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An extension of the synthesis of thiazolo [5,4d]pyrimidines of Weidel and of Fischer has been carried out. 2-Methylthiazo-
10[5,4-d]pyrimidine-5,7-diol has been converted into the ,5,7-dichloro analog and hence into the 5,7-diamine. The previ-
ously reported synthesis of thiazolo [4,5-d]pyrimidines has been shown to he unreliable and an alternate synthesis has been developed.
The recent publication concerning thiazolo [5,4- converted thiazolo [4,5-d]pyrimidine-5,7-diol into cl]pyrimidinesl prompts us a t this time to submit a 6-amino-2,4,5-trichloropyrimidine whose structure report of our findings with these compounds as well was confirmed by conversion into 5-chloro-2,4,6as with certain thiazolo [4,5-d]pyrimidines. triaminopyrimidines by ammonia, a reaction indiThiazolo [5,4-d]pyrimidine-5,7-diol and its 2- cating the presence and point of attachment of the methyl- and 2-phenyl-' analogs were prepared from pyrimidine ring. Ultraviolet absorption spectra of thiouramil by the action of formic acid, acetic anhy- these compounds is shown in Figs. 1 , 2 and 3. dride and benzoic anhydride, respectively, in accord with and in extension of previous work.2,3 Experimental From 2-methylthiazolo [5,4-d]pyrimidine-5,T-diol Thiazolo[5,4-d]pyrimidine-5,7-diol.-A suspension of 1 g. and phosphorus oxychloride, 5,7-dichloro-2-methyI- of thiouramil2~3in 20 ml. of 85% formic acid was refluxed thiazolo [5,4-d]pyrirnidine was obtained which with four hours, cooled and filtered. The product was dissolved aqueous ammonia was converted into 5,7-diamino- in 35 ml. of hot ammonium hydroxide, treated with Norite, and reprecipitated with hot dilute hydrochloric acid to yield 2-methylthiazolo [5,4-d]pyrimidine. The latter 0.9 g. of a faintly yellow powder which did not melt below compound has been submitted to the National Can- 360". cer Institute for pharmacological evaluation. Anal. Calcd. for C S H Z N ~ O ~N, S :24.8; S, 18.9. Found: Our attempts to prepare thiazolo [4,5-d]pyrimi- N,24.8; S, 19.0. dines from bromobarbituric acid and thioamides4 2-Phenylthiazolo [5,4-d] pyrimidine-5,7-diol. -'A mixture have been unsuccessful. Both mono- and dibro- of 1.5 g. of thiouramil and 15 g . of benzoic anhydride was heated on a steam-bath for three hours and a t 170' for onemobarbituric acid formed with thioformamide a half hour. After cooling ether was added and the product sulfur-free product which we have been unable to filtered and washed thoroughly with ether leaving 2.0 g. of purify, while with thioacetamide a smooth conver- material melting well above 360' with decomposition. sion to barbituric acid and sulfur was observed. For analysis a portion was crystallized from 50% acetic acid. A n d Calcd. for CIIH,S:IO?S: N , 17.1; S, 13.1. Found: These results have now been confirmed.6 The action of sodium hypobromite upon thia- S , 17.2; S, 13.2. [5,4-d]pyrimidine.-A mixture of 0.5 zole-4,5-dicarboxamide and its 2-methyl- and 2- g. 5,7-Dichlorothiazolo of thiazolo[5,4-d]pyrimidine-5,7-dioland 5 g. of phosphenyl analogs has given rise t o compounds which phorus oxychloride was heated for 12 hours a t 200°,cooled we now regard as thiazolo [4,5-d]pyrimidine-5,7-dioland poured onto 30 g. of crushed ice. The product was and its 2-methyl- and 2-phenyl analogs (further ex- filtered, dried, crystallized from methanol and sublimed z'ucuo to give 0.1 g. of white crystals melting a t 148.5amples of pyrimidine formation from 1,2-diamidesfi), in 119.5'. An