Preparation of Tetrahydrothienoazocinone Derivatives

Abstract

Three regioisomeric thieno[c]azocine derivatives were prepared in six steps from bromothiophene carboxylic acids. The reaction sequence started with an esterification with isopropyl alcohol. The resulting esters were submitted to a Heck reaction with tert-butyl acrylate followed by catalytic hydrogenation. Subsequent Dieckmann condensation gave cyclopentathiophenes with a cyclic β-oxo ester motif, which were α-alkylated with phenacyl bromide to furnish 1,4-diketones. The latter were converted in the key step, a bismuth-catalyzed ring transformation with methylamine, yielding the racemic eightmembered ring lactams, that is, tetrahydrothieno[2,3-c]-, [3,2-c]-, and -[3,4-c]azocine derivatives in overall yields of 25%, 16% and 12%, respectively.Some years ago, a new, elegant, and relatively simple route to prepare unsaturated 2-azocanone derivatives 1 (1,2,3,4,5,6-hexahydroazocin-2-ones, Figure 1) was discovered. 2 The reaction proceeded by a bismuth-catalyzed ringtransformation of five-membered ring oxo esters 4 containing a 1,4-diketone moiety 3 and primary amines R 1 NH 2 . Since these products 1 exist in a folded conformation, they represent an attractive molecular scaffold for combinatorial chemistry. In our continuing efforts to identify sophisticated structural motifs as a basis for combinatorial library synthesis in drug discovery, we are interested in such nonplanar and easily accessible scaffolds that provide several points of diversification. Such three-dimensional scaffolds open additional opportunities for adapting the shape of drug molecules to the requirements of binding sites on biological targets. Therefore, we have already explored scaffolds 1 as the basis of library synthesis. 4 Two points of diversity in structures 1 are the residues R 1 at N-1 and R 2 at C-8 originating from diketones 4 and primary amines, respectively. As an additional site for further diversifying functionalization (R 3 ) the carboxylate moiety at C-6 was selected, which could be converted with another amine R 3 NH 2 to carboxamides after saponification. As an extension of molecular diversity of the scaffold heterocyclic oxo esters were considered as starting materials, which resulted in thiazocane (X = S) 5 and diazocane (X = NR 4 ) 6 scaffolds 2 and 3. We have furthermore accessed benzo[c]-and pyrido[c]-annulated azocanes when starting with indane 7 and azaindane derivatives. 8 Compound 5 represents one of three regioisomeric pyrido[c]azocane motifs prepared by us. Figure 1 Some azocanones 1-3 and 5, precursor compound 4, and the antipsychotic drug olanzapine (6) N N R 2 R 1 O CONHR 3 5 X N R 2 R 1 O CONHR 3