Asymmetric Friedel–Crafts Alkylation of Indoles with Trifluoromethyl

Jan 2, 2018 - Compound 3ca was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 67% yield (53 mg): 55% ee; ...
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Article Cite This: J. Org. Chem. 2018, 83, 1160−1166

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Asymmetric Friedel−Crafts Alkylation of Indoles with Trifluoromethyl Pyruvate Catalyzed by a Dinuclear Zinc Catalyst Yuan-Zhao Hua, Jun-Wei Chen, Hua Yang,* and Min-Can Wang* College of Chemistry and Molecular Engineering, School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Science Road, Zhengzhou, Henan 450000, P. R. China S Supporting Information *

ABSTRACT: A bimetallic cooperative catalysis model has been reported for the asymmetric Friedel−Crafts (F−C) alkylation of indoles with trifluoromethyl pyruvates using Trost’s intramolecular dinuclear zinc complex as the catalyst. This dinuclear zinc catalyst was prepared in situ by reacting the chiral ligand (S,S)-L2b with 2 equiv of ZnEt2. A series of trifluoromethyl alcohol and indole-containing biological compounds were formed in moderate to good yields (up to 95%) with good enantioselectivity (up to 88% enantiomeric excess (ee)) in the presence of 10 mol % catalyst under mild conditions. A synergistic transition state model was proposed to explain the origin of the asymmetric induction.

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and Trost’s dinuclear zinc-ProPhenol catalysts.9 The bi- or multimetal catalysts have the advantage of a synergistic effect wherein which the two metal centers cooperatively activate two reactants and offer an attractive activation manifold in some bimolecular carbon−carbon bond-forming reactions. In view of this, bi- or multimetallic cooperative catalysis has proven to be a powerful strategy for realizing high reactivity and selectivity in asymmetric transformations.10 However, to the best of our knowledge, no chiral bi- or multimetallic cooperative catalysts have been applied to the asymmetric F−C alkylation of indoles with trifluoropyruvate. It is necessary to guide such enantioselective reactions by using the synergistic effect of bi- or multimetallic catalysts. In recent years, our work has been focused on exploring the use of dinuclear metal catalysts based on chiral multidenate semiazacrown ether ligands (S,S)-L111a and (S,S)-L29a in catalytic asymmetric syntheses (Scheme 1). The two intra-

INTRODUCTION Fluorinated compounds have attracted extensive attention in several science disciplines owing to their unique properties.1 Chiral trifluoromethylated compounds, as one of the important fluorine-containing compounds, are particularly interesting as their strong electron-withdrawing effect and the absolute configuration of their CF3 group lead to unique physical and biological properties.2 The enantioselective addition of trifluoromethyl pyruvate represents one of the most convenient and straightforward approaches in obtaining chiral trifluoromethylated compounds.3 Over the past several decades, the Friedel−Crafts (F−C) alkylation reaction of indoles with trifluoromethyl pyruvate has attracted much attention4,5 due to the ability of the reaction to produce trifluoromethyl alcohol and indole-containing biological compounds. Various chiral transition-metal complexes, such as chiral copper,5a−c titanium,5d zinc,5e ytterbium,5f calcium,5g and scandium,5h and chiral organocatalysts, such as cinchona alkaloids,5i phosphoric acid,5j and C3-symmetric cinchonine-squaramides,5k have been found to be effective in catalyzing enantioselective F−C alkylation reactions. Among the reported complexes, all of the metal catalysts were found to activate the substrates through mononuclear metal transition models. The chiral multimetallic catalysts were first reported by Shibasaki and co-workers in 1992.6 Following that report, several bi- and multimetal catalysts based on chiral ligands and other, different metals have been successfully developed, including bimetallic catalysts based on a tetraol ligand coined linked-BINOL derived from tethering the two BINOL units together using an ether linker,7 bimetallic Schiff base catalysts,8 © 2018 American Chemical Society

Scheme 1. Dinuclear Zinc Catalysts

Received: October 12, 2017 Published: January 2, 2018 1160

DOI: 10.1021/acs.joc.7b02599 J. Org. Chem. 2018, 83, 1160−1166

Article

The Journal of Organic Chemistry molecular dinuclear zinc catalysts have led to a number of efficient catalytic enantioselective transformations.10f,11,12 Though these two ligands have an equal effect on both the enantioselective alkynylation reaction9d,11e and the catalytic asymmetric F−C alkylation of pyrrole with chalcones11b,12c owing to their similarities in structure and function, their catalytic performances on those same reactions are sometimes different. The dinuclear zinc-AzePhenol catalyst has been shown to be more efficient in the asymmetric copolymerization of epoxides with CO29b,c,11a,c and in the domino Michael/ hemiketalization reaction.11d However, the performance of Trost’s dinuclear zinc-ProPhenol catalyst is better than that of the dinuclear zinc-AzePhenol catalyst in the tandem Michael addition/acetalization of cyclic 1,3-diketones with β,γ-unsaturated α-ketoesters12a and asymmetric F−C alkylation reaction between indoles and 2-(4-methoxyphenylimino)acetate.12b As a part of our continuing project on the application of dinuclear zinc catalysts in asymmetric transformations, we herein report the first example of a synergistic model of the catalyzed asymmetric F−C alkylation of indoles with trifluoropyruvates using a dinuclear zinc catalyst which affords valuable chiral trifluoromethylated indoles in moderate to good yields (up to 95%) with up to 88% enantiomeric excess (ee).

