HETEROCYCLES

Paper | Regular issue | Vol. 78, No. 2, 2009, pp. 337-345
Received, 6th July, 2008, Accepted, 19th September, 2008, Published online, 25th September, 2008.
DOI: 10.3987/COM-08-11481

■ Synthesis of Tetra- and Penta-heterocyclic Compounds Incorporated Isoquinoline Moiety

Tayseer A. Abdallah,* Hamdi M. Hassaneen, and Hayam A. Abdelhadi

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

Abstract

7-Amino-2,3-dimethoxy-9-phenyl-5,6,9,6a-tetrahydropyridino[2,1-a]isoquinoline-8,10-dicarbonitrile 5 was prepared via Michael addition reaction of benzylidenemalononitrile 2 with isoquinoline-1-carbonitrile 1. Reaction of 5 with triethyl orthoformate and formamide led to the formation of the corresponding 4-ethoxymethylene and 4-aminopyrimidine derivatives of benzo[a]quinolizines 6 and 7, respectively. Compound 6 reacted with hydrazine to give imino-amino compound 8. The latter compound reacted with formic acid, triethy1 orthoformate, acetic anhydride or benzoy1 chloride to give the triazolopyrimidine derivatives 9, 10 and 11, respectively. Compound 8 reacted with hydrazonoy1 halides 12, 13 and diethy1 oxalate to give triazinopyrimidine and triazolopyrimidine derivatives 16, 17 and 20, respectively.

INTRODUCTION
The considerable biological and medicinal activities of azoloazines have stimulated considerable interest in the synthesis and chemistry of these compounds.1-4 Although several examples of the azoloazines incorporated 1,2,4-triazole moiety have been reported in literature 1-4 there is no any example, to our knowledge, reported contains 1,2,4-triazole ring fused with pyrimidopyridoisoquinoline ring. In continuation of our previous work3-5, 7-10 on the use of isoquinoline derivatives for the synthesis of heterocyclic compounds we wish to report the synthesis of some triazolo[1,5-e]pyrimidine and triazino[2',3'-6,1]pyrimidine.

RESULTS AND DISCUSSION
Treatment of benzylidene malononitrile 2 with 6, 7-dimethoxy-3, 4-dihydroisoquinoline-1-carbonitrile 1 in boiling acetonitrile in the presence of piperidine afforded a single product as evidenced by TLC analysis. Structure 5 was assigned to the reaction product on the basis of elemental analyses and spectral data (MS, IR, 1H and 13C NMR), for example the 1H NMR spectrum of the product revealed signals at δ 4.2 (s, 2H, NH2) and 4.3 (s,1H) ppm assignable to proton of pyridine ring in addition to the signals of the dihydroisoquinoline moiety. Also the IR spectra showed two nitrile absorption bands at 2197 and 2185 in addition to bands at 3415 and 3336 cm-1 characteristic to the amino group. From the previous data, the product resulting from reaction of 2 with 1 was assigned 7-amino-2,3-dimethoxy-9-phenyl-5,6,9,6a-tetrahydropyridino[2,1-a]isoquinoline-8,10-dicarbonitrile 5. The product 5 was also prepared in one step by refluxing equimolar amounts of 1, benzaldehyde and malononitrile. The reaction started with Michael addition to give 3 which upon cyclization led to the formation of 5.

Reaction of 5 with triethyl orthoformate in acetic anhydride at reflux afforded the ethoxymethyleneamino derivative 6 in almost quantitative yield (Scheme 2). The 1H NMR spectrum of the product revealed characteristic signals for ethoxy group at δ 1.4 (t, J = 7 Hz, 3H) and 4.4 (q, J = 7Hz, 2H) as well as a signal at δ 7.9 ppm assignable to a proton of CHOEt. Also, the IR spectrum of 6 revealed the absence of the bands of the amino group. The above data together with the 13C NMR confirmed that the product assigned structure 6.
When compound 5 was refluxed with formamide it gave 7. The structure of the latter product was established on the basis of its alternative synthesis from 6 and methanolic ammonia (Scheme 2). Both IR and 1H NMR spectroscopic data of the product were consistent with its assigned structure 7.
Treatment of 6 with hydrazine hydrate in ethanol at room temperature gave 8. The structure of 8 was confirmed by its analytical and spectroscopic data and their chemical reactions outlined in schemes 2 and 3. Reaction of 8 with formic acid or triethyl orthoformate at reflux afforded 9. The formation of triazole ring involving both amino and imino groups was evidenced by the absence of their absorption bands in the IR spectrum of 9.

