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Synthesis 2024; 56(14): 2277-2283
DOI: 10.1055/s-0043-1763690
paper

One-Pot N-α-C(sp3)–H Bond Functionalisation Cascade for the Synthesis of Polysubstituted Imidazoles

Vikas D. Kadu  ∗
a   School of Chemical Sciences, Punyashlok Ahilyadevi Holkar Solapur University, Solapur 413255, Maharashtra, India
,
Naga Chandradudu Sankala
b   Department of Chemistry, College of Engineering, Rayalseema University, Kurnool 518002, Andhra Pradesh, India
,
Mahesh G. Hublikar
a   School of Chemical Sciences, Punyashlok Ahilyadevi Holkar Solapur University, Solapur 413255, Maharashtra, India
,
Shahaji I. Bansode
a   School of Chemical Sciences, Punyashlok Ahilyadevi Holkar Solapur University, Solapur 413255, Maharashtra, India
,
Raghunath B. Bhosale
a   School of Chemical Sciences, Punyashlok Ahilyadevi Holkar Solapur University, Solapur 413255, Maharashtra, India
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Abstract

A one-pot eco-friendly oxidative N-α-C(sp3)–H bond functionalisation of arylmethylamines for the synthesis of tetrasubstituted imidazoles is demonstrated. The substrate scope of these amines has been well-explored with different substrates, such as 1,2-diketones, an α-hydroxy ketone and phenylacetophenone. In the presence of FeCl3 catalyst and green oxidant O2, the easily accessible substrates afforded tetrasubstituted imidazoles in up to 94% yield.


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Key words

imidazoles - iron catalysis - oxidative coupling - N-α-C(sp3)–H functionalisation - one-pot reaction

The most privileged nitrogen-containing azole motif has attracted increased attention of medicinal chemists due to its diverse relevance.[1] [2] [3] [4] [5] Especially, five-membered nitrogen-containing imidazoles have a broad range of pharmaceutical significance and different applications.[5–14] Bioactive molecules like histidine, biotin and histamine possess a nitrogen-containing imidazole nucleus.[15,16] In addition, imidazoles have revealed different biological activities such as antibacterial,[17] antifungal,[12] antituberculosis,[18] analgesic,[19] anthelmintic,[20] anti-inflammatory[21] and antitumor activities.[22] Interestingly, drug molecules containing an imidazole moiety (apoptozole, losartan, eprosartan and olmesartan) have augmented attention in recent decades (Figure [1]).[23] [24] [25] [26] The great therapeutic assets of imidazole-linked drugs have encouraged medicinal chemists in the search for chemotherapeutic agents. Additionally, the amphoteric nature of the imidazole motif functions toward anions and/or cations selectively.[27] Also, the imidazole nucleus plays a crucial role in various ionic liquids.[28] [29] [30] Furthermore, the imidazole core has different applications as functionalised materials.[31] [32] [33] [34] [35] [36] [37] [38] These nitrogen-containing molecules also have photophysical properties.[39] [40] [41] [42] [43] In this context, progress in designing imidazole molecules by simple and eco-friendly methods has turned out to be a main attraction in organic synthesis.

Zoom Image
Figure 1 Drug molecules with a nitrogen-containing benzylimidazole moiety

The carbonyl compound and ammonium salt condensation developed by Debus and Radziszewski is used as a traditional method for the synthesis of imidazoles. There are various reports for the synthesis of trisubstituted imidazoles from substrates like aldehydes, imines, amidines, amides, nitriles, benzylamines, isocyanides and amino acids.[44] [45] [46] [47] [48] [49] Lamentably, there are limited reports for tetrasubstituted imidazole synthesis. In particular, aldehyde, benzil, amine and NH4OAc with acid catalysts is used for the synthesis of tetrasubstituted imidazoles.[50–52]

