TRYPTAMINES, CARBOLINES, AND RELATED COMPOUNDS: PART X. AN ALTERNATIVE SYNTHESIS, AND THE NITRATION, OF Δ-Carboline

Abstract

6-Carboline, together with 8-carboline, has been synthesized in reasonably good yield by the Fischer cyclization of cyclohexanone 3-pyridylhydrazone followed by dehydrogenation of the separated tetrahydro derivatives. The isomer ratios of products formed in this and similar reactions are discussed. Nitration of 6-carboline gives a mixture of the 6-and 8-nitro derivatives, the latter being the predominant product. The magnitude of the dipole moment of 6-carboline is appreciably higher than that predicted from n~olecular orbital calculations (15).The first unaillbiguous synthesis of 6-carboline'"1) was described in Part VIII of this series (I), in which the cyclizatioil of 3-azido-2-phenylpyridine was reported to give variable )~ields of (I). In order to study the substitution reactioils of this ring system a synthesis giving inore reproducible yields was required. An alternative method of obtaining the 6-carboline ring system was sought and found in the Fischer cyclization of cyclohexailone 3-pyridylhydrazone (11).The Fischer cyclization of pyridylhydrazones has been found by a nuinber of worlters to talte place with greater difficulty than the cyclization of the correspondiilg phenylhydrazones. Perkin and Robinsoil were unable to effect the cyclization of acetone 2-quinolylhydrazone (2), a i d Fargher and Furness (3) and Oltuda and Robisoil (4) obtained similar negative results using a number of 2-pyridylhydrazones. Cleino and Holt prepared 1-methyl-5,6,7,8-tetrahydro-p-carbolii in low ~~i e l d from cyclohexailoile 2-n1ethy1-3-pyridylh)~drazone and zinc chloride (5j. A moderate yield of 5,6,7,8-tetrahydro-a-carboline was obtained by heating cyclohexanone 2-pyridylhydrazone with polyphosphoric acid (4). Ficlten and Kendall have recently examined the cyclizatioil of the pyridylhydrazones of isopropylinethyl ltetone to give the corresponding azaindole derivatives (6). They found that heating with zinc chloride to a relatively high temperature (210-250") was necessary to effect ring closure. I t is interesting to note, as well, that isopropylmetl~yl ltetone 3-pyridylhydrazone was reported by these authors to give exclusively 2,3,3-trimethyl-313-4-azaindole; i.e. cyclization had occurred a t the a-position of the pyridine ring only. Similarly, Taltahashi, Sailtachi, Goto, and Shiinamura (7) obtained ~-chloro-2-inethyl-4-azaindole from acetone 2-chloro-5-pyridylhyclrazone.3-Hydrazinop3~ridine reacted with cyclohexanone to give the required cyclohexanone 3-pyridylhydrazone (11), which was somewhat unstable in air but could be kept for long periods in a closed container in the refrigerator. Cyclization was effected by fusion of (11) with zinc chloride a t 250" and gave a high yield (94%) of a mixture of 6,7,8,9-tetrahydro-6-carboline (111) (63%) and 5,6,7,8-tetrahydro-P-carboline (IV) (37%). The structures of (111) and (IV) were established by dehydrogenation to the corresponding fully aromatic structures. The dehydrogenations were carried out by heating the coinpound with 10% palladiuin-charcoal in boiling me...

Síntese sustentável de compostos heterocíclicos. Azaindole – um núcleo privilegiado em química medicinal

“…Embora esta abordagem seja semelhante à usada para a síntese de in-Artigos doles a partir de anilinas, a natureza eletrodeficiente do anel piridina altera as propriedades eletrónicas do sistema conjugado, o que faz com que os métodos clássicos de síntese de indole não resultem, ou não sejam tão eficientes, quando aplicados a este núcleo [7]. Por exemplo, a síntese de Fischer quando aplicada a hidrazinilpiridinas não resulta exceto quando estas possuem um grupo eletrodoador, formando-se, nesses casos, 4-azaindole e 6-azaindole em rendimentos moderados a bons [8][9][10]. Outro método clássico é a síntese de Bartoli que, quando aplicado à síntese de azaindole, requer o uso de um grande excesso de reagente de Grignard e apenas permite obter o 4-azaindole e o 6-azaindole com rendimentos baixos [11].…”

Carbolines. Part I: Comparison of some methods for the synthesis of α-, γ-, and δ-carbolines (a review)

“…A similar thermal process has been used to prepare numerous g-carboline derivatives [65 -67], including a large group of polycyclic compounds containing the g-carboline moiety [ [80]. In this respect, the method based on reacting cyclohexanone 3-pyridylhydrazone is characteristic.…”

“…The starting compounds (79,80) and target d-carboline (81) were synthesized according to Scheme 27. g,d-Biscarboline 82 was synthesized in this study by an analogous method (Scheme 28) [135].…”

Investigação de Aminopiridinas Não Halogenadas como Substratos Promissores para a Síntese de Azaindoles

“…Por exemplo, a síntese de Fischer quando aplicada a hidrazinilpiridinas não resulta [10][11][12], exceto quando estas possuem um grupo eletrodoador, resultando na síntese do 4-azaindole e do 6-azaindole, em rendimentos moderados a bons. Outro método clássico é a síntese de Bartoli que, quando aplicada à síntese de azaindoles, requer o uso de um grande excesso de reagente de Grignard e apenas permite obter o 4-azaindole e o 6-azaindole com rendimentos baixos [13].…”