59th Annual Report on Research 2014

2. Specific Objectives. The research proposed in the PRF proposal (PRF#52224-UNI3) seeks to address four aims concerning the development of Ni-catalyzed direct arylations using C–O electrophiles: (1) To develop reaction conditions for the intramolecular sp² C–H arylation; (2) To apply the conditions from Aim 1 toward the development of intermolecular reactions; (3) To perform detailed mechanistic studies on the direct arylation of sp² C–H bonds; (4) To apply the insights gained from Aims 1-3 toward accomplishing sp³ C–H arylations

3. Significant Results. Aim 1 (intramolecular sp² C–H arylation): Last year we reported the development of a method for the Ni(COD)₂/dcype-catalyzed intramolecular coupling of C–H bonds with C–O electrophiles. While exploring this project we discovered that dcype is an efficient ligand for an analogous Pd-catalyzed intramolecular C–H arylation using C–O electrophiles. As shown in Scheme 1, Pd-catalyzed transformation has a scope similar to the previously reported Ni-catalyzed reactions. A protocol for the sequential mesylation/arylation starting with phenol substrates has been accomplished for the intramolecular C–C bond forming reactions (Scheme 2). We hope that the insights gained from these Pd-catalyzed reactions can be applied toward the development of analogous Ni-catalyzed C–H bond formations using aryl mesylates (ACS Catal. 2014, 4, 2395).

Aim 2 (intermolecular reactions): During this year we have obtained preliminary results for Ni-catalyzed intermolecular arylation of perfluoroarene C–H bonds using aryl carbamates as electrophiles (Scheme 3).   Further studies will involve the exploration of the scope of these reactions with respect to both the carbamate and the perfluoroarene substrates. Analogous to the intramolecular reactions described in Scheme 1, we have accomplished intermolecular Pd-catalyzed arylation of azole C–H bonds using aryl mesylates as electrophiles (Schemes 4 and 5). We have also obtained preliminary results for the Pd-catalyzed intermolecular coupling of nitroarenes with C–O electrophiles. We are currently exploring the scope and limitation of these reactions. We hope that the insights gained from these studies can inform the development of analogous Ni-catalyzed intermolecular reactions using mesylates (ACS Catal. 2014, 4, 2395). Aim 3 (mechanistic studies on the direct arylation of sp² C–H bonds;): During this year we have obtained preliminary mechanistic insights for Pd-catalyzed C–H arylations using aryl mesylates. As shown in Schemes 6 and 7, these reactions exhibit a significant inter- and intramolecular primary K.I. E. We have also conducted experiments to gain insight into the electronic requirements of these reactions (ACS Catal. 2014, 4, 2395).

Aim 4 (sp³ C–H arylations): During this year we have published an example of Ni⁰-mediated coupling of aryl halides (halide = I, Cl, Br) with alkyl C–H bonds adjacent to a nitrogen atom in benzamide substrates (Scheme 8). Electronically diverse isoindolinones can be obtained using this method in good to excellent yields. The use of tert-butoxide bases is important for the efficiency of these reactions. These arylations exhibit selectivity for the preferential arylation of more substituted alkyl C–H bonds. This observed selectivity together with other studies suggest a mechanism involving radical intermediates for these transformations (Scheme 9). Future efforts will be directed toward the development of analogous transformations using C–O electrophiles (Org. Lett. 2013, 15, 5986).

4. Key Outcomes/Achievements. The majority of the work described herein has been disseminated in peer-reviewed manuscripts over the past year. It has also enabled the generation of preliminary results for future manuscripts that we plan to publish. The grant has been invaluable toward obtaining preliminary results that has allowed the PI to receive the NIH Area grant.

The grant has directly supported the training of 4 undergraduate students for research in organometallic chemistry. Additionally, it has indirectly supported the research projects of five additional undergraduate students by enabling the purchase of supplies for the projects. Finally, the grant has supported the professional development of both the PI and the undergraduate students by funding their travel to a number of chemistry conferences.