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Synlett 2011(9): 1313-1317  
DOI: 10.1055/s-0030-1260549
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Electrosynthesis of Fluorinated Benzo[b]thiophene Derivatives

Bin Yin, Shinsuke Inagi, Toshio Fuchigami*
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 226-8502, Japan
Fax: +81(45)9245406; e-Mail: fuchi@echem.titech.ac.jp;
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Publikationsverlauf

Received 25 February 2011
Publikationsdatum:
05. Mai 2011 (online)

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Abstract

Anodic fluorination of benzo[b]thiophene derivatives provided a complex mixture of di- and trifluorinated products. On the other hand, anodic fluorination of 3-oxo-2,3-dihydrobenzo[b]thiophene and methyl 3-oxo-2,3-dihydrobenzo[b]thiophene-2-carboxylate gave the corresponding monofluorinated products ­selectively in moderate yields. Anodic fluorination of methyl α-(2-cyanophenylthio)acetate followed by intramolecular cyclization provided 3-amino-2-fluorobenzo[b]thiophene in excellent yield.

Key words

fluorine - heterocycles - cyclization - sulfur - electron transfer

    References and Notes

  • 1a Mesangeau C. Yous S. Chavatte P. Ferry G. Audinot V. Boutin JA. Delagrange P. Bennejean C. Renard P. Lesieur D. J. Enz. Inhib. Med. Chem.  2003,  18:  119 
    Google Scholar
  • 1b Connor DT. Cetenko WA. Mullican MD. Sorenson RJ. Unangst PC. Weikert RJ. Adolphson RL. Kennedy JA. Thueson DO. Wright CD. Conroy MC. J. Med. Chem.  1992,  35:  958 
    Google Scholar
  • 1c Graham SL. Shepard KL. Anderson PS. Baldwin JJ. Best DB. Christy ME. Freedman MB. Gautheron P. Habecker CN. J. Med. Chem.  1989,  32:  2548 
    Google Scholar
  • 2a Fluorinated Heterocyclic Compounds: Synthesis, Chemistry and Applications   Petrov VA. Wiley; Hoboken: 2009. 
    Google Scholar
  • 2b Buscemi S. Pace A. Piccionello AP. Pibiri I. Vivona N. Heterocycles  2005,  65:  387 
    Google Scholar
  • 2c Buscemi S. Pace A. Piccionello AP. Macaluso G. Vivona N. J. Org. Chem.  2005,  70:  3288 
    Google Scholar
  • 2d Pace A. Pibiri I. Buscemi S. Vivona N. Heterocycles  2004,  63:  2627 
    Google Scholar
  • 3 Dawood KM. Fuchigami T. J. Org. Chem.  2004,  69:  5302 
    CrossrefGoogle Scholar
  • 4 Yin B. Inagi S. Fuchigami T. Tetrahedron  2010,  66:  6820 
    CrossrefGoogle Scholar
  • 5 Fuchigami T. Shimojo M. Konno A. J. Org. Chem.  1995,  60:  3459 
    CrossrefGoogle Scholar
  • 6 Oh K. Kim H. Cardelli F. Bwititi T. Martynow AM. J. Org. Chem.  2008,  73:  2432 
    CrossrefGoogle Scholar
  • 7a Nobumasa K. Chie K. Michio K. Sulfur Lett.  1986,  4:  101 
    Google Scholar
  • 7b Cabiddu MG. Cabiddu S. Cadoni E. Demontis S. Fattuoni C. Melis S. Tetrahedron  2002,  58:  4529 
    Google Scholar
  • 8 Frisch MJ. Trucks GW. Schlegel HB. Scuseria GE. Robb MA. Cheeseman JR. Montgomery JA. Vreven T. Kudin KN. Burant JC. Millam JM. Iyengar SS. Tomasi J. Barone V. Mennucci B. Cossi M. Scalmani G. Rega N. Petersson GA. Nakatsuji H. Hada M. Ehara M. Toyota K. Fukuda R. Hasegawa J. Ishida M. Nakajima T. Honda Y. Kitao O. Nakai H. Klene M. Li X. Knox JE. Hratchian HP. Cross JB. Bakken V. Adamo C. Jaramillo J. Gomperts R. Stratmann RE. Yazyev O. Austin AJ. Cammi R. Pomelli C. Ochterski JW. Ayala PY. Morokuma K. Voth GA. Salvador P. Dannenberg JJ. Zakrzewski VG. Dapprich S. Daniels AD. Strain MC. Farkas O. Malick DK. Rabuck AD. Raghavachari K. Foresman JB. Ortiz JV. Cui Q. Baboul AG. Clifford S. Cioslowski J. Stefanov BB. Liu G. Liashenko A. Piskorz P. Komaromi I. Martin RL. Fox DJ. Keith T. Al-Laham MA. Peng CY. Nanayakkara A. Challacombe M. Gill PMW. Johnson B. Chen W. Wong MW. Gonzalez C. Pople JA. Gaussian 03, Version C.01   Gaussian Inc.; Wallingford (CT): 2004. 
    Google Scholar
  • 9a Xie H. Ng D. Savinov SN. Dey B. Kwong PD. Wyatt R. Smith AB. Hendrickson WA. J. Med. Chem.  2007,  50:  4898 
    Google Scholar
  • 9b Zlotin SG. Kislitsin PG. Kucherov FA. Gakh AA. Heterocycles  2006,  68:  1109 
    Google Scholar
  • 10 Erian AW. Konno A. Fuchigami T. J. Org. Chem.  1995,  60:  7654 
    CrossrefGoogle Scholar
  • 11a Cabiddu M. Cabiddu S. Cadoni E. Demontis S. Fattuoni C. Melis S. Tetrahedron  2002,  58:  4529 
    Google Scholar
  • 11b Naso F. Capozzi MAM. Bottoni A. Calvaresi M. Bertolasi V. Capitelli F. Cardellicchio C. Chem. Eur. J.  2009,  15:  13417 
    Google Scholar
  • 11c Zarghi A. Faizi M. Shafaghi B. Ahadian A. Khojastehpoor HR. Zanganeh V. Tabatabai SA. Shafiee A. Bioorg. Med. Chem. Lett.  2005,  15:  3126 
    Google Scholar
  • 11d Romagnoli R. Baraldi PG. Carrion MD. Cara CL. Preti D. Fruttarolo F. Pavani MG. Tabrizi MA. Tolomeo M. Grimaudo S. Cristina AD. Balzarina J. Hadfield JA. Brancale A. Hamel E. J. Med. Chem.  2007,  50:  2273 
    Google Scholar
  • 12 Shimizu M. Kikumoto H. Konakahara T. Gama Y. Shibuya I. Heterocycles  1999,  51:  300 
    Google Scholar
  • 13a Yoon VC. Mariano PS. Acc. Chem. Rec.  1992,  25:  233 
    Google Scholar
  • 13b Fuchigami T. Ichikawa S. J. Org. Chem.  1994,  59:  607 
    Google Scholar
14

