Zinc-Catalyzed Enantioselective [3 + 3] Annulation for Synthesis of Chiral Spiro[indoline-3,4′-thiopyrano[2,3-b]indole] Derivatives

With a dinuclear zinc-ProPhenol complex as a catalyst, an efficient and novel [3 + 3] annulation of indoline-2-thiones and isatylidene malononitriles has been successfully developed via the Brønsted base and Lewis acid cooperative activation model. This practical methodology gives access to a broad range of chiral spiro[indoline-3,4′-thiopyrano[2,3-b]indole] derivatives in good yields with excellent levels of enantioselectivities (up to 88% yield and 99% ee).


Introduction
Sulfur-containing heterocyclic compounds are prevalent in various numerous pharmaceutically useful molecules and natural products [1][2][3]. Among these, the thiopyran fused indole skeleton is an attractive structural moiety because of its remarkable biological activities [4][5][6]. For instance, the tetrahydrothiopyrano [2,3-b]indole (THTPI) derivatives exhibit analgesic activities. On the other hand, the oxindole frameworks bearing a spirocyclic quaternary stereocenter at the C3 position [7][8][9][10][11] are very privileged heterocyclic motifs owing to their wide ranging biological significance and high versatility as important building blocks. They have attracted widespread attention from chemists for their intrinsic complexity as well as rigidity. As is expected, integrating these two bioactive moieties to generate a fascinating spirocyclic skeleton, spiro[indoline-3,4 -thiopyrano [2,3-b]indole], would be synthetically valuable and pharmaceutically desirable, and might offer a structurally diversified molecules library for drug discovery.
The Friedel-Crafts reaction [12,13] has emerged as a powerful chemical tool for the construction of new C-C bonds, and it has been widely used to realize asymmetric transformations of aromatics and heteroaromatics [14,15]. In the past few years, dinuclear metal-ProPhenol catalysts, which feature both Lewis acidic and Brønsted basic sites, have emerged as a powerful chemical tool for asymmetric transformations and attracted much attention in this field [16][17][18]. For instance, the Trost group [19] first reported the use of a dinuclear zinc complex in Friedel-Crafts alkylations of unprotected pyrroles with nitroalkenes via deprotonation of the amino group in 2008. Subsequently, the same strategy was successfully applied to the catalytic asymmetric Friedel-Crafts alkylations of unprotected pyrroles [20] and indoles [21][22][23] with various electrophiles. Recently, our group [24] uncovered an enantioselective Friedel-Crafts alkylation/cyclization with a dinuclear zinc complex through deprotonation of the phenolic hydroxyl group of 3-aminophenols. However, the catalytic generation of active carbon nucleophiles from thioamides via deprotonation of the sulfydryl group with the dinuclear zinc catalysts (Scheme 1a) is underexplored.

Optimization of Reaction Conditions
Initially, we investigated the reaction of 1-methylindoline-2-thione 1a and 2-(2-oxoindolin-3-ylidene)malononitrile 2a in the presence of 10 mol % of dinuclear zinc catalyst in situ generated from 10 mol % of ligand L1 and 20 mol % of ZnEt 2 in tetrahydrofuran (THF) at rt. Delightfully, the cascade [3 + 3] annulation process proceeded smoothly to furnish the desired spirocyclic product 3a in 57% yield and 80% enantioselectivity ( Table 1, entry 1). Encouraged by those promising results, we next examined a series of chiral ligands, including ProPhenol ligands (L2-L5) and AzePhenol ligands (L7-L9). The screening results indicated that CF 3 substituted ProPhenol ligands were better promotors compared with other substitutional groups, and L4 bearing 4-CF 3 C 6 H 4 group was proven to be the best choice for this cascade transformation, which provided the cyclization product 3a in 85% yield and 99% ee ( Table 1, entry 4). ligands, including ProPhenol ligands (L2-L5) and AzePhenol ligands (L7-L9). The screening results indicated that CF3 substituted ProPhenol ligands were better promotors compared with other substitutional groups, and L4 bearing 4-CF3C6H4 group was proven to be the best choice for this cascade transformation, which provided the cyclization product 3a in 85% yield and 99% ee ( Table 1, entry 4).

Substrate Scope
With the optimized reaction conditions in hand, we first examined the substrate scope of indoline-2-thiones 1 by reacting with 2-(2-oxoindolin-3-ylidene)malononitrile 2a, and the results are summarized in Scheme 2. Firstly, the influence of the N-protecting groups of indoline-2-thiones was investigated. Interestingly, when the N-H indoline-2thiones was tried, the corresponding product 3b was produced in 73% yield and 90% ee. As for the substrates of N-ethyl, N-benzyl, N-allyl substituted indoline-2-thiones, all the [3 + 3] annulations gave the expected products 3c-3e in 65-83% yields and 94-99% ee values, respectively. Subsequently, indoline-2-thiones 1 bearing substituents (from electron donating to electron with-drawing) at the C-5 position were well tolerated for this cyclization, which furnished the corresponding products 3f-3j in 45-63% yields with 87-99% ee values. Furthermore, substitutions at the 6-position (6-Cl and 6-Br) and 7-position (7-F and 7-Br) were also tolerated, giving the corresponding products 3k-3n in good yields with 85-99% ee values. It was worth noting that the Br substituent at the 5 or 7-position of the indoline-2-thione had a negative effect on both the yield and enantioselectivity. Gratifyingly, 5,7-diMe substituted indoline-2-thione could also be subject to this transformation, delivering the annulation product 3o in 68% yield and 99% ee.

