Synthesis of Dihydropyranones and Furanones
syn-3,6-Dimethyl-2-(4-methoxyphenyl)-2,3-dihydropy-
ran-4-one (2b). A solution of 1b (0.24 g, 1.03 mmol) in toluene
(0.5 mmol/ml) was added to PdCl2 (18.9 mg, 0.1 mmol) and
CuCl (10.5, 0.1 mmol), followed by PBS (pH 7.4, 0.5 mmol/
mL). The resulting mixture was stirred at 50 °C for 3.5 days.
Upon cooling, the reaction mixture was diluted with Et2O and
filtered through a pad of silica gel. Purification by silica gel
chromatography on silica (1:3, EtOAc:hexane) gave 2b as a
colorless oil in 63% yield, de ) 98%; vmax (film/cm-1) 1667, 1615;
δH (400 MHz, CDCl3) 0.91 (3H, d, J ) 7.5 Hz), 2.11 (3H, s),
2.48 (1H, qd, J ) 7.5 and 3.4 Hz), 3.84 (3H, s), 5.37 (1H, s),
5.45 (1H, d, J ) 3.4 Hz), 6.94 (2H, d, J ) 8.8 Hz), 7.34 (2H, d,
J ) 8.8 Hz); δC (100 MHz, CDCl3) 10.0, 20.9, 45.0, 55.3, 82.7,
103.6, 113.9, 127.9, 128.8, 159.3, 173.7, 197.7; m/z 233.1180
(C14H17O3 requires 233.1178).
dried over MgSO4 and concentrated in vacuo to give a residue
further purified by silica gel chromatography (1:7, EtOAc:
hexane) to give 5 as a colorless oil in 89% yield, with E/Z )
88/12 (2.38 g, 10.9 mmol); vmax (film/cm-1) 1711, 1650; δH (400
MHz, CDCl3) 1.30 (3H, t, J ) 7.1 Hz), 1.80 (3H, s), 2.50 (2H,
q, J ) 7.6 Hz), 2.77 (2H, t, J ) 7.6 Hz), 4.20 (2H, q, J ) 7.1
Hz), 6.82 (1H, tq, J ) 7.6 and 1.5 Hz), 7.19-7.33 (5H, m); δC
(100 MHz, CDCl3) 12.3, 14.3, 30.6, 34.7, 60.4, 126.1, 128.3,
128.4, 128.5, 140.8, 141.3, 168.1; m/z 219.1368 (C14H19O2
requires 219.1385).
syn-N,2,2,4-Tetramethyl-5-phenylethyl-1,3-dioxolane-
4-carboxamide (8). 8 was obtained from nBuLi (7 equiv) and
N,O-dimethylhydroxyamine (5 equiv) and 7 in THF. Purifica-
tion by silica gel chromatography (1:3, EtOAc:hexane) gave
syn-8 in 82% and anti-8 in 18% yield (100% yield overall), both
as colorless oils. For syn-8: vmax (film/cm-1) 1645; δH (400 MHz,
CDCl3) 1.34 (3H, s), 1.35 (3H, s), 1.50 (3H, s), 1.85 (1H, m),
2.05 (1H, m), 2.75 (1H, ddd, J ) 14.0 10.8, and 6.3 Hz), 2.92
(1H, ddd, J ) 14.3, 12.1, and 4.2 Hz), 3.26 (3H, bs), 3.71 (3H,
s), 4.45 (1H, ddd, J ) 10.1, 2.2, and 1.5 Hz), 7.17-7.31 (5H,
m); δC (100 MHz, CDCl3) 25.6, 28.6, 32.5, 33.4, 61.0, 80.0, 82.9,
107.9, 125.8, 128.3, 128.5, 142.0, 172.8; m/z 308.1822 (C17H26-
NO4 requires 308.1862).
