[CONTRIBUTION FROM
THE
DEPARTMENT OF CHEMISTRY OF COLUMBIA UNIVERSITY]
7-METHOXY-%ACETYL- AND 7-METHOXY-g-ACETYL-1,2,3,4-TETRAHYDROPHENANTMRENE AND AMINO CARBINOLS DERIVED 'FROM THEM' JOHN M. GRIFFIXG
AND
ROBERT C. ELDERFIELD
Received June 6 , 1945
Since dialkylamino carbinols derived from 1,2,3,4-tetrahydrophenanthrene have been shown to possess distinct antimalarial activity against avian malaria, it became of importance to study the effect of nuclear substituents on this activit,y. The present paper records tbe results of an investigation of the synthesis of certain methoxytetrahydrophenanthrene derivatives which was undertaken as part of a broad general program in collaboration with the Kational Institute of Health. A study of the synthesis of 7-methoxytetrahydrophenanthrene according to the methods used by Hill, Short, and Higginbottom (1) to synthesize 7methoxy-8-methyltetrahydrophenanthreneand by Short, Stromberg, and Wiles (2) to synthesize 1-methyl-7-methoxytetrahydrophenanthrenewas carried out. However, this method, utilizing in the first step the requisite naphthalene nucleus in a condensation with succinic anhydride under the conditions of a Friedel-Crafts reaction, proved to be impractical after a very thorough study carried out independently from the present work (3). Therefore, the direct introduction of substituents into the tetrahydrophenanthrene molecule has been investigated. Previous work by Bachmann and Cronyn (4) had shown that the direct halogenation of tetrahydrophenanthrene results in the formation of the 9halogeno derivatives, which are obviously of no use in so far as the present objective is concerned. Of possible use for the introduction of a substituent in the 7-position is the 7-aminotetrahydrophenanthrenedescribed by Bachmann and Cronyn (4), which was obtained by Beckmann rearrangement of the oxime of 7-acetyltetrahydrophenanthrene followed by hydrolysis of the resulting acetamino derivative. However, in the 'Friedel-Crafts reaction between tetrahydrophenanthrene and either acetyl chloride or acetic anhydride, the 7acetyl derivative constitutes but a minor part of the total reaction product, and its separation from the larger amount of 9-acetyl derivative, which is the major product, requires a long and t,edious fractional crystallization. No reference occurs in the literature to the direct sulfonation of tetrahydrophenanthrene, and since the sulfonic acid group can be readily converted to a variety of other groups, this approach appeared to be worthy of study. As a dialkyl naphthalene derivative, tetrahydrophenanthrene on sulfonation could be expected to lead to a series of sulfonic acids: the 6-, 7-, or 10-sulfonic acid by 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 Columbia University. 123
124
J. M. GRJFFINQ AND R. C. ELDERFIELD
sulfonation in one of the P-positions, or the 5-, 8-, or 9-sulfonic acid by sulfonation in one of the a-positions, depending on the temperature a t which the sulfonation is carried out. When tetrahydrophenanthrene was sulfonated under experimental conditions which mould be expected to lead to the p-sulfonic acid ( 5 ) , a good yield of tetrahydrophenanihrene-7-sulfonic acid (11) m-as obtained. The position of the sulfonic acid group was demonstrated by conversion of the sodium salt to the phenol, 7-hydroxytetrahydrophenanthrene (111) by fusion with potassium hydroxide. Methylation of I11 with dimethylsulfate yielded 7-methoxytetrahydrophenanthrene (IV), which mas then dehydrogenated with selenium t o 2-methoxyphenanthrene (V), The low temperature sulfonation of tetrahydrophenanthrene mas not successful despite the use of a number of experimental conditions in which the temperature, strength of sulfuric acid, and time of reaction was varied. Likewise the use of a variety of salts for the isolation of the reaction product led to no uniform material. With the successful preparation of 7-hydroxy- and 7-methoxytetrahydrophenanthrene in reasonably good yield, the route to the desired final derivatives, N,N-dialkylamino carbinols of the general type shown in XXII containing nuclear substituents was open. In the present paper the synthesis of representative members of two series of such amino carbinols derived from 7-methoxytetrahydrophenanthrene is described. Other nuclear substituted amino carbinols will be described in another communication ( 6 ) . When 7-methoxytetrahydrophenanthreneis treated with either acetyl chloride or acetic anhydride under the conditions of the Friedel-Crafts reaction, a mixture of 7-methoxy-8-acetyltetrahydrophenanthrene(VI) and 7-methoxv-9-acetyltetrahydrophenanthrene (VII) results. These can be separated by fractional crystallization, although it was found more convenient to prepare both acetyl derivatives as indicated belon-. Changing the solvent in which the reaction was carried out and other conditions did not appear to affect markedly the proportions of isomers obtained. For the preparation of the 9-acetyl derivative, it was found that if the FriedelCrafts reaction is carried out on 7-acetoxytetrahydrophenanthrene,only 7-acetoxy-9-acetyltetrahydropherianthrene (VIII) results. Hydrolysis of the acetoxy group in VI11 followed by methylation of IX gives VI1 in good yield. Likewise, it proved to be more conrenient to prepare VI by Fries rearrangement of 7acetoxytetrahydrophenanthrene (XVIII), follov-ed by methylation of 7-hydroxy-8-acetyltetrahydropheiianthrene (XIX). The position of the acetyl group in VI was established by reduction of VI to oily 7-methoxy-S-ethyltetrahydrophenanthrene(X) by the Clemmensen method. X has been described as an oil by Miyasaka and Nomura (7), who prepared no solid derivatives. In order to place the ethyl group in X definitely, it was dehydrogenated to l-ethyl-2-methoxyphenanthrene (XI). This was identical with an authentic sample. Alternate unsuccessful methods to place the acetyl group in VI involved application of the Gattermitnn reaction to 7-hydroxytetrahydrophenanthrene
125
TETRAHYDROPHENANTHRENE AMINO CARBINOLS
I11
:I1
IV
VI
VI1
V
CzHs XI
XVIII
VI11
n
n
COCHa
CO CHs IX
I11
XVIII
1
d;
Ho\
XI1
XI11
xv
XIV
I
J.
