Facile construction of novel imidazolidine-spirooxindoles via diastereoselective cycloaddition of N-acylhydrazine-derived imines with 3-isothiocyanato oxindoles

Abstract

In the presence of 10 mol% of Na₂CO₃, the desired imidazolidine-spirooxindoles were obtained in 81–99% yield with up to 99 : 1 dr by means of the diastereoselective [3 + 2] cycloaddition of N-acylhydrazine-derived imines with 3-isothiocyanato oxindoles. Single-crystal X-ray structure analysis was conducted to determine the relative stereochemistry of the imidazolidine-spirooxindoles. Diastereoselective access to the imidazolidine-spirooxindoles was hypothesized by the proposed mechanism.

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1. Introduction

Imidazolidine-spirooxindoles constitute a class of medicinally and biologically important molecules, which were demonstrated to possess a wide range of biological activities, as presented in Fig. 1.¹ So far, a number of synthetic methodologies have been developed for the synthesis of various spirooxindoles.² However, only limited progress has been gained in the construction of the structurally diverse imidazolidine-spirooxindoles. For instances, several synthetic methodologies were employed in the racemic synthesis of imidazolidine-spirooxindoles.³ In the case of the enantioselective synthesis of the imidazolidine-spirooxindoles, only three examples have been reported to date in the literature.⁴ Therefore, it is needed necessarily to develop more concise and efficient methodologies for the construction of structurally and stereochemically diverse imidazolidine-spirooxindoles.

Fig. 1 Representative bioactive imidazolidinespirooxindoles.

Encouraged by the previous findings in the synthesis of imidazolidine-spirooxindoles, in this work we designed the novel imidazolidine-spirooxindoles bearing medicinally and pharmaceutically important hydrazide moiety⁵ as shown in Fig. 1. By using 10 mol% of Na₂CO₃ as base, we accomplished the construction of the target molecules via the [3 + 2] cycloadditions of N-acylhydrazine-based imines with 3-isothiocyanato oxindoles in excellent chemical yields with excellent diastereoselectivities. Noticeably, as compared with literature works^3,4 using Na₂CO₃ as base possessed several merits such as environmental friendliness, low cost and operational simplicity as well. To the best of our knowledge, no such a work has been reported in the literature to date.

2. Results and discussion

Initially, the effect of basic bases was investigated on the chemical yield and diastereoselectivity of the [3 + 2] cycloaddition of 1a and 2a as presented in Table 1. As for NH₄Cl, it provided 3aa in 68% yield with >99 : 1 dr (Table 1, entry 9). In the case of the other bases, all of them gave rise to 3aa in 79–94% yields with >99 : 1 drs (Table 2, entries 1–8). Apparently, Na₂CO₃ functioned most efficiently in the [3 + 2] cycloaddition among all the bases by considering both chemical yield and diastereoselectivity in the [3 + 2] cycloaddition of 1a and 2a (Table 1, entry 2).

Table 1 Screening of bases in the [3 + 2] cycloaddition^a

Entry	Base	Time (min)	Yield^b (%)	dr^c
a Reactions were carried out with 0.1 mmol of 1a and 0.1 mmol of 2a in the presence of 10 mol% of base in 1.0 mL of CH2Cl2 at room temperature.b Isolated yield.c Determined by ^1H NMR spectroscopy.
1	K2CO3	60	91	>99 : 1
2	Na2CO3	60	94	>99 : 1
3	Cs2CO3	60	80	>99 : 1
4	KOH	60	79	>99 : 1
5	NaOH	60	82	>99 : 1
6	NaOAc	60	88	>99 : 1
7	NaHCO3	60	87	>99 : 1
8	NH4NO3	120	89	>99 : 1
9	NH4Cl	120	68	>99 : 1

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Table 2 Screening of the solvent effect in the [3 + 2] cycloaddition^a

