An official website of the United States government
Abstract Herein, a general approach to intermolecular benzylic C(sp3)−H alkylation of methyl‐substituted arenes is reported using metal carbenes derived fromN‐aryl‐α‐diazo‐β‐amidoesters and dirhodium catalysts. Alkylated products were formed in up to 81 % yield with demonstrated functional group tolerance, outpacing previous literature. The unique amide‐ester scaffolding can be exploited through various derivatizations for broad synthetic utility and provides a starting point for the development of selectivity rules and reactivity profiles for these intermolecular C(sp3)−H functionalizations.
more »
« less
Attenuating N ‐Oxyl Decomposition for Improved Hydrogen Atom Transfer Catalysts
Abstract The design ofN‐oxyl hydrogen atom transfer catalysts has proven challenging to date. Previous efforts have focused on the functionalization of the archetype, phthalimide‐N‐oxyl. Driven in part by the limited options for modification of this structure, this strategy has provided only modest improvements in reactivity and/or solubility. Our previous mechanistic efforts suggested that while the electron‐withdrawing carbonyls of the phthalimide are necessary to maximize the O−H bond dissociation enthalpy of the HAT product hydroxylamine and overall reaction thermodynamics, they undergo nucleophilic substitution leading to catalyst decomposition. In an attempt to minimize this vulnerability, we report the characterization ofN‐oxyl catalysts wherein the aryl ring in PINO is replaced with the combination of a substituted heteroatom and quaternary carbon. By rendering one carbonyl carbon less electrophilic and the other less sterically accessible, the correspondingN1‐aryl‐hydantoin‐N3‐oxyl radical showed significantly higher stability than PINO as well as a modest improvement in reactivity. This proof‐of‐principle in new scaffold design may accelerate future HAT catalyst discovery and development.
more »
« less
- Award ID(s):
- 2033714
- PAR ID:
- 10577054
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Angewandte Chemie International Edition
- Volume:
- 63
- Issue:
- 21
- ISSN:
- 1433-7851
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract All threeN‐methylated andN‐protonated hydroxypyridinium BArF4–salt isomers were synthesized and their hydrogen bond donating abilities were investigated. DFT and G4 theory computations along with IR spectroscopic measurements were found to be effective methods for predicting the catalytic activities of these O–H and N–H Brønsted acids. A UV‐vis titration approach for rapidly quantifying hydrogen bond donating ability revealed that carbon‐hydrogen bonds also can participate in electrostatic interactions, but the presence of multiple equilibrium complexes results in a limitation of this method. In the methylated series of hydroxypyridines, the ortho and para isomers displayed modest rate enhancements relative to the meta derivative. Protonation introduces a new acidic site and the ortho hydroxypyridinium ion salt is a significantly more active catalyst than all of the other species examined. This is indicative of bidentate activation by the N–H and O–H acidic sites, and suggests a new design strategy for improving charge‐enhanced catalysts.more » « less
-
Abstract The amination of aryl halides with palladium catalysts (Buchwald‐Hartwig amination) is a widely used transformation in synthetic and drug discovery chemistry. In this report, we demonstrate that a monometallic 2‐phosphinoimidazole Pd catalyst exhibits comparable or enhanced reactivity when compared to all ligands screened for room temperature amination of aryl chlorides with secondary amines. The di‐tert‐butylphosphine derivative showed extremely high reactivity while the di‐isopropyl variant led to almost complete loss of catalytic activity. Computational and experimental mechanistic and kinetic studies indicate that a monometallic Pd structure rather than a bimetallic Pd structure is key to fast catalysis. The di‐tert‐butylphosphine ligand has fast catalysis because it thermodynamically disfavors the formation of a much less active bimetallic Pd complex. A wide substrate scope is demonstrated for the arylation of secondary amines with aryl chlorides using our new catalyst system.more » « less
-
Abstract Strained rings are increasingly important for the design of pharmaceutical candidates, but cross‐coupling of strained rings remains challenging. An attractive, but underdeveloped, approach to diverse functionalized carbocyclic and heterocyclic frameworks containing all‐carbon quaternary centers is the coupling of abundant strained‐ring carboxylic acids with abundant aryl halides. Herein we disclose the development of a nickel‐catalyzed cross‐electrophile approach that couples a variety of strained ringN‐hydroxyphthalimide (NHP) esters, derived from the carboxylic acid in one step, with various aryl and heteroaryl halides under reductive conditions. The chemistry is enabled by the discovery of methods to control NHP ester reactivity, by tuning the solvent or using modified NHP esters, and the discovery thatt‐BuBpyCamCN, an L2X ligand, avoids problematic side reactions. This method can be run in flow and in 96‐well plates.more » « less
-
Abstract A nickel‐catalyzed asymmetric diarylation reaction of vinylarenes enables the preparation of chiral α,α,β‐triarylated ethane scaffolds, which exist in a number of biologically active molecules. The use of reducing conditions with aryl bromides as coupling partners obviates the need for stoichiometric organometallic reagents and tolerates a broad range of functional groups. The application of anN‐oxyl radical as a ligand to a nickel catalyst represents a novel approach to facilitate nickel‐catalyzed cross‐coupling reactions.more » « less
