was added, and the resulting mixture was stirred at room
temperature overnight. The aqueous layer was extracted with
CH2Cl2, washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The crude oil was filtered
through a plug of silica gel (Et2O), and dibutylphthalate (internal
standard) and acetone (2 mL) were added. The 8/9 ratio was
determined to be 8 : 92 by GC as specified in ‘Materials and
methods’. The crude oil was purified by flash chromatography
on silica gel (pentane–diethyl ether = 75 : 25 to 40 : 60) to give
a mixture of 8 and 9 (41.6 mg, 40% from 1) as a colorless oil.
bromobenzene (0.95 mL, 7.89 mmol) and stirring was continued
for 2 h.32 In a separate flask, CuI (9.4 mg, 0.005 mmol) was added
to 1,3-cyclohexadien-2-yl triflate (1.13 g, 4.95 mmol) in THF
◦
(10 mL) at 0 C. The Grignard reagent was then added slowly
via cannula and the yellow suspension was stirred for 20 min
before being hydrolyzed with saturated aqueous NH4Cl. The
aqueous phase was extracted with Et2O, the combined organic
phases dried over MgSO4, filtered and concentrated. The crude
oil was quickly filtered through neutral alumina (Et2O) to give
the title compound (1.3 g, quant.) as a colorless oil. This diene is
known to undergo rapid decomposition upon standing at room
temperature, and was therefore used rapidly without further
purification or characterization.23
Procedure B: Aqueous toluene (Table 1, entries 2 and 3).
A
dry Schlenk flask, equipped with a septum and a magnetic
stirring bar, was charged with 35.8 mg (20 mol.%) of zinc
triflate. The solids were dried under high vacuum at 125 ◦C
overnight, with magnetic stirring. The Schlenk flask was cooled
under vacuum and flushed with dried argon. A solution of
a-acetoxynitroso dienophile 1 (100 mg, 0.49 mmol) in dry
toluene (1.2 mL) was added dropwise and the suspension
was cooled to 0 ◦C. The required volume of deionised water
was then added via a microsyringe (2–10 equivalents). After
1 min, 1,3-cyclohexadiene (0.24 mL, 2.46 mmol) was added
dropwise. Reaction time, work-up, 8/9 ratio determination and
purification were performed as in Procedure A.
Tert-butyl (1R*,4S*)-5-benzo-1,3-dioxol-5-yl-2-oxa-3-azabi-
cyclo[2.2.2]oct-5-ene-3-carboxylate (17-pr) and tert-butyl (1R*,
4S*)-6-Benzo-1,3-dioxol-5-yl-2-oxa-3-azabicyclo[2.2.2]oct-5-ene-
3-carboxylate (17-ds). To
a dispersion of dienophile 1
(100 mg, 0.49 mmol) in water (1.25 mL) was added a solution
of 5-(cyclohexa-1,5-dienyl)benzo[1,3]dioxolane 16 (197 mg,
0.98 mmol) in THF (1.25 mL). The reaction mixture was stirred
at room temperature for 30 min, hydrolyzed with aqueous
HCl (1 N, 2 mL) and the biphasic solution stirred for 45 min.
Aqueous NaOH (20 mol%) was added dropwise at 0 ◦C so that
the mixture was pH ∼10. A solution of Boc2O (220 mg, 1 mmol)
in THF (5 mL) was added and the resulting mixture was stirred
at room temperature overnight. The aqueous layer was extracted
with CH2Cl2, washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The regioisomeric ratio
Procedure C: Water (Table 1, entries 4 and 5). In a 10 mL
flask was charged with 1 (100 mg, 0.49 mmol). Water (1.2 mL)
was added with rapid stirring to ensure efficient dispersion
of the reactants. 1,3-Cyclohexadiene (0.24 mL, 2.46 mmol)
was then added dropwise. Reaction time, work-up, 8/9 ra-
tio determination and purification were performed as in
Procedure A.
1
(17-pr/17-ds = 50 : 50) was determined by H NMR (C6D6).
