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ABSTRACT
In this paper the importance of microwave assisted synthesis of
fused heterocyclic compounds has been discussed extensively.
Microwave assisted organic synthesis is an enabling technology for
Synthesis.
For Correspondence:
drug development process. Since the last few years, high speed
Anshul Chawla *
Address:
Asst. Professor
Pharmaceutical chemistry
CT Institute of
displaying
Pharmaceutical Sciences,
antimicrobial,
Shahpur, Jalandhar
(Punjab)-144020.
broad
spectrum
cytotoxic
antimycobacterial,
of
to
biological
tumor
anticonvulsant,
activities
cells,
like
anticancer,
anti-inflammatory,
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INTRODUCTION:
Conventional thermal heating suffers from common limitations such as drastic reaction
conditions,
time consuming, excessive use of solvent and several side reactions. Rapid expansion and popularity
of assisting a wide range of organic reactions by exposure to microwave have been accompanied by
achieving reactions under solvent-free conditions, reducing reaction times, and increasing the yield
of products and even selectivity. Moreover, in addition to the economic impact, there are additional
advantages such as the use of noncorrosive, inexpensive, and environment friendly catalysts, thus
leading to eco-friendly approaches known as green chemistry, in comparison with their
conventional thermal heating counterpart. [1]
Some publications recognize the twelve principles of green chemistry, like prevention, atom
economy, less hazardous chemical synthesis, designing safer chemicals, safer solvents and
auxiliaries, design for energy efficiency, use of renewable feedstocks reduce derivatives, catalysis,
design for degradation, real-time analysis for pollution prevention, inherently safer chemistry for
accident prevention. [2] As anyone who has ever spilled the contents of a food container onto the
floor well knows, it is better to not make a mess than to clean it up once made. As applied to green
chemistry, this basic rule means that waste prevention is much better than waste cleanup. Failure to
follow this simple rule has resulted in most of the
causing problems throughout the world today. One of the most effective ways to prevent generation
of wastes is to make sure that insofar as possible all materials involved in making a product should
be incorporated into the final product. Therefore, the practice of green chemistry is largely about
incorporation of all raw materials into the product, if at all possible. The practice of green chemistry
is making substantial progress in designing chemicals and new approaches to the use of chemicals
such that effectiveness is retained and even enhanced while toxicity is reduced. [3] This section
addresses the main ones of these. The growing number of publications in microwave-assisted
synthesis includes virtually all types of chemical reactions such as additions, cycloadditions,
substitutions, eliminations, fragmentations etc. All these have attracted our attention to review the
available literature on the role of microwaves in the field of heterocyclic chemistry, bearing in mind
that most biologically active compounds are heterocyclics. Heterocycles have either fused benzene
or other heterocyclic rings. The fused heterocyclic compounds are located according to the
heterocycle that was built under microwave irradiation or as a reaction of these heterocyclics acting
as precursors. [4] In the present review, we are trying to highlight some of the applications of
microwave methodology in heterocyclic chemistry. Fused heterocyclic compounds are reviewed by
presenting their methods of preparation of the desired ring, through microwaves. As their biological
actions such as antimicrobial activity through DNA gyrase-B, antioxidant activity against
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superoxide and hydroxyl radicals, antimicrobial activity against E. coli and S. aureus, antibiotic and
cytotoxic activities, anti-inflammatory, antiaging, and anticancer activity, potent nonpeptidic
inhibitors of HIV protease. They exhibit a broad range of biological activities including
anticoagulation, antifungal, anti-psoriasis etc. [5] Undoubtedly, microwaves are going to be highly
important in future synthesis of heterocyclic compounds.
Nomenclature of the fused ring system:
As the present review deals with the synthesis of heterocyclic fused ring systems, its nomenclature
is herewith shortly discussed. The nomenclature follows the following rules:
1) The individual components are named without any application of fused ring system.
2) The parent component is represented in the fusion name by citing it last in the name. The parent
component is the one with highest priority according to the following criteria:
a) A heterocyclic component containing the heteroatom occurring earliest in the order: N,
F, Cl, Br, I, O, S, Se, Te, P, As, Sb, Bi, Si, Ge, Sn, Pb, B, Hg.
b) A component containing the larger ring.
c) A component containing the greater number of heteroatoms.
d) A component containing the greater variety of heteroatoms.
3) The attached component is then added as a prefix to the parent component. In the name of
the prefix, the terminal 'e' is changed to 'o'.
4) The bonds of the parent component are indicated by a,b,c...starting with the bond normally
occupying the 1,2 positions. The atoms of the attached component are numbered as usual,
following the order of numbers in the original heterocycle.
