UC Santa Barbara

Carbon–nitrogen bonds abound in chemistry and biology, and, as such, it is essential for contemporary organic chemists to develop better methods for their synthesis. The current state of the art in this field is the SN2 addition, the reductive amination and the Buchwald-Hartwig amination, among others. These approaches are widely used yet suffer, however, from overalkylation, potential tautomerizations and the use of rare transition metal catalysts, respectively. Inspired by the materials synthesis carried out across the UCSB Campus Green from the Chemistry Department, we developed a novel single electron method for the synthesis of these bonds. Specifically, we used electron deficient alkyl halides and low valent copper catalysts to form a transient carbon-centered radical, which can add into a nitrosoarene nitrogen in a nucleophilic-like fashion, furnishing our desired C¬–N bond. This approach allows for high-yielding bond formation with mild conditions onto sterically congested molecules, among other benefits. In my first example of this work, we developed an ipso-substitution allowing access to electron rich nitrosoarenes, which had previously been relatively inaccessible. We employed this method in a three-component-two-step-one-pot coupling to access sterically hindered anilines. We next used this method in the synthesis of N¬–O macrocycles and amino alcohols. In the final application of this synthetic method, brominated pyrroloindolines were aminated in excellent yields using this radical based method. We employed this method at gram scales in the key step of a total synthesis of the natural product (+)-asperazine A.