Palladium-Catalyzed Arylation of Ethyl Cyanoacetate. Fluorescence Resonance Energy Transfer as a Tool for Reaction Discovery

Shaun R. Stauffer, Neil A. Beare, James P. Stambuli and John F. Hartwig*

*Department of Chemistry, Yale University P.O. Box 208107, New Haven, Connecticut 06520-8107

S. R. Stauffer, N. A. Beare, J. P. Stambuli, J. F. Hartwig, J. Am. Chem. Soc., 2001, 123, 4641-4642.

DOI: 10.1021/ja0157402

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Abstract

α-Aryl cyanoacetates are useful intermediates in the preparation of amino alcohols, β-amino acids, and arylacetic acids. The discovery and optimization of a new method for bond construction using high-throughput screening provided a mild arylation of cyanoesters with broad reaction scope and the ability to construct materials with highly hindered quaternary carbons.

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FRET assay with a reagent containing a fluorophore and a second containing a quencher

Details

The document describes the discovery and optimization of a new palladium-catalyzed method for the arylation of ethyl cyanoacetate using a high-throughput screening approach based on fluorescence resonance energy transfer (FRET). This method allows for rapid evaluation of catalyst activity, significantly accelerating reaction discovery. The FRET assay measures product yields in about 1 second per sample, making it more efficient and less instrument-intensive than traditional methods.

The study utilized a 96-well format to screen 113 different ligands, identifying 12 effective ones for further optimization. The optimal precatalysts were found to be [(allyl)PdCl]₂ and CpPd(allyl), with Na₃PO₄ as the most effective base. The reactions were conducted in toluene at 70 °C, achieving high yields even with deactivated and ortho-substituted aryl bromides and chlorides. The process also allowed for the formation of highly hindered quaternary carbons and could be performed at room temperature with certain ligands.

The methodology is general and useful for synthesizing β-arylamines, alcohols, and diarylacetic acids. Future studies will focus on enantioselective reactions and understanding the reaction mechanism. The work was supported by the NIH, and additional supporting information is available online.

Screening of Homogeneous Catalysts by Fluorescence Resonance Energy Transfer. Identification of Catalysts for Room-Temperature Heck Reactions

J. P. Stambuli, S. R. Stauffer, K. H. Shaughnessy, J. F. Hartwig, J. Am. Chem. Soc., 2001, 123, 2677-2678.

Synthesis, Characterization, and Reactivity of Arylpalladium Cyanoalkyl Complexes: Selection of Catalysts for the α-Arylation of Nitriles

D. A. Culkin, J. F. Hartwig, J. Am. Chem. Soc., 2002, 124, 9330-9331.

Efficient Synthesis of α-Aryl Esters by Room-Temperature Palladium-Catalyzed Coupling of Aryl Halides with Ester Enolates

M. Jørgensen, S. Lee, X. Liu, J. P. Wolkowski, J. F. Hartwig, J. Am. Chem. Soc., 2002, 124, 12557-12565.

Key Words

Arylation

ID: J48-Y2001