Alkylation of Sulfonamides with Trichloroacetimidates under Thermal Conditions

Abstract

An intermolecular alkylation of sulfonamides with trichloroacetimidates is reported. This transformation does not require an exogenous acid, base, or transition metal catalyst, instead the addition occurs in refluxing toluene without additives. The sulfonamide alkylation partner appears to be only limited by sterics, with unsubstituted sulfonamides providing better yields than more encumbered N-alkyl sulfonamides. The trichloroacetimidate alkylating agent must be a stable cation precursor for the substitution reaction to proceed under these conditions. Graphical abstractThe sulfonamide functional group has played an important role in the development of numerous pharmaceuticals. While best known as antibiotics, sulfonamide scaffolds provide a diverse range of biological activity including antitumor, antiviral, diuretic, antiinflammatory and anti-hypertensive properties. 1 Summaries of the top selling pharmaceuticals clearly demonstrate that sulfonamides are well represented in these valuable structures. 2 Data on recently approved pharmaceuticals indicate that sulfonamides continue to be popular in drug discovery, 3 with recent publications in the medicinal chemistry field corroborating that the investigation of sulfonamide-containing structures is ongoing. 4 Sulfonamides also have proven useful in agricultural and insecticidal applications. 5

Reductions of Imines Using Zirconocene Chloride Hydride

“…13 C NMR (151 MHz, CDCl 3 ): δ = 142.6, 129.2, 128.2, 126.4, 54.0, 42.0, 24.2 ppm. Spectral data are in agreement with literature data . MS (APCI, m/z ): calcd.…”

Visible-Light, Iodine-Promoted Formation of N-Sulfonyl Imines and N-Alkylsulfonamides from Aldehydes and Hypervalent Iodine Reagents

“…All N -alkylsulfonamides were isolated according to general procedure. Products 3aa [ 68 ], 3ae [ 69 ], 3ba [ 68 ], 3bb [ 70 ], 3bf [ 71 ], 3ca [ 68 ], 3da [ 72 ], 3ea [ 68 ], 3eb [ 70 ], 3ee [ 69 ], 3ha [ 73 ], 3hb [ 74 ], 3ia [ 75 ], 3ja [ 73 ], 3ka [ 73 ], 3la [ 72 ], and 3ma [ 72 ] have been reported, and the characterizational data was in agreement with literature values (spectra and full characterization available in ESI). Additional N -alkylsulfonamides display the characterizational data shown below.…”

Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target

“…Routes 2). The most common strategies are treatment with bases to subtract the proton followed by alkylation with alkyl halides, Mitsunobu reaction, use of other alkylating agents under thermal conditions, and metal‐mediated (Cu, Pd, and Ru) coupling of various types of reagents, especially for N ‐arylation purposes. Olefins have also been used for intermolecular or intramolecular alkylations of sulfonamides …”