[CONTRIBUTION FROM THE CHEMOTHERAPY DIVISION, STAMFORD LABORATORIES, AMERICANCYANAMID COMPANY]
RESEARCH
HYDROLYSIS AND AMINOLYSIS OF CERTAIN METHOXYPYRIMIDINES ROBERT G . SHEPHERD
AND
JACKSON P. ENGLISH
Received January 6, 19.47
In order to extend the study of the antimalarial activity (1) of certain phenylsulfonamidopyrimidines, members of this group containing the basic side chain associated with high activity in other series (2) were prepared. Although such a substitution had given rise (3) to an inactive sulfanilamide, 2-sulfanilamido-4(3-diethylaminopropylamino)pyrimidine, the metanilamides were investigated since they have been shown (1) to act by a different mechanism. Furthermore, it was of interest to remove the amphoteric characteristics of such compounds by N-alkylation of the sulfonamide group. To prepare these types of compounds it was planned to prepare the required 2-phenylsulfonamido-4-methoxypyrimidines,N-alkylate these, and replace the methoxyl with the desired side chain by a procedure which has been described (3). The second and third steps of this proposed scheme showed some interesting variations from their expected behavior. It is the purpose of this paper to describe the results with the p-chloro- and m-nitro-phenylsulfonamides. Methylation was effected either by diazomethane or by dimethyl sulfate and the results are summarized in Chart I. In the first method, alcohol rather than ether, which has been used previously (4), was employed as solvent to increase the speed of the reaction. Dimethyl sulfate was employed in aqueous alkali. With both reagents, the same two of the three possible monomethylated products were formed. This behavior is in contrast to that of 2-sulfanilamidopyrimidine reported here, and previous results with 2-metanilamidopyrimidine (1). These compounds give the "-methyl derivatives exclusively with diazomethane and 2-sulfanilamidopyrimidine is not alkylated satisfactorily with dimethyl sulfate (4). The two products in both series were troublesome to separate, but solvent extraction was found to remove the lower-melting one preferentially in both cases. The structures of the methylated compounds were determined by degradation with 65% sulfuric acid at 140". When the low-melting compounds (IV, Chart I) were treated with this reagent, uracil, confirmed by conversion into 5-bromouracil and 1,3-&methyluracil, and a volatile organic base resulted. The high-melting isomers (11, Chart I) gave 1-methyluracil by this treatment. I n this fashion it was established that the low-melting compounds (IV) were the "-methylated derivatives and the high-melting isomers (11)were the l-methyl2-phenylsulf onimido-1,2-dihydropyrimidines. When dimethyl sulfate was used as the alkylating agent a third, alkali-soluble, product was formed. This compound was isomeric with the starting material and was shown to have structure 111, or the tautomeric equivalents, by acid hydrolysis to 1-methyluracil. This material was found to originate from basic 446
REACTIONS OF METHOXYPYRIMIDINES
U
+
+
447
448
ROBERT G. SHEPHERD AND JACKSON P. ENGLISH
hydrolysis of the alkylation product I1 rather than rearrangement' of I. In addition, the reverse change of I11 into I1 can be accomplished by alkylation with dimethyl sulfate a t low temperature. This O-methylation is surprising, as uracil is reported to methylate only on the nitrogen ( 5 ) . The melting points of the two types of methylated products bear the same relation to each other as did the analogous products from sulfathiazole and sulfapyridine. There the "-methyl derivatives melted about 100" lower than the starting materials, and the ring N-methylated compounds had melting points approximating those of the starting materials (4). The relative amounts of compounds of type IV to those of type I1 (Chart I) formed with the two reagents differed markedly. Diazomethane gave a ring-N to "-methyl ratio of 1:3 while with dimethyl sulfate the same ratio was 3.5: 1. In the latter case the reaction was complicated by the hydrolysis of the