In the following spectral data of novel compounds, the chemical shifts for ¹9F NMR spectra are given in δ (ppm) with monofluorobenzene (C6H5F, δ = -36.5 ppm) as an internal standard.
General Procedure for Anodic Fluorination of Substrates 1, 5, 7, and 8: Electrolysis was conducted with platinum anode and cathode (1 × 1 cm²) in 0.3 M HF salt/solvent (2 mL) containing 0.1 mmol substrate using an undivided cell at ambient temperature.¹5 After the substrate was completely consumed (monitored by TLC), the electrolytic solution was passed through a short column filled with silica gel using EtOAc as an eluent. After removal of the solvent, the residue was purified via column chromatography on silica gel using hexane-EtOAc as an eluent.
2-Acetyl-2-fluorobenzo[ b ]thiophen-3(2 H )-one (4b): ¹9F NMR (254 MHz, CDCl3) δ = -72.60 (s, 1 F). MS: m/z = 210 [M+], 191 [M+ - F], 167 [M+ - Ac].
Methyl 2-Fluoro-3-oxo-2,3-dihydrobenzo[ b ]thiophene-2-carboxylate (4d): pale yellow solid; mp 85-86 ˚C. ¹H NMR (270 MHz, CDCl3): δ = 3.86 (s, 3 H), 7.33 (td, 1 H, J = 7.4, 0.8 Hz), 7.39 (d, 1 H, J = 8.1 Hz), 7.66 (td, 1 H, J = 7.7, 1.4 Hz), 7.84 (ddd, 1 H, J = 8.1, 1.1, 0.5 Hz). ¹9F NMR (254 MHz, CDCl3): δ = -72.10 (s, 1 F). ¹³C NMR (68 MHz, CDCl3): δ = 53.83 (d, J = 1.1 Hz), 98.19 (d, J = 239.7 Hz), 124.36 (d, J = 2.2 Hz), 126.29, 126.57, 128.41, 137.59, 148.81, 165.37 (d, J = 32.9 Hz), 191.55 (d, J = 16.1 Hz). MS: m/z = 226 [M+], 167 [M+ - COOMe], 139 [M+ - COOMe - CO], 76, 59. HRMS (ESI): m/z [M + Na+] calcd for C10H7FO3SNa: 248.9998; found: 248.9999.
2-Fluorobenzo[ b ]thiophen-3(2 H )-one (6): Due to its instability, this compound could not be purified by column chromatography on silica gel. Only characteristic methyne proton signal on ¹H NMR is shown as follows.
¹H NMR (270 MHz, CDCl3): δ = 6.79 (d, 1 H, J = 49.9 Hz). ¹9F NMR (254 MHz, CDCl3): δ = -91.47 (d, 1 F, J = 49.9 Hz). MS: m/z = 168 [M+].
Methyl 2-[(α-Fluoro)-α-(methoxycarbonyl)methylthio]-benzoate (9a): colorless oil. ¹H NMR (270 MHz, CDCl3): δ = 3.80 (s, 3 H), 3.93 (s, 3 H), 6.27 (d, 1 H, J = 53.5 Hz), 7.36 (td, 1 H, J = 7.6, 1.1 Hz), 7.52 (td, 1 H, J = 7.8, 1.6 Hz), 7.68 (dd, 1 H, J = 8.1, 1.1 Hz), 7.93 (dd, 1 H, J = 7.8, 1.4 Hz). ¹9F NMR (254 MHz, CDCl3): δ = -82.82 (d, 1 F, J = 53.5 Hz). ¹³C NMR (68 MHz, CDCl3): δ = 30.91, 52.44, 93.53 (d, J = 230.3 Hz), 127.32, 130.23 (d, J = 2.2 Hz), 130.78 (d, J = 2.2 Hz), 130.91, 132.69, 134.76 (d, J = 3.4 Hz), 165.81 (d, J = 28.4 Hz), 166.75. MS: m/z = 258 [M+], 238, 226, 199, 179, 167, 152, 137, 121, 108, 76, 63. HRMS (ESI): m/z [M + Na+] calcd for C11H11FO4SNa: 281.0260; found: 281.0262.
