Starting with diethyl (2-furfuryl) -malonate, obtained by
reduction of diethyl (2-furfurylidene) -malonate with aluminum
amalgam in wet ether, several new or hitherto insufficiently
characterized 1- or/and 5-substituted 5-(2-furfuryl) -barbituric and
-thiobarbituric acids, have been prepared

B. Glunčić

K. Jakopčić

N . Krvavica

V. Hahn

English

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CR 0 AT IC A CHEMIC A ACT A 38 (1966) 119 CCA-416 547 .854.5.05 Original Scientific Paper Preparation of Some New Substituted 5-(2' -Furfuryl)-barbituric and -thiobarbituric Acids* B. Gluncic**, K. JakopCic, N . Krvavica, and V. Hahn Laboratory of Organic Chemistry, Faculty of Technology, University of Zagreb and Research Department, »Pliva«, Pharmaceutical and Chemical Works , Zagreb, Croatia, Yugoslavia . Received January 24, 1966 Starting with diethyl (2-furfuryl) -malonate, obtained by reduction of diethyl (2-furfurylidene) -malonate with aluminum amalgam in wet ether, several new or hitherto insufficiently characterized 1- or/and 5-substituted 5-(2-furfuryl) -barbituric and -thiobarbituric acids, have been prepared. Among the very numerous known barbituric and thiobarbituric acid derivatives which are of interest for their pharmacodynamical properties, only a limited number (about fifteen), containing a 2-furfuryl group, have been described or mentioned in literature,1 and only one of them, i.e. 5-isopropyl-5--(2-furfuryl)-barbituric acid, is in clinical use. 2 The aim of the present work was to prepare several new or hitherto insufficiently characterized 1- or/and 5-substituted 5-(2-furfuryl)-barbituric and -thiobarbituric acids, in order to make them available for pharmacological testing. The synthesis of these compounds has been accomplished in the following way: ~ /COOC2Hs ~,.../-CH =C o 'cooc,Hs ~-(A l (N a OC2Hsl ff1 CO - NR1 ~,...>CH2 / '\. 0 'c c=x R/ '\. / •NH 2·CX·NHR1 CO-NH (I - VIII) * Studies in the Furan Series. XII. Part XI. D. B i 1 o vi c and V. H ah n, Croat. Chem. Acta 37 (1965) 185. ** Taken in part from the Thesis of B. Gluncic, submitted to the University of Zagreb (1964), in partial fulfilment of the requirements for the degree of Doctor 0£ Chemistry (Ph. D.) ---No. I II III IV v VI VII VlII TABLE 1 Derivatives of 5-(2-Furfuryl)--barbituric and -thiobarbituric Acids 0-co-NR, CHi I "-.. 0 'c C =X / "'-I R CO-NH I I I Yield of I Calc'd., 0/l'J Found, O/o R Ri I x I crude I prod. I Ofo C2H5 H 0 65 H CHa 0 75 C2H5 CH3 0 68 i-C3H7 CH a 0 I 8 CH2CH = CH2 CH a 0 83 C2H5 H s 67 i-CaH1 H s 60 CH2CH = CH2 H s 43 a After crystallization b Recrystallized from ethanol c Reported5 m. p. 144.5-145° C d Recrystallized first from ethanol and then from isopropanol Mp, oca I 160-llJlb,c 95-96d 115--116b 86-87e,f 8o-8rn 180-18lh 178-179e 152-153e Formula I I c H N c C11H12N204 55.93 5.12 11.86 55.76 C10H10N20,1 54.05 4.54 12.61 53.99 C12H14N204 57.59 5.64 11.20 57.66 C1aH16N204 59.08 6.10 10.60 59.40 C13H14N204 59.53 5.38 10.68 59.44 C11H12N203S 52.36 4.79 11.11 52.26 C12H14N20aS 54..12 5.30 10.52 54.43 C12H12N20aS 54.53 4.58 10.60 54.67 e Recrystallized from dilute ethanol (1 : 1) Reported10 m. p. 73-75° C g Recrystallized from dilute ethanol (1 : 2) 11 Recrystallized first from ethanol and then from n-butanol I H I N 5.03 11.95 4.42 12.88 5.68 11.48 6.14 10.89 5.12 10.93 