TETRAHYDROISOQUINOLINO ALCOHOLS DERIVED FROM

J. Org. Chem. , 1940, 05 (5), pp 528–543. DOI: 10.1021/jo01211a006. Publication Date: September 1940. ACS Legacy Archive. Cite this:J. Org. Chem. 19...
0 downloads 0 Views 1005KB Size
Download PDF
[CONTRIBUTION FROM THE COBB CHEMICAL LABORATORY, UNIVERefTY 6F VIRQINIA, AND THE NATIONAL INSTITUTE O F HEALTH]

TETRAHYDROISOQUINOLINO ALCOHOLS DERIVED FROM TETRAHYDRONAPHTHALENEI ERICH MOSETTIG AND EVERETTE L. MAY

Received M a y 81, lQ@

Chemical and pharmacological investigations carried out in our laboratories seem to indicate that the phenanthrene nucleus may not be essential in producing a morphine-like, or more specifically, an analgesic action. Several years ago we showed e.g. that amino alcohols of the dibenzofuran series exhibit even higher analgesic effects than the corresponding phenanthrylamino alcohols (1, 2). More recently, it was found that this holds true also for the corresponding derivatives of the carbazole series (3, 2). From these results it appears possible that a certain arrangement of the functional groups attached to any ring skeleton of adequate size may bring about the desired physiological effects. Among our phenanthrylamino alcohols, the so-called cyclic amino alcohols of type A and B, and the analogous “3,4 derivatives” (4,5 ) were found to be most promising (2), and we decided therefore to synthesize corresponding compounds derived from tetrahydronaphthalene.

OH

OH

NR2

0YCH2

[yJNR2

0

/

0

4

Type A

Type B

We employed in these syntheses a-tetralone (I),its methoxy and acetoxy derivatives carrying the substituent in position 6 or 7 (VI, XI), and as 1 The work reported in this paper is part of a unification of effort by a number of agencies having responsibility for the solution of the problem of drug addiction. The organizations taking part are: The Rockefeller Foundation, the National Research Council, the U. S. Public Health Service, the U. S. Bureau of Narcotics, the University of Virginia, and the University of Michigan. Publication authorized by the Surgeon General U. S. P. H . S.

528

TETRAHYDROKSOQUINOLINO ALCOHOLS

529

basic components, tetrahydroisoquinoline and 6-methoxytetrahydroisoquinoline. The amino ketones, except VII-b, were prepared according to the method of Mannich, Borkowsky, and Wan Ho Lin (6), employing aqueous formaldehyde, which proved to be superior to the Mannich procedure with paraformaldehyde (7)z. In two instances, namely in the preparation of XII-b and XIII-b, a yellow, crystalline, non-basic byproduct was isolated. It probably was formed by the condensation of two moles of the cyclic ketone with two moles of formaldehyde. It was impossible to effect condensation of p-tetralone, formaldehyde, and tetrahydroisoquinoline by either of the above-mentioned Mannich procedures. Almost immediately a viscous resin-like substance was formed, and the secondary amine was recovered unchanged. The catalytic reduction of the amino ketones to the corresponding amino alcohols did not offer any particular difficulties. The hydrochlorides, dissolved or suspended in aqueous ethanol, usually absorbed ten to twenty per cent in excess of the calculated amount of hydrogen, the reduction coming to a standstill at this point. In accordance with our previous analogous experiments only one of the two possible diastereoisomeric amino alcohols was obtained. When the catalytic reduction of the amino ketones I1 and XII-b in the form of base was attempted, hydrogenolysis took place, with the formation of tetrahydroisoquinoline and the respective a-tetralone derivatives. The tendency of the amino alcohols IX-a and X-b to lose the elements of water with the formation of an alicyclic double bond, when dissolved in alcoholic hydrogen chloride, is noteworthy. Amino alcohol X-a was stable in alcoholic hydrogen chloride, but lost a molecule of water when dissolved in a mixture of pyridine and acetic anhydride. The resulting dihydronaphthalene derivatives (from IX-a and X-b) absorbed two moles of hydrogen rapidly in the catalytic reduction, yielding by hydrogenolysis 2-methyltetralines and tetrahydroisoquinoline derivatives. Of amino alcohols having the basic group attached directly to the tetrahydronaphthalene nucleus, only the simplest member, namely XVII, could be prepared by exchange of the bromine atom of XVI with the tetrahydroisoquinolino group. Since, in the formation of XVII, the addition of tetrahydroisoquinoline to an intermediate ethylene oxide 1 We believe t h a t we can safely exclude the possibility that the tetrahydroisoquinolinomethyl group RCnHoNCHz- has entered a position of the unsaturated benzene nucleus of the methoxy- or acetoxy-a-tetralones (cf. Auwers and Dombrowski, 8). In order to support this view, we attempted t o condense 1- and 2methoxy-naphthalene with formaldehyde (and paraformaldehyde) and tetrahydroisoquinoline under the conditions imposed in the syntheses of the amino ketones. We recovered practically the whole amount of methoxynaphthalenes unchanged.

530

ERIC# M68E!lYIa AND E. It. MAY

&

8 ‘du

\

&

TETRtlHYDROISOQUINOLINO ALCOHOLS

.

c

Y m

x

H

531

532

ERICH MOSETTIG AND E. L. MAY

derivative may be involved, a structural formula with the substituents occupying the inverted positions (the hydroxyl in position 2 and the basic group in position 1) must also be taken into consideration (9). Attempts to prepare other amino alcohols of this type via the corresponding amino ketones were unsuccessful. The oily 2-bromo-l-keto-6-methoxy-l , 2,3,4tetrahydronaphthalene was quite unstable. When it was brought into reaction with tetrahydroisoquinoline in dry ether, a mixture resulted which soon became dark red, and no homogeneous or crystalline products could be isolated. The isomeric 7-methoxybromo ketone is a crystalline compound of moderate stability in the atmosphere, but when mixed in ethereal or benzene solutions with bases, it seemed to lose hydrogen bromide readily, and the desired exchange of the bromine with the tetrahydroisoquinolino group could not be effected.

XVII. (?)

XVI.

