Synthesis of 2-Substituted Pyrazolo [3,4-d]pyrimides

Auxt. I. Chum. 1991. 44. 1795-180! Synthesis of 2-Substituted Pyrazolo[3,4-d lpyrimidines Ronald 1. Quinn.” Peter J. Scammells.‘ Colin H. 1.. Kermardc and Graham Smith” A Division of Science and Technology. crimth University. Nathan. Old. 4111. ' Author to whom correspondence should be addressed. C Chemistry Department. University of Queensland. old. 4072. 9 School of Chemistry. Queensland University of Technology. Brisbane. 0Jd. 4000. Abstract The reaction of 1-acetyl-2-phenylhydrazine with ethoxymethylenemalononitrile yielded [(4-cyano-1-phenylpyrazol-3-yl):mlnomethylenelpropanedlnltrlle. Hydrolysis followed by annulatlon with methyl Isocyanate provided a synthetic route to 2~phenyIpyrazoIo[3,4» d lpyrlmldlnes. Introduction The xanthines caffeine and theophylline are classical adenosine antagonists. Stmcture/activity analysis of a series of xanthine derivatives has led to the de- velopment of more potent adenosine antagonists, and 8-phenyltheophylline was 1000 times more potent than theophylline in displacing Pfllcyclohexyladenosine from A1 adenosine receptors in a competitive binding assay.‘ We have found that 1-substituted 4-amino-5-methylpyrazolo[3.4-dlpyrimldin-L 0035 also show adenosine receptor affinityf if the heterocyclic rings of xanthlnes and pyrazolo[3.4-dlpyrimidines bind to the adenosine receptor in a similar ori- entation. N2 substituents on pyrazolo[3.4-dlpyrlmidines correspond to C8 substituents on xanthines. Therefore 2-substituted pyrazolo[3.4-d]PYI'imidines are interesting synthetic targets. 2-Substituted pyrazolo[3.4-dlpyrimidines may be synthesized from 1- substituted 3-amlnopyrazole-4»carbonitriles/carboxylates. the syntheses of which generally involve the condensation of ethoxymethylene derivatives with different types of hydrazines.“ Phenylhydrazine. however. reacts with ethoxymethylenemalononitrile to produce the isomeric 5-amino~l- phenylpyrazole-4-carbon!true.‘ The electron-withdrawing nature of the phenyl group reduces the nucleophilicity of the adjacent or nitrogen of the hydrazine, an effect resulting in nucleophilic attack by the [3 nitrogen, followed by cyclization. The addition of a second and stronger electron-withdrawing group to the B nitrogen of the hydrazine results in nucleophilic attack by the (X ‘ Bruns, R. E, Daly. J. W. and Snyder. S. H., Proc. Natl Acad. Sci. LLS.A., i983. so, 2077. 2 Harden. F. A. Qulllll. R. J.. and Scammells. P. J., J. Med. Chem, 1991. 34. 2392. 3 Robins. R, K.. I. Am. Chem. S012. 1956. 73. 784. ‘ Chang. C. C.. and Robins, R. K., J. Org. Chem. 1956. 21, I240. Manuscrlpl received 2 April 1991 0004-9425/9]/12179530100 1796 Short Communications nitrogen. 1~Acetyl~2~methylhydrazine reacts with cyano(ethoxymethylene)ace- tate to produce ethyl 3-amino-I-methylpyra2ole-4-carboxylate in low yields after hydrolysis and cyclization.“ Only one pyrazole with an aromatic substituent has been prepared by this method. 