[CONTRIBUTION FROM
THE
DEPARTMENT O F CHEMISTRY
OF
COLUMBIA UNIVERSITY]
PROOF OF T H E POSITION OF T H E ACETYL GROUP IS CERTAIN 9-ACETYL-3-SUBSTITUTED RETENES. DIALKYLAMIKO CARBINOLS FROM 9-ACETYL-3-CHLORORETESE' ROBERT C. ELDERFIELD, THOMAS N. DODD, JR., AKD WALTER J. GENSLER Received November 16, 1946
In a previous communication, the synthesis of a number of representative retene-3-dialkylamino carbinols has been described (1). These substances showed a low order of antimalarial activity when tested against avian malaria (2). Since phenanthrene-9-amino carbinols, particularly certain of those carrying halogen substituents, with the amino carbinol group in the 9-position displayed a relatively high order of activity (3), it appeared to be of interest to explore analogous retene derivatives, in view of the potential availability of retene in practically unlimited amounts. Furthermore, a nuclear substituent can be readily introduced into the 3-position of retene through the easily prepared 3-acetyl retene, and with such a substituent present, a new acetyl group mould presumably enter either the 9- or 10-positions, thus opening up a series of drugs closely analogous to the more active phenanthrene types. At the same time, information would be obtained as to the influence of the position of the amino carbinol side chain on antimalarial activity in the retene series. Based on experience in the phenanthrene series (3), chlorine was selected as the substituent to be introduced in the 3-position of retene. Several references to the direct chlorination of retene appear in the literature, in most of which the isolation of no well defined product is reported. Karrman (4) has very recently reported the isolation of 9- (or 10-)-chlororetene in very small yield from the react,ion products of the chlorination of retene according to Komppa and Wahlforss (5). I n any event, little likelihood of success seemed probable if the introduction of the chlorine was attempted by direct chlorination. Therefore the chlorine atom was introduced by the series of reactions I-V proceeding from 3-acetylretene (I) in which the position of the acetyl group has been demonstrated by Campbell and Todd (6). 3-Acetaminoretene (111) has been prepared previously (7) in low yield by Beckmann rearrangement of the oxime (11). Application of the method of Bachmann and Boatner (8) to the rearrangement of the oxime (11) has resulted in greatly improved yields of 111. In this connection it is interesting to note that only the trans-form of the oxime (11) was encountered in the present work, as evidenced by complete rearrangement of 11. Bachmann and Boatner (8) obtained mixtures of cis- and trans-oximes in the formation of the four acetylphenanthrenes, namely, the 1-, 2-, 3-, and 9-derivatives, studied by them. Replacement of the amino group by halogen in phenanthrene derivatives has 1 The work described in this paper was done in part under a contract, recommended by the Committee on Medical Research, between the Office of Scientific Research andDevelopment and Columbia University. 393
394
R. C. ELDERFIELD, T. N. DODD, JR., AND W. J. GENSLER
I
I
CH3CO
CH3 C II
HON
I
CHsCOm
I1
NHz
I1t
IV
Cl
v
been reported by Bachmann and Boatner (9) and very recently by Schultz and co-workers (10). The former workers isolated the double salt of 1-,2-, and 3-phenanthrene diazonium derivatives with mercuric chloride, followed by decomposition of the latter in the presence of the appropriate potassium halide. The latter workers dealt exclusively with the 9-phenanthrene halides. By employing a modification of the usual Sandmeyer reaction i t has now been possible to prepare 3-chlororetene (V) in yields substantially higher than those reported heretofore for analogous phenanthrene compounds? Thus a monochlororetene of definite structure has been prepared for the first time. 3-Chlororetene (V) readily underwent the Friedel-Crafts reaction with acetic anhydride to yield 9-acetyl-3-chlororetene the structure of which was demonstrated as follows. Campbell, Soffer, and Steadman (11) report a similar reaction with 3-methoxy- or 3-acetoxy-retene, and assign either the 9- or 10-position to the acetyl group introduced, with the 9-position favored by analogy based on observations of Fieser and Young (12), in which a certain amount of steric hindrance relative to the 10-position is noted in certain coupling reactions of 1-alkylphenanthrenes. On the assumption that the chlorine iu V exerts the same orienting influence, or lack of it, as do the methoxyl and acetoxyl groups, the new acetyl group in (VI) may accordingly be assigned either the 9- or 10-positions. This assumption was proved by the formation of the same 3-chlororetenequinone (VII) on oxidation of either V or VI. The 10-position as the location of the
* Equally satisfactory results have been obtained in the preparation of 2- and 3- chlorophenanthrene by this method. Details of these experiments will appear elsewhere.
