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Turk J Chem
(2014) 38: 1 – 27
c⃝ TUBITAK
doi:10.3906/kim-1304-35
Turkish Journal of Chemistry
http :// journa l s . tub i tak .gov . t r/chem/
Research Article
Azolylimidazoles: Synthetic strategies and medicinal applications
Bakr Fathy ABDELWAHAB1,2, Rizk Elsayed KHIDRE3,4,∗
1Applied Organic Chemistry Department, National Research Centre, Dokki, Giza, Egypt2Shaqra University, Al Dawadmi, Saudi Arabia
3Chemical Industries Division, National Research Centre, Dokki, Giza, Egypt4Chemistry Department, Faculty of Science, Jazan University, Saudi Arabia
Received: 15.04.2013 • Accepted: 04.08.2013 • Published Online: 16.12.2013 • Printed: 20.01.2014
Abstract:The current review summarizes the known routes to different azoles linked directly to imidazole. This review is
divided into classes based on the type of azoles connected to an imidazole ring. Some medical applications are mentioned.
Key words: Imidazoles, azoles, imidazolylthiazoles, imidazolylthiadiazoles, applications
1. Introduction
Imidazole and its derivatives are an important class of heterocycles. Medicinal properties of imidazole com-
pounds include anticancer,1 antimicrobial,2−4 antibacterial,5 antifungal,6 and antioxidant activities.7 Molecules
having an imidazole ring linked directly to an azole ring find applications in different fields of science. For exam-
ple, imidazolyl-thiazoles and triazoles have been proved to possess antibacterial, antifungal, antischistosomaci-
dal, protozoacide, and schistosomacide activities.8−10 Imidazolylpyrazolylvinylpyridine is useful as an inhibitor
of ATP-protein kinase interactions.11 Moreover, imidazolylthiadiazoles showed antibacterial, antifungal, and
antiarrhythmic activities.12,13 In addition, bis(indolyl)imidazole, known as topsentin, is a marine natural prod-
uct and inhibited the proliferation of cultured human and murine tumor cells.14−16 Also, indolylimidazoles
are useful as an antidepressant,17 and act as protein kinase C inhibitors.18,19 As a continuation of our very
recently published review article concerning the synthesis of biologically active heterocyclic systems,20−23 we
prepared this review to present for the reader a survey of the literature on different azoles linked directly with
an imidazole nucleus. Some of the medicinal applications are also mentioned.
2. Pyrrolylimidazoles
The reaction of imidazo[4,5-c ]isoxazole-6-carboxylate ester 1 with either acetylenic esters or ketones 2, in boiling
toluene or neat, involved the addition of 2 molecules of an alkyne followed by ring opening and fragmentation,
leading to the formation of (2-pyrrol-2-yl)imidazoles 3 in 37%–62% yields (Scheme 1).24
2-Pyrrolyloxazolines 5 were readily obtained from 1-methyl-1H -pyrrole-2-carboxylic acid 4 by refluxing
with thionyl chloride, followed by treatment with 2-amino-2-methylpropan-1-ol and finally reaction with thionyl
chloride in boiling toluene. Quaternization of the oxazoline nitrogen followed by reaction with ethylene diamine
in boiling acetonitrile gave 2-pyrrolylimidazole 7 in 87% yield. Moreover, oxazoline 5 can be converted directly
to 7, in 79%–92% yield, by refluxing with ethylene diamine and aceteonitrile (Scheme 2).25,26
∗Correspondence: [email protected]
1
ABDELWAHAB and KHIDRE/Turk J Chem
N
N N
O
Me CO2MeR2R1
PhMe, or neat
N
Me
R1R2
N
HN
R2
R1
1
2
3
R1 R2 Yield %
CO2Me CO2Me 62CO2Et CO2Et 37CF3 CO2Et 51COMe COMe 40
Scheme 1
N
Me
CO2H
i) SOCI2, reflux, 2 h;
ii) H2NC(Me)2CH2OH,CH2Cl2, 20 °C 16 h;iii) SOCI2, PhMe, 20°C, 16 h
83-95 %
N
MeO
N
MeI, 20 °C, 24 h91 -100%%
N
MeO
N
Me I
H 2NCH 2CH 2
NH 2,
reflux, 10 h
N
Me HN
N i) H2NCH2CH2NH2,reflux, 10 h
ii) MeCN79%-92%
87%
4
5
6
7
Scheme 2
The reaction of pyrrole-2-carbaldehyde 8 with benzil derivative 9 in acetic acid in the presence of