Instead of these, the synthesis of tetrasubstituted imidazoles by cyclisation of aliphatic amines and ketones under aerobic conditions in the presence of sulfur catalyst has been reported, in which a long reaction time of up to 36 hours was required for reaction completion.[53] As well, the oxidation of alkynes to α-halo ketones and subsequent condensation with amidine has been described for the synthesis of tetrasubstituted imidazoles where the strong oxidant IBX was used as the catalyst.[54] Afterward, polysubstituted imidazole synthesis was developed from benzils and arylmethylamines in the presence of silver carbonate (Ag2CO3) catalyst;[55] but, a long reaction time and the use of an excess amount of Ag2CO3 (2.0 equiv) are the shortcomings to afford the final products. Further, tetrasubstituted imidazoles were achieved from N-(2-oxo)amides and ammonium trifluoroacetate at a high reaction temperature of 150 °C, by Nguyen and co-workers.[56] After that, Wang and co-workers demonstrated photocatalysed substituted imidazole synthesis­ from amines and benzils using Mo–ZnIn2S4 photocatalyst;[57] however, there are limitations of a tedious process of photocatalyst preparation, separation from product and purification challenges. In recent times, NiCl2·6H2O/Ni(OAc)2·4H2O-catalysed polysubstituted imidazole synthesis from benzylamines and benzils was described, where the catalyst was used in an excess amount (3.0 equiv).[58] Furthermore, CuI-catalysed 2,4,5-trisubstituted and tetrasubstituted imidazole synthesis has been accomplished.[45] [59] Also, I2-catalysed tetrasubstituted imidazole synthesis from benzylamine and benzil/benzoin substrates was achieved in the presence of excess K2CO3 base (3.0 equiv).[60] Accordingly, a continuation of the development of competent protocols for the synthesis of polysubstituted imidazoles is very timely.

In recent years, a decreased abundance and the high-cost factor of catalysts, with significant toxicity, have pointed to late-transition-metal catalysts as an appealing alternative pursuit. The first-row transition metals exhibit excellent catalytic activities in various organic transformations. Among them, the significant advantages of iron salts, such as being inexpensive, environmentally benign, and easily amenable to nitrogen, oxygen and phosphorus ligands, as well as their availability in various oxidation states, have led to augmented significance with immense interest being gained.[61] [62] [63] [64] [65] [66] [67] Undiversified iron catalysis bears the possibility to allow an accountable paradigm for chemical synthesis and a sustained catalyst economy, at the same time providing substantial economic reward.[68] As well, the designing of different N-heterocycles with amines as a building block as an alternative route in organic transformations has had increased attention in recent years.[59] , [69] [70] [71] [72] [73] [74] Due to its utility of complex molecule construction in total synthesis, organic transformation via benzylic α-C(sp3)–N bond functionalisation has emerged as a robust and fascinating tool for lead discovery through rapid preclinical research.[75] Also, organic transformations with aerobic/molecular oxygen as oxidant have become a delightful platform to generate innovative chemistry.[76] [77] [78] [79] In this context, we report herein iron-catalysed synthesis of polysubstituted imidazoles from benzylamines in the presence of oxygen as sole oxidant.

Table 1 Optimisation of the Reaction Conditionsa

Entry

Catalyst

Solvent

Time (h)

Yield (%)b

 1

Fe(OAc)2

toluene

18

35

 2

Fe(acac)3

toluene

18

28

 3

FeSO4·7H2O

toluene

18

40

 4

FeCl2·4H2O

toluene

18

54

 5

Fe(NO3)3·9H2O

toluene

18

60

 6

Fe(ClO4)2·xH2O

toluene

18

72

 7

FeCl3

toluene

18

82

 8c

FeCl3

toluene

 9

91

 9c,d

FeCl3

toluene

 9

91

10c,e

FeCl3

toluene

 9

84

11c

FeCl3

chlorobenzene

 9

86

12c

FeCl3

benzene

 9

75

13c

FeCl3

DMSO

12

79

14c

FeCl3

1,4-dioxane

12

82

15f

FeCl3

toluene

12

25

16g

FeCl3

toluene

12

80

a Reaction conditions: 1a (2.1 mmol), 2a (1.0 mmol), catalyst (10 mol%), solvent (1 mL), 110 °C, in air.

b Isolated yield.

c Under O2 balloon.

d Catalyst (5 mol%) was used

e Catalyst (3 mol%) was used.

f Under N2 balloon.

g Reaction was carried out at 80 °C.

