The Journal of Organic Chemistry
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mL, 19 mmol), [PdCl(η3-C3H5)]2 (0.017 g, 0.047 mmol), and PPh3
(0.049 g, 0.19 mmol) were mixed and dissolved in DMA (4 mL) in a
glovebox under argon atmosphere. The reaction mixture was removed
from the glovebox and stirred overnight at 80 °C, and then it was
diluted with Et2O (25 mL) and CH2Cl2 (25 mL). The organic phase
was washed with H2O (50 mL), the water phase was extracted with
CH2Cl2, and then the organic phases were joined and washed with
brine (50 mL). The organic phase was then dried with Na2SO4,
filtered, and concentrated in vacuo. The crude product was purified by
flash chromatography on silica gel using pentane/CH2Cl2/EtOAc
(30:10:1) as eluent. This afforded the title compound 2b as a yellow
The reaction system was removed from the glovebox and stirred for 20
h at 120 °C, and then it was diluted with Et2O (20 mL) and CH2Cl2
(20 mL) and filtered through Celite. The filtrate was washed with H2O
(2 × 20 mL) and brine (1 × 20 mL), dried with Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified twice by flash
chromatography on silica gel using first CH2Cl2 and then CH2Cl2/
pentane/EtOAc (5:5:1) as eluents. This afforded the title compound
7b as a yellow solid (54 mg, 0.11 mmol, 45%): mp 179.5−183.2 °C;
1H NMR (400 MHz, CDCl3) δ (ppm) 7.98−7.96 (m, 2H), 7.63 (ddd,
J = 12.8 Hz, J = 8.8 Hz, J = 2.4 Hz, 2H), 7.54 (t, J = 8.0 Hz, 1H),
7.24−6.94 (m, 8H), 3.93 (s, 6H), 3.92 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 166.72 (13C), 166.70 (13C), 160.8 (d, JC−F =248.8
Hz), 159.05, 159.02, 138.5 (d, JC−F = 8.3 Hz), 131.74, 131.66, 130.15,
1
solid (0.40 g, 0.93 mmol, 99%): mp 216.8−223.6 °C; H NMR (400
MHz, CDCl3) δ (ppm) 7.57 (dd, J = 8 Hz, J = 4 Hz, 2H), 7.53 (t, J = 8
Hz, 1H), 7.36 (ddd, J = 12 Hz, J = 12 Hz, J = 4 Hz, 2H), 7.25−7.17
(m, 2H), 6.92 (d, J = 8 Hz, 2H), 3.93 (s, 6H); 19F NMR (377 MHz,
CDCl3) δ (ppm) −118.6 (dd, J = 15 Hz, J = 7.5 Hz); LRMS
(MALDI) m/z calcd for C24H15D4Cl2FO2 [M + H+] 433.1, found
433.6. Compound 2b did not provide a signal on the LC-TOF
instrument, and hence, a HRMS of this compound was not possible.
General Procedure for the Alkoxycarbonylation of 2a and
2b. The alkoxycarbonylation of 2a and 2b was performed in a two-
chamber reaction vessel with a total volume of 20 mL using either 9-
methylfluorene-9-carbonyl chloride or 9-methylfluorene-9-[13C]-car-
bonyl chloride as the source of carbon monoxide. The two chambers
were loaded in an argon filled glovebox. Chamber 1 was loaded with
the substrates and reactants needed for the alkoxycarbonylation, and
chamber 2 was loaded with 9-methylfluorene-9-carbonyl chloride or 9-
methylfluorene-9-[13C]-carbonyl chloride, Pd(dba)2 (3.3 mol %), P(t-
Bu)3 (3.3 mol %), PEG 5000 monomethyl ether (0.5 g), and DIPEA.
The chambers were sealed with a screw cap, 2 mm stabilizing PTFE
disk, and a 2 mm thick PTFE-lined silicone disk before taking it out of
the glovebox and heating at the appropriate temperature.
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130.07, 129.9 (d, JC− C = 5.0 Hz), 129.5 (d, JC− C = 4.0 Hz), 129.4 (d,
JC−F = 5.0 Hz), 128.4 (2C), 127.3 (d, JC−F = 4.0 Hz), 126.5 (d, JC−F
=
2.0 Hz), 124.4 (d, JC−F = 12.6 Hz), 122.7 (d, JC−F = 2.8 Hz), 120.9 (d,
JC−F = 3.2 Hz), 120.0 (d, JC−F = 3.0 Hz), 113.3 (d, JC−F = 23.2 Hz),
112.6 (2C), 56.4 (2C), 52.4 (2C); 19F NMR (377 MHz, CDCl3) δ
(ppm) −118.6 (dd, J = 11.3 Hz, J = 7.5 Hz); HRMS (ESI) m/z calcd
for C2613C2H25FO6 [M + Na+] 501.1600, found 501.1588.
