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Enantioselective aza-Morita–Baylis–Hillman reaction between acrylates and N-Boc isatin ketimines: asymmetric construction of chiral 3-substituted-3-aminooxindoles† Xuan Zhao, Tian-Ze Li, Jing-Ying Qian, Feng Sha* and Xin-Yan Wu*
Received 30th June 2014, Accepted 15th August 2014 DOI: 10.1039/c4ob01358a
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
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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 ubiquitous structures in many natural products and pharmaceutics.1 In the past few years, a variety of methods for preparing these compounds have been explored.1b,c Among these the enantioselective addition of nucleophiles to isatin-derived ketimines is one of the most efficient and straightforward methods.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 construct 3-substituted-3-amino-2-oxindoles with a chiral quaternary carbon center. However, the enantioselective aza-Morita– Baylis–Hillman reaction involving isatin-derived ketimine has been rarely described.3,4 In the enantioselective aza-Morita–Baylis–Hillman (azaMBH) reaction, a C–C bond forming reaction between electron-deficient olefins and imines is a well-known, powerful protocol for providing densely functionalized chiral amines.5 The imine electrophiles in aza-MBH reaction are mainly focused on activated aldimines, such as tosylimines, nosylimines, SES-imines and phosphinoylimines. Very recently, Shi and co-workers reported an asymmetric aza-MBH reaction of methyl vinyl ketone (MVK) with isatin-derived ketimines catalyzed by chiral β-isocupreidine (β-ICD) and bifunctional phosphine derived from BINOL.3a Meanwhile, Sasai’s group
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 † Electronic supplementary information (ESI) available: Experimental procedure of 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 file of compound ent-8l. CCDC 981628. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob01358a
8072 | Org. Biomol. Chem., 2014, 12, 8072–8078
reported an asymmetric aza-MBH reaction of methyl/ethyl vinyl ketone with ketimines derived from acyclic α-keto esters catalyzed by P-chirogenic organocatalysts, and an example of isatin-derived ketimine was described.3b Chen and coworkers developed an enantioselective aza-MBH reaction of acrolein and ketimines derived from β,γ-unsaturated α-ketoesters catalyzed by the combination of β-ICD association with BINOL or tertiary amine-thiourea.6 However, the enantioselective azaMBH reaction of ketimines with acrylates is still undeveloped. We have found in recent studies that the chiral cyclohexane-based bifunctional phosphines are highly efficient in the asymmetric MBH reaction using acrylates as the nucleophiles, which are less reactive than MVK.4d,e,7 On the other hand, these chiral bifunctional phosphines are effective organocatalysts for the MBH reaction between acrylates and isatins, providing 3-hydroxy-2-oxindoles containing a chiral quaternary carbon center.4d,e Therefore, chiral cyclohexanebased bifunctional phosphines would be conceivable catalysts for the aza-MBH reaction to construct 3-substituted-3-amino2-oxindoles. Herein we report an enantioselective aza-MBH reaction between acrylates and ketimines derived from isatins with chiral bifunctional phosphine-squaramide as the organocatalyst.
Results and discussion Initially an aza-MBH reaction of isatin-derived ketimine 6a with benzyl acrylate was conducted as a model reaction to screen a suitable chiral bifunctional phosphine organocatalyst (Fig. 1). The reactions were performed at 25 °C in CH2Cl2 using 10 mol% chiral catalysts, and the results are summarized in Table 1. The results indicated that the reactivity and the enantioselectivity were sensitive to the H-bonding donor of the chiral cyclohexane-based organocatalysts (entries 1–4). In
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Fig. 1
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Structures of the chiral bifunctional phosphines screened.
Table 1 Screening of chiral bifunctional phosphine organocatalysts for the aza-MBH reaction of isatin-derived N-Boc ketimines with benzyl acrylatea
Entry
Catalyst
Time (h)
Yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13d 14e 15 f
1 2 3 4a 4b 4c 4d 4e 4f 4g 4h 5 4e 4e 4e
0.5 24 8 1 1 24 48 24 24 25 24 24 24 24 72
99 94 97 95 95 93 89 98 81 82 75 81 99 99 80
51 37 43 69 68 72 80 82 58 61 67 −40 84 84 82
a Unless 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 HPLC using 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%.