Also the 1H NMR spectrum of 9 revealed two characteristic signals at δ 8.3 (s,1H, triazolo-CH) and at δ 9.1 (s, 1H, pyrimidine-CH)ppm. Similarly, when compound 8 was refluxed in acetic anhydride or benzoyl chloride in pyridine, it afforded the corresponding 10-methyl and 10-phenyl derivatives 10 and 11 which were assigned on both elemental analyses and spectroscopic data. For example, the 1H NMR spectra of 10 and 11 revealed the absence of the proton in triazole ring at δ 8.3 appeared in compound 9; instead, it showed a singlet signal at δ 2.5 ppm assignable to a methyl group in 10.
The reaction of 8 with C-acylhydrazonoyl halides 12a,b in refluxing chloroform in the presence of triethylamine affordcd in cach case, a single product as evidenced by TLC analysis. The intermediates 15 were discarded on the basis of imino-nitrogen are more basic, and in turn more nucleophilic, than that of the amino group. The results of elemental analyses of the products were found to be consistent with 16A and its tautomeric structure 16B, furthermore, the electronic absorption spectra of the isolated products excludes the hydrazone structure 16A since they revealed a characteristic absorption maxima at λ 361 (log ε 4.43) and λ 400 (log ε 4.4) assignable to arylazo chromophore.13 Accordingly, the product obtained from the reaction of 8 with 12a,b was assigned structure 16Ba, 16Bb.

The latter structure was further evidenced by spectroscopic data, for example the 1H NMR spectrum of 16B showed that a signal of δ 9.1ppm corresponding to NH disappeared upon shaking the solution of 16Ba with deuterium oxide. The IR spectrum of 16Bb exhibited an NH absorption band at 3212 cm-1.
C-Ethoxycarbonylhydrazonoyl halide 13 reacted under similar rection condition with 8 to give compound 17 and the IR spectrum of 17 showed two bands at 3209 and 1636 cm-1 assignable to the hydrazone NH and amido carbony1 groups, respectively. Its UV spectrum in ethanol revealed two bands in the regions λmax250-300(log ε4.42) and λmax300-360(log ε 4.22) nm assignable to hydrazone chromophoure15 (Scheme 3). Refluxing of 8 with diethy1 oxalate afforded a single product whose elemental analysis and mass spectra were consistent with C28H24N6O4 formula (Scheme 4).

Thus, formula 22 was discarded for the isolated product. Two possible structures were assigned for the resulting product 20 or 21. The former was assigned to be the isolated product on the basis of its transformation to 9. Thus saponification of 20 gave 9 via decarboxylation of the resulting acid (Scheme 4). The structure of the product 20 was confirmed by it analytical and spectroscopic data.

EXPERIMENTAL
All melting points were determined on a Gallenkamp electrothermal apparatus and are uncorrected. IR spectra (KBr) were recorded on a Pye Unicam SP-300 IR spectrophotometer and Testscan Shimadzu FTIR 8000 series 1H NMR and 13C NMR spectra were recorded on a Varian Gemini 200 and Varian EM 390 spectrometers for solution in deuterated chloroform using TMS as internal standard. Mass spectra were recorded on a GCMS- QP 1000 Ex Shimadzu, Japan. Elemental analyses were carried out at the Micro analytical Centre of Cairo University. The hydrazonoyl halides 12a14, 12b15 and 1316 were prepared as previously described.

