Asymmetric Michael Addition of 2-Acetyl Azaarenes to β-CF3-β-(3

Article Cite This: J. Org. Chem. 2019, 84, 191−203

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Asymmetric Michael Addition of 2‑Acetyl Azaarenes to β‑CF3‑β-(3indolyl)nitroalkenes Catalyzed by a Cobalt(II)/(imidazolineoxazoline) Complex Cong Wang, Nan Li, Wen-Jing Zhu, Jun-Fang Gong,* and Mao-Ping Song* College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Zhengzhou University, Zhengzhou 450001, People’s Republic of China

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S Supporting Information *

ABSTRACT: The first enantioselective Michael addition of 2-acetyl azaarenes to β-CF3-β-(3-indolyl)nitroalkenes has been successfully achieved in the presence of a Co(II)/ (imidazoline-oxazoline) complex as the catalyst. The reaction affords a series of CF3- and 3-indole-containing adducts featuring a trifluoromethylated all-carbon quaternary stereocenter in good to excellent yields (up to 99%) and enantioselectivities (up to 96% ee). Furthermore, the functional groups in the adducts including CO, NO2, and the azaarene provide a large variety of useful transformations, leading to the formation of valuable intermediates such as optically active secondary alcohol, pyrroline, ester, and pyrrolidinone which all contain a 3-substituted indole and a trifluoromethylated all-carbon quaternary stereocenter.

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INTRODUCTION Indoles are a class of important aromatic nitrogen-containing heterocycles which are ubiquitous structural motifs in natural products, pharmaceuticals, and synthetic chemicals.1 In particular, indole derivatives bearing chiral functional groups at the 3-position have been found in many biologically active natural products and therapeutic agents.1b,2 On the other hand, organic compounds possessing a trifluoromethyl group at the tertiary or quaternary stereogenic carbon center play a unique and significant role in medicinal and agricultural chemistry, as well as in material sciences.3 Therefore, the exploitation of simple and efficient methods for the asymmetric construction of compounds that contain both a 3-substituted indole and a trifluoromethylated carbon stereocenter would be of great value, and a number of strategies have been devised. One of the most straightforward approaches to synthesize these compounds is the use of catalytic enantioselective Friedel− Crafts alkylation4 of indoles with CF3-containing electrophiles. Consequently, a great number of such reactions have been successfully developed where trifluoropyruvates,5 trifluoromethyl ketones,6 trifluoroethylidene malonates,7 β-trifluoromethyl-α,β-unsaturated ketones,8 β-trifluoromethyl-β-aryl nitroalkenes,9,10 as well as 1-trifluoromethyl-3,4-dihydro-β-carbolines11 were employed as electrophiles to react with indoles. In general, the reactions proceeded well in the presence of appropriate organo- or transition-metal catalysts, providing structurally diversified trifluoromethylated indole derivatives in high yields with good to excellent enantioselectivities. Besides Friedel−Crafts reactions, an alternative direct and convenient approach to the chiral target molecules involves the reactions of prochiral CF3-containing 3-indoles. Surprisingly, reports on such reactions12−14 are rather limited despite the © 2018 American Chemical Society

fact that the availability of prochiral CF3-containing indoles such as β-CF3-β-indole enones and β-CF3-β-indole nitroalkenes is not a problem. Among the few examples, Yan and Wang reported a sulfa-Michael-aldol reaction between 2mercaptobenzaldehydes and β-CF3-β-indole enones catalyzed by a squaramide, which produced 2-CF3-2-indole-substituted thiochromanes featuring a CF3-containing heteroquaternary stereocenter in high yields with excellent stereoselectivities (>20:1 dr, up to 99% ee).13 In addition, Kang, He, and Liu demonstrated that the Michael addition of malonates to βCF3-β-indole nitroalkenes could be achieved in the presence of a thiourea catalyst, giving the corresponding adducts in high yields and enantioselectivities (up to 90% ee).14 This reaction affords very versatile building blocks containing not only a trifluoromethylated 3-indole but additionally an all-carbon quaternary stereocenter which constitutes an important structural element in natural products and pharmaceuticals,15 as well as ester and nitro groups which can offer various useful transformations. Cobalt-catalyzed asymmetric transformations provide attractive alternatives for the synthesis of optically active compounds due to the low cost and toxicity of cobalt in comparison with precious transition metals such as palladium, rhodium, iridium, and platinum. Much attention has been paid in this field in the past two decades, and impressive progress has been made.16 For example, various preformed or in situ-formed chiral cobalt complexes have been applied to asymmetric Michael addition of different types of nucleophiles to α,β- or α,β,γ,δ-unsaturated carbonyl compounds and nitroalkenes. Some of them, though Received: October 8, 2018 Published: December 13, 2018 191

DOI: 10.1021/acs.joc.8b02601 J. Org. Chem. 2019, 84, 191−203

Article

The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa

probably not very much, exhibited excellent enantioselectivities.17 Further, adducts bearing an all-carbon quaternary stereocenter were obtained in the addition of β-ketoesters17a,b and β-ketoamides17d to alkynones or nitroalkenes. In a previous study, we found that the cobalt(II) complex with hybrid imidazoline-oxazoline ligand derived from 2,2-dimethylmalonic acid was an effective catalyst for enantioselective Michael addition of 2-acetyl azaarenes to β-CF3-β-aryl nitroalkenes, furnishing a range of chiral compounds with a trifluoromethylated all-carbon quaternary stereocenter in good yields with enantioselectivity of up to 98% ee.18 We envisioned that β-CF3-β-indole nitroalkenes would also be an excellent acceptor for Co-catalyzed Michael addition. Moreover, considering the importance of chiral trifluoromethylated indole derivatives, it is highly desirable to investigate the asymmetric reactions involving β-CF3-β-indole nitroalkenes. Therefore, we report herein the first example of enantioselective Michael addition of 2-acetyl azaarenes to β-CF3-β-indole nitroalkenes catalyzed by the cobalt complexes (Scheme 1). To the best of

entry

Scheme 1. Co-catalyzed Enantioselective Michael Addition of 2-Acetyl Azaarenes to β-CF3-β-indole Nitroalkenes

our knowledge, there was only one report on the Michael addition concerning β-CF3 -β-indole nitroalkenes (vide supra).14 It is noted that the obtained chiral adducts also contain various aromatic N-heterocycles (azaarenes) which are widespread in pharmaceuticals and other biologically active compounds. These adducts can undergo a variety of useful transformations to afford diverse trifluoromethylated indole derivatives featuring an all-carbon quaternary stereocenter. The results are shown as below.

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RESULTS AND DISCUSSION We started our study by choosing the addition of commercially available 2-acetyl pyridine 1a to β-CF3 -β-(3-indolyl)nitroalkene 2a as a model (Table 1). The reaction was initially carried out on a 0.2 mmol scale with 1.5 equiv of 2a using 10 mol % of Co(acac)2 in combination with 12 mol % of chiral imidazoline-oxazoline ligand L1 as the catalyst in methyl tertbutyl ether (MTBE) at 20 °C based on our previous work.18 Pleasingly, the desired adduct 3aa could be obtained in almost quantitative yield with a good enantioselectivity of 84% ee (entry 1). Then the reaction conditions were roughly optimized by changing the ratio of 1a to 2a, MTBE as well as its amount, and reaction temperature (entries 2−7). It was found that the best results were achieved when 1a reacted with 2a in a 1:1 ratio in 1.5 mL of MTBE at 20 °C for 24 h (96% yield with 89% ee, entry 4). Although the enantioselectivity of 89% under this circumstance was not as high as expected, the reaction showed the advantage of mild conditions, particularly no requirement of excess substrate. Next, the potential of other chiral ligands including imidazoline-oxazoline ligands L2 and L3 as well as the related bis(imidazoline) ligand L4 and bis(oxazoline) L5 was surveyed. All of them afforded obviously inferior results in terms of both yield and enantioselectivity when compared with the ligand L1 (entries 8−11 vs 4). For

1a/2a

L

1

1/1.5

L1

2

1/1

L1

3

1/1

L1

4

1/1

L1

5

1/1

L1

6

1.25/1

L1

7

1/1

L1

8

1/1

L2

9

1/1

L3

10

1/1

L4

11

1/1

L5

12e

1/1

L1

13f

1/1

L1

14g

1/1

L1

solvent (amount) MTBE (1.2 mL) MTBE (1.2 mL) MTBE (1.0 mL) MTBE (1.5 mL) MTBE (2.0 mL) MTBE (1.5 mL) (i-Pr)2O (1.5 mL) MTBE (1.5 mL) MTBE (1.5 mL) MTBE (1.5 mL) MTBE (1.5 mL) MTBE (1.5 mL) MTBE (1.5 mL) MTBE (1.5 mL)

T (°C)

time (h)

yieldb (%)

eec,d (%)

20

24

99

84

20

24

97

87

rt

36

96

84

20

24

96

89

20

24

91

81

20

24

99

85

20

24

87

89

20

24

78

21

20

24

88

71

20

24

66

14

20

24

58

79

20

24

84

79

20

24

85

89

20

24

n.d.

a

Reaction conditions unless noted otherwise: 1a (0.2 mmol), 2a (0.2 mmol), Co(acac)2 (10 mol %), L (12 mol %), MTBE (1.5 mL), 20 °C, 24 h, rt: about 10−15 °C. bIsolated yield. cDetermined by chiral HPLC analysis. dThe absolute configuration of 3aa was determined to be S according to the X-ray crystal diffraction analysis (vide infra). e5 mol % of Co(acac)2, 6 mol % of L1. f10 mol % of Co(acac)2, 11 mol % of L1. gThe Ts protective group in 2a was replaced by Boc group.

example, the reaction in the presence of the ligand L5 which is structurally very close to the ligand L1 produced the adduct 3aa in 58% yield with 79% ee (entry 11). In addition, lowering the catalyst loading led to decreased yield and/or ee value (entries 12 and 13). Finally, it was observed that the Ts protective group in 2a was crucial for the addition since no reaction occurred when Ts was replaced by a Boc group (entry 14). Under the optimal reaction conditions (Table 1, entry 4), the substrate scope concerning both the nitroalkenes and 2acetyl azaarenes was explored. The results are shown in Table 2. First, a series of different substituted β-CF3-β-(3-indolyl)nitroalkenes (2b−2g) were applied to the reactions with 2acetyl pyridine 1a. Pleasingly, excellent yields and enantioselectivities were consistently achieved in the case of 5- and 6192

DOI: 10.1021/acs.joc.8b02601 J. Org. Chem. 2019, 84, 191−203

Article

The Journal of Organic Chemistry Table 2. Substrate Scope of the Reactiona

entry

Ar

R

time (h)

product

yieldb (%)

eec,d (%)

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

2-pyridinyl 2-pyridinyl 2-pyridinyl 2-pyridinyl 2-pyridinyl 2-pyridinyl 2-pyridinyl 2-thiazolyl 2-thiazolyl 2-thiazolyl 2-thiazolyl 2-thiazolyl 2-thiazolyl 2-thiazolyl 2-thiazolyl 2-thiazolyl 2-thiazolyl 2-thiazolyl 2-pyrazinyl 2-pyrazinyl 2-pyrazinyl 2-pyrazinyl 2-pyrazinyl 2-pyrazinyl 2-pyrazinyl 2-pyrazinyl 2-pyrazinyl 2-quinolinyl 2-quinoxalinyl N-methyl-2-imidazolyl N-methyl-2-imidazolyl 2-benzothiazolyl 2-pyrimidinyl

H 4-F 4-Me 5-Cl 5-Br 5-Me 6-Me H 5-Cl 5-Br 5-Me 6-Me 5-F 5-OMe 5-COOMe 6-Br 7-Me 7-OMe H 5-Cl 5-Br 5-Me 6-Me 5-F 5-COOMe 7-Me 7-OMe 5-Br 5-Br 5-Cl 5-Br 5-Br 5-Br

24 24 48 24 24 24 24 72 72 72 72 72 72 120 72 72 72 72 72 96 72 96 96 96 96 96 96 96 120 96 96 120 96

3aa 3ab 3ac 3ad 3ae 3af 3ag 3ba 3bd 3be 3bf 3bg 3bh 3bi 3bj 3bk 3bl 3bm 3ca 3cd 3ce 3cf 3cg 3ch 3cj 3cl 3cm 3de 3ee 3fd 3fe 3ge 3he

