 2 eq I 2
DMF, r. t., ~ 7h
R
N
NH
RA
O
O
N
R"
1) 1. 1 eq,I 2
80 0 C, ~ 4 h
2) 2 eq. DBU
80 0 C, ~ 4 h
CH 3 ,
Ar - O
Ar -
Ar -
N
N
O
O
O
O
R
R
R'
R'
R=TMS,alkyl,ph,H
R 1 =Ar,alkyl,vinyl
R'
R
DPEPhos:
N
O
R"
PPh 2
O
PPh 2
R: alkyl,Ph, vinyl
R': OR"
alkyl(R'=R)
Ph(R'=R)
R: alkyl,Ph, vinyl
R': OR"
alkyl(R'=R)
Ph(R'=R)
intermediate α-amido-β-ketoesters, which in turn can
be dehydrated to afford 1,3-oxazoles or reacted with
Lawesson’s reagent to furnish 1,3-thiazoles.
Ar -
O
N
PPh3
Ar'
1.2 eq
O
+
Cl CH 3
1) toluene, reflux, 3 h
2) 1. 1 eq. H 2
O, Reflux, 3 - 4 h
3) 10 eq NaOH ( 2M aq.)
r.t., 15 min
J.F.Sanz-Cervera et al in 2009 [17] reporetd a method
in which a small library of compounds with oxazole
and thiazole scaffolds and structural diversity in both
positions 2 and 5 has been synthesized.double acylation
of a protected glycine affords intermediate alpha-amido
-beta-ketoester,which in turn can be dehydratedto afford
1,3-oxazolesor reacted with Lawesson’s reagent to
furnish 1,3-thiazoles.
R
A tandem reaction of a vinyliminophosphorane with
various acylchlorides gives unexpectedly 2,4,5-
trisubstituted oxazoles in a one-pot fashion.
Ar
O
O
NH
R'
2 eq PPh
3
, 2 eq I
2
CH Cl , r. t., 15 - 60 min
CO 2 Bn 2 2
E. Merkul., O. Grotkopp,et al in 2009 [18] proposed a
method n which substituted oxazoles-5-ylethanones can
be synthesized in a consecutive three component sequence
starting with amidation of propargylamine with
an acid chloride followed by cross coupling with another
acid chloride. Therefore this diversity – oriented
one-pot approach to substituted oxazoles can be considered
as an amidation coupling cycloisomerisation
(ACCI) sequence.
R
O
R: Ar,vinyl
A.Herrera, R. Martinez et al in 2006 [19] described a
reaction in which 1-methyl thioacetone with different
nitriles in the presence of triflicanhydrides gave 2-
substituetd 5-methyl4-methyl thio group at the C4 position
can easily be removed with Raney nickel.4-methyl
sulfonyl derivatives were prepared by oxidation of the
MeS group with m-CPBA.
SMe
+ Cl
N
PPh 3
Cl
2 eq
O
O
O
H 2 N
1)1 eq
CH
H 3 C
1 eq NEt , THF r.t., 1h
3
2) 2 mol -% PdCl (PPh ) 2 3 2
HN
4 mol - % CuI, NEt 3
R
1 eq Ar'COCl r.t., 1h
2 eq.Tf 2 O
CH 2 Cl 2
R
N
1)toluene,reflux 3hrs
2)1.1 eq.H 2 O,reflux,3-4hrs
3)10.eq.NaOH(2M eq)
r.t..,15mts.
O
SMe
OTf
O
O
Ar'
O
R
O
Ar -
R'
N
CO 2 Bn
Ar
A
R
1 eq PTSA.H 2
o
60 0 C, 1 h
1eq.R-CN
0 0 C,3d
HO
Ar'
R: Ar", alkyl
R, R': Ar, alkyl
R
R
N
N
N
OH
Ar 1
R ; Ar' ,alkyl
O
O
421
O
Ar'
SMe

L. Joseph et al /International Journal of Pharmaceutical Sciences Letters 2014 Vol. 4 (4)| 417-431
G. Cuny, R. Gamez et al in 2004 [20] proposed that the
reaction of aldehydes and ketones ,including aliphatic and
aromatic ones with amides of alpha-isocyano-betaphenylpropionic
acid in toluene in the presence of lithium
amide give 2,4,5-trisubstituted oxazoles in good to excellent
yield.
NC
Ph
O
N
R'
C.Wang, J.Zhang et al [22] reported a highly efficient
copper –catalysed tandem oxidative cyclization give
spolysubstituted oxazoles from easily available starting
materials under mild conditions. This is an attractive alternative
method for the synthesis of oxazoles derivatives.
Ar NH 2
+
R''
+ R
O
H
1eq.LiBr
toluene,60 0 C,4hr
J.F Sanz-Cervera et al in 2009 proposed that a small library
of compounds with oxazoles and thiazoles scaffolds
and structural diversity in both positions 2 and 5 has been
synthesized. Double acylation of a protected glycine affords
intermediate alpha amido-beta ketoesters, which in
turn can be dehydrated to afford 1,3-oxazoles or reacted
with Lawesson’s reagent to furnish 1,3- thiazoles.
R
Ding.J ,Orem et al in 2012 reported tandem reaction of a
vinyliminophosphorane with various acylchlorides gives
unexpectedly 2,4,5 –trisubstituted oxazoles in a one pot
fashion.
E. Merkul, O. Grotkopp et al in 2009 described a synthesize
in which oxazoles-5-ylethanonesbcan be synthesized
in a consecutive three component sequence starting with
amidation of propargylamine with an acid chloride followed
by cross coupling with another acid chloride
.therefore this diversity oriented one-pot approach to
substituted oxazoles can be considered as an amidation
coupling cycloisomerisation (ACCI) sequence.
