Table of Contents
Organic Chemistry International
Volume 2011, Article ID 980765, 7 pages
http://dx.doi.org/10.1155/2011/980765
Research Article

Copper(I)-BINOL Catalyzed Domino Synthesis of 1,4-Benzoxathiines through -O Bond Formation

Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India

Received 1 March 2011; Revised 29 April 2011; Accepted 13 June 2011

Academic Editor: Ashraf Aly Shehata

Copyright © 2011 Chiranjeevi Korupalli et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

1,4-benzoxathiine moieties can be synthesized by domino 2 ring opening of epoxide with o-halothiophenols followed by the copper(I)-BINOL catalyzed Ullmann-type coupling cyclization (intramolecular -O bond formation) with moderate to good yields.

1. Introduction

Sulfur-containing heterocycles are found in numerous natural products and biologically active pharmaceutical products [14]. Particularly the compounds containing 1,4-benzoxathiine motifs have attracted considerable interest during the past few years due to their interesting biological activities [58]. Framework of 1,4-benzoxathiine is present in a variety of biologically active compounds such as (3-hydroxy-4-methoxyphenyl)-1,4-benzoxathiine 1, a sweetening agent [9]; (dihydrobenzoxathiinyloxy)acetic acids 2, potential antihypertensive agents with diuretic properties [10]; syn-2,3-bis-aryl-substituted dihydrobenzoxathiine 3, an estrogenic agent [11]; hydroxy substituted 4-thiaflavan 4, an antioxidant agent [12] (Figure 1). 1,4-Benzoxathiine motifs are also used as radical scavengers [13]; metal chelators [14]; and hydroperoxide quenchers [15].

fig1
Figure 1: Some of the 1,4-benzoxathiine motif containing biologically important molecules.

Conventionally, 1,4-benzoxathiine motifs are synthesized by the treatment of 2-mercaptophenol with 1,2-dibromoethane in presence of sodiumethoxide [16]. 1,4-benzoxathiine moieties are also synthesized by multistep reaction [9, 10]. Nair et al., described the synthesis of 1,4-benzoxathiine moiety by the cycloaddition reaction of 4-isopropyl-2-thio-1,2-benzoquinone which is generated in situ from N-(2-hydroxy-5-isopropylphenylsulfanyl)-phthalimide with the reaction of alloocimene in the presence of pyridine in dry chloroform [17].

However, these literature protocols have several limitations such as multi-step process, less availability of starting materials, harsh reaction conditions, usage of strong bases, polar and high boiling solvents such as DMF and low yields. Therefore, there is a need to develop an efficient protocol for the synthesis of 1,4-benzoxathiines. For the first time we have developed a simple, mild, and efficient copper-catalyzed domino process to prepare 1,4-benzoxathiine skeleton from readily available starting materials (Scheme 1).

980765.sch.001
Scheme 1

As part of our continuous effort towards copper-catalyzed -heteroatom bond formation and its application in important heterocycles synthesis [1824], herein, for the first time, we report a new domino synthesis of the 1,4-benzoxathiine skeleton from easily available epoxides and o-halothiophenols using epoxide ring opening followed by intramolecular Ullmann type coupling cyclization. The reaction is very effective and high yielding process using the economically cheap ligand BINOL.

2. Results and Discussion

At the outset, the domino reaction for the synthesis of (±)-trans-1,2,3,4,4a,10a-hexahydro phenoxathiine 7 was carried out from cyclohexeneoxide 5 with o-bromothiophenol 6 by a base-mediated domino epoxide ring opening reaction followed by Ullmann coupling cyclization in the presence of 20 mole % of CuI and BINAM (1,1′-binaphthyl-2,2′-diamine) L1 in acetonitrile solvent at 120°C in sealed tube. The reaction provided 12% yield of pure product 7 in 80 h (Table 1, entry 1). To increase the efficiency of the reaction we screened different oxygen- and nitrogen-based ligands L1L8 (Figure 2) and the results are summarized in Table 1. Among them BINOL (1-(2-hydroxynaphthalen-1-yl)naphthalen-2-ol) L5 turned out to be the best ligand for the synthesis of 1,4-phenoxathiine 7 with 62% isolated yield (entry 5). It is important to mention that in the absence of ligand, the reaction did not offer even trace amount of coupling product 7 which indicates that ligand is mandatory for this reaction.

