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Article

Squaramide-Catalyzed Asymmetric Michael Addition/Cyclization Reaction for the Synthesis of Chiral Bisspiro Barbituric Acid–Oxindole Derivatives

by
De-Jun Qiao
and
Da-Ming Du
*
Key Laboratory of Medicinal Molecule Science and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, China
*
Author to whom correspondence should be addressed.
Molecules 2025, 30(9), 2000; https://doi.org/10.3390/molecules30092000
Submission received: 27 March 2025 / Revised: 25 April 2025 / Accepted: 28 April 2025 / Published: 30 April 2025
(This article belongs to the Special Issue Current Development of Asymmetric Catalysis and Synthesis)
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Abstract

An efficient stereoselective strategy for the synthesis of chiral bisspiro barbituric acid–oxindole derivatives was developed. The asymmetric Michael addition/cyclization tandem reaction between benzylidene barbituric acids and oxindolylmalonitriles was catalyzed by squaramide catalyst, and the corresponding spirocyclic products were obtained in good-to-high yields (up to 97%) with excellent stereoselectivities (up to >99% ee, >20:1 dr). At the same time, the practicality of the reaction was verified by the gram-scale preparation reaction.

Graphical Abstract

1. Introduction

Barbituric acid was first discovered and named by German chemist Adolf von Baeyer in 1864 [1]. The methylene group at the C5 position of barbituric acid is highly reactive [pka(DMSO) 8.4] due to the influence of two adjacent electron-withdrawing carbonyl groups, so many chemical reactions take place at this position, such as the common Michael addition reaction, substitution reaction, chelation reaction, and Knoevenagel condensation reaction [2]. The biological activity of a series of barbiturates has attracted the attention of many scientists in the field of medicinal chemistry. Barbituric acid derivatives are widely used as anesthetics [3] and sedatives [4] and have anti-convulsant [5], anti-diabetic [6], anti-bacterial [7], anti-cancer [8], and other properties (Figure 1a). When the two H atoms of methylene at 5-position of barbituric acid are replaced by hydrocarbon groups or heterocycles, they can also be used as drug intermediates, such as barbiturates involved in the treatment of certain types of epilepsy [9]. Meanwhile, alkylidene barbituric acids are good Michael acceptors (Figure 1b), which can be applied for constructing many other barbituric acid derivatives [10]. In addition to being biologically active, the photophysical properties of barbiturate derivatives [11] have also been used for colorimetric or thermal detection [12] and have provided some promising dyes or fluorescent probes [13,14]. These applications indicate that barbiturate derivatives have very broad potential value.
As mentioned above, barbituric acid derivatives are easily deprotonated owing to their rather low pKa value. Catalytic asymmetric transformations of barbituric acid derivatives have received much attention in recent years for synthesis of chiral barbituric acid derivatives [10]. For example, Rawal et al. reported an enantioselective Michael addition of N,N′-disubstituted barbituric acid derivatives to β-nitro olefins using chiral thiosquaramide as a bifunctional organocatalyst (Scheme 1a) [15]. The addition products were obtained in high yields with excellent enantioselectivity at catalyst loading as low as 0.5 mol% in toluene at room temperature. Wang and co-workers [16] developed an enantioselective organocatalytic Michael addition of N,N′-dialkylbarbituric acid derivatives to enones using 10 mol% quinine-derived squaramide catalyst, a series of Michael adducts were obtained in 44–99% yields with 91–99% ee in o-xylene at room temperature (Scheme 1b). Chen and co-workers [17] developed a tertiary amine-thiourea-catalyzed domino Michael-oxa-Michael addition reaction of N,N′-dimethyl barbituric acid and Morita–Baylis-Hillman (MBH) acetate of nitroalkene; the corresponding tetrahydropyrano bicycles were obtained up to 95% yields with dr > 19:1 and up to 95% ee in CH2Cl2 at 25 °C (Scheme 1c).
Alkylidene barbituric acids as reactive electron-poor alkene derivatives also attracted the attention of researchers in recent years; for example, Zhao’s group reported on a racemic [3 + 2] cycloaddition between alkylidene barbiturates and 3-isothiocyanato oxindoles catalyzed by Et3N [18]. In 2016, Zhao et al. developed an epi-quinine-thiourea-based thiourea-catalyzed enantioselective version in chloroform, and the corresponding spirobarbiturates were obtained in 80–99% yield with 9:1 to >20:1 dr and 18–99% ee [19]. Guo and co-worker an enantioselective phosphine-catalyzed [3 + 2] annulation of alkylidene barbiturates with MBH adducts, and spirobarbiturates were obtained in excellent diastereoselectivities (4;1–>20:1 dr) and high-to-excellent enantioselectivities (81–99% ee) (Scheme 1e) [20]. Our group developed a squaramide-catalyzed asymmetric Michael/Mannich [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethyl isatin ketimines and barbiturate-based olefins. The corresponding dispirobarbituric acid derivatives were obtained in excellent yields (up to 99% yield) and excellent stereoselectivities (up to 99:1 dr and >99% ee) (Scheme 1f) [21].
Molecules 30 02000 sch001
Scheme 1. Examples for asymmetric synthesis of barbituric acid derivatives. (a) Rawal’s work [15], (b) Wang’s work [16], (c) Chen’s work [17], (d) Zhao’s work [19], (e) Guo’s work [20], and (f) Du’s work [21].
Scheme 1. Examples for asymmetric synthesis of barbituric acid derivatives. (a) Rawal’s work [15], (b) Wang’s work [16], (c) Chen’s work [17], (d) Zhao’s work [19], (e) Guo’s work [20], and (f) Du’s work [21].
Molecules 30 02000 sch001
In the above-mentioned reports [19,21], the oxindole skeleton also played a crucial role, as these reagents are prone to undergo the tandem reaction with electron-deficient alkenes to construct spirooxindole derivatives. The catalytic asymmetric synthesis of chiral spirooxindoles has also received wide attention in recent years [22]. Continuing on our research project for squaramide-catalytic asymmetric reactions [23], herein, the asymmetric Michael addition/cyclization tandem reaction between barbituric acid derivatives and oxindole derivatives was developed using chiral squaramide as catalyst in order to obtain chiral bisspiro barbituric acid–oxindole derivatives, which may provide potential candidates for future drug design and biological activity research.

