[CONTRIBUTION FROM
THE
NOYES CHEMICAL LABORATORY, UNIVERSITY
O F ILLINOIS]
SOME NOVEL REACTIONS OF 4-&UINAZOLONE'~2 XELSON J. LEONARD
AND
DAVID Y . CURTIS3
Received January 8, 1946
The usual method of synthesis of 4-aminoquinazolines (111) involves the conversion of 4-quinazolone (I) to 4-choloroquinazoline (11) and the treatment of I1 with the desired amine (1). Preliminary work with heterocyclic compounds closely related to quinazoline made it a,ppear necessary to circumvent the chloro intermediate corresponding to 11. Accordingly, model experiments have been carried out in the quinaxoline series in an attempt t o bring about the conversion of I to I11 by some other route. This paper describes the methylation of 4-
0
I
C1
I1
I
I
I
I 0 CH3
IV
NHR
I11
quinazolone (I) t o 4-methoxyquinazoline (IV) and the reactions of these two compounds with ammonia and certain amines. The utilization of the methyl ether (IV) was suggested by the researches of Magidson and Grigorowsky (2), who proposed that the phenyl ether (VI) is an intermediate in the preparation of Atabrine (VII) by the treatment of 6,9-dichloro-2-methoxyacridme (V)with 4-amino-1-diethylaminopentane in phenol. In support of this hypothesis, these workers prepared 6-chloro-2-methoxy-9-phenoxyacridine (VI) and treated it with the diamine. In this reaction, the yields of 1 The work described in this paper was done under a contract, recommended by the Committee on Medical Research, between the Office of Scientific Research and Development and the University of Illinois. 2 A recent paper by Tomisek and Christensen (14) appeared after preparation of this manuscript, submission of which was delayed by the absence of the senior author on a n overseas mission. 3 Present address : Converse Memorial Laboratory, Harvard University, Cambridge, Mass. 341
342
NELSON J. LEOX'4RD -4KD DAVID Y. CURTIN
VI I Atabrine were as good as those which had been obtained from the chloro compound (V) and the diamine. In the quinoline series, 4-alkoxyquinolines have been found to react with ammonium salts, either alone or in the presence of ammonia or alkyl amines, to give 4-aminoquinoline (3). I n the quinazoline series, an example of an analogous replacement is found in the conversion of 2-ethoxy4-quinasolone (VIII) to 2-amino-4-quinazolone (IX) by means of ethanolic ammonia a t 100" (4). 0
VI11
IX
4-Quinazolone can be obtained readily by heating anthranilic acid with formamide, according to the method of Niementowsky (5). Alkylation of 4-quinazolone with methyl and ethyl iodide and methyl sulfate has been discussed by Bogert and Sei1 (6). They concluded that alkylation with methyl iodide and ethanolic alkali gave only the 3-methyl-4-quinasolone and that methyl sulfate behaved similarly. When ethyl iodide was used, the probability of obtaining the O-ethyl compound appeared greater. The action of methyl iodide on the silver salt gave both the O-methyl and N-methyl derivatives. In this case, also, with the ethyl iodide the 0-ethyl derivative was more likely to be formed. Methylation of 2- and 4-pyridones and -quinolones with diazomethane has been found, in general, to give the O-methyl product (7). Diazomethane, therefore, seemed to be the most promising methylating agent for 4-quinazolone. All of the possible methylation products of 4-quinazolone have been reported in the literature. 4-Methoxyquinazoline (IV), m.p. 35.4", has been prepared by Bogert and May (8) by the treatment of 4-chloroquinasoline (11) with sodium methoxide. 3-Methyl-4-quinazolone (XI), m.p. 71", was prepared by Knape (9)
NOVEL REACTIOXS OF
4-QVINAZOLOXE
343
both by the action of methyl iodide on the sodium salt of 4-quinazolone and by the ring closure of X. 2-Methyl-4-quinazolone melts a t 238-239" (10). 1Methyl-4-quinazolone (XIII),m.p. 123-124", was obtained by &ape but, unfortunately, in amount insufficient for analysis.