ammonium acetate led to formation of pyrrolylimidazole 10 in high yield, which was useful as an inflammation
inhibitor (Scheme 3).27
N
NH
HN
Ar
Ar
NH
CHO
O
O Ar
Ar
+
Ar = 4-MeOC6H4
NH4OAc
AcOH
8 9 10
Scheme 3
3. Imidazolylpyrazoles
Imidazolyl-2-pyrazoline derivative 12, having antibacterial and antifungal activities, was prepared starting from
chalcone 11 by reaction with phenylhydrazine (Scheme 4).28
2
ABDELWAHAB and KHIDRE/Turk J Chem
N
N
S
Me
MeO
ArPhNHNH2
N
NSMe
MeN
Ar
N
Ph
11 12Ar = 4-ClC6H4
Scheme 4
In the same fashion, imidazolylpyrazoles 14 were prepared, in 65%–80% yields, by reaction of chalcone
13 with hydrazine hydrate in refluxing ethanol for 10–20 h followed by diluting with water (Scheme 5).29,30
R
OH
O
N
N
Cl
Me
NH2NH2 .H2O
R
OH
N
N
N
Cl
MeNH
R H MeO Me ClYield% 65 76 73 80
1314
Scheme 5
5-Formyl-1-methyl-2-(methylthio)imidazole 15 reacted with methyl ketones followed by cyclocondensa-
tion of 16 with hydrazine hydrate gave imidazolyl-2-pyrazolines 17, which have antimicrobial activity (Scheme
6).28
N
NS
Me
Me
O
H
O
Ar Me
N
NS
Me
Me
O
Ar
NH2NH2 .H2O
N
NS
Me
MeN
Ar
HN
15 16
17
Scheme 6
Similarly, imidazolylpyrazolines 19 were prepared by condensation of the corresponding imidazolepropenones
18 with phenylhydrazine (Scheme 7).31
3
ABDELWAHAB and KHIDRE/Turk J Chem
N
NCl NMe2
X
O
R
PhNHNH2N
NCl NMe2
X
NR N Ph
R = Ph, 4-BrC6H4, 4-ClC6H4, 4-MeOC6H4, 4-PhC6H4,2-(5-(2-chlorophenyl)thienyl); X = H, F, Cl, Br
18 19
Scheme 7
The reaction of β -diketones 20 with phenylhydrazine afforded 5-aryl-3-(1-methyl-5-nitro-2-imidazolyl)-
1-phenylpyrazole 21 and 3-aryl-5-(1-methyl-5-nitro-2-imidazolyl)-1-phenylpyrazole 22 (Scheme 8).32
Ar = Ph, 4-O2NC6H4, 4-BrC6H4, 4-ClC6H4, 4-MeOC6H4
N
NO2N
Me OO
Ar PhNHNH2
N
NO2N
Me N N
Ar
Ph
N
NO2N
Me N N
Ar
Ph
+
20 21 22
Scheme 8
Benzylideneimidazolylpyrazolinones 25, as potential antimicrobial and acetylcholinesterase inhibitory
agents, were prepared from the corresponding benzylideneoxazolones 23 and the aminopyrazolone 24 (Scheme
9).33
R = H, Cl, MeO; R1 = H, MeO; R2 = H, OH; R3 = Me, Ph
ON
R3
O
R2
R1
R+ N
NO
Ph
Me
Me
H2N
NN
R3
O
R2
R1
R
N
N
O
MeMe
Ph
23 24 25
Scheme 9
By treatment of imidazo[2,1-f ]pyrazolo[3,4-d ]pyrimidines 26 with diluted sodium hydroxide solution,
ring opening took place at the 4-position and 5-amino-4-(imidazol-2-yl)- pyrazoles 27 were obtained in about
45% yields (Scheme 10).34
4
ABDELWAHAB and KHIDRE/Turk J Chem
N
N
N N
N
R
CH3
dil NaOH
45%
N
NH
H2NN
N
R
CH326
27R = H, Ph
Scheme 10
The reaction of the C(α)-dianions with electrophilic-nucleophilic reagents has extended to the conden-
sation of C(α)-dianions of phenylhydrazoxylate 28 (in the presence of an excess amount of LDA) with ethyl
4-methyl-5-imidazolecarboxylate 29 to give lithiated intermediate, which was cyclized to imidazolylpyrazoles
30 under acidic conditions (Scheme 11).35
N
CH2Li
ArNPh
Li
N N
H3C CO2Et
Li
+
NN
ArPh
N
HNH3C
Ar = Ph (20%)Ar = 4-MeC6H4 (53%)
28 2930
Scheme 11
The 1-methyl-5-nitro-1H-imidazole-2-carbaldehyde 31 was treated with methylhydrazine to give hydra-
zone 32. Bromination of 32 using NBS and cyclization with malononitrile yield 34, which is used as a bacteri-
cide, particularly in animal feeds (Scheme 12).36
N
N
O2N
CHOMe
MeNHNH2N
N
O2N
MeN
HN Me
NBS
N
N
O2N
MeN
HN Me
Br
CH2(CN)2
N
NO2N
Me
NN
NCNH2
Me
31 3233
34
Scheme 12
Imidazolylpyrazole hydrochloride 34, used in the treatment of diseases linked to the modulation of
cannabinoid receptors in animals, was prepared from 5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-methyl-1H -pyrazole-
3-carboxylic acid ethyl ester 33, via reduction with diisobutylaluminum hydride, then Swern oxidation with
5
ABDELWAHAB and KHIDRE/Turk J Chem
oxalyl chloride/DMSO in dichloromethane, followed by reaction with formamide/4-methylbenzenesulfonic acid
in dichloromethane containing chlorotrimethylsilane. Then the obtained product was dehydrated with POCl3
