Synthesis of 1-functionalized di- and tetramethyl-3,4-dihydrobenzofuro[3,2-g]-and [2,3-h]isoquinoline derivatives

Linear and angular 1-substituted derivatives of 3,3-di- and 3,3,4,4-tetramethyl-3,4-dihydrobenzofuroisoquinoline were obtained under Ritter reaction conditions, and the stereochemical features of these compounds were analyzed.

Fused ring systems containing two heterocycles have long attracted the attention of researchers. For example, derivatives of α-, β-, and γ-carbolines form a large group of alkaloids,1 which includes isocryptolepin.2 Derivatives of pyrido[4,3-b]carbazole, such as ellipticine, are well known natural compounds.3 ^, 4 The anticancer alkaloid lamellarin is another example of annulated heterocycles that contain various heteroatoms.5

We have previously shown that the condensation of arenes containing electron-donating substituents at an ortho position with α-branched aldehydes and nitriles in concentrated sulfuric acid gave 3,4-dihydroisoquinoline derivatives.6 ^– 13

In the current work, we studied the possibility of preparing 1-R-3,3-dimethyl- and 1-R-3,3,4,4-tetramethyl-3,4-dihydrobenzofuroisoquinolines as heterocyclic systems with two different heteroatoms in separate rings, starting from dibenzofuran under the Ritter reaction condition. The reaction could be assumed to follow a similar mechanism as the reactions of structurally related compounds, anisole,14 оrtho-substituted anisoles,15 ^, 16 and 2,6-dialkylphenols17 with α-branched aldehydes and nitriles. This mechanism would have resulted in derivatives of 2-azaspiro[4.5]deca-1,6,9-trien-8-ones 1 (Scheme 1). The interaction of dibenzofuran, isobutyraldehyde, and methylthiocyanate in concentrated sulfuric acid medium was found to produce trace amounts of the regioisomeric 3,3-dimethyl-3,4-dihydrobenzofuroisoquinolines 2а and 3а (as a 7:1 mixture according to GC-MS analysis of the reaction mixture). Increasing the reaction duration from 1 to 4 h did not significantly change the yield of compounds 2а and 3а, and products of type 1 were not detected.

Scheme 1

In order to increase the yields of 3,3-dimethyl-3,4-dihydrobenzofuroisoquinolines 2 and 3, a linear synthesis was performed starting from 1-(dibenzo[b,d]furan-2-yl)-2-methylpropan-1-ol (4) and nitriles 5a–d,i in concentrated sulfuric acid (Scheme 2). Procedures have been described in the literature for the preparation of benzofuro-[2,3-g]isoquinolines,18 ^– 20 benzofuro[2,3-h]isoquinolines,21 and benzofuro[3,2-g]isoquinolines,22 ^– 24 while no examples were found for the synthesis of 3,4-dihydrobenzofuro[3,2-g]-and [2,3-h]isoquinolines.

Scheme 2

The reaction products were formed in 31–80% total yield and were purified by crystallization (2b,i) or separated by column chromatography. The ratio of isomers 2 and 3 depended on the properties of nitrile: for aliphatic nitriles, regioselective formation of compounds of type 2 was observed, but aromatic nitriles gave a mixture of regioisomers 2 and 3 in 1:0 to 1:2 ratio. The structure of compounds 2а–d,i and 3с,d was established from IR, ¹Н and ¹³С NMR, mass spectrometry, and elemental analysis data. The structure of compounds 2i and 3с was additionally confirmed by COSY, HSQC, and HMBC 2D NMR experiments, that enabled a complete assignment of all ¹H and ¹³C NMR signals. ¹Н NMR spectra of compounds 2а–d,i and 3с contained a singlet due to the СН₃ group at the С-3 atom and a singlet of the 4-СН₂ group. ¹Н NMR spectrum of compound 3d contained two 3-СН₃ singlets at 0.93 and 1.50 ppm, while the 4-СН₂ protons gave two doublets at 2.66 and 2.88 ppm with the geminal spin-spin coupling constant of 15.0 Hz. The aromatic Н-6 proton signal in ¹Н NMR spectra of the linear molecules 2а–d,i was observed in the downfield region of 7.74–7.92 ppm (the numbering of atoms is presented in Scheme 2). The analogous Н-11 proton in the spectra of angular molecules 3с,d was observed at an upfield position (5.84 and 6.29 ppm, respectively), indicating the proximity of aromatic ring of the substituent at position 1 to the Н-11 proton in benzofuran system, and confirming the proposed structure of 3,4-dihydrobenzofuro[2,3-h]isoquinolines 3с,d.

The proposed reaction mechanism involves the formation of carbimmonium ion А 6 and an attack by its electrophilic center at one of the ortho positions (paths а1, а2), or an ipso attack with the formation of the spiro-σ-complex В0 (path b), followed by 1,2-sigmatropic shift at the С(1)–arene bond,25 which also can proceed in two directions (Scheme 3).

Scheme 3

Shklyaev with coworkers25 have shown that the molecule of 2-(4-methoxyphenyl)-3,3-dimethylbutan-2-ol containing four adjacent methyl groups reacted with nitriles, forming 1-R-6-methoxy-3,3,4,4-tetramethyl-3,4-dihydroisoquinolines, i.e., the mutual arrangement of methoxy group and alkyl chain in the ring had changed, likely due to the reaction occurring analogously to path b, followed by a sigmatropic shift at the С(4)–arene bond. We attempted to change the regioselectivity of heterocyclization reaction also in the case of dibenzofuran by introducing additional methyl groups in the carbinol. We established that the reaction of 2-(dibenzo[b,d]furan-2-yl)-3,3-dimethylbutan-2-ol (6) with nitriles 5a–h,j in concentrated sulfuric acid gave a mixture of regioisomers 7 and 8 (Scheme 4), while compounds of types 9 and 10 were not detected. Therefore, we consider it more likely that the reaction occurs by paths а1, а2. This was confirmed by semiempirical modeling of the reaction pathway by the РМ3 method. According to calculations, the intermediates В1 and В2 were more stable by 2–5 kcal/mol compared to В0.

Scheme 4

The mixtures of regioisomers 7 and 8 formed with the total yields of 33–68% were separated by column chromatography (the ratio of isomers 7 and 8 was from 1:0 to 1:10 and depended on the character of nitriles in a similar way as in the case of compounds 2 and 3). The structure of compounds 7a–h,j and 8c–g was established from IR, ¹Н and ¹³С NMR, mass spectroscopy, and elemental analysis data. The structure of compounds 7e,f and 8c (Figs. 1–3) was proved by X-ray structural analysis.

Figure 1

Structure of compound 7е with atoms represented by thermal vibration ellipsoids of 50% probability.

Figure 2

Structure of compound 7f with atoms represented by thermal vibration ellipsoids of 50% probability.

Figure 3

Structure of compound 8с with atoms represented by thermal vibration ellipsoids of 50% probability.

The molecules presented in Figures 1–3 were chiral due to the non-planar half-chair conformation of dihydropyridine ring and the orientation of substituent at position 1 out of the dibenzofuran ring plane. As indicated by the considered computational models, all compounds 8 in this regard are similar to compound 8с, while compounds 7 are similar to compounds 7e,f. The crystals of these compounds belonged to centrosymmetric space groups. The lack of molecular symmetry elements and the apparently high energy barriers to the inversion of dihydropyridine ring, as discussed below, point to cocrystallization of two enantiomeric forms, i.e., the crystals of compounds 7e,f and 8c are racemates.

