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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM077635-04
Application #
7858240
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Hagan, Ann A
Project Start
2007-06-05
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$245,236
Indirect Cost
Name
University of Houston
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
036837920
City
Houston
State
TX
Country
United States
Zip Code
77204
Mesgar, Milad; Daugulis, Olafs (2017) Synthesis of 1,2-Bis(trifluoromethylthio)arenes via Aryne Intermediates. Org Lett 19:4247-4250
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
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 sp(2) 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
Mesgar, Milad; Daugulis, Olafs (2016) Silylaryl Halides Can Replace Triflates as Aryne Precursors. Org Lett 18:3910-3
Roane, James; Daugulis, Olafs (2016) A General Method for Aminoquinoline-Directed, Copper-Catalyzed sp(2) C-H Bond Amination. J Am Chem Soc 138:4601-7
Grigorjeva, Liene; Daugulis, Olafs (2015) Cobalt-promoted dimerization of aminoquinoline benzamides. Org Lett 17:1204-7

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