CHARLES C. PRICEAND VIRGILBOEKELHEIDE
1246
and 4-chloro-5,7-dibromoquinoline and their condensation with a primary-tertiary diamine are described. Nitration of 4,7-dichloroquinoline yields the 8[CONTRIBUTION FROM
THE KOYES
Vol. 6s
nitro derivative which was converted to 4,7,8trichloroquinoline. RENSSELAER, KEW
RECEIVED APRIL 5, 1946
YORK
CHEMICAL LABORATORY, UNIVERSITY OF ILLINOIS]
A Synthesis of Substituted 4-Aminoquinolines1 BY CHARLESC. PRICE^
AND
VIRGILBOEKELHEIDE
A number of 4-aminoquinoline derivatives, es- Although this method of ring closure has been pecially those with a 7-chlorine atom, have been widely used in the synthesis of isoquinolines,6 and found to possess marked antimalarial a c t i ~ i t y . ~ . 'was also used by Drozdov' in the synthesis of The usual procedure for their preparathn involves atabrine, i t has apparently never been applied to treatment of the requisite 4-chloroquinoline with the synthesis of quinolines before. Since the the proper diamine side-chain. The synthesis of quinolines desired were those with a halogen in the 4-hydroxyquinolines, necessary as intermediates 7-position, the reaction was studied only with in this type of preparation, has been discussed in P-m-chloroanilinoacrylamides. Undoubtedly the reaction could be extended to other 0-arylaminoa recent series of papers from this Laboratory.6 The present investigation was undertaken to acrylamides. find a general method of synthesis of the quinoline A desirable feature of this method of preparing nucleus which would directly introduce an amino quinolines is the ready availability of the @-arylor a substituted amino group a t the 4-position of aminoacrylamides. Claisen* discovered that anithe quinoline nucleus. This has been accom- line would react with ethoxymethylenemalonic plished successfully by the cyclodehydration of a ester to give p-anilino-a-carbethoxyacrylicester. number of P-anilinoacrylamides according to the Bandg had previously shown that 0-anilino-acarbethoxyacrylic ester would react with another following scheme. molecule of aniline to give P-anilino-a-carbethoxyNHRi I acrylanilide. Unfortunately, this reaction is suitable only when it is desired that the amide group be the same as the amino group on the &carbon atom. Otherwise a mixture of products results. It was found, however, that the desired P-mchloroanilinoacrylamides could be obtained by Ri R* suitably modifying the above reaction. This was done by first preparing the proper amide of an I, -COOC*Hs acid having an adjacent active methylene group \Cl and by then allowing this amide to react directly with ethyl orthoformate and m-chloroaniline.k 11, - 0C l -COOCzHs This method proved to be very satisfactory and 111, -CN is illustrated below.
--
--a
NHRi
c'1
IV,
, c=o
-0 __
V, -(CH*)SCH3 1-1, -(CH.)jCHa
VII, --(CHz),CN VIII, -- -(CHz)jCN
-CN
-CN -CN -CN -CN
(1) T h e work (described in this paper was done under a contract, recommended by the Committee on Medical Research, between t h e Office uf Scientific Research and Development and the University of
a/'
v
\"-cH=C
Illinoi.;
12) Present address, University of Notre Dame, Notre Dame, Indiana (3) (a) Andersug, Breitner and Jung (to Winthrop Chemical Co.), U. S. Patent 2,333,970: C. A , , 36, 3771 (1941); (b) ( t o I. G. Farbenindustrie, German Patent 683.692; C. A , , 36, 4973 (1942). (4) Icnsch, Z. angeu?. Chrm., 60, 891 (1937). (5) (a) Price and Roberts, THISJ O U R N A L , 68, 1204 (1946); (b) Price, Leonard and Herbrandson, ibid., 68, 1251 (1946); (c) Snyder and Jones, ibid., 68, 1253 (1940); (d) Price and Roberts, i b i d . , 68, 1255 (1946): (e) Price, Leonard and Reitsema, ibid., 68, 1256 (1946); (f) Leonard, Herbrandson and van Heyningen, ibid., 68, 1279 (1946).
