[CONTRIBUTION FROM T H E
RESEARCH LABORATORIES OF THE
UPJ,OHN COMPANY ]
PHYSIOLOGICALLY ACTIVE INDANAMINES NATHAN LEVIN*, BOYD E. GRAHAM, AND H. G. KOLLOFF
Received April ir, 1944 INTRODUCTION
In connection with the studies in these Laboratories on physiologically active amines chemically related to ephedrine, it appeared of interest to include an investigation of a series of indanamines of the general formula (I):
I
I1
Structurally, these indanamines form an interesting group of compounds; they are characterized by the presence of the phenethylamine skeleton (11) and, further, they may be looked upon as indane analogs of the well-known phenylisopropylamines. Thus, 2-aminoindane (111) is the indane analog corresponding to amphetamine (IV) ;an analogous structural relationship is found with 2-amino-lindanol (“indanolamine”) (V) and propadrine (phenylpropanolamine) (VI) : H2
U-(&J2 C H \C”2
H c\H
OH
C\H
P H I : :
111
IV
V
OH C H
0 ” ~ VI
The effect of N-alkylation on pressor activity of primary amines structurally related to phenethylamine is well known (1); however, studies of the effects produced by such structural modifications on other physiological functions, such as bronchodilator activity, are incomplete. In view of the number of N-substituted phenylalkylamine derivatives which have been described as active bronchodilators in recent patents (2,3), and the structural analogy of the phenylisopropylamines and the corresponding indane analogs, it was desirable to prepare a group of N-alkyl and N-aralkyl-2-aminoindanes and 2-amino-1-indanols for pharmacological study. 2-Aminoindane has been previously prepared (4-7) and studied pharmacologically (4,8)but there is no mention in the literature of N-substituted derivatives. In order to make available for pharamacologicalstudy a group of N-substituted 1 Presented April 6, 1944 before the Division of Medicinal Chemistry, a t the Cleveland Meeting of the American Chemical Society, and released through the courtesy of Walter J. Murphy, Editor of Chemical and Engineering News. * Present address, Schering Corp., Bloomfield, N. J.
380
PHYSIOLOGICALLY ACTIVE INDANAMINES
381
2-aminoindanes, a search was first made for a satisfactory method of making the primary amine. The chief objection to the use of 2-indanone oxime as an intermediate is the lack of a suitable method of reduction. Thus, Benedickt (6) reduced the oxime with sodium amalgam in acetic acid but reported only traces of 2-aminoindane. Huckel and his associates (7) carried out the reduction using sodium and alcohol and obtained a mixture of isomeric amines. Catalytic reduction, using platinum black catalyst, gave the secondary amine, diindanylamine, only (7). Using platinum oxide catalyst, the primary amine was formed, but from 43 g. of oxime only 20 g. (about 3Oa/o) of 2-aminoindanehydrochloride was obtained; the reaction proceeded very slowly, two days being required to reduce 5 g. of oxime (7). In the present investigation, a study was made of the Hartung method of catalytic reduction with the anticipation that 2-aminoindane might be obtained pure and in good yields. Using palladinized Norit catalyst in absolute ethanol containing anhydrous hydrogen chloride according to the general procedure (9-11), reduction failed to take place. However, when active palladium catalysts were used, hydrogen uptake occurred smoothly and reduction proceeded to completion; it was possible to reduce several portions of 0.03 mole of oxime within 8 to 10 hours a t room temperature with the formation of 2-aminoindane hydrochloride in practically quantitative yields. Active palladium catalysts were prepared by shaking palladium chloride with Norit in 0.5 N or 1.0 N aqueous sodium acetate solutions instead of distilled water as previously employed (9). These catalysts are extremely active, sensitive, and pyrophoric and c k e must be used in working with them.2 The reaction of ammonia with 2-bromo-1-indanol for the preparation of “indanolamine” (V) has been reported by various workers (12-14). However, subsequent studies by Braun and Weissbach (15) showed that ammonia and amines react with 2-bromo-1-indanol to form 1-amino-2-indanol derivatives (VII) and not 2-amino-1-indanols (VIII),
; :NI
OH C H /\/H\CBr
r I
HNRe
VI1
OH
VIII 2 One of the authors (N. L.) became acquainted with these catalysts in the course of his doctorate studies under Dr. Walter H. Hartung a t the University of Maryland. A paper describing the properties and uses of active palladium catalysts will be published when sufficient information is obtained. (Hartung, personal communication).
