Abstract
The de novo construction of enantioenriched 3-hydroxyindolenines and 3-oxindoles from easily available starting materials has been highly desired. Herein, an enantioselectively intermolecular direct [3 + 2] annulation of aryl amine with 2,3-diketoesters to construct 3-hydroxyindolenines with a chiral tertiary alcohol has been disclosed. The results of control experiments and DFT calculation revealed that π − π interaction plays a pivotal role in the enantioselectivity-determining process of [3 + 2] annulation. The following unusual concerted [1,2]-ester migration provides a family of chiral 3-oxindoles in good to excellent yields with excellent enantioselectivity.
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Introduction
Chiral 3-oxindole is a prominent structural motif found in numerous natural products1,2,3,4 and exhibits extensive bioactivities5,6,7,8 and fluorescence property9. Continuous endeavors have been devoted to the enantioselective synthesis of such moiety starting from indole and its derivatives during the past two decades. For instance, Kawasaki, Xu, Hou and Chan groups developed the protocols for chiral 3-oxindoles through the reaction of 2-monosubstituted 3-oxindoles with a series of electrophiles in the presence of cinchona analogs or palladium/chiral phosphine ligand as the chiral auxiliary (Fig. 1a)10,11,12,13. You group successfully built chiral 3-oxindoles starting from racemic spiro indolin-3-ones as the electrophiles through chiral phosphoric acid (CPA) catalyzed enantioselective Friedel–Crafts alkylation of indoles (Fig. 1b)14. Glorius and Xu’s groups independently described the synthesis of chiral spiro-3-oindoles via organocatalyzed formal [3 + 2] annulation of aurones with 1,3-dipoles (Fig. 1c)15,16. With 2-monosubstituted indoles as the starting materials, considerable achievements on the catalyzed enantioselective 3-oxindole synthesis have been contributed via the indole oxidation and enantioselective nucleophilic addition process under organo-catalysis (Fig. 1d)17,18,19,20,21,22,23,24. Xiao and Jiang’s groups developed a CPA catalyzed enantioselective 3-oxindole synthesis via the photo-induced aerobic oxidation and semi-pinacol rearrangement independently (Fig. 1e)25,26. In spite of the above elegant achievement, de novo simultaneously building 3-oxindole ring and a chiral quaternary carbon via asymmetric catalysis has been far behind.
a–e Previous synthesis of chiral 3-oxindoles from indole derivatives. f This work: enantioselective de novo construction of 3-oxindoles from arylamines. CPA chiral phosphoric acid.
Herein, we disclosed a de novo enantioselective synthesis of 3-oxindole starting from simple arylamines and 2,3-diketoesters9. A formal [3 + 2] annulation catalyzed by CPA followed by rare [1,2]-ester migration was involved in this transformation (Fig. 1f)10. To realize this de novo construction of chiral 3-oxindoles, main problems as follows should be overcome: (1) the low reactivity of ketone27,28,29; (2) the ortho- selectivity of C-H addition should be controlled since para-selectivity is usually preferred30,31,32,33,34 with para- non-hindered aryl amines35,36,37,38; (3) difficulty in 1,2-ester migration; (4) the enantioselective control of [3 + 2] annulation and 1,2-ester migration. The DFT calculation revealed that the CPA catalyzed ortho-C-H addition with ketones39 was the rate- and enantioselectivity-determining step for the [3 + 2] annulation process. And an exclusive enantioselective [1,2]-ester migration40,41 occurred through a concerted three-membered ring transition state.
