1
I1
I11
XI
b
\ Ron lMeL'/
VI
SO('].
Me
x tion. Finally, IX was obtained in good yield by the reaction of XI with methylenetriphenylphosphorane. Hydrogenation of IX (free base) with PtOx gave the 10a-Me derivative XI1 and the 10P-Me derivative XI11 in 7.4 and 24.6% yields6 together with the secondary amine XIV (mixture of the diastereoisomers)' (Scheme 11). On the other hand, hydrogenation in the presence of 15% HC1 in EtOH4a gave two products, XI11 (85yo) and XI1 (12%), respectively. S m r spectrum of XI1 showed the signal of the secondary Me at T 9.1, while the p isomer XI11 showed the signal at 7 8.7. This paralleled the reported observation in the benzomorphan series.8 0-Demethylation of XI1 and XI11 with 48% HBr gave the respective phenolic derivatives XV and XVI. Wolff-Kishner reduction of XI gave a mixture of the deoxo derivative XVII and the dihydronaphthalene (6) Stereospecific formation of t h e a-Me derivative has been reported for t h e benzomorphan derivative. See ref 4a. (7) Hydrogenation of t h e I S ' H C I in E t O H also gave these t h e e products. See the Experimental Section. ( 8 ) S. E. Fullerton, E. L. &ray, and E , L). l3ecker. J . O r y . Ciiem., 27, 2144 (IUtiP).
VII, R = Me VIII. R = H
derivative XVIIIag (Scheme 111). llethylation of XVIIIa gave XVIIIb, ident,ical with the product obtained by exhaustive methylation of XVII. Demethylation of XVII afforded the phenolic derivative XIX. CrOs oxidat,ion1Oof XVII gave the 9-oxo derivat'ive XX. The methoperchlorat'e X X I b prepared from X X was also obt,ained from I1 by a series of react'ions (Scheme IV), although t'he reaction of X X l V . H B r with YH40H11gave t'he cyclized product in a very low yield according to the concurrent production of an eliminat,ion product XXV. This confirms the st'ructure of XX and hence that, of XVII. These compounds were tested for analgetic activit,? by t8hehot platmemethod.12 Analget'ic activity of the (9) Concurrent elimination of t h e a-amino group during t h e IVolffIiishner reduction of a i-membered a-aminoketone has been reported. S?e N . J . Leonard and 8.Gelfand. J . A m e r . C h e m . Soc., 11, 3269 (1955). (10) S.Ohshiro. Tetrahedron, 10, 1 i 5 (1960). (11) (a) E. L. M a y and J . G. hlurphy. J . Ory. C h e m . , 20, 257 (1955); ( h ) H. ICugita, S . Saito. and E. L. M a y , J . .)fed. P h a r m . C h e m . , 6, 357
(1962).
(12) N . 1%. E d d y and L). Leiinlracli, J . P h u r m , i c d . 6 r p . ?'her.. 101, 885 (1'353). Tlie tests were conducted b y L)r. G . Hayashi and associates in t h e Clinical I'harlnaaolo-y Department.
SCHEME IV Me0
XVII
rroI
ns,n
-
.X-
----t
Y&xs Me"
-
NMe
Me"
NMe?
