The Journal of Organic Chemistry
Page 8 of 11
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4ꢀmethoxyꢀ3ꢀmethylphenol (6l1): white solid; 1H NMR (400 MHz,
CDCl3): δ = 6.70 (d, J = 8.6 Hz, 1H), 6.66 (d, J = 3.1 Hz, 1H),
6.62 (dd, J = 8.6, 3.1 Hz, 1H), 4.71 (br s, 1H), 3.78 (s, 3H), 2.19
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 152.2, 149.2,
128.2, 118.1, 112.6, 111.4, 56.1, 16.3 ppm.69
3ꢀmethoxyꢀ2ꢀmethylphenol (6l2): white solid; 1H NMR (400 MHz,
CDCl3): δ = 7.03 (t, J = 8.5 Hz, 1H), 6.51 – 6.41 (m, 2H), 4.68 (s,
1H), 3.82 (s, 3H), 2.12 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 158.8, 154.6, 126.6, 112.2, 108.2, 103.2, 55.8, 8.1
ppm.70
2ꢀmethoxyꢀ3ꢀmethylphenol (6l3): white solid; 1H NMR (400 MHz,
CDCl3): δ = 6.91 (t, J = 7.8 Hz, 1H), 6.80 (dd, J = 8.1, 1.6 Hz,
1H), 6.73 – 6.66 (m, 1H), 5.61 (s, 1H), 3.80 (s, 3H), 2.30 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ = 149.0, 145.6, 131.0,
124.7, 122.6, 113.2, 60.8, 16.1 ppm.71
Nꢀ(2ꢀhydroxyphenyl)benzamide (6o2): white solid; 1H NMR (400
MHz, DMSOꢀd6): δ = 9.74 (s, 1H), 9.51 (s, 1H), 8.01 – 7.94 (m,
2H), 7.69 (dd, J = 7.9, 1.6 Hz, 1H), 7.63 – 7.57 (m, 1H), 7.56 –
7.49 (m, 2H), 7.08 – 7.00 (m, 1H), 6.93 (dd, J = 8.1, 1.5 Hz, 1H),
6.84 (td, J = 7.6, 1.5 Hz, 1H)ppm; 13C NMR (100 MHz, DMSOꢀ
d6): δ = 165.2, 149.3, 134.4, 131.7, 128.5, 127.5, 125.9, 125.7,
124.1, 119.0, 116.0 ppm.78
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Procedure for the Synthesis of 4-Hydroxy[2.2]paracyclophane
(6p1). [2.2]paracyclophane (0.21, 1 mmol) was placed inside a 25
mL flask equipped with a magnetic stirrer bar. A mixture of
CHCl3/PFB (1:1, 8 mL) and P4 (0.09 g, 0.5 mmol) were subseꢀ
quently added. The flask was placed inside an oil bath heated to
40 °C for 24h. The reaction mixture was then cooled to room
temperature and diluted with EtOAc (15 mL) and stirred with a
saturated solution of Na2S2O5 (10 mL) for 2 h. After separation of
the layers, the aqueous phase was extracted with EtOAc (2 × 15
mL). The combined organic extracts were washed with brine (15
mL) and dried over anhydrous MgSO4 and concentrated under
reduced pressure. The residue was hydrolyzed overnight using 5
ml of methylamine (33 wt.% in ethanol). Ethanol was removed
under reduced pressure and the crude product was purified by
column chromatography (nꢀhexane/ethyl acetate 16/1 → 5/1) to
give 6p1 (160 mg, 71%), 6p2 (10 mg, 4%) and 6p3 (15 mg, 6%).
4ꢀhydroxy[2.2]paracyclophane (6p1): pale yellow solid; 1H NMR
(400 MHz, CDCl3): δ = 7.01 (dd, J = 7.8, 1.9 Hz, 1H), 6.56 (dd, J
= 7.8, 1.9 Hz, 1H), 6.45 (dd, J = 7.8, 1.9 Hz, 1H), 6.42 – 6.36 (m,
2H), 6.27 (dd, J = 7.8, 1.7 Hz, 1H), 5.54 (d, J = 1.7 Hz, 1H), 4.44
(s, 1H), 3.39 – 3.28 (m, 1H), 3.16 – 2.86 (m, 6H), 2.72 – 2.61 (m,
1H) ppm; 13C NMR (100 MHz, CDCl3): δ = 153.8, 142.1, 139.7,
138.9, 135.6, 133.7, 132.9, 132.0, 128.1, 125.6, 125.2, 122.7,
35.4, 34.9, 33.9, 31.2 ppm.79
2ꢀMethoxyꢀ5ꢀphenylphenol (6m1) and 5ꢀMethoxyꢀ2ꢀphenylphenol
(6m2). Prepared following general procedure B. The residue was
purified by column chromatography (pentane/Et2O 16/1 → 7/1) to
give the products 6m1 (21 mg, 21%) and 6m2 (4 mg, 4%).