Results and Discussion: Investigation of reaction conditions
1-Naphthylamine 1a and 2,3-diketoester 2a were chosen as the substrates to initiate our investigation with (R)-5a as the catalyst, toluene as solvent, at room temperature for 40 h. The 3aa was isolated and heated for another 20 h and (S)-4aa was obtained in 95% yield with 45% ee. A family of chiral BINOL CPAs as the catalysts were then examined (Table 1, entries 1-4). The bulky BINOL-(R)-CPAs and condensed aromatics substituted BINOL-(R)-CPAs produced opposite enantiomer 4aa, which indicated that different coordination patterns might exist for the bulky and condensed aromatics substituted CPAs in this catalytic system. Firstly, the sterically bulky CPAs were surveyed (Table 1, entries 5-7). The bulkier BINOL-(R)-CPAs gave the product 4aa with better enantioselectivity (Table 1, entries1-2, 5-7). Especially, (R)-5c with 2,4,6-trisisopropylphenyl group at the para-position of the aryl ring in BINOL-(R)-CPA produced (S)-4aa with 81% ee (entry 7). To accelerate the reaction rate at room temperature of step b, TsOH·H2O was added as promotor (entries 5-9). The evaluation of different solvents showed that the chlorinated hydrocarbon gave better enantioselectivity with the bulky CPAs (Supplementary Table 1 in Supplementary Information). The combination of CH2Cl2 and ODCB (1,2-dichlorobenzene) (4:1) improved the ee to 88% (entry 8). Increasing the amount of solvent (CH2Cl2: ODCB = 4:1) to 4 mL, 91% ee of (S)-4aa was obtained (entry 9). Thereafter, the further evaluation of spirocyclic-based CPAs (entries 10-12) showed that 9-anthryl spirocyclic CPA (R)-6b gave good enantioselectivity (68% ee). Solvents were surveyed with (S)-6b as the catalyst (entries 13-14) and AcOiPr gave the best enantioselectivity (88% ee). Increasing the amount of AcOiPr to 4 mL, 92% ee of (S)-4aa was obtained (entry 15).
Scope
With the optimized reaction conditions in hand, the substrate scope was next examined (Fig. 2). 2,3-Diketoesters 2 with alkyl (R) groups, including methyl, n-butyl, benzyl and n-heptyl, reacted smoothly with 1a to generate 4ab-4ae with high yields and enantioselectivity. The para-substituted halogen (2f-2h), electron-withdrawing groups (2i-2k) and methyl (2 l) in phenyl group of 2 gave the desired products with excellent yields (88–99%) and enantioselectivity (94-96%). -OMe group (2 m) resulted in 4am with 78% ee and 97% yield using 0.5 mL of solvent. The substrates 2 with meta-substituted group could afford the product with excellent yield and ee (4an, 90% yield, 94% ee). The ortho-substituents gave product with good yield and low ee (4ao, 80% yield, 20% ee). Gratifyingly, using (R)-5c as the catalyst, 4:1 ratio of CH2Cl2 and ODCB as the solvent, (S)−4ao was obtained in excellent yield with 86% ee. Substrates 2 with 2-furyl or 2-thienyl groups produced 4ap and 4aq with excellent ee (96% and 97%). A successful gram-scale synthesis of 4aq demonstrated the practicality of this reaction. The alkenyl substituted diketoester was applicable for this transformation (4ar, 85% yield, 90% ee). Then, the tolerance of substituents on the 1-naphthylamine were evaluated. Cyclopropyl (1b), phenyl (1c), 1-naphthyl (1d), 3-thienyl (1e), bromo (1f, 1g), chloro (1h) and methoxy (1i) groups at the different position were tolerated well and the corresponding products were provided smoothly with good to excellent yields (61-99%) and excellent enantioselectivity (94-99% ee) using 2q as the reaction partner. Among them, product 4dq with two stereogenic centers of a chiral quaternary carbon and an axially chiral center (1:1 dr). In addition, 1-aminoanthracene (1j) worked well, providing 4jq in 93% yield and 97% ee. Interestingly, the reaction of 3-fluoranthenamine (1k) and 2q produced the opposite enantiomer product 4kq in 99% yield and 96% ee. 1-Dibenzofuranamine (1l) also produced the desired product 4lq with excellent ee of 96% in moderate yield. Moreover, the reaction of 4-aminoindole (1m) and 2q gave the product 4mq with 81% yield and 97% ee. 7-Aminoindole (1n) provided 4nq in 22% yield and with 62% ee. While, simple aniline could not transform to the desired product 4oq under the standard reaction conditions.
Reaction conditions: 1 (0.05 mmol), 2 (0.055 mmol), (S)-6b (10 mol %), AcOiPr (4 mL), rt, 7 d, TsOH·H2O (1.0 equiv) was added in one-pot at the second step at room temperature for 10 h. aAcOiPr (0.5 mL). b(R)-5c (10 mol %), CH2Cl2: ODCB (4: 1, 0.5 mL), 40 °C. cAcOiPr (1 mL).
