enantioselective aza-morita–baylis–hillman reaction between acrylates and n-boc isatin...

Organic &Biomolecular Chemistry

PAPER

Cite this: Org. Biomol. Chem., 2014,12, 8072

Received 30th June 2014,Accepted 15th August 2014

DOI: 10.1039/c4ob01358a

www.rsc.org/obc

Enantioselective aza-Morita–Baylis–Hillmanreaction between acrylates and N-Boc isatinketimines: asymmetric construction of chiral3-substituted-3-aminooxindoles†

Xuan Zhao, Tian-Ze Li, Jing-Ying Qian, Feng Sha* and Xin-Yan Wu*

The first enantioselective aza-Morita–Baylis–Hillman reaction of acrylates with ketimines derived from

isatins has been developed. With 2 mol% of chiral bifunctional phosphine-squaramide 4e, optically active

3-substituted-3-amino-2-oxindoles were obtained in excellent yields with up to 91% ee.

Introduction

Quaternary 3-amino-2-oxindole motifs are important and ubi-quitous structures in many natural products and pharmaceu-tics.1 In the past few years, a variety of methods for preparingthese compounds have been explored.1b,c Among these theenantioselective addition of nucleophiles to isatin-derived keti-mines is one of the most efficient and straightforward meth-ods.1b,c,2,3 Organocatalytic enantioselective addition reactions,such as the aza-Friedel–Crafts reaction,2a Mannich reaction2b–h

and Strecker reaction,2i–k have been developed to construct3-substituted-3-amino-2-oxindoles with a chiral quaternarycarbon center. However, the enantioselective aza-Morita–Baylis–Hillman reaction involving isatin-derived ketimine hasbeen rarely described.3,4

In the enantioselective aza-Morita–Baylis–Hillman (aza-MBH) reaction, a C–C bond forming reaction between elec-tron-deficient olefins and imines is a well-known, powerfulprotocol for providing densely functionalized chiral amines.5

The imine electrophiles in aza-MBH reaction are mainlyfocused on activated aldimines, such as tosylimines, nosyl-imines, SES-imines and phosphinoylimines. Very recently, Shiand co-workers reported an asymmetric aza-MBH reaction ofmethyl vinyl ketone (MVK) with isatin-derived ketimines cata-lyzed by chiral β-isocupreidine (β-ICD) and bifunctionalphosphine derived from BINOL.3a Meanwhile, Sasai’s group

reported an asymmetric aza-MBH reaction of methyl/ethylvinyl ketone with ketimines derived from acyclic α-keto esterscatalyzed by P-chirogenic organocatalysts, and an example ofisatin-derived ketimine was described.3b Chen and coworkersdeveloped an enantioselective aza-MBH reaction of acroleinand ketimines derived from β,γ-unsaturated α-ketoesters cata-lyzed by the combination of β-ICD association with BINOL ortertiary amine-thiourea.6 However, the enantioselective aza-MBH reaction of ketimines with acrylates is still undeveloped.

We have found in recent studies that the chiral cyclo-hexane-based bifunctional phosphines are highly efficient inthe asymmetric MBH reaction using acrylates as the nucleo-philes, which are less reactive than MVK.4d,e,7 On the otherhand, these chiral bifunctional phosphines are effectiveorganocatalysts for the MBH reaction between acrylates andisatins, providing 3-hydroxy-2-oxindoles containing a chiralquaternary carbon center.4d,e Therefore, chiral cyclohexane-based bifunctional phosphines would be conceivable catalystsfor the aza-MBH reaction to construct 3-substituted-3-amino-2-oxindoles. Herein we report an enantioselective aza-MBHreaction between acrylates and ketimines derived from isatinswith chiral bifunctional phosphine-squaramide as theorganocatalyst.

Results and discussion

Initially an aza-MBH reaction of isatin-derived ketimine 6awith benzyl acrylate was conducted as a model reaction toscreen a suitable chiral bifunctional phosphine organocatalyst(Fig. 1). The reactions were performed at 25 °C in CH2Cl2using 10 mol% chiral catalysts, and the results are summar-ized in Table 1. The results indicated that the reactivity andthe enantioselectivity were sensitive to the H-bonding donor ofthe chiral cyclohexane-based organocatalysts (entries 1–4). In

†Electronic supplementary information (ESI) available: Experimental procedureof chiral catalysts 4d, 4e and ent-4e; copies of NMR spectra of chiral catalysts 4d,4e, ent-4e and the products; copies of HPLC spectra of the products; the CIF fileof compound ent-8l. CCDC 981628. For ESI and crystallographic data in CIF orother electronic format see DOI: 10.1039/c4ob01358a

Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China

University of Science and Technology, 130 Meilong Road, Shanghai 200237,

P. R. China. E-mail: [email protected]; Tel: +86-21-64252011

8072 | Org. Biomol. Chem., 2014, 12, 8072–8078 This journal is © The Royal Society of Chemistry 2014

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the presence of the phosphine-thiourea catalyst 1,7a,8 the aza-MBH reaction could be completed in half an hour, producingchiral 3-amino-2-oxindole in excellent yield with moderateenantioselectivity (entry 1). Phosphine-squaramide 4a4e pro-vided higher enantioselectivity than the correspondingthiourea 1, amide 2 and ethoxy squaramide 39 (entry 4 vs. 1–3).Therefore phosphine-squaramides containing differentalkyl scaffolds were evaluated (entries 4–11). The phosphine-squaramides 4a–4e bearing aliphatic scaffolds exhibited betteryields and enantioselectivities than 4f–4h bearing aromaticscaffolds (entries 4–8 vs. 9–11). The squaramides 4a and 4bwith a long-chain aliphatic group were so reactive that the aza-MBH reaction was accomplished in one hour (entries 4 and 5).The additional chiral group in the alkyl squaramide moietycould improve the enantioselectivity of the aza-MBH reaction

(entries 7 and 8 vs. 6). The L-valine-derived phosphine-thiourea510 was observed to be less reactive than the chiral cyclo-hexane-based phosphine-thiourea 1 for the reaction, and alonger reaction time was required (entry 12 vs. 1). Thephosphine-squaramide 4e proved to be the best organocatalystfor the model reaction, providing the desired product 8a in98% yield and 82% ee (entry 8). Then the catalyst loading of 4ewas examined. The aza-MBH reaction could be achieved with areduced amount of catalyst loading with as low as 2 mol% 4e,giving a similar result to using 10 mol% 4e (entries 13 and 14vs. 8). However, further decrease of the catalyst loading to1 mol% led to significant decrease in the yield with retainedenantioselectivity (entry 15).

