Rhodium-catalyzed C–H selective amination of 2,4-diarylquinazolines with N -fluorobenzenesulfonimide

Abstract

A rhodium-catalyzed C–H selective amination of 2,4-diarylquinazolines has been developed with the commercially available N-fluorobenzenesulfonimide as the amino source. This approach offers a unique route for direct C–H amidation and demonstrates remarkable functional group tolerance and regioselectivity.

Keywords

C–H activation NFSI quinazolines rhodium catalyst

Introduction

Amino-substituted quinazoline derivatives exhibit a variety of biological activities, such as hypnosis, sedation, pain relief, anticonvulsant, anti-inflammatory, blood pressure lowering, and antibacterial.¹ Especially, in the field of anti-tumor, quinazoline derivatives have unique effects (Figure 1).² Due to their potential applications, a variety of methods have been developed for the synthesis of these products.³ Currently, the most commonly used method for the synthesis of amino quinazolines is the S_NAr substitution reaction of 4-chloroquinazolines with amines under the acid or base conditions.⁴ In addition, the coupling reaction of 4-(4-methylphenyl)quinazoline using sulfonate with secondary amine is also a convenient method to obtain amino-substituted quinazoline derivatives.⁵ Recently, N-fluorobenzenesulfonimide (NFSI) as a nitrogen source to realize the 4-amination reaction of quinazolinones under mild conditions was developed by Peng’s group.⁶ In 2015, a rhodium-catalyzed direct amination of arene C–H bonds using azides as the nitrogen source was developed by Chang and co-workers.⁷ Subsequently, Peng’s group developed an efficient rhodium-catalyzed C–H bond-activated amination reaction of azides with 2,4-diarylquinazolines.⁸ Considering the importance of amino-substituted quinazolines and the long reaction time, poor product selectivity (mono-aminated products and di-aminated products), and certain safety hazards in the use of azides. Therefore, the development of an efficient method for the synthesis of amino quinazolines is still desirable in organic synthesis and drug research.

Figure 1.

Biologically active compounds.

NFSI is not only a good reagent for forming C–F bonds but also a good reagent for forming C–N bonds and has a wide range of applications in organic synthesis.⁹ Recently, NFSI was also found to be an efficient amino source in both sp² and sp³ C–H amidations (Scheme 1).¹⁰ In 2010, a significant achievement was made by Zhang group in the palladium-catalyzed C–H amination reaction of aromatic hydrocarbons using NFSI as a nitrogen source. This methodology avoided prefunctionalization of coupling partners and is more efficient and environmentally friendly.¹¹ Subsequently, Ritter, Itami, Li, and other groups achieved oxidative C–H amination of (hetero)arenes using NFSI as a nitrogen source in the presence of Rh, Cu, and Fe, as well as metal-free conditions.¹² As part of our continuing interest in developing based on quinazoline C–H activation research, we envisioned whether direct C–H amination of quinazoline could be achieved using NFSI as the nitrogen source.

Scheme 1.

Methodologies for C–H amination using NFSI.

Cancer cell inhibition rate

At a solubility of 8 μmolL⁻¹, the MTT method was used to detect the inhibitory rate of 19 compounds on the gastric cancer cell SGC-7901, breast cancer cells MCF-7, liver cancer cell HepG2, and colorectal cancer cell HCT116.

Results and discussions

To begin our investigation, 2-(o-tolyl)-4-(p-tolyl)quinazoline 1a was chosen as the model substrate and NFSI as the nitrogen source, with Pd(OAc)₂ as catalyst in the DCE at 100 °C. The reaction proceeded to give product 2a with 18% yield using NaHCO₃ as base (Table 1, entry 1), but no product was obtained in the absence of base (Table 1, entry 2). And 19% yield of product 2a was obtained using KF as base (Table 1, entry 2). Subsequently, the effect of the amount of base on the reaction was investigated, and it was found that increasing the amount of base could increase the yield (Table 1, entries 3–8). Further investigation of the temperature found that no matter whether the temperature was raised or lowered, the reaction yield would decrease slightly. The effect of solvents on the activity was examined (Table 1, entries 12–16), and DCE also gave the best result. Furthermore, different palladium metal precursors were examined and only moderate yields were obtained. To our delight, 85% yield of 2a was obtained using [RhCp*Cl₂]₂/AgSbF₆ as catalyst in the same conditions. In addition, the base has no effect on the reaction, 84% yield of 2a was obtained in the absence of KF (Table 1, entry 19). AgSbF₆ has played a certain role in improving the performance of Rh catalysts. Without AgSbF₆, the target product can only be obtained with 60% yield (Table 1, entry 21). Obviously, the reaction will not occur when the Rh catalyst is removed. Therefore, the optimal conditions were established: [RhCp*Cl₂]₂/AgSbF₆, DCE, and 80°°C.

