Letter pubs.acs.org/OrgLett
Chiral-at-Metal Rh(III) Complex-Catalyzed Decarboxylative Michael Addition of β‑Keto Acids with α,β-Unsaturated 2‑Acyl Imidazoles or Pyridine Shi-Wu Li, Jun Gong, and Qiang Kang* Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou 350002, China S Supporting Information *
ABSTRACT: A newly prepared chiral-at-metal Rh(III) complex-catalyzed, highly efficient enantioselective decarboxylative Michael addition of β-keto acids with α,β-unsaturated 2acyl imidazoles or pyridine has been developed, affording the corresponding adducts in 94−98% yield with up to 96% enantioselectivity. This protocol exhibits remarkable reactivity, as the complex with a Rh(III) loading as low as 0.05 mol % can catalyze the decarboxylative Michael addition on a gram scale without loss of enantioselectivity.
T
he asymmetric decarboxylative addition reaction1 is one of the most important and powerful methods to achieve enantioenriched building blocks and key frameworks of natural products via C−C bond formation. β-Keto acids as surrogates of ketones are good nucleophilic candidates for the formation of ketone enolate equivalents under mild reaction conditions. Consequently, considerable attention has been given to the development of catalytic asymmetric decarboxylative reactions of β-keto acids or malonic acid half-thioesters (MAHTs) with various electrophiles2 such as nitroalkenes,3 carbonyl compounds,4 alkyl halides,5 and imines.6 A variety of organocatalysts have been developed for highly enantioselective decarboxylative addition reactions in recent years. For instance, Lubkoll and Wennemers7 realized the first examples of enantioselective MAHT addition reactions with nitroolefins, catalyzed by cinchona alkaloid derivatives. However, the use of chiral Lewis acid complexes for decarboxylative addition,8 especially for decarboxylative Michael addition of β-carbonyl acids with electron-deficient alkenes, has been quite limited.9,10 In 2007, the Evans group reported the first elegant work of enantioselective decarboxylative Michael reaction of β-keto acids with nitroalkenes catalyzed by Ni(II)−diamine complexes (Scheme 1a).9 Later, Shibasaki, Matsunaga and co-workers realized the asymmetric decarboxylative 1,4-addition reaction of MAHTs with nitroalkenes catalyzed by a heterobimetallic Ni/ La−salan complex (Scheme 1b).10 Despite these impressive achievements, the development of efficient and highly enantioselective protocols for decarboxylative addition is still in great demand to overcome problems such as high catalyst loading (usually 10−20 mol %), long reaction time, and relatively narrow substrate scope. Recently, the Meggers group designed and synthesized a novel class of Lewis acid catalysts named chiral-at-metal complexes,11 in which the metal center serves not only as a © XXXX American Chemical Society
Scheme 1. Enantioselective Decarboxylative Michael Additions Catalyzed by Chiral Lewis Acid Complexes
Lewis acid but also as the exclusive source of chirality.12 The high configurational inertness of these complexes results in high catalytic efficiency and enantioselectivity.13 A number of elegant transformations have been successfully achieved with relatively lower catalyst loadings.14,15 As a continuation of our interest in the development of chiral-at-metal Rh(III) complexes in catalytic asymmetric reactions,16 here we report an enantioselective decarboxylative addition of β-keto acids with α,βunsaturated 2-acyl imidazoles17 or pyridine catalyzed by chiralat-metal Rh(III) complexes (Scheme 1c). Received: January 21, 2017
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DOI: 10.1021/acs.orglett.7b00220 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 2. Substrate Scope: β-Keto Acids 1a
We commenced our studies by testing the reaction between commercially available β-keto acid 1a and α,β-unsaturated 2acyl imidazole 2a in the presence of 2 mol % chiral-at-metal Rh(III) complex Λ-Rh115a in THF at 32 °C. To our delight, the decarboxylative Michael addition product 3a was obtained in 94% yield with 86% ee (Table 1, entry 1). Encouraged by Table 1. Optimization of the Reaction Conditionsa
entry 1 2 3 4 5 6d 7
Λ-Rh (x) Λ-Rh1 Λ-Rh2 Λ-Rh3 Λ-Rh4 − Λ-Rh4 Λ-Rh4
(2) (2) (2) (2) (2) (1)
solvent
time (h)
yield (%)
THF THF THF THF THF THF THF
7 13 12 6 24 5 8
94 96 86 98 − 96 97
b
ee (%)
a Reaction conditions: 0.24 mmol of 1, 0.2 mmol of 2a, and 1 mol % Λ-Rh4 in THF (0.05 M) at 32 °C under an argon atmosphere. Yields of isolated products 3 are shown. Enantiomeric excesses were determined via HPLC analysis on a chiral stationary phase.
c
86 82 90 93 − 92 93
Notably, an alkyl-substituted β-keto acid exhibited good reactivity in the title reaction, delivering the decarboxylative Michael addition product 3k in 98% yield with 96% ee. Further investigation of the substrate scope of α,βunsaturated 2-acyl imidazoles and pyridine was carried out (Scheme 3). The introduction of electron-donating and electron-withdrawing groups on the phenyl ring of α,βunsaturated 2-acyl imidazoles had little influence on the enantioselectivity. The desired products 4a−f were obtained in high yields (94−98%) with excellent enantioselectivies (95− 96%). The Michael acceptor substrates with 1-naphthyl or
a Reaction conditions: 1a (0.12 mmol), 2a (0.1 mmol), and Λ-Rh (2 mol %) in the solvent (2 mL) at 32 °C under an argon atmosphere. b Isolated yields. cDetermined by chiral HPLC analysis. d0.5 mL of THF was employed.
