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Communication

Catalytic Enantioselective Addition of Me2Zn to Isatins

Departament de Química Orgànica, Facultat de Química, Universitat de València, Dr. Moliner 50, Burjassot 46100 (València), Spain
*
Authors to whom correspondence should be addressed.
Catalysts 2017, 7(12), 387; https://doi.org/10.3390/catal7120387
Submission received: 15 November 2017 / Revised: 7 December 2017 / Accepted: 8 December 2017 / Published: 13 December 2017
(This article belongs to the Special Issue Catalyzed Synthesis of Natural Products)

Abstract

:
Chiral α-hydroxyamide L5 derived from (S)-(+)-mandelic acid catalyzes the enantioselective addition of dimethylzinc to isatins affording the corresponding chiral 3-hydroxy-3-methyl-2-oxindoles with good yields and er up to 90:10. Furthermore, several chemical transformations were performed with the 3-hydroxy-2-oxindoles obtained.

Graphical Abstract

1. Introduction

3-Substituted-3-hydroxy-2-oxindole are an important class of compounds that have shown a broad range of biological activities. This scaffold is present in a large variety of natural and synthetic compounds that exhibit pharmaceutical properties [1,2,3,4,5,6,7,8]. Structure–activity relationship studies have shown that the biological activities of these compounds are significantly affected both by the configuration of the C3 and its substitution pattern [9,10,11]. Therefore, in the last years, the asymmetric synthesis of chiral 3-substituted-3-hydroxy-2-oxindoles have become a hot topic in organic synthesis [12,13]. The synthesis includes allylation [14,15], crotylation [16], arylation [17,18] and decarboxylative cyanomethylation [19] of isatines, as well as the palladium catalyzed intramolecular arylation [20]. The particular interest is the 3-hydroxy-3-methyl-2-oxindole structure, which is present in several natural products such as convolutamydine C [21] and synthetic compounds with biological activities or drug candidates such as compound 2a [22], compound A [23] and compound B [24] (Figure 1).
There are few methodologies for the synthesis of chiral 3-hydroxy-3-methyl-2-oxindoles in the literature, and the number of catalytic enantioselective examples is scarce. For example, the asymmetric oxidation of 3-methylindolin-2-one has been described for the synthesis of such compounds [25,26,27]. However, the most direct and versatile methodology is the enantioselective nucleophilic addition of organometallic reagents to isatins (Scheme 1). In this context, the addition of dialkylzinc reagents to isatins represents an attractive procedure for this purpose [28,29,30,31,32,33]. Nevertheless, only the group of Shibashaki [34] described just one example of the enantioselective addition of Me2Zn catalyzed by a proline-derived aminodiol ligand, obtaining the corresponding 3-hydroxy-3-methyl-2-oxindole in 82% yield and 88:12 enantiomeric ratio. In view of this lack of methodologies for the synthesis of such compounds, we decide to study the asymmetric addition of Me2Zn to isatins catalyzed by α-hydroxyamides derived from (S)-(+)-mandelic acid as chiral ligands [35,36,37,38,39,40].

2. Results

We initiated our studies by evaluating on the addition of Me2Zn to N-benzylisatine (1a) in the presence of a series of chiral α-hydroxyamides derived from (S)-(+)-mandelic acid as ligands. A 1.2 M Me2Zn solution in toluene (7 eq.) was added dropwise to a solution of ligand L1 (0.2 eq.) in 1 mL of toluene at room temperature. After 30 min, a solution of N-benzylisatine (1a) in 1 mL of toluene was added and the mixture was stirred for 1 h. The corresponding (S)-1-benzyl-3-hydroxy-3-methylindolin-2-one (2a) was obtained in 87% yield with 77.5:22.5 enantiomeric ratio (entry 1, Table 1). After, different solvents such as CH2Cl2, ClCH2CH2Cl, THF and Et2O were tested (entries 2–5, Table 1). When CH2Cl2 and Et2O were used as solvent, the corresponding product 2a was obtained with higher enantiomeric ratio, while coordinating solvents such as THF have a detrimental effect in both conversion and enantioselectivity of the reaction (entry 4, Table 1). Therefore, we decided to continue the optimization process with CH2Cl2 due to solubility problems of the starting material in Et2O. With the best solvent, different α-hydroxyamides (Figure 1) were tested as chiral ligands (entries 6–15, Table 1). First, we evaluated the influence of group attached to the nitrogen atom of the amide (Bn, Ph or tBu, entries 1, 6 and 7), obtaining the best enantioselectivity with ligand L1. Then, the influence of the substituent in the chiral center of the ligand was evaluated (entry 8). With the corresponding α-hydroxy-N-benzylamide L4 derived from (S)-3-phenyllactic acid, product 2a was afforded with lower er of 75:25. Therefore, we continue the optimization process with α-hydroxiamides derived from (S)-(+)-mandelic acid (L5L11). We evaluated the influence of the presence of different groups in the aromatic ring of the amide. Ligand L5, prepared from (S)-(+)-mandelic acid and 4-chlorobenzylamine gave the best enantioselectivity on the reaction, obtaining the chiral alcohol with 95% yield and 85:15 er (entry 9). The introduction of an additional methyl group in the benzylic position of the group attached to the nitrogen atom of the amide (entries 14 and 15) had a slightly deleterious effect on the enantioselectivity of the reaction.
Consequently, L5 was chosen for further optimization (Table 2). Lowering the reaction temperature (entries 1–3, Table 2) had a detrimental effect both in yield and enantioselectivity of the reaction. By decreasing the number of the equivalents of Me2Zn, we could improve the enantiomeric ratio to 90:10 in the reaction (entry 6). At this point, we study the effect of the use of additives [34] (entries 7–10) on the enantioselectivity of the reaction. The addition of alcohols had an interesting effect, MeOH inhibits the reaction, while when iPrOH or tBuOH were added the enantiomeric ratio decreased slightly. Finally, when Ti(OiPr)4 was used as an additive, the corresponding tertiary alcohol 2a was obtained with very low enantioselectivity (entry 10). Therefore, we decided as optimized reaction conditions the ones presented in entry 6, Table 2.
With the optimized reaction conditions established, the scope of the reaction was explored (see Supplementary Materials). Initially, N-substitution of the oxindole nitrogen atom was evaluated. Groups such as benzyl, methyl [41], allyl or propargyl were tolerated (entries 1, 3–5, Table 3), providing the corresponding tertiary alcohols with good enantioselectivities. However, unprotected free NH group on isatin was not tolerated (entry 2, Table 3), and the corresponding product 2b was obtained with lower yield and enantioselectivity, as well when the protecting group was acetyl (entry 7) or Ts (entry 8).
Next, the effect of substitution in the benzene ring of the N-benzyl protected isatins was studied (Scheme 2). A reduction in the catalyst loading to 10 mol% was also investigated, observing similar conversion and enantioselectivity. Different electron-donating (Me or MeO) or electron-withdrawing (F or Cl) in positions 5, 6 and 7, were tolerated and the corresponding chiral tertiary alcohols were obtained with good yields and enantiomeric ratios from 80:20 to 90:10. However, the presence of a strong electron-withdrawing group (NO2) led to a considerable decrease in the enantiomeric ratio of the reaction product.
To evaluate the potential scalability of the asymmetric addition of Me2Zn to isatins, this procedure was also performed on a 1 mmol scale. As shown in Scheme 3, the corresponding product 2a was isolated in 98% yield and 88:12 enantiomeric ratio (er).
To highlight the synthetic utility of this methodology, we have applied several chemical transformations (Scheme 4). We tried to reduce the amide moiety of the oxindole 2a with LiAlH4, however the epoxide 3a was obtained. We had some problems to purify epoxide 3a due to its instability. Nevertheless, we could react compound 3a with TMSCN, to afford smoothly the corresponding chiral indoline 4a with 2 stereogenic centers in 65% yield and without losing the enantiomeric purity of compound 2a.