3 0O RETENE
395
DERIVATIVES
COCHa
C1 VI 0
0
I
c1 VI1 acetyl group in VI was definitely eliminated by the reaction shown in formulas VIII-XI.
CH3
I
wD C-NOH
-
c11
- CH(CHS)2
VI11
-
NH2 @ a C H ( C E *)2
cI1
IX N H 2
&CH -
-
(CH3)z
X
OH
T
XI On Beckmann rearrangement of the oxime of VI (VIII), 3-chloro-9-acetaminoretene was obtained, which on hydrolysis readily yielded 3-chloro-9-aminoretene (IX). Catalytic removal of the chlorine in IX gave 9-aminoretene (X). X was also prepared by the Bucherer reaction from 9-retenol (XI) which has been synthesized by Fieser and Young (12). Samples of X prepared by either
396
R. C. ELDERFIELD, T. N . DODD, JR., AND W. J. GENSLER
route were identical, as were the hydrochlorides and acetyl derivatives of the substance prepared in the two ways. Since the structure of 9-methoxyretene has been rigidly established by its total synthesis by Keimatsu, Ishiguro, and Sumi (13), i t follows that the structure assigned to 9-retenol by Fieser and Young on the basis of steric considerations is correct, and further, that the acetyl group in VI is in the 9-position. In an alternate scheme for carrying out the above correlation, conversion of IX to 3-chloro-9-hydroxyreteneover the diazonium reaction was attempted. Difficulty was encountered in carrying out the diazotization, possibly due to the extreme insolubility of salts of IX in water. In one experiment 3-chlororetenequinone was isolated from the reaction products. Likewise an attempt was made to reduce 3-chlororetenequinone to 3-chloro-9acetoxyretene by the procedure of Fieser and Young (12) for the similar reduction of retenequinone. Only 3-chloro-9 ,10-diacetoxyretene could be isolated from the reaction products. Finally, in order to furnish confirmatory evidence in support of Campbell, Soff er, and Steadman's view that 3-methoxy- and 3-acetoxy-retene acylate probably in the 9-position in the Freidel-Crafts reaction, 3-acetaminoretene (111)was subjected to acetylation with acetic anhydride. The product, 3-acetamino-9-acetylretene in turn was hydrolyzed to 3-amino-9-acetylretene from which 3-chloro-9-acetylretene (VI) and 9-acetyl-3-retenol (XII) were prepared by the diazonium reaction. COCH3 CH3
IT1
---f
CO CH3
&0 CH3
I
-\
&'aCH(C€€3)z
I
-+
CH (CHA2
NH2
CH3 CONH CO CH3
CO CH3 CH (CH3)
I
c1
OH VI
XI1
The sample of VI thus prepared was identical with VI prepared by acetylation of 3-chlororetene, the structure of which has been demonstrated above. Likewise the sample of XI1 mas identical with a sample of XI1 prepared by the method of Campbell, Soffer, and Steadman. Therefore the fact that 3-acetoxy- and 3-methoxy-retene acetylate in the 9-position in the Friedel-Crafts reaction has been rigidly proved. The generalization therefore appears warranted, that if an ortho, para orienting group is present in the 3-position in retene, introduction of an acyl group by the Friedel-Crafts reaction takes place in the 9-position.
3 0O RETENE
397
DERIVATIVES
Before arriving a t the above satisfactory synthesis for 3-aminoretene, preparation of this was undertaken by the reactions shown below.
I
CH, CO
COOH
I
XI11
R
CONHz
XIV
IV R = N H 2 XV R = CN
Retene-3-carboxylic acid (XIII) (5, 14) and its amide (XIV) ( 5 ) have been prepared by methods more convenient than those heretofore described. Attempted conversion of XIV to the amine IV, failed despite the use of a variety of conditions. XIV was however converted smoothly to the nitrile, (XV) which in turn failed to undergo the Friedel-Crafts reaction. The synthesis of representative dialkylamino carbinols (XVI) from VI proceeded readily using the general methods employed in the preparation of the retene-3-amino carbinols (1). Of these the di-n-amyl derivative (XVI, R = nC&l) was found to have a quinacrine equivalent of 4 when tested against gallinaceum malaria (15). A higher avian activity than that of the retene-3amino carbinols has thus been achieved.
wD
CHOHCHzNRz
-
- cH
cI1
XVI EXPERIMENTAL3
3-Acetaminoretene (IIZ). This has been prepared in 35% yield by Cassaday and Bogert (7). The method of Bachmann and Boatner (8) for the synthesis of 3-aminophenanthrene here used gives much higher yields. To a stirred suspension of 136 g. of the oxime (16) of 3-acetylretene (1) in 1500 ml. of dry benzene cooled in a n ice-bath was added during two minutes 107 g. of phosphorus pentachloride. The mixture was left in the ice-bath for fifteen minutes and then allowed t o stand a t room temperature for three hours, during which the solid dissolved practically completely. On pouring into 1500 ml. of ice and water and
* All melting points are corrected except where otherwise stated.
