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. 2015 Nov 25;137(46):14812-8.
doi: 10.1021/jacs.5b10219. Epub 2015 Nov 13.

Mechanistic Studies Lead to Dramatically Improved Reaction Conditions for the Cu-Catalyzed Asymmetric Hydroamination of Olefins

Jeffrey S Bandar  1 , Michael T Pirnot  1 , Stephen L Buchwald  1
Affiliations

Mechanistic Studies Lead to Dramatically Improved Reaction Conditions for the Cu-Catalyzed Asymmetric Hydroamination of Olefins

Jeffrey S Bandar et al. J Am Chem Soc. .

Abstract

Enantioselective copper(I) hydride (CuH)-catalyzed hydroamination has undergone significant development 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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Proposed Catalytic Cycle for CuH-Catalyzed Hydroamination of Styrene
Scheme 2
Scheme 2. Reaction Progress Monitored by in Situ 19F NMR
L = DTBM-SEGPHOS; 1 equiv of 1-fluoronaphthalene added as internal standard.
Scheme 3
Scheme 3. Model System Used for Initial-Rate Kinetics Determined by GC Analysis and the Observed Rate Orders
L = DTBM-SEGPHOS.
Scheme 4
Scheme 4. (a) Hammett Study with Para-Substituted Styrenes; (b) Hammett Study with Para-Substituted Amine-O-benzoates
Each data point is the average of two experiments with standard deviations included as error bars; L = DTBM-SEGPHOS.
Scheme 5
Scheme 5. Nonlinear Effect Study on the Enantiomeric Composition of DTBM-SEGPHOS and Amine Product 4
Scheme 6
Scheme 6. Hammett Plot for the Enantiomeric Ratio of Hydroamination Products Using Para-Substituted Styrenes
er = enantiomeric ratio; L = DTBM-SEGPHOS.
Scheme 7
Scheme 7. Hydroamination of Styrene-α,β,β-d3 (6) under Standard Reaction Conditions
Reaction monitored by 1H NMR spectroscopy. L = DTBM-SEGPHOS.
Scheme 8
Scheme 8. Effect of Amine Electrophile on Initial-Rate Kinetics
L = DTBM-SEGPHOS.
Scheme 9
Scheme 9. Modified Catalytic Cycle for the CuH-Catalyzed Hydroamination of Styrene
See this image and copyright information in PMC

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