96 66 n.d. 97 99 95 96 85 94 95 86 81 86 84 81 86 77 76 78 92 83 84 83 80 87 72 67 80 69 65 69 57 56

89 91 91 90 93 91 94 95 95 95 93 94 94 95 93 92 94 92 95 95 95 94 94 96 94 94 86 94 96 96 95 31

a Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), Co(acac)2 (10 mol %), L1 (12 mol %), MTBE (1.5 mL), 20 °C. bIsolated yield. cDetermined by chiral HPLC. dThe absolute configurations of the products 3ab−3he were assigned to be S by analogy.

adducts could be easily utilized for further elaboration. Similarly to 2-acetyl pyridine and thiazole, 2-acetyl pyrazine also reacted smoothly with 2a and nitroalkenes containing an electron-withdrawing or electron-donating group on the indole ring to give the corresponding adducts 3ca−3cm in 67−92% yields with 92−96% ee (entries 19−27). In comparison with 2acetyl pyridine, 2-acetyl quinoline exhibited much lower reactivity in the addition to 5-Br indole nitroalkene 2e, producing the adduct 3de in 80% yield with 86% ee after 96 h (entry 28 vs 5). Similar phenomena were observed for 2-acetyl quinoxaline and benzothiazole when they reacted with the nitroalkene 2e. In both cases, the stereocontrol was excellent (94% and 95% ee) while their reactivity was lower than that of 2-acetyl pyrazine and thiazole, respectively (entry 29 vs 21 and 32 vs 10). Notably, addition of N-methyl-2-acetyl imidazole to 2d or 2e proceeded well, furnishing the adducts 3fd and 3fe with ee values as high as 96%, though the yields were not very high (65% and 69%, respectively, entries 30 and 31). Finally, it was found that 2-acetyl pyrimidine was not a good partner for

substituted indole nitroalkenes (95−99% yields and 90−93% ee, entries 4−7). For 4-F-substituted indole nitroalkene 2b, an excellent ee value of 91% could still be obtained, albeit with a decreased yield of 66% (entry 2). Additionally, the reaction was totally inhibited when 4-Me indole nitroalkene 2c was used as the Michael acceptor (entry 3). The low reactivity of these 4-substituted indole nitroalkenes was much likely caused by the steric hindrance of the 4-substituent. Subsequently, the reactions of 2-acetyl thiazole with various nitroalkenes were carried out. To our delight, the enantioselectivities were invariably excellent (92−95% ee) and slightly higher than those of 2-acetyl pyridine, although a longer reaction time was needed for ensuring high yields (76−95%, entries 8−18). Thus, the nitroalkene 2a and nitroalkenes bearing either an electron-withdrawing group such as F, Cl, Br, and COOMe or an electron-donating group such as Me and OMe at the 5-, 6-, or 7-position of indole ring were all demonstrated to be effective reaction partners for 2-acetyl thiazole. It is worth mentioning that the F, Cl, Br, and COOMe groups in the 193

DOI: 10.1021/acs.joc.8b02601 J. Org. Chem. 2019, 84, 191−203

Article

The Journal of Organic Chemistry

ee and 65% yield with 96% ee, respectively (Scheme 3c). The compounds 7 are also very valuable intermediates since both CO2Me and NO2 can offer quite a number of useful transformations. For example, 7a and 7b were successfully transformed into the γ-lactams 8a and 8b, respectively, by reaction with NiCl2/NaBH4 in EtOH.14,22 Interestingly, it was found that the Br substitutent in 7a was removed during the reaction (Scheme 3c). The absolute configuration of the new adduct 3aa was determined to be S on the basis of X-ray crystallographic analysis (see Figure S1 in the Supporting Information). According to the observed stereochemical outcome as well as the literature reports,18,20b a possible pathway for the formation of the (S)-adduct is proposed (Scheme 4). As

2e which gave the desired adduct 3he in low yield and enantioselectivity (entry 33). To further demonstrate the synthetic utility of the present system, a series of transformations have been carried out. First, it is worthy of note that the addition can be readily scaled up. When 0.61 g of 2-acetyl pyrazine 1c reacted with equivalent of nitroalkene 2e (2.45 g, 5 mmol) in the presence of 8 mol % of chiral cobalt complex, 2.45 g of the adduct 3ce was isolated in good chemical yield and excellent enantioselectivity (Scheme 2). Then removal of the N-Ts group in the adducts 3 was Scheme 2. Gram-Scale Asymmetric Michael Addition of 1c to 2e

Scheme 4. Possible Stereochemical Pathway

attempted. It was found that this could be easily achieved without any loss in the enantioselectivity via a single step by using cesium carbonate (Scheme 3a).19 Next, transformations based on the functional groups of the adducts 3 including NO2, CO, and even the azaarene were investigated. Thus, the diastereoisomeric secondary alcohols 5a and 5b were readily obtained in a ratio of 1.2:1 and in a combined yield of 84% with 96% ee (for both isomers) by reduction of the carbonyl in 3ca with NaBH4 (Scheme 3b). When 3ca was treated with Fe and AcOH in THF/MeOH at 65 °C,20 the pyrroline derivative 6 was produced in a good yield without any loss of enantioselectivity (Scheme 3b). The formation of 6 includes reduction of NO2 to NH2 and subsequent intramolecular condensation between CO and NH2. In addition, the acyl imidazole moiety in the adducts 3fe and 3fd could be converted into an ester group21 which was accomplished by treatment of 3fe or 3fd with MeOTf, followed by DBU, furnishing the methyl esters 7a and 7b in 67% yield with 97%

shown in Scheme 4, interaction of 2-acetyl azaarene 1 with chiral Co(II)/L1 complex generates the cationic Co(II) enolate. Meanwhile, nitroalkene 2 also interacts with the catalyst by coordination of the NO2 group to the Co(II) center, which makes the nitroalkene activated. To minimize unfavorable steric repulsions between the nitroalkene and the phenyl group of ligand L1, Re-face attack of the nitroalkene by

Scheme 3. Transformations of the Adducts

194

DOI: 10.1021/acs.joc.8b02601 J. Org. Chem. 2019, 84, 191−203

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The Journal of Organic Chemistry

(q, J = 33.4 Hz), 126.9, 121.7 (q, J = 274.4 Hz), 115.2 (d, J = 9.4 Hz), 114.1 (d, J = 25.6 Hz), 108.1 (d, J = 4.1 Hz), 105.6 (d, J = 24.9 Hz), 21.6; 19F NMR (376 MHz, CDCl3): δ −66.7, −117.4; HRMS (positive ESI): [M + Na]+ calcd for C18H12F4N2NaO4S: 451.0352, Found: 451.0351. (E)-5-Methoxycarbonyl-1-tosyl-3-(3,3,3-trifluoro-1-nitroprop-1en-2-yl)-1H-indole (2j). With petroleum ether/EtOAc (50/1) as eluent; yellow solid (1.258 g, 67%); mp: 147.8−150.1 °C. 1H NMR (400 MHz, CDCl3): δ 8.09−8.06 (m, 1H), 8.02−7.99 (m, 2H), 7.87 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 1.2 Hz, 1H), 7.29 (d, J = 8.1 Hz, 2H), 3.91 (s, 3H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 166.5, 146.2, 141.7 (d, J = 6.3 Hz), 136.9, 134.2, 130.3, 128.5 (q, J = 33.1 Hz), 128.4, 128.1, 127.01, 126.95, 126.5, 121.9, 121.7 (q, J = 274.3 Hz), 113.7, 108.8, 52.3, 21.6; 19F NMR (376 MHz, CDCl3): δ −66.8; HRMS (positive ESI): [M + Na]+ calcd for C20H15F3N2NaO6S: 491.0501, Found: 491.0500. (E)-6-Bromo-1-tosyl-3-(3,3,3-trifluoro-1-nitroprop-1-en-2-yl)-1Hindole (2k). With petroleum ether/EtOAc (50/1) as eluent; yellow solid (1.804 g, 92%); mp: 112.0−113.0 °C. 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 1.4 Hz, 1H), 7.79−7.77 (m, 3H), 7.67 (d, J = 1.3 Hz, 1H), 7.39 (dd, J = 1.7, 8.5 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.5 Hz, 1H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 146.2, 141.2 (d, J = 6.2 Hz), 135.1, 134.2, 130.4, 128.5 (q, J = 33.2 Hz), 127.7, 127.0, 126.9, 121.7 (q, J = 274.3 Hz), 120.8, 119.6, 117.0, 108.2, 21.7; 19F NMR (376 MHz, CDCl3): δ −66.7; HRMS (positive ESI): [M + Na]+ calcd for C18H12BrF3N2NaO4S: 510.9551, Found: 510.9553. (E)-7-Methyl-1-tosyl-3-(3,3,3-trifluoro-1-nitroprop-1-en-2-yl)-1Hindole (2l). With petroleum ether/EtOAc (50/1) as eluent; yellow solid (1.344 g, 79%); mp: 123.5−124.5 °C. 1H NMR (400 MHz, CDCl3): δ 8.02 (s, 1H), 7.72 (d, J = 1.3 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 7.18−7.14 (m, 1H), 7.09−7.07 (m, 2H), 2.55 (s, 3H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 145.4, 141.3 (d, J = 6.2 Hz), 136.2, 134.7, 130.5, 130.2, 130.0, 129.4, 129.3 (q, J = 33.0 Hz), 126.5, 125.5, 124.6, 121.8 (q, J = 274.3 Hz), 117.2, 108.2, 21.6; 19F NMR (376 MHz, CDCl3): δ −67.0; HRMS (positive ESI): [M + Na]+ calcd for C19H15F3N2NaO4S: 447.0602, Found: 447.0601. (E)-7-Methoxy-1-tosyl-3-(3,3,3-trifluoro-1-nitroprop-1-en-2-yl)1H-indole (2m). With petroleum ether/EtOAc (50/1) as eluent; yellow solid (1.245 g, 71%); mp: 109.7−110.6 °C. 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 1.2 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.18−7.14 (m, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 7.9 Hz, 1H), 3.71 (s, 3H), 2.41 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 147.6, 145.0, 140.8 (d, J = 6.2 Hz), 136.3, 130.6, 129.6, 129.4, 129.3 (q, J = 32.9 Hz), 127.5, 125.1, 124.6, 121.9 (q, J = 274.3 Hz), 111.8, 107.7, 106.6, 55.5, 21.6; 19F NMR (376 MHz, CDCl3): δ −66.7; HRMS (positive ESI): [M + Na]+ calcd for C19H15F3N2NaO5S: 463.0551, Found: 463.0550. General Procedure for the Catalytic Michael Addition Reactions. To a Schlenk tube were added Co(acac)2 (5.1 mg, 0.020 mmol) and ligand L1 (10.2 mg, 0.024 mmol) under an argon atmosphere. MTBE (1.5 mL) was then added through a syringe. The resulting mixture was stirred at room temperature for 1 h, after which 2-acetyl azaarene (0.2 mmol) and nitroalkene (0.2 mmol) were added successively. The mixture was stirred at 20 °C until the reaction was completed (monitored by TLC). The reaction mixture was purified by chromatography on silica gel plates to afford the product. The corresponding racemic products were prepared by the reaction of an equivalent amount of 2-acetyl azaarene (0.2 mmol) and nitroalkene (0.2 mmol) in the presence of 20 mol % of Co(acac)2 in MTBE (1.5 mL) at 40 °C for 24−120 h. Procedure of the Gram-Scale Experiment. To a Schlenk tube were added Co(acac)2 (101.7 mg, 0.40 mmol) and ligand L1 (203.3 mg, 0.48 mmol) under an argon atmosphere. MTBE (35 mL) was then added through a syringe. The resulting mixture was stirred at room temperature for 1 h, after which 2-acetyl pyrazine 1c (610.5 mg, 5 mmol) and the nitroalkene 2e (2446.5 mg, 5 mmol) were added successively. The mixture was stirred at 20 °C until the reaction was completed (monitored by TLC). The solvent was evaporated under

the enolate is favored, which leads to the formation of (S)isomers.

