Copper-catalyzed aerobic oxidative decarboxylative amination of arylacetic acids: a facile access to 2-arylquinazolines

Abstract

An efficient copper-catalyzed oxidative decarboxylative amination of arylacetic acids with 2-aminobenzoketones and ammonium acetate under an oxygen atmosphere was first developed. This reaction represents a novel avenue for 2-arylquinazolines in good to excellent yields via multiple C–N bond formations. This protocol features inexpensive copper as the catalyst, molecular oxygen as the sole oxidant, H₂O and CO₂ as wastes, and a broad substrate scope.

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Introduction

Quinazolines are important structural units found in many natural products and pharmaceuticals such as lapatinib, prazosin, Iressa, erlotinib and linagliptin (Fig. 1).¹ Due to their good biological activities, recently, a variety of substrates, such as 2-aminobenzonitriles or anthranilic acids,² 2-halobenzaldehydes,³ 2-halobenzylamines,⁴ 2-aminobenzylamines,⁵N-arylamidines⁶ and 2-aminobenzoketones⁷ have been used as raw materials for the synthesis of 2-arylquinazolines. However, these methods usually required the use of either strongly acidic (or basic) conditions or excess peroxide reagents. Therefore, the development of more environmentally friendly methods remains highly desirable.

Fig. 1 Quinazolines as core structures in drugs.

In the past decades, transition-metal-catalyzed decarboxylative couplings have emerged as important strategies for direct C–X bond formations because of atom and step economical advantages.⁸ Recently, the decarboxylative reactions involving the cleavage of C(sp³)–COOH bonds were reported for the construction of C–C,⁹ C–F(Cl),¹⁰ C–O,¹¹ C–N,¹² C–P¹³ and C–S.¹⁴ More recently, arylacetic acids as cheap and available substrates were employed for single C–N bond formation via oxidative decarboxylations (Scheme 1).¹⁵ To the best of our knowledge, the construction of multiple C–N bonds with arylacetic acids as substrates has rarely been reported. Herein, we report a method for the synthesis of quinazolines via copper-catalyzed oxidative decarboxylative amination of arylacetic acids. Two C–N bonds were formed in a one-pot reaction under oxygen conditions.

Scheme 1 New strategies for C–N formation through oxidative decarboxylations of arylacetic acids.

Results and discussion

Initially, 2-aminobenzophenone (1a) and 4-chlorophenylacetic acid (2a) were chosen as model substrates to optimize the reaction conditions. As depicted in Table 1, the catalyst, oxidant, nitrogen source and solvent obviously affected the efficiency of this reaction. First, the reaction of 1a (0.2 mmol), 2a (2.0 equiv.) and ammonium acetate (2.0 equiv.) in DMSO (1 mL) at 120 °C for 20 h using copper acetate (20 mol%) as catalyst and oxygen as oxidant, gave 2-(4-chlorophenyl)-4-phenylquinazoline (3aa) in 78% isolated yield (Table 1, entry 1). Among various solvents employed, NMP gave the highest 97% yield (Table 1, entries 2–4). When other nitrogen sources such as ammonia (25% in water) and ammonium chloride were used instead of ammonium acetate, no better result was obtained (Table 1, entries 5 and 6). Expectedly, in the absence of nitrogen source, no desired product 3aa was detected (Table 1, entry 7). Subsequently, examination of various peroxides, such as tert-butyl hydroperoxide (TBHP, 70% in water), di-tert-butylperoxide (DTBP) or air, didn't obtain better results (Table 1, entries 8–10). However, none of 3aa was obtained under nitrogen atmosphere, which indicated that molecular oxygen is essential for this reaction (Table 1, entry 11). In addition, when various copper catalysts, such as Cu(OTf)₂, CuBr₂, CuI and CuBr, were used in this reaction, CuBr₂ gave the same yield with Cu(OAc)₂ and other copper catalysts gave lower yields than Cu(OAc)₂ (Table 1, entries 12–15). In the absence of copper catalyst, the reaction did not smoothly proceed (Table 1, entry 16). Thus, an optimal set of conditions are determined as described in entry 3.

