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Highly enantioselective reaction of 2-oxindoles with (3-indolyl)methanols by cooperative Catalysis of a Lewis acid and organocatalyst† Chuan-Li Ren,a,b Tao Zhang,a,b Xing-Yong Wang,c Tao Wu,c Jing Ma,*c Qing-Qing Xuan,a,b Feng Wei,a,b Hong-Yan Huang,a,b Dong Wanga and Li Liu*a

Received 24th September 2014, Accepted 13th October 2014 DOI: 10.1039/c4ob02035a www.rsc.org/obc

An efficient cooperative biscinchona alkaloid and Lewis acid catalytic system was developed in the enantioselective α-alkylation of 2-oxindoles with (3-indolyl)( phenyl)methanols to provide (2-oxindole)linker-indole derivatives in good yields (70–83%) with high enantioselectivities (81%–92%).

Introduction The structural unit bearing both the indole and oxindole moiety broadly exists in biologically and pharmaceutically active compounds. Among them, indole-linker-2-oxindole derivatives have attracted considerable attention, which display anti-cancer and inhibition properties (Fig. 1).1 Many synthetic methods have been developed to access compounds with an indole ring directly connected to a 2-oxindole ring.2 However, there are few examples of the synthesis of indolelinker-(2-oxindole) compounds, especially the synthesis of chiral compounds.3 The catalytic enantioselective α-alkylation of carbonyl compounds has attracted considerable attention as an efficient C–C bond-forming strategy in organic synthesis.4 By enamine catalysis via the covalent activation mode, the α-alkylation of aldehydes and ketones with alcohols has made great progress.5 However, the enantioselective direct α-alkylation of amides is less reported.6 Recently, (3-indolyl)methanol was considered as an ideal electrophile owing to its easy accessibility and utility in the synthesis of indole alkaloids.7 Under chiral phosphoric acid catalysis, highly enantioselectivities could be achieved in the α-alkylation of ketones or its derivatives such as enamides with (3-indolyl)methanol.8 In 2013 we reported a Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China. E-mail: [email protected]; Fax: +86 10 6255 4449; Tel: +86 10 6255 4614 b Graduate School of Chinese Academy of Sciences, Beijing 100049, China c School of Chemistry and Chemical Engineering, Institute of Theoretical and Computational Chemistry, Key Laboratory of Mesoscopic Chemistry of MOE, Nanjing University, Nanjing, Jiangsu 210093, China † Electronic supplementary information (ESI) available: Experimental procedures, characterization data, and chiral chromatographic analysis for all new compounds. See DOI: 10.1039/c4ob02035a

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Fig. 1

Biologically active indole-linker-2-oxindole derivatives.

the asymmetric α-alkylation of 2-oxindoles with Michler’s hydrol catalyzed by biscinchona alkaloid [(DHQD)2PHAL]/ Brønsted acid via the non-covalent activation mode.6 We envisioned that as a synthetic route, the enantioselective α-alkylation of 2-oxindole with (3-indolyl)methanol should be a convenient and practical approach to obtain chiral 2-oxindolelinker-indole compounds (Scheme 1).9 The combination of transition metal catalysts and organocatalysts has emerged as a powerful tool for the development of innovative transformations. The cooperative catalytic system has been widely applied in the α-alkylation of carbonyl compounds to enhance the reactivity, improve the efficiency and enforce the stereocontrol of existing reactions.10 However, it is noteworthy that most of the organocatalysts used in the cooperative catalytic system with a Lewis acid are chiral secondary

Scheme 1

α-alkylation of 2-oxindole with (3-indolyl)methanol.

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or primary amines, which are able to activate the carbonyl substrate through a covalent mode.11 To date, the combination of chiral tertiary amine catalysts with achiral Lewis acids in catalytic enantioselective reactions is still rare.12 Herein, we report the enantioselective α-alkylation of 2-oxindoles with (3-indolyl)( phenyl)methanols catalyzed by the cooperative catalysts of chiral bis-cinchona alkaloid with an achiral Lewis acid through the non-covalent mode, affording chiral 2-oxindole-linker-indole derivatives in good yields and diastereoselectivities with high enantioselectivities.

