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L. Dolci et al. / Bioorg. Med. Chem. 7 (1999) 467±479
aluminum chloride in 200 mL of dichloromethane. In
another ¯ame-dried ¯ask equipped with an addition
funnel was stirred 37.98 g (0.22 mol, MW 170.40) of
bis(trimethylsilyl)acetylene in 200 mL of dichloro-
methane. The latter solution was cooled to 0 ꢀC in an
ice-water bath. After 30 min, the solution of the p-
toluenesulfonyl chloride-aluminium chloride complex
was quickly ®ltered through a glass-wool plug into the
addition funnel. The residue was washed with 10 mL of
dichloromethane which was also added to the funnel.
The complex was added to the cold silylacetylene solu-
tion keeping the temperature between 5 and 10 ꢀC. After
the addition was ®nished, the mixture was allowed to
room temperature for one day. The mixture was
hydrolyzed by pouring it into a slurry of 200 mL of 20%
hydrochloric acid and ice. The organic layer was sepa-
rated. The aqueous layer was extracted twice with
50 mL of dichloromethane. The organic layers were
collected and washed three times with 100 mL of water
and once with 100 mL of brine. After drying over
anhydrous magnesium sulfate, the solvent was evapo-
rated to give a brown solid. Recrystallization in heptane
gave 43.88 g (78%) of p-tolyl 2-(trimethylsilyl)ethynyl
sulfone as creamy crystals: Rf 0.06 (heptane/EtOAc, 90/
10); mp 83 ꢀC (lit.43 81±82 ꢀC); 1H NMR (CD2Cl2,
298.0 K) d 7.85 (d, J 8.1 Hz, 2H), 7.37 (d, J 8.1 Hz, 2H),
2.42 (s, 3H), 0.21 (s, 9H); 13C NMR (CD2Cl2, 298.0 K) d
146.5 [C], 139.3 [C], 130.8 [CH], 128.1 [CH], 101.9 [C],
99.3 [C], 22.2 [CH3], 0.7 [CH3]; MS C12H16O2SSi, 270
[M+NH4+].
3.0 Hz, 1H), 7.37 (d, J 6.0 Hz, 2H), 6.88 (b, 2H), 5.32 (b,
1
1H), 5.14 (s, 1H), 2.42 (s, 3H), 1.31 (s, 9H); H NMR
(DMSO-d6, 352.0 K) d 7.72 (d, J 8.4 Hz, 2H), 7.70 (s, 1H),
7.44 (d, J 8.1 Hz, 2H), 6.95 (s, 2H), 5.33 (s, 1H), 5.13 (s,
1H), 2.41 (s, 3H), 1.26 (s, 9H); 13C NMR (DMSO-d6,
352.0K) d 158.8 [C], 153.5 [C], 153.4 [CH], 145.0 [C],
143.1 [CH], 142.0 [CH], 136.1 [C], 130.4 [CH], 127.9 [CH],
80.8 [C], 68.2 [CH], 66.9 [CH], 27.9 [CH3], 21.3 [CH3];
MS C18H21NO4S 365 [M+NH4+].
endo-2-(p-Tolyl-sulfone)-7-tert-butoxycarbonyl-7-azabi-
cyclo[2.2.1]hept-2-ene (10). To 5.12 g (14.75 mmol, MW
347.44) of 9 in 200 mL of acetonitrile was added 1.00 g
Pd/C (10% Pd content). The reaction vessel was purged
®rst with argon and then carefully with hydrogen.
400 mL (17.78 mmol, 1.2 equiv*) of hydrogen was led
into the reaction mixture with vigorous stirring at room
temperature. After the addition was complete, the cata-
lyst was removed by ®ltration over Celite1 and the sol-
vent was evaporated in vacuo. 5.09 g (99%) of 10 was
obtained as a white solid: Rf 0.51 (heptane/EtOAc, 1/1);
mp 141±143 ꢀC; 1H NMR (CD2Cl2, 298.0 K) d 7.78 (d, J
9.0 Hz, 2H), 7.38 (d, J 9.0 Hz, 2H), 7.02 (s, 1H), 4.79 (s,
1H), 4.74 (d, J 3.0 Hz, 1H), 2.43 (s, 3H), 1.97 (bt, 2H),
1.26 (b, 2H), 1.20 (s, 9H); 1H NMR (DMSO-d6,
333.0 K) d 7.78 (d, J 9.0 Hz, 2H), 7.47 (d, J 9.0 Hz, 2H),
7.15 (d, J 2.1 Hz, 1H), 4.74 (s, 1H), 4.70 (d, J 1.2 Hz,
1H), 2.42 (s, 3H), 1.90 (bt, 2H), 1.19 (s, 9H), 1.11 (b,
2H); 13C NMR (CD2Cl2, 298.0 K) d 155.0 [C], 149.2 [C],
145.3 [C], 144.1 [CH], 137.3 [C], 130.4 [CH], 128.2 [CH],
80.7 [C], 62.2 [CH], 61.2 [CH], 27.9 [CH3], 25.4 [CH2],
24.4 [CH2], 21.7 [CH3]; 13C NMR (DMSO-d6, 333.0 K)
d 154.1 [C], 148.0 [C], 144.7 [C], 144.6 [CH], 136.7 [C],
130.2 [CH], 127.5 [CH], 79.9 [C], 61.7 [CH], 60.5 [CH],
27.5 [CH3], 24.6 [CH2], 23.6 [CH2], 21.0 [CH3]; MS
C18H23NO4S, 367 [M+NH4+].
