THIOMETHYL BARBITURATE DERIVATIVES
April, 1945
[CONTRIBUTION FROM THE
655
RESEARCH LABORATORIES OF THE MALTBIE CHEMICAL CO.]
Thioether Barbiturates. I. Thiomethyl Derivatives BY L. A. WALTER, L. H.GOODSON' AND RUSSEL J. FOSBINDER We have prepared, for pharmacological investigation, a series of barbituric acids of the structure R-S-CH,
ChNH
\c'
Experimental
\
co
where R and R' are various hydrocarbon groups. In addition, we have prepared some members of similar series of thiobarbituric and N-methylbarbituric acids. These compounds were prepared in the usual manner from the corresponding disubstituted malonic esters and urea or substituted urea. The yields were generally good with all the compounds except those where R' was a phenyl group. One of the barbituric acids was oxidized to the sulfone and one to the sulfoxide with hydrogen peroxide in glacial acetic acid. The intermediate malonic esters were obtained in 6C-90% yields by the reaction of monosubstituted sodio-malonicesters with alkyl chloromethyl sulfides in an inert solvent such as toluene. With alcohol as the solvent the very reactive chlorides gave considerable sulfur-oxygen formal, R-SCH20GH6, even at low temperatures, and where R and R' were large groups the formal was the major product. When one mole of an alkyl chloromethyl sulfide reacted with one mole of sodio-malonic ester the product was almost exclusively the disubstituted malonic ester. This result was not unexpected since the great activity of the chloromethyl sulfides indicated the R-S- group was capable of a much greater degree of dynamic electron release than were the doubly bonded carbon atoms in an allyl group. In the latter case the release of H
The pharmacology of the barbituric acids described inthis and the succeeding papers of this series will be published in detail elsewhere.
N N
Mercaptans.-The ethyl, n-butyl aqd I-butyl mercaptans were Eastman Kodak Co. products. The others were prepared from alkyl bromides or chlorides and thioureazfs using water as a solvent for very reactive halides, alcohol for those less reactive, and absolute alcohol for the least reactive. Where alcohol was used it was removed by distillation and the isothiourea salt dissolved in water before decomposing it with 0.9 mole of sodium hydroxide and 0.1 mole of sodium carbonate. The mercaptan was distilled from this mixture, separated from the water, dried over calcium chloride, and distilled. TABLE I CHLOROMETHYL SULFIDES R-S-CH2Cl B. 'C. Methyl 105-107 Ethyl' 127-129 n-Propyl 149-150 138-131) Isopropyl* AllylC 52-55 n-Butyl 64-66 s-Butyl' 58-59 160-161 Isobutyl &Butyl 57-58 n-Amyl 172-176 %Pentylb 73-76 Isoamyl 91Y3 n-Hexyl 105-106 Cyclohexylb 101-103 Z-Ethyl)-butyl 87-88 1-Methyl)heptyl-' 78-80
R
p., Yield, mm. % Formula 760 60 CzHiClS 760 60 760 93 C4HgCIS 760 85 ClHsCIS 15 57 CiHiClS 16 80 CsHiiClS 11 78 CrHriClS 760 75 CsHiiClS 12 24 CrHiiClS 760 73 GHiaCIS 13 79 CsHixClS 30 70 GHirClS 22 71 CTHIKIS 1 3 . 5 90 CiHlzClS CiHiiClS 9 74
2
63
CsHieCIS
Chlorine, % Calcd. Found 36.75 36.65 28.47 28.47 28.92 25.58 25.58 25.58 25.58 23.23 23.23 23.23 21.27 21.53 21.27
28.50 28.87 28.82 25.63 25.25 25.72 20.97" 23.46, 23.19 23.36 21.42 21.71 21.33
18.20
18.14
'All the compounds except this one are stable when pure. The sample saved for analysis partially decomposed even though sealed in a dark glass ampule and there was insufficient material for re-purification. The freshly prepared compound was used immediately to prepare a malonic ester. The barbituric acid prepared from the U. S. Patent 2,354,ester gave a satisfactory analysis. 230. U. S. Patent 2,354,229.
