A convenient acess to thienyl-substituted phthalazines

AConvenient Access to Thienyl-substituted Phthalazines M. Manuela M. Raposo,a* Ana M. B. A. Sampaioaand G. Kirschb aCentro de Química, Universidade do Minho, Campus de Gualtar 4710-057 Braga, Portugal bLaboratoire d'Ingénierie Moléculaire et Biochimie Pharmacologique, UFR SciFA/Université de Metz, 1, Boulevard Arago, Metz Technopôle, 57078 Metz Cedex 3, France Received November 3, 2004 Asynthesis of 1-alkoxyand 1-aminosubstituted 4-(2-thienyl)-phthalazines is described from haloderivatives of 4-(2-thienyl)-1-(2H)-phthalazinone 3. J. Heterocyclic Chem., 42, 1245 (2005). Introduction. The practical interest upon phthalazine derivatives is based on their widespread applications [1-4]. Phthalazines, like others members of the isomeric diazine series, have found wide applications as therapeutic agents [2,5-28]. Phthalazines are also commonly used as ligands in transition metal catalysis, [29-34] as chemiluminescent materials [35-38] and for optical applications [39]. Despite their significance, there are only a limited number of routes for the synthesis of phthalazines. The most commonly employed approach is through o-disubstituted benzenes. Thus, condensation of 1,2-diacylbenzenes or their aldehyde counterparts with hydrazine derivatives gives 1,4-disubstitutedor the parent unsubstituted phthalazines, respectively [1-3,5-7,9-10,12,40-47]. Recently, palladium catalyzed coupling reactions were also applied in the phthalazine series [48-49]. Guery et al [48] obtained several new phthalazine derivatives through Suzuki coupling. Due to the nature of the phthalazine nucleus, synthesis of new derivatives becomes an important issue. There has been little reported in the literature concerning 2-thienylsubstituted phthalazines [17-18,50-51]. The synthesis of thienylsubstituted phthalazines 4a,6 and 7was achieved through similar reactions used earlier in the synthesis of phenyl-phthalazines [40-47]. 1-Alkoxyand 1-amino-phthalazine derivatives were obtained from halo-derivatives 4a-bof the phthalazinone 3. Compound 3 was obtained by cyclization of acyl benzoates 2a-busing hydrazine hydrate. The latter was made through a FriedelCrafts reaction between thiophene and phthalic acid monochloride esters 1a-b. Earlier,several authors [46-47] described the synthesis and the evaluation of the biological activity of 1-aminophthalazines with structure similar to thienyl-phthalazines 7.These studies showed that the substitution of the phenyl ring in phenyl-phthalazines (or phenyl-pyridazines) by an electron rich heterocycle such as furane or thiophene improve the biological activities for these compounds. Thus, we decide to synthesize several 1-amino-4-thienylphthalazines to see if the potential biological activities for these compounds will be improve. Chlorine, bromine and triflate thienyl-substituted phthalazines 4and 5were synthesized in order to be used as precursors on the synthesis of 1-alkoxyand 1-amino-phthalazines 6-7.These derivatives could also be used in the future, as coupling components in palladium catalyzed cross-coupling reactions to obtain more complex molecules with potential applications in NLO [52]. For this kind of application the substitution of the phenyl ring by the thiophene ring was already demonstrated to be very important [53]. Results and Discussion The 2-thienyl-subtituted benzoates 2a-bwere obtained in good yields (75-81%), by the standard method of Friedel-Crafts reaction of thiophene with o-phthalic acid mono alkyl ester chlorides 1a-b.These compounds were subsequently cyclized by condensation with hydrazine hydrate to give phthalazinone 3in 91% yield from benzoate 2a or in 84% yield from benzoate 2b (Scheme 1, Table 1). Phthalazinone 