54
A. Bermejo Góme et al. / Journal of Fluorine Chemistry 194 (2017) 51–57
at 100 MHz, 19F NMR spectra were recorded at 377 MHz with a
Bruker Advance spectrometer. 1H and 13C NMR chemical shifts (
19%). 1H NMR (400 MHz, CDCl3, TMS):
d= 4.84 (td, J(H,H) = 11.0,
d
)
4.5 Hz,1H), 2.09–2.04 (m, 1H), 1.97–1.87 (m, 1H), 1.77–1.69 (m, 2H),
1.58–1.47 (m, 2H),1.18–1.07 (m, 2H), 0.97–0.85 (m,1H), 0.95 (d, J(H,
H) = 6.6 Hz, 3H), 0.92 (d, J(H,H) = 7.0 Hz, 3H), 0.79 (d, J(H,H) = 7.0 Hz,
are reported in ppm from tetramethylsilane, using the residual
solvent resonance (CHCl3: dH 7.26 and CDCl3: dC 77.0) as an internal
reference. Coupling constants (J) are given in Hz. High-resolution
mass spectra (HRMS) were recorded with a Bruker microTOF ESI-
TOF mass spectrometer. We were not able to obtain high-
resolution mass data for some of the substrates/products.
Therefore, we provide EI mass data in the characterization. NMR
3H). 13C NMR (100 MHz, CDCl3, TMS):
d
= 159.4 (t, J(C,F) = 30.8 Hz),
109.1 (t, J(C,F) = 314.8 Hz), 79.7, 46.9, 40.0, 34.1, 31.6, 26.3, 23.5, 22.0,
20.7, 16.3. 19F NMR (377 MHz, CDCl3):
= À60.63 (d, J(F,
F) = 162.7 Hz, 1F), À61.04 (d, J(F,F) = 162.8 Hz, 1F). HRMS (ESI): m/
calcd for C12H19O279BrF2 + Na+: 335.0429 [M+Na]+; found:
d
z
yields were calculated using
a
,a
,a
-trifluorotoluene or 2,2,2-
335.0429.
trifluoroacetophenone as internal standards.
4.2.5. 2-Phenoxyethyl 2-bromo-2,2-difluoroacetate (1f)
4.2. General procedure A for the synthesis of bromodifluoroacetates
1b–f, 1h
Following the general procedure A from 2-phenoxyethanol
(425 mg). Purification by column chromatography (SiO2; EtOAc/
Pentane 1:20) afforded the title compound as a colorless oil
In a 20 mL glass vial the corresponding alcohol (3.08 mmol, 1
equiv.) was dissolved in hexane (5 mL) under an atmosphere of
air. Ethyl 2-bromo-2,2-difluoroacetate (12.3 mmol, 4 equiv., 2.5 g)
was added followed by 2 drops of concentrated H2SO4 and the
reaction was stirred at room temperature for 16 h. The reaction
was quenched with Na2CO3 (satd. aq, 10 mL), extracted with
EtOAc (3 Â10 mL) and washed with Na2CO3 (satd. aq). The
combined organic phases were dried over MgSO4 and the solvent
was removed under reduced pressure. Purification by column
chromatography afforded the desired esters.
(405 mg, 45%). 1H NMR (400 MHz, CDCl3, TMS):
d
= 7.33–7.28 (m,
2H), 7.02–6.98 (m,1H), 6.94–6.90 (m, 2H), 4.71–4.69 (m, 2H), 4.29–
4.26 (m, 2H). 13C NMR (100 MHz, CDCl3, TMS):
= 159.7 (t, J(C,
F) = 31.7 Hz), 158.2, 129.7, 121.7, 114.9, 108.6 (t, J(C,F) = 314.1 Hz),
d
66.3, 65.2. 19F NMR (377 MHz, CDCl3):
d
= À60.84. HRMS (ESI): m/z
calcd for C10H9O379BrF2 + Na+: 316.9595 [M+Na]+; found: 316.9599.
4.2.6. Benzyl 2-bromo-2,2-difluoroacetate (1h)
Following the general procedure
A from benzyl alcohol
(333 mg). Purification by column chromatography (SiO2; EtOAc/
Pentane 1:40) afforded the title compound as a colorless oil
4.2.1. Dodecyl 2-bromo-2,2-difluoroacetate (1b)
(367 mg, 45%). 1H NMR (400 MHz, CDCl3, TMS):
d
= 7.42–7.38 (m,
= 159.6 (t, J(C,
F) = 31.5 Hz), 133.6, 129.3, 129.0, 128.7, 108.9 (t, J(C,F) = 314.4 Hz),
69.9. 19F NMR (377 MHz, CDCl3):
= À60.70.
Following the general procedure A from dodecanol (573 mg).
Purification by column chromatography (SiO2; EtOAc/Pentane
1:10) afforded the title compound as a colorless oil (801 mg, 76%).
5H), 5.36 (s, 2H). 13C NMR (100 MHz, CDCl3, TMS):
d
d
1H NMR (400 MHz, CDCl3, TMS):
d
= 4.35 (t, J(H,H) = 6.7 Hz, 2H),
1.78–1.71 (m, 2H), 1.43-1.26 (m, 18H), 0.90–0.86 (m, 3H). 13C NMR
(100 MHz, CDCl3, TMS): = 159.8 (t, J(C,F) = 31.1 Hz), 108.9 (t, J(C,
F) = 314.3 Hz), 68.7, 32.1, 29.8, 29.7, 29.6, 29.5, 29.2, 28.3, 25.7, 22.8,
4.3. 6-(1,3-Dioxoisoindolin-2-yl)hexyl 2-bromo-2,2-difluoroacetate
(1g)
d
14.3. 19F NMR (377 MHz, CDCl3):
d
= À60.66.
