A Highly Efficient Conversion of Primary or Secondary Alcohols into Fluorides with n-Perfluorobutanesulfonyl Fluoride-Tetrabutylammonium Triphenyldifluorosilicate

Abstract

Direct fluorination of primary and secondary alcohols by a combination of perfluoro-1-butanesulfonyl fluoride (PBSF) and tetrabutylammonium triphenyldifluorosilicate (TBAT) under mild conditions provides the corresponding fluorides in high yields. With this combination, elimination side reactions could be significantly suppressed and chiral secondary alcohols were less prone to epimerization at the reaction center.

Key words

fluorination - elimination - stereoselectivity - PBSF - TBAT

References and Notes

• 1a Bennua-Skalmowski B. Vorbrueggen H. Tetrahedron Lett.  1995,  36:  2611 
• 1b Vorbrüggen H. Synthesis  2008,  1165 
• 2 Yin J. Zarkowsky DS. Thomas DW. Zhao MM. Huffman MA. Org. Lett.  2004,  6:  1465 
• 3 Picher AS. Ammon HL. DeShong P. J. Am. Chem. Soc.  1995,  117:  5166 
• 6 Takamastu S. Katayama S. Hirose N. De Cock E. Schelkens G. Demillequand M. Brepoels J. Izawa K. Nucleosides, Nucleotides Nucleic Acids  2002,  21:  849 
• 7a Bennua-Skalmowski B. Krolikiewicz K. Vorbrüggen H. Bull. Soc. Chim. Belg.  1994,  103:  453 
• 7b Bennua-Skalmowski B. Klar U. Vorbrüggen H. Synthesis  2008,  1175 
• 8 Handy CJ. Lam Y.-F. DeShong P. J. Org. Chem.  2000,  65:  3542 
• 10 Klar U. Neef G. Vorbrüggen H. Tetrahedron Lett.  1996,  37:  7497 
• 11a Barlos K. Papaioannou D. Patrianakou S. Tsegenidis T. Liebigs Ann. Chem.  1986,  1950 
• 11b Baldwin JE. North M. Flinn A. Moloney MG. Tetrahedron  1989,  45:  1453 

4

These side products were determined by LC-MS or other means. For details, please see ref. 12.

