Air Tolerant Cadiot-Chodkiewicz and Sonogashira Cross-Couplings

Alfred K. K. Fung, Madison J. Sowden, Michelle L. Coote, Michael S. Sherburn*

*Research School of Chemistry, Australian National University, Canberra, Australian Capital Territory 2601, Australia, Email: Michael.Sherburnanu.edu.au

A. K. K. Fung, M. J. Sowden, M. L. Coote, M. S. Sherburn, Org. Lett., 2023, 25, 8145-8149.

DOI: 10.1021/acs.orglett.3c03314

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Abstract

The use of ascorbate as a reductant in Cadiot-Chodkiewicz couplings leads to a suppression of unwanted side reactions like reductive homocoupling of the 1-haloalkyne and oxidative Glaser reactions of the terminal alkyne. The reaction provides excellent yields with a roughly stoichiometric ratio of reactants without inert gas atmosphere. A system for Sonogashira coupling was also established.

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buta-1,3-diyne synthesis through sp−sp couplings between terminal alkynes and haloalkynes.

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Standard Procedure for Cadiot-Chodkiewicz Cross-Couplings

To a stirred, cooled (ice bath) suspension of ethanol (0.5 mL), CuBr (3.6 mg, 0.025 mmol, 10 mol%) and sodium ascorbate (50 mg, 0.25 mmol, 1.0 mol. equiv) in a vial open to the air was added a solution of the terminal alkyne (0.30 mmol, 1.2 mol. equiv.) in ethanol (0.5 mL) followed by n-butylamine (52 µL, 0.25 mmol, 1.0 mol. equiv.). A solution of 1-bromoalkyne (0.25 mmol) in ethanol (0.5 mL) was added, the reaction mixture was removed from the ice bath and allowed to stir at room temp for 30 minutes. Work up, isolation and purification were performed as described below and in the supporting information.

5-Phenylpenta-2,4-diynoic acid

Work up: the reaction mixture was diluted with Et₂O (30 mL) and extracted with 1 M aqueous NaOH (3 × 10 mL). The combined aqueous phase was acidified with 2M aqueous HCl (60 mL) and the product was extracted into Et₂O (3 × 20 mL). The combined organic phase was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the product.
Purification: no purification was required.

Octa-1,3-diyn-1-ylbenzene

Work up: the reaction mixture was concentrated under reduced pressure.
Purification: column chromatography (100% PS 30-40 °C)

4-Methyl-N-(nona-2,4-diyn-1-yl)benzenesulfonamide

Work up: the reaction mixture was concentrated under reduced pressure.
Purification: column chromatography (30% diethyl ether in PS 30-40 °C)

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Key Words

Cadiot-Chodkiewicz Coupling, ascorbate, diynes

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ID: J54-Y2023