\/
I
I
COCHs
CHBO\
1
CN
\/
CHNOH
XIX
XVI
XVII
I 1
CHaO \
I
\/
CO CHa
is"
VI
I
CHao
COCII~B~
xx
I
\/
\
I CHOHCHtNRf XXII 126
COCH,NR* XXI
127
TETRAHYDROPHENANTHRENE AMINO CARBINOLS
(111). This yielded 7-hydroxytetrahydrophenanthrene-%aldehyde (XII). That the course of the Gattermann reaction on I11 paralleled that with p-naphtho1 was shown by reduction of XI1 t o 7-hydroxy-8-methyltetrahydrophenanthrene (‘XIII)and methylation of XI11 to the corresponding methoxyl derivative (XIV). On dehydrogenation with selenium, XIV gave a substance agreeing in properties with the 1-methyl-2-methoxyphenanthrenedescribed by Hill, Short, and Higginbottom (1). The plan then was to oxidize the aldehyde group in XV to carboxyl and to compare the acid obtained in this way n-ith the acid obtained by oxidation of the acetyl group in VI. However, all attempts a t oxidation of the aldehyde group in XV failed. It was possible to prepare an oxime of XV (XVI) and from this t o prepare a nitrile (XVII) by the action of acetic anhydride. Again all attempts a t hydrolysis of the nitrile in XVII to carboxyl failed. An attempt to oxidize the acetyl group in VI to the desired acid gave a very poor yield. I n contrast, the acetyl group in VIT was readily oxidized t o the acid with hypochlorite solution. The position of the acetyl group in VI1 has been proved by Mighton and Elderfield (8).
x:xm
COCHNi
xxv
CO CHlBr XXVI
XXIV
CHOHCH~NRZ XXVII
For the synthesis of the amino carbinols, two general methods are available, both of which have been found advantageous in the present work. The more convenient and direct method (XX-XXII) was satisfactory for the preparation of amino carbinols derived from VI. This involves bromination of the acetyl derivative, condensation of the bromo ketone with an appropriat,e amine, and reduction of the amino ketone with aluminum isopropoxide to the carbinol. I n the series of amino carbinols derived from VII, the formation of bromomethyl ketones (XXVI) by direct bromination of VI1 was accompanied by a considerable amount of nuclear bromination, presumably in the 8-position. The ease of halogenation of the 8-position in 7-methoxytetrahydrophenanthrene is evidenced by the ready formation of 7-methoxy-8-chlorotetrahydrophenan-
128
J. M. GRIFFING AND R. C. ELDERFIELD
threne by fusion with phosphorus pentachloride (6) and by the bromination of the analogous 2-propionyl-6-methoxynaphthalene (9), which yields 2-(2-bromopropionyl)-5-bromo-6-met~hoxynaphthalene. Therefore, XXVI was prepared by oxidation to the acid and conversion of this to the bromo ketone through the acid chloride and diazo ketone (XXIII-XXVI). The amino carbinols (XXVII) were then prepared in the same manner as those from XX. EXPERIMENTAL
All melting points are corrected for stem exposure. Sodium tetrahydrophenanthrene-7-suZjonabe(ZI). To 150 g. (0.825 mole) of 1,2,3,4tetrahydrophenanthrene brought quickly to a temperature of 160-165', 90 cc. of concentrated sulfuric acid (sp. gr. 1.84) was added over a period of three minutes with vigorous stirring. The mixture was heated a t 160-165' for three additional minutes and then poured into 800 cc. of water. The aqueous solution was boiled with charcoal and filtered with suction. The excess sulfuric acid was neutralized with 35 g. of sodium carbonate, and the solution was then saturated with 80-100 g. of sodium chloride a t the boiling point and then boiled for fifteen minutes. The suspension was cooled to 0' and the sodium sulfonate filtered. The salt was recrystallized from a~ small an amount of boiling water containing another 20 g. of sodium chloride as was required to dissolve the sulfonate. The product, a white flaky solid (approximately 100 g.), was obtained by cooling to O", filtering, and drying in an oven. To characterize the sulfonic acid, the p-toluidine salt (5) was made. To 0.5 g. of the purified sodium salt, dissolved in boiling water, 0.5 g. of p-toluidine and 2 cc. of concentrated hydrochloric acid was added. Needles separated almost a t once; m.p. with decomposition 293-295' after recrystallization from boiling water. C, 68.3; H, 6.3. Anal. Calc'd for CZIHZ~NOSS: Found: C, 68.5; H, 6.2 Potassium hydroxide fusion of sodium 1 ,P,S,&tetrahydrophenanthrene-7-sulfonate:7-hydrozytetrahydrophenanthrene (ZZZ). In a 500-cc. nickel crucible, fitted with a copper stirrer and a thermometer sheathed with copper, were placed 300 g. of potassium hydroxide and 5 cc. of water. The crucible was heated with a burner and 100 g. of dry recrystallized sodium tetrahydrophenanthrene sulfonate, well pulverized, was added with stirring, when the temperature of the molten potassium hydroxide was 225-230". The temperature was raised quickly to 3NI-305' and maintained a t this temperature for five minutes, after which the reaction product, while still hot, was carefully poured into a liter of ice. The aqueous solution was acidified with concentrated hydrochloric acid, cooled by adding ice, and filtered. The product was redissolved in the minimum amount of aqueous sodium hydroxide solution and the solution filtered. The phenol was reprecipitated with acetic acid, washed with water, dilute sodium bicarbonate solution, and finally with water. The yield of crude dried phenol was 6 9 3 % . It crystallized in the form of colorless needles from carbon tetrachloride, and melted a t 133-134'. Anal. Calc'd for C ~ ~ H I C, ~ O84.8; : H, 7.1. Found: C, 84.7; H, 7.3. 