HETEROCYCLES

Paper | Regular issue | Vol. 78, No. 6, 2009, pp. 1507-1522
Received, 11th January, 2009, Accepted, 19th February, 2009, Published online, 20th February, 2009.
DOI: 10.3987/COM-09-11648

■ A Facile Access for Synthesis of Novel Isoquinoline-Based Heterocycles

Hamdi M. Hassaneen,* Tayseer A. Abdallah,* and Enas M. Awad

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

Abstract

Hydrazonoyl halides 2, 7 and 12 react with alkyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)carboxylate 1 to give 4-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-2,5-diaryl-2,4-dihydropyrazol-3-one 6, alkyl 2-arylazo-5,6-dihydro-8,9-dimethoxy-3-alkyl(or aryl)pyrrolo[2,1-a]isoquin-oline-1-carboxylate 10 and alkyl 2-(2-arylhydrazono)-2,3,5,6-tetrahydro-8,9-dimethoxy-3-oxopyrrolo[2,1-a]isoquinoline-1-carboxylate 15, respectively. The structures of the new compounds were elucidated on the basis of elemental analyses, spectral data and X-ray crystallographic analyses.

INTRODUCTION
Isoquinolines are a very interesting class of compounds because of their wide range significant biological and pharmaceutical activities.1-3 In view of our interest in developing efficient routes for synthesis of isoquinolines–based heterocycles,4-7 we study in this article the reaction of different types of hydrazonoyl halide 2,7 and 12 with isoquinoline derivatives 1A,B under different conditions .

RESULTS AND DISCUSSION
In our preliminary communication7 we report that compound 2a reacted with isoquinoline 1B to give the corresponding hydrazone structure of type 5. The identity of the product from this reaction has to be reinvestigated. Accordingly, we have studied the reaction of methyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)acetate 1A with hydrazonoyl halides 2a-f at room temperature in chloroform in the presence of triethylamine to give amidrazone of type 3 as single product (Scheme 1). The structure of the product was established based on X-ray crystallographic analysis of methyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-3-(2-phenylhydrazono)-3-phenylpropanoate (3Aa) (Figure 1). The 1H NMR spectrum of the formed product revealed the absence of olefinic proton -OCO-CH= and indicated two NH bands, thus structures 4 and 5 were excluded (Scheme 1).

Furthermore structure 3A was confirmed by refluxing 3A in chloroform for 2 h to give only one cyclized product of type 6 via elimination of methanol. Structure 6 was confirmed by elemental analyses and spectral data (IR, MS, 1H NMR, and 13C NMR). The product 6 can also obtained directly by reaction of hydrazonoyl halide 2 with 1A in refluxing chloroform in the presence of triethylamine. Also structure 6c,d,f were further confirmed by their alternate synthesis via reaction of 1B with hydrazonoyl halide 2c,d,f, in chloroform in the presence of triethylamine under reflux. The products obtained are identical in all respects (mp, mixed mp, spectral data) with those obtained from reaction of 1A with 2c,d,f.

Next, we study the reaction of α-ketohydrazonoyl halides of type 7 with isoquinoline derivatives 1. The reaction gives one product in each case as evidenced by TLC. The isolated products 10 gave satisfactory elemental analyses and spectroscopic data (IR, MS, 1H NMR, and 13C NMR) for the proposed structure. In addition, single crystal X-ray analysis of one example of the reaction products namely ethyl 2-(2-(4-chlorophenyl)azo)-5,6-dihydro-8,9-dimethoxy-3-(2-thienyl)pyrrolo[2,1-a]isoquinoline-1-carboxylate 10Bf (Figure 2) provided a good evidence for the formation of the structure 10 and ruled out the other possible structure 11 as outlined in Scheme 2.
A conceivable reaction mechanism proposed pathway for the formation of 10 from 1 and 7 is outlined in Scheme 2. The reaction involves initial nucleophilic substitution to give 8, which tautomarize to give 9, the latter is then cyclized via elimination of water to give 10.
Finally, we study the reaction of hydrazonoyl halides of type 12 with the starting compound 1B. Thus compound 12 reacts with 1B at room temperature to give the substitution product 14B. Structure of 14B was confirmed based on spectral data (IR, MS, 1H NMR, and 13C NMR). Moreover, structure 14B was confirmed by X-ray crystallographic analysis of 1,4-diethyl 3-(2-(4-chlorophenyl)hydrazono)-2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)succinate 14Bd (Figure 3).

Structure 13 was ruled out based on the absence of the olefinic proton OCOCH= in 1H NMR spectra and on X-ray data of 14Bd. Also, the 1H NMR spectra indicated in all cases, two NH bands and hence structure 14B was considered most likely. On the other hand, reaction of hydrazonoyl halides 12 with 1B in refluxing chloroform in the presence of triethylamine gave only in each case, one cyclized product that can be either 15 or 16 (Scheme 3). The 1H NMR spectra, in all cases, revealed triplet and quartet signals assignable to the ethoxycarbonyl group. The IR spectra showed one NH band. Also, the mass spectrum of each compound gave an intense peak corresponding to the molecular ion peak. Also structure 15 formed via cyclization of compound 14B by refluxing in glacial acetic acid. Also, structure 15 was confirmed by alternate synthesis of 15Ba via stirring equimolar amounts of 12h with 1B in the presence of triethylamine in chloroform at room temperature. Refluxing the latter product 14h in glacial acetic acid gave a product which was found to be identical in all physical and spectral data with structure 15Ba (Scheme 3).

