azolylimidazoles: synthetic strategies and medicinal applications

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  • Turk J Chem

    (2014) 38: 1 27

    c TUBITAKdoi: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, Egypt

    2Shaqra University, Al Dawadmi, Saudi Arabia3Chemical 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,24 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.810 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.1416 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,2023 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: rizkkhidre@yahoo.com

    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, 20C, 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 1020 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 -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()-dianions with electrophilic-nucleophilic reagents has extended to the conden-

    sation of C()-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 32 33

    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-methy

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