Friedel–Crafts Reaction of Acylsilanes: Highly Chemoselective Synthesis of 1-Hydroxy-bis(indolyl)methanes and 1-Silyl-bis(indolyl)methanes Derivatives

A novel double Friedel–Crafts reaction of acylsilanes in water is described. This strategy enables synthesis of bis(indolyl)methane derivatives with 1-hydroxy or 1-silyl substituents in moderate to high yield. Compared to the 1-silyl-bis(indolyl)methane derivatives from indole substrate, 1-hydroxy-bis(indolyl)methane derivatives were synthesized from the 5-hydroxyindole, and the hydrogen bonds in the 5-hydroxyindole play a crucial role in regulating the reaction selectivity.


Results
Using water as a reaction medium has been attracting considerable attention, as water is a non-toxic, green and readily available solvent [30][31][32][33][34][35]. Compared to an organic solvent, significant reaction acceleration was often observed when using water as the solvent [36][37][38][39]. Moreover, a reaction does not occur unless the solvent is water in some cases. Considering the unique ability, the Friedel-Crafts reaction of oxindole 1a and acylsilane 2a was firstly investigated in water (Table 1). Gratifyingly, with p-toluenesulfonic acid (PTSA) as the catalyst, a double Friedel-Crafts reaction occurred, yielding the desired product (3a) in a 43% yield. Encouraged by these results, a variety of other Brønsted acids were examined to improve the yield (Table 1, entries 2-7). A high yield of 72% for 3a was achieved when the reaction was carried out using camphorsulfonic acid (CSA) as the catalyst (Table 1, entry 2). Compared to the strong acidic catalyst, a suitable acidic CSA is beneficial to the products. Subsequently, a series of polar or nonpolar solvents, including CH 2 Cl 2 , toluene, DMF, THF and EtOH, were investigated and inferior yields were observed (Table 1, entries [8][9][10][11][12]. Solvent screening showed that the reaction was accelerated dramatically in water. Reducing the amount of catalyst leads to a decrease in the yield of the reaction, and even if the reaction time is extended, the yield does not increase (Table 1, entries 13-14).  With the optimized conditions in hand, we explored the scope of various silyl glyoxylates under standard reaction conditions, and various silicon-containing BIMs compounds were successfully obtained (Scheme 2). Generally, the double Friedel-Crafts reaction between indole and silyl glyoxylate containing different ester groups worked well (3a-3o). For example, a substrate with 1-naphthalenyl ester group was applicable, generating the desired product 3e in 75% yield. However, a lower yield of 22% (3d) was observed when the substrate with tert-butyl ester product was employed. We speculate that the steric hindrance effect of the bulk of tert-butyl affects the reaction yield. Next, indoles bearing the alkyl and halogen substituents, such as Me, tert-butyl, F and Cl, were competent in this reaction, generating the corresponding products in moderate yield (3f-3h). Both electron-withdrawing (NO2) and electron-donating (MeO) groups attached to the indole could afford the desired products (3l-3n) in high yields. Interestingly, a new product of bis(indolyl)methanes with 1-hydroxy substituent (3o') was formed when 5-hydroxyindole was employed as the substrate. To our delight, the hydrogen bonds from 5-hydroxyindole have a regulating effect on the generation of two products of 3o and 3o'. It should be noted that the desilication product of bis(indolyl)methanes with 1-hydroxy substituent products (3o') was not easy to obtain by a common strategy. Moreover, no reaction was observed when 2-methylindole and 1-methylindole were used as the substrate (3p and 3q) ( With the optimized conditions in hand, we explored the scope of various silyl glyoxylates under standard reaction conditions, and various silicon-containing BIMs compounds were successfully obtained (Scheme 2). Generally, the double Friedel-Crafts reaction between indole and silyl glyoxylate