The angular molecules of compounds 8с–g, similarly to compound 3c, gave ¹Н NMR spectra with H-11 and H-10 proton signals shifted upfield (5.89–6.75 ppm), that we explained by shielding of these atoms by the aromatic ring Е (Fig. 4), confirmed by X-ray structural analysis data for compound 8c. Thus, the measured distance between the center of pyridine ring and the H-11 atom (in the structural experiment this proton was located at the С(5) atom, Fig. 3) was 2.75 Å, comparable to the length of hydrogen bonds. It is entirely possible that a proton at such distance interacts with the π-electron system of aromatic ring.

Figure 4

¹Н NMR signal evolution for compound 8g over the temperature range from –20 to +95°С.

¹Н NMR spectra of compounds 7с–h,j and 8с,e–g acquired at room temperature showed a significant broadening of signals from four methyl groups С(3)(СН₃)₂ and С(4)(СН₃)₂, while the spectra of compounds 8f,g also featured broadening of Н-11, Н-10, and Н-3' signals (atom numbering is given in Fig. 4). This can be attributed to the D ring inversion (half-chair – half-chair inversion), accompanied by oscillations of substituent at position 1. This inversion is not degenerate in the case of compounds 7d,f, 8f,g with substituted aryl groups and compounds 7c, 8с with pyridyl groups. The inversion energy barriers for compounds 7, 8 were established as the energy differences between conformers and the transition states, and according to semiempirical РМ3 calculations were found to be 6–7 kcal/mol for compounds 7 and 9–10 kcal/mol for compounds 8. Analogous calculations for 3,3-dimethyl derivatives gave much lower values: 1–2 kcal/mol for compounds 2 and 3–4 kcal/mol for compounds 3. The three times higher energy barrier, in our opinion, explains the qualitative difference between the narrow signals of dimethyl derivatives and the broadened signals of tetramethyl derivatives: the rate of conformational change at room temperature, as reflected by dynamic NMR data, corresponds to fast exchange rate in the first case and moderate exchange rate in the second case.

The example of compounds 7d–g was used to study the temperature dependence of ¹Н NMR spectra for the linear molecules 7. The evolution of upfield part in ¹H NMR spectrum of compound 7e is shown in Figure 5. The axial and equatorial methyl groups were observed at –50°С as four slightly broadened singlets, and the signals of vicinal groups were closer together. The equatorial and axial signals merged at around 0°С, and the narrow singlets at 95°С corresponded to geminal methyl groups. The coalescence of signals for compounds 7f,g was observed at higher temperatures (30–40°С), pointing to slower inversion.

Figure 5

¹Н NMR signal evolution for compound 7е over the temperature range from –50 to +95°С.

The temperature evolution of ¹Н NMR spectra for the angular compounds 8 was studied in the case of compounds 8c,d,g. Compound 8d was different than the rest of the series, because its methyl groups gave four narrow signals at room temperature, instead of only below 0°С. The slower inversion was likely associated with the existence of a hydrogen bond between the ring nitrogen atom and the ortho-amino group. A noticeable signal broadening occurred only above 40°С, but coalescence – at approximately 100°С. For compounds 8c,g, coalescence was observed at approximately 50°С.

The changes in ¹H NMR spectrum of compound 8g are shown in Figure 4. The broadened signals of Н-11, Н-3', and Н-10 protons observed in the downfield region of spectrum at +20°С were transformed at +95°С into two doublets and a triplet, respectively. The four broadened methyl group signals did not fully evolve into two broadened singlets over the same temperature interval. When the temperature was decreased to –20°С, a weaker secondary series of signals was clearly observed due to another conformer (integrated intensity ratio ~10:3), that can also be considered as rotational isomer with the opposite position of bromine atom (see the Supplementary information file).

The possibility of aryl group rotation around the С(1)–С(1') bond at position 1 of the angular molecules 8d–g must be rejected, since semiempirical РМ3 calculations involving variation of the torsion angle C(11с)–C(1)–C(1')–C(2') showed more than 240 kcal/mol energy disadvantage of the eclipsed conformer (at approximately 180° angle), compared to the preferred conformer (at approximately 90° angle), when rotating through the less hindered side. This energy barrier was substantial also for compounds 7d–g and 8с, reaching 32–49 kcal/mol, but for compound 7c it was only 5 kcal/mol, which was already comparable to the calculated energy barrier to inversion. Crystals of the linear compound 7f and angular compound 8c lacked rotational isomers according to X-ray structural analysis: the substituents apparently occupied only one, energetically favored position (Figs. 2 and 3).

We have thus shown that the interaction of 1-(dibenzo-[b,d]furan-2-yl)-2-methylpropan-1-ol or 2-(dibenzo[b,d]-furan-2-yl)-3,3-dimethylbutan-2-ol with aliphatic nitriles under the Ritter reaction conditions occurred regioselectively, forming 1-substituted 3,3-di- and 3,3,4,4-tetramethyl-3,4-dihydrobenzofuro[3,2-g]isoquinolines, while reactions with aromatic nitriles gave a mixture of the respective 3,3-di- and 3,3,4,4-tetramethyl-3,4-dihydrobenzofuro[3,2-g]-and [2,3-h]isoquinolines. The presence of four instead of two methyl groups in the annulated dihydropyridine ring slowed its inversion (half-chair – half-chair transition), observed as a broadening of certain ¹Н NMR signals.

Experimental

IR spectra were recorded for thin films on a Bruker IFS-66/S FT-IR spectrometer. ¹Н and ¹³С NMR spectra were recorded on a Varian Mercury plus 300 instrument (300 and 75 MHz, respectively) in CDCl₃, with HMDS as internal standard (0.055 ppm). Dynamic ¹Н NMR experiments were performed on a Varian Mercury plus 300 instrument (300 MHz) in CDCl₃ (from –50 to +40°С) and in DMSO-d ₆ (20–95°С). Two-dimensional NMR experiments (¹H–¹³C HSQC, ¹H–¹³C HMBC, and ¹H–¹H COSY) for compounds 3c and 2i were performed on a Bruker Avance III HD spectrometer (400 MHz). Mass spectra and chromatograms were recorded on an Agilent Technologies 6890N/5975B GC-MS instrument (HP-5ms column, 30 m × 0.25 mm, 0.25 μm, carrier gas – helium, EI ionization, 70 eV). The analysis of compounds 2i and 7j revealed decarbethoxylation products, formed by thermal decomposition of compounds in the evaporator, which were identical chromatographically and by mass spectra to compounds 2b and 7b, respectively. Elemental analysis was performed on a Leco CHNS-932 analyzer. Melting points were determined on a Stuart SMP40 apparatus. The reaction progress and purity of the obtained compounds were controlled by TLC on Sorbfil plates (UV-254), visualization under UV light and by 0.5% solution of parachloranil in toluene. Silica gel from Alfa Aesar (0.06–0.20 mm) was used for column chromatography. Computational modeling of molecules was performed with the HyperChem 7.01 (trial version) software. The transition states between the inversed forms were identified by the synchronous transit method.

