S(vi) in three-component sulfonamide synthesis: use of sulfuric chloride as a linchpin in palladium-catalyzed Suzuki–Miyaura coupling

Sulfuric chloride is used as the source of the –SO₂– group in a palladium-catalyzed three-component synthesis of sulfonamides. Suzuki–Miyaura coupling between the in situ generated sulfamoyl chlorides and boronic acids gives rise to diverse sulfonamides in moderate to high yields with excellent reaction selectivity. Although this transformation is not workable for primary amines or anilines, the results show high functional group tolerance. With the solving of the desulfonylation problem and utilization of cheap and easily accessible sulfuric chloride as the source of sulfur dioxide, redox-neutral three-component synthesis of sulfonamides is first achieved.

Sulfuric chloride is used as the source of the –SO₂– group in a palladium-catalyzed three-component synthesis of sulfonamides.

Since its development in the 1970s,¹ Suzuki–Miyaura coupling has become a widely used synthetic step in diverse areas. With two of the most widely sourced materials, organoborons and alkyl/aryl halides, a number of C–C coupling reactions are established and the Suzuki–Miyaura reaction has successfully acted as the key step in the synthesis of medicines and agrochemicals.²In addition to the well-known aryl halides and esters, various other substrates such as acid chlorides,³ anhydrides,⁴ diazonium salts⁵ and sulfonyl chlorides⁶ were also reported for the coupling in the past decades. As far as acid chlorides are concerned, carbamoyl chlorides were successfully transformed to the corresponding benzamides in the early years of the 21st century.⁷ However, the use of sulfamoyl chlorides as coupling partners is challenging due to the strong electron-withdrawing properties of the sulfonyl group, which cause the tendency of desulfonylation to form tertiary amines.Synthesis of sulfonyl-containing compounds, especially sulfones and sulfonamides, via the insertion of sulfur dioxide has been extensively studied during the last decade.⁸ A series of sulfur-containing surrogates have been developed as the source of the –SO₂– group. Willis and co-workers first reported the use of DABCO·(SO₂)₂, a bench-stable solid adduct of DABCO and gaseous SO₂ discovered by Santos and Mello,^9a as the source of sulfur dioxide in the synthesis of sulfonylhydrazines.^9b Soon after, alkali metal metabisulfites were found to provide sulfur dioxide for the formation of sulfonyl compounds.¹⁰ In the recent developments in this field, DABCO·(SO₂)₂ and metabisulfites have become the most popular SO₂ surrogates for the insertion of sulfur dioxide.⁸ However, the practical applications of sulfur dioxide insertion reactions are limited by atom-efficiency problems and the unique properties of reactants. For instance, the three-component synthesis of aryl sulfonylhydrazines using aryl halides, SO₂ surrogates and hydrazines by a SO₂-doped Buchward–Hartwig reaction was realized in the earliest developments in this field.¹⁰ However, similar transformations from aryl halides and amines to the corresponding sulfonamides still remain unresolved (Scheme 1a).^11,12Open in a separate windowScheme 1Synthetic approaches to sulfonamides.In order to provide a simple and efficient method for the three-component synthesis of aryl sulfonamides without the pre-synthesis of sulfonyl chlorides, many scientists have made various attempts. Interestingly, the use of arylboronic acids instead of aryl halides provided an alternative route. An oxidative reaction between boronic acids, DABCO·(SO₂)₂ and amines for the preparation of aryl sulfonamides at high temperature was realized,¹² while reductive couplings of boronic acids, SO₂ surrogates and nitroarenes were also reported (Scheme 1b).¹³ However, due to the reversed electronic properties of boronic acids from halides, additional additives and restrictions had to be considered. Extra oxidants and harsh conditions were usually used, and some of the transformations required “oxidative” substrates, such as nitroarenes and chloroamines.¹⁴Early in 2020, a reductive hydrosulfonamination of alkenes by sulfamoyl chlorides was reported,¹⁵ which gave us the inspiration to use in situ generated sulfamoyl chlorides as the electrophile for the synthesis of aryl sulfonamides by Suzuki–Miyaura coupling. In this way, sulfamoyl chlorides could be formed by nucleophilic substitution of an amine to sulfuric chloride, and the S(vi) central atom introduced into the reaction could reverse the electronic properties of the amine, which would eliminate the addition of oxidants (Scheme 1c). With the utilization of boronic acids as the coupling partner, a palladium-catalyzed Suzuki–Miyaura coupling could provide the sulfonamide products. Compared with traditional attempts, reversing the electronic properties of an amine from nucleophilic to electrophilic could reverse the whole reaction process, and two-step synthesis starting from the amine side could bypass the existing difficulty of S–N bond forming reductive elimination.¹² Instead, a C–S bond formation could be the key for success (Scheme 2). In this proposed route, the presence of a base would be essential to remove the acid generated in situ during the reaction process. Additionally, we expected that the addition of a ligand would improve the oxidative addition of Pd(0) to sulfamoyl chloride, thus leading to the desired sulfonamide product.Open in a separate windowScheme 2Comparison between the traditional route and designed work.As designed based on our assumption, we used a commercialized sulfamoyl chloride intermediate A, which would be generated from morpholine 1a and SO₂Cl₂, to start our early investigations. The results showed that the direct Suzuki–Miyaura coupling of sulfamoyl chloride intermediate A and 2-naphthaleneboronic acid 2a mostly led to the generation of byproduct 3a′ with traditional phosphine ligands added to the reaction, and the desired product 3a was obtained in poor yields (