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N. R. Irlapati et al. / Tetrahedron 62 (2006) 4603–4614
Di-de-t-butylated phenol 37. nmax (neat)/cmK1 3243brm,
2938m, 1704w, 1647s, 1612s, 1541w, 1516m, 1428m,
title compound 41 as a white solid, mp O250 8C. nmax
(neat)/cmK1 3377brm, 2961s, 1600m, 1360s, 1316s, 1295s,
1181s, 1022m; dH (400 MHz, CDCl3) 1.36 (d, JZ7.0 Hz,
12H), 3.49 (septet, JZ7.0 Hz, 2H), 4.90 (s, 2H), 7.40 (t, JZ
7.0 Hz, 1H), 7.47 (t, JZ7.0 Hz, 2H), 7.53 (d, JZ7.0 Hz,
2H), 8.07 (s, 2H); dC (100.6 MHz, CDCl3) 24.1, 26.6, 76.4,
127.4, 128.0, 128.6, 131.7, 137.4, 141.5, 157.2; m/z (ESI-)
311 [(MKH)K, 100%]; HRMS: found 311.1824 (MKH)K.
C19H24BO3 requires 311.1819.
1
1272m, 1263m; H NMR (500 MHz, CDCl3) dH 1.05–1.11
(m, 2H), 1.17–1.28 (m, 1H), 1.30–1.80 (m, 9H), 2.02–2.11
(m, 2H), 2.81 (s, 3H), 4.72–4.78 (m, 1H), 4.94 (d, JZ
7.0 Hz, 1H), 5.72 (brs, 1H), 6.96 (d, JZ8.5 Hz, 2H), 7.18 (d,
JZ8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) dC 22.4, 22.8,
22.9, 23.0, 24.5, 26.8, 31.4, 45.5, 55.9, 84.3, 107.1, 107.8,
116.1, 122.8, 131.3, 144.9, 154.3, 156.3, 173.1, 204.9,
205.4; m/z (ESIC) 412 (MHC, 100%); HRMS: found
412.1755 (MHC). C23H26NO6 requires 412.1760.
4.1.16. 3-Acetyl-N-benzyloxy-5-[(40-benzyloxy-30,50-di-
isopropyl)phenyl]-4-hydroxy-2(1H)-pyridone 42. To a
solution of 4-benzyloxy-3,5-di-isopropylphenylboronic
acid 41 (92 mg, 0.29 mmol, 1.0 equiv), and 3-acetyl-
N-benzyloxy-5-bromo-4-hydroxy-2-pyridone 28 (98 mg,
0.29 mmol, 1.0 equiv) in 4:1 mixture of toluene/ethanol
(1.25 mL) was added a 2 M aqueous sodium carbonate
solution (1.25 mL), followed by tetrakis(triphenyl-
phosphine)palladium(0) (17 mg, 0.014 mmol, 0.05 equiv).
The resulting mixture was heated at reflux for 12 h before
being cooled to rt and partitioned in a 1:1 mixture of ethyl
acetate/water (20 mL). The phases were separated, and the
organic layer was washed with brine (10 mL), dried
(MgSO4) and filtered. The filtrate was evaporated under
vacuum. The crude product was purified by flash column
chromatography (silica gel, 3% ethyl acetate in DCM) to
yield 110 mg (71%) of the title compound 42 as a yellow
gum. nmax (neat)/cmK1 2963s, 1668s, 1609s, 1536m,
1454m, 1413m, 1377m, 1308m, 1223m; dH (400 MHz,
CDCl3) 1.26 (d, JZ7.0 Hz, 12H), 2.89 (s, 3H), 3.42 (septet,
JZ7.0 Hz, 2H), 4.83 (s, 2H), 5.33 (s, 2H), 6.90 (s, 2H), 7.21
(s, 1H), 7.38–7.51 (m, 10H); dC (100.6 MHz, CDCl3) 24.1,
26.6, 31.6, 76.5, 78.8, 107.9, 112.6, 124.9, 127.4, 127.9,
128.0, 128.5, 129.0, 129.8, 130.5, 133.7, 137.5, 141.0,
142.0, 153.0, 158.1, 174.0, 206.1; HRMS: found 524.2434
(MKH)K. C33H34NO5 requires 524.2437.
Monode-alkylated phenol 38. nmax (neat)/cmK1 3243brm,
2939m, 1705w, 1648s, 1613s, 1541w, 1515m, 1428m,
1
1272m, 1263m; H NMR (400 MHz, CDCl3) dH 1.05–1.11
(m, 2H), 1.17–1.28 (m, 1H), 1.30–1.80 (m, 18H), 2.02–2.13
(m, 2H), 2.82 (s, 3H), 4.75–4.79 (m, 1H), 4.89 (d, JZ
7.5 Hz, 1H), 5.02 (s, 1H), 6.77 (d, JZ8.0 Hz, 1H), 7.01 (dd,
JZ8.0, 2.0 Hz, 1H), 7.15 (d, JZ2.0 Hz, 1H,); m/z (ESI-)
466 [(MKH)K, 100%); HRMS: found 466.2231 (MKH)K.
C27H32NO6 requires 466.2230.
4.1.14. 4-Benzyloxy-3,5-di-isopropylbromobenzene 40.
