The Journal of Organic Chemistry
Note
(s, 1H), 3.89 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 146.5, 145.8,
obtained by simple workup because all the reagents are water-
soluble and easily removable during aqueous workup. (4) The
developed protocol is highly scalable. We successfully carried
out a 20 g scale reaction, thereby demonstrating its utility in
large-scale preparation. Moreover, we briefly showed that C−
O(alkyl) coupling reaction between aryl halides and glycolic
acid can be achieved under the slightly modified conditions.
Overall, we believe that the developed reaction method should
be considered an important advancement in the copper-
catalytic preparation of functionalized phenols.
121.6, 120.3, 114.6, 110.8, 56.0.
4-(Benzyloxy)phenol (2i):29 white solid (188 mg, 94%); H NMR
1
(500 MHz, CDCl3) δ 7.49−7.26 (m, 5H), 6.85 (dd, J = 7.5, 5.0 Hz,
2H), 6.74 (dd, J = 8.5, 4.0 Hz, 2H), 5.00 (s, 2H), 4.68 (s, 1H); 13C
NMR (125 MHz, CDCl3) δ 153.2, 149.9, 137.5, 128.8, 128.2, 127.77,
127.76, 116.3, 71.1.
2,3-Dihydrobenzo[b][1,4]dioxin-6-ol (2j):30 colorless liquid (140
1
mg, 92%); H NMR (500 MHz, CDCl3) δ 6.72 (d, J = 8.5 Hz, 1H),
6.39 (d, J = 3.0 Hz, 1H), 6.33 (dd, J = 8.5, 3.0 Hz, 1H), 4.51 (s, 1H),
4.27−4.17 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 149.9, 143.9,
136.9, 117.7, 108.4, 104.4, 64.8, 64.3.
Resorcinol (2k):22 white solid (102 mg, 93%); 1H NMR (500 MHz,
CDCl3) δ 7.09 (t, J = 8.0 Hz, 1H), 6.43−6.38 (m, 2H), 6.36 (t, J = 2.5
Hz, 1H), 4.73 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 157.0, 130.3,
108.1, 103.0.
EXPERIMENTAL SECTION
■
General Considerations. All reagents and solvents were obtained
from commercial suppliers and used without purification. The purity
of copper catalysts is greater than 97%. Deionized water was used. All
4-(Dimethylamino)phenol (2l):31 brown solid (105 mg, 77%, 8 h);
1H NMR (500 MHz, DMSO-d6) δ 8.60 (s, 1H), 6.65−6.60 (m, 4H),
2.74 (s, 6H); 13C NMR (125 MHz, DMSO-d6) δ 149.6, 144.8, 115.9,
115.3, 42.0.
manipulations were carried out under Ar. H and 13C NMR spectra
1
were recorded on a 500 MHz spectrometer (125 MHz for 13C).
Multiplicities are indicated as s (singlet), d (doublet), t (triplet), q
(quintet), and m (multiplet), and coupling constants (J) are reported
in hertz. GC−MS analysis conducted on a GC−MSD system and
products described in GC yield were accorded to the authentic
samples/n-dodecane calibration standard from GC−MSD. Column
chromatography was performed on silica gel 60 (230−400 mesh) and
TLC was performed on silica gel 60 F254 glass plate.
1-(4-Hydroxyphenyl)ethanone (2m):18 yellow solid (120 mg,
1
88%); H NMR (500 MHz, CDCl3) δ 7.93−7.91 (m, 2H), 7.09−
6.75 (m, 2H), 6.45 (s, 1H), 2.59 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 198.2, 161.0, 131.2, 129.8, 115.5, 26.3.
4-Hydroxybenzoic acid (2n):21 white solid (131 mg, 95%); 1H
NMR (500 MHz, DMSO-d6) δ 12.42 (s, 1H), 10.21 (s, 1H), 7.78 (d, J
= 8.5 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H); 13C NMR (125 MHz,
DMSO-d6) δ 167.9, 162.2, 132.1, 122.0, 115.8.