In the beginning, benzylamine (1a, 2.1 mmol) and benzil (2a, 1 mmol) were examined as representative substrates to optimise the reaction conditions. Up to 35% yield of the tetrasubstituted imidazole 3aa was observed after 18 hours, upon catalysis by 10 mol% Fe(OAc)2 catalyst under aerobic conditions at 110 °C (Table [1], entry 1). To improve the yield of the desired product, various types of iron salts, such as Fe(acac)2, FeSO4·7H2O, FeCl2·4H2O, Fe(NO3)3·9H2O, Fe(ClO4)2 and FeCl3, were examined in a reaction time of up to 18 hours (Table [1], entries 2–7). Among them, FeCl3 afforded the best results and 82% of anticipated product 3aa was achieved (Table [1], entry 7). Gratifyingly, the yield of the desired product was enhanced from 82% to 91% within 9 hours of reaction time after the same transformation was investigated under oxygen atmosphere (Table [1], entry 8). Furthermore, a catalyst loading study was performed where the same result was replicated with 5 mol% FeCl3 catalyst. In the next step, a lower yield was observed after the catalyst loading was lowered from 5 mol% to 3 mol%, due to incomplete reaction after 9 hours (Table [1], entry 10). Afterward, the solvent effect was studied, and the results are depicted in Table [1], entries 11–14. The best results were achieved with toluene as the reaction medium. Furthermore, the effect of nitrogen atmosphere on the reactivity was examined, and up to 25% of the desired product was obtained (Table [1], entry 15). Finally, the reaction was conducted at lower temperature (80 °C), where product 3aa was obtained in decreased yield (Table [1], entry 16). Therefore, the optimised reaction conditions for the synthesis of polysubstituted imidazoles are benzylamine (1a, 2.1 mmol), benzil (2a, 1.0 mmol), FeCl3 (5 mol%) as catalyst, in toluene (1 mL) at 110 °C under oxygen atmosphere (Table [1], entry 9).

Initially, the substrate scope was explored with various amines and 1,2-diketones 2 for the synthesis of polysubstituted imidazoles using the optimised reaction conditions (Scheme [1]). Substituted amines with functional groups like halogens, methoxy, piperonyl, trifluoromethyl, pyridinyl and thiophenyl were studied, and the anticipated products were accomplished in good to excellent yields. In this, the electron-donating p-substituted (4-Me and 4-OMe) arylmethylamines gave slightly higher yields of the anticipated products (3ab, 92%; 3ac, 94%) than the halogenated p-substituted (4-F, 4-Cl and 4-Br) benzylamines which gave 3ad (84%), 3ae (90%) and 3af (88%), respectively. The sterically hindered o-methoxybenzylamine and 2-chlorobenzylamine afforded the corresponding products 3ag and 3ah in 82% and 80% yield, respectively. Also, 2-chlorobenzylamine furnished product 3ai in 86% yield when examined with 4,4′-dibromo-substituted benzil substrate. Next, arylmethylamine with a methylenedioxy functionality on the aromatic ring also afforded the anticipated product 3aj, in 90% yield (Scheme [1]). Similarly, 3,4-dichlorobenzylamine and 3,5-bis(trifluoromethyl)benzylamine provided the consistent desired products 3ak (81%) and 3al (78%) in good yields without any difficulty under the optimised reaction parameters. Moreover, heteroarylmethylamines such as 4-picolylamine and 2-thiophenemethylamine also delivered the anticipated products (3am, 68%; 3an, 82%) successfully (Scheme [1]).

Zoom Image
Scheme 1 Substrate scope for tetrasubstituted imidazole synthesis. Reagents and conditions: 1 (2.1 mmol), 2 (1.0 mmol), catalyst (5 mol%), toluene (1 mL), 110 °C, under O2 balloon. Isolated yields.

