Introduction

Isatins (indoline-2,3-diones) possessing an indole motif with a ketone and a γ-lactam moiety occur in numerous natural substances . Isatins have many interesting aspects in organic reactions and potential applications. The versatile reactivity of isatins used both as an electrophiles and nucleophiles and their easy availability have made them to become valuable building blocks in organic synthesis. Nucleophilic additions or spiroannulation of the highly reactive carbonyl group at the C-3 position of isatins have various fascinating applications in organic synthesis, which allowed transformation of isatins into various biologically important 3-substituted and spirooxindole derivatives . The unique molecular architecture and remarkable pharmacological activities have made spirooxindole one of the hottest synthetic targets with fruitful chemical and steric selectivity .

In recent years, the readily available Morita–Baylis–Hillman (MBH) carbonates of isatins have been recognized as one of the most powerful synthons for the construction of various spirooxindole skeletons . MBH carbonates of isatins can be easily obtained via base-promoted MBH reactions of isatins with alkyl acrylates, acrylonitrile, and other activated alkenes . Due to the stronger electron-withdrawing effect of the oxindole motif, MBH carbonates of isatins showed higher reactivity than that of the normal MBH carbonates of normal ketones . In the presence of a Lewis base, MBH carbonates of isatins can be easily converted to activated allylic ylides, which in turn can undergo allylic substitution and annulation reactions to give diverse 3-substituted and spirooxindole derivatives . Inspired by these elegant synthetic methodologies and in continuation of our aim to develop domino reactions based on MBH carbonates of isatins for efficient construction of diverse polycyclic spiroindolinones , herein, we wish to report the nucleophilic substitution reactions of various N- and P-containing nucleophiles to MBH carbonates of isatins and convenient synthesis of diverse functionalized 3-substituted oxindole derivatives.

Results and Discussion

Initially, the reaction conditions were briefly examined by using MBH nitrile of isatin 1a and p-toluidine (2a) as model reaction. It was found that the reaction did not proceed in DMF as solvent (Table 1). When the reaction was carried out in dichloromethane, dichloroethane, acetonitrile, and toluene, the expected product 3a was produced in low yields (entries 2–5 in Table 1). The reaction in toluene at elevated temperature resulted in a slight increase of the yield (entries 6 and 7 in Table 1). In the presence of 20 mol % of DMAP, the reaction in toluene at room temperature afforded the product 3a in 72% yield. However, increasing the amount of DMAP decreased the yield (entries 8–10 in Table 1). Additionally, stronger bases such as DABCO, DBU, triethylamine, and K2CO3 also resulted in the significant reduction of the yields. Therefore, the reaction of MBH nitrile of isatins and arylamines can be simply carried out in toluene at room temperature in the presence of a catalytic amount of DMAP.

Table 1: Optimization of reaction conditions.a

Entry Base Solvent T [°C] Time [h] Yield [%]b 1 – DMF rt 4 – 2 – CH2Cl2 rt 4 12 3 – DCE rt 4 15 4 – CH3CN rt 4 18 5 – toluene rt 4 20 6 – toluene 60 4 39 7 – toluene 80 4 47 8 DMAP (0.2 equiv) toluene rt 1 72 9 DMAP (0.3 equiv) toluene rt 4 45 10 DMAP (0.5 equiv) toluene rt 1 36 11 DABCO (0.2 equiv) toluene rt 1 <10 12 DBU (0.3 equiv) toluene rt 4 15 13 Et3N (0.3 equiv) toluene rt 4 <10 14 K2CO3 (0.3 equiv) toluene rt 4 20

aReaction conditions: MBH nitrile of isatin (0.1 mmol), p-toludine (0.1 mmol), solvent (5.0 mL); bIsolated yield.

With the optimized reaction conditions in hands, the scope of the reaction was investigated by using various MBH nitriles of isatins and aromatic amines in the reaction. The results are summarized in Scheme 1. All reactions proceeded smoothly to give the expected allylic SN2-substituted products 3a–i in satisfactory yields. Aromatic amines with various substituents could be employed in the reaction to give the expected products. N-Methylaniline and n-butylamine were also successfully converted to the desired products 3h and 3i in 72% and 63% yields, respectively. The structures of compounds 3a–i were fully characterized by various spectroscopy techniques.

Scheme 1: Reaction of arylamines and MBH carbonates of isatins. Reaction conditions: MBH carbonate of isatin (0.1 mmol), aromatic amine (0.1 mmol), DMAP (0.02 mmol, 20 mol %), toluene (5.0 mL), rt, 1 h; yields refer to isolated yields.

In order to show the universality of the substitution reaction, MBH maleimides of isatins 4 were also employed in the reaction. In the absence of any base as promoter, the reaction of MBH maleimides of isatins with various aromatic amines in toluene at 65 °C gave the expected substitution products 5a–n in high yields (Scheme 2). The substituents showed a marginal effect on the yields. In addition, a secondary arylamine such N-methylaniline and aliphatic amine (n-butylamine) also gave the expected products 5m and 5n in satisfactory yields. It should be pointed out that no base promoter is needed in the reaction, which is assumed to be due to the much higher reactivity of MBH maleimides of isatins compared to the above-mentioned MBH nitriles and formats of isatins. The single crystal structures of the compounds 5a and 5j were successfully determined (Figure 1 and Figure 2). From Figure 1 and Figure 2, it can be found that the C=C bond is located in the unit of the pyrrolidine-2,5-dione, while the scaffold of indolin-2-one is connected via a C–C single bond with the unit of the pyrrolidine-2,5-dione. Therefore, an allyl rearrangement must proceed in the reaction process, which is very different to that of the above mentioned reactions of MBH nitriles and formates of isatins.