the presence of the phosphine-thiourea catalyst 1,7a,8 the azaMBH reaction could be completed in half an hour, producing chiral 3-amino-2-oxindole in excellent yield with moderate enantioselectivity (entry 1). Phosphine-squaramide 4a4e provided higher enantioselectivity than the corresponding thiourea 1, amide 2 and ethoxy squaramide 39 (entry 4 vs. 1–3). Therefore phosphine-squaramides containing different alkyl scaffolds were evaluated (entries 4–11). The phosphinesquaramides 4a–4e bearing aliphatic scaffolds exhibited better yields and enantioselectivities than 4f–4h bearing aromatic scaffolds (entries 4–8 vs. 9–11). The squaramides 4a and 4b with a long-chain aliphatic group were so reactive that the azaMBH reaction was accomplished in one hour (entries 4 and 5). The additional chiral group in the alkyl squaramide moiety could improve the enantioselectivity of the aza-MBH reaction
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(entries 7 and 8 vs. 6). The L-valine-derived phosphine-thiourea 510 was observed to be less reactive than the chiral cyclohexane-based phosphine-thiourea 1 for the reaction, and a longer reaction time was required (entry 12 vs. 1). The phosphine-squaramide 4e proved to be the best organocatalyst for the model reaction, providing the desired product 8a in 98% yield and 82% ee (entry 8). Then the catalyst loading of 4e was examined. The aza-MBH reaction could be achieved with a reduced amount of catalyst loading with as low as 2 mol% 4e, giving a similar result to using 10 mol% 4e (entries 13 and 14 vs. 8). However, further decrease of the catalyst loading to 1 mol% led to significant decrease in the yield with retained enantioselectivity (entry 15). The reaction conditions of the aza-MBH reaction were then probed with 2 mol% of organocatalyst 4e (Table 2). Less polar solvents such as toluene, CH2Cl2 and CHCl3 resulted in excellent yields (91–99%) with 79–84% ee (entries 1–3). In the case of ether, moderate yield was obtained and a longer time was 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 acrylates catalyzed by phosphine-squaramide.4e In the polar solvents such as EtOAc and DMF, the aza-MBH products were provided in moderate yields (entries 6 and 7). The aza-MBH reaction in CH3CN was decelerated than that in CH2Cl2, while the enantioselectivity was slightly improved (entry 8 vs. 2). The different substrate concentrations in CH2Cl2 resulted in the
Table 2
Optimization of the reaction conditionsa
Entry
Solvent
Temp. (°C)
Time (d)
Yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9f 10g 11 12 13 14 15 16h
Toluene CH2Cl2 CHCl3 Et2O THF EtOAc DMF CH3CN CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 1 : 2 CH2Cl2–CH3CN 1 : 1 CH2Cl2–CH3CN 2 : 1 CH2Cl2–CH3CN 1 : 2 CH2Cl2–CH3CN
25 25 25 25 25 25 25 25 25 25 0 40 25 25 25 25
3 1 1 4 4 3 3 3 1 1 3.5 0.3 2 1.5 1.2 2
91 99 97 78 NRd 52 64 94 99 99 72 100 95 97 99 98
79 84 80 78 nde 78 79 87 84 84 87 83 87 86 86 86
a Unless 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 using Chiralcel OD-H column. d No reaction. e Not determined. f The reaction was conducted in 2 mL solvent. g The reaction was conducted in 0.67 mL solvent. h The amount of benzyl acrylate was 1.0 mmol.
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same enantioselectivities and yields (entries 2, 9, 10). The enantioselectivity was not sensitive to the reaction temperature, and a lower reaction temperature resulted in a longer reaction time (entries 2, 11 and 12). To attain high enantioselectivity with a reasonable reaction time, a mixed solvent system of CH2Cl2 with CH3CN was surveyed. The results indicated that at a mixing ratio of CH2Cl2–CH3CN = 1 : 2 (v/v), the best 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 obvious change in the enantioselectivity using unbranched alkyl acrylates as the Michael donors, while n-butyl acrylate was less reactive than others (entries 1–4). Due to steric hindrance, t-butyl acrylate was inactive under the typical reaction conditions (entry 5). The chiral catalytic system was also not suitable for phenyl acrylate as the reaction only gave the product with 43% yield and 2% ee (entry 6). Further exploration of the substrate scope was concentrated on varying the substituents on the isatin-derived ketimines. The aza-MBH reaction tolerated well all the N-Boc-1-methyl ketimine substrates with either electron-withdrawing or
Table 3
Substrate scope of the enantioselective aza-MBH reactionsa
Entry
R1
R2
8
Time (d)
Yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 f
H H H H H H 4-Br 5-F 5-Cl 5-Br 5-Me 5-MeO 6-Cl 6-Br 7-F 7-Cl 7-Br 7-CF3 7-Me 5-Me 5-MeO H
Bn Me Et n-Bu t-Bu Ph Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Me Me Bn
8a 8b 8c 8d — 8e — 8f 8g 8h 8i 8j 8k 8l 8m 8n 8o 8p 8q 8r 8s 8a
2 3.5 3.5 5 5 6 4 2 1.5 2 2.5 3.5 1.5 1.5 2 2.5 2 6 5 7 7 3
95 88 87 58 NRd 43 NR 98 94 97 99 99 95 99 95 95 99 80 98 94 93 93
87 89 88 87 nde 2 nd 81 81 80 88 89 82 82 84 82 80 70 89 91 90 87
a Unless 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 were determined by HPLC using Chiralcel OD-H column or Chiralpak AD-H column. d No reaction. e Not determined. f The reaction was conducted in 1 mmol scale.