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CONCLUSION In summary, we have developed a Co(II)-catalyzed highly enantioselective Michael addition of 2-acetyl azaarenes to βCF3-β-(3-indolyl)nitroalkenes. A series of 3-substituted indole derivatives featuring a trifluoromethylated all-carbon quaternary stereocenter can be prepared in high yields with excellent enantioselectivities. The important features of the method are mild reaction conditions including no requirement of excess substrate, cost-effective catalyst, broad substrate scope, high yield, and excellent enantioselectivity. Moreover, the method provides convenient approaches to optically active secondary alcohol, pyrroline, ester, and pyrrolidinone which all contain a 3-substituted indole and a trifluoromethylated all-carbon quaternary stereocenter.

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EXPERIMENTAL SECTION

General Procedures. Solvents were dried with standard methods and freshly distilled prior to use if needed. The imidazoline-oxazoline ligands L1−L3,18 the bis(imidazoline) L423 and the bis(oxazoline) ligand L5,241-(quinolin-2-yl)ethanone 1d,25 and β-CF3-β-(3-indolyl)nitroalkenes 214 were prepared according to the literature methods. All other chemicals were used as purchased. 1H, 13C{1H}, and 19F NMR spectra were recorded on a Bruker DPX-400 spectrometer with CDCl3 as the solvent and TMS as an internal standard. HRMS was determined on a Waters Q-Tof Micro MS/MS System ESI spectrometer. The enantiomeric excesses of (R)- and (S)-enantiomers were determined by HPLC analysis over a chiral column with a UV detector. The absolute configuration of the major enantiomer was assigned by X-ray diffraction analysis. Melting points were measured on a WC-1 instrument and uncorrected. Optical rotations were recorded on a PerkinElmer 341 polarimeter. Synthesis of the β-CF3-β-(3-indolyl)nitroalkenes. The nitroalkenes 2 were synthesized according to the procedure reported by Kang, He, and Liu.14 The analytical data of the new nitroalkenes are given as follows. (E)-4-Fluoro-1-tosyl-3-(3,3,3-trifluoro-1-nitroprop-1-en-2-yl)-1Hindole (2b). With petroleum ether/EtOAc (50/1) as eluent; yellow solid (1.601 g, 94%); mp: 100.8−101.6 °C. 1H NMR (400 MHz, CDCl3): δ 7.79−7.76 (m, 4H), 7.66 (d, J = 1.2 Hz, 1H), 7.34−7.29 (m, 3H), 6.96−6.91 (m, 1H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.8 (d, J = 248.0 Hz), 146.2, 141.3 (d, J = 5.7 Hz), 136.3 (d, J = 8.1 Hz), 134.2, 130.3, 129.4 (q, J = 32.7 Hz), 127.1, 127.0, 126.7 (d, J = 8.0 Hz), 121.8 (q, J = 274.1 Hz), 117.2 (d, J = 18.4 Hz), 110.02 (d, J = 4.0 Hz), 110.01 (d, J = 18.9 Hz), 105.9, 21.6; 19 F NMR (376 MHz, CDCl3): δ −67.2, −122.5; HRMS (positive ESI): [M + Na]+ calcd for C18H12F4N2NaO4S: 451.0352, Found: 451.0349. (E)-6-Methyl-1-tosyl-3-(3,3,3-trifluoro-1-nitroprop-1-en-2-yl)-1Hindole (2g). With petroleum ether/EtOAc (50/1) as eluent; yellow solid (1.376 g, 81%); mp: 95.9−97.3 °C. 1H NMR (400 MHz, CDCl3): δ 7.78−7.75 (m, 4H), 7.65 (d, J = 1.2 Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 0.9 Hz, 2H), 2.47 (s, 3H), 2.37 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 145.7, 140.7 (d, J = 6.2 Hz), 136.2, 134.9, 134.6, 130.2, 129.1 (q, J = 33.1 Hz), 126.9, 126.8, 125.9, 125.7, 121.9 (q, J = 274.5 Hz), 119.2, 114.0, 108.4, 21.9, 21.6; 19F NMR (376 MHz, CDCl3): δ −66.7; HRMS (positive ESI): [M + Na]+ calcd for C19H15F3N2NaO4S: 447.0602, Found: 447.0602. (E)-5-Fluoro-1-tosyl-3-(3,3,3-trifluoro-1-nitroprop-1-en-2-yl)-1Hindole (2h). With petroleum ether/EtOAc (50/1) as eluent; yellow solid (1.320 g, 77%); mp: 108.1−109.0 °C. 1H NMR (400 MHz, CDCl3): δ 7.92 (dd, J = 4.3, 9.2 Hz, 1H), 7.85 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 1.2 Hz, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.13− 7.08 (m, 1H), 6.91 (dd, J = 2.4, 8.5 Hz, 1H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 160.0 (d, J = 241.4 Hz), 146.1, 141.2 (d, J = 6.2 Hz), 134.2, 130.8, 130.3, 129.2 (d, J = 10.1 Hz), 129.0, 128.6 195

DOI: 10.1021/acs.joc.8b02601 J. Org. Chem. 2019, 84, 191−203

Article

The Journal of Organic Chemistry

CDCl3): δ 196.6, 152.4, 149.2, 145.8, 137.2, 134.2, 134.0, 130.2, 129.5, 128.2, 128.0, 127.7, 126.8, 125.8 (d, J = 283.1 Hz), 124.2 (d, J = 2.6 Hz), 121.9, 117.5, 115.2, 114.7, 74.0, 48.2 (q, J = 27.1 Hz), 34.9, 21.6; 19F NMR (376 MHz, CDCl3): δ −72.4; HRMS (positive ESI): [M + Na]+ calcd for C25H19BrF3N3NaO5S: 632.0079, Found: 632.0078. (S)-4,4,4-Trifluoro-3-(5-methyl-1-tosyl-1H-indol-3-yl)-3-(nitromethyl)-1-(pyridin-2-yl)butan-1-one (3af). With petroleum ether/ EtOAc (5/1) as eluent; white solid (104.1 mg, 95%); mp: 81.1−82.4 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (80/20) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 11.3 min (minor), 16.7 min (major), 93% ee. [α]20 D = −32 (c 0.112, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.75−8.74 (m, 1H), 7.94−7.91 (m, 1H), 7.83−7.79 (m, 2H), 7.65−7.63 (m, 3H), 7.53− 7.49 (m, 1H), 7.46 (s, 1H), 7.20 (d, J = 8.1 Hz, 2H), 7.09 (dd, J = 0.7, 8.5 Hz, 1H), 5.79 (d, J = 12.5 Hz, 1H), 5.67 (d, J = 12.5 Hz, 1H), 4.75 (d, J = 19.0 Hz, 1H), 4.35 (d, J = 19.0 Hz, 1H), 2.32 (s, 3H), 2.31 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 196.7, 152.6, 149.1, 145.4, 137.1, 134.6, 133.6, 133.4, 130.0, 128.1, 127.9, 126.8, 126.7, 126.6, 126.0 (q, J = 283.3 Hz), 121.9, 121.4 (d, J = 1.9 Hz), 115.1, 113.6, 74.1, 48.3 (q, J = 27.1 Hz), 35.0, 21.6, 21.5; 19F NMR (376 MHz, CDCl3): δ −72.3; HRMS (positive ESI): [M + Na]+ calcd for C26H22F3N3NaO5S: 568.1130, Found: 568.1132. (S)-4,4,4-Trifluoro-3-(6-methyl-1-tosyl-1H-indol-3-yl)-3-(nitromethyl)-1-(pyridin-2-yl)butan-1-one (3ag). With petroleum ether/ EtOAc (5/1) as eluent; white solid (105.1 mg, 96%); mp: 68.5−70.4 °C. The enantiomeric excess was determined on a Daicel Chiralpak IC column with n-hexane/2-propanol (80/20) and flow rate 1.0 mL/ min and detected at a UV wavelength of 254 nm. Retention times: 13.1 min (major), 16.3 min (minor), 91% ee. [α]20 D = −34 (c 0.097, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.73 (d, J = 4.5 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.81 (dt, J = 1.6, 7.7 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.62 (s,1H), 7.55 (d, J = 8.4 Hz, 1H), 7.52− 7.49 (m, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.01 (d, J = 8.4 Hz, 1H), 5.78 (d, J = 12.5 Hz, 1H), 5.67 (d, J = 12.5 Hz, 1H), 4.69 (d, J = 19.0 Hz, 1H), 4.39 (d, J = 19.0 Hz, 1H), 2.39 (s, 3H), 2.32 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 196.7, 152.6, 149.1, 145.4, 137.1, 135.8, 135.5, 134.7, 130.0, 127.9, 126.8, 126.0 (q, J = 283.3 Hz), 125.9, 125.6, 125.4, 121.9, 121.0 (d, J = 2.0 Hz), 115.3, 114.0, 74.0, 48.3 (q, J = 27.0 Hz), 35.1, 21.65, 21.57; 19F NMR (376 MHz, CDCl3): δ −72.4; HRMS (positive ESI): [M + Na]+ calcd for C26H22F3N3NaO5S: 568.1130, Found: 568.1131. (S)-4,4,4-Trifluoro-3-(nitromethyl)-1-(thiazol-2-yl)-3-(1-tosyl-1Hindol-3-yl)butan-1-one (3ba). With petroleum ether/EtOAc (5/1) as eluent; white solid (91.3 mg, 85%); mp: 123.7−124.7 °C. The enantiomeric excess was determined on a Daicel Chiralpak AS-H column with n-hexane/2-propanol (75/25) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 22.9 min (minor), 38.1 min (major), 94% ee. [α]20 D = −25 (c 0.110, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 3.0 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 3.0 Hz, 1H), 7.69−7.67 (m, 4H), 7.33−7.29 (m, 1H), 7.26−7.20 (m, 3H), 5.70 (s, 2H), 4.53 (d, J = 18.6 Hz, 1H), 4.43 (d, J = 18.7 Hz, 1H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 188.6, 165.9, 145.6, 145.1, 135.4, 134.5, 130.1, 127.6, 127.3, 126.9, 126.5, 125.7 (q, J = 283.4 Hz), 125.2, 123.9, 121.4 (d, J = 2.6 Hz), 114.9, 114.0, 73.8, 48.2 (q, J = 27.4 Hz), 36.2, 21.6; 19F NMR (376 MHz, CDCl3): δ −72.2; HRMS (positive ESI): [M + Na]+ calcd for C23H18F3N3NaO5S2: 560.0538, Found: 560.0537. (S)-3-(5-Chloro-1-tosyl-1H-indol-3-yl)-4,4,4-trifluoro-3-(nitromethyl)-1-(thiazol-2-yl)butan-1-one (3bd). With petroleum ether/ EtOAc (5/1) as eluent; white solid (108.1 mg, 94%); mp: 142.8− 145.0 °C. The enantiomeric excess was determined on a Daicel Chiralpak IC column with n-hexane/2-propanol (85/15) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 16.6 min (major), 22.2 min (minor), 95% ee. [α]20 D = −8 (c 0.100, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 3.0 Hz, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.75 (d, J = 3.0 Hz, 1H), 7.71 (s, 1H), 7.67−7.65 (m, 3H), 7.28−7.24 (m, 3H), 5.67 (d, J = 12.8