General procedure :
Synthesis of 7-amino-2,3-dimethoxy-9-phenyl-5,6,9,6a-tetrahydropyridino[2,1-a]isoquinoline-8,10-dicarbonitrile 5.
To a solution of benzylidene malononitrile 2 (0.77g, 5mmol) and 6,7-dimethoxy-3,4-dihydroisoquinoline-1-acetoniotrile 1 (1.15g, 5mmol) in acetonitrile (40 mL) was added 3-4 drops of piperidine at rt. The reaction mixture was refluxed for 3 h, 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 MeCN to give 5: mp 210 ºC (MeCN); 78% yield; IR (KBr): υ 3415, 3336 (NH2), 2197, 2185 (CN) cm-1; 1H NMR (CDCl3) δ 2.8 (m,2H), 3.4 (m ,1H), 3.8 (m, 1H), 3.8 (s, 3H), 3.9 (s, 3H), 4.2 (s, 2H), 4.3 (s,1H), 6.7(s,1H), 7.2-7.4 (m, 5H), 7.7 (s, 1H); 13C NMR (CDCl3): δ 41.1, 56.0 110.0, 110.6, 126.3, 127.7, 129.0 ( CH3 CH); 28.6, 41.9, 85.4, 120.4, 121.0, 129.2, 142.8, 145.4, 147.8, 151.1, 152.4, 167.2, 167.5 (CH2, C,CN); m/z 384. Anal. Calcd for C23H20N4O2: C, 71.84; H, 5.24; N, 14.58. Found: C, 72.06; H, 5.02; N, 14.33 %.
Synthesis of 2,3-dimethoxy-7-(N-ethoxymethylene)-9-phenyl-5,6,9,6atetrahydropyridino[2,1-a] isoquinoline -8,10-dicarbonitrile 6.
7-Amino-2,3-dimethoxy-9-phenyl-5,6,9,6a-tetrahydropyridino[2,1-a]isoquinoline-8,10-dicarbonitrile 5 (1.9g, 5 mmol) was dissolved in acetic anhydride (30 mL), to the resulting solution, triethyl orthoformate (0.74g, 5 mmol) was added and the mixture was refluxed for 5 h. The excess acetic anhydride was distilled off under reduced pressure and the solid that precipitated on cooling was filtered and crystallized from EtOH to give 6: mp 172 oC (EtOH); 86% yield; IR (KBr): υ 2198, 2183 (2CN), 1638 (N = CHOEt) cm-1; 1H NMR (CDCl3): δ 1.4 (t, J = 7 Hz, 3H), 2.8 (m, 2H), 3.5 (m, 1H), 3.7 (m, 1H), 3.8 (s, 6H), 4.4 (q, J = 7 Hz, 2H), 4.5 (s, 1H), 6.6 (s, 1H) , 7.1- 7.3 (m, 5H), 7.8 (s, 1H), 7.9 (s, 1H); 13C NMR (CDCl3): δ 13.8, 42.5, 56.1, 56.2, 110.4, 111.3, 127.4, 128.1, 129.3, 153.7 (CH3, CH); 27.0, 42.4, 64.4, 72.1, 81.9, 119.6, 120.1, 121.5, 131.0, 143.2, 145.6, 147.7, 151.4, 153.7, (CH2, C, CN); m/z 440. Anal. Calcd for C26H24N4O3: C, 70.87; H, 5.49; N, 12.72. Found: C, 70.72; H, 5.36; N, 12.48 %.
Synthesis of 4-amino-8,9-dimethoxy-5-phenyl-5,11,12,12a-tetrahydroisoquinolino[2',1'-6,1] pyridine
[2,3-d] pyrimidine-6-carbonitrile 7.
Method A: A mixture of 5 (1.9g, 5 mmol) and formamide (10 mL) was refluxed for 3 h. The reaction mixture was cooled and added to cold water with stirring. The solid formed was collected and crystallized from DMF to give 7: mp 225 oC (DMF); 83% yield; IR (KBr): υ 3500, 3300 (NH2), 2198 (CN) cm-1; Anal. Calcd for C24H21N5O2: C, 70.04; H, 5.14; N, 17.03. Found: C, 70.36; H, 4.81; N, 17.25 %.
Method B: A compound 6 (2.2 g, 5 mmol) was treated with methanolic ammonia (10 mL) at rt for 6 h. The solid that separated was collected and crystallized from DMF to give a compound which identical in all respects (mp, mixed mp, IR) with that compound prepared by method A .