1-Acetyl-2-phenylhydiazine reacted with ethoxymethylenemalonic ester to produce ethyl 3-hydroxy-1-phenylpyrazole-4- ca.rboxylate.9 The synthesis of 2-alkylpyrazolo[3,4-dlpyrimidines has been primarily undertaken by using 1~alkyl-3-aminopyrazole-4-carboxylates and 1-alkyl-3» aminopyrazole~4~carboxamides. These pyrazoles have been condensed with urea, thiourea. isocyanates. isothiocyanates. guanidine and formamide to produce a wide range of 2-alkylpyrazolo[3.4-d]pyrimidines.‘° The isocyanate reactions were of particular interest. The addition of ethyl 3-amino-i-methylpyrazo|e-4- carboxylate to methyl isocyanate generated an intermediate urea. Base-catalysed cyclization of this urea yielded 2,5-dimethyl-2H-pyrazolo[3.4-d]PYrimidin- 4,6(5H.7H)-dione. This compound represents a 1.8~dimethyl pyrazolo[3,4- dlpyrimidine analogue of xanthine.‘° We now report the synthesis of 3-amino-1-phenylpyrazole-4-carbonitrile from 1-acetyl-2~phenylhydrazine and ethoxymethylenemalononitrile, and its annulation with methyl isocyanate to yield a 2-phenylpyrazolo[3,4-dlpyrimidine. Results and Discussion The reaction of 1-acetyl-2-phenylhydrazine and ethoxymethylenemalononitrlle was attempted by using a modified literature procedure.” The reactants were refluxed in ethanol for 12 h. Analysis of the reaction mixture by thin-layer chromatography indicated that no reaction had occurred. Longer reaction times produced no reaction. 1-Acetyl-2-phenylhydrazine was much less reactive than phenylhydrazine in this system. NC / NQ mo - " ,c.clloEi Nc \ / E" m» :c=c_u N / NC }ll (2) 0/ \CH, (1) incl. H20 NH H c NC ) ‘N / CH3NCO ’ N N 4.-—j )\ s / NaOCH3 ~N/ 0 N N "2" J. (4) (3) Scheme 1 5 Schmidt. P.. Eichenberger. K.. and Druey, _l.. Helv. Chim. Acta. 1958. 41, 1052. 6 Schmidt, P.. Elchenberger, l(.. Wilhelm M.. and Druey. J., Helv. Chim. Acm, 1959. 42. 349. 7Schmldt. P.. Eichenberger, K.. Wilhelm M.. and Dnley, ,l.. Helv. Chim. Acla. 1959, 42. 753. 5 Schmidt. P.. Eichenberger. l(.. and Wilhelm. M.. Angew. Chzm.. 1961. 73, 15. 9 Michaelis. A.. and Remy, E., Ber. Dtsch. Chem. £75.. 1907. 1020. '0 Dnxev. J.. Schmidt. P.. and Elchenberger, l(.. U.S. Pat. 3,098,075 (1963). Short Communlcatlons 1797 1-Acetyl-2-phenylhydrazine (1) and ethoxymethylenemalononitrile (see Scheme 1) were stirred in equimolar quantities in phosphoryl chloride at 100’ for 1 h. The reaction was quenched with water; a solid was collected by suction filtration. and recrystallized from methanol. The spectral information was inconsistent with the expected structure. although the n.m.r. data indicated that a pyrazole had been formed. The ‘H n.m.r. spectrum contained a one-proton singlet at 6 8-45 for H5 of the pyrazole ring, and a five-proton multiplet from 6 7-38 to 7-87 for the phenyl protons. The “C n.m.r. spectrum contained peaks at 6 84-9 (C4). 136-1 (CS) and 149-4 (C3) for the carbons of the pyrazole ring, and 6 119-1 (C 2’, C6’), 128-0 (C4’). 129-7 (C3’, C5‘) and 138-1 (C 1’) for the phenyl carbons. However. instead of only one nitrile group. three nitrile groups were readily descernible from the i.r. (2208. 2210 and 2220 cm") and ‘3C n.m.r. (6 112-1. 