Highly Efficient Tetranuclear Zn II 2 Ln III 2 Catalysts for the Friedel – Crafts Alkylation of Indoles and Nitrostyrenes

We demonstrate for the first time the high efficacy of tetranuclear Zn2Ln2 coordination clusters (CCs) as catalysts for the Friedel–Crafts (FC) alkylation of indoles with a range of trans-β-nitrostyrenes. The reaction proceeds in good to excellent yields (76%–99%) at room temperature with catalyst loadings as low as 1.0 mol %.

Scheme 1. Versatile intermediates in organic synthesis derived from Indolylnitroalkanes.
In 3d/4f chemistry, only a few polynuclear CCs have been successfully used as homogenous catalysts [54][55][56].We recently initiated a project on the synthesis of 3d/4f CCs stabilized by the Schiff base organic ligand H2L [(E)-(2-hydroxy-3-methoxybenzylidene-amino)phenol], that would display catalytic properties [57][58][59].We also reported the synthesis and characterisation of a series of isoskeletal [60] tetranuclear Zn II  2 Ln III 2 CCs formulated as [Zn II 2 Ln III 2 L 4 (NO 3 ) 2 (DMF) 2 ] (1Ln) where Ln is Y (1Y), Sm (1Sm), Eu (1Eu) Gd (1Gd), Dy (1Dy), Tb (1Tb) and Yb (1Yb) possessing a defect dicubane topology (Figure 1).These compounds can be synthesized quantitatively in two steps, up to multigram scale and are air stable for a few months.We showed that these bimetallic species remain intact in organic and aqueous solutions, by ESI-MS studies, EPR studies for 1Gd and NMR studies for 1Y analogues.This precise topology shows that the Zn and the Ln centres are very close (approximately 3.3 Å), permitting both metals to coordinate to the substrates and promote the coupling reaction.Compounds 1Y and 1Dy showed high efficiency as catalysts, at room temperature, with low catalytic loadings in FC alkylation of indole with aldehydes leading to bis-indolylmethane derivatives [59].A study of the suitability of 1Ln as catalysts in FC alkylation of indole with nitrostyrene is presented herein.
nitroalkenes and ortho-substituted indoles [41].However, some of the reported protocols have drawbacks such as high catalyst loading, long reaction time, the need for additives, low temperature (0 to −20 °C) and multi-step designed ligands, thus limiting their practical applications.
In 3d/4f chemistry, only a few polynuclear CCs have been successfully used as homogenous catalysts [54][55][56].We recently initiated a project on the synthesis of 3d/4f CCs stabilized by the Schiff base organic ligand H2L [(E)-(2-hydroxy-3-methoxybenzylidene-amino)phenol], that would display catalytic properties [57][58][59].We also reported the synthesis and characterisation of a series of isoskeletal [60] tetranuclear Zn II 2Ln III 2 CCs formulated as [Zn II 2Ln III 2L4(NO3)2(DMF)2] (1Ln) where Ln is Y (1Y), Sm (1Sm), Eu (1Eu) Gd (1Gd), Dy (1Dy), Tb (1Tb) and Yb (1Yb) possessing a defect dicubane topology (Figure 1).These compounds can be synthesized quantitatively in two steps, up to multigram scale and are air stable for a few months.We showed that these bimetallic species remain intact in organic and aqueous solutions, by ESI-MS studies, EPR studies for 1Gd and NMR studies for 1Y analogues.This precise topology shows that the Zn and the Ln centres are very close (approximately 3.3 Å), permitting both metals to coordinate to the substrates and promote the coupling reaction.Compounds 1Y and 1Dy showed high efficiency as catalysts, at room temperature, with low catalytic loadings in FC alkylation of indole with aldehydes leading to bis-indolylmethane derivatives [59].A study of the suitability of 1Ln as catalysts in FC alkylation of indole with nitrostyrene is presented herein.

