1996
C. K. CAIN,M. F. MALLETTE AND E. C. TAYLOR, JR. [CONTRIBUTION FRO31 THE
BAKERLABORATORY O F CHEMISTRY AT
Vol.
G8
CORNELL UNIVERSITY]
Pyrimido [4,5-b]pyrazines. I. Synthesis of 6,7-Symmetrically Substituted Derivatives * BY
c. K. CAIN, M. F. M.4LLETT.E
AND
E.
c. TAYLOR, JR.
The pyrimido[4,5-b]pyrazine nucleus, I , is present in a number of naturally occurring substances.
Recently Totter7 has used a similar reaction to prepare leucopterin from 4-hydroxy-2,5,G-triaminopyrimidine salts and oxalic acid. It will be noted that xanthopterin and leucopc s /?4\., /5\?\ terin have an amino group in the 2-position while $ c CC the lumazines have a hydroxyl group in that posiI tion. A search of the literature reveals few comc 2 cIi 'CI pounds having the 2-amino group present. I n \l/'\S/ N N order to study the preparation of molecules of I these types and the effect of various substituents Among these may be mentioned xanthopterin, 2- on the ultraviolet absorption spectrum, we have amipo - 4,6 - dihydroxypyrimido [4,5-b]pyrazine, prepared a series of compounds represented by and leucopterin, 2-amino-4,6,7-trihydroxypyri- formulas I1 and 111 where R=H, CH, or phenyl, mido [4,5-b]pyrazine, which are pigments isolated as well as compounds having phenanthro and acefrom butterfly wings. The flavins, represented naphtho groups fused onto the pyrimidopyraby riboflavin, are benzo derivatives of this same zine nucleus. nucleus. It has been reported2 that Vitamin Bc C-OH N C-OH N // \C/ \\ or Folic Acid may contain this same nucleus. I n \\ 3C-R hC-R addition to the biological significance of such 1 I l l compounds, Ellingson, et a1.,3 and Weijlard, et ~ l . , ~HO-C I l Cl C-R HzN-C C C-R have shown that such compounds may serve as a convenient source of substituted pyrazines when I1 I11 the pyrimidine portion is cleaved b y the action of acids or bases under strenuous conditions. A list of the compounds studied, together with I n view of the importance of such compounds, the starting materials used in the preparation, we have begun a study of the synthesis of a num- solvent used for recrystallization and significant ber of derivatives of the nucleus with a hope of data from the ultraviolet absorption spectra of improving the methods of synthesis of those solutions in 0.1 N sodium hydroxide is included in compounds reported in the literature as well as Table I. Spectra of the diaminopyrimidines the preparation of new compounds of possible have been included for comparison. biological or synthetic application. Since moleAnalytical samples of compounds 2-10 were cules of this type cannot in general be character- used to prepare solutions for measurement of abized satisfactorily by melting points, we have de- sorption spectra. Samples of compounds 1, 11 termined their ultraviolet absorption spectra. and 12 were purified by recrystallization from The most general method of synthesis involves water and dried in vacuo. the use of a substituted pyrimidine as one of the The Synthesis, properties and identification of reactants and formation of the pyrazine ring by isomers resulting from the reaction between direaction between 1,2-diamino groups and 1,2-di- aminopyrimidines and unsymmetrical dicarbonyl carbonyl groups. Using this method, Kuhn and compounds are to be subjects of forthcoming Cook6 prepared 2,3-dihydroxypyrimido[4,5-b] communications. Biological testing of the compyrazine (for which they suggested the name pounds described is in progress and will be relumazine) by interaction of 5,6-diamino-2,4-dihy- ported elsewhere. droxypyrimidine and glyoxal. The same authors Experimental as well as Ganapti6 varied the dicarbonyl com5,6-Diamino-Z,4-dihydroxypyrimidie Bisulfite.-Our pound to prepare several substituted lumazines. "
q/
(1) The work presented in this paper was supported in part by grants from the Nutrition Foundation, Inc., and from the Wyeth Institute of Applied Biochemistry. It represents a part of a collaborative project entitled "Newer Members of the B Group of Vitamins." (2) Mitchell, THISJOURNAL, 66, 274 (1944); Bloom, Vandenbelt, Binkley, O'Dell and Pfiffner, Scieirce, 100, 296 (1944). (3) Ellinssun, Henry and McDonald, THIS J O U R K A L , 67, 1711 (1945). (4) Weiilard, Tiijhler and Erickson, ibid., 67, 802 (1945). (5) Kuhn and Couk, Be?., 70, 761 (1937). (6) Gannpti, J . i'?idian Cheni. S O L .14, , G27 (1937).
synthesis of this compound is essentially that of Bogert and Davidson.* Since the yield is appreciably better and the method involves fewer isolations of intermediates, the procedure is reported in detail. To a solution of sodium ethoxide prepared by dissolving 92 g. (4 moles) of sodium in 2000 ml. of absolute ethanol, 120 g. (2 moles) of urea and 212 ml. (2 moles) of ethyl cyanoacetate were added. The mixture was refluxed for three hours on a hot water-bath. The solid which had precipitated was collected by filtration, washed thoroughly (7) Totter, J. Bid. Chcm., 164, 105 (1944). (8) Bogert and Davidson, THIS JOURNAL, 66. 1668 (1933).
Oct.,
19/46
1997
S Y N T N E S I S OF 6,7-SYMMETRICALLY SUBSTITUTED PYRIMIDO [4,5-b]PYKAZINES
TABLE I Starting materials Pyrimidine -C=O Structure
Ref.
1 II,R = R = H
4, 5
Cpd.
2 3
111, I< = R
= 1%
4, 5
11, R = R = CHa
4 111, I< = R = CHs 5
11, R = K =
6 111, I1 =
R
=
-cI>
-'> \-
-y /--\
7
11, ItI