Lois May of these laboratories.
Microanalyses by Miss
398
R. C. ELDERFIELD, T. N. DODD, JR., AND W. J. GENSLER
stirring for two hours the acetamino compound separated as a very fmely divided yellow solid. After filtering and washing with dilute alcohol, 122 g. (90%) of material melting a t 238.5-240.5' was obtained. A sample recrystallized from a large volume of alcohol melted at 241-241.5'. Cassaday and Bogert (7) report 240-241". 8-Aminoretene (IV). A mixture of 121 g. of crude 3-acetaminoretene7 1750 ml. of alcohol and 180 ml. of hydrochloric acid (sp. gr. 1.19) was heated under reflux for six hours, during which the solid dissolved. This was treated with carbon, and excess ammonia was carefully added to the hot solution. The aminoretene hydrochloride crystallizes if its solution is allowed to cool. The ammoniacal solution was poured into 2.5 1. of ice-water whereupon 93 g. (90%) of crude 3-aminoretene separated. This was used directly for the next reaction. Cassaday and Bogert (7) prepared 3-aminoretene by alkaline hydrolysis of the acetamino compound. S-Chlororetene ( V ) . For the Sandmeyer reaction on 3-aminoretene, either the free base or the hydrochloride may be used, but use of the latter has been found to result in purer 3-chlororetene. A warm solution of 93 g. of 3-aminoretene in 1500 ml. of dry ether was carefully cooled in an ice-bath so as to maintain a supersaturated solution. Dry hydrogen chloride was then carefully passed over the solution until precipitation of the hydrochloride was complete. The yield of material melting with decomposition a t 269-275" was theoretical. Cassaday and Bogert (7) report the melting point as 267-273" dec. A solution of 150 g. of 3-aminoretene hydrochloride in 2500 ml. of glacial acetic acid and 1050 ml. of hydrochloric acid (sp.gr. 1.19) was cooled to -3" in a 5-liter three-necked flaek equipped with an efficient mechanical stirrer, thermometer, dropping-funnel, and gas outlet tube. To this was added a solution of 105 g. of sodium nitrite in 195 ml. of water with stirring during one hour a t such a rate that the inside temperature did not exceed 0". Strong external cooling was necessary. The red-orange solution was stirred a t 0" for a n additional three hours. A solution of 90 g. of urea in 250 ml. of water was added during one hour while the inside temperature was kept below 3", and the solution was stirred for another thirty minutes at 3". Meanwhile a solution of cuprous chloride was prepared by adding a hot solution of 113 g. of sodium bisulfite and 78 g. of sodium hydroxide in 900 ml. of water to a boiling solution of 525 g. of copper sulfate pentahydrate and 143 g. of sodium chloride in 1800 ml. of water. After cooling, the cuprous chloride was filtered and washed with water. It was then disTo this was added solved in 1050 ml. of hydrochloric acid (sp.gr. 1.19) and cooled t o -5'. the cold diazonium solution with stirring during one minute. Very little heat was evolved. The mixture was left overnight at room temperature, then stirred for five hours and the tan solid (143 g.) was filtered and washed thoroughly with water. This was dissolved in 1200 ml. of ether and treated with decolorizing carbon. The light amber solution was concentrated to a quarter of its volume and 1200 ml. of methanol was added. Crystallization of the chlororetene as yellow-tan cubes was rapid. After recrystallization from the same solvents the material melted at 108-109'. All the mother liquors were combined, evaporated and the residue distilled a t 0.01 mm., collecting the fraction boiling a t 155-165". This was recrystallized as before, yielding further pure material. The total yield was 104 g. (74%). d n a l . Calc'd for CIIH1,Cl: C, 80.4; H, 6.4. Found: C, S0.5; H , 6.4. S-Chloro-9-acetylretenc ( V I ) . To a solution of 91 g. of 3-chlororetene in 900 ml. of dry nitrobenzene contained in a flask equipped with a n efficient mechanical stirrer, thermometer, aluminum chloride addition tube, and a gas outlet tube was added 40 ml. of acetic anhydride. After cooling to 3", at which temperature the nitrobenzene began to freeze, 113 g. of anhydrous aluminum chloride was added with stirring during one and one-half hours and the inside temperature was lowered to -1". The mixture was protected from moisture and stirred for a n additional two hours a t -1" and then allowed to stand at room temperature overnight. After stirring for three hours a t room temperature, i t was cooled to 0", stirred for another hour and the solid was filtered off. The complex was washed at 0' with petroleum ether until free of nitrobenzene. The light orange solid was broken up and