Results
The first step was to optimize the reaction conditions for the alkylation of indole.We screened several reaction parameters, such as the use of different catalysts (Table 1, entries 1-9), solvents (Table 1, entries 10-14), temperature (Table 1, entries 15-17) and catalyst loading (Table 1, entries 18-20).We studied the reaction between indole (0.50 mmol) 2 and nitroalkene (0.50 mmol) 3 in EtOH at room temperature and a catalyst loading of 1.0 mol % (Table 1 entries 1-9).A blank experiment in the absence of the 3d/4f CCs catalyst showed no conversion (Table 1, entry 1) and very low conversions were obtained in the presence of Dy or Zn salts (Table 1, entries 2-3).The reactions with 1Dy and 1Y after 24 h show very high yields, 99% and 94%, respectively.(Table 1, entries 4-5).Other catalysts such as 1Eu, 1Gd, 1Nd and 1Tb showed lower yields (Table 1, entries 1-6).Therefore, 1Dy was the best choice for this FC reaction.We then decided to identify the influence of the solvent on the catalytic performance.Our catalyst showed high activity in ethanol with 99% yield of the desired product 4a (Table 1, entry 4).Solvents such as THF, water, acetonitrile and N,N'-dimethylformamide

Results
The first step was to optimize the reaction conditions for the alkylation of indole.We screened several reaction parameters, such as the use of different catalysts (Table 1, entries 1-9), solvents (Table 1, entries 10-14), temperature (Table 1, entries 15-17) and catalyst loading (Table 1, entries 18-20).We studied the reaction between indole (0.50 mmol) 2 and nitroalkene (0.50 mmol) 3 in EtOH at room temperature and a catalyst loading of 1.0 mol % (Table 1 entries 1-9).A blank experiment in the absence of the 3d/4f CCs catalyst showed no conversion (Table 1, entry 1) and very low conversions were obtained in the presence of Dy or Zn salts (Table 1, entries 2-3).The reactions with 1Dy and 1Y after 24 h show very high yields, 99% and 94%, respectively.(Table 1, entries 4-5).Other catalysts such as 1Eu, 1Gd, 1Nd and 1Tb showed lower yields (Table 1, entries 1-6).Therefore, 1Dy was the best choice for this FC reaction.We then decided to identify the influence of the solvent on the catalytic performance.Our catalyst showed high activity in ethanol with 99% yield of the desired product 4a (Table 1, entry 4).Solvents such as THF, water, acetonitrile and N,N'-dimethylformamide (DMF) had a negative influence on the catalytic activity; therefore, ethanol was the best choice for further studies.At room temperature, the yield of 4a was 99%, but only 5% at 0 • C. Lower yields were obtained at 60 • C (Table 1, entry 18), so the following reactions were made at this temperature.As shown in Table 1, it was sufficient to use a catalyst loading of 1.0 mol % to obtain a yield up to 99% (Table 1,  entry 4).An increase of the catalyst loading from 1.0 mol % to 5 mol % led to a remarkable decrease in the yield of the desired product 4a (Table 1, entries [19][20].This finding can be explained due to the low solubility of the catalyst.Further, a decrease in the catalyst loading to 0.5 mol % also showed lower yield of the desired product 4a (Table 1, entry 18).Therefore, we used 1.0 mol % 1Dy in ethanol at room temperature for further experiments.(DMF) had a negative influence on the catalytic activity; therefore, ethanol was the best choice for further studies.At room temperature, the yield of 4a was 99%, but only 5% at 0 °C.Lower yields were obtained at 60 °C (Table 1, entry 18), so the following reactions were made at this temperature.As shown in Table 1, it was sufficient to use a catalyst loading of 1.0 mol % to obtain a yield up to 99% (Table 1, entry 4).An increase of the catalyst loading from 1.0 mol % to 5 mol % led to a remarkable decrease in the yield of the desired product 4a (Table 1, entries [19][20].This finding can be explained due to the low solubility of the catalyst.Further, a decrease in the catalyst loading to 0.5 mol % also showed