The tetrahydroisoquinolino alcohols IV, V, IX-a, IX-b, X-a, X-b, XTV-a, XIV-b, XV-a, XV-b, and XVII were investigated pharmacologically by Dr. Eddy a t the University of Michigan (10). All of the group except X-a and XVII are very convulsant and toxic, and sub-convulsant doses produced little or no analgesic effect. Coincidentally with convulsions, sensibility was reduced. Compound XVII had little effect of any kind. Compound X-a showed a brief analgesic effect a t 75 mg. per kg., and was not convulsant up to 100 mg. per kg. All members of this group were emetic, and although this effect vaned considerably, no relationthip between it and any structural characteristics was apparent. In spite of the marked convulsant action and the absence of a definite quieting effect, a moderate fall in body temperature followed the administration of each compound of the group except XVII. EXPERIMENTAL

I-Keto-i,,??,S, &tetrahydronaphthalene (I) was prepared according to Martin and Fieser (11). The Clemmensen reduction of @-benzoylpropionicacid (12) was carried out according to Martin (13). 1-Keto-6-methoxy-l,I,d,4-tetrahydromphthalee (VI-b) waa prepared according to Robinson and Schlittler (14).

TETRAEYDROISOQUINOLINO ALCOHOLS

533

I-KetoB-hydroxy-l,i?,3, 4-tetrahydronaphthalene (VI-a). The above compound was demethylated according to Haberland (15); yield of hydroxy ketone, 65%. l-Keto-6-acetoxy-l,d,8,4-tetrahydronuphthaEene (VI-c). A mixture of 6.5 g. of ketone VI-a, 15 cc. of pyridine, and 10 cc. of acetic anhydride was allowed t o stand for twenty-four hours at room temperature. The solvent was evaporated in a vacuum and the crystalline residue was recrystallized from dilute ethanol; colorless stout prisms, m.p. 61-62' (corr.), yield 92%. The analytical sample was purified by sublimation. Anal. Calc'd for C12H1208: C, 70.57; H, 5.93. Found: C, 70.04; H, 6.14. f-Keto-7-methoxy-l,d,3,4-tetrahydronaphthaZene (XI-b) was prepared according t o Haworth and Sheldrick (16). The reduction of @-(4-methoxybenzoyl)propionic acid was carried out according to Martin (13). l-Keto-7-hydroxy-l,2,3,4-tetrahydronaphthalene(XI-a). Five grams of XI-b was dissolved in a mixture of 25 cc. of glacial acetic acid and 50 cc. of 48% aqueous hydrobromic acid. The solution was boiled for two hours and poured into cold water. The precipitate was filtered and dissolved in dilute sodium hydroxide, avoiding a n excess. The solution was decolorized with carbon, filtered, and the hydroxy ketone was precipitated with dilute hydrochloric acid. It was recrystallized from dilute ethanol, yield 70%. The compound sublimed readily in an oil-pump vacuum; m.p. 162-164" (corr.). Anal. Calc'd for CloHtoOl: C, 74.04; H, 6.21. Found: C, 73.67; H, 6.10. l-Keto-7-acetoxy-l, 8,5,4-tetrahydronaphthaZene(XI-c). This compound was prepared like its isomer, VI-c. It crystallized from dilute alcohol in colorless rectangular prisms, m.p. 79-80" (corr.), and could be readily sublimed. I : 70.57; H, 5.93. Anal. Calc'd for C I ~ H I ~ OC, Found: C, 70.42; H, 6.06. d-Bromo-1-keto-7-methoxy-1,d, 3,4-tetrahydronaphthalene. T o an ethereal solution of 2 g. of XI-b was added rapidly 2 g. of bromine in 10 cc. of dry ether. The reactionmixture became colorless almost immediately. The ethereal solution was washed with water and dried. The oily residue left on evaporation soon became crystalline, and was purified by recrystallization from 80% ethanol; colorless leaflets, m.p. 78-80" (corr.), yield 72%. The substance is highly lachrimative, and irritating to the skin. Anal. Calc'd for C I ~ H ~ I B r 0C, 2 :51.78; H, 4.35. Found: C, 51.27; H, 4.27. Attempts to exchange the bromine atom with the tetrahydroisoquinolino or piperidino group were unsuccessful. 6'-Methoxy-f , 8 , 3 , 4-tetrahydroisoquinoline was prepared according to Helfer (17), without, however, isolating the formaldehyde condensation-product of @-(m-methoxypheny1)ethylamine. The hydrochloride melted a t 233-234'. Amino ketones and Amino alcohols l-Keto-d-[(l ,B, 3,4-tetrahydro-2-isoquinolyl)methyl]-f, 8 , 3 , 4-tetrahydronaphthalene (11). A mixture of 5 g. of a-tetralone (I), 4 g. (1.2 molecular equivalents) of 30% aqueous formaldehyde solution, and 6.1 g. (1.05 molecular equivalents) of tetrahydroisoquinoline hydrochloride was heated for one-half hour on the steam-bath in an atmosphere of nitrogen (mechanical stirring). The resulting brown, viscous mass was dissolved in water, and the solution was extracted with ether. The amino ketone was liberated by addition of ammonia to the aqueous layer, and was ex-