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electron-donating groups at 5-, 6- or 7-positions (entries 8–21). The electron-donating group exhibited a positive effect on the enantioselectivity, while the electron-withdrawing group exhibited a negative effect. Isatin-derived ketimine with a substituent at the 4-position is unreactive for the aza-MBH reaction under the identical reaction conditions, probably due to steric hindrance (entry 7).2i,q,3a A large scale synthesis using 1 mmol N-Boc isatin ketimine 6a also provided an excellent yield (93%) and enantioselectivity (87% ee) (entry 22). To determine the absolute configuration of 3-amino-2oxindoles with a chiral quaternary carbon center, the enantiomer of the aza-MBH product 8l (ent-8l) was acquired using the enantiomer of 4e as a chiral catalyst. The single crystal of ent-8l was obtained by recrystallization from n-hexane–CH2Cl2, and the configuration of the stereocenters was determined to be R by X-ray crystallography (Fig. 2). Therefore, the aza-MBH product 8l should be of S configuration, and the configurations of other adducts 8 were assigned by analogy. According to the above-mentioned experimental results and the related reports,2b,8a,11 a probable transition-state structure was proposed as shown in Fig. 3. The electrophilic squaramide of the chiral catalyst activates the ketimine through hydrogenbonding interactions,2b then the chiral cyclohexyl scaffold forces the phosphinoyl associated enolate8a,11 to attack the activated ketimine from the Si-face to form the adducts in S configuration.
Fig. 2
X-ray crystal structure of ent-8l.
Fig. 3
Proposed transition state.
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Conclusions
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In summary, we have explored the first example of enantioselective aza-Morita–Baylis–Hillman reaction of acrylates with isatin-derived N-Boc ketimines. The chiral bifunctional phosphine-squaramide 4e was an efficient organocatalyst for this reaction. With 2 mol% of 4e in 1 : 2 CH2Cl2–CH3CN, the azaMBH reaction could be carried out at 25 °C to provide the desired products in up to 91% ee and good-to-excellent yields (up to 99%).
Experimental section General information Melting points were taken without correction. Optical rotations were measured on a WZZ-2A digital polarimeter at the wavelength of the sodium D-line (589 nm). 1H, 13C NMR spectra were recorded on a Bruker 400 spectrometer. The chemical shifts of 1H NMR and 13C NMR spectra were referenced to tetramethylsilane (δ 0.00) using CDCl3 as the solvent. IR spectra were recorded on a Nicolet Magna-I 550 spectrometer. High resolution mass spectra (HRMS) were recorded on a Micromass GCT with electron spray ionization (ESI) resource. HPLC analysis was performed on Waters equipment using the Daicel Chiralcel OD-H or Chiralpak AD-H column. Dichloromethane, chloroform, ethyl acetate and acetonitrile were distilled from CaH2. Toluene, ether and THF were distilled from sodium-benzophenone. DMF was dried over CaH2 and distilled under reduced pressure. Thin-layer chromatography (TLC) was performed on Silicycle 10–40 μm silica gel plates. Column chromatography was performed using silica gel (300–400 mesh) eluting with ethyl acetate and petroleum ether. Chiral bifunctional phosphine organocatalysts 1–5 were prepared according to literature procedures.4e,8–10 All substituted N-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 : 2 CH2Cl2–CH3CN was added acrylate (0.6 mmol) at 25 °C. After 10 min stirring at this temperature, isatin-derived N-Boc ketimine (0.2 mmol) was added. The reaction mixture was stirred at 25 °C (monitoring by TLC). After the reaction was complete, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel to afford the desired adducts and the ee values were determined by HPLC analysis with a chiral column. (S)-Benzyl 2-(3-(tert-butoxycarbonyl)-1-methyl-2-oxoindolin3-yl)acrylate (8a). White solid, 95% yield, 87% ee, mp 1 102.5–102.9 °C; [α]25 D −76.3 (c 0.68, CH2Cl2); H 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,
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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-H column, λ = 254 nm, eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1): tR = 14.09 min (minor), 17.85 min (major). (S)-Methyl 2-(3-(tert-butoxycarbonyl)-1-methyl-2-oxoindolin3-yl)acrylate (8b). White solid, 88% yield, 89% ee, mp 1 143.5–143.8 °C; [α]25 D −82.4 (c 0.54, CH2Cl2); H 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-oxoindolin3-yl)acrylate (8c). White solid, 87% yield, 88% ee, mp 1 112.9–113.2 °C; [α]25 D −83.3 (c 0.52, CH2Cl2); H 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-oxoindolin3-yl)acrylate (8d). White solid, 58% yield, 87% ee, mp 1 96.4–96.6 °C; [α]25 D −60.5 (c 0.38, CH2Cl2); H 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 mL min−1): tR = 7.63 min (minor), 9.73 min (major). (S)-Phenyl 2-(3-(tert-butoxycarbonyl)-1-methyl-2-oxoindolin3-yl)acrylate (8e). White solid, 43% yield, 2% ee, mp 158.3–159.6 °C; 1H NMR (CDCl3, 400 MHz): δ 7.55 (d, J = 7.6 Hz, 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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C 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 mL min−1): tR = 11.02 min (major), 13.02 min (minor). (S)-Benzyl 2-(3-(tert-butoxycarbonyl)-5-fluoro-1-methyl-2oxoindolin-3-yl)acrylate (8f ). White solid, 98% yield, 81% ee, 1 mp 134.7–135.0 °C; [α]25 D −67.3 (c 0.72, CH2Cl2); H 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 = 25.2 Hz), 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-2oxoindolin-3-yl)acrylate (8g). White solid, 94% yield, 81% ee, 1 mp 98.6–99.2 °C; [α]25 D −62.7 (c 0.71, CH2Cl2); H 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): δ 174.1, 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-H column, λ = 254 nm, eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1): tR = 12.75 min (minor), 16.83 min (major). (S)-Benzyl 2-(5-bromo-3-(tert-butoxycarbonyl)-1-methyl-2oxoindolin-3-yl)acrylate (8h). White solid, 97% yield, 80% ee, 1 mp 139.0–139.7 °C; [α]25 D −55.5 (c 0.81, CH2Cl2); H 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 mL min−1): tR = 13.28 min (minor), 17.52 min (major). (S)-Benzyl 2-(3-(tert-butoxycarbonyl)-1,5-dimethyl-2-oxoindolin-3-yl)acrylate (8i). Colorless syrup, 99% yield, 88% ee, [α]25 D −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 =
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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-2oxoindolin-3-yl)acrylate (8j). Colorless syrup, 99% yield, 89% 1 ee, [α]25 D −58.1 (c 0.74, CH2Cl2); H 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): ν 3132, 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-2oxoindolin-3-yl)acrylate (8k). White solid, 95% yield, 82% ee, 1 mp 151.1–151.9 °C; [α]25 D −34.1 (c 0.69, CH2Cl2); H 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-2oxoindolin-3-yl)acrylate (8l). White solid, 99% yield, 82% ee, 1 mp 159.7–161.0 °C; [α]25 D −55.1 (c 0.79, CH2Cl2); H 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 = 2.0 Hz, 1H), 6.42 (s, 1H), 5.96 (s, 1H), 5.94 (s, 1H), 5.09 (d, J = 12.4 Hz, 1H), 5.04 (d, J = 12.4 Hz, 1H), 3.09 (s, 3H), 1.32 (s, 9H); 13 C 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 ([M + H]+): 501.1025, found: 501.1018; HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1): tR = 12.35 min (minor), 16.95 min (major). (S)-Benzyl 2-(3-(tert-butoxycarbonyl)-7-fluoro-1-methyl-2oxoindolin-3-yl)acrylate (8m). White solid, 95% yield, 84% ee, 1 mp 109.5–110.3 °C; [α]25 D −62.1 (c 0.70, CH2Cl2); H 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-2oxoindolin-3-yl)acrylate (8n). White solid, 95% yield, 82% ee, 1 mp 102.2–102.9 °C; [α]25 D −59.6 (c 0.72, CH2Cl2); H 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 ([M + H]+): 457.1530, found: 457.1530; HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1): tR = 10.23 min (minor), 12.01 min (major). (S)-Benzyl 2-(7-bromo-3-(tert-butoxycarbonyl)-1-methyl-2oxoindolin-3-yl)acrylate (8o). Colorless syrup, 99% yield, 80% 1 ee, [α]25 D −47.8 (c 0.68, CH2Cl2); H NMR (CDCl3, 400 MHz): δ 7.39–7.33 (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 ([M + H]+): 501.1025, found: 501.1028; HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1): tR = 11.90 min (minor), 14.88 min (major). (S)-Benzyl 2-(3-(tert-butoxycarbonyl)-1-methyl-2-oxo-7-(trifluoromethyl)indolin-3-yl)acrylate (8p). White solid, 80% yield, 70% ee, mp 112.6–113.4 °C; [α]25 D −36.9 (c 0.65, CH2Cl2); 1 H 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 for C25H25F3N2NaO5 ([M + Na]+): 513.1613, found: 513.1608; HPLC analysis (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).
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(S)-Benzyl 2-(3-(tert-butoxycarbonyl)-1,7-dimethyl-2-oxoindolin3-yl)acrylate (8q). Colorless syrup, 98% yield, 89% ee, 1 [α]25 H NMR (CDCl3, 400 MHz): D −59.2 (c 0.71, CH2Cl2); 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-oxoindolin-3-yl)acrylate (8r). White solid, 94% yield, 91% ee, mp 1 121.5–122.0 °C; [α]25 D −98.2 (c 0.57, CH2Cl2); H 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 for C19H25N2O5 ([M + H]+): 361.1763, found: 361.1759; HPLC analysis (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-2oxoindolin-3-yl)acrylate (8s). White solid, 93% yield, 90% ee, 1 mp 97.8–98.9 °C; [α]25 D −93.1 (c 0.58, CH2Cl2); H 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); 13 C 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 for C19H24N2NaO6 ([M + Na]+): 399.1532, found: 399.1527; HPLC analysis (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 National Natural Science Foundation of China (21242007, 21102043) and the Fundamental Research Funds for the Central Universities.