3 ,%RETENE
DERIVATIVES
399
added to a stirred mixture of 600 g. of ice and 200 ml. of hydrochloric acid (sp.gr. 1.19). After thirty minutes the cream colored precipitate was extracted with several portions of chloroform. The combined extracts were washed with sodium bicarbonate solution, dried, and the solvent removed, leaving a n amber oil which solidified rapidly. This was dissolved in 225 ml. of hot ether and on cooling 37 g. of long white needles separated. The mother liquors were treated with carbon, evaporated and the residue was crystallized from alcohol using seeds from the first crop, and a second crop of material was obtained. After recrystallization from alcohol the substance melted a t 114'. The yield was 48 g. (46%). Anal. Calc'd for CeoHl&lO: C, 77.3; H, 6.2. Found: C, 77.3; H, 6.2. 3-Chloro-9-acetylretene oxime. When 3-chloro-9-acetylretene (7 g.) was refluxed with 4 g. of hydroxylamine hydrochloride in 100 ml. of alcohol for three hours and the solution evaporated to 55 ml. and cooled, 7 g. of oxime was obtained. One recrystallization from alcohol yielded a mixture of the cis- and trans-oximes as non-homogeneous needles which melted a t 159.5-162.5". Further separation of the isomers was not attempted. 8-ChZororeteneqwinone ( V U ) . A . From 3-chlororetene. The general method of Komppa and Wahlforss (5) was used. To a warm solution of 1.1 g. of 3-chlororetene in 3.5 ml. of glacial acetic acid was added a solution of 1.9 g. of chromic acid in 10ml. of acetic acid during five minutes. After refluxing for ten minutes, the mixture was cooled and the solid which separated was filtered off and washed with water. Two recrystallizations from 150 ml. of methanol gave 0.35 g. of yellow-orange needles melting a t 210-210.5". Anal. Calc'd for ClsH&lO~: C, 72.3; H, 5.1. Found: C, 72.1; H, 5.1. 9-Chloioretophenazine. To a suspension of the above quinone (0.1 g.) in 4 ml. of hot glacial acetic acid was added a solution of 0.13 g. of o-phenylenediamine dihydrochloride and 0.1 g. of fused sodium acetate in the minimum amount of 70% alcohol. After refluxing for ten minutes the mixture was cooled and the precipitate was recrystallized from glacial acetic acid yielding the phenazine as pale yellow needles melting a t 179.5-180.5'. Anal. Calc'd for C24Hl&lNs: C, 77.8; H, 5.2. Found: C, 77.7; H, 5.1. B . From 3-chloro-9-acetylretene. The general method of Fieser and Young (12) was used. To a solution of 0.5 g. of 3-chloro-9-acetylretene in 1.4 ml. of warm glacial acetic acid was added a solution of 0.75 g. of chromic acid in 4 ml. of glacial acetic acid during five minutes. The mixture was refluxed for ten minutes, hot water was added, and, after cooling, the solid (0.24 9.)was filtered off and dissolved in hot alcohol, and 10 ml. of a hot saturated solution of sodium bisulfite was added. Suscient water was added to dissolve precipitated sodium bisulfite. The solution was filtered and acidified with hydrochloric acid. On warming, 3-chlororctenequinone crystallized. After recrystallization from methanol, it melted at 210- 210.5" and did not depress the melting point of 3-chlororetenequinone prepared from 3-chlororetene. The phenazine prepared from the above quinone melted a t 176.5177.5" and did not depress the melting point of the phenazine prepared previously. 3-Chloro-9,lO-diacetoxyretene. T o a suspension of 0.2 g. of 3-chiororetene quinone in 1.4 ml. of hot glacial acetic acid, 0.08 g. of zinc dust was slowly added and the mixture was boiled for thirty minutes. The initial orange mixture became very dark and then began to lighten in color. At fifteen-minute intervals four additional 0.06-g. portions of zinc dust mere added to the boilingsolution. -4solution of 0.3 g. of fused sodium acetate in4.5ml. of aceticanhydride was added to the mixture which was then refluxed for one hour. After cooling, the solution was decanted from unreacted zinc into 40 ml. of cold water. After boiling to decompose the acetic anhydride, a mixture of 3-chloro-9,lO-diacetoxyreteneand 3-chloro-9-acetoxyreteneseparated. After several recrystallizations from ether, the dincetoxy compound formed fluffy needles which melted a t 212-213". A n a l . Calc'd for C22H21C104: C , 68.7; 11, 5.5. Found: C, 68.8; H, 5.5.
