[CONTRIBUTION FROM NOYESCHEMICAL LABORATORY, UNIVERSITY OF ILLINOIS]
SOME NITRO DERIVATIVES OF 2,4- AND 2,6-DIMETHYLQUINOLINE' CHARLES C. PRICE: BERNARD H. VELZEN? AND DAVID B. GUTHRIE'
Received August 12,1946
The high antimalarial activity of pamaquine (Plasmochin) suggested that other 8-aminoquinoline drugs be prepared for evaluation. The present paper describes some experimental observations which arose from the preparation of 2,4- and 2,6-dimethyl-8-nitroquinolineas intermediates for this purpose. According to Roberts and Turner (l),2,bdimethylquinoline may be nitrated readily at low temperatures to produce a compound melting at 119'. This was assigned the structure of the 8-nitro derivative, since on reduction and diazotization it could be converted to 8-chloro-2,4-dimethylquinoline, identical with an authentic sample. Roberts and Turner (1) further reported the Baeyer synthesis on 0- and p-nitroaniline to yield products, m.p. 145-147' and 159-162', respectively, but stated that the former could not have been the expected 2,4dimethyl-8-nitroquinoline. When the nitration of 2 ,Fdimethylquinoline was carried out according to the directions of Roberts and Turner (l),a good yield of crude nitro derivatives was obtained. A small sample recrystallized from alcohol had the melting point (120") reported by Roberts and Turner. However, a similar recrystallization of the bulk of the nitroquinoline yielded a material melting at 110-138'. Careful fractionation by dilute sulfuric acid extraction followed by recrystallization gave two pure dimethylnitroquinolines, m.p. 149-150" and 163-164'. These melting points correspond well with the products from the Baeyer synthesis carried out by Roberts and Turner (1). They therefore have been assigned the structure of 2,4-dimethyl-8- and -6-nitroquinoliie, respectively.
I, m.p. 150' r
1
11, m.p. 164' -a
cH3
I
co
1The work reported herein was carried out under a contract, recommended by the Committee on Medical Research, between the Office of Scientific Research and Development and the University of Illinois. *Present address: University of Notre Dame, Indiana. *Present address: The Upjohn Company, Kalamszoo, Michigan. 'Present address: The Monsanto Chemical Company, St. Louis, Missouri. 203
204
C. C. PRICE, B. H. VELZEN, ASD D. B. GUTHRIE
A diagram of the melting points of mixtures of these two substances (Fig. 1) indicates that the material obtained by Roberts and Turner was the eutectic mixture containing two moles of the 8-nitro derivative (I)to one of 6-nitro (11). Early attempts to prepare 8-nitro-2,6-dimethylquinolineby the Doebnervon Miller reaction on 3-nitrol-aminotoluene gave only about 1% yields (2). The modified procedure of Mills, Harris, and Lambourne (3) gave a 25% yield of the desired product, isolated as white crystals, m.p. 116-117". CHO
111, m.p. 117" 2,6-Dimethylquinoline mas nitrated readily in good yield to form a substance
(IV) not identical with the 8-nitro derivative (111). The nitro group probably entered the 5-position, although the possibility of the formation of the 7-isomer has not been excluded.
NO2
IV, m.p. 107'
1
(H)
VI, m.p. 212" lHK0,
COCH3
I
VII, m.p. 295'
V, m.p. 190'
NITRO DERIVATIVES OF DIMETHYLQUINOLINES
205
EXPERIMENTAL5
A'itration of $,4-dimethylquinoline. A solution of 204 g. of 2,4-dimethylquinoline [prepared in 88% yield according t o the directions of Coombes (4)l in 1020 g. of concentrated sulfuric acid was cooled to 5" in an ice-bath. While this solution was stirred vigorously, a mixture of 193 g. of fuming nitric acid ( d . 1.4) and 387 g. of concentrated sulfuric acid (d. 1.84) was added slowly, maintaining the temperature at 5f2". The mixture was poured on ice, made alkaline with ammonium hydroxide, and filtered. There was collected 324 g. of a wet, brown solid, m.p. 90-110°. A small sample recrystallized from aqueous ethanol melted at 118-120". Recrystallization of the major portion from an ethanol-water mixture gave 220 g. (84.3%) of a pale brown solid, m.p. 110-138". Five grams of this latter material was fractionally recrystallized from 100 cc. of 95% ethanol and 50 cc. of water. The warm mixture was treated with Darco, filtered, and then cooled. The first crop of crystals weighed 1.5 g., m.p. 144-147". Each succeeding crop of crystals was obtained by evaporating the liltrate to one-half its volume and cooling. The last crop was obtained by diluting the filtrate with a large volume of water. The following crops were obtained. Crop. N o .