534

ERICH MOSETTIG AND E. L. MAY

tracted with ether. The oily residue from the ethereal solution became crystalline (7.4 g., m.p. 86-91") on treatment with 95% ethanol. It crystallized from 95% ethanol in the form of large rhombic plates of m.p. 90-91' (corr.), yield 6.6 g. (66%). Anal. Calc'd for CSOHS~NO: N, 4.81. Found: N,5.01. The picrate was formed by mixing the components in warm ethanolic solution. It crystallized from ethanol in yellow rectangular prisms that softened at 86" and melted a t 118-120". Anal. Calc'd for C M H U N ~ ON, ~ : 10.77. Found: N, 10.51. 1 - H y d r o x y - 2 - [(1,2,3,4-tetrahydro-2-isoquinolyl)methyl] -1,8,3,4-tetrahydronaphthalene (IV). Catalytic reduction of base 11. A mixture of one part of I1 (1-5 g.) and one-twentieth part of platinum oxide in thirty parts of absolute ethanol absorbed fairly rapidly 1.25 molecular equivalents of hydrogen. The catalyst was filtered, the solvent evaporated, and aqueous dilute hydrochloric acid was added t o the oily residue, whereby a part remained undissolved. This non-basic product was extracted with ether and distilled in an oil-pump vacuum. It gave readily a semicarbazone (of l-keto-2-methyl-l,2,3,4-tetrahydronaphthalene), which crystallized from 95% ethanol in plates melting at 198-200". Anal. Calc'd for ClzH16N80: N, 19.35. Found: N, 19.41. From the aqueous acid layer pure tetrahydroisoquinoline was obtained by making the solution alkaline and extracting i t with ether. It was characterized as the hydrochloride (m.p. 196-198"). The mixture melting point with an authentic sample gave no depression. The ketone (as semicarbazone) was obtained in a yield of approximately 50%. The tetrahydroisoquinoline was formed nearly quantitatively. Catalytic reduction of the hydrochloride of 11. This salt proved to be hygroscopic, and could be obtained crystalline but once. Therefore the following procedure was adopted: Two grams of the amino ketone was dissolved in dilute ethanolic hydrogen chloride, and the solvent and excess of hydrogen chloride were removed in a vacuum desiccator over calcium chloride and potassium hydroxide. The amorphous solid was hydrogenated in 80 cc. of 95% ethanol with 0.1 g. of platinum oxide. The hydrogen absorption proceeded slowly, and usually i t was necessary t o add new catalyst. As a rule, about 1.5 moles of hydrogen was absorbed. The amino alcohol hydrochloride crystallized from an absolute ethanol-acetone-ether mixture in colorless small leaflets that melted with decomposition at 202-203";yield, 0.9 g., 44%. A n a l . Calc'd for C ~ O H ~ ~ C I N C,O72.81; : H, 7.33;C1, 10.75. Found: C, 73.19;H, 6.95;C1, 10.81. The base crystallized from 95% ethanol in colorless prisms of m.p. 94.5-95"(corr.). Anal. Calc'd for C ~ O H ~ ~ C, N O81.87; : H, 7.90. Found: C, 82.10;H, 7.59. 1 - K e t o - 2 - [ ( 6- methoxy - 1,2,5,4 - tetrahydro - 2 - isoquinolyl)methyl] - 1,9,3,4 tetrahydronaphthalene (111). This amino ketone was prepared like amino ketone I1 but the time of heating was extended to 40 minutes, and 20% aqueous formaldehyde solution was employed. Four grams of a-tetralone (I), 5 g. of formaldehyde soluhydrochloride gave 6 g. tion, and 5.7g. of 6-methoxy-l,2,3,4-tetrahydroisoquinoline (68% yield) of amino ketone of m.p. 95'. It was converted to the hydrochloride in acetone solution. The salt crystallized from an ethanol-ether mixture in the form of glittering leaflets with a buff tint. These softened a t 146' and melted with decomposition a t 219-221'. A n a l . Calc'd for C21H24ClN02: N, 3.91. Found: N, 3.83. 1 - Hydroxy - 8 - [ ( 6- methoxy - l , S , S , 4 - tetrahydro - 8 - isoquinoly2)methyl] - l , 2 , 3,4-tetrahydronaphthalene(V). Four and five-tenths grams of the hydrochloride of

TETRAHYDROISOQUINOLWO ALCOHOLS

535

amino ketone 111 with 0.15 g. of platinum oxide in 140 cc. of 95% ethanol absorbed the required amount of hydrogen in six t o ten hours. The resulting hydrochloride of the amino alcohol was converted to the base, the latter was extracted with ether and reconverted to the hydrochloride; m.p. 182.5-184', yield, 3.4 g. (75%). It crystallized from absolute ethanol in colorless leaflets of m.p. 185-186". Anal. Calc'd for C21H2aClN02:C, 70.08;H, 7.28. Found: C, 69.96;H, 6.96. The amino alcohol crystallized from 95% ethanol in the form of prisms of map. 95.5-96" (corr.). Anal. Calc'd for CZIHZSNO~: C, 77.98;HI 7.79. Found: C, 77.72;HI 7.86. 1 - Keto - 6 - methoxy - 2 - [ ( 1 , 8 , 8 , 4- tetrahydro - 2 - isoquino1yl)methyll - 1,2,3,4 tetrahydronaphthalene (VII-b). A mixture of 5 g. of 1-keto-6-methoxy-lJ2,3,4tetrahydronaphthalene (VI-b), 2.2 g. of paraformaldehyde, 5.2 g. of tetrahydroisoquinoline hydrochloride, and 25 cc. of isoamyl alcohol was rapidly heated t o boiling. The solution was kept boiling under reflux for eight minutes. A few drops of alcoholic hydrogen chloride was added in order to depolymerize the excess of paraformaldehyde. The cooled solution was diluted with water and non-basic material was extracted with ether. The aqueous layer was made ammoniacal and was again extracted with ether. The oily ethereal residue was dissolved in the minimum amount of alcoholic hydrogen chloride. By slow alternate additions of ether and acetone, the amino ketone hydrochloride was obtained in crystalline form (7.4 g., m.p. 142145"). It crystallized from absolute ethanol in small, colorless leaflets and melted a t 146-147'; yield, 6.3 g. (63%). Anal. Calc'd for C ~ I H Z ~ C ~ N, X O3.91. ~: Found: N, 4.14. 1 - H y d r o x y - 6 - m e t h o x y - 2 - [(1,2,8,4-tetrahydro-2-isoquinolyZ)methyl] -lJ2,8, 4-tetrahydronaphthalene (IX-b). Six grams of the hydrochloride of amino ketone VII-b with 0.25g. of platinum oxide in 240 cc. of absolute ethanol was hydrogenated until the absorption came to a standstill (in some experiments 0.05 g. of platinum oxide was added in order to bring the reduction t o completion). The amino alcohol hydrochloride separated as a white, finely divided precipitate as the reduction proceeded. Ten t o twenty per cent in excess of the calculated amount of hydrogen was absorbed. Water was added to the reduction-mixture in order t o dissolve the hydrochloride, the solution was filtered, and the alcohol was removed in a vacuum. The base was liberated and extracted with ether. The ethereal solution left on evaporation an oily base. By dissolving this in alcoholic hydrogen chloride, and carefully adding acetone and ether, the hydrochloride was obtained crystalline in a yield of 70% (4.2 g.), and usually needed no further purification. Purification is more conveniently accomplished through the base than by recrystallization of the salt from an ethanol-acetone-ether mixture. The hydrochloride consisted of tiny felted needles that melted with decomposition a t 178-179'. Anal. Calc'd for CZlH&lN02: C, 70.08; H, 7.28. Found: C, 69.71;HI 7.43. The oily base became crystalline after some time, and crystallized from 95% ethanol in white plates, m.p. 125.5-126' (corr.). C,~77.98; : H, 7.80;N, 4.33. Anal. Calc'd for C Z I H Z ~ N O Found: C, 77.52;HI 7.71;N,4.43. 1 -Keto - 6 - methoxy - 2 - [(6- methoxy - 1 , 2 , 3 , 4 - tetrahydro - 8 - isoquinolyt)methyl] 1 ,b, 8 , 44etrahydronaphthaZene (VIII-b). This compound was prepared like amino ketone 111. Three grams of l-keto-6-methoxy-l,2,3,4-tetrahydronaphthalene

