A telescoped diastereoselective synthesis of phthalimido-substituted spiro-oxazoline oxindoles via an aziridine expansion strategy

Abstract

A diastereoselective efficient synthesis of 5′H-spiro[indoline-3,2′-oxazol]-2-ones bearing a pharmacophore phthalimide fragment was developed. The approach is based on the thermal ring opening of spiro-aroyl-N-phthalimidoaziridine oxindoles, which are readily accessible via aminoaziridination of methylideneoxindoles. The formation of the final spiro compounds proceeds through the generation of azomethine ylides, followed by a selective 1,5-electrocyclization involving the aroyl carbonyl group and a formal 1,3-migration of the phthalimide substituent. The mechanism was confirmed by DFT calculations.

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Introduction

Spirocyclic scaffolds are found in various approved drugs, drug candidates and natural products.¹ Among them, the spirooxindole heterocyclic scaffold occupies a privileged position.² This is due to its rigidity and unique 3D-structure, including a hydrogen bond donor–acceptor amide fragment and a hydrophobic aromatic part. Numerous synthetic approaches have been developed to access spirooxindoles bearing different carbo- or heterocyclic units.³ Majority of the latter contain a saturated five-membered ring with one heteroatom, such as pyrrolidine or tetrahydrofuran.^2a Compounds with an unsaturated ring with more than one heteroatom, for example pyrazoline or isoxazoline, are rarer and mainly accessible via 1,3-dipolar cycloaddition reactions.^3d In 2021, the synthesis of a new class of spirooxindoles, namely 5′H-spiro[indoline-3,2′-oxazol]-2-ones, was first reported.⁴ It is based on a copper-catalyzed regioselective (3 + 2) annulation of malonate-tethered acyl oximes with isatins (Scheme 1a).

Scheme 1 Synthetic approaches to access spiro-2,5-dihydrooxazole oxindoles.

Given the importance of spirooxindole derivatives and in continuation of our efforts toward the synthesis of 3-oxazolines,⁵ in this work, we aimed to develop a novel approach to access the 5′H-spiro[indoline-3,2′-oxazol]-2-one scaffold. Aziridines, which are strained three-membered heterocycles, have proven themselves as convenient substrates for the synthesis of more complex heterocycles.⁶ For example, it is known that 2,5-dihydrooxazoles with a phthalimide group (PhthN) are formed along with the corresponding oxazoles upon the thermolysis of certain N-phthalimidoaziridines (Scheme 1b), such as 2-benzoyl-3-styrylaziridine^7a and thienyl-substituted diacetylaziridines.^7b In this case, the formation of 2,5-dihydrooxazoles is accompanied by a shift of the phthalimide fragment from the nitrogen atom to the carbon atom. We envisioned that the desired spiro-2,5-dihydrooxazole oxindoles could be constructed via thermal transformation of N-phthalimidoaziridines obtained from the corresponding acylmethylideneoxindoles (Scheme 1c). To our delight, this assumption worked, and the target products were formed as single diastereomers. The advantages of this approach are the synthetic availability of substrates, the use of a telescoped methodology and an opportunity of introducing an additional pharmacophore – the phthalimide fragment. Notably, phthalimide derivatives exhibit anti-inflammatory, anti-Alzheimer, antiepileptic, antiplatelet, anticancer, antibacterial, antifungal, antiparasitic, antiviral, and antidiabetic properties, among others.⁸

It should be noted that spiro-aziridine oxindoles with a phthalimide substituent at the aziridine nitrogen have not been described in the literature.⁹ Only a range of spiro-aziridine oxindoles bearing carbon^10a or sulfur^10b substituents at the aziridine nitrogen have been reported. To the best of our knowledge, no transformations of such aziridines into oxazole derivatives have been reported.

Results and discussion

Firstly, a series of variously substituted spirocyclic aziridines 2a–d were obtained in good yields as single diastereomers from the corresponding (E)-methylideneoxindoles 1a–d using N-aminophthalimide and lead tetraacetate in dichloromethane (DCM) (Scheme 2).¹¹ The structures of aziridines 2a–d were determined using nuclear magnetic resonance (NMR) spectra and high-resolution mass spectra (HRMS).

Scheme 2 Synthesis of spiro-aziridine oxindoles 2. Isolated yields are given.