0 CH3
C1
1
I
NaOCH3
IV
I1
M.p. 35"
X
XI M.p. 71"
04 0
CONH2
-+ heat NCHO
I1
\
\N/
I
I
CH3
CH3
XI1
XI11 M.P. 123-124"
4-Quinazolone was treated with diazomethane. 4-Methoxyquinazoline was isolated by vacuum distillation in 20% yield and the only other product obtained was a crystalline solid, m.p. 103.5-105.5", which was shown by analysis to be isomeric with 4-methoxyquinazoline. The melting point of this compound is not in agreement with that of any of the three most probable products, but its structure was not investigated further. The crude 4-methoxyquinazoline reacted with methanolic ammonia in a bomb to give 4-aminoquinazoline (XIV) which has recently been prepared by Dewar (11) from 4-chloroquinazoline and ammonia. h'H2 c1 oca I
I
IV
XIV
I
I1
344
NELSOPU' J. LEONARD AND DhVID Y. CURTIN
The difficulty of obtaining the intermediate 4-methoxyquinaxoiine from 4quinazolone (I) led t o an investigation of the direct amination of I. Such amination could be effected in a t least 20% yield by the use of methanolic ammonia a t 200". When 4-quinazolone was heated a t 140" with n-butylamine, the product was 3-butyl-4-quinazolone (XV) rather than 4-butylaminoquinazoline. A small amount of o-amino-K-butylbenzamide (XVI) was also isolated. Compound XV has been prepared by Bogert and May (8) from the sodium salt of 4-quinazolone and butyl iodide, while XVI has been prepared by Clark and Wagner (12) by the action of butylamine on isatoic anhydride (XYII).
0
XHf
H XVII
XVI M.p. 84"
Similarly, y-diethj aninopropylamine reactel, with 4-quinazolone to give 3(~-diethylaminopropyl)-4-quinaxolone (XVIII) which was isolated as the picrate. The same compound was obtained from the reaction of y-diethylaminopropyl chloride with the sodium salt of 4-quinazolone.
0
0
345
NOVEL REtlCTIONS O F 4-QUINAZOLOSE
A satisfactory mechanism for the reaction of n-butylamine with 4-quinazolone should account for the formation of both o-amino-N-butylbenzamide and 3butyl-4-quinazolone. Such a mechanism requires that ring-opening occur. The f ollon-ing series of intermediates would appear to constitute a logical explanation of the course of the reaction. The formamidine X I X would be expected H
I
-
SHR
-0
-Hf
COXHR ----+
\
\x//
N=CH--KHHC/ l/
0
0
CONHR
to be the first stable intermediate. Ring closure of XIX by internal addition, followed by the elimination of ammonia, would provide 3-butyl-4-quinazolone. Although no water was present during the reaction to hydrolyze the amidme (XIX), $hat which had failed to undergo cyclization would be expected t o be converted readily to o-amino-N-butylbenzamide when the crude reaction product mas later treated with water. EXPERIMENTAL4
4-Quinazolone was prepared from anthranilic acid and formamide by the method of Niementowski (5). Reaction of 4-quinazolone with diazomethane. 4-Methoxyquinazoline. A solution of diazomethrne (4.2 g., 0.10 mole) in 150 cc. of ether was prepared by the directions of Arndt 4 All melting points are corrected. Microanalyses by Miss Theta Spoor and Miss Lillian Hruda.
346
NELSOS J. LEONARD AND DAVID Y. CURTIN
(13) by adding 15 g. of nitrosomethylurea to 50 cc. of 40y0 potassium hydroxide and 150 cc. of diethyl ether a t 5" with mechanical stirring. When the solid had dissolved, the ether layer was separated and dried over 10 g. of potassium hydroxide pellets. I t was then filtered and added without distillation to a suspension of 5.0 g. (0.034mole) of 4-quinazolone in 10 cc. of methanol. Nitrogen was evolved immediately and the suspension was stirred mechanically at room temperature. The quinazolone dissolved completely in about four hours. The solution was filtered, 50 cc. of distilled water was added, and the mixture was shaken until the excess diazomethane was decomposed. The ether layer was separated and dried over 10 g. of magnesium sulfate and the ether removed. The residue was distilled under reduced pressure over a n oil-bath at 200". The fraction boiling at 141-164" at 18 mm. (1.1 g.) was collected. It melted a t 15-20" and was impure 4-methoxyquinazoline which had been reported previously by Bogert and May (8) to melt at 35.4'. The crude product was used in the next reaction without further purification. The residue from the vacuum distillation (1.9 9.) solidified on cooling and melted a t 103.5105.5' after recrystallization from petroleum ether (b.p. 90-110'). Its composition was shown by analysis to be that of a n isomer of 4-methoxyquinazoline. 