7-Yethozy-1 ,P,S,4-tetrahydrophenanthrene(ZV). To a solution of 183 g. (0.93 mole) of crude dry phenol, obtained as above, in 500 cc. of water and 500 cc. of acetone containing 62 g. of 85% potassium hydroxide (0.94 mole), 89 cc. (118 g., 0.94 mole) of dimethyl sulfate was added dropwise, with vigorous stirring a t room temperature. The reaction mixture was warmed to reflux for two hours after the final addition, and allowed to stand overnight at room temperature. The acetone layer was separated, and the aqueous layer was extracted with three 100-cc. portions of ether. The extracts and original acetone solution were combined, washed with water, and dried over anhydrous magnesium sulfate. After removal of the solvent, the product was distilled in uucuo using a short Vigreux column
TETFbIHYDROPHENANTHRENE AMINO CARBINOLS
129
and the fraction boiling a t 160-163"/0.5 mm. was collected. The yield of crystalline solid from methanol was 184.5 g. (84%). It mdted at 59-60'. Cook, Hewett, and Robinson (IO),who prepared this compound in an impure state from the corresponding methyl ether of the octahydrophenanthrol (unsaturated only in the ring containing the methoxyl group) by partial dehydrogenation over platinum black at 300', report the melting point 60-61'. Dehydrogenation of 7-methoxy-l,&,S,4-tetrahydrophenanthrene. A mixture of 2.2 g. of 7-methoxy-112,3,4-tetrahydrophenanthreneand 2 g. of selenium in a two-foot Pyrex tube was heated a t 300" for eight hours,afterwhich another 0.5 g. of selenium was added and the reaction continued for six more hours. There was no further evolution of hydrogen selenide, and the solidified methoxyphenanthrene was extracted with ether and filtered. Evaporation of the solvent and recrystallization of the solid residue from 95% ethanol gave 1.8 g. of product melting a t 96-97", The picrate (from ethanol) melted a t 124-125'. Mixtures of varying percentage samples of 2-methoxyphenanthrene prepared from 7-methoxytetrahydrophenanthrene and 2-methoxyphenanthrene (courtesy of Dr. E. Mosettig) melted a t 96-97". Mixtures of varying percentages of the picrates melted at 124-125'. Acetyl-7-methoxy-l,8,9,&tetrahydrophenanthrene(VI and VZZ). To an ice-salt cooled, well stirred mixture of 78 g. (0.58 mole) of ttluminum chloride, loo0 cc. of carbon disulfide, 700 cc. of sym.-tetrachlorethane, and 57 g. (0.56 mole) of dry acetic anhydride, prepared according to the method of Bachmann and Cronyn (4) by dissolving the aluminum chloride in the solvents warmed to 45' followed by cooling to 0' in an ice-salt bath, a solution of 59 g. (0.278 mole) of 7-methoxy-l,2,3,4-tetrahydrophenanthrene in 200 cc. of carbon disulfide was added dropwise. Stirring was continued for two hours after the final addition, and the reaction mixture was placed in the refrigerator for twenty-four hours. After decanting off the solvent and air drying the residue, the complex was hydrolyzed by the addition of ice and 5% hydrochloric acid. The product was extracted with three 200-cc. portions of ether; the extracts were combined, washed with water, and dried. The product was distilled i n vacuo, the fraction boiling at 155-160°/.002 mm. being collected. The yield of a mixture of plates and needles, which separated when the distillate was crystallized from 95% ethanol, was 58 g. (820j0). The mixture was separated in poor yields by fractional crystallization from 95% ethanol and gave plates and needles: VI, 1m.p. of colorless plates 101.5-102.5'. Anal Calc'd for C17H1s02: C, 80.3; H, 7.1. Found: C, S0.2; H, 7.2. VII, m.p. of colorless needles 90-91". Anal Calc'd for C17Hls02: C, 80.3; H, '7.1. Found: C, 80.3; H, 7.1. Low temperature favored the predominance of isomer (VI), while higher temperatures gave lower total yields, with isomer (VII) predominating. 7-Meihoxy-9-acetyE-1,2,S,~-tetrahydrophenanthrene (VZZ). Owing to the difficulty of obtaining pure isomer (VII) by the above method, it was prepared by methylation of 7hydroxy-9-acetyltetrahydrophenanthrene,which was obtained by hydrolysis of the corresponding 7-acetoxy derivative the synthesis of which will be described by Mighton and Elderfield (8). From 40 g. of the acetoxy derivative (VIII), 32.7 g. of the hydroxy derivative ( I X ) was obtained. TO a solution of 85 g. (0.354 mole) of 7-hydroxy-9-acetyl-l,2,3,4-tetrahydrophenanthrene in 500 cc. of acetone was added a solution of 23.4 g. of 85% potassium hydroxide (0.354 mole) in 100 cc. of water. The mixture was heated to reflux and 34 cc. (45.4 g. or 0.354 mole) of dimethyl sulfate was added with stirring. Heating was continued for six hours followed by the addition of the same amounts of potassium hydroxide solution and dimethyl sulfate as before. The reaction mixture was allowed to stand at room temperature overnight. The crystalline product remaining after the removal of acetone was filtered by suction and gave 69 g. ('77%) of needles melting a t 90-91" after two recrystallizations from 95% ethanol. This material when mixed with varying percentages of isomer (1711) melted at 90-91".
