[CONTRIBUTION FROM THE
LABORATORY OF THE UNIVERSITY OF SOUTHERN CALIFORNIA]
CHEMICAL
SYNTHESIS OF ~-DIBI~KYLAMINOMETHYL-4-BENZYLOXY-lNAPHTHALENEMETHANOLS' RONALD F. BROWN, GEORGE M. BRYAN,
AND
HERMAN I. ENOS, JR.
Received March 26, 1946
At the suggestion of Dr. Lyondon F. Small of the National Institute of Health, an attempt was made to synthesize potential antimalarial substances in the a-dialkylaminomethyl-4-hydroxy1-naphthalenemethanol series (I). OH H-&--CH2NR2 I
OH
I The most apparent route to compounds of this type, involving condensation of 1-chloroaceto-4-hydroxynaphthalene(1) and a secondary amine, proved not to be feasible. Reaction of 1-chloroaceto4-hydroxynaphthalenewith dibutylamine, for example, produced only amorphous red tars. The failure of a similar amino ketone synthesis has been reported by Tutin, Caton, and Hann (2) who isolated only red tarry material from the reaction of p-hydroxyphenacyl chloride with ammonia. Proceeding on the hypothesis that the free phenolic group of l-chloroaceto-4hydroxynaphthalene interferes with the anticipated amine condensation, an attempt was made to protect the hydroxyl group by benzylation (3), complete the synthesis, and, as the final step, to remove the protecting group by catalytic hydrogen01ysis. COCHzBr COCH3 COCH, I I I
I
OH
II
0 CH2 CsH5 I11
I
oCHzCd&
Iv
1 The work described in this paper was done under a contract, recommended by the Committee on Medical Research, between the Office of Scientific Research and Development and the University of Southern California. The Survey Number, designated SN, identifies a drug in the records of the Survey of Antimalarial Drugs. The antimalarial activity of those compounds to which such a number has been assigned will be tabulated in a forthcoming monograph. 384
4-BENZYLOXY- 1-NAPHTHALENEMETHANOLS
OH
I
CHCH2Br I
385
OH
I
CHCHzNRz I
I
0 CH2 CsHs V
VI; R = n-Propyl VII; R = n-Butyl
1-Acetro-4-hydroxynaphthalene (11), prepared by the method of Akram and Desai (4), was benzylated in 60% yield by means of benzyldimethylphenylammonium chloride in boiling 20% sodium carbonate solution. The resulting benzyloxyketone (111) was then brominated in boiling anhydrous ether to give IV in 75% yield, along with a small quantity of a dibromo ketone. Reduction of IV to the bromohydrin V was effected in 70% yield by means of aluminum isopropoxide. Amino alcohols VI and VI1 were obtained by treatment of the bromohydrin with the appropriate secondary amine in a sealed tube a t 100-130". Unfortunately, attempted catalytic hydrogenolysis of VI yielded a dihydronaphthalene derivative instead of the desired c~-dipropylaminomethyl-4-hydroxy-lnaphthalenemethanol. EXPERIMENTAL^ i-AcetoJ-benzyloxynaphthalene(III). In a five-liter three-neck flask equipped with a mercury-sealed stirrer, reflux condenser, and dropping-funnel, was placed a solution of 319 g. (2.10 moles) of 1-aceto-4-hydroxynaphthalene(3) dissolved in 2700 cc. of 20% sodium carbonate solution. During the course of three hours, 573 g. (2.31 moles) of benzyldimethylphenylammonium chloride dissolved in 1000 cc. of water was added dropwise t o the stirred refluxing solution. The mixture was allowed to cool and 1000 cc. of benzene was added. The benzene solution was washed with 5% sodium hydroxide, then with 6 N hydrochloric acid, and finally with water. The crude product, which separated from the solution after most of the solvent had been removed by distillation, was filtered off, washed with a little cold benzene, and leached with 800 cc. of 95% ethanol under reflux for four hours. The leaching flask and its contents were cooled t o room temperature and the l-aceto-4benzyloxynaphthalene was filtered off and dried; yield 325 g. (64.3%); m.p. 116-117'. 