Synthesis of partially hydrogenated isoquinoline derivatives by condensation of 2,4-diacetyl-3-aryl(hetaryl)-5-hydroxy-5-methylcyclohexanones with malononitrile and its dimer and a study of their alkylation

New derivatives of partially hydrogenated isoquinolines were obtained by condensation of 2,4-diacetyl-3-aryl(hetaryl)-5-hydroxy-5-methylcyclohexanones with malononitrile and its dimer, 2-amino-1,1,3-tricyano-1-propene, and alkylation reactions of the obtained compounds were studied.

β-Cycloketols 1 have shown antimicrobial activity1 and are available as reagents for the synthesis of biologically active heterocyclic compounds.2 The reactions of these compounds with hydrazine and hydroxylamine have received most attention,3 while several studies report also their condensation reactions with СН acids – cyanoacetamide,4 cyanothioacetamide,4 ^, 5 cyanoselenoacetamide6, and 1-phenyl-1Н-pyrazol-5Н-one.7

In order to further the understanding of reactivity of 2,4-diacetyl-3-aryl(hetaryl)-5-hydroxy-5-methylcyclohexanones 1a–g,5 ^– 7 in the current work, we studied their condensation with malononitrile (2) and its dimer, 2-amino-1,1,3-tricyano-1-propene (3) (Scheme 1). These reactions occurred at 60°С in anhydrous ethanol in the presence of morpholine and produced 7-acetyl-8-aryl(hetaryl)-6-hydroxy-1,6-dimethyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitriles 4a–e (method I) or 2-[7-acetyl-8-aryl (hetaryl)-4-cyano-6-hydroxy-1,6-dimethyl-5,6,7,8-tetrahydroisoquinolin-3(2Н)-ylidene]malononitriles 5a–c,f,g, respectively.

Scheme 1

The likely mechanism for the formation of the indicated partially hydrogenated isoquinolines 4а–е was the following. At first, a Knoevenagel condensation gave the alkene А that could enolize in basic medium to the intermediate В, with further intramolecular cyclization to the iminopyran С. The intermediate B underwent a Dimroth recyclization8 to the final product 4. Compounds 4а–е were also obtained by counter synthesis through condensation of cycloketols 1а–е with cyanoacetamide (6) in the presence of morpholine (method II).4 We should note that compounds 4a,b were previously prepared by condensation of the substituted cyclohexanones 1a,b with cyanoacetamide (6) upon heating in ethanol in the presence of sodium methoxide.4

Compounds 5a–с,f,g were apparently formed by a mechanism similar to the scheme given for substituted isoquinolinones 4a–e: the Knoevenagel alkene D underwent intramolecular cyclization to a pyridine system, resulting in 3-dicyanomethylene-substituted partially hydrogenated isoquinoline derivatives 5a–c,f,g.

The structures of the synthesized compounds 4a–e, 5a–c,f,g were confirmed by spectral data. The IR spectra contained characteristic stretching vibration bands of the conjugated cyano group and carbonyl group at 2157–2236 and 1687–1715 cm^–1, respectively. All carbon atoms in these molecules gave the expected ¹³С NMR signals in the appropriate regions. All the substituents and the cyclohexane fragment gave ¹Н NMR signals with characteristic splitting patterns.4 ^, 5

The presence of several reaction centers in the partially hydrogenated isoquinoline systems 4, 5, namely, NH, OH, and C=O groups, allowed to perform reactions with alkylating agents 7a–c. Alkylation of substituted 3-cyano-1,2-dihydropyridin-2-ones usually leads to a mixture of N- and О-alkyl derivatives.9 ^, 10 In the current study, we showed that reactions of isoquinolinone 4с with alkyl halides 7a–c in DMF at 50°С in the presence of 10% aqueous KОН gave the respective N-alkyl derivatives 8a–c. The IR spectra of the synthesized compounds 8a–c were found to be quite informative for structural characterization, thus proving the regioselectivity of the studied alkylation reaction. For example, the IR spectra of compounds 8a–c contained not only the absorption bands of functional groups, but also showed the characteristic stretching vibrations of the isoquinoline ring amide moiety at 1621–1634 cm^–1.11

