Perfluoroalkylation of β-Ketoesters Enabled by

Letter Cite This: Org. Lett. 2018, 20, 461−464

pubs.acs.org/OrgLett

Enantioselective Di-/Perfluoroalkylation of β‑Ketoesters Enabled by Cooperative Photoredox/Nickel Catalysis Jing Liu,†,§ Wei Ding,†,§ Quan-Quan Zhou,† Dan Liu,† Liang-Qiu Lu,*,† and Wen-Jing Xiao*,†,‡ †

Hubei International Scientific and Technological Cooperation Base of Pesticide and Green Synthesis, Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, P. R. China ‡ State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China S Supporting Information *

ABSTRACT: Efficient and enantioselective radical difluoroalkylation and perfluoroalkylation reactions of β-ketoesters were successfully developed through an asymmetric photoredox and nickel catalysis cascade. This protocol provides Rf-containing quaternary stereocenters in up to 67% yield and 95:5 er with ethyl iododifluoroacetate and perfluoroalkyl iodides (C3F7I and C4F9I) as radical sources under extremely mild conditions.

F

selective, efficient, and sustainable way.6 In particular, this strategy has been well developed for asymmetric fluoroalkylations.7 In 2009, the Macmillan group first described an asymmetric α-trifluoromethylation of aldehydes by merging enamine catalysis and photoredox catalysis.4g Different from this dual catalysis strategy, the Gade group in 2012 reported an enantioselective trifluoromethylation of cyclic β-ketoesters masterly through a single asymmetric Cu catalysis.4d Recently, Melchiorre and co-workers disclosed the strategy of electron donor−acceptor EDA complex activation for the enantioselective perfluoroalkylation of β-ketoesters.4h Soon after, Meggers and co-workers elegantly used their unique chiral iridium complex as efficient bifunctional photocatalysts to achieve enantioselective radical perfluoroalkylations of 2-acyl imidazoles.4i To our surprise, although many difluoroalkylation reactions with photogenerated CF2 radicals have been reported,8 enantioselective difluoroalkylation processes remain largely unexplored. Very recently, our group demonstrated that a chiral nickel complex with a difunctionalized chiral bisoxazoline ligand can successfully catalyze the asymmetric aerobic oxidation of β-ketoesters.9 As a continuation of our work in the field of organic photochemical synthesis,10 we herein describe a visible light-driven enantioselective difluoroalkylation of βketoesters. Initially, we investigated this reaction with 1-adamantyl ester 1a and ethyl bromodifluoroacetate 2a as the model substrates using Ir[dF(CF3)ppy]2(dtbbpy)PF6 as the photocatalyst under the irradiation of 7 W blue LEDs. As illustrated in entry 1 in Table 1, preliminary studies showed that Ni(acac)2 and chiral ligand L1 gave the difluoroalkylation product in modest yield

luorine-containing compounds usually play unique roles in agrochemicals, pharmaceuticals, and functional materials.1 It is well established that the introduction of fluorine atoms into organic molecules can significantly improve the physical and chemical properties of the compounds. In this context, chiral fluorine-containing biologically active compounds have attracted considerable interest due to their superior lipophilicity, bioavailability, and metabolic stability in Figure 1.2 Thus, a

Figure 1. Compounds of medicinal interest containing C−F, C− CF2R, and C−CF3 at stereocenters.

number of efficient methods have been developed to prepare chiral organic fluorine-containing molecules. However, in contrast to the elegant advances of enantioselective fluorination,3 trifluoroalkylation, and perfluoroalkylation,4 the analogous difluoroalkylations have been less explored.5 In recent years, visible light driven asymmetric catalysis has had a substantial impact on synthetic chemistry in a highly © 2018 American Chemical Society

