Organocatalytic Asymmetric α-Sulfenylation of 2-Substituted Indolin-3

Jun 4, 2019 - We also investigated the effects of reaction temperatures on the .... when we extend the substrate scopes of N-(arylthio)succinimides, ...
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Article Cite This: J. Org. Chem. 2019, 84, 8168−8176

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Organocatalytic Asymmetric α‑Sulfenylation of 2‑Substituted Indolin-3-ones: A Strategy for the Synthesis of Chiral 2,2Disubstituted Indole-3-ones with S- and N‑Containing Heteroquaternary Carbon Stereocenter Yong-Long Zhao,*,†,§ Xing-Hai Fei,†,§ Yong-Qin Tang,† Peng-Fei Xu,‡ Fen-Fen Yang,† Bin He,† Xiao-Zhong Fu,† Yuan-Yong Yang,† Meng Zhou,† Yuan-Hu Mao,† Yong-Xi Dong,† and Chun Li† Downloaded via IDAHO STATE UNIV on July 17, 2019 at 16:45:17 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

†

State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmacy, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang 550004, P. R. China ‡ State Key Laboratory of Applied Organic Chemistry and College of Chemistry & Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China S Supporting Information *

ABSTRACT: An organocatalytic asymmetric α-sulfenylation of 2-substituted indolin-3-ones with N-(alkylthio or arylthio)succinimides has been developed for the first time using Cinchona-derived squaramide as the catalyst. Various chiral 2,2disubstituted indole-3-ones with S- and N-containing heteroquaternary carbon stereocenters were obtained with up to 98% yield and 99% ee.

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heteroquaternary carbon centers bearing a sulfur atom.3 Despite these significant advances, it should be noted that the routes to construct the heteroquaternary carbon stereocenter bearing a sulfur and a nitrogen atom are still challenging and generally lacking. Therefore, the development of efficient αsulfenylation of unprecedented nucleophiles to construct these valuable building blocks is still highly desirable. Recently, because of the importance of C2-quaternary indolin-3-one skeletons in natural products and biologically active molecules,4 much of the effort was focused on the reactions of nucleophilic indole-3-ones with electrophiles.5 In 2017, two examples of organocatalytic asymmetric amination of 2-substituted indolin-3-ones were reported by Lu et al. and Subba Reddy et al. (Scheme 1a), respectively.5b,c However, there were no reports on the direct asymmetric αsulfenylation of nucleophilic indole-3-ones with electrophilic sulfur reagents. With our ongoing interest in the study of organocatalysis and indolin-3-one chemistry,5d,6 we envisaged

INTRODUCTION The indole-like skeletons with an S- and N-containing heteroquaternary carbon stereocenter at C2 positions represent an important class of structural motifs, which are incorporated into natural products and biologically active molecules (Figure 1).1 For example, erucalexin is a cruciferous phytoalexin.1a,b Gliotoxin, gliotoxin E, gliotoxin G, and glionitrin A are representative members of epipolythiodioxopiperazines, that are, fungal metabolites with multiple bioactivities.1c,d Scabrisins, isolated from Xanthoparmelia scabrosa, have antitumor activities.1e,f Despite the importance of the structure and biological activity, however, the stereoselective methods to construct these indole-like skeletons are generally lacking.1b To date, various protocols for the asymmetric C−S bond formation have been developed.2,3 In particular, organocatalytic α-sulfenylation of nucleophilic carbonyl compounds (such as aldehydes,3b 1,3-dicarbonyl compounds,3c,h,i 3substituted oxindoles,3d,e azlactones,3a β-naphthols,3i and so on) with electrophilic sulfur reagents has been proven to be an effective method for the formation of stereogenic © 2019 American Chemical Society

Received: April 25, 2019 Published: June 4, 2019 8168

DOI: 10.1021/acs.joc.9b01142 J. Org. Chem. 2019, 84, 8168−8176

Article

The Journal of Organic Chemistry

Figure 1. Representative indole-like natural products with S- and N-containing heteroquaternary carbon stereocenters at the C2 positions.

Scheme 1. Organocatalytic Asymmetric Amination and Sulfenylation of Indole-3-ones at the C2 Positions

the main reason for the poor selectivity of N-(arylthio)succinimides. With the established optimal reaction conditions, we next investigated the substrate scopes of this asymmetric αsulfenylation of nucleophilic indole-3-ones 1 with electrophilic sulfur reagents 2 catalyzed by Cinchona alkaloid-derived squaramide E (Table 2). We first examined the asymmetric α-sulfenylation reactions of indole-3-one 1a with N(alkylthio)succinimides 2. The results revealed that the different N-(alkylthio)succinimides 2 could offer the desired adducts 3b−j with 68−98% yield and with 88−99% ee. However, when N-(cyclohexylthio)succinimide was applied to this reaction, the corresponding products 3k was obtained with poor selectivity (64% ee). Next, we further investigated the effect of different substitutions of indole-3-ones 1 on this asymmetric sulfenylation reaction with virous N-(alkylthio)succinimides 2. The presence of a halide on the aromatic ring of indole-3-ones 1 (e.g., 5-Cl, 5-Br) could be tolerated in this reaction and the desired products 3o−r were afforded with good yields (80−88%) and good to excellent ee values (80− 94%). The indole-3-one 1 having a 7-methyl group on the aromatic ring afforded the desired adducts 3n with 85% yield and 91% ee while 3m with a distinct drop in yield andenantioselectivity (68% yield and 68% ee). Using the N(alkylthio)succinimides as the electrophilic sulfur reagents, the indole-3-ones 1 bearing a propargyl group on the nitrogen atom, thieno[2,3-b]pyrroles and 2-ethyl azodicarboxylates have been also applied to this reaction, which gave the desired products 3u, 3l, 3s, and 3t with good to excellent results (85−94% yields and 81−92% ee). To extend the substrate scopes of N-(arylthio)succinimides and improve the corresponding enantioselectivity, we also tested this asymmetric α-sulfenylation of virous N-(arylthio)succinimides with nucleophilic indole-3-ones bearing a propargyl or acetyl group on the nitrogen atom. Unfortunately, when we extend the substrate scopes of N-(arylthio)succinimides, only poor to moderate enantioselectivity (9−68% ee) was obtained with the desired products 3a and 3v−z, which may be caused by the background reactions of higher reactivity N-(arylthio)succinimides (Table 1, entries 15 and 22).

that the indolin-3-one skeletons possessing S- and Ncontaining heteroquaternary carbon stereocenters at the C2 positions could be created via a organocatalytic αsulfenylation of indolin-3-ones 1 (Scheme 1b).

