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. 2015 Nov 1;6(11):6649-6653.
doi: 10.1039/c5sc02558c. Epub 2015 Aug 10.

Practical and economic lithiations of functionalized arenes and heteroarenes using Cy2NLi in the presence of Mg, Zn or La halides in a continuous flow

Matthias R Becker  1 , Maximilian A Ganiek  1 , Paul Knochel  1
Affiliations

Practical and economic lithiations of functionalized arenes and heteroarenes using Cy2NLi in the presence of Mg, Zn or La halides in a continuous flow

Matthias R Becker et al. Chem Sci. .

Abstract

The economic amide base lithium dicyclohexylamide (Cy2NLi) allows fast and convenient (40 s, 0 °C) in situ trapping flow metalations of a broad range of functionalized arenes, heteroarenes and acrylate derivatives in the presence of various metal salts (ZnCl2·2LiCl, MgCl2, LaCl3·2LiCl). The resulting Zn-, Mg- or La-organometallic intermediates are trapped with various electrophiles in high yields. These flow metalations are easily scaled-up without further optimization.

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Figures

Scheme 1
Scheme 1. Continuous flow set-up for in situ trapping metalations using TMPLi in the presence of metal salts (Met-X = ZnCl2·2LiCl, MgCl2, CuCN·2LiCl, LaCl3·2LiCl) and subsequent batch quenching with electrophiles (E+).
Scheme 2
Scheme 2. Continuous flow in situ trapping zincation of 1-bromo-4-fluorobenzene (1a) using TMPLi and Cy2NLi and subsequent Pd-catalyzed Negishi cross-coupling with ethyl 4-iodobenzoate in a batch reactor.
Scheme 3
Scheme 3. In situ trapping magnesiation of (E)-methyl 3-methoxyacrylate (6) using Cy2NLi in a flow reactor.
Scheme 4
Scheme 4. In situ trapping magnesiation and zincation of (E)-ethyl 3-(dimethylamino)acrylate (9) using Cy2NLi in a flow reactor.
See this image and copyright information in PMC

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