Carboline derivatives

Anhydro-bases derived from quaternary )S-carbolinium salts are reduced to p /r-A-substituted-l,2,3,4-tetrahydro-j8-carboline derivatives on hydrogenation over Adams catalyst in methanol solution made alkaline to ensure the presence of anhydro-base. ... 

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... 

Polycyclic derivatives have been prepared by straightforward amide formation. The tetracyclic amide 166 was obtained by reductive cyclization of 3-o-nitrophenylindole-2-carboxylic acid (165).22 When l-(2 -ethoxycarbonylskatyl)isoquinoline (167) was heated the pentacyclic j8-carboline derivative 168 was formed. If,... 

Decomposition of the diazonium salt of 2-amino-iV-methyl-iV-3 -pyridylaniline (205) in aqueous acid solution with copper powder at room temperature gave overall yields of cyclized products consisting of a mixture of i id-iV-methyl-3-carboline (206) (47.5%) and ind-N-methyl-jS-carboUne (207) (25.5%), in agreement with the proposed homolytic character of the reaction under these conditions. This constituted the first unambiguous synthesis of a simple 3-carboline derivative. 

The tetracyclic y-carboline derivative 233 was obtained via an interesting ring contraction when the seven-membered ring compound 232 was heated with selenium. 

Hi) Dehydrogenation. j3-Carboline derivatives may be obtained from tetrahydro-)3-carbohnes by zinc dust distillation or high temperatmre dehydrogenation with selenium or palladium black. Many of the complex indole alkaloids may be degraded, with bond cleavage, to yield simple )3-carbolines under these conditions and this approach has become a standard method in structural elucidations. Examples are numerous but outside the scope of this review. 

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. 

The alkylation of carboline derivatives has been repeatedly studied. The first quaternary A-alkyl carbolinium salts to be described were those prepared in connection with the elucidation of the structure of harmine (methiodide, methochloride, and methosulfate Other j8-carbolinium salts were subsequently prepared in connection with systematic studies of the site of alkylation and of the... 

Reaction of j8-carboline derivatives with hydrogen peroxide or perbenzoic acid and of S-carboline with peracetic acid yields the corresponding yr-A-oxide (e.g. 280). 

It is possible that the 7-methoxy group is necessary to render the benzene ring of these j8-carboline derivatives susceptible to oxidative attack. However, a y-carboline derivative (285) has been reported to undergo an analogous oxidation and decarboxylation. ... 

The reactivity of the 1-methyl group and of corresponding positions (i.e., a-carbon atoms) in other l-alkyl-j8-carbolines, analogous to that in a-picoline, quinaldine, and isoquinaldine, is due to the acidity of this center. Deprotonation yields a resonance-stabilized anion (288) which reacts readily with electrophilic reagents. Metallation with phenyl-lithium of the 1-methyl group of a l-methyl-j8-carboline derivative in which the indole nitrogen is protected, first described by Woodward... 

Only in one case was the structure of the adduct rigorously established, but it would appear most likely that these adducts are 1-cyano- or 1 -hydroxylamino-1,2,3,4-tetrahydro-j8-carboline derivatives (308). 

Acetylation of a 3,4-dihydro-j8-carboline derivative has been reported. O. Fischer described an A-acetylharmaline which was formulated as 310 since on controlled permanganate oxidation it yielded a neutral product (311), which on hydrolysis gave 7-methoxy-l-oxo-l,2,3,4-tetrahydro-j8-carboline (313) the constitution of 313... 

An analogous acylation reaction has been described in another 3,4-dihydro-j8-carboline derivative. The amide 315, on Bischler-Napieralski ring closure with phosphorus oxychloride, yields an... 

Tertiary p2/ -V-alkyl-l,2,3,4-tetrahydro-j8- and -y-carboline derivatives can be quaternized at the same site to give 2,2-dialkyl-l,2,3,4-tetrahydro-j8- and -y-carbolinium... 

Acylation of l,2,3,4-tetrahydro-j8-carboline derivatives takes place preferentially at the pyr-N. Thus l,2,3,4-tetrahydro-j8-carboline yields a 2-formyl and a 2-acetyl derivative, which give 2-methyl- ... 

A number of intramolecular rearrangements of 1,2,3,4-tetrahydro-j8-carboline derivatives have been reported. Some of these lead into other naturally occurring heterocyclic ring systems and are therefore of particular interest. 

The acid-catalyzed conversion of the l,2,3,4-tetrahydro-j8-carboline derivative 337 (R = CHg) into the strychnine-type ring system 338 has been attributed to an equilibrium involving the protonated Schiff s base 339 of tryptamine (i.e., the intermediate in the Pictet-Spengler type synthesis of tetrahydro-j8-carbolines, cf. Section III, A, 1, a), and the a- (337) and the j8-condensation products (340). 

The same general intermediate (342 X = OOH) may be invoked in the reaction of tetrahydro-)S-carboline derivatives with perbenzoic acid 285 ozone.From the reaction [342 (X = OOH)- 353- ... 

The Hofmann and Emde degradation of tetrahydro-j8-carboline derivatives has been reported in a number of instances, but only in one... 

Ring cleavage of l-oxo-l,2,3,4-tetrahydro-jS-carboline derivatives (374) may be accomplished by base-catalyzed hydrolysis to yield tryptamine-2-carboxylic acids (375). In the case of the 1,9-dimethyl derivative decarboxylation accompanied acid-catalyzed ring-opening, and the corresponding tryptamine (376) was obtained directly. 

Palladium dehydrogenation of the hexahydro-jS-carboline derivative dihydrodesoxyajmaline (381) yielded, among other degradation products which included fully aromatic )3-carboline derivatives, the two substituted indoles 382 and 383. ... 

Mannich reaction, and this method has recently been extended and repeatedly applied (see Section IV, B, 2). It involves treating a 1-m-hydroxybenzyl-1,2,3,4-tetrahydro-jS-carboline derivative (389) with formaldehyde at pH 4.4. When the aqueous solution of the hydrochloride of the hydroxymethyl derivative so formed is made basic with sodium carbonate, the pentacyclic base (390) precipitates. 

The benzindolopyrrocoline system (413) was obtained by oxidative cyclization of the l-benzyl-l,2,3,4-tetrahydro-j8-carboline derivative (337 R = H or CHg) using either ferricyanide or silver oxide, a reaction analogous to that described by Robinson and by Schopf... 

Anhydro-bases derived from 3,4-dihydro-)3-carboline derivatives have received much less attention than those of the carboline series. 

Formation of a quinonoid carboline-type anhydro-base requires loss of resonance stabilization of the indole moiety. In the carboline anhydro-bases this is counterbalanced by the preservation of a 677 system in the hetero ring. No such balancing factor is present in the case of 3,4-dihydro-j3-carboline derivatives. Formation of the exocyclic anhydro-base in the latter case preserves benzenoid resonance. It is noteworthy that in the two cases where formation of a carboUne-type anhydro-base was reported in dihydro derivatives additional aromatic conjugation is present. 

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