The Journal of Organic Chemistry
Note
over magnesium sulfate, filtered, and evaporated to dryness. The
residue was purified by chromatography on silica gel (hexanes/ethyl
acetate 4:1 → 2:1), affording the target compound as a yellow
crystalline solid (5.46 g, 51% yield): mp 84 °C; 1H NMR (CDCl3, 400
(d, J = 10.95 Hz, 1H), 3.50 (s, 2H); 13C NMR (DMSO-d6, 101 MHz)
δ ppm 171.7, 160.6, 158.2, 153.1, 152.9, 132.0, 114.7, 113.9, 113.7,
103.7, 103.4, 33.1. HRMS: m/z calcd for C8H7ClFO3 (M + H)+:
205.0068. Found: 205.0064. IR: 3399, 2961, 1694, 1622, 1587, 1501,
4
3
MHz) δ ppm 7.63 (d, JH,F = 7.6 Hz, 1H), 6.75 (d, JH,F = 11.5 Hz,
1H), 5.71 (d, J = 6.4 Hz, 1H), 3.93 (s, 3H), 2.81 (d, J = 6.1 Hz, 1H);
13C NMR (DMSO-d6, 100 MHz) δ ppm 159.0 (1JC,F = 250.6 Hz),
157.2 (3JC,F = 10.4 Hz), 129.1, 118.4, 117.7, 115.2 (3JC,F = 14.8 Hz),
100.6 (2JC,F = 26.9 Hz), 57.1, 56.6. HRMS: m/z Calcd. for C8H7ClFO2
(M − CN): 189.0113. Found: 189.0113. IR: 3428, 1622, 1585, 1496,
1467, 1443, 1397, 1306, 1242, 1197, 1138, 1074, 1050, 1029, 985, 935,
1444, 1423, 1405, 1242, 1203, 1127 cm−1
.
General Procedures for Reduction. Procedure A. A 20 mL
Wheaton vial equipped with a stirbar was charged with 1.0 g of
substrate, sodium iodide (0.3 equiv), and phosphorous acid (1.5
equiv). The vial was flushed with N2 and charged with 1.7 mL of H2O
and 3.3 mL of methanesulfonic acid. The reaction was then heated to
95 °C and monitored by LC until no further conversion to product
was observed. When complete, the reaction was cooled to rt and
worked up accordingly.
887, 832, 819, 732, 706 cm−1
.
2-(5-Chloro-2-fluoro-4-methoxyphenyl)acetic acid (9). 2-(5-
Chloro-2-fluoro-4-methoxyphenyl)-2-hydroxyacetonitrile (500 mg,
2.32 mmol) was suspended in hydroiodic acid (2 mL) and heated
to 80 °C for 15 h. The reaction mixture was cooled to rt and water was
added (10 mL). The precipitated solids were isolated by vacuum
filtration and rinsed with water (3 × 2 mL). The material was dried on
the filter under a stream of nitrogen, affording the target compound as
Procedure B. A 20 mL Wheaton vial equipped with a stirbar was
charged with 1.0 g of substrate, sodium iodide (0.3 equiv), and
phosphorous acid (1.5 equiv). The vial was flushed with N2 and
charged with 3.0 mL of H2O and 2.0 mL of methanesulfonic acid. The
reaction was then heated to 40 °C and monitored by LC until no
further conversion to product was observed. The reaction was cooled
to rt and worked up accordingly.
1
a brown crystalline solid (400 mg, 80% yield): mp 165 °C; H NMR
Phenylacetic Acid15 (Table 2, Entry 1). Procedure A was
followed using mandelic acid (1.0 g, 6.6 mmol). The reaction was
heated for 2 days until conversion was complete. Work-up was
performed by extraction into isopropyl acetate (IPAC) (2 × 5 vol)
followed by purification by column chromatography (SiO2; IPAC).