Entry	Solvent	Time (min)	Yield^b (%)	dr^c
a Reactions were carried out with 0.1 mmol of 1a, and 0.1 mmol of 2a in the presence of 10 mol% of Na2CO3 in 1.0 mL of solvents examined at room temperature.b Isolated yield.c Determined by ^1H NMR spectroscopy.
1	CHCl3	60	96	>99 : 1
2	Toluene	60	73	>99 : 1
3	EtOH	60	81	>99 : 1
4	THF	60	64	>99 : 1
5	DCE	60	89	>99 : 1

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Subsequently, under catalysis of 10 mol% of Na₂CO₃, the solvent effect was examined on the chemical yield and diastereoselectivity of the [3 + 2] cycloaddition of 1a and 2a as outlined in Table 2. In all the cases, the [3 + 2] cycloaddition went to completion readily, thus producing 3aa in excellent diastereoselectivities (Table 2, entries 1–5). In contrast, the solvent used in the [3 + 2] cycloaddition influenced the chemical yield drastically. For instances, the use of THF as solvent generated 3aa in 64% yield (Table 2, entry 4). In contrast to THF, the chemical yield of 3aa was increased from 64% to 73% using toluene as solvent (Table 2, entries 2 vs.4). In regard to other solvents, the chemical yield of 3aa was varied in the range from 81% to 96% (Table 2, entries 1, 3 & 5). Accordingly, among all the solvents screened, CHCl₃ worked best, and delivered product 3aa in the highest chemical yield (Table 2, entry 1). At current stage, the optimal reaction condition for the [3 + 2] cycloaddition of 1a and 2a was decided as follows: the cycloaddition reaction was carried in the presence of 10 mol% of Na₂CO₃ in CHCl₃ at room temperature.

By using the optimal reaction conditions, the reaction scope of the [3 + 2] cycloaddition of 1 and 2 was extended as listed in Table 3. Noticeably, in most cases, products 3 were formed in excellent chemical yields and diastereoselectivities (Table 3, entries 1–2, 4–9, 11–13 & 15–17). In terms of other cases, the chemical yield of 3 ranged from 81% to 84%, and the diastereoselectivity was changed in the range from 80 : 20 to >99 : 1 (Table 3, entries 3, 10 & 14). The single crystal X-ray analysis was used to determine the relative configuration of 3aa as depicted in Fig. 2.⁶ According to the determined relative stereochemistry of 3aa, the relative configuration of other imidazolidine-spirooxindoles 3 was also characterized similarly as shown in Table 3. Moreover, we examined the enantioseletive organocatalytic [3 + 2] cycloaddition of 1a and 2a. However, in all cases, product 3aa was obtained as racemate (see details in ESI†).

Table 3 Extension substrate scope of the [3 + 2] cycloaddition^a

Entry	1 (R1, R2)	2 (R3, R4)	3	Time (min)	Yield^b (%)	dr^c
a Reactions were carried out with 0.1 mmol of 1 and 0.1 mmol of 2 in the presence of 10 mol% of Na2CO3 in 1.0 mL of CHCl3 at room temperature.b Isolated yield.c Determined by ^1H NMR spectroscopy.
1	1a (C6H5, C6H5)	2a (H, Bn)	3aa	60	96	>99 : 1
2	1b (4-Pyridine, C6H5)	2a (H, Bn)	3ba	60	93	>99 : 1
3	1c (Me, C6H5)	2a (H, Bn)	3ca	120	81	>80 : 20
4	1d (C6H5, 4-F-C6H4)	2a (H, Bn)	3da	60	95	>99 : 1
5	1e (C6H5, 4-Cl-C6H4)	2a (H, Bn)	3ea	60	97	>99 : 1
6	1f (C6H5, 4-Br-C6H4)	2a (H, Bn)	3fa	60	92	>99 : 1
7	1g (C6H5, 4-Me-C6H4)	2a (H, Bn)	3ga	60	99	>99 : 1
8	1h (C6H5, 3,4,5-tri-MeO-C6H2)	2a (H, Bn)	3ha	60	97	>99 : 1
9	1i (C6H5, 3-Cl-C6H4)	2a (H, Bn)	3ia	120	90	>99 : 1
10	1j (C6H5, 4-CN-C6H4)	2a (H, Bn)	3ja	120	82	>99 : 1
11	1k (C6H5, 2-Br-C6H4)	2a (H, Bn)	3ka	120	93	>99 : 1
12	1l (C6H5, 3,4-di-MeO-C6H3)	2a (H, Bn)	3la	60	98	>99 : 1
13	1m (C6H5, 4-Me-C6H4)	2a (H, Bn)	3ma	60	97	>99 : 1
14	1n (C6H5, 4-CF3-C6H4)	2a (H, Bn)	3na	120	84	>99 : 1
15	1a (C6H5, C6H5)	2b (Me, Bn)	3ab	120	93	>99 : 1
16	1a (C6H5, C6H5)	2c (F, Bn)	3ac	60	92	>99 : 1
17	1a (C6H5, C6H5)	2d (H, Me)	3ad	60	94	>99 : 1

