June, 1935
AMINOALCOHOLS DERIVED FROM OCTANTHRENE [CONTRIBUTION FROM THE COBB CHEMICAL LABORATORY, UNIVERSITY OF VIRGIMA, NO.
1107 1561
Studies in the Phenanthrene Series. VIII. Amino Alcohols Derived from 1,2,3,4,5,6,7,8-O~tahydrophenanthrene~ BY
JACOB VAN DE
KAMPAND ERICHMOSETTIG
Pharmacological investigations2have shown that some of the phenanthrene derivatives with the side chain -CHOHCH2N=3 and -CHOHCHN=4 ex-
The catalytic reduction of the amino ketones to the corresponding amino alcohols does not offer any difficulties. Of the propanolamines I apparently only one of the possible diastereomeric CH8 forms was obtained. Acetyl- and propionylhibit in the cat a certain resemblance to morphine. octanthrene yield on oxidation with sodium hypoSince the fundamental hydrocarbon skeleton of chlorite the acid known as octanthrene-g-carmorphine is a hydrogenated phenanthrene nucleus, boxylic acid. This acid is identical with that obthe synthesis of hydrogenated phenanthrene derivtained by catalytic reduction of phenanthrene-9atives carrying these alkamine side chains has carboxylic acid. The hitherto assumed 9-posibeen undertaken in the hope of attaining still more tion of the carboxyl group in octanthrene-9active compounds. carboxylic acid, as well as the position of the Among the known partially hydrogenated chloroacetyl, acetyl and propionyl groups in the phenanthrenes the 1,2,3,4,5,6,7,8-octahydrooctanthrene derivatives here described, is thus phenanthrene or “ ~ t a n t h r e n e ”appears ~ espedemonstrated. cially convenient as starting material for the inTable I gives a summary of the reactions and troduction of substituents. By the Friedel and compounds dealt with in this paper. It is inCrafts reaction with chloroacetyl chloride the 9tended to attempt the preparation of analogous w-chloroacetyloctanthrene of Schroeter6 can be prepared, in which, however, the halogen atom amino alcohols derived from 9,10-dihydro-, 1,2,3,4reacts with secondary amines only slowly. There- tetrahydro- and 1,2,3,4,9,10,11,12-octahydrophenfore we prepared the w-bromoacetyl derivative by anthrene. We are indebted to Mr. Lyon Southworth of bromination of 9-acetyloctanthrene. The bromine is easily exchanged for the dimethylamino, this Laboratory for many of the analyses appeardiethylamino and piperidino groups. Attempts ing in tbis paper. to prepare in the same way, with monomethylExperimental and monoethyiamine, the secondary amino kePreparationof 1,2,3,4,5,6,7,8-0ctahydrophenanthrene.tones were without results. The primary amino Three hundred and fifty-six grams (2 moles) of phenanketone is obtained by the reduction of isonitroso- threne,6 40 cc. of dry decahydronaphthalene’ and 10 acetyloctanthrene with stannous chloride. In to 12 g. of Raney nickel catalyst* were heated, with an analogous way, the corresponding homologous constant shaking, in a hydrogen atmosphere at 120’ under amino ketones were prepared from 9-propionyl- an initial pressure varying from 1600 to 2100 lb., in the octanthrene. The exchange of the a-bromine apparatus (contents 750 cc.) described by Adkins and Cramer.9 atom with the monomethylamino and monoHydrogen absorption started at 120’. From two to ethylamino group in a-bromopropionyloctan- eight days were required for absorption of the amount of threne proceeds very well, quite in contrast to hydrogen necessary for the formation of octahydrothe corresponding experiments with w-bromoacet- phenanthrene. Every two days a fresh amount of 10 to 12 g. of catalyst was added. The end of the reduction was yloctanthrene. (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. (2) Nathan B. Eddy, unpublished results. (3) (a) Mosettig and van de Kamp, THISJOURNAL, 66, 3448 (1933); (b) Burger and Mosettig, ibid., 56, 1745 (1934). (4) Mosettig and Czerwin, unpublished results. ( 5 ) Schroeter, Ber., 57, 2025 (1924). The trivial name proposed by Schroeter will be used as a convenient abbreviatiou.
evident by a marked drop in the rate of hydrogen absorp-
(6) The phenanthrene used in these reductions was a product purified according t o Cohen and Cormier, THISJOURNAL, 6.2, 4363 (1930), subsequently heated with sodium a t 200’ for two hours, and finally distilled. (7) Mosettig and van de Kamp, ibid., 65,2996 (1933), footnote 10. (8) This catalyst was prepared according t o directions of Covert and Adkins, ibid., 64,4116 (1932). It was then washed with absolute ethyl alcohol and suhsequently with decahydronaphthalene until the latter showed no turbidity. The nickel was kept under dry decahydronapbthalene. (9) Adkins and Crarner. ibid., 68, 4349 (1930).