(E,E)-1-Fluoro-2,5-bis(3-methoxy[13C]carbonyl-4-methoxy)-
1,1′,2,2′-tetradeuterostyrylbenzene (7c). Chamber 1: (E,E)-1-
Fluoro-2,5-bis(3-chloro-4-methoxy)-1,1′,2,2′-tetradeutero-styrylben-
zene (2b) (108 mg, 0.250 mmol), MeOH (203 μL, 5.00 mmol),
K2CO3 (104 mg, 0.750 mmol), dcpp·2HBF4 (25 mg, 0.040 mmol),
Pd(OAc)2 (5.0 mg, 0.020 mmol), pulverized 4 Å molecular sieves (140
mg) were mixed in DMSO (1 mL). Chamber 2: Pd(dba)2 (14 mg,
0.025 mmol), P(t-Bu)3 (5.0 mg, 0.025 mmol), 9-methylfluorene-9-
[13C]-carbonyl chloride (183 mg, 0.750 mmol), PEG 5000
monomethyl ether (0.5 g) and DIPEA (196 μL, 1.13 mmol). The
reaction system was removed from the glovebox and stirred for 20 h at
120 °C where after it was diluted with Et2O (20 mL) and CH2Cl2 (20
mL) and filtered through Celite. The filtrate was washed with H2O (2
× 20 mL) and brine (1 × 20 mL), dried with Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified twice by flash
chromatography on silica gel using first CH2Cl2 and then CH2Cl2/
Pentane/EtOAc (5:5:1) as eluents. This afforded the title compound
7c as a yellow solid (69 mg, 0.14 mmol, 46%): mp 177.8−180.7 °C;
1H NMR (400 MHz, CDCl3) δ (ppm) 7.97−7.96 (m, 2H), 7.60 (ddd,
(E,E)-1-Fluoro-2,5-bis(3-methoxycarbonyl-4-methoxy)-
styrylbenzene (7a). Chamber 1: (E,E)-1-Fluoro-2,5-bis(3-chloro-4-
methoxy)styrylbenzene (2a) (107 mg, 0.250 mmol), MeOH (203 μL,
5.00 mmol), K2CO3 (104 mg, 0.750 mmol), dcpp·2HBF4 (25 mg,
0.040 mmol), Pd(OAc)2 (5.0 mg, 0.020 mmol), and pulverized 4 Å
molecular sieves (140 mg) were mixed in DMSO (1 mL). Chamber 2:
Pd(dba)2 (14 mg, 0.025 mmol), P(t-Bu)3 (5.0 mg, 0.025 mmol), 9-
methylfluorene-9-carbonyl chloride (182 mg, 0.750 mmol), PEG 5000
monomethyl ether (0.5 g), and DIPEA (196 μL, 1.13 mmol). The
reaction system was removed from the glovebox and stirred for 20 h at
120 °C, and then it was diluted with Et2O (20 mL) and CH2Cl2 (20
mL) and filtered through Celite. The filtrate was washed with H2O (2
× 20 mL) and brine (1 × 20 mL), dried with Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified twice by flash
chromatography on silica gel using first CH2Cl2 and then CH2Cl2/
pentane/EtOAc (5:5:1) as eluents. This afforded the title compound
7a as a yellow solid (75 mg, 0.16 mmol, 63%): mp 179.0−182.2 °C;
1H NMR (400 MHz, CDCl3) δ (ppm) 7.96 (dd, J = 4.0 Hz, J = 2.4
J = 12.8 Hz, J = 8.4 Hz, J = 2.0 Hz, 2H), 7.53 (t, J = 8.0 Hz, 1H), 7.23
(dd, J = 8.0 Hz, J = 1.2 Hz, 1H), 7.18 (dd, J = 12.0 Hz, J = 1.2 Hz,
1H), 6.97 (dd, J = 8.8 Hz, J = 1.6 Hz, 2H), 3.93 (s, 6H), 3.92 (s, 6H);
13C NMR (100 MHz, CDCl3) δ (ppm) 166.49 (13C), 166.46 (13C),
160.6 (d, JC−F =249 Hz), 158.79, 158.76, 138.2 (d, JC−F = 8.1 Hz),
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131.5, 131.4, 129.9, 129.8, 129.6 (d, JC− C = 5.0 Hz), 129.2 (d, JC−
=
C
4.0 Hz), 127.0 (d, JC−F = 4.0 Hz), 124.1 (d, JC−F = 13.1 Hz), 122.4 (d,
JC−F = 3.0 Hz), 120.6 (d, JC−F = 3.0 Hz), 119.9 (d, JC−F = 3.0 Hz),
113.1 (d, JC−F = 22.2 Hz), 112.3 (2C), 56.2 (2C), 52.1 (2C); 19F
NMR (377 MHz, CDCl3) δ (ppm) −118.5 (dd, J = 12.4 Hz, J = 8.3
Hz); HRMS (ESI) m/z calcd for C2613C2H21D4FO6 [M + Na+]
505.1851, found 505.1850. The C−D carbon signals are so small due
to the deuterium coupling that they disappear from the 13C NMR
spectrum.
