Acta Chim. Slov. 2003, 50, 15-28. 15 SOME NUCLEOPHILIC CYCLIZATION REACTIONS WITH 3-[4-(BENZO[l,3]DIOXOLYLMETHYLENE)PYRAZOLYL]QUINOLONE Elham S. Othman Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, Cairo 11711, Egypt.*< E-mail: quinolinone@yahoo.com fPresent address: Department of Chemistry, Faculty of Education for Girls, Abha P.O. Box 142, Saudi Arabia Kingdom. Received J 9-03-2002 Abstract Cyclization of 3 -[4-(Benzo[1,3]dioxolylmethylene)-5-oxo-3-pyrazolyl] -4-hydroxy-1-methyl-quinolin-2(l//)-one with certain bifunctional nucleophilic reagents is described. The cyclization reactions led to the formation of many biologically interesting fused heterocyclic systems derived from pyrazolinone and bearing quinolinone moiety e.g. pyrazolopyrazole, isoxazolopyrazole, pyrazolopyrimidine, pyrazolothiazine, pyrazolopyridine, dipyrazolo-pyridine, dipyrazolopyran and many pyrazolopyran derivatives. The stractures of aH the new products were checked with analytical and spectral methods. Introduction Pyrazole derivatives have attracted particular interests during the last twenty-five years due to use of such ring system as the core structure in many drug substances, covering wide range of pharmacological applications.1_6 Recently an important natural mediator of inflammation Leucettamine B was isolated and since then attempts to synthesis this compound and its analogues were continued.7 We found that Leucettamine B is of near structure to a pyrazolinone derivative that described in ours previous work.8 O CH3 NX N 3 O ~0 O H3C OH N NH b o Leucettamine B 2 This encouraged us to use the titled pyrazolylquinolinone to obtain other new heteropolycyclic derivatives including both quinolinone and pyrazole moieties in one Elham S. Othman: Some Nucleophilic Cyclization Reactions JVith 3-[4-(Benzo[l,3]dioxolylmethylene)... 16 Acta Chim. Slov. 2003, 50, 15-28. molecular frame. These novel heterocyclic systems are expected to sustain interesting biological activities. Herein we go for derivation of an arylidenepyrazolinone utilizing the well-known Mc/wre/ addition reaction with certain N, O, S and C-nucleophiles.9 Results and discussion Recently we have described the synthesis of 3-[4-(Benzo[l,3]dioxolylmethylene)-5-oxo-3-pyrazolyl]-4-hydroxy-l-methylquinolin-2(l#)-one (2) from Knoevenagel condensation of the active methylene pyrazolinone 1 with piperonaldehyde in the presence of freshly fused sodium acetate in glacial acetic acid.8 Addition-condensation cyclization of the compound 2 with hydrazine hydrate and/or hydroxylamine hydrochloride, involving exo-cyclic enone grouping, led to the formation of the fused five-membered rings pyrazolopyrazole 3 and pyrazoloisoxazole 4, respectively. On the other hand six-membered heterocyclo-pyrazoles were achieved via similar addition-condensation cyclization reactions with different 1,3-bidentate nucleophiles. Thus, treatment of compound 2 with guanidine hydrochloride gave the pyrazolopyrimidine 5, which its lH NMR spectrum (DMSO) revealed the presence of five broad signals at 5: 8.85, 9.70, 11.90, 12.46 and 14.20 ppm, disappear on deutration, indicating that this compound assumes iminotetrahydropyrimidine form. Also IR spectrum of this compound showed the same structural phenomenon, as there is no indication for specific absorption vibrations of amino group, instead broad absorption band centered at v: 3246 cm"1 is observed due to different N-H groups. Reaction of the compound 2 with thioacetamide, in the presence of piperidine as catalyst, afforded pyrazolothiazine 6. The 'H NMR