[CONTRIBUTION FROM THE ORGANIC CHEMISTRY
LABORATORIES, COLUMBIA
UNIVERSITY ]
THE SEARCH FOR SUPERIOR DRUGS FOR TROPICAL DISEASES. 111. FURTHER EXPERIMENTS I N THE QUINOLINE GROUP FERNANDA MISANI
AND
MARSTON TAYLOR BOGERT
Received June 12, 19.46
In a recent communication (l),the authors reported the results of certain experiments in the quinoline and phenanthroline groups, involving the use of either the Skraup or the Conrad-Limpach-Knorr reactions. The present paper records a few syntheses, likewise in the quinoline group, but employing either the Doebner Pyruvic Acid or the Combes reaction. THE DOEBNER P Y R W I C ACID REACTION
The Doebner reaction (2, 3, 4) consisting in the condensation of an aromatic amine with a pyruvic acid and an aldehyde, in alcoholic solution, to substituted cinchoninic acids, has been studied frequently with reference to its mechanism (5, 6 , 7 , 8) and the results of these studies are summarized in the following reactions : CsHsNHz
+ OCHR + CeH6N:CHR CtjH6N:CHR + CH3COCOOH +
I
V
uNyI(3 + 0 1
N
+ \ PH C /
\ / C I
COOH I1
b
I
IR
COOH I11
(yNy7HR
\
PH2
CH
I
COOH IV
This assumes the forniation first of the anil, the addition of the pyruvic acid to this anil, and the cyclization then of the resultant substituted alpha-ketogamma-anilinobutyric acid (I) t o either a cinchoninic acid (111),or a diketopyrrolidine (Ti), as the final product, depending upon the amine, the substituents present, and the conditions of the experiment. The formation of the cinchoninic from the dihydrocinchoninic acid (11) is due t o a dismutation of the latter, whereby the tetrahydro acid (IV) is also produced. Since the amount of tetrahydro product is always less than that of the cinchoninic acid, some of the initial anil is reduced to the secondary amine. Further, it has 458
459
EXPERIMENTS I N T H E QUINOLIXE GROUP
been claimed that the diketopyrrolidine may condense to a Schiff base with unchanged initial primary amine. Garzarolli and Thurnlackh (9) postulated as an intermediate in the interaction of aniline, benzaldehyde, and pyruvic acid, the alpha-keto-gamma-anilinogamma-phenylbutyric acid (I). Simon and Maugin (10) assumed a similar type of intermediate, but in both cases experimental evidence was not supplied. Bodforss (11) found that when benzalpyruvic acid was treated with aniline, it yielded the anil of cinnamylformic acid (VI), which, on boiling, produced the corresponding diketopyrrolidine (VIII). He assumed that the anil formed first a 4-membered heterocycle (VII), which rearranged to the diketopyrrolidine. €Io\$-ever,only diketopyrrolidines were observed in this reaction and no cinchoninic acids. Hence it is unlikely that the anil of cinnamylformic acid is the initial intermediate of the Doebner synthesis, since both diketopyrrolidines and cinchoriinic acids have been isolated in many cases from the same reaction mixture, which viould indicate that they both are derived from the same intermediate. PhCH:CHCCOOH
II
NPh
VI
+ PhCHCH:CCOOH
I
PhN--I
I
VI1
4
PhCHCHzCO PhI!J---CO I
VI11
Borsche (6), from the reaction between aniline, benzaldehyde and phenylpyruvic acid, separated a compound to which he attributed the structure of the diketopyrrolidine (V) , although he asserted that such compounds are rarely isolated in this reaction, because they generally take up a further molecule of the base with formation of an anil. This work by Borsche supported the hypothesis of the intermediate (I),which could readily cyclize to a diketopyrrolidine (V). In a later paper, however, Borsche (7) reported that he could not obtain a positive test from the reaction of the diketopyrrolidine with either phenylhydrazine, stimicarbazide or