Intrigued by the above results, we further explored various secondary and tertiary amines as substrates (Scheme [2]). N-Protected secondary amines such as N-benzylbenzylamine (dibenzylamine, 1o) and N-methylbenzylamine (N-methyl-1-phenylmethanamine, 1p) offered 3aa as the major product in 68% and 62% yield, respectively (Scheme [2]). Moreover, N-protected tertiary amines such as N-benzyl-N-methyl-1-phenylmethanamine (dibenzylmethylamine, 1q) and tribenzylamine (1r) also furnished the expected product 3aa as the major product in 61% and 65% yield, respectively (Scheme [2]). It is noteworthy that the optimised reaction conditions were examined with primary amine 1a as well as secondary and tertiary amines 1o–1r which furnished the corresponding tetrasubstituted imidazole 3aa in good yields. Interestingly, the substrate scope was further extended with benzoin (2b) as substrate, instead of benzil, with different substituted arylmethylamines under the optimised reaction conditions, and the corresponding products 3aa, 3ab, 3ac and 3ae were afforded in 90%, 91%, 93% and 88% yield, respectively (Scheme [2]). After that, phenylacetophenone (2c) was also examined with benzylamine under the same optimised conditions, where product 3aa was achieved in up to 65% yield (Scheme [2]).

Zoom Image
Scheme 2 Substrate scope. Reagents and conditions: 1 (2.1 mmol), 2 (1.0 mmol), catalyst (5 mol%), toluene (1 mL), 110 °C, under O2 balloon. Isolated yields.

From the above experimental results and relevant literature,[59] [70] [74] , [80] [81] [82] [83] [84] a possible mechanism for polysubstituted imidazole formation is summarised in Scheme [3]. At first, oxidative addition of amine 1a in the presence of iron catalyst generates benzylimine (4) intermediate and FeCl3 catalyst. Further reaction of benzylimine (4) with amine 1a generates 5b. By liberation of ammonia as a sole byproduct, adduct 5b gets further converted into another imine 5a, and are in equilibrium with each other. Subsequently, condensation between benzil (2a) and amine 5b takes place and forms intermediate 6 which possibly presents itself in different isomeric forms, namely 6a, 6b, 6c and 6d, which are also formed by 2c after oxidation into 2a. Out of these various isomers, 6a is sterically more favourable for the further reaction to afford the anticipated polysubstituted imidazole product as compared to the less stable isomers 6c and 6d due to the sterically unfavourable Ph–Ph interaction of two bulky phenyl rings. Also, the rigid isomer 6b presents itself as the trans-geometrical isomer with restricted rotation of the C–N bond, which is unfeasible for conversion into the more favourable form 7. As a result, isomer 6a is transformed into form 7 and further converted into 8 via cyclisation. Then, aromatisation of 8 leads to the formation of final product 3aa with the formation of H2O as a sole byproduct. On the other hand, the benzoin (2b) and amine 5b reaction gives intermediate 9 which further cyclises into 10, and formation of intermediate 11 takes place.[85] Then, formation of the same final product 3aa occurs via oxidation in the presence of O2 and iron catalyst.

Zoom Image
Scheme 3 Plausible reaction mechanism

In summary, an efficient and facile protocol for the synthesis of polysubstituted imidazole scaffolds from easily available substrates has been developed. The synthesised products were furnished smoothly with good tolerance, indicating the utility of the iron-catalysed oxidative condensation approach to further access other nitrogen heterocyclic cores and for mechanistic investigations.

A Büchi melting point apparatus was utilised for recording melting points, which are uncorrected. Distilled solvents were used in reactions. TLC was performed on 0.25-mm silica gel plates to study reaction progress, using a UV lamp for visualisation. 1H NMR and 13C NMR spectra were recorded on a Bruker NMR spectrometer at 400 MHz and 100 MHz, respectively, and 13C NMR (DEPT) information is specified in parentheses as C, CH, CH2 and CH3.


