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Abstract

Selective mono-aza-Michael additions of divinyl ketones with 3-(arylimino)indolin-2-ones in the presence of cesium carbonate are described. N-Enone-functionalized 3-(arylimino)indolin-2-ones were efficiently synthesized in satisfactory yield. The salient features of this protocol are high regioselectivity, high yield, and mild conditions.

Keywords

3-(arylimino)indolin-2-one divinyl ketone high regioselectivity mono-aza-Michael addition synthesis

Graphical Abstract

Introduction

The indolin-2-one framework bearing various functional groups at the N-position is a privileged heterocyclic motif that is found in many bioactive natural products and pharmaceutically active compounds.^1,2 One important method for the N-functionalization of indolin-2-one is the aza-Michael addition. However, the 3-position is more active than the 1-position for indolin-2-one making the Michael addition to C-3 more favorable.^3–5 Therefore, 3-substituted indolin-2-ones may be better candidates for aza-Michael additions. 3-(Arylimino)indolin-2-ones, synthesized by reactions of isatins with aromatic amines,⁶ may act as good aza-Michael donors. For example, Imanzadeh et al.⁷ reported the aza-Michael additions of 3-(arylimino)indolin-2-ones with fumaric esters; Zari⁸ described the thiourea catalyzed asymmetric aza-Michael additions of 3-(arylimino)indolin-2-ones with unsaturated 1,4-diketoesters; Metsala⁹ investigated these aza-Michael reactions by means of density functional theory (DFT) calculations; and Metsala¹⁰ also performed conformational analyses across reaction paths for these aza-Michael reactions.

Divinyl ketones (e.g. 1,4-dien-3-ones) have been used as Michael acceptors in recent years to synthesize spiro-, cyano-, and other important compounds.^11–19 However, divinyl ketones as Michael acceptors have problems of regioselective control and can undergo 1,2-addition and two kinds of 1,4-addition reactions.

Herein, we report the regioselective mono-aza-Michael additions of divinyl ketones with 3-(arylimino)indolin-2-ones under mild, transition metal-free and acid-free conditions to synthesize N-enone-functionalized 3-(arylimino)indolin-2-ones bearing both C=C and C=N functional groups.

Results and discussion

In previous work, the reactions of 3-(arylimino)indolin-2-ones with enones had been reported, which could give the aza-Michael addition products in satisfactory yields.²⁰ In order to compare enones and divinyl ketones, the aza-Michael additions of 3-(arylimino)indolin-2-ones with divinyl ketones were investigated. Initially, (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one (1a) was selected as a substrate and reacted with 1 equiv. of (E)-3-(phenylimino)indolin-2-one (2a), which was synthesized by reaction of isatin with aniline, and isolated from the E-Z mixture (ca. 87:13). The reaction was attempted using a variety of bases at different temperatures in various solvents. When the reaction was carried out using KOH as the base in CH₂Cl₂, one product was isolated in 52% yield and was identified as (E)-1-((E)-3-oxo-1,5-diphenylpent-4-en-1-yl)-3-(phenylimino)indolin-2-one (3aa). This result indicated that the reaction of 1a with 1 equiv. of 2a proceeded by only a single 1,4-conjugate addition. No 1,2-adduct was observed. When 1a was reacted with 2 equiv. of 2a, the product still was 3aa, and no double 1,4-conjugate addition product was isolated. These results implied that the reaction between 1a and 2a was highly regioselective for a carbon, carbon double-bond of 1a (Scheme 1).

Scheme 1.

Regioselective addition of 1a with 2a.

In order to optimize further the reaction conditions for the model reaction, other bases including inorganic bases, such as NaOH, K₂CO₃, Na₂CO₃, CsF, and Cs₂CO₃, and organic bases, such as Et₃N, 1,4-diazabicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyridine (DMAP), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), were examined for the reaction (Table 1, entries 2−5 and Supporting information, Table S1). Of these, Cs₂CO₃ as a base gave the best yield of the desired product 3aa (entry 4). The effect of the amount of base on the yield of 3aa was also tested (entries 4, 6−8). It was found that when the amount of Cs₂CO₃ was reduced to 0.5 equiv., the highest yield of 3aa was obtained (entry 6). The choice of solvent also had an effect on the yield of the reaction. Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), MeOH, 1,4-dioxane, and tetrahydrofuran (THF) were not suitable for the reaction (entries 14−18). Meanwhile, the reactions in MeCN and ClCH₂CH₂Cl gave 3aa in moderate yields (Supporting information, Table S1). The highest yield was obtained using CH₂Cl₂ as the solvent (entry 6). In addition, increasing the temperature from room temperature to 50 °C caused a reduction in the yield of 3aa because of an increase in by-products (entry 9). Changing the ratio of 1a to 2a from 1:1 to 1:2 did not improve the yield of 3aa (entry 10).

Table 1.

Optimization of the reaction conditions.^a


Entry	Base (equiv.)	Solvent	Yield (%)^b
1	KOH (1)	CH₂Cl₂	52
2	NaOH (1)	CH₂Cl₂	40
3	CsF (1)	CH₂Cl₂	35
4	Cs₂CO₃ (1)	CH₂Cl₂	67
5	DBU (1)	CH₂Cl₂	43
6	Cs₂CO₃ (0.5)	CH₂Cl₂	70
7	Cs₂CO₃ (1.5)	CH₂Cl₂	69
8	Cs₂CO₃ (2)	CH₂Cl₂	65
9^c	Cs₂CO₃ (0.5)	CH₂Cl₂	Trace
10^d	Cs₂CO₃ (0.5)	CH₂Cl₂	53

Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), and base (appropriate amount) in solvent (3 mL) at room temperature for 8 h.