2. Results and Discussion

2.1. Optimization of Reaction Conditions

To verify our hypothesis, the asymmetric Michael/cyclization reaction of substrates 1a and 2a in the presence of quinine-derived squaramide C1 was selected as the model reaction. We were pleased to find that the asymmetric Michael/cyclization reaction could be completed within 8 h in the presence of 10 mol% C1 at room temperature and obtained the desired product 3aa in 88% yield with excellent stereoselectivity (>20:1 dr, 86% ee) (Table 1, entry 1). Encouraged by these excellent results, we screened several organocatalysts with different frameworks for this asymmetric Michael/cyclization reaction (Figure 2) (Table 1, entries 2–12). However, the catalytic yields using catalysts C2, C3, and C9 were low (Figure 2) (Table 1, entries 2–12), and the remaining catalysts achieved high yields (>80%) and stereoselectivity (>20:1 dr, >75% ee) (Table 1, entry 2–12). Considering yield and stereoselectivity, C5 has the best catalytic effect (Table 1, entry 5).
In order to further improve the reaction efficiency, squaramide C5 was used as a catalyst to optimize other reaction conditions. The effects of solvent, catalyst loading, and reaction temperature on the reaction were evaluated in detail (Table 1, entries 13−19). Solvents play an integral role in the reaction, so we evaluated five other organic solvents, acetonitrile, toluene, THF, chloroform, and methyl tert-butyl ether (MTBE) (Table 1, entries 13−17). However, a series of results show that dichloromethane is still the best solvent. Then, we studied the effect of catalyst loading on the reaction. As the amount of catalyst was halved, the yield and stereoselectivity of the product unfortunately decreased (Table 1, entry 18). As the reaction temperature decreased, the yield of the product did not increase, and its enantioselectivity gradually decreased (Table 1, entry 19). By comparison, the optimal conditions were determined to be benzylidenebarbituric acid and oxindolylmalonitrile as raw materials in the molar ratio of 1.2:1, with 10 mol% C5 as catalyst, in CH2Cl2 solvent, at room temperature for 8 h.

2.2. Substrate Scope

After the optimum reaction conditions were obtained, the applicability of different substrates to the asymmetric Michael/cyclization reaction was investigated. The result is shown in Scheme 2. Firstly, the effect of benzylidene barbituric acid substrate on the reaction was studied, and the effect of different substitution groups on the reaction was explored. The results show that steric hindrance had a great effect on the reaction. When benzene rings in benzylidenes were meta-substituted or para-substituted, the reaction occurred normally (3aa–ja), but when benzene rings in benzylidenes were ortho-substituted, the corresponding substrates did not react with 2a (3la–oa). The electron effect of substituents also affected the course of the reaction. For electron-withdrawing groups, the substituted substrates bearing bromo- or chloro-substituents showed good yield and stereoselectivity. The substrate with a para-substituted fluoro group was an exception, and the stereoselectivity of the corresponding product was relatively poor, which was considered to be due to the strong electron-withdrawing withdrawing of fluorine. For electron-donating groups, methyl- or methoxy-substituted substrates behaved generally similarly as compared to the bromo-substituted substrate. In addition, the comparison of the yield and enantioselectivity of thienyl-, furanyl-, and pyridinyl-substituted substrates is very interesting. The reaction yield and enantioselectivity of thienyl-substituted substrate were very good (3da), the yield and enantioselectivity of furanyl-substituted substrate were moderate (3fa), and the reaction of pyridinyl-substituted substrate did not occur (3na). This may be ascribed to the electronic effect of these three different heterocycles.
After studying the effect of benzylidene substituents of benzylidene barbituric acids on the reaction, the effect of the N-protecting group of oxindolylmalonitriles on the reaction was studied. When R1 was a benzyl group or a methyl group, the reaction maintained high selectivity and high efficiency (3aa and 3ab). Subsequently, the different substituents on the phenyl rings of oxindolylmalonitriles were studied. We found that the stereoselectivity of substrates bearing electron-withdrawing substituted indole-phenyl rings was generally better than that of substrates bearing electron-donating substituents. Among the electron-withdrawing groups as substituents (3ac, 3ae–aj), all of them maintained excellent yields and stereoselectivities except for the 2-fluoro-substituent. As for the electron-donating groups, the dimethyl-substituted substrate performed better than the monomethyl-substituted substrate (3ad, 3ak).

2.3. Scaled-Up Synthesis

In order to further demonstrate the application value of this synthetic method, the gram-scale experiment was conducted under optimized conditions. As shown in Scheme 3, the gram-scale asymmetric Michael/cyclization reaction of 1a and 2a proceeded smoothly, and the product 3aa was obtained in 88% yield with excellent stereoselectivity (>20:1 dr, 95% ee).

2.4. Absolute Configuration

The absolute configuration of the chiral product 3ha was determined by X-ray diffraction analysis and was found to be (2′R,3S) (CCDC 2431390) (Figure 3). The absolute configurations of other chiral products were assigned by analogy.

2.5. Reaction Mechanism

According to the absolute configuration of the tandem product 3ha and the catalytic mode of the chiral bifunctional squaramide for a similar reaction [24], a possible transition state model of the catalytic reaction was proposed (Scheme 4). On the one hand, oxindolylmalonitrile 2a is partially deprotonated by the tertiary amine of catalyst C5. On the other hand, benzylidene barbituric acid 1a is activated by forming two hydrogen bonds in the N-H of the squaramide part. Subsequently, the deprotonated-activated oxindolylmalonitrile attacks the Si-face of the electron-deficient unsaturated barbituric acid 1a through the transition state A, and the intermolecular Michael addition reaction occurs. At the same time, the resulting Michael addition intermediates undergo further intramolecular cyclization reaction to obtain B. Finally, the molecular isomerization reaction occurs to obtain the desired bisspirocyclic product 3aa, and the bifunctional squaramide catalyst C5 is regenerated to enter the next catalytic cycle of reaction.

3. Materials and Methods

3.1. General Information

Commercially available compounds were used without further purification. Solvents were dried according to standard procedures. Column chromatography was performed with silica gel (200−300 mesh). Melting points were determined with a WRX-4 melting-point apparatus and were uncorrected. 1H NMR spectra were measured with Bruker Ascend 400 MHz spectrometer and Bruker Ascend 700 MHz spectrometer (Bruker, Karlsurhe, Germany); chemical shifts were reported in δ (ppm) units relative to tetramethylsilane (TMS) as internal standard. 13C NMR spectra were measured at 101 MHz with 400 MHz spectrometer and measured at 176 MHz with 700 MHz spectrometer; chemical shifts are reported in ppm relative to tetramethylsilane and referenced to solvent peak (CDCl3, δC = 77.00; DMSO, δC = 39.43). High-resolution mass spectra (Electron spray ionization) were measured with an Agilent 6520 Accurate-Mass Q-TOF MS system (Agilent, Santa Clara, CA, USA) equipped with an electrospray ionization (ESI) source. Optical rotations were measured with a Krüss P8000 polarimeter (Krüss, Hamburg, Germany). Optical rotations at the indicated concentration with the units of g/100 mL. Enantiomeric excesses were determined by chiral HPLC analysis using an Agilent 1200 LC instrument (Agilent, Santa Clara, CA, USA) with a Daicel Chiralpak ADH, IA, or IC column (Daicel, Beijing, China).

