NOTES

6. J. E. I-IAZELL a11d I<. E. RUSSELL. Can. J . Chem. 36, 1729 (1958). 7. J. C. McGown~, T. POWELL, and I<. RAW. J . Chcm. Soc. 3103 (1959). 8. J. S. HOGG, D. H. LOHMANN, and I<. E. RUSSELL. To be published. 9. E. S. COOK and A. J. HILL. J . An1. Chcm. Soc. 62, 1995 (19-i0).

THE CONDENSATION OF RHODANINE AND DERIVATIVES WITH 4-ANTIPYRINALDEHYDE

FREDERICK J. AI,LAN' AND G. GR-11-IAM ALLAN'

More than three-quarters of a century has elapsed since antipyrine (Ia) was introduced into medicine by Knorr as an antipyretic and analgesic (1). Altllough pyrazolone anal- gesics have now virtually vanished from the scene in North America and the Scandinavian countries (2), they are still widely used in other areas and considerable efforts have been expended to improve their pharmacological properties (3, 4). 111 recent years seine

of this effort has been focused on 4-antipyrinaldehyle (Ib)%and its derivatives (5-14), principally in connection wit11 antineuralgic and febrifugal effects. While insecticidal pyrazolones have been described (15-17), other nonanalgesic applications of 4-anti- pyrinaldehyde or its derivatives have received little attention other than brief reports of tuberculostatic (18) and bacteriostatic activity (10).

(2.. I< = 1-1 6. R = CHO C. R = SFT

in SII (% = 1-11 Srst (% = ethyl) S.,II (Z = allvl)

As part of a study of potential bacteriostats (20, 21), rhodanine has been condensed with a variety of carbonyl-containing compounds (22-29), including the highly effective monoheterocyclic furnn and thiophen aldehydes (30). I-Iowever, no rhodanine con- densation products have been prepared which contain a carbonyl-derived moiety com- prising a five-memberecl ring with two heteroatoms. The pyrazolone aldehycle (Ib) was

' T o wlzo7n enquiries sholild be addressed. 2Present address: Eleclrocl~e~~zicals Departnrent, E . I . dzi Po721 de iVcnzoz~rs & Co., Inc., I I f z lnz i ,~glo~~, Ilel.,

U.S. A . 3175 111e early li teralz~re Ilzis aldehydic S ~ ~ Z L C ~ I L Y C was erroneoz~sly assigned to a71 isot~zeric kcton(, ( 6 )

Can. J. Cl~rm. Vol. 39 (l'J(i1)

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therefore condensed with rhodanine, and its 3-ethyl, -allyl, -phenyl, and -carboxymethyl relatives, using sodium acetate in a mixture of acetic acid and anhydride as the con- densing medium (21). The products," (Ic) to (Ig), separated from the reaction mixture in an almost pure state.

5-[4-(l-Phe~zyl-2,S-dimethylpyrazol-5-onyl)methylene]rhodanine (Ic) A mixture of 4-antipyrinaldehyde (216 mg, 0.001 mole) and rhodanine (133 mg, 0.001

mole) in acetic acid (1 ml) to which sodium acetate (200 mg) and acetic anhydride (0.1 ml) had been added, was refluxed for 30 minutes. The reaction mixture was allowed to cool when crystals separated. Recrystallization from dimethylforma~nide-ethanol gave (Ic) as small golden yellow needles (102 mg, yield 31%) m.p. 325-327" with decom- position. Calc. for C15H13N302S2 (331.402): C, 51.36; H, 3.95. Found: C, 54.21 ; HI 3.76y0. The following coinpou~lds were similarly prepared.

3-Ethy1-5-[~-(1-~1zcnyl-2,3-dimethylpyrazo1-5-ony)methyee]rhodae (Id) Orange plates (300 mg, yield 33y0) m.p. 26.5-267O, crystallized froin ethanol-benzene-

dimethylformamide. Calc. for Cl7Hl7N302S2 (359.462): C, 56.79; HI 4.77. Found: C, 56.48; I-I, 5.08%.

3-Allyl-5-[~-(1-~heny1-2,3-dimethy1pyrazo1-5-oy)methyee]rhodane (Ie) Golden yellow blades (425 mg, yield 57%) m.p. 203-204", crystallized from acetic

acid. Calc. for CIaI-Il7N302SZ (371.472): C, 58.18; H, 4.61. Found: C, 58.32; H, 4.72%.