3was already synthesized by BuuHoï et al [50],by condensation of 2-(2'-thienyl)-2-oxobenzoic acid with hydrazine hydrate. Bromine, chlorine and triflate substituted phthalazines play an important role in diazine chemistry since they offer the potential for further funcionalization. By nucleophilic displacement of the halogen or the triflate groups, numerous otherwise inaccessible diazines become available. To this end we have synthesized and characterized several haloand triflate phthalazine derivatives. From 3,bromo, chloro and triflate derivatives were prepared by reaction respectively with phosphoryl halides and triflic anhydride. The chloride 4a,bromide 4b,and triflate 5were obtained with respectively 87, 94 and 30% yield. 1-Chloro-4-(2'-thienyl)-phthalazine 4a has been already reported in a patent [51], by condensation of 1,4-dichlorophthalazine with thienyllithium. No data about the derivative are given. The triflate derivative 5was prepared according to a modified version [54],of the procedure described by Toussaint [55] et al.Reaction of 3with a great excess of the brominating agent gave only the dibromo derivative 4c in 62% yield. Mass spectrum of 4c showed the characteristic pattern for a comNov-Dec 2005 1245 M. M. M. Raposo, A. M. B. A. Sampaio and G. Kirsch 1246 Vol. 42 pound with two bromine atoms with molecular ions at m/z 372 (M+, 2x81Br, 45), 370 (M+,79Br 81Br, 85) and 368 (M+,2x79Br, 45). The 1HNMR spectrum revealed two doublets: one at δ7.23 (3'-H) and the other at δ7.46 (4'-H). On the basis of these data, the 1-bromo-4-(5'- bromo-thieno-2-yl)-phthalazine structure 4c was assigned to this product (Scheme 1). 1-Halophthalazines reacted to the alkoxy derivatives 6abwhen refluxing with the alkoxyde in the corresponding alcohol. Compounds 6a and 6b,were obtained in good yields (Scheme 2, Table 2). Arylaminoand piperidinylphthalazine derivatives show anti thrombotic properties, anti malarial activity and are useful for treatment of septic shock, multi-organ failure, chronic rheumatoid arthritis, multiple sclerosis, SLE, AIDS, hepatitis, type-II diabetes etc. [2,21,47]. In order to synthesize several new 1-(alkyl)arylamino-4- (2'-thienyl)-phathazines, 1-chloro-4-(2'-thienyl)-phthalazine 4a was reacted with an excess of piperidine or an excess of several arylamines, in refluxing acetone [56], for 3-15 h, to yield 1-(alkyl)arylamino-4-(2'-thienyl)-phthazines 7a-e inmoderate to good yields (47-84%) (Scheme 2, Table 2). It has been reported that 3-hydrazino-6-(2-pyrrolyl)- pyridazine can be obtained from the reaction of hydrazine hydrate with 3-chloro-6-(2-pyrrolyl)pyridazine in refluxed n-butanol [57]. Using an analogous route, we hoped to prepare 1-hydrazino-4-(2'-thieny)- phthalazine but we observed that 1-chloro-4-(2'-thienyl)- phthalazine 4a failed to react with hydrazine hydrate to produce the corresponding phthalazine derivative. In our hands chloro-phthalazine 4a reacted with hydrazine hydrate in boiling butanol to afford a brown solution from which an orange solid precipitated. The solution revealed to be a mixture of two compounds (tlc). "Flash" chromatography of this mixture on silica with increasing amounts of diethyl ether in light petroleum gave the thienyl-phthalazinone 3in 87% yield. The second compound eluted was an orange solid, mp 233.7-234.9 ºC. Mass spectrum of this compound showed the molecular ion at 452.0880 (C24H16N6S2) and an ion at m/z 226 (19%) owing the cleavage into two simple units. The IR spectrum showed one absorption band at 3376 cm-1 (NH). 