Table 1. Effect of Ligand Structure on the Friedel−Crafts Alkylation Reaction of Indole 1a and Ethyl Trifluoromethyl Pyruvate 2aa

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RESULTS AND DISCUSSION Our investigation began with the evaluation of the ability of chiral multidenate semiazacrown ether ligands L1 and L2 to promote the Friedel−Crafts reaction of unprotected indole 1a with ethyl trifluoromethyl pyruvate 2a using CH2Cl2 as the solvent. In the presence of 10 mol % L1 and 20 mol % ZnEt2, the reaction of indole 1a and ethyl trifluoromethyl pyruvate 2a gave the desired product 3a in 83% yield but only 4% ee at room temperature (25 °C) for 24 h (Table 1, entries 1 and 2). However, the similar Trost’s ligand L2a showed a better performance in terms of enantioselectivity (60% ee) under the same conditions. Encouraged by this result, we further examined a series of L2 with various substitutions on the diaryl carbinol moiety, such as electron-rich groups, electron-deficient groups, a big, sterically hindered 2-naphthyl group, and a heteroaromatic ring 2thiophene group. The results are summarized in Table 1 (entries 3−8). It was found that ligand L2b with slightly electron-deficient 4-chlorophenyl groups gave the best result (69% ee, Table 1, entry 4). In further investigations, variations of the reaction conditions, including the use of different solvents, metal reagents, temperatures, additives, catalyst loadings, and ratios of 1a to 2a, were examined using ligand L2b (Table 2). Several solvents were tested in the presence of 10 mol % catalyst at 25 °C for 24 h. The reaction proceeded smoothly in CH2Cl2, toluene, THF, CH3CN, and CHCl3 with different enantioselectivities (26−69% ee, Table 2, entries 1−5, respectively). The results indicated that CH2Cl2 was effective for the reaction with an 83% yield and 69% ee (Table 2, entry 1). Changing the metal reagent from ZnEt2 to Zn(CH3)2 or n Bu2Mg12b,13 led to a reduction of the ee values (Table 2, entries 6 and 7, respectively). Decreasing the temperature from 25 to 10 °C resulted in an improvement of the product’s ee value to 76% (Table 2, entry 8). However, the enantioselectivities were slightly reduced when the temperature was decreased to 0, −20, and −40 °C and prolonged reaction times were required (Table 2, entries 9−11, respectively). The addition of

entry

L

time (h)

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8

L1a L1b L2a L2b L2c L2d L2e L2f

24 24 24 24 24 24 24 24

76 83 90 83 81 87 90 81

4 4 60 69 68 67 64 56

a Unless otherwise noted, all reactions were conducted with 1a (0.25 mmol), 2a (0.25 mmol), L (10 mol %), and ZnEt2 (20 mol %) in dry CH2Cl2 (2 mL) under N2 at 25 °C for 24 h. bIsolated yields. c Determined by HPLC analysis.

Table 2. Further Optimization of Reaction Conditionsa

entry

solvent

temp (°C)

x

yield (%)b

ee (%)c

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

CH2Cl2 toluene THF CH3CN CHCl3 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2

25 25 25 25 25 25 25 10 0 −20 −40 10 10 10 10

10 10 10 10 10 10 10 10 10 10 10 10 5 15 20

83 86 71 75 84 86 70 86 87 73 72 86 81 86 88

69 39 43 26 47 67 0 76 68 70 70 60 66 75 73

a Unless otherwise noted, reactions were performed with 1a (0.250 mmol) and 2a (0.25 mmol) using 10 mol % L2b and 20 mol % ZnEt2. b Isolated yields. cDetermined by HPLC. dZnMe2 was used. eMg(nBu)2 was used. fReaction time was prolonged. gIn the presence of 30 mg of 4 Å molecular sieves.

4 Å molecular sieves as an additive proved to have a negative effect on enantioselectivity. A decrease in the catalyst loading to 5 mol % caused the lowering of both yield and enantioselectivity (Table 2, entry 13). When the catalyst loading was increased from 10 to 15 and 20 mol %, the yields 1161

DOI: 10.1021/acs.joc.7b02599 J. Org. Chem. 2018, 83, 1160−1166

Article

The Journal of Organic Chemistry

Crafts reaction, and most of the desired products were obtained in good enantioselectivities (>80% ee) except for the 6-fluoro substituted products (Table 3, entries 11−22). Substrates with the strong electron-withdrawing groups NO2 and CO2Me gave corresponding products with decreased ee values (Table 3, entries 23−26). When 7-nitroindole was used, almost no desired product could be obtained even when the reaction time was prolonged to 72 h (Table 3, entry 27). 2-Methyl and phenyl substituted indoles were also tested, and the resulting ee values were poor (Table 3, entries 28 and 29, respectively). The effect of big, sterically hindered phenyl and methyl groups might be responsible for the decrease in enantioselectivities. Furthermore, when N-benzylindole 1q and N-acetylindoline 1r were treated with 2a under the optimal conditions, no reaction was observed, which was in accordance with previous reports (Scheme 2).9e,11b,12b This finding demonstrated that the hydrogen atom on the N atom of indole was critical for this Friedel−Crafts reaction.

