Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Enantioselective Radical Hydroacylation of Enals with α‑Ketoacids Enabled by Photoredox/Amine Cocatalysis Jia-Jia Zhao, Hong-Hao Zhang, Xu Shen, and Shouyun Yu* State Key Laboratory of Analytical Chemistry for Life Science, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
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S Supporting Information *
ABSTRACT: A photoredox/amine-cocatalyzed enantioselective radical hydroacylation of enals with α-ketoacids is described. Acyl radicals generated from α-ketoacids act as the acylation reagent with the iminium ions. This strategy provides an efficient way to access synthetically challenging 1,4-dicarbonyl compounds in an enantioselective manner. The reactions of various enals with α-ketoacids show the generality and limitations of this method.
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like to report another version of the enantioselective radical hydroacylation of enals with α-ketoacids enabled by photoredox/amine dual catalysis (Figure 1c).8,9 It is envisaged that photo-oxidation of an α-ketoacid with an excited photocatalyst delivers an acyl radical (I) together with a low valent photocatalyst.10 Simultaneously, condensation of an enal with an amine forms an iminium ion (II).11 The acyl radical (I) adds onto the iminium ion (II) to generate a radical intermediate (III), which undergoes reduction and hydrolysis to give the hydroacylation product (vide infra). Notably, the overall redox neutral process eradicates the use of sacrificed external reductants and there is no need for α-ketoacids to be preactivated. Enantioselectivity may be encouraged if an appropriate chiral amine is used. The reaction parameters of photoredox/amine-cocatalyzed radical hydroacylation were established using phenylglyoxylic acid (1a) and trans-cinnamaldehyde (2a) as the coupling partners. Chiral amines and photocatalysts were first investigated, and the representative results were shown in Table 1 (for the comprehensive condition optimization, see the Supporting Information (SI)). A mixture of phenylglyoxylic acid (1a) (1.5 equiv) and cinnamaldehyde (2a) (1 equiv) in acetonitrile was irradiated with white LED strips at 0 °C for 24 h in the presence of photocatalyst Ru(bpz)3(PF6)2 (I, 2 mol %) and a chiral amine (A1, 20 mol %),12 and radical hydroacylation product 3a could be isolated with 20% yield and 66% ee (entry 1). Chiral amine A213 gave improved results in terms of yield (55%) and enantioselectivity (74% ee) (entry 2) while chiral amines A314 (entry 3) and A415 (entry 4) were not suitable in this reaction. Several other photocatalysts, such
etones are one of the most important and synthetically valuable compounds, which serve as versatile building blocks for the synthesis of complex natural products and pharmaceuticals.1 The direct hydroacylation of alkenes and alkynes is one of the most straightforward approaches for the synthesis of ketones.2 Transition-metal-catalyzed hydroacylation with aldehydes predominates in this field.2a Major problems for these catalyst systems are an undesired decarbonylation and regioselectivity issue.3 Alternatively, the Stetter reaction catalyzed by a cyanide anion or N-heterocyclic carbenes (NHCs) provides a strategy for the synthesis of 1,4dicarbonyl compounds and related derivatives from aldehydes and Michael acceptors using an umpolung strategy.4 Despite these advances, the development of good complements to this classic ionic hydroacylation from readily available coupling partners, especially in an enantioselective manner, is highly desirable and valuable. The radical hydroacylation of alkenes with acid derivatives enabled by the state-of-the-art photoredox catalysis has recently emerged as a novel strategy for the synthesis of ketones (Figure 1a).5,6 Mechanistically, acids are activated as mixed hydrides or acyl chlorides, which are photochemically reduced to give acyl radicals. Trapping of acyl radicals with alkenes gives alkyl radicals, which are finally terminated with reductants to give the hydroacylation products. Gilmour and co-workers reported an EDA-mediated radical Stetter reaction of enals with α-ketoacids (top, Figure 1b).7a These elegant studies expanded the scope of hydroacylation of alkenes assisted by the single electron transfer process, but no enantioselectivity was observed. Enantioselective radical hydroacylation of alkenes remains a synthetic challenge. Melchiorre and co-workers reported a visible-light-mediated enatioselective acyl radical addition to enals with 4-acyl-1,4-dihydropyridines very recently (bottom, Figure 1b).7b Herein, we would © XXXX American Chemical Society
Received: December 1, 2018
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DOI: 10.1021/acs.orglett.8b03840 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Table 1. Optimization of Reaction Conditionsa
Figure 1. Photoredox-catalyzed hydroacylation of alkenes.