1HNMR spectrum revealed a broad singlet (2H) at 10.65 δdue to the NHprotons. On the basis of these data, the bis-1,2-[4'-(2''-thienyl)phthalazine-1-yl]- hydrazine structure 8(8%) was assigned to this product (Scheme 2, Table 2). The reaction of 4a with hydrazine hydrate, under these conditions, gave the oxo derivative 3in high yield and not the hydrazino derivative, probably due to the hydrolysis of chloro phthalazine 4a [2,20,58]. Table 2 Synthesis of 1-Alkoxyand 1-Amino-substituted Phthalazine Derivatives 6a-b,7a-eand Dimmer 8from 1-Halophthalazine Derivatives 4a-b Compound R Yield (%) IR υmax [cm-1] 6a Me 73 ----- 6b Et 88 ----- 7a Piperidino 84 ----- 7b 4-Methoxyanilino 47 3418 (NH) 7c 2,4-Dimethoxyanilino 52 3434 (NH) 7d 4-Cyanoanilino 62 3409 (NH), 2213 (CN) 7e 4-Nitroanilino 71 3281 (NH) 8------ 9 3376 (NH) In summary, we report the synthesis of several derivatives of thienyl-substituted phthalazines in order to obtain new derivatives which could exhibit biological activity or in order to be used as precursors on the synthesis of more complex molecules. The examination of biological activity of compounds 7a-eand 8are in course. Table 1 Synthesis of Benzoates 2a-b, Phthalazinone 3and Phthalazine Derivatives 4a-cand 5 Compound Yield (%) IR υmax [cm-1] 2a 81 1724 (C=O) 1649 (C=O) 2b 75 1718 (C=O) 1650 (C=O) 391 3301 (NH), 1665 (C=O) 4a 99 ----- 4b 87 ----- 4c 62 ----- 530 ----- AConvenient Access to Thienyl-substituted Phthalazines Nov-Dec 2005 1247 EXPERIMENTAL 1Hnmr spectra were obtained on a Varian Unity Plus Spectrometer at 300 MHz and 13Cnmr were determined on a Varian Unity Plus Spectrometer at 75.4 MHz using the solvent peak as internal reference. The solvents are indicated in parenthesis before the chemical shift values (δrelative to TMS). Mp's were determined on a Gallenkamp apparatus and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer 1600 FTIR spectrophotometer. EI mass spectra EI (70 eV) and hrms were run on a Unicam GC-MS 120. Elemental analysis was carried out on a Leco CHNS-932. Column chromatography was performed on Merck silica gel 60 (Art 9385). Light petroleum refers to solvent boiling in the range 40-60 °C. General Procedure for the Preparation of Acid chlorides 1a-b. The phthalic acid monoalkyl esters (70 mmol) were dissolved in 50 mL of dry dichloromethane and then thionyl chloride (12.5 g, 105 mmol) was added and the mixture was heated at reflux for 4-4.5 h. Evaporation of the solvent under reduced pressure gave the crude acid chlorides 1which were used without further purification in the Friedel-Crafts reactions. Phthalic Monoacid Monomethyl Ester Chloride 1a. This compound was obtained in quantitative yield as a colorless oil; _Hnmr (deuteriochloroform) δ3.87 (s, 3H, OCH3), 7.60-7.67 (m, 2H, 2xAr-H), 7.75-7.80 (m, 1H, Ar-H), 7.82-7.86 (m, 1H, ArH), ir (nujol) ν 2854, 1791 (C=O, acid chloride), 1710 (C=O, ester), 1578, 1488, 1457, 1414, 1386, 1375, 1356, 1343, 1285, 1248, 1181, 1165, 1145, 1128, 1104, 1074, 1037, 995, 826 cm-1. Phthalic Monoacid Monoethyl Ester Chloride 1b. This compound was obtained in 95% yield as a colorless oil; _Hnmr (deuteriochloroform): δ1.40 (t, 3H, OCH2CH3, J = 7.2 Hz), 4.40 (q, 2H, OCH2CH3,J=7.2 Hz), 7.60-7.65 (m, 2H, 2xAr-H), 7.72-7.76 (m, 1H, Ar-H), 7.84-7.88 (m, 1H, Ar-H), ir (nujol) ν 2860, 1785 (C=O, acid chloride), 1695 (C=O, ester), 1580, 1450, 1465, 1430, 1380, 1360, 1350, 1330, 1230, 1170, 1130, 1096, 1050, 980, 820 cm-1. General Procedure for the Friedel-Crafts Reaction. Acid chloride 1(17.2 g, 114 mmol) and thiophene (9.59 g, 114 mmol/9.03 mL), in dry dichloromethane (200 mL), were added dropwise to a stirred solution of stannic chloride (32.7 g/14.7 mL, 125 mmol,) in dry dichloromethane (200 mL), at 0 ºC. After the addition, the mixture was stirred overnight at rt and then poured onto ice-water (1000 mL), acidified with con. HCl and stirred at 0ºC during 1 h. This mixture was extracted with dichloromethane (3x50 mL) and the