Organofluorine compounds are of great importance to many disciplines of the chemical sciences and are prevalent in the pharmaceutical and agrochemical sciences. Of these compounds, trifluoromethyl aromatic compounds are especially important and they have found broad use in both the treatment of disease and in agricultural chemicals. Given the critical nature of this motif, the direct installation of trifluoromethyl (CF3) residues onto existing aromatic compounds is an important goal for synthetic organic chemistry and much research has been devoted toward this end. While there are several useful methods for the incorporation of CF3 functionality into aromatic systems, they are limited to substrates that contain preinstaled functional groups. For example, the most powerful existing arene trifluoromethylation techniques utilize either aryl halide substrates or biaryl substrates that contain specific directing groups. Currently, no method exists for the trifluoromethylation of substrates outside of these boundaries and the introduction of such a technology would greatly streamline the synthesis of CF3-containing aromatic compounds. Furthermore, heteroaromatic compounds are ubiquitous in medicines and the direct trifluoromethylation of heterocyclic compounds (such as the -azine or -azole heterocyclic families) would represent a significant advance in the technologies that enable drug and agrochemical discovery. The proposed research seeks to address this problem by applying underlying principles from cross coupling and C-H functionalization technologies to introduce a chemical method to achieve the direct oxidative C-H trifluoromethylation of heteroaromatic compounds. More specifically, the proposed work would splice together individual aspects of two existing palladium catalyzed processes that individually accomplish CF3 cross coupling and C-H functionalization, respectively. The successful merger of these technologies would result in a general catalytic method for the direct transformation of an organic carbon-hydrogen bond with a carbon-carbon (CF3) bond in a selective fashion. The realization of this ideal would provide practitioners of chemical synthesis with a powerful tool for the rapid construction of highly important lead compounds or drug candidates. Moreover, the proposed technology would enable the direct installation of trifluoromethyl functionalities into late-stage intermediates that would otherwise be extremely difficult, if not impossible to accomplish. This ability would have a powerful impact on the identification and development of chemical entities that enable the treatment of disease or the production of food.

Public Health Relevance

Organic molecules that contain aromatic trifluoromethyl groups are important to the treatment of a number of critical diseases (such as HIV, type-II diabetes, depression etc.) and to the technologies that enable the global agricultural industry. The direct construction of this type of molecule from easily obtained materials is difficult (if not impossible) and the proposed research, if successful, would greatly simplify this endeavor.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM099187-03
Application #
8523916
Study Section
Special Emphasis Panel (ZRG1-F04A-G (20))
Program Officer
Lees, Robert G
Project Start
2011-08-15
Project End
2014-08-14
Budget Start
2013-08-15
Budget End
2014-08-14
Support Year
3
Fiscal Year
2013
Total Cost
$52,190
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139