The reaction conditions of the aza-MBH reaction were thenprobed with 2 mol% of organocatalyst 4e (Table 2). Less polarsolvents such as toluene, CH2Cl2 and CHCl3 resulted inexcellent yields (91–99%) with 79–84% ee (entries 1–3). In thecase of ether, moderate yield was obtained and a longer timewas required, due to the low conversion rate of the substrates(entry 4). The aza-MBH reaction was inactive in THF (entry 5),different from the MBH reaction of isatins and acrylatescatalyzed by phosphine-squaramide.4e In the polar solventssuch as EtOAc and DMF, the aza-MBH products were providedin moderate yields (entries 6 and 7). The aza-MBH reaction inCH3CN was decelerated than that in CH2Cl2, while theenantioselectivity was slightly improved (entry 8 vs. 2). Thedifferent substrate concentrations in CH2Cl2 resulted in the

Fig. 1 Structures of the chiral bifunctional phosphines screened.

Table 1 Screening of chiral bifunctional phosphine organocatalysts forthe aza-MBH reaction of isatin-derived N-Boc ketimines with benzylacrylatea

Entry Catalyst Time (h) Yieldb (%) eec (%)

1 1 0.5 99 512 2 24 94 373 3 8 97 434 4a 1 95 695 4b 1 95 686 4c 24 93 727 4d 48 89 808 4e 24 98 829 4f 24 81 5810 4g 25 82 6111 4h 24 75 6712 5 24 81 −4013d 4e 24 99 8414e 4e 24 99 8415 f 4e 72 80 82

aUnless stated otherwise, the reactions were conducted with 6a(0.2 mmol), 7a (0.6 mmol) and catalyst (0.02 mmol) in CH2Cl2 (1 mL)at 25 °C. b Isolated yield. c The ee values were determined by HPLCusing Chiralcel OD-H column. d The catalyst loading was 5 mol%.e The catalyst loading was 2 mol%. f The catalyst loading was 1 mol%.

Table 2 Optimization of the reaction conditionsa

Entry SolventTemp.(°C)

Time(d)

Yieldb

(%)eec

(%)

1 Toluene 25 3 91 792 CH2Cl2 25 1 99 843 CHCl3 25 1 97 804 Et2O 25 4 78 785 THF 25 4 NRd nde

6 EtOAc 25 3 52 787 DMF 25 3 64 798 CH3CN 25 3 94 879 f CH2Cl2 25 1 99 8410g CH2Cl2 25 1 99 8411 CH2Cl2 0 3.5 72 8712 CH2Cl2 40 0.3 100 8313 1 : 2 CH2Cl2–CH3CN 25 2 95 8714 1 : 1 CH2Cl2–CH3CN 25 1.5 97 8615 2 : 1 CH2Cl2–CH3CN 25 1.2 99 8616h 1 : 2 CH2Cl2–CH3CN 25 2 98 86

aUnless stated otherwise, the reactions were conducted with 6a(0.2 mmol), 7a (0.6 mmol) and 4e (0.004 mmol) in the solvent (1 mL).b Isolated yield. c The ee values were determined by HPLC usingChiralcel OD-H column. dNo reaction. eNot determined. f The reactionwas conducted in 2 mL solvent. g The reaction was conducted in0.67 mL solvent. h The amount of benzyl acrylate was 1.0 mmol.

Organic & Biomolecular Chemistry Paper

This journal is © The Royal Society of Chemistry 2014 Org. Biomol. Chem., 2014, 12, 8072–8078 | 8073

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same enantioselectivities and yields (entries 2, 9, 10). Theenantioselectivity was not sensitive to the reaction tempera-ture, and a lower reaction temperature resulted in a longerreaction time (entries 2, 11 and 12). To attain high enantio-selectivity with a reasonable reaction time, a mixed solventsystem of CH2Cl2 with CH3CN was surveyed. The results indi-cated that at a mixing ratio of CH2Cl2–CH3CN = 1 : 2 (v/v), thebest reactivities were obtained (entries 13–16).

Under the established optimal reaction conditions [2 mol%4e, 3 equiv. of acrylate in 1 : 2 CH2Cl2–CH3CN (0.2 M) at 25 °C],the substrate scope of the aza-MBH reaction was investigated(Table 3). The results showed that there was no obviouschange in the enantioselectivity using unbranched alkyl acry-lates as the Michael donors, while n-butyl acrylate was lessreactive than others (entries 1–4). Due to steric hindrance,t-butyl acrylate was inactive under the typical reaction con-ditions (entry 5). The chiral catalytic system was also not suit-able for phenyl acrylate as the reaction only gave the productwith 43% yield and 2% ee (entry 6).

Further exploration of the substrate scope was concentratedon varying the substituents on the isatin-derived ketimines.The aza-MBH reaction tolerated well all the N-Boc-1-methylketimine substrates with either electron-withdrawing or

electron-donating groups at 5-, 6- or 7-positions (entries 8–21).The electron-donating group exhibited a positive effect on theenantioselectivity, while the electron-withdrawing groupexhibited a negative effect. Isatin-derived ketimine with a sub-stituent at the 4-position is unreactive for the aza-MBH reac-tion under the identical reaction conditions, probably due tosteric hindrance (entry 7).2i,q,3a A large scale synthesis using1 mmol N-Boc isatin ketimine 6a also provided an excellentyield (93%) and enantioselectivity (87% ee) (entry 22).