1-(Dibenzo[ b,d ]furan-2-yl)-2-methylpropan-1-one. Isobutyryl chloride (11 ml, 105 mmol) was added to a stirred suspension of AlCl₃ (16.0 g, 120 mmol) in dichloroethane (40 ml), while cooling in ice bath. A solution of dibenzofuran (16.8 g, 100 mmol) in dichloroethane (40 ml) was then added, while maintaining at 20°С. The mixture was stirred for 1 h, left overnight at room temperature, and then carefully poured on crushed ice (60 g). The quenched mixture was treated with concd. HCl (4 ml) and the layers were separated. The aqueous layer was extracted with dichloroethane. The organic layer and extracts were washed with water, then with 2% NaOH solution (25 ml) and again with water, and dried over anhydrous Na₂SO₄. Dichloroethane was removed by distillation.26a The product was purified by distillation at 248–249°С (18 mmHg). Yield 17.5 g (73%), white precipitate, mp 55–57°С (МеОН) (mp 57°С27). IR spectrum, ν, cm^–1: 3063, 2971, 1678, 1591, 1198. ¹H NMR spectrum, δ, ppm (J, Hz): 1.27 (6Н, d, J = 6.6, 2СН₃); 3.67 (1H, sept, J = 6.6, СН); 7.37 (1Н, td, J = 7.8, J = 1.2, Н Ar); 7.48 (1Н, td, J = 7.8, J = 1.2, Н Ar); 7.58 (1Н, dd, J = 7.8, J = 1.2, Н Ar); 7.59 (1Н, d, J = 9.0, Н Ar); 7.99 (1Н, dd, J = 7.8, J = 1.2, Н Ar); 8.10 (1Н, dd, J = 9.0, J = 1.8, Н Ar); 8.58 (1Н, d, J = 1.8, Н Ar). ¹³C NMR spectrum, δ, ppm: 19.2; 35.2; 111.3; 111.6; 120.7; 121.3; 123.1; 123.5; 124.3; 127.6; 127.7; 131.1; 156.5; 158.4; 203.3. Mass spectrum, m/z (I _rel, %): 238 [M]⁺ (19), 195 [M–С₃Н₇]⁺ (100), 167 [M–COС₃Н₇]⁺ (23), 139 (34). Found, %: С 80.39; Н 5.82. C₁₆H₁₄O₂. Calculated, %: С 80.65; Н 5.92.

1-(Dibenzo[ b,d ]furan-2-yl)-2-methylpropan-1-ol (4). A solution of 1-(dibenzo[b,d]furan-2-yl)-2-methylpropan-1-one (19.0 g, 80 mmol) in EtOH (100 ml) was added to a stirred and cooled suspension of NaBH₄ (3.0 g, 80 mmol) in EtOH (40 ml). The mixture was stirred for 2 h at 30°С, then for 1 h at 20–25°С. Ethanol was removed by distillation, then 10% aqueous NaOH solution (30 ml) was added. The mixture was extracted with Et₂O and dried over anhydrous Na₂SO₄. Et₂O was removed by distillation. Yield 13.1 g (68%), white precipitate, mp 64–66°С (hexane). IR spectrum, ν, cm^–1: 3405, 3054, 2961, 2874, 1595, 1474, 1196. ¹H NMR spectrum, δ, ppm (J, Hz): 0.81 (3Н, d, J = 6.6, СН₃); 1.46 (3Н, d, J = 6.6, СН₃); 1.95 (1Н, br. s, ОН); 1.98–2.09 (1Н, m, (СН₃)СН); 4.51 (1Н, d, J = 7.2, СНОН); 7.24–7.57 (4Н, m, Н Ar); 7.90–7.95 (2Н, m, Н Ar). ¹³C NMR spectrum, δ, ppm: 18.3; 19.0; 35.5; 80.0; 111.0; 111.5; 118.4; 120.5; 122.5; 124.0; 124.1; 125.7; 127.0; 138.3; 155.5; 156.4. Mass spectrum, m/z (I _rel, %): 240 [М]⁺ (12), 197 [M–С₃Н₇]⁺ (100), 169 (79), 141 (16), 139 (19), 115 (11). Found, %: С 79.68; Н 6.68. C₁₆H₁₆O₂. Calculated, %: С 79.97; Н 6.71.

1-(Dibenzo[ b,d ]furan-2-yl)-2,2-dimethylpropan-1-one. Trimethylacetyl chloride (12.5 ml, 105 mmol) was added to a stirred suspension of AlCl₃ (16.0 g, 120 mmol) and dibenzofuran (16.8 g, 100 mmol) in dichloroethane (60 ml), while cooling with ice water. The further procedure followed the synthesis of 1-(dibenzo[b,d]furan-2-yl)-2-methylpropan-1-one. The product was purified by distillation at 192–193°С (5 mmHg). Yield 15.3 g (61%), white crystals, mp 60.5–61.0°С (hexane). IR spectrum, ν, cm^–1: 3064, 2972, 1673, 1593, 1469. ¹H NMR spectrum, δ, ppm (J, Hz): 1.43 (9Н, s, 3СН₃); 7.37 (1Н, td, J = 7.5, J = 1.2, Н Ar); 7.49 (1Н, td, J = 7.5, J = 1.2, Н Ar); 7.56 (1Н, d, J = 8.4, Н Ar); 7.58 (1Н, d, J = 8.4, Н Ar); 7.91 (1Н, dd, J = 8.7, J = 1.8, Н Ar); 7.98 (1Н, dd, J = 7.5, J = 0.9, Н Ar); 8.38 (1Н, d, J = 1.8, Н Ar). ¹³C NMR spectrum, δ, ppm: 28.2; 28.4; 44.1; 111.0; 111.8; 120.8; 121.4; 123.1; 123.8; 124.0; 127.7; 128.1; 133.1; 156.7; 157.4; 207.7. Mass spectrum, m/z (I _rel, %): 252 [M]⁺ (5), 195 [M–С₄Н₉]⁺ (100), 167 [M–COС₄Н₉]⁺ (15), 139 (29). Found, %: С 80.65; Н 6.70. C₁₇H₁₆O₂. Calculated, %: С 80.93; Н 6.39.

2-(Dibenzo[ b,d ]furan-2-yl)-3,3-dimethylbutan-2-ol (6). A solution of MeI (5.2 ml, 84 mmol) in Et₂O (20 ml) was added dropwise to a cooled suspension of Mg (1.75 g, 72 mmol) in Et₂O (10 ml). The mixture was then heated on a water bath for 30 min, stirred, and treated by dropwise addition of 1-(dibenzo[b,d]furan-2-yl)-2,2-dimethylpropan-1-one (15.0 g, 60 mmol) in Et₂O (20 ml). After the addition was complete, the mixture was heated on a water bath for additional 2 h and left overnight. Crushed ice (7 g) was added and the quenched mixture was washed with 30% aqueous NH₄Cl solution. The ether layer was separated, while the aqueous layer was extracted with Et2O (3×20 ml). The combined ether layers were washed with water and dried over anhydrous Na₂SO₄. Ether was evaporated,26b and the residue was purified by distillation at 203°С (5 mmHg). Yield 11.2 g (70%), white crystals, mp 82–83°С (hexane). IR spectrum, ν, cm^–1: 3574, 3480, 3057, 2969, 1594, 1470. ¹H NMR spectrum, δ, ppm (J, Hz): 0.95 (9Н, s, 3СН₃); 1.67 (3Н, s, СН₃); 1.76 (1Н, s, ОН); 7.29 (1Н, td, J = 7.5, J = 1.2, Н Ar); 7.36–7.44 (2Н, m, Н Ar); 7.51 (2H, t, J = 7.5, Н Ar); 7.92 (1Н, d, J = 7.5, Н Ar); 8.02 (1Н, d, J = 1.2, Н Ar). ¹³C NMR spectrum, δ, ppm: 25.7; 25.8; 38.1; 78.7; 109.8; 111.6; 119.1; 120.5; 122.5; 123.1; 124.5; 126.5; 126.9; 140.8; 154.9; 156.5. Mass spectrum, m/z (I _rel, %): 268 [M]⁺ (0.3), 211 [M–С₄Н₉]⁺ (68), 193 [M–H₂O–С₄Н₉]⁺ (15). Found, %: С 80.34; Н 7.54. C₁₈H₂₀O₂. Calculated, %: С 80.56; Н 7.51.