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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E. Rémond, F. A. Arteaga, Y. Yoshida, V. Sridharan, J. Bayardon, S. Jugé and H. Sasai, Chem. Commun., 2013, 49, 8392. 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, RSC Adv., 2012, 2, 6042. For reviews on the asymmetric aza-Morita–Baylis–Hillman reactions, 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. Y. Yao, J.-L. Li, Q.-Q. Zhou, L. Dong and Y.-C. Chen, Chem. – Eur. J., 2013, 19, 9447. (a) K. Yuan, H.-L. Song, Y.-J. Hu and X.-Y. Wu, Tetrahedron, 2009, 65, 8185; (b) W.-H. Yang, F. Sha, X. Zhang, K. Yuan and X.-Y. Wu, Chin. J. Chem., 2012, 30, 2652. (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. H.-L. Song, K. Yuan and X.-Y. Wu, Chem. Commun., 2011, 47, 1012. (a) J.-J. Gong, T.-Z. Li, K. Pan and X.-Y. Wu, Chem. Commun., 2011, 47, 1491; (b) J.-J. Gong, K. Yuan, H.-L. Song and X.-Y. Wu, Tetrahedron, 2010, 66, 2439; (c) J.-J. Gong, K. Yuan and X.-Y. Wu, Tetrahedron: Asymmetry, 2009, 20, 2117. 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 ketimines: asymmetric construction of chiral 3-substituted-3-aminooxindoles† Xuan Zhao, Tian-Ze Li, Jing-Ying Qian, Feng Sha* and Xin-Yan Wu*
Received 30th June 2014, Accepted 15th August 2014 DOI: 10.1039/c4ob01358a
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
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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 ubiquitous structures in many natural products and pharmaceutics.1 In the past few years, a variety of methods for preparing these compounds have been explored.1b,c Among these the enantioselective addition of nucleophiles to isatin-derived ketimines is one of the most efficient and straightforward methods.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 construct 3-substituted-3-amino-2-oxindoles with a chiral quaternary carbon center. However, the enantioselective aza-Morita– Baylis–Hillman reaction involving isatin-derived ketimine has been rarely described.3,4 In the enantioselective aza-Morita–Baylis–Hillman (azaMBH) reaction, a C–C bond forming reaction between electron-deficient olefins and imines is a well-known, powerful protocol for providing densely functionalized chiral amines.5 The imine electrophiles in aza-MBH reaction are mainly focused on activated aldimines, such as tosylimines, nosylimines, SES-imines and phosphinoylimines. Very recently, Shi and co-workers reported an asymmetric aza-MBH reaction of methyl vinyl ketone (MVK) with isatin-derived ketimines catalyzed by chiral β-isocupreidine (β-ICD) and bifunctional phosphine derived from BINOL.3a Meanwhile, Sasai’s group
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 † Electronic supplementary information (ESI) available: Experimental procedure of 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 file of compound ent-8l. CCDC 981628. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob01358a
8072 | Org. Biomol. Chem., 2014, 12, 8072–8078
reported an asymmetric aza-MBH reaction of methyl/ethyl vinyl ketone with ketimines derived from acyclic α-keto esters catalyzed by P-chirogenic organocatalysts, and an example of isatin-derived ketimine was described.3b Chen and coworkers developed an enantioselective aza-MBH reaction of acrolein and ketimines derived from β,γ-unsaturated α-ketoesters catalyzed by the combination of β-ICD association with BINOL or tertiary amine-thiourea.6 However, the enantioselective azaMBH reaction of ketimines with acrylates is still undeveloped. We have found in recent studies that the chiral cyclohexane-based bifunctional phosphines are highly efficient in the asymmetric MBH reaction using acrylates as the nucleophiles, which are less reactive than MVK.4d,e,7 On the other hand, these chiral bifunctional phosphines are effective organocatalysts for the MBH reaction between acrylates and isatins, providing 3-hydroxy-2-oxindoles containing a chiral quaternary carbon center.4d,e Therefore, chiral cyclohexanebased bifunctional phosphines would be conceivable catalysts for the aza-MBH reaction to construct 3-substituted-3-amino2-oxindoles. Herein we report an enantioselective aza-MBH reaction between acrylates and ketimines derived from isatins with chiral bifunctional phosphine-squaramide as the organocatalyst.
Results and discussion Initially an aza-MBH reaction of isatin-derived ketimine 6a with benzyl acrylate was conducted as a model reaction to screen a suitable chiral bifunctional phosphine organocatalyst (Fig. 1). The reactions were performed at 25 °C in CH2Cl2 using 10 mol% chiral catalysts, and the results are summarized in Table 1. The results indicated that the reactivity and the enantioselectivity were sensitive to the H-bonding donor of the chiral cyclohexane-based organocatalysts (entries 1–4). In
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Fig. 1
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Structures of the chiral bifunctional phosphines screened.
Table 1 Screening of chiral bifunctional phosphine organocatalysts for the aza-MBH reaction of isatin-derived N-Boc ketimines with benzyl acrylatea
Entry
Catalyst
Time (h)
Yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13d 14e 15 f
1 2 3 4a 4b 4c 4d 4e 4f 4g 4h 5 4e 4e 4e
0.5 24 8 1 1 24 48 24 24 25 24 24 24 24 72
99 94 97 95 95 93 89 98 81 82 75 81 99 99 80
51 37 43 69 68 72 80 82 58 61 67 −40 84 84 82
a Unless 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 HPLC using 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%.