in THF, and finally reacted with o -trifluoromethyl benzyl amine hydrochloride (Scheme 13).37
N N
CO2EtMe
Cl
ClN
N NN
Me
Cl
Cl
CF3a. [H]b.[O]c.HCONH2/4-MeC6H4SO3H/CH2Cl2
d.-H2Oe.2-(CF3)C6H4CH2NH2 HCl
3536
(a) [H] = (Me2CHCH2)2AlH; (b) [O] = (CO2)2Cl2/DMSO in CH2Cl2(d) -H2O; POCl3
Scheme 13
Cyclocondensation of cyanopyrazole 37 with propane-1,2-diamine gave 1,3-dimethyl-5-(4-methyl-4,5-
dihydro-1H -imidazol-2-yl)-1H -pyrazol-4-amine 38, which was used as intermediate for the synthesis of the
antipsychotic 1H -imidazo[1,2-c ]pyrazolo[3,4-e ]pyrimidines (Scheme 14).38,39
H2NCH2CHMeNH2NN
NH2Me
CN
Me
NN
NH2Me
Me
NH
N
Me
37 38 (86%)
Scheme 14
Treatment of 1,3-dimethyl-4-nitro-5-pyrazolecarboxamide 39 with ethane-1,2-diamine, followed by re-
duction using diisobutylaluminum hydride gave 2-(4-amino-1,3-dimethyl-5-pyrazolyl)imidazoline 40 (Scheme
15).40
NN
O
NH2
NO2Me
Me
N
HN
N
N
Me
Me
NH21.H2NCH2CH2NH2
2. [H]
39 40[H] = (Me2CHCH2)2AlH
Scheme 15
Imidazole derivative 42 was prepared from 5-oxo-4-(2-phenylhydrazono)-4,5-dihydro-1H -pyrazole-3-carbal-
dehyde 41 in good yield by reaction with o -phenylene diamine (Scheme 16).41
Imidazolylpyrazoles 45 were obtained in excellent yields by refluxing a mixture of 3-substituted-1H -
pyrazole-4-carbaldehydes 43, 1,2-diketones 44, and ammonium acetate in acetic acid via the Debus reaction
(Scheme 17).42
6
ABDELWAHAB and KHIDRE/Turk J Chem
N
NH
O
OHC
NNH
Ph NH2
NH2
NHN
O
NHN
Ph
HN
HN
+
41 42
Scheme 16
NNH
CHOAr1
+
O
OAr2
Ar2NH4OAc/AcOH
reflux, 6 h70%-86%
NNH
Ar1 NH
NAr2
Ar2
Ar1 = 4-PhC6H4, 2,4-Cl2C6H3, 2,5-Cl2C6H3, 4-MeC6H4, 4-MeSC6H4;
Ar2 = Ph, 4-BrC6H4
4344 45
Scheme 17
4. Imidazolylthiazoles
Ring closure of arylthiourea derivatives 46 with ethyl bromoacetate followed by chlorination of the resulting
2-phenylaminothiazol-4-ones 47 with phosphorus oxychloride yielded (4-chlorothiazol-2-yl)phenylamines 48 as
intermediates. The latter intermediate was transformed into [4-(imida-zol-1-yl)thiazol-2-yl]phenylamines 50, in
22%–83% yields, by nucleophilic substitution using an excess amount of imidazoles 49 in the presence of base
in DMF at 80 ◦C (Scheme 18). The obtained imidazolylthiazols 50 were used as potent colchicine site binding
tubulin inhibitors.43
S
NH2NH
ArBrCH2CO2Et
EtOH, 60 °C20%-80%
S
NNH
ArO POCl3
S
NNH
ArCl
N
NH
R1
R2
DMF, 80 °C22%-83%
S
NNH
Ar NN
R1
R2
Ar = Ph, 4-BrC6H4, 4-OMeC6H4, 4-MeC6H4, 3-BrC6H4, 3-OMeC6H4
R1 = R2 = H, Me
46 47
48
49
50
Scheme 18
7
ABDELWAHAB and KHIDRE/Turk J Chem
4-(4-Methyl-5-imidazolyl) thiazole 52 was prepared by the reaction of 4-methyl-5-bromoacetylimidazole
51 with either thioacetamide (R = Me) or thiourea (R = NH2) in refluxing methanol (Scheme 19).44
N
NH
O
Br
MeS
R NH2 N
NH
N
Me
S
R
51 52
R = Me, NH2
MeOH
Scheme 19
5-Methyl-1-(3-phenoxymethyl)imidazole-4-thiocarboxamide 53 was refluxed with chloroacetone for 13
h to give 4-(4-methylthiazol-2-yl)-5-methyl-1-(3-phenoxyphenyl)imidazole 54, which acts as a benzodiazepine
receptor ligand (Scheme 20).45
NN
OPh MeS
N
Me
NN
OPh MeS
NH2
O
MeCl
53 54
Scheme 20
2-(1-Methyl-5-nitro-2-imidazolyl)thiazoles 57, with amebicidal, bactericidal, fungicidal, and trichomonaci-
dal activities, were prepared by cyclocondensation of α -bromoketones 56 with 5-nitro-2-imidazolethiocarboxamide
55 in refluxing protic solvent (Scheme 21).46
N
N
Me
O2N S
NH2
R
O
BrN
N
MeO2N
S
N R
R = Me, EtO2C
+
55 5756
Scheme 21
2-Amino-4-arylthiazoles 58 were reacted with carbon disulfide and then with methyl iodide to give 59,
which underwent cyclocondensation with 2,2-dimethoxyethanamine 60 to give thiazolyl(methylthio)imidazoles
61 (Scheme 22).47
Ar = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 2-MeC6H4
N
S
Ar
NH2
1. CS2
2. MeI
N
S
Ar
NH
S
SMe
(MeO)2CHCH2NH2N
S
Ar
N
NMeS58 59 61
60
Scheme 22
8
ABDELWAHAB and KHIDRE/Turk J Chem