Reaction of 1-(dibenzo[ b,d ]furan-2-yl)-2-methylpropan-1-ol (4) or 2-(dibenzo[ b,d ]furan-2-yl)-3,3-dimethylbutan-2-ol (6) with nitriles 5a–j (General method). A mixture of nitrile 5a–j (2.0 mmol) and compound 4 or 6 (2.0 mmol) in СН₂Сl₂ (1 ml) was added dropwise to stirred, cooled (5–10°С) 93% H₂SO₄ (1 ml). The reaction mixture was stirred for 1 h at 20–25°С, then poured on crushed ice (15–20 g) that was mixed with aqueous ammonia (6 ml). The mixture was extracted with СН₂Сl₂ (3×10 ml), the combined extracts were washed with H₂O and dried over anhydrous Na₂SO₄. The solvent was removed by distillation, and the residue was crystallized or separated by chromatography.

3,3-Dimethyl-1-methylsulfanyl-3,4-dihydrobenzofuro-[3,2 -g ]isoquinoline (2a) was obtained from compounds 4 and 5а. Purification by crystallization. Yield 340 mg (57%), light-yellow crystalline powder, mp 130–132°С (EtOH). IR spectrum, ν, cm^–1: 1660, 1596, 1566, 1514. ¹H NMR spectrum, δ, ppm (J, Hz): 1.22 (6Н, s, 3-(СН₃)₂); 2.46 (3Н, s, SСН₃); 2.83 (2Н, s, 4-СН₂); 7.31 (1Н, t, J = 7.5, Н Ar); 7.45 (1Н, t, J = 7.8, Н Ar); 7.54 (1Н, d, J = 8.1, Н Ar); 7.66 (1Н, s, Н-5); 7.87 (1Н, s, Н-11); 7.89 (1Н, d, J = 7.8, Н-6). ¹³C NMR spectrum, δ, ppm: 12.4; 28.2; 39.6; 56.1; 108.0; 111.7; 119.5; 120.8; 122.7; 123.4; 125.9; 127.2; 127.6; 130.6; 154.7; 157.0; 160.0. Mass spectrum, m/z (I _rel, %): 295 [M]⁺ (38), 294 [M–Н]⁺ (23), 280 [M–СН₃]⁺ (100), 206 (31). Found, %: С 73.26; Н 5.86; N 4.41; S 10.61. C₁₈H₁₇NOS. Calculated, %: С 73.19; Н 5.80; N 4.74; S 10.85.

1,3,3-Trimethyl-3,4-dihydrobenzofuro[3,2- g ]isoquinoline (2b) was obtained from compounds 4 and 5b and purified by chromatography (eluent 15:1 СН₂Сl₂–acetone). Yield 160 mg (31%), light-yellow crystalline powder, mp 105–107°С (EtOAc–hexane). R _f 0.25 (СН₂Сl₂–acetone, 10:1). IR spectrum, ν, cm^–1: 2963, 2923, 1623, 1570, 1454. ¹H NMR spectrum, δ, ppm (J, Hz): 1.23 (6Н, s, 3-(СН₃)₂); 2.46 (3Н, s, 1-СН₃); 2.83 (2Н, s, 4-СН₂); 7.34 (1Н, td, J = 7.5, J = 0.9, Н Ar); 7.47 (1Н, td, J = 7.8, J = 0.9, Н Ar); 7.57 (1Н, d, J = 8.7, Н Ar); 7.68 (2Н, s, Н-5,11); 7.93 (1Н, d, J = 7.5, Н-6). ¹³C NMR spectrum, δ, ppm: 23.6; 27.9; 39.3; 54.1; 108.7; 111.8; 119.7; 120.9; 122.9; 123.6; 127.6; 127.7; 131.1; 155.1; 157.1. Mass spectrum, m/z (I _rel, %): 263 [М]⁺ (100), 262 [M–Н]⁺ (20), 248 [M–СН₃]⁺ (85), 222 [M–C₃H₅]₊ (13), 221 [M–C₃H₆]⁺ (72), 220 (29), 207 [M–C₄H₈]⁺ (15), 206 (16), 205 (28). Found, %: С 82.11; Н 6.75; N 5.00. C₁₈H₁₇NO. Calculated, %: С 82.10; Н 6.51; N 5.32.

3,3-Dimethyl-1-(pyridin-2-yl)-3,4-dihydrobenzofuro-[3,2- g ]isoquinoline (2c) and 3,3-dimethyl-1-(pyridin-2-yl)-3,4-dihydrobenzofuro[2,3 -h ]isoquinoline (3c) were obtained from compounds 4 and 5с. The mixture was separated by column chromatography (eluent 20:1 СН₂Сl₂–acetone).

Compound 2с. Yield 160 mg (25%), white crystalline powder, mp 109–111°С (EtOAc–hexane). R _f 0.23 (10:1 СН₂Сl₂–acetone). ¹H NMR spectrum, δ, ppm (J, Hz): 1.28 (6Н, s, 3-(СН₃)₂); 2.92 (2Н, s, 4-СН₂); 7.24–7.33 (2Н, m, H Ar); 7.39 (1Н, td, J = 7.7, J = 1.2, Н Ar); 7.46 (1Н, d, J = 7.8, Н Ar); 7.51 (1Н, s, Н-5); 7.69 (1Н, s, Н-11); 7.74–7.81 (2Н, m, Н Ar); 7.88 (1Н, d, J = 7.5, Н Ar); 8.62 (1Н, d, J = 4.8, Н Py). ¹³C NMR spectrum, δ, ppm: 27.4; 39.2; 55.2; 111.7 (2С); 119.7; 120.9; 122.7; 123.7 (2С); 124.0; 126.0 (2С); 127.7; 132.1; 137.0; 148.5; 154.7; 157.1; 157.5; 162.8. Mass spectrum, m/z (I _rel, %): 326 [M]⁺ (32), 311 [M–СН₃]⁺ (100), 270 [M–C₄H₈]⁺ (39). Found, %: С 80.75; Н 5.49; N 8.46. C₂₂H₁₈N₂O. Calculated, %: С 80.96; Н 5.56; N 8.58.

Compound 3c. Yield 360 mg (55%), white crystalline powder, mp 138–140°С (EtOH). R _f 0.40 (10:1 СН₂Сl₂–acetone). IR spectrum, ν, cm^–1: 1585, 1564, 1464. ¹H NMR spectrum (400 MHz, CDCl₃), δ, ppm (J, Hz): 1.37 (6Н, s, 3-(СН₃)₂); 2.94 (2Н, s, 4-СН₂); 5.84 (1Н, d, J = 7.8, Н-11); 6.79 (1Н, td, J = 7.7, J = 1.2, Н-10); 7.28 (1Н, td, J = 7.8, J = 1.2, Н-9); 7.32–7.40 (2Н, m, Н-5, H-5 Py); 7.49 (1Н, d, J = 8.1, Н-8); 7.65 (1Н, d, J = 8.4, Н-6); 7.86 (1Н, td, J = 7.8, J = 1.8, Н-4 Py); 8.00 (1Н, d, J = 7.5, Н-3 Py); 8.49 (1Н, d, J = 4.2, Н-6 Py). ¹³C NMR spectrum, δ, ppm: 26.6 (СН₃); 39.4 (4-СН₂); 54.4 (С-3); 110.8 (С-8); 113.6 (С-6); 121.0 (С-11а(С-11b)); 121.5 (С-10); 122.3 (С-11b (С-11a)); 123.1 (С-3 Py); 123.3 (С-11); 123.6 (С-5 Py); 126.3 (С-9); 126.8 (С-5); 133.1 (С-4а,11с); 136.8 (C-4 Py); 149.1 (C-6 Py); 155.4 (C-6a); 156.2 (C-7a); 158.3 (C-2 Py); 162.7 (C-1). Mass spectrum, m/z (I _rel, %): 326 [M]⁺ (36), 311 [M–СН₃]⁺ (100), 270 [M–C₄H₈]⁺ (44). Found, %: С 80.69; Н 5.58; N 8.51. C₂₂H₁₈N₂O. Calculated, %: С 80.96; Н 5.56; N 8.58.

