[COKTRIBUTION
FROM TEE
DEPARTM~NT O F CHEMISTRY OF COLUMBIA UNIVERSITY ]
3-(2-DIALKYLAMIKO-l-HYDROXYETHYL) RETENE DERIVATIVES' THOMAS N. DODD, JR.,CHARLES H. SCHRAMM,
AND
ROBERT C. ELDERFIELD
Received January 8, 19.66
The observation that certain dialkylamino carbinols derived from phenanthrene possess high antimalarial activity (1) suggested the possibility that similar derivatives of retene (1-methyl-7-isopropylphenanthrene):I, might also possess the same property. The use of retene presents obvious advantages over phenanthrene for a variety of reasons. RetJeneis potentially available in practically unlimited amounts at a low cost, and, perhaps more important, in its reaction to yield acetylretene, the primary compound leading to dialkylamino carbinols, it yields but one isomer. Phenanthrene, on the other hand, yields at least two acetyl derivatives under the same conditions, and the isolation of one or more of these as a pure compound involves a t best a long and tedious procedure. Accordingly, a series of retene-3-amino carbinols derived from 3-acetylretene has been prepared.
COCH3
I1
I
I
C 0CHzNRz
COCHzBr
I11
IV
V 3-Acetylretene (11)was prepared by a modification of the procedure of Campbell and Todd (2) and 3-(w-bromoacetyl)retene (111)was prepared according to Adelson and Bogert (3). Reaction of bromoacetylretene with an appropriate secondary amine led to retene-3dialkylamino ketones (IV) which were in turn 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 Columbia University. 253
254
DODD, JR., SCHRAMM, A N D ELDERFIELD
reduced to retene-3dialkylaniino carbinols (V) by the use of aluminum isopropoxide (4). Most of the latter were obtained m crystalline salts only with great difficulty, and in most cases it wm necessary to distill the free bases in a molecular still in order to secure adequate purification. The properties of the hydrochlorides of the amino carbinols thus prepared are shown in Table I. Screening tests against avhn malaria on several retene-3dialkylamino carbinols have been carried out, and the details will be reported elsewhere. It will be sufficient at this point to state that none of the substances showed significant antimalarial activity. Whether this is due to the presence of the two alkyl groups in positions 1and 7 or whether it is due to the introduction of the dialkylamino carbinol group in position 3 in contrast to position 9 in the active phenanthrene derivatives is not apparent at present. TABLE I HYDROCHLORIDES OF 3-(2-DIALKYL~INO-~-HYDROXYETHYL)RETENE DERIVATIVES ANAL.
SN2
M.P.
'C.
-6601 5998
5481 6905 6600 6906 7165
253-258 129-129.5 204.5-205.5 146-147 171.5-172.5 126-127 149-150 79-80 E6-87
I
Calc'd C
H
74.0 74.7 75.4 76.6 76.6 77.2 77.2 78.0 78.4
7.9 8.4 8.8 9.4 9.4 9.6 9.6 10.2 10.4
I
Found H
C
I
74.4 74.9 75.3 76.5 76.5 77.3 77.6 77.7 78.4
I
8.1 8.5 8.8 9.3 9.4 9.6 9.6 10.5 10.6
EXPERIMENTAL
All boiling and melting points are corrected for stem exposure. 3-Acetylretene. This was prepared by a modification of the procedure described by Campbell and Todd (2). Since the present method includes what a t first sight appear t o be minor variations, but also since i t gives almost double the yield reported by Campbell and Todd, it is given in detail. [n order to secure satisfactory yields, it is vital that pure retene be used. Enough crude retene (m.p. 80-85") t o fill a 2-liter Claisen flask two-thirds full was melted and poured into such a flask. The retene was then distilled at 1 mm. pressure, the fraction boiling at 175-189" being collected. The solidified retene i n the receiver was melted and poured into 5.5 1. of alcohol contained in a 12-1. flask, and warmed until all the retene was in solution. After cooling, the retene was filtered off and dried in vacuo over calcium chloride for forty-eight hours. As so obtained, retene melts at 98" with preliminary softening at 96". It is vital that all traces of alcohol and moisture be removed from the retene for subsequent success in the Friedel-Crafts reaction. A 3-liter three-necked flask was equipped with a mercury sealed mechanical stirrer, a trap for hydrogen chloride, an internal thermometer, and a 500-ml. Erlenmeyer flask at2 The Survey Number, designated SN, identifies a drug in the records of the Survey of Antimalarial Drugs. The antinlalarial activities of those compounds to which Survey Numbers have been assigned will be tabulated i n a forthcoming monograph.