electrons CHz=CHCH2CH(COOCzHs)zincreased the acidity of the malonic ester to such an extent that, in its preparation by the usual procedure, Chloromethyl Sulfides.-Bohme's procedure was used 20-30% of diallylmalonic ester was obtained. as described for the first five members of the series. The The di-alkylthiomethyl malonic ester did not hydrogen chloride must be added carefully with runs of low boiling mercaptans larger than one mole as the initial give the Corresponding barbituric acid when con- reaction is vigorous. The higher members of the series densed with urea in the usual manner. Instead, were insoluble in concentrated hydrochloric acid and the some complex reaction took place and a sulfur- aqueous layer was separated before drying the product by free sodium salt precipitated after a few minutes stirring it vigorously with calcium chloride for several hours t 0'. &Butyl chloromethyl sulfide decomposes rapidly r&uxing. This salt was very insoluble in water awhen impure and must be distilled immediately after dryand the free acid was not precipitated by acetic ing the trude product for one hour acid. Analysis of the free acid gave values for Malonic Esters.-Three-tenths mole of alkyl malonic nitrogen checking with that theoretically con- ester was added to a solution of 0.3 mole of sodium in 150 of absolute alcohol. As much alcohol was removed as tained by two barbituric acid nuclei-plus an addi- cc. would distill a t 10-30 mm. on a water-bath, and the residue tional methylene group. This product was not was dissolved in 300-500 cc. of dry toluene. This solution investigated further. was chilled to 0' and 0.3 mole of chloromethyl sulfide The alkyl chloromethyl sulfides were prepared slowly added. The mixture was stirred until neutral, washed with water and distilled. by a slight modification of Bohme's procedure.la (1) Prewnt address: George A. Breon h C0.i H a n ~ Citv, e
(la) BaLme, Bw.,
1818 (1938),
Mo.
(2) "Organic Syntheses," Vol. 21, p. 36. (3) Backer and D r b , h. Lrao. chim., 61, 289 (1932).
1,. A. WALTER,I;. H. GOODSON AND RUSSELJ. FOSBINDER
656
TABLE I1 R---S-CH*
Vol. 67
CO-NH
BARBITURIC .4CIDS'
Malonic ester Fraction usedb.6d Mm.
B. p.. *C. 104-1G6 102-105 114-110 107-109 94-96 104-107 118-119 108-109 113-114 125-127 107-109 114-116 115-117 123-126 123-125 120-124 149-151 124-126 132-146 105-107 121-122 105-106 107-109 110-112 135-140 114-117 121-122 133-136 125-128 142-145 142-145 135-138 128-130 112-115 111-115 103-104 131-135 118-120 118-124 138-140 133-138
12
n'
M. p., *C., uneor.
Nitrogen, % Calcd. Found
Methyl Isobutyl 118-120 11.47 11.51 s-Butyl 133.5-135 iMethyl 11.47 11.53 8-Methallyl Methyl 180-181.5 P 11.56 11.52 1-Methylbutyl 124-127 Methyl 10.84 1.5 10.93 Methyl 149.5-151 Ethyl 12.96 12.92 1.2 161-162 Ethyl Ethyl 12.16 2 12.20 n-Propyl 169-170 11.47 Ethyl 11.61 2 Isopropyl 138-139 Ethyl 11.47 11.47 1.8 131-132 Allyl Ethyl 11.56 2 5 11.67 151-152 n-butyl Ethyl 10.84 2 10.90 146.5-147 Isobutyl Ethyl 11.04 0.8 10.84 128-131 Ethyl s-Rutyl 15 11.03 10.84 133-133.5 8-Methallyl Ethyl 1 10.97 10.93 121-122 Ethyl Isoamyl 1.7' 10.17 10.29 l-Methylbutyl 103-106' Ethyl 10.29 1 10.30 A-1- (1-Methylhuteiiyl) 111-113 Ethyl 15 10.66 10.36 Phenyl 10.21 205.6-206 Ethyl 12 10.07 hexyl 110.5-1 11 0 8 Uthyl 9.79 10.00 A-1-Cyclohcxenyl 170-171.5 Ethyl 1 9.93 9.92 Ethyl 131-132 n-Propyl 11.48 1 11.43 Allyl 105,5-106.5 n-Propyl 1.2 10.66 10.93 Ethyl 152-1 53 Isopropyl 11.48 2 11.48 133.5-134.5 Isopropyl 10.85 Isopropyl 10.84 1.4 165-166 