382
LEVIN, GRAHAM, AND KOLLOFF
and, as to be expected, the data recorded by previous workers (12-14, 16-18) are misleading? In view of the above findings, it was decided to include the preparation of a group of N-substituted l-amino-2-indanols for pharmacological study and comparison with the isomeric 2-amino-1-indanols. 2-Amino-l-indanol (V) has been obtained by the catalytic hydrogenation of 2-isonitroso-l-indanone:
0
0
OH
According to the patent literature (19), reduction directly to the amino alcohol occurred in the presence of colloidal palladium, but with palladinized charcoal catalyst, reaction stopped at the amino ketone stage. When this point was reached, nickel catalyst was added and the reduction completed a t 80” and 10 atmospheres pressure. In the present study, the general method of Hartung (10,ll) was applied. The first two equivalents of hydrogen were taken up with ease; when this point was reached there was a sharp break in hydrogen absorption, and, if reaction was allowed to continue, reduction to the amino alcohol proceeded very slowly and generally not to completion. The addition of fresh palladinized Norit facilitated reaction and reduction to the amino alcohol occurred readily at room temperature. By this procedure, formation of the amino ketone and subsequent reduction to the 2-amino-l-indanol were practically quantitative. N-Benzal derivatives of 2-aminoindane and 2-amino-l-indanol were prepared from the amine hydrochlorides and these were catalytically reduced to the corresponding benzyl derivatives. A study was made of the possible application of several benzal derivatives in the preparation of N-methylindanamines according to the Decker and Becker alkylation method (20). When methyl iodide was employed as the alkylating agent, reaction failed completely. 2-Methylaminoindane, the analog corresponding to N-methylamphetamine, was finally obtained in low yields by the reaction of methyl sulfate with a-piperonilidenaminoindane and hydrolyzing the quaternary salt formed. Attempts to prepare 2-methylamino-l-indanol,the indane analog of ephedrine, by the same method have thus far failed. The pharmacological data for ten indanamines are of particular interest and a summarized report follows. The 2-aminoindane hydrochlorides (IX, XIII, XVI), given intravenously in white rats, are less toxic than amphetamine hydrochloride. Compared to 1-ephedrine, they are more effective bronchodilators as shown by the bronchial perfusion of isolated rabbit lung method of Sollmann and von Oettingen (21). 2-Benzylaminoindane (XIII) shows a regular and rather 3 Swanson [ J .Am. Pharm. Assoc., 11, 1125, (1932)l studied the pharmacological properties of an “indanolamine” described as 2-amino-l-indanol. However, no mention n.as made of the method by which i t was prepared.
383
PHYSIOLOGICALLY ACTIVE INDANAMINES
efficient bronchial action and, on the basis of the experimental data obtained, is rated as a ('good'' bronchodilator. The 1-amino-2-indanols (XXVII, XXX, XXXI, XXXIII), though lacking the phenethylamine structure, and the 2-amino-1-indanols (XIX, XXVI) are active bronchodilators; in general, members of both series show a regular bronchial action. Both primary amines, 2-amino-1-indanol (XIX) and 1-amino-2-indanol (XXVII) have low acute toxicities. N-Alkylation serves to increase toxicity, the increase being in proportion to the degree of substitution; with this, however, there is no significant change in bronchodilator activity. For all practical purposes, members of all three series, given intravenously in dogs, have little or no effect on blood pressure. 2-Amino-1-indanone (XVII) is an active bronchodilator and shows regularity. TABLE I N-SUBS~TUTED 2-AMINOINDANES
-_ NO.
-IX X 3; I
SR,
2W (uncorr.) 56-67"
CsHllClN CieHi,N
8.27 8.27 20.93 20.89 6.346.20
93.5-95.5
Ci7HiaNo?.
5.285.07 5.565.70 5 . 4 5.66 13.66 13.72
x 11
100-101
X I 11
205b
Ci7Hi7NO CieHiBCIN
XIV
2 3 4 ~(uncorr.)
C I ~ H I S C I N O4.61 ~ 4.74 11.7 -11.8
xv
233" (uncorr.) 210c
C17H,&lNO CiOH14ClN
XVI a
e
4.84 5.07 12.26 12.31 7.63 7.72 19.35 19.30
Dimorphic mixture. Darkens with slow rise in temperature 'Decomposes.
Its ,acute toxicity is rather low, and on blood pressure it is slightly depressant. This amino ketone gives a characteristic red coloration on epidermis and paper. EXPERIMENTAL
All melting points reported (unless otherwise indicated) were taken with an Anschutz thermometer entire stem immersed in bath. The microanalyses were carried out by C. H. Emerson and Wm. A . Struck of our Analytical Laboratories. Amzne hydrochlorides. The hydrochloride salts of the amines, except those isolated as such from the reaction mixtures n'ere obtained by treating an absolute ethanolic solution of the amine with absolute ethanolic hydrogen chloride and precipitating the salt by the addition O F excess anhydrous ether. All of the amine hydrochlorides were obtained as colorless crystals. Catalytic hydrogenations. Catalytic hydrogenations using palladium catalysts were carried out by shaking an alcoholic solution of the substance t o be reduced in an atmosphere
384
LEVIN, GRAHAM, AND KOLLOFF
of hydrogen delivered from a graduated cylinder under a pressure of approximately 30 inches of water. The reaction flask was connected a hydrogen delivery train by means of neoprene tubing; no rubber connections were employed. Palladinized Norit catalysts were prepared by shaking an aqueous solution of palladium chloride (Bishop) with Norit in an atmosphere of hydrogen until saturated (9). The palladinized Norit was filtered with suction, washed well with water, then ethanol and finally with absolute ethanol and dried with suction. The active palladium catalysts were prepared in 0.5 or 1.0 N aqueous sodium acetate and were employed while alcohol-moist to prevent ignition. The Schiff bases were reduced at room temperature in a Parr catalytic hydrogenator (22) in the presence of platinum oxide catalyst (American Platinum Works); 0.02 g. of catalyst was used per 0.01 mole of Schiff base. TABLE I1 N-SUBSTITUTED 2-AMINO-1-INDANOLS
NITy % CHLORINE
NO.
XIX
xx
NRr
M.P."C.
XXIII XXIV
xxv
XXVI
~
m
2 6
m
$ - 3> 3 3
__--
21
-NHs. HCl
/
171-1720
-N=CHCeHdOCHs
1
171.8-173.0
C17H17N02
-NHCH~C,H,~>CH,.
