Catalyst-Free Synthesis of 2,4-Disubstituted-1H-imidazoles through [3 + 2] Cyclization of Vinyl Azides with Amidines

Abstract

A facile and efficient route for the synthesis of 2,4-disubstituted imidazoles from benzimidamides and vinyl azides through [3 + 2] cyclization under catalyst-free conditions has been described. The method is compatible for a broad range of functional groups with good to excellent yields.

Introduction

Imidazoles are the most valuable five-membered heterocyclic compounds found in many natural products, biological systems, pharmaceuticals, and agro chemicals.^1,2 Additionally, imidazole derivatives have been reported to possess pharmacological properties such as antiplasmodial,³ antitumor,⁴ and antifungal.⁵ Consequently, many efforts have been made in the past decade on the synthesis of those privileged scaffolds. The reported methods include reaction of amidines with halo (nitro)alkenes,⁶ haloketones,⁷ alkyne/haloakynes,⁸ and other methods.⁹ Although these methods are elegant and appear to be developed specifically for obtaining multisubstituted imidazole derivatives, in organic synthesis, the site-selective synthesis of the desired products is still an attractive and challenging task. Our intention is to develop a method for selective synthesis of 2,4-disubstituted imidazoles using easily available starting reagents under mild reaction conditions. Hence, the synthesis of imidazoles with free N–H and C-5 position for further (N1 and C-5) functionalization of such scaffolds is of continued interest.

Results and Discussion

Despite these advances, to our knowledge, the oxidative cyclization of vinyl azides with benzamidines has remained elusive in literatures. In continuation of our studies on the synthesis of fused N-heterocycles,¹⁰ we report herein a facile method for the synthesis of 2,4-disubstituted imidazoles with 1,8-diazabicyclo(5,4,0)undec-7-ene (DBU) promoted by the oxidative cyclization of vinyl azides with benzamidines under mild conditions (Scheme 1).

Scheme 1.

We began our study by taking benzimidamide hydrochloride (1a) and (1-azidovinyl) benzene (2a) as the model substrates. The results are summarized in Table 1. Initially, the reaction of 1a and 2a was performed using 10 mol % of iodine as catalyst in acetonitrile at room temperature for 8 h; the desired product (3a) formation was not observed (Table 1, entry 1). When the reaction was carried out at 65 °C, with 20 mol % of catalyst, trace amount of 3a was observed (Table 1, entry 2). Under the same conditions, when K₂CO₃ was used as a base, 23% yields of the desired product 3a was isolated (Table 1, entry 3). A similar yield was observed without the iodine source (Table 1, entry 4). In view of this reaction, we turned our attention to vary the reaction temperature (to 80 °C) and other common solvents such as 1,2-dichloroethane (DCE), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and toluene; consequently, the yield varied between 45 and 67% (Table 1, entries 5–9). Further, we screened various inorganic and organic bases (Na₂CO₃, Cs₂CO₃, tBuOK, Et₃N, DBU, DBN, and DABCO) in acetonitrile as the solvent (Table 1, entries 10–16) [DBN: 1,5-diazabicyclo[4,3,0]non-5-ene; DABCO: 1,4-diazabicyclo[2.2.2]octane]. Interestingly, with DBU as the base, 89% yield of the desired product was obtained (entry 14). No further improvement in the yield was observed while performing the reaction with other solvents such as DMSO, N-methyl-2-pyrrolidone (NMP), and water with DBU as the base (Table 1, entries 17–19). The reaction without DBU in acetonitrile as the solvent, no product formation was observed (entry 20). After screening for various parameters, the optimum conditions identified for the present transformation are as follows: 1.5 equiv of 1a, 1.0 equiv of 2a, and 1.5 equiv of DBU as the base in acetonitrile at 80 °C (Table 1, entry 14).

