Preparation, Thermal Stability and Carbonyl Addition Reactions of 2,5-Difluorophenyl Lithium and 2,5-Difluorophenyl Grignard

Abstract

The generation of 2,5-difluorophenyl lithium 2 by lithiation of 1,4-difluorobenzene with BuLi in THF, with and without amine additives, has been surveyed. Thermal stability data of the organolithium species 2 generated with and without TMEDA were determined and the synthetic utility of 2 in the addition to aldehyde and ketone electrophiles is described. Preparation and stability of the corresponding organomagnesium reagent 1, generated by ­bromine-magnesium exchange of 1-bromo-2,5-difluorobenzene with isopropylmagnesium chloride, was also examined.

Key words

metalations - organometallic reagents - addition reactions - magnesium-bromine exchange - thermal stability

References

• 1a Abarbri M. Dehmel F. Knochel P. Tetrahedron Lett.  1999,  40:  7449 
• 1b For a recent review, see: Knochel P. Dohle W. Gommermann N. Kneisel FF. Kopp F. Korn T. Sapountzis I. Vu VA. Angew. Chem. Int. Ed.  2003,  42:  4302 
• 2 Leazer JL. Cvetovich R. Tsay F.-R. Dolling U. Vickery T. Bachert D. J. Org. Chem.  2003,  68:  3695 
• Halogen-magnesium exchange reactions employing organomagnesium ate complexes have been reported:
• 3a Inoue A. Kitagawa K. Shinokubo H. Oshima K. J. Org. Chem.  2001,  66:  4333 
• 3b Mase T. Houpis IN. Akao A. Dorziotis I. Emerson K. Hoang T. Iida T. Itoh T. Kamei K. Kato S. Kato Y. Kawasaki M. Lang F. Lee J. Lynch J. Maligres P. Molina A. Nemoto T. Okada S. Reamer R. Song JZ. Tschaen D. Wada T. Zewge D. Volante RP. Reider PJ. Tomimoto K. J. Org. Chem.  2001,  66:  6775 
• 5a ortho-Halophenyl lithiums are well known benzyne precursors at elevated temperatures, see inter alia: Kessar SV. In Comprehensive Organic Synthesis   Trost BM. Fleming I. Paquette LA. Pergamon Press; Oxford: 1991.  Vol. 4:  Chap. 2.3. p.483-515  
• 5b

  Attempts to characterise the degradation products by LCMS were unsuccessful.

• 7a Ong HH. Profitt JA. Anderson VB. Kruse H. Wilker JC. Geyer HM. J. Med. Chem.  1981,  24:  74 
• 7b Bridges AJ. Patt WC. Stickney TM. J. Org. Chem.  1990,  55:  773 
• 7c

  We have found MTBE to be an excellent alternative to THF for this bromine-lithium exchange.

• 8a Nichols DA. J. Chem. Soc. (A)  1969,  10:  1471 
• 8b Morrow GW. Swenton JS. Filppi JA. Wolgemuth RL. J. Org. Chem.  1987,  52:  713 
• 8c Schlosser M. Katsoulos G. Takagishi S. Synlett  1990,  747 
• 9 An ab initio study encompassing 2,5-difluorophenyl lithium (2) has been reported, see: Streitweiser A. Abu-Hasanyan F. Neuhaus A. Brown F. J. Org. Chem.  1996,  61:  3151 
• 10a Chalk AJ. Hoogeboom TJ. J. Organomet. Chem.  1968,  11:  615 
• 10b For a discussion of the role of TMEDA as additive, see: Collum DA. Acc. Chem. Res.  1992,  25:  448 

4

An aliquot was quenched into 10 equiv of PhCHO in THF at ambient and assayed versus authentic adduct 4 (R¹ = H, R² = Ph) by reverse phase HPLC with UV detection at 210 nm on a Zorbax SB Phenyl 250 × 4.6 mm column.

6

For example, Aldrich 2003 catalogue prices: 1-Bromo-2,5-difluorobenzene (24795-2) £648/mol, £3.36/g; 1,4-difluorobenzene (D10220-2) £88/mol, £0.77/g.

