ALKYLENE-BRIDGED 5,6-DIHMROXYQUINOLINES
Nov., 1948 [CONTRIBUTION FROM THE
DIVISION OF MEDICINAL CHEMISTRY, THESQUIBB
INSTITUTE FOR
3621 MEDICINAL RESEARCH]
Some Derivatives of Alkylene-Bridged 5,6-Dihydroxyq~inoline~~ BY
w.A. LO",
HARRY
L.YALE, JOHN T.SHEEHAN AND JACK BERNSTEIN
An enhancement of antimalarial activity by responding quinoline derivative by the various modification of the quinoline nucleus in the pa.ma- Skraup methods.".l2 This could be attributed quine type occurs when a second RO- group is to the lability of the isopropylidenedioxy groupsubstituted in the 5 - p o ~ i t i o n . lThis ~ ~ ~paper deals ing since none of the starting material was recovwith the synthesis of related compounds contain- ered. ing the 5,6-methylenedioxy-, 5,6-ethylenedioxyPharmacological Studies.'*-In two series of and 5,6-isopropylidenedioxy groups. Compounds Test G-llb against Plasmodium lophurae in the of this type have been proposed during the ma- duckling, 5,6-ethylenedioxy-8-(isopropylaminolaria research program,a but apparently no report amy1amino)-quinoline gave Q-values of 60 and 80; of their successful preparation has been published ; against Plasmodium cathemerium the same comthe preparation of 6,7-methylenedioxyquinoline pound gave Q-values of 60 and 80. In one series by the reaction of 6-aminopiperonal and metha- of tests against Plasmodium lophurae 5,6-methylzonic acid has been des~ribed.~ enedioxy - 8- (diethylaminopropy1amino)-quinoline The preparation of the alkylene bridged 5,6- gave a Q-value of 30. dihydroxyquinoline prototypes is illustrated by Experimental Partlaa the series of reactions involved in the synthesis of 5,6- ethylenedioxy-&(isopropylaminoamylamino)1,2-Methylenedioxybenzene1* and 4-nitro-1,2-methylquinoline: resorcinol + 1,4-benzodioxane 4- ene-dioxybenzenels were prepared according t o the literanitro-1,4-benzodioxae 3 4-amino-l,4benzodi- ture methods. 4-Acetamido-l,2-methylenedioxybenzenehas been deoxane 3 4-acetamido-l,4-benzodioxane3 bni- scribed previously's but was prepared for the first time via tro-4-acetamido-l,4-benzodioxane 3 5-nitro-4- a catalytic reduction of the nitro compound. A mixture amino-1,4-benzodioxane -> 5,6-ethylenediox:y-8- of 16.7 g. (0.1 mole) of 4-nitro-l,2-methylenedioxybenzene, 0.3 g. of 5% palladium on charcoal and 150 ml. of nitroquinoline. absolute ethanol was sbaken a t room temperature under 50 Along with 5,6-ethylenedioxy-8-nitroquino-pounds pressure of hydrogen. Reduction was complete in line, as a by-product of the 60-second Skraup re- about twenty minutes. Five runs were carried out in this action,2.6 there was obtained 5,6-dihydro~y-8~-ni-manner, combined, filtered free of catalyst and the alcohol troquinoline. The formation of 5-hydrox:y-6- removed under reduced pressure. The oily residue crystalwhen treated with 150 ml. of acetic anhydride. methoxy-8-nitroquinoline during a 90-second lized Acetylation was completed by an additional one hour of Skraup reaction with 4-acetamino-5-nitrovera- heating on the steam-bath. The crystalline 4-acetamido1,2-methylenedioxybenzene separated out on cooling. trole has been reported.2 5,6-Methylenedioxy-8-aminoquinoline could not After filtering and washing with water the solid weighed g. (67% yield), m. p. 135-136" (lit.'6 135'). be condensed with isopropylaminoamyl chlo.ride 605-Nitro~-acetamido-1,2-methylenedioxybenzene was hydrochloride or 1-isopropylamino-4-bromopen- prepared according to the method of Jones and Robinson.16 tane hydrobromide under the usual c~ndition.s.~J S-Nitro-4-amino-l,2-methylenedioxybenzenehas been but no experimental details were given. In the However, a condensation with diethylamino- prepared16 work the preparation was carried out as follows: propyl chloride was eventually effected by using present a mixture of 121 g. (0.54 mole) of the 5-nitro-4-acetamidosodamide as the condensing agent 18 a method orig- 1,2-methylenedioxybenzene,363 ml. of absolute ethanol inally described by Eislebe for introducing the and 726 ml. of concd. hydrochloric acid was refluxed and dialkylaminoethyl group into active methylene stirred for one-half hour, then poured into one liter of water. The solution was made alkaline with concd. anicompounds and later extended by Dewar'O for the monia and the precipitated solid was filtered, washed with dialkylaminoalkylation of substituted anilines. mater and air-dried. A quantitative yield of 5-nitro-4It was not possible to convert 5-nitro-4-aceta- amino-l,2-methylenedioxybenzene was obtained, 98 g., mido-l,2-isopropylidenedioxybenzeneto the !cor- rn.p. 199-195O (lit.I6 198"). --f
(la) Presented before the Division of Medicinal Chemistry, 113th Meeting, American Chemical Society, Chicago, Ill., April 1!3-23, 1948. ( l h ) F. Y. Wiselogle, "Survey of Antimalarial Dram 1941-1!)45." Vol. I I , Part 11, J. W. Edwards, Ann Arbor, Michigan, 1946, PP.
