Home Ligand- and catalyst-free intramolecular C-S bond formation: direct access to indalothiochromen- 4-ones
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Ligand- and catalyst-free intramolecular C-S bond formation: direct access to indalothiochromen- 4-ones

  • T.A. Jenifer Vijay , Nagarakere C. Sandhya , C.S. Pavankumar , Kanchugarakoppal S. Rangappa EMAIL logo and Kempegowda Mantelingu EMAIL logo
Published/Copyright: June 2, 2015
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 21 Issue 3

Abstract

An efficient ligand- and catalyst-free intramolecular S-arylation leading to the direct synthesis of indalothiochromen-4-ones from simple dithioesters under mild conditions has been developed. This method is particularly noteworthy given its experimental simplicity, high generality, and good functional group toleration.

Keywords: dithioesters; indalothiochromen-4-ones; S-arylation; Vilsmeier-Haack reaction

The indole subunits have always fascinated the researchers for their recurrent presence in most of the biologically active natural products [1–5]. The polycyclic annulated indole compounds have drawn the interest of chemists to design their synthesis and study their interaction with enzymes in biological systems [6–10]. For example, polycyclic indole alkaloids such as ajmaline [11], ervincidine [12], alistonitrine [13], MGM-16, and mitragynine [14] are important in both biology and medicinal chemistry.

A wide range of sulfur-heterocyclic scaffolds such as thiopyrans and fused-thiopyran derivatives, including benzothiopyrans, have been reported for their biological activity [15–19]. Annulation of the indole ring to the thiopyran makes it even more interesting in the synthetic and biological perspective [9, 20, 21]. On the basis of these considerations and our interest in developing new synthetic strategies for the synthesis of biologically viable heterocycles [22–28], we herein report an improved method for the synthesis of indalothiochromen-4-ones.

The literature reports reveal only a few synthetic methods for the construction of indalothiochromen-4-ones. The earliest report on the synthesis of such compounds is the reaction of propiolic acid and 3-mercaptoindole followed by treatment with phosphoric acid [29], but this method has not attracted much attention. Indoline-2-thione was exploited more as a starting material than any other reactants [21, 30–33]. The thio-Claisen rearrangement of 2-(4′-aryloxybut-2′-ynylthio)-1-methylindole derived from indoline-2-thione and 1-aryloxy-4-chlorobut-2-yne has also been reported [34]. On the other hand, the use of dithioesters as a sulfur source to afford indalothiochromen-4-ones has not been explored yet to the best of our knowledge. Herein, we report the new and efficient synthesis of indalothiochromen-4-ones by the reaction of simple 1-(2-chloro-1H-indol-3-yl)ethanone and dithioesters under basic conditions at room temperature.

The starting materials N-alkyl/aryl indoles 1a-c were synthesized according to the reported method [35]. Initially, the Vilsmeier-Haack reaction of oxindoles (A) yielded 3-acetyl 2-chloro indoles (B). These products were next, either benzylated or methylated using benzyl bromide and methyl iodide, respectively (Scheme 1). The starting materials dithioesters were also synthesized by the known method with slight modifications. The aryl halides were converted into Grignard reagents, which were further allowed to react with carbon disulfide to form a thiocarbonyl-thio salt. Subsequently, treatment of the thiocarbonyl-thio salt with an alkyl halide yielded the desired dithioesters 2a-j[36]. As can be seen from Scheme 1, 1-(2-chloro-1H-indol-3-yl)ethanone (1a) was treated with dithioester 2a in DMF in the presence of sodium hydride at room temperature to furnish 2-phenyl-thiopyrano[2,3-b]indol-4-(9H)-one thiochromone (3a) in good yield. The mildest conditions possible under which the reaction of compound 1a with dithioester 2a would proceed with a synthetically useful rate were investigated. The reaction conducted under reflux in DMF in the presence of NaH (1.5 Eq) required 24 h to reach completion and provided the desired product 3a in 40% yield. The use of other bases than NaH, including K2CO3, TEA, KOH,t-BuOK, and MeONa, gave rise to significantly lower yields or no product 3a at all.

Scheme 1 Synthesis route of 2-aryl/heteroaryl-thiopyrano[2,3-b]indol-4-(9H)–ones.
Scheme 1

Synthesis route of 2-aryl/heteroaryl-thiopyrano[2,3-b]indol-4-(9H)–ones.

