1 -Methyl-3,4-dihydro-/3-carboline, reaction

This dimeric formulation also accounts for the thermal disproportionation of the compound into a mixture of 2-methyl-l,2,3,4-tetrahydro-jS-carbohne and 2-methyl-jS-carboline anhydro-base. Normal pseudobase formation (453 R = CHs ) takes place in the case of 9-methyl-3,4-dihydro-j3-carbohne methiodide (452 R = CHg). Neither the dimeric anhydro-base nor the -methyl pseudo-base undergo a base-catalyzed disproportionation reaction to give the 1,2,3,4-tetrahydro-and the l-oxo-l,2,3,4-tetrahydro-jS-carboline in a manner analogous... 

For the preparation of 3,4-dihydro-/3-carbolines the Bischler-Napieralski reaction is widely used (510R74). Since this reaction requires rather drastic conditions, A-acetyl tryptophan and its analogs yielded l-methyl-/8-carboline (harman) rather than l-methyl-3,3-dihydro-j8-carboline-3-carboxylic acid derivatives owing to accompanying decarboxylation and aromatization (41JCS153 50JA2962). 

A similar reaction sequence starting from tryptophan yields 1-methyl-3,4-dihydro-j8-carboline-3-carboxylic acid (465). This compound has been shown to undergo photochemical oxidation to l-methyl-jS-carboline-3-carbo lic acid (466). Such a sequence of events may account for the biogenetic origin of the amino acid 466. 

Most of the substitution reactions of di-, tetra, and hexa-hydro-carbolines and of their oxo derivatives are similar to those of the parent indole or indolenine derivatives. Nitration and bromination of harma-line (l-methyl-3,4-dihydro-j8-carbolme) are referred to in Section IV, A, 1. Sulfonation and azO COupling ° proceed as expected for indole derivatives. The preparation of chlorinated and iodinated derivatives of 6-nitroharmaline has been reported,but their structures have not been established. 

Alkylation of 3,4-dihydro-j8-carboline methiodide (371 R = H) and of 1-methyl-3,4-dihydrO jS-carboline methiodide (371 R = CH3) in alkaline solution is accompanied by ring cleavage, and gives quaternary 3-acyltryptamine derivatives (372) or their acetals (373) depending on reaction conditions. 

The indolo analogue 25 was prepared (86AP659) by alkylation of 9-methyl-3,4-dihydro-/3-carboline 23 with phenacyl bromide followed by perchloric acid to give 24. Reaction of 24 with hydrazine hydrate gave triazinopyridoindole 25, which underwent 1,126-dehydrogenation with Hg(II)-EDTA (86AP659). 

For the synthesis of the natural blue pigment trichotomine dimethyl ester, L-Trp-OMe was used as a starting material. The first step of this synthesis was conversion into methyl l-methyl-3,4-dihydro-/8-carboline-3-carboxylate with acetyl chloride in TFA (85JOC3322). An improved method starts from the corresponding thioamides via thioiminium salts which cyclize spontaneously in refluxing solvent (82CPB4226). A-Formyl-tryptophan also cyclized readily with no side reactions (68CJC3404). 

Dodd and co-workers (5) reported the first known synthesis of 11//-indolizino[8,7-h]indoles by the cycloaddition reaction of a nonstabilized ylide 21 and diethylacetylene dicarboxylate (DEAD). The azomethine ylide, formed by the alkylation of the 3,4-dihydro-p-carboline (22) with trimethylsilyl methyl triflate to the triflate salt, followed by in situ desilyation with cesium fluoride, underwent cycloaddition with DEAD at low temperature. The expected major cycloadduct 23 was isolated, along with quantities of a minor product 24, presumed to have been formed by initial reaction of the ylide with 1 equiv of DEAD and the intermediate undergoing reaction with a further equivalent of DEAD before cyclization. Dodd offers no explanation for the unexpected position of the double bond in the newly generated five-membered ring, although it is most likely due to post-reaction isomerization to the thermodynamically more stable p-amino acrylate system (Scheme 3.5). 

Flavopereirine (283), which is the ethyl derivative of 273, was synthesized by the reaction of 279-283. The condensation of l-methyl-3,4-dihydro-j8-carboline (279) and ethyl ethoxymethyleneacetoacetate gave diketone 280, which was reduced under Huang-Minlon conditions to afford 281. Amide 281 was reduced with LAH then oxidized with DDQ to afford 283 (84H233). 

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