General Procedure for Cu(OH)2-Catalyzed Synthesis of
Phenols. A Schlenk tube was charged with aryl halides (1) (1.0
mmol), Cu(OH)2 (4.9 mg, 0.05 mmol), glycolic acid (22.8 mg, 0.3
mmol), NaOH (240 mg, 6.0 mmol), and DMSO/H2O (1.5 mL/1.5
mL). The mixture was stirred at 120 °C for 6 h under Ar. The reaction
mixture was allowed to cool to room temperature, poured into 3 mL
water, and then acidified to pH = 1 with 2 N HCl. The aqueous phase
was extracted twice with EtOAc, and the combined organic layer was
washed with H2O and brine, dried over anhydrous MgSO4, and
concentrated under vacuum. Purification of the crude product by
column chromatography (EtOAc/n-hexane) afforded the phenols (2).
Phenol (2a):18 colorless liquid (93 mg, 99%); 1H NMR (500 MHz,
CDCl3) δ 7.54−7.08 (m, 2H), 6.99−6.89 (m, 1H), 6.86−6.78 (m,
2H), 5.84 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 155.4, 130.1,
121.3, 115.7.
3-Nitrophenol (2o):21 yellow solid (135 mg, 97%); H NMR (500
1
MHz, CDCl3) δ 7.86−7.78 (m, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.42 (t, J
= 8.0 Hz, 1H), 7.20−7.18 (m, 1H), 5.50 (s, 1H); 13C NMR (125
MHz, CDCl3) δ 156.2, 149.2, 130.3, 121.9, 115.9, 110.5.
3-Hydroxybenzoic acid (2p):12 white solid (137 mg, 99%); 1H
NMR (500 MHz, DMSO-d6) δ 12.81 (s, 1H), 9.77 (s, 1H), 7.37−7.27
(m, 3H), 6.99 (d, J = 5.5 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ
167.2, 157.3, 131.9, 129.4, 119.8, 119.7, 115.7.
3-Chlorophenol (2q):21 white solid (125 mg, 98%); 1H NMR (500
MHz, CDCl3) δ 7.16 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.86
(s, 1H), 6.76−6.58 (m, 1H), 4.96 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 156.2, 134.9, 130.5, 121.1, 115.9, 113.7.
4-Chlorophenol (2r):21 colorless liquid (127 mg, 99%); H NMR
1
o-Cresol (2b):21 white solid (105 mg, 97%); H NMR (500 MHz,
1
(500 MHz, CDCl3) δ 7.22−7.15 (m, 2H), 6.84−6.69 (m, 2H), 5.37 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 154.1, 129.9, 126.1, 117.0.
CDCl3) δ 7.14−7.07 (m, 2H), 6.86 (dd, J = 9.5, 5.5 Hz, 1H), 6.78 (dd,
J = 8.0, 4.0 Hz, 1H), 4.68 (s, 1H), 2.26 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 153.7, 131.0, 127.1, 123.7, 120.7, 114.8, 15.7.
2-Bromophenol (2s):30 white solid (160 mg, 99%); H NMR (500
1
MHz, CDCl3) δ 7.46 (d, J = 8.0 Hz, 1H), 7.22 (dd, J = 10.5, 4.5 Hz,
1H), 7.02 (d, J = 8.0 Hz, 1H), 6.80 (dd, J = 10.5, 4.5 Hz, 1H), 5.49 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 152.4, 132.2, 129.3, 122.0,
116.3, 110.4.
3,5-Dimethylphenol (2c):21 pale yellow solid (117 mg, 96%); H
1
NMR (500 MHz, CDCl3) δ 6.58 (s, 1H), 6.46 (s, 2H), 4.76 (s, 1H),
2.26 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 161.8, 157.6, 94.5, 93.4,
55.6.
Pyrocatechol (2t):22 white solid (84 mg, 76%, 24 h, 10 mol %
2,6-Dimethylphenol (2d):20 white solid (106 mg, 87%); H NMR
1
1
Cu(OH)2, 0.5 equiv glycolic acid); H NMR (500 MHz, CDCl3) δ
6.87 (d, J = 3.5 Hz, 2H), 6.84−6.79 (m, 2H), 5.09 (s, 2H); 13C NMR
(125 MHz, CDCl3) δ 143.4, 121.3, 115.5.
