Page 9 of 13
The Journal of Organic Chemistry
4-Cyanocatechol (5k) From 2-methoxy-4-cyanophenol (4k); off-
2',3',4'-Trihydroxyacetophenone (5r) Light yellow solid; yield:
0.197g (23%); mp 169 – 170 oC; Rf = 0.26 (PE/EA 3:1). 1H NMR
(400 MHz, DMSO-d6) δ 12.61 (br s, 1H), 10.04 (br s, 1H), 8.71
(brs, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.41 (d, J = 8.8 Hz, 1H), 2.52
(s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 204.0, 153.0,
152.6, 132.6, 123.6, 113.6, 108.1, 26.8. Unreacted 4r was
recovered: 0.198 g (20%).
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white solid; yield: 0.641 g (94%); mp 153 – 154 C; Rf = 0.39
(PE/EA 1:1). 1H NMR (400 MHz, DMSO-d6) δ 7.11 (dd, J1 = 8.2
Hz, J2 = 2.0 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 6.86 (d, J = 8.2 Hz,
1H). From 2-methoxy-5-cyanophenol (4kꞌ); yield: 0.559 g (82%).
Protocatechualdehyde (5l) From vanillin (4l); yellow solid; yield:
0.609 g (88%); mp 151 – 152 oC; Rf = 0.38 (PE/EA 1:1). 1H NMR
(400 MHz, DMSO-d6) δ 9.84 (br s, 2H), 9.70 (s, 1H), 7.27 (d, J =
8.0 Hz, 1H), 7.25 (s, 1H), 6.92 (d, J = 8.0 Hz, 1H). From isovanillin
(4lꞌ); yield: 0.574 g (83%). From ethylvanillin (6b); yield: 0.462 g
(60%). From vanillin (4l, 0.432 g, 2.84 mmol) using Al(OEt)3
(0.461g, 2.84 mmol, 1 eq) and NaI (1.275 g, 8.51 mmol, 3 eq);
yield: 0.228 g (58%).
5-Methoxysalicylaldehyde (7a) Light yellow liquid; yield: 0.361
1
g (47%); Rf = 0.58 (PE/EA 10:1). H NMR (400 MHz, CDCl3) δ
10.65 (s, 1H), 9.83 (s, 1H), 7.13 (dd, J1 = 9.0 Hz, J2 = 3.1 Hz, 1H),
6.98 (d, J = 3.1 Hz, 1H), 6.91 (d, J = 9.0 Hz, 1H), 3.80 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 196.2, 156.0, 152.7, 125.2,
120.0, 118.6, 115.2, 55.9.
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3',4'-dihydroxyacetophenone (5m) From acetovanillone (4m);
off-white solid; yield: 0.721 g (94%); mp 118 – 119 oC (lit.31 115-
117 oC); Rf = 0.35 (PE/EA 1:1). 1H NMR (400 MHz, DMSO-d6) δ
9.60 (br s, 2H), 7.35 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.34 (d, J =
2.4 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 2.43 (s, 3H). From
isoacetovanillone (4mꞌ); yield: 0.617 g (81%). Demethylation by
DMC-AlI3; from 4m; yield: 0.740 g (97%).
4-Methoxysalicylaldehyde (7b) White solid; yield: 0.631 g (82%);
mp 39 – 41 oC; Rf = 0.67 (PE/EA 3:1). 1H NMR (400 MHz, DMSO-
d6) δ 11.06 (br s, 1H), 10.00 (s, 1H), 7.62 (d, J = 8.7 Hz, 1H), 6.56
(dd, J1 = 8.7 Hz, J2 = 2.4 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 3.81 (s,
3H).
2'-Hydroxy-5'-methoxyacetophenone (7c) Light yellow solid;
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yield: 0.708 g (85%); mp 47 – 48 C; Rf = 0.81 (PE/EA 3:1). H
NMR (400 MHz, CDCl3) δ 11.86 (s, 1H), 7.16 (d, J = 3.0 Hz, 1H),
7.11 (dd, J1 = 9.0 Hz, J2 = 3.1 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H),
3.80 (s, 3H), 2.62 (s, 3H).
Gram-scale synthesis of 3',4'-dihydroxyacetophenone (5m) A
mixture of aluminum powder (0.869 g) and iodine (5.443 g, 21.45
mmol) and MeCN (80 mL) was stirred for about 0.5 h at 80 oC in
an oil bath to give a suspension AlI3 (14.3 mmol, 1.1 eq). To the
mixture was charged DMF-DMA (2.325 g, 19.51 mmol, 1.5 eq)
followed by acetovanillone 4m (2.160 g, 13 mmol). After stirring
2'-Hydroxy-4'-methoxyacetophenone (Paeonol, 7d) Colorless
liquid; yield: 0.670 g (80%); Rf = 0.56 (PE/EA 10:1). 1H NMR (400
MHz, CDCl3) δ 12.75 (s, 1H), 7.60 (d, J = 8.8 Hz, 1H), 6.42 (dd, J1
= 8.8 Hz, J2 = 1.1 Hz, 1H), 6.39 (d, J = 1.4 Hz, 1H), 3.81 (s, 3H),
2.53 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 202.6, 166.1,
165.2, 132.3, 113.9, 107.5, 100.8, 55.5, 26.1.
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for 18 h at 80 C, the mixture was cooled to room temperature,
acidified with dilute HCl (2M, 10 mL), extracted with EA (50
mL⨯3). The organic phases were combined, washed with saturated
Na2S2O3 and brine, and dried over MgSO4. After filtration, the
solvents were removed by rotary evaporator, and the residue was
purified by column chromatography (eluent: PE/EA = 1:1). Yield:
1.808 g (91%).