To determine the absolute configuration of 3-amino-2-oxindoles with a chiral quaternary carbon center, the enantio-mer of the aza-MBH product 8l (ent-8l) was acquired using theenantiomer of 4e as a chiral catalyst. The single crystal ofent-8l was obtained by recrystallization from n-hexane–CH2Cl2,and the configuration of the stereocenters was determined tobe R by X-ray crystallography (Fig. 2). Therefore, the aza-MBHproduct 8l should be of S configuration, and the configur-ations of other adducts 8 were assigned by analogy.

According to the above-mentioned experimental results andthe related reports,2b,8a,11 a probable transition-state structurewas proposed as shown in Fig. 3. The electrophilic squaramideof the chiral catalyst activates the ketimine through hydrogen-bonding interactions,2b then the chiral cyclohexyl scaffoldforces the phosphinoyl associated enolate8a,11 to attack theactivated ketimine from the Si-face to form the adducts in Sconfiguration.

Table 3 Substrate scope of the enantioselective aza-MBH reactionsa

Entry R1 R2 8 Time (d) Yieldb (%) eec (%)

1 H Bn 8a 2 95 872 H Me 8b 3.5 88 893 H Et 8c 3.5 87 884 H n-Bu 8d 5 58 875 H t-Bu — 5 NRd nde

6 H Ph 8e 6 43 27 4-Br Bn — 4 NR nd8 5-F Bn 8f 2 98 819 5-Cl Bn 8g 1.5 94 8110 5-Br Bn 8h 2 97 8011 5-Me Bn 8i 2.5 99 8812 5-MeO Bn 8j 3.5 99 8913 6-Cl Bn 8k 1.5 95 8214 6-Br Bn 8l 1.5 99 8215 7-F Bn 8m 2 95 8416 7-Cl Bn 8n 2.5 95 8217 7-Br Bn 8o 2 99 8018 7-CF3 Bn 8p 6 80 7019 7-Me Bn 8q 5 98 8920 5-Me Me 8r 7 94 9121 5-MeO Me 8s 7 93 9022 f H Bn 8a 3 93 87

aUnless stated otherwise, the reactions were conducted with 6(0.2 mmol), 7 (0.6 mmol), and 4e (0.004 mmol) in CH2Cl2 (0.33 mL)and CH3CN (0.67 mL) at 25 °C. b Isolated yield. c The ee values weredetermined by HPLC using Chiralcel OD-H column or Chiralpak AD-Hcolumn. dNo reaction. eNot determined. f The reaction was conductedin 1 mmol scale.

Fig. 2 X-ray crystal structure of ent-8l.

Fig. 3 Proposed transition state.

Paper Organic & Biomolecular Chemistry


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Conclusions

In summary, we have explored the first example of enantio-selective aza-Morita–Baylis–Hillman reaction of acrylates withisatin-derived N-Boc ketimines. The chiral bifunctional phos-phine-squaramide 4e was an efficient organocatalyst for thisreaction. With 2 mol% of 4e in 1 : 2 CH2Cl2–CH3CN, the aza-MBH reaction could be carried out at 25 °C to provide thedesired products in up to 91% ee and good-to-excellent yields(up to 99%).

Experimental sectionGeneral information

Melting points were taken without correction. Optical rotationswere measured on a WZZ-2A digital polarimeter at the wave-length of the sodium D-line (589 nm). 1H, 13C NMR spectrawere recorded on a Bruker 400 spectrometer. The chemicalshifts of 1H NMR and 13C NMR spectra were referenced totetramethylsilane (δ 0.00) using CDCl3 as the solvent. IRspectra were recorded on a Nicolet Magna-I 550 spectrometer.High resolution mass spectra (HRMS) were recorded on aMicromass GCT with electron spray ionization (ESI) resource.HPLC analysis was performed on Waters equipment using theDaicel Chiralcel OD-H or Chiralpak AD-H column.

Dichloromethane, chloroform, ethyl acetate and acetonitrilewere distilled from CaH2. Toluene, ether and THF were dis-tilled from sodium-benzophenone. DMF was dried over CaH2

and distilled under reduced pressure. Thin-layer chromato-graphy (TLC) was performed on Silicycle 10–40 μm silica gelplates. Column chromatography was performed using silicagel (300–400 mesh) eluting with ethyl acetate and petroleumether.

Chiral bifunctional phosphine organocatalysts 1–5 were pre-pared according to literature procedures.4e,8–10 All substitutedN-Boc ketimines were synthesized according to the literature.2b

General procedure for the aza-Morita–Baylis–Hillman reaction

To a solution of chiral catalyst 4e (0.004 mmol) in 1 mL 1 : 2CH2Cl2–CH3CN was added acrylate (0.6 mmol) at 25 °C. After10 min stirring at this temperature, isatin-derived N-Boc ket-imine (0.2 mmol) was added. The reaction mixture was stirredat 25 °C (monitoring by TLC). After the reaction was complete,the solvent was removed under reduced pressure and theresidue was purified by flash column chromatography on silicagel to afford the desired adducts and the ee values were deter-mined by HPLC analysis with a chiral column.

(S)-Benzyl 2-(3-(tert-butoxycarbonyl)-1-methyl-2-oxoindolin-3-yl)acrylate (8a). White solid, 95% yield, 87% ee, mp102.5–102.9 °C; [α]25D −76.3 (c 0.68, CH2Cl2);

1H NMR (CDCl3,400 MHz): δ 7.44 (d, J = 7.2 Hz, 1H), 7.34–7.28 (m, 4H), 7.23–7.21(m, 2H), 7.01 (td, J = 7.6, 0.4 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H),6.38 (s, 1H), 6.09 (s, 1H), 5.91 (s, 1H), 5.09 (s, 2H), 3.15 (s, 3H),1.29 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 174.4, 165.4,153.9, 143.8, 136.9, 135.0, 129.3, 129.1, 128.6, 128.5, 128.4,

128.0, 124.9, 122.8, 108.4, 80.4, 67.2, 64.0, 28.1, 26.6; IR (KBr,cm−1): ν 3301, 3124, 2976, 1708, 1611, 1519, 1493, 1400, 1282,1163, 1088, 957, 758, 698; HRMS (ESI) calcd for C24H26N2NaO5

([M + Na]+): 445.1739, found: 445.1742; HPLC analysis (OD-Hcolumn, λ = 254 nm, eluent: hexane–2-propanol = 90/10, flowrate: 0.9 mL min−1): tR = 14.09 min (minor), 17.85 min (major).

