A new and facile synthetic approach to substituted 2-thioxoquinazolin-4-ones by the annulation of a pyrimidine derivative

Summary A new and facile synthesis of 2-thioxoquinazolin-4-ones by introducing a benzenoid system in the pyrimidine moiety by reacting ethoxymethylene derivatives of 1,3-diarylthiobarbituric acids (DTBA) with active methylene compounds, such as malononitrile and ethyl cyanoacetate, in presence of ZnCl2 has been developed.

There are two approaches for the solution-phase parallel synthesis of 2-thioxoquinazolin-4-ones [22]. The first approach is based on the reaction of methyl anthranilates with isothiocyanates in refluxing pyridine or DMF. The second approach involves briefly heating 2-(methylcarboxy)-benzeneisothiocyanates in isopropyl alcohol with a wide variety of primary aliphatic or aromatic amines and their derivatives. Thus, most of the methods for the preparation of such compounds start with the benzene ring in place followed by construction of the pyrimidine ring. We have developed a new facile and convenient synthetic approach to 2-thioxoquinazolin-4-ones by constructing the benzene ring onto an existing pyrimidine moiety.
As a part of our synthetic strategy, 1,3-diarylthiobarbituric acids (DTBA) were used as precursors for the synthesis of various fused heterocyclic compounds. In recent years, we have reported one-pot cyclizations of DTBA with hydrazine [23,24], hydroxylamine [25], guanidine [26], etc. In addition, one-pot cyclizations of DTBA-derived arylidenes have also been reported. Recently, we reported the synthesis of fused heterocycles from ethoxymethylene derivatives of DTBA [27]. In continuation of our work on the synthesis of fused heterocycles [28,29], we herein report full details of the work and studies related to the synthesis of 2-thioxoquinazolin-4-ones from the reaction of ethoxymethylene derivatives of DTBA and active methylene compounds, such as, malononitrile and ethylcyanoacetate.

Results and Discussion
DTBA are among the simplest synthetic intermediates and can be easily prepared in a one-pot reaction by treating 1,3-diaryl thioureas with malonic acid in the presence of acetyl chloride. DTBA undergoes condensation with ethyl orthoformate to give the condensation products, 5-ethoxymethylene-1,3-diaryl-2thiobarbituric acids 1. These condensation products possess three electrophilic centers and can undergo cyclocondensation with various nucleophiles to give a number of fused heterocyclic systems that contain a pyrimidine ring. Thus, treatment of 1 with malononitrile in presence of NH 4 OAc with ZnCl 2 as catalyst in refluxing acetic acid gives the corresponding 2-thioxoquinazolin-4-ones 2 in 78-85% overall yields (Scheme 1).
During the optimization of the cyclization of ethoxymethylene derivatives of DTBA with malononitrile, the choice of the base proved to be an important parameter. The use of NEt 3 (TEA) or piperidine (in DCM or ethanol) resulted in the formation of complex mixtures (Table 1, entries 1-4). Screening at different temperatures demonstrates that some of the catalysts failed to react at room temperature (rt) and also even after heating under However, when this reaction was repeated in refluxing solvent the yield was increased. In contrast, the use of NH 4 OAc in refluxing acetic acid resulted in a clean cyclization to give the desired product. Dehydration and decarboxylation induced by the higher temperature and the acid produces the required quinazoline. To obtain the optimal conditions, a variety of catalysts were also investigated to detect the catalytic activities of different metal ions and acetate in the production of 2a (Table 2). It was found that NH 4 OAc/AcOH in ZnCl 2 was the most effective ( Table 2, entries 1 and 7-13); CuCl 2 and HgCl 2 also promoted the reactions, but the yields were poor, 22% and 12%, respectively ( Table 2, entries 2 and  3). Other catalysts, including FeCl 3 , AlCl 3 etc. failed to afford any 2a (Table 2, entries 4-6). We further found that the best yield of 2a was obtained when 5 equiv of ZnCl 2 was used ( Table 2, entry 13). The excessive amount of ZnCl 2 for the annulation is probably due to the chelating effect of zinc ion. Thus, the NH 4 OAc/AcOH combination in ZnCl 2 was found to be the best and gave the highest yield of 2b (85%) after refluxing for 6 h. HgCl 2 (1 equiv) a 12 4 FeCl 3 (1 equiv) a 0 5 AlCl 3 (1 equiv) a 0 6 SnCl 2 (1 equiv) a 0 7 ZnCl 2 (0.5 equiv) a 18 8 ZnCl 2 (2 equiv) a 45 9 ZnCl 2 (5 equiv, 2 h) a 62 10 ZnCl 2 (5 equiv, rt, 4 h) 28 11 ZnCl 2 (5 equiv, rt, 6 h) 38 12 ZnCl 2 (5 equiv, 4 h) a 74 13 ZnCl 2 (5 equiv, 6 h) a 85 a Reactions were carried out with NH 4 OAc and AcOH at reflux. b Isolated yield.
After optimizing the conditions, various DTBAs were used to react with malononitrile and the results are listed in Table 3. On the basis of the above noted results, a possible reaction mechanism is shown in Scheme 2. The reaction of the 5-ethoxymethylene-1,3-diaryl-2-thiobarbituric acids with malononitrile gave intermediate A, which undergoes intramolecular cyclization to form the intermediate B, and then acid hydrolysis of B afforded 2. Further evidence is that the reaction of 5-ethoxymethylene-1,3-diaryl-2-thiobarbituric acids with malononitrile under the standard conditions. This reaction only gave quinazolines and no other products were detected. In addition, this proposed mechanism was also confirmed from the literature [30,31]. The reaction of 5-ethoxymethylene-1,3-diaryl-2-thiobarbituric acids 1 with ethylcyanoacetate in presence of ammonium acetate and acetic acid with ZnCl 2 as a catalyst afforded 7-hydroxy-2,3-dihydro-2-thioxo-1,3-diarylquinazolin-4(1H)ones 3 in 76-87% overall yields (Scheme 3) [32,33] and these results are listed in Table 4.

Supporting Information
Supporting Information File 1 Experimental part.