Synthesis of Benzo[4,5]imidazo[1,2-c]pyrimidin-1-amines and Their Analogs via Copper-Catalyzed C–N Coupling and Cyclization

Abstract

2-(2-Bromovinyl)benzimidazoles and 2-(2-bromophenyl)benzimidazoles react with cyanamide by microwave irradiation in dimethylformamide in the presence of a catalytic amount of CuI along with a base to give the corresponding benzo[4,5]imidazo[1,2-c]pyrimidin-1-amines and benzo[4,5]imidazo[1,2-c]quinazolin-6-amines, respectively, in moderate to good yields. 2-(2-Bromophenyl)indoles also react with cyanamide under similar conditions to afford indolo[1,2-c]quinazolin-6-amines. The reaction pathway seems to proceed via a sequence such as intermolecular C–N coupling, C–N formative cyclization, and tautomerization.

Introduction

Besides a class of homonuclear N-heterocyclic compounds, their N-fused hybrid structures frequently exhibit characteristic biological activities that are not shown in each homonuclear scaffold. Thus, many synthetic methods for such hybrid structures have been developed and tested for biological activities.¹ It is known that benzimidazole-fused pyrimidines, benzo[4,5]imidazo[1,2-a]pyrimidines, also exhibit diverse biological activities and fluorescent properties (Scheme 1, A).²⁻⁴ However, in contrast to the well-known synthetic methods and biological activities for benzo[4,5]imidazo[1,2-a]pyrimidines, those for benzo[4,5]imidazo[1,2-c]pyrimidines are relatively rare (Scheme 1, B). It is reported that such a scaffold can be synthesized by the initial addition of 2-cyanomethylbenzimidazole to trichloroacetonitrile and the condensation of the resulting adduct with ethyl orthoformate.⁵ Goekjian and co-workers have demonstrated that a series of functionalized benzo[4,5]imidazo[1,2-c]pyrimidines can also be prepared by aza-Graebe–Ullmann coupling and palladium-catalyzed Buchwald–Hartwig coupling protocols starting from 4,6-dichloropyrimidine and benzotriazole, thus showing activity against anaplastic lymphoma kinase.⁶ The course of our continuing studies aiming to develop a new protocol for transition-metal-catalyzed coupling and cyclization reactions led us to seek for a new synthetic method for benzo[4,5]imidazo[1,2-c]pyrimidines.⁷ This report describes copper-catalyzed coupling and cyclization of 2-(2-bromovinyl)benzimidazoles with cyanamide, leading to a class of benzo[4,5]imidazo[1,2-c]pyrimidines under microwave irradiation (Scheme 2).^8,9 To the best of our knowledge, two reports are found for the synthesis of N-fused hybrid scaffolds using cyanamide. Fu et al. have shown that 2-bromo-N-(2-halophenyl)benzamides and N-(2-halophenyl)propiolamides are coupled and cyclized with cyanamide in the presence of a copper catalyst along with a ligand to form benzimidazo[2,1-b]quinazolin-12(6H)-ones and benzo[4,5]imidazo[1,2-a]pyrimidin-4(10H)-ones, respectively (Scheme 3).¹⁰ The present work shows another example for the synthesis of N-fused hybrid scaffolds using cyanamide.

Scheme 1. Two N-Fused Modes of Benzimidazole and Pyrimidine.

Scheme 2. Examples of Biologically Active Molecules Containing 2-Aminopyrimidine Scaffold.

Scheme 3. Copper-Catalyzed Synthesis of N-Fused Heterocycles Using Cyanamide.