To a stirred suspension of sodium hydride (60% dispersion
in mineral oil, 176 mg, 4.41 mmol, 1.2 equiv) in THF
(10 mL) at 0 8C was added dropwise a solution of 4-bromo-
2,6-di-isopropylphenol26 (0.94 g, 3.67 mmol, 1.0 equiv).
After stirring for 1 h at 25 8C, the reaction mixture was
cooled down to 0 8C prior to the addition of benzyl bromide
(0.46 mL, 3.85 mmol, 1.05 equiv). The resulting mixture
was stirred at 40 8C for 12 h. The reaction mixture was
cooled to rt before the addition of water (20 mL) and the
aqueous layer was extracted with diethyl ether (3!15 mL).
The combined organic layers were washed with water (2!
10 mL), brine (10 mL), dried (MgSO4) and filtered. The
filtrate was evaporated under vacuum. The crude product
was purified by flash column chromatography (silica gel,
2% diethyl ether in 30–40 petroleum ether) to yield 1.10 g
(86%) of title compound 40 as a clear oil. nmax (neat)/cmK1
2963s, 1574m, 1497m, 1456s, 1325s, 1184s; dH (400 MHz,
CDCl3) 1.25 (d, JZ7.0 Hz, 12H), 3.39 (septet, JZ7.0 Hz,
2H), 4.83 (s, 2H), 7.27 (s, 2H), 7.41 (t, JZ7.0 Hz, 1H), 7.47
(t, JZ7.0 Hz, 2H), 7.52 (d, JZ7.0 Hz, 2H); dC (100.6 MHz,
CDCl3) 23.9, 26.8, 76.5, 118.1, 127.3, 127.4, 128.1, 128.4,
137.3, 144.4, 152.2.
4.1.17. 3-Acetyl-1,4-dihydroxy-5-[(30,50-di-isopropyl-40-
hydroxy)phenyl]-2(1H)-p0yridone 43. 0 A mixture of
3-acetyl-N-benzyloxy-5-(4 -benzyloxy-3 ,50-di-isopropyl-
phenyl)-4-hydroxy-2(1H)-pyridone 42 (100 mg, 0.19 mmol,
1.0 equiv) and 10% palladium on carbon (100 mg) in dioxane
(5 mL) was stirred under hydrogen (balloon) atmosphere at
25 8C for 2 h. The reaction mixture was filtered, the solid
residue was washed with dioxane (20 mL) and the combined
filtrates were evaporated under vacuum to yield 80 mg (96%)
of the 3-acetyl-N-hydroxy-5-(40-benzyloxy-30,50-di-isopro-
pylphenyl)-4-hydroxy-2(1H)-pyridone as a yellow solid, mp
202–203 8C. The crude product was used as such for next step
without further purification. nmax (neat)/cmK1 3174m, 2963m,
1648s, 1613s, 1429s, 1323m, 1248m, 1212w, 1123m, 722m;
dH (400 MHz, CDCl3) 1.27 (d, JZ7.0 Hz, 12H), 2.83 (s, 3H),
3.48 (septet, JZ7.0 Hz, 2H), 4.87 (s, 2H), 7.23 (s, 2H), 7.39 (t,
JZ7.0 Hz, 1H, 7.45 (t, JZ7.0 Hz, 2H), 7.53 (d, JZ7.0 Hz,
2H), 7.94 (s, 1H); dC (100.6 MHz, CDCl3) 22.7, 24.1, 26.7,
76.5, 107.9, 112.6, 125.0, 127.3, 127.9, 128.0, 128.6, 133.9,
137.5, 142.2, 153.2, 158.1, 174.0, 206.1;m/z (ESI-)434 [(MK
H)K, 100%]; HRMS: found 434.1964 (MKH)K. C26H28NO5
requires 434.1967.
4.1.15. 4-Benzyloxy-3,5-di-isopropylphenylboronic acid
41. To a K78 8C cooled solution of 4-benzyloxy-3,5-di-
isopropylbromobenzene 40 (1.00 g, 2.89 mmol, 1.0 equiv)
in THF (25 mL) was added dropwise a 1.5 M solution of
tert-butyl lithium in hexanes (4.04 mL, 6.06 mmol,
2.1 equiv). The reaction mixture was brought to 25 8C and
after stirring for 1 h at 25 8C, the reaction mixture was
cooled to K78 8C prior to the addition of trimethyl borate
(0.97 mL, 8.67 mmol, 3.0 equiv). The reaction was left
overnight at 25 8C prior to the addition of saturated
ammonium chloride solution (50 mL). The resulting
mixture was stirred at 25 8C for 2 h and the aqueous layer
was extracted with ethyl acetate (3!25 mL). The combined
organic layers were washed with brine (25 mL), dried
(MgSO4) and filtered. The filtrate was evaporated under
vacuum. The crude product was purified by recrystallization
(30% ethyl acetate in hexane) to yield 450 mg (50%) of the
To a K78 8C coole0d solution of 3-acetyl-1,4-dihydroxy-5-
(40-benzyloxy-30,5 -di-isopropylphenyl)-2(1H)-pyridone
(60 mg, 0.14 mmol, 1.0 equiv) in DCM was added 1 Mboron