3-Methyl-4-quinazolone has been reported by Knape (9) to melt at 71" when recrystallized from petroleum ether. 1-Methyl-4-quinazolone was also prepared by Knape (9) and was reported to melt a t 123-124", although insufficient material was available for an analysis. The structure of the compound melting a t 103-105" is therefore uncertain. It was soluble in acid and insoluble in alkali. Anal. Calc'd for CgHeN20: C, 67.47; H, 5.03; N, 17.49. Found: C, 67.64; H, 5.21; ZT, 17.40. Reaction of 4-methoxypinazoline with ammonia. 4-Aminoquinazoline. The impure 4-methoxyquinazoline (1.1 9.) obtained above was heated in a bomb with 10 cc. of liquid ammonia and 10 cc. of methanol at 140" for sixteen hours. The yellowish crystals which had precipitated were collected (0.3 g . ) and recrystallized from an ethanol-water mixture; m.p.-268.5-269.5". The melting point reported by Dewar (11) for 4-aminoquinaxoline was 260". Since Dewar failed to report any derivative of 4-aminoquinazoline the picrate was prepared in ethanol, in which it was extremely insoluble, and was recrystallized from diIute aqueous acetic acid. It melted with decomposition at 288-290". Anal. Calc'd for CsH~Na.C&13N30~: C, 44.92; H, 2.69; S , 22.46. Found: C, 44.90; H, 2.72; N , 21.86. Reaction of 4-quinazolone with ammonia. &Aminoquinazoline. 4-Quinazolone (1.0 g.) was heated in a bomb with 10 cc. of liquid ammonia and 10 cc. of methanol at 200" for twentyfour hours. The solvent was removed, a few cubic centimeters of 15N ammonia was added, and the solution filtered. 4-Aminoquinazoline (0.2 g., 20% yield) was obtained, as shown by the melting point and mixed melting point with the sample obtained above, and also by the melting point of the picrate. Reaction of 4-quinazolone with butylamine. 8-Butyl-4-quinazolone and o-amino-N-but ylbenzamide. 4-Quinazolone (5.0 g., 0.034 mole) was heated in a bomb at 150" for twentyfour hours with 13 cc. (9.5 g., 0.13 mole) of freshly distilled n-butylamine. After the removal by distillation of excess butylamine the product was shaken with 20 cc. of 10% aqueous sodium hydroxide and 50 cc. of ether. The alkali layer was extracted with an additional 25-cc. portion of ether. The ether extracts were combined and dried over magnesium sulfate. The ether was distilled and the last of the volatile solvent removed under reduced pressure. The oil remaining uws boiled for 10 minutes with 14 cc. of 85% sulfuric acid in order to remove impurities susceptible to hydrolysis. The solution was diluted and made basic t o litmus with sodium hydroxide solution. The crude insoluble compound which separated was collected on a filter, washed with water, and dried. The yield was 2.5 g. It was purified by reprecipitation from warm dilute (36% of the theoretical), m.p. 64-70'. hydrochloric acid containing activated charcoal and recrystallization from a n ethanol-
NOVEL REACTIONS OF 4-QUINAZOLONE
347
water mixture. The purified solid melted a t 71-72", the melting point reported by Bogert and May (8) for 3-butyl-4-quinazolone. Since no derivative is reported in the literature the picrate was prepared and recrystallized from ethanol. It sintered at 151" and melted at 154-155" to a light yellow liquid. Anal. Calc'd for Cl8H17N608: C, 50.11; H, 3.97. Found: C, 50.05; H, 3.86. In a second experiment, 4-quinazolone (5.0 g., 0.034 mole) was heated at 150" with 13 cc. (9.5 g., 0.13 mole) of n-butylamine. After addition of ether, extraction with alkali and removal of ether and butylamine, two grams of oil remained which solidified on cooling (m.p. 30-40'). On repeated recrystallization from petroleum ether (b.p. 90-110") a very small amount of waxy solid, m.p. 83-85' remained. This melting point is in agreement with that reported by Clark and Wagner (83-34") (12) for o-amino-N-butylbenzamide. The identity of the solid was further confirmed by analysis. Anal. Calc'd for CIIHdZO: C, 68.73; H, 8.93; N, 14.58. Found: C, 68.55; H, 8.38; N, 14.72. The presence of 3-butyl-4-quinazolone in the mixture was shown by evaporation to dryness of the filtrates obtained in the preparation of the analytical sample. The solid (0.3 g.) obtained was refluxed ten minutes with 5 cc. of 85y0sulfuric acid. The solution was diluted and made alkaline with aqueous sodium hydroxide. The insoluble white solid (0.1-0.2 g.) which remained was washed with water and recrystallized from water-ethanol solution. It was shown by melting point and mixed melting point to be identical with the 3-butyl-4-quinazolone obtained above. Reaction of 4-quinazolone with 7-diethylaminopropylamine. 