Table 1 Optimization of reaction conditions^a

Entry	Cat	[N]	[O]	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [N] (0.4 mmol), catalyst (0.04 mmol), solvent (1 mL), 120 °C, 20 h. b Isolated yield. c 4 equiv. of peroxide reagent was used under N2.
1	Cu(OAc)2	NH4OAc	O2	DMSO	78
2	Cu(OAc)2	NH4OAc	O2	DMF	85
3	Cu(OAc)2	NH4OAc	O2	NMP	97
4	Cu(OAc)2	NH4OAc	O2	CH3CN	27
5	Cu(OAc)2	NH3(aq)	O2	NMP	85
6	Cu(OAc)2	NH4Cl	O2	NMP	35
7	Cu(OAc)2		O2	NMP	0
8	Cu(OAc)2	NH4OAc	TBHP^c	NMP	40
9	Cu(OAc)2	NH4OAc	DTBP^c	NMP	41
10	Cu(OAc)2	NH4OAc	Air	NMP	78
11	Cu(OAc)2	NH4OAc	N2	NMP	Trace
12	Cu(OTf)2	NH4OAc	O2	NMP	96
13	CuBr2	NH4OAc	O2	NMP	97
14	CuI	NH4OAc	O2	NMP	77
15	CuBr	NH4OAc	O2	NMP	78
16		NH4OAc	O2	NMP	0

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Under the optimal reaction conditions, we investigated the scope of various arylacetic acids 2a–2o for the synthesis of quinazolines (Table 2). First, when a variety of substituted phenylacetic acids 2a–2m were employed in this reaction, the corresponding products 3aa–3am could be obtained in 17–99% yields (Table 2, entries 1–13). It is noteworthy that phenylacetic acids bearing electron-withdrawing groups (4-CF₃, 4-F or 4-Cl) gave the desired products in higher yields than electron-donating groups (4-Me or 4-OMe) on the phenyl ring (Table 2, entries 1, 3, 7, 10, and 13). Moreover, the position of the substituents on the phenyl ring had some effect on yields (Table 2, entries 1, 5–6 and 10–12). ortho-Substituted substrates usually gave lower yields of the products compared to meta- and para-substituted substrates, probably because of steric hindrance. In addition, 1-naphthylacetic acid and 2-thienyl acetic acid also gave the corresponding products in 65% and 80% yields, respectively (Table 2, entries 14 and 15).

Table 2 The scope of various arylacetic acids^a

Entry	Ar		Product	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), NH4OAc (0.4 mmol), Cu(OAc)2 (0.04 mmol), NMP (1 mL), O2 (1 atm), 120 °C, 20 h. b Isolated yield.
1	4-Cl-Ph	2a	3aa	97
2	Ph	2b	3ab	88
3	4-F-Ph	2c	3ac	95
4	4-Br-Ph	2d	3ad	82
5	3-Cl-Ph	2e	3ae	97
6	2-Cl-Ph	2f	3af	93
7	4-CF3-Ph	2g	3ag	99
8	4-CN-Ph	2h	3ah	75
9	4-NO2-Ph	2i	3ai	17
10	4-Me-Ph	2j	3aj	89
11	3-Me-Ph	2k	3ak	85
12	2-Me-Ph	2l	3al	74
13	4-OMe-Ph	2m	3am	52
14	1-Naphthyl	2n	3an	65
15	2-Thienyl	2o	3ao	80

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Subsequently, we investigated the scope of ortho-carbonyl-substituted anilines under the optimized reaction conditions (Table 3). First, the reaction of 1b–1g with an aryl group as R¹ substituent and phenylacetic acid (2b) gave the corresponding products 3bb–3gb in 92–97% yields (Table 3, entries 1–6). Moreover, substrates 1h–1n with an aliphatic group as R¹ substituent also gave the desired products 3hb–3nb in 10–90% yields. It is noteworthy that substrates 1i and 1j gave a unexpected 2-phenylquinazoline (3ib′ or 3jb′) by copper-catalyzed C–C bond cleavage (Table 3, entries 8 and 9). Finally, when 2-amino-5-chlorobenzophenone (1o) and 2-amino-5-nitrobenzophenone (1p) were employed as the substrates, the desired products 3ob and 3pb were obtained in 80% and 33% yields, respectively (Table 3, entries 14 and 15). Notably, F, Cl, Br, CN and NO₂ group of the substrates remained intact during all the reactions, providing an additional handle for further derivatization.