lower yield of the desired product 4a (Table 1, entry 18).Therefore, we used 1.0 mol % 1Dy in ethanol at room temperature for further experiments.To explore the scope of the reaction, various nitroalkenes were treated with indole (Table 2).In the first experiments R' was aromatic (Table 2, entries 1-8).Several catalytic systems gave slightly lower yields due to the electronic effect of para substitution of the phenyl group of aromatic nitroalkenes.In all these cases, very good yields were obtained, ranging from 92% for the 4-fluoro substrate 4d to 98% for the tolyl substituted compound 4b.A slight improvement of the yield up to 99% was observed by use of a heteroaromatic nitroalkene bearing a furan substituent (entry 8).The effect of substitution of the indole is also shown in Table 2 (entries 9-15).The substituent at position 5 of the indole had little effect on yield except for the electron-drawing group (-NO2) (Table 2 To explore the scope of the reaction, various nitroalkenes were treated with indole (Table 2).In the first experiments R' was aromatic (Table 2, entries 1-8).Several catalytic systems gave slightly lower yields due to the electronic effect of para substitution of the phenyl group of aromatic nitroalkenes.In all these cases, very good yields were obtained, ranging from 92% for the 4-fluoro substrate 4d to 98% for the tolyl substituted compound 4b.A slight improvement of the yield up to 99% was observed by use of a heteroaromatic nitroalkene bearing a furan substituent (entry 8).The effect of substitution of the indole is also shown in Table 2 (entries 9-15).The substituent at position 5 of the indole had little effect on yield except for the electron-drawing group (-NO 2 ) (Table 2, entry 12).Further, we investigated the reaction of N-alkylated and 2-methyl indole with various nitrostyrenes.The results are summarized in Table 3.The products were isolated in good to excellent yields (Table 3, entries 1-10).A change of the substituent at the nitrogen atom in 5, and at position 2 of the indole did not show any profound effect on the yield of the desired product (99%, Table 3, entries 1 and 6).Compound 6h was characterized via single crystal X-ray crystallography (see Figure S1).
Further, we investigated the reaction of N-alkylated and 2-methyl indole with various nitrostyrenes.The results are summarized in Table 3.The products were isolated in good to excellent yields (Table 3, entries 1-10).A change of the substituent at the nitrogen atom in 5, and at position 2 of the indole did not show any profound effect on the yield of the desired product (99%, Table 3, entries 1 and 6).Compound 6h was characterized via single crystal X-ray crystallography (see Figure S1).
Further, we investigated the reaction of N-alkylated and 2-methyl indole with various nitrostyrenes.The results are summarized in Table 3.The products were isolated in good to excellent yields (Table 3, entries 1-10).A change of the substituent at the nitrogen atom in 5, and at position 2 of the indole did not show any profound effect on the yield of the desired product (99%, Table 3, entries 1 and 6).Compound 6h was characterized via single crystal X-ray crystallography (see Figure S1).The substrate binding of trans-β-nitrostyrene 3a by 1Dy was investigated by UV-Vis spectroscopy in a water/ethanol solution.A 0.1 mM solution trans-β-nitrostyrene 3a exhibited a strong absorption at 320 nm.The 1Dy was added to the solution and absorption was recorded over 3 h with 5 min intervals between measurements.It was observed (Figure S2) that the intensities of the peak at 320 nm gradually decreased.The quenching of band may be attributed to the bonding of nitrostyrene with 1Dy through weak Van der Waals interactions.Similar quenching was observed with the indole substrate (Figure S3), indicating the binding behaviour of both substrates to 1Dy.Thus both substrates can be activated after coordination with the two metal centres in 1Dy which favours the