Therefore, the reaction was optimized by varying the amount of the base NaH, solvent, and temperature. The reaction was found to proceed efficiently at room temperature with the highest yield of 60% of 3aobtained in the presence of 2.5 Eq of NaH. A decrease in the amount of NaH to 2.0 Eq had negative effect on the yield of 3a (55%), whereas the use of 3.0 Eq did not lead to any significant increase in the yield compared to the application of 2.5 Eq of NaH. Screening of various solvents, including toluene, THF, diethyl ether and DMF, showed that DMF is the most suitable medium. The reaction of 1a with 2a showed no improvement upon raising the temperature. Subsequently, the reactions of N-alkyl/aryl indole derivatives 1a-c with wide range of dithioesters 2a-jwere evaluated under the optimized conditions. In all cases, the products were obtained in moderate to good yield at room temperature.

Interestingly, the LCMS analysis of crude product 3h suggested a contamination with a trace amount of 9-benzyl-2-(4-(methylthio)phenyl)thiopyrano[2,3-b]indol-4(9H)-one [28, 37] (not shown). The suggested SNAr substitution reaction of the halogen atom by the methylthio group did not take place with 4-chlorophenyl and 4-bromophenyl substituted indalothiochromen-4-ones 3f,g. The heterocyclic dithioesters of benzothiophene 2i and thiophene 2j underwent the reaction with 1aand 1c, efficiently furnishing the corresponding indalothiochromen-4-ones 3i, 3j,and 3min 63%, 56%, and 63% yields, respectively. 6-Bromo substituted indalothiochromen-4-ones 3nand 3owere obtained in the respective yields of 52% and 48%. The structures of all these products were characterized and confirmed by spectral analyses.

We propose that the reaction proceeds according to the mechanism shown in Scheme 2, exemplified by the particular reaction of 1a with 2a. The carbanion intermediate X undergoes a reaction with dithioester 2a to afford 1,3-thioketone Y, which then undergoes keto-enol tautomerization to generate another intermediate product Z. Finally, an intramolecular addition of mercapto group in Z followed by elimination of halide ion led to the formation of the observed product 3a.

Scheme 2
Scheme 2

Experimental details

All materials were purchased from known commercial sources and used without further purification. Thin layer chromatography (TLC) analysis was performed with silica gel 60F254 aluminum sheets (Merck). Mixtures of hexanes and ethyl acetate in different ratios were used in TLC analysis. Melting points were determined in open capillaries and are uncorrected. Infrared (IR) spectra were recorded on FT-IR spectrometer in KBr pellets. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were collected at NMR Facility, IOE, University of Mysore.

One-pot synthesis of indalothiochromen-4-ones 3a-o

A solution of N,N-dimethylformamide (DMF, 10.5 mL, 3 Eq) in dichloromethane (20 mL) was treated dropwise at 0°C with a solution of phosphorus oxychloride (11 mL, 3 Eq) in dichloromethane (20 mL). The mixture was stirred for 15 min, then treated slowly with a solution of 2-oxindole (A, 5 g, 1 Eq) in chloroform (20 mL), and stirred under reflux for 5 h. After the addition of crushed ice and stirring for an additional 20 min, the separation of two layers was observed. The aqueous layer was adjusted to pH 7 with sodium acetate. The mixture was left at room temperature overnight, and then the resultant precipitate of product B was collected by filtration, washed with water, and dried [35].

Next, a mixture of compound B (2.5 g) and potassium hydroxide (1.25 g, 1.5 Eq) in dry DMF (10 mL) was stirred for 10 min before treatment with benzyl bromide (1.4 mL, 1.1 Eq). The mixture was stirred at room temperature until substrate B was completely consumed, as monitored by TLC analysis. The mixture was then poured into water and extracted with ethyl acetate. The organic extract was dried over sodium sulfate and concentrated. The residue of product 1awas crystallized from diethyl ether.

A solution of compound 1 (1.0 mmol, 1.0 Eq) in DMF (2 mL) was added at 0°C to a 60% suspension of NaH in mineral oil (2.5 mmol, 2.5 Eq), and the mixture was stirred for 15 min at room temperature. Then a solution of dithioester 2 (1.0 mmol, 1.0 Eq) in DMF (2 mL) was added over a period of 10 min at 0°C, and the mixture was stirred at room temperature for an additional 7 h. The progress of the reaction was monitored by TLC. The mixture was poured into water and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with brine (25 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the crude product was passed through a small plug of silica eluting with hexane/ethyl acetate (8:2) to afford indalothiochromen-4-ones 3a-o. Representative products are characterized as follows. Characterization of all compounds is given in Supplementary Information.

