2-Acyl(aroyl)-1,1,3,3-tetracyanopropenides 7^*. Synthesis of 4-amino-1-aryl-6-halo-1-hydroxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-с]pyridine-7-carbonitriles

The reaction of 2-acyl(aroyl)-1,1,3,3-tetracyanopropenides with gaseous hydrogen halides was used to obtain 2-amino-3-aroyl(acyl)-6-halopyridine-3,5-dicarbonitriles, which were subsequently converted to the respective 4-amino-1-aryl-6-halo-1-hydroxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitriles by treatment with concentrated sulfuric acid, followed by aqueous workup.

2-Acyl(aroyl)-1,1,3,3-tetracyanopropenides are relatively easily available2 and have attracted interest as promising precursors for the synthesis of various polyfunctional heterocyclic compounds. 2-Acyl(aroyl)-1,1,3,3-tetracyanopropenides have been used as starting materials for the development of preparative methods for the synthesis of substituted furans,3,4,5, ^– 6 pyridines,6,7,8, ^– 9 as well as the fused ring systems of furo[3,4-c]pyridine1 and thieno[2,3-b]-pyridine.10 It has been noted that the interaction of propenides 1 with hydrogen halides in formic acid also resulted in the formation of 4-amino-1-aryl-6-halo-1-hydroxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitriles as by-products in low yields. Pyrrolo[3,4-c]-pyridines are of interest as scaffolds for the synthesis of biologically active compounds. The examples of such derivatives include ligands of serotonin 5-HT₃ receptor,11 caspase-3 inhibitors,12 and anthelmintic agents.13 The 1-hydroxy-3-oxo-1-pyridylpyrrolo[3,4-c]pyridine fragment represents a structural feature of the INH-NAD adduct, which is formed in vivo from the prodrug isoniazid and NAD and suppresses the development of Mycobacterium tuberculosis.14,15,16, ^– 17 Synthetic analogs of INH-NAD adduct that contain the pyrrolo[3,4-c]pyridine ring system in their structure have been studied as potential tuberculostatic drugs.14,15,16,17, ^– 18

In the current work, we studied the possibilities for the synthesis of pyrrolo[3,4-c]pyridine derivatives from propenides 1a–f through 6-halopyridine intermediates 2, 3 a–f, which were obtained according to a previously published procedure6 by treating a solution of propenide 1a–f in isopropyl alcohol with gaseous hydrogen halide (НСl, HBr) at 85°С for 15–20 min (Scheme 1, Table 1).

Scheme 1

Table 1. Substituents and yields of compounds 2, 3 а–f

The transformation of pyridine derivatives 2, 3 a–f to the respective pyrrolo[3,4-с]pyridines 4, 5 a–f was achieved by two methods. The first one (method I) was based on the reaction of pyridines 2, 3 a–f with water in the presence of a basic catalyst. A drawback of this method was the occurrence of a side reaction involving the substitution of halide with a hydroxy group with the formation of pyrrolo[3,4-с]pyridones 6a–f as impurities (Scheme 2, Table 2), which required laborious purification of the target products and lowered their yields. The substitution of bromide was especially facile, and for that reason the yields of pyrrolo[3,4-с]pyridines 5 a–f obtained by this method were below 15% (not presented in Table). It was established experimentally that the optimum conditions for the synthesis of pyrrolo[3,4-с]pyridines 4, 5 a–f involved treatment with aqueous alcohol solution of NaOH and performing the reaction at room temperature, while complete conversion to pyrrolo[3,4-с]pyridones 6a–f was better achieved by heating at reflux in aqueous DMSO solution of NaOH. Pyridones 6 are known compounds, which were previously obtained by a reaction of 3-acyl(aroyl)-cyclopropane-1,1,2,2-tetracarbonitriles with sodium hydroxide. 19 By using this alternative method of synthesis, we were able to obtain 4-amino-1-(tert-butyl)-1-hydroxy-3,6-dioxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile (6а), which was not accessible via the direct method.

Scheme 2

Table 2. Substituents and yields of compounds 4, 5

The presumed mechanism of this reaction involved an addition of hydroxide ion to the carbonyl group, furan ring closure and subsequent iminolactone–lactam rearrangement (Scheme 2). In our opinion, the fact that this reaction proceeded under mild conditions precluded the alternative route starting from an addition of hydroxide ion to the nitrile group.