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Imidazoles 3; General Procedure

In a round-bottom flask equipped with an O2 balloon, arylmethylamine 1 (2.1 mmol), 1,2-diketone/benzoin/phenylacetophenone 2 (1.0 mmol) and FeCl3 (5 mol%) were stirred in toluene (1 mL) at 110 °C. The progress of the reaction was monitored by TLC; after completion, the reaction mixture was cooled to room temperature. Then, it was adsorbed onto basic alumina for purification using column chromatography (hexane/ethyl acetate) to obtain the anticipated tetrasubstituted imidazole product 3. Characterisation data of the pure polysubstituted imidazole products are given below.


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1-Benzyl-2,4,5-triphenyl-1H-imidazole (3aa)

Yield: 351 mg (91%); white solid; mp 161–163 °C (Lit.[59] 163–166 °C).

1H NMR (400 MHz, CDCl3): δ = 5.14 (s, 2 H, CH2), 6.83 (m, 2 H, ArH), 7.17–7.43 (m, 14 H, ArH), 7.60–7.62 (m, 2 H, ArH), 7.68–7.70 (m, 2 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 48.3, 126.0, 126.4, 126.8, 127.4, 128.0, 128.6, 128.6, 128.6, 128.8, 128.9, 129.1, 130.1, 131.0, 131.1, 131.1, 134.5, 137.6, 138.1, 148.1.

13C NMR (DEPT-135, 100 MHz, CDCl3): δ = 48.3 (down), 126.0 (up, =CH, ArH), 126.4, 126.8, 127.4, 128.1, 128.6, 128.8, 128.9, 129.1, 131.1.


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1-(4-Methylbenzyl)-4,5-diphenyl-2-p-tolyl-1H-imidazole (3ab)

Yield: 380.8 mg (92%); white solid; mp 133–135 °C (Lit.[59] 132–134 °C).

1H NMR (400 MHz, CDCl3): δ = 2.31 (s, 3 H, CH3), 2.40 (s, 3 H, CH3), 5.09 (s, 2 H, CH2), 6.73 (d, J = 7.6 Hz, 2 H, ArH), 7.04 (d, J = 8.0 Hz, 2 H, ArH), 7.14–7.28 (m, 7 H, ArH), 7.32–7.38 (m, 3 H, ArH), 7.56–7.61 (m, 4 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 21.1, 21.4, 48.0, 125.9, 126.3, 126.8, 127.4, 128.1, 128.2, 128.5, 128.8, 129.0, 129.3, 129.9, 131.1, 131.2, 134.7, 134.7, 136.9, 138.0, 138.8, 148.2.

13C NMR (DEPT-135, 100 MHz, CDCl3): δ = 21.1 (up, Ar-CH3), 21.4 (up, Ar-CH3), 48.0 (down, N-CH2-Ar), 125.9 (up =CH, ArH), 126.3, 126.8, 127.4, 128.1, 128.2, 128.5, 128.8, 129.0, 129.3, 129.9, 131.1.


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1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazole (3ac)

Yield: 419 mg (94%); off-white solid; mp 151–153 °C (Lit.[59] 153–155 °C).

1H NMR (400 MHz, CDCl3): δ = 3.78 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 5.05 (s, 2 H, CH2), 6.71–6.90 (m, 4 H, ArH), 6.92–6.97 (m, 2 H, ArH), 7.13–7.46 (m, 8 H, ArH), 7.57–7.58 (m, 4 H, ArH).


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1-(4-Fluorobenzyl)-2-(4-fluorophenyl)-4,5-diphenyl-1H-imidazole (3ad)

Yield: 354 mg (84%); white solid; mp 157–161 °C (Lit.[59] 159–162 °C).

1H NMR (400 MHz, CDCl3): δ = 5.06 (s, 2 H), 6.72–6.76 (m, 2 H), 6.88–6.94 (m, 2 H), 7.09–7.25 (m, 7 H), 7.34–7.40 (m, 3 H), 7.56–7.63 (m, 4 H).