Isolated yields.

Reaction condition: 50 °C.

Reaction condition: 1a:2a = 1:2.

With the optimized reaction conditions in hand, the generality of this reaction was examined for the reactions of various divinyl ketones with 3-(arylimino)indolin-2-ones in CH₂Cl₂ at room temperature using Cs₂CO₃ as the base. The reactions were first tested using various divinyl ketones (1a−i) and 2a. As shown in Table 2, divinyl ketones bearing electron-donating groups (Me, MeO) and electron-withdrawing groups (CF₃, Cl, Br) on the aromatic rings gave the corresponding mono-aza-Michael addition products in satisfactory yields (3aa−3ha). It was also found that ortho-substituted divinyl ketones (3ba) afforded slightly lower yield than meta- and para-substituted divinyl ketones because of the increased steric hindrance. In addition, a divinyl ketone bearing a thiophen-2-yl heterocycle also gave the corresponding product in a moderate yield (3ia). Aliphatic divinyl ketones did not produce the desired products.

Table 2.

The reactions of various divinyl ketones with 2a.^a

Reaction conditions: 1a−i (0.3 mmol), 2a (0.36 mmol), and Cs₂CO₃ (0.15 mmol) in CH₂Cl₂ (3 mL) at room temperature for 8 h.

The scope of the reactions of 1a with various 3-(arylimino)indolin-2-ones (2b−m) was also examined (Table 3). The reactions tolerated a wide range of indolin-2-ones bearing substituted arylimino groups (R² = Me, MeO, F, and Cl) and afforded the corresponding products in satisfactory yields (3ab−3ag). 3-(Arylimino)indolin-2-ones bearing disubstituted arylimino groups also allowed the easy synthesis of the corresponding products in moderate to high yields (3ah, 3ai). 3-(Arylimino)indolin-2-ones bearing substituents on the indolin-2-one rings (R³ = 5-Cl, 5-Me) also gave the corresponding products in good yield (3aj−3am).

Table 3.

The reactions of 1a with various 3-(arylimino)indolin-2-ones.^a

Reaction conditions: 1a (0.3 mmol), 2b−m (0.36 mmol), and Cs₂CO₃ (0.15 mmol) in CH₂Cl₂ (3 mL) at room temperature for 8 h. Isolated yields.

The reaction of 1a with 2a was also extended to the gram scale (Scheme 2). The reaction of 1a (1.17 g) and 2a (1.33 g) in CH₂Cl₂ (40 mL) in the presence of Cs₂CO₃ (0.41 g) was performed under the optimized conditions to give 3aa (1.51 g) in a 66% isolated yield. The success of this gram scale reaction further showed the potency of optimized conditions for bulk processes.

Scheme 2.

Gram-scale synthesis of 3aa.

A plausible mechanism is proposed for the reaction of 1a with 2a (Scheme 3). 3-(Phenylimino)indolin-2-one (2a) is deprotonated by the Cs₂CO₃ to form 3-(phenylimino)indolin-2-one anion A. Then, the 1,4-addition of A to the divinyl ketone 1a affords the intermediate B. Intermediate B then undergoes protonation to give the enolic intermediate C. C readily tautomerizes to produce the final product 3aa.

Scheme 3.

The proposed mechanism for formation of product 3aa.

Conclusion

In conclusion, an efficient method for mono-aza-Michael additions of symmetric divinyl ketones with 3-(arylimino)indolin-2-ones using cesium carbonate as the base has been developed. This protocol has advantages of high regioselectivity, high yields, and mild conditions. This will be a useful alternative for the synthesis of N-enone-functionalized indolin-2-ones. Owing to the compatibility of multiple functional groups, such as C=C, C=O, C=N, and aryl rings, with the reaction, the resulting compounds will have many applications for the synthesis of other useful fine chemicals.

Experimental

General information

¹H NMR and ¹³C NMR spectra were obtained with Mercury-400BB and Mercury-600BB instruments using CDCl₃ as solvent and Me₄Si as the internal standard. High-resolution mass spectra (HRMS) (ESI) were obtained with a Bruker Daltonics APEX II 47e and Orbitrap Elite mass spectrometer. Divinyl ketones^21,22 and 3-(arylimino)indolin-2-ones^6,23 were synthesized according to literature procedures.

The general procedure for the mono-aza-Michael additions of divinyl ketones with 3-(arylimino)indolin-2-ones: synthesis of 3aa−3ia and 3ab−3am

A mixture of divinyl ketone (0.3 mmol), 3-(arylimino)indolin-2-one (0.36 mmol), and cesium carbonate (0.15 mmol) in methylene chloride (3 mL) was stirred under air at room temperature for 8 h. Then, the resulting mixture was extracted with ethyl acetate (2 × 5 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residues were isolated by column chromatography using petroleum ether and ethyl acetate (v/v 5:1) as eluent to give pure product. Analytical data for the products are given below.