Herbicidal thiazolylimidazolones 64 were prepared by treatment of 2-amino-5-substituted thiazoles 62
with phosgene, which gave 1,3-di(thiazol-2-yl)urea 63. Reaction of the latter with 2,2-dimethoxy-N -methylethanamine
followed by cyclization under thermal conditions and acylation afforded 64 (Scheme 23).48−51
N
S N
NOMe
R2R1N
S NH2
R1(COCl)2
N
S
NH
R1
O
N
S
NH
R1
MeNHCH2CH(OMe)2
, R2COCl or EtNH2
R1 = Me, Br; R2 = 2-furyl-CO2, PhOCH2CO2, 3-pyridyl-CO2, EtNH
62 63 64
Scheme 23
1-(5-Nitro-2-thiazolyl)-∆2 -imidazoline derivative 67, used as schistosomacides, protozoacides, and bacte-
ricides, were prepared by the reaction of 2-bromo-5-nitrothiazole 65 with 2-methoxy-2-imidazoline 66 in DMSO
(Scheme 24).52
N
SO2N N
N
MeO
N
SO2N Br
HN
N
MeO
+
DMSO
65 66 67
Scheme 24
1-(Thiazol-2-yl)-2-methyl-4-(substituted benzylidene)-5-imidazolones 70 were obtained in 45%–60% yield
by treatment of the corresponding oxazolones 68 with 2-amino-1,3-thiazole 69 in refluxing galacial acetic acid
(Scheme 25).53
NN
S
N
Me
Ar
O
ON
Me
Ar
O
H2N
S
N+
Ar = 3,4-Cl2C6H3, 2,4-Cl2C6H3, 2-O2N-3,4-(MeO)2C6H2, 4-ClC6H4,Ph, 3,4-methylenedioxyphenyl, 2-MeOC6H4, 4-Cl-2-(MeO)C6H3, 2,4-(MeO)2C6H3
68 69 70
45%-60%
AcOH, reflux
Scheme 25
Thiazolylimidazolines 73 were prepared by reaction of N -(4-phenylthiazol-2-yl)- ethylenediamine 71 with
ethyl alkimidate hydrochloride 72 in 56%–86% yields (Scheme 26).54
R = Me, Ph, benzyl, 5-nitrofur-2-yl
N
S NH
NH2R OEt
NH .HCl
+N
S
NN
R71 72 73
56%-86 %
Scheme 26
9
ABDELWAHAB and KHIDRE/Turk J Chem
Microwave-assisted synthesis of a novel class of imidazolylthiazolidin-4-ones has been reported, in 2
steps, by reacting a mixture of 5-phenyl-1H -imidazol-2-amine 74 and 2,5-disubstituted benzaldehyde 75 in dry
toluene using 5 mol% of Yb(OTf)3 as catalyst, followed by reaction with mercaptoacetic acid under microwave
irradiation (Scheme 27).55
N
N
R1
R2
NH2 +
CHO
X1X2 Yb(OTf)3
dry tolueneref lux
N
N
R1
R2
N
X1X2
X1 = X2= ClX1 = Cl, X2 = FX1 = X2 = F
HS CO2H
dry tolueneMW, 30 min20%-88%
N
N
R1
R2
N
X1
X2
O
S
74 75 76
77
Scheme 27
5. Imidazolylisoxazoles
Ceric ammonium nitrate (CAN) acted as an efficient catalyst for the synthesis of 1-(1H -imidazol-4-yl)isoxazoles
81 and 83 in a 4-component 1-pot condensation of benzil 78; aromatic aldehydes 79; isoxazolamines 80, 82;
and ammonium acetate, respectively (Scheme 28).56,57
NO
NH2
Me
NH4OAc10% CAN
N
NPh
Ph
Ar
O
N
Me
Ar = Ph, 2-Cl, 2-Me,4-OMe
85%-95%
O
OPh
Ph
+ ArCHO
NO
NH2
NH4OAc10% CAN N
N Ph
Ph
Ar
Ar = Ph, 2-ClC6H4, 2-MeC6H4,4-OMeC6H4; R = Me, CH=CH-Ph
85%-95%
R
Me
NO
R Me
78 79
80
81
82
83
Scheme 28
10
ABDELWAHAB and KHIDRE/Turk J Chem
2-(Phenyl)-3-(2-butyl-4-chloro-1H -imidazolyl)-5-butylate isoxazolidine 87 was synthesized by the con-
densation of E− isomer of nitrone 86 with butyl acrylate in an inert solvent. The condensation of N -
phenylhydroxylamine with aldehyde 84 in the presence of Brønsted acid catalyst 85 yielded E− isomer of
nitrone 86. The 1,3-dipolar cycloaddition of nitrone 86 with butyl acrylate gave a mixture of regioisomers, 87
and 88. The major isomer 87 was separated by column chromatography on silica gel (Scheme 29).15,58
NHN
CHOCl
Bu
+ PhNHOHMgCl2/CH2Cl2
cat. (85)NHN
Cl
Bu
N
Ph
O CO2Bu
NH
N
Cl
Bu
N
Ph
O
CO2Bu
toluene, reflux 38 h
NH
N
Cl
Bu
N
Ph
O
CO2Bu
+
major minor
Cat. = OH
OH
CF3
CF3
CF3
CF3
67% 59%84 86
85
87 88
Scheme 29
1-Methyl-5-nitro-1H -imidazole-2-carbaldehyde 31 was treated with N -methylhydroxylamine hydrochlo-
ride to affored nitrone 89, which was transformed into 90 and 91 when treated with methyl acrylate and methyl
propiolate, respectively (Scheme 30).59
N
N
NO2
Me
OHCMeNHOH .HCl
N
N
NO2
MeN
Me
CO2Me
N
NNO2
Me
N
MeO
O
MeO2C
CO2MeN
NNO2
Me
N
Me
O
MeO2C
31 89 90
91
Scheme 30
11
ABDELWAHAB and KHIDRE/Turk J Chem
Imidazolylisoxazoles 93 were prepared by reaction of C(α)-dianions of oximes 92 with electrophilic-
