1. Chemoselective and Regioselective Oxidative
Couplings of Aromatic Heterocycles
Brenton DeBoef, Department of Chemistry, University of Rhode Island, Kingston, RI
Summary
Classification of Non-Directed Oxidative Coupling Reactions
Class I (low pH) Class III (buffered) Class IV (high pH)
Oxidative coupling is a powerful method by which two unfunctionalized substrates can be directly coupled to form a new C-C bond. We have hypothesized that the variety of reaction conditions that exist for the oxidative formation of biaryl C-C bonds from unfunctionalized arenes may be classified according to their relative pH. A systematic study involving benzofuran substrates has validated this hypothesis. The resulting rubric can be applied to predict the best conditions for the oxidative coupling of a given substrate. The data suggests that high pH reactions proceed via a proton abstraction mechanism, while those at low pH proceed via electrophilic palladation.
Class I II
III IV
Oxidant
H4PMo11VO40 + O2
K2CO3 + air
AgOAc or Cu(OAc)2
Solvent
AcOH or PivOH
PivOH
Dioxane
% Yield (2 : 3)
81% (>99:1)
n/a
74% (1:1)
84% (1:6)
Reaction Time
25 min.
3 hrs.
12 hrs.
Oxidative Coupling as an Efficient Method for Synthesizing Biaryls
Class I : DeBoef, et.al. Org. Lett., 2007, 9, 3137–3139.
Class II: Fagnou et al. J. Org. Chem., 2008, 73 , 5022–5028.
(Incompatible with intermolecular reaction)
Class III: DeBoef, et.al. Org. Lett., 2007, 9, 3137–3139.
Fagnou et al. Science 2007, 316,
Fagnou et al. J. Am. Chem. Soc. 2007, 129, 12072–12073.
Class IV: DeBoef, et al. Tetrahedron Lett., 2008, 49,
Mechanistic Insight
Need for Milder Conditions
Acknowledgements
This work was supported by the National Science Foundation (CAREER ), the Petroleum Research Fund (47019-G1) and a Pilot/Feasibility Grant from the Rhode Island INBRE Program (NIH-NCRR P20RR016457).