636

ERICH MOSETTIG AND E. L. MAY

(VI-b), 3 g. of 20% formaldehyde, and 3.8 g. of 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave 5.8 g. (88% yield) of amino ketone hydrochloride melting at 126-127'. It crystallized from an absolute ethanol-ether mixture in colorless warts which melted at 127-128", evolved gas a t 160", resolidified and melted again at 218' with decomposition. Anal. Calc'd for CzzH2eClNOa: N, 3.61. Found: N,3.44. The base was oily. 1 -Hydroxy - 6 - methoxy - d - [(6- methoxy - 1,6,3,4 - tetrahydro - 8 - isoquinolyl) methyl]-1,%, S,.&tetrahydronaphthalene (X-b). Four grams of the hydrochloride of amino ketone VIII-b and 0.15 g.'of platinum oxide in 160 cc. of 95% ethanol absorbed ten t o twenty per cent in excess of the calculated amount of hydrogen in four to eight hours. The solution was filtered and the solvent evaporated in a water-pump vacuum. The oily hydrochloride was dissolved in a small amount of water, and the base was precipitated with aqueous ammonia. On addition of ether, the base became crystalline. It was filtered and recrystallized from 80% ethanol; tiny felted needles, m.p. 124.5-125' (corr.), yield, 2.5 g. (69%). Sublimation in an oil-pump vacuum a t 100-110" did not change the melting point. A n a l . Calc'd for CzaHzTNOs: C, 74.76;HI 7.70. Found: C, 74.77;HI 7.90. In the attempt to reconvert the base to its hydrochloride by adding ethanolic hydrogen chloride to the acetone solution of the base at room temperature, the amino alcohol lost the elements of one molecule of water. It was converted thereby pre3,Q-tetrahydro-%-isoquinolyl)methyl1-3, 4sumably into 6-methoxy-2-[(6-methoxy-1 ,%, dihydronaphthalene hydrochloride. This crystallized from absolute ethanol in fernlike leaflets melting at 201-202.5'. Anal. Calc'd for CzzH2&1N02: C1, 9.53. Found: C1, 9.92. The base is decidedly more soluble in ether and less soluble in ethanol than the amino alcohol X-b. It crystallized from 95% ethanol in the form of glittering white leaflets, and melted at 135.5-136' (corr.). Anal. Calc'd for C Z S H Z ~ N O C,~78.77; : H, 7.52. Found: C, 78.29;HI 7.39. In a n attempt t o acetylate the amino alcohol X-b in the usual manner (in pyridine solution with acetic anhydride) the same anhydro compound of m.p. 135.5-136' was obtained. When the hydrochloride of the above base was reduced catalytically (platinum oxide, ethanol), two moles of hydrogen was absorbed. A basic and a non-basic product were separated from the reaction-mixture. The base (yield 75%) could be identified, in the form of its hydrochloride, as 6-methoxytetrahydroisoquinoline (melting point, and mixture melting point with an authentic sample). The nonbasic reduction-product, an oil, was purified by distillation in a n oil-pump vacuum. It had a fruity odor and was considered to be 6-methoxy-2-methyl-l,2,3,4-tetrahydronaphthalene. Anal. Calc'd for C12HlaO: C, 81.78;H I 9.15. Found: C, 81.44;HI 9.04. 1 - Keto - 6 - acetoxy - 8 - [(f ,d,3,4 - tetrahydro -I - isoquinolyl)methyll - 1,8,3,4tetrahydronaphthalene (VII-c). Three grams of l-keto-6-acetoxy-1,2,3,4-tetrahydronaphthalene (VI-c), 2.75 g. of tetrahydroisoquinoline hydrochloride, and 2.7 g. of 20% formaldehyde were heated on the steam-bath for 15 to 20 minutes in an atmosphere of nitrogen (mechanical stirring). The mixture became homogeneous after five minutes, whereupon i t turned increasingly viscous. The crude, semi-solid

