INTRODUCTION

The pyrrolo[2,1-a]isoquinoline ring system is the main structural fragment of many natural compounds [1–3], including Lamellarin alkaloids [4]. Most natural pyrrolo[2,1-a]isoquinoline derivatives were found to exhibit various biological activities [5–10]. Chemists’ interest in searching for new efficient methods of synthe­sis of analogs of that heterocyclic system con­stantly increases. In recent time, multicomponent and cascade reactions have been extensively used for the prepara­tion of new substituted pyrrolo[2,1-a]iso­quinolines starting from isoquinolines or their partially hydro­genated isoquinoline derivatives and alkenes or alkynes [11–20].

RESULTS AND DISCUSSION

We have developed two three-component syntheses of 3-substituted pyrrolo[2,1-a]isoquinolines via domino reaction of 1-aroyl-3,4-dihydroisoquinolines containing an imino ketone fragment with electron-deficient terminal alkynes such as methyl propynoate and acetylacetylene. The third component was a CH acid (N,N′-dimethylbarbituric acid, dimedone, acetyl­acetone, ethyl acetoacetate, or malonic acid derivatives) [21] or an NH acid (cyclic amides or azoles) [22]. The goal of the present study was to find out how the use of dimethyl acetylenedicarboxylate (DMAD) in com­bina­tion with CH or NH acids in three-component reactions with 1-aroyl-3,4-dihydroisoquinolines could change the transformation direction.

The possibility of a reaction to occur is determined by the charge on the anionic center of zwitterion A and its ability to abstract a proton from the third component to generate intermediate B (Scheme 1). In the reaction with DMAD, the charge on the anionic center in the corresponding intermediate A is lower than in those derived from methyl propynoate and acetylacetylene due to the presence of two electron-withdrawing ester groups, which could lead to a change in the reaction direction or inhibition of the process.

Scheme
scheme 1

1.

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By studying the reactions of 1-aroyl-3,4-dihydro­isoquinolines 1a–1c with DMAD and CH acids we found that in the case of fairly strong CH acids, such as N,N′-dimethylbarbituric acid (3a), dimedone (3b), and acetylacetone (3c), under microwave irradiation at 130°C the products were pyrrolo[2,1-a]isoquinolines 4–6 which were obtained in moderate yields (Scheme 2).

Scheme
scheme 2

2.

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1-Aroyl-3,4-dihydroisoquinolines 1a–1c reacted with DMAD and strong CH acids in a more com­plicated fashion than with terminal alkynes. Pyrrolo­[2,1-a]isoquinolines 4–6 were formed as a result of three-component reaction followed by rearrangement involving transfer of the methoxycarbonyl group. It should be noted that no such transformations were observed in the reaction with terminal alkynes [21]. The described process is driven by the aromatization of five-membered nitrogen-containing intermediate F (Scheme 3). The reactions with a weaker CH acid, acetylacetone (3c), were accompanied by the formation of pyrrolo[2,1-a]isoquinolines 7a–7c in addition to the three-component condensation products. Compounds 7a–7c are formed as a result of concurrent two-com­ponent reaction whose mechanism was described by us previously [23].

Scheme
scheme 3

3.

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The structure of pyrroloisoquinolines 4–6 was confirmed by spectral data (see Experimental). The 1H NMR spectra of 4–6 showed no singlet signals assignable to enolic proton or proton at the tertiary carbon atom of the CH acid moiety [21], whereas two singlets belonging to the ester methoxy groups were present. Further confirmation of the proposed structure of pyrrolo[2,1-a]isoquinolines 4–6 was obtained by studying two-dimensional NMR correlation spectra of 5b and 6a (Figs. 1, 2).

Fig. 1.
figure 1

Key 1H–13C HMBC correlations in molecule 5b.

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Fig. 2.
figure 2

Key NOE (dashed arrows) and 1H–13C HMBC cor­relations (solid arrows) in molecule 6a.

