March 1969
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.)(;10). Analyses were performed by Dr. A. E. Bernhardt, IIulheim, West Germany; where indicated onlj- by symbols of the elements the analytical results obtained for those elements are within +0.4% of the theoretical values. Mixtures of cis- and trans-4-Chloromethyl-2-phenyl-l,3dioxolane (Ila and IIb).--4 1 : l mixture of these isomers, bp %+-loo0 ( 3 mm), was obtained from 1,2-dihydroxy-3-chloropropane and benzaldehyde, according to the method of Fournean and Chantaloux.6 Repeated fractional distillation of this mixture through a Teflon spinning-band column (Sester Faust) afforded two enriched fractions (indicated by glpc and nmr) contaiiiiiig 3 : 1 of I I a and IIb, respectively, bp 96-98" ( 3 mm), and 2 : l of I I b and IIa, respectively, bp 100-102" ( 3 mm). Numerons intermediate fractions were a1.o obtained. Glpc (200' isothermal; He 30 ml/min) retention times were 10 and 1'2 min for IIa aiid IIb, respectively. S m r 7 absorption was observed a t T 2.7 (aromatic multiplet), 4.16 [singlet C2-H (IIb)], 4.36 [singlet, C,-H (IIa)], Z.7-6.4 (multiplet Ca-H and C r H ) , 6.67 (doublet,
CH?C1). Mixtures of cis- and trans-4-Dimethylaminomethyl-2-phenyl1,3-dioxolane Methiodide (IIIa and IIIb).-A 1: 1 mixture was ohtained from a 1 : 1 mixture of the chloromethyl-l,3-dioxolanes (IIa and IIb), according to the method of Fourneau and Chantaloiix,6 and had mp 152-1.54" (lit.6 mp 1.33'). A 4 : 1 mixture of IIIa and IIIb, respectively, was obtained by fractional crystallization of the methiodides derived from the fraction of 4-chloromet h~-l-2-phenyl-1,3-dioxolaneenriched in I I a and had mp 162164' from acetone. Anal. ( c 1 3 H d S 0 , ) C, H, I, X. A 4: 1 mixture of I I I b and IIIa, respectively, was obtained by fract ioiial crystallization of the methiodides derived from the 4-chloromethyl-2-phenyl-l,3-dioxolane enriched in I I b and had mp 168-170" from acetone. Anal. (C13H,,INO,) C, H, I, N. Kmr peaks of the above mixtures were at I 2.32 (aromatic inidtiplet), 3.91 [singlet, C2-H (IIIb)], 4.12 [singlet, C2-H ( I I I a ) ] , 5.80-6..56 (milltiplet, G - H , Cj-H, -CH2X), and 6.66 (iiiiglet, XCH3).