130
J. M. GRIFFING AND R. C. ELDERFIELD
7-Methoxy-8-acetyl-1,I,3,4-tetrahydrophenanthrene ( V I ) . In this case also in order to avoid tbe troublesome separation of isomers when the Friedel-Crafts reaction was carried out directly on IV, the rearrangement of Fries (11) was applied to 7-acetoxy-l,2,3,4-tetrahydrophenanthrene (XVIII). A solution of 50 g. (0.208 mole) of the acetoxy compound (VIII) (8) in 100 cc. of carbon disulfide was cooled in an ice-bath and 29 g. (0.216 mole) of anhydrous aluminum chloride was added slowly with stirring. The reaction mixture was refluxed for one hour on the steam-bath. The carbon disulfide was removed and the residue was heated at 120-180" for four hours. The cake was hydrolyzed with ice and 5% hydrochloric acid and the product was filtered, dissolved in aqueous sodium hydroxide, reprecipitated with hydrochloric acid, and washed. The yield of crude product was 30 g. (60%). For purification it was distilled in vucuo and boiled at 160-170"/0.2-0.3 mm. After recrystallization from ethanol and water, from which it separated as lustrous plates, it melted a t 86.6-87.5". Anal. Calc'd for ClsHlsOz: C,80.0; H, 6.7. Found: C, 80.2; H, 6.9. T o a solution of 10 g. (0.04 mole) of the acetyl phenol in 100 cc. of water and 100 cc. of acetone containing 2.7 g. (0.041 mole) of 85% potassium hydroxide, 5.3 g. of dimethyl sulfate (0.042 mole) was added dropwise with stirring a t room temperature, and the mixture was refluxed six hours and allowed to stand overnight. The acetone was distilled off and the product filtered after cooling. Recrystallization from ethanol using decolorizing carbon (Norit-A) gave lustrous plates melting a t 101.5-102.5". Melting points of varying percentage samples of the product and isomer (VI) obtained from the Friedel-Crafts reaction, showed no depression. 7-Methoxy-8-ethyl-f, S,3,4-tetmhydrophenanthrene ( X ) . Fifty grams of mossy zinc in a 500-cc. flask was washed with 10% hydrochloric acid and amalgamated by shaking for five minutes with a solution of 5 g. of mercuric chloride and 10 cc. of concentrated hydrochloric acid in 100 cc. of water. A mixture of 3 g. of 7-methoxy-8-acetyl-l,2,3,4-tetrahydrophenanthrene, 100 cc. of glacial acetic acid, 100 cc. of concentrated hydrochloric acid, 100 cc. of water, and 40 cc. of toluene was added, and the mixture was refluxed for twenty-four hours. Two additional 40-cc. portions of concentrated hydrochloric acid were added after sixteen and twenty hours. The solution was cooled, the toluene layer drawn off, and the zinc washed with ether. The aqueous solution was extracted with four 200-cc. portions of ether, and the ether and toluene solutions combined and washed with 10% sodium hydroxide and then with water. After drying the combined extracts, the solvents were removed, leaving a viscous, pale yellow oil, This compound is reported an oil by Miyasaka and Nomura (7). I-Ethyl-d-methoxyphenanthrene (XI). A mixture of the pale yellow oil obtained above and 3 g. of selenium powder wan heated a t 300-310" for fifteen hours in a two-foot Pyrex glass tube (fitted with a gas outlet to the hood). The cooled residue was extracted with ether, and the ether filtered. The residue, after removal of the ether, was taken up in methanol, from which 1.5 g. (54% from the acetyl-methoxy compound) of l-ethyl-2methoxyphenanthrene separated. It melted a t 126-128". 1-Ethyl-2-methoxyphennthrene was synthesized according to the method of Miyasaka (courand Nomura (7). From 11 g. of 4-keto-7-methoxy-l,2,3,4-tetrahydrophenanthrene tesy of Dr. L. Goldman of Cooper Union), 3.5 g. of 4-keto-7-methoxy-8-acetyl-l,2,3,4tetrahydrophenanthrene, melting a t 155-157" after recrystallization from methanol (Miyasaka and Nomura report 155-157"), and 4.5 g. of free phenol from the basic extract, were obtained. Three grams of 4-keto-7-methoxy-8-acetyl-l,2,3,4-tetrahydrophenanthrene was reduced by the Clemmensen method to give the oil described by Miyasaka and Nomura. This was subjected to dehydrogenation with selenium, as they describe, and l-ethyl-2methoxyphenanthrene melting a t 126-128" was obtained. Mixed melting points of varying percentage samples of the compound obtained as described above and 1-ethyl-2-methoxyphenanthrene were 126-128O, indicating their identity and establishing the position of the original acetyl group.
