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. 2018 Aug 15;140(32):10363-10367.
doi: 10.1021/jacs.8b06527. Epub 2018 Aug 2.

Ligand-Enabled β-C(sp3)-H Olefination of Free Carboxylic Acids

Zhe Zhuang  1 , Chang-Bin Yu  1 , Gang Chen  1 , Qing-Feng Wu  1 , Yi Hsiao  2 , Candice L Joe  2 , Jennifer X Qiao  3 , Michael A Poss  3 , Jin-Quan Yu  1
Affiliations

Ligand-Enabled β-C(sp3)-H Olefination of Free Carboxylic Acids

Zhe Zhuang et al. J Am Chem Soc. .

Abstract

An acetyl-protected aminoethyl phenyl thioether has been developed to promote C(sp3)-H activation. Significant ligand enhancement is demonstrated by the realization of the first Pd(II)-catalyzed olefination of C(sp3)-H bonds of free carboxylic acids without using an auxiliary. Subsequent lactonization of the olefinated product via 1,4 addition provided exclusively monoselectivity in the presence of multiple β-C-H bonds. The product γ-lactone can be readily opened to give either the highly valuable β-olefinated or γ-hydroxylated aliphatic acids. Considering the challenges in developing Heck couplings using alkyl halides, this reaction offers a useful alternative.

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Figures

Figure 1.
Figure 1.
Bioactive Compounds Containing γ-Lactone and Derivatives
Scheme 1.
Scheme 1.. Gram-Scale Experiment and Synthetic Application
a Conditions A: 1a (12.0 mmol), 2a (2.0 eq), Pd(TFA)2 (10 mol%), L14 (10 mol%), Na2HPO4.7H2O (1.0 eq), Ag2CO3 (1.0 eq), HFIP, 120 oC, 12 h. b Conditions B: 3a (0.2 mmol), 6N HCl, 80 oC, overnight. c Conditions C: 3a (1.0 mmol), NaOH (4.0 eq), EtOH/H2O, reflux. d Conditions D: 3a (0.2 mmol), LAH (4.0 eq), THF, rt.
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