combined organic extracts were washed with a solution of (5 %) NaOH (3x100 mL), water (2x100 mL) and dried (MgSO4). Evaporation of the solvent under reduced pressure gave the crude acyl benzoates 2as oils that were purified by "flash" chromatography on silica with increasing amounts of ether in light petroleum as eluent. Methyl-2-(thiophene-2-carbonyl)benzoate (2a). This compound was obtained in 81% yield as a colorless solid, mp 67-68 ºC; 1Hnmr (deuteriochloroform): δ3.70 (s, 3H, OCH3), 7.08 (m, 1H, 4'-H), 7.28 (dd, 1H, 3'-H, J = 3.5, 1.2 Hz), 7.50 (dd, 1H, 3 or 6-H, J = 7.8, 1.5 Hz), 7.59 (dt, 1H, 4 or 5-H, J =7.8, 1.5 Hz), 7.65 (dt, 1H, 5 or 4-H, J = 7.8, 1.5 Hz); 7.71 (dd, 1H, 5'-H, J = 4.8, 1.2 Hz), 8.05 (dd, 1H, 6 or 3-H, J = 7.8, 1.5 Hz); ir (nujol) ν 3104, 2952, 1724 (C=O, ester), 1649 (C=O, cetone), 1596, 1576, 1515, 1485, 1434, 1412, 1355, 1287, 1321, 1085, 1050, 962, 895, 849, 824, 775, 737, 670, 642 cm-1; ms: m/z (%) =246 (M+,92), 215 (36), 187 (7), 163 (100), 111 (100), 76 (40), 69 (20), 57 (58), 50 (75). Anal. Calcd. for C13H10O3S: C, 63.42; H, 4.06; S, 13.02. Found: C, 63.38; H, 4.17; S, 13.06. Ethyl-2-(thiophene-2-carbonyl)benzoate (2b). This compound was obtained in 75% yield as a beige solid, mp 65-67 ºC; 1Hnmr (deuteriochloroform): δ1.14 (t, 3H, OCH2CH3, J =6.7 Hz), 4.15 (q, 2H, OCH2CH3, J = 6.7 Hz), 7.08 (m, 1H, 4'-H), 7.28 (dd, 1H, 3-H, J = 3.7, 1.2 Hz), 7.49 (dd, 1H, 3 or 6-H, J = 7.5, 1.5 Hz); 7.58 (dt, 1H, 4 or 5-H, J = 7.5, 1.5 Hz), 7.65 (dt, 1H, 5 or 4H, J = 7.5, 1.5 Hz), 7.71 (dd, 1H, 5'-H, J = 5.0, 1.2 Hz), 8.06 (dd, 1H, 6or 3-H, J = 7.5, 1.5 Hz); ir (nujol) ν 3098, 1718 (C=O, ester), 1650 (C=O, cetone), 1595, 1575, 1514, 1411, 1336, 1288, 1132, 1076, 1046, 1040, 1017, 841, 777, 734, 718 cm-1;ms: m/z (%) = 260 (M+, 82), 215 (86), 217 (10), 187 (27), 171 (14), 149 (68), 115 (33), 111 (100), 105 (15), 83 (16), 76 (39), 65 (21), 57 (11), 50 (20). M. M. M. Raposo, A. M. B. A. Sampaio and G. Kirsch Anal. Calcd. for C14H12O3S: C, 64.62; H, 4.61; S, 12.32. Found: C, 64.60; H, 4.63; S, 12.44. Synthesis of 4-(2'-Thienyl)-1-(2H)-phthalazinone (3). Amixture of benzoate 2a-b(5 g, 20 mmol) and hydrazine hydrate (1.5 g, 30 mmol, 1.45 mL) was heated at reflux in ethanol (35 mL) for l6 h. The mixture was left at -4 ºC overnight. After cooling the obtained crystals were collected by filtration and washed with ethanol to give the pure phthalazinone 3[17-18], [42]. This compound was obtained in 91 % yield from benzoate 2aand in 84 % yield from benzoate 2bascolorless needles (ethanol), mp 197-198 ºC, (lit. [42] 195 ºC); 1Hnmr (deuteriochloroform) δ7.25-7.27 (m, 1H, 4'-H), 7.48 (dd, 1H, 3'-H, J = 3.3, 1.2 Hz), 7.52 (dd, 1H, 5'-H, J = 5.4, 1.2 Hz), 7.80-7.92 (m, 2H, 6 and 7-H), 8.15 (dd, 1H, 5 or 8-H, J = 7.5, 2.4 Hz), 8.54 (dd, 1H,8or 5-H, J = 7.5, 2.4 Hz), 10.6 (br. s., 1H, NH); ir (nujol) ν 3301 (NH), 1665 (C=O), 1582, 1431, 1351, 1329, 1229, 1196, 1156, 1083, 1030, 907, 893, 845, 776, 740, 727, 699, 680, 666, 648 cm-1;ms: m/z (%) = 228 (M+,100), 227 (44), 199 (17), 171 (52), 149 (26), 145 (5), 139 (6), 127 (22), 111 (10), 97 (25), 83 (42), 81 (51); hrms: m/z calc. for C12H8N2OS: 228.0357; found 228.0352. Anal. Calcd. for C12H8N2OS: C, 63.12, H, 3.51, N, 12.27, S, 14.05. Found: C, 63.22, H, 3.67, N, 12.25, S, 14.19. General Procedure for the Synthesis of 1-Halo-4-(2'-thienyl)- phthalazines 4a-b. Amixture of 4-(2-thienyl)-1-(2H)-phthalazinone 3(1 g, 4.4 mmol), and POX3(X=Cl or Br) (8.8 mmol), was heated for 4 h at 110-120 ºC. This mixture was cooled till rt and then poured onto ice-water, basified with a solution of ammonia (2 M)and stirred for 15 min. to give a solid which was filtered and washed with water and light petroleum to give the pure 1-halo-4-(2-thienyl)- phthalazines 4a-b. 