The main goal of the proposed research is to develop new and useful transformations using carbon-hydrogen bond functionalization reactions. Use of C-H bonds as a transformable functional group is advantageous since these bonds are typically the most abundant functionality in organic molecules, and most starting materials that are available on large scale contain only carbon-carbon and carbon-hydrogen bonds. Direct conversion of these bonds to the desired functionality shortens synthetic pathways saving reagents, solvents, and labor. However, obvious problems, such as low reactivity of alkane sp3 C-H bonds and difficulty to attain regioselective functionalization of these bonds, have prevented widespread use of C-H functionalization methodology. Our efforts are directed towards addressing these issues in the context of pharmaceutically relevant transformations. Specifically, the project will focus on the auxiliary-directed alkane C-H bond functionalization and group 11 metal-catalyzed sp3 C-H bond functionalization via carbene intermediates. We have a substantial amount of preliminary data showing that proposed chemistry is viable and may lead to useful methodology. We will develop second-generation auxiliaries for sp3 C-H bond functionalization that will replace aminoquinoline directing group and address its remaining challenges. Specifically, monodentate 1- aminopyridine and pyrazole derivatives will be used to direct sp3 C-H bond functionalization. The key difference from first-generation auxiliaries is easier removal, lack or product inhibition, possibility of ligand- accelerated catalysis while matching the outstanding directing abilities of aminoquinoline, and ability to functionalize ?-positions in amine derivatives. These studies will have important implications, and have already resulted in superior auxiliaries for arylation of sp3 C-H bonds. The reactions arising from C-H bond activation will complement the current methods for C-C and C-heteroatom bond formation and will have a substantial impact on synthetic methodology. We have obtained preliminary results showing that non-directed group 11 metal-catalyzed sp3 C-H bond functionalization with alkyl diazo and fluorinated diazo compounds is feasible. These unique transformations cannot be easily achieved by using other methodology. The new catalysts should allow for unprecedented late- stage functionalization of medicinally relevant molecules.
The specific aims of the research are as follows: 1. New auxiliary and reaction development for directed C-H functionalization, 2. Enantioselective C-H bond functionalization, 3. Group 11 metal-catalyzed C-H functionalization via carbenoid intermediates.

Public Health Relevance

The primary goal of the proposed research is to develop new and useful transformations using carbon- hydrogen bond functionalization reactions. We propose new transformations that will lead to more efficient pathways for making pharmaceutical intermediates. These more efficient methods may lead to lower-cost production of medications. Furthermore, our methods should allow for quick, efficient, and economical synthesis of drug analogues that will be useful in designing and testing new medicines.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Yang, Jiong
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University of Houston
Schools of Arts and Sciences
United States
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Nguyen, Tung Thanh; Grigorjeva, Liene; Daugulis, Olafs (2018) Cobalt-Catalyzed Coupling of Benzoic Acid C-H Bonds with Alkynes, Styrenes, and 1,3-Dienes. Angew Chem Int Ed Engl 57:1688-1691
Kwak, Se Hun; Gulia, Nurbey; Daugulis, Olafs (2018) Synthesis of Unsymmetrical 2,6-Diarylanilines by Palladium-Catalyzed C-H Bond Functionalization Methodology. J Org Chem 83:5844-5850
Mesgar, Milad; Nguyen-Le, Justin; Daugulis, Olafs (2018) New Hindered Amide Base for Aryne Insertion into Si-P, Si-S, Si-N, and C-C Bonds. J Am Chem Soc :
Nguyen, Tung Thanh; Daugulis, Olafs (2017) Palladium-catalyzed, aminoquinoline-directed arylation of phosphonamidate and phosphinic amide sp3 C-H bonds. Chem Commun (Camb) 53:4609-4611
Mesgar, Milad; Daugulis, Olafs (2017) Synthesis of 1,2-Bis(trifluoromethylthio)arenes via Aryne Intermediates. Org Lett 19:4247-4250
Gulia, Nurbey; Daugulis, Olafs (2017) Palladium-Catalyzed Pyrazole-Directed sp3 C-H Bond Arylation for the Synthesis of ?-Phenethylamines. Angew Chem Int Ed Engl 56:3630-3634
Nguyen, Tung Thanh; Grigorjeva, Liene; Daugulis, Olafs (2017) Aminoquinoline-directed, cobalt-catalyzed carbonylation of sulfonamide sp2 C-H bonds. Chem Commun (Camb) 53:5136-5138
Kocen, Andrew L; Brookhart, Maurice; Daugulis, Olafs (2017) Palladium-catalysed alkene chain-running isomerization. Chem Commun (Camb) 53:10010-10013
Nguyen, Tung Thanh; Grigorjeva, Liene; Daugulis, Olafs (2016) Cobalt-Catalyzed, Aminoquinoline-Directed Functionalization of Phosphinic Amide sp2 C-H Bonds. ACS Catal 6:551-554
Klimovica, Kristine; Kirschbaum, Kristin; Daugulis, Olafs (2016) Synthesis and Properties of ""Sandwich"" Diimine-Coinage Metal Ethylene Complexes. Organometallics 35:2938-2943

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