Introduction

Fused triazole and pyrimidine ring systems have been an interesting topic in the fields of medicinal and agricultural chemistry for many years [1, 2]. Among their important effects, some triazolopyrimidine derivatives are known as dual thrombin/factor Xa inhibitors [3], blood pressure regulators [4], antibacterial agents [5], human adenosine A2a and A3 receptor ligands [6], and cardiovascular vasodilators [7]. Additionally, many triazolopyrimidine-2-sulfonamide derivatives, such as florasulam, flumetsulam, and metosulam, are commercially available as acetolactate synthase-inhibiting herbicides [8, 9]. Recently some new substituted pyrimidine derivatives have been synthesized, which exhibit analgesic, anti-inflammatory, antiparkinsonian, and androgenic–anabolic activities [10–12].

It is well known that multicomponent reactions (MCR) consisting of two or more synthetic steps, which are carried out without isolation of any intermediate, allow to reduce time and save money, energy, and raw materials. Also, the development of simple synthetic routes for widely used organic compounds from readily available reagents is one of the major tasks in organic synthesis.

Many literature reports concerning the synthesis of systems incorporating a triazolopyrimidine moiety [13] either start from reaction of hydrazine with an acid derivative (orthoformate [14] or activated acids [15]) or via oxidative cyclization of a hydrazone with reagents such as N-Bromosuccinimide (NBS) [16], lithium iodide or sodium carbonate [17], Pb(OAc)4 [18], FeCl3 [19], and iodobenzene diacetate [20].

In this paper, we report the first synthesis of some amino derivatives of triazolopyrimidine by three-component condensation of aromatic aldehydes, ethyl cyanoacetate, and 3,5-diamino-1,2,4-triazole in alkaline ethanol.

Results and discussion

One of the most widely used routes for preparation of 2-amino-1,2,4-triazolo[1,5-a]pyrimidines is cyclocondensation of 3,5-diamino-1,2,4-triazole with unsaturated aldehydes and ketones followed by heteroaromatization of the resulting 2-amino-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidines [21, 22]. There is no report concerning one-pot synthesis of 2-amino-[1,2,4]triazolopyrimidine compounds using aromatic aldehydes, ethyl cyanoacetate, and 3,5-diamino-1,2,4-triazole. Of course synthesis of 2-amino-6-hydroxy-4-arylpyrimidine-5-carbonitriles has been developed by three-component condensation of aromatic aldehydes, ethyl cyanoacetate, and guanidine hydrochloride [23]. The target products 5a–5i were synthesized by a three-component condensation procedure as shown in Table 1. Firstly, the aromatic aldehyde 1 reacted with ethyl cyanoacetate (2) to afford intermediate 3, which cyclized with 3,5-diamino-1,2,4-triazole (4) to give 2-amino-[1,2,4]triazolopyrimidines 5a–5i. The formation of the products 5a–5i is assumed to take place via an initial addition of the more nucleophilic endocyclic nitrogen in 3,5-diamino-1,2,4-triazole to the intermediate 3 with subsequent intramolecular cyclization and aromatization to give the final products 5a–5i, adapting a mechanism postulated by Shaaban [24]. The method exploited works well with a variety of aromatic aldehydes as well as heteroaromatic aldehydes to afford corresponding 2-amino-[1,2,4]triazolopyrimidine derivatives in excellent yields (Table 1). We reasoned that electron-donating as well as electron-withdrawing groups present in aryl aldehydes do not alter the theme of the method in terms of yield. The mass spectrum of compound 5a, taken as an example of the prepared series, revealed a molecular ion peak at m/z = 252. Its 1H NMR spectrum revealed a broad singlet signal at δ = 3.4 ppm due to NH2 protons and multiple signals at δ = 6.9–7.9 ppm due to phenyl protons, in addition to a singlet signal at 13.1 ppm due to the OH proton. With this encouraging result in hand, we attempted the synthesis of some 2-(cyanoamino)-4-hydroxypyrimidine-5-carbonitrile compounds. Products 7a–7h were synthesized by a three-component condensation procedure as shown in Table 2. Firstly, the aromatic aldehyde 1 reacted with ethyl cyanoacetate (2) to afford intermediate 3, which cyclized with cyanoguanidine hydrochloride (6) to give 2-(cyanoamino)-4-hydroxypyrimidine-5-carbonitriles 7a–7h.

