Hexachlorocyclotriphosphazene (HCCP)-Mediated Direct Formation of Thioethers and Ethers from Quinazolin-4(3H)-ones

A hexachlorocyclotriphosphazene (HCCP)-mediated direct formation of quinazoline (thio)ethers from quinazolin-4(3H)-ones has been developed. Treatment of quinazolin-4(3H)-ones with HCCP, diisopropylethylamine (DIPEA), and thiophenols resulted in formation of the corresponding 4-arylthioquinazoline derivatives in moderate to excellent yields. This method has also been utilized to prepare 4-aryloxyquinazoline and 4-alkoxyquinazoline derivatives using phenols and sodium alkoxides as the nucleophiles.


OPEN ACCESS
Generally, 4-arylthioquinazolines and 4-aryloxyquinazolines are obtained through S N Ar substitution of electron-deficient 4-chloroquinazolines with the appropriate thiophenols or phenols in the presence of a base [9][10][11][12][13][14][15][16][17][18][19]. The common method for preparation of 4-chloroquinazolines is the chlorination of corresponding quinazolin-4(3H)-ones. The chlorination reagents used include SOCl 2 , POCl 3 , PCl 5 or their combinations, and the chlorination reactions are usually performed under harsh conditions. However, these chlorination reagents are not environmentally friendly, and some sensitive functional groups may be destroyed under the chlorination conditions. In addition, many 4-chloroquinazoline derivatives are moisture sensitive, thus special treatments are required for their purification and storage.
As a part of our research program focused on quinazoline chemistry [22,23], we have recently, reported that hexachlorocyclotriphosphazene (Cl 6 N 3 P 3 , HCCP) can be used as an inexpensive and readily available activating reagent in the direct amination of quinazolin-4(3H)-ones (1) [24]. In the reaction, quinazolin-4(3H)-ones are activated in situ with HCCP to generate the highly reactive phosphonium intermediate 2, then amines can nucleophilically attack 2 to form 4-aminoquinazolines. Thus, we speculated that other nucleophiles, such as thiophenol and phenol ones, might attack 2 to form the corresponding products. Herein, we report a HCCP-mediated, single-pot, facile synthesis of thioethers and ethers from quinazolin-4(3H)-ones in moderate to excellent yields (Scheme 1).

Results and Discussion
Initially, the reaction of quinazolin-4(3H)-one (1a) and thiophenol was investigated as the model reaction to establish the feasibility of the strategy and to optimize the reaction conditions. The effects of solvent, base, temperature and HCCP loading, etc., were evaluated for this model reaction, and the results are summarized in Table 1.  Compared with triethylamine (TEA), K 2 CO 3 and Cs 2 CO 3 (entries 1-3), diisopropylethylamine (DIPEA) was found to be the most effective in the model reaction of 1a and thiophenol (entry 4). The results in Table 1 show that the solvent can greatly affect the reaction, and acetonitrile led to much better yield of product 3 than tetrahydrofuran, N,N-dimethylformamide or dichloromethane (entries 4-7). According to Scheme 1, 1.0 equiv. HCCP loading was enough, but we found that increasing the HCCP loading from 1.0 to 1.1 equiv. resulted in 5% yield increases (entry 8 versus entry 4). After in situ activation of 1a with HCCP at room temperature for 1 h, the S N Ar substitution of phosphonium intermediate 2a (R 1 = H) with thiophenol was performed at 45 °C. At both lower and higher temperature, the yield of 3 decreased (entries 9 and 10). Like the HCCP-mediated direct amination of quinazolin-4(3H)-ones with amines [24], when the thiophenol nucleophile attacks 2a, two competitive S N Ar substitutions were possible, either on the C-O bond or P-Cl bond. Thus, five to six equiv. of thiophenol and DIPEA were needed in this reaction. It was found variation of the amount of thiophenol or DPIEA from 6.0 equiv. to 5.0 equiv. did not significantly change the results (entry 4 versus entries 11 and 13), whereas upon decreasing the amount of thiophenol or DPIEA to 4.0 equiv., the yield of 3 was obviously decreased (entries 12 and 14). On the basis of these experimental data, the optimal reaction conditions were: 1.1 equiv. of HCCP, 5.0 equiv. of DIPEA, 5.0 equiv. of thiophenol, 45 °C of reaction temperature and acetonitrile as the reaction solvent, and these were employed in the following studies.

General
1 H-NMR (500 MHz) and 13 C-NMR (125 MHz) spectra were obtained on a Bruker Avance III spectrometer. CDCl 3 and DMSO-d 6 were used as the solvent with tetramethylsilane (TMS) as the internal standard. Low and high resolution mass spectra were recorded in the ESI mode on an Agilent 6210 LC/TOF mass spectrometer. Melting points were measured using XRL-1 melting point instrument and are uncorrected. Quinazolin-4(3H)-ones were synthesized from anthranilic acids and formamidine acetate, and their structures were confirmed by MS, 1 H-NMR, and 13 C-NMR. Other reagents were purchased from supplier and used without any further treatment.

General Procedure for HCCP-Mediated Formation of Thioethers and Ethers from Quinazolin-4(3H)-ones
Quinazolin-4(3H)-ones (1, 0.5 mmol), HCCP (171.2 mg, 0.55 mmol, 1.1 equiv.), DIPEA (323.8 mg, 2.5 mmol, 5 equiv.), and CH 3 CN (5 mL) were added to a nitrogen purged vial. The reaction mixture was stirred at room temperature for 1 h as activation time. Then nucleophile (2.5 mmol, 5 equiv. was added, and the reaction mixture was stirred at 45 °C for 23 h. The reaction mixture was partially concentrated under reduced pressure. The crude product was separated on a silica gel plate with ethyl acetate-hexane (1:10 or 1:5) as eluent. Then the area corresponding to the product was scraped off the TLC plate, and extracted with dichloromethane. The extract was concentrated to afford the corresponding products (3-29).    (18

Conclusions
In summary, we have successfully developed an HCCP-mediated direct formation of thioethers (4-arylthioquinazolines) from quinazolin-4(3H)-ones and thiophenols in moderate to excellent yields. This method has also been utilized to prepare quinazoline ethers, including 4-aryloxyquinazolines and 4-alkoxyquinazolines, using phenols and sodium alkoxides as the nucleophiles. This direct formation of quinazoline (thio)ethers is mild, convenient, and suitable for a wide range of less expensive nucleophiles. This methodology would facilitate the syntheses of 4-arylthioquinazoline and 4-aryloxyquinazoline derivatives in medicinal chemistry.