216-217e (un-
11.11 11.12 C I ~ H ~ ~ C I N 4.384.48 O,
HC1 -NHCHpCaHaOCHa. HCl -NHCHsCHpCeHs * HCI -NHCHpC@H6 -NHCHJ?!eHB. HC1
212-213 4.554.7511.60 11.49 CI~H~~CINO Z 182d Cl?H,&INO 4.844.99 12.24 12.28 144.6-145.0 5.86 5.94 C16H17NO (225c uncorr.) C16H18CINO 5.08 5.10 12.89 13.11
XXI XXII
BXPIBICAL POXXULA
COHi2ClNO CieHiSNO
7.557.3719.1419.29 5.91 5.96
C I ~ H ~ S N O4.98 ~ 4.95 5.24 5.30
corr.)
Calc'd for C, 58.22; H, 6.47. Found C, 58.40; H, 6.26. Forms red melt. 0 Decomposes. d Darkens with slow rise in temperature. a Decomposes with effervescence. SYNTHESIS O F INTERMEDIATES
2-Bromo-1-indanol. 2-Bromo-I-indanol was prepared in 85% yields according to the method recently described by Suter and Milne (23). The procedures of Pope and Read (13, 14) and Read and Hurst (24) gave much lower yields. I-Zndanone. Decomposition of 2-bromo-I-indanol in 7% aqueous sulfuric acid according to the procedure of Porter and Suter (25) gave 7242% yields of crude I-indanone. The Friedel-Craft cyclization of phenylpropionyl chloride (26, 27), according t o the following modified procedure gave good results: To 84.3 g. (0.5 mole) of phenylpropionyl chloride (b.p. 122-123°/20 mm.), dissolved in 250 cc. of anhydrous carbon disulfide, is added, in divided portions, 80.0 g. (0.6 mole) of anhydrous aluminum chloride. After gentle refluxing, the aluminum chloride complex is decomposed and the product separated by steam distillation. The yield of pure I-indanone distilling a t 118-120°/13 mm. is 55.6 g. (84.3%). 9-Zsonitroso-1-indanone.The general nitrosation procedure recently described by Levin and Hartung (28) was applied. Twelve and three-tenths grams (0.105 mole) of freshly
385
PHYSIOLOGICALLY ACTIVE INDANAMINES
distilled butyl nitrite is added to a solution of 13.2 g. (0.1 mole) of I-indanone in 200 cc. of ether (U.S.P.) with stirring and simultaneous introduction of anhydrous hydrogen chloride. The isonitroso ketone precipitates out during the course of the reaction; after all of the nitrite is in, 200 cc. of benzene is added and the mixture cooled. The product is removed by filtration, washed well with ether and dried; yield, 14.0 g. (87%). Recrystallization from dilute ethanol gives colorless crystals darkening at 200". 2'-Zndanone. 2-Indanone was prepared by several procedures. The method of Porter and Suter (25), involving the acid decomposition of 1,a-indene glycol (from the alkaline hydrolysis of the 2-bromo-I-indanol) gave an over-all yield of only 28%. The acid hydrolysis of 2-methoxy-I-indanol according to the method of Read and Hurst (24) gave 60% yields TABLE I11
N-SUBSTITUTED 1-AhiINO-2-INDANOLS CHLORINE %
NRt
NO.
"
2
--~9
-___ XXVII -NHa XXVIII XXIX
xxx
XXXI XXXII XXXIII
:YxxIv xxxv XXXVI SXXVII XXXVIII
*
HCla
232O (uncorr.) 164.2-165.2 193-194d 174-175 183-184 222-223d (uncorr.) 02-103 203c 202-203 211d 125-126 205-206d 172.CF173.3 175.8-177.0 22jf (uncorr.)
2
3
2_
C9H&IN0
7.557.6t
CleH16NO CI?I&'INOI CioHi4ClNO CIiHi&lNO CizHisClNO
5.91 6.0; 5.245.2: 7.02 7.24 17.8 17.65 6.56 6.6: 6.15 6. If 15.60 15.73
Ci6Hi7NO 5.86 5.6t Ci6HisCINO 5.08 5. I! Ci7H~oClNOz 4.554.5f Ci4HzoCINO 5.52 5.6t ClltIl9NO 5.57 5.7! Ci7HtoClNO 4.844.7: Ci7HioC1NO 4.84 5.0; C13H17NO2 6.39 6.5: C13HlsClNOa
11.60 11.51 14.00 14.25 12.24 12.16 12.24 12.33 13.9 14.01
Previously described by Pope and Read (13, 14). Previously described by Braun (15). e Previously described by Braun (16). d Decomposes. e Darkens with slow rise in temperature. f Decornposes with effervescence. a
of crude 2-indanone. The procedure described by Heusler and Schieffer (29) in which the intermediary 2-methoxy-I-indanol was first isolated and purified before acid hydrolysis appeared 1o be the most satisfactory; this method gave I-indanone in over-all yields of 63% according to the following procedure: 2-Methoxy-I-indanol is first prepared by refluxing for one hour a mixture of 127.8 g. (0.6 mole) of 2-bromo-1-indanol and a solution of 30.0 g. (1 3 moles) of sodium in 300 cc. of methanol. Approximately one-half of the solvent is recovered and the reaction mixture is diluted with 1 liter of water; after cooling, the dark oil which separates is extracted with ether. The ether extracts are dried over anhydrous potmsium carbonate, the solvent is recovered and the product distilled. The yield of colorless 2-methouy-1-indanol distilling a t 149-152"/11-12 mm. is 70.4 g . (82.4%).
