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.

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Azocines fused with aromatic or heterocyclic systems have been characterized with diverse biological activity [1][2][3][4]. The few known methods for the synthesis of thienoazocines have multiple steps and typically involve difficult to obtain starting materials [5][6][7][8][9]. We have previously developed a preparative method for the synthesis of tetrahydrothieno[3,2-d]azocines based on tetrahydropyridine ring expansion by two carbon atoms in Gewald tetrahydrothieno[2,3-с]pyridines through reactions with electron-deficient alkynes [4]. The transformation of 1-aryl-substituted benzothieno[2,3-с]pyridines by interaction with alkynes gave not only benzothienoazocines, but also spiro[2-arylidenebenzothieno-3,4'-tetrahydropyridines] [10]. However, 2-chlorobenzyltetrahydrothieno[3,2-с]pyridine (ticlopidine) and its 2-formyl-substituted derivative reacted with dimethyl acetylenedicarboxylate (DMAD) and methylpropiolate with difficulty only in refluxing methanol and 2-propanol, forming mixtures dominated by tetrahydropyridine fragment cleavage products with the participation of alcohol molecules, as well as debenzylation products [11]. The expected tetrahydrothieno-[2,3-d]azocines were not isolated. The transformations of 1-aryl-substituted tetrahydrothieno[2,3-с]pyridines by the action of alkynes involved the formation of open-chain carbocation B as a result of (Ar)C(1)-N + bond cleavage in the initial zwitterion А [12].

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The First Example of 4,7,8,9-Tetrahydrothieno-[2,3-d]azocine Synthesis by Domino Reaction of 4-Aryl-4,5,6,7-tetrahydrothieno[3,2-c]pyridines with Activated Alkynes. -It is shown that the expansion of the tetrahydropyridine fragment requires the presence of an aryl substituent at position 4 of the tetrahydrothieno[3,2-c]pyridines as it stabilizes the intermediate acyclic zwitterion. -(VOSKRESSENSKY*, L. G.; BORISOVA, T. N.; CHERVYAKOVA, T. M.; MATVEEVA, M. D.; GALAKTIONOVA, D. V.; TOLKUNOV, S. V.; TOLKUNOVA, V. S.; ERESKO, A. B.; VARLAMOV, A. V.; Chem. Heterocycl. Compd. (N. Y., NY, U. S.) 50 (2014) 9, 1338-1345, http://dx.