Alkylation of the partially hydrogenated isoquinoline 5b with benzyl chloride (7a) under conditions analogous to those described above also occurred regioselectively, but at the С-2 atom of malononitrile fragment. The reaction apparently involved the formation of prototropic tautomer E and the respective carbanion F, and led to the corresponding product, 2-[7-acetyl-4-cyano-6-hydroxy-1,6-dimethyl-8-(4-methylphenyl)-5,6,7,8-tetrahydroisoquinolin-3-yl]-2-benzylmalononitrile (9). We should note that the same regioselectivity of alkylation was also observed for 1-alkyl-(aryl)-3-dicyanomethylene-4-cyano-substituted carbo[c]-annelated pyridines,12 which are isostructural analogs of compound 5. This could probably be explained by the rapid exchange of NH protons in the isoquinoline ring. The X-ray structural analysis data obtained for a related compound, 3-cyano-2-dicyanomethylene-5,6-dimethyl-1,2-dihydropyridine, indicated a planar structure with aromatic properties,13 which could contribute to the NH acidity.

The structure of compound 9 was confirmed by its spectral characteristics, especially the ¹³C NMR spectrum, which contained 10 aliphatic carbon signals in the appropriate regions. In the case of N-alkylation product, the aliphatic region should contain nine signals. We should also note the restricted rotation of the benzyl fragment in this molecule, apparently due to steric obstacles, which was observed as nonequivalence of methylene group protons and, as a consequence, splitting of these signals in two doublets with ² J = 14.0 Hz. The IR spectrum of isoquinoline 9 featured characteristic absorption bands due to all functional groups present in the molecule, except the nonconjugated nitrile groups, which may be unobservable according to the literature data.14

Mass spectra of the majority of synthesized compounds contained molecular ion peaks with m/z values in accordance with the "nitrogen rule".15

Thus, condensation of 2,4-diacetyl-3-aryl(hetaryl)-5-hydroxy-5-methylcyclohexanones with malononitrile or its dimer, 2-amino-1,1,3-tricyano-1-propene, was used to synthesize 7-acetyl-8-aryl(hetaryl)-6-hydroxy-1,6-dimethyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitriles and 7-acetyl-2-(8-aryl(hetaryl)-4-cyano-6-hydroxy-1,6-dimethyl-5,6,7,8-tetrahydroisoquinolin-3(2Н)-ylidene)malononitriles, respectively. Alkylation of substituted 3-oxoisoquinolines occurred at nitrogen atom, while (isoquinolin-3(2Н)-ylidene)malononitriles were alkylated at the С-2 atom of the malononitrile fragment.

Experimental

IR spectra were recorded on a Perkin Elmer Spectrum One FTIR spectrometer in KBr pellets. ¹Н and ¹³С NMR spectra were acquired on a Bruker Avance 400 spectrometer (400 and 100 MHz, respectively) in DMSO-d ₆ with TMS as internal standard. Mass spectra were recorded on an MKh-1321 mass spectrometer (70 eV) with direct introduction of sample into the ion source. Elemental analysis was performed on a Eurovector EA-3000 instrument. Melting points were determined on a Kofler hot bench. The reaction progress and the purity of the obtained compounds were controlled by TLC on Silufol UV-254 plates, eluent was 3:5 acetone–hexane, visualization with iodine vapor and under UV light.

2,4-Diacetyl-3-aryl(hetaryl)-5-hydroxy-5-methylcyclohexanones 1а–g were obtained according to a published procedure.3

Preparation of Compounds 4а–е (General Method).

Method I. A suspension of substituted cyclohexanone 1a–e (6 mmol) in anhydrous EtOH (20 ml) was treated by addition of malononitrile (2) (0.40 g, 6 mmol). The reaction mixture was stirred for 15 min at room temperature, then morpholine (0.52 ml, 6 mmol) was added; the stirred reaction mixture was heated to 60°С, then heating was abruptly stopped and the mixture was cooled to 15°С over 1 h. The precipitate formed was filtered off after 24 h, washed with EtOH, hexane, and recrystallized from EtOH.