vacuum, and the residue was purified by column chromatography on silica gel (petroleum ether/EtOAc, 15/1, v/v) to afford the product 3ce (2.45 g, 80% yield, 95% ee). (S)-4,4,4-Trifluoro-3-(nitromethyl)-1-(pyridin-2-yl)-3-(1-tosyl-1Hindol-3-yl)butan-1-one (3aa). With petroleum ether/EtOAc (3/1) as eluent; white solid (101.8 mg, 96%); mp: 70.1−71.8 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (83/17) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 16.8 min (minor), 26.1 min (major), 89% ee. [α]20 D = −28 (c 0.107, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.77−8.75 (m, 1H), 7.96− 7.93 (m, 2H), 7.87−7.83 (m, 1H), 7.70−7.66 (m, 4H), 7.56−7.53 (m, 1H), 7.31−7.18 (m, 4H), 5.77 (d, J = 12.6 Hz, 1H), 5.69 (d, J = 12.5 Hz, 1H), 4.68 (d, J = 19.0 Hz, 1H), 4.41 (d, J = 19.0 Hz, 1H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 196.7, 152.6, 149.2, 145.5, 137.1, 135.3, 134.5, 130.1, 127.9, 127.8, 126.9, 126.6, 126.0 (q, J = 283.1 Hz), 125.1, 123.8, 121.9, 121.5 (d, J = 2.3 Hz), 115.3, 113.9, 73.9, 48.3 (q, J = 27.1 Hz), 35.2, 21.6; 19F NMR (376 MHz, CDCl3): δ −72.4; HRMS (positive ESI): [M + Na]+ calcd for C25H20F3N3NaO5S: 554.0973, Found: 554.0975. (S)-4,4,4-Trifluoro-3-(4-fluoro-1-tosyl-1H-indol-3-yl)-3-(nitromethyl)-1-(pyridin-2-yl)butan-1-one (3ab). With petroleum ether/ EtOAc (5/1) as eluent; white solid (72.7 mg, 66%); mp: 69.3−71.2 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (80/20) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 12.4 min (minor), 22.0 min (major), 91% ee. [α]20 D = −17 (c 0.103, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.74−8.73 (m, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.87−7.83 (m, 1H), 7.80−7.77 (m, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.54−7.51 (m, 1H), 7.29−7.23 (m, 3H), 6.96 (dd, J = 8.0, 12.7 Hz, 1H), 5.79 (dd, J = 3.2, 12.9 Hz, 1H), 5.65 (dd, J = 2.0, 12.9 Hz, 1H), 4.48 (s, 2H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 195.7, 153.7 (d, J = 246.1 Hz), 151.7, 148.1, 144.8, 136.4 (d, J = 8.9 Hz), 136.1, 133.1, 129.1, 126.8, 126.4, 125.9, 125.1 (d, J = 9.1 Hz), 124.6 (q, J = 283.4 Hz), 120.9, 115.8 (d, J = 18.3 Hz), 112.8, 109.3 (d, J = 24.2 Hz), 109.1 (d, J = 3.7 Hz), 73.8 (d, J = 14.7 Hz), 47.2 (q, J = 26.9 Hz), 35.4 (d, J = 6.0 Hz), 20.6; 19F NMR (376 MHz, CDCl3): δ −71.8 (d, J = 14.7 Hz), −109.2 (q, J = 14.7 Hz); HRMS (positive ESI): [M + Na]+ calcd for C25H19F4N3NaO5S: 572.0879, Found: 572.0882. (S)-3-(5-Chloro-1-tosyl-1H-indol-3-yl)-4,4,4-trifluoro-3-(nitromethyl)-1-(pyridin-2-yl)butan-1-one (3ad). With petroleum ether/ EtOAc (3/1) as eluent; white solid (110.3 mg, 97%); mp: 67.1−68.6 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (80/20) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 15.7 min (minor), 24.3 min (major), 91% ee. [α]20 D = −26 (c 0.106, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.77 (d, J = 4.7 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.87−7.82 (m, 2H), 7.71 (s, 1H), 7.68−7.64 (m, 3H), 7.56−7.52 (m, 1H), 7.26−7.23 (m, 3H), 5.74 (d, J = 12.4 Hz, 1H), 5.62 (d, J = 12.4 Hz, 1H), 4.68 (d, J = 19.0 Hz, 1H), 4.36 (d, J = 19.0 Hz, 1H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 196.6, 152.4, 149.2, 145.8, 137.2, 134.2, 133.7, 130.2, 129.8, 129.0, 128.0, 127.8, 126.8, 125.8 (q, J = 283.1 Hz), 125.5, 121.9, 121.2 (d, J = 2.4 Hz), 114.9, 73.9, 48.2 (q, J = 27.1 Hz), 35.0, 21.6; 19F NMR (376 MHz, CDCl3): δ −72.4; HRMS (positive ESI): [M + Na]+ calcd for C25H19ClF3N3NaO5S: 588.0584, Found: 588.0585. (S)-3-(5-Bromo-1-tosyl-1H-indol-3-yl)-4,4,4-trifluoro-3-(nitromethyl)-1-(pyridin-2-yl)butan-1-one (3ae). With petroleum ether/ EtOAc (4/1) as eluent; white solid (121.6 mg, 99%); mp: 76.8−78.0 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (85/15) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 16.0 min (minor), 24.1 min (major), 90% ee. [α]20 D = −19 (c 0.108, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.78 (d, J = 4.6 Hz, 1H), 7.94−7.92 (m, 1H), 7.87−7.79 (m, 3H), 7.69−7.64 (m, 3H), 7.56−7.53 (m, 1H), 7.39−7.36 (m, 1H), 7.26−7.24 (m, 2H), 5.74 (d, J = 12.4 Hz, 1H), 5.61 (d, J = 12.4 Hz, 1H), 4.70 (d, J = 18.9 Hz, 1H), 4.34 (d, J = 19.0 Hz, 1H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, 196

DOI: 10.1021/acs.joc.8b02601 J. Org. Chem. 2019, 84, 191−203

Article

The Journal of Organic Chemistry Hz, 1H), 5.63 (d, J = 12.8 Hz, 1H), 4.49 (d, J = 18.6 Hz, 1H), 4.40 (d, J = 18.6 Hz, 1H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 188.4, 165.7, 145.9, 145.1, 134.1, 133.7, 130.2, 129.9, 128.7, 127.8, 127.5, 126.9, 125.7, 125.6 (q, J = 283.2 Hz), 121.1 (d, J = 2.7 Hz), 115.0, 114.4, 73.7, 48.1 (q, J = 27.2 Hz), 36.1, 21.7; 19F NMR (376 MHz, CDCl3): δ −72.2; HRMS (positive ESI): [M + Na]+ calcd for C23H17ClF3N3NaO5S2: 594.0148, Found: 594.0147. (S)-3-(5-Bromo-1-tosyl-1H-indol-3-yl)-4,4,4-trifluoro-3-(nitromethyl)-1-(thiazol-2-yl)butan-1-one (3be). With petroleum ether/ EtOAc (5/1) as eluent; white solid (117.0 mg, 95%); mp: 74.2−76.5 °C. The enantiomeric excess was determined on a Daicel Chiralpak IC column with n-hexane/2-propanol (85/15) and flow rate 1.0 mL/ min and detected at a UV wavelength of 254 nm. Retention times: 16.6 min (major), 22.5 min (minor), 95% ee. [α]20 D = −1 (c 0.121, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 3.0 Hz, 1H), 7.82 (d, J = 9.0 Hz, 2H), 7.76 (d, J = 3.0 Hz, 1H), 7.67 (s, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.40 (dd, J = 1.7, 8.8 Hz, 1H), 7.27−7.25 (m, 2H), 5.67 (d, J = 12.7 Hz, 1H), 5.62 (d, J = 12.7 Hz, 1H), 4.49 (d, J = 18.6 Hz, 1H), 4.39 (d, J = 18.6 Hz, 1H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 188.4, 166.7, 145.9, 145.1, 134.1, 134.0, 130.2, 129.2, 128.3, 127.7, 127.5, 126.9, 125.6 (q, J = 287.0 Hz), 124.1 (d, J = 2.9 Hz), 117.6, 115.3, 114.3, 73.8, 48.1 (q, J = 27.5 Hz), 36.1, 21.7; 19 F NMR (376 MHz, CDCl3): δ −72.2; HRMS (positive ESI): [M + Na]+ calcd for C23H17BrF3N3NaO5S2: 637.9643, Found: 637.9645. (S)-4,4,4-Trifluoro-3-(5-methyl-1-tosyl-1H-indol-3-yl)-3-(nitromethyl)-1-(thiazol-2-yl)butan-1-one (3bf). With petroleum ether/ EtOAc (5/1) as eluent; white solid (95.1 mg, 86%); mp: 68.3−69.4 °C. The enantiomeric excess was determined on a Daicel Chiralpak IC column with n-hexane/2-propanol (75/25) and flow rate 1.0 mL/ min and detected at a UV wavelength of 254 nm. Retention times: 11.3 min (major), 14.4 min (minor), 95% ee. [α]20 D = −3 (c 0.101, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 3.0 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 2.9 Hz, 1H), 7.66−7.64 (m, 3H), 7.44 (s, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.5 Hz, 1H), 5.72 (d, J = 12.8 Hz, 1H), 5.67 (d, J = 12.8 Hz, 1H), 4.56 (d, J = 18.6 Hz, 1H), 4.39 (d, J = 18.6 Hz, 1H), 2.34 (s, 3H), 2.32 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 188.6, 166.0, 145.5, 145.0, 134.5, 133.6, 130.1, 127.9, 127.3, 126.8, 126.7, 126.6, 125.8 (q, J = 283.3 Hz), 121.30, 121.28, 114.7, 113.6, 73.9, 48.2 (q, J = 27.2 Hz), 36.1, 21.6, 21.5; 19F NMR (376 MHz, CDCl3): δ −72.2; HRMS (positive ESI): [M + Na]+ calcd for C24H20F3N3NaO5S2: 574.0694, Found: 574.0695. (S)-4,4,4-Trifluoro-3-(6-methyl-1-tosyl-1H-indol-3-yl)-3-(nitromethyl)-1-(thiazol-2-yl)butan-1-one (3bg). With petroleum ether/ EtOAc (4/1) as eluent; white solid (89.5 mg, 81%); mp: 72.6−73.7 °C. The enantiomeric excess was determined on a Daicel Chiralpak IC column with n-hexane/2-propanol (85/15) and flow rate 1.0 mL/ min and detected at a UV wavelength of 254 nm. Retention times: 14.6 min (major), 18.0 min (minor), 93% ee. [α]20 D = −19 (c 0.112, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 3.0 Hz, 1H), 7.75 (s, 1H), 7.72 (d, J = 3.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.61 (s, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.2 Hz, 2H), 7.04 (d, J = 8.4 Hz, 1H), 5.71 (d, J = 12.8 Hz, 1H), 5.67 (d, J = 12.8 Hz, 1H), 4.53 (d, J = 18.6 Hz, 1H), 4.40 (d, J = 18.7 Hz, 1H), 2.41 (s, 3H), 2.33 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 188.6, 165.9, 145.5, 145.0, 135.8, 135.6, 134.6, 130.1, 127.3, 126.8, 125.85, 125.77 (q, J = 283.4 Hz), 125.4 (d, J = 12.0 Hz), 121.5, 120.9 (d, J = 2.2 Hz), 114.9, 114.0, 73.8, 48.2 (q, J = 27.2 Hz), 36.2, 21.7, 21.6; 19F NMR (376 MHz, CDCl3): δ −72.3; HRMS (positive ESI): [M + Na]+ calcd for C24H20F3N3NaO5S2: 574.0694, Found: 574.0695. (S)-4,4,4-Trifluoro-3-(5-fluoro-1-tosyl-1H-indol-3-yl)-3-(nitromethyl)-1-(thiazol-2-yl)butan-1-one (3bh). With petroleum ether/ EtOAc (5/1) as eluent; white solid (96.1 mg, 86%); mp: 167.7−169.0 °C. The enantiomeric excess was determined on a Daicel Chiralpak IC column with n-hexane/2-propanol (85/15) and flow rate 1.0 mL/ min and detected at a UV wavelength of 254 nm. Retention times: 12.5 min (major), 15.4 min (minor), 94% ee. [α]20 D = −4 (c 0.106, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 3.0 Hz, 1H), 7.90 (dd, J = 4.6, 9.2 Hz, 1H), 7.75 (d, J = 3.0 Hz, 1H), 7.72 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 9.4 Hz, 1H), 7.26 (d, J = 8.2 Hz,