were maintained, but the enantioselectivities were somewhat reduced (Table 2, entries 14 and 15, respectively). Extensive screening showed that the optimal conditions were as follows: 10 mol % ligand L2b, 20 mol % ZnEt2, indole 1a (0.25 mmol), and ethyl trifluoromethyl pyruvate 2a (0.25 mmol) in CH2Cl2 at 10 °C for 24 h. In order to evaluate the generality of the substrates, we subsequently tested an array of substituted indoles under the optimal conditions. As summarized in Table 3, the substituted Table 3. Catalytic Asymmetric Friedel−Crafts Reaction of Various Indoles 1 and Trifluoromethyl Pyruvate 2a

entry

R1

R2

product

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

H H 4-OMe 4-OMe 5-OMe 5-OMe 5-Me 5-Me 6-Me 6-Me 5-F 5-F 5-Cl 5-Cl 5-Br 5-Br 6-F 6-F 6-Cl 6-Cl 6-Br 6-Br 5-NO2 5-NO2 6-CO2Me 6-CO2Me 7-NO2 2-Me 2-Ph

Et Me Et Me Et Me Et Me Et Me Et Me Et Me Et Me Et Me Et Me Et Me Et Me Et Me Et Et Et

3aa 3ab 3ba 3bb 3ca 3cb 3da 3db 3ea 3eb 3fa 3fb 3ga 3gb 3ha 3hb 3ia 3ib 3ja 3jb 3ka 3kb 3la 3lb 3ma 3mb 3na 3oa 3pa

86 75 75 78 67 85 93 86 40 66 95 85 95 86 91 83 90 86 77 81 86 91 75 83 66 81 trace 79 72

76 70 88 84 55 55 72 65 9 48 84 74 82 86 85 84 52 63 84 80 77 83 76 62 40 47 − 13 27

Scheme 2. Catalytic Asymmetric Friedel−Crafts Alkylation Reaction of Indole 1q or 1r with 2a

The absolute stereochemistry of the products was determined to be S-configuration by optical rotation according to previous reports.5a A transition state model that accounts for the observed sense of asymmetric induction is provided based on these experimental results and previous reports on the mechanism of dinuclear zinc catalysis (Scheme 3).9a,b,12b The two zinc Scheme 3. Transition State Model

centers are situated sufficiently close to each other to allow a synergistic effect in this Friedel−Crafts alkylation reaction. One zinc center activates indole by deprotonation accompanied by the formation of 1 equiv of ethane, and the other zinc center activates trifluoromethyl pyruvate by zinc−oxygen coordination. Then, the nucleophilic attack of indole on the si face of the coordinated trifluoromethyl pyruvate affords the observed stereochemical outcome. Finally, a proton transfer with another free indole releases the product and re-forms the catalyst. The dinuclear zinc structure of the catalyst remains intact throughout the alkylation reaction.

a

Unless otherwise noted, reactions were performed with 1 (0.250 mmol) and 2 (0.25 mmol) using 10 mol % L2b and 20 mol % ZnEt2. b Isolated yields. cDetermined by HPLC.

group of indoles played an important role in controlling the reaction activity and enantioselectivity. Most indoles bearing different groups furnished corresponding products in good yield and good enantioselectivity. Substrates with the strong electron-donating group MeO at 4-position of the phenyl ring gave good results in terms of an 88% ee. This result was much better than that of 5-methoxy indole (Table 3, entries 3−6). The slightly weak electron-donating group Me at the 5- or 6position of the phenyl ring led to a decrease in the products’ ee values (9−72%, Table 3, entries 7−10). Halogen groups on indoles were beneficial to this catalytic asymmetric Friedel−

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CONCLUSION In summary, Trost’s dinuclear zinc catalysts have been evaluated in the catalytic asymmetric Friedel−Crafts alkylation of unprotected indoles with trifluoromethyl pyruvate. It is the 1162

