Addition of Ethyl Bromodifluoroacetate to Lactones: Reactivity and ­Stereoselectivity

Abstract

Reformatsky-type additions, under various metal­mediated activation, of ethyl bromodifluoroacetate toward a series of unactivated lactones and various sugar lactones proceeded with medium to good yields and in a completely diastereoselective ­manner.

addition reactions - fluorine - lactones - carbohydrates - stereoselectivity

References

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Method A. To a suspension of zinc [19] (7 equiv, 15.7 mmol) in anhyd THF (31 mL) warmed to reflux temperature were added ethyl bromodifluoroacetate (3 equiv, 6.7 mmol) and the desired lactone (1 equiv, 2.24 mmol) in anhyd THF (31 mL). The reaction was stirred at the same temperature under inert atmosphere during a variable period between 2.30-4 h depending of the substrate. The resulting mixture was then diluted with 1 N aq HCl and stirred for 10 min before extraction with CH₂Cl₂. The extracts were dried over anhyd MgSO₄. After removal of the solvent under reduced pressure, the crude mixture thus obtained was subjected to flash silica gel chromatography.
Method B.
To a suspension of zinc (7 equiv, 7 mmol) in anhyd THF (12 mL) was added Cp₂TiCl₂ (0.05 equiv, 0.05 mmol) at r.t. The initial reddish color was turned to easily identifiable green color after 2-3 min, the corresponding lactone (1 equiv, 1 mmol) was then added in anhyd THF (12 mL). Finally ethyl bromodifluoroacetate (5 equiv, 5 mmol) in anhyd THF (6 mL) was added. The reaction was stirred at the same temperature under inert atmosphere for 12 h. The resulting mixture was then diluted with 1 N aq HCl and stirred for 10 min before extraction with CH₂Cl₂. The extracts were dried over anhyd MgSO₄. After removal of the solvent under reduced pressure, the crude material thus obtained was subjected to flash silica gel chromatography.
Method C.
To a mixture of (3.5 equiv, 1.33 mmol) of Zn and CeCl₃ (0.06 equiv, 0.023 mmol) in anhyd THF (3 mL) was added a solution of the required lactone (1 equiv, 0.38 mmol) in anhyd THF (6 mL) at r.t. Ethyl bromodifluoroacetate (3 equiv, 1.8 mmol) was added. The reaction mixture was stirred at the same temperature under inert atmosphere for 2-3 h. The resulting mixture was then diluted with 1 N aq HCl and stirred for 10 min before extraction with CH₂Cl₂. The extracts were dried over anhyd MgSO₄. After removal of the solvent under reduced pressure, the crude material thus obtained was subjected to flash silica gel chromatography.
Method D.
To a solution of the required lactone (0.22 mmol, 1 equiv) in anhyd and degassed THF (20 mL) was added, at r.t. and under argon, ethyl bromodifluoroacetate (0.66 mmol, 3 equiv). At this moment, a 0.037 M solution of SmI₂ (50 mL, 8.40 equiv) was added, at r.t., until the blue color persisted. The reaction was stirred at the same temperature until the blue color disappeared and the mixture turned yellow. The resulting mixture was poured into a solution of NaHCO₃ (30 mL) and stirred for 10 min before extraction with CH₂Cl₂. The extracts were dried over anhyd MgSO₄. After removal of the solvent under reduced pressure, the crude material thus obtained was subjected to flash silica gel chromatography.

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Ethyl 2-{(2 R ,3 R ,4 S ,5 R ,6 R )-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]-tetrahydro-2-hydroxy-2 H -pyran-2-yl}-2,2-difluoroacetate ( 10). Procedure A: column chromatography (cyclohexane-EtOAc = 25:1) of the crude product gave a colorless syrup (73%); [α]_D ²⁰ +49.8 (c 0.616, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.23-7.17 (m, 18 H), 7.12-7.09 (m, 2 H), 4.80 (s, 1 H), 4.73 (m, 4 H), 4.55-4.37 (m, 3 H), 4.15 (q, 2 H, J = 7.17 Hz), 4.10 (m, 1 H), 3.95-3.90 (m, 3 H), 3.68-3.51 (m, 3 H), 1.16 (t, 3 H, J = 7.17 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 162.82 (t, ² J _CF = 30.8 Hz), 138.26, 138.16, 137.90, 137.45, 128.29, 127.82, 127.60, 127.52, 112.30 (dd, J _CF = 263.6 Hz, J _CF = 259.6 Hz), 96.08 (dd, J _CF = 28.17 Hz, J _CF = 26.4 Hz), 83.28, 78.12, 77.33, 75.88, 75.17, 74.97, 73.31, 72.54, 68.16, 63.21, 13.78. ¹⁹F NMR (282 MHz, CDCl₃): δ = -119.94 (d, 1 F, J _FF = 256.5 Hz), -117.63 (d, 1 F, J _FF = 256.5 Hz). MS (EI): 685.3 [M + Na]. Anal. Calcd for C₃₈H₄₀F₂O₈: C, 68.87; H, 6.08. Found: C, 68.56; H, 5.79.

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