4.51 11.03 5.06 10.62 4.56 10.78 ..... t'-:> 0 ~ 0 '" c z 0 H 0 t>J ..., :io. ~ PREPARATION OF SOME NEW SUBSTITUTED BARBITTJRIC ACIDS 121 Reduction of diethyl (2-furfurylidene)-malonate (A)3 with amalgamated aluminum in wet ether4 yielded an oily product, from which by fractionation 35-400/o of diethyl (2-furfuryl)-malonate (B) 5 could be isolated. The rest was a high boiling viscous oil, which proved to be the product of reductive dimeri-zation (»hydrodimerization« 6) of A. The reduction of A and of related compounds with aluminum amalg'am has been studied in detail in our laboratories7 ; the results of this work will be published later. Diethyl (2-furfuryl)-malonate (B) was alkylated in the usual way8 to yield the cor responding diethyl alkyl- (or allyl) 2-furfuryl-malonates. Conden-sation of the disubstituted malonic esters with urea, N-methylurea or thiourea, was carried out according to the procedure described by Inman and Bitler, 9 the solution of sodium ethoxide beeing added gradually to the mixture of the reactants in order to minimize formation of by-products. In this manner the barbituric and thiobarbituric acid derivatives I-VIII, listed in Table 1, have been prepared. The yields were satisfactory in most cases. The crude products could be purified by recrystallization from appropriate solvents, except IV and V, which were obtained in pure form after reprecipitation from aqueous ammonium hydroxide solutions with carbon dioxide.11 Two of the prepared barbituric acid derivatives (I and IV) have been prepared earlier in a somewhat different way5•10 ; nevertheless, they a re included in this paper because the reported melting points differ sensib ly from those found in our experiments. The prepared compounds have been tested on mice for hypnotic activity .* All the compounds, except I, caused toxic effects (convulsions, tremor), although in several cases hypnotic activity could be established. A detailed report on pharmacological investigations will* be published elsewhere. EXPERIMENTAL** Materials Diethyl (2-furfuryl)-malonate (B), b. p . 148-152°/12 mm., n6° 1.4610 (lit. 5 b. p . 125-1270/4 mm., nb0 1.4591), has been prepared by reduction of diethyl (2-furfuryli-dene)-malonate (A), b. p. 170-1720/12 mm., m. p . 40-41 o (lit.3 b. p. 173-175°/15 mm., m . p. 43°), with aluminum amalgam in wet ether.4 Details of the preparation will be reported in one of the following papers of this series. Alkylation of diethyl (2-furfuryl)-malonate (B) was carried out in the usual way,8 using freshly dehydrated absolute ethanol and a slight (100/o) excess of sodium and of the appropriate alkyl (or allyl) bromide. In this manner the following esters have been obtained: diethyl ethyl-(2-furfuryl)-malonate, b . p. 153-156°/16 mm., n6° 1.4620 (lit.5 b. p. 135-136°'/5 mm.), yield 840/o ; diethyl isopropyl-(2-furfuryl)-malo-nate, b. p . 