Easy and efficient one-pot synthesis of pyrazolo[1,5-c]quinazolines under mild copper-catalyzed conditions

Abstract

An easy and efficient method has been developed for the synthesis of pyrazolo[1,5-c]quinazolines via one-pot two-step reactions of readily available substituted 1-(2-halophenyl)-3-akylprop-2-yn-1-ones, hydrazine hydrochloride and amidine hydrochlorides under mild conditions, and the corresponding pyrazolo[1,5-c]quinazolines were obtained in good to excellent yields. The novel method affords a new strategy for the construction of diverse and useful poly N-heterocyclic compounds.

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Introduction

N-Heterocycles are widely found in natural products and biologically active molecules, and they play key roles in the pharmaceutical and agrochemical industries.¹ Pyrazoles are important building blocks of man-made biologically active compounds such as celecoxib, fipronil, lonazolac and viagra, although they are rarely found in natural products.² Quinazolines show various biological and medicinal properties. For example, they have been used as potent tyrosine kinase and cellular phosphorylation inhibitors,³ ligands for benzodiazepine and γ-aminobutyric acid (GABA) receptors in the central nervous system (CNS)⁴ or as DNA binders,⁵ and anticancer,⁶ antiviral,⁷ and antitubercular agents.⁸ Some quinazolines have been popular drugs such as Erlotinib, used in the treatment of several types of tumors,⁹ Prazosin as an α-adrenergic blocker,¹⁰ and Iressa as an epidermal growth factor receptor inhibitor approved by the Food and Drug Administration in the USA for the treatment of lung cancer.¹¹

N-Fused heterocycles of pyrazoles and quinazolines, pyrazoloquinazolines (Fig. 1), exhibit some biological functions, and they have been used as potent IκB kinase and phosphodiesterase 10A inhibitors,^12,13 AMPA and kainate receptor and Gly/NMDA receptor antagonists.^14,15 However, the methods for the synthesis of pyrazoloquinazolines are very limited.^12–15 In the past ten years, copper-catalyzed couplings have attracted much attention for their wide applications,¹⁶ and various N-heterocycles were synthesized via the copper-catalyzed coupling strategy by other groups¹⁷ and us.¹⁸ Herein, we report a new, easy and efficient one-pot synthesis of pyrazoloquinazolines under copper-catalyzed conditions.

Fig. 1 Pyrazoloquinazoline as an N-fused heterocycle of pyrazole and quinazoline.

Results and discussion

Considering the ready availability of the substrates, the reaction of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one (1a), hydrazine hydrochloride and acetamidine hydrochloride (2a) was chosen as the model to optimize the reaction conditions including copper-catalysts, ligands, bases, solvents and temperature under nitrogen atmosphere. As shown in Table 1, the reaction of the three components is a one-pot two-step process: coupling of 1a with hydrazine hydrochloride in DMSO first led to intermediate Ia in the presence of Cs₂CO₃ at 80 °C for 12 h, and then treatment of Ia with 2a provided the target product (3a) under copper-catalysis for 24 h (see Schemes 1 and 2). First, the effect of the ligands was investigated by using 10 mol% CuI as the catalyst, Cs₂CO₃ as the base, DMSO as the solvent (entries 1–4), the reaction was performed at 80 °C for the first step and at room temperature for the second step, and the results showed that the highest yield was provided in the absence of a ligand (entry 4). Several copper catalysts were screened (compare entries 4–9), and CuI exhibited the highest activity (entry 4). No target product was observed in the absence of copper catalyst (entry 10). K₂CO₃ and K₃PO₄ were used as the bases (entries 11 and 12), and they gave lower yields than Cs₂CO₃. DMF and 1,4-dioxane were attempted as the solvents (entries 13 and 14), and DMSO was the most suitable (compare entries 4, 13 and 14). We investigated different reaction temperatures (compare entries 4, 15 and 16), and room temperature was a good choice (entry 4).