Then we focused on the investigation of simple anilines as the substrates (Fig. 3). Fortunately, N-alkyl anilines could be directly transformed to the desired products in one pot after a series of condition optimizations. For example, Product 4pq was produced in 82% yield with 89% ee using (S)−6b as the catalyst, benzene as solvent, 5 Å molecular sieve as additive at 40 °C. Various linear alkyl groups, such as methyl, ethyl, n-butyl and allyl, substituted anilines could be transformed to the desired products with 91–92% ee. In addition, N-isopropylaniline could give the product 4tq in 89% yield with 84% ee. The multiple substituents could be tolerated, such as alkyl, halogen, electron donating and withdrawing groups. Methyl and methoxy at the meta-position of N-methylaniline could provide products 4wq and 4xq in excellent yields with 96% ee. N-Methylaniline bearing fluoro, chloro, bromo and iodo groups at the meta-position could deliver the desired products in excellent yields with good ee (4xq-4Aq, 89–93% ee). The para substituted N-methylaniline offered the product 4Cq with 82% ee. The ortho position was linked to N atom with a six mumbled ring, products 4Fq-4Iq could be obtained with 84–89% ee. An enantioenriched unnatural fluorescent amino acid (4Jq) was prepared starting from lysine. A variety of drug molecules (e.g., ibuprofen, isoxepac, indomethacin, and probenecid) were well tolerated, providing the desired 3‑oxindoles in good yields with 90–91% ee (4Kq-4Nq).
Reaction conditions: 1 (0.05 mmol), 2 (0.06 mmol), (S)-6b (10 mol %), 5 Å MS (50 mg), benzene (1 mL), 40 °C, 7 d. a3 d.
Mechanistic investigation
To validate if the 3-hydroxyindolenine 3 was a key intermediate, the control experiment of 1a and 2q using (S)-6b as the catalyst was conducted (Fig. 4a). 3aq was obtained in 99% yield with 98% ee. This result implied that this methodology could also be used for catalytic enantioselective synthesis of chiral 3-hydroxyindolenines, and the nucleophilic addition of ortho-C-H to carbonyl group might be the determining step of enantioselectivity. In addition, the isolated chiral 3aq (98% ee) was transformed to the final product 4aq with 97% ee after treated with TsOH·H2O, which demonstrated that the exclusive 1,2-ester migration occurred after nucleophilic addition of ortho-C-H to carbonyl group. With the diphenyl phosphate as the catalyst, only 47% yield of rac-3aq was obtained as well as ketimine 7 as the by-product. The isolated 7 could be transformed to the 4aq with 98% ee under the standard conditions.
a Control experiments. b Hammett analysis of ortho-Friedel-Crafts addition of 1-naphthylamine to 2,3-diketoesters.
The condensations of a series of 2,3-diketoesters with 1-naphthylamine were performed to illustrate the impact of the electronic effect on the step of enantioselective ortho addition (Fig. 4b). A positive value (0.74) was observed based on the Hammett analysis, implying that the reaction rate of the 2,3-diketoester with electron-withdrawing groups at the para position to the central carbonyl was faster than that of substrates with electron-donating groups, indicating that the ortho-Friedel-Crafts addition to carbonyl group might be the rate-limiting step for the formation of 3-hydroxyindolenine 3aq.
To elaborate the detailed reaction mechanism and control factor of the enantioselectivity, density functional theory (DFT) calculations42,43 were conducted on the reaction 1-naphthylamine 1a and 2,3-diketoester 2q in the presence of the CPA (S)-6b catalyst. The relative free energy profiles were calculated by M06-2X density functional, which was already parametrized to account for dispersion interaction44. As shown in Fig. 5, capture of 1-naphthylamine 1a and 2,3-diketoester 2q by CPA (S)-6b through hydrogen bonding successively could generate Int5 with an endergonic free energy of 2.0 kcal/mol. The subsequent intramolecular nucleophilic addition of 1-naphthylamine 1a at the carbonyl group of 2,3-diketoester 2q via transition state TS6-RS furnished the zwitterionic intermediate Int7-RS, requiring an activation-free energy of 9.3 kcal/mol. The dehydro-aromatization then occurs rapidly via transition state TS8-R to generate the tertiary alcohol intermediate Int9-R. Isomerization of Int9-R followed by intramolecular nucleophilic addition of amino at carbonyl group via transition state TS11-R with an activation energy barrier of 8.9 kcal/mol could afford ammonium Int12-R. Deprotonation of Int12-R generates the diol Int14-R. Eliminating one molecule of water of the resulting diol Int14-R gives the isolated 3-hydroxyindolenine 3aq. Based on the calculated results, the nucleophilic addition of 1-naphthylamine 1a at the carbonyl group of 2,3-diketoester 2q via transition state TS6-RS could be considered as an irreversible and rate-determination step for the formation of 3-hydroxyindolenine 3aq. Following that, we interrogated four possible enantioselective nucleophilic addition scenarios of 1-naphthylamine 1a to the 2,3-diketoester 2q via transition state TS6-RS, TS6-RR, TS6-SR, and TS6-SS (Fig. 6), which depicted that the nucleophilic addition of 1a to 2q via transition state TS6-RS was 4.1 kcal/mol lower than that of transition state TS6-SR, indicating that high enantioselectivity would be observed theoretically and experimentally.
