Behaviour of Some Activated Nitriles Toward Barbituric, Thiobarbituric Acids and 3-Methyl-1-Phenylpyrazol-5-one

Transcription

1 Jour nal of the Chi nese Chem i cal So ci ety, 2000, 47, Behaviour of Some Activated Nitriles Toward Barbituric, Thiobarbituric Acids and 3-Methyl-1-Phenylpyrazol-5-one H. M. F. Madkour*, M. R. Mahmoud, M. H. Nassar and M. M. Habashy Synthetic Org. Chem. Lab., Chem. Dept., Faculty of Science, Ain Shams University, Abbassiya, Cairo, Egypt The ef fect of some ac tive meth y lene con tain ing heterocyclic com pounds, namely bar bi tu ric, thiobarbituric ac ids and 3-mehtyl-1-phenylpyrazol-5-one on -cyano-3,4,5-trimethoxycinnamonitrile and ethyl -cyano- 3,4,5- trimethoxycinnamate 1a,b was in ves ti gated. The struc ture of the new prod ucts was sub stan ti ated from their IR, 1 H NMR and mass spec tra. INTRODUCTION Re cently, it has been re ported that 1 the re ac tion of chalcones with bar bi tu ric or thiobarbituric acid may af ford pyranopyrimidine de riv a tives in the pres ence of P 2 O 5 or it may pro ceed via sim ple sub sti tu tion with triethanolamine, 2 de pend ing on the re ac tion con di tions. Also, the re ac tion of -cyanocinnamonitrile with bar bi - tu ric acid af forded pyranopyrimidine, 3 arylidene de riv a tive 4 or sim ple sub sti tu tion prod uct. 5 The pres ent work stud ies the be hav iour of -cyano - cinnamonitrile de riv a tive 1a,b and chalcone 4 to ward bar bi tu - ric and/or thiobarbituric acid 2a,b. Thus, when com pound 1a,b and/or com pound 4 was sub mit ted to re act with com - pound 2a,b in refluxing pyridine af forded the arylidine de riv - a tive 3a,b [cf. Scheme I]. struc ture. This struc ture gets fur ther sup port from mass spec - tros copy. It has been ob served that elec tron im pact (EI) spec - tra have many com mon fea tures. The first of which is that the high est re corded peak rep re sent ing the mo lec u lar ion peak (m/z 306 & 322). The sec ond is the sim i lar ity in their EI frag - men ta tion pat terns. The com mon frag men ta tion path ways are rep re sented in Chart 1. Scheme I Chart 1 The struc ture of com pounds 3a,b was ex plored by 1 H NMR, mo lec u lar weight de ter mi na tion us ing field desorption mass spec tros copy as well as the chem i cal ev i dence. The 1 H NMR spec trum of 3 (Y=O,S) in DMSO-d 6 dis played sig nals from low to high field at (ppm) 11.5, 11.4 (two s, 2H, 2NH), 8.4 (s, 1H, olefinic pro ton), 7.9 (br. s, 2H, ar o matic pro tons) and 3.95 (br. s, 9H, 3 OMe) which agree well with the as signed Fur ther more, the arylidene de riv a tives 3a,b show iden - tity (lr, TLC, m.p and m.m.p with an au then tic sam ple pre - pared by stir ring 3,4,5-trimethoxybenzaldehyde with bar bi tu - ric and/or thiobarbituric ac ids in refluxing ace tic acid. A pos - si ble path way for the for ma tion of the arylidene de riv a tives may be rep re sented by Scheme II. The di verse bi o log i cal ac tiv i ties of fused pyra zoles have stim u lated con sid er able re search in this field It has been re ported 12 that the pyrazolone de riv a tive 5 re acted with -cyanocinnamonitrile in the pres ence of piperidine to yield the 1:1 adduct 6. On the other hand, it has been also claimed 13 that the above men tioned re ac tion af forded two prod ucts in stead of com pound 6 [cf. Scheme III].

