Synthesis and Reactivity of [1,2,4]Triazolo-annelated Quinazolines

This paper reports the synthesis of phenyl-substituted 2-alkoxy(methylsulfanyl)-1,2,4-triazolo[1,5-a]quinazolines starting from N-cyanoimidocarbonates and substituted hydrazinobenzoic acids as building blocks. Thionation or chlorination of the inherent lactam moiety in the target compounds followed by treatment with multifunctional nucleophiles provided access to a variety of derivatives.


Introduction
Triazolo-annelated quinazolines are known to constitute a pharmacologically interesting class of compounds. For instance, the novel compound Ia is effective adenosine antagonist whereas the related compound Ib was found to be benzodiazepine receptor antagonist [1][2][3]. The recently reported 1,2,4triazoloquinazolines of type II were also found to exhibit promising antihistaminic activity against histamine induced bronchospasms and showed negligible sedation, compared to chlorpheniramine maleate, and could therefore serve as lead molecules for further modification to obtain a clinically useful class of non-sedative antihistamines [4,5]. Furthermore, some triazoloquinazolines IIIa which originated from N-cyanoimidocarbonates as synthons, have been described as potent protein kinase inhibitors [6].
In our previous paper on the 1,2,4-triazolo [1,5-a]quinazolines series IIIb, the corresponding alkylated derivatives have been proven as excellent agents for controlling the plant growth diseases OPEN ACCESS caused by fungal pathogens, and some chlorinated compounds have shown an interesting affinity towards adenosine receptors [7].

Results and Discussion
The cornerstone of the strategy for the synthesis of our target products was the preparation of compounds 5a-h (Scheme 1, Table 1). The first step, the preparation of several dialkyl N-cyanoimidocarbonates 1 from equimolar amounts of cyanogen bromide and the corresponding alcohol was reported previously [8]. In addition, it has been found that, the reaction of cyanamide with carbon disulfide in the presence of KOH followed by the alkylation with methyl iodide gives dimethyl Ncyanoimidodithiocarbonate [9]. Scheme 1. Synthesis of [1,2,4]triazolo [1,5- Diazotization of the corresponding anthranilic acids [10] followed by the reduction with sulphur dioxide afforded the substituted 2-hydrazinobenzoic acids 2. Based on the high reactivity of Ncyanoimidocarbonates towards hydrazines to produce 1,2,4-triazole derivatives [11][12][13], reaction of 1 with 2 in ethanol in the presence of triethylamine under ice cooling analogously provided the intermediate 1,2,4-triazole derivatives 4, which upon treatment with hydrochoric acid produced the target [1,2,4]triazolo[1,5-a]quinazolin-5-ones 5a-h in 50-68% yield [14]. The structures of the novel compounds 5a-h have been established on the basis of their IR, 1 H-NMR and 13 C-NMR spectra and microanalysis.
The IR spectra of compounds 5a-h are characterized by a strong (C=O)-stretching band at 1,685-1,712 cm −1 .
Similarly, the corresponding thioxo derivatives 13a,b could be obtained in 56 and 61 % yield from the reaction of 10 with carbon disulfide in a molar ratio of 1:10 in refluxing pyridine for 2 h [26]. The IR spectra of 12 display strong (C=O) absorption bands at 1,702 and 1,711 cm −1 , and the 13 C-NMR spectra of 13 are characterized by a (C=S) resonance at 185.05 and 185.73 ppm. Replacement of the chlorine in compounds 9 by different hydrazides occurred smoothly in refluxing toluene to produce the [1,2,4]triazoloquinazolin-5-yl-carbohydrazides 14a,b in 65 and 76% yield [27]. The IR spectra of 14 are characterized by a strong (C=O) absorption band at 1,660, 1,673 and a weak (NH) absorption band at 3,184, 3,207 cm −1 , respectively. Like the reaction with hydrazides, the corresponding reaction of compounds 9 with carbazides according to literature [27] produced the respective [1,2,4]triazoloquinazolin-5-yl-hydrazine-carboxylic acid esters of type 15a,b in 75 and 80% yield as colorless solids. The IR spectra of 15 display a strong (C=O) absorption band at 1,708, 1,718 and a weak (NH) absorption band at 3,198, 3,261 cm −1 .
After having successfully elaborated the synthesis of the carbohydrazides 14, we became interested in seeing whether these compounds could be cyclo-condensed to the novel bis [1,2,4]triazoloquinazolines of type 16. In fact when amidrazones 14 were treated with phosphorus oxychloride at refluxing temperature for 2 h, followed by subsequent neutralization with saturated potassium carbonate solution or aqueous ammonia, the desired compounds 16a,b were obtained in 70 and 75% yield [28]. The completion of the internal cyclization was monitored by IR spectroscopy: disappearance of the (C=O) and (NH) absorption bands at 1,660, 1,673 and 3,184, 3,207 cm −1 signaled complete conversion of 14 to the tetracyclic compounds 16. When 5-chloro[1,2,4]triazoloquinazolines 9 were reacted with sodium azide in a molar ratio of 1:1.  Table 2) [29].
The aforementioned facile nucleophilic displacement of the chlorine atom in 9 prompted us to investigate the reaction of 9 with methyl 3-amino-thiophene-2-carboxylate, which theoretically should provide access to the novel pentacyclic compounds of type 18. Thus, when compounds 9 were reacted with methyl 3-amino-thiophene-2-carboxylate in absolute dioxane in a molar ratio of 1:1.6, followed by addition of sodium hydride, the target compounds 18a,b could be isolated from the reaction mixture in 69 and 81% yield [27]. The IR spectra of compounds 18 are characterized by (C=O) stretching bands at 1,670 and 1,677 cm −1 . Table 2. Prepared compounds 10-18.

