192 J . Org. Chem., Vol. 67, No. 1, 2002
Herr et al.
Meth yl 5-Nor bor n en e-2-ca r boxim id a te Hyd r och lor id e
(5, 1:1 Exo/En d o Mixtu r e). Hydrogen chloride gas (about 3
equiv, by weight) was introduced into a solution of 5-nor-
bornene-2-carbonitrile (12, 55 g, 462 mmol) and anhydrous
methanol (19 mL, 462 mmol) in anhydrous diethyl ether (300
mL) at 0 °C over a 1 h period through a gas inlet tube below
the surface of the reaction mixture. The gas flow was termi-
nated, and the reaction mixture was stirred for 1 h, after which
the mixture was placed in the freezer for 3 days. The
precipitate was collected by vacuum filtration and washed with
anhydrous diethyl ether (100 mL). The solids were dried
overnight (30 mmHg vacuum, 50 °C) to produce 5 as an off-
white solid (71.4 g, 82% yield): mp (DSC) 181 °C; 1H NMR
(CDCl3) δ 6.31 (dd, 1H, J ) 3.1, 5.8 Hz), 6.20 (t, 2H, J ) 3.5
Hz), 5.91 (dd, 1H, J ) 2.5, 5.8 Hz), 4.32 (s, 3H), 4.23 (s, 3H),
3.53 (s, 1H), 3.16 (s, 1H), 3.03 (s, 1H), 2.87-2.84 (m, 1H), 2.13-
2.06 (m, 1H), 1.66-1.60 (m, 3H), 1.54-1.43 (m, 5H); 13C NMR
(CDCl3) δ 182.7, 181.7, 178.5, 177.2, 139.8, 138.6, 138.5, 138.1,
136.1, 132.4, 131.2, 61.0, 60.7, 50.3, 48.2, 48.1, 47.3, 46.8, 46.6,
46.4, 44.6, 44.3, 43.2, 42.9, 42.8, 42.6, 42.1, 41.8, 37.6, 31.3,
and the precipitate was collected by vacuum filtration and
washed with ether (30 mL). The filtrate solution was concen-
trated to a volume of about 50 mL and cooled at 0 °C to stand
for 1 h. The resulting precipitate was collected by vacuum
filtration and washed with cold ether (10 mL). The two crops
of solids were combined and dried overnight (30 mmHg
vacuum, 50 °C) to produce 15 as an off-white powder (5.0 g,
61% yield): mp 168-170 °C; TLC Rf (50% ethyl acetate/
hexanes) ) 0.51; 1H NMR (CDCl3) δ 7.37-7.31 (m, 6H), 7.13-
7.08 (m, 4H), 6.31-6.27 (m, 1H), 6.20-6.05 (m, 2H), 5.95-
5.90 (m, 1H), 5.15-4.90 (m, 4H), 4.32-4.18 (m, 4H), 3.40-
3.30 (m, 1H), 3.25-3.20 (m, 1H), 3.20-3.10 (m, 4H), 3.10-
2.95 (m, 2H), 2.95-2.80 (m, 2H), 2.70-2.60 (m, 1H), 2.40-
2.30 (m, 1H), 1.95-1.85 (m, 2H), 1.55-1.40 (m, 4H), 1.40-
1.35 (m, 4H), 1.35-1.20 (m, 6H), 0.95-0.75 (m, 6H); 13C NMR
(CDCl3) δ 161.9, 154.9, 154.7, 154.5, 152.4, 151.2, 138.8, 137.7,
136.1, 135.5, 132.3, 129.2, 128.5, 127.6, 127.3, 60.8, 60.7, 50.0,
47.8, 47.4, 46.9, 46.4, 42.8, 42.5, 42.2, 37.3, 31.8, 31.1, 23.0,
22.9, 14.5, 11.5, 11.4; IR (KBr) 3356, 2967, 2875, 1718, 1665,
1508 cm-1; CI MS m/z 423 (M + H)+, 364. The 1H NMR
spectrum was consistent with a 1:1 mixture of the exo and
endo structures.