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The key C–H interactions were most clearly seen in the correlation spectra of 6a. The 1H NMR spectrum of 6a showed signals of protons in the benzene ring, protons on C7 and C10, two methylene groups, and six methyl groups. This means that the methyl groups in the acetylacetone moiety are nonequivalent, i.e., the acetylacetone residue lost its symmetry. The 13C NMR spectrum of 6a contained 27 signals, only one of which belonged to the carbonyl group of the CH acid residue. There were two more carbonyl carbon signals at δC 152.0 and 159.2 ppm, the first of which was assigned to the carbonate fragment. The substitution positions were determined by analysis of the 1H–1H NOE and 1H–13C HMBC correlations. To identify long-range spin–spin couplings, the 1H–13C HMBC spectrum optimized for a coupling constant of 2 Hz was recorded. Likewise, we examined the structure of compound 5b which was also characterized by asym­metry of the dimedone residue.

The obtained results can be explained by the following scheme. Successive generation of zwitterion A, proton abstraction from CH acid (intermediate B), and addition of CH nucleophile produces zwitterion C. Next follow five-membered ring closure as a result of attack of the anionic center on the carbonyl group (inter­mediate D), proton transfer to the oxygen atom at C1, and enolization with the formation of structure E. Further dehydration and migration of the methoxy­carbonyl group through intermediate F lead to aro­matization of the pyrrole ring and formation of final products 4–6 (Scheme 3).

The reactions of drotaveraldine (1c) with dimethyl acetylenedicarboxylate (2) and weak CH acids, such as malononitrile (3d), ethyl cyanoacetate (3e), and ethyl acetoacetate (3f), resulted in the formation of the two-component condensation product, previously described [23] 1-oxopyrrolo[2,1-a]isoquinoline 7c (63–77%; Scheme 4). As might be expected, zwitterion A derived from 1c and DMAD (Scheme 3) is incapable of depro­tonating weak CH acids, in contrast to the reactions with terminal alkynes [21].

Scheme
scheme 4

4.

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No three-component condensation products were formed in the reaction of 1c with dimethyl acetylene­dicarboxylate 2 and strong NH acids (succinimide, phthalimide, 1,3-benzoxazol-2-one). In all cases, the reaction mixtures contained 1-oxopyrrolo[2,1-a]iso­quinoline 7c which was detected by HPLC. Presum­ably, the reactions with NH acids involve generation of intermediates A–D, but no aromatization of the pyrrole ring occurs due to the lack of possibility for the migration of methoxycarbonyl to the NH acid residue.

EXPERIMENTAL

Initial compounds 1a–1c were synthesized as described previously [24]. Commercially available reagents from Alfa Aesar were used. The melting points were measured in open capillary tubes on a Stuart SMP 30 melting point apparatus. Microwave-assisted reactions were carried out in an Anton Paar Monowave 300 microwave reactor. Sorbfil STKh-1Å plates (particle size 5–17 μm) were used for thin-layer chromatography, visualization was done by treatment with a solution of potassium permanganate. Column chromatography was performed on Silicagel 60 (0.060–0.200 mm; Acros Organics). The 1H and 13C NMR spectra were recorded on a Jeol JNM ECA spectrometer with Fourier transform at 600 and 151 MHz, respectively; the chemical shifts were measured relative to the residual proton and carbon signals of the solvent (CHCl3, δ 7.26 ppm; CDCl3, δC 77.16 ppm). The high-resolution mass spectra were obtained on a Bruker maXis QTOF instrument (tandem quadrupole/time-of-flight mass analyzer) equipped with an electrospray ionization source (positive ioniza­tion mode); a.m.u. range 50–3000; external calibration was performed using a low-concentration tuning mix (Agilent Technologies); samples were injected with a 500-μL Hamilton RN 1750 syringe; grounded spray­ing needle, capillary voltage 4500 V, end plate dis­place­ment BH: –500 V; injection flow rate was main­tained at 3 μL/min using a syringe pump; nebulizer gas nitrogen (1.0 bar); drying gas flow rate 4.0 L/min at 200°C; the data were processed using Bruker Data Analysis 4.0 software. The IR spectra were recorded in KBr on an InfraLUM FT 801 spectrometer.

Compounds 4–7 (general procedure). CH Acid 3a–3f was added to a solution of 1-aroyl-3,4-dihydro­isoquinoline 1a–1c and dimethyl acetylenedicar­box­ylate (2) in 5 mL of anhydrous acetonitrile. The mixture was heated in a hermetically closed vessel in a micro­wave reactor at 130°C for 20–60 min. The progress of reactions was monitored by TLC using ethyl acetate–hexane (1:1) as eluent. After completion of the reaction, the mixture was cooled, and the solvent was evaporated. Compounds 4a–4c and 5a–5c were isolated by recrystallization of the residue from ethyl acetate–hexane. Compounds 6a–6c and 7a–7c were isolated by column chromatography using ethyl acetate–hexane (gradient elution, 1:10 to 1:3) or by crystallization of the residue from ethyl acetate–hexane.

