Enantioselective Synthesis of gem-Diaryl Benzofuran-3(2H)-ones via

Letter pubs.acs.org/OrgLett

Enantioselective Synthesis of gem-Diaryl Benzofuran-3(2H)‑ones via One-Pot Asymmetric Rhodium/Palladium Relay Catalysis Zong-Feng Zhang,†,‡,∥ Dong-Xing Zhu,‡,§,∥ Wen-Wen Chen,‡,§ Bin Xu,*,† and Ming-Hua Xu*,‡,§ †

Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444, China State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China § University of Chinese Academy of Sciences, Beijing 100049, China ‡

S Supporting Information *

ABSTRACT: An asymmetric dual-metal relay catalysis strategy that combines Rh/chiral sulfur-olefin-catalyzed enantioselective 1,2-addition with a Pd-catalyzed intramolecular C−O coupling has been developed. The method allows rapid and efficient synthesis of quaternary carbon-containing gem-diaryl benzofuran-3(2H)-ones in good yields in a highly enantioselective manner (up to 99% ee) through a simple one-pot cascade reaction.

B

ric variant, is underdeveloped, as it is often difficult to control each metal binding with a specific ligand due to the undesired metal−ligand interaction.12 Here we wish to report our development of a bimetallic asymmetric relay catalysis approach for the straightforward synthesis of highly enantiomerically enriched gem-diaryl benzofuran-3(2H)-ones. In an earlier work, we demonstrated a highly enantioselective rhodium/chiral sulfur-olefin ligand (SOL)13-catalyzed 1,2addition of arylboronic acids to α-diketones for efficient synthesis of chiral α-hydroxyketone derivatives bearing a quaternary carbon stereocenter (Scheme 1a).14 In considering

enzofuran-3(2H)-ones are important structural motifs prevalently present in many natural products and biologically interesting compounds.1 Among them, 2,2disubstituted benzofuran-3(2H)-ones bearing a tetrasusbtituted stereogenic center constitute the core skeletons of a number of pharmaceutically active agents such as Mutisicoumaranone A,1b Griseofulvin, 1c,d Geodin, 1e Linobiflavonoid, 1f,g and Sch 2025961h with antifungal, antipsychotic, and anticancer properties. Consequently, methods enabling convenient access to 2,2disubstituted benzofuran-3(2H)-ones in a stereoselective fashion are of great importance. However, despite considerable efforts,2,3 efficient approaches for asymmetric synthesis of 2,2disubstituted benzofuranone scaffold are relatively rare. Successful examples mainly include the asymmetric intramolecular Stetter reaction,4 Michael/Stetter cascade,5 Michael/ Aldol reaction6 of 2-substituted benzofuran-3-ones, Claisen rearrangements of benzofuran allylic ethers,7 and enantioselective Michael-type addition of β-ketoesters.8 Despite these impressive advances, the strategy that would allow the stereoselective assembly of 2,2-gem-diaryl benzofuran-3(2H)ones remains undeveloped.9 To our knowledge, efficient enantioselective access to quaternary stereocenter-containing benzofuranones that possess two structurally similar aryl groups could be problematic because of the difficulty in stereofacial differentiation. Domino catalysis has been proven as an attractive strategy to rapidly generate complex molecules, as it can ideally merge different modes of catalysis into a single reaction vessel.10 In the past few years, remarkable progress has been made in bimetallic relay catalysis in which two transition metals are independently involved in catalytic cycles in a cascade manner.11 However, multiligand-involved domino catalysis, especially the asymmet© 2017 American Chemical Society