spectrum of the product 6 represents two methyl singlets at 5: 2.21 and 3.68 ppm, due to 6-methylpyrazolothiazine and N-methylquinolinone, respectively. These results along with IR spectrum and elemental data emphasis that an addition of S-thioacetamide to the methylene of enone moiety took plače and followed by condensation of the amino group with the oxo-pyrazoline. The reactivity of compound 2 towards Michael reaction with some C-nucleophiles was investigated when its reaction with certain active methylene compounds was carried out in the presences of suitable basic catalyst. It is well known that Michael addition reactions of activated alkenes with Elham S. Othman: Some Nucleophilic Cyclization Reactions JVith 3-[4-(Benzo[l,3]dioxolylmethylene)... Acta Chim. Slov. 2003, 50, 15-28. 17 Scheme 1 o o CH, a AcONa AcOH O O O- N2H4.H20 dioxane NH2OH.HCl DMF NH A, DMF/piperidine S A DMF/piperidine NC^. 'NH H OH N"N\ H ' " ^N -NH O - H oh i\rN\ H 1 " ^y -o OH N^\ H ' " /^ P A O- / 4 H -N y= NH VN ^Or ,- CH // O H OH N^N\ 11 A— CH O o-^y H OH N^N\ H " )-\ O CN DMF/piperidine o^y 7 C-nucleophiles lead to the formation of (C-C) extra bond at the position of addition; hence to affect a consequent cyclization it is worthwhile to use the proper reagent of 1 CHO O O 5 6 O Elham S. Othman: Some Nucleophilic Cyclization Reactions JVith 3-[4-(Benzo[l,3]dioxolylmethylene)... 18 Acta Chim. Slov. 2003, 50, 15-28. general formula (X-CH2-Y). These selected reagents must contain appropriate X and Y groups which are capable for a further intramolecular reaction with the tautomeric (NH-C=O^N=C-OH) of the pyrazoline moiety. The reaction of compound 2 with cyanacetamide was considered and the product was characterized as pyrazolopyridone 7 (Scheme 1). The presence of the specific absorption peak of (C=N) group, at v: 2220 cm"1 in its IR spectrum besides broad band at v: 3227 cm"1 due to (N-H) and two carbonyl absorption vibrations at 1665 and 1645 cm"1 due to both pyridone and quinolinone moieties, respectively, suggested that an addition reaction occurred at first followed by intramolecular condensation of the enolized pyrazolinone (C=0) with the acetamide (NH2) group. Scheme 2 O .NH N-N H H DMF/piperidine 3 ( J O 8 O^ O o- NC> .CONHNH H OH N"\ TT N O CH I ° o-^y O N-N H H DMF/piperidine CN NH 10 O-^V O Surprisingly, it was found that reaction of compound 2 with cyanoaceto-hydrazide does not lead to the expected pyrazolinopyrazole 9 but instead the dipyrazolopyridine 8 had been obtained. The structure of compound 8 was established on basis of its spectral and analytical data, in which there is no evidence for (N=C-CH2-CO) grouping in both 9 Elham S. Othman: Some Nucleophilic Cyclization Reactions JVith 3-[4-(Benzo[l,3]dioxolylmethylene)... Acta Chim. Slov. 2003, 50, 15-28. 19 *H NMR and IR spectra. This leads to a hypothetical suggestion that firstly cyanoacetohydrazide might be cyclized, giving 3-imino-5-oxopyrazolidine, which consequentially reacts with compound 2. This proposition was verified when the commercially available 3-imino-5-oxopyrazolidine was reacted with compound 2 at the same conditions to give the same product 8 This is in conformity to findings cited for similar reactions in the literature.10 Similarly, reaction of compound 2 with pyrazolidene-3,5-dione gave the dipyrazolopyranone 10. Structure of the latter product was elucidated upon basis of its spectral and analytical results. Thus, lH NMR spectrum revealed a set of four deuterium exchangeable protons confirming the presence of three different pyrazole/pyrazoline (N-H) groups in addition to the (O-H) group. This is coincident with the outputs of reading IR chart for compound 10, which showed two absorption vibrational bands due to stretching of (C=0) at v: 1668 and 1630 cm"1 of both pyrazolinone and quinolinone carbonyls (Scheme 2). Reaction of some cycloalkanones namely; cyclopentanone, cyclohexanone and tetralone with compound 2, in dioxane in the presence of piperidine as catalyst, furnished the polycyclic systems: cyclopentano[5,6]pyranopyrazole 11, chromeno-pyrazole 12 and pyrazolobenzo[h]chromene 13, respectively (Scheme 3). The lH NMR spectra of the pyranopyrazoles 11 and 12 revealed multiplets in the range of 5: 1.4-2.25 ppm due to (CH2)n cyclic chain protons. Also, the multi-functional pyranopyrazoles 14, 16, 17 and 19 were prepared via similar cyclization process used here above replacing these cyclic ketones with certain acyclic active methylene compounds, which always leads to 5,6-disubstiuted pyranopyrazoles. Thus, the reaction of compound 2 with acetylacetone yielded 5-acetyl-6-methylpyranopyrazole 14, while addition-condensation reaction of compound 2 with p-ketoesters; ethyl acetoacetate and/or ethyl 3-(4-hydroxy-l-methyl-2-ox-l,2-dihydroquinolin-3-yl)-3-oxopropanoate (15) gave the ethyl 6-methyl-3-quinolinyl-pyranopyrazole-5-carboxylates 16a and ethyl 3,6-di(quinolinyl)-pyranopyrazole-5-carboxylates 16b, respectively (Scheme 3). IR spectra of these esters evidently revealed the characteristic carbonyl absorption vibrational bands due to carboxylate groups. Also, lH NMR spectra of the esters 16a,b obviously showed the presence of an ethyl group set of protons for each of them. These results arose the conclusion that without any doubt Elham S. Othman: Some Nucleophilic Cyclization Reactions JVith 3-[4-(Benzo[l,3]dioxolylmethylene)... 20 Acta Chim. Slov. 2003, 50, 15-28. Scheme 3 /r-NH2 CH3 fi ^ 19 O-^V a O 18 DMF piperidine CH dioxane/piperidine O dioxane/piperidine dioxane/piperidine O O H3C CH dioxane/piperidine dioxane/piperidine R = CH OH NO CH3 NC^_/C02R dioxane/piperidine a b R = H O 12 O 13 O^ 7 />—CH, v T "°/rAs Vch3 CH // lo^ b 14 CO C H O 16a,b | >^o ^ x°(r\ co?R O 17a,b O^ O O O NC CO C H R 2a"l R O b a O 1 C2H5 Elham S. Othman: Some Nucleophilic Cyclization Reactions JVith 3-[4-(Benzo[l,3]dioxolylmethylene)... Acta Chim. Slov. 2003, 50, 15-28. 21 carboxylate group is not involved in the intramolecular condensation reaction but the keto-group does. Treatment of compound 2 with cyanoacetic acid and/or ethyl cyanoacetate, under the same conditions, resulted in the amino-carboxylic acid 17a and amino-ester 17b, respectively (Scheme 3). Apparently, the latter cyclization process proceeds through two addition steps; the first one is intermolecular addition of the active methylene to the enone (C=C) moiety in compound 2, the second step is intramolecular addition of enolic (OH) to a nitrile group. This asserted the non-existence of condensation reaction between either carboxylic or ester groups. Othenvise we have to expect presence of characteristic band due to (C=N) group in IR spectra of such products. This probability was perfectly excluded, as the spectra of both derivatives 17a and 17b do not show this ?(C=N) and instead characteristic ?(NH2) appear at 3420 and 3310 cm"1, in addition to ?(C=0) at 1705 cm"1 of the acid 17a and ?