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Fig. 2 X-ray single crystal structure of 3aa.

To shed light on the generation of 3aa in diastereoselectivity, the plausible reaction mechanism was suggested on the basis of the related previously published works^2a,4c,7 for the [3 + 2] cycloaddition of 1a and 2a as described in Scheme 1. Deprotonated by Na₂CO₃, 2a was converted into enolate 5. The subsequent [3 + 2] cycloaddition of enolate 5 with 1a afforded intermediate 6 by following a cascade nucleophilic addition/cyclization sequence as depicted in the transition state (TS). At last, the protonation of 6 resulted in the diastereoselective formation of 3aa.

Scheme 1 Proposed mechanism for the [3 + 2] cycloaddition.

3. Conclusions

In conclusion, the novel [3 + 2] cycloaddition of N-acylhadrazine-based imines with 3-isothiocyanato oxindoles was first accomplished in this work. The desired imidazolidine-spirooxindoles 3 were formed in excellent chemical yields and diastereoselectivities through the [3 + 2] cycloaddition. Currently, to develop other novel [3 + 2] cycloaddition of N-acylhydrazine-based imines with other chemical entities is ongoing in our organic lab, will be reported in due course.

4. Experimental section

4.1 General information

Unless noted otherwise, all reagents were commercially available and used without further purification. All solvents were distilled from the appropriate drying agents immediately before use. Reactions were monitored by TLC carried out on 0.25 mm SDS silica gel coated glass plates (60F254) and compounds were detected with UV light. The compound melting point was determined by a melting point instrument. NMR spectra were recorded on 400 MHz instrument and calibrated using tetramethylsilane (TMS) as internal reference. High resolution mass spectra (HRMS) were recorded under electrospray ionization (ESI) conditions.

4.2 Typical procedure for the diastereoselective synthesis of imidazolidine-spirooxindoles

Na₂CO₃ (0.01 mmol) was added to a mixture of N-acylhadrazine-based imines 1 (0.1 mmol) and 3-isothiocyanato oxindoles 2 (0.1 mmol) in anhydrous CHCl₃ (1.0 mL). The reaction mixture was stirred at room temperature for 1–2 h. After completion of the reaction, the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4 : 1) to afford the pure products 3 as white powder (81–99% yield; 80 : 20–>99 : 1 dr).

N-(1′-Benzyl-2′-oxo-5-phenyl-2-thioxospiro[imidazolidine-4,3′-indolin]-1yl)benzamide (3aa). 48.4 mg, 96% yield, dr > 99 : 1; white powder, mp 107–109 °C; ¹H NMR (400 MHz, DMSO): δ 10.91 (s, 1H), 9.87 (s, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.36–7.261 (m, 6H), 7.18–7.11 (m, 2H), 7.09–7.08 (m, 4H), 6.97 (t, J = 7.6 Hz, 1H), 6.74 (d, J = 8 Hz, 1H), 5.86 (s, 1H), 4.99 (d, J = 16 Hz, 1H), 4.86 (d, J = 8 Hz, 1H); ¹³C NMR (100 MHz, DMSO): δ 186.7, 173.6, 166.1, 142.0, 136.0, 132.6, 132.4, 130.4, 129.0, 128.9, 128.5, 128.0, 127.9, 127.8, 126.3, 125.7, 123.0, 110.0, 72.8, 68.6, 43.7; HRMS (ESI) calculated for C₃₀H₂₅N₄O₂S [M + H]⁺: 505.16927, found 505.16830.

