Three-Step Synthesis of (Thio)xanthene and Dibenzothiepine/Dibenzoxepine by an Intramolecular Mizoroki-Heck Reaction of Diaryl (Thio)Ethers

Abstract

We present a novel three-step protocol for preparing xanthene/thioxanthene and dibenzothiepine/dibenzoxepine from readily available starting materials. The Mizoroki-Heck cyclization as the final step was optimized to afford full conversion of the corresponding diaryl (thio)ethers and furthermore to achieve reasonably good selectivity between the 6-exo and the 7-endo products.

fused-ring systems - Heck reaction - heterocycles - palladium - sulfur

References and Notes

1 Bøgesø KP. Bang-Andersen B. In Textbook of Drug Design and Discovery   4th ed.:  Krogsgaard-Larsen P. Strømgaard K. Madsen U. CRC Press; Boca Raton: 2010.  p.299 

2a Acton D. Hill G. Tait BS. J. Med. Chem.  1983,  26:  1131 

2b Vyas NS. Patel NH. Nijran KS. Al-Nahhas A. Puri BK. Expert Rev. Neurother.  2011,  11:  37 

3a Dahl T. Tornøe CW. Bang-Andersen B. Nielsen P. Jørgensen M. Angew. Chem. Int. Ed.  2008,  47:  1726 

3b Jepsen TH. Larsen M. Jørgensen M. Solanko KA. Bond AD. Kadziola A. Nielsen MB. Eur. J. Org. Chem.  2011,  53 

3c Jepsen TH. Larsen M. Jørgensen M. Nielsen MB. Tetrahedron Lett.  2011,  52:  4045 

4a Loudon JD. Sloan ADB. Summers LA. J. Chem. Soc.  1957,  3814 

4b Anet FAL. Bavin PMG. Can. J. Chem.  1956,  34:  991 

4c Anet FAL. Bavin PMG. Can. J. Chem.  1957,  35:  1084 

4d Bergmann ED. Rabinovitz M. J. Org. Chem.  1960,  25:  828 

4e Fouche J. Bull. Soc. Chim. Fr.  1970,  13 

4f Jilek JO. Sindelar K. Pomykace J. Horesovs O. Pelz K. Svatek E. Kakac B. Holubek J. Metysova J. Protiva M. Collect. Czech. Chem. Commun.  1973,  38:  115 

4g Sindelar K. Holubek J. Ryska M. Svatek E. Urban J. Grimova J. Cervena I. Hrubantova M. Protiva M. Collect. Czech. Chem. Commun.  1983,  48:  1187 

4h Jilek J. Pomykacek J. Holubek J. Svatek E. Ryska M. Protiva M. Collect. Czech. Chem. Commun.  1984,  49:  603 

4i Okabayashi I. Fujiwara H. J. Heterocycl. Chem.  1984,  21:  1401 

4j Kluba M. Harwood J. Casey PK. Ternay AL. J. Heterocycl. Chem.  1985,  22:  1261 

4k Huisgen R. Li X. Mloston G. Fulka C. Eur. J. Org. Chem.  2000,  1695 

4l Fujii T. Hao W. Yoshimura T. Heteroat. Chem.  2004,  15:  246 

4m Amriou S. Perepichka IF. Batsanov AS. Bryce MR. Rovira C. Vidal-Gancedo J. Chem. Eur. J.  2006,  12:  5481 

4n Shirani H. Janosik T. J. Org. Chem.  2007,  72:  8984 

4o Saito M. Yamamoto T. Osaka I. Miyazaki E. Takimiya K. Kuwabara H. Ikeda M. Tetrahedron Lett.  2010,  51:  5277 

5 Tsvelikhovsky D. Buchwald SL. J. Am. Chem. Soc.  2010,  132:  14048 

6a Mizoroki T. Mori K. Ozaki A. Bull. Chem. Soc. Jpn.  1971,  44:  581 

6b Heck RF. Nolley JP. J. Org. Chem.  1972,  37:  2320 

6c Beletskaya IP. Cheprakov AV. Chem. Rev.  2000,  100:  3009 

6d Dounay AB. Overman LE. Chem. Rev.  2003,  103:  2945 

6e Bräse S. de Meijere A. In Metal-Catalyzed Cross-Coupling Reactions   2nd ed.:  de Meijere A. Diederich F. Wiley-VCH; Weinheim: 2004.  p.217-316  

7a Coghlan MJ, Jadhav PK, Droste JJ, Green JE, and Matthews DP. inventors; Int. Patent,  WO2005066153A1. 