Table 1 Synthesis of 5-methyl-2-phenylpyrazolo[1,5-c]quinazoline (3a) via a one-pot two-step reaction of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one (1a), hydrazine hydrochloride and acetamidine hydrochloride (2a): optimization of conditions^a

Entry	Cat.	Ligand	Base	Solvent	Temp. (°C)	Yield (%)^b
a Reaction conditions: under nitrogen atmosphere, 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one (1a) (0.25 mmol), hydrazine hydrochloride (0.375 mmol), acetamidine hydrochloride (2a) (1 mmol), catalyst (0.025 mmol), ligand (0.05 mmol), base (1.5 mmol), solvent (2 mL), reaction time (12 h for the first step; 24 h for the second step). b Isolated yield from 1a to 3a.
1	CuI	DMEDA	Cs2CO3	DMSO	rt	74
2	CuI	L-proline	Cs2CO3	DMSO	rt	58
3	CuI	pipecolinic acid	Cs2CO3	DMSO	rt	78
4	CuI	—	Cs2CO3	DMSO	rt	89
5	CuBr	—	Cs2CO3	DMSO	rt	85
6	CuCl	—	Cs2CO3	DMSO	rt	82
7	Cu2O	—	Cs2CO3	DMSO	rt	84
8	Cu(OAc)2	—	Cs2CO3	DMSO	rt	77
9	CuCl2	—	Cs2CO3	DMSO	rt	80
10	—	—	Cs2CO3	DMSO	rt	0
11	CuI	—	K2CO3	DMSO	rt	79
12	CuI	—	K3PO4	DMSO	rt	41
13	CuI	—	Cs2CO3	DMF	rt	84
14	CuI	—	Cs2CO3	dioxane	rt	37
15	CuI	—	Cs2CO3	DMSO	40	81
16	CuI	—	Cs2CO3	DMSO	60	82

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Scheme 1 (A) Coupling of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one (1a) with hydrazine hydrochloride leading to 5-(2-bromophenyl)-3-phenyl-1H-pyrazole (Ia). (B) Copper-catalyzed reaction of Ia with acetamidine hydrochloride (2a) leading to 3a.

Scheme 2 Possible mechanism for the synthesis of pyrazolo[1,5-c]quinazolines.

The substrate scope for the synthesis of pyrazolo[1,5-c]quinazoline derivatives from one-pot two-step reactions of substituted 1-(2-halophenyl)-3-alkylprop-2-yn-1-ones, hydrazine hydrochloride, and amidine hydrochlorides was investigated under the optimized conditions (10 mol% CuI as the catalyst, 6 equiv. of Cs₂CO₃ as the base in DMSO under nitrogen atmosphere). As shown in Table 2, the tested substrates afforded good to excellent yields. For the substrates 1-(2-bromophenyl)-3-alkylprop-2-yn-1-ones, the reactions performed very well at room temperature when amidines were used as the partners (see entries 1–7 and 9–22). The reaction at 80 °C provided target product 3h in 61% yield when guanidine was applied as the partner (entry 8). The substrate with a C–Cl bond, 1-(2-chlorophenyl)-3-phenylprop-2-yn-1-one, also gave the target product (3a) in 71% yield when the temperature was raised to 80 °C (entry 23). Interestingly, no extra ligand and additive were required in the reactions above, and the results showed that the pyrazole group in 5-(2-halophenyl)-3-phenyl-1H-pyrazoles (I) from the first step coupling of 1-(2-halophenyl)-3-alkylprop-2-yn-1-ones with hydrazine was of ortho substituent effect (see Schemes 1 and 2).^18a In addition, the one-pot two-step reactions could tolerate some functional groups such as ethers (entries 9–12), C–Cl bonds (entries 13–16), and cyano groups (entries 17–19).

