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Article

Zinc-Catalyzed Enantioselective [3 + 3] Annulation for Synthesis of Chiral Spiro[indoline-3,4′-thiopyrano[2,3-b]indole] Derivatives

by
Tian-Tian Liu
,
Yu Chen
,
Guang-Jian Mei
,
Yuan-Zhao Hua
*,
Shi-Kun Jia
* and
Min-Can Wang
*
Green Catalysis Center, College of Chemistry, Zhengzhou University, Zhengzhou 450001, China
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(3), 1056; https://doi.org/10.3390/molecules28031056
Submission received: 15 December 2022 / Revised: 12 January 2023 / Accepted: 16 January 2023 / Published: 20 January 2023
(This article belongs to the Special Issue Recent Advances of Catalytic Asymmetric Synthesis)
Browse Figures
Versions Notes

Abstract

:
With a dinuclear zinc-ProPhenol complex as a catalyst, an efficient and novel [3 + 3] annulation of indoline-2-thiones and isatylidene malononitriles has been successfully developed via the Brønsted base and Lewis acid cooperative activation model. This practical methodology gives access to a broad range of chiral spiro[indoline-3,4′-thiopyrano[2,3-b]indole] derivatives in good yields with excellent levels of enantioselectivities (up to 88% yield and 99% ee).

1. Introduction

Sulfur-containing heterocyclic compounds are prevalent in various numerous pharmaceutically useful molecules and natural products [1,2,3]. Among these, the thiopyran fused indole skeleton is an attractive structural moiety because of its remarkable biological activities [4,5,6]. For instance, the tetrahydrothiopyrano [2,3-b]indole (THTPI) derivatives exhibit analgesic activities. On the other hand, the oxindole frameworks bearing a spirocyclic quaternary stereocenter at the C3 position [7,8,9,10,11] are very privileged heterocyclic motifs owing to their wide ranging biological significance and high versatility as important building blocks. They have attracted widespread attention from chemists for their intrinsic complexity as well as rigidity. As is expected, integrating these two bioactive moieties to generate a fascinating spirocyclic skeleton, spiro[indoline-3,4′-thiopyrano[2,3-b]indole], would be synthetically valuable and pharmaceutically desirable, and might offer a structurally diversified molecules library for drug discovery.
The Friedel–Crafts reaction [12,13] has emerged as a powerful chemical tool for the construction of new C–C bonds, and it has been widely used to realize asymmetric transformations of aromatics and heteroaromatics [14,15]. In the past few years, dinuclear metal-ProPhenol catalysts, which feature both Lewis acidic and Brønsted basic sites, have emerged as a powerful chemical tool for asymmetric transformations and attracted much attention in this field [16,17,18]. For instance, the Trost group [19] first reported the use of a dinuclear zinc complex in Friedel–Crafts alkylations of unprotected pyrroles with nitroalkenes via deprotonation of the amino group in 2008. Subsequently, the same strategy was successfully applied to the catalytic asymmetric Friedel–Crafts alkylations of unprotected pyrroles [20] and indoles [21,22,23] with various electrophiles. Recently, our group [24] uncovered an enantioselective Friedel–Crafts alkylation/cyclization with a dinuclear zinc complex through deprotonation of the phenolic hydroxyl group of 3-aminophenols. However, the catalytic generation of active carbon nucleophiles from thioamides via deprotonation of the sulfydryl group with the dinuclear zinc catalysts (Scheme 1a) is underexplored.
Thioamides are widely utilized as useful precursors for the synthesis of a broad range of heterocyclic compounds by exploiting their multiple nucleophilic characters [25]. The employment of thioamides as carbon pronucleophiles in enantioselective C-C bond-forming reactions is challenging in view of the competitions of the S–H functionalization or the N–H functionalization. To solve this problem, the Shibasaki group [26,27,28,29,30,31,32,33] strategically developed a soft Lewis acid/Brønsted base cooperative catalyst to generate the active carbon nucleophile from thioamides by exploiting the soft Lewis basic nature of the sulfur atom. As a kind of thioamides, indoline-2-thiones usually serve as 1,3-binucleophilic synthons for the construction of various indole-fused sulfur-containing ring structures [34,35,36]. In recent years, many asymmetric organocatalytic strategies [37,38,39,40,41,42,43] successfully applied to the indoline-2-thiones involved cascade annulations. For example, in 2014, Wang group [37] developed a highly efficient asymmetric cascade thio-Michael cyclization reaction by a DPEN-derived chiral thiourea. However, there are no reports on metal-catalyzed asymmetric cascade annulations of the indoline-2-thiones. Herein, we describe the application of Bronsted base and Lewis acid cooperative activation [44,45,46,47] to the synthesis of spiro[indoline-3,4′-thiopyrano[2,3-b]indole] derivatives via the Friedel–Crafts alkylation/cyclization tandem reactions of indoline-2-thiones and isatylidene malononitriles [48,49,50,51] (Scheme 1b).

2. Results

2.1. Optimization of Reaction Conditions

Initially, we investigated the reaction of 1-methylindoline-2-thione 1a and 2-(2-oxoindolin-3-ylidene)malononitrile 2a in the presence of 10 mol % of dinuclear zinc catalyst in situ generated from 10 mol % of ligand L1 and 20 mol % of ZnEt2 in tetrahydrofuran (THF) at rt. Delightfully, the cascade [3 + 3] annulation process proceeded smoothly to furnish the desired spirocyclic product 3a in 57% yield and 80% enantioselectivity (Table 1, entry 1). Encouraged by those promising results, we next examined a series of chiral ligands, including ProPhenol ligands (L2–L5) and AzePhenol ligands (L7–L9). The screening results indicated that CF3 substituted ProPhenol ligands were better promotors compared with other substitutional groups, and L4 bearing 4-CF3C6H4 group was proven to be the best choice for this cascade transformation, which provided the cyclization product 3a in 85% yield and 99% ee (Table 1, entry 4).

