Asymmetric FriedelâCrafts Alkylation of Indoles with Trifluoromethyl

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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 J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02599 • Publication Date (Web): 02 Jan 2018 Downloaded from http://pubs.acs.org on January 2, 2018

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The Journal of Organic Chemistry

Asymmetric Friedel–Crafts Alkylation of Indoles with Trifluoromethyl Pyruvate Catalyzed by a Dinuclear Zinc Catalyst Yuan-Zhao Hua, Jun-Wei Chen, Hua Yang,* Min-Can Wang*

College of Chemistry and Molecular Engineering, School of Pharmaceutical Sciences, Zhengzhou University;

No. 100, Science Road, Zhengzhou City, Henan province 450000, P. R. China

E-mail: [email protected]; [email protected]

F 3C

2

N H

Ar Ar

O

OR2 10 mol% Cat.

+ F3C O

DCM, 10 oC 24 h

R1

Et

O

Zn Zn

CO2R

O R1

OH

N

O

Ar Ar

N

N H 29 examples yield up to 95% Ar = 4-ClC6H4 ee up to 88% Trost's dinuclear zinc-ProPhenol catalyst

ABSTRACT: Bimetallic cooperative catalysis model has been reported in asymmetric Friedel–Crafts (F–C)

alkylation of indoles with trifluoromethyl pyruvates by using Trost’s intramolecular dinuclear zinc complex as

catalyst. This dinuclear zinc catalyst was prepared in situ by reacting the chiral ligand (S,S)-L2b with two

equivalents 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 % catalysts under mild conditions. A synergistic transition state model was

proposed to explain the origin of the asymmetric induction.

INTRODUCTION Fluorinated compounds has 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 the strong electron-withdrawing effect and the absolute configuration of the CF3 group lead to unique physical and biological properties.2 The enantioselective addition of trifluoromethyl pyruvate

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The Journal of Organic Chemistry 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 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

represents one of the most convenient and straightforward approaches to obtain chiral trifluoromethylated

compounds.3

Over the past decades, the Friedel–Crafts (F–C) alkylation reaction of indoles with trifluoromethyl pyruvate

has attracted much attention,4,5 which can obtain the 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 this enantioselective F–

C alkylation reactions. Among those reports, all the metal catalysts activate the substrates through

mononuclear metal transition models.

The chiral multimetallic catalysts were first reported by Shibasaki and co-workers in 1992.6 After that, several

bi- or multi-metal catalysts based on chiral ligands and different metals have been successfully developed,

including bimetallic catalysts based on a tetraol ligand coined linked-BINOL derived from tethering the two

BINOL units by an ether linker,7 bimetallic Schiff base catalysts,8 and Trost’s dinuclear zinc-ProPhenol

catalysts.9 The bi- or multi-metal catalysts have the advantages of synergistic effect that 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 multi-metallic 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.

Scheme 1. Dinuclear zinc catalysts


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In recent years, Our work has been focused on exploring the use of dinuclear metal catalysts based on

chiral multidenate semi-azacrown ether ligands (S,S)-L111a and (S,S)-L29a in catalytic asymmetric synthesis

(Scheme 1). The two intramolecular dinuclear zinc catalysts have led to a number of efficient catalytic

enantioselective transformations.10f,11,12 Though these two ligands make equal effect in enantioselective

alkynylation reaction9d,11e and catalytic asymmetric F–C alkylation of pyrrole with chalcones11b,12c owing to their

similarity in structure and function, their catalytic performances on the same reactions are different sometimes.