(S)-Methyl 2-(3-(tert-butoxycarbonyl)-1-methyl-2-oxoindolin-3-yl)acrylate (8b). White solid, 88% yield, 89% ee, mp143.5–143.8 °C; [α]25D −82.4 (c 0.54, CH2Cl2);

1H NMR (CDCl3,400 MHz): δ 7.45 (d, J = 7.2 Hz, 1H), 7.30 (td, J = 7.6, 1.2 Hz,1H), 7.04 (td, J = 7.6, 0.4 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.31(s, 1H), 6.18 (s, 1H), 5.88 (s, 1H), 3.72 (s, 3H), 3.28 (s, 3H), 1.30(s, 9H); 13C NMR (CDCl3, 100 MHz): δ 174.6, 166.1, 154.0,143.8, 136.8, 129.3, 129.2, 127.7, 124.6, 122.8, 108.3, 80.4, 64.1,52.4, 28.1, 26.7; IR (KBr, cm−1): ν 3276, 3142, 3006, 1738, 1705,1610, 1516, 1472, 1400, 1321, 1276, 1174, 1088, 989, 762;HRMS (ESI) calcd for C18H22N2NaO5 ([M + Na]+): 369.1426,found: 369.1422; HPLC analysis (OD-H column, λ = 254 nm,eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1): tR= 11.05 min (minor), 15.81 min (major).

(S)-Ethyl 2-(3-(tert-butoxycarbonyl)-1-methyl-2-oxoindolin-3-yl)acrylate (8c). White solid, 87% yield, 88% ee, mp112.9–113.2 °C; [α]25D −83.3 (c 0.52, CH2Cl2);

1H NMR (CDCl3,400 MHz): δ 7.46 (d, J = 7.2 Hz, 1H), 7.30 (td, J = 7.6, 1.2 Hz,1H), 7.04 (td, J = 7.6, 0.4 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.32(s, 1H), 6.17 (s, 1H), 5.87 (s, 1H), 4.15 (qd, J = 7.2, 1.2 Hz, 2H),3.28 (s, 3H), 1.30 (s, 9H), 1.21 (t, J = 7.2 Hz, 3H); 13C NMR(CDCl3, 100 MHz): δ 174.6, 165.6, 154.0, 143.8, 137.1, 129.3,129.3, 127.4, 124.7, 122.8, 108.3, 80.3, 64.0, 61.4, 28.1, 26.7,14.0; IR (KBr, cm−1): ν 3313, 3124, 2985, 1704, 1613, 1519,1475, 1399, 1312, 1251, 1170, 1130, 1051, 983, 769; HRMS(ESI) calcd for C19H24N2NaO5 ([M + Na]+): 383.1583, found:383.1588; HPLC analysis (OD-H column, λ = 254 nm, eluent:hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1): tR =9.12 min (minor), 11.73 min (major).

(S)-Butyl 2-(3-(tert-butoxycarbonyl)-1-methyl-2-oxoindolin-3-yl)acrylate (8d). White solid, 58% yield, 87% ee, mp96.4–96.6 °C; [α]25D −60.5 (c 0.38, CH2Cl2);

1H NMR (CDCl3,400 MHz): δ 7.45 (d, J = 6.8 Hz, 1H), 7.30 (td, J = 7.6, 1.2 Hz,1H), 7.03 (td, J = 7.6, 0.8 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.31(s, 1H), 6.18 (s, 1H), 5.86 (s, 1H), 4.11 (t, J = 6.8 Hz, 2H), 3.28(s, 3H), 1.60–1.53 (m, 2H), 1.35–1.27 (m, 2H), 1.30 (s, 9H), 0.90(t, J = 7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 174.6, 165.7,154.0, 143.8, 137.1, 129.3, 127.4, 124.7, 122.8 (×2), 108.3, 80.3,65.3, 64.0, 30.4, 28.1, 26.7, 19.1, 13.7; IR (KBr, cm−1): ν 3417,3128, 2968, 1719, 1612, 1465, 1400, 1317, 1254, 1172, 1089,1004, 889, 760; HRMS (ESI) calcd for C21H29N2O5 ([M + H]+):389.2076, found: 389.2075; HPLC analysis (OD-H column, λ =254 nm, eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mLmin−1): tR = 7.63 min (minor), 9.73 min (major).

(S)-Phenyl 2-(3-(tert-butoxycarbonyl)-1-methyl-2-oxoindolin-3-yl)acrylate (8e). White solid, 43% yield, 2% ee, mp158.3–159.6 °C; 1H NMR (CDCl3, 400 MHz): δ 7.55 (d, J = 7.6Hz, 1H), 7.37–7.31 (m, 3H), 7.22 (t, J = 7.6 Hz, 1H), 7.07 (td, J =7.6, 0.8 Hz, 1H), 6.97–6.94 (m, 2H), 6.85 (d, J = 7.6 Hz, 1H),6.61 (s, 1H), 6.10 (s, 1H), 6.05 (s, 1H), 3.28 (s, 3H), 1.31 (s, 9H);



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13C NMR (CDCl3, 100 MHz): δ 174.4, 164.2, 154.0, 150.2, 143.9,136.7, 129.5 (×2), 129.1, 129.0, 126.2, 125.0, 122.9, 121.4, 108.5,80.5, 64.0, 28.2, 26.8; IR (KBr, cm−1): ν 3420, 3126, 2977, 1733,1716, 1612, 1492, 1401, 1313, 1279, 1195, 1165, 1137, 1088,1006, 759; HRMS (ESI) calcd for C23H24N2NaO5 ([M + Na]+):431.1583, found: 431.1578; HPLC analysis (OD-H column, λ =254 nm, eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mLmin−1): tR = 11.02 min (major), 13.02 min (minor).