5,6-Methylenedioxy-8-nitroquinoline.-Method B12 w%s followed except that the operating temperature was g0-70 , The yield from a 0.1 mole run was 11 g. (50%), m. p. 191-192 Anal. Calcd. for C1@H&Ot: C, 55.05; H, 2.75; N, 12.84. Found: C, 54.97; H, 2.69; N, 13.08.
(2) Elderfield, cf 41.. THIS JOURNAL, 68, 1684 (1946). (3) Private comm.unication from F. Y. Wiselogle. (4) Clemo and Swan, J . Chcm. SOC.,867 (1945). (5) Drake, el ai., THIS JOURNAL, 68, 1536 (1946). (6) Drake, et at., i b i d . , 68, 1529 (1946). (7) Elderfield. ef ol., ;bid., 68, 1524 (1946). (8) This method will be reported in detail by Dr. J. T. Sheehm in a forthcoming puhlication from these laboratories. !9) Eisleb, Bcr., 74, 1433 (1941). (101 Dewar, ihid.. 619 (1944).
(11) Yale, THISJOURNAL, 69, 1230 (1947). (12) Yale and Bernstein, ibid., TO, 254 (1948). (13) The pharmacological s t u d i u were carried out by the Division of Pharmacology, Squibb Institute for Medical Research. (13a) All melting points are uncorrected. (14) Shorygin, Simanovskaya aad Bogdanova, J . Ccn. Ckcm., C y . S. S. R.,8, 975 (1938); C.A . , 85, 3777 (1939). (16) Perkin. Robinson and Thomas. J . Chcm. Soc., 95, 1979 (1909). (16) Jones and Robinson, J . Chcm. SOC., ill, 903 (1917)
1231-1233.
'.
3622
W. A. L o n , HARRYL. YALE, JOHN T. SHEEHAN AND JACK BERNSTEIN
VOl. 70
5-Nitro-Q-amino-l,4-benzodiorane.-The hydrolysis of 5,6-Methylenedioxy-8-a1nincquinolhe.-A suspension of 10.9 g. (0.05 mole) of 5,6-methylenedioxy-8-nitroquino- the above derivative was effected as described a b o y for line and 10 g. of 5% palladium on charcoal in 130 ml. of the methylene derivative; yield 96%, m. p. 150-151 ethyl acetate was hydrogenated at room temperature and Anal. Calcd. for C ~ H ~ N Z O C,~ 48.97; : H, 4.11; N, 50 pounds pressure of hydrogen. The product isolated in 14.28. Found: C, 48.57; H, 4.03; N, 14.64. the :sua1 manner weighed 6.0 g. (63% yield), m. p. 1165,6-Ethylenedioxy-S-nitroquinoline. (a) The Sixty117 Second Skraup.-A procedure essentially that employed Anal. Calcd. for C ~ O H ~ N ~C, O Z63.82; : H, 4.25;' N, by Elderfields was used. Our procedure is described in 14.89. Found: C, 63.56; H, 4.25; N, 14.86. detail because of certain changes which facilitate the me5,6-Methylenedioxy-8- (3-diethyla~ninopropylamino) chanical operations involved. Into a beaker set in an oilquinoline.-Four grams of sodamide wet with toluene was bath and equipped with a mechanical stirrer and two longstemmed separatory funnels which extended t o the bottom added t o a solution of 15 g. (0.08 mole) of 5,6-methylenedioxy-8-aminoquinoline, 12.4 g. (0.083 mole) of diethyl- of the beaker, was placed a mixture of 12 g. (0.055 mole) of aminopropyl chloride and 75 ml. of distilled toluene, The 5-nitro-4-acetamido-1,4-benzodioxane,7 g. (0.031 mole) mixture was heated in an oil-bath t o 70' and kept at this of arsenic pentoxide and 40 ml. of high-test glycerol. One temperature for half an hour during which time there was a funnel contained 15 ml. of concd. sulfuric oxide and the constant evolution of ammonia. The bath tempwature other 150 ml. of ice-water. The oil-bath was heated to 150" while the mixture was was then raised t o 115" over a period of half an hour and maintained at this temperature for five hours, when the stirred vigorously. The flame was removed and all the evolution of ammonia had ceased. After cooling t o room sulfuric acid was added below the surface of the mixture. temperature, 8 g. of unreacted starting material crystal- An immediate exothermic