4-Benzyloxy-I-bromoacetonaphthuZene ( I V ) . Eighty-five grams (0.308 mole) of 1-aceto-4benzyloxynaphthalene was placed in a five-liter three-necked flask equipped with a mercury-sealed stirrer, a dropping-funnel, and a reflux condenser and dissolved in 4000 cc. of anhydrous ether under gentle reflux. One hundred cc. of a saturated solution of anhydrous hydrogen chloride in ether was added. The ether solution was maintained at reflux temperature while 51.6 g. (0.324 mole) of dry bromine dissolved in 400 cc. of dry carbon tetrachloride was added dropwise in the course of two hours. The reaction mixture was then concentrated to a volume of 200 cc. by distillation of the solvents. The crude bromo ketone which icrystallized when the solution was cooled to room temperature was filtered off and recrystallized from 200 cc. of carbon tetrachloride; yield, 82 g . (75%) of 4-benzyloxy-lbromoacet onaphthalene ; m .p. 105-107 '. 2.411 melting points are corrected. Analyses by Bruce Day and Richard N e d , The University of California a t Los Angeles.
386
R. F. BROWN, 0. M. BRYAN, AND H. I. ENOS, JR.
Anal. Calc'd for CloHlaBrO2: C, 64.24; H, 4.26. Found: C, 64.68; H, 4.40. If undiluted bromine was used or if the solution of bromine in carbon tetrachloride was added too rapidly, the formation of dibromo ketone increased to such an extent that it became possible to separate manually rectangular plates of this compound from the needlelike crystals of the monobromo ketone in the crude reaction product. The preparation of the dibromo ketone is described below. 4-Benzyloxy-l-dibromoacetonaphthalene. To a solution of 2.43 g. of 1-aceto-4-benzyloxynaphthalene dissolved in 150 cc. of anhydrous ether was added 5 cc. of a saturated solution of anhydrous hydrogen chloride in ether. Bromine (0.9 cc.) was added t o the ether solution during two hours. The color faded rapidly after each drop of bromine had been added'untilO.45 cc. had been consumed but disappeared slowly during the addition of the remaining 0.45 cc. The ether solution was washed consecutively with water, sodium thiosulfate solution, and 5% sodium bicarbonate solution. After a fins1 washing with water it was dried with anhydrous sodium sulfate and concentrated to svolume of 100 cc. The first crop of crystals (2.34 g.) had the m.p. 130.8-131"; a second crop (0.52 g.) had the m.p. 129.8130.8'; total yield, 75%. One recrystallization from 95% ethanol raised the m.p. of the first fraction t o 131.6-132". Anal. Calc'd for CloHlrBr~O~: C, 52.56; H, 3.25. Found: C, 53.14; H, 3.30. 4-Benzyloxy-a-~romomethyl-l -naphthalsnemethanol (V). To 28.13 g. of 4-benzyloxy-1bromoacetonaphthalene contained in a one-liter conical flask was added 400 cc. of hot 3 N aluminum isopropoxide in isopropyl alcohol. The reaction mixture was heated to reflux for twenty minutes and 150 cc. of isopropyl alcohol was distilled through a take-off condenser. The reaction flask was then cooled for three minutes under the water tap and its contents were then poured into a mixture of 200 cc. of 12 N hydrochloric acid and 400 g. of ice. After thirty minutes, the supernatant liquid was decanted from the solid residue and extracted twice with ether. The combined ether extract was used to dissolve the solid residue. The ether solution was washed with 5% sodium bicarbonate and with water. The dried