TETRAHYDROPHENANTHRENE AMINO CARBINOLS
131
7-Hydroxyl-l ,I,3,4-tetrahydrophenanthrene-8-aldehyde(XZZ) . Following the procedure of Adams and Levine (12), 34.7 g. (0.175 mole) of 7-hydroxy-1,2,3,4-tetrahydrophenanthrene, 31 g. (0.265mole) of zinc cyanide, and 4.3 g. of potassium chloride were added t o 300 cc. of anhydrous ether. Dry hydrogen chloride gas was passed rapidly into the well stirred suspension for four hours, during which an oil separated out and solidified. After decanting off the ether, the residue was taken up in 150 cc. of ethanol and 50 cc. of water and refluxed for ten minutes. The light t a n product was filtered off after cooling, and after purification through the bisulfite addition product and recrystallization from 95% ethanol using decolorizing carbon (Korit-A), 26.8 g (68%) of light yellow needles melting at 116.5117.5"was obtained. A n a l . Calc'd for C15I%1402:C, 79.6;H, 6.2. Found: C, 79.8;H, 6.2. The oxime was prepared by refluxing a solution of 25 g. (0.11 mole) of the aldehyde and 12.5g. (0.153mole) of hydroxylamine sulfate in 150 cc. of dry pyridine and 500 cc. of absolute ethanol for twenty-four hours on the steam-bath. After removing the alcohol, the pyridine solution was poured into ice. The yield of colorless micro needles, melting a t 221-222' was 25.2 g. (95%). A n a l . Calc'd for Cl&H&O2: C, 74.7;H, 6.3. Found: C, 74.6;H, 6.2. 7-~fydroxy-8-methyl-l, 8,S, 4-tetrahydrophenanthrene (XZZZ). Twenty-four grams (0.106 mole) of 7-hydroxy-l,2,3,4-tetrahydrophenanthrene-S-aldehyde, 48 g. of amalgamated zinc, 83 cc. of concentrated hydrochloric acid, 40 cc. of toluene, 20 cc. of acetic acid, and 30 cc. of water was heated to reflux for thirty-four hours. The toluene layer was separated while still hot, and the aqueous layer and zinc residue were washed with two 50-cc. portions of toluene. From the combined toluene extracts 7 g. of crystalline material melting at 170-172" was obtained on cooling to 0". From the mother liquor only unreduced starting material could be isolated. Recrystallization of the product from toluene gave glistening plates melting a t 171-172". Anal. Calc'd for C16HlbO: C, 84.9;H, 7.6. Found: C, 85.2;H, 7.7. 7-Mefhory-8-methyl-l,8,3,4-tetrahydrophenanthrene (XZV). Two and one-tenth grams (0.01 mole) of 7-hydroxy-8-methyl-l,2,3,4-tetrahydrophenanthrene was added to a solution of 1 g. of 85% potassium hydroxide (0.015mole) in 20 cc. of water and 10 cc. of acetone. To the stirred solution, 1.45 cc. (0.0153 mole) of dimethyl sulfate was added dropwise. After stirring for three hours, the solution was allowed to stand overnight at room temperature, 200 cc. of rvater was added, and the product filtered. From ethanol 1.5 g. (67%) of glistening scales, melting a t 111-112",was obtained. Hill, Short, and Higginbottom report the melting point 111-112". I-Methyl-8-niethoxyphenanthrene. A mixture of 1.7 g. of 7-methoxy-8-methyl-l,2,3,4tetrahycirophenanthrene with 2 g. of selenium was heated in a two-foot Pyrex tube for seventeen hours a t 300". The reaction mixture was thoroughly extracted with hot benzene, filtered, and the residue recrystallized from chloroform-petroleum ether, and finally from 95% ethanol, giving colorless plates melting at 160.5-161'. Hill, Short, and Higginbottom (1)report 161". The corresponding phenol was prepared according to the method of Hill, Short, and Higginbottom. It melted a t 196-197.5". They report 196-197". Y-Methoxy-l,8,3,4-tetrahydrophenanthrene-8-aldeh~de (XV). Following aprocedure of Mundici (13), 1.9 g. of 7-hydroxy-l,2,3,4-tetrshydrophenanthrene-8-aldehyde was converted to the sodium salt by dissolving the compound in the necessary amount of hot ethanol and to this adding another solution containing the theoretical amount of sodium dissolved in ethanol. One and nine-tenths grams of a fine yellow precipitate formed, which was filtered and dried in a n oven at 120" for fifteen minutes. T o a stirred boiling suspension of 1.9 g. (0.0077mole) of the sodium salt i n 20 cc. of anhydrous toluene was added dropwise 0.9 cc. (0.0095 mole) of dimethyl sulfate, and refluxing was continued for two hours. After adding 100 cc. of water, the toluene layer m-as washed with 2% sodium hydroxide solution
