May, 1950
SOME SUBSTITUTED
[CONTRIBUTION FROM
THE
2181
%ARYLQUINOLINES
CHEMICAL LABORATORY OF IOWA STATECOLLEGE ]
Some Substituted 2-Arylquinolines BY HENRYGILMANAND DAVIDA. SHIRLEY In connection with a study of the anti-malarial properties of certain substituted 2-arylquinolines11 the addition of aryllithium compounds to the azomethine linkage of quinoline and related typeszta proved to be a useful synthetic technique for the preparation of the needed intermediates. The present work has involved an examination of the applicability of this reaction to a variety of dialkylaminoaryllithium compounds in their reaction of addition with quinoline, substituted quinolines, benzo [ flquinoline, acridine and 2-arylpyridines. The basic reaction involved is represented below using 9-dimethylaminophenyllithium and 6-chlo-
as long as the 6-position of the pyridine ring is open. It should be pointed out, however, that aryllithium compounds have been shown to add to the 1,2-position of 2-arylq~inolines.~ @-Dimethylaminophenyllithium added to acridine in the lJ9-position corroborating the earlier work of Zieglers and Bergmann’ who showed that n-butyllithium and phenyllithium with acridine gave 9-n-butyl- and 9-phenylacridane. 9-(4’-Dimethylarninopheny1)-acridanewas isolated in 61% yield and was converted to 9- (4’-dirnethylaminophenyl)-acridine by nitrobenzene in quantitative yield. Experimental
Compounds formed by the addition of various aryllithium compounds t o quinoline and quinoNMe, line derivatives are summarized in Table I. In order t o illustrate the general procedure used, the preparation of 2-(4‘-dimethylaminophenyl) L1 6-chloroquinoline from 6-chloroquinoline and p-dimethylaminophenyllithium is described. ~HIO p-Dimethylaminophenyllithium was prepared by addition of 55 g. (0.275 mole) of p-bromodimethylaniline to 6.0 g. (0.87 g. atom) of lithium C6H6N02 metal in ether. The yield of organometallic compound (determined by the titration of an aliquot with standard acid)* was in the range 85-95% in various preparations. Other aryl111 H I1 lithium compounds prepared in this work and roquinoline. Addition of the aryllithium to 6- the yield’ obtained were p-diethylaminophenyl- (84%), o-dimethylaminophenyl- (92%) and m-dimethylaminochloroquinoline followed by hydrolysis of the N- phenyl(94%) .s lithio compound (I) gives 1,2-dihydro-2-(4’-di1,2 - D a y dro -2 - (4 ’-dimeth ylaminophen yl) -6 -chloro methylaminophenyl)-6-chloroquinoline (11) which quinoline (11).-To a solution of 16.5 g. (0.10 mole) of 6on oxidation with nitrobenzene is converted to chloroquinoline in 100 ml. of ether was added a solution of mole of P-dimethylaminophenyllithium in 175 ml. of 2 - (4- dimethy~am~nopheny~) 6 chloroquino~ine 0.10 ether. The addition required thirty minutes, and a (111). Isolation of the intermediate dihydro corn- yellow precipitate formed during this time. The reaction pound I1 was not effected in the majority of the mixture was stirred for an additional thirty minutes and types studied, and only the oxidized form 111 then hydrolyzed by the addition of 100 ml. of water. The ether layer was separated and extracted with three porappeared in the product from the hydro~ysisof tions of dilute hydrochloric acid. The combined extracts the initial addition compound 1- This may be due were poured into excess dilute ammonium hydroxide which either t o oxidation by contact with air of the di- precipitated a yellow, oily solid. This solid was recryshydro compound 11 or to loss of lithium hydride tallized twice from petroleum ether (b. p. 80-110”) and gave 1z.5 g. (44%) of light yellow needles which melted a t from the addition compound I prior to hydroly- 95-96 sis. Anal. Calcd. for C1TH1,NnCl: N, 9.84. Found: N, 2- (4’-Dimethylaminophenyl)-pyridine4 reacted 9.94. with p-dimethylaminophenyllithium to form 2,62 - (4 ’-Dimethylaminophenyl) -6-chloroquinoline .-A bis-(4’-dimethyIaminophenyl)-pyridine by the solution of 6.5 g. (0.023 mole) of 1,2-dihydro-2-(4‘-diaddition of the organolithium compound to the methylaminophenyl) -6-chloroquinoline in 26 ml. of nitrobenzene was heated to boiling. Cooling the solution preazomethine linkage in the l16-position in the 2- cipitated 5 g. of orange-yellow small crystals. These were aV1PYridine- The Possibifity of addition of the recrystallized from benzene to givz 4.6 g. (69%) of light organometallic to the 1,a-azomethine linkage of yellow prisms melting a t 200-201
c1aaNMe ‘
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the 2-arylpyridine t o give 2,2-bis-(4‘-dimethylaminophenyll-pyridine has not been excluded, but i t appeared unlikely that the organometallic compound would add to the 2-substituted lI2-position (1) Gilman, Towle and Spatz, THISJOURNAL, 68, 2017 (1946). (2) Gilman and Spatz, {bid., 66, 621 (1944). (3) Gilman, Christian and Spatz, ibid., 67, 979 (1945). (4) Prepared by addition of P-dimethylaminophenyllithium to pyridine; cf. “Organic Syntheses,” Coll. Vol. 11, 1943, p. 517.
