Microwave-assisted green construction of imidazole-fused hybrid scaffolds using 2-aminobenzimidazoles as building blocks

Abstract

A class of trinuclear imidazole-fused hybrid scaffolds was constructed by the reaction of 2-(2-bromoaryl)- and 2-(2-bromovinyl)imidazoles with 2-aminobenzimidazoles as building blocks in the presence of a base under microwave irradiation. A nucleophilic aromatic substitution followed by cyclization is proposed as a reaction pathway of this green process.

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Introduction

Diverse synthetic methods for the construction of N-fused hybrid scaffolds have been developed due to their characteristic properties that are not shown in each homonuclear heterocycle.¹ In connection with this report, it is known that trinuclear N-fused hybrid structure A, benzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline, exhibits biological activities and photoelectronic properties (Scheme 1).^2,3 However, in contrast to well-known synthetic methods of each homonuclear quinazoline, imidazole and benzimidazole, several synthetic methods are reported for their trinuclear N-fused hybrid structures with a limited substrate scope.⁴ It is reported that bis(o-haloaryl)carbodiimides react with imidazole in the presence of CuI and 1,10-phenanthroline as a ligand along with a base to afford such a trinuclear compound via several sequential processes such as nucleophilic addition, tautomerization, intramolecular Ullmann-type C–N coupling, and intramolecular sp² C–H arylation (Scheme 2, route a).⁵ Kumar and co-workers demonstrated that 2-(2-bromophenyl)imidazoles are C–N coupled and oxidatively cyclized with benzimidazole by subsequent treatment of CuI and Pd(OAc)₂/Cu(OAc)₂ (or Cu(OAc)₂) to give such a trinuclear compound (Scheme 2, route b).^2,6 Such a similar coupling and cyclization for the construction of such a trinuclear compound was also exemplified by multistep processes starting from 1-benzyl-4,5-diphenyl-1H-imidazole/2-chlorobenzimidazole and 2-fluorobenzonitrile/benzimidazole, respectively (Scheme 2, routes c and d).³ However, these precedents still have some drawbacks such as limitation of substrate scope, the requirement of transition metal catalysts and contamination of residual metals in products, and tedious multistep processes. As part of our continuing studies directed toward transition metal-catalyzed and transition metal-free synthesis of polynuclear N-fused hybrid scaffolds,⁷ we recently reported that compounds B–D can be formed by double nucleophilic aromatic substitution of 2-(2-bromoaryl)- and 2-(2-bromovinyl)benzimidazoles with 2-aminoazoles in the presence of a base (Scheme 1).^8,9 This work started during the course of the extension of such a transition metal-free double nucleophilic aromatic substitution to synthesize polynuclear N-fused hybrid scaffolds. This report shows an example of the green construction of trinuclear N-fused hybrid structure A by transition metal-free double C(sp²)–N coupling between 2-(2-bromoaryl)-4,5-diaryl-1H-imidazoles and 2-aminobenzimidazoles under microwave irradiation (Scheme 2, route e).^10,11 The present protocol can also be extended to the reaction of 2-(2-bromovinyl)imidazoles with 2-aminobenzimidazole to produce trinuclear N-fused hybrid structure E (Scheme 2, route f).

Scheme 1 Trinuclear N-fused hybrid scaffolds.

Scheme 2 Synthetic routes for trinuclear N-fused hybrid scaffolds.