(E)-1-((E)-3-Oxo-1,5-diphenylpent-4-en-1-yl)-3-(phenylimino)indolin-2-one (3aa): Orange solid (96 mg, 70%). m.p. 103−105 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.65 (d, J = 16.2 Hz, 1H), 7.59–7.52 (m, 4H), 7.41–7.36 (m, 7H), 7.34–7.28 (m, 2H), 7.22 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.96 (d, J = 7.8 Hz, 2H), 6.80 (d, J = 16.2 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 6.58 (d, J = 7.7 Hz, 1H), 5.82 (dd, J = 8.9, 5.4 Hz, 1H), 4.47 (dd, J = 17.5, 8.9 Hz, 1H), 3.56 (dd, J = 17.5, 5.6 Hz, 1H).¹³C NMR (150 MHz, CDCl₃) δ 196.8, 163.6, 154.2, 150.4, 147.6, 143.8, 138.6, 134.3, 134.0, 130.7, 129.4, 129.0, 128.9, 128.5, 128.2, 127.3, 126.2, 125.8, 125.1, 122.5, 117.7, 115.9, 110.5, 53.3, 43.0. HRMS (ESI): Calcd for C₃₁H₂₄N₂O₂ [M+H]⁺: 457.1911; found: 457.1910.

(E)-1-((E)-3-Oxo-1,5-di-o-tolylpent-4-en-1-yl)-3-(phenylimino)indolin-2-one (3ba): Orange solid (72 mg, 50%). m.p. 76−78 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.94 (d, J = 16.0 Hz, 1H), 7.67 (dd, J = 7.1, 1.9 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.40 (dd, J = 8.4, 7.4 Hz, 2H), 7.28 (td, J = 7.5, 1.5 Hz, 2H), 7.25 (d, J = 1.4 Hz, 1H), 7.23 (d, J = 1.7 Hz, 1H), 7.22–7.19 (m, 4H), 6.96 (dd, J = 8.5, 1.2 Hz, 2H), 6.85 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 16.1 Hz, 1H), 6.69 (td, J = 7.7, 0.9 Hz, 1H), 6.58 (dd, J = 7.7, 1.3 Hz, 1H), 5.92 (dd, J = 9.9, 4.5 Hz, 1H), 4.58 (dd, J = 17.3, 9.9 Hz, 1H), 3.24 (dd, J = 17.3, 4.5 Hz, 1H), 2.48 (s, 3H), 2.44 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 197.0, 164.0, 154.3, 150.5, 148.0, 141.4, 138.4 136.7, 135.2, 134.1, 133.4, 131.2, 131.0, 130.5, 129.5, 128.3, 127.3, 126.9, 126.8, 126.6, 126.5, 126.2, 125.3, 122.6, 117.8, 116.0, 110.7, 51.3, 42.8, 20.0, 19.7. HRMS (ESI): Calcd for C₃₃H₂₈N₂O₂ [M+H]⁺: 485.2224; found: 485.2222.

(E)-1-((E)-3-Oxo-1,5-di-m-tolylpent-4-en-1-yl)-3-(phenylimino)indolin-2-one (3ca): Orange solid (94 mg, 65%). m.p. 80−82 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.94 (d, J = 16.0 Hz, 1H), 7.67 (dd, J = 7.1, 1.9 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.40 (dd, J = 8.4, 7.4 Hz, 2H), 7.28 (td, J = 7.5, 1.5 Hz, 2H), 7.25 (d, J = 1.4 Hz, 1H), 7.23 (d, J = 1.7 Hz, 1H), 7.22–7.19 (m, 4H), 6.96 (dd, J = 8.5, 1.2 Hz, 2H), 6.85 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 16.1 Hz, 1H), 6.69 (td, J = 7.7, 0.9 Hz, 1H), 6.58 (dd, J = 7.7, 1.3 Hz, 1H), 5.92 (dd, J = 9.9, 4.5 Hz, 1H), 4.58 (dd, J = 17.3, 9.9 Hz, 1H), 3.24 (dd, J = 17.3, 4.5 Hz, 1H), 2.48 (s, 3H), 2.44 (s, 3H).¹³C NMR (150 MHz, CDCl₃) δ 197.0, 164.0, 154.3, 150.5, 148.0, 141.4, 138.4, 136.7, 135.2, 134.1, 133.4, 131.2, 131.0, 130.5, 129.5, 128.3, 127.3, 126.9, 126.8, 126.6, 126.5, 126.2, 125.3, 122.6, 117.8, 116.0, 110.7, 51.3, 42.8, 20.0, 19.7. HRMS (ESI): Calcd for C₃₃H₂₈N₂O₂ [M+H]⁺: 485.2224; found: 485.2223.

(E)-1-((E)-3-Oxo-1,5-di-p-tolylpent-4-en-1-yl)-3-(phenylimino)indolin-2-one (3da): Orange solid (123 mg, 85%). m.p. 175 °C−176 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.62 (d, J = 16.2 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 7.39 (dd, J = 8.4, 7.4 Hz, 2H), 7.29 (td, J = 7.9, 1.3 Hz, 1H), 7.22 (dt, J = 7.5, 1.2 Hz, 1H), 7.19 (t, J = 8.2 Hz, 4H), 7.04 (d, J = 8.0 Hz, 1H), 6.95 (dd, J = 8.5, 1.1 Hz, 2H), 6.76 (d, J = 16.2 Hz, 1H), 6.69 (td, J = 7.7, 1.0 Hz, 1H), 6.57 (dd, J = 7.8, 1.2 Hz, 1H), 5.80 (dd, J = 8.9, 5.5 Hz, 1H), 4.41 (dd, J = 17.3, 8.9 Hz, 1H), 3.54 (dd, J = 17.3, 5.5 Hz, 1H), 2.37 (s, 3H), 2.33 (s, 3H).¹³C NMR (150 MHz, CDCl₃) δ 196.9, 163.6, 154.3, 150.4, 147.6, 143.9, 141.2, 137.9, 135.7, 134.0, 131.5, 129.7, 129.6, 129.3, 128.5, 127.2, 126.1, 125.1, 124.9, 122.4, 117.7, 115.9, 110.6, 53.1, 42.9, 21.5, 21.1. HRMS (ESI): Calcd for C₃₃H₂₈N₂O₂ [M+H]⁺: 485.2224; found: 485.2226.