Results and discussion At first, the model reaction between N-Boc-3-benzyl-2-oxindole 1a and (1H-indol-3-yl)( phenyl)methanol 2a was conducted in the presence of 4c or Cu(OTf )2 alone, respectively. However, the results were utterly disappointing (Table 1, entries 1 and 2). Thus, we turned to the combination of an organocatalyst with a Lewis acid catalyst. Initially, the reaction was carried out in the presence of monocinchona alkaloid 4a (20 mol%) with Cu(OTf )2 (10 mol%) in dichloromethane (DCM, 0.5 mL) at room temperature. It afforded the desired product 3a as a mixture of syn- and anti-diastereoisomers in 55% yield with low diastereoselectivity (dr = 1 : 1), and the enantioselectivity of the major isomer was poor (4% ee) (Table 1, entry 3). Moreover, the minor isomer was racemic. On the basis of the analysis of the 1H NMR NOE results, the relative configuration of the major diastereoisomer was deduced as syn (see ESI†).

Table 1

Screening catalysts for the reaction of 1a with 2aa

Entry

Cat.

Lewis acid

drb

Yieldc (%)

eed (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15h 16i

4c — 4a 4b 4c 4d 4e 4f 4c 4c 4c 4c 4c 4c 4c 4c

— Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 AgOTf In(OTf)3 Zn(OTf)2 CuCl2 CuSO4 CuCl Cu(OTf)2 Cu(OTf)2

N.De — 1:1 3:1 3:1 4:1 1:1 1:1 2:1 2:1 2:1 2:1 1:1 1:1 5:1 5:1

10 N.R f 55 79 74 95 74 61 80 75 76 80 65 47 70 80

13 — 4 73 80 −66g −10g −20g 39 36 13 59 64 56 85 92

a

1a (0.2 mmol) and 2a (0.1 mmol) in DCM (0.5 mL). b syn/anti determined by 1H NMR. c Isolated yield.. d ee of syn-3a determined by chiral HPLC. e Not detected. f No reaction. g Opposite enantiomer was obtained. h In CH3NO2 (0.5 mL). i 1a : 2a = 3 : 1 in CH3NO2 (1 mL).

Org. Biomol. Chem.

Fig. 2

Organocatalysts used in the reaction of 1a with 2a.

It is reported that the biscinchona alkaloids could provide a stronger interaction with substrates than monocinchona alkaloids.13 Several biscinchona alkaloids used in the reaction of 1a with 2a are listed in Fig. 2. To our delight, using (DHQ)2PHAL (4b) and (DHQD)2PHAL (4c) with Cu(OTf )2 as cooperative catalysts, the enantioselectivities of syn-3a were dramatically increased to 73% ee and 80% ee, respectively (entries 4 and 5). We also determined that the linker between the two cinchona units had a great influence on the enantioselectivity. Although the catalyst 4d with Cu(OTf )2 obtained a higher yield and dr, the stereoselectivity was reversed and the ee value decreased to −66% (entry 6). When the linker (PHAL) was changed to the anthracene-9,10-dione unit (4e) and 2,5-diphenylpyrimidine unit (4f), the enantioselectivities sharply decreased to −10% and −20%, respectively (entries 7 and 8). On the basis of the results above, 4c turned out to be the ideal choice as an organocatalyst, which can provide 74% yield of 3a with 3 : 1 dr and 80% ee of syn-3a. Subsequently, we screened a range of metal salts as Lewis acid catalysts in the reaction of 1a with 2a and the results are summarized in Table 1. It was determined that the Cu(II) salts were superior to other metal salts, including AgOTf, Zn(OTf )2 and In(OTf )3. Among the Cu(II) salts, Cu(OTf )2 afforded the best enantioselectivity (Table 1, entry 5 vs. entries 12 and 13). The Cu(I) salt provided a moderate yield and stereoselectivity (entry 14). After screening various solvents, the best solvent for the reaction was CH3NO2 (see ESI†). The dr of the product 3a was improved to 5 : 1 and the enantioselectivity of syn-3a was enhanced to 85% ee (entry 15). Upon conducting the reaction in CH3NO2 (1 mL) and the ratio of 1a to 2a was changed to 3 : 1 from 2 : 1, the best result was obtained (80% yield of 3a with 5 : 1 dr, and 92% ee of syn-3a) (entry 16). Having established the optimal reaction conditions, we explored the substrate scope of N-Boc-2-oxindoles. Either electron-rich or electron-deficient groups on the benzylic rings at