3.2. Experimental Materials for Tandem Reactions

First, 1a–1j were prepared according to literature reported by Neumann and co-workers [25]. Then, 2a–2k were prepared according to literature reported by Lin and co-workers [24]. The chiral organocatalysts were prepared by following the reported procedures [26,27,28,29].

3.3. Procedure for the Synthesis of Racemates of 3

To a dried small vial, benzylidene barbituric acid 1 (0.24 mmol), oxindolylmalonitrile 2 (0.2 mmol), Et3N (1.0 mg, 0.01 mmol, 0.05 equiv.), and CH2Cl2 (1 mL) were added. After stirring at room temperature under air without gas protection for 8 h, the reaction mixture was concentrated and directly purified by silica gel column chromatography to afford the racemates of 3.

3.4. Procedure for the Asymmetric Michael/Cyclization Reaction

To a dried small vial, barbituric acid 1 (0.24 mmol), oxindolylmalonitrile 2 (0.2 mmol), chiral organocatalyst C5 (5.08 mg, 0.01 mmol, 0.05 equiv), and CH2Cl2 (1.0 mL) were added. After stirring at room temperature under air without gas protection for 8 h, the reaction mixture was concentrated and directly purified by silica gel column chromatography (200–300 mesh) using ethyl acetate/petroleum ether (1:2) as eluent to afford the desired products 3.
(2′R,3S)-4′-Amino-1,1″,3″-trimethyl-2,2″,4″,6″-tetraoxo-2′-phenyl-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3aa). According to the general procedure from 1a (58.6 mg, 0.24 mmol) and 2a (42.2 mg, 0.2 mmol) to obtain 85.6 mg (94% yield) compound 3aa as a yellow solid, m.p. 192−195 °C. HPLC (Daicel Chiralpak ADH, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 9.2 min (major), >99% ee. [α]D25 = +9.9 (c = 0.5, CH2Cl2). 1H NMR (700 MHz, DMSO-d6): δ 8.05 (dd, J1 = 7.7 Hz, J2 = 0.7 Hz, 1H), 7.28 (td, J1 = 7.7 Hz, J2 = 1.4 Hz 1H), 7.15–7.18 (m, 4H), 7.06 (t, J = 8.0 Hz, 2H), 6.86 (d, J = 7.7 Hz, 1H), 6.76 (d, J = 7.0 Hz, 2H), 4.24 (s, 1H), 3.07 (s, 3H), 2.99 (s, 3H), 2.87 (s, 3H) ppm. 13C NMR (176 MHz, DMSO-d6): δ 176.5, 168.6, 167.8, 158.4, 149.8, 143.0, 131.1, 129.4, 129.3, 129.0, 128.3, 128.0, 127.3, 122.3, 116.3, 108.7, 78.5, 68.1, 64.8, 63.4, 28.5, 28.3, 26.4 ppm. (see Supplementary Materials) HRMS (ESI): m/z calcd. for C25H22N5O4 [M + H]+ 456.1666, found 456.1686.
(2′R,3S)-4′-Amino-2′-(4-chlorophenyl)-1,1″,3″-trimethyl-2,2″,4″,6″-tetraoxo-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3ba). According to the general procedure from 1b (66.7 mg, 0.24 mmol) and 2a (42.2 mg, 0.2 mmol) to obtain 82.2 mg (84% yield) compound 3ba as a yellow solid, m.p. 183–185 °C. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 6.8 min (minor), tR = 9.4 min (major), 86% ee. [α]D25 = +12.2 (c = 0.34, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 7.2 Hz, 1H), 7.29–7.25 (m, 1H), 7.17 (td, J1 = 7.6 Hz, J2 = 0.8 Hz, 1H), 7.01 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 7.6 Hz, 1H), 5.65 (s, 2H), 4.37 (s, 1H), 3.20 (s, 3H), 3.03 (s, 3H), 2.98 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ 176.8, 168.6, 167.1, 158.0, 149.8, 143.9, 135.6, 131.1, 129.8, 129.3, 128.5, 128.2, 127.3, 123.2, 115.3, 108.7, 83.2, 68.6, 64.6, 63.9, 29.3, 28.9, 26.8 ppm. HRMS (ESI): m/z calcd. for C25H21ClN5O4 [M + H]+ 490.1277, found 490.1301.
(2′R,3S)-4′-Amino-1,1″,3″-trimethyl-2′-(naphthalen-2-yl)-2,2″,4″,6″-tetraoxo-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3ca). According to the general procedure from 1c (70.6 mg, 0.24 mmol) and 2a (42.2 mg, 0.2 mmol) to obtain 93.0 mg (92% yield) compound 3ca as a yellow solid, m.p. 201–203 °C. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 13.0 min (minor), tR = 16.7 min (major), 83% ee. [α]D25 = +16.5 (c = 0.5, CH2Cl2). 1H NMR (400 MHz, DMSO-d6): δ 8.18 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 9.4 Hz, 2H), 7.61 (td, J1 = 7.6 Hz, J2 = 1.0 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.32–7.22 (m, 4H), 7.12 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 5.49 (s, 1H), 2.88 (s, 3H), 2.81 (s, 3H), 2.60 (s, 3H) ppm. 13C NMR (101 MHz, DMSO-d6): δ 176.5, 168.7, 168.0, 158.5, 149.4, 143.1, 133.0, 131.9, 129.4, 129.3, 129.1, 128.5, 127.5, 127.2, 126.7, 125.9, 123.8, 122.5, 120.7, 116.3, 108.9, 79.1, 68.3, 63.6, 55.9, 28.3, 26.4 ppm. HRMS (ESI): m/z calcd. for C29H24N5O4 [M + H]+ 506.1823, found 506.1818.
