A number of imino- and cyano-iminobarbituric acid derivatives has been prepared in good yield by gradually adding sodium methoxide - as condensation catalyst - to some substituted cyanoacetic and malonic esters reacting with urea, dicyandiamide
and guanidine

D. Dvornik

P. Hammes

S. M. Djokić

English

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AR H I V Z A K E M I JU 26 (1954) Preparation oi Some lmino- and Cyano-imino-substituted Barbiturates D. Dvornik, S. M. Djokic and P. Hammes* Research Department, »Pliva« Pharmaceutical and Chemical Works, Zagreb, Croatia, Yugoslavia Received January 29, 1954. A. number of imino- and cyano-iminobarbituric acid deriva-tives has been prepared ;in good yield by gradually adding sodium methoxide - as condensation catalyst - to some substituted cyanoacetic and malonic esters reacting with urea, dicyandiamide and guanidine. 15 Barbiturates are prepared usually by condensing a substituted cyanoacetic or malonic ester with urea, guanidine or dicyandiamide in the presence of an alkali metal alkoxide as condensation catalyst; the corresponding imino- and cyano-imino-intermediates are then subjected to acid hydrolysis. The conden-sation is carried out in the presence of an excess of the condensing agent, usually sodium ethoxide, at relatively high concentration of sodium, and high temperatures, and sometimes under pressure. A disadvantage of such procedure resides in the fact that cleavage, mostly decarboxylation of the substituted cyanocetic or malonic ester takes place1• 2• 3, 4• 5, resulting in a decrease of yield due to the formation of undesired byproducts4• 6, 7 (e. g. 35°/o in the case of ethyl ethyl-phenylmalonate and urea8). To suppress this ester decomposition catalyzed by sodium ethoxide, the condensation of cyanoacetic or malonic esters with urea or its derivates was carried out by adding the catalizing ethanolic sodium ethoxide solution to the reaction mixture gradually, i. e. at a rate at which the condensation occurs and controlling the temperature of reaction3• 5• I" The principle of gradual addition of the condensation catalyst to the re~ action mixture was later applied to. sodium methoxide, which was used in the condensation of ethyl malonate with urea9• The gradual addition of sodium methoxide as condensing agent has now been extended to condensations of some substituted cyanoacetic and malonic esters with urea, guanidine nitrate and dicyandiamide. Thus, a number of imino- and cyano-imino-derivatives was prepared in good yield, which after acid hydrolysis gave the corresponding barbiturates. The derivatives prepared are listed belo~. * In colLaborarbion wiith V. Popovic from the Chemical Department, Military Technical Institute. 16 a) R = CHs; : b) R = CHs; c) R = CHs; d) R = CHs; e) R = C2Hs; f) R = C2Hs ; _g) R = C2Hs ; h) R = C2Hs; D . oDVORNIK S. M. DJOKIC AND P . HAMMES I. X = NH; Y = H; Z = 0 X ,Z = NH; Y = H X,Z = NH; Y = CN X,Z = O; Y = H X = NH; Y = H; Z = 0 X,Z = NH; Y = H X,Z = NH; Y = CN X ,Z = 0; Y = H a) R ""' H ; b) R = H; c) R = CHs; d) R = CHs; e) R = CHs; f) R = CHs; g) R = C2Hs; h) R = C2Hs; i) R = C2Hs; EXPERIMENTAL* II . X = H; X = CN; X = H; X = H; X = CN ; X = H; X = H; X = CN; X = H; · General procedure: Y = NH Y = NH