Results and discussion

Based on our recent report on transition metal-free coupling and cyclization of 2-(2-bromoaryl)- and 2-(2-bromovinyl)benzimidazoles with 2-aminoazoles leading to trinuclear N-fused hybrid scaffolds, we optimized the reaction conditions with 2-(2-bromophenyl)-4,5-diphenyl-1H-imidazole (1a) and 2-aminobenzimidazole (2a) as model substrates to produce trinuclear N-fused hybrid compound 3a effectively (Table 1).⁸ Treatment of 1a with 1.5 equiv. of 2a in DMF in the presence of K₃PO₄ (1 equiv.) at 150 °C for 2 h under microwave irradiation (120 W of initial power) produced 3a in 39% isolated yield with complete conversion of 1a (Table 1, entry 1). Although it is still obscure why such an excess amount of base is needed for the effective formation of 3a, the yield of 3a gradually increased with an increase of the molar ratio of K₃PO₄ to 1a up to 3 (Table 1, entries 2–4).^9a The yield of 3a also increases on prolonging the reaction time up to 2 h and a lower yield of 3a was observed with a short reaction time nevertheless complete conversion of 1a (Table 1, entries 3, 5, and 6). Lower yield of 3a was observed with incomplete conversion of 1a under lower reaction temperature, and the yield increased with the increase in temperature up to 150 °C (Table 1, entries 3, 7, and 8). Among solvents examined in combination with K₃PO₄ under the employed conditions, DMF was found to be of choice in terms of both the yield of 3a and complete conversion of 1a (Table 1, entries 3, 9, and 10). No significant change of the yield of 3a was observed with higher molar ratio of [2a]/[1a] (Table 1, entry 11). The reaction also proceeded with other bases such as KO^tBu, K₂CO₃, and Cs₂CO₃ with complete conversion of 1a and similar activities to that of K₃PO₄ under the employed conditions, and K₂CO₃ was shown to be the base of choice (Table 1, entries 3, 12–14). However, as is the case for our recent report on the reaction of 2-(2-bromoaryl)- and 2-(2-bromovinyl)benzimidazoles with 2-aminoazoles, 3a was not produced at all in the absence of base and no other spots were observed except for both substrates on TLC (Table 1, entry 15).⁸

Table 1 Optimization of conditions for the reaction of 1a with 2a^a

Entry	[Base]/[1a]	Base	Solvent	Temp. (°C)	Time (h)	Conv. of 1a (%)	Yield^b (%)
a Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), base, DMF (3 mL), under microwave irradiation (120 W of initial power).b Isolated yield.c [2a]/[1a] = 2.d Usual heating (5 mL screw-capped vial).
1	1	K3PO4	DMF	150	2	100	39
2	2	K3PO4	DMF	150	2	100	54
3	3	K3PO4	DMF	150	2	100	65
4	4	K3PO4	DMF	150	2	100	66
5	3	K3PO4	DMF	150	3	100	66
6	3	K3PO4	DMF	150	1	100	29
7	3	K3PO4	DMF	100	2	66	34
8	3	K3PO4	DMF	125	2	85	41
9	3	K3PO4	HMPA	150	2	100	47
10	3	K3PO4	DMSO	150	2	97	0
11^c	3	K3PO4	DMF	150	2	100	66
12	3	KO^tBu	DMF	150	2	100	58
13	3	K2CO3	DMF	150	2	100	76
14	3	Cs2CO3	DMF	150	2	100	68
15	3	—	DMF	150	2	0	0
16^d	3	K2CO3	DMF	150	20	100	33

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Similar treatment of 1a with 2a under usual heating conditions screw-capped vial, 150 °C for 20 h resulted in only 33% yield of 3a along with several unidentifiable side products with complete conversion of 1a (Table 1, entry 16).

After the reaction conditions had been optimized, various 2-(2-bromoaryl)- and 2-(2-bromovinyl)imidazoles 1 were subjected to the reaction with 2-aminobenzimidazoles 2, and the representative are shown in Table 2.^12–14 2-(2-Bromoaryl)imidazoles 1b–d having electron-donating and withdrawing substituents on the bromoaryl moiety were also coupled and cyclized with 2a to give the corresponding trinuclear N-fused hybrid scaffolds 3b–d in 60–63% yields, irrespective of the electronic nature of such substituents. With 2-(2-bromophenyl)-4,5-diaryl-1H-imidazoles 1e–i having electron-donating and withdrawing substituents on the phenyl moiety attached to imidazole ring, the corresponding trinuclear N-fused hybrid scaffolds 3e–i were also formed in 63–71% yields. Prolonging the reaction time up to 4 h was needed for an allowable yield of 3e, 3g and 3h from the reaction with the corresponding 2-(2-bromophenyl)imidazoles (1e, 1g and 1h). The reaction of 2-(2-bromophenyl)-4,5-diheteroarylimidazole 1j with 2a also proceeded to give the corresponding trinuclear N-fused compound 3j in similar yield. Performing the reaction of 1a with dimethyl- and dichloro-substituted 2-aminobenzimidazoles (2b and 2c) also afforded the corresponding trinuclear N-fused hybrid scaffolds (3k and 3l). Here again, prolonging the reaction time was necessary for the effective formation of 3l from the reaction of 1a and 2c. However, no expected cyclized product was observed with the reaction of 2-(1-bromonaphthalen-2-yl)-4,5-diphenyl-1H-imidazole (1k) and 2a, a considerable amount of 2-(naphthalen-2-yl)-4,5-diphenyl-1H-imidazole 4 by debromination of 1k being produced in 57% yield with 59% conversion of 1k. It is known that aryl bromides were reduced to the corresponding arenes in the presence of a base by DMF as hydrogen source.¹⁵ Similar treatment of 2-(2-bromovinyl)imidazoles 1l–p having alkyl and phenyl substituents on vinyl moiety with 2-aminobenzimidazoles 2a–c under the employed conditions also afforded the corresponding imidazole-fused hybrid compounds 3m–s irrespective of the identity of such substituents. To the best of our knowledge, there are no reports on the synthetic method and biological activity of such a scaffold.

