Aromatic Ring-Opening of 2-Fluorobenzothiophenes by Alkyllithiums

Abstract

Diphenylacetylenes are obtained when alkyllithium ­reagents are added to 3-aryl-2-fluorobenzothiophenes at low temperature. The aromatic ring-opening mechanism involves a nucleophilic addition of the alkyllithium to the sulfur atom of the thiophene. The resulting 2,2-diaryl-1-fluorovinyl anion subsequently undergoes a Fritsch-Buttenburg-Wiechell rearrangement to ­afford the diphenylacetylene.

Key words

ring-opening - Fritsch-Buttenberg-Wiechell rearrangements - benzothiophenes - alkyllithium reagents - addition to sulfur

References

• 1a Dickinson RP. Iddon B. J. Chem. Soc. C  1970,  2592 
• 1b Karlsson JO. Svensson A. Gronowitz S. J. Org. Chem.  1984,  49:  2018 
• 1c Iddon B. Heterocycles  1983,  20:  1127 
• 2 Hill B. De Vleeschauwer M. Houde K. Belley M. Synlett  1998,  407 
• 3 Hallberg A. Frejd T. Gronowitz S. Chem. Scr.  1979,  13:  186 
• 4 Lithiation of 9a with BuLi in THF at -78 °C, in the presence of TMEDA, followed by reaction with iodine,¹⁹ yielded quantitatively 2-iodo-3-phenylbenzothiophene. Trifluoromethylation of this iodide (2.0 g) was then performed in 59% yield with CF₃I (2.3 mL) and copper (5.0 g) in pyridine (13 ml) at 130 °C for 24 h. See: Kobayashi Y. Yamamoto K. Kumadaki I. Tetrahedron Lett.  1979,  42:  4071 ; for a related procedure
• The reverse of this reaction, the synthesis of benzothio-phenes from phenylacetylenes, has been reported by:
• 6a Flynn BL. Verdier-Pinard P. Hamel E. Org. Lett.  2001,  3:  651 
• 6b Yue D. Larock RC. J. Org. Chem.  2002,  67:  1905 
• 6c Aitken RA. Burns G. Tetrahedron Lett.  1987,  28:  3717 
• For recent articles describing FBW rearrangements, see:
• 8a Creton E. Rezaeï H. Marek I. Normant JF. Tetrahedron Lett.  1999,  40:  1899 
• 8b Mouriès V. Waschbüsch R. Carran J. Savignac P. Synthesis  1998,  271 
• 8c Shi Shun ALK. Chernick ET. Eisler S. Tykwinski RR. J. Org. Chem.  2003,  68:  1339 
• 9 Köbrich G. Angew. Chem., Int. Ed. Engl.  1967,  6:  41 
• 10 Smuszkovicz J. Modest EJ. J. Am. Chem. Soc.  1950,  72:  571 
• 11 Miyaura N. Yanagi T. Suzuki A. Synth. Commun.  1981,  11:  513 
• 12 Differding E. Ofner H. Synlett  1991,  187 
• 13 Werner LH. Schroeder DC. Ricca S. J. Am. Chem. Soc.  1957,  79:  1675 
• 14 Echavarren AM. Stille JK. J. Am. Chem. Soc.  1987,  109:  5478 
• 16 The structure of 11 was confirmed by 2D-NOE studies. This reaction was also described by: Mulvaney JE. Gardlund ZG. Gardlund SL. J. Am. Chem. Soc.  1963,  85:  3897 
• 19 Yoshida S. Fujii M. Aso Y. Otsubo T. Ogura F. J. Org. Chem.  1994,  59:  3077 
• 20 Soderquist JA. Matos K. Rane A. Ramos J. Tetrahedron Lett.  1995,  36:  2401 

5

The structure of the diphenylacetylene 5a was confirmed by its preparation via an alternative synthetic route. o-Bromo-thiophenol was butylated with butyl iodide in the presence of NaH in DMF. Phenylacetylene was converted to its lithium salt and treated with B-MeO-9-BBN in situ to form a tetrahedral borate complex, which was reacted with 1-bromo-2-(butylthio)benzene in the presence of Pd(0) [20] to yield 5a.

7

The first step was found to be rate limiting based on the following observations. 1) The FBW rearrangement was reported repeatedly to occur rapidly and at temperature below -20 °C. [8] 2) We haven’t been able to isolate any of the non-rearranged products from the intermediate 2,2-diaryl-1-fluorovinyllithium 8, even when the reaction was quenched at -78 °C (first entry in Table [1] ). 3) In most reactions where there is no diphenylacetylene produced, the major product isolated is the starting benzothiophene 7.