132
J. M. GI;:IFFISG AND R. C . ELDEIWIELD
followed by water. The residue from evaporation of the toluene crystallized from acetone and gave 1 g. (55%) of light yellow prisms melting a t 142.5-143.5". Anal. Calc'd for C I B H ~ ~C', O 80.0; ~ : H, 6.7. Found: C, 79.9;H, 6.El. All attempts to convert the methoxy aldehyde into the methoxy acid resulted only in the recovery of starting material. Likewise, a variety of conditions failed to hydrolyze the methoxy nitrile to the methoxy acid. 7-Methoxy-f,2,3,4-tetrahydrophenanthrene-8-aldehyde oxiino ( X V f ) . A solution of 10 g. (0.0415 mole) of the aldehyde and 4.9 g. (0.06mole) of hydroxylamine sulfate in 60 cc. of dry pyridine and 200 cc. of absolute ethanol was refluxed for twenty-four hours on the steambath. The alcohol was removed and the pyridine solution poured into water. The yield of highly refractive needles from ethanol, melting a t 198-199",was 9.3g. (87.5%). Anal. Calc'd for CleH1,SO:: C, 75.2;H, 6.7. Found: C,75.3;H, 6.E. 7-.%i'ethoxy-8-cyano-1,2,d,4-tet~ahydrophenanthrene( X V I I ) . h solution of 5 g. of 7methoxytetrahydrophenanthrenc4-aldehydeoxime in 125 cc. of dry acetic anhydride was held at reflux for eight hours. The reaction mixture, after cooling, was poured into 500 cc. of cold water with stirring, and the solid material filtered. Recrystallization from 95% ethanol gave 4.1 g. (88.5%) of ari3orescent plates melting a t 186-187" Anal. Cale'd for C16HlSSO: C,81.0; H, 6.4. Found: C, 50.8; H, 6.4. 7-Methoxy-l ,2,3,4-tetruhydrophenanthrene-9-carboxylic aczd ( X X I I I ) . Sixty-eight grams (0.96 mole) of chlorine was bubbled into a well stirred mixture of 82 g. (2.G2mole) of sodium hydroxide in400 cc. of water and 500 g. of crushed ice. The reactionmixture tested alkaline t o litmus. Fifty and eight-tenths grams (0.2mole) of 7-methoxy-9-acetyl-l,2,3,4-tetrahydrophenanthrene and 100 cc. cf purified dioxane were added. The mixture was warmed t o 75",and after a few minutes a vigorous exothermic reaction took place, requiring external cooling. The reaction was maintained a t 75-80' for a n additional one-half hour, followed by distillation of 300 cc. of the solution, filtration hot, decomposition of excess hypochlorite with 20 g. of sodium bisulfite in aqueous solution with stirring, and acidification with 80 cc. of concentrated hydrochloric acid. The precipitated acid was filtered after cooling and air dried. Recrystallization from ethanol yielded 48 g. (94%) of colorless needles which melted a t 227-229'. Anal. Calc'd for ClaH1603: C , 75.0;H,6.3. Found: C, 75.3,74.8;IT, 6.3,6.4. 7-Methoxy-i , 2,9,4-tetrahydrophenanthrene-9-acid chloride ( X X I V ) A mixture of 50 cc. (83 g., 0.7 mole) of purified thionyl chloride, 70 cc. of dry, thiophene-free benzene, and 40 g. (0.156mole) of 7-methoxy-l,2,3,4-tetrahydrophenanthrene-9-carboxylic acid was heated t o reflux for two hours with careful exclusion of moisture, followed by removal of solvent and excess thionyl chloride by distillation in vacuo. Another 100 cc. of dry benzene was distilled from the residue, which was then taken up in 70 cc. of hot benzene and filtered. The acid chloride crystallized in fine colorless needles, melting at 139-141', and was used in the subsequent reaction at once i,o avoid hydrolysis. T o characterize the acid chloride, the p-toluide was made. The residue left after rernoving the benzene from the reaction mixture of equivalent amounts of the acid chloride and p-toluidine crystallized in slender colorless needles from 95% ethanol, m.p. 207-208'. Anal. Calc'd for C23H23N02: C, 80.0; H, 6.7. Found: C , 79.9;H, 6.5 7-Methoxy-l,2,3,4-tetrahydrophenanthrene-9-diazomethyl ketone ( X X V ) . To a n ice cold, well stirred solution of diazomethane [from 30 g., (0.29 mole) of nitrosomethylureal in 500 cc. of dry ether and 200 cc. of dry benzene, was added 20 g. (0.073mole) of the acid chloride in small portions. After the addition was complete, the solution was allowed t o come t o room temperature and stirring was continued for five hours. Excess diazomethane and ether were removed in vacuo below 30°, and the diazo ketone crystallized from the cold
.