methoxyl group which has been mentioned above. The rapid hydrolysis of the methoxy compounds (11) by dilute alkali at 80" was unexpected, since 2-sulfanilamido-4methoxypyrimidine had been prepared by hydrolysis of the W-acetyl derivative with boiling 2.5 N alkali for one hour (6). In the present work, stability of the methoxyl groups to alkaline hydrolysis was found t o be characteristic of the sulfonamides I, the "-methyl derivatives I V and of 2-amino-4-methoxypyrimidine. However, certain 2-amino alkoxypyrimidines do show instability (7) with respect to alkyl interchange but only on long heating with sodium alkoxides at 170". The application of these or less drastic conditions to the types of compounds in Table I would be expected to reveal stability variations similar t o those recorded. In attempting the preparation of the proposed dialkylaminoalkylamino compounds it was found that 3-diethylaminopropylamine was considerably more reactive with the methoxypyrimidines (I) than was 5-diethylamino-2-pentylamine. A similar effect of the branching of chains on amine reactivity has been observed by Wright and Elderfield (8) in the case of a-bromo ketones. The metanilamide, and the 3-nitro- and 4-chloro-phenylsulfonamidesof structure I reacted a t 110-120" with the substituted propylamine as did the analogous sulfanilamide (3). Although the ring N-methylated compounds of structure I1 were somewhat less reactive, the method was still applicable. 2-Amino-4-methoxypyrimidinerequired a much higher temperature, which is in keeping with the reported comparative reactivity of 2-sulfanilamido-4methoxypyrimidine and 2-amino-4-methoxypyrimidinewith ammonia (3). The "-methylated derivatives (structure IV) were essentially unreactive to 3-diethylaminopropylamine even at 190" where extensive decomposition occurred. A summary of the reactions which have been discussed above is shown in Table I. It is readily seen that the reactions with aqueous alkali and with the amine are not parallel. The reactivity of the ring-N methylated compounds (11) might be explained on the basis of the similarity of their structure to an imino 1 Attempted rearrangement of the sulfonamides (I) with dimethyl sulfate in ethylene dichloride was unsuccessful; cf. Hilbert and Johnson, J . Am. Chem. Soc., 62, 2001 (1930).
449
REACTIONS O F METHOXYPYRIMIDINES
ether, which would be expected to behave in a similar manner. However, the "amidines" formed from I1 by amination (compounds L and h',Table 11) are very stable to alkali. The difference between the unmethylated (I) and N1methylated (IV) compounds in their reaction with the amine is assumed t o be due to the activating effect of the negative sulfonamide ion formed in the first case. The reduction of N1-methyl-2-(m-nitrophenylsulfonamido)-$-methoxypyrimidine to the metanilamide proceeded smoothly with Raney nickel a t 70" and 3 atmospheres. When the same conditions were used with 2-(3-nitrophenylsulTABLE I REACTIONS OF METHOXYPYRIMIDINE DERIVATIVES AMINATED BY
EFFECT OF ALKALI
(CzHs)zN(CHi)aNHz at
Unchanged
190"
Unchanged
110-120°
Unchanged
not a t 190"
Hydrolyzed
120-130"
fonimido)-l-methyl-4-(3-diethylaminopropylamino)-l, 2-&hydropyrimidine, a complete conversion to the hydrazo compound took place. The compounds listed in Table I1 showed no activity against a sporozoiteinduced Plasmodium gallinaceum infection in chicks in tests conducted in this Laboratory under the direction of Dr. Sterling Brackett. EXPERIMENTAL
4-Chlorobenzenesulfonyl Chloride (9) From sodium 4-chlorobenzenesulfonate. Eighty-seven grams (0.405 mole) of finely powdered sodium 4-chlorobenzenesulfonate (Eastman White Label) was shaken with 84.6 g. (0.405 mole) of phosphorus pentachloride. Within five minutes the mixture liquefied and evolved heat. After standing for a half-hour, the slurry waa heated on the steam-bath for another half-hour and then,stirred into crushed ice and water. The resulting gummy
450
ROBERT G . SHEPHERD AND JACKSON P. ENGLISH
TABLE I1 SULFONAMIDOPYRIMIDINE DERIVATIVES ANALYSES,) KPP
NAME
-
"C.
