Sept. 5, 1952
SYNTHESIS OF 5-CARBETHOXYURACILS
Anal. Calcd. for C9H8O4: C, 60.00; H , 4.74; CHBO, 17.22. Found: C, 59.99; H , 4.70; CHaO, 17.25. 5-Carboxyvanillic Acid (X) . From 5-Carboxyvanillin.Silver oxide (0.017 mole, freshly prepd. from 5.8 g. of silver nitrate) was covered with 50 cc. of water and treated with 5.1 g. (0.128 mole) of C.P. sodium hydroxide. This mixture a t 47' was treated with 3.3 g. (0.017 mole) of 5-carboxyvanillin and heated to 65', a t which point a reaction took place. The source of heat was removed and the temperature rose to 73". The reaction mixture was cooled and filtered, and the silver precipitate was washed with water. The filtrate was acidified with dilute sulfuric acid and cooled. The white fluffy precipitate was filtered, washed with water, and dried to yiEld 3.3 g. (94.3%) of 5-carboxyvanillic acid melting a t 282 ; this did not depress the melting points with a sample of 5-carboxyvanillic acid isolated in the nitrobenzene oxidations described above or with that isolated from metallic oxide oxidations of lignin materials4-8 Anal. Calcd. for CsHsOc: C, 50.93; H , 3.80; CHaO, 14.63. Found: C, 50.88; H , 3.80; CHaO, 14.60. Under certain conditions of crystallization from water a dihydrate of 5-carboxyvanillic acid is obtained. This product is obtained as fluffy white needles with the same melting point and ultraviolet absorption spectrum as the anhydrous product. However, during the melting point deter-
[COSTRIBUTION FROM
THE
4267
mination, dehydration is observed a t temperatures above 110'. Anal. Calcd. for C ~ H 8 0 ~ 2 H z 0 C, : 43.56; H , 4.87; CH30, 12.50. Found: C, 43.75; H , 4.77; CHIO, 12.54. Drying of this compound a t 105' yielded the theoretical amount of moisture. From's-Formylvanillic Acid.-Silver oxide was prepared, covered with water, and treated with sodium hydroxide exactly as above. This mixture a t 40' was treated with 5formylvanillic acid in the same manner; a reaction took place raising the temperature to 52'. The reaction mixture was treated as above to yield 100% of 5-carboxyvanillic acid melting a t 283-2234' and not depressing a mixed melting point with authentic 5-carboxyvanillic acid. From 5-Formylvanillin.-Similar oxidation of &formylvanillin with twice as much silver oxide but with the same amount of alkali resulted in the formation of 5-carboxyvanillic acid as the main product, together with some bisulfite-soluble 5-carboxyvanillin and a little resinous material which was not characterized.
Acknowledgment.-The authors wish to thank Mr. Donald McDonnell for the analyses and spectra reported in this paper. APPLETOS,~VISCONSIN
LILLYRESEARCH LABORATORIES]
The Synthesis of 5-Carbethoxyuracils BY CALVERT W. WHITEHEAD RECEIVED FEBRUARY 15, 1952 Diethyl ethoxymethylenemalonate undergoes condensation with urea and K-substituted ureas. The condensation has been carried out by heating the ethoxymethylenemalonate with N,N'-dimethylurea to obtain directly 1,3-dimethyl-5carbethoxyuracil; with N-methylurea to obtain 3-methyl-5-carbethoxyuraciland with higher N-alkylureas to obtain alkylureidomethylenemalonates which were converted to the 3-alkyl-5-carbethoxyuracil in the presence of a basic catalyst. The condensation was also carried out with urea and a number of N-alkyl- and N-arylureas with diethyl ethoxymethylenemalonate in alcoholic solution in the presence of a base catalyst to obtain directly the 5-carbethoxyuracil in good yield. These uracils containing a functional ester group made possible the convet;lient preparation of a number of new heterocyclic acids and amides some of which have shown diuretic activity in animals.