_
386
LEVIN, GRAHAM, AND KOLLOFF
Hydrolysis of 2-methoxy-1-indanol is carried out by refluxing for one hour a mixture of 49.2 g. (0.3 mole) of the methoxy alcohol with a solution of 66.0 cc. of concentrated sulfuric acid in 360 cc. of water. Steam distillation gives 2-indanone which, on cooling, forms colorless crystals, m.p. 56-57"; yield, 29.5 g. (74.5%). 2-Indanone resinifies slowly even a t low temperatures; accordingly, its immediate conversion to the oxime is desirable. B-lndanone oxime. The use of heat in the oximation of 2-indanone, particularly in the presence of alkali, results in decomposition. The following procedure gives excellent results : Twenty-nine and seven-tenths grams (0.225 mole) of 2-indanone is dissolved in 150 cc. of pyridine and a solution of 18.8 g. (0.270 mole) of hydroxylamine hydrochloride in 60 cc. of dilute ethanol is added with cooling and agitation. After standing at room temperature for 48 hours, the reaction mixture is stirred into 500 cc. of ice water; the precipitated oxime is filtered with suction and washed well with cold water. Recrystallization from hot 60% ethanol gives colorless crystals of 2-indanone oxime, decomposing a t 152-153"; yield, 31.5 g. (95.2%). SYNTHESIS OF AMINES
IX. 2-Aminoindane hydrochloride. Using active palladium catalysts, 2-indanone oxime was reduced to the primary amine in good yields according to the following procedure: To a suspension of 4.4 g. (0.03 mole) of 2-indanone oxime in 100 cc. of absolute ethanol containing 3.3 g. (0.09 mole) of hydrogen chloride is added 3.0 g. of active palladinized Norit (10%) and 0.3 g. of crystalline palladium chloride. Hydrogen uptake proceeds smoothly and, after shaking for approximately eight hours, reduction is complete. The reaction mixture is then warmed on a steam-bath to keep the amine hydrochloride in solution; the catalyst is removed and the filtrate concentrated under slightly reduced pressure in a current of dry air and finally dried in vacuo. The crystals of 2-aminoindane hydrochloride, after recrystallization from absolute ethanol-ether, darken at 220" (uncorr.) (slow rise in temperature); yield, 4.9 g. (96.3y0). X . 2-Benzalaminoindane. A mixture of 8.5 g. (0.05 mole) of 2-aminoindane hydrochloride, 5.0 cc. (0.05 mole) of benzaldehyde, and 4.6 g. (0.055 mole) of sodium bicarbonate in 75 cc. of alcohol is refluxed on a steam-bath for two hours. The reaction mixture is then allowed to cool to room temperature and diluted with 200 cc. of water. After thorough chilling, the crystals are removed by filtration and dried with suction. Recrystallization from dilute alcohol with the addition of Norit gives 10.6 g. (95.5%) of colorless crystals, melting a t 58-67'. The product is recrystallized from ligroin for analysis. No significant change in melting point occurs after several recrystallizations from ligroin, and, in view of the fact that indane derivatives exhibit dimorphism, i t may be presumed that this product is a mixture of dimorphic forms. No attempt was made to separate the crystalline forms; purity of the product was indicated by its reduction to 2-benxylaminoindane ( X I I I ) . X I . 2-Piperonylidenumznoindane. Using the above procedure, from 5.1 g. (0.03 mole) of 2-aminoindane hydrochloride, 4.8 g. (0.032 mole) of piperonal and 2.6 g. (0.031 mole) of' sodium bicarbonate in 50 cc. of ethanol, there is obtained 2-piperonylidenaminoindane which forms small, colorless needles from ethanol (600/0);m.p. 93.5-95.5"; yield, 5.9-6.3g. (73.7-79.2%). XII. 2-Anisalaminoindane. From 5.1 g. (0.03 mole) of 2-aminoindane hydrochloride, 3.6 g. (0.03 mole) of anisaldehyde and 3.4 g. (0.04 mole) of sodium bicarbonate in 50 cc. of ethanol, there is obtained, after recrystallization from dilute ethanol, 6.9 g. (90.8%) of colorless crystals, m.p. 1OO-10lo. X I I I . 2-Benzylaminoindane hydrochloride. Using platinum oxide catalyst, 4.4 g. (0.02 mole) of 2-benzalaminoindane (m.p. 58-67') dissolved in 25 cc. of absolute ethanol gives 4.6 g. (90%) of benzylaminoindane hydrochloride, which begins to darken a t 205". XIV. 2-Piperonylaminoindane hydrochloride. 2-Piperonylidenaminoindane (5.3 g., 0.02 mole) dissolved in 100 cc. of absolute ethanol gives on catalytic reduction 5.9 g. (96.7%) of colorless flakes decomposing at 234" (uncorr.).
