HETEROCYCLES

Paper | Regular issue | Vol. 85, No. 12, 2012, pp. 2933-2947
Received, 25th August, 2012, Accepted, 1st October, 2012, Published online, 10th October, 2012.
DOI: 10.3987/COM-12-12572

■ Synthesis and Reactivity of 2-Chloro-3-formylpyrido[2,1-a]isoquinoline Derivative. A Novel Routes to Pyrazolo[3',4':4,5]pyrido[2,1-a]isoquinoline and Isoquinolino[2,1-g][1,6]naphthyridines

Hamdi M. Hassaneen,* Wagnat W. Wardkhan, and Yasmin Sh. Mohammed

Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt

Abstract

Treatment of 2-hydroxy-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbonitrile 2 with POCl3/DMF gave 2-chloro-3-formylpyrido[2,1-a]isoquinoline derivative 3. Compound 3 reacted with hydrazines 5a-d to give the condensation products 6a-d. Cyclization of 6a gave pyrazolo[3',4':4,5]pyrido[2,1-a]isoquinoline derivative 7. Treatment of 3 with ethoxycarbonylmethylenetriphenylphosphorane 10 afforded (E)-ethyl 3-(2-chloro-1-cyano-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate 11. Azidation of 11 yielded the corresponding azido compound 12. Reduction of 12 gave the corresponding amino compound 13 which upon cyclization gave the novel tetracyclic product 14. Compound 12 reacted with triphenylphosphine to give phosphorane compound 15, which reacted with phenyl isothiocyanate to give a novel isoquinolino[2,1-g][1,6]naphthyridine derivative 18. Refluxing of 11 with amines 19a-c and thiophenols 22a-d in ethanol produced the corresponding substitution products 20a-c and 23a-d, respectively. Cyclization of 20a afforded isoquinolino[2,1-g][1,6]naphthyridine derivative 21.

INTRODUCTION
Fused isoquinoline derivatives represent a very interesting class of compounds due to their significant biological and pharmaceutical activities.1-4 Therefore, the synthesis of fused ring system incorporating isoquinoline moiety is an attractive goal for many authors.5-17 Recently, we have been involved in the synthesis and chemistry of several fused isoqinoline derivatives.18-29 In the present paper, we introduce a new and general route to pyrido[2,1-a]isoquinoline containing many reactive sites. The aim of this study, on one hand is to prepare a novel tetracyclic compounds starting from readily obtainable materials in good yields and on the other hand, to prepare compounds that might have pharmacological activity.

RESULTS AND DISCUSSION
In the last decade our group has been interested in the synthesis of fused heterocyclic compounds incorporating isoquinoline moiety starting with 1-cyanomethylisoquinoline 1.24-29 In conjunction with this work we report here the synthesis of the starting 2-chloro-3-formyl-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbonitrile (3) (Scheme 1). Treatment of 1-cyanomethylisoquinoline 1 with diethyl malonate in nitrobenzene and refluxed for 30 min gave 2-hydroxy-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbonitrile (2) in 92% yield.30 Treatment of 2 with the Vilsmeier-Haak reagent (POCl3/DMF) at 60-70 °C for 5 h with stirring gave a single compound which analyzed correctly for C17H13ClN2O4. This was confirmed by 1H NMR analysis of the crude reaction product in which only one singlet signal for formyl group was observed. Although the reaction of 2 with Vilsmeier-Haak reagent can lead to 3 and/or its isomer 4-chloro-3-formyl-9,10-dimethoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-1-carbonitrile (4). The latter compound 4 was discarded on the basis of spectral analysis. The IR spectrum exhibited an absorption band at ν 1657 cm-1 due to the amide group. In addition, single crystal X-ray analysis provided a good evidence for the formation of structure 3 (Figure 1) and ruled out the other possible structure 4 as outlined in Scheme 1.

Refluxing of 3 with arylhydrazines 5a-d in ethanol afforded the condensation products 6a-d in excellent yields (90-95%) (Scheme 2). The structures of compounds 6a-d were confirmed by elemental and spectral analyses. The IR spectra of compounds 6a-d revealed the absence of C=O absorption of formyl group and showed an NH stretch at about ν 3228 cm-1. Their mass spectra showed the molecular ion peaks. 1H NMR spectra revealed the absence of the formyl group at δ 10.14 ppm. Refluxing 6a in a mixture of 1,2-dichlorobenzene/pyridine for 20 h led directly to pyrazolo[3',4':4,5]pyrido[2,1-a]isoquinoline 7 in 65% yield, via elimination of hydrogen chloride (Scheme 2). The structure of compound 7 was confirmed by elemental and spectral analyses. Mass spectrum showed a molecular ion peak at m/z 398 and its IR spectrum revealed the absence of NH band. The reaction of 3 with hydrazine hydrate under the same conditions afforded directly the fused pyrazole 2,3-dimethoxy-8-oxo-5,6,8,11-tetrahydropyrazolo[3',4':4,5]pyrido[2,1-a]isoquinoline-12-carbonitrile (9) which undoubtedly resulted via elimination of hydrogen chloride from the resulting condensation intermediate 8. The structure of 9 was confirmed by both elemental and spectral analyses.

