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F. Stazi et al.
PAPER
(2-Nitrophenyl)acetonitrile
tracted with EtOAc (2 × 50 mL). The combined organic layers were
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The resulting material was dried under a high vacuum for several
hours to give a reddish oil; yield: 9.5 g (>99%; uncorrected).
1H NMR (600 MHz, CDCl3): d = 1.33 (t, J = 7.2 Hz, 3 H), 4.31 (q,
J = 7.2 Hz, 2 H), 4.88 (s, 1 H), 7.80 (d, J = 8.1 Hz, 1 H), 8.07 (dd,
J = 8.1, 1.5 Hz, 1 H), 8.82 (d, 1.5 Hz, 1 H).
A soln of ethyl cyano(2-nitrophenyl)acetate (1.87 g, 7.99 mmol) in
a mixture of DMSO (4 mL) and brine (1 mL) was heated at 120 °C
until the reaction was complete (7 h), then cooled to r.t. The result-
ing mixture was diluted with EtOAc (20 mL) and H2O (5 mL), and
the biphasic system was separated. The organic layer was washed
successively with H2O (5 mL) and brine (5 mL) then dried (Na2SO4)
and concentrated under reduced pressure. A brown solid was ob-
tained that was purified by precipitation in EtOAc (6 mL) and cy-
clohexane (10 mL) to give a yellow solid; yield: 0.75 g (58%).
13C NMR (100.52 MHz, CDCl3): d = 13.81, 41.02, 64.22, 114.03,
120.87, 121.06, 129.27, 137.10, 148.90, 149.34, 163.40.
19F NMR (376 MHz, CDCl3): d = –68.12 (s, 3 F).
MS (ESI): m/z [M + H]+ = 259.
HRMS (ESI): m/z [M – H]– calcd for C11H9F3N2O2: 257.0538;
1H NMR (400 MHz, DMSO-d6): d = 4.35 (s, 2 H), 7.66 (ddd, 1 H),
7.71–7.76 (m, 1 H), 7.83 (dt, 1 H), 8.16 (dd, 1 H).
13C NMR (100.52 MHz, DMSO-d6): d = 21.54, 117.85, 125.41,
126.36, 129.68, 131.70, 134.60, 147.63.
MS (ESI): m/z [M + H]+ = 163.
HRMS (ESI): m/z [M – H]– calcd for C8H6N2O2: 161.0351; found:
found: 257.0544.
[6-(Trifluoromethyl)pyridin-3-yl]acetonitrile
A soln of ethyl cyano[6-(trifluoromethyl)pyridin-3-yl]acetate (9.5
g, 36.79 mmol) in DMSO (100 mL) was treated with brine (50 mL).
The resulting orange soln was heated to 110–120 °C. After 2 h, the
mixture was cooled to 25 °C, diluted with EtOAc (100 mL), and
washed successively with H2O (100 mL) and brine (100 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated under
reduced pressure to give an oil that was purified on silica gel
(EtOAc–cyclohexane, 1:1); yield: 3.42 g (50%).
1H NMR (600 MHz, CDCl3): d = 3.89 (s, 2 H), 7.75 (d, J = 8.1 Hz,
1 H), 7.94 (dd, J = 8.1, 1.7 Hz, 1 H), 8.70 (d, 1.7 Hz, 1 H).
13C NMR (150.81 MHz, CDCl3): d = 21.15, 115.93, 120.76 (q,
J = 2.6 Hz), 120.77 (q, J = 274.0 Hz), 129.31, 136.92, 148.17 (q,
J = 34.8 Hz), 149.27.
161.0350.
Ethyl Cyano(2-cyanophenyl)acetate
K2CO3 (325 mesh; 3.3 g, 23.88 mmol) and BnN+Et3Cl– (21.6 mg,
0.10 mmol) were added to a soln of 2-fluorobenzonitrile (1.1 g, 9.08
mmol) and EtO2CCH2CN (853 mL, 8.02 mmol) in DMSO (4.5 mL)
at r.t. under N2, and the resulting mixture was heated to 90 °C and
stirred for 12 h. The mixture then was cooled to r.t., diluted with
EtOAc (10 mL), and poured into cooled 6 M HCl (20 mL). The bi-
phasic system was separated, and the aqueous phase was extracted
with EtOAc (15 mL). The combined organic layers were washed
with H2O then dried (Na2SO4) and concentrated under reduced pres-
sure to give an oil; yield: 1.6 g (82%).
1H NMR (400 MHz, DMSO-d6): d = 1.23 (t, J = 7.12 Hz, 3 H), 4.26
(q, J = 7.16 Hz, 2 H), 6.07 (s, 1 H), 7.65–7.72 (m, 2 H), 7.81–7.87
(m, 1 H), 8.00–8.03 (m, 1 H).
13C NMR (100.52 MHz, DMSO-d6): d = 13.74, 41.63, 63.25,
111.84, 115.36, 116.35, 130.05, 130.25, 133.82, 134.16, 134.23,
163.97.