2.2. Substrate Scope

With the optimized reaction conditions in hand, we first examined the substrate scope of indoline-2-thiones 1 by reacting with 2-(2-oxoindolin-3-ylidene)malononitrile 2a, and the results are summarized in Scheme 2. Firstly, the influence of the N-protecting groups of indoline-2-thiones was investigated. Interestingly, when the N-H indoline-2-thiones was tried, the corresponding product 3b was produced in 73% yield and 90% ee. As for the substrates of N-ethyl, N-benzyl, N-allyl substituted indoline-2-thiones, all the [3 + 3] annulations gave the expected products 3c–3e in 65–83% yields and 94–99% ee values, respectively. Subsequently, indoline-2-thiones 1 bearing substituents (from electron donating to electron with-drawing) at the C-5 position were well tolerated for this cyclization, which furnished the corresponding products 3f–3j in 45–63% yields with 87–99% ee values. Furthermore, substitutions at the 6-position (6-Cl and 6-Br) and 7-position (7-F and 7-Br) were also tolerated, giving the corresponding products 3k–3n in good yields with 85–99% ee values. It was worth noting that the Br substituent at the 5 or 7-position of the indoline-2-thione had a negative effect on both the yield and enantioselectivity. Gratifyingly, 5,7-diMe substituted indoline-2-thione could also be subject to this transformation, delivering the annulation product 3o in 68% yield and 99% ee.
Next, we explored the substrate generality of isatylidene malononitriles in this [3 + 3] annulation by focusing our attention on the reaction of the 1-methylindoline-2-thione 1a with various isatylidene malononitriles 2, and the results are summarized in Scheme 3. In general, all the reactions proceeded favourably to afford the desired products in good yields. It was proven that the isatylidene malononitriles bearing electron-withdrawing or -donating groups at the 5-, 6-, and 7-positions were well tolerated for this transformation, which furnished the corresponding products 3p–3x in 50–88% yields with 90–99% ee values.

2.3. X-ray Diffraction Analysis

The relative and absolute configurations of the product 3g were unequivocally determined as R by single crystal X-ray diffraction analysis [52] and applied to all other products 3 (Figure 1). Single crystal X-ray diffraction is shown in Supplementary Materials Figure S54.

2.4. Gram-Scale Reaction and Derivation

To demonstrate the potential utility of this methodology, a gram-scale synthesis of 1a (4 mmol) and 2a (4 mmol) was performed, and the [3 + 3] annulation reactions occurred smoothly under standard conditions, giving the spiro[indoline-3,4′-thiopyrano[2,3-b]indole] 3a in 75% yield (1.07 g) and 99% ee (Scheme 4a). Further transformation of 3i was preformed, the cyano and amino groups of 3i underwent annulations with acetic anhydride in pyridine, affording cyclization product 4 in 58% yield and 99% ee (Scheme 4b).

2.5. Plausible Mechanism

Based on the experimental results and previous literature reports [24,53], a plausible reaction mechanism for this Friedel–Crafts alkylation/cyclization is illustrated in Scheme 5. First, the dinuclear zinc complex Zn2EtL4 was prepared in situ when ligand L4 is treated with 2 equiv of Et2Zn. Then, indoline-2-thione 1a was converted into its thioenolate form via the deprotonation process by the dinuclear zinc complex, along with the release of 1 equiv of ethane. Subsequently, the coordination of alkylidene azlactone 2a from the less hindered face to both zinc atoms led to the formation of intermediate A, which underwent the Michael addition reaction and proton shift to afford the complex B. Next, an intramolecular thio-Pinner reaction proceeded to furnish the annulation. Finally, the catalytic cycle was restarted after a proton exchange of intermediate C with another indoline-2-thione 1a, followed by the release of the activated species A and spiro[indoline-3,4′-thiopyrano[2,3-b]indole] 3a.

3. Conclusions

In conclusion, we disclose a novel and efficient asymmetric tandem [3 + 3] annulation of indoline-2-thiones and isatylidene malononitriles. Using the chiral metal catalyst, a series of optically pure spiro[indoline-3,4′-thiopyrano[2,3-b]indole] derivatives were obtained with good to excellent yields and enantioselectivities under mild conditions. To demonstrate the promising applicability of the methodology, a gram-scale experiment, and the derivatization of the product were also successfully performed. A Brønsted base and Lewis acid cooperatively activate activation mode was proposed and further investigations in the polyfunctional heterocycles are ongoing in our laboratory.

4. Materials and Methods

4.1. General Information

All reactions were carried out under an atmosphere of argon using oven-dried glassware. Super dry solvents and metal catalysts were purchased from chemical companies and used without further treatment. Flash column chromatography was performed using silica gel (300–400 mesh). 1H NMR,13C NMR, 19F NMR spectra were recorded in DMSO-d6 on a 400 MHz spectrometer; chemical shifts are reported in ppm with the solvent signals as reference, and coupling constants (J) are given in Hertz. NMR spectra are given in the Supplementary Materials Figures S1–S28. The peak information is described as: s = singlet, d = doublet, t = triplet, q = quartet, m= multiplet. High-resolution mass spectra (HRMS) were obtained using an Agilent LC-MSAD-Trap-XCT instrument (Shanghai, China) using electrospray ionization time-of-flight (ESI-TOF). The high performance liquid chromatography (HPLC) performed on instrument consisted of the JASCO model PU-1580 intelligent HPLC pump (Zhengzhou, China) and the JASCO model UV-1575 intelligent UV-vis detector (254 nm) (Zhengzhou, China) using Daicel Chiralpak IA (4.6 mm × 250 mm) columns (Shanghai, China).HPLC are shown in Supplementary Materials Figures S29–S53. Melting points were determined using YRT-3 melting point apparatus. Optical rotations were measured with Perkin Elmer, model 341 Polarimeter (Zhengzhou, China). The instrumentation used for the crystal measurement is Bruker APEX-II CCD (Shanghai, China).