Table 2 One-pot two-step synthesis of pyrazolo[1,5-c]quinazolines under copper-catalyzed conditions^a

Entry	1	2	3 (Yield^b)
a Reaction conditions: under nitrogen atmosphere, 1-(2-halophenyl)-3-alkylprop-2-yn-1-one (1) (0.25 mmol), hydrazine hydrochloride (0.375 mmol), amidine hydrochloride (2) (1 mmol), CuI (0.025 mmol), Cs2CO3 (1.5 mmol), DMSO (2 mL), reaction time (12 h for the first step; 24 h for the second step). Temperature (80 °C for entries 8 and 23; room temperature (∼25 °C) for the others). b Isolated yield.
1
2	1a
3	1a
4	1a
5	1a
6	1a
7	1a
8	1a
9		2a
10	1b	2c
11	1b	2d
12	1b	2e
13		2a
14	1c	2c
15	1c	2d
16	1c	2e
17		2a
18	1d	2d
19	1d	2e
20		2a
21	1e	2d
22	1e	2e
23		2a

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As shown in Scheme 1, two control experiments were performed in order to explore the one-pot two-step reaction mechanism. First, coupling of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one with hydrazine hydrochloride in the presence of Cs₂CO₃ gave 5-(2-bromophenyl)-3-phenyl-1H-pyrazole (Ia) in 89% yield (Scheme 1A), whose structure was identified by NMR and MS. The copper-catalyzed reaction of Ia with acetamidine hydrochloride (2a) afforded the target product 3a in 92% yield under the standard conditions (Scheme 1B). Therefore, a possible mechanism for the synthesis of pyrazolo[1,5-c]quinazolines was proposed in Scheme 2. Firstly, coupling of 1-(2-halophenyl)-3-alkylprop-2-yn-1-one (1) with hydrazine provides intermediate I, and N-arylation of I with amidine (2) gives II. Finally, intramolecular nucleophilic attack of the NH of pyrazole to the amidine group in II affords the target product (3) freeing ammonia.

Conclusions

We have developed a convenient and efficient one-pot two-step method for the synthesis of pyrazolo[1,5-c]quinazoline derivatives. The protocol uses readily available substituted 1-(2-halophenyl)-3-akylprop-2-yn-1-ones, hydrazine hydrochloride and amidine hydrochlorides as the starting materials, inexpensive CuI as the catalyst, and the corresponding pyrazolo[1,5-c]quinazolines were obtained in good to excellent yields. The second copper-catalyzed reactions proceeded very well under mild conditions (at room temperature for most of the reactions). The novel method provides diverse and useful N-fused heterocyclic compounds for combinatorial chemistry and medicinal chemistry.

Experimental section

General methods

All reactions were carried out under nitrogen atmosphere. Proton and carbon magnetic resonance spectra (¹H NMR and ¹³C NMR) were recorded using tetramethylsilane (TMS) in the solvent of CDCl₃ as the internal standard (¹H NMR: TMS at 0.00 ppm, CDCl₃ at 7.26 ppm; ¹³C NMR: CDCl₃ at 77.0 ppm) or tetramethylsilane (TMS) in the solvent of DMSO-d₆ as the internal standard (¹H NMR: TMS at 0.00 ppm, DMSO at 2.50 ppm; ¹³C NMR: DMSO at 40.0 ppm).

Synthesis of compounds 1a–f

Compounds 1a–f were prepared according to previous procedures.^19–21

General procedure for the synthesis of compounds 3a–v

Substituted 1-(2-halophenyl)-3-akylprop-2-yn-1-one (1) (0.25 mmol), hydrazine hydrochloride (0.375 mmol), Cs₂CO₃ (1.5 mmol, 492 mg), DMSO (2 mL) were added to a 25 ml Schlenk tube charged with a magnetic stirrer, and the mixture was stirred at 80 °C for 12 h. The resulting solution was cooled to room temperature, and then amidine hydrochloride (2) (1 mmol) and CuI (0.025 mmol, 4.8 mg) were added to the tube under nitrogen atmosphere. The mixture was stirred at room temperature or 80 °C (see Table 2 for the details) under nitrogen atmosphere for 24 h. After completion of the reaction, the resulting solution was cooled to room temperature. The solvent was removed with the aid of a rotary evaporator, and the residue was purified by column chromatography on silica gel to provide the desired product (3a–v).