Table 2 Scope of reaction^a

a Reaction conditions: 1 (0.3 mmol), 2 (0.45 mmol), K₂CO₃ (0.9 mmol), DMF (3 mL), under microwave irradiation (120 W of initial power) at 150 °C, for 2 h.b For 4 h.

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On the other hand, a one-pot reaction starting from 2-bromobenzaldehyde (5) and benzil (6) under microwave irradiation renders the synthesis of 3a practical.¹³ Treatment of 5 with equimolar amount of 6 in the presence of NH₄OAc and AcOH in EtOH at 70 °C under microwave irradiation followed by removal of solvent afforded a white solid. Subsequent addition of 2a, K₂CO₃ and DMF to the microwave reaction tube containing a white solid and heating at 150 °C for 3 h produced 3a in 63% yield (eqn (1)).

The present reaction seems to proceed via an initial formation of a C–N coupled intermediate 8 by an addition–elimination nucleophilic aromatic substitution by way of a resonance-stabilized carbanion, Meisenheimer complex 7 generated by a nucleophilic attack of 2a to the carbon attached to Br in 1 (Scheme 3).¹⁶ The ortho-substituted imidazole group of 1 facilitates the formation of such a Meisenheimer complex 7 by further electron delocalization over phenyl and imidazole rings. Fortunately, a C–N coupled intermediate 8a could be isolated in 18% yield from the reaction of 1c with 2a under the optimized conditions (eqn (2)). Performing the reaction of 1c with 2a for 4 h under the employed conditions resulted in 68% yield of 3c with complete disappearance of 8a. The intermediate 8a thus isolated was readily cyclized under the optimized conditions to give 3c in 74% yield (eqn (3)). These results indicate a doubtless evidence for the formation of such a C–N coupled intermediate 8 during the reaction course between 1 and 2. Subsequent intramolecular nucleophilic addition in intermediate 8 produces an intermediate 9, which triggers β-elimination to give 3 with the evolution of ammonia (Scheme 3).¹⁷ The evolution of ammonia was testified by the color change of Nessler's reagent, an alkali solution of K₂HgI₄.¹⁸

Scheme 3 A plausible reaction pathway.

Conclusions

In summary, we developed a transition metal-free synthesis of trinuclear imidazole-fused hybrid scaffolds by K₂CO₃-mediated coupling and cyclization of 2-(2-bromoaryl)- and 2-(2-bromovinyl)imidazoles with 2-aminobenzimidazoles as building blocks under microwave irradiation. The present protocol provides a green synthetic method for such trinuclear N-fused hybrid scaffolds. Further challenges on the green construction of polynuclear N-fused hybrid scaffolds via transition metal-free C(sp²)–N coupling are in progress.

Experimental

General information

¹H (500 MHz) and ¹³C NMR (125 MHz) spectra were recorded on a Bruker Avance Digital 500 spectrometer. Melting points were determined on a microscopic melting point apparatus (Stanford Research Inc. MPA 100 automated melting point apparatus). High-resolution mass data were recorded using electronic ionization (HRMS-EI, magnetic sector-electric sector double focusing mass analyzer) at Korea Basic Science Institute, Daegu Center, Korea. All reactions were carried out in a sealed tube under microwave irradiation (CEM, Discover LabMate) and the reaction temperature was maintained by an external infrared sensor. The products were isolated by TLC (a glass plate coated with Kieselgel 60 GF₂₅₄, Merck). 2-(2-Bromoaryl)- and 2-(2-bromovinyl)-4,5-diaryl-1H-imidazoles 1 were synthesized from the corresponding aldehydes and 1,2-diarylethane-1,2-diones (see ESI†).^12,13 2-Aminobenzimidazoles 2 were prepared from 1,2-phenylenediamines and cyanogen bromide by known methods.¹⁹ Other commercially available organic and inorganic reagents were used without further purification.