Next, stirring of 3 with ethoxycarbonylmethylene triphenylphosphorane 10 in chloroform at room temperature gave (E)-ethyl 3-(2-chloro-1-cyano-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate (11) (Scheme 3). The structure of 11 was based on its elemental and spectral analyses. The 1H NMR spectrum showed two doublets at δ 7.88 and 7.38 ppm with coupling constant J = 16 Hz that indicated a trans configuration for the vinylic protons, also it showed two signals at δ 4.27 (q, 2H) and 1.31 (t, 3H) ppm for ethoxycarbonyl group in addition to signals of pyrido[2,1-a]isoquinoline moiety. Its mass spectrum showed the molecular ion peak at m/z 414 and its IR spectrum revealed two carbonyl bands at ν 1693 and 1651 cm-1 assignable to α,β-unsaturated ester and amide C=O groups, respectively. A further evidence for the assigned structure 11 is provided by its 13C NMR spectrum which revealed two signals at δ 167 and 158 ppm assignable to C atoms of α,β-unsaturated ester and amide carbonyl groups.

Stirring of 11 with sodium azide in dioxane/water mixture for 3 h at room temperature gave the corresponding azido derivative 12 (Scheme 3). The structure of 12 was confirmed by elemental and spectral analyses. Thus, the IR spectrum gave a band at ν 2129 cm-1 assignable to azide group. Compound 12 was used to construct a novel tetracyclic system. Stirring of 12 with sodium dithionite in methanol/water mixture at room temperature for 24 h afforded the corresponding amino compound 13 (Scheme 3). The structure of compound 13 was confirmed by elemental and spectral analyses. In the IR analysis, while the azide stretch was missing (~ 2129 cm-1), two new bands for the amino groups were clearly visible (3336 and 3251 cm-1). Refluxing 13 in dimethylformamide for 100 h afforded the corresponding compound 14 via an intramolecular cyclization and elimination of ethanol (Scheme 3). The structure of compound 14 was established on the basis of elemental and spectral analyses. IR spectrum indicated the absence of bands of amino group and showed two bands at ν 3201 and 1654 cm-1 assignable to NH and amide C=O groups. Its 1H NMR spectrum showed the absence of triplet and quartet signals of ethyl group.
Tetracyclic system that incorporated naphthyridine moiety was prepared via iminophosphorane compound 15. Refluxing 12 with triphenylphosphine in ether afforded the iminophosphorane 15 in an excellent yield. The IR spectrum revealed the absence of the azide group. The structure of 15 was further proved on the basis of elemental and spectral analyses. A novel ethyl 13-cyano-2,3-dimethoxy-8-oxo-11-(phenylamino)-6,8-dihydro-5H-isoquinolino[2,1-g][1,6]naphthyridine-10-carboxylate (18) was obtained in 80% yield via refluxing iminophosphorane 15 with phenyl isothiocyanate in 1,2-dichlorobenzene for 6 h (Scheme 4). The pathway of formation of the novel tetracyclic system 18 can be explained by an initial Aza-Wittig type reaction between the iminophosphorane group and phenyl isothiocyanate to give the reactive intermediate carbodimide 16, which yields a further intermediate 17 via intramolecular cyclization by nucleophilic attack of the β-carbon atom of the vinyl moiety. The latter undergoes a proton shift to give the final product 18 (Scheme 4).31

Because of the high reactivity of chlorine atom in compound 11, we directed our strategy to construct new derivatives of another novel tetracyclic system 21 containing naphthyridine moiety. Refluxing 11 with amine derivatives 19a-c in ethanol for 6 h afforded the substitution products (E)-ethyl 3-(2-aralkylamino-1-cyano-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate20a-c (Scheme 5). The structure of each product 20a-c was confirmed by elemental and spectral analyses. Refluxing of compound 20a in dimethylformamide for 90 h afforded the fused tetracyclic compound, namely 12-benzyl-2,3-dimethoxy-8,11-dioxo-6,8,11,12-tetrahydro-5H-isoquinolino[2,1-g][1,6]naphthyridine-13-carbonitrile (21) (Scheme 5). A conceivable reaction pathway for the formation of 21 from 20a occurred by intramolecular cyclocondensation between the amino and ester groups. The structure of 21 was confirmed by elemental and spectral analysis. Its 1H NMR spectrum indicated the absence of triplet and quartet signals assigned to ethoxycarbonyl group. The IR spectrum showed the absence of the bands at ν 3394 and 1697 cm-1 assigned to NH and ester carbonyl groups, respectively, and showed a band at ν 1658 cm-1 assigned to amide carbonyl group.

Also, refluxing of 11 with sulfur nucleophiles 22a-d in ethanol in the presence of triethylamine afforded the substitution products 23a-d (Scheme 6). The structures of the products 23a-d were confirmed on the basis of their elemental and spectral analyses.

EXPERIMENTAL
Melting points were determined on a Stuart melting point apparatus and are uncorrected. IR spectra were measured as KBr pellets on a FTIR Bruker-Vector 22 spectrophotometer. The 1H NMR and 13C NMR spectra were recorded in CDCl3 or DMSO-d6 on a Varian Mercury VXR at 300 spectrometer (300 MHz for 1H NMR and 75 MHz for 13C NMR) using TMS as internal standard. Chemical shifts are reported in δ units (ppm). Mass spectra were measured on a Shimadzu GCMS-Q-1000 EX mass spectrometer at 70 eV. Elemental analyses were performed at the Microanalytical Center, Cairo University. Isoquinoline-1- acetonitrile 1,32 2-hydroxy-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbo- nitrile 230 were prepared according to the procedures in the literature.