Table 3 The scope of various amines ortho-carbonyl anilines^a

Entry	R^1	R^2		Product	Yield^b (%)
a Reaction conditions: 1 (0.2 mmol), 2b (0.4 mmol), NH4OAc (0.4 mmol), Cu(OAc)2 (0.04 mmol), NMP (1 mL), O2 (1 atm), 120 °C, 20 h. b Isolated yield. c Isolated yield of 2-phenylquinazoline was given in parenthesis.
1	4-F-Ph	H	1b	3bb	96
2	4-Cl-Ph	H	1c	3cb	93
3	4-Br-Ph	H	1b	3db	94
4	3,5-Di-F-Ph	H	1e	3eb	97
5	4-Me-Ph	H	1f	3fb	92
6	2-Naphthyl	H	1g	3gb	93
7	Me	H	1h	3hb	30
8	n-Bu	H	1i	3ib(3ib′)	15(30)^c
9	Hexadecyl	H	1j	3jb(3jb′)	10(35)^c
10	i-Pr	H	1k	3kb	85
11	t-Bu	H	1l	3lb	80
12	Cyclopropyl	H	1m	3mb	90
13	Cyclopentyl	H	1n	3nb	85
14	Ph	5-Cl	1o	3ob	80
15	Ph	5-NO2	1p	3pb	33

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To gain an insight into the reaction mechanism, several control experiments were conducted (Scheme 2). Firstly, we observed that the reaction was completely inhibited in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as a radical scavenger (Scheme 2a). This observation implied that the reaction might proceed via a radical pathway. When phenylacetic acid was performed under standard conditions, benzaldehyde was obtained in 35% yield (Scheme 2b). Then when 1a and benzaldehyde, instead of 2b were carried out under standard conditions, 3ab was obtained in 95% yield. However, when other possible intermediates, such as toluene, benzoic acid, benzonitrile, 2-oxo-2-phenylacetic acid and benzamide were tested, 3ab was not detected (Scheme 2c). These results indicated that benzaldehyde may be the intermediate of this reaction.

Scheme 2 Control experiments.

On the basis of results described above and previous reports,¹⁵ a plausible mechanism is proposed for the formation of the quinazolines (Scheme 3). Initially, the coordination of 2b to Cu(OAc)₂ and subsequent ligand exchange generates a copper complex A. Then B was formed though decarboxylation of A. Subsequently, oxygen insertion to B gives a copper species C, which is transformed into a copper species D and the intermediate benzaldehyde via β–H elimination. D in the presence of HOAc regenerates Cu(OAc)₂. Then the intermediate benzaldehyde and 4 which was generated by condensation of 1a and nitrogen source, give the intermediate 5. Finally, the product 3ab is obtained via a tandem intramolecular nucleophilic addition and condensation–oxidative aromatization 5 in the presence of Cu(II)/O₂.^15a

Scheme 3 A proposed mechanism.

Conclusions

In summary, we have developed a copper-catalyzed aerobic decarboxylative amination of arylacetic acids with 2-aminobenzoketones and ammonium acetate, affording 2-arylquinazolines in moderate to excellent yields. Multiple C–N bonds are formed in a one-pot process via C–H/C–C cleavage. Compared with previous reports, this novel protocol is distinguished by (1) cheap copper catalysis, (2) operational simplicity, (3) molecular oxygen as the sole oxidant (4) H₂O and CO₂ as wastes, and (5) a broad substrate scope. Further studies are ongoing to expand the synthetic utility of this versatile catalytic system.

Experimental

General information

Unless otherwise indicated, all commercial reagents and solvents were used without additional purification. Chemical shifts (in ppm) of ¹H NMR spectra were referenced to tetramethylsilane (δ = 0 ppm) in CDCl₃ as an internal standard. ¹³C NMR spectra were calibrated with CDCl₃ (δ = 77.16 ppm). HRMS (EI) was recorded on a TOF mass analyzer.

General procedure for the synthesis of 2-arylquinazolines

Substrate 1 (0.2 mmol), 2 (0.4 mmol), NH₄OAc (30.8 mg, 0.4 mmol), Cu(OAc)₂ (8 mg, 0.04 mmol) and NMP (1.0 mL) were successively added to a 10 mL of reaction tube with three-way valve. After three times of oxygen displacement, the mixture was stirred using oxygen balloon at 120 °C as monitored by TLC. The solution was then cooled to r.t. and quenched by saturated NaHCO₃ solution. The aqueous layers was extracted with EtOAc (3 × 10 mL), the combined organic layers were dried over Na₂SO₄, filtered, and evaporated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether : ethyl acetate = 15 : 1) to afford the desired 2-arylquinazolines 3.

