Synthesis of 6-aryl-Substituted Azocino-[5,4-b]indoles from 1-aryl-Substituted 2-Ethyltetrahydro-β-Carbolines

Abstract

We optimized the reaction of tetrahydropyridine ring expansion in 1-aryl-substituted tetrahydro-β-carbolines by the action of activated alkynes and achieved higher than 70% yields of the target indoloazocines. The substituents in the 1-aryl ring and at the indole nitrogen atom were shown to affect the rate and selectivity of this transformation.Indoles fused with medium-sized rings attract the attention of synthetic and medicinal chemists due to their remarkable and diverse biological activity. Azocinoindoles containing two pharmacophore fragments are a part of many alkaloids [1,2]. However, only few methods for the synthesis of azocinoindoles have been described, with multiple stages and low yields of the target products [3]. We have previously proposed a method for the synthesis of tetrahydroazocino[5,4-b]-and tetrahydroazocino[4,5-b]indoles based on a domino reaction of the tetrahydropyridine fragment expansion in β-and γ-carbolines, by using activated alkynes [4,5]. The yields of 6-methyl(isopropyl, benzyl)tetrahydroazocino [5,4-b]indoles in acetonitrile were 40-50%. The reaction in methanol was accompanied by cleavage of the carboline tetrahydropyridine ring with the participation of a methanol molecule [5]. The 6-aryl-substituted tetrahydroazocino[5,4-b]indoles gave only 6-(2-fluorophenyl)-and 6-(4-fluorophenyl)tetrahydroazocinoindoles in the aforementioned domino reaction.In the case of 1-(m-fluorophenyl)-substituted β-carboline transformation by the action of dimethyl ester of acetylene dicarboxylic acid (DMAD) in the presence of indole or 5-methoxyindole, the initial ammonium zwitterion А was shown to undergo cleavage at the С(1)-N bond, giving an "open" cation В. The electrophilic substitution of the latter in indole "trap" produced a diindolylarylmethane [6].Initial biological screening showed that the azocino[5,4-b]-and azocino [4,5-b]indoles are effective inhibitors of acetyl-and butyrylcholine esterases, and can be further developed as drugs against neurodegeneration [5]. Azocines condensed with 4-aminopyrimidine fragment exhibited high cytotoxic activity during the initial screening. However, no chemical transformations of tetrahydroazocinoindoles have been studied thus far.

Recent Advances on the Synthesis and Application of Tetrahydro‐β‐Carbolines

“…Changing 1‐substitution from alkyl to aryl, the reaction of the corresponding tetrahydro‐ β ‐carbolines with acetylacetylene or tosylacetylene in methanol and acetonitrile gave the 5‐acetyl‐6‐fluorophenyl‐ and 5‐tosylazocino‐[5,4 ‐b ]indoles, respectively. Later, the same group extended the reaction by using several 1‐aryl‐substituted tetrahydro‐ β ‐carbolines and activated alkynes affording the desired indoloazocines in good yields [91b] …”

Recent Advances in the Synthesis of Hydrogenated Azocine-Containing­ Molecules

“…Over the last 8 years this method was successfully applied to the synthesis of various annulated azocines: triazolopyrimido[4,5- d ]azocines 21 , 7 8 tetrahydro[1]benzothieno[3,2- d ]azocines 22 , 9 hexahydropyrimido[4,5- d ]azocines 23 and -[5,4- d ]azocines 24 , 10 tetrahydropyrimido[4,5- d ]azo­cines 25 , 11 tetrahydrobenzofuro[3,2- d ]azocine 26 , 12 tetrahydrothieno[2,3- d ]azocines 27 , 13 tetrahydroazocino[5,4- b ]indoles 28 , 14 15 hexahydropyrimidothieno[3,2- d ]azocines 29 , 16 17 and benzo[ d ]azocines 30 , 18 including systems obtained for the first time, tetrahydrothieno[3,2- d ]azocines 31 19 and tetrahydrochromeno[4,3- d ]azocine 32 (Figure 1 ). 20…”

Facile synthesis of the azocino[4,3-b]indole framework of strychnopivotine and other Strychnos alkaloids

“…[16][17][18][19][20][21][22] The critical part in such attempts has been the closure of the eight-membered azocine ring for which a wide variety of synthetic approaches have been reported. [23][24][25][26][27][28][29] In conjunction with our interest in the synthesis of indole-type alkaloids our aim was to synthesize a bridged tetracyclic framework of the ABDE rings by starting from a 4-N-substituted 4-aminocarbazole derivative (ABE rings) able to undergo the ring closure at position 2 of the carbazole ring, which could be a useful model for the access to key substructures and analogs of Strychnos alkaloids.…”