Scheme 1. Bimetallic Asymmetric Relay Catalysis Strategy

Received: April 11, 2017 Published: May 9, 2017 2726

DOI: 10.1021/acs.orglett.7b01070 Org. Lett. 2017, 19, 2726−2729

Letter

Organic Letters the gem-diaryl benzofuran-3-one framework, we envisioned an unprecedented dual-metal relay catalysis strategy for an asymmetric cascade reaction of ortho-halogen-substituted αdiketones with arylboronic acids, combining rhodium-catalyzed enantioselective arylation with palladium-catalyzed intramolecular C−O coupling (Scheme 1b). The use of bimetallic Rh/Pd asymmetric catalysis in a cascade manner has been pioneered by Lautens.15 To enable the desired transformation, however, overcoming the competitive intermolecular C−C coupling between the halides and arylboronic acids is a considerable challenge. Our initial study began with α-diketone 1a and ptolylboronic acid 2a as the model substrates and cinnamyl sulfonamide L1 as the chiral ligand.14 As Pd-catalyzed C−O coupling usually require a higher temperature to proceed, we planned to control the reaction sequence by adjusting the temperature (rt to 60 °C). To our delight, the desired benzofuran-3-one product 3a was obtained in 99% ee in the presence of [Rh(coe)2Cl]2/L1 and Pd(OAc)2/X-Phos in toluene, albeit with a slightly low yield (39% yield) (Table 1, entry 1). Encouraged by this promising result, we then screened several other phosphorus ligands (such as S-Phos, JohnPhos,

PhDavePhos, DPPF, and DPPP). However, no better results were obtained (Table 1, entries 2−6). In most cases, a considerable proportion of C−C coupling byproducts were gained due to the undesired Suzuki reaction of 1a or the formed α-tertiary hydroxyketone intermediate with 2a under palladium catalysis. Gratifyingly, when 1-(2-chlorophenyl)-2phenylethane-1,2-dione 1b was employed as the substrate, the yield dramatically increased to 65% while maintaining the excellent enantioselectivity (99% ee) (entry 1 vs 7). Lowering the amount of boronic acid 2a can further improve the yield (entry 8). Moreover, a higher loading of Rh catalyst (5 mol %) was found to be beneficial for the reaction, affording the product 3a in 85% yield with 99% ee (entry 9). Among the bases tested (entries 9−13), K3PO4 was found to be the best and K2CO3 could give product with comparable results (entry 10). Varying the solvent did not furnish better results (entries 14 and 15). Interestingly, when increasing the temperature from 60 to 100 °C for the Pd-catalyzed C−O coupling step, a slightly better yield could be achieved (90% yield and 99% ee) (entry 16). With the optimal conditions established, we then investigated the substrate scope of this domino reaction (Scheme 2). To our delight, the reaction can tolerate various arylboronic acids with diverse electronic and steric properties to afford the corresponding gem-diaryl benzofuran-3-one products 3 in high yields (81−99%) with uniformly excellent enantioselectivities (97−99% ee) (3a−3k). In some cases, prolonging the reaction time at room temperature was necessary to ensure the completion of the first 1,2-addition reaction, thus giving satisfactory yields of final products (3c−e, 3g, 3i, 3k). Importantly, a variety of α-diketones possessing electrondonating or -withdrawing substituents on the phenyl ring are all competent reaction partners, affording 3 in satisfactory yields (74−98%) with excellent enantiomeric excesses (97−99% ee) (3l−3z, 3A). Notably, substrates equipped with electronwithdrawing F, CF3 groups at the para or meta position of the Ar1 aryl ring underwent reaction with 2 smoothly to provide the corresponding 3 in particularly high yields (3l, 3q vs 3o, 3m vs 3p, 3n vs 3o′, 3t vs 3s). We also found that introducing substituents onto the C5/C6 position of the Cl-substituted benzene ring did not have a significant impact on the yield and enantioselectivity (3w−3z, 3A). Moreover, the reaction allows the preparation of both enantiomers under the same conditions by simply reversing the Ar1 and Ar2 groups in substrates (e.g., 3o vs 3o′). It is noteworthy that the stereochemical outcome of these transformations is dominated by the rhodium/chiral sulfurolefin catalysis. The absolute configuration of the carbon stereocenter of 3t was determined to be R by X-ray crystallographic analysis16 (Figure 1); thus, the stereochemistry of the other benzofuranone products could be assigned by analogy. The proposed dual catalytic cycle for the transformation of α-diketone 1 and arylboronic acid 2 into 2,2-gem-diaryl benzofuran-3-ones 3 is depicted in Scheme 3. Initially, an aryl rhodium intermediate is formed through transmetalation of active [Rh]−OH species with aryl boronic acid 2, followed by insertion and hydrolysis to afford the arylation product 4. In the second catalytic cycle, in situ generated Pd(0) oxidatively adds to the C−Cl bond of the resulting arylation product 4 to form intermediate C, which undergoes deprotonation to afford palladacycle intermediate D. The final cyclized benzofuranone