containing different ester groups worked well (3a-3o). For example, a substrate with 1-naphthalenyl ester group was applicable, generating the desired product 3e in 75% yield. However, a lower yield of 22% (3d) was observed when the substrate with tert-butyl ester product was employed. We speculate that the steric hindrance effect of the bulk of tert-butyl affects the reaction yield. Next, indoles bearing the alkyl and halogen substituents, such as Me, tert-butyl, F and Cl, were competent in this reaction, generating the corresponding products in moderate yield (3f-3h). Both electron-withdrawing (NO 2 ) and electron-donating (MeO) groups attached to the indole could afford the desired products (3l-3n) in high yields. Interestingly, a new product of bis(indolyl)methanes with 1-hydroxy substituent (3o') was formed when 5-hydroxyindole was employed as the substrate. To our delight, the hydrogen bonds from 5-hydroxyindole have a regulating effect on the generation of two products of 3o and 3o'. It should be noted that the desilication product of bis(indolyl)methanes with 1-hydroxy substituent products (3o') was not easy to obtain by a common strategy. Moreover, no reaction was observed when 2-methylindole and 1-methylindole were used as the substrate (3p and 3q) (details appear in Supplementary Materials).
To further broaden the substrate scope, the less reactive acylsilanes were investigated. However, no desired product of 5aa'-5aa"' was obtained when the reaction of indole (1a) and acylsilanes (4a'-4a"') was carried out under the optimized conditions (Scheme 3a). Considering the bulk steric hindrance effect of silyl substituents (TIPS, TBS and TES), the small size of TMS (4a) was employed to explore the possibility of the reactions. However, two desired products of 5ab and 5ab' were obtained in low yield (Scheme 3b). Based on a regulating effect of hydrogen bonds [40][41][42] (see Scheme 3c or Scheme 2), the reaction of 5-hydroxyindole was employed as the substrate under the optimized conditions. Fortunately, the desilication product of bis(indolyl)methanes with 1-hydroxy substituent product (5a) was obtained, and bis(indolyl)methanes with 1-silyl substituent product (5a') were completely suppressed. These results clearly indicated that hydrogen bonds from the 5-hydroxyindole are a crucial factor in controlling reaction selectivity (Scheme 3d).
Moreover, the hydroxyl group at different positions on indole, including 4-hydroxyindole, 6-hydroxyindole and 7-hydroxyindole, was employed as the substrate; however, a trace amount of the desired product was obtained. These results showed that 5-hydroxyindole is benefit to the desilication product. However, the exact mechanism was unclear (see SI for details). To further broaden the substrate scope, the less reactive acylsilanes were investigated. However, no desired product of 5aa'-5aa''' was obtained when the reaction of indole (1a) and acylsilanes (4a'-4a''') was carried out under the optimized conditions (Scheme 3a). Considering the bulk steric hindrance effect of silyl substituents (TIPS, TBS and TES), the small size of TMS (4a) was employed to explore the possibility of the reactions. However, two desired products of 5ab and 5ab' were obtained in low yield (Scheme 3b). Based on a regulating effect of hydrogen bonds [40][41][42] (see Scheme 3c or Scheme 2), the reaction of 5-hydroxyindole was employed as the substrate under the optimized conditions. Fortunately, the desilication product of bis(indolyl)methanes with 1-hydroxy substituent product (5a) was obtained, and bis(indolyl)methanes with 1-silyl substituent (Scheme 3d). Moreover, the hydroxyl group at different positions on indole, including 4hydroxyindole, 6-hydroxyindole and 7-hydroxyindole, was employed as the substrate; however, a trace amount of the desired product was obtained. These results showed that 5-hydroxyindole is benefit to the desilication product. However, the exact mechanism was unclear (see SI for details).

