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83230251.Pdf View metadata, citation and similar papers at core.ac.uk brought to you by CORE This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. provided by DSpace@MIT Article pubs.acs.org/JACS Mechanistic Studies Lead to Dramatically Improved Reaction Conditions for the Cu-Catalyzed Asymmetric Hydroamination of Olefins Jeffrey S. Bandar,† Michael T. Pirnot,† and Stephen L. Buchwald* Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States *S Supporting Information ABSTRACT: Enantioselective copper(I) hydride (CuH)- catalyzed hydroamination has undergone significant develop- ment over the past several years. To gain a general understanding of the factors governing these reactions, kinetic and spectroscopic studies were performed on the CuH- catalyzed hydroamination of styrene. Reaction profile analysis, rate order assessment, and Hammett studies indicate that the turnover-limiting step is regeneration of the CuH catalyst by reaction with a silane, with a phosphine-ligated copper(I) benzoate as the catalyst resting state. Spectroscopic, electrospray ionization mass spectrometry, and nonlinear effect studies are consistent with a monomeric active catalyst. With this insight, targeted reagent optimization led to the development of an optimized protocol with an operationally simple setup (ligated copper(II) precatalyst, open to air) and short reaction times (<30 min). This improved protocol is amenable to a diverse range of alkene and alkyne substrate classes. ■ INTRODUCTION Scheme 1. Proposed Catalytic Cycle for CuH-Catalyzed Due to their importance and ubiquity, significant efforts have Hydroamination of Styrene been made toward the construction of enantioenriched amines.1 Hydroamination, the formal addition of a nitrogen and hydrogen atom across a carbon−carbon π-bond, represents a particularly attractive and direct method for appending amino groups onto a molecule. Although significant progress has been achieved in this regard using late transition metal catalysis, a number of drawbacks have limited the utilization of these methodologies.2 In the context of intermolecular hydro- amination, these methods furnish products with moderate stereoselectivity and rely on the use of activated alkenes, such as vinyl arenes and acrylate derivatives, while unactivated alkenes typically fail to react. Similarly, lanthanide and early transition metal catalysts have shown promise as hydroamination systems although further developments are needed to address the generally limited substrate scope.3 The development of a general approach for regio- and enantioselective hydro- amination of a broad range of alkene classes remains an important challenge.4 In 2013, Miura’s5 and our lab6 disclosed contemporaneous reports describing a new method of styrene hydroamination that involves a copper(I) hydride (CuH) catalyst and amine electrophiles to generate α-chiral amines in excellent yields and enantioselectivities. Since then, CuH- * catalyzed hydroamination has been extended to a wide scope of into L CuH 1 presumably forms copper(I) alkyl species 2. substrate classes, including vinyl silanes, terminal alkenes, Interception of 2 by amine electrophile 3 generates chiral amine 4 and phosphine-ligated copper(I) benzoate (L*CuOBz, 5). internal unactivated alkenes, alkynes, and strained cyclic * * alkenes.7,8 Regeneration of L CuH 1 from L CuOBz complex 5 closes A general catalytic cycle for the hydroamination of styrene is the catalytic cycle. shown in Scheme 1. Formation of the phosphine-ligated CuH catalyst (L*CuH, 1) occurs from the combination of Received: September 29, 2015 fi Cu(OAc)2, a phosphine ligand, and silane. Ole n insertion Published: November 1, 2015 © 2015 American Chemical Society 14812 DOI: 10.1021/jacs.5b10219 J. Am. Chem. Soc. 2015, 137, 14812−14818 Journal of the American Chemical Society Article Given that this CuH-catalyzed hydroamination strategy has (Scheme 3). Corroborating our full kinetic analysis, initial- undergone rapid development in terms of substrate scope, we rate kinetics demonstrated that the reaction was zero-order in felt a general understanding and improvement of these processes would be welcomed. In particular, identification of Scheme 3. Model System Used for Initial-Rate Kinetics a the turnover-limiting step and resting state of the copper Determined by GC Analysis and the Observed Rate Orders catalyst might provide a foundation for the development of a more efficient and practical protocol. Herein, we report detailed kinetic and spectroscopic studies of the CuH-catalyzed hydroamination of styrene. These studies have provided evidence that the phosphine-ligated CuOBz complex 5 is the resting state of the catalyst and the