N‐(Morpholine‐4‐dithio)phthalimide: A Shelf‐Stable, Bilateral Platform Molecule Enabling Access to Diverse Unsymmetrical Disulfides

• Published in: Angewandte Chemie International Edition Vol. 62; no. 18; pp. e202219156 - n/a
• Main Authors: Asanuma, Hayato, Kanemoto, Kazuya, Watanabe, Tokiharu, Fukuzawa, Shin‐ichi
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 24.04.2023; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Acid Activation; Allylation; Aromatic compounds; Chemistry; Chemistry, Multidisciplinary; C−S Bond Formation; Disulfides; Divergence; Morpholine; Nucleophiles; Phthalimide; Phthalimides; Physical Sciences; Protonation; Reagents; Science & Technology; Shelving; Sulfur; REAGENT; ORGANIC SULFUR CHEMISTRY; DRUG CONJUGATE; SULFIDES; Disulfides; REACTIVITY; ANTIBODY; C-S Bond Formation; Allylation; DELIVERY; Acid Activation; CARBONIC-ANHYDRASE IX; CHEMICAL-SYNTHESIS; ARYL; Sulfur; C−S Bond Formation
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202219156

Synthetic methods for unsymmetrical disulfides are greatly needed owing to their applications in drug discovery, linker chemistry, and materials sciences. In this study, a new shelf‐stable and easy‐to‐prepare bilateral disulfurating platform molecule, N‐(morpholine‐4‐dithio)phthalimide, has been developed for the divergent synthesis of unsymmetrical disulfides. The amino and imide leaving groups of this reagent can be orthogonally transformed. Under acidic conditions, the amino moiety undergoes selective protonation and thus can be displaced by various carbon nucleophiles, such as allyl trimethylsilanes, alkynyl silanes, and electron‐rich arenes, leaving the phthalimide moiety untouched. Meanwhile, the phthalimide leaving group is amenable to substitution under basic or neutral conditions. The combination of these transformations provides rapid access to diverse unsymmetrical disulfides through two C−S bond‐forming reactions. A shelf‐stable and easy‐to‐prepare disulfurating reagent with chemoselectively displaceable amino and imide leaving groups is described. Protonation of this reagent promotes exclusive displacement of the amino group with various neutral carbon nucleophiles. The resulting dithiophthalimides are amenable to diverse substitution reactions under basic or neutral conditions, thus enabling expedient access to structurally diverse unsymmetrical disulfides.