(E)-4-Hydroxy-1-phenyl-4-methylpent-1-en-3-one (3a).18
A mixture of 3-hydroxy-3-methyl-2-butanone (0.8 mL, 7.58
mmol), LiOH‚H2O (63 mg, 1.516 mmol), and benzaldehyde
(1.54 mL, 15.17 mmol) in MeOH (20 mL) and H2O (75 mL)
was stirred overnight at room temperature. The MeOH was
removed in vacuo and water was added. The aqueous layer
was extracted with CH2Cl2. The combined organic layers were
dried and concentrated in vacuo and the crude product was
purified by silica gel chromatography (1:6, EtOAc:hexane) to
give 3a in 66% yield as a pale yellow oil; vmax (film/cm-1) 3444,
1680; δH (400 MHz, CDCl3) 1.44 (6H, s), 4.00 (1H, s), 7.02 (1H,
d, J ) 15.4 Hz), 7.40 (3H, m), 7.58 (2H, m), 7.82 (1H, d, J )
15.4 Hz); δC (100 MHz, CDCl3) 26.4, 75.4, 118.4, 125.8, 128.8,
130.8, 134.1, 145.4, 202.3; m/z 191.1075 (C12H15O2 requires
191.1072).
syn-1-(2,2,4-Trimethyl-5-phenylethyl-1,3-dioxolane-4-
yl)-prop-2-en-1-one (9). 9 was obtained from freshly prepared
1-propenylmagnesium bromide (2.5 equiv) and syn-8 in THF.
Purification by silica gel chromatography (1:5, EtOAc:hexane)
gave syn-9 as a pale yellow oil in 91% yield. vmax (film/cm-1
)
1643; δH (400 MHz, CDCl3) 1.24 (3H, s), 1.38 (3H, s), 1.52 (3H,
s), 1.86 (2H, m), 1.91 (3H, dd, J ) 6.8 and 1.7 Hz), 2.68 (1H,
ddd, J ) 13.6, 9.9, and 6.8 Hz), 2.86 (1H, ddd, J ) 13.6, 9.9,
and 6.0 Hz), 4.07 (1H, dd, J ) 8.5 and 4.4 Hz), 6.80 (1H, dq,
J ) 15.3 and 1.7 Hz), 7.02 (1H, dq, J ) 15.3 and 6.8 Hz), 7.17-
7.31 (5H, m); δC (100 MHz, CDCl3) 18.5, 19.3, 26.0, 28.5, 31.7,
33.0, 78.4, 86.6, 108.5, 125.2, 125.9, 128.3, 128.4, 141.9, 145.2,
200.9; m/z 289.1789 (C18H25O3 requires 289.1804).
(E)-2-Hydroxy-2-methyl-7-phenylhept-4-en-3-one (3c).19
As adopted from literature, the aldol reaction employed
3-hydroxy-3-methyl-2-butanone (1 mL, 10 mmol), 3-phenyl-
n
propionaldehyde (0.87 mL, 6.6 mmol), BuLi (2.3 M solution
in hexanes, 10.63 mL, 25 mmol), and diisopropylamine (3.5
mL, 25 mmol) in THF (40 mL) to give the intermediate 2,5-
dihydroxy-2-methyl-7-phenylheptan-3-one (0.72 g, 3 mmol) in
46% yield. The dehydration employed CeCl3‚7H2O (1.37 g, 3.7
mmol), NaI (0.55 g, 3.7 mmol), and 2,5-dihydroxy-2-methyl-
7-phenylheptan-3-one (0.58 g, 2.45 mmol) in anhydrous MeCN
(35 mL). Purification by silica gel chromatography (1:4 EtOAc:
hexane) gave 3c (0.41 g) in 77% yield, as a pale orange oil;
vmax (film/cm-1) 3446, 2973, 1617, 1630; δH (400 MHz, CDCl3)
1.35 (6H, s), 2.60 (2H, q, J ) 7.0 Hz), 2.82 (2H, t, J ) 7.3 Hz),
3.95 (1H, bs), 6.38 (1H, dt, J ) 15.4 and 1.5 Hz), 7.18 (1H, dt,
J ) 15.0 and 7.0 Hz), 7.18-7.32 (5H, m); δC (100 MHz, CDCl3)
26.2, 34.2, 34.4, 75.1, 122.9, 126.2, 128.3, 128.5, 140.5, 149.4,
202.3; m/z 219.1371 (C14H19O2 requires 219.1385).