Method II. The procedure was analogous to method I, except that cyanoacetamide (6) (0.50 g, 6 mmol) was used instead of malononitrile (2).

7-Acetyl-6-hydroxy-1,6-dimethyl-3-oxo-8-phenyl-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (4a). Yield 1.80 g (89%, method I), 1.85 g (91%, method II), white powder, mp 235–237°С (mp 247–264°С⁴). Mass spectrum, m/z (I _rel, %): 336 [M]⁺ (1), 318 [М–Н₂О]⁺ (2), 275 [М–Н₂О–CH₃CO]⁺ (100), 261 (11), 199 (19), 77 [C₆H₅]⁺ (12), 43 [CH₃CO]⁺ (89).

7-Acetyl-6-hydroxy-1,6-dimethyl-8-(4-methylphenyl)-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (4b). Yield 1.70 g (81%, method I), 1.95 g (93%, method II), white powder, mp 255–257°С (mp 267–268°С⁴). Mass spectrum, m/z (I _rel, %): 349 [M–Н]⁺ (1), 332 [М–Н₂О]⁺ (1), 312 (10), 289 [М–Н₂О–CH₃CO]⁺ (100), 276 (15), 199 (9), 105 (6), 91 [C₆H₅CH₂]⁺ (6), 44 [CH₃COH]⁺ (31), 30 (28).

7-Acetyl-8-(furan-2-yl)-6-hydroxy-1,6-dimethyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (4c). Yield 1.70 g (87%, method I), 1.85 g (94%, method II), white powder, fluorescent under UV light, mp 235–237°С. IR spectrum, ν, cm^–1: 3364 (ОН), 3005 (NH), 2221 (СN), 1715 (C=O), 1655 (NHCO). ¹H NMR spectrum, δ, ppm (J, Hz): 1.25 (3Н, s, СН₃); 1.96 (3Н, s, СН₃); 2.18 (3Н, s, СН₃); 2.80 (1Н, d, J = 16.5, 5-CH_A); 2.93–3.02 (2Н, m, 5-CH_B, 7-CH); 4.50 (1Н, d, J = 4.6, 8-CH); 5.01 (1Н, br. s, ОН); 6.08 (1Н, s, Н-3 Fur); 6.33 (1Н, s, Н-4 Fur); 7.52 (1Н, s, Н-5 Fur); 12.41 (1Н, br. s, NH). ¹³C NMR spectrum, δ, ppm: 17.1; 28.0; 30.7; 34.9; 43.4; 61.8; 67.9; 98.8; 106.4; 110.4; 112.5; 115.9; 141.9; 150.4; 155.2; 158.6; 159.8; 208.4. Mass spectrum, m/z (I _rel, %): 326 [M]⁺ (1), 308 [М–Н₂О]⁺ (2), 283 [М–CH₃CO]⁺ (3), 265 [М–Н₂О–CH₃CO]⁺ (100), 251 (11), 237 (8), 223 (53), 43 [CH₃CO]⁺ (72). Found, %: C66.16; H5.41; N 8.49. C₁₈H₁₈N₂O₄. Calculated, %: C66.25; H5.56; N 8.58.