DOI: 10.1021/acs.joc.7b02599 J. Org. Chem. 2018, 83, 1160−1166

Article

The Journal of Organic Chemistry

CDCl3) δ 168.5, 151.3, 137.9, 123.6, 123.4, 115.3, 109.4, 105.8, 101.1, 62.9, 55.6, 13.9; IR (neat) 3414, 2919, 1730, 1488, 1215, 1104, 771, 677 cm−1. (S)-Methyl 3,3,3-Trifluoro-2-hydroxy-2-(4-methoxy-1H-indol-3yl)propanoate (3bb).14 Compound 3bb was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 78% yield (59 mg): 84% ee; [α]D25 = +20.4 (c = 0.47, in CHCl3); the ee value was determined by HPLC (Chiralpak IB, hexane/i-PrOH = 80/20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 20.35 min, tR (minor) = 28.55 min; 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.28−7.26 (m, 1H), 7.18−7.14 (m, 1H), 7.04−7.02 (m, 1H), 6.62−6.60 (m, 1H), 6.45 (s, 1H), 3.98 (s, 3H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.1, 151.3, 137.9, 125.2, 123.7, 123.4, 122.3, 115.3, 109.3, 105.8, 101.2, 55.7, 53.7; IR (neat) 3361, 2917, 1755, 1486, 1284, 1166, 759, 684 cm−1. (S)-Ethyl 3,3,3-Trifluoro-2-hydroxy-2-(5-methoxy-1H-indol-3-yl)propanoate (3ca). 2c Compound 3ca was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 67% yield (53 mg): 55% ee; [α]D25 = +10.0 (c = 0.27, in CHCl3); the ee value was determined by HPLC (Chiralpak OD-H, hexane/i-PrOH = 80/20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 6.65 min, tR (minor) = 8.36 min; 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.32 (dd, J = 19.6, 2.6 Hz, 2H), 7.14 (d, J = 8.8 Hz, 1H), 6.85 (dd, J = 9.0, 2.8 Hz, 1H), 4.49 (s, 1H), 4.45−4.39 (m, 1H), 4.35−4.27 (m, 1H), 3.82 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.4, 154.4, 131.5, 125.6, 125.03, 125.02, 122.2, 113.1, 112.2, 108.0, 102.7, 64.2, 55.8, 13.9; IR (neat) 3414, 2919, 1730, 1488, 1215, 1104, 771, 677 cm−1. (S)-Methyl 3,3,3-Trifluoro-2-hydroxy-2-(5-methoxy-1H-indol-3yl)propanoate (3cb).2c Compound 3cb was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 85% yield (64 mg): 55% ee; [α]D25 = +4.3 (c = 0.81, in CHCl3); the ee value was determined by HPLC (Chiralpak OJ, hexane/i-PrOH = 80/20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 46.66 min, tR (minor) = 36.57 min; 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.24−7.21 (m, 1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 4.34 (s, 1H), 3.93 (s, 3H), 3.84 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 169.9, 154.6, 131.4, 125.7, 125.0, 124.9, 113.2, 112.1, 108.1, 102.6, 55.8, 54.4; IR (neat) 3361, 2917, 1755, 1486, 1284, 1166, 759, 684 cm−1. (S)-Ethyl 3,3,3-Trifluoro-2-hydroxy-2-(5-methyl-1H-indol-3-yl)propanoate (3da). 2c Compound 3da was purified by flash chromatography (petroleum ether/EtOAc = 4/1) to afford a colorless oil in 93% yield (70 mg): 72% ee; [α]D25 = +4.5 (c = 0.35, in CHCl3); the ee value was determined by HPLC (Chiralpak OD-H, hexane/iPrOH = 80/20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 5.57 min, tR (minor) = 6.97 min; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.65 (s, 1H), 7.25−7.23 (m, 1H), 7.15−7.11 (m, 1H), 7.03−7.01 (m, 1H), 4.46−4.27 (m, 3H), 2.43 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 169.5, 134.7, 129.8, 125.3, 125.1, 124.5, 124.3, 122.21, 120.5, 111.1, 107.9, 64.2, 21.6, 13.9; IR (neat) 3465, 2919, 1727, 1442, 1227, 1172, 743, 680 cm−1. (S)-Methyl 3,3,3-Trifluoro-2-hydroxy-2-(5-methyl-1H-indol-3-yl)propanoate (3db).2c Compound 3db was purified by flash chromatography (petroleum ether/EtOAc = 4/1) to afford a colorless oil in 86% yield (62 mg): 65% ee; [α]D25 = +8.7 (c = 0.32, in CHCl3); the ee value was determined by HPLC (Chiralpak OD-H, hexane/iPrOH = 80/20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 14.92 min, tR (minor) = 19.80 min; 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.60 (s, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.03 (dd, J = 8.4, 1.6 Hz, 1H), 4.37 (s, 1H), 3.89 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.0, 134.6, 130.0, 127.8, 125.3, 125.0, 124.4, 122.1, 120.2, 111.2, 107.7, 54.5, 21.6; IR (neat) 3435, 2964, 1744, 1441, 1293, 1168, 782, 680 cm−1. (S)-Ethyl 3,3,3-Trifluoro-2-hydroxy-2-(6-methyl-1H-indol-3-yl)propanoate (3ea). 5g Compound 3ea was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 40% yield (30 mg): 9% ee; [α]D25 < + 0.5 (c = 0.15, in CHCl3); the ee value was determined by HPLC (Chiralpak OD-H, hexane/iPrOH = 80/20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 5.54

first application of a dinuclear metal catalyst’s synergistic effect in this reaction. When indole 1b and the ethyl ester of 3,3,3trifluoropyruvic acid 2a are employed as reaction substrates and the reaction is performed in CH 2 Cl 2 at 10 °C, an enantioselectivitiy of 88% ee is recorded. A transition state model is put forward to explain the synergistic effect and the origin of the asymmetric induction. Further exploration of the applications of those dinuclear metal catalysts to other asymmetric reactions is currently underway in our group.

