The Journal of Organic Chemistry
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sequentially with 2 M HCl (2 × 50 mL) and brine (50 mL). The
organic layer was then dried (MgSO4), filtered, and concentrated
under reduced pressure. The resulting product was typically analyzed
directly. If necessary, the product was further purified by column
chromatography, as indicated.
154.8 (4 × 4°Ar). HRMS m/z (ESI−): found 183.0812 [M − H]−;
C13H11O requires 183.0815.
3′-Methylbiphenyl-4-ol (9).56 175 mg isolated after purification
by flash column chromatography (5% methanol in dichloromethane),
95% yield. Mp = 52−54 °C. IR (νmax, KBr) = 3368, 1597, 1455, 1237,
1
4′-Methylbiphenyl-4-carboxylic Acid (2).54 178 mg isolated,
782. H NMR (400 MHz, CDCl3): δ 2.43 (3H, s, CH3), 5.67 (1H, s,
OH), 6.93 (2H, d, J = 8.6, CHAr), 7.16 (1H, d, J = 7, CHAr), 7.31−7.40
(3H, m, CHAr), 7.50 (2H, d, J = 8.6, CHAr). 13C NMR (100 MHz,
CDCl3): δ 21.6 (CH3), 115.7, 123.9, 127.50, 127.57, 128.43, 128.68 (6
× CHAr), 134.1, 138.3, 140.8, 155.0 (4 × 4°Ar). HRMS m/z (ESI−):
found 183.0814 [M − H]−; C13H11O requires 183.0815.
84% yield, no purification was required. Mp = 250−252 °C. IR (νmax
,
KBr) = 3431, 2919, 1680, 1301, 768. 1H NMR (400 MHz, DMSO-d6):
δ 2.36 (3H, s, CH3), 7.30 (2H, d, J = 8.0, CHAr), 7.63 (2H, d, J = 8.0,
CHAr), 7.75 (2H, d, J = 8.4, CHAr), 8.00 (2H, d, J = 8.4, CHAr), 12.94
(1H, s, CO2H). 13C NMR (100 MHz, DMSO-d6): δ 20.7 (CH3),
126.4, 126.7 (CHAr), 129.3 (4°Ar), 129.7, 129.9 (CHAr), 136.1, 137.7,
144.2 (3 × 4°Ar), 167.1 (CO). HRMS m/z (ESI−): found 211.0766
[M − H]−; C14H11O2 requires 211.0765.
Synthesis of Felbinac (10) in Unpurified Tap Water. 4-
Bromophenylacetic acid (1.00 g, 4.70 mmol) and phenylboronic acid
(680 mg, 5.58 mmol) were added to a 125 mL conical flask. City of
Tulsa tap water (10 mL) was added to the reaction vessel along with
sodium carbonate (1.10 g, 10.4 mmol). The resulting mixture was
stirred until all material had dissolved. After this time, 4.7 mL of the
palladium-melamine catalyst solution was added in a single portion.
This aqueous catalyst solution was 1 mM in Pd, resulting in a catalyst
loading of 0.1 mol % (0.0047 mmol Pd). The reaction was then placed
in an oil bath preheated to 80 °C and stirred (open to air) for 2 h.
After this time, the reaction was removed from heat and cooled to 0
°C. Then 1 M HCl was added to the reaction mixture (15 mL), and
the organic material was extracted with ethyl acetate (100 mL). The
organic layer was then washed with brine (25 mL), dried (MgSO4),
filtered, and concentrated under reduced pressure to provide felbinac
as an analytically pure white solid (998 mg, 99% yield). Spectroscopic
data was consistent with that previously reported.57 Mp = 155−158
3′-Methylbiphenyl-4-carboxylic Acid (3).55 210 mg isolated,
99% yield, no purification was required. Mp = 198−200 °C. IR (νmax
,
KBr) = 3436, 2914, 1685, 1284, 770. 1H NMR (400 MHz, DMSO-d6):
δ 2.38 (s, 3H, CH3), 7.23 (1H, d, J = 7.5, CHAr), 7.37 (1H, t, J = 7.4,
CHAr), 7.51 (1H, d, J = 7.7, CHAr), 7.55 (1H, s, CHAr), 7.77 (2H, d, J
= 6.1, CHAr), 8.01 (2H, d, J = 6.1, CHAr). 13C NMR (100 MHz,
DMSO-d6): δ 21.1 (CH3), 124.1, 126.8, 127.6, 128.89, 128.94, 129.6,
129.9 (6 × CHAr and 1 × 4°Ar), 138.3, 139.0, 144.4 (3 × 4°Ar), 167.2
(CO). HRMS m/z (ESI−): found 211.0768 [M − H]−; C14H11O2
requires 211.0765.