Synthesis of 2-chloro-3-formyl-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido-[2,1-a]isoquinoline-1-carbonitrile (3): Phosphoryl chloride (70.0 g, 0.46 mol) was added dropwise over a period 30 min to DMF (12.0 g, 0.24 mol) at 0 °C. To the resulting mixture, compound 2 (40.0 g, 0.13 mol) was added and the reaction mixture was stirred at 60–70 °C for 5 h. After cooling, the reaction mixture was poured into cold H2O (500 mL) and left for 3 h. The solid product was collected, washed with EtOH and crystallized from DMF to give compound 3 as orange crystals, mp 262-264 °C (DMF), 85% yield; IR (KBr) ν 2214 (CN), 1720 (C=O), 1657 (C=O) cm-1; 1H NMR (DMSO) δ 2.98 (m, 2H), 3.84 (s, 3H), 3.91 (s, 3H), 4.11 (m, 2H), 7.15 (s, 1H), 7.89 (s, 1H), 10.14 (s, 1H) ppm; MS, m/z (%): 345 (M++2, 9.9), 344 (M+, 23.4), 316 (100.0), 301 (77.4). Anal. Calcd for C17H13ClN2O4: C, 59.23; H, 3.80; Cl, 10.28; N, 8.13. Found: C, 59.10; H, 3.60; Cl, 10.41; N, 7.91.

Synthesis of (E)-3-((2-arylhydrazono)methyl)-2-chloro-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbonitrile (6a-d): General procedure - A mixture of 3 (1.0 g, 3.0 mmol) and arylhydrazines 5 (3.0 mmol) in EtOH (30 mL) was refluxed for 5 h. The reaction mixture was cooled and the solid that separated was collected, dried and crystallized from DMF to give the condensation products 6a-d in excellent yields (90-95%).

(E)-2-Chloro-9,10-dimethoxy-4-oxo-3-((2-phenylhydrazono)methyl)-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbonitrile (6a): Orange crystals, mp 210-212 °C, 90% yield; IR (KBr) ν 3228 (NH), 2218 (CN), 1674 (C=O) cm-1; 1H NMR (DMSO) δ 2.94 (m, 2H), 3.75 (s, 3H), 3.88 (s, 3H), 4.11 (m, 2H), 7.05-7.26 (m, 5H), 7.86 (s, 1H), 7.94 (s, 1H), 8.12 (s, 1H), 10.81 (s, 1H) ppm; 13C NMR (DMSO) δ 26.48, 40.23, 55.63, 55.86, 90.38, 110.76, 111.47, 112.16, 117.11, 117.64, 119.42, 119.81, 129.10, 130.13, 133.14, 137.61, 144.48, 146.74, 147.91, 152.16, 158.82 ppm; MS, m/z (%): 436 (M++2, 4.1), 434 (M+, 8.9), 398 (92.0), 383 (100.0). Anal. Calcd for C23H19ClN4O3: C, 63.52; H, 4.40; Cl, 8.15; N, 12.88. Found: C, 63.31; H, 4.30; Cl, 8.01; N, 12.61.

(E)-2-Chloro-9,10-dimethoxy-3-((2-(4-nitrophenyl)hydrazono)methyl)-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbonitrile (6b): Red crystals, mp 302-304 °C, 95% yield; IR (KBr) ν 3282 (NH), 2214 (CN), 1639 (C=O) cm-1; 1H NMR (DMSO) δ 2.95 (m, 2H), 3.79 (s, 3H), 3.86 (s, 3H), 4.10 (m, 2H), 7.00 (s, 1H), 7.10 (d, 2H), 7.85 (s, 1H), 8.11 (d, 2H), 8.26 (s, 1H), 11.58 (s, 1H) ppm; 13C NMR (DMSO) δ 26.45, 40.44, 55.76, 55.99, 90.48, 110.89, 111.73, 112.07, 116.98, 117.58, 118.69, 126.16, 133.57, 135.74, 138.98, 140.20, 146.91, 149.30, 150.01, 152.61, 158.84 ppm; MS, m/z (%): 481 (M++2, 15.1), 479 (M+, 33.3), 443 (100.0), 428 (92.5). Anal. Calcd for C23H18ClN5O5: C, 57.57; H, 3.78; Cl, 7.39; N, 14.59. Found: C, 57.61; H, 3.61; Cl, 7.21; N, 14.41.

(E)-2-Chloro-3-((2-(4-chlorophenyl)hydrazono)methyl)-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbonitrile (6c): Orange crystals, mp 250-252 °C, 90% yield; IR (KBr) ν 3262 (NH), 2215 (CN), 1637 (C=O) cm-1; 1H NMR (DMSO) δ 2.94 (m, 2H), 3.79 (s, 3H), 3.88 (s, 3H), 4.12 (m, 2H), 7.13 (s, 1H), 7.18 (d, 2H), 7.86 (d, 2H), 8.08 (s, 1H), 8.24 (s, 1H), 10.56 (s, 1H) ppm; 13C NMR (DMSO) δ 26.32, 40.21, 55.80, 55.98, 90.32, 110.89, 111.67, 112.04, 117.04, 117.87, 119.06, 125.12, 130.81, 136.67, 137.00, 139.17, 146.90, 148.58, 150.09, 152.94, 158.99 ppm; MS, m/z (%): 472 (M++4, 10.2), 470 (M++2, 6.8), 468 (M+, 1.0), 84 (100.0). Anal. Calcd for C23H18Cl2N4O3: C, 58.86; H, 3.87; Cl, 15.11; N, 11.94. Found: C, 58.73; H, 3.94; Cl, 15.33; N, 11.72.