PHYSIOLOGICALLY ACTIVE INDANAMINES
387
S V . .%(p-Methoxybenzyl)amznoindane. Using 50 cc. of glacial acetic acid as the solvent, 5.0 g. (0.02 mole) of 2-anisalaminoindane is catalytically reduced to the corresponding benzylaniine derivative. The hydrochloride salt of 2-(p-methoxybenzyl)aminoindane forms small, colorless flakes, which, after recrystallization from methanol-acetone, decompose a t >!33" (uncorr.); yield, 5.4 g. (93.1y0). XVI. 2-Methylarnznoindane hydrochlorzde. The following modification of the DeckerBwker method (20, 30) was adapted for the preparation of 2-methylaminoindane hydrochloride In a 500 cc. round-bottom flask are placed 5.6 g . (0.02 mole) of 2-piperonylidenaniinoindane, 2.9 cc. (0.03 mole) of freshly-distilled methyl sulfate, and 125 cc. of anhydrous et hylbenzene. The reaction flask is thoroughly flushed with nitrogen, securely stoppered and heated on a steam-bath. A heavy, dark oil separates and, after heating for 50 hours, the flask is cooled to room temperature; 100 cc. of diluted methanol (8:l) is added and the mixture pefluxed for one-half hour. Following the addition of 5 cc. of concentrated hydrochloric acid, the condenser is arranged for downward distillation and the methanol recovered, after which the ethylbenzene is removed in a current of steam. The aqueous solution remaining is then cooled, extracted with ether, and made strongly alkaline with Concentrated ammonia (28%). The dark purple amine is extracted with ether and the ether extracts are treated with dilute hydrochloric acid. The acid extracts are evaporated to dryness on a steam-bath and dried i n vacuo. Recrystallization of the residue from absolute ethanol-ether, n i t h the addition of a little ?;orit, gives colorless crystals decomposing at 210"; yield, 0.8 g . (21.6%). XVII. 2-Amino-1 -indanone hydrochlorzde. To 8.1 g. (0.05 mole) of 2-isonitroso-lindanone suspended in 100 cc. of absolute alcohol containing 5.5 g. (0.15 mole) of hydrogen chloride IS added 3.0 g. of 10% palladinized S o r i t ; the mixture is shaken in an atmosphere of hydrogen as described under Catalytic hydrogenations. Two equivalents of hydrogen arl: taken up in 20 to 25 minutes and the reduction comes to a standstill; the reaction flask is then warmed on a steam-bath t o disdolve the amino ketone hydrochloride and the catalyst is removed. The filtrate is concentrated to one-half its original volume and treated with C Y C ~ S Sanhydrous ether. After chilling, the precipitated 2-amino-1-indanone hydrochloride is filtered, vashed well with ether and recrystallized from anhydrous methanolether. ELy this procedure, 9.0 g. (97 801,) of colorless crystals, darkening at 200", is obtained. T t e same catalyst can be employed in the reduction of subsequent batches of the isonitroso ketone. Anal. Calc'd for CaHloCINO: IK,7.63. Found: N, 7.67. Diindeno [1,2-b, 1',2'-elpyrazine is obtained by treating 1.9 g. (0.01 mole) of 2-aminoI-indanone hydrochloride dissolved in 25 cc. of warm methanol with 100 cc. of diluted ammonia (5%). After standing at room temperature for 72 hours, the red precipitate obtained is separated by filtration and dried with suction; yield, 1.0 g. Recrystallization from acetoneligroin with the addition of a little S o r i t gives pale yellow crystals. The sample for analysis, after recrystallization from benzene-ligroin, forms small, pale yellow flakes which become red a t 265" (uncorr.). Winans and Adkins (31) obtained this pyrazine (which was reported to melt a t 270-271") by reducing 2-isonitroso-1-indanone in the presence of Raney nickel a t elevated temperature and pressure. Anal. Calc'd for C18H12N2: C, 84.4; H, 4.71; N , 10.9. Found : C, 84.43; H, 5.02; K, 10.83. S V I I I . 2-Benzal-1-indunone. To a suspension of 3.7 g. (0.02 mole) of 2-amino-1-indanone in 100 cc. of alcohol are added 2.0 cc. (0.02 mole) of benzaldehyde and 1.7 g. (0.02 mole) of sodium bicarbonate. The flask is thoroughly flushed with nitrogen and shaken for 10 hours at room temperature. After standing dvernight, 150 cc. of water is added, the mixture cooled and filtered, and the red precipitate obtained is then dried in vacuo. Recrystallization from benzene-ligroin gives 1.0 g. (21.3%) of pale yellow crystals. On heating, 2-benzal-1-indanone becomes pink a t about 200" and decomposes at 215". . 4 d . Calc'd for CleH13NO: N , 5.96; Found: X, 5.89.
