Synthesis of Pyrimidine- and Quinazoline-Fused Benzimidazole-4,7-diones Using Combinatorial Cyclocondensation and Oxidation.

β-Bromo-α,β-unsaturated aldehydes and 2-bromobenzaldehydes react with 4,7-dimethoxy-1H-benzo[d]imidazole-2-amine by microwave irradiation in dimethylformamide in the presence of a base to give the corresponding dimethoxy-substituted benzo[4,5]imidazo[1,2-a]pyrimidines and benzo[4,5]imidazo[1,2-a]quinazolines, respectively, in moderate to good yields. Oxidation of such N-fused hybrid scaffolds by aqueous ceric ammonium nitrate affords pyrimidine- and quinazoline-fused benzimidazole-4,7-diones in high yields.

Introduction

Besides homonuclear n class="Disease">N-heterocyclic compounds, many synthetic methods for their N-fused hybrid scaffolds have been attempted and developed because of characteristic biological activities that are not shown in each homonuclear scaffolds. It is known that homonuclear pyrimidine- and benzimidazolequinone (1H-benzo[d]imidazole-4,7-dione)-containing compounds show diverse biological activities, such as anticancer, antimalarial, antitumor, antiproliferative, and cytotoxic properties.[1,2] There are two N-fused modes of such homonuclear N-heterocycles, benzo[4,5]imidazo[1,2-a]pyrimidine-6,9-diones (Scheme , A) and benzo[4,5]imidazo[1,2-c]pyrimidine-6,9-diones (Scheme , B). In contrast to many synthetic methods for other N-fused hybrid scaffolds, limited examples for the synthesis of such N-fused hybrid scaffolds A and B are known. It is reported that N-fused hybrid scaffold A can be synthesized by the reaction of 2-aminopyrimidine with p-chloranil (2,3,5,6-tetrachloro-1,4-benzoquinone) followed by subsequent treatment with diethylamine and HCl (Scheme ).[3] We reported on the synthesis of N-fused hybrid scaffold B by step-by-step copper-catalyzed coupling and cyclization of 2-(2-bromovinyl)-4,7-dimethoxybenzimidazoles with primary amides to form pyrimidine-fused 4,7-dimethoxybenzimidazoles, and oxidation of such intermediates by aqueous ceric ammonium nitrate (CAN) (Scheme ).[4] As part of our continuing studies directed toward transition metal–catalyzed and transition metal–free cyclization reactions for heterocycles,[5] we have shown several new synthetic protocols for N-fused hybrid scaffolds.[6] Among them, β-bromo-α,β-unsaturated aldehydes were found to be cyclocondensed with 2-aminobenzimidazole in the presence of a base under microwave irradiation to give pyrimidine-fused benzimidazoles, benzo[4,5]imidazo[1,2-a]pyrimidines.[7,8] Under these circumstances, the present work started during the course of a combinatorial extension of such protocols to develop a new synthetic approach for N-fused hybrid scaffolds. Herein we provide another example for the synthetic method of N-fused hybrid scaffold A by sequential cyclocondensation between β-bromo-α,β-unsaturated aldehydes and 2-aminobenzimidazole analogue, 4,7-dimethoxy-1H-benzo[d]imidazole-2-amine and oxidation (Scheme ).

Scheme 1

Two N-Fused Modes of Benzimidazolequinone and Pyrimidine

Scheme 2

Synthesis of Benzo[4,5]imidazo[1,2-a]pyrimidine-6,9-diones A and Benzo[4,5]imidazo[1,2-c]pyrimidine-6,9-diones B

Results and Discussion

First, we optimized the reaction conditions to produce precursors, n class="Chemical">dimethoxy-substituted benzo[4,5]imidazo[1,2-a]pyrimidines of N-fused hybrid scaffold A effectively. On the basis of recent reports on transition metal–free cyclocondensation of β-bromo-α,β-unsaturated aldehydes and 2-halobenzaldehydes with 2-aminobenzimidazole,[7,9]Table shows several attempted results for the cyclocondensation of 2-bromocyclohex-1-enecarbaldehyde (1a) with 4,7-dimethoxy-1H-benzo[d]imidazole-2-amine (2a) under various reaction conditions, leading to 8,11-dimethoxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]quinazoline (3a). The starting 2a was prepared from 3,6-dimethoxybenzene-1,2-diamine[2b,10] and cyanogen bromide using similar methods reported.[11] Treatment of 1a with equimolar amount of 2a in dimethylformamide (DMF) at 110 °C for 1 h in the presence of K2CO3 under microwave irradiation afforded 3a in 64% isolated yield (Table , entry 1). The molar ratio of 2a to 1a, although not significant, affected the yield of 3a, and the yield increased with the increase in the molar ratio up to 1.2 without other identifiable by-products (Table , entries 1–3). Lower yield of 3a was observed under lower reaction temperature, and the yield increased with the increase in temperature up to 110 °C (Table , entries 2, 4, and 5). Prolonging the reaction time up to 1 h was needed for the effective formation of 3a with complete conversion of 1a (Table , entries 2, 6, and 7). In contrast to the reaction between β-bromo-α,β-unsaturated aldehydes and 2-aminobenzimidazoles,[7] further addition of magnesium sulfate resulted in rather decreased yield of 3a (Table , entry 8). The reaction also proceeded in the presence of other inorganic bases such as K3PO4, NaOBu, NaOAc, Cs2CO3, and CsF, but the yields of 3a were generally lower than that obtained in the presence of K2CO3 (Table , entries 9–13).[12] Unlike the previous cyclocondensation of β-bromo-α,β-unsaturated aldehydes and 2-aminobenzimidazoles, no allowable yield of 3a was observed with Et3N (Table , entry 14). When 1a was treated with 2a under usual heating conditions (screw-capped vial) for 10 h, 3a was obtained in 52% yield (Table , entry 15).