Table 1. Optimization of Conditions for 3a^a.

entry	catalyst (mol %)	base (1.5 equiv)	temp (°C)	solvent	yield (%)
1	I2 (10)		rt	CH3CN
2	l2 (20)		65	CH3CN	traces
3	l2 (20)	K2CO3	65	CH3CN	23
4		K2CO3	65	CH3CN	22
5		K2CO3	80	CH3CN	55
6		K2CO3	80	DCE	49
7		K2CO3	80	DMF	67
8		K2CO3	80	DMSO	55
9		K2CO3	80	toluene	45
10		Na2CO3	80	CH3CN	51
11		Cs2CO3	80	CH3CN	42
12		tBuOK	80	CH3CN	61
13		Et3N	80	CH3CN	44
14		DBU	80	CH3CN	89
15		DBN	80	CH3CN	73
16		DABCO	80	CH3CN	69
17		DBU	80	DMSO	72
18		DBU	80	NMP	65
19		DBU	80	H2O	45
20			80	CH3CN	nr

^aReaction conditions, unless otherwise stated: 0.3 mmol of 1a, 0.2 mmol of 2a, 0.3 mmol of base, and 2 mL of solvent were placed in a reaction tube, 8 h, isolated yield.

Under the optimized reaction conditions, the scope and generality of the reaction were investigated and the results are summarized in Scheme 2. Initially, we performed the reaction of benzimidamide hydrochloride (1a) with various vinyl azides 2 and the reactions were found to be very facile with both electron-rich and electron-deficient groups (−Me, −OMe, −tBu, −Br, and −F) at the para position of vinyl azides and the desired products 3b–f were obtained in good to excellent yields (80–94%). One of the product 3f was also confirmed by the single-crystal X-ray diffraction analysis (CCDC No. 1556865). The presence of −NO₂, −Me, or −OMe group at either the ortho or meta position of vinyl azides produced the corresponding products 3g–j in moderate to good yields (67–79%).

Scheme 2. Substrate Scope of Various Vinyl Azides with Benzamidine (1a).

Reaction conditions: 0.3 mmol of 1a, 0.2 mmol of 2, 0.3 mmol DBU, 2.0 mL CH₃CN were placed in a reaction tube at 80° C, 8 h, isolated yields.

To expand the scope of the present transformation, we explored the reactivity of the substituted benzamidines substrate with various vinyl azides, and the results are compiled in Scheme 3. The electron-donating and electron-withdrawing (−Me, −Br, −Cl, and −NO₂) substituents at the para position of benzamidine reacted smoothly with (1-azidovinyl) benzene and produced the corresponding products 5a–d in good yields (66–87%). Interestingly, the presence of strong electron-donating benzamidines such as 4-aminobenzimidamide hydrochloride and 4-hydroxybenzimidamide hydrochloride reacted with 2a and gave the products 5e and 5f in 70 and 33% yields, respectively. Interestingly, the procedure is amenable to nicotinimidamide hydrochloride and cyclopropane carboximidamide and affords the differently decorated products 5g and 5h in 60 and 72% yield, respectively. Additionally, we evaluated the substrate scope of various benzamidines as well as vinyl azides (having both electron-rich and electron-deficient groups in both the rings at either position ortho/meta/para), which afforded the desired products 5i–r in good yields (63–92%). The presence of electron-releasing groups (5n), electron-withdrawing groups (5o and 5p), or halogens (5l and 5o) on both the rings provided good yields of products. The results from Schemes 2 and 3 demonstrate the versatility of the reactions with a high degree of functional group tolerance and with a broad substrate scope. It may be noted that halide-substituted derivatives were well tolerated and could be further applied in traditional cross-coupling reactions. Unfortunately, the present transformation is not suitable for aliphatic benzimidamides with vinyl azide.

Scheme 3. Substrate Scope of Various Benzamidines and Vinyl Azides.

Reaction conditions: 0.3 mmol of 4, 0.2 mmol of 2, 0.3 mmol of base, and 2 mL of solvent were placed in a reaction tube, isolated yields, DBU as a base and CH₃CN as a solvent, 8 h.

Dry acetonitrile was used.

To validate the process for scale-up studies (gram scale), we performed the reaction of 1a with 1-(1-azidovinyl)-4-bromobenzene under optimized conditions and obtained the corresponding product 3f in 72% yield (2.15 g) (Scheme 4). This study indicates the feasibility of the method for industrial/commercial production.

Scheme 4. Gram Scale Preparation.