151-156°/11 mm., n;g1 1.4635 (lit .12 b. p. 157-160°/10 mm.), yield 770/o; diethyl allyl-(2-furfuryl)-malonate, b. p. 161-162°/12 mm., nb0 1.4705, yield 850/o. Preparation of the substituted 5-(2-furfuryl)-barbituric and -thiobarbituric acids (Table 1) General procedure To the boiling mixture of 30 mmoles of the freshly distilled substituted malonic ester, 45 mmoles of the corresponding urea, and 20 ml. of dehydrated abs. etha nol, * Experiments by Dr. H . Krnjevic ** Melting points are uncorrected 122 B. GLUNCIC ET AL. the solution of sodium ethoxide prepared from 1.5 g. (65 mgatoms) of sodium and 35 ml. of dehydrated abs. ethanol was gradually added during 4-5 hours. Thereafter, boiling was continued for 6-8 hrs., the solvent evaporated in vacuo, the residue dissolved in 40 ml. of water, the resulting solution extracted with 2 X 10 ml. of ether, and then acidified with diluted hydrochloric acid (1 : 1). After cooling and standing for several hrs., the crude barbituric (or thiobarbituric) acid was filtered off. In the case of compounds IV and V, a partially crystallized oily product was obtained. After dissolution in about 10 ml. of 10°/fr aqueous ammonium hydroxide the impurities were extracted with two 10 ml. portions of ether and the product precipitated by introduction of gaseous carbon dioxide into the aqueous layer. The crude products were crystallized from appropriate solvents. In the pure form they are obtained as colorless crystals with sharp melting points. Acknowledgement. The authors wish to thank Mrs. I. Gustak-Masek for the microanalyses. REFERENCES 1. Cf. W. J. Dor an in wMedicinal Chemistry«, Vol. IV., J. Wiley and Sons, Inc., New York, 1959, pp. 104, 164, 206, 212, 2.13. 2. B. He 1 wig, »Moderne Arzneimittel«, 2. Aufl., Wissenschaftliche Verlagsgesell-schaft, Stuttgart, 1961. S. 145. 3. A. Hintz, G. Meyer, and G. Sch u king, Ber. 76 B (1943) 676. 4. A. I. Voge 1, J. Chem. Soc. 1927, 594, 1985; id. ibid. 1928, 1019. 5. W. R. Kirner and G . H. Richter, J. Am. Chem. Soc. 51 (1929) 3131., 6. The term »hydrodimerization« was used by I. L . Kn u n j an c and N. P . Ga m-b a r j an, Uspehi Him. 23 (1954) 781. 7. B. G 1 u n c i c, Thesis, Zagreb, 1964. 8. Cf. E. Four n ea u, »Preparation des medicaments organiques«, Librairie J .-B. Bailliere et Fils, Paris, 1921, p. 301. 9. N. T. Inman a n d W. P. Bit 1 er, U.S. 2,358,072 (1944) : cf. Chem. Abstr. 39 (1945) 1020.1 10. Chem. Fa b r i k Dr. J. Wier n i k & Co. A. G., Brit. 468, 503 (1935); cf. Chem. Zentr. 1937 II 3039. 11 . E. H . Vo 1wi1 er and D. L. Taber n, U.S. 2,153,729 (1939). 12. G. He i 1 n er, F. 797,152 (1936) and U.S. 2,035,317 (1936); cf. Chem. Zentr. 1936 II 1579. IZVOD Priprava nekih novih supstituiranih 5-(2-furfuril)-barbiturnih i -tiobarbiturnih kiselina B. Gluncic, K. JakopCic, N. Krvavica i V. Hahn Polazeci od dietil-estera 2-furfuril-malonske kiseline, koji je dobiven redukcijom dietil-estera 2-furfuriliden-malonske kiseline pomocu aluminijeva amalgama u vla-:foom eteru,4,7 pripravljeno je viSe novih ili ranije nedovoljno karakteriziranih d<3ri-vata 5-(2-furfuril)-barbiturne, odnosno -tiobarbiturne kiseline (I-VIII, vidi tabelu 1). Pripravljeni spojevi bili su .podvrgnuti farmakoloskom ispitivanju na bijelim miSevima (pokusi dr H. Krnjevica). U vise je slucajeva ustanovljeno hipnotsko djelo-vanje, no svi su spojevi, osim 5-etil-5-(2-furfuril)-barbiturne kiseline (I), pokazali toksicne efekte kod pokusnih Zivotinja (konvulzije, tremor). ZA VOD ZA ORGANSKU KEMIJU TEHNOLOSKIFAKULTET, ZAGREB ISTRAZIV ACK! INSTITUT » PLIVA« TVORNICA FARMACEUTSKIH I KEMIJSKIH PROIZVODA, ZAGREB Primljeno 24. sijecnja 1966. 

Preparation of Some New Substituted 5-(2\u27 -Furfuryl)-barbituric and -thiobarbituric Acids

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