Synthesis of 3-amino-8,9-dimethoxy-4-imino-5-phenyl-5,11,12,12a-tetrahydroisoquinolino[2',1'-6,1]pyridine[2,3-d] pyrimidine-6-carbonitrile 8.
A mixture of 6 (2.2 g, 5 mmol) and hydrazine hydrate (5 mL) was stirred for 4 h in EtOH (20 mL) at rt. The solid that separated was filtered and crystallized from AcOH to give product 8: mp 199 oC (AcOH); 63% yield; IR (KBr): υ 3311, 3142, 3060 (NH, NH2), 2181 (CN) cm-1; 1H NMR (CDCl3): δ 2.8 (m, 2H), 3.7 (m, 1H), 3.8 (s, 3H), 3.9 (s, 3H), 4.5 (m, 1H), 4.6 (s,1H), 4.8 (s, 2H), 5.9 (s, 1H), 6.7 (s, 1H), 7.2-7.3 (m, 5H), 7.8 (s,1H), 8.0 (s, 1H); 13C NMR (DMSO): 55.5, 55.6, 120.9, 122.0, 126.0, 127.1, 127.3, 128.4, 131.6, 149.5, 150.6, (CH3, CH); 28.4, 79.9, 97.1, 110.8, 110.9, 119.3, 143.9, 145.6, 146.2, 146.5, 154.0(CH2, C, CN); m/z 426. Anal. Calcd for C24H22N6O2: C, 67.57; H, 5.20; N, 19.71. Found: C, 67.81; H, 5.43; N, 19.94 %.
Synthesis of 4,5-dimethoxy-8-phenyl-1,2,8,11a,13b-pentahydroisoquinoline[2',1'-6,11]pyridino[2,3-d]1,2,4-triazolo[1,5-e]pyrimidine-7-carbonitrile 9.
A solution of compound 8 (2.1g, 5 mmol) in formic acid or triethyl othoformate (5 mL) was refluxed for 5 h. The reaction mixture was cooled and the solid that precipitated was collected and crystallized from EtOH to give product 9: mp 233 °C (EtOH); 66% yield; IR (KBr): υ 2183 (CN) cm-1; 1H NMR (CDC13): δ 3.0 (m, 2H), 3.9 (s, 3H), 4.0 (s, 3H), 4.1 (m, 1H), 4.5 (m, 1H), 5.5 (s, 1H), 6.8 (s, 1H), 7.2-7.5 (m, 5H), 7.9 (s, 1H), 8.3 (s, 1H), 9.1 (s, 1H). Anal. Calcd for C25H20N6O2: C, 68.77; H, 4.62; N, 19.26. Found: C, 68.52; H, 4.43; N, 19.50%.
Synthesis of 4,5-dimethoxy-10-methyl-8-phenyl-1,2,8,11a,13b-pentahydroisoquinoline[2',1'-6,1] pyridino[2,3-d]1,2,4-triazolo[1,5-e]pyrimidine-7-carbonitrile 10.
A solution of 8 (2.1g, 5 mmol) in acetic anhydride (20 mL) was refluxed for 3 h. The mixture was cooled and the solid that separated was collected and crystallized from AcOH to give product 10: mp 246 °C (AcOH); 67% yield; IR (KBr): υ 2185 (CN) cm-1; 1H NMR (CDC13): δ 2.5 (s, 3H), 2.9 (m, 2H), 3.9 (m, 1H), 3.9 (s, 3H), 4.0 (s, 3H), 4.4 (m, 1H), 5.4 (s, 1H), 6.7 (s, 1H), 7.2-7.5 (m, 5H), 7.8 (s, 1H), 8.9 (s, 1H); 13C NMR (DMSO): 14.2, 55.6, 55.7, 121.5, 121.8, 127.4, 128.8, 129.0, 131.6, 131.9, 146.6, 150.8, (CH3, CH); 28.2, 79.8, 99.2, 110.9, 119.1, 138.9, 143.0, 144.9, 146.2, 151.1, 151.7, 166.1(CH2, C, CN); m/z 450. Anal. Calcd for C26H22N6O2: C, 69.30; H, 4.92; N, 18.66. Found: C, 69.46; H, 4.75; N, 18.48 %.
Synthesis of 4,5-dimethoxy-8,10-phenyl-1,2,8,11a,13b-pentahydroisoquinoline[2',1'-6,l]pyridino[2,3-d]1,2,4-triazolo[1,5-e]pyrimidine-7-carbonitrile 11.
To a solution of 8 (2.1 g, 5 mmol) in pyridine (10 mL) benzoyl chloride (0.7 mL, 5 mmol) was added. The mixture was refluxed for 4 h, then cooled and poured into cooled hydrochloric acid (10%) with stirring. The solid that precipitated was collected, washed with cold water and finally crystallized from DMF to give product 11: mp 276 °C (DMF); 65% yield; IR (KBr): υ 2186 (CN) cm-1; 1H NMR (CDC13): δ 3.0 (m, 2H), 3.9 (s, 3H), 4.0 (s, 3H), 4.1 (m, 1H), 4.5 (m, 1H), 5.6 (s, 1H), 6.8 (s,1H), 7.3 (s, 1H), 7.2-8.8 (m, 10H), 9.1 (s, 1H); m/z 512. Anal. Calcd for C31H24N6O2: C, 72.62; H, 4.72; N, 16.40. Found: C, 72.40; H, 4.51; N, 16.17 %.