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Examination of the substrate scopea

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General methods

1

2

b

Entry

R

R

P3

dr

1 2 3 4 5 6 7 8 9 10 11 12

1a, Bn 1b, 3-CH3-Bn 1c, 3-Cl-Bn 1d, 3-OCH3-Bn 1e, 4-CH3-Bn 1f, 4-Cl-Bn 1g, 4-OCH3-Bn 1h, Naphtylmethyl 1a, Bn 1a, Bn 1a, Bn 1a, Bn

2a, H 2a, H 2a, H 2a, H 2a, H 2a, H 2a, H 2a, H 2b, Cl 2c, Br 2d, OMe 2e, Me

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l

5:1 5:1 7:1 5:1 4:1 4:1 3:1 4:1 3:1 3:1 7:1 6:1

Yieldc (%)

eed (%)

80 83 75 77 70 82 70 73 71 70 75 73

92 91 88 91 87 86 81 83 84 84 86 90

a

Reaction conditions: 1a (0.3 mmol), 2a (0.1 mmol) in CH3NO2 (1 mL) at room temperature. b Determined by 1H NMR. c Isolated yield of diastereoisomeric mixture. d The ee of syn-isomer as the major product was determined by chiral HPLC. The anti-isomer is racemic.

C-3 position of the indole ring were tolerable and afforded the corresponding products 3a–g in 70–83% yields with up to 7 : 1 dr and 92% ee of syn-products (Table 2, entries 1–7). The metasubstituent on the benzyl ring of 2-oxindoles (1b–d) can provide relatively higher ee value than the para substituent (1e–g) (entries 2–4 vs. 5–7). The N-Boc-3-naphthylmethyl-2-oxindole (1h) also smoothly reacted with 2a to afford the product 3h in 73% yield with 4 : 1 dr and 83% ee of syn-3h (entry 8). The substituents on the 5-position of the indole ring of (3-indolyl)methanol (2b–e) were also examined (entries 9–12). The alcohols 2d and 2e derived from 5-methoxyindole and 5-methylindole reacted with 1a to offer the product 3k with 7 : 1 dr and 86% ee of syn-3k, and 3l with 6 : 1 dr and 90% ee of syn3l, respectively (entries 11–12). If an electron-withdrawing group was introduced to indole ring (2b–c), it would lead to a slight decrease of the dr and enantioselectivity (entries 9–10). The absolute configuration of syn-3f was deduced as (R,R) by Vibrational Circular Dichroism (VCD) spectroscopy analysis (see ESI†).14

Conclusions In summary, we have developed an efficient cooperative chiral biscinchona alkaloid (DHQD)2PHAL and Cu(OTf )2 system to catalyze the enantioselective α-alkylation of N-Boc-3-benzyl-2oxindole with (3-indolyl)( phenyl)methanol. The reaction provided chiral (2-oxindole)-linker-indole derivatives in good yields and diastereoselectivities and high enantioselectivities. We believe the cooperative catalytic system will trigger more asymmetric reactions.

