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Communication

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

by
Qi Li
†,
Xiu-Xia Liang
†,
Wang Zhang
and
Man-Yi Han
*
Key Laboratory of Green and Precise Synthetic Chemistry and Applications, Ministry of Education, College of Chemistry and Materials Science, Huaibei Normal University, Huaibei 235000, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2023, 28(15), 5685; https://doi.org/10.3390/molecules28155685
Submission received: 18 May 2023 / Revised: 21 July 2023 / Accepted: 24 July 2023 / Published: 27 July 2023
(This article belongs to the Special Issue Novel Organic Synthetic Route to Heterocyclic Compounds)
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Abstract

:
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.

1. Introduction

As an important class of indole alkaloids, bis(indolyl)methanes (BIM) broadly exist in many bioactive natural products [1,2,3,4,5], such as streptindole [6], arsindoline A [7], trisindoline [8], and a wide range of biological activities, such as antibacterial, antitumor and antileishmanial properties, were shown in these related compounds (Scheme 1a). Therefore, the synthesis of a bis(indolyl)methane (BIM) type of structure has attracted broad attention in synthetic chemistry [1,9,10,11,12,13,14,15,16]. Generally, 3-alkyl-bis(indolyl)methanes were obtained easily via a Lewis or Brønsted acid-catalyzed double Friedel–Crafts reaction between indole and carbonyl compounds (Scheme 1b). Moreover, photoredox catalysis-induced bisindolylations were also successfully employed by C-H bond cleavage [13,14]. However, the synthesis of bis(indolyl)methanes with 1-hydroxy or 1-silyl substituents remains challenging and less explored, probably due to the lesser stability of the hydroxy group and the silyl group in Lewis acid or Brønsted acid reaction conditions. Therefore, the development of an alternative synthetic method for BIM’s derivatives remains a challenging subject.
Acylsilanes are valuable organosilicon reagents in an umpolung reaction, and a C-Si or C-O bond could be synthesized by nucleophilic addition using the proton conditions or Brook rearrangement with high nucleophilicity of reagents [17,18,19,20,21,22,23,24,25,26,27,28,29]. In this regard, various reaction types, including nucleophilic addition, the carbene reaction, the Prins reaction and the Brook reaction were successfully achieved [17,18,29]. However, the Friedel–Crafts reaction of acylsilanes is less explored. Considering the unique reactivity of carbonyl groups, we wonder whether bis(indolyl)methanes with 1-silylsubstituent could be synthesized by a double Friedel–Crafts reaction of acylsilanes. Moreover, bis(indolyl)methanes with 1-hydroxy substituent could be yielded if Brook rearrangement occurred before the second Friedel–Crafts reaction. Herein, we disclose a novel double Friedel–Crafts reaction of acylsilanes, generating the bis(indolyl)methanes with 1-silyl substituent products. With the assistance of a hydrogen-bond, bis(indolyl)methanes with a 1-hydroxy substituent were successfully obtained in moderate yields (Scheme 1c).

2. 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 CH2Cl2, toluene, DMF, THF and EtOH, were investigated and inferior yields were observed (Table 1, entries 8–12). 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) (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).
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.

3. Materials and Methods

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

4. 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: https://www.mdpi.com/article/10.3390/molecules28155685/s1. Characterization data for product 3 and 5, including 1H- and 13C-NMR spectroscopies, are available online: 1. The reaction of acylsilane with indole containing hydroxy groups at different positions; 1. 1H and 13C NMR spectra of the products.

Author Contributions

Conceptualization, M.-Y.H.; methodology, Q.L. and X.-X.L.; formal analysis, Q.L. and X.-X.L.; investigation, Q.L. and W.Z.; data curation, Q.L. and X.-X.L.; writing—original draft preparation, Q.L.; writing—review and editing, M.-Y.H.; supervision, M.-Y.H.; project administration, M.-Y.H. All authors have read and agreed to the published version of the manuscript.

Funding

We gratefully acknowledge the University Natural Science Research Project of Anhui Province (KJ2021ZD0057) and the Young Scholars in WanJiang Scholars Program of Anhui Province (03106032) for financial support.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