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RESULTS AND DISCUSSION Initially, the direct asymmetric sulfenylation of indole-3-one 1a with N-(arylthio)succinimide 2a was chosen as the model reaction (Table 1, entries 1−13). By screening various Cinchona alkaloid-derived catalysts A−H in toluene at room temperature (Table 1, entries 1−8), Cinchona alkaloidderived squaramide E was found to be the most promising catalyst for this sulfenylation reaction albeit only 44% ee and 86% yield of the desired adduct 3a was obtained (Table 1, entry 5). Then, different solvents such as tetrahydrofuran (THF), toluene, CH2Cl2, and xylene were optimized to improve the reaction enantioselectivity (Table 1, entries 5 and 9−11). The results showed that THF was the optimal choice and the value of ee was increased to 65% (Table 1, entry 10). We also investigated the effects of reaction temperatures on the sulfenylation of indole-3-one 1a by N(arylthio)succinimide 2a and found no obvious improvement of the ee value (Table 1, entries 10 and 12−15). To further improve the enantioselectivity of the sulfenylation of indole3-ones at the C2 positions, we replaced the electrophilic sulfur reagent 2a with N-(alkylthio)succinimide 2b (Table 1, entries 16−22). To our delight, the desired product 3b was obtained in 85% yield with 90% ee (Table 1, entry 16). Encouraged by these results, we then optimized the effects of reaction temperatures and catalyst loading again (Table 1, entries 17−21) and eventually found that this reaction could be finished in 2 h in the presence of Cinchona alkaloidderived squaramide E (5 mol %) in THF at 0 °C, and the desired product 3b was obtained with the best results of 92% yield and 97% ee (Table 1, entry 18). Under the optimal reaction conditions, we also investigated the effects of background reactions (Table 1, entries 15 and 22), and the results showed that N-(arylthio)succinimide 2a had higher reactivity than N-(alkylthio)succinimide 2b, which may be 8169

DOI: 10.1021/acs.joc.9b01142 J. Org. Chem. 2019, 84, 8168−8176

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

entry

S source

cat.

solvent

T (°C)

time (h)

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18d 19e 20f 21g 22

2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2b 2b 2b 2b 2b 2b

A B C D E F G H E E E E E E

toluene toluene toluene toluene toluene toluene toluene toluene CH2Cl2 THF xylene THF THF THF THF THF THF THF THF THF THF THF

25 25 25 25 25 25 25 25 25 25 25 0 50 −30 −30 25 0 0 0 0 0 0

0.8 1 1 2 0.8 1.5 2 2 2 2 0.6 2 2 2 2 2 2 2 2 2 2 2

80 76 80 93 86 90 90 92 70 86 76 90 85 86 76 85 87 92 90 90 85 31

−20 −20 22 22 44 22 8 0 54 65 36 18 59 9

E E E E E E

90 96 97 94 92 84

a

Reactions were performed with 0.1 mmol of 1a, 0.12 mmol of 2a or 2b, and 0.01 mmol of the catalyst in 1.0 mL of the solvent. bYield of the isolated product. cDetermined by HPLC on a chiral stationary phase (OD-H column). d0.005 mmol of catalyst E was used. e0.003 mmol of catalyst E was used. f0.002 mmol of catalyst E was used. g0.001 mmol of catalyst E was used.

To demonstrate the potential application of this sulfenylation reaction, the oxidation of the sulfenylation adduct 3p was performed using mCPBA as the oxidant.3l The reaction proceeded smoothly to afford the corresponding sulfone 4p product with 88% yield and without undermining the ee value (Scheme 2). In addition, the large-scale synthesis of 3d was also performed under the optimized conditions at −10 to 0 °C and the corresponding product 3d was afforded with 71% yield and 94% ee (Scheme 3). The absolute configuration of the sulfenylation adducts 3 in this asymmetric α-sulfenylation reaction was determined by Xray crystal diffraction of compound 3c (Table 2).8 As shown in Scheme 4, a possible reaction mechanism was also proposed to account for the observed stereoselectivity. A highly nucleophilic enolate species may be first generated by

Scheme 2. Synthetic Transformations of Product 3p to 4p

the interaction of the tertiary amine group of the bifunctional catalyst E and indolin-3-ones 1 while the electrophilicity of N-(alkylthio or arylthio)succinimides 2 may be enhanced by the hydrogen-bonding interaction with the squaramide moiety of E. As a consequence, organocatalytic asymmetric 8170

DOI: 10.1021/acs.joc.9b01142 J. Org. Chem. 2019, 84, 8168−8176

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The Journal of Organic Chemistry Table 2. Substrate Scopesa

a Unless otherwise specified, the reactions were performed with 0.1 mmol of 1, 0.12 mmol of 2, and 0.005 mmol of catalyst E in 1.0 mL of THF at 0 °C for 2 h. bIsolated yield after flash chromatography. cThe ee values of 3 were determined by chiral HPLC analysis (OD-H column). dReaction time was 7 h. eReaction performed at 25 °C.

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CONCLUSIONS In summary, we have developed the first example of an organocatalyzed asymmetric α-sulfenylation reaction of nucleophilic 2-substituted indolin-3-ones with electrophilic N-(alkylthio or arylthio)succinimides. This transformation utilized Cinchona alkaloid-derived squaramide as the efficient catalyst and virous chiral 2,2-disubstituted indole-3-ones with S- and N-containing hetero-quaternary carbon stereocenters were obtained with up to 99% ee and 98% yield. This work not only provides an efficient strategy for constructing the indole skeletons containing a heteroquaternary carbon

Scheme 3. Large-Scale Synthesis of the Product 3d

sulfenylation of indole-3-ones at the C2 positions via a Reface attack occurs to generate products 3 (Scheme 3).3e,h 8171