The second method (method II) was based on the use of acidic catalysis. It should be noted that acidic catalysis generally was not very effective for performing this type of process: even when pyridine 2b was refluxed for many hours in aqueous acetic acid medium in the presence of H₂SO₄, the procedure led to the formation of only trace amounts of compound 4b. Another method based on stepwise treatment of pyridines 2, 3 a–e first with concentrated H₂SO₄ and then with water was found to be superior. The reaction under these conditions proceeded quickly with an exothermic effect and gave high yields of compounds 4, 5 а–е. The likely sequence of reactions included the formation of cationic furopyridine intermediate А (Scheme 3), as the solution of pyridines 2, 3 а–е in concentrated H₂SO₄ had a bright-red color. The addition of water resulted in hydration and iminolactone–lactam rearrangement. This method was not suitable for the preparation of derivatives 4f and 5f containing a thiophene moiety that was unstable in the presence of H₂SO₄.

Scheme 3

In order to confirm the proposed sequence of mechanistic steps and to exclude a possible mechanism involving Ritter cyclization, the reaction of pyridine 2b with methanol was performed under analogous conditions. It was expected that the process in this case should stop with the formation of iminofuran В (Scheme 4) or pyrrolopyridine С (in the case of Ritter reaction), but according to the data of NMR spectra the main product was 4-amino-6-chloro-1-methoxy-3-oxo-1-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile (7) (Scheme 4). The formation of compound 7 was also confirmed by its hydrolysis leading to the formation of pyrrolo[3,4-c]- pyridine 4b upon heating in dilute H₂SO₄.

Scheme 4

Pyrrolo[3,4-c]pyridines 4, 5 a–e were isolated as white crystalline solids that were readily soluble in polar organic solvents. Some of them formed stable solvates with 2-propanol.

The proposed structure of the synthesized compounds was supported by ¹Н and ¹³С NMR spectroscopy, mass spectrometry, and was in agreement with IR spectral data and the results of elemental analysis. ¹Н NMR spectra of pyrrolo[3,4-c]pyridines 4, 5 a–e contained two broadened singlets at 7.32–8.57 ppm, which were assigned to the amino group linked to pyridine ring. The hydroxy group proton was represented in ¹Н NMR spectra by a singlet in the range of 6.78–8.57 ppm. The aryl substituents were observed by their characteristic signals.

The structure of pyridines 2, 3 a–e featured two nitrile groups at ortho position relative to the carbonyl group, and for this reason the formation of two positional isomers 4', 5' a–e and 4”, 5” a–e could be expected (Fig. 1). According to TLC data and NMR spectra, the reaction occurred regioselectively with the formation of only one of the possible isomers. The structure of compounds 4b and 5а was proved by X-ray crystallographic analysis (Figs. 2, 3). Thus, we demonstrated the general applicability of this process where the heterocyclization involved a cyano group adjacent with the amino group, leading to the formation of isomers 4', 5' a–e.

Figure 1.

The possible isomers of compounds 4, 5 with different configuration of amino group and halogen atom relative to the other groups.

Figure 2.

Molecular structure of compound 4b solvated with 2-propanol with atoms represented by thermal vibration ellipsoids of 50% probability. Symmetry codes: (i) –x, –y, –z; (ii) –x, 1–y, –z; (iii) –1+x, y, –1+z; (iv) –0.5+x, 0.5–y, –0.5+z.

Figure 3.

Molecular structure of compound 5а according to X-ray structural analysis, with atoms represented by thermal vibration ellipsoids of 50% probability. Symmetry codes: (i) –x, 1–y, 1–z; (ii) –x, –0.5+y, 0.5–z.

The crystal lattice formation for both compounds was largely controlled by hydrogen bonding interactions. The crystal of compound 4b contained molecules linked by centrosymmetric N(2)–H(2)···O(2) hydrogen bonds (2.997 Å) from one side and N(1)–H(31)···N(3) hydrogen bonds (3.039 Å) from the other side. This resulted in the formation of a chain along the crystallographic axis b. The adjacent chains were linked by O(3)–H(32)···О(1), O(3)–H(32)···О(2), and N(3)–H(2)···O(3) hydrogen bonds with solvated 2-propanol molecule (2.716 Å, 2.682 Å, and 3.272 Å, respectively). The molecules in crystals of compound 5а formed centrosymmetric dimers linked by N(2)–H(2)···O(1) hydrogen bonds (2.844 Å). Besides that, O(2)–H(3)···N(1) hydrogen bond (2.860 Å) existed between the hydroxy group and the pyridine nitrogen atom.