R
O
Ar
O
N
H
Cl
O
R
O
O
R'
O
COOBn
R'
+
Ar
N
Cl
PPh 3
0.1 eq.Cu(OAc).H 2 O
2 eq.tBuOOH,1.2 eq.I 2
DMF ,r.t.at 7 hrs
2 eq.PPh 3. 2 eq.I 2
CH 2 Cl 2 .r.t..,15-60 min
1.2 eq
O
R
1,1 eq H 2N
1 eq.NEt 3,THF, r.t.,1 hr
2, 2 mol %PdCl 2 (PPh 3 ) 2
4 mol %CuI,1 eq.NEt 3
1 eq.Ar'COCl,r t,1 hr
Ar
N
N
O
1,toluene,reflux,3hr
2,1.1 eq.H2O,reflux,3-4 hr
3,10 eq.NaOH (2M aq)
r.t,15 min
R
HN
O
r
Ar'
O
HO
R
O
R'
R
COOBn
O
R
1 eq
PTSA.H 2 O
60 0 C,1 hr
R'
N
N
O
R''
N
R'
Ph
R; alkyl,Ph,vinyl
R''; OR''
alkyl(R'=R)
Ph (R'=R)
R,R' ;Ar,alkyl
N
R
OH
Ar
R ; Ar,alkyl
O
O
Ar'
A.Herrea, R.Martinez-Alvarez, et al in 2006 proposed a
reaction of 1-(methylthio) acetone with different nitriles
in the presence of triflic anhydride gave 2-
substituted 5-methyl-4-methylthio-1,3- oxazole in good
yield methylthio group at the C 4 position can easily be
removed with Raney n ickel.4 methyl sulfonylderivatives
were prepared by oxidation of the MeS group
with m- CPBA.
MeS
G.Cuny.R.Gamez-Montano,J.Zhu, et al in 2004 [27]
reported a reaction of aldehydes and ketones including
aliphatic and aromatic ones,with amides of α-isocyanoβ-phenylpropionic
acid in toluene in the presence of
lithium bromide gives 2,4,5-trisunstituted oxazoles in
good to excellent yield.
NC
2 eq
O
2 eq.Tf 2 O O 1 eq.R-CN
CH 2 Cl 2
0 0 C,1 hr
SMe
OTf
G.Bastug,C.Eviolitte,et al in 2012 described a reaction
in which the ortho substituted anilines with functionalized
orthoesters yields benzoxazole, Benzothiazole,
and benzimidazole derivatives in an efficient and connective
methodology the versatility of this approach
enables the development of new libraries of heterocycles
containing multifunctional sites.
R
0 0 C 3d N
P.J.Boissarie, Z.E Hamilton et al proposed an efficient
and convenient three component coupling of aryl halides
amino alcohols and tert- butyl isocyanide under
palladium catalysis provide a range of oxazolines in
excellent yield the use of 1,2-amino phenols instead of
amino alcohols enables the synthesis of benzoxazoles.
R
Ph
O
N
R'
NH 2
YH
H
N
Br
R''
O
+
+
R'
1.3 eq
O
R
1-1.5 eq
OR'
OMe
OR'
R''
H
1 eq.LiBr
toluene,60 0 C,4hr
1eqBF 3 .OEt 2
DCM,r.t.2-4hrs
5 mol %CuO,nanoparticles
1.5 eq.K 2 CO 3 ,OR Cs 2 co 3
DMSO,110 0 C,12-30 hr
P.Saha T.Ramana et al in 2009 proposed that an experimentally
simple, general, efficient and ligand free
synthesis of substituted benzimidazoles, 2-amino benz
imidazoles 2-amino benzothiazoles and Benzoxazoles
via intramolecular cyclization of bromoaryl derivatives
R
HO
R
R
N
O
N
R
O
R'
O
N
Y
R''
N
Y;O,S,NH
R';alkyl
R''; alkyl
422
SMe
Ph
R'
R''
R' ; Ar(K 2 CO 3 )
alkyl (Cs 2 CO 3 )

L. Joseph et al /International Journal of Pharmaceutical Sciences Letters 2014 Vol. 4 (4)| 417-431
is catalyzed by copper (ii) oxide nanoparticle in DMSO
under air. The heterogeneous catalyst can be recovered
and recycled without loss of activity.
C.Y Chen, T.Andreani et al 2011 proposed a divergent
and regioselective synthesis of either 3-substituted benzisoxazoles
or 2-substituted benzoxazoles from readily
accessible ortho hydroxy aryl N-H ketimines proceeds in
two distinct pathways through a common N-Cl imine
intermediate (a) N-O bond formation to form benisoxazoles
under anhydrous conditions and (b) NaOCl mediated
Beckmann- type rearrangement to form benzoxazole
respectively .
R
R'
OH
N
H
3 eq.NaOCl
(10% aq)
iPrOH
r.t,10-30 min
Table 2. Pharmacological Activity of Oxazole and its
Derivatives
Chemical structure
O
N
Treatment of type II
diabetes.
N
O
CH 3
O
S
O
CH 3
O
OH
Insulin sensitizing effects,
treatment of
type II diabetes
N
CH 3
O
O
O
S
N
H
Ditazole is a platelet
aggregation inhibitor
N
O
OH
OH
Oxazolone
Heterocyclic 1 compounds which have a characteristic role
in the synthesis of several organic molecules including
amino acids, amino alcohols, thiamine, amides, peptides
and poly functional compounds are called oxazolones.
