S-Carbolines

Perhaps the most important application of the Mannich reaction is in the synthesis of 3-dialkylaminoindoles. Intramolecular versions of this reaction are also possible, as illustrated by the formation of the /S-carboline (73). 

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 the present review the carboline, rather than the pyridoindole, nomenclature is adopted with the numbering for a-, jS-, y-, and S-carbolines shown in structures 5-8, respectively, as recommended by the Editor of the Journal of the Chemical Society in his Report on Nomenclature, 1952, ° and by the Definitive I.U.P.A.C., 1957, rules of organic nomenclature (Rule B—2.11). In the interest of clarity. 

The quaternary salts themselves, orp /r-A-unsubstituted )S-carbolines, are stable to hydrogenation under these conditions. 

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). 

Finally, mention should be made of the addition of nucleophilic reagents to the 1-position of 3,4-dihydro-j8-carbolines, Cyanide has been reported to yield adducts with harmaline, 6-nitroharm-aline, and 2-methylharmalinium salt similarly, hydroxylamine forms adducts with harmaline, 3,4-dihydro-j8-carboline (307 R = H), and l-phenyl-3,4-dihydro-)S-carboline (307 R =... 

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 interesting work of Hahn and Hansel, who prepared a tetracyclic lactam by intramolecular cyclization of the condensation product of tryptamine and a-ketoglutaric acid, is referred to in Section IV, B, 2. Condensation of tryptamine with a,a -diketopimelic acid (403) led, presumably by way of the 1-substituted tetrahydro-)S-carboline (404), which could not be isolated, to a product to which the tetracyclic structure 405 was assigned. 

The ultraviolet absorption spectra of 3,4-dihydro-jS-carboline derivatives exhibit a dependence on pH similar to that shown by the speetra of the fully aromatie compounds. 3,4-Dihydro-/S-carboline and 1-methyl- and 7-methoxy-l-methyl-3,4-dihydro-jS-carbo-line serve as examples. The quaternary 3,4-dihydro-jS-earbolin-ium salts obtained on p /r-A-alkylation of these dihydro-j3-earbo-lines show a bathoehromic shift of 5 mp, eompared to the... 

Competition binding studies showing that when using compounds like jS-CCE (ethyl- S-carboline-3-carboxylate), which bind to the benzodiazepine receptor, the displacement curve for [ H]flunitrazepam was shallow in the hippocampus and... 

Various intermediates (uracil, thymine, pyrazoline, /S-carboline, and dihydroquinoline derivatives) have been prepared in this way [142-147]. 

Pyrrolopyridines are quaternized at the pyridine nitrogen by methyl iodide (often at room temperature). Sodium hydroxide treatment of the methiodide of pyrrolo[2,3-6]pyridine gives a stable free base which reacts with a second molecule of methyl iodide, this time at the pyrrole nitrogen (Scheme 4). The resonance stabilization of the free base is shown by its stability towards boiling 20% sodium hydroxide, which rapidly hydrolyzes l-methyl-2-pyridoneimine (55JA6554). The same procedure with S-carboline leads to the 1,5-dimethyl quaternary salt (19) which on pyrolysis yields the 5-methyl derivative (20 Scheme 5) (60CJC2152). 

On the other hand, the Fischer cyclization of cyclohexanone 3-pyridylhydrazone (183) gave a mixture (94% yield) of 6,7,8,9-tetra-hydro-S-carboline (184) and 5,6,7,8-tetrahydro-jS-carboline (185).416 The ratio of 184 to 185 was 63 37, cyclization at the a-position taking place with greater ease than at the y-position. The 3-quinolyl-hydrazone of a-tetralone gave only one product on heating with zinc... 

Efforts to synthesize apoharmine (1, R = Me) by Fischer cyclization of ethyl pyruvate 2-methyl-3-pyridylhydrazone failed, whereas its cyclohexanone hydrazone gave tetrahydroharman (27, R = Me) in 11 % yield on heating with zinc chloride. This yield seems quite low compared to the 94 % yield of a 2 1 mixture of tetrahydro-S-carboline (28) and tetrahydro-j8-carboline (27, R = H), respectively, obtained from cyclohexanone 3-pyridylhydrazone under similar conditions. Okuda and Robison were able to cyclize cyclohexanone 2-pyridyl-hydrazone to 5,6,7,8-tetrahydro-a-carboline in 53 %yield on heating in polyphosphoric acid, but the acetaldehyde, acetone, and pyruvic acid... 

Treatment of tetrahydro-/S-carboline 7 with solid potassium permanganate provides iminc The ethyl ester group is stable... 

---