The reaction pathway that seems to be reasonable for the formation of 15 from 1 and 12 is outlined in Scheme 3. It is proposed that the reaction involves a nucleophilic substitution to give 14. The latter in turn cyclized on heating via elimination of ethanol or methanol to give 15.

EXPERIMENTAL
All melting points are uncorrected and were measured on a Gallenkamp apparatus. IR spectra were recorded on Shimadzu FT-IR 8101 PC infrared spectrophotometer. NMR spectra were determined in CDCl3 or DMSO-d6 at 200 MHz (1H NMR) and at 75 MHz (13C NMR) on a Varian Mercury VX 200 NMR spectrometer using TMS as an internal standard. Mass spectra were measured on a GCMS-QP1000 EX spectrometer at 70 e.V. Elemental analyses were carried out at the Microanalytical Center of Cairo University. Alkyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)carboxylate 1,8 hydrazo-noyl halides 2,9 710 and 1211 were prepared according to the procedures reported in literature.

Synthesis of methyl (or ethyl) 3-(2-arylhydrazono)-2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)propanoate 3
To a solution of the appropriate hydrazonoyl halide 2 (5 mmol) and 1A,B (5 mmol) in CHCl3 (30 mL) was added triethylamine (1.4 mL, 10 mmol). The reaction mixture was stirred at rt for 4 h. The solvent was evaporated under reduced pressure and the residue was triturated with MeOH (10 mL) where it is solidified. The crude product was collected and recrystallized from EtOH.

Methyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-3-(2-phenylhydrzono)-3-phenylpropanoate 3Aa: Yellowish green crystals; mp 197-199 °C; yield (83%); IR (KBr) ν 1711 (C=O), 3250 (NH) cm-1; 1H NMR (CDCl3) δ 2.66-2.99 (m, 2H, isoquinoline-CH2), 3.34-3.58 (m, 2H, isoquinoline-CH2), 3.41 (s, 3H, ester-CH3), 3.59 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 6.54-7.80 (m, 12H, Ar H), 8.14 (s, 1H, NH), 10.55 (s, 1H, NH); 13C NMR (CDCl3) 31.3, 41.0, 53.0, 57.6, 57.7, 82.4, 112.1, 113.3, 115.1, 121.7, 122.6, 127.7, 129.4, 130.1,131.2, 132.9, 141.7, 145.9, 146.9, 149.3, 152.8, 160.5, 172.3. Anal. Calcd for C27H27N3O4: C, 70.88; H, 5.95; N, 9.18. Found: C, 70.59; H, 5.73; N, 9.34%.

Methyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-3-(2-phenylhydrazono)-3-strylpropanoate 3Ab: Yellow crystals; mp 182-183 °C; yield (75%); IR(KBr) ν 1640 (C=O), 3257, 3312 (2NH) cm-1; 1H NMR (CDCl3) δ 2.68-3.00 (m, 2H, isoquinoline-CH2), 3.25-3.50 (m, 2H, isoquinoline-CH2), 3.55 (s, 3H, ester-CH3), 3.63 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 6.36 (d, 1H, J = 12Hz, CH=CH), 6.44 (d, 1H, J = 12Hz, CH=CH), 6.57 (s, 1H, isoquinoline-CH), 6.80-7.38 (m, 11H, Ar H), 8.18 (s, 1H, NH), 10.50 (s, 1H, NH); 13C NMR (CDCl3) 29.3, 38.9, 51.0, 55.7, 55.9, 79.1, 110.1, 111.1, 113.0, 119.9, 120.6, 126.5, 127.2, 128.4, 129.1, 129.9, 130.7, 137.4, 144.3, 145.9, 147.4, 150.8, 155.6, 158.7, 170.0; MS: m/z 483 (M+, 2.9%), 454, 422, 393, 363, 178 , 121, 103. Anal. Calcd for C29H29N3O4: C, 72.03; H, 6.05; N, 8.69. Found: C, 71.85; H; 6.37; N, 8.51%.

Methyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-3-(2-(4-nitrophenyl)hydrazono)-3-(2-thienyl)propanoate 3Ad: Orange crystals; mp 200-202 °C; yield (85%); IR (KBr) ν 1636 (C=O), 3241, 3389 (2NH) cm-1; 1H NMR (DMSO-d6) δ 2.15-2.24 (m, 2H, isoquinoline-CH2), 3.18-3.24 (m, 2H, isoquinoline-CH2), 3.60 (s, 3H, ester-CH3), 3.69 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 6.87 (s, 1H, isoquinoline-CH), 7.0 (s, 1H, isoquinoline-CH), 7.18-8.3 (m, 8H, Ar H) 8.40 (s, 1H, NH); MS: m/z 508 (M+, 1.7%), 462, 432, 178.0, 93. Anal. Calcd for C25H24N4O6S: C, 59.04; H, 4.76; N, 11.02; S, 6.30. Found: C, 59.29; H; 4.54; N, 11.17; S, 6.48%.

Methyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-3-(2-phenylhydrazono)-3-(2-thienyl)propanoate 3Ae: Yellow crystals; mp 202-204 °C; yield (81%); IR (KBr) ν 1634 (C=O), 3252 (NH) cm-1; 13C NMR (DMSO-d6) 30.2, 52.2, 56.6, 57.2, 58.0, 83.2, 112.5, 112.7, 114.5, 120.6, 122.3, 125.2, 126.8, 128.9, 130.6, 133.3, 140.6, 147.2,148.2, 149.1, 152.1, 159.3, 170.5; MS: m/z 463 (M+, 51.6%), 434, 402, 312, 298, 282, 263, 232, 200, 91. Anal. Calcd for C25H25N3O4S: C, 64.78; H, 5.44, N, 9.06; S, 6.92. Found: C, 64.58; H, 5.27; N, 8.94; S, 7.16%.

Ethyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-3-(2-(4-nitrophenyl)hydrazono)-3-phenylpropanoate 3Bc: Red crystals; mp 141-143 °C; yield (70%); IR (KBr) ν 1634 ((C=O), 3235 (NH) cm-1; 1H NMR δ (CDCl3) 0.97-1.04 (t, 3H, J = 7Hz, ester-CH3), 2.75-2.88 (m, 2H, isoquinoline-CH2), 3.38 (s, 3H, OCH3), 3.4-3.72 (m, 2H, isoquinoline-CH2), 3.78 (s, 3H, OCH3), 4.01-4.11 (q, 2H, J = 7Hz, ester-CH2), 6.54-8.16 (m, 11H, Ar H), 8.52 (s, 1H, NH), 10.56 (s, 1H, NH); MS: m/z 517 (M+, 2.6%), 486, 470, 441. Anal. Calcd for C28H28N4O6: C, 65.11; H, 5.46; N, 10.85. Found: C, 65.28; H, 5.57; N, 10.73 %.

Ethyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-3-(2-(4-nitrophenyl)hydrazono)-3-(2-thienyl)propanoate 3Bd: Yellow crystals; mp 135-136 °C; yield (72%); IR (KBr) ν 1631 (C=O), 3244 (NH) cm-1; 1H NMR δ (CDCl3) 1.04-1.11 (t, 3H, J = 7Hz, ester-CH3), 2.65-3.00 (m, 2H, isoquinoline-CH2), 3.25-3.45 (m, 2H, isoquinoline-CH2), 3.52 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.00-4.20 (q, 2H, J = 7Hz, ester-CH2) 6.57-8.16 (m, 9H, Ar H), 8.44 (s, 1H, NH), 10.57 (s, 1H, NH); 13C NMR (DMSO-d6) 12.9, 36.3, 41.8, 54.9, 55.2, 59.4, 78.6, 111.9, 112.2, 112.7, 119.8, 123.9, 124.4, 126.8, 126.9, 128.1, 131.6, 132.8, 143.0, 145.5, 146.3, 146.3, 149.3, 161.9; MS: m/z 522 (M+, 2.6%), 476, 447,144. Anal. Calcd for C26H26N4O6S: C, 59.76; H, 5.02; N, 10.72; S, 6.14. Found: C, 59.62; H, 5.33; N, 10.60; S, 6.35%.

Ethyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-3-(2-phenylhydrazono)-3-(2-thienyl)- propanoate 3Be: Yellow crystals; mp 178-180 °C; yield (74%); IR (KBr) ν 1630 (C=O), 3261 (NH) cm-1; 1H NMR (CDCl3) δ 1.00 (t, 3H, J = 7Hz, ester-CH3), 2.56-2.90 (m, 2H, isoquinoline-CH2), 3.20-3.40 (m, 2H, isoquinoline-CH2), 3.48 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.91 (q, 2H, J = 7Hz, ester-CH2), 6.49-7.19 (m, 10H, Ar H), 7.91 (s, 1H, NH), 10.45 (s, 1H, NH); 13C NMR (CDCl3) 16.6, 31.3, 40.9, 57.7, 61.4, 83.1, 112.1, 113.3, 115.0, 121.7, 122.7, 126.1, 127.0, 128.7, 131.1, 132.7, 142.2, 146.8, 148.6, 149.4, 152.8, 160.7, 171.5. MS: m/z 477 (M+, 97.8%), 402, 339, 298, 205, 91. Anal. Calcd for C26H27N3O4S: C, 65.39; H, 5.70; N, 8.80; S, 6.71. Found: C, 65.50; H, 5.42; N, 8.61; S, 6.54%.

Ethyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-3-(2-(4-nitrophenyl)hydrazono)-3-(2-furyl)propanoate 3Bf: Red crystals; mp 174-175 °C; yield (74%); IR (KBr) ν 1635 (C=O), 3245 (NH) cm-1; 1H NMR (CDCl3) δ 1.04-1.11 (t, 3H, J = 7Hz, ester-CH3), 2.68-3.00 (m, 2H, isoquinoline-CH2), 3.26-3.60 (m, 2H, isoquinoline-CH2), 3.53 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 4.00-4.23 (q, 2H, J = 7Hz, ester-CH2), 6.24-8.15 (m, 9H, Ar H), 8.54 (s, 1H, NH), 10.55 (s, 1H, NH); Anal. Calcd for C26H26N4O7: C, 61.65; H, 5.17; N, 11.06. Found: C, 61.43; H, 5.33; N, 11.25 %.

Synthesis of 4-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-2,5-diaryl-2,4-dihydropyrazol-3-one 6
To a solution of the appropriate hydrazonoyl halide 2 (5 mmol) and 1 (5 mmol) in CHCl3 (30 mL) was added triethylamine (1.4 mL, 10 mmol) at rt. The reaction mixture was refluxed for 6 h then left to cool to rt. The solvent was evaporated under reduced pressure and the residue was triturated with MeOH (10 mL) where it solidified. The crude product was collected and crystallized from suitable solvent to give product 6.