Table 1.

The optimization of amination of quinazoline 1a.


Entry	Cat	Base	t/h	T/°C	Solvent	Yield
1	Pd(OAc)₂	NaHCO₃ (1.0 eq)	24	100	DCE	18
2	–	NaHCO₃ (1.0 eq)	24	100	DCE	NR
3	Pd(OAc)₂	KF (1.0 eq)	24	100	DCE	19
4	Pd(OAc)₂	KF (0.5 eq)	24	100	DCE	10
5	Pd(OAc)₂	KF (1.5 eq)	24	100	DCE	40
6	Pd(OAc)₂	KF (2.0 eq)	24	100	DCE	43
7	Pd(OAc)₂	KF (3.0 eq)	24	100	DCE	45
8	Pd(OAc)₂	KF (4.0 eq)	24	100	DCE	39
9	Pd(OAc)₂	KF (1.5 eq)	24	120	DCE	35
10	Pd(OAc)₂	KF (1.5 eq)	24	80	DCE	33
11	Pd(OAc)₂	KF (1.5 eq)	24	100	DCM	21
12	Pd(OAc)₂	KF (1.5 eq)	24	100	1,4-dioxane	trace
13	Pd(OAc)₂	KF (1.5 eq)	24	100	toluene	trace
14	Pd(OAc)₂	KF (1.5 eq)	24	100	DMF	trace
15	Pd(OAc)₂	KF (1.5 eq)	24	100	DMSO	trace
16	Pd(OAc)₂	KF (1.5 eq)	24	100	CH₂Cl₂	30
17	PdCl₂	KF (1.5 eq)	24	100	DCE	37
18	Pd(PPh₃)₄	KF (1.5 eq)	24	100	DCE	32
19	[RhCp*Cl₂]₂, AgSbF₆ (8 mol %)	KF (1.5 eq)	3	80	DCE	85
20	[RhCp*Cl₂]₂, AgSbF₆ (8 mol %)	–	3	80	DCE	84
21	[RhCp*Cl₂]₂	–	3	80	DCE	60
22	AgSbF₆ (8 mol %)	–	3	80	DCE	Trace

Reaction conditions: 1a (0.2 mmol), NFSI (2.0 equiv.), cat (1 mol %), and solvent (2.0 mL).

DCE: Dichloroethane; DCM: Dichloromethane; DMF: N,N-Dimethylformamide; DMSO: Dimethyl sulfoxide.

Under the optimized conditions, the substrate scope of this Rh-catalyzed C–H amidation of 2,4-diarylquinazolines with NFSI was explored (Table 2). First, we investigated the effect of steric hindrance of substituents on the 4-position aryl on the reaction and found that steric hindrance had a certain impact on the activity. For example, when the methyl group is in the para position, giving the target product 2a with 85% yield, while the ortho-methyl substrate is unfavorable for the reaction, and only 60% yield of the target product 2c can be obtained. The electronic effect of substituents also has an obvious influence on the reaction. When there is an electron-withdrawing group F on the benzene ring, the reaction efficiency is greatly reduced, and the yield is only 45%. Subsequently, the effect of substituents on the aryl ring at the 2-position on the reaction was explored, and all reactions gave the target product with excellent yields. However, when the quinazoline ring contains electron-withdrawing group chlorine, the reaction efficiency is reduced. Substrates 2j and 2k can only generate target products with yields of 57% and 60%, respectively. However, the reaction efficiency increases when there is an electron-donating group (CH₃O) on the quinazoline, 89% and 90% yields of the target product for 2l and 2m, respectively. To our delight, this catalytic system can also achieve selective monoamination with high yield when the ortho-position of the 2-aryl group has no substituent. However, under standard conditions, no production of the target product was observed when the nitrogen on 3,4-dihydroquinoxaline was protected by methyl groups. These experimental results indicated that the coordination of N atom at position 3 with Rh catalyst drives this C–H bond functionalization reaction.