(5) ~ i and ~1 ~~ibid,, ~69, i 877~~(1947).~ ~ , (e) Ziegler and Zeiser, Ann., 486, 174 (1931). (7) Bergmann, Blum-Bergmann and Christiani, ibid., 483, 80 (lg30). (8) Gilman. Wilkinson, Fishel and Meyers, ibid., 46. 150 (1923). (9) Preparations of the 0- and m-bromodimethylaniline, used for the formation of the corresponding aryllithium compounds, were made by the action of dimethyl sulfate and sodium carbonate on oand m-bromoaniline in accordance with the procedure of Abbott, Doctoral Dissertation, Iowa State College, 1942, p. 163.
HENRYGILMANAND DAVIDA. SHIRLEY
2182
Vol. 72
TABLE I DERIVATIVES OF QUINOLINE Derivative
M. p. or b. p. Yield, OC. Mm. Yo
2- (4’-Diethylaminophenyl)99-99.5 2- (4’-Diethylaminophenyl) -6-chloro123 2-(4‘-Diethylaminophe nyl) -8-methyl110 2- (4’-Diethylaminophenyl)-6.methoxy151.5-152 2-(2’-Dimethylnminophenyl)218-218 2-(2’-Dimethylaminophenyl)-8-methgl- 153-159 2-(3’-Dimethylaminopheny1)103-104 2-(3’-Dimethylaminophenyl)-8-methyl- 188-171 2- (2’- Dimethylamino-5’-methylphenyl)- 212-217 2- (2’-Dimethylamino-5’-methylphenyt)8-methyl200-202 2-(4’-Dimethylaminophenyl)-6-~hloro- 200-201
27 30 28 22 34
Formula
3 0.1
35
0.1 0.1
7 28 28
CiaHnN: CisHioClNs CmHnN; CloHaN;O CirH~sNz ClrHliNr CnHuN: CirHiaN: CiaHliN:
0.1 . 28 33
CIDHMN: CirHioClNs
Anal. Calcd. for ChH15ClN2: N, 9.91. Found: N, 10.01. The picrate derivative consisted of orange-red minute crystals which melted a t 221 ’with decomposition. Anal. Calcd. for C23HlgClN507: N, 13.70. Found: N, 13.58. In Table I1 are listed the products from the reaction of dialkylaminophenyllithiums with some compounds other than quinoline which contain the azomethine linkage.