Characterization data for the products

2-(4-Chlorophenyl)-4-phenylquinazoline (3aa)⁷. Yield: 97% (61.4 mg); white solid; mp: 190–192 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.65 (d, J = 8.4 Hz, 2H), 8.18–8.12 (m, 2H), 7.92–7.85 (m, 3H), 7.64–7.54 (m, 4H), 7.48 (d, J = 8.4 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 168.7, 159.3, 151.9, 137.6, 136.9, 136.7, 133.9, 130.3, 130.21, 130.18, 129.2, 128.9, 128.7, 127.4, 127.2, 121.8.

2,4-Diphenylquinazoline (3ab)⁷. Yield: 88% (49.6 mg); light yellow solid; mp: 117–119 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.72–8.68 (m, 2H), 8.18–8.10 (m, 2H), 7.90–7.85 (m, 3H), 7.62–7.56 (m, 3H), 7.55–7.47 (m, 4H); ¹³C NMR (100 MHz, CDCl₃): δ 168.5, 160.3, 152.0, 138.2, 137.8, 133.7, 130.7, 130.3, 130.1, 129.2, 128.8, 128.7, 127.15, 127.14, 121.8.

2-(4-Fluorophenyl)-4-phenylquinazoline (3ac)⁷. Yield: 95% (57 mg); white solid; mp: 153–155 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.73–8.67 (m, 2H), 8.15–8.10 (m, 2H), 7.91–7.85 (m, 3H), 7.62–7.58 (m, 3H), 7.57–7.52 (m, 1H), 7.23–7.16 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 168.6, 164.8 (d, J_C–F = 248.6 Hz), 159.4, 152.0, 137.7, 134.5 (d, J_C–F = 2.8 Hz), 133.8, 130.9 (d, J_C–F = 8.6 Hz), 130.3, 130.1, 129.2, 128.7, 127.2, 126.8, 121.7, 115.6 (d, J_C–F = 21.3 Hz).

2-(4-Bromophenyl)-4-phenylquinazoline (3ad)⁷. Yield: 82% (59.2 mg); white solid; mp: 192–194 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.60–8.56 (m, 2H), 8.16–8.11 (m, 2H), 7.92–7.86 (m, 3H), 7.67–7.50 (m, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 168.6, 159.4, 152.0, 137.6, 137.2, 133.9, 131.8, 130.4, 130.3, 130.2, 129.2, 128.7, 127.4, 127.2, 125.5, 121.9.

2-(3-Chlorophenyl)-4-phenylquinazoline (3ae)⁷. Yield: 97% (61.4 mg); white solid; mp: 116–118 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.70 (s, 1H), 8.61–8.58 (m, 1H), 8.19–8.12 (m, 2H), 7.93–7.86 (m, 3H), 7.64–7.55 (m, 4H), 7.49–7.43 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 168.7, 159.0, 151.9, 137.6, 134.8, 133.9, 130.6, 130.3, 130.2, 129.9, 129.3, 128.8, 128.7, 127.6, 127.2, 126.9, 122.0.

2-(2-Chlorophenyl)-4-phenylquinazoline (3af)⁷. Yield: 93% (58.8 mg); white solid; mp: 93–95 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.27–8.19 (m, 2H), 7.98–7.86 (m, 4H), 7.67–7.62 (m, 1H), 7.60–7.52 (m, 4H), 7.44–7.37 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 168.7, 161.2, 151.2, 138.2, 137.2, 134.2, 133.2, 132.0, 130.7, 130.5, 130.4, 130.3, 128.9, 128.8, 128.1, 127.2, 127.0, 121.5.

4-Phenyl-2-(4-(trifluoromethyl)phenyl)quinazoline (3ag)⁷. Yield: 99% (69.3 mg); white solid; mp: 124–126 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.82 (d, J = 8.0 Hz, 2H), 8.21 (d, J = 8.4 Hz, 1H), 8.15 (dd, J₁ = 8.4 Hz, J₂ = 0.8 Hz, 1H), 7.95–7.87 (m, 3H), 7.77 (d, J = 8.4 Hz, 2H), 7.55–7.47 (m, 4H); ¹³C NMR (100 MHz, CDCl₃): δ 168.9, 158.8, 151.7, 141.4, 137.5, 134.1, 132.2 (q, J_C–F = 32 Hz), 130.3, 129.2, 129.1, 128.8, 127.8, 127.3, 125.7, 125.6 (q, J_C–F = 3.6 Hz), 124.4 (q, J_C–F = 270.6 Hz), 122.0.