7-Acetyl-6-hydroxy-1,6-dimethyl-8-(5-methylfuran-2-yl)-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (4d). Yield 1.73 g (85%, method I), 1.80 g (88%, method II), white powder, mp 237–240°С. IR spectrum, ν, cm^–1: 3426 (ОН), 3248 (NH), 2236 (СN), 1695 (C=O), 1671 (NHCO). ¹H NMR spectrum, δ, ppm (J, Hz): 1.26 (3Н, s, СН₃); 2.00 (3Н, s, СН₃); 2.16 (3Н, s, СН₃); 2.18 (3Н, s, СН₃); 2.79 (1Н, d, J = 15.0, 5-CH_A); 2.84–3.02 (2Н, m, 5-CH_B, 7-CH); 4.41 (1Н, d, J = 4.5, 8-CH); 4.98 (1Н, br. s, ОН); 5.91 (2Н, d, J = 2.1, Н-3,4 Fur). The NH proton signal was not observed apparently due to fast deuterium exchange. ¹³C NMR spectrum, δ, ppm: 11.9; 16.1; 26.9; 29.5; 33.7; 42.1; 60.4; 66.8; 97.6; 105.0; 105.8; 111.4; 114.7; 149.2 (2C); 152.0; 157.4; 158.6; 207.3. Mass spectrum, m/z (I _rel, %): [M]⁺ was absent, 322 [М–Н₂О]⁺ (3), 279 [М–Н₂О–CH₃CO]⁺ (91), 265 (10), 237 (14), 198 (4), 169 (4), 77 (5), 44 [CH₃COH]⁺ (100). Found, %: C 66.93; H 5.85; N 8.15. C₁₉H₂₀N₂O₄. Calculated, %: C 67.05; H 5.92; N 8.23.

7-Acetyl-6-hydroxy-1,6-dimethyl-3-oxo-8-(pyridin-3-yl)-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (4e). Yield 1.72 g (85%, method I), 1.82 g (90%, method II), white powder, mp 257–259°С. IR spectrum, ν, cm^–1: 3429 (ОН), 3270 (NH), 2220 (СN), 1695 (C=O), 1665 (NHCO). ¹H NMR spectrum, δ, ppm (J, Hz): 1.27 (3Н, s, СН₃); 1.76 (3Н, s, СН₃); 2.07 (3Н, s, СН₃); 2.87 (1Н, d, J = 10.1) and 4.35 (1Н, d, J = 10.1, 5-CH₂); 3.01 (1Н, s, 7-CH); 3.75 (1Н, s, 8-CH); 4.74 (1Н, br. s, ОН); 7.21 (1Н, t, J = 7.7, H-5 Py); 7.43 (1Н, d, J = 7.6, H-4 Py); 8.27 (1Н, s, H-2 Py); 8.35 (1Н, d, J = 7.4, H-6 Py); 12.31 (1Н, br. s, NH). ¹³C NMR spectrum, δ, ppm: 19.2; 28.5; 31.9; 44.9; 66.4; 68.5; 99.9; 115.4; 116.7; 116.8; 124.3; 136.0; 140.7; 148.4; 150.1; 151.0; 151.1; 160.6; 209.5. Mass spectrum, m/z (I _rel, %): [M]⁺ was absent, 319 [М–Н₂О]⁺ (4), 294 [М–CH₃CO]⁺ (8), 276 [М–Н₂О–CH₃CO]⁺ (100), 236 (4), 199 (14), 104 (3), 79 [C₆H₅+2Н]⁺ (9), 43 [CH₃CO]⁺ (48), 44 [CH₃COH]⁺ (48), 30 (31). Found, %: C 67.48; H 5.52; N 12.32. C₁₉H₁₉N₃O₃. Calculated, %: C 67.64; H 5.68; N 12.45.

Preparation of compounds 5а–с,f,g (General Method). A suspension of cyclohexanone 1a–c,f,g (6 mmol) in anhydrous EtOH (30 ml) was treated by addition of malononitrile dimer 3 (0.80 g, 6 mmol) and sodium ethoxide solution prepared from sodium metal (0.14 g, 6 mmol) and anhydrous EtOH (5 ml). The reaction mixture was refluxed for 1 h in a flask with a reflux condenser and left at room temperature. After 48 h the reaction mixture was diluted with 10% HCl to рН 7, the precipitate formed was filtered off, washed with water, then with EtOH, hexane, and recrystallized from n-BuOH.