2 938 J. Chin. Chem. Soc., Vol. 47, No. 4B, 2000 Madkour et al. Scheme II Chart 2 Scheme III Be cause of the strik ing bi o log i cal ac tiv ity of fused pyra - zoles, and to ex tend the pres ent work, equimolar amounts of 1a and 5 were refluxed in ab so lute eth a nol in the pres ence of piperidine as a cat a lytic base. Af ter 15 min utes an in sol u ble frac tion was iso lated as colour less crys tals, 13%, and de tected to be the oxino bispyrazole 7 and the re ac tion was com pleted for 3 h. Re moval of most of the sol vent and acid i fi ca tion with di luted ace tic acid af forded the 1:1 adduct 8a or 8b as pale yel - low crys tals; 44% and 46% yield, re spec tively [cf., Scheme I]. The struc ture of 7 is elu ci dated ex clu sively from its IR and mass spec tral data be side the cor rect an a lyt i cal data and chem - i cal ev i dence. Thus, the IR spec trum of 7 lacks C=O and CN. The mass spec trum of 7 is rep re sented in Chart 2 which is in ac cor dance with the pro posed struc ture. Fur ther more, the bis-pyrazole de riv a tive 7 shows iden tity (IR, m.p. and mixed m.p., TLC) with an au then tic sam ple syn the sized by stir ring 3,4,5-trimethoxybenzaldehyde with 5 in ab so lute eth a nol in the pres ence of a cat a lytic amount of piperidine for 15 min utes [cf. Scheme I]. Struc ture of the adduct 8a is based upon: (i) The el e men tal anal y sis which gave sat is fac tory re - sults. (ii) The IR dis played NH 2 at 3485, 3373 and 3223 cm-1, CN at 2205 cm -1 and C=N at 1622 cm -1. (iii) The 1 H NMR spec trum (DMSO-d 6) ex hib its sig nals at (ppm) (m, 5H, ph), 6.8 (s, 2H, arom. pro tons), 5.0 (s, 1H, CHAr), (two s, 9H; 3 OMe) and 2.3 (s, 3H, Me). (iv) EI frag men ta tion of 8a in volves pri mary loss of CN fol lowed by H-abstraction to give the rad i cal cat ion of m/z = 393/100%; base peak). There is also a loss of form al de hyde mol e cule to give the ion of m/z = 363 (84.0%) which is the ma - jor daugh ter. Suc ces sive loss of two mol e cules of form al de - hyde re sulted in the rad i cal cat ion of m/z = 303 (5.1%). The ten ta tive frag men ta tion pat tern of 8a is rep re sented in Chart 3. The IR spec trum of the adduct 8b lacks CO of es ter and dis played OH(br) cen tered at 3913 cm -1, CH 2941 cm -1, CN at 2216 cm -1, C=N at 1620 cm -1 and C=C at 1595 cm -1. The 1 H NMR spec trum of 8b (DMSO-d 6) ex hib its sig - nals from low to high field at (ppm) (m, 5H, ph), 6.9 (s, 2H, ar o matic pro tons), 5.0 (s, 1H, CHAr), (two s, 9H, 3 OMe), and 2.4 (s, 3H, Me). The mass spec trum of 8b which is in ac cord with the as signed struc ture is rep re sented in Chart 4. The for ma tion of the oxino bis-pyrazole de riv a tive 7