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 1H and 13C 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 1H NMR, while CDCl3 was used as an internal standard (δ = 77.0 ppm) for 13C 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 H2O (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 (Na2SO4), and evaporated. The residue was further purified by silica gel chromatography (petroleum ether/EtOAc as eluent) to afford the desired product 3.
  • Benzyl 2-(tert-butyldimethylsilyl)-2,2-di(1H-indol-3-yl)acetate (3a); isolated by column chromatography (EtOAc/petroleum ether = 1:6); (35.6 mg, 72% yield); red amorphous solid; 1H NMR (600 MHz, CDCl3) δ 8.06 (s, 2H), 7.52 (d, J = 2.6 Hz, 2H), 7.25 (d, J = 7.2 Hz, 2H), 7.17 (t, J = 7.2 Hz, 1H), 7.12 (t, J = 7.5 Hz, 2H), 6.98 (t, J = 7.5 Hz, 2H), 6.91 (d, J = 7.5 Hz, 2H), 6.80 (d, J = 8.1 Hz, 2H), 6.65 (t, J = 7.5 Hz, 2H), 5.07 (s, 2H), 0.71 (s, 9H), 0.29 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 175.0, 136.0, 135.8, 128.1, 127.9, 127.8, 127.6, 124.1, 121.4, 121.3, 118.8, 115.2, 110.6, 66.4, 44.6, 28.0, 20.1, −3.2; IR (cm−1) 3301, 3057, 2931, 2857, 1706, 1591, 1520, 1458, 1418; HRMS (ESI) m/z calcd for C31H35N2O2Si (M + H)+ 495.2468, found 495.2468.
  • Ethyl 2-(tert-butyldimethylsilyl)-2,2-di(1H-indol-3-yl)acetate (3b); isolated by column chromatography (EtOAc/petroleum ether = 1:8); (29.8 mg, 69% yield); red amorphous solid; 1H NMR (600 MHz, CDCl3) δ 8.08 (s, 2H), 7.48 (s, 2H), 7.24 (d, J = 7.8 Hz, 2H), 6.98 (t, J = 7.2 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.68 (t, J = 7.2 Hz, 2H), 4.13–4.09 (m, 2H), 1.05 (t, J = 7.2 Hz, 3H) 0.73 (s, 9H), 0.35 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 175.2, 135.8, 127.8, 124.1, 121.4, 121.3, 118.7, 115.4, 110.6, 60.6, 44.4, 28.0, 20.0, 14.0, −3.1; HRMS (ESI) m/z calcd for C26H32N2O2SiNa (M + Na)+ 455.2125, found 455.2125.
  • Cyclohexyl 2-(tert-butyldimethylsilyl)-2,2-di(1H-indol-3-yl)acetate (3c); isolated by column chromatography (EtOAc/petroleum ether = 1:6); (25.8 mg, 53% yield); red amorphous solid; 1H NMR (600 MHz, CDCl3) δ 8.07 (s, 2H), 7.46 (s, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.97 (t, J = 7.2 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.67 (t, J = 7.2 Hz, 2H), 4.84–4.85 (m, 1H), 1.58–1.68 (m, 2H), 1.28–1.37 (m, 4H), 1.13–1.21 (m, 4H), 0.70 (s, 9H), 0.39 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 174.6, 135.8, 127.8, 124.1, 121.2, 118.6, 115.5, 110.5, 72.7, 44.6, 31.2, 27.9, 23.2, 20.0, −2.9; IR (cm−1) 3351, 3054, 2931, 2856, 1694, 1455, 1415, 1338, 1205; HRMS (ESI) m/z calcd for C30H38N2O2SiNa (M + Na)+ 509.2595, found 509.2597.
  • tert-Butyl 2-(tert-butyldimethylsilyl)-2,2-di(1H-indol-3-yl)acetate (3d); isolated by column chromatography (EtOAc/petroleum ether = 1:5); (10.1 mg, 22% yield); red amorphous solid; 1H NMR (600 MHz, CDCl3) δ 8.04 (s, 2H), 7.38 (s, 2H), 7.26 (d, J = 1.4 Hz, 2H), 7.25 (s, 1H), 6.98 (t, J = 7.5 Hz, 2H), 6.89 (d, J = 8.0 Hz, 1H), 6.68 (t, J = 7.6 Hz, 2H), 1.25 (s, 9H), 0.61 (s, 9H), 0.42 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 174.0, 135.9, 127.8, 124.0, 122.0, 121.2, 118.6, 115.8, 110.5, 80.4, 45.3, 27.9, 27.8, 19.9, −2.8; HRMS (ESI) m/z calcd for C28H36N2O2SiNa (M + Na)+ 483.2444, found 483.2444.
  • Naphthalen-1-yl 2-(tert-butyldimethylsilyl)-2,2-di(1H-indol-3-yl)acetate (3e); isolated by column chromatography (EtOAc/petroleum ether = 1:6); (39.8 mg, 75% yield); red amorphous solid; 1H NMR (600 MHz, CDCl3) δ 8.01 (s, 2H), 7.72 (dd, J = 17.6, 8.2 Hz, 2H), 7.49 (s, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 8.1 Hz, 3H), 7.21 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 7.0 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.5 Hz, 2H), 6.86 (d, J = 8.2 Hz, 2H), 6.66 (t, J = 7.6 Hz, 2H), 5.48 (s, 2H), 0.69 (s, 9H), 0.23 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 175.3, 135.8, 133.3, 131.5, 131.4, 128.8, 128.1, 127.8, 127.0, 125.9, 125.5, 124.9, 124.1, 123.7, 121.33, 121.27, 118.8, 115.1, 110.6, 65.2, 44.6, 27.9, 20.0, −3.3; HRMS (ESI) m/z calcd for C35H36N2O2SiNa (M + Na)+ 567.2438, found 567.2442.