Substrate Scope
With the optimized reaction conditions in hand, we first examined the substrate scope of indoline-2-thiones 1 by reacting with 2-(2-oxoindolin-3-ylidene)malononitrile 2a, and the results are summarized in Scheme 2. Firstly, the influence of the N-protecting groups of indoline-2-thiones was investigated. Interestingly, when the N-H indoline-2thiones was tried, the corresponding product 3b was produced in 73% yield and 90% ee. As for the substrates of N-ethyl, N-benzyl, N-allyl substituted indoline-2-thiones, all the [3 + 3] annulations gave the expected products 3c-3e in 65-83% yields and 94-99% ee values, respectively. Subsequently, indoline-2-thiones 1 bearing substituents (from electron donating to electron with-drawing) at the C-5 position were well tolerated for this cyclization, which furnished the corresponding products 3f-3j in 45-63% yields with 87-99% ee values. Furthermore, substitutions at the 6-position (6-Cl and 6-Br) and 7position (7-F and 7-Br) were also tolerated, giving the corresponding products 3k-3n in good yields with 85-99% ee values. It was worth noting that the Br substituent at the 5 or 7-position of the indoline-2-thione had a negative effect on both the yield and enantioselectivity. Gratifyingly, 5,7-diMe substituted indoline-2-thione could also be subject to this transformation, delivering the annulation product 3o in 68% yield and 99% ee.
Next, we explored the substrate generality of isatylidene malononitriles in this [3 + 3] annulation by focusing our attention on the reaction of the 1-methylindoline-2-thione 1a with various isatylidene malononitriles 2, and the results are summarized in Scheme 3. In general, all the reactions proceeded favourably to afford the desired products in good yields. It was proven that the isatylidene malononitriles bearing electron-withdrawing or -donating groups at the 5-, 6-, and 7-positions were well tolerated for this transformation, which furnished the corresponding products 3p-3x in 50-88% yields with 90-99% ee values. Next, we explored the substrate generality of isatylidene malononitriles in this [3 + 3] annulation by focusing our attention on the reaction of the 1-methylindoline-2-thione 1a with various isatylidene malononitriles 2, and the results are summarized in Scheme 3. In general, all the reactions proceeded favourably to afford the desired products in good yields. It was proven that the isatylidene malononitriles bearing electron-withdrawing or -donating groups at the 5-, 6-, and 7-positions were well tolerated for this transformation, which furnished the corresponding products 3p-3x in 50-88% yields with 90-99% ee values.
Next, we explored the substrate generality of isatylidene malononitriles in this [3 + 3] annulation by focusing our attention on the reaction of the 1-methylindoline-2-thione 1a with various isatylidene malononitriles 2, and the results are summarized in Scheme 3. In general, all the reactions proceeded favourably to afford the desired products in good yields. It was proven that the isatylidene malononitriles bearing electron-withdrawing or -donating groups at the 5-, 6-, and 7-positions were well tolerated for this transformation, which furnished the corresponding products 3p-3x in 50-88% yields with 90-99% ee values.

Plausible Mechanism
Based on the experimental results and previous literature reports [24,53], a reaction mechanism for this Friedel-Crafts alkylation/cyclization is illustrated in 5. First, the dinuclear zinc complex Zn2EtL4 was prepared in situ when ligand L4

Plausible Mechanism
Based on the experimental results and previous literature reports [24,53], a plausible reaction mechanism for this Friedel-Crafts alkylation/cyclization is illustrated in Scheme 5. First, the dinuclear zinc complex Zn 2 EtL4 was prepared in situ when ligand L4 is treated with 2 equiv of Et 2 Zn. Then, indoline-2-thione 1a was converted into its thioenolate form via the deprotonation process by the dinuclear zinc complex, along with the release of 1 equiv

Conclusions
In conclusion, we disclose a novel and efficient asymmetric tandem [3 + 3] annulation of indoline-2-thiones and isatylidene malononitriles. Using the chiral metal catalyst, a series of optically pure spiro[indoline-3,4 -thiopyrano [2,3-b]indole] derivatives were obtained with good to excellent yields and enantioselectivities under mild conditions. To demonstrate the promising applicability of the methodology, a gram-scale experiment, and the derivatization of the product were also successfully performed. A Brønsted base and Lewis acid cooperatively activate activation mode was proposed and further investigations in the polyfunctional heterocycles are ongoing in our laboratory.

General Information
All reactions were carried out under an atmosphere of argon using oven-dried glassware. Super dry solvents and metal catalysts were purchased from chemical companies and used without further treatment. Flash column chromatography was performed using silica gel (300-400 mesh). 1 H NMR, 13

Materials
Indoline-2-thiones [54] and isatylidene malononitriles [55] were synthesized according to the literature. Other reagents were obtained from commercial sources and used without further purification.

Procedure for the Asymmetric Synthesis of Compound 3
Under a nitrogen atmosphere, a solution of diethylzinc (40 µL, 1.0 M in hexane, 0.04 mmol) was added dropwise to a solution of L4 (0.02 mmol, 19.0 mg) in THF (2 mL). After the mixture was stirred for 30 min at room temperature, 1-methylindoline-2-thione 1a (0.2 mmol, 32.6 mg) and 2-(2-oxoindolin-3-ylidene) malononitrile 2a (0.2 mmol, 39.1 mg) were added. The reaction mixture was stirred for 24 h at the same temperature. The reaction was quenched with a HCl solution (1 M, 2 mL), and the organic layer was extracted with CH 2 Cl 2 (3 × 5 mL). The combined organic layer was washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure by using a rotary evaporator. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (2:1) to afford the desired product 3.