Qiaomei Jin‡
*ab,
Dongjian Zhang‡ab and
Jian Zhang
*ab
aAffiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu, China. E-mail: jqmxy@163.com; zjwonderful@hotmail.com
bLaboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China
First published on 19th August 2020
A [3 + 2] annulation/C-arylation of isatin N,N′-cyclic azomethine imine 1,3-dipole 1 with in situ generated arynes has been established for the synthesis of 3,3-disubstituted oxindole scaffolds. These highly functionalized scaffolds were assembled in moderate yields (up to 85% yield). The novel spirooxindole scaffolds displayed moderate antitumor activities, which represented promising lead compounds for antitumor drug discovery.
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Fig. 1 Representative biologically active compounds containing the 3,3-disubstituted oxindole skeleton. |
Recently, 1,3-dipolar cycloadditions (1,3-DCs) are among the most powerful approaches for the construction of carbon–carbon bonds and heterocycles.7 And the Wang's group reported an abnormal [3 + 2] cycloaddition of a new isatin N,N′-cyclic azomethine imine 1,3-dipoles with maleimides, an unusual Michael reaction between these 1,3-dipoles with β-nitrostyrenes and an abnormal [3 + 2] cycloaddition between these 1,3-dipoles and 3-methyleneoxindole, which are very scarce examples of 1,3-dipolar cycloaddition reaction (Scheme 1a).8 After that, we disclosed an DMAP-catalyzed direct alkylation at the a-position of the cyclic amine of these isatin N,N′-cyclic azomethine imine 1,3-dipoles with Morita–Baylis–Hillman carbonates and developed an efficient way to synthesize seven-membered heterocyclic spirooxindoles via a [3 + 4] cycloaddition reaction of these 1,3-dipoles with N-(ortho-chloromethyl)aryl amides (Scheme 1a).9 Furthermore, the Moghaddam's group reported an unexpected abnormal [3 + 3] tandem Michael addition/N-cyclization of these 1,3-dipoles and 2-arylidenemalononitrile under DABCO catalysis (Scheme 1a).10 During the course of the studies on these isatin N,N′-cyclic azomethine imine 1,3-dipoles, the related studies envisioned that these 1,3–dipoles have been utilized as valuable building blocks in cycloaddition reactions with alkenes. Given our ongoing interest in 1,3-dipolar cycloaddition and spirooxindole alkaloids, we envisioned the reaction of the isatin N,N′-cyclic azomethine imine 1,3-dipoles and arynes would be one approach to obtaining new pyrazole-spirooxindole derivatives via [3 + 2] cycloadditions (Scheme 1b).
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Scheme 1 (a) Previous reports of isatin N,N′-cyclic azomethine imine 1,3-dipoles. (b) Design of the new [3 + 2] cycloaddition. |
Our investigations started with the screening of the reaction between the isatin N,N′-cyclic azomethine imine 1,3-dipole 1a and the unsubstituted aryne precursor 2a in the presence of CsF in CH3CN at room temperature for 2 h. To our delight, the desired product 3a was obtained in 20% yield (entry 1, Table 1). In order to improve the yield of the reaction product we used TBAF and KF instead of CsF as the fluoride source. Unfortunately, these two fluoride sources did not perform well (entries 2 and 3, Table 1). Performing the reaction in the presence of 18-crown-6 and CsF increased the yield to 55% (entry 4, Table 1). This result indicates that the 18-crown-6 has a remarkable influence on the yield. When the reaction was carried out at 50 °C, the reaction yields were not improved (entry 5, Table 1). Subsequently, a few more experiments were performed by changing the amount of CsF and 18-crown-6 (entries 6–9, Table 1). Interestingly, an improved yield of 67% was observed when the reaction was performed using 2.5 equiv. of CsF as a fluoride source and 3.0 equiv. of 18-crown-6 as an additive (entry 9, Table 1). And no improvements were observed with increasing the loadings of CsF (entries 7 and 8, Table 1). Finally, we investigated the reaction media by screening some common solvents, such as DMF, CH2Cl2, THF, 1,4-dioxane, EA, DCE and MeOH (entries 10–17, Table 1). The brief screening of the reaction solvent proved that THF was the best choice with respect to yields (entry 12, Table 1). Thus, the best reaction conditions utilized the isatin N,N′-cyclic azomethine imine 1,3-dipole 1a (1.0 equiv.), aryne precursor 2a (1.25 equiv.), CsF (2.5 equiv.) as the fluoride source and 18-crown-6 (3.0 equiv.) as the additive at room temperature.