Calculated free energy profiles for the chiral phosphoric acid catalyzed ortho-Friedel-Crafts addition of 1-naphthylamine 1a and 2,3-diketoester 2q (G = 9-anthryl, R1 = CO2Et, Ar = thienyl). The values given in kcal/mol are the relative free energies calculated by the SMD (diethylether)/M06-2X/6-311+g(d,p)//SMD(diethylether)/M06-2X/6-31 g(d) method in diethylether.
Non-covalent Interaction (NCI) analysis for the key transition states TS6-RS, TS6-RR, TS6-SR, and TS6-SS.
To shine a light on the origin of the enantioselectivity, we further conducted the non-covalent Interaction (NCI) analysis for the key transition states TS6-RS, TS6-RR, TS6-SR, and TS6-SS. As shown in Fig. 6, the optimal matching factor for transition state TS6-RS not only originated from the π − π interaction (highlighted by blue circles) between the 9-anthryl groups in the arm of CPA catalyst and 1-naphthylamine 1a and 2,3-diketoester 2q, respectively, but also from the π − π interaction between naphthyl moiety of 1a and thiazolyl moiety of 2a. On the contrary, owing to hydrogen bonding interaction between CPA and 1-naphthylamine 1a leading to an outward naphthyl moiety of 1a, which erased the π − π interaction between the 9-anthryl groups of CPA catalyst and 1a. Therefore, a relatively higher activation free energy would be assigned to the transition state TS6-SR. Similarly, the deficiency of π − π interaction between naphthyl moiety of 1a and thiazolyl moiety of 2a owing to the opposite direction of those two moieties in transition state TS6-RR and TS6-SS, resulting in unfavorable processes. Therefore, DFT calculation depicted that the π − π interaction plays a pivotal role in the enantioselectivity-determining process.
As shown in Fig. 7 DFT calculation was further employed to disclose the mechanism for the TsOH-catalyzed intramolecular 1,2-eater migration of 3-hydroxyindolenines 3aq. The binding of TsOH with 3aq through hydrogen bonding produced intermediate Int15. The following hydrogen transfer from TsOH to imine could generate zwitterionic intermediate Int17. Subsequently, the intramolecular 1,2-ester migration proceeds via transition state TS18 to afford the product 4aq accompanied by regenerating of TsOH with exergonic free energy of 9.5 kcal/mol. Optimized geometric for the transition states TS18 showed that the bond length of the forming and breaking C-C bond was 2.01 and 2.01 Angstrom, respectively, suggesting that a concerted migration process could occur. Therefore, the chirality information of 3-hydroxyindolenine 3aq could deliver completely to 3-oxindoles 4aq, which was well consistent with experimental observations.
The values given in kcal/mol are the relative free energies calculated by the SMD (diethylether)/M06-2X/6-311+g(d,p)//SMD(diethylether)/M06-2X/6-31 g(d) method in diethylether. The blue values of geometric information are the bond lengths given in angstroms.
Synthetic application
Recently, donor-acceptor energy transfer rigid system has been proved to be effective to enlarge the Stokes shifts45,46. The 2,2-disubstituted 3-oxindoles with amino and carbonyl groups as donor-acceptor system in a rigid ring might possess good photophysical properties. The fluorescence spectra of 4aq and 4qq in water were recorded (Fig. 8). The strong fluorescence was exhibited and the maximum emission wavelengths (493 and 534 nm) were recorded. The stokes shifts were up to 75 and 105 nm respectively. Their photophysical properties in water would benefit their biological application.
Absorption and fluorescence spectra of 4aq (a) and 4qq (b).
