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Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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When Ethyl Isocyanoacetate Meets Isatins: A 1,3-Dipolar/Inverse 1,3Dipolar/Olefination Reaction for Access to 3‑Ylideneoxindoles Wen-Kui Yuan,† Tao Cui,† Wei Liu,‡ Li-Rong Wen,*,† and Ming Li*,† †

State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of Science & Technology, Qingdao 266042, China ‡ University and College Key Lab of Natural Product Chemistry and Application in Xinjiang, Yili Normal University, Yining 835000, China S Supporting Information *

ABSTRACT: A new CuI/1,10-phen-catalyzed reaction for the synthesis of 3-ylideneoxindoles from readily available isatins and ethyl isocyanoacetate, in which ethyl isocyanoacetate acts as a latent two-carbon donor like the Wittig reagent, is reported. A tandem procedure including 1,3-dipolar cycloaddition/inverse 1,3-dipolar ring opening/olefination allows the preparation of 3ylideneoxindoles with broad functional group tolerance.

Scheme 1. Reported Synthetic Strategies of 3Ylideneoxindoles

3-Ylideneoxindole is a prominent skeleton of pharmacological importance; it appears as the core structural motif in a variety of bioactive molecules exhibiting potent antifungal,1 antiproliferative,2 antiviral,3 and anti-inflammatory activities.4 Furthermore, 3-ylideneoxindoles as key intermediates and versatile building blocks have also been applied in the synthesis of diverse spirocyclic oxindoles.5 Thus, the development of novel efficient strategies for the assembly of 3-ylideneoxindoles is one of the most active areas in modern synthetic organic chemistry. The reported synthetic methods for 3-ylideneoxindoles can be typically classified into two classes. The first class mainly focuses on the utility of isatins as building blocks through the Wittig reaction (Scheme 1a,b).6,7 Another class involves basemediated phenoxide cyclization or palladium-catalyzed aromatic C−H functionalization (Scheme 1c,d).8,9 Although these methods are efficient, they suffer from some difficulties such as use of hazardous or toxic reagents, generating much waste and poor atom economy, or the use of expensive palladium catalysts and requirement of elaborately designed or inaccessible substrates, which limit their application. Isocyanoacetates 10 and isatins 11 are two classes of commercially available starting materials. Isocyanoacetates are a useful building block for tandem reactions due to their unusual reactivity for generating multiple bonds in a one-pot process.12 Directing this tunable reactivity with metal or nonmetal catalysts provides rapid access to a large array of complex structures ideally functionalized for medicinal applications.13 Recently, Franz and co-workers reported a regio- and stereoselective cyclization between isatins and 5-methoxyoxazoles to afford spirooxindole oxazolines at room temperature.14 In addition, Shi and co-workers developed an efficient [3 + 2] cycloaddition reaction of isocyanoacetates to isatins to © XXXX American Chemical Society

give optically active spirooxindole oxazolines at room temperature.15 A careful survey of the literature revealed that the application of the reactive spirooxindole oxazolines to form 3ylideneoxindole in organic synthesis is largely unexplored. In our study, when we conducted the reactions of ethyl isocyanoacetate with isatins by copper catalysis at a higher temperature (110 °C), an unexpected 3-ylideneoxindole compound 3 was obtained, which might be converted via inverse 1,3-dipolar process at elevated temperature from Received: January 22, 2018

A

DOI: 10.1021/acs.orglett.8b00217 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Table 1. Optimization of Reaction Conditions for 3aa

intermediate spirooxindole oxazolines 4 in situ generated through 1,3-dipolar cycloaddition (Scheme 2). This approach Scheme 2. Present Synthetic Strategy of 3-Ylideneoxindoles