Table 2.

Examples of Regioselective Amination of 2,4-Diarylquinazolines

To demonstrate the practicality of this methodology, we screened the inhibitory activity of aminated 2,4-diarylquinazoline derivatives on gastric cancer cell SGC-7901, breast cancer cell MCF-7, liver cancer cell HepG2, and colon cancer cell HCT116 (Table 3). Although they have certain activity at 0.8 μmolL⁻¹, they are not very high. The 19 compounds had the highest inhibition rate of 16.87% on the gastric cancer cell SGC-7901 at a solubility of 8 μmolL⁻¹, the highest inhibition rate on the breast cancer cells MCF-7 was 68.32% (2m), and the highest inhibition rate on the liver cancer cell HepG2 as well as the highest inhibition rate for HCT116: colorectal cancer cell is 14.42%. It can be seen that compound 2m has a certain potential for breast cancer cells MCF-7. In the next step, we will further carry out research on the inhibitory mechanism of compounds on breast cancer cells MCF-7, in order to find compounds with good activity.

Table 3.

Biological activity of 2,4-diaryl quinazoline derivatives^a (inhibition ratio at 8 μmolL⁻¹).

Compound	SGC-7901	MCF-7	HepG2	HCT116
2a	9.82	11.79	8.53	8.27
2b	6.13	–	–	10.56
2c	–	–	1.07	9.26
2d	6.25	6.98	1.17	13.41
2e	6.34	–	–	5.16
2f	8.64	6.91	–	4.62
2g	6.45	–	17.81	1.62
2h	6.74	–	22.54	2.72
2i	6.84	–	3.85	14.42
2j	6.16	–	5.86	1.78
2k	–	–	14.22	2.12
2l	6.41	2.81	2.55	0.1
2m	–	68.32	–	8.34
2n	–	–	–	2.34
2o	–	–	–	6.53
2p	5.97	1.55	5.92	1.66
2q	6.02	–	–	9.96
2r	–	–	–	11.28
2s	16.87	–	–	–

SGC-7901: gastric cancer cell; MCF-7: breast cancer cells; HepG2: liver cancer cell; HCT116: colorectal cancer cell.

Conclusion

In conclusion, we have developed a direct amination reaction of 2,4-diarylquinazoline ortho C–H bond with NFSI as amine source and quinazoline as guiding group under rhodium catalyst. The reaction does not require a base, only a simple classical [RhCp*Cl₂]₂/AgSbF₆ catalytic system is needed, and it is applied to the determination of anti-tumor activity. The preliminary results show that this series of products generally has low inhibitory activity on breast cancer cell MCF-7, gastric cancer cell SGC-7901, colon cancer cell HCT116, and liver cancer cell HepG2. However, there is a certain potential for breast cancer cells MCF-7, which provides space for follow-up research.

Experimental

General information

All reactions were performed in reaction tubes under atmosphere (air). Flash column chromatography was performed using silica gel (60 Å pore size, 32–63 µm, standard grade). Analytical thin-layer chromatography was performed using glass plates pre-coated with 0.25 mm 230–400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Thin-layer chromatography plates were visualized by exposure to ultraviolet light. Organic solutions were concentrated on rotary evaporators at ~20 Torr (house vacuum) at 25–35 °C. Commercial reagents and solvents were used as received. Nuclear magnetic resonance (NMR) spectra are recorded in parts per million from internal tetramethylsilane on the δ scale.