2-[7-Acetyl-4-cyano-6-hydroxy-1,6-dimethyl-8-phenyl-5,6,7,8-tetrahydroisoquinolin-3(2 Н )-ylidene]malononitrile (5a). Yield 1.57 g (68%), yellow crystals, fluorescent under UV light, mp 285–288°С. IR spectrum, ν, cm^–1: 3411 (ОН), 2922 (NH), 2210, 2191, 2157 (CN), 1704 (C=O). ¹H NMR spectrum, δ, ppm (J, Hz): 1.22 (3Н, s, СН₃); 1.74 (3Н, s, СН₃); 2.01 (3Н, s, СН₃); 2.72–2.84 (2Н, m, 5-CH_A, 7-CH); the signal of second 5-СН₂ proton overlapped with residual water signal; 4.30 (1Н, d, J = 10.9, 8-CH); 4.47 (1Н, br. s, ОН); 6.96 (2Н, d, J = 7.4, Н Ph); 7.13 (1Н, t, J = 7.3, Н Ph); 7.21 (2Н, t, J = 7.3, НPh). The signal of NH proton was not observed, apparently due to fast deuterium exchange. Mass spectrum, m/z (I _rel, %): 384 [M]⁺ (3), 367 [M+Н–Н₂О]⁺ (63), 366 [М–Н₂О]⁺ (13), 352 [М+Н–Н₂О–СН₃]⁺ (95), 289 [M–Н₂О–C₆H₅]⁺ (100), 274 [М–Н₂О–C₆H₅–СН₃]⁺ (6), 183 (10), 176 (13), 168 (11), 77 [C₆H₅]⁺ (3), 60 (30), 44 [CH₃COH]⁺ (47), 43 [CH₃CO]⁺ (7). Found, %: C 71.66; H 5.11; N 14.45. C₂₃H₂₀N₄O₂. Calculated, %: C 71.86; H 5.24; N 14.57.

2-[7-Acetyl-4-cyano-6-hydroxy-1,6-dimethyl-8-(4-methylphenyl)-5,6,7,8-tetrahydroisoquinolin-3(2 Н )-ylidene]-malononitrile (5b). Yield 1.86 g (78%), orange powder, mp 246–247°С. IR spectrum, ν, cm^–1: 3437 (ОН), 2923 (NН), 2222, 2203, 2182 (СN), 1697 (C=O). ¹H NMR spectrum, δ, ppm (J, Hz): 1.28 (3Н, s, СН₃); 2.03 (3Н, s, СН₃); 2.04 (3Н, s, СН₃); 2.29 (3Н, s, СН₃); 2.81–2.98 (2Н, m, 5-CH_A, 7-CH); 3.15 (1Н, d, J=19.4, 5-CH_B); 4.36 (1Н, d, J = 10.2, 8-CH); 6.93 (2Н, d, J = 7.8, Н Ar); 7.04 (2Н, d, J = 7.8, Н Ar). The NН and ОН proton signals were not observed apparently due to fast deuterium exchange. Mass spectrum, m/z (I _rel, %): 398 [M]⁺ (2), 380 [M–Н₂О]⁺ (2), 337 [М–Н₂О–CH₃CO]⁺ (84), 323 [М+Н–Н₂О–CH₃CO]⁺ (20), 247 [М+Н–Н₂О–CH₃CO–С₆Н₄СН₃]⁺ (21), 161 (8), 91 [С₆Н₄СН₃]⁺ (10), 44 [CH₃COH]⁺ (100), 30 (25). Found, %: C 72.20; H 5.43; N 13.92. C₂₄H₂₂N₄O₂. Calculated, %: C 72.34; H 5.57; N 14.06.