7b Cong Z. Miki T. Urakawa O. Nishino H. J. Org. Chem.  2009,  74:  3978 

8 Okuma K. Nojima A. Nahoko M. Shioji K. Org. Lett.  2009,  11:  169 

9

Synthesis of 2-(2-Bromophenylsulfanyl)benzaldehyde (5a): 2-Fluorobenzaldehyde (3; 2.0 g, 16 mmol), 2-bromo-thiophenol (4a; 3.0 g, 16 mmol) and anhyd K₂CO₃ (3.29 g, 23.8 mmol) were dissolved in MeCN (10 mL) and stirred at 100 ˚C for 30 min under MW conditions. The crude reaction mixture was evaporated onto Celite and purified using column chromatography on silica gel (eluent: heptane → 30% EtOAc in heptane). The title compound was obtained as a colorless solid (3.97 g, 84%); R _f 0.61 (EtOAc-heptane, 1:2); mp 49-50 ˚C. ^¹H NMR (600 MHz, CDCl₃): δ = 10.39 (s, 1 H), 7.95 (dd, J = 7.6, 1.7 Hz, 1 H), 7.66 (dd, J = 7.9, 1.3 Hz, 1 H), 7.48-7.51 (m, 1 H), 7.43 (m, 1 H), 7.24-7.28 (m, 1 H), 7.14-7.21 (m, 3 H). ^¹³C NMR (151 MHz, CDCl₃): δ = 191.8, 138.8, 135.7, 134.6, 134.4, 133.6, 133.3, 131.8, 131.6, 129.3, 128.4, 127.5, 126.4. GC-MS: m/z = 392 [M⁺]. Anal. Calcd for C₁₃H₉BrOS: C, 53.26; H, 3.09. Found: C, 53.22; H, 3.05.
Synthesis of 2-(2-Bromophenoxy)benzaldehyde (5b):
2-Fluorobenzaldehyde (3; 2.0 g, 16 mmol), 2-bromophenol (4b; 2.8 g, 16 mmol), and anhyd K₂CO₃ (3.29 g, 23.8 mmol) were dissolved in anhyd DMF (20 mL) and the mixture was refluxed for 2 h. The mixture was then diluted with EtOAc (30 mL) and brine (100 mL); the layers were separated and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with 2 M aq NaOH (2 × 20 mL) and H₂O (20 mL), dried with MgSO₄, filtered, concentrated in vacuo onto Celite, and purified using column chromatography on silica gel (eluent: heptane → 30% EtOAc in heptane). Compound 5b was obtained as a pale-yellow solid (3.19 g, 71%); R _f 0.60 (EtOAc-heptane, 1:2); mp 62-63 ˚C. ^¹H NMR (600 MHz, CDCl₃): δ = 10.60 (s, 1 H), 7.96 (dd, J = 7.8, 1.6 Hz, 1 H), 7.66-7.70 (m, 1 H), 7.50 (m, 1 H), 7.32-7.37 (m, 1 H), 7.19 (td, J = 7.7, 0.8 Hz, 1 H), 7.10 (m, 2 H), 6.74 (d, J = 8.4 Hz, 1 H). ^¹³C NMR (151 MHz, CDCl₃): δ = 189.2, 159.4, 152.5, 135.7, 134.2, 129.0, 128.6, 126.3, 126.1, 123.3, 121.7, 116.9, 115.5. GC-MS: m/z = 276 [M⁺]. Anal. Calcd for C₁₃H₉BrO₂: C, 56.34; H, 3.27. Found: C, 56.39; H, 3.25.
Synthesis of 2-Bromophenyl-2-vinylphenylsulfane (6a): Methyltriphenylphosphonium iodide (3.31 g, 8.19 mmol) was dissolved in anhyd THF (50 mL) and the solution was cooled to 0 ˚C under an argon atmosphere. t-BuOK (1.15 g, 10.2 mmol) was added by which the solution turned yellow and after stirring for 10 min, compound 5a (2.00 g, 6.82 mmol) was added and the mixture was allowed to reach r.t. and stirred for 1.5 h. The crude mixture was concentrated in vacuo directly onto Celite and purified using column chromatography on silica gel (eluent: heptane → 30% EtOAc in heptane). Compound 6a was obtained as a yellow solid (1.98 g, 100%); R _f 0.77 (EtOAc-heptane, 1:2); mp 58-59 ˚C. ^¹H NMR (600 MHz, CDCl₃): δ = 7.69 (dd, J = 7.9, 1.2 Hz, 1 H), 7.53 (dd, J = 7.9, 1.3 Hz, 1 H), 7.48 (dd, J = 7.7, 1.3 Hz, 1 H), 7.42 (m, 1 H), 7.29 (td, J = 7.6, 1.4 Hz, 1 H), 7.18 (dd, J = 17.4, 11.0 Hz, 1 H), 7.07-7.10 (m, 1 H), 6.97 (td, J = 7.6, 1.5 Hz, 1 H), 6.63 (dd, J = 8.0, 1.5 Hz, 1 H), 5.73 (dd, J = 17.4, 0.9 Hz, 1 H), 5.29 (dd, J = 11.0, 0.9 Hz, 1 H). ^¹³C NMR (151 MHz, CDCl₃): δ = 141.3, 138.9, 136.0, 134.4, 132.8, 130.3, 129.7, 128.9, 128.2, 127.7, 126.5, 126.4, 121.6, 116.7. GC-MS: m/z = 290 [M⁺]. Anal. Calcd for C₁₄H₁₁BrS: C, 57.74; H, 3.81. Found: C, 53.72; H, 3.85.