Y = O Y = NH Y = NH Y = O Y = NH Y = NH Y = O To a boiling suspension of the ester (0,1 mole) and urea (0,15 mole) in methanol (25 ml) ,. a methanolic .solution of sodium methoxide (prepared from 0,22 g-atom sodium and 100 ml. of methanol) was added gradually with stirring over a period · of six to eight hours. The mixture was refluxed for additional three hours and the methanol evaporated to drynes under reduced pressure. The residue was dissolved in cold water (150 ml), the solution extracted with ether (4H ml), decolorized with charcoal and gradually acidified with diluted hydrochloric acid (150/o) w hile cooled and agitated. The precipitate was collected on a filter and washed with water. The imino- and cyano-imino-derivatives (0,1 mole) were hydrolized by boiling with diluted sulfuric acid (13 ml of 25°.'o). A. Condensation with urea 5-(1-cyclohexenyl)-4-imino-5-methylbarbituric acid [I a] Prepared from ethyl cyclohexenyl-methyl-cyanoaieetate and urea as described in the General procedure.. Yield: 68,40/o. Whiite crystalline powder (absolute ethanol), m. p. 247-2540 with decomposition. Although the add was reported earlier, its melting po,Lnt was not mentioned10• Anal. 2,912 mg sUJbst: 0,49 ml N2 (21°, 762 mm) C11H15N30 2 (221 ,26) calc 'd: N 19,000/o found: N 19,19°/o Hydrolysis (n:ine hou;rs) gave 5-(1 -cyclohexenyl)-5 -methylbarbituric acid [I d] . SHky needles (water) , m. p. 190-200° (205-208° Uillcorr.). Anal. 4,020 mg :sub st.: 0,45 ml N2 (200, 750 mm) C11H1-iN 20 s (222,24) calc'd: N 12,620/o found: N 12,640/o 5-(1 -cyclohexenyl)-5-ethyl-4-iminobarbituric acid [I e] Prepared :Urom ethyl cyclo hexenyl-ethyl-cyanocetate and urea as described in the General procedure. YieLd : 61,70/o. White crystalline po-wder (absolute eth anol), m . p. 259L-2,62° with decompos.i:tioin. The earlier reported melting point was W5~ with decom.positionn. * The melting points were determined w it.h a Kofler micro melting point aipparatus unless otherwise indicated. !MINO- AND CYArNO-IMINO'-SUBSTITUT'BD BARBITURATES 17 Hydrolysis (seven hours) gave 5-(1-cyclohexenyl)-5-ethyl-barbituric acid [I h], :m. p. 172- 175° (unco1rr.). The product showed no melti.ng poi.nit deprression with a.n .<J:uthentic sample. · B. Condensation with guanidine nitrate The procedure was essentially the same as described for urea, with the dif-ference that 1,3 mole of guan:idine nitrate and 3,15 g at.am sodi!U1Il in the corres-ponding excess of metharnol ;per mule of ester we·r·e used . . 5-(l-cyclohexenyl)-2,4-diimino-5-ethylbarbituric acid [I b] Prepared from ethyl cyclohexenyl-methyl-cyano~tcetate and guarnidine nLtrat;e .as described in the General procedure with the difference that the residue after '1:lvaiporation of methanol was insoluble in water. Yield: 79,40/o. Whirte rpowder (since soluble in ac.ids, the product was reprecipitated from 20°/o hydrochloric acid I 250/o ·.