Product was isolated as a white solid (615 mg, 90.5% LCAP, 90.2%
(CDCl3, 400 MHz) δ ppm 7.28 (d, 4JH,F = 7.6 Hz, 1H), 6.71 (d, 3JH,F
=
10.9 Hz, 1H), 3.89 (s, 3H), 3.64 (s, 2H); 13C NMR (DMSO-d6, 100
MHz) δ ppm 176.2, 160.0 (1JC,F = 247.1 Hz), 155.4 (3JC,F = 10.4 Hz),
131.9, 117.5, 112.9 (3JC,F = 17.3 Hz), 100.4 (2JC,F = 27.8 Hz), 56.4,
32.2. HRMS: m/z Calcd. for C9H9ClFO3 (M + H)+: 219.0219. Found:
219.0217. IR: 3431, 1699, 1624, 1502, 1451, 1409, 1305, 1240, 1203,
1
1189, 1138, 1052, 910, 886, 843, 828, 725 cm−1
.
LCWP, 68.7% yield): H NMR (DMSO-d6, 400 MHz) δ ppm 12.30
(br s, 1H), 7.33−7.21 (comp, 5H), 3.56 (s, 2H); 13C NMR (DMSO-
d6, 100 MHz) δ ppm 172.7, 135.0, 129.4, 128.2, 126.6, 40.7. HRMS:
m/z calculated for C8H9O2 (M + H)+: 137.0597. Found: 137.0596. IR:
3033, 2971, 2655, 1691, 1407, 1337, 1228, 1186, 892, 839, 752, 699,
677 cm−1.
Sodium 2-(5-Chloro-2-fluoro-4-hydroxyphenyl)-2-hydroxya-
cetate. A 100 L jacketed reactor was set at 5 °C and purged with
nitrogen. 2-Chloro-5-fluorophenol (14.000 kg, 95.9 mol, 1.0 equiv),
sodium chloride (4.764 kg, 81.5 mol, 0.85 equiv), glyoxylic acid (50 wt
%, 17.041 kg, 115.1 mol, 1.2 equiv), and water (15.260 kg, 1.09 vol)
were charged to the reactor. The reaction temperature was maintained
below 40 °C, and 10 N sodium hydroxide (26.237 kg, 172.6 mol, 1.8
equiv) was added to the reactor (typically pH 9 ± 0.5 at end of the
addition). The reaction was heated to 35 °C for ≥21 h until reaction
completion (target is ≤3% 2-chloro-5-fluorophenol), then cooled to
20 °C. The pH was adjusted to 5.9 ± 0.1 by charging concd HCl at a
rate to maintain the temperature below 40 °C. The reactor contents
were cooled to 5 °C over a period of 4 h and aged for ≥2 h. The
mixture was filtered, and the solid product was washed with aqueous
sodium chloride solution cooled to 5 °C (sodium chloride (2.800 kg,
47.9 mol, 0.5 equiv) and water (25.200 kg)). The product was dried
under a vacuum to yield 24.8 kg, 21.593 kg (corrected), 89.1 mol,
93%: mp 101 °C; 1H NMR (DMSO-d6, 400 MHz) δ ppm 7.14 (d, J =
7.63 Hz, 1H), 6.68 (d, J = 11.35 Hz, 1H), 4.62 (s, 1H), 3.41 (br s,
2H); 13C NMR (DMSO-d6, 101 MHz) δ ppm 174.1, 160.1, 157.7,
153.1, 153.0, 128.5, 122.4, 114.7, 103.5, 103.3, 66.9. HRMS: m/z calcd
for C8H6ClFNaO4 (M + H)+: 242.9836. Found: 242.9832. IR: 3653,
3560, 3495, 3324, 2435, 1688, 1613, 1566, 1511, 1323, 1287, 1241,
1127 cm−1.
4-Bromophenylacetic Acid16 (Table 2, Entry 2). Procedure A
was followed using 4-bromomandelic acid (1.0 g, 4.3 mmol). The
reaction was heated for 3 days until complete. The solution was cooled
to 0 °C and the product was isolated by filtration, washed with cold
water, and dried to constant mass under a vacuum at 40 °C. Product
was isolated as an off-white crystalline solid (809 mg, 98.7% LCAP,
1
83.6% LCWP, 86.9% yield): H NMR (DMSO-d6, 400 MHz) δ ppm
12.40 (br s, 1H), 7.50 (d, J = 7.5 Hz, 2H), 7.23 (d, J = 7.5 Hz, 2H),
3.57 (s, 2H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 172.3, 134.5,
131.7, 131.0, 119.8, 39.9. HRMS: m/z calculated for C8H8BrO2 (M +
H)+: 214.9708. Found: 214.9705. IR: 2917, 1694, 1488, 1405, 1337,
1245, 1170, 1071, 1014, 926, 854, 802, 728 cm−1
.