entry 1 2 3

is quite simple and might open a new window for the direct conversion of isocyanoacetates with isatins into well-known 3ylideneoxindoles. In this reaction, ethyl isocyanoacetate serves as a two-carbon donor like the Wittig reagent, thereby expanding the reactive mode of isocyanoacetates. Based on our ongoing interest in isonitriles chemistry,16 herein we report a CuI/1,10-phen-catalyzed reaction for the synthesis of 3ylideneoxindoles from readily available isatins and ethyl isocyanoacetate (Scheme 2). The reaction of 1-methylisatin (1a) with ethyl isocyanoacetate (2) was used as the model reaction to optimize reaction conditions, including catalysts, ligands, bases, solvents, and temperatures (Table 1). Initially, a mixture of 1a and 2 without any additive in toluene was stirred at 110 °C for 6 h, and only 41% yield of aimed product 3a was obtained (Table 1, entry 1). Then various copper salts such as Cu(OTf)2, CuSO4·5H2O, CuI, CuCl, and CuBr were examined, and the results showed that 0.1 equiv of CuI worked more efficiently than other catalysts, giving 66% yield of 3a (entries 2−6). Next, ligands were screened. Delightfully, the addition of 1,10-phen (L1) (0.1 equiv) increased the yield of 3a to 83% (entry 7). Different ligands such as L-proline (L2) and HKA (heterocyclic ketene aminal) such as 3-(imidazolidin-2-ylidene)pentane-2,4-dione (L3)17 were examined, but they were inferior to 1,10-phen (entries 8 and 9). The addition of a base such as TEA and Cs2CO3 was adverse to the reaction (entries 10 and 11). Solvent screening with DMF, DMSO, 1,4-dioxane, and CH3CN revealed that polar solvents are also unfavorable to the reaction (entries 12−15). Changing the amount and ratio of CuI/1,10phen did not further improve the reaction yield (entries 16− 18). Finally, the reaction temperature was investigated, and the results showed raising or lowering reaction temperature were not beneficial to the reaction (entries 19 and 20). With the optimized reaction conditions in hand, we evaluated the substrate scope and generality of the reaction, and the results are summarized in Figure 1. As can be seen from Figure 1, a wide scope of isatins could be successfully utilized to afford the desired products 3, including various halogen− substituted isatins. In particular, unprotected isatins can be well tolerated (3i−u). The relative configuration of 3-ylideneoxindoles 3 was unambiguously determined by X-ray diffraction analysis of 3i (Figure S1). Delightedly, under the same conditions, acenaphthylene-1,2dione 5 could also react with ethyl isocyanoacetate (2)

cat. (equiv)

ligand (equiv)

4 5 6 7 8 9 10 11 12 13 14

Cu(OTf)2 (0.1) CuSO4·5H2O (0.1) CuI (0.1) CuCl (0.1) CuBr (0.1) CuI (0.1) CuI (0.1) CuI (0.1) CuI (0.1) CuI (0.1) CuI (0.1) CuI (0.1) CuI (0.1)

L1 L2 L3 L1 L1 L1 L1 L1

(0.1) (0.1) (0.1) (0.1) (0.1) (0.1) (0.1) (0.1)

15 16 17 18 19 20

CuI CuI CuI CuI CuI CuI

L1 L1 L1 L1 L1 L1

(0.1) (0.2) (0.05) (0.15) (0.1) (0.1)

(0.1) (0.1) (0.05) (0.15) (0.1) (0.1)

temp (°C)

yieldb (%)

toluene toluene toluene

110 110 110

41 48 51

toluene toluene toluene toluene toluene toluene toluene toluene DMF DMSO 1,4dioxane CH3CN toluene toluene toluene toluene toluene

110 110 110 110 110 110 110 110 110 110 110

66 52 55 83 44 56 tracec NPd trace trace 55

110 110 110 110 130 100

51 73 57 81 77 66

solvent

a

Reaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), solvent (2 mL) in sealed tube. bIsolated yield. cTEA (2 equiv) was added. dCs2CO3 (2 equiv) was added. L1 = 1,10-phen, L2 = L-proline, L3 = 3(imidazolidin-2-ylidene)pentane-2,4-dione.