-aqueous sodium hydro}Cide solution), m. rp. 245-253° with decomposition. An:al. 1,539 mg sUJbst.: 0,35 ml N2 (23°, 75·1 mm) C11H16N40 (220,27) calc'd: N 25,43°/o found: N 25,390/o Hydrolysis (twelve hours) gave 5-(1-cyclohexenyl)-5-methylbarbituric acid [Id], :m . p. 205- 2.iD0 (uncorr.). The pr'odruct showed no melting poiillt depression with a :sample obtained as described earrlier . .5-(l-cyclohexenyl)-2,4-diimino-5-ethylbarbituric acid [I f] Prepared from ethyl cyclohexenyl- ethyl-cyanoacetate and guanidine nitrate as described in the General procedure; the residue after the evaporation of methanol ·wars insoluble in waiter. Yield: 890/o. White powder (since soluble in acids, the product was reprecipitated from 200/o hydrochloric acid I 250/o aqueous sodium hydro-.xide solution), m. p. 248-2530 with decomposition.* Anal. 3,590 mg subst.: 0,75 ml N2 (19°, 75'1 mm) C12H1sN40 (234,29) calc'd: N 23,910/o found : N 23,680/o Hydrolysis (nine hours) gave 5-(1 - cyclohexenyl)-5-ethylbarbituric acid [I h], :m. p. 175i-i7·6° (uncorrr.). The product showed no melting po'int depression with an .authentic sample . . 2-imino-5-phenylbarbituric acid [II a] Prepoo-ed from ethyl phenylmalonate and guanidine nitrate as described in the General procedure:. Yield: 860/o. White powder (reprecipitated from 100/o aqueous ·sodium hydroxide solution/ 10°/o hydrochloric acid), m. p. 33•3-336° w.ith decompo-,siticin. Anal. 4,144 mg subst.: 0,76 ml N2 (22°, 750 mm) C10H9Na02 (203,21) calc'd: N 20,68°/o found: N 20,530/o Hydroly1sis (eighteen hours) gave 5-phenylbarbituric acid [II c], m. p. 250° with ·decomposLtion . The earlier r .erported meltmg point was 250° 12• The product showed no melting point depresion with a sample prepared. from ethyl phenyl~alonate and ·µrea . * H. Lund 11 obtained this product by the magnesium methoxide catalized -oeyclization of cyclohexenyl-ethyl-cyanoacetyl-guan.idin.e. No melting point has been '.reported. 18 D. DVO'RINillK S. Ml. DJOKIC AND .P. HAMMES 2-imino-5-methyl-5-phenylbarbituric acid [II d] Prepared from ,e'thyl methyl-phenylmalonate and guanidine nitrate as· desoribedl in the Generail. .procedll['e. Yield: 860/o. White IP'owder (reprecipi>tated from 10% equeoU1S sodium hydroocide soluti()[l/ 100/o hydrnchlodc acid), m. p. higher ·than 360°' with decomposition (runcorr.). Anal. 3,778 mg swbst.: 0,64 ml N2 (20°, 750 mm) C11H11Ns02 (217,24) calc'd: N 19,350/o found: N 19,110/o Hydrolysis (seven hours) gave 5-methyL- 5-phenyLbarbituric acid [II f], m. p .. 226°. The melrtiing point repo,rted is 220° 12• · 2-imino-5-ethyl-5-phenylbarbituric acid [II g] Prepared from ethyl ethyl~phenylmalonate and guanid:ine nitrate as described irn the General ,procedure. Y:ield: 93,50/o. White powder (reprecipitated from 100/o aqueous. sodium hydroxdde sol'Ution/ 100/o hydiro.chloric add), m. p. 3,13~3150 with decompo--sition. AIIlal. 5,379 mg subst.: 0,87 ml N2 (21°, 754 'mm) C12H1aNa02 (231,24) calc'd: N 18,160/o fo'Uild: N 18,290/o Hydrolysis (twelve hours) gave 5-ethyL-5-phenyLbarbituric acid [II i], m. p .. 175-176° (wncoir:r.). 'The producrt show.ed no melting iPOint depressd:on with an_ authentic sampLe. C. Condensation with dicyandiamide The procedure was essentially the same as described for urea with the diffe--rence, that 1,5 mole of dicyandiamide was used per mole of ester. 1-cyano-5-(1-cyclohexenyl)-2,4-diimino-5-methylbarbituric acid [I c] Prepared from ethyl cyclohexenyl-methyl- cyanoacetate and dicyandiamide as; described in ;the General procedure. Yli:eld: 85,60/o. Orystalliine powder (700/o ethanol), m. p. 266-272° with decomposition. The earlier reported m elting point was: 2650 13* . Hydrolysis (nine hours) gave 5- (1 - cydohexenyi)-5-methyibarbit:ur ic acid {I d]" m. p. 198-202° (uncorT.). The product showed no melting point depresisd.on with a &ample obrta.iined as described earlier. 