Table 1

Optimization of Conditions for the Reaction of 1a with 2aa

entry	[1a]/[2a]	base	temp. (°C)	time (h)	yield (%)
1	1/1	K2CO3	110	1	64
2	1/1.2	K2CO3	110	1	68
3	1/1.5	K2CO3	110	1	69
4	1/1.2	K2CO3	85	1	43
5	1/1.2	K2CO3	135	1	68
6	1/1.2	K2CO3	110	0.5	51
7	1/1.2	K2CO3	110	2	70
8b	1/1.2	K2CO3	110	1	57
9	1/1.2	K3PO4	110	1	54
10	1/1.2	NaOtBu	110	1	26
11	1/1.2	NaOAc	110	1	40
12	1/1.2	Cs2CO3	110	1	39
13	1/1.2	CsF	110	1	45
14	1/1.2	Et3N	110	1	28
15c	1/1.2	K2CO3	110	10	52

1a (0.3 mmol), base (0.9 mmol), additive (0.6 mmol), microwave irradiation (100 W initial power), DMF (3 mL), unless otherwise stated.

Further addition of MgSO4 (0.6 mmol).

Under usual heating (screw-capped vial).

Having optimized the reaction conditions, various β-bromo-α,β-unsaturated aldehydes 1 were subjected to the reaction with 2a to investigate the reaction scope, and several representative results are summarized in Table . The cyclocondensation of n class="Chemical">2-bromocyclohex-1-enecarbaldehydes (1b and 1c) with 2a also proceeded to give the corresponding pyrimidine-fused benzimidazoles (3b and 3c) in similar yields, irrespective of the presence of the methyl and phenyl substituents on 1b and 1c. With cyclic β-bromo-α,β-unsaturated aldehydes 1d–f having various ring sizes, the corresponding N-fused scaffolds 3d–f were also formed in 72–82% yields. The reaction of benzo-fused β-bromo-α,β-unsaturated aldehydes 1g took place with 2a to give 8,11-dimethoxy-13,14-dihydrobenzo[f]benzo[4,5]imidazo[1,2-a]quinazoline (3g) in 21% yield along with its dehydrogenated product 3g′ (35% yield). Performing the reaction for prolonging reaction time (2 h) under the employed conditions solely afforded 3g′ in 61% yield. This result indicates that 3g′ is produced by dehydrogenation of 3g initially formed by the cyclization of 1g. Such a similar dehydrogenation was observed by our recent reports on coupling and cyclizaton reactions using similar benzo-fused six-membered ring substrates.[5c,5d,6b,6c] Acyclic β-bromo-α,β-unsaturated aldehydes 1h–o having alkyl and aryl substituents were also cyclocondensed with 2a to afford pyrimidine-fused benzimidazoles 3h–o in 55–67% yields and the product yield was not significantly affected by the identity of such substituents.

Table 2

Cyclocondensation of 1 with 2a Leading to 3a

Reaction conditions: 1 (0.3 mmol), 2 (0.36 mmol), K2CO3 (0.9 mmol), DMF (3 mL), 110 °C, 1 h, under microwave irradiation (100 W of initial power).

Reaction conditions: 1 (0.3 mmol), 2 (0.36 mmol), K2CO3 (0.9 mmol), n class="Chemical">DMF (3 mL), 110 °C, 1 h, under microwave irradiation (100 W of initial power).

Similar treatment of 2-bromobenzaldehydes (1p and 1q) with 2a under the employed conditions produced the corresponding n class="Chemical">quinazoline-fused benzimidazoles (3p and 3q) in 71 and 50% yields, respectively. Benzo-fused analogue 1r also reacted with 2a to give such a hybrid scaffold 3r in 63% yield. In contrast to many synthetic methods for pyrimidine-fused benzimidazoles,[8] benzo[4,5]imidazo[1,2-a]pyrimidines, limited examples are known for the construction of quinazoline-fused benzimidazoles, benzo[4,5]imidazo[1,2-a]quinazolines.[4,5]imidazo[1,2-. ACS Comb. Sci.. 2014 ">9,13,14] Wang and Singh reported that N-(2-benzimidazoyl)-2-aminobenzamides react with 2-bromobenzaldehydes in the presence or absence of CuI and l-proline to afford benzo[4,5]imidazo[1,2-a]quinazolines via Ullmann-type C–N coupling followed by double C–N bond cleavage.[13] Such a similar C–N coupling for eventual formation of benzo[4,5]imidazo[1,2-a]quinazoline was also exemplified by copper-catalyzed reaction between 2-bromobenzoic acid and 2-aminobenzimidazole.[14] However, to the best of our knowledge, no reports are found for the biological activities of such scaffolds.

As to the reaction pathway, although it is not certain, this seems to proceed via an initial formation of Schiff base by condensation between 1 and 2a. This is followed by intramolen class="Chemical">cular nucleophilic aromatic substitution under basic conditions to give 3.[9] A reviewer commented on how 1 will behave in reactions with unsymmetrically substituted 2-aminobenzimidazoles having electron-donating and electron-withdrawing groups. The reaction of 2-bromobenzaldehyde (1p) with unsymmetrically substituted 2-aminobenzimidazoles (2b and 2c) under the employed conditions afforded the corresponding cyclocondensation products (3s and 3t) as isomeric mixtures in 30 and 19% yields, respectively (Scheme , see Supporting Information for 1H NMR spectra).[11a]

Scheme 3

Reactions with Unsymmetrically Substituted 2-Aminobenzimidazoles

Oxidation of all pyrimidine- and n class="Chemical">quinazoline-fused dimethoxybenzimidazoles 3a–r shown in Table except for 3g by treatment of CAN in aqueous acetonitrile afforded benzo[4,5]imidazo[1,2-a]pyrimidine-6,9-diones and benzo[4,5]imidazo[1,2-a]quinazoline-8,11-diones, respectively, in high yields (Table ).[2b,2j,15] Not fully understood, 3g′ was readily oxidized to the corresponding benzimidazolequinone 4g in similar yield, whereas no expected oxidation product was observed with 3g. No reports for benzo[4,5]imidazo[1,2-a]quinazoline-8,11-diones are known for synthetic methods and biological activities.

Table 3

Oxidation of 3–4 with CANa

Reaction conditions: 3 (0.1 mmol), CAN (0.3 mmol), acetonitrile/H2O (4 mL), 0 °C, 20 min.

Reaction conditions: 3 (0.1 mmol), CAN (0.3 mmol), acetonitrile/n class="Chemical">H2O (4 mL), 0 °C, 20 min.

