Mol Divers DOI 10.1007/s11030-015-9590-6

COMPREHENSIVE REVIEW

Current advances in the synthesis and biological potencies of tri- and tetra-substituted 1H-imidazoles Majid M. Heravi1 · Mansoureh Daraie1 · Vahideh Zadsirjan1

Received: 14 August 2014 / Accepted: 25 March 2015 © Springer International Publishing Switzerland 2015

Abstract In this report, we review the current chemistry progress and in particular the synthesis approaches of triand tetra-substituted imidazoles. Keywords Tri-aryl-1H -imidazoles · Tetra-aryl-1H imidazoles · Biological activity

Introduction Imidazole (1,3-diaza-2,4-cyclopentadiene) is a five-membered organic compound with the formula C3 H4 N2 , with three carbons and two nitrogens, set at positions 1 and 3. Its derivatives are extensively represented in a variety of natural products such as histamine, histidine, biotin, alkaloids and nucleic acids. They are frequently found as constituents of various synthetic medicines, including widely prescribed drugs, such as cimetidine (tagamet) 1, etomidate (amidate) 2, ketoconazole 3 (recently discontinued in several countries), and the well-known antifungal clotrimazole 4 (Fig. 1) [1]. Thus, imidazole is an entity of great interest, and the synthesis of its derivatives from long-past and recent years has received the attention of synthetic and medicinal chemists to create new derivatives and explore their biological and pharmacological potentials. Historically, imidazoles 7 were first synthesized from glyoxal 5 ammonia and formaldehyde This article is dedicated to Professor Abbas Shafiee, who taught me how to synthesize, Clotrimazole (Structure 4 of this review) at bench scale, in 1982.

B 1

Majid M. Heravi [email protected] Department of Chemistry, School of Science, Alzahra University, Vanak, Tehran, Iran

6 ammonia by Heinrich Debus in 1858 [2]. This procedure, while giving relatively low yields, is still being used for the synthesis of different C-substituted imidazoles (Scheme 1). Recent advances and developments in the application of organometallic catalysts, co-ordination chemistry, and environmentally benign chemistry have significantly progressed the frontier of imidazoles to the synthesis and applications of imidazole derivatives as ionic liquids [3,4] and relatively stable N -heterocyclic carbenes [5–7]. As a result, both the introduction of new methodologies and the developments of the already reported synthesis of imidazoles have created great interest in universities’ research laboratories as well as in industry. Consequently, an increasing amount of worldwide research has grown in the area of synthesis, functionalization, and derivatization of the imidazole scaffold [8–21]. A literature survey revealed several useful reviews on the synthesis of imidazoles [22–26]—among them a comprehensive review published in Tetrahedron in 2007 [22]. We are involved in heterocyclic chemistry [27–34] and focus on enhancing recent developments and progress in organic chemistry especially in the area of name reactions [35–38]. In line with our interest, considering the importance of the imidazole moiety and prompted by the mentioned comprehensive review [22], we aimed for an update and extension of its usefulness focusing on the synthesis of imidazoles. However, due to enormous activities in different aspects of imidazole chemistry and the large number of new references, we are focusing this review on the chemistry and applications of tri- and tetra-substituted imidazoles. Thus, the main intention of this report is to survey the methods reported in the literature up to 2014 for the synthesis of tri- and tetrasubstituted 1H -imidazoles. In addition, this review outlines and discusses data regarding the biological activities of these heterocycles to make it more useful for medicinal chemists, pharmacists, and pharmacologists.

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Fig. 1 Examples of synthetic imidazole drugs: cimetidine 1, etomidate 2, ketoconazole 3, and clotrimazole 4

Scheme 1 Synthesis of imidazole derivatives 7 using glyoxal 5, formaldehyde 6, and ammonia

Syntheses of vicinal tri- and tetra-aryl-substituted 1H-imidazoles Synthesis of 1,2,4-tri-aryl-1H-imidazoles In 2009, a new series of 1,2,4–tri-substituted nitrogen heterocycles acting as inhibitors of transforming expansion factor β type 1 receptor (ALK5) were synthesized by Li and co-workers [39]. As shown in Scheme 2, the reaction of substituted cyanobenzene 8 with substituted aniline 9 in tetrahydrofuran, catalyzed by NaN(SiMe3 )2 afforded substituted amidines 10 as an intermediate [40]. Then, the amidines 10 reacted with 4-bromoacetylbenzonitrile or 1-bromo3,3-dimethyl-butan-2-one to provide the desired 1,2,4-trisubstituted imidazoles 11 or 12, respectively. Finally, the nitrile group of 12 can be transformed to a carboxamide group by the reaction with potassium hydroxide in t-BuOH at reflux temperature to create compounds 13. The ALK4/5/7inhibitory activity of the compounds was assessed using an ALK4/5/7 autophosphorylation assay where some compounds exhibited good-to-excellent inhibition against ALK5,

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with the compound 13c exhibiting moderate-to-good ALK5 inhibition profile and only weak cytotoxicity. On the other hand, compound 13c showed better ALK5 selectivity against ALK4/ALK7 (about 10-fold) in comparison with SB431542, a well-established ALK5 inhibitor [39]. The regio- and stereoselective alkenylations of imidazoles were achieved using nickel/Lewis acid binary catalysis via activation of C–H bond and insertion of alkynes stereoselectively to provide a different range of substituted imidazoles with high atom economy. In general, straight functionalization of imidazoles catalyzed by transition metal C–H bond activation is a facile and convenient alternative considering both in terms of economy of atom and step. For C(2)-alkenylation, various imidazoles 14a–c and alkynes 15a–d were reacted in the presence of catalytic amounts of Ni(-cod)2 , P(t-Bu)3 , and AlMe3 at 100 ◦ C in toluene to produce the corresponding adducts 16 (Scheme 3) [41]. On the other hand, the C(5)-alkenylation of 2-substituted imidazoles was achieved easily from the reaction of the 2-substituted imidazoles 14e,f and alkynes 15e,f using Ni(cod)2 , PCyp3 , and AlMe3 as catalysts to afford the desired C(5)-alkenylated products 16 in good yields. Notably, using P(t-Bu)3 as a ligand provided regioselective C(2)alkenylation exclusively, whereas PCyp3 is efficient for the C(5)-alkenylation of C(2)-substituted imidazoles. This method can be used for the reaction differently substituted imidazoles with various internal alkynes to create a wide variety of tri-substituted ethenes with high regio- and stereoselectivities in relatively good yields (Scheme 4) [41]. In 2009, Husain and co-workers described the preparation of tri-substituted imidazoles by reacting disubstituted imidazoles with chlorobenzene using a catalytic amount of triethylamine (TEA) [42]. For the synthesis of the desired tri-substituted imidazoles 20a–i, the corresponding phenylglyoxals 18a,b were initially synthesized via stirring of acetophenone/4-chloroacetophenone 17 in dioxane with selenium dioxide under reflux conditions. Then, aromatic aldehydes 18a,b reacted in the presence of ammonium acetate to yield disubstituted imidazoles 19a–i. Finally, tri-substituted imidazoles 20a–i were constructed by reacting disubstituted imidazole 19a–i with chlorobenzene using a catalytic amount of triethylamine (TEA). Their antiinflammatory and antimicrobial activities of di- and trisubstituted imidazoles were studied. As a result, products 20c and 20g exhibited significant anti-inflammatory activity, causing very low ulcerogenicity. Other compounds such as 19f, 19i, 20d, 20f, 20h, and 20i showed also considerable antimicrobial activity (Scheme 5) [42]. A series of novel 1,2,4-tri-substituted-1H -imidazole derivatives 24a–o with anticonvulsant activity were synthesized by Husain in 2011 [43]. N -(3-acetyl-4-hydroxyphenyl) acetamide 21 in the presence of SeO2 yielded N -[4-hydroxy3-(2-oxoacetyl)phenyl] acetamide 22. Phenylglyoxal 22 was

Mol Divers Scheme 2 A novel series of 1,2,4-tri-substituted nitrogen heterocycles as inhibitors of transforming expansion factor β type 1 receptor (ALK5)

Scheme 3 Nickel/AlMe3 catalyzed C-2 alkenylation of imidazoles

Scheme 4 Nickel/AlMe3 catalyzed C(5)-alkenylation of 2-substituted imidazoles

treated with various aromatic aldehydes in the presence of ammonium acetate in acetic acid to yield the disubstituted imidazoles 23a–o. Then, 2,4-disubstituted-1H -imidazoles

3a–o reacted with chlorobenzene in the presence of triethylamine to yield 1,2,4-tri-substituted-1H -imidazole derivatives 24a–o. Remarkably, these imidazoles showed potential

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Mol Divers Scheme 5 Synthesis of tri-substituted imidazoles 20a–i catalyzed by triethylamine (TEA)

anticonvulsant properties adding a new class of potent compounds [44–46]. Notably, in a routine anticonvulsant screening, only compound 24k exhibited potency, almost equal to that of the approved prescription drugs, phenytoin and carbamazepine. Compounds 24a, 24c, 24e, 24l, and 24n passed the routine test successfully with no sign of neurological discrepancy as a common side effect. Several 1,2,4-tri-substituted-1H -imidazole derivatives showed anticonvulsant potential in MES screening. Some compounds (24b, 24c, 24d, 24f, 24i, 24k, 24l, and 24n) were more lipophilic and more active. Compounds 24a, 24e, 24g, 24h, 24m and 24o were also lipophilic but showed less activity in the MES test (Scheme 6) [43]. As depicted in Scheme 7 in a novel and efficient procedure, a variety of substituted ketones 25 with benzylamines 26 using CuI/BF3 ·Et2 O/O2 system reacted to yield unexpectedly 1,2,4-tri-substituted imidazoles 27 in good yield. Consequently, this method offers a facile, practical, and atom-economic route for the development of polysubstituted imidazoles using gentle conditions. This strategy involves the elimination of eight hydrogen atoms, the functionalization of four C(sp3 )-H bonds, and the formation of three new C–N bonds in one operation [47]. In another effort, aliphatic ketone 3,3-dimethylbutan-2one 28 was treated with compound 26 in the presence of CuI/BF3 ·Et2 O under an O2 atmosphere to construct the required tri-substituted imidazole derivative 29 in 56 % yield (Scheme 8). As a result, a novel, one-step approach was established for the preparation of the highly substituted imidazoles. Remarkably, when BF3 ·Et2 O was used as a co-