(S)-Benzyl 2-(3-(tert-butoxycarbonyl)-5-fluoro-1-methyl-2-oxoindolin-3-yl)acrylate (8f). White solid, 98% yield, 81% ee,mp 134.7–135.0 °C; [α]25D −67.3 (c 0.72, CH2Cl2);

1H NMR(CDCl3, 400 MHz): δ 7.35–7.33 (m, 3H), 7.26–7.23 (m, 3H), 6.99(td, J = 8.8, 2.4 Hz, 1H), 6.68 (dd, J = 8.4, 4.0 Hz, 1H), 6.42 (s,1H), 6.03 (s, 1H), 5.94 (s, 1H), 5.11 (s, 2H), 3.15 (s, 3H), 1.32 (s,9H); 13C NMR (CDCl3, 100 MHz): δ 174.2, 165.1, 159.2 (d, J =239.3 Hz), 153.9, 139.8, 136.4, 134.9, 130.6 (d, J = 7.2 Hz),128.6 (×2), 128.5, 128.4, 115.4 (d, J = 23.3 Hz), 113.3 (d, J = 25.2Hz), 108.8 (d, J = 8.0 Hz), 80.6, 67.3, 64.1, 28.2, 26.7; IR (KBr,cm−1): ν 3298, 2981, 1711, 1608, 1520, 1495, 1369, 1280, 1166;HRMS (ESI) calcd for C24H26FN2O5 ([M + H]+): 441.1826,found: 441.1826; HPLC analysis (OD-H column, λ = 254 nm,eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1):tR = 12.20 min (minor), 15.77 min (major).

(S)-Benzyl 2-(3-(tert-butoxycarbonyl)-5-chloro-1-methyl-2-oxoindolin-3-yl)acrylate (8g). White solid, 94% yield, 81% ee,mp 98.6–99.2 °C; [α]25D −62.7 (c 0.71, CH2Cl2);

1H NMR (CDCl3,400 MHz): δ 7.45 (d, J = 2.0 Hz, 1H), 7.37–7.33 (m, 3H),7.27–7.23 (m, 3H), 6.69 (d, J = 8.4 Hz, 1H), 6.43 (s, 1H), 6.04 (s,1H), 5.94 (s, 1H), 5.13 (d, J = 12.0 Hz, 1H), 5.10 (d, J = 12.4 Hz,1H), 3.15 (s, 3H), 1.32 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ174.1, 165.1, 153.8, 142.5, 136.4, 134.9, 130.7, 129.2, 128.7,128.6 (×2), 128.4, 128.1, 125.3, 109.3, 80.7, 67.4, 63.9, 28.2,26.7; IR (KBr, cm−1): ν 3301, 2981, 1712, 1601, 1519, 1489,1368, 1280, 1163; HRMS (ESI) calcd for C24H26ClN2O5

([M + H]+): 457.1530, found: 457.1535; HPLC analysis (OD-Hcolumn, λ = 254 nm, eluent: hexane–2-propanol = 90/10, flowrate: 0.9 mL min−1): tR = 12.75 min (minor), 16.83 min (major).

(S)-Benzyl 2-(5-bromo-3-(tert-butoxycarbonyl)-1-methyl-2-oxoindolin-3-yl)acrylate (8h). White solid, 97% yield, 80% ee,mp 139.0–139.7 °C; [α]25D −55.5 (c 0.81, CH2Cl2);

1H NMR(CDCl3, 400 MHz): δ 7.58 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.4,2.0 Hz, 1H), 7.38–7.33 (m, 3H), 7.25–7.23 (m, 2H), 6.64 (d, J =8.0 Hz, 1H), 6.43 (s, 1H), 6.05 (s, 1H), 5.94 (s, 1H), 5.14 (d, J =12.4 Hz, 1H), 5.09 (d, J = 12.4 Hz, 1H), 3.14 (s, 3H), 1.32 (s,9H); 13C NMR (CDCl3, 100 MHz): δ 174.0, 165.0, 153.8, 143.0,136.4, 134.9, 132.1, 131.1, 128.7 (×2), 128.6, 128.4, 127.9, 115.4,109.9, 80.7, 67.4, 63.8, 28.2, 26.7; IR (KBr, cm−1): ν 3343, 2974,1718, 1609, 1491, 1398, 1366, 1253, 1158, 1100, 951, 823, 758,701; HRMS (ESI) calcd for C24H25BrNaN2O5 ([M + Na]+):523.0845, found: 523.0840; HPLC analysis (OD-H column, λ =254 nm, eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mLmin−1): tR = 13.28 min (minor), 17.52 min (major).

(S)-Benzyl 2-(3-(tert-butoxycarbonyl)-1,5-dimethyl-2-oxoindo-lin-3-yl)acrylate (8i). Colorless syrup, 99% yield, 88% ee, [α]25D−85.4 (c 0.72, CH2Cl2);

1H NMR (CDCl3, 400 MHz): δ 7.35–7.29(m, 3H), 7.26–7.22 (m, 3H),7.08 (d, J = 7.6 Hz, 1H), 6.66 (d, J =

8.0 Hz, 1H), 6.37 (s, 1H), 6.09 (s, 1H), 5.89 (s, 1H), 5.11 (s, 2H),3.13 (s, 3H), 2.28 (s, 3H), 1.30 (s, 9H); 13C NMR (CDCl3,100 MHz): δ 174.4, 165.5, 154.0, 141.4, 137.0, 135.1, 132.3,129.5, 129.1, 128.6, 128.5, 128.4, 127.9, 125.5, 108.1, 80.3, 67.2,64.1, 28.2, 26.6, 21.2; IR (KBr, cm−1): ν 3141, 2979, 1723, 1620,1501, 1394, 1367, 1252, 1160, 1093, 1001, 810, 751, 699; HRMS(ESI) calcd for C25H28N2NaO5 ([M + Na]+): 459.1896, found:459.1901; HPLC analysis (OD-H column, λ = 254 nm, eluent:hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1): tR =11.69 min (minor), 14.45 min (major).