Conclusions

In summary, we have shown that β-bromo-α,β-unsaturated aldehydes and n class="Chemical">2-bromobenzaldehydes trigger cyclocondensation with 4,7-dimethoxy-1H-benzo[d]imidazole-2-amine under microwave irradiation in the presence of a base to form the corresponding dimethoxy-substituted benzo[4,5]imidazo[1,2-a]pyrimidines and benzo[4,5]imidazo[1,2-a]quinazolines, respectively. Such scaffolds could be oxidized into benzo[4,5]imidazo[1,2-a]pyrimidine-6,9-diones and benzo[4,5]imidazo[1,2-a]quinazoline-8,11-diones by treatment with aqueous CAN. The present reaction would be served as a useful method for designing and synthesizing bioreductive quinone-based drugs. Further studies on the synthesis of unprecedented benzimidazole-based 1,4-quinone-containing N-fused hybrid scaffolds using the present protocol are expected.

Experimental Section

General Information

1H and n class="Chemical">13C NMR spectra were obtained at 500 and 125 MHz, respectively, in DMSO-d6 or CDCl3. Melting points were measured on a microscopic melting point apparatus. High-resolution mass data were recorded using electronic ionization (HRMS-EI, magnetic sector–electric sector double focusing mass analyzer) at the Korea Basic Science Center (Daegu). All microwave reactions (CEM, Discover LabMate) were performed in a 5 mL tube, and maintenance of the reaction temperature was monitored by an external infrared sensor. The crude reaction mixtures were purified by thin-layer (a glass plate coated with Kieselgel 60 GF254, Merck) chromatography. The starting aldehydes were prepared from the corresponding ketones according to literature procedures.[16] 4,7-Dimethoxy-1H-benzo[d]imidazole-2-amine (2a) was prepared from 3,6-dimethoxybenzene-1,2-diamine and cyanogen bromide using the procedure shown below.[17] 3,6-Dimethoxybenzene-1,2-diamine was synthesized by a known method from hydroquinone via a three-step sequence (methylation, nitration, reduction).[2b,10] All other commercially available chemicals were used without further purification.

Synthesis of 4,7-Dimethoxy-1H-benzo[d]imidazole-2-amine (2a)

To a solution of 3,6-dimethoxybenzene-1,2-diamine (1.682 g, 10 mmol) in n class="Chemical">MeOH/H2O (100 mL, 1:1), cyanogen bromide (3.178 g, 30 mmol) was added. The reaction mixture was stirred at 50 °C for 3 h. After the mixture was cooled to room temperature, neutralized with 10% aqueous NaOH solution (to pH = 10), and extracted with EtOAc (50 mL, 3 times), the combined organic layer was dried over Na2SO4. Removal of the solvent left a crude mixture, which was purified by a short silica gel column (dichloromethane/MeOH = 7:3) to yield a pale yellow solid 2a (1.777 g, 92%). 1H NMR (500 MHz, DMSO-d6): δ 3.85 (s, 6H), 6.75 (s, 2H), 7.75 (s, 2H). 13C NMR (125 MHz, DMSO-d6): δ 56.01, 104.6, 122.1, 140.0, 151.3. HRMS (EI): calcd for C9H11N3O2 (M+), 193.0851; found, 193.0849.

General Procedure for the Synthesis of 3

To a 5 mL microwave reaction tube, 1 (0.3 mmol), 2a (0.070 g, 0.36 mmol), K2CO3 (0.124 g, 0.9 mmol), and n class="Chemical">DMF (3 mL) were added. After stirring at room temperature for 5 min, the reaction mixture was heated at 110 °C for 1 h by microwave irradiation (100 W initial power). The mixture was cooled to room temperature and filtered through a short silica gel column (ethyl acetate) to eliminate inorganic components. Evaporation of the solvent under reduced pressure gave a crude mixture, which was purified by TLC (dichloromethane/methanol = 97/3) to give 3. Spectroscopic data for all products are shown below.

8,11-Dimethoxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]quinazoline (3a)

Rf = 0.34. Pale yellow solid (58 mg, 68%). mp 192–195 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 1.86–1.90 (m, 2H), 1.93–1.98 (m, 2H), 2.85–2.87 (m, 2H), 3.04–3.07 (m, 2H), 4.02 (s, 3H), 4.07 (s, 3H), 6.61 (d, J = 8.6 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 8.90 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 22.5, 22.6, 26.3, 33.8, 55.9, 56.9, 100.9, 106.3, 116.9, 117.5, 133.7, 136.8, 143.5, 145.6, 149.5, 165.9. HRMS (EI): calcd for C16H17N3O2 (M+), 283.1321; found, 283.1318.

8,11-Dimethoxy-3-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]quinazoline (3b)

Rf = 0.35. Pale yellow solid (50 mg, 56%). mp 179–181 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 1.14 (d, J = 6.6 Hz, 3H), 1.54–1.62 (m, 1H), 1.93–2.01 (m, 1H), 2.02–2.07 (m, 1H), 2.45–2.50 (m, 1H), 2.92–2.96 (m, 1H), 2.99–3.06 (m, 1H), 3.15–3.21 (m, 1H), 4.03 (s, 3H), 4.07 (s, 3H), 6.62 (d, J = 8.6 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 8.91 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 21.5, 28.9, 30.6, 33.2, 34.6, 55.8, 56.9, 100.8, 106.2, 116.4, 117.4, 133.5, 136.8, 143.4, 145.6, 149.5, 165.6. HRMS (EI): calcd for C17H19N3O2 (M+), 297.1477; found, 297.1474.

8,11-Dimethoxy-3-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]quinazoline (3c)

Rf = 0.32. Pale yellow solid (69 mg, 64%). mp 197–199 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 2.10–2.16 (m, 1H), 2.28–2.32 (m, 1H), 2.96–3.02 (m, 1H), 3.06–3.20 (m, 3H), 3.27–3.32 (m, 1H), 4.01 (s, 3H), 4.07 (s, 3H), 6.63 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 7.26–7.27 (m, 1H), 7.29–7.31 (m, 2H), 7.35–7.38 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 29.7, 33.7, 34.2, 40.1, 55.8, 56.9, 100.9, 106.3, 116.3, 117.4, 126.7, 126.8, 128.7, 133.7, 136.8, 143.4, 144.9, 145.6, 149.5, 165.0. HRMS (EI): calcd for C22H21N3O2 (M+), 359.1634; found, 359.1632.