General procedure for rhodium-catalyzed C–H selective amination of 2,4-diarylquinazolines with NFSI

An oven-dried reaction vessel was charged with [RhCp*Cl₂]₂ (1.2 mg, 1 mol%), AgSbF₆ (9.4 mg, 8 mol%), DCE (2.0 mL), 2,4-diarylquinazolines (1, 0.2 mmol), and NFSI (126 mg, 0.4 mmol, 2.0 equiv.) under air. The vessel was sealed and heated at 80 °C (oil bath temperature) for 24 h. The resulting mixture was cooled to room temperature, filtered through a short silica gel pad, transferred to the silica gel column directly, and eluted with hexanes and ethyl acetate (30:1 to 20:1) to give products 2.

Compound Characterization

N-(3-methyl-2-(4-(p-tolyl)quinazolin-2-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide (2a)

Yellow solid, 85% yield, mp = 170–179°C; ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 7.7 Hz, 4H), 7.72 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 7.9 Hz, 1H), 7.47–7.38 (m, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.28 (d, J = 8.2 Hz, 3H), 7.18 (dd, J = 10.3, 5.3 Hz, 1H), 7.10 (t, J = 7.8 Hz, 4H), 6.76 (d, J = 7.9 Hz, 1H), 2.38 (s, 3H), 2.23 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.9, 158.6, 149.7, 139.7, 139.3, 139.0, 138.3, 133.1, 132.5, 132.3, 132.1, 131.9, 129.6, 128.5, 128.2, 127.7, 127.6, 127.2, 126.7, 126.5, 126.0, 120.1, 20.4, 20.1; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₄H₂₈N₃O₄S₂⁺ 606.1521, found 606.1524.

N-(3-methyl-2-(4-(m-tolyl)quinazolin-2-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide (2b)

Yellow solid, 73% yield, mp = 175–179°C; ¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, J = 7.4 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 7.6 Hz, 4H), 7.79 (t, J = 7.3 Hz, 1H), 7.72 (d, J = 7.7 Hz, 2H), 7.52 (t, J = 7.1 Hz, 1H), 7.45–7.36 (m, 3H), 7.23 (d, J = 7.3 Hz, 2H), 7.15 (t, J = 7.6 Hz, 4H), 7.11 (s, 1H), 2.50 (s, 3H), 2.43 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 158.1, 140.9, 140.6, 140.3, 134.5, 133.9, 133.4, 133.0, 132.6, 131.4, 130.3, 129.69, 129.28, 128.8, 128.2, 127.8, 127.4, 126.3, 120.9, 21.4, 21.1; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₄H₂₈N₃O₄S₂⁺ 606.1521, found 606.1526.

N-(3-methyl-2-(4-(o-tolyl)quinazolin-2-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide (2c)

Yellow solid, 60% yield, mp = 172–177°C; ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J = 8.4 Hz, 1H), 7.87–7.83 (m, 1H), 7.77 (d, J = 7.8 Hz, 4H), 7.54 (d, J = 7.4 Hz, 1H), 7.51–7.46 (m, 1H), 7.41 (t, J = 7.3 Hz, 2H), 7.31 (d, J = 7.6 Hz, 3H), 7.27–7.17 (m, 6H), 7.09 (t, J = 7.8 Hz, 1H), 6.56 (d, J = 7.9 Hz, 1H), 2.24 (s, 3H), 2.01 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 169.7, 160.3, 150.3, 141.5, 139.6, 138.8, 136.8, 136.1, 133.6, 133.5, 132.9, 132.5, 130.1, 129.5, 129.3, 129.1, 128.3, 127.8, 127.0, 125.7, 122.4, 20.9, 19.9; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₄H₂₈N₃O₄S₂⁺ 606.1521, found 606.1525.

N-(3-methyl-2-(4-phenylquinazolin-2-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide (2d)

Yellow solid, 87% yield, mp = 171–178°C; ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.86 (dd, J = 5.9, 4.7 Hz, 1H), 7.80 (dd, J = 6.5, 3.1 Hz, 2H), 7.77 (d, J = 7.5 Hz, 4H), 7.57–7.53 (m, 1H), 7.51–7.44 (m, 4H), 7.35 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H), 7.20–7.16 (m, 1H), 7.12 (t, J = 7.9 Hz, 4H), 6.76 (d, J = 7.9 Hz, 1H), 2.23 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.8, 159.8, 150.9, 139.9, 139.3, 137.0, 133.4, 133.3, 133.1, 132.9, 130.5, 130.2, 129.9, 129.5, 129.3, 129.2, 128.5, 128.4, 128.2, 127.7, 126.9, 121.1, 21.1; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₃H₂₆N₃O₄S₂⁺ 592.1365, found 592.1362.