DOI: 10.1021/acs.joc.9b01142 J. Org. Chem. 2019, 84, 8168−8176

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The Journal of Organic Chemistry Scheme 4. Proposed Mechanism for Asymmetric Sulfenylation of Indole-3-ones

solution of electrophilic sulfur reagents 2d (2.58 mmol in 3.0 mL THF) under stirring at −10 °C. Then, the resulting mixture was allowed to be stirred at 0 °C for 12 h (as judged by TLC analysis). The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (EtOAc/PE = 1/8 to 1/ 15) to afford the desired products 3d with 71% yield and 94% ee. Synthetic Transformations of Product 3p to 4p. To a solution of organosulfur compounds 3p (60 mg, 0.14 mmol, 80% ee) in CH2Cl2 (2.0 mL) was added mCPBA (29 mg, 0.17 mmol) under stirring at room temperature. Stirring was continued for 5 h (as judged by TLC analysis) under drying tube. Then, evaporation of the solvent gave crude product. The crude product was directly purified by flash column chromatography (EtOAc/PE = 1/10) to afford the desired white solid product 4p with 88% yield and 80% ee. Analytical Data of 3a−z and 4p. Methyl (R)-1-Acetyl-3-oxo-2(p-tolylthio)indoline-2-carboxylate (3a). White solid; reaction time: 2 h; yield: 84% (29.8 mg); mp 140−141 °C; 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 7.55−7.35 (m, 2H), 7.15 (d, J = 8.1 Hz, 2H), 7.00 (t, J = 7.5 Hz, 1H), 6.80 (d, J = 7.9 Hz, 2H), 3.85 (s, 3H), 2.54 (s, 3H), 2.11 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 191.1, 169.1, 164.8, 153.7, 140.7, 137.5, 136.9, 129.4, 124.3, 122.0, 121.6, 118.0, 54.4, 29.6, 24.8, 21.0. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/ i-PrOH = 90/10, flow rate 1 mL/min, λ = 254 nm), tR = 7.92 min (major), tR = 10.19 min (minor), 65% ee; [α]20 D = −118.6 (c 0.53, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C19H18NO4S, 356.0957; found [M + H]+, 356.0954. Methyl (R)-1-Acetyl-2-(benzylthio)-3-oxoindoline-2-carboxylate (3b). White solid; reaction time: 2 h; yield: 92% (32.7 mg); mp 84−85 °C; 1H NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 7.91−7.56 (m, 2H), 7.33−7.23 (m, 1H), 7.21−7.11 (m, 3H), 7.04 (dd, J = 6.5, J = 2.9 Hz, 2H), 3.82 (s, 3H), 3.81 (d, J = 12.8 Hz, 1H), 3.66 (d, J = 12.8 Hz, 1H), 2.37 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 190.3, 169.1, 165.1, 138.1, 135.2, 128.7, 128.4, 127.4, 124.9, 118.6, 76.9, 54.3, 33.7, 24.5. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 98/2, flow rate 0.6 mL/min, λ = 254 nm), tR = 57.18 min (major), tR = 62.40 min (minor), 97% ee; [α]D20 = −237.1 (c 0.53, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C19H18NO4S, 356.0957; found [M + H]+, 356.0952. Methyl (R)-1-Acetyl-2-((4-chlorobenzyl)thio)-3-oxoindoline-2carboxylate (3c). White solid; reaction time: 2 h; yield: 84% (32.7 mg); mp 83−84 °C; 1H NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 7.80−7.55 (m, 2H), 7.30−7.18 (m, 1H), 7.18−7.06 (m, 2H), 6.95−7.05 (m, 2H), 3.83 (s, 3H), 3.80 (d, J = 13.2 Hz, 1H), 3.67 (d, J = 13.2 Hz, 1H), 2.40 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 190.1, 169.0, 165.0, 138.2, 133.9, 133.2, 130.1, 128.5, 124.9, 121.3, 118.7, 77.2, 54.4, 33.3, 24.4. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 98/2, flow rate 0.6 mL/min, λ = 254 nm), tR = 56.94 min (major), tR = 73.98 min (minor), 94% ee; [α]20 D = −194.6 (c 0.52, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C19H17ClNO4S, 390.0561; found [M + H]+, 390.0559. Methyl (R)-1-Acetyl-2-((2-chlorobenzyl)thio)-3-oxoindoline-2carboxylate (3d). White solid; reaction time: 2 h; yield: 88%

stereocenter bearing sulfur and nitrogen atoms at the C2 positions but also is an important complement to current 3oxindole chemistry. The investigation and application of activated indolin-3-one derivatives into other new organocatalytic asymmetric reactions are currently ongoing in our laboratories.

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EXPERIMENTAL SECTION

General Information. All experiments were monitored by analytical thin-layer chromatography (TLC). TLC was performed on silica gel plates with an F-254 indicator and compounds were visualized by irradiation with UV light and/or by treatment with a solution of phosphomolybdic acid in ethanol followed by heating. Flash chromatography was carried out utilizing silica gel (200−300 mesh). 1H NMR, 13C NMR, and 19F NMR spectra were recorded on a JNM-ECS400 (400M) spectrometer (400 MHz 1H, 100 MHz 13 C, 376 MHz 19F). The spectra were recorded in CDCl3 as the solvent at room temperature otherwise stated, 1H, 19F, and 13C NMR chemical shifts are reported in ppm relative to the residual solvent peak as an internal standard: CDCl3 (1H NMR: δ 7.26, singlet; 13C NMR: δ 77.0, triplet). Data for 1H NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, dd = doublet), integration, coupling constant (Hz), and assignment. Data for 13C NMR are reported as chemical shift. High-resolution mass spectrometry (HRMS) were performed on a Thermofisher (Vanquish (UPLC)Q-Exactive Plus) mass instrument (Orbitrap-ESI), and methanol was used to dissolve the sample. Enantiomeric excess values were determined by HPLC using a Chiralcel OD-H column on Essential LC-16 series and eluting with i-PrOH and n-hexane. Optical rotation was measured on the IP-digi 300 polarimeter with [α]20 D values reported in degrees at 20 °C; concentration (c) is in g/100 mL. Starting Materials. Chemicals and solvents were either purchased from commercial suppliers (such as Energy-chemical, Alfa, Aladdin) or purified by standard procedures as specified in Purification of Laboratory Chemicals, 4th ed. (Armarego, W. L. F.; Perrin, D. D. Butterworth Heinemann: 1997). Petroleum ether (PE) and ethyl acetate (EtOAc) were distilled, anhydrous CH2Cl2 and MeCN were freshly distilled from CaH2, and stored under N2 atmosphere, THF, and toluene were freshly distilled from sodium/ benzophenone before use. The substrate of nucleophilic indole-3ones 15d,7a−c and various N-(alkylthio or arylthio)succinimides 23a,i were prepared by following the publish procedures. General Procedure for the Organocatalytic Asymmetric αSulfenylation of Indolin-3-ones at the C2 Positions. To a solution of organocatalyst E (0.005 mmol, 5.0 mol %) and nucleophilic indole-3-ones 1 (0.1 mmol) in THF (1.0 mL) was added electrophilic sulfur reagents 2 (0.12 mmol) under stirring at 0 or 25 °C. After the required period of time (as judged by TLC analysis), the reaction mixture was directly purified by flash column chromatography (EtOAc/PE = 1/8 to 1/15) to afford the desired products 3. The Large-Scale Synthesis of the Product 3d. To a solution of organocatalyst E (0.108 mmol, 5.0 mol %) and nucleophilic indole-3-ones 1a (2.15 mmol) in THF (20 mL) was dropped the 8172