5-Methyl-2-phenylpyrazolo[1,5-c]quinazoline (3a). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 57 mg (89%) using 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one (1a) as the substrate; 46 mg (71%) using 1-(2-chlorophenyl)-3-phenylprop-2-yn-1-one (1g) as the substrate. White solid, mp 129–131 °C. ¹H NMR (CDCl₃, 300 MHz) δ 8.00 (m, 3H), 7.84 (m, 1H), 7.60 (m, 1H), 7.44 (m, 4H), 7.19 (s, 1H), 3.01 (s, 3H). ¹³C NMR (CDCl₃, 75 MHz) δ 154.8, 148.6, 140.5, 139.8, 132.6, 129.7, 129.2, 128.9, 127.9, 127.1, 126.8, 123.2, 119.5, 95.5, 20.2. HR-MS (ESI) [M+H]⁺m/z calcd for C₁₇H₁₄N₃ 260.1188, found 260.1195.

5-Ethyl-2-phenylpyrazolo[1,5-c]quinazoline (3b). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 58 mg (85%). White solid, mp 86–88 °C. ¹H NMR (CDCl₃, 300 MHz) δ 8.00 (m, 2H), 7.91 (m, 2H), 7.57 (m, 1H), 7.42 (m, 4H), 7.14 (s, 1H), 3.39 (dd, 2H, J = 7.6 Hz), 1.54 (t, 3H, J = 7.6 Hz). ¹³C NMR (CDCl₃, 75 MHz) δ 154.5, 152.4, 140.5, 139.9, 132.8, 129.6, 129.1, 128.9, 128.2, 127.0, 126.8, 123.1, 119.5, 95.3, 26.4, 10.6. HR-MS (ESI) [M+H]⁺m/z calcd for C₁₈H₁₆N₃ 274.1344, found 274.1346.

2-Phenyl-5-propylpyrazolo[1,5-c]quinazoline (3c). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 66 mg (92%). White solid, mp 83–85 °C. ¹H NMR (CDCl₃, 300 MHz) δ 8.02 (m, 2H), 7.95 (m, 1H), 7.87 (m, 1H), 7.58 (m, 1H), 7.43 (m, 4H), 7.18 (s, 1H), 3.39 (t, 2H, J = 7.6 Hz), 2.07 (m, 2H), 1.13 (t, 3H, J = 7.6 Hz). ¹³C NMR (CDCl₃, 75 MHz) δ 154.5, 151.5, 140.6, 139.9, 132.8, 129.6, 129.1, 128.9, 128.2, 127.0, 126.8, 123.1, 119.5, 95.3, 34.8, 19.9, 14.2. HR-MS (ESI) [M+H]⁺m/z calcd for C₁₉H₁₈N₃ 288.1501, found 288.1507.

5-Cyclopropyl-2-phenylpyrazolo[1,5-c]quinazoline (3d). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 60 mg (84%). White solid, mp 93–95 °C. ¹H NMR (CDCl₃, 300 MHz) δ 8.03 (m, 2H), 7.93 (m, 1H), 7.72 (m, 1H), 7.43 (m, 5H), 7.19 (s, 1H), 3.31 (m, 1H), 1.45 (m, 2H), 1.24 (m, 2H). ¹³C NMR (CDCl₃, 75 MHz) δ 154.6, 152.9, 140.6, 140.1, 132.8, 129.6, 129.0, 128.9, 127.8, 126.9, 126.4, 123.1, 119.1, 95.4, 11.1, 10.3. HR-MS (ESI) [M+H]⁺m/z calcd for C₁₉H₁₆N₃ 286.1344, found 286.1345.

2,5-Diphenylpyrazolo[1,5-c]quinazoline (3e). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 75 mg (94%). White solid, mp 102–104 °C. ¹H NMR (CDCl₃, 300 MHz) δ 8.50 (m, 2H), 7.96 (m, 4H), 7.55 (m, 4H), 7.42 (m, 4H), 7.23 (s, 1H). ¹³C NMR (CDCl₃, 75 MHz) δ 154.6, 147.6, 141.9, 140.1, 132.9, 132.5, 131.0, 130.8, 129.8, 129.2, 128.9, 128.8, 128.2, 127.6, 126.9, 123.1, 119.6, 95.3. HR-MS (ESI) [M+H]⁺m/z calcd for C₂₂H₁₆N₃ 322.1344, found 322.1349.