4.2. Materials

Indoline-2-thiones [54] and isatylidene malononitriles [55] were synthesized according to the literature. Other reagents were obtained from commercial sources and used without further purification.

4.3. Procedure for the Asymmetric Synthesis of Compound 3

Under a nitrogen atmosphere, a solution of diethylzinc (40 μL, 1.0 M in hexane, 0.04 mmol) was added dropwise to a solution of L4 (0.02 mmol, 19.0 mg) in THF (2 mL). After the mixture was stirred for 30 min at room temperature, 1-methylindoline-2-thione 1a (0.2 mmol, 32.6 mg) and 2-(2-oxoindolin-3-ylidene) malononitrile 2a (0.2 mmol, 39.1 mg) were added. The reaction mixture was stirred for 24 h at the same temperature. The reaction was quenched with a HCl solution (1 M, 2 mL), and the organic layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic layer was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure by using a rotary evaporator. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (2:1) to afford the desired product 3.
(R)-2′-amino-9′-methyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3a). We followed the general procedure, using 1a (0.2 mmol, 32.6 mg), 2a (0.2 mmol, 39.1 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3a as a yellow solid (60.9 mg, 85% yield); [α]D20 = −3.21 (c = 1.0, EA, 99% ee); m.p. = 267.0–267.9 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.32 − 7.24 (m, 1H), 7.17 (s, 2H), 7.11 − 6.98 (m, 3H), 6.97 − 6.91 (m, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.36 (d, J = 8.1 Hz, 1H), 3.70 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.3, 152.8, 142.0, 137.9, 134.1, 129.5, 125.5, 125.3, 124.4, 123.0, 121.8, 120.3, 118.0, 117.2, 110.3, 110.0, 103.3, 72.4, 52.3, 30.7; HRMS (ESI): m/z [M + H]+ calcd for [C20H15N4OS]+: 359.0961, found: 359.0959; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 12.28 min and tminor = 29.95 min.
(R)-2′-amino-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3b). We followed the general procedure, using 1b (0.2 mmol, 30.1 mg), 2a (0.2 mmol, 39.1 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3b as a yellow solid (50.2 mg, 73% yield); [α]D20 =−10.69 (c = 1.0, EA, 90% ee); m.p. = 271.0–271.9 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 10.72 (s, 1H), 7.29 (m, 2H), 7.06 (s, 2H), 7.02 − 6.92 (m, 4H), 6.75 (t, J = 7.5 Hz, 1H), 6.37 (d, J = 8.0 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 178.4, 153.6, 142.0, 136.9, 134.2, 129.4, 125.4, 124.7, 123.02, 122.95, 121.8, 120.0, 118.1, 117.0, 111.5, 110.2, 103.7, 72.1, 51.9; HRMS (ESI): m/z [M + H]+ calcd for [C19H13N4OS]+: 345.0805, found: 345.0805; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tminor = 9.50 min, and tmajor = 23.29 min.
(R)-2′-amino-9′-ethyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3c). We followed the general procedure, using 1c (0.2 mmol, 35.2 mg), 2a (0.2 mmol, 39.1 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3c as a yellow solid (46.9 mg, 65% yield); [α]D20 = −25.56 (c = 1.0, EA, 99% ee); m.p. = 265.5–266.4 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.16 (s, 2H), 7.08 − 6.99 (m, 3H), 6.96 (m, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 4.17 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.2, 152.7, 142.0, 136.9, 134.1, 129.5, 125.5, 124.6, 124.2, 123.0, 121.9, 120.3, 118.0, 117.3, 110.3, 109.9, 103.5, 72.5, 52.2, 39.2, 15.4; HRMS (ESI): m/z [M + H]+ calcd for [C21H17N4OS]+: 373.1118, found: 373.1120; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 10.44 min, and tminor = 31.64 min.
(R)-2′-amino-9′-benzyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3d). We followed the general procedure, using 1d (0.2 mmol, 48.2 mg), 2a (0.2 mmol, 39.1 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3d as a yellow solid (72.1 mg, 83% yield); [α]D20 = −4.78 (c = 1.0, EA, 94% ee); m.p. = 247.9–248.6 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.38 − 7.28 (m, 4H), 7.13 (m, 4H), 7.07 − 7.01 (m, 3H), 6.99 − 6.94 (m, 1H), 6.81 (t, J = 7.8 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 5.43 (s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 178.2, 152.7, 142.0, 137.7, 137.4, 134.1, 129.6, 129.3, 128.1, 127.0, 125.5, 125.1, 124.7, 123.0, 122.1, 120.6, 117.9, 117.4, 110.34, 110.31, 104.1, 72.4, 52.3, 47.4; HRMS (ESI): m/z [M + H]+ calcd for [C26H19N4OS]+: 435.1274, found: 435.1275; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 11.92 min, and tminor = 39.08 min.
(R)-9′-allyl-2′-amino-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3e). We followed the general procedure, using 1e (0.2 mmol, 35.5 mg), 2a (0.2 mmol, 39.1 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3e as a yellow solid (59.9 mg, 78% yield); [α]D20 = −47.31 (c = 1.0, EA, 98% ee); m.p. = 292.1–292.9 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.28 (m, 1H), 7.13 (s, 2H), 7.10 − 6.98 (m, 3H), 6.94 (t, J = 7.5 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 6.26 − 5.46 (m, 1H), 5.33 − 4.99 (m, 1H), 5.00 − 4.84 (m, 1H), 4.79 (d, J = 4.4 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 176.3, 150.9, 140.1, 135.5, 132.2, 131.5, 127.6, 123.5, 123.0, 122.6, 121.1, 120.0, 118.5, 116.0, 115.6, 115.4, 108.4, 108.3, 102.0, 70.5, 50.3, 44.5; HRMS (ESI): m/z [M + H]+ calcd for [C22H17N4OS]+: 385.1118, found: 385.1117; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 10.18 min, and tminor = 31.62 min.
