Cross-dehydrogenative couplings between indoles and β-keto esters

Ligand-assisted ligand tautomerization and dehydrogenation via a proton-assisted electron transfer to Pd(II)

Mikko V. Leskinen, Ádám Madarász, Kai Tai Yip, Aini Vuorinen, I. Pápai, Antti J. Neuvonen, Petri M. Pihko

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Cross-dehydrogenative coupling reactions between β-ketoesters and electron-rich arenes, such as indoles, proceed with high regiochemical fidelity with a range of β-ketoesters and indoles. The mechanism of the reaction between a prototypical β-ketoester, ethyl 2-oxocyclopentanonecarboxylate, and N-methylindole has been studied experimentally by monitoring the temporal course of the reaction by 1H NMR, kinetic isotope effect studies, and control experiments. DFT calculations have been carried out using a dispersion-corrected range-separated hybrid functional (?B97X-D) to explore the basic elementary steps of the catalytic cycle. The experimental results indicate that the reaction proceeds via two catalytic cycles. Cycle A, the dehydrogenation cycle, produces an enone intermediate. The dehydrogenation is assisted by N-methylindole, which acts as a ligand for Pd(II). The computational studies agree with this conclusion, and identify the turnover-limiting step of the dehydrogenation step, which involves a change in the coordination mode of the β-keto ester ligand from an O,O′-chelate to an α-C-bound Pd enolate. This ligand tautomerization event is assisted by the p-bound indole ligand. Subsequent scission of the β′-C-H bond takes place via a proton-assisted electron transfer mechanism, where Pd(II) acts as an electron sink and the trifluoroacetate ligand acts as a proton acceptor, to produce the Pd(0) complex of the enone intermediate. The coupling is completed in cycle B, where the enone is coupled with indole. Pd(TFA)2 and TFA-catalyzed pathways were examined experimentally and computationally for this cycle, and both were found to be viable routes for the coupling step.

Original languageEnglish
Pages (from-to)6453-6462
Number of pages10
JournalJournal of the American Chemical Society
Volume136
Issue number17
DOIs
Publication statusPublished - Apr 30 2014

Fingerprint

Indoles
Dehydrogenation
Protons
Esters
Ligands
Electrons
Trifluoroacetic Acid
Discrete Fourier transforms
Isotopes
Nuclear magnetic resonance
Hydrogen
Kinetics
Monitoring
Experiments

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Cross-dehydrogenative couplings between indoles and β-keto esters : Ligand-assisted ligand tautomerization and dehydrogenation via a proton-assisted electron transfer to Pd(II). / Leskinen, Mikko V.; Madarász, Ádám; Yip, Kai Tai; Vuorinen, Aini; Pápai, I.; Neuvonen, Antti J.; Pihko, Petri M.

In: Journal of the American Chemical Society, Vol. 136, No. 17, 30.04.2014, p. 6453-6462.

Research output: Contribution to journalArticle

Leskinen, Mikko V. ; Madarász, Ádám ; Yip, Kai Tai ; Vuorinen, Aini ; Pápai, I. ; Neuvonen, Antti J. ; Pihko, Petri M. / Cross-dehydrogenative couplings between indoles and β-keto esters : Ligand-assisted ligand tautomerization and dehydrogenation via a proton-assisted electron transfer to Pd(II). In: Journal of the American Chemical Society. 2014 ; Vol. 136, No. 17. pp. 6453-6462.
@article{cbffdb46fdc9483eab51a6645dd0a0ae,
title = "Cross-dehydrogenative couplings between indoles and β-keto esters: Ligand-assisted ligand tautomerization and dehydrogenation via a proton-assisted electron transfer to Pd(II)",
abstract = "Cross-dehydrogenative coupling reactions between β-ketoesters and electron-rich arenes, such as indoles, proceed with high regiochemical fidelity with a range of β-ketoesters and indoles. The mechanism of the reaction between a prototypical β-ketoester, ethyl 2-oxocyclopentanonecarboxylate, and N-methylindole has been studied experimentally by monitoring the temporal course of the reaction by 1H NMR, kinetic isotope effect studies, and control experiments. DFT calculations have been carried out using a dispersion-corrected range-separated hybrid functional (?B97X-D) to explore the basic elementary steps of the catalytic cycle. The experimental results indicate that the reaction proceeds via two catalytic cycles. Cycle A, the dehydrogenation cycle, produces an enone intermediate. The dehydrogenation is assisted by N-methylindole, which acts as a ligand for Pd(II). The computational studies agree with this conclusion, and identify the turnover-limiting step of the dehydrogenation step, which involves a change in the coordination mode of the β-keto ester ligand from an O,O′-chelate to an α-C-bound Pd enolate. This ligand tautomerization event is assisted by the p-bound indole ligand. Subsequent scission of the β′-C-H bond takes place via a proton-assisted electron transfer mechanism, where Pd(II) acts as an electron sink and the trifluoroacetate ligand acts as a proton acceptor, to produce the Pd(0) complex of the enone intermediate. The coupling is completed in cycle B, where the enone is coupled with indole. Pd(TFA)2 and TFA-catalyzed pathways were examined experimentally and computationally for this cycle, and both were found to be viable routes for the coupling step.",
author = "Leskinen, {Mikko V.} and {\'A}d{\'a}m Madar{\'a}sz and Yip, {Kai Tai} and Aini Vuorinen and I. P{\'a}pai and Neuvonen, {Antti J.} and Pihko, {Petri M.}",
year = "2014",
month = "4",
day = "30",
doi = "10.1021/ja501681y",
language = "English",
volume = "136",
pages = "6453--6462",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "17",