  • Ethyl 2-(tert-butyldimethylsilyl)-2,2-bis(6-methyl-1H-indol-3-yl)acetate (3f); isolated by column chromatography (EtOAc/petroleum ether = 1:5); (34.0 mg, 74% yield); red amorphous solid; 1H NMR (600 MHz, CDCl3) δ 7.92 (s, 2H), 7.38 (d, J= 2.4 Hz, 2H), 7.02–7.00 (s, 2H), 6.74 (d, J = 8.4 Hz, 2H), 6.52 (dd, J = 7.8 Hz, 1.8 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 1.06 (t, J = 7.2 Hz, 3H), 0.73 (s, 9H), 0.34 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 175.2, 136.3, 130.8, 125.7, 123.5, 121.1, 120.6, 115.3, 110.6, 60.6, 44.4, 28.0, 21.5, 20.0, 14.1, −3.0; HRMS (ESI) m/z calcd for C28H36N2O2SiNa (M + Na)+ 483.2438, found 483.2435.
  • Ethyl 2-(tert-butyldimethylsilyl)-2,2-bis(7-methyl-1H-indol-3-yl)acetate (3g); isolated by column chromatography (EtOAc/petroleum ether = 1:5); (21.6 mg, 47% yield); red amorphous solid; 1H NMR (600 MHz, CDCl3) δ 7.99 (s, 2H), 7.49 (d, J = 3.0 Hz, 2H), 6.78 (d, J = 4.8 Hz, 2H), 6.70 (d, J = 2.4 Hz, 2H), 6.61 (dd, J = 7.2 Hz, 6.6 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 2.43 (s, 6H), 1.06 (t, J =7.2 Hz, 3H), 0.73 (s, 9H), 0.34 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 175.2, 135.4, 127.3, 123.9, 121.9, 119.4, 119.3, 118.8, 116,0, 60.6, 44.6, 28.1, 20.0, 16.5, 14.1, −3.0; HRMS (ESI) m/z calcd for C28H36N2O2Si (M + H)+ 461.2624, found 461.2622.
  • Ethyl 2,2-bis(5-(tert-butyl)-1H-indol-3-yl)-2-(tert-butyldimethylsilyl)acetate (3h); isolated by column chromatography (EtOAc/petroleum ether = 1:6); (18.5 mg, 34% yield); red amorphous solid; 1H NMR (600 MHz, CDCl3) δ 7.98 (s, 2H), 7.54 (d, J = 2.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.00 (dd, J = 8.4 Hz, 1.8 Hz, 2H), 6.67 (s, 2H), 4.11 (q, J = 7.2 Hz, 2H), 1.08 (t, J = 7.2 Hz, 3H), 0.98 (s, 18H), 0.77 (s, 9H), 0.35 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 175.4, 140.8, 134.1, 127.8, 124.11, 119.0, 118.0, 115.2, 109.5, 60.5, 44.4, 34.1, 31.6, 28.2, 20.1, 14.1, −3.1; HRMS (ESI) m/z calcd for C34H48N2O2SiNa (M + Na)+ 567.3377, found 567.3379.
  • Benzyl 2-(tert-butyldimethylsilyl)-2,2-bis(4-fluoro-1H-indol-3-yl)acetate (3i); isolated by column chromatography (EtOAc/petroleum ether = 1:5); (38.8 mg, 69% yield); red amorphous solid; 1H NMR (600 MHz, CDCl3) δ 8.15 (s, 2H), 7.76 (s, 2H), 7.13–7.16 (m, 1H), 7.08–7.11 (m, 2H), 7.03 (d, J = 7.8 Hz, 2H), 6.90–6.86 (m, 4H), 6.35 (q, J = 7.8 Hz, 2H), 5.11 (s,2H), 0.94 (s, 9H), 0.26 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 175.1, 156.2 (d, JC-F = 246 Hz), 138.8 (d, JC-F = 12 Hz), 135.9, 128.0, 127.6, 127.4, 124.8 (d, JC-F = 3 Hz), 121.5 (d, JC-F = 9 Hz), 116.1 (d, JC-F = 19.5 Hz), 115.6 (d, JC-F = 4.5 Hz), 106.9 (d, JC-F = 12 Hz), 104.9 (d, JC-F = 22.5 Hz), 66.6, 44.9, 28.7, 20.3, −3.5; IR (cm−1) 3469, 3034, 2931, 2858, 1698, 1574, 1498, 1471, 1223; HRMS (ESI) m/z calcd for C31H33F2N2O2Si (M + H)+ 531.2279, found 531.2276.
  • Benzyl 2-(tert-butyldimethylsilyl)-2,2-bis(5-fluoro-1H-indol-3-yl)acetate (3j); isolated by column chromatography (EtOAc/petroleum ether = 1:6); (34.5 mg, 65% yield); red amorphous solid; 1H NMR (600 MHz, CDCl3) δ 8.12 (s, 2H), 7.50 (d, J = 2.5 Hz, 2H), 7.20–7.16 (m, 1H), 7.16–7.12 (m, 2H), 6.94–6.90 (m, 4H), 6.64 (dd, J = 9.0, 5.4 Hz, 2H), 6.64–6.38 (m, 2H), 5.08 (s, 2H), 0.72 (s, 9H), 0.27 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 174.8, 159.4 (d, JC-F = 237 Hz), 154.2 (d, JC-F = 64.5 Hz), 135.8, 128.0 (d, JC-F = 28.5 Hz), 127.7, 124.3 (d, JC-F = 3 Hz), 124.2, 122.0 (d, JC-F = 9 Hz), 115.1, 107.7 (d, JC-F = 24 Hz), 96.8 (d, JC-F = 25.5 Hz), 66.5, 66.5, 44.4, 27.9, 20.0, 1.0, −3.3; HRMS (ESI) m/z calcd for C31H33F2N2O2Si (M + H)+ 531.2279, found 531.2274.