3. Materials and Methods

3.1. General Information

Reactions were carried out under nitrogen in test tubes or round bottom flasks oven-dried overnight at 120 °C. Dicloromethane, 1,2-dichloroethane and toluene were distilled from CaH2. Tetrahydrofuran (THF) and Et2O were distilled from sodium benzophenone ketyl. Reactions were monitored by TLC (thin layer chromatography) analysis using Merck Silica Gel 60 F-254 thin layer plates. Flash column chromatography was performed on Merck silica gel 60, 0.040–0.063 mm. Melting points were determined in capillary tubes. NMR (Nuclear Magnetic Resonance) spectra were run in a Bruker DPX300 spectrometer (Bruker, Billerica, MA, USA) at 300 MHz for 1H and at 75 MHz for 13C using residual non-deuterated solvent as internal standard (CHCl3: δ 7.26 and 77.0 ppm). Chemical shifts are given in ppm. The carbon type was determined by DEPT (Distortionless Enhancement by Polarization Transfer) experiments. High resolution mass spectra (ESI) were recorded on a TRIPLETOFT5600 spectrometer (AB Sciex, Warrington, UK) equipped with an electrospray source with a capillary voltage of 4.5 kV (ESI). Specific optical rotations were measured using sodium light (D line 589 nm). Chiral HPLC (High performance liquid chromatography) analyses were performed in a chromatograph equipped with a UV diode-array detector using chiral stationary columns from Daicel. 1.2 M Me2Zn solution in toluene was purchased from Acros (Geel, Belgium). Chiral α-hydroxyamides were prepared as described in the literature [35]. Commercially available isatins were used as received. N-protected isatins 1 were prepared as described in the literature [42].

3.2. Typical Procedures and Characterization Data for Compounds 2

3.2.1. General Procedure for the Enantioselective Addition of Me2Zn to Isatins

A 1.2 M Me2Zn solution in toluene (0.17 mL, 0.2 mmol) was added dropwise on a solution of L5 (5.5 mg, 0.02 mmol or 2.25 mg, 0.01 mmol) in CH2Cl2 (1 mL) at room temperature under nitrogen. After stirring 30 min, a solution of isatin 1 (0.1 mmol) in CH2Cl2 (1.0 mL) was added via syringe. The reaction was stirred until the reaction was complete (TLC). The reaction mixture was quenched with NH4Cl (10 mL), extracted with CH2Cl2 (3 × 15 mL), washed with brine (10 mL), dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel afforded compound 2.