turnover-limiting step a entails regeneration of the CuH catalyst via its reaction with a L = DTBM-SEGPHOS. silane reagent. Through this mechanistic insight, rational optimization of several parameters has led to short reaction styrene and amine electrophile 3 across a range of times (<30 min) and operational simplicity (simple copper(II) concentrations for each component. In addition, a clear first- fi precatalyst and open to air) for an array of ole n and alkyne order dependence was observed for diethoxymethylsilane fi substrates. Similarly, a separate modi ed protocol is amenable (DEMS) and an apparent fractional-order11 was observed to the use of low loadings of the chiral ligand (0.1−0.2 mol %). while simultaneously changing the concentration of Cu(OAc)2 This is important as it is the most expensive component of this and DTBM-SEGPHOS. catalyst system. Hammett studies were conducted to determine the impact that electronic variation of the styrene and the amine ■ RESULTS AND DISCUSSION electrophile components had on the rate of hydroamination.12 Mechanistic Studies of the CuH-Catalyzed Hydro- In the first Hammett study, a series of para-substituted styrenes amination of Styrene. The hydroamination of styrenes was reacted with amine electrophile 3 at similar rates (Scheme 4a), chosen as the model system for our detailed kinetic studies. To implying that the olefin is most likely not involved in the begin, the reaction profile for the hydroamination of 4- turnover-limiting step of this process. A second Hammett study fluorostyrene was studied. In our initial report, we detailed a showed that electronic variation of the amine electrophile had a reaction time of 36 h to give the desired product in 86% yield significant impact on the rate of styrene hydroamination 6 19 σ and 97% ee. Using in situ F NMR spectroscopy, the reaction, (Scheme 4b). A linear correlation was observed with para under the previously reported conditions, was found to be Hammett constants (ρ = −0.71, R2 = 0.97) indicating more complete in approximately 9 h. Moreover, the process appeared electron rich amine-O-benzoates led to increased reaction 9 to be overall zero-order in substrate (Scheme 2). Same-excess rates.13 The observations described above suggested that regener- Scheme 2. Reaction Progress Monitored by in Situ 19F ation of the CuH catalyst 1 from the presumed ligated CuOBz a NMR complex 5 and silane is the turnover-limiting step of the CuH- catalyzed hydroamination process (Scheme 1).14 This inter- pretation is supported by (a) the zero-order dependence on styrene and amine electrophile; (b) the first-order dependence on the silane, DEMS; and (c) the linear free energy relationship between the Hammett electronic parameter of the amine electrophile benzoate and the initial rate. The enhanced initial rates observed with more electron-rich benzoates is consistent with a faster transmetalation of phosphine-ligated CuOBz complex 5 with silane. Interestingly, independent initial-rate measurements collected with diphenylsilane and deutero- diphenylsilane (Ph2SiD2) of the model reaction did not show ff ± a measurable kinetic isotope e ect (KIE) (kH/kD= 1.06 0.10).15 The fractional order dependence observed while manipulat- ing [Cu(OAc)2] and [DTBM-SEGPHOS] inspired a closer examination of the active catalytic species. A series of studies were employed to investigate the possible nature of the copper catalyst in the CuH-catalyzed hydroamination of styrene. a fl L = DTBM-SEGPHOS; 1 equiv of 1- uoronaphthalene added as Historically, CuH complexes with sterically unencumbered internal standard. ligands have been isolated as higher-order species and − aggregates.16 19 Our initial 31P NMR studies on the CuH 10 experiments were also conducted and displayed a similar catalyst solution (Cu(OAc)2,(S)-DTBM-SEGPHOS, and reaction profile, indicating that catalyst deactivation and DEMS in THF)20 did not allow identification of a distinct product inhibition were not significant in this system (see CuH species. However, the major new species observed in the Supporting Information for details). spectrum does have a similar 31P NMR shift and peak shape Initial rate experiments were next performed with styrene attributed to phosphine-ligated CuH clusters reported in the and amine electrophile 3 to gather more detailed information literature.21 When this CuH solution was subjected to the about the catalytic cycle of this hydroamination process model hydroamination reaction, 31P NMR showed that a new 14813 DOI: 10.1021/jacs.5b10219 J. Am. Chem. Soc. 2015, 137, 14812−14818 Journal of the American Chemical Society Article Scheme 4. (a) Hammett Study with Para-Substituted an active catalyst being of
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