1 2 3 4 5
Wl.
1.50 1.40 0.45 0.59 0.16
M.P.
144-147" 117-147' 115-138" 79-84' 75-90"
The first crop was recrystallized twice from 50% ethanol giving white needles of 8nitro-$,4-dimelhyZquinoline, m.p. 149.5-150'. Anal. Calc'd for C11HloN202: C, 65.34; H, 4.99; N, 13.86. Found: C, 65.19; H , 5.01; N, 14.25. The crude nitration mixture above (m.p. 90-110") was repeatedly extracted with very dilute hot sulfuric acid until the insoluble residue melted at 139-143'. The 8-nitro derivative, with the nitro group ortho to the quinoline nitrogen would, of course, be expected t o be less basic than the other isomers and thus less soluble in dilute acid. The acidsoluble fraction was precipitated and re-extracted. The second acid-soluble fraction, on recrystallization from aqueous acetone, melted a t 162-164". This material, 6-nitro-8, 4-dimethyEquinoZine,was sublimed for analysis, m.p. 163-164.' Anal. Calc'd for C11HlON202: N, 13.86. Found: N, 13.69. Data on the melting points of mixtures of these two isomers are summarized in Fig. 1. Preparation of 8-nitro-8,4-dimethylquinolineb y the Baeyer reaction. A rapid stream of dry hydrogen chloride was passed into a vigorously-agitated mixture of 96 g. of paraldehyde and 160 g. of anhydrous acetone. After three hours the passage of gas was stopped; the mixture weighed 404 g. and was allowed to stand at room temperature for four days. oNitroaniline (35 g.) was thoroughly mixed by grinding with 62 cc. of concentrated hydrochloric acid and 14 g. of nitrobenzene was added. To this mixture was added 57 g. of the ethylideneacetone solution as prepared above and the whole was heated at 100" for ten hours. The reaction mixture was extracted with three 200-cc. portions of ether. The water layer was made alkaline with sodium hydroxide and filtered. The solid material was dissolved in hot ethanol, enough water was added to make the solution cloudy and the mixture was then boiled with Darco. From the cooled filtrate, 5.5 g. of a yellow product was isolated, m.p. 145-147". After one recrystallization from an ethanol-water mixture, i t melted at 149-150'. A mixed melting point with the nitro compound obtained by fractional recrystallization (see above) showed no depression. This would seem to establish definitely the melting point of &nitro-$,4-dimethylquinolineas 149.5-150'. 6Analyses by Miss Theta Spoor and Mr. Harold Clark.
All melting points are corrected.
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C. C. PRICE, B. H. VELZEN, AND D. B. GU!P€lRIE
d-Nitro-d,6-dimethylquinoline. The procedure employed was essentially that of Mills, Harris, and Lambourne (3). A mixture of 505 g. (3.32 moles) of 3-nitrol-aminotoluene and 1128 cc. of concentrated hydrochloric acid was cooled in an ice-bath. T o this mixture was added in small portions 365.2 g. (8.3 moles) of acetaldehyde dissolved in 91 cc. of water. After addition was completed, the mixture was kept cold for one-half hour and 270 g. (1.99 mole) of zinc chloride was added. The mixture was then boiled under reflux for four hours. The cooled reaction mixture was filtered and the filtrate made alkaline with sodium hydroxide. The brown-green precipitate was collected and taken up in ethanol and again filtered to remove zinc salts. The boiling alcoholic filtrate was diluted just to cloudiness, treated with Darco and filtered. After a second treatment with Darco, the filtrate on cooling and further dilution m.p. 114-115'. After two with water gave 170 g. (25.4%) of 8-nitro-d,6-dimethylquinoline, recrystallizations from an ethanol-water mixture, the colorless crystals melted a t 116-117".