(C=0) at 1730 cm"1 of the ester 17b. Malononitrile was reacted with compound 2 to give the 6-amino-pyranopyrazole-5-carbonitrile 19. Here again two addition steps take plače to afford such cyclization product. Alternatively, piperonalidene-malononitrile 18 was reacted with pyrazolinone 1 under the same conditions cited here before and the product of this reaction was identified identical in every respect to the latterly obtained compound 19. This confirms what we have discussed herein about the two-step addition cyclization reaction and highlights that C-C bond formation via Michael addition is previously to cyclization involving intramolecular addition of (OH) to a nitrile group. Conclusions Reaction of arylidenepyrazolinone with certain nucleophilic reagents under Michael reaction conditions leads to formation of different multi-functional polycyclic derivatives of pyrazole. In general the cyclic active methylene compounds give linear polycyclic compounds while acyclic active methylene nitriles give substituted pyranopyrazoles. Addition-cyclization takes plače in preference faster than its competitive condensation reaction whenever it is possible. Elham S. Othman: Some Nucleophilic Cyclization Reactions JVith 3-[4-(Benzo[l,3]dioxolylmethylene)... 22 Acta Chim. Slov. 2003, 50, 15-28. Experimental Melting points are uncorrected and were determined in open capillary tubes on a digital Gallen-Kamp MFB-595. IR spectra were taken on a Perkin-Elmer FT-IR 1650 spectrophotometer (v, cm"1), using samples in KBr disks. lH NMR spectra were recorded on a Bruker AC200 (200 MHz) spectrometer (5, ppm), using DMSO-J6 as solvent and TMS as internal standard. 3-[4-(Benzo[l,3]dioxol-5-yl)-l,4,5,6-tetrahydropyrazolo[3,4-c]pyrazol-3-yl]-4-hydroxy-l-methylquinolin-2(lH)-one (3). A mixture of compound 2 (3.89 g, 0.01 mol) and hydrazine hydrate (0.5 mL, 0.01 mol), in dioxane (50 mL), was heated under reflux for 4h. The solid deposits so formed during the course of the reaction were filtered off, washed with ethanol (10 mL) and crystallized from DMF to give yellow crystals of the product 3 (2.66 g, 66%), m.p. 270-2 °C. Anal. Calculated for C2iH17N504 (403.40): C, 62.53; H, 4.25; N, 17.36. Found: C, 62.70; H, 4.00; N, 17.10. IR, v: 3240, 3220-3180 (N-H, O-H), 1628 (C=0), 1600 (C=N), 1581, 1504, 1450, 1396, 1230, and 1119. 'H NMR, 5: 3.66 (s, 3H, N-CH3), 5.53 (s, 1H, C4-Hpyrazoline), 5.95 (s, 2H, O-CH2-0), 6.63 (br s, 1H, N-H), 7.25-8.12 (m, 7H, Harom), 10.30 (br s, 1H, N-H), 10.43 (br s, 1H, N-Hpyrazoie) and 14.02 (br s, 1H, O-H). 3-[3-(Benzo[l,3]dioxol-5-yl)-3,6-dihydropyrazolo[3,4-c]isoxazol-4-yl]-4-hydroxy-l-methylquinolin-2(lH)-one (4). A mixture of equimolar amounts (0.01 mol) of compound 2 (3.89 g) and hydroxylamine hydrochloride (0.7 g), in DMF (30 mL), was treated with triethylamine (0.1 mL) and heated under reflux for 3h. The yellow crystals so separated on cooling were collected by filtration and recrystallized from DMF affording the product 4 (2.38 g, 59%), m.p. 267-8 °C. Anal. Calculated for C2iHi6N405 (404.39): C, 62.37; H, 3.99; N, 13.85. Found: C, 62.20; H, 3.80; N, 13.80. IR, v: 3240-3120 (N-H, O-H), 1650 (C=0), 1610 (C=N), 1590, 1505, 1442, 1157 and 1103. lH NMR, 5: 3.64 (s, 3H, N-CH3), 5.96 (s, 2H, 0-CH2-0), 6.43 (s, 1H, C3-Hisoxazoiine), 7.15-8.10 (m, 7H, H^), 9.55 (br s, 1H, N-H), 11.25 (br s, 1H, N-Hpyrazoie) and 14.12 (br s, 1H, O-H). Elham S. Othman: Some Nucleophilic Cyclization Reactions JVith 3-[4-(Benzo[l,3]dioxolylmethylene)... Acta Chim. Slov. 2003, 50, 15-28. 