13C NMR (100 MHz, CDCl3): δ = 47.6, 115.5, 115.6, 115.7, 115.9, 126.5, 126.8, 127.1, 127.2, 127.6, 127.7, 127.9, 128.2, 128.6, 128.8, 129.0, 130.0, 130.8, 130.9, 131.0, 132.9, 133.0, 134.2, 138.2, 147.1, 160.8, 161.9, 163.2, 164.4.

13C NMR (DEPT-135, 100 MHz, CDCl3): δ = 47.6, 115.5, 115.6, 115.7, 115.9, 126.5, 126.8, 127.6, 127.7, 128.2, 128.8, 129.0, 130.9, 131.0.


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1-(4-Chlorobenzyl)-2-(4-chlorophenyl)-4,5-diphenyl-1H-imidazole (3ae)

Yield: 408.6 mg (90%); white solid; mp 158–160 °C (Lit.[59] 159–162 °C).

1H NMR (400 MHz, CDCl3): δ = 5.06 (s, 2 H), 6.73 (d, J = 8.8 Hz, 2 H), 7.16–7.24 (m, 7 H), 7.36–7.40 (m, 5 H), 7.54–7.59 (m, 4 H).

13C NMR (100 MHz, CDCl3): δ = 47.7, 126.6, 126.8, 127.3, 128.2, 128.9, 129.0, 129.2, 130.2, 130.6, 131.0, 133.4, 135.2, 135.7, 146.8.

13C NMR (DEPT-135, 100 MHz, CDCl3): δ = 47.7, 126.8, 127.3, 128.2, 128.9, 129.0, 130.2, 131.0.


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1-(4-Bromobenzyl)-2-(4-bromophenyl)-4,5-diphenyl-1H-imidazole (3af)

Yield: 476 mg (88%); white solid; mp 127–129 °C (Lit.[59] 128–130 °C).

1H NMR (400 MHz, CDCl3): δ = 5.05 (s, 2 H), 6.72 (d, J = 8.0 Hz, 2 H), 7.16–7.22 (m, 7 H), 7.34–7.39 (m, 5 H), 7.53–7.57 (m, 4 H).

13C NMR (100 MHz, CDCl3): δ = 47.7, 126.6, 126.8, 127.3, 128.2, 128.9, 129.0, 129.2, 130.2, 130.6, 130.9, 133.4, 135.2, 135.8, 146.8.


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1-(2-Methoxybenzyl)-2-(2-methoxyphenyl)-4,5-diphenyl-1H-imidazole (3ag)

Yield: 366 mg (82%); yellow solid; mp 129–131 °C (Lit.[59] 132–134 °C).

1H NMR (400 MHz, CDCl3): δ = 3.72 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 4.99 (s, 2 H, CH2), 6.64–6.71 (m, 4 H, ArH), 6.88 (d, J = 10 Hz, 2 H, ArH), 7.11–7.19 (m, 5 H, ArH), 7.23–7.34 (m, 3 H, ArH), 7.44–7.54 (m, 4 H, ArH).

HRMS (ESI): m/z calcd for C30H27N2O2 [M + H]+: 447.2073; found: 447.2075.


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1-(2-Chlorobenzyl)-2-(2-chlorophenyl)-4,5-diphenyl-1H-imidazole (3ah)

Yield: 363 mg (80%); white solid; mp 140–143 °C (Lit.[59] 142–144 °C).

1H NMR (400 MHz, CDCl3): δ = 5.05 (s, 2 H), 6.63 (dd, J = 8.2, 2.2 Hz, 1 H), 6.86 (d, J = 2.0 Hz, 1 H), 7.18–7.27 (m, 6 H), 7.31 (d, J = 8.4 Hz, 1 H), 7.37–7.55 (m, 8 H), 7.79 (d, J = 2 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 47.4, 125.2, 126.8, 126.9, 127.7, 128.1, 128.2, 129.2, 129.2, 130.2, 130.4, 130.5, 130.7, 130.8, 130.9, 131.0, 132.0, 133.1, 133.2, 133.5, 133.8, 137.0, 138.8, 145.5.