JACOB VAN DE
KAWPAND ERICHMOSETTIG
VOl. 57
TABLE I
+ 9-COCHzC1
+ -COCHzN(CHs)z
-9-COCHs __
U -COCH=NOH
r+
JI
-1
-COCHBrCHs
+9-COCHzCHsI
-COCCH8
11
NOH
A - C O C H C H S
I
NHr
tion.10 After removal of catalyst and solvent, the reduc- minum chloride was added in small portions in the course of tion product was distilled in an oil pump vacuum and one hour. After this, stirring was continued for five more then purified through the sodium sulfonate according to hours and the temperature maintained a t -15'. Schroeter.s The regenerated hydrocarbon was rectified, The yields of the acid, chloroacetyl-, acetyl- and prob. p. 179-180' (20 mm.), n% 1.5669.'' Cooled in ice, it pionyl- derivative were 87, 89, 98.5 and 47%, respectively. readily crystallized t o a mass of colorless needles.12 In our The acid gave no depression in melting point when mixed experiments the yield varied from 70 to 85%, the better with a sample of the acid which results from saponification yield being obtained at the lower temperature (120'). of the product formed by catalytic reduction (4 moles of Anal. Calcd. for C~J-IIS:C , 90.25; H, 9.75. Found: hydrogen) of phenanthrene-Q-carboxylic acid ethyl ester with platinum in glacial acetic acid. C, 90.31; H , 9.66. Oxidations of both 9-acetyl- and 9-propionyl-1,2,3,4,Friedel and Crafts Reactions.-For the preparation of 1,2,3,4,5,6,7,8-octahydrophenanthrene-9-carboxylicacid, 5,6,7,8-octahydrophenanthrenewith a 2% sodium hypochlorite solution gave 1,2,3,4,5,6,7,8-octahydrophenan9-w-chloroacetyl-, 9-acetyl- and 9-propionyl-1,2,3,4,5,6,7,8-octahydrophenanthrene,the Friedel and Crafts reaction threne-9-carboxylic acid. This acid and its methyl ester gave no depression in melting points with samples was applied t o 1,2,3,4,5,6,7,8-octahydrophenanthrene. To a solution of 1 part of 1,2,3,4,5,6,7,8-octahydro- of the acid mentioned above, and its methyl ester, rephenanthrene in 10 parts of carbon disulfide, cooled to spectively. The ketones were brominated'* to the O-w-bromoacetyl-15O, the acid chloridelS was added, and 2 moles of aluand 9-cu-bromopropionyl-1,2,3,4,5,6,7,8-octahydrophenan(10) At temperatures of 140° a satisfactory yield of octahydrothrene, respectively. The bromine atom in these bromo phenanthrene was obtained in a shorter time. At 150' the yield was ketones was exchanged with primary and secondary considerably smaller due t o the formation of higher hydrogenated amines, to form secondary and tertiary amino ketones. products. At 175' only higher hydrogenated products were formed. From 9-acetyl- and 9-propionyl-1,2,3,4,5,6,7,8-octahydro(11) Auwers, Ann., 490, 259 (1930), measured nP% 1.5868 on Schroeter's product. phenanthrene the isonitroso derivatives16 were prepared (12) Schroeter gives the m. p. a8 16.7". (13) In the case of acetyl-, propionyl- and chloroacetyl chloride, a 10% excess was used, with oxalyl chloride, 100% excess. Schroeter, in the preparation of w-chloroacetyloctanthrene,heated the hydrow b o s with the w i d chloride and Q trace of phosphorus pentoxide.
(14) The bromination was carried out in absolute ether as described previously (see reference 3a). (15) The yield of the isonitroso derivatives varied between 30 and 50% of the theoretical.
