Transition metal catalyzed cross-coupling is one of the most powerful synthetic methods and is used extensively in the preparation of active pharmaceutical ingredients. The goal of this work is to use fundamental mechanistic studies to develop improved Ni and Pd catalysts for new and existing cross-coupling reactions. Recently, our group developed the commercially available precatalyst scaffold (?3-1-tBu-indenyl)Pd(L)(Cl) (IndPdL, L = N-Heterocyclic carbene (NHC) or PR3), which generates highly active catalysts for a range of important cross-coupling reactions. To design even better catalysts, which can facilitate new reactions and operate at milder conditions, we will perform detailed mechanistic studies using IndPdL derived systems, involving both experiment and theory. Our studies will encompass all aspects of the catalytic process including elucidating the pathway for precatalyst activation, understanding the elementary steps in catalytic cycles and determining the catalyst decomposition pathway. Initially, we will study the mechanism of activation of IndPdL to the monoligated Pd0 active species under a variety of conditions used for cross-coupling. This will be the first comprehensive study of the activation of any cross-coupling precatalyst under a range of commonly used reaction conditions. This information will be used in combination with knowledge of the fundamental steps in catalysis, which will be gained through stoichiometric studies and kinetics experiments, to rationally develop systems for fluoride free Hiyama reactions with aryl chlorides, carbamates and sulfamates and Suzuki-Miyaura couplings with 2-aryl and 2-alkylaziridines. The discovery of Ni catalysts with comparable activity to Pd systems is preferred because Ni is cheaper, more abundant and has lower levels of toxicity. Accordingly, we will also use an approach based on rational design to develop Ni based catalysts for cross-coupling. In preliminary results we showed that several highly active Ni precatalysts for the Suzuki-Miyaura reaction rapidly form a NiI complex under catalytic conditions. Here, we will establish the role of NiI species in catalysis with systems supported by monodentate and bidentate phosphine ligands, as well as NHC ligands. This information will be used to develop improved systems for the Suzuki-Miyaura and Buchwald-Hartwig reactions with aryl carbamates and sulfamates. A major additional benefit of our mechanistic approach is that the general trends we elucidate in regard to catalyst design and reaction conditions for Ni and Pd catalyzed cross-coupling will be generalizable to a plethora of other reactions, which are relevant to the synthesis of pharmaceuticals, but will not specifically be studied in this proposal.

Public Health Relevance

The project is relevant to the NIH's mission because it will develop more efficient methods for synthesizing pharmaceuticals. Specifically, Ni and Pd catalyzed cross-coupling reactions are currently utilized to prepare a number of active pharmaceutical ingredients. If the efficiency of Ni and Pd catalyzed cross-coupling is improved or new reactions are developed, this will make it more cost effective to produce a range of pharmaceuticals, which are used to treat a number of different diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM120162-04
Application #
9699503
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Yang, Jiong
Project Start
2016-08-01
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Yale University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Dardir, Amira H; Melvin, Patrick R; Davis, Ryan M et al. (2018) Rapidly Activating Pd-Precatalyst for Suzuki-Miyaura and Buchwald-Hartwig Couplings of Aryl Esters. J Org Chem 83:469-477
Beromi, Megan Mohadjer; Banerjee, Gourab; Brudvig, Gary W et al. (2018) Nickel(I) Aryl Species: Synthesis, Properties, and Catalytic Activity. ACS Catal 8:2526-2533
Mohadjer Beromi, Megan; Nova, Ainara; Balcells, David et al. (2017) Mechanistic Study of an Improved Ni Precatalyst for Suzuki-Miyaura Reactions of Aryl Sulfamates: Understanding the Role of Ni(I) Species. J Am Chem Soc 139:922-936
Melvin, Patrick R; Nova, Ainara; Balcells, David et al. (2017) DFT Investigation of Suzuki-Miyaura Reactions with Aryl Sulfamates Using a Dialkylbiarylphosphine-Ligated Palladium Catalyst. Organometallics 36:3664-3675
Hazari, Nilay; Melvin, Patrick R; Beromi, Megan Mohadjer (2017) Well-defined nickel and palladium precatalysts for cross-coupling. Nat Rev Chem 1:
Melvin, Patrick R; Hazari, Nilay; Beromi, Megan Mohadjer et al. (2016) Pd-Catalyzed Suzuki-Miyaura and Hiyama-Denmark Couplings of Aryl Sulfamates. Org Lett 18:5784-5787