}

TY - JOUR

T1 - Cross-dehydrogenative couplings between indoles and β-keto esters

T2 - Ligand-assisted ligand tautomerization and dehydrogenation via a proton-assisted electron transfer to Pd(II)

AU - Leskinen, Mikko V.

AU - Madarász, Ádám

AU - Yip, Kai Tai

AU - Vuorinen, Aini

AU - Pápai, I.

AU - Neuvonen, Antti J.

AU - Pihko, Petri M.

PY - 2014/4/30

Y1 - 2014/4/30

N2 - Cross-dehydrogenative coupling reactions between β-ketoesters and electron-rich arenes, such as indoles, proceed with high regiochemical fidelity with a range of β-ketoesters and indoles. The mechanism of the reaction between a prototypical β-ketoester, ethyl 2-oxocyclopentanonecarboxylate, and N-methylindole has been studied experimentally by monitoring the temporal course of the reaction by 1H NMR, kinetic isotope effect studies, and control experiments. DFT calculations have been carried out using a dispersion-corrected range-separated hybrid functional (?B97X-D) to explore the basic elementary steps of the catalytic cycle. The experimental results indicate that the reaction proceeds via two catalytic cycles. Cycle A, the dehydrogenation cycle, produces an enone intermediate. The dehydrogenation is assisted by N-methylindole, which acts as a ligand for Pd(II). The computational studies agree with this conclusion, and identify the turnover-limiting step of the dehydrogenation step, which involves a change in the coordination mode of the β-keto ester ligand from an O,O′-chelate to an α-C-bound Pd enolate. This ligand tautomerization event is assisted by the p-bound indole ligand. Subsequent scission of the β′-C-H bond takes place via a proton-assisted electron transfer mechanism, where Pd(II) acts as an electron sink and the trifluoroacetate ligand acts as a proton acceptor, to produce the Pd(0) complex of the enone intermediate. The coupling is completed in cycle B, where the enone is coupled with indole. Pd(TFA)2 and TFA-catalyzed pathways were examined experimentally and computationally for this cycle, and both were found to be viable routes for the coupling step.

AB - Cross-dehydrogenative coupling reactions between β-ketoesters and electron-rich arenes, such as indoles, proceed with high regiochemical fidelity with a range of β-ketoesters and indoles. The mechanism of the reaction between a prototypical β-ketoester, ethyl 2-oxocyclopentanonecarboxylate, and N-methylindole has been studied experimentally by monitoring the temporal course of the reaction by 1H NMR, kinetic isotope effect studies, and control experiments. DFT calculations have been carried out using a dispersion-corrected range-separated hybrid functional (?B97X-D) to explore the basic elementary steps of the catalytic cycle. The experimental results indicate that the reaction proceeds via two catalytic cycles. Cycle A, the dehydrogenation cycle, produces an enone intermediate. The dehydrogenation is assisted by N-methylindole, which acts as a ligand for Pd(II). The computational studies agree with this conclusion, and identify the turnover-limiting step of the dehydrogenation step, which involves a change in the coordination mode of the β-keto ester ligand from an O,O′-chelate to an α-C-bound Pd enolate. This ligand tautomerization event is assisted by the p-bound indole ligand. Subsequent scission of the β′-C-H bond takes place via a proton-assisted electron transfer mechanism, where Pd(II) acts as an electron sink and the trifluoroacetate ligand acts as a proton acceptor, to produce the Pd(0) complex of the enone intermediate. The coupling is completed in cycle B, where the enone is coupled with indole. Pd(TFA)2 and TFA-catalyzed pathways were examined experimentally and computationally for this cycle, and both were found to be viable routes for the coupling step.

UR - http://www.scopus.com/inward/record.url?scp=84899767820&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899767820&partnerID=8YFLogxK

U2 - 10.1021/ja501681y

DO - 10.1021/ja501681y

M3 - Article

VL - 136

SP - 6453

EP - 6462

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 17

ER -