TETRAHYDROISOQUINOLINO ALCOHOLS

537

amino ketone hydrochloride was dissolved in acetone, from which i t crystallized immediately in a pure state (yield, 81%). The salt crystallized from absolute ethanol in colorless needles melting at 151-152'. Anal. Calc'd for CzzHzrCINOs:N, 3.63. Found: N, 3.65. 1 - Keto - 6 - hydroxy - I - [(1,8,3,4 - tetrahydro - I - isoquinoly1)methyll - i,d,B,4 tetrahydronaphthalene (VII-a). Four grams of the hydrochloride of VII-c was boiled in 40 cc. of 8% methanolic potassium hydroxide for three minutes. The precipitated potassium salt was brought into solution by addition of water, and the base was obtained in crystalline form (80% yield) by adding aqueous ammonium chloride dropwise to the solution. The base crystallized from 95% ethanol in colorless leaflets which melted with decomposition at 156-157'. Anal. Calc'd for CzJI21NO~:N, 4.56. Found: N, 4.47. The hydrochloride was obtained by adding ethanolic hydrogen chloride t o a n acetone solution of the base. It crystallized from absolute ethanol in long needles, m.p. 158-160' (decomp.). Anal. Calc'd for C2JIZZC1NOZ: N, 4.07. Found: N, 4.23. 1 -Hydroxy - 6 - acetoxy - I- [ ( l , I , S , 4 - tetrahydro - I-isoquinolyl) methyl] - I,d,3,4tetrahydronaphthalene (IX-e). Two grams of the hydrochloride of amino ketone VII-c and 0.15 g. of platinum oxide in 150 cc. of 95% ethanol absorbed the required amount of hydrogen in approximately ten hours. By dissolving the oily reductionproduct (freed of catalyst) in acetone and allowing i t t o crystallize, 1.7 g. (84%) of crystalline hydrochloride, melting a t 189-192.5' with decomposition was obtained. It crystallized from an absolute ethanol-ether mixture in the form of small white leaflets, m.p. 194.5-195.5' (decomp.). Anal. Calc'd for C22H28ClNOs:C1, 9.14. Found: C1, 9.41. 1,6 - Dihydroxy - 8 - [ ( l , I , S , 4 - tetrahydro - d - isoquinolyl) methyl] - l,d,S,4tetrahydronaphthalene (IX-a). A suspension of 2.4 g. of the hydrochloride of VII-a and 0.15 g. of platinum oxide in 200 cc. of 90% ethanol absorbed ten per cent in excess of the calculated amount of hydrogen in 18 hours. The reduction was interrupted, and the oily hydrochloride, after removal of the catalyst and evaporation of the solvent, was dissolved in a small volume of absolute ethanol, from which i t crystallized gradually (yield, 1.55 g., 65%). It consisted of leaflets which melted a t 105107" with gas evolution, resolidified and melted again at 190-196" with decomposition. The mother liquor of this hydrochloride yielded, by addition of ether, 0.2 g. of starting material. 0.5 HzO: C, 67.68; H, 7.06; HzO, 2.54. Anal. Calc'd for CZJIz&lN02 Found: C, 67.09; H, 7.10; HzO, 4.51. The high value of the water analysis may be accounted for by assuming that under the conditions of the determination of water of hydration (nine hours a t 90-100° in a water-pump vacuum) the alcoholic hydroxyl was partially eliminated in the form of water. The amino alcohol, obtained by dissolving the hydrochloride in dilute potassium hydroxide and adding ammonium chloride to the solution, crystallized from 80% methanol i n large colorless needles and melted unsharply at 111-121" with evolution of gas. N O C, Z 73.37; H, 7.70. Anal. Calc'd for C ~ ~ ~ Z ~ HzO: Found: C, 72.92, 72.85; H, 7.42, 7.47. In an attempt to determine the water of hydration, the compound was dried in an oil-pump vacuum, but i t began to darken at 70-80', and changed gradually t o a dark brown oil.

+

+

538

ERICH MOSETTIG AND E. L. MAY

6 - Hydroxy - 8 - [ ( l,8,S,4- tetrahydro - 8 - isoquinolyl)methyZ] - S,4- dihydronaphthalene. When the amino alcohol IX-c was saponified in methanolic potassium hydroxide solution, as described above in an analogous experiment, the phenolic amino alcohol of 114-120" (decomp.), obviously identical with the base IX-a described in the preceding paragraph, was obtained in nearly quantitative yield. In the attempt to prepare the hydrochloride of this compound by addition of alcoholic hydrogen chloride to its alcoholic solution, a crystalline hydrochloride was obtained that melted a t 156-164" with gas evolution. Assuming (from analytical data) that elimination of the alcoholic hydroxyl group had taken place, but perhaps not gone to completion, the product was boiled for five minutes with a solution of 25% methanolic hydrogen chloride. A hydrochloride, which by analysis was shown to lack the elements of one molecule of water, was obtained in the form of triangular prisms melting at 187-188" (decomp.). Anal. Calc'd for CZDHZ2ClNO: C, 73.25;H, 6.76;C1, 10.81. Found: C, 72.74;H, 6.66;C1, 10.36. (Calc'd for CzoH&1NO2: C, 69.44;H, 6.99.) When this hydrochloride was recrystallized from methanol a compound was obtained that consisted of white needles, and melted at 126-128.5' with gas evolution. It apparently contained a molecule of methanol of crystallization. Anal. Calc'd for CZOH~ZCINO CH,OH: C, 70.08;H, 7.28. Found: C, 70.21,70.28;H, 7.26,7.05. The hydrochloride of m.p. 126-128.5' could be reconverted t o the hydrochloride of m.p. 187-188" by boiling with methanolic hydrogen chloride. When it was recrystallized from absolute ethanol i t consisted of triangular prisms and needles. Acetyl derivative. The hydrochloride of m.p. 156-164' (from ethanol) was treated with a n excess of acetic anhydride in pyridine solution in the usual manner. The resulting hydrochloride crystallized from an absolute ethanol-ether mixture in white clusters, and melted with decomposition at 204-206.5'. Anal. Calc'd for C22H2,C1N02: C1, 9.59. Found: C1, 10.11. The dihydro base itself was obtained either from the hydrochloride of m.p. 156164" or from the hydrochloride of m.p. 187-188", or from a mixture of both, by precipitating i t from its alkaline solution with ammonium chloride. It crystallized from 95% ethanol in dull, white leaflets melting a t 136-137" (corr.). Anal. Calc'd for CZOHZINO: N, 4.81. Found: N, 4.65. By catalytic hydrogenation of the hydrochloride of m.p. 156-164" (0.5 g.) in 95% ethanol (30cc.) using platinum oxide catalyst (0.025 g.), two moles of hydrogen were absorbed rapidly. The basic reaction-product was identified as tetrahydroisoquinoline hydrochloride of m.p. 194-196". The non-basic, alkali-soluble reactionproduct was purified by sublimation in a vacuum a t 80", and melted at 88-88.5' (corr.). ~ : 81.44; H, 8.69. Anal. Calc'd for C I I H ~ , C, Found: C, 81.68; H, 8.61. It was considered to be 6-hydroxy-2-methyl-l,2,3,4-tetrahydronaphthalene. l-Keto-6-acetoxy-8-[(6-methoxy-l,8,S, 4-tetrahydro-d-isoquinolyl)methyZl-1,9 , 3, 4tetrahydronaphthalene (VIII-c). This compound was prepared like the analogous amino ketone VII-c. Three grams of l-keto-6-acetoxy-l,2,3,4-tetrahydronaphthalene (VI-c), 3 g. of 6-methoxy-l,2,3,4-tetrahydroisoquinoline hydrochloride, and 2.5 g. of 20% aqueous formaldehyde were heated for twenty-five minutes, and gave 4.5 g. of amino ketone hydrochloride (74% yield), precipitated i n crystalline form from acetone. It crystallized from absolute ethanol in the form of colorless leaflets which softened at 162' and melted at 200-202" with decomposition.