Methyl 8,9-dimethoxy-3-{6-[(methoxycarbonyl)­oxy]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro­py­rimidin-5-yl}-1-phenyl-5,6-dihydropyrrolo[2,1-a]­isoquinoline-2-carboxylate (4a) was synthesized from 0.51 mmol of 1a, 0.51 mmol of 2, and 0.66 mmol of 3a. Yield 0.123 g (42%), white crystals, mp 184–186°C. IR spectrum, ν, cm–1: 1793, 1715, 1680 (C=O). 1H NMR spectrum, δ, ppm: 2.96 t (2H, 6-H, J = 6.5 Hz), 3.26 s (3H, 9-OCH3), 3.45 s (3H, NCH3), 3.47 s (3H, 2-CO2CH3), 3.48 s (3H, NCH3), 3.74 s (3H, OCO2CH3), 3.83 s (3H, 8-OCH3), 3.87–3.93 m (2H, 5-H), 6.33 s (1H, 10-H), 6.66 s (1H, 7-H), 7.27–7.32 m (1H, Harom), 7.33–7.42 m (4H, Harom). 13C NMR spec­trum, δC, ppm: 29.0, 29.1, 30.5, 42.6, 50.8, 55.1, 56.0, 57.0, 95.6, 108.0, 111.0, 114.0, 121.5, 121.7, 123.9, 125.1, 126.9, 128.1 (2C), 128.2, 131.0 (2C), 137.0, 147.4, 147.5, 150.2, 150.7, 153.5, 161.8, 164.8. Mass spectrum: m/z: 575.1909 [M]+. C30H29N3O9. Calculat­ed: M 575.1898.

Methyl 1-(4-fluorophenyl)-8,9-dimethoxy-3-{6-[(methoxycarbonyl)oxy]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl}-5,6-dihydro­pyrrolo[2,1-a]isoquinoline-2-carboxylate (4b) was synthesized from 0.48 mmol of 1b, 0.48 mmol of 2, and 0.62 mmol of 3a. Yield 0.102 g (36%), white crystals, mp 191–192°C. IR spectrum, ν, cm–1: 1794, 1715, 1677 (C=O). 1H NMR spectrum, δ, ppm: 2.96 t (2H, 6-H, J = 6.3 Hz), 3.34 s (3H, 9-OCH3), 3.45 s (3H, NCH3), 3.47 s (3H, 2-CO2CH3), 3.49 s (3H, NCH3), 3.74 s (3H, OCO2CH3), 3.85 s (3H, 8-OCH3), 3.87–3.91 m (2H, 5-H), 6.33 s (1H, 10-H), 6.67 s (1H, 7-H), 7.00–7.13 m (2H, Harom), 7.34 d (2H, Harom, J = 5.6 Hz). 13C NMR spectrum, δC, ppm: 29.0, 29.1, 30.5, 42.6, 50.8, 55.2, 56.0, 57.0, 95.6, 107.9, 111.1, 115.1 d (2C, J = 21.2 Hz), 120.4, 121.3, 124.0, 125.3, 128.4, 132.7 d (2C, J = 8.0 Hz), 132.8 d (J = 3.3 Hz), 147.5, 147.7, 147.7, 150.2, 150.7, 153.5, 161.7, 162.1 d (J = 245.4 Hz), 164.7. Mass spectrum: m/z 594.1891 [M + H]+. C30H28FN3O9. Calculated: [M + H]+ 594.1882.