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EXPERIMENTAL SECTION

General Method. Solvents were dried with standard methods and freshly distilled prior to use as needed. All reactions sensitive to air or moisture were carried out under nitrogen using standard Schlenk and vacuum line techniques. The chiral ligands L111b and L29a,12b were synthesized according to reported procedures. Indoles and trifluoromethyl pyruvate were used as purchased. NMR spectra were recorded on a 400 or 600 MHz spectrometer with CDCl3 or (CD3)2SO as the solvent, and TMS was used as an internal reference (400 or 600 MHz for 1H and 100 or 150 MHz for 13C). HRMS values were determined on a Q-TOF Micro LC/MS System ESI spectrometer. Enantiomeric excess values were determined with HPLC (chiral column, mobile phase hexane/i-PrOH). General Procedure for the Asymmetric Friedel−Crafts Alkylation Reaction of Indoles and Trifluoromethyl Pyruvate. Under a nitrogen atmosphere, a solution of diethylzinc (50 μL, 1.0 M in hexane, 0.05 mmol) was added dropwise to a solution of L2b (19.4 mg, 0.025 mmol) in CH2Cl2 (2 mL). After the mixture was stirred for 30 min at room temperature, the temperature of the mixture was lowered to 10 °C. Then, indole 1 (0.25 mmol) and trifluoromethyl pyruvate 2 (0.25 mmol) were added. The reaction mixture was stirred for 24 h at the same temperature. The reaction was quenched with HCl solution (1 M, 2 mL), and the organic layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic layer was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure by using a rotary evaporator. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (2/1) to afford the desired product 3. (S)-Ethyl 3,3,3-Trifluoro-2-hydroxy-2-(1H-indol-3-yl)propanoate (3aa).5b Compound 3aa was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 86% yield (62 mg): 76% ee; [α]D25 = +11.3 (c = 0.38, in CHCl3); the ee value was determined by HPLC (Chiralpak AS, hexane/i-PrOH = 90/ 10, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 16.41 min, tR (minor) = 24.68 min; 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.42 (s, 1H), 7.34−7.32 (m, 1H), 7.24−7.13 (m, 2H), 4.49−4.30 (m, 3H), 1.33 (t, J = 7.2 Hz, 3H); IR (neat) 3415, 2924, 1732, 1478, 1225, 1168, 747, 677 cm−1. (S)-Methyl 3,3,3-Trifluoro-2-hydroxy-2-(1H-indol-3-yl)propanoate (3ab). 5b Compound 3ab was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 75% yield (62 mg): 70% ee; [α]D25 = −18.2 (c = 0.33, in CHCl3); the ee value was determined by HPLC (Chiralpak AS, hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 20.15 min, tR (minor) = 26.78 min; 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.20−7.11 (m, 4H), 4.44 (s, 1H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.0, 136.3, 127.8, 125.0, 124.5, 122.7, 122.1, 120.7, 119.3, 108.2, 54.5; IR (neat) 3404, 2959, 1738, 1452, 1291, 1171, 740, 676 cm−1. (S)-Ethyl 3,3,3-Trifluoro-2-hydroxy-2-(4-methoxy-1H-indol-3-yl)propanoate (3ba). 5g Compound 3ba was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 75% yield (59 mg): 88% ee; [α]D25 = −25.2 (c = 0.43, in CHCl3); the ee value was determined by HPLC (Chiralpak IB, hexane/i-PrOH = 80/20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 17.16 min, tR (minor) = 23.73 min; 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.27 (s, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.46 (s, 1H), 4.38−4.24 (m, 2H), 3.96 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, 1163

DOI: 10.1021/acs.joc.7b02599 J. Org. Chem. 2018, 83, 1160−1166

Article

The Journal of Organic Chemistry min, tR (minor) = 10.94 min; 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 6.8 Hz, 1H), 6.98 (d, J = 7.6 Hz, 2H), 4.46−4.38 (m, 2H), 4.34−4.26 (m, 1H), 2.42 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.5, 136.8, 132.6, 125.0, 123.88, 123.86, 122.3, 122.2, 120.5, 111.4, 108.2, 64.3, 21.6, 13.9; IR (neat) 3415, 2924, 1739, 1453, 1225, 1168, 741, 677 cm−1. (S)-Methyl 3,3,3-Trifluoro-2-hydroxy-2-(6-methyl-1H-indol-3-yl)propanoate (3eb). Compound 3eb was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 66% yield (47 mg): 48% ee; [α]D25 = +16.0 (c = 0.56, in CHCl3); the ee value was determined by HPLC (Chiralpak OJ, hexane/i-PrOH = 80/ 20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 46.73 min, tR (minor) = 38.41 min; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.33−7.32 (m, 1H), 7.12 (s, 1H), 6.99 (dd, J = 8.3, 1.5 Hz, 1H), 4.33 (s, 1H), 3.92 (s, 3H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.0, 136.8, 132.7, 124.9, 123.7, 123.7, 122.9, 122.5, 122.1, 120.5, 111.3, 108.4, 54.4, 21.6; IR (neat) 3409, 2959, 1738, 1452, 1291, 1171, 742, 676 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C13H13F3NO3+ 288.0842, found 288.0840. (S)-Ethyl 3,3,3-Trifluoro-2-(5-fluoro-1H-indol-3-yl)-2-hydroxypropanoate (3fa). Compound 3fa was purified by flash chromatography (petroleum ether/EtOAc = 4/1) to afford a colorless oil in 95% yield (72 mg): 84% ee; [α]D25 = +16.1 (c = 0.40, in CHCl3); the ee value was determined by HPLC (Chiralpak OD-H, hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 9.96 min, tR (minor) = 11.52 min; 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.85−7.81 (m, 1H), 7.40 (s, 1H), 7.02−6.90 (m, 2H), 4.50−4.35 (m, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.2, 161.2, 158.9, 124.8, 122.3, 122.2, 121.7, 109.5, 109.3, 97.7, 97.4, 64.4, 13.9; IR (neat) 3418, 2986, 1730, 1487, 1224, 1169, 751, 680 cm−1. (S)-Methyl 3,3,3-Trifluoro-2-(5-fluoro-1H-indol-3-yl)-2-hydroxypropanoate (3fb). 2c Compound 3fb was purified by flash chromatography (petroleum ether/EtOAc = 4/1) to afford a colorless oil in 85% yield (62 mg): 74% ee; [α]D25 = +8.5 (c = 0.67, in CHCl3); the ee value was determined by HPLC (Chiralpak IA, hexane/i-PrOH = 80/20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 9.91 min, tR (minor) = 11.67 min; 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.53 (dd, J = 10.3, 2.5 Hz, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.27−7.24 (m, 1H), 6.99−6.94 (m, 1H), 4.41 (s, 1H), 3.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 159.3, 157.0, 132.8, 126.1, 124.8, 122.0, 112.0, 111.5, 106.3, 106.1, 54.6; IR (neat) 3417, 2987, 1732, 1488, 1299, 1169, 738, 680 cm−1. (S)-Ethyl 2-(5-Chloro-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate (3ga).2c Compound 3ga was purified by flash chromatography (petroleum ether/EtOAc = 4/1) to afford a colorless oil in 95% yield (76 mg): 82% ee; [α]D25 = +17.3 (c = 0.52, in CHCl3); the ee value was determined by HPLC (Chiralpak IA, hexane/i-PrOH = 80/ 20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 7.86 min, tR (minor) = 9.65 min; 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 1.2 Hz, 1H), 7.13−7.10 (m, 1H), 4.49−4.32 (m, 3H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.2, 136.7, 128.7, 125.1, 124.8, 123.8, 122.3, 122.0, 121.3, 111.2, 108.9, 64.4, 13.9; IR (neat) 3419, 2985, 1732, 1464, 1297, 1107, 755, 680 cm−1. (S)-Methyl 2-(5-Chloro-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate (3gb). 2c Compound 3gb was purified by flash chromatography (petroleum ether/EtOAc = 4/1) to afford a colorless oil in 86% yield (66 mg): 86% ee; [α]D25 = +13.4 (c = 0.47, in CHCl3); the ee value was determined by HPLC (Chiralpak OJ, hexane/i-PrOH = 80/20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 15.51 min, tR (minor) = 16.37 min; 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.88 (d, J = 1.6 Hz, 1H), 7.48 (d, J = 2.7 Hz, 1H), 7.30−7.26 (m, 1H), 7.19−7.17 (m, 1H), 4.41 (s, 1H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 167.4, 136.7, 128.7, 127.7, 125.1, 125.1, 124.8, 124.7, 121.9, 121.4, 111.3, 108.6, 54.6; IR (neat) 3419, 2961, 1740, 1463, 1291, 1173, 732, 667 cm−1. (S)-Ethyl 2-(5-Bromo-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate (3ha).2c Compound 3ha was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 91%

