6-Nitro-7-tosylquinazolin-4(3H)-one

Abstract

Sulfones are important building blocks in the construction of biologically active molecules or functional materials. The sulfonyl functional group in sulfones is so versatile that it can act as either a nucleophile, an electrophile, or a radical in different organic reactions. Recently, quinazoline sulfones have been used to build asymmetrical ether derivatives as inhibitors of signaling pathways governed by tyrosine kinases and the epidermal growth factor-receptor. In this paper, we report a facile synthesis of a novel quinazoline sulfone, 6-nitro-7-tosylquinazolin-4(3H)-one (III), using the modified protocol from 7-chloro-6-nitroquinazolin-4(3H)-one (I) and sodium p-toluenesulfinate (II). The structure of the title compound III was determined using mass-spectrometry, FT-IR, ¹H-NMR, ¹³C-NMR, DEPT, HSQC (Heteronuclear single quantum coherence), HMBC (Heteronuclear Multiple Bond Correlation Spectroscopy) spectroscopies, and PXRD analysis.

1. Introduction

Sulfones (R-SO₂-R’) have been known for over 100 years with widespread applications in organic synthesis, agrochemicals, polymers, and especially pharmaceuticals [1]. Indeed, many important drug substances containing sulfonyl moiety such as amisulpride, bicalutamide, dapsone, diazoxide, eletriptan, laropiprant, rofecoxib, sulbactam, sulfoxone, tazobactam, and tinidazole have been approved for the treatment of various diseases [1,2,3,4]. Moreover, sulfones serve as versatile intermediates in many synthetic routes, which can function as nucleophiles, electrophiles, or even radicals in a wide range of synthetic reactions [5,6]. These unique properties of sulfones enable rapid and convenient derivatization of many core structures, including the quinazoline moiety. The latter is widely present in many biologically active compounds exhibiting inhibition against cancer [7,8], HIV [9], bacterial [10], and fungal diseases [11,12].

Given this versatility, the synthesis of sulfone has attracted a great deal of attention by researchers, and numerous synthetic strategies have been reported [3,5,6,13,14]. The four traditional and still most common approaches for preparing sulfones are the oxidation of the corresponding sulfides or sulfoxides, alkylation of sulfinate salts, Friedel-Crafts-type sulfonylation of arenes, and addition reactions to alkenes or alkynes [1,2]. Among those, the alkylation of sulfinate salts is suitable for a broad range of alkylating agents. This approach affords sulfone products in good to excellent yields via simple and reproducible reaction conditions [5,15]. The main disadvantage of this reaction, however, is due to the modest availability of sulfinate salts [1,5,16].

Although the rich chemistry of sulfones is widely appreciated and significant advances have been achieved for the preparation of sulfones, opportunities for further exploration still remain. For example, the conversion of diaryl sulfones into asymmetrical ethers has been rarely reported and limited to a couple of references [17,18]. In these reported synthetic routes, the synthesis of asymmetrical ethers was all conducted with sodium benzenesulfinate. The protocol is briefly described as follows: The sodium sulfinates as nucleophiles were reacted with quinazoline halides activated by the electron withdrawing group (-NO₂) in DMF to form sulfones. The resulted sulfones as electrophiles were further reacted with alcohols in a t-butoxide base to obtain the desired asymmetrical ethers (Scheme 1). It is important to note that this reaction mechanism retains the chirality of the alcohols, which offers a feasible way to produce pure stereoisomers of interest.

To further develop the above mentioned strategy, in this paper, we present the synthesis and spectral data of novel sulfone, 6-nitro-7-tosylquinazolin-4(3H)-one (III), which is an analog of reported compound in [18], 6-nitro-7-(phenylsulfonyl)quinazolin-4(3H)-one. Methyl group acting as an electron donor is likely to increase the nucleophilicity of the p-toluenesulfinate, which enables a faster coupling reaction with aryl chlorides to form sulfones in comparable high yields.

2. Results and Discussion

The target compound III was prepared from 7-chloro-6-nitroquinazolin-4(3H)-one (I) and sodium p-toluenesulfinate (II) in 81.7% of yield (Scheme 2). The synthetic procedure was based on [17,18] with some changes.