1-cyano-5-( cyclohexenyl)-2 ,4-diimino-5-ethylbarbituric acid, [I g] Prepared from ethyl cyclohexenyl-ethyl-cyainoacetarte and d:icyiandiamide as described ilI1 the General procedure. Yield: 870/o. Orystalline rpowder (600/o ethanol) ~ m. p. 253-2560 w1th decomposition. AIIlal. 10,588 mg subst.: 23,520 mg C02 6,310 mg H20 1,462 mg subst.: 0,343 ml N2 (22°, 762 mm) C1aH17N50 (259,31) calc'd : C 60,21 ; H 6,61; N 27,010/o found: C 60,62; H 6,67; N 27,210/o * Ger. Pat. 590,175 and Fr. Pat. 753,178 describe the same subject. The sub-stance obtained apparrently from erthyl cyclohexenyl-methyl- cya:naacet.ate and di-cyan:diamide has been referred erroneously as 5- (1-cycl'ohexenyl)-5-methyl-6-tmino-3-cyano-barbi1buric acid borth ilil C. A. 28 (1934) 781 and :in Chem. Zentr. 1934, I, 894.: The correct formula, a·s descr~bed 1n this paper has been reported iJn Chem. Zen'tr-1934, I, 1354. IMI:NO- ANID CYANO~IMJNO-SUBSTI'DUTED B!AiRJBITURATES 19 Hydrolysis (ten hours) gave 5-(1-cyclohexenyL)-5-ethylbarbituric acid [I h], m. p. 171-174° (uncorr.). The product showed no melting point depression with an authentic ·sample. 1-cyano-2-imino-5-phenylbarbituric acid [II b] P.repared ~ ,ethyl p~enylmalonate and dicyandiamide as descri:ood in the General .procedure. Y:ield: 79,50/o. White powder (re.precipitated from 150/o: aqueous sodium hydlroxide soJution/ 100/o hydrochloric acid), m. rp·. 280-293° with slow de-composition :firom 269° on. Anal. 1,806 mg subst.: 0,39 ml N2 (220, 759 mm) C11HsN402 (228,20) calc'd: N ~.550/o found: N 24,440/o Hydrolysis (eleven hours) gave 5-phenylbarbituric acid (II c), m. p. 248-252° ('l.llilcorr.). The product showed no melting point depression with a sample obtained as descr~bed earlier. 1-cyano-2-imino-5-methyl-5-phenylbarbituric acid [II e] Pre.pa:r·ed from ethyl methyl-phenylmalonate and dicyandi:amide as .descrjibed in the General procedure. Yield: 89,50/o. White crysttalliine pbwder (800/o ethanol), m. p . 2'36-241° with decomposition. Anal. 1;845 mg su:bst.: 0,37 ml N2 (19°, 763 mm) C12H10N402 (242,23) caJc'd: N 23,130/o found: N 23,150/o Hydrolysis (eleven hours) (25°/o hydrochloric acid) gave 5-methyl-5-phenylbar-bituric acid [II f], m. p. 22'6-228° (u:nooir:r.). The product showed no mel!ting podnt d epression with a sample obtained as d escribed eadier. 1-cyano-2-imino-5-ethyl-5-phenylbarbituric acid [II h] Prepared from ethyl ethyl-phenylmalonate an<d dky.andiamide as described in the General procedure. Yield: 860/o. White crystalline powder (500/o ethanol), m . p . 220"-2250with decomposJtion . The melting point reported .is 2230 13, 14. Hydrolysis (ten hours) gave 5- ethyl-5-phenyl barbituric acid [II i], m. p. 177° (uncorr.). The product showed no melting point depression w1th ain authentic sample. The microanalyses and melti1I1g pnint determLnations were carried out by N . M anger from our Miior'ochemioal laborafory and by Prof. L.. Fili~ovic from the Chemical Instiitute, Faculty of Scienoe, Zagreb. REFERENCES 1. A. C. C ope, S. M. Mc El v.a in, J . Am. Chem. Soc. 54 (19'32) 4311. 