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catalyst combined with CuI, a higher reactivity was observed [47]. The suggested mechanism for this reaction is presented in Scheme 9. Enamine 30’ created via tautomerization of imine 30 from 25 and 26 is oxidized to 32 [48]. Then, the intermediate 32 is attacked by another molecule of 26 to generate intermediate 33. Subsequent dehydration of 33 under Lewis acidic conditions creates intermediate 34. Ultimately, intermediate 34 undergoes an annulation to form intermediate 35. Then, a subsequent proton removal affords 37. Finally, further oxidation of 37 yielded the desired product 27. A general and convenient procedure was developed for the synthesis of some antimicrobial Mannich bases containing an imidazole moiety. Remarkably, there are not many reports describing the preparation and biological studies of such compounds. A number of Mannich bases, 3-substituted aminomethyl-5-(2-methyl-4-nitro-1-imidazomethyl)-1,3,4oxadiazole-2-thiones, showing antimicrobial activity were developed by Frank and co-workers [49]. For the synthesis of Mannich bases, 2-methyl-4-nitro-1H -imidazole 38 was reacted with ethyl chloroacetate 39 using potassium carbonate in dry acetone resulting in ethyl (2-methyl-4-nitro-1H imidazol-1-yl) acetate 40. Then, the corresponding ester was subjected to hydrazinolysis to yield 1-[2-(hydrazinooxy)2-oxoethyl]-2-methyl-4-nitro-1H -imidazole 41. Then, compound 41 was refluxed in KOH and carbon disulfide in ethanol to furnish novel 5-[(2-methyl-4-nitro-1H -imidazol1-yl)methyl]-1,3,4-oxadiazole-2(3H )-thione 42. As shown in Scheme 10, new Mannich bases 43a–j can be produced by the treatment of 1,3,4-oxadiazole with suitable amines

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Scheme 6 A strategy for synthesis of the substituted imidazoles (23a–o, 24a–o) Scheme 7 Imidazole synthesis from ketones and benzyl-amine

Scheme 8 Synthesis of tri-substituted imidazole derivative 29 from the reaction of 28 and 26

and 40 % formaldehyde in moderate-to-good yields. Compounds 43b–j revealed high antifungal activity against C. albicans with low MIC values. Compound 43c containing a fluoro group showed about fivefold enhanced activity against T. mentagrophytes compared to the known fluconazole. The

antifungal strength of a number of tested compounds prevailed over their antibacterial activities. The remarkable potency and facile synthesis of Mannich bases bearing imidazole scaffold make them very promising antifungal candidates [49].

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Scheme 9 Suggested mechanism for the synthesis of imidazole 27

A novel and practical method led to the synthesis of multisubstituted imidazoles through a stepwise [3 + 2] cycloaddition of different nitro olefins to N -aryl benzamidines catalyzed by iron (III) in DMF under air atmosphere. This protocol has merits of being facile, atom-economic, ecofriendly, having good yield, and highly regioselective. This method showed several advantages for the synthesis of tri- or tetra-substituted imidazoles by copper-catalyzed [3 + 2] cycloaddition [50]. The advantages include using an inexpensive and less-toxic catalyst, ligand-free conditions, easy operation, being environmentally benign, and without the need for specific atmosphere. As shown in Scheme 11, different nitro olefins 45 and N - p-tolylbenzamidine 44 were reacted to yield various multisubstituted imidazoles 46 in moderate-to-good yields. Remarkably, the nature of the substituent on the aromatic rings is somehow influential on the yields of the obtained products. In general, the aromatic ring-bearing electron-releasing groups (e.g., methyl and methoxy groups) afforded lower yields than those carry-

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ing electron-withdrawing groups (e.g., fluoro-, chloro-, and trifluoromethyl groups) [51]. To explore the mechanism of the reaction, several control experiments were manipulated. The reaction of 44 and 45 was performed in the absence of FeCl3 in DMF at 90 ◦ C under air for 4 h and found to be fruitless. Compound 46 was obtained in high yield even if 44 and 45 were reacted under N2 protection. Thus, it can be speculated that the NO2 group is the terminal oxidant in this protocol. A proposed mechanism for this reaction is illustrated in Scheme 12. Initially, the intermediate 47 is formed from Michael addition of N - p-tolylbenzamidine 44 to 1-(2-nitrovinyl)-benzene 45. FeCl3 , serving as Lewis acid catalyst, converts 47 to another intermediate 48 via intramolecular nucleophilic addition. Subsequently, the final product 46 was produced from intermediate 48 via removal of nitroxyl (HNO) and H2 O. As shown in Scheme 13, an efficient preparation of the di-tert-butoxycarbonyl (Boc) protected 2-AI 53 was developed for the synthesis of a series of 2-amino-substituted

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Scheme 10 Facile synthesis of Mannich bases bearing an imidazole scaffold

Scheme 11 Synthesis of various multisubstituted imidazoles 46 from N - p-tolylbenzamidine and nitroolefins

Scheme 12 A proposed mechanism for the synthesis of multisubstituted imidazoles 46

analogs of 2-AIT 49. Several compounds of this kind showed an enhanced capability to inhibit biofilms of three diverse MRSA strains in comparison with their parent compound 49 [52]. α-Bromoketone 51, which is generated by isomerization of 2-octyn-1-ol 50 under “zipper” [53] conditions [54], is subjected to Jones oxidation to afford oct-7-ynoic acid. The crude carboxylic acid is treated with oxalyl chloride to provide the desired acyl chloride, with successive reaction with diazomethane followed by quenching of the intermediate diazoketone using aqueous HBr to form α-bromoketone 51. The sodium salt of 1,3-di-Boc-guanidine 52 (to overcome the lack of nucleophilicity) created by the treatment with sodium hydride, reacted with compound 51 to yield a mixture of di-Boc-protected 2-aminoimidazole, which is easily transformed into the corresponding imidazole 53 by treatment with mesyl chloride [52]. Substitution on the 2-amino group of 53 using different alkyl halides in the presence of sodium hydride gives alkynes 54, which afforded triazoles 58 in excellent yields (75–97 %)

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Mol Divers Scheme 13 Synthetic 2-AIT derivatives 49 (Biofilm inhibitor) and synthetic approach to di-Boc 2-amino imidazole 53

N H2N N H

5N

N N

NH O

4

49

1) ethylenediamine, NaH 2) CrO3, H2SO4, H2O, acetone

OH

H

O Br

3) 1) CH2N2, Et2O-CH2Cl2, 0 °C 2) aq HBr 50

51

NBoc 51 +

BocN

1) di-Boc guanidine, NaH DMF, 4h 0 °C to r.t.

NHBoc H

N NBoc

NH2

Na 52

2) MsCl, Et3N, CH2Cl2, 1h

53

Scheme 14 Substitution on the 2-amino group of 53 using different alkyl halides with sodium hydride

upon subjection to the copper-catalyzed azide-alkyne Huisgen cycloaddition as an example of click reaction, with azide 56 [55] and compound 57. Removal of the Boc groups from 57 was achieved with TFA/CH2 Cl2 (Schemes 14, 15). Thus, a general method using 1,3-di-Boc-guanidine for the selective synthesis of 2-amino-substituted derivatives has been introduced. These derivatives showed improved biofilm inhibition

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activities versus a series of MRSA strains in comparison with the unsubstituted mother compound, with aliphatic and benzyl substitution providing the highest potencies. Recently, Neuville and co-workers described a proficient and regioselective route for the synthesis of 1,2,4tri-substituted imidazoles in modest-to-good yields through copper-catalyzed oxidative diamination of terminal alkynes

Mol Divers Scheme 15 General method for the synthesis of 2-aminoimidazoles 58

Scheme 16 Cu-Catalyzed synthesis of imidazoles: N -substituted amidines 61

by amidines. Following up Stahl’s studies [56] to further assess the reactivity of amidines to acetylenes, N -substituted amidines 59 containing several functional groups (e.g., alkyl, ether, ester, nitro, halo, and a broad range of terminal alkynes), alkynes 60 (e.g., aryl, primary and tertiary alkyls, cyclopropyl, and silyl-substituted alkynes) reacted in the presence of CuCl2 ·2H2 O, pyridine, Na2 CO3 , O2 (1 atm) to yield the desired 1,2,4-triarylimidazoles 61 in 39–74 % yields. It should be mentioned that benzamidine itself was not well suited in this protocol due to the formation of 1,4diphenylbuta-1,3-diyne (Scheme 16) [57]. Recently, the preparation of several new 1,2,4-tri-substituted imidazoles, 1-(benzo[1,3]dioxol-5-yl)-2-(6-methylpyridin-2-yl)-4-substituted imidazoles containing a methyleneamino linkage on the 4-position of the core ring was reported [58]. Some of them act as inhibitors of transforming expansion factor-β type I receptor (ALK5). For the preparation of 1,2,4-tri-substituted imidazole derivatives 72a–d, benzo[d][1,3]dioxol-5-amine 62 was reacted with sodium bis(trimethylsilyl)amide in anhydrous THF under nitrogen atmosphere, followed by treatment with 6-methylpicolinonitrile 63 to provide N -(benzo[d][1,3]dioxol-5-yl)-6-methyl picolinimidamide 64 in 86 % yield [59]. Cyclization of the

amidine 64 by treatment with ethyl 3-bromo-2-oxopropanoate and NaHCO3 in i-propanol was achieved to create the imidazole 65 in 43.3 % yields. Subsequently, the ester group of 65 by reduction with LiAlH4 was transformed into hydroxymethyl to yield (N -(benzo[d][1,3]dioxol-5-yl)-2-(6methylpyridin-2-yl)-1H -imidazol-4-yl)-methanol 66 in high yield [60]. The primary alcohol 66 was treated with SOCl2 under reflux in CH2 Cl2 to yield the corresponding chlorinated compound 67 [61]. Imidazolyl methylene chloride 67 was reacted with potassium phthalimide in anhydrous DMF to yield Gabriel adduct 68, which was purified and characterized before being subjected to hydrazinolysis to yield the corresponding primary amine 69 [62]. The primary amine 69 was condensed with 2,2,2-trichloroethyl chloroformate mediated with triethylamine (Et3 N) in anhydrous THF to create compound 70. The corresponding unsymmetric ureas 72a–c were effectively prepared through the reaction of compound 70 with amines 71a–c in DMSO, catalyzed by N,N -diisopropylethylamine (DIEA) in 52.5–89.4 % yields [63]. Urea 72d can be formed by ammonolysis of 2,2,2trichloroethyl phenylcarbamate 70 in 67.5 % yield (Scheme 17). On the other hand, the amines 73a–b were alkylated by imidazolyl methylene chloride 67 to yield 1,2,4-trisubstituted imidazole derivatives 74a–b in 42.8–55 % yields [64]. The nitrile functionality of compound 74b by treatment with 28 % H2 O2 and 20 % NaOH aqueous solution in acetone was transformed to carboxamide to furnish the target molecule 74c in relatively low yield [65]. Finally, as shown in Scheme 18, N -(benzo[d][1,3]dioxol-5-yl)-2-(6methylpyridin-2-yl)-1H -imidazole-4-carboxamide 75 was synthesized by ammonolysis of the ester group of the compound 65 to carboxamide in the presence of NH3 /MeOH solution to construct carboxamide 75 in 55.6 % yield.