I4-Chlorophenylsulfonyl-2-amino-4-methoxy-Pme 244-245 -2-imino-l-methyl-l , 2-dihydro- 164-165 pyrimidone-4 -2-met hylamino 4 -methoxy -Pm 85-86 -2-imino-1-methyl-4-methoxy-211-212 1,2-dihydro-Pm
A
B C D
3-Nitrophenylsulfonyl-2-imino-l-methyl-l,2-dihydro207-208 pyrimidone-4d -2-methylamino-4-methoxy-Pm 115-1 16 216-217 -2-imino-1-methyl-4-methoxylt2-dihydro-Pm
E F G
Nl-methyl-2-nietanilamido-4- 15C-151 methoxy-Pm ??-me thyl-2-sulfadttmido-E" 188-189
13
J
4-Chlorophenylsulfonyl-2-amino-4-(3-diethylaminopro225-226 pylamino) -Pm -2-imino - 1-methyl -4 - (3-diet h yl - 184-185 aminopropylamino) -Pm
K L
M 2-Metanilamido-4-(3-diethyl- 225-227' aminopropylamino) -Pm 2- (3-Nitrophenylsulfonimido) 171 l-methyl-4-(3-diethylaminopropylamino) -1,2-dihydroPm 1,2-bis[3-([1-Methyl4-(3-die- 278-2801 thylaminopropylamino) -2pyrimidonyl]sulfamyl)phenyllhydrazine
-
N
0
-
EMPIBICAL FORMWLA
-Calc'd -C H N - --- C
% Found H N --
i4. 1.4 44.2 1.4 14. 1.4 14.044.4 1.8 14.0
13.4 13.4
13.3 13.1
12.1 1.3 18.1 42.71 1.6 18.1 17.3 17.3
17.2 17.1
19.0
18.9
50.1 L. 6 21.2 50.1 L.621.0
51. i.1 17.651.2, j.3 17.4 52. i.4 17.0 52.5' 1.6 17.1 53. 3.922.253.7 7.3 22.0 51.
19.9 51.21
20.0
55.
21.5 55.3,
21.5
-
Corrected. The melting points above 200' were somewhat dependent on the rate of heating. b Reported values are the average of two values differing by less than 0.3. Analyses were performed in this Laboratory under the direction of Dr. J. A. Kuck. c Pm = Pyrimidine. d Sulfur analysis-Calc'd 10.3%; found 10.5%. e Determined by the Van Slyke wet combustion method. f On rapid heating, melts sharply a t 212", resolidifies and melts completely at 225227". When heated slowly, sintering occurs at 212' and melting a t 225-227'. With decomposition using rapid heating. 5
REACTIONS OF METHOXYPYRIMIDINES
45 1
solid quickly turned to white platelets which were thoroughly washed with water and dried in uacuo; yield 95%; m.p. 51-53'. A trace of insoluble material and color was removed by recrystallization (charcoal) from petroleum ether (1-2 cc./g.) ; yield 85% of white needles melting at 52-54'. From 4-chlorobenzenediazoniumchlorick. Meerwein et al. (10) reported an 80% yield of this sulfonyl chloride from "boiling under reflux a solution of 4-chlorobenzenediazonium chloride in liquid sulfur dioxide with anhydrous cupric chloride." Under the conditions described below, chlorine replacement was the main reaction with only a small amount of sulfonyl chloride formation. A solution of 12.8 g. (0.1mole) of 4-chloroaniline in 20 cc. of concentrated hydrochloric acid was treated with a 50% solution of 0.1 mole of sodium nitrite in the cold. This was then refluxed for one hour with several volumes of liquid sulfur dioxide and 14 g. of anhydrous cupric chloride. After allowing evaporation of most of the sulfur dioxide, crushed ice waa added. A sample of the solid which separated gave some hydrochloric acid on heating with water. Conversion to 4-chlorobenzenesulfonamide (10) (m.p. 145") with ammonia occurred to a small extent but the main product was a neutral substance melting at 53" [p-dichlorobenzene (ll)] aa does the desired sulfonyl chloride. A similar experiment with 4-nitroaniline confirmed the predominance of chlorine replacement of the diazonium group by the formation of a neutral chloride. A small amount of 4-nitrobenzenesulfonyl chloride was demonstrated by conversion to the sulfonamide (12) (m.p. 178") with ammonia. When the diazotization of 4-chloroaniline was carried out with nitrosylsulfuric acid, the major portion of diazonium compound remained unchanged during the subsequent treatment. 1-(~-Chlorophenykul~onamido)-~-methoxypyrimidine (A in Table ZZ). A solution of 6.2 g. (0.05 mole) of 2-amino-4-methoxypyrimidine (13) and 13.3 g. (25% excess) of 4-chlorobenzenesulfonyl chloride in 8 cc. (0.1 mole) of dry pyridine was warmed to 60" and then cooled to keep the temperature below 70". The reaction mixture which solidified within a half-hour was kept at 70-80" on the steam-bath for one hour. This crystalline solid was then separated from the by-products by treatment with 20 cc. of boiling glacial acetic acid and a t r a t i o n at 20". The product was purified by recrystallization from glacial acetic acid (15 cc./g.) with charcoal treatment; yield 54%. Because of the prevention of proper cooling by the solidification of the reaction mixture, on a larger scale the acid chloride must be added in two portions, allowing dissipation of the heat of reaction of each portion. The same procedure was used to prepare 8-(S-nitrophenylsulfonmido)-~-methoxypy7imidine (1) in 50% yield. .