5) The numbering of the final condensed heterocycle is carried out independently, starting at
an atom adjacent to a bridged-head atom, whereby heteroatoms receive the smallest possible
number. [6]
Evolution of Some Heterocyclic Compounds:
All most all the heterocyclic compounds have most potent pharmacological activities, some of them
are reported here as important heterocyclic compounds viz sulfa drugs (1933, as first antibacterial
drug), penicillin (1940, as antibiotics), chloroquine (1945, as antimalarial), methyldopa (1950, as
antidiabetic), chlorthiazide (1957, as diuretic), adrenergic -blocker (1958, as coronary vasodilator),
semi synthetic penicillins (1960, as antibacterial), trimethoprim (1965, as antimicrobial), disodium
chromoglycoate (1967, as antiallergic). [7]
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Compounds
without N,O,S
Compounds with
nitrogen
With
1N
With
2N
With
4N
Compounds with
oxygen
With
1O
Compounds with
N,S
With
2O
a) Naphthalene
b) Anthracene
c) Coronene
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a) Quinoline
N
b) Indole
c) Isoindole
NH
N
H
d) Acridine
H
N
e) Azepine
N
g) Carbazole
f) Pyrrole
N
H
h) Quinoxaline
N
N
b) Indazole
a) Pyrazole
N
H
c) Imidazole
N
N
H
d) Quinazoline
N
H
e) Benzimidazole
H
N
N
(iii) Compounds with 4 nitrogens :
N
a) Purine
N
N
b) Pteridine
N
N
H
N
N
N
N
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a) Benzofuran
O
c) Xanthene
b) Chromene
O
a) Coumarin
O
a) Benzothiophene
S
a) Benzoxazole
N
O
a) Benzothiazole
N
S
respectively)
saturated with
sulfur
a sealed
poly(tetrafluoroethylene) acid digestion vessel and irradiated in microwave for 30 min at 150 Watts
(23% of energy efficiency). [8]
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NH2
H2O, 150OC
(1)
(2)
HO
OH
+
O
Cl
K2CO3
dry IMF, 800C
O
O
(3)
(4)
NH2NH2H2O
O
N
H
O
O
N
H
O
R - CHO H N
2
R
HN
H+, MW
O
O
N
H
NH2
(5)
(6)
anthracene (7) and methyl acrylate (8 ) in xylene (an excellent energy transfer medium) was
irradiated (1000 W) in a microwave oven for 6-8 min, compound (9) was obtained in 70-85% yield.
[10]
6-8 min
MW Irrad.
+
CO2Me
(8)
(7)
24 hr
sealed tube
48 hr
reflux
CO2Me
70-85%
81%
84%
(9)
2. 9- Haloanthracene: Place a nucleophile and an aryl halide (0.1 mmol) in an appropriate solvent
(NMP or DMSO, 1 ml) in a reaction vessel (12 ml). A base [t-BuOK or CsOH (1.1 equiv vs
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- 181 - | P a g e
nucleophile)] or CuI (as indicated in the text) could be added to enhance the reactivity. The reaction
vessel was then placed in microwave reactor and irradiated. [11]
R
Nucleophile, solvent
Microwave
(11)
(10)
Reactions of 9-halophenanthrene with nucleophiles
X
Nucleophile, solvent
R
(13)
(12) Microwave
Reactions of haloanthracene with nucleophiles
O
O
O
a
O
b
(14)
(15)
O
(16)
O
O
O
O
(17)
(18)
(19)
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OCH3
NaOCH3
Cl TBAB/H2O
mw
N
(20)
R
N
(21)
OCH3
OCH3
NaOAc/AcOH
R
N
OCH3
mw
N
H
(23)
(22)
R3
O
R
+ R3
NH2
R1
(24)
O
+
R
(27)
NH2
R2
InCl3/SiO2
MW
R
N
(26)
(25)
R2
InCl3/SiO2
R1
MW
N
(29) H
(28)
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COOMe
N3
NH
R
R
(30)
(31)
Scheme2. Synthesis of indole-2-carboxylates, Reagents and conditions: (i) MW, n-hexane, 2000C,
10 min, 15 bar.
2.
Spiro compound 36/37: Compound (32) (2 mmol) and malononitrile (2 mmol) in absolute
ethanol (5-10 ml) in the absence/presence of piperidine (1 drop) was mixed and the mixture was
irradiated at 340/275 watts. As the reactants disappeared, (34)/ (35) was added, mixed thoroughly
and again irradiated. [16]
S
C6H5N
CN
CN
CN
CH2
CN
NH
S
O
C6H5N
(34)
N O A/B/C/D
H
(32)
N
H
O
NH2
NH
N O
H
(36)
(33)
CN
O
O
O
NH2 (35)
X
S
NH
C6H5N
(33)
(34)
N
H
CN
OH
NH
C6H5N
CH
CN
O
CN
N
H
(37)
CH
O
NH
C 6H 5N
CN
N
H
3.