additional 0.05 g . of purified material was obalthough they differ widely in properties from those tained from the original acidic filtrate by neutralization. r e p ~ r t e d . ~To eliminate the possibility that a :lnal. Calcd. for CjHS,SCI?: N, 20.4; S, 15.5. Found: somewhat unusual oxidation had occurred, 2 - S , 20.4; S, 15.5. methylthiazolo [4,5-d]pyridazine-4,7-diol was y e 5,7-Dichloro-2-methylthiazolo [ 5,4-d] pyrimidine was prepared from diethyl 2-methylthiazole-4,5-dicarboxyl- pared analogously from 3 g. of 2-methylthiazolo[5,4-d]pyrimand 50 g . of phosphorus oxychloride at 170". ate7 and hydrazine and shown to differ from the idine-5,7-diola The yield of white crystals melting a t 109-110" was 2.7 g. above 2-methylthiazolo [4,5-d]pyrimidine- 3,7 -diol .4nal. Calcd. for CGH~N:ISCI~: S , 19.1; S,14.6. Found: (Fig. 1). N,19.0; S,14.7. Surprisingly, and in contrast to the behavior of 5,7-Diamino-2-methylthiazolo[5,4-d] pyrimidine.-A mix2 - methylthiazolo[5,4 - dlpyrimidine - 5,7 - diol, ture of 1 g. of 5,7-dichloro-2-methylthiazolo[5,4-d]pyrimineither thiazolo[4,5-d]pyrimidine-5,7-dioInor its dine arid 15 ml. of concentrated ammonium hydroxide was for four hours at I,%' chilled and filtered. The %methyl analog react with phosphorus oxychlo- heated cornbiued crude product from five such reactions weighed ride or phosphorus pentachloride under usual con- 2 g. and was crystallized twice from methanol to give 1.2 g. ditions. (A conceivable parallel has been observed of white crystals melting at 255-257', in reasonable agreein the inert behavior of 2,4-dihydroxy-G-aminopy- ment with the value previously rep0rted.l .4nal. Calcd. for CGH~NSS:S , 38.7; S, 17.7. Found: rimidine toward phosphorus oxychloride in contrast t o the ready reaction of 4,6-dihydroxy-2- N , 38.7; S , 17.7. Thiazole4,5-dicarboxamide.-Fifteen grams of diethyl aminopyrimidine.) However, action of excess thiazole-l,5-dicarboxylategand 40 ml. of concentrated amphosphorus pentachloride a t 200' unexpectedly monium hydroxide gave 9 g. of crude product melting from (1) I 4 Falco arid 1 1 IT I l l t r h i n g s r H h J o i K h A I , 72, :3207 (lcl50) ?) E Flscher arid I, \ih 4 i i i t 288, l i 7 (1895) '3) H Weidel and I* Niemilowirz, Monnlsh 16, 721 (1895) (4) H E r l e n m e i e r nnd 1% P Furgcr I l r i . C h ~ i i i 4;tn 26, ?R6 1943) 30, 585 (1947) ( 5 ) €1 P Furger i b t d , 53, 1689 (1950) if?) R A Baxter a n d F S Spring, J Chem S O L , 22'3 i 1947) i:) T Roubleff A n n 259, 253 (1890)
A portion was crystallized from water, washed 280-295'. with dilute ammonia and dried a t 100' in vacuo to form white crystals, n1.p. 298-300' (dec.). -4nal. Calcd. for C3HjNa02S: N , 24.6; S, 18.7. Found: S , 24.6; S, 18.8. ..-.-__I
(8) S. j.Childress and R. L. McKee, THISJOURNAL, 72, 4271 (1950). (9) H. Erlenmeyer a n d H. von Meyerburg, Helv. Chim. A c l o . 20, 20.2 (1037).
Aug., 1951
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THIAZOLOPYRIMIDINES
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1.o
200
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300
350
m. Fig. 1.-Absorption spectra in water solution: -, 2methylthiazolo [4,5-d]pyrimidine-5,7-diol; - - - - - -, 2-methylthiazolo[5,4-d]pyrimidine-5,7-diol;- -.- -. , 2-methylthiazolo [4,5-d]pyridazine-4,7-diol.
I
200
250
300
360
w. Fig. 2.-Absorption spectra in 0.001 molar sodium sodium hydroxide: - - - - - , thiazolo [5,4-d]pyrimidine5,7-diol; --, 2-methylthiazolo [5,4-d]pyrimidine-5,7-diol; , 2-phenylthiazolo[5,4-d]pyrimidine-5,7-diol.