tab1
Table 1: Ligand screening for Cu-catalyzed domino reaction for the synthesis of 1,4-benzoxathiine moietya.
980765.fig.002
Figure 2: Ligands screened for the Cu-catalyzed domino reaction.

The reaction was optimized further with different copper salts, solvents, bases, and different ratios of Cu salt-L5 and results are summarized in Table 2. Although several Cu salts catalyzed the reaction, CuI turned out to be the best Cu salt of choice in view of yield (entry 1 versus entries 2–7). Acetonitrile is the best choice of solvent among the solvents examined (entry 1 versus entries 8–11); Cs2CO3 is the best choice of the base (entry 1 versus entries 12, 13). It was also found that decreasing CuI-L5 catalyst loading from 20 mol% each of CuI and L5 to 10 mol% each of CuI and L5 reduced the yield drastically (entry 14) and other Cu : L5 ratios also reduced the yields of the cyclized product 7 (entry 15). In the absence of CuI or L5 or both, the reaction did not afford even trace amount of coupling product (entries 16–18). It is important to mention that both Cu salt and ligand are mandatory for coupling reaction. In the absence of base, the reaction did not proceed (entry 19). On lowering the temperature from 120°C to 82°C we did not observe any coupling product.

tab2
Table 2: Cu salt, solvent, base screening for domino synthesis of 1,4-benzoxathiine moietya.

Using the above-mentioned optimized reaction conditions we initiated our investigation into the scope of the CuI-L5 complex catalyzed domino epoxide opening and Ullmann coupling cyclization for the synthesis of 1,4-benzoxathiine skeleton from various epoxides and o-halo thiophenols and the results are summarized in Tables 3 and 4. Both o-bromo and o-iodo thiophenols reacted with various epoxides and provided corresponding products with more or less the same yields. In all the cases the products were observed along with respective ring opening product.

tab3
Table 3: Scope of the domino reaction with various epoxides and o-bromothiophenol for the synthesis of 1,4-benzoxathiine moietiesa.
tab4
Table 4: Scope of the domino reaction with various epoxides and o-iodothiophenol for the synthesis of 1,4-benzoxathiine moietiesa.

The possible mechanism for the formation of the 1,4-benzoxathiine moiety by domino epoxide opening followed by Ullmann coupling cyclization is shown in Figure 3. First o-bromothiophenol 5 is deprotonated by base to give thiophenolate ion 15 which then opens epoxide in fashion to give opened product 16. The coordination of oxygen of 16 with CuI to give complex 17 followed by oxidative addition gives compound 18. Which then undergoes reductive elimination to give the product (±)-trans-1,2,3,4,4a,10a-hexahydro phenoxathiine 7, then the copper catalyst is regenerated which enters into the catalytic cycle.

980765.fig.003
Figure 3: Possible mechanism for the domino synthesis of 1,4-benzoxathiine moiety.

In conclusion, for the first time we have demonstrated a novel and efficient protocol for the synthesis of very important 1,4-benzoxathiine motifs by a domino epoxide opening reaction followed by Ullmann coupling cyclization using easily available CuI-BINOL complex as catalyst. A variety of 1,4-benzoxathiine motifs have been synthesized from corresponding epoxides and o-halo thiophenols in moderate to good yields under relatively mild conditions.