Methyl 1-(3,4-diethoxyphenyl)-8,9-diethoxy-3-{6-[(methoxycarbonyl)oxy]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl}-5,6-dihydro­pyrrolo[2,1-a]isoquinoline-2-carboxylate (4c) was synthesized from 0.36 mmol of 1c, 0.36 mmol of 2, and 0.47 mmol of 3a. Yield 0.156 g (62%), white crystals, mp 182–183°C. IR spectrum, ν, cm–1: 1795, 1715, 1676 (C=O). 1H NMR spectrum, δ, ppm: 1.16 t (3H, OCH2CH3, J = 6.8 Hz), 1.39–1.44 m (6H, OCH2CH3), 1.47 t (3H, OCH2CH3, J = 6.8 Hz), 2.93 t (2H, 6-H, J = 6.3 Hz), 3.44 s (3H, NCH3), 3.46 s (3H, 2-CO2CH3), 3.48 s (3H, NCH3), 3.55 q (2H, OCH2CH3, J = 6.8 Hz), 3.74 s (3H, OCO2CH3), 3.88 t (2H, 5-H, J = 6.3 Hz), 4.01–4.07 m (4H, OCH2CH3), 4.12 q (2H, OCH2CH3, J = 6.8 Hz), 6.47 s (1H, 10-H), 6.66 s (1H, 7-H), 6.73–6.95 m (3H, Harom). 13C NMR spectrum, δC, ppm: 14.7, 14.9, 15.0, 15.1, 29.0 (2C), 30.4, 42.6, 50.8, 57.0, 63.8, 64.6, 64.7 (2C), 64.8, 95.8, 109.6, 113.1, 113.5, 114.2, 121.3, 121.7, 123.7, 125.0, 128.3, 129.7, 147.1, 147.2, 147.7, 147.8, 148.6, 150.2, 150.8, 153.4, 161.8, 164.9. Mass spectrum: m/z 692.2821 [M + H]+. C36H41N3O11. Calculated: [M + H]+ 692.2814.

Methyl 8,9-dimethoxy-3-{2-[(methoxycarbonyl)­oxy]-4,4-dimethyl-6-oxocyclohex-1-en-1-yl}-1-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate (5a) was synthesized from 0.51 mmol of 1a, 1.02 mmol of 2, and 0.51 mmol of 3b. Yield 0.154 g (54%), white crystals, mp 158–159°C. IR spec­trum, ν, cm–1: 1761, 1697 (C=O). 1H NMR spectrum, δ, ppm: 1.23 s (3H, 4′-CH3), 1.27 s (3H, 4′-CH3), 2.46–2.59 m (2H, 5′-H), 2.63–2.77 m (2H, 3′-H), 2.92 t (2H, 6-H, J = 6.5 Hz), 3.24 s (3H, 9-OCH3), 3.49 s (3H, 2-CO2CH3), 3.72 s (3H, OCO2CH3), 3.73–3.80 m (2H, 5-H), 3.82 s (3H, 8-OCH3), 6.33 s (1H, 10-H), 6.63 s (1H, 7-H), 7.26–7.31 m (1H, Harom), 7.33–7.41 m (4H, Harom). 13C NMR spectrum, δC, ppm: 28.2, 28.5, 29.1, 32.6, 42.6, 42.7, 50.7, 51.3, 55.1, 55.9, 56.0, 107.9, 110.9, 113.8, 120.8, 121.7, 122.0, 124.6, 125.7, 126.8, 127.6, 128.2 (2C), 131.0 (2C), 137.0, 147.3, 147.4, 151.7, 164.8, 165.8, 197.4. Mass spectrum: m/z 560.2273 [M + H]+. C32H33NO8. Calculated: [M + H]+ 560.2279.