CN
O
NH2
X
N
H
CN
(38)
and potassium tert-butoxide (268 mg, 2.8 mmol) were mixed and it was irradiated in a microwave
oven (power 1000W) for 20 minutes, reaching a maximum temperature of 330 C. [17]
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+ 3 MgBr
NO2
(39)
N
H
(41)
(40)
Bartoli synthesis
NH2
NH
R
(46)
N
H
(44)
O
2. MeSC(CO)R3
3. base
4. Raney - Ni
NaOEt
3600C
Madelung synthesis
1. t-BuOCl
N
R
(47)
O
(48)
Gassman synthesis
N
H
(42)
Hegedus synthesis
1. DMF/DMA
N
NO2 2.Ni/H2
H
(43)
Batcho- Leimgruber synthesis
1. Pd(II)
2. red
CO2Et
+
H2N
(45)
CO2Et
HO
N
H
(50)
(49) Nenitzescu synthesis
CH3
Br
+
N
H
NH2
(51)
(52)
(53)
t- BuOK
N
H
(54)
N
H
40%
t- BuOK
MW, Tmax 1800 C
N
H
(55)
O
N
(56)
N
H
64%
t- BuOK
MW, Tmax
R
0
160 C N
N
H
(57)
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OMe
SOnPh
PhSCl
90%
OMe (58)
m-CPBA
Cl
59a
OMe (59)
n=0
59b
n=2
DBU
90%
OMe
SO2Ph
CNCH2CO2Et
OMe
OMe
(60)
OMe
R
N
H
NH
tert-BuOK/THF
(61) 85%
MeO
i. LiAlH4
ii. TFA
H
N
R
(62)
MeO
1.
OMe
OMe
OMe
O
R
NH2
O +
(63) O
63, R = H
63, R = Me
R4
R2
R
(64)
R
N
R1
X
R2
R3
X
(65) O R5
R4 (66)
66a-n(R = H, X = C, 34-97%)
67o ( R =H, X = N, 43%)
68a-m (R = Me, X=C, 63-97%)
d) Acridine: Acridine, C13H9N, is an organic compound and a nitrogen heterocycle. Acridine is also
used to describe compounds containing the C13N tricycle. Acridine is structurally related to
anthracene with one of the central CH groups is replaced by nitrogen.
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1. 10-Aryl-3,3,6,6-tetramethyl-1,2,3,4,5,6,7,8,9,10-decahydroacridine-1,8-dioxime (74):
Compound (69) (0.25 mmol), hydroxylamine hydrochloride (1.2 mmol) and sodium acetate (2
mmol) was mixed in ethanol (1 ml) and the mixture was irradiated for 3 min. [20]
O
O
+
ArNH2
Me
O
Me (69)
(70)
HCO2H
1500C, 23 h or Me
Me
MWI 12 min
Ar
71a Ar =Ph71b Ar =4-Cl-C6H471c Ar =pyrid -2-yl
NH2
HCO2H
Me
Me
Me
(71)
Me
NH2OH, HCl or
PhNHNH2
NR
O
O
O
CHO (69)
Me
Me
OH
O
NR
O
Me
Me
(72)
Me
Me Me
Me
O
(73)
Me (74)
Me
N
Ar
N NH2
N NH2
PhCHO
Me
N N = CHPh
O PhCHO/EtOH
Me
(81)
(75)
Me
Me
O
Ph
N N
H
Ph O
(76)
(80)
PhCHO Me
Me
Me
Me
N
N
Me
(77)
Me
Me
Me
O
CHPh
O
N
O
N
H
O
(83)
Me
Me
HO
CHPh
N
(79)
Me
Me
(78)
NH2
CHPh
O
Ph O
N
H
Ph
O
2
HCl
Me
Me
Me
Me
OHHO
(82)
Me
Me
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2.
Substituted 9-(1, 2, 3-Triazol-1-yl) acridines: 9-azidoacridine (0.005 mol) was mixed with
appropriate acetylene (0.015 mol) in toluene (10 cm3) and the mixture was irradiated in the
microwave at 80C (2535 W input power) till the completion of reaction. [21]
N
N
N3
1
+ RC
N
(84)
CR
N
N
R2
MWI
(85)
R2
R1
R1
+
N
(86)
(87)
(88)
O
(89) O
OC2H5
Ethanol /H+
NH2NH2H2O
MW / 4-5 min
R3
OHC
R2
(93)
H2N
R3
R2
N
N
N
R
NH2
(90)
Ethanol / H +
MW / 2-3 min
(91)
O
NH2
R1
R
O
R1 MW / 2-3 min
Triethyl ortho formate
R3
NH
(92)
R2
R1
H2N
R
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was carried out at temperature 105 C, run time 60 min, power high (pressure ca.2 bar). [23]
R
R'
O
+H
OH
N3
i-Pr2NLi
1. MsCl,Et3N
R
R
CH2Cl2
R DMSO
R'
R'
or n-BuLi
'
'
2. NaN3, DMF
R
R
(97)
BF3 - Et2O
(96)
or(PhO)2P(O)N3
THF
(CH2Cl)2
DIAD,Ph3P,THF
ZnCl2
MW or
H
R N R''
''
(95)
(94)
R'
Synthesis of pyroles .