Results and Discussion

Treatment of 2-(2-bromocyclohex-1-en-1-yl)-1H-benzo[d]imidazole (1a) with 2 equiv of cyanamide (2) in dimethylformamide (DMF) in the presence of a catalytic amount of CuI (10 mol %) and K₂CO₃ at 100 °C for 30 min under microwave irradiation (100 W of initial power) afforded 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (3a) in 51% yield (Table 1, entry 1) with incomplete conversion of 1a. Prolonging the reaction time up to 1 h was needed for the effective formation of 3a with complete conversion of 1a; however, the reaction was accompanied by several unidentifiable side products (Table 1, entry 2).a^,b The reaction temperature was also critical for the effective formation of 3a, and the yield raised with the increase in temperature up to 100 °C (Table 1, entries 2–4, 14, and 16). When used with K₂CO₃ as a base and DMF as a solvent, copper salts such as CuCl, CuBr, and Cu(OAc)₂·H₂O showed lower catalytic activities than did CuI (Table 1, entries 5–7). Performing the reaction using copper powder combined with l-proline and copper powder resulted in lower yield of 3a (Table 1, entries 8 and 9).c The reaction also proceeded in the presence of other bases such as NaOAc, KOH, NaO^tBu, and Cs₂CO₃ in combination with CuI and DMF, but the yield of 3a was lower than that when K₂CO₃ was employed (Table 1, entries 10–13). However, an activity similar to that of K₂CO₃ was observed with K₃PO₄ (Table 1, entry 14). Here again, further addition of l-proline gave no change in the yield of 3a (Table 1, entry 15). Among the solvents examined in combination with CuI and K₃PO₄, DMF was found to be of choice (Table 1, entries 14 and 17–19). No expected product was observed in the absence of copper catalyst, and 1a was recovered almost completely (Table 1, entries 20–23).

Table 1. Optimization of Conditions for the Reaction of 1a and 2^a.

entry	Cu catalyst	base	solvent	temp (°C)	yieldb (%)
1c	CuI	K2CO3	DMF	100	51
2	CuI	K2CO3	DMF	100	77
3	CuI	K2CO3	DMF	80	62
4	CuI	K2CO3	DMF	120	76
5	CuCl	K2CO3	DMF	100	54
6	CuBr	K2CO3	DMF	100	65
7	Cu(OAc)2·H2O	K2CO3	DMF	100	57
8	Cu powder	K2CO3	DMF	100	47
9d	Cu powder	K2CO3	DMF	100	49
10	CuI	NaOAc	DMF	100	54
11	CuI	KOH	DMF	100	63
12	CuI	NaOtBu	DMF	100	71
13	CuI	Cs2CO3	DMF	100	44
14	CuI	K3PO4	DMF	100	79
15d	CuI	K3PO4	DMF	100	79
16	CuI	K3PO4	DMF	120	78
17	CuI	K3PO4	DMSO	100	73
18	CuI	K3PO4	1,4-dioxane	100	26
19	CuI	K3PO4	toluene	100	38
20		K3PO4	DMF	100	0
21		K2CO3	DMF	100	0
22		KOH	DMF	100	0
23		NaOtBu	DMF	100	0

^aReaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), Cu catalyst (0.03 mmol), base (0.6 mmol), solvent (3 mL), under microwave irradiation (100 W of initial power), 1 h, unless otherwise stated.

^bIsolated yield.

^cReaction time: 30 min.

^dIn the presence of l-proline (0.12 mmol).

After the reaction conditions had been optimized, various 2-(2-bromovinyl)benzimidazoles 1 were subjected to the reaction with cyanamide 2 to investigate the reaction scope, and several representative results are summarized in Table 2. The six-membered 2-(2-bromovinyl)benzimidazoles (1b and 1c) reacted with 2 to give the corresponding benzo[4,5]imidazo[1,2-c]pyrimidin-1-amines (3b and 3c), irrespective of the presence of the methyl and phenyl substituents on 1b and 1c. The coupling and cyclization with 1d having a dimethyl substituent on the benzimidazole moiety also proceeded to give the corresponding benzo[4,5]imidazo[1,2-c]pyrimidin-1-amine 3d. With cyclic 2-(2-bromovinyl)benzimidazoles 1e–h having various ring sizes, the corresponding coupled and cyclized products, benzo[4,5]imidazo[1,2-c]pyrimidin-1-amines 3e–h, were also formed, as expected, in the range of 57–83% yields. Lower reaction yield, not yet explained, was observed with 1e. For testing the effect of the position of bromide and benzimidazole groups on benzo-fused 2-(2-bromovinyl)benzimidazoles, 1i and 1j were employed. The coupling and cyclization took place irrespective of the position, and both cases are accompanied by the dehydrogenation of benzo[4,5]imidazo[1,2-c]pyrimidin-1-amines initially formed by the coupling and cyclization of 1i and 1j with 2 under the employed conditions. The coupling and cyclization product 3i formed from 1i was partially dehydrogenated to 3i′, whereas the product from 1j was completely dehydrogenated to 3j. Such a similar dehydrogenation was observed by our recent reports on copper-catalyzed coupling and cyclization of β-bromo-α,β-unsaturated carboxylic acids with terminal alkynes and palladium-catalyzed carbonylative cyclization of 2-(2-bromovinyl)benzimidazoles.¹² The reaction of acyclic 2-(2-bromovinyl)benzimidazole 1k with 2 also afforded the coupled and cyclized product 3k; however, the yield was lower than that when cyclic 2-(2-bromovinyl)benzimidazoles were used. Similar treatment of 2-(2-bromoaryl)benzimidazoles 1l–n and 2-(2-bromoaryl)imidazole 1o with 2 under the employed conditions also afforded the coupling and cyclization products 3l–o in 69–85% yields. It is known that benzimidazole- and imidazole-fused quinazolines, benzo[4,5]imidazo[1,2-c]quinazolines and imidazo[1,2-c]quinazolines, have a wide spectrum of biological activities and act as commercial drugs.¹³