(E)-3-((2-(4-Bromophenyl)hydrazono)methyl)-2-chloro-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbonitrile (6d): Orange crystals, mp 240 °C, 93% yield; IR (KBr) ν 3260 (NH), 2214 (CN), 1647 (C=O) cm-1; 1H NMR (DMSO) δ 2.94 (m, 2H), 3.79 (s, 3H), 3.88 (s, 3H), 4.12 (m, 2H), 7.13 (s, 1H), 7.18 (d, 2H), 7.86 (s, 1H), 8.08 (d, 2H), 8.24 (s, 1H), 10.56 (s, 1H) ppm; 13C NMR (DMSO) δ 26.22, 40.20, 55.79, 55.99, 90.37, 110.09, 111.72, 112.03, 117.14, 117.87, 118.55, 124.06, 130.82, 134.53, 136.87, 139.25, 146.44, 148.59, 150.09, 152.73, 158.68 ppm; MS, m/z (%): 516 (M++4, 8.5), 514 (M++2, 36.2), 512 (M+, 26.9), 460 (100.0). Anal. Calcd for C23H18BrClN4O3: C, 53.77; H, 3.53; Br, 15.55; Cl, 6.90; N, 10.90. Found: C, 53.79; H, 3.80; Br, 15.30; Cl, 7.03; N, 10.71.

Synthesis of 2,3-dimethoxy-8-oxo-11-phenyl-5,6,8,11-tetrahydropyrazolo[3',4':4,5]pyrido[2,1-a]isoquinoline-12-carbonitrile (7): Refluxing of 6a (0.8 g, 2.0 mmol) in a mixture of 1,2-dichlorobenzene and pyridine (30 mL, 1:1) for 20 h. The solvent was evaporated under vaccum and the residue was triturated with EtOH to give orange solid. The product was collected and crystallized from DMF to give 7 as orange crystals, mp 280-282 °C, 65% yield; IR (KBr) ν 2210 (CN), 1678 (C=O) cm-1; 1H NMR (DMSO) δ 2.03 (t, 2H), 3.74 (s, 3H), 3.85 (s, 3H), 4.14 (t, 2H), 7.10 (s, 1H), 7.55-7.64 (m, 5H), 7.72 (s, 1H), 8.44 (s, 1H) ppm; 13C NMR (DMSO) δ 27.27, 40.13, 55.74, 55.89, 75.32, 110.85, 111.50, 112.54, 115.78, 118.71, 127.40, 128.90, 129.72, 130.79, 133.60, 137.67, 140.07, 146.62, 150.07, 152.01, 156.41 ppm; MS, m/z (%): 398 (M+, 94.8), 383 (100.0), 382 (65.5). Anal. Calcd for C23H18N4O3: C, 69.34; H, 4.55; N, 14.06. Found: C, 69.12; H, 4.31; N, 13.89.

Synthesis of 2,3-dimethoxy-8-oxo-5,6,8,11-tetrahydropyrazolo[3',4':4,5]pyrido[2,1-a]isoquinoline-12-carbonitrile (9): A mixture of 3 (1.0 g, 3.0 mmol) and hydrazine hydrate (0.3 g, 6.0 mmol) was refluxed for 5 h then cooled. The solid that separated was collected, dried and crystallized from DMF to give 9 as pale yellow crystals, mp 308-310 °C, 70% yield; IR (KBr) ν 3217 (NH), 2229 (CN), 1670 (C=O) cm-1; 1H NMR (DMSO) δ 2.89 (m, 2H), 3.80 (s, 3H), 3.85 (s, 3H), 4.09 (m, 2H), 7.06 (s, 1H), 7.58 (s, 1H), 7.82 (s, 1H), 14.15 (s, 1H) ppm; 13C NMR (DMSO) δ 27.44, 40.13, 55.69, 55.87, 82.01, 110.06, 110.91, 111.73, 117.25, 119.07, 131.51, 132.84, 134.25, 146.90, 148.07, 151.60, 161.94 ppm; MS, m/z (%): 322 (M+, 90.6), 307 (100.0). Anal. Calcd for C17H14N4O3: C, 63.35; H, 4.38; N, 17.38. Found: C, 63.22; H, 4.12; N, 17.41.

Synthesis of (E)-ethyl 3-(2-chloro-1-cyano-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate (11): To a solution of [(ethoxycarbonyl)methylene]triphenylphosphorane (6.96 g, 20.0 mmol) in CHCl3 (50 mL), compound 3 (6.88 g, 20.0 mmol) was added. The reaction mixture was stirred for 3 h at room temperature then evaporated to dryness under reduced pressure. EtOH (30 mL) was added to the residue and the solid formed was filtered, washed with EtOH and crystallized from MeCN to give compound 11 as yellow crystals, mp 230-232 °C, 68% yield; IR (KBr) ν 2221 (CN), 1693 (C=O), 1651 (C=O) cm-1; 1H NMR (CDCl3) δ 1.31 (t, 3H), 2.93 (m, 2H), 3.96 (s, 3H), 4.02 (s, 3H), 4.21 (m, 2H), 4.27 (q, 2H), 6.80 (s, 1H), 7.38 (d, J = 16 Hz, 1H), 7.88 (d, J = 16 Hz, 1H), 7.91 (s, 1H) ppm; 13C NMR (CDCl3) δ 14.20, 27.53, 40.40, 56.20, 56.34, 60.54, 90.57, 110.14, 111.62, 116.42, 117.84, 119.47, 124.99, 132.56, 134.28, 147.08, 147.96, 149.87, 153.18, 158.37, 167.37 ppm; MS, m/z (%): 416 (M++2, 5.6), 414 (M+, 16.3), 341 (100.0). Anal. Calcd for C21H19ClN2O5: C, 60.80; H, 4.62; Cl, 8.55; N, 6.75. Found: C, 60.71; H, 4.50; Cl, 8.41; N, 6.51.

