NOTES
Oct. 20, 1953
TABLE I
5425 Chlorine, % Calcd. Found
42 p . , oc.
148-148. jZ 48.6 48.3 1-Methylpyridinium chloroferrate( 111) 80 38.6 38.2 1-Benzylpyridinium chloroferrate( 111) 193-1 94 46.4 46.5 1,2-Dimethylpyridinium chloroferrate( 111) 118-118.5 46.4 46.3 1,4-Dimethylpyridinium chloroferrate( 111) 70 37.2 36.9 1-Methyl-2-benzylpyridinium chloroferrate( 111) 204-2053 44.4 44.1 1,2,6-TrimethyIpyridinium chloroferrate( 111) 195-196 41.5 41.2 1-Methylquinolinium chloroferrate(II1) 165-166 1,2-Dimethylquinolinium chloroferrate(II1) 39.9 39.6 97-98 1-Methyl-6-methoxyquinolinium chloroferrate( 111) 38.2 37.9 108.5-109 32 7 32.4 2-Methyl-3,5-diphenylisoxazolium chloroferrate( 111) 143- 144' 2-Methyl-3-phenyl-5-p-bromophenylisoxazolium chloroferrate(II1) 139- 140 2-Methyl-3-p-bromophenyl-5-phenylisoxazolium chloroferrate( 111) 1626 2-Methyl-3,4,5-triphenylisoxazolium chloroferrate( 111) 2-Methyl-3-p-brornophenyl-5-phenylisoxazolinium chloroferrate(III), m.p. 115-116", calcd. for Cl~HljBrNOFeCL: C, 37.3; H, 2.94. Found: C, 37.4; H, 2.66. 2,5-Dirnethyl-3-phenylbenzisoxazoliumchloroferrate(III), m.p. 95-96', calcd. for CliH14NOFeC14: C, 42.70; H,3. 3 Found: C, 42.85; H, 3.1. 3,5-Dimethyl-2-phenylbenzoxazoliumchloroferrate(III), m.p. 1-12-1-13°, calcd. for CljHi4KOFeCl4: C, 42.7; 13, B.8. Found: C, 42.6; H , 3.2.
to hydrolyze the excess ester, and concentrated aqueous ferric chloride solution is added until precipitation of the salt is complete. The intermediate methosulfate and chloride are not isolated. This procedure works not only for those heterocyclic compounds like pyridine and picoline t h a t react vigorously with dimethyl sulfate, but also for such highly hindered and weakly basic heterocycles as 3,4,5-triphenylisoxazole. If the heterocyclic compound reacts too vigorously with dimethyl sulfate, benzyl chloride can be used instead: l-benzylpyridinium chloroferrate(II1) is an example of a derivative prepared by this variant procedure. The chloroferrates(II1) t h a t we have prepared (Table I) are yellow solids, varying from greenishyellow to orange-yellow . They are sparingly soluble in glacial acetic acid a t room temperature and quite soluble by comparison in the same solvent hot, so that they are readily purified by crystallization from acetic acid. Most of them are conveniently analyzed for ionic chlorine by the Volhard procedure and, since they contain ferric iron, i t is not necessary to add an indicator. The chloroferrates(II1) from the heterocyclic compounds that contain oxygen as well as nitrogen in the ring develop purple colored solutions on addition of silver nitrate. With these colored solutions the end-point on titration with thiocyanate is not readily determined. Carbon and hydrogen analyses are therefore preferred, although the alternative procedure of ashing and determining iron can be used. The salts listed in Tab€e I were prepared either because we needed them for identification or because the heterocyclic compounds were available to us. They do not constitute an exhaustive test of the usefulness of the chloroferrates(II1). Although such a test will have to wait upon more extended use of these derivatives, we can indicate the limitations we have observed so far. One heterocyclic compound, 3,5-diphenylisoxazoline, yielded an oil ( 2 ) M. Scholtz, Arch. Pharm., 247, 5 (19041, prepared this chloroferrate(II1) but did not report a melting point. (3) R . LukeS and hf. Jurehk, Chem. L i s l y , 37, 177 (1943); C. A . 39, 2506 (1946). (1) A . H . R l a t t , '1'111s l < I I i H s . + r , 71, 1 H i 2 (l!IJ$!) i . 8 1 11 1' E u h l r r nlltl .A I f . Hlalt. i h i d . , 6 0 , 1222 ( I Y 2 Y J
rather than a crystalline chloroferrate(II1). The chloroferrates(II1) from two compounds t h a t contained more than one C=N linkage [2,3-diphenylquinoxaline and 1,4-bis-(6,7-dimethoxy-l-isoquinoly1)-butane] did not have good physical properties. Otherwise we have encountered no complications in the preparation and use of the chloroferrates(II1). Experimental