XXIa, X = Br I,. x = CIO$
Y&Me2 Me
XH'
M
XXII
orated. The residue was converted into a picrate in EtOH (3.7 g, 98%), mp 151-154'. Hydrogenation of IX. a.-Free base I X (1.5 g) n'as hydrogenated with PtOz (200 mg) in EtOH (15 hr). The crude base in Et20 was converted into its picrate and filtered to give 1.22 g, mp 131-140'. The base regenerated from the picrate was dissolved in MezCO and converted into the hydrochloride (520 mg), mp 112-116", recrystallized from Me2C0 to give 2'-methoxy-2,6,10~-trimethyl-7,8-homobenzomorphan (XIII).HCI (425 mg, 24.6%) had mp 118-121"; nmr (free base), T 8.7 (d, 3, J = 7Hz, 10p-CH3). Anal. ( C I ~ H Z ~ C ~ N O . H ZC,H,K. O) The free base was recovered from the combined MezCO and converted into the picrate in EtOH, filtered, recrystallized from EtOH t o give 2'-methoxy-2,6,10a-trimethyl-7$-homobenzomorphan (XII) epicrate (210 mg, 7.4y0): mp 148-152"; analytical sample, mp 153-155'; nmr (free base), 7 9.1 (d, 3, J = 7 Ha, ~ O ~ ) Free base was re10a-CHs). Anal. ( C Z ~ H Z ~ NC,H,N. covered from the mother liquor of the first picrate, converted into hydrochloride (0.65 g), recrystallized from AcOEt to give XIV.HC1 (0.56 g, 32.4y0): mp 127-130'; analytical sample, mp 130-132°.15 Anal. (CleH2sClNO) C,H,N. Reaction of XIV with TsCl gave an oily N-tosylate in quantitative yield. b.-IX.HCl was hydrogenated likewise and worked up in a similar way to give XIII.HC1 (15%), XII.picrate (20%), and XIV.HC1 (33%). I n another run XIII.HCI, XII.picrate, and XIV.HC1 were obtained in 62.3%, 1170, and 7.2% yields, respectively. c.-IX.HC1 (1.4 g ) was hydrogenated in EtOH (15 ml) in the presence of 15y0 HC1 (30 ml), EtOH was evaporated and the residue was recrystallized from MezCO to give XIII.HC1 (1.19 g, 85y0), mp 118-121". The base was recovered from the filtrate (Me2CO)and converted into XII.picrate (340 mg, 12%), mp 150-152". (15) Nmr (free base) showed t w o secondary CHssignals at 7 8.66 and 9.05 respectively. Furthermore, each signal of NCHs, OCHa, and tertiary CHa was split into t w o peaks. These s u g g ~ s tSIV is a mixture of diastereoisomers.
NMe,
1 XXIII
XXIV
2'-Hydroxy-2,6,10~-trimethy1-7,8-homobenzomorphan (XV) of XI1 with 48% HBr (20-min reflux) HBr.-0-Demethylation gave 56y0 of XV.HBr, mp 217-220" (from Me2CO-EtOHEt20). Anal. (C16H24BrNO)C,H,N. 2'-Hydroxy-2,6,1Op-trimethyl-7,8-homobenzomorphan(XVI) HBr, mp 209-212" (from Me2CO-EtOH-EhO), was obtained NO) in 86.5% yield. Anal. ( C I B H ~ ~ B ~ C,H,N. 2'-Methoxy-2,6-dimethyl-7,8-homobenzomorphan (XVII) . HC1.-A mixture of X I (4 g), KOH (4 g), NHzNHz.HzO(4 ml), and diethyleneglycol (35 ml) was refluxed for 2 hr, the condenser was taken off and the mixture was heated to 175', stirred for 30 min a t that temperature, and cooled. HsO and Et20 were added, the organic phase was separated, washed with H20, dried, and evaporated. The crude base in Me2C0 gave XVI1.HCl(O.67 g), mp 160-163'. The base recovered from the mother liquor (MeXCO) was chromatographed on A1203 and eluted Kith C&-EtzO (7:3) to give additional XVII (0.85 g as the hydrochloride, total yield, 35%), mp 163-165" (from ble2CO.H20)C,H,EtOH-Et20), ir, 3400 cm-l. Anal. (C16Hz4C1N0 N. The methiodide was prepared in hle2C0, mp 229-231' (from C,H,N. 1,2-Dihydro-7-methoxyEtOH). Anal. (C17H~61NO) 1-methyl-1- (3-methylaminopropyl)naphthalene (XVIIIa) was obtained from the Et20 eluate: hydrochloride, 1.1 e (25%). mD 105-108" (from lLle&O), uv (&keOH), 272 mp (E 15;800).'-inai. (CiaHz4ClNO) C,H.N. 1,2-Dihydro-l-(3-dimethylaminopropyl)-7-methoxy-l-methylnaphthalene (XVIIIb) .HCl. a.-XVIIIa was methylated with Me2S04in Et20 (1-hr reflux): hydrochloride, mp 139-140" (from hIe&O-EtzO); uv (MeOH), 272 mp ( E 15,500). Anal. (C17H26ClXO) C,H,X. b.-The methiodide of XVII (250 mg) was refluxed with 10% NaOH (10 ml) for 20 min, extracted with Et20, dried, and evaporated. The free base (180 mg) gave XVIIIb.HC1 (170 mg, 88'%), mp 138-140" (from Me2CO-EtsO). 2'-Hydroxy-2,6-dimethyl-7,8-homobenzomorphan(XIX).HBr. -0-Demethylation of XVII .HCl with 48y0 HBr n a s carried out in a usual manner: mp 245-247" (from EtOH); 8iy0yield. Anal. (ClsH22RrNO)C,H,K.