3-Phenyl-5-[4-(l-phenyl-2,3-dimethylpyrazol-5-onyl)methylene]rhonine (If) Bright orange plates (43.5 mg, yield 54%) 1n.p. 266-268" with darkening, crystallized

from ethanol-dimethylforina~~~ide. Calc. for CZ1H 17N302S2 (407.502) : C, 61.9; H, 4.17. Found: C, 61.62; I-I, 4.03%.

3-Carboxymethyl-5-[4-(l-phenyl-2,3-dimethylpyrazol-5-onyl)methylene]rhodanine (Ig) Orange-yellow needles (200 mg, yield 26y0) 1n.p. 260-262O, crystallized from ethanol-

dimethylformamide. Calc. for CliHI5N3O4S2 (389.442): C, 52.44; H , 3.88. Found: C, 52.65; H, 3.72%.

1. L. I<NoI~I~. Ber. 17, 546, 2032 (1884). 2. T. L. J ~ c o n s . I n Heterocyclic compounds. Vol. 5. Edited by R. C. Elderfield. John Wiley & Sons,

Inc., New York. 1957. p. 153. 3. L. GOODMAN and A. GILMAN. The ~harmacoloeical basis of theraaeutics. 2nd ed. The Macmillan

Co., New York. 1955. pp. 318-323: -

4. L. A. GREENBERG. Antipyrine. Hillhouse Press, New Haven. 1950. 5. I<. BODENDORF, J. MILDNER, and T. LEHMAN. Ann. 563, 1 (1949). 6. I<. BODENDORF and A. POPELAK. Ann. 566, 84 (1950). 7. K. BODENDORF and H. RAAF. Ann. 592, 26 (1955). 8. M. RIDI. Gazz. chim. ital. 71, 95, 100, 106 (1941); 77, 3 (1947). 9. M. RIDI and S. CHECCHI. Ann. chim. (Rome), 43, 816 (1953).

10. M. PASSERINI, M. RIDI, and G. Losco. Gazz. chim. ital. 80, 803 (1950). 11. J. LEDRUT and G. COA~BES. Bull. soc. chim. France, 127, 786 (1950). 12. J. LEDRUT, G. COMBES, and H. SWIERKOT. Bull. soc. chim. France, 185 (1952). 13. A. WINTERNITZ, J. LEDRUT, and G. COMBES. Bull. soc. chim. France, 398 (1952). 14. G. COMBES, M. I;. HEBBELYNCK, and J. LEDRUT. Bull. soc. chim. France, 315 (1953). 15. R. GASSEI~. Ber. schweiz. botan. Ges. 62, 66 (1952). 16. G. R. FERGUSON and C. C. ALEXANDER. J. Agr. Food Chem. 1, 888 (1953). 17. H. GYSIN. Chimia Switz. 8, 205, 221 (1954). 18. J. KLOSA. Arch. Pharm. 288, 217 (1955); 288, 545 (1955).

*Fungicidal and bacteriostatic evaluation of which we hope to pr~blisiz later elsewhere. 5~Melting points are uncorrected.

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NOTES 13YD

19. J. £1. 'T. LHDKUT, to Luxema S. A., 1.S. Patent 30. 2,650,219 (ilugust 25, 1953). Equivalent Brit. Patent No. 688,225 (March 4. 1953).

20. I;. J. ALLAN and G. G. ALLAN. ' ~ e c . i rar . chirn. I n press. 21. F. J . ALLAN and G. G. ALLAN. J. Org. Chem. 23, 639 (1958). 22. G. G. ALLAH, D. MACLEAN, and G. T. NEWBOLD. J. Chem. Soc. 5053 (1952). 23. F. J. ALLAN, G. G. ALLAN, and J. B. THOMSON. J. Org. Chem. 23, 112 (1958). 24. 1;. J. ALLAN, G. G. ALLAN, and J . B. THOMSON. Can. J. Chem. 36, 1579 (1958). 25. F. J. ALLAN and G. G. ALLAN. Rec. trav. chim. 78, 67 (1059). 26. F. J. ALLAN, G. G. ALLAN, and C. M'F. NI'NEIL. Nature, 184, 1637 (1959). 27. F. 1. ALLAN and G. G. AI.T.AN. Rec. trav. chim. 78. 375 (1958). .-- . . 28. F. I[. ALLAN, G. G. ALLAN, G. CRANK, and J. JACK. ' ~ e c : trav: chim. 79, 247 (1960). 29. 1:. J. ALLAN, G. G. ALLAN, and G. CRANK. J . ilppl. Chem. 11,68 (1961). 30. F. C. BROWN, C. I<. BRADSHER, and fi:. N. IAAIVTOlv. Ind. Eng. Chem. 45, 1027 (1953).

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