3,4-Dihydro-/?-carboline

Fig. 5. Synthesis of tetrahydro-zS-carbolines. dihydro-/3-carbolines. and /3-carbolines.

Conducted in an intramolecular sense, both Mannich and Vilsmeier reactions have been much used for the construction of tetrahydro-/3-carbolines (dihydro-/ -carbolines), such as are found in many indole alkaloids (/ -carboline is the widely-used, trivial name for the pyrido[3,4-Z>]indole). 

Among the 3-carboline alkaloids of marine origin, two important classes are eudistomins and manzamines. The eudistomin-type alkaloids form a wide class of polysubstituted P-carbolines, dihydro-, and tetrahydro-P-carbolines most of the members of the class have been isolated from ascidians belonging to the genus Eudistoma, but other sources are the generaRitterella, Pseudodistoma, Didemnum, Synoicum, and Lissoclinum. 

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... 

In a recent paper, Schopf and Steuer ° describe the synthesis under physiological conditions of rutaecarpine from 4 5-dihydro-3-carboline perchlorate and a-aminobenzaldehyde. 

A large number of compounds containing an extended 3,4-dihydro-/5-carbolinium system (82) have been converted similarly into the corresponding tetrahydro-j8-carboline derivatives (83a and 83b). In many cases the reaction is stereospecific and one or the other of the epimers 83a and 83b has been isolated as the sole or major product. Sodium and ethanoH tin and hydrochloric acid zinc and... 

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. 

Those epimers of 1,2,3,4-tetrahydro-j8-carbolines of general structure 139, in which the hydrogen on carbon-1 of the carboline moiety is axial, are converted into the corresponding 3,4-dihydro- -carbolinium salts (141) by mercuric acetate oxidation. Sodium dichromate... 

The photochemical conversion of the 2-bromo derivative 144, derived from l-o-methylphenyl-l,2,3,4-tetrahydro-j8-carboline by treatment with hypobromite, into a dihydro-j8-carboline, regarded as 145, has been reported. ... 

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. ... 

Dehydration of a spirocyclic quaternary salt such as 147 gives rise to a 3,4-dihydro-y-carboline (148). This reaction is not, however, of general applicability since both 149 (R = C2H5) and 149 (R = CH2C6H5) yield the fully aromatic carbolinium salt 150 under the same conditions. 

Another approach to the l-oxo-l,2-dihydro-j8-carboline system is that due to King and Stiller. When 2-ethoxy carbonyl-3-formyl-indole is condensed with hippuric acid the azlactone 162 is formed, which, with 10% methanolic potassium hydroxide, gives a mixture of the orthoester 163 and the potassium salt 164. 

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. ... 

Dilute acid permanganate/ acid dichromate, 290-294 perbenzoic acid have also been employed in the aromatization of 3,4-dihydro-j3-carbolines. 

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. ... 

A number of unsuccessful attempts to dehydrogenate dihydro-j8-carbolines have been reported. ... 

Nitration of quinindoline gave the expected 9-nitro derivative (261). A single mononitro compound was formed from the 3,4-dihydro-jS-carboline, harmaline this was 6-nitroharmaline, since on oxidation it yielded 3-nitro-4-methoxybenzoic acid. 

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. 

Dihydro-l-oxo-3,4-benz-j8-carboline (166) reacted with phosphorus oxychloride and one mole of phosphorus pentachloride at 110° to give l-chloro-3,4-benz-j8-carboline (264). When, however, more than one mole of phosphorus pentachloride was used 265 was obtained, presumably by chlorination of 264. This chlorinating action of phosphorus pentachloride is analogous to that observed when an... 

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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