It is convenient to add liquid heterocyclic compounds (e.g., pyridine) dropwise to excess dimethyl sulfate and to add dimethyl sulfate to solid heterocyclic compounds. The usual quantities are 0.5 ml. or g. of the heterocyclic compound and 1.5ml. of dimethyl sulfate. These reactants are heated on a steam-bath for three hours then left to cool. Five ml. of hydrochloric acid (one part concentrated acid and one part water) is added and, after the excess dimethyl sulfate has been hydrolyzed, 5 rnl. of ferric chloride solution (two parts of FeCla6Hz0in one part of water) is added. Usually the salt crystallizes a t once. Occasionally it appears as an oil that crystallizes on standing overnight. The crystalline salt is filtered, washed with a little glacial acetic acid, and crystallized from the same solvent. Reactive heterocyclic compounds add dimethyl sulfate in less than the three hours prescribed above. If the heterocyclic compound is heavily substituted near the C=X linkage, longer heating may be necessary. A convenient test for completeness of reaction is the formation of a clear solution when the excess dimethyl sulfate has been hydrolyzed. DEPARTMENT OF CHEMISTRY QUEENSCOLLEGE FLUSHING 67, KEW YORK ____
3-Substituted Thiophenes. X. Derivatives
Barbituric Acid
BY E. CAMPAICNE AND ROBERT L. PATRICK RECEIVED APRIL 19, 1955
The 2-thienyl analog of phenobarbital, 5-(% thieny1)-5ethylbarbituric acid, was prepared by Blicke and Zienty,2 and found to have the same order of activity as phenobarbital in the rat, being slightly less hypnotic but also slightly less toxic. 5-(2-Thenyl)-5-ethylbarbituric acid, prepared by Owen and N ~ r d was , ~ found to be qualitatively (1) Contribution No. 679. Taken from part of a thesis submitted by R . L. Patrick in partial fulfillment of the requirements for the degree Doctor of Philosophy at Indiana University, June, 1950. (?) F. 1'. Blicke and h f , P. Zienty, THIS J ( > I T R N A l . , 63. 2945 (1941). 13) L.I . UWFU aud 1:. 1'. Kurd, J . 01E . ( ' h f u i . , 15, 888 (1U.iO).
3426
Vol. 77
NOTES
similar to its benzyl analog in causing convulsions, qualitatively different from its 2-thienyl isomer2 but the thiophene derivative was again apparently in that it produced sedation but no hypnosis or less active and less toxic than the corresponding analgesia a t dose levels of 100, 140 and 200 mg./kg. benzene compound. It was therefore interesting to Experimental prepare some 3-thienyl substituted barbituric acids, Ethyl 3-Thieny1acetate.-A of 56 nil. of coiicd. in order to compare their physiological activities sulfuric acid dissolved in 186 mixture ml. of absolute ethanol and with that of the 2-thienyl and phenyl analogs. 112 g. (0.91 mole) of 3-thienylacetonitrile6 was refluxed for The synthesis of the desired barbituric and 2- seven hours, cooled, and poured into 200 ml. of water. thiobarbituric acids was accomplished in satis- After washing and drying the oily layer which separated, it distilled through a short Vigreux column, and 89.5 g. factory yields by the conventional condensation of was (627,) of a colorless oil boiling from 107-115° a t 6 mm. \ v x substituted malonic esters and urea or thiourea in obtained. the presence of ethoxide ions. The intermediate -4nnI. Calcd. for CBHloO&: S, 20.06. Found: S, 19.91. substituted malonic esters were prepared by alkylDiethyl 3-Thienylmalonate.-A procedure wa5 used ating diethyl :3-thenylmalonate5or diethyl 3-thienyl- similar to that described by \:ogel* for the phenyl analog. malonate in the usual manner. Diethyl :3-thienyl- \\'hen 79 g. (0.49 mole) of ethyl 3-thienylacetate was treated 73 g. (0.5 mole) of freshly distilled diethyl oxalate in malonate was prepared by carbethoxylation of with the manner described, a nearly quantitative yield of crude ethyl %thienylacetate, using diethyl oxalate to form diethyl 3-thienylosaloacetate was obtained. This crude product was not purified, but was decarbonylated directly. the oxaloacetate which then was decarbonylated. Although the substituted barbituric acids are Slow decarbonylation at 210' for six hours, as described by \'ogel,* yielded 55 g. (45%) of redistilled diethyl 3-thienylfrequently recrystallized from water, apparently ninlonate. The use of powdered soft glass in the decarthe formation of hydrates is not commonly en- boiiylation reaction caused a much more rapid evolution o f countered. However, in the course of this in- carbon monoxide, but the yield of product was only 29%. Alkylation of Thenyl- and Thienylma1onates.