A mild, convenient synthesis of sulfinic acid salts and sulfonamides from alkyl and aryl halides

A general, mild, and convenient method has been developed for the synthesis of various alkyl and aryl sulfinic acid salts and sulfonamides from the corresponding halides. Key to the success of this methodology is the design and facile synthesis of sodium 3-methoxy-3-oxopropane-1-sulfinate (SMOPS), a reagent that serves to introduce the protected sulfinate moiety directly to the substrate, thus avoiding the use of oxidizing and other harsh reaction conditions such as organolithium or Grignard reagents. Many functional groups, as well as heterocycles, are tolerated in the sequence. © 2002 Published by Elsevier Science Ltd. The sulfonamide group is found in many therapeutic agents, including drugs for the treatment of bacterial and viral infections. More recently, it has been found to be a key constituent of a new class of cyclooxygenase inhibitors such as Celecoxib and Valdecoxib. The most commonly used synthetic method to make sulfonamides involves the reaction of ammonia with sulfonyl chlorides. Although the method is sufficient, its utility is limited to the availability of sulfonyl chlorides, which can only be prepared under rather harsh oxidizing or strong Lewis acidic conditions. Alternatively, sulfonamides can be obtained by reacting sulfinic acid salts with an electrophilic nitrogen source such as hydroxylamine-O-sulfonic acid or bis(2,2,2-trichloroethyl)azodicarboxylate. The latter method is particularly attractive due to the mildness of the reaction conditions and the possibility to introduce the sulfonamide group at later stage of a multi-step synthesis. However, the success of the process lies in the availability of the required sulfinic acid salt. The existing synthetic approaches to sulfinic acid salts either involve the use of organolithium or Grignard reagents, which are incompatible with a host of functional groups, or involve tedious, multi-step syntheses. Furthermore, the purity of the sulfinates is not sufficiently high due to an inability to isolate the hygroscopic salt. Here, we report a novel, convenient strategy for the synthesis of sulfinic acid salts from alkyl and aryl halides under very mild conditions, and for their subsequent conversion to sulfonamides. For the synthesis of alkyl sulfonamides, the entire process can be carried out in a one-pot operation. -Phenylsulfonylketones 1 have been used as a template to prepare a variety of -substituted enones. The key step of the process is the -elimination of the phenylsulfinate after an appropriate substituent is introduced through an alkylation reaction of the intermediate sulfone anion (Scheme 1, Eq. (1)). Based on the same principle, we envisioned that a sulfinate derivative such as sodium 3-methoxy-3-oxopropane-1-sulfinate (SMOPS) 2 can serve as a donor for the sulfinate moiety through a simple alkylation and subsequently be removed by a -elimination (Scheme 1, Eq. (2)). The reaction of the resulting sulfinate 3 with an electrophilic nitrogen source would provide an easy access to various sulfonamides. We began our study by designing a synthesis of SMOPS, whose only known synthesis is unsuitable for its isolation and characterization, due to contamination Scheme 1. * Corresponding author. Tel.: +1-514-428-3235; fax: +1-514-428-4900; e-mail: zhaoyin–[email protected] 0040-4039/02/$ see front matter © 2002 Published by Elsevier Science Ltd. PII: S0040 -4039 (02 )02073 -7 J. M. Baskin, Z. Wang / Tetrahedron Letters 43 (2002) 8479–8483 8480 of the product with borate salts and benzothiazole, though the synthesis is useful for providing SMOPS as an intermediate for further reactions. A new and practical preparation of SMOPS is shown in Scheme 2. Conjugate addition of methyl 3-mercaptopropionate to methyl vinyl ketone, followed by Na2WO4-catalyzed oxidation with H2O2, generated sulfone 5. -Elimination of 5 was achieved by treatment with 1 equiv. of NaOMe in a mixture of THF and MeOH. Thus, multigram quantities of SMOPS can be isolated in nearquantitative yield from sulfone 5 as a stable white solid simply by evaporation of the solvent under reduced pressure. With SMOPS in hand, a one-pot synthesis of alkyl sulfonamides from alkyl halides was explored. In particular, the solvent must be compatible with all three steps in the sequence—alkylation, -elimination, and sulfonamide formation. After screening a number of solvents, DMSO was found to suit the need for the one-pot operation. In addition to promoting the alkylation reaction due to its highly polar, aprotic nature, DMSO also provides a more homogeneous reaction medium for the sulfonamide formation step since many alkyl and aryl sulfinic acid sodium salts have limited solubility in water, which is the solvent in the original procedure involving hydroxylamine-O-sulfonic acid as the electrophilic nitrogen source. The second step, the -elimination of the resulting intermediate sulfone, could be accomplished by treatment either with NaOMe or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU). Thus, a diverse range of alkyl sulfonamides 6a–h was generated, using a one-pot procedure, with satisfactory yields (Table 1). The intermediate sulfones from alkylation of SMOPS with halides in Table 1 can be obtained in >95% yields for all cases after a simple aqueous workup. Additionally, to isolate the intermediate sodium sulfinates, the resulting sulfones can be treated with 1 equiv. NaOMe in a THF/MeOH mixture. The corresponding sodium sulfinates can be isolated quantitatively by evaporation of the solvent under reduced pressure, an identical procedure to the last step in the synthesis of SMOPS. This new approach to alkyl sulfonamide formation offers several advantages over the traditional methods Table 1. One-pot formation of alkyl sulfonamides