(2′R,3S)-4′-Amino-1,1″,3″-trimethyl-2,2″,4″,6″-tetraoxo-2′-(thiophen-2-yl)-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3da). According to the general procedure from 1d (60.0 mg, 0.24 mmol) and 2a (42.2 mg, 0.2 mmol) to obtain 75.6 mg (82% yield) compound 3da as a brown solid, m.p. 214–215 °C. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol/ethyl acetate = 80:10:10, flow rate 1.0 mL/min, detection at 254 nm): tR = 19.3 min (minor), tR = 26.4 min (major); >99% ee. [α]D25 = +18.5 (c = 0.4, CH2Cl2). 1H NMR (700 MHz, DMSO-d6): δ 8.06 (d, J = 7.7 Hz, 1H), 7.36–7.32 (m, 2H), 7.20–7.16 (m, 3H), 6.94 (d, J = 7.7 Hz, 1H), 6.78 (dd, J1 = 4.9 Hz, J2 = 4.2 Hz, 1H), 6.68 (d, J = 3.5 Hz, 1H), 4.62 (s, 1H), 3.18 (s, 3H), 3.05 (s, 3H), 2.85 (s, 3H) ppm. 13C NMR (176 MHz, DMSO-d6): δ 176.2, 168.3, 167.3, 158.0, 150.0, 143.4, 132.5, 129.8, 129.4, 128.2, 128.0, 127.8, 126.3, 122.4, 116.2, 108.7, 78.5, 68.4, 63.0, 59.7, 28.7, 28.6, 26.5 ppm. HRMS (ESI): m/z calcd. for C23H20N5O4S [M + H]+ 462.1231, found 462.1253.
(2′R,3S)-4′-Amino-1,1″,3″-trimethyl-2,2″,4″,6″-tetraoxo-2′-(m-tolyl)-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3ea). According to the general procedure from 1e (61.92 mg, 0.24 mmol) and 2a (42.2 mg, 0.2 mmol) to obtain 79.7 mg (85% yield) compound 3ea as a white solid, m.p. 194–196 °C. HPLC (Daicel Chiralpak ADH, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 6.5 min (minor), tR = 11.5 min (major), 78% ee. [α]D25 = +14.8 (c = 0.5, CH2Cl2). 1H NMR (400 MHz, DMSO-d6): δ 8.06 (dd, J1 = 7.6 Hz, J2 = 0.8 Hz, 1H), 7.28 (td, J = 7.6 Hz, J2 = 1.2 Hz, 1H), 7.17 (t, J = 7.2 Hz, 3H), 6.98–6.91 (m, 2H), 6.85 (d, J = 7.6 Hz, 1H), 6.58 (s, 1H), 6.54 (d, J = 7.2 Hz, 1H), 4.20 (s, 1H), 3.08 (s, 3H), 2.98 (s, 3H), 2.86 (s, 3H), 2.03 (s, 3H) ppm. 13C NMR (101 MHz, DMSO-d6): δ 176.5, 168.6, 167.8, 158.4, 149.8, 143.0, 137.2, 131.1, 130.1, 129.5, 129.2, 128.4, 127.8, 127.3, 126.4, 122.1, 116.3, 108.7, 78.5, 68.1, 64.7, 63.4, 28.5, 28.3, 26.4, 20.5. ppm. HRMS (ESI): m/z calcd. for C26H24N5O4 [M + H]+ 470.1823, found 470.1812.
(2′R,3S)-4′-Amino-2′-(furan-2-yl)-1,1″,3″-trimethyl-2,2″,4″,6″-tetraoxo-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3fa). According to the general procedure from 1f (56.2 mg, 0.24 mmol) and 2a (42.2 mg, 0.2 mmol) to obtain 64.1 mg (72% yield) compound 3fa as a brown solid, m.p. 174–176 °C. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 6.6 min (minor), tR = 8.2 min (major), 55% ee. [α]D25 = −2.0 (c = 0.33, CH2Cl2). 1H NMR (700 MHz, DMSO-d6): δ 7.93 (dd, J = 7.7 Hz, 1H), 7.38 (d, J = 1.4 Hz, 1H), 7.32 (td, J1 = 7.7 Hz, J2 = 0.7 Hz, 1H), 7.17–7.12 (m, 3H), 6.97 (d, J = 7.7 Hz, 1H), 6.15 (dd, J1 = 3.2 Hz, J2 = 1.8 Hz, 1H), 5.74 (d, J = 2.8 Hz, 1H), 4.41 (s, 1H), 3.19 (s, 3H), 3.10 (s, 3H), 2.94 (s, 3H) ppm. 13C NMR (176 MHz, DMSO-d6): δ 176.0, 168.2, 167.2, 157.7, 150.2, 145.9, 144.0, 142.9, 129.3, 128.2, 127.4, 122.3, 116.0, 110.7, 110.4, 108.6, 78.8, 66.9, 61.7, 56.5, 28.7, 28.6, 26.5 ppm. HRMS (ESI): m/z calcd. for C23H20N5O5 [M + H]+ 446.1459, found 446.1472.
(2′R,3S)-4′-Amino-2′-(4-fluorophenyl)-1,1″,3″-trimethyl-2,2″,4″,6″-tetraoxo-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3ga). According to the general procedure from 1g (62.9 mg, 0.24 mmol) and 2a (42.2 mg, 0.2 mmol) to obtain 80.4 mg (85% yield) compound 3ga as a pink solid, m.p. 178–179 °C. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol/ethyl acetate = 80:15:5, flow rate 1.0 mL/min, detection at 254 nm): tR = 13.4 min (minor), tR = 21.9 min (major); 59% ee. [α]D25 = +9.0 (c = 0.8, CH2Cl2). 1H NMR (700 MHz, DMSO-d6): δ 8.03 (d, J = 7.0 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.20–7.16 (m, 3H), 6.94–6.88 (m, 3H), 6.83–6.80 (m, 2H), 4.25 (s, 1H), 3.09 (s, 3H), 3.01 (s, 3H), 2.91 (s, 3H) ppm. 13C NMR (176 MHz, DMSO-d6): δ 176.4, 168.5, 167.7, 162.1 (1JC–F = 246.9 Hz), 158.3, 149.9, 143.0, 131.5 (3JC–F = 8.3 Hz), 129.4, 128.1, 127.3 (4JC–F = 2.6 Hz), 127.2, 122.4, 116.2, 115.0 (2JC–F = 21.5 Hz), 108.8, 78.3, 67.9, 63.7, 63.4, 28.6, 28.4, 26.4 ppm. 19F NMR (659 MHz, DMSO-d6): δ −112.1. HRMS (ESI): m/z calcd. for C25H21FN5O4 [M + H]+ 474.1572, found 474.1587.
