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.
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.
|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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