Certain natural and synthetic oxazolone also including
benzoxazolone derivatives possess important biological -
R
N
O
R' ;alkyl
Name of compound
(2S)-2-methoxy-3-[-4-[2-(5-
methyl-2-phenyl-4-oxazolyl)
ethoxy]-7-benzothiophenyl]
propanoic acid.
(Aleglitazar)
5-[(4-[3-(5-methyl-2-phenyl-
1,3-oxazol-4-yl)propanoyl)
phenyl)methyl]-1,3-
thiazolodine-2,4-dione
(Darglitazone)
2,2 1 -(4,5-Diphenyloxazol-2-
ylazanediyl)diethanol
R'
activities; such as antimicrobial, anti inflammatory,
anticancer, anti-HIV, anti angiogenic, anticonvulsant,
antitumor, antagonistic, sedative and cardio tonic activity.
Various alkaloid skeletons, immunomodulators and
biosensors or photosensitive composition devices for
proteins are constructed using oxazolones as synthones.
They exhibit promising photo physical and photochemical
activities, so they are used in semiconductor
devices such as electro photographic photoreceptors
and in non-linear optical materials.
Oxazolone [27] has cyclooxygenase-2 inhibitory property
and tyrosinase inhibitory property. Oxazol-5(4H)-
ones, also known as azlactones, is readily prepared
from N-protected amino acids by dehydration. Ringopening
of oxazolone leading to an enantiomerically
enriched N-protected phenylalanine esters and peptidoalcohols.
Oxazolone show interesting behavior towards
polymerization and condensation leading to homo
polymers, telomeres, condensation reagents, peptides,
herbicides, fungicides, pesticides and agrochemical
intermediates. Oxazolone plays very vital role in the
manufacturing of various biologically active drugs as
analgesic, anti-inflammatory, antidepressant, anticancer,
anti-microbial, anti-diabetic and anti obesity.
Synthesis- Scheme 1
Synthesis of oxazolone from indolmycin In the presence
of carbonyldiimidazole (CDI) K. Shankaran et al
reported that the benzoxazolone prepared from pyridine
analogues in good yields.
NH 2
CDI, CH 2
Cl 2
H
H 3 C N OH 3 C N
Scheme 2
Synthesis of benzoxazol-2(3H)-ones from 1-(2-
hydroxyphenyl) ureas Benzoxazol-2(3H)-ones were
synthesized in excellent yields by refluxing 1,1'-
carbonyldiimidazole and 2-aminophenol in dry THF
for 4h by Nachman et al.
O
N N
H
NH 2
N
R 1 OH THF R 1 O
R 2 R 2
Scheme 3
Synthesis of 4-methyloxazol-2-one using carbon dioxide
Michele C. Kelly et al reported that highly alkali-labile
oxazolone was prepared upon hydrolysis of guanine.
Wide variety of oxidation reactions were targeted on
the most susceptible DNA which are mediated by OH
radicals, singlet oxygen, peroxynitrite and one electron
oxidants.
H
N
O
O
423
O

N H 2
HN
HO
N
L. Joseph et al /International Journal of Pharmaceutical Sciences Letters 2014 Vol. 4 (4)| 417-431
O 2
, H 2
O
H
N
N
O
N
H 2 N
H 2 N
O
N
O
NH 2
NH 2
NH 2
CH 3
Table 3. Pharmacological activities of Oxazolones and its
derivatives
Chemical structure
C H 3
H
N
O
O
O
O
O
Antimicrobial
O
Antimicrobial
N
Cl
O
N
O
N + O -
Nitric oxide synthase Inhibitor
Name of compound
5-Methyl-3Hbenzooxazol-2-one
2-(2-Chloro-4-nitro-
phenyl)-4-
furan -2-ylmethylene-
4H-oxazol-5-
one
4-(3-Chloro-
benzylidene)-2-
phenyl-4H-oxazol-5-
one
ISOXAZOLE
Isoxazole [1] is an azole with an oxygen atom next to the
nitrogen. It is also the class of compounds containing this
ring. Isoxazolyl is the univalent radical derived from
isoxazole. Isoxazole rings are found in some natural products,
such as ibotenic acid. Isoxazoles also form the basis
for a number of drugs, including the COX-2 inhibitor
valdecoxib. A derivative, furoxan, is a nitric oxidedonor.
An isoxazolyl group is found in many beta-lactamase
-resistant antibiotics, such as cloxacillin, dicloxacilllin
and flucloxacillin. The synthetic androgenic steroid
danazol also has an isoxazole ring. Isoxazoles are
useful isosteres of pyridine, and have been found to inhibit
voltage-gated sodium channels to control pain, enable
the construction of tetracycline antibiotic derivatives,
and as treatment of depression.
Synthesis- SCHEME 1
AuCl 3 -catalyzed [37] cycloisomerization of α,βacetylenic
oximes leads to substituted isoxazoles in very
good yields under moderate reaction conditions. The
methodology is amenable for the selective synthesis of 3-
substituted, 5-substituted or 3,5-disubstituted isoxazoles.
SCHEME 2
Cycloadditions of copper (I) acetylides to azides and
nitrile oxides provide ready access to 1,4-disubstituted
1,2,3-triazoles and 3,4-disubstituted isoxazoles, respectively.
The process is highly reliable and exhibits an
unusually wide scope with respect to both components.
Computational studies revealed a nonconcerted mechanism
involving unprecedented metallacycle intermediates
[8].