2.
(98)
bromoacetate (0.50 g, 3 mmol) and Zn-Cu couple (0.4 g) and place it in a 25-ml beaker and was
inserted into a screw-capped Teflon beaker and irradiated in a microwave oven at high power for 10
min to get the pure product (101) (0.41 g, 71%). [24]
Ar
Ar
O Zn - Cu
CN +
MW/ solvent - free HN
(99) BrH2C
OEt
O
(100)
O
NH
Ar
(101)
Br2
N
H
(102)
00C
Br
Br
BrCH2COOC2H5
N
N
KOH/DMF
H (103)
Microwave
(104) CH2COOH
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2. 6,7,8,9-tetrahydro-1-methoxy-3-nitro-5H-carbazole: The intermediate 6,7,8,9-tetrahydro-1methoxy-3-nitro-5H-carbazole (106) was obtained by an indole-modified Fischer synthesis from 2methoxy-4-nitro-hydrazine (105) by microwave-assisted one-pot synthesis, in order to shorten the
synthetic pathway to our final compounds (Scheme 1A and B). The synthesis of tetra hydro pyrido
carbazoles was done by condensing 2-ethoxy-4-nitro-phenyl hydrazine
cyclohexanone and this was submitted to acid cyclization to carbazole (106).The optimization of the
method was done with the aim of increasing the yield: first, the power set point was 100 W and the
temperature reached was 1000C. The conditions were then maintained constant by a cooling system
for 6 min yielding 67% (experiment 1). [26]
A
O2N
c) cyclohexanone,
O2N
acetic acid
N
H
MW
NHNH2
OCH3
(105) OCH
3
(107)
a) cyclohexanone
O2N
b) H2SO4 4%
R
B
NHNH2
MW
c) cyclohexanone,
acetic acid
N
(109)
R
(108)
b) CH3COOH, H2SO4
a) cyclohexanone
NH N
OCH3
(106)
N
H
NHN
N
(110)
R
3. N-arylation of carbazoles: Add 9H-Carbazole (1.0 mmol), Cs2CO3 (1.0 mmol), iodobenzene
(1.1 mmol), CuI (0.1 mmol), and DMF (2 ml) to a 5-mL vial. Sealed the vial with a crimp cap and
placed the vial in a microwave cavity. Irradiate vial at 220 0C. N-Phenyl-carbazole (114) was
obtained (96% yield) as a white solid. [27]
Br
+
N
H
10 mol% Cu
1 eq Base,2200c
Microwave, 1h
(111)
N
(112) Ph
N
H
(113)
N
Ar
(114)
R2
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NH2
(115)
H
N
OH
OH
H
N
N
H
H
N
ii
N NHNH2
(117)
(116)
keto - enol tautomerism
O
iv
O
N
(118)
H
N
iii
N
N
N
(120)
(119)
R1
N
N
R
(ii) a) Pyrazole: Pyrazole is the organic compound with the formula C3H3N2H. It is a heterocycle
characterized by a 5-membered ring of three carbon atoms and two adjacent nitrogen centres.
Pyrazoles are also the class of compounds that have the ring C3N2 with adjacent nitrogen centres.
1. 3, 5-Disubstituted pyrazolyl Derivatives (127): Add ethanol (10 ml) to a solution of compound
(124) (1.0 g, 5.7 mmol) in -diketone (5.7 mmol), and the reaction mixture was irradiated in a
domestic microwave oven at an emitted power of 400 W till the completion of reaction. [29]
NH2
NH2
(121)
OH
H
N
OH
N
H
(122)
H
N
ii
O
(123)
N NHNH2
(124)
N
N
iv
(125)
iii
H
N
R1
N
(127)
N
N
R
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2.