Further transformations of enantioenriched 3-oxindoles were performed to illustrate the synthetic potential of this reaction (Fig. 9). Reduction of 4aq with BH3·DMS resulted in a chiral amino alcohol 8 with 90% ee. The following cyclization with 1,1’-carbonyldiimidazole (CDI) under DMAP catalysis afforded the polycyclic compound 9 with 92% ee. The catalytic hydrogenation of 4ar delivered alkyl substituted 3-oxindole 10 with 94% ee. The reducted products 11 and 12 could be obtained respectively through controlling reaction time from 4qq. Treated with Lawesson’s reagent, indoline-3-thione 13 was afforded and exhibited a maximum absorption wavelength of 523 nm. All the resulted obtained above showed the advantage of the current protocol as it is difficultly accessible by other means.
a Reduction reaction to amino alcohol of 4aq. DMS = dimethyl sulfide. b Cyclocarbonylation of 8, DMAP = 4-dimethylaminopyridine, CDI = 1,1’-carbonyldiimidazole. c Alkene hydrogenation of 4ar. d Carbonyl reduction of 4qq. e Reduction reaction to amino alcohol of 4qq. f Treated with Lawesson’s reagent of 4qq.
In summary, we have developed an organocatalyzed de novo construction of chiral 3-hydroxyindolenines and 3‑oxindoles with excellent yields and enantioselectivity starting from simple primary aryl amines and 2,3-diketoesters. The reaction was initiated by an intermolecular direct ortho-regioselective C-H addition to ketone carbonyl group. The following heteroanulation gave 3-hydroxyindolenines with a chiral tertiary carbon center. Followed by a rare enantioselective [1,2]-ester migration afforded the chiral 3-oxindoles. The DFT calculation depicted that the π − π interaction played a pivotal role in the enantioselectivity-determining process and a concerted 1,2-ester migration was demonstrated.
Methods
General procedure for de novo construction of chiral 3‑oxindoles with primary amines
The amine 1 (0.05 mmol), 2,3-diketoester 2 (0.055 mmol) and (S)-6b (10 mol %) were dissolved in AcOiPr. The reaction mixture was stirred at room temperature for 7 d. Then the TsOH·H2O (1.0 equiv) was added. The reaction mixture was stirred at room temperature for another 10 h. The solvent was removed in vacuo and the crude product was separated by flash column chromatography on silica gel to afford product 4.
General procedure for de novo construction of chiral 3‑oxindoles with secondary amines
The amine 1 (0.05 mmol), 2,3-diketoester 2 (0.06 mmol), (S)-6b (10 mol %) and 5 Å MS (50 mg) was added in benzene. The reaction mixture was stirred at 40 °C for indicated time. Then the crude product was separated by flash column chromatography on silica gel to afford product 4.
Data availability
The authors declare that the data relating to the characterization of products, experimental protocols and the computational studies are available within this article and its Supplementary Information. Source data are provided in this paper. The X-ray crystallographic coordinates for structure 4bq reported in this study have been deposited at the Cambridge Crystallographic Data Center (CCDC), under deposition numbers 2262643. These data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif. Data can also be obtained from the corresponding author upon request. Source data are provided with this paper.
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Acknowledgements
We greatly acknowledge financial support from the Science and Technology department of Henan Province (232102310366 to Y.Wang, 242102310465 to H.C.) and Open Grant from the Pingyuan Laboratory (2023PY-OP-0208 to X.C.). Y. Wang. thanks Ph. D Shikun Jia (Zhengzhou University) and Prof. Hua Wu (Shanghai Jiao Tong University) for valuable discussions.
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Y.Wang and X.C. conceived the work. Y.Wang designed, conducted the experiments, analysed the data and wrote the manuscript. Y.Li conducted part of experiments under the supervision of Y.Wang. H.Chen performed the DFT calculations and wrote the calculation part of the manuscript. Y.Lan. and C.P. took part in the discussion. X.C and Y.Wu revised the manuscript.
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Nature Communications thanks Guangxun Li and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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Wang, Y., Li, Y., Chen, H. et al. Enantioselective de novo construction of 3‑oxindoles via organocatalyzed formal [3 + 2] annulation from simple arylamines. Nat Commun 15, 6183 (2024). https://doi.org/10.1038/s41467-024-50400-2
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DOI: https://doi.org/10.1038/s41467-024-50400-2