Since N-phthalimidoaziridines spiro-fused with oxindoles are unknown, we examined the behaviour of the obtained aziridines 2 upon heating. For these compounds, the cleavage of the aziridine C–C bond to form an azomethine ylide followed by its cyclization involving the adjacent C=O bond to a fused oxazole derivative can be anticipated, similar to the behavior reported for N-phthalimidoaziridines spiro-fused with indane-1,3-dione.¹² Heating of phenyl-substituted aziridines 2a and b resulted in the formation of previously unknown diaminooxindole derivatives 3a and b, which are formed as a result of a 1,2-migration of a phthalimide substituent, likely in the azomethine ylide (Scheme 3). A similar reaction was observed for the in situ generated phenylaziridine 2e with a Boc substituent at the oxindole nitrogen. The structures of compounds 3a, b, and e were determined on the basis of 2D NMR spectra and HRMS. The cyclization of the ylide to the fused oxazole derivative does not occur. The isomerization into the imine was also the major process during the heating of aziridine 2b with an excess of dimethyl acetylenedicarboxylate or dimethyl maleate, and potential 1,3-dipolar cycloaddition was not observed. Unfortunately, aziridine 2c with an ester group underwent non-selective decomposition upon heating in the temperature range of 60–140 °C. The addition of BF₃·OEt₂ or copper(II) complexes did not lead to any selective transformations.

Scheme 3 Thermolysis of phenyl-substituted aziridines 2: synthesis of diaminooxindoles 3. Isolated yields are given.

Heating of benzoylaziridine 2d at 100 °C for 4 h led to the target aziridine ring expansion product with a formal 1,3-migration of the phthalimide substituent, spirocyclic 3-oxazoline 4a, which was isolated by column chromatography as a single diastereomer in 67% yield (Scheme 4). The second diastereomer 4a′ was detected in trace amounts in the reaction mixture by ¹H NMR spectroscopy. The structure of product 4a was determined using 2D NMR spectra and HRMS and confirmed by the X-ray diffraction analysis. The phthalimide substituent in the product is trans-oriented to the amide part of the oxindole. In this case, cyclization involving the C=O bond of the amide group again does not occur.

Scheme 4 Thermolysis of benzoyl-substituted aziridine 2d: synthesis of spiro-2,5-dihydrooxazole oxindole 4a. Isolated yield is given.

A brief optimization of the conditions for the synthesis of spirocyclic dihydrooxazole 4a showed that heating in toluene at 120 °C is optimal (yield 75%, reaction time 45 min). It is also possible to carry out both steps of the one-pot reaction in DCM without any loss of efficiency (the second step is conducted in an Ace pressure tube at 120 °C).

To study the reaction scope, a series of (aroylmethylidene)oxindoles (1f–p) were synthesized by the Wittig reaction from isatins and acylphosphonium ylides. All methylideneoxindoles were formed selectively as E-isomers. Further syntheses of spiro-2,5-dihydrooxazole oxindoles 4 were carried out as a telecoped process without isolation of intermediate aziridines 2 (in all cases, they were detected by TLC). It was shown (Scheme 5) that the method is tolerant toward a variety of substituents on the aroyl group. The product yield decreased when a strong electron-withdrawing substituent, nitro group, was introduced in the benzoyl fragment. Biphenyl, 2-naphthyl, and 2-thienyl substituents were successfully incorporated into the oxazoline moiety of products 4e, 4f, and 4g, respectively. In the latter case, the yield was lower. The spiro compound 4h without a substituent at the nitrogen atom of the oxindole was obtained, albeit in a low yield (side products were formed at the second step). Variation of substituents on the aromatic part of the oxindole fragment was examined. The 7-fluoro- and 5-nitro derivatives 4i and 4j were synthesized in good yields. Spirooxazoline 4k with a methoxy group at C5 of the oxindole was not obtained. Attempts to prepare compounds 4l and 4m by heating the acetylaziridine and the aziridine bearing a Boc group at the oxindole nitrogen under the same conditions led to non-selective decomposition. Probably, in these cases, the cyclization to spirooxazoline becomes unfavorable and the intermediate azomethine ylide undergoes decomposition.

Scheme 5 Scope of spiro-2,5-dihydrooxazole oxindoles 4. Isolated yields for 2 steps are given. ^a Synthesis at the 2 mmol scale.

The reaction of (Z)-methylideneoxindole 1d′ for preparing another oxazoline diastereomer 4a′ using the same procedure failed. A complex mixture of products was formed, containing, according to the ¹H NMR spectrum, small amounts of diastereomeric oxazolines 4a and 4a′. We also tested other aziridinating reagents (3-amino-2-methylquinazolin-4(3H)-one and 2-amino-1H-benzo[de]isoquinolinone-1,3(2H)-dione) in place of N-aminophthalimide under the same conditions, but methylideneoxindole 1d did not react with them.

