INTRODUCTION (2)

© 2014 American Chemical Society 2555 dx.doi.org/10.1021/ja411912p | J. Am. Chem. Soc. 2014, 136, 2555−2563

 

■ INTRODUCTION

Amination reactions are crucial to the synthesis of medicinally important compounds.

The amination of C−H bonds provides a route to N-alkyl and N-aryl amine derivatives that avoids typical functional group interconversions and reactants containing a functional group already present at the position where a C−N bond is desired. Intermolecular reactions that convert unactivated C−H bonds to C−N bonds are particularly challenging to achieve, but such reactions could directly modify complex molecules, create chemical feedstocks, or create functionalized polymers.1,2

 

Methods for the oxidation of alkanes by the combination of peroxides and iron complexes have been developed,3−12 but intermolecular functionalization of purely unactivated C−H bonds with reagents that form products containing common nitrogen-based functionality are rare.13

Most intermolecular amidations of C−H bonds have been catalyzed by copper complexes and occur at benzylic or allylic positions.

 

A few intermolecular aminations of C−H bonds occur with nitrene precursors to form sulfonamides.14−26 Reactions catalyzed by dirhodium complexes are the most developed for the synthesis of complex molecules.15,27  Although remarkable developments and applications have been reported for intramolecular reactions, intermolecular reactions are more limited.

 

The selectivity of these reactions depends on the electron density at the C−H bond of the substrate, such that the preferred sites of reactions are tertiary, benzylic, and secondary C−H bonds.14,28 When a nitrene is the reactive intermediate, the nitrogen-based reagent is limited to those containing just one substituent.

We sought an alternative route to the intermolecular functionalization of alkyl C−H bonds that could form N-alkyl amides, carbamates, and imides, in addition to the formation of sulfonamides. Amides, carbamates, and imides are more common synthetic intermediates or final products than those generated by prior copper-catalyzed reactions with alkyl C−H bonds.29

We also sought to conduct these transformations with readily accessible complexes of first-row metals. Although copper-catalyzed reactions at allylic and benzylic C−H bonds with carboxylic acids and sulfonamides in the presence of peroxides is well-known (Karasch-Sosnovsky reaction),30−35 and the mechanism of these reactions has been studied,34,36−40 the amidation of C−H bonds with such reagents has been limited to reactions at benzylic C−H bonds.32,33

 

Article

© 2014 American Chemical Society 2555 dx.doi.org/10.1021/ja411912p | J. Am. Chem. Soc. 2014, 136, 2555−2563

 

 

We report the reactions of common amides, carbamates, and imides with alkanes to form N-alkyl derivatives with simple copper catalysts and a peroxide (Scheme 1).

 

The amidation of alkanes under our catalytic conditions preferentially forms the products from amidation at secondary sites over tertiary sites and even leads to the functionalization of primary C−H bonds in some cases.

 

Mechanistic data from the stoichiometric reactions of isolated copper amidate or imidate complexes

indicate that the transformation of alkanes to N-alkyl products likely occurs by the reactions of a alkyl radicals with copper(II) amidate and imidate complexes.