23 3-[4-(Benzo[l,3]dioxol-5-yl)-6-imino-4,5,6,7-tetrahydropyrazolo[3,4-d|-pyri-midin-3-yl]-4-hydroxy-l-methylquinolin-2(lH)-one (5). A mixture of compound 2 (3.89 g, 0.01 mol), guanidine hydrochloride (0.97 g, 0.01 mol) and piperidine (0.1 mL), in DMF (30 mL), was heated under reflux for 3h. The mixture was left to cool at room temperature, poured onto cold water and then acidified with few drops of dilute hydrochloric acid. The solid precipitate so obtained was filtered off, washed with ethanol (20 mL) and crystallized from DMF-water (3:1) to give pale brown crystals of the product 5 (2.49 g, 58%), m.p. >300 °C. Anal. Calculated for C22Hi8N604 (430.43): C, 61.39; H, 4.22; N, 19.52. Found: C, 61.60; H, 4.10; N, 19.40. IR, v: 3246-3164 (N-H, O-H), 1648 (C=0), 1622 (C=N), 1584, 1509, 1459 and 1120. 'H NMR, 5: 3.68 (s, 3H, N-CH3), 6.09 (s, 2H, 0-CH2-0), 6.15 (s, 1H, C4-Hpyrimidine), 7.05-8.11 (m, 7H, Harom), 8.85 (br s, 1H, N-Himino), 9.70 (br s, 1H, N-Hpyrimidine), 10.90 (br s, 1H, N-Hpyrimidine), 11.38 (br s, 1H, N-Hpyrazoie) and 14.25 (br s, 1H, O-H). 3-[4-(Benzo[l,3]dioxol-5-yl)-6-methyl-l,2-dihydropyrazolo[3,4-d|[l,3]thiazin-3-yl]-4-hydroxy-l-methylquinolin-2(lH)-one (6). To a mixture of compound 2 (3 89 g, 0.01 mol), thioacetamide (0.75 g, 0.01 mol), in DMF (30 mL), piperidine (0.1 mL) was added and the mixture was heated under reflux for 4h. Aftenvards the reaction mixture was left to cool acidified with few drops of dilute acetic acid to give a yellowish-brown precipitate. The solid precipitate was collected by filtration and crystallized from DMF-water (4:1) to give the product 6 (3.26 g, 73%), m.p. >300 °C. Anal. Calculated for C23Hi8N404S (446.49): C, 61.87; H, 4.06; S, 7.18. Found: C, 61.80; H, 3.80; S, 6.90. IR, v: 3247-3173 (N-H, O-H), 1647 (C=0), 1620 (C=N), 1585, 1508, 1455, 1241 and 1110. 'H NMR, 5: 2.21 (s, 3H, CH3), 3.64 (s, 3H, N-CH3), 5.15 (s, 1H, Hthiazine), 5.90 (s, 2H, 0-CH2-0), 7.15-8.12 (m, 7H, Harom), 10.97 (br s, 1H, N-Hpyrazoie) and 14.35 (br s, 1H, O-H). 4-(Benzo[l,3]dioxol-5-yl)-3-(4-hydroxy-l-methyl-2-oxo-l,2-dihydroquinolin-3-yl)-6-oxo-4,5,6,7-tetrahydropyrazolo[3,4-b]pyridine-5-carbonitrile (7). To a solution of compound 2 (3.89 g, 0.01 mol), in DMF (50 mL), cyanoacetamide (0.85 g, 0.01 mol) Elham S. Othman: Some Nucleophilic Cyclization Reactions JVith 3-[4-(Benzo[l,3]dioxolylmethylene)... 24 Acta Chim. Slov. 2003, 50, 15-28. and piperidine (0.1 mL) were added and the mixture was heated under reflux for 4h. Then the reaction mixture was cooled acidified with dilute acetic acid till precipitation. The solid precipitate was filtered off and crystallized from DMF to give the nitrile 7 (3.05 g, 67%), m.p. >300 °C. Anal. Calculated for C24Hi7N505 (455.43): C, 63.30; H, 3.76; N, 15.38. Found: C, 63.10; H, 3.60; N, 15.20. IR, v: 3227-3192 (N-H, O-H), 2220 (ON), 1665 (C=Opyrido„e), 1645 (C=Oquinoio„e), 1620 (C=N), 1583, 1505, 1449 and 1120. 'H NMR, 5: 3.58 (s, 3H, N-CH3), 4.14 (d, 1H, C3-Hpyridone), 4.88 (d, 1H, C4-Hpyridone), 5.95 (s, 2H, 0-CH2-0), 7.16-8.05 (m, 7H, Harom), 10.46 (br s, 1H, N-Hpyrazoie), 10.92 (br s, 1H, N-Hpyridone) and 13.97 (br s, 1H, O-H). 4-(Benzo[l,3]dioxol-5-yl)-5-(4-hydroxy-l-methyl-2-oxo-l,2-dihydroquinolin-3-yl)-l,4,7,8-tetrahydro-2i/-dipyrazolo[3,4-6; 4 ,3-e]pyridin-3-one (8). Procedure A. Using the same method for preparation of compound 7, compound 2 (3.89 g, 0.01 mol) was reacted with cyanoacetohydrazide (1 g, 0.01 mol) and piperidine (0.1 mL), in boiling DMF (50 mL) and worked up as above. The product was crystallized from DMF to result in dipyrazolopyridone 8 (3.48 g, 74%), m.p. >300 °C. Anal. Calculated for C24Hi8N605 (470.45): C, 61.28; H, 3.86; N, 17.86. Found: C, 61.10; H, 3.80; N, 17.60. IR, v: 3241-3196 (N-H, O-H), 1670 (C=Opyrazoiinone), 1635 (C=Oquinoione), 1612 (C=N), 1600, 1585, 1508, 1435 