Received: December 7, 2017 Published: January 9, 2018 461

DOI: 10.1021/acs.orglett.7b03826 Org. Lett. 2018, 20, 461−464

Letter

Organic Letters Table 1. Optimization of Conditionsa

Scheme 1. Substrate Scope of β-Ketoestersa,b,c

entry

Lewis acid

solvent

ligand

yieldb (%)

erc

1 2 3 4 5 6 7 8 9 10 11 12 13d 14d,e 15d,e,f 16d,e,g

Ni(acac)2 Cu(acac)2 Zn(acac)2 Ni(OTf)2 Ni(ClO4)2 NiBr2·glyme NiBr2·glyme NiBr2·glyme NiBr2·glyme NiBr2·glyme NiBr2·glyme NiBr2·glyme NiBr2·glyme NiBr2·glyme NiBr2·glyme NiBr2·glyme

1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane DME CH2Cl2 toluene DME DME DME DME DME DME DME

L1 L1 L1 L1 L1 L1 L1 L1 L1 L2 L3 L4 L1 L1 L1 L1

48 trace 29 42 21 62 62 10 25 55 40 30 66 67 trace trace

84:16 56:44 77:23 85:15 89:11 90:10 62:38 77:23 83:17 78:22 52:48 92:8 94:6

a

1a (0.2 mmol), 2a (0.4 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (3 mol %), Lewis acid/ligand (10 mol %), and NaHCO3 (2.0 equiv) in 0.67 mL of solvent at rt under irradiation of 7 W blue LEDs for 30 h. b Isolated yields. cDetermined by chiral HPLC analysis. dICF2CO2Et was used. e20 mol % of Lewis acid/ligand was used. fWithout visible light irradiation. gWithout photocatalyst.

a c

Reaction conditions: as indicated in entry 14, Table 1. bIsolated yield. er was determined by chiral HPLC analysis.

enantioselectivities (47−61% yields and 86.5:13.5−94:6 er). Moreover, disubstituted 1-indanone-derived substrates were also examined and could be successfully transformed into difluoroalkylation products 3lb−3mb in modest yields and 93.5:6.5−94.5:5.5 er. Notably, the quaternary stereocenter of 3mb was established to be in the S-configuration through single-crystal X-ray diffraction analysis. In contrast, when sixmembered cyclic substrate 1n was subjected to these reaction conditions, product 3nb was obtained in only 55:45 er; an acyclic substrate was ineffective under the standard conditions.11 To demonstrate the utility of this cooperative catalytic system further, we next simply examined the asymmetric photochemical perfluoroalkylation of β-ketoesters (Scheme 2). By employing fac-Ir(ppy)3 as photocatalyst, the reactions of β-ketoester 1a with C3F7I or C4F9I proceeded well and gave desired products 3ac and 3ad in moderate yields and good enantioselectivity. Notably, substrates 1k and 1m could

and with modest stereocontrol (48% yield and 84:16 er). Surveying Ni catalyst for this photoreaction revealed that NiBr2·glyme improved the yield and enantioselectivity (entries 4−6). As for the solvents, ethereal solvents improved the enantioselectivity (entries 7−9). We thus chose DME as the solvent to investigate the effect of the ligand on the reaction. It was found that commercially available 2,2′-linked bis(oxazoline) ligand L1 gave better enantioselectivity than other chiral oxazoline ligands L2−L4 (entry 7 vs entries 10− 12; more details are provided in the Supporting Information). A slightly increased yield and enantioselectivity were observed when ethyl iododifluoroacetate was used (entry 13:66% yield and 92:8 er). Finally, the stereoselectivity could be further improved by increasing the catalyst loading to 20 mol %, which provided product 3aa in 67% yield and 94:6 er (entry 14). Control experiments indicated that both visible light and the photocatalyst were essential for this transformation (entries 15 and 16). With the optimal conditions in hand, we probed the generality of this asymmetric difluoroalkylation protocol. As highlighted in Scheme 1, β-ketoester substrates bearing either electron-donating groups 1b or electron-withdrawing groups 1c−e on the aromatic ring were well tolerated in the reaction and provided the products 3bb−eb in 55−67% yields and 90.5:9.5−93:7 er. 5-Triflate-substituted substrate 1f also proved to be suitable for this reaction and afforded product 3fb in 45% yield and 89:11 er. The installation of substituents at the 4- and 6- positions had little influence on the reaction outcomes, and 3gb−kb were produced in moderate yields and good

Scheme 2. Preliminary Results for the Perfluoroalkylation of β-Ketoestersa,b,c

a Reaction conditions: as indicated in entry 14, Table 1, with facIr(ppy)3 (3 mol %) as the photocatalyst. bIsolated yield. cer was determined by chiral HPLC analysis.