To investigate the mechanism of formation of spirooxazolines 4 in greater detail, density functional theory (DFT) calculations (B3LYP/6-31+g(d,p), polarizable continuum model (PCM) for toluene, 373 K) were performed for the transformations of N-phthalimidoaziridine 2d (Scheme 6). It was found that 2d undergoes a conrotatory electrocyclic ring opening to form ylide 5 with a barrier of 24.5 kcal mol⁻¹ (TS1); ylide 5 is less stable than the starting aziridine by 4.3 kcal mol⁻¹. Further 1,5-electrocyclization involving a benzoyl group proceeds stereoselectively to give spiro-4-oxazoline 6 (red line), in which the phthalimide substituent is cis-oriented to the aromatic part of the oxindole, with a relatively low barrier (TS2, 12.9 kcal mol⁻¹). It is noteworthy that this reaction is reversible since the ring opening of oxazoline 6 back to ylide 5 also has quite a low barrier (16.5 kcal mol⁻¹). Finally, after formal 1,3-shift of a phthalimide substituent, the thermodynamically more favourable isomeric spiro-3-oxazoline 4a is formed. Likely, this is a stepwise reaction in which the phthalimide anion initially leaves and then attaches to the carbon atom. The observed high diastereoselectivity of the oxazoline formation is probably related to the specific stereochemistry of intermediate 6. The 1,3-migration of the phthalimide substituent takes place on the same side of the oxazoline ring. Our calculations also showed that diastereomer 4a′ is more stable than 4a by 0.7 kcal mol⁻¹. So, the high diastereoselectivity of oxazoline formation cannot be accounted for by thermodynamic factors.

Scheme 6 DFT calculation results for transformations of aziridine 2d.

An alternative cyclization pathway of ylide 5, namely 1,5-electrocyclization onto the amide fragment (Scheme 6, blue line), according to the calculations, proceeds stereoselectively to afford the trans-isomer of the fused dihydrooxazole 7, but it has a much higher barrier (TS3, 21.8 kcal mol⁻¹) than the cyclization leading to the spiro compound 6. The reason for this is the low relative thermodynamic stability of compound 7 compared to ylide 5, which is attributed to the instability of the 4-oxazoline moiety,¹³ which is further increased in the 5–5 fused ring system. Indeed, while 1,3-dipolar cycloadditions of azomethine ylides derived from isatin are well known, 1,5-electrocyclization to give a fused 4-oxazoline has not been reported.¹⁴

It should be noted that, despite extensive knowledge of 1,5-electrocyclizations,¹⁵ such cyclizations of acylazomethine ylides have only been sparsely studied and are rarely discussed in the literature.^5,16 In the transition states TS2 and TS3, the dihedral angle indicated in Scheme 6 is close to 180°. That is, lone pair electrons of the oxygen atom are involved in the bonding.¹⁷ Thus, both 1,5-electrocyclizations of ylide 5, leading to structures 6 and 7, can be referred to as pseudopericyclic reactions.

Finally, we demonstrated that the phthalimide fragment in spiro compounds 4 can be transformed. Thus, the reaction of compound 4a with sodium cyanoborohydride in a DCM–MeOH system led to the amino-substituted spiro-2,5-dihydrooxazole oxindole 8 in good yield (Scheme 7). The structure of compound 8 was determined using NMR spectra and HRMS. Obviously, this compound is formed by the methanolysis of the phthalimide fragment in 4a.

Scheme 7 Synthesis of compound 8via transformation of the phthalimide group. Isolated yield is given.

Conclusions

Previously unknown N-phthalimidoaziridines spiro-fused with oxindole were obtained by oxidative aminoaziridination of 3-methylideneoxindoles. Thermolysis of phenyl-substituted aziridines proceeded with a 1,2-migration of the phthalimide substituent to give 3-phthalimido-3-(benzylideneamino)oxindoles in good yields. In contrast, thermolysis of aroyl-substituted aziridines led to a novel diastereoselective and efficient synthesis of spiro-2,5-dihydrooxazole oxindoles. The formation of these compounds involves selective 1,5-electrocyclization of the azomethine ylide with participation of the aroyl carbonyl group and formal 1,3-migration of the phthalimide substituent. According to DFT calculations, cyclization of the azomethine ylide onto the aroyl group is kinetically and thermodynamically favoured compared to the cyclization on the amide carbonyl. The features of the developed approach toward spiro-2,5-dihydrooxazole oxindoles are the synthetic availability of substrates, the use of a telescoped methodology and the opportunity of introducing an additional pharmacophore – the phthalimide fragment.

Experimental

General procedure for the synthesis of aziridines 2

Methylideneoxindole 1 (1 mmol), N-aminophthalimide (243 mg, 1.5 mmol) and anhydrous K₂CO₃ (1.11 g, 8 mmol) were placed in a round-bottom flask and anhydrous DCM (20 mL) was added. The flask was purged with argon, sealed with a septum and a solution of Pb(OAc)₄ (665 mg, 1.5 mmol) in anhydrous DCM (7 mL) was added using a syringe at 0 °C within 15 min. After the reaction was completed (monitored by TLC), the resulting mixture was passed through a Celite plug, the solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel to give aziridines 2.

2-((2RS,3SR)-1′-Methyl-2′-oxo-3-phenylspiro[aziridine-2,3′-indolin]-1-yl)isoindoline-1,3-dione (2a). Compound 2a (316 mg, yield 80%) was obtained from methylideneoxindole 1a (235 mg, 1 mmol) according to the general procedure; eluent for chromatography: EtOAc–hexane, 1 : 4.