Synthesis of 1-Bromo-2-(2-vinylphenoxy)benzene (6b): Methyltriphenylphosphonium iodide (5.51 g, 13.6 mmol) was dissolved in anhyd THF (50 mL) and the solution was cooled to 0 ˚C under an argon atmosphere. t-BuOK (1.64 g, 14.6 mmol) was added by which the solution turned yellow and after stirring for 10 min, compound 5b (2.7 g, 9.7 mmol) was added and the mixture was allowed to reach r.t. and subsequently stirred for 1 h. The crude mixture was concentrated in vacuo directly onto Celite and purified using column chromatography on silica gel (eluent: heptane → 30% EtOAc in heptane). Compound 6b was obtained as a pale-yellow oil (2.49 g, 93%); R _f 0.76 (EtOAc-heptane, 1:2). ^¹H NMR (600 MHz, CDCl₃): δ = 7.62 (m, 2 H), 7.18-7.23 (m, 2 H), 7.14 (t, J = 7.4 Hz, 1 H), 6.93-7.04 (m, 2 H), 6.82 (dd, J = 8.1, 0.8 Hz, 1 H), 6.76 (dd, J = 8.2, 1.4 Hz, 1 H), 5.81 (dd, J = 17.7, 1.1 Hz, 1 H), 5.30 (dd, J = 11.1, 1.1 Hz, 1 H). ^¹³C NMR (151 MHz, CDCl₃): δ = 154.2, 153.2, 133.7, 130.7, 129.3, 129.0, 128.6, 126.8, 124.3, 124.3, 119.2, 118.9, 115.7, 113.7. GC-MS: m/z = 274 [M⁺]. Anal. Calcd for C₁₄H₁₁BrO: C, 61.11; H, 4.03. Found: C, 61.20; H, 4.02.
Synthesis of Thioxanthene (1a) and Dibenzothiepine (2a; Entry 1, Table 1): A microwave vial was purged with anhyd dioxane (2.0 mL) and then compound 6a (0.29 g, 1.0 mmol), DavePhos (29.5 mg, 0.075 mmol), Pd₂(dba)₃ (22.9 mg, 0.0250 mmol), and t-BuONa (144 mg, 1.50 mmol) were added to this vial under a flow of argon and finally the tube was capped. The mixture was heated for 30 min at 180 ˚C under MW conditions for full conversion of starting material. Judged from LC-MS and GC-MS, the reaction mixture contained a 30:70 ratio of 1a/2a and it was concentrated in vacuo directly onto Celite and purified using column chromatography on silica gel (eluent: heptane → 30% EtOAc in heptane). Compounds 1a (59 mg, 28%) and 2a (124 mg, 59%) were obtained as colorless oils and the characterization data were in accordance with the literature data.^4i,m
Synthesis of Xanthene (1b)/Xanthone (7) and Dibenzoxepine (2b; Entry 1, Table 2): The procedure described above for preparing compounds 1a and 2a was followed using anhyd toluene (2.0 mL), compound 6b (0.150 g, 0.545 mmol), DavePhos (12.9 mg, 0.0327 mmol), Pd_{2 (}dba)₃ (9.98 mg, 0.0109 mmol), and t-BuONa (78.6 mg, 0.818 mmol). The mixture was heated for 30 min at 180 ˚C under MW conditions. Judged from LC-MS and GC-MS, the reaction mixture contained a 1:1 ratio of 1b/2b and it was concentrated in vacuo directly onto Celite and purified using column chromatography on silica gel (eluent: heptane → 30% EtOAc in heptane). Compound 2b was isolated as a colorless solid (47 mg, 44%). During workup compound 1b underwent conversion into xanthone (7), which was isolated as a colorless solid (44 mg, 41%). Characterization data of 2b and 7 were in accordance with the literature data.^¹0

10a Drake JAG. Jones DW. Spectrochim. Acta, Part A  1981,  37:  77 

10b Dubrovskiy AV. Larock RC. Org. Lett.  2010,  12:  3117