solution was concentrated to a volume of 100 cc. and 50 cc. of carbon tetrachloride was added. After the volume of the solution had been reduced to 50 cc. by distillation, 25 cc. of petroleum ether (30-60') was added in small amounts with intermittent heating. The 4-benzyloxy-a-bromomethyl-1-naphthalenemethanolwhich crystallized from the solution weighed 20.14 g. (71%); m.p. 84-85'. Anal. Cslc'd for ClpHl,BrOn: Br, 22.4. Found: Br, 22.4. /t-Benzylo.y-a-dipropylaminomethyl-l-naphthalenemethanol(SN-l1,&3;V I ) . A solution in 30 cc. of dipropylof 15.58 g. of 4-benzyloxy-a-bromomethyl-1-naphthalenemethanol amine was heated in a sealed tube a t 100" for twelve hours. The dipropylamine hydrochloride which was filtered off from the reaction mixture weighed 8.01 g. (100%). The filtrate was steam distilled in the presence of 25% sodium hydroxide solution for two hours in order to remove unreacted dipropylamine, and the gummy yellow residue was then dissolved in ether. The addition of a few cc. of petroleum ether to the dry ethereal solution caused the separation of a small amount of tan solid which was filtered off and discarded. The only hydrochloride, which was formed when sutficient anhydrous hydrogen chloride in anhydrous ether was added to the filtrate, was dissolved in the minimum amount of absolute ethanol a t the boiling point of the solution and anhydrous ether was slowly added t o the point of incipient crystallization. After standing overnight a t 0", the solution deposited hydro8.34 g. (47.5%) of 4-benayloxy-a-dipropylaminomethyl-l-naphthalenemethanol chloride; m.p. 130-132". Anal. Calc'd for CpsHa2ClNO~:C, 72.50; H, 7.79. Found: C, 72.31; H, 7.93. ~-Benzyloxya-dibutylaminomethyl-l-naphthalenemethanol (SN-10,~Ol;VZZ). Upon being heated to 130' for fourteen hours, a mixture of 7.82 g. of 4-benzyloxy-a-bromomethyl-l-
4-BENZYLOXY- 1-NAPKFHALEKEMETHANOLS
387
naphthalenemethanol and 14.2 g. of dibutylamine yielded 4.45 g. (60%) of 4-benzyloxy-adibutylaminomethyl-l-naphthalenemethanol isolated as the hydrochloride ; m.p. 140-142'. Anal. Calc'd for CnrH&lNOz: C, 73.36; H, 8.21. Found: C, 73.74; H, 8.42. (t-Be~~zyZoxy-~-dibutyZuminomethyl-1-dihydronaphthaZenemethanoZ. 4-Benzyloxy-u-dibutylaminomethyl-1 -naphthalenemethanol hydrochloride (17.68 9.) was hydrogenated at 40 lbs./in.* with 0.5 g. of platinum oxide as catalyst. The crystalline material obtained after the removal of solvent i n vacuo was leached with distilled water at room temperature overnight and recrystallized from absolute ethanol. There was obtained 8.49 g. of a substance which melted at 140-142". A mixture of this material with VI1 melted at 119-126'. The reduction product did not give a positive test for a phenolic group with 10% aqueous ferric chloride although the aqueous extract of the crude reduction product produced a brilliant violet color with this reagent. Anal. Calc'd for CZ~H&lKO~:C, 73.03, H, 8.63. Found: C, 73.18; H, 8.57. SUMMARY
Synthesis of the potential antimalarials a-dipropylaminomethyl-4-benzyloxy1-naphthalenemethanol and ~~-dibutylaminomethyl-4-benzyloxy-l-naphhalenemethanol, from l-acet0-4-hydroxynaphthalene,has been described. LOS
ANGELES 7, CALIF: REFERENCES
(1) HOUBEN, Ber., 69, 2878 (1926); see a150 HOUBEN AND FISHER, Ber,, 60, 1759 (1927). (2) TUTIN, CATON,AND HANN, J. Chem. SOC.,2133 (1909). (3) E. M. FRY,National Institute of Health, private communication. Ber., (4) AKRAMAND DESAI, Proc. Indian. Acad. Sci., 11A. 149 (1940); compare HOUBEN, 59, 2878 (1926), and WITT AND BRAWN, Ber., 47, 3222 (1914).