White solid, mp 156–157 °C.

¹H NMR (400 MHz, CDCl₃) δ 7.94–7.66 (m, 4H), 7.60–7.53 (m, 2H), 7.45–7.37 (m, 3H), 7.33 (td, J = 7.6, 1.3 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 6.86 (td, J = 7.7, 1.0 Hz, 1H), 6.39 (dd, J = 7.6, 1.3 Hz, 1H), 5.00 (s, 1H), 3.32 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 169.0, 164.6, 144.8, 134.0, 131.9, 130.6 (br), 130.0 (br), 129.3, 128.5, 128.4, 128.4, 123.6, 123.2, 122.4, 122.4, 108.4, 57.1, 52.1, 26.8.

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₂₄H₁₇N₃NaO₃⁺ 418.1162; found 418.1161.

2-((2RS,3SR)-2′-Oxo-3-phenylspiro[aziridine-2,3′-indolin]-1-yl)isoindoline-1,3-dione (2b). Compound 2b (226 mg, yield 59%) was obtained from methylideneoxindole 1b (221 mg, 1 mmol) according to the general procedure; eluent for chromatography: EtOAc–CH₂Cl₂, 1 : 10.

Beige solid, mp 123–125 °C (dec.)

¹H NMR (400 MHz, CDCl₃) δ 7.84–7.69 (m, 5H), 7.55–7.54 (m, 2H), 7.43–7.36 (m, 3H), 7.26–7.19 (t, J = 7.7 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.35 (d, J = 7.5 Hz, 1H), 4.95 (s, 1H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.6, 141.9, 134.2, 131.9, 129.4, 128.7, 128.63, 128.60, 124.2, 123.4, 122.9, 122.6, 110.3, 57.6, 52.4.

HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₂₃H₁₆N₃O₃⁺ 382.1186; found 382.1189.

Methyl (2RS,3RS)-1-(1,3-dioxoisoindolin-2-yl)-1′-methyl-2′-oxospiro[aziridine-2,3′-indoline]-3-carboxylate (2c). Compound 2c (309 mg, yield 82%) was obtained from methylideneoxindole 1c (217 mg, 1 mmol) according to the general procedure; eluent for chromatography: EtOAc–hexane, 1 : 4.

White solid, mp 153–155 °C.

¹H NMR (400 MHz, CDCl₃) δ 7.88–7.69 (m, 4H), 7.53–7.39 (m, 2H), 7.15 (td, J = 7.7, 1.1 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 4.44 (s, 1H), 3.90 (s, 3H), 3.28 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 167.4, 165.0, 163.9 (br), 145.0, 134.1, 130.2, 130.0 (br), 124.1, 123.4, 123.2, 121.3, 108.8, 52.9, 52.7, 50.7, 26.9.

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₂₀H₁₅N₃NaO₅⁺ 400.0904; found 400.0905.

2-((2RS,3RS)-3-Benzoyl-1′-methyl-2′-oxospiro[aziridine-2,3′-indolin]-1-yl)isoindoline-1,3-dione (2d). Compound 2d (300 mg, yield 71%) was obtained from ethylideneoxindole 1d (263 mg, 1 mmol) according to the general procedure; eluent for chromatography: EtOAc–hexane, 1 : 4.

White solid, mp 146–149 °C.

¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J = 7.0 Hz, 2H), 7.95–7.69 (m, 4H), 7.65–7.58 (m, 1H), 7.49 (t, J = 7.8 Hz, 2H), 7.38 (td, J = 7.9, 1.3 Hz, 1H), 7.28–7.25 (m, 1H), 7.06 (td, J = 7.6, 1.0 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 5.25 (s, 1H), 3.32 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 189.4, 167.7, 164.2, 144.8, 135.8, 134.2, 134.2, 130.3 (br), 130.1, 129.7 (br), 128.9, 128.7, 124.2, 123.4, 123.2, 121.3, 108.8, 56.3, 52.0, 27.0.

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₂₅H₁₇N₃NaO₄⁺ 446.1111; found 446.1110.

General procedure for the synthesis of diaminooxindoles 3

A solution of aziridines 2a, 2b, and 2e (0.15 mmol) in anhydrous toluene (2 mL) in a screw-cap tube was stirred at 100 °C (oil bath temperature) for 1.5 h. After the reaction was completed (monitored by TLC), the solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel to give diaminooxindoles 3.

(E)-2-(3-(Benzylideneamino)-1-methyl-2-oxoindolin-3-yl)isoindoline-1,3-dione (3a). Compound 3a (34.8 mg, yield 58%) was obtained from aziridine 2a (60 mg, 0.15 mmol) according to the general procedure; eluent for chromatography: EtOAc–hexane, 1 : 3.

Pale-yellow solid, mp 186–189 °C.

