www.acsprf.org

The grant received from the ACS Petroleum Research Fund (for January 2010 to August 2012) is focused primarily on the design and development of novel chemical reactions that use carbon dioxide (CO₂) in an asymmetric fashion. CO₂ is an abundant, inexpensive, and nontoxic material, an ideal synthon for fine chemical production. Its inertness, however, necessitates the use of appropriate transition metal and organocatalysts for its activation. Our initial work demonstrated the use of low-valent nickel(0) and palladium(0) catalysts for the catalytic activation of CO₂ and we achieved the first broad-scope and functional group tolerant carboxylation of organozinc reagents under mild conditions.¹ Based on these initial studies, we sought to expand this work to asymmetric variants primarily focusing on the reaction of a racemic mixture of secondary organozinc reagents in catalytic carboxylations. This work can impact our ability to prepare valuable chiral materials from a simple feedstock. To evaluate the feasibility of our proposal, we attempted Ni-catalyzed carboxylation of symmetrical cyclohexylzinc bromide and observed clean conversion to the carboxylic acid. Delighted by this result, we attempted the carboxylation of a racemic secondary organozinc reagent. Our analysis indicates that significant scrambling was observed and carboxylation occurred at other secondary carbon atoms on the backbone. This observation is in agreement with recently reported cross-coupling reaction between Grignard reagents and aryl bromides in which ligand control is critical for minimizing isomerisation of this type.³ Our current efforts are focusing around the use of nitrogen-based ligands (e.g., oxazolines) for overcoming the regioselectivity challenge. We have also explored the possibility of rhodium- or copper-catalyzed tandem cyclization/carboxylation of unactivated alkenes, as well as iron- or gold-catalyzed intramolecular asymmetric hydro- and arylcarboxylation of unactivated alkenes (proposals II and III). Thus far, we have not been able to observe carboxylic acid or carbonate/carbamate formation. Efforts toward these types of CO₂ incorporation are ongoing in our laboratories. We are also pursuing tandem C-–H activation/carboxylation based on our own expertise in the field of palladium- and rhodium-catalyzed C-H functionalizations.⁴

Impact on my career and students. The discovery of catalytic carboxylation reactions has greatly increased the visibility of my group and my research program to the scientific community, leading to recognition in the form of various awards and prizes (e.g., ACS Arthur C. Cope Scholar Award, Alfred P. Sloan Research Fellowship). In addition, I have presented portions of our work, supported by ACS, at over fifty lectures during this funding period (January 2010 to present). I have gratefully acknowledged the support from ACS PRF during these presentations at Universities, private companies, and conferences. My student Charles has been able to make significant progress in this challenging area. Charles has also attended numerous conferences (e.g., ACS National Meeting) and has received excellent feedback and suggestions. The assistance made available from the Grant will undoubtedly positively impact his career. The preliminary results that we have obtained thus far will be used to drive further research in catalytic carboxylations.

A postdoctoral fellow has recently joined the group that is following up these results and working toward developing a suitable catalyst system for regio- and enantioselective carboxylation of organozinc reagents. In particular,bwe are designing a suitable ligand framework that will not only minimize the isomerisation problem, but allow us to achieve high levels of enantioselective induction. Efforts toward asymmetric alkene functionalizations (which are presumably intermediates in the isomerisation processs) are also underway. Based on recent reports in the literature, this process may will complement our originally proposed enantioselective functionalization of secondary organozinc reagents.⁵We plan to recruit other students to this project over the next year. Other than acknowledgements in conference presentations, future publications will also include a statement of gratitude to the ACS Petroleum Research Fund.

References

Yeung, C. S.; Dong, V. M. Beyond Aresta's complex: Ni- and Pd-catalyzed organozinc coupling with CO₂. J. Am. Chem. Soc. 2008, 130, 7826.

Yeung, C. S.; Dong, V. M. Unpublished work.

Joshi-Pangu, A.; Wang, C.-Y.; Biscoe, M. R. Nickel-Catalyzed Kumada Cross-Coupling Reactions of Tertiary Alkylmagnesium Halides and Aryl Bromides/Triflates. J. Am. Chem. Soc. 2011, 133, 8478.

For an example, see: Zhao, X.; Yeung, C. S.; Dong, V. M. Palladium-catalyzed ortho-Arylation of O-Phenylcarbamates with Simple Arenes and Sodium Persulfate. J. Am. Chem. Soc. 2010, 132, 5837.

(a) Williams, C. M.; Johnson, J. B.; Rovis, T. Nickel-Catalyzed Reductive Carboxylation of Styrenes Using CO₂. J. Am. Chem. Soc. 2008, 130, 14936. (b) Takaya, J.; Iwasawa, N. Hydrocarboxylation of Allenes with CO₂ Catalyzed by Silyl Pincer-Type Palladium Complex. J. Am. Chem. Soc. 2008, 130, 15254.