[CONTRIBUTION FROM
CHEMISTRY DEPARTMENT OF THE UNIVERSITY OF CALIFORNIA, LOS ANGELES]
THE
SUBSTITUTED a-DIALKYLAMINOALKYL-1-NAPHTHALENEMETHANOLS. IV. SUBSTITUTED a-NAPHTHYLETHYLENE OXIDES AND DERIVED AMINO ALCOHOLS' S. WINSTEIN, THOMAS L. JACOBS, ROBERT B. HENDERSON, JOHN H. ROBSON, AND BRUCE F. DAY Received October 16, 1946
In the preparation of substituted a-dialkylaminomethyl-l-naphthalenemethanols of the type I11 from halohydrins I (1) derived from the corresponding halaketones, there were in some cases advantages in the preliminary preparation and isolation of the corresponding naphthylethylene oxide 11. Thus, several oxides of this type have been prepared by us and used for the purpose mentioned. The results are reported in this paper.
0
/ \ -
CH-CHt I
03
Y
I1
I
CH(0H)CHzNRz I
I11 Short treatment of the halohydrins (1) with alcoholic alkali at room temperature gave rise to the oxides in nearly quantitative yield. Their properties are summarized in Table I. Of the five oxides described here, four are low-melting solids, the 4-methoxy derivative being an oil. Naphthylethylene oxides of the type I1 have apparently not been studied previously, but can be handled well if ordinary precautions are taken. These substances are quite sensitive to heat and traces of acid. Thus molecular distil-
* This work was done under a contract, recommended by the Committee on Medical Research, between the Office of Scientific Research and Development and the University of California, Los Angeles. 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 numbers have been assigned will be tabulated in a forthcoming monograph. 167
158
WINSTEIN, JACOBS, HENDERSON, ROBSON, DAY
lation of 4-methoxy-1-naphthylethyleneoxide I1 (Y = 4-OCHJ at 5 X mm. was successful. However, clistillation at 0.5-1.0 mm. yielded the rearranged aldehyde which formed a bisulfite addition compound and an oxime and gave a positive Schiff's test immediately. The oxide gave only a faint Schiff's test, the color deepening slowly. The residue in the flask after the distillation at 0.5-1.0 mm. consisted largely of a high-melting solid which had the composition of the dioxane IV, a type substance sometimes produced from oxides (2). In the case of the 4-bromo-1-naphthylethylene oxide one preparation gave rise, apparently through the action of water and an accidental trace of acid, to a difTABLE I OXIDESY(hHaCHOCH2FROM HALOHYDRINS
I Y
4-OCHs 4-C1 4-Br 6-C1 7-C1 a
b
ALP.
'C
oil. 49 49-50 32.5-32.8 40.241.0
ANALYSIS
I
I
Calc'd
Found
%C
%H
%C
%H
77.98 70.41
6.04 4.43
77.78 70.43
5.90 4.61
4.43 4.43
70.13 70.37
4.57 4.59
b
70.41 70.41
,: 1.625-1.626. Not analyzed.
IV ferent substance whose analysis corresponded to the g ~ c o 1 l The molecular weight of the material and the analysis of the acetate ester were confirmatory. The conversion of the oxides to the amino alcohols was accomplished in high yield very conveniently by heating an equimolar mixture of the oxide and dialkylamine for the requisite time. The progress of the ring-opening reaction may be followed easily by measurement of the refractive index of the reaction mixture. This method was used to follow the course of the reaction of several amines with the 4-methoxyl-naphthyl- and the 4-bromo-1-naphthyl-ethylene oxide. The results are shown graphically in Fig. 1. For these oxides a working temperature of 100-125" gave a convenient rate of reaction. There are some advantages to the preparation of the amino alcohols through the oxides rather than directly from the halohydrin. First, there is no necessity
NAPHTHALENE AMINO ALCOHOLS.
