Use of Conjugated Dienones in Cyclialkylations
J . Org. Chem., Vol. 62, No. 20, 1997 6949
5.15 (m, 2 H), 5.90-6.05 (m, 1 H), 6.68 (br s, 1 H), 6.77 (d, 1
H, J ) 7.9 Hz), 7.13 (d, 1 H, J ) 7.8 Hz); 13C NMR (75.5 MHz)
156.7 (s), 138.5 (s), 137.5 (d), 134.7 (s), 125.9 (d), 120.5 (d),
115.7 (t), 110.7 (d), 55.3 (q), 40.2 (t), 26.4 (d), 22.7 (q) ppm; IR
mmol) and methyl acrylate (1.0 mL, 11.0 mmol) using protocol
I to afford 1.78 g of crude 4-[4′-isopropyl-3′-methoxyphenyl]-
2,4-dimethylcyclohexane-1,3-dione which was converted, using
procedure J , to 820 mg (30% from 77) of enone 78 as a light
yellow oil which was homogeneous by TLC analysis [H:E, 3:1,
Rf(78) ) 0.19]: 1H NMR (250 MHz) δ 1.17 (d, 6 H, J ) 6.9
Hz), 1.39 (s, 3 H), 1.75 (s, 3 H), 1.95-2.10 (m, 1 H), 2.25-2.55
(m, 3 H), 3.24 (septet, 1 H, J ) 6.9 Hz), 3.70 (s, 3 H), 3.76 (s,
3 H), 6.63 (d, 1 H, J ) 1.8 Hz), 6.75 (dd, 1 H, J ) 1.8 Hz, 7.9
Hz), 7.09 (d, 1 H, J ) 7.9 Hz); 13C NMR (62.7 MHz) 201.3 (s),
170.2 (s), 156.6 (s), 141.1 (s), 135.0 (s), 125.6 (d), 117.8 (d),
114.0 (s), 108.6 (d), 55.2 (q), 54.8 (q), 47.8 (s), 33.8 (t), 27.2 (q),
26.4 (d), 22.6 (q), 22.6 (t), 7.9 (q) ppm; IR (film) 1650, 1625
cm-1; MS, m/z 302 (M+).
(film) 3076, 1637, 1608, 1578, 1502, 1464, 1418, 914, 817 cm-1
;
MS, m/z 158 (M+ - MeOH). Anal. Calcd for C13H18O: C, 82.05;
H, 9.54. Found: C, 82.16; H, 9.47.
5-[2′,3′-E p oxyp r op yl]-2-isop r op yl-1-m et h oxyb en zen e
(74). Arene 73 (8.44 g, 4.44 mmol) was dissolved in CH2Cl2
(150 mL) followed by the addition of 18.63 g (0.22 mol) of
NaHCO3. The mixture was cooled to -5 °C, and 18.00 g of
MCPBA (85%, 8.87 mmol) was added in small portions. The
reaction mixture was stirred and allowed to warm to rt over a
4-h period. The solids were then filtered, and the filtrate was
washed with saturated aqueous NaHCO3 (15 mL). Standard
ethereal workup, followed by chromagotraphy (elution with
H:E, 4:1), gave 5.95 g of epoxide 74 (65%) which was homo-
geneous by TLC analysis [H:E, 4:1, Rf(74) ) 0.30]: 1H NMR
(250 MHz) δ 1.20 (d, 6 H, J ) 6.9 Hz), 2.58 (dd, 1 H, J ) 2.7
Hz, 4.7 Hz), 2.80-2.88 (m, 3 H), 3.16-3.20 (m, 1 H), 3.29
(septet, 1 H, J ) 6.9 Hz), 3.83 (s, 3 H), 6.74 (br s, 1 H), 6.81 (d,
1 H, J ) 7.8 Hz), 7.15 (d, 1 H, J ) 7.6 Hz); 13C NMR (62.5
MHz) 156.7 (s), 135.6 (s), 135.2 (s), 125.9 (d), 120.8 (d), 111.0
(d), 55.2 (q), 52.5 (d), 46.9 (t), 38.7 (t), 26.4 (d), 22.6 (q) ppm;
IR (film) 1613, 1576, 1505, 1463, 1040 cm-1; MS, m/z 206 (M+).
