K. Prasain et al. / Bioorg. Med. Chem. 20 (2012) 1679–1689
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ether, washed with water and brine, dried (MgSO4), concentrated,
and column chromatographed on silica gel using hexane and
dichloromethane (1:1) as eluant to give 3.7 g (70% yield) of com-
pound 26 and 0.84 g (11% yield) of 5-chloro-3,4-bis-(t-butyldi-
methylsilyloxy)benzaldehyde. Compound 26 was crystallized
from diethyl ether to provide single crystals and its structure
was unequivocally identified by a single-crystal X-ray analysis.
1H NMR d 9.76 (s, 1H, CHO), 7.51 (d, J = 2.8 Hz, 1H), 7.27 (d,
J = 2.8 Hz, 1H), 6.24 (s, 1H, OH), 1.03 (s, 9H), 0.32 (s, 6H); 13C
NMR d 189.9, 149.9, 144.2, 129.4, 126.8, 120.7, 115.9, 25.8, 18.4,
ꢀ4.2; HRMS calcd for C13H20ClO3Si (M+H+) 287.0870, found
287.0858.
108.6, 60.7, 25.8 (3C), 18.4, ꢀ4.5; HRMS calcd for C13H22ClO3Si
(M+H+) 289.1027, found 289.1041.
4.16. 2-Bromo-5-(tert-butyldimethylsilyloxy)-3-chloro-4-
methoxyphenol (30)
To a solution of 90 mg (0.31 mmol) of 29 in 2 mL of DMF under
argon was added 61 mg (0.34 mmol) of N-bromosuccinimide, and
the solution was stirred at 25 °C for 12 h. It was diluted with
diethyl ether, washed with water and brine, dried (MgSO4), con-
centrated, and column chromatographed on silica gel using a mix-
ture of hexane and diethyl ether (10:1) as eluant to give 85 mg
(74% yield) of 30: Mp 44–45 °C; 1H NMR d 6.55 (s, 1H), 5.42 (s,
1H, OH), 3.77 (s, 3H), 1.01 (s, 9H), 0.20 (s, 6H); 13C NMR d 150.2,
149.6, 143.1, 124.2, 107.2, 103.0, 60.8, 25.8 (3C), 18.5, ꢀ4.5; HRMS
calcd for C13H21BrClO3Si (M+H+) 367.0132, found 367.0142.
5-Chloro-3,4-bis-(t-butyldimethylsilyloxy)benzaldehyde:
1H
NMR d 9.78 (s, 1H), 7.50 (d, J = 2 Hz, 1H), 7.29 (d, J = 2 Hz, 1H),
1.05 (s, 9H), 0.99 (s, 9H), 0.27 (s, 6H), 0.24 (s, 6H); 13C NMR d
190.1, 149.9, 149.4, 130.3, 128.0, 126.0, 119.0, 26.3 (3C), 26.2
(3C), 19.0, ꢀ3.2, ꢀ3.4; HRMS calcd for C19H34ClO3Si2 (M+H+)
401.1735, found 401.1747.
4.17. 4-Bromo-5-chloro-6-methoxybenzene-1,3-diol (6)
4.13. 3-(tert-Butyldimethylsilyloxy)-5-chloro-4-
methoxybenzaldehyde (27)
To a solution of 50 mg (0.14 mmol) of 30 in 2 mL of THF under
argon at 0 °C, was added 0.14 mL (0.14 mmol) of n-Bu4NF (1 M
solution in THF), and the solution was stirred at 0 °C for 30 min.
It was diluted with dichloromethane, washed with water and
brine, dried (MgSO4), concentrated, and column chromatographed
on silica gel using a gradient mixture of dichloromethane and
To a solution of 0.17 g (0.59 mmol) of compound 26 in 3 mL of
dichloromethane at 0 °C under argon, were added 0.26 g
(1.2 mmol) of proton sponge and 0.18 g (1.2 mmol) of trim-
ethyloxonium tetrafluoroborate and the mixture was stirred at
0 °C for 8 h. The reaction mixture was diluted with water and ex-
tracted twice with diethyl ether. The combined extract was
washed with water and brine, dried (MgSO4), concentrated, and
column chromatographed on silica gel using a mixture of hexane
and diethyl ether (10:1) as eluant to give 0.35 (79% yield) of 27:
1H NMR d 9.67 (s, 1H, CHO), 7.31 (d, J = 2 Hz, 1H), 7.06 (d,
J = 2 Hz, 1H), 3.69 (s, 3H), 0.81 (s, 9H), 0.02 (s, 6H); 13C NMR d
190.1, 153.4, 150.9, 132.8, 129.8, 125.5, 119.9, 60.7, 25.8, 18.4,
ꢀ4.4; HRMS calcd for C14H22ClO3Si (M+H+) 301.1027, found
301.1421; negative ion detection mode: C14H20ClO3Si (MꢀH)
299.0870, found 298.9978.
methanol as eluants to give 23 mg (67% yield) of 6. IR (neat)
m
3321 (br s), 3260, 2917, 1589, 1421, 1241, 984, 800; 1H NMR d
6.65 (s, 1H), 3.87 (s, 3H); 13C NMR d 150.5, 150.0, 138.7, 127.5,
101.8, 101.7, 61.5; HRMS calcd for C7H7BrClO3 (M+H+) 252.9267,
found 252.9279.
