2 iG4
EDWARD C. T.LYLOR A N D ~ ' I L L I A M R. SHERMAN
duced pressure. Sublimation of the residue a t 150' (0.05 mm.) yielded 3.2 g. (63%) of white needles, m.p. 163-165'. Recrystallization from water yielded a hydrate which decomposed on heating above 100".
[ C O S T R I B U T I O Y FROM THE
Pteridines.
XVII.
Yo]. s1
Anal. Calcd. for CsHleNa: C, 50.0; H, 0.3; X, 13.5. Found: C, 50.0; H, 6.3; N, 43.5.
I'RISCETOX, S. ]
FRICK CHEMICAL LABORATORY, PRINCETON UNIVERSITY, CHEMISTRY, UNIVERSITYOF ILLIXOIS]
-4ND THE KOYES
LABORATORY OF
2,4,6,7-Tetrachloropteridine. The Synthesis of 5,6,7,8-Tetrahydropteridine'
Reactions of
c.
B Y EDWARD TAYLOR~ .4XD IvILLIAM R.SHERMAN3 RECEIVED ?;OVEMRER 13, 1957
ii procedure suitable for the preparation of large quantities of 2,4,6,i-tetrahydroxypteridine(I) is given. Lithium aluminum hydride reduction of 2,4,6,7-tetrachloropteridirie(11), prepared from I by chlorination, yields 2,4-dichloro-5,6,7,8tetrnhydropteridine (III), which upon catalytic reduction gives 6,6,7,8-tetrahydropteridine (XI). The structures of these reduction prnducts are independently established. Reasons for the stability of I11 and XI, in contrast to the instability of ~,J-dichloropteridine(V) and pteridine ( X I ) , and the failure of attempts to dehydrogenate X I t o X I I , are discussed. Catalytic reduction of 2,4,6,7-tetrachloropteridineyields a purple solid which is rapidly converted in the presence of air to 2,4-dichloro-0-liydroxy-;,8-dihydropteridine (I'III), Those structure is established by a n independent synthesis and by further reduction to 6-hydroxy-7,8-dihydropteridine (X). Amination of I11 yields 2,4-diamino-5,6,7,8-tetrahydropteridine ( S I I I ) , which is readi!y oxidized through 2,4-diaminodihydropteridine(XIV) to 2,4-diaminopteridine (XV). Sodium bxohydride reduction of Xl'in dimethplformamide solution yields XI\'. Amination of I1 under strenuous conditions yields 2,4,6,7..tetrarniiiopteridine (XVII) hydrochloride, which condenses with alloxan, oxalic acid and formamide to give 2,4diamino-7,0-dihydrox~pteridyl(6,7-g)pteridine(XIX), 2-amino-4,7,8-trihydroxypyrazino(2,3-g)pteridine(SX) and a formyl derivative of 3,4-dia1iiinoimidazo(4,5-g)~teridine(XXI), respectively.
The first preparation of I , which may be regarded -4lthough 2,4,6,7-tetrachloropteridine(11) has been known since 1031,4 relatively little has been as the pteridine analog of uric acid, was reported by reported concerning its chemical reactivity or its Wieland' arid involved nitrous acid hydrolysis of use in pteridine synthesis. This compound was the %amino group of leucopterin (2-amino-1,6,7prepared by Schopf4by the chlorination of 2,4,6,7- trihydroxypteridine). Purrmann* later described tetrahydroxypteridirie (I) with a mixture of phos- a direct synthesis of I by the fusion of 2,4-dihywith oxalic acid unphorus pentachloride and phosphorus oxychloride. droxy-5,B-diaminopyrimidine It was demonstrated that I1 could be partially hy- der reduced pressure. Several minor modificadrolyzed in met ether solution or in warm 0.75 LV tions of this condensation have since been resodium hydroxide to a dichlorodihydroxypteridine ported which utilize the pyrimidine sulfate with' which was assumed to he 2,4-dichloro-G,7-dihydroxy-and without9 the addition of sodium acetate. Alpteridine, and that it could be converted to I by though these methods give satisfactory yields of I heating a t 140" for six and one-half hours in 25y0 in small-scale preparations, attempts to scale up the sodium hydroxide. Schiipf further demonstrated reaction to preparative amounts have resulted, in in a preliminary experiment that partial amination our hands, in drastically lower yields. A s a result, of I1 took place under very mild conditions, al- we have described in the Experimental section a though the product of the amination was not de- further modification of this condensation which intermined. Afore recently, Cain and Schenker5m6 volves fusion of the hydrochloride salt of 2,1-dihywith oxalic acid, and have found that all of the chlorine atoms of TI may droxy-5,B-diaminopyrimidine be replaced by alkylamino groups under sufficiently which gives consistently satisfactory yields of I in strenuous conditions, and the order of replacement large-scale runs. 2,4,G,7-Tetrachloropteridine(11) was then preof the chlorine atoms has been deterniined. No pared from I by previously described procedures, further reactions of I1 have been reported. 2,4,G,~-Tetrachloropter~~ine (11) thus appeared except that the product was best purified by vacto be an accessible, reactive intermediate amenable uum sublimation rather than by recrystallization. to use in further pteridine syntheses, and the pres- Reduction of I1 in ether or tetrahydrofuran soluent communication presents the results of our fur- tion with lithium alurninum hydride yielded a dither investigations with this compound. However, chlorotetrahydropteridine in almost quantitative since relatively large amounts of I1 were desired, it yield. This product mas assigned the structure 2-4was found necessary to re-examine the existing dichloro-5,G,7,8-tetrahydropteridine(111) on the methods for the preparation of ?,4,6,7-tetrahy- basis of the following evidence: (1) The ultraviolet absorption spectrum of 111 is similar to that given droxypteridine (I), its immediate precursor. except that by 2,4-dichloro-5,6-diaminopyrimidine, ( 1 ) Fur the previous paper in this szrirs, see E . C . Ta?l
