The Journal of Organic Chemistry
Note
CDCl3): δ 199.8, 133.4, 132.5, 130.3, 128.6, 128.3, 127.6, 127.6, 127.1,
126.4, 126.0, 47.7, 46.9; HRMS [M + H]+ for C13H11ClO calcd
219.0571, found 219.0573.
solid which was slurried (with stirring) in a mixture of EtOAc (7 mL)
and n-heptane (14 mL) for 2 h. The slurry was filtered, and the cake
was displaced with 1:2 EtOAc/n-heptane (8 mL) and then n-heptane
(6 mL). Drying under vacuum with an N2 sweep afforded 2.12 g of 15
as a white solid; mp = 46.0−48.6 °C. An assay of the liquors showed a
loss of 0.460 g. Thus, the assay yield of 15 was 2.58 g (12.13 mmol,
73% assay yield). 1H NMR (400 MHz, CDCl3): δ 6.78 (d, J = 8.0 Hz,
1H), 6.71 (d, J = 1.8 Hz, 1H), 6.67 (dd, J1 = 8.0 Hz, J2 = 1.8 Hz, 1H),
5.96 (s, 2H), 4.11 (s, 2H), 3.80 (s, 2H); 13C{1H} NMR (100 MHz,
CDCl3): δ 200.0, 148.0, 147.0, 126.2, 122.6, 109.7, 108.5, 101.1, 47.5,
46.3; HRMS [M + H]+ for C10H9ClO3 calcd 213.0313, found
213.0311.
1-Chloro-3-(4-fluorophenyl)propan-2-one (11). As in the
representative procedure, a solution of 4-fluorophenylacetic acid
(1.815 g, 11.78 mmol) in MTBE (6.5 mL) was treated with i-PrMgCl
(22.7 mmol, 12.5 mL of 1.82 M in THF); a solution of 6 (1.20 g, 8.72
mmol) in MTBE (4.5 mL) was added. After typical workup, the
filtered solution was diluted to a 50 mL total in a volumetric flask and
assayed for a 1.548 g total (95% assay yield). Concentration to dryness
afforded a solid that was slurried in n-heptane (3 mL) for 2 h.
Filtration afforded 1.40 g of 11 as a white solid; mp = 38.3−40.6 °C.
An assay of the liquors showed a loss of 0.148 g of 11. 1H NMR (400
MHz, CDCl3): δ 7.22−7.16 (m, 2H), 7.07−7.00 (m, 2H), 4.11 (s,
2H), 3.88 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.5, 161.9
(d, JC−F = 245.9 Hz), 130.9 (d, JC−F = 8.1 Hz), 128.5 (d, JC−F = 3.6
Hz), 115.4 (d, JC−F = 21.7 Hz), 47.7, 45.4 ; HRMS [M + H]+ for
C9H8ClFO calcd 187.0320, found 187.0325.
1-(3-Bromophenyl)-3-chloropropan-2-one (12). As in the
representative procedure, a solution of 3-bromophenylacetic acid
(2.90 g, 13.5 mmol) in MTBE (8.5 mL) was treated with i-PrMgCl
(26.0 mmol, 14.3 mL of 1.82 M in THF); a solution of 6 (1.375 g,
10.0 mmol) in MTBE (4.5 mL) was added. After inverse quenching
into citric acid (20 mL), the pH was adjusted from 3.2 to 4 0.0 by
adding 5 N NaOH. Completion of the typical workup and
concentration of the crude solution afforded 2.29 g of 12 (9.30
mmol, 93% yield) as an oil (12 on occasion would crystallize to a solid
that melted near ambient temperature). 1H NMR (500 MHz, CDCl3):
δ 7.43 (ddd, J1 = 7.9 Hz, J2 = 3.3 Hz, J3 = 1.9 Hz, 1H), 7.38 (dd, J1 =
2.3 Hz, J2 = 1.9 Hz, 1H), 7.21 (dd, J1 = J2 = 7.9 Hz, 1H), 7.16−7.13
(m, 1H), 4.12 (s, 3H), 3.87 (s, 2H); 13C{1H} NMR (125 MHz,
CDCl3): δ 199.3, 135.0, 132.5, 130.6, 130.4, 128.2, 122.8, 47.8, 46.0;
HRMS [M + H]+ for C9H8BrClO calcd 246.9520, found 246. 9517.
