Carbon Dioxide as a Directing Group for C-H Functionalization Reactions

Project ID:  D2018-03

Background

The development of new strategies for elaboration of amines via C–H functionalization has been an important area of research over the last decade. Compounds made by this method are useful in a variety of industries, including the agrochemical and pharmaceutical industries. 

Numerous directing groups have been used for the directed C-H functionalization of amines and other heteroatom-bearing substrates.  However, these have mostly involved stoichiometric conversion of the amine into an amide, requiring significantly more steps and reduced atom economy. Other approaches have focused on in situ-installed directing groups, primarily through formation of imines that can be easily removed at the end of the reaction.  Although these strategies enjoy increased atom economy, they are less applicable to strongly oxidizing conditions.  In addition, the requisite formation of imines requires that these strategies can only be applied to primary amines.  Therefore, there is a need in the art for synthetic methods involving C-H functionalization that utilize different directing groups. 

Invention Description

The researchers at the University of Toledo have developed a method of functionalizing a C-H bond. This platform for carbon dioxide-directed C−H functionalization that allows facile access to structurally diverse compounds while simultaneously being viable for production scale of newly identified hits. A number of FDA approved drugs may be made by the method and could benefit from this efficient method.

Applications

•       Production of pharmaceuticals or herbicides, such as Sensipar, Duloxetine, Fingolimod, KRP203, B-3 adrenergic agonists, STTR4 agonists, and other gamma-aryl amines.

Advantages

• More direct and faster route to gamma-arylated amines, etc.
• Less waste, fewer steps
• Carbon dioxide can be easily pumped in and removed by vacuum
• Improved sustainability, selectivity, and effectiveness of C-H activation 
• Does not require primary amines
• Works using low cost in situ directing groups

IP Status:              US Patent Pending, 2019/0185392 A1

Publications:     Kapoor, Mohit; Chand-Thakuri, Pratibha; Young, Michael Carbon Dioxide-Mediated C(sp2)–H Arylation of Primary and Secondary Benzylamines ChemRxiv. Preprint.

                            Kapoor, Mohit; Liu, Daniel; Young, Michael Carbon Dioxide Mediated C(sp3)–H Arylation of Amine Substrates J. Am. Chem. Soc. May 22, 2018 (Web)

                            Cohen Karaline 12-year-old UT student is a published researcher. May 31, 2018