2-Phenyl-5-p-tolylpyrazolo[1,5-c]quinazoline (3f). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 60 mg (72%). White solid, mp 142–144 °C. ¹H NMR (CDCl₃, 300 MHz) δ 8.43 (m, 2H), 7.97 (m, 4H), 7.58 (m, 1H), 7.39 (m, 6H), 7.24 (s, 1H), 2.45 (s, 3H). ¹³C NMR (CDCl₃, 75 MHz) δ 154.6, 147.6, 141.9, 141.4, 140.2, 132.6, 130.8, 130.1, 129.7, 129.1, 128.9, 128.8, 128.2, 128.7, 127.4, 126.9, 123.0, 119.5, 95.2, 21.8. HR-MS (ESI) [M+H]⁺m/z calcd for C₂₃H₁₈N₃ 336.1501, found 336.1501.

2-Phenyl-5-(pyridin-4-yl)pyrazolo[1,5-c]quinazoline (3g). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 72 mg (89%). White solid, mp 206–208 °C. ¹H NMR (CDCl₃, 300 MHz) δ 8.86 (m, 2H), 8.48 (m, 2H), 8.01 (m, 4H), 7.55 (m, 5H), 7.29 (s, 1H). ¹³C NMR (CDCl₃, 75 MHz) δ 155.1, 150.1, 144.9, 141.9, 140.1, 139.7, 132.2, 130.1, 129.4, 129.1, 128.9, 128.5, 126.8, 124.4, 123.1, 119.8, 95.2. HR-MS (ESI) [M+H]⁺m/z calcd for C₂₁H₁₅N₄ 323.1297, found 323.1296.

2-Phenylpyrazolo[1,5-c]quinazolin-5-amine (3h). Eluent: petroleum ether–ethyl acetate (4 : 1). Yield 40 mg (61%). White solid, mp 241–243 °C. ¹H NMR (DMSO-d₆, 600 MHz) δ 8.10 (m, 2H), 8.05 (m, 1H), 7.69 (s, 1H), 7.60 (s, 2H), 7.52 (m, 4H), 7.44 (m, 1H), 7.30 (m, 1H). ¹³C NMR (DMSO-d₆, 150 MHz) δ 153.8, 145.5, 142.4, 141.3, 132.7, 130.3, 129.5, 129.4, 126.9, 125.2, 124.0, 123.2, 116.2, 96.7. HR-MS (ESI) [M+H]⁺m/z calcd for C₁₆H₁₃N₄ 261.1140, found 261.1147.

9-Methoxy-5-methyl-2-phenylpyrazolo[1,5-c]quinazoline (3i). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 67 mg (93%). White solid, mp 131–133 °C. ¹H NMR (CDCl₃, 300 MHz) δ 8.02 (m, 2H), 7.74 (m, 1H), 7.44 (m, 3H), 7.25 (m, 1H), 7.17 (m, 1H), 7.13 (s, 1H), 3.90 (s, 3H), 2.96 (s, 3H). ¹³C NMR (CDCl₃, 75 MHz) δ 158.4, 154.4, 146.4, 140.3, 134.4, 132.7, 129.4, 129.1, 128.9, 126.8, 120.3, 118.9, 104.2, 95.3, 55.7, 19.9. HR-MS (ESI) [M+H]⁺m/z calcd for C₁₈H₁₆N₃O 290.1293, found 290.1294.

9-Methoxy-2-phenyl-5-propylpyrazolo[1,5-c]quinazoline (3j). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 49 mg (62%). White solid, mp 115–117 °C. ¹H NMR (CDCl₃, 300 MHz) δ 8.01 (m, 2H), 7.77 (m, 1H), 7.41 (m, 3H), 7.25 (m, 1H), 7.15 (m, 2H), 3.90 (s, 3H), 3.32 (t, 2H, J = 7.9 Hz), 2.04 (m, 2H), 1.12 (t, 3H, J = 7.2 Hz). ¹³C NMR (CDCl₃, 75 MHz) δ 158.4, 154.2, 149.4, 140.4, 134.5, 132.8, 129.6, 129.0, 128.9, 126.8, 120.3, 118.8, 104.1, 95.1, 55.7, 34.7, 19.9, 14.2. HR-MS (ESI) [M+H]⁺m/z calcd for C₂₀H₂₀N₃O 318.1606, found 318.1601.