The dinuclear zinc-AzePhenol catalyst shows more efficient in asymmetric copolymerization of epoxides with

CO2,9b,9c,11a,11c and domino Michael/hemiketalization reaction.11d However, the performances of Trost’s

dinuclear zinc-ProPhenol catalyst are better than that of the dinuclear zinc-AzePhenol catalyst in the tandem

Michael addition/acetalizations of cyclic 1,3-diketons with β,γ-unsaturated α-ketoesters,12a and asymmetric F−C

alkylation reaction between indoles and 2-(4-methoxyphenylimino)acetate.12b

As a part of our continuing project on these dinuclear zinc catalysts’ application in asymmetric transformation,

Herein, we report the first example of synergistic model catalyzed asymmetric F–C alkylation of indoles with

trifluoropyruvates by using dinuclear zinc catalyst, which affords valuable chiral trifluoromethylated indoles in

moderate to good yields (up to 95%) and up to 88% enantiomeric excess (ee).

RESULT AND DISCUSSION Table 1. Effect of ligand structure on Friedel−Crafts alkylation reaction of indole 1a and ethyl

trifluoromethyl pyruvate 2aa



Entry

a

Page 4 of 18

b

c

L

Time (h)

Yield (%)

Ee (%)

1

L1a

24

76

4

2

L1b

24

83

4

3

L2a

24

90

60

4

L2b

24

83

69

5

L2c

24

81

68

6

L2d

24

87

67

7

L2e

24

90

64

8

L2f

24

81

56

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 oC for 24 h. bIsolated yields. cDetermined by HPLC analysis.

Initially, our investigation began with evaluating the ability of chiral multidenate semi-azacrown ether ligands

L1 and L2 to promote the Friedel−Crafts reaction of unprotected indole 1a with ethyl trifluoromethyl pyruvate 2a

using CH2Cl2 as 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

ºC) 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, big sterically hindered 2-naphthyl group, and

heteroaromatic ring 2-thiophene group. The results were summarized in Table 1 (entries 3–8). It was found that

ligand L2b with slightly electron-deficient 4-chloro-phenyl groups gave the best result (69% ee, Table 1, entry

4).


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Table 2. Further condition optimizationa

entry

solvent

temp (oC)

x

yield (%)b

ee (%)c

1

CH 2Cl2

25

10

83

69

2

Toluene

25

10

86

39

3

THF

25

10

71

43

4

CH3CN

25

10

75

26

5

CHCl3

25

10

84

47

6d

CH 2Cl2

25

10

86

67

e

CH 2Cl2

25

10

70

0

8

CH 2Cl2

10

10

86

76

9

CH 2Cl2

0

10

87

68

f

10

CH 2Cl2

-20

10

73

70

f

7

11

CH 2Cl2

-40

10

72

70

g

CH 2Cl2

10

10

86

60

13

CH 2Cl2

10

5

81

66

14

CH 2Cl2

10

15

86

75

15

CH 2Cl2

10

20

88

73

12

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 presence of 30 mg 4

Å MS.

In further investigation, various reaction conditions including solvents, metal reagent, temperature, additive,

catalyst loading, and ratio of 1a to 2a were examined using ligand L2b (Table 2).

Several solvents were tested in the presence of 10 mol % catalysts at 25 °C for 24 h. The reaction proceeded

smoothly in CH2Cl2, toluene, THF, CH3CN, and CHCl3 with different enantioselectivity (26-69% ee, Table 2,

entries 1-5). The results indicated that CH2Cl2 was effective for the reaction with 83% yield and 69% ee (Table 2,

entry 1).

Changing the metal reagents from ZnEt2 to Zn(CH3)2 or nBu2Mg12b,13 led to a reduction on ee values (Table 2,

entries 6 and 7). Decreasing temperature from 25 to 10 ºC resulted in an improvement of the product’s ee value



Page 6 of 18

to 76% (Table 2, entry 8). However, the enantioselectivities were slightly reduced when the temperature was

decreased to 0, -20, -40 °C, and prolonged reaction times were required (Table 2, entries 9-11). Additive 4 Å

MS proved to have 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). Upon increasing the catalyst loading from

10 to 15 and 20 mol %, the yields were maintained but the enantioselectivity were somewhat reduced (Table 2,

entries 14 and 15). 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 o

C for 24 h.