4-(3,4-Dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-2,4-dihydro-2-(4-nitrophenyl)phenylpyrazol-3-one 6c: Dark red crystals; mp 238-240 °C; (MeCN); yield (83%); IR (KBr) ν 1635 (C=O) cm-1, 1H NMR (DMSO-d6) δ 2.26 (m, 2H, isoquinoline-CH2), 3.06 (m, 2H, isoquinoline-CH2), 3.52 (s, 3H, OCH3), 3.65 (s, 3H, OCH3), 6.56 (s, 1H, isoquinoline-CH), 6.88 (s, 1H, isoquinoline-CH), 7.0-8.50 (m, 10H, Ar H); MS: m/z 470 (M+, 80.0%), 276, 226, 75. Anal. Calcd for C26H22N4O5: C, 66.37; H, 4.71; N, 11.91. Found: C, 66.54; H, 4.78; N, 12.07%.

4-(3,4-Dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-2,4-dihydro-2-(4-nitrophenyl)-5-(2-thienyl)pyrazol-3-one 6d: Red crystals; mp 252-254 °C; (dioxane); yield (86%); IR (KBr) ν 1642 (C=O), 3219 (NH) cm-1; 1H NMR (CDCl3) δ 2.96-3.03 (m, 2H, isoquinoline-CH2), 3.28 (s, 3H, OCH3), 3.62-3.65 (m, 2H, isoquinoline-CH2), 3.95 (s, 3H, OCH3) 6.60-8.46 (m, 9H, Ar H), 11.50 (s, 1H, NH); MS: m/z 476 (M+,100.0%), 298, 225, 204, 111, 90. Anal. Calcd for C24H20N4O5S: C, 60.49; H, 4.23; N, 11.76; S, 6.73. Found: C, 60.25; H, 4.57; N, 11.44; S, 6.48%.

4-(3,4-Dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-2,4-dihydro-2-(4-nitrophenyl)-5-(2-furyl)pyrazol-3-one 6f: Crimson red crystals; mp 272-274 °C; (DMF); yield (78%); IR (KBr) ν 1637 (C=O) cm-1; MS: m/z 460 (M+, 100.0%) 406, 323, 266, 75. Anal. Calcd for C24H20N4O6: C, 62.60; H, 4.38; N, 12.17. Found: C, 62.75; H, 4.02; N, 12.41%.

Synthesis of alkyl 2-arylazo-5,6-dihydro-8,9-dimethoxy-3-aryl(or alkyl)pyrrolo[2,1-a]isoquinoline-1-carboxylate 10
These compounds were prepared by the same method described for the synthesis of 6 using hydrazonoyl halide 7 instead of 2. The crude product was collected in each case and recrystallized from a suitable solvent.

Methyl 5,6-dihydro-8,9-dimethoxy-3-methyl-2-(2-phenylazo)pyrrolo[2,1-a]isoquinoline-1-carboxylate 10Aa: Yellow crystals; mp 183-185 °C (EtOH); yield (80%); IR (KBr) ν 1711 (C=O) cm-1, 1H NMR (CDCl3) δ 2.59 (s, 3H, CH3), 2.94-3.00 (m, 2H, isoquinoline-CH2), 3.88 (s, 6H, 2OCH3), 3.90 (s, 3H, ester-CH3), 3.92-4.00 (m, 2H, isoquinoline-CH2), 6.68-7.78 (m, 7H, Ar H); 13C NMR (DMSO-d6) 10.9, 29.4, 53.6, 57.2, 57.41, 103.1, 109.1, 113.8, 121.0, 123.2, 127.7, 129.6, 131.0, 136.2, 138.9, 149.7, 150.3, 154.3, 170.1. MS: m/z 405 (M+, 50.07%) 373, 311, 169, 77. Anal. Calcd for C23H23N3O4: C, 68.13; H, 5.72; N, 10.36. Found: C, 68.35; H, 5.86; N, 10.14%.

Methyl 5,6-dihydro-8,9-dimethoxy-2-(2-phenylazo)-3-(2-thienyl)pyrrolo[2,1-a]isoquinoline-1-carboxylate 10Ae: Yellowish orange crystals; mp 209-211 °C (AcOH); yield (84%); IR (KBr) ν 1705 (C=O) cm-1; 1H NMR (CDCl3) δ 2.94-2.98 (m, 2H, isoquinoline-CH2), 3.89 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 3.92 (s, 3H, ester-CH3), 4.20-4.27 (m, 2H, isoquinoline-CH2), 6.75-7.81 (m, 10H, Ar H); MS: m/z 473 (M+, 74.3%), 338, 295, 221, 148, 77. Anal. Calcd for C26H23N3O4S: C, 65.95; H, 4.90; N, 8.87; S, 6.77. Found: C, 66.15; H, 4.97; N, 8.67; S, 6.83%.

Ethyl 2-(2-(4-chlorophenyl)azo)-5,6-dihydro-8,9-dimethoxy-3-methylpyrrolo[2,1-a]isoquinoline-1-carboxylate 10Bb: Red crystals; mp 199-200 °C (Me CN); yield (76%); IR (KBr) ν 1704 (C=O) cm-1; 1H NMR (DMSO-d6) δ 1.31 (t, 3H, J = 7Hz, ester-CH3), 2.63 (s, 3H, CH3), 3.01-3.10 (m, 2H, isoquinoline-CH2), 3.93 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 4.00-4.10 (m, 2H, isoquinoline-CH2), 4.35 (q, 2H, J = 7Hz, ester-CH2), 6.76 (s, 1H, isoquinoline-CH), 7.30-7.80 (m, 5H, Ar H); 13C NMR (DMSO-d6), 11.4, 16.3, 30.6, 42.9, 58.9, 58.0, 63.1, 104.4, 108.5, 110.2, 113.7, 122.3, 125.1, 127.0, 130.9, 135.7, 136.6, 140.0, 150.4, 150.6, 153.7, 170.5; MS: m/z 453 (M+, 50.6%), 407, 270, 226, 111, 75, Anal. Calcd for C24H24N3O4Cl: C, 63.50; H, 5.33; N, 9.26. Found: C, 63.77; H, 5.15; N, 9.43%.