Ar
SCHEME 3
Various [26] 3-substituted and 3, 5-disubstituted isoxazoles
have been efficiently synthesized in good yields
by the reaction of N-hydroxyl-4-toluenesulfonamide
with α, β-unsaturated carbonyl compounds. This strategy
is associated with readily available starting materials,
mild conditions, high regioselectivity, and wide
scope.
Ar
AuCl 3 -catalyzed cycloisomerization of α,β-acetylenic
oximes leads to substituted isoxazoles in very good
yields under moderate reaction conditions. The methodology
is amenable for the selective synthesis of 3-
substituted, 5-substituted or 3,5-disubstituted isoxazoles.
Ar
OH
N
+ R
Cl
O
OH
N
Cl
H
4 eq
+ TsNHOH
+ R'
2mol %CuSO 4. 5H 2 O
10 mol-%sodium ascorbate
4.3 eq.KHCO 3
H 2 O/tBuOH(1:1),r.t,1-4 hr
5eq.K 2 CO 3
MeOH/H 2 O (9:1)
r.t.. 10hr
2mol-%CuSO 4. 5H 2 O
10mol-% sodium ascorbate
4.3 eq.KHCO 3
H 2 O/tBuOH(1:1),rt 1-4 hr
2.5eq.K 2 CO 3
60 0 C..,4hr
Cycloadditions of copper (I) acetylides to azides and
nitrile oxides provide ready access to 1,4-disubstituted
1,2,3-triazoles and 3,4-disubstituted isoxazoles, respectively.
The process is highly reliable and exhibits an
unusually wide scope with respect to both components.
Computational studies revealed a nonconcerted mechanism
involving unprecedented metallacycle intermediates.
Ar
Ar
N
O
R'
R;Ph,CH 2 OH
CO 2 H
N
R'
O
N
R: Ph,CH 2 OH,COOH
O
R
N
OH
R'
1 mol %AuCl 3
CH 2 Cl 2 .30 0 C ,10-30 min
R
N
O
R'
R ; Ph,Me,H
R' Ar,alkyl,SiMe 3, H
Ar
O
H
4 eq
+ TsNHOH
5eq.K 2 CO 3
MeOH/H 2 O (9:1)
r.t.. 10hr
2.5eq.K 2 CO 3
60 0 Ar
C..,4hr N
O
.
424

L. Joseph et al /International Journal of Pharmaceutical Sciences Letters 2014 Vol. 4 (4)| 417-431
Various 3-substituted and 3,5-disubstituted isoxazoles
have been efficiently synthesized in good yields by the
reaction of N-hydroxyl-4-toluenesulfonamide with α,βunsaturated
carbonyl compounds. This strategy is associated
with readily available starting materials, mild conditions,
high regioselectivity, and wide scope.
Ar
R'
N
O
N
1.5eq.MCPBA
DCM
rt.4hr
Enamine-triggered [3+2]-cycloaddition reactions of aldehydes
and N-hydroximidoyl chlorides in the presence of
triethylamine gives 3, 4,5-trisubstituted 5-(pyrrolidinyl)-
4,5-dihydroisoxazoles. Subsequent oxidation of the
cycloadducts offers a high yielding, regiospecific and
metal-free synthetic route for the synthesis of 3,4-
disubstituted isoxazoles. The sequential use of iron and
palladium catalysts in an uninterrupted four-step sequence
allows the synthesis of trisubstituted isoxazoles
from readily available propargylic alcohols. The advantages
of such a strategy are illustrated by the high overall
yields and the time-saving procedure.
Ar
OH
R :Me,Bu
R
+ 1.1 eq
CbzNHOH
The direct regioselective synthesis of 3,5-disubstituted
isoxazoles was achieved through a sequence involving a
net bromination of an electron-deficient alkene, in situ
generation of a nitrile oxide, 1,3-dipolar cycloaddition,
and loss of HBr from an intermediate bromoisoxazoline.
This one-pot process enables the direct synthesis of 3,5-
disubstituted isoxazoles from electron-deficient alkenes.
Ar
R'
N
1)5oml-%MeCN,60 0 C,2hr
2)2eq.Ar'-1,0.1 eqPd 2 dba 3 ,
0.2 eq.bpy, 4eqK 2 CO 3 ,50 0 C
3)removal of MeCN
4)MeOH,H 2 (1atm),r.t.2 hr
5)air,50 0 C,6hr
O
R' ; iPr,Ph
N
Ar
O
Ar'
R
R
Alumino-heteroles are obtained from simple precursors
in a fully chemo- and regioselective manner by a metalative
cyclisation. The carbon-aluminum bond is still
able to react further with several electrophiles, without
the need of transmetalation providing a straightforward
access to 3,4,5-trisubstituted isoxazoles and 1,3,4,5-
tetrasubstituted pyrazoles.
A large number of functionally substituted 2-alkyn-1-
one O-methyl oximes have been cyclized under mild
reaction conditions in the presence of ICl to give the
corresponding 4-iodoisoxazoles in moderate to excellent
yields. The resulting 4-iodoisoxazoles undergo
various palladium-catalyzed reactions to yield 3,4,5-
trisubstituted isoxazoles.
Ar
YH 1)1 eq.AlMe 3
HN toluene,r.t..,5 min
R
N
Cl
N
OH
Cl
2)1 eq,
50 0 C, 1hr
OMe
R'
R' AlMe 3 N
2 eq
+ I R
1.2 eq.ICI
A thermally promoted cycloaddition between alkynyliodides
and nitrile oxides offers excellent regioselectivity
and a broad scope with respect to both starting
materials. Further functionalization of the highly decorated
iodoisoxazole motifs can be achieved via Suzuki
cross-coupling.