the presence of the phosphine-thiourea catalyst 1,7a,8 the azaMBH reaction could be completed in half an hour, producing chiral 3-amino-2-oxindole in excellent yield with moderate enantioselectivity (entry 1). Phosphine-squaramide 4a4e provided higher enantioselectivity than the corresponding thiourea 1, amide 2 and ethoxy squaramide 39 (entry 4 vs. 1–3). Therefore phosphine-squaramides containing different alkyl scaffolds were evaluated (entries 4–11). The phosphinesquaramides 4a–4e bearing aliphatic scaffolds exhibited better yields and enantioselectivities than 4f–4h bearing aromatic scaffolds (entries 4–8 vs. 9–11). The squaramides 4a and 4b with a long-chain aliphatic group were so reactive that the azaMBH reaction was accomplished in one hour (entries 4 and 5). The additional chiral group in the alkyl squaramide moiety could improve the enantioselectivity of the aza-MBH reaction
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(entries 7 and 8 vs. 6). The L-valine-derived phosphine-thiourea 510 was observed to be less reactive than the chiral cyclohexane-based phosphine-thiourea 1 for the reaction, and a longer reaction time was required (entry 12 vs. 1). The phosphine-squaramide 4e proved to be the best organocatalyst for the model reaction, providing the desired product 8a in 98% yield and 82% ee (entry 8). Then the catalyst loading of 4e was examined. The aza-MBH reaction could be achieved with a reduced amount of catalyst loading with as low as 2 mol% 4e, giving a similar result to using 10 mol% 4e (entries 13 and 14 vs. 8). However, further decrease of the catalyst loading to 1 mol% led to significant decrease in the yield with retained enantioselectivity (entry 15). The reaction conditions of the aza-MBH reaction were then probed with 2 mol% of organocatalyst 4e (Table 2). Less polar solvents such as toluene, CH2Cl2 and CHCl3 resulted in excellent yields (91–99%) with 79–84% ee (entries 1–3). In the case of ether, moderate yield was obtained and a longer time was 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 acrylates catalyzed by phosphine-squaramide.4e In the polar solvents such as EtOAc and DMF, the aza-MBH products were provided in moderate yields (entries 6 and 7). The aza-MBH reaction in CH3CN was decelerated than that in CH2Cl2, while the enantioselectivity was slightly improved (entry 8 vs. 2). The different substrate concentrations in CH2Cl2 resulted in the
Table 2
Optimization of the reaction conditionsa
Entry
Solvent
Temp. (°C)
Time (d)
Yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9f 10g 11 12 13 14 15 16h
Toluene CH2Cl2 CHCl3 Et2O THF EtOAc DMF CH3CN CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 1 : 2 CH2Cl2–CH3CN 1 : 1 CH2Cl2–CH3CN 2 : 1 CH2Cl2–CH3CN 1 : 2 CH2Cl2–CH3CN
25 25 25 25 25 25 25 25 25 25 0 40 25 25 25 25
3 1 1 4 4 3 3 3 1 1 3.5 0.3 2 1.5 1.2 2
91 99 97 78 NRd 52 64 94 99 99 72 100 95 97 99 98
79 84 80 78 nde 78 79 87 84 84 87 83 87 86 86 86
a Unless 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 using Chiralcel OD-H column. d No reaction. e Not determined. f The reaction was conducted in 2 mL solvent. g The reaction was conducted in 0.67 mL solvent. h The amount of benzyl acrylate was 1.0 mmol.
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same enantioselectivities and yields (entries 2, 9, 10). The enantioselectivity was not sensitive to the reaction temperature, and a lower reaction temperature resulted in a longer reaction time (entries 2, 11 and 12). To attain high enantioselectivity with a reasonable reaction time, a mixed solvent system of CH2Cl2 with CH3CN was surveyed. The results indicated that at a mixing ratio of CH2Cl2–CH3CN = 1 : 2 (v/v), the best 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 obvious change in the enantioselectivity using unbranched alkyl acrylates as the Michael donors, while n-butyl acrylate was less reactive than others (entries 1–4). Due to steric hindrance, t-butyl acrylate was inactive under the typical reaction conditions (entry 5). The chiral catalytic system was also not suitable for phenyl acrylate as the reaction only gave the product with 43% yield and 2% ee (entry 6). Further exploration of the substrate scope was concentrated on varying the substituents on the isatin-derived ketimines. The aza-MBH reaction tolerated well all the N-Boc-1-methyl ketimine substrates with either electron-withdrawing or
Table 3
Substrate scope of the enantioselective aza-MBH reactionsa
Entry
R1
R2
8
Time (d)
Yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 f
H H H H H H 4-Br 5-F 5-Cl 5-Br 5-Me 5-MeO 6-Cl 6-Br 7-F 7-Cl 7-Br 7-CF3 7-Me 5-Me 5-MeO H
Bn Me Et n-Bu t-Bu Ph Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Me Me Bn
8a 8b 8c 8d — 8e — 8f 8g 8h 8i 8j 8k 8l 8m 8n 8o 8p 8q 8r 8s 8a
2 3.5 3.5 5 5 6 4 2 1.5 2 2.5 3.5 1.5 1.5 2 2.5 2 6 5 7 7 3
95 88 87 58 NRd 43 NR 98 94 97 99 99 95 99 95 95 99 80 98 94 93 93
87 89 88 87 nde 2 nd 81 81 80 88 89 82 82 84 82 80 70 89 91 90 87
a Unless 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 were determined by HPLC using Chiralcel OD-H column or Chiralpak AD-H column. d No reaction. e Not determined. f The reaction was conducted in 1 mmol scale.