Synthesis of 11,12-dimethoxy-2-phenylazo-14-phenyl-8,14,4a-trihydro-4H-benzo[a] 1,2,4-triazino[2',3'-6,1]pyrimidine[4,5-f]quinolizine-13-carbonitrile 16 and 17 ( general procedure ).
To a hot solution of 8 (2.1g, 5 mmol) and the appropriate hydrazonoyl halide (5 mmol) in CHCl3 (30 mL) was added triethylamine (0.7 mL, 5 mmol). The reaction mixture was refluxed for 18 h, and then the solvent was evaporated under reduced pressure. The crude product was collected and crystallized from DMF to give the products 16 and 17.
11,12-dimethoxy-2-phenylazo-3-methyl-14-phenyl-8,14a,4a-trihydro-4H-benzo-[a]1,2,4-triazino[2',3'-6,1] pyrimidine[4,5-f]quinolizine-13-cabonitrile 16Ba.
mp 297°C (DMF); 61% yield; IR (KBr): υ 3212 (NH), 2187 (CN) cm-1; 1H NMR (DMSO-d6): δ 2.1 (s, 3H), 3.0 (m,2H), 3.7 (s, 3H), 3.8 (s, 3H), 4.0 (m, 1H ) , 4.3 (m, 1H), 5.2 (s,1H), 6.8 (s,1H), 7.1 (s,1H), 7.2-7.8 (m, 9H), 8.3 (s,1H), 8.5 (s, 1H), 9.1 (s, 1H, NH); m/z 568. Anal. Calcd for C33H28N8O2: C, 69.68; H, 4.96; N, 19.71. Found: C, 69.91; H, 4.83; N, 19.54 %.
11,12-dimethoxy-3,14-diphenyl-2-phenylazo-8,14a,4a-trihydro-4H-benzo[a]1,2,4-triazino[2,3-6,1]- pyrimidine[4,5-f]quinolizine-13-carbonitrile 16 Bb.
mp 250 °C (DMF); 65% yield; IR (KBr): υ 3213 (NH), 2189 (CN) cm-1; m/z 630. Anal. Calcd for C38H30N8O2: C, 72.34; H, 4.79; N, 17.77. Found: C, 72.15; H, 4.63; N, 18.06 %.
11,12-dimethoxy-3-oxo-11,12-dimethoxy-2-phenylhydrazo-14-phenyl-8,14,4a-trihydro-2H,4H-benzo-[a]1,2,4-triazino[2',3'-6,1]pyrimidine[4,5-f]quinolizine-13- carbonitrile 17.
mp 190 °C (DMF); 64% yield; IR (KBr): υ 3309, 3209 (2NH), 2190 (CN); 1636 (CO) cm-1; 1H NMR (CDC13): δ 3.7 (m, 1H), 3.8 (s, 3H), 3.9 (s, 3H ), 4.0 (m, 2H), 4.4 (m, 1H), 5.1 (s, 1H), 6.6-8.2 (m, 15H); m/z 570. Anal. Calcd for C32H26N8O3: C, 67.33; H, 4.59; N, 19.64. Found: C, 67.54; H, 4.30; N, 19.44 %.
Synthesis of ethyl 7-cyano-4,5-dimethoxy-8-phenyl-1,2,8,11a,13b-pentahydroisoquinoline[2',1'-6,1]- pyridino[2,3-d]1,2,4-triazolo[1,5-e]pyrimidine-10-carboxylate 20.
To a solution of 8 (2.1 g, 5 mmol) in EtOH (30 mL), diethyl oxalate (0.73 g, 5 mmol) was added. The reaction mixture was refluxed for 3 h, then cooled and the product that separated was coolected and crystallized from DMF to give product 20: mp 235 °C (DMF); 60% yield; IR (KBr): υ 2195 (CN), 1715 (CO) cm-1; 1H NMR (CDC13): δ 1.4 (t, J = 7 Hz, 3H), 3.0 (m, 2H), 3.9 (s, 6H, 2CH3), 4.1 (m, 1H), 4.4 (m, 1H ) 4.5 (q, J = 7 Hz, 2H), 5.6 (s, 1H), 6.8 (s,1H), 7.2-7.5 (m, 5H),7.9 (s, 1H), 9.2 (s, 1H); m/z 508. Anal. Calcd for C28H24N6O4: C, 66.11; H, 4.75; N, 16.53. Found: C, 66.35; H, 4.97; N, 16.32 %.

