The primary goal of the proposed research is to develop new and useful transformations using carbon-hydrogen bond activation reactions. While 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 activation 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 will have a substantial impact on synthetic methodology. In this project, palladium-catalyzed arylation, alkylation, vinylation, and alkynylation of unactivated sp3 C-H bonds will be explored in context of synthesis of biologically relevant unnatural amino acid derivatives. Furthermore, we will explore palladium-catalyzed fluorination of unactivated sp3 C-H bonds. Additionally, we have obtained preliminary results showing that auxiliaries developed for the palladium-catalyzed C-H bond functionalization are effective for copper-catalyzed sp2 C-H bond arylation, sulfenylation, and amination. We have a substantial amount of preliminary data showing that proposed chemistry is viable and may lead to useful methodology.
The specific aims of the research are as follows: 1. New auxiliary and reaction development for sp3 C-H bond conversion to C-C bonds, 2. Fluorination of unactivated sp3 C-H bonds, 3. Auxiliary assisted, copper-catalyzed C-H bond functionalization.

Public Health Relevance

The primary goal of the proposed research is to develop new and useful transformations using carbon-hydrogen bond activation 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. Additionally, improved synthetic methods may allow production of complicated drug structures that currently would be too expensive.

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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Lees, Robert G
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University of Houston
Schools of Arts and Sciences
United States
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Truong, Thanh; Mesgar, Milad; Le, Ky Khac Anh et al. (2014) General method for functionalized polyaryl synthesis via aryne intermediates. J Am Chem Soc 136:8568-76
Grigorjeva, Liene; Daugulis, Olafs (2014) Cobalt-catalyzed direct carbonylation of aminoquinoline benzamides. Org Lett 16:4688-90
Grigorjeva, Liene; Daugulis, Olafs (2014) Cobalt-catalyzed, aminoquinoline-directed coupling of sp(2) C-H bonds with alkenes. Org Lett 16:4684-7
Grigorjeva, Liene; Daugulis, Olafs (2014) Cobalt-catalyzed, aminoquinoline-directed C(spĀ²)-H bond alkenylation by alkynes. Angew Chem Int Ed Engl 53:10209-12
Truong, Thanh; Klimovica, Kristine; Daugulis, Olafs (2013) Copper-catalyzed, directing group-assisted fluorination of arene and heteroarene C-H bonds. J Am Chem Soc 135:9342-5
Tran-Vu, Hung; Daugulis, Olafs (2013) Copper-Catalyzed Carboxylation of Aryl Iodides with Carbon Dioxide. ACS Catal 3:
Tran, Ly Dieu; Roane, James; Daugulis, Olafs (2013) Directed amination of non-acidic arene C-H bonds by a copper-silver catalytic system. Angew Chem Int Ed Engl 52:6043-6
Truong, Thanh; Daugulis, Olafs (2013) Divergent Reaction Pathways for Phenol Arylation by Arynes: Synthesis of Helicenes and 2-Arylphenols. Chem Sci 4:531-535
Nadres, Enrico T; Santos, Gerson Ivan Franco; Shabashov, Dmitry et al. (2013) Scope and limitations of auxiliary-assisted, palladium-catalyzed arylation and alkylation of sp2 and sp3 C-H bonds. J Org Chem 78:9689-714
Nadres, Enrico T; Daugulis, Olafs (2012) Heterocycle synthesis via direct C-H/N-H coupling. J Am Chem Soc 134:7-10

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