5-Cyclopropyl-9-methoxy-2-phenylpyrazolo[1,5-c]quinazoline (3k). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 65 mg (83%). White solid, mp 123–125 °C. ¹H NMR (CDCl₃, 300 MHz) δ 8.08 (m, 2H), 7.67 (m, 1H), 7.45 (m, 3H), 7.27 (m, 1H), 7.16 (m, 2H), 3.90 (s, 3H), 1.44 (m, 2H), 1.23 (m, 2H). ¹³C NMR (CDCl₃, 75 MHz) δ 157.9, 154.2, 150.6, 140.4, 134.7, 132.9, 129.3, 129.0, 128.9, 126.8, 119.7, 118.8, 104.1, 95.2, 55.7, 10.9, 9.9. HR-MS (ESI) [M+H]⁺m/z calcd for C₂₀H₁₈N₃O 316.1450, found 316.1451.

9-Methoxy-2,5-diphenylpyrazolo[1,5-c]quinazoline (3l). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 65 mg (74%). White solid, mp 144–145 °C. ¹H NMR (CDCl₃, 300 MHz) δ 8.39 (m, 2H), 7.90 (m, 2H), 7.78 (m, 1H), 7.45 (m, 3H), 7.33 (m, 3H), 7.20 (m, 1H), 7.10 (m, 2H), 3.90 (s, 3H). ¹³C NMR (CDCl₃, 75 MHz) δ 158.9, 154.4, 145.5, 141.7, 134.8, 133.0, 132.7, 130.7, 130.6, 130.4, 129.1, 128.8, 128.2, 126.8, 120.5, 119.2, 104.0, 95.1, 55.7. HR-MS (ESI) [M+H]⁺m/z calcd for C₂₃H₁₈N₃O 352.1450, found 352.1447.

9-Chloro-5-methyl-2-phenylpyrazolo[1,5-c]quinazoline (3m). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 51 mg (69%). White solid, mp 160–162 °C. ¹H NMR (CDCl₃, 300 MHz) δ 7.97 (m, 2H), 7.85 (m, 1H), 7.72 (m, 1H), 7.44 (m, 4H), 7.11 (s, 1H), 2.96 (s, 3H). ¹³C NMR (CDCl₃, 75 MHz) δ 154.9, 148.8, 139.3, 138.2, 132.6, 132.3, 130.0, 129.4, 129.3, 128.9, 126.8, 122.5, 120.5, 95.9, 20.1. HR-MS (ESI) [M+H]⁺m/z calcd for C₁₇H₁₃ClN₃ 294.0798, found 294.0801.

9-Chloro-2-phenyl-5-propylpyrazolo[1,5-c]quinazoline (3n). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 60 mg (75%). White solid, mp 144–145 °C. ¹H NMR (CDCl₃, 300 MHz) δ 7.98 (m, 2H), 7.89 (m, 1H), 7.76 (m, 1H), 7.44 (m, 4H), 7.14 (s, 1H), 3.33 (t, 2H, J = 7.2 Hz), 2.02 (m, 2H), 1.12 (t, 3H, J = 7.6 Hz). ¹³C NMR (CDCl₃, 75 MHz) δ 154.6, 151.7, 139.4, 138.3, 132.5, 132.4, 129.9, 129.7, 129.2, 128.9, 126.8, 122.4, 120.5, 95.8, 34.7, 19.7, 14.1. HR-MS (ESI) [M+H]⁺m/z calcd for C₁₉H₁₇ClN₃ 322.1111, found 322.1111.

