Bicyclo[1.1.1]pentyl Sulfoximines: Synthesis and Functionalizations

Abstract

Herein we present the first synthesis of bicyclo[1.1.1]pentyl (BCP) sulfoximines from the corresponding sulfides. Both BCPs and sulfoximines are bioisosteres used in medicinal chemistry and therefore desirable motifs. The access to BCP sulfides was enabled by the thiol addition to [1.1.1]propellane as published before. A broad scope with specific limitations was discovered for the sulfoximination. To diversify the sulfoximines, N‐acylations and N‐arylations were performed. As the N‐arylation was low yielding we optimized the copper(I) catalyzed reaction. A wide range of aryl iodides could be deployed and competitive reactions showed that aryl bromides react equally fast. In a scale‐up we prepared a suitable precursor for a BCP drug analogue. In this work several molecular structures could be determined by single‐crystal X‐ray diffraction.

Synthesis of Sulfoximines and Sulfonimidamides Using Hypervalent Iodine Mediated NH Transfer

“…However, notable extensions have displayed interesting selectivity and functional group tolerance. Bräse applied the reaction to bicyclo[1.1.1]pentyl (BCP) sulfides in the synthesis of BCP sulfoximines [ 87 ]. Zhang and Chen reported the tandem formation of sulfoximines from sulfides and intramolecular C–H amination, where (NH 4 ) 3 PO 4 ·3H 2 O was used as the ammonia source, and the reaction could be run at RT under air in methanol or in DMF [ 88 ].…”

A Novel Route towards Bicyclo[1.1.1]pentane Sulfoxides from a Bench-Stable Starting Material

“…6 Sulfoxides can also be converted into sulfoximines, which can be further functionalized, for example, by N -arylation. 7 As the interest in BCPs as bioisostere motifs in medicinal chemistry is continuously growing, there is also an increasing demand for novel synthetic methodologies to modify the BCP scaffold and combine it with other pharmacophoric motifs such as sulfoxides (Scheme 1 ).…”

Iodonitrene: a direct metal-free electrophilic aminating reagent

“…(B) Variation of sulfides as the starting materials. [43][44][45][46][47][48][49] substrates and/or conditions (Scheme 4B), for instance pyridinyl sulfides 4e (Reboul's group), 44,50 S-perfluoroalkylated sulfides 4f (Reboul's group), 51 thiophene-derived sulfides 4g (Bolm's group), 48 bicyclo[1.1.1]pentyl sulfides 4h (Bräse's group), 53 and β-thioglycosides 4i (Bull and Luisi's group). 54 Besides, sulfoximination of sulfides could be achieved to afford 4e under aqueous micellar conditions using the surfactant TPGS-750-M as an additive.…”