A highly efficient synthesis of triisopropylsilyldifluorobromopropyne yields a versatile gem-difluoromethylene building block

Abstract

Triisopropylsilyldifluorobromopropyne, readily prepared in excellent yield from the reaction of lithium triisopropylsilylacetylide with CF₂Br₂, provides a convenient entry into a functionalized CF₂ synthon.

References

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8. Under Ar atmosphere, a solution of triisopropylsilylacetylene (36 g, 0.2 mol) in THF (300 ml) was cooled to –20 °C. BuLi (125 ml, 1.6 M solution in hexane) was added via syringe and the resulting solution was stirred for 30 min before CF₂Br₂(62 g, 1.5 equiv.) was added. The solution was allowed to warm to room temperature and stirred for 9 h. After solvent removal, NH₄Cl (120 ml) was added and the oily layer was extracted with Et₂O (3 × 100 ml). Standard work-up gave the crude product as a viscous orange oil (92% yield by GC–MS) which was purified by distillation (bp 51–52 °C/0.1 mmHg) to yield 1(49.9 g, 81%); δ_H(300 MHz, CDCl₃) 1.11 (s, TIPS protons); δ_C(75 MHz, CDCl₃) 100.61 (t, ¹J_CF 290), 97.16 (t, ²J_CF 36.5), 95.1 (t, ³J_CF 4.7), 18.01, 11.28; δ_F– 32.60 (s, 2F); m/z(GC-MS) 312 (M⁺+ 1, 4), 310 (M⁺– 1, 4), 269 (14), 267 (14), 143 (27), 77 (100)(calc. for C₁₂H₂₁ SiF₂ Br: C, 46.33; H, 6.75. Found: C, 46.91; H, 6.83%). The triisopropylsilylacetylene starting material, purchased from GFS Co., contained diisopropylpropenylsilylacetylene (11%) and diisopropylpropylsilylacetylene (14%). Fractional distillation did not remove these impurities. The GC-MS analysis of 1 shows all three components were alkylated and their ratios perfectly match that of the starting material. The calculated C% and H% were based on the formula of triisopropylsilyldifluorobromopropyne. If the two impurities are removed from the calculation, the values found for C% and H% are 46.84 and 6.67%, respectively.
9. For a recent review of the TIPS group in organic chemistry see: C. Rücker, Chem. Rev., 1995, 95, 1009.
10. Similarly, whereas ynolates lack convenient methods for their generation a lithium silylynolate has been used in ketenylation reactions: H. Kai, K. Iwamoto, N. Chatani and S. Murai, J. Am. Chem. Soc., 1996, 118, 7634.
11. Selected data for 2: δ_H(300 MHz, CDCl₃) 1.06 (s, TIPS protons), 4.81 (t, 1H, ⁴J_HH 7.23), 4.30 (d, 2H, ⁴J_HH 7.23); m/z(GC-MS) 196 (M⁺), 157, 153, 125, 97, 83, 67. For 3: δ_H(300 MHz, CDCl₃) 1.09 (s, TIPS protons), 6.17 (t, ²J_HF 54.8); δ_F– 105.49 (s); m/z(GC-MS) 232 (M⁺), 189, 161, 133, 105, 81, 77. For 4: δ_H(300 MHz, CDCl₃) 1.11 (s, 21H, TIPS protons), 1.39 (t, 6H, ³J_HH 7.00), 4.32 (m, 4H); δ_F–96.79 (d, ²J_PF 109.01); δ_P 4.23 (t, ²J_PF 109.10); m/z(GC-MS) 325 (M⁺– 43), 297, 269, 153, 109, 81. For 6: δ_H(300 MHz, CDCl₃) 1.10 (s, TIPS protons); δ_F–99.01 (s, 4F); m/z(GC-MS) 462 (M⁺), 377, 307, 239, 183, 115, 77. For 7: δ_H(300 MHz, CDCl₃) 1.11 (s, TIPS protons); δ_F–28.13 (s); m/z(GC-MS) 315 (M⁺– 43), 265, 237, 189, 165, 119, 105, 77. For 8: δ_H(300 MHz, CDCl₃) 7.41–7.26 (m, 5H), 6.82 (d, 1H, ³J_HH 15.9), 6.26 (dd, 1H, ³J_HH 15.9, ³J_HH 6.2), 4.55 (m, 1H, CHOH), 2.05 (s, 1H, OH), 1.06 (s, 21 H, TIPS protons); δ_F–94.3 (d, 1F, ²J_FF 274), –96.7 (d, 1F, ²J_FF 274). For 9: δ_H(300 MHz, CDCl₃) 7.45–7.30 (m, 5H), 6.85 (dd, 1H, ⁴J_HH 0.9, ³J_HH 15.9), 6.24 (dd, 1H, ³J_HH 15.9, ³J_HH 6.3), 4.55 (m, 1H, CHOH), 2.85 (t, 1H, ³J_HF 5.0), 2.04 (s, 1 H); δ_F–95.9 (d, 1F, ²J_FF 277), –96.9 (d, 1F, ²J_FF 277); m/z(GC-MS) 206 (M⁺, 5),170 (3), 159 (2), 133 (100), 115 (30), 77 (26), 55 (46).
12. The major by-product is 3, an indication that, compared to the bromide, the triisopropylsilyldifluoropropyne anion is a better leaving group. For a leading reference on fluorinated phosphate mimics, see: D. O'Hagan and H. S. Rzepa, Chem. Commun., 1997, 645.
13. W. C. Sun, C. S. Ng and G. D. Prestwich, J. Org. Chem., 1992, 57, 132.
14. We have also prepared 8 in 73% yield by the reaction of lithium triisopropylsilylacetylide with CF₂I₂. However, the prohibitive cost of commercial CF₂I₂ will most likely limit its use in large-scale synthesis.