DMSO as a Methine Synthon: K2S2O8-Mediated Synthesis of Quinolines


DMSO as a Methine Synthon: K2S2O8-Mediated Synthesis of Quinolines

The quinoline structure is frequently found in pharmaceutically valuable compounds. Therefore, there are multiple routes to synthesize this heterocycle. Most of these routes, however, suffer from the involvement of delicate or exotic precursors and expensive transition metal catalysts.

Recently, the Singh group reported a new route to substituted quinolones 3 that starts with readily available aryl ketone 1, aniline 2, iron(III) chloride, potassium persulfate (K2S2O8), and dimethyl sulfoxide (DMSO) (Table 1).1 Dimethyl sulfoxide supplies a methine group in this oxidative annulation pathway.

Table 1: The synthesis of quinolines where DMSO provides a methine (=CH–) unit.

The yields in all cases are good, regardless of the electronic nature or position(s) of substituents on the acetophenone 1 or the aniline 2.

The reaction is thought to most likely proceed through the formation of an electrophilic iminium ion A which then undergoes nucleophilic attack by the enolate anion B to generate intermediate C (Scheme 1). Subsequent cyclization, loss of water, and oxidation produces substituted quinoline 4

Scheme 1: Proposed mechanistic pathway for the formation of quinoline using DMSO as a methine source.

The reaction does work without the inclusion of the FeCl3, but yields are improved when it is added to the reaction mixture. While it is shown playing a role in the mechanism, it is also thought to coordinate with aniline, thereby acting as a deterrent for a competing undesirable reaction where aniline reacts with the iminium ion A.

In summary, the Singh group has developed an oxidative annulation pathway where DMSO acts as a methine (=CH–) equivalent that is incorporated in the synthesized quinoline system. This method uses only readily available starting materials and tolerates a variety of substituents at all positions on the aromatic rings.

Debra D. Dolliver, Ph.D.

1Jadhav, S. D.; Singh, A. Org. Lett. 2017, 19, 5673.