Table 2. Scope of Coupling and Cyclization Reaction^a.

^aReaction conditions: 1 or 4a (0.3 mmol), 2 (0.6 mmol), CuI (0.03 mmol), K₃PO₄ (0.6 mmol), DMF (3 mL), 100 °C (with 1), 130 °C (with 4), 1 h, under microwave irradiation (100 W of initial power).

The present protocol can be extended to the reaction with 2-(2-bromophenyl)-1H-indoles 4 (Table 2). Similar treatment of 2-(2-bromophenyl)-1H-indole (4a) with 2 under the optimized conditions shown in Table 1 produced indolo[1,2-c]quinazolin-6-amine (5a) in 47% yield. However, further tuning with the reaction temperature resulted in an increased yield of 5a (73% yield at 130 °C). From the reaction of several 2-(2-bromophenyl)-1H-indoles 4b–d with 2, the corresponding coupled and cyclized indolo[1,2-c]quinazolin-6-amines 5b–d were also invariably produced irrespective of straight and branched alkyl chains on the indole moiety. It is also known that indole-fused quinazolines, indolo[1,2-c]quinazolines, exhibit biological activities such as antibacterial and antifungal properties.¹⁴

Although no additional experimental efforts for the reaction pathway were performed, the reaction seems to proceed via an initial formation of intermediate 6 by copper-catalyzed Ullmann-type coupling between 1 (or 4) and 2 (Scheme 4).¹⁵ This is followed by the intramolecular addition of N–H to CN to form 7, which triggers tautomerization to give product 3. The following experimental observation is worth noting as evidence for the formation of intermediate 6. We confirmed that a similar treatment of 2-(2-bromophenyl)-1-methyl-1H-benzo[d]imidazole (8) with 2 under the employed conditions afforded C–N-coupled product 9 in 78% yield (Scheme 5, see the Supporting Information). A similar pathway has already been proposed in copper-catalyzed coupling and cyclization reactions using cyanamide.^10,16

Scheme 4. Reaction Pathway.

Scheme 5. Experiment for Mechanism Study.

Conclusions

It has been shown that 2-(2-bromovinyl)benzimidazoles and their analogs are coupled and cyclized with cyanamide under microwave irradiation in the presence of CuI to give a class of N-fused hybrid scaffolds, benzo[4,5]imidazo[1,2-c]pyrimidin-1-amines and their analogs. The present reaction provides a new method for synthesizing several N-fused hybrid heterocycles from readily available starting compounds.

Experimental Section

General Information

¹H and ¹³C NMR spectra were recorded at 500 and 125 MHz, respectively, in DMSO-d₆ or CDCl₃. Melting points were determined on a microscopic melting point apparatus. High-resolution mass data were recorded using electron ionization (HRMS-EI, magnetic sector-electric sector double-focusing mass analyzer) at the Korea Basic Science Center, Daegu, Korea. All microwave reactions (CEM, Discover LabMate) were carried out in a sealed tube (5 mL), and the reaction temperature was maintained by an external infrared sensor. The isolation of pure products was carried out via thin-layer (a glass plate coated with Kieselgel 60 GF₂₅₄, Merck) chromatography (TLC). The starting 2-(2-bromovinyl)benzimidazoles and their analogs were prepared by literature procedures.¹⁷⁻¹⁹ Commercially available organic and inorganic compounds were used without further purification.