$-Metanilamido-4-methoxypyrimidine. A previous preparation (1) using a considerably longer heating time gave only about half the present yield due to the formation of an ammonia-insoluble by-product. Thirty-two grams (0.103 mole) of 2-(3-nitrophenylsulfonamido)-4-methoxypyrimidin was dissolved in 130 cc. of commercial ammonium sulfide solution plus 60 cc. of concentrated ammonia. Vigorous boiling for seven minutes produced a yellow precipitate which was redissolved by addition of 130 cc. more sulfide solution. A second precipitation resulted after further boiling for eight minutes and the red-brown solution along with the precipitate was added to 100 cc. of 10 N acetic acid. The amine was purified by solution in ammonia, (charcoal) and reprecipitation with dilute acetic acid; yield 89%.
Diazomethane Alkylation
Of .$-(S-nitroph.enylsulfommido)-4-methoxypyrimidine. The sulfonamide (62 9.) was powdered (80 mesh) and stirred in 600 cc. of absolute alcohol during the addition of 1-2 equivalents of diazomethane in ether. The reaction is conveniently conducted in a threenecked flask which is open to the air only through a long tube ending in a 1-mm. capillary
452
ROBERT G. SHEPHERD A S D JACKSON P. ENGLISH
tip. The reagent color was lost within twenty-five minutes and the mixture was then evaporated to dryness. To remove the N1-methyl-N1-(4-methoxy-2-pyrimidyl)-S-nitrobenzenesulfonamide (Compound F, Table 11), the powdered residue was shaken with 200 cc. of ethylene dichloride a t not above 20-25" until the resulting semi-transparent "gel" had changed to a fine white powder. After filtration, this insoluble portion was separated by 125 cc. of 2.5 N sodium hydroxide into starting material (18% recovery) and a 20T0 yield of 2-(9-nitrophenylsulfonimido)-f-methyl-4-methozy-l, 2-dihydropyrimidine(G) . The latter was recrystallized from 95% alcohol (50 cc./g.), after another cold ethylene dichloride extraction if the melting point was broad. The ethylene dichloride extract was evaporated to about 50 cc. and added to 4 volumes of methanol. This solution was seeded and set aside to crystallize slowly at 25". When other conditions or other solvents were used, the product separated as an oil. The yield of N1-methyl-N~-(~-methoxy-2-pyrimidyl)-5-nitrobenzenesulfonamide obtained after work-up of the mother liquors amounted to about 60%. Of R-(~-chlorophenylsulfonamido)-~-methoxypyrimidine. I n order to separate NImethyl-N1-(4-methoxy-%-pyrim~dyl)-~-chlorobenzenesulfonamide (C) from a similar alkylation mixture, i t was necessary to use a warm U.S.P. ether (6 cc./g.) extraction of the powdered evaporation residue. This compound was recovered by evaporation and purified by solution in glacial acetic acid (2.5 cc./g.). After charcoal treatment, the material was crystallized by rapid addition of one volume of water to turbidity. From the ether-insoluble portion of the reaction mixture was obtained 2-(4-chlorophenylsulfonimido)-imethyl-4-methozy-lI2-dihydropyrimidine (D)after removal of starting material with dilute alkali. This substance was recrystallized from hot glacial acetic acid (4 cc./g.). The yields of the two methyl derivatives were the same as obtained from the similar 3-nitro compound. Of 2-sulfanilamidopyrimidine. Ether was used as a reaction medium rather than alcohol in order to minimize alkylation of the anilino nitrogen (4). By the procedure reported for the corresponding metanilamide (1),N1-methyl-2-sulfanilamidopyrimidine (J)was prepared in 50% yield with a 40% recovery of starting material. I t s structure was assumed by analogy to the metanilamide and this is supported by the relationship of its melting point to that of the starting material predicted on the basis of work on other phenylsulfonamidoheterocycles (1, 4).