+

TETRAHYDROISOQUINOLINO ALCOHOLS

539

Anal. Calc'd for C~~HZ&INOI: N, 3.37. Found: N, 3.61. l-Hydroxy-6-acetoxy-8-[(6-methoxy-l, B , 3 , 4-tetrahydro-B-isoquimlyl)methyll -1, 8 , 3,4-tetrahydronaphthalene (X-c). Three grams of the hydrochloride of VIII-c and 0.15g. of platinum oxide in 100 cc. of 95% ethanol absorbed about 10% less than the required amount of hydrogen in about two hours. The resulting oily hydrochloride was dissolved in acetone, whereby 0.5 g. of a crystalline hydrochloride precipitated immediately. This was found to be 6-methoxy-l,2,3,4-tetrahydroisoquinoline hydrochloride (melting point and mixture melting point with an authentic sample). The filtrate was concentrated on the water-bath and allowed to cool. Two and two-tenths grams (73% yield) of the amino alcohol hydrochloride precipitated. It crystallized from an absolute ethanol-ether mixture in the form of small leaflets of m.p. 181.5-183'. Anal. Calc'd for CzsH2&1N04: C1, 8.49. Found: C1, 8.84. Since in the reduction-mixture no non-basic naphthalene derivatives could be detected, i t must be assumed that the 6-methoxy-l,2,3,4-tetrahydroisoquinoline hydrochloride did not result from a reductive fission, but must have been present in the sample of amino ketone hydrochloride which was subjected to catalytic reduction, for a slight excess of secondary amine hydrochloride was always used in the preparation of the amino ketone. 1 ,6-Dihydroxy-8-[(6-methoxy-l,B,3, ~-tetrahydro-8-isoquinolyl)methyll-l , 8, 3, 4tetrahydronaphthalene (X-a). The saponification of the hydrochloride of X-c, described above, yielded the phenolic amino alcohol in a yield of 80%. The latter was converted in the usual manner to the hydrochloride, which could be obtained crystalline with difficulty. It crystallized from an absolute ethanol-ether solution in colorless octahedra which melted a t 207-208". Anal. Calc'd for C21H&lN03: C, 67.09;H, 6.97. Found: C, 67.36; H, 6.56. The base crystallized from 95% ethanol in dull, white leaflets which melted at 145.5-146.5' (corr.). Anal. Calc'd for CziH26N03: N, 4.13. Found: IL', 4.43. In an attempt to acetylate the above hydrochloride in pyridine solution with acetic anhydride, the alcoholic hydroxyl group was obviously eliminated, while the phenolic hydroxyl was normally acetylated. The hydrochloride crystallized from absolute ethanol in large white leaflets melting at 203-204.5"with decomposition. Anal. Calc'd for C~sH2sClN03:C, 69.07; H, 6.55; C1, 8.87. Found: C, 68.41; H, 6.84; C1, 8.95, 8.95. (Calc'd for the normal diacetyl product C26HSOClNO6: C, 65.26; H, 6.58; C1, 7.72). l-Keto-7-methoxy-8-[ (1, B , 3,4-tetrahydro-d-isoquinolyl)methyl]-1,2, 3, 4-tetrahydronaphthalene (XII-b). This compound was prepared like its methoxyl-free analog, the amino ketone 11, by employing 9.5 g. of l-keto-7-methoxy-1,2,3,4tetrahydronaphthalene (XI-b). The base was purified by one crystallization from 95% ethanol; dull, white hexagonal prisms, m.p. 104-105° (corr.), yield, 13 g. (76%). Anal. Calc'd for C ~ ~ H Z ~ NOCHa, O Z : 9.65. Found: OCH,, 9.42. The hydrochloride became crystalline only after weeks of standing in ethanol. It crystallized from an ethanol-ether mixture in the form of colorless small warts melting at 119-120" (corr.). Anal. Calc'd for C21H2rClN02: N, 3.91. Found: N, 3.60. As by-product in this reaction, a yellow crystalline compound was obtained in yields varying from 5% to 10%. It would not form a semicarbazone under ordinary