  • Benzyl 2-(tert-butyldimethylsilyl)-2,2-bis(5-chloro-1H-indol-3-yl)acetate (3k); isolated by column chromatography (EtOAc/petroleum ether = 1:5); (44.4 mg, 79% yield); red amorphous solid; 1H NMR (600 MHz, CDCl3) δ 8.15 (s, 2H), 7.57 (s, 2H), 7.20–7.13 (m, 5H), 6.97 (d, J = 7.3 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.69 (s, 2H), 5.10 (s, 2H), 0.75 (s, 9H), 0.28 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 174.7, 135.6, 134.2, 128.6, 128.2, 128.1, 127.9, 125.5, 124.5, 121.9, 120.4, 114.6. 111.9, 66.8, 44.2, 28.0, 20.1, −3.3; IR (cm−1) 3468, 3032, 2933, 2858, 1705, 1565, 1463, 1412, 1257, 1189; HRMS (ESI) m/z calcd for C31H32Cl2N2O2SiNa (M + Na)+ 585.1502, found 585.1508.
  • Benzyl 2-(tert-butyldimethylsilyl)-2,2-bis(5-cyano-1H-indol-3-yl)acetate (3l); isolated by column chromatography (EtOAc/petroleum ether = 1:6); (33.7 mg, 62% yield); red amorphous solid; 1H NMR (600 MHz, DMSO-d6) δ 11.65 (d, J = 1.8 Hz, 2H), 7.79 (d, J = 2.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.23 (dd, J = 8.4 Hz, 1.8 Hz, 2H), 7.22–7.18 (m, 1H), 7.15 (t, J = 7.8 Hz, 2H), 7.00–6.93 (m, 2H), 6.75 (s, 2H), 5.09 (s, 2H), 0.66 (s, 9H), 0.24 (s, 6H); 13C NMR (150 MHz, DMSO-d6): δ 173.8, 137.8, 135.7, 128.1, 127.94, 127.91, 127.6, 126.8, 125.3, 123.3, 120.6, 114.2, 113.0, 100.0, 66.2, 43.6, 27.7, 19.7, −3.6; HRMS (ESI) m/z calcd for C33H32N4O2SiNa (M + Na)+ 567.2192, found 567.2193.
  • Dimethyl 3,3’-(2-((2-bromobenzyl)oxy)-1-(tert-butyldimethylsilyl)-2-oxoethane-1,1-diyl)bis(1H-indole-6-carboxylate) (3m); isolated by column chromatography (EtOAc/petroleum ether = 1:6); (51.6 mg, 75% yield); red amorphous solid; 1H NMR (600 MHz, CDCl3) δ 8.83 (d, J = 2.4 Hz, 2H), 8.06 (d, J = 1.2 Hz, 2H), 7.79 (d, J = 2.4 Hz, 2H), 7.32 (dd, J = 1.2, 7.8 Hz, 1H), 7.26 (dd, J = 1.2, 7.8 Hz, 2H), 6.95 (td, J = 1.8, 7.2 Hz, 1H), 6.86 (td, J = 1.8, 7.2 Hz, 1H), 6.67 (d, J = 9.0 Hz, 2H), 6.63 (dd, J = 1.8, 7.8 Hz, 1H), 5.16 (s 2H), 3.83 (s, 6H), 0.72 (s, 9H), 0.31 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 174.5, 168.2, 135.2, 134.9, 132.3, 131.2, 129.4, 129.2, 127.7, 127.0, 122.9, 122.8, 120.5, 119.8, 115.2, 113.4, 65.9, 51.8, 44.4, 27.9, 20.0, −3.4; HRMS (ESI) m/z calcd for C31H33BrN2O2SiNa (M + Na)+ 595.1387, found 595.1389.
  • Ethyl 2-(tert-butyldimethylsilyl)-2,2-bis(5-methoxy-1H-indol-3-yl)acetate (3n); isolated by column chromatography (EtOAc/petroleum ether = 1:6); (28.0 mg, 57% yield); red amorphous solid; 1H NMR (600 MHz, DMSO-d6) δ 10.66 (s, 2H), 7.33 (d, J = 2.4 Hz, 2H), 6.74 (d, J = 1.8 Hz, 2H), 6.43 (d, J = 9.0 Hz, 2H), 6.29 (dd, J = 9.0 Hz, 2.4 Hz, 2H), 3.99 (q, J = 7.2 Hz, 2H), 3.65 (s, 6H), 1.00 (t, J = 7.2 Hz, 3H), 0.65 (s, 9H), 0.25 (s, 6H); 13C NMR (150 MHz, DMSO-d6): δ 174.5, 154.7, 136.5, 123.2, 121.8, 121.0, 113.6, 107.8, 94.0, 59.9, 54.8, 43.7, 27.8, 19.7, 14.0, −3.3; HRMS (ESI) m/z calcd for C28H36N2O4SiNa (M + Na)+ 515.2337, found 515.2339.
  • Ethyl 2-(tert-butyldimethylsilyl)-2,2-bis(5-hydroxy-1H-indol-3-yl)acetate (3o); isolated by column chromatography (EtOAc/petroleum ether = 1:8); (7.9 mg, 17% yield); red amorphous solid; 1H NMR (600 MHz, DMSO-d6) δ 10.53 (s, 2H), 8.16 (s, 2H), 7.30 (s, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.40 (d, J = 8.4 Hz, 2H), 6.08 (s, 2H), 4.00 (q, J = 7.2 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H), 0.63 (s, 9H), 0.26 (s, 6H); 13C NMR (150 MHz, DMSO-d6): δ 174.5, 149.0, 130.5, 128.2, 125.2, 112.6, 111.0, 110.7, 105.2, 59.8, 43.7, 27.9, 19.7, 14.0, −2.9; HRMS (ESI) m/z calcd for C26H32N2O4SiNa (M + Na)+ 487.2024, found 487.2026.
