Electrosynthesis of Fluorinated Benzo[b]thiophene Derivatives

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 
• 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 
• 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 
• 2a Fluorinated Heterocyclic Compounds: Synthesis, Chemistry and Applications   Petrov VA. Wiley; Hoboken: 2009. 
• 2b Buscemi S. Pace A. Piccionello AP. Pibiri I. Vivona N. Heterocycles  2005,  65:  387 
• 2c Buscemi S. Pace A. Piccionello AP. Macaluso G. Vivona N. J. Org. Chem.  2005,  70:  3288 
• 2d Pace A. Pibiri I. Buscemi S. Vivona N. Heterocycles  2004,  63:  2627 
• 3 Dawood KM. Fuchigami T. J. Org. Chem.  2004,  69:  5302 
• 4 Yin B. Inagi S. Fuchigami T. Tetrahedron  2010,  66:  6820 
• 5 Fuchigami T. Shimojo M. Konno A. J. Org. Chem.  1995,  60:  3459 
• 6 Oh K. Kim H. Cardelli F. Bwititi T. Martynow AM. J. Org. Chem.  2008,  73:  2432 
• 7a Nobumasa K. Chie K. Michio K. Sulfur Lett.  1986,  4:  101 
• 7b Cabiddu MG. Cabiddu S. Cadoni E. Demontis S. Fattuoni C. Melis S. Tetrahedron  2002,  58:  4529 
• 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. 
• 9a Xie H. Ng D. Savinov SN. Dey B. Kwong PD. Wyatt R. Smith AB. Hendrickson WA. J. Med. Chem.  2007,  50:  4898 
• 9b Zlotin SG. Kislitsin PG. Kucherov FA. Gakh AA. Heterocycles  2006,  68:  1109 
• 10 Erian AW. Konno A. Fuchigami T. J. Org. Chem.  1995,  60:  7654 
• 11a Cabiddu M. Cabiddu S. Cadoni E. Demontis S. Fattuoni C. Melis S. Tetrahedron  2002,  58:  4529 
• 11b Naso F. Capozzi MAM. Bottoni A. Calvaresi M. Bertolasi V. Capitelli F. Cardellicchio C. Chem. Eur. J.  2009,  15:  13417 
• 11c Zarghi A. Faizi M. Shafaghi B. Ahadian A. Khojastehpoor HR. Zanganeh V. Tabatabai SA. Shafiee A. Bioorg. Med. Chem. Lett.  2005,  15:  3126 
• 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 
• 12 Shimizu M. Kikumoto H. Konakahara T. Gama Y. Shibuya I. Heterocycles  1999,  51:  300 
• 13a Yoon VC. Mariano PS. Acc. Chem. Rec.  1992,  25:  233 
• 13b Fuchigami T. Ichikawa S. J. Org. Chem.  1994,  59:  607 

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 cm^²) 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.