R
CH 2 Cl 2 ,r.t .,0.5 - 6 hrs
Y
Al
R'
4 eq
EX
r.t,o.n
1.05 eq.Na 2 CO 3 (0.025M)
in H 2 O,added over 24 hrs
DMF,100 0 C,24 hrs
N
R
N
R
Y
E
R'
E (EX)
D (MeODS) 25 eq
Cl(NCS),(NIS)
CONH 2 (Cl 3 )C-NCO
O
N
Ar
I
O
R'
R; alkyl
I
R
EWG 1.1eq.Br 2
+
CH 2 Cl 2
r.t,1-3hr
2 mol-%PdCl 2 (PPh 3 )
4 mol-%CuI
1.05 eq.Et 3 N
THF,r.t.,1 hr
HO
N
Cl
O
R
Ar
R'
EWG
Br
-
O
+ N +
1 eq. N
OH
Cl
Ar
1.1 eq.Et 3 N
MW,90 0 C,30 min
EWG
R
R'
O
O
O
N
Ar
Ar
N
+ R
PhSe
HON
1 eq.NCS
1.05 eq.NEt 3
CHCl 3,r.t.,12 hr
PhSe
O
N
A 1,3-dipolar cycloaddition of phenyl vinylic selenide
to nitrile oxides and subsequent oxidation-elimination
furnished 3-substituted isoxazoles with good yields in a
one-pot, two-step transformation.
R
+
O
N
SePh
R
30% H 2O 2
0 0 C,10 min. O
r.t, 20 min
N
R
R
The consecutive Sonogashira coupling of acid chlorides
with terminal alkynes, followed by 1,3-dipolar cycloaddition
under dielectric heating of in situ generated nitrile
oxides from hydroximinoyl chlorides furnishes isoxazoles
in moderate to good yields in the sense of a one-pot threecomponent
reaction
R NO 2
+ Ph
0.5 eq.DABCO
N
CHCl 3
60 0 C,20-80 hr
Ph
O
The dehydration of primary nitro compounds can be
performed by bases in the presence of dipolarophiles.
Among the organic bases examined, DABCO gave the
best results. The reaction is applicable to activated nitro
compounds and to phenylnitromethane and affords
425

L. Joseph et al /International Journal of Pharmaceutical Sciences Letters 2014 Vol. 4 (4)| 417-431
-affords isoxazoline derivatives in higher yields compared
with those of other methods. The reaction, however, is
not compatible with nitroalkanes.
R
O
H
1)1.05 eq.H 2 NOH.HCl,1.05 eqNaOH
tBuOH/H 2 O (1:1),30 min (TLC)
2)1.05 eq.TsN(Cl)Na.3H 2 O
3)1.05 eq. R' 3 mol - %CuSO 4
approx.3.7 mol-%Cu,r.t ,6 hr
3,5-Disubstituted isoxazoles are regioselectively obtained
in good yields by a mild and convenient one-pot,
three-step procedure utilizing a copper(I)-catalyzed
cycloaddition reaction between in situ generated nitrile
oxides and terminal acetylenes. Pyrazole or isoxazole
derivatives are prepared by a palladium-catalyzed fourcomponent
coupling of a terminal alkyne, hydrazine
(hydroxylamine), carbon monoxide under ambient pressure,
and an aryl iodide.
R
The reaction of various 2-alkyn-1-one O-methyl oximes
with ICl, I 2 , Br 2 , or PhSeBr provided 3,5-disubstituted 4-
halo(seleno)isoxazoles in good to excellent yields under
mild reaction conditions.
R
N
OMe
R'
1.2 eq.ICI
CH 2 Cl 2 . r.t...,
0.25- 0.75 hrs
A series of 4-alkyl-5-aminoisoxazoles have been synthesized
in high yield by nucleophilic addition of lithiated
alkyl nitriles to (α)-chlorooximes.
Various substituted benzisoxazoles have been prepared
by a [3 + 2] cycloaddition of nitrile oxides and arynes.
Both highly reactive intermediates, have been generated
in situ by fluoride anion from readily prepared aryne precursors
and chlorooximes. The reaction scope is quite
general, affording a novel, direct route to functionalized
benzisoxazoles under mild reaction conditions .
R
N
OH
Cl
2 eq
+
R'
SiMe 3
OTf
4 eq
+
Cl
R'
CN
R
N
N
OH
OH
4 eq.tBuOH
THF
78 0 C,15 min
6 eq.CsF
MeCN,r.t,8.5 hr
1.5 eq NCS
2 EQ.K 2 CO 3
R
N
R
O
R'
R
N
R
N
O
O
I
R'
R'
NH 2
R : Ar,alkyl
R' alkyl,benzyl,Ar
O
R
N
R : aryl,iPr,vinyl
R'
N
A divergent and regioselective synthesis of either 3-
substituted benzisoxazoles or 2-substituted benzoxazoles
from readily accessible ortho-hydroxyaryl N-H
ketimines proceeds in two distinct pathways through a
common N-Cl imine intermediate: (a) N-O bond formation
to form benzisoxazole under anhydrous conditions
and (b) NaOCl mediated Beckmann-type rearragement
to form benzoxazole, respectively.
