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Synlett 2004(9): 1646-1648  
DOI: 10.1055/s-2004-825592
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Jeremy P. Scott*, Sarah E. Brewer*, Antony J. Davies, Karel M. J. Brands
Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU, UK
Fax: +44(1992)452581; e-Mail: jeremy_scott@merck.com;
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Publication History

Received 24 February 2004
Publication Date:
18 May 2004 (online)

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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

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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. 1H 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.