An efficient one-pot, four-component reaction for the synthesis of dithiocarbamates using carbon disulfide, cyclic imines, acid chlorides, and commercially available primary or secondary amines has been developed by performing an acid chloride addition to a heterocyclic imine followed by subsequent nucleophilic substitution of in situ generated dithiocarbamic acid. With the aid of the newly developed and powerful multicomponent reaction, a direct route for the synthesis of 24 unknown dithiocarbamates in moderate to good yield under mild conditions is enabled.
By changing the dimethylamino
to a nitro group, a novel synthetic
access to the spirocyclic opioid analgesic cebranopadol was developed
that is much more efficient compared with the established route. On
the basis of the α-acidity of α-nitrotoluene, the two-fold
Michael addition to acrylate gave an acyclic precursor compound, which
was easily transformed by Dieckmann condensation and decarboxylation
to the cyclohexanone derivative needed for the annulation of the indole
ring by an oxa-Pictet–Spengler reaction. As an additional benefit,
the reduction of the nitro group furnished an amine, which could be
late-stage-diversified to carboxamides, sulfonamides, ureas, and N-alkyl congeners. The transformation of the nitro group
at the spirocyclic scaffold to the dimethylamino function of the actual
title compound was achieved in one step with zinc/formic acid/formaldehyde in 83% yield.
An optically active hexahydrocyclopenta[c]pyridine derivative with quaternary stereocenter was prepared as a new heterocyclic scaffold. Key reaction was the Pd‐catalyzed asymmetric allylic alkylation of a piperidine‐based β‐oxoester, which proceeded in very good yield with high level of enantioselectivity (90 %, 95 % ee). The α‐allyl moiety was transformed into a 1,4‐diketone by Pd‐catalyzed Wacker oxidation with molecular oxygen (89 %). This intermediate was cyclized in an intramolecular aldol reaction furnishing the cyclopentenone motif (86 %). Hydrogenation of the C–C double bond gave the cis‐annulated octahydrocyclopenta[c]pyridine (86 %), which was submitted to Fischer indolization (85 %). Although two regioisomers could be expected, only the angular constitution was observed. Relative and absolute configurations were established by X‐ray crystallography of a para‐iodo benzamide derivative. The utility of the title compound as scaffold is further highlighted by a number of synthetically useful transformations, for instance formation of carboxamides, sulfonamides, ureas and reductive aminations with aldehydes.
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