2.. A. C. Co IP e, S. M. Mc El v a in, J. Am. Chem. Soc. 54 (19'32) 4319. 3. M. T . Inman, W. P. B itler, US. Pat. 2,358,072 (19414); cit. from C . A. 39 (1945) 1020. 4. H. Asp e lund, O. Backm a n , Acta Acad. Aboensis Math. et Phys. 14 (1944) No . 14, p. 3. 5. M. A. Phi 11 i p s1, Brit. Pat. 590, 714 (1947); cit. from C. A . 42 (1948) 2987. 6. S. A. B u 1 g a c h, A . A. C he J" v y a k 'ova, Russ. Pat. 52,992 (19138); cit. from C. A. 34 (1940) 5094. 7. D. DVO Tl!'lik, Arhiv kem. 23 (1951) 197. 8. W. L . N elson, L. H. Cre tc he ir, J. Am. Chem. Soc. 50 (19128) 2758. 9. M. A. P h :i 1 H p s, Ind. Chemist 21 (1945) 678; cit. from C. A. 40 (1946) 1787. 10. Austr. Pat. 149,676 (1937); cit. from Chem. Z entr. 1937, II, 3198. 11. H . Lund, B er. 69 (1936) 1621. 12. Gen. Pat. 247.925; cit. from Chem. Z entr. 1934, II. 212. 13. L. Taub, W. Kropf, Ger. Pat. 590,175 (1933); cit. from Chem. Zentr. 1934, I, 1354. 14. Fr. Pat. 753,178 (1933); cit. from C. A. 28 (1934) 781. 20 D. DVORNIK S . M. DJOKIC AND P. HAMMES IZVOD Priprema nekih imino- i cijano-imino-supstituiranih barbiturata D. Dvornik, S. M. t)okic i P. Hammes Barbiturati se obieno pripremaju kondenzacijom supstituiranih cijanoctenih ili m alonskih estera s UireO!Ill Hi njenim derivatima uz neki alkoksid alkalnih metala kao kondenzaciono sredstvo i naknadnu hidrolizu imino- i cijano-imino-interme-dijera . Obicno se kondenzacije vrse suviskom Jmndenzac.iooog sredstva, najcesce natrium etoksida, uz relativno veliku koncentraciju natriuma, kod povisene tem-perature, pa ;i pod tLaikom. Vrsenje kondenzacije pod takvim uvj etim.a dovodi do cij·epanja, obiano deka:rboksilacije supstitukanih cij anoctenih ili malonskih esteral,, 2, 3, 4. 5, tj. do pada iskoristenja;, jer se stvaraju nefoljeni sporedni pro-dukti4. 7, s. Da se cijepajuce djelovanje natrium etoksida smanji, kondenzacija nekih cijanoctenih i malonskih estera vrsena j.e tako, da se e.tainolna otopina na-t r ium etoksida dodavala reakeionoj smjes;i postepeno, tj. brzinom, kojom se v'.I'Si kondenzacija3• 5• P11i!ndp postepenog rdodarvanja lmndenz:a.cionog s.redstva primi-jenjen je i na natrium metoksid kod kondenzacije etil malonata s u reom 9. U ovoj radnji pros.iren je princip pos:terpenog dodavanja natrium . metoksida kao kon-denzacionog sredSltva na kondenza cije nekih supstituiranih cijanoctenih i malonskih estera s ureom, guanidin nitratoan i dicij·andiiaanidom, pa je s do.brim iskoristenjem priredeno nekoliko imino- :i cij;;ino-imino-derivata, koji su hidrolizom u kiselom m1edliju prevedeni u odgovar.a jruce barbitUJraite. Kod izradivanja eksperimenitalnog dijela suradivao je i.ng. V. Popovic iz Tehnoloskog o djela Vojno-tehnj.okog ins·tituta. · Mikroainalize su j,zVTsili ing. N. Manger (u nasem mikroanalitickom laiborato-riju) 1 prof. L. Filipovic (u Kemijskom insti1utu Prirodoslovno-matematickog fa-.kulteta u Zagrequ). TaliSta je ·odredio :ing. N. Manger prema mikiroskopskoj metodi po. Kofleru. ISTRAZIV ACK! INSTITUT »PLIVA« TVORNICA FARMACEUTSKIH I KEMIJSKIH PROIZVODA ZAGREB Primljeno 29 .. januara 1954. 

Preparation of Some lmino- and Cyano-imino-substituted Barbiturates

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