-
2-Methylthiazole-4,5-dicarboxamidewas likewise pre3.0 * pared from 8 g. of crude diethyl 2-methylthiazole-4,5-dicarboxylate' and 20 ml. of concentrated ammonium hydroxide. The crude product weighed 4 g. and melted from 290-294". For analysis a portion was crystallized from 50% alcohol giving white crystals melting at 296' with decomposition. Anal. Calcd. for C ~ H I N ; ~ O S ~ S, 22.7; : S, 17.3. Found: N, 22.8; S, 17.2. 2-Phenylthiazole-4,5-dicarboxamide was similarly prepared in a crude yield of 2.5 g. from 3 g. of diethyl 2-phenylthiazole-4,5-dicarboxylate. 10 A portion was crystallized from glacial acetic acid to form white crystals, m.p. 319321". Anal. Calcd. for CilH9Kz0~S:S , 17.0; S, 13.0. Found: N, 17.2; S,13.0. Thiazolo[4,5-d]pyrimidine-5,7-diol.-Asolution of 1.8 g. of bromine in 28 ml. of water containing 3.6 g. of potassium hydroxide was prepared at 0" and added to 2 g. of thiazole4,5-dicarboxaniide. The mixture was stirred for three hours 200 250 300 350 at O0, additional hypobromite solution being added at intervals until the diamide dissolved. The solution was mp. allowed to stand overnight in the refrigerator, filtered from Fig. 3.--Ultraviolet absorption spectra in 0.001 molar a small amount of unreacted diamide and heated 20 minutes a t 80". The compound after precipitation with acetic acid, sodium hydroxide: - - - . -, thiazolo [4,5-d]pyrimidine-5,7filtration and washing with water weighed 1.3 g. and did diol; __ , 2-methylthiazolo [4,5-d]pyrimidine-5,7-diol; not melt below 360°.4 The compound was redissolved in , 2-phenylthiazolo[4,5-d]pyrimidine-5,7-diol. dilute ammonia, treated with Norite, and reprecipitated with dilute hvdrochloric acid: a slight yellow color persisted. and crystallized from water to give 0.3 g. of A n d . Calcd. for CjHiSaO?S: S, 24.8; S, 18.9. Found: evaporation material melting a t 197-199" and showing no depression N, 24.9; s, 19.0. when mixed with 2,4,6-triamino-5-chloropyrimidine .* One and one-half grams of this substance was heated with 2-Methylthiazolo[4,5-d]pyrimidine-5,7-diol.-Twograms 30 g. of phosphorus pentachloride for 12 hours a t 200°, of 2 methylthiazole - 4,5 - dicarboxamide when similarly added to 200 g. of crushed ice, and the solid filtered. After treated with hypobromite gave rise to 1.7 g. of product resublimation in VUCZLO, the product weighed 0.2 g. (m.p. 155- * taining a very pale yellow color and which did not melt below 165"). The acidic filtrate was made slightly alkaline 360°.4 (ammonia) giving 0.8 g. of light yellow needles melting from Anal. Calcd. for CeHjSa02S: S ,23.0; S, 17.5. Found: 165-168'. Sublimation in 'L'UCUO gave 0.7 g. of white crystals melting a t 170-171.5" and having a nitrogen content X, 23.0; S, 17.4. consistent with formulation as 6-amino-Z,4,5-trichloropy- 2-Phenylthiazolo [4,5-d]pyrimidine-5,7-diol.-When 1.8 g. of 2-phenylthiazole-4,5-dicarboxamidewas treated with as rimidine. as 56 ml. of potassium hypobromite, it did not comAnal. Calcd. for C4H1NaCld: N, 21.2. Found: 9, 21.1. much pletely dissolve and the yield of crude product was only 0.5 A mixture of 0.7 g. of this pyrimidine and 10 ml. of con- g. of material melting a t about 325'. A portion crystallized centrated ammonium hydroxide was heated overnight a t from 50% acetic acid appeared as light cream crystals lW", chilled and filtered. The solid was leached with a melting a t 331-332°.4 small amount of hot 95% alcohol and the residue crystallized Anal. Calcd. for CllH,N3O2S: S , 17.1; S, 13.1. Found: from 95% alcohol to give a small amount of a white crystalline product whose melting point, 299-300", was not de- X, 17.1; S, 13.1. pressed when mixed with 4,6-diamino-2,5-dichloropyrimi- 2-Methylthiazolo[4,5-d]pyridazine-4,7-diol.-When 1 g. dine.* The alcohol-soluble portion was recovered by of crude diethyl 2-methylthiazole-4,5-dicarboxylate'and 5 ml. of 85% hydrazine hydrate were allowed t o react for one hour in 10 ml. of alcohol a t room temperature, a product was (10) E. H. Huntress and K.Pfister, TRISJOURNAL,66, 2167 (1943).