In a ¯ask ®tted with a thermometer and an addition
funnel was stirred 27.08 g (0.11 mol, MW 252.41) of p-
tolyl 2-(trimethylsilyl)ethynyl sulfone in 300 mL of
methanol for 30 min. 350 mL of an aqueous solution
containing potassium carbonate (6.2Â10 3 M) and
potassium bicarbonate (6.2Â10 3 M) were placed in the
addition funnel. The buer was added keeping the tem-
perature near 30 ꢀC. After the addition was ®nished, a
white precipitate appeared. The mixture was diluted
with 200 mL of water and extracted with four portions
of 100 mL of dichloromethane. The organic layers were
washed twice with water and once with brine. After
drying over anhydrous magnesium sulfate, the solvent
was evaporated to give a creamy solid. Recrystallization
in heptane/EtOAc gave 14.27 g (79%) of 8 as white
crystals: Rf 0.08 (heptane/EtOAc, 90/10); mp 72 ꢀC
7-tert-Butoxycarbonyl-7-azabicyclo[2.2.1]hept-2-ene (11).
To 5.07 g (14.51 mmol, MW 349.45) of 10 in 30 mL of
a methanol/dry THF (1/2) solution was added 7.20 g
(60.01 mmol, MW 119.98) of NaH2PO4 and 7.80 g
(54.94 mmol, MW 141.96) of Na2HPO4. The reaction
vessel was then cooled to 70 ꢀC with an ethanol/liquid
nitrogen bath. 6% Na(Hg)y (8.90 g){ was added in small
portions and at the end of the addition the mixture was
allowed to return to rt. After one night, the solution was
(lit.43 74±75 ꢀC); H NMR (CD2Cl2, 298.0 K) d 7.85 (d,
1
* Overreduction with more hydrogen led to endo-2-(p-tolyl-sulfone)-7-
tert-butoxycarbonyl-7-azabicyclo[2.2.1]heptane: Rf 0.51 (heptane/
EtOAc, 1/1); 1H NMR (CD2Cl2, 298.0 K) d 7.78 (d, J 6.0 Hz, 2H), 7.38
(d, J 6.0 Hz, 2H), 4.30 (t, J 4.5 Hz, 1H), 4.26 (t, J 4.5 Hz, 1H), 3.55 (m,
1H), 2.48 (b, 1H), 2.43 (s, 3H), 1.99±1.66 (b, 5H), 1.39 (s, 9H); 13C
NMR (CD2Cl2, 298.0 K) d 155.0 [C], 145.3 [C], 137.8 [C], 130.1 [CH],
128.1 [CH], 80.4 [C], 64.9 [CH], 58.4 [CH], 58.1 [CH], 32.5 [CH2], 29.5
[CH2], 28.3 [CH3], 25.0 [CH2], 21.7 [CH3]; MS C18H25NO4S 352
[M+H+], 369 [M+NH4+].
J 7.5 Hz, 2H), 7.39 (d, J 7.2 Hz, 2H), 3.69 (s, 1H), 2.43
(s, 3H); 13C NMR (CD2Cl2, 298.0 K) d 147.1 [C], 138.5
[C], 130.9 [CH], 128.2 [CH], 82.6 [C], 80.9 [C], 22.2
[CH3]; MS C9H8O2S, 198 [M+NH4+].
endo-2-(p-Tolyl-sulfone)-7-tert-butoxycarbonyl-7-azabi-
cyclo[2.2.1]hepta-2,5-diene (9). In a ¯ask, 9.26 g (0.05 mol,
MW 180.22) of 8 and 21.5 mL (0.13 mol, MW 167.21, d
1.00, 2.5 equiv) of 7 were stirred at 80 ꢀC during 16 h.
The mixture was then concentrated and was coevaporated
twice with EtOAc. The black residue was chromato-
graphed on silica gel. Elution with heptane/EtOAc (95/5
to 70/30) gave 11.35 g (64%) of 9 as a yellow solid: Rf
0.29 (heptane/EtOAc, 60/40); mp 94 ꢀC; 1H NMR
(CD2Cl2, 295.4 K) d 7.73 (d, J 6.0 Hz, 2H), 7.58 (d, J
y
Prepared from Na (0.60 g) and Hg (9.50 g) according to the procedure
described in Vogel's Textbook of Practical Organic Chemistry, 5th ed.;
Longman Scienti®c & Technical, John Wiley & Sons: New York.
{
Overreduction with more Na(Hg) led to 7-tert-butoxycarbonyl-7-
azabicyclo[2.2.1]heptane: Rf 0.53 (heptane/EtOAc, 1/1); 1H NMR
(CD2Cl2, 298.0 K) d 4.12 (s, 2H), 1.71 (d, J 8.8 Hz, 4H), 1.41 (s, 9H),
1.38 (d, J 8.5 Hz, 4H); 1H NMR (DMSO-d6, 318.0 K) d 4.04 (s, 2H),
1.62 (d, J 4.5 Hz, 4H), 1.38 (s, 9H), 1.02 (d, J 7.5 Hz, 4H); 13C NMR
(CD2Cl2, 298.0 K) d 156.1 [C], 79.3 [C], 56.6 [CH], 29.9 [CH2], 28.4
[CH3], 24.0 [CH2].