5

Typical Procedure
The alcohol 4, TBAT in the amount indicated, base, and solvent (8 mL/mmol) were added in turn at the temperature indicated. Then PBSF (2.2 equiv) was introduced and stirring was continued for the time given. The final reaction mixture was directly assayed by HPLC or LC-MS, and the calculation of HPLC data gave conversion, dr value, and ratio of fluorination product/elimination product in the mixture. The final reaction mixture was then concentrated under reduced pressure and purified by flash chromatog-raphy (eluent: PE to PE-acetone) to give (2S,4S)-3a, and a mixture of 5 and 6 (not separated).
(2 S ,4 S )-Methyl 4-Fluoro-1-(4-methylphenylsulfonyl)-pyrrolidine-2-carboxylate [(2 S ,4 S )-3a]
White crystals; R _f  = 0.44 (PE-acetone, 70:30); mp 100-103 ˚C; [a]_D ^²4 -60 (c 0.94, EtOAc). IR (KBr): n = 3006, 2960, 1759, 1599, 1344, 673 cm^-¹. ^¹H NMR (600 MHz, CDCl₃): δ = 2.22 (dtd, J = 32.2, 12.3, 5.8 Hz, 1 H), 2.54 (dd, J = 15.2, 1.4 Hz, 1 H), 2.46 (s, 3 H), 3.58-3.68 (m, 2 H), 3.73 (s, 3 H), 4.67 (d, J = 9.4 Hz, 1 H), 5.21 (dd, J = 50.2, 3.2 Hz, 1 H),, 7.35 (d, J = 8.2 Hz, 2 H), 7.82 (d, J = 8.2 Hz, 2 H). ^¹³C NMR (600 MHz, CDCl₃): δ = 21.6, 37.4, 37.5, 52.6, 54.0, 54.2, 59.2, 91.4, 92.6, 127.6, 129.7, 144.0, 171.5. HRMS: m/z calcd for C₁₃H₁₆FNO₄S + Na: 324.0681; found: 324.0672. The absolute configuration of the 4-position was determined by NOE.
Mixture of Two Elimination Products: (2 S )-Methyl 1-(4-Methylphenylsulfonyl)-3,4-dihydropyrrole-2-carbox-ylate and (2 S )-Methyl 1-(4-Methylphenylsulfonyl)-4,5-dihydropyrrole-2-carboxylate (5 and 6)
White crystals; R _f  = 0.28 (PE-acetone, 80:20); mp 190-197 ˚C. LC-MS: t _R = 11.21 min; MS: m/z = 282 [M + 1]⁺, 304 [M + Na]⁺; t _R = 12.39 min; MS: m/z = 282 [M + 1]⁺, 304 [M + Na]⁺. IR (KBr): ν = 3100, 2961, 1765, 1598, 1098, 820, 802, 665 cm^-¹. ^¹H NMR (600 MHz, CDCl₃): δ = 2.45 (s, 3 H), 2.44 (s, 3 H), 2.66-2.90 (m, 2 H), 3.81 (s, 3 H), 4.10-4.30 (m, 3 H), 5.07-5.16 (m, 2 H), 5.65-5.70 (m, 1 H), 5.86-5.89 (m, 1 H), 6.39 (t, J = 2.0 Hz, 1 H), 7.33-7.36 (m, 4 H), 7.71 (d, J = 8.2 Hz, 2 H), 7.79 (d, J = 8.2 Hz, 2 H). HRMS: m/z calcd for C₁₃H₁₅NO₄S + Na: 304.0619; found: 304.0612.

9

Typical Procedure for the Synthesis of (2 S ,4 S )-Methyl 1-[4,4-Bis(3-methyl-2-thienyl)-3-buten-1-yl]-4-fluoropyr-rolidine-2-carboxylate (3g) To a mixture of alcohol 1g (1 equiv) and TBAT (0.8 equiv), i-Pr₂NEt (2.5 equiv) and toluene (8 mL per mmol of alcohol) were added in turns at r.t. The resulting mixture was stirred, and then PBSF (2.2 equiv) was introduced. The stirring was continued until TLC revealed complete conversion. The reaction mixture was concentrated under reduced pressure. The residual was mixed with a little bit of silica gel, air-dried, and finally purified by flash chromatography (SiO₂, 300-400 mesh; eluent: PE to PE-acetone) to give 3g as a yellow oil; [α]_D ^²4 -31 (c 0.89, EtOAc). IR (NaCl): ν = 3104, 3060, 2952, 2843, 1748, 1733, 1435, 1200, 1174, 715 cm^-¹. ^¹H NMR (600 MHz, CDCl₃): δ = 2.00 (s, 3 H), 2.03 (s, 3 H), 2.19-2.58 (m, 6 H), 2.93 (br s, 1 H), 3.20 (br s, 1 H), 3.33-3.42 (m, 1 H), 3.73 (s, 3 H), 5.13 (d, J = 59.8 Hz, 1 H), 6.04 (t, J = 6.6 Hz, 1 H), 6.76 (d, J = 3.8 Hz, 1 H), 6.84 (d, J = 3.8 Hz, 1 H), 7.05 (d, J = 3.8 Hz, 1 H), 7.21 (d, J = 3.8 Hz, 1 H). ^¹³C NMR (600 MHz, CDCl₃): d = 14.8, 28.7, 37.0, 37.1, 52.0, 53.6, 59.3, 59.4, 64.6, 91.0, 92.2, 122.7, 124.3, 128.7, 129.6, 131.2, 135.4, 139.5, 173.3. HRMS: m/z calcd for C₂₀H₂₄FNO₂S₂ + 1): 394.1310; found: 394.1316.