N-Heterocycle Synthesis via Bidentate-Auxiliary Directed Remote C-H Functionalization
Open Access
- Author:
- Nack, William Andrew
- Graduate Program:
- Chemistry
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- May 05, 2016
- Committee Members:
- Gong Chen, Dissertation Advisor/Co-Advisor
Gong Chen, Committee Chair/Co-Chair
Alexander Radosevich, Committee Member
Kenneth Feldman, Committee Member
Charles Anderson, Outside Member - Keywords:
- C-H Functionalization
Palladium
Catalysis
Heterocycles - Abstract:
- Saturated N-heterocycles are useful motifs in medicinal chemistry, but their application often hinges on limited synthetic methods. We have developed a strategy for the synthesis of the N-heterocycle 1,2,3,4-tetrahydroquinoline (THQ) using Pd-catalyzed C–H functionalization reactions. Beginning from an alkyl picolinamide, a picolinic acid (PA)-directed, Pd-catalyzed sp3 C–H arylation reaction yields a 3-arylpropylpicolinamide intermediate. This intermediate is then cyclized via a sequence of ortho sp2 C–H iodination followed by C–N cross coupling. We explored two methods for this critical iodination: a directed electrophilic aromatic substitution (EAS) method, and a Pd-catalyzed C–H iodination reaction. To demonstrate the scope of this strategy, a variety of substituted THQ scaffolds were synthesized, including (+)-angustureine. Finally, a mechanistic hypothesis for the directed EAS reaction is presented, integrating results from the recent literature with our own preliminary mechanistic studies. In the second chapter, a room temperature diastereoselective Pd-catalyzed C–H arylation reaction of 8-aminoquinoline (AQ) coupled cycloalkane carboxylic acids is described. Pd-catalyzed bidentate-auxiliary directed C–H arylation has been applied extensively for the synthesis of aryl cycloalkane moieties of natural products. We developed an improved room temperature protocol for cycloalkane C–H arylation and explored its scope. Further C–H functionalization reactions of the arylated products have been examined, and a mechanistic hypothesis is put forth which rationalizes the diastereoselectivity of the reaction, as well as observed reactivity trends.