Facile Quantum Yield Determination via NMR Actinometry

A simplified approach to quantum yield (ϕ) measurement using in situ LED NMR spectroscopy has been developed. The utility and performance of NMR actinometry has been demonstrated for the well-known chemical actinometers potassium ferrioxalate and <i>o</i>-nitrobenzaldehyde. A novel NMR-friendly actinometer, 2,4-dinitrobenzaldehyde, has been introduced for both 365 and 440 nm wavelengths. The method has been utilized successfully to measure the quantum yield of several recently published photochemical reactions

Tetramethylnorbornadiene, a Versatile Alkene for Cyclopentenone Synthesis through Intermolecular Pauson–Khand Reactions

1,2,3,4-Tetramethyl-bicyclo[2.2.1]hepta-2,5-diene (TMNBD, for <i>tetramethylnorbornadiene</i>) has been prepared and used successfully as an acetylene equivalent in the synthesis of substituted cyclopentenones. TMNBD is easily accessible on a multigram scale and displays excellent reactivity toward the intermolecular Pauson–Khand reaction. Conjugate additions on the resulting tricyclic compounds proceed with exquisite diastereoselectivity. The retro-Diels–Alder reaction of these TMNBD derivatives occurs under much smoother conditions than those required for its norbornadiene homologues

Mechanistic Insights into the Vanadium-Catalyzed Achmatowicz Rearrangement of Furfurol

The Achmatowicz rearrangement is a powerful method for the construction of pyranones from simple furan derivatives. Here, we describe the development of improved reaction conditions and an interrogation into the fate of the metal center during this interesting transformation. The reaction to form the synthetically important lactol, 6-hydroxy-2<i>H</i>-pyran-3­(6<i>H</i>)-one (<b>3</b>), proceeds cleanly in the presence of <i>tert</i>-butyl hydroperoxide (TBHP, <b>2</b>) using low loadings of VO­(O^<i>i</i>Pr)₃ as catalyst. The nonaqueous conditions developed herein allow for easy isolation of product <b>3</b> and synthetically important derivatives, a key advantage of this new protocol. Detailed experimental, spectroscopic, and kinetic studies along with kinetic modeling of the catalytic cycle support a positive-order dependence in both furfurol and TBHP concentrations, first-order dependence in catalyst (VO­(O^<i>i</i>Pr)₃), and a <i>negative</i> dependence on the 2-methyl-2-propanol (<b>4</b>) concentration. ⁵¹V-NMR spectroscopic studies revealed that 2-methyl-2-propanol (<b>4</b>) competes with substrates for binding to the metal center, rationalizing its inhibitory effect

Improved Preparation of a Key Hydroxylamine Intermediate for Relebactam: Rate Enhancement of Benzyl Ether Hydrogenolysis with DABCO

Previous methods to prepare a bicyclic <i>N</i>-hydroxyl urea intermediate in the synthesis of the potent β-lactamase inhibitor relebactam were effective, but deemed unsuitable for long-term use. Therefore, we developed an <i>in situ</i> protection protocol during hydrogenolysis and a robust deprotection/isolation sequence of this unstable intermediate employing a reactive crystallization. During the hydrogenation studies, we discovered a significant rate enhancement of <i>O-</i>benzyl ether hydrogenolysis in the presence of organic amine bases, especially DABCO. The broader utility of the application of organic bases on the hydrogenolysis of a range of <i>O</i>- and <i>N</i>-benzyl-containing substrates was demonstrated

Asymmetric Hydrogen Bonding Catalysis for the Synthesis of Dihydroquinazoline-Containing Antiviral, Letermovir

A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C₂-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,β-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4-dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues

Enantioselective Synthesis of Hemiaminals via Pd-Catalyzed C–N Coupling with Chiral Bisphosphine Mono-oxides

A novel approach to hemiaminal synthesis via palladium-catalyzed C–N coupling with chiral bisphosphine mono-oxides is described. This efficient new method exhibits a broad scope, provides a highly efficient synthesis of HCV drug candidate elbasvir, and has been applied to the synthesis of chiral <i>N,N</i>-acetals

Mono-Oxidation of Bidentate Bis-phosphines in Catalyst Activation: Kinetic and Mechanistic Studies of a Pd/Xantphos-Catalyzed C–H Functionalization

Kinetic, spectroscopic, crystallographic, and computational studies probing a Pd-catalyzed C–H arylation reaction reveal that mono-oxidation of the bis-phosphine ligand is critical for the formation of the active catalyst. The bis-phosphine mono-oxide is shown to be a hemilabile, bidentate ligand for palladium. Isolation of the oxidative addition adduct, with structural elucidation by X-ray analysis, showed that the mono-oxide was catalytically competent, giving the same reaction rate in the productive reaction as the Pd­(II)/xantphos precursor. A dual role for the carboxylate base in both catalyst activation and reaction turnover was demonstrated, along with the inhibiting effect of excess phosphine ligand. The generality of the role of phosphine mono-oxide complexes in Pd-catalyzed coupling processes is discussed