Thus, based on the use of 2-acyl(aroyl)-1,1,3,3-tetracyanopropenides, we have developed two-step methods for the synthesis of 4-amino-1-aryl-6-halo-1-hydroxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitriles under the conditions of either acidic or basic catalysis. The compounds obtained by the method that involved treatment with concd. Н2SO4 and then water were formed in high yields and did not contain impurities, but that method was limited to substrates lacking any acid-labile substituents. The method using basic catalysis gave lower yields, but was useful for obtaining compounds containing acid-labile substituents, for example, it was used for the synthesis of a thiophene derivative.

Experimental

IR spectra were recorded for Nujol mulls of compounds on an FSM-1202 FT-IR spectrometer. ¹Н and ¹³C NMR spectra were acquired on an Agilent DDR2 400 instrument (400 and 101 MHz, respectively) in DMSO-d ₆, using TMS as internal standard. Mass spectra were recorded on a Shimadzu GCMS-QP2010S DI instrument (EI ionization, 70 eV). Elemental analysis was performed on a vario MICRO cube CHN-analyzer. Melting points were determined on an Electrothermal IA 9000 series II instrument. The individuality of the synthesized compounds was confirmed by TLC method on Sorbfil PTSH-AF-A-UF plates, eluent EtOAc, visualization under UV light (254 nm) or by heating. 2-Acyl(aroyl)-1,1,3,3-tetracyanopropenides 1a–f 2 and 2-amino-3-aroyl(acyl)-6-halopyridine-3,5-dicarbonitriles 2a–c,6 3b,c,6 2d,7 and 3d 7 were obtained according to published procedures.

Synthesis of 2-amino-3-aroyl(acyl)-6-halopyridine-3,5-dicarbonitriles 2, 3 a–f (General method). A suspension of propenide 1a–f (5 mmol) in 2-PrOH (50 ml) was heated to reflux and, while continuing the heating and stirring, gaseous HCl or HBr was bubbled through the mixture until the reaction was complete (15–20 min). The mixture was then poured into water (200 ml), the precipitate that formed was filtered off and purified by recrystallization from a 1:4 mixture of MeCN–H₂O.

2-Amino-4-(4-bromobenzoyl)-6-chloropyridine-3,5-dicarbonitrile (2e). White crystals, mp >275°С (decomp.). IR spectrum, ν, cm^–1: 3201 (NH₂), 2220 (C≡N), 1682 (C=O). 1H NMR spectrum, δ, ppm: 7.83–7.89 (2H, m, H Ar); 7.93–7.99 (2H, m, H Ar); 8.46 (1H, br. s) and 8.97 (1H, br. s, NH₂). ¹³C NMR spectrum, δ, ppm: 190.0; 160.6; 157.9; 156.0; 133.3; 132.4; 132.3; 131.5; 114.1; 113.4; 93.0; 87.0. Mass spectrum, m/z (I _rel, %): 364/362/360 [М]⁺ (2.8/11.7/9.0), 185/183 [C₆H₄BrCO]⁺ (98/100), 157/155 [C₆H₄Br]⁺ (12/12). Found, %: C 46.36; H 1.70; N 15.45. C₁₄H₆BrClN₄O. Calculated, %: C 46.51; H 1.67; N 15.49.

2-Amino-6-chloro-4-[(thiophen-2-yl)carbonyl]pyridine-3,5-dicarbonitrile (2f). White crystals, mp 255–257°С (decomp.). IR spectrum, ν, cm^–1: 3211 (NH₂), 2217 (C≡N), 1662 (C=O). ¹H NMR spectrum, δ, ppm (J, Hz): 7.38 (1H, dd, ³ J = 4.2, ³ J = 4.8, H Ar); 8.05 (1H, d, ³ J = 3.8, H Ar); 8.40 (1H, d, ³ J = 4.8, H Ar); 8.45 (1H, br. s) and 8.97 (1H, br. s, NH₂). C NMR spectrum, δ, ppm: 182.3; 160.2; 157.2; 148.3; 141.0; 140.6; 138.0; 130.4; 115.3; 113.6; 96.2; 87.1. Mass spectrum, m/z (I _rel, %): 290/288 [М]⁺ (14/5), 116 (12), 111 [C₄H₃SCO]⁺ (100), 83 [C₄H₃S]⁺ (11). Found, %: C 49.98; H 1.79; N 19.51. C₁₂H₅ClN₄OS. Calculated, %: C 49.92; H 1.75; N 19.41.