To gain further insight into the reaction mechanism, some control experiments were performed (Scheme 5). The reaction of N-phenylbenzimidamide 6a was subjected with 2a under standard conditions, expect product 7a was not observed (Scheme 5, eq 1). This reaction suggests that the free NH₂ group (of amidine) is essential for such a transformation.^8b Further, the reaction of 1a with (1-bromovinyl) benzene (8) was conducted under optimized conditions; no reaction was observed, but 91% of 8 was recovered (Scheme 5, eq 2). It indicates that the direct removal of azide was not possible; the reaction may proceed via nitrene intermediate from vinyl azide (Scheme 5, eq 3). To ascertain whether the reaction proceeds by radical pathway or not, the reaction of 1a and 2a was checked with 2,2,6,6-tetramethylpiperidine-1-oxyl radical under optimized conditions, 86% of 3a was isolated. This rule outs the radical reaction route. Finally, benzimidamide 9 subjected with 2a in CH₃CN without DBU, 91% of the desired product 3a was obtained (Scheme 5, eq 4). This reaction and eq 1 (Scheme 5) together clarify the necessity of NH₂ (amidine) in the present transformation. Hence, the role of DBU is to neutralize the hydrochloride of 1a (benzimidamide hydrochloride).

Scheme 5. Control Experiments.

On the basis of the control experiments and literature reports,¹¹ a plausible reaction mechanism has been proposed (Scheme 6). Initially, benzimidamide hydrochloride (1a) neutralization by base (DBU) gives benzimidamide 9. The nucleophilic addition of 9 with (1-azidovinyl) benzene (2a) gives the intermediate I by the loss of N₂. The intermediate I undergoes cyclization (intermediate II) and the subsequent elimination of ammonia afford the desired product 3a.

Scheme 6. Plausible Mechanism.

Conclusions

In conclusion, we have demonstrated a new simple method for the synthesis of 2,4-disubstituted imidazole derivatives through [3 + 2] cyclization of benzamidines with vinyl azides. This methodology is applicable for the selective synthesis of 2,4-disubstituted imidazoles in good to excellent yields, with a high degree of functional group tolerance.

Experimental Section

General Information

All of the commercially available chemicals and reagents were used without any further purification unless otherwise indicated. ¹H and ¹³C NMR spectra were recorded at 500, 600 and 125, 150 MHz, respectively. The spectra were recorded in CDCl₃ and DMSO-d₆, as well as CD₃OD as a solvent. Multiplicity was indicated as follows: s (singlet); d (doublet); t (triplet); m (multiplet); dd (doublet of doublets), and so on. Coupling constant (J) was given in Hz. Chemical shifts are reported in δ relative to tetramethylsilane as an internal standard. The peaks around δ values of 7.26 (¹H NMR) and 77.0 (¹³C NMR) correspond to CDCl₃. The peaks around δ values of 2.50 (¹H NMR) and 39.9 (¹³C NMR) correspond to DMSO. The peak around δ values of 3.35 (¹H NMR) correspond to H₂O present in DMSO solvent. The peaks around δ values of 4.78 and 3.20 (¹H NMR) and 47.5 (¹³C NMR) correspond to CD₃OD. Progress of the reactions was monitored by thin-layer chromatography (TLC). Silica gel 100–200 mesh size was used for column chromatography using a hexane/ethyl acetate eluent unless otherwise indicated.

General Procedure for 3a

Benzimidamide hydrochloride 1a (47 mg, 0.3 mmol), (1-azidovinyl) benzene 2a (29 mg, 0.2 mmol), and DBU (45.6 mg, 0.3 mmol) were taken in a 10 mL reaction tube; to the mixture, 2.0 mL of acetonitrile was added. The reaction tube was placed in a preheated oil bath at 80 °C for 8 h (progress of the reaction was monitored by TLC). Then, the reaction mixture was allowed to attain room temperature; 10.0 mL of brine solution was extracted with ethyl acetate (3 × 15 mL) and dried with anhydrous Na₂SO₄. After the removal of solvent, the crude mixture was subjected to column chromatography on silica gel and 89% yield of the product 2,4-disubstituted imidazole (39.2 mg) 3a was isolated. (All of the vinyl azides employed in the present work were prepared by known procedure.¹²)

Characterization Data

2,4-Diphenyl-1H-imidazole (3a)

(Eluent: 10% EtOAc/hexane); 89% yield (39.2 mg); white solid; ¹H NMR (500 MHz, CDCl₃) δ 7.87 (d, J = 7.5 Hz, 2H), 7.75 (d, J = 7.0 Hz, 2H), 7.42–7.33 (m, 6H), 7.26 (t, J = 4.0 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 147.0, 130.0,128.8, 128.7, 127.0, 125.2, 124.9. HRMS calcd for C₁₅H₁₃N₂: 221.1079. Found: 221.1080.