388
LEVIN, GRAHAM, AND KOLLOFF
XIX. I-Amino-1-indanol. With a catalyst consisting of 3.0 g. of 10% palladinized Norit and 3.0 cc. of palladium chloride solution (IO%), it is possible to reduce several batches of 18.4 g. (0.1 mole) of 2-amino-1-indanone hydrochloride, suspended in 135 cc. of ethanol, to 2-amino-1-indanol i n about 40 minutes. The product is isolated as described under 2-amino-1-indanone hydrochloride; recrystallization from absolute alcohol-ether gives colorless crystals melting at 171-172'; yield, 18.0 g. (96.8%). The stereoisomeric forms of 2-amino-1-indanol hydrochloride melting at 206" and 176" are reported in the patent literature (19). The crude product obtained in this investigation melts at 164-165" and after several recrystallizations melts a t 171-172"; no attempt was made to separate the two forms. XX. 8-Benzalamino-f -indanol. A mixture of 6.5 g. (0.035 mole) of 2-amino-1-indanol hydrochloride, 3.5 cc. (0.035 mole) of benzaldehyde, and 2.8 cc. (0.035 mole) of pyridine in 100 cc. of ethanol is refluxed on a steam-bath for one hour, after which an excess of 10% sodium carbonate is added. The mixture is further refluxed for an additional 15 minutes and then concentrated to about one-half its original volume, whereupon crystals precipitate. An equal volume of water is added and, after chilling, the Schiff base is filtered off and dried with suction. Recrystallization from dilute ethanol gives 6.2 g. (74.7YG)of 2-benzalamino-1-indanol forming a red melt at 163-164'. XXI. 2-Piperonylidenamino-1 -indanol. From 4.3 g. (0.051 mole) of sodium bicarbonate, 9.3 g. (0.05 mole) of 2-amino-1-indanol, and 7.7 g. (0.051 mole) of piperonal in 150 cc. of ethanol colorless crystals of 2-piperonylidenamino-1-indanolare obtained; recrystallization from ethylene chloride-ligroin gives a product forming a red melt at 174.8-175.8'; yield, 11.0 g. (80%). XXII. I-Anisalamino-f-indanol.From 11.1g. (0.06 mole) of 2-amino-1-indanol hydrochloride, 7.9 cc. (0.065 mole) of anisaldehyde and 13.6 cc. (0.20 mole) of 28y0 ammonia in 100 cc. of ethanol, there is obtained, after recrystallization from benzene-ligroin, colorless crystals of 2-anisalamino-1-indanol, melting at 171.8-173.0'; yield, 14.0 g. (87%). XXIII. 2-Pipe-ronylamino-1-indanol hydrochloride. 2-Piperonylidenamino-1-indanol (4.2 g., 0.015 mole) is dissolved in a mixture of 100 cc. of absolute ethanol and 50 cc. of glacial acetic acid and catalytically reduced t o 2-piperonylamino-1-indanol.The yield of the colorless hydrochloride is 4.6 g. (98Qlo); recrystallization from absolute ethanol-ether gives crystals decomposing with effervescence at 216-217" (uncorr.). XXIV. I-(p-Methoxybenzy1amino)-1 -indanol hydrochloride. Reduction of 4.0 g. (0.015 mole) of 2-anisalamino-1-indanol dissolved in 50 cc. of glacial acetic acid gives 4.1 g. (90%) of 2-(p-methoxybenzylamino)-l-indanolisolated as the hydrochloride. The product consists of colorless crystals melting with effervescence a t 212-213". XXV. 2-Phenethylamino-1-indanolhydrochloride. A mixture of 3.7 g. (0.02 mole) of 2-amino-1-indanol hydrochloride, 3.7 g. (0.02 mole) of phcnethyl bromide and 2.3 g. (0.022 mole) of anhydrous sodium carbonate in 100 cc. of absolute alcohol is heated for 48 hours in an autoclave immersed in an oil-bath maintained a t 130-135". The reaction product is then diluted with water and treated with hydrochloric acid until strongly acid. After warming with Norit, the mixture is filtered and the filtrate made alkaline with concentrated ammonia. The purple precipitate obtained is separated by filtration, dried with suction, and then dissolved in absolute alcoholic hydrogen chloride. On the addition of absolute ether, colorless crystals darkening a t 175' are obtained. After several recrystallizations, the product begins to darken at 182' (slow rise in temperature) ; the yield is poor. XXVI. 2-Benzylamino-1 -indanol. ( a ) Catalytic reduction of R-benzalamino-1 -indanol. 2-Benzalamino-1-indanol (11.4 g., 0.05 mole) in 100 cc. of glacial acetic acid is Catalytically reduced to 2-benzylamino-1-indanol. Recrystallization of the free base from benzeneligroin gives 11.5 g. (97.1%) of colorless crystals forming a red melt at 144.4-145.0'. ( b ) Reductive benzylation. A mixture of 9.3 g . (0.05 mole) of 2-amino-1-indanol hydrochloride, 4.2 g. (0.05 mole) of sodium bicarbonate, 5.5 cc. (0.055 mole) of benzaldehyde, and 100 cc. of ethanol, contained in a hydrogenation bottle, is warmed on a steam-bath until the evolution of carbon dioxide ceases; 4.1 g. (0.05 mole) of anhydrous sodium acetate and