-Diethyl 3vestigation, two compounds were isolated from prepared as previously d e ~ c r i b e dmas , ~ obwater solutions which analyzed correctly for hy- thenylmalonate, tained in much better yield (81YG)when freshly distilled 3drates. These compounds retained water very thenyl bromide8 was used in its preparation. This comtenaciously, and may actually have different pound was converted to its sodium salt in absolute ethanol, structures. IYhen diethyl ethyl-(3-thenyl)-rnalon- aiid alkylated with ethyl iodide or allyl bromide, as described by \.'ogel.s In the same way, the ethyl- and allyl-3-thienylate was condensed with urea, two products were malonic esters were prepared by alkylation of diethyl 3isolated by fractional crystallization from water. thienylmalondte. The pertinent data on the preparation The lower melting compound analyzed correctly of the malonic esters are presented in Table I . for the desired barbituric acid, and produced the TaBLE 1 expected result in experimental animals. The h l A L O S I C ESTERS C O S T A I N I S G THE 3-TIiIESYL SUBSTITVEST higher melting product analyzed quite well for a RR'C( COOCzH,j)r monohydrate of 3-ethyl-5-(3-thenyl)-barbituric B.P. Yield, Sulfur, % acid. However, efforts to dehydrate this coni70 Formula Calcd. Found R Mm. K: 'C. pound were unsuccessful, as were efforts to form 3-Thenyl H 815 C;zHi&OaS 1 Z . H j 12 3 2 141-117 4 the hydrate by repeatedly recrystallizing the lower 3-Thenyl Ethyl 160-164 : 54 CirHzoOtS Il.2C1 1 1 . I 4 73 CijHioo~S 10.S1 10.80 melting compound from water. Unfortunately the 3-Thenyl Allyl Iz5-15i 3 43 Ci1Hia04S 1 8 . 2 4 13.6s 151-152 2 8-Thienyl H pharmacological tests were not carried out on this 3-Thirnyl 43 C>3H>aOiS 11.84 11.80 4 Ethyl 172-174 compound. When diethyl 3-thenalmalonate was 3-Thienyl Allyl 1.58- 154 !i 50 C M H I ~ O ~11 S .'14 11.2!J condensed with urea, bright yellow crystals were Diethyl 3-Thenalmalonate .-E sing the method of Alleii obtained which melted a t 161-1 62'. Analysis aiid Spangler'" for the b e n d analog, a mixture of 71.1 g. indicated that this product, which behaved in (0.44 mole) of freshly distilled diethyl malonate, 37 g. (0.4(j other respects like a barbituric acid, contained two mole) of freshly distilled 3-thenaldehyde,ll 4 mi of piperidine and 1.5 g. of 3-thenoic acid dissolved in 100 nil. of dry molecules of water. Previous in~estigators~,~,.' was refluxed for 24 hours, during which time only have commented on the unusual properties of the benzene 4 ml. of water was collected in the moisture trap. After benzalbarbituric acids. These compounds are washing and drying the benzene solution i t was distilled, brightly colored, insoluble in organic solvents, and and 57 g. (51yG)of diethyl 3-thenalmalonate, boiling from have abnormal melting points. For example, the 179-180" a t 7 mm., n% 1.5491, wascollected. Anal. Cdlcd. for C I ~ H ~ & SS, : 12.61. Found: s, 11.98. 2-thenal derivative melts with decomposition a t Barbituric Acids.-All of the substituted malonic esters iil :1:10-333' ,3 and the ?-furanal derivative decomTable I were converted to the corresponding barbituric acidx poses above 2803.6 No inention was made of blthe sodium ethoxide catalyzed condensation with urea, hydrate formation, however. In view of the low followed by recrystallization from water, as described by melting point and analysis of our product, it seems \'ogel.'Z Substitution of thiourea for urea in this preparaunlikely that this substance is a true thenalbarbi- tion gave adequate yields of the desired Z-thiobarbituric acids. turic acid. The isolation of 5-ethyl-5-(3-thenyl)-harbituricacid preThe barbituric acids were tested for hypnotic sented a difficulty not encountered in the other preparations. activity through the courtesy of the Sterling- \\'hen 17.1 g. (0.06 mole) of ethyl-(3-thenyl)-malonic ester was treated with excess urea in the usual manner, and the \\-intht-op Research Institute. Like their "thenyl acid precipitated in aqueous acid, 15 g. of crude analogs, the 5-(3-thenyl)-5-alkylbarbituricacids barbituric product, which melted from 150-164', was obtained. ThiS ______ produced convulsions in rats in doses of 100 mg./kg. A . I. Vogel. "Practical Organic Chemistry," Longmans, GI een However, 5-ethyl-5-(3-thienyl)-barbituric acid was and(8)Co., London, 1948, p . 869. 14) 13. A . Shonle and A . Moment, THISJ O U R N A L , 45, 243 (1928). ( 5 ) I?, Campaigne ant1 u'. C . 1TcC:rthv. ihid, 7 6 , 4406 (19J4) (0) A I . i ' o t i r a t l . ~ i i < il r l < t ~ ~ r t l , , ~ ~i:.. ~ i i , 34, XL!I 1'1!/1 I l', I ) [ ' l o C T I ~ V iivti 38. , , l < : 4 I ' I I I ~ ~ J c j t
,
(9) E. Campaigne and B. F. Tullar, Oyg. Syn$beses, 33, 96 (1953). ( I O ) C . F. H. Allen and F. W. Spangler, ibid., 26, 42 (1945). 111 1,' ~ ' , ~ r i i ~ ~ a t iI