(R)-2′-amino-6′-methoxy-9′-methyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3f). We followed the general procedure, using 1f (0.2 mmol, 39.3 mg), 2a (0.2 mmol, 39.1 mg), and L4 (0.02 mmol, 19.1 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3f as a yellow solid (47.3 mg, 61% yield); [α]D20 = + 1.92 (c = 1.0, EA, 99% ee); m.p. = 278.1–278.9 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 7.37 − 7.27 (m, 2H), 7.18 (s, 2H), 7.06 − 6.94 (m, 3H), 6.74 − 6.65 (m, 1H), 5.76 (d, J = 2.4 Hz, 1H), 3.66 (s, 3H), 3.43 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.2, 154.0, 153.1, 142.2, 133.9, 133.2, 129.6, 125.63, 125.55, 124.8, 123.0, 118.1, 110.63, 110.58, 110.1, 102.8, 100.1, 72.1, 55.4, 52.2, 30.8; HRMS (ESI): m/z [M + H]+ calcd for [C21H17N4O2S]+: 389.1067, found: 389.1075; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 14.13 min, and tminor = 32.41 min.
(R)-2′-amino-6′,9′-dimethyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3g). We followed the general procedure, using 1g (0.2 mmol, 35.6 mg), 2a (0.2 mmol, 39.1 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3g as a yellow solid (41 mg, 55% yield); [α]D20 = −9.26 (c = 1.0, EA, 99% ee); m.p. = 283.6–284.4 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.39 − 7.24 (m, 2H), 7.15 (s, 2H), 7.09 − 6.98 (m, 2H), 6.95 (m, 1H), 6.88 (d, J = 10.1 Hz, 1H), 6.11 (s, 1H), 3.67 (s, 3H), 2.11 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.3, 152.8, 142.0, 136.4, 134.2, 129.5, 128.7, 125.4, 125.0, 124.6, 123.2, 123.0, 118.0, 117.0, 110.2, 109.7, 102.8, 72.4, 52.3, 30.7, 21.7; HRMS (ESI): m/z [M + Na]+ calcd for [C21H16N4OSNa]+: 395.0937, found: 395.0944; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 11.09 min, and tminor = 23.70 min.
(R)-2′-amino-6′-fluoro-9′-methyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3h). We followed the general procedure, using 1h (0.2 mmol, 36.2 mg), 2a (0.2 mmol, 39.1 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3h as a yellow solid (47.4 mg, 63% yield); [α]D20 = −2.59 (c = 1.0, EA, 99% ee); m.p. = 296.8–297.4 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 7.47 (m, 1H), 7.32 (t, J = 8.3 Hz, 1H), 7.24 (s, 2H), 7.12 − 7.01 (m, 2H), 7.01 − 6.89 (m, 2H), 6.14 − 5.72 (m, 1H), 3.71 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.0, 157.5 (d, J = 233.4 Hz), 152.8, 142.0, 134.6, 133.5, 129.8, 127.5, 125.6, 124.4 (d, J = 10.4 Hz), 123.1, 117.9, 111.4 (d, J = 10.1 Hz), 110.3, 109.7 (d, J = 26.0 Hz), 103.3 (d, J = 4.4 Hz), 102.0 (d, J = 24.6 Hz), 72.0, 52.1, 31.0; 19F NMR (376 MHz, DMSO-d6) δ -124.46; HRMS (ESI): m/z [M + H]+ calcd for [C20H14FN4OS]+: 377.0867, found: 377.0868; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 11.12 min, and tminor = 34.71 min.
(R)-2′-amino-6′-chloro-9′-methyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3i). We followed the general procedure, using 1i (0.2 mmol, 39.6 mg), 2a (0.2 mmol, 39.1 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3i as a yellow solid (46.4 mg, 59% yield); [α]D20 = −6.15 (c = 1.0, EA, 99% ee); m.p. = 289.8–290.7 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.33 (t, J = 8.3 Hz, 1H), 7.25 (s, 2H), 7.20 − 7.01 (m, 3H), 6.98 (t, J = 7.7 Hz, 1H), 6.25 (d, J = 2.0 Hz, 1H), 3.71 (s, 3H): 13C NMR (101 MHz, DMSO-d6) δ 178.0, 152.7, 141.9, 136.4, 133.6, 129.8, 127.6, 125.5, 125.2, 124.9, 123.2, 121.6, 117.8, 116.2, 111.8, 110.3, 103.1, 72.1, 52.0, 31.0; HRMS (ESI): m/z [M + H]+ calcd for [C20H14ClN4OS]+: 393.0571, found: 393.0569; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 11.54 min, and tminor = 36.99 min.
(R)-2′-amino-6′-bromo-9′-methyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3j). We followed the general procedure, using 1j (0.2 mmol, 48.7 mg), 2a (0.2 mmol, 39.1 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3j as a yellow solid (39.4 mg, 45% yield); [α]D20 = −1.30 (c = 1.0, EA, 87% ee); m.p. = 295.6–296.3 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.35 − 7.29 (m, 1H), 7.25 (s, 2H), 7.20 − 7.16 (m, 1H), 7.15 − 7.01 (m, 2H), 7.01 − 6.96 (m, 1H), 6.41 (d, J = 1.9 Hz, 1H), 3.71 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.0, 152.7, 141.9, 136.7, 133.6, 129.8, 127.5, 125.9, 125.5, 124.2, 123.2, 119.3, 117.8, 112.9, 112.2, 110.3, 103.0, 72.05, 52.0, 31.0; HRMS (ESI): m/z [M + Na]+ calcd for [C20H13BrN4OSNa]+: 458.9886, found: 458.9889; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 11.73 min, and tminor = 38.58 min.
(R)-2′-amino-7′-chloro-9′-methyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3k). We followed the general procedure, using 1k (0.2 mmol, 39.3 mg), 2a (0.2 mmol, 39.1 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3k as a yellow solid (43.2 mg, 55% yield); [α]D20 = −6.54 (c = 1.0, EA, 97% ee); m.p. = 274.5–275.3 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.30 (m, 1H), 7.22 (s, 2H), 7.07 − 6.99 (m, 2H), 6.99 − 6.93 (m, 1H), 6.89 − 6.80 (m, 1H), 6.30 (d, J = 8.6 Hz, 1H), 3.71 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.1, 152.6, 141.9, 138.3, 133.8, 129.7, 126.8, 126.7, 125.5, 123.1, 120.6, 118.2, 117.8, 110.4, 110.2, 103.6, 72.2, 52.1, 30.9; HRMS (ESI): m/z [M + H]+ calcd for [C20H14ClN4OS]+: 393.0571, found: 393.0578; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 12.03 min, and tminor = 28.12 min.
(R)-2′-amino-7′-bromo-9′-methyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3l). We followed the general procedure, using 1l (0.2 mmol, 48.6 mg), 2a (0.2 mmol, 39.1 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3l as a yellow solid (52.5 mg, 60% yield); [α]D20 = −4.35 (c = 1.0, EA, 97% ee); m.p. = 297.7–298.3 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.75 (s, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.22 (s, 2H), 7.10 − 6.77 (m, 4H), 6.25 (d, J = 8.6 Hz, 1H), 3.71 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.0, 152.6, 141.9, 138.7, 133.8, 129.7, 126.7, 125.4, 123.3, 123.2, 123.1, 118.6, 117.8, 114.8, 113.0, 110.4, 103.6, 72.2, 52.1, 30.9; HRMS (ESI): m/z [M + H]+ calcd for [C20H14BrN4OS]+: 437.0066, found: 437.0067; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 13.08 min, and tminor = 30.39 min.
