Gold‐Catalyzed Intermolecular Anti‐Markovnikov Hydroamination of Alkylidenecyclopropanes

Abstract

The cationic gold phosphine complex [{PCy2(o‐biphenyl)}Au(NCMe)]+SbF6− (Cy=cyclohexyl) catalyzes the intermolecular, anti‐Markovnikov hydroamination reaction of monosubstituted and cis‐ and trans‐disubstituted alkylidenecyclopropanes (ACPs) with imidazolidin‐2‐ones and other nucleophiles. This reaction forms 1‐cyclopropyl alkylamine derivatives in high yield and with high regio‐ and diastereoselectivity. NMR spectroscopic analysis of gold π‐ACP complexes and control experiments point to the sp hybridization of the ACP internal alkene carbon atom as controlling the regiochemistry of the ACP hydroamination reaction.

Gold‐Catalyzed Intermolecular anti‐Markovnikov Hydroamination of Methylenecyclopropanes with 2‐Pyridones

“…We recently reported the gold‐catalyzed, intermolecular anti‐Markovnikov hydroamination of methylenecyclopropanes (MCPs) with imidazolidin‐2‐ones to form 1‐(cyclopropylmethyl)‐imidazolidin‐2‐ones 10. This transformation is unique among transition metal‐catalyzed hydroamination processes owing both to the anti‐Markovnikov regioselectivity and the absence of cyclopropyl CC bond cleavage and represents a new approach for the incorporation of substituted cyclopropanes into nitrogen‐containing molecules 11–14.…”

“…Included in this preliminary report was a single example of the hydroamination of the cyclohexyl‐fused MCP 1a with 5‐chloro‐2‐pyridone catalyzed by [( o ‐biphenylPCy 2 )Au(NCMe)] + SbF 6 − ( 2 ; 5 mol%) to form the 1‐(cyclopropylmethyl)pyridin‐2‐one 3aa in 79% yield with ≥25:1 regio‐ and diastereoselectivity [Eq. (1)] 10. Owing both to the importance of N ‐alkylated 2‐pyridones in natural products and medicinal chemistry and the limitations associated with the N ‐alkylation of 2‐pyridones, we sought to further develop the gold‐catalyzed hydroamination of MCPs with 2‐pyridones.…”

“…Employing the conditions optimized for the gold‐catalyzed hydroamination of MCPs with cyclic ureas,10 we evaluated the scope of the gold‐catalyzed hydroamination of MCP 1a as a function of the 2‐pyridone. Hydroamination of 1a was uniformly effective employing 5‐chloro‐, 5‐bromo‐, 5‐iodo‐ and 5‐fluoro‐2‐pyridones as nucleophile and was also effective for 2‐pyridones that possessed a 5‐nitro, 5‐trifluoromethyl, or 5‐carbomethoxy group (Table 1, entries 1–8).…”

“…Although the mechanism of the gold‐catalyzed hydroamination of MCPs remains speculative, the high trans ‐selectivity observed for the hydroamination of monosubstituted and cis ‐1,2‐disubstituted MCPs is reminiscent of the gold‐catalyzed hydroamination of 1,3‐disubstituted allenes16 and points to a mechanism involving outer‐sphere addition of the nucleophile to less stable cis π‐MCP complex cis ‐ I followed by protodeauration (Scheme ). 1 H NMR analysis of the gold π‐(2‐methylenecyclopropyl)benzene complex [ o ‐biphenylP( t‐ Bu) 2 ]Au(η 2 ‐ 1c ) ( 4 ) at −40 °C revealed an equilibrium ∼25:1 mixture of diastereomers (Δ G =1.5 kcal mol −1 ), presumably favoring trans ‐ 4 10. In any event, the rapid interconversion of cis ‐ 4 and trans ‐ 4 at −40 °C on the laboratory time scales ensures that isomerization of cis ‐ I and trans ‐ I is fast relative to catalyst turnover.…”

DFT Studies of Au(I) Catalysed Reactions: Anion Effects and Reaction Selectivity

“…reported a gold(I)‐catalysed hydroamination reaction of alkylidenecyclopropanes 13 (ACP) derivatives which resulted in the anti‐Markovnikov addition of imidazolidone 14 (Figure 17). [25] Couce‐Rios and co‐authors used DFT to explore the origins of the observed regioselectivity [26] …”