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All the starting materials were obtained from commercial suppliers and used directly. All of the substrates were prepared according to the original or modified literature procedures. All of the 1H and 13C NMR were recorded on a Bruker-AV 300 spectrometer and chemical shifts are reported in CDCl3 with tetramethylsilane as an internal standard. IR spectra were recorded on a NICOLET 6000 infrared spectrometer. Melting points were measured on a Beijing-Tiker X-4 apparatus without correction. HRMS spectra were recorded on Thermo Fish Scientific-Exactivemass spectrometer. In each case, the enantiomeric ratio was determined by chiral HPLC analysis on a Chiralpak column in comparison with authentic racemates. Optical rotation data was examined in CH2Cl2 solution and are reported as follows: [α]rt D (c in g per 100 mL of solvent). Column chromatography was performed using silica gel (200–300 mesh) eluting with ethyl acetate and petroleum ether. TLC was performed on glass-backed silica plates. General procedure for direct α-alkylation of 2-oxindoles To the mixture of catalyst 4c (0.02 mmol, 15.6 mg) and Lewis acid catalyst Cu(OTf )2 (0.01 mmol, 3.6 mg) in 1 mL CH3NO2, N-Boc-3-benzyl-2-oxindole 1a (0.3 mmol, 98 mg) was added. After stirring for 5 min, (1H-indol-3-yl)( phenyl)methanol 2a (0.1 mmol, 22.3 mg) was added to the mixture. The reaction system was stirred for 3 days at room temperature. After the completion of the reaction (monitored by TLC), the mixture was concentrated by vacuum. The product 3 was obtained by flash chromatography ( petroleum ether–ethyl acetate, 10 : 1 to 8 : 1). (R)-tert-Butyl-3-((R)-(1H-indol-3-yl)( phenyl)methyl)-3-benzyl2-oxoindoline-1-carboxylate (3a) 1 White solid. [α]20 D +144 (c 1.0, DCM). m.p. 103–104 °C. H NMR (300 MHz, CDCl3): δ 8.16 (s, 1H), δ 7.49 (t, J1 = 9.0 Hz, J2 = 6.0 Hz, 2H), δ 7.35 (d, J = 6.0 Hz, 2H), δ 7.24–7.16 (m, 6H), δ 7.08–7.04 (m, 2H), δ 7.01–6.89 (m, 4H), δ 6.78 (s, 1H), δ 6.73–6.71 (d, J = 6.0 Hz, 2H), δ 5.09 (s, 1H), δ 3.54 (d, J = 12 Hz, 1H), δ 2.97 (d, J = 15 Hz, 1H), δ 1.38 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 177.4, 148.7, 140.6, 139.2, 135.5, 135.4, 130.6, 130.0, 129.5, 128.3, 127.9, 127.7, 127.6, 126.9, 126.4, 125.3, 123.5, 122.2, 122.0, 119.4, 118.7, 114.7, 114.3, 110.8, 83.6, 58.5, 49.9, 44.5, 27.9. IR νmax (KBr, film, cm−1): 1149, 1250, 1464, 1732, 1778, 3351. HRMS (ESI): calcd for C35H32N2O3Na [M + 23]+ 551.2305; Found: 551.2304.

(R)-tert-Butyl-3-((R)-(1H-indol-3-yl)( phenyl)methyl)3-(3-methylbenzyl)-2-oxoindoline-1-carboxylate (3b) 1 White solid. [α]20 D +110 (c 0.9, DCM). m.p. 88–89 °C. H NMR (300 MHz, CDCl3): δ 8.08 (s, 1H), δ 7.40 (d, 2H), δ 7.27 (d, 2H), δ 7.15–7.08 (m, 6H), δ 7.00–6.91 (m, 3H), δ 6.76–6.67 (m, 3H), δ 6.46–6.40 (m, 2H), δ 5.00 (s, 1H), δ 3.46 (d, J = 12 Hz, 1H),