Ethyl Allyl 0.5 11.76 11.56 1-Methylbutyl 89-92' Allyl 9.85 1.8 10.08 Methyl 144-146 n-Butyl 11.48 2 11.46 106.5-107.5 Ethyl 10.87 n-Butyl 10.84 1 129-130.6 10.44 2 n-Propyl n-Butyl 10.29 Isopropyl 129-129.5 n-Butyl 10.29 1 10.31 Allyl 99-100 n-Butyl 10.29 10.37 3 n-Butyl 106-108 n-Butyl 9.76 9.79 2 Isobutyl 112-113 n-Butyl 9.77 9.79 1 S-Butyl 121-122 n-Butyl 9.79 0.8 9.50 154.5-155.5 Ethyl Isobutyl 15 11.06 10.84 130-130.5 Ethyl s-Butyl 11.03 10.84 1.5 Ethyl 186.7-187 t-Butyl 1 5 11.03 10.84 Ethyl 107.5-108.5 11 n-Amyl 10.10 10.29 Ethyl 120-121 Isoamyl 10.29 0.5 10.22 106.5-107.5 1-Methylbut yl Ethyl 10.29 10.13 1.2 n-Hexyl Ethyl 103.5-104.5 9.70 9.79 0 8 127-128 2-Ethylb~tyl Ethyl 10.01 9.79 0.8 162-163 Cyclohexyl Ethyl 9.86 9.96 144-147 1 Several of the malonic esters were analyzed for sulfur and without exception gave values U.S. Patent, 2,354,232. U. S. Patent checking with the theoretical. The authors are reasonably certain all were of 95% purity or better. The di-alkylthiomethyl malonic ester prepared was (n-C3Ht.SCH&C(COOGH&,b. p. 147-14Q0, at 1.2 2,354,231. mm. Wax-like. 1 1
(1
@
Barbituric Acids.-Two-tenths
mole of malonic ester
and 0.24 mole of urea were r d u x e d for twelve to eighteen hours with a solution of 0.42 mole of sodium in 150 cc. of absolute alcohol. The alcohol was removed i n vacuo on a
water-bath arid the residue dissolved in 150-200 cc. of water. This solution was extracted with ether and then acidified with acetic acid. The crude product was purified by crystaflization from alcohol or alcohol-water mixture. The yields were good. The thiobarbituric acids were prepared from thiourea in the same manner. They were usually contaminated with
a jelly-like impurity which was removed by filtering a concentrated ether solution of the crude product. The sodium salts of all the thiobarbituric acids crystaltized readily from absolute alcohol as solvates containing two molecules of alcohol. In those cases where the free acid waa not easily purified it was first purified as the sodium salt by several crystallizations from absolute alcohol. The alcohol-free salts were hygroscopic. The N-methyl barbiturates were prepared from the same proportions of ester and methy1 urea with 0.22 mole of sodium in 75 cc. of absolute alcohol.
April, 1045
(u-ALKYLTHIOALKYL
TABLEI11 R--S-CHn
CO-NH
\/
THIOBARBITURIC ACIDS
R' M. P., OC.. R' uncor. R 155-156 Methyl Isobutyl 145-146 Ethyl Ethyl Allyl 122-123 Ethyl 114-116 Ethyl J-BUtyl Ethyl Isobutyl 145-147 Ethyl LMethylbutyl 97-loo4 Isopropyl Ethyl 175-176 Allyl 1-Methylbutyl 75-80° r-Butyl n-Butyl 90-92 Isoamyl Ethyl 131.5-183 0
>s
nARBITURATE DRRIVATWRS
G67
TABLE IV R--S-CHn N-METHYLBARBITURIC ACIDS4
\c/
c' o
R'\CO-&
\CO-Nf
Nitrogen, % Formula Calcd. Found CioHbOlNaS, 10.76 10.47 G H i 4 0 i N A 11.37 11.41 CioHi4OrNYSi 10.84 10.99 CiiHilOiNrSI 10.21 10.31 CiiHitOINtSi 10.21 9.99 9.71 9.76 CirH.sQNrS: CinHiiOaNiS1 10.76 10.72 CiaHnOlNySa 9.32 9.36 CiaHnOrNaSa 9.26 9.27 CIIHSOO~N~SI 9.71 9.92
CO-N-CHs
R Ethyl Ethyl Ethyl Ethyl Ethyl Ethyl Ethyl n-Propyl Isopropyl n-Butyl
M. P QC.." R' uncor. Methyl 104-105 Ethyl 66.5-67.5 n-Propyl 102-104 Isopropyl 78-79 Allyl 63-65.5 Isobutyl 103-104 S-Butyl 75-79 Ethyl 73-75 Ethyl 87-88.6 Methyl 75-77
Formula CtHiaOaNsS CitHioOaNrS CiIHiaOrNd CiiHiaOaNYS CiiHisOiNrS Ci2HsOaNiS CirHroOiNtS CliHiiOaNd3 CIIHIIOINZS CiiHieOaNrS
Nitrogen, % Calcd. Found 12.19 12.00 11.47 11.46 10.84 10.94 10.84 11.00 10.93 10.86 10.28 10.35 10.28 10.07 10.84 11.10 10.84 10.72 10.84 11.01