In the reported syntheses of sulfones by sulfinates and aryl chlorides, the sulfinate salts have been widely used in excess to promote the completion of the reactions [19,20,21]. Equimolar mixtures of sodium sulfinates and aryl chlorides have also been used, however, little data on the yield were available to support any comparison [18]. According to [17] with the ratio of 1.3:1 (sodium sufinates:aryl chlorides), the reaction work-up was fairly simple and the sulfone product was separated by a simple precipitation with water. However, we observed that these conditions generated significant impurities, as indicated by TLC, and needed further proper purification.

In our synthesis, we adjusted the molar ratio of the starting materials and changed the work-up conditions. We found that the 1.2:1 molar ratio of sodium p-toluenesulfinate:aryl chloride was enough to facilitate the reaction completion and the reaction time was much quicker when using sodium p-toluenesulfinate in place of sodium benzenesulfinate (1 vs. 6 h until completion). Related to the work-up, acetone was first used to precipitate the excess sulfinate salt, which was then filtered out. Other impurities were removed by adding water to the concentrate containing DMF. The reasonably pure sulfone product was obtained without further purification in a good yield (81.7%), which is comparable to those reported in the literature [17].

The structure of compound III is different from its reported analog in [18], 6-nitro-7-(phenylsulfonyl)quinazolin-4(3H)-one, by a methyl group at position C-4′. This resulted in variations of ¹H- and ¹³C-NMR data signals of hydrogen and carbon at position C-4′. MS data showed a molecular ion peak at m/z 343.97 ([M − H]⁻) and 368.0330 ([M + Na]⁺), which indicated that the chloro-group at C-7 was successfully substituted by the nucleophilic p-toluenesulfinate salt. The absorption bands on the infrared spectrum, 1315 and 1145 cm⁻¹, demonstrated the presence of sulfone moiety in compound III. This was also supported by the ¹³C signals at 138.1 (C-7) and 136.4 ppm (C-1′), which indicated there was no O-alkylation reaction towards a sulfinate ester [22]. This result is similar to those reported, despite the fact that the exact underlying reason for the selectivity of sulfinate/sulfone formation was not clearly explained [1,23]. All obtained data by DEPT and 2D NMR experiments are in entire agreement with the structure of the title compound III (

Table 1. Two-dimensional (2D) NMR (HSQC and HMBC) correlations for the title compound III.

	Proton	H-2	H-5	H-8	H-2′	H-3′	H-5′	H-6′	H-7′	H-O/H-N
Carbon	ppm	8.39	8.59	8.47	7.92	7.49	7.49	7.92	2.41	12.96/3.35 *
C-2	149.9	x		γ
C-4	159.1	β	β
C-4a	126.4			β
C-5	124.0		x	γ
C-6	144.1			β
C-7	138.1		β
C-8	131.2	γ	γ
C-8a	151.0	β
C-1′	136.4					β	β
C-2′	128.1				x		γ	β	γ
C-3′	130.1					x	β		β
C-4′	145.5				β			β	α
C-5′	130.1					β	x		β
C-6′	128.1				β	γ		x	γ
C-7′	21.1					β	β		x

α: Due to a two-bond coupling (²J_CH); β: Due to a three-bond coupling (³J_CH); γ: Due to a four-bond coupling (⁴J_CH); x: Coupling by HSQC; *: The tautomeric NH signal is overlapped with a water signal at 3.35 ppm in DMSO-d₆.

). The amide-iminol tautomerism of quinazolin-4(3H)-one skeleton was again observed as previously reported [18] by ¹H-NMR, in which the O-H form generates a proton peak at 12.96 ppm and in the NH form this peak is recorded at 3.35 ppm (overlapped with water, SI). In addition, powder X-ray diffraction (PXRD) data were also collected as an effort to provide a comprehensive spectral data set for the title compound III (

Table 2. PXRD data for the title compound III.