2-(3,3-Dimethyl-3,4-dihydrobenzofuro[3,2- g ]isoquinolin-1-yl)aniline (2d) and 2-(3,3-dimethyl-3,4-dihydrobenzofuro[2,3- h ]isoquinolin-1-yl)aniline (3d) were obtained from compounds 4 and 5d. The mixture was separated by column chromatography (eluent 6:1 hexane–EtOAc).

Compound 2d. Yield 270 mg (40%), light-yellow crystals, mp 127.5–128.5°С (2-PrOH). R _f 0.20 (6:1 hexane–EtOAc). IR spectrum, ν, cm^–1: 3456, 3329, 2965, 2928, 1612, 1554, 1491. ¹H NMR spectrum, δ, ppm (J, Hz): 1.27 (6Н, s, 3-(СН₃)₂); 2.87 (2Н, s, 4-СН₂); 4.92 (2Н, br. s, NH₂); 6.67–6.74 (2H, m, Н Ar); 7.11–7.19 (2Н, m, Н Ar); 7.28 (1Н, t, J = 7.5, Н Ar); 7.37–7.48 (2Н, m, Н Ar); 7.42 (1Н, s, Н-5); 7.68 (1Н, s, H-11); 7.89 (1Н, d, J = 7.8, H Ar). ¹³C NMR spectrum, δ, ppm: 27.8; 39.1; 54.9; 99.9; 111.8; 116.9; 117.1; 119.7; 120.9; 121.7; 122.8; 123.5; 126.0; 127.1; 127.8; 129.8; 130.8; 132.2; 146.6; 154.7; 157.1; 164.4. Mass spectrum, m/z (I _rel, %): 340 [M]⁺ (30), 339 [M–Н]⁺ (100), 323 [M–NН₃]⁺ (8). Found, %: С 80.88; Н 5.91; N 8.17. C₂₃H₂₀N₂O. Calculated, %: С 81.15; Н 5.92; N 8.23.

Compound 3d. Yield 160 mg (23%), light-yellow crystalline powder, mp 179–181°С (2-PrOH). R _f 0.45 (6:1 hexane–EtOAc). IR spectrum, ν, cm^–1: 3456, 3321, 2967, 2928, 1611, 1583, 1552, 1491. ¹H NMR spectrum, δ, ppm (J, Hz): 0.93 (3Н, s) and 1.50 (3Н, s, 3-(СН₃)₂); 2.66 (1Н, d, J = 15.0) and 2.88 (1Н, d, J = 15.0, 4-СН₂); 5.53 (2Н, br. s, NH₂); 6.29–6.34 (2Н, m, H Ar); 6.74–6.79 (2Н, m, H Ar); 6.88 (1Н, d, J = 6.9, H Ar); 7.03 (1Н, t, J = 6.9, H Ar); 7.16–7.24 (2Н, m, H Ar); 7.36 (1Н, d, J = 8.7, H Ar); 7.53 (1Н, d, J = 7.8, H Ar). ¹³C NMR spectrum, δ, ppm: 23.2; 31.5; 40.0; 54.4; 100.0; 110.9; 113.7; 117.1; 117.8; 121.6; 122.1; 123.1; 125.6; 127.0; 127.1; 130.2; 130.9; 133.7; 155.8; 156.5; 164.4. Mass spectrum, m/z (I _rel, %): 340 [M]⁺ (100), 339 [M–Н]⁺ (73), 325 [M–СН₃]⁺ (64), 324 [M–NH₂]⁺ (33), 323 [M–NН₃]⁺ (15), 284 [M–C₄H₈]⁺ (30), 283 (42). Found, %: С 80.87; Н 5.75; N 8.02. C₂₃H₂₀N₂O. Calculated, %: С 81.15; Н 5.92; N 8.23.

Ethyl (3,3-dimethyl-3,4-dihydrobenzofuro[3,2 -g ]isoquinolin-1(2 Н )-ylidene)acetate (2i) was obtained from compounds 4 and 5i. Purification by crystallization. Yield 360 mg (53%), light-yellow crystalline powder, mp 163–164°С (EtOH). IR spectrum, ν, cm^–1: 3265, 2964, 1645, 1602, 1566, 1175. ¹H NMR spectrum (400 MHz, CDCl₃), δ, ppm (J, Hz) (the atom numbering is given in Scheme 2): 1.32 (6Н, s, 3-(СН₃)₂); 1.37 (3Н, t, J = 6.9, ОСН₂СН ₃); 2.97 (2Н, s, 4-СН₂); 4.22 (2Н, q, J = 6.9, ОСН ₂СН₃); 5.25 (1Н, s, =СНСO₂Et); 7.34 (1Н, td, J = 7.8, J = 0.9, Н-7); 7.49 (1Н, td, J = 7.8, J = 0.9, Н-8); 7.57 (1Н, d, J = 7.8, Н-9); 7.68 (1Н, s, Н-5); 7.88 (1Н, s, Н-11); 7.92 (1Н, d, J = 7.8, Н-6); 9.12 (1Н, br. s, NH). ¹³C NMR spectrum, δ, ppm: 14.6 (ОСН₂ СН₃); 28.4 (СН₃); 42.7 (4-СН₂); 49.0 (С-3); 58.8 (ОСН₂СН₃); 78.2 (=СНСO₂Et); 108.3 (C-11); 112.0 (C-9); 120.4 (C-5); 120.9 (C-6); 122.4 (C-7); 123.0 (C-5a); 125.8 (C-4a); 127.4 (C-5b); 127.5 (C-8); 129.6 (C-11a); 154.7 (C-1(С-10а)); 155.0 (C-1(С-10а)); 156.7 (С-9а); 170.8 (C=O). Found, %: С 74.93; Н 6.27; N 4.09. C₂₁H₂₁NO₃. Calculated, %: С 75.20; Н 6.31; N 4.18.

3,3,4,4-Tetramethyl-1-(methylsulfanyl)-3,4-dihydrobenzofuro[3,2- g ]isoquinoline (7a) was obtained from compounds 6 and 5а. Purification by crystallization. Yield 370 mg (57%), white crystals, mp 77–78°С (EtOH). IR spectrum, ν, cm^–1: 3060, 2975, 2925, 1601, 1456. ¹H NMR spectrum, δ, ppm (J, Hz): 1.18 (6Н, s, 3-(СН₃)₂); 1.31 (6Н, s, 4-(СН₃)₂); 2.46 (3Н, s, SСН₃); 7.33 (1Н, td, J = 7.5, J = 0.9, H-7); 7.45 (1Н, td, J = 7.8, J = 1.5, H-8); 7.55 (1Н, d, J = 8.1, H-9); 7.86 (1Н, s, H-5); 7.89 (1Н, s, H-11); 7.95 (1Н, br. d, J = 7.8, H-6). ¹³C NMR spectrum, δ, ppm: 12.4; 23.7; 39.5; 61.7; 107.9; 111.8; 116.0; 120.8; 122.8; 123.9; 126.3; 126.7; 127.7; 141.1; 154.3; 157.2; 159.1. Mass spectrum, m/z (I _rel, %): 323 [M]⁺ (13), 308 [M–СН³]⁺ (100), 251 (10), 219 (10), 218 (12). Found, %: С 74.03; Н 6.60; N 4.40; S 9.68. C₂₀H₂₁NOS. Calculated, %: С 74.27; Н 6.54; N 4.33; S 9.91.