2ꢀMethoxyꢀ5ꢀphenylphenol (6m1): white solid; 1H NMR (400
MHz, CDCl3): δ = 7.59 – 7.53 (m, 2H), 7.45 – 7.38 (m, 2H), 7.35
– 7.28 (m, 1H), 7.21 (d, J = 2.2 Hz, 1H), 7.10 (dd, J = 8.3, 2.2 Hz,
1H), 6.93 (d, J = 8.3 Hz, 1H), 5.67 (s, 1H), 3.94 (s, 3H) ppm; 13
C
NMR (100 MHz, CDCl3): δ = 146.3, 145.9, 140.9, 135.0, 128.8,
127.0, 126.9, 118.9, 113.5, 111.0, 56.2 ppm.72
5ꢀMethoxyꢀ2ꢀphenylphenol (6m2): white solid; 1H NMR (400
MHz, CDCl3): δ = 7.50 – 7.35 (m, 5H), 7.19 – 7.12 (m, 1H), 6.61
– 6.53 (m, 2H), 5.26 (s, 1H), 3.83 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 160.6, 153.4, 136.9, 130.7, 129.3, 129.1, 127.5,
120.8, 107.0, 101.3, 55.4 ppm.73
6ꢀMethoxyꢀ[1,1'ꢀbiphenyl]ꢀ3ꢀol (6n1), 2ꢀMethoxyꢀ[1,1'ꢀbiphenyl]ꢀ
3ꢀol (6n2) and 6ꢀMethoxyꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀol (6n3). Prepared
following general procedure B. The residue was purified by colꢀ
umn chromatography (nꢀhexane/ethyl acetate 7/1 → 3/1) to give
the products 6n1 (34 mg, 34%), 6n2 (23 mg, 23%) and 6n3 (18
mg, 18%).
Procedure
for
the
Synthesis
of
Dihy-
droxy[2.2]paracyclophanes (6p2 and 6p3). [2.2]paracyclophane
(0.21, 1 mmol) was placed inside a 25 mL flask equipped with a
magnetic stirrer bar. A mixture of CHCl3/PFB (1:1, 8 mL) and P4
(0.4 g, 2.2 mmol) were subsequently added. The flask was placed
inside an oil bath heated to 40 °C for 24h. The reaction mixture
was then cooled to room temperature and diluted with EtOAc (15
mL) and stirred with a saturated solution of Na2S2O5 (20 mL) for
2 h. After separation of the layers, the aqueous phase was extractꢀ
ed with EtOAc (2 × 15 mL). The combined organic extracts were
washed with brine (15 mL) and dried over anhydrous MgSO4 and
concentrated under reduced pressure. The residue was hydrolyzed
overnight using 10 ml of methylamine (33 wt.% in ethanol).
Ethanol was removed under reduced pressure and the crude prodꢀ
uct was purified by column chromatography (nꢀhexane/ethyl
acetate 16/1 → 5/1) to give 6p1 (41 mg, 18%), 6p2 (73 mg, 30%),
6p3 (58 mg, 24%).