yield (83 mg): 85% ee; [α]D25 = +14.8 (c = 0.39, in CHCl3); the ee value was determined by HPLC (Chiralpak IE, hexane/i-PrOH = 80/ 20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 9.66 min, tR (minor) = 8.26 min; 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.57 (dd, J = 10.4, 2.5 Hz, 1H), 7.42 (d, J = 2.9 Hz, 1H), 7.22−7.19 (m, 1H), 6.97−6.92 (m, 1H), 4.49 (s, 1H), 4.47−4.32 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.2, 159.3, 156.9, 132.9, 126.2, 125.5, 124.9, 112.2, 111.4, 111.1, 106.4, 64.4, 13.9; IR (neat) 3415, 2918, 1732, 1460, 1296, 1172, 754, 703 cm−1. (S)-Methyl 2-(5-Bromo-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate (3hb).2c Compound 3hb was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 83% yield (73 mg): 84% ee; [α]D25 = +2.0 (c = 0.36, in CHCl3); the ee value was determined by HPLC (Chiralpak OJ, hexane/i-PrOH = 80/20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 17.33 min, tR (minor) = 15.23 min; 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.45 (d, J = 2.8 Hz, 1H), 7.32−7.22 (m, 2H), 4.40 (s, 1H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.6, 134.9, 126.9, 125.8, 125.5, 124.7, 123.7, 121.9, 114.1, 112.8, 108.2, 54.6; IR (neat) 3418, 2917, 1738, 1456, 1289, 1171, 796, 704 cm−1. (S)-Ethyl 3,3,3-Trifluoro-2-(6-fluoro-1H-indol-3-yl)-2-hydroxypropanoate (3ia).2c Compound 3ia was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 90% yield (69 mg): 52% ee; [α]D25 = +5.6 (c = 0.45, in CHCl3); the ee value was determined by HPLC (Chiralpak OJ, hexane/i-PrOH = 80/20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 21.35 min, tR (minor) = 30.14 min; 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.83 (dd, J = 8.9, 5.4 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H), 7.01 (dd, J = 9.3, 2.4 Hz, 1H), 6.92 (td, J = 9.3, 2.4 Hz, 1H), 4.46−4.36 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.2, 161.2, 158.9, 124.8, 122.3, 122.2, 121.7, 109.5, 109.3, 97.7, 97.4, 64.4, 13.9; IR (neat) 3409, 2920, 1726, 1453, 1227, 1169, 754, 679 cm−1. (S)-Methyl 3,3,3-Trifluoro-2-(6-fluoro-1H-indol-3-yl)-2-hydroxypropanoate (3ib). Compound 3ib was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 86% yield (63 mg): 63% ee; [α]D25 = +6.0 (c = 0.56, in CHCl3); the ee value was determined by HPLC (Chiralpak AD, hexane/i-PrOH = 90/ 10, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 18.07 min, tR (minor) = 23.97 min; 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.79 (dd, J = 8.9, 5.3 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 9.3, 2.4 Hz, 1H), 6.95−6.90 (m, 1H), 4.40 (s, 1H), 3.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.8, 161.3, 158.9, 136.4, 136.3, 124.8, 124.73, 124.71, 122.05, 121.96, 121.7, 109.7, 109.5, 108.6, 97.7, 97.5, 54.6; IR (neat) 3412, 2959, 1739, 1453, 1280, 1171, 797, 704 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C12H10F4NO3+ 292.0591, found 292.0590. (S)-Ethyl 2-(6-Chloro-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate (3ja).5i Compound 3ja was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a white solid in 77% yield (62 mg): mp 116−117 °C; 84% ee; [α]D25 = +8.0 (c = 0.27, in CHCl3); the ee value was determined by HPLC (Chiralpak OD-H, hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 10.33 min, tR (minor) = 12.32 min; 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.12 (dd, J = 8.7, 1.9 Hz, 1H), 4.45− 4.33 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.1, 136.7, 128.7, 125.1, 124.8, 123.8, 122.3, 122.0, 121.3, 111.2, 108.9, 64.4, 13.9; IR (neat) 3356, 2964, 1734, 1452, 1223, 1171, 742, 703 cm−1. (S)-Methyl 2-(6-Chloro-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate (3jb). 14 Compound 3jb was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 81% yield (63 mg): 80% ee; [α]D25 = +18.7 (c = 0.74, in CHCl3); the ee value was determined by HPLC (Chiralpak OJ, hexane/i-PrOH = 80/20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 31.89 min, tR (minor) = 26.91 min; 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.35 (d, J = 2.7 Hz, 1H), 7.27 (d, J = 1.8 Hz, 1H), 7.11 (dd, J = 8.7, 1.6 Hz, 1H), 4.45 (s, 1H), 3.92 (d, J = 1.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 136.7, 128.7, 127.7, 125.1, 125.1, 124.8, 124.7, 121.9, 121.4, 111.3, 1164