N-(1′-Benzyl-2′-oxo-5-phenyl-2-thioxospiro[imidazolidine-4,3′-indolin]-1-yl)isonicotinamide (3ba). 47.0 mg, 93% yield, dr > 99 : 1; white powder, mp 243–245 °C; ¹H NMR (400 MHz, DMSO): δ 11.21 (s, 1H), 9.98 (s, 1H), 8.75 (d, J = 5.6 Hz, 2H), 7.34 (d, J = 6.4 Hz, 2H), 7.32–7.26 (m, 6H), 7.13–7.09 (m, 6H), 6.97 (t, J = 7.6 Hz, 1H), 6.75 (d, J = 8 Hz, 1H), 5.80 (s, 1H), 4.99 (d, J = 16 Hz, 1H), 4.86 (d, J = 8 Hz, 1H); ¹³C NMR (100 MHz, DMSO): δ 186.1, 173.8, 164.8, 150.9, 142.0, 136.0, 132.5, 130.4, 129.0, 128.9, 128.5, 128.0, 127.8, 127.8, 126.2, 125.8, 122.9, 121.7, 110.0, 72.8, 68.7, 43.7; HRMS (ESI) calculated for C₂₉H₂₄N₅O₂S [M + H]⁺: 506.16452, found 506.16385.

N-(1′-Benzyl-2′-oxo-5-phenyl-2-thioxospiro[imidazolidine-4,3′-indolin]-1-yl)acetamide (3ca). 35.8 mg, 81% yield, dr > 80 : 20; white powder, mp 126–128 °C; ¹H NMR (400 MHz, DMSO): δ 10.31 (s, 1H), 9.73 (s, 1H), 7.35–7.22 (m, 6H), 7.17–7.13 (m, 1H), 7.11–7.04 (m, 7H), 7.00 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 5.66 (s, 1H), 4.96 (d, J = 15.6 Hz, 1H), 4.83 (d, J = 16 Hz, 1H), 1.81 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 186.5, 173.7, 169.0, 142.0, 136.0, 132.5, 130.3, 129.0, 128.9, 128.5, 128.2, 128.0, 127.8, 126.9, 126.3, 125.7, 122.9, 109.9, 72.6, 68.4, 43.7, 21.2; HRMS (ESI) calculated for C₂₅H₂₃N₄O₂S [M + H]⁺: 443.15362, found 443.15302.

N-(1′-Benzyl-5-(4-fluorophenyl)-2′-oxo-2-thioxospiro[imidazolidine-4,3′-indolin]-1-yl)benzamide (3da). 49.6 mg, 95% yield, dr > 99 : 1; white powder, mp 134–136 °C; ¹H NMR (400 MHz, DMSO): δ 10.91 (s, 1H), 9.92 (s, 1H), 8.34 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.36–7.27 (m, 6H), 7.23–7.14 (m, 2H), 7.13–7.11 (m, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.92 (t, J = 8.8 Hz, 2H), 6.80 (d, J = 8 Hz, 1H), 5.83 (s, 1H), 4.99 (d, J = 16 Hz, 1H), 4.87 (d, J = 15.6 Hz, 1H); ¹³C NMR (100 MHz, DMSO): δ 186.6, 173.6, 166.1, 163.5, 161.1, 141.9, 136.0, 132.6, 130.5, 130.1, 130.0, 129.0, 128.6, 128.1, 127.9, 126.1, 125.7, 123.0, 115.5, 110.1, 72.3, 68.6, 43.7; ¹⁹F NMR (376 MHz, DMSO): δ −113.13; HRMS (ESI) calculated for C₃₀H₂₄FN₄O₂S [M + H]⁺: 523.15985, found 523.15900.