Scheme 3. Double Friedel-Crafts reaction to synthetic tertiary alcohol. [a]
The yield based on the recovery of starting materials.
Under the optimal reaction conditions, we further applied other less reactive acylsilanes to this reaction (Scheme 4). As shown in Scheme 3, the acylsilanes with an alkyl substituent, including Me, Et, tBu on the benzene ring, were amenable to this reaction, generating the desired products (5a-5e) in moderate yields. Moreover, the biphenyl and naphthyl substituted acylsilanes were performed smoothly with 5-hydroxyindole, affording the corresponding products (5f and 5g) in good yields. Similarly, the acylsilanes with F and Cl atom on the benzene ring were also efficiently transformed into the desired products (5i-5j) in high yields. Both electron-withdrawing groups and electron-donating groups were also compatible with the developed protocol, yielding the corresponding products (5l-5m) in moderate yield. Interestingly, the thienyl-substituted acylsilane is also suitable to the reaction, and the desired product (5n) was obtained in moderate yield (details appear in Supplementary Materials).
Based on the experimental results, two possible reaction pathways were proposed to understand the unusual reaction selectivity. As shown in Scheme 5, the carbonyl group of acylsilanes could also be activated by CSA, and the hydrogen bond from water and the 5hydroxyindole (1l) could react with the activated carbonyl group to afford the generate alkoxide intermediate I. Because the small size of TMS group is beneficial for Brook rearrangement, and the silyl enol ether intermediate II could be obtained from the intermediate I. These results indicate that it is more possible that the 5-hydroxyindole (1l) acts as a proton acid (OH) and the process occurs as an intermolecular process. Finally, another equivalent of 5-hydroxyindole (1l) reacts with silyl enol ether intermediate II to generate the desired product 5 after desilylation under the acid conditions. However, the role of the hydrogen bonding of 5-hydroxyindole is unclear in this transformation. Similarly, the carbonyl group could be activated by CSA and the hydrogen bond from water, and the indole could react with the activated carbonyl group to afford the tetrahedral intermediate Under the optimal reaction conditions, we further applied other less reactive acylsilanes to this reaction (Scheme 4). As shown in Scheme 3, the acylsilanes with an alkyl substituent, including Me, Et, tBu on the benzene ring, were amenable to this reaction, generating the desired products (5a-5e) in moderate yields. Moreover, the biphenyl and naphthyl substituted acylsilanes were performed smoothly with 5-hydroxyindole, affording the corresponding products (5f and 5g) in good yields. Similarly, the acylsilanes with F and Cl atom on the benzene ring were also efficiently transformed into the desired products (5i-5j) in high yields. Both electron-withdrawing groups and electron-donating groups were also compatible with the developed protocol, yielding the corresponding products (5l-5m) in moderate yield. Interestingly, the thienyl-substituted acylsilane is also suitable to the reaction, and the desired product (5n) was obtained in moderate yield (details appear in Supplementary Materials).
Based on the experimental results, two possible reaction pathways were proposed to understand the unusual reaction selectivity. As shown in Scheme 5, the carbonyl group of acylsilanes could also be activated by CSA, and the hydrogen bond from water and the 5-hydroxyindole (1l) could react with the activated carbonyl group to afford the generate alkoxide intermediate I. Because the small size of TMS group is beneficial for Brook rearrangement, and the silyl enol ether intermediate II could be obtained from the intermediate I.
These results indicate that it is more possible that the 5-hydroxyindole (1l) acts as a proton acid (OH) and the process occurs as an intermolecular process. Finally, another equivalent of 5-hydroxyindole (1l) reacts with silyl enol ether intermediate II to generate the desired product 5 after desilylation under the acid conditions. However, the role of the hydrogen bonding of 5-hydroxyindole is unclear in this transformation. Similarly, the carbonyl group could be activated by CSA and the hydrogen bond from water, and the indole could react with the activated carbonyl group to afford the tetrahedral intermediate III. Subsequently, the dehydration process is faster than the Brook rearrangement, and the azafulvene intermediate IV was generated by losing an equivalent amount of water. Another equivalent of 1a reacts with intermediate IV to afford the final product 3.
indole could react with the activated carbonyl group to afford the tetrahedral intermediate III. Subsequently, the dehydration process is faster than the Brook rearrangement, and the azafulvene intermediate IV was generated by losing an equivalent amount of water.

Materials and Methods
The detailed procedures for the synthesis and characterization of the products are given in Appendix A.

Conclusions
In summary, we developed a new strategy to synthesize bis(indolyl)methane derivatives with 1-hydroxy or 1-silyl substituents in moderate to high yield via double Friedel-Crafts reactions of acylsilanes in water. Hydrogen bonds from the 5-hydroxyindole are a crucial factor in controlling reaction selectivity between 1-silyl-bis(indolyl)methane derivatives and 1-hydroxy-bis(indolyl)methane derivatives. A variety of acylsilanes and indols were well tolerated under mild conditions. Further studies of new reactions of acylsilanes are currently underway in our laboratory.