hydroxylamine. Bucherer and Russischwili (8) treated a diketopyrrolidine with 80% sulfuric acid and claimed the isolation of alpha-keto-gamma-anilino-ganzma-phenylbutyric acid, but were unable to cyclize this t o the initial diketopyrrolidine. The Doebner pyruvic acid synthesis has been applied also to the preparation of substituted m- and p-phenanthrolines from 5- and G-aminoquinolines by Willgerodt and his co-workers (12, 13). Recently Borsche (14) obtained from 8aminoquinoline, benzaldehyde and pyruvic acid, a “sehr wechselnde Ausbeute” of’ the 2,3-diphenyl-l , 10-phenanthroline-4-carboxylic acid. In our own experiments with 6-methoxy-8-aminoquinoline (IX), paraldehyde, and pyruvic acid, we succeeded in isolating the intermediate methoxyquinolylaminoketovaleric acid (X), and characterized it also by the preparation of its butyl ester. A comparison between Borsche’s experimental work with 8-aminoquinoline and our own seems to indicate that the different course of the reaction may be due in part to the activating effect of the phenyl group in benzaldehyde and
460
MISANI AND BOGERT
X
IX
1 RCH-CO RCH--CR
I
I
I
RCH
I1 I
\ /
CO
N
NH HOC
I
COOH
OMe XI
-1
+
XI1 AcCH~AC
Me
I
R
C
/ \
NH I
XI11
CH I
XIV
Me
XV
To supply further evidence concerning the factors responsible for the different course of the reaction, we carried out condensations with 6-methoxy-&aminoquinoline, benzaldehyde, and phenylpyruvic acid in one case; and in another 8-aminoquinoline, acetaldehyde, and pyruvic acid.
EXPERIMENTS I N T H E QUINOLINE GROUP
461
Iliketopyrrolidines (XII) were isolated in both cases, but no anils. It has already been pointed out that enolization of the intermediate valeric acid derivative (XI) is necessary for the cyclization of the compound to a substituted cinchoninic type (XIII),and that the phenyl group of phenylpyruvic acid and benzaldehyde favors this enolization, resulting in the elimination of water between the enolic hydroxyl group and the hydrogen of the ring. Borsche's work bears this out,. However, when acetaldehyde and pyruvic acid were used with 8-aminoquinoline, there was less chance for this enolization, and the ring closure would then occur with elimination of water between the hydroxyl group of the carboxyl and the imino hydrogen, with production of the diketopyrrolidine derivative. The formation of the diketopyrrolidine in our onm experiments with 6-niethoxy-8-aminoquinoline,benzaldehyde, and phenylpyruvic acid, therefore, was not expected, and perhaps may be due to the stereointerference of the 6methosyl group. I t might be mentioned that Borsche (7) failed to isolate some of his putative diketopprrolidines in sufficient purity to be satisfactorily characterized. THE COMBES REACTIOK
This reaction, involving the condensation of primary aromatic amines with acetylacetone or other beta-diketones,follon-ed by cyclization to the corresponding 2,4-dimethylquinoline by means of sulfuric acid, was applied to 6-methoxy-8aminoquinoline, following the procedure of Johnson and Mathem (17), and gave an 85% yield of the primary condensation product, viz. 4-(6-methoxy-8-quinolylamino)pentene-3-one-2 (XIV), but we were unable to cyclize this to the desired 2,4-dimethy1-5-methoxy-lt 10-phenanthroline (XV). Ackiaowledgments. The 6-methoxy-8-aminoquinoline required for these experiments was generously supplied by the Winthrop Chemical Co., Inc., New York, X. Y., through the courtesy of its President, Dr. Theodore G. Klumpp. T o Miss Frances Marx and Miss Lois May, of the Columbia laboratories, we are indebted for the analytical results reported. EXPERIMENTAL
TJnless otherwise stated, all melting points have been corrected for thermometer stem exposure.