Table 1 Synthesis of 2-amino-[1,2,4]triazolopyrimidine derivatives
Full size table
Table 2 Synthesis of 2-(cyanoamino)-4-hydroxypyrimidine-5-carbonitriles
Full size table

We used a series of aromatic and heteroaromatic aldehydes having electron-donating as well as electron-withdrawing substituents to obtain the corresponding 2-(cyanoamino)-4-hydroxypyrimidine-5-carbonitriles (Table 2). As can be seen from Table 2, when aromatic aldehydes containing electron-donating groups were employed, a longer reaction time was required than those of electron-withdrawing groups on aromatic rings. The structures of all compounds were characterized by 1H NMR, 13C NMR, IR, MS, and elemental analyses.

Conclusion

Herein we report synthesis of several new 2-amino-5-hydroxy[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitriles 5a–5i and 2-(cyanoamino)-4-hydroxypyrimidine-5-carbonitriles 7a–7h via a simple and convenient method by three-component condensation of aromatic aldehydes, ethyl cyanoacetate, and 3,5-diamino-1,2,4-triazole or cyanoguanidine hydrochloride, respectively, in alkaline ethanol. The method exploited works well with a variety of aromatic aldehydes as well as heteroaromatic aldehydes to afford corresponding triazolopyrimidine and pyrimidine cyanamide derivatives in excellent yields (Tables 1, 2). Electron-donating as well as electron-withdrawing groups present in aryl aldehydes do not alter the theme of the method in terms of yield.

Experimental

All reagents and solvents were purchased from Merck and Aldrich and used without further purification. The reactions were carried out under an atmosphere of air unless otherwise specified. The elemental analyses for C, H, and N were performed using a Heraeus CHN-O-Rapid analyzer, and results agreed with calculated values. 1H NMR spectra were recorded at 500 MHz and 13C NMR spectra at 125 MHz on a Bruker spectrometer. Chemical shifts are reported in ppm relative to tetramethylsilane as internal standard. Mass spectra were taken by a Micromass Platform II in electrospray ionization (EI) mode (70 eV). Silica plates (Merck) were used for thin-layer chromatography (TLC) analysis.

General procedure for the synthesis of triazolopyrimidine derivatives

Aromatic aldehyde (10 mmol) and ethyl cyanoacetate (10 mmol) were added to 6 cm3 2 M NaOH solution in 25 cm3 ethanol. The mixture was stirred mechanically for 15 min, then 3,5-diamino-1,2,4-triazole (10 mmol) was added and the reaction mixture was refluxed until completion of reaction as monitored by TLC. After reaction completion (140–180 min), the reaction mixture was poured into iced water and neutralized by HCl (1:1) to get the desired product. The separated solid was filtered and washed with little distilled water to remove acid. Finally, the crude product was purified by recrystallization from ethanol to get pure product in almost quantitative yield.

2-Amino-5-hydroxy-7-phenyl[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5a, C12H8N6O)

White solid; m.p.: 182–184 °C (EtOH); IR (KBr): \( \bar{\nu } \) = 3,360, 3,310, 2,831, 2,229, 1,721, 1,583, 1,559, 1,460, 1,428, 1,262, 806 cm−1; UV–vis (95% EtOH): λ max = 420, 410, 265 nm; 1H NMR (CDCl3): δ = 3.9 (bs, 2H, NH2), 6.91–7.92 (m, 5H, Ar–H), 13.11 (bs, 1H, OH) ppm; 13C NMR (CDCl3): δ = 94.31, 112.61, 117.81, 118.53, 134.40, 148.13, 151.34, 153.47, 153.72, 164.75 ppm; MS (EI): m/z = 252 (M+), 225, 175, 147.