DOI: 10.1021/acs.joc.9b01142 J. Org. Chem. 2019, 84, 8168−8176

Article

The Journal of Organic Chemistry (34.2 mg); mp 143−144 °C; 1H NMR (400 MHz, CDCl3): δ 8.63 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.33− 7.09 (m, 5H), 3.89 (d, J = 12.4 Hz, 1H), 3.84 (s, 3H), 3.79 (d, J = 12.4 Hz, 1H), 2.42 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 190.2, 168.4, 165.1, 157.0, 138.2, 134.2, 132.9, 131.1, 129.6, 129.1, 126.9, 125.0, 118.4, 54.4, 31.1, 24.6. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.6 mL/min, λ = 254 nm), tR = 23.45 min (major), tR = 26.52 min (minor), 96% ee; [α]20 D = −227.6 (c 0.51, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C19H17ClNO4S, 390.0561; found [M + H]+, 390.0558. Methyl (R)-1-Acetyl-2-((2-bromobenzyl)thio)-3-oxoindoline-2carboxylate (3e). White solid; reaction time: 2 h; yield: 84% (36.4 mg); mp 101−102 °C; 1H NMR (400 MHz, CDCl3): δ 8.63 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.77−7.68 (m, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.33−7.25 (m, 1H), 7.23−7.00 (m, 3H), 3.90 (d, J = 12.4 Hz, 1H), 3.84 (s, 3H), 3.78 (d, J = 12.4 Hz, 1H), 2.43 (s, 3H); 13 C {1H} NMR (101 MHz, CDCl3): δ 190.2, 169.3, 165.0, 153.4, 138.4, 134.5, 132.9, 131.1, 129.3, 127.6, 125.0, 124.5, 121.2, 118.7, 77.2, 54.4, 33.7, 24.6. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.6 mL/min, λ = 254 nm), tR = 25.02 min (major), tR = 27.78 min (minor), 89% ee; [α]20 D = −237.7 (c 0.40, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H] + for C19H17BrNO 4S, 434.0056; found [M + H]+, 434.0052. Methyl(R)-1-Acetyl-3-oxo-2-((3-(trifluoromethyl)benzyl)thio)indoline-2-carboxylate (3f). White solid; reaction time: 2 h; yield: 94% (39.8 mg); mp 79−80 °C; 1H NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 7.81−7.59 (m, 2H), 7.47−7.37 (m, 1H), 7.32 (d, J = 5.2 Hz, 2H), 7.29−7.23 (m, 1H), 7.19 (s, 1H), 3.87 (d, J = 14.0 Hz, 1H), 3.83 (s, 3H), 3.74 (d, J = 14.0 Hz, 1H), 2.37 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 190.1, 168.8, 164.9, 138.3, 136.6, 132.0, 130.5 (q, J = 33.0 Hz), 129.0, 125.3 (q, J = 3.7 Hz), 125.0, 124.3, 123.7 (q, J = 273.6 Hz), 118.7, 77.2, 54.4, 33.4, 24.4; 19F NMR (CDCl3, 376 MHz): δ −62.5. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.6 mL/min, λ = 254 nm), tR = 28.82 min (major), tR = 36.90 min (minor), 89% ee; [α]20 D = −197.9 (c 0.98, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C20H17F3NO4S, 424.0825; found [M + H]+, 424.0821. Methyl (R)-1-Acetyl-2-((4-methoxybenzyl)thio)-3-oxoindoline-2carboxylate (3g). White solid; reaction time: 2 h; yield: 90% (34.7 mg); mp 112−113 °C; 1H NMR (400 MHz, CDCl3): δ 8.58 (s, 1H), 7.85−7.50 (m, 2H), 7.42−7.13 (m, 1H), 7.10−6.86 (m, 2H), 6.82−6.58 (m, 2H), 3.83 (s, 3H), 3.77 (d, J = 12.8 Hz, 1H), 3.76 (s, 3H), 3.63 (d, J = 12.8 Hz, 1H), 2.41 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 190.3, 165.2, 158.8, 138.1, 130.0, 126.7, 124.9, 118.7, 113.8, 76.9, 55.1, 54.4, 33.2, 24.4. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/ i-PrOH = 90/10, flow rate 0.6 mL/min, λ = 254 nm), tR = 32.68 min (major), tR = 39.74 min (minor), 88% ee; [α]20 D = −204.6 (c 0.78, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C20H20NO5S, 386.1057; found [M + H]+, 386.1053. Methyl (R)-1-Acetyl-3-oxo-2-((2,4,6-trimethylbenzyl)thio)indoline-2-carboxylate (3h). White solid; reaction time: 2 h; yield: 92% (36.5 mg); mp 137−138 °C; 1H NMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.80−7.70 (m, 1H), 7.36−7.29 (m, 1H), 6.79 (s, 2H), 3.94−3.80 (m, 4H), 3.72 (d, J = 10.0 Hz, 1H), 2.48 (s, 3H), 2.30 (s, 6H), 2.21 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 189.9, 171.2, 165.4, 138.3, 137.6, 137.5, 137.3, 129.1, 127.0, 125.2, 125.0, 118.8, 77.2, 54.4, 28.1, 24.4, 20.9, 19.2. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 98/2, flow rate 0.5 mL/min, λ = 254 nm), tR = 27.72 min (major), tR = 30.42 min (minor), 99% ee; [α]20 D = −228.4 (c 0.55, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C22H24NO4S, 398.1421; found [M + H]+, 398.1418. Methyl (R)-1-Acetyl-2-(ethylthio)-3-oxoindoline-2-carboxylate (3i). White solid; reaction time: 2 h; yield: 98% (28.7 mg); mp 68−69 °C; 1H NMR (400 MHz, CDCl3): δ 8.63 (s, 1H), 7.82 (d, J