2-Phenyl-4-(p-tolyl)-1H-imidazole (3b)

(Eluent: 10% EtOAc/hexane); 91% yield (42.8 mg); light yellow solid; ¹H NMR (500 MHz, CDCl₃) δ 7.87 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 7.0 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.5 Hz, 2H), 7.20 (d, J = 8.0, 2H), 2.36 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 146.8, 130.1, 129.4, 128.8, 128.7, 125.2, 124.8, 21.2. HRMS calcd for C₁₉H₂₀NO₂: 235.1235. Found: 235.1236.

4-(4-(tert-Butyl)phenyl)-2-phenyl-1H-imidazole (3c)

(Eluent: 10% EtOAc/hexane); 94% yield (47.1 mg); light yellow solid; ¹H NMR (600 MHz, CD₃OD) δ 7.90 (d, J = 6.5 Hz, 2H), 7.66 (d, J = 7.0 Hz, 2H), 7.43 (t, J = 6.0 Hz, 2H), 7.36 (t, J = 6.0 Hz, 1H), 7.32 (s, 1H), 6.94 (d, J = 7.5 Hz, 2H), 3.28 (s, 3H). ¹³C NMR (150 MHz, CD₃OD) δ159.1, 147.0, 130.0, 128.5, 128.4, 126.1, 125.3, 113.8, 54.4. HRMS calcd for C₁₆H₁₅N₂O: 251.1184. Found: 251.1180.

4-(4-(tert-Butyl)phenyl)-2-phenyl-1H-imidazole (3d)

(Eluent: 10% EtOAc/hexane); 89% yield (49.3 mg); white solid; melting point 204 °C ¹H NMR (600 MHz, CD₃OD) δ 7.91 (d, J = 6.0 Hz, 2H), 7.67 (d, J = 6.5 Hz, 2H), 7.45 (d, J = 6.5 Hz, 1H), 7.42 (d, J = 3.5, 2H), 7.40 (s, 1H), 7.39 (s, 1H), 7.36 (t, J = 6.5, 1H), 1.39 (s, 9H). ¹³C NMR (150 MHz, CD₃OD) δ 149.8, 147.3, 130.1, 128.5, 128.4, 125.3, 125.2, 124.5, 34.0, 30.4. HRMS calcd for C₁₉H₂₀N₂Na: 299.1524. Found: 299.1510.

4-(4-Fluorophenyl)-2-phenyl-1H-imidazole (3e)

(Eluent: 10% EtOAc/hexane); 81% yield (38.6 mg); white solid; ¹H NMR (500 MHz, CDCl₃) δ 7.89 (d, J = 8.0 Hz, 2H), 7.75 (s, 1H), 7.46 (t, J =7.5 Hz, 2H), 7.39 (t, J = 7.0 Hz, 1H), 7.33 (s, 1H), 7.26 (s, 2H), 7.09 (t, J = 8.5, 2H). ¹³C NMR (125 MHz, CDCl₃) δ 147.0, 129.9, 128.9, 126.6, 126.5, 125.2, 115.6, 115.4. HRMS calcd for C₁₅H₁₁N₂FNa: 261.0804. Found: 261.0794.

4-(4-Bromophenyl)-2-phenyl-1H-imidazole (3f)

(Eluent: 10% EtOAc/hexane); 80% yield (47.9 mg); yellow solid; ¹H NMR (600 MHz, CD₃OD) δ 7.90 (d, J = 6.5 Hz, 2H), 7.67 (d, J = 7.0 Hz, 2H), 7.50 (s, 1H), 7.48 (d, J = 2.5 Hz, 2H), 7.44 (t, J = 6.0, 2H), 7.37 (t, J = 6.0 Hz, 2H), 7.37 (t, J = 6.0 Hz, 1H). ¹³C NMR (150 MHz, CD₃OD) δ 147.7, 131.4, 130.0, 128.63, 126.60, 126.4, 125.4, 120.0. HRMS calcd for C₁₅H₁₂N₂Br: 299.0184. Found: 294.0172.