(2′R,3S)-4′-Amino-2′-(3-bromophenyl)-1,1″,3″-trimethyl-2,2″,4″,6″-tetraoxo-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3ha). According to the general procedure from 1h (77.3 mg, 0.24 mmol) and 2a (42.2 mg, 0.2 mmol) to obtain 103.4 mg (97% yield) compound 3ha as a pink solid, m.p. 194–195 °C. HPLC (Daicel Chiralpak ADH, n-hexane/2-propanol = 75:25, flow rate 1.0 mL/min, detection at 254 nm): tR = 11.8 min (minor), tR = 14.5 min (major); 89% ee. [α]D25 = +14.9 (c = 0.5, CH2Cl2). 1H NMR (700 MHz, DMSO-d6): δ 8.03 (d, J = 7.7 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.23–7.18 (m, 3H), 7.07 (t, J = 8.0 Hz, 1H), 6.93 (s, 1H), 6.90 (d, J = 7.7 Hz, 1H), 6.85 (d, J = 7.7 Hz, 1H), 4.20 (s, 1H), 3.10 (s, 3H), 3.01 (s, 3H), 2.92 (s, 3H) ppm. 13C NMR (176 MHz, DMSO-d6): δ 176.2, 168.2, 167.7, 158.2, 149.8, 143.0, 133.5, 131.9, 131.6, 130.3, 129.5, 129.1, 127.9, 127.1, 122.3, 121.0, 116.2, 109.0, 78.2, 67.9, 63.6, 63.3, 28.6, 28.3, 26.4 ppm. HRMS (ESI): m/z calcd. for C25H2179BrN5O4 [M + H]+ 534.0771, found 534.0786; calcd. for C25H2181BrN5O4 [M + H]+ 536.0751, found 536.0770.
(2′R,3S)-4′-Amino-2′-(3,4-dimethoxyphenyl)-1,1″,3″-trimethyl-2,2″,4″,6″-tetraoxo-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3ia). According to the general procedure from 1i (73.0 mg, 0.24 mmol) and 2a (42.2 mg, 0.2 mmol) to obtain 90.2 mg (93% yield) compound 3ia as a yellow solid, m.p. 203–205 °C. HPLC (Daicel Chiralpak ADH, n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min, detection at 254 nm): tR = 19.0 min (minor), tR = 21.3 min (major), 73% ee. [α]D25 = +49.1 (c = 0.7, CH2Cl2). 1H NMR (700 MHz, DMSO-d6): δ 8.10 (d, J = 7.7 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.18 (t, J = 7.7 Hz, 3H), 6.90 (d, J = 7.7 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.37 (dd, J1 = 8.0 Hz, J2 = 1.4 Hz, 1H), 6.21 (s, 1H), 4.17 (s, 1H), 3.61 (s, 3H), 3.33 (s, 3H), 3.11 (s, 3H), 3.00 (s, 3H), 2.87 (s, 3H) ppm. 13C NMR (176 MHz, DMSO-d6): δ 176.6, 168.7, 167.9, 158.5, 150.0, 148.9, 147.5, 143.2, 129.2, 128.8, 127.2, 123.0, 122.8, 122.1, 116.4, 111.5, 110.7, 108.9, 78.3, 68.2, 64.5, 63.5, 55.1, 55.0, 28.6, 28.4, 26.4 ppm. HRMS (ESI): m/z calcd. for C27H26N5O6 [M + H]+ 516.1878, found 516.1895.
(2′R,3S)-4′-Amino-2′-(4-bromophenyl)-1,1″,3″-trimethyl-2,2″,4″,6″-tetraoxo-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3ja). According to the general procedure from 1j (77.3 mg, 0.24 mmol) and 2a (42.2 mg, 0.2 mmol) to obtain 98.1 mg (92% yield) compound 3ja as a pink solid, m.p. 217–219 °C. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 7.5 min (minor), tR = 12.4 min (major); 84% ee. [α]D25 = +27.4 (c = 0.9, CH2Cl2). 1H NMR (400 MHz, DMSO-d6): δ 8.01 (dd, J1 = 7.6 Hz, J2 = 0.8 Hz, 1H), 7.32–7.27 (m, 3H), 7.20–7.15 (m, 3H), 6.88 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.8 Hz, 2H), 4.22 (s, 1H), 3.09 (s, 3H), 3.01 (s, 3H), 2.93 (s, 3H) ppm. 13C NMR (176 MHz, DMSO-d6): δ 176.4, 168.5, 167.8, 158.4, 149.9, 143.0, 131.5, 131.1, 130.5, 129.5, 128.0, 127.3, 122.6, 122.5, 116.3, 108.9, 78.4, 67.8, 63.9, 63.4, 28.7, 28.5, 26.5 ppm. HRMS (ESI): m/z calcd. for C25H2179BrN5O4 [M + H]+ 534.0771, found 534.0793; calcd. for C25H2181BrN5O4 [M + H]+ 536.0751, found 536.0777.
(2′R,3S)-4′-Amino-1-benzyl-1″,3″-dimethyl-2,2″,4″,6″-tetraoxo-2′-phenyl-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3ab). According to the general procedure from 1a (58.6 mg, 0.24 mmol) and 2b (57.4 mg, 0.2 mmol) to obtain 100.9 mg (95% yield) compound 3ab as a yellow solid, m.p. 165–167 °C. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 40.3 min (minor), tR = 24.9 min (major), >99% ee. [α]D25 = −11.4 (c = 0.4, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.17 (dd, J1 = 6.4 Hz, J2 = 1.4 Hz, 1H), 7.24–7.20 (m, 1H), 7.17–7.00 (m, 7H), 6.82 (d, J = 7.6 Hz, 2H), 6.61 (d, J = 7.6 Hz, 2H), 6.41 (d, J = 7.2 Hz, 1H), 5.60 (s, 2H), 5.02 (d, J = 16.4 Hz, 1H), 4.49 (d, J = 16.4 Hz, 1H), 4.44 (s, 1H), 3.13 (s, 3H), 2.93 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ 177.2, 168.6, 167.2, 158.2, 149.8, 142.3, 134.4, 130.5, 123.0, 129.55, 129.52, 128.5, 128.30, 128.27, 127.7, 127.2, 126.1, 123.1, 115.5, 109.5, 83.3, 68.8, 66.1, 64.1, 43.8, 29.1, 28.8 ppm. HRMS (ESI): m/z calcd. for C31H26N5O4 [M + H]+ 532.1979, found 532.2000.
(2′R,3S)-4′-Amino-6-chloro-1,1″,3″-trimethyl-2,2″,4″,6″-tetraoxo-2′-phenyl-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3ac). According to the general procedure from 1a (58.6 mg, 0.24 mmol) and 2c (49.0 mg, 0.2 mmol) to obtain 90.0 mg (92% yield) compound 3ac as a yellow solid, m.p. 172–174 °C. HPLC (Daicel Chiralpak ADH, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 8.0 min (minor), tR = 15.6 min (major), 91% ee. [α]D25 = −30.9 (c = 0.4, CH2Cl2). 1H NMR (700 MHz, DMSO-d6): δ 8.04 (d, J = 8.4 Hz, 1H), 7.25 (dd, J1 = 8.0 Hz, J2 = 2.2 Hz, 3H), 7.19 (t, J = 7.4 Hz, 1H), 7.11 (t, J = 7.7 Hz, 2H), 7.04 (d, J = 1.4 Hz, 1H), 6.75 (d, J = 7.7 Hz, 2H), 4.23 (s, 1H), 3.07 (s, 3H), 3.01 (s, 3H), 2.89 (s, 3H) ppm. 13C NMR (176 MHz, DMSO-d6): δ 176.6, 168.5, 167.9, 158.7, 149.8, 144.5, 133.8, 130.8, 129.3, 129.2, 128.6, 128.2, 127.2, 122.1, 116.1, 109.3, 77.9, 67.9, 64.7, 63.2, 28.6, 28.4, 26.6 ppm. HRMS (ESI): m/z calcd. for C25H21ClN5O4 [M + H]+ 490.1277, found 490.1300.