4-(4-Phenylquinazolin-2-yl)benzonitrile (3ah)^6b. Yield: 75% (46.0 mg); white solid; mp: 197–199 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.81 (dd, J₁ = 6.8 Hz, J₂ = 2.0 Hz, 2H), 8.19–8.15 (m, 2H), 7.96–7.91 (m, 1H), 7.89–7.86 (m, 2H), 7.82–7.78 (m, 2H), 7.64–7.59 (m, 4H); ¹³C NMR (100 MHz, CDCl₃): δ 168.8, 158.4, 151.9, 142.5, 137.4, 134.1, 132.4, 130.34, 130.29, 129.5, 129.2, 128.8, 128.1, 127.3, 122.1, 119.1, 113.9.

2-(4-Nitrophenyl)-4-phenylquinazoline (3ai)⁷. White solid (11.0 mg, 17%); mp: 195–197 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.90 (d, J = 8.8 Hz, 2H), 8.37 (d, J = 9.2 Hz, 2H), 8.23–8.17 (m, 2H), 7.99–7.93 (m, 1H), 7.91–7.88 (m, 2H), 7.67–7.61 (m, 4H); ¹³C NMR (100 MHz, CDCl₃): δ 169.0, 158.1, 151.9, 149.4, 144.2, 137.4, 134.2, 130.4, 130.3, 129.7, 129.5, 128.8, 128.2, 127.3, 123.8, 122.2.

4-Phenyl-2-(p-tolyl)quinazoline (3aj)⁷. Yield: 89% (52.7 mg); white solid; mp: 166–168 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.59 (d, J = 8.0 Hz, 2H), 8.21 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.95–7.85 (m, 3H), 7.62–7.58 (m, 3H), 7.55–7.50 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 2.44 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 168.5, 160.4, 152.0, 141.0, 137.9, 135.5, 133.7, 130.3, 130.1, 129.5, 129.1, 128.8, 128.7, 127.2, 127.0, 121.7, 21.7.

4-Phenyl-2-(m-tolyl)quinazoline (3ak)⁷. Yield: 85% (50.3 mg); white solid; mp: 115–117 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.21–8.15 (m, 2H), 8.00–7.97 (m, 1H), 7.94–7.89 (m, 1H), 7.88–7.84 (m, 2H), 7.62–7.56 (m, 4H), 7.37–7.32 (m, 3H), 2.67 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 168.3, 163.4, 151.6, 138.8, 137.57, 137.55, 133.8, 131.4, 130.9, 130.3, 130.1, 129.4, 129.1, 128.7, 127.5, 127.1, 126.1, 121.1, 21.4.

4-Phenyl-2-(o-tolyl)quinazoline (3al)⁷. Yield: 74% (43.8 mg); white solid; mp: 72–74 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.22–8.15 (m, 2H), 7.99–7.97 (m, 1H), 7.94–7.89 (m, 1H), 7.88–7.84 (m, 2H), 7.62–7.56 (m, 4H), 7.37–7.33 (m, 3H), 2.67 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 168.3, 163.4, 151.5, 138.7, 137.54, 137.52, 133.9, 131.4, 130.9, 130.3, 130.1, 129.5, 129.0, 128.7, 127.5, 127.1, 126.1, 121.1, 21.4.

2-(4-Methoxyphenyl)-4-phenylquinazoline (3am)⁷. Yield: 52% (32.4 mg); white solid; mp: 158–160 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.68–8.65 (m, 2H), 8.14 (d, J = 8.4 Hz, 1H), 8.09 (dd, J₁ = 8.4 Hz, J₂ = 0.8 Hz, 1H), 7.90–7.84 (m, 3H), 7.62–7.58 (m, 3H), 7.53–7.50 (m, 1H), 3.89 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 168.5, 162.0, 160.1, 151.8, 137.8, 133.7, 130.7, 130.6, 130.3, 130.1, 128.8, 128.7, 127.2, 126.8, 121.1, 114.0, 55.5.

