Article Cite This: J. Org. Chem. 2018, 83, 10922−10932
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Visible-Light-Activated Catalytic Enantioselective β‑Alkylation of α,β-Unsaturated 2‑Acyl Imidazoles Using Hantzsch Esters as Radical Reservoirs Francisco F. de Assis,†,‡ Xiaoqiang Huang,‡ Midori Akiyama,§ Ronaldo A. Pilli,† and Eric Meggers*,‡ †
Instituto de Química, Universidade Estadual de Campinas, Campinas, Sao Paulo 13084-971, Brazil Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse 4, 35043 Marburg, Germany § Department of Chemistry & Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan Downloaded via SAN FRANCISCO STATE UNIV on September 21, 2018 at 11:05:50 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
‡
S Supporting Information *
ABSTRACT: An efficient and practical method for the enantioselective β-functionalization of α,β-unsaturated 2-acyl imidazoles is described. The method uses a previously devised chiral-at-metal rhodium catalyst (Λ-RhS, 4 mol %) along with Hantzsch ester derivatives as alkyl radical sources. The rhodium complex exerts a dual role as the visible-light-absorbing unit upon substrate binding and as the asymmetric catalyst. The method provides up to quantitative yields with excellent enantioselectivities up to 98% ee and can be classified as a redox-neutral, electron-transfer-catalyzed reaction.
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INTRODUCTION The addition of alkyl radicals to acceptor-substituted alkenes under formation of a new C−C bond (Giese reaction) constitutes one of the most established radical reactions.1 Sibi and Porter were the first to introduce chiral Lewis acids to perform such reactions in a catalytic enantioselective fashion.2 However, the prevailing uncatalyzed background chemistry required typically very high catalyst loadings. Recently, photoredox catalysis 3,4 has been applied to catalytic enantioselective Giese reactions. In 2015, Yoon reported the conjugate addition of α-aminoalkyl radicals to α,β-unsaturated pyrazolidinones under photoredox conditions, reaching enantioselectivitites of up to 96% ee (Figure 1a).5 The dualcatalysis strategy uses [Ru(bpy)3]Cl2 as the photoredox catalyst to convert α-silylalkyl anilines into free radicals, while a Sc(III)/Pybox complex serves as the chiral Lewis acid to catalyze the radical conjugate addition and to provide the asymmetric induction. However, high loadings of the Sc(III)based Lewis acid are required, and the method is limited to αsilylalkyl anilines as radical precursors. Our group reported a more practical catalytic enantioselective Giese reaction. Organotrifluoroborates are converted to alkyl radicals under photoredox conditions, and a bis-cyclometalated rhodium © 2018 American Chemical Society
complex serves as a very efficient chiral Lewis acid to catalyze the enantioselective radical addition to α,β-unsaturated 2-acyl imidazoles or α,β-unsaturated N-acyl pyrazoles (Figure 1b).6,7 Intriguingly, at Lewis-acid catalyst loadings of just 4 mol %, up to 99% ee can be observed. However, two catalysts are required: a photoredox catalyst for the oxidative generation of the intermediate alkyl radicals and the chiral Lewis acid catalyst. In contrast, Kang recently devised a catalytic enantioselective Giese reaction under photoredox conditions for which just a single chiral rhodium catalyst is required.8 Although the results are very impressive with respect to low catalyst loadings and the obtained enantioselectivities, the system is limited to N-aryl tetrahydroisoquinolines as radical precursors (Figure 1c). Thus, despite the described progress, more general and more practical catalytic enantioselective Giese reactions are highly desirable. Recently, 4-alkyl-substituted Hantzsch ester (HE) derivatives have emerged as easily available, mild, and general reservoirs of alkyl radicals in photoredox reactions.9 Upon single-electron oxidation, the C−C bond to the alkyl group in Received: June 25, 2018 Published: July 20, 2018 10922
DOI: 10.1021/acs.joc.8b01588 J. Org. Chem. 2018, 83, 10922−10932
Article
The Journal of Organic Chemistry
Figure 1. Chiral Lewis-acid-catalyzed asymmetric radical conjugate additions reported by Yoon, Meggers, Kang, and the work presented in this study.
formation involving alkyl radicals generated from HEs such as radical additions to styrenes and acceptor-substituted olefins was recently reported by Cheng.14 With respect to applying 4alkyl HEs as radical precursors in asymmetric catalysis, we are only aware of a single study by Melchiorre on the asymmetric photoredox-mediated alkylation of aromatic enals.15 In this work, we report a robust and practical catalytic asymmetric Giese reaction that combines rhodium-based chiral Lewis acid catalysis with Hantzsch ester derivatives as convenient radical precursors (Figure 1d). Interestingly, no additional photoredox catalyst is required for this reaction, which allows functionalization of α,β-unsaturated 2-acyl imidazoles in the β position with a variety of alkyl groups.
the 4 position is cleaved homolytically to generate free alkyl radicals. The growing interest in these compounds can be traced back to their well-accessible oxidation potentials, their straightforward preparation from inexpensive starting materials, and a broad scope as precursors for a range of alkyl radicals. Cheng and Ma reported the use of 4-alkyl HEs as alkyl radical precursors under photoredox conditions in the synthesis of congested ketones containing all-carbon quaternary centers.10 Nishibayashi11 and independently Molander12 reported the combination of photoredox catalysis and nickel catalysis in the coupling of aryl halides or carboxylic acids with alkyl radicals generated from 4-alkyl HE derivatives. HE derivatives were also used as alkyl radical precursors in the radical alkylation of imines, as described by Yu.13 Another interesting trans10923
DOI: 10.1021/acs.joc.8b01588 J. Org. Chem. 2018, 83, 10922−10932
Article
The Journal of Organic Chemistry Table 1. Optimization of a Single Catalyst Systema
entry
subst.
catalyst
light
solvent
HE equiv
conc. (M)b
yield (%)c
ee (%)d
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19f
1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1a 1a 1b 1a 1b 1b
Λ-RhS (8 mol %) Λ-RhS (8 mol %) Λ-RhS (8 mol %) Λ-RhS (8 mol %) Δ-RhO (8 mol %) Δ-RhO (8 mol %) Λ-RhS (4 mol %) Λ-RhS (4 mol %) Λ-RhS (4 mol %) Λ-RhS (4 mol %) Λ-RhS (4 mol %) Λ-RhS (4 mol %) Λ-RhS (4 mol %) Λ-RhS (4 mol %) Λ-RhS (4 mol %) Λ-RhS (4 mol %) Λ-RhS (4 mol %) Λ-RhS (4 mol %) none
CFL CFL blue LEDs blue LEDs blue LEDs blue LEDs CFL CFL CFL CFL CFL CFL CFL CFL CFL CFL CFL CFL CFL
acetone acetone acetone acetone acetone acetone acetone acetone acetone acetone acetone acetone THF DMF CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 2.0 2.0 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2
0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.1 0.1 0.1
32 79 35 75 35 38 34 76 32 76 38 77
