Solid-supported 4-hydroxybenzaldehyde 8. p-Benzyl alcohol
resin (1.2 mmol g−1, 2.5 g, 3.0 mmol) was suspended in THF
(25 ml) and p-hydroxybenzaldehyde (1.86 g, 15.0 mmol) and PPh3
(3.93 g, 15.0 mmol) were added followed by DIAD (3.30, 2.8 ml,
15.0 mmol) in THF (2 ml). The mixture was agitated for 16 hours,
filtered and washed with DCM (3 × 20 ml) and dried under
reduced pressure. Loading: 95%; IR mmax/cm−1 1697 (CO).
for 16 hours. The resin was filtered and washed with THF–MeOH
(1 : 1) (3 × 10 ml), THF (3 × 10 ml) and DCM (3 × 10 ml) and
dried overnight under reduced pressure.
1-Phenylhex-2-yn-1-one 13m. Compound 13m (26 mg,
0.15 mmol, 35%) was prepared following the general procedure.
dH (300 MHz, CDCl3) 8.15 (2 H, d, J 8.0), 7.58 (1 H, m), 7.45 (2
H, m), 2.45 (2 H, t, J 7.2), 1.67 (2 H, tq, J 7.2, 7.0), 1.05 (3 H, t, J
7.1); dC (75 MHz, CDCl3) 178.2, 136.8, 133.9, 129.5, 128.4, 96.7,
79.7, 21.3, 21.1, 13.6; m/z (+FAB) 173.0966 (M + H+). C12H12O
requires 172.0888.
Solid-supported (E)-benzaldehyde O-methyl oxime 9. Resin 8
(2.4 g, 2.51 mmol) was suspended in DMF (20 ml) and O-
methylhydroxylamine hydrochloride (2.10 g, 25.1 mmol) and
DIPEA (3.24 g, 4.30 ml, 25.1 mmol) were added. The mixture was
heated at reflux for 8 hours. After cooling to room temperature
the resin was filtered and washed with DMF (3 × 20 ml), THF–
MeOH (1 : 1) (3 × 20 ml), THF (3 × 20 ml) and DCM (3 × 20 ml).
The resin was dried overnight under reduced pressure.
1-Phenylhex-5-en-3-one 13j. Compound 13j (21 mg,
0.12 mmol, 30%) was prepared following the general procedure.
dH (300 MHz, CDCl3) 7.15–7.37 (5 H, m), 5.90 (1 H, m), 5.15 (1
H, m), 5.11 (1 H, m), 3.17 (2 H, m), 2.92 (2 H, t, J 6.9), 2.75 (2 H,
t, J 6.9); dC (75 MHz, CDCl3) 193.2, 140.9, 130.0, 128.4, 128.3,
126.1, 118.9, 47.8, 43.8, 29.6; m/z (+FAB) 175.1121 (M + H+).
C12H14O requires 175.1123.
Solid-supported 4-((methoxyamino)methyl)phenol 10. Resin 9
(2.4 g, 2.36 mmol) was suspended in THF (20 ml) and NaCNBH3
(1.04 g, 16.5 mmol) was added. A mixture of MeOH–sulfuric acid
1-Phenylnonan-3-one 13k. Compound 13k (24 mg, 0.11 mmol,
27%) was prepared following the general procedure. dH (300 MHz,
CDCl3) 7.31 (2 H, m), 7.18 (3 H, m), 2.91 (2 H, t, J 7.2), 2.71 (2 H,
t, J 7.2), 2.35 (2 H, t, J 7.1), 1.53 (2 H, m), 1.27 (6 H, m), 0.88 (3
H, t, J 7.1); dC (75 MHz, CDCl3) 210.4, 141.1, 128.4, 128.3, 126.0,
44.2, 43.0, 31.5, 29.7, 28.8, 23.7, 22.4, 14.0; m/z (+FAB) 241.1568
(M + Na+). C15H22O requires 241.1568.
◦
(10 : 1) (5 ml) was added dropwise at 0 C and the mixture was
agitated for 16 hours at room temperature. The resin was filtered
and washed with water–MeOH (1 : 1) (5 × 20 ml), THF–MeOH
(1 : 1) (3 × 20 ml), THF (3 × 20 ml), and DCM (3 × 20 ml) and
dried overnight under reduced pressure.
Solid-supported Weinreb amide, R = Ph 11, R = (CH2)2Ph 12.
Resin 10 (2.0 g, 1.96 mmol) was suspended in dry DCM (20 ml)
and Et3N (1.39 g, 1.92 ml, 13.7 mmol) was added. The resin was
agitated for 20 min followed by dropwise addition of the acid
chloride (7 eqv.) in dry DCM (1 ml). After agitating for 16 h, the
resin was washed with water–MeOH (1 : 1) (3 × 15 ml), THF–
MeOH (1 : 1) (3 × 15 ml), THF (3 × 15 ml), and DCM (3 × 15 ml)
and dried overnight under reduced pressure. Loading: 60% (over
three steps); 11: IR mmax/cm−1 1610 (CO); 12: IR mmax/cm−1 1718
(CO).