The facility with which diethyl ethoxymethylenemalonate, CzHsOCH=C(COzCzH& condenses with basic nitrogen compounds has been demonstrated in reactions with ammonia,' amines, acetamidine3 and ethylis~thiourea.~The product from the lat1 R"NHCONHR'CH=C( C02CzHs)z ter reaction was 2-ethylmercapto-5-carbethoxyI1 6-oxypyrimidine. Wheeler4 reported that urea showed no sign of reacting with diethyl ethoxyR" I methylenemalonate a t 140' and a condensation was s not effected on standing in alkaline solutions. / 3 \ Other attempts to condense diethyl ethoxymethylenemalonate with urea or substituted ureas are not found in the literature. An investigation has been made into the condensation of diethyl ethoxyc methylenemalonate with urea and N-substituted 1 ureas as a method of synthesizing N-substitutedH 111 5-carbethoxyuracils and also as a study of the reactions of diethyl ethoxymethylenemalonate with When diethyl ethoxymethylenemalonate was weakly basic nitrogen compounds. heated with an equimolar quantity of an N-monoThe condensations proceeded according to the alkylurea a t 120°, ethanol was eliminated and the general equation corresponding diethyl alkylureidomethylenemalonate (11)was formed. In the case of the methylurei(1) L. Claisen, A n n . , 297, 77 (1897). ('2) C. C. Price and R . M. Roberts, THISJ O U R N A L , 68, 1204 (1946). domethylenemalonate (11, R' = H, R" = CHs), 13) T. A. Geissmdn, M . J. Schlatter, I. D. Webb and J , D. Roberts, further heating a t 150' gave the uracil (111). The J. 0i.g. Chern., 11, 741 (1946). higher alkyl homologs did not cyclize when they (4) €I. J. Wheeler, T. b.Johiison arid C . 0. Johns, A m Clieuz J . , 57, were heated a t 150' arid diethyl n-propylurcido 392 (1907).
niethylenemalonate actually was distilled under re- ethylate previously prepared from 2.3 g. of sodium. Diethyl duced pressure without change. ~ , ~ ' - ~ i ~ ethoxymethylenemaloriate ~ t h ~ l (21.6 g. or 0.1 mole) was added and the solution allowed to stand a t room temperature in :t urea reacted with diethyl ethoxylnethylenemalon- stoppered flask. After seven days the alcohol !\,as removed ate a t 120' to give the uracil, 111 (R'= R" = CHi) under reduced pressure and the residue dissolved in 50 ml. of directly, the internlediate ureide, 11, not being ob- cold water. The solution was made slightly acid by addition of dilute hydrochloric acid. The solid was filtered off tained. and dried. Recrystallization from alcohol yielded product Treatment of the ureides, 11, with sodium ethyl- melting at 197-200°. Repeated recrystallization from alcoate in absolute ethanol brought about cyclization hol produced 6 g. (21.8%) of product melting at 207-209°.4 to form the uracils, 111. Ai more convenient ..Ind. Calcd. for CsH14NzOb:C, 17.00; H , 6.13; N, method was to allow the N-substituted ureas, I, (R' 12.30. Found: C , 47.16; H,6.63; S,12.58. = H, R" = alkyl or aryl groups), to react with diS-Carbethoxyuracil.-Diethyl ureidomethylenemaloiiat e ethyl ethoxymethylenemalonat~ in ethanol in the (23 g. or 0.1 mole) was dissolved in 200 ml. of absolute alcohol containing 0.1 mole of sodium ethylate, prepared from presence Of One Of to 2.3 g. of sodium metal. The solution was allowed t o stand form the uracils, 111, directly and in high yields. for 12 hours then heated under reflux for five hours. T h e Urea itself gave diethyl ureidoinethylenemalonate alcohol was removed by reduced pressure distillation. Icewhich could be cyclized to the uracil, 111, (R'= water (50 ml.)was added to dissolve the residue. Thc product was precipitated by adding cold dilute hydrochloric It'' = when refluxed ethanol the presalce acid, The solid was filtered off and recrystallized from of sodium ethylate. ethyl alcohol, m.p. 232', yield 13 g. or 72%. In the condensation of monosubstituted ureas ..lnnl. Calcd. for c , H ~ N ~c ~, 45.70; ~ : 11, 4.35. Founti: with diethyl ethoxymethylenernalonate two them C , 15.16; 11, 4.82. retically possible ureides, 11, could be formed. 1,3-Dimethyl-5-carbethoxyuracil .