I R 'z
The use of 0-m-chloroanilinoacrylamides made i t necessary to establish the structure of the quinoline produced by this reaction. If cyclization occurred para t o the chlorine already present in the benzene ring, the resulting quinoline would (6) Kindler and Peschke, Arch. Phorm., 373, 236 (1934). (7) Drozdov. J Gcn. Chem. (U.S. S. R . ) , 8 , 1192 (1938). (8) Claisen, Ann.. 197, 77 (1897). (9) Band, ibid.. 985, 145 (189;).
July, 1946
SYNTHESIS OF %JBSTITUTED
4-AMINOQULNOLINES
124i
have the structure, IX, as written above. On the product. The cyclization of the P-m-chloroaniliother hand, the ring closure might possibly occur noacrylamides (Table 11) gave fair yields of the ortho to the chlorine present in the benzene ring corresponding quinolines in most cases. The and then the resulting quinoline would have the pre_pFration of 4-arylaminoquinoline (examples 1 chlorine atom in the 5-position. Since in every to a in Table 11) was accomplished in better yield case only one product was isolated, i t must be when the cyclization was carried out using phosassumed that cyclization occurred in one direc- phorus oxychloride than when phosphorus penttion, or, if both isomers are formed, one isomer oxide was used. On the other hand, the preparawas formed in such small amounts that i t was lost tion of 4-alkylaminoquinolines was successful in the isolation of the product. only when the cyclization was carried out using Cyclizations of I and I11 were shown to produce phosphorus pentoxide. quinolines with the chlorine atom in the 7-position The preparation of 4-alkylaminoquinolines in as represented by IX as follows. Cyclization of which the alkyl group contained an amino subI gave ethyl 4-m-chloroanilino-7-chloro-3-quin-stituent failed entirely. Thus the cyclization of olinecarboxylate (IX, R = m-ClCaHr, Rz = P-wz-chloroanilino-a-cyano-N- (4-diethylamino-1COOGH6j. This was hydrolyzed to give 4-nz- methylbuty1)-acrylamide to 7-chloro-4-(4-diethylchloroanilino-7-chloro-3-quinolinecarboxylic,xid amino- 1-methylbutylamino) - 3 -quinolinecarboni(IX, R2 = COOH) which was decarboxylated to trile was attempted repeatedly without success. give 4-m-chloroanilino-7-chloroquinoline.The Likewise, the one attempted cyclization of the structure of the latter was established by compari- cyanoamide (VII) gave only a tarry product. son with an authentic sample obtained from the The cyclization of the cyanoamide (VIII) was reaction of 4,7-dichloroquinoline with m-chloro- tried a number of times but the yield of 7-chloroaniline. Likewise, the cyclization of I11 with 4 - (5 - cyanopentylamino)-3-quinolinecarbonitrile phosphorus pentoxide gave 4-m-chloroanilino-7- never exceeded 12%. chloro-3-quinolinecarbonitrile (IX, R? = CN) Two of the compounds, 4-n-butylamino-7which was hydrolyzed to give 4-m-chloroanilino- chloro-3-quinolinecarbonitrile(SN-12,345)1° and 7-chloro-3-quinolinecarboxylicacid identical with 3-aminomethyl-4-n-butylamino -7-chloroquinoline that prepared from the ester above. (SN-12,265) were tested for activity against avian The cyclization of 111 and IV by the use of malaria and were both found to be inactive in the phosphorus oxychloride did not give the 3-quino- maximum dose tolerated. linecarbonitriles, but gave instead the correspondA number of unsuccessful schemes for the diing imidoethers. Apparently, the 3-quinoline- rect synthesis of 4-aminoquinolines were investicarbonitriles were