3 Ac ti vated Nitriles, Bar bi tu ric Acids J. Chin. Chem. Soc., Vol. 47, No. 4B, Scheme IV Cyclization of the acy clic Mi chael ad ducts via at tack of the ring car bonyl ei ther on the cyano or es ter func tional group yielded the prod ucts 8a and 8b re spec tively. EXPERIMENTAL Chart 3 Chart 4 from the re ac tion of 1a and/or 1b with 3-methyl-1- phenyl - pyrazolone 5 prob a bly pro ceeds via the ini tial Mi chael ad di tion to af ford acy clic Mi chael s adduct which then loses the ac tive meth y lene moi ety, i.e., malononitrile or ethyl cyano acetate to give the arylidene pyrazolone which could be at tacked by a new mol e cule of 5 fol lowed by cyclo dehydra tion step to yield the iso lated bis-pyrazole de riv a tive 7 [cf. Scheme IV]. Melting points are not cor rected. The IR spec tra were re corded in a Pye-Unicam SP 1200 spectrophotometer us ing KBr wa fer tech nique. The 1 H NMR spec tra were de ter mined on a Varian GEM INI 200 MHz NMR Spectrophotometer us ing DMSO-d 6 as sol vent and TMS as in ter nal stan dard. All chem i cal shifts are in ppm downfield from TMS. The el e men tal anal y sis were car ried out in the Cen tral Lab., Fac ulty of Sci ence, Ain Shams Uni ver sity, Abbassiya, Cairo, Egypt. Mass spec tra were re - corded on Shimadzu GC-MS-QP 1000 EX in stru ment. The pu rity of the syn the sised com pounds was con trolled by TLC. Re ac tion of -cyano-3,4,5-trimethoxycinnamonitrile 1a and/or ethyl -cyano-3,4,5-trimethoxycinnamate 1b with bar bi tu ric acid and/or thiobarbituric acid; Formation of 5-(3,4,5-trimethoxybenzylidene)bar bi tu ric or thio - barbituric acid 3a and/or 3b A mix ture of 1a (2.44 g, 0.01 mol) and/or 1b (2.91 g, 0.01 mol) and bar bi tu ric acid (1.28 g, 0.01 mol) or thio - barbituric acid (1.44 g, 0.01 mol) in pyridine (30 ml) was refluxed for 3 h. Most of the sol vent was dis tilled off and the re ac tion mix ture was cooled and acid i fied with ice-cold gla - cial ace tic acid. The solid which de pos ited was fil tered off, washed with cold wa ter, dried and recrystallized from the proper sol vent to give 3a and/or 3b [cf. Ta ble 1]. Re ac tion of chalcone 4 with barbituric and/or thio - barbituric acid, For ma tion of 3a or 3b A mix ture of chalcone 4 (3.28 g, 0.01 mol), and bar bi tu - ric acid (1.28 g, 0.01 mol) and/or thiobarbituric acid (1.44 g,

4 940 J. Chin. Chem. Soc., Vol. 47, No. 4B, 2000 Madkour et al. Ta ble 1. Phys i cal Char ac ter is tics of the New Com pounds Compd. Mol. F. Mol. M.P C Yield % Sol vent of Col our Wt.* Recryst.** 3a 3b 7 8a 8b C 14H 14N 2O 6 C 14 H 14 N 2 O 5 S C 30H 28N 4O 4 C 23 H 22 H 4 O 4 C 23H 21N 3O 5 (306) (322) (508) (418) (419) (78.6) (83.11) (13) (44) (46) E.A M CCl 4 CCl 4 B/L.p (Yel low) (Pink) (Colour less) (Pale yel low) (Pale yel low) * All el e men tal anal y sis (C,H,N) are in agree ment with the cal cu lated val ues. ** E.A. = Ethyl ac e tate, M = Meth a nol, B = Ben zene., L.P = Light pe tro leum mol) in pyridine (30 ml) was refluxed for 3 h. The re ac - tion mix ture was con cen trated, cooled, and acid i fied with ice cold ace tic acid. The solid which sep a rated out was fil tered off, washed with wa ter, dried and recrystallized from the suit - able sol vent to give 3a (26.7% yield) and/or 3b (42.4% yield). Re ac tion of bar bi tu ric and/or thiobarbituric acid with 3,4,5-trimethoxybenzaldehyde; Formation of an au then tic sam ple of 3a A mix ture of bar bi tu ric acid (1.28 g, 0.01 mol) or thiobarbituric acid (1.44 g, 0.01 mol) and 3,4,5- tri methoxy - benzaldehyde (1.96 g, 0.01 mol) in gla cial ace tic acid (30 ml) was