R'
R
R''
5 mol-%FeBr 2
O
MS4A
CH
N 2 Cl 2 ,40 0 C,16hr
3
Table 4. Pharmacological activity of Isoxazole and Its
Derivative
Chemical structure
C H 3
ABT-418- Treatment of
Alzheimer’s disease and
ADHD
N
O
OH
N
CH 3
O
H
C H 3
NH 2
N
OH
AMPA- Specific agonist
AMPA receptor, mimic
effect of neurotransmitter
glutamate
Used in combination with
metal compound in asymmetric
synthesis as a chiral
catalyst Bisoxazoline ligand
OXADIAZOLE
Oxadiazole [9] is a heterocyclic aromatic chemical
compound with the molecular formula C 2 H 2 N 2 O. There
are four isomers of oxadiazole:
O
O
N
N
O
N
O
O
N
R
R'
N
R''
O
R:H.Cl
R' : H,Me.OMe
R'' : Ar,alkyl
Name of compound
3-methyl-5-[(2S)-1-
methylpyrrolidin-2-
yl]-1,2-oxazole
2-amino-3-(3-
hydroxy-5-methylisoxazol-4-yl)
propanoic acid
2,6-Bis[4R]-4-phenyl
-2-oxazolinyl]
pyridine
O
O
OH
THF,r.t,12 hr
O
R' alkyl,Ar
N
N
1,2,3-OXADIAZOLE
N
N
N
1,2,4-OXADIAZOLE 1,2,5-OXADIAZOLE 1,3,4-OXADIAZOLE
N
N
426

L. Joseph et al /International Journal of Pharmaceutical Sciences Letters 2014 Vol. 4 (4)| 417-431
Out of its four possible isomers, 1, 3, 4-oxadiazole is
widely exploited for various applications. A numbers of
therapeutic agents such as HIV-integrase inhibitor raltagravir,
a nitrofuran antibacterial furamizole, a potent PDF
inhibitor BB-83698, antihypertensive agents tiodazosin
and nesapidil are based on 1,3,4-oxadiazole moiety. The
1, 3, 4-oxadiazole undergoes number of reactions including
electrophillic substitution, nucleophilic substitution,
thermal and photochemical. The present review
attempts to summarize the various routes of synthesis
and the reactions of 1, 3, 4-oxadiazole and its
derivatives and focus on their biological potential [21].
Synthesis- Scheme 1
A direct [23] access to symmetrical and unsymmetrical
2,5-disubstituted [1,3,4]-oxadiazoles has been accomplished
through an imine C-H functionalization of N-
arylidenearoyl hydrazide using a catalytic quantity of Cu
(OTf) 2 . These reactions can be performed in air atmosphere
and moisture making it exceptionally practical for
application in organic synthesis.
Ar
H
N
O
NH
Ar'
Scheme 2
A facile and general protocol [25] for the preparation of 2
-amino-1, 3, 4-oxadiazoles relies on a tosyl chloride/
pyridine-mediated cyclization of thiosemicarbazides that
consistently outperforms the analogous semicarbazide
cyclizations. Various 5-alkyl- and 5-aryl-2-amino-1,3,4-
oxadiazoles have been prepared in good yields.
R HN NH NH
Scheme 3
An oxidative [11] desulfurization approach enables the
construction of oxadiazole and thiadiazole heterocycles in
the presence of iodobenzene and Oxone. The use of iodobenzene
and the inexpensive readily available oxidant
Oxone makes the reaction system simple and versatile for
desulfurization.
Synthesis of 1, 3,4-oxadiazoles
Ar
Ar
O
HN
H
N
O
S
NH
O
N
S
NH
R'
Ar'
R
0.1 eq.Cu(OTf) 2
1 eq Cs 2 CO 3
DMF,AIR
110 0 C,10-24 HR
1.2 eq.TsCl
2.1 eq.pyridine
THF,60-70 0 C,20hrs
2 eq.PhI
4 eq.oxone
2 eq.NEt 3
MeOH,r.t,40 min
0.1 eqCu(OTf) 2
1 eq.Cs 2 CO 3
DMF,air,
110 0 C,10-24 hr
A direct access to symmetrical and unsymmetrical 2,5-
disubstituted [1,3,4]-oxadiazoles has been accomplished
Ar
Ar
R
Ar
N
N
O
N
N
O
N
O
N
N
NH
Ar'
NHR'
R
R : Ar,Et,Bn
O
N
Ar'
through an imine C-H functionalization of N-
arylidenearoylhydrazide using a catalytic quantity of
Cu(OTf) 2. These reactions can be performed in air atmosphere
and moisture making it exceptionally practical
for application in organic synthesis.
R
A facile and general protocol for the preparation of 2-
amino-1,3,4-oxadiazoles relies on a tosyl chloride/
pyridine-mediated cyclization of thiosemicarbazides
that consistently outperforms the analogous semicarbazide
cyclizations. Various 5-alkyl- and 5-aryl-2-amino-
1,3,4-oxadiazoles have been prepared in good yields.
Ar
O
HN N
H
HN
An oxidative desulfurization approach enables the construction
of oxadiazole and thiadiazole heterocycles in
the presence of iodobenzene and Oxone. The use of
iodobenzene and the inexpensive readily available oxidant
Oxone makes the reaction system simple and versatile
for desulfurization.
R
S
R'
1.2 EQ. TsCl
2.1 eq.pyridine
THF,60-70 0 C,20 hr N N
The reaction of a thiosemicarbazide intermediate with
EDC· HCl in DMSO or p-TsCl, triethylamine in N-
methyl-2-pyrrolidone gives the corresponding 2-amino-
1, 3,4-oxadiazoles and 2-amino-1,3,4- thiadiazoles
through regioselcective cyclization processes.