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δ 2.93 (d, J = 12 Hz, 1H), δ 1.95 (s, 3H), δ 1.31 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 177.4, 148.8, 140.7, 139.3, 137.0, 135.3, 130.9, 130.6, 128.2, 127.9, 128.3, 127.9, 127.7, 127.4, 127.1, 127.0, 126.9, 125.4, 123.4, 122.3, 122.0, 119.3, 118.7, 114.6, 114.4, 110.8, 83.6, 58.4, 49.8, 44.4, 27.9, 21.1. IR νmax (KBr, film, cm−1): 1150, 1252, 1461, 1731, 1782, 3358. HRMS (ESI): calcd for C36H34N2O3Na [M + 23]+ 565.2448; Found: 565.2453. (R)-tert-Butyl-3-((R)-(1H-indol-3-yl)( phenyl)methyl)-3-(3-chlorobenzyl)-2-oxoindoline-1-carboxylate (3c) 1 White solid. [α]20 D +105 (c 0.8, DCM). m.p. 77–78 °C. H NMR (300 MHz, CDCl3): δ 8.13 (s, 1H), δ 7.52 (t, J1 = 9.0 Hz, J2 = 9.0 Hz, 2H), δ 7.35 (d, 2H), δ 7.24–7.19 (m, 6H), δ 7.11–7.04 (m, 2H), δ 7.01–6.94 (m, 2H), δ 6.86–6.80 (m, 1H), δ 6.74–6.71 (m, 2H), δ 6.57–6.55 (d, J = 6.0 Hz, 1H) δ 5.07 (s, 1H), δ 3.54 (d, J = 12 Hz, 1H), δ 2.97 (d, J = 12 Hz, 1H), δ 1.40 (s, 9H). 13 C NMR (75 MHz, CDCl3): δ 177.1, 148.7, 140.6, 139.0, 137.5, 135.4, 133.3, 130.5, 130.1, 129.0, 128.7, 128.6, 128.1, 127.8, 127.1, 126.7, 126.3, 125.2, 123.7, 122.1, 122.0, 119.4, 118.7, 114.7, 114.2, 110.8, 83.9, 58.3, 49.8, 44.1, 27.8. IR νmax (KBr, film, cm−1): 1149, 1252, 1463, 1732, 1782, 3359. HRMS (ESI): calcd for C35H31ClN2O3Na [M + 23]+ 585.1915; Found: 585.1909.

(R)-tert-Butyl-3-((R)-(1H-indol-3-yl)(phenyl)methyl)-3-(3-methoxybenzyl)-2-oxoindoline-1-carboxylate (3d) 1 White solid. [α]20 D +129 (c 0.7, DCM). m.p. 84–85 °C. H NMR (300 MHz, CDCl3): δ 8.14 (s, 1H), δ 7.52–7.49 (d, J = 9.0 Hz, 2H), δ 7.46–7.30 (m, 2H), δ 7.24–7.17 (m, 6H), δ 7.10–6.95 (m, 3H), δ 6.87–6.81 (m, 1H), δ 6.77 (s, 1H), δ 6.53 (d, J = 9.0 Hz, 2H), δ 6.33 (d, J = 6.0 Hz, 1H), δ 6.22 (s, 1H), δ 5.09 (s, 1H), δ 3.56 (d, J = 12 Hz, 1H), δ 3.46 (s, 3H), δ 3.01 (d, J = 12 Hz, 1H), δ 1.38 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 177.3, 158.8, 148.7, 140.8, 139.2, 136.9, 135.4, 130.6, 129.6, 128.9, 128.5, 128.4, 127.8, 127.0, 125.3, 123.5, 122.5, 122.2, 122.0, 119.4, 118.7, 114.7, 114.5, 114.3, 113.0, 110.8, 83.7, 58.4, 54.9, 49.9, 44.5, 27.8. IR νmax (KBr, film, cm−1): 1150, 1250, 1464, 1730, 1781, 3355. HRMS (ESI): calcd for C36H34N2O4Na [M + 23]+ 581.2405; Found: 581.2411.