2-Phenyl-4-(o-tolyl)-1H-imidazole (3g)

(Eluent: 10% EtOAc/hexane); 72% yield (33.8 mg); yellow solid; ¹H NMR (500 MHz, CDCl₃) δ 7.89 (d, J = 7.5 Hz, 2H), 7.44 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.0, 1H), 7.26 (q, J = 6.0 Hz, 5H), 2.50 (s, 3H).¹³C NMR (125 MHz, CDCl₃) δ 147.1, 135.4, 130.8, 128.8, 128.7, 128.3, 127.4, 126.0, 125.2, 29.7. HRMS calcd for C₁₆H₁₅N₂: 235.1235. Found: 235.1241.

4-(2-Methoxyphenyl)-2-phenyl-1H-imidazole (3h)

(Eluent: 10% EtOAc/hexane); 67% yield (33.5 mg); light yellow solid; ¹H NMR (500 MHz, CDCl₃) δ 7.88 (d, J = 7.5 Hz, 2H), 7.58 (s, 1H), 7.45 (t, J = 7.5, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.26 (q, J = 7.5, 2H), 7.06 (m, 2H), 4.02 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 140.0, 128.8, 128.4, 124.9, 121.5, 111.4, 103.5, 55.8. HRMS calcd for C₁₆H₁₅N₂O: 251.1184. Found: 251.1178.

2-Phenyl-4-(m-tolyl)-1H-imidazole (3i)

(Eluent: 10% EtOAc/hexane); 79% yield (37.0 mg); yellow solid; ¹H NMR (500 MHz, CDCl₃) δ 7.87 (d, J = 7.5 Hz, 2H), 7.58 (s,1H), 7.51 (d, J = 7.5, 1H), 7.39 (t, J = 7.5 Hz, 2H), 7.35 (d, J = 5.0, 2H), 7.26 (t, J = 7.5, 2H), 7.08 (d, J = 7.5, 1H), 2.37 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 146.9, 138.3, 128.8, 128.68, 128.61, 127.8, 125.5, 125.2, 121.9, 21.4. HRMS calcd for C₁₆H₁₅N₂: 235.1235. Found: 235.1234.

4-(3-Nitrophenyl)-2-phenyl-1H-imidazole (3j)

(Eluent: 20% EtOAc/hexane); 67% yield (35.6 mg); brick red color solid; ¹H NMR (500 MHz, CDCl₃) δ 8.65 (s, 1H), 8.21 (d, J = 7.0 Hz, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 7.5 Hz, 2H), 7.56 (t, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.91 (d, J = 7.5 Hz, 2H), 7.42 (t, J = 7.0 Hz, 1H), 7.26 (s, 1H), 7.56 (t, J = 8.0 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 147.4, 130.8, 129.5, 129.2, 129.0, 125.3, 121.4, 119.6. HRMS calcd for C₁₅H₁₂N₃O₂: 266.0930. Found: 266.0921.

4-Phenyl-2-(p-tolyl)-1H-imidazole (5a)

(Eluent: 10% EtOAc/hexane); 87% yield (40.8 mg); light yellow solid; ¹H NMR (500 MHz, CDCl₃) δ 7.78 (d, J = 8.0 Hz, 2H), 7.41 (q, J = 7.5 Hz, 3H), 7.26 (q, J = 7.5 Hz, 5H), 2.39 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 147.1, 138.8, 129.5, 128.7, 127.0, 125.1, 124.8, 21.3. HRMS calcd for C₁₆H₁₅N₂: 235.1235. Found: 235.1237.

2-(4-Bromophenyl)-4-phenyl-1H-imidazole (5b)

(Eluent: 10% EtOAc/hexane); 85% yield (50.7 mg); yellow solid; melting point 198 °C ¹H NMR (500 MHz, CDCl₃) δ 7.72 (t, J = 8.0 Hz, 4H), 7.52 (d, J = 8.0 Hz, 2H), 7.40 (q, J = 7.5 Hz, 3H), 7.28 (t, J = 7.5 Hz, 1H).¹³C NMR (125 MHz, CDCl₃) δ 146.0, 132.0, 128.9, 128.7, 127.2, 126.7, 124.9, 128.8. HRMS calcd for C₁₅H₁₂N₂Br: 299.0184. Found: 299.0186.