DIALKYLAMINOHYDROXYETHYLRETENES
255
tached by a short length of Gooch tubing. T o a solution of 250 g. (1.067 moles) of purified retene in 1200 ml. of dry nitrobenzene contained in the flask was added 150 ml. (2.134 moles) of acetyl chloride (distilled from dimethylaniline). The flask was then immersed in an ice-salt freezing-bath and the contents chilled t o -5". Anhydrous aluminum chloride (290 g.) was then added very gradually with stirring and cooling from the Erlenmeyer flask a t such a rate that the internal temperature did not exceed -5". The addition of the aluminum chloride required from 1.5 to 3 hours, depending on the efficiency of the coolingbath. When all of the aluminum chloride had been added, the mixture was stirred for an additional 5 hours at -5" and then allowed t o stand in the refrigerator at 5" for 40 hours. If the temperature is properly controlled, the reaction mixture is reddish-orange in color throughout the addition of the aluminum chloride and finally becomes bright orange. Otherwise, the color varies from dark brown to pitch black and the yield suffers accordingly. The mixture was then poured very slowly into a vigorously stirred mixture of 3200 g. of cracked ice and 500 ml. of hydrochloric acid (sp. gr. 1.19) at a temperature below 0". The hydrolysis must take place below 0"; otherwise, undesirable side reactions occur with sudden evolution of hydrogen chloride. Ice should always be present during the hydrolysis. Stirring was continued for another hour. After decanting most of the aqueous layer, the oily nitrobenzene layer, which varied in color in different experiments from orange t o dark brown, W&B steam distilled until the nitrobenzene waa completely removed. With a n efficient system, this distillation requires 5-6 hours. After cooling, the solidified crude acetylretene waa filtered off, air dried, and treated with decolorizing carbon in 1.5-2.5 1. of boiling ether. The filtered solution was concentrated t o about 700 ml. and on cooling deposited 200 g. of 3-acetylretene which meltedat 98-99". On concentration of the mother liquors, a second crop of 30-40 g. melting a t 96-98' was obtained. The yield of first crop material was 68% and the total yield was78-82%. Campbell and Todd (2) report 3-acetylretene melting at 99.5-100". 8-(8-Dialliylamino-l-hydrozyethyl)retenederivatives ( V ) . The synthesis of 3-(2-din-hexyl-1-hydroxyethy1)retenemay be taken as typical of the method used for the synthesis of the amino carbinols. A solution of 14 g. of 3-(~-bromoacetyl)retene(111) (3), and 14.6 g. of di-n-hexylamine in 400 ml. of anhydrous ether was shaken mechanically overnight. After chilling i n a n ice-bath, 10 g. of di-n-liexylamine hydrobromide was filtered off. The ether filtrate was washed three times with water and dried over anhydrous magnesium sulfate. On removal of the ether at the water-pump, the amino ketone remained as a thick syrup. This was reduced directly with 165 ml. of N-aluminum isopropoxide solution in dry isopropanol, the acetone formed during the reduction being driven off through a short Vigreux column. From time to time additional isopropanol was added t o the reaction flask so that the volume of the mixture wits substantially constant. Reduction was complete in 1.5 hours (negative test for acetone with 2,4-dinitrophenylhydrazinein the distillate). The isopropanol was removed from the reaction mixture a t the water-pump, and the dark residue was tvorked up with 250 ml. of ether until all soluble material had dissolved. The ether solution was washed with two 65-ml. portions of 10% sodium hydroxide solution, then with three 200-ml. portions of water, and finally dried over anhydrous sodium sulfate. T o the ether solution of the amino carbinol, a dilute ethereal solution of hydrogen chloride was carefully added until no further immediate precipitation occurred. After refrigerating overnight, 1.1 g. of di-n-hexylamine hydrochloride was filtered off. More ethereal hydrogen chloride was added to the filtrate until a distinct turbidity appeared. After refrigerating overnight, 8.8 g. of the amino carbinol hydrochloride had crystallized. This was recrystallized from dry ethyl acetate, yielding 6.8 g . or 34% of the carbinol hydrochloride. The melting points and analyses of this and the other carbinols prepared are shown in Table I. In the cases of some of the carbinols, i t was necessary t o subject the free bases to distillation in a molecular still at about 0.01 mm. pressure before salts could be obtained. I n one or two cases, preliminary purification over the picrates aided in securing crystalline salts.
256
DODD, JR., SCHFLAMM, A N D ELDERFIELD
As a general rule, the amino ketones were not purified but were reduced directly. However, i t was possible to secure analytically pure samples of two of them. 5-(w-Di-n-buty1aminoacetyl)retane picrate was obtained by fusing 0.5 g. of the crude oily ketone with 0.5 g. of picric acid on the steam-bath. On taking the melt up in hot alcohol and cooling, the picrate crystallized. After recrystallization from alcohol, it melted at 152452.5'. Anal. Calc'd for C ~ ~ H U I N ~C,O64.3; ~ : H, 6.3. Found : C, 64.6; H, 6.2. Despite the fact that the amino ketone could be satisfactorily purified in this manner, i t was not possible t o obtain a well-defined salt of the carbinol after reduction. 3-(w-Diethylaminoacetg1)retene hydrobromide. Dry hydrogen bromide gas was very carefully passed over the surface of a dry ether solution of the amino ketone. At first a light granular precipitate settled out. This soon changed t o an oil. The oily amino ketone hydrobromide readily cryrgtallized from ethyl acetate and melted at 163-164" after recrystallization from the same solvent. Anal. Calc'd for C2bHa0BrNOb: C, 67.3; H, 7.1. Found : C, 67.0; H, 7.0.
The microanalyses here reported were done by the Misses Frances Marx and Lois May. SUMMARY
Nine 3-(2dialkylamino-l-hydroxyethyl)retenederivatives have been prepared for examination as antimalarial drugs. Details of an improved procedure for preparing 3-acetylretene are given. NEWYORK27, N. Y.
REFERENCES (1) (2) (3) (4)
MAYAND MOSETTING, J. Org. Chem., 11,l (1946). CAMPBELL AND TODD, J. Am. ('hem. Soc., 62,1287 (1940). ADELSON AND BOGERT, J . Am. Chem. Soc., 69, 1776 (1937). L. F. SMALL,Private Communication.