2′-Methylbiphenyl-4-carboxylic Acid (4).23 206 mg isolated
after purification by flash column chromatography (5% methanol in
dichloromethane), 97% yield. A 2.0 mmol portion of o-tolylboronic
acid was used in this reaction, along with 3.2 mmol of sodium
carbonate. All other conditions are prescribed in the general protocol.
Mp = 186−188 °C. IR (νmax, KBr) = 3368, 1597, 1455, 1237, 782. 1H
NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H, CH3), 7.17−7.27 (4H, m,
CHAr), 7.42 (2H, d, J = 8.5, CHAr), 7.97 (2H, d, J = 8.5, CHAr). 13C
NMR (100 MHz, DMSO-d6): δ 20.5 (CH3), 126.5, 128.3 (CHAr),
129.64, 129.67, 129.76, 129.78 (3 × CHAr and 1 × 4°Ar), 130.90
(CHAr), 135.1, 140.7, 146.1 (3 × 4°Ar), 167.6 (CO). HRMS m/z
(ESI−): found 211.0764 [M − H]−; C14H11O2 requires 211.0765.
2′,6′-Dimethylbiphenyl-4-carboxylic Acid (5). 217 mg isolated,
1
°C. IR (νmax, KBr) = 2955, 1685, 1250, 732. H NMR (400 MHz,
DMSO-d6): δ 3.63 (2H, s, CH2), 7.35−7.37 (3H, m, CHAr), 7.46 (2H,
t, J = 7.7, CHAr), 7.61 (2H, d, J = 8.1, CHAr), 7.66 (1H, d, J = 8.1,
CHAr), 12.40 (1H, bs, OH). 13C NMR (100 MHz, DMSO-d6): δ 40.21
(CH2), 126.47, 126.49, 127.23, 128.82 (4 × CHAr), 134.20, 138.45,
139.87 (3 × 4°Ar), 172.60 (CO). HRMS m/z (ESI−): found
211.0763 [M − H]−; C14H11O2 requires 211.0765.
Gram-Scale Synthesis of Felbinac (10) in Unpurified
Arkansas River Water. 4-Bromophenylacetic acid (1.00 g, 4.70
mmol), phenylboronic acid (626 mg, 5.14 mmol), and sodium
carbonate (1.06 g, 9.81 mmol) were dissolved in 5.4 mL of unfiltered
Arkansas River water by stirring in an oil bath at 80 °C for several
minutes. A 4.7 mL aliquot of the melamine-palladium catalyst solution
was added in one portion, and the mixture was vigorously stirred for 2
h open to air. The aqueous catalyst solution was 1 mM in Pd, resulting
in a catalyst loading of 0.1 mol % (0.0047 mmol Pd). The reaction was
subsequently cooled to room temperature, placed in an ice bath and
quenched with 2 M HCl (10 mL). The reaction mixture was
transferred to a separatory funnel, diluted with 100 mL of EtOAc, and
washed with 2 M HCl (2 × 50 mL) and then with brine (50 mL). The
organic layer was dried over MgSO4, filtered, and concentrated under
reduced pressure. The resulting product (feblinac) was isolated as a
white solid and did not require further purification (951 mg, 96%
yield). Spectroscopic data was consistent with that obtained in the
felbinac synthesis described in the previous experiment.