¹H NMR (400 MHz, CDCl₃) δ 8.25 (s, 1H), 7.85–7.78 (m, 4H), 7.73 (dd, J = 5.5, 3.1 Hz, 2H), 7.52 (dd, J = 7.4, 1.3 Hz, 1H), 7.48–7.38 (m, 4H), 7.14 (td, J = 7.6, 1.0 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H), 3.36 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.3, 167.0, 162.8, 143.9, 135.2, 134.2, 131.9, 131.6, 130.8, 129.2, 128.5, 126.4, 125.7, 123.3 (2C), 108.9, 79.4, 26.8.

HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₂₄H₁₉N₃O₃⁺ 396.1348; found 396.1345.

(E)-2-(3-(Benzylideneamino)-2-oxoindolin-3-yl)isoindoline-1,3-dione (3b). Compound 3b (38 mg, yield 67%) was obtained from aziridine 2b (57 mg, 0.15 mmol) according to the general procedure; eluent for chromatography: EtOAc–CH₂Cl₂, 5 : 7.

Pale-beige solid, mp 179–180 °C (dec.).

¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.89 (s, 1H), 7.89–7.81 (m, 4H), 7.73–7.71 (m, 2H), 7.47–7.26 (m, 5H), 7.09 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 171.5, 167.1, 162.9, 140.9, 135.4, 134.4, 132.1, 131.9, 131.0, 129.4, 128.7, 126.7, 126.3, 123.6, 110.9, 79.8.

HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₂₃H₁₆N₃O₃⁺ 382.1186; found 382.1188.

tert-Butyl (E)-3-(benzylideneamino)-3-(1,3-dioxoisoindolin-2-yl)-2-oxoindoline-1-carboxylate (3e). Compound 3e (88 mg, yield 41%) was obtained from methylideneoxindole 1e (152 mg, 0.44 mmol) according to the general procedures for the preparation of aziridines 2 and diaminooxindoles 3 without chromatographic purification of aziridine 2e. The crude aziridine 2e was diluted with anhydrous toluene (10 mL) and subjected to heating; eluent for chromatography: EtOAc–CH₂Cl₂, 1 : 30.

Pale-beige solid, mp 136–137 °C (dec.).

¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.82–7.79 (m, 4H), 7.74–7.70 (m, 2H), 7.51–7.38 (m, 5H), 7.22 (t, J = 7.5 Hz, 1H), 1.66 (s, 9H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 167.9, 167.0, 163.7, 149.2, 140.2, 135.3, 134.5, 132.0, 131.97, 131.1, 129.5, 128.7, 125.7, 125.6, 125.3, 123.6, 116.1, 85.0, 79.5, 28.2.

HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₂₈H₂₄N₃O₅⁺ 482.1711; found 482.1723.

General procedure for the synthesis of spiro-2,5-dihydrooxazole oxindoles 4

Methylideneoxindoles 1d,f–p (0.3 mmol), N-aminophthalimide (72.9 mg, 0.45 mmol) and anhydrous K₂CO₃ (334 mg, 2.4 mmol) were placed in a round-bottom flask and anhydrous DCM (6 mL) was added. The flask was purged with argon, sealed with a septum and a solution of Pb(OAc)₄ (199.4 mg, 0.45 mmol) in anhydrous DCM (2 mL) was added using a syringe at 0 °C within 15 min. After the reaction was completed (monitored by TLC), the resulting mixture was passed through a Celite plug and the solvent was removed in vacuo. The residual crude aziridines 2d and 2f–p was dissolved in anhydrous toluene (6 mL), placed in a screw-cap tube and stirred at 120 °C (oil bath temperature) for 35–120 min. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel to give spiro compounds 4. The details for each synthesis are indicated below.

2-((3RS,5′SR)-1-Methyl-2-oxo-5′-phenyl-5′H-spiro[indoline-3,2′-oxazol]-5′-yl)isoindoline-1,3-dione (4a).
Synthesis from methylideneoxindole 1d. Compound 4a (85 mg, yield 67%) was obtained from methylideneoxindole 1d (78.9 mg, 0.3 mmol) according to the general procedure [2^nd step: 50 min; eluent for chromatography: EtOAc–hexane, 1 : 1.75].
2 mmol scale synthesis. Compound 4a (455 mg, yield 54%) was obtained from methylideneoxindole 1d (526 mg, 2 mmol) according to the general procedure [2^nd step: 50 min; eluent for chromatography: EtOAc–hexane, 1 : 1.75], with a proportional increase in quantities of the reagents.
Synthesis from aziridine 2d. A solution of aziridine 2d (60 mg, 0.14 mmol) in anhydrous toluene (2 mL) was stirred at 100 °C for 4 h. After the reaction was completed (controlled by TLC), the solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (eluent: EtOAc–hexane, 1 : 1.75) to give product 4a (40.2 mg, yield 67%).

Pale-yellow solid, mp 240–241 °C.

¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 7.93 (dd, J = 5.5, 3.1 Hz, 2H), 7.85–7.77 (m, 4H), 7.47 (t, J = 7.5 Hz, 2H), 7.42–7.32 (m, 2H), 6.97–6.85 (m, 3H), 3.29 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.6, 166.8, 162.2, 143.8, 135.8, 134.8, 131.5, 131.4, 129.0, 128.9, 125.9, 125.1, 124.3, 124.0, 123.4, 108.8, 108.4, 100.4, 26.5.

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₂₅H₁₇N₃NaO₄⁺ 446.1111; found 446.1110.

2-((3RS,5′SR)-5′-(4-Methoxyphenyl)-1-methyl-2-oxo-5′H-spiro[indoline-3,2′-oxazol]-5′-yl)isoindoline-1,3-dione (4b). Compound 4b (99.2 mg, yield 73%) was obtained from methylideneoxindole 1f (87.9 mg, 0.3 mmol) according to the general procedure [2^nd step: 2 h; eluent for chromatography: EtOAc–hexane, 1 : 2].

Orange solid, mp 186–189 °C.

¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1H), 7.93 (dd, J = 5.5, 3.0 Hz, 2H), 7.83 (dd, J = 5.5, 3.0 Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H), 7.34 (td, J = 7.7, 1.5 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 6.96–6.91 (m, 1H), 6.91–6.84 (m, 2H), 3.83 (s, 3H), 3.29 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.7, 166.9, 162.3, 160.1, 143.9, 134.8, 131.6, 131.4, 127.9, 127.3, 125.3, 124.3, 124.0, 123.4, 114.3, 108.8, 108.2, 100.5, 55.3, 26.5.

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₂₆H₁₉N₃NaO₅⁺ 476.1217; found 476.1214.

2-((3RS,5′SR)-1-Methyl-5′-(4-nitrophenyl)-2-oxo-5′H-spiro[indoline-3,2′-oxazol]-5′-yl)isoindoline-1,3-dione (4c). Compound 4c (73 mg, yield 52%) was obtained from methylideneoxindole 1g (92.4 mg, 0.3 mmol) according to the general procedure [2^nd step: 35 min; eluent for chromatography: EtOAc–hexane, 1 : 2].

Orange solid, mp 251–252 °C (dec.).

¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1H), 8.33 (d, J = 9.0 Hz, 2H), 8.01 (d, J = 9.0 Hz, 2H), 7.95 (dd, J = 5.5, 3.0 Hz, 2H), 7.87 (dd, J = 5.5, 3.0 Hz, 2H), 7.36–7.41 (m, 1H), 7.01–6.97 (m, 1H), 6.95–6.90 (m, 2H), 3.31 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.3, 166.7, 160.8, 148.2, 143.8, 142.8, 135.2, 131.8, 131.3, 127.3, 124.6, 124.4, 124.2, 124.1, 123.6, 109.0 (2C), 99.4, 26.6.

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₂₅H₁₆N₄NaO₆⁺ 491.0962; found 491.0958.

2-((3RS,5′SR)-5′-(4-Chlorophenyl)-1-methyl-2-oxo-5′H-spiro[indoline-3,2′-oxazol]-5′-yl)isoindoline-1,3-dione (4d). Compound 4c (100 mg, yield 73%) was obtained from methylideneoxindole 1h (89.3 mg, 0.3 mmol) according to the general procedure [2^nd step: 40 min; eluent for chromatography: EtOAc–hexane, 1 : 2].

Pale-yellow solid, mp 224–226 °C.

¹H NMR (400 MHz, CDCl₃) δ 8.38 (s, 1H), 7.94 (dd, J = 5.5, 3.0 Hz, 2H), 7.84 (dd, J = 5.5, 3.0 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 8.7 Hz, 2H), 7.36 (td, J = 7.7, 1.4 Hz, 1H), 7.01–6.92 (m, 1H), 6.91–6.85 (m, 2H), 3.29 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.5, 166.8, 161.7, 143.8, 135.1, 134.9, 134.5, 131.5, 131.4, 129.1, 127.5, 124.9, 124.3, 124.1, 123.5, 108.9, 108.5, 99.9, 26.5.

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₂₅H₁₆³⁵ClN₃NaO₄⁺ 480.0722; found 480.0719.

2-((3RS,5′SR)-5′-([1,1′-Biphenyl]-4-yl)-1-methyl-2-oxo-5′H-spiro[indoline-3,2′-oxazol]-5′-yl)isoindoline-1,3-dione (4e). Compound 4e (90 mg, yield 60%) was obtained from methylideneoxindole 1i (80.7 mg, 0.3 mmol) according to the general procedure [2^nd step: 60 min; eluent for chromatography: EtOAc–hexane, 1 : 1.5].

Pale-orange solid, mp 253–254 °C (dec.).

¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H), 7.95 (dd, J = 5.5, 3.1 Hz, 2H), 7.88–7.83 (m, 4H), 7.69 (d, J = 8.4 Hz, 2H), 7.63–7.59 (m, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.40–7.32 (m, 2H), 7.01–6.87 (m, 3H), 3.31 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.6, 166.9, 162.1, 143.8, 141.9, 140.5, 134.9, 134.8, 131.5, 131.5, 128.7, 127.7, 127.5, 127.2, 126.4, 125.1, 124.3, 124.0, 123.4, 108.8, 108.5, 100.4, 26.5.

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₃₁H₂₁N₃NaO₄⁺ 522.1424; found 522.1422.

2-((3RS,5′SR)-1-Methyl-5′-(naphthalen-2-yl)-2-oxo-5′H-spiro[indoline-3,2′-oxazol]-5′-yl)isoindoline-1,3-dione (4f). Compound 4f (109.3 mg, yield 77%) was obtained from methylideneoxindole 1j (93.9 mg, 0.3 mmol) according to the general procedure [2^nd step: 50 min; eluent for chromatography: EtOAc–hexane, 1 : 3].

White solid, mp 256–257 °C.

¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H), 8.33 (d, J = 2.0 Hz, 1H), 7.97–7.90 (m, 4H), 7.89–7.81 (m, 4H), 7.55–7.48 (m, 2H), 7.36 (td, J = 7.3, 2.0 Hz, 1H), 7.00–6.92 (m, 2H), 6.89 (d, J = 7.8 Hz, 1H), 3.32 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.6, 166.9, 162.1, 143.9, 134.8, 133.4, 133.21, 133.15, 131.5, 131.4, 128.8, 128.7, 127.6, 126.7, 126.4, 125.9, 125.1, 124.3, 124.0, 123.4, 122.9, 108.8, 108.5, 100.6, 26.5.

HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₂₉H₂₀N₃O₄⁺ 474.1448; found 474.1454.

2-((3RS,5′RS)-1-Methyl-2-oxo-5′-(thiophen-2-yl)-5′H-spiro[indoline-3,2′-oxazol]-5′-yl)isoindoline-1,3-dione (4g). Compound 4g (65 mg, yield 51%) was obtained from methylideneoxindole 1k (93.9 mg, 0.3 mmol) according to the general procedure [2^nd step: 70 min; eluent for chromatography: EtOAc–hexane, 1 : 3].

Pale-orange solid, mp 214–216 °C (dec.).

¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 7.95 (dd, J = 5.5, 3.1 Hz, 2H), 7.84 (dd, J = 5.5, 3.1 Hz, 2H), 7.56 (dd, J = 3.7, 1.3 Hz, 1H), 7.42–7.32 (m, 2H), 7.08 (dd, J = 5.0, 3.7 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.86 (m, 2H), 3.28 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.2, 166.4, 161.2, 143.9, 139.4, 134.9, 131.5, 131.4, 127.8, 127.1, 127.0, 124.8, 124.2, 124.1, 123.3, 108.8, 108.2, 98.3, 26.5.

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₂₃H₁₅N₃NaO₄S⁺ 452.0675; found 452.0674.

2-((3RS,5′SR)-2-Oxo-5′-phenyl-5′H-spiro[indoline-3,2′-oxazol]-5′-yl)isoindoline-1,3-dione (4h). Compound 4h (29.5 mg, yield 24%) was obtained from methylideneoxindole 1l (74.7 mg, 0.3 mmol) according to the general procedure [2^nd step: 60 min; eluent for chromatography: EtOAc–hexane, 1 : 2].

Orange solid, mp 136–139 °C (dec.).

¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 7.94 (dd, J = 5.5, 3.0 Hz, 2H), 7.83 (dd, J = 5.5, 3.0 Hz, 2H), 7.81–7.74 (m, 2H), 7.57–7.43 (m, 3H), 7.43–7.36 (m, 1H), 7.28 (m, 1H), 6.98–6.84 (m, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.2, 166.9, 162.3, 140.9, 135.8, 134.8, 131.5, 131.4, 129.1, 128.8, 125.9, 125.5, 124.7, 124.0, 123.4, 110.8, 108.6, 100.4.

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₂₄H₁₅N₃NaO₄⁺ 432.0955; found 432.0954.

2-((3RS,5′SR)-7-Fluoro-1-methyl-2-oxo-5′-phenyl-5′H-spiro[indoline-3,2′-oxazol]-5′-yl)isoindoline-1,3-dione (4i). Compound 4i (107.4 mg, yield 76%) was obtained from methylideneoxindole 1m (93.3 mg, 0.3 mmol) according to the general procedure [2^nd step: 60 min; eluent for chromatography: EtOAc–hexane, 1 : 2].

White solid, mp 238–239 °C.

¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 7.93 (dd, J = 5.4, 3.0 Hz, 2H), 7.83 (dd, J = 5.4, 3.0 Hz, 2H), 7.78 (d, J = 7.6 Hz, 2H), 7.47 (dd, J = 8.5, 6.8 Hz, 2H), 7.43–7.36 (m, 1H), 7.08 (dd, J = 11.3, 8.4 Hz, 1H), 6.88 (td, J = 8.0, 4.2 Hz, 1H), 6.72–6.68 (m, 1H), 3.50 (d, J = 2.8 Hz, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.3, 166.8, 162.5, 147.8 (d, J = 245.3 Hz), 135.6, 134.9, 131.4, 130.4 (d, J = 8.9 Hz), 129.1, 128.9, 127.8 (d, J = 2.8 Hz), 125.9, 124.1 (d, J = 6.4 Hz), 124.0, 120.2 (d, J = 3.4 Hz), 119.4 (d, J = 19.4 Hz), 108.0 (d, J = 2.8 Hz), 100.6, 29.1 (d, J = 5.7 Hz).

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₂₅H₁₆FN₃NaO₄⁺ 464.1017; found 464.1013.

2-((3RS,5′SR)-1-Methyl-5-nitro-2-oxo-5′-phenyl-5′H-spiro[indoline-3,2′-oxazol]-5′-yl)isoindoline-1,3-dione (4j). Compound 4j (71.6 mg, yield 51%) was obtained from methylideneoxindole 1n (92.4 mg, 0.3 mmol) according to the general procedure [2^nd step: 60 min; eluent for chromatography: EtOAc–hexane, 1 : 2].

Pale-orange solid, mp 227–230 °C.

¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1H), 8.32 (dd, J = 8.6, 2.3 Hz, 1H), 7.97 (dd, J = 5.5, 3.1 Hz, 2H), 7.85 (dd, J = 5.5, 3.1 Hz, 2H), 7.80–7.70 (m, 3H), 7.49 (t, J = 7.6 Hz, 2H), 7.41–7.45 (m, 1H), 6.98 (d, J = 8.6 Hz, 1H), 3.37 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.7, 167.0, 163.6, 149.2, 143.8, 135.1, 135.0, 131.3, 129.3, 129.0, 128.2, 126.0, 125.8, 124.1, 120.4, 108.7, 106.8, 100.8, 27.0.

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₂₅H₁₆N₄NaO₆⁺ 491.0962; found 491.0958.

Synthesis of methyl 2-((2′RS,5′SR)-1-methyl-2-oxo-5′-phenyl-5′H-spiro[indoline-3,2′-oxazole]-5′-ylcarbamoyl)benzoate (8). To a solution of compound 4a (64 mg, 0.15 mmol) in a DCM–MeOH mixture (1 : 3, 2 mL) in a round-bottom flask, NaBH₃CN (94.5 mg, 1.5 mmol) was added portion-wise. The reaction vessel was equipped with a bubbler and the mixture was stirred for 12 h at room temperature. After the reaction was completed (monitored by TLC), the solvent was removed in vacuo, and water was added to the residue. The precipitate formed was filtered, dissolved in DCM, and the solution was dried over anhydrous Na₂SO₄. The solvent was removed in vacuo, and the crude product was purified by column chromatography on silica gel to give compound 8 (55 mg, yield 81%).

White solid, mp 220–223 °C.

¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.86–7.82 (m, 3H), 7.62–7.40 (m, 7H), 7.12 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 6.60 (s, 1H), 3.93 (s, 3H), 3.26 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 171.2, 168.9, 166.5, 163.8, 143.8, 138.4, 137.3, 132.4, 131.3, 130.4, 130.1, 129.3, 128.8, 128.7, 127.2, 126.33, 126.28, 126.0, 123.7, 108.4, 107.4, 100.2, 52.7, 26.5.

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₂₆H₂₁N₃NaO₅⁺ 478.1373; found 478.1372.

Author contributions

A. A. N., I. P. F., O. E. P., and A. S. P. conducted all the experiments and characterized the novel compounds. N. V. R. together with I. P. F. conceived the project and wrote the manuscript. N. V. R. performed the DFT calculations. A. S. P. contributed to the editing of the manuscript. All authors contributed to discussions.

Conflicts of interest

The authors declare no conflict of interest.

Data availability

The data supporting this article are included as part of the supplementary information (SI). Supplementary information: synthesis and characterization of compounds 1, calculation details, X-ray data for compound 4a, and ¹H, ¹³C and 2D NMR spectra. See DOI: https://doi.org/10.1039/d5ob01645b.

CCDC 2495681 contains the supplementary crystallographic data for this paper.¹⁸

Acknowledgements

We gratefully acknowledge the financial support from the Russian Science Foundation, grant 22-73-10184-P. This research used the facilities of the Magnetic Resonance Research Centre, Chemical Analysis and Materials Research Centre, Cryogenic Centre, and Centre for X-ray Diffraction Studies of the Research Park of St Petersburg State University.

References

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