Experiments w i t h the Doebner Pyruvic A c i d Reaction 1-(8-Quinolyl)-b-methyl-4,6-diketopyrrolidine. An absolute alcohol solution (70 cc.) of
2 g. of paraldehyde and 3.4g. of pyruvic acid was heated on the steam-bath and an absolute alcohol solution of 5 g. of 8-aminoquinoline added. After refluxing the mixture for two days, part of the alcohol was distilled off and a picrate prepared from the remaining solution. This picrate, purified by recrystallization from alcohol, formed yellow needles, m.p. 217218"; yield, 5%. A n a l . Calc'd for Cz~II1JSOs:N, 14.9. Found: Ii,15.1. The absence of any phenanthroline carboxylic acid in the reaction mixture was indicated by the fact that no product was isolated which was soluble in an aqueous sodium bicarbonate solution. 6-Methoxy-8-aminoquinoline acetaldehyde pyruvic acid. As noted above, Willgerodt (12, 13) has prepared m- and p-phenanthrolines by the action of acetaldehyde and pyruvic acid upon the appropriate aminoquinolines, but when we applied this reaction to
+
+
462
MISANI AND BOGERT
6-methoxy-8-aminoquinoline, the expected o-phenanthroline derivative ( S I I I ) was not the product. alpha-Keto-gamn~a-(6-methoxy-8-quinolylamino) valeric acid (X). il solution of 8.5 g. of 6-methoxy-8-aminoquinoline in 120 cc. of absolute alcohol was added to a boiling solution of 5 g. of pyruvic acid and 3 g. of paraldehyde in 120 cc. of absolute alcohol, in a flask provided with condenser and guard tube. A white precipitate separated almost immediately, but the mixture was kept refluxing on the steam-bath for 5 hours longer. The precipitate was then removed, and washed with alcohol. It proved t o be insoluble in organic solvents, but soluble in both acids and alkali, even in sodium bicarbonate solution. It was purified by repeated solution in dilute alkali and reprecipitation with dilute hydrochloric acid a t p H 3. It then formed white needles, m.p. 196-197’, but the test for the presence of a keto group was unsatisfactory. Yield, 15-2070. Anal. Calc’d for C15H1e?\’204:C, 62.5; H, 5.6; N,9.7. Found: C , 62.4; €I, 5.6; K,9.8. n - B u t y l ester. This was prepared by suspending 0.5 g. of the above acid in 20 cc. of n-butyl alcohol, adding 8-9 drops of sulfuric acid, and refluxing the mixture for 3 hours. Excess of butyl alcohol was then removed under diminished pressure. The residue was poured into water, the mixture made alkaline with sodium carbonate, the resulting precipit a t e removed and recrystallized several times from alcohol or acetone. It formed white needles, m.p. 166.5-168.5’; yield, 85%. A n a l . Calc’d for C1Ji24N20a: C, 66.3; H, 7.0. Found: C,66.5; H, 7.3. An attempt t o cyclize this ester through its enolic hydroxyl by the action of thionyl chloride upon a dry ether solution, with a drop of pyridine as catalyst, was unsuccessful, and the ester was recovered unaltered. 1-(6-Methoxy-8-quinolino) -d,S-diphenyl-4, 6-diketopyrrolidine (XII). An alcoholic solution of 5 g. of phenylpyruvic acid (18) and 3.1 g. of benzaldehyde was warmed on the steambath, a n alcoholic solution of 5.1 g. of 6-methoxy-8-aminoquinoline was added, and the mixture kept refluxing for 37 hours. The solvent was evaporated and the residue steamdistilled. The gummy residue was extracted with sodium hydroxide solution and the insoluble residue was dissolved in glacial acetic acid and diluted with water. The precipitate so obtained was readily soluble in organic solvents. Repeatedly crystallized from ether, i t formed white prisms, melting with decomposition at 257’; yield, 470. A n a l . Calc’d for C2eH&,Oa: C, 76.4; H, 4.9. Found: C, 75.8; H, 4.9. A solution of the compound gave a precipitate with 2,4-dinitrophenylhydrazine, which dissolved in alcoholic potassium hydroxide t o a red solution. Had any phenanthroline carboxylic acid been formed in this reaction, it should have separated in the initial stages of the process. Nor was any isolated by acidification of the sodium hydroxide extract of the gummy residue from the steam distillation. Experiments w i t h the Combes Reaction 4-(6-Methoxy-8-quinoZyZamino) pentene-8-one-2 (XIV) , was prepared from 6-methoxy-8aminoquinoline and freshly distilled acetylacetone, in the presence of a small quantity of Drierite, by the Combes reaction, following the procedure of Johnson and Mathews (17), except that the mixture was heated for only an hour and a half. By frequent crystallization of the crude product from alcohol or acetone, colorless rhombic prisms were obtained, m.p. 151-152’; yield, 85%. A n a l . Calc’d for C15H1GN202: C, 70.3; H,6.3. Found: C, 70.4;H, 6.5. Attempted cyclization of the methoxyquinolylamino pentenone (XIV) . I n the original Combes communication (15, 16), cyclization was effected by heating with sulfuric acid for 30minutes; but Johnson and Mathews (17) recently have shown that anhydrous hydrofluoric acid is a better reagent for this purpose, because of the sulfonation caused by the sulfuric acid.
