PAPER
Protic Additives in Michael Addition of Ethyl Bromodifluoroacetate
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tered on a pad of Celite to remove the insoluble materials. The fil-
trate was washed with aq 10% NH4Cl (5.8 mL) and concentrated
under reduced pressure to give crude 4a as a light yellow oil
(1.19 g) in 96% yield with >98% purity by 1H NMR analysis using
9-fluorenone as an internal standard. No column chromatography
was carried out.
1H NMR (500 MHz, CDCl3): δ = 4.32 (q, J = 7.2 Hz, 2 H), 4.15 (q
, J = 7.2 Hz, 2 H), 2.52 (m, 2 H), 2.41 (m, 2 H), 1.35 (t, J = 7.2 Hz,
3 H), 1.25 (t, J = 7.2 Hz, 3 H).
Ethyl 2,2-Difluoro-3-methyl-5-oxopentanoate (4g)
Yield: 0.56 g (58%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 9.77 (s, 1 H), 4.34 (q, J = 7.2 Hz,
2 H), 3.01–2.88 (m, 1 H), 2.84 (dd, J = 18.1, 4.0 Hz, 1 H), 2.46 (ddd,
J = 18.1, 8.9, 1.6 Hz, 1 H), 1.36 (t, J = 7.2 Hz, 3 H), 1.08 (d, J = 4.0
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 199.9, 163.9 (t, J = 33.0 Hz),
117.2 (t, J = 251.6 Hz), 63.2, 43.6 (t, J = 3.4 Hz), 32.6 (t, J = 21.8
Hz), 15.4, 14.1 (t, J = 4.4 Hz).
13C NMR (125 MHz, CDCl3): δ = 171.7, 163.9 (t, J = 40.0 Hz),
115.7 (t, J = 251.6 Hz), 64.8, 63.1, 61.0, 30.0 (t, J = 20.1 Hz), 26.7,
13.9 (t, J = 20.1 Hz).
GC/MS (EI): m/z = 194 [M+].
Ethyl 2,2-Difluoro-5-oxohexanoate (4h)
Yield: 0.88 g (90%); colorless oil.
GC/MS (EI): m/z = 224 [M+].
1H NMR (400 MHz, CDCl3): δ = 4.32 (q, J = 7.0 Hz, 2 H), 2.69 (t,
J = 7.9 Hz, 2 H), 2.43–2.31 (m, 2 H), 2.19 (s, 3 H), 1.36 (t, J = 7.0
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 206.1, 164.3 (t, J = 35.0 Hz),
116.0 (t, J = 251.6 Hz), 63.3, 35.7 (t, J = 10.1 Hz), 30.1, 28.8 (t, J =
20.1 Hz), 14.2.
Ethyl 2,2-Difluoro-2-(3-oxocyclohexyl)acetate (4b)
Yield: 1.07 g (97%); pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 4.35 (q, J = 7.0 Hz, 2 H), 2.70–
1.66 (m, 9 H), 1.37 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 209.1, 163.6 (t, J = 32.4 Hz),
116.1 (t, J = 252.6 Hz), 63.1, 42.5 (t, J = 23.4 Hz), 40.9, 39.7 (t, J =
3.6 Hz), 24.0, 23.4 (t, J = 4.2 Hz), 14.0.
GC/MS (EI): m/z = 194 [M+].
GC/MS (EI): m/z = 220 [M+].
Major Byproduct 6a
Yield: 0.222 g (15%); oil.
1H NMR (500 MHz, CDCl3): δ = 4.32 (q, J = 7.1 Hz, 2 H), 4.15 (dq,
J = 7.2, 2.0 Hz, 4 H), 3.69 9 (t, J = 6.4 Hz, 1 H), 2.78 (dt, J = 16.8,
6.4 Hz, 2 H), 1.35 (t, J = 7.1 Hz, 3 H), 1.28 (t, J = 7.2 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 167.7, 163.1 (t, J = 32.1 Hz),
114.6 (t, J = 249.8 Hz), 63.0, 61.8, 45.5, 33.2 (t, J = 23.8 Hz), 13.6,
13.5.