1-Chloro-4-(2'-thienyl)-phthalazine (4a). This compound was obtained in 99 % yield as a yellow solid mp 134.5-135.5 ºC (ether), (lit. [51] mp not quoted); 1H nmr (deuteriochloroform): δ7.27-7.30 (m, 1H, 4'-H), 7.64 (dd, 1H, 5'-H, J=5.3, 1.2 Hz), 7.70 (dd, 1H, 3'-H, J = 3.4, 1.2 Hz), 8.018.05 (m, 2H, 6 and 7-H), 8.40 (dd, 1H, 5 or 8-H, J = 8.6, 2.1 Hz), 8.52 (dd, 1H, 8 or 5-H, J = 8.6, 2.1 Hz); ir (nujol) ν 1564, 1529, 1483, 1434, 1374, 1364, 1288, 1263, 1074, 1018, 987, 853, 854, 846, 777, 701, 689, 666 cm-1;ms: m/z (%) = 248 (M+,37Cl, 37), 246 (M+,35Cl, 100), 228 (17), 211 (72), 182 (16), 139 (25), 109 (10), 91 (6); hrms: m/z calc. for C12H737ClN2S: 247.9989; found 247.9989. Anal. Calcd. for C12H7ClN2S: C, 58.41; H, 2.83; N, 11.35, S, 13.01. Found: C, 58.60; H, 3.01; N, 11.65; S, 13.35. 1-Bromo-4-(2'-thienyl)-phthalazine (4b). This compound was obtained in 87% yield as a beige solid, mp 177.8-178.2 ºC (ethyl acetate). 1Hnmr (deuteriochloroform): δ 7.27-7.30 (m, 1H, 4'-H), 7.64 (dd, 1H, 5'-H, J = 5.0, 1.2 Hz), 7.97-8.07 (m, 2H, 6 and 7-H), 8.36 (dd, 1H, 5 or 8-H, J = 8.9, 2.4 Hz), 8.48 (dd, 1H, 8 or 5-H, J = 8.9, 2.4 Hz); ir (nujol) ν 3646, 2923, 1526, 1515, 1432, 1362, 1326, 1278, 1162, 968, 877, 843, 774, 701, 664, 614, 503 cm-1;ms: m/z (%) = 292 (M+,81Br, 68), 290 (M+,79Br, 73), 228 (9), 211 (100), 182 (8), 139 (36), 113 (6), 102 (17), 91 (12); hrms: m/z calc. for C12H779BrN2S: 289.9513; found 289.9515. Anal. Calcd. for C12H7BrN2S: C, 49.49; H, 2.40; N, 9.62; S, 11.02. Found: C, 49.47; H, 2.62; N, 9.47; S, 10.88. Synthesis of 1-Bromo-4-(5'-bromo-thieno-2-yl)-phthalazine (4c). Amixture of 4-(2'-thienyl)-1-(2H)-phthalazinone 3(1g, 4.4 mmol), and POBr3(48.4 mmol), was heated for 4 h at 110-120 ºC. This mixture was cooled till rt and then poured onto icewater, basified with a solution of ammonia (2 M)and stirred for 15 min. to give a beige solid which was filtered and washed with water and light petroleum to give the crude phthalazine 4c as a beige solid. "Flash" chromatography of this solid with increasing amounts of ether in light petroleum gave the pure dibromophthazine 5c in 62% yield as a beige solid, mp 164.0-165.5 ºC; 1H nmr (deuteriochloroform): δ7.23 (d, 1H, 3' or 4'-H, J = 4 Hz), 7.46 (d, 1H, 4'or 3'-H , J = 4 Hz), 8.01-8.05 (m, 2H, 6 and 7-H), 8.35-8.38 (m, 1H, 5 or 8-H), 8.43-8.46 (m, 1H, 8 or 5-H); ir (nujol) ν 3851, 3646, 2924, 1562, 1516, 1434, 1364, 1326, 1278, 1162, 1118, 980, 971, 842, 805, 770, 698, 689, 664, 614, 506 cm1; ms: m/z (%) = 372 (M+, 2x81Br, 45), 370 (M+,79Br 81Br, 85), 368 (M+, 2x79Br, 45), 291 (100), 279 (97), 227 (7), 210 (14), 182 (39), 171 (7), 138 (21), 119 (9), 102 (11), 92 (44), 82 (45); hrms: m/z calc. for C12H679Br2N2S: 367.8618; found 367.8620. Anal. Calcd. for C12H6Br2N2S: C, 38.93; H, 1.62; N, 7.57; S, 8.67. Found: C, 39.15; H, 1.92; N, 7.76; S, 8.94. Synthesis of Trifluoromethanesulfonic Acid [4-(2'-Thienyl)- phthalazine-1-yl]Ester 5. Trifluoromethanesulfonic anhydride (0.372 g/0.22 mL, 1.32 mmol), was added slowly dropwise to a stirred ice cooled suspension of phthalazinone 3(0.2 g, 0.88 mmol) and triethylamine (0.134 g/0,18 mL, 1.32 mmol) in dichloromethane (20 mL). After 12 hours, the mixture was poured into water (30 mL and extracted with dichloromethane (3x50 mL). The combined organic extracts were washed with water (30 mL), dried with MgSO4and the solvent was evaporated under reduced pressure to give the crude trifluoromethanesulfonic acid [4-(2'-thienyl)- phthalazine-1-yl]ester 5which was purified by "flash" chromatography on silica with increasing amounts of ether in light petroleum as eluent. This compound was obtained in 30 % yield as a colorless solid, mp 133.2-134.0 ºC. 1Hnmr (deuteriochloroform): δ7.227.27 (m, 1H, 4'-H), 7.55 (br. d., 1H, 