3.2.2. General Procedure for the Non-Enantioselective Addition of Me2Zn to Isatins

A 1.2 M Me2Zn solution in toluene (0.17 mL, 0.2 mmol) was added dropwise on a solution of isatin 1 (0.1 mmol) in CH2Cl2 (2 mL) at room temperature under nitrogen. The reaction was stirred until the reaction was complete (TLC). The reaction mixture was quenched with NH4Cl (10 mL), extracted with CH2Cl2 (3 × 15 mL), washed with brine (10 mL), dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel afforded compound 2.
(S)-1-Benzyl-3-hydroxy-3-methylindolin-2-one (2a) [43,44,45]: Enantiomeric ratio (90:10) was determined by chiral HPLC (Chiralpak AD-H), hexane-iPrOH 80:20, 1 mL/min, major enantiomer rt = 9.3 min, minor enantiomer rt = 8.1 min. White solid; mp = 110–112 °C; [ α ] 20 D = −34.1 (c = 1.09, CHCl3) (90:10 er); 1H NMR (300 MHz, CDCl3) δ 7.40 (ddd, J = 7.4, 1.2, 0.6 Hz, 1H), 7.34–7.23 (m, 5H), 7.22–7.15 (m, 1H), 7.05 (td, J = 7.6, 0.7 Hz, 1H), 6.70 (d, J = 7.9 Hz, 1H), 4.94 (d, J = 15.7 Hz, 1H), 4.80 (d, J = 15.7 Hz, 1H), 2.90 (s, 1H), 1.65 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 178.56 (C), 141.91 (C), 135.44 (C), 131.30 (C), 129.53 (CH), 128.83 (CH), 127.70 (CH), 127.18 (CH), 123.49 (CH), 123.24 (CH), 109.56 (CH), 73.69 (C), 43.72 (CH2), 25.08 (CH3); HRMS (ESI) m/z: 254.1171 [M + H]+, C16H16NO2 required 254.1176.
(S)-3-Hydroxy-3-methylindolin-2-one (2b) [46,47,48]: Enantiomeric ratio (61:39) was determined by chiral HPLC (Chiralpak OD-H), hexane-iPrOH 80:20, 1 mL/min, major enantiomer rt = 5.9 min, minor enantiomer rt = 7.0 min. White solid; mp = 150–154 °C; [ α ] 20 D = −12.84 (c = 0.345, CHCl3) (61:39 er); 1H NMR (300 MHz, CDCl3) δ 7.76 (s, 1H), 7.40 (dd, J = 7.4, 0.6 Hz, 1H), 7.27 (td, J = 7.7, 1.3 Hz, 1H), 7.09 (td, J = 7.6, 1.0 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 2.82 (s, 1H), 1.62 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 180.59 (C), 140.11 (C), 132.09 (C), 130.07 (CH), 124.32 (CH), 123.67 (CH), 110.64 (CH), 74.28 (C), 25.25 (CH3).
(S)-3-Hydroxy-1,3-dimethylindolin-2-one (2c) [35,43,44,49]: Enantiomeric ratio (82:18) was determined by chiral HPLC (Chiralpak AS-H), hexane-iPrOH 90:10, 1.0 mL/min, major enantiomer rt = 15.4 min, minor enantiomer rt = 12.5 min. White solid; mp = 100–104 °C [ α ] 20 D = −31.8 (c = 0.59, CHCl3) (82:18 er); 1H NMR (300 MHz, CDCl3) δ 7.39 (ddd, J = 7.2, 1.3, 0.6 Hz, 1H), 7.30 (td, J = 7.7, 1.3 Hz, 1H), 7.08 (td, J = 7.5, 1.0 Hz, 1H), 6.82 (dt, J = 7.9, 0.8 Hz, 1H), 3.21 (s, 1H), 3.17 (s, 3H), 1.58 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 178.58 (C), 142.78 (C), 131.43 (C), 129.56 (CH), 123.40 (CH), 123.21 (CH), 108.47 (CH), 73.65 (C), 26.20 (CH3), 24.81 (CH3).
(S)-1-Allyl-3-hydroxy-3-methylindolin-2-one (2d): Enantiomeric ratio (87:13) was determined by chiral HPLC (Chiralpak AD-H), hexane-iPrOH 80:20, 1.0 mL/min, major enantiomer rt = 6.31 min, minor enantiomer rt = 5.90 min. Oil; [ α ] 20 D = −39.2 (c = 0.71, CHCl3) (87:13 er); 1H NMR (300 MHz, CDCl3) δ 7.40 (ddd, J = 7.4, 1.4, 0.6 Hz, 1H), 7.26 (td, J = 7.8, 1.4 Hz, 1H), 7.07 (td, J = 7.5, 1.0 Hz, 1H), 6.81 (dd, J = 7.9, 0.8 Hz, 1H), 5.81 (ddt, J = 17.3, 10.4, 5.3 Hz, 1H), 5.24–5.20 (m, 1H), 5.19−5.15 (m, 1H), 4.34 (ddt, J = 16.4, 5.2, 1.7 Hz, 1H), 4.23 (ddt, J = 16.4, 5.3, 1.7 Hz, 1H), 3.16 (s, 1H), 1.60 (s, 3H); 13C NMR (75 MHz, CDCl3) 178.31 (C), 141.95 (C), 131.39 (C), 131.05 (CH), 129.46 (CH), 123.48 (CH), 123.17 (CH), 117.67 (CH2), 109.39 (CH), 73.60 (C), 42.26(CH2), 25.01 (CH3); HRMS (ESI) m/z: 204.1013 [M + H]+, C12H14NO2 required 204.1019.
