Step‐Economical Route to 2‐Amido‐3‐bromobenzo[b]thiophenes via Ynamide Formation and Selectfluor‐Mediated Oxidative Bromocyclization

Abstract

A one‐pot synthesis of 2‐amido‐3‐bromobenzo[b]thiophenes based on C−N coupling and oxidative bromocyclization reactions was developed. This enables a modular approach to obtain diverse substituents at the C2 position of benzothiophenes by employing structurally modified sulfonamides. Oxidative cyclization was driven by Selectfluor and represents a previously unreported recycling method for the bromide anion byproducts of the C−N bond coupling step. The details of the study are described fully herein.

Microwave-Assisted Copper-Catalyzed Coupling of Bromoalkynes and Sulfonamides: Rapid Synthesis of N-Sulfonyl Ynamides

“…The 2thioanisole substituted bromoalkyne (3la) afforded a significantly lower yield than the 2-anisole substituted bromoalkyne (3ka) despite the complete conversion of the starting material because 2-amidobenzo [b]thiophene (3la') was formed by an annulation reaction via a keteniminium intermediate when methanol solvent was used. 22 Other types of arene substitutions, such as naphthyl, pyridyl, and thiophenyl, were also well-tolerated under the same conditions, resulting in high yields, respectively (3ma-3oa, 77-100 %). Bromoalkynes with aliphatic groups, such as n-pentyl and phenethyl, were coupled smoothly with sulfonamide 2a to give the corresponding products in good yields (3ma-3na, 72-75 %).…”

“…Recently, we observed noteworthy results using an alcohol as the solvent, which considerably reduced the reaction time in the Cu-catalyzed alkynylation of sulfonamides using bromoalkynes 22 compared to known procedures using toluene, 8a-d pyridine, 8e and dioxane 19a as solvents. Recent studies on the optimization of C-N coupling have revealed that microwave irradiation significantly accelerates the reaction rate.…”