Iron Catalyzed α-C-H Cyanation of Simple and Complex Tertiary Amines

This manuscript details the development of a general and mild protocol for the α-C-H cyanation of tertiary amines as well as its application in late stage functionalization. Suitable substrates include tertiary aliphatic, benzylic, and aniline-type substrates as well as complex substrates. Functional groups tolerated under the reaction conditions include various heterocycles, as well as ketones, amides, olefins, and alkynes. This broad substrate scope is remarkable, as comparable reaction protocols for α-C-H cyanation frequently occur via free radical mechanisms, and are thus fundamentally limited in their functional group tolerance. In contrast, the presented catalyst system tolerates functional groups that typically react with free radicals, suggesting an alternative reaction pathway. All components of the described system are readily available, allowing implementation of the presented methodology without the need for lengthy catalyst synthesis

Non-Directed, Copper Catalyzed Benzylic C-H Amination Avoiding Substrate Excess

We report the development of a benzylic C-H amination protocol that addresses two common drawbacks in non-directed, intermolecular benzylic C-H aminations: (i) the need to use an excess of substrate and (ii) the limitation to only introduce one type of nitrogen source. Key to this discovery is the use of the strong oxidant N-fluorobenzenesulfonimide (NFSI) in combination with a Cu/diimine ligand catalyst system and an added nitrogen nucleophile. The established conditions allow to lower the C-H substrate loading to 1.0 equivalent and provide up to 95% yield of C-H amination product. Furthermore, sulfonamides and benzamides can be employed as nitrogen sources/nucleophiles, resulting in access to a diverse product scope. </div

Iron-Catalyzed α-C-H Cyanation of Simple and Complex Tertiary Amines.

This manuscript details the development of a general and mild protocol for the α-C–H cyanation of tertiary amines and its application in late-stage functionalization. Suitable substrates include tertiary aliphatic, benzylic, and aniline-type substrates and complex substrates. Functional groups tolerated under the reaction conditions include various heterocycles and ketones, amides, olefins, and alkynes. This broad substrate scope is remarkable, as comparable reaction protocols for α-C–H cyanation frequently occur via free radical mechanisms and are thus fundamentally limited in their functional group tolerance. In contrast, the presented catalyst system tolerates functional groups that typically react with free radicals, suggesting an alternative reaction pathway. All components of the described catalyst system are readily available, allowing implementation of the presented methodology without the need for lengthy catalyst synthesis

Mechanistic Insights into Fe Catalyzed α-C-H Oxidations of Tertiary Amines

We report detailed mechanistic investigations of an iron-based catalyst system, which allows the α-C-H oxidation of a wide variety of amines, including acyclic tertiary aliphatic amines, to afford dealkylated or amide products. In contrast to other catalysts that affect α-C-H oxidations of tertiary amines, the system under investigation employs exclusively peroxy esters as oxidants. More common oxidants (e.g. tBuOOH) previously reported to affect amine oxidations via free radical pathways do not provide amine α-C-H oxidation products in combination with the herein described catalyst system. Motivated by this difference in reactivity to more common free radical systems, the investigations described herein employ initial rate kinetics, kinetic profiling, Eyring studies, kinetic isotope effect studies, Hammett studies, ligand coordination studies, and EPR studies to shed light on the Fe catalyst system. The obtained data suggest that the catalytic mechanism proceeds through C-H abstraction at a coordinated substrate molecule. This rate-determining step occurs either at an Fe(IV) oxo pathway or a 2-electron pathway at a Fe(II) intermediate with bound oxidant. We further show via kinetic profiling and EPR studies that catalyst activation follows a radical pathway, which is initiated by hydrolysis of PhCO3 tBu to tBuOOH in the reaction mixture. Overall, the obtained mechanistic data support a non-classical, Fe catalyzed pathway that requires substrate binding, thus inducing selectivity for α-C-H functionalization.<br /

Rücktitelbild: Remarkably High Reactivity of Pd(OAc) 2 /Pyridine Catalysts: Nondirected CH Oxygenation of Arenes (Angew. Chem. 40/2011)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87065/1/11119380_ftp.pd

Accessing diverse azole carboxylic acid building blocks via mild C-H carboxylation: Parallel, one-pot amide couplings and ML-guided substrate scope design

This manuscript describes a mild, functional group tolerant, and metal-free C-H carboxylation that enables direct access to azole-2-carboxylic acids, followed by amide couplings in one pot. This sequence accesses a large variety of azole-2-amides, demonstrating the significant expansion of the accessible chemical space, as compared to previously known methodologies. Key to the described reactivity is the use of silyl triflate reagents, which serve as reaction mediators in C-H deprotonation and stabilizers of (otherwise unstable) azole carboxylic acid intermediates. A diverse azole substrate scope designed via ma-chine learning-guided analysis demonstrates the broad utility of the sequence. DFT calculations provide insights into the role of silyl triflates in the reaction mechanism. Transferrable applications of the protocol are successfully established: (i) A low pressure (CO2 balloon) option for synthesizing azole-2-carboxylic acids without the need for high-pressure equipment; (ii) the use of 13CO2 for the synthesis of labeled compounds; and (iii) isocyanates as alternative electrophiles for direct C-H amidation. Fundamentally, the reported protocol expands the use of heterocycle C-H functionalization from late-stage functionalization applications towards its use in library synthesis. It provides general access to densely functionalized azole-2-carboxylic acid building blocks and demonstrates their one-pot use in diversifying amide couplings

Steric Control of Site Selectivity in the Pd-Catalyzed C–H Acetoxylation of Simple Arenes

This report describes the use of an oxidant and a ligand to control site selectivity in the Pd(OAc)₂-catalyzed C–H acetoxylation of simple arenes. The use of MesI(OAc)₂ as the terminal oxidant in combination with acridine as the ligand results in primarily sterically controlled selectivity. In contrast, with Pd(OAc)₂ as the catalyst and PhI(OAc)₂ as the oxidant, electronic effects dominate the selectivity of arene C–H acetoxylation

Rücktitelbild: Remarkably High Reactivity of Pd(OAc)2/Pyridine Catalysts: Nondirected CH Oxygenation of Arenes (Angew. Chem. 40/2011)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87065/1/11119380_ftp.pd

Back Cover: Remarkably High Reactivity of Pd(OAc) 2 /Pyridine Catalysts: Nondirected CH Oxygenation of Arenes (Angew. Chem. Int. Ed. 40/2011)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86930/1/11119214_ftp.pd