2-[7-Acetyl-4-cyano-8-(furan-2-yl)-6-hydroxy-1,6-dimethyl- 5,6,7,8-tetrahydroisoquinolin-3(2 Н )-ylidene]-malononitrile (5c). Yield 1.80 g (80%), yellow powder, fluorescent under UV light, mp 228–230°С. IR spectrum, ν, cm^–1: 3382 (ОН), 2924 (NН), 2224, 2202, 2176 (СN), 1693 (C=O). ¹H NMR spectrum, δ, ppm (J, Hz): 1.33 (3Н, s, СН₃); 2.19 (3Н, s, СН₃); 2.27 (3Н, s, СН₃); 2.86 (1Н, d, J = 14.0) and 2.99 (1Н, d, J = 14.0, 5-CH₂); 3.14 (1Н, d, J = 7.8, 7-CH); 4.60 (1Н, d, J = 7.8, 8-CH); 6.09 (1Н, s, Н-3 Fur); 6.30 (1Н, s, Н-4 Fur); 7.41 (1Н, d, J = 1.2, Н-5 Fur). The NН and ОН proton signals were not observed apparently due to fast deuterium exchange. Mass spectrum, m/z (I _rel, %): 375 [M+Н]⁺ (100). Found, %: C 67.23; H 4.76; N 14.80. C₂₁H₁₈N₄O₃. Calculated, %: C 67.37; H 4.85; N 14.96.

2-[7-Acetyl-4-cyano-6-hydroxy-8-(4-isopropylphenyl)-1,6-dimethyl-5,6,7,8-tetrahydroisoquinolin-3(2 Н )-ylidene]malononitrile (5f). Yield 1.94 g (76%), orange powder, mp 232–234°С. IR spectrum, ν, cm^–1: 3473 (ОН), 2924 (NН), 2218, 2201, 2177 (СN), 1693 (C=O). ¹H NMR spectrum, δ, ppm (J, Hz): 1.19 (6Н, d, J=6.9, СН(СН ₃)₂); 1.28 (3Н, s, СН₃); 2.03 (3Н, s, СН₃); 2.04 (3Н, s, СН₃); 2.79–2.85 (1Н, m, СНМе₂); 2.86–2.99 (2Н, m, 5-CH_A, 7-CH); 3.11 (1Н, d, J = 17.4, 5-CH_B); 4.36 (1Н, d, J = 10.0, 8-CH); 6.94 (2Н, d, J = 7.8, Н Ar); 7.08 (2Н, d, J = 7.8, Н Ar). The NН and ОН proton signals were not observed apparently due to fast deuterium exchange. Mass spectrum, m/z (I _rel, %): [M]⁺ was absent, 408 [M–Н₂О]⁺ (2), 365 [М–CH₃CO]⁺ (57), 351 [М+Н–Н₂О–CH₃CO–СН₃]⁺ (14), 247 (16), 44 [CH₃COН]⁺ (100). Found, %: C 73.12; H 6.00; N 13.04. C₂₆H₂₆N₄O₂. Calculated, %: C 73.22; H 6.14; N 13.14.

2-[7-Acetyl-4-cyano-6-hydroxy-1,6-dimethyl-8-(3-methoxyphenyl)-5,6,7,8-tetrahydroisoquinolin-3(2 Н )-ylidene]malononitrile (5g). Yield 2.01 g (81%), yellow powder, mp 235–237°С. IR spectrum, ν, cm^–1: 3448 (ОН), 2920 (NН), 2225, 2199, 2173 (СN), 1692 (C=O). ¹H NMR spectrum, δ, ppm (J, Hz): 1.28 (3Н, s, СН₃); 2.04 (3Н, s, СН₃); 2.06 (3Н, s, СН₃); 2.83–2.98 (2Н, m, 5-CH_A, 7-CH); 3.13 (1Н, d, J = 17.6, 5-CH_B); 3.73 (3Н, s, ОСН₃); 4.37 (1Н, d, J = 10.3, 8-CH); 5.55–6.61 (2Н, m, Н Ar); 6.70 (1Н, d, J = 9.4, Н Ar); 7.15 (1Н, t, J = 8.1, НAr). The NН and ОН proton signals were not observed apparently due to fast deuterium exchange. Mass spectrum, m/z (I _rel, %): 414 [M]⁺ (3), 396 [M–Н₂О]⁺ (3), 339 [М+Н–Н₂О–CH₃CO–СН₃]⁺ (9), 247 (24), 161 (45), 44 [CH₃COH]⁺ (100), 30 (70). Found, %: C 69.41; H 5.20; N 13.43. C₂₄H₂₂N₄O₃. Calculated, %: C 69.55; H 5.35; N.52.

