Donald A. Watson, PhD, Univeristy of Delaware
During our ligand synthesis studies, we required chemistry for the monoalkylation of a primary amide. We were struck by the lack of readily accomplished reaction conditions that accomplish this task without competitive over-alkylation. Our interest in this transformation, coupled with the clear need for new effective chemistry in this area, led us to investigate novel routes for amide alkylation. In particular, we were drawn to the notion of developing a catalytic version of a Lam-Chan reaction involving alkyl boronic esters or amides. Such a reaction would involve copper catalyzed C-N bond formation at an alkyl center. Whereas catalytic C-N bond formation at aromatic and vinylic centers has become well established over the course of the last two decades, the corresponding transformations involving alkyl centers remain extremely rare. In addition, such a transformation would be of direct petroleum relevance, as alkyl boronic reagents are typically derived from alkenes via hydroboration - thus successful development of this research program would allow for the overall animation of hydrocarbon starting materials.
Our initial entry into this area focused on the use of primary alkyl boronic acids as alkylating agents for primary amides. After initial investigations, we found that the use of catalytic copper(I) bromide, along with sodium trimethylsilanolate as the base and tert-butyl peroxide as an oxidant resulted in the highly selective monoalkylation of a wide variety of primary amides. The secondary amide products from this transformation can be quite varied, and can include carbocycles, heterocycles, aromatic rings, aryl chlorides, ethers, alkyl amides, free alcohols, nitriles, carbamates, strained rings, and steric encumbrance both alpha to the carbonyl as well as beta to the nitrogen of the amide. Yields for the transformations were generally high, and in no case were tertiary amide products observed. We found that secondary boronic acids can also be used in the reaction, however the yields in this case were highly variable and generally lower than those with primary substrates. Overall, this research represents a novel and powerful entry into secondary amides. More importantly, the transformation allows for the introduction of a nitrogen moiety into an alkyl (hydrocarbon derived) framework, and is one of the first examples of catalytic C-N bond formation at an alkyl center. This work was published in Organic Letters (Org. Lett. 2013, 15, 2314).
In the current directions for this portion of the research program are directed at expanding this copper catalyzed reaction to other classes of nucleophiles and alkyl boronate reagents. These studies will also be reported in due course.