HETEROCYCLES

Paper | Regular issue | Vol. 85, No. 6, 2012, pp. 1417-1426
Received, 17th March, 2012, Accepted, 24th April, 2012, Published online, 1st May, 2012.
DOI: 10.3987/COM-12-12466

■ Facile and Efficient Cyclization of Anthranilonitrile to 2,4-Dichloroquinazoline by Bis(trichloromethyl) Carbonate and Catalytic Amount Triphenylphosphine Oxide

Zhenhua Li, Danli Wu, and Weihui Zhong*

Key Laboratory of Pharmaceutical Engineering of Ministry of Educations, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310014, China

Abstract

2,4-Dichloroquinazolines were synthesized by the cyclization of anthranilonitrile using bis(trichloromethyl) carbonate (BTC) with the aid of catalytic amount of triphenylphosphine oxide (Ph3PO) at 120 °C. This method was also applied to the synthesis of 2,4-dichlorothieno[2,3-d]pyrimidine. The plausible mechanism is presented.

INTRODUCTION
Quinazoline derivatives have been shown to be promising pharmaceutical agents for the treatment of viral diseases1 and cancer.2,3 In addition, quinazoline derivatives often served as precursors to 2,4-dichloroquinazolines, which were widely used as intermediates in the synthesis of a variety of pharmaceutical agents.3,4 Important drugs of the quinazoline family in current use for the treatment of hypertension are prozocin,5 doxazosin,6 and so on (Figure 1).

The combination of pharmacological application and synthetic utility has generated interest in the development of methodology for the synthesis of quinazoline derivatives. 2,4-Dichloroquinazolines have been prepared in a conventional manner from the corresponding 2,4-dihydroxyquinazolines, which was prepared by antranylic acid,7 2-aminobenzoate8,9 or anthranilonitrile,10 etc, followed by chlorination using excess phosphoryl chloride.7-11 However, according to our knowledge, there have been few reports of the direct synthesis of 2,4-dichloroquinazolines from aniline analogues until now. The first example reported by Chi et al. described one-step cyclization of anthranilonitrile to 2,4-dichloroquinazoline using diphosgene and acetonitrile system.12 However, this method suffered from several drawbacks such as use of toxic diphosgene, harsh reaction conditions and relatively low yields.
Based on the postulated mechanism of this protocol and our previous studies on dichlorotriphenyl phosphine (PPh3Cl2),13,14 which can be generated in situ by bis(trichloromethyl) carbonate (BTC, triphosgene) and triphenylphosphine oxide (Ph3PO), we examined their reactivity the novel system combined by BTC and Ph3PO toward this reaction. As a result, we achieved facile and efficient one-pot synthesis of 2,4-dichloroquinazolines by the cyclization of anthranilonitrile using BTC with the aid of catalytic amount of Ph3PO. Herein, we wish to report our preliminary results in this area.

RESULTS AND DISCUSSION
Initially, we started our investigation using anthranilonitrile 1a as the model substrate to examine its behavior under different conditions. Upon treatment of 1a with 2.0 equiv BTC and 1.0 equiv Ph3PO at 100 oC for 3.0 h, the reaction proceeded smoothly as indicated by TLC and furnished one product with 85 % yield after workup and purification by column chromatography. From the spectral and analytical data, the product was characterized as 2,4-dichloroquinazoline 2a (Scheme 1).
Subsequently, the reaction conditions, including reaction temperature, solvent and the ration of 1a to BTC and Ph3PO, were then investigated. It was found that the reaction temperature at around 120 °C was effective for the reaction of 1a to form product 2a with the yield of 95%. Besides chlorobenzene, other solvents such as toulene, o-xylene and 1,1,2,2-tetrachloroethane were compared, but the conversion was relatively low. Moreover, experimental result revealed that the yield was not affected with a higher molar ratio of Ph3PO to 1a (Table 1, entry 2) or BTC to 1a (Table 1, entry 3).
Stimulated by our previous finding that dichlorotriphenylphosphine (PPh3Cl2) can be formed from Ph3PO and BTC,14 we reasoned that a reaction cycle could be established between Ph3PO and PPh3Cl2 in the above reaction. To our delight, when the protocol was applied, 2a were successfully obtained with 2.1 equiv BTC and a catalytic amount of Ph3PO (0.2 equiv) to give excellent yield of 2,4-dichloroquinazoline by prolonging the reaction time to 6 h (Table 1, entry 7), indicating that the reaction cycle could proceed smoothly. However, the yield was reduced significantly with 0.1 equiv. Ph3PO (Table 1, entry 8).