1,3,3,4,4-Pentamethyl-3,4-dihydrobenzofuro[3,2- g ]-isoquinoline (7b) was obtained from compounds 6 and 5b. Purification by crystallization. Yield 190 mg (33%), lightyellow crystals, mp 129–130°С (EtOAc). IR spectrum, ν, cm^–1: 3060 (br. s), 2973, 2924, 1630, 1575, 1457. ¹H NMR spectrum, δ, ppm (J, Hz): 1.32 (6Н, s, 3-СН₃); 1.89 (6Н, s, 4-СН₃); 2.49 (3Н, s, 1-СН₃); 7.35 (1Н, t, J = 7.5, H-7); 7.47 (1Н, t, J = 7.8, H-8); 7.57 (1Н, d, J = 8.4, H-9); 7.66 (1Н, s, Н-5); 7.92 (1Н, s, Н-11); 7.97 (1Н, d, J = 7.5, H-6). ¹³C NMR spectrum, δ, ppm: 23.3; 23.6; 24.1; 38.9; 59.5; 108.5; 111.8; 116.0; 120.8; 122.9; 123.9; 126.2; 126.8; 127.6; 141.7; 154.4; 157.2; 160.5. Mass spectrum, m/z (I _rel, %): 291 [M]⁺ (81), 290 [M–H]⁺ (44), 276 [M–СН₃]⁺ (41), 249 [M–С₃Н₆]⁺ (27), 248 [M–С₃Н₇]⁺ (37), 235 [M–С₄Н₈]⁺ (62), 234 [M–С₄Н₉]⁺ (100), 233 (18). Found, %: С 82.21; Н 7.33; N 4.55. C₂₀H₂₁NO. Calculated, %: С 82.44; Н 7.26; N 4.81.

3,3,4,4-Tetramethyl-1-(pyridin-2-yl)-3,4-dihydrobenzofuro[3,2- g ]isoquinoline (7c) and 3,3,4,4-tetramethyl-1-(pyridin-2-yl)-3,4-dihydrobenzofuro[2,3- h ]isoquinoline (8c) were obtained from compounds 6 and 5с. The mixture was separated by column chromatography (eluent 4:1 hexane–EtOAc).

Compound 7c. Yield 35 mg (impurity of compound 8с with 20% of ¹Н NMR signal intensity). ¹H NMR spectrum, δ, ppm (J, Hz): 1.30 (6Н, br. s, 3-СН₃); 1.42 (6Н, br. s, 4-СН₃); 7.31–7.40 (3Н, m, H Ar); 7.45 (1Н, td, J = 7.8, J = 1.2, H Ar); 7.51 (1Н, d, J = 7.5, H Ar); 7.53 (1Н, s, H-5); 7.84 (1Н, dd, J = 6.6, J = 1.5, H Ar); 7.97 (1Н, s, H-11); 7.98 (1Н, d, J = 6.9, H Ar); 8.70 (1Н, d, J = 4.5, H Py). Mass spectrum, m/z (I _rel, %): 354 [M]⁺ (13), 339 [M–СН₃]⁺ (100), 298 [M–С₄Н₈]⁺ (19), 297 [M–С₄Н₉]⁺ (11), 296 (18).

Compound 8c. Yield 326 mg (46%), colorless crystals, mp 186–186.5°С (EtOH). R _f 0.31 (2:1 hexane–EtOAc). IR spectrum, ν, cm^–1: 3060, 2975, 1582, 1464. ¹H NMR spectrum, δ, ppm (J, Hz): 0.97 (3Н, br. s, СН₃); 1.24 (3Н, br. s, СН₃); 1.52 (3Н, br. s, СН₃); 1.66 (3Н, br. s, СН₃); 5.89 (1Н, d, J = 8.1, H-11); 6.75 (1Н, td, J = 8.1, J = 1.2, H-10); 7.23 (1Н, ddd, J = 8.0, J = 7.5, J = 1.2, H-9); 7.31 (1Н, ddd, J = 7.4, J = 4.8, J = 1.2, H-5 Py); 7.44 (1Н, d, J = 7.8, H-5); 7.56 (1Н, d, J = 8.7, H-8); 7.66 (1Н, d, J = 8.4, H-6); 7.80 (1Н, td, J = 7.7, J = 1.2, H-4 Py); 7.93 (1Н, d, J = 7.8, H-3 Py); 8.46 (1Н, d, J = 4.8, H-6 Py). ¹³C NMR spectrum, δ, ppm: 21.5; 22.3; 24.2; 25.0; 39.5; 60.3; 111.1; 114.2; 120.9; 121.6; 121.8; 123.2; 123.3; 123.6 (2С); 123.8; 126.6; 137.0; 143.0; 149.4; 155.0; 156.5; 158.5; 162.4. Mass spectrum, m/z (I _rel, %): 354 [M]⁺ (20), 339 [M–СН₃]⁺ (100), 298 [M–С₄Н₈]⁺ (19), 297 [M–С₄Н₉]⁺ (13), 296 (23). Found, %: С 81.01; Н 6.23; N 7.84. C₂₄H₂₂N₂O. Calculated, %: С 81.33; Н 6.26; N 7.90.

2-(3,3,4,4-Tetramethyl-3,4-dihydrobenzofuro[3,2- g ]isoquinolin-1-yl)aniline (7d) and 2-(3,3,4,4-tetramethyl-3,4-dihydrobenzofuro[2,3- h ]isoquinolin-1-yl)aniline (8d) were obtained from compounds 6 and 5d. The mixture was separated by column chromatography (eluent 5:1 hexane–EtOAc).

Compound 7d. Yield 380 mg (51%), yellow crystals, mp 203–205°С (EtOAc). R _f 0.34 (5:1 hexane–EtOAc). IR spectrum, ν, cm^–1: 3441, 3342, 1607, 1452. ¹H NMR spectrum, δ, ppm (J, Hz): 1.28 (6Н, br. s, 3-СН₃); 1.41 (6Н, br. s, 4-СН₃); 4.89 (2Н, br. s, NH₂); 6.71–6.78 (2Н, m, H Ar); 7.14–7.22 (2Н, m, H Ar); 7.32 (1Н, t, J = 7.4, H Ar); 7.42 (1Н, s, H-5); 7.43 (1Н, t, J = 7.8, H Ar); 7.51 (1Н, d, J = 8.1, H Ar); 7.95 (1Н, s, H-11); 7.97 (1Н, d, J = 7.2, H Ar). ¹³C NMR spectrum, δ, ppm: 23.4; 38.5; 60.3; 111.6; 111.8; 115.3; 116.9; 117.2; 120.8; 122.1; 122.8; 123.8; 126.3; 126.4; 127.7; 129.8; 130.6; 142.5; 146.5; 154.1; 157.2; 164.2. Mass spectrum, m/z (I _rel, %): 368 [M]⁺ (35), 367 [M–H]⁺ (100), 353 [M–СН₃]⁺ (13). Found, %: С 81.21; Н 6.56; N 7.53. C₂₅H₂₄N₂O. Calculated, %: С 81.49; Н 6.57; N 7.60.

Compound 8d. Yield 130 mg (17%), light-yellow crystals, mp 163–165°С (2-PrOH). R _f 0.63 (5:1 hexane–EtOAc). IR spectrum, ν, cm^–1: 3469, 3344, 1606, 1459. ¹H NMR spectrum, δ, ppm (J, Hz): 0.93 (3Н, s, СН₃); 1.21 (3Н, s, СН₃); 1.46 (3Н, s, СН₃); 1.57 (3Н, s, СН₃); 5.64 (2Н, br. s, NH₂); 6.34 (1Н, t, J = 7.5, H-10); 6.49 (1Н, d, J = 8.1, H-11); 6.82 (1Н, d, J = 8.0, H Ar); 6.84 (1Н, d, J = 8.0, H Ar); 6.88 (1Н, t, J = 7.8, H Ar); 7.08 (1Н, t, J = 7.8, H Ar); 7.23 (1Н, t, J = 7.5, H Ar); 7.42 (1Н, d, J = 8.7, H Ar); 7.50 (1Н, d, J = 8.4, H Ar); 7.62 (1Н, d, J = 8.7, H Ar). ¹³C NMR spectrum, δ, ppm: 20.7 (СН₃); 22.0 (СН₃); 24.0 (СН₃); 24.9 (СН₃); 38.9; 59.1; 110.2; 113.0; 116.5; 117.2; 120.6; 121.5; 122.5; 122.7; 123.1; 125.1; 126.3; 129.5; 130.0; 142.7; 146.2; 154.6; 156.1; 163.3. Mass spectrum, m/z (I _rel, %): 368 [M]⁺ (100), 367 [M–H]⁺ (29), 353 [M–СН₃]⁺ (69), 352 [M–NН₂]⁺ (81), 337 [M–СН₃–NН₂]⁺ (19), 336 [M–СН₃–NН₃]⁺ (15), 325 (35), 312 [M–С₄Н₈]⁺ (35), 311 [M–С₄Н₉]⁺ (42), 310 (36). Found, %: С 81.23; Н 6.62; N 7.56. C₂₅H₂₄N₂O. Calculated, %: С 81.49; Н 6.57; N 7.60.