Entry | F-source (equiv.) | Additive (equiv.) | Solvent | Temp (°C) | Time (h) | Yield of 3ab (%) |
---|---|---|---|---|---|---|
a Unless noted otherwise, reaction of 1a (0.2 mmol), 2a (0.25 mmol), fluoride source (0.5 mmol) and 18-C-6 (0.6 mmol) was performed in 3.0 mL of solvent under Ar.b Isolated yield based on 1a. | ||||||
1 | CsF (2.0) | — | MeCN | rt | 2 | 20 |
2 | TBAF (2.0) | — | MeCN | rt | 2 | Trace |
3 | KF (2.0) | — | MeCN | rt | 2 | 15 |
4 | CsF (2.0) | 18-C-6 (2.0) | MeCN | rt | 2 | 55 |
5 | CsF (2.0) | 18-C-6 (2.0) | MeCN | 50 | 1 | 53 |
6 | CsF (2.5) | 18-C-6 (2.0) | MeCN | rt | 2 | 64 |
7 | CsF (3.0) | 18-C-6 (2.0) | MeCN | rt | 2 | 51 |
8 | CsF (4.0) | 18-C-6 (2.5) | MeCN | rt | 2 | 53 |
9 | CsF (2.5) | 18-C-6 (3.0) | MeCN | rt | 2 | 67 |
10 | CsF (2.5) | 18-C-6 (3.0) | DMF | rt | 2 | 45 |
11 | CsF (2.5) | 18-C-6 (3.0) | CH2Cl2 | rt | 2 | 33 |
12 | CsF (2.5) | 18-C-6 (3.0) | THF | rt | 2 | 72 |
13 | CsF (2.5) | 18-C-6 (3.5) | THF | rt | 2 | 69 |
14 | CsF (2.5) | 18-C-6 (3.0) | 1,4-Dioxane | rt | 2 | Trace |
15 | CsF (2.5) | 18-C-6 (3.0) | EA | rt | 4 | 55 |
16 | CsF (2.5) | 18-C-6 (3.0) | DCE | rt | 4 | 27 |
17 | CsF (2.5) | 18-C-6 (3.0) | MeOH | rt | 4 | 0 |
With the favorable reaction conditions established, the substrate scope and limitations of this catalyst-free self [3 + 2] cycloaddition of isatin N,N′-cyclic azomethine imine 1,3-dipole 1 with aryne precursors 2 were explored (Scheme 2). To our delight, most isatin N,N′-cyclic azomethine imines 1 and aryne precursors 2 were well tolerated. First, we evaluated the different 1,3-dipoles 1 with diverse substituents. It seems that the electronic nature of the substituents had intriguingly impact on the reaction. In general, substrates with electron-donating groups at the 5-position of 1 resulting in the formation of the cycloaddition products in good yields (3f: 78%; 3g: 85%). In addition, a few 1,3-dipoles 1 with diverse N-substituted groups, including that with a free NH group, showed inert reactivity and failed to deliver the expected product. Only N-methyl could smoothly afford the desired products with good results (3b: 57%). Interestingly, reactions carried out using the 1,3-dipoles 1 with electron-withdrawing groups resulted in the formation of the 3,3-disubstituted oxindole products in moderate yields (products 3h–3k), probably because the latter substituent would lower the nucleophilicity of the 1,3-dipoles 1. Next, the tolerance of substituents on the aryne moiety was also studied.
The cycloaddition products 3l–3o are formed in moderate to good yields when this reaction was performed using unsymmetrical 3-substituted or 4-substituted arynes generated from the precursors. The unsymmetrical 4-methyl aryne afforded an inseparable mixture of regioisomers 3m and 3m′ in 59% yield and a 1.47:
1 regioisomer ratio. Similarly, inseparable regioisomeric products were formed when the reaction was carried out using unsymmetrical 4-methoxy, 3-methyl and 3-methoxy arynes. Moreover, the unsymmetrical naphthalyne was well tolerated to furnish the separable regioisomeric products 3p and 3p′ in 78%.
In order to address the viability and potential synthetic application of this reaction, a gram-scale scale-up and several applications were carried out (Scheme 3). Under identified conditions, product 3a was obtained without a significant loss of efficiency (69%) with a 4 mmol scale (Scheme 3a). To further illustrate synthetic applications of this method, we conducted a Suzuki coupling of product 3j with N-Boc-1,2,5,6- tetrahydropyridine-4-boronic acid pinacol ester, and then deprotection of the Boc group, which afforded product 4 in 52% yield (Scheme 3b).
On the basis of our results and the previous studies,7d,8–10 two plausible mechanisms was proposed as illustrated in Scheme 4. One approach, the in situ generated aryne (formed by the fluoride induced 1,2-elimination from 2) reacts with the isatin N,N′-cyclic azomethine imines 1 to generate the final product 3 through a thermal [3 + 2] annulation. The other, the more stable intermediate I was formed by the tautomerism of 1 in the presence of a base. Then intermediate I underwent C-arylation reaction with the in situ generated aryne with a double bond shift to generate the final product 3h, 3i and 3j (Scheme 4).
Drawing inspiration from these 3,3-disubstituted oxindoles, a number of new drugs and lead compounds have been developed, especially in the field of anti-tumor.11 Therefore, the target compounds were assayed for in vitro antitumor activity against hepatocellular carcinoma (Hep3B) using the standard MTT method (Table 2). Unfortunately, most compounds showed little bioactivity against Hep3B cells. Among all the compounds, only 3j (4986.0 nM) and 4 (601.7 nM) showed good antitumor activities against Hep3B cells. And the results maybe suggest that these new 3,3-disubstituted oxindoles framework could be a new template for the design of novel anticancer molecules.
In summary, we have established an efficient method for the [3 + 2] annulation/C-arylation of isatin N,N′-cyclic azomethine imine 1,3-dipole 1 with in situ generated arynes, which constructed biologically important 3,3-disubstituted oxindoles in average good yields (up to 85% yield). The present methodology is both concise and mild, practical and one-pot method. The in vitro antitumor activity assay indicated that these scaffolds displayed moderate antitumor activities. Further chemical modification and biological exploration of these compounds are underway in our laboratory.
Footnotes |
† Electronic supplementary information (ESI) available: Experimental procedures and spectroscopic data. See DOI: 10.1039/d0ra06404a |
‡ These authors contributed equally to this work. |
This journal is © The Royal Society of Chemistry 2020 |