DimethylsulfateAlkylation Of $-(~-chlorophenyEsulfonamido)-~-methoxypyrimidine. Thirty-six grams (0.12 mole) of sulfonamide was dissolved in 335 cc. (0.84 mole) of a 2.5 N mixture of potassium and ammonium hydroxides (in 5: 1 molar ratio). Unlike sodium, potassium, or ammonium hydroxide, this mixture of alkalies keeps the starting material and the by-product (B) i n solution. With smaller volumes per gram, as below, these tmTo compounds can be separated by this mixed alkali. This was shaken with 57 cc. (0.6 mole) of dimethyl sulfate while cooling to maintain the temperature a t 40-50'. The oil present changed to a granular solid at the conclusion of the reaction. This alkylation mixture was separated by the procedure given under diazomethane into a 20% yield of N1-methyl-N1-(4-methoxy-R-pyrimidyl) -4-ehlorobenzenesulfona"de (C) and a 70yo yield of %-(4-chlorophenylsulfonimido)1-msthyl-4-methoxy-l,2-dihydropyrimidine(D) . If the temperature is allowed to go to 70°, none of the latter compound is obtained and a corresponding increase in the yield of hydrolysis product (compound B, Table 11) results. The reaction filtrate was precipitated by the addition of concentrated hydrochloric acid, The powdered precipitate was treated with vigorous shaking with the potassium-ammonium hydroxide mixture above (5 cc./g.) in which the starting material is extremely soluble. The solid dissolved and almost at once the salt of the isomeric 2-(4-~hZorophenylsuZfonimido)-l-methyl-f,2-dihydropyrimidone-4 (B) crystallized. This material was dissolved
REACTIOR'S O F METHOXYPYRIMIDINES
453
in warm water and added to dilute acetic acid. Final purification was accomplished by means of glacial acetic acid (2 cc./g.) ; yield 4%. Of I-(S-nitrophenylsulfonamido)-4-methoxypyrimidine.The same procedure as above was used except that sodium hydroxide was the most suitable alkali. The resulting alkylation mixture was separated by the method given under diazomethane into a 66% yield of 2-(S-nitrophenylsulfonimido)-1-methyl-~-methoxy-1,2-dihydropyrimidine (G) and a 20% (F). yield of ~'-methyl-N1-(4-methoxy-2-pyrimidyl)-S-nitrobenzenesulfonamide The reaction filtrate was treated with one-third the original amount of dimethyl sulfate and enough 10 N sodium hydroxide to maintain alkalinity. After charcoal treatment, the solution was acidified and cooled. Another precipitation from alkali gave pure R-(8-nitrophenylsu1fonimido)-I-methyl-1 ,I-dihydropyrimidone-C (E) in 10% yield. This material depressed the melting point of both the starting material and its high-melting methyl derivative (G).