(S)-Benzyl 2-(3-(tert-butoxycarbonyl)-5-methoxy-1-methyl-2-oxoindolin-3-yl)acrylate (8j). Colorless syrup, 99% yield, 89%ee, [α]25D −58.1 (c 0.74, CH2Cl2);

1H NMR (CDCl3, 400 MHz):δ 7.34–7.31 (m, 3H), 7.25–7.23 (m, 2H), 7.11 (d, J = 2.4 Hz, 1H),6.81 (dd, J = 8.4, 2.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.38 (s, 1H),6.11 (s, 1H), 5.91 (s, 1H), 5.11 (s, 2H), 3.73 (s, 3H), 3.13 (s, 3H),1.31 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 174.1, 165.4, 156.0,153.9, 137.3, 136.8, 135.1, 130.4, 128.6, 128.4, 128.3, 128.2, 113.8,112.1, 108.7, 80.3, 67.2, 64.3, 55.8, 28.2, 26.7; IR (KBr, cm−1): ν3132, 2978, 1722, 1606, 1499, 1393, 1367, 1289, 1160, 1034, 968,809, 742; HRMS (ESI) calcd for C25H29N2O6 ([M + H]+): 453.2026,found: 453.2029; HPLC analysis (OD-H column, λ = 254 nm,eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1): tR =16.43 min (minor), 20.60 min (major).

(S)-Benzyl 2-(3-(tert-butoxycarbonyl)-6-chloro-1-methyl-2-oxoindolin-3-yl)acrylate (8k). White solid, 95% yield, 82% ee,mp 151.1–151.9 °C; [α]25D −34.1 (c 0.69, CH2Cl2);

1H NMR(CDCl3, 400 MHz): δ 7.37–7.33 (m, 4H), 7.22–7.19 (m, 2H), 6.97(dd, J = 8.0, 2.0 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 6.42 (s, 1H),5.95 (s, 1H), 5.94 (s, 1H), 5.09 (d, J = 12.0 Hz, 1H), 5.05 (d, J =12.4 Hz, 1H), 3.10 (s, 3H), 1.32 (s, 9H); 13C NMR (CDCl3,100 MHz): δ 174.4, 165.1, 153.9, 145.1, 136.6, 135.1, 134.8,128.6, 128.5, 128.4, 127.3, 126.0, 122.5, 109.2, 80.6, 67.4, 63.5,28.2, 26.7; IR (KBr, cm−1): ν 3265, 3074, 2998, 1706, 1612,1523, 1400, 1371, 1279, 1251, 1172, 1074, 961, 879, 697; HRMS(ESI) calcd for C24H25ClN2NaO5 ([M + Na]+): 479.1350, found:479.1357; HPLC analysis (OD-H column, λ = 254 nm, eluent:hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1): tR =12.67 min (minor), 17.59 min (major).

(S)-Benzyl 2-(6-bromo-3-(tert-butoxycarbonyl)-1-methyl-2-oxoindolin-3-yl)acrylate (8l). White solid, 99% yield, 82% ee,mp 159.7–161.0 °C; [α]25D −55.1 (c 0.79, CH2Cl2);

1H NMR(CDCl3, 400 MHz): δ 7.36–7.34 (m, 3H), 7.30 (d, J = 8.0 Hz, 1H),7.21–7.19 (m, 2H), 7.13 (dd, J = 8.0, 2.0 Hz, 1H), 6.86 (d, J = 2.0Hz, 1H), 6.42 (s, 1H), 5.96 (s, 1H), 5.94 (s, 1H), 5.09 (d, J = 12.4Hz, 1H), 5.04 (d, J = 12.4 Hz, 1H), 3.09 (s, 3H), 1.32 (s, 9H);13C NMR (CDCl3, 100 MHz): δ 174.3, 165.1, 153.9, 145.2, 136.5,134.8, 128.6 (×2), 128.5, 128.4, 127.9, 126.4, 125.5, 123.0, 112.0,80.6, 67.4, 63.5, 28.2, 26.7; IR (KBr, cm−1): ν 3267, 1707, 1609,1400, 1370, 1171; HRMS (ESI) calcd for C24H26BrN2O5


(S)-Benzyl 2-(3-(tert-butoxycarbonyl)-7-fluoro-1-methyl-2-oxoindolin-3-yl)acrylate (8m). White solid, 95% yield, 84% ee,mp 109.5–110.3 °C; [α]25D −62.1 (c 0.70, CH2Cl2);

1H NMR



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(CDCl3, 400 MHz): δ 7.35–7.33 (m, 3H), 7.25–7.22 (m, 2H), 7.20(d, J = 7.2 Hz, 1H), 7.03–6.98 (m, 1H), 6.95–6.90 (m, 1H), 6.39(s, 1H), 6.11 (s, 1H), 5.91 (s, 1H), 5.10 (s, 2H), 3.35 (d, J =2.8 Hz, 3H), 1.31 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 174.2,165.2, 153.9, 147.7 (d, J = 242.1 Hz), 136.6, 134.9, 131.9 (d, J =2.5 Hz), 130.6 (d, J = 8.3 Hz), 128.7, 128.6, 128.4, 128.3, 123.2(d, J = 6.4 Hz), 120.5 (d, J = 2.8 Hz), 117.3 (d, J = 19.3 Hz), 80.6,67.4, 63.9, 29.1 (d, J = 6.0 Hz), 28.1; IR (KBr, cm−1): ν 3413,3150, 1723, 1630, 1497, 1481, 1399, 1370, 1282, 1239, 1165;HRMS (ESI) calcd for C24H25FN2NaO5 ([M + Na]+): 463.1645,found: 463.1641; HPLC analysis (OD-H column, λ = 254 nm,eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1):tR = 9.80 min (minor), 11.38 min (major).