__.__. -
SORMAN KILYRASCII AND JAMES LORNECAMEROS
3861
obtained which meltctl a t 187" after crystallization from alcohol. The analysis indicatwl that this wv.75 the di-hydra-
zide.
Vol. i 3
acid, the product weighed 0.3 g., was cream colored, and did not melt below 360'. Anal. Calcd. for C13HgN302S: N, 15.5; S, 11.8. Found: N,15.4; S , 11.8. 2-( p-Styryl)-thiazolo[4,5-d]pyrimidine-5,7-diolwas prepared similarly, 0.7 g. of 2-methylthiazolo[4,5-d]pyrimidine-5,7-diol yielding 0.3 g. of the recrystallized product, a yellow powder which melted at 329-331 with decomposition. Anal. Calcd. for C,?H,K:?O.S: N, 15.5; S, 11.8. Found: S , 13.5; S, 11.9
Anal. Calcd. for C&X60~S: X, 32.6; S, 14.9. Found: N, 32.4; S, 14.8. Seven grams of the above thiazole diester was dissolved in 50 ml. of ethanol, 5.3 g. of 85% hydrazine hydrate added and the mixture heated for 48 p u r s at 100' and, inadvertently, one-half hour a t 140 The solid product was filtered and washed with 50% acetic acid and with water leaving 2 g. of material ineltiiig from 332-355" (dcc ) A Acknowledgment.--We wish to thank Merck portion was crystallized from glacial acetic acid and from water to give a pale yellow powder which darkened slightly arid Company, Elkton, Virginia, for a generous gift above 300" and melted a t 3.55' with decomposition of thioformamide. We also wish to express our A n d . Calcd. for CsH,S,O?S: N,23 0 ; S, 17 3. ITountl: sincere appreciation to Dr. H. Erlenmeyer who S , 23 1; S, 17.4. most graciously undertook a reinvestigation of the 2-( @-Styrg1)-thiazolo[5,4-d]pyrimidine-5,7-diol was pre- reactions between bromobarbituric acid and cerpared by refluxing 0.7 g. of 2-methylthiazolo[5,4-d]pyrimi- tain thioamides. dine-5,7-diol in 10 g. of benzaldehyde containing 1 g. of zinc chloride. After crystallization twice from 90% acetic CHAPELHILL, SORTH CAROLINA RECEIVED MARCK 9,1951
[CONTRIBUTION FROM
THE
DEPARTMENT O F CHEMISTRY, UNIVERSITY OF SOUTHERN CALIFORNIA]
Derivatives of Sulfenic Acids. VI. The Synthesis of a-Nitro Sulfides BY NORMAN KHARASCH AND JAMES LORNECAMERON' The reaction of sulfenyl halides with the sodium salts of nitroalkanes leads t o the heretofore unreported a-nitro sulfides. A series of the new products hac. been prepared and evidence is given to substantiate their structures.
This paper reports the preparation of a series of a-nitro sulfides by the interaction of sulfenyl chlorides, bromides or thiocyanates with the sodium salts of nitroalkanes. The new products obtained are listed in Table I. Whereas the sulfeny-1 halides fail to react with nitroalkanes, the sodium salts react smoothly. The reaction presumably involves a nucleophilic attack on sulfur by the nitroalkane anion. ArSX [RR'CN02]Na+ -+
+
structure I1 would not be expected to behave in this manner. ( 2 ) As shown below, a-nitroethyl p-tolyl sulfone (IV) was obtained in three alternative ways: In i'0Y0 yield by oxidation of the product resulting from the reaction of p-toluenesulfenyl chloride and the sodium salt of nitroethane. (2) I n 71% yield
+
+
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I