(R)-2′-amino-8′-fluoro-9′-methyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3m). We followed the general procedure, using 1m (0.2 mmol, 36.4 mg), 2a (0.2 mmol, 39.1 mg), and L4 (0.02 mmol, 19.1 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3m as a yellow solid (37.6 mg, 50% yield); [α]D20 = −8.52 (c = 1.0, EA, 99% ee); m.p. = 283.4–284.1 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 7.33 − 7.27 (m, 1H), 7.23 (s, 2H), 7.01 (m, 2H), 6.96 (t, J = 7.5 Hz, 1H), 6.91 − 6.82 (m, 1H), 6.80 − 6.69 (m, 1H), 6.16 (d, J = 7.9 Hz, 1H), 3.87 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.0, 152.4, 149.4 (d, J = 242.9 Hz), 142.0, 133.8, 129.7, 128.3 (d, J = 5.1 Hz), 127.4, 125.5, 125.3 (d, J = 9.4 Hz), 123.1, 121.0 (d, J = 6.6 Hz), 117.8, 113.5, 110.4, 107.8 (d, J = 17.7 Hz), 104.4, 72.3, 52.3, 33.5 (d, J = 6.2 Hz); 19F NMR (376 MHz, DMSO-d6) δ -135.58; HRMS (ESI): m/z [M + H]+ calcd for [C20H14FN4OS]+: 377.0867, found: 377.0872; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 10.05 min, and tminor = 28.76 min.
(R)-2′-amino-8′-bromo-9′-methyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3n). We followed the general procedure, using 1n (0.2 mmol, 48.5 mg), 2a (0.2 mmol, 39.1 mg), and L4 (0.02 mmol, 19.1 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3n as a yellow solid (36.6 mg, 42% yield); [α]D20 = −2.61 (c = 1.0, EA, 85% ee); m.p. = 287.3–288.1 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.33 − 7.25 (m, 1H), 7.26 − 7.04 (m, 3H), 7.16 − 6.98 (m, 2H), 6.98 − 6.91 (m, 1H), 6.71 (t, J = 7.8 Hz, 1H), 6.56 − 6.18 (m, 1H), 4.03 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 177.9, 152.2, 141.9, 134.1, 133.7, 129.7, 128.6, 127.7, 127.1, 125.4, 123.1, 121.9, 117.7, 116.8, 110.4, 103.8, 103.2, 72.5, 52.1, 34.1; HRMS (ESI): m/z [M + H]+ calcd for [C20H14BrN4OS]+: 437.0066, found: 437.0071; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 12.63 min, and tminor = 38.47 min.
(R)-2′-amino-6′,8′,9′-trimethyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3o). We followed the general procedure, using 1o (0.2 mmol, 38.5 mg), 2a (0.2 mmol, 39.1 mg), and L4 (0.02 mmol, 19.1 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3o as a yellow solid (52.5 mg, 68% yield); [α]D20 = −20.38 (c = 1.0, EA, 99% ee); m.p. = 277.6–278.3 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 7.43 − 7.20 (m, 1H), 7.10 (s, 2H), 7.07 − 6.84 (m, 3H), 6.57 (s, 1H), 6.01 (s, 1H), 3.87 (s, 3H), 2.61 (s, 3H), 2.02 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.3, 152.6, 141.9, 135.2, 134.3, 129.4, 128.7, 126.3, 125.8, 125.6, 125.3, 122.9, 121.1, 118.0, 115.1, 110.1, 102.8, 72.7, 52.4, 34.0, 21.4, 19.8; HRMS (ESI): m/z [M + H]+ calcd for [C22H19N4OS]+: 387.1274, found: 387.1280; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 12.83 min, and tminor = 41.52 min.
(R)-2′-amino-5-methoxy-9′-methyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3p). We followed the general procedure, using 1a (0.2 mmol, 32.6 mg), 2b (0.2 mmol, 45.3 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3p as a yellow solid (58.2 mg, 75% yield); [α]D20 = +2.31 (c = 1.0, EA, 99% ee); m.p. = 263.5–264.4 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.18 (s, 2H), 7.06 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.89 − 6.79 (m, 2H), 6.60 (d, J = 2.5 Hz, 1H), 6.41 (d, J = 8.0 Hz, 1H), 3.71 (s, 3H), 3.61 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.1, 155.9, 152.8, 137.9, 135.4, 135.3, 125.3, 124.4, 121.8, 120.3, 118.0, 117.2, 114.4, 111.8, 110.8, 110.0, 103.2, 72.4, 55.8, 52.8, 30.7; HRMS (ESI): m/z [M + H]+ calcd for [C21H17N4O2S]+: 389.1067, found: 389.1073; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 14.28 min, and tminor = 38.69 min.
(R)-2′-amino-5,9′-dimethyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3q). We followed the general procedure, using 1a (0.2 mmol, 32.6 mg), 2c (0.2 mmol, 42.2 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3q as a yellow solid (37.9 mg, 51% yield); [α]D20 = +5.56 (c = 1.0, EA, 98% ee); m.p. = 260.8–261.4 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.15 (s, 2H), 7.10 − 7.01 (m, 2H), 6.89 (d, J = 7.8 Hz, 1H), 6.86 − 6.72 (m, 2H), 6.44 (d, J = 8.0 Hz, 1H), 3.70 (s, 3H), 2.16 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.2, 152.5, 139.4, 137.9, 134.4, 131.8, 129.8, 125.8, 125.1, 124.4, 121.8, 120.3, 118.0, 117.2, 110.0, 109.9, 103.3, 72.6, 52.4, 30.7, 21.0; HRMS (ESI): m/z [M + Na]+ calcd for [C21H16N4OSNa]+: 395.0937, found: 395.0940; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 80/20, flow rate = 1 mL/min, λ = 254 nm, tmajor = 21.84 min, and tminor = 62.98 min.
(R)-2′-amino-5-bromo-9′-methyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3r). We followed the general procedure, using 1a (0.2 mmol, 32.6 mg), 2d (0.2 mmol, 55.3 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3r as a yellow solid (43.7 mg, 50% yield); [α]D20 = +0.87 (c = 1.0, EA, 90% ee); m.p. = 260.8–261.4 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.52 − 7.43 (m, 2H), 7.27 (s, 2H), 7.15 (d, J = 2.1 Hz, 1H), 7.11 − 7.05 (m, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.88 − 6.82 (m, 1H), 6.43 (d, J = 8.0 Hz, 1H), 3.71 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 177.9, 153.1, 141.3, 137.9, 136.6, 132.4, 128.0, 125.6, 124.2, 122.0, 120.5, 117.9, 116.8, 114.6, 112.4, 110.1, 102.4, 71.5, 52.5, 30.7; HRMS (ESI): m/z [M + H]+ calcd for [C20H14BrN4OS]+: 437.0066, found: 437.0072; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 10.39 min, and tminor = 22.66 min.