400
R. C. ELDERFIELD, T. N. DODD, JR., AND W. J . GENSLER
The ether mother liquors contained 3-chloro-9-acetoxyreteneby analogy with the work of Fieser and Young (12) on 9-acetoxyretene, whose method was followed closely. This point was not investigated. 9-Aminoretene ( X ). 9-Acetoxyretene was prepared by reduction of retenequinone according t o Fieser and Young (12), except that the crude product was crystallized directly from a large volume of methanol, rather than subjecting i t to distillation. Hydrolysis of the acetoxyl group gave 9-retenol (12). A mixture of 5.5 g. of 9-retenol, 27.5 g. of a well stirred suspension of ammonium sulfite, prepared by passing sulfur dioxide into 19.5 ml. of ammonium hydroxide cooled in a n ice-bath until the weight increased 8 g., and 27.5 ml. of ammonium hydroxide (d. 0.9) was heated in a sealed tube for twenty-five hours a t 140". The cooled contents of the tube were extracted with ether, and the extract was washed with 5% sodium hydroxide solution, then with water, and dried over magnesium sulfate. Dry hydrogen chloride was carefully passed over the surface of the solution until no more precipitate was formed, yielding 3.5 g. (56%) of 9-aminoretene hydrochloride melting at 245248". The mother liquors were evaporated to dryness and the residue was recrystallized. from xylene (charcoal) yielding 2.3 g. (42%) of recovered g-retenol melting at 179-180. Decomposition of the amine hydrochloride by shaking with ether and 5% sodium hydroxide gave the free amine, which formed clusters of fluffy needles, melting a t 131.5132.5", after recrystallization from ether-petroleum ether. Anal. Calc'd for ClSHloN: C,86.7; H , 7.7. Found: C, 86.8; H, 7.5. 9-Acetaminoretene. The above amine (0.3 9.) was acetylated by refluxing with 6 ml. of acetic anhydride for ten minutes. After decomposition of the excess anhydride, the acetamino compound was recrystallized from ethyl acetate as white needles which melted at 210.5-21 1 A n d . Calc'd for CzoHzlSO: C, 82.4; H, 7.3. Found: C, 82.2; H, 7.2. 3-Chloro-9-acetaminoretene. T o a cooled suspension of 5.5 g . of crude 3-chloro-9-acetylretene oxime, prepared as above, in 90 ml. of dry benzene, 5.5 g. of phosphorus pentachloride was added. The mixture was boiled for fifteen minutes and the clear yellow solution was evaporated to about 45 ml. On pouring into 150 ml. of ice and water a finely divided solid separated. This was filtered off and washed thoroughly with water, yielding 4 g. of material melting at 233-235" with sintering a t 220". This probably contained some amide from the cis-oxime and was used directly in the next reaction. Pure material was, however, obtained by acetylation of 3-chloro-9-aniinoretene prepared as below. After recrystallization from ethyl acetate i t formed silky white needles which melted at 242 3-243'. Anal. Calc'd for CZoH2oClNO: C, 73.8; H, 6.2. Found: C, 73.9; H , 6.2. 8-Chloro-9-aminoretene ( I X ). A mixture of 4 g. of crude 3-chloro-Q-acetaminoretene, 225 ml. of alcohol, and 10 ml. of hydrochloric acid (sp.gr. 1.19) was refluxed for five hours. To the hot solution 13 ml. of ammonium hydroxide (d. 0.9) was carefully added. The residue obtained on evaporation to dryness was thoroughly extracted with ether and the combined ether extracts decolorized with carbon, Dry hydrogen chloride was carefully passed over the surface of the solution, and 2.5 g. of amine hydrochloride separated as white needles. After one recrystallization from alcohol, the amine hydrochloride, melting at 239242.5", was dissolved in the minimum amount of hot alcohol, and hot water was added t o the stirred solution until no more crystals separated. On cooling, a practially theoretical yield of the base separated. After recrystallization from ether it formed colorless small squares which melted a t 158.5-159.5". AnaE. Calc'd for ClsHtsClS: C, 76.2; H, 6.4. Found: C, 76.0; H, 6.3. Reduction of 3-chloro-9-aminoretene. A suspension of 0.5 g. of palladium on calcium carbonate catalyst (17) containing 10 mg. of palladium, in 40 ml. of alcohol was shaken in a O.
