Direct Synthesis of Unprotected 2-Azidoamines from Alkenes via an Iron-Catalyzed Difunctionalization Reaction

Abstract

<div> <p>Unprotected, primary 2-azidoamines are versatile precursors to vicinal diamines, which are among the most common motifs in biologically active compounds. Herein, we report their operationally simple synthesis through an iron-catalyzed difunctionalization of alkenes. A wide array of alkene substrates are tolerated, including complex drug-like molecules and a tripeptide. Facile derivatizations of the azidoamine group demonstrate the versatility of this masked diamine motif in chemoselective, orthogonal transformations. Applications of the methodology in the concise synthesis of RO 20-1724 and in a formal total synthesis of (±)-hamacanthin B further demonstrate the broad synthetic potential of this highly functional group tolerant reaction.</p> </div>

Design and Scalable Synthesis of N‐Alkylhydroxylamine Reagents for the Direct Iron‐Catalyzed Installation of Medicinally Relevant Amines**

“…In recent work, our group hypothesized that the aminoazidation and aminochlorination of alkenes proceed via a carbon‐centered radical [15, 22c] . We thus assumed that the novel methodologies presented herein follow a similar mechanistic pathway.…”

“…After a minor re‐optimization of the reaction conditions, [19] we were pleased to find that 4‐methoxystyrene could be converted to the N ‐methylamino alcohol 68 , an O ‐methylated derivative of the naturally occurring synephrine, in moderate yield (Scheme 6 A). Recently, our group also developed an aminoazidation reaction of alkenes to directly obtain primary, unprotected 2‐azidoamines [22c] . We hence sought to use the new reagents to directly access 2‐azidoamines.…”

Recent Advances in Nonprecious Metal Catalysis

“…The 1,2-functionalization of olefins, for example, is an attractive way to build molecular complexity from abundant olefin feedstocks. Morandi and co-workers published two papers as an extension of their original report, 70 describing the synthesis of unprotected secondary 2-chloro-N-alkyl amine 71 or 2-azidoamine 72 directly from terminal or cyclic olefins (Scheme 28). The short, three step synthesis of seven novel alkylating agents with medicinally relevant substitution is described.…”

Hydroxylamine‐Derived Reagent as a Dual Oxidant and Amino Group Donor for the Iron‐Catalyzed Preparation of Unprotected Sulfinamides from Thiols

“…Widely studied iron‐based enzymes have recently inspired a renewed interest in developing simple, homogeneous iron complexes for the oxidation and amination of organic substrates [75] . Toward this endeavour our group and others have been working on iron catalyzed aminofunctionalization of alkenes [76–82] using hydroxylamine derived reagents. Additionally, we and others reported aromatic C−H amination reactions [83–87] through the use of similar reagents.…”