Methyl 5,6-dihydro-8,9-dimethoxy-2-(2-phenylazo)-3-phenylpyrrolo[2,1-a]isoquinoline-1-carboxylate 10Ac: Dark red crystals; mp 210-212 °C (AcOH), yield (83%); IR (KBr) ν 1710 (C=O) cm-1; 1H NMR (DMSO-d6) δ 2.86-2.94 (m, 2H, isoquinoline-CH2), 3.84 (s, 3H, OCH3), 3.86 (s, 6H, isoquinoline OCH3 + ester-CH3), 4.00-4.09 (m, 2H, isoquinoline-CH2), 6.68-7.65 (m, 12H, Ar H). Anal. Calcd for C28H25N3O4: C, 71.93; H, 5.39; N, 8.99. Found: C, 71.88; H, 5.09; N, 8.74%.

Ethyl 2-(2-(4-chlorophenyl)azo)-5,6-dihydro-8,9-dimethoxy-3-phenylpyrrolo[2,1-a]isoquinoline-1-carboxylate 10Bd: Red crystals; mp 239-241 °C (Dioxane); yield (77%); 1H NMR (DMSO-d6) δ 1.31 (t, 3H, J = 7Hz, ester-CH3), 2.95-3.03 (m, 2H, isoquinoline-CH2), 3.93 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 4.10 (m, 2H, isoquinoline-CH2), 4.38 (q, 2H, J = 7Hz, ester-CH2), 6.76 (s, 1H, isoquinoline-CH), 7.35-7.65 (m, 10H, Ar H). Anal. Calcd for C29H26N3O4Cl: C, 67.50; H, 5.08; N, 8.14. Found: C, 67.68; H, 5.23; N, 8.37%.

Ethyl 2-(2-(4-chlorophenyl)azo)-5,6-dihydro-8,9-dimethoxy-3-(2-thienyl)pyrrolo[2,1-a]isoquinoline-1-carboxylate 10Bf: Dark red crystals; mp 194-196 °C (AcOH); yield (80%); MS: m/z 521 (M+, 69.6%) 338, 294, 148, 111, 75. Anal. Calcd for C27H24N3O4SCl: C, 62.12; H, 4.63; N, 8.05; S, 6.14. Found: C, 62.40; H, 4.58; N, 7.83; S, 6.40%.

Synthesis of 1,4-dialkyl-3-(2-arylhydrazono)-2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)succinate 14
These compounds were prepared by the same method described for the synthesis of 3 using hydrazonoyl halide 12 instead of 2. The crude product in each case was collected and recrystallized from EtOH.

1,4-Diethyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-3-(2-phenylhydrazono)succinate 14Ba: Yellowish orange crystals; mp169-170 °C; yield (82%); IR (KBr) ν 1631 (C=O), 1705 (C=O), 3263 (NH) cm-1; 1H NMR (CDCl3) δ 1.07-1.17 (m, 6H, 2CH3 ester), 2.60-3.02 (m, 2H, isoquinoline-CH2), 3.22-3.60 (m, 2H, isoquinoline-CH2), 3.64 ( s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.00-4.23 (m, 4H, 2CH2 ester), 6.63 (s, 1H, isoquinoline-CH), 6.91 (s, 1H, isoquinoline-CH), 6.94-7.30 (m, 5H, Ar H), 8.41 (s, 1H, NH), 10.41 (s, 1H, NH), 13C NMR (DMSO-d6) 13.9, 14.3 , 29.8, 38.6, 55.7, 59.1, 60.4, 79.0, 110.3 ,110.4, 113.8, 121.0, 121.5, 129.9, 131.1, 135.5, 143.4, 147.3, 151.0, 158.7, 166.5, 169.3; MS: m/z 467 (M+, 27.2%), 421, 376, 302 , 257, 205, 130, 77. Anal. Calcd for C25H29N3O6: C, 64.23; H, 6.25; N, 8.99. Found: C, 63.91; H, 6.46; N, 8.70%.

1,4-Diethyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-3-(2-(4-methoxyphenyl)hydrazono)succinate 14Bb: Yellowish green crystals; mp 178-180 °C; yield (73%); IR (KBr) ν 1632 (C=O), 1699 (C=O), 3250 (NH) cm-1, 1H NMR (DMSO-d6) δ 1.00-1.11 (m, 6H, 2CH3 ester), 2.52-2.95 (m, 2H, isoquinoline-CH2), 3.15-3.53 (m, 2H, isoquinoline-CH2), 3.59 (s, 3H, CH3OC6H4), 3.70 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.90-4.16 (m, 4H, 2CH2 ester), 6.58 (s, 1H, isoquinoline-CH), 6.70-6.90 (m, 2H, Ar H), 7.00-7.10 ( m, 2H, Ar H), 7.20 (s, 1H, Ar H), 8.26 (s, 1H, NH), 10.33 (s, 1H, NH); 13C NMR (DMSO-d6) 16.2, 16.6, 31.2, 41.0, 57.6, 57.9, 61.3, 62.5, 81.1, 112.2, 112.5, 116.7, 117.0, 123.1, 133.0, 136.4, 139.4, 149.4, 153.0, 156.8, 161.6, 167.4, 171.3, 182.8. MS: m/z 497 (M+, 55.8%), 451, 350, 205, 122. Anal. Cacld for C26H31N3O7: C, 62.76; H, 6.28; N, 8.44. Found: C, 62.51; H, 6.21; N, 8.23%.

