59th Annual Report on Research 2014

As reported in our previous annual report, pursing novel ligand designs for our proposed research project lead us to develop a new copper-catalyzed process for the mono-alkylation of primary amides using alkyl boronic esters. This novel reaction, related to the Lam-Chan process for the formation of C-N at aromatic carbon centers, is a rare example of catalytic C–N bond formation at an alkyl center. This later class of reactions has typically proven highly challenging, in large part, do to the propensity of alkyl organometallic compounds and intermediates to undergo beta-hydride elimination more rapidly than the desired reductive elimination to form C–N bonds.

As we previously reported, 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. This work was published in Organic Letters (Org. Lett. 2013, 15, 2314).

A major limitation of our initially reported protocol was our limited ability to prepare, handle and use functionalized alkyl boronic acids. These reagents are notoriously unstable compounds. In contrast, alkyl pinacol boronic esters are stable compounds, which can be prepared by a variety of means with a board range of functional group tolerance. Our initial protocol, however, was highly ineffective with these more desirable reagents.

During the most current grant period, we have worked to address this shortcoming. In the past 12 months, we have developed an new catalyst system, employing a novel ligand architecture, that dramatically increases the yield and scope of the alkyl C–N bond forming reaction using alkyl pinacol boronic esters. A remarkable range of hetereatomic and heterocyclic functionality, on both the amide and alkyl boronate coupling partners, can now be tolerated, leading to highly functionalized amide products. Results from these studies are currently being prepared for publication, and we hope to have one or more additional manuscripts submitted from this work in the near future.