(S)-Benzyl 2-(3-(tert-butoxycarbonyl)-7-chloro-1-methyl-2-oxoindolin-3-yl)acrylate (8n). White solid, 95% yield, 82% ee,mp 102.2–102.9 °C; [α]25D −59.6 (c 0.72, CH2Cl2);

1H NMR(CDCl3, 400 MHz): δ 7.35–7.31 (m, 3H), 7.30 (dd, J = 7.6,0.8 Hz, 1H), 7.25–7.22 (m, 2H), 7.19 (dd, J = 8.0, 1.2 Hz), 6.90(t, J = 8.0 Hz, 1H), 6.39 (s, 1H), 6.11 (s, 1H), 5.89 (s, 1H), 5.10 (s,2H), 3.52 (s, 3H), 1.31 (s, 9H); 13C NMR (CDCl3, 100 MHz):δ 174.8, 165.2, 153.8, 139.8, 136.6, 134.9, 132.0, 131.6, 128.7,128.5, 128.3 (×2), 123.4, 123.1, 115.7, 80.6, 67.4, 63.6, 30.1, 28.1;IR (KBr, cm−1): ν 3255, 3160, 2979, 1730, 1708, 1611, 1468,1400, 1367, 1169, 1111; HRMS (ESI) calcd for C24H26ClN2O5


(S)-Benzyl 2-(7-bromo-3-(tert-butoxycarbonyl)-1-methyl-2-oxoindolin-3-yl)acrylate (8o). Colorless syrup, 99% yield, 80%ee, [α]25D −47.8 (c 0.68, CH2Cl2);

1H NMR (CDCl3, 400 MHz): δ7.39–7.33 (m, 5H), 7.25–7.22 (m, 2H), 6.83 (t, J = 7.6 Hz, 1H),6.38 (s, 1H), 6.13 (s, 1H), 5.88 (s, 1H), 5.10 (s, 2H), 3.54 (s, 3H),1.30 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 175.0, 165.2, 153.8,141.2, 136.6, 134.9 (×2), 132.3, 128.7, 128.6, 128.3, 128.1, 123.8,123.6, 102.6, 80.7, 67.4, 63.5, 30.3, 28.1; IR (KBr, cm−1): ν 3400,3124, 2981, 1724, 1606, 1579, 1462, 1399, 1367, 1308, 1165,1104, 1056, 968, 740, 698; HRMS (ESI) calcd for C24H26BrN2O5


(S)-Benzyl 2-(3-(tert-butoxycarbonyl)-1-methyl-2-oxo-7-(tri-fluoromethyl)indolin-3-yl)acrylate (8p). White solid, 80%yield, 70% ee, mp 112.6–113.4 °C; [α]25D −36.9 (c 0.65, CH2Cl2);1H NMR (CDCl3, 400 MHz): δ 7.61–7.56 (m, 2H), 7.35–7.32 (m,3H), 7.25–7.23 (m, 2H), 7.06 (t, J = 8.0 Hz, 1H), 6.40 (s, 1H),6.15 (s, 1H), 5.90 (s, 1H), 5.11 (s, 2H), 3.41 (d, J = 2.4 Hz, 3H),1.28 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 175.5, 165.1, 153.8,141.9 (d, J = 1.1 Hz), 136.6, 134.9, 131.8, 128.6, 128.5 (×2),128.3, 128.0, 127.2 (q, J = 6.0 Hz), 124.9, 122.0, 112.6 (q, J =32.8 Hz), 80. 8, 67.4, 62.4, 29.4 (q, J = 6.4 Hz), 28.1; IR (KBr,cm−1): ν 3267, 3161, 2983, 1720, 1597, 1465, 1351, 1309, 1210,1175, 1095, 749, 702, 600; HRMS (ESI) calcd forC25H25F3N2NaO5 ([M + Na]+): 513.1613, found: 513.1608; HPLCanalysis (AD-H column, λ = 254 nm, eluent: hexane–2-propanol= 90/10, flow rate: 0.9 mL min−1): tR = 20.26 min (minor),34.02 min (major).

(S)-Benzyl 2-(3-(tert-butoxycarbonyl)-1,7-dimethyl-2-oxoindolin-3-yl)acrylate (8q). Colorless syrup, 98% yield, 89% ee,[α]25D −59.2 (c 0.71, CH2Cl2);

1H NMR (CDCl3, 400 MHz):δ 7.35–7.32 (m, 3H), 7.25–7.21 (m, 3H), 6.99 (d, J = 7.2 Hz, 1H),6.88 (t, J = 7.6 Hz, 1H), 6.34 (s, 1H), 6.16 (s, 1H), 5.86 (s, 1H),5.09 (s, 2H), 3.41 (s, 3H), 2.48 (s, 3H), 1.30 (s, 9H); 13C NMR(CDCl3, 100 MHz): δ 175.2, 165.5, 153.9, 141.5, 137.2, 135.1,133.1, 129.8, 128.6, 128.4, 128.3, 127.7, 122.6, 122.5, 119.8,80.2, 67.2, 63.5, 30.1, 28.2, 19.1; IR (KBr, cm−1): ν 3147, 2979,1723, 1603, 1458, 1397, 1366, 1278, 1247, 1164, 1070, 748, 698;HRMS (ESI) calcd for C25H28N2NaO5 ([M + Na]+): 459.1896,found: 459.1893; HPLC analysis (OD-H column, λ = 254 nm,eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1):tR = 13.35 min (minor), 20.58 min (major).