(2′R,3S)-4′-amino-1,1″,3″,5,7-pentamethyl-2,2″,4″,6″-tetraoxo-2′-phenyl-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3ad). According to the general procedure from 1a (58.6 mg, 0.24 mmol) and 2d (47.8 mg, 0.2 mmol) to obtain 86.9 mg (90% yield) compound 3ad as a white solid, m.p. 181–182 °C. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 56.3 min (minor), tR = 40.3 min (major), 90% ee. [α]D25 = −40.6 (c = 0.4, CH2Cl2). 1H NMR (700 MHz, DMSO-d6): δ 7.76 (s, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.13 (s, 2H), 7.07 (t, J = 7.7 Hz, 2H), 6.83 (s, 1H), 6.76 (d, J = 7.7 Hz, 2H), 4.22 (s, 1H), 3.23 (s, 3H), 3.07 (s, 3H), 2.84 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H) ppm. 13C NMR (176 MHz, DMSO-d6): δ 177.1, 168.7, 167.8, 158.2, 149.8, 138.5, 133.3, 131.3, 130.8, 129.5, 129.1, 128.9, 128.0, 126.0, 119.3, 116.5, 79.2, 68.2, 65.0, 63.0, 29.6, 28.5, 28.4, 20.7, 18.3 ppm. HRMS (ESI): m/z calcd. for C27H26N5O4 [M + H]+ 484.1979, found 484.1992.
(2′R,3S)-4′-Amino-6-fluoro-1,1″,3″-trimethyl-2,2″,4″,6″-tetraoxo-2′-phenyl-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3ae). According to the general procedure from 1a (58.6 mg, 0.24 mmol) and 2e (45.8 mg, 0.2 mmol) to obtain 79.5 mg (84% yield) compound 3ae as a white solid, m.p. 173–175 °C. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 9.4 min (minor), tR = 11.8 min (major), 82% ee. [α]D25 = −62.8 (c = 1, CH2Cl2). 1H NMR (700 MHz, DMSO-d6): δ 8.04 (dd, J1 = 7.7 Hz, J2 = 5.6 Hz, 1H), 7.23 (s, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.10 (t, J = 7.4 Hz, 2H), 7.01–6.98 (m, 1H), 6.86 (d, J = 9.1 Hz, 1H), 6.75 (d, J = 8.4 Hz, 2H), 4.22 (s, 1H), 3.07 (s, 3H), 3.00 (s, 3H), 2.88 (s, 3H) ppm. 13C NMR (176 MHz, DMSO-d6): δ 176.9, 168.6, 167.9, 162.8 (d, 1JC–F = 243.8 Hz), 158.5, 149.8, 144.8 (d, 2JC–F = 12.1 Hz), 130.9, 129.4, 129.1, 128.8 (d, 3JC–F = 9.7 Hz), 128.1, 124.0 (d, 4JC–F = 2.5 Hz), 116.2, 108.4 (d, 2JC–F = 22.2 Hz), 97.5 (d, 2JC–F = 27.6 Hz), 78.1, 68.0, 64.7, 63.1, 28.6, 28.4, 26.7 ppm. 19F NMR (659 MHz, DMSO-d6): δ −110.9. HRMS (ESI): m/z calcd. for C25H21FN5O4 [M + H]+ 474.1572, found 474.1602.
(2′R,3S)-4′-Amino-6-bromo-1,1″,3″-trimethyl-2,2″,4″,6″-tetraoxo-2′-phenyl-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3af). According to the general procedure from 1a (58.6 mg, 0.24 mmol) and 2f (57.8 mg, 0.2 mmol) to obtain 101.3 mg (95% yield) compound 3af as a white solid, m.p. 161–163 °C. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 17.9 min (major); >99% ee. [α]D25 = −42.4 (c = 0.5, CH2Cl2). 1H NMR (700 MHz, DMSO-d6): δ 7.97 (d, J = 7.7 Hz, 1H), 7.39 (dd, J1 = 8.0 Hz, J2 = 1.8 Hz, 1H), 7.25 (s, 2H), 7.19 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 1.4 Hz, 1H), 7.11 (t, J = 7.7 Hz, 2H), 6.75 (d, J = 7.7 Hz, 2H), 4.23 (s, 1H), 3.07 (s, 3H), 3.01 (s, 3H), 2.89 (s, 3H) ppm. 13C NMR (176 MHz, DMSO-d6): δ 176.4, 168.5, 167.8, 158.7, 149.8, 144.6, 130.8, 129.3, 129.2, 129.0, 128.2, 127.6, 125.0, 122.2, 116.1, 112.1, 77.9, 67.9, 64.3, 63.2, 28.6, 28.4, 26.6 ppm. HRMS (ESI): m/z calcd. for C25H2179BrN5O4 [M + H]+ 534.0771, found 534.0785; calcd. for C25H2181BrN5O4 [M + H]+ 536.0751, found 536.0765.
(2′R,3S)-4′-Amino-5-fluoro-1,1″,3″-trimethyl-2,2″,4″,6″-tetraoxo-2′-phenyl-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3ag). According to the general procedure from 1a (58.6 mg, 0.24 mmol) and 2g (45.8 mg, 0.2 mmol) to obtain 89.9 mg (95% yield) compound 3ag as a white solid, m.p. 201–203 °C. HPLC (Daicel Chiralpak ADH, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 18.7 min (minor), tR = 20.2 min (major); 95% ee. [α]D25 = −58.6 (c = 0.5, CH2Cl2). 1H NMR (700 MHz, DMSO-d6): δ 7.91 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.28 (s, 2H), 7.20–7.15 (m, 2H), 7.12 (t, J = 7.7 Hz, 2H), 6.90 (dd, J1 = 8.4 Hz, J2 = 4.2 Hz, 1H), 6.76 (d, J = 7.7 Hz, 2H), 4.26 (s, 1H), 3.07 (s, 3H), 3.00 (s, 3H), 2.91 (s, 3H) ppm. 13C NMR (176 MHz, DMSO-d6): δ 176.2, 168.5, 168.0, 158.8, 158.3 (1JC–F = 237.4 Hz), 149.8, 139.4, 130.8, 130.2 (3JC–F = 8.3 Hz), 129.23, 129.19, 128.3, 116.1, 115.7 (2JC–F = 23.4 Hz), 114.8 (2JC–F = 25.7 Hz), 109.8 (3JC–F = 8.3 Hz), 78.1, 67.9, 64.6, 63.8, 29.9, 28.6, 28.4, 26.6 ppm. 19F NMR (659 MHz, DMSO-d6) δ −120.1. HRMS (ESI): m/z calcd. for C25H21FN5O4 [M + H]+ 474.1572, found 474.1595.