159
IV
to remove excess secondary amine by steam-distillation or otherwise, this separation being difficult with the higher amines. Second, the product is more nearly pure and is usually obtained in higher yield. Table I1 summarizes the amino alcohols prepared from the substituted naphthylethylene oxides. Although an unsymmetrical oxide theoretically may open to give one or the other or a mixture of two isomeric amino alcohols, there is little doubt that 111
0
d';"' 03 / \
CH(OH)CH20H
HOH
,
I
I
Br
Br
v TABLE I1 AMINOALCOHOLSYCIoH&H(OH)CH~NR2FROM OXIDES ANALYSIS
SN
6409 9053 8725 8680 8677 10267 8732 7522 13264
Y
R I
4-OCHa 4-OCHs 4-Br 4-Br 4-Br 4-C1 4-C1 641 7-C1
Y.P. 'C
151-154 137-139 106-108c 126.5-128.0 40.5-41.3* 35.0-36.5' 34.4-34.8 33.5-34.5 151-154 123-125
1
Calc'd
%C
I
72.84
I
68.55 70.30 75.38 76.53 64.86 64.86
%H
1
Found
%C
Reference 1 (a) 10.12 I 73.09 9.04 9.59 9.94 10.44 7.89 7.89
68.81 70.22 75.18 76.43 64.83 64.72
I I
%Ef
10.05 8.93 9.53 10.00 10.45 7.97 8.14
Hvdr chloride.
* Free amino alcohol. Two crystalline modifications. M.p. of hydrochloride 106-108.5°. * M.p. of hydrochloride 93-94".
correctly represents the structure of the ethanolamines prepared by us. The opening of the oxide ring by an amine appears to be a bimolecular displacement (3) of the ring oxygen by an amine molecule. The available evidence is that when the oxide is of the type VI (e.g., propylene oxide, isobutylene oxide, styrene oxide), reaction takes place at the primary carbon atom in preference to the secondary or tertiary carbon atom (4, 5) even when this latter carbon atom carries an aromatic group (6).
160
WINSTEIN, JACOBS, HENDERSON, ROBSON, DAY EXPERIMENTAL
All melting points are correct8ed. Analyses were by Jack W. Ralls or Bruce Day. Preparation of oxides. To a solution of 0.10 mole of halohydrin (1) in 50 ml. or more of alcohol was added a solution of 0.15 mole of sodium or potassium hydroxide in 50-75 ml. of alcohol. Both solutions were at room temperature, and the mixture was shaken occasionally a t room temperature for fifteen minutes. Then 500 ml. of water was added and the oxide was extracted with two 200-ml. portions of ether. The combined ethereal extracts were washed with three 500-ml. portions of water and then dried over potassium carbonate. The product was reduced to constant weight by distillation of solvent first a t atmospheric
n
Y
I a n
FIG. 1. Plots of n: us. time for reactions of oxides with amines Curves I, I1 and I11 : 4-Methoxy-1-naphthylethylene oxide with di-n-amylamine at 100" (I) and 127" (11) and di-n-octylamine a t 100" (111). Curves IV, V and VI : 4-Bromo-1-naphthylethyleneoxide with di-n-amylamine at 104' (IV), di-n-octylamine a t 120" (V) and di-n-decylamine a t 120" (VI).
R
R
0
\ / \ CCHz \ /
HNRz
VI pressure, then at partially reduced pressure and finally a t approximately 2 mm., with the aid of a water-bath kept below MI". In the case of the 4-methoxy-I-naphthylethyleneoxide, the residue from the above treatment constituted a 96% yield of essentially pure material. The crude products from the preparations of the other ethylene oxides were recrystallized from petroleum ether, b.p. 60-70°, and dried in a vacuum desiccator which contained some paraffin. The yields were about 80%. The solid oxides turned to oils on exposure to air for a number of days but kept well for longer periods in closed bottles.
NAPHTHALENE AMINO ALCOHOLS.
