Regioselective oxidative arylation of indoles bearing N-alkyl protecting groups: dual C-H functionalization via a concerted metalation-deprotonation mechanism.

The most direct method for synthesizing 2-arylindoles is oxidative coupling of an arene with an indole. We have shown that both the activity and regioselectivity of this cross-coupling reaction are correlated with the acidity of the medium. This insight has been applied to predict the best conditions for the oxidative cross-coupling of N-alkylindoles, an important class of substrates that has heretofore been incompatible with the harsh conditions required for oxidative cross-coupling. Both experimental and computational data indicate that the mechanism for C-H palladation of both the indoles and simple arenes is best described as concerted metalation-deprotonation, regardless of the substitution on the arene.

[1]  C. Yeung,et al.  Palladium-catalyzed ortho-arylation of O-phenylcarbamates with simple arenes and sodium persulfate. , 2010, Journal of the American Chemical Society.

[2]  M. Bandini,et al.  Catalytic functionalization of indoles in a new dimension. , 2009, Angewandte Chemie.

[3]  G. McGlacken,et al.  Recent advances in aryl-aryl bond formation by direct arylation. , 2009, Chemical Society reviews.

[4]  M. Sanford,et al.  Mechanism of benzoquinone-promoted palladium-catalyzed oxidative cross-coupling reactions. , 2009, Journal of the American Chemical Society.

[5]  jin-quan yu,et al.  Palladium(II)-catalyzed C-H activation/C-C cross-coupling reactions: versatility and practicality. , 2009, Angewandte Chemie.

[6]  L. Djakovitch,et al.  Transition Metal‐Catalysed, Direct and Site‐Selective N1‐, C2‐ or C3‐Arylation of the Indole Nucleus: 20 Years of Improvements , 2009 .

[7]  Chao‐Jun Li.  Cross-dehydrogenative coupling (CDC): exploring C-C bond formations beyond functional group transformations. , 2009, Accounts of chemical research.

[8]  S. Gorelsky,et al.  Analysis of the concerted metalation-deprotonation mechanism in palladium-catalyzed direct arylation across a broad range of aromatic substrates. , 2008, Journal of the American Chemical Society.

[9]  Jeffrey M. Hammann,et al.  Oxidant-controlled regioselectivity in the oxidative arylation of N-acetylindoles. , 2008, Tetrahedron letters.

[10]  David R. Stuart,et al.  Intramolecular Pd(II)-catalyzed oxidative biaryl synthesis under air: reaction development and scope. , 2008, The Journal of organic chemistry.

[11]  S. Buchwald,et al.  Twofold C-H functionalization: palladium-catalyzed ortho arylation of anilides. , 2008, Organic letters.

[12]  Elisia Villemure,et al.  Elements of regiocontrol in palladium-catalyzed oxidative arene cross-coupling. , 2007, Journal of the American Chemical Society.

[13]  A. Echavarren,et al.  Palladium catalyzed arylation for the synthesis of polyarenes. , 2007, Organic & biomolecular chemistry.

[14]  Wenjun Lu,et al.  Palladium(II)-Catalyzed Coupling of p-Xylene via Regioselective C−H Activation in TFA , 2007 .

[15]  Brenton DeBoef,et al.  C-C bond formation via double C-H functionalization: aerobic oxidative coupling as a method for synthesizing heterocoupled biaryls. , 2007, Organic letters.

[16]  David R. Stuart,et al.  The Catalytic Cross-Coupling of Unactivated Arenes , 2007, Science.

[17]  John D. Hayler,et al.  Key green chemistry research areas—a perspective from pharmaceutical manufacturers , 2007 .

[18]  F. Maseras,et al.  Proton-abstraction mechanism in the palladium-catalyzed intramolecular arylation: substituent effects. , 2007, Journal of the American Chemical Society.

[19]  Mark E. Scott,et al.  Aryl-aryl bond formation by transition-metal-catalyzed direct arylation. , 2007, Chemical reviews.

[20]  C. Rowley,et al.  Catalytic intermolecular direct arylation of perfluorobenzenes. , 2006, Journal of the American Chemical Society.

[21]  Louis-Charles Campeau,et al.  Catalytic direct arylation with aryl chlorides, bromides, and iodides: intramolecular studies leading to new intermolecular reactions. , 2006, Journal of the American Chemical Society.

[22]  F. Maseras,et al.  Proton abstraction mechanism for the palladium-catalyzed intramolecular arylation. , 2006, Journal of the American Chemical Society.

[23]  M. Brown,et al.  Direct palladium-catalyzed C-2 and C-3 arylation of indoles: a mechanistic rationale for regioselectivity. , 2005, Journal of the American Chemical Society.

[24]  A. Kost,et al.  Chemistry of indoles , 1975 .

[25]  M. Rosenblum,et al.  Ring Effects in Autoxidation. A New Type of Camps Reaction1,2 , 1951 .