N-(2-(4-(4-fluorophenyl)quinazolin-2-yl)-3-methylphenyl)-N-(phenylsulfonyl)benzenesulfonamide (2e)

Yellow solid, 45% yield, mp = 173–179°C; ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.96–7.87 (m, 3H), 7.83 (d, J = 7.5 Hz, 4H), 7.65 (dd, J = 11.3, 4.0 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.4 Hz, 2H), 7.27–7.18 (m, 7H), 6.82 (d, J = 7.9 Hz, 1H), 2.30 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.77 (s), 163.9 (d, ¹J_C-F = 249 Hz), 159.9, 151.1, 141.0, 139.9, 139.3, 133.5, 133.4, 133.2, 133.2, 133.1, 133.0, 132.6 (d, ³J_C-F = 9 Hz), 129.4, 129.2, 128.6, 128.2, 127.9, 126.7, 121.1, 115.6 (d, ²J_C-F = 21 Hz), 21.1; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₃H₂₅FN₃O₄S₂⁺ 610.1271, found 610.1272.

N-(3-chloro-2-(4-(m-tolyl)quinazolin-2-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide (2f)

Yellow solid, 80% yield, mp = 174–178°C; ¹H NMR (400 MHz, CDCl₃) δ 8.48 (dd, J = 7.8, 1.4 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 7.6 Hz, 4H), 7.81 (t, J = 7.2 Hz, 1H), 7.68–7.61 (m, 2H), 7.55 (dd, J = 14.4, 7.0 Hz, 3H), 7.48 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 7.3 Hz, 1H), 7.24 (s, 1H), 7.16 (t, J = 7.7 Hz, 4H), 2.52 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.9, 158.1, 151.3, 140.6, 139.1, 138.5, 137.3, 133.7, 133.4, 133.3, 132.9, 132.6, 130.8, 130.7, 130.6, 130.4, 130.0, 128.8, 128.3, 128.1, 127.5, 127.3, 126.2, 121.0, 21.6; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₃H₂₅ClN₃O₄S₂⁺ 626.0975, found 626.0978.

N-(3-chloro-2-(4-(o-tolyl)quinazolin-2-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide (2g)

Yellow solid, 76% yield, mp = 174–179°C; ¹H NMR (400 MHz, CDCl₃) δ 8.53–8.48 (m, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 7.7 Hz, 2H), 7.78 (d, J = 7.0 Hz, 2H), 7.63–7.59 (m, 2H), 7.53 (t, J = 7.7 Hz, 3H), 7.46 (d, J = 7.3 Hz, 2H), 7.41–7.29 (m, 7H), 7.26 (s, 1H), 2.18 (s, 3H), 2.04 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.9, 157.8, 150.9, 138.9, 136.6, 136.5 135.8, 134.8, 133.6, 133.5, 133.3, 133.2, 130.9, 130.6, 130.4, 129.9, 129.8, 129.5, 129.4, 129.3, 127.6, 126.2, 125.6, 121.9, 21.03; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₃H₂₅ClN₃O₄S₂⁺ 626.0975, found 626.0977.

N-(4-methyl-2-(4-phenylquinazolin-2-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide (2h)

Yellow solid, 82% yield, mp = 176–181°C; ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J = 1.4 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 7.7 Hz, 4H), 7.83–7.78 (m, 3H), 7.59 (dd, J = 5.2, 1.7 Hz, 3H), 7.53 (t, J = 7.5 Hz, 1H), 7.34 (dd, J = 8.0, 1.7 Hz, 1H), 7.23 (td, J = 7.7, 3.0 Hz, 3H), 7.14 (t, J = 7.7 Hz, 4H), 2.49 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.6, 158.2, 151.2, 140.9, 140.6, 138.5, 137.2, 133.8, 133.1, 133.0, 132.5, 131.2, 131.0, 130.2, 129.8, 129.4, 128.7, 128.5, 128.1, 127.5, 126.1, 120.9, 21.4; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₃H₂₆N₃O₄S₂⁺ 592.1365, found 592.1362.