Having established the optimal conditions for the cyclization, We next turned our attention to exploring the scope and generality of this method for the synthesis of other 2,4-dichloroquinazolines. A wide range of substituted and structurally diverse anthranilonitriles 1 prepared by the reaction of appropriate substituted isatin15 were subjected to this reaction under similar conditions. The results were summarized in Table 2. Gratifyingly, under the optimized conditions, all the substrates listed in Table 2 afforded the desired products 2 in good to excellent yields. Table 2 indicated the following trends that compounds 1 with electron-donating groups produced the 2,4-dichloroquinazolines 2 in excellent yields (Table 2, entries 2–5), while with electron-withdrawing groups afforded the products in relatively lower yields (Table 3, entries 6–12). At this stage, it could be concluded that our protocol tolerates a wide variety of anthranilonitriles.

To further extend the scope and generality of this reaction, another example was attempted to show that this reaction is generally applicable to the synthesis of other pyrimidine-containing heterocyclic compounds. Substitued aminothiophene nitriles 3, which were prepared by the reaction of appropriate ketones, propanedinitriles, and elemental sulfur in the presence of Et2NH at 120 °C,16 reacted with BTC and Ph3PO under the similar conditions to afford 2,4-dichlorothieno[2,3-d]pyrimidines 4. The results showed that this reaction is a very reliable method for the synthesis of thienopyrimidines 4 with moderate to good yields.

On the basis of the above results and previous literatures,12,13 a reaction mechanism for the formation of 2,4-dichloroquinazolines from athranilonitrile is presented in Scheme 1. Athranilonitrile 1a first reacts with BTC to afford compound 5. Further reaction of 5 with Ph3PCl2 generated in situ from BTC and Ph3PO, forms the O-P bond and gets the intermediate 6. Finally primary chlorination of the C4 position, secondary chlorination of the C2 position is performed by the replacement of Ph3PO leaving group with chloride, to yield the corresponding 2,4-dichloroquinazoline 2a.

In summary, we have successfully developed a new method for the synthesis of 2,4-dichloroquinazolines by using BTC and Ph3PO. The mild cycle reaction condition, convenient operational procedure, and good yield were the notable advantages. Moreover, 2,4-dichlorothieno[2,3-d]pyrimidine can be synthesized from aminothiophene nitrile. It could therefore be concluded that our synthetic method has significant generality for the synthesis of many pyrimidine-containing heterocyclic compounds. We believe this strategy will bring a more practical alternative to the existing methods in the future.

EXPERIMENTAL
All reagents were purchased from commercial sources and used without treatment, unless otherwise indicated. Melting points (mp) were obtained on digital melting point apparatus WRS-1B and are uncorrected. 1H NMR, 13C NMR were recorded at VARAIN-400 on a 400 MHz and 100 MHz, respectively, and TMS as internal standard. IR spectra (KBr) were recorded on AVATAR-370. All reactions were monitored by TLC with GF254 silica gel coated plates. Column chromatography was carried out on silica gel.