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DOI: 10.1021/acs.orglett.7b03826 Org. Lett. 2018, 20, 461−464

Letter

Organic Letters undergo the same transformation smoothly with C3F9I to furnish desired products 3kc and 3mc in acceptable yields and selectivities. To elucidate the mechanism of this reaction, control experiments were performed under the standard conditions. First, the difluoroalkylation reaction was completely inhibited in the presence of 2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO, 4.0 equiv). Meanwhile, TEMPO−CF2CO2Et adduct 5 was observed in 76% yield as estimated by 19F NMR spectroscopy (Scheme 3, eq 1). Second, no α-oxyamination product 6 was Scheme 3. Control Experiments

Figure 2. Proposed Mechanism.

In conclusion, we have successfully developed an efficient and enantioselective radical difluoroalkylation of β-ketoesters through a combination of visible light photocatalysis and asymmetric Lewis acid catalysis. Corresponding products with chiral all-carbon quaternary stereocenters were prepared with good enantioselectivities (up to 95:5 er) under extremely mild conditions. Moreover, preliminary experiments demonstrated that this cooperative catalysis system can be successfully applied to the perfluoroalkylation of β-ketoesters.

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detected by HRMS from the reaction mixture in the presence or absence of ethyl bromodifluoroacetate 2b (Scheme 3, eq 2).12 Third, we could isolate adduct 7 in 54% yield when 4.0 equiv of 1,1-diphenylethylene was added to the reaction (Scheme 3, eq 3). These results suggest a CF2CO2Et radical pathway. We also observed that the continuous irradiation with visible light is essential for the reaction, which indicated that radical chain propagation might not be the predominant pathway (see the SI). Furthermore, the redox potential of the excited state of the photocatalyst (E[(Ir(III)*/Ir(IV)] = −0.89 V vs SCE) is higher than the Epc of substrate 2b (EPC = −1.21 V vs SCE).13,14 This indicated that an oxidative quenching cycle could be ruled out under our reaction conditions. Cyclic voltammetry of the Ni(II)/ligand complex ([Ni/L1]) showed an irreversible oxidation at +0.82 V versus Ag/AgCl in CH3CN corresponding to the oxidation of Ni(II) to Ni(III). Thus, single-electron transfer (SET) from [Ni/L1] to the photocatalyst (E[(Ir(III)*/Ir(II)] = +1.21 V vs SCE) is thermodynamically favorable. Finally, the fluorescence quenching experiments also demonstrated that the complex [Ni/L1] can severely diminish the intensity of the Ir(III)* emission (see the SI). On the basis of the above-mentioned experiments and related literature,9,15 a plausible photoredox catalytic pathway for this enantioselective radical difluoroalkylation was proposed as depicted in Figure 2. Photoexcitation of photocatalyst A with visible light results in the excited state of photocatalyst B, which can undergo reductive quenching by the complex D to give the complex E and Ir(II) photocatalyst C. Subsequent singleelectron oxidation of Ir(II) (E[(Ir(III)/Ir(II)] = −1.37 V vs SCE) by haloalkane 2b generates electrophilic radical G and regenerates the ground state of photocatalyst A.11 At the same time, substrate 1a is activated by the chiral Lewis acid to give nickel-enolate intermediate F, which could be trapped by radical G to afford the unstable intermediate H. Finally, the oxidation of [Ni/L1]− either by photoexcited state B or oxidation state E reforms the Ni(II) species ([Ni/L1]) and releases the final product.16

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03826. Detailed experimental procedures and full spectroscopic data for all compounds (PDF) Accession Codes

CCDC 1583359 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Liang-Qiu Lu: 0000-0003-2177-4729 Wen-Jing Xiao: 0000-0002-9318-6021 Author Contributions §