2-(1-Hydroxy-3-phenylpropyl)-2,5-dimethylfuran-3(2H)-
one (11). 11 was obtained from 5.7 mg of PdCl2 (0.032 mmol),
3.2 mg of CuCl (0.032 mmol), 4.5 mg of Na2HPO4 (0.032 mmol),
and 0.072 g of syn-5,6-dihydroxy-5-methyl-8-phenyloct-2-en-
4-one 10 (0.32 mmol) in anhydrous DME (2 mL). The reaction
mixture was stirred at 50 °C overnight. Purification by silica
gel chromatography (1:1; EtOAc:hexane) gave 11 as white solid
in 70% yield. Recrystallization from ethyl acetate. vmax (film/
cm-1) 3455, 1683, 1593; δH (400 MHz, CDCl3) 1.42 (3H, s), 1.65
(1H, dddd, J ) 14.0, 10.8, 9.6, and 4.8 Hz), 1.92 (1H, dddd, J
) 13.9, 9.6, 7.1, and 2.2 Hz), 2.25 (3H, s), 2.40 (1H, bs), 2.64
(1H, ddd, J ) 13.6, 9.3, and 7.1 Hz), 2.94 (1H, ddd, J ) 13.9,
9.8, and 4.8 Hz), 3.76 (1H, d, J ) 10.8 Hz), 5.41 (1H, s), 7.18-
7.31 (5H, m); δC (100 MHz, CDCl3) 17.0, 18.8, 32.0, 32.4, 73.6,
91.5, 104.0, 126.0, 128.4, 128.5, 141.6, 190.0, 207.0; m/z
246.1259 (C15H20O3 requires 246.1256).
2,2-Dimethyl-5-phenylfuran-3(2H)-one (Bullatenone)
(4a).7 4a was obtained from 300 mg of 3a (1.57 mmol), 27.96
mg (0.16 mmol) of PdCl2, 15.60 mg (0.16 mmol) of CuCl, and
22.37 mg (0.16 mmol) of Na2HPO4 in DME (3 mL). The
reaction mixture was left to stir at 48 °C for 4 days, followed
by 2 days at 80 °C. Purification by silica gel chromatography
(1:6, EtOAc:hexane) gave 4a as a crystalline white solid in 93%
yield; vmax (film/cm-1) 1681, 1607; δH (400 MHz, CDCl3) 1.48
(6H, s), 5.96 (1H, s), 7.44-7.56 (3H, m), 7.80-7.84 (2H, m); δC
(100 MHz, CDCl3) 23.1, 88.9, 98.5, 127.1, 128.8, 129.1, 132.6,
183.5, 207.0; m/z 189.0914 (C12H13O2 requires 189.0916).
(E)-Ethyl-2-methyl-5-phenylpent-2-enoate (5).26 Lithium
tert-butoxide (18.6 mL, 1 M in hexanes) was added to a solution
of triethyl-2-phosphonopropionate (4 mL, 18.6 mmol) and the
resulting torpid solution was stirred at room temperature for
15 min, upon which 3-phenylpropionaldehyde (1.63 mL, 12.3
mmol) was added over a 10 min interval. The resulting clear
reaction solution was stirred for a further hour, then washed
with water (4 × 100 mL). The combined organic layers were
Acknowledgment. This study was supported in
part by the EPSRC (GR/S68095/01), the Royal Society
(Research Grant RSRG 23219B), the European Com-
munity (COST Action D25), the Leverhulme Trust (F/
08 341/B), and the British Council (Chevening Schol-
arship, M.R.). We also thank Dr. A. R. Cowley (University
of Oxford) for providing us with the X-ray data.
Supporting Information Available: Experimental de-
tails of compounds 1b-d, 1f-g, 2c-g, 3b, 3d-f, 4b-f, 6, 7,
10, 12-14; 1H NMR and 13C NMR of selected compounds;
X-ray crytallographic data for 11. This material is available
(26) Browder, C. C.; Marmsaeter, F. P.; West, F. G. Org. Lett. 2001,
3, 3033-3035.
JO051274D
J. Org. Chem, Vol. 70, No. 21, 2005 8485