N-(1′-Benzyl-5-(4-chlorophenyl)-2′-oxo-2-thioxospiro[imidazolidine-4,3′-indolin]-1-yl)benzamide (3ea). 52.3 mg, 97% yield, dr > 99 : 1; white powder, mp 135–137 °C; ¹H NMR (400 MHz, DMSO): δ 10.90 (s, 1H), 9.93 (s, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 2H), 7.36–7.27 (m, 7H), 7.20–7.12 (m, 5H), 7.00 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 5.82 (s, 1H), 4.99 (d, J = 15.6 Hz, 1H), 4.88 (d, J = 15.6 Hz, 1H), ¹³C NMR (100 MHz, DMSO): δ 186.7, 173.5, 166.1, 141.9, 136.0133.5, 132.6, 132.5, 131.5130.6, 129.8, 129.0, 128.5, 128.0, 127.9, 126.0, 123.1, 110.2, 72.3, 68.5, 43.7; HRMS (ESI) calculated for C₃₀H₂₄ClN₄O₂S [M + H]⁺: 539.13030, found 539.12909.

N-(1′-Benzyl-5-(4-bromophenyl)-2′-oxo-2-thioxospiro[imidazolidine-4,3′-indolin]-1-yl)benzamide (3fa). 53.5 mg, 92% yield, dr > 99 : 1; white powder, mp 128–130 °C; ¹H NMR (400 MHz, DMSO): δ 10.90 (s, 1H), 9.92 (s, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.2 Hz, 2H), 7.35–7.26 (m, 8H), 7.17–7.11 (m, 3H), 7.00 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 5.79 (s, 1H), 4.98 (d, J = 15.6 Hz, 1H), 4.87 (d, J = 15.6 Hz, 1H), ¹³C NMR (100 MHz, DMSO): δ 186.7, 173.4, 166.1, 141.9, 136.0, 132.7, 132.5, 131.9, 131.5, 130.6, 130.1, 129.0, 128.1, 127.9, 126.0, 125.6, 123.1, 122.1, 110.2, 72.3, 68.4, 43.7; HRMS (ESI) calculated for C₃₀H₂₄BrN₄O₂S [M + H]⁺: 583.07979, found 583.07904.

N-(1′-Benzyl-5-(4-methoxyphenyl)-2′-oxo-2-thioxospiro[imidazolidine-4,3′-indolin]-1-yl)benzamide (3ga). 51.3 mg, 99% yield, dr > 99 : 1; white powder, mp 144–146 °C; ¹H NMR (400 MHz, DMSO): δ 10.86 (s, 1H), 9.82 (s, 1H), 7.83 (d, J = 7.2 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.46–7.24 (m, 6H), 7.15–7.08 (m, 3H), 7.01 (t, J = 7.6 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 8.0 Hz, 2H), 5.79 (s, 1H), 5.00 (d, J = 16.0 Hz, 1H), 4.83 (d, J = 16.0 Hz, 1H), 3.58 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 186.6, 173.7, 160.5, 166.0, 159.5, 142.0, 136.0, 132.6, 130.4, 129.4, 129.0, 128.7, 128.0, 127.9, 127.8, 126.9, 126.4, 125.7, 123.9, 123.0, 113.8, 110.1, 72.6, 68.7, 55.4, 43.6; HRMS (ESI) calculated for C₃₁H₂₇N₄O₃S [M + H]⁺: 535.17984, found 535.17896.

N-(1′-Benzyl-2′-oxo-2-thioxo-5-(3,4,5-trimethoxyphenyl)spiro[imidazolidine-4,3′-indolin]-1-yl)benzamide (3ha). 57.6 mg, 97% yield, dr > 99 : 1; white powder, mp 241–243 °C; ¹H NMR (400 MHz, DMSO): δ 10.90 (s, 1H), 9.87 (s, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.57 (d, J = 7.2 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.38 (d, J = 7.2 Hz, 1H), 7.27–7.24 (m, 5H), 7.13 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 16.0 Hz, 1H), 6.49 (s, 2H), 5.74 (s, 1H), 4.94 (q, J = 18.8 Hz, 2H), 3.60 (s, 6H), 3.49 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 186.6, 173.7, 166.1, 152.9, 142.1, 142.4, 137.6, 136.0, 132.7, 132.6, 130.5, 129.1, 129.0, 128.0, 127.9, 127.8, 127.5, 126.3, 126.0, 122.9, 110.1, 105.3, 73.0, 68.8, 60.3, 56.2, 43.7; HRMS (ESI) calculated for C₃₃H₃₁N₄O₅S [M + H]⁺: 595.20097, found 595.20020.