General procedure for the synthesis of 3. To a 10 mL microwave reaction tube, 1 (0.3 mmol), 2 (0.45 mmol), K₂CO₃ (0.124 g, 0.9 mmol), and DMF (3 mL) were added. After stirring the reaction mixture at room temperature for 5 min, it was heated at 150 °C for 2–4 h under microwave irradiation (120 W of initial power). The reaction mixture was cooled down to room temperature and filtered through a short silica gel column to eliminate inorganic residue using chloroform/MeOH = 7/3. Removal of the eluent under reduced pressure left a crude mixture, which was purified by thin layer chromatography (dichloromethane/MeOH = 99/1 or dichloromethane/hexane = 1/1) to obtain 3. All new products were characterized spectroscopically.

1,2-Diphenylbenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline (3a)^7g. Yield 76% (94 mg), white solid, mp 289–291 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.78 (dd, J = 7.9 and 1.5 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.78–7.74 (m, 1H), 7.67–7.50 (m, 9H), 7.44–7.36 (m, 2H), 7.32–7.24 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 142.1, 133.5, 132.8, 132.1, 130.5, 128.9, 128.3, 128.1, 128.0, 127.5, 125.5, 125.3, 124.0, 123.2, 120.8, 115.2, 114.8, 112.8.

6-Methyl-1,2-diphenylbenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline (3b). Yield 61% (78 mg), white solid, mp 268–270 °C. ¹H NMR (500 MHz, CD₂Cl₂) δ 8.60 (d, J = 8.0 Hz, 1H), 8.27–8.25 (m, 2H), 7.62–7.59 (m, 5H), 7.58–7.51 (m, 3H), 7.46–7.38 (m, 3H), 7.29–7.23 (m, 3H), 2.66 (s, 3H); ¹³C NMR (125 MHz, CD₂Cl₂) δ 142.4, 142.2, 142.1, 142.0, 141.4, 134.3, 133.3, 132.5, 130.9, 130.7, 129.2, 128.6, 128.5, 128.3, 127.8, 127.0, 125.7, 125.4, 124.4, 123.4, 120.5, 115.6, 113.5, 113.2, 22.5. HRMS (EI): m/z [M⁺] calcd for C₂₉H₂₀N₄: 424.1688, found 424.1686.

5-Methoxy-1,2-diphenylbenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline (3c). Yield 60% (79 mg), pale yellow solid, mp 273–275 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.32 (d, J = 9.1 Hz, 1H), 8.20 (d, J = 2.7 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.65–7.61 (m, 5H), 7.56–7.49 (m, 3H), 7.41–7.28 (m, 6H), 4.04 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 157.0, 142.1, 142.0, 133.6, 132.1, 130.0, 128.9, 128.3, 128.1 (128.12), 128.1 (128.07), 127.5, 127.0, 125.9, 123.7, 122.9, 120.8, 119.1, 116.3, 112.5, 107.1 56.1. HRMS (EI): m/z [M⁺] calcd for C₂₉H₂₀N₄O: 440.1637, found 440.1637.

5-Fluoro-1,2-diphenylbenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline (3d). Yield 63% (81 mg), white solid, mp 311–312 °C. ¹H NMR (500 MHz, CD₂Cl₂) δ 8.44–8.40 (m, 2H), 8.19 (d, J = 8.1 Hz, 1H), 7.63–7.49 (m, 9H), 7.47–7.44 (m, 1H), 7.42–7.40 (m, 1H), 7.31–7.26 (m, 3H); ¹³C NMR (125 MHz, CD₂Cl₂) δ 159.7 (d, ¹J_C–F = 244.7 Hz), 142.4, 142.0, 141.0, 139.9, 133.4, 132.0, 130.0, 129.8, 129.3, 129.0, 128.3, 128.2, 128.0, 127.7, 126.2, 124.1, 123.3, 121.0, 117.9, 117.7 (d, ⁴J_C–F = 3.9 Hz), 116.6 (d, ³J_C–F = 8.3 Hz), 112.4, 111.5 (d, ²J_C–F = 25 Hz). HRMS (EI): m/z [M⁺] calcd for C₂₈H₁₇FN₄: 428.1437, found 428.1433.

