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. 2015 Apr 22;137(15):4932-5.
doi: 10.1021/jacs.5b01784. Epub 2015 Apr 9.

Z-Selective Olefin Synthesis via Iron-Catalyzed Reductive Coupling of Alkyl Halides with Terminal Arylalkynes

Chi Wai Cheung  1 , Fedor E Zhurkin  1 , Xile Hu  1
Affiliations

Z-Selective Olefin Synthesis via Iron-Catalyzed Reductive Coupling of Alkyl Halides with Terminal Arylalkynes

Chi Wai Cheung et al. J Am Chem Soc. .

Abstract

Selective catalytic synthesis of Z-olefins has been challenging. Here we describe a method to produce 1,2-disubstituted olefins in high Z selectivity via reductive cross-coupling of alkyl halides with terminal arylalkynes. The method employs inexpensive and nontoxic catalyst (iron(II) bromide) and reductant (zinc). The substrate scope encompasses primary, secondary, and tertiary alkyl halides, and the reaction tolerates a large number of functional groups. The utility of the method is demonstrated in the synthesis of several pharmaceutically relevant molecules. Mechanistic study suggests that the reaction proceeds through an iron-catalyzed anti-selective carbozincation pathway.

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Figures

Figure 1
Figure 1
Z-Selective olefin synthesis by Fe-catalyzed reductive coupling of alkyl electrophiles with terminal arylalkynes.
Figure 2
Figure 2
Z-Olefin synthesis with secondary and tertiary alkyl iodides. The conditions were described in detail in the SI. (a) 4 d. (b) RI (2 equiv), Zn (2 equiv), I2 (3 mol %). (c) RI (3 equiv), Zn (3 equiv), I2 (5 mol %). (d) RI (2.5 equiv), Zn (2.5 equiv), I2 (5 mol %). (e) RI (5 equiv), Zn (5 equiv), I2 (10 mol %). (f) TMEDA (40 mol %) added. (g) FeBr2 (20 mol %), RI (6 equiv), Zn (6 equiv), I2 (10 mol %).
Figure 3
Figure 3
Z-Olefin synthesis with secondary and tertiary alkyl bromides. The conditions were described in detail in the SI. (a) RI (2 equiv), Zn (2 equiv), I2 (3 mol %), rt. (b) RI (3 equiv), Zn (3 equiv), I2 (5 mol %), rt.
Figure 4
Figure 4
Z-Olefin synthesis with primary alkyl substrates. The conditions were described in detail in the SI. (a) RI (3 equiv), Zn (3.5 equiv), TMSI (30 mol %). (b) 2 d. (c) RI (5 equiv), Zn (5.5 equiv), TMSI (50 mol %). (d) ROTs (3 equiv), Zn (3.5 equiv), TMSI (30 mol %), TBAI (1 equiv). (e) 60 °C, 3 d. (f) ROTs (5 equiv), Zn (5.5 equiv), TMSI (50 mol %), TBAI (2 equiv).
Figure 5
Figure 5
Synthesis of the bioactive molecules or their key intermediates for potential treatments of diseases.
Figure 6
Figure 6
Mechanistic study. (a) Radical clock experiment. (b) Trapping of alkenyl radical. (c) Trapping of alkenyl anion. (d) Proposed mechanism.
See this image and copyright information in PMC

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