MS (ESI): m/z [M + H]+ = 187.
HRMS (ESI): m/z [M – H]– calcd for C8H5F3N2: 185.0327; found:
185.0325.
Method C
Potassium (E,Z)-2-cyano-1-ethoxy-2-[2-fluoro-4-(trifluoro-
methyl)phenyl]ethylenolate (10):
HRMS (ESI): m/z [M – H]– calcd for C12H10N2O2: 213.0664; found:
A suspension of 3,4-F2C6H3CF3 (100 g, 549 mmol, 1.1 equiv) and
EtO2CCH2CN (53.2 mL, 500 mmol, 1 equiv), BnN+Et3 Cl– (11.4 g,
50 mmol, 0.1 equiv), and K2CO3 (325 mesh; 207 g, 1.5 mol, 3
equiv) in DMSO (300 mL) was stirred at 90 °C under N2 for 19 h.
The mixture was allowed to cool to 20 °C, diluted with EtOAc (500
mL), and then further cooled to 5 °C. 6 M HCl (500 mL) was added
dropwise, leading to precipitation of a white solid. The resulting
suspension was stirred for 30 min until the precipitate completely
dissolved. The biphasic system was separated, and the organic layer
was washed with H2O (2 × 300 mL) and brine (300 mL). The organ-
ic layer was dried (Na2SO4), filtered, and evaporated to dryness.
MTBE (300 mL) was added followed by t-BuOK (47 g, 418 mmol,
0.8 equiv) in small portions while the temperature was kept below
30 °C. The mixture was then concentrated under vacuum to give a
thick slurry. MeCN (500 mL) was added and the mixture was con-
centrated to 250 mL. The slurry was cooled at 5–8 °C and stirred for
10–12 h. The solid was filtered off, washed with MeCN (50 mL),
and dried under vacuum at 40 °C to give a pale yellow solid; yield:
143.4 g (96%).
213.0662.
2-(Cyanomethyl)benzonitrile
A soln of ethyl cyano(2-cyanophenyl)acetate (1.6 g, 7.47 mmol) in
DMSO (4 mL) and brine (1 mL) was heated at 120 °C until the re-
action was complete (7 h), then cooled to r.t. The resulting mixture
was diluted with EtOAc (20 mL) and H2O (5 mL), and the biphasic
system was separated. The organic layer was washed successively
with H2O (5 mL) and brine (5 mL) then dried (Na2SO4) and concen-
trated under reduced pressure. A brown solid was obtained that was
purified by precipitation in EtOAc (6 mL) and cyclohexane (10 mL)
to give a yellow solid; yield: 0.392 g (37%).
1H NMR (400 MHz, DMSO-d6): d = 4.35 (s, 2 H), 7.66 (ddd, 1 H),
7.71–7.76 (m, 1 H), 7.83 (dt, 1 H), 8.16 (dd, 1 H).
13C NMR (100.52 MHz, DMSO-d6): d = 21.54, 117.85, 125.41,
126.36, 129.68, 131.70, 134.60, 147.63.
MS (ESI): m/z [M + H]+ = 143.
HRMS (ESI): m/z [M – H]– calcd for C9H6N2: 141.0453; found:
1H NMR (400 MHz, DMSO-d6): d = 1.15 (t, J = 7.12 Hz, 3 H), 3.95
(q, J = 7.12 Hz, 2 H), 7.07–7.18 (m, 2 H), 8.25 (m, 1 H).
141.0450.
Ethyl Cyano[6-(trifluoromethyl)pyridin-3-yl]acetate
13C NMR (151 MHz, DMSO-d6): d = 168.1 (s), 154.7 (d, J = 243.6
Hz), 134.7 (d, J = 9.7 Hz), 125.9 (s), 125.4 (br. s), 124.5 (qd,
J = 269.7, 2.9 Hz), 119.8 (m), 118.2 (qd, J = 32.9, 7.7 Hz), 111.2
(dq, J = 26.1, 3.9 Hz), 56.6 (s), 50.3 (s), 15.1 (s).
19F NMR (376 MHz, DMSO-d6): d = –113.19 (m, 1 F) –59.41 (s, 3
F).
K2CO3 (11.3 g, 81.76 mmol) and BnN+Et3Cl– (0.68 g, 2.98 mmol)
were added to a soln of 5-fluoro-2-(trifluoromethyl)pyridine (5 g,
30.29 mmol) and EtO2CCH2CN (3.5 mL, 32.91 mmol) in DMSO
(50 mL). The resulting mixture was heated to 90 °C for 3 h then
cooled to r.t. The slurry was then diluted with EtOAc (50 mL) and
slowly treated with 6 M HCl (50 mL). The aqueous layer was ex-
Synthesis 2010, No. 19, 3332–3338 © Thieme Stuttgart · New York