3. Experimental Section

All reactions were carried out in sealed tubes under nitrogen atmosphere. All reagents are commercially available and used without further purification. 2-bromothiophenol, epoxides, CuI, and Cs2CO3 were purchased from Sigma-Aldrich Company. 2-iodothiophenol was prepared by literature procedure [25]. Ligands L2, L3, and L6 were prepared using literature procedure [2631]. Acetonitrile was dried over calcium hydride, freshly distilled, and used for reactions. Reaction temperatures were controlled by Varivolt temperature modulator, thin-layer chromatography (TLC) was performed using Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching. Silica gel (particle size 100–200 mesh) purchased from SRL India was used for chromatography. 1H and 13C NMR spectra were recorded on a Bruker 400 MHz instrument. 1H NMR spectra were reported relative to Me4Si (δ 0.0 ppm) or residual CHCl3 (δ 7.26 ppm). 13C NMR were reported relative to CDCl3 (δ 77.16 ppm). FTIR spectra were recorded on a Nicolet 6700 spectrometer and are reported in frequency of absorption (cm−1). High-resolution mass spectra (HRMS) were recorded on Q-Tof Micro mass spectrometer. GC-MS were recorded on JEOL GCMATE II mass spectrometer.

3.1. Typical Experimental Procedure

2-bromothiophenol (94.5 mg, 0.50 mmol), cyclohexeneoxide (49.1 mg, 0.5 mmol), BINOL L5 (28.6 mg, 0.1 mmol), CuI (19.2 mg, 0.1 mmol), and Cs2CO3 (325.8 mg, 1.0 mmol) were taken in a sealed tube and equipped with screw cap. The sealed tube was evacuated and backfilled with nitrogen. Acetonitrile (2 mL) was added to the reaction mixture at room temperature and the mixture was heated at 120°C. After 80 h (progress of the reaction was followed by TLC), the mixture was allowed to cool to room temperature and the solvent was removed by rotary evaporation. The crude residue was directly purified by column chromatography on silica gel (ethyl acetate/hexanes as eluents) to afford 63.8 mg (62%) of (±)-trans-1,2,3,4,4a,10a-hexahydrophenoxathiine (7) as a white solid. The trans geometry was confirmed by NOE experiment.

(±)-1,2,3,4,4a,10a-Hexahydrophenoxathiine (7) (see Figure 4)
White solid; mp 64-65°C; 0.43 (hexanes); FTIR (neat) 744, 1231, 1283, 2862, 2936, 3064 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.35–1.49 (m, 4H), 1.67–1.90 (m, 2H), 1.95–2.07 (m, 1H), 2.13–2.25 (m, 1H), 2.97–3.08 (m, 1H), 3.65–3.76 (m, 1H), 6.73–6.80 (m, 2H), 6.87–6.97 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 24.7 (C4), 25.4 (C3), 31.1 (C2), 32.4 (C5), 41.9 (C1), 78.2 (C6), 118.1 (C8), 119.1 (C12), 121.5 (C10), 125.4 (C9), 126.9 (C11), 151.7 (C7); HRMS [M + H+] Calcd for C12H15OS: 207.0844; found: 207.0848.

980765.fig.004
Figure 4

(±)-2,3,3a,9a-Tetrahydro-1H-benzo[b]cyclopenta[e][1,4]ox-athiine (9) (see Figure 5)
White solid; mp 62°C; 0.37 (hexanes); FTIR (neat) 742, 1217, 1278, 2878, 2962, 3061 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.54–2.05 (m, 4H), 2.18–2.43 (m, 2H), 3.04–3.21 (m, 1H), 3.95–4.11 (m, 1H), 6.83–6.94 (m, 2H), 7.01 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 19.2 (C3), 28.0 (C2), 28.9 (C4), 41.0 (C1), 81.9 (C5), 118.3 (C11), 118.8 (C7), 121.7 (C9), 125.7 (C8), 128.0 (C10), 152.5 (C6); GC-MS EI+: m/z = 192.

