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.

Chemoselective and Regioselective Oxidative Couplings of Aromatic Heterocycles

Brenton DeBoef, Department of Chemistry, University of Rhode Island, Kingston, RI 02881

This work was supported by the National Science Foundation (CAREER 0847222), the Petroleum Research Fund (47019-G1) and a Pilot/Feasibility Grant from the Rhode Island INBRE Program (NIH-NCRR P20RR016457).

Summary Classification of Non-Directed Oxidative Coupling Reactions

Oxidative Coupling as an Efficient Method for Synthesizing Biaryls

Class I (low pH) Class III (buffered) Class IV (high pH)

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, 1172-1175.

Fagnou et al. J. Am. Chem. Soc. 2007, 129, 12072–12073.Class IV: DeBoef, et al. Tetrahedron Lett., 2008, 49, 4050-4053.

Acknowledgements

Need for Milder Conditions

Class I II III IV

OxidantH4PMo11VO40

+ O2

K2CO3 +

air

AgOAc or Cu(OAc)2

AgOAc or Cu(OAc)2

SolventAcOH or PivOH

PivOHAcOH or PivOH

Dioxane

% Yield (2 : 3)

81% (>99:1) n/a 74% (1:1) 84% (1:6)

Reaction Time

25 min. n/a 3 hrs. 12 hrs.

Mechanistic Insight