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electron-donating groups at 5-, 6- or 7-positions (entries 8–21). The electron-donating group exhibited a positive effect on the enantioselectivity, while the electron-withdrawing group exhibited a negative effect. Isatin-derived ketimine with a substituent at the 4-position is unreactive for the aza-MBH reaction under the identical reaction conditions, probably due to steric hindrance (entry 7).2i,q,3a A large scale synthesis using 1 mmol N-Boc isatin ketimine 6a also provided an excellent yield (93%) and enantioselectivity (87% ee) (entry 22). To determine the absolute configuration of 3-amino-2oxindoles with a chiral quaternary carbon center, the enantiomer of the aza-MBH product 8l (ent-8l) was acquired using the enantiomer of 4e as a chiral catalyst. The single crystal of ent-8l was obtained by recrystallization from n-hexane–CH2Cl2, and the configuration of the stereocenters was determined to be R by X-ray crystallography (Fig. 2). Therefore, the aza-MBH product 8l should be of S configuration, and the configurations of other adducts 8 were assigned by analogy. According to the above-mentioned experimental results and the related reports,2b,8a,11 a probable transition-state structure was proposed as shown in Fig. 3. The electrophilic squaramide of the chiral catalyst activates the ketimine through hydrogenbonding interactions,2b then the chiral cyclohexyl scaffold forces the phosphinoyl associated enolate8a,11 to attack the activated ketimine from the Si-face to form the adducts in S configuration.
Fig. 2
X-ray crystal structure of ent-8l.
Fig. 3
Proposed transition state.
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Conclusions
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In summary, we have explored the first example of enantioselective aza-Morita–Baylis–Hillman reaction of acrylates with isatin-derived N-Boc ketimines. The chiral bifunctional phosphine-squaramide 4e was an efficient organocatalyst for this reaction. With 2 mol% of 4e in 1 : 2 CH2Cl2–CH3CN, the azaMBH reaction could be carried out at 25 °C to provide the desired products in up to 91% ee and good-to-excellent yields (up to 99%).
Experimental section General information Melting points were taken without correction. Optical rotations were measured on a WZZ-2A digital polarimeter at the wavelength of the sodium D-line (589 nm). 1H, 13C NMR spectra were recorded on a Bruker 400 spectrometer. The chemical shifts of 1H NMR and 13C NMR spectra were referenced to tetramethylsilane (δ 0.00) using CDCl3 as the solvent. IR spectra were recorded on a Nicolet Magna-I 550 spectrometer. High resolution mass spectra (HRMS) were recorded on a Micromass GCT with electron spray ionization (ESI) resource. HPLC analysis was performed on Waters equipment using the Daicel Chiralcel OD-H or Chiralpak AD-H column. Dichloromethane, chloroform, ethyl acetate and acetonitrile were distilled from CaH2. Toluene, ether and THF were distilled from sodium-benzophenone. DMF was dried over CaH2 and distilled under reduced pressure. Thin-layer chromatography (TLC) was performed on Silicycle 10–40 μm silica gel plates. Column chromatography was performed using silica gel (300–400 mesh) eluting with ethyl acetate and petroleum ether. Chiral bifunctional phosphine organocatalysts 1–5 were prepared according to literature procedures.4e,8–10 All substituted N-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 : 2 CH2Cl2–CH3CN was added acrylate (0.6 mmol) at 25 °C. After 10 min stirring at this temperature, isatin-derived N-Boc ketimine (0.2 mmol) was added. The reaction mixture was stirred at 25 °C (monitoring by TLC). After the reaction was complete, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel to afford the desired adducts and the ee values were determined by HPLC analysis with a chiral column. (S)-Benzyl 2-(3-(tert-butoxycarbonyl)-1-methyl-2-oxoindolin3-yl)acrylate (8a). White solid, 95% yield, 87% ee, mp 1 102.5–102.9 °C; [α]25 D −76.3 (c 0.68, CH2Cl2); H 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,
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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-H column, λ = 254 nm, eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1): tR = 14.09 min (minor), 17.85 min (major). (S)-Methyl 2-(3-(tert-butoxycarbonyl)-1-methyl-2-oxoindolin3-yl)acrylate (8b). White solid, 88% yield, 89% ee, mp 1 143.5–143.8 °C; [α]25 D −82.4 (c 0.54, CH2Cl2); H 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-oxoindolin3-yl)acrylate (8c). White solid, 87% yield, 88% ee, mp 1 112.9–113.2 °C; [α]25 D −83.3 (c 0.52, CH2Cl2); H 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-oxoindolin3-yl)acrylate (8d). White solid, 58% yield, 87% ee, mp 1 96.4–96.6 °C; [α]25 D −60.5 (c 0.38, CH2Cl2); H 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 mL min−1): tR = 7.63 min (minor), 9.73 min (major). (S)-Phenyl 2-(3-(tert-butoxycarbonyl)-1-methyl-2-oxoindolin3-yl)acrylate (8e). White solid, 43% yield, 2% ee, mp 158.3–159.6 °C; 1H NMR (CDCl3, 400 MHz): δ 7.55 (d, J = 7.6 Hz, 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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C 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 mL min−1): tR = 11.02 min (major), 13.02 min (minor). (S)-Benzyl 2-(3-(tert-butoxycarbonyl)-5-fluoro-1-methyl-2oxoindolin-3-yl)acrylate (8f ). White solid, 98% yield, 81% ee, 1 mp 134.7–135.0 °C; [α]25 D −67.3 (c 0.72, CH2Cl2); H 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 = 25.2 Hz), 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-2oxoindolin-3-yl)acrylate (8g). White solid, 94% yield, 81% ee, 1 mp 98.6–99.2 °C; [α]25 D −62.7 (c 0.71, CH2Cl2); H 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): δ 174.1, 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-H column, λ = 254 nm, eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1): tR = 12.75 min (minor), 16.83 min (major). (S)-Benzyl 2-(5-bromo-3-(tert-butoxycarbonyl)-1-methyl-2oxoindolin-3-yl)acrylate (8h). White solid, 97% yield, 80% ee, 1 mp 139.0–139.7 °C; [α]25 D −55.5 (c 0.81, CH2Cl2); H 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 mL min−1): tR = 13.28 min (minor), 17.52 min (major). (S)-Benzyl 2-(3-(tert-butoxycarbonyl)-1,5-dimethyl-2-oxoindolin-3-yl)acrylate (8i). Colorless syrup, 99% yield, 88% ee, [α]25 D −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 =
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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-2oxoindolin-3-yl)acrylate (8j). Colorless syrup, 99% yield, 89% 1 ee, [α]25 D −58.1 (c 0.74, CH2Cl2); H 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): ν 3132, 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-2oxoindolin-3-yl)acrylate (8k). White solid, 95% yield, 82% ee, 1 mp 151.1–151.9 °C; [α]25 D −34.1 (c 0.69, CH2Cl2); H 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-2oxoindolin-3-yl)acrylate (8l). White solid, 99% yield, 82% ee, 1 mp 159.7–161.0 °C; [α]25 D −55.1 (c 0.79, CH2Cl2); H 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 = 2.0 Hz, 1H), 6.42 (s, 1H), 5.96 (s, 1H), 5.94 (s, 1H), 5.09 (d, J = 12.4 Hz, 1H), 5.04 (d, J = 12.4 Hz, 1H), 3.09 (s, 3H), 1.32 (s, 9H); 13 C 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 ([M + H]+): 501.1025, found: 501.1018; HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1): tR = 12.35 min (minor), 16.95 min (major). (S)-Benzyl 2-(3-(tert-butoxycarbonyl)-7-fluoro-1-methyl-2oxoindolin-3-yl)acrylate (8m). White solid, 95% yield, 84% ee, 1 mp 109.5–110.3 °C; [α]25 D −62.1 (c 0.70, CH2Cl2); H 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-2oxoindolin-3-yl)acrylate (8n). White solid, 95% yield, 82% ee, 1 mp 102.2–102.9 °C; [α]25 D −59.6 (c 0.72, CH2Cl2); H 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 ([M + H]+): 457.1530, found: 457.1530; HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1): tR = 10.23 min (minor), 12.01 min (major). (S)-Benzyl 2-(7-bromo-3-(tert-butoxycarbonyl)-1-methyl-2oxoindolin-3-yl)acrylate (8o). Colorless syrup, 99% yield, 80% 1 ee, [α]25 D −47.8 (c 0.68, CH2Cl2); H NMR (CDCl3, 400 MHz): δ 7.39–7.33 (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 ([M + H]+): 501.1025, found: 501.1028; HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane–2-propanol = 90/10, flow rate: 0.9 mL min−1): tR = 11.90 min (minor), 14.88 min (major). (S)-Benzyl 2-(3-(tert-butoxycarbonyl)-1-methyl-2-oxo-7-(trifluoromethyl)indolin-3-yl)acrylate (8p). White solid, 80% yield, 70% ee, mp 112.6–113.4 °C; [α]25 D −36.9 (c 0.65, CH2Cl2); 1 H 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 for C25H25F3N2NaO5 ([M + Na]+): 513.1613, found: 513.1608; HPLC analysis (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).
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(S)-Benzyl 2-(3-(tert-butoxycarbonyl)-1,7-dimethyl-2-oxoindolin3-yl)acrylate (8q). Colorless syrup, 98% yield, 89% ee, 1 [α]25 H NMR (CDCl3, 400 MHz): D −59.2 (c 0.71, CH2Cl2); 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-oxoindolin-3-yl)acrylate (8r). White solid, 94% yield, 91% ee, mp 1 121.5–122.0 °C; [α]25 D −98.2 (c 0.57, CH2Cl2); H 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 for C19H25N2O5 ([M + H]+): 361.1763, found: 361.1759; HPLC analysis (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-2oxoindolin-3-yl)acrylate (8s). White solid, 93% yield, 90% ee, 1 mp 97.8–98.9 °C; [α]25 D −93.1 (c 0.58, CH2Cl2); H 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); 13 C 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 for C19H24N2NaO6 ([M + Na]+): 399.1532, found: 399.1527; HPLC analysis (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 National Natural Science Foundation of China (21242007, 21102043) and the Fundamental Research Funds for the Central Universities.
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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