Proof of Structure by Acid Degradation Of low-melting compounds (C and F, Table 11). One and a half grams of material was heated with 1.5 cc. of 68% sulfuric acid for one and a half hours in a bath at 145". After addition of two volumes of cold water, the clear solution was neutralized to about pH 6 and evaporated to dryness in vacuo. A small portion of the residue, on careful extraction of the salt with cold water, gave an organic fraction melting above 300" (uracil melts at 330"). The main portion of the powdered residue was used to prepare two derivatives. Half of this material was brominated in glacial acetic acid to give 5-bromouracil (14) melting at 293'. The other half of the residue was methylated with excess dimethyl sulfate and alkali to yield a compound melting at 123-124". The melting point was not depressed by an authentic sample of 1,3-dimethyluracil (5b) prepared by the alkylation of uracil. Of methyl derivatives (B,D,E,and G). The hydrolysis and evaporation to dryness were conducted as described above, except that 1 g. of material was used. I n one case (B), the addition of water after hydrolysis caused the separation of white needles which were found to be 4-chlorobenzenesulfonamide (50% yield). After filtration, the neutralization and evaporation were carried out as before. The powdered evaporation residue was washed with 5 cc. of cold absolute alcohol and then extracted twice with 13-cc. portions of hot alcohol. After evaporation of this extract to about 8 cc., a 70-8070 yield of crude material (m.p. 215") was obtained on cooling. Recrystallization from alcohol gave material melting a t '235-236' and giving no depression of the melting point of authentic 1-methyluracil (15). Interconversion of Methoxypyrimidines and P yrimidones Alkaline hydrolysis of methoxy compounds ( D and G). The methoxypyrimidine (0.2 g.) was boiled for two minutes with 2 cc. of 50% alcohol and 1 cc. of 8 iV potassium hydroxide, allowing evaporation of the alcohol. The resulting clear aqueous solution gave no evidence of starting material on dilution with ice. Precipitation with dilute hydrochloric acid gave products having the melting points of the pyrimidones B and E. These melting points were not depressed by mixing with samples of B and E isolated as by-products of the preparations of D and G employing dimethyl sulfate. When the methoxy compounds A, C, and F and 2-amino-4-methoxypyrimidinewere treated in the same x-ay, no change in melting point nor appearance of alkali solubility (with the last three compounds) occurred. The 4-aminopyrimidines, L and N , which correspond to the unstable methoxy derivatives, D and G, gave the same evidences of stability. Dimethyl sulfate alkylation of pyrimidones (Band E). The pyrimidone (0.3 9.) was dissolved in 9.2 cc. of water and 0.9 cc. of 8 N potassium hydroxide and shaken with 0.5 cc.
454
ROBERT G . SHEPHERD AND JACKSON P. ENGLISH
of dimethyl sulfate while maintaining the temperature a t 20'. When the reaction was conducted a t 50-60", the starting material was recovered. After a half-hour the turbid mixture changed to a suspension of crystals. A neutral solid was obtained by filtering the alkaline liquid and washing well with water. Without further purification, the products melted a t 212' (from B) and a t 217" (from E) and showed no depression of the melting points of the corresponding methoxypyrimidines, D and G. Therefore, the sole course of the reaction seemed to be 0-methylation. Unequivocal evidence for the 0-methylation was obtained in two ways. The first was reconversion of the products to alkali-soluble materials which were shown to be the pyrimidones B and E by mixed melting point comparisons. The second method was amination with the liberation of methanol by 3diethylaminopropylamine and formation of the acetic acid-soluble derivatives L and N. Neither of these reactions could occur with either of the two possible N-methyl products. Amination of 4-methoxypyrimidines ( A , D, and G) and 2-metanilamido-4-methxypyrimidine with ?kiiethylaminopropylamine. A mixture of one mole of methoxy compound A or the metanilamide and 1.5 moles of amine was immersed in a bath a t 115" (130" for compounds D and G) and stirred to a thick syrup within a few minutes. A gas was evolved, and after