2-Amino-6-bromo-4-pivaloylpyridine-3,5-dicarbonitrile (3a). White crystals, mp 250–252°С (decomp.). IR spectrum, ν, cm^–1: 3224 (NH₂), 2208 (C≡N), 1665 (C=O). ¹H NMR spectrum, δ, ppm: 1.29 (9H, s, С(CH₃)₃); 8.43 (1H, br. s) and 8.95 (1H, br. s, NH₂). ¹³C NMR spectrum, δ, ppm: 208.1; 160.1; 160.0; 148.4; 116.3; 114.5; 94.6; 85.3; 45.7; 27.2. Mass spectrum, m/z (I _rel, %): 308/306 [М]⁺ (3/3), 116 (11), 57 [C₄H₉]⁺ (100). Found, %: C 46.75; H 3.64; N 18.17. C₁₂H₁₁BrN₄O. Calculated, %: C 46.93; H 3.61; N 18.24.

2-Amino-6-bromo-4-(4-bromobenzoyl)pyridine-3,5-dicarbonitrile (3e). White crystals, mp >275°С (decomp.). IR spectrum, ν, cm^–1: 3209 (NH₂), 2221 (C≡N), 1665 (C=O). ¹H NMR spectrum, δ, ppm: 7.85–7.91 (2H, m, H Ar); 7.94–8.01 (2H, m, H Ar); 8.47 (1H, br. s) and 9.00 (1H, br. s, NH₂). ¹³C NMR spectrum, δ, ppm: 190.0; 160.2; 157.4; 148.4; 133.3; 132.4; 132.3; 131.4; 115.3; 113.5; 96.1; 87.0. Mass spectrum, m/z (I _rel, %): 408/406/404 [М]⁺ (4/9/5), 185/183 [C₆H₄BrCO]⁺ (98/100), 157/155 [C₆H₄Br]⁺ (17/17). Found, %: C 41.32; H 1.51; N 13.77. C₁₄H₆Br₂N₄O. Calculated, %: C 41.41; H 1.49; N 13.80.

2-Amino-6-bromo-4-[(thiophen-2-yl)carbonyl]pyridine-3,5-dicarbonitrile (3f). White crystals, mp 270–272°С (decomp.). IR spectrum, ν, cm^–1: 3213 (NH₂), 2217 (C≡N), 1667 (C=O). ¹H NMR spectrum, δ, ppm (J, Hz): 7.38 (1H, dd, ³ J = 4.0, ³ J = 4.8, H Ar); 8.07 (1H, dd, ³ J = 3.8, ⁴ J = 0.8, H Ar); 8.41 (1H, dd, ³ J = 4.8, ⁴ J = 0.8, H Ar); 8.45 (1H, br. s) and 8.97 (1H, br. s, NH₂). ¹³C NMR spectrum, δ, ppm: 182.3; 160.2; 157.2; 148.3; 141.0; 140.6; 140.0; 130.4; 115.3; 113.5; 96.2; 87.1. Mass spectrum, m/z (I _rel., %): 334/332 [М]⁺ (10/10), 116 (9), 111 [C₄H₃SCO]⁺ (100), 83 [C₄H₃S]⁺ (13). Found, %: C 43.35; H 1.55; N 16.92. C₁₂H₅BrN₄OS. Calculated, %: C 43.26; H 1.51; N 16.82.

Synthesis of 4-amino-1-aryl-6-halo-1-hydroxy-3-oxo-2,3-dihydro-1 H -pyrrolo[3,4- c ]pyridine-7-carbonitriles 4, 5 а–f (General method). Method I. A suspension of pyridine 2, 3 a–f (1.0 mmol) and NaOH (0.1 g, 2.5 mmol) was stirred in 1:1 mixture of 2-PrOH–H₂O (3 ml) until full dissolution, then maintained until the reaction was complete (control by TLC; pyridines 2, 3 a–f showed yellow-green fluorescence under UV light, pyrrolo[3,4-c]pyridines 4, 5 a–f showed blue fluorescence). The reaction mixture was then diluted with H₂O (5 ml), neutralized with 5% Н₂SO₄ solution, the precipitate that formed was filtered off and purified by recrystallization from 1:2 mixture of MeCN–H₂O.

Method II. A mixture of pyridine 2, 3 а–e (1 mmol) in concd. H₂SO₄ (1 ml) was stirred at room temperature until full dissolution (10–30 min), then diluted with H₂O (20 ml), and the white precipitate that formed was filtered off, washed with water until the washes became neutral, airdried, and purified by recrystallization.

