7598 J. Am. Chem. Soc., Vol. 121, No. 33, 1999
Cummins et al.
liquid: 1H NMR (270 MHz, CDCl3) δ 1.66 (m, 4H), 2.28 (m, 4H),
4.66 (m, 2H), 4.95 (m, 2H).
2-Acetoxy-1,2,3,4,5,6,7,8-octahydronaphthalene. A sample of 4 g
of 1,2-dimethylenecyclohexane (37 mmol) and a large excess (40 mL)
of vinyl acetate was placed in a 100 mL bomb. The mixture was heated
at 300 °C for 2 h and allowed to cool to ambient temperature. The
reaction products were concentrated under reduced pressure to remove
excess vinyl acetate. A yellow oil (4.4 g, 61%) was recovered and
analyzed by GC/MS. This product was used in the next step without
further purification.
1,2,3,4,5,6-Hexahydronaphthalene.13 At a rate of approximately
0.25 g per min, 750 mg of the acetate synthesized in the previous step
was dropped via an addition funnel into a 12 mm × 25 cm Pyrex
column packed to a depth of 17 cm with 3 mm Pyrex beads and heated
externally to 550 ( 15 °C by a tube furnace. The pyrolysate vapor
was conducted into a cooled (-78 °C) collection flask by a stream of
argon, which was introduced through the addition funnel (sealed to
the Pyrex column with Parafilm). A drying tube outlet was connected
to the receiving flask as a necessary outlet for excess pressure. The
pyrolysis products were washed with 3 × 15 mL of distilled water to
remove acetic acid and dried over Na2SO4. The major product was
purified by preparative gas chromatography; 1H NMR (270 MHz,
CDCl3) δ 1.57 (m, 1H), 1.66 (m, 4H), 1.85 (m, 1H), 2.03 (m, 4H),
2.17 (m, 2H), 5.71 (m, 2H). This spectrum matched spectra from the
literature.13
anti- and syn-7-Ethoxycarbonyl-5-methylenespiro[2.5]octane. To
20.0 g of 1,2-dimethylenecyclohexane (0.19 mol) and 60 mg of
rhodium(II) acetate dimer (0.14 mmol) suspended in 100 mL of Et2O
was added dropwise 21.1 g of ethyl diazoacetate (0.19 mol) dissolved
in 70 mL of Et2O over a period of 9 h. The crude products were passed
through a silica gel column and washed with 3 × 50 mL of CH2Cl2.
This material was concentrated to dryness, yielding 34.1 g of a clear
oil. Analysis by GC/MS indicated the presence of two diastereomers
with the expected molecular weight of 194. These compounds were
separated on a silica gel column (90/10 hexanes/ether). A total of 15
g of the more mobile ester was collected as a colorless oil: 1H NMR
(600 MHz, benzene-d6) δ 1.02 (t, 3H), 1.08 (dd, 1H), 1.20 (dd, 1H),
1.32-1.60 (m, 4 H), 1.63 (dd, 1 H), 1.68 (m, 1H), 1.92 (m, 1H), 2.12
(m, 2H), 4.02 (m, 2H), 4.52 (s, 1H), 4.56 (s, 1H); 13C NMR (150 MHz,
benzene-d6) δ 171.9, 151.6, 106.2, 60.6, 35.8, 35.3, 30.7, 28.6, 26.9,
26.2, 18.9, 14.8. A total of 3 g of the less mobile ester was collected
as a colorless oil: 1H NMR (600 MHz, benzene-d6) δ 0.58 (dd, 1H),
0.72 (m, 1H), 0.98 (t, 3H), 1.28 (m, 1H), 1.50 (m, 2H), 1.54 (dd, 1H),
1.64 (m, 3H), 1.90 (m, 1H), 2.22 (m, 1H), 3.93 (q, 2H), 4.82 (s, 1H),
4.87 (s, 1H); 13C NMR (150 MHz, benzene-d6) δ 170.6, 145.8, 110.1,
60.3, 39.2, 36.0, 35.9, 28.7, 28.6, 26.1, 17.6, 14.9. The structures and
relative geometries of these two products were confirmed by means of
carbon/hydrogen 2D correlations and selective proton irradiations. The
more mobile ester was assigned the anti stereochemistry, and the less
mobile ester was assigned the syn stereochemistry through 1D NOE
difference spectroscopy. HRMS (EI) calcd for the anti isomer:
C12H18O2, 194.13068; found 194.13206. HRMS (EI) calcd for the syn
isomer: C12H18O2, 194.13068; found 194.13021.
anti-7-Hydroxymethyl-5-methylenespiro[2.5]octane. A sample of
the anti ester (0.960 g, 4.95 mmol, 1 equiv) was dissolved in 8 mL of
anhydrous Et2O and added dropwise to a mixture of LiAlH4 (0.282 g,
7.42 mmol, 1.5 equiv) in 9 mL of refluxing anhydrous Et2O over 1 h.
The reaction was followed by TLC (80/20 hexanes/Et2O). Reflux was
maintained for another 1.5 h, at which time 10% NH4Cl (30 mL) was
carefully added to quench the reaction. The mixture was filtered to
remove the product, which was washed with excess ether and CH2Cl2.