reaction occurred and was allized out and was recovered by filtration. The toluene lowed t o continue for exactly sixty seconds. The oil-bath solution was washed with water and then extracted four was removed and the water added all at once below the times with 75-ml. portions of 5y0acetic acid. The com- surface of the reaction mixture. The reaction mixture was bined acid extracts were washed with three 25-ml. portions filtered t o remove any unreacted starting material and the of ether, then made alkaline with sodium hydroxide and the filtrate made strongly alkaline with 200 ml. of 20% sodium free oily base extracted with three 100-ml. portions of ether. hydroxide. The precipitate was filtered off, washed with The combined ether extracts were washed with water and water and redissolved in 40 ml. of 5% hydrochloric acid. dried over anhydrous potassium carbonate. The ether From the above alkaline filtrate after adjusting t o $H 4 was evaporated and the residue fractionated. The frac- there was obtained 4 g. of crude 5,6-dihydroxy-8-nitrotion boilingat 198-200" (1.4mm.),5.0g., (20%yield) was quinoline (see below). The acid solution containing the collected. Allowing for the recovered starting material, product was made alkaline with 11 ml. of concd. ammonia and the solid filtered off and dried. After crystallization the yield was 44%. Anal. Caicd. for CIIHSIN~OZ: C, 67.77; H, 7.64; H, from acetone there was obtained 5 g. ( 4 2 3 ) of 5,G-ethylenedioxy-8-nitroquinoline,m. p. 158-159 13.95. Found: C, 67.33; H, 7.62; N, 14.27. Anal. Calcd. for C11HaN204: C, 56.89; H, 3.44; N, 5,6-Methylenedioxy-8- (3-diethylPminopropylanino) 12.06. Found: C, 56.93; H, 3.63; N, 12.18. quinoline Monohydriodide .-Five grams (0.0166 mole) of 5,6-Dihydroxy-8&roquinolbe was recrystallized from the free base was dissolved in 30 ml. of 4% acetic acid and treated with a solution of 3 g. of potassium iodide in 10 ml. boiling water, even though the solubility is only about 0.5 of water. The product separated cleanly and was re- g. per liter. N o other suitable solvent could be found. crystallized from alcohol-ether; yield, 6 g. (84.3% yield) From water the coypound forms purple needles which do of a bright yellow crystalline solid, m. p. 154-155". not melt up t o 300 Anal. Calcd. for CJ16N90,: C, 52.43; H , 2.91; N, Anal. Calcd. for C1?H23NsO,.HI: C, 47.56; H, 5.59; 13.59. Found: C, 52.95; H, 3.24; N, 13.66. N, 9.79. Fourid: C, 47.68; H , 5.54; N, 9.86. (b) With Acrolein (Method A).ILYield, 36%. 5,6-Methylenedioxy-8- (3-diethylaminopropylarnino) (c) With Acrolein (see procedure above for methylenequinoline Dihydriodide.-The dihydriodide was prepared by dissolving the base in anhydrous ether and adding a dioxy derivative), yield 53 %. slight excess (3Yo) over the calculated amount of 57% 5,6-Ethylenedioxy-8-aminoquinoline.-A suspension of hydriodic acid. The product obtained in this manner, even 14.7 g. of 5,6-ethylenedioxy-8-nitroquinoline,100 ml. of after several recrystallizations from alcohol, was discolored ethyl acetate and 2.5 g. of 5% Pd on charcoal was reduced and somewhat unstable so that satisfactory analyses :odd catalytically a t room temperature and 45 pounds pressure not be obtained. The compound melted at 158-159 of hydrogen. The product was recrystallized from 75 ml. Anal. Calcd. for C17I-&?\l@r2HI: C, 36.63; H, 4.48; of 95y0 ethanol; yield 8.5 g. (66%), m. p. 73-74", b. p. 144' (0.3 mm.) (oil-bath at 204-208'). N, 7.54. Found: C , 37.57; H, 4.96; N, 7.66. Xngl. Calcd. for C11HloN~On: C, 65.33; H, 4.96; h', Attempted Condensations with 5,6-Methylenedii>xy-8aminoquinoline.