113-0 and 115-4) spectra. There were additional proton signals at 6 9-31 (one-proton singlet) and 12-19 (exchangeable one-proton singlet), and additional carbon signals at 6 55-7 (quaternary) and 156-5 (methlne). The structure was assigned as [(4-cyano-1-phenylpyrazol-3-yl)aminomethylene]propanedinitrile (2), from the reaction of an initially formed aminopyrazole with a second molecule of ethoxymethylenemalononitrile. NC /© \c N =C— / I H "C H (5) The quaternary, olefinic carbon of the 2.2-dicyanoethenylamino group had a surprisingly low chemical shift (6 55-7). in order to confirm this assignment. anilinomethylenemalononitrile (5) was synthesized by refluxing aniline and ethoxymethylenemalononitrile in ethanol.“ The i.r. spectrum of (5) showed two nitrile peaks at 2230 and 2220 cm". The ‘H n.m.r. spectrum contained a one-proton singlet at 6 8-49 for the methine proton, and the ‘3C n.m.r. spectrum contained peaks for a quaternary carbon at 6 51-8 and a methine carbon at 6 155-8 assignable to the double bond. The quaternary carbon of the 2.2-dicyanoethenylamino group had a chemical shift of 6 55-7 and 51-8 in (2) and (5) respectively. The structure of [(4-cyano-1-phenylpyiazol~3-yl)aminomethylene]propanedi- nitrile (2) was confirmed by X-ray crystallographic analysis performed on a crystal grown from methanol. A perspective drawing of compound (2) is shown in Fig. 1. with the corresponding atomic coordinates in Table 1. Reaction of equimolar amounts of 1-acetyl-2-phenylhydrazine and ethoxyme- thylenemalononitrile was repeated at a lower temperature; however. compound (2) was obtained as the only product. The yield of (2) was optimized by using 2 equiv. of ethoxymethylenemalononitrile. Hydrolysis of (2) with hydrochloric acid gave the required pyrazole (3). The i.r. spectrum showed the presence of only one nitrile peak at 2210 cm“. The ‘H n.m.r. spectrum contained an exchangeable two-proton singlet at 6 5-99 for the amine protons, a one-proton singlet at 6 8-92 for H5 of the pyrazole ring, and signals for the phenyl " Price. c. c.. and Boekelheide, v., 1. Am. Chem. Soc.. 1946, so. 1246. 1798 Short Communications ring. The ‘3C n.m.r. spectrum contained a peak at 6 114-1 for the nitrile carbon. peaks at 6 80-6 (C 4), 133-4 (C 5) and 158-0 (C 3) for the carbons of the pyrazole ring. and signals for the phenyl ring. 3-Amino-1-phenylpyrazole-4-carbonitrile reacted with methyl isocyanate in the presence of sodium methoxide in dimethylformamide at 60' for 4h. Neutralization with 1M hydrochloric acid. evaporation of the solvent, and recrystallization from aqueous dimethyl sulfoxide yielded 4-imino-5—methyl- 2-phenyl-4,5-dihydropyrazololi-I.4-dlpyrimidin-6(7H)-one (4). The molecular formula C12HnN50 was confirmed by microanalysis and high-resolution mass spectrometry. The i.r. spectrum showed the disappearance of the nitrile peak Fig. l. Perspective drawing of [(4-cyano-1-phenylpyrazoi-3-yl)aminomethylenelpropanedinl trlle (2). with the crystallographers' numbering scheme. Thble 1. Atomic coordinates of l(4€yaIIo-I.