540

ERICH MOSETTIG AND E. L. MAY

conditions. I t crystallized from acetone in yellow clusters, and melted at 138-139" (corr.). Analytical data indicated t h a t the compound might have resulted from the condensation of two moles of methoxytetralone with two moles of formaldehyde. Anal. Calc'd for 2CllH1202 2CH20 - 2H20 = C24H2404: C, 76.57; H, 6.42; M. wt., 376.4. Found: C, 76.31; H, 6.02; M. wt., 379 (average of 3 micro-Rast determinations). 1 -Hydroxy-7-methoxy-2- [ (f,2,9,4-tetrahydro-2-isoquinol y l ) methyl]-1 , 2, S 4-tetrahydronaphthalene (XIV-b). Two grams of the hydrochloride of the amino ketone XII-b and 0.1 g. of platinum oxide in 50 cc. of absolute ethanol absorbed one and one-fourth moles of hydrogen. The reduction-mixture yielded 1.4 g. (70%) of pure amino alcohol hydrochloride. It crystallized from absolute ethanol in glittering leaflets, m.p. 207.5-209' (decomp.). Anal. Calc'd for C21H2sClN02: C, 70.08;H, 7.28. Found: C, 69.66; H, 7.56. The base crystallized from 95% ethanol in tiny needles of m.p. 111.5-112" (corr.). Anal. Calc'd for C2lHz6NO2:OCHs, 9.59. Found: OCHa, 9.19. The acetyl derivative was obtained by dissolving the hydrochloride (0.3 g.) of the amino alcohol in a mixture of 1 cc. of acetic anhydride and 5 cc. of pyridine, and allowing the reaction-mixture to stand for twenty-four hours. The solvent was evaporated in a water-pump vacuum, and the oily residue was dissolved in acetone from which the hydrochloride of the acetyl derivative crystallized eventually in colorless, tiny needles of m.p. 167.5-169.5'. A crystallization from absolute ethanol did not raise the melting point. Anal. Calc'd for ClsHz&lNOa: C1, 8.82. Found: C1, 8.95. When the amino ketone XII-b itself was reduced catalytically, complete reductive fission obviously took place, the tetrahydroisoquinoline being obtained in a nearly quantitative yield (one molecular equivalent). I-Keto-7-methoxy-8-[(6-methoxy-f 2 , d , 4-tetrahydro-2-isoquinolyl)methyl]-1,2 , 3, &tetrahydronaphthalene (XIII-b). This compound was prepared like amino ketone I11 or VIII-b. By employing 4 g. of 7-methoxy-l-keto-1,2,3,4tetrahydronaphthalene (XI-b), 6 g. of amino ketone hydrochloride (68% yield) was obtained. It crystallized from an absolute ethanol-ether mixture as buff-tinted leaflets that softened a t 156' and melted a t 220-221" (decomp.). The base was oily. Anal. Calc'd for C ~ , H Z ~ C I N O N,~ :3.61. Found: N, 3.69. I n this experiment the same yellow non-basic compound was isolated as was obtained in the preparation of amino ketone XII-b. l-Hydroxy-7-methoxy-2-[(6-methoxy-1,2, ~,4-tetrahydro-2-isoquinolyl)methyl]-f,2 , 9,4-tetrahydronaph~halene(XV-b). Four grams of the hydrochloride of amino ketone XIII-b and 0.15 g. of platinum oxide in 140 cc. of 95% ethanol absorbed the required amount of hydrogen in seven hours. The amino alcohol, which is sparingly soluble in ether, was obtained from the reduction-mixture like its isomer X-b. It crystallized from 95% ethanol in colorless plates which melted at 135-135.5' (corr.) ; yield, 2.8 g. (77%). The compound sublimed readily in a n oil-pump vacuum at 125". Anal. Calc'd for C Z ~ H ~ ~ NC,O 74.76; S: H, 7.70. Found: C, 74.22, 74.52; H, 7.89, 7.25. The hydrochloride, prepared in acetone-alcoholic hydrogen chloride, could be obtained only in the form of an amorphous, white, and finely divided precipitate, which could be easily a t e r e d off. It melted without decomposition at 154-163"' and could be reconverted t o the pure amino alcohol.

+

TETRAHYDROISOQUINOLINO ALCOHOLS

541

The picrate crystallized from 95% ethanol in yellow leaflets, m.p. 150-151.5'. Anal. Calc'd for C28H8a4010:C, 57.73; H,5.19. Found: C, 57.47; H, 4.78. The acetyl derivative of the amino alcohol was prepared in pyridine with acetic anhydride. Its hydrochloride crystallized from absolute ethanol in short needles, m.p. 182.5-183.5". Anal. Calc'd for C~4H~oCINO~: C1, 8.21. Found: C1, 8.22. l-Keto-7-acetosy-8-[(1,8,5, 4-tetrahydro-~-isoquinolyl)methyl]-l , 8 , 5 , 4-tetrahydronaphthalene (XII-c). This amino ketone was prepared like its isomer VII-c, employing 3 g. of l-keto-7-acetoxy-1,2,3,4-tetrahydronaphthalene(XI-c). The reactionmixture became entirely solid. The crude hydrochloride was recrystallized from 95% ethanol, whereby i t was obtained in colorless leaflets of map.156.5-157.5"; yield, 61%.

Anal. Calc'd for C~ZH&lNO~:N, 3.63. Found: N, 3.64. l-Hydroxy-7-acetozy-8-[(1,8, 5,4-tetrahydro-8-isoquinolyl)methyll-l, 8 , 5, 4-tetrahydronaphthalene (XIV-c). Three grams of the hydrochloride of amino ketone XII-c and 0.1 g. of platinum oxide in 200 cc. of 95% ethanol absorbed one mole of hydrogen in about twenty hours. The catalyst was filtered off and the solvent evaporated in a water-pump vacuum. The remaining oily hydrochloride waa dissolved in acetone from which i t crystallized almost immediately in a practically pure state; yield, 2.4 g. (80%). It crystallized from an absolute ethanol-ether mixture in trapezoidal plates of m.p. 194-195". Anal. Calc'd for CzzH&INO~: C1, 9.14. Found: C1, 9.32. 1 7-Dihydrozy-l-[( 1 , 8 , 5, 4-tetrahydro-8-isoquinolyl)methyl]-i, 6 , 3, 4-tetrahydronaphthalene (XIV-a). One and five-tenthsgrams of the above hydrochloride of XIV-c was boiled for three minutes with 15 cc. of an 8% methanolic potassium hydroxide solution. The phenolic base was precipitated in crystalline form with ammonium chloride. It was dried and converted t o the hydrochloride. The salt crystallized from an absolute ethanol-ether mixture as colorless elliptical plates, m.p. 206-207.5' (decomp.); yield nearly quantitative. Anal. Calc'd for CZJhClNOz: C, 69.44; H, 6.99. Found: C, 69.19; HI 6.80. The base, which was obtained by dissolving the hydrochloride in aqueous potassium hydroxide and adding ammonium chloride, crystallized from 95% ethanol in colorless hexagons of m.p. 205-207' (decomp.). Anal. Calc'd for C ~ J I Z ~ N N, O ~4.53. : Found: N, 4.52. l-Keto-7-acetoxy-8--acetozy-l-[(6-methosy-l, 8 , 5,4-tetrahydro-8-isoquinolyl)methyll-f8 , 5 , 4tetrahydronaphthalene (XIII-c). This compound was prepared like its isomer VIII-c. The mixture of the reactants waa heated for thirty minutes. Three grams of l-keto-7-acetoxy-1,2,3,4-tetrahydronaphthalene (XI-c) gave 3.9 g. (64%) of amino ketone hydrochloride. It crystallized from acetone in colorless leaflets, which softened a t 158" and melted with decomposition a t 209-211'. A recrystallization from absolute ethanol did not change the melting point of the compound. Anal. Calc'd for Cz8H2&lNO~: N, 3.37. Found: N, 3.79. 1-Hydrozy-7-acetosy-8-[6-methoxy-l 8,3,4-tetrahydroJ-isoquinolyl)methyZ]-l ,8 , 3, 4-tetrahydronaphthalene (XV-c). In the catalytic reduction of the hydrochloride of amino ketone XIII-c (5.8 g.), the same experimental conditions were adhered to, solvent and catalyst being used in the same proportions as in the reduction of the isomeric VIII-c t o the amino alcohol X-c. The resulting oily hydrochloride was dissolved in acetone, whereby 1.3 g. of 6-methoxy-l,2,3,4-tetrahydroisoquinoline