1,4-Diethyl 3-(2-(3-chlorophenyl)hydrazono)-2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)succinate 14Bc: Yellowish orange crystals; mp 158-160 °C; yield (72%); IR (KBr) ν 1630 (C=O), 1704 (C=O), 3249 (NH) cm-1; 1H NMR (DMSO-d6) δ 1.07-1.16 (m, 6H, 2CH3 Ester), 2.60-3.00 (m, 2H, isoquinoline-CH2), 3.20-3.60 (m, 2H, isoquinoline-CH2), 3.70 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.00-4.18 (m, 4H, 2CH2 ester), 6.64 (s, 1H, isoquinoline-CH), 6.90 (s, 1H, isoquinoline-CH), 6.95-7.25 (m, 4H, Ar H), 8.38 (s, 1H, NH), 10.38 (s, 1H, NH); MS: m/z 501 (M+, 41.0%), 455, 404, 302, 257, 205, 63. Anal. Calcd for C25H28N3O6Cl: C, 59.81; H, 5.62; N, 8.37. Found: C, 59.62; H, 5.68; N, 8.27%.

1,4-Diethyl 3-(2-(4-chlorophenyl)hydrazono)-2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)succinate 14Bd: Pale orange crystals; mp 180-181 °C; yield (76%); IR (KBr) ν 1630(C=O), 1710 (C=O), 3248 (NH) cm-1, 1H NMR (DMSO-d6) δ 1.00-1.10 (m, 6H, 2CH3 Ester), 2.55-2.95 (m, 2H, isoquinoline-CH2), 3.15-3.50 (m, 2H, isoquinoline-CH2), 3.58 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.91-4.18 (m, 4H, 2CH2 ester), 6.58 (s, 1H, isoquinoline-CH), 6.80 (s, 1H, isoquinoline-CH), 7.00-7.19 (m, 4H, Ar H), 8.30 (s, 1H, NH), 10.30 (s, 1H, NH), MS: m/z 501 (M+, 41.2%), 455, 416, 354, 302, 242, 205, 111. Anal. Calcd for C25H28N3O6Cl: C, 59.81; H, 5.62; N, 8.37. Found: C, 59.72; H, 5.49; N, 8.58%.

1,4-Diethyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-3-(2-(3-methylphenyl)hydrazono)succinate 14Be: Yellow crystals; mp 140-142 °C; yield (72%); IR (KBr) ν 1630(C=O), 1716 (C=O), 3249 (NH) cm-1, 1H NMR (DMSO-d6) δ 1.07-1.18 (m, 6H, 2CH3 ester), 2.30 (s, 3H, CH3), 2.60-3.15 (m, 2H, isoquinoline-CH2), 3.20-3.60 (m, 2H, isoquinoline-CH2), 3.68 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.00-4.24 (m, 4H, 2CH2 ester), 6.62 (s, 1H, isoquinoline-CH), 6.70-7.20 (m, 5H, Ar H), 8.40 (s, 1H, NH), 10.40 (s, 1H, NH), MS: m/z 481(M+, 8.8%) 435, 389, 302, 257, 91. Anal. Calcd for C26H31N3O6: C, 64.85; H, 6.49; N, 8.73. Found: C, 64,73; H, 6.80; N, 8.97%.

1,4-Diethyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-3-(2-(4-methylphenyl)hydrazono)succinate 14Bf: Yellow crystals; mp 168-170 °C; yield (75%); IR (KBr) ν 1631(C=O), 1702 (C=O), 3250 (NH) cm-1; 1H NMR (CDCl3) δ 1.07-1.18 (m, 6H, 2CH3 ester), 2.28 (s, 3H, CH3), 2.60-3.03 (m, 2H, isoquinoline-CH2), 3.22-3.59 (m, 2H, isoquinoline-CH2), 3.64 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 4.0-4.26 (m, 4H, 2CH2 ester), 6.63 (s, 1H, isoquinoline-CH), 6.89 (s, 1H, isoquinoline-CH), 7.06 (m, 4H, Ar H), 8.37 (s, 1H, NH), 10.39 (s, 1H, NH). MS: m/z 481 (M+, 66.7%), 435, 257, 205, 112, 91. Anal. Calcd for C26H31N3O6: C, 64.85; H, 6.49; N, 8.73. Found: C, 64.80; H, 6.86; N, 8.60%.

1-Ethyl 2-(3,4-dihydro-6,7-dimethoxy-2H-isoquinoline-1-ylidene)-3-(2-phenylhydrazono)-4-methylsuccinate 14Bh: Pale orange crystals; mp189-190 °C; yield (79%); IR (KBr) ν 1631 (C=O), 1709(C=O), 3243 (NH) cm-1, 1H NMR (DMSO-d6) δ 1.04 (t, 3H, J = 7Hz, ester-CH3), 2.58-3.00 (m, 2H, isoquinoline-CH2), 3.20-3.50 (m, 2H, isoquinoline-CH2), 3.54 (s, 3H, OCH3), 3.60 (s, 3H, OCH3), 3.80 (s, 3H, COOCH3), 3.95 (q, 2H, J = 7Hz, ester-CH2), 6.57 (s, 1H, isoquinoline-CH), 6.81 (s, 1H, isoquinoline-CH), 6.88-7.29 (m, 5H, Ar H), 10.34 (s, 1H, NH); 13C NMR (DMSO-d6)16.6, 31.1, 40.9, 54.0, 57.8, 61.3, 81.0, 112.4, 116.0, 123.0, 123.6, 131.2, 133.1, 137.2, 145.3, 149.4, 153.0, 161.6, 168.0, 171.1; MS: m/z 453 (M+, 27.4%), 421, 375, 288, 205, 115, 77. Anal. Calcd for C24H27N3O6: C, 63.56; H, 6.00; N, 9.27. Found: C, 63.43; H, 5.67; N, 9.01%.