(S)-3-Hydroxy-3-methyl-1-(prop-2-yn-1-yl)indolin-2-one (2e): Enantiomeric ratio (83.5:16.5) was determined by chiral HPLC (Chiralpak IC), hexane-iPrOH 90:10, 1.0 mL/min, major enantiomer rt = 21.2 min, minor enantiomer rt = 16.9 min. White solid; mp = 84–86 °C; [ α ] 20 D = −25.3 (c = 0.66, CHCl3) (83.5:16.5 er); 1H NMR (300 MHz, CDCl3) δ 7.43 (ddd, J = 7.4, 1.4, 0.6 Hz, 1H), 7.35 (td, J = 7.7, 1.3 Hz, 1H), 7.14 (td, J = 7.5, 1.0 Hz, 1H), 7.06 (dt, J = 7.8, 0.8 Hz, 1H), 4.53 (dd, J = 17.7, 2.5 Hz, 1H), 4.41 (dd, J = 17.7, 2.5 Hz, 1H), 3.08 (s, 1H), 2.24 (t, J = 2.5 Hz, 1H), 1.61 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 177.52 (C), 140.86 (C), 131.24 (C), 129.58 (CH), 123.59 (CH), 123.52 (CH), 109.57 (CH), 73.69 (C), 73.66 (C), 72.62 (CH), 29.34 (CH2), 24.81 (CH3); HRMS (ESI) m/z: 202.0862 [M + H]+, C12H12NO2 required 202.0863.
Methyl 2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)acetate (2f): Enantiomeric ratio (72:28) was determined by chiral HPLC quiral (Chiralpak IC), hexane-iPrOH 90:10, 1.0 mL/min, major enantiomer rt = 52.8 min, minor enantiomer rt = 57.2 min. Yelow solid; mp = 142–144 °C [ α ] 20 D = +1.91 (c = 0.82, CHCl3) (72:28 er); 1H NMR (300 MHz, CDCl3) δ 7.35 (dd, J = 7.3, 1.3 Hz, 1H), 7.21 (dd, J = 7.8, 1.3 Hz, 1H), 7.04 (td, J = 7.5, 1.0 Hz, 1H), 6.65 (dd, J = 7.8, 0.8 Hz, 1H), 4.44 (d, J = 17.6 Hz, 1H), 4.29 (d, J = 17.5 Hz, 1H), 3.67 (s, 3H), 3.06 (s, 1H), 1.55 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 178.37 (C), 167.96 (C), 141.34 (C), 131.22 (C), 129.58 (CH), 128.90 (CH), 123.59 (CH), 108.43 (CH), 73.59 (C), 52.66 (CH3), 41.09 (CH2), 24.84 (CH3); HRMS (ESI) m/z: 236.0913 [M + H]+, C12H14NO4 required 236.0917.
1-Acetyl-3-hydroxy-3-methylindolin-2-one (2g) [50]: Enantiomeric ratio (54:46) was determined by chiral HPLC (Chiralpak IC), hexane-iPrOH 90:10, 1.0 mL/min, major enantiomer rt = 8.3 min, minor enantiomer rt = 7.2 min. White solid; mp = 109–110 °C; [ α ] 20 D = −4.8 (c = 0.465, CHCl3) (54:46 er); 1H NMR (300 MHz, CDCl3) δ 8.26–8.20 (m, 1H), 7.46 (ddd, J = 7.3, 1.5, 0.6 Hz, 1H), 7.38 (ddd, J = 8.3, 7.6, 1.5 Hz, 1H), 7.26 (td, J = 7.4, 1.1 Hz, 1H), 2.81 (s, 1H), 2.66 (s, 3H), 1.65 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 179.04 (C), 170.74 (C), 139.10 (C), 130.33 (C), 130.15 (CH), 125.81 (CH), 123.23 (CH), 116.90 (CH), 73.59 (C), 26.47 (CH3), 25.65 (CH3); HRMS (ESI) m/z: 228.0632 [M + Na]+, C11H11NO3Na required 228.0631.
3-Hydroxy-3-methyl-1-tosylindolin-2-one (2h): Enantiomeric ratio (72:28) was determined by chiral HPLC (Chiralpak AD-H), hexane-iPrOH 80:20, 1.0 mL/min, major enantiomer rt = 11.7 min, minor enantiomer rt = 13.2 min. White solid; mp = 93–95 °C; [ α ] 20 D = +7.07 (c = 0.355, CHCl3) (72:28 er); 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 2H), 7.91 (dd, J = 8.6, 1.0 Hz, 1H), 7.44–7.35 (m, 2H), 7.32 (dd, J = 8.7, 0.7 Hz, 2H), 7.25–7.18 (m, 1H), 2.56 (s, 1H), 2.41 (s, 3H), 1.56 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 176.82 (C), 145.89 (C), 138.08 (C), 134.83 (C), 130.36 (CH), 130.16 (C), 129.89 (CH), 127.87 (CH), 127.70 (CH), 125.45 (CH), 113.87 (CH), 73.64 (C), 25.75 (CH3), 21.70 (CH3); HRMS (ESI) m/z: 300.0689 [M − H2O]+, C16H14NO3S required 300.0689.