converted to the corresponding gated. For example, the Schiff base from oimidochlorides under the conditions used in the aminobenzonitrile and acetaldehyde was treated cyclization, which were transformed to the imino- with lithium diethylamide in the hope that a cyethers on treatment with alcohol and ether in the clization would occur similar to that of dinitriles usual manner for working up the products. The carried out by Ziegler.'l However, this reaction structure of the iminoether (IX, R1 = m- failed to give 4-aminoquinoline, probably due to CICbH4, RB == C(=NH)OC2Ho) was confirmed the rapid polymerization of the Schiff base. by analysis and by hydrolysis to the correspondAnother scheme was to effect ring closure being acid. tween an aromatic nucleus and a nitrile group. It Reduction of the 3-quinolinecarbonitriles was thought that such a cyclization might be acformed by cyclization of V, VI and VI11 could be complished under the conditions of the Hoesch carried out using Raney nickel catalyst to give reaction. When the reaction was attempted with the corresponding 3-aminomethylquinolines. 0-anilino-a-chloropropionitrile or with 0-arylThus, 4-n-butylamino-7-chloro-3-quinolinecarboamino-a-cyanoacrylonitriles,it was entirely unnitrile was hydrogenated to 3-aminomethyl-4-n- successful. butylamino-7-chloroquinoline(X). Likewise, 7Experimental12 chloro-4- (5-cyanopentylamino)-3-quinolinecarbo- The Preparation of 8-m-Chloroanilinoacry1amides.bonitrile was hydrogenated to 4- (6-aminohexyl- The results of these experiments are given in Table I. The general procedure employed was as follows. Ethyl amino)-3-aminomethyl-7-chloroquinoline(XI). NHCHICH~CH~CHI
NII(CHr)aNHz
Most of the results of this investigation are summarized in Tables I and 11. The preparation of 0-m-chloroahilinoacrylamides (Table I ) was carried out in very good yields. Losses of material occurred mainly during the purification of the
cyanoacetate (0.25 mole) and the proper amine (0.25 mole) were placed in a Claisen flask, and the mixture was heated until sufficient alcohol (14 ml., 0.25 mole) had distilled to show that the aniide formation was complete. The temperature required t o effect amide formation varied from 125' for aliphatic amines t o 180' for aryl amines. Then, t o the crude amide which was not allowed t o cool
(IO) The Survey Number, designated SN-, refers to the number assigned a drug by the Survey of Antimalarial Drugs. T h e activities of these compounds will be tabulated in a forthcoming monograph. (11) Ziegler, Awn., 604, 94 (1933). (12) All melting points corrected. Analyses by Miss Theta Spoor and Miss Lillian Hruda.
1248
CHARLES
c. PRICE AND VIRGIL BOEKELHEIDE
Vol. 68
TABLE I SUBSTITUTED &m-CHLOROANILINOACRYLAMlDES Yield,
Carbon
Analyses,
% -Hydrogen Found
8-m-Chloroanilinoacryl amides
%
M. p . , ' C ,
Calcd.
Found
Calcd.
a-Carbethoxy-m-chloroanilide
90 72 78 65 91 87 95 80
114 143-144 164-166 138-140 99-100 90-92 201-202 110-1 11
57.00 57.00 57.85 64.54 60.54 62.84
57.21 57.16 58.15 64.56 60.67 62.96 56.36 60.65
4.22 4.22 3.34 4.04 5.77 6.55 4.01 5.41
a-Carbethoxy-p-chloroanilide a-Cyano-m-chloroanilide a-Cyanoanilide a-Cyano-N-n-butyl a-Cyano-N-n-hexyl or-Cyano-N-(2-cyanoethyl) -amide cu-Cyano-N-(5-cyanopetityl)-aniide
56.83 60.66
TABLE I1 SUBSTITUTED 4-AMINO-7-CHLOROQLlINOLI"S
Analyses, %--Carbon Hydrogen Calcd. Found Calcd. Found
7 -
7- Chioroquinoiines
4-m-Chloroanilino-3-carbethoxy b
Yield, %"
