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One-Pot DMSO-Assisted Synthesis of Thiophenes from Alkenes and Conjugated Dienes

Thiophenes are of interest to synthetic chemists because they are often core structural units in natural products, pharmaceuticals, and functional materials. Therefore, much work has been done to incorporate sulfur into carbon substrates with the hopes that the new sulfur-containing compounds while ultimately be cyclized to form the thiophene unit. Many of these sulfuration reactions involve substitution of or addition to the carbon substrate. Therefore, the carbon substrate must contain functionalization prior to the sulfuration reaction. Recently, the Liang, Deng, and Yang group have demonstrated the atom-economical, one-pot, direct sulfuration and annulation of substituted buta-1-enes and 1,4-diaryl-1,3-butadienes to form highly substituted thiophenes.[i] This reaction proceeds through direct C–H activation.

This group developed the methods shown in Tables 1 and 2 starting from an alkene or a diene, respectively. After reaction optimization, it was found that using DMSO as the solvent when beginning with an alkene (Table 1) resulted in superior yields. With these conditions, the reaction was tested for substrate scope. As can be seen, the reaction tolerated various groups at the R1, R2, and R3 positions.

 

When starting from a 1,3-diene (Table 2), it was found that using a 1:1 DMSO/NMP mixture led to a slightly higher yield in the optimization study with 1,4-diphenyl-1,3-butadiene (96% with 1:1 DMSO/NMP vs. 82% with DMSO alone). Therefore, the substrate scope was tested with this solvent mixture for this reaction.

Mechanistic studies, including GC analysis of the product mixture and deuterium incorporation experiments pointed to a mechanism in which DMSO participates as an oxidizing agent by converting an isolated alkene bond into a conjugated diene. Therefore, DMSO is critical to the success of this reaction.

This reaction, which does not require prefunctionalization of the carbon substrate, exotic starting materials, or complex procedures, provides a straightforward route to highly functionalized thiophenes. DMSO participates in the reaction, and is therefore essential for this transformation.

 

Debra D. Dolliver, Ph.D.

[1] Chen, L.; Hao, M.; Zhu, X.; Liang, Y.; Deng, G.; Yang, Y. Org. Lett. 2018, 20, 7392.

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