980765.fig.005
Figure 5

(±)-5a,6,7,8,9,10,11,11a-Octahydrobenzo[b]cycloocta[e][1,4]oxathiine (11) (see Figure 6)
White solid; mp 57°C; 0.42 (hexanes); FTIR (neat) 746, 1233, 1295, 2859, 2920, 3050 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.42–2.34 (m, 12H), 3.39–3.46 (m, 1H), 4.03–4.11 (m, 1H), 6.80–6.87 (m, 2H), 6.94–7.00 (m, 1H), 7.02–7.08 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 23.9 (C6), 25.6 (C3), 25.9 (C4), 26.4 (C5), 29.0 (C2), 31.9 (C7), 42.5 (C1), 80.5 (C8), 118.1 (C10), 120.2 (C14), 121.3 (C12), 125.3 (C11), 126.7 (C13), 152.4 (C9); HRMS [M+H+] Calcd for C14H19OS: 235.1157; found: 235.1160.

980765.fig.006
Figure 6

(±)-2-Phenyl-2,3-dihydrobenzo[b][1,4]oxathiine (13) (see [9], Figure 7)
Semisolid; 0.32 (hexanes); FTIR (neat) 695, 744, 1233, 2924, 3058 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.02 (dd, J = 13.2 Hz, 1.6 Hz, 1H), 3.17 (dd, J = 13.2 Hz, 9.6 Hz, 1H), 5.12 (dd, J = 9.6 Hz, 2 Hz, 1H), 6.79–6.89 (m, 2H), 6.93–6.99 (m, 1H), 7.05 (dd, J = 7.8 Hz, 1.6 Hz, 1H), 7.27–7.38 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 32.1 (C1), 76.7 (C2), 117.4 (C12), 118.9 (C8), 121.8 (C10), 125.8 (C9), 126.2 , 127.4 (C11), 128.6 (C6), 128.9 , 140.4 (C3), 152.5 (C7); GC-MS EI+: m/z = 230.

980765.fig.007
Figure 7

Acknowledgments

The authors thank DST (project no. SR/S1/OC-06/2008), New Delhi for the financial support. C. Korupalli and A. Dandapat thank CSIR, New Delhi for junior research fellowship and D. J. C. Prasad thanks UGC, New Delhi, for senior research fellowship. The authors thank DST, New Delhi, for the funding for the 400 MHz NMR instrument to the Department of Chemistry, IIT-Madras under the IRPHA scheme, and ESI-MS facility under the FIST programme.

