The malononitrile dimer is an attractive organic reagent containing several reactive centers with different nature allowing to construct a diversity of polyfunctional derivatives. For example, some recent works were dedicated to the application of malononitrile dimer in synthesis of new condensed heterocyclic systems, such as furo[3,2-c]-isothiazole,1 furo[3,2-c]isoselenazole,2 pyrido[3',2':5,6]-pyrano[3,2-c]carbazoles,3 1,8-naphthyridines,4 chromeno-[2,3-b]pyridines,5 pyrido[3,2-c]pyridazines,6 and pyrido-[3,2-a]indolizines.7 These studies demonstrated the large potential of malononitrile dimer for preparation of new ring systems, which can be studied and developed further.

Recently, we reported a new variation of domino process providing access to polyfunctional [1,2,3]triazolo-[4,5-b]pyridines via the reaction of aryl azides with malononitrile dimer.8 The reaction occurred in two steps through the formation of 5-aminotriazole intermediate, which underwent spontaneous cyclization leading to the pyridine ring annulation. The scope of the reaction was demonstrated on 9 compounds with various substituents in the aromatic ring. However, aryl or hetaryl azides that have carbonyl center in ortho position to azide moiety have not been studied in the reaction with malononitrile dimer. It was previously shown that such azides reacted with activated acetonitriles to form condensed [1,2,3]triazolo-[1,5-a]pyrimidines.9 Such reaction proceeds rapidly (generally during the mixing of the reagents) and leads to the triazolopyrimidine formation in excellent yields, as it was described in a number of our articles.9 Therefore, we decided to examine ortho-substituted aryl azides in the reaction with malononitrile dimer to identify the direction of reaction and to find out which system, [1,2,3]triazolo-[1,5-a]pyrimidine or [1,2,3]triazolo[4,5-b]pyridine, will be formed preferably (Scheme 1).

scheme 1

Scheme 1

The reactions of azides 1a–g with malononitrile dimer (2) were carried out under standard protocol8 by refluxing their solutions in methanol with sodium methylate until the precipitate was formed. It was found, that in the case of o-alkoxycarbonyl azides 1a–c, reaction proceeds in a chemoselective manner leading to only one of the two possible fused heterocyclic compounds. Thus, [1,2,3]triazolo[1,5-a]quinazolines 3a–c (Scheme 2) were isolated in excellent yields after 1 min refluxing.

scheme 2

Scheme 2

The reaction occurred similarly in the case of alkyl azidothiophenecarboxylates 1d–f, allowing to obtain thieno-[2,3-e]- or [3,2-e][1,2,3]triazolo[1,5-a]pyrimidines 3d–f in high yields (Scheme 3).

scheme 3

Scheme 3

The structure of the o-alkoxycarbonyl azides had only a slight effect on the reaction yields. Replacement of the alkoxycarbonyl group with nitrile group did not change the course of reaction. Thus, the interaction of 2-azidobenzonitrile 1g with malononitrile dimer (2) led to the selective formation of 5-amino[1,2,3]triazolo[1,5-a]-quinazoline 3g in high yield (Scheme 4). But the reaction of ortho-nitro and acetyl azides resulted in the formation of tarry mixtures.

scheme 4

Scheme 4

The HPLC-MS analysis data confirmed that compounds 3a–g were the single products of the reaction, pointing to the good selectivity of the process.

It should be noted that in the 1H NMR spectra of compounds 3a–f, signals of NH protons of pyrimidinone ring were not observed. It can be explained by the fact that due to the electron-withdrawing effect of 1,2,3-triazole ring the NH proton apparently has a significant acidity and a tautomeric equilibrium of 5-oxo and hydroxy forms is formed. Moreover, compounds 3a–f are poorly soluble in most organic solvents, particularly in DMSO. Thus, an additional heating of samples in DMSO-d6 was required to homogenize the solution. Under these conditions, NH protons were exchanged rapidly with deuterium atoms of the surrounding deuterated solvent. And as a result, the NH proton signal is not observed in spectra. Enamine proton signals (=C–NH2) in compounds 3a–g were found as two broad signals at 8.08–8.18 and 8.23–8.96 ppm.

13C NMR spectra and 1Н–13C HMBC experiments clearly indicate the formation of [1,2,3]triazolo[1,5-a]-pyrimidines by the presence of the signal of central carbon atom in the dicyanomethylene fragment (=C(CN)2) with the chemical shift in 42.2–42.6 ppm range. Other characteristic carbon chemical shifts for compounds 3a–f are given in Figure 1. Due to the amine-imine tautomerism in the (aminomethylidene)malononitrile fragment, which leads to easy rotation of malonodinitrile moiety, carbon atoms of two CN groups give a common signal (compounds 3a–c). It is interesting that the non-equivalence of both CN groups is observed in the carbon NMR spectra of compounds 3d–f, containing the thiophene ring. Probably the electron-rich thiophene ring increases the electron density on nitrogen atom of the pyrimidine ring leading to the formation of stable hydrogen bonds with the hydrogen atom of the amino group (=C–NH2). As a result, tautomeric shifts and conformation conversions (rotation of malonodinitrile fragment) were inhibited to form stable configuration with nonequivalent CN groups. In 13C NMR spectra of compounds 3d–f, two neighboring signals are detected at 118.2–118.5 ppm with the chemical shifts difference of 0.2 ppm.

