Diastereoselective Three-Component 1,3-Dipolar Cycloaddition to Access Functionalized β-Tetrahydrocarboline- and Tetrahydroisoquinoline-Fused Spirooxindoles

A chemselective catalyst-free three-component 1,3-dipolar cycloaddition has been described. The unique polycyclic THPI and THIQs were creatively employed as dipolarophiles, which led to the formation of functionalized β-tetrahydrocarboline- and tetrahydroisoquinoline-fused spirooxindoles in 60–94% of yields with excellent diastereoselectivities (10: 1−>99: 1 dr). This reaction not only realizes a concise THPI- or THIQs-based 1,3-dipolar cycloaddition, but also provides a practical strategy for the construction of two distinctive spirooxindole skeletons.


Results and Discussion
To establish the feasibility of this cascade cyclization as well as to optimize the reaction conditions, the three-component 1,3-dipolar cycloaddition of isatin (1a), THPI (2), and (E)-1-methyl-3-(2-nitrovinyl)-1H-indole (3a) was selected as the model reaction.As shown in Table 1, the solvent, temperature, and time were screened successively.Initially, the model reaction was performed in EtOH at room temperature for 8 h, the desired β-tetrahydrocarboline-fused spirooxindole 4a was isolated in a 53% yield with excellent diastereoselectivity (>20: 1 dr).Then, diverse solvents (including proton solvents and aprotic solvents) were screened systematically to further optimize the reaction (entries [1][2][3][4][5][6][7][8][9][10][11][12].The model reaction proceeded smoothly in the all screened solvents except water, which may attribute to the poor dissolution of substrates.Pleasingly, the best reactivity and selectivity were obtained when MeOH was employed (entry 2).To optimize the reactivity, we then investigated the effect of temperature on this cyclization process (entries 2, [13][14]).Significantly, the reactivity increased with increasing temperature.Furthermore, appropriately extending the time (to 12 h) is beneficial for the reaction (entries 14-15) and maintained excellent diastereoselectivity, while there was no significantly increase in yield when further extending the time to 24 h (entries [15][16].Overall, the best reaction conditions for synthesizing functionalized β-tetrahydrocarboline-fused spirooxindoles are achieved by employing isatins ( 1  a All reactions were carried out with 1a (0.5 mmol), 2 (0.5 mmol), and 3a (0.5 mmol) in the corresponding solvents (5 mL) at corresponding temperatures; b Isolated yields, >20: 1 dr by 1 H NMR analysis via the signal of NH; c room temperature.
a All reactions were carried out with 1 (0.5 mmol), 5 (0.5 mmol), and 7 (0.5 mmol) in MeOH under reflux for 12 h; b Isolated yields; c The dr values was determined by 1 H NMR analys signal of NH.
A proposed transition state for the stereochemistry was proposed based on perimental results and previous reports [51 -53] (Scheme 2).Initially, the isatinazomethine ylides were generated in situ via the condensation of isatins (1) and T Then, the intermolecular 1,3-dipolar cycloaddition subsequently executed via do-approach pathway and realized the stereochemistry control of desired produ steric hindrance between the bulky indole moiety of 3-(2-nitrovinyl)-1H-indoles isatin proved plays the key role in the stereochemistry and the excellent diastereos ties.

General Information
Reagents were of the highest commercial grade (Adamas), the solvents were AR, and were used without further purification.NMR spectra were recorded on a Bruker DRX 400 ( 1 H: 400 MHz, 13 C: 100 MHz) with TMS as the internal standard.Chemical shifts (δ) were expressed in ppm, J values were given in Hz, and deuterated DMSO-d 6 was used as a solvent.IR spectra were recorded on an FT-IR Thermo Nicolet Avatar 360 using KBr pellet.The mass spectroscopic data were obtained from an Agilient 6550 Q-TOF & Thermo Fisher-QE spectrometer.Melting points were determined with an SGWX-4 melting-point apparatus.The reactions were monitored by thin-layer chromatography (TLC) with silica gel GF 254 , and all compounds were visualized by UV and sprayed with H 2 SO 4 (10%) in ethanol, followed by heating.A suitable single crystal was selected and analyzed with Rigaku XtaLab Synergy.The 1 H and 13 C NMR spectras for compounds 4, 6, 8, and single crystal X-ray diffraction study data of compound 4c, 6b were included in Supplementary Materials.