(S)-Methyl 2-(3-(tert-butoxycarbonyl)-1,5-dimethyl-2-oxoindo-lin-3-yl)acrylate (8r). White solid, 94% yield, 91% ee, mp121.5–122.0 °C; [α]25D −98.2 (c 0.57, CH2Cl2);

1H NMR (CDCl3,400 MHz): δ 7.26 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.74 (d, J =8.0 Hz, 1H), 6.30 (s, 1H), 6.17 (s, 1H), 5.86 (s, 1H), 3.73 (s, 3H),3.26 (s, 3H), 2.31 (s, 3H), 1.30 (s, 9H); 13C NMR (CDCl3,100 MHz): δ 174.5, 166.1, 154.0, 141.4, 136.9, 132.3, 129.6,129.3, 127.7, 125.3, 108.1, 80.3, 64.2, 52.4, 28.2, 26.7, 21.2; IR(KBr, cm−1): ν 3307, 3132, 2986, 1717, 1624, 1511, 1442, 1400,1366, 1323, 1253, 1169, 1101, 810, 694; HRMS (ESI) calcd forC19H25N2O5 ([M + H]+): 361.1763, found: 361.1759; HPLC ana-lysis (OD-H column, λ = 254 nm, eluent: hexane–2-propanol =90/10, flow rate: 0.9 mL min−1): tR = 10.81 min (minor),14.97 min (major).

(S)-Methyl 2-(3-(tert-butoxycarbonyl)-5-methoxy-1-methyl-2-oxoindolin-3-yl)acrylate (8s). White solid, 93% yield, 90% ee,mp 97.8–98.9 °C; [α]25D −93.1 (c 0.58, CH2Cl2);

1H NMR (CDCl3,400 MHz): δ 7.10 (d, J = 2.8 Hz, 1H), 6.83 (dd, J = 8.4, 2.4 Hz,1H), 6.75 (d, J = 8.4 Hz, 1H), 6.31 (s, 1H), 6.19 (s, 1H), 5.87 (s,1H), 3.77 (s, 3H), 3.73 (s, 3H), 3.26 (s, 3H), 1.31 (s, 9H);13C NMR (CDCl3, 100 MHz): δ 174.2, 165.0, 156.0, 154.0, 137.3,136.7, 130.6, 127.9, 113.6, 112.0, 108.6, 80.4, 64.4, 55.8, 52.4,28.2, 26.8; IR (KBr, cm−1): ν 3134, 2979, 1722, 1605, 1499,1394, 1367, 1289, 1161, 1034, 870, 812; HRMS (ESI) calcd forC19H24N2NaO6 ([M + Na]+): 399.1532, found: 399.1527; HPLCanalysis (OD-H column, λ = 254 nm, eluent: hexane–2-propanol= 90/10, flow rate: 0.9 mL min−1): tR = 14.76 min (minor),23.14 min (major).

Acknowledgements

We are grateful for the financial support from the NationalNatural Science Foundation of China (21242007, 21102043)and the Fundamental Research Funds for the CentralUniversities.

Notes and references

1 For reviews, see: (a) F. Zhou, Y.-L. Liu and J. Zhou, Adv.Synth. Catal., 2010, 352, 1381; (b) P. Chauhan and



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S. S. Chimni, Tetrahedron: Asymmetry, 2013, 24, 343;(c) Z.-Y. Cao, Y.-H. Wang, X.-P. Zeng and J. Zhou, Tetra-hedron Lett., 2014, 55, 2571.

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3 For enantioselective aza-MBH reaction of isatin-derivedketimines, see: (a) F.-L. Hu, Y. Wei, M. Shi, S. Pindi andG. Li, Org. Biomol. Chem., 2013, 11, 1921; (b) S. Takizawa,

E. Rémond, F. A. Arteaga, Y. Yoshida, V. Sridharan,J. Bayardon, S. Jugé and H. Sasai, Chem. Commun., 2013,49, 8392.

4 For enantioselective MBH reaction of isatins, see:(a) Y.-L. Liu, B.-L. Wang, J.-J. Cao, L. Chen, Y.-X. Zhang,C. Wang and J. Zhou, J. Am. Chem. Soc., 2010, 132, 15176;(b) X.-Y. Guan, Y. Wei and M. Shi, Chem. – Eur. J., 2010, 16,13617; (c) F. Zhong, G.-Y. Chen and Y. Lu, Org. Lett., 2011,13, 82; (d) C.-C. Wang and X.-Y. Wu, Tetrahedron, 2011, 16,2974; (e) J.-Y. Qian, C.-C. Wang, F. Sha and X.-Y. Wu, RSCAdv., 2012, 2, 6042.

5 For reviews on the asymmetric aza-Morita–Baylis–Hillmanreactions, see: (a) G. Masson, C. Housseman and J. Zhu,Angew. Chem., Int. Ed., 2007, 46, 4614; (b) V. Declerck,J. Martinez and F. Lamaty, Chem. Rev., 2009, 109, 1;(c) Y. Wei and M. Shi, Acc. Chem. Res., 2010, 43, 1005;(d) Y. Wei and M. Shi, Chem. Rev., 2013, 113, 6659;(e) Y. Wei and M. Shi, Chin. Sci. Bull., 2010, 55, 1699.

6 Y. Yao, J.-L. Li, Q.-Q. Zhou, L. Dong and Y.-C. Chen, Chem.– Eur. J., 2013, 19, 9447.

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8 (a) K. Yuan, L. Zhang, H.-L. Song, Y. Hu and X.-Y. Wu,Tetrahedron Lett., 2008, 49, 6262; (b) K. Yuan, H.-L. Song,Y. Hu, J.-F. Fang and X.-Y. Wu, Tetrahedron: Asymmetry,2010, 21, 903.

9 H.-L. Song, K. Yuan and X.-Y. Wu, Chem. Commun., 2011,47, 1012.

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11 Y.-Q. Fang and E. N. Jacobsen, J. Am. Chem. Soc., 2008, 130,5660.



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enantioselective aza-morita–baylis–hillman reaction between acrylates and n-boc isatin...

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