R1
CO - CH3 + H - C
R2
(128)
C2H5OH
Microwave NaOH
-H2O
C
R2
Microwave
CH
(129)
CH
(130)
Microwave
OC - NH - NH2
S
H2N C NH - NH2
Basic alumina / K2CO3
R1
R1
N
R2
O
(131)
N
C
R1
R2
N
C
H2N S
N (132)
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2. 2-{(2E)-2-[1-(2- chlorophenyl) ethylidene] hydrazino}-3 substituted phenyl -1, 8naphthyridine (138) :Mix 3-aryl-2-hydrazino-1, 8- naphthyridines (136) (0.01 mol), substituted
acetophenones (137) (0.01 mol) and methanol (30 ml) with a few drops of glacial acetic acid and
then exposed to microwave irradiation at 150 watts for 2 min to give product (139). [32]
Cl
Ar
Cl
O
Ar
Ar
N
C
N N N
+ H3C
DMF/KOH
C
Methanol/ N N NH
N
N N NHNH2
MW
(137) CH3COOH
(138)
(139)
CH3
CH3
(136)
c) Imidazole: Imidazole is an organic compound with the formula (CH)2N(NH)CH. It is a colourless
solid that dissolves in water to give mildly alkaline solution. In chemistry, it is an aromatic
heterocycle, classified as a diazole and as an alkaloid.
1.
20% N2H4/ETOH
N
MW,120 0C
N
H2N
R1
N
H
(141)
R1
(140)
2.
O2N
3.
CH2CONHNH2
N
+ RCO2H
N CH3
(143)
(142)
POCl3, MW
N
O2N
POCl3,
R
N
N CH3
(144)
ammonium acetate (4 mmol) and glacial acetic acid (0.6 g) in a tube and mixed thoroughly. The
mixture was irradiated in the microwave oven with 638W for 5 minutes. [35]
- 193 - | P a g e
Ph
O
HOAc
N
+ ArCHO + NH4OAc
Ar
MW Ph
(146)
N
(147)
O
H
(145)
(148)
R
R
O
O
N
R R
NH2-(CH2)n-NH2
[]n N
N1
N1
R
R
R
R
CH2O/MeOH/MWI
(152)
O
R
R
N
(151)
(150)
R
H2N
NH2
2a H
2b Me
CH2O/MeOH/MWI
O
N
R R
NH
MeOH/MWI
N1
N
n N'
1
(153)
- 194 - | P a g e
(154) gives dithiazole (164). It was converted exclusively into the angular 2, 7-dicyano-9ethoxythiazoloquinazoline (165) with cuprous iodide. [37]
Cl
NH2
R
X
(154)
S+
Cl- S
Cl
(45)
S
Cl
CuI,pyridine
CN
X=Br
S S
X
(155)
pyridine, r.t.
ROH
N
Nah
CN
N
OR
X=CN
NC
H2N
S SNC
NO2
N
a
N
Cl
(159)
(158)
NH2 e
N
NC
NO2
b
NC
OEt Br
OEt Br
NC
(162)
NO2
N
N
(160)
S S
(163)
NH2
d
N
NC
N
(161)
O
CN
Cl
N
(157)
OEt
OEt
(156)
OEt S
f
N
NC
N
(164)
S
N
g HN
N
(165)
Reagents and conditions (for time and yields of steps b, c, f and g: see Table 1): (a) 1, pyridine, rt,
10 h, 78%; (b) NaH, EtOH, reflux; (c) SnCl2.2H2O, EtOH, 70C; (d) Br2, CH3COOH, rt, 4 h, 74%;
(e) 1, pyridine, rt, 4 h, 66%; (f) CuCN,pyridine, reflux; (g) HCl, reflux
e) Benzimidazole: Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic
compound consists of the fusion of benzene and imidazole.
1. Benzimidazole: Mix o-phenylene diamine (166) and formic acid (167) and place the mixture in a
microwave oven. [38]
NH2
NH2
+
(166)
2.
OH O 10% NaOH
(167)
H
N
N
(168)
- 195 - | P a g e
under microwave irradiation (Scheme 1). The reactions were performed without solvent in only 60 s
as a maximum time. [39]
NH2 O
+
NH2 H
(169)
Ar + Na2S2O5
Ar
irradiation
(30-60 sec)
(171)
(170)
Microwave
N
H
(172)
(75-94%)
Preparation of 2-(alkyloxyaryl)-1H-benzimidazolederivatives
Compound (175) was obtained with low yield from (Scheme 1), using an excess of alkylating agent
iodoethane (Scheme 2). When microwave irradiation time was extended, it was possible to observe a
decrease of the yield due to formation of several by products.
N
N
H HO
+ CH3CH2I(Excess)
K2CO3
Acetone
(174)
(173)
(175)
Synthesis of 2-(2-ethoxyphenyl)-1 ethyl-1H-benzimidazole (177)
3. 1, 3-diarylpyrazino [1, 2-a] benzimidazoles (181): Compound (180) (1 mmol) and ammonium
acetate (10 mmol) was mixed in 0.5 ml of acetic acid. Irradiate the mixture at power 600W in
microwave oven for 2 min. [40]
R
N
N
H
R
i, ii
Cl
N
H
(177)
(176)
+
(178)
O
R
O
Br
R'
(179)
iii
N
N
iv
O
O
N
N
N
(181)
(180)
R'
R'
Reagents and conditions; (i)(C2H5)3N, pyridine, stirring at RT; (ii) NaOH, H2O, reflux;
(iii) K2CO3, CH3COCH3, stirring at RT; (iv) CH3COONH4, CH3COOH, MW irradiation,2 min.