9,12-Dimethoxy-2,3,4,5-tetrahydro-1H-benzo[4,5]imidazo[1,2-a]cyclohepta[e]pyrimidine (3d)

Rf = 0.36. Pale yellow solid (64 mg, 72%). mp 225–226 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 1.74–1.78 (m, 2H), 1.89–1.93 (m, 2H), 1.94–1.99 (m, 2H), 2.87–2.89 (m, 2H), 3.56–3.58 (m, 2H), 3.95 (s, 3H), 4.04 (s, 3H), 6.64 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 8.47 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 25.1, 27.3, 30.7, 32.0, 34.0, 56.3, 56.4, 102.0, 105.8, 118.8, 122.6, 138.4, 142.3, 145.8, 151.5, 154.0, 156.1. HRMS (EI): calcd for C17H19N3O2 (M+), 297.1477; found, 297.1474.

10,13-Dimethoxy-1,2,3,4,5,6-hexahydrobenzo[4,5]imidazo[1,2-a]cycloocta[e]pyrimidine (3e)

Rf = 0.42. Pale yellow solid (77 mg, 82%). mp 186–187 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 1.34–1.38 (m, 2H), 1.44–1.49 (m, 2H), 1.72–1.77 (m, 2H), 1.88–1.93 (m, 2H), 2.80–2.82 (m, 2H), 3.65–3.68 (m, 2H), 6.65 (d, J = 8.6 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 8.45 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 25.7, 26.1, 29.0, 29.4, 29.6, 31.7, 55.9, 56.3, 102.2, 105.3, 118.8, 119.8, 138.0, 141.5, 145.8, 150.7, 151.3, 156.5. HRMS (EI): calcd for C18H21N3O2 (M+), 311.1634; found, 311.1632.

14,17-Dimethoxy-1,2,3,4,5,6,7,8,9,10-decahydrobenzo[4,5]imidazo[1,2-a]cyclododeca[e]pyrimidine (3f)

Rf = 0.47. Pale yellow solid (83 mg, 75%). mp 195–198 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 1.39–1.46 (m, 8H), 1.50–1.60 (m, 4H), 1.63–1.68 (m, 2H), 1.77–1.83 (m, 2H), 2.78–2.81 (m, 2H), 3.64–3.68 (m, 2H), 6.71 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 8.57 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 21.9, 22.8, 24.6, 24.7, 25.5, 25.9, 26.5, 27.0, 28.2, 29.7, 56.0, 56.4, 102.3, 105.4, 119.3, 119.5, 138.1, 141.9, 146.0, 151.1, 151.3, 157.6. HRMS (EI): calcd for C22H29N3O2 (M+), 367.2260; found, 367.2258.

8,11-Dimethoxy-13,14-dihydrobenzo[f]benzo[4,5]imidazo[1,2-a]quinazoline (3g)

Rf = 0.39. Pale yellow solid (21 mg, 21%). mp 171–174 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 3.06–3.09 (m, 2H), 3.21–3.24 (m, 2H), 4.07 (s, 3H), 4.09 (s, 3H), 6.68 (d, J = 8.6 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 7.31–7.32 (m, 2H), 7.35–7.40 (m, 1H), 7.71 (d, J = 7.6 Hz, 1H), 9.45 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 28.2, 33.2, 56.0, 56.8, 101.6, 106.5, 116.0, 118.0, 122.8, 127.5, 128.4, 128.7, 129.7, 130.2, 136.5, 136.6, 143.4, 145.7, 149.1, 165.7. HRMS (EI): calcd for C20H17N3O2 (M+), 331.1321; found, 331.1320.

8,11-Dimethoxy[f]benzo[4,5]imidazo[1,2-a]quinazoline (3g′)

Rf = 0.37. Pale yellow solid (35 mg, 35%). mp 194–196 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 3.87 (s, 3H), 3.92 (s, 3H), 6.61 (d, J = 8.6 Hz, 1H), 6.66 (d, J = 8.6 Hz, 1H), 7.34–7.37 (m, 1H), 7.45–7.48 (m, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 9.4 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 9.03 (d, J = 9.4 Hz, 1H), 9.65 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 56.5, 57.1, 105.0, 105.5, 113.0, 119.3, 120.6, 121.5, 126.7, 128.9, 129.1, 129.4, 130.0, 134.8, 137.3, 138.2, 141.3, 146.7, 150.1, 152.8. HRMS (EI): calcd for C20H15N3O2 (M+), 329.1164; found, 329.1161.

6,9-Dimethoxy-4-phenylbenzo[4,5]imidazo[1,2-a]pyrimidine (3h)

Rf = 0.27. Pale yellow solid (57 mg, 62%). mp 68–71 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 3.11 (s, 3H), 4.06 (s, 3H), 6.45 (d, J = 8.6 Hz, 1H), 6.75 (d, J = 4.2 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 7.43–7.55 (m, 5H), 8.75 (d, J = 4.2 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 55.3, 56.6, 102.1, 106.3, 109.2, 118.6, 126.9, 128.0, 129.7, 136.9, 137.8, 142.3, 145.5, 150.9, 151.7, 154.2. HRMS (EI): calcd for C18H15N3O2 (M+), 305.1164; found, 305.1166.

6,9-Dimethoxy-3-methyl-4-phenylbenzo[4,5]imidazo[1,2-a]pyrimidine (3i)

Rf = 0.38. Pale yellow solid (58 mg, 61%). mp 215–218 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 2.13 (s, 3H), 3.06 (s, 3H), 4.04 (s, 3H), 6.36 (d, J = 8.6 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 7.31–7.32 (m, 2H), 7.51–7.53 (m, 3H), 8.67 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 15.9, 55.6, 56.4, 101.7, 105.7, 115.5, 118.6, 128.2, 128.3, 129.2, 135.6, 137.8, 142.1, 145.4, 147.2, 151.0, 157.4. HRMS (EI): calcd for C19H17N3O2 (M+), 319.1321; found, 319.1319.