(R)-tert-Butyl-3-((R)-(1H-indol-3-yl)(phenyl)methyl)-3-(4-methylbenzyl)-2-oxoindoline-1-carboxylate (3e) 1 White solid. [α]20 D +86 (c 0.54, DCM). m.p. 100–101 °C. H NMR (300 MHz, CDCl3): δ 8.00 (s, 1H), δ 7.51 (d, J = 9 Hz, 2H), δ 7.37–7.34 (m, 2H), δ 7.24–7.18 (m, 6H), δ 7.09–7.04 (m, 2H), δ 7.01–6.99 (m, 1H), δ 6.72 (t, J = 6.0 Hz, J = 9.0 Hz, 3H), δ 6.59 (d, J = 6.0 Hz, 2H), δ 5.08 (s, 1H), δ 3.54 (d, J = 12 Hz, 1H), δ 2.97 (d, J = 12 Hz, 1H), δ 2.12 (s, 3H), δ 1.37 (s, 9H). 13 C NMR (75 MHz, CDCl3): δ 177.3, 148.8, 140.8, 139.2, 135.8, 135.3, 132.3, 130.6, 129.8, 129.6, 129.1, 128.3, 128.0, 127.7, 126.9, 125.3, 123.4, 122.0, 121.9, 119.4, 118.8, 114.7, 114.5, 110.7, 83.5, 58.4, 49.8, 44.0, 27.8, 20.9. IR νmax (KBr, film, cm−1): 1149, 1252, 1459, 1731, 1783, 3356. HRMS (ESI): calcd for C36H34N2O3Na [M + 23]+ 565.2462; Found: 565.2458.

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(R)-tert-Butyl-3-((R)-(1H-indol-3-yl)( phenyl)methyl)-3-(4-chlorobenzyl)-2-oxoindoline-1-carboxylate (3f ) 1 White solid. [α]20 D +105 (c 0.9, DCM). m.p. 120–121 °C. H NMR (300 MHz, CDCl3): δ 8.14 (s, 1H), δ 7.52–7.42 (m, 2H), δ 7.34–7.31 (m, 3H), δ 7.24–7.18 (m, 5H), δ 7.09–7.04 (m, 2H), δ 6.99–6.98, (m, 1H), δ 6.88 (t, J1 = 9.0 Hz, J2 = 9.0 Hz, 2H), δ 6.77 (s, 1H), δ 6.64 (d, J1 = 9.0 Hz, 2H), δ 5.06 (s, 1H), δ 2.97 (d, J = 12 Hz, 1H), δ 2.99–2.95 (d, J = 12 Hz, 1H), δ 1.38 (s, 9H). 13 C NMR (75 MHz, CDCl3): δ 177.2, 148.5, 140.6, 139.0, 135.3, 134.0, 132.3, 131.3, 130.5, 129.2, 128.6, 127.8, 127.7, 127.3, 127.0, 125.1, 123.6, 122.1, 122.0, 119.4, 118.6, 114.8, 114.2, 110.8, 83.9, 58.4, 49.9, 43.6, 27.8. IR νmax (KBr, film, cm−1): 1148, 1252, 1463, 1731, 1777, 3346. HRMS (ESI): calcd for C35H31ClN2O3Na [M + 23]+ 585.1915; Found: 585.1914.

(R)-tert-Butyl-3-((R)-(1H-indol-3-yl)(phenyl)methyl)-3-(4-methoxybenzyl)-2-oxoindoline-1-carboxylate (3g) 1 White solid. [α]20 D +91 (c 0.54, DCM). m.p. 123–124 °C. H NMR (300 MHz, CDCl3): δ 8.08 (s, 1H), δ 7.50 (d, J = 6.0 Hz, 2H), δ 7.44 (d, J = 6.0 Hz, 2H), δ 7.24–7.16 (m, 6H), δ 7.08–6.98 (m, 3H), δ 6.73 (s, 1H), δ 6.63 (d, J = 9.0 Hz, 2H), δ 6.45 (m, 2H), δ 5.07 (s, 1H), δ 3.60 (s, 3H), δ 3.51 (d, J = 6.0 Hz, 1H), δ 2.96 (d, J = 12 Hz, 1H), δ 1.38 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 177.6, 158.1, 148.7, 140.7, 139.2, 135.3, 131.0, 139.6, 129.6, 129.0, 128.3, 127.7, 127.4, 126.9, 125.2, 123.5, 122.1, 122.0, 119.4, 118.7, 114.7, 114.4, 113.0, 110.8, 83.6, 58.5, 55.0, 49.8, 43.6, 27.9. IR νmax (KBr, film, cm−1): 1149, 1250, 1461, 1730, 1778, 3357. HRMS (ESI): calcd for C36H34N2O4Na [M + 23]+ 581.2411; Found: 581.2407.