KOTES
321
rats.j Attempts have been made to develop theoretical structure-activity relationships for these and other psychotomimetic compound^.^^' Because of the high CNS activity shown by S,S-dimethyl-j-methoxytryptamine, the synthesis of the structurally related tricyclic indole, 0-methylnordehydrobufotenine (6met hoxy-5-methyl-l,3,4,5-tetrahydropyrrolo [4,3,2-d,e 1quinoline, IIc), was undertaken. The synthetic route is parallel to the method for synthesis of 1,3,4,5-tetra-
Ia, R,= NKH,),; R, = NO, b, R, = CN; R, = NO, C,
Rl=CN;R2=NOy
IIa, R = H b, R = CHO C, R=CH3
111
hydropyrrolo [4,3,2-cZ,e]quinoline8 and dehydrobufotenineSg Recently, an alternate synthesis of the tetrahydropyrroloquinoline ring system has been reported from IY-methyl-j-bromotryptamine and an alkyllithium to form 5-methyl-1,3,4,5-tetrahydropyrrolo[4,3,2-d,e]quinoline cia an intramolecular aryne addiThe Synthesis of tion reaction.1° Treatment of 5-methoxygramine with 0-3lethylnordehj-drobufotenine, concentrated HSOa afforded 5-methoxy-4-nitrogramine (Ia) which was quaternized with ?*fe2S04and then a New Psychoactive Indole' converted to 5-methoxy-4-nitroindolyl-3-acetonitrile (Ib) with SaCS. Catalytic hydrogenation of I b F R I DG. H. LEE, with Pd-C in E t 0 - k at approximately 65' yielded 5Regis Chenizcal Company, Chicago, Illznois 60610 methoxy-4-aminoindolyl-3-acetonitrile(IC) instead of the expected product, G-methoxy-l,3,4,5tetrahydroJOHK W. DALY, pyrrolo [4,3,2-d,e]quinoline (IIa) . I n ethanol the same Laboratory of Chemistry, hydrogenation of l b yielded two products: the de.\-aizona1 Instztuie of drthrztzs and Metabolic Diseases, sired 6-niethoxy-1,3,4,5-tetrahydropyrrolo[4,3,2-d,e]a(iona1 Instztutes of Health, Refhesda, J l a r ~ l a n d ZOOl4 quinoline (IIa) and 7-methoxy-1,2,3,4,5,6-hexahydroIUD ALBERTA. I I I S I ~ pyrrolo [4,3,2-cl,e]quinoline (111). Reaction of I I a with formic-acetic anhydride formed the S-formyl derivaPsychopharmacology Research B?anch, tive (IIb). Reduction Jvith diborane resulted in the lYatzonal Insfztuie of Xenia1 Health, formation of 0-methylnordehydrobufotenine(IIc). Chet y Chase, Maryland 20203 Pharmacology.-Pharmacologic activity n-as deRecezved July 31, 1968 termined in squirrel monkeys trained in the Wisconsin General Test Apparatus by Dr. E. T. L-yeno and hi. X variety of indoleethylamines including KJ-diassociates in the Biobehavioral Science Laboratory of methyltryptamine,? S , S - d i m e t h y l - 4 - hydroxytryptStanford Research Institute using published techamine (psilocin), and S,S-dimethyl-6-hydroxytrypt- niques." The median effective dose (EDjo) of IIc amine4 have been reported to have hallucinogenic that disrupted the ability to discriminate between activity. Of these psychoactive indoleethylamines, S,S-dimethyl-5-methoxytryptamine exhibits the high( 5 ) P. K. Gessner, D. D. Godse, A. H . Iirull, and J. 11. 1\Ic1lullan, Li/e est activity in disrupting conditioned responses in Sei., 7 , 267 (1968). L\
(1) This investigation was supported h y t h e Psychopharmacology Re-
Bearch Branch, National Institute of Mental Health, Contract Sd-43-pIi3021. (2) 8. Saara in "Psychotropic Drugs," S. Garattini and V. Ghetti, E d . , Elserier Publishing Co., Amsterdam, 1957, pp 460-467. (3) h. Hofmann, -1.Frey, H. O t t , T. Petrizilka, and F. Troxler, Ezperientia, 14, 397 (1958). (4) Y. Szara and E . Hearst, S n n . S. Y . A c a d . Sci., 96, 134 (1962).
(6) S. H. Snyder and C. R. Nerril, Proc. S a t l . Actid. Sci. U . S., 54, 258 (1905). ( 7 ) S. H. Snyder and E. Richelson, ibid., in press. ( 8 ) J. B. Hester, J r . , J . Org. Chem., 29, 1158 (1964). (9) IT. F. Gannon, 3 . D. Benigni, J. Suzuki, and J. W ,Daly, Tetrahedron Letters, 1531 (1967). (10) M. Julia, Y. Huang, and J. Igolen, Compt. Rend., 266, 110 (1967). (11) E. T. Uyeno, L. 5. Otis, and C . Mitoma, Comm. Beh. Bioi., A 1, 83 (1968).