3,3,4,4-Tetramethyl-1-phenyl-3,4-dihydrobenzofuro-[3,2- g ]isoquinoline (7e) and 3,3,4,4-tetramethyl-1-phenyl-3,4-dihydrobenzofuro[2,3- h ]isoquinoline (8e) were obtained from compounds 6 and 5e. The mixture was separated by column chromatography (eluent 5:1 hexane–EtOAc).

Compound 7e. Yield 280 mg (40%), white crystals, mp 144–145°С (EtOH). R _f 0.64 (5:1 hexane–EtOAc). IR spectrum, ν, cm^–1: 3061, 2974, 1612, 1568. ¹H NMR spectrum, δ, ppm (J, Hz): 1.29 (3Н, br. s, СН₃); 1.42 (9Н, br. s, 3СН₃); 7.35 (1Н, td, J = 7.4, J = 1.2, H Ar); 7.36 (1Н, s, H-5); 7.43–7.49 (4Н, m, H Ar); 7.52 (1Н, d, J = 7.8, H Ar); 7.57–7.61 (2Н, m, H Ar); 7.98 (1H, s, H-11); 7.99 (1Н, d, J = 7.8, H Ar). ¹³C NMR spectrum, δ, ppm: 23.1 (2С); 24.1 (2С); 38.9; 60.4; 111.4; 111.8; 116.0; 120.9; 122.9; 123.9; 126.3; 127.7; 128.3 (2С); 128.8 (2С); 129.1; 139.5; 142.6; 154.1; 157.3. Mass spectrum, m/z (I _rel, %): 353 [M]⁺ (100), 352 [M–Н]⁺ (100), 338 [M–СН₃]⁺ (22), 337 (14), 322 (12), 310 [M–С₃Н₇]⁺ (23), 298 (17), 297 [M–С₄Н₈]⁺ (80), 296 [M–С₄Н₉]⁺ (80), 295 (16), 282 (24), 281 (58). Found, %: С 85.06; Н 6.50; N 4.04. C₂₅H₂₃NO. Calculated, %: С 84.95; Н 6.56; N 3.96.

Compound 8e. Yield 30 mg (4%), white crystalline powder, mp 172.5–174°С (2-PrOH). R _f 0.75 (5:1 hexane–EtOAc). ¹H NMR spectrum, δ, ppm (J, Hz): 0.85 (3Н, br. s, СН₃); 1.14 (3Н, br. s, СН₃); 1.42 (3Н, br. s, СН₃); 1.57 (3Н, br. s, СН₃); 6.01 (1Н, d, J = 8.1, H Ar); 6.67 (1Н, td, J = 7.7, J = 1.2, H Ar); 7.00–7.60 (2Н Ar, not localized);7.16 (1Н, td, J = 7.8, J = 1.2, H Ar); 7.30–7.37 (3Н, m, H Ar); 7.48 (1Н, d, J = 8.4, H Ar); 7.59 (1Н, d, J = 8.4, H Ar); 7.99 (1Н, br. s, H Ar). ¹³C NMR spectrum, δ, ppm: 20.8; 22.5; 24.6; 25.4; 39.8; 60.0; 111.0; 114.1; 115.4 (2С); 121.9; 123.4; 123.5; 125.2 (2С); 126.9; 128.2; 129.6; 129.8; 140.4; 143.6; 155.2; 156.6. Mass spectrum, m/z (I _rel, %): 353 [M]⁺ (52), 352 [M–Н]⁺ (21), 310 [M–С₃Н₇]⁺ (19), 297 [M–С₄Н₈]⁺ (54), 296 [M–С₄Н₉]⁺ (100), 295 (13), 282 (16), 281 (55). Found, %: С 84.66; Н 6.67; N 3.69. C₂₅H₂₃NO. Calculated, %: С 84.95; Н 6.56; N 3.96.

1-(2-Methoxyphenyl)-3,3,4,4-tetramethyl-3,4-dihydrobenzofuro[3,2-g]isoquinoline (7f) and 1-(2-methoxyphenyl)-3,3,4,4-tetramethyl-3,4-dihydrobenzofuro[2,3- h ]isoquinoline (8f) were obtained from compounds 6 and 5f. The mixture was separated by column chromatography (eluent 5:1 hexane–EtOAc).

Compound 7f. Yield 290 mg (38%), colorless crystals, mp 202.5–203.5°С (EtOAc). R _f 0.25 (5:1 hexane–EtOAc). IR spectrum, ν, cm^–1: 2979, 2967, 2937, 1612, 1600, 1571. ¹H NMR spectrum, δ, ppm (J, Hz): 1.16 (6Н, br. s, 3-(СН₃)₂); 1.46 (6Н, br. s, 4-(СН₃)₂); 3.64 (3Н, s, ОСН₃); 6.93 (1Н, d, J = 8.1, H Ar); 7.05 (1Н, td, J = 7.5, J = 0.9, H Ar); 7.10 (1Н, s, H-5); 7.30–7.50 (5Н, m, H Ar); 7.95 (1Н, s, H-11); 7.97 (1Н, d, J = 8.1, H Ar). Mass spectrum, m/z (I _rel, %): 383 [M]⁺ (45), 382 [M–Н]⁺ (36), 368 [M–СН₃]⁺ (12), 353 [M–СН₂O]⁺ (29), 352 [M–СН₃O]⁺ (100), 327 [M–С₄Н₈]⁺ (13), 326 [M–С₄Н₉]⁺ (14), 312 (18). Found, %: С 81.32; Н 6.42; N 3.74. C₂₆H₂₅NO₂. Calculated, %: С 81.43; Н 6.57; N 3.65.

Compound 8f. Yield 160 mg (21%), colorless crystals, mp 154–155°С (hexane). R _f 0.43 (5:1 hexane–EtOAc). ¹H NMR spectrum, δ, ppm (J, Hz): 0.98 (3Н, br. s, СН₃); 1.26 (3Н, br. s, СН₃); 1.49 (3Н, br. s, СН₃); 1.61 (3Н, br. s, СН₃); 3.03 (3Н, s, ОСН₃); 6.10 (1Н, br. s, H-10); 6.65 (1Н, br. s, H-11); 6.73 (1Н, t, J = 7.5, H Ar); 7.19–7.25 (2Н, m, H Ar); 7.37–7.42 (2Н, m, H Ar); 7.53 (1Н, d, J = 8.4, H Ar); 7.60 (1Н, d, J = 8.4, H Ar); 7.86 (1H, br. s, H Ar). Mass spectrum, m/z (I _rel, %): 383 [M]⁺ (22), 353 [M–СН₂O]⁺ (28), 352 [M–СН₃O]⁺ (100), 337 (13), 327 [M–С₄Н₈]⁺ (11), 326 [M–С₄Н₉]⁺ (21), 311 (13). Found, %: С 81.23; Н 6.47; N 3.72. C₂₆H₂₅NO₂. Calculated, %: С 81.43; Н 6.57; N 3.65.