3'-H, J = 3.6 Hz), 7.60 (br. d., 1H, 5'-H, J = 5.4 Hz), 7.92 (dt, 1H, 6 or 7-H, J = 7.5, 1.2 Hz), 7.98 (dt, 1H, 7 or 6-H, J = 7.5, 1.2 Hz), 8.18 (br. d., 1H, 5-H, J = 8.1 Hz), 8.55 (br. d., 1H, 8-H, J = 8.1 Hz); 13Cnmr (deuteriochloroform): δ30.8, 117.3, 121.6, 127.7, 127.9, 128.6, 129.1, 130.2, 133.2, 134.7, 135.7, 145.2, 158.0; ir (nujol) ν 3851, 3646, 2924, 1714, 1592, 1548, 1428, 1366, 1324, 1281, 1253, 1230, 1197, 1130, 1121, 1086, 1049, 1023, 925, 859, 849, 789, 848, 777, 730, 684, 618, 591, 573 cm-1;ms: m/z (%) = 360 (M+,41), 199 (100), 228 (17), 171 (45), 127 (12), 85 (6); hrms: m/z calc. for C13H7F3N2O3S2: 359.9850; found 359.9851. Anal. Calcd. for C13H7F3N2O3S2:C, 43.33; H, 1.94; N, 7.78; S, 17.78. Found: C, 43.67; H, 2.23; N, 7.53; S, 17.49. General Procedure for the Preparation of 1-Alkoxy-4-(2'- thienyl)-phthalazines 6a-b. Halophthalazine 4a was heated at reflux with NaOR (R=Me or Et) in methanol or ethanol (45 mL) for 4 h., and then cooled and the solvent was removed under reduced pressure to give an orange solid. This solid was poured into water (50 mL), and neutralized 1248 Vol. 42 AConvenient Access to Thienyl-substituted Phthalazines with a solution of HCL (10%). The reaction mixture was then extracted with dichloromethane (2x40 mL). The organic extract was dried with MgSO4and the solvent was evaporated under reduced pressure to give the crude 1-alkoxy-4-(2-thienyl)-phtalazines 6a-bwhich were purified by "flash" chromatography on silica with increasing amounts of ether in light petroleum as eluent. 1-Methoxy-4-(2'-thienyl)-phthalazine (6a). This compound was obtained in 73 % yield as a colorless solid, mp 104.5-105.1 ºC; 1Hnmr (deuteriochloroform): δ4.32 (s, 3H, OCH3), 7.22-7.27 (m, 1H, 4'-H), 7.55 (dd, 1H, 5'-H, J = 5.5, 1.2 Hz), 7.62 (dd, 1H, J = 3.3, 1.2 Hz, 3'-H), 7.88-7.91 (m, 2H, 6 and 7-H), 8.30 (dd, 1H, 5 or 8-H, J = 9.0, 2.2 Hz), 8.40 (dd, 1H, 8 or 5-H, J = 9.0, 2.2 Hz); 13Cnmr (deuteriochloroform): δ 54.9, 120.0, 123.3, 125.3, 127.0, 127.3, 127.9, 128.4, 131.7, 132.4, 139.0, 150.5, 159.7; ir (nujol) ν 2923, 1614, 1578, 1541, 1515, 1494, 1433, 1364, 1325, 1278, 1201, 1105, 1051, 969, 852, 843, 786, 774, 701, 686, 664, 615 cm-1;ms: m/z (%) = 242 (M+, 100), 213 (40), 199 (6), 171 (33), 127 (11), 110 (16), 103 (15), 85 (5); hrms: m/z calc. for C13H10N2OS 242.0512; found 242.0514. Anal. Calcd. for C13H10N2OS: C, 64.45; H, 4.13; N, 11.57; S, 13.25. Found: C, 64.49; H, 4.34; N, 11.40; S, 13.21. 1-Ethoxy-4-(2'-thienyl)-phthalazine (6b). This compound was obtained in 88 % yield as a colorless solid, mp 97.9-99.0 ºC; 1Hnmr (deuteriochloroform): δ1.58 (t, 3H, OCH2CH3,J=6.9 Hz), 4.79 (q, 2H, OCH2CH3,J=6.9 Hz), 7.22-7.27 (m, 1H, 4'-H), 7.54 (dd, 1H, 5'-H, J = 5.0, 1.0 Hz), 7.61 (1H, dd, 3'-H, J = 3.6, 1.0 Hz), 7.87-7.91 (m, 2H, 6 and 7-H), 8.31-8.34 (m,1H, 8-H), 8.38-8.41 (m, 1H, 5-H); 13Cnmr (deuteriochloroform): δ14.6, 63.4, 120.1, 123.4, 125.3, 127.0, 127.3, 127.8, 128.3, 131.6, 132.3, 139.2, 150.2, 159.4; ir (nujol) ν 2924, 1575, 1536, 1492, 1441, 1413, 1342, 1309, 1166, 1101, 1047, 1024, 927, 877, 774 cm-1;ms: m/z (%) = 256 (M+,42), 241 (71), 228 (100), 211(12), 199 (17), 171 (58), 139 (5), 127 (19), 110 (16), 103 (12), 84 (7); hrms: m/z calc. for C14H12N2OS: 256.0670; found 256.0668. Anal. Calcd. for C14H12N2OS: C, 65.62; H, 4.69; N, 10.94; S, 12.52. Found C, 65.69; H, 4.90; N, 10.50; S, 12.27. General Procedure for the Synthesis of 1-(Alkyl)arylamino-4-(2'- thienyl)-phthalazines 7a-e. Amine (2.43 mmol), water (0.017 mL) and one drop of HCl (37%) were added to a stirred solution of 1-chloro-4-(2'-thienyl)- phthalazine 4a (4.2 g, 0.81 mmol) in acetone (20 mL). This mixture was heated at reflux for 3-15 h then cooled and the amine chlorohydrate separated by filtration