3 0O RETENE
DERIVATIVES
401
Paal duck with hydrogen at atmospheric pressure until saturated. To this was added 0.1 g. of 3-chloro-9-aminoretene through a n addition tube without opening the duck. After one and one-half hours, one equivalent of hydrogen had been absorbed and reduction ceased. The filtrate from the catalyst was evaporated to dryness yielding 9-aminoretene, which was isolated and purified as the hydrochloride. The melting points of the free amine, its hydrochloride, and the acetamino derivative agreed with those for the corresponding derivatives prepared as above from 9-retenol, and the melting points of mixtures of the three compounds prepared by the two methods were not depressed. 9-Acetamino-Q-ucetylrete~e. T o a well stirred paste of 84 g. of 3-acetaminoretene in 800 ml. of dry carbon bisulfide and 54 ml. of acetic anhydride a t room temperature, in a 3-liter flask equipped with a n efficient stirrer, reflux condenser, inside thermometer, and a n addition tube for addition of solids, 154 g. of anhydrous aluminum chloride was added over twenty minutes, during which the mixture warmed up to 40". It was then refluxed for two hours. The condenser was set downward for distillation and a liter separatory funnel was connected to the flask. Water (loo0 ml.) was added dropwise to the stirred solution, the heat of hydrolysis causing distillation of the solvent. The aqueous suspension was heated for an additional hour on the steam-bath, cooled, and filtered, yielding 75 g. of crude product. This was treated with charcoal in a large volume of acetone, yielding 3-acetaminog-acetylretene as lustrous white needles melting a t 265.5-266.5'. After working u p the mother liquors, the total yield was 62 g. (65'%). A n a l . Calc'd for C22HlaN02: C , 79.3; H, 7.0. Found: C, 79.3; H, 7.0. 3-Amino-9-acetyhetene. The above acetamino compound (1.5 g.) was refluxed with 4 ml. of hydrochloric acid (sp.gr. 1.19) and 30 ml. of alcohol for five hours. After making the solution ammoniacal, i t was worked u p as in the previous case by evaporation to dryness and extraction of the residue with ether. Passage of dry hydrogen chloride over the ether solution of the base precipitated 1.2 g. of amine hydrochloride, which charred without melting a t 216". The hydrochloride was decomposed as in the preceding ease by precipitation of its hot alcoholic solution with hot water. The amine formed pale yellow, long, thin needles which melted a t 17-1.5-175.5". N O82.4; : H, 7.3. Anal. Calc'd for C ~ O H ~ ~ C, Found: C, 82.3; H, 7.2. 9-Acetyl-3-retenol ( X I I ). A crude sample of 9-acetyl-3-reteno14 prepared by acetylation of 3-acetoxyretene and hydrolysis of the product according t o the method of Campbell, Sofier, and Steadman (11) was recrystallized from methanol; needles melting a t 249.5250 5". Campbell, Soffer, and Steadman (11) report the melting point as 247-248" but did not analyze their sample. Anal. Calc'd for C20H2002: C, 82.2; H, 6.9. Found: C, 82.0; H, 6.9. ,Y-Acetyl-b-retenol f r o m 3-amino-9-acetylretene. 9-Acetyl-3-aminoretene (50 mg.) was ground up with 3.7 ml. of 0.1 N hydrochloric acid. T o the ice-cold stirred suspension was added during thirty seconds a solution of 14 mg. of sodium nitrite in 1ml. of water. After stirring for five minutes, the solution was filtered from a small amount of insoluble material and warmed on the steam-bath. When nitrogen evolution ceased, the mixture was cooled, and the pinkish flocculent crystals were recrystallized three times from methanol with one treatment with carbon, The phenol formed fluffy needles which melted a t 249.5-250.5", and the melting point was not depressed on admixture with an authentic sample of 9-acetyl3-ret enol. ilcetylation of the above phenol by refluxing with acetic anhydride for ten minutes yielded 3-acetoxy-9-acetylreteneas white plates which melted a t 169-170". The mixed melting point with a n authentic sample was not depressed. Campbell, Soffer, and Steadman (11) prepared what they considered either 9- or 10-acetyl-3-acetoxyreteneby applica4
Courtesy of Dr. Chester €3. Kremer of these laboratories.