2-(Naphthalen-1-yl)-4-phenylquinazoline (3an)⁷. Yield: 65% (43.2 mg); light yellow solid; mp: 171–173 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.76 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.27 (dd, J₁ = 7.6 Hz, J₂ = 0.8 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.01–7.88 (m, 5H), 7.68–7.50 (m, 7H); ¹³C NMR (100 MHz, CDCl₃): δ 169.1, 162.6, 151.1, 137.4, 134.33, 134.30, 131.4, 130.8, 130.4, 130.3, 130.2, 128.8, 128.7, 128.6, 127.9, 127.3, 127.0, 126.1, 126.0, 125.5, 125.0, 121.4.

4-Phenyl-2-(thiophen-2-yl)quinazoline (3ao). Yield: 80% (46.0 mg); light yellow solid; mp: 151–153 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.25–8.23 (m, 1H), 8.12–8.06 (m, 2H), 7.88–7.83 (m, 3H), 7.61–7.57 (m, 3H), 7.53–7.48 (m, 2H), 7.20–7.17 (m, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 168.7, 157.2, 151.7, 144.1, 137.3, 134.0, 130.3, 130.22, 130.15, 129.7, 128.7, 128.4, 127.3, 126.9, 121.6; HRMS (EI): calcd for C₁₈H₁₂N₂S [M]⁺ 288.0721, found 288.0710.

4-(4-Fluorophenyl)-2-phenylquinazoline (3bb)⁷. Yield: 96% (57.6 mg); white solid; mp: 144–146 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.70–8.66 (m, 2H), 8.18 (d, J = 8.4 Hz, 1H), 8.11–8.08 (m, 1H), 7.93–7.87 (m, 3H), 7.59–7.50 (m, 4H), 7.32–7.27 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 167.4, 164.1 (d, J = 248.8 Hz), 160.3, 152.1, 138.1, 133.9 (d, J = 3.5 Hz), 133.8, 132.4 (d, J = 8.3 Hz), 130.8, 129.4, 128.8, 128.7, 127.3, 126.9, 121.7, 115.8 (d, J = 21.7 Hz).

4-(4-Chlorophenyl)-2-phenylquinazoline (3cb). Yield: 93% (58.8 mg); white solid; mp: 151–153 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.69–8.66 (m, 2H), 8.16 (d, J = 8.4 Hz, 1H), 8.16 (d, J₁ = 8.4 Hz, J₂ = 0.8 Hz, 1H), 7.91–7.81 (m, 3H), 7.59–7.49 (m, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 167.2, 160.3, 152.1, 138.1, 136.4, 136.2, 133.9, 131.7, 130.8, 129.4, 129.0, 128.8, 128.7, 127.4, 126.7, 121.6; HRMS (EI): calcd for C₂₀H₁₃ClN₂ [M]⁺ 316.0767, found 316.0742.

4-(4-Bromophenyl)-2-phenylquinazoline (3db)⁷. Yield: 94% (67.8 mg); white solid; mp: 154–156 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.69–8.66 (m, 2H), 8.16 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.92–7.87 (m, 1H), 7.79–7.72 (m, 4H), 7.58–7.50 (m, 4H); ¹³C NMR (100 MHz, CDCl₃): δ 167.3, 160.3, 152.1, 138.0, 136.6, 133.9, 131.94, 131.88, 130.8, 129.4, 128.8, 128.7, 127.4, 126.7, 124.8, 121.5.

4-(3,5-Difluorophenyl)-2-phenylquinazoline (3eb). Yield: 97% (61.7 mg); white solid; mp: 161–163 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.69–8.65 (m, 2H), 8.19 (d, J = 8.4 Hz, 1H), 8.08 (dd, J₁ = 8.4 Hz, J₂ = 0.8 Hz, 1H), 7.95–7.90 (m, 1H), 7.62–7.51 (m, 4H), 7.44–7.41 (m, 2H), 7.08–7.02 (m, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 165.9, 163.2 (dd, J_C–F1 = 248.2 Hz, J_C–F2 = 12.4 Hz), 160.3, 152.2, 140.8 (t, J_C–F = 9.2 Hz), 137.8, 134.2, 131.0, 129.5, 128.8, 127.7, 126.3, 121.3, 113.4 (dd, J_C–F1 = 18.9 Hz, J_C–F2 = 7.4 Hz), 105.5 (d, J = 25.0 Hz); HRMS (EI): calcd for C₂₀H₁₂F₂N₂ [M]⁺ 318.0969, found 318.0949.