4-Amino-1-( tert -butyl)-6-chloro-1-hydroxy-3-oxo-2,3-dihydro-1 H -pyrrolo[3,4- c ]pyridine-7-carbonitrile (4a). White crystals, mp 260–265°С (decomp.). IR spectrum, ν, cm^–1: 3365 (OH), 3272, 3211 (NH₂), 2225 (C≡N), 1710 (C=O). ¹H NMR spectrum, δ, ppm: 0.98 (9H, s, С(CH₃)₃); 6.79 (1H, br. s, OH); 7.37 (1H, br. s) and 8.41 (1H, br. s, NH₂); 8.96 (1H, s, NH). ¹³C NMR spectrum, δ, ppm: 166.9; 164.3; 156.4; 155.7; 116.2; 108.9; 93.2; 92.3; 40.8; 26.1. Mass spectrum, m/z (I _rel, %): 264/262 [М–H₂O]⁺ (0.3/1), 238 (3), 179 (8), 57 [C4H9]⁺ (100). Found, %: C 51.53; H 4.64; N 20.03. C₁₂H₁₃ClN₄O₂. Calculated, %: C 51.35; H 4.67; N 19.96.

4-Amino-6-chloro-1-hydroxy-3-oxo-1-phenyl-2,3-dihydro-1 H -pyrrolo[3,4- c ]pyridine-7-carbonitrile (4b). White crystals, mp >210°С (decomp.). IR spectrum, ν, cm^–1: 3654 (OH), 3480, 3292 (NH₂), 2213 (C≡N), 1684 (C=O). ¹H NMR spectrum, δ, ppm: 7.31–7.40 (4H, m, H Ph, ОН); 7.40–7.49 (3H, m, H Ph, NH_A); 8.55 (1H, br. s, NH_B); 9.44 (1Н, s, NH). ¹³C NMR spectrum, δ, ppm: 167.2; 165.3; 156.5; 155.1; 138.3; 129.0; 128.6; 126.6; 113.7; 106.9; 90.3; 87.1. Mass spectrum, m/z (I _rel, %): 302/300 [М]⁺ (1/2), 284/282 [М–H₂O]⁺ (3/8), 103 [PhCN]⁺ (16), 77 [Ph]⁺ (32), 51 (100). Found, %: C 56.09; H 2.99; N 18.69. C₁₄H₉ClN₄O₂. Calculated, %: C 55.92; H 3.02; N 18.63.

Compound 4b was also obtained by hydrolysis of 4-amino-6-chloro-1-methoxy-3-oxo-1-phenyl-2,3-dihydro-1Н-pyrrolo[3,4-c]pyridine-7-carbonitrile (7). A suspension of pyrrolopyridine 7 (100 mg, 0.3 mmol) in 10% H₂SO₄ solution (2 ml) was refluxed with stirring for 2 min, then cooled, the precipitate was filtered off, washed with water, dried, and purified by recrystallization. Yield 42 mg (44%).

4-Amino-6-chloro-1-hydroxy-1-(4-methylphenyl)-3-oxo-2,3-dihydro-1 H -pyrrolo[3,4- c ]pyridine-7-carbonitrile (4c). White crystals, mp >250°С (decomp.). IR spectrum, ν, cm^–1: 3633 (OH), 3481, 3277 (NH₂), 2216 (C≡N), 1689 (C=O) ¹H NMR spectrum, δ, ppm: 2.28 (3H, s, СН₃); 7.15–7.17 (2H, m, H Ar); 7.32–7.33 (2H, m, H Ar); 7.35 (1H, br. s) and 7.51 (1H, br. s, NH₂); 7.41 (1H, s, ОН); 9.38 (1Н, s, NH). ¹³C NMR spectrum, δ, ppm: 167.1; 165.5; 156.5; 155.1; 138.3; 135.5; 129.2; 126.6; 117.8; 106.8; 90.4; 87.1; 21.1. Mass spectrum, m/z (I _rel, %): 316/314 [М]⁺ (0.3/1), 298/296 [М–H₂O]⁺ (4/12), 91 [C₆H₄CH₃]⁺ (100). Found, %: C 57.41; H 3.50; N 17.85. C₁₅H₁₁ClN₄O₂. Calculated, %: C 57.24; H 3.52; N 17.80.