Synthesis of (E)-ethyl 3-(2-azido-1-cyano-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate (12): A solution of 11 (2.07 g, 5.0 mmol) in dioxane-water mixture (4:1, v/v 60 mL) was treated with a solution of sodium azide (0.65 g, 10.0 mmol) in the same solvent. The reaction mixture was vigorously stirred for 3 h at room temperature then diluted with water (100 mL). The solid that precipitated was collected and crystallized from MeCN to afford compound 12 as yellow crystals, mp 260-262 °C, 80% yield; IR (KBr) ν 2210 (CN), 2129 (N3), 1697 (C=O), 1662 (C=O) cm-1; 1H NMR (CDCl3) δ 1.29 (t, 3H), 2.91 (m, 2H), 3.96 (s, 3H), 4.02 (s, 3H), 4.18 (m, 2H), 4.25 (q ,2H), 6.80 (s, 1H), 7.20 (d, J = 16 Hz, 1H), 7.78 (d, J = 16 Hz, 1H), 7.85 (s, 1H) ppm; 13C NMR (CDCl3) δ 14.19, 27.53, 40.07, 56.18, 56.33, 60.41, 84.13, 110.20, 111.72, 112.52, 115.58, 117.81, 123.29, 132.66, 132.96, 147.68, 147.88, 150.96, 153.20, 159.20, 167.48 ppm; MS, m/z (%): 393 (M+-N2, 100.0), 347 (78.6), 332 (85.7). Anal. Calcd for C21H19N5O5: C, 59.85; H, 4.54; N, 16.62. Found: C, 59.71; H, 4.32; N, 16.41.

Synthesis of (E)-ethyl 3-(2-amino-1-cyano-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate (13): To a stirred suspension of 12 (2.1 g, 5.0 mmol) in 4:1 MeOH-H2O (40 mL), sodium dithionite (4.0 g, 20.0 mol) was added portionwise. The reaction mixture was stirred for 24 h then poured into H2O (20 mL). The resulting solid product was filtered, washed with H2O and crystallized from DMF to give compound 13 as yellow crystals, mp 218-220 °C, 67% yield; IR (KBr) ν 3336-3251 (NH2), 2206 (CN), 1708 (C=O), 1627 (C=O) cm-1; 1H NMR (DMSO) δ 1.22 (t, 3H), 2.86 (m, 2H), 3.81 (s, 3H), 3.85 (s, 3H), 4.00 (m, 2H), 4.13 (q, 2H), 7.08 (s, 1H), 7.09 (s, 2H), 7.19 (d, J = 16 Hz, 1H), 7.77 (d, J = 16 Hz, 1H), 7.80 (s, 1H) ppm; 13C NMR (DMSO) δ 14.36, 26.95, 40.13, 55.89, 56.02, 59.34, 79.35, 97.35, 110.93, 111.83, 115.80, 117.66, 118.17, 133.35, 135.95, 146.75, 150.45, 152.23, 154.55, 159.17, 167.97 ppm; MS, m/z (%): 395 (M+, 11.5), 322 (100.0), 75 (90.4). Anal. Calcd for C21H21N3O5: C, 63.79; H, 5.35; N, 10.63. Found: C, 63.61; H, 5.50; N, 10.31.

Synthesis of 2,3-dimethoxy-8,11-dioxo-6,8,11,12-tetrahydro-5H-isoquinolino[2,1-g][1,6]naphthyridine-13-carbonitrile (14): A suspension of 13 (1.18 g, 3.0 mmol) in DMF was refluxed for 100 h. The solvent was evaporated under reduced pressure and the residue was triturated with EtOH. The solid formed was collected, dried and crystallized from DMF to give 14 as yellow crystals, mp 260-262 °C, 65% yield; IR (KBr) ν 3201 (NH), 2214 (CN), 1654 (C=O), 1630 (C=O) cm-1; 1H NMR (DMSO) δ 2.92 (m, 2H), 3.81 (s, 3H), 3.88 (s, 3H), 4.15 (m, 2H), 6.51 (d, J = 9 Hz, 1H), 6.81 (s, 1H), 7.53 (d, J = 9 Hz, 1H), 8.10 (s, 1H), 8.52 (s, 1H) ppm; MS, m/z (%): 349 (M+, 84.3), 348 (48.0), 334 (100.0). Anal. Calcd for C19H15N3O4: C, 65.32; H, 4.33; N, 12.03. Found: C, 65.50; H, 4.12; N, 12.20.