2-(4-Chlorophenyl)-4-phenyl-1H-imidazole (5c)

(Eluent: 10% EtOAc/hexane); 81% yield (41.3 mg); white solid; ¹H NMR (600 MHz, CD₃OD) δ 7.88 (d, J = 6.5, Hz, 2H), 7.73 (d, J = 6.5 Hz, 2H), 7.44 (d, J = 6.0 Hz, 3H), 7.37 (t, J = 6.5 Hz, 2H), 7.23 (t, J = 6.0 Hz, 1H). ¹³C NMR (150 MHz, CD₃OD) δ 145.9, 134.6, 131.2, 129.1, 128.7, 128.6, 128.5, 126.4, 124.9. HRMS calcd for C₁₅H₁₂N₂Cl: 255.0689. Found: 255.0694.

2-(4-Nitrophenyl)-4-phenyl-1H-imidazole (5d)

(Eluent: 20% EtOAc/hexane); 69% yield (36.6 mg); brick red color solid; ¹H NMR (600 MHz, CD₃OD) δ 8.29 (d, J = 8.0 Hz, 2H), 8.05 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 7.5 Hz, 2H), 7.47 (s, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.0, 1H). ¹³C NMR (150 MHz, CD₃OD) δ 146.3, 134.2, 128.84, 128.73, 128.4, 126.8, 124.7. HRMS calcd for C₁₅H₁₂N₃O₂: 266.0930 Found: 266.0928.

4-(4-Phenyl-1H-imidazol-2-yl)aniline (5e)

(Eluent: 75% EtOAc/hexane); 70% yield (33.1 mg); gray color solid; melting point 199 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.60 (d, J = 6.5 Hz, 2H), 7.49 (d, J = 6.0 Hz, 2H), 7.33 (d, J = 6.0, 2H), 7.26 (s, 1H), 6.97 (s, 1H), 6.42 (d, J = 6.0 Hz, 2H). ¹³C NMR (150 MHz, CDCl₃) δ 150.8, 148.4, 146.4, 127.6, 125.6, 124.8, 114.7. HRMS calcd for C₁₅H₁₄N₃: 236.1188. Found: 236.1181.

4-(4-Phenyl-1H-imidazol-2-yl)phenol (5f)

(Eluent: 65% EtOAc/hexane); 33% yield (15.7 mg); white color solid; ¹H NMR (600 MHz, DMSO-d₆) δ 12.3 (s, 1H), 9.65 (s, 1H), 7.79 (q, J = 6.5 Hz, 4H), 7.61 (s, 1H), 7.31 (t, J = 6.5, 2H), 7.14 (t, J = 6.0 Hz, 1H), 6.80 (d, J = 7.0, 2H). ¹³C NMR (150 MHz, DMSO-d₆) δ 158.1, 135.4, 128.9, 127.0, 126.4, 124.7, 122.4, 115.9, 113.8. HRMS calcd for C15H13N₂O: 237.1028. Found: 237.1031.

3-(4-Phenyl-1H-imidazol-2-yl)pyridine (5g)

(Eluent: 80% EtOAc/hexane); 60% yield (26.4 mg); white solid; ¹H NMR (600 MHz, DMSO-d₆) δ 9.0 (s, 1H), 8.52 (s, 1H), 8.31 (d, J = 7.0, 1H), 7.66 (d, J = 7.5 Hz, 2H), 7.26 (q, J = 7.5, 2H), 7.41 (t, J = 5.0 Hz, 3H), 7.35 (t, J = 4.0 Hz, 1H), 7.26 (s, 1H). ¹³C NMR (150 MHz, DMSO-d₆) δ 148.8, 146.0, 143.2, 141.4, 134.2, 132.0, 128.8, 128.4, 126.3, 124.3, 123.7, 114.9. HRMS calcd for C₁₄H₁₂N₃: 221.1031. Found: 221.1026.