General procedure for the synthesis of 2,4-dichloroquinazolines (2a~2l)
To an ice-cold magnetically stirred solution of PhCl (5 mL) and Ph3PO (0.17 g, 0.6 mmol), added four drops of Et3N, bis(trichlormethyl)carbonate (0.63 g, 2.1 mmol/6 mL PhCl) was added dropwise. The reaction mixture was placed to room temperature for 30 min. Then athranilonitriles 1a~1l (3 mmol) was added, rise the temperature to 120 °C for 6 h. When the reaction was completed, poured the mixture into water and extracted with EtOAc. After dryness and condensation, the crude reaction product was separated by column chromatography using 10% EtOAc in petroleum ether as eluent to afford pure 2a~2l.
2,4-Dichloroquinazolines (2a).
White solid, mp 119.3–121.0 °C (lit.,3 118 oC). 1H NMR (400MHz, CDCl3) δH: 8.26 (d, J = 8.4 Hz, 1H), 8.01–7.97 (m, 2H), 7.76 – 7.70 (m, 1H). 13C NMR (100 MHz, CDCl3) δC: 163.7, 154.9, 152.1, 135.9, 129.0, 127.8, 125.8, 122.2.
2,4-Dichloro-6-methoxyquinazoline (2b).
White solid, mp 170–171 °C (lit.,17 171 oC). 1H NMR (400 MHz, CDCl3) δH: 7.89 (d, J = 9.2 Hz, 1H), 7.60 (dd, J = 9.2, 2.8 Hz, 1H), 7.40 (d, J = 2.8 Hz, 1H), 3.99 (s, 3H). 13C NMR (100 MHz, CDCl3) δC: 161.5, 159.4, 152.5, 148.4, 129.3, 129.0, 123.3, 102.9, 56.0.
2,4-Dichloro-6-methylquinazoline (2c).
White solid, mp 140–141 °C (lit.,18 140–141 °C). 1H NMR (400 MHz, CDCl3) δH: 8.00 (s, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.80 (dd, J = 8.6, 1.8 Hz, 1H), 2.61 (s, 3H). 13C NMR (100 MHz, CDCl3) δC: 162.9, 154.0, 150.8, 139.8, 138.2, 127.5, 124.5, 122.2, 22.0.
2,4-Dichloro-6,7-dimethoxyquinazoline (2d).
White soli, mp 160.8–161.7 °C (lit.,8 157–159°C). 1H NMR (400 MHz, CDCl3) δH: 7.33 (s, 1H), 7.25 (s, 1H), 4.07 (s, 3H), 4.05 (s, 3H). 13C NMR (101 MHz, CDCl3) δC: 159.9, 157.6, 153.4, 151.4, 150.4, 117.7, 106.21, 102.7, 56.8, 56.5. IR (KBr): νmax = 1611, 1546, 1505, 1401, 1238, 1205, 1142, 848 cm-1. MS (ESI): =259.1 ([M+H]+).
2,4-Dichloro-5,7-dimethylquinazoline (2e).
White solid, mp 140.2–143.1 °C. 1H NMR (400 MHz, CDCl3) δH: 7.59 (s, 1H), 7.30 (s, 1H), 2.96 (s, 3H), 2.52 (s, 3H). 13C NMR (100 MHz, CDCl3) δC: 162.2, 154.6, 154.0, 146.5, 136.2, 134.2, 125.7, 120.0, 24.8, 21.9. HRMS(ESI) C10H9Cl2N2 ([M+H]+): calcd. 227.0143, found 227.0148.
2,4,6-Trichloroquinazoline (2f).
White solid, mp 132.5–135.8 °C (lit., 22 129.1–130.8 °C). 1H NMR (400 MHz, CDCl3) δH: 8.22 (d, J = 2.0 Hz, 1H), 7.98–7.88 (m, 2H). 13C NMR (100 MHz, CDCl3) δC: 162.6, 155.2, 150.6, 136.9, 135.07, 129.5, 124.7, 122.8.
2,4,8-Trichloroquinazoline (2g).
White solid. mp 150.8–152.9 °C (lit.,19 no data). 1H NMR (400 MHz, CDCl3) δH: 8.19 (dd, J = 8.8, 1.2 Hz, 1H), 8.07 (dd, J = 7.6, 1.2 Hz, 1H), 7.65 (dd, J = 8.2, 7.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δC: 164.2, 155.8, 148.9, 135.7, 132.6, 128.8, 124.7, 123.4.