1,2-Di-o-tolylbenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline (3e). Yield 63% (83 mg), pale yellow solid, mp 250–253 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.72 (dd, J = 7.9 and 1.3 Hz, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.16–8.14 (m, 1H), 7.72–7.69 (m, 1H), 7.64–7.62 (m, 1H), 7.54–7.51 (m, 1H), 7.40–7.33 (m, 3H), 7.30–7.27 (m, 2H), 7.21–7.17 (m, 4H), 7.09–7.05 (m, 1H), 2.34 (s, 3H), 2.15 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 143.6, 142.3, 141.2, 140.5, 139.3, 137.5, 133.0, 132.8, 132.1, 130.8, 130.4, 130.3 (130.28), 130.3 (130.27), 129.7, 129.4, 128.9, 128.0, 126.2, 125.4, 125.3 (125.32), 125.3 (125.29), 125.2, 123.9, 123.0, 120.8, 115.4, 114.8, 112.7, 20.5, 20.4. HRMS (EI): m/z [M⁺] calcd for C₃₀H₂₂N₄: 438.1844, found 438.1841.

1,2-Di-p-tolylbenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline (3f). Yield 71% (93 mg), white solid, mp 300–302 °C. ¹H NMR (500 MHz, CD₂Cl₂) δ 8.71 (dd, J = 7.9 and 1.2 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.78–7.75 (m, 1H), 7.64–7.62 (m, 1H), 7.59–7.56 (m, 1H), 7.50–7.47 (m, 4H), 7.45–7.38 (m, 2H), 7.34 (d, J = 7.8 Hz, 2H), 7.10 (d, J = 7.9 Hz, 2H), 2.52 (s, 3H), 2.33 (s, 3H); ¹³C NMR (125 MHz, CD₂Cl₂) δ 142.4, 141.9, 140.9, 139.4, 137.8, 133.2, 132.3, 130.9, 130.7, 129.3 (129.27), 129.3 (129.25), 128.2, 127.7, 125.8, 125.7, 125.6, 124.5, 123.5, 120.5, 115.6, 115.3, 113.4, 21.7, 21.3. HRMS (EI): m/z [M⁺] calcd for C₃₀H₂₂N₄: 438.1844, found 438.1842.

1,2-Bis(4-methoxyphenyl)benzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline (3g)⁶. Yield 64% (90 mg), pale yellow solid, mp 250–253 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.75 (dd, J = 7.9 and 1.2 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 7.5 Hz, 1H), 7.74–7.71 (m, 1H), 7.69–7.67 (m, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.56–7.51 (m, 3H), 7.42–7.35 (m, 2H), 7.04 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 3.94 (s, 3H), 3.81 (s, 3H);¹³C NMR (125 MHz, CDCl₃) δ 160.0, 159.1, 142.2, 141.8, 141.5, 140.4, 133.4, 132.7, 130.2, 129.2, 126.4, 125.4, 125.2, 124.7, 123.9, 123.0, 122.3, 120.8, 115.3, 114.7, 114.3, 113.8, 113.7, 112.8, 55.3, 55.2.

1,2-Bis(4-fluorophenyl)benzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline (3h)⁶. Yield 67% (90 mg), white solid, mp 308–309 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.75 (d, J = 7.9 Hz, 1H), 8.41 (d, J = 8.5 Hz, 1H), 8.19 (d, J = 7.7 Hz, 1H), 7.78–7.75 (m, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.62–7.56 (m, 5H), 7.44–7.38 (m, 2H), 7.21 (t, J = 8.7 Hz, 2H), 7.00 (t, J = 8.7 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 163.3 (d, ¹J_C–F = 247.1 Hz), 162.4 (d, ¹J_C–F = 245.7 Hz), 142.0, 141.4, 141.2, 140.8, 133.0 (d, ³J_C–F = 8.4 Hz), 132.8, 130.2, 129.7 (d, ³J_C–F = 8.1 Hz), 129.6 (d, ⁴J_C–F = 3.3 Hz), 125.8 (d, ⁴J_C–F = 3.9 Hz), 125.5, 125.4, 124.4, 124.1, 123.3, 120.8, 115.4 (d, ²J_C–F = 21.7 Hz), 115.3 (d, ²J_C–F = 21.4 Hz), 115.1, 114.8, 112.8.