References

  1. D. N. Jones, Comprehensive Organic Chemistry, vol. 3, D. H. Barton, and D. W. Ollis, Eds., Pergamon Press, New York, NY, USA, 1979.
  2. C. M. Rayner, “Synthesis of thiols, selenols, sulfides, selenides, sulfoxides, selenoxides, sulfones and selenones,” Contemporary Organic Synthesis, vol. 3, pp. 499–533, 1996. View at Google Scholar
  3. T. Kondo and T. A. Mitsudo, “Metal-catalyzed carbon-sulfur bond formation,” Chemical Reviews, vol. 100, no. 8, pp. 3205–3220, 2000. View at Publisher · View at Google Scholar · View at Scopus
  4. S. V. Ley and A. W. Thomas, “Modern synthetic methods for copper-mediated C(aryl)-O, C(aryl)-N, and C(aryl)-S bond formation,” Angewandte Chemie. International Edition, vol. 42, no. 44, pp. 5400–5449, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  5. L. Merlini, A. Zanarott, A. Pelter, M. P. Rochefort, and R. Hänsel, “Biomimetic synthesis of natural silybin,” Journal of the Chemical Society, Chemical Communications, no. 16, p. 695, 1979. View at Publisher · View at Google Scholar · View at Scopus
  6. P. Bosseray, G. Guillaumet, G. Coudert, and H. Wassermann, “Synthesis of polyether carboxylic acids with a benzodioxinic subunit,” Tetrahedron Letters, vol. 30, no. 11, pp. 1387–1390, 1989. View at Google Scholar · View at Scopus
  7. S. Tsukamoto, H. Kato, H. Hirota, and N. Fusetani, “3,4-dihydroxystyrene dimers, inducers of larval metamorphosis in ascidians, from a marine sponge Jaspis sp,” Tetrahedron, vol. 50, no. 48, pp. 13583–13592, 1994. View at Publisher · View at Google Scholar · View at Scopus
  8. B. Achari, S. B. Mandal, P. K. Dutta, and C. Chowdhury, “Perspectives on 1,4-benzodioxins, 1,4-benzoxazines and their 2,3-dihydro derivatives,” Synlett, no. 14, pp. 2449–2467, 2004. View at Publisher · View at Google Scholar · View at Scopus
  9. A. Arnoldi, A. Bassoli, R. Caputo, L. Merlini, G. Palumbo, and S. Pedatella, “Synthesis of 3-aryl-1,4-benzoxathianes: application to the preparation of a sweet compound,” Journal of the Chemical Society, Perkin Transactions 1, vol. 9, pp. 1241–1244, 1994. View at Google Scholar · View at Scopus
  10. J. J. Tegeler, H. H. Ong, and J. A. Profitt, “Synthesis of (dihydrobenzoxathiinyloxy)acetic acids,” Journal of Heterocyclic Chemistry, vol. 20, no. 4, pp. 867–870, 1983. View at Google Scholar · View at Scopus
  11. P. Buzzini, S. Menichetti, C. Pagliuca, C. Viglianisi, E. Branda, and B. Turchetti, “Antimycotic activity of 4-thioisosteres of flavonoids towards yeast and yeast-like microorganisms,” Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 13, pp. 3731–3733, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  12. G. Capozzi, P. Lo Nostro, S. Menichetti, C. Nativi, and P. Sarri, “Easy synthesis of polyphenolic 4-thiaflavans with a double-faced antioxidant activity,” Chemical Communications, no. 6, pp. 551–552, 2001. View at Google Scholar · View at Scopus
  13. R. Amorati, M. G. Fumo, G. F. Pedulli, S. Menichetti, C. Pagliuca, and C. Viglianisi, “Antioxidant and antiradical activity of hydroxy-substituted 4-thiaflavanes,” Helvetica Chimica Acta, vol. 89, no. 10, pp. 2462–2472, 2006. View at Publisher · View at Google Scholar · View at Scopus
  14. M. Lodovici, S. Menichetti, C. Viglianisi, S. Caldini, and E. Giuliani, “Polyhydroxylated 4-thiaflavans as multipotent antioxidants: protective effect on oxidative DNA damage in vitro,” Bioorganic and Medicinal Chemistry Letters, vol. 16, no. 7, pp. 1957–1960, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  15. R. Amorati, F. Catarzi, S. Menichetti, G. F. Pedulli, and C. Viglianisi, “Effect of ortho-SR groups on O-H bond strength and H-atom donating ability of phenols: a possible role for the tyr-cys link in galactose oxidase active site?” Journal of the American Chemical Society, vol. 130, no. 1, pp. 237–244, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. W. E. Parham and J. D. Jones, “Heterocyclic vinyl ethers. IV. Benzo-1,4-oxathiadiene and benzo-1,4-dithiadiene,” Journal of the American Chemical Society, vol. 76, no. 4, pp. 1068–1074, 1954. View at Google Scholar · View at Scopus