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0.1 g. of platinum oxide catalyst are then added and the reaction bottle shaken a t room temperature (initial hydrogen pressure 60 pounds). The theoretical amount of hydrogen is taken up in about five hours, after which the amino alcohol is isolated as in procedure (a). There is obtained 10.9 g. of crude product which, after several recrystallizations, gives colorless crystals forming a red melt a t 144-145"; a mixed melting point determination with pure 2-benzylamino-1-indanol shows no lowering. The hydrochloride salt of 2-benzylamino-I-indanol forms colorless crystals decomposing a t 225" (uncorr.). S S V I I . I-Amino-2-indanol hydrochloride. This was prepared according to the procedure of Pope and Read (13,14). From 21.3 g. (0.1 mole) of 2-bromo-1-indanol and 205 cc. of ammonia (28p/c),there is obtained 8.5 g. (56%) of I-amino-2-indanol rrielting a t 126-127'; the hydrochloride salt begins to darken at 232" (uncorr.). S X V I I I . 1-Benzalamino-2-indanol. The procedure of Pope and Read (13) was used; from 4.5 g. (0.03 mole) of 1-amino-2-indanol and 3.0 cc. (0.03 mole) of benzaldehyde dissolved in 50 cc. of alcohol, there is obtained 6.7 g. (94.4%) of practically colorless crystals melting a t 162". Recrystallization from benzene gives colorless crystals, melting at 164.2165.2"; a mixed melting point determination with 2-benzalamino-I-indanol (m.p. 163-164') produces a lowering to 140-142". XXIX. 1-Anisahmino-2-indanol. From 6.0 g. (0.04 mole) of 1-amino-2-indanol and 4.8 cc. (0.04 mole) of anisaldehyde in 100 cc. of ethanol, there is obtained l-anisalamino-2indanol, which, after recrystallization from toluene, forms colorless flakes decomposing at 193-194"; yield, 10.2 g. (95.3%). XXX. 1-Methylamino-8-indanol hydrochloride. Using the method of Braun and Weissbach (15), from 21.3 g. (0.1 mole) of 2-bromo-I-indanol and 150 cc. of 35% aqueous methylamine there is obtained 13.0 g. (65.2%) of 1-methylamino-2-indanol isolated as the hydrochloride Lialt; m.p. 174-175'. X X X I , 1-Dimethylamino-2-indanol hydrochloride. Braun (16) obtained this amine by refluxing 2-bromo-1-indanol with excess dimethylamine in benzene. I n these studies 1-dimethylamino-2-indanolwas prepared by shaking 10.7 g. (0.05 mole) of 2-bromo-lindanol with 50 cc. of aqueous dimethylamine (33%) a t room temperature for 40 hours; the yield of product isolated as the hydrochloride salt is 6.0 g. (56%); m.p. 183-184". XXXII. 1-Isopropylamino-2-indanolhydrochloride. A mixture of 10.7 g. (0.05 mole) of 2-bromo-I-indanol and 42.7 cc. (0.5 mole) of isopropylamine is shaken at room temperature for 40 hours. The insoluble material is removed by filtration and the filtrate concentrated t o :t small volume. After treatment with dilute hydrochloric acid and Norit, the mixture is filtered while hot. To the cooled filtrate is added an excess of 20% aqueous sodium hydroxide; the colorless crystals of the base are filtered and dried an vacuo. Conversion of the free base to the hydrochloride salt gives colorless crystals decomposing at 222-223' (uncorr.); yield, 7.2 g. (63%). XXXIII. 1-Benzylamino-d-indanol hydrochloride. ( a ) From 2-bromo-1 -indanol and benzylamine. A mixture of 42.6 g. (0.2 mole) of 2-bromo-1-indanol and 45.7 cc. (0.42 mole) of benzylamine dissolved in 150 cc. of anhydrous benzene is refluxed on a steam-bath for 48 hours. The precipitated benzylamine hydrochloride is removed by filtration and the filtrate treated with absolut'e hydrogen chloride. The crude hydrochloride salt of l-benzylamino-2-indanol thus obtained is dissolved in warm water and treated with excess 30% aqueous sodium hydroxide. The yield of colorless crystals, after recrystallization from dilute ethanol is 20 g. (41.8%); m.p. 102-103°. The hydrochloride salt decomposes a t 203". ( b ) B y the catalytic reduction of I-benzalamino-6-indanol.By the general procedure, 5.9 g . i(0.025 mole) of 1-benzalamino-2-indanol is catalytically reduced to l-benzylamino2-indanol in practically quantitative yields; the product is identical with that prepared from the kiromohydrin and benzylamine. XXXIV. I-(p-Methoxybenzy1)amino-9-indanol.From 5.3 g. (0.02 mole) of l-anisalamino-2-indanol dissolved in 50 cc. of glacial acetic acid, there is obtained by catalytic
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reduction practically quantitative yields of 1-(p-methoxybenzyl)amino-2-indanolisolated as the hydrochloride salt; m.p. 202-203". XXXV. 1-Piperidyl-8-indanol hydrochloride. A mixture of 21.3 g. (0.1 mole) of 2-bromo1-indanol and 39.8 g. (0.4 mole) of piperidine, dissolved i n 100 cc. of anhydrous ethylbenzene, is heated on a steam-bath for 40 hours. The precipitated piperidine hydrobromide is separated and the filtrate distilled under reduced pressure to remove unreacted piperidine. After cooling, the undistilled portion is treated with excess absolute ethanolic hydrogen chloride and on the addition of absolute ether the hydrochloride of 1-piperidyl2-indanol precipitates out. Recrystallization from absolute ethanol-ether gives colorless crystals decomposing