Synthesis of (E)-ethyl 3-(1-cyano-9,10-dimethoxy-4-oxo-2-((triphenylphosphoranylidene)amino)-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate (15): A solution of 12 (2.1 g, 5.0 mmol) and triphenylphosphine (1.3 g, 5.0 mmol) in dry Et2O (25 mL) was refluxed for 1 h and cooled. The solid that precipitated was filtered, washed with EtOH and crystallized from MeCN to give compound 15 as yellow crystals, mp 240-242 °C, 90% yield; IR (KBr) ν 2202 (CN), 1693 (C=O), 1643 (C=O) cm-1; 1H NMR (DMSO) δ 1.08 (t, 3H), 2.91 (m, 2H), 3.70 (s, 3H), 3.84 (s, 3H), 3.95 (m, 2H), 4.01 (q, 2H), 6.87 (d, J = 16 Hz, 1H), 7.04 (s, 1H), 7.45-7.76 (m, 15H), 7.78 (d, J = 16 Hz, 1H), 7.83 (s, 1H) ppm; 13C NMR (CDCl3) δ 14.02, 26.88, 40.33, 55.59, 55.70, 58.72, 84.60, 110.72, 112.06, 114.89, 118.33, 127.51, 128.56, 128.72, 129.95, 132.08, 132.21, 132.85, 138.68, 146.52, 149.21, 151.81, 153.01, 159.77, 167.34 ppm; MS, m/z (%): 655 (M+, 5.9), 582 (26.1), 262 (100.0). Anal. Calcd for C39H34N3O5P: C, 71.44; H, 5.23; N, 6.41; P, 14.72. Found: C, 71.19; H, 5.40; N, 6.32; P, 14.53.

Synthesis of ethyl 13-cyano-2,3-dimethoxy-8-oxo-11-(phenylamino)-6,8-dihydro-5H-isoquinolino[2,1-g][1,6]naphthyridine-10-carboxylate (18): Phenyl isothiocyanate (0.12 g, 1.0 mmol) was added to a solution of 15 (0.65 g, 1.0 mmol) in 1,2-dichlorobenzene (10 mL). The reaction mixture was refluxed for 5 h and then the solvent was removed under reduced pressure. The solid was filtered and crystallized from DMF to give compound 18 as yellow crystals, mp 280-282 °C, 70% yield; IR (KBr) ν 3255 (NH), 2206 (CN), 1693 (C=O), 1662 (C=O) cm-1; 1H NMR (CDCl3) δ 1.41 (t, 3H), 2.88 (m, 2H), 3.96 (s, 3H), 4.02 (s, 3H), 4.13 (m, 2H), 4.38 (q, 2H), 6.72 (s, 1H), 7.00-7.97 (m, 5H), 8.07 (s, 1H), 8.88 (s, 1H), 10.75 (s, 1H) ppm; 13C NMR (CDCl3) δ 14.12, 27.93, 39.95, 56.09, 56.45, 61.79, 88.15, 108.22, 109.98, 110.18, 112.21, 117.89, 119.12, 120.40, 123.38, 128.71, 132.32, 138.65, 140.96, 147.71, 151.00, 152.33, 155.64, 156.20, 160.05, 166.53 ppm; MS, m/z (%): 496 (M+, 100.0), 450 (12.46), 423 (20.8). Anal. Calcd for C28H24N4O5: C, 67.73; H, 4.87; N, 11.28. Found: C, 67.61; H, 4.91; N, 11.01.

Synthesis of (E)-ethyl 3-(2-aralkylamino-1-cyano-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate (20a-c): General procedure - A mixture of compound 11 (1.0 g, 3.0 mmol) and amines 19a-c (3.0 mmol) in absolute EtOH (50 mL) was refluxed for 6 h. The solvent was evaporated then cooled. The resulting solid product was collected, washed with EtOH and crystallized from MeCN to give compounds 20a-c.

(E)-Ethyl 3-(2-(benzylamino)-1-cyano-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate (20a): Yellow crystals, mp 142-144 °C, 85% yield; IR (KBr) ν 3394 (NH), 2194 (CN), 1697 (C=O), 1643 (C=O) cm-1; 1H NMR (DMSO) δ 1.20 (t, 3H), 2.88 (t, 2H), 3.78 (s, 3H), 3.85 (s, 3H), 4.03 (t, 2H), 4.11 (q, 2H), 4.79 (d, 2H), 7.07 (s, 1H), 7.11 (d, J = 16 Hz, 1H), 7.24-7.40 (m, 6H), 7.56 (s, 1H), 7.74 (d, J = 16 Hz, 1H) ppm; 13C NMR (DMSO) δ 14.33, 26.70, 40.14, 50.13, 55.76, 55.95, 59.46, 80.37, 101.45, 110.88, 112.57, 116.87, 117.92, 118.96, 127.82, 127.48, 128.45, 133.57, 136.28, 138.92, 146.68, 151.82, 152.57, 156.00, 159.24, 167.81 ppm; MS, m/z (%): 485 (M+, 7.4), 412 (50.3), 91 (100.0). Anal. Calcd for C28H27N3O5: C, 69.26; H, 5.61; N, 8.65. Found: C, 68.98; H, 5.82; N, 8.51.