Methyl 1-(4-fluorophenyl)-8,9-dimethoxy-3-{2-[(methoxycarbonyl)oxy]-4,4-dimethyl-6-oxocyclo­hex-1-en-1-yl}-5,6-dihydropyrrolo[2,1-a]isoquino­line-2-carboxylate (5b) was synthesized from 0.48 mmol of 1b, 0.96 mmol of 2, and 0.48 mmol of 3b. Yield 0.124 g (45%), white crystals, mp 187–188°C. IR spectrum, ν, cm–1: 1760, 1697 (C=O). 1H NMR spectrum, δ, ppm: 1.24 s (3H, 4′-CH3), 1.28 s (3H, 4′-CH3), 2.47–2.60 m (2H, 5′-H), 2.67–2.76 m (2H, 3′-H), 2.89–2.95 m (2H, 6-H), 3.33 s (3H, 9-OCH3), 3.51 s (3H, 2-CO2CH3), 3.70–3.77 m (4H, 5-H, OCO2CH3), 3.77–3.82 m (1H, 5-H), 3.84 s (3H, 8-OCH3), 6.34 s (1H, 10-H), 6.65 s (1H, 7-H), 7.09 t (2H, Harom, J = 8.5 Hz), 7.29–7.44 m (2H, Harom). 13C NMR spectrum, δC, ppm: 28.2 (4′-CH3), 28.5 (4′-CH3), 29.1 (C6), 32.7 (C4′), 42.6 (C3′), 42.7 (C5), 50.8 (2-COOCH3), 51.2 (C5′), 55.2 (9-OCH3), 55.9 (OCO2CH3), 56.0 (8-OCH3), 107.7 (C10), 111.0 (C7), 113.9 (C2), 115.0 d (2C, Cm, J = 21.2 Hz), 120.7 (C1), 120.8 (C1′), 121.5 (C10a), 124.8 (C6a), 126.0 (C3), 127.8 (C1a), 132.6 d (2C, Co, J = 7.6 Hz), 132.8 d (Ci, J = 3.3 Hz), 147.5 (C8), 147.5 (C9), 151.6 (OCOO), 162.1 d (Cp, J = 245.2 Hz), 164.7 (2-COO), 165.9 (C2′), 197.3 (C6′). Mass spectrum: m/z 578.2164 [M + H]+. C32H32FNO8. Calculated: [M + H]+ 578.2185.

Methyl 1-(3,4-diethoxyphenyl)-8,9-diethoxy-3-{2-[(methoxycarbonyl)oxy]-4,4-dimethyl-6-oxo­cyclohex-1-en-1-yl}-5,6-dihydropyrrolo[2,1-a]iso­quinoline-2-carboxylate (5c) was synthesized from 0.36 mmol of 1c, 0.73 mmol of 2, and 0.36 mmol of 3b. Yield 0.169 g (70%), white crystals, mp 148–149°C. IR spectrum, ν, cm–1: 1762, 1691 (C=O). 1H NMR spectrum, δ, ppm: 1.16 t (3H, OCH2CH3, J = 7.0 Hz), 1.23 s (3H, 4′-CH3), 1.27 s (3H, 4′-CH3), 1.37–1.42 m (6H, OCH2CH3), 1.45 t (3H, OCH2CH3, J = 7.0 Hz), 2.45–2.60 m (2H, 5′-H), 2.66–2.76 m (2H, 3′-H), 2.89 t (2H, 6-H, J = 6.4 Hz), 3.49 s (3H, 2-CO2CH3), 3.54 q (2H, OCH2CH3, J = 7.0 Hz), 3.68–3.81 m (5H, 5-H, OCO2CH3), 4.04 q (4H, OCH2CH3, J = 7.0 Hz), 4.11 q (2H, OCH2CH3, J = 7.0 Hz), 6.47 s (1H, 10-H), 6.64 s (1H, 7-H), 6.84–6.96 m (3H, Harom). 13C NMR spectrum, δC, ppm: 14.6, 14.9, 14.9, 15.0, 28.3, 28.4, 29.1, 32.6, 42.5, 42.7, 50.7, 51.2, 55.8, 63.7, 64.5, 64.7 (2C), 109.4, 113.0, 113.4, 114.0, 116.4, 120.9, 121.6, 121.9, 123.1, 124.4, 125.8, 127.7, 129.6, 146.9, 147.1, 147.6, 148.5, 151.7, 164.9, 165.6, 197.4. Mass spectrum: m/z 675.3042 [M]+. C38H45NO10. Calculated: M 675.3038.