= 7.6 Hz, 1H), 7.77−7.70 (m, 1H), 7.34−7.26 (m, 1H), 3.83 (s, 3H), 2.70−2.30 (m, 5H), 1.12 (t, J = 7.6 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 190.7, 169.4, 165.2, 153.4, 138.3, 125.0, 121.3, 118.5, 77.2, 54.3, 24.5, 22.8, 13.4. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.6 mL/min, λ = 254 nm), tR = 15.18 min (major), tR = 17.77 min (minor), 90% ee; [α]20 D = −230.6 (c 0.87, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C14H16NO4S, 294.0795; found [M + H]+, 294.0792. Methyl (R)-1-Acetyl-2-(isopropylthio)-3-oxoindoline-2-carboxylate (3j). White solid; reaction time: 2 h; yield: 82% (25.2 mg); mp 117−118 °C; 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.80−7.70 (m, 1H), 7.35−7.28 (m, 1H), 3.83 (s, 3H), 2.95−2.75 (m, 1H), 2.45 (s, 3H), 1.17 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 191.1, 169.6, 165.2, 138.4, 125.1, 124.9, 121.4, 77.2, 54.5, 34.3, 29.7, 24.6 (24.65, 24.61). The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 98/2, flow rate 0.6 mL/min, λ = 254 nm), tR = 23.09 min (major), tR = 27.26 min (minor), 95% ee; [α]20 D = −191.9 (c 0.28, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C15H18NO4S, 308.0951; found [M + H]+, 308.0947. Methyl (R)-1-Acetyl-2-(cyclohexylthio)-3-oxoindoline-2-carboxylate (3k). White solid; reaction time: 2 h; yield: 92% (31.9 mg); mp 100−101 °C; 1H NMR (400 MHz, CDCl3): δ 8.63 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.78−7.70 (m, 1H), 7.30 (t, J = 7.6 Hz, 1H), 3.83 (s, 3H), 2.75−2.55 (m, 1H), 2.45 (s, 3H), 1.90−1.00 (m, 10H); 13C {1H} NMR (101 MHz, CDCl3): δ 191.2, 169.8, 165.5, 138.4, 125.2, 125.0, 121.6, 118.9, 54.6, 42.3, 34.8, 34.6, 25.8, 25.2, 24.8. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 98/2, flow rate 0.5 mL/min, λ = 254 nm), tR = 26.99 min (major), tR = 29.50 min (minor), 64% ee; [α]20 D = −161.76 (c 0.52, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C18H22NO4S, 348.1264; found [M + H]+, 348.1261. Ethyl (R)-1-Acetyl-2-(benzylthio)-3-oxoindoline-2-carboxylate (3l). Colorless oil; reaction time: 2 h; yield: 85% (31.4 mg); 1H NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 7.90−7.56 (m, 2H), 7.29−7.23 (m, 1H), 7.20−7.13 (m, 3H), 7.08−7.02 (m, 2H), 4.30 (qd, J = 6.8 Hz, J = 2.4 Hz, 2H), 3.81 (d, J = 12.8 Hz, 1H), 3.64 (d, J = 12.8 Hz, 1H), 2.39 (s, 3H), 1.26 (t, J = 6.8 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 190.5, 169.1, 164.5, 153.2, 138.0, 135.3, 128.7, 128.4, 127.4, 124.8, 121.3, 118.7, 76.9, 63.9, 33.7, 24.5, 13.9. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 98/2, flow rate 0.6 mL/min, λ = 254 nm), tR = 40.28 min (major), tR = 43.84 min (minor), 92% ee; [α]20 D = −197.0 (c 0.69, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C20H20NO4S, 370.1108; found [M + H]+, 370.1103. Methyl (R)-1-Acetyl-2-(benzylthio)-7-methyl-3-oxoindoline-2carboxylate (3m). White solid; reaction time: 2 h; yield: 68% (25.1 mg); mp 86−87 °C; 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.19−7.13 (m, 3H), 7.10−6.97 (m, 2H), 3.83 (s, 3H), 3.82 (d, J = 12.8 Hz, 1H), 3.68 (d, J = 12.8 Hz, 1H), 2.36 (s, 3H), 2.18 (s, 3H); 13 C {1H} NMR (101 MHz, CDCl3): δ 191.3, 168.7, 165.6, 152.4, 140.6, 135.5, 129.5, 128.7, 128.4, 127.4, 125.7, 123.7, 122.5, 78.0, 54.4, 33.7, 23.9, 21.3. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 98/2, flow rate 0.6 mL/min, λ = 254 nm), tR = 41.01 min (minor), tR = 47.43 min (major), 68% ee; [α]D20 = −121.2 (c 0.85, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C20H20NO4S, 370.1108; found [M + H]+, 370.1104. Methyl (R)-1-Acetyl-2-(ethylthio)-7-methyl-3-oxoindoline-2-carboxylate (3n). White solid; reaction time: 2 h; yield: 85% (26.1 mg); mp 86−87 °C; 1H NMR (400 MHz, CDCl3): δ 7.75−7.63 (m, 1H), 7.60−7.52 (m, 1H), 7.33−7.21 (m, 1H), 3.89−3.81 (m, 3H), 2.58−2.40 (m, 2H), 2.40−2.33 (m, 3H), 2.30−2.25 (m, 3H), 1.14−1.07 (m, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 191.8, 168.8, 165.7, 152.5, 140.6, 129.4, 125.7, 123.7, 122.5, 78.0, 54.4, 8173