Compound 7g. Yield 380 mg (44%), white crystals, mp 216–218°С (EtOAc). R _f 0.10 (20:1 hexane–acetone). IR spectrum, ν, cm^–1: 2973, 1608, 1568, 1449. ¹H NMR spectrum, δ, ppm (J, Hz): 1.18 (3Н, br. s, СН₃); 1.44 (3Н, br. s, СН₃); 1.50 (6Н, br. s, 2СН₃); 7.01 (1H, s, H-5); 7.21–7.32 (2Н, m, H Ar); 7.38–7.47 (4Н, m, H Ar); 7.60 (1Н, d, J = 8.1, H Ar); 7.94 (1Н, d, J = 7.8, H Ar); 7.96 (1H, s, H-11). ¹³C NMR spectrum, δ, ppm: 22.5; 23.5; 24.2; 38.8; 60.7; 110.3; 111.7; 116.2; 120.8; 122.1; 122.8; 123.8; 125.7; 126.6; 127.6; 127.7; 129.9; 130.7; 132.9; 140.3; 141.4; 154.2; 157.2; 163.9. Mass spectrum, m/z (I _rel, %): 431 [M]⁺ (10), 375 [M–С₄Н₈]⁺ (15), 374 [M–С₄Н₉]⁺ (10), 352 [M–Br]⁺ (100), 337 [M–CH₃–Br]⁺ (41), 322 (16), 294 (13), 293 (12), 279 (16). Found, %: С 69.13; Н 5.07; N 3.20. C₂₅H₂₂BrNO. Calculated, %: С 69.45; Н 5.13; N 3.24.

Compound 8g. Yield 170 mg (20%), colorless crystals, mp 153.5–154.5°С (EtOAc). R _f 0.23 (20:1 hexane–acetone). IR spectrum, ν, cm^–1: 2977, 2934, 1626, 1602, 1587, 1462. ¹H NMR spectrum, δ, ppm (J, Hz): 1.01 (3Н, br. s, СН₃); 1.36 (3Н, br. s, СН₃); 1.47 (3Н, br. s, СН₃); 1.60 (3Н, br. s, СН₃); 5.99 (1Н, br. s, H-11); 6.75 (1Н, br. s, H-10); 7.10–7.80 (1Н Ar, not localized); 7.20–7.26 (3Н, m, H Ar); 7.43 (1Н, dd, J = 7.8, J = 0.6, H Ar); 7.55 (1Н, d, J = 8.4, H Ar); 7.64 (1Н, d, J = 8.4, H Ar); 7.93 (1Н, br. s, H-3'). ¹³C NMR spectrum, δ, ppm: 20.9; 23.1; 23.6; 25.2; 39.3; 60.0; 111.1; 114.3; 120.7; 122.0; 123.1; 123.8; 124.0; 126.9; 128.3; 130.4; 132.5; 133.8; 141.9; 155.2; 156.6; 163.0. Mass spectrum, m/z (I _rel, %): 431 [M]⁺ (7), 374 [M–С₄Н₉]⁺ (10), 352 [M–Br]⁺ (100), 337 [M–CH₃–Br]⁺ (34), 322 (13), 294 (10), 293 (9), 279 (16). Found, %: С 69.68; Н 4.82; N 3.07. C₂₅H₂₂BrNO. Calculated, %: С 69.45; Н 5.13; N 3.24.

1-Isobutyl-3,3,4,4-tetramethyl-3,4-dihydrobenzofuro-[3,2- g ]isoquinoline (7h) was obtained from compounds 6 and 5h and purified by chromatography (eluent 7:1 hexane–EtOAc). Yield 323 mg (49%), thick colorless oil. R _f 0.40 (7:1 hexane–EtOAc). IR spectrum, ν, cm^–1: 2969, 2932, 2868, 1624, 1573. ¹H NMR spectrum, δ, ppm (J, Hz): 1.00 (6Н, d, J = 6.6, СН(СН₃)₂); 1.18 (6Н, br. s, 3-(СН₃)₂); 1.32 (6Н, br. s, 4-(СН₃)₂); 2.06–2.19 (1Н, m, СН(СН₃)₂); 2.68 (2Н, d, J = 6.6, СН₂СН(СН₃)₂); 7.33 (1Н, td, J = 7.5, J = 0.9, H-7); 7.45 (1Н, td, J = 7.5, J = 1.5, H-8); 7.55 (1Н, d, J = 8.4, H-9); 7.64 (1Н, s, H-5); 7.92 (1Н, s, H-11); 7.95 (1Н, d, J = 7.8, H-6). Mass spectrum, m/z (I _rel, %): 333 [M]⁺ (64), 332 [M–Н]⁺ (44), 318 [M–СН₃]⁺ (100), 291 [M–С₃Н₆]⁺ (70), 290 [M–С₃Н₇]⁺ (60), 277 [M–С₄Н₈]⁺ (14), 276 [M–С₄Н₉]⁺ (53), 262 (14); 261 (19), 260 (13), 249 (21), 248 (12), 235 (39), 234 (89), 233 (32), 231 (19), 220 (25), 219 (35), 217 (72). Found, %: С 82.96; Н 8.42; N 4.12. C₂₃H₂₇NO. Calculated, %: С 82.84; Н 8.16; N 4.20.

Methyl 2-(3,3,4,4-tetramethyl-3,4-dihydrobenzofuro-[3,2- g ]isoquinolin-1(2 Н )-ylidene)acetate (7j) was obtained from compounds 6 and 5j. Purification by crystallization. Yield 400 mg (57%), light-yellow crystals, mp 146–147°С (EtOH). IR spectrum, ν, cm^–1: 3281, 2977, 1648, 1602, 1447. ¹H NMR spectrum, δ, ppm (J, Hz): 1.34 (12Н, br. s, 3-(СН₃)₂, 4-(СН₃)₂); 3.71 (3Н, s, ОСН₃); 5.17 (1Н, s, =СНСO₂Me); 7.31 (1Н, td, J = 7.5, J = 1.2, H-7); 7.43 (1Н, td, J = 7.4, J = 1.2, H-8); 7.52 (1Н, d, J = 8.1, H-9); 7.80 (1Н, s, H-5); 7.90 (1H, s, H-11); 7.92 (1Н, d, J = 7.5, H-6); 9.03 (1Н, br. s, NH). ¹³C NMR spectrum, δ, ppm: 24.4; 41.0; 50.1; 54.7; 76.8; 108.2; 111.7; 116.3; 120.7; 122.8; 123.6; 126.5; 127.5; 127.8; 140.3; 154.5; 155.3; 157.1; 171.5. Found, %: С 75.27; Н 6.60; N 3.67. C₂₂H₂₃NO₃. Calculated, %: С 75.62; Н 6.63; N 4.01.

X-ray structural analysis of compounds 7е,f and 8с. Monocrystals of compounds 7e,f and 8c were obtained by crystallization from acetone. X-ray diffraction experiments were performed at 295(2) K on an Xcalibur-3 diffractometer with CCD detector (МоKα radiation, graphite monochromator, ω-scanning). The structures of compounds were solved by direct method with SHELXS-97 software.28 Parameters were refined by using SHELXL-97 software in anisotropic approximation (isotropically for hydrogen atoms). The crystallographic data for compounds 8c, 7f, and 7е were deposited at the Cambridge Crystallographic Data Center (deposits CCDC 1434242, CCDC 1434243, and CCDC 1434244, respectively).

The Supplementary information file, containing drawings of conformers for compound 8g, is available online at http://springerlink.bibliotecabuap.elogim.com/journal/10593.

This work received financial support from the Russian Foundation for Basic Research (grant 13-03-00184).