542

ERICH MOSETTIQ AND E. L. MAY

hydrochloride precipitated immediately. From the concentrated filtrate, 2.9 g. of the expected amino alcohol hydrochloride crystallized. It was recrystallized from an absolute ethanol-ether mixture; fine, short needles, m.p. 149-160'. Anal. Calc'd for CzsH2&1NO4: C1, 8.49. Found: C1, 8.85. From the mother liquors, 0.9 g. of the phenolic amino alcohol XV-a was recovered by treatment with methanolic potassium hydroxide. Also in this experiment the appearance of the 6-methoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride must be explained by assuming that i t was present in the amino ketone hydrochloride subjected to hydrogenation. 1,7-Dihydroxy-2-[(6methoxy-f,.8,3,~-tetrahydro-2-isoquinolyl)methyl]-f, 2, 3, 4tetrahydronaphthalene (XV-a). The saponification of the acetoxy compound XV-c was carried out as above. The phenolic base was dissolved in the minimum of warm alcohol and when alcoholic hydrogen chloride was added, the hydrochloride precipitated readily in a pure crystalline form (78%). It crystallized from an alcoholether mixture in small white plates of m.p. 209". Anal. Calc'd for Cz1Hz8ClNO3:C, 67.09; H, 6.97. Found: C, 66.86,66.72;H, 6.73,6.73. The base crystallized from 95% ethanol in the form of banana-shaped needles of m.p. 173-174.5' (corr.). Anal. Calc'd for CllHpaNOs: N, 4.13. Found: N,4.27. l-Hydroxy-2-(1,8 , 3 ,4-tetrahydroJ-isoquinolyl)-t,2,3,4-tetrahydronaphthalene (1) (XVII). To a solution of 5 g. of 2-bromo-l-hydroxy-l,2,3,4-tetrahydronaphthalene (XVI) (18)in 25 cc. of benzene was added 6.5 g. of tetrahydroisoquinoline, and the mixture was boiled under reflux for sixteen to twenty hours. As the reaction proceeded, tetrahydroisoquinoline hydrobromide separated gradually from the solution. The benzene filtrate left on evaporation a brown, viscous oil that solidified slowly. By crystallization from 95% ethanol, 4 g. (66% yield) of an amino alcohol melting at 133-134" was obtained in the form of white, hexagonal prisms. After another recrystallization the compound melted a t 133.5-134" (corr.). Anal. Calc'd for C1PH21NO: C, 81.67;H, 7.58. Found: C, 82.02; H, 7.41. No crystalline hydrochloride or picrate could be obtained. SUMMARY

The amino alcohol 1-hydroxy-2-[ (1 ,2 ,3 ,4-tetrahydro-2-isoquinoly1)methyl]-1 ,2,3 ,4-tetrahydronaphthalene1 and various derivatives of it carrying a hydroxyl, or acetoxyl, or methoxyl group in the naphthalene portion, or in the isoquinoline portion, or in both, have been obtained by catalytic reduction of the corresponding amino ketones. The latter were obtained by the Mannich method, condensation of a-tetralone and its proper derivatives with formaldehyde and tetrahydroisoquinoline or 6-methoxytetrahydroisoquinoline. The lower homologous amino alcohol, 1-hydroxy+ ,2,3,4-tetrahydro-2isoquinoly1)-1 ,2 ,3 ,4-tetrahydronaphthalene (?) was prepared by exchanging the bromine atom of 2-bromo-1-hydroxytetrahydronaphthalene with tetrahydroisoquinoline. WASHINGTON,D. C.

TETRAHYDROISOQUINOLINO ALCOHOLS

543

REFERENCES (1) MOSETTIG AND ROBINSON, J. Am. Chem. Soc., 67, 2186 (1935). "Studies on Drug Addiction," (2) SMALL,EDDY,MOSETTIG,AND HIMMELSBACH, Supplement No. 138 to the Public Health Reports (1938). (3) RUBERGAND SMALL, J. Am. Chem. Soc., 80, 1591 (1938). AND BURGER, J. A m . Chem. SOC.,67,2189 (1935). (4) MOSETTIG (5) BURGER AND MOSETTIG, J. Am. Chem. Soc., 68, 1570 (1936). A N D WANHo LIN, Arch. Pharm., 276, 54 (1937). (6) MANNICH, BORKOWSKY, AND LAMMERING, Ber. , 66,3510 (1922). VANDE KAMPAND MOSETTIG, (7) MANNICH J . A m . Chem. Soc., 68, 1568 (1936). (8) AUWERSAND DOMBROWSKI, Ann., 844, 280 (1906). (9) VON BRAUN,BRAUNSDORF, AND KIRSCHBAUM, Ber., 66, 3648 (1922). VON BRAUNAND WEISSBACH,Ber. Bs, 3052 (1930). (10) EDDY,unpublished results. Organic Syntheses, XV, 77 (1935). (11) MARTINAND FIESER, AND ALLEN, Organic Syntheses, X I I I , 12 (1933). (12) SOMMERVILLE (13) MARTIN,J. A m . Chem. SOC.,68,1438 (1936). Cf.OVERBAUGH, ALLEN,MARTIN, A N D FIESER,Organic Syntheses, XV, 64 (1935). (14) RAPSON AND ROBINSON, J . Chem. Soc., 1936, 1285. ROBINSON AND SCHLITTLER, J . Chem. Soc., 1936, 1288. Ber., 69, 138 (1936). (15) HABERLAND, (16) HAWORTH AND SHELDRICK, J . Chem. Soc., 1934, 1951. (17) HELFER,Helv. Chim. Acta, 7 , 945 (1924). (18) VONBRAUN AND KIRSCHBAUM, Ber., 64,597 (1921). STRAUS AND ROHRBACHER, Ber., 84, 40 (1921).