2H), 7.05 (dt, J = 2.3, 8.9 Hz, 1H), 5.65 (s, 2H), 4.47 (d, J = 18.6 Hz, 1H), 4.41 (d, J = 18.6 Hz, 1H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 188.4, 165.7, 159.5 (d, J = 239.8 Hz), 145.8, 145.1, 134.2, 131.7, 130.2, 128.5 (d, J = 9.6 Hz), 128.2, 127.4, 126.8, 125.7 (q, J = 283.4 Hz), 115.1 (d, J = 9.5 Hz), 114.9 (d, J = 3.7 Hz), 113.5 (d, J = 25.4 Hz), 107.4 (d, J = 23.1 Hz), 73.6, 48.1 (q, J = 27.4 Hz), 36.0, 21.6; 19F NMR (376 MHz, CDCl3): δ −72.2, −117.8; HRMS (positive ESI): [M + Na]+ calcd for C23H17F4N3NaO5S2 578.0443, Found: 578.0445. (S)-4,4,4-Trifluoro-3-(5-methoxy-1-tosyl-1H-indol-3-yl)-3-(nitromethyl)-1-(thiazol-2-yl)butan-1-one (3bi). With petroleum ether/ EtOAc (5/1) as eluent; white solid (95.2 mg, 84%); mp: 69.7−71.0 °C. The enantiomeric excess was determined on a Daicel Chiralpak IC column with n-hexane/2-propanol (75/25) and flow rate 1.0 mL/ min and detected at a UV wavelength of 254 nm. Retention times: 15.7 min (major), 20.4 min (minor), 94% ee. [α]20 D = −12 (c 0.102, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 2.9 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.74 (d, J = 2.9 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.61 (s, 1H), 7.23 (d, J = 8.1 Hz, 2H), 7.07 (s, 1H), 6.92−6.89 (m, 1H), 5.70 (d, J = 12.6 Hz, 1H), 5.62 (d, J = 12.6 Hz, 1H), 4.58 (d, J = 18.7 Hz, 1H), 4.35 (d, J = 18.7 Hz, 1H), 3.74 (s, 3H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 188.4, 165.9, 156.5, 145.5, 145.0, 134.4, 130.1, 128.6, 127.4, 127.2, 126.8, 125.8 (d, J = 281.6 Hz), 114.8, 114.1, 104.3 (d, J = 2.6 Hz), 73.9, 55.7, 48.1 (q, J = 27.2 Hz), 35.9, 21.6; 19F NMR (376 MHz, CDCl3): δ −72.3; HRMS (positive ESI): [M + Na]+ calcd for C24H20F3N3NaO6S2: 590.0643, Found: 590.0645. (S)-4,4,4-Trifluoro-3-(5-methoxycarbonyl-1-tosyl-1H-indol-3-yl)3-(nitromethyl)-1-(thiazol-2-yl)butan-1-one (3bj). With petroleum ether/EtOAc (3/1) as eluent; white solid (96.7 mg, 81%); mp: 72.1− 73.7 °C. The enantiomeric excess was determined on a Daicel Chiralpak IC column with n-hexane/2-propanol (70/30) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 12.7 min (major), 18.8 min (minor), 95% ee. [α]20 D = −2 (c 0.105, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 8.07 (d, J = 3.0 Hz, 1H), 8.03−7.98 (m, 2H), 7.80 (s, 1H), 7.74 (d, J = 3.0 Hz, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 5.72 (s, 2H), 4.55 (d, J = 18.6 Hz, 1H), 4.46 (d, J = 18.6 Hz, 1H), 3.99 (s, 3H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 188.5, 166.6, 165.8, 146.0, 145.1, 137.8, 134.1, 130.2, 127.9, 127.4 (d, J = 1.9 Hz), 126.9, 126.4, 126.0, 125.6 (q, J = 283.5 Hz), 123.5 (d, J = 2.2 Hz), 121.4, 115.5, 113.7, 73.9, 52.3, 48.2 (q, J = 27.3 Hz), 36.3, 21.6; 19 F NMR (376 MHz, CDCl3): δ −72.1; HRMS (positive ESI): [M + Na]+ calcd for C25H20F3N3NaO7S2: 618.0592, Found: 618.0592. (S)-3-(6-Bromo-1-tosyl-1H-indol-3-yl)-4,4,4-trifluoro-3-(nitromethyl)-1-(thiazol-2-yl)butan-1-one (3bk). With petroleum ether/ EtOAc (5/1) as eluent; white solid (105.6 mg, 86%); mp: 72.4−73.6 °C. The enantiomeric excess was determined on a Daicel Chiralpak IC column with n-hexane/2-propanol (80/20) and flow rate 1.0 mL/ min and detected at a UV wavelength of 254 nm. Retention times: 9.9 min (major), 12.7 min (minor), 93% ee. [α]20 D = −12 (c 0.111, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.13 (d, J = 1.7 Hz, 1H), 8.08 (d, J = 3.0 Hz, 1H), 7.76 (d, J = 3.0 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.64 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.34 (dd, J = 1.7, 8.7 Hz, 1H), 7.29 (d, J = 8.3 Hz, 2H), 5.67 (d, J = 13.4 Hz, 1H), 5.64 (d, J = 13.2 Hz, 1H), 4.49 (d, J = 18.6 Hz, 1H), 4.40 (d, J = 18.6 Hz, 1H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 188.4, 165.8, 145.9, 145.1, 136.0, 134.2, 130.3, 127.5, 127.3, 126.9, 126.5, 125.6 (q, J = 283.7 Hz), 122.5 (d, J = 2.7 Hz), 119.2, 117.0, 114.8, 73.7, 48.1 (q, J = 27.3 Hz), 36.1, 21.7; 19F NMR (376 MHz, CDCl3): δ −72.3; HRMS (positive ESI): [M + Na]+ calcd for C23H17BrF3N3NaO5S2: 637.9643, Found: 637.9645. (S)-4,4,4-Trifluoro-3-(7-methyl-1-tosyl-1H-indol-3-yl)-3-(nitromethyl)-1-(thiazol-2-yl)butan-1-one (3bl). With petroleum ether/ EtOAc (5/1) as eluent; white solid (84.4 mg, 77%); mp: 70.6−72.0 °C. The enantiomeric excess was determined on a Daicel Chiralpak IA column with n-hexane/2-propanol (85/15) and flow rate 1.0 mL/ min and detected at a UV wavelength of 254 nm. Retention times: 13.0 min (major), 15.9 min (minor), 92% ee. [α]20 D = −47 (c 0.102, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 3.0 Hz, 1H), 197

DOI: 10.1021/acs.joc.8b02601 J. Org. Chem. 2019, 84, 191−203

Article

The Journal of Organic Chemistry

0.109, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 9.12 (d, J = 1.2 Hz, 1H), 8.83 (d, J = 2.4 Hz, 1H), 8.74 (d, J = 1.6 Hz, 1H), 7.82−7.80 (m, 2H), 7.68−7.65 (m, 3H), 7.40−7.38 (m, 1H), 7.28−7.26 (m, 2H), 5.70 (d, J = 12.4 Hz, 1H), 5.60 (d, J = 12.4 Hz, 1H), 4.57 (d, J = 19.1 Hz, 1H), 4.35 (d, J = 19.0 Hz, 1H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 195.9, 148.7, 146.6, 146.0, 143.7, 143.6, 134.1, 134.0, 130.2, 129.3, 128.3, 127.5, 126.9, 125.7 (q, J = 283.3 Hz), 124.1 (d, J = 2.6 Hz), 117.6, 115.3, 114.3, 73.9, 48.0 (q, J = 27.5 Hz), 35.1, 21.7; 19F NMR (376 MHz, CDCl3): δ −72.4; HRMS (positive ESI): [M + Na]+ calcd for C24H18BrF3N4NaO5S: 633.0031, Found: 633.0033. (S)-4,4,4-Trifluoro-3-(5-methyl-1-tosyl-1H-indol-3-yl)-3-(nitromethyl)-1-(pyrazin-2-yl)butan-1-one (3cf). With petroleum ether/ EtOAc (3/1) as eluent; white solid (92.0 mg, 84%); mp: 68.6−69.8 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (75/25) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 9.7 min (minor), 13.0 min (major), 95% ee. [α]20 D = −31 (c 0.100, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 9.13 (s, 1H), 8.81 (s, 1H), 8.71 (s, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.62 (s, 1H), 7.42 (s, 1H), 7.23 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.3 Hz, 1H), 5.73 (d, J = 12.6 Hz, 1H), 5.66 (d, J = 12.5 Hz, 1H), 4.60 (d, J = 19.1 Hz, 1H), 4.38 (d, J = 19.1 Hz, 1H), 2.34 (s, 6H); 13 C{1H} NMR (100 MHz, CDCl3): δ 195.0, 147.5, 145.8, 144.4, 142.6 (d, J = 7.7 Hz), 133.5, 132.5 (d, J = 10.2 Hz), 129.0, 127.8, 126.9, 125.8, 125.7, 125.5, 124.8 (q, J = 283.5 Hz), 120.6, 120.2 (d, J = 2.3 Hz), 113.7, 112.6, 72.8, 47.1 (q, J = 27.2 Hz), 34.2, 20.54, 20.51; 19 F NMR (376 MHz, CDCl3): δ −72.4; HRMS (positive ESI): [M + Na]+ calcd for C25H21F3N4NaO5S: 569.1082, Found: 569.1084. (S)-4,4,4-Trifluoro-3-(6-methyl-1-tosyl-1H-indol-3-yl)-3-(nitromethyl)-1-(pyrazin-2-yl)butan-1-one (3cg). With petroleum ether/ EtOAc (3/1) as eluent; white solid (90.8 mg, 83%); mp: 72.0−74.0 °C. The enantiomeric excess was determined on a Daicel Chiralpak IC column with n-hexane/2-propanol (80/20) and flow rate 1.0 mL/ min and detected at a UV wavelength of 254 nm. Retention times: 21.8 min (minor), 24.8 min (major), 94% ee. [α]20 D = −47 (c 0.112, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 9.12 (d, J = 1.4 Hz, 1H), 8.80 (d, J = 2.4 Hz, 1H), 8.69 (dd, J = 1.5, 2.4 Hz, 1H), 7.75 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.60 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.02 (dd, J = 0.9, 7.5 Hz, 1H), 5.73 (d, J = 12.6 Hz, 1H), 5.66 (d, J = 12.5 Hz, 1H), 4.58 (d, J = 19.1 Hz, 1H), 4.39 (d, J = 19.2 Hz, 1H), 2.41 (s, 3H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 196.0, 148.6, 146.8, 145.5, 143.6 (d, J = 1.2 Hz), 135.8, 135.6, 134.6, 130.1, 126.8, 125.9 (q, J = 283.4 Hz), 125.8, 125.44, 125.40, 121.6, 120.9 (d, J = 2.2 Hz), 114.9, 114.0, 73.8, 48.1 (q, J = 27.2 Hz), 35.3, 21.7, 21.6; 19F NMR (376 MHz, CDCl3): δ −72.5; HRMS (positive ESI): [M + Na]+ calcd for C25H21F3N4NaO5S: 569.1082, Found: 569.1082. (S)-4,4,4-Trifluoro-3-(5-fluoro-1-tosyl-1H-indol-3-yl)-3-(nitromethyl)-1-(pyrazin-2-yl)butan-1-one (3ch). With petroleum ether/ EtOAc (3/1) as eluent; white solid (87.9 mg, 80%); mp: 152.3−153.5 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (80/20) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 14.4 min (minor), 20.5 min (major), 94% ee. [α]20 D = −18 (c 0.106, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 9.13 (d, J = 1.4 Hz, 1H), 8.83 (d, J = 2.4 Hz, 1H), 8.72 (dd, J = 1.5, 2.4 Hz, 1H), 7.90 (dd, J = 4.6, 9.2 Hz, 1H), 7.70−7.67 (m, 3H), 7.33 (d, J = 9.6 Hz, 1H), 7.28−7.26 (m, 2H), 7.04 (dt, J = 2.4, 8.9 Hz, 1H), 5.69 (d, J = 12.6 Hz, 1H), 5.62 (d, J = 12.5 Hz, 1H), 4.52 (d, J = 19.1 Hz, 1H), 4.40 (d, J = 19.2 Hz, 1H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 195.9, 159.5 (d, J = 239.5 Hz), 148.7, 146.7, 145.8, 143.65, 143.62, 134.2, 131.7, 130.2, 128.5 (d, J = 9.6 Hz), 128.0, 126.8, 125.8 (q, J = 283.2 Hz), 115.0 (d, J = 9.6 Hz), 114.9 (d, J = 2.6 Hz), 113.5 (d, J = 25.4 Hz), 107.3 (d, J = 25.8 Hz), 73.7, 48.0 (q, J = 27.3 Hz), 35.1, 21.6; 19F NMR (376 MHz, CDCl3): δ −72.4, −117.8; HRMS (positive ESI): [M + Na]+ calcd for C24H18F4N4NaO5S: 573.0832, Found: 573.0834. (S)-4,4,4-Trifluoro-3-(5-methoxycarbonyl-1-tosyl-1H-indol-3-yl)3-(nitromethyl)-1-(pyrazin-2-yl)butan-1-one (3cj). With petroleum