6ꢀMethoxyꢀ[1,1'ꢀbiphenyl]ꢀ3ꢀol (
6n1): colorless oil; 1H NMR
(400 MHz, CDCl3): δ = 7.55 – 7.49 (m, 2H), 7.44 – 7.37 (m, 2H),
7.36 – 7.30 (m, 1H), 6.87 (d, J = 8.7 Hz, 1H), 6.83 (d, J = 3.0 Hz,
1H), 6.78 (dd, J = 8.7, 3.1 Hz, 1H), 4.72 (br s, 1H), 3.74(s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ = 150.9, 149.6, 138.2,
132.0, 129.5, 128.2, 127.2, 118.0, 114.7, 113.1, 56.5 ppm.74
2ꢀMethoxyꢀ[1,1'ꢀbiphenyl]ꢀ3ꢀol (6n2): white solid; 1H NMR (400
MHz, CDCl3): δ = 7.61 – 7.56 (m, 2H), 7.47 – 7.40 (m, 2H), 7.39
– 7.33 (m, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.97 (dd, J = 8.1, 1.7 Hz,
1H), 6.88 (dd, J = 7.6, 1.7 Hz, 1H), 5.93 (s, 1H), 3.43 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ = 149.3, 144.5, 138.1,
134.4, 128.9, 128.6, 127.6, 124.8, 122.3, 114.5, 60.8 ppm.75
6ꢀMethoxyꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀol (6n3): colorless oil; 1H NMR (400
MHz, CDCl3): δ = 7.53 – 7.47 (m, 2H), 7.44 – 7.34 (m, 3H), 7.22
(t, J = 8.3 Hz, 1H), 6.67 (dd, J = 8.2, 1.0 Hz, 1H), 6.57 (dd, J =
8.3, 1.0 Hz, 1H), 4.99 (s, 1H), 3.73 (s, 3H) ppm; 13C NMR (100
MHz, CDCl3): δ = 157.5, 153.8, 132.5, 130.9, 129.3, 129.3, 128.2,
117.2, 108.5, 103.3, 56.0 ppm.76
4,16ꢀDihydroxy[2.2]paracyclophane
(
6p2): white crystal; 1H
NMR (400 MHz, Acetoneꢀd6): δ = 7.57 (d, J = 7.3 Hz, 2H), 6.84
(d, J = 7.6 Hz, 1H), 6.53 (dd, J = 7.6, 1.7 Hz, 1H), 6.26 (d, J = 7.7
Hz, 1H), 6.08 (dd, J = 7.7, 1.8 Hz, 1H), 5.66 (dd, J = 5.9, 1.7 Hz,
2H), 3.42 (ddd, J = 12.9, 10.0, 2.6 Hz, 1H), 3.25 – 3.15 (m, 1H),
3.00 – 2.90 (m, 1H), 2.89 – 2.78 (m, 3H), 2.78 – 2.68 (m, 1H),
2.58 – 2.48 (m, 1H) ppm; 13C NMR (100 MHz, Acetoneꢀd6): δ =
156.6, 156.4, 142.1, 141.4, 135.0, 130.8, 126.7, 125.6, 124.1,
123.2, 122.3, 121.8, 35.1, 33.9, 31.3, 30.5 ppm.80
Nꢀ(4ꢀhydroxyphenyl)benzamide
(
6o1
)
and
Nꢀ(2ꢀ
hydroxyphenyl)benzamide 6o2). Prepared following general
(
4,12ꢀDihydroxy[2.2]paracyclophane
(
6p3): white crystal; 1H
procedure A. The residue was purified by column chromatogꢀ
raphy (pentane/Et2O 3/1 → 1/1) to give the products 6o1 (29 mg,
28%) and 6o2 (29 mg, 28%).
Nꢀ(4ꢀhydroxyphenyl)benzamide (6o1): yellow solid; 1H NMR
(400 MHz, DMSOꢀd6): δ = 10.01 (s, 1H), 9.24 (s, 1H), 7.96 –
7.88 (m, 2H), 7.59 – 7.47 (m, 5H), 6.77 – 6.70 (m, 2H) ppm; 13C
NMR (100 MHz, DMSOꢀd6): δ = 164.9, 153.7, 135.1, 131.2,
130.7, 128.3, 127.5, 122.3, 114.9 ppm.77
NMR (400 MHz, Acetoneꢀd6): δ = 7.43 (s, 2H), 6.38 (d, J = 7.7
Hz, 2H), 6.26 (d, J = 1.7 Hz, 2H), 6.08 (dd, J = 7.7, 1.7 Hz, 2H),
3.38 – 3.29 (m, 2H), 2.91 – 2.84 (m, 4H), 2.57 – 2.46 (m, 2H)
ppm; 13C NMR (100 MHz, Acetoneꢀd6): δ = 156.3, 143.1, 136.3,
125.7, 124.9, 118.7, 34.2, 31.9 ppm.51
Procedure for the Oxidation of Guaiacol Estrogen. Prepared
according general procedure A, following an acidic workup. The
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