Hz, 2H), 7.59 (ddd, J = 13.2 Hz, J = 8.8 Hz, J = 2.4 Hz, 2H), 7.52 (t, J
= 8 Hz, 1H), 7.23−6.91 (m, 8H), 3.92 (s, 6H), 3.92 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 166.72, 166.70, 160.8 (d, JC−F
=249 Hz), 159.04, 159.01, 138.5 (d, JC−F = 8.3 Hz), 131.74, 131.65,
130.13, 130.05, 129.9, 129.5, 129.3 (d, JC−F = 4.9 Hz), 128.4 (2C),
(E,E)-1-Fluoro-2,5-bis(3-methoxycarbonyl-4-hydroxy)-styryl-
benzene (8a). (E,E)-1-Fluoro-2,5-bis(3-methoxycarbonyl-4-
methoxy)styrylbenzene (7a) (47 mg, 0.099 mmol) was dissolved in
dry CH2Cl2 (15 mL) under argon atmosphere. The solution was
cooled to −78 °C, and BBr3 was added dropwise (1 M in hexane, 0.75
mL, 0.75 mmol). The mixture was subsequently allowed to warm to rt
and cooled to 0 °C, at which point the reaction was quenched with
H2O. The mixture was extracted with CH2Cl2 (2 × 15 mL), and the
organic phase washed with brine (2 × 15 mL), dried with Na2SO4,
filtered, and concentrated in vacuo. This afforded the title compound
127.3 (d, JC−F = 4.3 Hz), 126.5 (d, JC−F = 2.3 Hz), 124.4 (d, JC−F
=
12.6 Hz), 122.7 (d, JC−F = 2.8 Hz), 120.5 (d, JC−F = 3.2 Hz), 120.0 (d,
JC−F = 3.1 Hz), 113.3 (d, JC−F = 23.2 Hz), 112.6 (2C), 56.4 (2C),
52.37, 52.36; 19F NMR (377 MHz, CDCl3) δ (ppm) −118.6 (dd, J =
12.1 Hz, J = 7.9 Hz); HRMS (ESI) m/z calcd for C28H25FO6 [M +
Na+] 499.1533, found 499.1540.
(E,E)-1-Fluoro-2,5-bis(3-methoxy[13C]carbonyl-4-methoxy)-
styrylbenzene (7b). Chamber 1: (E,E)-1-Fluoro-2,5-bis(3-chloro-4-
methoxy)-styrylbenzene (2a) (107 mg, 0.250 mmol), MeOH (203 μL,
5.00 mmol), K2CO3 (104 mg, 0.750 mmol), dcpp·2HBF4 (25 mg,
0.040 mmol), Pd(OAc)2 (5.0 mg, 0.020 mmol), and pulverized 4 Å
molecular sieves (140 mg) were mixed in DMSO (1 mL). Chamber 2:
Pd(dba)2 (14 mg, 0.025 mmol), P(t-Bu)3 (5.0 mg, 0.025 mmol), 9-
methylfluorene-9-[13C]-carbonyl chloride (183 mg, 0.750 mmol), PEG
5000 monomethyl ether (0.5 g), and DIPEA (196 μL, 1.13 mmol).
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8a as a yellow solid (42 mg, 0.094 mmol, 95%): mp 223 °C dec; H
NMR (400 MHz, CDCl3) δ (ppm) 10.81 (s, 2H), 7.98 (dd, J = 7.6 Hz,
J = 2.4 Hz, 2H), 7.67 (ddd, J = 10.8 Hz, J = 9.2 Hz, J = 2.4 Hz, 2H),
7.55 (t, J = 8.0 Hz, 1H), 7.24−6.91 (m, 8H), 4.00 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 170.33, 170.28, 161.43, 161.40, 160.6 (d,
JC−F =249 Hz), 138.3 (d, JC−F = 8.3 Hz), 133.4, 133.4, 129.4 (d, JC−F
=
5.2 Hz), 128.9, 128.5, 128.4, 128.20, 128.18, 127.0 (d, JC−F = 4.3 Hz),
5361
dx.doi.org/10.1021/jo300746x | J. Org. Chem. 2012, 77, 5357−5363