TETRAHYDROPHENANTHRENE AMINO CARBINOLS
133
benzene in clusters of fine colorless needles, melting with decomposition at 125-126'. The diazo ketone decomposes on standing at room temperature and was therefore used a t once t o prepare the bromo or chloro ketones. 7-Methoxy-9-(w-bromoacetyl)~ ,3, 3,Q-tetrahydrophenanthrene ( X X V I ) . The benzene solution of the diazo ketone from the previous reaction was filtered and transferred t o a 500-cc. three-necked flask immersed in a water bath a t 15-20'. Fifteen cubic centimeters of 48% hydrobromic acid was added dropwise with stirring, and stirring was continued for one hour after the final addition. Excess hydrobromic acid was neutralized with aqueous potassium carbonate; the benzene solution n a s washed with water and dried over anhydrous magnesium sulfate. The benzene was concentrated to 100 cc., maintaining the temperature of the bath below 60°,and to the warm solution 100 cc. of pentane was added. The crystalline bromo ketone separated in clumps of pale yellow needles which melted at 95-96'. Yield, 15 g. (62y0 from the acid chloride). The chloro ketone, which is more stable, WBB made in the same way, using concentrated hydrochloric acid (sp. gr. 1.19) in place of hydrobromic acid. It crystallized in fine, pale yellow needles from isopropyl ether, and melted at 102-103". Varying percentage samples of the bromo ketones prepared as above and by the method described for X X melted a t 95-96'. To characterize the bromo ketone, the benzoate was made by refluxing equivalent amounts of sodium benzoate and the bromo ketone in 50% ethanol for two hours. On cooling, a silky mass of fine needles of the benzoate crystallized and melted, after recrystallization from 95% ethanol, a t 145-146". Anal. Calc'd for CZ~HZZO~: C, 77.0; H, 5.9. Found: C, 76.7; H, 5.9. 'I-Methoxy-l,8,9,4-tetrahydrophenanthrene-9-chZorohydrin. A method furnished by Dr. T. L. Jacobs (14) was followed. Twenty grams (0.069 mole) of the chloro ketone was refluxed for thirty minutes with a solution of 70.4 g. (0.345 mole) of aluminum isopropoxide i n 200 cc. of dry isopropyl alcohol. The rertction mixture was then poured into a mixture of ice and 200 cc. of 1:l hydrochloric acid with stirring, followed by dilution to 2 liters. Upon recrystallization from 95% ethanol, 18 g. (89%) of the chlorohydrin separated in clusters of micro needles, melting a t 157-158'. Anal. Calc'd for CtrHlsCIOz: C, 70.2; H, 6.6. Found: C, 69.9; H, 6.8. 7-Methoxy-9-(2-dimethylamino-1-hydroxyethyl)-1,2,3,4-tetrahydrophenanthrene.To a well stirred solution of 6 g. (0.133 mole) of dimethylamine in 60 cc. of anhydrous ether in 8 flask cooled below 10' in a cold water-bath, and provided with a nitrogen inlet tube, 11 g. (0.33 mole) of (XXVI) was added slowly and the stirring was continued for three hours. The dimethylamine hydrobromide was filtered off, after bringing the temperature of the ether to -5'. The ether solution was washed with water and dried over anhydrous magnesium sulfate. After removing the solvent and excess dimethylamine in vacuo from the oily free base in the flask used for reduction, 60 cc. of 1 iM aluminum isopropoxide and 50 cc. of dry isopropyl alcohol were added, arid the flask was fitted with a 12-inch Vigreux column provided with a dropping-funnel for continuous addition of dry isopropyl alcohol. Distillation was continued for a n hour after the distillate gave a negative test for acetone with 2,4-dinitrophenylhydrazinereagent. The isopropyl alcohol was removed and the residue treated with an excess of 10% sodium hydroxide nTith warming t o ensure complete solution of the aluminum salts. The amino carbinol was extracted with ether after cooling, and the ether extract dried thoroughly with anhydrous magnesium sulfate. The dimethylamino carbinol hydrochloride was precipitated by adding dry ethereal hydrogen chloride t o the ice cold solution, allowing the first turbidity to crystallize before adding any additional hydrogen chloride gas. Eight grams (72%) of crude amino carbinol hydrochloride precipitated and was washed with anhydrous ether. After recrystallization from ethyl acetate and acetone, 5 g. of analytically pure clusters of colorless needles was obtained, which melted at 183-184.5". Anal. Calc'd for C19H&lXOz: C, 67.9; H, 7.8. Found: C, 67.8; H, 7.8.