3-Butyl-6,9-dimethoxy-4-phenylbenzo[4,5]imidazo[1,2-a]pyrimidine (3j)

Rf = 0.39. Pale yellow solid (73 mg, 67%). mp 148–151 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 0.79 (t, J = 7.4 Hz, 3H), 1.19–1.26 (m, 2H), 1.42–1.48 (m, 2H), 2.42–2.45 (m, 2H), 3.06 (s, 3H), 4.04 (s, 3H), 6.36 (d, J = 8.6 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 7.32–7.35 (m, 2H), 7.48–7.53 (m, 3H), 8.69 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 13.6, 22.3, 28.9, 33.4, 55.7, 56.4, 101.7, 105.6, 118.8, 120.4, 128.0, 128.5, 129.2, 135.0, 137.8, 142.1, 145.4, 147.0, 150.8, 157.3. HRMS (EI): calcd for C22H23N3O2 (M+), 361.1790; found, 361.1788.

3-Isopropyl-6,9-dimethoxy-4-phenylbenzo[4,5]imidazo[1,2-a]pyrimidine (3k)

Rf = 0.34. Pale yellow solid (65 mg, 62%). mp 152–157 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 1.22 (d, J = 7.0 Hz, 6H), 2.75–2.84 (m, 1H), 3.06 (s, 3H), 4.04 (s, 3H), 6.35 (d, J = 8.6 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 7.32–7.34 (m, 2H), 7.51–7.53 (m, 3H), 8.83 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 23.4, 27.5, 55.8, 56.5, 101.7, 105.6, 118.9, 125.4, 128.1, 128.6, 129.2, 134.9, 138.0, 142.1, 145.5, 146.0, 150.6, 154.8. HRMS (EI): calcd for C21H21N3O2 (M+), 347.1634; found, 347.1632.

6,9-Dimethoxy-3,4-diphenylbenzo[4,5]imidazo[1,2-a]pyrimidine (3l)

Rf = 0.41. Pale yellow solid (66 mg, 58%). mp 222–223 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 4.02 (s, 3H), 4.09 (s, 3H), 6.68 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 7.24–7.28 (m, 4H), 7.31–7.37 (m, 4H), 7.51–7.53 (m, 2H), 9.19 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 55.9, 56.9, 101.6, 106.8, 117.7, 121.3, 127.83, 127.84, 128.7, 129.5, 129.9, 130.2, 136.0, 136.5, 137.4, 137.9, 143.5, 145.7, 149.2, 162.3. HRMS (EI): calcd for C24H19N3O2 (M+), 381.1477; found, 381.1474.

4-Ethyl-6,9-dimethoxy-3-methylbenzo[4,5]imidazo[1,2-a]pyrimidine (3m)

Rf = 0.42. Pale yellow solid (45 mg, 55%). mp 133–135 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 1.41 (t, J = 7.4 Hz, 3H), 2.34 (d, J = 1.1 Hz, 3H), 2.90 (q, J = 7.4 Hz, 2H), 4.03 (s, 3H), 4.08 (s, 3H), 6.62 (d, J = 8.6 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 8.89 (q, J = 1.1 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 11.0, 15.8, 29.4, 55.8, 57.1, 100.9, 106.4, 115.3, 117.5, 133.3, 136.6, 143.3, 145.7, 149.8, 169.0. HRMS (EI): calcd for C15H17N3O2 (M+), 271.1321; found, 271.1318.

6,9-Dimethoxy-4-(naphthalen-2-yl)benzo[4,5]imidazo[1,2-a]pyrimidine (3n)

Rf = 0.38. Pale yellow solid (65 mg, 61%). mp 154–157 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 2.77 (s, 3H), 4.07 (s, 3H), 6.40 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 3.9 Hz, 1H), 7.49 (dd, J = 8.5 and 1.6 Hz, 1H), 7.56–7.62 (m, 2H), 7.90–7.94 (m, 3H), 8.03 (s, 1H), 8.79 (d, J = 3.9 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 54.9, 56.5, 102.2, 106.3, 109.5, 118.7, 124.5, 126.3, 126.9, 127.28, 127.32, 127.8, 128.4, 132.7, 133.7, 134.3, 137.9, 142.2, 145.6, 150.9, 151.7, 154.2. HRMS (EI): calcd for C22H17N3O2 (M+), 355.1321; found, 355.1318.

4-(Furan-3-yl)-6,9-dimethoxybenzo[4,5]imidazo[1,2-a]pyrimidine (3o)

Rf = 0.36. Pale yellow solid (50 mg, 57%). mp 127–128 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 4.05 (s, 3H), 4.10 (s, 3H), 6.63 (dd, J = 3.5 and 1.7 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 6.85 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.49 (dd, J = 3.5 and 0.5 Hz, 1H), 7.64–7.65 (m, 1H), 9.22 (d, J = 7.2 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 55.9, 57.2, 101.6, 102.7, 107.1, 111.8, 113.1, 113.5, 118.0, 136.5, 143.3, 144.1, 145.3, 145.6, 152.2, 152.3. HRMS (EI): calcd for C16H13N3O3 (M+), 295.0957; found, 295.0954.

8,11-Dimethoxybenzo[4,5]imidazo[1,2-a]quinazoline (3p)

Rf = 0.37. Pale yellow solid (59 mg, 71%). mp 210–214 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 4.06 (s, 3H), 4.07 (s, 3H), 6.89 (s, 2H), 7.52–7.55 (m, 1H), 7.86–7.90 (m, 1H), 7.95 (dd, J = 7.8 and 1.5 Hz, 1H), 9.11 (s, 1H), 9.38 (d, J = 8.7 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 56.5, 57.1, 105.2, 105.6, 119.1, 120.3, 121.1, 124.8, 129.2, 133.9, 136.6, 138.0, 141.1, 146.8, 150.0, 158.4. HRMS (EI): calcd for C16H13N3O2 (M+), 279.1008; found, 279.1009.