(R)-2′-amino-6-methoxy-9′-methyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3s). We followed the general procedure, using 1a (0.2 mmol, 32.6 mg), 2e (0.2 mmol, 45.2 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3s as a yellow solid (66 mg, 85% yield); [α]D20 = +3.08 (c = 1.0, EA, 99% ee); m.p. = 243.5–244.3 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.12 (s, 2H), 7.08 − 7.01 (m, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.87 − 6.76 (m, 1H), 6.55 (d, J = 2.3 Hz, 1H), 6.52 − 6.44 (m, 1H), 6.39 (d, J = 8.0 Hz, 1H), 3.77 (s, 3H), 3.69 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.8, 160.5, 152.5, 143.2, 137.9, 126.2, 126.0, 125.2, 124.5, 121.8, 120.3, 118.0, 117.3, 109.9, 107.8, 103.6, 96.9, 72.8, 55.7, 51.8, 30.7; HRMS (ESI): m/z [M + H]+ calcd for [C21H17N4O2S]+: 389.1067, found: 389.1067; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 14.13 min, and tminor = 36.74 min.
(R)-2′-amino-7,9′-dimethyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3t). We followed the general procedure, using 1a (0.2 mmol, 32.6 mg), 2f (0.2 mmol, 42.1 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3t as a yellow solid (65.5 mg, 88% yield); [α]D20 = +3.33 (c = 1.0, EA, 97% ee); m.p. = 268.4–269.1 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.36 − 6.89 (m, 4H), 6.99 − 6.60 (m, 3H), 6.36 (d, J = 8.0 Hz, 1H), 3.71 (s, 3H), 2.34 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.7, 152.7, 140.6, 137.9, 133.8, 130.7, 125.2, 124.4, 122.9, 122.8, 121.8, 120.3, 119.5, 118.0, 117.3, 109.9, 103.5, 72.6, 52.5, 30.7, 17.0; HRMS (ESI): m/z [M + H]+ calcd for [C21H17N4OS]+: 373.1118, found: 373.1121; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 11.65 min, and tminor = 22.90 min.
(R)-2′-amino-7-fluoro-9′-methyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3u). We followed the general procedure, using 1a (0.2 mmol, 32.6 mg), 2g (0.2 mmol, 43.3 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3u as a yellow solid (63.2 mg, 84% yield); [α]D20 = +6.30 (c = 1.0, EA, 92% ee); m.p. = 268.4–269.1 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.32 − 7.16 (m, 3H), 7.11 − 7.04 (m, 1H), 7.02 − 6.94 (m, 1H), 6.92 − 6.81 (m, 2H), 6.40 (d, J = 8.0 Hz, 1H), 3.71 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.1, 153.0, 146.8 (d, J = 243.2 Hz), 137.9, 136.9 (d, J = 3.2 Hz), 129.0 (d, J = 12.5 Hz), 125.4, 124.2, 124.0 (d, J = 5.7 Hz), 122.0, 121.5, 120.5, 117.9, 116.9, 116.5 (d, J = 17.0 Hz), 110.1, 102.6, 71.8, 52.6 (d, J = 2.8 Hz), 30.7; 19F NMR (376 MHz, DMSO-d6) δ -132.63; HRMS (ESI): m/z [M + Na]+ calcd for [C20H13FN4OSNa]+: 399.0686, found: 399.0684; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 11.72 min, and tminor = 38.81 min.
(R)-2′-amino-7-chloro-9′-methyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3v). We followed the general procedure, using 1a (0.2 mmol, 32.6 mg), 2h (0.2 mmol, 46.1 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3v as a yellow solid (64.3 mg, 82% yield); [α]D20 = +8.85 (c = 1.0, EA, 94% ee); m.p. = 265.3–265.9 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.41 − 7.33 (m, 1H), 7.29 (s, 2H), 7.13 − 7.03 (m, 1H), 7.05 − 6.91 (m, 2H), 6.93 − 6.80 (m, 1H), 6.38 (d, J = 7.9 Hz, 1H), 3.71 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.3, 153.1, 139.7, 137.9, 135.9, 129.5, 125.5, 124.4, 124.20, 124.16, 122.0, 120.5, 117.9, 116.8, 114.6, 110.1, 102.6, 71.7, 53.2, 30.7; HRMS (ESI): m/z [M + H]+ calcd for [C20H14ClN4OS]+: 393.0571, found: 393.0569; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 13.00 min, and tminor = 37.30 min.
(R)-2′-amino-7-bromo-9′-methyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3w). Followed the general procedure, using 1a (0.2 mmol, 32.6 mg), 2i (0.2 mmol, 55.2 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3w as a yellow solid (69 mg, 79% yield); [α]D20 = +3.91 (c = 1.0, EA, 94% ee); m.p. = 264.9–265.7 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.63 − 7.34 (m, 2H), 7.28 (s, 2H), 7.20 − 6.96 (m, 2H), 7.00 − 6.72 (m, 2H), 6.37 (d, J = 8.0 Hz, 1H), 3.72 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.2, 153.1, 141.4, 137.9, 135.8, 132.4, 125.4, 124.8, 124.6, 124.2, 122.0, 120.5, 117.9, 116.8, 110.1, 102.7, 102.6, 71.7, 53.4, 30.8; HRMS (ESI): m/z [M + H]+ calcd for [C20H14BrN4OS]+: 437.0066, found: 437.0076; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 15.01 min, and tminor = 39.45 min.
(R)-2′-amino-5,7,9′-trimethyl-2-oxo-9′H-spiro[indoline-3,4′-thiopyrano[2,3-b]indole]-3′-carbonitrile (3x). Followed the general procedure, using 1a (0.2 mmol, 32.6 mg), 2j (0.2 mmol, 45.2 mg), and L4 (0.02 mmol, 19.0 mg). Purified by flash column chromatography (petroleum ether/ethyl acetate 2:1) to afford 3x as a yellow solid (60.2 mg, 78% yield); [α]D20 = +6.54 (c = 1.0, EA, 94% ee); m.p. = 251.8–252.5 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.33 − 6.95 (m, 3H), 6.90 (d, J = 1.8 Hz, 1H), 6.82 (t, J = 7.4 Hz, 1H), 6.65 (d, J = 1.7 Hz, 1H), 6.45 (d, J = 8.0 Hz, 1H), 3.70 (s, 3H), 2.31 (s, 3H), 2.13 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 178.7, 152.4, 138.0, 137.9, 134.1, 131.7, 131.2, 125.0, 124.4, 123.1, 121.8, 120.3, 119.2, 118.1, 117.3, 109.9, 103.6, 72.8, 52.6, 30.7, 20.9, 16.9; HRMS (ESI): m/z [M + H]+ calcd for [C22H19BrN4OS]+: 387.1274, found: 387.1274; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 10.11 min, and tminor = 20.57 min.