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Scheme 17 Synthesis of 1,2,4-tri-substituted imidazole derivatives 72a–c

Synthesis of 1,2,5-tri-aryl-1H-imidazoles Shaw and co-workers reported a multistep method for the development of tri- and tetra-alkyl-substituted imidazoles beginning from easily accessible thioamides under mild con-

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ditions [66]. This reaction is performed regiospecifically giving tetra-alkyl substituted imidazoles. Thus, the substituted amino alcohol was added to a thioamide, followed by oxidation with PDC. Furthermore, aryl substitution at both 4- and 5-positions, which is possible, performs well.

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Scheme 18 Synthesis of 1,2,4-tri-substituted imidazole derivatives 74a–c and N -(benzo[d][1,3]dioxol-5-yl)-2-(6-methylpyridin-2-yl)-1H imidazole-4-carboxamide 75

Dissimilar to most imidazole synthesis, acid-sensitive functionality is well tolerated, giving an opportunity to conduct the reactions under mild conditions. Consequently, a fruitful approach toward tri-alkyl-substituted imidazoles under mild conditions was described. Notably, that imidazole formation was achieved smoothly and with no loss of the N -Boc group. Amide bond generation would allow assimilation of the first two substituents (R3 and R4 ), and the remaining two substituents (R1 and R2 ) are attached by an amino alcohol to afford tetra-substituted imidazoles after being oxidized and cyclized. The EDC reaction of 3-phenylpropan-1-amine 76 and 3(4-fluorophenyl) propanoic acid 77 was achieved providing the corresponding amide in excellent yield. Then, it was treated with Lawesson’s reagent [67] to afford the desired thioamide 78. The latter is then condensed with a substituted vicinal amino alcohol 79 in the presence of mercury (II) chloride to afford the intermediate amidine 80. Pyridinium dichromate (PDC) was added to the amidine 5 directly to afford imidazole 81 in good yields. Substituted amino alcohols 79, where R1 = H can be obtained from the reduction of appropriate amino acids. Despite the limited commercial availability of some amino alcohols, the aforementioned strategy is useful for the other desired noncommercially purchasable, substituted amino alcohols. The facile synthesis

of commercially purchasable tri-substituted isomer, where R2 = H was accomplished using a two-step but one-pot reaction beginning from an appropriate aliphatic aldehyde. Aldehyde is initially reacted with trimethylsilyl cyanide to produce the silyl-protected cyanohydrin and then subjected to reduction conditions using lithium aluminum hydride to obtain the desired amino alcohol. 1,2,5-Trialkyl-substituted derivatives can be synthesized from amino alcohols as the branched, fluorinated, and oxygenated alkyl substituents. This method is well matched with aryl-substituted amino alcohols, giving the 5-arylsubstituted imidazole. 1,2,4,5-Tetra-substituted imidazoles bearing either one or two aryl substituents were synthesized in good yield. The cyclohexane-fused analogs are used in a fascinating route for the synthesis of partially saturated benzimidazoles. An appealing application of this protocol is outlined by the preparation of differently substituted tetraalkyl imidazoles. The cyclohexyl analog was also prepared, starting from the respective disubstituted amino alcohol reacting with thioamide 78. Further, forbearance of the N -Boc-protected piperidine moiety shows the mild conditions required for this methodology (Scheme 19, 20) [66]. This strategy is found particularly efficient when various R1 and/or R2 were tolerated in a two-step synthesis of the corresponding imi-

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Scheme 19 Synthesis of substituted imidazoles and amino alcohols

dazoles starting from thioamide. The desired products were obtained through easy work-up and purification procedures. This sequential reaction is performed under mild conditions, affording compounds carrying acid-sensitive functionality. Moclobemide 82 is a selective and reversible inhibitor of Monoamine oxidase-A and can be applied as an antidepressant. Three moclobemide analogs were constructed by displacing moclobemide phenyl group with substituted imidazoles [68]. It has been found that compounds including nitrogen rings, and particularly imidazole, offer more sites for binding to amino acids within proteins and enzymes. As a result, N -[(4-morpholinyl) ethyl)]-1-benzyl-2-(alkylthio)1H -imidazole-5-carboxamides 89a–c with antidepressant activity were prepared by Hosseinzadeh and co-workers in 2008 [68]. Analogs 89a–c are found to be more potent than moclobemide. For the synthesis of compounds 84– 88 [69], benzylamine hydrochloride 83 was reacted with 1,3-dihydroxyacetone dimmer and potassium thiocyanate to afford 5-hydroxymethyl-2-mercapto-1-benzylimidazole 84. Then, compound 84 was reacted with alkyl halides

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being alkylated to yield 2-alkylthio-1-benzyl-5hydroxymethylimidazole 85. Oxidation of compound 85 with manganese dioxide occurred to create 86 which was further subjected to oxidation upon treatment in alkaline solution of silver nitrate (boiling) to afford 2-alkylthio-1benzylimidazole-5-carboxylic acid 87. Subsequently, compound 87 was transformed into its acid halide 88. Finally, N -[2-(4-morpholinyl)ethyl)]-1-benzyl-2-(alkylthio)-1H -imi dazole-5-carboxamides 89a–c were obtained from the treatment of 2-morpholinoethylamine and a solution of 88 in dry THF (Scheme 21). Consequently, substitution of electron-deficient 4-chlorophenyl in moclobemide with substituted electron-deficient ring imidazole in analogs 89a–c enhanced antidepressant activity and increased their toxicity [68]. In an approach toward the synthesis of imidazole derivative 93, n-hexylamine 90 was initially transformed into the desired xanthate via treatment with carbon disulfide. Significantly, xanthate with propargyl amine 91 at reflux conditions in water did not afford compound 92, but yielded the imi-

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Scheme 20 Formation of variously substituted imidazoles with different R1 and R2

Scheme 21 Synthesis of N -[2-(4-morpholinyl)ethyl)]-1benzyl-2-(alkylthio)-1H imidazole-5-carboxamides 89a–c

dazole derivative 93 as the main product (35 %), together with symmetric dihexyl thiourea 94 in small amount (24 %) (Schemes 22, 23) [70]. A facile method for the synthesis of symmetric and unsymmetric substituted thiourea derivatives involves the condensation between readily obtainable chemicals such as amines and carbon disulfide under green conditions. This strategy works effortlessly with aliphatic primary amines to yield different di- and tri-substituted thiourea derivatives.

The present protocol is also practically viable in synthesizing different substituted 2-mercapto imidazoles [70]. Synthesis of 1,4,5-tri-aryl-1H-imidazoles The development of various tri-substituted imidazoles can be achieved using laboratory microwave oven in a very short time and good yield. Using six different amines, six products were obtained in fairly good yields. In a one-pot,

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Scheme 22 Synthesis of imidazole derivatives

four-component reaction, benzil 100, ammonium acetate, paraformaldehyde, and amine mediated by formic acid in dry DMF under MW irradiation were reacted to yield the imidazole derivatives 101 in excellent purities, high yields, and with diverse substituents. For the development of 20 different 1,4,5-tri-substituted imidazoles, more than 20 amines were used. Notably, the reaction of simple amines such as substituted anilines and amines bearing only alkyl chains was found to be more efficient. The steric hindrance due to bulky groups or highly electronegative groups on the carbon adjacent to the carbon-bearing amine may be the reasons for such a difference in reactivity. All the obtained compounds were evaluated for anti-inflammatory potency in a rat paw Scheme 23 A plausible mechanism for the formation of imidazole derivatives

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edema model and reported good potency when applied orally (Scheme 24) [71]. As shown in a proposed mechanism in Scheme 25, ammonia is liberated from ammonium acetate upon heating in acidic conditions (acidic silica was used). First, one molecule of ammonia reacts with aldehyde to generate imine 104, the second one reacts with a carboxyl group of benzil 100 creating an imine 103. The imine of aldehyde (C=NH) shows higher reactivity toward the C=O group of benzil, whereas the imine of benzil was expected to react with reactive methylene group (CH=NH) of aldehyde via, loss of one molecule of water which led to cyclization to construct imidazole ring. Umarani and co-workers demonstrated an elegant procedure for the preparation of several diverse N,N -di substituted 2,4,5-triphenyl-1H -imidazole-1-yl-methanamine hybrids 107 [72]. The 2-substituted-4,5-diphenyl imidazole core can be prepared by the reaction of benzil 100 with 2,3,4trimethoxy benzaldehyde 105 using ammonium acetate in boiling glacial acetic acid. Then, the corresponding diphenyl imidazole analogs are subjected to a Mannich condensation reaction with benzaldehyde and different substituted aromatic secondary amines to create triphenyl imidazole derivatives in 46–68 % yields (Scheme 26). All these new synthesized compounds were evaluated for in vitro antiinflammatory, antibacterial, and antifungal activities. It was found that some of them showed good anti-inflammatory potency and better antimicrobial activity against bacterial strains Staphylococcus aureus, Pseudomonas aeruginosa, and fungal strain Candida albicans. Anti-inflammatory screening revealed that all the synthesized moieties were remarkably potent in comparison with the well-known and prescribed drug, diclofenac sodium [72].