5-[2′-Hydr oxybu tyl]-2-isopr opyl-1-m eth oxyben zen e (75).
To a cold (-30 °C) solution of cuprous iodide (1.08 g, 5.70
mmol) suspended in ether (40 mL) was added 19.0 mL of
methylmagnesium bromide (5.70 mmmol, 1 M solution in
ether) followed by the addition of 5.87 g of epoxide 74 (2.85
mmol). The reaction mixture was stirred at -30 °C for 4 h,
warmed to -10 °C, and carefully quenched with saturated
NH4Cl. Standard ethereal workup, followed by chromatogra-
phy (elution with H:E, 2:1), gave 5.88 g of alcohol 75 (93%)
which was homogeneous by TLC analysis [H:E, 2:1, Rf(75) )
0.27]: 1H NMR (250 MHz) δ 1.02 (t, 3 H, J ) 7.3 Hz), 1.22 (d,
6 H, J ) 7.0 Hz), 1.50-1.65 (m, 2 H), 2.60 (dd, 1 H, J ) 13.8
Hz, 8.5 Hz), 2.83 (dd, 1 H, J ) 13.8 Hz, 5.5 Hz), 3.27 (septet,
1 H, J ) 7.0 Hz), 3.70-3.80 (m, 1 H), 3.84 (s, 3 H), 6.72 (d, 1
H, J ) 1.0 Hz), 6.80 (dd, 1 H, J ) 7.7 Hz, 1.0 Hz), 7.16 (d, 1 H,
J ) 7.7 Hz); 13C NMR (62.5 MHz) 156.8 (s), 136.9 (s), 135.0
(s), 126.1 (d), 121.3 (d), 111.4 (d), 74.0 (d), 55.3 (q), 43.5 (t),
29.6 (t), 26.4 (d), 22.7 (q), 10.1 (q) ppm; IR (film) 3389, 1608,
1576, 1505, 1096, 1040 cm-1; MS, m/z 222 (M+).
2-[4′-Isop r op yl-3′-m eth oxyp h en yl]bu ta n -3-on e (76). Al-
cohol 75 (620 mg, 2.81 mmol) was oxidized using procedure
F. Chromatography (elution with H:E, 4:1) of the residue gave
560 mg of butanone 76 (90%) which was homogeneous by TLC
analysis [H:E, 3:1, Rf(76) ) 0.38]: 1H NMR (250 MHz) δ 1.03
(t, 3 H, J ) 7.3 Hz), 1.20 (d, 6 H, J ) 7.1 Hz), 2.49 (q, 2 H, J
) 7.3 Hz), 3.29 (septet, 1 H, J ) 7.1 Hz), 3.65 (s, 2 H), 3.82 (s,
3 H), 6.68 (d, 1 H, J ) 1.2 Hz), 6.77 (dd, 1 H, J ) 7.7 Hz, 1.2
Hz), 7.15 (d, 1 H, J ) 7.7 Hz); 13C NMR (62.5 MHz) 209.3 (s),
156.8 (s), 135.6 (s), 132.7 (s), 126.1 (d), 121.4 (d), 111.2 (d),
55.3 (q), 49.8 (t), 35.0 (t), 26.4 (d), 22.6 (q), 7.7 (q) ppm; IR
(film) 1689, 1604, 1580, 1500, 1256 cm-1; MS, m/z 220 (M+).
Anal. Calcd for C14H20O2: C, 76.32; H, 9.15. Found: C, 76.21;
H, 9.30.
2-[4′-Isop r op yl-3′-m et h oxyp h en yl]p en t a n -3-on e (77).
