Leber et al.
CdN), 700 (s); MS (m/z) 166 (M, 21%), 151 (28%), 138 (37%),
123 (100%), 106 (40%), 91 (40%), 79 (94%), 77 (68%), 70 (72%),
60 (67%).
1.43 (s, 1H), 1.27 (m, 1H), 1.13 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 135.4 (HCd), 131.9 (HCd), 69.4 (HCO), 37.7 (HC),
35.7 (H2C), 30.0 (HC), 25.9 (H2C), 17.2 (H2C). endo-Bicyclo[2.2.2]-
oct-5-en-2-ol (6b): 1H NMR (500 MHz, CDCl3) δ 6.45 (t, 1H),
6.12 (t, 1H), 3.93 (br m, 1H), 2.73 (br m, 1H), 2.58 (br m, 1H),
1.98 (ddd, 1H), 1.64 (s, 1H), 1.34 (m, 3H), 1.12 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 136.9 (HCd), 129.7 (HCd), 70.5 (HCO),
39.2 (H2C), 37.8 (HC), 30.1 (HC), 24.0 (H2C), 21.8 (H2C).
5-Methoxybicyclo[2.2.2]oct-2-ene (2). To a suspension of 132
mg (5.5 mmol) of sodium hydride (220 mg of a 60% dispersion in
mineral oil, which was removed by rinsing with pentane) in 10
mL of anhydrous THF was added dropwise a solution of 0.30 g
(2.4 mmol) of 6 in 20 mL of THF. After 2 h, 1.5 mL (3.4 g, 24
mmol) of methyl iodide was added to the reaction mixture, which
was then stirred overnight. The reaction mixture was quenched with
enough methanol to dissolve the solid and then diluted with 100
mL of ether. The organic material was washed four times with
water, dried over MgSO4, filtered, and concentrated under reduced
pressure to afford crude 2 (0.13 g, 38%), a 29:71 mixture of 2a:
2b, respectively, as determined by GC analysis. IR (cm-1) 3040
(w), 1620 (w), 1100 (s), 710 (s); MS (m/z) 138 (M, 100%), 123
(82%), 91 (79%), 79 (40%). Epimeric separation was achieved via
preparative GC. 5-exo-Methoxybicyclo[2.2.2]oct-2-ene (2a): 1H
NMR (500 MHz, CDCl3) δ 6.27 (t, 1H), 6.13 (t, 1H), 3.28 (s, 3H),
3.29-3.27 (m, 1H), 2.74 (br m, 1H), 2.46 (br m, 1H), 1.89 (ddd,
1H), 1.71 (ddt, 1H), 1.58 (m, 1H), 1.23 (m, 1H), 1.15 (dt, 1H),
1.04 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 136.2 (HCd), 131.6
(HCd), 78.5 (HCO), 56.1 (H3CO), 33.5 (H2C), 33.2 (HC), 29.8
(HC), 25.8 (H2C), 17.5 (H2C). 5-endo-Methoxybicyclo[2.2.2]oct-
2-ene (2b): 1H NMR (500 MHz, CDCl3) δ 6.36 (t, 1H), 6.09 (t,
1H), 3.49 (m, 1H), 3.26 (s, 3H), 2.84 (br s, 1H), 2.54 (br s, 1H),
1.84 (ddd, 1H), 1.34 (m, 2H), 1.28 (m, 1H), 1.16 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 135.2 (HCd), 130.0 (HCd), 80.1
(HCO), 55.5 (H3CO), 35.7 (H2C), 33.4 (HC), 29.8 (HC), 24.3 (H2C),
22.0 (H2C).