Mol Divers Scheme 24 Synthesis of 1-substituted-4,5-diphenyl imidazole derivatives 101

Scheme 25 Proposed mechanism for the synthesis of imidazole derivatives 101

Scheme 26 Synthesis of triphenyl imidazole derivatives 107

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Mol Divers Scheme 27 Synthesis of 2,4,5-tri-aryl-1H -imidazoles

Synthesis of 2,4,5-tri-aryl-1H-imidazoles Several methodologies have been developed for the synthesis of imidazoles. In general, 2,4,5-tri-substituted imidazoles are synthesized via a three-component cyclo-condensation of 1,2-diketone or α-hydroxyketone or α-ketomonoxime with an appropriate aldehyde and ammonium acetate. The appropriate 1,2-dicarbonyl compounds, aldehydes and ammonia, were used by Japp and Radziszewski successfully to synthesize the first imidazole core to yield 2,4,5-triphenylimidazoles 108 back in 1882 (Scheme 27) [73–76]. Heterocyclic compounds having 2,4,5-tri-substituted and 1,2,4,5-tetra-substituted imidazoles in their structures possess a versatile range of pharmacological activities. Some of them are used as anti-inflammatory agents [77], several act as kinase inhibitors [78], and some other as anti-bacterial agents [79], glucagon receptor antagonist [80], and MAP kinase inhibitor [81]. They are also acting as modulators of Pgp-mediated multidrug resistance [82], and as ligands of the Src SH2 protein [83]. A few of them are prescribed antitumor drugs [84]. Some others are approved as inhibitors of mammalian 15-LOX [85]. Several substituted imidazoles are also acting as CB1 cannabinoid receptor antagonists [86], and some others are proven to be active as inhibitors of B-Raf kinase [87]. An efficient and convenient method for the synthesis of the highly substituted imidazoles has been reported via the multicomponent condensation of an appropriate 1,2-diketone, an aldehyde, an amine, and ammonium acetate as the nitrogen source, catalyzed by a wide range of catalysts. The synthetic strategy for the synthesis of 2,4,5-tri-substituted imidazoles is mainly based on the cyclo-condensation of a 1,2-diketone with an aldehyde using ammonium acetate. Other methods have also been developed for the synthesis of 2,4,5-tri-substituted imidazoles. In the last ten years, several methods have appeared in a vast number of journals for the synthesis of tri-substituted imidazoles where different catalytic systems are used, such as ionic liquids ([Hmim]TFA [88], [Et3 NH]HSO4 [89], TBAB [90], [EMIM]OAc [91], [Hmim]HSO4 [92], [HeMIM]BF4 [93], etc.), metal salts [Yb(OTf)3 [94], Y(NO3 )3 ·6H2 O [95], Eu(OTf)3 [96], InCl3 ·3H2 O [97], ZrCl4 [98], ZrOCl2 · 8ZrOCl2 O [99], BiCl3 [100], and supported ionic liquidlike phase (SILLP) [101]. Inorganic or organic matrix-

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supported catalysts and nano catalysts (bioglycerol-based carbon catalysts) [102], nano-SnCl4 ·SiO2 [103], BF3 -SiO2 [104], HClO4 -SiO2 [105], NaHSO4 /silica gel [106], silica sulfuric acid [107], NiCl2 ·6H2 O/Al2 O3 [108], HBF4 -SiO2 [109], Amberlyst A-15 [110], polymer-supported ZnCl2 [111], SBA-15/TFE (SBA-15/2,2,2-trifluoroethanol) [112], SBA-Pr-SO3 H [113], silica-supported tin oxide nanoparticles (SiO2 :SnO2 ) [114], ferric(III) nitrate supported on kieselguhr (Fe(NO3 )3-Kie) [115], zeolite-supported reagents [116], nanocrystalline MgO [117], nano-crystalline sulfated zirconia [118], magnetic Fe3 O4 nanoparticles [119], heteropolyacids [120] organocatalysts, such as L-proline [121], DABCO [122], enzymes (e.g., Lipase [123], papain [124]), trichloromelamine [125]), p-toluene sulfonic acid [126], ammonium chloride (NH4 Cl) [127], NaH2 PO4 [128], mercaptopropylsilica [129], sodium bisulfate [130], ceric ammonium nitrate [131], morpholinium hydrogen sulphate [132], diethyl ammonium hydrogen phosphate [133], sulfated tin oxide [134], urea/hydrogen peroxide [135], silicabound propylpiperazine N -sulfamic [136], tetrabutylammonium bromide (TBAB) [137], sodium bisulfate [128], potassium aluminum sulfate (alum) [138], l-cysteine [139], clays, zeolite, and nano-crystalline sulfated zirconia (SZ) [140], under microwave [141–143] or ultrasonic irradiation, solvent-free or classical conditions, and uncatalyzed condition [144]. A series of substituted imidazoles including 2-alkylsulfanyl-4-(4-fluorophenyl)-5-pyridinyl-1H -imidazoles 109, 2-alkylsulfanyl-4-(4-fluorophenyl)-1-methyl-5-pyridinyl-1H -imidazoles 110, and 2-alkylsulfanyl-4-(4-fluorophenyl)-5-(2-aminopyridin-4-yl)-1H -imidazoles 111 were synthesized, and their biological activities were screened. Some of them turned out to be inhibitors of p38 MAP kinase and TNF-α release (Fig. 2). It should be mentioned that the synthesized imidazoles having the substituents at the imidazole-C2 -thio position showed binding with the ribose site as well as interaction with the phosphate binding site of the p38 MAP kinase [145]. The key intermediate for the synthesis of the 4-(4(4-fluorophenyl)-2-(alkylthio)-1H -imidazol-5-yl) pyridines 109 and thione 120 was formed in accordance with the strategy presented by Lantos [146] as depicted in Scheme 28. Initially, (4-fluorophenyl)-acetonitrile 112 was reacted with methyl isonicotinate 113 to yield cyanoketone 114. The

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Fig. 2 2-Alkylsulfanyl-4-(4-fluorophenyl)-5-pyridinyl-1H -imidazoles 109, 2-alkylsulfanyl-4-(4-fluorophenyl)-1-methyl-5-pyridinyl-1H imidazoles 110, and 2-alkylsulfanyl-4-(4-fluorophenyl)-5-(2-aminopyridin-4-yl)-1H -imidazoles 111

Scheme 28 Synthesis of 2-alkylsulfanyl-4-(4-fluorophenyl)-1-methyl-5-pyridinyl-1H -imidazoles 109a–f

nitrile group of the latter was subjected to hydrolysis and decarboxylation to afford ethanone 115, which upon treatment with sodium acetate and hydroxylamine hydrochloride, yielded the respective oxime 116. Upon tosylation, oxime 116 was converted into tosylate 117, which was then submitted to a Neber rearrangement [147] to yield aziridine 118. The (R)-amino ketone 119 was obtained from the aziridine 118 upon treatment with aqueous hydrochloride and reacted in situ with KSCN to afford the corresponding thione 120. The

transformation of the desired compounds 109a–f was eventually achieved by treatment of thione 120 with the appropriate alkyl bromides and t-BuOK in t-butyl alcohol [146]. The synthesis of 2-alkylsulfanyl-4-(4-fluorophenyl)-1methyl-5-pyridinyl-1H -imidazoles 110 (Scheme 29) was successfully achieved using 2-(4-fluorophenyl)-1-(pyridin4-yl)ethan-1,2-dion-2-oxime 121 as precursor [148]. The oxime 121 initially reacted with 1,3,5-trimethyl-1,3,5triazine to generate the N -oxide 122, which upon treatment

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Scheme 29 Preparation of 2-alkylsulfanyl-4-(4-fluorophenyl)-5-pyridinyl-1H -imidazole 110

with 2,2,4,4-tetramethyl cyclobutane-1,3-dithione afforded 4-(4-fluorophenyl)-1-methyl-5-(pyridin-4-yl)-1H -imidazole2-thione 123 as key intermediate. Treatment of thione 123 with NaOMe and subsequent reaction of the generated corresponding thio anion with 3-bromopropane-1,2-diol resulted in compound 110 [145]. 2-Alkylsulfanyl-4-(4-fluorophenyl)-5-(2-aminopyridin-4 -yl) imidazoles 111a–v were synthesized using the key intermediates N -boc-protected N -alkyl-4-methylpyridin-2yl-amines 115 via two independent pathways [149]. The 5(2-aminopyridin-4-yl)-substituted imidazoles 111a–v were synthesized from a simple, multistep synthesis approach. Picolines 125a–i were initially transformed into the ethanones 126a–i via the reaction with ethyl 4-fluorobenzoate in the presence of NaHMDS. Ethanones 126a–i upon treatment with an excess of sodium nitrite in acetic acid at ambient temperature were transformed into the α-hydroxyimino ketones 127a–i. These ketones were reduced to yield the corresponding hydrochlorides with a simultaneous deprotection of the Boc group upon treatment with methanolic hydrogen chloride and Pd/C under hydrogen atmosphere at ambient pressure and temperature to afford 128a–i. Cyclization was accomplished upon the treatment of 129a–i with potassium thiocyanate to afford 129a–i, which were transformed into the desired 111a–v via nucleophilic substitutions with different alkyl halides in the presence of t-BuOK or NaOMe (Schemes 30, 31). Compound 111w was synthesized using 4-(4-fluorophenyl)-5-(2-fluoropyridin-4-yl)-1,3dihydroimidazole-2-thione 130 as a precursor (Scheme 32). Thione 130 and 2-bromoethanol reacted to afford 2-(4-(4fluorophenyl)-5-(2-fluoropyridin-4-yl)-1H -imidazol-2-ylt-

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hio) ethanol 131. Finally, the fluorine atom of 131 was replaced under MW irradiation with an excess of the amine in a solventless system to afford the amino derivative 111w. The synthesis and biological data of a series of 2-thio-substituted 4-(4-fluorophenyl)-5-pyridinyl-1H -imidazoles were reported, encouraging a research group to synthesize the very potent p38 MAP kinase inhibitors 111h, 111i, 111u, 111v, and 111w. It was found that the substituents at the 2-thio position contribute to biological activities only to a small extent. The IC50 values undergo just minor variations in the enzyme assay for compounds 111f, 111j–m, and 111s and compounds 111h, 111n, 111o, 111t, and 111u in comparison to the variation of IC50 values achieved by replacing the pyridine-C2-amino moiety. Compounds 109a, 110a, and 111h and 111i, all having the 2,3-dihydroxypropyl moiety at the 2-position of the imidazole core, showed a distinct decrease in the inhibitory potency of p38 MAP kinase. Remarkably, this potency was increased by introduction of a methyl group at the imidazole N1-position. More remarkable increase in potency was observed via introduction of 2-amino substituents, and thus, it is considered as the most favorable derivatization. Substituents placed at the imidazole-C2 position showed good inhibition of TNF- α release (compared, for example, to compounds 111a and 111p, 111s and 111f, and 111h and 111t). Within both series 109 and 111, the 2-hydroxyethyl substituent at the 2-thio position exhibited the highest potency in the kinase screening. The 3-hydroxypropyl group gave the second highest activity [145]. Kim and co-workers disclosed the synthesis of novel benzenesulfonamide-substituted 4-(6-alkylpyridin-2-yl)-5-

Mol Divers Scheme 30 Synthesis of the 2-(N -alkylamino)pyridinylsubstituted 1,3-dihydroimidazole-2-thiones scaffolds 129a–i

