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. 2020 May 1;25(9):2128.
doi: 10.3390/molecules25092128.

Conjugate Addition of Grignard Reagents to Thiochromones Catalyzed by Copper Salts: A Unified Approach to Both 2-Alkylthiochroman-4-One and Thioflavanone

Tania J Bellinger  1 , Teavian Harvin  1 , Ti'Bran Pickens-Flynn  1 , Nataleigh Austin  1 , Samuel H Whitaker  1 , Mai Ling C Tang Yuk Tutein  1 , Dabria T Hukins  1 , Nichele Deese  1 , Fenghai Guo  1   2
Affiliations

Conjugate Addition of Grignard Reagents to Thiochromones Catalyzed by Copper Salts: A Unified Approach to Both 2-Alkylthiochroman-4-One and Thioflavanone

Tania J Bellinger et al. Molecules. .

Abstract

Grignard reagents undergo conjugate addition to thiochromones catalyzed by copper salts to afford 2-substituted-thiochroman-4-ones, both 2-alkylthiochroman-4-ones and thioflavanones (2-arylthiochroman-4-ones), in good yields with trimethylsilyl chloride (TMSCl) as an additive. The best yields of 1,4-adducts can be attained with CuCN∙2LiCl as the copper source. Excellent yields of 2-alkyl-substituted thiochroman-4-ones and thioflavanones (2-aryl substituted) are attained with a broad range of Grignard reagents. This approach works well with both alkyl and aromatic Grignard reagents, thus providing a unified synthetic approach to privileged 2-substituted thiochroman-4-ones and a potential valuable precursor for further synthetic applications towards many pharmaceutically active molecules. The use of commercially available and/or readily prepared Grignard reagents will expedite the synthesis of a large library of both 2-alkyl substituted thiochroman-4-ones and thioflavanones for additional synthetic applications.

Keywords: 2-alkylthiochroman-4-ones; Grignard reagents; conjugate addition; thiochroman-4-ones; thiochromones; thioflavanones.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Copper-catalyzed conjugate addition of Grignard reagents to thiochromones.
Scheme 1
Scheme 1
Optimization of 1,4-conjugate addition of n-butyl magnesium chloride to thiochromone. a. Reagents were prepared by adding n-BuMgCl to copper salts in THF. b. Yields are based on isolated products by column chromatography.
Scheme 2
Scheme 2
The scope of Grignard reagents in conjugate addition to thiochromone. a. All the reactions were performed using 1.5 equiv of RMgX in the presence of 2.0 equiv of TMSCI unless noted otherwise. b. RMgX were commercially available or prepared from corresponding RX in THF and used as a THF solution. c. Yields are based on isolated products by column chromatography.
Scheme 3
Scheme 3
Scope of the substituted thiochromones with n-BuMgCl. a. All the reactions were performed using 1.5 equiv of BuMgCl in the presence of 2.0 equiv of TMSCI unless noted otherwise. b. RMgX were commercially available or prepared from corresponding RX in THF and used as a THF solution. c. Yields are based on isolated products by column chromatography.
Scheme 4
Scheme 4
Reactions of PhMgBr with substituted thiochromones. a. All the reactions were performed using 1.5 equiv of PhMgBr in the presence of 2.0 equiv of TMSCI unless noted otherwise. b. PhMgBr were commercially available. c. Yields are based on isolated products by column chromatography.
Scheme 5
Scheme 5
Synthetic applications of thioflavanones.
See this image and copyright information in PMC

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