N-(1′-Benzyl-5-(3-chlorophenyl)-2′-oxo-2-thioxospiro[imidazolidine-4,3′-indolin]-1-yl)benzamide (3ia). 48.4 mg, 90% yield, dr > 99 : 1; white powder, mp 135–137 °C; ¹H NMR (400 MHz, DMSO): δ 10.93 (s, 1H), 9.88 (s, 1H), 7.86 (d, J = 7.2 Hz, 3H), 7.56 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.40 (d, J = 7.2 Hz, 2H), 7.35–7.11 (m, 5H), 7.11–7.06 (m, 2H), 6.91 (d, J = 7.2 Hz, 1H), 6.82–6.78 (m, 2H), 6.18 (s, 1H), 5.04 (d, J = 15.6 Hz, 1H), 4.80 (d, J = 15.6 Hz, 1H); ¹³C NMR (100 MHz, DMSO): δ 186.6, 173.5, 166.2, 142.0, 136.0, 135.0, 133.5, 132.6, 132.5, 130.6, 130.4, 129.1, 129.0, 128.0, 127.9, 127.8, 127.7, 126.5, 125.9, 125.7, 123.0, 110.2, 72.1, 68.4, 43.8; HRMS (ESI) calculated for C₃₀H₂₄ClN₄O₂S [M + H]⁺: 539.13030, found 539.12958.

N-(1′-Benzyl-5-(4-cyanophenyl)-2′-oxo-2-thioxospiro[imidazolidine-4,3′-indolin]-1-yl)benzamide (3ja). 43.3 mg, 82% yield, dr > 99 : 1; white powder, mp 122–124 °C; ¹H NMR (400 MHz, DMSO): δ 10.90 (s, 1H), 10.00 (s, 1H), 7.83 (d, J = 8 Hz, 2H), 7.60–7.56 (m, 3H), 7.49 (t, J = 7.6 Hz, 2H), 7.38–7.30 (m, 7H), 7.23 (d, J = 7.2 Hz, 1H), 7.14 (t, J = 8 Hz, 1H), 6.98 (t, J = 7.2 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 5.88 (s, 1H), 4.94 (q, J = 10.8 Hz, 2H); ¹³C NMR (100 MHz, DMSO): δ 186.7, 173.3, 166.2, 141.9, 138.3, 136.0, 133.2, 132.7, 132.5, 130.7, 129.1, 129.0, 128.8, 128.7, 128.1, 128.0, 127.9, 127.1, 125.7, 125.6, 123.1, 118.6, 111.7, 110.3, 72.3, 68.3, 43.8; HRMS (ESI) calculated for C₃₁H₂₄N₅O₂S [M + H]⁺: 530.16452, found 530.16364.

N-(1′-Benzyl-5-(2-bromophenyl)-2′-oxo-2-thioxospiro[imidazolid-ine-4,3′-indolin]-1-yl)benzamide (3ka). 54.1 mg, 93% yield, dr > 99 : 1; white powder, mp 129–131 °C; ¹H NMR (400 MHz, DMSO): δ 10.95 (s, 1H), 9.94 (s, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.57 (d, J = 7.2 Hz, 1H), 7.49 (t, J = 7.2 Hz, 2H), 7.36–7.27 (m, 7H), 7.17–6.98 (m, 5H), 6.77 (d, J = 7.6 Hz, 1H), 5.84 (s, 1H), 5.02 (d, J = 15.6 Hz, 1H), 4.86 (d, J = 15.6 Hz, 1H); ¹³C NMR (100 MHz, DMSO): δ 185.0, 174.4, 166.0, 143.0, 135.9, 133.3, 133.0, 132.6, 135.8, 130.6, 1131.2, 130.7, 130.4, 128.9, 128.1, 128.0, 127.7, 126.3, 125.6, 123.0, 122.6, 109.9, 70.8, 67.1, 44.0; HRMS (ESI) calculated for C₃₀H₂₄BrN₄O₂S [M + H]⁺: 583.07979, found 583.07947.