2-Amino-5-hydroxy-7-(4-hydroxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5b, C12H8N6O2)

Yellow solid; m.p.: 192–194 °C (EtOH); IR (KBr): \( \bar{\nu } \) = 3,341, 3,315, 2,842, 2,230, 1,625, 1,589, 1,568, 1,462, 1,425, 1,232, 805 cm−1; UV–vis (95% EtOH): λ max = 415, 413, 260 nm; 1H NMR (CDCl3): δ = 3.30 (bs, 2H, NH2), 3.51 (bs, 1H, OH), 7.16 (d, J = 9.1 Hz, 2H, Ar–H), 7.15 (d, J = 9.1 Hz, 2H, Ar–H), 8.75 (bs, 1H, OH) ppm; 13C NMR (CDCl3): δ = 96.22, 113.63, 116.56, 122.93, 133.63, 147.00, 150.31, 152.49, 166.03, 166.71 ppm; MS (EI): m/z = 268 (M+), 242, 191, 165.

2-Amino-5-hydroxy-7-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5c, C13H10N6O2)

White solid; m.p.: 102–104 °C (EtOH); IR (KBr): \( \bar{\nu } \) = 3,345, 3,321, 2,835, 2,227, 1,740, 1,585, 1,567, 1,471, 1,452, 1,244, 802 cm−1; UV–vis (95% EtOH): λ max = 421, 417, 250 nm; 1H NMR (CDCl3): δ = 3.83 (bs, 2H, NH2), 3.85 (s, 3H, CH3), 7.14 (d, J = 8.9 Hz, 2H, Ar–H), 8.06 (d, J = 8.9 Hz, 2H, Ar–H), 8.30 (s, 1H, OH) ppm; 13C NMR (CDCl3): δ = 53.73, 98.24, 114.94, 116.18, 123.90, 133.50, 145.13, 154.53, 155.41, 162.85, 163.56 ppm; MS (EI): m/z = 282 (M+), 252, 227, 211, 135.

2-Amino-7-(4-(dimethylamino)phenyl)-5-hydroxy-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5d, C14H13N7O)

Yellow solid; m.p.: 225–226 °C (EtOH); IR (KBr): \( \bar{\nu } \) = 3,361, 3,318, 2,830, 2,230, 1,716, 1,582, 1,562, 1,459, 1,450, 1,231, 800 cm−1; UV–vis (95% EtOH): λ max = 426, 411, 256 nm; 1H NMR (CDCl3): δ = 3.06 (s, 6H, CH3), 3.31 (bs, 2H, NH2), 6.81 (d, J = 9.1 Hz, 2H, Ar–H), 7.92 (d, J = 9.1 Hz, 2H, Ar–H), 13.27 (s, 1H, OH) ppm; 13C NMR (CDCl3): δ = 42.12, 96.21, 111.64, 117.88, 118.39, 133.43, 133.50, 142.16, 148.73, 153.47, 153.72, 164.75 ppm; MS (EI): m/z = 295 (M+), 279, 270, 252, 176, 151, 135.

2-Amino-5-hydroxy-7-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5e, C13H10N6O)

White solid; m.p.: 234–235 °C (EtOH); IR (KBr): \( \bar{\nu } \) = 3,352, 3,323, 2,228, 1,700, 1,574, 1,559, 1,449, 1,445, 1,237, 814 cm−1; UV–vis (95% EtOH): λ max = 413, 410, 242 nm; 1H NMR (CDCl3): δ = 2.21 (s, 3H, CH3), 3.51 (bs, 2H, NH2), 7.01 (d, J = 8.2 Hz, 2H, Ar–H), 7.98 (d, J = 8.2 Hz, 2H, Ar–H), 12.21 (s, 1H, OH) ppm; 13C NMR (CDCl3): δ = 43.12, 93.40, 112.16, 117.81, 119.23, 132.85, 133.17, 140.20, 148.13, 151.79, 152.74, 165.83 ppm; MS (EI): m/z = 266 (M+), 252, 250, 241, 176, 151, 135.