1-Phenyloct-4-yn-3-one 13q. Compound 13q (22 mg,
0.13 mmol, 31%) was prepared following the general procedure.
dH (300 MHz, CDCl3) 7.25 (2 H, m), 7.08–7.12 (3 H, m), 2.90 (2
H, t, J 7.0), 2.75 (2 H, t, J 7.0), 2.10 (2 H, t, J 6.9), 1.55 (2 H, tq,
J 7.0, 7.0), 0.93 (3 H, t, J 7.0); dC (75 MHz, CDCl3) 187.8, 140.7,
128.6, 127.5, 126.3, 98.6, 91.9, 43.8, 32.7, 21.3, 20.3, 13.5; m/z
(+FAB) 223.1106 (M + Na+). C14H16O requires 223.1099.
6-(Mercaptopyridine-3-yl)methanol 22. To an ice-cooled solu-
tion of LiAlH4 (1 M in THF, 58 mmol, 58.0 ml) in dry THF
(200 ml) was added 6-mercaptonicotinic acid (6.0 g, 38.8 mmol) in
small portions. After stirring for 16 hours, the mixture was cooled
to 0 ◦C and cold water (2.4 ml) was added slowly followed by
NaOH (aq) (4 M, 2.4 ml) and additional cold water (6.8 ml). The
mixture was filtered and the solid was extracted repeatedly with
a mixture of EtOAc–MeOH 9 : 1. The filtrate was concentrated
under reduced pressure and purified by column chromatography
(eluent: EtOAc–MeOH 9 : 1) to give compound 22 (3.06 g,
21.6 mmol, 56%) as a yellow solid. Mp.: 85–87 ◦C; dH (300 MHz,
CDCl3) 7.98 (1 H, s), 7.75 (1 H, m), 7.61 (1 H, m), 4.68 (2 H, s);
dC (75 MHz, CDCl3) 176.8, 137.8, 136.0, 133.2, 128.1, 60.1; m/z
(+EI) 141.
General procedure for synthesis of carbonyl compounds using
solid-supported Weinreb amides 11 and 12. To an ice-cooled sus-
pension of the solid-bound Weinreb amides 11 (0.5 g, 0.43 mmol)
or 12 (0.5 g, 0.41 mmol) in dry THF (5 ml), was added the
nucleophilic reagent (4 eqv.) dropwise under argon. After agitating
for one hour, HCl (aq) (1M)–THF (1 : 1) (2 ml) was added slowly.
The mixture was agitated for an additional 15 min, filtered and
washed with THF (3 × 5 ml) and DCM (3 × 5 ml). The filtrate
was evaporated to dryness, dissolved in EtOAc–hexane (1 : 1) and
passed through a short silica gel column. The solvent was removed
under reduced pressure and the product was dried overnight.
General procedure for preparation of lithiated nucleophiles
(6-Tritylthio)pyridine-3-yl)methanol 23. Compound 22 (6.0 g,
42.6 mmol) was dissolved in dry DCM–dry THF (1 : 1) (150 ml)
and Et3N (8.60 g, 11.8 ml, 85.1 mmol) was added. The solution was
cooled to 0 ◦C and triphenylchloromethane (13.05 g, 46.8 mmol)
in dry THF (60 ml) was added slowly. After stirring for 3 hours, the
solvent was removed under reduced pressure and the residue was
dissolved in EtOAc and washed with saturated NaHCO3 (aq) (2 ×
100 ml) and saturated NaCl (aq) (2 × 100 ml). The organic phase
was dried over Na2SO4, concentrated under reduced pressure and
the crude product was purified by column chromatography (eluent:
hexane–EtOAc 8 : 1 to 2 : 1) to give compound 23 (13.5 g,
The substrate was dissolved in dry THF at 0 ◦C under argon and n-
BuLi (1 eqv.) was added dropwise. The mixture was stirred at 0 ◦C
for 30 min and then added dropwise to the solid-bound Weinreb
amide.
General procedure for reacylation of used resin 14. The spent
resin was washed with water–MeOH (1 : 1) (3 × 5 ml), MeOH (3 ×
5 ml), THF (3 × 5 ml), and DCM (3 × 5 ml) and dried overnight
under reduced pressure. Dry DCM (5 ml) was added to the resin
followed by Et3N (7 eqv.). After 30 min, the acid chloride (7 eqv.)
in DCM (1 ml) was added dropwise, and the mixture was agitated
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 4497–4505 | 4503
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