Figure 1.
figure 1

Characteristic chemical shifts (ppm) in 13C NMR spectra of triazolopyrimidines 3a–f.

Full size image

The assignment of downfield signals in carbon NMR spectra of compounds 3a–f, in particular, of carbonyl (C=O) signal at 160.2–166.3 ppm, was carried out by comparing the spectra of compounds 3a–f with those of [1,2,3]triazolo[1,5-a]pyrimidines prepared previously.9 Enamine carbon signals (=C–NH2) in compounds 3a–f were found at 159.7–160.8 ppm.

In summary, the selectivity of the domino reaction of the (het)aryl azides, containing the carbonyl center in the ortho position to the azido group, with malononitrile dimer was studied and new [1,2,3]triazolo[1,5-a]quinazolines, thieno-[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine, and thieno[3,2-e]-[1,2,3]triazolo[1,5-a]pyrimidines, having polyfunctional aminodicyanovinyl fragment at position 4 of triazole ring were synthesized.

Experimental

1Н and 13C NMR spectra (400 and 100 MHz, respectively), and 1Н–13C HMBC spectra were acquired on a Varian Mercury 400 instrument in DMSO-d6 with TMS as internal standard. HPLC-MS analysis was performed by using an Agilent 1100 Series high-performance liquid chromatograph equipped with a diode array and mass-selective Agilent LC/MSD SL detector, chemical ionization at atmospheric pressure (ionization agent NH4+). Elemental analysis was performed on a Carlo Erba 1106 analyzer. Melting points were measured on a Boetius apparatus.

Starting azides 1a–g were prepared from the corresponding amines as was described in our previous work.9a,b,d

Synthesis of [1,2,3]triazolo[1,5- a ]pyrimidines 3a–g (General method). Malononitrile dimer (2) 1.32 g (10.0 mmol) was dissolved in a minimal quantity of methanol under reflux. Then the obtained solution was added to a solution of appropriate azide 1a–g (10.0 mmol) and NaOMe (540 mg, 10.0 mmol) in dry MeOH (25 ml), and the mixture was refluxed until the precipitate was formed. When TLC monitoring (DCM–MeOH, 10:1) indicated that starting azide had disappeared, the suspension was filtered and the solid product was washed with H2O and MeOH to give the target triazole as a white, crystalline solid.

[Amino(5-oxo-4,5-dihydro[1,2,3]triazolo[1,5- a ]quinazolin-3-yl)methylidene]propanedinitrile (3a). Yield 2.22 g (80%). Mp >300°C. 1H NMR spectrum, δ, ppm (J, Hz): 8.96 (1H, s, NH2); 8.35–8.06 (3H, m, H-6,9, NH2); 7.83 (1H, t, J = 6.6, H-8); 7.57 (1H, t, J = 6.6, H-7). 13C NMR spectrum, δ, ppm: 166.3 (CO); 160.8 (=C–NH2); 146.5 (C-3a); 134.8 (C-9a); 133.2 (C-8); 128.8 (C-7); 127.1 (C-6); 121.8 (C-5a); 120.2 (C-3); 118.9 (C-9); 114.4 (2CN); 42.3 (C(CN)2). Mass spectrum, m/z (Irel, %): 278 [M+H]+ (100). Found, %: C 56.37; H 2.59; N 35.28. C13H7N7O. Calculated, %: C 56.32; H 2.55; N 35.37.

[Amino(7-chloro-5-oxo-4,5-dihydro[1,2,3]triazolo[1,5- a ]-quinazolin-3-yl)methylidene]propanedinitrile (3b). Yield 2.58 g (83%). Mp >300°C. 1H NMR spectrum, δ, ppm (J, Hz): 8.60 (2H, s, NH2); 8.20 (1H, d, J = 7.8, H-8); 8.19 (1H, s, H-6); 8.09 (1H, s, NH); 7.86 (1H, d, J = 7.8, H-9). 13C NMR spectrum, δ, ppm: 165.2 (CO); 160.7 (=C–NH2); 146.4 (C-3a); 134.2 (C-7) 133.6 (C-9a); 133.3 (C-9); 131.6 (C-8); 128.1 (C-6); 120.4 (C-3); 120.4 (C-5a); 117.0 (2CN); 42.6 (C(CN)2). Mass spectrum, m/z (Irel, %): 312 [M+H]+ (100). Found, %: C 50.17; H 1.85; N 31.41. C13H6ClN7O. Calculated, %: C 50.10; H 1.94; N 31.46.