4-Amino-6-chloro-1-hydroxy-1-(4-methoxyphenyl)-3-oxo-2,3-dihydro-1 H -pyrrolo[3,4- c ]pyridine-7-carbonitrile (4d). White crystals, mp 266–268°С (decomp.). IR spectrum, ν, cm^–1: 3657 (OH), 3481, 3293 (NH₂), 2216 (C≡N), 1688 (C=O). ¹H NMR spectrum, δ, ppm: 3.76 (3H, s, OCH₃); 6.86–6.92 (2H, m, H Ar); 7.35–7.41 (4H, m, H Ar, ОН, NH_A); 8.42 (1H, br. s, NH_B); 9.41 (1Н, s, NH). ¹³C NMR spectrum, δ, ppm: 167.0; 165.9; 159.8; 159.5; 155.1; 130.3; 128.0 (CH); 114.2 (CH); 114.0; 106.8; 90.0; 87.0; 55.6. Mass spectrum, m/z (I _rel, %): 332/330 [М]⁺ (1/2), 317/315 [М–CH₃]⁺ (2/7), 314/312 [М–H₂O]⁺ (5/15), 107 CH₃OC₆H₄]⁺ (66), 57 (100). Found, %: C 54.52; H 3.44; N 16.79. C₁₅H₁₁ClN₄O₃. Calculated, %: C 54.48; H 3.35; N 16.94.

4-Amino-1-(4-bromophenyl)-6-chloro-1-hydroxy-3-oxo-2,3-dihydro-1 H -pyrrolo[3,4- c ]pyridine-7-carbonitrile (4e). White crystals, mp >210°С (decomp.). IR spectrum, ν, cm^–1: 3652 (OH), 3485, 3286 (NH₂), 2218 (C≡N), 1682 (C=O). ¹H NMR spectrum, δ, ppm: 7.41–7.48 (3H, m, H Ar, ОН); 7.52 (1H, br. s) and 8.57 (1H, br. s, NH₂); 7.57–7.59 (2H, m, H Ar); 9.47 (1Н, s, NH). ¹³C NMR spectrum, δ, ppm: 167.0; 164.8; 156.5; 155.2; 137.8; 131.6; 129.0; 122.4; 113.7; 106.9; 90.1; 86.7. Mass spectrum, m/z (I _rel, %): 364/362/360 [М–H₂O]⁺ (2/8/6), 185/183 [C₆H₄BrCO]⁺ (26/27), 157/155 [C₆H₄Br]⁺ (30/31), 43 (100). Found, %: C 44.40; H 2.10; N 14.79. C₁₄H₈BrClN₄O₂. Calculated, %: C 44.30; H 2.12; N 14.76.

4-Amino-6-chloro-1-hydroxy-3-oxo-1-(thiophen-2-yl)-2,3-dihydro-1 H -pyrrolo[3,4- c ]pyridine-7-carbonitrile (4f). White crystals, mp >190°С (decomp.). IR spectrum, ν, cm^–1:3627 (OH), 3479, 3281 (NH₂), 2219 (C≡N), 1688 (C=O). ¹H NMR spectrum, δ, ppm (J, Hz): 6.99–7.05 (1H, m, H Ar); 7.12 (1H, dd, ³ J = 4.8, ³ J = 1.0, H Ar); 7.48 (1H, br. s) and 8.52 (1H, br. s, NH₂); 7.54 (1H, dd, ³ J = 5.0, ³ J = 1.0, H Ar); 7.63 (1H, s, ОН); 9.64 (1Н, s, NH). ¹³C NMR spectrum, δ, ppm: 167.0; 164.1; 156.5; 147.4; 144.0; 127.1; 126.3; 125.1; 112.8; 105.1; 93.6; 86.6. Found, %: C 47.08; H 2.33; N 18.22. C₁₂H₇ClN₄O₂S. Calculated, %: C 46.99; H 2.30; N 18.27.

4-Amino-6-bromo-1-( tert -butyl)-1-hydroxy-3-oxo-2,3-dihydro-1 H -pyrrolo[3,4- c ]pyridine-7-carbonitrile (5a). White crystals, mp >270°С (decomp.). IR spectrum, ν, cm^–1: 3366 (OH), 3275, 3211 (NH₂), 2225 (C≡N), 1710 (C=O). ¹H NMR spectrum, δ, ppm: 0.98 (9H, s, С(CH₃)₃); 6.78 (1H, br. s, OH); 7.37 (1H, br. s) and 8.42 (1H, br. s, NH₂); 8.94 (1H, s, NH). ¹³C NMR spectrum, δ, ppm: 167.1; 163.9; 156.3; 148.1; 117.4; 109.0; 95.6; 93.2; 40.8; 26.2. Mass spectrum, m/z (I _rel., %): 308/306 [M–H₂O]⁺ (1/1), 278 (3), 222 (8), 116 (20), 57 [C₄H₉]⁺ (100). Found, %: C 44.41; H 4.13; N 17.21. C₁₂H₁₃BrN₄O₂. Calculated, %: C 44.33; H 4.03; N 17.23.