13C NMR (DEPT-135, 100 MHz, CDCl3): δ = 47.4, 125.2, 126.8, 126.8, 127.7, 128.1, 128.2, 129.2, 129.2, 130.7, 130.8, 130.9.

HRMS (ESI): m/z calcd for C28H20Cl2N2 [M + H]+: 455.1004; found: 455.1113.


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4,5-Bis(4-bromophenyl)-1-(2-chlorobenzyl)-2-(2-chlorophenyl)-1H-imidazole (3ai)

Yield: 524 mg (86%); white solid; mp 187–190 °C (Lit.[59] 186–188 °C).

1H NMR (400 MHz, CDCl3): δ = 5.04 (s, 2 H), 6.63 (d, J = 8.0 Hz, 1 H), 7.10–7.18 (m, 4 H), 7.26–7.28 (m, 2 H), 7.30–7.52 (m, 9 H).


#

2-(Benzo[d][1,3]dioxol-5-yl)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-4,5-diphenyl-1H-imidazole (3aj)

Yield: 426.6 mg (90%); white solid; mp 173–175 °C (Lit.[59] 175–177 °C).

1H NMR (400 MHz, CDCl3): δ = 5.02 (s, 2 H, CH2), 5.93 (s, 2 H, OCH2), 6.02 (s, 2 H, OCH2), 6.28 (d, J = 0.8 Hz, 1 H, ArH), 6.28 (d, J = 1.6 Hz, 1 H, ArH), 6.64 (d, J = 8.4 Hz, 1 H, ArH), 6.86 (d, J = 8 Hz, 1 H, ArH), 7.14–7.28 (m, 7 H, ArH), 7.37–7.39 (m, 3 H, ArH), 7.56–7.58 (m, 2 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 47.9, 101.1, 101.3, 106.6, 108.2, 108.5, 109.7, 119.4, 123.1, 124.8, 126.4, 126.8, 127.0, 128.1, 128.6, 128.6, 128.8, 129.8, 131.1, 131.3, 134.4, 137.9, 146.8, 147.6, 147.8, 147.9, 148.2.

13C NMR (DEPT-135, 100 MHz, CDCl3): δ = 47.9, 101.1, 101.3, 106.6, 108.2, 108.5, 109.7, 119.4, 123.1, 126.4, 128.1, 128.6, 128.8, 131.1.


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1-(3,4-Dichlorobenzyl)-2-(3,4-dichlorophenyl)-4,5-diphenyl-1H-imidazole (3ak)

Yield: 422.8 mg (81%); white solid; mp 158–162 °C (Lit.[59] 158–161 °C).

1H NMR (400 MHz, CDCl3): δ = 5.04 (s, 2 H), 6.67 (m, 1 H), 7.08–7.48 (m, 13 H), 7.59–7.61 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 45.8, 126.5, 126.7, 126.9, 127.6, 128.1, 128.5, 128.8, 129.0, 129.1, 129.7, 129.8, 130.2, 130.6, 130.8, 130.9, 131.8, 132.6, 134.3, 134.6, 134.7, 138.0, 145.5.

13C NMR (DEPT-135, 100 MHz, CDCl3): δ = 45.8, 126.5, 126.7, 126.9, 127.6, 128.1, 128.5, 128.8, 129.0, 129.1, 129.7, 129.8, 130.8, 130.9, 132.6.

HRMS (ESI): m/z calcd for C28H18Cl4N2 [M + H]+: 525.2679; found: 525.0286.


#

1-(3,5-Bis(trifluoromethyl)benzyl)-2-(3,5-bis(trifluoromethyl)phenyl)-4,5-diphenyl-1H-imidazole (3al)

Yield: 513 mg (78%); faint yellow solid; mp 130–132 °C (Lit.[59] 128–130 °C).