(E)-1-((E)-1,5-Bis(4-methoxyphenyl)-3-oxopent-4-en-1-yl)-3-(phenylimino)indolin-2-one (3ea): Orange solid (108 mg, 70%). m.p. 186 °C−187 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 16.2 Hz, 1H), 7.49 (dd, J = 8.9, 7.2 Hz, 4H), 7.41–7.36 (m, 2H), 7.30 (td, J = 7.8, 1.3 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.93 (dd, J = 8.5, 1.2 Hz, 2H), 6.89 (dd, J = 8.8, 7.1 Hz, 4H), 6.72–6.63 (m, 2H), 6.55 (dd, J = 7.7, 1.3 Hz, 1H), 5.77 (dd, J = 8.7, 5.6 Hz, 1H), 4.36 (dd, J = 17.2, 8.7 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.53 (dd, J = 17.2, 5.6 Hz, 1H).¹³C NMR (100 MHz, CDCl₃) δ 196.9, 163.6, 161.9, 159.4, 154.4, 150.5, 147.7, 143.7, 134.1, 130.8, 130.3, 129.4, 128.8, 127.0, 126.2, 125.2, 123.7, 122.5, 117.7, 115.9, 114.5, 114.3, 110.6, 55.5, 55.4, 52.8, 43.0. HRMS (ESI): Calcd for C₃₃H₂₈N₂O₄ [M+H]⁺: 517.2122; found: 517.2120.

(E)-1-((E)-3-Oxo-1,5-bis(4-(trifluoromethyl)phenyl)pent-4-en-1-yl)-3-(phenylimino)indolin-2-one (3fa): Orange solid (130 mg, 73%). m.p. 98 °C−100 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.70 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 16.3 Hz, 1H), 7.64–7.62 (m, 5H), 7.59 (s, 1H), 7.40 (dd, J = 8.4, 7.4 Hz, 2H), 7.34 (td, J = 7.9, 1.3 Hz, 1H), 7.25–7.20 (m, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.97–6.94 (m, 2H), 6.86 (d, J = 16.3 Hz, 1H), 6.75 (td, J = 7.7, 0.9 Hz, 1H), 6.63 (dd, J = 7.7, 1.2 Hz, 1H), 5.83 (dd, J = 8.7, 5.5 Hz, 1H), 4.49 (dd, J = 17.7, 8.7 Hz, 1H), 3.61 (dd, J = 17.7, 5.4 Hz, 1H).¹³C NMR (150 MHz, CDCl₃) δ 196.1, 163.8, 153.9, 150.3, 147.2, 142.6, 142.2, 137.7, 134.2, 132.3 (q, J = 32.7 Hz), 130.7 (q, J = 32.6 Hz), 129.5, 128.7, 127.9, 127.7, 126.5, 126.1 (q, J = 3.6 Hz), 126.0 (q, J = 3.7 Hz), 125.5, 124.9, 124.8, 123.0, 117.7, 116.0, 110.3, 53.0, 43.3. HRMS (ESI): Calcd for C₃₃H₂₂F₆N₂O₂ [M+H]⁺: 593.1658; found: 593.1657.

(E)-1-((E)-1,5-Bis(4-chlorophenyl)-3-oxopent-4-en-1-yl)-3-(phenylimino)indolin-2-one (3ga): Orange solid (104 mg, 66%). m.p. 186 °C−187 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.58 (d, J = 16.2 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.40 (dd, J = 8.4, 7.4 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.35–7.31 (m, 3H), 7.22 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.96–6.93 (m, 2H), 6.75 (d, J = 16.2 Hz, 1H), 6.72 (dd, J = 7.6, 0.9 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 5.74 (dd, J = 8.7, 5.6 Hz, 1H), 4.40 (dd, J = 17.5, 8.7 Hz, 1H), 3.54 (dd, J = 17.5, 5.6 Hz, 1H).¹³C NMR (150 MHz, CDCl₃) δ 196.4, 163.8, 154.1, 150.4, 147.4, 142.6, 137.2, 136.9, 134.3, 134.2, 132.8, 129.7, 129.5, 129.4, 129.3, 128.9, 126.4, 126.1, 125.4, 122.9, 117.8, 116.0, 110.4, 52.8, 43.2. HRMS (ESI): Calcd for C₃₁H₂₂Cl₂N₂O₂ [M+H]⁺: 525.1131; found: 525.1131.

(E)-1-((E)-1,5-Bis(4-bromophenyl)-3-oxopent-4-en-1-yl)-3-(phenylimino)indolin-2-one (3ha): Orange solid (110 mg, 60%). m.p. 189 °C−190 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.56 (d, J = 16.2 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.42–7.37 (m, 4H), 7.32 (td, J = 7.8, 1.3 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.94 (d, J = 7.3 Hz, 2H), 6.76 (d, J = 16.2 Hz, 1H), 6.73 (t, J = 7.2 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 5.72 (dd, J = 8.6, 5.6 Hz, 1H), 4.40 (dd, J = 17.5, 8.6 Hz, 1H), 3.53 (dd, J = 17.5, 5.6 Hz, 1H).¹³C NMR (150 MHz, CDCl₃) δ 196.4, 163.8, 154.1, 150.4, 147.3, 142.7, 137.8, 134.2, 133.2, 132.4, 132.3, 129.9, 129.5, 129.2, 126.4, 126.2, 125.4, 125.3, 122.9, 122.4, 117.8, 116.0, 110.4, 52.9, 43.2. HRMS (ESI): Calcd for C₃₁H₂₂Br₂N₂O₂ [M+H]⁺: 613.0121; found: 613.0120.

