SNAr or Sulfonylation? Chemoselective Amination of Halo(het)arene Sulfonyl Halides for Synthetic Applications and Ultralarge Compound Library Design.

The chemoselectivity of halo(het)arene sulfonyl halide aminations is studied thoroughly under parallel synthesis conditions, and the scope and limitations of the method are established. It is shown that SNAr-reactive sulfonyl halides typically undergo sulfonamide synthesis during the first step; the second amination is also possible provided that the SNAr-active center is sufficiently reactive. On the contrary, sulfonyl fluorides bearing an arylating moiety undergo selective transformation at the latter reactive center under proper control. Further sulfur-fluoride exchange (SuFEx) is also possible, which can be especially valuable for some sulfonyl halide classes. The developed two-step parallel double amination protocol provides access to a 6.67-billion compound synthetically tractable REAL-type chemical space (76% expected synthesis success rate).

Chemoselective Reactions of Functionalized Sulfonyl Halides.

Chemoselective transformations of functionalized sulfonyl fluorides and chlorides are surveyed comprehensively. It is shown that sulfonyl fluorides provide an excellent selectivity control in their reactions. Thus, numerous conditions are tolerated by the SO2 F group - from amide and ester formation to directed ortho-lithiation and transition-metal-catalyzed cross-couplings. Meanwhile, sulfur (VI) fluoride exchange (SuFEx) is also compatible with numerous functional groups, thus confirming its title of "another click reaction". On the contrary, with a few exceptions, most transformations of functionalized sulfonyl chlorides typically occur at the SO2 Cl moiety.

Bypassing Sulfonyl Halides: Synthesis of Sulfonamides from Other Sulfur-Containing Building Blocks.

This review disclosed synthetic approaches to sulfonyl amides from non-sulfonyl halogenated precursors. Known methods were systematized into groups and subgroups according to the type of starting organosulfur compound. Thiols, disulfides, and sulfonamides form a group of S(II)-containing precursors, which are used in oxidative amination reactions. An important and versatile group for oxidative amination is represented with S(IV)-containing compounds, i. e., sufinates, sulfinamides, DMSO, N-sulfinyl-O-(tert-butyl)hydroxylamine, etc. A series of S(VI)-containing precursors for amination reactions (except sulfonyl halides) include sulfonic acids, sulfonyl azides, thiosulfonates, and sulfones. All approaches are represented with the most prominent examples of the resulting sulfonamides, which could be obtained in high yields mostly via short reaction sequences. Promising electrochemical methods for the preparation of sulfonamides from thiols, disulfides, sulfonamides, sulfinic acid derivatives, and dimethyl sulfoxide under mild and green conditions are also highlighted.

Synthesis of α-C-Stereochemically Pure Secondary Sulfonamides.

A convenient "green" stereoretentive approach to sp3-enriched secondary sulfonamides bearing an asymmetric center at the α position to the sulfur atom is described. The method relies on the electrophilic amination of the corresponding stereochemically pure sulfinates with N-alkylhydroxylamine sulfonic acids (in turn easily prepared from N-alkylhydroxylamine and HSO3Cl). It is shown that the efficiency of the approach is governed mainly by steric factors; its tolerance to several functional groups (e.g., ether, phthalimide, or N-Boc carbamate) is also demonstrated.