M. p . , ' C .
A57 B21 A65 B25
121-123 143-144 290-295
Molecular formula
4.32 4.28 3.40 4.05 5.85 6.75 4.06 5.35
7
CiaHi402N2C12 59.83 C I ~ H I ~ O ~ N Z C I , 59.83 CieHoNaClz 61.20
59.79 3 . 8 8 3.95 4-p-Chloroanilino-3-carbethox y 59.76 3.88 3.96 4-m-Chloroanilino-3-cyano" 62.29 2 . 8 8 2.69 4-m-Chloroanilino-3-carboximino ether (as the hydrochloride)d A45 278-280 CieHlsONaCla.HC1 54.47 54.24 4.03 3.96 4-Anilino-3-carboximino-methylethere A48 CirH14ONaCl 65.50 65.82 4.50 4.53 163-164 4-n-Butylamino-3-ryano CirHlrN~Cl 64.75 64.75 5 . 3 9 5.43 B65 146-147 4-n-Hexylamino-3-cyano ClBH18N3C1 66.82 67.20 6.31 6.44 B50 133-134 CieHoNaClz 64.31 64.40 5.06 5.25 4- (5-Cyanopentyl)-3-cyano B12 160-161 A . Cyclization was carried out using Poc13. B. Cyclization was carried out using PzOj. The hydrochloride melted a t 260:. Anal. Calcd. for CI~H~~OZNZCIZ.HCI: C, 54.35; H, 3.80. Found: C, 54.50; H, 3.71: The dipicrate melted a t 215 . Anal. Calcd. for C I ~ H I , O Z N ~ C ~ Z . ~C, C ~48.82; H ~ ~ H, ~ N2.88. ~ : Found: C, 49.07; H, 2.91. cThis compound was highly insoluble and very difficult to purify. Its structure was established by the fact that it could be acid. This hydrolyzed with methanolic potassium hydroxide to give 4-m-chloroanilino-7-chloro-3-quinolinecarboxylic acid by treatment with 10% sodium hycompound was hydrolyzed to 4-m-chloroanilino-7-chloro-3-quinolinecarboxylic droxide. 8 This comDound was also analyzed for nitrogen. Anal. Calcd. for C ~ ~ H I ~ O N ~N,C I13.49. : Found: N, 13.54.
*
more than necessary, there was added m-chloroaniline ride were removed in vacuo. The red gummy residue (0.25 mole) and ethyl orthoformate (0.25 mole). The re- was then treated with 50 ml. of ethyl or methyl alcohol and sulting mixture was heated a t 120 to 140" until sufficient warmed until all of the residue dissolved. The yellow alcohol (42 ml., 0.75 mole) had distilled to show that the granular hydrochlorides usually separated when the reaction was complete. The contents of the flask were alcohol solution was cooled and the precipitation was compoured into a beaker and allowed to cool. The solid prod- pleted by adding an excess of ether. The hydrochloride uct thus obtained was purified by crystallization from was then removed by filtration, washed with ether and ethanol. All of the P-m-chloroanilinoacrylamideswere dried. Usually, the quinoline hydrochlorides were conobtained as white, fluffy needles. verted to the free base by warming them with aqueous The preparation of B-nc-chloroanilino-c-carbethoxypotassium carbonate for fifteen minutes. The free quinoacrylo-p-chloroanilide differed from the above procedure line bases could be purified by crystallization from either in that carbethoxyaceto-p-chloroanilide13was first pre- alcohol or benzene. All of the quinolines obtained in this pared and then treated directly with m-chloroaniline and way were light yellow solids. ethyl orthoformate. An attempt to apply this method to the preparation The preparation of B-m-chloroanilino-a-carbethoxy- of 4-alkylamino-7-chloroquinolines produced only tarry acrylo-m-chloroanilide was carricd out by merely heating products. m-chloroaniline (U.50 mole) with ethoxyrnethylenemalonic (b) Method B.-Phosphorus pentoxide14(100 g,) was added to a solution of the proper P-m-chloroanilinoacrylester (0.25 mole) a t 110" for one-half hour. The Preparation of Substituted 4-AminoT7-chloroquino- amide (0.1 mole) in purified technical xylene (500 ml.). lines.