IV
161
It is advisable to rinse the required glassware with ammonia before drying in order to guard against the contamination of the oxide by acid. One preparation of 4-bromo-1-naphthylethylene oxide by the above method yielded a n oil insoluble in hexane and easily recrystallized from benzene to give a solid, m.p. 126.5128.0' and Rast (7)molecular weight 271 f 15 (theoretical for glycol 266). Anal. Calc'd for C12HIlBrOl: C, 53.95;H, 4.15. Found: C, 53.97;H, 4.03. A 1.0-g.portion of this material was acetylated with acetyl chloride in pyridine at room temperature to yield a n ester, m.p. 103.0-104.5",0.89 g., (60%), after several recrystallizations from hexane. Anal, Calc'd for ClsHlbBrOl: C, 54.72;H, 4.31. Found: C, 54.38;H, 4.18. Distillation and rearrangement of 4-methozy-i-naphthylethyleneoxide. Molecular distillation of crude oxide n: 1.6252,a t 5 X 10- mm. on an apparatus of the type described by Riegel (8) yielded a clear colorless product, n: 1.6255. Distillation of oxide at 0.5-1.0mm. from a modified Claisen flask gave a clear distillate at 142-144', ng 1.6208,which soon solidified; m.p. 47.548.5" after recrystallization from ligroin of b.p. 60-70". This distillate formed a bisulfite addition product, and a n oxime, m.p. 132-134'. Anal. Calc'd for ClsHlaNOs: C, 72.54;H , 6.09. Found: C, 72.23;H, 6.40. The solid distillate, dissolved in alcohol, gave a n immediate deep purple color with Schiff's reagent; the oxide only a light pink which became purple only on standing overnight. The residue from the above distillation at 0.5-1.0 mm. yielded, on washing with ether, a white solid, m.p. 240-241', after recrystallization from benzene. Anal. Calc'd for C26HZ40(: C, 77.98;H, 6.04. Found: C, 77.78;H, 6.01. Conversion of oxides to amino alcohols. An equimolar mixture of oxide and dialkylamines was warmed and shaken until homogeneous and then kept in a sealed tube or a stoppered flask heated, usually at 120°, for eight to twenty-four hours either in a furnace or an oilbath. I n judging the extent of the reaction, the refractive index was measured either on separate samples in small sealed tubes or on a sample withdrawn from the main flask. Plots of the data obtained in this way are giveninFig. 1. After the heating period, the amino alcohols were either recrystallized one or more times from methyl or ethyl alcohol or alcohol-hexane mixtures, or taken up in anhydrous ether and precipitated as the hydrochlorides with ethereal hydrogen chloride. The hydrochlorides were recrystallized from methanol-ether, acetone-ether, or ethanol-ether. The crude yields of amino alcohol were usually very high, the yield of recrystallized amino alcohol or its hydrochloride usually about SO%. SUMMARY
A series of substituted a-naphthylethylene oxides (Cmethoxy-, 4-chloro-P 4-bromo-, 6-chloro-, and 7-chloro-) has been prepared. The oxides have been converted smoothly to a number of dialkylaminoethanols. Los ANGELES,CALIF. 3 The dialkylamines were supplied in some caaes by Dr. Elderfield and co-workers at Columbia University.
162
WINSTEIN, JACOBS, HENDERSON, ROBSON, DAY
REFERENCES (1) (a) WINSTEIN,JACOBS, HLNDERSON, AND FLORSHEIM, J . Org. Chem., 11, 150 (1946); (b) BROWN,JACOBS, WINSTEIN,LEVY,Moss, AND OTT, J . Org. Chem., 11, 163 WINSTEIN, HENDERSON,BOND, RALLS, SEYMOUR,AND (1946) ; (c) JACOBS, FLORSHEIM, J . Org. Chem., in press. (2) (a) COHEN,MARSHALL, AND WOODMAN, J . Chem. Soc., 107, 898 (1915); (b) DANILOV AND VENUS-DANILOVA, Ber., 60, 1050 (1927); (c) FAVORSKI, J . Russ. Phys.Chem. SOC.,38, 741 (1906); Chem. Zentr., I, 15 (1907). (3) HAMMETT, “Physical Organic Chemistry,” hlcGraw-Hill Book Company, Inc., New York, 1940, Chapter13V and VI. (4) KRASSUSKY AND STEPHANOIFF, J . prakt. Chem., 116,321 (1927). (5) WINSTEINA N D BUCKLES, J . Am. Chem. Soc., 64,2780 (1942); Footnote 25. (6) (a) TIFFENEAU AND FOURPIEAU, Compt. rend., 146, 697 (1908); (b) KITCHENAND POLLARD,J . Org. Chem., 8, 342 (1943); ( e ) EMERSON, J . Am. Chem. Soc., 67, 516 (1945). (7) SMITH AND YOUNG, J . Biol. Chem., 76, 289 (1927). (8) RIEGEL,BEISWANGER, AND LANZL, Ind. Eng. Chem., Anal. Ed., 16,417 (1943).