(quinoxalin-6-yl) imidazoles 140a-l, which are used as for transforming factor-β type-1 receptor kinase inhibition [150]. Quinoxaline-6-carboxylic acid 133 was treated with (COCl)2 in toluene to create quinoxaline-6-carbonyl chloride 134 in good yield. Compound 134 was coupled with the pyridines 135a–f in anhydrous THF using n-BuLi and Et2 AlCl in hexane to afford quinoxalinyl monoketones 136a–f in 25–75 % yields. Then, compounds 136a–f in DMSO were oxidized using HBr providing quinoxalinyl diketones 137a–f in 20–78 % yields. Compounds 137a–f in MeOH/t-BuOMe reacted with either phenylacetaldehyde 138a or hydrocinnamaldehyde 138b and NH4 OAc to yield pyridin-2-ylimidazoles 139a–l in 23–72 % yields. Chlorosulfonylation of 139a–l was accomplished using ClSO3 H in CH2 Cl2 which upon exposure to NH4 OH yielded pyridin-2-ylimidazolesulfonamides 140a–l in 12– 59 % yields. Notably, all products were more selective for ALK5 inhibition than p38 α MAP kinase inhibition in comparison with 132. This method presented the first special attempt to introduce a p-sulfonamide functionality into the phenyl group and ethylene linkage in the devise of ATP-competitive inhibitors of ALK5. Among them, 4-[5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H imidazol-2-ylmethyl] benzenesul fonamide 140b and 4-[5(6-ethylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H -imidazol-2-yl methyl] benzenesulfonamide 140c showed more than 90 %

inhibition in a luciferase reporter screening (Scheme 33) [150]. A novel and convenient multicomponent procedure was developed for the synthesis of different poly-substituted 2-(pyridin-2-yl) imidazoles using 2-cyanopyridine 141, aromatic aldehydes, and NH4 OAc/primary amine. It should be mentioned that when aromatic primary amines were applied as substrates, tri-substituted 2-(pyridin-2-yl) imidazoles 145 were created [151]. On the other hand, when several aliphatic primary amines were employed as substrates, both di- and tri-substituted 2-(pyridin-2-yl) imidazoles 143 and 144 were prepared in a one-pot manner. A variety of poly-substituted 2-(pyridin-2-yl) imidazoles were prepared from 2-cyanopyridine, aromatic aldehydes, and NH4 OAc/primary amines in acetic acid at 170 ◦ C. Compared with Tu et al.’s strategy, under solvent-free conditions and microwave-irradiation [151], not only a series of disubstituted 2-(pyridin-2-yl) imidazoles but also various trisubstituted 2-(pyridin-2-yl) imidazoles could be efficiently prepared. Noticeably, in a one-pot reaction, when aliphatic primary amines were employed, both di- and tri-substituted 2-(pyridin-2-yl) imidazoles 143 and 144 were formed. The new method was also found to be effective for the synthesis of 4,5-di-substituted 2-(pyridin-2-yl) imidazoles. 1,4,5-Tri-substituted 2-(pyridin-2-yl) imidazoles were prepared with high yields through the multicomponent

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Scheme 31 Synthesis of compounds 111a–v via nucleophilic substitution of imidazole-2-thiones 129a–i

Scheme 32 Preparation of compound 111w

reaction of 2-cyanopyridine, diverse aldehydes, and primary aromatic amines instead of NH4 OAc. Both aromatic aldehydes and primary amines containing either electronwithdrawing or electron-donating groups led to the desired imidazole derivatives. Consequently, a new and extremely robust protocol was developed for the synthesis of different di- or tri-aryl (heteraryl)- substituted 2-(pyridin-2-yl)

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imidazoles using structurally simple and easily accessible precursors. Furthermore, when aliphatic primary amines containing beta-hydrogen were applied, both di- and trisubstituted 2-(pyridin-2-yl) imidazoles could be prepared via a one-pot reaction (Scheme 34) [152]. A plausible mechanism for the synthesis of polysubstituted 2-(pyridin-2-yl) imidazoles 142–145 is shown in

Mol Divers Scheme 33 Synthesis of benzenesulfonamide-substituted 4-(6-alkylpyridin-2-yl)-5(quinoxalin-6-yl)imidazoles 140a–l

Scheme 35. Initially, the aromatic aldehyde and the amine yield the imine 146 in the presence of ammonium acetate. Second, a three-component reaction takes place involving the imine 146, 2-cyanopyridine 141, and second molecule of aromatic aldehyde, in an acidic medium. This important step proceeds smoothly to make the imidazole moiety [152].

2,4,5-Tri-substituted imidazoles 153 and imidazo[1,5a]quinoxalin-4(5H )-ones 154 were synthesized using a simple, efficient, one-pot and three-component reaction, starting from 3-aroylquinoxalin-2(1H )-ones 152 as hetero analogs of α-diketones in methanol under reflux conditions. Condensation of quinoxalin-2(1H )-ones 152 with various arylalde-

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Scheme 34 Novel strategy for the synthesis of poly-substituted 2-(pyridin-2-yl)imidazoles

Scheme 35 A plausible mechanism for the synthesis of poly-substituted 2-(pyridin-2-yl)imidazole

hydes (substituted aldehydes and 3-pyridinecarboxaldehyde) and ammonium acetate in boiling methanol occurred to create functionalized imidazoles. Remarkably, the existence of the ortho-iminoanilide substituent at position 4 of imidazoles 153 makes them suitable for further reactions (Scheme 36) [153]. In the next step, upon treatment with ammonium acetate in acetic acid, the four imidazole derivatives 153a,c,e,h are cyclized to afford 2-(imidazol-4-yl)benzimidazoles 155a–d in high yields (Scheme 37) [153].

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This method yields products in high yields using commercially available and inexpensive 3-aroylquinoxalin-2(1H )ones as precursors requiring a simple work-up procedure and isolates the final products in pure form without the need of chromatographic separations. The proposed mechanism for the formation of imidazo [1,5-a]quinoxalin-4(5H )-ones and benzimidazoles is depicted in Scheme 38. In the first step, the diamine intermediate 156 is formed, then condenses with the 3-aroylquinoxalin-2(1H )-one 152, followed by dehydration to yield the imino intermediate 157 which is then converted

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Scheme 36 Condensation of quinoxalin-2(1H )-ones 152, arylaldehydes and ammonium acetate under various conditions

into compounds 153 and 154 through two different routes (I and II). Route I proceeds via a cascade reactions including (a) acid-catalyzed ring-closure of intermediate 158 with the generation of spiro-compound 159, (b) acid-catalyzed ring-opening of spiro-compound 160 with the creation of the imidazole derivative 161, which upon rearrangement yields imidazole derivative 162 via a [1,5] hydrogen shift, and (c) the reaction of the resulting intermediate with an appropriate aldehyde to afford compound 153. Pathway II involves the tautomerism of intermediate 157 with the generation of compound 163, which after undergoing an acid-catalyzed intramolecular cyclization affords 165. The final product 154 is synthesized via the liberation of ammonia from intermediate 166. It is clear that the gener-

Scheme 37 Efficient method for the synthesis of 2-(imidazol-4yl)benzimidazoles 155a–d

ation of 2-(imidazol-4-yl)benzimidazoles 155a–d involves ammonolysis of imidazoles 153a,c,e,h to create the corresponding ortho-aminoanilide derivative 162 in the first step.

Scheme 38 Proposed mechanism for the formation of imidazole 153. Pathway I: acid-catalyzed ring-closure and ring-opening

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Mol Divers Scheme 39 Proposed mechanism for the synthesis of imidazole 154. Pathway II: a novel acid-catalyzed imidazo annulation of quinoxalin-2(1H )-ones

Scheme 40 Proposed mechanism for the synthesis of 2-(imidazol-4yl)benzimidazoles 155a–d

The second step involves a fast and classical intramolecular nucleophilic attack of the amino group on the carbonyl group with the generation of intermediate hydroxy-derivative 167 with subsequent removal of water (Schemes 39, 40) [153]. Imidazole-substituted porphyrines are useful compounds showing optical, electronic, and catalytic properties [154, 155]. Imidazole-substituted phthalocyanines can also be utilized in photodynamic therapy [156], electron transfer process [157], and the synthesis of polymeric phthalocyanines [158]. A new type of metal-free phthalocyanine and the respective Zn-, Ni-, Co- and Cu-complexes with peripheral tetra-imidazole substituents were introduced in 2012 [159]. A phthalonitrile derivative 170 was prepared in fair yields from the reaction between 168 and 4-nitrophthalonitrile 169 in dry DMF in the presence of anhydrous K2 CO3 to yield basic reaction conditions. Subsequently, compound 170 was transformed to compound 171 by heating at 160 ◦ C under N2 atmosphere in dry N , N -dimethyl aminoethanol. Products 172–175 were obtained by a similar procedure, albeit, with the addition of the respective metal salts (ZnCH3 COO2 , CoCl2 , CuCl2 , NiCl2 ) (Scheme 41) [159].

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Zhang and his group demonstrated a facile and environmental-friendly method for the development of 2substituted-4,5-di(2-furyl) imidazoles 178 containing furan rings from 1,2-di(furan-2-yl)-2-oxoethyl carboxylates 176 using alumina as a conventional and easily available solid support under combination of solventless and microwaveirradiation conditions (Scheme 42) [160]. This pathway was also used for the generation of tri-substituted imidazoles containing benzene rings. However, the yields were found to be much lower than those achieved for tri-substituted imidazoles bearing furan rings [161]. Several 1,2-di(furan-2-yl)-2-oxoethyl carboxylates were easily prepared by the esterification of furan (1,2-di(furan-2-yl)-2hydroxyethanone generated from furfural [162] using acyl chlorides, and pyridine as catalyst in high yields under mild reaction conditions. Then, the preparation of tri-substituted imidazoles bearing a furan ring was accomplished, beginning from 1,2-di(furan-2-yl)-2-oxoethyl carboxylates 176. The nucleophilic addition and subsequent self-cycloaddition reaction of 1,2-di(furan-2-yl)-2-oxoethyl carboxylates using ammonium acetate was carried out easily. A range of 1,2-

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Scheme 41 A new type of metal-free phthalocyanine and the corresponding Zn-, Ni-, Co-, and Cu-complexes with peripherally tetra-imidazole substituents Scheme 42 Route to trisubstituted imidazoles containing furan rings

di(furan-2-yl)-2-oxoethyl carboxylates 177 reacted using ammonia under microwave irradiation to yield compounds 178 in high yields. This procedure has many advantages including speed (5-10 min), moderate-to-high yields, and an easy-to-operate procedure [160]. The proposed mechanism for the formation of trisubstituted imidazoles 178 containing a furan ring, starting from 1,2-di(furan-2-yl)-2-oxoethyl carboxylic esters 179,

is illustrated in Scheme 43. Ammonium acetate yields acetic acid upon decomposition, which acts as a catalyst to form the expected hydrogen bond with the carboxyl moiety of the latter. Consequently, the electrophilicity of the carboxyl carbon is remarkably enhanced, resulting in the acceleration of the subsequent nucleophilic addition along with self-cycloaddition using ammonia to yield the 1,2di(furan-2-yl)-2-oxoethyl carboxylates-ammonia adduct and

