Synthesis of Functionalized Bridged Bicyclic Sulfonamides with a Bridgehead Nitrogen Atom

Abstract

Two approaches to the synthesis of functionalized bridged bicyclic sulfonamides with a bridgehead nitrogen atom were developed. The target compounds were obtained either by introduction of a CH2SO2 bridge into functionalized monocyclic substrates or by final‐step carboxylation of parent bicyclic cores. The described methods allowed preparation of the final products on a multigram scale.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…Thus, saturated aminoheterocycles 19 bearing a sulfonyl fluoride group easily underwent cyclization to bridged bicyclic sultams 20 (Scheme 15, B). [175][176][177][178] A related approach to spirocyclic sultams 21 relied on the intramolecular reductive sulfonylation of cyanoalkyl sulfonyl fluorides 22 via the formation of aminoalkyl sulfonyl fluorides 23 (Scheme 15, C). [179] Another example relied on annulative SuFEx reaction of arylsubstituted ethenesulfonyl fluorides 24 as bis-electrophiles with ketones bearing an activated methylene group [180][181][182] or pyrazolones [181][182][183] for the synthesis of 6-membered δ-sultones 25 (Scheme 15D).…”

Chemoselective Reactions of Functionalized Sulfonyl Halides

“…[57,190] Also, the SO 2 F group was compatible with Boc or Cbz deprotection conditions; the corresponding amino sulfonyl fluorides could be obtained as salts (Scheme 26). [24,25,[191][192][193] Other transformation tolerating the SO 2 F moiety included: oxime formation; [194] aldol condensation (Scheme 27); [195] Scheme 18. Examples of sulfonyl fluoride alkylation at the α position.…”

“… [57,190] Also, the SO 2 F group was compatible with Boc or Cbz deprotection conditions; the corresponding amino sulfonyl fluorides could be obtained as salts (Scheme 26). [24,25,191–193] Other transformation tolerating the SO 2 F moiety included: oxime formation; [194] aldol condensation (Scheme 27); [195] Horner−Wadsworth−Emmons reaction (Scheme 28); [166] reaction of anilines with SF 4 (providing sulfurimidoyl difluoride of type 21 , Scheme 29); [196] Pinner‐type reactions of nitriles 22 with alcohols or amines providing iminoesters or amidines, respectively (Scheme 30). [197] …”

Convenient Approach to Bicyclic Sultams

“…Various effective methods for synthesizing polynuclear systems are based on closure of a saturated cycle. The methodology is amendable to the preparation of sultams via cyclization of amino sulfonyl chlorides, 9 dianion alkylation, 10,11 cyclization of N,O-dimesylate derivatives of cyclic amino alcohols, [12][13][14] Diels-Alder reactions, 15,16 [3+2] cycloaddition, 17 sulfa-Dieckmann condensation, 18,19 ring-closing metathesis reactions, 20,21 intramolecular Heck reaction, 22 intramolecular oxa-Michael and Baylis-Hillman reactions, 23 intramolecular bromine-catalyzed aziridination, 24 one-pot Sonogashira coupling-cyclization 25 and others. The same approach (i.e., closure of a sultam ring) is almost the only method of preparing benzo-and heteroaryl-annulated sultams.…”