9-Chloro-5-cyclopropyl-2-phenylpyrazolo[1,5-c]quinazoline (3o). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 60 mg (75%). White solid, mp 150–152 °C. ¹H NMR (CDCl₃, 300 MHz) δ 7.90 (m, 2H), 7.75 (m, 1H), 7.51 (m, 1H), 7.32 (m, 4H), 7.03 (s, 1H), 3.18 (m, 1H), 1.33 (m, 2H), 1.13(m, 2H). ¹³C NMR (CDCl₃, 75 MHz) δ 154.7, 153.2, 139.4, 138.5, 132.5, 131.7, 129.9, 129.3, 129.2, 128.9, 126.8, 122.4, 119.9, 95.8, 11.0, 10.6. HR-MS (ESI) [M+H]⁺m/z calcd for C₁₉H₁₅ClN₃ 320.0955, found 320.0955.

9-Chloro-2,5-diphenylpyrazolo[1,5-c]quinazoline (3p). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 65 mg (74%). White solid, mp 159–161 °C. ¹H NMR (CDCl₃, 300 MHz) δ 8.50 (m, 2H), 7.94 (m, 3H), 7.86 (m, 1H), 7.52 (m, 4H), 7.40 (m, 3H), 7.21 (s, 1H). ¹³C NMR (CDCl₃, 75 MHz) δ 154.9, 147.6, 140.8, 138.5, 133.1, 132.5, 132.2, 131.2, 130.8, 130.3, 130.2, 129.3, 128.9, 128.2, 126.8, 122.4, 120.5, 95.8. HR-MS (ESI) [M+H]⁺m/z calcd for C₂₂H₁₅ClN₃ 356.0955, found 356.0950.

4-(5-Methylpyrazolo[1,5-c]quinazolin-2-yl)benzonitrile (3q). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 52 mg (73%). White solid, mp 236–237 °C. ¹H NMR (CDCl₃, 300 MHz) δ 8.14 (m, 2H), 8.01 (m, 1H), 7.89 (m, 1H), 7.75 (m, 2H), 7.65 (m, 1H), 7.56 (m, 1H), 7.28 (s, 1H), 3.03 (s, 3H). ¹³C NMR (CDCl₃, 75 MHz) δ 152.6, 148.4, 140.9, 139.8, 137.0, 132.7, 130.1, 128.2, 127.5, 127.2, 123.2, 119.4, 118.9, 112.5, 95.9, 20.1. HR-MS (ESI) [M+H]⁺m/z calcd for C₁₈H₁₃N₄ 285.1140, found 285.1143.

4-(5-Cyclopropylpyrazolo[1,5-c]quinazolin-2-yl)benzonitrile (3r). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 55 mg (71%). White solid, mp 232–234 °C. ¹H NMR (CDCl₃, 300 MHz) δ 8.16 (m, 2H), 8.00 (m, 1H), 7.78 (m, 3H), 7.61 (m, 1H), 7.50 (m, 1H), 7.31 (s, 1H), 3.31 (m, 1H), 1.50 (m, 2H), 1.27 (m, 2H). ¹³C NMR (CDCl₃, 75 MHz) δ 152.7, 152.4, 141.0, 140.0, 137.2, 132.7, 130.0, 128.0, 127.2, 126.7, 123.1, 118.9, 118.8, 112.3, 95.7, 10.9, 10.5. HR-MS (ESI) [M+H]⁺m/z calcd for C₂₀H₁₅N₄ 311.1297, found 311.1306.

4-(5-Phenylpyrazolo[1,5-c]quinazolin-2-yl)benzonitrile (3s). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 64 mg (74%). White solid, mp 229–231 °C. ¹H NMR (CDCl₃, 300 MHz) δ 8.47 (m, 2H), 8.05 (m, 4H), 7.68 (m, 3H), 7.59 (m, 4H), 7.34 (s, 1H). ¹³C NMR (CDCl₃, 75 MHz) δ 152.5, 147.4, 142.3, 140.1, 136.9, 132.7, 132.5, 131.2, 130.6, 130.3, 129.0, 128.3, 127.9, 127.2, 126.7, 123.0, 119.4, 118.9, 112.5, 95.7. HR-MS (ESI) [M+H]⁺m/z calcd for C₂₃H₁₅N₄ 347.1297, found 347.1292.