2-Cyclopropyl-4-phenyl-1H-imidazole (5h)

(Eluent: 30% EtOAc/hexane); 72% yield (26.5 mg); white solid; melting point 160 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.64 (broad peak, 2H), 7.35 (t, J = 6.5,2H), 7.21 (t, J = 6.5, 1H), 7.16 (s, 1H), 1.99–1.94 (m, 1H), 1.02–0.95 (m, 4H). ¹³C NMR (150 MHz, CDCl₃) δ 128.7, 126.7, 124.7, 9.24, 7.44. HRMS calcd for C₁₂H₁₃N₂: 185.1079. Found: 185.1077.

4-(4-Fluorophenyl)-2-(p-tolyl)-1H-imidazole (5i)

(Eluent: 10% EtOAc/hexane); 87% yield (43.8 mg); white solid; melting point 180 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.75 (t, J = 7.0 Hz, 4H), 7.27 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 6.5, 2H), 7.06 (t, J = 7.0 Hz, 2H), 2.37 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 162.8 (d, J = 203.6), 138.9, 129.5, 127.2, 126.60 (d, J = 6.37 Hz), 125.1, 115.6 (d, J = 17.7 Hz), 21.3. HRMS calcd for C₁₆H₁₄N₂F: 253.1141. Found: 253.1153.

4-(4-Fluorophenyl)-2-(4-nitrophenyl)-1H-imidazole (5j)

(Eluent: 20% EtOAc/hexane); 72% yield (41.0 mg); brick red solid; melting point 216 °C. ¹H NMR (600 MHz, DMSO-d₆) δ 13.34 (s, 1H), 8.70 (s, 1H), 8.37 (d, J = 7.0 Hz, 2H), 8.34 (d, J = 6.5, 1H), 8.28 (d, J = 7.5 Hz, 2H), 8.24 (s, 1H), 8.10 (d, J = 7.0 Hz, 1H), 7.70 (t, J = 7.0 Hz, 1H). ¹³C NMR (150 MHz, DMSO-d₆) δ 148.8, 147.2, 144.9, 144.8, 140.6, 136.4, 131.2, 130.7, 126.3, 124.9, 121.6, 119.0, 118.6. HRMS calcd for C₁₅H₁₁N₃O₂F: 284.0835. Found: 284.0836.

4-(4-Bromophenyl)-2-(p-tolyl)-1H-imidazole (5k)

(Eluent: 10% EtOAc/hexane); 92% yield (57.7 mg); light yellow solid; melting point 210 °C. ¹H NMR (600 MHz, CD₃OD) δ 7.79 (d, J = 6.5 Hz, 2H), 7.67 (d, J = 7.5 Hz, 2H), 7.51 (d, J = 6.5, 2H), 7.47 (s, 1H), 7.27 (d, J = 6.5, 2H), 2.36 (s, 3H). ¹³C NMR (150 MHz, CD₃OD) δ 149.2, 140.1, 132.6, 130.4, 128.4, 127.6, 126.6, 121.2, 21.2. HRMS calcd for C₁₆H₁₄N₂Br: 313.0340. Found: 313.0349.

4-(4-Bromophenyl)-2-(4-chlorophenyl)-1H-imidazole (5l)

(Eluent: 10% EtOAc/hexane); 79% yield (52.4 mg); light yellow solid; melting point 200 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.78 (d, J = 6.5 Hz, 2H), 7.64 (d, J = 6.5 Hz, 2H), 7.51 (d, J = 6.5, 2H), 7.38 (d, J = 7.0 Hz, 2H), 7.34 (s, 1H), 7.25 (s, 1H). ¹³C NMR (150 MHz, CDCl₃) δ 146.1, 134.8, 131.7, 129.1, 128.2, 126.5, 120.8. HRMS calcd for C₁₅H₁₁N₂ClBr: 332.9794. Found: 332.9796.

4-(4-Chlorophenyl)-2-cyclopropyl-1H-imidazole (5m)

(Eluent: 10% EtOAc/hexane); 67% yield (29.4 mg); white solid; melting point 164 °C. ¹H NMR (600 MHz, DMSO-d₆) δ 11.90 (s, 1H),7.73 (s, 1H), 7.65 (d, J = 5.0 Hz,1H), 7.54 (s, 1H), 7.33 (t, J = 6.5 Hz, 1H), 7.18 (d, J = 6.0 Hz, 1H), 1.97–1.93 (m, 1H), 0.92–0.90 (m, 2H), 0.89–0.85 (m, 2H). ¹³C NMR (150 MHz, DMSO-d₆) δ 130.7, 125.8, 124.0, 123.0, 113.4, 9.6, 7.5. HRMS calcd for C₁₉H₂₀NO₂: 219.0689. Found: 219.0690.