and 1120. *H NMR, 5: 3.65 (s, 3H, N-CH3), 3.86 (s, 1H, C4-Hpyridine), 6.10 (s, 2H, 0-CH2-0), 7.20-8.12 (m, 7H, H^), 8.85 (br s, 1H, N-Hpyridine), 9.28 (br d, 1H, N-Hpyrazoione), 10.80 (br s, 1H, N-Hpyrazoie), 11.60 (br d, 1H, N-Hpyrazoione) and 14.14 (br s, 1H, O-H). Procedure B. A mixture of equimolar amounts (0.005 mol) of each of compound 2 (1.95 g) and 3-imino-5-oxopyrazolidene (0.5 g), in DMF (25 mL), was treated with two drops of piperidine and heated under reflux for 5h. The brown crystals so separated on hot were collected by filtration and recrystallized from DMF affording compound 8 (2.16 g, 92%), identified by m.p., mixed m.p. and spectra. 4-(Benzo[l,3]dioxol-5-yl)-5-(4-hydroxy-l-methyl-2-oxo-l,2-dihydroquinolin-3-yl)-l,4,7,8-tetrahydro-2i/-dipyrazolo[3,4-6; 4 ,3-e]pyran-3-one (10). A mixture of equimolar amounts (0.005 mol) of each of compound 2 (1.95 g) and pyrazolidene-3,5- Elham S. Othman: Some Nucleophilic Cyclization Reactions JVith 3-[4-(Benzo[l,3]dioxolylmethylene)... Acta Chim. Slov. 2003, 50, 15-28. 25 dione (0.51 g), in DMF (25 mL), was treated with two drops of piperidine and heated under reflux for 5h. The deep brown precipitate so formed on hot was filtered off and recrystallized from DMF affording dipyrazolopyran 10 (1.96 g, 83%), m.p. >300 °C. Anal. Calculated for C24Hi7N506 (471.43): C, 61.15; H, 3.63; N, 14.86. Found: C, 60.90; H, 3.50; N, 14.60. IR, v: 3236-3190 (N-H, O-H), 1668 (C=Opyrazoiinone), 1630 (C=Oquinoio„e), 1608 (C=N), 1600, 1583, 1505, 1445 and 1120. 'H NMR, 5: 3.58 (s, 3H, N-CH3), 3.95 (s, 1H, C4-Hpyran), 6.12 (s, 2H, 0-CH2-0), 7.22-8.08 (m, 7H, Harom), 9.56 (br d, 1H, N-Hpyrazoione), 10.95 (br s, 1H, N-Hpyrazoie), 11.70 (br d, 1H, N-Hpyrazoione) and 14.14 (br s, 1H, O-H). Reaction of Active Methylene Compounds With Pyrazolinone 2. General Procedure. To a mixture of compound 2 (3.89 g, 0.01 mol) and the proper active methylene compound (0.01 mol), in dioxane (50 mL), piperidine (0.1 mL) was added and the reaction mixture was heated under reflux on a boiling-water bath for 2-4h. Aftenvards, the reaction mixture was left to cool and acidified using dilute acetic acid till complete precipitation. The precipitate so obtained was filtered off, washed thoroughly with cold ethanol (10 mL) and crystallized to give pyranopyrazoles 11-14, 16a,b and 17a,b. 4-(Benzo[l,3]dioxol-5-yl)-3-(4-hydroxy-l-methyl-2-oxo-l,2-dihydroquinolin-3-yl)-4,5,6,7-tetrahydro-cyclopentano[5,6]pyrano[2,3-c]pyrazole (11). This compound was prepared from compound 2 and cyclopentanone (0.9 mL), yield (2.87 g, 63%), m.p. 298-9 °C (dioxane). Anal. Calculated for C26H2iN305 (455.47): C, 68.56; H, 4.65; N, 9.23. Found: C, 68.40; H, 4.40; N, 9.00. IR, v: 3240-3110 (N-H, O-H), 1640 (C=0), 1620 (C=N), 1580, 1505, 1442 and 1118. 'H NMR, 5: 1.90-2.25 (m, 6H, (CH2)3), 3.65 (s, 3H, N-CH3), 3.88 (s, 1H, C4-Hpyran), 5.95 (s, 2H, 0-CH2-0), 7.20-8.11 (m, 7H, Harom), 11.80 (br s, 1H, N-H) and 14.05 (br s, 1H, O-H). 4-(Benzo[l,3]dioxol-5-yl)-3-(4-hydroxy-l-methyl-2-oxo-l,2-dihydroquinolin-3-yl)-l,4,5,6,7,8-hexahydrochromeno[2,3-c]pyrazole (12). This compound was obtained from compound 2 and cyclohexanone (1 mL), yield (3.38 g, 72%), m.p. 300-2 °C Elham S. Othman: Some Nucleophilic Cyclization Reactions JVith 3-[4-(Benzo[l,3]dioxolylmethylene)... 26 Acta Chim. Slov. 2003, 50, 15-28. (dioxane). Anal. Calculated for C27H23N305 (469.50): C, 69.07; H, 4.94; N, 8.95. Found: C, 68.80; H, 4.80; N, 8.90. IR, v: 3280-3120 (N-H, O-H), 1635 (C=0), 1610 (C=N), 1581, 1535, 1495, 1444 and 1110. 