General Procedure for the Synthesis of Compounds 8
A mixture of isatins (1, 0.5 mmol), THIQs (5, 0.5 mmol), and ethyl (Z)-2-(2-oxoindolin-3-ylidene) acetates (7, 0.5 mmol) in MeOH was stirred under reflux conditions for 12 h and indicated by TLC.Then, the reaction mixture was allowed to cool to room temperature and extracted with dichloromethane (3×50 mL).The combined organic layers were washed with saturated brine solution (20 mL), followed by drying over MgSO 4 and evaporating in vacuo.The crude product was purified by column chromatography to give the pure title compounds.

Table 2 . 23 a
The synthesis of functionalized β-tetrahydrocarboline-fused spirooxindoles 4 a,b,c .Molecules 2024, 29, x FOR PEER REVIEW 5 of All reactions were carried out with 1 (0.5 mmol), 2 (0.5 mmol), and 3 (0.5 mmol) in MeOH (5 mL) under reflux for 15 h; b isolated yields; c the dr values were determined by 1 H NMR analysis via the signal of NH.To further explore the scope of this 1,3-dipolar cycloaddition, and develop an effective THIQs-based method via catalyst-free strategy, the three-component cycloaddition of isatins (1), 3-(2-nitrovinyl)-1H-indoles (3), and (THIQs) 5 was described under the optimized a All reactions were carried out with 1 (0.5 mmol), 2 (0.5 mmol), and 3 (0.5 mmol) in MeOH (5 mL) under reflux for 15 h; b isolated yields; c the dr values were determined by 1 H NMR analysis via the signal of NH.
yields with excellent diastereoselectivities (all >99: 1 dr).Diverse isatins (1), 3-(2-nitrovinyl)-1H-indoles (3) and (THIQs) 5 bearing various different electron properties and substitution patterns, have been systematically evaluated, and the structure and practicability of this cascade cyclization were also clarified by the X-ray crystallographic analysis (CCDC: 2339410) and gram-level experiment of 6b separately.It is worth noting that the high-purity products 6 were obtained by the simple filtration and recrystallization for the most examples.This 1,3-dipolar cycloaddition not only establishes a THIQ-based catalyst-free synthesis strategy, but also provides a concise, easy-operation synthetic pathway for functionalized spirooxindoles.

Table 4 .Table 3 .
The synthesis of functionalized spirooxindoles 8 a,b,c .erated for all tested substrates, affording desired functionalized spirooxindoles 6 in 61-94% yields with excellent diastereoselectivities (all >99: 1 dr).Diverse isatins (1), 3-(2-nitrovinyl)-1H-indoles (3) and (THIQs) 5 bearing various different electron properties and substitution patterns, have been systematically evaluated, and the structure and practicability of this cascade cyclization were also clarified by the X-ray crystallographic analysis (CCDC: 2339410) and gram-level experiment of 6b separately.It is worth noting that the high-purity products 6 were obtained by the simple filtration and recrystallization for the most examples.This 1,3-dipolar cycloaddition not only establishes a THIQ-based catalyst-free synthesis strategy, but also provides a concise, easy-operation synthetic pathway for functionalized spirooxindoles.The synthesis of functionalized spirooxindoles 6 a,b,c .a All reactions were carried out with 1 (0.5 mmol), 3 (0.5 mmol), and 5 (0.5 mmol) in MeOH (5 mL) under reflux for 12 h; b Isolation of recrystallized yields; c All >99: 1 dr, determined by 1 H NMR analysis via the signal of NH.

Table 4 . 23 a
The synthesis of functionalized spirooxindoles 8 a,b,c .Molecules 2024, 29, x FOR PEER REVIEW 7 of All reactions were carried out with 1 (0.5 mmol), 5 (0.5 mmol), and 7 (0.5 mmol) in MeOH (5 mL) under reflux for 12 h; b Isolated yields; c The dr values was determined by 1 H NMR analysis via the signal of NH.

a
-nitrovinyl)-1H-indoles (3) and isatin proved plays the key role in the stereochemistry and the excellent diastereoselectivi-All reactions were carried out with 1 (0.5 mmol), 5 (0.5 mmol), and 7 (0.5 mmol) in MeOH (5 mL) under reflux for 12 h; b Isolated yields; c The dr values was determined by 1 H NMR analysis via the signal of NH.

Table 1 .
Optimized reaction conditions a,b .

Table 1 .
Optimized reaction conditions a,b .

Table 3 .
The synthesis of functionalized spirooxindoles 6 a,b,c .

Table 4 .
The synthesis of functionalized spirooxindoles 8 a,b,c .