-sym- Dimethylurea However, only one homogeneous substance was ob- (44 g . or 0.5 rl1ole) anti diethyl ethoxymethylenemalonate (108g. or 0.5 mole) were mixed in a long-necked flask and tained upon cyclization to the uracil, III. heated in an oil-bath a t 120" for 24 hours. Upon cooling product from Illethylurea Was Saponified and de- the mass solidified and was dissolved in hot ethyl acetate. carboxylated to obtain 3-methyluracil melting at Charcoal was added and the solution filtered. The product not ~-lllethy~uracil which lnelts at was allowed to crystallize, yield 66 g. (62%',!.,m.p. 112". 174-17505 411analytical sample was prepared by recrystallizing several 2 3 2 ~ , a-Ilso, the product from phenylurea was tinics from ethyl alcohol, m.p. 112". hydrolyzed to 3-phen~l-:,-carboxyuracil, 1ii.p. 240" A n d . Caled. for C9HI2S2O4:C , 51.20; 13, 5.72; S, and decarboxylated to 3-pheiiyluracil, imp. 244- 13.21. ~ ; ~ , c, ~ ~31,172; ~ ~ l €1, : 5.88; s,12.92, 246c.7 This shows the condensation to occur ex3-Methyl-5-carboxyuracil,-s-~~ethylurea(14.8 g. or 0.2 elusively between the unsubstituted nitrogen oi the inole) a n t i diethyl ethoxyirlethylenernalorlate (43.2 g. or 0.2 urea alld the ethoxyInethplene group of the ester. mole) were mixed and heated a t 120" for 24 hours. The of alcohol had ceased after this time and the di5-carbe~oxyuracilsprepared by the met~l- erolution ethyl methylureidomethyleneinalonate could not he induced ods described are listed in Table 1 with the OVer-all to crystallize. This Inaterial was then heated at 1500 and yields and the method of preparation indicated. the evolution of ethanol continued until the mass solidified. Amides (Table 11) having various degrees of wa- Recrystallization from alcohol yicldzd 16 g. (41%) of 3ter solubility, were prepared from the esters in the ' ~ ' ~ ~ j~ was added ~ to ~ 5u ~ usual manner by heating with the desired anline. of 10% sotiium hy&,xitle so~utioll. The solution Also, the esters were readily saponified to the acids warmer1 on t.he steam-hath for two hours. The solution \vas (Table 111). .\lkylation of a numl>er of t h e :]-sub- acidified with dilute hydrochloric acid and allowed to cool. carrietl out, us- The free acid crystallized out a n d was collected on the filterstitutetl-3.-carl,etho~yuracils ing funnel and dried, yield 8.5 g. (98%). Crystallization ing dimethyl or diethyl sulfate (Table I, inethod e). frolll ;llcohol a protluct melting at 2420. The diuretic activity of some of these compounds nul. Calctl. for C6H6?J~0,: N, 16.17. Fountl: S , was determined in catheterized feinale dogs anes- I thetized with a barbiturate. Doses of 0.5 g. or 3-Methyluracil.-3-Methyl-5-carhoxyuraciI ( 2 g.) was 1.0 g. of the uracil were given orally, or doses of 2.3 heated in B test-tube p l a c ~ din a Koods metal bath at 2Stjo. Aftcr ten minutes the evolution of carbon dioxide ceased. nlg~/kg.to 10 lng./kg. ~ v e r e intravenously, The test-tube was removed from the bath and its contents The flow of urine was IlOtCd Over a foUr-hOur peric)(i. (iissolveti ill alcohol. The solution was clarified with charThe results were coi1iI)ared with those obt:iinccl 011 c o d , filtered and allowed to cool. 3-Methyluraci1,~m.p. the saiiic anini:tl when given intravenous doses o i :L 374--175", was obtained in 90% yield. ?t-Propylureidomethylenemalonate.-N-Propylcollllllercial~y a17ailable lrlercurial tliuretic ill ;i (lose iircaDiethyl (10.2 g. or 0.1 mole) and diethyl ethoxymethyleneinalequivalent to 0.73 tt.1 3.0 mg. oi inercury per kg. of^ (21.6 g . or 0.1 mole) mixed and heated in opell body weight. Results of the testing are included flask in an oil-bath a t 110' for 12 hours. The resulting oil in Tat)les 11 and 111, The phar11i;Lcological evalu- could not be induced to crystallize and was distilled through ations were Inacle by I;,E;,~l~~~~arid E, 13, ~ ~ t , } :t ~ srnall i ~ claisen ~ ~ distilling head, h.p. 165-1'ino ( I Innl.), yipld 50%. both of this 1,aboratory. :Inul. Calccl. for Ct?T-Izr,S?@s: C , 52.9.i; 13, 7.36; S, Acknowledgment.-The author is grateful to 10.29. ~ ~ c, 53.26; ~ H, ~ 7.64;~ s, 9.88. ~ d : W. L. Brown, H. L. Hunter and W. J. SChenCk for 3-n-Propyl-5-carbomethoxyuracil.-Diethyl n-propylureitIoincthylene1na101~ate(14.5 g. or 0.05 mole) was dissolved the microanalyses reported here. Experimental Diethyl Ureidonlethylenema'onate.-'Tre~ (6.0 g. or 0.1 mole) was added tn 150 lid. of ethanol containing sodium . .____-I
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and
A m , Cile,n, J , , 3,, R28 (1307j,
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