Sodium Bicyclo[1.1.1]pentanesulfinate: A Bench‐Stable Precursor for Bicyclo[1.1.1]pentylsulfones and Bicyclo‐ [1.1.1]pentanesulfonamides

Abstract

Herein, we present the synthesis of the bench‐stable sodium bicyclo[1.1.1]pentanesulfinate (BCP‐SO2Na) and its application in the synthesis of bicyclo[1.1.1]pentyl (BCP) sulfones and sulfonamides. The salt can be obtained in a four‐step procedure from commercially available precursors in multigram scale without the need for column chromatography or crystallization. Sulfinates are known to be useful precursors in radical and nucleophilic reactions and are widely used in medicinal chemistry. This building block enables access to BCP sulfones and sulfonamides avoiding the volatile [1.1.1]propellane which is favorable for the extension of SAR studies. Further, BCP‐SO2Na enables the synthesis of products that were not available with previous methods. A chlorination of BCP‐SO2Na and subsequent reaction with a Grignard reagent provides a new route to BCP sulfoxides. Several products were analyzed by single‐crystal X‐ray diffraction.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…[408] In line with the emerging building block types discussed in the other sections of this review, synthetic approaches to BCPcontaining suflonyl fluorides, sulfinates, and trifluoroborates were studied. Thus, [1.1.1]propellane ring opening with thiols was first reported by works of Semmler [409] and Wiberg; [410] later Bräse and co-workers developed an efficient method, [411] which was later used by them to obtain bicyclo[1.1.1]pentyl sulfinate (86), [412] as well as sulfoximines 87 (Scheme 49).…”

3‐Carboxy‐/3‐Aminobicyclo[1.1.1]pentane‐Derived Sulfonamides and Sulfonyl Fluorides – Advanced Bifunctional Reagents for Organic Synthesis and Drug Discovery

“…Further steps included oxidation of the sulfide moiety and nucleophilic cleavage of the 2‐pyridyl moiety and led to the corresponding sulfinates. This reaction sequence is similar to that used recently by Bräse and co‐workers; however, utility of their method is limited to the terminal bicyclo[1.1.1]pentyl derivatives. The sulfinates were transformed into the target sulfonyl fluorides or sulfonamides upon electrophilic fluorination and amination, respectively.…”

“…While this work was in preparation, Bräse and co‐workers described an elegant synthesis of the parent bicyclo[1.1.1]pentyl sulfinate 9 , as well as demonstrated its utility for the preparation of sulfonamides and other sulfur (VI) compounds (Scheme ) . Since utility of this method is limited by monosubstituted bicyclo[1.1.1]pentane derivatives, herein we describe an approach to the gram‐scale synthesis of novel 1,3‐disubstituted bicyclo[1.1.1]pentane‐derived sulfonyl fluorides 10 and sulfonamides 11 (Figure ).…”

One-Pot Synthesis of Sulfonamides from Unactivated Acids and Amines via Aromatic Decarboxylative Halosulfonylation

“…An inexpensive and commercially available BCP substrate, 3-(methoxycarbonyl)-BCP-1-carboxylic acid, was efficiently converted to the corresponding sulfonamide ( 24 , 63% yield). While BCPs bearing a sulfonamide exit vector have been reported in the literature, they previously have been accessed via a 5-step synthetic sequence . Beyond this BCP scaffold, cyclopropanes were also readily functionalized in high yield ( 25 , 64% yield, see SI for additional examples and limitations).…”