June, 1935
AMINOALCOHOLS DEtRIV€i!D FROM
OCTANTHRENE
1109
TABLE I1
Derivatives of 1,2,3,4,5,6,7,8-0ctahydtophenanthrene Solvent 9-Acetyl-* MeOH -Oxime MeOH -Semicarbazone MeOH S-Propionyl-* MeOH -Oxime MeOH 9-u-Bromoacetyl-* EtOH 9-a-Bromopropionyl-* *-9-Carboxylic EtOH, acid AcOH -Methyl ester MeOH 9-(2-Amino-l-oxo)-ethyl-* hydrochloride Hz0 -Picrate EtOH 9-(2-Amino-l-hyEtOH droxy) -ethyl-* Hz0 -Hydrochloride EtOH ether -Picrate EtOH 9-(2-Dimethylamino-1-oxo)-ethyl-* EtOH hydrochlorideC ether -Picrate EtOH 9-(2-Dimethylamino1-hydroxy)ethyl-* EtOH -Hydrochloride EtOH ether -Picrate EtOH 9-(2-Diethylamino1-oxo)-ethyl-* EtOH perchlorate' ether -Picrate EtOH 9- ( 2 -Diethylamino1-hydroxy)EtOH ethyl-* Ha0 -Hydrochloride ElOH 4ether -Picrate EtOH
+ +
Appearance" Rectangular plates Plates Plates Prisms Needles Needles Oil
Formula
Carbon % Calcd. F'ound
8.83
8.57
71.53 71.49 84.24 84.35
8.13 9.16
8.04 9.08
CIEI-IH,DO Ci6HnON CirHraONa CirHzzO ClrHzaON CtoHloOBr CirHzlOBr
Prisms Prisms
241-242 45
CiiH180z CisHzoOz
Leaflets Prisms Needle clusters
232-234* dec. CldHzzONCl 215-216 dec. C Z P H Z ~ O B N ~ 103-104
CisHzsON
Hydrogen % Nitrogen % Calcd. FoLnd Calcd. Fdund
84.15 84.00
68-59 158.5-159.5 191.5-193 52.5-53 146-147 55-56
Plates
236-237, gd dec. 116-117
Plates
80-80.5
5.76
5.98
5.45
5.67
78.21 78.39 78.64 78.28
7.88 8.26
C1, 12.68 12.71
78.31 78.00
9.45
11.87
11.73
4.97 11.82
5.08 11.96
9.42
C1, 11.52 11.51
CwHrsOsN4
Diamonds Plates
217-218 193-194
Plates Needles
165-166 CzoHsoOsNCI 144.5-145.5 CzeHsrOsNr
25.97 25.01
7.94 8.35
CisHpsONCl
CisHnrON
Halogen, yo Calcd. Found
Br, 26.03 Br, 24 89
Leaflets 263.5-254 CI~HZIONCI Needles 208.5-209.5 dec. CtzHm0eN1
+ Plates
+
M. p., OC.
79.06
79.00
9.96
11.20
11.35
4.52 11.16
4.62 11.42
9.85
CIBHZBONCI CziHsoOsNi
+
3.51 3.66 10.61 10.79
+
9-(2-Piperidino-1oxo)-ethyl-* Acetontperchloratec ether -Picrate &OH 9- (2-Piperidino-lhydroxy) -ethyl-e* -Hydrochloride EtOH -Picrate EtOH 9-(2-Amino-1-oxo)-propyl-* hydrochloride Et OH -Picrate EtOH 9-(2-Amino-l-hydroxy)n-propyl-* EtOH -Hydrochloride EtOH ether -Picrate EtOH 9- (2-Dimethylamino1-0x0)-propyl-* RtOH -1perchlorateC ether -Picrate EtOH 9- (2-Dimethylamino1-hydroxy)-npropyl-* hydro- EtOH 4chlorideh ether -Picrat e WOH 9- (2-Diethylamino1-oxo)-propyl-* EtOH 4perchloratec ether 9-(2-Diethylamino1-hydroxy).n-propyLi* -Hydrochloride EtOH ether 9-(2-Piperidino.1oxo)-propyl-* EtOH hydrochlorideC ether
+
+
+
Plates
72.6-73
CroHnON
7R67
79.71
10.37 10.38
Prisms 148-149 Rectangular plates 159-160
CzoHnONCI CisHa~OaNd
10.57 10.85
Needles Needles
220 5-232 116.5-117
CnHaaOsNCl CzrHszOsNr
3.40 3.63 10.37 10.57
Needles Prisms Blades
86-86.5 227-227.5 164.6-165.5
CnHaiON 80.45 80 12 CziHszONCI C17HdrOsNr
Needles Needles
231-233 dec. 181-182 dec.