about fifteen minutes the mixture was again stirred to control foaming during the solidification. The solid was heated for a total of one and a half hours and then ground to a paste with 600 cc. of water. The product was separated from a small amount of byproduct by solution in 2.5 N acetic acid (2 cc./g.) and charcoal treatment. The material was recovered by precipitation with base (to pH 8) and seeding to prevent gumming. The base-soluble products (K and M in Table 11) were then dissolved in 1 N alkali (4 cc./g.) and reprecipitated with dilute hydrochloric acid (to pH 8) with seeding. The N-methylated sulfonamides (L and N) were instead recrystallized from methanol (2 cc./g.). The yields were 70-80%. An insoluble monohydrochloride (m.p. 274" dec.) of 2-(4-chlorophenylsulfonamido)-4(3-diethylaminopropylamino)pyrimidine (K) was obtained by neutralization of an acid solution to pH 7-8. Acetic acid was used in the purifications for this reason and because i t separated a small amount of by-product soluble in dilute hydrochloric acid. When 2-amino-4-methoxypyrimidine was treated in the same manner a t 115" for one-half hour or a t 180" for ten minutes, 80% of the starting material was recovered. However, after one and a half hours at the latter temperature, no appreciable amount of starting material was present. When the branched amine, 5-diethy1amino-2-aminopentanel was heated with 2-(4-chlorophenylsulfonamido)-4-methoxypyrimidine (A) and 2-metanilamido-4-methoxypyrimidine for one and a half hours a t 120", the starting materials were recovered. N~-Methyl-%-metanilamido-4-methoxypyrimidine (H).Reduction of the corresponding nitro compound (F) with Raney nickel in absolute alcohol a t three atmospheres pressure was complete in about half an hour a t 70". The product was recrystallized from methanol; yield 80%. Hydrazo compound (0, Table ZI). Seventeen grams of the nitro intermediate (N) was dissolved in 100 cc. of absolute alcohol and shaken with Raney nickel under hydrogen a t 40 lb. pressure. Absorption of 2.5 moles of hydrogen occurred rapidly and heavy crystallization took place. Addition of 1 mole of glacial acetic acid dissolved the solid and gave a neutral solution. Further treatment a t this point with Raney nickel or platinum oxide did not carry the reduction on to the amine. After separation of the catalyst, the product was precipitated with alkali and recrystallized from methanol (20 cc./g.). An alcoholic solution of the neutral acetate or a suspension of the white product in alkali became orange on aeration, presumably as a result of azo formation. The melting point and solubility of the product were not altered by stannous chloride treatment a t 60" and only a small amount of diazotizable arylamine was formed.
REACTIONS O F METHOXYPYRIMIDINES
455
SUMMARY
The alkylation of certain methoxypyrimidines with diazomethane and dimethyl sulfate has yielded a mixture of products whose quantitative relationship and structures have been determined. A 4-pyrimidone derivative was found to alkylate exclusively on the oxygen with dimethyl sulfate. The effect of structure on the stability of various methoxypyrimidinea with respect to alkaline hydrolysis and to aminolysis has been investigated. STAMFORD, CONNECTICUT REFERENCES
(1) ENGLISH,CLARK,SHEPHERD, MARSON, KRAPCHO, AM) ROBLIN,J . Am. Chem. Soc., 68, 1039 (1946). (2) “A Survey of Antimalarial Drugs, 1941-1945,” F. Y. Wiselogle, Editor. (3) CLARK,ENGLISH,WINNEK,MARSON,COLE,AM) CLAPP,J. Am. Chem. SOC.,68, 96 (1946). (4) SHEPHERD, BRATTON, AND BLANCHARD, J. Am. Chem. SOC.,64, 2532 (1942). (5) (a) JOHNSON AND HEYL,Am. Chem. J., 37, 635 (1907); (b) DAVIDSON AND BAUDISCH, J. Am. Chem. SOC.,48, 2379 (1926). (6) ROBLIN,WINNEK,AND ENGLISH,J. Am. Chem. Soc., 64, 567 (1942). (7) ROSE AND TUEY, J. Chem. SOC.,81 (1946). (8) WRIGHTAND ELDERFIELD, J. Org. Chem., 11, 114 (1946). (9) GOSLICH,Ann., 180, 107 (1876). (10) MEERWEIN, BUECHNER, AND EMSTER,J. prakt. Chem., (2) 162, 237 (1939). (11) HEILSTEIN, KURBATOV, Ann., 176, 33 (1875). Rec. trau. chim., 20, 129 (1901). (12) RLANKSMA, (13) ADAMSAND WHITMORE,J. Am. Chem. SOC.,67, 737 (1945). Am. Chem. J., 29,486 (1903). (14) WHEELERAND MERRIAM, Am. Chem. J., 43, 35 (1909). (15) (a) WHEELERAND JOHNSON, (b) BEHREND AND TWRM, Ann., 323, 160 (1902).