Table 1. Optimization of Reaction Conditions for One-Pot Dual-Metal Asymmetric Relay Catalysisa

entry

1

ligand

base (aq)

solvent

yieldb (%)

eec (%)

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

1a 1a 1a 1a 1a 1a 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b

X-Phos S-Phos JohnPhos PhDavePhos DPPF DPPP X-Phos X-Phos X-Phos X-Phos X-Phos X-Phos X-Phos X-Phos X-Phos X-Phos

K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K2CO3 Cs2CO3 KOH KF K3PO4 K3PO4 K3PO4

toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene dioxane DMF toluene

39 32 13 9 NR NR 65 72 85 83 17 32 36 72 53 90

99 99 99 97 − − 99 99 99 99 99 99 99 99 96 99

a

Reaction conditions: 1 (0.25 mmol, 1 equiv), 2a (0.5 mmol, 2 equiv), [Rh(COE)2Cl]2 (1.5 mol %), and L1 (3.3 mol %) were stirred in toluene (1 mL) at room temperature for 30 min, and then Pd(OAc)2 (5 mol %), ligand (10 mol %), and base (1.5 M aq, 3 equiv) were added. The mixture was stirred at room temperature for 1 h and then at 60 °C for 18 h, unless otherwise noted. bIsolated yield. cDetermined by chiral HPLC analysis. d1.5 equiv of 2a was employed. e5 mol % of [Rh] and 5.5 mol % of L1 were employed. fThe mixture was later stirred at 100 °C for 18 h. 2727

DOI: 10.1021/acs.orglett.7b01070 Org. Lett. 2017, 19, 2726−2729

Letter

Organic Letters Scheme 2. One-Pot Asymmetric Rh/Pd Catalysis for Synthesis of gem-Diaryl Benzofuran-3-onesa,b,c

Figure 1. X-ray crystal structure of 3t.

Scheme 3. Proposed Bimetallic Catalytic Cycle

with excellent enantioselectivities, without intereference from the coexisting palladium catalyst. The substrate scope of the reaction was relatively broad, enabling the use of a wide range of ortho-Cl-substituted α-diketones and various arylboronic acids. These interesting gem-diaryl chiral benzofuran-3(2H)ones may find application in related biological studies such as antifungal and anticancer research and offer new opportunities for drug discovery projects.

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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.7b01070. Experimental procedures and spectroscopic data of all new compounds (PDF) X-ray crystal structure data for (R)-3t (CIF)

a

Reaction conditions: 1 (0.25 mmol, 1 equiv), 2a (0.375 mmol, 1.5 equiv), [Rh(COE)2Cl]2 (2.5 mol %), and L1 (5.5 mol %) were stirred in toluene (1 mL) at room temperature for 30 min, then Pd(OAc)2 (5 mol %), X-Phos (10 mol %), and K3PO4 (1.5 M aq, 3 equiv) were added. The mixture was stirred at rt for 1 h, then at 100 °C for 18 h, unless otherwise noted. bIsolated yield. cDetermined by chiral HPLC analysis. dThe mixture was first stirred at room temperature for 6 h. e 10 mmol % of Pd(OAc)2 and 20 mmol % of X-Phos were employed. f The mixture was first stirred at room temperature for 2 h.