CirHn~0NCl C?sftzaOsNa
Plates
164-164.5
Ci7HnON
I
78.70 78.57
9.97
9.72
C1, 10.50
10.56
C1, 11.32
11.33
9.91 10.33
10.52
4.77 11.52
4.84 11.80
9.67
Diamonds 278-279 Ci7Hz60NCI Prisms 224-224.51 dec. CzaHzeOsNn
11.48 11.77
Rectangular plates 198.5-200 CigHzaOsNCl Plates 185-1P6 dec.@Cz~Hso08N4
5.63 3.59 10.90 10.91
CI, 11.99 12.12
Hexagonal plates 227-228 Needles 174-174.5
CioHaoONCl 70.43 70.43 CsHesOsNd
Plates
209-210
CziH3zO~NCI
Oi 1 Plates
210-211
CniHssON 79.93 CziHsrONCI
Blades
181-182
CnHszONCI
9.34
c1, 10.95 11.08
9.52 10.85 lO.Y2
3.39 79.86
10.55
3.56
10.79 C1, 10.08 10.25
3.87
4.01
1110
JACOB VAN DE
KAMPAND ERICHMOSETTIG
Vol. 57
TABLE I1 (Concluded) Derivatives of 1,2,3,4,5,6,7,8-0ctahydrophenanthrene Solvent Appearance" 9-(2-Piperidino-l-hydroxy)n-propyl-* EtOH Plates Prisms -Hydrochloride EtOH g-(Z-Methylamino1-oxo)-propyl-* EtOH hydrochloride7 ether Prisms -Picrate EtOH Plates 9-(2-Methylamino-2-hydroxy)Prisms n-propyl-* EtOH -Hydrochloride EtOH iDiamonds ether -Picrate EtOH Plates 9-(2-Ethylamino-l0x0)-propyl-* EtOH f hydrochloride? ether Plates -Picrate EtOH Blades 9-(2-Ethylamino- l-hydroxyjPrisms n-propyl-e* . .. -Hydrochloride EtOH f Rectangular ether plates
M. p., "C.
Carbon, % Calcd. Found
Formula
126.5-127.5 CatHssON 80.67 80.95 235-236 CzmHs40NCl
Hydrogen, % Nitrogen, % Calcd. Found Calcd. Found 10.16
Halogen, % Calcd. Found
10.24 3.85
4.04
C1,
9.75
9.95
C1, 11.45
11.45
C1, 10.95
10.96
+
223-224.5 ClsHmsONCl 192-193 dec.k C2&aOaN4
4.55 4.70 11.20 11.18
129.5-130
ClaHmrON
79.06 79.04
218-219 179-180
ClsHmsONCl C~Hso0sNd
11.16
226-228 163-164
CloH2sONCl CrHso0aN1
4.85 4.53 10.90 10.95
124.5-125
CIPHZ~ON 79.38
118-119
ClpHsoONCl
79.62
9.96
9.84
11.31
10.18 10.33 4.33
4.22
All substances are colorless, with the exception of the picrates which are all yellow. Turns brown a t 225'. The exchange of the bromine atom with the amine was effected in ethereal solutions as described in a previous paper, see reference 3a. Sinters a t 226". Sublimed a t 0.01 mm. I Sinters at 223'. Sinters a t 180'. The free base is oily. The exchange of the bromine atom with the amine was effected by heating a solution of the Distilled a t 0.01 mm. bromo ketone in dry benzene with the amine in a pressure flask a t 50-55'. Sinters at 189'. according to Claisen and Manassel6 and were reduced to the corresponding amino ketones with stannous chloride and concentrated hydrochloric acid in the presence of a trace of tin." The exchange of the bromine atom in w-bromoacetyl1 , 2 , 3 , 4 , 5 , 6 . 7 , 8 octahydrophenanthrene with primary amines has so far failed t o give any satisfactory results. All the aniino ketones were reduced catalytically with platinum oxide in ethyl alcohol, either as the free base or preferably as the hydrochloride, t o the corresponding amino alcohols.'* In Table [I the data concerning these compounds are presented. In order to avoid frequent repetition of the
-
(16) Claisen and Manasse, Ber., BO, 2194 (1887). (17) Rupe, ibid., BE, 251 (1895); Mills, J . Chem. Soc., 1567 (1934). (18) The method of preparing the secondary and tertiary propanolamines in this series is in principle the same as that first applied by Eberhard, Arch. Pharm., 265, 62 (1915), more recently by Hyde, Browning and Adams, THIS JOURNAL, 60, 2287 (1928) in the preparation of ephedrine and its homologs.
name 1,2,3,4,5,6,7,8-octahydrophenanthrene,it is indicated by *.
Summary The preparation of a series of amino alcohols derived from 1,2,3,4,5,6,7,8-octahydrophenanthrene is described. From 9-acetyl-1,2,3,4,5,6,7,8-octahydrophenanthrenederivatives carrying the side chain -CHOHCH2NR2 (NR2 being the amino, dimethylamino, diethylamino, or piperidino group) are obtained. From 9-propionyl1,2,3,4,5,6,7,8-octahydrophenanthrene, derivatives with the side chain -CHOHCH(CH3)NR2 (NRa being the amino, dimethylamino, diethylamino, piperidino, monomethylamino, or monoethylamino group) are obtained. UNIVERSITY, VA.
RECEIVED APRIL13, 1935
