The primary goal of the proposed research is to develop new and useful transformations using electrophilic carbon-hydrogen bond activation reactions mediated by transition metal complexes. Extensive synthetic methodology has been developed based on oxidative addition reactions of C-X bonds (X=halogen, heteroatom). Catalytic C-C bond forming reactions arising from C-H bond activations are less common despite the wider availability, price, and environmental advantages of the starting hydrocarbons compared to functionalized compounds. The reactions arising from C-H bond activation will complement the current methods for C-C bond formation and have a substantial impact on synthetic methodology. In this project, palladium-catalyzed coupling of C-H bonds with C-X bonds will be investigated leading to new and general methods for C-C bond formation. Preliminary studies suggest that the proposed chemistry is viable and will yield unique reactions useful in the synthesis of compounds of medicinal and biological interest. We have already achieved the first general palladium-catalyzed C-H activation/C-C coupling sequences at unactivated sp3 centers.
The specific aims of the research are as follows: A. Expansion of the C-H activation/C-C bond formation method generality and convenience. A general method for alkylation/arylation/alkenylation of directing group containing arenes will be developed. Both ortho- and meta, para selectivity in these reactions should be accessible depending on the reaction conditions as described in Preliminary results section. A method for the arylation of unfunctionalized arenes will be developed. New auxiliaries for the arylation of sp3 C-H bonds will be investigated. B. Development of diastereoselective reactions. By using chiral auxiliaries, diastereoselective C-H bond arylations and alkylations will be achieved. This methodology will be tested in the synthesis of pharmaceutically relevant compounds. C. Mechanistic investigations. Mechanistic understanding should allow us to rationally improve the methodology developed during the preliminary studies, and to develop improved second-generation processes. The new methodologies developed in this research will lead to more efficient routes to Pharmaceuticals and their precursors. Substantial shortening of the reported routes to pharmaceutically relevant compounds are proposed.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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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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