1,2-Bis(4-chlorophenyl)benzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline (3i). Yield 65% (93 mg), white solid, mp 302–303 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.73 (d, J = 7.9 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.78–7.74 (m, 1H), 7.69–7.68 (m, 1H), 7.58–7.48 (m, 7H), 7.44–7.38 (m, 2H), 7.28 (d, J = 8.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 142.0, 141.3, 141.1, 141.0, 135.2, 133.6, 133.4, 132.8, 131.8, 130.7, 130.1, 129.2, 128.6 (128.61), 128.6 (128.59), 128.2, 125.5, 125.4, 124.5, 124.2, 123.4, 120.8, 114.9, 114.8, 112.8. HRMS (EI): m/z [M⁺] calcd for C₂₈H₁₆Cl₂N₄: 478.0752, found 478.0751.

1,2-Di(furan-2-yl)benzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline (3j). Yield 60% (70 mg), pale yellow solid, mp 245–247 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.76 (dd, J = 7.9 and 1.4 Hz, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.16–8.14 (m, 1H), 7.79–7.73 (m, 3H), 7.56–7.53 (m, 2H), 7.43–7.38 (m, 2H), 6.91 (dd, J = 3.3 and 0.8 Hz, 1H), 6.72 (dd, J = 3.3 and 1.9 Hz, 1H), 6.58 (dd, J = 3.4 and 0.7 Hz, 1H), 6.40 (dd, J = 3.4 and 1.8 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 147.7, 143.9, 142.9, 142.2, 142.1, 141.2, 140.5, 137.6, 133.1, 131.1, 130.3, 125.9, 125.3, 124.2, 123.3, 120.9, 114.8, 114.7, 114.5, 114.2, 112.8, 111.4, 111.3, 108.9. HRMS (EI): m/z [M⁺] calcd for C₂₄H₁₄N₄O₂: 390.1117, found 390.1118.

10,11-Dimethyl-1,2-diphenylbenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline (3k). Yield 70% (92 mg), white solid, mp 311–313 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.76 (dd, J = 7.9 and 1.4 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.76–7.73 (m, 1H), 7.64–7.59 (m, 4H), 7.56–7.48 (m, 4H), 7.42 (s, 1H), 7.30–7.27 (m, 2H), 7.25–7.22 (m, 1H), 2.48 (s, 3H), 2.36 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 141.9, 140.7, 140.5, 133.7, 133.2, 132.9 (132.94), 132.9 (132.91), 132.1, 130.1, 129.3, 128.9, 128.8, 128.3, 128.1, 128.0, 127.4, 125.6, 125.4, 125.0, 121.0, 115.1, 114.7, 113.2, 20.9, 20.1. HRMS (EI): m/z [M⁺] calcd for C₃₀H₂₂N₄: 438.1844, found 438.1847.

10,11-Dichloro-1,2-diphenylbenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline (3l). Yield 61% (88 mg), white solid, mp 304–306 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.78 (dd, J = 7.9 and 1.2 Hz, 1H), 8.28 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.80–7.76 (m, 1H), 7.74 (s, 1H), 7.64–7.49 (m, 8H), 7.31–7.27 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 142.6, 142.3, 141.6, 140.5, 133.2, 132.1, 132.0, 130.7, 129.7, 129.3, 129.2, 129.1, 128.3, 128.2 (128.2463), 128.2 (128.17), 127.9, 127.7, 126.8, 126.0, 125.7, 121.7, 115.3, 114.5, 114.2. HRMS (EI): m/z [M⁺] calcd for C₂₈H₁₆Cl₂N₄: 478.0752, found 478.0750.