7.88 (s, 1H), 7.71 (d, J = 3.0 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.11−7.08 (m, 1H), 7.01 (d, J = 7.4 Hz, 1H), 5.76 (d, J = 12.7 Hz, 1H), 5.70 (d, J = 12.7 Hz, 1H), 4.61 (d, J = 18.6 Hz, 1H), 4.42 (d, J = 18.7 Hz, 1H), 2.53 (s, 3H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 188.6, 165.9, 145.2, 145.0, 136.2, 135.7, 130.3, 129.7, 128.9, 127.3, 126.4, 125.8 (q, J = 283.7 Hz), 125.6, 124.2, 119.1 (d, J = 2.7 Hz), 114.2, 74.1, 48.2 (q, J = 27.4 Hz), 36.1, 22.0, 21.6; 19F NMR (376 MHz, CDCl3): δ −71.9; HRMS (positive ESI): [M + Na]+ calcd for C24H20F3N3NaO5S2: 574.0694, Found: 574.0696. (S)-4,4,4-Trifluoro-3-(7-methoxy-1-tosyl-1H-indol-3-yl)-3-(nitromethyl)-1-(thiazol-2-yl)butan-1-one (3bm). With petroleum ether/ EtOAc (5/1) as eluent; white solid (86.3 mg, 76%); mp: 69.3−71.2 °C. The enantiomeric excess was determined on a Daicel Chiralpak AS-H column with n-hexane/2-propanol (75/25) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 20.6 min (major), 29.0 min (minor), 94% ee. [α]20 D = −33 (c 0.105, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 3.0 Hz, 1H), 7.91 (s, 1H), 7.71 (d, J = 3.0 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.30−7.27 (m, 3H), 7.12−7.08 (m, 1H), 6.67 (d, J = 8.0 Hz, 1H), 5.77 (d, J = 12.7 Hz, 1H), 5.71 (d, J = 12.7 Hz, 1H), 4.60 (d, J = 18.6 Hz, 1H), 4.44 (d, J = 18.7 Hz, 1H), 3.64 (s, 3H), 2.38 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 188.6, 166.0, 147.5, 145.0, 144.7, 136.7, 130.3, 129.6, 128.6, 127.2, 125.9 (q, J = 282.7 Hz), 125.6, 124.6, 113.6, 112.7, 107.2, 74.0, 55.4 (d, J = 2.3 Hz), 48.2 (q, J = 27.2 Hz), 36.1, 21.6 (d, J = 2.1 Hz); 19F NMR (376 MHz, CDCl3): δ −72.1; HRMS (positive ESI): [M + Na]+ calcd for C24H20F3N3NaO6S2: 590.0643, Found: 590.0643. (S)-4,4,4-Trifluoro-3-(nitromethyl)-1-(pyrazin-2-yl)-3-(1-tosyl-1Hindol-3-yl)butan-1-one (3ca). With petroleum ether/EtOAc (3/1) as eluent; white solid (83.6 mg, 78%); mp: 66.2−67.5 °C. The enantiomeric excess was determined on a Daicel Chiralpak AS-H column with n-hexane/2-propanol (90/10) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 36.0 min (minor), 44.1 min (major), 92% ee. [α]20 D = −45 (c 0.101, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 9.13 (d, J = 1.2 Hz, 1H), 8.82 (d, J = 2.4 Hz, 1H), 8.72−8.71 (m, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.70 (s, 1H), 7.68−7.65 (m, 3H), 7.32−7.28 (m, 1H), 7.26− 7.20 (m, 3H), 5.73 (d, J = 12.6 Hz, 1H), 5.68 (d, J = 12.6 Hz, 1H), 4.57 (d, J = 19.1 Hz, 1H), 4.42 (d, J = 19.1 Hz, 1H), 2.35 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 196.0, 148.6, 146.8, 145.6, 143.6, 135.3, 134.5, 130.1, 127.7, 126.9, 126.4, 125.9 (q, J = 283.3 Hz), 125.2, 123.8, 121.3 (d, J = 2.5 Hz), 114.9, 114.0, 73.8, 48.1 (q, J = 27.2 Hz), 35.4, 21.6; 19F NMR (376 MHz, CDCl3): δ −72.4; HRMS (positive ESI): [M + Na]+ calcd for C24H19F3N4NaO5S: 555.0926, Found: 555.0925. (S)-3-(5-Chloro-1-tosyl-1H-indol-3-yl)-4,4,4-trifluoro-3-(nitromethyl)-1-(pyrazin-2-yl)butan-1-one (3cd). With petroleum ether/ EtOAc (5/1) as eluent; white solid (104.7 mg, 92%); mp: 64.7−65.5 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (85/15) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 16.3 min (minor), 22.2 min (major), 95% ee. [α]20 D = −27 (c 0.112, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 9.12 (d, J = 1.4 Hz, 1H), 8.82 (d, J = 2.4 Hz, 1H), 8.72 (dd, J = 1.5, 2.4 Hz, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.70−7.65 (m, 4H), 7.27−7.24 (m, 3H), 5.70 (d, J = 12.5 Hz, 1H), 5.61 (d, J = 12.5 Hz, 1H), 4.56 (d, J = 19.1 Hz, 1H), 4.38 (d, J = 19.1 Hz, 1H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 195.9, 148.7, 146.7, 146.0, 143.6, 134.2, 133.7, 130.2, 129.9, 128.8, 127.7, 126.8, 125.7 (q, J = 283.3 Hz), 125.6, 121.1 (d, J = 2.7 Hz), 115.0, 114.5, 73.8, 48.0 (q, J = 27.3 Hz), 35.1, 21.6; 19F NMR (376 MHz, CDCl3): δ −72.4; HRMS (positive ESI): [M + Na]+ calcd for C24H18ClF3N4NaO5S: 589.0536, Found: 589.0536. (S)-3-(5-Bromo-1-tosyl-1H-indol-3-yl)-4,4,4-trifluoro-3-(nitromethyl)-1-(pyrazin-2-yl)butan-1-one (3ce). With petroleum ether/ EtOAc (3/1) as eluent; white solid (101.2 mg, 83%); mp: 68.1−69.2 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (80/20) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 14.3 min (minor), 19.0 min (major), 95% ee. [α]20 D = −21 (c 198

DOI: 10.1021/acs.joc.8b02601 J. Org. Chem. 2019, 84, 191−203

Article

The Journal of Organic Chemistry

Hz), 124.4 (d, J = 2.3 Hz), 117.8, 117.6, 115.3, 114.9, 74.1, 48.4 (q, J = 27.1 Hz), 34.8, 21.6; 19F NMR (376 MHz, CDCl3): δ −72.3; HRMS (positive ESI): [M + Na]+ calcd for C29H21BrF3N3NaO5S: 682.0235, Found: 682.0239. (S)-3-(5-Bromo-1-tosyl-1H-indol-3-yl)-4,4,4-trifluoro-3-(nitromethyl)-1-(quinoxalin-2-yl)butan-1-one (3ee). With petroleum ether/EtOAc (3/1) as eluent; white solid (91.1 mg, 69%); mp: 71.7−72.9 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (80/20) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 11.6 min (minor), 20.0 min (major), 94% ee. [α]20 D = −74 (c 0.099, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 9.35 (s, 1H), 8.34−8.32 (m, 1H), 8.20−8.17 (m, 1H), 7.96−7.89 (m, 3H), 7.81 (d, J = 8.9 Hz, 1H), 7.73 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.37 (dd, J = 1.6, 7.2 Hz, 1H), 7.25 (d, J = 8.2 Hz, 2H), 5.76 (d, J = 12.5 Hz, 1H), 5.65 (d, J = 12.5 Hz, 1H), 4.77 (d, J = 18.8 Hz, 1H), 4.53 (d, J = 18.9 Hz, 1H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 195.2, 144.9, 144.4, 143.3, 141.6, 139.8, 133.1, 133.0, 131.9, 130.2, 129.7, 129.2, 128.4 (d, J = 8.0 Hz), 127.2, 126.5, 125.8, 124.7 (q, J = 283.4 Hz), 123.2 (d, J = 2.4 Hz), 120.5, 116.5, 114.3, 113.4, 72.9, 47.1 (q, J = 27.3 Hz), 33.8, 20.6; 19F NMR (376 MHz, CDCl3): δ −72.3; HRMS (positive ESI): [M + Na]+ calcd for C28H20BrF3N4NaO5S: 683.0188, Found: 683.0187. (S)-3-(5-Chloro-1-tosyl-1H-indol-3-yl)-4,4,4-trifluoro-1-(1-methyl-1H-imidazol-2-yl)-3-(nitromethyl)butan-1-one (3fd). With petroleum ether/EtOAc (2/1) as eluent; white solid (74.2 mg, 65%); mp: 66.9−67.8 °C. The enantiomeric excess was determined on a Daicel Chiralpak IA column with n-hexane/2-propanol (85/15) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 17.3 min (minor), 20.5 min (major), 96% ee. [α]20 D = −13.9 (c 0.726, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 8.9 Hz, 1H), 7.74 (s, 1H), 7.69−7.67 (m, 3H), 7.27−7.21 (m, 4H), 7.07 (s, 1H), 5.70 (d, J = 12.7 Hz, 1H), 5.63 (d, J = 12.7 Hz, 1H), 4.46 (d, J = 18.2 Hz, 1H), 4.30 (d, J = 18.2 Hz, 1H), 3.89 (s, 3H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 186.8, 145.8, 142.4, 134.2, 133.6, 130.2, 129.9, 129.7, 128.9, 128.0, 127.9, 126.9, 125.7 (q, J = 283.5 Hz), 125.5, 121.3 (d, J = 2.5 Hz), 114.9, 73.9, 48.2 (q, J = 27.0 Hz), 36.1, 21.7; 19F NMR (376 MHz, CDCl3): δ −72.2; HRMS (positive ESI): [M + H]+ calcd for C24H21ClF3N4O5S: 569.0873, Found: 569.0872. (S)-3-(5-Bromo-1-tosyl-1H-indol-3-yl)-4,4,4-trifluoro-1-(1-methyl-1H-imidazol-2-yl)-3-(nitromethyl)butan-1-one (3fe). With petroleum ether/EtOAc (2/1) as eluent; white solid (84.9 mg, 69%); mp: 103.1−104.9 °C. The enantiomeric excess was determined on a Daicel Chiralpak IC column with n-hexane/2-propanol (85/15) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 15.3 min (major), 17.3 min (minor), 96% ee. [α]20 D = −12 (c 0.107, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.83−7.81 (m, 2H), 7.72 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.39 (dd, J = 1.7, 8.8 Hz, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 0.8 Hz, 1H), 7.07 (s, 1H), 5.69 (d, J = 12.7 Hz, 1H), 5.62 (d, J = 12.7 Hz, 1H), 4.47 (d, J = 18.2 Hz, 1H), 4.29 (d, J = 18.2 Hz, 1H), 3.89 (s, 3H), 2.36 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 186.8, 145.8, 142.4, 134.3, 134.0, 130.1 (d, J = 18.8 Hz), 129.7, 129.4, 128.2, 128.0, 127.8, 126.9, 125.7 (q, J = 283.5 Hz), 124.3 (d, J = 2.7 Hz), 117.5, 115.2, 114.8, 74.0, 48.3 (q, J = 27.0 Hz), 36.2, 36.1, 21.6; 19F NMR (376 MHz, CDCl3): δ −72.2; HRMS (positive ESI): [M + Na]+ calcd for C24H20BrF3N4NaO5S: 635.0188, Found: 635.0187. (S)-1-(Benzo[d]thiazol-2-yl)-3-(5-bromo-1-tosyl-1H-indol-3-yl)4,4,4-trifluoro-3-(nitromethyl)butan-1-one (3ge). With petroleum ether/EtOAc (3/1) as eluent; white solid (75.7 mg, 57%); mp: 84.1− 85.5 °C. The enantiomeric excess was determined on a Daicel Chiralpak IC column with n-hexane/2-propanol (80/20) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 11.4 min (major), 15.2 min (minor), 95% ee. [α]20 D = −56 (c 0.101, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.29 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.86 (s, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.70 (s, 1H), 7.66−7.56 (m, 4H), 7.39 (dd, J = 1.6, 8.8 Hz, 1H), 7.25 (d, J = 8.2 Hz, 2H), 5.68 (d, J = 12.8 Hz, 1H), 5.63 (d, J = 12.8 Hz, 1H), 4.61 (d, J = 18.6 Hz, 1H), 4.50 (d, J = 18.6 Hz, 1H),

