Indoles N-methylation

Collins, M.A., Neafsey, E.J., Matsubara, K., Cobuzzi, Jr., R.J. and Rollema, H. (1992) Indole-N-methylated beta-carbolinium ions as potential brain-bioactivated neurotoxins. Brain Res. 570 154—160. 

Martinez and Joule (273) have described a very general route to the 6//-pyrido[4,3-ft]carbazole system involving y-aminoenone intermediates. Ketalization of 682 followed by indole N-methylation, pyridine N-methylation, and sodium borohydride reduction afforded 683. Mannich condensation gave a product which was hydrolyzed to the y-aminoenone 684. When 684 was refluxed in 50% aqueous acetic acid the hydroxy tetrahydro 6//-pyrido[4,3-Z> Jcarbazole 685 was produced in 25% yield. 

In a more general approach toward pentacyclic heteroaromatics from tricyclic ketones, treatment of the N-methylated derivative of 112 with p-tolylhydrazine, followed by Fischer indolization of the resulting phenylhydrazone in a mixture of trifluoroacetic acid and acetic acid, produced only a low yield of 114, although this method proved to be considerably mrae efficient for synthesis of analogous systems containing other heteroatoms than nitrogen (98SC1239). 

Dialkylindolines and 1,3-dialkylindoles are formed in poor yield (<10%) from the reaction of ethyl- or phenymagnesium bromide with 2-chloro-N-methyl-N-allylaniline in the presence of catalytic quantities of (bistriphenylphosphine)nickel dichloride.72 In a modification of this procedure, the allyl derivatives can be converted by stoichiometric amounts of tetrakis(triphenylphosphine)nickel into 1,3-dialkylindoles in moderate yield72 (Scheme 43) an initial process of oxidative addition and ensuing cyclization of arylnickel intermediates is thought to occur. In contrast to the nickel system,72 it has proved possible to achieve the indole synthesis by means of catalytic quantities of palladium acetate.73 It is preferable to use... 

Comins and Killpack have also investigated the lithiation of a small number of N-protected indole-3-carboxaldehydes, using lithium N-methyl-piperazide to form the a-amino alkoxide, and found that decomposition occurred with the A -benzenesulfonyl, N-ter/-butoxycarbonyl, and A -di-methylcarbamyl derivatives (87JOC104). Success was achieved with the N-methoxymethyl derivative 19, although no attempt was made to subsequently remove the normally difficult to hydrolyze methoxymethyl protecting group. Therefore the real viability of this method as a route to... 

The principal reason that DMT must be administer parenterally is its rapid and efficient metabolism. It can be oxidized to the N-oxide. It can be cyclized to b-carbolines, both with and without an N-methyl group. It can be N-dealkylated to form NMT and simple tryptamine itself. Best known is its oxidative destruction, by the monoamine oxidase system, to the inactive indoleacetic acid. There is a wild biochemical conversion process known for tryptophan that involves an enzymatic conversion to kynurenine by the removal of the indole-2-carbon. A similar product, N,N-dimethylkynuramine or DMK, has been seen with DMT, when it was added to whole human blood in vitro. 

Before this is closed, a couple of points need be made regarding nomenclature. Older literature uses alpha for the 2-position of the indole ring. Thus, alpha-methyltryptamine, in early literature, refers to the indole-2-methyl, not to a side-chain methyl derivative. Throughout TiHKAL, the numbers are devoted to the indole ring, and the alpha and beta terms to the side-chain. And the use of the letter N refers to the side-chain amino nitrogen atom. The pyrrole nitrogen is the indole position 1. 

TRYPTAMINE, N-BUTYL-N-METHYL INDOLE, 3-[2-(BUTYLMETHYLAMINO)ETHYL] N-BUTYL-N-METHYLTRYPTAMINE 3-[2-(BUTYLMETHYLAMINO)ETHYL]-INDOLE... 

TRYPTAMINE, N-ISOPROPYL-N-METHYL-5,6-METHYLENEDIOXY INDOLE, 3-[2-(ISOPROPYLMETHYLAMINO)ETHYL]-5,6-METHYLENEDIOXY N-ISOPROPYL-N-METHYL-5,6-METHYLENEDIOXYTRYPTAMINE 3-[2-(ISOPROPYLMETHYLAMINO)ETHYL]-5,6-METHYLENEDIOXYINDOLE 5H-1,3-DIOXOLO-[4,5-F]INDOLE-7-ETHANEAMINE, N-METHYL-N-ISOPROPYL... 

TRYPTAMINE, 5-METHOXY-N,N-DIMETHYL INDOLE, 5-METHOXY-3-[2-(DIMETHYLAMINO)ETHYL] 5-METHOXY-N,N-DIMETHYLTRYPTAMINE 5-METHOXY-3-[2-(DIMETHYLAMINO)ETHYL]INDOLE N,N,0-TRIMETHYLSEROTONIN N,N,0-TMS BUFOTENINE METHYL ETHER O-METHYLBUFOTENINE OMB... 

N,0-DMS NOR-5-MEO-DMT TRYPTAMINE, 5-METHOXY-N-METHYL INDOLE, 5-METHOXY-3-[2-(METHYLAMINO)ETHYL] SEROTONIN, N,O-DIMETHYL 5-METHOXY-N-METHYLTRYPTAMINE 5-METHOXY-3-[2-(METHYLAMINO)ETHYL]INDOLE N,0-DIMETHYLSEROTONIN... 

Novel indole-2-carboxylates as ligands for the strychnine-insensitive N-methyl-D-aspartate-linked glycine receptor, J. Med. Chem. 1991, 34, 1283-1292. 

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