Shao Y, Yao W, Liu J, Zhu K, Li Y * East China Normal University, Shanghai, P. R.
China
Copper-Catalyzed Selective Synthesis of Highly Substituted Pyridones by the Reaction
of Enaminones with Alkynes.
Synthesis 2012;
44: 3301-3306
Key words
pyridones - enaminones - alkynes - copper catalysis
Significance
Reported is the copper-catalyzed synthesis of substituted pyridones from the reaction
of dialkyl acetylenedicarboxylates with enaminones. Although simple dialkyl acetylenedicarboxylates
(e.g. dimethyl acetylenedicarboxylate, DMAD) are commercially available, the enaminones
must be synthesized. A method for their synthesis was not explicitly disclosed, but
a quick search of the literature provides several different methods (e.g. a one-pot
Sonogashira coupling of an acid chloride with ethynyltrimethylsilane followed by the
addition of an amine and methanol; A. S. Karpov,
T. J. J. Müller Org. Lett. 2003, 5, 3451). A mechanism for the reaction was proposed and studied through the isolation
of intermediate A. This was re-subjected to the reaction conditions but did not generate product until
more DMAD was added and the temperature was raised. This suggests that DMAD may be
involved with the copper in generating a catalytically active species for the subsequent
cyclization.
Comment
Pyridones are important building blocks for the synthesis of substituted pyridines
and other heterocycles and also represent pharmacologically relevant structures in
their own right (e.g. M. A. Ciufolini, B. K. Chan Heterocycles 2007, 74, 101). Thus, the current method should be a useful addition to the plethora of established
synthetic routes as it operates under mild conditions and uses inexpensive and easily
synthesized starting materials. The reaction was optimized with respect to catalyst,
catalyst stoichiometry and solvent. In addition, it was found that the reaction must
be conducted under inert atmosphere to avoid the formation of pyrrole byproducts.
The substrate scope was modestly examined and showed that the yields are generally
good for enaminones with electron-donating groups and good to moderate for enaminones
with electron-withdrawing groups. The reaction was relatively insensitive to the electronics
of the enaminone carbonyl unit.