Table 3. Catalytic asymmetric Friedel-Crafts reaction of various indoles 1 and trifluoromethyl pyruvate

2a

Entry

R1

R2

Product

Yield (%)b

Ee (%)c

1

H

Et

3aa

86

76

2

H

Me

3ab

75

70

3

4-OMe

Et

3ba

75

88

4

4-OMe

Me

3bb

78

84

5

5-OMe

Et

3ca

67

55

6

5-OMe

Me

3cb

85

55

7

5-Me

Et

3da

93

72

8

5-Me

Me

3db

86

65

9

6-Me

Et

3ea

40

9

10

6-Me

Me

3eb

66

48

11

5-F

Et

3fa

95

84

12

5-F

Me

3fb

85

74

13

5-Cl

Et

3ga

95

82

14

5-Cl

Me

3gb

86

86

15

5-Br

Et

3ha

91

85

16

5-Br

Me

3hb

83

84

17

6-F

Et

3ia

90

52

18

6-F

Me

3ib

86

63


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19

6-Cl

Et

20

6-Cl

21

6-Br

22

6-Br

23

5-NO

24

5-NO

25

3ja

77

84

Me

3jb

81

80

Et

3ka

86

77

Me

3kb

91

83

2

Et

3la

75

76

2

Me

3lb

83

62

6-CO2Me

Et

3ma

66

40

26

6-CO2Me

Me

3mb

81

47

27d

7-NO 2

Et

3na

trace

-

28

2-Me

Et

3oa

79

13

29

2-Ph

Et

3pa

72

27

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.

In order to evaluate the generality of substrates, we subsequently tested an array of substituted indoles

under the optimal conditions. As summarized in Table 3, the substituted group of indoles played an important

role in controlling the reaction activity and enantioselectivity. Most of indoles bearing different groups furnished

corresponding products in good yield and enantioselectivity. Substrates with a strongly electron-donating group

MeO at 4-position of the phenyl ring gave good results in terms of 88% ee. This result was much better than

that of 5-methoxy indole (Table 3, entries 3-6). Slightly weak electron-donating group Me at 5- or 6-position of

the phenyl ring led to decrease of the products’ ee values (9-72%, Table 3, entries 7-10). Halogen groups on

indoles were beneficial to this catalytic asymmetric Friedel-Crafts reaction, and most of the desired products

were obtained in good enantioselectivities (>80% ee) except the 6-fluoro substituted products (Table 3, entries

11-22). Substrates with a strongly electron-withdrawing group NO2 and CO2Me gave the corresponding

products in decreased ee values (Table 3, entries 23-26). When 7-nitroindole was used, almost no desired

product could be obtained even if the reaction time was prolonged to 72 h (Table 3, entry 27). 2-Methyl or

phenyl substituted indoles were also tested and the ee values were poor (Table 3, entries 28 and 29). The big

sterically hindered effect of phenyl and methyl groups might be responsible for the decrease in

enantioselectivities.



Scheme 2. Catalytic asymmetric Friedel−Crafts alkylation reaction of indoles 1q, 1r with 2a

Furthermore, when N-benzyllindole 1q and N-acetylindoline 1r, respectively, were treated with 2a under the

optimal conditions, no reaction was observed, which was in accordance with the previous reports (Scheme

2).9e,11b,12b This finding demonstrated the hydrogen atom on the N atom of indole was critical for this

Friedel−Crafts reaction.

The absolute stereochemistry of the products was determined to be S-configuration by optical rotation

according to previous reports.5a

Scheme 3. Transition state model

A transition state model that accounts for the observed sense of asymmetric induction is provided on the

basis of these experimental results and the previous reports on mechanism of dinuclear zinc catalysis (Scheme

3).[9a,9b,12b] The two zinc 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 the deprotonation accompanied with the

formation of one equivalent of ethane, and the other zinc center activates trifluoromethyl pyruvate by

zinc-oxygen coordination. Then nucleophilic attack of indole on the Si-face of the coordinated trifluoromethyl

pyruvate affords the observed stereo-chemical outcome. Finally, a proton transfer with another free indole

releases the product and reform the catalyst. The dinuclear zinc structure of the catalyst remains intact

throughout the alkylation reaction.