-Utilizing procedures which were success- 13.86. Found: C, 65.45; H.4.77; N. 14.03. ful in condensing other 8-aminoquinolines, a number of 5,6-Ethylenedioxy-8-!isoprop laminoamylamino) -quinoattempts were made to condense isopropylaminoamy I chlo- line Monohydrochloride and donophosphate.-The conride hydrochloride and 1-isopropylamino-4-bromopentane densation mas carried out under the conditions described for hydrobromide with 5,6-methylenedioxy-8-aminoc~uino-SS 13,2766using 23.5 g. (0.165 mole) of thenucleus. 16.8 g. line, but without success. (0.034 mole) of isopropylaminoamyl chloride hydrochloride 1,4-Benzodioxane was prepared according to the method and 21 ml. of water. The monohydrochloride crystallized of Ghoshl? and was converted t o 4-nitro-1,4-benzodioxane from hot water, m. p. 12t?1-126~,24.3 g., 79.070 yield. according to the directions of Vorlander.18 4-Amino-1,4'Anal. Calcd. for Ct9HZaN~O~Cl:N, 11.50; C1, 9.71. benzodioxane was not isolated but was converted directly Found: N, 11.29; C1, 9.85. to the 4-acetamidobenzodioxane,19as described above for The monohydrochloride was converted to the monophosthe methylene compound. 5-Nitro-4-acetamido-l,4-benzodioxane was prepared phate in the usual manner,' the yield 23.5 g. (65.4%) of a according to the method of Jones and RobinsdJn16 f i x the bright yellow crystalline product, m. p. 216-218". Anal. Calcd. for CtpHloNsOaP: N, 9.84; P , 7.26. methylene compound; yield, 9270, m. p. 179 Anal. Calccl. for C1~H10N*O6:C, 50.42; H, 4.20; N, Found: N, 9.60; P, 7.20. 1,2-Isopropylidenedioxybenzene and 4-nitro-1,2-iso11.76. Found: C, 50.26; H,4.38; N, 11.78. propylidenedioxybenzene were prepared according t o the (17) Ghosli, J. Chcm. Soc., 107, 1588 (1915). literature methods.20
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-
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(18) Vorlander, Ann.. %EO, 206 (1894). (19) Moureau A n n rhim 171 18, 100 (1899).
(20)Slooff, Rrc. tray. chim.. 64. 995 (1935).
Nov., 1948
3623
ALKYLATIONOF THIOPHENE WITH OLEFINS
Attempted preparation of 5,6-isopropylidenedioxy-S4-Acetamido-1,2-isopropylidenedioxybenzenewas prepared as described for the corresponding methylene- and nitroquinoline: (a) Method A, with acrolein.-Carried ethylenedioxy- compounds. A small portion of the prod- out in the usual manner there was obtained no acid-soluble uct was puri6ed for analysis, m. p. 107-108', after re- material. The principal product was a black acid incrystallization from a mixture of ethyl acetate and hex:ane. soluble gum, which was somewhat soluble in b o i l i y ethaAnal. Calcd. for CllHlsNOs: C, 63.73; H, 0.28; N, nol, giving a red solid which did not melt up to 250 (b) Method B, with phosphoric acid at 25' and 40 ";none 6.76. Found: C,63.60; H, 5.99; N,6.67. S-Nitro-4-acetamido-1,Z -isopropylidenedioxybenz:ene of the desired quinoline compound was obtained. was obtained in the manner described for the correspcmdAcknowledgment.-The authors are indebted ing methylene- and ethylenedioxy- compounds, m. p. to Dr. Elliott Shaw and Miss Kathryn A. Losee 162-163' after recrystallization from 95% ethanol. The yield, based on the 4-nitro-l,2-isopropylidenedioxy~~en-for their assistance in certain phases of the experimental work. The microanalyses were carzene, was 85%. Anal. Calcd. for CllHIZN*OS: C, 52.35; H, 4.77; N, ried out by Mr. J. F. Alicino of this Institute. 11.12. Found: C, 52.28; H, 4.87; N, 11.32.
