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. 2020 Jul 27;59(31):12853-12859.
doi: 10.1002/anie.202003271. Epub 2020 Jun 5.

Distal γ-C(sp3 )-H Olefination of Ketone Derivatives and Free Carboxylic Acids

Han Seul Park  1 , Zhoulong Fan  1 , Ru-Yi Zhu  1 , Jin-Quan Yu  1
Affiliations

Distal γ-C(sp3 )-H Olefination of Ketone Derivatives and Free Carboxylic Acids

Han Seul Park et al. Angew Chem Int Ed Engl. .

Abstract

Reported herein is the distal γ-C(sp3 )-H olefination of ketone derivatives and free carboxylic acids. Fine tuning of a previously reported imino-acid directing group and using the ligand combination of a mono-N-protected amino acid (MPAA) and an electron-deficient 2-pyridone were critical for the γ-C(sp3 )-H olefination of ketone substrates. In addition, MPAAs enabled the γ-C(sp3 )-H olefination of free carboxylic acids to form diverse six-membered lactones. Besides alkyl carboxylic acids, benzylic C(sp3 )-H bonds also could be functionalized to form 3,4-dihydroisocoumarin structures in a single step from 2-methyl benzoic acid derivatives. The utility of these protocols was demonstrated in large scale reactions and diversification of the γ-C(sp3 )-H olefinated products.

Keywords: C(sp3)−H activation; amino acids; olefins; palladium; synthetic methods.

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Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Figures

Scheme 1.
Scheme 1.
Pd(II)-Catalyzed C(sp3)–H Activation of Ketones and Free Carboxylic Acids
Scheme 2.
Scheme 2.
Competition Experiment, conditions: 1a (0.05 mmol), 1a’ (0.05 mmol), Pd(OAc)2 (10 mol%, 0.01 mmol), L5 (20 mol%, 0.02 mmol), L14 (20 mol%, 0.02 mmol), ethyl acrylate (3.0 equiv, 0.3 mmol), AgOAc (2.0 equiv, 0.2 mmol), Ag2CO3 (1.0 equiv, 0.1 mmol), HFIP (1 mL), 120 °C, 6 h, Combined yield of mono/di products determined by 1H NMR analysis of the crude mixture using CH2Br2 as the internal standard. Yields were calculated based on the initial amount of substrates.
Scheme 3.
Scheme 3.
Synthetic Applications: a) 1a (2.0 mmol, 1.0 equiv), ethyl acrylate (3.0 equiv), Pd(OAc)2 (10 mol%), L5 (20 mol%), L14 (20 mol%), AgOAc (2.0 equiv), Ag2CO3 (1.0 equiv), HFIP (20.0 mL), 120 °C, oxygen atmosphere, 40 h. b) 4a (2.0 mmol, 1.0 equiv), benzyl acrylate (2.0 equiv), Pd(OAc)2 (10 mol%), L2 (10 mol%), Na2HPO4•7H2O (1.0 equiv), Ag2CO3 (2.0 equiv), HFIP (20.0 mL), 120 °C, under air, 24 h. c) H2, Pd/C, MeOH, RT, 15 h. d) NaBH4 (1.0 equiv), THF, 0 °C, 4 h. e) LiHMDS (1.0 equiv), THF, −78 °C, 3 h, f) LiHMDS (1.2 equiv), THF, −78 °C, 3 h. g) LiAlH4 (4.0 equiv), THF, 0 °C to RT, 10 h. h) 6 M HCl (aq.), 80 °C, 12 h.
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