General Procedure for the Synthesis of 3

A 10 mL microwave reaction tube was charged with 1 (0.3 mmol) and 2 (0.025 g, 0.6 mmol) together with CuI (0.006 g, 0.03 mmol), K₃PO₄ (0.127 g, 0.6 mmol), and DMF (3 mL). The reaction mixture was heated to 100 °C for 1 h by microwave irradiation at 100 W initial power. The mixture was then cooled to room temperature and filtered through a short silica gel column (ethyl acetate) to remove inorganic components. Removal of the solvent left a crude mixture that was separated by TLC (dichloromethane/MeOH = 19:1) to give 3. Except for known 3l,²⁰ all new products were characterized spectroscopically.

1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (3a)

White solid (56 mg, 79%). mp 251–253 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 1.78–1.84 (m, 4H), 2.61–2.63 (m, 2H), 2.76–2.78 (m, 2H), 7.27–7.30 (m, 3H), 7.44–7.47 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 8.33 (d, J = 8.3 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ 21.9, 22.5, 30.9, 106.8, 114.3, 118.1, 120.5, 125.2, 127.2, 144.8, 147.0, 150.7, 151.5. HRMS (EI) anal. calcd for C₁₄H₁₄N₄ (M⁺): 238.1218. Found: 238.1218.

2-Methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (3b)

White solid (58 mg, 77%). mp 264–266 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 1.09 (d, J = 6.5 Hz, 3H), 1.42–1.50 (m, 1H), 1.86–1.97 (m, 2H), 2.26–2.31 (m, 1H), 2.61–2.72 (m, 2H), 2.95–3.00 (m, 1H), 7.27–7.30 (m, 3H), 7.44–7.47 (m, 1H), 7.71 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ 21.5, 27.9, 30.5, 30.6, 30.8, 106.3, 114.2, 118.1, 120.4, 125.1, 127.2, 144.8, 147.0, 150.7, 151.0. HRMS (EI) anal. calcd for C₁₅H₁₆N₄ (M⁺): 252.1375. Found: 252.1372.

2-Phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (3c)

White solid (62 mg, 66%). mp 231–233 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 1.97–2.07 (m, 2H), 2.68–2.73 (m, 1H), 2.76–2.87 (m, 2H), 3.02–3.06 (m, 1H), 3.14–3.18 (m, 1H), 7.22–7.25 (m, 1H), 7.28–7.37 (m, 7H), 7.44–7.47 (m, 1H), 7.71 (d, J = 8.1 Hz, 1H), 8.35 (d, J = 8.3 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ 29.5, 30.3, 31.1, 38.9, 106.3, 114.3, 118.2, 120.5, 125.2, 126.2, 126.8, 127.2, 128.4, 144.8, 146.0, 147.1, 150.5, 151.0. HRMS (EI) anal. calcd for C₂₀H₁₈N₄ (M⁺): 314.1531. Found: 314.1528.

9,10-Dimethyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (3d)

White solid (51 mg, 64%). mp 243–245 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 1.75–1.83 (m, 4H), 2.36 (s, 3H), 2.39 (s, 3H), 2.58–2.60 (m, 2H), 2.72–2.75 (m, 2H), 7.19 (s, 2H), 7.49 (s, 1H), 8.14 (s, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ 19.9, 20.0, 21.9, 22.4, 22.5, 30.8, 106.7, 114.2, 118.2, 125.5, 129.1, 133.6, 143.3, 146.7, 150.1, 150.5. HRMS (EI) anal. calcd for C₁₆H₁₈N₄ (M⁺): 266.1531. Found: 266.1531.

2,3-Dihydro-1H-benzo[4,5]imidazo[1,2-c]cyclopenta[e]pyrimidin-5-amine (3e)

White solid (38 mg, 57%). mp 236–238 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 2.10–2.16 (m, 2H), 2.83–2.86 (m, 2H), 2.97–2.99 (m, 2H), 7.28–7.31 (m, 1H), 7.43 (s, 2H), 7.45–7.48 (m, 1H), 7.70 (d, J = 8.1 Hz, 1H), 8.34 (d, J = 8.3 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ 21.6, 27.6, 34.1, 109.5, 114.2, 118.1, 120.3, 125.3, 127.1, 144.9, 148.9, 149.6, 160.2. HRMS (EI) anal. calcd for C₁₃H₁₂N₄ (M⁺): 224.1062. Found: 224.1060.