(E)-1-((E)-3-Oxo-1,5-di(thiophen-2-yl)pent-4-en-1-yl)-3-(phenylimino)indolin-2-one (3ia): Orange solid (71 mg, 51%). m.p. 55 °C−57 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.76 (d, J = 15.8 Hz, 1H), 7.42 (d, J = 5.1 Hz, 1H), 7.40 (dd, J = 8.4, 7.4 Hz, 2H), 7.34 (td, J = 7.8, 1.3 Hz, 1H), 7.31 (d, J = 3.2 Hz, 1H), 7.24 (dd, J = 5.1, 1.2 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 7.22–7.18 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.07 (dd, J = 5.0, 3.6 Hz, 1H), 6.99–6.92 (m, 3H), 6.73 (td, J = 7.7, 0.9 Hz, 1H), 6.61–6.55 (m, 2H), 6.10 (dd, J = 8.6, 5.4 Hz, 1H), 4.31 (dd, J = 17.3, 8.6 Hz, 1H), 3.61 (dd, J = 17.2, 5.5 Hz, 1H).¹³C NMR (150 MHz, CDCl₃) δ 195.7, 163.2, 154.1, 150.5, 147.1, 141.1, 139.7, 136.6, 134.2, 132.4, 129.6, 129.5, 128.5, 127.1, 126.4, 126.3, 125.5, 125.3, 124.4, 122.7, 117.8, 116.1, 110.5, 48.5, 43.8. HRMS (ESI): Calcd for C₂₇H₂₀N₂O₂S₂ [M+H]⁺: 469.1039; found: 469.1037.

(E)-1-((E)-3-Oxo-1,5-diphenylpent-4-en-1-yl)-3-(o-tolylimino)indolin-2-one (3ab): Orange solid (114 mg, 81%). m.p. 69 °C−70 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.65 (d, J = 16.2 Hz, 1H), 7.61–7.52 (m, 4H), 7.42–7.36 (m, 5H), 7.34–7.29 (m, 2H), 7.27 (dd, J = 5.9, 2.2 Hz, 1H), 7.22–7.16 (m, 1H), 7.12 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.85–6.76 (m, 2H), 6.70 (t, J = 7.6 Hz, 1H), 6.47 (d, J = 7.7 Hz, 1H), 5.84 (dd, J = 8.7, 5.4 Hz, 1H), 4.44 (dd, J = 17.4, 8.7 Hz, 1H), 3.60 (dd, J = 17.4, 5.4 Hz, 1H), 2.10 (s, 3H).¹³C NMR (150 MHz, CDCl₃) δ 196.8, 163.5, 154.1, 149.2, 147.3, 143.9, 138.7, 134.3, 134.0, 130.9, 130.7, 129.0, 129.0, 128.5, 128.2, 127.3, 126.7, 126.1, 125.8, 125.1, 122.7, 116.6, 116.2, 110.5, 53.3, 43.0, 17.7. HRMS (ESI): Calcd for C₃₂H₂₆N₂O₂ [M+H]⁺: 471.2067; found: 471.2065.

(E)-1-((E)-3-Oxo-1,5-diphenylpent-4-en-1-yl)-3-(m-tolylimino)indolin-2-one (3ac): Orange solid (103 mg, 71%). m.p. 69 °C−70 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J = 16.3 Hz, 1H), 7.59–7.52 (m, 4H), 7.40–7.37 (m, 5H), 7.35 (s, 1H), 7.32 (d, J = 1.3 Hz, 1H), 7.31–7.29 (m, 1H), 7.28 (d, J = 3.1 Hz, 1H), 7.03 (dd, J = 7.8, 5.4 Hz, 2H), 6.80 (d, J = 16.3 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.72 (td, J = 7.7, 1.0 Hz, 1H), 6.61 (dd, J = 7.7, 1.3 Hz, 1H), 5.81 (dd, J = 9.0, 5.4 Hz, 1H), 4.47 (dd, J = 17.5, 9.0 Hz, 1H), 3.55 (dd, J = 17.5, 5.4 Hz, 1H), 2.35 (s, 3H).¹³C NMR (150 MHz, CDCl₃) δ 196.8, 163.6, 154.0, 150.4, 147.5, 143.8, 139.3, 138.6, 134.3, 133.9, 130.7, 129.2, 129.0, 128.9, 128.5, 128.1, 127.3, 126.2, 125.9, 125.8, 122.5, 118.1, 115.9, 114.6, 110.5, 53.3, 43.0, 21.5. HRMS (ESI): Calcd for C₃₂H₂₆N₂O₂ [M+H]⁺: 471.2067; found: 471.2066.