Preparation of Compounds 8a–c, 9 (General Method). A stirred solution of substituted isoquinoline 4с, 5b (2 mmol) in DMF (10 ml) was treated by adding 10% aqueous KОН solution (1.12 ml, 2 mmol), followed by alkylating agent 7а–с (2 mmol). The reaction mixture was stirred and slowly heated for 30 min, until 50°С temperature was reached, then diluted with equal amount of Н₂О and left at room temperature. The precipitate formed was filtered off after 48 h, washed with water, EtOH, hexane, and recrystallized from EtOH (compounds 8a–c) or n-BuOH (compound 9).

7-Acetyl-2-benzyl-8-(furan-2-yl)-6-hydroxy-1,6-dimethyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (8a). Yield 0.76 g (91%), white powder, mp 118–119°С. IR spectrum, ν, cm^–1: 3350 (ОН), 2221 (СN), 1703 (C=O), 1634 (N–C=O). ¹H NMR spectrum, δ, ppm (J, Hz): 1.32 (3Н, s, СН₃); 2.13 (3Н, s, СН₃); 2.21 (3Н, s, СН₃); 2.81–2.95 (2Н, m, 5-CH_A, 7-CH); the signal of second 5-СН₂ proton overlapped with residual water signal; 4.54 (1Н, d, J = 6.8, 8-CH); 4.93 (1Н, br. s, ОН); 5.40 (2Н, s, NCH₂); 5.90 (1Н, s, Н-3 Fur); 6.24 (1Н, s, Н-4 Fur); 7.10 (2Н, d, J= 7.5, HPh); 7.24 (1Н, t, J = 7.2, H Ph); 7.26–7.41 (3Н, m, Н-5 Fur, H Ph). Mass spectrum, m/z (I _rel, %): [M]⁺ was absent, 214 (41), 213 (47), 186 (22), 185 (10), 137 (26), 105 (100), 77 (70), 70 (21), 68 (11), 51 (19), 44 [CH₃COH]⁺ (8). Found, %: C 71.88; H 5.67; N 6.59. C₂₅H₂₄N₂O₄. Calculated, %: C 72.10; H 5.81; N 6.73.

7-Acetyl-8-(furan-2-yl)-6-hydroxy-1,2,6-trimethyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (8b). Yield 0.48 g (71%), white powder, mp 168–170°С. IR spectrum, ν, cm^–1: 3354 (ОН), 2204 (СN), 1700 (C=O), 1626 (N–C=O). ¹H NMR spectrum, δ, ppm (J, Hz): 1.30 (3Н, s, СН₃); 2.22 (3Н, s, СН₃); 2.24 (3Н, s, СН₃); 2.84 (3Н, s, СН₃); 3.01–3.28 (2Н, m, 5-CH_A, 7-CH); 4.44 (1Н, d, J = 4.4, 8-CH); 4.90 (2Н, br. s, 5-CH_B, ОН); 5.99 (1Н, s, Н-3 Fur); 6.28 (1Н, s, Н-4 Fur); 7.41 (1Н, s, Н-5 Fur). Mass spectrum, m/z (I _rel, %): 340 [M]⁺ (1), 322 [М–Н₂О]⁺ (3), 297 [М–CH₃CO]⁺ (6), 280 [М+Н–Н₂О–CH₃CO]⁺ (21), 279 [М–Н₂О–CH₃CO]⁺ (100), 265 [М+Н–Н₂О–CH₃CO–СН₃]⁺ (20), 264 [М–Н₂О–CH₃CO]⁺ (12), 56 (16), 44 [CH₃COH]⁺ (33), 30 (53). Found, %: C 66.89; H 5.77; N 8.10. C₁₉H₂₀N₂O₄. Calculated, %: C 67.05; H 5.92; N 8.23.