General
Melting points (ºC) were determined on open glass capillaries using a Mettler FP 62 apparatus and are uncorrected. Elemental analyses (C, H, N, S) were in full agreement with the proposed structures within ± 0.4% of the theoretical values, and were carried out with a Heraeus CHN-O-Rapid Instrument. The IR (KBr) spectra were recorded on a Shimadzu FT-IR 8300. 1 H-NMR (400 MHz) and 13 C-NMR (100 MHz) spectra were recorded on a Bruker AMX 400 spectrometer and chemical shifts are giving in a (ppm) downfield from tetramethylsilane (TMS) as an internal standard, DMSO is used as solvent. Mass spectra were recorded on a Finnigan MAT 311A and on a VG 70-250S (VG Analytical) instrument. Follow up of the reactions and checking the purity of compounds was made by TLC on DC-Mikrokarten polygram SIL G/UV 254, from the Macherey-Nagel Firm, Duren Thickness: 0.25 m. Column chromatography was conducted on silica gel (ICN Silica 100-200, active 60 Å)

Chemistry
3.2.1. Synthesis of compounds 5a-h 10 mmol of substituted hydrazinobenzoic acid 2 was added portionwise to a stirred solution of 1 (10 mmol) in EtOH (20 mL) at 0 o C. Afterwards triethylamine (30 mmol) was added dropwise over a period of 30 min. After the addition was complete, the reaction mixture was left to stir overnight at room temperature. Acidification of the mixture was performed by conc. HCl under ice cooling followed by refluxing for 1-3 h. After cooling, the mixture was poured into ice/water, the resulting solid was filtered, washed with water and dried. Recrystallization from THF gave analytically pure colored cpmpounds 5a-h. [1,2,4]

Synthesis of compounds 6a-d
To a solution of 5 (1 mmol) in DMF (5 mL) was added potassium carbonate (1.2 mmol) portion wise over a period of 10 min at room temperature. After stirring for 20 min, the appropriate alkyl halide (1.5 mmol) was added dropwise and the reaction mixture was stirred for 18 h at room temperature. The mixture was poured into ice/water, the precipitate was filtered off, washed with water and dried. Analytically pure products 6a-d were obtained after recrystallization from THF. [1,2,4]

Synthesis of compounds 7a-d
A solution of 5 (1 mmol) in dry THF (5 mL) was added dropwise to a stirred suspension of LiAlH 4 (3 mmol) in dry THF (10 mL). After stirring at room temperature for 3 h, water (0.4 mL) was added carefully and the mixture was stirred for an additional 30 min. The reaction mixture was filtered and the solvent removed under reduced pressure, the residue was dissolved in THF and passed through a short column chromatography, the solvent was removed under reduced pressure, and the obtained solid was recrystallized from EtOAc/n-hexane.  [1,2,4]triazolo [1,5-a] [1,2,4]triazolo [1,5-a]

Synthesis of compounds 15a,b
A mixture of 9 (1 mmol) and benzyl carbazate or ethyl carbazate (2.2 mmol) was refluxed in benzene (10 mL) for 2.5 h. The solvent was removed under reduced pressure, the resulting solid was filtered off and recrystallized from MeOH.

Synthesis of compounds 16a,b
A mixture of 14 (0.5 mmol) and POCl 3 (5 mL) was refluxed at 100 o C for 2 h. After cooling, the excess of POCl 3 was removed under reduced pressure and the residue was treated with saturated aqueous solution of K 2 CO 3 under ice cooling. The resulting solids were collected by filtration and recrystallized from MeOH to afford 16a,b as colored pure products. [1,2,4]triazolo [1,5-