References

1. M. H. Elnagdi, N. Al Awdi, and A. W. Erian, Comprehensive Heterocyclic Chem. II, 1990, A. R. Katrizky and C. W. Rees, Eserier, Amsterdam, 7,431.
2. J. Quiroga, B. Insuasty, A. Hormoza, D. Gamerara, and L. Dominguez, J. Heterocycl. Chem., 1999, 36, 11. CrossRef
3. N. M. Elwan, H. A. Abdelhadi, T. A. Abdallah, and H. M. Hassaneen, Tetrahedron, 1996, 52, 3451. CrossRef
4. H. M. Hassaneen, H. A. Abdelhadi, and T. A. Abdallah, Tetrahedron, 2001, 57, 10133. CrossRef
5. H. A. Abdelhadi, N. M. Elwan, T. A. Abdallah, and H. M. Hassaneen, J. Chem. Res. (S), 1996, 292.
6. H. A. Abdelhadi, T. A. Abdallah, and H. M. Hassaneen, Heterocycles, 1995, 41, 1999. CrossRef
7. T. A. Abdallah, Synth. Commun., 2002, 32, 2459. CrossRef
8. T. A. Abdallah, H. A. Abdelhadi, A. A. Ibrahim, and H. M. Hassaneen, Synth. Commun., 2002, 32, 581. CrossRef
9. T. A. Abdallah and K. M. Dawood, Tetrahedron, 2008, 64, 7890. CrossRef
10. T. A. Abdallah, Heterocycles, 2008, 75, 2779. CrossRef
11. Ostling Ofversikt Finska Vetenskaps Soc For handl, 1915, 57A, No 11, 1 (Chem. Abstr., 1921, 15, 2829.
12. H. T. Openshaw and N. Whittaker, J. Chem. Soc., 1961, 4939. CrossRef
13. (a) A. Buraway, A. G. Salem, and A. R. Thompson, J. Chem. Soc., 1952, 4793; CrossRef (b) H. C. Yao, J. Org. Chem., 1964, 29, 2959; CrossRef (c) H. C. Yao and R. Resnick, J. Am. Chem. Soc., 1962, 84, 3514; CrossRef (d) A. S. Shawali, M. I. Ali, M. M. Naoum, and A. l. Elansari, Tetrahedron, 1972, 29, 3805. CrossRef
14. N. F. Eweiss and A. O. Abdelhamid, J. Heterocycl. Chem., 1980, 17, 1713. CrossRef
15. A. S. Shawali and A. O. Abdelhamid, Bull. Chem. Soc. Japan, 1976, 49, 321. CrossRef
16. A. S. Shawali, N. F. Eweiss, H. M. Hassaneen, and M. Sami, Bull. Chem. Soc. Japan, 1975, 48, 365. CrossRef