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CONCLUSION In summary, Trost’s dinuclear zinc catalysts have been evaluated in catalytic asymmetric Friedel–Crafts

alkylation of unprotected indoles with trifluoromethyl pyruvate. It is the first application of dinuclear metal

catalyst’s synergistic effect in this reaction. When indole 1b and the ethyl ester of 3,3,3-trifluoropyruvic acid 2a

are employed as reaction substrates and the reaction is performed in CH2Cl2 at 10 oC, an enantioselectivitiy of

88% ee is recorded. A transition state model is put forward to explain synergistic effect and the origin of the

asymmetric induction. Further exploring of the applications of those dinuclear metal catalysts to other

asymmetric reactions is currently underway in our group.

EXPERIMENTAL SECTION General Method. Solvents were dried with standard methods and freshly distilled prior to use if needed. All

reactions sensitive to air or moisture were carried out under nitrogen using standard Schlenk and vacuum line

techniques. The chiral ProPhenol ligands L1[11b] and L2[9a,12b] were synthesized according to reported

procedures. Indoles and trifluoromethyl pyruvate were used as purchased. NMR spectra were recorded on 400

MHz NMR or 600 MHz spectrometer with CDCl3 or (CD3)2SO as the solvent and TMS as an internal reference (400 MHz or 600 MHz for 1H and 100 MHz or 150 MHz for

13

C). HRMS were determined on a Q-TOF Micro

LC/MS System ESI spectrometer. Enantiomeric excesses 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 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 stirring for 30 min at room temperature, the temperature was lowered to 10 oC. Then, indole 1 (0.25 mmol) and trifluoromethyl pyruvate 2



Page 10 of 18

(0.25 mmol) were added respectively. The reaction mixture was stirred for 24 h at the same temperature. The

reaction was quenched with HCl solution (1M, 2 mL) and extracted with CH2Cl2 (5 mL x 3). 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 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 SA, 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

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 SA, 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);

13

C 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 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);

13

C NMR (100 MHz, 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-3-yl)propanoate (3bb).14 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),


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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 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);

13

C 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-3-yl)propanoate (3cb).2c 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); 13C 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 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/ i-PrOH = 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 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/ i-PrOH = 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 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/ i-PrOH = 80/20,



Page 12 of 18

flow rate 1.0 mL/min, λ = 254 nm), tR (major) = 5.54 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);

13

C 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). 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).2c

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); 13

C 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 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);

13

C 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 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);

13

C 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.


Page 13 of 18 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 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(S)-Methyl 2-(5-chloro-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate (3gb).2c 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 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);

13

C 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 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


(3ia).2c

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);

13

C 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


(3ib).

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



Page 14 of 18

(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);

13

C 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

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 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);

13

C 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, 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 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). 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);

13

C NMR (100 MHz, CDCl3) δ 169.7, 137.1, 127.7, 125.0, 125.0, 125.0, 124.8, 124.0, 124.0,


Page 15 of 18 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 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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

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

Purified

by flash

chromatography (petroleum ether/EtOAc = 5/1) to afford a yellow crystalline solid in 83% yield (66 mg); mp = 139–140 oC; 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-2-yl)-1H-indole-6-carboxylate (3ma).15 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);

13

C

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-oxopropan-2-yl)-1H-indole-6-carboxylate (3mb). 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, 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);

13

C 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 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 Purified by flash chromatography (petroleum ether/EtOAc = 3/1) to afford a yellow solid in 72% yield (65 mg); mp = 140–142 oC; 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.

ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.

Detail 1H, 13C NMR, and chiral HPLC chromatograms data for compounds 3.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]; [email protected]

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS We are grateful to the National Natural Sciences Foundation of China (NNSFC: 21272216), and the

Department of Science and Technology of Henan Province for financial supports.

REFERENCE


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