N-(1′-Benzyl-5-(3,4-dimethoxyphenyl)-2′-oxo-2-thioxospiro[imid-azolidine-4,3′-indolin]-1-yl)benzamide (3la). 55.2 mg, 98% yield, dr > 99 : 1; white powder, mp 143–145 °C; ¹H NMR (400 MHz, DMSO): δ 10.85 (s, 1H), 9.82 (s, 1H), 7.84 (d, J = 7.2 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.50–7.43 (m, 3H), 7.33–7.27 (m, 3H), 7.22–7.21 (m, 2H), 7.16–7.12 (m, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.94 (s, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.34 (d, J = 7.6 Hz, 1H), 6.58–6.55 (m, 1H), 5.73 (s, 1H), 5.00 (d, J = 16 Hz, 1H), 4.83 (d, J = 16 Hz, 1H), 3.61 (s, 3H), 3.59 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 186.5, 173.8, 166.0, 149.1, 148.5, 142.0, 135.9, 132.7, 132.5, 130.4, 129.0, 127.9, 127.6, 126.6, 126.0, 124.3, 122.8, 120.7, 111.9, 111.2, 110.0, 73.0, 69.1, 55.7, 43.6; HRMS (ESI) calculated for C₃₂H₂₈N₄O₄S [M + H]⁺: 565.19040, found 565.18951.

N-(1′-Benzyl-2′-oxo-2-thioxo-5-(p-tolyl)spiro[imidazolidine-4,3′-indolin]-1-yl)benzamide (3ma). 50.2 mg, 97% yield, dr > 99 : 1; white powder, mp 214–216 °C; ¹H NMR (400 MHz, DMSO): δ 10.89 (s, 1H), 9.86 (s, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.35–7.7.24 (m, 4H), 7.13–7.06 (m, 5H), 6.99 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.6 Hz, 2H), 6.73 (d, J = 8.0 Hz, 1H), 5.84 (s, 1H), 4.99 (d, J = 8 Hz, 1H), 4.87 (d, J = 15.6 Hz, 1H), 2.09 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 186.6, 173.7, 166.0, 142.0, 138.1, 135.9, 132.6, 132.5, 130.4, 129.3, 129.1, 129.0, 128.0, 127.9, 127.7, 126.4, 125.8, 130.0, 110.1, 72.7, 68.7, 43.7; HRMS (ESI) calculated for C₃₁H₂₇N₄O₂S [M + H]⁺: 519.18492, found 519.18427.

N-(1′-Benzyl-2′-oxo-2-thioxo-5-(4-(trifluoromethyl)phenyl)spiro[imidazolidine-4,3′-indolin]-1-yl)benzamide (3na). 48.1 mg, 84% yield, dr > 99 : 1; white powder, mp 138–141 °C; ¹H NMR (400 MHz, DMSO): δ 10.95 (s, 1H), 9.99 (s, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.50–7.40 (m, 4H), 7.39–7.26 (m, 8H), 7.13 (t, J = 7.2 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 5.90 (s, 1H), 4.94 (q, J = 15.6 Hz, 2H); ¹³C NMR (100 MHz, DMSO): δ 187.4, 173.6, 167.1, 141.0, 135.3, 134.4, 132.3, 131.9, 131.0, 130.7, 128.9, 128.6, 128.4, 128.1, 127.5, 127.4, 126.6, 125.1, 124.8, 123.9, 109.8, 75.1, 68.8, 44.5; ¹⁹F NMR (376 MHz, DMSO): δ −61.22; HRMS (ESI) calculated for C₃₁H₂₄F₃N₄O₂S [M + H]⁺: 573.15666, found 573.15564.