DOI: 10.1021/acs.joc.7b02599 J. Org. Chem. 2018, 83, 1160−1166

Article

The Journal of Organic Chemistry

hexane/i-PrOH = 80/20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 52.17 min, tR (minor) = 42.56 min; 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.16−8.12 (m, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.83 (dd, J = 8.6, 1.5 Hz, 1H), 7.63 (d, J = 2.8 Hz, 1H), 4.42 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 167.9, 135.7, 128.8, 127.5, 124.8, 124.5, 121.9, 121.5, 120.8, 113.8, 109.0, 54.6, 52.1; IR (neat) 3479, 3328, 1736, 1439, 1273, 1178, 770, 743 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C14H13F3NO5+ 332.0740, found 332.0736. (R)-Ethyl 3,3,3-Trifluoro-2-hydroxy-2-(2-methyl-1H-indol-3-yl)propanoate (3oa). 2c Compound 3oa was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 79% yield (57 mg): 13% ee; [α]D25 < +0.8 (c = 0.21, in CHCl3); the ee value was determined by HPLC (Chiralpak AD, hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 18.10 min, tR (minor) = 14.55 min; 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.81−7.73 (m, 1H), 7.21−7.02 (m, 3H), 4.43−4.23 (m, 2H), 4.07 (s, 1H), 2.40 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.4, 135.4, 134.7, 126.8, 125.5, 122.6, 121.6, 120.4, 120.3, 120.2, 110.5, 103.8, 63.6, 13.8; IR (neat) 3361, 2919, 1720, 1459, 1240, 739, 699 cm−1. (R)-Ethyl 3,3,3-Trifluoro-2-hydroxy-2-(2-phenyl-1H-indol-3-yl)propanoate (3pa). 5a Compound 3pa was purified by flash chromatography (petroleum ether/EtOAc = 3/1) to afford a yellow solid in 72% yield (65 mg): mp 140−142 °C; 27% ee; [α]D25 = +1.4 (c = 0.36, in CHCl3); the ee value was determined by HPLC (Chiralpak AS, hexane/i-PrOH = 95/5, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 33.55 min, tR (minor) = 40.73 min; 1H NMR (400 MHz, (CD3)2SO) δ 11.58 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.48−7.41 (m, 5H), 7.37 (d, J = 8.0 Hz, 2H), 7.15 (t, J = 7.3 Hz, 1H), 3.53−3.44 (m, 1H), 3.26−3.18 (m, 1H), 0.93 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, (CD3)2SO) δ 167.6, 138.1, 135.7, 132.6, 130.6, 129.0, 128.1, 127.5, 126.7, 123.8, 122.7, 122.1, 119.8, 111.5, 105.7, 61.5, 13.8; IR (neat) 3324, 2922, 1726, 1453, 1249, 745, 701 cm−1.