.
5-Nitro4-amino-1,2-isopropglidenedioxybenzene w2s
Summary prepared by the hydrolysis of the corresponding acetaniido compound in the same manner as described for the methylThe preparation of several prototype alkylene ene- and ethylenedioxy- compounds. Employing 4:) g. bridged 5,6-dihydroxyquinoline compounds is de(0.18 mole) of 5-nitro-4-acetamido-1,2-isopropylid~~1iedioxybenzene and 350 ml. of 1.3 N ethanolic hydrochloric scribed. The compounds have shown fairly high acid there was obtained 30 g. (SOTo yield) of product, E . p. activity against Plasmodium lophurae and Plas123.5-124.5 after recrystallization from aqueous ethanol. modium cathemerium in the duckling. Anal. Calcd. €or CdHloNsOd: C, 51.42; H, 4.79; N, 13.33. Found: C, 51.35; H, 5.07; N, 13.38. NEWBRUNSWICK, N. J. RECEIVED MAY8, 1948 O,
[A CONTRIBUTIONFROM SOCONY-VACUUM LABORATORJES, A DIVISION OF %CONY-VACUUM OIL Co., INC., RESEARCH AND DEVELOPMENT DEPARTMENT]
Alkylation of Thiophene with Olefins BY PHILIP D. CAESAR^ The direct alkylation of thiophene with olelins and alcohols in the presence of alumina-silica type catalysts and of 100% phosphoric acid was reported by Kutz and Corson.2 In contrast to their observations, it has been found in this Laboratory that thiophene can be alkylated with olefins under suitable conditions in the presence of sulfuric acid, aluminum chloride, or boron trifluoride4iet:hyl ether complex without excessive decomposition or resinification of the thiophene. Other suitable alkylation catalysts were found to be fluoacids of boron trifluoride with water, ethyl acetate, ethyl alcohol and acetic acid. The olefinic alkylating agents employed were isobutylehe, trimethylethylene, 1-pentene, diisobutylene, 1-octene and 1hexadecene. There are two primary factors which determine the selection of the catalyst. One is the reactivity of the olefinic alkylating agent and the other is the relative proportion of mono- and dialkylthiophene desired. If a reactive olefin such as isobutylene, trimethylethylene or diisobutylene is used, any of the catalysts described above, with the possible exception of aluminum chloride and concentrated sulfuric acid, will give satisfactory yields of the corresponding alkylthiophenes a t moderate temperatures and atmospheric pressure (see Table I). The alkylation of thiophene with the relatively unreactive, straight chain olefins such as l-pen(1) Present address: Department of Chemistry, University of Illinois, Urbana, Illinois. (2) Kntz and Corwn, TEISJOURNAL, 68, 1477 (1946)
tene, 1-octene or 1-hexadecene, takes place most satisfactorily in the presence of strong catalysts such as 90-96% sulfuric acid or boron trifluoridewater complex. TABLE I CATALYTIC ALKYLATIONOF THIOPHENE WITH OLEFINS: MOLERATIOOF REACTANTS 3 1.0 Olefin form. g. r-C4H8 116
Catalyst form. 75% His04
s-CdHa
75% H?SOc 90% H¶SOd 60% HtSO4
116" i-CdHa 26 i-CdHs 24 i-CIHa 117 iGHs 110 r-CcHa 110'' i-CcHs 50 i-C6HlO 70 i-CDH1o 140 i-CIH1o 140 (i-C~Hs)i 1120 (i-CdHa): (i-CaHa)n 1-CSH14
1-CsHia 1-CsHis 1-CiaHo
1650"
55 76 56 112 224
H~BO~FI BFrether BFrether AlCli 75% HiSol HaBOzFz BFrether 80% HzSOh BFrether AlCla
BFrether 96% HzSOi BFs.Hz0 BFs-HzO
Time, Temp.,b
hr. 15 3 15 4 42 1 42 1 10 3 10 3 10 4 3 2 15 2 20 3 20 3 120 4 100 4 1 5 25 2 15 5 80 2 80 2 g.
mono.'
67 67
61 56