Methyl α-Fluoro-α-(2-cyanophenylthio)acetate (9c): colorless oil. ¹H NMR (270 MHz, CDCl3): δ = 3.78 (s, 3 H), 6.13 (d, 1 H, J = 50.5 Hz), 7.53 (td, 1 H, J = 7.6, 1.4 Hz), 7.62 (td, 1 H, J = 7.8, 1.6 Hz), 7.76 (t, 1 H, J = 8.1 Hz), 7.76 (td, 1 H, J = 7.8, 0.3 Hz). ¹9F NMR (254 MHz, CDCl3): δ = -83.84 (d, 1 F, J = 50.5 Hz). ¹³C NMR (68 MHz, CDCl3): δ = 53.24, 92.37 (d, J = 233.7 Hz), 116.55, 118.16 (d, J = 2.2 Hz), 130.06, 132.39 (d, J = 1.7 Hz), 133.12, 133.89, 136.23 (d, J = 1.2 Hz), 164.90 (d, J = 30.1 Hz). MS: m/z = 225 [M+], 207, 193, 166, 146, 134, 117, 102, 90, 75. HRMS (ESI): m/z [M + Na+] calcd for C10H8FNO2SNa: 248.0157; found: 248.0157.
α-Fluoro-α-(benzylthio)benzonitrile (9d): Due to its instability, this compound could not be purified by column chromatography on silica gel. Only characteristic methyne proton signal on ¹H NMR is shown as follows.
¹H NMR (270 MHz, CDCl3): δ = 6.89 (d, 1 H, J = 54.8 Hz). ¹9F NMR (254 MHz, CDCl3) δ = -70.18 (d, 1 F, J = 54.8 Hz). MS: m/z = 243 [M+], 223, 134, 109. HRMS (ESI): m/z [M + Na+] calcd for C14H10FNSNa: 266.0416; found: 266.0409.
General Procedure for Intramolecular Cyclization of Anodically Fluorinated Product 9: A solution of 9 (0.1 mmol) in MeCN or MeOH (5 mL) containing potassium carbonate (0.15 mmol, 1.5 equiv) was stirred at r.t. for 5 h or 3 h. After filtration of insoluble material, the filtrate was concentrated under reduced pressure to give the imino product 10 or the amino product 11.
Methyl 2-Fluoro-3-imino-2,3-dihydrobenzo[ b ]-thiophene-2-carboxylate (10c): ¹9F NMR (254 MHz, CDCl3): δ = -72.08 (s, 1 F). MS: m/z = 225 [M+], 206 [M+ - F], 166 [M+ - COOMe], 147.
3-Amino-2-fluorobenzo[ b ]thiophene (11c): dark green solid; mp 141-142 ˚C. IR (KBr): 3384, 3303 cm-¹. ¹H NMR (270 MHz, CDCl3): δ = 3.52 (br s, 2 H), 7.30 (td, 1 H, J = 7.8, 1.6 Hz), 7.37 (td, 1 H, J = 7.6, 1.4 Hz), 7.50 (ddd, 1 H, J = 7.8, 1.4, 0.8 Hz), 7.61 (dd, 1 H, J = 7.3, 1.1 Hz). ¹9F NMR (254 MHz, CDCl3): δ = -75.55 (s, 1 F). ¹³C NMR (68 MHz, CDCl3): δ = 118.55 (d, J = 7.8 Hz), 119.54 (d, J = 6.7 Hz), 122.74 (d, J = 1.2 Hz), 124.34 (d, J = 4.5 Hz), 124.42, 128.85 (d, J = 2.8 Hz), 131.63 (d, J = 3.9 Hz), 144.33 (d, J = 278.3 Hz). MS: m/z = 168 [M + H]+, 167 [M+]. HRMS (ESI): m/z [M + H+] calcd for C8H7FNS: 168.0283; found: 168.0274.

15

Scale-up of the electrochemical reaction step may be possible by using a larger setup or a flow cell.