EXPERIMENTS I N THE QUINOLINE GROUP
463
I n our experiments, when the acetylacetone condensation product was mixed with concentrated sulfuric acid, no action was observed below 90". After 20 minutes a t 90-95", the mixture was cooled, poured into ice-water, made alkaline with ammonium hydroxide, extracted with ether, the extract dried with potassium carbonate, and the ether removed. The oily residue proved t o be 6-methoxy-8-aminoquinoline, showing that the original condensation product had been split into its initial components. tn a second experiment, the condensation product mas dissolved in xylene and refluxed for 3 hours over phosphorus pentoxide. The product recovered was the unchanged initial material. tn a third experiment, the condensation product was subjected to the action of anhydrous hydrofluoric acid, with the result that the side chainwas cleaved and nocyclieation occurred. SUMMARY
1. The Doebner Pyruvic Acid Reaction has been studied with %amino-, and 6-methoxy-8-amino-quinoline, using acetaldehyde and benzaldehyde, pyruvic, and phenylpyruvic acids. 2. When 8-aminoquinoline reacts with paraldehyde and pyruvic acid, the diketopyrrolidine is the product isolated. 3. But when an alcoholic solution of the 6-methoxy-8-aminoquinoline is warmed with paraldehyde and pyruvic acid, there precipitates immediately the primary condensation product, ie., the gamma-(6-methoxy-8-quinolylamino)alpha-ketovaleric acid (X), which cannot be cyclized to either a diketopyrrolidine or a phenanthrene carboxylic acid. 4. The interaction of 6-1-r,ethoxy-8-aminoquinoline, benzaldehyde, and phenylpyruvic acid yields a diketopyrrolidine. 5 . The Combes Reaction applied to 6-methoxy-8-aminoquinoline, gives the primary condensation product only, ie., the methoxyquinolylaminopentenone (XIV), which is not cyclized to the desired phenanthroline under the conditions employed. NEWYORK27,Ii.Y. REFERENCES (1) MISANIAND BOGERT, J . Org. Chem., in press. (2) DOEBNER, Ann., 242, 265 (1887). (3) DOEBNER AND GIESEKE, Ann., 242, 290 (1887). (4) DOEBNER, Ann., 249, 98 (1888). (5) CIUSAAND MUSAJO,Gam. chim. ital., 69, 796 (1929). Ber., 41, 3884 (1908). (6) BORSCHE, Ber., 42, 4072 (1909). (7) BORSCKE, (8) BUCHERER AND RUSSISCHWILI, J. prakt. Chem. [2],128, 89 (1%' (9) GhRZAROLLI AND THURNLACKH, B e y . , 32, 2274 (1899). (10) SIMONAND MAUGIN,Compt. rend., 144, 1275 (1907). (11) BODFORSS, Ann. Chim., 466, 41 (1927). (12) WILLGERODT AND JABLONSKI, Ber., 33, 2918 (1900). AND VON NEANDER, Ber., 33, 2928 (1900). (13) WILLGERODT (14) BORSCHE AND WAGNER-ROEMMICK, Ann. chim.,644, 280 (1940'1 (15) COMBES, Bull. SOC. chim. [2], 49, 89 (1888). (16) COMBES, Compt. rend., 106, 142 (1888). AND MATHEWS, J . Am. Chem. SOC.,66, 210 (1944). (17) JOHNSON (18) Organic Syntheses, 19, 77 (1939).