N-(1′-Benzyl-5′-methyl-2′-oxo-5-phenyl-2-thioxospiro[imidazo-lidine-4,3′-indolin]-1-yl)benzamide (3ab). 48.7 mg, 93% yield, dr > 99 : 1; white powder, mp 121–123 °C; ¹H NMR (400 MHz, DMSO): δ 10.87 (s, 1H), 9.84 (s, 1H), 7.83 (d, J = 7.2 Hz, 2H), 7.82–7.55 (m, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.34–7.23 (m, 5H), 7.16–7.08 (m, 6H), 6.91 (d, J = 8 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 5.83 (s, 1H), 4.96 (d, J = 16.0 Hz, 1H), 4.82 (d, J = 16.0 Hz, 1H), 2.20 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 187.6, 173.9, 167.0, 138.7, 134.5, 133.5, 132.3, 132.1, 131.5, 130.5, 128.8, 128.7, 128.5, 128.1, 127.9, 127.6, 127.4, 127.1, 125.4, 109.3, 75.7, 69.1, 44.4, 21.0; HRMS (ESI) calculated for C₃₁H₂₇N₄O₂S [M + H]⁺: 519.18492, found 519.18463.

N-(1′-Benzyl-5′-fluoro-2′-oxo-5-phenyl-2-thioxospiro[imidazolidine-4,3′-indolin]-1-yl)benzamide (3ac). 48.1 mg, 92% yield, dr > 99 : 1; white powder, mp 133–135 °C; ¹H NMR (400 MHz, DMSO): δ 10.90 (s, 1H), 9.90 (s, 1H), 7.84–7.82 (m, 2H), 7.59–7.55 (m, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.36–7.25 (m, 5H), 7.17–7.11 (m, 5H), 7.05–6.97 (m, 2H), 6.79–6.75 (m, 1H), 5.84 (s, 1H), 4.99 (d, J = 15.6. Hz, 1H), 4.87 (d, J = 15.6 Hz, 1H); ¹³C NMR (100 MHz, DMSO): 187.4, 173.8, 170.0, 160.5, 158.1, 137.0, 134.1, 132.2, 131.0, 129.0, 128.9, 128.7, 128.6, 128.4, 128.1, 127.8, 127.6, 127.1, 127.0, 117.0, 116.7, 114.9, 114.6, 110.5, 110.4, 69.0, 44.6; ¹⁹F NMR (376 MHz, DMSO): δ −120.25; HRMS (ESI) calculated for C₃₀H₂₄FN₄O₂S [M + H]⁺: 523.15985, found 523.15936.

N-(1′-Methyl-2′-oxo-5-phenyl-2-thioxospiro[imidazolidine-4,3′-indolin]-1-yl)benzamide (3ad). 40.2 mg, 94% yield, dr > 99 : 1; white powder, mp 187–189 °C; ¹H NMR (400 MHz, DMSO): δ 10.89 (s, 1H), 9.68 (s, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.24–7.08 (m, 7H), 6.97 (t, J = 7.2 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 5.79 (s, 1H), 3.14 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 186.7, 173.5, 166.0, 142.8, 132.7, 132.6, 130.4, 129.0, 128.7, 128.5, 127.9, 127.5, 126.2, 125.4, 122.8, 109.3, 72.6, 68.6, 27.1; HRMS (ESI) calculated for C₂₄H₂₁N₄O₂S [M + H]⁺: 429.13797, found 429.13718.

Acknowledgements

We thank Beijing Municipal Commission of Education (No. JC015001200902),Beijing Municipal Natural Science Foundation (No. 7102010, No. 2122008), Basic Research Foundation of Beijing University of Technology (X4015001201101), Funding Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality (No. PHR201008025), Doctoral Scientific Research Start-up Foundation of Beijing University of Technology (No. 52015001200701) for financial supports.

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Footnote

† Electronic supplementary information (ESI) available: Copies of NMR spectra for all products related to this acticle; X-ray single crystal structure analysis data for 3aa. CCDC 1416439. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra01962e

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