University of Illinois

M Christina White

Jinpeng Zhao

Aaron L Petronico

Paul E Gormisky

Chloe Wendell

Jennifer R Griffin

Rulin Ma

Anasheh Sookezian

Shauna M Paradine

Joseph R Clark

Stephen E Ammann

Mark S Chen

Kaibo Feng

Wei Liu

A chemoselective and reactive Mn(CF-PDP) catalyst system that enables for the first time the strategic advantages of late-stage aliphatic C&#x2014;H hydroxylation to be leveraged in aromatic compounds. This discovery will benefit small molecule therapeutics by enabling the rapid diversification of aromatic drugs and natural products and identification of their metabolites.

Chemoselective methylene hydroxylation in aromatic molecules

Reactions that directly install nitrogen into C&#x2014;H bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Selective intramolecular C&#x2014;H amination reactions that achieve high levels of reactivity, while maintaining excellent site-selectivity and functional-group tolerance is a challenging problem. Herein is reported a manganese perchlorophthalocyanine catalyst [Mn(ClPc)] for intermolecular benzylic C&#x2014;H amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site-selectivity. In the presence of Br&#xf8;nsted or Lewis acid, the [Mn(ClPc)]-catalyzed C&#x2014;H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies indicate that C&#x2014;H amination proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C&#x2014;H cleavage is the rate-determining step of the reaction. Collectively these mechanistic features contrast previous base-metal catalyzed C&#x2014;H aminations. The catalyst can be a compound of Formula I: 

Manganese (III) catalyzed C&#x2014;H aminations

The enantioselective synthesis of isochroman motifs has been accomplished via Pd(II)-catalyzed allylic C&#x2014;H oxidation from terminal olefin precursors. Critical to the success of this goal was the development and utilization of a novel chiral aryl sulfoxide-oxazoline (ArSOX) ligand. The allylic C&#x2014;H oxidation reaction proceeds with the broadest scope and highest levels asymmetric induction reported to date (avg. 92% ee, 13 examples &#x2265;90% ee). Additionally, C(sp)-N fragment coupling reaction between abundant terminal olefins and N-triflyl protected aliphatic and aromatic amines via Pd(II)/sulfoxide (SOX) catalyzed intermolecular allylic C&#x2014;H amination is disclosed. A range of 52 allylic amines are furnished in good yields (avg. 76%) and excellent regio- and stereoselectivity (avg. &#x3e;20:1 linear:branched, &#x3e;20:1 E:Z). For the first time, a variety of singly activated aromatic and aliphatic nitrogen nucleophiles, including ones with stereochemical elements, can be used in fragment coupling stiochiometries for intermolecular C&#x2014;H amination reactions.

Sulfoxide ligand metal catalyzed oxidation of olefins

The invention provides simple small molecule, non-heme iron catalyst systems with broad substrate scope that can predictably enhance or overturn a substrate's inherent reactivity preference for sp3-hybridized C&#x2014;H bond oxidation. The invention also provides methods for selective aliphatic C&#x2014;H bond oxidation. Furthermore, a structure-based catalyst reactivity model is disclosed that quantitatively correlates the innate physical properties of the substrate to the site-selectivities observed as a function of the catalyst. The catalyst systems can be used in combination with oxidants such as hydrogen peroxide to effect highly selective oxidations of unactivated sp3 C&#x2014;H bonds over a broad range of substrates.

Catalyst-controlled aliphatic C&#x2014;H oxidations

The invention provides novel manganese catalysts such as [Mn(BuPc)], which are general for the amination of all types of C(sp)-H bonds (aliphatic, allylic, propargylic, benzylic, ethereal), including strong 1aliphatic C&#x2014;H bonds, while achieving excellent chemoselectivity, stereospecificity, and high functional group tolerance. We demonstrate the late-stage diversification of bioactive complex molecules that encompass the range of C(sp)-H bond types, such as selective 1C&#x2014;H aminations of betulinic acid and pleuromutilin derivatives. The catalysts' unprecedented balance of reactivity and selectivity is in part attributed to its mechanism of C&#x2014;H amination that lies between stepwise and concerted.

General catalyst for C-H functionalization

A composition including a complex of a metal, a tetradentate ligand, at least one ancillary ligand, and a counterion may be used for selective spC&#x2014;H bond oxidation. The tetradentate ligand may include a N-heterocyclic-N,N'-bis(pyridyl)-ethane-1,2-diamine group or a N,N&#x2032;-bis(heterocyclic)-N,N&#x2032;-bis(pyridyl)-ethane-1,2-diamine group. The composition can be used in combination with HOto effect highly selective oxidations of unactivated spC&#x2014;H bonds over a broad range of substrates. The site of oxidation can be predicted, based on the electronic and/or steric environment of the C&#x2014;H bond. In addition, the oxidation reaction does not require the presence of directing groups in the substrate.

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Champaign, IL, United States of America

M Christina White