3-Fluoro-8,11-dimethoxybenzo[4,5]imidazo[1,2-a]quinazoline (3q)

Rf = 0.53. Pale yellow solid (45 mg, 50%). mp 214–217 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 4.06 (s, 3H), 4.07 (s, 3H), 6.89 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 7.61–7.64 (m, 2H), 9.07 (s, 1H), 9.44–9.47 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 56.3, 57.0, 105.1, 105.5, 113.7 (d, 2JC–F = 22.0 Hz, 1C), 119.8 (d, 3JC–F = 7.5 Hz, 1C), 120.9, 121.7 (d, 2JC–F = 23.3 Hz, 1C), 122.6 (d, 3JC–F = 7.3 Hz, 1C), 134.5, 136.5, 140.8, 146.8, 149.6, 157.0 (d, 4JC–F = 3.0 Hz, 1C), 158.9 (d, 1JC–F = 246.0 Hz, 1C). HRMS (EI): calcd for C16H12FN3O2 (M+), 297.0914; found, 297.0912.

10,13-Dimethoxybenzo[h]benzo[4,5]imidazo[1,2-a]quinazoline (3r)

Rf = 0.39. Pale yellow solid (62 mg, 63%). mp 223–225 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 3.51 (s, 3H), 4.14 (s, 3H), 6.74 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 7.45 (dd, J = 7.5 and 7.4 Hz, 1H), 7.72 (dd, J = 7.5 and 7.5 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.96–7.97 (m, 1H), 8.45–8.47 (m, 1H), 9.17 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 54.7, 56.7, 103.1, 105.8, 116.8, 122.7, 123.1, 123.4, 124.8, 125.2, 126.3, 127.1, 129.6, 135.4, 137.1, 137.6, 143.3, 146.2, 151.6, 156.7. HRMS (EI): calcd for C20H15N3O2 (M+), 329.1164; found, 329.1162.

General Procedure for the Oxidation of 3–4

A solution of CAN (0.165 g, 0.3 mmol) in acetonitrile/n class="Chemical">H2O (9:1, 2 mL) was added dropwise to a stirred solution of 3 (0.1 mmol) in acetonitrile/H2O (7:3, 2 mL) in an ice bath. After stirring for 20 min in the ice bath, the reaction mixture was poured into cold water and then extracted with ethyl acetate (20 mL, 3 times). Evaporation of the combined solvent under reduced pressure and recrystallization from dichloromethane and hexane mixture gave 4.

1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]quinazoline-8,11-dione (4a)

Rf = 0.47. Brown solid (22 mg, 85%). mp 236–238 °C. 1H NMR (500 MHz, n class="Chemical">DMSO-d6): δ 1.79–1.82 (m, 2H), 1.87–1.92 (m, 2H), 2.90–2.92 (m, 2H), 2.98–3.00 (m, 2H), 6.81 (d, J = 10.4 Hz, 1H), 6.87 (d, J = 10.4 Hz, 1H), 9.13 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ 21.4, 21.6, 25.3, 33.0, 120.7, 123.8, 132.9, 136.4, 137.4, 144.0, 149.3, 166.9, 176.4, 182.2. HRMS (EI): calcd for C14H11N3O2 (M+), 253.0851; found, 253.0854.

3-Methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]quinazoline-8,11-dione (4b)

Rf = 0.54. Brown solid (21 mg, 80%). mp 219–221 °C. 1H NMR (500 MHz, n class="Chemical">DMSO-d6): δ 1.06 (d, J = 6.6 Hz, 3H), 1.46–1.54 (m, 1H), 1.88–1.99 (m, 2H), 2.36–2.42 (m, 1H), 2.83–2.88 (m, 1H), 2.91–2.98 (m, 1H), 3.07–3.13 (m, 1H), 6.81 (d, J = 10.4 Hz, 1H), 6.87 (d, J = 10.4 Hz, 1H), 8.83 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ 22.7, 30.1, 31.8, 34.4, 35.8, 120.6, 121.6, 134.7, 138.0, 144.6, 146.8, 150.7, 166.8, 178.2, 180.4. HRMS (EI): calcd for C15H13N3O2 (M+), 267.1008; found, 267.1009.

3-Phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]quinazoline-8,11-dione (4c)

Rf = 0.42. Brown solid (25 mg, 76%). mp 237–239 °C. 1H NMR (500 MHz, n class="Chemical">DMSO-d6): δ 2.08–2.16 (m, 1H), 2.28–2.32 (m, 1H), 2.96–3.02 (m, 1H), 3.06–3.13 (m, 1H), 3.14–3.20 (m, 2H), 3.27–3.32 (m, 1H), 6.80 (d, J = 10.3 Hz, 1H), 6.89 (d, J = 10.3 Hz, 1H), 7.26–7.27 (m, 1H), 7.29–7.31 (m, 2H), 7.35–7.38 (m, 2H), 8.95 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ 29.1, 33.1, 33.6, 38.1, 118.7, 119.8, 126.12, 126.14, 128.1, 133.1, 136.2, 142.8, 144.3, 145.0, 148.8, 164.3, 179.4, 181.5. HRMS (EI): calcd for C20H15N3O2 (M+), 329.1164; found, 329.1162.

2,3,4,5-Tetrahydro-1H-benzo[4,5]imidazo[1,2-a]cyclohepta[e]pyrimidine-9,12-dione (4d)

Rf = 0.58. Brown solid (19 mg, 71%). mp 190–192 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 1.81–1.85 (m, 2H), 1.97–2.04 (m, 4H), 2.94–2.96 (m, 2H), 3.64–3.66 (m, 2H), 6.72 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 8.54 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 25.1, 27.4, 30.7, 32.0, 34.0, 120.2, 123.2, 132.3, 135.8, 136.8, 143.4, 148.7, 166.3, 175.8, 181.6. HRMS (EI): calcd for C15H13N3O2 (M+), 267.1008; found, 267.1006.

1,2,3,4,5,6-Hexahydrobenzo[4,5]imidazo[1,2-a]cycloocta[e]pyrimidine-10,13-dione (4e)

Rf = 0.56. Brown solid (23 mg, 81%). mp 194–196 °C. 1H NMR (500 MHz, n class="Chemical">DMSO-d6): δ 1.25–1.29 (m, 2H), 1.41–1.45 (m, 2H), 1.70–1.74 (m, 2H), 1.76–1.81 (m, 2H), 2.92–2.94 (m, 2H), 3.74–3.76 (m, 2H), 6.85 (d, J = 10.3 Hz, 1H), 6.89 (d, J = 10.3 Hz, 1H), 8.75 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ 25.0, 25.6, 28.0, 28.6, 29.2, 31.4, 123.2, 126.1, 133.9, 140.4, 146.6, 151.3, 151.9, 157.4, 174.3, 182.2. HRMS (EI): calcd for C16H15N3O2 (M+), 281.1164; found, 281.1167.