8-Methoxybicyclo[4.2.0]oct-2-ene (1). To a solution of 3.37 g
(30.0 mmol) of potassium tert-butoxide in 25 mL of anhydrous
DMSO was added 3.23 g (19.4 mmol) of 4 via syringe over 5-6
h. The reaction mixture was stirred overnight and then quenched
with water and extracted with pentane. The organic extract was
washed seven times with water, dried over MgSO4, filtered, and
concentrated by simple distillation. The crude product (1.22 g, 46%)
consisted of a 26:74 (as determined by GC) mixture of 1a:1b,
respectively. IR (cm-1) 3015 (w), 1120 (s), 730 (s); MS (m/z) 138
(M, 100%), 109 (31%), 96 (83%), 95 (43%), 82 (56%), 81 (81%),
67 (74%). Separation of the epimers was achieved via preparative
GC. 8-exo-Methoxybicyclo[4.2.0]oct-2-ene (1a): 1H NMR (500
MHz, CDCl3) δ 5.80 (dd, 2H), 3.61 (dd, 1H), 3.24 (s, 3H), 2.59
(br s, 1H), 2.36 (m, 1H), 1.95 (m, 4H), 1.75 (m, 1H), 1.39 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 128.9 (HCd), 128.0 (HCd),
81.7 (HCO), 55.8 (H3CO), 41.2 (HC), 31.4 (H2C), 26.7 (H2C), 25.6
(HC), 22.6 (H2C). 8-endo-Methoxybicyclo[4.2.0]oct-2-ene (1b): 1H
NMR (500 MHz, CDCl3) δ 5.98 (br m, 1H), 5.72 (br d, 1H), 3.95
(dd, 1H), 3.24 (s, 3H), 2.94 (br s, 1H), 2.19 (br m, 1H), 2.14 (m,
1H), 2.07 (m, 2H), 1.73 (dd, 1H), 1.54 (m, 1H), 1.39 (m, 1H); 13
C
NMR (125 MHz, CDCl3) δ 129.3 (HCd), 124.5 (HCd), 76.8
(HCO), 56.1 (H3CO), 38.5 (HC), 30.0 (H2C), 24.1 (HC), 21.1 (H2C),
21.0 (H2C).
Bicyclo[2.2.2]oct-5-en-2-one (5). To a solution of 27 mg of
hydroquinone in 20 mL (0.18 mol) of 1,3-cyclohexadiene was added
10 mL (11 g, 0.12 mol) of 2-chloroacrylonitrile (pretreated with
potassium hydroxide pellets from which it was decanted before
addition). The reaction mixture was heated at reflux overnight in
the dark at 90 °C, an additional 10 mL of 1,3-cyclohexadiene was
added, and the reaction mixture was again heated at reflux
overnight. The brown reaction mixture was diluted with 15 mL of
CH2Cl2, and the resultant solution was filtered through a short silica
gel column and concentrated under reduced pressure to yield 6.9 g
of a dark brown liquid. IR (cm-1) 3040 (w), 2240 (w), 1650 (w),
710 (s).
7-Methoxybicyclo[3.2.0]hept-2-enes (7). To a solution of 6.0
mL (0.19 mol) of anhydrous hydrazine in 15 mL of absolute ethanol
was added 3.4 g (0.025 mol) of 7-methoxybicyclo[3.2.0]hept-2-
en-6-one14 dissolved in 6 mL of absolute ethanol. After the reaction
mixture was heated overnight at 60 °C, the reaction mixture was
poured into 40 mL of water and worked up in a fashion analogous
to that employed for preparing 4 to afford the crude hydrazone
(2.60 g, 70%). IR (cm-1) 3340 (m), 3280 (w), 3025 (w), 1615 (m),
1090 (s), 720 (s). The low-temperature Wolff-Kishner reduction
to prepare 7 was then accomplished using conditions similar to
those employed for the synthesis of compound 1. Conversion of
2.53 g of 7-methoxybicyclo[3.2.0]hept-2-en-6-one hydrazone to 7
was accomplished in 28% yield. Anal. Calcd for C8H12O: C, 77.37;
H, 9.74. Found: C, 76.70; H, 9.78. MS (m/z) 124 (2%), 66 (100%).