Methyl 8,9-dimethoxy-3-{(2E)-2-[(methoxycar­bonyl)oxy]-4-oxopent-2-en-3-yl}-1-phenyl-5,6-di­hydropyrrolo[2,1-a]isoquinoline-2-carboxylate (6a) was synthesized from 0.51 mmol of 1a, 0.76 mmol of 2, and 0.76 mmol of 3c. Yield 0.145 g (55%), white crystals, mp 133–134°C. IR spectrum, ν, cm–1: 1752, 1719, 1696 (C=O). 1H NMR spectrum, δ, ppm: 2.14 s (3H, 5′-H), 2.51 s (3H, 1′-H), 2.91–3.02 m (2H, 6-H), 3.28 s (3H, 9-OCH3), 3.55 s (3H, 2-CO2CH3), 3.71 s (3H, OCO2CH3), 3.79–3.84 m (1H, 5-H), 3.84 s (3H, 8-OCH3), 3.94–4.02 m (1H, 5-H), 6.40 s (1H, 10-H), 6.68 s (1H, 7-H), 7.30–7.34 m (1H, Harom), 7.36– 7.43 m (4H, Harom). 13C NMR spectrum, δC, ppm: 19.1 (C1′), 29.2 (C6), 30.3 (C5′), 42.4 (C5), 50.9 (2-CO2CH3), 55.2 (9-OCH3), 55.7 (OCO2CH3), 56.1 (8-OCH3), 107.9 (C10), 111.0 (C7), 114.0 (C2), 121.5 (C10a), 121.7 (C3′), 122.2 (C1), 124.6 (C6a), 127.1 (Cp), 127.4 (C1a), 128.3 (2C, Cm), 129.4 (C3), 130.9 (2C, Co), 136.4 (Ci), 147.56 (C8), 147.63 (C9), 152.0 (OCOO), 159.2 (C2′), 164.8 (2-COO), 198.3 (C4′). Mass spec­trum: m/z 519.1887 [M]+. C29H29NO8. Calculated: M 519.1888.

Methyl 1-(4-fluorophenyl)-8,9-dimethoxy-3-{(2E)-2-[(methoxycarbonyl)oxy]-4-oxopent-2-en-3-yl}-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carbox­ylate (6b) was synthesized from 0.48 mmol of 1b, 0.72 mmol of 2, and 0.72 mmol of 3c. Yield 0.075 g (29%), white crystals, mp 154–155°C. IR spectrum, ν, cm–1: 1754, 1715, 1697 (C=O). 1H NMR spectrum, δ, ppm: 2.13 s (3H, 5′-H), 2.51 s (3H, 1′-H), 2.89–3.03 m (2H, 6-H), 3.35 s (3H, 9-OCH3), 3.56 s (3H, 2-CO2CH3), 3.71 s (3H, OCO2CH3), 3.79–3.84 m (1H, 5-H), 3.85 s (3H, 8-OCH3), 3.95–4.00 m (1H, 5-H), 6.40 s (1H, 10-H), 6.69 s (1H, 7-H), 7.09–7.13 m (2H, Harom), 7.33–7.38 m (2H, Harom). 13C NMR spectrum, δC, ppm: 19.1, 29.2, 30.3, 42.4, 50.9, 55.2, 55.7, 56.1, 107.8, 111.1, 114.0, 115.2 d (2C, J = 21.0 Hz), 120.9, 121.3, 121.7, 124.8, 127.6, 129.6, 132.3 d (J = 3.2 Hz), 132.6 d (2C, J = 7.4 Hz), 147.7, 147.7, 152.0, 159.3, 162.2 d (J = 245.7 Hz), 164.7, 198.2. Mass spectrum: m/z 537.1805 [M]+. C29H28FNO8. Calculated: M 537.1793.

Methyl 1-(3,4-diethoxyphenyl)-8,9-diethoxy-3-{(2E)-2-[(methoxycarbonyl)oxy]-4-oxopent-2-en-3-yl}-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carbox­ylate (6c) was synthesized from 0.36 mmol of 1c, 0.55 mmol of 2, and 0.55 mmol of 3c. Yield 0.061 g (27%), white crystals, mp 156–157°C. IR spectrum, ν, cm–1: 1755, 1715, 1696 (C=O). 1H NMR spectrum, δ, ppm: 1.18 t (3H, OCH2CH3, J = 6.9 Hz), 1.36–1.43 m (6H, OCH2CH3), 1.47 t (3H, OCH2CH3, J = 6.9 Hz), 2.13 s (3H, 5′-H), 2.51 s (3H, 1′-H), 2.84–3.03 m (2H, 6-H), 3.53–3.58 m (5H, OCH2CH3, 2-CO2CH3), 3.71 s (3H, OCO2CH3), 3.76–3.87 m (1H, 5-H), 3.93–3.99 m (1H, 5-H), 4.06 q (4H, OCH2CH3, J = 6.9 Hz), 4.13 q (2H, OCH2CH3, J = 6.9 Hz), 6.54 s (1H, 10-H), 6.68 s (1H, 7-H), 6.85–6.94 m (3H, Harom). 13C NMR spec­trum, δC, ppm: 14.6, 14.9, 14.9, 15.0, 19.0, 29.2, 30.3, 42.3, 50.8, 55.6, 63.8, 64.6, 64.7, 64.7, 109.4, 113.1, 113.5, 114.1, 116.4, 121.6, 121.7, 121.8, 123.1 (2C), 124.4, 127.4, 128.9, 129.3, 147.1, 147.3, 147.8, 152.0, 159.0, 164.8, 198.3. Mass spectrum: m/z 635.2728 [M]+. C35H41NO10. Calculated: M 635.2725.