nucleophilic reagent ethyl 4-methyl-5-imidazolcarboxylate 27 in the presence of an excess amount of LDA
(Scheme 31).35,60
N
CH2Li
Ar OLi +NLiN
H3C CO2Et 1. THF
2. HCl-H2O
NH
N
H3C
N O
Ar
Ar = 4-CH3C6H4, 4-MeOC6H4, 3,4-(MeO)2C6H3
16%-50%2792 93
Scheme 31
2-Hydroxychalcone 13 underwent oxidative cyclization in treatment with I2 in refluxing DMSO to
produce flavonones 94. The reaction of 94 with hydroxylamine hydrochloride gave the imidazolylisoxazole
95 in 80% yield (Scheme 32).29,61
MeO
OH
O
N
NCl
Me
DMSO, I2
MeO O
O
N
N
ClMe
NH2OH.HCl
MeO
OH
O
N
NCl
MeN
13 94
95
80%
Scheme 32
6. Oxazolylimidazoles
The reaction between ethyl (Z)-3-dimethylamino-2-isocyanoacrylate 96 and arenesulfenyl chlorides 97 gave
(oxazolidinyl)imidazolecarboxylates 103 in 69%–78% yields via the intermediates 98–102 (Scheme 33).62
12
ABDELWAHAB and KHIDRE/Turk J Chem
CO2Et
N+
C-
Me2N+ ArSCl
CH2Cl2 EtO2C N
NMe2H
SAr
Cl ArSCl EtO2C N
NMe2H
SAr
Cl
ArS
Cl
- MeClN
N
SAr
Me
H
Cl
ArS
EtO2CCO2Et
N+
C-
N
Me
Me
N
N
SAr
Me
H
ArS
EtO2C
N
Cl
CO2Et
H
Me2N
- EtCl
N
N
SAr
Me
H
ArS
EtO2C
O N
O NMe2
H
- ArSH
N
N
SAr
MeEtO2C
O N
ONMe2
H
9697
98 99
100
101
102 103
Ar Yield %
Ph 75
4-ClC6H4 78
4-MeC6H4 69
Scheme 33
7. Imidazolyltriazoles
Imidazolyl-1,2,3-triazolio-5-olates 107 or 110 were obtained in about 80% yield by the reaction of ethyl 4-diazo-
4H -imidazole-5-carboxylate 104 with proline 105 or p -tolyl-N -methylglycine 108 followed by the reaction of
the obtained 106 or 109 with acetic anhydride, respectively (Scheme 34).63
N
N N2
CO2Et
NH
CO2HN
NH
N
CO2Et
NN
HO2C
Ac2O
N NH
NEtO2C
NN
O
HN
HO2C
Me
ArN
NH
N
CO2Et
NNMe
HO2C Ar
Ac2O
N NH
NEtO2C
NN
O
Ar
Me
Ar = 4-tolyl
104
105
106 107
108
109 110
Scheme 34
13
ABDELWAHAB and KHIDRE/Turk J Chem
Imidazolyltriazoles 113 were prepared by cyclocondensation reaction of 4-amino-5-cyanotriazoles 112
with diamines 111 in the presence of P2S5 as catalyst (Scheme 35).64
NH2
NH2R2 N
N
N
R1
H2N
NC
+
N
N
N
R1
H2N
N
HN
R2
P2S570-80 °C
33-79 %
R1 = PhCH2, 4-ClC6H4CH2, 2,4-Cl2C6H3CH2, R2 = H, Me
111 112 113
Scheme 35
Diazotization of 1-acetamido-5-amino-4-cyanoimidazole 114 using sodium nitrite in aqueous acetic acid
followed by reaction with sodium azide gave 5-azido-4-cyanoimidazole 115 in 94% yield. Reaction of 115 with
active methylene compounds 116 in the presence of a base led to imidazolyltriazoles 117 (Scheme 36).65
N
NNC
H2N
Me
O
HN 1. AcOH
2. NaNO23. NaN3
N
NH
CN
N3
MeCOCH2R1
N
NH
NC
N
NN
Me
R1
R1 = COMe, COPh,CO2Et
114 115
116
117
Scheme 36
The imidazolyltriazole 120 was prepared by treatment of ethyl 1H -imidazole-2-carbimidate 118 with
acetohydrazide to give 119, which was then cyclized in acetic acid (Scheme 37).66
N
NH
NH
OEt
MeCONHNH2N
NH
NH
HNNH
O
Me
AcOH N
NH
N
NNH
Me
118 119 120
Scheme 37
The reaction of 2-hydrazino-2-imidazoline 121 with ethyl N -cyanoformimidate 122 gave triazoleamine
derivative 123 (Scheme 38).67
N
HN
NH2
NH OEt
N
NC+
N
HN
N N
N
NH2
121 122 123
Scheme 38
14
ABDELWAHAB and KHIDRE/Turk J Chem
Condensation of 1-methyl-2-methylsulfonyl-5-(nitro)imidazole 124 with the sodium salts of triazolidine-
diones 125 gave the imidazolyltriazolidinediones 126 (Scheme 39).68
N
N NO2
S
O
O
Me
Me
+ N
HN
HN
O
O
R
N
NO2NMe
N
HN
N
O
OR
R = Me, Et, allyl,Pr, Bu, 3,4,5-(MeO)3C6H2, PhCH=CH, PhCH2CH2, 2-phenylcyclopropyl
124125 126
Scheme 39
The synthesis of substituted 4H -1,2,4-triazole 128 from 5(4)-methyl-1(3)H -imidazole-4(5)-carboxylic
acid hydrazide 127 was reported via reaction with carbon disulfide followed by hydrazine hydrate (Scheme
40).69
N
NH
Me
O
NH
NH2
1. CS2/KOH/EtOH
2. NH2NH2.H2O/EtOH
N
NH
Me
N
N
NSH
NH2
127 128
Scheme 40
Reaction of imidazole 129 with methyl hydrazine gave 130. Thermolysis of 130 in refluxing PhMe-
MeOH containing trifluroactic acid gave an equimolar mixture of 5-amino-1-benzyl-4-cyanoimidazole 131 and
triazole 132 (Scheme 41).70
N
N
Ph
NC
NCH
MeO
MeNHNH2