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Scheme 43 Proposed mechanism for the generation of trisubstituted imidazoles

the expected desired compound. As a result, a solvent-free microwave-assisted one-pot reaction on the surface of alumina offers a facile and effective procedure for the synthesis of tri-substituted imidazoles. This route was also used for the preparation of tri-substituted imidazoles carrying benzene rings, 4,5-dipenyl-2-styryl-1H -imidazole, and 2-(furan-2yl) vinyl-4,5-dipenyl-1H -imidazole in 83.3 % and 77.6 % yields, respectively [160]. A novel series of 4-aryl-5-(3,4,5-trimethoxyphenyl)-2alkylthio-1H -imidazoles 196 showing cytotoxic properties and tubulin inhibitory activity were synthesized by Shafiee and co-workers in 2013 [163]. Various benzoins

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and ammonium thiocyanate were reacted to create 4,5diaryl-1H -imidazole-2(3H )-thiones [164]. The symmetric benzoins 192a,b can be prepared through the cyanide ioncatalyzed reaction of 3,4-dimethoxy 191 or 3,4,5-trimethoxy benzaldehyde 190. Alternatively, for the preparation of unsymmetric benzoins, 3,4,5-trimethoxybenzaldehyde 190 was treated with benzoyl chloride and potassium cyanide in aqueous potassium hydroxide and tetrabutylammonium hydrogen sulfate to create cyanohydrinbenzoate 193. Subsequently, different methoxy benzaldehydes were reacted with cyanohydrins to afford the corresponding benzoin benzoate. Then, hydrolysis of the latter was achieved using acetoni-

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Scheme 44 Synthesis of symmetric and unsymmetric benzoins 192

trile and sodium hydroxide under an argon atmosphere to yield the corresponding unsymmetric benzoins 192c–g [165] (Scheme 44). The reaction of various benzoins with 10fold excess of ammonium thiocyanate in n-butanol yielded the required 4,5-diaryl-1H -imidazole-2 (3H )-thiones 194a– g. At the final stage, compounds 194a–g were alkylated using alkyl iodides in basic media to produce 4-aryl-5(3,4,5-trimethoxyphenyl)-2-alkylthio-1H -imidazole derivatives 195, 196a–g (Scheme 45). Most of these products exhibited moderate-to-potent cytotoxic activity against four cell lines (HT-29, MCF-7, NIH-3T3, AGS). The SAR study showed that 3,4,5-trimethoxyphenyl moiety on ring A and 4-methoxy substituent on ring B gave an improved effect on the cytotoxicity activity. Compound 195g bearing 3,4,5trimethoxyphenyl moiety on ring A and 4-methoxy substituent on ring B showed effective cytotoxic activity against all cell lines [163]. Three novel 2-[5-(4-substitutedphenyl)furan-2-yl]-4,5diphenyl-1H -imidazole derivatives 198a–c were prepared by Abdula and co-workers in 2013 [166]. The antimicrobial screenings of these derivatives against several grampositive and gram-negative species like Candida albicans were studied using a well-diffusion method. These novel derivatives were determined as good antimicrobial agents. To describe the activity of the new derivatives, the binding affinity of the compounds against glucosamine-6-phosphate synthase, the target enzyme for the antimicrobial agents,

was explored. Docking calculations reflected the activity trends of the compounds as new discovered hits, such as 5-(4-substituted phenyl)furan-2-carboxaldehydes 197a–c − prepared by the treatment of the diazonium salts RPhN+ 2 Cl and furan-2-carboxaldehyde under cuprous chloride (Meerwein method) [167]. Then, aldehyde compounds 197a–c, benzyl and ammonium acetate mixture in refluxing glacial acetic acid, produced new 2-[5-(4-substitutedphenyl)furan2-yl]-4,5-diphenyl-1H -imidazole derivatives 198a–c in high yields (Scheme 46) [166]. The metal-free, acid-promoted synthesis of tri-substituted imidazole derivatives was reported through a simple, efficient, and ecofriendly multicomponent methodology by Wang and co-workers in 2013 [168]. The reaction was performed easily using a variety of functionalities to create the imidazole scaffolds in good to high yields. This new procedure was developed for the synthesis of substituted imidazole derivatives using an alkyne, aldehyde, and ammonium acetate in the presence pivalic acid (PivOH) via a one-pot, multicomponent reaction. This method affords an imidazole core containing diverse structures in high-to-excellent yields. As shown in Scheme 47, different alkyl and aryl aldehydes and internal alkynes 199 reacted with NH4 OAc and PivOH DMSO/H2 O = 1:1 via a one-pot route to form a number of 2,4,5-imidazole derivatives 200 including different substituents containing electron-deficient and electron-rich functional groups on the aromatic moieties 200. Signifi-

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Mol Divers

Compounds

R1

R2

R3

R4

R5

R6

195a

OCH3

OCH3

OCH3

OCH3

H

CH3

196a

OCH3

OCH3

OCH3

OCH3

H

CH2CH3

195b

H

H

OCH3

OCH3

H

CH3

196b

H

H

OCH3

OCH3

H

CH2CH3

195c

OCH3

H

OCH3

OCH3

H

CH3

196c

OCH3

H

OCH3

OCH3

H

CH2CH3

195d

OCH3

H

OCH3

H

OCH3

CH3

196d

OCH3

H

OCH3

H

OCH3

CH2CH3

195e

OCH3

H

H

OCH3

OCH3

CH3

196e

OCH3

H

H

OCH3

OCH3

CH2CH3

195f

OCH3

H

H

H

OCH3

CH3

196f

OCH3

H

H

H

OCH3

CH2CH3

195g

OCH3

H

OCH3

H

H

CH3

196g

OCH3

H

OCH3

H

H

CH2CH3

Scheme 45 Novel series of 4-aryl-5-(3,4,5-trimethoxyphenyl)-2-alkylthio-1H -imidazole derivatives

cantly, an imidazole derivative which has 3,4,5-trimethoxy groups in its ring B 200 has been synthesized efficiently in good yields. It has been found that the presence of the

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3,4,5-trimethoxy moiety on ring B of 200 is essential for the observed antitubulin and anticancer activity [169]. The mild reaction conditions, simple work-up procedure, and

Mol Divers Scheme 46 Preparation of imidazole derivatives 198a–c

Scheme 47 A three-component reaction for the synthesis of imidazoles

Scheme 48 Synthesis of dimeric imidazole derivative

high yields make this strategy a practical and ideal approach, avoiding the common use of transition metal catalysts. According to this strategy, a dimer derivative of imidazole can be synthesized from 1,4-bis(phenylethynyl)benzene 201 and benzaldehyde. From this reaction, 1-(2,5-diphenyl-1H imidazol-4-yl)-4-(2,4-diphenyl-1H -imidazol-5-yl) benzene 202 was prepared with 55 % yield (Scheme 48). The corresponding compound would produce the imidazole core, which is applicable in medicinal chemistry and OLED devices [170]. A proposed mechanism for the acid-promoted construction of imidazole is illustrated in Scheme 49, in which alkyne 199 is oxidized using pivalic acid in DMSO to produce intermediate 203a. Then, the aldehyde is treated with two molecules of ammonium acetate to afford the intermediate 204 (Path A) [171]. Alternatively, an aldehyde is reacted with one molecule of ammonium acetate and aniline to create

intermediate 205 (Path B). Eventually, both intermediates are subjected to a cyclocondensation with 203a to afford the corresponding compounds 200a and 206a. Some methods such as the Negishi-type cross-coupling reaction [172], three-component cyclocondensation [173], and NaBH4 -mediated cyclization [174] have been employed for the synthesis of highly functionalized 2-(2 -azaaryl) imidazoles. Among them, a very facile approach is a threecomponent reaction for the synthesis of 2-(pyridin-2-yl) imidazoles (Pyim). This reaction requires 1,2-diketones for a multistep reaction including benzoin condensation followed by oxidation. A one-pot synthesis of 2-(2 -azaaryl) imidazole derivatives 208 via multicomponent domino reactions (MDRs) of azaarylamidine requiring the Umpolung process was presented in 2013 [175]. Novel multicomponent reactions of azaarylamidines with aromatic aldehydes were conducted to form polyfunctionalized imidazoles 208

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Mol Divers Scheme 49 Plausible reaction mechanism for the acid-promoted construction of imidazole

(Scheme 50). Notable aspects of this chemistry are that a new Umpolung was obtained cleanly under mild conditions with no use of any metal or carbine as catalyst. From this strategy, triaryl imidazoles were easily synthesized in a domino fashion avoiding the use of 1,2-diketones and α-hydroxyketones. A short and efficient three-component domino [3+1+1] heterocyclization resulting in highly substituted 2-(2 -azaaryl) imidazoles was conducted using K2 CO3 under microwave assisted conditions. The reactions tolerate a wide substrate scope, which includes a broad range of commercially available aromatic aldehydes and heteroaryl-amidines. This three-component domino [3 + 1 + 1] heterocyclization is considered as an alternative strategy for one-pot synthesis of a series of 2-(2 -azaaryl) imidazoles with the simultaneous formation of three sigma bonds. The facile, accessible starting materials, the wide compatibility of aromatic aldehyde substrates, and the generality of this reaction make it practical from the synthetic point of view. Certain substituted imidazoles obtained from this approach illustrate biological activities, revealing this kind of heterocyles can be interesting from the biological point of view. Picolinamidine 207 was reacted with arylaldehydes using K2 CO3 under MW irradiation to offer 2-(2 -azaaryl) imidazoles of type 208 in good yield [175]. A mechanism has been suggested for the generation of tri-substituted 2-(2 -azaaryl) imidazole derivatives. The reaction employs a ring-closure cascade process, which involves a sequential initial condensation, nucleophilic addition, Umpolung (210 to 211) [176,177], intramolecular nucleophilic addition (211 to 212), and finally, to dehydration (Scheme 51). It has been suggested and reasoned that

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Scheme 50 The three-component synthesis of 2-(2 -azaaryl)imidazoles

the reaction direction highly depends on the intramolecular hydrogen bond formation, since it stabilizes the hydrogen ion and forms stable zwitterions 210. Zwitterions 210 then transfer the proton to the end of the aldimines which are then subjected to an Umpolung process to furnish relatively stable zwitterions 211. Due to the more conjugated system, the charge separation is maximized, and thus the carbon anion is stabilized. Subsequently, zwitterions 211 undergo cyclization of the carbon anion to afford the desired compound 208. This reaction also has several attractive features: a) the process is environmentally benign since water is produced as sole by-product, b) the use of a metal or carbene catalyst is not required, c) the work-up procedure is convenient as it only requires simple filtration of the products, d) starting materials 2-azaarylamidines and aromatic aldehydes are easily accessible, and e) the atom-economy and bond-forming economy of

Mol Divers Scheme 51 Proposed mechanism for the formation of imidazole derivative 208