Figure 1. Synthesis of products 3. Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), CuI (0.05 mmol), 1,10-phen (0.05 mmol), toluene (2 mL) in sealed tube, 110 °C. Isolated yield. E/Z = 5.67:1 for 3b.

smoothly to give rise to ethyl 2-(2-oxoacenaphthylen-1(2H)ylidene)acetate 6 (Scheme 3). B

DOI: 10.1021/acs.orglett.8b00217 Org. Lett. XXXX, XXX, XXX−XXX

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(7%). Next, two comparative experiments were performed with 4i as the substrate at 110 °C for 4 h to indicate the effect of copper catalyst on the reaction (Schemes 6b,c). It was found that in the absence or presence of CuI/1,10-phen intermediate 4i could convert smoothly to the desired product 3i in similar yields. These two results suggested that copper catalyst does not work for this ring-opening reaction. On the basis of the above experimental results and relevant reports,18 a plausible catalytic cycle mechanism for the formation of 3-ylideneoxindoles 3 is proposed (Scheme 7).

Scheme 3. Reaction of Acenaphthylene-1,2-dione with 2

Isocyanoacetamides 7 instead of ethyl isocyanoacetate (2) were also successfully employed to react with isatins such as 5bromo-1-methylindoline-2,3-dione 1f for the synthesis of 3ylideneoxindoles; however, the yield was only 36%, suggesting the reactivity of isocyanoacetamide is inferior to that of isocyanoacetate (Scheme 4).

Scheme 7. Possible Reaction Mechanism

Scheme 4. Reaction of Isocyanoacetamide 7 with Isatin 1f

With the aim of evaluating the practicality of this catalytic process, a gram-scale experiment was performed with 1c (1.76 g, 9.0 mmol) and 2 (1.22 g 10.8 mmol), yielding the corresponding product 3c in 60% (1.43 g) (Scheme 5).

First, the reaction of ethyl isocyanoacetate 2 with CuI in the presence of a ligand forms the intermediate [I]. Intermediate [I] takes place a formal [3 + 2] cycloaddition into isatins 1 to generate the cyclic organocopper intermediate of spirooxindole oxazolines [II], which is then transformed to spirooxindole oxazoline intermediate 4 as well as the intermediate [I] for a new cycle. Finally, 4 undergoes an inverse 1,3-dipolar ringopening/olefination reaction to form product 3 at 110 °C with an elimination of isocyanic acid that can form in situ cyanuric acid (as confirmed by 1H NMR analysis, see the SI). In summary, a versatile strategy has been devopled for the straightforward synthesis of 3-ylideneoxindoles through a copper(I)-catalyzed [3 + 2] cycloaddition of isocyanoacetates to isatins and inverse 1,3-dipolar ring-opening/olefination tandem reaction, in which isocyanoacetates act as a latent two-carbon donor like the Wittig reagent. This novel method is complementary to the classical Wittig reaction in that it is wellsuited to the convenient preparation of 3-ylideneoxindoles, which are widespread in pharmaceutically relevant compounds. The applications of this reaction in organic synthesis are currently in progress.

Scheme 5. Gram-Scale Synthesis of 3c

Next, our attention was shifted to elucidate a reasonable mechanism of this transformation. Notably, during the investigation of this interesting transformation reaction under the standard conditions, we noticed a trace intermediate by TLC, which disappeared gradually with time expanding. In order to obtain the intermediate, the reaction of isatin (1i) with 2 was conducted at relatively low 80 °C for 1 h (Scheme 6a). To our delight, a spirooxindole oxazoline intermediate 4i was obtained in 43% yield along with 3-ylidene oxindole 3i

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Scheme 6. Control Experiments

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00217. Experimental procedures, characterization, and spectral data (PDF) Accession Codes

CCDC 990185 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge C

DOI: 10.1021/acs.orglett.8b00217 Org. Lett. XXXX, XXX, XXX−XXX

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Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

* E-mail: [email protected]. * E-mail: [email protected]. ORCID

Li-Rong Wen: 0000-0001-7976-0878 Ming Li: 0000-0003-4906-936X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (21572110 and 21372137) and the Natural Science Foundation of Shandong Province (ZR2014BM006).

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DOI: 10.1021/acs.orglett.8b00217 Org. Lett. XXXX, XXX, XXX−XXX