2-Amino-5-hydroxy-7-(4-nitrophenyl)[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5f, C12H7N7O3)

Brown solid; m.p.: 160–163 °C (EtOH); IR (KBr): \( \bar{\nu } \) = 3,355, 3,319, 2,815, 2,233, 1,710, 1,579, 1,562, 1,450, 1,447, 1,231, 804 cm−1; UV–vis (95% EtOH): λ max = 417, 415, 248 nm; 1H NMR (CDCl3): δ = 3.12 (bs, 2H, NH2), 7.21 (d, J = 8.6 Hz, 2H, Ar–H), 8.09 (d, J = 8.6 Hz, 2H, Ar–H), 11.01 (s, 1H, OH) ppm; 13C NMR (CDCl3): δ = 95.42, 112.19, 116.57, 119.24, 133.81, 134.46, 140.55, 147.18, 150.93, 152.63, 166.43 ppm; MS (EI): m/z = 297 (M+), 281, 272, 252, 176, 151, 135.

2-Amino-7-(3,5-dimethoxyphenyl)-5-hydroxy[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5g, C14H12N6O3)

Brown solid; m.p.: 172–175 °C (EtOH); IR (KBr): \( \bar{\nu } \) = 3,349, 3,310, 2,838, 2,222, 1,708, 1,580, 1,566, 1,452, 1,448, 1,220, 825 cm−1; UV–vis (95% EtOH): λ max = 421, 410, 241 nm; 1H NMR (CDCl3): δ = 3.80 (s, 3H, CH3), 3.81 (s, 3H, CH3), 3.28 (bs, 2H, NH2), 6.09 (s, 1H, Ar–H), 8.02 (s, 2H, Ar–H), 9.22 (s, 1H, OH) ppm; 13C NMR (CDCl3): δ = 54.12, 55.09, 98.58, 114.23, 117.35, 123.04, 133.92, 135.43, 148.27, 151.13, 153.60, 167.12 ppm; MS (EI): m/z = 312 (M+), 287, 282, 252, 176.

2-Amino-5-hydroxy-7-(4-pyridyl)[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5h, C11H7N7O)

Yellow solid; m.p.: 229–231 °C (EtOH); IR (KBr): \( \bar{\nu } \) = 3,347, 3,316, 2,840, 2,214, 1,702, 1,586, 1,583, 1,450, 1,443, 1,271, 815 cm−1; UV–vis (95% EtOH): λ max = 426, 407, 246 nm; 1H NMR (CDCl3): δ = 3.41 (bs, 2H, NH2), 7.41 (d, J = 8.2 Hz, 2H, Py-H), 8.23 (d, J = 8.2 Hz, 2H, Py-H), 9.81 (s, 1H, OH) ppm; 13C NMR (CDCl3): δ = 97.23, 113.27, 118.31, 122.63, 132.25, 147.20, 152.62, 155.61, 168.44 ppm; MS (EI): m/z = 253 (M+), 228, 229, 176.

2-Amino-5-hydroxy-7-(2-thienyl)[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5i, C10H6N6OS)

Red solid; m.p.: 229–231 °C (EtOH); IR (KBr): \( \bar{\nu } \) = 3,340, 3,320, 2,218, 1,717, 1,580, 1,575, 1,430, 1,449, 1,201, 805 cm−1; UV–vis (95% EtOH): λ max = 416, 410, 241 nm; 1H NMR (CDCl3): δ = 3.55 (bs, 2H, NH2), 7.34 (dd, J = 8.2, 7.3 Hz, 1H, Th–H), 8.05 (d, J = 8.2 Hz, 1H, Th–H), 8.20 (d, J = 7.3 Hz, 1H, Th–H), 9.81 (s, 1H, OH) ppm; 13C NMR (CDCl3): δ = 97.50, 116.79, 128.68, 128.83, 135.49, 137.17, 139.36, 140.25, 147.77, 162.61 ppm; MS (EI): m/z = 258 (M+), 228, 229, 176.