(S)-3-Hydroxy-3-methyl-1-(naphthalen-1-ylmethyl)indolin-2-one (2i): Enantiomeric ratio (87:13) was determined by chiral HPLC (Chiralpak AS-H), hexane-iPrOH 80:20, 1.0 mL/min, major enantiomer rt = 14.3 min, minor enantiomer rt = 10.9 min. White solid, mp = 131–133 °C; [ α ] 20 D = −19.06 (c = 1.23, CHCl3) (87:13 er); 1H NMR (300 MHz, CDCl3) δ 8.12–8.06 (m, 1H), 7.89 (dd, J = 8.1, 1.5 Hz, 1H), 7.79 (dt, J = 8.2, 1.0 Hz, 1H), 7.64–7.49 (m, 2H), 7.47–7.42 (m, 1H), 7.37 (dd, J = 8.2, 7.1 Hz, 1H), 7.28 (dd, J = 7.1, 1.2 Hz, 1H), 7.12 (dd, J = 7.7, 1.5 Hz, 1H), 7.09–7.02 (m, 1H), 6.68 (dt, J = 8.0, 0.9 Hz, 1H), 5.52 (d, J = 16.2 Hz, 1H), 5.21 (d, J = 16.2 Hz, 1H), 3.32 (s, 1H), 1.72 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 178.84 (C), 142.14 (C), 133.83 (C), 131.44 (C), 130.97 (C), 130.19 (C), 129.49 (CH), 128.93 (CH), 128.40 (CH), 126.56 (CH), 126.0 (CH), 125.25 (CH), 124.52 (CH), 123.44 (CH), 123.27 (CH), 122.75 (CH), 109.95 (CH), 73.78 (C), 41.97 (CH2), 25.19 (CH3); HRMS (ESI) m/z: 304.1332 [M + H]+, C20H18NO2 required 304.1332.
(S)-1-Benzyl-3-hydroxy-5-methoxy-3-methylindolin-2-one (2j): Enantiomeric ratio (89.5:10.5) was determined by chiral HPLC (Chiralpak AD-H), hexane-iPrOH 80:20, 1.0 mL/min, major enantiomer rt = 14.1 min, minor enantiomer rt = 10.3 min. Oil; [ α ] 20 D = −36.51 (c = 1.09, CHCl3) (89.5:10.5 er); 1H NMR (300 MHz, CDCl3) δ 7.43–7.17 (m, 5H), 7.04 (d, J = 2.6 Hz, 1H), 6.71 (dd, J = 8.6, 2.6 Hz, 1H), 6.59 (d, J = 8.5 Hz, 1H), 4.92 (d, J = 15.6 Hz, 1H), 4.77 (d, J = 15.7 Hz, 1H), 3.76 (s, 3H), 3.47 (s, 1H), 1.66 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 178.54 (C), 156.45 (C), 135.48 (C), 135.02 (C), 132.68 (C), 128.79 (CH), 127.64 (CH), 127.14 (CH), 114.08 (CH), 110.48 (CH), 110.11 (CH), 74.06 (C), 55.76 (CH3), 43.76 (CH2), 25.19 (CH3); HRMS (ESI) m/z: 284.1280 [M + H]+, C17H18NO3 required 284.1281.
(S)-1-Benzyl-3-hydroxy-3,5-dimethylindolin-2-one (2k) [44]: Enantiomeric ratio (89:11) was determined by chiral HPLC (Chiralpak AD-H), hexane-iPrOH 80:20, 1.0 mL/min, major enantiomer rt = 8.4 min, minor enantiomer rt = 7.0 min. White solid; mp = 131–132 °C; [ α ] 20 D = −2.33 (c = 0.81, CHCl3) (89:11 er); 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J = 2.0 Hz, 1H), 7.37–7.21 (m, 6H), 6.58 (dd, J = 8.5, 0.9 Hz, 1H), 4.93 (d, J = 15.7 Hz, 1H), 4.80 (d, J = 15.7 Hz, 1H), 3.11 (s, 1H), 1.66 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 178.09 (C), 140.87 (C), 134.92 (C), 133.27 (C), 132.31 (CH), 128.94 (CH), 127.90 (CH), 127.11 (CH), 126.96 (CH), 116.03 (C), 111.11 (CH), 73.67 (C), 43.81 (CH2), 25.08 (CH3); HRMS (ESI) m/z: 268.1331 [M + H]+, C17H18NO2 required 268.1332.
(S)-1-Benzyl-5-chloro-3-hydroxy-3-methylindolin-2-one (2l): Enantiomeric ratio (80:20) was determined by chiral HPLC (Chiralpak AD-H), hexane-iPrOH 80:20, 1.0 mL/min, major enantiomer rt = 8.8 min, minor enantiomer rt = 6.8 min. White siolid; mp = 159–161 °C; [ α ] 20 D = −29.37 (c = 0.985, CHCl3) (80:20 er); 1H NMR (300 MHz, CDCl3) δ 7.39 (d, J = 2.1 Hz, 1H), 7.34–7.21 (m, 5H), 7.16 (dd, J = 8.4, 2.2 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 4.93 (d, J = 15.7 Hz, 1H), 4.79 (d, J = 15.7 Hz, 1H), 3.40 (s, 1H), 2.30 (s, 3H), 1.66 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 178.35 (C), 140.29 (C), 134.94 (C), 133.08 (C), 133.03 (CH), 129.34 (CH), 128.92 (C), 128.77 (CH), 127.87 (CH), 127.10 (CH), 124.19 (CH), 110.61 (CH), 73.73 (C), 43.82 (CH2), 25.05 (CH3), 20.98 (CH3). HRMS (ESI) m/z: 288.0782 [M + H]+, C16H15ClNO2 required 288.0786.
(S)-1-Benzyl-3-hydroxy-3-methyl-5-nitroindolin-2-one (2m): Enantiomeric ratio (58.5:41.5) was determined by chiral HPLC (Chiralpak AD-H), hexane-iPrOH 80:20, 1.0 mL/min, major enantiomer rt = 12.8 min, minor enantiomer rt = 10.2 min. Oil; [ α ] 20 D = −10.9 (c = 1.07, CHCl3) (58.5:41.5 er); 1H NMR (300 MHz, CDCl3) δ 8.29 (d, J = 2.2 Hz, 1H), 8.15 (ddd, J = 8.8, 2.4, 0.8 Hz, 1H), 7.42–7.19 (m, 5H), 6.80 (dd, J = 8.5, 0.8 Hz, 1H), 4.99 (d, J = 15.8 Hz, 1H), 4.88 (d, J = 15.7 Hz, 1H), 3.67 (s,1H), 1.72 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 178.95 (C), 147.41 (C), 143.93 (C), 134.24 (C), 132.27 (C), 129.12 (CH), 128.22 (CH), 127.10 (CH), 126.48 (CH), 119.61 (CH), 109.33 (CH), 73.29 (C), 44.10 (CH2), 24.90 (CH3); HRMS (ESI) m/z: 298.1027 [M + H]+, C16H15N2O4 required 299.1026.