Synthesis of alkyl 2-(2-arylhydrazono)-2,3,5,6-tetrahydro-8,9-dimethoxy-3-oxopyrrolo[2,1-a]isoquino-line-1-carboxylate 15
These compounds were prepared by the same method described for the synthesis of 6 by using hydrazonoyl halide 12 instead of 2. The product was collected and crystallized from suitable solvent.

Methyl 2,3,5,6-tetrahydro-8,9-dimethoxy-3-oxo-2-(2-phenylhydrazono)pyrrolo[2,1-a]isoquinoline-1-carboxylate 15Aa: Dark red crystals; mp 181-183 °C (EtOH); yield (86%); 1H NMR (CDCl3) δ 2.91-3.00 (m, 2H, isoquinoline-CH2), 3.75-3.81 (m, 2H, isoquinoline-CH2), 3.84 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 3.94 (s, 3H, ester-CH3), 6.64-7.78 (m, 7H, Ar H), 12.57 (s, 1H, NH); MS: m/z 407 (M+, 48.1%), 375, 242, 200, 77. Anal. Calcd for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 64.57; H, 4.96; N, 10.54%.

Ethyl 2,3,5,6-tetrahydro-8,9-dimethoxy-3-oxo-2-(2-phenylhydrazono)pyrrolo[2,1-a]isoquinoline-1-carboxylate 15Ba: Red crystals; mp 217-219 °C (MeCN); yield (84%); IR (KBr) ν 1666(C=O) cm-1, 1H NMR (DMSO-d6) δ 1.36 (t, 3H, J = 7Hz, ester-CH3), 2.90 (m, 2H, isoquinoline-CH2), 3.75 (m, 2H, isoquinoline-CH2), 3.87 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.29 (q, 2H, J = 7Hz, ester-CH2), 6.65 (s, 1H, isoquinoline-CH), 7.15-7.35 (m, 5H, Ar H), 8.04 (s, 1H, Ar H), 13.09 (s, 1H, NH); MS: m/z 421 (M+, 30.9%), 375, 200, 77. Anal. Calcd for C23H23N3O5: C, 65.55; H, 5.50; N, 9.97. Found: C, 65.69; H, 5.4; N, 10.07%.

Ethyl 2,3,5,6-tetrahydro-8,9-dimethoxy-2-(2-(4-methoxyphenyl)hydrazono)-3-oxopyrrolo[2,1- a]isoquinoline-1-carboxylate 15Bb: Orange crystals; 190-192 °C (AcOH); yield (77%); 1H NMR (CDCl3) δ 1.42-1.49 (t, 3H, J = 7Hz, ester-CH3), 2.91-3.00 (m, 2H, isoquinoline-CH2), 3.80-3.90 (m, 2H, isoquinoline-CH2), 3.84 (s, 3H, OCH3), 3.95 (s, 6H, 2OCH3), 4.35-4.48 (q, 2H, J = 7Hz, ester-CH2), 6.71-8.09 (m, 6H, Ar H), 13.24 (s, 1H, NH); MS: m/z 451 (M+, 50.0%), 405, 203, 173, 149, 107, 77. Anal. Calcd for C24H25N3O6: C, 63.85; H, 5.58; N, 9.31. Found: C, 63.64; H, 5.38; N, 9.52%.

Ethyl 2-(2-(3-chlorophenyl)hydrazono)-2,3,5,6-tetrahydro-8,9-dimethoxy-3-oxopyrrolo[2,1-a]isoquino-
line-1-carboxylate 15Bc: Scarlet orange crystals;180-182 °C (AcOH); yield (81%); IR (KBr) ν 1670 (C=O), 1692 (C=O) cm-1; 1H NMR (DMSO-d6) δ 1.38 (t, 3H, J = 7Hz, ester-CH3), 2.89 (m, 2H, isoquinoline-CH2), 3.73 (m, 2H, isoquinoline-CH2), 3.80 (s, 3H, OCH3), 3.88 (s, 3H, OCH3) 4.25 (q, 2H, J = 7Hz, ester-CH2), 6.65 (s, 1H, isoquinoline-CH), 6.88-7.40 (m, 4H, Ar H), 8.05 (s, 1H, Ar H), 13.00 (s, 1H, NH); MS: m/z 455 (M+, 50.0%), 355, 319, 173, 127, 77. Anal. Calcd for C23H22N3O5Cl: C, 60.59, H, 4.86, N, 9.22. Found: C, 60.72; H, 4.99; N, 8.96%.

Ethyl 2-(2-(4-chlorophenyl)hydrazono)-2,3,5,6-tetrahydro-8,9-dimethoxy-3-oxopyrrolo[2,1-a]isoquinoline-1-carboxylate 15Bd: Yellow crystals; mp 210-211 °C (dioxane); yield (79%); IR(KBr) ν1673 (C=O), 1701 (C=O) cm-1; 1H NMR (DMSO-d6) δ 1.43 (t, 3H, J = 7Hz, ester-CH3), 2.96 (m, 2H, isoquinoline-CH2), 3.83 (m, 2H, isoquinoline-CH2), 3.94 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 4.28 (q, 2H, J = 7Hz, ester-CH2), 6.71 (s, 1H, isoquinoline-CH), 7.23-7.30 (m, 4H, Ar H), 8.10 (s, 1H, Ar H), 13.12 (s, 1H, NH); MS: m/z 455 (M+, 46.2%), 389, 292, 172, 91. Anal. Calcd for C23H22N3O5Cl: C, 60.59; H, 4.86; N, 9.22. Found: C, 60.54; H, 5.16; N, 8.97%.