402
R. C. ELDERFIELD, T. N. DODD. JR., AND W. J. GENSLER
tion of the Friedel-Crafts reaction to 3-acetoxyretene. The melting point reported by them is 169-170". 8-Chloro-9-acetylretenefrom 8-amino-O-acetylretene. To a n ice-cold solution of diazotized 3-amino-9-acetylretene prepared from 50 mg. of the amine as above was added 1 ml. of a n ice-cold cuprous chloride solution prepared as described under the synthesis of 3-chlororetene. After allowing the mixture t o come to room temperature it was stirred for four hours. The solid material which separated was collected, dissolved in ether, and the filtered solution was evaporated, leaving a rapidly crystallitiing oil. After two recrystallizations from alcohol, white needles melting a t 113-114" were obtained. The mixed melting point with a sample prepared from 3-chlororetene as given above was not depressed. Retene-$-carboxylic acid ( X I I I ) A solution of sodium hypochlorite prepared by passing 58 g. of chlorine into a solution of 80 g. of sodium hydroxide in 110 ml. of water and 450 g. of ice, was placed in a 3-liter flask equipped with a stirrer and thermometer and mounted on a steam-bath, in such a manner than an ice-bath could be quicklysubstituted,and warmed to 60". T o this stirred solution was added 50 g. of 3-acetylretene (1) and the mixture was warmed to 65". No apparent reaction took place. The steam-bath was removed and 250 ml. of dioxane was added. After a few seconds the temperature began t o rise rapidly, the ice-bath was quickly applied and the temperature was held at 70-75". The solid dissolved rapidly and the reaction was over in five minutes. The stirred mixture was allowed to cool to room temperature, during which the sodium salt of the acid precipitated. Excess chlorine was removed by addition of sodium bisulfite (5-10 g.) and the mixture was acidified with hydrochloric acid. On cooling, 51 g. (100%) of retene-3-carboxylic acid separated. The crude acid melted at 231-234". Adelson and Bogert (14a), who prepared the acid from 3-acetylretene using sodium hypoiodite, report the melting point 238-238.5". Retene-3-carboxylic acid amide ( X I V ) . T o a suspension of 52 g. of the above acid in 125 ml. of ether was added 54.5 ml. of pure thionyl chloride. No violent reaction occurred. After standing for twenty-four hours protected from moisture, the mixture was concentrated to dryness under reduced pressure a t room temperature. To the tan crystalline residue, 350 ml. of benzene was added followed by 250 g. of ice and 100 ml. of ammonium hydroxide (d. 0.9) slowly and with stirring. The white flocculent amide weighed52 g. (100%) and melted at 229-232'. Komppa and Wahlforss (5) report the melting point of the amide as 224-226" (uncorr.) . $-Cyanoretene ( X V ) . An intimately ground mixture of 2 g. of the above amide and 3 g. of phosphorus pentachloride was heated on the steam-bath with protection frommoisture for one and one-half hours. The hard residue was broken up, 100 ml. of water was added, and the solid was collected and washed with water. After recrystallization from alcohol The yield was practically the nitrile formed fluffy needles which melted at 155.5-156'. quantitative. A n a l . Calc'd for CIBHIIN: C, 88.1; H, 6.6. Found: C, 87.7; H, 6.6. $-Chloro-9-(w-bromoacetyZ)retene.To a solution of 48 g. of 3-chloro-9-acetylretene in 1 liter of refluxing ether was added dropwise with stirring over a period of two hours a solution of 24.2 g. of bromine in 175 ml. of carbon tetrachloride. Heat was withdrawn and the solution was stirred for a n additional hour. It was then allowed to stand overnight protected from light and moisture. After washing with water, dilute sodium bicarbonate solution, and again with water, the organic solution was dried with magnesium sulfate and concentrated to about 1100 ml. On cooling in a n ice-bath 6 g. of white crystals separated (Fraction A) which melted a t 125-138". The filtrate was concentrated to 850 nil., and on chilling in a n ice-bath yielded 2 g. of material melting a t 106-132". By successive evaporations, finally to dryness, other fractions were obtained which melted variously from 7%93O. All such fractions were separately fractionally recrystallized from ether, yielding a main fraction (32 g . ) , after removal of three sparingly soluble fractions, which melted a t 8688". Concentration of the mother liquors from this yielded a second main fraction (6 9.) melting a t 88-87". Recrystallization of the above two main fractions from niethanol gave 35 g. of the monobromo derivative which melted at 88-89".
.
