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

Abstract

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].

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…”

Conjugate addition of an ynone containing azulene with a tertiary amine

“…For Path A, Voskressensky and co-workers proposed a carbocation mechanism that involved generation of a benzyl carbocation as a result of C-N + bond cleavage in an ammonium salt 10. 18 If the present reaction proceeded via the generation of a carbocation, an ethyl cation should be generated as an intermediate. The ethyl cation is a primary carbocation, therefore Path A is not the reaction pathway.…”