(S)-1-Benzyl-6-chloro-3-hydroxy-3-methylindolin-2-one (2n): Enantiomeric ratio (84:16) was determined by chiral HPLC (Chiralpak AD-H), hexane-iPrOH 80:20, 1.0 mL/min, major enantiomer rt = 7.3 min, minor enantiomer rt = 6.8 min. White solid; mp = 140–141 °C; [ α ] 20 D = −18.3 (c = 1.15, CHCl3) (84:16 er); 1H NMR (300 MHz, CDCl3) δ 7.38–7.22 (m, 6H), 7.04 (dd, J = 7.9, 1.8 Hz, 1H), 6.71 (d, J = 1.7 Hz, 1H), 4.92 (d, J = 15.7 Hz, 1H), 4.76 (d, J = 15.8 Hz, 1H), 3.36 (s, 1H), 1.65 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 178.68 (C), 143.08 (C), 135.23 (C), 134.86 (C), 129.77 (C), 128.97 (CH), 127.92 (CH), 127.10 (CH), 124.50 (CH), 123.19 (CH), 110.18 (CH), 73.38 (C), 43.80 (CH2), 25.02 (CH3); HRMS (ESI) m/z: 288.0783 [M + H]+, C16H15ClNO2 required 288.0786.
(S)-1-Benzyl-7-fluoro-3-hydroxy-3-methylindolin-2-one (2o): Enantiomeric ratio (85:15) was determined by chiral HPLC (Chiralpak AD-H), hexane-iPrOH 80:20, 1.0 mL/min, major enantiomer rt = 7.7 min, minor enantiomer rt = 6.6 min. White solid; mp = 106–108 °C; [ α ] 20 D = −20.85 (c = 0.93, CHCl3) (85:15 er); 1H NMR (300 MHz, CDCl3) δ 7.34–7.24 (m, 5H), 7.23–7.19 (m, 1H), 7.06–6.93 (m, 2H), 5.05 (d, J = 16.6 Hz, 1H), 4.98 (d, J = 16.6 Hz, 1H), 3.32 (s, 1H), 1.65 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 178. 47 (C), 147.57 (d, JC-F = 244.9 Hz, C), 136.62 (C), 134.32 (d, JC-F = 2.8 Hz, C), 128.62 (CH), 128.36 (d, JC-F = 8.7 Hz, C), 127.63 (CH), 127.35 (d, JC-F = 1.4 Hz, CH), 124.12 (d, JC-F = 6.4 Hz, CH), 119.39 (d, JC-F = 3.3 Hz, CH), 117.67 (d, JC-F = 19.6 Hz, CH), 73.74 (d, JC-F = 2.6 Hz, C), 45.29 (d, JC-F = 4.7 Hz, CH2), 25.22 (CH3); HRMS (ESI) m/z: 272.1077 [M + H]+, C16H15FNO2 required 272.1070.
(S)-1-Benzyl-7-chloro-3-hydroxy-3-methylindolin-2-one (2p): Enantiomeric ratio (83:17) was determined by chiral HPLC (Chiralpak AD-H), hexane-iPrOH 80:20, 1.0 mL/min, major enantiomer rt = 9.0 min, minor enantiomer rt = 7.3 min. White solid; mp = 175–176 °C; [ α ] 20 D = −18.92 (c = 0.945, CHCl3) (83:17 er); 1H NMR (300 MHz, CDCl3) δ 7.40–7.15 (m, 7H), 7.02 (dd, J = 8.2, 7.3 Hz, 1H), 5.32 (s, 2H), 3.25 (s, 1H), 1.66 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 179.35 (C), 137.95 (C), 137.07 (C), 134.31 (C), 132.02 (CH), 128.61 (CH), 127.24 (CH), 126.33 (CH), 124.30 (CH), 122.15 (CH), 115.87 (C), 73.06 (C), 44.75 (CH2), 25.42 (CH3); HRMS (ESI) m/z: 288.0783 [M + H]+, C16H15ClNO2 required 288.0786.
(S)-1-Benzyl-3-hydroxy-3,5,7-trimethylindolin-2-one (2q): Enantiomeric ratio (89:11) was determined by chiral HPLC (Chiralpak AD-H), hexane-iPrOH 80:20, 1.0 mL/min, major enantiomer rt = 9.6 min, minor enantiomer rt = 7.6 min. White solid; mp = 142–145 °C; [ α ] 20 D = −37.19 (c = 0.855, CHCl3) (89:11 er); 1H NMR (300 MHz, CDCl3) δ 7.38–7.20 (m, 3H), 7.16–7.11 (m, 3H), 6.78 (dq, J = 1.7, 0.7 Hz, 1H), 5.17 (d, J = 16.6 Hz, 1H),5.10 (d, J = 16.6 Hz, 1H), 3.14 (s, 1H), 2.28 (s, 3H), 2.20 (s, 3H), 1.67 (s, 3H). 13C RMN (75 MHz, CDCl3) δ 179.72 (C), 137.33 (C), 137.25 (C), 133.80 (CH), 133.00 (C), 132.22 (C), 128.85 (CH), 127.20 (CH), 125.57 (CH), 122.15 (CH), 120.05 (C), 73.03 (C), 44.84 (CH2), 25.49 (CH3), 20.66(CH3), 18.50 (CH3); HRMS (ESI) m/z: 282.1485 [M + H]+, C18H20NO2 required 282.1489.