1-Chloro-3-(2-methoxyphenyl)propan-2-one (13). As in the
representative procedure, a solution of 3-methoxyphenylacetic acid
(2.24 g, 13.5 mmol) in MTBE (9 mL) and THF (6 mL) was treated
with i-PrMgCl (26.0 mmol, 14.3 mL of 1.82 M in THF); a solution of
6 (1.375 g, 10.0 mmol) in MTBE (4.5 mL) and THF (2 mL) was
added. Following the typical workup, purification by silica gel
chromatography (0 to 30% gradient of ethyl acetate/hexanes)
afforded, after concentration, 1.49 g of 13 (7.485 mmol, 75% yield)
as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.29 (ddd, J1 = J2 =
8.0 Hz, J3 = 1.6 Hz, 1H), 7.16 (dd, J1 = 7.4 Hz, J2 = 1.6 Hz, 1H), 6.94
(ddd, J1 = J2 = 7.4 Hz, J3 = 0.9 Hz, 1H), 6.91−6.87 (m, 1H), 4.17 (s,
2H), 3.82 (s, 2H), 3.82 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
199.8, 157.0, 131.1, 128.9, 122.1, 120.7, 110.4, 55.2, 48.2, 41.9; HRMS
[M + H]+ for C10H11ClO2 calcd 199.0520, found 199.0520.
1-Chloro-3-(3-methoxyphenyl)propan-2-one (14). As in the
representative procedure, a solution of 3-methoxyphenylacetic acid
(2.24 g, 13.5 mmol) in MTBE (9 mL) and THF (6 mL) was treated
with i-PrMgCl (26.0 mmol, 14.3 mL of 1.82 M in THF); a solution of
6 (1.375 g, 10.0 mmol) in MTBE (4.5 mL) and THF (2 mL) was
added. Following the typical workup, purification by silica gel
chromatography (0 to 30% gradient of ethyl acetate/hexanes)
afforded, after concentration, 1.72 g of 14 (8.67 mmol, 87% yield)
as a colorless oil. 1H NMR (400 MHz, d6-dmso): δ 7.23 (dd, J1 = J2 =
7.9 Hz, 1H), 6.85−6.80 (m, 1H), 6.80−6.74 (m, 2H), 4.61 (s, 2H),
3.83 (s, 2H), 3.73 (s, 3H); 13C{1H} NMR (100 MHz, d6-dmso): δ
199.4, 159.2, 153.3, 129.3, 121.9, 115.4, 112.2, 54.9, 49.1, 45.7; HRMS
[M + H]+ for C10H11ClO2 calcd 199.0520, found 199.0525.
1-(Benzo[d][1,3]dioxol-5-yl)-3-chloropropan-2-one (15). As
in the representative procedure, a solution of 3,4-(methylenedioxy)-
phenylacetic acid (3.92 g, 31.75 mmol) in MTBE (20 mL) and THF
(10 mL) was treated with i-PrMgCl (43.5 mmol, 25.0 mL of 1.74 M in
THF); a solution of 6 (2.30 g, 16.73 mmol) in THF (8 mL) was
added. After 30 min, the reaction mixture was inverse quenched into
15% citric acid (30 mL), and the resulting pH = 3.2 aqueous phase was
treated with 5 N NaOH until pH = 4.0. Otherwise typical workup
(modified as follows: 10 mL MTBE extraction, 3 × 15 mL wash with
10% K2CO3 and 20 mL brine wash) afforded, after concentration, a
4-(3-Chloro-2-oxopropyl)benzonitrile (16). As in the repre-
sentative procedure, a solution of 4-cyanophenylacetic acid (1.08 g,
6.70 mmol) in THF (10 mL) was treated with i-PrMgCl (13.26 mmol,
7.15 mL of 1.82 M in THF); a solution of 6 (0.688 g, 5.0 mmol) in
THF (4 mL) was added. After typical workup, the filtered solution was
concentrated to a solid mixture of 6 and 16. This mixture was slurried
in MTBE (4 mL), and n-heptane (4 mL) was added over 1 h. The
resulting slurry was stirred for 2 h and then filtered. The cake was
displacement-washed with 1:1 MTBE/n-heptane (1 mL) and then n-
heptane (1 mL). Drying under vacuum with an N2 sweep afforded 416
mg of 16 as a white solid; mp = 95.5−96.4 °C. An assay of the liquors
showed a loss of 38 mg. Thus, the assay yield of 16 was 454 mg (2.345
1
mmol, 47% assay yield). H NMR (400 MHz, CDCl3): δ 7.68−7.61
(m, 2H), 7.37−7.31 (m, 2H), 4.13 (s, 2H), 4.00 (s, 2H); 13C{1H}
NMR: (100 MHz, CDCl3) δ 198.7, 138.1, 132.2, 130.3, 118.5, 111.2,
47.8, 46.0; HRMS [M + H]+ for C10H8ClNO calcd 194.0367, found
194.0364.