N-(4-chloro-2-(4-(p-tolyl)quinazolin-2-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide (2i)

Yellow solid, 84% yield, mp = 169–177°C; ¹H NMR (400 MHz, CDCl₃) δ 8.41 (d, J = 2.5 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.98–7.90 (m, 2H), 7.78 (d, J = 7.8 Hz, 4H), 7.64 (d, J = 7.9 Hz, 2H), 7.55–7.49 (m, 1H), 7.43 (dd, J = 8.4, 2.5 Hz, 1H), 7.35 (d, J = 7.8 Hz, 2H), 7.18 (t, J = 4.2 Hz, 3H), 7.08 (t, J = 7.7 Hz, 4H), 2.44 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.8, 155.9, 150.3, 139.3, 135.8, 134.8, 133.6, 132.3, 132.1, 131.8, 131.2, 129.4, 129.2, 129.0, 128.8, 128.5, 128.3, 127.8, 127.3, 126.8, 125.2, 120.1, 20.5; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₃H₂₅ClN₃O₄S₂⁺ 626.0975, found 626.0977.

N-(2-(6-chloro-4-(p-tolyl)quinazolin-2-yl)-3-methylphenyl)-N-(phenylsulfonyl)benzenesulfonamide (2j)

Yellow solid, 57% yield, mp = 173–177°C; ¹H NMR (400 MHz, CDCl₃) δ 8.01 (dd, J = 5.5, 3.2 Hz, 2H), 7.83–7.71 (m, 5H), 7.68 (d, J = 8.0 Hz, 2H), 7.38–7.28 (m, 5H), 7.24–7.10 (m, 5H), 6.79 (d, J = 7.9 Hz, 1H), 2.40 (s, 3H), 2.24 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.8, 160.0, 149.6, 140.7, 140.5, 140.0, 139.5, 134.1, 133.7, 133.4, 133.3, 133.2, 133.1, 131.2, 130.4, 129.5, 129.4, 129.2, 128.7, 128.3, 125.7, 121.6, 21.5, 21.3; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₄H₂₇ClN₃O₄S₂⁺ 640.1132, found 640.1135.

N-(2-(6-chloro-4-(o-tolyl)quinazolin-2-yl)-3-methylphenyl)-N-(phenylsulfonyl)benzenesulfonamide (2k)

Yellow solid, 60% yield, mp = 173–176°C; ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J = 9.0 Hz, 1H), 7.85 (dd, J = 9.0, 2.3 Hz, 1H), 7.78 (d, J = 7.8 Hz, 4H), 7.58 (d, J = 2.2 Hz, 1H), 7.52 (t, J = 7.4 Hz, 2H), 7.45–7.30 (m, 9H), 7.17 (t, J = 7.8 Hz, 1H), 6.62 (d, J = 7.9 Hz, 1H), 2.33 (s, 3H), 2.11 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.8, 160.5, 148.8, 141.2, 139.6, 138.8, 136.1, 136.0, 134.6, 133.6, 133.5, 132.9, 132.7, 130.9, 130.4, 129.4, 129.3, 129.2, 129.1, 128.4, 128.3, 125.9, 125.6, 122.9, 20.9, 19.8; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₄H₂₇ClN₃O₄S₂⁺ 640.1132, found 640.1137.

N-(2-(6-methoxy-4-(p-tolyl)quinazolin-2-yl)-3-methylphenyl)-N-(phenylsulfonyl)benzenesulfonamide (2l)

Yellow solid, 89% yield, mp = 175–179°C; ¹H NMR (400 MHz, CDCl₃) δ 8.01–7.92 (m, 1H), 7.76 (d, J = 8.0 Hz, 4H), 7.71 (d, J = 7.7 Hz, 2H), 7.47 (d, J = 9.2 Hz, 1H), 7.34–7.27 (m, 6H), 7.19–7.11 (m, 5H), 6.76 (d, J = 8.0 Hz, 1H), 3.80 (s, 3H), 2.37 (s, 1H), 2.22 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 165.9, 158.6, 157.9, 147.3, 141.1, 140.9, 140.0, 139.8, 139.4, 134.6, 133.2, 133.0, 130.8, 130.1, 129.5, 129.2, 128.3, 128.1, 125.8, 121.9, 104.2, 55.7, 21.4, 21.2; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₅H₃₀N₃O₅S₂⁺ 636.1627, found 636.1629.