11

All new compounds gave satisfactory spectroscopic and/or elemental data:
1-(2,5-Difluorophenyl)-2,2-dimethylpropan-1-ol (colourless oil): ¹H NMR (400 MHz, CD₂Cl₂): d = 7.25-7.20 (1 H, m), 7.06-6.93 (2 H, m), 4.80 (1 H, d, J = 4.0 Hz), 2.04 (1 H, d, J = 4.0 Hz), 0.96 (9 H, s). ¹³C NMR (100 MHz, CD₂Cl₂): δ = 158.3 (d, J = 259 Hz), 156.0 (d, J = 257 Hz), 131.3 (dd, J = 7, 16 Hz), 115.8 (dd, J = 9, 27 Hz), 115.5 (dd, J = 5, 22 Hz), 114.9 (dd, J = 9, 24 Hz), 74.3, 36.2, 25.4. Anal. Calcd for C₁₁H₁₄F₂O: C, 65.98; H, 7.05; F, 18.98. Found: C, 65.99; H, 7.13; F, 18.61. (2,5-Difluorophenyl)(pyridin-3-yl)methanol: ^{Mp 102-104 °C. 1}H NMR (400 MHz, CD₂Cl₂): d = 8.34-8.31 (1 H, m), 8.32-8.20 (1 H, m), 7.65-7.61 (1 H, m), 7.27-7.22 (1 H, m), 7.18-7.13 (1 H, m), 6.92-6.83 (2 H, m), 5.30 (1 H, br s). ¹³C NMR (100 MHz, CD₂Cl₂): d = 159.0 (dd, J = 2, 241 Hz), 155.4 (dd, J = 2, 240 Hz), 148.3, 147.6, 138.8, 134.6, 132.6 (dd, J = 7, 16 Hz), 123.7, 116.4 (dd, J = 8, 24 Hz), 115.4 (dd, J = 8, 24 Hz), 113.9 (dd, J = 5, 25 Hz), 67.0 (d, J = 3 Hz). Anal. Calcd for C₁₂H₉F₂NO: C, 65.16; H, 4.10; N, 6.33; F, 17.18. Found: C, 65.04; H, 4.09; N, 6.43; F, 17.15.
8-(2,5-Difluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol: Mp 112-114 °C. ¹H NMR (400 MHz, CDCl₃): d = 7.27-7.21 (1 H, m), 7.00-6.85 (2 H, m), 3.95 (4 H, s), 2.42 (1 H, br s), 2.36-2.28 (2 H, m), 2.15-2.03 (2 H, m), 1.88-1.70 (4 H, m). ¹³C NMR (100 MHz, CDCl₃): d = 158.6 (d, J = 259 Hz), 156.2 (d, J = 258 Hz), 136.8 (dd, J = 6, 13 Hz), 117.3 (dd, J = 8, 27 Hz), 114.6 (dd, J = 9, 24 Hz), 113.7 (dd, J = 5, 26 Hz), 108.2, 71.6, 64.3, 34.2, 30.3. Anal. Calcd for C₁₄H₁₆F₂O₃: C, 62.22; H, 5.97; F, 14.06. Found: C, 62.33; H, 5.98; F, 14.02.
1-Benzyl-4-(2,5-difluorophenyl) piperidin-4-ol: Mp 63-65 °C. ¹H NMR (400 MHz, CD₂Cl₂): d = 7.42-7.26 (6 H, m), 7.12-6.93 (2 H, m), 3.60 (2 H, s), 2.83-2.76 (2 H, m), 2.54-2.46 (2 H, m), 2.42-2.32 (2 H, m), 2.20 (1 H, br s), 1.78-1.72 (2 H, m). ¹³C NMR (100 MHz, CD₂Cl₂): d = 158.7 (d, J = 253 Hz), 156.3 (d, J = 254 Hz), 138.9, 137.0 (dd, J = 7, 13 Hz), 129.0, 128.1, 126.9, 117.3 (dd, J = 9, 27 Hz), 114.7 (dd, J = 9, 24 Hz), 113.8 (dd, J = 5, 26 Hz), 70.6, 63.0, 49.0, 36.3. Anal. Calcd for C₁₈H₁₉F₂NO: C, 71.27; H, 6.31; N, 4.62. Found: C, 71.29; H, 6.31; N, 4.63.

12

Addition reactions of organolithium 2 to the carbonyl substrates illustrated, other than 1,4-cyclohexanedione mono-ethylene ketal, have not been evaluated in the absence of TMEDA.