(E)-1-((E)-3-Oxo-1,5-diphenylpent-4-en-1-yl)-3-(p-tolylimino)indolin-2-one (3ad): Orange solid (100 mg, 69%). m.p. 70 °C−72 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.64 (d, J = 16.2 Hz, 1H), 7.57 (d, J = 7.6 Hz, 2H), 7.55–7.52 (m, 2H), 7.40–7.35 (m, 5H), 7.32–7.28 (m, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 8.3 Hz, 2H), 6.80 (d, J = 16.2 Hz, 1H), 6.75–6.72 (m, 2H), 5.82 (dd, J = 8.9, 5.4 Hz, 1H), 4.46 (dd, J = 17.4, 8.9 Hz, 1H), 3.56 (dd, J = 17.4, 5.4 Hz, 1H), 2.39 (s, 3H).¹³C NMR (150 MHz, CDCl₃) δ 196.9, 163.8, 154.0, 147.8, 147.6, 143.9, 138.8, 135.0, 134.3, 133.9, 130.8, 130.0, 129.0, 129.0, 128.5, 128.2, 127.4, 126.1, 125.9, 122.5, 118.0, 116.1, 110.5, 53.3, 43.1, 21.1. HRMS (ESI): Calcd for C₃₂H₂₆N₂O₂ [M+H]⁺: 471.2067; found: 471.2065.

(E)-3-((3-Methoxyphenyl)imino)-1-((E)-3-oxo-1,5-diphenylpent-4-en-1-yl)indolin-2-one (3ae): Orange red solid (76 mg, 52%). m.p. 54 °C−56 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.64 (d, J = 16.3 Hz, 1H), 7.56 (d, J = 7.3 Hz, 2H), 7.54 (dd, J = 6.5, 3.1 Hz, 2H), 7.40–7.36 (m, 5H), 7.32–7.27 (m, 3H), 7.06–7.03 (m, 1H), 6.80 (d, J = 16.3 Hz, 1H), 6.77–6.74 (m, 1H), 6.73 (dd, J = 7.6, 0.9 Hz, 1H), 6.67 (dd, J = 7.7, 1.3 Hz, 1H), 6.53 (dd, J = 3.7, 1.6 Hz, 2H), 5.79 (dd, J = 8.9, 5.4 Hz, 1H), 4.47 (dd, J = 17.5, 9.0 Hz, 1H), 3.78 (s, 3H), 3.55 (dd, J = 17.5, 5.3 Hz, 1H).¹³C NMR (150 MHz, CDCl₃) δ 196.9, 163.7, 160.7, 154.4, 151.8, 147.7, 144.0, 138.8, 134.4, 134.2, 130.8, 130.4, 129.1, 128.6, 128.3, 127.4, 126.5, 125.9, 122.7, 115.9, 111.3, 110.6, 109.7, 103.2, 55.5, 53.5, 43.2. HRMS (ESI): Calcd for C₃₂H₂₆N₂O₃ [M+H]⁺: 487.2016; found: 487.2014.

(E)-3-((4-Fluorophenyl)imino)-1-((E)-3-oxo-1,5-diphenylpent-4-en-1-yl)indolin-2-one (3af):

Orange solid (102 mg, 72%). m.p. 76 °C−78 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.64 (d, J = 16.2 Hz, 1H), 7.56 (d, J = 7.4 Hz, 2H), 7.53 (dd, J = 7.3, 2.3 Hz, 2H), 7.41–7.35 (m, 5H), 7.32 (d, J = 7.8 Hz, 2H), 7.10 (t, J = 8.6 Hz, 2H), 7.05 (d, J = 8.1 Hz, 1H), 6.94 (dd, J = 8.8, 4.8 Hz, 2H), 6.79 (d, J = 16.2 Hz, 1H), 6.77–6.72 (m, 1H), 6.68 (d, J = 7.7 Hz, 1H), 5.80 (dd, J = 9.1, 5.2 Hz, 1H), 4.48 (dd, J = 17.5, 9.1 Hz, 1H), 3.53 (dd, J = 17.5, 5.2 Hz, 1H). ¹³C NMR (150 MHz, CDCl₃) δ 196.8, 163.5, 160.5 (d, J = 244.4 Hz), 154.6, 147.7, 146.2 (d, J = 2.9 Hz), 143.9, 138.6, 134.2, 134.2, 130.7, 129.0, 128.9, 128.5, 128.2, 127.2, 125.8 (d, J = 25.3 Hz), 122.5, 119.5 (d, J = 8.0 Hz), 116.3, 116.2, 115.7, 110.6, 53.4, 43.0. HRMS (ESI): Calcd for C₃₁H₂₃FN₂O₂ [M+H]⁺ 475.1816, found 475.1816.

(E)-3-((4-Chlorophenyl)imino)-1-((E)-3-oxo-1,5-diphenylpent-4-en-1-yl)indolin-2-one (3ag): Orange solid (79 mg, 54%). m.p. 150 °C−151 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.64 (d, J = 16.3 Hz, 1H), 7.58–7.52 (m, 4H), 7.40−7.39 (m, 3H), 7.38−7.35 (m, 4H), 7.35–7.31 (m, 2H), 7.05 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 16.3 Hz, 1H), 6.77–6.75 (m, 1H), 6.67 (d, J = 7.7 Hz, 1H), 5.79 (dd, J = 9.1, 5.2 Hz, 1H), 4.48 (dd, J = 17.4, 9.1 Hz, 1H), 3.53 (dd, J = 17.5, 5.2 Hz, 1H).¹³C NMR (150 MHz, CDCl₃) δ 196.9, 163.5, 154.7, 148.8, 147.9, 144.0, 138.6, 134.5, 134.3, 130.9, 130.7, 129.7, 129.1, 129.1, 128.6, 128.3, 127.4, 126.2, 125.9, 122.7, 119.4, 115.8, 110.8, 53.5, 43.1. HRMS (ESI): Calcd for C₃₁H₂₃ClN₂O₂ [M+H]⁺: 491.1521; found: 491.1520.