15

All new compounds gave satisfactory analytical and spectroscopic data. Selected data:
1-( tert -Butylthio)-2-[(4-methoxyphenyl)ethynyl]benzene ( 5d): ¹H NMR (500 MHz, acetone): δ = 7.67 (d, 1 H, J = 7.7 Hz), 7.64 (dd, 1 H, J = 1.0, 7.6 Hz), 7.54 (d, 2 H, J = 8.8 Hz), 7.46-7.44 (m, 1 H), 7.41-7.37 (m, 1 H), 7.01 (d, 2 H, J = 8.8 Hz), 3.86 (s, 3 H), 1.37 (s, 9 H). ¹³C NMR (126 MHz, acetone): δ = 160.49, 139.14, 135.01, 133.26, 133.00, 131.43, 129.35, 128.33, 115.83, 114.65, 93.56, 88.61, 55.25, 47.74, 31.04. IR (neat): 2216 cm^-1. HRMS (FAB, glycerol): m/z calcd for C₁₉H₂₀OS [M⁺]: 296.1234; found: 296.1236. Anal. Calcd for C₁₉H₂₀OS: C, 76.98; H, 6.80; S, 10.82. Found: C, 76.98; H, 7.04; S, 9.97.
1-( tert -Butylthio)-4-chloro-2-(phenylethynyl)benzene ( 5g): ¹H NMR (500 MHz, acetone): δ = 7.68 (m, 2 H), 7.63-7.61 (m, 2 H), 7.48-7.44 (m, 4 H), 1.38 (s, 9 H). ¹³C NMR (126 MHz, acetone): δ = 140.44, 134.93, 134.19, 132.65, 132.55, 131.90, 129.36, 129.09, 128.83, 123.31, 94.60, 88.54, 48.24, 30.97. IR (neat): 2220 cm^-1. HRMS (FAB, glycerol): m/z calcd for C₁₈H₁₇ClS [M⁺]: 300.0740; found: 300.0738. Anal. Calcd for C₁₈H₁₇ClS: C, 71.86; H, 5.70; S, 10.66. Found: C, 71.93; H, 5.90; S, 10.27.
2-Fluoro-3-(4-methoxyphenyl)benzothiophene ( 7b): ¹H NMR (500 MHz, acetone): δ = 7.91-7.87 (m, 1 H), 7.72-7.68 (m, 1 H), 7.52 (d, 2 H, J = 8.1 Hz), 7.46-7.40 (m, 2 H), 7.14-7.12 (m, 2 H), 3.89 (s, 3 H). ¹³C NMR (126 MHz, acetone): δ = 160.00, 159.31 (d, J = 289 Hz), 136.49 (d, J = 3.9 Hz), 131.02 (d, J = 2.6 Hz), 130.89, 125.80, 125.30 (d, J = 4.6 Hz), 123.35, 123.28, 122.87 (d, J = 6.0 Hz), 117.13 (d, J = 7.3 Hz), 114.74, 55.18. MS (+APCI): m/e 258.0 [M⁺]. Anal. Calcd for C₁₅H₁₁FOS: C, 69.75; H, 4.29; S, 12.41. Found: C, 69.84; H, 4.34; S, 12.28.
5-Chloro-2-fluoro-3-phenylbenzothiophene ( 7c): ¹H NMR (500 MHz, acetone): δ = 7.99 (d, 1 H, J = 8.6 Hz), 7.67 (d, 1 H, J = 2.0 Hz), 7.61 (m, 4 H), 7.52 (m, 1 H), 7.46 (dd, 1 H, J = 2.0, 8.6 Hz). ¹³C NMR (126 MHz, acetone): δ = 161.58 (d, J = 291 Hz), 138.02 (d, J = 4.3 Hz), 132.28, 131.06, 130.11, 129.92, 129.82 (d, J = 2.9 Hz), 129.24, 126.08 (d, J = 4.1 Hz), 125.56, 122.71 (d, J = 6.2 Hz), 117.71 (d, J = 8.0 Hz). MS (+APCI): m/e 262.0 [M⁺], 264.0. Anal. Calcd for C₁₄H₈ClFS: C, 64.00; H, 3.07. Found: C, 64.45; H, 3.00.

17

2-Chloro-3-phenylbenzothiophene was prepared in 64% yield from 9a by lithiation with BuLi at -78 °C followed by reaction with N-chlorosuccinimide.

18

The same reaction with s-BuLi yielded only 3-phenyl-benzothiophene 13.