DMSO/Tertiary Amine Activation of Elemental Sulfur: A New Route to Thioaurones

Recent work by the Nguyen group has revealed that DMSO, in combination with a tertiary amine (e.g., Et₃N or NMP), works to activate elemental sulfur such that it participates in a reaction to form two C–S bonds, producing thioaurones 2 (Table 1).¹ Thioaurone-type compounds are interesting dye/photoswitch materials, usually made via processes that involve sulfides and thiols.² Therefore, these reactions are generally done under malodorous conditions. The method described by the Nguyen group avoids the use or generation of these volatile odor-causing compounds. Additionally, the Nguyen method works well for most compounds under room temperature conditions. Notably, several solvents/additives were screened in the optimization of this reaction, and DMSO proved to be essential for achieving good yields at low temperatures.

Starting with 2′-nitrochalcones 1, which are readily accessed through aldol condensations, a variety of thioaurones were synthesized using this one-pot method (Table 1). Because the thioaurone products generally have low solubilities in DMSO, the isolation method simply involves filtration and washing with common laboratory solvents.

Isolated yields for compounds containing electron-withdrawing groups on ring B are good to excellent (entries 1–5 and 14). Yields with electron-donating substituents on ring A or B at room temperature are more modest at room temperature (entries 6, 8, 10, 12), but raising the temperature to 50–60° produces good yield of the corresponding thioaurone (entries 7, 9, 11, 13).

Table 1: Optimized conditions and yields for formation of Thioaurones 2.

This reaction also works with larger aromatic and heteroaromatic systems at ring B with yields of 87% and 89% when B is 1-naphthyl and 2-naphthyl, respectively; yields of 92% and 94% (when run at 60° C in NMP) when B is 2-thiophenyl and 3-thiophenyl, respectively. (The yields for the thiophenyl compounds were lower when run at room temperature in Et₃N: 55% and 60%, respectively.)

When electron-donating substituents were placed on ring A, the yields were also diminished. For instance, 4,5-dimethoxy substitution on ring A results in 20% yield at room temperature; however, 72% yield is realized at 60° C.

This reaction also produces good yields (at higher temperatures) when the B ring contains sterically demanding substituents. For instance, 2,4,6-trimethyl substituents on ring B produces 20% yield at room temperature, 52% yield at 50°, and 86% yield at 80°.

The authors have proposed a mechanism for the reaction in which the nitrochalcone undergoes Michael addition by the amine. The resulting enolate anion then adds to elemental sulfur (S₈) at the position alpha to the carbonyl. An ensuing fragmentation of S₇, cyclization, and loss of a nitrite ion and an ammonium ion results in the thioaurone.

To demonstrate additional synthetic utility for this method, the authors changed the position of the nitro group in the starting chalcone from ring A to ring B, i.e., 2-nitrochalcone 3 instead of 2′-nitrochalcone 1, and they subjected this material to the same reaction conditions. This reaction resulted in 2-benzoylbenzothiazole 4 in good yield (Equation 1).

Equation 1: DMSO/Et₃N activation of elemental sulfur using 2-nitrochalcone as the starting material.

These investigators have shown that there is a straightforward and relatively green method to form thioaurones without using malodorous thiols or sulfides. This method benefits from using low value elemental sulfur and converting it into added-value thioaurones in a one-pot method that generally works at room temperature.

Debra D. Dolliver, Ph.D.

References

1. Nguyen, T. B.; Retailleau, P., Cooperative Activating Effect of Tertiary Amine/DMSO on Elemental Sulfur: Direct Access to Thioaurones from 2′-Nitrochalcones under Mild Conditions. Org. Lett. 2018, 20 (1), 186-189.
2. Wiedbrauk, S.; Maerz, B.; Samoylova, E.; Reiner, A.; Trommer, F.; Mayer, P.; Zinth, W.; Dube, H., Twisted Hemithioindigo Photoswitches: Solvent Polarity Determines the Type of Light-Induced Rotations. J. Am. Chem. Soc. 2016, 138 (37), 12219-1222