(500 MHz, CDCl3) δ 7.00−6.97 (m, 1H), 6.97−6.95 (m, 1H), 6.75 (t,
J = 7.5 Hz, 1H), 4.59 (s, 1H), 2.25 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 152.4, 128.8, 123.2, 120.4, 16.1 .
1-(2-Hydroxyphenyl)ethanone (2u):18 yellow solid (100 mg, 73%,
12 h, 10 mol % Cu(OH)2); 1H NMR (500 MHz, CDCl3) δ 12.26 (s,
1H), 7.74 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 6.5 Hz, 1H), 7.07−6.75 (m,
2H), 2.64 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 204.8, 162.6,
136.7, 130.9, 120.0, 119.2, 118.7, 26.9.
Biphenyl-4-ol (2e):18 white solid (153 mg, 90%); H NMR (500
1
MHz, CDCl3) δ 7.55−7.53 (m, 2H), 7.50−7.47 (m, 2H), 7.40 (t, J =
8.0 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H), 6.92−6.87 (m, 2H), 4.76 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 155.0, 140.8, 134.2, 128.7,
128.4, 126.71, 126.70, 115.7.
3,5-Bis(trifluoromethyl)phenol (2v):19 colorless liquid (196 mg,
85%, 24 h, 10 mol % Cu(OH)2); 1H NMR (500 MHz, CDCl3) δ 7.43
(s, 1H), 7.28 (s, 2H), 6.67 (s, 1H); 13C NMR (125 MHz, CDCl3) δ
156.7, 133.0 (q, J = 33.2 Hz, −CF3), 123.3 (q, J = 271.1 Hz, −CF3),
116.0, 114.3.
Naphthalen-1-ol (2f):21 gray solid (130 mg, 90%); H NMR (500
1
MHz, CDCl3) δ 8.26−8.11 (m, 1H), 7.80 (dd, J = 5.0, 4.0 Hz, 1H),
7.50−7.38 (m, 3H), 7.27 (dd, J = 8.0, 7.5 Hz, 1H), 6.75 (d, J = 7.5 Hz,
1H), 5.33 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 151.4, 135.0,
127.9, 126.7, 126.0, 125.5, 124.5, 121.7, 121.0, 108.9.
4-Nitrophenol (2w):21 yellow solid (132 mg, 95%, 10 mol %
Cu(OH)2); 1H NMR (500 MHz, CDCl3) δ 8.24−8.12 (m, 2H),
7.03−6.87 (m, 2H), 5.76 (s, 1H); 13C NMR (125 MHz, CDCl3) δ
161.1, 141.6, 126.3, 115.7.
Naphthalen-2-ol (2g):21 pink solid (135 mg, 94%); 1H NMR (500
MHz, CDCl3) δ 7.76 (t, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.43
(t, J = 7.0 Hz, 1H), 7.33 (t, J = 7.0 Hz, 1H), 7.15 (s, 1H), 7.10 (dd, J =
8.5, 2.5 Hz, 1H), 4.98 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 153.3,
134.6, 129.8, 128.9, 127.8, 126.5, 126.4, 123.6, 117.7, 109.5.
General Procedure for CuI-Catalyzed C−O Coupling of Aryl
Iodides and Glycolic Acid. A Schlenk tube was charged with aryl
iodides (1) (1.0 mmol), glycolic acid (228 mg, 3.0 mmol), CuI (19.0
mg, 0.1 mmol), Cs2CO3 (1.95 g, 6.0 mmol), and DMSO/H2O (2 mL/
2-Methoxyphenol (2h):20 yellow solid (118 mg, 95%, 12 h); H
1
NMR (500 MHz, CDCl3) δ 6.92 (m, 1H), 6.89−6.83 (m, 3H), 5.62
D
dx.doi.org/10.1021/jo400702z | J. Org. Chem. XXXX, XXX, XXX−XXX