2,3,4,5-Tetrahydro-1H-benzo[4,5]imidazo[1,2-c]cyclohepta[e]pyrimidin-7-amine (3f)

White solid (63 mg, 83%). mp 257–259 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 1.59–1.62 (m, 4H), 1.80–1.82 (m, 2H), 2.79–2.82 (m, 2H), 3.02–3.04 (m, 2H), 7.25–7.28 (m, 1H), 7.32 (br s, 2H), 7.43–7.46 (m, 1H), 7.70 (d, J = 8.1 Hz, 1H), 8.34 (d, J = 8.3 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ 25.3, 25.7, 27.1, 32.0, 37.3, 111.5, 114.3, 117.8, 120.0, 125.2, 127.4, 144.9, 146.8, 151.4, 157.3. HRMS (EI) anal. calcd for C₁₅H₁₆N₄ (M⁺): 252.1375. Found: 252.1373.

1,2,3,4,5,6-Hexahydrobenzo[4,5]imidazo[1,2-c]cycloocta[e]pyrimidin-8-amine (3g)

White solid (64 mg, 80%). mp 251–252 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 1.33–1.41 (m, 4H), 1.64–1.73 (m, 4H), 2.73–2.75 (m, 2H), 2.97–3.00 (m, 2H), 7.26–7.29 (m, 1H), 7.32 (br s, 2H), 7.44–7.47 (m, 1H), 7.73 (d, J = 8.1 Hz, 1H), 8.34 (d, J = 8.3 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ 24.4, 25.6, 26.1, 29.5, 29.7, 32.6, 109.6, 114.2, 118.0, 120.2, 125.2, 127.3, 145.0, 147.5, 150.8, 154.3. HRMS (EI) anal. calcd for C₁₆H₁₈N₄ (M⁺): 266.1531. Found: 266.1531.

1,2,3,4,5,6,7,8,9,10-Decahydrobenzo[4,5]imidazo[1,2-c]cyclododeca[e]pyrimidin-12-amine (3h)

White solid (75 mg, 78%). mp 240–242 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 1.25–1.39 (m, 8H), 1.48–1.52 (m, 4H), 1.79–1.86 (m, 4H), 2.60–2.63 (m, 2H), 2.84–2.87 (m, 2H), 7.23 (br s, 2H), 7.27–7.30 (m, 1H), 7.44–7.47 (m, 1H), 7.74 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ 21.9, 22.5, 23.7, 23.9, 25.0, 25.4, 26.4, 26.7, 30.0, 110.0, 114.3, 118.1, 120.4, 125.2, 127.0, 144.9, 146.9, 151.3, 154.1. HRMS (EI) anal. calcd for C₂₀H₂₆N₄ (M⁺): 322.2157. Found: 322.2159.

5,6-Dihydrobenzo[f]benzo[4,5]imidazo[1,2-c]quinazolin-8-amine (3i)

White solid (48 mg, 56%). mp 227–228 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 2.85–2.89 (m, 2H), 2.93–2.96 (m, 2H), 7.16–7.19 (m, 1H), 7.26 (d, J = 7.3 Hz, 1H), 7.32–7.37 (m, 2H), 7.51–7.54 (m, 1H), 7.76 (s, 2H), 7.85 (d, J = 7.8 Hz, 1H), 8.41 (d, J = 8.3 Hz, 1H), 9.09 (dd, J = 7.9 and 1.0 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ 30.5, 30.7, 105.0, 114.2, 118.4, 120.9, 125.6, 125.8, 126.1, 126.2, 126.4, 127.3, 131.4, 134.5, 144.9, 148.2, 148.3, 154.9. HRMS (EI) anal. calcd for C₁₈H₁₄N₄ (M⁺): 286.1218. Found: 286.1219.