at 211'; yield, 15.6 g. (61.5%). The p-nitrobenzoate ester of 1-piperidyl-2-indanol hydrochloride is prepared by heating a mixture of 5.1 g. (0.02 mole) of 1-piperidyl-2-indanol hydrochloride and 18.6 g. (0.10 mole) of p-nitrobenzoyl chloride on a steam-bath for three hours and then a t 120" for two hours. On the addition of ether, pale yellow crystals are obtained, which decompose at 225" (uncorr.); yield, 7.0 g. (84.3%). The free base is obtained by dissolving the hydrochloride in hot water and neutralizing with dilute sodium hydroxide solution. Recrystallization from acetone-water gives small flakes of 1-piperidyl-2-indanol p-nitrobenzoate melting a t 155.8-156.5'. Anal. Calc'd for C ~ I H ~ ~ N Z O ~ .C1, H C8.8. I: Found: C1, 8.8. Calc'd for CzlHe2Nt04: N, 7.63. Found: N , 7.62. XXXVI. 1-Phenethylamino-2-indanolhydrochloride. This amine is prepared by the procedure given for 1-benzylamino-2-indanol hydrochloride. From 12.8 g. (0.06 mole) of 2-bromo-1-indanol and 14.5 g. (0.12 mole) of phenethylamine (Eastman Kodak) in 100 cc. of benzene, there is obtained 4.0 g. (26.3%) of 1-phenethylamino-2-indanolmelting at 125-126' after recrystallization from dilute ethanol. Conversion to the hydrochloride gives 4.1 g. of colorless crystals, decomposing at 205-206'. XXXVII. 1-Methylbenzylamino-2-indanolhydrochloride. Fourteen and nine-tenths grams (0.07 mole) of 2-bromo-1-indanol and 19.4 g. (0.16 mole) of methylbenzylamine are dissolved in 100 cc. of decalin and the solution is heated on a steam-bath for 50 hours. The precipitated methylbenzylamine hydrobromide is separated and the unreacted methylbenzylamine is recovered by distilling at 2-3 mm. until the distillate gives no precipitate with alcoholic hydrogen chloride. The product is then isolated as the hydrochloride; yield, 9.5 g. (46.8%). After several recrystallizations from ethanol-ethyl acetate, the 1-methylbenzylamino-2-indanolhydrochloride me1ts a t 172.O-173.3'. XXXVIII. 1 -Morpholinyl-2-indanol hydrochloride. Fourteen and seven-tenths grams (0.07 mole) of 2-bromo-1-indanol and 26.4 g. (0.30 mole) of morpholine dissolved in 100 cc. of anhydrous benzene, contained in a securely stoppered flask, are heated on a steam-bath for 80 hours; the precipitated morpholine hydrochloride is filtered off and the filtrate treated with alcoholic hydrogen chloride. The crystals obtained are filtered off and dissolved i n warm water; on the addition of 30% aqueous sodium hydroxide, 1-morpholinyl-2-indanol precipitates' out; yield, 9.2 g. (60.1%). Recrystallization from benzene-ligroin gives colorless crystals melting a t 175.8-177.0'. The hydrochloride, recrystallized from absolute ethanol-ether, decomposes with effervescence at 225" (uncorr.). SUMMARY
1. The preparation of a group of N-substituted derivatives of 2-aminoindane, 2-amino-l-indano1, and 1-amino-Sindanol is described. 2. A summarized pharmacological report for ten derivatives indicates that several are active bronchodilators, although they have little or no effect on blood pressure. KALAMAZOO, MICH.
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(2) Ger. Patents: 615,412 (1935); 644,909 (1937); 699,249 (1940); 699,250 (1940); 697,805 (1940). (3) C. S. Patents: 2,088,941 (1937); 2,234,933 (1941); 2,298,630 (1942); 2,293,874; 2,293,875; 2,293,876; 2,293,877 (1939). (4) KENNER AND MATHEWS, J . Chem. SOC.,106, 745 (1914). (5) BORBCHE AND POMMER, Ber., 64, 102 (1921). (6) BENZDICKT, Ann., 276, 351 (1893). YANTSCHULEWITSCH, SACHS, AND NERDEL, Ann.,'618, 155 (1935). (7) HUCKEL, (8) KIESE,Arch. exptl. Path. Pharmakol., 178,356 (1935). J . Am. Chem. Soc., 60,3370 (1928). (9) HAR'TUNG, J . Am. Chem. Soc., 61,2262 (1929). (10) HAR'ruxG . ~ N DMUNCH, (11) HARTUNG, J . Am. Chem. Soc., 63,2248 (1931). Ber., 26, 1538 (1893). (12) SPILKER, (13) POPE: AND READ,J . Chem. SOC., 99,2071 (1911). (14) POPE: A N D READ,J . Chem. SOC., 101,758 (1912). AND WEISSBACH, Ber., 63,3052 (1930). (15) BRAIJN AND KIRSCHBAUM, Ber., 66, 3648 (1922). (16) BRAUN,BRAUNSDORF, AND DUVIGNEAUD, J . Am. Chem. SOC.,46,2093 (1924). (17) MARVEL J. Phurmacol., 7, 121 (1915). (18) IREDA, (19) Ger. Patent: 598,142 (1934); Fr. Patent: 749,028 (1934). AND BECKER, Ann., 396,328 (1913). (20) DECKER, AND YON OETTINGEN, Proc. SOC.Exptl. Biol. Med., 26, 692 (1928). (21) SOLLMANN (22) Organic Xvntheses, Coll. Vol. I, (1941), 61. (23) SUTERBND MILNE,J . Am. Chem. Soc., 62,3473 (1940). (24:) REAL)AND HURST,J . Chem. Soc., 121, 2550 (1922). AND SUTER, J . Am. Chem. SOC.,87,2022 (1935). (25) PORTER 66,480 (1894). (26:) KIPPING,J . Chem. SOC., AND PIGGOTT, J . Chem. SOC.,116,143 (1919); 123, 1469 (1923). (27:) INGOLD J. Org. Chem., 7,408 (1942). (28) LEVINAND HARTUNG, AND SCHIEFFER, Ber., 32, 28 (1899). (2911 HEUSLER (30) WOODRUFF, J . Am. Chem. Soc., 62, 922 (1940). AND ADKINS,J . Am. Chem. SOC., 66,4167 (1933). (31) WINANS