2-Hydroxybenzonitrile (9a) Off-white solid; yield: 0.060 g
(10%); mp 92 – 94 oC; Rf = 0.32 (PE/EA 3:1). 1H NMR (400 MHz,
CDCl3) δ 7.51 (dd, J1 = 7.8, 1.7 Hz, 1H), 7.47 (ddd, J1 = 9.0 Hz, J2
= 7.5 Hz, J3 = 1.7 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.98 (td, J1 =
7.6 Hz, J2 = 1.0 Hz, 1H), 6.81 (br s, 1H). Unreacted 8a was
recovered: 0.546 g (82%).
4-(3,4-Dihydroxyphenyl)butan-2-one (5n) Off-white solid; yield:
0.473 g (52%); mp 78 – 81 oC (lit.32 85 – 86 oC); Rf = 0.35 (PE/EA
1:1). 1H NMR (400 MHz, CDCl3) δ 6.76 (d, J = 8.0 Hz, 1H), 6.70
(d, J = 2.1 Hz, 1H), 6.59 (dd, J1 = 8.1 Hz, J2 = 2.1 Hz, 1H), 6.02 (br
s, 1H), 5.80 (br s, 1H), 2.84 – 2.67 (m, 4H), 2.15 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 210.1, 143.7, 142.0, 133.6, 120.5,
115.4, 115.4, 45.4, 30.2, 29.1.
4-Cyanophenol (9b) Off-white solid; yield: 0.051 g (8%); mp 111
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– 112 C; Rf = 0.38 (PE/EA 3:1). H NMR (400 MHz, CDCl3) δ
7.56 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 6.88 (br s, 1H).
Unreacted 8b was recovered: 0.489 g (73%).
(E)-4-(3,4-Dihydroxyphenyl)but-3-en-2-one (5o) Light yellow
solid; yield: 0.550 g (61%); mp 172 – 174 oC (lit.32 177-178 oC); Rf
= 0.30 (PE/EA 1:1). 1H NMR (400 MHz, DMSO-d6) δ 9.42 (br s,
2H), 7.46 (d, J = 16.2 Hz, 1H), 7.07 (s, 1H), 7.01 (d, J = 7.8 Hz,
1H), 6.78 (d, J = 8.1 Hz, 1H), 6.49 (d, J = 16.2 Hz, 1H), 2.28 (s,
3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 198.3, 148.9, 146.1,
144.5, 126.2, 124.4, 122.1, 116.3, 115.2, 27.6.
1-Naphthol (9c) Pale yellow solid; yield: 0.136 g (18%); mp 93 –
95 oC; Rf = 0.84 (PE/EA 3:1). 1H NMR (400 MHz, CDCl3) δ 8.17
(ddt, J1 = 6.1 Hz, J2 = 3.4 Hz, J3 = 0.9 Hz, 1H), 7.86 – 7.75 (m,
1H), 7.53 – 7.46 (m, 2H), 7.44 (d, J = 8.3 Hz, 1H), 7.30 (dd, J1 =
8.3 Hz, J2 = 7.4 Hz, 1H), 6.80 (dd, J1 = 7.5 Hz, J2 = 1.0 Hz, 1H),
5.31 (br s, 1H).
3,4-Dihydroxybenzophenone
(9d)
From
3,4-
N-(3,4-Dihydroxybenzyl)nonanamide
(5p)
From
N-
dimethoxybenzophenone (8e, 0.485 g, 2 mmol); light yellow solid;
vanillylnonanamide (4p, 0.587 g, 2 mmol); off-white solid; yield:
yield: 0.168 g (39%); mp 133 – 134 oC (lit.31 132 – 134 oC); Rf =
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0.277 g (49%); mp 97 – 98 C; Rf = 0.13 (PE/EA 1:1). H NMR
(400 MHz, CDCl3) δ 8.41 (br s, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.79
(d, J = 8 Hz, 1H), 6.60 (dd, J1 = 8.0 Hz, J2 = 1.9 Hz, 1H), 6.49 (br
s, 1H), 6.07 (t, J = 6.0 Hz, 1H), 4.27 (d, J = 5.9 Hz, 2H), 2.20 (t, J
= 7.7 Hz, 2H), 1.61 (q, J = 7.3 Hz, 2H), 1.36 – 1.12 (m, 10H), 0.86
(t, J = 6.8 Hz, 3H).
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0.47 (PE/EA 1:1). H NMR (400 MHz, DMSO-d6) δ 9.73 (br s,
2H), 7.65 (d, J = 6.7 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.52 (t, J =
7.4 Hz, 2H), 7.26 (d, J = 2.1 Hz, 1H), 7.12 (dd, J1 = 8.2 Hz, J2 =
2.1 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 194.9, 151.2, 145.7, 138.8, 132.1, 129.5, 128.7, 128.7,
124.0, 117.4, 115.6. Unreacted 8e was recovered: 0.218 g (44%).
3-Bromo-4,5-dihydroxybenzaldehyde (5q) Yellow solid; yield:
0.894 g (82%); Rf = 0.19 (PE/EA 1:1). 1H NMR (400 MHz, DMSO-
d6) δ 10.46 (br s, 2H), 9.70 (s, 1H), 7.57 (s, 1H), 7.25 (s, 1H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 191.0, 149.8, 147.0, 129.5,
127.8, 113.2, 109.9.
4-Chlorophenol (9e) From 4-chlorophenyl allyl ether (8h, 0.337
g, 2 mmol); colorless liquid; yield: 0.005 g (1%); Rf = 0.31 (PE/EA
10:1). 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.9 Hz, 2H), 6.75
(d, J = 8.9 Hz, 2H), 6.12 (br s, 1H). 13C{1H} NMR (101 MHz,
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