1,2-Diphenyl-4,5,6,7-tetrahydrobenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline (3m). Yield 44% (55 mg), white solid, mp 290–292 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.94 (d, J = 8.3 Hz, 1H), 7.63–7.61 (m, 1H), 7.59–7.57 (m, 4H), 7.51–7.46 (m, 3H), 7.34–7.30 (m, 1H), 7.28–7.21 (m, 4H), 3.41–3.39 (m, 2H), 3.15–3.12 (m, 2H), 2.14–2.11 (m, 2H), 2.01–1.96 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 142.8, 142.1, 141.8, 141.6, 133.9 (133.92), 133.9 (133.86), 132.2, 130.1, 129.8, 128.6, 128.2, 128.0, 127.3, 124.2, 123.7, 121.8, 120.4, 113.4, 109.8, 27.0, 23.1, 22.4, 21.1. HRMS (EI): m/z [M⁺] calcd for C₂₈H₂₂N₄: 414.1844, found 414.1843.

4-Methyl-1,2,5-triphenylbenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]pyrimidine (3n). Yield 63% (85 mg), pale yellow solid, mp 200–202 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.70–7.60 (m, 7H), 7.56–7.48 (m, 6H), 7.30–7.22 (m, 3H), 7.20–7.17 (m, 1H), 6.86–6.83 (m, 1H), 5.90 (d, J = 8.4 Hz, 1H), 2.40 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 143.3, 142.5, 141.7, 134.0, 133.9, 132.2 (132.19), 132.2 (132.16), 130.2, 130.1, 130.0, 129.5, 128.7, 128.3, 128.2, 128.0, 127.4, 124.9, 123.6, 121.5, 120.0, 112.8, 109.7, 12.7. HRMS (EI): m/z [M⁺] calcd for C₃₁H₂₂N₄: 450.1844, found 450.1846.

4-Isopropyl-1,2,5-triphenylbenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]pyrimidine (3o). Yield 59% (85 mg), white solid, mp 284–286 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.71–7.63 (m, 7H), 7.59–7.46 (m, 6H), 7.32–7.21 (m, 3H), 7.15 (t, J = 7.6 Hz, 1H), 6.80 (t, J = 7.7 Hz, 1H), 5.67 (d, J = 8.4 Hz, 1H), 3.04 (q, J = 7.0 Hz, 1H), 1.59 (d, J = 7.0 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 141.8, 141.7, 141.6, 141.4, 134.1, 132.9, 132.6, 132.2, 130.5, 130.2, 130.0, 129.7, 129.6, 128.7, 128.1 (128.1470), 128.1 (128.08), 128.0, 127.3, 123.8, 123.5, 121.4, 119.9, 118.9, 112.8, 29.3, 21.3. HRMS (EI): m/z [M⁺] calcd for C₃₃H₂₆N₄: 478.2157, found 478.2155.

4-Butyl-1,2,5-triphenylbenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]pyrimidine (3p). Yield 62% (92 mg), pale yellow solid, mp 226–229 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.71–7.62 (m, 7H), 7.55–7.49 (m, 6H), 7.30–7.22 (m, 3H), 7.19–7.15 (m, 1H), 6.85–6.81 (m, 1H), 5.80 (d, J = 8.4 Hz, 1H), 2.78 (t, J = 7.9 Hz, 2H), 1.81–1.75 (m, 2H), 1.39–1.32 (m, 2H), 0.88–0.85 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 142.8, 142.3, 141.7, 141.6, 134.0, 133.9, 132.2, 132.0, 130.2 (130.22), 130.2 (130.20), 129.6, 129.4, 128.7, 128.2 (128.20), 128.2 (128.17), 128.0, 127.4, 124.5, 123.6, 121.4, 119.9, 114.5, 112.8, 32.0, 26.7, 22.7, 13.8. HRMS (EI): m/z [M⁺] calcd for C₃₄H₂₈N₄: 492.2314, found 492.2316.

1,2,4,5-Tetraphenylbenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]pyrimidine (3q). Yield 60% (92 mg), white solid, mp 308–309 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.67–7.65 (m, 2H), 7.58–7.48 (m, 7H), 7.46–7.39 (m, 6H), 7.30–7.26 (m, 3H), 7.24–7.17 (m, 4H), 6.87–6.84 (m, 1H), 5.90 (d, J = 8.4 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 142.9, 142.7, 142.0, 141.7, 134.8, 133.7, 132.4, 132.2, 131.7, 131.5, 130.8, 130.1, 129.9, 129.8, 128.9, 128.8, 128.2, 128.1 (128.08), 128.1 (128.06), 127.8, 127.6, 127.4, 124.7, 123.9, 121.6, 120.1, 115.6, 113.3. HRMS (EI): m/z [M⁺] calcd for C₃₆H₂₄N₄: 512.2001, found 512.2000.