In a 50 mL bottom flask 2-(6-hydroxyhexyl)isoindoline-1,3-
dione (2.0 mmol, 1 equiv., 495 mg) and Et3N (4.0 mmol, 2 equiv.,
405 mg) were dissolved in dichloromethane (20 mL) under an
atmosphere of argon. 2-Bromo-2,2-difluoroacetyl chloride
(2.8 mmol, 1.4 equiv., 541 mg) was added dropwise and the
reaction was stirred at 0 ꢀC for 2 h. The reaction was quenched
with NH4Cl (satd. aq, 10 mL) and extracted with dichloromethane
(3 Â10 mL). The combined organic phases were dried over MgSO4
and the solvent was removed under reduced pressure. Purification
by column chromatography (SiO2; EtOAc/Pentane 1:10) afforded
the title compound as a colorless oil (492 mg, 61%). 1H NMR
HRMS (ESI): m/z calcd for C14H24O279BrF2 + Na+: 364.0820 [M
+Na]+; found: 364.0821.
4.2.2. 5-Phenylpentyl 2-bromo-2,2-difluoroacetate (1c)
Following the general procedure A from 5-phenylpentan-1-ol
(505 mg). Purification by column chromatography (SiO2; EtOAc/
Pentane 1:10) afforded the title compound as a colorless oil
(744 mg, 75%). 1H NMR (400 MHz, CDCl3, TMS):
d= 7.30–7.26 (m,
2H), 7.20–7.16 (m, 3H), 4.35 (t, J(H,H) = 6.6 Hz, 2H),), 2.66–2.62 (m,
2H), 1.82–1.75 (m, 2H), 1.72–1.64 (m, 2H), 1.48–1.41 (m, 2H). 13C
NMR (100 MHz, CDCl3, TMS):
d
= 159.8 (t, J(C,F) = 31.2 Hz), 142.2,
(400 MHz, CDCl3, TMS):
4.34 (t, J(H,H) = 6.6 Hz, 2H), 3.71–3.67 (m, 2H), 1.79–1.67 (m, 4H),
1.50–1.36 (m, 4H). 13C NMR (100 MHz, CDCl3, TMS):
= 168.6, 159.7
d= 7.87–7.82 (m, 2H), 7.74–7.69 (m, 2H),
128.5, 128.4, 125.9, 108.9 (t, J(C,F) = 314.3 Hz), 68.4, 35.8, 30.9, 28.1,
25.2. 19F NMR (377 MHz, CDCl3):
d
= À60.72. HRMS (ESI): m/z calcd
d
for C13H15O279BrF2 + Na+: 343.0116 [M+Na]+; found: 343.0113.
(t, J(C,F) = 31.2 Hz), 134.0, 132.2, 123.3, 108.9 (t, J(C,F) = 314.3 Hz),
68.4, 37.9, 28.5, 28.1, 26.4, 25.3. 19F NMR (377 MHz, CDCl3):
4.2.3. 1-Adamantaneethyl 2-bromo-2,2-difluoroacetate (1d)
Following the general procedure A from 1-adamantaneethanol
(554 mg). Purification by column chromatography (SiO2; EtOAc/
Pentane 1:10) afforded the title compound as a colorless oil
d
= À60.71. HRMS (ESI): m/z calcd for C16H16O4N79BrF2 + Na+:
426.0123 [M+Na]+; found: 426.0133.
4.4. 2-Bromo-2,2-difluoro-1-phenylethan-1-one (1i)
(732 mg, 71%). 1H NMR (400 MHz, CDCl3, TMS):
d
= 4.41 (t, J(H,
H) = 7.3 Hz, 2H), 2.00–1.95 (m, 3H), 1.75–1.69 (m, 3H), 1.66–1.61 (m,
3H), 1.56–1.52 (m, 8H). 13C NMR (100 MHz, CDCl3, TMS):
= 159.8
(t, J(C,F) = 31.1 Hz), 109.0 (t, J(C,F) = 314.4 Hz), 65.3, 42.5, 41.9, 37.0,
Following the reported procedure with slight modifications
[20]: a solution of bromobenzene (15.0 mmol, 1.1 equiv., 2.36 g) in
dry Et2O (3 mL) was added dropwise to a suspension of Mg
(18.0 mmol,1.32 equiv., 437 mg) in dry Et2O (20 mL) in a sealed MW
vial. The reaction was heated at 50 ꢀC after the addition of 1.5 mL of
the solution and then it was stirred at room temperature (the
reaction is refluxing with the slow addition of the solution of 2-
bromoethylbenzene). After the reflux is stopped, the reaction
mixture was heated at 50 ꢀC for 2 h. To a solution of ethyl 2-bromo-
2,2-difluoroacetate (13.64 mmol, 1.0 equiv., 2.77 g) in dry Et2O
(14 mL) at À78 ꢀC, the readily prepared phenethylmagnesium
d
31.9, 28.6. 19F NMR (377 MHz, CDCl3):
d
= À60.66. HRMS (ESI): m/z
calcd for C14H19O279BrF2 + Na+: 359.0429 [M+Na]+; found:
359.0433.
4.2.4. (À)-Menthyl 2-bromo-2,2-difluoroacetate (1e)
Following the general procedure A from (À)-menthol (554 mg).
Purification by column chromatography (SiO2; EtOAc/Pentane
1:10) afforded the title compound as a light yellow oil (186 mg,