Peak n	2θ (°)	d (Å)	I/Imax (%)	Peak n	2θ (°)	d (Å)	I/Imax (%)
1	9.10	9.7182	2.62	33	27.50	3.2435	32.51
2	10.14	8.7237	15.07	34	28.00	3.1867	4.07
3	13.44	6.5882	12.25	35	28.38	3.1449	2.89
4	14.82	5.9777	32.83	36	28.62	3.1191	3.10
5	14.98	5.9142	21.45	37	28.84	3.0958	2.89
6	15.72	5.6374	2.90	38	29.44	3.0340	5.20
7	16.98	5.2218	3.27	39	29.58	3.0200	4.90
8	17.64	5.0279	18.57	40	29.98	2.9806	15.55
9	18.58	4.7756	2.63	41	30.36	2.9442	24.54
10	18.94	4.6857	17.02	42	30.64	2.9179	12.06
11	19.28	4.6038	2.78	43	31.68	2.8244	6.73
12	19.56	4.5385	3.03	44	32.32	2.7700	3.47
13	20.08	4.4221	5.31	45	33.04	2.7112	5.59
14	20.46	4.3409	7.16	46	33.58	2.6689	3.12
15	20.94	4.2424	12.21	47	34.72	2.5838	6.32
16	21.22	4.1871	4.31	48	35.26	2.5454	16.83
17	21.44	4.1446	5.36	49	35.82	2.5069	4.50
18	21.92	4.0549	32.29	50	36.48	2.4631	12.13
19	22.22	4.0009	7.79	51	37.32	2.4095	4.11
20	22.44	3.9621	6.36	52	37.70	2.3861	3.54
21	22.80	3.9004	56.53	53	38.24	2.3537	3.03
22	23.06	3.8570	15.41	54	38.44	2.3419	4.59
23	23.60	3.7699	11.32	55	38.68	2.3279	3.24
24	23.92	3.7202	20.49	56	39.10	2.3039	3.73
25	24.22	3.6748	100.00	57	39.86	2.2617	8.51
26	24.56	3.6247	7.13	58	40.68	2.2179	5.07
27	25.02	3.5591	4.07	59	44.48	2.0369	7.64
28	25.42	3.5040	5.61	60	45.32	2.0011	4.04
29	25.62	3.4771	4.57	61	45.60	1.9894	3.44
30	25.88	3.4428	4.43	62	46.56	1.9506	3.19
31	26.50	3.3636	21.83	63	48.48	1.8778	3.61
32	27.14	3.2857	5.69

).

On the whole, using the amended reaction conditions and work-up procedures, compound III has been synthesized for the first time in a good yield, high purity without further purification, and much quicker time of reaction. These results can be useful for extensive research on sulfones, especially aryl and quinazoline sulfones, as well as the synthesis of asymmetrical ethers with a high level of stereoselectivity.

All the mass, FT-IR, ¹H-NMR, ¹³C-NMR, DEPT, HSQC, HMBC, and PXRD spectra are presented in the Supplementary Material File.

3. Materials and Methods

3.1. General Information

7-Chloro-6-nitroquinazolin-4(3H)-one (compound I, m.p 263.5–265.0 °C, R_f 0.34, dichloromethane/methanol, 20:1) was prepared from the 2-amino-4-chlorobenzoic acid according to [24]. Sodium p-toluenesulfinate (compound II, 95.0%) was purchased from AK Scientific (Union City, CA, USA). Acetone (99.7%) and methanol (MeOH, 99.8%) were obtained from Samchun (Gyeonggi-do, Korea). Dichloromethane (DCM, 99.5%), N,N-dimethylformamide (DMF, 99.5%), ethyl acetate (99.5%), n-hexane (95.0%) were purchased from Xilong Scientific Co., Ltd. (Shantou, China). The chemicals were used as received without further purification.

