Aryl Sulfonamides made easy

Sulfonamide moieties are ubiquitous across commercial drugs and have been used in a wide range of therapeutic areas such as antimicrobial, diuretics, antiretrovirals and antiinflammatories. Among the drugs featuring sulfonamides are COX-2 inhibitor Celebrex (1), HIV protease inhibitor Amprenavir (2) and WHO’s list of essential medicine Sulfadiazine (3) (Figure 1).

Michael Fig 1 30-11-2015

Figure 1. Sulfonamide-containing drugs

Synthetically, sulfonamides can be readily accessed from (hetero)aryl or alkyl sulfonyl chlorides and amines. These sulfonyl chlorides have often the tendency to be instable due to their reactivity and their preparation itself can be challenging.

Of the many reported methods for the preparation of aryl sulfonyl chlorides, the main access still remains via aromatic electrophilic substitution. However, this methodology is dependent upon the aromatic characteristic of the arenes employed toward the electrophilic substitutions. Of the other methods available, worth mentioning is the conversion of thiol derivatives under oxidative conditions, often limiting the compatibility with other functional groups.

Mike Willis previously reported the preparation of aryl ammonium sulfinates under palladium-catalysed sulfination of aryl iodides. Based on the understanding that DABSO (Scheme 1) could be used as a convenient surrogate of SO2 gas in a number of transformations, Willis has shown that ammonium sulfinates could be readily obtained from aryl halides (Scheme 1).

Michael Scheme 1 30-11-2015

Scheme 1. Palladium catalysed cross coupling of aryl iodide with DABSO

To evaluate the scope of the reaction, the sulfinates were converted to the corresponding sulfones in situ by reaction with bromo tert-butyl acetate as the electrophile (Figure 2).

Michael Fig 2 30-11-2015

Figure 2. Sulfones from ammonium sulfonates

Shortly after, Willis also reported a simple and efficient one-pot synthesis of (hetero)aryl sulfonamides obtained from magnesium sulfonates prepared in situ with DABSO and a Grignard reagent and a N-chloro-amine as the electrophilic partner, also generated in situ from bleach and the relevant amine (Figure 3).

Michael Fig 3 30-11-2015

Figure 3. Organometallic reagent scope for the one-pot preparation of sulfonamides

In his latest publication, Willis reports a combination of the previous two DABSO-based methodologies where the ammonium sulfonate intermediate obtained from palladium catalysed sulfination of an (hetero)aryl iodide is further reacted with an amine in the presence of sodium hypochlorite (Scheme 2). Both electron withdrawing and donating groups are tolerated on the aryl moiety. More interesting however is the compatibility of the reaction conditions with the presence of other functional groups (esters, nitriles, ketones, phenols) but also thiols, allowing for the presence of sulfur atoms at different oxidative levels in the same molecule.

Michael Scheme 2 30-11-2015

Scheme 2.

The scope of the amines also tolerated was examined and the telescoped two steps, one pot procedure is highly tolerant of vulnerable functional groups. Example 4b in the table below clearly highlights how tolerant the reaction is to sensitive functionalities with both methyl thiol and acetal moieties untouched (Figure 4).

Michael Fig 4 30-11-2015

Figure 4. Reaction scope

Willis clearly exemplifies over a few publications how having access to an easy to handle surrogate of SO2 allows for the rapid development of novel reactions to prepare key functional groups such as sulphonamides.

Blog written by Michael Paradowski


Palladium-Catalyzed Synthesis of Ammonium Sulfinates from Aryl Halides and a Sulfur Dioxide Surrogate: A Gas- and Reductant-Free Process; Edward J. Emmett, Barry R. Hayter, and Michael C. Willis*; Angew. Chem. Int . Ed. 2014, 53, 10204 –10208

Combining Organometallic Reagents, the Sulfur Dioxide Surrogate DABSO, and Amines: A One-Pot Preparation of Sulfonamides, Amenable to Array Synthesis; Alex S. Deeming, Claire J. Russell, and Michael C. Willis*; Angew. Chem. Int. Ed. 2015, 54, 1168 –1171

One-Pot Sulfonamide Synthesis Exploiting the Palladium-Catalyzed Sulfination of Aryl Iodides; Emmanuel Ferrer Flegeau, Jack M. Harrison, Michael C. Willis*; Synlett, 2015, DOI: 10.1055/s-0035-1560578.

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