  • Ethyl 2-(tert-butyldimethylsilyl)-2,2-bis(5-hydroxy-1H-indol-3-yl)acetate (3o’); isolated by column chromatography (EtOAc/petroleum ether = 1:5); (9.2 mg, 25% yield); red amorphous solid; 1H NMR (600 MHz, DMSO-d6) δ 10.62 (s, 2H), 8.59 (s, 2H), 7.13 (d, J = 8.6 Hz, 2H), 7.03 (s, 2H), 6.81 (s, 2H), 6.58 (d, J = 8.4 Hz, 2H), 5.14 (s, 1H), 4.10 (q, J = 7.2 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, DMSO-d6): δ 172.8, 150.2, 130.9, 127.1, 124.1, 111.8, 111.4, 111.3, 102.9, 60.2, 40.6, 14.2; HRMS (ESI) m/z calcd for C20H18N2O5 (M-(H2O) + H)+ 349.1188, found 349.1184.
  • 3,3’-(Phenyl(trimethylsilyl)methylene)bis(1H-indole) (5ab); isolated by column chromatography (EtOAc/petroleum ether = 1:6); (6.3 mg, 16% yield); red amorphous solid; 1H NMR (600 MHz, CDCl3) δ 7.96 (s, 2H), 7.37 (d, J = 7.8 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.23 (t, J = 7.6 Hz, 2H), 7.16 (t, J = 7.2 Hz, 1H), 7.08 (t, J = 7.6 Hz, 2H), 7.00 (d, J = 8.2 Hz, 2H), 6.89 (s, 2H), 6.80 (t, J = 7.6 Hz, 2H), 0.14 (s, 9H); 13C NMR (150 MHz, CDCl3): δ 146.1, 136.7, 129.4, 127.6, 127.4, 125.1, 123.8, 122.9, 121.4, 121.3, 118.5, 110.9, 1.0; HRMS (ESI) m/z calcd for C26H26N2SiNa (M + Na)+ 417.1758, found 417.1755.
  • Di(1H-indol-3-yl)(phenyl)methanol (5ab’); isolated by column chromatography (EtOAc/petroleum ether = 1:8); (10.1 mg, 30% yield); red amorphous solid; 1H NMR (600 MHz, CDCl3) δ 7.87 (s, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.34–7.36 (m, 4H), 7.29 (t, J = 7.5 Hz, 2H), 7.21–7.23 (m, 1H), 7.16–7.19 (m, 2H), 7.01 (t, J = 7.5 Hz, 2H), 6.64 (s, 2H), 5.90 (s, 1H); 13C NMR (150 MHz, CDCl3):δ 144.0, 136.7, 128.7, 128.2, 127.0, 126.1, 123.6, 121.9, 119.9, 119.7, 119.2, 111.0, 40.2; HRMS (ESI) m/z calcd for C23H17N2 (M-(H2O) + H)+ 321.1391, found 321.1395.
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 H2O (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 (Na2SO4) and evaporated. The residue was further purified by silica gel chromatography (petroleum ether/EtOAc as eluent) to afford the desired product 5.
  • 3,3’-(Hydroxy(phenyl)methylene)bis(1H-indol-5-ol) (5a); isolated by column chromatography (EtOAc/petroleum ether = 1:5); (14.1 mg, 83% yield); red amorphous solid; 1H NMR (600 MHz, acetone-d6) δ 9.70 (s, 2H), 7.61 (s, 2H), 7.41–7.39 (m, 2H), 7.28 (t, J = 7.6 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 6.79 (d, J = 2.3 Hz, 2H), 6.72 (dd, J = 8.3, 2.5 Hz, 4H), 5.73 (s, 1H); 13C NMR (150 MHz, acetone-d6):δ 151.2, 145.8, 132.8, 129.5, 128.79, 128.76, 126.6, 125.2, 118.9, 112.5, 112.2, 104.5, 41.2; HRMS (ESI) m/z calcd for C23H17N2O2 (M-(H2O) + H)+ 353.1289, found 353.1285.
  • 3,3’-(Hydroxy(p-tolyl)methylene)bis(1H-indol-5-ol) (5b); isolated by column chromatography (EtOAc/petroleum ether = 1:5); (23.0 mg, 60% yield); red amorphous solid; 1H NMR (600 MHz, acetone-d6) δ 9.68 (s, 2H), 7.53 (s, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 7.8 Hz, 2H), 6.76 (d, J = 2.4 Hz, 2H), 6.70 (t, J = 1.8 Hz, 3H), 6.68 (d, J = 2.4 Hz, 1H), 5.66 (s, 1H), 2.29 (s, 3H); 13C NMR (150 MHz, acetone-d6):δ 151.2, 142.9, 135.7, 132.8, 129.4, 128.8, 125.2, 119.1, 112.5, 112.2, 104.5, 40.8, 21.1; IR (cm−1) 3378, 2922, 2856, 1704, 1584, 1459, 1362, 1184; HRMS (ESI) m/z calcd for C24H19N2O2 (M-(H2O) + H)+ 367.1441, found 367.1441.
  • 3,3’-(Hydroxy(m-tolyl)methylene)bis(1H-indol-5-ol) (5c); isolated by column chromatography (EtOAc/petroleum ether = 1:6); (23.4 mg, 61% yield); red amorphous solid; 1H NMR (600 MHz, acetone-d6) δ 9.68 (s, 2H), 7.52 (s, 2H), 7.23 (d, J = 1.8 Hz, 1H), 7.21 (d, J = 8.7 Hz, 2H), 7.17–7.13 (m, 2H), 7.01–6.99 (m, 1H), 6.76 (d, J = 2.4 Hz, 2H), 6.70–6.69 (m, 3H), 6.68 (d, J = 2.4 Hz, 1H), 5.66 (s, 1H), 2.26 (s, 3H); 13C NMR (150 MHz, acetone-d6): δ 151.2, 145.9, 138.0, 132.8, 130.2, 128.9, 128.7, 127.3, 126.6, 125.2, 119.1, 112.5, 112.2, 104.5, 41.2, 21.6; HRMS (ESI) m/z calcd for C24H19N2O2 (M-(H2O) + H)+ 367.1441, found 367.1442.