Butanone 76 (500 mg, 2.36 mmol) was treated with NaH (60%
suspension in mineral oil, 104 mg, 2.60 mmol) and iodo-
methane (0.44 mL, 7.08 mmol) using procedure G. Standard
ethereal workup, followed by chromatography (elution with
H:E, 5:1), gave 400 mg of pentanone 77 (75%) which was
homogeneous by TLC analysis [H:E, 4:1, Rf(77) ) 0.49]: 1H
NMR (250 MHz) δ 0.97 (t, 3 H, J ) 7.3 Hz), 1.19 (d, 6 H, J )
6.9 Hz), 1.38 (d, 3 H, J ) 7.2 Hz), 2.31-2.47 (m, 2 H), 3.26
(septet, 1 H, J ) 6.9 Hz), 3.72 (q, 1 H, J ) 7.1 Hz), 3.81 (s, 3
H), 6.64 (d, 1 H, J ) 1.5 Hz), 6.77 (dd, 1 H, J ) 7.8 Hz, 1.5
Hz), 7.13 (d, 1 H, J ) 7.8 Hz); 13C NMR (62.5 MHz) 211.7 (s),
157.0 (s), 139.1 (s), 135.6 (s), 126.2 (d), 119.9 (d), 109.3 (d),
55.2 (q), 52.5 (d), 34.0 (t), 26.4 (d), 22.5 (q), 17.4 (q), 7.9 (q)
ppm; IR (film) 2966, 2872, 1717, 1609, 1576 cm-1; MS, m/z
234 (M+).
4-[4′-Isop r op yl-3′-m et h oxyp h en yl]-2,4-d im et h yl-3-vi-
n ylcycloh ex-2-en on e (79). Enone 78 (800 mg, 2.65 mmol)
was treated with excess vinyllithium (13.20 mmol) using
procedure K to provide 710 mg of dienone 79 (90%) as a bright
yellow solid which was homogeneous by TLC analysis [H:E,
4:1, Rf
(79) ) 0.31]: mp 43-44 °C; 1H NMR (250 MHz) δ 1.19
(d, 6 H, J ) 6.8 Hz), 1.60 (s, 3 H), 2.00 (s, 3 H), 2.04-2.15 (m,
2 H), 2.30-2.42 (m, 2 H), 3.26 (septet, 1 H, J ) 6.8 Hz), 3.78
(s, 3 H), 5.15 (dd, 1 H, J ) 1.5 Hz, 18.0 Hz), 5.40 (dd,1 H, J )
1.5 Hz, 11.7 Hz), 6.23 (dd, 1 H, J ) 18.0 Hz, 11.7 Hz), 6.72 (d,
1 H, J ) 1.6 Hz), 6.81 (dd, 1 H, J ) 7.9 Hz, 1.6 Hz), 7.12 (d, 1
H, J ) 7.9 Hz); 13C NMR (62.5 MHz) 199.6 (s), 157.7 (s), 156.7
(s), 143.9 (s), 135.1 (s), 134.2 (d), 132.6 (s), 125.7 (d), 122.3 (t),
118.9 (d), 108.9 (d), 55.3 (q), 43.5 (s), 39.8 (t), 34.3 (t), 26.9 (q),
26.4 (d), 22.6 (q), 12.9 (q) ppm; IR (film) 1690, 1606, 1571 cm-1
;
MS, m/z 298 (M+). Anal. Calcd for C20H26O2: C, 80.50; H, 8.78.
Found: C, 80.65; H, 8.70.