..0
20
40
60
80
Z , 8-AM'rp- Z , C - d r ' m e t h y / ~ ~o/ine ~'n
FIG.1. MELTINGPOINT DIAGRAM FOR MIXTURES OF 6- AND ~-NITFLO-~,~-DIMETHYLQUINOLINE
Anal. Calc'd for Cl~HloNaOz: C, 65.34; H, 4.99; N, 13.86. Found: C, 65.21; H, 4.99; N, 14.20. This material is apparently the same substance as that reported by Bartow and McCollum (2) as a red solid, m.p. 114". Nitration of d , 6-dimethylquinoline. A 25-g. sample of 2,6-dimethylquinoline (5) was dissolved in 125 cc. of concentrated sulfuric acid. To this stirred mixture, cooled to 5" in an ice-bath, was added slowly a mixture of 24 g. of fuming nitric acid (d. 1.5) and 48 g. of concentrated sulfuric acid ( d . 1.84). Immediately after the addition was completed, the mixture was poured into a beaker containing ice and the solution was made alkaline with ammonium hydroxide. The pale yellow precipitate, m.p. 95-97', was recrystallized from an ethanol-water mixture to give 28.0 g. (85.5%) of white needles, m.p. 104-107". After two additional recrystallizations from alcohol, the product melted at 106-107". Anal. Calc'd for CllHloN~Oz:C, 65.34; H, 4.99; N, 13.86. Found: C, 65.15; H, 4.89; N, 14.06. The most likely structure for this material would appear t o be that of 6-nitro-2,6-&-
NITRO DERIVATIVES OF DIMETHYLQUINOLINES
207
methylquinoline. The investigation was terminated, however, before i t was possible t o establish the position of the nitro group. 6-Amino-2,B-dimethylquinoline.A mixture of 25 g. (0.123 mole) of the nitroquinoline and 250 cc. of 50% glacial acetic acid was warmed on a steam-bath. T o the vigorouslyagitated mixture, 20.7 g. (0.37gram-atom) of iron (100 mesh) was added in small portions during a period of one and one-half hours. Heating was continued for thirty minutes after addition was completed. The mixture was made alkaline with sodium hydroxide and filtered. The collected precipitate, in a Soxhlet extractor, was extracted for fortyeight hours with 500 cc. of ethanol. The ethanolic extract was concentrated t o 100 cc. and enough water was added t o make the boiling solution faintly cloudy. After treatment with Darco, the solution was filtered, cooled, and diluted with water, giving 18.4 g. (85.570) of the amino compound, m.p. 189189.5". It was recrystallized twice from 50% ethanol as white needles, m.p. 189-189.5'. Anal. Calc'd for CllHlzNz: C, 76.70;H, 7.03;N, 16.27. Found: C, 76.65;H, 6.90;N, 16.45. Acetylation in boiling acetic anhydride produced 5-acetamino-.2,6-dimethylquznoline, which crystallized from 50% ethanol as white needles, m.p. 211-212". Anal. Calc'd for ClrH,aNzO: C, 72.67;H , 6.59. Found: C, 72.73;H, 6.71. 8-Nitro-2-acetamino-2,6-dimethylquinoline. T o 1 g. of 5-acetamino-2,6-dimethylquinoline in 5 cc. of concentrated sulfuric acid was added 1.5 cc. of fuming nitric acid in 1.5 cc. of concentrated sulfuric acid. The solution was allowed to come t o room temperature, poured onto ice, and the precipitate was recrystallized several times from aqueous ethanol to yield 8-nitro-6-acetamino-2,6-dinzethyl~~~noZine as long, colorless needles, map. 292-294" (aluminum block). -4nal. Calc'd for ClaH13N303: C, 60.22;H I 5.05. Found: C, 60.55;H , 5.01. SUMW4RY
It, has been shown that the product, melting a t lm", obtained by nitration of 2,4-dimethylquinoline is not pure 8-nitro-2,4-dimethylquinolineas reported by Roberts and Turner but is the eutectic mixture of two parts of the 8-nitro derivative, m.p. 150",and one of the 6-nitro derivative, m.p. 164'. The nitration of 2,6-dimethylquinoline produced a compound not identical with the 8-nitro derivative and presumed to be 5-nitro-2,6-dimethylquinoline URBANA, ILL. REFERENCES
(1) ROBERTS AND TURNER, J. Chem. SOC.,1832 (1927). AND MCCOLLUM, J . Am. Chem. SOC.,26, 700 (1904). (2) BARTOW (3) MILLS,HARRIS,AND LAMBOURNE, J. Chem. Soc., 119, 1294 (1921). (4) COOXBES,Bull. SOC. chiwk., 49, 89 (1888). (5) DOEBNER A N D VON MILLER,Ber., 16, 2470 (1883).