  • 3,3’-((4-ethylphenyl)(hydroxy)methylene)bis(1H-indol-5-ol) (5d); isolated by column chromatography (EtOAc/petroleum ether = 1:5); (21.9 mg, 55% yield); red amorphous solid; 1H NMR (600 MHz, acetone-d6) δ 9.68 (s, 2H), 7.50 (s, 2H), 7.29–7.27 (m, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.12–7.11(m, 2H), 6.75 (d, J = 2.4 Hz, 2H), 6.70 (dd, J = 0.9, 2.4 Hz, 2H), 6.68 (d, J = 2.4 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 5.66 (s, 1H), 2.61 (q, J = 7.5 Hz, 2H), 1.20 (t, J = 7.8 Hz, 3H); 13C NMR (150 MHz, acetone-d6):δ 151.2, 143.2, 142.3, 132.9, 129.5, 128.9, 128.2, 125.2, 119.2, 112.5, 112.2, 104.5, 40.9, 16.1; IR (cm−1) 3305, 2964, 2929, 2869, 1704, 1584, 1458, 1361, 1168; HRMS (ESI) m/z calcd for C25H21N2O2 (M-(H2O) + H)+ 381.1598, found 381.1597.
  • 3,3’-((4-(tert-Butyl)phenyl)(hydroxy)methylene)bis(1H-indol-5-ol) (5e); isolated by column chromatography (EtOAc/petroleum ether = 1:6); (15.3 mg, 36% yield); red amorphous solid; 1H NMR (600 MHz, acetone-d6) δ 9.69(s, 2H), 7.52 (s, 1H), 7.29 (d, J = 2.1 Hz, 5H), 7.19 (d, J = 8.4 Hz, 3H), 6.75 (d, J = 2.4 Hz, 2H), 6.69 (d, J = 1.8 Hz, 2H), 6.67 (d, J = 2.4 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 5.65 (s, 1H), 1.28 (s, 9H); 13C NMR (150 MHz, acetone-d6): δ 151.3, 149.1, 142.9, 132.8, 129.1, 128.9, 125.6, 125.2, 119.2, 112.5, 112.2, 104.5, 40.7, 34.9, 31.8; HRMS (ESI) m/z calcd for C27H25N2O2 (M-(H2O) + H)+ 409.1911, found 409.1911.
  • 3,3’-([1,1’-Biphenyl]-4-yl(hydroxy)methylene)bis(1H-indol-5-ol) (5f); isolated by column chromatography (EtOAc/petroleum ether = 1:6); (8.5 mg, 52%) yield); red amorphous solid; 1H NMR (600 MHz, acetone-d6) δ 9.74 (s, 2H), 7.66–7.65 (m, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.52 (s, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.43 (t, J =7.2 Hz, 2H), 7.32 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 2.4 Hz, 2H), 6.77 (dd, J = 1.8, 9.6 Hz, 4H), 6.69 (dd, J = 2.4, 8.4 Hz, 2H), 5.76 (s, 1H); 13C NMR (150 MHz, acetone-d6): δ 151.3, 145.3, 141.8, 139.3, 132.9, 130.1, 129.7, 128.9, 127.9, 127.6, 127.3, 125.3, 118.8, 112.5, 112.3, 104.5, 40.9; HRMS (ESI) m/z calcd for C29H21N2O2 (M-(H2O) + H)+ 429.1598, found 429.1600.
  • 3,3’-(Hydroxy(naphthalen-2-yl)methylene)bis(1H-indol-5-ol) (5g); isolated by column chromatography (EtOAc/petroleum ether = 1:5); (23.9 mg, 83% yield); red amorphous solid; 1H NMR (600 MHz, acetone-d6) δ 9.75 (s, 2H), 7.86–7.83 (m, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.77–7.74 (m, 1H), 7.58 (dd, J = 1.8, 8.4 Hz, 1H), 7.51 (s, 2H), 7.44–7.41 (m, 2H), 7.23 (d, J = 8.4 Hz, 2H), 6.77 (dd, J = 2.4, 10.2 Hz, 4H), 6.69 (dd, J = 2.4, 8.4 Hz, 2H), 5.89 (s, 1H); 13C NMR (150 MHz, acetone-d6): δ 151.3, 143.6, 134.6, 133.3, 132.9, 128.9, 128.8, 128.5, 128.4, 128.2, 127.3, 126.6, 126.0, 125.4, 118.7, 112.6, 112.3, 104.5, 41.4; HRMS (ESI) m/z calcd for C27H19N2O2 (M-(H2O) + H)+ 403.1441, found403.1442.
  • 3,3’-((4-fluorophenyl)(hydroxy)methylene)bis(1H-indol-5-ol) (5h); isolated by column chromatography (EtOAc/petroleum ether = 1:5); (20.6 mg, 70% yield); red amorphous solid; 1H NMR (600 MHz, acetone-d6) δ 9.73 (s, 2H), 7.57 (s, 2H), 7.40–7.36 (m, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.05–7.01 (m, 2H), 6.75 (d, J = 2.4 Hz, 2H), 6.71 (dd, J = 8.6, 2.4 Hz, 4H), 5.72 (s, 1H); 13C NMR (150 MHz, acetone-d6): δ 162.1 (d, JC-F = 240 Hz),151.3, 141.9 (d, JC-F = 3 Hz), 132.8, 131.1 (d, JC-F = 7.5 Hz), 128.7, 125.2, 118.8, 115.3 (d, JC-F = 21 Hz), 112.4 (d, JC-F = 39 Hz), 104.4, 40.5; HRMS (ESI) m/z calcd for C23H16FN2O2 (M-(H2O) + H)+ 371.1190, found 371.1190.