as iridium-based photocatalysts Ir(ppy)2(dtbbpy)PF6 (II) and Ir(dFCF3ppy)2(dtbbpy)PF6 (III) and organic dye fluorescein (IV), were examined (entries 5−7), but none of them proved to be superior to Ru(bpz)3(PF6)2 (I). The solvent effect was explored, and it was found that no other solvent was better than CH3CN (entries 8 and 9). Improved yield (90%) and enantioselectivity (80% ee) were observed when higher loadings of α-ketoacid (3 equiv) and photocatalyst (5 mol %) were employed at lower temperature (−20 °C) (entry 10). No reaction was observed without visible light irradiation (entry 11), and both the chiral amine and the Ru-based photocatalyst were necessary for this transformation (entries 12 and 13). We next investigated the generality and limitations of this enantioselective radical hydroacylation (Figure 2). A variety of α-ketoacids reacted with cinnamaldehyde (2a) under our established conditions, and the corresponding 1,4-dicarbonyl compounds 3a−3n were produced in moderated to good yields (44−99%) and good enantioselectivities (62−80% ee). Aromatic α-ketoacids with an electron-donating group, such as OMe (3b), an electron-neutral group, such as methyl group (3c), or electron-withdrawing groups, such as F (3d), at the para position, gave good yields of the respective products. Substituents at the meta (3e−3f) or ortho (3g−3i) position on the phenyl ring were well suited to this transformation, affording satisfactory yields (70−99%) of the corresponding products with good enantioselectivities (74−80% ee). Trisubstituted aromatic α-ketoacid was also compatible in this reaction and provided the product 3j in excellent yield (97%) and good enantioselectivity (74% ee). Thiophene-
entry
PC
amine
solvent
yield (%)b
ee (%)c
1 2 3 4 5 6 7 8 9 10d 11e 12 13
I I I I II III IV I I I I − I
A1 A2 A3 A4 A2 A2 A2 A2 A2 A2 A2 A2 −
CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH2Cl2 PhCF3 CH3CN CH3CN CH3CN CH3CN
20 55 20 13 N.R. 21 18 26 15 90 N.R. 13 trace
66 74 10 25 − 72 72 39 33 80 − 80 −
a
Reaction conditions: a mixture of 1a (0.15 mmol), 2a (0.1 mmol), amine (20 mol %), and photocatalyst (2 mol %) in the indicated solvent (1.0 mL) was irradiated by white LED strips for 24 h at 0 °C. b Isolated yield. cEnantiomeric excess (ee) values were determined by HPLC on a chiral stationary phase. dA solution of 1a (0.3 mmol), 2a (0.1 mmol), amine (20 mol %), and photocatalyst (5 mol %) in the indicated solvent (1.0 mL) was irradiated by white LED strips for 60 h at −20 °C. e In dark. TIPS = triisopropylsilyl; TDS = thexyldimethylsilyl.
derived ketoacid could also undergo this reaction, but with low efficiency (3k, 44% yield, 62% ee). Primary, secondary, and tertiary aliphatic α-ketoacids were also good coupling partners to give the corresponding products 3l−3n with similar reactivity (64−75% yields, and 70−80% ee). We next examined enal partners (Figure 2b). Cinnamaldehyde derivatives with substituents at different positions on the phenyl ring were well suited to this transformation, affording satisfactory yields of the corresponding products 3o−3u with 74−93% yields and 62−76% ee. Notably, the reaction could perform at the 2 mmol scale as demonstrated by the synthesis of 3f, which were isolated with 83% yield and 79% ee. B
DOI: 10.1021/acs.orglett.8b03840 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
Figure 2. Scope of enantioselective radical acylation of enals. Reaction parameters: a mixture of 1 (0.3 mmol), 2 (0.1 mmol), amine A2 (20 mol %), and photocatalyst I (5 mol %) in CH3CN (1.0 mL) was irradiated by white LED strips for 60 h at −20 °C. a 2 mmol scale.
Based on control experiments and literature precedents on photoredox/amine dual catalysis,9,11 a plausible reaction pathway is proposed (Figure 3). The excited Ru(II) complex (Ru(II)*) is reductively quenched by an α-ketoacid 1 leading to an acyl radical 410 together with CO2, a proton, and a Ru(I) complex, which was supported by the Stern−Volmer analysis (for details, see the SI). Meanwhile, an iminium ion 7 is
generated by the assistance of a proton from an enal 2 and an amine catalyst 6.11 The acyl radical 4 is then trapped by the iminium ion 7 to generate a radical species 8. This radical 8 is reduced by the Ru(I) complex to regenerate Ru(II) closing the photocatalytic cycle, delivering an enamine 5. Ultimately, tautomerization and hydrolysis of the enamine 5 produce the product 3, closing the amine catalytic cycle. The quantum yield of this reaction was determined to be 0.22 (for details, see the SI), which strongly suggests that this reaction proceeds through a photoredox pathway rather than a radical propagation. In conclusion, we have demonstrated an enantioselective radical hydroacylation of enals with α-ketoacids enabled by photoredox/amine dual catalysis. Acyl radicals generated from α-ketoacids act as the acylation reagent with the iminium ions. This strategy provides an efficient way to access 1,4-dicarbonyl compounds in an enantioselective manner and serves as an alternative and potential complement to the Stetter reaction. The reactions of various enals with α-ketoacids show the limitations and generality of this method. This dual photoredox/amine catalytic system will provide new opportunities for enantioselective radical additions, which is ongoing in our laboratory.
Figure 3. Proposed mechanism. C
DOI: 10.1021/acs.orglett.8b03840 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03840. Experimental details, NMR spectra, details of experiments (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Shouyun Yu: 0000-0003-4292-4714 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation of China (21672098 and 21732003) and the National Key Research and Development Program of China (2018YFC0310900) is acknowledged.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b03840 Org. Lett. XXXX, XXX, XXX−XXX