2-Phenyl-4-(p-tolyl)quinazoline (3fb)⁷. Yield: 92% (54.5 mg); white solid; mp: 128–130 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.71–8.68 (m, 2H), 8.16–8.11 (m, 2H), 7.89–7.81 (m, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.55–7.48 (m, 4H), 7.38 (d, J = 8.0 Hz, 2H), 2.47 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 168.4, 160.3, 152.0, 140.3, 138.3, 135.0, 133.6, 130.6, 130.3, 129.4, 129.1, 128.7, 128.6, 127.2, 127.0, 121.8, 21.6.

4-(Naphthalen-2-yl)-2-phenylquinazoline (3gb). Yield: 93% (61.7 mg); white solid; mp: 164–166 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.75–8.71 (m, 2H), 8.34 (s, 1H), 8.22–8.16 (m, 2H), 8.07–7.94 (m, 4H), 7.92–7.86 (m, 4H), 7.62–7.50 (m, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 168.5, 160.3, 152.0, 138.2, 135.1, 134.1, 133.8, 133.0, 130.8, 130.5, 129.2, 128.88, 128.86, 128.7, 128.5, 128.0, 127.43, 127.36, 127.3, 127.2, 126.8, 122.0; HRMS (EI): calcd for C₂₄H₁₆N₂ [M]⁺ 332.1313, found 332.1299.

4-Methyl-2-phenylquinazoline (3hb)⁷. Yield: 30% (13.2 mg); light yellow solid; mp: 88–90 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.64–8.61 (m, 2H), 8.12–8.06 (m, 2H), 7.88–7.85 (m, 1H), 7.59–7.48 (m, 4H), 3.01 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 168.6, 160.2, 152.2, 138.2, 133.8, 130.6, 129.2, 128.8, 128.7, 127.1, 125.1, 123.1, 22.2.

4-Butyl-2-phenylquinazoline (3ib)⁷. Yield: 15% (7.8 mg); light yellow solid; mp: 45–47 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.66–8.61 (m, 2H), 8.12–8.06 (m, 2H), 7.85–7.81 (m, 1H), 7.57–7.48 (m, 4H), 3.32 (t, J = 7.6 Hz, 2H), 2.01–1.92 (m, 2H), 1.54 (sext, J = 7.6 Hz, 2H), 1.02 (t, J = 7.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 171.7, 160.2, 150.8, 138.6, 133.4, 130.5, 129.5, 128.7, 128.6, 126.8, 124.7, 122.7, 34.4, 30.8, 22.9, 14.1.

2-Phenylquinazoline (3ib′)⁷. Yield: 30% (12.3 mg); light yellow solid; mp: 97–99 °C; ¹H NMR (400 MHz, CDCl₃): δ 9.47 (s, 1H), 8.64–8.61 (m, 2H), 8.10 (dd, J₁ = 8.4 Hz, J₂ = 0.4 Hz, 1H), 7.94–7.88 (m, 2H), 7.64–7.59 (m, 1H), 7.56–7.50 (m, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 161.2, 160.6, 150.9, 138.2, 134.3, 130.8, 128.80, 128.79, 128.7, 127.4, 127.3, 123.8.

4-Hexadecyl-2-phenylquinazoline (3jb)⁷. Yield: 10% (8.6 mg); light yellow solid; mp: 66–68 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.66–8.61 (m, 2H), 8.13–8.08 (m, 2H), 7.87–7.82 (m, 1H), 7.59–7.48 (m, 4H), 3.33 (t, J = 7.6 Hz, 2H), 1.97 (quint, J = 7.6 Hz, 2H), 1.54–1.47 (m, 2H), 1.44–1.36 (m, 2H), 1.27–1.20 (m, 22H), 0.88 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 171.8, 160.2, 150.8, 138.5, 133.5, 130.5, 129.5, 128.8, 128.7, 126.9, 124.8, 122.7, 34.8, 32.1, 29.85, 29.83, 29.75, 29.68, 29.5, 28.8, 22.8, 14.3.

2-Phenylquinazoline (3jb′)⁷. Yield: 35% (14.4 mg); light yellow solid; mp: 97–99 °C; ¹H NMR (400 MHz, CDCl₃): δ 9.47 (s, 1H), 8.64–8.61 (m, 2H), 8.10 (dd, J₁ = 8.4 Hz, J₂ = 0.4 Hz, 1H), 7.94–7.88 (m, 2H), 7.64–7.59 (m, 1H), 7.56–7.50 (m, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 161.2, 160.6, 150.9, 138.2, 134.3, 130.8, 128.80, 128.79, 128.7, 127.4, 127.3, 123.8.