- 196 - | P a g e
drop~0.2 mmol). At the temperature of 1600C only the Schiff bases (184) were isolated, with
exception of the 1-naphthyl derivative, which was formed at 2500C. Increasing the temperature to
250 0C led to the synthesis of only derivatives (185), with exception of the bromosubstituted ones,
which were formed at 200 0C to afford compounds (184) or (185). [41]
R2
N
N
H
(182)
NH2
R1
COMe
R1
N
N
H
(183)
R2
Me
(184)
N
N
R1
R2
R1
Me O
(185)
R2
Reagents and conditions: (a) MW irradiation, 160 C, 4e10 min; (b) MW irradiation, 2500C, 5-10
min including catalytic amount of acetic acid in both cases (molar ratio of
benzimidazole:ketone:acetic acid 1:2.1:0.2).
0
O
+
NH2
(186)
Microwave
Ar + Na2S2O5
irradiation
(187) (188) (30-60 sec)
N
Ar
N
H
(189)
(75-94%)
Preparation of 2-(alkyloxyaryl)-1H-benzimidazolederivatives
N
N
N
H HO
+ CH3CH2I(Excess)
(191)
K2CO3
Acetone
N
O
(192)
(190)
Synthesis of 2-(2-ethoxyphenyl)-1 ethyl-1H-benzimidazole (192)
- 197 - | P a g e
[1,3]diazepine-7,9-dione (194) (0.17 g, 0.5 mmol) in THF (1 ml) in a 10 ml pressure vial, HMDS (1
ml). Microwave irradiation was applied (200 W, 160C) for 20 min. The resulting yellow solution
was hydrolyzed with 4 ml of methanol while still warm (ca. 50C). Compound (196) (0.15 g, 91%)
was obtained as a yellow oil. [43]
O
H3 C
O
H
N
O
O N NH
(193)
( )n
193(n = 0)
194(n = 1)
195(n = 2)
H 3C
HMDS / THF
N
O
(194)
( )n
196(n = 1)
197(n =2)
b) Pteridine: Pteridine is a chemical compound composed of fused pyrimidine and pyrazine rings.
A pteridine is also a group of heterocyclic compounds containing a wide variety of substitutions on
this structure. Pterins and flavins are classes of substituted pteridines that have important biological
activity.
1. Pterin sugars: Synthesis was done by a simple direct condensation without addition of sodium
bisulphite or hydrazine hydrate under microwave irradiation. A mixture of triamine (198) and
methylglyoxal was irradiated in an open flask using a household microwave oven to obtain 70%
yield. Condensation with 1, 3-dihydroxyacetone (DHA) and 1, 1-dichloroacetone also led to the
formation of (199) a only, but in a poor yield. However, this condensation reaction further prompted
us to irradiate the triamine (198) and aldohexoses, which gave the pterin sugar derivatives (199) c
and (199) e with the expected side-chain length and functionality at each of the four carbon atoms.
[44]
O
HN
H2N
NH2
HN
carbonyl compound
MW
RHN N
N NH2
(198)
R'
N
(199)
- 198 - | P a g e
III) (i) a) Benzofuran: Benzofuran is the heterocyclic compound consisting of fused benzene and
furan rings. This colourless liquid is a component of coal tar. Benzofuran is the "parent" of many
related compounds with more complex structures.
1. Benzo[b]-furan derivatives: Thoroughly mix potassium carbonate (2.70 g, 20 mmol), TBAB
(0.16 g, 0.50 mmol), and a salicylaldehyde derivative (5.0 mmol) and placed the mixture in an open
conical glass flask. Then add dropwise a chloroacetate ester (10 mmol), the mixture was thoroughly
stirred with a spatula for a few seconds, place mixture in a domestic microwave oven, and irradiated
for 810 min. [45]
CHO
R1
R
+ Cl-CH2-CO2 -R3
K2CO3/TBAB
OH
mw, 8-10 min
(201)
(200)
R3:Et
R3:CH2CH=CH2
OH
CHO + Cl-CH -CO -R3 K2CO3/TBAB
2
2
mw,8-10 min
(203)
(204)
R1
R
CO2-R3
(202)
R3:cyclohexayl
O
CO2-R3
(205)
(b) Chromene: Benzopyran is an polycyclic organic compound that results from the fusion of a
benzene ring to a heterocyclic pyran ring. According to IUPAC nomenclature it is called chromene.