DOI: 10.1021/acs.joc.9b01142 J. Org. Chem. 2019, 84, 8168−8176

Article

The Journal of Organic Chemistry

[α]20 D = −142.42 (c 0.50, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C17H16NO4S2, 362.0515; found [M + H]+, 362.0512. Methyl(R)-6-Acetyl-5-(ethylthio)-4-oxo-5,6-dihydro-4H-thieno[2,3-b]pyrrole-5-carboxylate (3t). White solid; reaction time: 2 h; yield: 88% (26.3 mg); mp 140−141 °C; 1H NMR (400 MHz, CDCl3): δ 7.05 (d, J = 5.2 Hz, 1H), 6.99 (d, J = 5.2 Hz, 1H), 3.85 (s, 3H), 2.58−2.46 (m, 1H), 2.43 (s, 3H), 2.41−2.32 (m, 1H), 1.14 (t, J = 7.2 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 181.7, 168.7, 166.1, 164.0, 124.7, 124.5, 117.3, 83.6, 54.5, 22.8, 22.0, 13.4. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.6 mL/min, λ = 254 nm), tR = 23.38 min (major), tR = 38.29 min (minor), 92% ee; [α]20 D = −195.9 (c 0.52, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C12H14NO4S2, 300.0359; found [M + H]+, 300.0356. Methyl (R)-2-(Benzylthio)-3-oxo-1-(prop-2-yn-1-yl)indoline-2carboxylate (3u). Yellow oil; reaction time: 7 h; yield: 85% (29.8 mg); 1H NMR (400 MHz, CDCl3): δ 7.74−7.47 (m, 2H), 7.20− 7.00 (m, 5H), 6.95−6.75 (m, 2H), 4.39−4.17 (m, 1H), 4.05−3.90 (m, 1H), 3.78−3.68 (m, 3H), 3.67−3.51 (m, 2H), 2.31 (s, 1H); 13C {1H} NMR (101 MHz, CDCl3): δ 192.6, 165.3, 158.2, 138.2, 135.9, 129.0, 128.3, 127.3, 125.3, 119.4, 118.9, 109.5, 80.4, 78.0, 72.6, 53.7, 33.3, 32.4. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.6 mL/ min, λ = 254 nm), tR = 25.00 min (minor), tR = 26.82 min (major), 88% ee; [α]20 D = −301.7 (c 0.93, CHCl3); HRMS (Orbitrap-ESI) m/ z: calcd [M + H]+ for C20H18NO3S, 352.1002; found [M + H]+, 352.0999. Methyl (R)-1-Acetyl-2-((2-chlorophenyl)thio)-3-oxoindoline-2carboxylate (3v). White solid; reaction time: 2 h; yield: 80% (30.0 mg); mp 176−177 °C; 1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 7.6 Hz, 1H), 7.70−7.40 (m, 3H), 7.20−7.10 (m, 1H), 7.09− 6.91 (m, 3H), 3.88 (s, 3H), 2.56 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 190.7, 169.3, 164.9, 153.6, 141.0, 139.8, 137.8, 131.9, 130.1, 126.9, 124.6, 124.2, 121.5, 118.1, 54.6, 24.6. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.6 mL/min, λ = 254 nm), tR = 27.41 min (major), tR = 36.57 min (minor), 62% ee; [α]20 D = −136.3 (c 0.48, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C18H15ClNO4S, 376.0405; found [M + H]+, 376.0401. Methyl (R)-1-Acetyl-2-((2,4-dimethylphenyl)thio)-3-oxoindoline2-carboxylate (3w). White solid; reaction time: 2 h; yield: 70% (25.8 mg); mp 114−115 °C; 1H NMR (400 MHz, CDCl3): δ 8.35 (d, J = 8.0 Hz, 1H), 7.61−7.39 (m, 2H), 7.15 (d, J = 7.2 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.76 (s, 1H), 6.66 (d, J = 8.0 Hz, 1H), 3.88 (s, 3H), 2.55 (s, 3H), 2.33 (s, 3H), 2.09 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 191.0, 169.2, 165.2, 153.5, 143.9, 140.8, 138.2, 137.5, 131.2, 126.9, 124.4, 124.0, 121.5, 118.0, 54.4, 24.6, 20.9, 20.7. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.6 mL/min, λ = 254 nm), tR = 16.96 min (major), tR = 20.20 min (minor), 6% ee; [α]20 D = −12.3 (c 0.52, CHCl3); HRMS (OrbitrapESI) m/z: calcd [M + H]+ for C20H20NO4S, 370.1108; found [M + H]+, 370.1103. Methyl (R)-1-Acetyl-2-((4-methoxyphenyl)thio)-3-oxoindoline-2carboxylate (3x). White solid; reaction time: 2 h; yield: 83% (30.8 mg); mp 142−143 °C; 1H NMR (400 MHz, CDCl3): δ 8.31 (d, J = 7.4 Hz, 1H), 7.60−7.40 (m, 2H), 7.23−7.15 (m, 2H), 7.02 (t, J = 7.6 Hz, 1H), 6.60−6.40 (m, 2H), 3.86 (s, 3H), 3.62 (s, 3H), 2.54 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 191.5, 169.5, 165.1, 161.6, 154.0, 138.7, 137.9, 124.7, 124.4, 121.8, 118.3, 116.4, 114.5, 55.5, 54.7, 25.0. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.6 mL/min, λ = 254 nm), tR = 30.56 min (major), tR = 45.27 min (minor), 56% ee; [α]D20 = −120.7 (c 0.53, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C19H18NO5S, 372.0900; found [M + H]+, 372.0896. Methyl (R)-1-Acetyl-2-((4-bromophenyl)thio)-3-oxoindoline-2carboxylate (3y). White solid; reaction time: 2 h; yield: 86% (35.9 mg); mp 178−179 °C; 1H NMR (400 MHz, CDCl3): δ 8.32

