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Issue 28, 2018
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Selective oxymetalation of terminal alkynes via 6-endo cyclization: mechanistic investigation and application to the efficient synthesis of 4-substituted isocoumarins

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Abstract

The cyclization of heteroatom-containing alkynes with π acidic metal salts is an attractive method to prepare heterocycles because the starting materials are readily available and the organometallic compounds are useful synthetic intermediates. A new organometallic species in the heterocyclization provides an opportunity to synthesize heterocycles that are difficult to obtain. Herein, we describe a novel cyclic oxymetalation of 2-alkynylbenzoate with indium or gallium salts that proceeds with an unusual regioselectivity to give isocoumarins bearing a carbon–metal bond at the 4-position. This new type of metalated isocoumarin provided 3-unsubstituted isocoumarins that have seldom been investigated despite their important pharmacological properties. Indium and gallium salts showed high performance in the selective 6-endo cyclization of terminal alkynes while boron or other metals such as Al, Au, and Ag caused 5-exo cyclization or decomposition of terminal alkynes, respectively. The metalated isocoumarin and its reaction intermediate were unambiguously identified by X-ray crystallographic analysis. The theoretical calculation of potential energy profiles showed that oxyindation could proceed via 6-endo cyclization under thermodynamic control while previously reported oxyboration would give a 5-membered ring under kinetic control. The investigation of electrostatic potential maps suggested that the differences in the atomic characters of indium, boron and their ligands would contribute to such a regioselective switch. The metalated isocoumarins were applied to organic synthetic reactions. The halogenation of metalated isocoumarins proceeded to afford 4-halogenated isocoumarins bearing various functional groups. The palladium-catalyzed cross coupling of organometallic species with organic halides gave various 4-substituted isocoumarins. A formal total synthesis of oosponol, which exhibits strong antifungal activity, was accomplished.

Graphical abstract: Selective oxymetalation of terminal alkynes via 6-endo cyclization: mechanistic investigation and application to the efficient synthesis of 4-substituted isocoumarins

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Publication details

The article was received on 04 Apr 2018, accepted on 13 Jun 2018 and first published on 15 Jun 2018


Article type: Edge Article
DOI: 10.1039/C8SC01537F
Citation: Chem. Sci., 2018,9, 6041-6052
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    Selective oxymetalation of terminal alkynes via 6-endo cyclization: mechanistic investigation and application to the efficient synthesis of 4-substituted isocoumarins

    Y. Kita, T. Yata, Y. Nishimoto, K. Chiba and M. Yasuda, Chem. Sci., 2018, 9, 6041
    DOI: 10.1039/C8SC01537F

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