4.4. Procedure for the Scaled-Up Synthesis of Compound 3a

Under a nitrogen atmosphere, a solution of diethylzinc (800 μL, 1.0 M in hexane, 0.8 mmol) was added dropwise to a solution of L4 (0.4 mmol, 0.364 g) in THF (10 mL). After the mixture was stirred for 30 min at room temperature. Then, 1-methylindoline-2-thione 1a (4.0 mmol, 0.652 g) and 2-(2-oxoindolin-3-ylidene)malononitrile 2a (4.0 mmol, 0.78 g) were added. The reaction mixture was stirred for 24 h at the same temperature. The reaction was quenched with NH4Cl solution (10 mL), and the organic layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic layer was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure by using a rotary evaporator. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (2:1) to afford the desired product 3a (1.07g) as a yellow solid.

4.5. Procedure for the Synthesis of Compound 4

Compound 3i (0.1 mmol, 39.2 mg) and pyridine (0.1 mmol) were added to Ac2O (0.5 mL), and the mixture was stirred at 25 °C for 8 h. The reaction was quenched with water, and extracted with CH2Cl2 (3 × 5 mL). The organic layers were dried over Na2SO4 and concentrated. Then the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) to provide product 4 as a yellow solid.
7′-chloro-2′,10′-dimethyl-10′H-spiro[indoline-3,5′-pyrimido[5′,4′:5,6]thiopyrano[2,3-b]indole]-2,4′(3′H)-dione (4). Purified by flash column chromatography (petroleum ether/ethyl acetate 5:1) to afford 4 as a white solid (25.2 mg, 58% yield); [α]D20 = +1.74 (c = 1.0, EA, 99% ee); m.p. = 278.8–279.6 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 8.2 Hz, 1H), 7.64 − 7.52 (m, 4H), 7.37 − 7.27 (m, 2H), 7.19 − 7.10 (m, 1H), 5.97 (d, J = 2.0 Hz, 1H), 3.80 (s, 3H), 2.62 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 177.5, 171.1, 154.0, 139.8, 136.5, 131.5, 130.2, 128.4, 126.7, 125.9, 125.2, 125.1, 121.9, 117.5, 116.4, 116.1, 112.0, 102.6, 71.6, 52.4, 31.2, 26.7; HRMS (ESI): m/z [M + H]+ calcd for [C22H16ClN4O2S]+: 435.0677, found: 435.0684; HPLC: Daicel Chiralpak IA, n-hexane/i-PrOH = 70/30, flow rate = 1 mL/min, λ = 254 nm, tmajor = 7.31 min, and tminor = 10.17 min.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28031056/s1, Figures S1–S28: NMR Spectra; Figures S29–S53: HPLC; Figure S54: Single-crystal X-ray diffraction.