1,2,3,4,5,6,7,8,9,10-Decahydrobenzo[4,5]imidazo[1,2-a]cyclododeca[e]pyrimidine-14,17-dione (4f)

Rf = 0.54. Brown solid (29 mg, 85%). mp 198–200 °C. 1H NMR (500 MHz, n class="Chemical">DMSO-d6): δ 1.41–149 (m, 8H), 1.53–1.63 (m, 4H), 1.66–1.71 (m, 2H), 1.80–1.86 (m, 2H), 2.82–2.85 (m, 2H), 3.67–3.70 (m, 2H), 6.85 (d, J = 10.3 Hz, 1H), 6.91 (d, J = 10.3 Hz, 1H), 8.83 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ 21.6, 21.9, 24.8, 25.1, 25.3, 25.6, 25.7, 26.0, 27.1, 28.7, 123.6, 125.5, 134.0, 140.3, 146.7, 151.1, 151.6, 158.4, 174.5, 182.1. HRMS (EI): calcd for C20H23N3O2 (M+), 337.1790; found, 337.1789.

Benzo[f]benzo[4,5]imidazo[1,2-a]quinazoline-8,11-dione (4g)

Rf = 0.42. Brown solid (24 mg, 81%). mp 223–225 °C. 1H NMR (500 MHz, n class="Chemical">CDCl3): δ 6.81 (d, J = 10.3 Hz, 1H), 6.88 (d, J = 10.3 Hz, 1H), 7.70–7.73 (m, 1H), 7.81–7.84 (m, 1H), 8.03 (d, J = 8.0 Hz, 1H), 8.34 (d, J = 9.4 Hz, 1H), 8.72 (d, J = 8.4 Hz, 1H), 9.75 (d, J = 9.4 Hz, 1H), 10.07 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 115.8, 118.7, 122.1, 125.7, 128.4, 128.9, 129.6, 130.0, 131.6, 134.9, 136.5, 137.2, 139.7, 146.5, 151.2, 153.9, 175.5, 181.5. HRMS (EI): calcd for C18H9N3O2 (M+), 299.0695; found, 299.0695.

4-Phenylbenzo[4,5]imidazo[1,2-a]pyrimidine-6,9-dione (4h)

Rf = 0.50. Brown solid (23 mg, 83%). mp 108–110 °C. 1H NMR (500 MHz, n class="Chemical">DMSO-d6): δ 6.69 (d, J = 10.4 Hz, 1H), 6.81 (d, J = 10.4 Hz, 1H), 7.44 (d, J = 4.5 Hz, 1H), 7.48–7.53 (m, 2H), 7.55–7.58 (m, 1H), 7.59–7.62 (m, 2H), 8.96 (d, J = 4.5 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ 114.5, 123.4, 127.3, 128.1, 130.5, 133.8, 134.5, 139.1, 146.0, 149.8, 152.2, 155.6, 173.6, 182.3. HRMS (EI): calcd for C16H9N3O2 (M+), 275.0695; found, 275.0693.

3-Methyl-4-phenylbenzo[4,5]imidazo[1,2-a]pyrimidine-6,9-dione (4i)

Rf = 0.44. Brown solid (21 mg, 72%). mp 211–212 °C. 1H NMR (500 MHz, n class="Chemical">DMSO-d6): δ 2.17 (s, 3H), 6.56 (d, J = 10.4 Hz, 1H), 6.75 (d, J = 10.4 Hz, 1H), 7.47–7.55 (m, 5H), 8.92 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ 15.5, 121.4, 122.9, 128.2, 128.4, 129.8, 132.7, 134.3, 139.2, 145.7, 146.7, 151.3, 158.4, 173.2, 182.2. HRMS (EI): calcd for C17H11N3O2 (M+), 289.0851; found, 289.0849.

3-Butyl-4-phenylbenzo[4,5]imidazo[1,2-a]pyrimidine-6,9-dione (4j)

Rf = 0.55. Brown solid (26 mg, 78%). mp 188–191 °C. 1H NMR (500 MHz, n class="Chemical">DMSO-d6): δ 0.71 (t, J = 7.4 Hz, 3H), 0.81–0.89 (m, 2H), 1.12–1.19 (m, 2H), 1.38–1.44 (m, 2H), 6.56 (d, J = 10.4 Hz, 1H), 6.75 (d, J = 10.4 Hz, 1H), 7.47–7.57 (m, 5H), 8.95 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ 13.4, 21.6, 28.0, 32.1, 123.1, 125.6, 128.1, 128.6, 129.8, 132.3, 134.2, 139.2, 145.7, 146.7, 151.1, 158.2, 173.2, 182.2. HRMS (EI): calcd for C20H17N3O2 (M+), 331.1321; found, 331.1324.

3-Isopropyl-4-phenylbenzo[4,5]imidazo[1,2-a]pyrimidine-6,9-dione (4k)

Rf = 0.44. Brown solid (24 mg, 75%). mp 194–197 °C. 1H NMR (500 MHz, n class="Chemical">DMSO-d6): δ 1.21 (d, J = 7.0 Hz, 6H), 2.73–2.81 (m, 1H), 6.54 (d, J = 10.3 Hz, 1H), 6.75 (d, J = 10.3 Hz, 1H), 7.46–7.53 (m, 5H), 9.11 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ 22.1, 26.9, 122.6, 127.6, 128.2, 129.3, 130.1, 131.7, 133.7, 138.7, 145.3, 145.4, 150.3, 155.4, 172.6, 181.6. HRMS (EI): calcd for C19H15N3O2 (M+), 317.1164; found, 317.1166.