9-Benzyl-2-phenylthiopyrano[2,3-b]indol-4(9H)-one (3a)

Compound 3a was obtained by the reaction of 1a and 2a in 60% yield as a pale brown solid; mp 164–166°C; 1H NMR (CDCl3): δ 8.65 (d, J = 4.8 Hz, 1H), 7.60 (t, J = 3.6 Hz, 2H), 7.46–7.45 (m, 3H), 7.38–7.36 (m, 3H), 7.29–7.25 (m, 4H), 7.14 (d, J = 6.4 Hz, 2H), 5.43 (s, 2H); 13C NMR (CDCl3): δ 178.6, 143.9, 142.9, 137.9, 136.5, 134.6, 130.3, 129.0, 127.2, 127.0, 126.6, 124.7, 122.7, 122.4, 114.2, 108.9, 48.2; IR: 1597, 1481, 1474, 1419, 1334, 873, 750, 743, 717, 612 cm−1; MS (ESI): m/z = 368.1 (M +). Anal. Calcd for C24H17NOS: C, 78.45; H, 4.66; N, 3.81. Found: C, 78.43; H, 4.64; N, 3.79.

9-Benzyl-2-(3,4,5-trimethoxyphenyl)thiopyrano[2,3-b]indol-4(9H)-one (3e)

Compound 3e was obtained by the reaction of 1a and 2e in 76% yield as pale yellow solid; mp 169–171°C; 1H NMR (DMSO-d6): δ 8.43 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.42 (t, J = 7. 2 Hz, 1H), 7.44–7.23 (m, 7H), 7.02 (s, 2H), 5.73 (s, 2H), 3.89 (s, 6H), 3.73 (s, 3H); 13C NMR (DMSO-d6): δ 177.8, 153.8, 144.1, 142.7, 138.1, 136.0, 131.8, 129.3, 128.4, 127. 5, 126.2, 125.0, 124.4, 122.6, 121.8, 110.7, 105.1, 60.6, 56.6, 48.0; IR: 1599, 1505, 1479, 1420, 1332, 1249, 1126, 1008, 829, 758, 667 cm−1; MS (ESI): m/z = 458.7 (M +). Anal. Calcd for C24H16ClNOS: C, 70.88; H, 5.07; N, 3.06. Found: C, 70.85; H, 5.05; N, 3.05.

9-Benzyl-2-(4-fluorophenyl)thiopyrano[2,3-b]indol-4(9H)- one (3h)

Compound 3h was obtained by the reaction of 1a and 2h in 53% yield as creamy solid; mp 155–157°C; 1H NMR (CDCl3): δ 8.59 (d, J = 4.8 Hz, 1H), 7.61–7.57 (m, 2H), 7.42–7.25 (m, 7H), 7.20–7.13 (m, 4H), 5.47 (s, 2H); 13C NMR (CDCl3): δ 165.3, 162.8, 138.0, 134.3, 132.3, 129.2, 128.3, 126.1, 125.1, 124.3, 122.7, 116.4, 109.0, 48.4; IR: 1607, 1486, 1452, 1230, 1162, 1107, 1334, 833, 746, 559 cm−1; MS (ESI): m/z = 386.6 (M +). Anal. Calcd for C24H16ClNOS: C, 74.78; H, 4.18; N, 3.63. Found: C, 74.76; H, 4.16; N, 3.62.

2-(Benzo[b]thiophen-3-yl)-9-benzylthiopyrano[2,3-b]indol-4(9H)-one (3j)

Compound 3j was obtained by the reaction of 1a and 2j in 56% yield as amber solid; mp 145–149°C; 1H NMR (CDCl3): δ 8.47 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.85–7.75 (m, 4H), 7.42–7.31 (m, 5H), 7.25–7.18 (m, 2H), 7.12 (d, J = 7.6 Hz, 1H), 5.51 (s, 2H); 13C NMR (CDCl3): δ 182.1, 147.8, 141.1, 137.5, 135.9, 132.1, 129.3, 128.8, 128.6, 127.6, 126.6, 125.1, 124.6, 122.5, 122.2, 121.4, 119.8, 112.5, 110.9, 109.9, 60.7; IR: 1586, 1480, 1424, 1419, 1266, 1117, 755, 752, 733, 401 cm−1; MS (ESI): m/z = 423.8 (M +). Anal. Calcd for C26H17NOS2: C, 73.73; H, 4.05; N, 3.31. Found: C, 73.72; H, 4.03; N, 3.30.