The melting point was determined using a SRS EZ-Melt apparatus (Stanford Research Systems, Sunnyvale, CA, USA) and was uncorrected. MS was performed at an LTQ Orbitrap XL™ (Thermo Scientific, Waltham, MA, USA) system in an electrospray ionization (ESI) mode. The FT-IR spectrum was recorded by a Shimadzu spectrometer (Kyoto, Japan). Nuclear magnetic resonance (¹H, ¹³C, DEPT, HSQC, and HMBC) experiments were measured on a Bruker Ascend spectrometer (Billerica, MA, USA) at 500 MHz for proton and 125 MHz for carbon-13 using DMSO-d₆ as the solvent and tetramethylsilane (TMS) as an internal standard. Powder X-ray diffraction (PXRD) was performed on a D8-Advance Bruker AXS diffractometer (Karlsruhe, Germany) with CuKα radiation (λ = 1.541874 Å) at room temperature, 40 mA and 40 kV (Göbel mirror; θ–2θ scan; 2θ= 2–60 °; step size = 0.020 °; scan speed = 0.6 s/step). The PXRD data were analyzed by Match! version 3.11.1.183 64-bit (Crystal Impact, Bonn, Germany, author: Dr. Holger Putz, serial number: 7.3.9.2015001.0001). The reaction mixtures were monitored, and the purity of the compounds was checked by thin-layer chromatography (TLC) on silica gel 60 F₂₅₄ plates (Merck, Darmstadt, Germany).

3.2. Synthetic Procedure

6-Nitro-7-tosylquinazolin-4(3H)-one (III)

The synthetic procedure for compound III was based on [17,18] with some modifications.

7-Chloro-6-nitroquinazolin-4(3H)-one (compound I, 2.0 g, 8.87 mmol, 1 eq) and sodium p-toluenesulfinate (compound II, 1.90 g, 10.66 mmol, 1.2 eq) were suspended at 20 °C in DMF (20 mL), then heated to 90 °C and kept for 1 h at this temperature. After completion of the reaction as indicated by TLC, the reaction mixture was cooled, diluted with acetone (60 mL), and the precipitate was filtered to remove the residual sulfinate salt. The filtrate was distilled by a rotary vacuum to recover acetone. The concentrate was then diluted with water (80 mL) and the precipitate was collected by vacuum filtration, washed three times with water (5 mL each time). The resulting solid was dried at 60 °C for 3 h to obtain 6-nitro-7-tosylquinazolin-4(3H)-one (III) as a yellow solid (2.50 g, 81.7%). M.p 280.5–282.0 °C. TLC R_f 0.23 (n-hexane/ethyl acetate, 1:3). LR-MS (ESI⁻, MeOH/DCM), m/z: Calculated for C₁₅H₁₁N₃O₅S [M − H]⁻ 344.03, found 343.97. HR-MS (ESI⁺, MeOH), m/z: Calculated for [M + Na]⁺: 368.0317, found: 368.0330. FT-IR (KBr), ν_max (cm⁻¹): 3180 (N-H); 3078, 3020 (C-H); 1685 (C=O); 1598 (C=N); 1527, 1490 (C=C); 1350 (NO₂); 1315, 1145 (SO₂). ¹H-NMR (DMSO-d₆), δ (ppm): 8.59 (s, 1 H, H-5); 8.47 (s, 1 H, H-8); 8.39 (s, 1 H, H-2); 7.92 (d, J = 8.50 Hz, 2 H, H-2′, H-6′); 7.49 (d, J = 8.00 Hz, 2 H, H-3′, H-5′); 2.41 (s, 1 H, H-7′). ¹³C-NMR (DMSO-d₆), δ (ppm): 159.1 (C-4); 151.0 (C-8a); 149.9 (C-2); 145.5 (C-4′); 144.1 (C-6); 138.1 (C-7); 136.4 (C-1′); 131.2 (C-8); 130.1 (C-3′, C-5′); 128.1 (C-2′, C-6′); 126.4 (C-4a); 124.0 (C-5); 21.1 (C-7′).

4. Conclusions

A new sulfone, 6-nitro-7-tosylquinazolin-4(3H)-one, was synthesized from 7-chloro-6-nitroquinazolin-4(3H)-one and sodium p-toluenesulfinate. The use of p-toluenesulfinate in place of benzenesulfinate demonstrated a significantly quicker reaction and a cleaner product in a comparably high yield (81.7%). The target compound has been fully characterized by the melting point, mass-spectrometry, FT-IR, ¹H-NMR, ¹³C-NMR, DEPT, HSQC, HMBC spectroscopies, and PXRD analysis.