-The preparation of substituted 4-amino-7-chloro- The mixture was boiled under reflux with good stirring for quinolines was carried out by treating the proper p-m- four to six hours. As the reactions proceeded the phoschloroanilinoacrylamide with either phosphorus oxy- phorus pentoxide darkened and became lumpy. At the chloride in boiling benzene (method A) or phosphorus conclusion of the reaction the mixture was cooled and the solid material was removed by filtration. T h e solid prodpentoxide in boiling xylene (method B). The results of these experiments are given in Table 11. The general pro- uct on the filter was washed several times with benzene to remove as much neutral organic material as possible. The cedure is outlined below. (a) Method A.-Phosphorus oxychloride (0.2 mole) residue was then dropped onto chopped ice (300 9.) to dewas added to a solution of the proper p-m-chloro- compose the excess phosphorus pentoxide. The insoluble atiilinoacrylamide (0.1 mole) in 400 ml. of dry benzene phosphate salt of the quinoline separated and was re(thiophene-free). The solution was then gently boiled nioved by filtration. The crude phosphate was then confor six to ten hours. As the reaction proceeded the solu- verted to the free quinoline base by warming with 10 tion turned a dark red and the hydrochloride salt of the (14) For this reaction it is best that the phosphorus pentoxide be product began to precipitate. At the conclusion of the reartiori the benzene and the excess phosphorus oxychlo- as finely divided as possible. T h e highest yields were obtained using (13) Chattaway and hlnson, J . Cham. Suc.. 97. 341 (IYIO).
phosphorus pentoxide supplied by the J . T. Baker Chemical Co., Phillipsburg, New Jersey.
July, 1946
A SYNTHESIS OF SUBSTITUTED 4-AMINOQUINOLINES
1249
N sodium hydroxide (200 ml.). The free quinoline base with picric acid in ethanol. The dipicrate was crystalwas removed by filtration, dried and crystallized from a lized from aqueous ethanol as yellow needles, m. p. 163minimum amount of benzene. All of the quinolines ob- 164". tained in this way were light yellow solids with the exAnal. Calcd. for C16He3N~Cl.2C6H307N3:c , 44.00; H, ception of 4-m-chloroanilino-7-chloro-3-quinolinecarboni- 3.83. Found: C, 44.63: H, 4.00. trile, which was brick red in color. N-( 4-Diethylamino-l-methylbutyl)-cyanoacetamide.4-m-Chloroanilino-7-chloro-3-quinolinecarboxylicAcid. Ethyl cyanoacetate (28.0 g., 0.25 mole) and 4-amino-l-Ethyl 4-m-chloroanilino-7-chloro-3-quinolinecaroxylate, diethylaminopentane (40.0 g., 0.25 mole) were heated toXI, (4.0 9.) was dissolved in 25y0 methanolic potassium gether a t 150' until the required amount of alcohol (14 ml.) hydroxide solution (30 ml.). The solution was allowed had distilled. The product was then distilled under to stand for several hours and then the methanol was reduced pressure. There was obtained 30.0 g. (54%) removed in vacuo. The residue was dissolved in water, of a water-white oil; b. p. 165-170' (2 mm.); n Z 31.4748. ~ filtered and acidified. The acid which precipitated was reAnal. Calcd. for Cl2H230N3: C, 64.00; H, 10.22. moved by filtration and dried. There was obtained 3 5 g. Found: C, 63.85; H , 10.35. (95%) of a yellow powder, m. p. 266', dec. The acid was Attempted Preparation of 7-Chloro-4-(4-diethylaminoinsoluble in all of the common solvents and it was difficult 1 -methyl- butylamino)-3-quinolinecarbonitrile.-A mixt o purify a sample for analysis. ture of N-(4-diethylamino-l-methylbutyl)-cyanoacetAnal. Calcd. for ClsHlo02N?C12: C, 57.60; H, 3.03. amide (56.2 g., 0.25 mole), m-chloroaniline (31.8 g., 0.25 Found: C, 56.74; H, 3.29. mole) and ethyl orthoformate (37.0 g., 0.25 mole) was 4-m-Chloroanilino-7-chloroquinoline.