3-(pDiethylaminopropy1)4quinazoZone. Five grams (0.034 mole) of 4-hydroxyquinazoline was heated in a bomb for twenty-four hours a t 150" with 13 cc. (10 g . , 0.072 mole) of 7-diethylaminopropylamine. When the bomb was cooled and opened, a gas with an ammoniacal odor escaped. The solution was evaporated on a steam-cone under reduced pressure. The oil remaining was added t o 20 cc. of benzene and the solution was extracted with 10 cc. of aqueous 20% sodium hydroxide. The water solution was separated and extracted with 10 cc. of benzene. The combined benzene extracts were dried over magnesium sulfate and filtered. Carbon disulfide (10 cc.) was added to the solution in order to remove the excess 7-diethylaminopropylamine. The dithiocarbamate of the latter separated as an oil. Acetone (30cc. ) was added to cause it to solidify. The solid &-as removed and rinsed with benzene. The filtrate was evaporated, dissolved in 50 c:c. of ethanol, and the solution added to 16 g. (0.070 mole) of picric acid dissolved in 500 cc of hot ethanol. The solution was allowed to cool slowly and was decanted from a small amount of dark oil which first separated. The crystalline picrate which then precipitated was collected and washed with cold dilute ethanol. Eighteen grams (74'%), m.p. 146-153", was obtained. The 3-(7-diethylaminopropyl) -4 quznazolone dipzcrate was purified for analysis by recrystallization from ethanol to a pale liquid. and methyl cellosolve. It then melted a t la!-161" Anal. Calc'd for C1sHd-sO.2CeHsNsO7: 13,45.19; H, 3.79; N, 17.57. Found: C, 45.38; H, 4.18; N, 17 67. When the above reaction was carried out a t 200" for twenty-four hours the product was quite dark and the picrate was induced t o crystallize only with considerable difficulty. 3-(7-Dzethylaminopropyl) -4-guinazolone was also prepared by refluxing a suspension of 3.0 g. (0.020 mole) of 4-quinazolone, 9.0 g. (0 060 mole) of 7-diethylaminopropyl chloride, and 1.2 g. (0.020 mole) of potassium hydroxide for fourteen hours. The residual oil was added t o a hot solution of 9.2 g. (0.040 mole) of picric acid in 200 cc. of ethanol. The picrate separated almost immediately as an oil but solidified on cooling to a light yellow solid. It was collected and washed thoroughly with 95% ethanol and melted et 152-155' (1.8 g.). On furthey recrystallization, the melting point was raised to 158-160" and a mixed melting point wvj th the compound prepared above showed no depression.
348
NELSON J. LEONARD bND DAVID Y. CURTIN SUMMARY
1. 4-Quinazolone has been found to react with diazomethane to give 4-methoxyquinazoline and a considerable amount of an unidentified monomethylation product. 2. 4-Methoxyquinazoline and 4-quinazolone were converted to 4-aminoquinazoline by treatment with methanolic ammonia under pressure. 3. Treatment of 4-quinazolone with n-butylamine or y-diethylaminopropylamine yielded the 3-alkyl-4-quinazolone. A possible course for this reactioh has been proposed. URBANA,ILL. REFERENCES (1) MAGIDSON AND GOLOVCHINSKAYA, J . Gen. Chem. (U.S.S.R.),8, 1797 (1938). (2) MAGIDSON AND GRIGOROWSKY, Ber., 69, 396 (1936). (3) German Patent 708,116 (1941) [Chem. Abstr., 37, 5084 (1943)l. (4) GRIESS,Ber., 2, 417 (1869). See also Beilstein, 24, 374 (4th Ed.). (5) NIEMENTOWSKY, J. prakt. Chem., [2] 61, 564 (1895). (6) BOGERT AND SEIL,J . Am. Chem. SOC.,29, 517 (1907). Chem. Revs., 36,133,173 (1944). (7) BERGSTROM, (8) BOGERT AND MAY,J . Am. Chem. SOC., 31,507 (1909). (9) KNAPE,J . prakt. Chem., [2] 43, 216 (1890). (10) BOGERT AND GOTTHELF, J . Am. Chem. SOC.,22, 528 (1900). (11) DEWAR,J . Chem. Soc., 615 (1944). J . O r g . Chem., 9, 55 (1944). (12) CLARKAND WAGNER, (13) ARNDT,Org. Syntheses, Coll. Vol. 11, John Wiley and Sons, Inc., New York, 1943, p. 166. AND CHRISTENSEN, J. A m . Chem. soc., 67,2112 (1945). (14) TOMISEK