'H NMR, 5: 1.40-2.24 (m, 8H, (CH2)4), 3.62 (s, 3H, N-CH3), 3.82 (s, 1H, C4-Hpyran), 5.92 (s, 2H, 0-CH2-0), 7.15-8.05 (m, 7H, Harom), 11.90 (br s, 1H, N-H) and 13.95 (br s, 1H, O-H). 7-(Benzo[l,3]dioxol-5-yl)-8-(4-hydroxy-l-methyl-2-oxo-l,2-dihydroquinolin-3-yl)-5,6,7-trihydropyrazolo[3,4-c]benzo[h]chromene (13). This compound was obtained from compound 2 and a-tetralone (1.36 mL), yield (3.2 g, 62%), m.p. 220-2 °C (dioxane). Anal. Calculated for C3iH23N305 (517.55): C, 71.94; H, 4.48; N, 8.12. Found: C, 72.00; H, 4.30; N, 7.90. IR, v: 3225-3180 (N-H, O-H), 1632 (C=0), 1608 (C=N), 1589, 1546, 1504, 1449 and 1118. 'H NMR, 5: 2.65-2.80 (m, 4H, (CH2)2), 3.65 (s, 3H, N-CH3), 3.97 (s, 1H, C4-Hpyran), 5.95 (s, 2H, 0-CH2-0), 7.05-8.11 (m, 11H, Harom), 11.85 (br s, 1H, N-H) and 14.30 (br s, 1H, O-H). 3-[5-Acetyl-4-(benzo[l,3]dioxol-5-yl)-6-methyl-l,4-dihydropyrano[2,3-c]-pyra-zol-3-yl]-4-hydroxy-l-methylquinolin-2(lH)-one (14). This compound was prepared from compound 2 and acetylacetone (1 mL), yield (2.7 g, 57%), m.p. 235-7 °C (dioxane). Anal. Calculated for C26H21N306 (471.47): C, 66.24; H, 4.49; N, 8.91. Found: C, 66.10; H, 4.50; N, 8.80. IR, v: 3217-3168 (N-H, O-H), 1705 (C=OaCetyi), 1632 (C=Oquinoione), 1600 (C=N), 1589, 1540, 1445 and 1110. 'H NMR, 5: 2.15 (s, 3H, CH3), 2.25 (s, 3H, COCH3), 3.65 (s, 3H, N-CH3), 4.10 (s, 1H, C4-Hpyran), 5.96 (s, 2H, 0-CH2-0), 7.15-8.10 (m, 7H, Harom), 11.45 (br s, 1H, N-H) and 13.29 (br s, 1H, O-H). Ethyl 4-(benzo[l,3]dioxol-5-yl)-3-(4-hydroxy-l-methyl-2-oxo-l,2-dihydro-quin-olin-3-yl)-6-methyl-l,4-dihydropyrano[2,3-c]pyrazole-5-carboxylate (16a). This ester was formed from compound 2 and ethyl acetoacetate (1.3 mL), yield (3.15 g, 63%), m.p. 234 °C (ethanol). Anal. Calculated for C27H23N307 (501.50): C, 64.67; H, 4.62; N, 8.38. Found: C, 64.50; H, 4.60; N, 8.30. IR, v: 3240-3120 (N-H, O-H), 1722 (C=Oester), 1646 (C=Oquinoione), 1605 (C=N), 1598, 1550, 1495, 1440, 1125 and 1110. lH NMR, 5: 1.23 (t, 3H, OCH2-C^), 2.35 (s, 3H, a-CH3), 3.60 (s, 3H, N-CH3), 4.03 (q, Elham S. Othman: Some Nucleophilic Cyclization Reactions JVith 3-[4-(Benzo[l,3]dioxolylmethylene)... Acta Chim. Slov. 2003, 50, 15-28. 27 2H, OCHt-CH3\ 4.40 (s, 1H, C4-Hpyran), 5.98 (s, 2H, 0-CH2-0), 7.10-8.05 (m, 7H, Harom), 11.90 (br s, 1H, N-H) and 14.25 (br s, 1H, O-H). Ethyl 4-(benzo[l,3]dioxol-5-yl)-3,6-di(4-hydroxy-l-methyl-2-oxo-l,2-dihydro-quinolin-3-yl)-l,4-dihydropyrano[2,3-c]pyrazole-5-carboxylate (16b). This ester was obtained from compound 2 and ethyl 3-quinolinyl-3-oxopropanoate 1511 (2.89 g), yield (3.96 g, 60%), m.p. 244-5 °C (acetone). Anal. Calculated for C36H28N409 (660.65): C, 65.45; H, 4.27; N, 8.48. Found: C, 65.30; H, 4.10; N, 8.40. IR, v: 3240-2720 (br, N-H, O-H), 1725 (C=Oester), 1645-1635 (C=Oquinoione), 1610 (C=N), 1586, 1545, 1485, 1443, 1212 and 1120. 6-Amino-4-(benzo[l,3]dioxol-5-yl)-3-(4-hydroxy-l-methyl-2-oxo-l,2-dihydro-quinolin-3-yl)-l,4-dihydropyrano[2,3-c]pyrazole-5-carboxylic acid (17a). This acid was obtained from compound 2 and cyanoacetic acid (0.85 g), yield (3.9 g, 82%), m.p. 263-5 °C (dioxane). Anal. Calculated for C24Hi8N407 (474.43): C, 60.76; H, 3.83; N, 11.81. Found: C, 60.70; H, 3.70; N, 11.80. IR, v: 3435, 3340 (NH2), 3210-2600 (H- bonded O-H), 1705 (C=Ocarboxyiic), 1647 (C=Oquinoio„e), 1618 (C=N), 1593, 1545, 1492, 1445 and 1120. 