24.0, 22.8, 21.3, 13.4. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.6 mL/min, λ = 254 nm), tR = 14.91 min (major), tR = 16.39 min (minor), 91% ee; [α]20 D = −309.6 (c 0.52, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C15H18NO4S, 308.0951; found [M + H]+, 308.0949. Methyl (R)-1-Acetyl-2-(benzylthio)-5-chloro-3-oxoindoline-2carboxylate (3o). White solid; reaction time: 2 h; yield: 87% (33.8 mg); mp 102−103 °C; 1H NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 7.65−7.58 (m, 2H), 7.20−7.13 (m, 3H), 7.08−7.00 (m, 2H), 3.83 (d, J = 13.2 Hz, 1H), 3.82 (s, 3H), 3.69 (d, J = 13.2 Hz, 1H), 2.38 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 189.2, 168.7, 164.8, 137.6, 134.9, 130.5, 128.8, 128.5, 127.5, 124.1, 119.9, 77.2, 54.5, 34.0, 24.4. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 98/2, flow rate 0.6 mL/min, λ = 254 nm), tR = 47.05 min (minor), tR = 51.06 min (major), 92% ee; [α]20 D = −179.7 (c 0.49, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H] + for C19H 17ClNO4S, 390.0561; found [M + H]+, 390.0557. Methyl (R)-1-Acetyl-2-(benzylthio)-5-bromo-3-oxoindoline-2carboxylate (3p). White solid; reaction time: 2 h; yield: 88% (38.2 mg); mp 112−113 °C; 1H NMR (400 MHz, CDCl3): δ 8.43 (s, 1H), 7.76 (d, J = 6.7 Hz, 2H), 7.23−6.94 (m, 5H), 3.82 (d, J = 6.6 Hz, 4H), 3.68 (dd, J = 13.2 Hz, J = 6.4 Hz, 1H), 2.37 (s, 3H); 13 C {1H} NMR (101 MHz, CDCl3): δ 189.2, 169.2, 164.9, 140.6, 135.1, 128.9, 128.6, 127.6, 127.3, 123.3, 120.5, 117.9, 77.3, 54.7, 34.1, 24.5. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.6 mL/ min, λ = 254 nm), tR = 25.49 min (minor), tR = 28.05 min (major), 80% ee; [α]20 D = −284.2 (c 0.50, CHCl3); HRMS (Orbitrap-ESI) m/ z: calcd [M + H]+ for C19H17BrNO4S, 434.0056; found [M + H]+, 434.0053. Methyl(R)-1-Acetyl-5-bromo-2-((2-bromobenzyl)thio)-3-oxoindoline-2-carboxylate (3q). White solid; reaction time: 2 h; yield: 80% (41.0 mg); mp 93−94 °C; 1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.25−7.15 (m, 2H), 7.12−7.04 (m, 1H), 3.94 (d, J = 12.4 Hz, 1H), 3.84 (s, 3H), 3.80 (d, J = 12.4 Hz, 1H), 2.41 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 189.0, 168.8, 164.7, 140.7, 134.5, 133.0, 131.2, 127.7, 127.3, 124.6, 117.9, 77.2, 54.6, 33.9, 24.5. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 98/2, flow rate 0.6 mL/min, λ = 254 nm), tR = 55.67 min (minor), tR = 58.66 min (major), 94% ee; [α]20 D = −191.3 (c 0.51, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + NH 4 ] + for C19H19Br2N2O4S, 530.9406; found [M + NH4]+, 530.9404. Methyl (R)-1-Acetyl-5-bromo-2-(ethylthio)-3-oxoindoline-2-carboxylate (3r). White solid; reaction time: 2 h; yield: 88% (32.6 mg); mp 85−86 °C; 1H NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.8 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 3.83 (s, 3H), 2.63−2.45 (m, 2H), 2.43 (s, 3H), 1.14 (t, J = 7.6 Hz, 3H); 13 C {1H} NMR (101 MHz, CDCl3): δ 189.3, 169.2, 164.8, 151.9, 140.6, 127.3, 123.2, 120.1, 117.9, 77.2, 54.4, 24.4, 22.9, 13.4. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.6 mL/min, λ = 254 nm), tR = 15.02 min (major), tR = 16.25 min (minor), 90% ee; [α]20 D = −163.5 (c 0.51, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C14H15BrNO4S, 371.9900; found [M + H]+, 371.9897. Methyl(R)-6-Acetyl-5-(benzylthio)-4-oxo-5,6-dihydro-4H-thieno[2,3-b]pyrrole-5-carboxylate (3s). White solid; reaction time: 2 h; yield: 94% (33.9 mg); mp 153−154 °C; 1H NMR (400 MHz, CDCl3): δ 7.25−7.15 (m, 3H), 7.10−6.90 (m, 4H), 3.84 (s, 3H), 3.77 (d, J = 13.6 Hz, 1H), 3.60 (d, J = 13.6 Hz, 1H), 2.34 (s, 3H); 13 C {1H} NMR (101 MHz, CDCl3): δ 181.2, 169.0, 165.8, 163.9, 135.1, 128.6, 128.4, 127.6, 124.7, 124.6, 117.2, 83.6, 54.6, 34.0, 21.9. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.6 mL/min, λ = 254 nm), tR = 43.50 min (major), tR = 51.46 min (minor), 81% ee; 8174

DOI: 10.1021/acs.joc.9b01142 J. Org. Chem. 2019, 84, 8168−8176

Article

The Journal of Organic Chemistry (s, 1H), 7.65−7.40 (m, 2H), 7.20−7.10 (m, 4H), 7.08 (t, J = 7.2 Hz, 1H), 3.86 (s, 3H), 2.54 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 190.6, 170.2, 164.7, 138.4, 138.0, 131.9, 125.5, 124.8, 124.3, 118.1, 54.6, 24.7. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.6 mL/min, λ = 254 nm), tR = 32.10 min (major), tR = 51.33 min (minor), 68% ee; [α]20 D = −128.9 (c 0.50, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H] + for C18H15BrNO 4S, 419.9900; found [M + H]+, 419.9895. Methyl (R)-3-Oxo-1-(prop-2-yn-1-yl)-2-(p-tolylthio)indoline-2carboxylate (3z). White solid; reaction time: 7 h; yield: 85% (29.8 mg); mp 114−115 °C; 1H NMR (400 MHz, CDCl3): δ 7.45−7.35 (m, 2H), 7.35−7.21 (m, 2H), 6.93−6.87 (m, 2H), 6.87− 6.81 (m, 1H), 6.70 (s, 1H), 4.53 (dd, J = 18.2, J = 2.4 Hz, 1H), 4.28 (dd, J = 18.2, J = 2.4 Hz, 1H), 3.77 (s, 3H), 2.31 (s, 1H), 2.18 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 192.6, 165.3, 158.4, 140.0, 137.8, 136.5, 129.7, 129.4, 126.4, 125.1, 123.4, 119.0, 108.8, 82.6, 77.8, 72.5, 53.6, 32.7, 21.1. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 98/2, flow rate 0.6 mL/min, λ = 254 nm), tR = 51.14 min (major), tR = 48.61 min (minor), 31% ee; [α]20 D = −173.9 (c 0.51, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C20H18NO3S, 352.1002; found [M + H]+, 352.0995. Methyl(R)-1-Acetyl-2-(benzylsulfonyl)-5-bromo-3-oxoindoline-2carboxylate (4p). White solid; reaction time: 4 h; yield: 88% (40.9 mg); mp 92−93 °C; 1H NMR (400 MHz, CDCl3): δ 8.15 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 7.43−7.33 (m, 5H), 5.06 (d, J = 13.6 Hz, 1H), 4.96 (d, J = 13.6 Hz, 1H), 3.90 (s, 3H), 2.48 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 188.4, 168.5, 162.0, 141.0, 132.1, 129.4, 128.8, 128.3, 124.8, 118.4, 88.6, 57.5, 54.4, 24.7. The enantiomeric excess was determined by HPLC with an OD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.6 mL/min, λ = 254 nm), tR = 36.12 min (major), tR = 53.67 min (minor), 80% ee; [α]20 D = −480.6 (c 0.51, CHCl3); HRMS (Orbitrap-ESI) m/z: calcd [M + H]+ for C19H17BrNO6S, 465.9955; found [M + H]+, 465.9955.

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graduate Training Program for Innovation & Entrepreneurship of Guizhou Province (no. 2018520343) are also acknowledged.