affording a pale brown solution. This organic solution was evaporated under reduced pressure to give a crude solid that was dissolved in dichloromethane and the solution obtained was basified with a solution of ammonia (2 M), extracted with chloroform (3x30 mL) and washed with water (3x30 mL). The combined organic extracts were dried and the solvent was evaporated under reduced pressure to give the crude 1-(alkyl)aryl-4-(2'-thienyl)-phthalazines 7a-ewhich were purified by recrystallization or by "flash" chromatography on silica with increasing amounts of ether in light petroleum as eluent. 1-Piperidino-4-(2'-thienyl)-phthalazine (7a). This compound was obtained in a 84% yield as a beige solid, mp 125.3-126.3 ºC; 1HNMR (deuteriochloroform): δ1.70-1.80 (m, 2H, CH2), 1.80-2.00 (m, 4H, 2xCH2), 3.40-3.60 (m, 4H, 2xNCH2), 7.20-7.24 (m, 1H, 4'-H), 7.52 (dd, 1H, 5'-H, J = 4.9, 1.2 Hz), 7.60 (1H, dd, 3'-H, J = 3.2, 1.2 Hz), 7.78-7.80 (m, 2H, 6 and 7-H), 8.08-8.14 (m, 1H, 5 or 8-H), 8.38-8.44 (m, 1H, 8 or 5H); 13Cnmr (deuteriochloroform): δ24.7, 26.0, 53.4, 121.8, 125.0, 125.9, 126.6, 127.3, 127.7, 128.2, 130.9, 131.5, 139.7, 149.7, 159.9; ir (nujol) ν 1571, 1489, 1438, 1403, 1306, 1288, 1256, 1215, 1150, 1135, 1114, 1041, 1031, 1111, 931, 913, 874, 846, 892, 848, 695 cm-1;ms: m/z (%) = 295 ( M+,53), 294 (20), 266 (38), 252 (7), 239 (21), 227 (8), 213 (40), 196 (10), 171 (16), 129 (6), 110 (16), 103 (15), 84 (100); hrms: m/z calc. for C17H17N3S: 295.1144; found 295.1144. Anal. Calcd. for C17H17N3S:C, 69.14; H, 5.76; N, 14.23; S, 10.87. Found: C, 68.90; H, 5.94; N, 13.94; S, 10.92. 1-(4-Methoxyanilino)-4-(2'-thienyl)-phthalazine (7b). This compound was obtained in 47% yield as a yellow solid, mp 140.0-141.0 ºC (ether). 1Hnmr (dimethylsulfoxide-d6): δ 3.76 (s, 3H, OCH3), 6.86 (d, 2H, 3'' and 5'' or 2'' and 6''-H, J = 9.0 Hz), 7.23-7.28 (m, 1H, 4'-H), 7.64 (dd, 1H, 3'-H, J = 3.6, 1.0 Hz), 7.72 (dd, 1H, 5'-H, J = 5.4, 1.0 Hz), 7.78 (d, 2H, 2'' and 6'' or 3'' and 5''-H, J = 9.0 Hz), 7.96-8.06 (m, 2H, 6 and 7-H), 8.32-8.37 (m, 1H, 5 or 8-H), 8.60-8.64 (m, 1H, 8 or 5-H), 9.21 (br. s., 1H, NH); 13Cnmr (dimethylsulfoxide-d6)δ79.2, 113.6, 118.1, 122.8, 123.3, 124.9, 125.1, 127.6, 127.8, 127.9, 131.7, 132.5, 133.3, 139.6, 146.6, 151.8, 155.0; ir (nujol) ν 3418 (NH), 1616, 1547, 1508, 1382, 1238, 1175, 1032, 838, 768, 708, 646 cm-1; ms: m/z (%) = 333 ( M+,100), 332 (73), 318 (38), 311 (19), 171 (3), 166 (5), 122 (4), 102 (5), 92 (4); hrms: m/z calc. for C19H15N3OS: 333.0936; found 333.0929. Anal. Calcd. for C19H15N3OS: C, 68.45; H, 4.50; N, 12.61; S, 9.63. Found: C, 68.70; H, 4.72; N, 12.83; S, 9.90. 1-(2,4-Dimethoxyanilino)-4-(2'-thienyl)-phthalazine (7c). This compound was obtained in 52% yield as a yellow solid, mp 228.6-229.7 ºC (dichloromethane); 1Hnmr (dimethylsulfoxide-d6): δ3.80 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 6.70 (dd, 1H, 5''-H, J = 8.7, 2.4 Hz), 6.80 (d, 1H, 3''-H, J = 2.4 Hz), 7.30-7.36 (m, 1H, 4'-H), 7.39 (d, 1H, 6''-H, J = 8.7 Hz), 7.78 (br. d., 1H, 3'- H, J = 3.6 Hz), 7.89 (br. d., 1H, 5'-H, J = 4.8 Hz), 8.20-8.30 (m, 2H, 6 and 7-H), 8.44-8.91 (m, 1H, 5 or 8-H), 8.89-8.98 (m, 1H, 8 or 5-H), 11.30 (br. s., 1H, NH); ir (nujol) ν 3434 (NH), 1608, 1582, 1507, 1461, 1302, 1207, 1161, 1110, 1024, 890, 842, 816, 784, 759, 662 cm-1;ms: m/z (%) = 363 (M+,40), 362 (4), 348 (14), 332 (100), 226 (10), 211 (10), 182 (6); hrms: m/z calc. for C20H17N3O2S: 363.1041; found 363.1041. Anal. Calcd. for C20H17N3O2S: C, 66.10; H, 4.68; N, 11.57; S, 8.83. Found: C, 66.30; H, 4.90; N, 11.75; S, 9.10. 