4-Amino-6-bromo-1-hydroxy-3-oxo-1-phenyl-2,3-dihydro-1 H -pyrrolo[3,4- c ]pyridine-7-carbonitrile (5b). White crystals, mp >270°С (decomp.). IR spectrum, ν, cm^–1: 3649 (OH), 3482, 3275 (NH₂), 2217 (C≡N), 1678 (C=O). ¹H NMR spectrum, δ, ppm (J, Hz): 7.32–7.40 (5H, m, H Ph, ОН, NH_A); 7.42–7.49 (2H, m, H Ph); 8.53 (1H, br. s, NH_B); 9.40 (1Н, s, NH). ¹³C NMR spectrum, δ, ppm: 167.2; 165.0; 156.5; 147.3; 138.3; 129.0; 128.6; 126.6; 114.9; 107.0; 93.7; 87.1. Mass spectrum, m/z (I _rel, %): 346/344 [М]⁺ (1/1), 328/326 [М–H₂O]⁺ (11/11), 103 [PhCN]⁺ (25), 77 [Ph]⁺ (30), 51 (100). Found, %: C 48.81; H 2.72; N 16.09. C₁₄H₉BrN₄O₂. Calculated, %: C 48.72; H 2.63; N 16.23.

4-Amino-6-bromo-1-hydroxy-1-(4-methylphenyl)-3-oxo-2,3-dihydro-1 H -pyrrolo[3,4- c ]pyridine-7-carbonitrile (5c). White crystals, mp >270°С (decomp.). IR spectrum, ν, cm^–1: 3642 (OH), 3479, 3293 (NH₂), 2217 (C≡N), 1678 (C=O). ¹H NMR spectrum, δ, ppm: 2.30 (3H, s, CH₃); 7.17–7.20 (2H, m, H Ar); 7.31–7.38 (3H, m, H Ar, OH); 7.40 (1H, br. s) and 8.54 (1H, br. s, NH₂); 9.38 (1Н, s, NH). ¹³C NMR spectrum, δ, ppm: 167.2; 165.1; 156.5; 147.3; 138.3; 135.3; 129.2; 126.2; 114.9; 106.9; 93.7; 87.1; 21.1. Mass spectrum, m/z (I _rel, %): 360/358 [М]⁺ (1/1), 342/340 [М–H₂O]⁺ (9/9), 91 [C₆H₄CH₃]⁺ (100). Found, %: C 50.24; H 3.17; N 15.47. C₁₅H₁₁BrN₄O₂. Calculated, %: C 50.16; H 3.09; N 15.60.

4-Amino-6-bromo-1-hydroxy-1-(4-methoxyphenyl)-3-oxo-2,3-dihydro-1 H -pyrrolo[3,4- c ]pyridine-7-carbonitrile (5d). White crystals, mp 270–272°С (decomp.). IR spectrum, ν, cm^–1: 3651 (OH), 3478, 3294 (NH₂), 2216 (C≡N), 1694 (C=O). ¹H NMR spectrum, δ, ppm: 3.75 (3H, s, CH₃); 6.88–6.93 (2H, m, H Ar); 7.32–7.44 (4H, m, H Ar, OH, NH_A); 8.49 (1H, br. s, NH_B); 9.36 (1Н, s, NH). ¹³C NMR spectrum, δ, ppm: 167.0; 165.6; 159.8; 156.5; 155.1; 130.1; 128.0 (CH); 113.9 (CH); 113.8; 106.8; 90.2; 87.0; 55.6. Mass spectrum, m/z (I _rel, %): 376/374 [М]⁺ (1/1), 361/359 [М–CH₃]⁺ (5/5), 358/356 [М–H₂O]⁺ (16/16), 107 [CH₃OC₆H₄]⁺ (56), 43 (100). Found, %: C 48.12; H 3.04; N 14.81. C₁₅H₁₁BrN₄O₃. Calculated, %: C 48.02; H 2.96; N 14.93.