'H NMR, 5: 3.64 (s, 3H, N-CH3), 4.80 (s, 1H, C4-Hpyran), 5.95 (s, 2H, 0-CH2-0), 7.12-8.08 (m, 7H, Harom), 8.95 (br s, 2H, NH2), 11.30 (br s, 1H, N-H), 13.95 (br s, 1H, 0-Hquinoiinoi) and 14.58 (br s, 1H, 0-HcarboxyHc). Ethyl 6-amino-4-(benzo[l,3]dioxol-5-yl)-3-(4-hydroxy-l-methyl-2-oxo-l,2-dihy-dro-quinolin-3-yl)-l,4-dihydropyrano[2,3-c]pyrazole-5-carboxylate (17b). This ester was obtained from compound 2 and ethyl cyanoacetate (1 mL), yield (3.97 g, 79%), m.p. 175-7 °C (dioxane). Anal. Calculated for C26H22N407 (502.49): C, 62.15; H, 4.41; N, 11.15. Found: C, 62.00; H, 4.40; N, 11.10. IR, v: 3420, 3310 (NH2), 3182 (N-H), 1730 (C=OeSter), 1635 (C=Oquinoio„e), 1612 (C=N), 1590, 1550, 1495, 1445 and 1110. 6-Amino-4-(benzo[l,3]dioxol-5-yl)-3-(4-hydroxy-l-methyl-2-oxo-l,2-dihydro-quinolin-3-yl)-l,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (19). A mixture of equimolar amounts (0.01 mol) of compound 2 (3.89 g) and malononitrile (0.65 g), in DMF (30 mL), was treated with 3 drops of piperidine and heated under reflux for 3h. On Elham S. Othman: Some Nucleophilic Cyclization Reactions JVith 3-[4-(Benzo[l,3]dioxolylmethylene)... 28 Acta Chim. Slov. 2003, 50, 15-28. cooling of the reaction mixture, yellow crystals were separated, which were filtered off and recrystallized from dioxane to yield the nitrile 19 (3.8 g, 83%), m.p. 266 °C. Anal. Calculated for C24H17N5O5 (455.43): C, 63.30; H, 3.76; N, 15.38. Found: C, 63.20; H, 3.60; N, 15.40. IR, ?: 3440, 3355 (NH2), 3250-3190 (N-H, O-H), 2206 (ON), 1635 (C=Oquinoio„e), 1620 (C=N), 1600, 1585, 1550, 1492 and 1120. 'H NMR, ?: 3.62 (s, 3H, N-CH3), 4.40 (s, 1H, C4-Hpyran), 5.95 (s, 2H, 0-CH2-0), 6.82 (br s, 2H, NH2), 7.20-8.05 (m, 7H, Harom), 11.32 (br s, 1H, N-H) and 13.90 (br s, 1H, O-H). The same product 19, m.p., mixed m.p. and spectra, was obtained using the same procedure above from compound 1 (2.57 g) and piperonalidenemalononitrile 18 (1.98 g), yield (3.28g, 72%). References and Notes 1. Baldwin, J. J.; Lumma, P. K.; Novello, F. C.; Ponticello, G. S.; Sprague, J. M.; Duggan, D. E. J. Med. Chem. 1977, 20, 1189–1193. 2. G. B. Patent 2, 149, 402 1985; Beck, J. R.; Lynch, M. P.; Chem. Abstr. 1985, 103, 141938. 3. E. P. Patent 289, 879 1989; Okada, I.; Okui, S.; Takahashi, Y.; Fukuchi, T.; Chem. Abstr. 1989, 110, 96234. 4. J. P. Patent 05, 255, 316 1993; Ishikawa, H.; Moritia, T.; Oono, T.; Nakamura, T.; Taniguchi, M.; Yoshizawa, H.; Yochihara, M.; Chem. Abstr. 1994, 120, 99438. 5. Gursoy, A.; Demirayak, S.; Capan, G.; Erol, K. Euro. J. Med. Chem. 2000, 35, 359–364. 6. Kucukguzel, S. G.; Rollas, S.; Erdeniz, H.; Kiraz, M.; Ekinci, A. C.; Vidin, A. Euro. J. Med. Chem. 2000, 35, 761–771. 7. Roue, N.; Bergman, J. Tetrahedron 1999, 55, 14729–14738. 8. Abass, M.; Othman, E. S. Synth. Commun. 2001, 31, 3361–3376. 9. El-Shafei, A. k.; Sultan, A. A.; Soliman, A. M.; Ahmed, E. A. Synth. Commun. 1995, 25, 3211– 3218. 10. El-Sayed, A. M.; El-Saghier, A. M. M.; Mohamed, M. A. A.; El-Shafei, A. k. Gazz. Chim. Ital. 1997, 127, 605–608. 11. Ibrahim, S. S.; Abdel-Halim, A. M.; Ismail, M. M.; Othman, E. S. Indian J. Heterocycl. Chem. 1994, 4, 125–130. Povzetek Opisana je reakcija ciklizacije 3-[4-(benzo[1,3]dioksolilmetilen)-5-okso-3-pirazolil]-4-hidroksi-1-metil-kinolin-2(1H)-ona z nekaterimi bifunkcionalnimi nukleofilnimi reagenti. Pri reakcijah ciklizacije se tvorijo številni biološko zanimivi kondenzirani heterociklični sistemi, ki nastajajo iz pirazolinonov in vsebujejo kinolinonski strukturni del, kot so pirazolopirazol, izooksazolopirazol, pirazolopirimidin, pirazolotiazin, pirazolopiridin, dipirazolopiridin, dipirazolopiran in številni derivati pirazolopirana. Strukture vseh novih spojin so preverjene z analitskimi in spektroskopskimi metodami. Elham S. Othman: Some Nucleophilic Cyclization Reactions JVith 3-[4-(Benzo[l,3]dioxolylmethylene)...