Scheme 52 Synthesis of 1,2,4,5-tetra-substituted imidazoles

the reaction are high. In addition, two C=O bonds are broken and three new δ-bonds are generated upon Umpolung-based MDRs in a one-pot reaction. Another significant aspect of this tandem reaction is that multiple intermolecular chemical bond cleavages and formations occur concurrently. Synthesis of 1,2,4,5-tetra-aryl-1H-imidazoles Several protocols have been developed for the synthesis of 1,2,4,5-tetra-substituted imidazoles. One of them involves the four-component reaction of a 1,2-diketone, α-hydroxyketone, or α-ketomonoxime with an aldehyde, primary amine, and ammonium acetate to afford 1,2,4,5-tetrasubstituted imidazoles under microwave-assisted conditions. Thus, tetra-substituted imidazoles 213 were obtained via the four-component reaction of aldehydes, 1,2-diketones 100, amines, and ammonium acetate. A simple and green protocol (Scheme 52) via the reaction of benzyl, aldehydes, ammonium acetate, and primary amines in the presence of Amberlyst A-15 has been reported [110]. The synthesis of 1,2,4,5-tetra-substituted imidazoles has also been performed via a four-component, one-pot reaction of a 1,2-diketone, α-hydroxyketone or α-ketomonoxime with an appropriate aldehyde, primary amine and ammonium acetate under various conditions. Several catalyzed reactions

were published for the synthesis of 1,2,4,5-tetra-substituted imidazoles using catalysts such as Y(NO3 )3 ·6H2 O [95], InCl3 ·3H2 O [97], ZrOCl2 ·8H2 O [99], BiCl3 [100], bioglycerol-based recyclable carbon catalyst [102], Amberlyst A-15 [110], SBA-15/TFE (SBA-15/2,2,2trifluoroethanol) [112], SBA-Pr-SO3 H [113], silicasupported tin oxide nanoparticles [114], magnetic Fe3 O4 nanoparticles [119], L-proline [121], p-toluene sulfonic acid (PTSA) [126], solvent-free conditions with sodium dihydrogen phosphate [128], microwave irradiation [141–143], FeCl3 ·6H2 O [178], fluoroboric acid adsorbed on silica-gel (HBF4 -SiO2 ) [179], NHC (N -Heterocyclic Carbene) [180], trifluoroacetic acid [181], a novel organometallic catalyst (PSNP-CA) [182], MCM-41 [183], nano-TiCl4 ·SiO2 [184], and clay-supported titanium catalyst [185]. Highly substituted imidazole derivatives can be created using a new four-component and three-step reaction from alkoxyallenes, amines, iodine and nitriles with excellent yields. It should be mentioned that alkoxyallenes are extremely efficient 3-building blocks for the preparation of different heterocycles. In this simple and synthetically useful method, methoxyallene 214 was first deprotonated with n-BuLi in THF, and then aldimine 215 was added to produce α-allenyl amine 216 with excellent yield. Then, the crude 216 was dissolved in acetonitrile 217 and reacted in the presence of

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Scheme 53 Synthesis of 1-iodoethenyl-substituted imidazole derivative 219

iodine at ambient temperature to produce the intermediate dihydroimidazole derivative 218. Ultimately, compound 218 was treated with trifluoro methanesulfonic acid to yield the 1-iodoethenyl-substituted imidazole derivative 219 with high overall yield (Scheme 53) [186]. This method can be modified by replacing the nitrile with imine components. The highest yields of imidazoles were achieved when acetonitrile 217 was used. However, propionitrile and benzonitrile were also found suitable. This novel four-component reaction [187] proceeded by (a) attack of iodine to the central carbon Scheme 54 Synthesis of imidazole derivatives 220–223 from imidazole 219

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of allene of 216, (b) a Ritter-type addition reaction [188] of nitrile 217 onto the allyl cation as an intermediate, and (c) nucleophilic ring closure via the attack of the amino group to the nitrilium ion to afford 218. The ultimate elimination step resulting in imidazole 219 was preferably conducted in the presence of strong trifluoro methanesulfonic acid as a catalyst (Scheme 53). The imidazole derivatives prepared in this way could be further characterized via functionalization on the 1-iodoethenyl side chain. For this purpose, as shown in Scheme 54, the corresponding imidazoles 220–223 can be prepared from imidazole 219. Recently, sugar-annulated imidazoles have attracted a lot of attention, and the synthesis of C-glycosyl tetra-substituted imidazoles was attempted. New C-linked imidazole derivatives demonstrated high antibacterial activity. Sharma et al. [189] reported an effective strategy for the synthesis of trisubstituted glycosyl imidazoles under ZrCl4 . The synthesis of tetra-substituted imidazoles was reported by Nagarapu and co-workers [190]. They developed the preparation of mono glycosylated tetra-substituted imidazoles by parallel synthesis employing an appropriate carbohydrate component as one of the reactants [191]. A novel route for the formation of tetra-substituted imidazole derivatives using a glycosyl moiety at C-2 position was achieved utilizing a four-component reaction involving benzil, aromatic amines, mannose diacetonide 224, and ammonium acetate in the presence of 1.0 mol% of K5 CoW12 O40 ·3H2 O at 140 ◦ C under solvent-free conditions to yield mannosyl imidazoles 225a–d in fair yields. All the products were evaluated for antibacterial and antifungal activities.

Mol Divers Scheme 55 Synthesis of novel tetra-substituted imidazole derivatives using glycosyl moiety at C-2 position

Scheme 56 Synthesis of novel tetra-substituted new (C-2 chiral) imidazolyl sugars 228

The desired C-2 chiral polyhydroxy imidazole 226 was prepared from 225a by cleavage of the acetal moiety with Dowex (50WX8-H+ ) in EtOH:H2 O (1:1) at 60 ◦ C in relatively high yield as colorless solid (Scheme 55). On the other hand, the hitherto novel tetra-substituted (C-2 chiral) imidazolyl sugars 228a–d were formed utilizing benzil, different sugar aldehydes, amines, ammonium acetate, and K5 CoW12 O40 ·3H2 O (Scheme 56). Remarkably, in the absence of PDTC, the four-component condensation reaction did not proceed. Antibacterial and antifungal activities of all novel synthesized products 225a–d, 226, and 228a–d were evaluated, showing high activity against Gram-negative and Gram-positive bacteria. Compounds 225c, 225d, 228c, and 228d demonstrated moderate antibacterial activity against Pseudomonas aeruginosa. On the other hand, compounds 228d were more potent toward Gram-positive bacteria (e.g., Bacillus subtilis). All products were also tested for antifungal activity using an agar cup diffusion method and employing well established Amphotericin-B as standard. However, these products exhibited no antifungal activity [191]. In 2010, Gleave and co-workers demonstrated the preparation of a series of tetra-substituted-imidazoles as P2X7 antagonists utilizing a combination of homologation and cyclization synthetic steps [192]. As depicted in Scheme

57, the required intermediates can be prepared by a twostep method. Glycine or alanine 229 was coupled with an acid chloride with transitory protection of the acid terminus using chlorotrimethylsilane (TMSCl). The intermediate carboxylic acids 230 were transformed to the imidazolides using 1,10-carbonyldiimidazole (CDI), to which was added the magnesium enolate of mono-ethyl malonate, followed by decarboxylation which resulted in the corresponding cyclization precursors 231 in good-to-high yields. Imidazole formation was accomplished upon heating the keto-amide 231, amine, and acetic acid in xylenes using a Dean–Stark apparatus in moderate-to-good yield. After the ester cleavage by lithium hydroxide followed by amide coupling, the desired products 233 were formed [192]. An efficient method was developed for the preparation of new 2-butyl-4-chloro-1-methylimidazole-embedded chalcones 237a–r and pyrazoles 239a–r as angiotensinconverting enzyme (ACE) inhibitors [193]. The synthesis of 2-butyl-4-chloroimidazole-5-carboxaldehyde 234, an important intermediate in the construction of an Angiotensin II antagonist Losartan, was reported starting from valeronitrile [194]. N -Methylation of 234 occurred using CH3 I, NaH in DMF to afford the methylimidazole derivative 235 in high yield. Then, equivalent amounts of imidazole 235

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Mol Divers Scheme 57 Synthesis of tetra-substituted imidazoles 233

Scheme 58 Synthesis of 2-butyl-4-chloro-1methylimidazole-derived chalcone 237h and its derivative 238

and 2-acetyl thiophene 236h were treated with 10 % sodium hydroxide in methanol to yield chalcone 237h in 83 % yield. In a similar fashion, compound 235 was reacted with 2-acetylthiophene 236h and sodium methoxide to yield compound 238 with 8 % yield. Such formation of 238 could be attributed to the Michael addition of 236h to the conjugated enone 237h. When 10 % aqueous NaOH under the same reaction conditions was used, the formation of compound 238 was not detected even in the presence of an excess of 2-acetylthiophene 236h. Thus, different aryl or heteroaryl methyl ketones 236a–r were treated with imidazole 235 in 10 % aqueous NaOH in methanol under mild reaction conditions (Scheme 58). All the reactions progressed to completion and afforded the desired chalcones 237a–r in excellent yields (73–88 %) (Scheme 59). In addition, the chalcones 237a–r were condensed with hydrazine hydrate in refluxing acetic acid. The NMR, IR, and mass spectral analyses of pyrazole derivatives disclosed that the acetic acid also entered the condensation process and gave pyrazoles 239a–r as N -acyl derivatives (Scheme 60). Among chalcones 237a–r, three products,

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namely, (E)-3-(2-butyl-4-chloro-1-methyl-1H -imidazol-5yl)-1-(5-chlorothiophen-2-yl)prop-2-enone 237i, (E)-3-(2butyl-4-chloro-1-methyl-1H -imidazol-5-yl)-1-(1H -pyrrol2-yl)prop-2-enone 237l, and (E)-3-(2-butyl-4-chloro-1methyl-1H -imidazol-5-yl)-1-(dibenzo[b, d] thiophen-2-yl) prop-2-enone 237q were found as the most active ACE inhibitors. The comparison of ACE-inhibitory activity (IC50 ) of different chalcones and flavonoids, which were synthetic and naturally occurring, with imidazole chalcones 237i, 237l and 237q showed ∼100-fold more activity (Scheme 59) [193]. Polyhalogenated derivatives of imidazoles demonstrate various biological properties such as antiviral [195] and insecticidal activity [196], and are selective inhibitors of cyclooxygenase [197]. A simple method was created for the synthesis of 5-formyl-2,4-dichloro derivatives consisting in the formylation of 1-alkyl-(aryl) imidazolidine-2,4diones (hydantoins) [198] with Vilsmeier–Haack reagent. In this procedure, imidazolidine-2,4-diones 240 were heated at 90 ◦ C with DMF and POCl3 in a 1:2:5 ratio followed by hydrolysis to yield 2,4-dichloro-1-aryl(alkyl)-

Mol Divers

Scheme 59 Synthesis of 2-butyl-4-chloro-1-methylimidazole-derived chalcones 237a–r

Scheme 60 Synthesis of 2-butyl-4-chloro-1methylimidazole-derived pyrazoles

1H -imidazole-5-carbaldehydes 242 in 47–52 % yield. This reaction likely proceeded via the formation of 241, which on treatment with excess phosphorus oxychloride were transformed into target compounds 242 (Scheme 61) [199]. 2,4-Dichloro-1-aryl(alkyl)-1H -imidazole-5-carbaldehydes 242 are important imidazole derivatives with three reaction sites, and the reactions with nucleophilic reagents are most typical. 1-Alkyl(aryl)-2,4-dichloro-1H -imidazole5-carbaldehydes 242 reacted with sodium azide, sodium alcoholates, with phenols, thiols, and secondary cycloalkylamines to replace the chloride group in the position 2 of the imidazole ring. Notably, the reaction with primary amines led to condensation products at the aldehyde group. The desired products 244–248 can be prepared from compound 242 (Scheme 62) [200].