1H NMR (400 MHz, CDCl3): δ = 5.33 (s, 2 H), 7.30–7.39 (m, 7 H), 7.40 (t, J = 4.0 Hz, 3 H), 7.54–7.67 (m, 2 H), 7.81 (s, 1 H), 8.01 (s, 1 H), 8.16 (s, 2 H).

13C NMR (100 MHz, DMSO-d 6): δ = 47.6, 121.1, 121.5, 121.6, 122.3, 124.2, 124.3, 126.2, 126.7, 127.4, 128.2, 129.1, 129.3, 129.9, 130.2, 130.5, 130.8, 131.4, 133.1, 133.8, 137.6, 140.0, 144.1.


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4-(4,5-Diphenyl-1-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)pyridine (3am)

Yield: 303 mg (68%); yellow solid; mp 125–127 °C (Lit.[58] 124–126 °C).

1H NMR (400 MHz, CDCl3): δ = 5.24 (s, 2 H, CH2), 7.18–7.32 (m, 8 H, ArH), 7.45–7.47 (m, 3 H, ArH), 7.56–7.58 (m, 2 H, ArH), 7.72–8.27 (m, 5 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 47.9, 126.5, 126.8, 127.2, 128.3, 128.9, 129.5, 129.6, 129.8, 130.8, 131.0, 132.2, 132.6, 132.7, 133.3, 138.8, 139.4, 144.7.

13C NMR (DEPT-135, 100 MHz, CDCl3): δ = 47.9, 126.5, 126.8, 127.2, 127.4, 128.3, 128.9, 129.5, 129.6, 130.8.


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4,5-Diphenyl-2-(thiophen-2-yl)-1-(thiophen-2-ylmethyl)-1H-imidazole (3an)

Yield: 326 mg (82%); white solid; mp 167–169 °C (Lit.[59] 169–171 °C).

1H NMR (400 MHz, CDCl3): δ = 5.33 (s, 2 H, CH2), 6.60 (dd, J = 3.6, 1.6 Hz, 1 H, ArH), 6.89 (dd, J = 3.6, 1.6 Hz, 1 H, ArH), 7.10 (dd, J = 3.6, 1.6 Hz, 1 H, ArH), 7.17–7.25 (m, 4 H, ArH), 7.28–7.34 (m, 3 H, ArH), 7.40–7.46 (m, 4 H, ArH), 7.55–7.58 (m, 2 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 44.1, 125.2, 125.4, 126.6, 126.7, 126.8, 126.9, 127.2, 127.3, 127.5, 128.1, 128.5, 129.0, 130.2, 130.5, 131.1, 132.5, 134.1, 138.3, 139.8, 141.7.

13C NMR (DEPT-135, 100 MHz, CDCl3): δ = 44.1 (down, N-CH2-Ar), 125.2 (up, =CH), 126.6 (up, =CH), 126.7 (up, =CH), 126.8 (st, up, =CH × 2), 126.9 (up, =CH), 127.2 (up, =CH), 127.5 (up, =CH), 128.1 (st, up, =CH × 2), 128.9 (up, =CH), 129.0 (st, up, =CH × 2), 131.1 (st, up, =CH × 2).


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10-1055/s-0043-1763690.
  • Supporting Information

Corresponding Author

Vikas D. Kadu
School of Chemical Sciences, Punyashlok Ahilyadevi Holkar Solapur University
Solapur 413255, Maharashtra
India   

Publication History

Received: 29 December 2023

Accepted after revision: 04 March 2024

Article published online:
25 March 2024

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Figure 1 Drug molecules with a nitrogen-containing benzylimidazole moiety
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Scheme 1 Substrate scope for tetrasubstituted imidazole synthesis. Reagents and conditions: 1 (2.1 mmol), 2 (1.0 mmol), catalyst (5 mol%), toluene (1 mL), 110 °C, under O2 balloon. Isolated yields.
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Scheme 2 Substrate scope. Reagents and conditions: 1 (2.1 mmol), 2 (1.0 mmol), catalyst (5 mol%), toluene (1 mL), 110 °C, under O2 balloon. Isolated yields.
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Scheme 3 Plausible reaction mechanism