these promising results, we synthesized and examined the chiral Rh(III) complexes Λ-Rh2,15e Λ-Rh3,16b and Λ-Rh4 in the title reaction (entries 2−4). The newly prepared catalyst Λ-Rh418 was the superior one in terms of reactivity and enantioselectivity, giving the desired product in 98% yield with 93% ee (entry 4), which might be attributed to the sterically bulky substitution on the cyclometalated phenyl moiety. In the absence of catalyst, the reaction did not afford any product. Further screening of solvents revealed that THF gave the best yield and enantioselectivity (for details, see the Supporting Information). Furthermore, increasing the concentration of the reaction had no influence on the outcome of the reaction (entry 6). Further decreasing the catalyst loading to 1 mol % under similar reaction conditions still afforded 3a in 97% yield with 93% ee (entry 7). With the optimized reaction conditions in hand (Table 1, entry 7), different β-keto acids were employed to test the generality of this asymmetric decarboxylative Michael addition process (Scheme 2). First, β-keto acids with electron-withdrawing substituted phenyl ring were evaluated, and in all cases (3b−e), high yields (95−98%) with excellent enantioselectivities (90−94%) were achieved. However, a β-keto acid bearing a strong electron-withdrawing substituent (NO2) could not afford the desired product 3f. β-Keto acids with electrondonating substituents such as 4-Me, 4-OMe, and 3,4-(OMe)2 worked smoothly to afford the corresponding adducts (3g−i) in excellent yields and enantioselectivities. A 2-thienylsubstituted β-keto acid was tolerated under the optimal reaction conditions to afford 3j in 98% yield with 96% ee.
Scheme 3. Substrate Scope: α,β-Unsaturated 2-Acyl Imidazoles 2a
Reaction conditions: 0.24 mmol of 1j, 0.2 mmol of 2, and 1 mol % ΛRh4 in THF (0.05 M) at 32 °C under an argon atmosphere. Yields of isolated products 4 are shown. Enantiomeric excesses were determined via HPLC analysis on a chiral stationary phase. a
B
DOI: 10.1021/acs.orglett.7b00220 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters heteroaromatic substituents worked well, affording 4g−i in 94− 97% yield with 93−96% ee. Methyl, ethyl, and styrylsubstituted α,β-unsaturated 2-acyl imidazoles were also tolerated well, yielding the corresponding products (4j−l) in excellent yields (96−98%) with good to excellent enantioselectivies (88−94%). Moreover, replacing the N-methyl group of the α,β-unsaturated 2-acyl imidazole with an N-isopropyl or Nphenyl group had no significant influence on the reactivity and enantioselectivity. Finally, when 2-pyridyl was used in place of the N-methylimidazole, the desired product 4o was obtained in 95% yield with 92% ee.19 The absolute configuration of product 4a was assigned as S by single-crystal X-ray analysis (for details, see the Supporting Information).18 To demonstrate the practicality of this protocol, a gram-scale reaction of α,β-unsaturated 2-acyl imidazole 2d (1.2 g/4.14 mmol) with β-keto acid 1j (0.85 g/5 mmol) was conducted in the presence of 0.1 mol % Λ-Rh4. Gratifyingly, the reaction proceeded smoothly to afford 4a in 98% yield with 96% ee. Remarkably, when a loading of Λ-Rh4 as low as 0.05 mol % (2.0 mg) was employed, the reaction of 2d on a 4.14 mmol scale (1.2 g) with 1j (3.0 equiv) could be completed in 72 h, delivering the desired product 4a in 93% yield (1860 catalyst turnovers) without loss of enantioselectivity (96% ee) (Scheme 4, eq 1). In addition, the imidazole moiety of the products
Rh(III) complex through bidentate N,O-coordination to form intermediate B. β-Keto acid 1a then attacks intermediate B from the Re face to afford intermediate C in a fashion stereochemically controlled by the chiral Rh(III) complex. Next, intermediate D is generated from intermediate C through decarboxylation with release of CO2. The desired product 3a is released from intermediate D by ligand exchange with 1a, and a new catalytic cycle is initiated. In summary, we have synthesized a new chiral-at-metal Rh(III) complex (Λ-Rh4) to promote a highly efficient asymmetric decarboxylative Michael addition of β-keto acids with α,β-unsaturated 2-acyl imidazoles or pyridine. The corresponding adducts were obtained in good yields (94− 98%) with excellent enantioselectivities (88−96%). Remarkably, this protocol exhibits extraordinary advantages in terms of reactivity and enantioselectivity, given the fact that a loading of Λ-Rh4 as low as 0.05 mol % can catalyze the title reaction on a gram scale without loss of enantioselectivity. Further research on the development of new types of chiral-at-metal Rh(III) complexes and their application in asymmetric reactions are ongoing in our laboratory.
Scheme 4. Gram-Scale Experiments and Synthetic Transformation of Product 4a
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00220. X-ray data for compound 4a, experimental procedures, characterization data, and copies of 1H and 13C NMR spectra and HPLC chromatograms for the obtained compounds (PDF)
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ASSOCIATED CONTENT
S Supporting Information *
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Qiang Kang: 0000-0002-9939-0875 Notes
could be easily transferred to other functional groups. For example, the removal of the imidazole moiety of 4a worked smoothly, affording ester 5 in 90% yield without loss of enantiomeric excess (96% ee) (Scheme 4, eq 2). The proposed mechanism for this reaction is shown in Figure 1. The 2-acyl imidazole substrate 2a is activated by the chiral
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Prof. Daqiang Yuan (Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences) for his kind help with X-ray analysis. This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant XDB20000000) and the 100 Talents Program of the Chinese Academy of Sciences.
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REFERENCES
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Figure 1. Proposed mechanism and transition-state model. C
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Organic Letters
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