(E)-Ethyl 3-(1-cyano-2-(cyclohexylamino)-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate (20b): Yellow crystals, mp 138-140 °C, 82% yield; IR (KBr) ν 3386 (NH), 2206 (CN), 1689 (C=O), 1651 (C=O) cm-1; 1H NMR (DMSO) δ 1.22 (t, 3H), 1.24 (m, 10H), 2.90 (m, 2H), 3.81 (s, 3H), 3.86 (s, 3H), 4.04 (m, 2H), 4.12 (q, 2H), 4.18 (m, 1H), 6.18 (d, 1H), 7.05 (d, J = 16 Hz, 1H), 7.09 (s, 1H), 7.63 (d, J = 16 Hz, 1H), 7.79 (s, 1H) ppm; 13C NMR (DMSO) δ 14.33, 24.81, 24.94, 26.78, 33.89, 40.40, 55.86, 55.97, 57.57, 59.52, 82.13, 102.42, 110.88, 112.75, 116.36, 118.12, 118.74, 133.57, 137.11, 146.70, 151.39, 152.49, 156.36, 159.39, 167.88 ppm; MS, m/z (%): 477 (M+, 69.7), 476 (100.0), 340 (87.9). Anal. Calcd for C27H31N3O5: C, 67.91; H, 6.54; N, 8.80. Found: C, 67.70; H, 6.66; N, 8.70.

(E)-Ethyl 3-(1-cyano-2-((3,4-dimethoxyphenethyl)amino)-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate (20c): Yellow crystals, mp 137-139 °C, 85% yield; IR (KBr) ν 3402 (NH), 2210 (CN), 1697 (C=O), 1647 (C=O) cm-1; 1H NMR (DMSO) δ 1.22 (t, 3H), 2.90 (t, 2H), 2.95 (m, 2H), 3.63 (s, 3H), 3.65 (s, 3H), 3.72 (t, 2H), 3.82 (s, 3H), 3.86 (s, 3H), 4.02 (m, 2H), 4.14 (q, 2H), 6.75-6.83 (m, 3H), 7.02 (d, J = 16 Hz, 1H), 7.08 (s, 1H), 7.33 (t, 1H), 7.67 (d, J = 16 Hz, 1H), 7.79 (s, 1H) ppm; 13C NMR (DMSO) δ 14.37, 26.75, 40.44, 49.47, 55.13, 55.44, 55.79, 55.97, 59.54, 80.47, 100.64, 110.93, 111.85, 112.62, 116.03, 117.89, 118.91, 120.80, 123.20, 131.00, 133.60, 135.21, 136.70, 146.52, 147.37, 148.54, 151.59, 152.54, 156.44, 159.85, 167.96 ppm; MS, m/z (%): 559 (M+, 12.5), 334 (61.7), 164 (100.0). Anal. Calcd for C31H33N3O7: C, 66.53; H, 5.94; N, 7.51. Found: C, 66.44; H, 5.71; N, 7.81.

Synthesis of 12-benzyl-2,3-dimethoxy-8,11-dioxo-6,8,11,12-tetrahydro-5H-isoquinolino[2,1-g][1,6]naphthyridine-13-carbonitrile (21): A solution of 20a (0.48 g, 1.0 mmol) in DMF (20 mL) was refluxed for 96 h. The solvent was evaporated under reduced pressure and EtOH (10 mL) was added to the residue. The solid precipitated was collected, dried and crystallized from DMF to give 21 as yellow crystals, mp 240-242 °C, 80% yield; IR (KBr) ν 2206 (CN), 1658 (C=O), 1650 (C=O) cm-1; 1H NMR (DMSO) δ 2.91 (m, 2H), 3.73 (s, 3H), 3.86 (s, 3H), 4.11 (m, 2H), 5.92 (s, 2H), 6.62 (d, J = 9 Hz, 1H), 7.08-7.35 (m, 7H), 8.17 (d, J = 9 Hz, 1H) ppm; 13C NMR (DMSO) δ 26.70, 40.32, 47.25, 55.78, 55.92, 78.09, 106.93, 110.75, 113.32, 117.85, 118.42, 118.91, 126.14, 126.80, 128.26, 134.11, 136.65, 136.86, 146.35, 146.50, 152.94, 153.48, 158.30, 162.16 ppm; MS, m/z (%): 439 (M+, 24.1), 408 (45.0), 91 (100.0). Anal. Calcd for C26H21N3O4: C, 71.06; H, 4.82; N, 9.56. Found: C, 70.85; H, 4.71; N, 9.68.

Synthesis of (E)-ethyl 3-(2-arylthio)-1-cyano-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate (23a-d): General procedure - These compounds were prepared as previously described for the synthesis of 20 using arylthiols 22 in the presence of triethylamine instead of amines 19. The resulting solid product was collected, washed with EtOH and crystallized from DMF to give compounds 23a-d.

(E)-Ethyl 3-(1-cyano-9,10-dimethoxy-4-oxo-2-(phenylthio)-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate (23a): Yellow crystals, mp 180-182 °C, 90% yield; IR (KBr) ν 2210 (CN), 1705 (C=O), 1654 (C=O) cm-1; 1H NMR (DMSO) δ 1.26 (t, 3H), 3.00 (m, 2H), 3.79 (s, 3H), 3.91 (s, 3H), 4.10 (m, 2H), 4.11 (q, 2H), 7.00 (s, 1H), 7.03-7.20 (m, 5H), 7.14 (d, 1H), 7.79 (s, 1H), 8.06 (d, 1H) ppm; 13C NMR (DMSO) δ 14.14, 26.45, 40.24, 55.69, 56.01, 60.00, 93.21, 110.62, 112.11, 116.91, 117.65, 121.72, 123.12, 130.16, 130.39, 134.25, 136.08, 137.90, 147.64, 147.89, 148.32, 150.99, 152.52, 158.36, 166.67 ppm; MS, m/z (%): 488 (M+, 14.3), 415 (100.0). Anal. Calcd for C27H24N2O5S: C, 66.39; H, 4.95; N, 5.73; S, 6.55. Found: C, 66.11; H, 4.71; N, 5.61; S, 6.40.