  • 3,3’-((3-Fluorophenyl)(hydroxy)methylene)bis(1H-indol-5-ol) (5i); isolated by column chromatography (EtOAc/petroleum ether = 1:5); (20.2 mg, 52% yield); red amorphous solid; 1H NMR (600 MHz, acetone-d6) δ 9.76 (s, 2H), 7.56 (s, 2H), 7.32–7.29 (m, 1H), 7.23 (d, J = 9.0 Hz, 3H), 7.12–7.09 (m, 1H), 6.96–6.93 (m, 1H), 6.76 (s, 4H), 6.70 (dd, J = 2.4, 6.0 Hz, 2H), 5.75 (s, 1H); 13C NMR (150 MHz, acetone-d6):δ 163.7 (d, JC-F = 241.5 Hz), 151.4, 149.1 (d, JC-F = 6 Hz), 132.8, 130.5 (d, JC-F = 7.5 Hz), 128.7, 125.5 (d, JC-F = 3 Hz), 125.3, 118.3, 116.1 (d, JC-F = 21 Hz), 113.2 (d, JC-F = 21 Hz), 112.5 (d, JC-F = 36 Hz), 104.3, 41.0; HRMS (ESI) m/z calcd for C23H16FN2O2 (M-(H2O) + H)+ 371.1190, found 371.1191.
  • 3,3’-((3-Chlorophenyl)(hydroxy)methylene)bis(1H-indol-5-ol) (5j); isolated by column chromatography (EtOAc/petroleum ether = 1:3); (24.6 mg, 61% yield); red amorphous solid; 1H NMR (600 MHz, acetone-d6) δ 9.81 (s, 2H), 7.60 (d, J = 9.0 Hz, 2H), 7.38 (s, 1H), 7.34–7.28 (m, 2H), 7.22 (d, J = 8.4 Hz, 4H), 6.73 (s, 4H), 6.69–6.67 (m, 2H), 5.72 (s, 1H); 13C NMR (150 MHz, acetone-d6):δ 151.4, 148.6, 134.2, 132.8, 130.5, 129.4, 128.6, 128.1, 126.7, 125.3, 118.2, 112.6, 112.4, 104.3, 40.9; IR (cm−1) 3304, 2921, 2851, 1697, 1585, 1463, 1423, 1363, 1187; HRMS (ESI) m/z calcd for C23H16ClN2O2 (M-(H2O) + H)+ 387.0895, found 387.0894.
  • 3,3’-((4-Chlorophenyl)(hydroxy)methylene)bis(1H-indol-5-ol) (5k); isolated by column chromatography (EtOAc/petroleum ether = 1:5); (23.8 mg, 59% yield); red amorphous solid; 1H NMR (600 MHz, acetone-d6) δ 9.75 (s, 2H), 7.55 (s, 2H), 7.38–7.35 (m, 2H), 7.31– 7.28 (m, 2H), 7.23 (d, J = 6.0 Hz, 1H), 6.75–6.71 (m, 4H), 6.70 (dd, J = 2.4, 9.0 Hz, 2H), 5.71 (s, 1H); 13C NMR (150 MHz, acetone-d6):δ 151.3, 144.9, 132.8, 131.8, 131.2, 128.8, 128.7, 125.3, 118.4, 112.6, 112.4, 104.4, 40.6; HRMS (ESI) m/z calcd for C23H16ClN2O2 (M-(H2O) + H)+ 387.0895, found 387.0895.
  • 3,3’-(Hydroxy(3-methoxyphenyl)methylene)bis(1H-indol-5-ol) (5l); isolated by column chromatography (EtOAc/petroleum ether = 1:5); (24.4 mg, 61% yield); red amorphous solid; 1H NMR (600 MHz, acetone-d6) δ 9.70 (s, 2H), 7.53 (s, 2H), 7.17–7.22 (m, 3H), 6.96–6.98 (m, 2H), 6.77 (d, J = 6.0 Hz, 2H), 6.74 (d, J = 6.0 Hz, 2H), 6.68 (dd, J = 8.4 Hz, 2.4 Hz, 2H), 5.68 (s, 1H), 3.71 (s, 3H); 13C NMR (150 MHz, acetone-d6): δ 160.5, 151.1, 147.5, 132.7, 128.7, 125.1, 121.8, 118.7, 115.6, 112.4, 111.4, 104.4, 55.1, 41.2; HRMS (ESI) m/z calcd for C24H21N2O4 (M + H)+ 401.14958, found 401.14975.
  • 1-(4-(Hydroxybis(5-hydroxy-1H-indol-3-yl)methyl)phenyl)pentan-1-one (5m); isolated by column chromatography (EtOAc/petroleum ether = 1:5); (24.5 mg, 55% yield); red amorphous solid; 1H NMR (600 MHz, acetone-d6) δ 9.76 (s, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.55 (s, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 1.8 Hz, 4H), 6.70 (dd, J = 2.4, 8.4 Hz, 2H), 5.79 (s, 1H), 2.99 (t, J = 7.2 Hz, 2H), 1.69–1.64 (m, 2H), 1.42–1.36 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, acetone-d6):δ 200.1, 151.42, 151.37, 136.1, 132.9, 128.8, 125.4, 118.2, 112.7, 112.4, 104.3, 41.4, 38.6, 27.3, 23.1, 14.3; HRMS (ESI) m/z calcd for C28H25N2O3 (M-(H2O) + H)+ 437.1865, found 437.1868.
  • 3,3’-(Hydroxy(thiophen-2-yl)methylene)bis(1H-indol-5-ol) (5n); isolated by column chromatography (EtOAc/petroleum ether = 1:3); (15.0 mg, 40% yield); red amorphous solid; 1H NMR (600 MHz, acetone-d6) δ 9.74 (s, 2H), 7.56 (s, 2H), 7.24–7.22 (m, 3H), 6.92–6.91 (m, 4H), 6.86 (d, J = 2.4 Hz, 2H), 6.72(dd, J = 2.4, 6.0 Hz, 2H), 6.01 (s, 1H); 13C NMR (150 MHz, acetone-d6): δ 151.3, 150.6, 132.7, 128.5, 127.0, 125.5, 124.8, 124.1, 119.0, 112.6, 112.1, 104.4, 36.3; HRMS (ESI) m/z calcd for C21H15N2O2S (M-(H2O) + H)+ 359.0854, found 359.0852.

