978
ORGANIC AND BIOLOGICAL. [CONTRIBUTIONS PROM THE SHEFFIELD LABORATORY OF YALE UNIVERSITY. ]
RESEARCHES ON PYRIMIDINES: THIOCYTOSINE-5-CARBOXYLIC ACID. [FIFTY-SECOND PAPER.] B Y T R E A TB. JOHNSON A N D JOSEPHA. A X B L U R .
Received April
12,
1911.
Ethyl cyanoacetate, CNCH,COOC,H,, condenses with thiourea and guanidine1 in the presence of alcohol and sodium ethylate, and cyanoacetic acid with urea in presence of phosphorus oxychloride, giving the pyrimidines-4-iminobarbituric I, 2-thio-4-iminobarbituric 11, and 2,4-diiminobarbituric acids 111. These iminopyrimidines undergo hydrolysis easily with dilute acids, giving ammonia and the same pyrimidines a s are obtained by condensation of diethyl malonate with urea, thiourea, and guanidine, viz.:barbituric IV,thiobarbituric V, and 2-iminobarbituric acids V I ? NH-CO
'
NH-CO
I
CO
CH,
I
I
NH-C
: NH
I. NH-CO
I
CO
I
1
CH,
/
NH-CO IV.
I
CS
I
NH-CO
/
CH,
NH-C 11.
1
:N H
I
I
CH,
NH-C
1
: NH
111.
NH-CO
I
I
HN:C
'
CS
CH,
I
I
NH-CO V.
NH-CO
I
HN:C
I
/
CH,
I
NH-CO VI.
Notwithstanding the reactivity of these two esters towards urea, thiourea and guanidine, attempts to obtain mercaptopyrimidines by condensing them with the simple pseudothioureas have been unsuccessful. Wheelers examined the behavior of the strongly acid esters-ethyl acetyl~yanoacetate~ VII, triethyl oxalomalonatej VIII, and diethyl oxaloacetatea IX-towards pseudoethylthiourea and observed, in every case, that the esters did not react to give pyrimidines but formed stable addition products or salts with the pseudourea. On the other hand, Johnson7 observed that the higher homolog of diethyl oxalacetate or diethyl oxalopropionate,8 X, condenses smoothly with pseudoethylthiourea, giving 2 -ethylmercap to-4-carbethoxy-g -methyl-6-oxypyrimidine : Traube, Ber., 33, 1371,3035; Ann., 331, 64. Michael, J. puakt. Chem.,[z] 35, 456;49, 3 6 ; Traube, Ber., 26, 2553. A m . Chem. J., 38, 358. ' Haller, Ann. chim. phys., [6] 17,207. Bouveault, Bull. SOC. chim.,[3] rg, 78. Wislicenus, Ann., 246, 317. J . Biol. Chem., 3 , 299. * Wislicenus and Kiesewetter, Ber., jx, 194.
'
RESEARCHES O N PYRIMIDINES.
CH,COCH (CN) COOC,H,
979
C,H,OOCCOCH(COOC,H,) VIII.
VII.
C,H,OOCCOCH,COOC,H, IX.
C,H,OOCOCH(CH,)COOC,H, X.
Although diethyl malonate and ethyl cyanoacetate do not condense with pseudothioureas, on the other hand their corresponding ethoxymethylene derivatives, viz. : diethyl ethoxymethylenemalonate, * X I , and ethyl a-cyano-P-etlioxyacrylate,2 X I I , react smoothly, giving pyrimidines : C,H,OCH : C(CN)COOC,H,
C,H,OCH : C(COOC,H,), XI.
XII.
Wheeler, Johnson and Johns, for example, condensed the malonate, XI, with pseudoethylthiourea and obtained 2-ethylmercapto-5-carbethoxy-6-oxypyrimidine. Johnson3 later investigated the action of ethyl a-cyano-p-ethoxyacrylate, X I I , on pseudoethylthiourea and made the interesting observation that this ester reacts, in two ways, with the pseudourea, giving a mixture of z-ethylmercapto-~-cyano-6-oxypyrimidine, XIV, and 2-ethylmercapto-scarbethoxy-6-aminopyrimidine,XV. The formation of the latter pyrimidine was analogous to that of 2-thio-4-iminobarbituric acid from thiourea and ethyl cyanoacetate. I n continuing our study of the reactivity of ethyl a-cyano-g-ethoxyacrylate, XII, it seemed of interest to examin the behavior of this ester towards thiourea. We now find that i t reacts with thiourea in a manner analogous to ethyl cyanoacetate, giving an aminopyrimidine. In fact, i t condenses, apparently, in one manner only, giving an excellent yield of 2-thi0-4-carbethoxy-G-aminopyrimidine, X I I I . We obtained no evidence of the formation of z-thio-5-cyano-6-oxypyrimidine, XVI. The reaction is expressed by the following equation : NH,
I
CS
CN
+
~
NH,
N==C
I
C . COOC,H,
I
CS
I
I1
. NH, C . COOC,H,+C,H,OH 1
'I
NH- CH XIII.
CHOC,H6
2-Thio-5-carbethoxy-6-aminopyrimidine, X I I I , is converted quantitatively into thiocytosine-5-carboxylicacid, XVIII, by saponification with alkali. This pyrimidine crystallizes from water with one molecule of water while the corresponding cytosine acid4separates from water in an anhydrous condition. Especially interesting was the behavior of the Claisen, Ann., 297, 75. De Bollemont, Compt. rend.,
128,
1338;129, 5.
39. Am. Chem. J . , 42, 506. Am. Chem. J . , 38, 599.
' Wheeler and Johns,
Bull,
SOC.
chim., [3]
25,
18,28,
980
ORGANIC AND BIOLOGICAL,.
I
/I
NH-CH XVI.
I1
CHOC,H, XII.
I
I/
NH--CH XIII.
4
98 1
RESEARCHES ON PYRIMIDINES.
capto-6-aminopyrirnidine or cytosine-5-carboxylic acid, depending on the conditions employed. We now find that 2,6-dioxypyrimidine-5-acetamide, XX, reacts with bromine in a manner similar to ~-ethylmercapto-6-aminopyrimidine-5carboxamide and adds the halogen a t the double bond of the pyrimidine ring, giving 2,6 - dioxy - 4,5 - dibromohexahydropyrimidine - 5 - acetamide, XXIV. We obtained no evidence of the formation of bromoamides having the constitutions represented by formulas X X I I and XXIII. When the dibromide, XXIV, was warmed gently with alkali i t was transformed into a substance having the composition and properties of 2,6-dioxy-4,5dihydroxyhexahydropyrirnidine-5-acetamide,XXV. This transformation, however, was not smooth and the yield of the hexahydro compound was small. The constitution of this dihydroxypyrimidine, XXV, was established by the facts that ammonia was evolved when it was digested with alkali, and that i t underwent reduction with hydriodic acid, giving 2,6-dioxypyrimidine-5-aceticacid, XXVI, and ammonium iodide. This pyrimidine acid is not reduced a t the double bond by digestion with hydriodic acid. NH-CO
I
NH-CO
t
CO
CCH,CONHBr
I
I)
NH-CH XXII.
I
-L
I
1
I
It
CO
NH-CH XXI.
1
I
I
CH,CONHBr
co c( I I Br NH-CHBr XXIII.
NH-CO---J
I
NH-CO
r+
t
I
1
CCH,NH,
I
CO
-r
NH-CO
CCH,CONH, I It NH-CH-1
i+ NH-co CH,CONH, 1 I +CO CCH,COOH I II OH h H CHOH NH-CH xxv. XXVI. NH-CO