(2′R,3S)-4′-Amino-5-bromo-1,1″,3″-trimethyl-2,2″,4″,6″-tetraoxo-2′-phenyl-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3ah). According to the general procedure from 1a (58.6 mg, 0.24 mmol) and 2h (57.8 mg, 0.2 mmol) to obtain 101.3 mg (95% yield) compound 3ah as a white solid, m.p. 192–194 °C. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min, detection at 254 nm): tR = 14.1 min (minor), tR = 11.3 min (major), >99% ee. [α]D25 = −211.6 (c = 0.8, CH2Cl2). 1H NMR (700 MHz, DMSO-d6): δ 8.23 (d, J = 2.1 Hz, 1H), 7.50 (dd, J1 = 8.4 Hz, J2 = 2.1 Hz, 1H), 7.30 (s, 2H), 7.19 (t, J = 7.4 Hz, 1H), 7.12 (t, J = 7.7 Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 7.0 Hz, 2H), 4.24 (s, 1H), 3.07 (s, 3H), 2.99 (s, 3H), 2.90 (s, 3H) ppm. 13C NMR (176 MHz, DMSO-d6): δ 176.0, 168.4, 167.9, 158.8, 149.7, 142.3, 132.0, 130.8, 130.7, 130.0, 129.23, 129.18, 128.3, 116.1, 114.2, 110.8, 77.9, 67.8, 64.6, 63.5, 28.6, 28.4, 26.6 ppm. HRMS (ESI): m/z calcd. for C25H2179BrN5O4 [M + H]+ 534.0771, found 534.0786; calcd. for C25H2181BrN5O4 [M + H]+ 536.0751, found 536.0769.
(2′R,3S)-4′-Amino-5-chloro-1,1″,3″-trimethyl-2,2″,4″,6″-tetraoxo-2′-phenyl-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3ai). According to the general procedure from 1a (58.6 mg, 0.24 mmol) and 2i (49.0 mg, 0.2 mmol) to obtain 90.0 mg (92% yield) compound 3ai as a white solid, m.p. 201–204 °C. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): tR = 45.7 min (minor), tR = 32.5 min (major); >99% ee. [α]D25 = −100.6 (c = 0.5, CH2Cl2). 1H NMR (700 MHz, DMSO-d6): δ 8.11 (d, J = 2.8 Hz, 1H), 7.37 (dd, J1 = 8.4 Hz, J2 = 2.8 Hz, 1H), 7.30 (s, 2H), 7.19 (t, J = 7.7 Hz, 1H), 7.12 (t, J = 7.7 Hz, 2H), 6.92 (d, J = 7.7 Hz, 1H), 6.75 (dd, J1 = 8.4 Hz, J2 = 1.4 Hz, 2H), 4.25 (s, 1H), 3.08 (s, 3H), 3.00 (s, 3H), 2.91 (s, 3H) ppm. 13C NMR (176 MHz, DMSO-d6): δ 176.1, 168.4, 168.0, 158.8, 149.74, 142.0, 130.7, 130.4, 129.23, 129.19, 128.3, 127.2, 126.5, 116.1, 110.4, 77.9, 67.8, 64.6, 63.6, 28.6, 28.4, 26.6 ppm. HRMS (ESI): m/z calcd. for C25H21ClN5O4 [M + H]+ 490.1277, found 490.1304.
(2′R,3S)-4′-Amino-1,1″,3″-trimethyl-2,2″,4″,6″-tetraoxo-2′-phenyl-7-(trifluoromethyl)-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3aj). According to the general procedure from 1a (58.6 mg, 0.24 mmol) and 2j (55.8 mg, 0.2 mmol) to obtain 88.9 mg (85% yield) compound 3aj as a white solid, m.p. 177–179 °C. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 5.6 min (minor), tR = 7.6 min (major); 83% ee. [α]D25 = −60.8 (c = 0.5, CH2Cl2). 1H NMR (700 MHz, DMSO-d6): δ 8.37 (d, J = 7.0 Hz, 1H), 7.64 (dd, J1 = 8.0 Hz, J2 = 1.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 3H), 7.17 (t, J = 7.4 Hz, 1H), 7.07 (t, J = 7.7 Hz, 2H), 6.67 (d, J = 7.0 Hz, 2H), 4.22 (s, 1H), 3.14 (s, 3H), 3.08 (s, 3H), 2.89 (s, 3H) ppm. 13C NMR (176 MHz, DMSO-d6): δ 178.0, 168.5, 167.8, 159.3, 149.8, 140.6, 131.4, 131.3, 130.4, 129.2, 128.1, 127.3, 127.2 (q, 3JC–F = 5.5 Hz), 123.2 (q, 1JC–F = 271.2 Hz), 122.2, 116.0, 110.9 (q, 2JC–F = 32.7 Hz), 77.2, 67.8, 65.3, 62.2, 29.0 (q, JC–F = 5.8 Hz), 28.6, 28.4 ppm. 19F NMR (659 MHz, DMSO-d6): δ −52.1. HRMS (ESI): m/z calcd. for C26H21F3N5O4 [M + H]+ 524.1540, found 524.1559.
(2′R,3S)-4′-Amino-1,1″,3″,7-tetramethyl-2,2″,4″,6″-tetraoxo-2′-phenyl-1″,3″,4″,6″-tetrahydro-2″H-dispiro[indoline-3,1′-cyclopentane-3′,5″-pyrimidin]-4′-ene-5′-carbonitrile (3ak). According to the general procedure from 1a (58.6 mg, 0.24 mmol) and 2k (45.0 mg, 0.2 mmol) to obtain 89.1 mg (95% yield) compound 3ak as a white solid, m.p. 182–185 °C. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 7.5 min (minor), tR = 9.3 min (major); 82% ee. [α]D25 = 23.4 (c = 0.4, CH2Cl2). 1H NMR (700 MHz, DMSO-d6): δ 7.92 (d, J = 6.3 Hz, 1H), 7.18–7.14 (m, 3H), 7.08–7.01 (m, 3H), 6.75 (d, J = 7.7 Hz, 2H), 4.23 (s, 1H), 3.27 (s, 3H), 3.07 (s, 3H), 2.84 (s, 3H), 2.38 (s, 3H) ppm. 13C NMR (176 MHz, DMSO-d6): δ 177.2, 168.7, 167.8, 158.3, 149.8, 140.8, 132.9, 131.2, 129.5, 129.0, 128.0, 125.4, 122.1, 119.7, 116.4, 79.0, 68.2, 65.0, 62.9, 29.6, 28.5, 28.3, 18.4 ppm. HRMS (ESI): m/z calcd. for C26H24N5O4 [M + H]+ 470.1823, found 470.1834.