3,4-Diphenylbenzo[4,5]imidazo[1,2-a]pyrimidine-6,9-dione (4l)

Rf = 0.51. Brown solid (25 mg, 72%). mp 222–223 °C. 1H NMR (500 MHz, n class="Chemical">DMSO-d6): δ 6.91 (d, J = 10.5 Hz, 1H), 6.96 (d, J = 10.5 Hz, 1H), 7.30–7.32 (m, 2H), 7.34–7.37 (m, 2H), 7.40–7.44 (m, 6H), 9.18 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ 121.3, 126.4, 128.1, 128.4, 128.8, 129.59, 129.61, 129.9, 134.8, 135.0, 136.8, 137.2, 137.4, 144.7, 149.2, 162.8, 176.7, 181.9. HRMS (EI): calcd for C22H13N3O2 (M+), 351.1008; found, 351.1010.

4-Ethyl-3-methylbenzo[4,5]imidazo[1,2-a]pyrimidine-6,9-dione (4m)

Rf = 0.47. Brown solid (18 mg, 74%). mp 173–175 °C. 1H NMR (500 MHz, n class="Chemical">DMSO-d6): δ 1.27 (t, J = 7.3 Hz, 3H), 2.36 (d, J = 1.0 Hz, 3H), 2.90 (q, J = 7.3 Hz, 2H), 6.77 (d, J = 10.4 Hz, 1H), 6.83 (d, J = 10.4 Hz, 1H), 9.02 (q, J = 1.0 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ 10.3, 15.0, 28.5, 120.8, 122.8, 132.2, 136.3, 137.3, 143.4, 149.5, 170.1, 176.4, 182.00. HRMS (EI): calcd for C13H11N3O2 (M+), 241.0851; found, 241.0852.

4-(Naphthalen-2-yl)benzo[4,5]imidazo[1,2-a]pyrimidine-6,9-dione (4n)

Rf = 0.51. Brown solid (25 mg, 76%). mp 184–187 °C. 1H NMR (500 MHz, n class="Chemical">DMSO-d6): δ 6.89 (d, J = 10.4 Hz, 1H), 6.95 (d, J = 10.4 Hz, 1H), 7.64–7.69 (m, 3H), 8.14–8.18 (m, 2H), 8.30 (d, J = 7.2 Hz, 1H), 8.43–8.45 (m, 1H), 8.96 (s, 1H), 9.46 (d, J = 7.2 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ 110.3, 116.7, 123.7, 126.8, 127.5, 128.0, 128.4, 128.7, 129.0, 132.6, 132.9, 134.3, 136.1, 136.4, 137.2, 144.6, 150.2, 160.9, 176.6, 181.9. HRMS (EI): calcd for C20H11N3O2 (M+), 325.0851; found, 325.0850.

4-(Furan-3-yl)benzo[4,5]imidazo[1,2-a]pyrimidine-6,9-dione (4o)

Rf = 0.45. Brown solid (19 mg, 72%). mp 157–158 °C. 1H NMR (500 MHz, n class="Chemical">DMSO-d6): δ 6.84 (dd, J = 3.6 and 1.8 Hz, 1H), 6.86 (d, J = 10.5 Hz, 1H), 6.91 (d, J = 10.5 Hz, 1H), 7.65 (dd, J = 3.6 and 0.6 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H), 8.11–8.114 (m, 1H), 9.36 (d, J = 7.2 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ 109.0, 113.6, 115.5, 121.8, 136.5, 136.54, 137.4, 144.6, 147.7, 150.1, 150.6, 152.0, 176.6, 182.0. HRMS (EI): calcd for C14H7N3O3 (M+), 265.0487; found, 265.0485.

Benzo[4,5]imidazo[1,2-a]quinazoline-8,11-dione (4p)

Rf = 0.40. Brown solid (20 mg, 82%). mp 253–255 °C. 1H NMR (500 MHz, n class="Chemical">DMSO-d6): δ 6.91 (d, J = 10.3 Hz, 1H), 7.00 (d, J = 10.3 Hz, 1H), 7.84–7.87 (m, 1H), 8.13–8.15 (m, 1H), 8.34–8.36 (m, 1H), 9.49 (s, 1H), 9.60–9.62 (m, 1H). 13C NMR (125 MHz, DMSO-d6): δ 119.5, 120.0, 126.5, 127.9, 130.0, 134.5, 135.8, 139.3, 144.3, 150.0, 159.7, 175.8, 181.7. HRMS (EI): calcd for C14H7N3O2 (M+), 249.0538; found, 249.0535.

3-Fluorobenzo[4,5]imidazo[1,2-a]quinazoline-8,11-dione (4q)

Rf = 0.54. Brown solid (20 mg, 74%). mp 254–257 °C. 1H NMR (500 MHz, n class="Chemical">DMSO-d6): δ 6.94 (d, J = 10.3 Hz, 1H), 7.04 (d, J = 10.3 Hz, 1H), 7.90–7.93 (m, 2H), 9.48 (s, 1H), 9.73–9.76 (m, 1H). 13C NMR (125 MHz, DMSO-d6): δ 112.1 (d, 2JC–F = 22.0 Hz, 1C), 118.2 (d, 3JC–F = 7.5 Hz, 1C), 120.1 (d, 2JC–F = 23.3 Hz, 1C), 121.0 (d, 3JC–F = 7.3 Hz, 1C), 126.7, 132.9, 134.9, 139.2, 145.2, 148.0, 155.4 (d, 4JC–F = 3.0 Hz, 1C), 157.3 (d, 1JC–F = 246.0 Hz, 1C), 174.8, 181.8. HRMS (EI): calcd for C14H6FN3O2 (M+), 267.0444; found, 267.0447.

Benzo[h]benzo[4,5]imidazo[1,2-a]quinazoline-10,13-dione (4r)

Rf = 0.43. Brown solid (21 mg, 71%). mp 251–253 °C. 1H NMR (500 MHz, n class="Chemical">DMSO-d6): δ 6.92 (d, J = 10.3 Hz, 1H), 7.01 (d, J = 10.3 Hz, 1H), 7.68–7.72 (m, 1H), 7.91–7.94 (m, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.34 (d, J = 8.5 Hz, 1H), 9.66 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ 119.3, 122.2, 123.4, 125.9, 126.3, 127.8, 127.9, 128.8, 130.4, 134.5, 134.8, 139.5, 145.4, 151.5, 158.0, 159.5, 175.0, 182.4. HRMS (EI): calcd for C18H9N3O2 (M+), 299.0695; found, 299.0692.