heated un der re flux for 30 min utes. The re ac tion mix ture was con cen trated, di luted with ice cold wa ter. The solid de - pos ited was fil tered off, dried and recrystallized from the proper sol vent to yield 3a (77.3% yield) and/or 3b (86.1% yield). Re ac tion of 1a with 3-methyl-1-phenylpyrazol-5-one 5; For ma tion of 4H-3,5-dimethyl-1,7-diphenyl-4-(3,4,5- trimethoxyphenyl)oxino[2,3-c:6,5- c] bis-pyrazole 7 and 4H-6-amino-5-cyano-3-methyl-1-phenyl-4-(3,4,5- trimethoxyphenyl)pyrano[2,3-c]pyrazole 8a and/or 4H-5-cyano-6-hydroxy-3-methyl-1-phenyl-4-(3,4,5- trimethoxyphenyl)pyrano[2,3-c]pyrazole 8b A mix ture of the arylidene de riv a tive 1a (2.4 g, 0.01 mol) and/or 1b (2.91 g, 0.01 mol) and 3-methyl-1- phenyl - pyrazol-5-one 5 (1.74 g, 0.01 mol) in ab so lute eth a nol (30 ml) was refluxed in the pres ence of a cat a lytic amount of piperidine. Af ter 15 min utes, the colour less in sol u ble prod uct was fil tered off, dried and recrystallized from the proper sol - vent to give 7. The fil trate was refluxed up to 3 h. Most of the sol vent was dis tilled off and the re ac tion mix ture was cooled and acid i fied with ice cold ace tic acid. The de pos ited solid was fil tered off, dried and recrystallized from the suit able sol - vent to give 8a and/or 8b [cf. Ta ble 1]. Re ac tion of 5 with 3,4,5-trimethoxybenzaldehyde; For ma - tion of an au then tic sam ple of 7 A mix ture of 3,4,5-trimethoxybenzaldehyde (1.96 g, 0.01 mol) and 3-methyl-1-phenylpyrazol-5-one 5 (1.74 g, 0.01 mol) in ab so lute eth a nol (30 ml) in the pres ence of a cat - a lytic amount of piperidine was refluxed for 15 min utes. The in sol u ble prod uct was fil tered off, dried and recrystallized from the proper sol vent to give 7. Re ceived No vem ber 11, Key Words Bar bi tu ric and thiobarbituric ac ids; Pyrazolone; Ac ti vated nitriles. REFERENCES 1. Ahluwalia, V.; Kumar, K.; Alauddin, M.; Khandi, C.; Mallika, N. Synth. Commun. 1990, 20(9), Ahluwalia, V. K.; Aggarwal, R.; Alauddin, M.; Gill, G.; Khanduri, C. H. Heterocycles. 1990, 31(1), Sharamin, Yu A.; Klokol, G. V. J. Org. Chem. (USSR) 1984, 20, Abdel-Latif, F. F. In dian J. Chem. Sect. B. 1991, 30(3), Ibrahim, M. K. A.; El-Moghayar, M. R. H.; Sharaf, M. A. F. In dian J. Chem. Sect. B. 1987, 26, Koyama, G.; Umezawa, H. J. Antibiot. 1965, 18A, 175; Chem. Abstr. 1965, 63, 15158d. 7. Robins, R. K.; Townsend, L. B.; Cassidy, F. C.; Geroter, J. F.; Lewis, A. F.; Miller, R. L. J. Het. Chem. 1963, 3, El-Nagdi, M. H.; El-Moghayer, M. R. H.; El-Fahham, H. A.; Sallam, M. M. M.; Alnima, H. H. J. Het. Chem. 1980, 17, 209.

5 Ac ti vated Nitriles, Bar bi tu ric Acids J. Chin. Chem. Soc., Vol. 47, No. 4B, El-Nagdi, M. H.; Fahmy, S. M; Hafez, E. A. A.; El-Moghayer, M. R. H.; Amer, S. A. R. J. Het. Chem. 1979, 16, El-Nagdi, M. H.; Hafez, E. A. A.; El-Fahham, H. A.; Kandeel, E. M. J. Het. Chem. 1980, 17, El-Nagdi, M. H.; El-Moghayer, M. R. H.; Fleita, D. H.; Hafez, E. A. A.; Fahmy, S. M. J. Org. Chem. 1976, 41, Abdou, S.; Fahmy, S. M.; Sadek, K. U.; El-Nagdi, M. H. Heterocycles. 1981, 16(12), Sharamin, Yu A.; Promonenkov, V. K. J. Org. Chem. (USSR) 1982, 18,