Benzo[f]benzo[4,5]imidazo[1,2-c]quinazolin-8-amine (3i′)

White solid (24 mg, 28%). mp 236–238 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 7.48–7.51 (m, 1H), 7.59–7.63 (m, 2H), 7.65 (d, J = 8.9 Hz, 1H), 7.67 (br s, 2H), 7.81–7.84 (m, 1H), 8.05 (d, J = 8.1 Hz, 2H), 8.16 (d, J = 8.8 Hz, 1H), 8.52 (d, J = 8.3 Hz, 1H), 10.34 (d, J = 8.6 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ 107.2, 114.4, 119.0, 122.2, 124.9, 125.0, 125.4, 126.4, 126.8, 127.9, 128.5, 129.5, 129.9, 132.7, 144.2, 145.7, 147.5, 148.7. HRMS (EI) anal. calcd for C₁₈H₁₂N₄ (M⁺): 284.1062. Found: 284.1060.

Benzo[h]benzo[4,5]imidazo[1,2-c]quinazolin-8-amine (3j)

White solid (66 mg, 77%). mp 233–236 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 7.41–7.44 (m, 1H), 7.52–7.56 (m, 2H), 7.58 (d, J = 8.8 Hz, 1H), 7.60 (br s, 2H), 7.74–7.77 (m, 1H), 7.97–7.99 (m, 2H), 8.09 (d, J = 8.8 Hz, 1H), 8.34 (d, J = 8.3 Hz, 1H), 9.97 (d, J = 8.6 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ 106.8, 114.5, 119.1, 122.3, 125.1, 125.2, 125.6, 126.3, 126.7, 127.8, 128.6, 129.5, 130.2, 132.6, 144.1, 145.6, 147.5, 149.5. HRMS (EI) anal. calcd for C₁₈H₁₂N₄ (M⁺): 284.1062. Found: 284.1060.

4-Methyl-3-phenylbenzo[4,5]imidazo[1,2-c]pyrimidin-1-amine (3k)

White solid (42 mg, 51%). mp 276–278 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 2.40 (s, 3H), 7.20–7.22 (m, 2H), 7.48–7.51 (m, 1H), 7.54–7.56 (m, 2H), 7.60 (br s, 2H), 7.95 (d, J = 8.3 Hz, 2H), 8.16–8.18 (m, 2H). ¹³C NMR (125 MHz, DMSO-d₆): δ 14.7, 114.6, 114.9, 120.5, 121.4, 125.8, 127.7, 128.6, 129.3, 130.2, 131.0, 131.7, 145.0, 146.3, 151.3. HRMS (EI) anal. calcd for C₁₇H₁₄N₄ (M⁺): 274.1218. Found: 274.1220.

Benzo[4,5]imidazo[1,2-c]quinazolin-6-amine (3l)

White solid (60 mg, 85%). mp > 300 °C (lit.²⁰ mp > 300 °C). ¹H NMR (500 MHz, DMSO-d₆): δ 7.35–7.38 (m, 1H), 7.42–7.46 (m, 3H), 7.51–7.55 (m, 2H), 7.63–7.67 (m, 1H), 7.91 (d, J = 8.0 Hz, 1H), 8.40 (dd, J = 7.8 and 0.8 Hz, 1H), 8.43 (d, J = 8.3 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ 114.3, 114.7, 119.1, 122.3, 123.1, 123.8, 124.3, 125.0, 128.2, 131.8, 143.9, 144.6, 146.5, 148.4.

9,10-Dimethylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (3m)

White solid (55 mg, 70%). mp 271–273 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 2.40 (s, 3H), 2.44 (s, 3H), 7.32–7.35 (m, 1H), 7.38 (br s, 2H), 7.48 (d, J = 8.2 Hz, 1H), 7.60–7.63 (m, 1H), 7.66 (s, 1H), 8.24 (s, 1H), 8.34 (d, J = 7.9 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ 20.0, 20.1, 114.3, 114.8, 119.0, 123.0, 123.6, 124.3, 126.5, 131.3, 131.4, 133.8, 142.4, 144.5, 146.4, 147.7. HRMS (EI) anal. calcd for C₁₆H₁₄N₄ (M⁺): 262.1218. Found: 262.1215.

8,11-Dimethoxybenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (3n)

White solid (61 mg, 69%). mp 285–287 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 3.97 (s, 3H), 4.07 (s, 3H), 7.01 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 7.29–7.32 (m, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.59–7.62 (m, 1H), 8.31 (br s, 2H), 8.35–8.36 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ 55.9, 57.9, 106.3, 106.4, 114.2, 119.1, 122.6, 123.7, 123.8, 131.7, 136.0, 139.0, 144.7, 145.4, 146.0, 148.0. HRMS (EI) anal. calcd for C₁₆H₁₄N₄O₂ (M⁺): 294.1117. Found: 294.1120.