General procedure for the synthesis of (cyanoamino) pyrimidine derivatives

Aromatic aldehyde (10 mmol) and ethyl cyanoacetate (10 mmol) were added to 6 cm3 2 M NaOH solution in 25 cm3 ethanol. The mixture was stirred mechanically for 15 min, then cyanoguanidine hydrochloride (10 mmol) was added and the reaction mixture was refluxed until completion of reaction as monitored by TLC. After reaction completion (140–160 min), the reaction mixture was poured into iced water and neutralized by HCl (1:1) to get the desired product. The separated solid was filtered and washed with little distilled water to remove acid. Finally, the crude product was purified by recrystallization from ethanol to get pure product in almost quantitative yield.

2-(Cyanoamino)-4-hydroxy-6-phenylpyrimidine-5-carbonitrile (7a, C12H7N5O)

White solid; m.p.: 120–122 °C (EtOH); IR (KBr): \( \bar{\nu } \) = 3,342, 3,319, 2,232, 1,705, 1,575, 1,566, 1,420, 1,410, 822 cm−1; UV–vis (95% EtOH): λ max = 375, 252 nm; 1H NMR (CDCl3): δ = 4.13 (bs, 1H, NH), 7.01–8.02 (m, 5H, Ar–H), 8.43 (s, 1H, OH) ppm; 13C NMR (CDCl3): δ = 94.11, 112.24, 116.60, 118.35, 134.81, 136.35, 152.74, 153.04, 147.77, 164.56 ppm; MS (EI): m/z = 237 (M+), 212, 197, 161, 96.

2-(Cyanoamino)-4-hydroxy-6-(4-hydroxyphenyl)pyrimidine-5-carbonitrile (7b, C12H7N5O2)

White solid; m.p.: 166–168 °C (EtOH); IR (KBr): \( \bar{\nu } \) = 3,432, 3,220, 2,905, 2,247, 1,715, 1,676, 1,575, 1,566, 1,432, 1,420, 834 cm−1; UV–vis (95% EtOH): λ max = 382, 262 nm; 1H NMR (CDCl3): δ = 3.70 (s, 1H, NH), 4.52 (s, 1H, OH), 6.89 (d, J = 8.1 Hz, 2H, Ar–H), 7.85 (d, J = 8.1 Hz, 2H, Ar–H), 8.16 (s, 1H, OH) ppm; 13C NMR (CDCl3): δ = 93.10, 113.21, 117.69, 118.36, 133.82, 137.30, 147.67, 151.46, 153.55, 165.16 ppm; MS (EI): m/z = 253 (M+), 228, 161.

2-(Cyanoamino)-4-hydroxy-6-(4-methoxyphenyl)pyrimidine-5-carbonitrile (7c, C13H9N5O2)

White solid; m.p.: 122–124 °C (EtOH); IR (KBr): \( \bar{\nu } \) = 3,339, 3,210, 2,825, 2,243, 1,668, 1,583, 1,562, 1,421, 804 cm−1; UV–vis (95% EtOH): λ max = 371, 261 nm; 1H NMR (CDCl3): δ = 2.82 (bs, 1H, NH), 3.87 (s, 3H, CH3), 7.14–8.01 (m, 4H, Ar–H), 8.10 (s, 1H, OH) ppm; 13C NMR (CDCl3): δ = 53.26, 96.18, 113.14, 116.57, 117.64, 130.76, 135.30, 150.04, 153.67, 146.71, 163.55 ppm; MS (EI): m/z = 267 (M+), 237, 161.

2-(Cyanoamino)-4-(4-(dimethylamino)phenyl)-6-hydroxypyrimidine-5-carbonitrile (7d, C14H12N6O)

Red solid; m.p.: 140–142 °C (EtOH); IR (KBr): \( \bar{\nu } \) = 3,341, 3,247, 2,827, 2,251, 1,670, 1,572, 1,558, 1,449, 813 cm−1; UV–vis (95% EtOH): λ max = 368, 268 nm; 1H NMR (CDCl3): δ = 3.07 (s, 6H, CH3), 3.78 (bs, 1H, NH), 6.82 (d, J = 7.9 Hz, 2H, Ar–H), 7.95 (d, J = 7.9 Hz, 2H, Ar–H), 8.10 (s, 1H, OH) ppm; 13C NMR (CDCl3): δ = 52.62, 91.69, 111.70, 117.51, 118.27, 133.81, 153.77, 154.26, 163.98 ppm; MS (EI): m/z = 280 (M+), 237, 161.

