A Highly Enantioselective Zirconium Catalyst for Intramolecular Alkene Hydroamination: Significant Isotope Effects on Rate and Stereoselectivity

Abstract

Asymmetric olefin hydroamination/cyclization is a promising method for the synthesis of optically active cyclic amines.[1] To date, the most selective catalysts are C 2 -symmetric rare earth and zirconium complexes. [2,3] These C 2 -symmetric catalysts contrast with seminal C 1 -symmetric ansa-lanthanidocenes that epimerize under catalytic conditions.[4] Despite advances, current asymmetric hydroamination/cyclization catalysts are highly sensitive to substrate substitution patterns.Two distinct pathways have been proposed for C À N bond formation in zirconium-catalyzed processes:[1b] olefin insertion into a M À NR 2 bond (Scheme 1, Mechanism A)[5] and aabstraction followed by [2p + 2p] cycloaddition (Mechanism B). [3,6] These two pathways can be difficult to distinguish because of conflicting observations, including large deuterium isotope effects and first-or second-order rate laws.Our research group has recently described an achiral catalyst [{PhB(C 5 H 4 )(Ox Me 2 ) 2 }Zr(NMe 2 ) 2 ] (1; Ox Me 2 = 4,4-dimethyl-2-oxazolinyl) that cyclizes aminoalkene compounds at room temperature. [7] This unusually high activity motivated the preparation of optically active oxazolinylborate analogues that might provide highly reactive, robust, and non-epimerizable complexes. Herein, we report a chiral catalyst that provides pyrrolidine derivatives with excellent enantiopurity. Our data, including a unique deuterium isotope effect on enantioselectivity, unambiguously rules out both pathways of Scheme 1.Precatalyst preparation is outlined in Equations (1) and (2).[8] Deprotonation of the oxazoline substrate 2 H-Ox iPr,Me 2 by nBuLi and subsequent treatment with 0.5 equivalents of PhBCl 2 provided chiral borane 2.[9] A crude sample of 2 was then treated with NaC 5 H 5 in THF and gave 3-H 2 as a mixture of C 5 H 5 isomers; one isomer is shown in Equation (1) A catalytic amount of 4 (2-10 mol %) and primary aminoalkenes 5 a-9 a rapidly yielded pyrrolidines 5 b-9 b with enantiomeric excesses ranging from 89 % to 98 % (see Table 1). Although the reaction rate is sensitive to catalyst and substrate concentration, the enantioselectivity is not. The catalyst can be recycled once without loss of activity or enantioselectivity. The secondary aminoalkene 5 a-NMe was not cyclized by 4, even upon heating for 12 hours at 80, 120, 140, or 170 8C. However, upon addition of nPrNH 2 , 20% conversion into 5 b was observed at room temperature.Significantly, the ee values obtained with 4 as the catalyst are the highest to date for unprotected pyrrolidines 5 b, 6 b,

Iridium-Catalyzed, Intermolecular Hydroetherification of Unactivated Aliphatic Alkenes with Phenols

“…In addition, Sadow and co-workers reported that zirconium [69] and yttrium [70] complexes coordinated by similar ligand frameworks catalyze hydroamination, and the mechanistic data in this study imply that these reactions occur through the same six-membered transition state as that proposed for reactions of the alkaline earth systems. Sub- sequently, Schafer and co-workers proposed a similar transition state for the hydroamination of primary and secondary aminoalkenes catalyzed by zirconium complexes ligated by a tethered bis(ureate).…”

Transition‐Metal‐Catalyzed Hydroamination Reactions

“…Stoichiometric experiments also helped to clarify the preferred seven-coordinate environment of this sterically accessible precatalyst. A recently disclosed mechanistic proposal from Sadow and coworkers [63] showed that H (or D) transfer is required to assist with a turnover-limiting ring closure step (Scheme 15.11 and Scheme 15.12). This alternative mechanistic profile, called proton-assisted C-N bond formation, has been further investigated computationally, and important insights into this cooperative mechanistic profile have been obtained independently by Tobisch [36].…”

“…These previous reports illustrate the challenge of designing selective and well-defined asymmetric catalysts for this reaction. While most of these contributions have been reviewed recently [72], the most significant recent contribution is from the Sadow laboratories whereby a chiral zwitterionic Zr complex can achieve enantiomeric excesses up to 98%, the highest reported to date, and furthermore, enantiomeric excesses in the 90% range and above are achieved for most disubstituted substrates leading to pyrrolidine products (Table 15.10) [63]. Impressively, these results are attained in a timely manner (<8 h) at room temperature giving excellent yields.…”

“…This focused topic has been comprehensively reviewed by Hultzsch [280] and is briefly summarized in the comprehensive review of 2008 [10]. Most published contributions have focused on the use of rare earth and early transition metal (Section 15.2.5) catalysts and indeed these have been some of the most successful examples reported to date [43,63,64,66,67,[74][75][76][77][78][79][80][81][82][83][84][85][281][282][283][284][285][286][287][288], likely because of the clear mechanistic requirement of a reactive M-N bond (single or double, depending on the mechanistic proposal) in the catalytic cycle. In late transition metals, where many reactions have been shown to proceed via outer-sphere amine addition to coordinated alkene, it is challenging to control such additions distal to the metal.…”

Fluorocarbon compatibilized gold-silica nanocomposites for recyclable regioselective hydroamination of alkynes in a fluorous biphasic system

“…For asymmetric hydroamination reactions, their main catalytic pathways can be attributed to a variety of metals [16], bases [17] and Bronsted acids [18]. Late transition metals (Ir, Pd, Au, Rh) are highly attractive and desirable for asymmetric hyroaminations due to higher functional group tolerance for both inert-and intramolecular variants, lowest air and moisture sensitivity and provide higher enantioselectivities [19].…”