conjugate addition of the nucleophiles.Similar studies were conducted with Zn(OTf) 2 and Dy(OTf) 3 to determine the preference of each substrate for the Ln III or Zn II metal centres.In 3a a greater rate of quenching with Dy(OTf) 3 than Zn(OTf) 2 is shown, whereas with 2a the rates are similar.This may suggest that 3a preferentially binds to the Dy III centre.The 1Dy catalyst for both substrates demonstrates a greater rate of quenching than either Zn(OTf) 2 or Dy(OTf) 2 , perhaps indicating a stronger interaction with the metal centres in tandem.Based on the above results and the crystal structure of 1Dy [59] in which a nitrate group chelates to Dy (trans-β-nitrostyrene can be considered as an alternative to nitrate), a plausible mechanism and transition state can be proposed shown in Scheme 2. We envision that the nitroalkenes are activated by chelation to Dy III [44] and π-π stacking between the phenyl group of the coordinating ligand L and the phenyl group of nitroalkenes.In addition, the indole substrate will bond to the Zn II through the nitrogen atom and bring the two organic moieties efficiently close to favour the formation of the alkylated product.The substrate binding of trans-β-nitrostyrene 3a by 1Dy was investigated by UV-Vis spectroscopy in a water/ethanol solution.A 0.1 mM solution trans-β-nitrostyrene 3a exhibited a strong absorption at 320 nm.The 1Dy was added to the solution and absorption was recorded over 3 h with 5 min intervals between measurements.It was observed (Figure S2) that the intensities of the peak at 320 nm gradually decreased.The quenching of band may be attributed to the bonding of nitrostyrene with 1Dy through weak Van der Waals interactions.Similar quenching was observed with the indole substrate (Figure S3), indicating the binding behaviour of both substrates to 1Dy.Thus both substrates can be activated after coordination with the two metal centres in 1Dy which favours the conjugate addition of the nucleophiles.Similar studies were conducted with Zn(OTf)2 and Dy(OTf)3 to determine the preference of each substrate for the Ln III or Zn II metal centres.In 3a a greater rate of quenching with Dy(OTf)3 than Zn(OTf)2 is shown, whereas with 2a the rates are similar.This may suggest that 3a preferentially binds to the Dy III centre.The 1Dy catalyst for both substrates demonstrates a greater rate of quenching than either Zn(OTf)2 or Dy(OTf)2, perhaps indicating a stronger interaction with the metal centres in tandem.Based on the above results and the crystal structure of 1Dy [59] in which a nitrate group chelates to Dy (trans-β-nitrostyrene can be considered as an alternative to nitrate), a plausible mechanism and transition state can be proposed shown in Scheme 2. We envision that the nitroalkenes are activated by chelation to Dy III [44] and π-π stacking between the phenyl group of the coordinating ligand L and the phenyl group of nitroalkenes.In addition, the indole substrate will bond to the Zn II through the nitrogen atom and bring the two organic moieties efficiently close to favour the formation of the alkylated product.

Figure 1 .
Figure 1.Molecular structure of 1Ln.Colour code: Zn II : grey; Ln III : light blue; O: red; N: blue.C and H atoms are omitted for clarity.

Figure 1 .
Figure 1.Molecular structure of 1Ln.Colour code: Zn II : grey; Ln III : light blue; O: red; N: blue.C and H atoms are omitted for clarity.

Scheme 2 .
Scheme 2. (a) A plausible mechanism for the FC alkylation; (b) Proposed transition state model of catalyst.Scheme 2. (a) A plausible mechanism for the FC alkylation; (b) Proposed transition state model of catalyst.

Table 2 .
Scope of the Friedel-Crafts (FC) alkylation of Indoles with various nitro-styrenes catalysed by 1Dy a .

Table 2 .
Scope of the Friedel-Crafts (FC) alkylation of Indoles with various nitro-styrenes catalysed by 1Dy a .

Table 2 .
Scope of the Friedel-Crafts (FC) alkylation of Indoles with various nitro-styrenes catalysed by 1Dy a .