N-(2-(6-methoxy-4-(m-tolyl)quinazolin-2-yl)-3-methylphenyl)-N-(phenylsulfonyl)benzenesulfonamide (2m)

Yellow solid, 90% yield, mp = 176–180°C; ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J = 9.2 Hz, 1H), 7.85 (d, J = 7.5 Hz, 4H), 7.72 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.57 (dd, J = 9.2, 2.7 Hz, 1H), 7.45–7.33 (m, 6H), 7.23 (dd, J = 14.8, 6.8 Hz, 5H), 6.82 (d, J = 7.9 Hz, 1H), 3.89 (s, 3H), 2.46 (s, 3H), 2.30 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.4, 158.6, 157.9, 147.2, 141.1, 140.1, 139.4, 138.5, 137.3, 133.3, 133.1, 133.0, 130.9, 130.8, 130.5, 129.5, 129.3, 128.4, 128.2, 127.1, 126.0, 122.1, 104.4, 55.7, 21.5, 21.2; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₅H₃₀N₃O₅S₂⁺ 636.1627, found 636.1629.

N-(2-(4-(4-cyanophenyl)quinazolin-2-yl)-5-methylphenyl)-N-(phenylsulfonyl)benzenesulfonamide (2n)

Yellow solid, 90% yield, mp = 163–173°C; ¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.90 (t, J = 6.7 Hz, 4H), 7.85 (dd, J = 7.8, 6.4 Hz, 7H), 7.57 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.28 (d, J = 7.4 Hz, 1H), 7.17 (t, J = 7.7 Hz, 4H), 7.07 (s, 1H), 2.43 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 165.5, 158.5, 151.6, 141.5, 141.2, 140.5, 135.9, 134.0, 133.5, 133.1, 132.8, 132.3, 131.5, 130.9, 130.2, 128.9, 128.2, 128.0, 126.4, 125.2, 120.5, 118.4, 113.7, 21.1; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₄H₂₅N₄O₄S₂⁺ 617.1317, found 617.1319.

N-(2-(4-(4-chlorophenyl)quinazolin-2-yl)-5-methoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide (2o)

Yellow solid, 88% yield, mp = 165–175°C; ¹H NMR (400 MHz, CDCl₃) δ 8.42 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 7.6 Hz, 5H), 7.81–7.77 (m, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.5 Hz, 2H), 7.16 (t, J = 7.8 Hz, 5H), 6.79 (d, J = 2.6 Hz, 1H), 3.84 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.5, 160.9, 151.5, 141.5, 141.2, 140.6, 136.3, 134.8, 134.4, 133.1, 132.7, 132.3, 131.5, 130.0, 128.9, 128.8, 128.2, 128.0, 127.4, 125.6, 118.7, 116.5, 55.6; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₃H₂₅ClN₃O₅S₂⁺ 642.0924, found 642.0929.

N-(5-methoxy-2-(4-(p-tolyl)quinazolin-2-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide (2p)

Yellow solid, 75% yield, mp = 177–182°C; ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 7.5 Hz, 4H), 7.76 (t, J = 7.5 Hz, 1H), 7.70 (d, J = 7.9 Hz, 2H), 7.49 (t, J = 7.5 Hz, 1H), 7.40 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 7.3 Hz, 2H), 7.15 (t, J = 7.6 Hz, 5H), 6.81 (d, J = 2.5 Hz, 1H), 3.83 (s, 3H), 2.50 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.4, 159.9, 150.5, 141.4, 141.3, 140.5, 136.2, 134.7, 134.5, 133.1, 132.6, 132.2, 131.4, 130.2, 129.2, 128.8, 128.2, 127.1, 126.1, 120.8, 118.7, 116.4, 55.6, 21.4; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₄H₂₈N₃O₅S₂⁺ 622.1470, found 622.1472.