(R)-tert-Butyl-3-((R)-(1H-indol-3-yl)(phenyl)methyl)-3-(naphthalen2-ylmethyl)-2-oxoindoline-1-carboxylate (3h) White solid. [α]20 D +155 (c 0.65, DCM). m.p. 180–181 °C. 1 H NMR (300 MHz, CDCl3): δ 8.24 (s, 1H), δ 7.52–7.47 (t, J1 = 9.0 Hz, J2 = 6.0 Hz, 2H), δ 7.36–7.34 (d, J = 6.0 Hz, 2H), δ 7.90–7.84 (m, 1H), δ 7.63–7.50 (m, 2H), δ 7.48–7.42 (m, 1H), δ 7.41–7.28 (m, 3H), δ 727–7.25 (m, 3H), δ 7.21–7.18 (m, 3H), δ 7.12–6.94 (m, 7H), δ 6.80–6.71 (m, 1H), δ 5.22 (s, 1H), δ 4.15 (d, J = 12 Hz, 1H), δ 3.62 (d, J = 15 Hz, 1H), δ 1.28 (s, 9H). 13 C NMR (75 MHz, CDCl3): δ 177.8, 148.7, 140.5, 139.4, 135.5, 133.5, 132.2, 132.0, 130.6, 129.6, 129.2, 128.3, 128.2, 128.0, 127.9, 127.8, 127.3, 126.9, 125.6, 125.3, 125.1, 124.6, 124.5, 123.6, 122.5, 122.0, 119.4, 118.7, 114.5, 110.9, 83.6, 58.2, 50.2, 39.2, 27.7. IR νmax (KBr, film, cm−1): 1149, 1250, 1464, 1730, 1775, 3358. HRMS (ESI): calcd for C39H34N2O3Na [M + 23]+ 601.2462; Found: 601.2456. (R)-tert-Butyl-3-benzyl-3-((R)-(5-chloro-1H-indol-3-yl)( phenyl)methyl)-2-oxoindoline-1-carboxylate (3i) 1 White solid. [α]20 D +124(c 0.96, DCM). m.p. 97–98 °C. H NMR (300 MHz, CDCl3): δ 8.73 (s, 1H), δ 7.42 (d, J = 12 Hz, 2H), δ 7.30–7.28 (m, 4H), δ 7.17–7.14 (m, 5H), δ 7.04–6.90 (m, 5H), δ 6.73 (d, J = 6.0 Hz, 2H), δ 4.98 (s, 1H), δ 3.64 (d, J = 15 Hz, 1H), δ 3.04 (d, J = 12 Hz, 1H), 1.40 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 177.8, 148.6, 140.4, 138.8, 135.3, 133.9, 130.3, 129.9,

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129.4, 129.0, 128.4, 127.8, 127.6, 127.0, 126.5, 125.2, 125.1, 124.2, 123.7, 122.2, 118.0, 114.7, 113.8, 112.0, 84.0, 58.6, 50.1, 44.2, 27.9. IR νmax (KBr, film, cm−1): 1149, 1252, 1465, 1732, 1781, 3348. HRMS (ESI): calcd for C35H31ClN2O3Na [M + 23]+ 585.1915; Found: 585.1914.

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(R)-tert-Butyl-3-benzyl-3-((R)-(5-bromo-1H-indol-3-yl)( phenyl)methyl)-2-oxoindoline-1-carboxylate (3j) 1 White solid. [α]20 D +142(c 1.0, DCM). m.p. 108–109 °C. H NMR (300 MHz, CDCl3): δ 8.86 (s, 1H), δ 7.59 (s, 1H), δ 7.42–7.39 (m, 1H), δ 7.28–7.26 (m, 3H), δ 7.23–7.19 (m, 3H), δ 7.16–7.12 (m, 5H), δ 6.97–6.89 (m, 3H), δ 6.73 (d, J = 6.0 Hz, 1H), δ 4.97 (s, 1H), δ 3.60 (d, J = 12 Hz, 1H), δ 3.05 (d, J = 12 Hz, 1H), 1.40 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 178.0, 148.6, 140.3, 138.8, 135.4, 134.2, 130.2, 129.9, 129.6, 129.5, 128.5, 127.8, 127.6, 127.0, 126.5, 125.1, 124.7, 124.3, 123.8, 121.0, 114.7, 113.6, 112.6, 112.5, 84.0, 58.7, 50.1, 44.2, 27.9. IR νmax (KBr, film, cm−1): 1149, 1251, 1462, 1731, 1780, 3344. HRMS (ESI): calcd for C35H31BrN2O3Na [M + 23]+ 629.1410; Found: 629.1408.