N
N
Ph
NC
NCH
N
H2N
Me
PhMe-MeOH
CF3CO2H
N
N N
Ph
N
N
NH2
Ph
N
NNC
Ph
H2N
+
129 130
131 132
Scheme 41
8. Imidazolylthiadiazoles
2-Chloro-1,3,4-thiadiazole 134 was obtained from 1-methyl-5-nitroimidazole-5-carbaldehyde 31 by reacting with
thiosemicarbazide in the presence of HCl to afford the corresponding thiosemicarbazone, which upon cyclization
15
ABDELWAHAB and KHIDRE/Turk J Chem
with ammonium ferric sulfate gave 2-amino-1,3,4-thiadiazole 133 followed by diazotization of amine 133 in HCl
solution, in the presence of copper powder. The reaction of compound 134 with piperazine in refluxing ethanol
gave N -piperazinyl compound 135. N -Aroylation of the piperazine 135 with appropriate benzoyl chlorides
or thiophen-2-carbonyl chlorides afforded 136 in 77%–85% yields, which are useful as anti-leishmanial agents
(Scheme 42).71
N
N
Me
CHOO2N
S
H2N NH
NH2
1) EtOH, HCl, reflux
N
N
MeO2N
S
NN
NH2
2) NH4(FeSO4)2
H2O, ref lux
N
N
MeO2N
S
NN
Cl
N
N
MeO2N
S
NN
N
NH
NaNO2, HCl, Cu
piperazine,
EtOH, reflux
RCOCl
C6H6/pyridinereflux
N
N
MeO2N
S
NN
N
N
O
R
R = Ph, 2-ClC6H4, 3-ClC6H4, 4-ClC6H4, 2-thien, 5-Cl-2-thien, 5-Br-2-thien
31 133
134 135
136
Scheme 42
Thiol 138 was treated with phenylchloroformate and then oxidized to give 139, which was aminated with
dimethyl amine and treated with 2,2-dimethoxy-N -methylethanamine and then hydrolysis of the acetal group
was followed by cyclization to give 140, which is useful as a herbicide (Scheme 43).72
NN
SH2N
SH
1. PhOCOCl
2. [O]
NN
SNH
SO2ClPhO
1. Me2NH
2. (MeO)2CHCH2NHMe3. H2O
NN
SN
SO2
N
O
Me
OH
NMe2
138 139
140
O
Scheme 43
5-Substituted 2-(1-imidazolyl)-1,3,4-thiadiazoles 143 were prepared in 30%–74% yield by treating N ,N ’-
(thiocarbonyl)diimidazole 142 in dry toluene with an equimolar amount of diazomethane, diazoethyl acetate,
2-furyl diazomethyl ketone, or 2-thienyl diazomethyl ketone 141 in the presence of triethyl amine (Scheme
44).73−76
16
ABDELWAHAB and KHIDRE/Turk J Chem
S
N
N
NN
O
N+-N X
CH2N2
N2CHCO2Et
+ PhMe/Et3NN
N
N N
S R
142
141
143
R = H, CO2Et, 2-furyl, 2-thien; X = O, S
Scheme 44
The synthesis of 3-methyl-5-(1-methyl-5-nitro-1H -imidazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-amine 145
was conducted by treating ethyl 1H -imidazole-2-carbimidate 118 with acetohydrazide to give 144, followed by
cyclization with P2S5 (Scheme 45).77
NN
S
N
NO2N
Me
Me
NH2N
NH
NH
OEt
MeCONHNH2
N
NH
NH
HNNH
OMe
P2S5
118 144 145
Scheme 45
2-Amino-5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole 147 was prepared by treatment of 1-oximino-
1-(1-methyl-5-nitro-2-imidazolyl)-2-phenylglyoxal 146 with benzoyl chloride, followed by treatment with sodium
methoxide and thiosemicarbazide and cyclization of the intermediate with HCl (Scheme 46).78
S
NN N
NNO2
Me
H2N
N
O
Ph
N
NNO2
Me
OH
1. PhCOCl
2. NaOMe
3. NH2NHCSNH24. HCl
146 147
Scheme 46
Herbicidal thiadiazole derivatives 153 were prepared by treating the amines 148 with phosgene, followed
by reacting with aminoethanols 150 followed by chlorination and then cyclization with base (Scheme 47).79
17
ABDELWAHAB and KHIDRE/Turk J Chem
R = t-Bu, R1 = Me; R = CF3, R1 = Me, Et
NN
SN
N
OR R1
NN
S
NH2
R
CO(Cl)2 NN
S NH
RN N
SNH
RO
R1NHCH2CH2OH
NN
S NH
RO
N
R1
OHNN
S NH
RO
N
R1
ClSOCl2
base
148149
151152
153
150
Scheme 47
9. Indolylimidazoles
Oxidation of 1-methoxymethyl-3-acetyl-2-chloroindole 154 with selenium dioxide afforded the 3-indolylglyoxal
hydrate 155 in 96% yield, which was converted into the corresponding azide 156 in 80% yield by treatment with
polymeric quaternary ammonium azide (QN3). The reaction of 155 and 156 with N ,N -dimethylguanidine in
ethanol at –30 ◦C gave 157 and 158 in 91% and 95% yields, respectively (Scheme 48).80
NCl
OMe
MOM
SeO2, dioxane
100 °C N
Cl
O(HO)2HC
MOM
Q-N3
MeCN, rtN
Cl
MOM
NHN
O
Me2N
NN3
O(HO)2HC
MOM
N
NH2
HN
Me
Me
N
NH2
HN
Me
Me
N
NH2
MOM
NHN
O
Me2N