4.18. 2-Amino-4-methylphenol (7) and 2-amino-4-
(hydroxymethyl)phenol (8)
A mixture of 0.30 g (1.8 mmol) of 4-hydroxy-3-nitrobenzalde-
hyde (31) and 0.15 g of 10% Pd/C in 30 mL of ethanol was shaken
on a hydrogenator under 30 psi atmosphere of hydrogen for 4 h.
The reaction mixture was filtered through Celite and carefully
washed with ethyl acetate. The filtrate was concentrated and col-
umn chromatographed on silica gel using a mixture of dichloro-
methane and methane (9:1) as eluant to give 91 mg (41% yield)
4.14. 3-(tert-Butyldimethylsilyloxy)-5-chloro-4-methoxyphenyl
formate (28)
To a solution of 0.21 g (0.70 mmol) of aldehyde 27 in 2 mL of
dichloromethane under argon, was added 0.18 g (1.1 mmol) of
m-chloroperbenzoic acid (70%), and the solution was heated to re-
flux for 8 h. The reaction solution was diluted with 5 mL of aqueous
sodium thiosulfate and extracted twice with diethyl ether. The
combined extract was washed with saturated aqueous NaHCO3,
water, and brine, dried (MgSO4), concentrated, and column chro-
matographed on silica gel using a mixture of hexane and diethyl
ether (10:1) as eluant to give 0.16 g (71% yield) of 28. 1H NMR d
8.23 (s, 1H, OCHO), 6.83 (d, J = 2.6 Hz, 1H), 6.59 (d, J = 2.6 Hz, 1H),
3.81 (s, 3H), 1.01 (s, 9H), 0.21 (s, 6H); 13C NMR d 158.9, 150.7,
146.6, 145.4, 129.1, 115.8, 113.6, 60.7, 25.8 (3C), 18.4, ꢀ4.5; HRMS
calcd for C14H22ClO4Si (M+H+) 317.0976, found 317.1355.
of 723 and 0.10 g (41% yield) of 8.24 Compound 7: IR (neat)
3370 (sharp, m), 3301 (sharp, m), 2921, 1601, 1519, 1458, 1388,
m
1286, 878, 800 cmꢀ1 1H NMR d 6.62 (d, J = 7.6 Hz, 1H), 6.58 (d,
;
J = 1.6 Hz, 1H), 6.48 (dd, J = 7.6, 1.6 Hz, 1H), 2.21 (s, 3H); 13C NMR
d 141.9, 134.4, 131.2, 120.0, 118.1, 115.4, 20.9. Compound 8: IR
(neat)
m
3387 (sharp, m), 3313 (sharp, m), 3047 (broad), 2802,
1605, 1515, 1454, 1364, 1286, 1221, 1155, 1008, 816 cmꢀ1
;
1H
NMR (D2O) d 6.88 (d, J = 1.2 Hz, 1H), 6.85 (d, J = 8 Hz, 1H), 6.77
(dd, J = 8, 1.2 Hz, 1H), 4.49 (s, 2H); 13C NMR (DMSO-d6) d 142.9,
136.1, 133.5, 114.9, 113.8, 113.4, 63.3.
4.19. 2-(3,5-Di-tert-butyl-4-hydroxyphenyl)-2-methylpropanal
(11)
4.15. 3-(tert-Butyldimethylsilyloxy)-5-chloro-4-methoxyphenol
(29)
A solution of 0.17 g (0.61 mmol) of 2,6-di-t-butyl-4-(1,1-di-
methyl-2-hydroxyethyl)phenol (10)25 and 0.21 g (0.73 mmol) of
IBX in 3 mL of DMSO was stirred under argon at 25 °C for 12 h, di-
luted with dichloromethane, washed with water and brine, dried
(MgSO4), and concentrated to give 0.17 g (99% yield) of aldehyde
11. Spectral data and TLC indicated the compound is pure and
was used in subsequent reactions without purification. IR (neat)
A solution of 0.16 g (0.50 mmol) of compound 28 and 0.34 g
(2.50 mmol) of K2CO3 in 5 ml of methanol was stirred at 25 °C for
4 h and diluted with diethyl ether. The mixture was washed with
water and brine, dried (MgSO4), concentrated, and column chro-
matographed on silica gel using a mixture of hexane and diethyl
ether (10:1) as eluant to give 0.14 g (95% yield) of 29: 1H NMR d
6.48 (d, J = 2.6 Hz, 1H), 6.29 (d, J = 2.6 Hz, 1H), 3.75 (s, 3H), 1.01
(s, 9H), 0.20 (s, 6H); 13C NMR d 152.0, 150.7, 142.6, 128.1, 110.8,
m
3603 (OH), 2952, 2900, 2700 (C–H aldehyde), 1714 (C=O alde-
hyde), 1435, 1360, 1230, 1141, 1120, 903, 826, 744; 1H NMR d
9.45 (s, 1H, CHO), 7.06 (s, 2H, Ar), 5.22 (s, 1H, OH), 1.44 (s, 24H,
Me); 13C NMR d 202.8 (C=O), 153.1, 136.2 (2C), 131.4, 123.6 (2C),