J.L. and W.D. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (Nos. 21472057, 21572074, 21772052, and 21772053) and the Program of Introducing Talents of Discipline to Universities of China (111 Program, B17019) for support of this research. 463

DOI: 10.1021/acs.orglett.7b03826 Org. Lett. 2018, 20, 461−464

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Organic Letters

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(e) Wang, L.; Wei, X.-J.; Jia, W.-L.; Zhong, J.-J.; Wu, L.-Z.; Liu, Q. Org. Lett. 2014, 16, 5842. (f) Tang, X. J.; Dolbier, W. R., Jr. Angew. Chem., Int. Ed. 2015, 54, 4246. (g) Arai, Y.; Tomita, R.; Ando, G.; Koike, T.; Akita, M. Chem. - Eur. J. 2016, 22, 1262. (h) Lin, Q.-Y.; Xu, X.-H.; Zhang, K.; Qing, F.-L. Angew. Chem., Int. Ed. 2016, 55, 1479. (i) Xu, P.; Wang, G.; Zhu, Y.; Li, W.; Cheng, Y.; Li, S.; Zhu, C. Angew. Chem., Int. Ed. 2016, 55, 2939. (j) Zhang, H.-R.; Chen, D.-Q.; Han, Y.-P.; Qiu, Y.-F.; Jin, D.-P.; Liu, X.-Y. Chem. Commun. 2016, 52, 11827. (k) Xiao, T.; Li, L.; Xie, Y.; Mao, Z. W.; Zhou, L. Org. Lett. 2016, 18, 1004. (9) Ding, W.; Lu, L.-Q.; Zhou, Q.-Q.; Wei, Y.; Chen, J.-R.; Xiao, W.-J. J. Am. Chem. Soc. 2017, 139, 63. (10) For selected work from our group, see: (a) Feng, Z.-J.; Xuan, J.; Xia, X.-D.; Ding, W.; Guo, W.; Chen, J.-R.; Zou, Y.-Q.; Lu, L.-Q.; Xiao, W.-J. Org. Biomol. Chem. 2014, 12, 2037. (b) Ding, W.; Zhou, Q.-Q.; Xuan, J.; Li, T.-R.; Lu, L.-Q.; Xiao, W.-J. Tetrahedron Lett. 2014, 55, 4648. (c) Xuan, J.; Zeng, T.-T.; Feng, Z.-J.; Deng, Q.-H.; Chen, J.-R.; Lu, L.-Q.; Xiao, W.-J.; Alper, H. Angew. Chem., Int. Ed. 2015, 54, 1625. (11) Other substrates like β-keto amide, aliphatic cyclic β-keto esters, and 3-indolinone-derived substrates are not feasible for this transformation. See the Supporting Information for more details. (12) In our previous work, the β-keto ester 1a could well undergo the photocatalytic α-oxyamination; see ref. 9. (13) Lowry, M. S.; Goldsmith, J. I.; Slinker, J. D.; Rohl, R.; Pascal, R. A.; Malliaras, G. G.; Bernhard, S. Chem. Mater. 2005, 17, 5712. (14) Zhong, J.-J.; Yang, C.; Chang, X.-D.; Zou, C.; Lu, W.; Che, C.M. Chem. Commun. 2017, 53, 8948. (15) For selected examples, see: (a) Huo, H.; Shen, X.; Wang, C.; Zhang, L.; Röse, P.; Chen, L.-A.; Harms, K.; Marsch, M.; Hilt, G.; Meggers, E. Nature 2014, 515, 100. (b) Zhu, Y.; Zhang, L.; Luo, S. J. Am. Chem. Soc. 2014, 136, 14642. (16) For selected examples for disproportionation of Ni(I) species, see: (a) Bour, J. R.; Camasso, N. M.; Meucci, E. A.; Kampf, J. W.; Canty, A. J.; Sanford, M. S. J. Am. Chem. Soc. 2016, 138, 16105. (b) Lee, E.; Börgel, J.; Ritter, T. Angew. Chem., Int. Ed. 2017, 56, 6966.

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DOI: 10.1021/acs.orglett.7b03826 Org. Lett. 2018, 20, 461−464