The crude oil was purified by flash chromatography on silica
gel (heptane–EtOAc = 80 : 20 to 70 :30) to give a mixture of
17-pr and 17-ds (80.2 mg, 49%) as a waxy solid. An analytical
sample was prepared by preparative TLC (heptane–EtOAc =
60 : 40). 17-pr: White crystals, mp 98 ◦C; mmax/cm−1 3069, 2976,
2935, 1738, 1694, 1505, 1488, 1248, 1160, 1080, 1038, 939, 810;
1H NMR (400 MHz, CDCl3) d 7.03–7.00 (2H, 2 × H-Ar), 6.79
(1H, d, J 8.6 Hz, H-Ar), 6.55 (1H, dd, J 2.4 and 6.1 Hz, C(6)H),
5.95 (2H, 2 × OCH2O), 5.14 (1H, m, C(4)H), 4.84 (1H, m,
C(1)H), 2.25–2.15 (2H, C(7)H + C(8)H), 1.54 (1H, m, C(7)H),
1.41 (1H, m, C(8)H), 1.32 (9H, s, 3 × Me); 13C NMR (100 MHz,
CDCl3) 157.3, 148.0, 147.6, 142.5, 129.7, 121.5, 119.1, 108.1,
105.3, 101.1, 81.6, 71.1, 52.3, 27.9, 20.9, 24.2; m/z HRMS (ESI,
Na+): calcd for [2M + Na+] 685.2737, found 685.2732. 17-ds:
Waxy solid; mmax/cm−1 2977, 2937, 1699, 1505, 1489, 1251, 1234,
1159, 1038, 933, 810; 1H NMR (400 MHz, CDCl3) d 6.90 (2H,
d, J 6.8 Hz, 2 × H-Ar), 6.81 (1H, m, H-Ar), 6.64 (1H, dd, J
1.8 and 5.6 Hz, C(5)H), 5.98 (2H, s, 2 × OCH2O), 5.17 (1H, m,
C(4)H), 4.87 (1H, dt, J 3.0 and 6.4 Hz, C(1)H), 2.38–2.13 (2H,
C(7)H + C(8)H), 1.57–1.43 (11H, C(7)H + C(8)H), including
(1R*,5S*) Tert-butyl 7-oxa-6-aza-bicyclo[3.2.2]non-8-ene-6-
carboxylate (11b)
◦
White crystals, mp 75 C (lit.,11 50–53 ◦C); mmax/cm−1 2977,
1
2933, 1736, 1686, 1366, 1247, 1167, 1084, 860, 826; H NMR
(250 MHz, CDCl3) d 6.34 (1H, ddd, J 1.3, 6.5 and 9.0 Hz,
=
=
CH CH), 6.14 (1H, ddd, J 1.8, 6.3 and 9.0 Hz, CH CH),
4.75 (2H, m, CHO, CHN), 1.93–1.66 (4H, m, 2 × CH2), 1.60–
1.20 (2H, m, CH2), 1.46 (9H, s, 3 × Me); 13C NMR (90 MHz,
CDCl3) 156.1, 129.3, 127.5, 80.9, 74.8, 54.2, 30.5, 28.1, 27.4,
18.3. These spectroscopic data were in agreement with those
previously reported.11
Synthesis of diene 16
1,3-Cyclohexadien-2-yl triflate. To a solution of diisopropy-
lamine (1.89 mL, 14.4 mmol) in THF (20 mL) at 0 ◦C
was added n-BuLi (9.0 mL, 14.4 mmol). After 30 min,
the LDA solution was cooled to −78 ◦C, a solution of 2-
cyclohexenone (1.27 mL, 13.1 mmol) in THF (20 mL) added
via cannula, and stirring continued for 30 min. A solution
of N-phenyltrifluoromethanesulfonimide (5.12 g, 14.3 mmol)
in THF (20 mL) was then added and the reaction mixture
allowed to warm slowly to 0 ◦C. After 2 h, the solution was
concentrated. The residue was diluted with Et2O, washed with
water and the organic phase was dried over sodium sulfate,
filtered and concentrated. The crude oil was purified by flash
chromatography on silica gel (pentane) to give the dienyl triflate
(1.63 g, 55%) as a colorless oil. 1H NMR (250 MHz, CDCl3) d
6.0 (1H, td, J 4.2 and 10.0 Hz, CCHCHCH2), 5.8 (1H, qd, J1H–19F
2 Hz, J1H–1H 10.3 Hz, CH2CHC), 5.7 (1H, dt, J 2.3 and 4.5 Hz,
CH2CHCHC), 2.4–2.3 (2H, 2 × CH2CH2), 2.3–2.2 (2H, 2 ×
CH2CH2); 13C NMR (62.5 MHz, CDCl3) d 146.0, 131.5, 120.7,
118.6 (q, J13C–19F = 318.6 Hz), 114.7, 21.4, 21.3. Spectroscopic
data were in agreement with those previously reported.31
1
1.46 (9H, s, 3 × Me); H NMR (400 MHz, C6D6) d 6.51 (1H,
s), 6.30 (2H), 6.08 (1H, dd, J 2.8 and 9.2 Hz), 5.04 (2H, s), 4.61
(2H, s), 1.74–1.69 (2H), 1.14 (9H, s), 0.85–0.62 (2H); 13C NMR
(100 MHz, CDCl3) 157.5, 148.1, 147.6, 142.8, 129.9, 122.9,
118.7, 108.3, 105.4, 101.1, 81.5, 72.8, 50.4, 28.1, 23.8, 21.4; MS
(ESI, Na+): 354.1 (56, [M + Na+]), 685.3 (100, [2M + Na+]);
m/z HRMS (ESI, Na+): calcd for [M + Na+] 354.1312, found
354.1321.
Tert-butyl (1S*,4R*)-2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-
carboxylate (11) and 4-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-
yl)-2,2-dimethyl-1,3-dioxan-5-one (26). To a suspension of
dienophile 1 (87 mg, 0.428 mmol) in deionised water (1.1 mL)
at 0 ◦C was added freshly distilled cyclopentadiene (105 lL,
1.28 mmol). After 25 min the characteristic blue color of 1
disappeared and the solution turned yellow. A solution of
sodium hydroxide (20% in water, 1 mL) was added dropwise,
followed by di-tert-butyl dicarbonate (187 mg, 0.856 mmol)
in THF (5 mL). The reaction mixture was stirred overnight.
Brine was added and the aqueous phase was extracted with
CH2Cl2. The combined organic phases were dried over MgSO4,
5-(Cyclohexa-1,5-dienyl)benzo[1,3]dioxolane (16). To a sus-
pension of magnesium turnings (0.18 g, 7.43 mmol) in THF
(4 mL) at room temperature was added 1,2-methylenedioxy-4-
4 4 0 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 9 5 – 4 4 0 1