2-(Cyanoamino)-4-hydroxy-6-(4-methylphenyl)pyrimidine-5-carbonitrile (7e, C13H9N5O)

White solid; m.p.: 89–102 °C (EtOH); IR (KBr): \( \bar{\nu } \) = 3,336, 3,232, 2,810, 2,262, 1,690, 1,562, 1,551, 1,440, 823 cm−1; UV–vis (95% EtOH): λ max = 354, 262 nm; 1H NMR (CDCl3): δ = 2.57 (s, 3H, CH3), 3.61 (bs, 1H, NH), 6.80 (d, J = 8.1 Hz, 2H, Ar–H), 7.21 (d, J = 8.1 Hz, 2H, Ar–H), 8.26 (s, 1H, OH) ppm; 13C NMR (CDCl3): δ = 28.67, 90.55, 112.10, 116.48, 117.49, 132.80, 151.73, 154.44, 165.67 ppm; MS (EI): m/z = 251 (M+), 237, 161.

2-(Cyanoamino)-4-hydroxy-6-(4-nitrophenyl)pyrimidine-5-carbonitrile (7f, C12H6N6O3)

Orange solid; m.p.: 130–132 °C (EtOH); IR (KBr): \( \bar{\nu } \) = 3,382, 3,210, 2,843, 2,223, 1,681, 1,556, 1,429, 838 cm−1; UV–vis (95% EtOH): λ max = 371, 261 nm; 1H NMR (CDCl3): δ = 6.13 (bs, 1H, NH), 7.23–8.21 (m, 4H, Ar–H), 8.71 (s, 1H, OH) ppm; 13C NMR (CDCl3): δ = 99.87, 113.15, 116.44, 118.24, 133.46, 134. 25, 152.13, 153.56, 166.51 ppm; MS (EI): m/z = 282 (M+), 237, 161.

2-(Cyanoamino)-6-(3,5-dimethoxyphenyl)-4-hydroxypyrimidine-5-carbonitrile (7g, C14H11N5O3)

Yellow solid; m.p.: 118–120 °C (EtOH); IR (KBr): \( \bar{\nu } = 3{,}341, \) = 3,341, 3,320, 2,841, 2,227, 1,640, 1,565, 1,451, 1,440, 815 cm−1; UV–vis (95% EtOH): λ max = 356, 251 nm; 1H NMR (CDCl3): δ = 3.76 (s, 3H, CH3), 3.79 (s, 3H, CH3), 3.91 (bs, 1H, NH), 6.23 (s, 1H, Ar–H), 8.35 (s, 2H, Ar–H), 8.20 (s, 1H, OH) ppm; 13C NMR (CDCl3): δ = 53.10, 54.22, 95.51, 113.21, 116.61, 128.55, 132.91, 134.81, 147.20, 152.19, 155.65, 166.19 ppm; MS (EI): m/z = 397 (M+), 267, 237.

2-(Cyanoamino)-4-hydroxy-6-(4-pyridyl)pyrimidine-5-carbonitrile (7h, C11H6N6O)

Yellow solid; m.p.: 190–192 °C (EtOH); IR (KBr): \( \bar{\nu } \) = 3,351, 3,326, 2,821, 2,219, 1,652, 1,580, 1,456, 1,441, 805 cm−1; UV–vis (95% EtOH): λ max = 352, 257 nm; 1H NMR (CDCl3): δ = 3.81 (bs, 1H, NH), 7.40 (d, J = 8.0 Hz, 2H, Py-H), 8.15 (d, J = 8.0 Hz, 2H, Py-H), 9.63 (s, 1H, OH) ppm; 13C NMR (CDCl3): δ = 93.66, 113.56, 117.41, 123.51, 133.20, 135.41, 153.66, 155.60, 166.53 ppm; MS (EI): m/z = 238 (M+), 161.