Catalyst Recovery under Homogeneous Conditions in
Water. 4-Bromobenzoic acid (200 mg, 1.0 mmol), phenylboronic
acid (145 mg, 1.19 mmol), and sodium carbonate (238 mg, 2.25
mmol) were added to a 25 mL round-bottom flask. H2O (4.0 mL) was
added to the reaction flask, and the stirred mixture was heated to 80
°C to dissolve. The melamine-palladium catalyst solution (1 mL of a 1
mM solution in water, 0.001 mmol Pd) was then added, and the
reaction was stirred, open to air, at 80 °C for 30 min. After this time,
the reaction was cool to 0 °C, the precipitated product was isolated by
filtration, and the filtrate was saved for a subsequent reaction (see
below). The solid product was transferred to a 50 mL beaker,
suspended in 2 M HCl (10 mL), and then transferred into a separatory
funnel along with EtOAc (35 mL). The organic layer was separated
and then washed with brine (50 mL) before drying (MgSO4), filtering,
and concentrating under reduced pressure. The product, 4-phenyl-
benzoic acid (1), was spectroscopically identical to the compound
synthesized in Scheme 1 (185 mg isolated, 93% yield). The filtrate
96% yield, no purification was required. Mp = 255−260 °C. IR (νmax
,
KBr) = 3385, 2909, 1685, 1060, 753. 1H NMR (400 MHz, DMSO-d6):
δ 2.27 (6H, s, 2 × CH3), 6.91 (2H, d, J = 7.8, CHAr), 7.06 (1H, t, J =
7.8, CHAr), 7.71 (2H, d, J = 6.8, CHAr), 7.88 (2H, d, J = 6.8, CHAr),
8.16 (1H, s, OH). 13C NMR (100 MHz, DMSO-d6): δ 22.4 (CH3),
126.0 (CHAr), 127.3 (4°Ar), 127.7 (CHAr), 130.5 (4°Ar), 131.7 (CHAr),
132.1 (CHAr), 138.8 (4°Ar) 167.08 (CO). HRMS m/z (ESI−):
found 225.0916 [M − H]−; C15H13O2 requires 225.0921.
4′-Methylbiphenyl-3-carboxylic Acid (6). 210 mg isolated, 99%
yield, no purification was required. Mp = 181−184 °C. IR (νmax, KBr)
= 3448, 2922, 1696, 1309, 753.1H NMR (400 MHz, DMSO-d6): δ
2.36 (3H, s, CH3), 7.30 (2H, d, J = 7.8, CHAr), 7.59−7.61 (3H, m,
CHAr), 7.90 (1H, d, J = 7.6, CHAr), 7.97 (1H, d, J = 7.6, CHAr), 8.22
(1H, s, CHAr). 13C NMR (100 MHz, DMSO-d6): δ 21.1 (CH3), 127.0,
127.5, 128.4, 129.7, 130.1, 131.2, 131.9, 136.8, 137.7, 140.8 (10 × Ar),
167.7 (CO). HRMS m/z (ESI−): found 211.0761 [M − H]−;
C14H11O2 requires 211.0765.
4-Phenylphenol (7).23 158 mg isolated, 93% yield, no purification
was required. Mp = 157−158 °C. IR (νmax, KBr): 3396, 3032, 2925,
2848, 1486, 748. 1H NMR (400 MHz, DMSO-d6): δ 6.83 (2H, d, J =
7.0), 7.23 (1H, t, J = 5.9), 7.35 (2H, t, J = 7.0), 7.44 (2H, d, J = 7.0),
7.53 (2H, d, J = 7.8), 9.53 (1H, s, OH). 13C NMR (100 MHz, DMSO-
d6): δ 116.2, 126.4, 126.8, 128.2, 129.4 (5 × CHAr), 131.4, 140.7, 157.6
(3 × 4°Ar). HRMS m/z (ESI−): found 169.0655 [M − H]−; C12H9O
requires 169.0659.
4′-Methylbiphenyl-4-ol (8).56 182 mg isolated after purification
by flash column chromatography (5% methanol in dichloromethane),
99% yield. Mp = 143−145 °C. IR (νmax, KBr) = 3422, 1615, 1500,
1
1264, 807. H NMR (400 MHz, CDCl3): δ 2.39 (3H, s, CH3), 5.22
(1H, s, OH), 6.90 (2H, d, J = 8.6, CHAr), 7.23 (2H, d, J = 8.6, CHAr),
7.43−7.47 (4H, m, CHAr).13C NMR (100 MHz, CDCl3): δ 21.1
(CH3), 115.6, 126.6, 128.2, 129.4 (4 × CHAr), 133.9, 136.4, 137.9,
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dx.doi.org/10.1021/jo402799t | J. Org. Chem. 2014, 79, 2094−2104