4-(4-(4-(tert-Butyl)phenyl)-1H-imidazol-2-yl)aniline (5n)

(Eluent: 75% EtOAc/hexane); 72% yield (42.3 mg); gray color solid; melting point 218 °C. ¹H NMR (600 MHz, DMSO-d₆) δ 12.16 (s, 1H), 7.76 (s, 2H), 7.72 (s, 2H),7.53 (s, 1H), 7.43 (s, 2H), 6.67 (t, J = 2.5 Hz, 2H), 5.39 (s, 2H), 1.36 (s, 9H). ¹³C NMR (150 MHz, DMSO-d₆) δ 149.4, 126.7, 125.6, 124.4, 114.1, 31.7. HRMS calcd for C₁₉H₂₂N₃: 292.1814. Found: 292.1815.

2, 4-Bis(4-bromophenyl)-1H-imidazole (5o)

(Eluent: 10% EtOAc/hexane); 85% yield (64.2 mg); yellow color solid; melting point 194 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.85 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 6.5 Hz, 2H), 7.64 (d, J = 9.5, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.39 (s, 1H). ¹³C NMR (150 MHz, CDCl₃) δ 146.0, 132.1, 137.7, 128.7, 126.7, 126.5, 123.0, 120.8. HRMS calcd for C₁₅H₁₁N₂Br₂: 376.9289. Found: 376.9285.

4-(3-Nitrophenyl)-2-(4-nitrophenyl)-1H-imidazole (5p)

(Eluent: 85% EtOAc/hexane); 69% yield (43.1 mg); brick red color solid; ¹H NMR (600 MHz, CD₃OD) δ 8.60 (s, 1H), 8.25 (d, J = 7.5 Hz, 2H), 8.10 (q, J = 6.5, 3H), 8.02 (d, J = 6.5 Hz, 1H), 7.74 (s, 1H), 7.54 (t, J = 7.0 Hz, 1H). ¹³C NMR (150 MHz, CD₃OD) δ 148.7, 147.5, 145.4, 135.5, 130.4, 129.5, 125.7, 123.7, 121.0, 118.9. HRMS calcd for C₁₅H₁₁N₄O₄: 311.0780. Found: 311.0779.

2-(4-Bromophenyl)-4-(2-methoxyphenyl)-1H-imidazole (5q)

(Eluent: 10% EtOAc/hexane); 63% yield (41.4 mg); yellow solid; melting point 198 °C. ¹H NMR (600 MHz, CD₃OD) δ 7.87 (d, J = 6.0 Hz, 1H), 7.83 (d, J = 7.5 Hz, 2H), 7.61 (d, J = 7.5, 2H), 7.55 (s, 1H), 7.24 (t, J = 6.0 Hz, 1H), 7.06 (d, J = 7.0, 1H), 7.00 (t, J = 6.0 Hz, 1H) 3.92 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 152.8, 143.8, 131.1, 128.3, 125.4, 121.5, 55.0. HRMS calcd for C₁₆H₁₄N₂OBr: 329.0289. Found: 329.0280.

2-(4-Chlorophenyl)-4-(o-tolyl)-1H-imidazole (5r)

(Eluent: 10% EtOAc/hexane); 70% yield (37.6 mg); light yellow solid; melting point 191 °C. ¹H NMR (600 MHz, CD₃OD) δ 7.80 (d, J = 7.5 Hz, 2H), 7.43 (m, 2H), 7.36 (d, J = 6.5, 2H), 7.18 (m, 2H), 7.14 (m, 2H), 7.10 (s, 1H) 2.34 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 145.5, 135.7, 134.2, 130.3, 128.8, 128.7, 127.3, 126.7, 125.5, 19.8. HRMS calcd for C₁₆H₁₄N₂Cl: 269.0846. Found: 269.0843.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.7b00969.

• Copies of NMR spectra for all of the compounds and HRMS spectra for all of the compounds (PDF)

• Crystallographic data (CIF)

The authors declare no competing financial interest.