N-(phenylsulfonyl)-N-(2-(4-(p-tolyl)quinazolin-2-yl)phenyl)benzenesulfonamide (2q)

Yellow solid, 85% yield, mp = 171–177°C; ¹H NMR (400 MHz, CDCl₃) δ 8.47 (dd, J = 7.8, 1.3 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.6 Hz, 4H), 7.80 (t, J = 7.6 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.64 (t, J = 7.1 Hz, 1H), 7.57–7.50 (m, 2H), 7.41 (d, J = 7.9 Hz, 2H), 7.33 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.4 Hz, 2H), 7.15 (t, J = 7.7 Hz, 4H), 2.50 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.8, 158.1, 151.2, 140.6, 140.3, 139.1, 134.5, 133.7, 133.5, 133.4, 132.9, 132.7, 130.6, 130.5, 130.3, 129.9, 129.3, 128.8, 128.2, 127.6, 126.2, 121.0, 21.5; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₃H₂₆N₃O₅S₂⁺ 592.1365, found 592.1362.

N-(2-(4-(4-chlorophenyl)quinazolin-2-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide (2r)

Yellow solid, 82% yield, mp = 174–176°C; ¹H NMR (400 MHz, CDCl₃) δ 8.36 (dd, J = 7.8, 1.5 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.80–7.77 (m, 4H), 7.75 (dd, J = 8.3, 1.2 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.57 (td, J = 7.7, 1.1 Hz, 1H), 7.50 (d, J = 8.4 Hz, 3H), 7.46 (dd, J = 7.6, 1.5 Hz, 1H), 7.24 (dd, J = 7.9, 1.0 Hz, 1H), 7.18 (d, J = 7.4 Hz, 2H), 7.08 (t, J = 7.7 Hz, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 166.4, 158.3, 151.5, 140.5, 139.1, 136.4, 135.6, 133.7, 133.4, 133.3, 133.2, 132.7, 131.6, 130.6, 130.5, 130.1, 128.8, 128.2, 127.8, 126.4, 125.7, 120.8; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₂H₂₃ClN₃O₄S₂⁺ 612.0819, found 612.0812.

N-(2-(6-methoxy-4-(naphthalen-1-yl)quinazolin-2-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide (2s)

Yellow solid, 93% yield, mp = 180–187°C; ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H), 8.07–7.97 (m, 4H), 7.82 (d, J = 7.7 Hz, 2H), 7.68 (d, J = 7.2 Hz, 1H), 7.63–7.54 (m, 4H), 7.51–7.42 (m, 4H), 7.36 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 7.12 (t, J = 7.4 Hz, 2H), 6.73 (d, J = 2.6 Hz, 1H), 3.62 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.2, 158.6, 156.2, 147.4, 138.8, 134.9, 133.9, 133.6, 133.4, 133.2, 133.0, 132.4, 131.5, 130.6, 130.1, 129.7, 129.1, 128.8, 128.5, 128.1, 127.7, 126.6, 126.3, 126.1, 125.8, 125.1, 123.5, 103.6, 55.5; HRMS (ESI) m/z [M + H]⁺ calcd for C₃₇H₂₈N₃O₅S₂⁺ 658.1470, found 658.1472.

Supplemental Material

sj-docx-1-chl-10.1177_17475198231226425 – Supplemental material for Rhodium-catalyzed C–H selective amination of 2,4-diarylquinazolines with N-fluorobenzenesulfonimide

Supplemental material, sj-docx-1-chl-10.1177_17475198231226425 for Rhodium-catalyzed C–H selective amination of 2,4-diarylquinazolines with N-fluorobenzenesulfonimide by Wei Gao, Lifang Hu, Fang Gao, Guozhu Hu and Xueying Zhou in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was funded by the Training Program for Academic and Technical Leaders of Major Discipline in Jiangxi Province-Young Talent Project (20212bcj23013), the Key R&D Program of Jiangxi Science and Technology Department (20212bbf63046), the development and commercialization of the camphor tree essential oil source (i) (2020-05-02), and the synthesis of heterocyclic derivatives and their inhibitory activities against anthracnose of Camellia (innovation project 2022: 26).

ORCID iD

Xueying Zhou

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