9-Methyl-3,4-dihydro-/3-carboline

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). 

Palladium dehydrogenation of l,2,3,4-tetrahydro-j8-carboline-3-carboxylic acid or its ethyl ester has been reported to take place with loss of the carboxyl or carbethoxyl group, yielding j3-carboline. On the other hand, it has been reported that palladium dehydrogenation of either 1-methyl-1,2,3,4-tetrahydro-j8-carboline-3-carboxylic acid or 1,3-dicarboxyhc acid yields l-methyl-3,4-dihydro-j8-carbohne-3-carboxyhc acid and not l-methyl-jS-carboline. ... 

Methyl-3,4-dihydro-j3-carboline-3-carboxylic acid has been reported to undergo photochemical and pyrolyticoxidation to yield a mixture containing l-methyl-j8-carboline and l-methyl-j8-carboline-3-carboxylic acid. The methyl ester of this 3,4-dihydro-j8-carboline acid appears to be oxidized to methyl l-methyl-j8-carboline-3-carboxylate on alumina chromatography. ... 

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... 

The ultraviolet absorption spectra of carboline derivatives have been repeatedly recorded. Since the basic jpyr-N in the carbohnes and in 3,4-dihydro-jS-carbolines is part of a conjugated system, protonation affects the electronic absorption spectra significantly. It is unfortunate therefore that the spectra of the protonated, as well as those of the unprotonated, species have not been reported in all instances. Protonation leads to a bathochromic shift of 20-30 mp,. This is illustrated by the absorption of j3-carboline, 1-methyl-jS-carboline, 7-methoxy-l-methyl-jS-carbohne, and the salts of these compounds. 

The utilization of the Robinson annellation method for the synthesis of cory-nanthe-type alkaloids has been thoroughly investigated by Kametani and coworkers (149-152). The tetracyclic ring system was efficiently formed via the Michael addition of dimethyl 3-methoxyallylidenemalonate (247) to the enamine derived from 3,4-dihydro-1 -methyl-(3-carboline (150). Alkylation of 248, followed by hydrolysis and decarboxylation, resulted in a mixture of stereosiomeric enamides 250 and 251. Hydrogenation of 250 afforded two lactams in a ratio of 2 1 in favor of the pseudo stereoisomer 253 over the normal isomer 252. On the other hand, catalytic reduction of 251 gave 254 as the sole product in nearly quantitative yield. Deprotection of 254, followed by lithium aluminum hydride reduction, yielded ( )-corynantheidol (255) with alio relative configuration of stereo centers at C-3, C-15 and C-20. Similar transformations of 252 and 253 lead to ( )-dihydrocorynantheol and ( )-hirsutinol (238), respectively, from which the latter is identical with ( )-3-epidihydrocorynantheol (149-151.). 

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). 

HARMALINE,- P-CARBOLINE, 3,4-DIHYDRO-7-METHOXY-l-METHYL 3,4-DfflYDRO-7-METHOXY-l-METHYL-p-CARBOLINE 3,4-DIHYDROHARMINE 7-METHOXYHARMALAN HARMADINE... 

An extension of Kametani s earlier synthesis has afforded a neat synthesis of rutaecarpine (24) and hortiacine (10-methoxyrutaecarpine).22" In this modification, the presence of a trifluoromethyl group in (23) (instead of hydrogen, as in Kametani s synthesis) increases the electrophilicity of the protonated form, and also provides a useful leaving group for the final stage of the synthesis a dehydrogenation step is therefore unnecessary (Scheme 3). Rutaecarpine has also been synthesized.226 11-Methoxyrutaecarpine has been simply synthesized by condensation of 7-methoxy- 1-oxo-l,2-dihydro-/ -carboline with methyl anthranilate and phosphorus oxychloride.22c... 

Harmaline (= 3,4-Dihydroharmine Harmidine) (dihydro P-carboline, indole) Harman (= l-Methyl-p5-carboline)... 

The structure inhibitory activity relationships among numerous P-carboline alkaloids was studied. Harmine was found to inhibit the actions of cyclic adenosine monophosphate (cAMP) phosphodiesterase (ICS0 69.3 x 10 5 M). Among the di- and tri-substituted P-carbolines, the O-methylated P-carbolines and the O-acetylated p-carbolines had higher inhibitory activity than the corresponding hydroxy p-carbolines, while the dihydro- and tetrahydro-derivatives were not potent inhibitors [271]. 

Dihydro-l-methyl-y -carboline refluxed 1 hr. with hydrazine hydrate and KOH in diethylene glycol under. Ng 2-ethyltryptamine. Y 92%. — This is a simple synthesis of the little known 2-alkyltryptamines. F. e. s. I. Fleming and J. Harley-Mason, Soc. (C) 1966, 425. 

Using this system of nomenclature the compounds which are most commonly encountered in the older literature and are there designated by trivial names are described as follows harmine = 7-methoxy-l-methyl-jS-carboline, harmol = 7-hydroxy-l-methyl-j3-carboline, harman= 1-methyl-j8-carboline, norharmine = 7-methoxy-)S-carboline, norharman = /3-carlx>-line, harmaUne = 7-methoxy-l-methyl-3,4-dihydro-j8-carboline, harmalol = 7-hy iroxy-l-methyl-3,4-dihydro-/5-carboline, and harmalan = 1-methyl-3,4-dihydro-j8-carboline. 

Whereas oxidation of l-methyl-l,2,3,4-tetrahydro-)8-carboline (461 R = R = H) itself does not take place readily, oxidation of 1-methyl-l,2,3,4-tetrahydro-)5-carboline-3-carboxylic acid (17 R = CH3) with acid dichromate gives l-methyl-j8-carboline (463 R = H) in high yield. Modelled on this finding, the biogenetic origin of l-methyl-)5-carboline from tryptophan (15) by way of the tetrahydro-jS-carbohne-3-carboxylic acid, without the intermediate formation of a 3,4-dihydro-j8-carboline, has been proposed.This sequence cannot account for the biogenetic origin of l-methyl-j8-carboline-3-carboxylic acid (466), which was recently isolated from Aspidosperma pcAy-neuron ... 

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. 

Apart from the syntheses already quoted as of possible biological interest, mention must be made of a series which are primarily of chemical interest. Kermack, Perkin and Rob mson prepared norharman, i.e., /S-carboline (VII) by warming A-methylindole-2-carboxyacetalylamide (XVIII) with alcoholic hydrogen chloride, thereby converting it into 2-keto-l-methyl-2 3-dihydro-/S-carboline (XIX), which on distillation... 

Dihydro-j8-carboline itself, the parent compound of the group, whose original preparation from A -formyltryptamine was doubtful, has now been describedand characterized. Its 9-methyl and 6-methoxy derivatives have also been prepared. 

Non-oxidative conversion of a tetrahydro-)8-carboline into a 3,4-dihydro derivative has also been described. Dehydration of 1-hydroxymethyl-1,2,3,4-tetrahydro-j8-carboline (146) yielded 1-methyl-3,4-dihydro-j8-carboline (135). Harmaline and l-methyl-3,4-dihydro-j8-carboline-3-carboxylic acid were obtained in an analogous manner. ... 

It is interesting to note that whereas 7-methoxy-l-methyl-l,2,3,4-tetrahydro-jS-carboline condenses with diazobenzenesulfonic acid to give an azo compound (presumably the 6-arylazo derivative) and 7-methoxy-l-methyl-3,4-dihydro-j8-carbohne gives a bisazo compound, none of the fully aromatic j8-carboline derivatives studied by Perkin and Robinson underwent azo-coupling. 

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. 

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