  17. V. Nair, B. Mathew, S. Thomas, M. Vairamani, and S. Prabhakar, “Novel cycloadditions of ortho-thioquinones with acyclic dienes: expeditious synthesis of 1,4-benzooxathiines,” Journal of the Chemical Society. Perkin Transactions 1, no. 22, pp. 3020–3024, 2001. View at Google Scholar · View at Scopus
  18. A. B. Naidu, E. A. Jaseer, and G. Sekar, “General, mild, and intermolecular Ullmann-type synthesis of diaryl and alkyl aryl ethers catalyzed by diol-copper(I) complex,” Journal of Organic Chemistry, vol. 74, no. 10, pp. 3675–3679, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  19. R. K. Rao, A. B. Naidu, and G. Sekar, “Highly efficient copper-catalyzed domino ring opening and goldberg coupling cyclization for the synthesis of 3,4-dihydro-2H-1,4-benzoxazines,” Organic Letters, vol. 11, no. 9, pp. 1923–1926, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  20. D. J. C. Prasad and G. Sekar, “An efficient copper-catalyzed synthesis of hexahydro-1H- phenothiazines,” Organic and Biomolecular Chemistry, vol. 7, no. 24, pp. 5091–5097, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. D. J. C. Prasad, A. B. Naidu, and G. Sekar, “An efficient intermolecular C(aryl)-S bond forming reaction catalyzed by BINAM-copper(II) complex,” Tetrahedron Letters, vol. 50, no. 13, pp. 1411–1415, 2009. View at Publisher · View at Google Scholar · View at Scopus
  22. D. J. C. Prasad and G. Sekar, “An efficient, mild and intermolecular ullmann-type synthesis of thioethers catalyzed by a diol-copper(I) complex,” Synthesis, no. 1, pp. 79–84, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. K. G. Thakur, E. A. Jaseer, A. B. Naidu, and G. Sekar, “An efficient copper(I) complex catalyzed Sonogashira type cross-coupling of aryl halides with terminal alkynes,” Tetrahedron Letters, vol. 50, no. 24, pp. 2865–2869, 2009. View at Publisher · View at Google Scholar · View at Scopus
  24. E. A. Jaseer, D. J. C. Prasad, A. Dandapat, and G. Sekar, “An efficient copper(II)-catalyzed synthesis of benzothiazoles through intramolecular coupling-cyclization of N-(2-chlorophenyl)benzothioamides,” Tetrahedron Letters, vol. 51, no. 38, pp. 5009–5012, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. W. J. Xiao and H. Alper, “Regioselective carbonylative heteroannulation of o-iodothiophenols with allenes and carbon monoxide catalyzed by a palladium complex: a novel and efficient access to thiochroman-4-one derivatives,” Journal of Organic Chemistry, vol. 64, no. 26, pp. 9646–9652, 1999. View at Publisher · View at Google Scholar · View at Scopus
  26. W. E. Bachmann and L. B. Scott, “The reaction of anthracene with maleic and fumaric acid and their derivatives and with citraconic anhydride and mesaconic acid,” Journal of the American Chemical Society, vol. 70, no. 4, pp. 1458–1461, 1948. View at Google Scholar · View at Scopus
  27. L. Thunberg and S. Allenmark, “Evaluation of a chiral stationary phase derived from a simple Diels-Alder reaction,” Chirality, vol. 15, no. 5, pp. 400–408, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. M. J. Brienne and J. Jacques, “Mixtures of optical antipodes. VI. 9,10-dihydro-9,10-ethanoanthracene derivatives,” Bulletin de la Société Chimique de France, pp. 190–197, 1973. View at Google Scholar
  29. L. Thunberg and S. Allenmark, “Asymmetric cycloaddition routes to both enantiomers of trans-9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboxylic acid,” Tetrahedron Asymmetry, vol. 14, no. 10, pp. 1317–1322, 2003. View at Publisher · View at Google Scholar · View at Scopus
  30. M. Shi, W. L. Duan, and G. B. Rong, “Axially dissymmetric N-thioacylated (S)-(-)-1,1′-binaphthyl-2, 2′-diamine ligands for copper-catalyzed asymmetric Michael addition of diethylzinc to α,β-unsaturated ketone,” Chirality, vol. 16, no. 9, pp. 642–651, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  31. I. Aillaud, K. Wright, J. Collin, E. Schulz, and J. P. Mazaleyrat, “New axially chiral atropos and tropos secondary diamines as ligands for enantioselective intramolecular hydroamination,” Tetrahedron Asymmetry, vol. 19, no. 1, pp. 82–92, 2008. View at Publisher · View at Google Scholar · View at Scopus