ether/EtOAc (3/1) as eluent; white solid (103.2 mg, 87%); mp: 68.1−70.0 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (75/25) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 13.4 min (minor), 17.8 min (major), 96% ee. [α]20 D = −18 (c 0.104, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 9.11 (d, J = 1.4 Hz, 1H), 8.82 (d, J = 2.4 Hz, 1H), 8.73 (dd, J = 1.5, 2.2 Hz, 1H), 8.38 (s, 1H), 7.99 (s, 2H), 7.77 (s, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 5.74 (d, J = 12.5 Hz, 1H), 5.69 (d, J = 12.5 Hz, 1H), 4.63 (d, J = 19.0 Hz, 1H), 4.44 (d, J = 19.1 Hz, 1H), 3.89 (s, 3H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 195.0, 165.5, 147.6, 145.7, 145.0, 142.6, 136.7, 133.1, 129.2, 126.7, 126.5, 125.9, 125.3, 124.9, 124.7 (q, J = 283.4 Hz), 122.4 (d, J = 2.0 Hz), 114.4, 112.7, 72.9, 51.3, 47.1 (q, J = 27.3 Hz), 34.3, 20.6; 19F NMR (376 MHz, CDCl3): δ −72.4; HRMS (positive ESI): [M + Na]+ calcd for C26H21F3N4NaO7S: 613.0981, Found: 613.0982. (S)-4,4,4-Trifluoro-3-(7-methyl-1-tosyl-1H-indol-3-yl)-3-(nitromethyl)-1-(pyrazin-2-yl)butan-1-one (3cl). With petroleum ether/ EtOAc (3/1) as eluent; white solid (79.2 mg, 72%); mp: 62.0−63.5 °C. The enantiomeric excess was determined on a Daicel Chiralpak IC column with n-hexane/2-propanol (80/20) and flow rate 1.0 mL/ min and detected at a UV wavelength of 254 nm. Retention times: 22.4 min (minor), 26.7 min (major), 94% ee. [α]20 D = −68 (c 0.111, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 9.15 (d, J = 1.4 Hz, 1H), 8.81 (d, J = 2.4 Hz, 1H), 8.71 (dd, J = 1.5, 2.4 Hz, 1H), 7.87 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 7.11−7.07 (m, 1H), 7.01 (d, J = 7.3 Hz, 1H), 5.77 (d, J = 12.5 Hz, 1H), 5.69 (d, J = 12.5 Hz, 1H), 4.66 (d, J = 19.1 Hz, 1H), 4.41 (d, J = 19.2 Hz, 1H), 2.52 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 196.1, 148.6, 146.8, 145.2, 143.64, 143.62, 136.2, 135.7, 130.2, 130.1, 129.7, 128.9, 126.4, 125.9 (q, J = 283.4 Hz), 125.6, 124.2, 119.0 (d, J = 2.7 Hz), 114.2, 74.1, 48.1 (q, J = 27.4 Hz), 35.2, 21.9, 21.6; 19F NMR (376 MHz, CDCl3): δ −72.1; HRMS (positive ESI): [M + Na]+ calcd for C25H21F3N4NaO5S: 569.1082, Found: 569.1084. (S)-4,4,4-Trifluoro-3-(7-methoxy-1-tosyl-1H-indol-3-yl)-3-(nitromethyl)-1-(pyrazin-2-yl)butan-1-one (3cm). With petroleum ether/ EtOAc (3/1) as eluent; white solid (75.5 mg, 67%); mp: 72.8−74.3 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (90/10) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 36.9 min (minor), 41.3 min (major), 94% ee. [α]20 D = −72 (c 0.108, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 9.17 (d, J = 1.4 Hz, 1H), 8.81 (d, J = 2.5 Hz, 1H), 8.71 (dd, J = 1.5, 2.4 Hz, 1H), 7.90 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.30−7.25 (m, 3H), 7.11−7.07 (m, 1H), 6.67 (d, J = 8.0 Hz, 1H), 5.79 (d, J = 12.5 Hz, 1H), 5.70 (d, J = 12.5 Hz, 1H), 4.65 (d, J = 19.1 Hz, 1H), 4.41 (d, J = 19.2 Hz, 1H), 3.64 (s, 3H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 196.1, 148.5, 147.6, 146.9, 144.7, 143.7 (d, J = 6.5 Hz), 136.7, 130.4, 129.6, 128.6, 127.2, 126.0 (q, J = 282.5 Hz), 125.6, 124.6, 121.7, 113.6, 112.7, 107.1, 74.0, 55.3 (d, J = 1.9 Hz), 48.1 (q, J = 27.2 Hz), 35.3, 21.6 (d, J = 1.4 Hz); 19F NMR (376 MHz, CDCl3): δ −72.3; HRMS (positive ESI): [M + Na]+ calcd for C25H21F3N4NaO6S: 585.1032, Found: 585.1034. (S)-3-(5-Bromo-1-tosyl-1H-indol-3-yl)-4,4,4-trifluoro-3-(nitromethyl)-1-(quinolin-2-yl)butan-1-one (3de). With petroleum ether/ EtOAc (3/1) as eluent; white solid (105.2 mg, 80%); mp: 83.7−85.9 °C. The enantiomeric excess was determined on a Daicel Chiralpak IC column with n-hexane/2-propanol (80/20) and flow rate 1.0 mL/ min and detected at a UV wavelength of 254 nm. Retention times: 12.8 min (major), 21.4 min (minor), 86% ee. [α]20 D = −102 (c 0.102, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.35 (d, J = 8.5 Hz, 1H), 8.28 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.95 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.87−7.83 (m, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.74 (s,1H), 7.72−7.68 (m, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.36 (dd, J = 1.7, 8.8 Hz, 1H), 7.23 (d, J = 8.1 Hz, 2H), 5.77 (d, J = 12.5 Hz, 1H), 5.68 (d, J = 12.6 Hz, 1H), 4.88 (d, J = 18.7 Hz, 1H), 4.55 (d, J = 18.7 Hz, 1H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 197.0, 152.0, 147.1, 145.8, 137.4, 134.2, 134.1, 130.9, 130.4, 130.2, 129.9, 129.6, 129.2, 128.2, 127.72, 127.66, 126.8, 125.9 (q, J = 283.4 199

DOI: 10.1021/acs.joc.8b02601 J. Org. Chem. 2019, 84, 191−203

Article

The Journal of Organic Chemistry 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 190.1, 164.9, 153.3, 145.9, 137.5, 134.13, 134.10, 130.2, 129.2, 128.4, 128.3, 127.7, 127.4, 126.8, 125.9, 125.6 (q, J = 285.2 Hz), 124.2 (d, J = 2.8 Hz), 122.4, 117.6, 115.3, 114.3, 73.8, 48.2 (q, J = 27.3 Hz), 36.2, 21.6; 19F NMR (376 MHz, CDCl3): δ −72.1; HRMS (positive ESI): [M + Na]+ calcd for C27H19BrF3N3NaO5S2: 687.9799, Found: 687.9802. (S)-3-(5-Bromo-1-tosyl-1H-indol-3-yl)-4,4,4-trifluoro-3-(nitromethyl)-1-(pyrimidin-2-yl)butan-1-one (3he). With petroleum ether/EtOAc (2/1) as eluent; white solid (68.1 mg, 56%); mp: 89.3−91.4 °C. The enantiomeric excess was determined on a Daicel Chiralpak IC column with n-hexane/2-propanol (80/20) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 16.8 min (major), 22.9 min (minor), 31% ee. [α]20 D = −8 (c 0.115, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.99 (d, J = 4.8 Hz, 2H), 7.83 (s, 1H), 7.80 (d, J = 8.9 Hz, 1H), 7.70−7.68 (m, 3H), 7.54 (t, J = 4.9 Hz, 1H), 7.38 (dd, J = 1.8, 8.9 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 5.71 (d, J = 12.4 Hz, 1H), 5.60 (d, J = 12.4 Hz, 1H), 4.65 (d, J = 19.3 Hz, 1H), 4.43 (d, J = 19.3 Hz, 1H), 2.36 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 194.1, 159.1, 157.9, 145.9, 134.1, 134.0, 130.3, 129.4, 128.2, 127.5, 126.9, 125.7 (q, J = 283.3 Hz), 124.1 (d, J = 2.5 Hz), 123.7, 117.5, 115.2, 114.1, 73.8, 48.1 (q, J = 27.2 Hz), 36.4, 21.6; 19F NMR (376 MHz, CDCl3): δ −72.4; HRMS (positive ESI): [M + Na]+ calcd for C24H18BrF3N4NaO5S: 633.0031, Found: 633.0032. (S)-3-(5-Chloro-1H-indol-3-yl)-4,4,4-trifluoro-3-(nitromethyl)-1(thiazol-2-yl)butan-1-one (4). To a Schlenk tube were added adduct 3bd (57.2 mg, 0.1 mmol), THF (1.0 mL), MeOH (0.5 mL), and Cs2CO3(97.8 mg, 0.3 mmol) sequentially at room temperature under an Ar atmosphere. Then the reaction mixture was stirred at 40 °C for 8 h. After cooling down to room temperature, the mixture was filtrated through Celite and washed with ethyl acetate (20 mL). The organic solvent was evaporated under vacuum, and the residue was purified by chromatography on silica gel plates (petroleum ether/ EtOAc, 5/1) to give 4 (30.5 mg, 73% yield). White solid, mp: 65.4− 66.7 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (80/20) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 9.5 min (minor), 12.1 min (major), 95% ee. [α]20 D = −19 (c 0.103, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 8.08 (d, J = 3.0 Hz, 1H), 7.73 (d, J = 3.0 Hz, 2H), 7.24 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 2.9 Hz, 1H), 7.14 (dd, J = 1.8, 8.7 Hz, 1H), 5.74 (d, J = 12.6 Hz, 1H), 5.66 (d, J = 12.6 Hz, 1H), 4.60 (d, J = 18.6 Hz, 1H), 4.38 (d, J = 18.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 189.2, 166.1, 145.0, 135.1, 127.3, 126.6, 126.1 (q, J = 283.4 Hz), 125.6, 125.2, 123.3, 120.2 (d, J = 2.6 Hz), 112.9, 108.4, 74.2, 48.2 (q, J = 27.0 Hz), 36.3; 19F NMR (376 MHz, CDCl3): δ −72.7; HRMS (positive ESI): [M + Na]+ calcd for C16H11ClF3N3NaO3S: 440.0059, Found: 440.0062. (3S)-4,4,4-Trifluoro-3-(nitromethyl)-1-(pyrazin-2-yl)-3-(1-tosyl1H-indol-3-yl)butan-1-ol (5). NaBH4 (10.1 mg, 0.268 mmol) was added to a solution of the adduct 3ca (71.3 mg, 0.134 mmol) in anhydrous MeOH (2 mL) at 0 °C, and stirred for 1 h. After treatment of the reaction mixture with a saturated aqueous NH4Cl solution at 0 °C, the two phases were separated and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by chromatography on silica gel plates (CH2Cl2/MeOH, 20/1) to afford the diastereomeric secondary alcohols 5a and 5b in a ratio of 1.2:1. The major isomer 5a (40.8 mg, 46% yield), colorless oil. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (85/15) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 22.3 min (major), 31.7 min (minor), 96% ee. 1 [α]20 D = +56 (c 0.100, CH2Cl2). H NMR (400 MHz, CDCl3): δ 8.54−8.53 (m, 1H), 8.51 (d, J = 2.5 Hz, 1H), 8.40 (d, J = 1.3 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.81 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.1 Hz, 1H), 7.41−7.37 (m, 1H), 7.34−7.30 (m, 1H), 7.25 (d, J = 8.3 Hz, 2H), 5.80 (d, J = 12.1 Hz, 1H), 5.46 (d, J = 12.1 Hz, 1H), 4.60−4.56 (m, 1H), 3.74 (d, J = 8.1 Hz, 1H), 2.95 (dd, J = 1.8, 15.3 Hz, 1H), 2.83 (dd, J = 10.6, 15.3 Hz, 1H), 2.34 (s, 3H);