2,3-Diphenylimidazo[1,2-c]quinazolin-5-amine (3o)

White solid (70 mg, 69%). mp 289–292 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 6.04 (br s, 2H), 7.23–7.29 (m, 3H), 7.35–7.38 (m, 1H), 7.46–7.51 (m, 3H), 7.55–7.59 (m, 1H), 7.60–7.70 (m, 5H), 8.36 (dd, J = 7.9 and 1.2 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ 115.5, 121.2, 122.3, 123.3, 124.2, 127.2, 127.5, 128.2, 129.2, 130.1, 130.2, 130.3, 132.1, 133.5, 140.4, 142.5, 143.8, 144.6. HRMS (EI) anal. calcd for C₂₂H₁₆N₄ (M⁺): 336.1375. Found: 336.1373.

Indolo[1,2-c]quinazolin-6-amine (5a)

Pale yellow solid (51 mg, 73%). mp 249–252 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 7.13 (br s, 2H), 7.17–7.24 (m, 1H), 7.29–7.44 (m, 5H), 7.79 (d, J = 7.4 Hz, 1H), 8.10 (dd. J = 7.8 and 1.0 Hz, 1H), 8.38 (d, J = 8.1 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃): δ 95.8, 113.4, 118.0, 121.0, 122.1, 122.9, 123.6, 124.0, 124.4, 129.3, 130.7, 130.9, 136.1, 140.4, 146.6. HRMS (EI) anal. calcd for C₁₅H₁₁N₃ (M⁺): 233.0953. Found: 233.0951.

12-Methylindolo[1,2-c]quinazolin-6-amine (5b)

Pale yellow solid (44 mg, 59%). mp 217–219 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 2.73 (s, 3H), 7.01 (s, 2H), 7.24–7.27 (m, 1H), 7.35–2.44 (m, 4H), 7.86 (d, J = 7.8 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃): δ 10.9, 106.9, 113.4, 118.9, 119.8, 122.4, 123.1, 123.7, 123.8, 124.2, 128.4, 129.5, 130.6, 131.8, 140.9, 146.9. HRMS (EI) anal. calcd for C₁₆H₁₃N₃ (M⁺): 247.1109. Found: 247.1108.

12-Butylindolo[1,2-c]quinazolin-6-amine (5c)

Pale yellow solid (48 mg, 55%). mp 204–205 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 0.95 (t, J = 7.4 Hz, 3H), 1.44–1.51 (m, 2H), 1.65–1.71 (m, 2H), 3.23 (t, J = 7.6 Hz, 2H), 7.00 (br s, 2H), 7.26–7.28 (m, 1H), 7.35–7.38 (m, 2H), 7.40–7.43 (m, 2H), 7.83 (d, J = 7.8 Hz, 1H), 8.10 (d, J = 7.9 Hz, 1H), 8.32 (d, J = 8.3 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃): δ 14.1, 23.0, 24.8, 31.7, 112.6, 113.5, 118.9, 119.5, 122.4, 123.0, 123.6, 123.7, 124.5, 128.4, 129.6, 130.2, 131.6, 141.2, 147.0. HRMS (EI) anal. calcd for C₁₉H₁₉N₃ (M⁺): 289.1579. Found: 289.1580.

12-Isopropylindolo[1,2-c]quinazolin-6-amine (5d)

Pale yellow solid (45 mg, 54%). mp 184–186 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 1.57 (d, J = 7.1 Hz, 6H), 4.09 (sep, J = 7.1 Hz, 1H), 6.95 (s, 2H), 7.22–7.25 (m, 1H), 7.32–7.42 (m, 4H), 8.04 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃): δ 22.2, 26.5, 113.9, 118.6, 119.4, 121.4, 122.1, 122.7, 123.5, 124.0, 124.4, 128.5, 129.5, 129.9, 130.6, 141.6, 147.1. HRMS (EI) anal. calcd for C₁₈H₁₇N₃ (M⁺): 275.1422. Found: 275.1420.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.7b00693.

• ¹H and ¹³C NMR spectra and HRMS data for all new products (PDF)

The authors declare no competing financial interest.