4-Isopropyl-2-phenylquinazoline (3kb)⁷. Yield: 85% (42.1 mg); light yellow solid; mp: 64–66 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.71–8.68 (m, 2H), 8.14–8.09 (m, 2H), 7.84–7.79 (m, 1H), 7.56–7.48 (m, 4H), 3.93 (heptet, J = 7.2 Hz, 1H), 1.50 (d, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 175.8, 160.0, 150.8, 138.5, 133.3, 130.6, 129.5, 128.6, 128.6, 126.8, 124.2, 121.8, 31.4, 21.9.

4-(tert-Butyl)-2-phenylquinazoline (3lb)⁷. Yield: 80% (41.9 mg); light yellow solid; mp: 70–72 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.70–8.67 (m, 2H), 8.46–8.43 (m, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.83–7.78 (m, 1H), 7.56–7.48 (m, 4H), 1.72 (s, 9H); ¹³C NMR (100 MHz, CDCl₃): δ 176.6, 159.0, 152.1, 138.6, 132.5, 130.5, 130.4, 128.7, 128.6, 126.7, 125.8, 121.7, 40.7, 30.8.

4-Cyclopropyl-2-phenylquinazoline (3mb)⁷. Yield: 90% (44.3 mg); light yellow solid; mp: 103–105 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.61–8.58 (m, 2H), 8.30–8.27 (m, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.87–7.82 (m, 1H), 7.60–7.55 (m, 1H), 7.53–7.46 (m, 3H), 2.84–2.77 (m, 1H), 1.58–1.53 (m, 2H), 1.28–1.23 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 172.8, 159.9, 150.2, 138.4, 133.5, 130.6, 129.2, 128.7, 128.6, 126.8, 124.5, 123.1, 29.8, 13.2, 12.4.

4-Cyclopentyl-2-phenylquinazoline (3nb)⁷. Yield: 85% (46.6 mg); light yellow solid; mp: 79–81 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.68–8.65 (m, 2H), 8.18–8.15 (m, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.85–7.80 (m, 1H), 7.58–7.47 (m, 4H), 4.09–4.04 (m, 1H), 2.25–2.14 (m, 2H), 2.00–1.95 (m, 2H), 1.85–1.80 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 174.5, 160.0, 151.0, 138.8, 133.1, 130.4, 129.5, 128.7, 128.6, 126.6, 124.7, 122.6, 42.7, 32.7, 26.4.

6-Chloro-2,4-diphenylquinazoline (3ob)⁷. Yield: 80% (50.6 mg); light yellow solid; mp: 190–192 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.69–8.66 (m, 2H), 8.12–8.08 (m, 2H), 7.88–7.84 (m, 2H), 7.82–7.79 (m, 1H), 7.63–7.59 (m, 3H), 7.56–7.49 (m, 3H), 2.25–2.14 (m, 2H), 2.00–1.95 (m, 2H), 1.85–1.80 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 167.7, 160.5, 150.5, 137.8, 137.2, 134.7, 132.8, 130.96, 130.93, 130.4, 130.2, 128.9, 128.8, 128.7, 125.9, 122.3.

6-Nitro-2,4-diphenylquinazoline (3pb)⁷. Yield: 33% (21.6 mg); light yellow solid; mp: 248–250 °C; ¹H NMR (400 MHz, CDCl₃): δ 9.07 (d, J = 2.5 Hz, 1H), 8.76–8.73 (m, 2H), 8.68–8.63 (m, 1H), 8.29 (d, J = 9.2 Hz, 1H), 7.94–7.90 (m, 2H), 7.69–7.67 (m, 3H), 7.58–7.55 (m, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 170.7, 163.0, 154.5, 145.6, 137.1, 136.5, 132.0, 131.2, 131.1, 130.4, 129.4, 129.2, 128.9, 127.2, 124.4, 120.6.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (21502177), Science and Technology Research Key Project of Department of Education of Henan Province (15A150005) and the Doctoral Research Foundation of Zhengzhou University of Light Industry (2014BSJJ032).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra. See DOI: 10.1039/c6ra04195g

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