Cycliza tion of 79 To Give 80. A solution of 100 mg of 79
(0.34 mmol) and 410 µL of BF3‚Et2O (3.35 mmol) in 8 mL of
CH2Cl2 was refluxed for 8 h. The reaction mixture was diluted
with 10 mL of ether and quenched with 10 mL of saturated
aqueous NaHCO3. Standard ethereal workup, followed by
chromatography (elution with H:E, 3:1), gave 87 mg of known
enone 80 (87% yield) as a white solid which was homogeneous
by TLC analysis [H:E, 3:1, Rf(80) ) 0.23]: mp 91-92 °C (lit.30
mp 91-92 °C); 1H NMR (250 MHz) δ 1.18 (d, 3 H, J ) 7.0
Hz), 1.21 (d, 3 H, J ) 7.0 Hz), 1.53 (s, 3 H), 1.84 (s, 3 H), 2.00-
2.20 (m, 1 H), 2.30-2.45 (m, 1 H), 2.47-2.53 (m, 1 H), 2.55-
2.60 (m, 1 H), 2.65-3.00 (m, 4 H), 3.26 (septet, 1 H, J ) 7.0
Hz), 3.82 (s, 3 H), 6.73 (s, 1 H), 6.92 (s, 1 H); 13C NMR (62.5
MHz) 198.1 (s), 162.6 (s), 155.7 (s), 142.5 (s), 134.9 (s), 128.4
(s), 127.2 (s), 125.8 (d), 107.4 (d), 55.4 (q), 39.6 (s), 36.1 (t),
34.1 (t), 29.3 (t), 27.5 (t), 26.8 (q), 26.3 (d), 22.6 (q), 10.8 (q)
ppm; IR (film) 1686, 1614 cm-1; MS, m/z 298 (M+).
2-[2′,3′-Dim e t h oxy-4′-isop r op ylp h e n yl]cycloh e x-2-
en on e (81). To a solution of isopropylveratrole (5.0 g, 27.78
mmol) dissolved in 45 mL of dry ether at 0 °C was added 12.8
mL (32.00 mmol) of n-butyllithium (2.5 M solution in hexanes),
and the mixture was stirred for 3 h at rt. The resulting
solution of the organolithium reagent was used directly
without purification or characterization.
The above solution of organolithium reagent was reacted
with epoxide 1 (2.50 g, 13.89 mmol) using procedure A to give
3.52 g of recovered isopropylveratrole and 1.95 g of enone 81
(51%) which was homogeneous by TLC analysis [H:E, 1:1,
Rf(81) ) 0.31]: 1H NMR (250 MHz) δ 1.22 (d, 6 H, J ) 6.7
Hz), 2.14 (pentet, 2 H, J ) 6.6 Hz), 2.49-2.64 (m, 4 H), 3.32
(septet, 1 H, J ) 6.6 Hz), 3.77 (s, 3 H), 3.84 (s, 3 H), 6.86 (ABq,
2 H, ∆νAB ) 42.5 Hz, J AB ) 8.0 Hz), 6.91 (t, 1 H, J ) 4.0 Hz);
13C NMR (62.7 MHz) 197.9 (s), 150.3 (s), 149.9 (s), 146.1 (d),
142.8 (s), 136.6 (s), 129.2 (s), 125.1 (d), 120.9 (d), 60.4 (q), 60.1
(q), 36.6 (t), 26.7 (d), 26.3 (t), 23.5 (q), 23.1 (t) ppm; IR (film)
1679, 1453, 1405, 1268 cm-1; MS, m/z 274 (M+). Anal. Calcd
for C17H22O3: C, 74.42; H, 8.09. Found: C, 74.31; H, 8.13.
2-[2′,3′-Dim eth oxy-4′-isop r op ylp h en yl]-6,6-d im eth ylcy-
cloh ex-2-en on e (82). The procedure used for the preparation
of 2-[2′,3′-dimethoxy-4′-isopropylphenyl]-6-methylcyclohex-2-
enone were presented earlier as procedure L.
This enone (1.20 g, 4.17 mmol) was further alkylated with
iodomethane using procedure K to provide 1.21 g of enone 82
(95%) which was homogeneous by TLC analysis [H:E, 2:1,
Rf(82) ) 0.75]: 1H NMR (250 MHz) δ 1.21 (d, 6 H, J ) 6.8
Hz), 1.22 (s, 6 H), 1.94 (t, 2 H, J ) 6.2 Hz), 2.47-2.54 (m, 2
2,4-Dim eth yl-6-[4′-isopr opyl-3′-m eth oxyph en yl]-3-m eth -
oxycycloh ex-2-en on e (78). The above pentanone derivative
(2.30 g, 9.81 mmol) was treated with KO-t-Bu (1.21 g, 11.0