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AUTHOR INFORMATION

Corresponding Authors

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

product 3 would then be produced after reductive elimination, regenerating the catalytic active Pd(0) species. In summary, we have demonstrated an asymmetric bimetallic relay catalysis strategy that allows rapid and efficient assembly of quaternary carbon-containing gem-diaryl benzofuran-3-ones in good yields in a highly stereoselective manner through a simple one-pot reaction, merging Rh/SOL-catalyzed enantioselective 1,2-addition with a Pd-catalyzed intramolecular C−O coupling. The initial rhodium-catalyzed arylation reaction provides efficient access to chiral α-tertiary hydroxyketones

ORCID

Bin Xu: 0000-0002-9251-6930 Ming-Hua Xu: 0000-0002-1692-2718 Author Contributions ∥

Z.-F.Z. and D.-X.Z. contributed equally.

Notes

The authors declare no competing financial interest. 2728

DOI: 10.1021/acs.orglett.7b01070 Org. Lett. 2017, 19, 2726−2729

Letter

Organic Letters

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(12) For examples of multiligand-involved asymmetric domino catalysis, see: (a) Hansmann, M. M.; Hashmi, A. S. K.; Lautens, M. Org. Lett. 2013, 15, 3226. (b) Nahra, F.; Macé, Y.; Lambin, D.; Riant, O. Angew. Chem., Int. Ed. 2013, 52, 3208. (c) Friedman, A. A.; Panteleev, J.; Tsoung, J.; Huynh, V.; Lautens, M. Angew. Chem., Int. Ed. 2013, 52, 9755. (d) Tsoung, J.; Panteleev, J.; Tesch, M.; Lautens, M. Org. Lett. 2014, 16, 110. (e) Huo, X.; He, R.; Zhang, X.; Zhang, W. J. Am. Chem. Soc. 2016, 138, 11093. (f) Yamamoto, K.; Qureshi, Z.; Lautens, M. Org. Lett. 2016, 18, 4954. (g) Lied, F.; Ž ugelj, H. B.; Kress, S.; Štefane, B.; Glorius, F.; Lautens, M. ACS Catal. 2017, 7, 1378. (13) For a focus review on our development of chiral sulfur-olefin ligands for asymmetric catalysis, see: Li, Y.; Xu, M.-H. Chem. Commun. 2014, 50, 3771. (14) (a) Zhu, T.-S.; Jin, S.-S.; Xu, M.-H. Angew. Chem., Int. Ed. 2012, 51, 780. (b) Zhu, T.-S.; Chen, J.-P.; Xu, M.-H. Chem. - Eur. J. 2013, 19, 865. (15) (a) Panteleev, J.; Zhang, L.; Lautens, M. Angew. Chem., Int. Ed. 2011, 50, 9089. (b) Zhang, L.; Qureshi, Z.; Sonaglia, L.; Lautens, M. Angew. Chem., Int. Ed. 2014, 53, 13850. (c) Ye, J.; Limouni, A.; Zaichuk, S.; Lautens, M. Angew. Chem., Int. Ed. 2015, 54, 3116. (16) Crystallographic data for (R)-3t (C21H15FO2): T = 205 K; Cu Kα radiation, λ = 1.54178 Å; crystal system: Monoclinic, P21; unit cell dimensions: a = 6.2656 (5) Å, b = 15.4462 (11) Å, c = 8.1799 (6) Å, α = 90°, β = 94.209 (3)°, γ = 90°; θ = 5.4°−0.2°; V = 789.51 (10) Å3; Z = 2; ρcalc = 1.339 Mg/m3; F(000) = 332; 2394 reflections with I > 2σ(I), Rint = 0.031, wR(F2) = 0.084; 7341 measured reflections, 2447 independent reflections; Flack parameter: 0.06 (6). See Supporting Information for details.

ACKNOWLEDGMENTS We thank the National Science Foundation of China (21325209, 21472205, 81521005) and the Shanghai Municipal Committee of Science and Technology (Program of Shanghai Academic Research Leader, 14XD1404400) for financial support.

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REFERENCES

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DOI: 10.1021/acs.orglett.7b01070 Org. Lett. 2017, 19, 2726−2729