Scheme 2: Reaction of arylamines and MBH maleimides of isatins. Reaction conditions: MBH maleimide of isatin (0.1 mmol), aromatic amine (0.1 mmol), toluene (5.0 mL), 65 °C, 1 h; yields refer to isolated yields.

Figure 1: Single crystal structure of compound 5a.

Figure 2: Single crystal structure of compound 5j.

It has been reported that triphenylphosphine can catalyze the cycloaddition reaction of MBH carbonates of isatins with some activated alkenes to give diverse spirooxindoles . The reaction of triphenylphosphine with MBH nitriles of isatins in acetonitrile at room temperature quickly gave red solid products 6a–d in high yields (Scheme 3). In this reaction, triphenylphosphine acted as a nucleophile to finish an allylic SN2 reaction. The obtained triphenylphosphaneylidenes are stable, which can be isolated and were fully characterized via various spectroscopy methods. The further annulation reaction did not proceed under the reaction conditions. The similar reaction of triphenylphosphine and MBH maleimides of isatins also resulted in the corresponding triphenylphosphaneylidenes 6e and 6f in satisfactory yields. The single crystal structure of the compound 6e was determined by X-ray diffraction (Figure 3).

Scheme 3: Reactions of MBH carbonates of isatins and triphenylphosphine. Reaction conditions: MBH carbonate of isatin (0.1 mmol), triphenylphosphine (0.1 mmol), CH3CN (5.0 mL), rt, 2 h; yields refer to isolated yields.

Figure 3: Single crystal structure of compound 6e.

The similar reaction of more nucleophilic tri(tert-butyl)phosphine and MBH carbonate of isatin resulted in a mixture of products. After carefully screening the reaction conditions, we found that DABCO successfully promoted reaction of tri(tert-butyl)phosphine and MBH carbonates of isatins in toluene at 80 °C for three hours. These conditions resulted in mixtures of conjugated triene cis/trans-isomers 7a–d and 8a–d with nearly 4:1 ratios (Table 2). It should be pointed out that similar conjugated trienes have been obtained by DABCO-catalyzed dimerization of MBH carbonates of isatin in ODCB at high temperature (150 °C), which could be converted to bisspirooxindole derivatives via the isomerization of the double bond and a sequential thermal 6π-electrocyclic ring-closure process . Here, the novel triene derivatives can be prepared under relative mild reaction conditions with good steric selectivity. The single crystal structures of compounds 7a and 8a were successfully determined by X-ray diffraction method (Figure 4 and Figure 5). From the crystal structures, it can be found that the compound 7a has an E,E,E-configuration, while the compound 8a has a Z,E,E-configuration.

Table 2: Dimerization of MBH carbonates of isatins.a

Entry R1 R2 Compd Yield [%]b Compd Yield [%]b 1 H Bn 7a 63 8a 15 2 CH3 n-Bu 7b 62 8b 14 3 Cl n-Bu 7c 66 8c 12 4 F Bn 7d 65 8d 13

aReaction conditions: MBH carbonate of isatin (0.1 mmol), tri(n-butyl)phosphine (0.1 mmol), DABCO (0.04 mmol), toluene (5.0 mL), 80 °C, 2 h; bIsolated yield.

Figure 4: Single crystal structure of compound 7a.

Figure 5: Single crystal structure of compound 8a.

On the basis of the above experiments and the previously published results , a plausible reaction mechanism was proposed in Scheme 4 to explain the formation of the various oxindole derivatives. At first, a Lewis base attack at the α-position of the MBH nitrile of isatin resulted in the intermediate A with elimination of carbon dioxide and tert-butoxide ion. Secondly, the product 3 was produced by the SN2 substitution of the Lewis base by the arylamine. When MBH maleimides of isatin were used in the reaction, a direct Michael addition of the arylamine to the C=C bond of the maleimide unit and sequential elimination of carbon dioxide and tert-butoxide ion gives the intermediate B, which in turn undergoes an allylic rearrangement to afford the product 5. In this process, no extra addition of Lewis base is needed. When triphenylphosphine or tri(n-butyl)phosphine were involved in the reaction, the similar SN2’ substitution of tri(n-butyl)phosphine with the elimination of carbon dioxide and tert-butoxide anion gives the phosphonium salt C. Then, the deprotonation of phosphonium salt C by the tert-butoxide anion affords the zwitterionic intermediate D. In the case of triphenylphosphine, the similar zwitterionic intermediate D is stable and could be isolated as the product 6. In the case of tri(n-butyl)phosphine, Michael addition of the more activated zwitterionic intermediate D to MBH formate of isatin resulted in the intermediate E. Then, the elimination of carbon dioxide and tert-butoxide anion gives the intermediate F. Finally, the base-promoted elimination of tri(n-butyl)phosphine resulted in the Z/E isomers of the triene derivatives 7 or 8.

Scheme 4: Proposed reaction mechanism for the various compounds.

Conclusion

In summary, we have investigated nucleophilic substitution reactions of various N- and P-containing nucleophiles to MBH carbonates of isatins. It is interesting to find that diverse functionalized 3-substituted oxindole derivatives were successfully prepared in satisfactory yields and with high diastereoselectivity. In addition, the base-promoted dimerization of MBH carbonates of isatin afforded the ethylene-bridged bis(3-methylene)oxindole derivatives with nearly 4:1 ratios. This reaction not only clarified the essence of the substitution reaction of MBH carbonates of isatin with various N-, P-containing nucleophiles, but also led to the development of a synthetic protocol for the convenient synthesis of 30 diversely substituted oxindole derivatives.

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