Gold(I)-Catalyzed Hydrofunctionalization of Alkenes and Alkylidenecyclopropanes with Carbon and Nitrogen Nucleophiles

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Timmerman, Jacob Charles

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The transition metal-catalyzed hydroamination of a C−C multiple bond represents an efficient entry into the synthesis of nitrogen-containing heterocycles and acyclic amine derivatives. Nonetheless, the development of general methods for catalytic hydroamination has been met with challenge along the way. Gold(I)-catalysis has shown particular activity for catalytic hydroamination, especially in the context of allenes and alkynes. However, the development of gold(I)-catalyzed methods for the hydroamination of simple alkenes has lagged behind significantly. Chapter 1 will review the area of gold(I)-catalyzed hydroamination of unactivated and activated alkenes from 2006 to the present. Additionally, the hydroamination of 1,3-dienes and dehydrative amination of underivitized allylic alcohols will also be reviewed. In an effort to glean revelatory information for the further development of gold(I)-catalyzed hydroamination, particular attention will be made to experimental mechanistic analysis and the study of putative reaction intermediates.

The cationic gold phosphine complex [(P(t-Bu)2o-biphenyl)Au(NCMe)]+ SbF6–catalyzes the intramolecular hydroamination of 6-alkenyl-2-pyridones to form 1,6-carboannulated 2-pyridones in high yield. The hydroamination of 6-(γ-alkenyl)-2-pyridones was effective for monosubstituted and 1,1- and 1,2-disubstituted aliphatic alkenes, and the method was likewise effective for the hydroamination of 6-(δ-alkenyl)-2-pyridones. Spectroscopic analysis of mixtures of 6-(3-butenyl)-2-pyridone, (2.2)AuCl, and AgSbF6 established the N-bound 2-hydroxypyridine complex [(2.2)Au(NC6H3-2-OH-6-CH2CH2CH=CH2)]+ SbF6– as the catalyst resting state.

The cationic gold phosphine complex [(PCy2o-biphenyl)Au(NCMe)]+ SbF6– catalyzes the selective intermolecular, anti-Markovnikov hydroamination of the C=C bond of monosubstituted and cis- and trans-disubstituted alkylidenecyclopropanes (ACPs) with 1-methyl-imidazolidin-2-one to form 1-cyclopropyl alkylamine derivatives in high yield and with high regio- and diastereoselectivity. This method was likewise effective for other classes of nitrogen nucleophiles, such as 2-pyridones and 1,2,3-benzotriazole. Mechanistic studies on the intermolecular, anti-Markovnikov hydroamination of ACPs with 1-methyl-2-imidazolidione were conducted in an effort to reveal the catalyst resting state, the overall kinetic order of the reaction, as well as the nature of both the C−N bond formation and protodeauration steps of the reaction. It was found that the title reaction exhibited first order behavior in ACP, 1-methyl-2-imidazolidinone, and gold catalyst. Further, the reaction exhibited behavior consistent with product inhibition and showed inverse first-order behavior in 1,3-dimethyl-2-imidazolidinone. Kinetic analysis was consistent with a scenario involving turnover-limiting C−N bond formation, followed by facile protodeauration. Computational analysis of the gold-catalyzed ACP hydroamination likewise supports turnover-limiting C−N bond formation. DFT analysis also revealed that a stronger C−Au and C−N bond in the anti-Markovnikov pathway favors the observed regiochemistry of the reaction. Similarly, Fukui analysis on the purported gold-π-ACP intermediate reveals electrophilic character at the terminal alkene carbon atom in the presence of an incoming nucleophile.

Cationic gold complexes containing an N-heterocyclic carbene ligand catalyze the intermolecular anti-Markovnikov hydroarylation of monosubstituted and cis- and trans-disubstituted methylenecyclopropanes (MCPs) with N-alkyl and 1,2-dialkyl indoles to form the corresponding 3-(cyclopropylmethyl)indoles in high regio- and diastereoselectivity and in good to excellent chemical yield.







Timmerman, Jacob Charles (2017). Gold(I)-Catalyzed Hydrofunctionalization of Alkenes and Alkylidenecyclopropanes with Carbon and Nitrogen Nucleophiles. Dissertation, Duke University. Retrieved from


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