Author Contributions

T.-T.L. and Y.C. performed the experiments, acquired and analyzed the original data. S.-K.J. and Y.-Z.H. wrote the preliminary manuscript. S.-K.J. and G.-J.M. reviewed and edited the manuscript. M.-C.W. designed the research plan, supervised the experiments, modified all figures and schemes, analyzed and checked all the data, and revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

We are grateful to the National Natural Science Foundation of China (NNSFC 21871237).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors are thankful to the Zhengzhou University for help in conducting this study.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 3 are available from the authors.

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Molecules 28 01056 sch001 550
Scheme 1. Previous reports and this work. ((a) Dinuclear zinc-catalyzed asymmetric Freidel-Crafts alkylation’s (b) This work: Dinuclear zinc-catalyzed asymmetric [3 + 3] annulation of indoline-2-thiones and isatylidene malononitriles.).
Scheme 1. Previous reports and this work. ((a) Dinuclear zinc-catalyzed asymmetric Freidel-Crafts alkylation’s (b) This work: Dinuclear zinc-catalyzed asymmetric [3 + 3] annulation of indoline-2-thiones and isatylidene malononitriles.).
Molecules 28 01056 sch001
Molecules 28 01056 sch002 550
Scheme 2. Substrate scope of indoline-2-thiones. Reaction conditions: 10 mol % of L4, 20 mol % of ZnEt2, 0.20 mmol 1 and 0.20 mmol 2a in 2 mL THF.
Scheme 2. Substrate scope of indoline-2-thiones. Reaction conditions: 10 mol % of L4, 20 mol % of ZnEt2, 0.20 mmol 1 and 0.20 mmol 2a in 2 mL THF.
Molecules 28 01056 sch002
Molecules 28 01056 sch003 550
Scheme 3. Substrate scope of isatylidene malononitriles. Reaction conditions: 10 mol % of L4, 20 mol % of ZnEt2, 0.20 mmol 1a and 0.20 mmol 2 in 2 mL THF.
Scheme 3. Substrate scope of isatylidene malononitriles. Reaction conditions: 10 mol % of L4, 20 mol % of ZnEt2, 0.20 mmol 1a and 0.20 mmol 2 in 2 mL THF.
Molecules 28 01056 sch003
Molecules 28 01056 g001 550
Figure 1. Crystal structures of 3g (CCDC 2177975) detected by Bruker APEX-II CCD (the thermal ellipsoids are drawn at a 30% probability level).
Figure 1. Crystal structures of 3g (CCDC 2177975) detected by Bruker APEX-II CCD (the thermal ellipsoids are drawn at a 30% probability level).
Molecules 28 01056 g001
Molecules 28 01056 sch004 550
Scheme 4. Gram-scale reaction (a) and derivation (b).
Scheme 4. Gram-scale reaction (a) and derivation (b).
Molecules 28 01056 sch004
Molecules 28 01056 sch005 550
Scheme 5. Plausible mechanism.
Scheme 5. Plausible mechanism.
Molecules 28 01056 sch005
Table
Table 1. Condition Optimization a.
Table 1. Condition Optimization a.
Molecules 28 01056 i001
EntryLigandYield bEe c (%)
1L15780
2L24163
3L37899
4L48599
5L54334
6L65768
7L73623
8L84037
9L97297
a Unless otherwise noted, all reactions were conducted with 10 mol % of ligand, 20 mol % of ZnEt2, 0.10 mmol 1a, and 0.10 mmol 2a in 2 mL THF. b Isolated yields. c The enantiomeric excess (ee) value was determined by HPLC analysis.
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Liu, T.-T.; Chen, Y.; Mei, G.-J.; Hua, Y.-Z.; Jia, S.-K.; Wang, M.-C. Zinc-Catalyzed Enantioselective [3 + 3] Annulation for Synthesis of Chiral Spiro[indoline-3,4′-thiopyrano[2,3-b]indole] Derivatives. Molecules 2023, 28, 1056. https://doi.org/10.3390/molecules28031056

AMA Style

Liu T-T, Chen Y, Mei G-J, Hua Y-Z, Jia S-K, Wang M-C. Zinc-Catalyzed Enantioselective [3 + 3] Annulation for Synthesis of Chiral Spiro[indoline-3,4′-thiopyrano[2,3-b]indole] Derivatives. Molecules. 2023; 28(3):1056. https://doi.org/10.3390/molecules28031056

Chicago/Turabian Style

Liu, Tian-Tian, Yu Chen, Guang-Jian Mei, Yuan-Zhao Hua, Shi-Kun Jia, and Min-Can Wang. 2023. "Zinc-Catalyzed Enantioselective [3 + 3] Annulation for Synthesis of Chiral Spiro[indoline-3,4′-thiopyrano[2,3-b]indole] Derivatives" Molecules 28, no. 3: 1056. https://doi.org/10.3390/molecules28031056

APA Style

Liu, T. -T., Chen, Y., Mei, G. -J., Hua, Y. -Z., Jia, S. -K., & Wang, M. -C. (2023). Zinc-Catalyzed Enantioselective [3 + 3] Annulation for Synthesis of Chiral Spiro[indoline-3,4′-thiopyrano[2,3-b]indole] Derivatives. Molecules, 28(3), 1056. https://doi.org/10.3390/molecules28031056

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