U. S. Patent 2,364,233.
Wax-like.
The condensation of di-n-propylthiomethyl malonic ester with urea gave an insoluble sodium salt which was filtered from the reaction mixture and recrystallized from water. It contained no sulfur. The free acid was obtained by acidifying an aqueous solution of the salt with hydrochloric acid to Congo red. It was very insoluble in all the common solvents. decomDosed at 280-285'. and contained 2O.22yOnitrogen. 5-Eth~llsulfonemeth~l-5-~butvl Barbituric Acid.-The 5-ethyl~hiomethyl-5-i~obutylbar~turic acid was oxidized with excess hydrogen peroxide in glacial acetic acid.' The product decomposed at 214-215'. A n d . Calcd. for CIIH1aO,NnS: N, 9.65. Found: N, 9.66. (4) Pomerantz and Connor, Tms JOURNAL, 61, 3144 (1939).
5-Ethylsulfoxymethyl-5-isoamyl Barbituric Acid.-Two
moles of 6-ethylthiomethyl-5-isoamylbarbituric acid was oxidized with one mole of hydrogen peroxide as described above. The product was separated easily from the excess starting material by crystallization from alcohol. It decomposed at 221-223'. Anal. Calcd. for C I ~ H ~ ~ O ~ N, N Z9.71. S: Found: N, 9.71.
Summary Some 5-alkylthiomethyl-5-alkyl barbituric, thiobarbituric, and N-methylbarbituric acids and the intermediates used in their preparation are described. A sulfone and a sulfoxide of representative barbituric acids are also described. NEWARK, N. J.
RECEIVED NOVEMBER 4, 1944
[CONTRIBUTION FROM THE RESEARCH LABORATORIES OF THE MALTBIE CHEMICAL CO.]
Thioether Barbiturates. II. or-Alkylthioalkyl Derivatives BY L. A. WALTER,L. H. GOOD SON^ AND RUSSELJ. FOSBINDER
of barbituric acids varied from thirty to seventy per cent. except where R' was a secondary group. In the latter case the yield was poor, probably due R' to steric effects, though the intermediate malonic I R-S-C CO-NH ester was obtained in excellent yield. \ The preparation of thiobarbituric acids where , , C 4 and (S) R' was a secondary group such as isopropyl or 3-pentyl presented some difficulty as they were Rt/ 'CO-NH in which R, R' and R' represent primary and not obtained when the condensations were carried secondary alkyl qroups. Compounds where either out in the manner described.* Under those or both R and R were unsaturated were prepared conditions we were able to isolate only the monobut none were prepaied where R' was unsatu- alkyl thiobarbituric acids which resulted from the rated. In order to avoid difficulties in purifying cleavage of the thioalkyl group from the desired the products we limited the alkyl groups to those barbituric acid and probably from the intercontaining no asymmetric carbon atom. Com- mediate malonic ester as well. By employing pounds of the above structure where R, R', or the general method of Cope,*whereby less sodium ethoxide, more alcohol, more thiourea and a R' represents a tertiary group appeared less shorter reflux time were used (i. e., refiuxing 0.1 feasible and their synthesis was rpt attempted. 0.15 mole of thiourea, and 0.16 mole mole of ester, The barbituric acids were made from the corresponding disubstituted malonic esters by the of sodium ethoxide in 150 cc. of absolute alcohol procedure given in the first paper.* The yields for six hours), low yields of these thiobarbituric acids were obtained. The instability of these (1) R a t nddreu: George A. Breon h CO., K.luu City, Mo. This paper describes a series of barbituric and thiobarbituric acids of the structure
'\A
(2) Wnlter, Ooodlon nnd Forbinder, W r JOWU~AL, 67,666 (1046)).
(8) Cops nnd Ha&.
W . ,61, 98 (lOa9).