EtOH, -30 °C
154155
156
157
158
Scheme 48
2-Methyl-1H -indole-3-carbaldehyde 159 was condensed with benzil in the presence of ammonium acetate
in refluxing AcOH to yield 3-(4,5-diphenyl-1H -imidazol-2-yl)-2-methyl-1H -indole 160 (Scheme 49).81
18
ABDELWAHAB and KHIDRE/Turk J Chem
NH
Me
CHO
+
O
O Ph
Ph
AcOH/NH4OAc
NH
Me
NHN
Ph
Ph
159 160
Scheme 49
A 2-step regioselective synthesis of indolyl imidazole 163 was reported by the reaction of α -azidoacetyl
indole 161 with carboxylic acids 162 in the presence of trimethyl phosphines followed by cyclization using
ammonium acetate under microwave irradiation (Scheme 50).82
NH
N3O
+ RCO2H
1) PMe3, THF, rt2) NH4OAc, DMF/MW
35%-53% overall yield NH
NH
N R
161 162 163
Scheme 50
The preparation of 4-(3-indolyl)imidazoles 165 as phosphodiesterase inhibitors has been reported. Re-
fluxing N -(2-acetoxyethyl)-3-(4-methoxyphenylglyoxylyl)indoles 164 with aldehydes in acetic acid in the pres-
ence of ammonium acetate gave 3-(5-(4-methoxyphenyl)-2-(thiophen-2-yl)-1H -imidazol-4-yl)-1H -indoles 165
(Scheme 51).83−85
N
O
MeO
RR1
Ar CHO
NNH
S
OMe
N
R
R1
AcOH/NH4OAc
R = Cl,
R = NO2 , R1 =H
OO
Me
R1 = Ar = 2-thienyl
Ar = 2-thienyl
R = R1 = H, Ar = 4-MeC6H4
164 165
O
Scheme 51
Preparation of 5-(substituted phenyl)-4-(3-indolyl)imidazoles 170 as phosphodiesterase inhibitors was
reported by reaction of 4-(benzyloxy)phenylacetic acid 166 with indolylmagnesium bromide 167 to give 2-
(4-benzyloxyphenyl)-1-(3-indolyl)ethanone 168. Then oxidation of 168 with selenium dioxide followed by
19
ABDELWAHAB and KHIDRE/Turk J Chem
reaction with benzaldehyde and ammonium acetate gave 5-(4-benzyloxyphenyl)-4-(3-indolyl)-2-phenylimidazole
170 (Scheme 52).86
O
OH
OPh
NH
NH
OPh
OBrMg
+
SeO2
NH
O
Ph
OO
PhCHO
NH4OAc
NHN
Ph
HN
OPh
166 167 168
169 170
Scheme 52
Indolylimidazolinones 173 were prepared from the reaction between 3-amino-2-phenylindole 171 and the
oxazolones 172 (Scheme 53).56
R = Ph, substituted Ph, PhCH=CH
NH
Ph
NH2
NO
Ph
RO
+
NH
Ph
N N
Ph
RO
171 172 173
Scheme 53
4-(3-Indolyl)-5-(hetero)aryl-2-substituted-imidazoles 177, as anti-inflammatory, analgesic, and antipyretic
agents, were prepared by treatment of oxalyldichloride with indole 174 followed by reaction of the ob-
tained 175 with anisole to give 1-(3-indolyl)-2-(4-methoxyphenyl)ethanedione 176. Reaction of 176 with
2-fluorobenzaldehyde in acetic acid and in the presence of ammonium acetate under reflux conditions gave
177 (Scheme 54).87,88
20
ABDELWAHAB and KHIDRE/Turk J Chem
R1 = 4-MeOC6H4, R2 = 2-FC6H4, 2-benzofuryl
HN
NH
N
R1
R2
HN
+ (COCl)2
HN
OO
Cl anisole/AlCl3R1
NH
OO
AcOH/NH4OAc
174 175 176
177
R2CHO
Scheme 54
Indolylimidazoles 181 were obtained by heating a mixture of imidazole with acyl chlorides 178 to afford
the diacetyl imidazolium salts 179 in 7%–95% yields. Treatment of 179 with indoles 180 in acyl chloride as
solvent for 2 h afforded the 1,3-diacyl-2-(3‘-indolyl)-4-imidazoles 181 after dilution with water (Scheme 55).89
NH
N
RCOCl
HN
N
COR
COR
Cl
N
R1
R2
N
N
COR
COR
NR1
R2
R = Me, Ph, CHBrCHMe2, 2-thien; R1, R2 = Me, H
178
179
180
181
Scheme 55
10. Imidazolylbenzimidazoles
2-(Imidazol-4-yl-4’)benzimidazole 183 was synthesized by the reaction of imidazole-4-dithiocarboxylic acid 182
with an equimolar amount of o-phenylenediamine (Scheme 56).90
N
NH
N
HNN
HN
CS2H
+
NH2
NH2
NaOH/H2O
182 183
Scheme 56
2-(N ,N ’-dimethylbenzimidazolon-5-yl)-4,5-diarylimidazoles 185 were prepared by cyclocondensation of
5-formyl-1,3-dimethyl-2-benzimidazolinone 184 with the corresponding diketones in boiling acetic acid contain-
ing ammonium acetate in 49%–80% yields (Scheme 57).91
21
ABDELWAHAB and KHIDRE/Turk J Chem
Ar = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4, 4-EtOC6H4, 4-NO2C6H4
N
N
O
Me
Me
N
N
O
Me
Me
O
H
N
NH
ArAr
Ar O
O
AcOH/NH4OAc
184 185
Ar
Scheme 57