3,4-Methylenedioxyphenylacetic Acid17 (Table 2, Entry 3).
Procedure B was followed using 3,4-(methylenedioxy)mandelic acid
(1.0 g, 5.1 mmol). The reaction was heated for 2 days until complete.
The solution was cooled to 0 °C and filtered, and the solid was washed
with cold water and dried under a vacuum to constant mass at rt.
Product isolated as a white solid (851 mg, 98.4% LCAP, 99.6% LCWP,
1
92.6% yield): H NMR (DMSO-d6, 400 MHz) δ ppm 12.25 (br s,
2-(5-Chloro-2-fluoro-4-hydroxyphenyl)acetic Acid (3). A
jacketed reactor was set at 15 ± 10 °C and purged with nitrogen
prior to proceeding. The reactor was then charged with 3-chloro-6-
fluoro-4-hydroxy-mandelic acid sodium salt (11.7 g (adjusted for 85%
LCWP), 41.2 mmol, 1.0 equiv), sodium iodide (617.5 mg, 4.12 mmol,
0.10 equiv), phosphorous acid (3.38 g, 41.2 mmol, 1.0 equiv), water
(25 mL, 2.5 vol), and concd HCl (25 mL, 2.5 vol). The stirred mixture
was heated to an internal temperature of 80 ± 5 °C for 18 h until
reaction completion (target is <0.5 LCAP mandelic acid). The
reaction starts homogeneous then goes heterogeneous after around 5 h
because of the low solubility of the product in HCl. The reaction was
cooled to 0 ± 5 °C over a period of 4 h and held at 0 °C for 3 h. The
mixture was filtered and the solid product washed with cold brine (12
mL) to provide solid (10.54 g). The crude product was loaded back
into a flask and slurried with water (50 mL) for 17 h. The mixture was
cooled to 0 °C and held at 0 °C for 3 h. The mixture was filtered and
the solid product washed with cold water (6 mL) to provide solid
1H), 6.84−6.82 (m, 2H), 6.71 (dd, J = 7.8, 1.8 Hz, 1H), 5.98 (s, 2H),
3.47 (s, 2H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 172.7, 147.1,
145.9, 128.6, 122.4, 109.8, 107.9, 100.8, 40.2. HRMS: m/z calculated
for C9H9O4 (M + H)+: 181.0495. Found: 181.0494. IR: 2909, 1692,
1500, 1408, 1249, 1181, 1035, 922, 784, 690 cm−1
.
4-Hydroxyphenylacetic Acid18 (Table 2, Entry 4). Procedure
B was followed using 4-hydroxymandelic acid (1.0 g, 5.9 mmol). The
reaction was heated for 2 days until complete. After cooling to rt, the
solution was extracted with IPAC (2 × 5 vol) and concentrated to
dryness. Product was purified by column chromatography (SiO2; 3:1
heptanes/IPAC). Product isolated as a pale pink solid (523 mg, 62.2%
1
LCAP, 61.3% LCWP, 52.8% yield): H NMR (DMSO-d6, 400 MHz)
δ ppm 12.10 (br s, 1H), 9.24 (br s, 1H), 7.03 (d, J = 8.5 Hz, 2H), 6.68
(d, J = 8.5 Hz, 2H), 3.41 (s, 2H); 13C NMR (DMSO-d6, 100 MHz) δ
ppm 173.1, 156.0, 130.2, 125.1, 115.0, 39.9. HRMS: m/z calculated for
C8H9O3 (M + H)+: 153.0546. Found: 153.0544. IR: 3249, 2982, 1704,
1601, 1517, 1446, 1409, 1211, 1190, 1170, 902, 822, 788 cm−1
.
2-Phenylpropionic Acid19 (Table 2, Entry 5). Procedure A was
1
(6.91 g, 82% yield): mp 140 °C; H NMR (DMSO-d6, 400 MHz) δ
ppm 12.43 (br s, 1H), 10.54 (br s, 1H), 7.32 (d, J = 8.02 Hz, 1H), 6.75
followed using 2-hydroxy-2-phenylpropionic acid (740 mg, 4.5 mmol)
9522
dx.doi.org/10.1021/jo2018087|J. Org. Chem. 2011, 76, 9519−9524