134
J. M. QRIFFING AND R. C. ELDERFIELD
7-Methoxy-9-(d-diethylamino-l -hydroxyethyl)- I $ , $,4-tetrahydrophenanthrene. The procedure was essentially that outlined above, using an excess of diethylamine, except t h a t stirring was continued in a stream of nitrogen for eight hours. From 2 g. of bromo ketone, 1.1 g. (50.5%) of amino carbinol hydrochloride was obtained, which cryetallized from ethvl acetate in clumps of needles and melted at 180-181'. Anal. Calc'd for C:IH~oC1N02:C, 69.3; H, 8.3. Found: C, 69.3; H, 8.3 Attempts to synthesize the corresponding diamylamino carbinol both from the bromo ketone and the chlorohydrin (14)resulted only in the precipitation of a n oil with ethereal hydrogen chloride, which did not crystallize. 'Y-Methoxy-8-(w-bromoacetyl) -1,I,3,4-fetrahydrophenanthrene ( X X ). To a well stirred mixture of 4 g. (0.0156 mole) of 7-methoxy-8-acetyl-l,2,3,4-tetrahydrophenanthrene in 75 cc. of glacial acetic acid cooled t o 10" in a cold water-bath, 5 drops of acetic acid saturated with hydrogen bromide at 0" wafi added, followed by 0.85 cc. of bromine, dropwise, while a stream of carbon dioxide gas wits passed through the solution. The mixture was stirred fifteen minutes after the final addition, and then the mixture was poured over 100 g. of ice with stirring. The crude crystalline product was filtered off and recrystallized from isopropyl ether using decolorizing carbon (Norit-A) and avoiding heat as much as possible. The yield of micro prisms melting a t 96.5-97.5" w-as 4.5 g. (86%). The bromo ketone decomposes slowly on standing at room temperature, and rapidly if heated. For this reason i t was used at once in the subsequent reactions. 7-Methoxy-8-(I-dimethylamino-l -hydroxyethyE)-I,I,3,4-tetrahydrophenanthrene. The procedure was essentially that outlined for 7-methoxy-9-(2-dimethylamino-l-hydroxyethyl)-l,2,3,4-tetrahydrophenaxithrene,with the exception that the 8-bromo ketone is less reactive and required a longer period of standing under a nitrogen atmosphere to get a n almost complete theoretical recovery of amine hydrobromide. The bromo ketone was added to excess dimethylamine in ether contained in a bottle. The air was replaced by nitrogen and the bottle stoppered and allowed to stand with occasional shaking for twelve hours. The amine hydrobromide was filtered off after cooling in ice, and the procedure outlined i n detail previously followed. A 50% yield of micro needles melting a t 224-225' was obtained. Anal. Calc'd for CleH2&lhTOn: C, 67.9; H, 7.8. Found: C, 67.9;H, 7.9. 7-Methoxy-8-(S-diethylamino-l -hydroxyethyl)-1,I,3,Q-tetrahydrophenanthrene. The procedure outlined above was followed, but condensation required forty-eight hours. A 40% yield of micro needles from acetone-ethyl acetate, melting a t 177-178",was obtained. Anal. Calc'd for C21H30ClNOZ: C, 69.3; H, 8.3. Found: C, 69.1; H, 8.4. 7-Methoxy-8-(I-di-n-amylamifi 0-1 -hydroxyethyl)-1 ,I, 3,4-tetrahydrophenanthrene. The procedure outlined above was followed except that an equivalent amount of di-n-amylamine was used instead of a n excess, and after decomposing the reduction product with sodium hydroxide, the alkaline solution was steam distilled t o remove unreacted diamylamine, and the aqueous layer was extracted with ether t o recover the amino alcohol. A 32% yield of micro needles, melting at 183-184", was obtained after recrystallizing the product from ethyl acetate. Anal. Calc'd. for CsrH&lNOt: C, 72.4; H, 9.4. Found: C, 72.2; H, 9.5.
The microanalyses here reported were done by the Misses Frances E. Marx and Lois E. May. SUMMARY
1. 7-Methoxy-l,2,3,4-tetrahydrophenanthrene has been prepared from tetrahydrophenanthrene-7-sulfonic acid.
TETRAHYDROPHENANTHRENE AMINO CARBINOLS
135
2. Since acetylation of 7-methoxy-l , 2,3,4-tetrahydrophenanthrene by the Friedel-Crafts method leads to a difficultly separable mixture of the 8- and 9-acetyl derivatives, alternate syntheses of the two latter compounds are described. 3. The synthesis of representative 7-methoxy-l , 2,3,4-tetrahydrophenanthrene-8- and 9-N , N-dialkylamino carbinols is described. NEW YORK27, N. Y. REFERENCES
(1) (2) (3) (4) (5) (6)
(7) (8) (9) (10) (11) (12) (13) (14)
HILL, SHORT,AND HIGGINBOTTOM, J. Chem. SOC.,317 (1936). SHORT, STROMBERO, AND WILES, J. Chem. SOC., 319 (1936). CLAYTON, GOLDMAN, AND SHERMAN, Unpublished results. Private communication. BACHMANN AND CRONYN, J. Org. Chem., 8, 456 (1943). FIESER, “Experiments in Organic Chemistry,” 2nd Ed. p. 142, D. C. Heath & Co., New York, 1941. KUPCHAN AND ELDERFIELD, J. Org. Chem., 11, 136 (1946). MIYASAKA AND NOMURA, J . Pharm. soc. Japan, 80, 321 (1940). MIQHTONAND ELDERFIELD, J. Org. Chem. in press. HAWORTH AND SHELDRICK, J . Chem. SOC.,864 (1934). COOK,HEWETTAND ROBINSON, J. Chem. Soc., 168 (1939). FRIES,Ber., 64, 709 (1924). ADAMS AND LEVINE,J. A m . Chem. SOC., 46,2373 (1923). MUNDICI,Gazz. chim. ital., 39, 11, 126 (1909). JACOBS,Private Communication.