Nitrogen, % M..p., “C. Calcd. Found picrate 10.13 9.03 9.85 9.15 11.30 10.89 11.30 10.8g 10.69
10.17 9.25 9.84 9.40 11.39 10.98 11.10 10.98 10.91
210 224-228 187 228 181 171.5-172 170-171 189 178
10.14 10.38 178-177 9.91 10.01 221
Nitrogen, % Calcd. Found 13.88 18.82 CrsHnrNsOl 13.01 12.98 CZSHZPCIN~O, 13.50 13.75 CisHzsNsOi 13.09 13.22 CnaHzsNsOi 14.69 14.90 CzaHioNsOi 14.28 14.32 C~rHziNsO7 CnrHisNsOi 14.69 14.51 14.28 14.30 CuHz1Ns07 14.28 14.41 QrHziN~Or Formula
czsHnsNrO7 CziHirClNrOr
13.88 13.60 13.70 13.68
TABLE I11 DIHYDROINTERMEDIATE COMPOUNDS FROM ADDITIONOF ARYLLITHIUM COMPOUNDS TO AZOMETHINE LINKAGES Compound R = -(4’4methylaminophenyl)
Mo.g,
Yield,
%
Formula
Nitrogen, % Calcd. Found
1,2-Dihydro-2-R-6-chloroquinoline 95-96 44 Ci7H17ClNs 9.84 9.94 3,4-Dihydro-3-R-benzo(f) quinoline 138-139 62 C ~ H I I O N ~9.35 9.44
TABLE I1 MISCELLANEOUS PRODUCTSFROM ADDITIONOF ARYL- 9-R-acridane 196 61 CziHzoNz 9.33 9.24 LITHIUMS TO AZOMETHINE LINKAGES reactions similar in most respects to the commonly known Product effects of poison ivy. R’ = 4’-dimethylaminophenyl M. p., Yield, Nitrogen, % All of the compounds prepared in this research were tested R 4’-diethylaminophenyl OC. ?& Calcd. Found for possible activity in causing dermatitis, and only the 2- (R)-pyridine‘ 79-8OP 31 12.39 12.68 2-(4’-diethylaminophenyl)-quinoline showed activity in 2,6-Bis-(R’)-pyridineb 246-248 22 13.23 13.33 this respect. This compound was, however, only approximately one tenth as active as 2-(4’-dimethylaminophemyl) 3-(R’)-benzo(f)quinolineC249-250d 56 .,. ... quinoline. 9- (R’)-acridine 285-286e 61 .., ... A number of other quinoline and pyridine types available 9- (R)-acridine 196-197’ 6 .. . . . . from other research programs in this laboratory were evaluated for possible skin irritation activity. Of forty a Formula, C1SH18N2. Picrate derivative, m. p. 188’, of these types tested, the following showed some activity: calcd. for C21H~lN607: N, 15.40. Found: N, 15.30. 2-(4’-[2”,5’’-dimethyl-l”* Formula, C21HlaNa. Prepared by reaction of p-dimethyl- 2-(4’-aminophenyl)-q~inoline,~ pyrryl] -phenyl)-quinoline,lO 1- (2’-pyridyl) - 2 - (3”-nitroaminophenyllithium and 2-(4’-dimethylaminophenyl)- phenyl) -ethylene,” and 2-(4’-dimethylaminophenyl) -8pyridine. Picrate derivative, m. p. 238-239’. Calcd. for methylquinoline.1 CZlH2aN8: N, 13.29. Found: N , 13.11. Prepared by None of these compounds was as active as the 2-(4’Sachs and Steinert, Ber., 37, 1743 61904), by another dimethylaminophenyl) -quinoline. method and reported to melt a t 245 e Prepared by Summary Ullmann, Bader and Lobhardt, Ber., 40,4796J 1907), by anUllmann other method and reported to melt a t 279 1. Several new 2-arylquinolines have been and co-workers, loc. cit., report 197’ as the m. p. of this prepared by addition of aryllithium compounds compound. 0 B. p. 205-210’ (0.1 mm.).
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Table I11 lists the intermediate dihydro compounds isolated in this work. During the course of earlier work in this laboratory on 2arylquinolines,’ it was noted that 2-(4’-dimethylaminophenyl) -quinoline in dilute solution caused a severe dermatitis when brought into contact with the skin. While individuals differed markedly in their susceptibility, it appeared in a few orienting experiments that solutions as dilute as 0.01% of 2-(4’-dimethylaminophenyl) -quinoline in benzene caused erythema a t the point of application in 50y0 of eight individuals tested. Tests were conducted by application of approximately two drops of a benzene solution of known concentration to the upper arm of the test subject. More concentrated solutions caused severe
to the azomethine linkage of quinoline and some of its derivatives followed by hydrolysis and oxidation of the intermediate dihydro compound. 2. Similar addition reactions have been carried out with pyridine, acridine, and benzoquinoline types. 3. Some observations have been made relating to the effect of skin irritation caused by certain 2arylquinoline types.
AMES,IOWA
RECEIVED SEPTEMBER 3, 1949
(10) Prepared by Dr. S. M. Spatz. (11) Prepared by Mr. George Karmis.