Ar
N
H
O
O
HN
S
OH
S
NH
N
H
R
NH
N
H
O
Ar
2 eq.PhI
4 EQ.Oxone
2 eq.NEt 3
MeOH,r.t,40 min
1.2 eq,EDC.HCl
DMSO
60 0 C,2 hr
+
Ph3 P N NC + R
O
4 eq
H
CH 2 Cl 2
R.T,24 hr
HN
R
N-Isocyaniminotriphenylphosphorane, aldehydes, and
benzoic acids undergo a one-pot, three-component reaction
under mild conditions to afford 2-aryl-5-
hydroxyalkyl-1, 3,4-oxadiazoles in good yields. Symmetric
and unsymmetric 1, 3,4-oxadiazoles were synthesized
in situ from hydrazine hydrate and the corresponding
2-acyl-4,5-dichloropyridazin-3-ones as acylating
agents in polyphosphoric acid (PPA) or
BF 3·OEt 2 in excellent yields. A simple and straightforward
method for the direct carboxylation of aromatic
heterocycles such as oxazoles, thiazoles, and oxadiazoles
using CO 2 as the C1 source requires no metal
catalyst and only Cs 2 CO 3 as the base. A good functional
group tolerance is achieved.
R
N
O
N
Ar
N
O
O
N
N
Ar
O
NH
427
NHR'
R : Ar,Bn
R
R;benzyl,
Ar,alkyl
N
R
OH

L. Joseph et al /International Journal of Pharmaceutical Sciences Letters 2014 Vol. 4 (4)| 417-431
Synthesis of 1, 2,4-oxadiazoles
PTSA-ZnCl 2 is an efficient and mild catalyst for the synthesis
of 3,5-disubstituted-1,2,4-oxadiazoles from amidoximes
and organic nitriles.
R
Ar CN
OH + NC R'
N
1eq.NH 2 OH (50%)aq.
AcOH (cat)
neat MW,100 0 C,1 MIN
0.3 eq.PTSA
0.3 eq.ZnCl 2
DMF.80 0 C,4-8 hrs
or MeCN (R'=Me),70 0 C,1-2 h
Ar
NH 2
NOH
R
O
O
R
1eq
O
O
N
N
O
Ar
N
R'
R,R' : Ar.alkyl
benzyl
O
N
R
R ; H,Me
SYNTHESIS- Scheme 1
A four-step [10] synthesis of cis-3,5-disubstituted morpholines
from enantiomerically pure amino alcohols is
described. The key step in the synthesis is a Pdcatalyzed
carboamination reaction between a substituted
ethanolamine derivative and an aryl or alkenyl
bromide. By this method morpholine derivatives were
prepared by Branden R Rosen, jhon p wolfe et al.
HN
OH
Boc
3 steps
Ar
HN
O
R
R'-Br
Pd-catalyst
base
R'
Ar
N
O
R
20:1 dr
A one-pot reaction between nitriles, hydroxylamine
and Meldrum’s acids under microwave irradiation and
solvent-free conditions gives 3,5-disubstituted 1,2,4-
oxadiazoles in good to excellent yields.
Scheme 2
OH
H 3C
+
COCl
R 1
R 2
10% NaOH
stirring
R 3
R 2
R 1
anhydr.AlCl 3
80-90 0 C
Ar
OH
N
NH 2
+ HO
O
R
O
OEt
1.1 eq.DCC
dioxane
110 0 C,8-12 hr
Ar
N
N
O
R
O
OEt
R 3
H 3C
O
O
R 2
A series of α-amino acid-derived 1,2,4-oxadiazoles have
been synthesized via a convenient and inexpensive onepot
protocol in good yields and in relatively short reaction
times.
Table 5. Pharmacological activity of Oxadiazole and its
derivatives
Chemical structure
O
N
N
O
O
Pharmacological action
Anti mycobacterial
R3
R 1
OH
O
anhydr.K 2CO 3
DMSO
CH 3
a;R 1 =R 2 =H,R 3 =OCH 3
c;R 1 =CH 3 ,R 2 =R 3 =H
e;R 1= R 3 =H,R 2 =Cl
g; R 1 =R 2 =H,R 3 =Br
i ;R 1 =R 2 =H,R 3 =Cl
Cl
N
R 3
O
R 2
H 3C
R 1
O
O
b; R 1 =R 2 =H,R 3 =CH 3
d ; R 1 =R 3 =H,R 2 =CH 3
f ; R 1 =Br,R 2 =R 3 =H
H ; R 1 =R 2 =H,R 3 =F
j ; ;R1=R 2 =R 3 =H
N
O
C H 3
N
O
N
N
O
N
N
O
N
O
S
Morpholine
Morpholine[20] is an organic chemical compound having
the chemical formula O(CH 2 CH 2 ) 2 NH. This heterocycle,
pictured at right, features both amine and ether functional
groups. Because of the amine, morpholine is a base;
its conjugate acid is called morpholinium. For example,
neutralizing morpholine with hydrochloric acid makes the
salts morpholinium chloride.
Br
O CH3
Anti convulsant
Anti inflammatory
substituted 2-methylphenyl benzoates (3a-j) were synthesized
by stirring 2-methyl phenol (1, 1 equivalent)
with corresponding benzoyl chlorides (2a-j, 1 equivalent)
for 30 minutes in alkaline medium using 10%
sodium hydroxide solution with excellent yield (85–
90%). Substituted hydroxyl benzophenones (4a-j) were
synthesized by refluxing a mixture of 3a-j (1 equivalent)
and anhydrous aluminium chloride (1.5 equivalents)
for 20 minutes with 80–83% yield. Condensation
of 4a-j (1 equivalent) with 4-(2-chloroethyl) morpholine
hydrochloride (1 equivalent) for 3 hours in
presence of anhydrous potassium carbonate (1.5
equivalents) and dimethyl sulphoxide furnished substituted
benzophenone-N-ethyl morpholine ethers with 70
–75% yield.