(E)-3-((4-Chloro-2-methylphenyl)imino)-1-((E)-3-oxo-1,5-diphenylpent-4-en-1-yl)indolin-2-one (3ah): Orange solid (125 mg, 83%). m.p. 61 °C−62 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.64 (d, J = 16.2 Hz, 1H), 7.57 (d, J = 7.2 Hz, 2H), 7.53 (dd, J = 7.4, 2.3 Hz, 2H), 7.41–7.35 (m, 5H), 7.34–7.31 (m, 2H), 7.26 (d, J = 2.4 Hz, 1H), 7.16 (dd, J = 8.4, 2.3 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 16.2 Hz, 1H), 6.75 (t, J = 7.6 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.57 (dd, J = 7.7, 1.2 Hz, 1H), 5.82 (dd, J = 8.9, 5.4 Hz, 1H), 4.43 (dd, J = 17.3, 8.9 Hz, 1H), 3.56 (dd, J = 17.3, 5.4 Hz, 1H), 2.08 (s, 3H).¹³C NMR (150 MHz, CDCl₃) δ 196.8, 163.3, 154.5, 147.6, 147.5, 143.9, 138.6, 134.4, 134.3, 130.8, 130.2, 129.1, 129.0, 128.5, 128.5, 128.3, 127.3, 127.3, 126.8, 125.8, 125.7, 122.9, 118.1, 116.1, 110.7, 53.4, 43.0, 17.7. HRMS (ESI): Calcd for C₃₂H₂₅ClN₂O₂ [M+H]⁺: 505.1677; found: 505.1675.

(E)-3-((3,5-Dichlorophenyl)imino)-1-((E)-3-oxo-1,5-diphenylpent-4-en-1-yl)indolin-2-one (3ai): Orange solid (96 mg, 61%). m.p. 56 °C−57 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.63 (d, J = 16.2 Hz, 1H), 7.56–7.52 (m, 4H), 7.41–7.36 (m, 6H), 7.32 (t, J = 7.4 Hz, 1H), 7.20 (t, J = 1.9 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 1.8 Hz, 2H), 6.82–6.77 (m, 2H), 6.64 (dd, J = 7.8, 1.2 Hz, 1H), 5.78 (dd, J = 9.3, 5.1 Hz, 1H), 4.46 (dd, J = 17.4, 9.3 Hz, 1H), 3.51 (dd, J = 17.4, 5.1 Hz, 1H).¹³C NMR (150 MHz, CDCl₃) δ 196.8, 163.2, 155.4, 152.2, 148.1, 144.1, 138.4, 136.0, 135.0, 134.3, 130.9, 129.2, 129.1, 128.6, 128.4, 127.3, 126.5, 125.8, 123.0, 117.2, 116.4, 115.4, 111.0, 53.6, 43.0. HRMS (ESI): Calcd for C₃₁H₂₂Cl₂N₂O₂ [M+H]⁺: 525.1131; found: 525.1130.

(E)-5-Chloro-1-((E)-3-oxo-1,5-diphenylpent-4-en-1-yl)-3-(phenylimino)indolin-2-one (3aj): Orange solid (97 mg, 66%). m.p. 57 °C−59 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J = 16.2 Hz, 1H), 7.54 (d, J = 7.4 Hz, 4H), 7.44–7.35 (m, 8H), 7.32–7.26 (m, 2H), 7.00–6.94 (m, 3H), 6.80 (d, J = 16.1 Hz, 1H), 6.55 (d, J = 2.1 Hz, 1H), 5.76 (dd, J = 9.3, 5.0 Hz, 1H), 4.49 (dd, J = 17.6, 9.2 Hz, 1H), 3.51 (dd, J = 17.6, 5.0 Hz, 1H).¹³C NMR (150 MHz, CDCl₃) δ 196.8, 163.2, 153.1, 149.8, 146.1, 144.1, 138.3, 134.3, 133.6, 130.9, 129.6, 129.2, 129.1, 128.6, 128.4, 128.1, 127.3, 126.1, 125.8, 125.8, 117.7, 116.8, 111.8, 53.7, 43.0. HRMS (ESI): Calcd for C₃₁H₂₃ClN₂O₂ [M+H]⁺: 491.1521; found: 491.1520.

(E)-5-Methyl-1-((E)-3-oxo-1,5-diphenylpent-4-en-1-yl)-3-(phenylimino)indolin-2-one (3ak): Orange solid (107 mg, 76%). m.p. 47 °C−49 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J = 16.3 Hz, 1H), 7.58–7.51 (m, 4H), 7.40–7.34 (m, 6H), 7.33–7.27 (m, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.10 (dd, J = 8.2, 1.8 Hz, 1H), 7.00–6.90 (m, 3H), 6.80 (d, J = 16.2 Hz, 1H), 6.36 (s, 1H), 5.80 (dd, J = 8.9, 5.4 Hz, 1H), 4.44 (dd, J = 17.4, 8.9 Hz, 1H), 3.55 (dd, J = 17.4, 5.3 Hz, 1H), 2.01 (s, 3H).¹³C NMR (100 MHz, CDCl₃) δ 196.9, 163.7, 154.5, 150.5, 145.4, 143.9, 138.7, 134.5, 134.3, 132.1, 130.8, 129.4, 129.0, 128.5, 128.2, 127.3, 126.8, 125.8, 125.2, 119.0, 117.7, 115.9, 110.4, 53.2, 43.0, 20.8. HRMS (ESI): Calcd for C₃₂H₂₆N₂O₂ [M+H]⁺: 471.2067; found: 471.2065.