3.5. Gram-Scale Synthesis of 3aa

To a dried 50 mL round-bottom flask, benzylidene barbituric acid 1a (1.17 g, 4.8 mmol), oxindolylmalonitrile 2a (0.84 g, 4.0 mmol), chiral organocatalyst C5 (101.6 mg, 0.2 mmol, 0.05 equiv), and CH2Cl2 (20 mL) were added. After stirring at room temperature for 8 h, the reaction mixture was concentrated and directly purified by silica gel column chromatography (200–300 mesh) using ethyl acetate/petroleum ether (1:2) as eluent to afford the desired product 3aa (1.6 g, 88% yield).

4. Conclusions

In summary, we developed an efficient and practical asymmetric Michael/cyclization reaction of benzylidene barbituric acids with oxindolylmalonitriles at room temperature. Using a squaramide catalyst, a series of chiral bisspiro barbituric acid derivatives were obtained in high yields (72–97%) with high-to-excellent stereoselectivities (up to >99% ee and >20:1 dr). In addition, the practicability of the reaction was verified by the preparation of the product at the gram-scale.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules30092000/s1, Copies of 1H and 13C NMR spectra, HPLC chromatograms for all new compounds.

Author Contributions

D.-J.Q. wrote the preliminary manuscript and performed the experiments and acquired and analyzed the original data; D.-M.D. designed the research plan, supervised the experiments, modified all figures and schemes, analyzed and checked all the data, and revised this manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within this article and Supplementary Materials.

Acknowledgments

We thank the Analysis and Testing Center of the Beijing Institute of Technology for the measurement of NMR and mass spectrometry.

Conflicts of Interest

Authors declare no conflict of interest.

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Molecules 30 02000 g001
Figure 1. Examples of barbituric acid derivatives. (a) barbituric acid derivatives in pharmaceuticals, (b) alkylidene barbituric acids.
Figure 1. Examples of barbituric acid derivatives. (a) barbituric acid derivatives in pharmaceuticals, (b) alkylidene barbituric acids.
Molecules 30 02000 g001
Molecules 30 02000 g002
Figure 2. The screened squaramide and thiourea organocatalysts.
Figure 2. The screened squaramide and thiourea organocatalysts.
Molecules 30 02000 g002
Molecules 30 02000 sch002
Scheme 2. The substrate scope for benzylidene barbituric acids and oxindoles. Unless otherwise noted, the reaction was performed in CH2Cl2 (1.5 mL) with 1 (0.24 mmol), 2 (0.20 mmol), and catalyst C5 (0.02 mmol) at room temperature under air for 8 h. The dr values were determined by 1H NMR, and the ee values were determined by HPLC.
Scheme 2. The substrate scope for benzylidene barbituric acids and oxindoles. Unless otherwise noted, the reaction was performed in CH2Cl2 (1.5 mL) with 1 (0.24 mmol), 2 (0.20 mmol), and catalyst C5 (0.02 mmol) at room temperature under air for 8 h. The dr values were determined by 1H NMR, and the ee values were determined by HPLC.
Molecules 30 02000 sch002
Molecules 30 02000 sch003
Scheme 3. Gram-scale synthesis of 3aa.
Scheme 3. Gram-scale synthesis of 3aa.
Molecules 30 02000 sch003
Molecules 30 02000 g003
Figure 3. X-ray crystal structure of 3ha (Displacement ellipsoids are drawn at the 50% probability level; the included solvent molecules were omitted for clarity).
Figure 3. X-ray crystal structure of 3ha (Displacement ellipsoids are drawn at the 50% probability level; the included solvent molecules were omitted for clarity).
Molecules 30 02000 g003
Molecules 30 02000 sch004
Scheme 4. Proposed reaction mechanism.
Scheme 4. Proposed reaction mechanism.
Molecules 30 02000 sch004
Table 1. Optimization of reaction conditions a..
Table 1. Optimization of reaction conditions a..
Molecules 30 02000 i001
Entry aSolventCatalystYield b (%)dr cee d (%)
1CH2Cl2C186>20:188
2CH2Cl2C277>20:165
3CH2Cl2C382>20:150
4CH2Cl2C485>20:183
5CH2Cl2C594>20:1>99
6CH2Cl2C683>20:182
7CH2Cl2C775>20:187
8CH2Cl2C888>20:185
9CH2Cl2C992>20:153
10CH2Cl2C1085>20:181
11CH2Cl2C1180>20:182
12CH2Cl2C1277>20:174
13MeCNC568>20:125
14PhMeC572>20:180
15THFC572>20:147
16CHCl3C592>20:197
17MTBEC557>20:15
18 eCH2Cl2C580>20:188
19 fCH2Cl2C586>20:194
a Unless otherwise specified, reactions were conducted with 1a (0.24 mmol), 2a (0.20 mmol), and catalyst (10 mol%) in solvent (1.5 mL) at room temperature under air for 8 h. b Isolated yield after column chromatography purification. c Determined by 1H NMR analysis. d Enantiomeric excess (ee) was determined by HPLC analysis. e 5 mol% catalyst was used. f The reaction was performed at 0 °C for 24 h.
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Qiao, D.-J.; Du, D.-M. Squaramide-Catalyzed Asymmetric Michael Addition/Cyclization Reaction for the Synthesis of Chiral Bisspiro Barbituric Acid–Oxindole Derivatives. Molecules 2025, 30, 2000. https://doi.org/10.3390/molecules30092000

AMA Style

Qiao D-J, Du D-M. Squaramide-Catalyzed Asymmetric Michael Addition/Cyclization Reaction for the Synthesis of Chiral Bisspiro Barbituric Acid–Oxindole Derivatives. Molecules. 2025; 30(9):2000. https://doi.org/10.3390/molecules30092000

Chicago/Turabian Style

Qiao, De-Jun, and Da-Ming Du. 2025. "Squaramide-Catalyzed Asymmetric Michael Addition/Cyclization Reaction for the Synthesis of Chiral Bisspiro Barbituric Acid–Oxindole Derivatives" Molecules 30, no. 9: 2000. https://doi.org/10.3390/molecules30092000

APA Style

Qiao, D.-J., & Du, D.-M. (2025). Squaramide-Catalyzed Asymmetric Michael Addition/Cyclization Reaction for the Synthesis of Chiral Bisspiro Barbituric Acid–Oxindole Derivatives. Molecules, 30(9), 2000. https://doi.org/10.3390/molecules30092000

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