4-Amino-6-bromo-1-(4-bromophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1 H -pyrrolo[3,4- c ]pyridine-7-carbonitrile (5e). White crystals, mp >210°С (decomp.). IR spectrum, ν, cm^–1: 3650 (OH), 3491, 3274 (NH₂), 2220 (C≡N), 1683 (C=O). ¹H NMR spectrum, δ, ppm: 7.38–7.41 (4H, m, H Ar, ОН, NH_A); 7.55–7.57 (2H, m, H Ar); 8.56 (1H, br. s, NH_B); 9.43 (1Н, s, NH). ¹³C NMR spectrum, δ, ppm: 167.2; 164.4; 156.5; 147.3; 137.8; 131.6; 129.0; 122.4; 114.9; 107.0; 93.5; 86.7. Mass spectrum, m/z (I _rel, %): 408/406/404 [М–H₂O]⁺ (5/10/5), 185/183 [C₆H₄BrCO]⁺ (16/16), 157/155 [C₆H₄Br]⁺ (24/25), 43 (100). Found, %: C 39.80; H 1.98; N 13.12. C₁₄H₈Br₂N₄O₂. Calculated, %: C 39.65; H 1.90; N 13.21.

4-Amino-1-( tert -butyl)-1-hydroxy-3,6-dioxo-2,3,5,6-tetrahydro-1 H -pyrrolo[3,4- c ]pyridine-7-carbonitrile (6а). Pyridine 2а (260 mg, 1 mmol) was added to a solution of NaOH (100 mg, 2.5 mmol) in a 1:1 mixture of DMSO–Н₂О (2 ml). The mixture was refluxed for 2 min, then cooled, treated with Н₂О (5 ml), neutralized with 5% Н₂SO₄ solution, the precipitate that formed was filtered off and purified by recrystallization from a 1:5 MeCN–EtOH mixture. Yield 186 mg (71%), white crystals, mp 238–240°С (decomp.). IR spectrum, ν, cm^–1: 3602 (OH), 3270, 3212 (NH₂), 2222 (C≡N), 1705, 1691 (C=O). ¹H NMR spectrum, δ, ppm: 0.99 (9H, s, С(CH₃)₃); 6.52 (1H, s, OH); 7.35 (2H, br. s, NH₂); 8.50 (1H, s, NH); 11.40 (1H, s, NH). ¹³C NMR spectrum, δ, ppm: 168.6; 165.2; 162.1; 151.3; 115.8; 92.3; 89.1; 79.2; 40.7; 26.2. Found, %: C 55.04; H 5.40; N 21.31. C₁₂H₁₄N₄O₃. Calculated, %: C 54.96; H 5.38; N 21.36.

4-Amino-6-chloro-1-methoxy-3-oxo-1-phenyl-2,3-dihydro-1 Н -pyrrolo[3,4- c ]pyridine-7-carbonitrile (7). A mixture of pyridine 2c (280 mg, 1 mmol) and concd. H₂SO₄ (1 ml) was stirred until full dissolution. Then MeOH (10 ml) was added, the white precipitate that formed was filtered off, washed with water until the washes became neutral, air-dried, and purified by recrystallization from a 1:4 mixture of MeCN–H₂O. Yield 198 mg (63%), white crystals, mp >210°С (decomp.). IR spectrum, ν, cm^–1: 3461, 3255 (NH₂), 2224 (C≡N), 1682 (C=O). ¹H NMR spectrum, δ, ppm: 3.20 (3H, s, OCH₃); 7.34–7.44 (3H, m, H Ph); 7.46–7.49 (2H, m, H Ph); 7.53 (1H, br. s) and 8.68 (1H, br. s, NH₂); 9.40 (1Н, s, NH). ¹³C NMR spectrum, δ, ppm: 167.5; 161.8; 156.5; 155.7; 137.2; 129.4; 128.8; 126.7; 113.6; 108.0; 91.5; 90.2; 50.9. Found, %: C 57.14; H 3.57; N 17.71. C₁₅H₁₁ClN₄O₂. Calculated, %: C 57.24; H 3.52; N 17.80.

X-ray structural study of compounds 4b, 5a. Crystals suitable for X-ray structural analysis were obtained by slow evaporation of solvent at room temperature: compound 4b – from a 1:1 mixture of MeСN–2-PrOH, compound 5a – from MeСN. Crystallographic studies were performed on a STOE diffractometer with Pilatus100K detector, focussing mirror collimation, CuKα-radiation (λ 1.54186 Å). Unit cell parameters and tables of structure factors were obtained by using the STOE X-Area (STOE&Cie GmbH) software.20 The compound structures were solved by direct method and refined by using the SHELX software.21 The positions and thermal parameters of non-hydrogen atoms were refined in full-matrix anisotropic approximation. The hydrogen atom positions were calculated or determined from difference Fourier syntheses and refined according to the "rider" model or freely in isotropic approximation. Visualization was performed with the DIAMOND program.22 The complete X-ray structural dataset was deposited at the Cambridge Crystallographic Data Center (deposits CCDC 1523242 (compound 4b) and ССDC 1523243 (compound 5a)).