[Amino(7-bromo-5-oxo-4,5-dihydro[1,2,3]triazolo[1,5- a ]-quinazolin-3-yl)methylidene]propanedinitrile (3c). Yield 2.98 g (84%). Mp >300°C. 1H NMR spectrum, δ, ppm (J, Hz): 8.86 (1H, s, NH2); 8.22 (1H, s, H-6); 8.18 (1H, s, NH2); 8.14 (1H, d, J = 8.7, H-9); 7.99 (1H, d, J = 8.7, H-8). 13C NMR spectrum, δ, ppm: 165.0 (CO); 160.7 (=C–NH2); 146.4 (C-3a); 136.8 (C-9a); 136.0 (C-8); 133.9 (C-4); 131.1 (C-6); 120.7 (C-9); 120.4 (C-3); 119.7 (C-5a); 117.2 (2CN); 42.6 (C(CN)2). Mass spectrum, m/z (Irel, %): 356 [М(79Br)+H]+ (100), 358 [М(81Br)+H]+ (97). Found, %: C 43.75; H 1.75; N 27.58. C13H6BrN7O. Calculated, %: C 43.84; H 1.70; N 27.53.

[Amino(5-oxo-4,5-dihydrothieno[2,3- e ][1,2,3]triazolo-[1,5- a ]pyrimidin-3-yl)methylidene]propanedinitrile (3d). Yield 2.38 g (84%). Mp 258–259°C. 1H NMR spectrum, δ, ppm (J, Hz): 8.63 (1H, s, NH2); 8.12 (2H, br. s, H-7, NH2); 7.27 (1H, d, J = 5.2, H-8). 13C NMR spectrum, δ, ppm: 160.2 (CO); 159.7 (=C–NH2); 152.3 (C-8a); 147.2 (C-3a); 136.3 (C-7); 124.3 (C-8); 120.5 (C-3); 118.5 (CN); 118.3 (CN); 110.4 (C-5a); 42.2 (C(CN)2). Mass spectrum, m/z (Irel, %): 284 [M+H]+ (100). Found, %: C 46.71; H 1.72; N 34.72. C11H5N7OS. Calculated, %: C 46.64; H 1.78; N 34.61.

[Amino(6,7-dimethyl-5-oxo-4,5-dihydrothieno[3,2- e ]-[1,2,3]triazolo[1,5- a ]pyrimidin-3-yl)methylidene]propanedinitrile (3e). Yield 2.77 g (89%). Mp >300°C. 1H NMR spectrum, δ, ppm: 8.23 (1H, s, NH2); 8.09 (1H, s, NH2); 2.41 (3H, s, CH3); 2.27 (3H, s, CH3). 13C NMR spectrum, δ, ppm: 164.9 (CO); 159.9 (=C–NH2); 152.9 (C-8a); 145.1 (C-3a); 128.0 (C-6); 123.2 (C-7); 120.1 (C-3); 118.4 (CN); 118.2 (CN); 112.8 (C-5a); 42.5 (C(CN)2); 13.8 (CH3); 13.1 (CH3). Mass spectrum, m/z (Irel, %): 312 [M+H]+ (100). Found, %: C 50.08; H 2.93; N 31.44. C13H9N7OS. Calculated, %: C 50.15; H 2.91; N 31.49.

[Amino(5-oxo-4,5,6,7,8,9-hexahydrobenzo[4,5]thieno-[3,2- e ][1,2,3]triazolo[1,5- a ]pyrimidin-3-yl)methylidene]-propanedinitrile (3f). Yield 3.07 g (91%). Mp >300°C. 1H NMR spectrum, δ, ppm: 8.28 (1H, s, NH2); 8.08 (1H, s, NH2); 2.92 (2H, br. s, CH2); 2.64 (2H, br. s, CH2); 1.78 (4H, br. s, CH2). 13C NMR spectrum, δ, ppm: 165.5 (CO); 159.9 (=C–NH2); 152.6 (C-10a); 145.2 (C-3a); 130.4 (C-5b); 126.3 (C-11); 120.2 (C-3); 118.4 (CN); 118.2 (CN); 111.9 (C-5a); 42.5 (C(CN)2); 26.2 (CH2); 25.1 (CH2); 23.1 (CH2); 22.5 (CH2). Mass spectrum, m/z (Irel, %): 338 [M+H]+ (100). Found, %: C 53.49; H 3.23; N 29.00. C15H11N7OS. Calculated, %: C 53.40; H 3.29; N 29.06.

[Amino(5-amino[1,2,3]triazolo[1,5- a ]quinazolin-3-yl)-methylidene]propanedinitrile (3g). Yield 2.54 g (92%). Mp >300°C. 1H NMR spectrum, δ, ppm (J, Hz): 8.68 (2H, s, NH2); 8.44 (2H, d, J = 7.8, H-6,9); 8.23 (1H, s, NH2); 8.06 (1H, t, J = 7.5, H-8); 7.78 (1H, t, J = 7.5, H-7). 13C NMR spectrum, δ, ppm: 160.4 (=C–NH2(C-5)); 158.9 (C-5(=C–NH2)); 141.9 (C-3a); 135.7 (C-8); 133.6 (C-9a); 128.6 (C-7); 126.4 (C-6); 123.3 (C-3); 117.4 (C-9); 115.8 (2CN); 112.0 (C-5a); 45.7 (C(CN)2). Mass spectrum, m/z (Irel, %): 277 [M+H]+ (100). Found, %: C 56.49; H 2.97; N 40.51. C13H8N8. Calculated, %: C 56.52; H 2.92; N 40.56.