108.6, 54.6; IR (neat) 3416, 2960, 1738, 1452, 1283, 1171, 732, 666 cm−1. (S)-Ethyl 2-(6-Bromo-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate (3ka).15 Compound 3ka was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 86% yield (79 mg): 77% ee; [α]D25 = +8.0 (c = 0.36, in CHCl3); the ee value was determined by HPLC (Chiralpak AD, hexane/i-PrOH = 80/ 20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 16.99 min, tR (minor) = 32.64 min; 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.81 (dd, J = 8.9, 5.3 Hz, 1H), 7.35 (d, J = 2.7 Hz, 1H), 6.97 (dd, J = 9.4, 2.3 Hz, 1H), 6.91 (td, J = 9.2, 2.4 Hz, 1H), 4.48−4.32 (m, 3H), 1.33−1.30 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.2, 161.2, 158.8, 136.3, 124.8, 124.8, 121.7, 109.3, 108.7, 97.7, 64.4, 13.9; IR (neat) 3356, 2964, 1734, 1452, 1223, 1171, 742, 703 cm−1. (S)-Methyl 2-(6-Bromo-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate (3kb). Compound 3kb was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 91% yield (80 mg): 83% ee; [α]D25 = +16.9 (c = 0.69, in CHCl3); the ee value was determined by HPLC (Chiralpak IB, hexane/i-PrOH = 90/ 10, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 12.58 min, tR (minor) = 11.91 min; 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H), 7.27−7.20 (m, 1H), 4.48 (s, 1H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 137.1, 127.7, 125.0, 125.0, 125.0, 124.8, 124.0, 124.0, 122.2, 122.0, 119.1, 116.3, 114.4, 108.5, 54.6; IR (neat) 3412, 2959, 1739, 1453, 1280, 1171, 742, 704 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C12H10BrF3NO3+ 351.9791, found 351.9790. (S)-Ethyl 3,3,3-Trifluoro-2-hydroxy-2-(5-nitro-1H-indol-3-yl)propanoate (3la).2c Compound 3la was purified by flash chromatography (petroleum ether/EtOAc = 5/1) to afford a colorless oil in 74% yield (61 mg): 76% ee; [α]D25 = +7.0 (c = 0.37, in CHCl3); the ee value was determined by HPLC (Chiralpak IF, hexane/i-PrOH = 95/ 5, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 16.77 min, tR (minor) = 23.48 min; 1H NMR (400 MHz, (CD3)2SO) δ 12.13 (s, 1H), 8.75 (d, J = 2.1 Hz, 1H), 8.04 (dd, J = 9.0, 2.3 Hz, 1H), 7.81 (s, 1H), 7.75 (d, J = 2.6 Hz, 1H), 7.61 (d, J = 9.4 Hz, 1H), 4.37−4.25 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, (CD3)2SO) δ 168.0, 141.4, 140.1, 129.5, 125.9, 124.7, 123.1, 118.2, 117.4, 113.1, 111.2, 63.0, 14.2; IR (neat) 3298, 2917, 1732, 1478, 1323, 1176, 735, 709 cm−1. (S)-Methyl 3,3,3-Trifluoro-2-hydroxy-2-(5-nitro-1H-indol-3-yl)propanoate (3lb).2c Compound 3lb was purified by flash chromatography (petroleum ether/EtOAc = 5/1) to afford a yellow crystalline solid in 83% yield (66 mg): mp 139−140 °C; 62% ee; [α]D25 = −6.6 (c = 0.33, in CHCl3); the ee value was determined by HPLC (Chiralpak AD, hexane/i-PrOH = 80/20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 10.49 min, tR (minor) = 7.44 min; 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J = 2.0 Hz, 1H), 8.77 (s, 1H), 8.15 (dd, J = 9.0, 2.2 Hz, 1H), 7.68 (d, J = 2.7 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 4.48 (s, 1H), 4.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.2, 142.6, 139.3, 127.6, 124.7, 121.7, 119.0, 118.4, 111.5, 111.1, 54.9; IR (neat) 3350, 2920, 1742, 1523, 1433, 1170, 748, 679 cm−1. (S)-Methyl 3-(3-Ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2yl)-1H-indole-6-carboxylate (3ma).15 Compound 3ma was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 66% yield (57 mg): 40% ee; [α]D25 = +5.2 (c = 0.29, in CHCl3); the ee value was determined by HPLC (Chiralpak OJ, hexane/i-PrOH = 80/20, flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 39.18 min, tR (minor) = 32.07 min; 1H NMR (400 MHz, CDCl3) δ 8.96−8.88 (m, 1H), 8.12 (dd, J = 1.5, 0.7 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.82 (dd, J = 8.6, 1.5 Hz, 1H), 7.62 (d, J = 2.8 Hz, 1H), 4.52 (s, 1H), 4.49−4.32 (m, 2H), 3.93 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.1, 168.1, 135.8, 128.8, 127.7, 124.9, 124.3, 122.0, 121.3, 120.9, 113.8, 109.1, 64.4, 52.1, 13.9; IR (neat) 3415, 2918, 1739, 1453, 1225, 1168, 741, 677 cm−1. (S)-Methyl 3-(1,1,1-Trifluoro-2-hydroxy-3-methoxy-3-oxopropan2-yl)-1H-indole-6-carboxylate (3mb). Compound 3mb was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to afford a colorless oil in 81% yield (67 mg): 47% ee; [α]D25 = −3.1 (c = 0.32, in CHCl3); the ee value was determined by HPLC (Chiralpak OJ,

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02599. Detailed 1H and 13C NMR spectra and chiral HPLC chromatogram data for compounds 3 (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Yuan-Zhao Hua: 0000-0002-4680-3680 Min-Can Wang: 0000-0002-3817-3607 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (NSFC: 21272216) and the Department of Science and Technology of Henan Province for financial support.

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REFERENCES

(1) (a) Organofluorine Compounds; Hiyama, T., Ed.; Springer: Heidelberg, Germany, 2001. (b) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, and Applications; Wiley-VCH: New York, 2004. (2) (a) Riether, D.; Harcken, C.; Razavi, H.; Kuzmich, D.; Gilmore, T.; Bentzien, J.; Pack, E. J., Jr.; Souza, D.; Nelson, R. M.; Kukulka, A.; Fadra, T. N.; Zuvela-Jelaska, L.; Pelletier, J.; Dinallo, R.; Panzenbeck, M.; Torcellini, C.; Nabozny, G. H.; Thomson, D. S. J. Med. Chem. 1165

DOI: 10.1021/acs.joc.7b02599 J. Org. Chem. 2018, 83, 1160−1166

Article

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DOI: 10.1021/acs.joc.7b02599 J. Org. Chem. 2018, 83, 1160−1166