3.3. Procedures and Characterization Data for Compounds 3a and 4a

(1aS,6bS)-2-benzyl-6b-methyl-1a,6b-dihydro-2H-oxireno[2,3-b]indole (3a): A 1 M LiAlH4 solution in THF (0.2 mL, 0.2 mmol) was added dropwise on a solution of 2a (0.1 mmol) in THF (5 mL) at room temperature under nitrogen. The reaction was warmed to 75 °C and stirred until the reaction was complete (TLC). The reaction mixture was quenched with NH4Cl (10 mL), extracted with dichloromethane (3 × 20 mL), washed with brine (10 mL), dried over MgSO4 and dried under reduced pressure. The crude was used for the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 7.36–7.14 (m, 6H), 7.05 (td, J = 7.7, 1.3 Hz, 1H), 6.67 (ddt, J = 8.2, 7.4, 0.8 Hz, 1H), 6.34 (dd, J = 7.8, 0.8 Hz, 1H), 4.54 (s, 1H), 4.45 (d, J = 15.6 Hz, 1H), 4.23 (d, J = 15.7 Hz, 1H), 1.47 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 148.45 (C), 138.10 (C), 131.72 (C), 129.94 (CH), 128.80 (CH), 127.17 (CH), 127.00 (CH), 123.15 (CH), 118.79 (CH), 107.51 (CH), 92.77 (CH), 75.79 (C), 48.51 (CH2), 24.33 (CH3).
(2R,3S)-1-benzyl-3-hydroxy-3-methylindoline-2-carbonitrile (4a): TMSCN (37 µL, 0.294 mmol) was added dropwise on a solution of 3a (0.1 mmol) in CH2Cl2 (2 mL) at room temperature under nitrogen. The reaction was stirred until the reaction was complete (TLC). Finally, the reaction mixture was directly poured into the column chromatography, using hexanes:EtOAc (95:5) as eluent to afford product 4a. Enantiomeric ratio (89:11) was determined by chiral HPLC (Chiralpak AD-H), hexane-iPrOH 80:20, 1.0 mL/min, major enantiomer rt = 7.9 min, minor enantiomer rt = 18.7 min. Oil; [ α ] 20 D = −46.57 (c = 0.505, CHCl3) (89:11 er); 1H NMR (300 MHz, CDCl3) δ 7.43–7.19 (m, 7H), 6.89 (td, J = 7.5, 0.9 Hz, 1H), 6.68 (dt, J = 8.1, 0.7 Hz, 1H), 4.71 (d, J = 14.8 Hz, 1H), 4.19 (d, J = 14.9 Hz, 1H), 4.04 (s, 1H), 2.55 (s, 1H), 1.64 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 148.38 (C), 135.77 (C), 132.15 (C), 130.38 (CH), 128.90 (CH), 128.25 (CH), 128.01 (CH), 122.89 (CH), 120.36 (CH), 115.48 (C), 109.24 (CH), 78.41 (C), 66.88 (CH), 50.95 (CH2), 25.36 (CH3); HRMS (ESI) m/z: 265.1329 [M + H]+, C17H17N2O required 265.1335.

4. Conclusions

We have developed a catalytic enantioselective addition of Me2Zn to isatins catalyzed by a chiral Zn(II) complex using as chiral ligand a α-hydroxyamide derived from (S)-mandelic acid. The corresponding chiral 3-hydroxy-3-methyl-2-oxindoles are obtained with good yields and enantioselectivities. The enantioselectivities are comparable to the example described by Shibashaki [34] with a bifunctional proline-derived amino alcohol. The advantages of our system are that the catalyst is easily prepared in a one-step procedure, the reaction time is shorter and no slow addition of the reagent is required, leading to simplified procedures. Moreover, several transformations have been done with the corresponding chiral tertiary alcohols obtained.

Supplementary Materials

The following are available online at www.mdpi.com/2073-4344/7/12/387/s1, 1H and 13C NMR spectra, and HPLC chromatograms of all compounds.

Acknowledgments

Financial support from the MINECO (Ministerio de Economía, Industria y Competitividad, Gobierno de España; CTQ2013-47494-P). C.V. thanks MINECO for a JdC contract. Access to NMR and MS (Mass Spectrometry) facilities from the Servei central de suport a la investigació experimental (SCSIE)-UV is also acknowledged.

