H
K. P. Melnykov et al.
Paper
Synthesis
NaHC03 (800 mL). The organic phase was dried over MgS04, filtered
and concentrated in vacuo. The residue was purified by column chro-
matography (silica gel, gradient hexanes to hexanes–EtOAc, 95:5).
CH2Cl2 (3 × 100 mL). The combined organic extracts were dried over
Na2SO4 and concentrated under reduced pressure to give crude prod-
uct 36, which was used in the next step without characterization.
Product 36 was dissolved in MeOH (30 mL), 10% Pd/C (1.30 g) was
added under an argon atmosphere, and the mixture was hydrogenat-
ed with H2 (1 atm) at r.t. overnight. The catalyst was filtered off, and
the filtrates were subjected to fractional distillation in vacuo.
Yield: 30.2 g (66%); yellowish liquid.
1H NMR (400 MHz, CDCl3): δ = 7.43–7.35 (m, 5 H), 4.93 (d, J = 11.3 Hz,
1 H), 4.64 (d, J = 11.4 Hz, 1 H), 4.49 (dd, J = 8.2, 7.2 Hz, 1 H), 3.46 (dd,
J = 18.5, 8.2 Hz, 1 H), 3.36 (dd, J = 18.5, 7.2 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 190.9, 135.6, 128.2, 128.0, 127.8, 87.8,
76.4, 72.8, 48.7.
Yield: 3.37 g (56% from 35).
Spectral and physical data were identical to those described above.
LCMS (CI): m/z = 245/247 [MH]+, 106 [C6H5CHO]+.
3,3-Difluorocyclobutanone (21)
Anal. Calcd for C11H10Cl2O2: C, 53.90; H, 4.11; Cl, 28.93. Found: C,
53.52; H, 4.43; Cl, 28.83.
Alcohol 20 (1.66 g, 15.6 mmol) was added to a suspension of PCC
(4.37 g, 20.2 mmol) in CH2Cl2 (30 mL). The reaction mixture was
stirred at r.t. overnight, then Et2O (60 mL) was added, and the result-
ing mixture was passed through a silica gel pad to remove the chro-
mium salts. The filtrates were subjected to fractional distillation at at-
mospheric pressure.
3-(Benzyloxy)cyclobutanone (34)23,28
Compound 32 (24.5 g, 0.100 mol) was dissolved in AcOH (300 mL).
Zinc dust (32.3 g, 0.500 mol) was added, and the reaction mixture was
stirred at r.t. for 2 h and then reflux for 4 h. The mixture was diluted
with H2O (1.5 L), neutralized with solid NaHCO3, and extracted with
EtOAc (3 × 500 mL). The organic layer was washed with brine (500
mL), dried over Na2SO4, and concentrated in vacuo. The residue was
purified by vacuum distillation.
Yield: 0.632 g (39%); colorless liquid; bp 87–90°C/1 atm.
1H NMR (400 MHz, CDCl3): δ = 3.60 (t, J = 10.1 Hz, 4 H).
13C NMR (125 MHz, CDCl3): δ = 196.7 (t, J = 18.2 Hz), 115.9 (t, J = 271
Hz), 58.1 (t, J = 26.5 Hz).
Yield: 12.7 g (72%); yellowish liquid; bp 72–74 °C/0.1 mmHg (Lit.29
97–102 °C/0.3 mmHg).
1H NMR (400 MHz, CDCl3): δ = 7.44–7.28 (m, 5 H), 4.53 (s, 2 H), 4.41–
19F NMR (376 MHz, CDCl3): δ = –101.7.
GSMS (EI): m/z = 91 [CF2=CHC(O)]+, 64 [CF2CH2]+, 57 [C3H2F]+.
Anal. Calcd for C4H4F2O: C, 45.29; H, 3.80. Found: C, 45.45; H, 3.71.
4.33 (m, 1 H), 3.28–3.10 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 204.8, 137.3, 128.6, 128.0, 127.9, 71.7,
63.7, 54.2.
GCMS (EI): m/z = 176 [M]+.
Acknowledgment
The work was funded by Enamine Ltd. The authors thank Prof. Andrey
Tolmachev for his encouragement and support, Dr. Bohdan B. Kurpil’
for his participation in the compound synthesis, and Mr. Bohdan
Vashchenko for his help with manuscript preparation.
Anal. Calcd for C11H12O2: C, 74.98; H, 6.86. Found: C, 74.79; H, 7.20.
3,3-Difluorocyclobutanol (20)
Method A (from 33): Morpholin-4-ylsulfur trifluoride (Morph-DAST;
31.4 g, 0.179 mol) was added to a stirred solution of ketone 33 (20.0
g, 0.140 mol) in CH2Cl2 (200 mL) at 0 °C for 20 min; then, the resulting
mixture was additionally stirred at r.t. for 3 d. The reaction mixture
was poured into sat. aq NaHCO3 (200 mL) and extracted with CH2Cl2
(3 × 200 mL). The combined organic extracts were dried over Na2SO4
and evaporated in vacuo to give crude product 35, which was used in
the subsequent step without further spectral characterization. Prod-
uct 35 was dissolved in dioxane (160 mL), and 10% HCl in dioxane (16
mL) was added. The resulting mixture was heated at 60 °C overnight,
then diluted with CH2Cl2 (200 mL), dried over Na2SO4, and subjected
to fractional distillation in vacuo.
Supporting Information
Supporting information for this article is available online at
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References
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Yield: 7.97 g (53% from 33); yellowish liquid; bp 84–86 °C/300
mmHg.
1H NMR (500 MHz, CDCl3): δ = 4.33 (dquin, J = 13.1, 7.3 Hz, 1 H), 2.90
(tt, J = 12.6, 6.7 Hz, 2 H), 2.52 (qd, J = 15.6, 5.7 Hz, 2 H), 2.40 (br s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 117.9 (dd, J = 283, 269 Hz), 57.1 (dd,
J = 18.8, 6.7 Hz), 45.4 (dd, J = 23.2, 21.1 Hz).
19F NMR (376 MHz, CDCl3): δ = –84.7 (d, J = 200 Hz), –98.7 (d, J = 200
Hz).
GCMS (EI): m/z = 71 [M – H2O–F]+, 43 [C2H3O]+.
Anal. Calcd for C4H6F2O: C, 44.45; H, 5.60. Found: C, 44.31; H, 5.20.
Method B (from 34): To a stirred solution of 34 (9.80 g, 55.7 mmol) in
CH2Cl2 (100 mL), Morph-DAST (15.4 g, 88.0 mol) was added slowly at
0 °C. The resulting reaction mixture was warmed to r.t. and stirred for
3 d, then poured into sat aq NaHCO3 (300 mL) and extracted with
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I