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 at the first step; the second amination is also possible provided that the SNAr-active center has sufficient reactivity. On the contrary, sulfonyl fluorides bearing an arylating moiety undergo selective transformation at the latter reactive center under proper temperature control. Further sulfur-fluoride exchange (SuFEx) reaction 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 7-Bln synthetically tractable REAL-type chemical space (nearly 70% expected synthesis success rate).