(E)-Ethyl 3-(2-((2-aminophenyl)thio)-1-cyano-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate (23b): Yellow crystals, mp 200-202 °C, 77% yield; IR (KBr) ν 3448-3348 (NH2), 2214 (CN), 1697 (C=O), 1654 (C=O) cm-1; 1H NMR (DMSO) δ 1.14 (t, 3H), 2.97 (m, 2H), 3.74 (s, 3H), 3.78 (s, 2H), 3.88 (s, 3H), 4.08 (m, 2H), 4.17 (q, 2H), 6.50-7.05 (m, 4H), 7.08 (d, 1H), 7.14 (s, 1H), 7.78 (s, 1H), 7.91 (d, 1H) ppm; 13C NMR (DMSO) δ 14.12, 26.35, 40.23, 55.60, 55.90, 59.91, 92.21, 110.75, 112.00, 114.83, 115.48, 117.33, 117.64, 121.97, 122.19, 123.04, 129.29, 132.17, 133.61, 137.59, 146.62, 147.59, 149.84, 150.30, 152.90, 158.05, 166.49 ppm; MS, m/z (%): 503 (M+, 9.13), 430 (74.7), 424 (100.0), 314 (88.6). Anal. Calcd for C27H25N3O5S: C, 64.41; H, 5.00; N, 8.35; S, 6.36. Found: C, 64.21; H, 4.87; N, 8.21; S, 6.22.

(E)-Ethyl 3-(2-((4-chlorophenyl)thio)-1-cyano-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate (23c): Yellow crystals, mp 172-174 °C, 81% yield; IR (KBr) ν 2215 (CN), 1682 (C=O), 1653 (C=O) cm-1; 1H NMR (DMSO) δ 1.25(t, 3H), 2.99 (m, 2H), 3.80 (s, 3H), 3.91 (s, 3H), 4.06 (m, 2H), 4.18 (q, 2H), 6.98 (s, 1H), 7.10-7.33 (m, 4H), 7.30 (d, 1H), 7.82 (s, 1H), 8.12 (d, 1H) ppm; 13C NMR (DMSO) δ 14.11, 26.45, 40.13, 55.72, 56.00, 59.68, 93.04, 110.52, 112.09, 116.91, 117.77, 121.85, 123.02, 133.21, 135.88, 136.13, 136.99, 137.90, 148.35, 148.82, 148.91, 151.12, 152.48, 158.34, 166.57 ppm; MS, m/z (%): 524 (M++2, 5.2), 522 (M+, 11.9), 449 (100.0), 448 (88.3). Anal. Calcd for C27H23ClN2O5S: C, 62.01; H, 4.43; Cl, 6.78; N, 5.36; S, 6.12. Found: C, 62.20; H, 4.22; Cl, 6.51; N, 5.22; S, 6.01.

(E)-Ethyl 3-(1-cyano-9,10-dimethoxy-4-oxo-2-(p-tolylthio)-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate (23d): Yellow crystals, mp 198-200 °C, 85% yield; IR (KBr) ν 2218 (CN), 1705 (C=O), 1658 (C=O) cm-1; 1H NMR (DMSO) δ 1.21 (t, 3H), 2.21 (s, 3H), 2.96 (m, 2H), 3.76 (s, 3H), 3.93 (s, 3H), 4.08 (m, 2H), 4.13 (q, 2H), 7.11 (s, 1H), 7.14-7.22 (m, 4H), 7.25 (d, 1H), 7.76 (s, 1H), 8.02 (d, 1H) ppm; 13C NMR (DMSO) δ 14.16, 20.59, 26.42, 40.36, 55.72, 56.02, 60.13, 93.34, 110.85, 112.06, 117.56, 117.77, 122.71, 123.38, 129.21, 130.33, 133.78, 137.17, 137.90, 146.80, 147.55, 148.30, 150.80, 152.74, 158.41, 166.76 ppm; MS, m/z (%): 502 (M+, 11.1), 430 (33.3), 429 (100.0). Anal. Calcd for C28H26N2O5S: C, 66.92; H, 5.22; N, 5.75; S, 6.37. Found: C, 66.71; H, 5.41; N, 5.51; S, 6.60.

X-Ray structure determination of compound 3
The X-ray diffraction measurement was made on using maXus (Bruker Nonius, Delft & MacScience, Japan) at temperature 298 K and wavelength 0.71073 Å; radiation: Mo Kα. Crystal data for compound 3: C17H13ClN2O4 , Mr = 344.754, space group: Monoclinic, P21/c; unit cell dimensions: a = 23.5106 (6) Å, b = 17.7940 (4) Å, c = 7.2843 (2) Å, α = 90.00°, β = 90.1421 (9)°, γ = 90.00; volume: 3047.36 (13) Å3; Z = 8; calculated density: Dx = 1.503 Mg m-3; absorption coefficient: μ = 0.28 mm-1; reflection 12763 measured, θmax = 27.57°. Crystallographic data for the structural analysis of compound 3 has been deposited with the Cambridge Crystallographic Data Centre (CCDC) under the number 871967. Copies of the information may be obtained free of charge from The Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Tel: +44 (0)1223 762911; www: http://www.ccdc.cam.ac.uk).

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