3 ,I)-RETENE
DERIVATIVES
403
Anal. Calc'd for Cd318BrC10: C, 61.6; H, 4.7. Found: C, 61.5;H I 4.7. Faction A above was recrystallized thrice from ether and gave a substance melting at 168-173'. A further recrystallization from methanol gave material melting at 174r178O t o a milky melt. Presumably this is largely the w-dibromo derivative. Anal. Calc'dfor CnoHrrBrzC10: Total halogen: 41.7. Found: Total halogen 38.9. 9-Chloro-9-(di-n-amylaminomethyl)retene methanol. To a solution of 15.1 g. of di-namylamine in 100 ml. of anhydrous ether was added a solution of 18.7 g. of 3-chloro-9-(wbromoacety1)retene in 500 ml. of anhydrous ether. Dry nitrogen was passed through the solution to remove atmospheric oxygen and the stoppered container was left overnight at room temperature protected from light. After filtering off the precipitated diamylamine hydrobromide, dry hydrogen chloride was carefully passed over the surface of the chilled solution. The amino ketone hydrochloride separated as a white solid. It is important t o avoid an excess of hydrogen chloride, as this causes the product t o separate as an oil, rerefractory to crystallization. The hydrochloride formed plates melting at 193.5-195" on recrystallization from alcohol. It was not purified further for the next step. The yield was 15 g. (62%). The above amino ketone hydrochloride (15 g.) was placed in a flask equipped with a n eight-inch Vigreux column together with 50 ml. of dry isopropanol and 40 ml. of 3 Nsolution of aluminum isopropoxide in isopropanol. The mixture was heated i n a n atmosphere of dry nitrogen, and the acetone formed was distilled off from the steam-bath. Additional dry isopropanol was added occasionally to maintain the volume of the mixture. When the acetone was all removed (negative test with 2,4-dinitrophenylhydrazinein the distillate), the isopropanol was carefully removed under reduced pressure. The residual t a n fluffy mass was dissolved in warm ether and washed n i t h 2% sodium hydroxide solution and then with water. Crystallization of the amino carbinol hydrochloride was difficult. T o a small chilled aliquot of the dried ether solution was added one-third of a n equivalent of standard ethereal hydrogen chloride (based on a n assumed 10070 yield). Evaporation of the solvent yielded a n oil which was dis3olved in hot ethyl acetate. Careful addition of ligroin followed by ishilling and scratching produced seed crystals. This procedure was repeated with the main batch to which the seed crystals had been added, evcept tliat one equivalent of hydrogen chloride n-as used. Recrystallization of the crude product from ethyl acetate-ligroin gave 12 g (bOyc',lof the *.mino carbinol hydrochloride as white cubes melting at 162.5163.5". A n d . Calc'd for C8&~C12h%: c, 71.4;11, 8.7. Found: C, 71.1; H, 8.6. J-Chloro-Q-(-dzethyln"methyl)retene methanol. This was prepared as was the above compound. Seed crystals were obtained directly from the ether test solution without use of ethyl acetate. The main batch crystallized from ethyl acetate-ligroin as white needles melting a t 192.5-193.5". The yield nras 3070. d n a ? . Calc'd for CzJ181C12RO: C, 68.6; H I 7.4. Found: C, 68.4;H, 7.6. YEW YORK27, K.Y .
REFERENCES (1) DODD, SCHRAMM, AND ELDERFIELD, J . Org. Chem., 11, 253 (1946). (2) "Antimalarial Drugs 1941-1946", Edwards Brothers, Ann Arbor, Xlich., 1946. (3) L. F. S x m L , private communication. (4) KARRMAN, Svensk Kem. Tid.,66, 195 (1944);Chem. Abstr., 40, 4052 (1946). AND WAHLFORSS, J . Am. Chem. SOC.,62, 5009 (1930). (5) KOMPPA (6) CAMPBELL AND TODD, J . Am. Chem. SOC., 62,1287 (1940). (7) C.4SSADAY A S D BOGERT,J. ATrL. Chem. S O C . , 63, 703 (1911).
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R. C. ELDERFIELD, T. N . DODD, JR., AND W. J. GENSLER
BACHMANN AND BOATNER, J . A m . Chem. SOC.,68, 2097 (1936). BACHMANN AND BOATNER, J . A m . Chem. SOC.,68, 2194 (1936). SCHULTZ et al., J . Org. Chem., 11, 307 (1946). AND STEADMAN, J . A m . Chem. SOC.,64,425 (1942). CAMPBELL, SOFFER, FIESERAND YOUXG, J . A m . Chem. SOC.,63, 4120 (1931). KEIMATSU, ISHIGURO, AND SUMI,J . Pharm. SOC.Japan, 66,588 (1936). (a) ADELSON AND BOGERT, J . A m . Chem. SOC.,68, 653 (1936); (b) 69, 1776 (1937); (c) BOGERT AND HASSELSTROM, Proc. Nat. Acad. S c i . , 18,417 (1932). (15) COATNEY AND COOPER, unpublished results. (16) BOGERT AND HASSELSTROM, J . A m . Chem. SOC.,63, 3462 (1931). (17) BUSCHAND STOVE,Ber., 49, 1063 (1916).
(8) (9) (10) (11) (12) (13) (14)
