azolylimidazoles: synthetic strategies and medicinal applications

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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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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azolylimidazoles: synthetic strategies and medicinal applications

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