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(1) (a) Pedras, M. S. C.; Sarma-Mamillapalle, V. K. The cruciferous phytoalexins rapalexin A, brussalexin A and erucalexin: Chemistry and metabolism in Leptosphaeria maculans. Bioorg. Med. Chem. 2012, 20, 3991−3996. (b) Pedras, M. S. C.; Suchy, M.; Ahiahonu, P. W. K. Unprecedented chemical structure and biomimetic synthesis of erucalexin, a phytoalexin from the wild crucifer Erucastrum gallicum. Org. Biomol. Chem. 2006, 4, 691−701. (c) Forseth, R. R.; Fox, E. M.; Chung, D.; Howlett, B. J.; Keller, N. P.; Schroeder, F. C. Identification of Cryptic Products of the Gliotoxin Gene Cluster Using NMR-Based Comparative Metabolomics and a Model for Gliotoxin Biosynthesis. J. Am. Chem. Soc. 2011, 133, 9678−9681. (d) Park, H. B.; Kwon, H. C.; Lee, C.-H.; Yang, H. O. Glionitrin A, an Antibiotic−Antitumor Metabolite Derived from Competitive Interaction between Abandoned Mine Microbes. J. Nat. Prod. 2009, 72, 248−252. (e) Begg, W. R.; Elix, J. A.; Jones, A. J. Nonacyclic amides from lichens of the genus. Tetrahedron Lett. 1978, 19, 1047−1050. (f) Ernst-Russell, M. A.; Elix, J. A.; Chai, C. L. L.; Hockless, D. C. R.; Hurne, A. M.; Waring, P. Structure Revision and Cytotoxic Activity of the Scabrosin Esters, Epidithiopiperazinediones from the Lichen Xanthoparmelia scabrosa. Aust. J. Chem. 1999, 52, 279−283. (2) (a) Chauhan, P.; Mahajan, S.; Enders, D. Organocatalytic Carbon-Sulfur Bond-Forming Reactions. Chem. Rev. 2014, 114, 8807−8864. (b) Lu, H.-H.; Zhang, F.-G.; Meng, X.-G.; Duan, S.-W.; Xiao, W.-J. Enantioselective Michael Reactions of β, β-Disubstituted Nitroalkenes: A New Approach to β2,2-Amino Acids with HeteroQuaternary Stereocenters. Org. Lett. 2009, 11, 3946−3949. (c) Leow, D.; Lin, S.; Chittimalla, S. K.; Fu, X.; Tan, C.-H. Enantioselective Protonation Catalyzed by a Chiral Bicyclic Guanidine Derivative. Angew. Chem., Int. Ed. 2008, 47, 5641− 5645. (d) Liu, Y.; Sun, B.; Wang, B.; Wakem, M.; Deng, L. Catalytic Asymmetric Conjugate Addition of Simple Alkyl Thiols to α,βUnsaturatedN-Acylated Oxazolidin-2-ones with Bifunctional Catalysts. J. Am. Chem. Soc. 2009, 131, 418−419. (e) Kimmel, K. L.; Robak, M. T.; Ellman, J. A. Enantioselective Addition of Thioacetic Acid to Nitroalkenes viaN-Sulfinyl Urea Organocatalysis. J. Am. Chem. Soc. 2009, 131, 8754−8755. (f) Tian, X.; Cassani, C.; Liu, Y.; Moran, A.; Urakawa, A.; Galzerano, P.; Arceo, E.; Melchiorre, P. Diastereodivergent Asymmetric Sulfa-Michael Additions of αBranched Enones using a Single Chiral Organic Catalyst. J. Am. Chem. Soc. 2011, 133, 17934−17941. (3) For selected examples of asymmetric α-sulfenylation, see: (a) Qiao, B.; Liu, X.; Duan, S.; Yan, L.; Jiang, Z. Highly Enantioselective Organocatalytic α-Sulfenylation of Azlactones. Org. Lett. 2014, 16, 672−675. (b) Zhao, G.-L.; Rios, R.; Vesely, J.; Eriksson, L.; Córdova, A. Organocatalytic Enantioselective Aminosulfenylation of α,β-Unsaturated Aldehydes. Angew. Chem., Int. Ed. 2008, 47, 8468−8472. (c) Wang, X.; Yang, T.; Cheng, X.; Shen, Q. Enantioselective Electrophilic Trifluoromethylthiolation of β-Ketoesters: A Case of Reactivity and Selectivity Bias for Organocatalysis. Angew. Chem., Int. Ed. 2013, 52, 12860−12864. (d) Zhu, X.-L.; Xu, J.-H.; Cheng, D.-J.; Zhao, L.-J.; Liu, X.-Y.; Tan, B. In Situ Generation of Electrophilic Trifluoromethylthio Reagents for Enantioselective Trifluoromethylthiolation of Oxindoles. Org. Lett. 2014, 16, 2192−2195. (e) Huang, L.; Li, J.; Zhao, Y.; Ye, X.; Liu, Y.; Yan, L.; Tan, C.-H.; Liu, H.; Jiang, Z. Chiral Bicyclic GuanidineCatalyzed Enantioselective Sulfenylation of Oxindoles and Benzofuran-2(3H)-ones. J. Org. Chem. 2015, 80, 8933−8941. (f) Denmark, S. E.; Jaunet, A. Catalytic, Enantioselective, Intramolecular Carbosulfenylation of Olefins. J. Am. Chem. Soc. 2013, 135, 6419−6422. (g) Denmark, S. E.; Chi, H. M. Catalytic, Enantioselective, Intramolecular Carbosulfenylation of Olefins. Mechanistic Aspects: A Remarkable Case of Negative Catalysis. J. Am. Chem. Soc. 2014,

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b01142. 1 H NMR, 13C NMR spectra for 3a−z and 4p; 19F NMR spectra for 3f; HPLC of 3a−z and 4p; X-ray structures of 3c (PDF) Crystallographic data of 3a (CIF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

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

Yong-Long Zhao: 0000-0002-9751-1602 Peng-Fei Xu: 0000-0002-5746-758X Yuan-Yong Yang: 0000-0003-1878-6614 Author Contributions §

Y.-L. Z. and X.-H. F. made equal contribution to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (grants. 21502030, 21662010, 81660348 and 81703356) and PhD early development program of Guizhou Medical University (J[2014]017). Financial support from the Science & Technology Program of Guizhou Province (QKHPTRC[2018]5779-68) and Under8175

DOI: 10.1021/acs.joc.9b01142 J. Org. Chem. 2019, 84, 8168−8176

Article

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DOI: 10.1021/acs.joc.9b01142 J. Org. Chem. 2019, 84, 8168−8176