-phenylpyrazol-3-'yl)anIll.IomeIIIyIenel- propanedinilrile (2) Atom X/a V/b Z/c Atom X/a Y/b Z/c N(1) 0«6s77(2) 0~2a13(4) D-64590) C(16) 0600314) 0421217) 0-731911) N(2) 0~67s4(2) 0423814) 0-6011(1) N(31) 0-7755(2) D-0903(4) o«s1s2(1) C(3) 0- 7637(2) 0- 207245) 0- 56754)) C(32) o -6966(3) -0 ~ 1006(5) 0 -499311) c(4) 04332442) 0416215) 0-5900(1) C(33) 0-699113) —o-2262(5) 0-4505(1) C(5) 0479313) 0456716) 0-6400(1) C(34) 0-7882(3) -0-1690(5) 0«4093(1) C(11) 0-6001(3) 0-2516(5) 04539441) N435) 17-86036) -0- 1251(6) 0-376511) C(12) 0-517:-1(3) o~o5o9(6) 0~6e8s(1l C(36) 0-611513) -0-431416) 0-439211) C(13) 0432913) 04125848) 0-7315(2) N(37) 0-5425(3) -0-5966(5) 0430211) C(14) 0431913) 0495018) 0-7737(1) C(41) 0-9361(3) 0-557115) 0-5653(1) C(15) 0-5160(4) 0-3937(7) 0~7739(1) N142) 1-018843) 0-6699(5) 0550611) Short Communications 1799 at 2210cn1“, and the appearance of a carbonyl stretch at 1720 cm“ and NH stretches at 3120 and 3450cn-F1. The ‘H n.m.r. spectrum contained a three~proton singlet at 5 2-87 for the methyl group. two exchangeable one-proton singlets at 5 8~24 and 11~27 for the NH protons. a one-proton singlet at 6 9-02 for H3 of the pyrazolu[3,4-dlpyrimidine ring, and signals for the phenyl ring. The “C n.m.r. spectrum contained a peak at 6 26-8 for the methyl carbon, peaks at 5 102-7 (C3a). 1282 (C3). 150-0 (C4), 1515 (C 7a) and 158«8 (C6) for the carbons of the pyrazolo[Ei,4-dlpyrimidlne ring, and signals for the phenyl ring. Bperimenlal Melting points were determined on a Gallenkamp melting point apparatus and are uncorrected. Infrared spectra were recorded as Ker disks on a Jasca lR-B10 instniment. ‘H and “C n.m.r. spectra were run on a Bruker WM-250 spectrometer at 250-2 and 62-BMHz respectively. The type of carbon was assigned by using the om pulse sequence; q, methyl: t, methylene: d. methlne; 5. quaternary. (CD3)2S0 was used as solvent and internal standard. Microanalyses were determined by the Australian Microanalytlcal Service. Melboume. Mass spectra were recorded on a Kratos MS-25 spectrometer. X-Ray crystallographic analysis was determined at 296 K on an Enrai—Nonius CAD-4 four Ie diffractometer in conventional 29/9 scan mode. Reaction of 1-Acelyl-2-phenylliiydnzine with Ethnxymethylannnnlononitrile Method A 1-Acetyl-2-plienylhydrazine (o- 5 g. 3- 3 mmol) and elhoxymethylenelnalononitrile to-41 g. 3-3 mmol) were refluxed in absolute ethanol for 12 h. The solvent was evaporated to produce a crude solid. A quantitative yield of starting material was isolated. Method B 1-Acetyl-2-phenylhydrazine (0-5 3, 3~ 3 mmol) and ethoxymethylenemalononiirile (041 g. 3-3 mmol) were stirred at 100‘ in phosphoryl chloride (0- 56 g, 3 -7 mmol) lot 1 h. The reaction was quenched with water; the solid was collected by suction filtration. and recrystallized from methanol to give [(4-cyuno-1-phenylpyrazol-3-yllizminomethylenejpropanedlnltrile (2). yield 32%, i'n.p. 225-228‘ (Found: C, 64-6; H, 3-2; N, 32-4. C14H3Ns requires C. 64~5; H1 3-1; N, 32-3%). i.r. (KBr) Vmax 3210, 3150, 2220, 2210, 2208 cn1'l. ‘H n.n'l.r. 5 7-38-7-87, m. phenyl: 845. s, H 5:9»31.s.methlne; 12-19. br s. NH. '3C n.rn.r. 6 SSA7, s. quaternary: SL9. 5. C4; 112-1, s. CN;113-0, s, CN: 115-4, s, CN: 119-]. d, C2’,6'; 128~0. d. C4’; 1297. d. C3’.5’; 136-1. d, C5:138-1, s, C1’;149~4, 5, C3: 1565. d. methine. Crystal/refinement dam.—Cr4H3Ne, M 260 3, monoclinic. space group P2;/n, a 9732(2). 17 S~S66il). c 23-659(6)A. 3 97.390)‘, V 1271-ots)A3. Dc iZ=4) 1-359gcm‘3, Ftooo) S36. Monochromatic Mo Kat radiation (Ii 071073 A). A prismatic crystal was cleaved to give 3 specimen 0~35 by 0