-Two grams of 4- heated together until the required quantity of alcohol m-chloroanilino-7-chloro-3-quinolinecarboxylicacid was (42 ml., 0.75 mole) had distilled. When the product was heated in a test-tube a t the temperature necessary to cooled, a thick red oil was obtained. This oil did not melt the acid. When evolution of carbon dioxide had solidify and it decomposed when distillation under high ceased, t h e tube was cooled and the resulting solid was vacuum was attempted. Therefore, the crude product was removed. Crystallization of this solid from ethanol treated directly according t o the procedures for cyclizayielded 5 g. (86%) of large white shining plates, ITI. p. tion. BotH methods A and B were tried. I n each case the 223-225 . product was a thick red oil which could not be converted Anal. Calcd. for C15HIONZClZ: C, 62.28; H, 3.46. t o a solid derivative and which decomposed when distillaFound: C, 62.31; H , 3.56. tion was attempted. Attempted Cyclization of the Schiff Base.-Freshly dis4-m-Chloroanilino-7-chloroquinoline was also prepared by the method of Banks." A few drops of hydrochloric tilled acetaldehyde (9.0 g., 0.2 mole) was added to a soluacid were added to a mixture of 4,7-dichloroquinoline (2.0 tion of' o-amin~benzonitrile'~(24.0 g., 0.2 mole) in dry g.) and m-chloroaniline (1.3 g.) in water (100 ml.) and the ether (150 ml.), The dark red solution of the Schiff base mixture was heated t o a gentle boil. Within a few minutes was dried, cooled to 10" and a solution of lithium diethylthe hydrochloride salt of the product began to precipitate. amine (prepared by treating 15 g. of phenyllithium in 50 The reaction mixture was heated for an additional ten ml. of ether with 14 g. of dry diethylamine) was added minutes before the hydrochloride salt was removed by slowly with stirring. The reaction mixture was stirred at IO" for two hours and was then decomposed with water. filtration. The free quinoline base was then obtained by warmiiig the hydrochloride with 10% sodium hydroxide. Separation of the ether layer and removal of the ether left Crystallization of the free quinoline from ethanol yielded a thick red oil. No identifiable material could be obtained 2.8 g. of large white shining plates, m. p. 223-5'. When from the oil. Attempted Ring Closure of a Nitrile Group with the a sample of this product was mixed with the sample above, Aromatic Nucleus.-Zinc chloride ( 8 g.) was added t o a the mixture showed the same melting point. (9.0 g., 0.05 3-Aminomethyl-~4-n-butylamino-7-chloroquinoline (X),- solution of p-anilino-a-chloropropionitrile18 mole) in ether (150 ml.). The mixture was stirred for Raney nickel catalyst ( 3 9.) was added t o a solution of 4-n-butylainino-7-chloro-3-quinolinecarbonitrile ( 19.0 g.) three hours while dry hydrogen chloride gas was passed in. in 1Oyo alcoholic ammonia (300 ml.). The mixture was Precipitation of the hydrochloride occurred. When the shaken under a pressure of hydrogen of one-half atrnos- ether was removed and the residue was made basic the was recovered. phere until the expected quantity of hydrogen was ab- 8-anilino-a-chloropropionitrile The experiment was repeated several times with other sorbed. The catalyst was then removed by filtration and the solvent was removed in vacuo. There was thus ob- solvents. When sufficient dioxane was used precipitation of the hydrochloride salt did not occur but here again the tained 19.0 g. (99%) of a light yellow solid, m. p. 110-112'. Crystallization of the crude product from benzene gave 0-anilino-a-chloropropionitrilewas recovered almost completely. light yellow needles, m. p. 114-115". The experiments were also repeated using 8-anilino-aAnal. Calcd. for C,aH18S3Cl: C, 63.76; H, 6 . 8 8 . cyanoacrylonitrile and p-m-chloroanilino-cr-cyanoacryloFound: C, 63.95; H , 7.06. A sample of 3-atninomethyl-4-n-butylaniino-7-chloro-nitrile, respectively, in place of p-anilino-a-chloroproquinoline (SS-12,26