C{1H} NMR (100 MHz, CDCl3): δ 156.4 (d, J = 4.3 Hz), 145.7, 144.1, 143.5, 142.2, 135.3, 134.5, 130.2, 128.1, 126.9, 126.4, 126.1 (q, J = 283.7 Hz), 125.5, 124.1, 121.6, 114.4, 114.1, 76.2, 68.7, 49.9 (q, J = 26.8 Hz), 36.3, 21.6 (d, J = 4.3 Hz); 19F NMR (376 MHz, CDCl3): δ −71.6; HRMS (positive ESI): [M + Na]+ calcd for C24H21F3N4NaO5S: 557.1082, Found: 557.1082. The minor isomer 5b (34.2 mg, 38% yield), colorless oil. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (85/15) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 16.4 min (major), 26.8 min (minor), 96% ee. 1 [α]20 D = −42.9 (c 0.102, CH2Cl2). H NMR (400 MHz, CDCl3): δ 8.66 (d, J = 1.3 Hz, 1H), 8.56 (d, J = 2.6 Hz, 1H), 8.54−8.53 (m, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 9.2 Hz, 2H), 7.33−7.29 (m, 1H), 7.26−7.22 (m, 3H), 5.77 (d, J = 14.2 Hz, 1H), 5.49 (d, J = 14.1 Hz, 1H), 5.35−5.31 (m, 1H), 3.81 (d, 7.1 Hz, 1H), 2.91 (dd, J = 10.6, 15.3 Hz, 1H), 2.81 (dd, J = 2.3, 15.2 Hz, 1H), 2.33 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 156.2, 145.5, 144.2, 143.4, 142.7, 135.2, 134.6, 130.1, 127.8, 126.8, 126.5, 126.4 (q, J = 280.7 Hz), 125.1, 123.7, 121.3, 116.2, 114.0, 74.4, 68.6, 49.2 (q, J = 25.8 Hz), 39.6, 21.6 (d, J = 4.2 Hz); 19F NMR (376 MHz, CDCl3): δ −69.0; HRMS (positive ESI): [M + H]+ calcd for C24H22F3N4O5S: 535.1263, Found: 535.1261. (S)-3-(5-(Pyrazin-2-yl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol3-yl)-1-tosyl-1H-indole (6). To a 10 mL Schlenk were added 3ca (53.2 mg, 0.1 mmol), acetic acid (90.0 μL, 16.0 equiv), Fe (251 mg, 45.0 equiv), THF (1.0 mL), and MeOH (0.5 mL) successively at room temperature under an Ar atmosphere. The resulting mixture was heated at 65 °C for 3 h. After cooling down to room temperature, the reaction mixture was filtrated through Celite and rinsed with EtOAc. The organic phase was washed with saturated NaHCO3, brine in succession. After that, the resulting solution was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by chromatography on silica gel plates (petroleum ether/EtOAc, 3/1) to give 6 (36.6 mg, 76% yield). White solid, mp: 68.1−69.2 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (80/20) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 10.6 min (major), 22.1 min (minor), 92% ee. [α]20 D = −47 (c 0.133, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 9.41 (d, J = 1.4 Hz, 1H), 8.65 (d, J = 2.6 Hz, 1H), 8.61−8.60 (m, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.65 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.37−7.32 (m, 1H), 7.28−7.23 (m, 3H), 5.01 (dd, J = 2.1, 17.7 Hz, 1H), 4.70 (d, J = 17.7 Hz, 1H), 4.04 (dd, J = 2.2, 18.6 Hz, 1H), 3.71 (d, J = 18.6 Hz, 1H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.9, 147.1, 145.8, 145.3, 143.9, 143.7, 135.3, 134.9, 130.0, 128.6, 127.7 (q, J = 280.3 Hz), 126.9, 125.1, 124.8, 123.6, 120.7, 119.3, 113.9, 69.1, 50.4 (q, J = 26.9 Hz), 43.7, 21.6; 19F NMR (376 MHz, CDCl3): δ −75.6; HRMS (positive ESI): [M + Na]+ calcd for C24H19F3N4NaO2S: 507.1079, Found: 507.1077. Synthesis of the Methyl Esters 7. A solution of 3fe (60.0 mg, 0.098 mmol) or 3fd (74.0 mg, 0.13 mmol) and 4 Å MS (30 mg) in acetonitrile (2 mL; 2.5 mL for 3fd) was stirred at room temperature for 10 min under an Ar atmosphere before MeOTf (1.1 equiv) was added. After stirring vigorously at room temperature for 12 h, MeOH (1 mL; 1.5 mL for 3fd) and DBU (0.1 mL; 0.15 mL for 3fd) were added. The reaction was stirred for another 1 h. Then, the resulting mixture was separated with water, and the aqueous phase was extracted with CH2Cl2 (10 mL × 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by chromatography on silica gel plates to give the esters 7. (S)-Methyl 3-(5-bromo-1-tosyl-1H-indol-3-yl)-4,4,4-trifluoro-3(nitromethyl)butanoate (7a). With petroleum ether/EtOAc (1/1) as eluent; colorless oil (37.1 mg, 67%). The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2propanol (90/10) and flow rate 1.0 mL/min and detected at a UV wavelength of 210 nm. Retention times: 12.7 min (minor), 19.0 min 1 (major), 97% ee. [α]20 D = +7 (c 0.085, CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 8.9 Hz, 1H), 7.75 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.65−7.63 (m, 1H), 7.44 (dd, J = 1.6, 8.9 Hz, 1H), 7.27−7.25 13

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DOI: 10.1021/acs.joc.8b02601 J. Org. Chem. 2019, 84, 191−203

The Journal of Organic Chemistry

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(m, 2H), 5.61 (d, J = 13.2 Hz, 1H), 5.51 (d, J = 13.2 Hz, 1H), 3.70 (s, 3H), 3.53 (d, J = 17.0 Hz, 1H), 3.48 (d, J = 16.9 Hz, 1H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.0, 146.0, 134.2, 134.0, 130.2, 129.2, 128.4, 127.6, 126.9, 125.5 (q, J = 280.4 Hz), 123.9, 117.6, 115.4, 114.2, 73.3, 52.4 (d, J = 4.5 Hz), 47.9 (q, J = 27.1 Hz), 33.6, 21.6 (d, J = 3.9 Hz); 19F NMR (376 MHz, CDCl3): δ −72.0; HRMS (positive ESI): [M + H]+ calcd for C21H19BrF3N2O6S: 563.0099, Found: 563.0098. (S)-Methyl 3-(5-chloro-1-tosyl-1H-indol-3-yl)-4,4,4-trifluoro-3(nitromethyl)butanoate (7b). With petroleum ether/EtOAc (4/1) as eluent; white solid (44.0 mg, 65%); mp: 33.8−34.6 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2-propanol (90/10) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 14.0 min (minor), 22.3 min (major), 96% ee. [α]20 D = +8.2 (c 0.482, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.9 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.65 (s, 1H), 7.58 (s, 1H), 7.31 (dd, J = 1.9, 8.9 Hz, 1H), 7.27−7.25 (m, 2H), 5.62 (d, J = 13.2 Hz, 1H), 5.51 (d, J = 13.2 Hz, 1H), 3.71 (s, 3H), 3.53 (d, J = 17.0 Hz, 1H), 3.49 (d, J = 17.0 Hz, 1H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.0, 144.9, 133.1, 132.6, 129.2, 128.9, 127.6, 126.7, 125.8, 124.7, 124.4 (q, J = 283.4 Hz), 119.9 (d, J = 2.9 Hz), 114.0, 113.2, 72.2, 51.4, 46.8 (q, J = 27.1 Hz), 32.5, 20.6; 19F NMR (376 MHz, CDCl3): δ −72.0; HRMS (positive ESI): [M + Na]+ calcd for C21H18ClF3N2NaO6S: 541.0424, Found: 541.0423. Synthesis of the γ-Lactams 8. To a 25 mL oven-dried vial under an Ar atmosphere were added 7a (37.1 mg, 0.066 mmol) or 7b (37.9 mg, 0.073 mmol), NiCl2 (1.5 equiv), NaBH4 (1.5 equiv; 15 equiv for 7b), and ethanol (2 mL; 2.5 mL for 7b) successively at 0 °C. Then the mixture was stirred for 9 h (24 h for 7b) at room temperature, after which the reaction was quenched with a solution of saturated NaHCO3 and extracted with CH2Cl2 (10 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by chromatography on silica gel plates to afford the products 8. (S)-4-(1-Tosyl-1H-indol-3-yl)-4-(trifluoromethyl)pyrrolidin-2-one (8a). With petroleum ether/EtOAc (1/1) as eluent; white solid (12.8 mg, 46%); mp: 112.1−112.9 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with n-hexane/2propanol (92/8) and flow rate 1.0 mL/min and detected at a UV wavelength of 210 nm. Retention times: 37.1 min (minor), 41.4 min 1 (major), 96% ee. [α]20 D = −6 (c 0.100, CH2Cl2). H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.59 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.38−7.34 (m, 1H), 7.28−7.25 (m, 3H), 6.46 (br s, 1H), 4.14 (d, J = 10.6 Hz, 1H), 3.95 (d, J = 10.7 Hz, 1H), 3.12 (d, J = 17.5 Hz, 1H), 3.00 (d, J = 17.5 Hz, 1H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 174.2, 145.5, 135.3, 134.8, 130.1, 128.2, 127.1 (q, J = 280.8 Hz), 127.0, 125.3, 125.1, 123.7, 120.5, 118.2, 114.0, 47.7 (q, J = 28.1 Hz), 37.3, 29.7, 21.6; 19F NMR (376 MHz, CDCl3): δ −76.0; HRMS (positive ESI): [M + H]+ calcd for C20H18F3N2O3S: 423.0990, Found: 423.1007. (S)-4-(5-Chloro-1-tosyl-1H-indol-3-yl)-4-(trifluoromethyl)pyrrolidin-2-one (8b). With petroleum ether/EtOAc (1/3) as eluent; white solid (14.3 mg, 43%); mp: 235.2−236.6 °C. The enantiomeric excess was determined on a Daicel Chiralpak AD-H column with nhexane/2-propanol (85/15) and flow rate 1.0 mL/min and detected at a UV wavelength of 254 nm. Retention times: 15.1 min (major), 1 21.7 min (minor), 88% ee. [α]20 D = −4.5 (c 0.400, CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 8.9 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.54 (s, 1H), 7.34 (s, 1H), 7.24 (dd, J = 1.8, 8.9 Hz, 1H), 7.21− 7.19 (m, 2H), 6.36 (br s, 1H), 4.08 (d, J = 10.6 Hz, 1H), 3.84 (d, J = 10.6 Hz, 1H), 3.04 (d, J = 17.4 Hz, 1H), 2.89 (d, J = 17.4 Hz, 1H), 2.30 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 172.8, 144.9, 133.4, 132.6, 129.2, 128.7, 128.3, 125.89, 125.86 (q, J = 280.7 Hz), 125.5, 124.7, 119.2, 116.7, 114.0, 46.5 (q, J = 27.5 Hz), 36.1, 28.7, 20.6; 19F NMR (376 MHz, CDCl3): δ −75.9; HRMS (positive ESI): [M + H]+ calcd for C20H17ClF3N2O3S: 457.0601, Found: 457.0602.

Article

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02601. Crystallographic details for the adduct 3aa. NMR spectra of the new nitroalkenes 2, NMR spectra of the adducts 3 and the transformed products 4−8 as well as their chiral HPLC spectra (PDF) Crystallographic data for the adduct 3aa (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*Tel./Fax: (+86)-371-6776-3869. E-mail: [email protected] (J.-F.G.). *Tel./Fax: (+86)-371-6776-3869. E-mail: [email protected] (M.-P.S.). ORCID

Jun-Fang Gong: 0000-0002-5299-1323 Mao-Ping Song: 0000-0003-3883-2622 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (21472176 and 21672192) for the financial support of this work.

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REFERENCES

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DOI: 10.1021/acs.joc.8b02601 J. Org. Chem. 2019, 84, 191−203

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The Journal of Organic Chemistry

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DOI: 10.1021/acs.joc.8b02601 J. Org. Chem. 2019, 84, 191−203

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DOI: 10.1021/acs.joc.8b02601 J. Org. Chem. 2019, 84, 191−203