4,8,9-Trimethyl-1,2,5-triphenylbenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]pyrimidine (3r). Yield 58% (83 mg), white solid, mp 283–286 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.70–7.58 (m, 7H), 7.54–7.47 (m, 6H), 7.33 (s, 1H), 7.29–7.23 (m, 2H), 5.59 (s, 1H), 2.40 (s, 3H), 2.22 (s, 3H), 2.01 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 143.3, 142.3, 141.1, 140.1, 134.1, 134.0, 132.6, 132.4, 132.2, 130.2, 130.1, 130.0, 129.6, 129.4, 128.8, 128.6, 128.2, 128.0, 127.8, 127.3, 124.7, 120.0, 113.2, 109.0, 20.6, 20.0, 12.6. HRMS (EI): m/z [M⁺] calcd for C₃₃H₂₆N₄: 478.2157, found 478.2155.

8,9-Dichloro-4-methyl-1,2,5-triphenylbenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]pyrimidine (3s). Yield 46% (72 mg), white solid, mp 289–292 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.75–7.67 (m, 3H), 7.65 (s, 1H), 7.64–7.58 (m, 4H), 7.56–7.48 (m, 5H), 7.30–7.23 (m, 3H), 5.87 (s, 1H), 2.41 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 142.9, 141.2, 133.7, 133.6, 132.2, 131.4, 130.8, 130.1 (130.08), 130.1 (130.07), 130.0, 129.8, 129.1, 128.6, 128.5, 128.4, 128.3, 128.0, 127.8, 125.2, 125.1, 121.0, 114.5, 114.4, 110.9, 12.8. HRMS (EI): m/z [M⁺] calcd for C₃₁H₂₀Cl₂N₄: 518.1065, found 518.1063.

1-(2-(4,5-Diphenyl-1H-imidazol-2-yl)-4-methoxyphenyl)-1H-benzo[d]imidazol-2-amine (8a). Yield 18% (25 mg), white solid, mp 263–265 °C. ¹H NMR (500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.43–7.37 (m, 6H), 7.24 (d, J = 5.8 Hz, 1H), 7.17–7.09 (m, 6H), 6.95–6.92 (m, 1H), 6.76–6.73 (m, 1H), 6.53 (d, J = 6.0 Hz, 1H), 5.97 (s, 2H), 3.94 (s, 3H); ¹³C NMR (125 MHz, DMSO-d₆) δ 159.5, 155.4, 143.0, 142.3, 136.7, 136.5, 134.7, 132.0, 131.0, 129.8, 128.6, 128.5, 127.9, 127.8, 127.7, 126.6, 126.1, 124.3, 120.2, 118.2, 115.2, 114.5, 113.6, 107.5, 55.8. HRMS (EI): m/z [M⁺] calcd for C₂₉H₂₃N₅O: 457.1903, found 457.1903.

One-pot procedure for the synthesis of 3a. To a 10 mL microwave reaction tube, 5 (0.056 g, 0.3 mmol), 6 (0.063 g, 0.3 mmol), NH₄OAc (0.093 g, 1.2 mmol), AcOH (75 μL), and EtOH (3 mL) were added. After the reaction mixture was heated at 70 °C for 1 h under microwave irradiation (100 W of initial power), solvents were removed under reduced pressure, water soluble components were removed by decantation using H₂O several times, and organic residues were washed with EtOAc/hexane (1/15). To the reaction tube containing a white solid dried under vacuum, 2a (0.060 g, 0.45 mmol), K₂CO₃ (0.124 g, 0.9 mmol), and DMF (3 mL) were added. The reaction mixture was stirred at 150 °C for 2 h under microwave irradiation (120 W of initial power). A workup procedure similar to that described above afforded 3a (77 mg, 63%).

Cyclization of 8a to 3c. To a 10 mL microwave reaction tube, 8a (0.030 g, 0.065 mmol), K₂CO₃ (0.026 g, 0.19 mmol), and DMF (3 mL) were added. After stirring the reaction mixture at room temperature for 5 min, it was heated at 150 °C for 2 h under microwave irradiation (120 W of initial power). Similar work-up procedure described above afforded 3c (21 mg, 74%).

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT) (2020R1F1A1054806).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/d1ra04396j

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