TiCl₄-Mediated Direct N-Alkylation of Sulfonamides with Inactive Ethers

Abstract

A TiCl₄-mediated intermolecular or intramolecular direct N-alkylation reaction of sulfonamides with inactive ethers as alkylating agents was successfully achieved. This method provides a novel approach towards N-alkyl sulfonamides from inactive ethers via an easy workup procedure.

N-alkylation - Lewis acid - N-alkyl sulfonamide - dialkyl ether - titanium tetrachloride

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General Procedure for the Transformation
Sulfonamide (0.50 mmol), ether (12.0 equiv, 6.0 mmol) and Cl₂CHCHCl₂ (2.0 mL) were combined in a pressure tube equipped with a stir bar, the mixture was stirred about 10 min, then TiCl₄ (6.0 equiv, 3.0 mmol) was added, and the reaction mixture was heated to 120 ˚C for the given time. After the starting material has disappeared (monitored by TLC), the reaction mixture was cooled to r.t. and treated with H₂O (5.0 mL) to decompose the exceed TiCl₄, then filtered, and the filtrate was extracted with EtOAc (3 × 10 mL).
The combined organic layers was dried over Na₂SO₄ and concentrated in vacuo, the corresponding residue was purified by flash column chromatography (silica gel) to furnish the target product. All the products are known compounds and are identified using ^¹H NMR, LRMS, and
IR by comparison with previously reported data (see Supporting Information for complete details).