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Molecules 28 05685 sch001 550
Scheme 1. Strategies to access bis(indolyl)methanes derivatives via a double Friedel–Crafts reaction.
Scheme 1. Strategies to access bis(indolyl)methanes derivatives via a double Friedel–Crafts reaction.
Molecules 28 05685 sch001
Molecules 28 05685 sch002 550
Scheme 2. Scope of silyl glyoxylate. (Reaction conditions: 1 (0.25 mmol), silyl glyoxylate 2 (0.10 mmol), and CSA (30 mol%) in water (1.0 mL) at room temperature were stirred for the indicated time.).
Scheme 2. Scope of silyl glyoxylate. (Reaction conditions: 1 (0.25 mmol), silyl glyoxylate 2 (0.10 mmol), and CSA (30 mol%) in water (1.0 mL) at room temperature were stirred for the indicated time.).
Molecules 28 05685 sch002
Molecules 28 05685 sch003 550
Scheme 3. Double Friedel–Crafts reaction to synthetic tertiary alcohol. [a] The yield based on the recovery of starting materials.
Scheme 3. Double Friedel–Crafts reaction to synthetic tertiary alcohol. [a] The yield based on the recovery of starting materials.
Molecules 28 05685 sch003
Molecules 28 05685 sch004 550
Scheme 4. Scope of acylsilanes. (Reaction conditions: 1 (0.25 mmol), acylsilane 2 (0.10 mmol), and CSA (30 mol%) in water (1.0 mL) at room temperature were stirred for the indicated time. [a] Yield based on the recovery of starting materials. (TMS = trimethylsilyl).
Scheme 4. Scope of acylsilanes. (Reaction conditions: 1 (0.25 mmol), acylsilane 2 (0.10 mmol), and CSA (30 mol%) in water (1.0 mL) at room temperature were stirred for the indicated time. [a] Yield based on the recovery of starting materials. (TMS = trimethylsilyl).
Molecules 28 05685 sch004
Molecules 28 05685 sch005 550
Scheme 5. Proposed Reaction Mechanism.
Scheme 5. Proposed Reaction Mechanism.
Molecules 28 05685 sch005
Table
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 28 05685 i001
EntryCatalystSolventTime (h)Yield (%) b
1PTSAH2O2443
2CSAH2O1072
3MeSO3HH2O24-
4Benzoic acidH2O7033
5p-Fluorobenzoic acidH2O6928
63,5-Dinitrobenzoic acidH2O10437
7CH3CO2HH2O325
8CSACH2Cl21024
9CSAtoluene1020
10CSADMF1011
11CSATHF1028
12CSAEtOH1027
13CSA cH2O2853
14CSA dH2O3238
a Reaction conditions: 1a (0.25 mmol), 2 (0.10 mmol) in solvent (1.0 mL) at room temperature was stirred for the indicated time. b Isolated yield. c 20 mol% catalyst was used. d 10 mol% catalyst was used. TBS = tert-butyldimethylsily.
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Li, Q.; Liang, X.-X.; Zhang, W.; Han, M.-Y. Friedel–Crafts Reaction of Acylsilanes: Highly Chemoselective Synthesis of 1-Hydroxy-bis(indolyl)methanes and 1-Silyl-bis(indolyl)methanes Derivatives. Molecules 2023, 28, 5685. https://doi.org/10.3390/molecules28155685

AMA Style

Li Q, Liang X-X, Zhang W, Han M-Y. Friedel–Crafts Reaction of Acylsilanes: Highly Chemoselective Synthesis of 1-Hydroxy-bis(indolyl)methanes and 1-Silyl-bis(indolyl)methanes Derivatives. Molecules. 2023; 28(15):5685. https://doi.org/10.3390/molecules28155685

Chicago/Turabian Style

Li, Qi, Xiu-Xia Liang, Wang Zhang, and Man-Yi Han. 2023. "Friedel–Crafts Reaction of Acylsilanes: Highly Chemoselective Synthesis of 1-Hydroxy-bis(indolyl)methanes and 1-Silyl-bis(indolyl)methanes Derivatives" Molecules 28, no. 15: 5685. https://doi.org/10.3390/molecules28155685

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