Author Contributions

C.V. and J.R.P. conceived and designed the experiments; A.d.C. performed the experiments; C.V. and A.d.C. analyzed the data; G.B. contributed reagents/materials/analysis tools; C.V. and J.R.P wrote the paper. All authors read, revised and approved the final manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Biologically active 3-hydroxy-3-methyl-2-oxindole compounds.
Figure 1. Biologically active 3-hydroxy-3-methyl-2-oxindole compounds.
Catalysts 07 00387 g001
Scheme 1. Asymmetric methodologies for the synthesis of 3-hydroxy-3-methyl-2-oxindole compounds.
Scheme 1. Asymmetric methodologies for the synthesis of 3-hydroxy-3-methyl-2-oxindole compounds.
Catalysts 07 00387 sch001
Scheme 2. Scope of the enantioselective addition of Me2Zn to isatins. Reaction conditions: 0.1 mmol 1, 1.2 M Me2Zn in toluene (0.2 mmol), and L5 in CH2Cl2 (2 mL). Isolated yield after column chromatography. Enantiomeric ratio determined by chiral HPLC. a 20 mol% of L5 was used. b 10 mol% of L5 was used.
Scheme 2. Scope of the enantioselective addition of Me2Zn to isatins. Reaction conditions: 0.1 mmol 1, 1.2 M Me2Zn in toluene (0.2 mmol), and L5 in CH2Cl2 (2 mL). Isolated yield after column chromatography. Enantiomeric ratio determined by chiral HPLC. a 20 mol% of L5 was used. b 10 mol% of L5 was used.
Catalysts 07 00387 sch002
Scheme 3. 1 mmol scale reaction. Reaction conditions: 1 mmol 1, 1.2 M Me2Zn in toluene (2 mmol), and L5 (20 mol%) in CH2Cl2 (20 mL). Isolated yield after column chromatography. Enantiomeric ratio determined by chiral HPLC.
Scheme 3. 1 mmol scale reaction. Reaction conditions: 1 mmol 1, 1.2 M Me2Zn in toluene (2 mmol), and L5 (20 mol%) in CH2Cl2 (20 mL). Isolated yield after column chromatography. Enantiomeric ratio determined by chiral HPLC.
Catalysts 07 00387 sch003
Scheme 4. Synthetic transformations of chiral 3-hydroxy-3-methyl-2-oxindole 2a.
Scheme 4. Synthetic transformations of chiral 3-hydroxy-3-methyl-2-oxindole 2a.
Catalysts 07 00387 sch004
Table 1. Optimization of the reaction conditions.
Table 1. Optimization of the reaction conditions.
Catalysts 07 00387 i001
Entry [a]Ligand (20 mol%)SolventYield (%) [b]er [c]
1L1toluene8777.5:22.5
2L1CH2Cl29082:18
3L1ClCH2CH2Cl7874:26
4L1THF4461.5:38.5
5L1Et2O7182.5:17.5
6L2CH2Cl28770.5:29.5
7L3CH2Cl29957:43
8L4CH2Cl28875:25
9L5CH2Cl29585:15
10L6CH2Cl29283:17
11L7CH2Cl27182:18
12L8CH2Cl27774:26
13L9CH2Cl28660.5:39.5
14L10CH2Cl28474:26
15L11CH2Cl29980:20
[a] Reaction conditions: 0.1 mmol 1a, 1.2 M Me2Zn in toluene (0.7 mmol), and ligand in dry solvent (2 mL) at rt for 1 h. [b] Isolated yield after column chromatography. [c] Enantiomeric ratio determined by chiral HPLC.
Table 2. Optimization of the reaction conditions.
Table 2. Optimization of the reaction conditions.
Catalysts 07 00387 i002
Entry [a]T (°C)Additive (X mol%)Yield (%) [b]er [c]
1−20-6775:25
20-7279.5:20.5
310-8684.5:15.5
4rt-9585:15
5 [d]rt-8989:11
6 [e]rt-8590:10
7 [e,f]rtMeOH (40 mol%)--
8 [e,g]rtiPrOH (40 mol%)8688:12
9 [e,g]rttBuOH (40 mol%)4886.5:13.5
10 [e,g]rtTi(OiPr)4 (100 mol%)5157:43
[a] Reaction conditions: 0.1 mmol 1a, 1.2 M Me2Zn in toluene (0.7 mmol), and L5 (20 mol%) in CH2Cl2 (2 mL) for 1 h. [b] Isolated yield after column chromatography. [c] Enantiomeric excess determined by chiral HPLC. [d] 0.35 mmol of Me2Zn was used. [e] 0.2 mmol of Me2Zn was used. [f] The reaction time was 24 h. [g] The reaction time was 4 h.
Table 3. Evaluation of the protecting group of the isatin.
Table 3. Evaluation of the protecting group of the isatin.
Catalysts 07 00387 i003
Entry [a]R11t (h)2Y (%) [b]er [c]
1Bn-1a12a8590:10
2 [d]H1b42b4761:39
3Me1c32c6682:18
4allyl1d32d7187:13
5propargyl1e22e6583.5:16.5
6CH2CO2Me1f32f7072:28
7COMe1g22g4555:45
8Ts1h22h3672:28
9 Catalysts 07 00387 i0041i12i8187:13
[a] Reaction conditions: 0.1 mmol 1, 1.2 M Me2Zn in toluene (0.2 mmol), and L5 (20 mol%) in CH2Cl2 (2 mL). [b] Isolated yield after column chromatography. [c] Enantiomeric ratio determined by chiral HPLC. [d] 0.3 mmol of Me2Zn was used.

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Vila, C.; Del Campo, A.; Blay, G.; Pedro, J.R. Catalytic Enantioselective Addition of Me2Zn to Isatins. Catalysts 2017, 7, 387. https://doi.org/10.3390/catal7120387

AMA Style

Vila C, Del Campo A, Blay G, Pedro JR. Catalytic Enantioselective Addition of Me2Zn to Isatins. Catalysts. 2017; 7(12):387. https://doi.org/10.3390/catal7120387

Chicago/Turabian Style

Vila, Carlos, Andrés Del Campo, Gonzalo Blay, and José R. Pedro. 2017. "Catalytic Enantioselective Addition of Me2Zn to Isatins" Catalysts 7, no. 12: 387. https://doi.org/10.3390/catal7120387

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