6-Bromo-9-methyl-2-(p-tolyl)thiopyrano[2,3-b]indol-4(9H)- one (3n)

Compound 3n was obtained by the reaction of 1c and 2b in 52% yield as pale brown solid; mp 168–170 °C; 1H NMR (CDCl3): δ 8.73 (s, 2H), 8.59 (d, J = 6.8 Hz, 1H), 7.41 (dd, J = 6.6, 1.2 Hz, 2H), 7.34–7.29 (m, 2H), 6.94 (d, J = 8.8 Hz, 1H), 3.81 (s, 3H), 2.12 (s, 3H); 13C NMR (CDCl3): δ 176.8, 147.9, 138.0, 136.4, 134.8, 129.0, 128.8, 128.7, 126.3, 124.7, 123.5, 121.1, 113.8, 111.8, 110.2, 36.6, 21.3; IR: 1594, 1480, 1424, 1363,1234, 1194, 1052, 1016, 851, 810, 732, 705 cm−1; MS (ESI): m/z = 322.12 (M +). Anal. Calcd for C19H14BrNOS: C, 59.38; H, 3.67; N, 3.64. Found: C, 59.36; H, 3.66; N, 3.63.

Supplementary material

Experimental procedures for 1a-c and 2a-j and characterization of the remaining products 3 are available as supplementary material on the journal’s website.

Corresponding authors: Kanchugarakoppal S. Rangappa and Kempegowda Mantelingu, Department of Studies in Chemistry, Manasagangothri, University of Mysore, Mysore 570006, India, e-mail: (K.S. Rangappa); (K. Mantelingu)

Acknowledgments

The Ministry of Human Resource Development (MHRD) and the University Grant Commission (UGC), New Delhi, India, are acknowledged for recognizing the University of Mysore as the Institute of Excellence and for the financial assistance. We also thank NMR Facility, IOE, University of Mysore, Manasagangotri, Mysore, India, for spectral data.

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Supplemental Material

The online version of this article (DOI: 10.1515/hc-2014-0206) offers supplementary material, available to authorized users.

Received: 2015-1-9
Accepted: 2015-3-10
Published Online: 2015-6-2
Published in Print: 2015-6-1

©2015 by De Gruyter

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Synthesis of quinazolines and quinazolinones via palladium-mediated approach
  4. Media with photoinduced irreversible fluorescence
  5. Synthesis of quinolines and acridines by the reaction of 2-(perfluoroalkyl)anilines with lithium and Grignard reagents
  6. Preliminary Communications
  7. Synthesis of tricyclic indolizidines from ethyl isocyanoacetate
  8. Ligand- and catalyst-free intramolecular C-S bond formation: direct access to indalothiochromen- 4-ones
  9. Research Articles
  10. Preparation of optically active 4-substituted γ-lactones by lipase-catalyzed optical resolution
  11. One-pot synthesis of 4-alkyl-2-amino-4H-chromene derivatives
  12. Ring transformation and antimicrobial activity of indolyl-substituted 2(3H)-furanones
https://doi.org/10.1515/hc-2014-0206
Keywords for this article
dithioesters; indalothiochromen-4-ones; S-arylation; Vilsmeier-Haack reaction
Creative Commons
BY-NC-ND 3.0

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Synthesis of quinazolines and quinazolinones via palladium-mediated approach
  4. Media with photoinduced irreversible fluorescence
  5. Synthesis of quinolines and acridines by the reaction of 2-(perfluoroalkyl)anilines with lithium and Grignard reagents
  6. Preliminary Communications
  7. Synthesis of tricyclic indolizidines from ethyl isocyanoacetate
  8. Ligand- and catalyst-free intramolecular C-S bond formation: direct access to indalothiochromen- 4-ones
  9. Research Articles
  10. Preparation of optically active 4-substituted γ-lactones by lipase-catalyzed optical resolution
  11. One-pot synthesis of 4-alkyl-2-amino-4H-chromene derivatives
  12. Ring transformation and antimicrobial activity of indolyl-substituted 2(3H)-furanones
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