The aqueous layer was extracted with 50 mL of Et2O, and the combined
organic layers were dried over Na2SO4. A total of 583 mg (78%) of
anti alcohol was recovered as a colorless oil, which was used in the
subsequent step without further purification: 1H NMR (270 MHz,
CDCl3) δ 0.29 (m, 1H), 0.86 (m, 1H), 1.24 (m, 2H), 1.59 (m, 7H),
2.24 (m, 1H), 3.71 (m, 2H), 4.56 (s, 1H), 4.60 (s, 1H); HRMS (EI)
calcd for C10H16O 152.12012, found 152.12111.
syn-7-Hydroxymethyl-5-methylenespiro[2.5]octane. A sample of
the syn ester (3 g, 15.5 mmol) was dissolved in anhydrous Et2O (20
mL) and added dropwise to a mixture of LiAlH4 (1.02 g, 26.8 mmol)
in 25 mL of refluxing anhydrous Et2O over 1.5 h. The reaction was
followed by TLC (80/20 hexanes/Et2O). Reflux was maintained for
another 1.25 h, at which time 6 mL of 10% NH4Cl was carefully added
to quench the reaction. The mixture was filtered to remove the product,
which was washed with excess ether and CH2Cl2. The aqueous layer
was extracted with 10 mL of Et2O, and the combined organic layers
were dried over Na2SO4. The organic layers were concentrated to give
2.2 g (93%) of syn alcohol as a colorless oil, which was used in the
subsequent step without further purification: 1H NMR (270 MHz,
CDCl3) δ 0.51 (m, 1H), 0.71 (m, 1H), 0.82-2.10 (m, 9H), 2.23 (m,
1H), 3.66 (m, 2H), 4.59 (s, 1H), 4.79 (s, 1H); HRMS (EI) calcd for
C10H16O 152.12012, found 152.11918.
anti-5-Methylenespiro[2.5]octane-7-carboxaldehyde. A sample of
the anti alcohol (580 mg, 3.8 mmol, 1 equiv) dissolved in 10 mL of
dry CH2Cl2 was rapidly charged into a heterogeneous mixture of PCC
(1.23 g, 5.7 mmol, 1.5 equiv) in 12 mL of dry CH2Cl2. The mixture
immediately turned black. The reaction was followed by TLC (85/15
hexanes/Et2O) and diluted with 3 × 5 mL of Et2O upon completion (1
h). The crude product was filtered through Flourisil and concentrated
under reduced pressure to yield 443 mg (77%) of a pale yellow oil:
1H NMR (270 MHz, CDCl3) δ 1.29-2.24 (m, 10H), 2.32 (m, 1H),
4.64 (s, 1H), 4.68 (s, 1H), 9.54 (d, 1H, J ) 4.8 Hz); HRMS (EI) calcd
for C10H13O+ (the acylium ion) 149.09664, found 149.09687.
Stereochemistry of anti- and syn-7-Ethoxycarbonyl-5-methylene-
spiro[2.5]octane. One-dimensional nuclear Overhauser enhancement
difference spectroscopy (NOEDS)14 at 600 MHz was used to prove
the structure of the anti and syn esters (labeling as shown below). For
these experiments, selective (ca. 35 Hz) irradiation was applied for 5
s, followed by a 10 ms recovery delay, a 45° read pulse, and data
acquisition. Successive on-resonance experiments and one off-resonance
experiment for reference were collected in a supercycle for long-time
averaging. Difference spectra were calculated and integrated using
standard tools of the Vnmr software (Varian). The observed NOE data
are listed below. Additional information was provided by comparative
assignment of the carbon resonances, using gradient-selected 13C,1H-
HSQC spectra.15
syn-5-Methylenespiro[2.5]octane-7-carboxaldehyde. A sample of
the syn alcohol (2 g, 13.2 mmol, 1 equiv) dissolved in 40 mL of dry
CH2Cl2 was rapidly charged into a heterogeneous mixture of PCC (4.3
g, 19.9 mmol, 1.5 equiv) in 50 mL of dry CH2Cl2. The mixture
immediately turned black. The reaction was followed by TLC (85/15
hexanes/Et2O) and diluted with 3 × 20 mL of Et2O upon completion
(2 h). The crude product was filtered through Flourisil and concentrated
under reduced pressure to yield 1.5 g (76%) of a pale yellow oil.
(13) Cargill, R. L.; Peet, N. P.; Pond, D. M.; Bundy, W. A.; Sears, A.
B. J. Org. Chem. 1980, 45, 4001. Paquette, L. A.; Chamot, E.; Browne, A.
R. J. Am. Chem. Soc. 1980, 102, 637.
1
Analysis of this product by H NMR indicated that the desired syn
(14) Sanders, J. K. M.; Mersh, J. D. Prog. Nucl. Magn. Reson. Spectrosc.
1982, 15, 353.
(15) Kay, L. E.; Keifer, P.; Saarinen, T. J. Am. Chem. Soc. 1992, 114,
10663.