2,4-Dichloro-7-fluoroquinazoline (2h).
White solid, mp 142.3–145.1°C (lit.,20 no data). 1H NMR (400 MHz, CDCl3) δH: 8.34–8.24 (m, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.54–7.44 (m, 1H). 13C NMR (100 MHz, CDCl3) δC: 161.5 (d, J1 = 295 Hz), 158.1 (s), 150.9 (s), 148.7 (d, J3 = 14 Hz), 123.8(d, J3= 11 Hz), 114.5 (s), 114.2 (d, J3=16 Hz), 106.9 (d, J2 = 28 Hz).
2,4-Dichloro-6-fluoroquinazoline (2i).
White solid, mp 135.7–137.2 °C (lit.,22 no data). 1H NMR (400 MHz, CDCl3) δH: 8.03 (dd, J = 9.2, 4.8 Hz, 1H), 7.87 (dd, J = 8.0, 2.8 Hz, 1H), 7.79–7.70 (m, 1H). 13C NMR (100 MHz, CDCl3) δC: 163.0 (d, J4 = 6 Hz), 161.1 (d, J1 = 252 Hz), 154.5 (d, J4 = 3 Hz), 149.2 (s), 130.7 (d, J4 = 9 Hz), 126.4 (d, J2 = 26 Hz), 123.1 (d, J3 = 10 Hz), 109.7 (d, J2 = 24 Hz).
6-Bromo-2,4-dichloroquinazoline (2j).
White solid, mp 131.0–136.1 °C (lit.,23 no data). 1H NMR (400MHz, CDCl3) δH: 8.40 (d, J = 2.0Hz, 1H), 8.04 (dd, J = 8.8, 2.0 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δC: 162.5, 155.2, 150.8, 139.5, 129.5, 128.4, 123.2, 123.1.
2,4-Dichloro-6-nitroquinazoline (2k).
White solid, mp 121.1–123.4 °C (lit.,7 122–124 oC). 1H NMR (400 MHz, CDCl3) δH: 9.16 (d, J =2.4, Hz, 1H), 8.73 (dd, J = 9.2, 2.4Hz, 1H), 8.16 (dd, J = 9.2, 0.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δC: 162.3, 155.1, 150.6, 139.3, 129.3, 127.9, 123.0, 122.9.
2,4,5,7-Tetrachloroquinazoline (2l).
White solid. mp 100.3–101.2 °C (lit.,4b no data). 1H NMR (400MHz, CDCl3) δH: 7.90 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δC: 162.0, 156.0, 154.5, 141.3, 132.5, 126.8, 118.8.
2,4-Dichloro-5,6-dimethylthieno[2,3-d]pyrimidine (4a).
White solid. mp 150.6–153.7 °C (lit.,21 no data). 1H NMR (400 MHz, CDCl3) δH: 2.51 (s, 6H).13C NMR (100 MHz, CDCl3) δC: 169.4, 153.7, 152.4, 136.5, 127.7, 124.7, 14.2, 14.1.
2,4-Dichloro-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidine (4b).
Pale yellow solid, mp 169.8–174.6 °C (lit.,21 178–180 °C). 1H NMR (400 MHz, CDCl3) δH: 3.07 (t, J = 4.2 Hz, 1H), 2.86 (t, J = 4.2 Hz, 1H), 1.92 (dt, J = 6.1, 2.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δC: 170.2, 153.6, 152.6, 139.9, 127.3, 126.9, 26.2, 26.1, 22.4, 22.2.
2,4-Dichloro-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidine (4c).
Pale yellow solid. mp 129.8–133.5 °C (lit.,21 134–135 oC). 1H NMR (400 MHz, CDCl3) δH: 3.21–3.10 (m, 2H), 3.06 (dd, J = 10.4, 4.2 Hz, 2H), 2.62 – 2.46 (m, 2H).13C NMR (101 MHz, CDCl3) δ: 174.7, 153.3, 152.3, 145.0, 135.8, 124.6, 30.3, 29.3, 27.4.

ACKNOWLEDGEMENTS
We thank the National Natural Science Foundation of China [21076194] for financial support.

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