3-(3-Chloro-2-oxopropyl)benzonitrile (17). As in the repre-
sentative procedure, a solution of 3-cyanophenylacetic acid (2.17 g,
13.5 mmol) in MTBE (10 mL) and THF (6 mL) was treated with i-
PrMgCl (26.0 mmol, 14.3 mL of 1.82 M in THF); a solution of 6
(1.375 g, 10.0 mmol) in MTBE (5 mL) and THF (2 mL) was added.
After typical workup, the filtered solution was concentrated to a solid
mixture of 6 and 16. This mixture was slurried in MTBE (6 mL) for 5
h and then filtered. The cake was displacement-washed with MTBE (3
mL). Drying under vacuum with an N2 sweep afforded 1.005 g of 17 as
a white solid; mp = 94.0−96.0 °C. An assay of the liquors showed a
loss of 333 mg. Thus, the assay yield of 17 was 1.338 g (6.91 mmol,
69% assay yield). 1H NMR (400 MHz, CDCl3): δ 7.63−7.57 (m, 1H),
7.54−7.50 (m, 1H), 7.49−7.44 (m, 2H), 4.14 (s, 2H), 3.98 (s, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 199.0, 134.3, 134.2, 133.1,
129.6, 118.5, 112.9, 47.8, 45.5; HRMS [M + H]+ for C10H8ClNO calcd
194.0367, found 193.0365.
1-Chloro-3-(3-(trifluoromethyl)phenyl)propan-2-one (18). As
in the representative procedure, a solution of 3-trifluoromethylphenyl-
acetic acid (2.76 g, 13.5 mmol) in MTBE (10 mL) was treated with i-
PrMgCl (26.0 mmol, 17.5 mL of 1.48 M in THF); a solution of 6
(1.375 g, 10.0 mmol) in THF (7 mL) was added. After typical workup,
the filtered solution was concentrated to a solid which was slurried in
MTBE (0.5 mL) and n-heptane (3 mL) and stirred for 1 h before the
slurry was filtered. The cake was displacement-washed with n-heptane
(3.5 mL). Drying under vacuum with an N2 sweep afforded 1.674 g of
1
18 (7.07 mmol, 71% yield) as a white solid; mp = 41.3−43.3 °C. H
NMR (400 MHz, CDCl3): δ 7.60−7.56 (m, 1H), 7.53−7.48 (m, 2H),
7.45−7.41 (m, 1H), 4.16 (s, 2H), 4.02 (s, 2H); 13C{1H} NMR (100
MHz, CDCl3): δ 199.3, 133.7, 133.0, 131.1 (q, JC−F = 32.5 Hz), 129.3,
126.3 (q, JC−F = 3.8 Hz), 124.3 (q, JC−F = 3.8 Hz), 123.9 (q, JC−F
=
272.3 Hz), 47.8, 46.0; HRMS [M + H]+ for C10H8ClF3O calcd
237.0289, found 236.0297.
Dicyclohexylammonium 2-(4-Cyanophenyl)-4-(methoxy-
(methyl)amino)-4-oxobutanoate (19). A mixture of 4-cyano-
phenylacetic acid and (free acid) 19 (∼100 mg) in a 1:4 HPLC
ratio from the K2CO3 washes was diluted with EtOH (1 mL) and
treated with H2SO4 (15 μL) to selectively esterify 4-cyanophenylacetic
acid. The remaining solution of (free acid) 19 was treated with Cy2NH
(200 μL) resulted in crystallization of 19 (93 mg) as a white solid; mp
1
= 155.7−156.4 °C. H NMR (400 MHz, CDCl3): δ 7.59−7.55 (m,
2H), 7.49−7.45 (m, 2H), 3.98 (dd, J1 = 10.1 Hz, J2 = 5.2 Hz, 1H), 3.67
8921
dx.doi.org/10.1021/jo5016486 | J. Org. Chem. 2014, 79, 8917−8925