Scheme 3
Morpholine may be produced by the dehydration of
diethanolamine with sulfuric acid was prepared by
Klaus Weissermel, Hans-Jürgen Arpe, Charlet R. Lindley,
Stephen Hawkins et al.
428

HO
L. Joseph et al /International Journal of Pharmaceutical Sciences Letters 2014 Vol. 4 (4)| 417-431
H
N
OH
H 2 SO 4
H 2 O
Pharmacological activity of Morpholine &its derivatives
4-Phenyl morpholine derivatives have been reported to
possess anti-inflammatory antimicrobial and central
nervous system activities . Schiff bases have been reported
to possess biological properties apart from antimicrobial
activities . In our previous work , it was observed
that substitution of 4-phenyl morpholine to quinazoline
moiety results in potent analgesic, anti-inflammatory, and
antimicrobial activities.
Synthesis of isoxazolyltriazole derivatives as fungicides
With a view to obtaining biologically active isoxazole
derivatives containing triazole moiety, synthesis of a series
of compounds have been conceived and the synthetic
strategy is described in the Scheme 3. The triazole moiety
has been found to be an important taxophore to exhibit
fungitoxic properties inhibiting the cell wall synthesis and
also known as C-14 demethylation inhibitor (to act as
fungicide). Most of the exploited azole fungicides contain
an aromatic ring system, and to the best of the author’s
knowledge no compound with isoxazole heterocyclic
moiety has so for been synthesized and studied for their
fungitoxic properties.
Scheme 3
O
R
CH 3 COOEt
COOEt (NH 2 -OH) 2 H 2 SO 4
R R
NaOMe
MeOH
7a-k
MeOH
8a-k
Transesterification
R
K 2 CO 3
Acetonitrile
O
N
13a-k
COOEt
HN
N
N
N
12
N
N
R
O
O
O
11a-k
N
CH 2 Cl
SOCl 2, DMF
Heptane R
65-8 0 C
The target molecule 5-aryl-3-(4H-1,2,4-triazol-4-yl
methyl) isoxazole (13a-k) is prepared by N-alkylation of
1H-1,2,4-triazole (12) with 5-aryl-3-chloromethyl- isoxazole
under mild basic conditions using different bases in
polar solvent (Scheme 5). The yields obtained are in the
range of 80-90 %. The possibility of formation of C-4
alkylated product is ruled out based on the unequivocal
characterization of the product using spectral data. The
target molecule 5-aryl-3-(4H-1,2,4-triazol-4-yl methyl)
isoxazole (13a-k) is prepared by N-alkylation of 1H-1,2,4
-triazole (12) with 5-aryl-3-chloromethyl- isoxazole under
mild basic conditions using different bases in polar
solvent (Scheme 5). The yields obtained are in the range
of 80-90 %. The possibility of formation of C-4 alkylated
product is ruled out based on the unequivocal characterization
of the product using spectral data.
O
9a-k
O
10a-k
N
N
H
N
O
COOMe
NaBH 4
AlCl 3 , THF
Reflux
R = H, 2-Cl, 2-OMe, 3-Cl, 3-OMe, 4-Me, 4-Cl, 4-Br, 4-F, 4-OMe, 2,4-diOMe.
CH 2 OH
Scheme 4
R
O
N
HN N
CH 2 Cl +
N
K 2 CO 3 , CH 3 CN
Reflux
11a-k 12 13a-k
R = H, 2-Cl, 2-OMe, 3-Cl, 3-OMe, 4-Me, 4-Cl, 4-Br, 4-F, 4-OMe, 2,4-diOMe
Preparation of 2-isoxazolyl benzimidazole derivatives
Some of the benzimidazole derivatives containing a
heterocyclic moiety at 2-position are thiabendazole
(17) and cambendazole (18) which are commercially
important.
N
N
N
S
N
H
H
Thiabendazole (17) Cambendazole (18)
To synthesize novel 2-isoxazolyl substituted
benz- imidazoles using N-butyl-N,N-dimethyl-aphenylethylammonium
bromide (16) as the catalyst.
Retro synthetic analysis of target molecules requires
appropriately substituted 5-aryl-3-isoxazol carbaldehyde
(19a-i) as an active intermediate. The sequence of
synthetic methodology is depicted below (Scheme 6)
and each step of synthesis has been discussed in detail.
The reaction of o-phenylenenediamine (OPDA) and 5-
aryl-3-isoxazolecarbaldehyde at reflux temperature of
1,2-dichloroethane in the presence of 10 mol % of catalyst
for 3-4 hours to give title compounds (21a-m).
R 1
O N
9 a-i
COOMe
Reduction
i-PrOCOHN
R 1 = H, 2-Cl, 3-Cl, 3-OMe, 4-Me, 4-Cl, 4-Br, 4-F, 4-OMe. R = H, OMe
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Cite this article as:
Lincy Joseph, Mathew George and Surekha SR.
Synthetic Strategy and Therapeutic Utility of Oxygen
and Nitrogen Containing Heterocyclic Compounds.
Int. J. Pharm. Sci. Lett. 2014 : 4: (2) 417-431
Source of Support: Nil.
Conflict of interest: None declared.
431