Direct Stereospecific Synthesis of Unprotected N-H and N-Me Aziridines from Olefins

Abstract

Despite the prevalence of the N-H aziridine motif in bioactive natural products and the clear advantages of this unprotected parent structure over N-protected derivatives as a synthetic building block, no practical methods have emerged for direct synthesis of this compound class from unfunctionalized olefins. Here, we present a mild, versatile method for the direct stereospecific conversion of structurally diverse mono-, di-, tri- and tetra-substituted olefins to N-H aziridines using O-(2,4-dinitrophenyl)hydroxylamine (DPH) via homogeneous rhodium catalysis with no external oxidants. This method is operationally simple (i.e., one-pot), scalable and fast at ambient temperature, furnishing N-H aziridines in good-to-excellent yields. Likewise, N-alkyl aziridines are prepared from N-alkylated DPH derivatives. Quantum-mechanical calculations suggest a plausible Rh-nitrene pathway.

Dirhodium-catalyzed C-H arene amination using hydroxylamines

“…Based upon a combination of experimental observations and theoretical considerations, we anticipated a reaction dichotomy could be achievable between dirhodium-catalyzed aziridination, as reported previously by our laboratories (33), and direct arene amination. Following a systematic investigation, proof-of-principle for arene amination vs. aziridination was demonstrated (Fig.…”

Catalytic Asymmetric Dearomatization by Transition-Metal Catalysis: A Method for Transformations of Aromatic Compounds

“…This type of reaction is particularly attractive because the products, 3a-amino-pyrroloindolines, are key structural motifs of Recently, Jat et al 95 proved that 4-(dinitrophenyl)-hydroxylamine (DPH) is a versatile amination reagent for aziridination of polysubstituted olefins catalyzed by Rh 2 (esp) 2 . The combination of DPH and Rh 2 (esp) 2 (esp = a,a,a 0 ,a 0 -tetramethyl-1,3-benzenedipropionic acid) was found to promote the dearomatization process of tryptamine derivatives through an aziridination and cyclization sequence by Shen et al 96 (Scheme 30).…”

Direct and Stereospecific Synthesis of N‐H and N‐Alkyl Aziridines from Unactivated Olefins Using Hydroxylamine‐O‐Sulfonic Acids

“…To enable a direct comparison on the reactivity and efficiency, this new aziridination method was tested on several substrates that required prolonged reaction time with the DPH protocol. [7] Gratifyingly, the reaction times were reduced under HOSA conditions in all cases, while similar or higher isolated yields were obtained (Table 2, entries 1 & 10–13). As a representative example, the reaction time required for the aziridination of the natural product cholesterol was reduced from 48 h to 2.5 h, and only half of the original Rh 2 (esp) 2 catalyst loading (1 mol% vs 2 mol%) was required (Table 2, entry 13).…”

“…[7] To the best of our knowledge, it is still the only reported method with a general scope that can achieve N –H and N –Me aziridination on unactivated olefins. This transformation provides good to excellent yields of the aziridines for a large variety of olefin substrates, while tolerating a wide range of functional groups.…”