There are two isomers of benzopyran that vary by the orientation of the fusion of the two rings
compared to the oxygen, resulting in 1-benzopyran (chromene) and 2-benzopyran (isochromene)
the number denotes where the oxygen atom is located by standard naphthalene-like nomenclature.
1.
- 199 - | P a g e
OH i)ArCl
CH3COONa
ii)AlCl3
R
(206)
OH
OH
R
(207)
O
(208) O
NaOH
30% H2O2
EtOH
R1
R
(210)
2.
O
O
C R2
O
R -COCl
CM MWM R
R1
OH
(209)
O
C
NO2
H+
K2CO3 / TBAB
HO -CH2CH2 -NO2
O H
R
MW 140 w 2 min
(211)
(210)
3.
(10 mmol), malononitrile (236) (10 mmol) and Cyclohexanedione/Dimedon (237) (10 mmol) in
ethanolic NaOH (5 mmol, 10 mL) and irradiated in microwave oven at 350 W (50% of output
power) for 140-170 sec, to get the pure solid product (238). [48]
- 200 - | P a g e
H3C
CHO
H3C
N
DMF
Cl
CHO
H3C
N
R1
(213)
(212)
R1
(215)
OH
K2CO3
R2
R2
R1
(214)
CHO
(219)
(215)
O
H3C N N
+
NaOH, Ethanol
+
O
O
NC R3
MWI 350W,
CN
R1
O 140-170S 3
R
R2 (216)
(217)
R3
O NH2
CN
CN -H2O
(216)
R1
R2
NC
(218)
O
Pyz +
DMF
POCl3
CHO
H3C
Pyz
NC
NC
R3
3
R
HO
CN
(220)
Hetarylidene
-nitrile
Pyz O
NC
H2N
Pyz
R3
R3
HO
R3
R3
(221)
Pyz O
NC
HN
O
H
R3
R3
(222)
c) Xanthene: Xanthene (9H-xanthene, 10H-9-oxaanthracene) is a yellow organic heterocyclic
compound. Its chemical formula is C13H10O.
1. 1, 3-Dialkylxanthines (1 and 2): 1 g of 5,6-diamino-1,3-dialkyluracil (5 mmol of 3 or 4 mmol of
4, respectively) and triethyl orthoformate (6 ml) was mixed and it was subjected to microwave
irradiation for 5 min (120 W, 160C) in a 10 ml pressure tube, with stirring. [49]
- 201 - | P a g e
O
NH2
N NH2
R3 (223)
H
N
N
R3
N
(224)
HC(OEt)
MW
5 min/ 1600 C
mixed with (226) (1.0 mmol) and 4-hydroxy coumarin (4.0 mmol) in 4 mL of DMF and 5 drops of
acetic acid was added. The mixture was heated in a microwave for about 5 min. [50]
O
O(OCH2)
(225) OH
DMF
+
Microwave
O(CH2)nO
CHO
(226)
O
O
O
OH OH
CHO
O
OH OH
(227)
Synthesis of tetrakis-(4-hydroxy-2H-1-benzopyran-2-ones)
2. 3-Acetylcoumarin (230): Catalytic amount of piperidine (0.2ml, 1.64 mmoles) was added to a
mixture of salicyaldehyde (0.86 ml, 81.89 mmoles) and ethyl acetoacetate (11.5mL, 90.13 mmoles)
and swirled thoroughly. The mixture was then irradiated in microwave oven at 400 W for 1 min.
Filter the solid product, dried, and recrystallized from methanol to obtain pure 3-acetyl coumarin
(230) in appropriate yield. [51]
O
CHO
CH3
Piperidine
+ CH3COCH2CO2C2H5
MWI
O O
OH
(230)
(229)
(228)
Microwave assisted synthesis of 3-acetylcoumarin
- 202 - | P a g e
at
240
(40%)
power,
to
afford
the
compounds
R1
(266).
[52]
R1
O
R
7
OH
(231)
5
O
R1
6
(a)
R
4O
R 8 9
O 2
1
R2
4'
'
OH
(231)
+
(b)
R2
R2
(234)
Br
O
(232)
O2N
(233)
4. Coumarins: Condensation of phenols (267) with -keto esters (268) gives the coumarins
(Scheme 1). A mixture was irradiated with microwaves of low power (200 W). The temperature of
the reaction mixture started to rise. After 30 s of irradiation, the microwave oven was switched off.