GC/MS (EI): m/z = 296 [M+].
HRMS (EI): m/z [M]+ calcd for C12H18F2O6: 206.1072; found:
Ethyl 2,2-Difluoro-3-methyl-5-oxoheptanoate (4c)
Yield: 1.02 g (92%); pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 4.32 (q, J = 7.0 Hz, 2 H), 2.97–
2.84 (m, 1 H), 2.77 (dd, J = 17.7, 4.0 Hz, 1 H), 2.48–2.38 (m, 3 H),
1.36 (t, J = 7.0 Hz, 3 H), 1.07 (t, J = 7.3 Hz, 3 H), 1.01 (d, J = 7.0
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 208.6, 164.2 (t, J = 30.2 Hz),
117.5 (t, J = 251.6 Hz), 63.2, 41.8, 36.7, 33.9 (t, J = 22.1 Hz), 14.2,
13.3 (t, J = 4.5 Hz), 7.9.
205.1066.
GC/MS (EI): m/z = 222 [M+].
Ethyl 2,2-Difluoro-5-oxo-3,5-diphenylhexanoate (4d)
Supporting Information for this article is available online at
are spectroscopic data (1H and 13C NMR spectra of the Michael ad-
Yield: 0.59 g (35%); white solid; mp 65–66 °C.
1H NMR (400 MHz, CDCl3): δ = 7.94–7.92 (m, 2 H), 7.57–7.53 (m,
1 H), 7.46–7.43 (m, 2 H), 7.37–7.35 (m, 2 H), 7.29–7.23 (m, 3 H),
4.36–4.24 (m, 1 H), 4.14 (q, J = 7.0 Hz, 2 H), 3.67 (s, 1 H), 3.65 (d
J = 2.4 Hz, 1 H), 1.14 (t, J = 7.0 Hz, 3 H).
ducts, 4a–h, and byproduct 6a).SnoIufproi
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References
13C NMR (100 MHz, CDCl3): δ = 196.6, 163.9 (t, J = 30.2 Hz),
136.9, 135.6, 135.5, 134.3, 133.9, 130.1, 129.1, 128.9, 117.0 (t, J =
256.6 Hz), 63.3, 45.6 (t, J = 20.1 Hz), 37.9, 14.1.
(1) O’Hagan, D.; Schaffrath, C.; Cobb, S. L.; Hamilton, J. T. G.;
Murphy, C. D. Nature 2002, 416, 279.
LC/MS (ESI): m/z = 333 [M + H+].
(2) (a) Bölm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn,
B.; Muller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem
2004, 5, 637. (b) Thayer, A. M. Chem. Eng. News 2006, 84
(23), 15. (c) Hagmann, W. K. J. Med. Chem. 2008, 51, 4358.
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(5) (a) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619.
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789.
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Ethyl 4-Cyano-2,2-difluorobutanoate (4e)
Yield: 0.81 g (91%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 4.37 (q, J = 7.0 Hz, 2 H), 2.63 (m,
2 H), 2.48 (m, 2 H), 1.38 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.2 (t, J = 35.2 Hz), 118.1,
114.6 (t, J = 50.3 Hz), 63.4, 30.8 (t, J = 25.2 Hz), 14.1, 10.6 (t, J =
7.0 Hz).
GC/MS (EI) m/z = 177 [M+].
Ethyl 2,2-Difluoro-4-(benzenesulfonyl)butanoate (4f)
Yield: 1.24 g (85%); viscous oil.
1H NMR (400 MHz, CDCl3): δ = 7.98–7.96 (m, 2 H), 7.82–7.78 (m,
1 H), 7.72–7.65 (m, 2 H), 4.27 (q, J = 7.0 Hz, 2 H), 3.57–3.48 (m, 2
H), 2.50–2.40 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 163.3 (t, J = 30.2 Hz), 138.7,
134.7, 130.0, 128.4, 114.7 (t, J = 251.6 Hz), 63.9, 49.3 (t, J = 10.1
Hz), 28.6 (t, J = 251.6 Hz), 14.2.
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211923.
GC/MS (EI): m/z = 219 [M+ – CO2Et].
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3165–3170