2-n-Hexyl-5-methylpyrazolo[1,5-c]quinazoline (3t). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 50 mg (75%). Yellow oil. ¹H NMR (CDCl₃, 300 MHz) δ 7.91 (m, 1H), 7.82 (m, 1H), 7.57 (m, 1H), 7.46 (m, 1H), 6.76 (s, 1H), 2.96 (s, 3H), 2.87 (t, 2H, J = 7.6 Hz), 1.78 (m, 2H), 1.35 (m, 6H), 0.89 (t, 3H, J = 7.2 Hz). ¹³C NMR (CDCl₃, 75 MHz) δ 158.1, 148.3, 139.9, 139.8, 129.4, 127.8, 126.8, 123.1, 119.5, 97.3, 31.7, 29.7, 29.2, 28.8, 22.7, 20.3, 14.2. HR-MS (ESI) [M+H]⁺m/z calcd for C₁₇H₂₂N₃ 268.1814, found 268.1819.

5-Cyclopropyl-2-n-hexylpyrazolo[1,5-c]quinazoline (3u). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 47 mg (64%). Yellow oil. ¹H NMR (CDCl₃, 300 MHz) δ 7.90 (m, 1H), 7.73 (m, 1H), 7.52 (m, 1H), 7.42 (m, 1H), 6.77 (s, 1H), 3.18 (m, 1H), 2.89 (t, 2H, J = 7.9 Hz), 1.80 (m, 2H), 1.40 (m, 8H), 1.20 (m, 2H), 0.89 (t, 3H, J = 7.2 Hz). ¹³C NMR (CDCl₃, 75 MHz) δ 157.9, 152.6, 140.0, 129.3, 127.6, 126.1, 123.0, 118.9, 97.1, 31.7, 29.7, 29.3, 28.9, 22.7, 14.2, 11.1, 10.1. HR-MS (ESI) [M+H]⁺m/z calcd for C₁₉H₂₄N₃ 294.1970, found 294.1971.

2-n-Hexyl-5-phenylpyrazolo[1,5-c]quinazoline (3v). Eluent: petroleum ether–ethyl acetate (5 : 1). Yield 49 mg (60%). Yellow oil. ¹H NMR (CDCl₃, 300 MHz) δ 8.41 (m, 2H), 7.98 (m, 2H), 7.54 (m, 5H), 6.84 (s, 1H), 2.87 (t, 2H, J = 7.6 Hz), 1.77 (m, 2H), 1.35 (m, 6H), 0.89 (t, 3H, J = 6.9 Hz). ¹³C NMR (CDCl₃, 75 MHz) δ 158.2, 147.6, 141.3, 140.1, 133.1, 130.9, 130.5, 129.6, 128.7, 128.2, 127.4, 123.0, 119.6, 97.2, 31.7, 29.5, 29.3, 28.8, 22.7, 14.2. HR-MS (ESI) [M+H]⁺m/z calcd for C₂₂H₂₄N₃ 330.1970, found 330.1972.

5-(2-Bromophenyl)-3-phenyl-1H-pyrazole (Ia). Eluent: petroleum ether–ethyl acetate (3 : 1). Yield 66 mg (89%). Light yellow solid. ¹H NMR (CDCl₃, 300 MHz) δ 7.65 (m, 4H), 7.31 (m, 5H), 6.94 (s, 1H). ¹³C NMR (CDCl₃, 75 MHz) δ133.9, 131.0, 129.8, 128.9, 128.3, 127.7, 125.8, 121.8, 103.8. ESIMS [M+H]⁺m/z 299.2, 301.2, [M+Na]⁺m/z 322.0, 323.0.

Acknowledgements

The authors wish to thank the National Natural Science Foundation of China (Grant Nos. 20972083 and 21172128), and the Ministry of Science and Technology of China (Grant No. 2012CB722605) for financial support.

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Footnote

† Electronic Supplementary Information (ESI) available: ¹H and ¹³C NMR spectra of compounds 3a–v and Ia. See DOI: 10.1039/c2ra21929h

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