1-(4-Cyanoanilino)-4-(2'-thienyl)-phthalazine (7d). This compound was obtained in a 62% yield as a colorless solid, mp 247.8-249.2 ºC; 1Hnmr (dimethylsulfoxide-d6): δ7.267.32 (m, 1H, 4'-H), 7.74 (br. d., 1H, 3'-H, J = 3.3 Hz), 7.80 (m, 3H, 5', 2'' and 6''-H), 8.06 (m, 2H, 6 and 7-H), 8.18 (d, 2H, 3'' and 5''- H, J = 9.3 Hz), 8.44 (br. d., 1H, 5 or 8-H, J = 9.0 Hz), 8.66 (br. d., 1H, 5 or 8-H, J = 9.0 Hz), 9.78 (br. s., 1H, NH); 13Cnmr (dimethylsulfoxide-d6): δ103.0, 118.8, 119.5, 119.9, 123.0, 125.0, 125.4, 128.0, 128.4, 128.8, 132.2, 132.9, 133.1, 139.0, 145.1, 148.5, 151.2; ir (nujol) ν 3409 (NH), 2213 (CN), 1601, 1510, 1442, 1329, 1281, 1245, 1173, 1099, 1045, 925, 837, 781, 737, 625 cm-1; ms: m/z (%) = 328 (M+,62), 327 (100), 171 (6), 102 (6); hrms: m/z calc. for C19H12N4S: 328.0783; found 328.0769. Nov-Dec 2005 1249 M. M. M. Raposo, A. M. B. A. Sampaio and G. Kirsch Anal. Calcd. for C19H12N4S: C, 69.50; H, 3.65; N, 17.07; S, 9.77. Found: C, 69.75; H, 3.90; N, 17.32; S, 10.01. 1-(4-Nitroanilino)-4-(2'-thienyl)-phthalazine (7e). This compound was obtained in a 71% yield as a pale yellow solid, mp 226.3-228.3 ºC (acetone); 1Hnmr (dimethylsulfoxided6): δ7.31-7.34 (m, 1H, 4'-H), 7.78 (dd, 1H, 3'-H, J = 3.7, 1.2 Hz), 7.84 (dd, 1H, 5'-H, J = 5.6, 1.2 Hz), 8.06-8.16 (m, 2H, 6 and 7-H), 8.20 (d, 2H, 2'' and 6''-H, J = 9.3 Hz), 8.30 (d, 2H, 3'' and 5''-H, J = 9.3 Hz), 8.47 (dd, 1H, 5 or 8-H, J = 8.4, 1.5 Hz), 8.73 (dd, 1H, 8 or 5-H, J = 8.4, 1.5 Hz), 10.2 (br. s., 1H, NH); 13Cnmr (dimethylsulfoxide-d6): δ120.5, 121.4, 124.5, 124.9, 126.1, 126.8, 128.3, 130.3, 130.9, 133.8, 134.5, 134.8, 142.4, 145.6, 148.1, 151.6; ir (nujol) ν 3281 (NH), 1608, 1560, 1500, 1379, 1324, 1180, 1105, 854, 782, 748, 712, 649 cm-1;ms: m/z (%) = 348 (M+,84), 347 (100), 301 (31), 211(8), 171 (6); hrms: m/z calc. for C18H12N4O2S: 348.0681; found 348.0675. Anal. Calcd. for C18H12N4O2S: C, 62.06; H, 3.45; N, 16.09; S, 9.21. Found: C, 62.20; H, 3.81; N, 15.30; S, 9.43. Synthesis of the Dimmer 1,2-Bis-[4-(thiophene-2-yl)phthalazine-1-yl]-hydrazine (8). Amixture of 1-chlorophthalazine 4a (0.2 g, 0.8 mmol) and hydrazine hydrate (2.4 mL) in butanol (20 mL) was heated at reflux for 6 h. The mixture was allowed to stand 1 h at rt. After this time an orange solid precipitated. The solid formed, the dimmer 1,2-bis-[4-(thiophene-2-yl)phthalazine-1-yl]-hydrazine 8 was separated by filtration and washed several times with ether to afford a pale brown solution. This organic solution was extracted with ethyl acetate (2x30 mL), and the combined organic extracts were washed with water (30 mL) and dried with MgSO4. Evaporation of the solvent under reduced pressure gave an oil which was purify by "flash" chromatography on silica with increasing amounts of ether in light petroleum as eluent. The first compound eluted was the phthalazinone 3in a yield of 87% as a pale brown oil. The second component eluted was the dimmer 8. This compound was obtained in a 9% overall yield as an orange solid mp 233.7-234.9 ºC (dichloromethane); 1Hnmr δ(deuteriochloroform): 7.16-7.20 (m, 2H, 2x4''-H), 7.40-7.48 (m, 4H, 2x (3'' and 5''-H)), 7.58-7.70 (m, 4H, 2x (6' and 7'-H)), 7.94 (dd, 2H, 2x (5' or 8'-H), J = 7.8, 2.1 Hz), 8.42 (dd, 2H, 2x (8' or 5'-H), J = 7.8, 2.1 Hz), 10.65 (br. s., 2H, 2xNH); ir (nujol) ν 3376 (NH), 1611, 1570, 1455, 1390, 1349, 1231, 1192, 1141, 1090, 1031, 923, 849, 797, 769, 701, 666 cm-1;ms: m/z (%) = 452 (M+, 100), 436 (61), 393(7), 226 (19), 211(26), 196 (20), 171 88), 140 (6), 129 (8), 110 (10), 103 (10), 84 (3); hrms: m/z calc. for C24H16N6S2: 452.0878; found 452.0880. Anal. Calcd. for C24H16N6S2: C, 63.70; H, 3.54; N, 18.58; S, 14.18. Found: C, 63.80; H, 3.81; N, 18.30; S, 14.32. Acknowledgements. Thanks are due to Foundation for Science and Technology (Portugal) for financial support through IBQF (UM) and through FEDER, POCTI (ref. POCTI/QUI/37816/2001). REFERENCES AND NOTES [1] W. J. 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