Antihypertensive benzimidazolones 191 were prepared by N -formylation of 2-nitroaniline followed by
treatment with sulfurylchloride to give 2-nitrophenylcarbonimidic dichloride 188. Reaction of 188 with ethane-
1,2-diamine followed by reduction with Raney Ni gave 190, which then was cyclized with urea to produce 191
(Scheme 58).92
N
HN
HN
NH2
NH
N
O
N
HN
urea
NO2
NH2
NO2
NH
CHO
SO2Cl2
NO2
N
ClCl
H2NNH2
N
HN
HN
NO2Raney Ni
HCHO
186 187 188
189 190 191
Scheme 58
11. Medicinal applications
5-Oxoimidazoline 192 showed antibacterial and antifungal activity,8 and imidazoline 193 showed pronounced
antischistosomacidal activity.9 Also 1-(5-nitro-2-thiazolyl)imidazolinyl derivatives 194 and their salts were used
as bactericides, protozoacides, and schistosomacides (Figure 1).10
N
N
O
Ph
N
SCO2Me
N OMe
Ph
N
S
NN OR
OO2N
R = COR1, R1 = alkyl, 2-furyl, cyclohexyl
192 193
N
SO2N
N N R
NOR1
R = H, lower alkylR1 = H, lower alkyl, tetrahydropyranyl
194
Figure 1. Chemical structures of compounds 192–194.
3-(2-Butyl-4-chloro-1H -imidazolyl)-isoxazoline 195 was used as a cholinesterase inhibitor.17 Imida-
zolylpyrazolylvinylpyridine 196 was useful as an inhibitor of ATP-protein kinase interactions.11 Thiadiazoly-
loxyphenylurea 197 was used as a protein kinase inhibitor.93 4-Substituted-3(1H)-imidazol-1,2,5-thiadiazoles
198 were useful as antiarrhythmic agents.12 2-(Methylsulfonyl)-5-(1-methyl-5-nitro-2-imidazolyl)1,3,4-thiadiazole
22
ABDELWAHAB and KHIDRE/Turk J Chem
199 showed significant antibacterial and antifungal activity.13 Also imidazolylthiadiazoles 200 are useful as po-
tent anti-Trypanosoma cruzi drugs (Figure 2).94−96
HN
N
Bu
Cl
ON
CN
195
HN
N
NH
N
NHN
CF3
Et
196
NH
O
NH
O
S N
N
NN
F3C
Cl
197
NNS
N O(CH2)3NEt2
N
198
N
N
MeO2N
S
NN
SO2Me
199
N
N
MeO2N
S
NN
NH2
200
Figure 2. Chemical structures of compounds 195–200.
2-(4,5-Dihydro-1H -imidazolyl)-dihydro-1H -indoles 201 are antidepressants.17 Topsentin 202, a bis(indolyl)imidazole
marine natural product, inhibited the proliferation of cultured human and murine tumor cells at micromolar
concentrations.14−16 Indolylimidazolone 203 acts as a protein kinase C inhibitor.18,19 4-(3-Indolyl)imidazole
derivatives 204 are useful as interleukin 6 production inhibitors.97 Indolylimidazole derivatives 205 are used
as Flt-1 and topoisomerase inhibitors (Figure 3).98
N HN
NF
MeNH
HO
O
N
HN
NH
HN
N
O
NH
N
Me
HN
NH
N R1
R2
R1 = 4-MeC6H4, R2 = 4-CF3C6H4
NH
N
N
R
R = alkyl, alkoxyalkyl
201 202 203
204 205
Figure 3. Chemical structures of compounds 201–205.
5-Imidazol-1-yl-1H -benzimidazoles 206 act as interleukin-1 inhibitors.99 Imidazolylbenzothiazole deriva-
tives 207 are used as antithrombotics and inhibited collagen-induced blood platelet aggregation in platelet-rich
plasma of a rabbit (Figure 4).100
23
ABDELWAHAB and KHIDRE/Turk J Chem
NH
NS
Me
MeNN
NH
N
Me
N
NH
Me
N
MeO
206207
Figure 4. Chemical structures of compounds 206 and 207.
Substituted imidazolylthiadiazoles are useful as antiprotozoal agents101 and bactericides and are effec-
tive against ascarids.102 Thiazolylimidazoles 208 act as microsomal triglyceride transfer protein (MTP) and/or
apoprotein B (ApoB) inhibitors useful in the treatment of dyslipidemia and related diseases.103 Pyrrolylim-
idazole 209 was used as an antibiotic and antitumor agent.26 Also, 4,5-dichloroimidazole-2-carboxylic acid
derivative 210 is useful as an herbicidal and fungicidal (Figure 5).62
N
S
N
NMe
Ph
EtN
O
Me
OF3C
N NH
OPh
N
N
N
HNO
NCl
Cl
208 209
210
Figure 5. Chemical structures of compounds 208–210.
12. Conclusion
This survey has attempted to summarize the synthetic methods and medicinal applications of different azoles
directly attached to an imidazole nucleus in recent years. In the future we will publish a review article covering
the fused imidazole nucleus with different azoles.
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