(E)-5-Methyl-1-((E)-3-oxo-1,5-diphenylpent-4-en-1-yl)-3-(p-tolylimino)indolin-2-one (3al): Orange solid (99 mg, 68%). m.p. 67 °C−69 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J = 16.2 Hz, 1H), 7.57–7.51 (m, 4H), 7.40–7.34 (m, 5H), 7.32–7.29 (m, 1H), 7.22–7.18 (m, 2H), 7.12–7.09 (m, 1H), 6.92–6.88 (m, 3H), 6.79 (d, J = 16.2 Hz, 1H), 6.56 (s, 1H), 5.80 (dd, J = 8.9, 5.5 Hz, 1H), 4.44 (dd, J = 17.4, 8.9 Hz, 1H), 3.55 (dd, J = 17.4, 5.5 Hz, 1H), 2.39 (s, 3H), 2.04 (s, 3H).¹³C NMR (150 MHz, CDCl₃) δ 196.9, 163.8, 154.1, 147.7, 145.4, 143.9, 138.8, 135.0, 134.4, 132.0, 130.7, 129.9, 129.2, 129.0, 128.5, 128.2, 127.3, 126.6, 126.6, 125.9, 118.1, 116.1, 110.3, 53.3, 43.1, 21.1, 20.9. HRMS (ESI): Calcd for C₃₃H₂₈N₂O₂ [M+H]⁺: 485.2224; found: 485.2223.

(E)-3-((3-Chlorophenyl)imino)-5-methyl-1-((E)-3-oxo-1,5-diphenylpent-4-en-1-yl)indolin-2-one (3am): Orange solid (129 mg, 85%). m.p. 73 °C−75 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.64 (d, J = 16.3 Hz, 1H), 7.56–7.51 (m, 4H), 7.40–7.35 (m, 6H), 7.31 (dd, J = 7.7, 3.1 Hz, 2H), 7.14 (dd, J = 8.1, 1.0 Hz, 1H), 6.98 (t, J = 2.0 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.84 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 6.79 (d, J = 16.2 Hz, 1H), 6.41 (s, 1H), 5.79 (dd, J = 9.1, 5.3 Hz, 1H), 4.43 (dd, J = 17.4, 9.1 Hz, 1H), 3.53 (dd, J = 17.4, 5.3 Hz, 1H), 2.05 (s, 3H).¹³C NMR (150 MHz, CDCl₃) δ 196.9, 163.5, 155.1, 151.6, 145.7, 143.9, 138.6, 135.1, 135.0, 134.3, 132.3, 130.8, 130.6, 129.1, 129.0, 128.5, 128.3, 127.3, 126.9, 125.9, 125.1, 118.1, 116.1, 115.7, 110.6, 53.4, 43.0, 20.9. HRMS (ESI): Calcd for C₃₂H₂₅ClN₂O₂ [M+H]⁺: 505.1677; found: 505.1676.

Supplemental Material

Supporting_information – Supplemental material for Regioselective mono-aza-Michael additions of divinyl ketones with 3-(arylimino)indolin-2-ones: Synthesis of N-enone-functionalized 3-(arylimino)indolin-2-ones

Supplemental material, Supporting_information for Regioselective mono-aza-Michael additions of divinyl ketones with 3-(arylimino)indolin-2-ones: Synthesis of N-enone-functionalized 3-(arylimino)indolin-2-ones by Xiao Chen and Zheng Li in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors thank the National Natural Science Foundation of China (21462038) for the financial support of this work.

ORCID iD

Zheng Li

Supplemental material

Supplemental material for this article is available online.

References

Kaur

Singh

Chadha

, et al. Eur J Med Chem 2016; 123: 858.

Bergman

Adv Heterocycl Chem 2015; 117: 1.

Chen

, et al. Eur J Org Chem 2012; 1318.

Yang

J Chem Res 2017; 41: 168.

Song

Chem Pap 2018; 72: 1379.

Quan

Jin

, et al. Chem Biol Drug Des 2016; 87: 342.

Imanzadeh

Soltanizadeh

Khodayari

, et al. Chin J Chem 2012; 30: 891.

Zari

Kudrjashova

Pehk

, et al. Org Lett 2014; 16: 1740.

Metsala

Zari

Kanger

Chem Cat Chem 2016; 8: 2961.

10.

Metsala

Zari

Kanger

Comput Theor Chem 2017; 1117: 30.

11.

Xing

Feng

Wang

, et al. Adv Synth Catal 2018; 360: 1704.

12.

Feng

Shi

, et al. Org Lett 2016; 18: 324.

13.

Liu

, et al. Chem Commun 2011; 47: 3992.

14.

Liu

Niu

, et al. Chin J Chem 2017; 35: 1231.

15.

Zhan

Huang

Tetrahedron 2014; 70: 176.

16.

Luo

Wang

Peng

, et al. Chin J Chem 2012; 30: 2703.

17.

, et al. J Heterocycl Chem 2017; 54: 3410.

18.

Barakat

Al-Majid

Soliman

, et al. Molecules 2015; 20: 20642.

19.

Liu

Z. J

Chem Res 2015; 39: 44.

20.

Zari

Metsala

Kudrjashova

, et al. Synthesis 2015; 47: 875.

21.

Motiur Rahman

AFM

Ali

Jahng

, et al. Molecules 2012; 17: 571.

22.

Hazarkhani

Kumar

Kondiram

KS.

Synth Commun 2010; 40: 2887.

23.

Shi

Shang

, et al. Chin J Chem 2016; 34: 901.

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