Separation of epimers 7a and 7b from a mixture that was 9:91
7a:7b by GC analysis was achieved using preparative GC. 7-exo-
Methoxybicyclo[3.2.0]hept-2-ene (7a): 1H NMR (300 MHz, CDCl3)
δ 5.76 (m, 1H), 5.70 (m, 1H), 3.56 (ddd, 1H), 3.25 (s, 3H), 3.18
(m, 1H), 2.91 (m, 1H), 2.57 (qq, 1H), 2.16 (m, 2H), 1.88 (pent,
1H); 13C NMR (75 MHz, CDCl3) δ 132.1 (HCd), 130.5 (HCd),
82.4 (HCO), 55.4 (H3CO), 53.0 (HC), 40.3 (H2C), 34.4 (H2C), 31.6
To a solution of the viscous residue in 95 mL of DMSO was
slowly added an aqueous solution of 11.6 g of KOH in 20 mL of
water over 4 h with continuous stirring. Stirring was continued for
an additional 20 h; 200 mL of water was added, and the aqueous
solution was extracted five times with pentane. The organic extract
was washed with brine, dried over MgSO4, filtered, and concen-
trated under reduced pressure to afford 2.6 g (0.021 mol, 18%
overall) of 5 as a white crystalline solid (mp 85-88 °C). IR (cm-1
)
3040 (w), 1725 (s), 1610 (w), 700 (s); MS (m/z) 122 (23%), 80
(100%), 79 (88%), 39 (17%); 1H NMR (500 MHz, CDCl3) δ 6.45
(t, 1H), 6.17 (t, 1H), 3.10 (br t, 1H), 2.96 (m, 1H), 2.00 (m, 1H),
2.00 (m, 1H), 1.83 (m, 1H), 1.67 (m, 2H), 1.52 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 213.2 (CdO), 137.0 (HCd), 128.4 (HCd),
48.5 (HC), 40.5 (H2C), 32.3 (HC), 24.2 (H2C), 22.5 (H2C).
Bicyclo[2.2.2]oct-5-en-2-ol (6). To a solution of 0.38 g (3.1
mmol) of 5 in 25 mL of anhydrous THF at 0 °C was added 6.0 mL
of 1.0 M LiAlH4 in THF slowly via syringe. After the addition
was complete, the reaction was allowed to warm to rt and stirred
for 4 h. It was then cooled to 0 °C and quenched with cold ethanol.
The reaction mixture was treated sequentially with satd NH4Cl,
ether, 1 N HCl, and water. After separation of the ether layer, the
aqueous layer was extracted four more times with ether. The
combined organic extracts were then washed with satd NaHCO3,
1 N HCl, water, and brine, dried over MgSO4, filtered, and
concentrated at reduced pressure to yield 6 (0.32 g, 84%) as a white
solid (mp 159-163 °C). IR (cm-1) 3310 (m), 3040 (w), 1725 (s),
1615 (w), 710 (s). Flash chromatography from Florisil using 95:5
pentane:ether separated the epimers; the exo alcohol was the first
eluting component.36 exo-Bicyclo[2.2.2]oct-5-en-2-ol (6a): 1H
NMR (500 MHz, CDCl3) δ 6.26 (t, 1H), 6.18 (t, 1H), 3.83 (br d,
1H), 2.51 (br m, 2H), 2.04 (m, 1H), 1.83 (m, 1H), 1.64 (m, 1H),
1
(HC). 7-endo-Methoxybicyclo[3.2.0]hept-2-ene (7b): H NMR (300
MHz, CDCl3) δ 5.88 (m, 1H), 5. 75 (m, 1H), 3.98 (dd, 1H), 3.54
(m, 1H), 3.22 (s, 3H), 2.45 (m, 3H), 2.14 (dq, 1H), 1.60 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 133.1 (HCd), 129.2 (HCd), 75.8
(HCO), 55.6 (H3CO), 52.6 (HC), 40.4 (H2C), 35.2 (H2C), 27.7 (HC).
5-Methoxybicyclo[2.2.1]hept-2-enes (8). A sample of 1.7 g
(0.073 mol) of sodium hydride (2.9 g of a 60% dispersion in mineral
oil, which was removed by rinsing with pentane) was suspended
in 20 mL of anhydrous THF under nitrogen. A solution of 6.0 g
(0.055 mol) of 5-norbornen-2-ol in 10 mL of THF was then added
(36) Brown, R. S.; Marcinko, R. W. J. Am. Chem. Soc. 1977, 99, 6500-
6505.
918 J. Org. Chem., Vol. 72, No. 3, 2007