[53]
R
+
R
OH O
(235)
CHO
+
OH
(239)
CH2CO2Et
(240)
R'
(236)
CH2(CO2Et)2
R'
(237)
(238)
CO2Et
O O
(241)
- 203 - | P a g e
CN
CH3
+ ArCH2O + CH2(CN)2
O
(244)
(243)
NH2
O O
(245)
(242)
SH
+
H2N
(246)
2 -methoxyethanol
(247)
Piperidine, MWI
4-6 min
N
(248)
Ar
Synthesis of 1, 5-benzothiazepines.
2. 2-arylbenzo[b]thiophenes: The cyclization with the symmetrical substrate 1g having two ortho
methoxy groups on aromatic rings was performed at 1300C within 1 h in the microwave, the reaction
took place smoothly to provide the desired compound (250) together with starting material 1g. By
increasing the temperature to 1600C, the reaction went to completion and (250). [56]
R1
XR
(249)
R1
X
(250)
X = O,S
Reaction of ortho-substituted arylalkynes 1 with PTSA in EtOH: synthesis of 2-arylbenzo[b]furans
and 2-arylbenzo[b]thiophenes
3.
Benzo[b]thiophenes: Benzaldehydes (251) were reacted with rhodanine and after hydrolysis with
sodium hydroxide to obtains, the corresponding b-aryl-amercaptoacrylic acids (252) in good yeilds.
The acids (252) can then be cyclised and decarboxylated to give the corresponding
benzo[b]thiophenes (253). The reaction was carried out directly on a 170mmol scale in a 1L round
bottomed flask in a microwave oven at 2000C.
Full Text Available On www.ijupbs.com
- 204 - | P a g e
COOH
H
i),ii)
SH
iii), iv)
s
(253)
(252)
(251)
i)
R
COOH
H ii), iii)
F
(255)
(254)
(256)
NH2
a)
NH
+ Cl
OH
(257)
base
(258)
b)
OMe
(257)
microwave
OMe
OMe
(261)
Lewis Acid
(260)
O
O Ph
(259)
O
NH2 Cl
+
OH
Ph
OMe
N
OMe
O
(262)
OMe
- 205 - | P a g e
PCC / Silica
Z
R
Ar
N
(264)
Ar CH2Cl2 , rt
N
(263)
Z = S,O
Z
PIFA ( 1.05 eqiv), EtOH R
ZH
Ar
N (267)
ArCHO
0
+
R
( 1.0 equiv ) MW, 80 C, 15 min
NH2
(266)
( 1.1 eqiv )
(265)
Biological activities
Half of the therapeutic agents consist of heterocyclic compounds. A large number of efforts were
made to collect the matter for different biological activities exhibited by the heterocyclic
compounds. The practice of medicinal chemistry is devoted to the discovery and development of
new agents for treating disease. Therefore, an important aspect of medicinal chemistry has been to
establish a relationship between chemical structure and pharmacological activity. Several
benz fused heterocyclic systems as indole, benzothiazole, benzimidazole, benzoxazole and many
more, have been studied and found to possess interesting pharmacological activities viz naphthalene
(anti microbial
[60]
microbial agent
[63]
, cytotoxic activity
[64]
[61]
) , anti- inflammatory
), quinoline ( anticancer
[65]
[62]
, antimycobacterial[66],
[71]
PPARgamma modulators
[73]
[74]
[72]
anthracene (anti
[70]
, anti oxidant
, antitumor agent
[75]
, anti
cancer activities [76], azepine (anti-cancer [77], antiviral[78], anticonvulsant[79], antidepressant[80], antiinsecticidal[81], vasopressin (AVP) antagonist [82], pyrrole (antimicrobial [83], carbazole (antibacterial,
anti-tumor
[84]
, quinoxaline (antimicrobial
inflammatory, antioxidant
[88]
, anti HIV
[91]
[85]
[89]
, antidepressant
[86]
, anti cancer
, antibacterial (antifungal)
[92]
[87]
[90]
, anti-
, indazole
[101]
- 206 - | P a g e
, anti tumour
[108]
, anti psychotic
[109]
[105]
, anti diabetic
[110]
, anti malarial
[111]
[106]
, anti fungal
, anti oxidant
[112]
anti obesity [113], benzimidazole (anti microbial [114] , cytotoxic, diuretic [115], purine (anti cancer [116]
, anti fungal [117], pteridine (anti leishmainial [118], benzofuran (anti microbial, anti inflammatory [119],
analgesic[120], anti depressant[121], anti convulsant[122], anti tumour[123], anti diabetic[124], anti HIV[125],
anti oxidant
[126]
anti microbial
[130]
and anthelmintic
[127]
, anti leishmanial
antihyperglycemic[136],
, anti inflammatory
analgesic[137],
anti
[133]
[131]
[128],
[129]
cancer[138]
antitubercular
[139]
[134]
, CNS[135],
benzothiazole
- 207 - | P a g e
- 208 - | P a g e
some pyrazol-1-ylquinoxalin-2(1h)-one
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