Supplementary Materials:
The following supporting information can be downloaded at: www.mdpi.com/xxx/s1. Characterization data for product 3 and 5, including 1 H-and 13 C-NMR spectroscopies, are available online.

Data Availability Statement:
The data presented in this study are available in this article.

Conflicts of Interest: The authors declare no conflicts of interest.
Sample Availability: Samples of the compounds are available from the authors.

Appendix A. Experimental Section
Chemicals and analytical-grade solvents were purchased from commercial suppliers and used without further purification unless otherwise stated. Flash column chromatography was performed on silica gels (200-300 mesh). General 1 H and 13 C NMR spectra were recorded on a Bruker 600 MHz NMR spectrometer. Chemical shifts were reported in ppm, and the coupling constants J are given in Hz. Tetramethylsilane (TMS, δ = 0.00 ppm) or CHCl3 (δ = 7.27 ppm) served as an internal standard for 1 H NMR, while CDCl3 was used as an internal standard (δ = 77.0 ppm) for 13 C NMR. HRMS data were obtained on a Bruker Apex II mass instrument (ESI) or an Agilent Technologies 6540 UHD Accurate-Mass Q-Scheme 5. Proposed Reaction Mechanism.

Materials and Methods
The detailed procedures for the synthesis and characterization of the products are given in Appendix A.

Conclusions
In summary, we developed a new strategy to synthesize bis(indolyl)methane derivatives with 1-hydroxy or 1-silyl substituents in moderate to high yield via double Friedel-Crafts reactions of acylsilanes in water. Hydrogen bonds from the 5-hydroxyindole are a crucial factor in controlling reaction selectivity between 1-silyl-bis(indolyl)methane derivatives and 1-hydroxy-bis(indolyl)methane derivatives. A variety of acylsilanes and indols were well tolerated under mild conditions. Further studies of new reactions of acylsilanes are currently underway in our laboratory.

Data Availability Statement:
The data presented in this study are available in this article.

Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are available from the authors.

Appendix A. Experimental Section
Chemicals and analytical-grade solvents were purchased from commercial suppliers and used without further purification unless otherwise stated. Flash column chromatography was performed on silica gels (200-300 mesh). General 1 H and 13 C NMR spectra were recorded on a Bruker 600 MHz NMR spectrometer. Chemical shifts were reported in ppm, and the coupling constants J are given in Hz. Tetramethylsilane (TMS, δ = 0.00 ppm) or CHCl 3 (δ = 7.27 ppm) served as an internal standard for 1 H NMR, while CDCl 3 was used as an internal standard (δ = 77.0 ppm) for 13 C NMR. HRMS data were obtained on a Bruker Apex II mass instrument (ESI) or an Agilent Technologies 6540 UHD Accurate-Mass Q-TOF LC/MS (ESI). Silyl glyoxylates were prepared according to the literature procedure [41][42][43]. Acylsianes were prepared according to the literature procedure [28,[44][45][46].
General procedure for Friedel-Crafts reaction of silyl glyoxylates. A mixture of indole derivative 1 (0.25 mmol), silyl glyoxylate 2 (0.10 mmol), and CSA (30 mol%) in H 2 O (1.0 mL) was stirred at room temperature for the indicated reaction time. The reaction mixture was extracted twice with 15 mL of ethyl acetate; combined organic phases were washed with brine, dried (Na 2 SO 4 ), and evaporated. The residue was further purified by silica gel chromatography (petroleum ether/EtOAc as eluent) to afford the desired product 3.   General procedure for Friedel-Crafts reaction of acylsilanes. A mixture of acylsianes 3 (0.10 mmol), 5-hydroxyindole 1l (0.25 mmol) and CSA (30 mol%) in H 2 O (1.0 mL) was stirred at room temperature for the indicated time. Then, the mixture was extracted twice with EtOAc (10 mL), and the combined organic phases were washed with brine, dried