Dimethyl 8,9-dimethoxy-1-oxo-10b-phenyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2,3-dicarboxylate (7a). Yield 0.026 g (12%), white crystals, mp 175–179°C. IR spectrum, ν, cm–1: 1745, 1698 (C=O). 1H NMR spectrum, δ, ppm: 2.76–2.85 m (1H, 6-H), 3.07–3.17 m (1H, 5-H), 3.49–3.56 m (1H, 6-H), 3.66–3.72 m (1H, 5-H), 3.79 s (3H, 3-CO2CH3), 3.87 s (3H, 9-OCH3), 3.88 s (3H, 8-OCH3), 4.06 s (3H, 2-CO2CH3), 6.64 s (1H, 10-H), 7.04–7.10 m (2H, Harom), 7.28–7.32 m (3H, Harom), 7.47 s (1H, 7-H). 13C NMR spectrum, δC, ppm: 29.8, 41.9, 51.7, 53.9, 56.0, 56.3, 75.5, 102.3, 110.2, 110.9, 123.6, 125.4, 127.8 (2C), 128.9, 129.0 (2C), 138.9, 148.1, 149.1, 161.8, 163.4, 169.2, 194.8. Mass spectrum (LCMS, ESI): m/z 438 [M + H]+. C24H23NO7. Calculated: M + H 438.

Dimethyl 10b-(4-fluorophenyl)-8,9-dimethoxy-1-oxo-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2,3-dicarboxylate (7b). Yield 0.134 g (64%), white crystals, mp 155–158°C. IR spectrum, ν, cm–1: 1738, 1697 (C=O). 1H NMR spectrum, δ, ppm: 2.77–2.84 m (1H, 6-H), 3.08–3.17 m (1H, 5-H), 3.46–3.53 m (1H, 6-H), 3.67–3.72 m (1H, 5-H), 3.79 s (3H, 3-CO2CH3), 3.87 s (3H, 9-OCH3), 3.88 s (3H, 8-OCH3), 4.06 s (3H, 2-CO2CH3), 6.63 s (1H, 10-H), 6.99 t (2H, Harom, J = 8.6 Hz), 7.03–7.07 m (2H, Harom), 7.43 s (1H, 7-H). 13C NMR spectrum, δC, ppm: 29.7, 41.9, 51.7, 53.9, 56.0, 56.2, 74.8, 102.3, 109.9, 110.9, 115.9 d (2C, J = 21.7 Hz), 123.3, 125.3, 129.8 d (2C, J = 8.6 Hz), 134.8 d (J = 3.6 Hz), 148.2, 149.2, 161.7, 162.9 d (J = 249.2 Hz), 163.2, 169.3, 194.7. Mass spectrum (LCMS, ESI): m/z 456 [M + H]+. C24H22FNO7. Calculated: M + H 456.

Dimethyl 10b-(3,4-diethoxyphenyl)-8,9-diethoxy-1-oxo-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquino­line-2,3-dicarboxylate (7c) was synthesized from 0.73 mmol of 3d, 3e, or 3f, 0.36 mmol of 1c, and 0.73 mmol of 2. Yield 0.151 g (75%, from 3d), 0.155 g (77%, from 3e), 0.127 g (63%, from 3f). The IR and 1H and 13C NMR spectral data were identical to those reported in [23].

CONCLUSIONS

Dimethyl acetylenedicarboxylate can be involved in three-component domino reactions with 1-aroyl-3,4-dihydroisoquinolines and strong CH acids. Unlike similar reactions with electron-deficient terminal alkynes, the transformation sequence includes migra­tion of methoxycarbonyl group and participation of enolized CH acid. Weak CH and NH acids do not react as the third component, so that two-component con­densation products are formed.