The most used conventional route for preparation of 1,2,4,5-tetra-substituted imidazoles is the cyclocondensation of 1,2-dicarbonyl compound [122] or 2-hydroxy-1,2diphenylethanone [201], aldehyde and ammonium acetate or amine, as well as the reaction between 1,2-dicarbonyl compounds, aromatic amines and aromatic cyanides [202], and the nucleophilic substitution reaction of a tri-substituted imidazole with benzyl chloride [203]. The synthesis of imidazoles bearing furan rings were rarely reported [122,201–203] since the furan ring have some chemical properties, such as being electron rich, having lower resonance energy, easily being ring-opened with a Bronsted acid. These properties may be responsible for the small number of reports in the literature regarding the synthesis of imidazoles bearing furan ring as a substituent

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Mol Divers Scheme 61 Synthesis of 2,4-dichloro-1-aryl(alkyl)-1H imidazole-5-carbaldehydes 242

Scheme 62 Synthesis of 245–248 from 1-alkyl(aryl)-2,4-dichloro-1H imidazole-5-carbaldehydes 242

[161]. While the biological and pharmacological potency of tetra-substituted imidazoles have been extensively investigated, their luminescence properties have been largely overlooked, except for 1-R1 -2-R-4,5-dialkyl-1H -imidazoles [204]. A series of new tetra-substituted imidazoles 253 with furan rings were constructed by the treatment of 2-R-4,5di(furan-2-yl) imidazoles 250 and benzyl chlorides or allyl chloride in the presence of sodium hydride [203] to yield 1-R1 -2-R-4,5-di(furan-2-yl)-1H -imidazole derivatives 253; they were obtained in good yields. The luminescence properties of the synthesized compounds were tested and showed potential (Scheme 63) [205]. Recently, Zhao and co-workers synthesized three tetraaryl imidazole derivatives 255a–c containing a thiazole moiety using 1-butyl-3-methylimidazolium ([Bmin]Br) in a one-pot operation [206]. These type of imidazole derivatives have extensive applications in coordination chemistry and supra-molecular chemistry and are suitable ligands for transition metal ions [207]. Due to their fluorescence and chemiluminescence properties, they also have considerable analytical applications [208]. As shown in Scheme 64, tetraaryl imidazoles containing thiazole groups can be constructed through a common one-pot, four-component operation. Benzil [209], 2-aminothiazole 254, benzaldehydes, and ammonium acetate

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were reacted in the presence of [Bmin]Br to yield the desired compounds 255a–c in good yields. The complexation properties of products 255a–c were investigated for a variety of heavy metal and transition metal cations such as Ca2+ , Cd2+ , Cu2+ , Hg2+ , Mn2+ , Ni2+ , Pb2+ , Zn2+ , Fe3+ , Na+ , Al3+ , Mg2+ , Ag+ , Cr3+ using UV–Vis and fluorescence spectra. As a result, compound 255a showed excellent selectivity and sensitivity for Cr3+ ions in which the complexation ratio of compound 255a and Cr3+ is 1:1 [206]. In 2013, Ceschi and co-workers demonstrated a facile and convenient procedure for the preparation of tacrinelophine and lophineelophine dimers through a one-pot, four-component condensation reaction using InCl3 as a catalyst. The capability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC50 values in a nanomolar concentration scale were evaluated for these dimers [213]. A new series of hybrids tacrine-2,4,5-triphenyl1H -imidazole (or tacrine-lophine hybrids) were synthesized as inhibitors of AChE and BuChE. As an expansion to the four-component strategy for tetra-substituted imidazoles, a novel class of bis-(2,4,5-triphenyl-1H -imidazoles) or bis(n)lophines was prepared. The remarkable step is the one-pot four-component approach to 1,2,4,5-tetra-substituted imi-

Mol Divers Scheme 63 Synthesis of new tetra-substituted imidazoles containing furan rings 253

Scheme 64 One-pot synthesis of tetra-aryl imidazoles bearing thiazole group

dazoles catalyzed by a Lewis acid. The general synthesis for the new hybrids tacrine-2,4,5-triphenylimidazole 257a– g, 258a–g, 259a–g, 260 and 261 is illustrated in Scheme 65. The key stage is the one-pot four-component reaction of 9aminoalkylamino-1,2,3,4-tetrahydroacridines 256a–e, benzyl, various substituted aromatic aldehydes, and NH4 OAc catalyzed by a Lewis acid. A previously reported strategy was employed to synthesize 9-chloro-1,2,3,4-tetrahydroacridine via the cyclization of anthranilic acid with cyclohexanone [210,211]. For the introduction of a side chain, various alkylenediamines were reacted with 9-chloro-1,2,3,4tetrahydroacridine to create the 9-aminoalkylamino-1,2,3,4tetrahydroacridines in high to excellent yields [212]. This developed strategy was successfully used in the synthesis of tacrine-2,4,5-triphenyl-1H -imidazole 257a–g, 258a–g, 259a–g, 260 and 261 with a lophine framework substituted at the meta or para position of the 2-phenyl imidazole ring. The strategy depicted in Scheme 66 was applied for

the synthesis of bis(n)-lophines 262a–e. Tacrine-lophine hybrids were found to be potent and selective inhibitors of cholinesterases. Several tetra-substituted imidazoles, a novel series of bis-(2,4,5-triphenyl-1H -imidazoles), bis(n)lophines were synthesized via the four-component strategy and tested against AChE and BuChE, and several of them were found to be active and selective inhibitors of these 2 targets. The non-tacrine bis(8)-lophine 262c showed selective AChE inhibitory potency [213]. Noticeably, certain heterocyclic molecules, such as imidazoles with N1, C2, C4 and C5 positions substituted with different groups, are utilized broadly as emitting layers in OLEDs for efficient blue [214–216] and white light applications [217]. Imidazole-substituted isoquinoline derivatives as π-conjugated compounds, and especially compounds with a phenanthrene moiety, served as a single-emitting component for emitting a nearly “pure” white light having stable CIE coordinates under a variety of driving voltages.

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Mol Divers

Scheme 65 Synthesis of new hybrids tacrine-2,4,5triphenylimidazoles 257a–g, 258a–g, 259a–g, 260 and 261 Scheme 66 Synthesis of tetra-substituted imidazoles, a novel series of bis-(2,4,5triphenyl-1H -imidazoles) or bis(n)-lophines

4-Bromoisoquinoline and 4-formylphenylboronic acid 264 (both, commercially available and affordable) reacted in the presence of Pd[PPh3 ]4 and K2 CO3 in THF under a nitrogen atmosphere to yield 4-(isoquinolin-4-yl)benzaldehyde 265 in high purity and good yields. Generally, compound 265 can be readily prepared via Suzuki coupling reaction. Compound 265 was then subjected to a multicomponent cyclization with the corresponding diketone and amine in the presence of ammonium acetate and acetic acid to afford the target compounds 266–269 (Scheme 67) [217]. Several imidazoles such as 273f–i exhibit antifungal activity along with good anti mycobacterial activity [218]. The aryl phenyl ether moiety is extensively used as a pesticide and found to be essential in drug molecular design

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[219]. Singh and co-workers demonstrated the optimization of a number of novel compounds in which the imidazole motif is directly attached to position 4, and the presence of aryl phenyl ether at the position 3 of pyrazole ring is also shown to improve their antifungal activity. The synthesis of products 273a–i can be accomplished through a three-step reaction, which involves an N -alkylation of imidazole with the substituted bromoacetophenone 270a–i. The desired 1-[4-(4-chloro-phenoxy)-phenyl]-2-imidazol-1yl-ethanones 271a–i [220] afforded α, β-unsaturated ketones 272a–i upon condensation with substituted benzaldehyde. Finally, compounds 272a–i reacted with hydrazine or substituted hydrazine to furnish products 273a–i. Remarkably, via introduction of an aryl phenyl ether group on the imida-

Mol Divers

Scheme 67 Substituted imidazoles coupled to isoquinoline derivatives

Scheme 68 Synthesis of several imidazoles with antifungal activity along with good antimycobacterial activity

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Mol Divers

Scheme 69 Synthesis of tetra-substituted imidazoles 206a–j

zole ring, a novel type of fungicidal candidate was introduced (Scheme 68) [221]. For the synthesis of tetra-substituted imidazoles 206a– r in good-to-high yields, a four-component reaction was reported. The reactions of suitable amines, aldehydes, and internal alkynes 199 (diphenylacetylene), PivOH and NH4 OAc in (DMSO/H2 O = 1:1) yield diverse products [168]. In addition, the properties of these analogs were investigated for their fluorescence emission and UV absorption, and compound 206k [211,222] was found to show high potency for photodynamic therapy (PDT) of skin cancer [223] and is a good candidate for being used in organic electroluminescent devices (Scheme 69) [224,225].

Conclusions In this short report, we highlight the recent advances in the synthesis of diverse imidazoles, some of which were evaluated for their biological activity and found to be promising. The present review reveals that imidazole as a hetero-atomic planar five-member ring system shows a diverse chemistry with interesting physical and chemical properties which may be exploited via formation of a wide range of derivatives showing a variety of interesting pharmacological potencies. The chemistry of imidazoles bearing two aryl groups on adjacent positions has flourished since the 1980s, but the most remarkable progress of imidazole derivatives, both from the synthetic point of view and with regard to the pharmacological-screening aspects, have been achieved in the last decade. In spite of several protocols and methodologies in hand, because of the importance of this compound class, further efforts for the design and development of

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efficient synthetic approaches are still ongoing, and new breakthroughs particularly in scalable synthetic routes are eagerly awaited. Acknowledgments The authors are thankful to the Department of Chemistry for the honors and moral support, and the Alzahra University Research Council for financial supports.

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