(R)-tert-Butyl-3-benzyl-3-((R)-(5-methoxy-1H-indol-3-yl)(phenyl)methyl)-2-oxoindoline-1-carboxylate (3k) 1 White solid. [α]20 D +104(c 0.6, DCM). m.p. 100–101 °C. H NMR (300 MHz, CDCl3): δ 7.95 (s, 1H), δ 7.49 (d, J = 12 Hz, 2H), δ 7.39–7.35 (m, 2H), δ 7.26–7.16 (m, 6H), δ 7.12 (d, J = 9.0 Hz, 1H), δ 6.98–6.90 (m, 4H), δ 6.77–6.66 (m, 4H), δ 5.03 (s, 1H), δ 3.79 (s, 3H), δ 3.58 (d, J = 15 Hz, 1H), δ 3.00 (d, J = 15 Hz, 1H), 1.39 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 177.4, 154.0, 148.7, 140.6, 139.2, 135.4, 130.6, 130.5, 129.9, 129.4, 128.3, 128.2, 127.8, 127.5, 127.0, 126.4, 125.3, 123.5, 122.8, 114.7, 114.2, 112.1, 111.4, 100.9, 83.6, 58.3, 55.9, 49.8, 44.6, 27.9, 22.7. IR νmax (KBr, film, cm−1): 1150, 1252, 1464, 1730, 1782, 3360. HRMS (ESI): calcd for C36H34N2O4Na [M + 23]+ 581.2411; Found: 581.2407.

(R)-tert-Butyl-3-benzyl-3-((R)-(5-methyl-1H-indol-3-yl)( phenyl)methyl)-2-oxoindoline-1-carboxylate (3l) 1 White solid. [α]20 D +110(c 1, DCM). m.p. 92–93 °C. H NMR (300 MHz, CDCl3): δ 7.93 (s, 1H), δ 6.99 (d, J = 9.0 Hz, 2H), δ 7.37 (d, J = 6.0 Hz, 3H), δ 7.24–7.18 (m, 6H), δ 6.95–6.90 (m, 5H), δ 6.72 (d, J = 6.0 Hz, 2H), δ 6.64 (s, 1H), δ 5.06 (s, 1H), δ 3.59 (d, J = 15 Hz, 1H), δ 3.00 (d, J = 12 Hz, 1H), δ 2.38 (s, 3H), δ 1.37 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 177.4, 148.7, 140.7, 139.2, 135.5, 133.7, 130.6, 129.9, 129.5, 129.0, 128.5, 128.3, 128.1, 127.7, 127.5, 126.9, 126.4, 126.0, 125.2, 123.5, 118.3, 114.7, 113.8, 110.5, 83.6, 58.5, 49.8, 44.5, 27.9, 21.5. IR νmax (KBr, film, cm−1): 1149, 1252, 1465, 1732, 1782, 3373. HRMS (ESI): calcd for C36H34N2O3Na [M + 23]+ 565.2462; Found: 565.2459.

Acknowledgements We thank the National Natural Science Foundation of China, Ministry of Science and Technology (no. 2010CB833305 and 2011CB808600) and the Chinese Academy of Sciences for the financial support.

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Highly enantioselective reaction of 2-oxindoles with (3-indolyl)methanols by cooperative catalysis of a Lewis acid and organocatalyst.

An efficient cooperative biscinchona alkaloid and Lewis acid catalytic system was developed in the enantioselective α-alkylation of 2-oxindoles with (...
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