7-Acetyl-2-allyl-8-(furan-2-yl)-6-hydroxy-1,6-dimethyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (8c). Yield 0.55 g (82%), white powder, mp 133–135°С. IR spectrum, ν, cm^–1: 3324 (ОН), 2208 (СN), 1695 (C=O), 1621 (N–C=O). ¹H NMR spectrum, δ, ppm (J, Hz): 1.29 (3Н, s, СН₃); 2.13 (3Н, s, СН₃); 2.22 (3Н, s, СН₃); 2.86–2.99 (2Н, m, 5-CH_A, 7-CH); 4.55 (1Н, d, J = 17.0, 5-CH_B); 4.80 (1Н, d, J= 4.8, 8-CH); 4.82–5.11 (3Н, br. s, ОН and NСН₂); 5.25 (1Н, d, J _cis = 5.2) and 5.43 (1Н, d, J _trans = 17.0, СH=СН ₂); 5.95 (1Н, s, Н-3 Fur); 6.01–6.18 (1Н, m, СН=CH₂); 6.28 (1Н, s, Н-4 Fur); 7.38 (1Н, s, Н-5 Fur). Mass spectrum, m/z (I _rel, %): 366 [M]⁺ (3), 348 [М–Н₂О]⁺ (3), 323 [М–CH₃CO]⁺ (9), 306 [М+Н–Н₂О–CH₃CO]⁺ (23), 305 [М–Н₂О–CH₃CO]⁺ (100), 265 (13), 44 [CH₃CO]⁺ (38), 42 (28). Found, %: C 68.70; H 5.88; N 7.59. C₂₁H₂₂N₂O₄. Calculated, %: C 68.84; H 6.05; N 7.65.

2-[7-Acetyl-4-cyano-6-hydroxy-1,6-dimethyl-8-(4-methylphenyl)-5,6,7,8-tetrahydroisoquinolin-3-yl]-2-benzylmalononitrile (9). Yield 0.60 g (60%), white needles, mp 208–210°С IR spectrum, ν, cm^–1: 3455 (ОН), 2213 (СN), 1687 (C=O). ¹H NMR spectrum, δ, ppm (J, Hz): 1.33 (3Н, s, СН₃); 2.06 (3Н, s, СН₃); 2.10 (3Н, s, СН₃); 2.29 (3Н, s, СН₃); 2.99 (1Н, d, J = 10.1, 7-CH); 3.07 (1Н, d, J = 17.4) and 3.33 (1Н, d, J=17.4, 5-CH₂); 3.76 (1Н, d, J = 14.0) and 3.82 (1Н, d, J = 14.0, СН ₂Ph); 4.55 (1Н, d, J = 10.1, 8-CH); 4.77 (1Н, br. s, ОН); 6.86 (2Н, d, J = 7.5, Н Ar); 7.05 (2Н, d, J = 7.5, Н Ar); 7.32–7.41 (5Н, m, Н Ph). ¹³C NMR spectrum, δ, ppm: 21.1; 25.0; 28.1; 31.7; 42.8; 43.3; 44.2; 47.0; 66.5; 68.0; 105.8; 113.5; 113.7; 114.5; 128.6 (2С); 129.1 (2С); 129.2; 129.8 (2С); 130.9 (2С); 132.6; 136.2; 136.3; 140.4; 148.1; 152.2; 161.7; 209.6. Mass spectrum, m/z (I _rel, %): 489 [M+H]⁺ (2), 488 [M]⁺ (3), 470 [M–Н₂О]⁺ (6), 427 [М–CH₃CO–Н₂О]⁺ (64), 337 (12), 92 [C₆H₅CH₃]⁺ (12), 91 [C₆H₅CH₂]⁺ (100), 90 [C₆H₅CH]⁺ (27), 65 (12), 43 [CH₃CO]⁺ (48), 32 (7). Found, %: C 76.05; H 5.59; N 11.30. C₃₁H₂₈N₄O₂. Calculated, %: C 76.21; H 5.78; N 11.47.