Ethyl 2,3,5,6-tetrahydro-8,9-dimethoxy-2-(2-(3-methylphenyl)hydrazono)-3-oxopyrrolo[2,1-a]isoquino- line-1-carboxylate 15Be: Orange crystals; mp175-177 °C (MeCN); yield (83%); IR (KBr) ν 1663 (C=O), 1692 (C=O) cm-1; 1H NMR (CDCl3) δ 1.42-1.49 (t, 3H, J = 7Hz, ester-CH3), 2.34 (s, 3H, CH3), 2.42 (m, 2H, isoquinoline-CH2), 3.80 (m, 2H, isoquinoline-CH2), 3.91 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 4.33 (q, 2H, J = 7Hz, ester-CH2), 6.69 (s, 1H, isoquinoline-CH), 6.80-7.24 (m, 4H, Ar H), 8.09 (s, 1H, Ar H),13.10 (s, 1H, NH); MS: m/z 435 (M+, 65.7%), 389, 334, 290, 200, 91. Anal. Calcd for C24H25N3O5: C, 66.19; H, 5.79; N, 9.65. Found: C, 66.42; H, 5.48; N, 9.49%.

Ethyl 2,3,5,6-tetrahydro-8,9-dimethoxy-2-(2-(4-methylphenyl)hydrazono)-3-oxopyrrolo[2,1-a]isoquinoline-1-carboxylate 15Bf: Red crystals; mp 198-200 °C (dioxane); yield (75%); IR (KBr) ν 1665 (C=O), 1685 (C=O) cm-1; 1H NMR (DMSO-d6) δ 1.41 (t, 3H, J = 7Hz, ester-CH3), 2.32 (s, 3H, CH3), 2.93 (m, 2H, isoquinoline-CH2), 3.80 (m, 2H, isoquinoline-CH2), 3.91 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.23 (q, 2H, J = 7Hz, ester-CH2), 6.69 (s, 1H, isoquinoline-CH), 7.12-7.27 (m, 4H, Ar H), 8.09 (s, 1H, Ar H), 13.16 (s, 1H, NH); MS: m/z 435 (M+, 54.3%), 389, 200, 91. Anal. Calcd for C24H25N3O5: C, 66.19; H, 5.79; N, 9.65. Found: C, 65.93; H, 5.69; N, 9.74%.

Ethyl 2,3,5,6-tetrahydro-8,9-dimethoxy-2-(2-(4-nitrophenyl)hydrazono)-3-oxopyrrolo[2,1-a]isoquinoline-1-carboxylate 15Bg: Dark red crystals; mp 229-230 °C (DMF); yield (74%); IR (KBr) ν 1680 (C=O) cm-1, 1H NMR (DMSO-d6) δ 1.32 (t, 3H, J = 7Hz, ester-CH3), 2.80-2.90 (m, 2H, isoquinoline-CH2), 3.65-3.74 (m, 2H, isoquinoline-CH2), 3.80 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.26 (q, 2H, J = 7Hz, ester-CH2), 6.58 (s, 1H, isoquinoline-CH), 7.16-7.25 (m, 2H, Ar H), 7.97(s, 1H, Ar H), 8.05-8.12 (m, 2H, Ar H), 13.04 (s, 1H, NH); 13C NMR (DMSO-d6) 16.5, 30.7, 38.4, 58.0, 58.2, 62.7, 102.4, 108.5, 112.7, 115.1, 115.7, 119.7, 127.8, 132.6, 135.2, 144.6, 145.8, 149.8, 149.9, 153.8, 161.0, 165.7. MS: m/z 466 (M+, 100.0%), 422, 361, 256, 127, 80. Anal. Calcd for C23H22N4O7: C, 59.22; H, 4.75; N, 12.01. Found: C, 59.51; H, 4.45; N, 11.84%.

3.5 X-Ray Structure Determination of Compounds 3Aa, 10Bf and 14Bd
The X-ray diffraction measurement was made on using maXus (Bruker Nonius, Delft & MacScience, Japan) at temperature 300 (2) K and wavelength 0.71073 Å; radiation: Mo Kα. Crystal data for compound 3Aa C27H27N3O4: unit cell parameters: 14.3017(4) Å, b = 14.6465 (6) Å, c = 14.8867 (9) Å, α = 79.152 (2)°, β = 62.653 (2)°, γ = 61.117 (4)°.
Crystal data for compound 10Bf C27H24N3O4SCl: a = 11.5763(4) Å, b = 16.6564 (6) Å, c = 14.1166 (5) Å, β = 111.297 (2) ° and crystal data for compound 14Bd C25H28N3O6Cl: a = 8.1648(2) Å, b = 16.8715 (5) Å, c = 19.2972 (9) Å, β = 105.52 (18) °, space group: P 21/c.
Crystallographic data for the structural analysis of compounds 14Bd, 10Bf and 3Aa has been deposited with the Cambridge Crystallographic Data Centre (CCDC) under the numbers 703102-703104 respectively. Copies of the information may be obtained free of charge from The Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44-01223-336033; e-mail: deposit@ccdc.cam.ac.uk or www:http://www.ccdc.cam.ac.uk).

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