30.8, 30.1, 30.0; IR (KBr) 3378, 3194, 2974, 1655, 1405 cm-1
;
CI MS m/z 275 (M + H)+, 152, 138. The 1H NMR spectrum
was consistent with a 1:1 mixture of the exo and endo
structures.
1-n -P r op yl-3,9-d ih yd r o-9-ben zyl-8-[2-n or bor n -5-en yl]-
1H-p u r in e-2,6-d ion e (16, 1:1 Exo/En d o Mixtu r e). Sodium
methoxide (8.7 mL, 40 mmol, 25% in methanol) was added to
a solution of 15 (1:1 exo/endo mixture, 3.4 g, 8.0 mmol) in
anhydrous methanol (80 mL) at room temperature under
nitrogen, and the reaction mixture was heated at reflux to stir
for 1.5 h. The mixture was cooled to room temperature, and
the solvent was removed under reduced pressure. The residue
was charged with 2 N HCl solution (50 mL) and extracted with
methylene chloride (2 × 100 mL). The combined organic
extracts were washed with brine (1 × 100 mL) and dried
(MgSO4). The solvent was removed under reduced pressure
to produce a colorless oil, which crystallized upon standing to
produce 16 as an off-white solid (2.9 g, 96% yield): mp (DSC)
235 °C; TLC Rf (5% methanol/chloroform) ) 0.56; 1H NMR
(CDCl3) δ 7.40-7.30 (m, 6H), 7.10-6.95 (m, 4H), 6.30-6.25
(m, 1H), 6.20-6.05 (m, 2H), 5.85-5.80 (m, 1H), 5.35 (s, 2H),
5.28 (d, 2H, J ) 8.8 Hz), 3.90-3.80 (q, 4H, J ) 7.3 Hz), 3.66
(s, 4H), 3.23-3.10 (m, 2H), 3.10-2.90 (m, 2H), 2.73 (s, 1H),
2.55-2.45 (m, 1H), 2.31-2.25 (m, 1H), 2.09-1.99 (m, 1H),
1.95-1.78 (m, 1H), 1.65-1.45 (m, 2H), 1.45-1.28 (m, 2H), 0.92
(t, 3H, J ) 7.2 Hz), 0.86 (t, 3H, J ) 7.2 Hz); 13C NMR (CDCl3)
δ 138.7, 137.6, 135.6, 132.0, 129.2, 128.5, 126.1, 125.6, 49.8,
47.6, 46.7, 46.5, 46.1, 42.5, 42.0, 36.6, 36.4, 31.7, 31.0, 21.1,
Eth yl 5-Am in o-2-[2-n or bor n -5-en yl]-1-ben zyl-1H-im i-
d a zole-4-ca r boxyla te (3, 1:1 Exo/En d o Mixtu r e). A mix-
ture of 2-cyanoglycine ethyl ester (4,3-5 11.8 g, 92 mmol) and
5 (1:1 exo/endo mixture, 19.1 g, 101 mmol) in anhydrous
chloroform (150 mL) under nitrogen was heated at reflux to
stir for 1.5 h. The mixture was cooled to room temperature
and filtered through a short plug of Celite, rinsing the solid
support with chloroform (200 mL). The filtrate was partially
concentrated to a final volume of about 150 mL and charged
with benzylamine (11.1 mL, 101 mmol), and the mixture was
heated at reflux to stir for 21 h. The mixture was cooled to
room temperature; the solvent was removed under reduced
pressure to produce an orange solid, which was purified by
flash column chromatography on silica gel, eluting with
methanol/methylene chloride (1:99), to produce 3 as a yellow
solid (14.3 g, 46% yield): mp (DSC) 249 °C; TLC Rf (5%
1
methanol/chloroform) ) 0.66, 0.60; H NMR (CDCl3) δ 7.45-
7.30 (m, 6H), 7.13-7.05 (m, 4H), 6.27-6.23 (m, 1H), 6.13-
6.07 (m, 2H), 5.92-5.85 (m, 1H), 5.15-5.03 (m, 4H), 4.71 (s,
2H), 4.62 (s, 2H), 4.42-4.28 (m, 4H), 3.23-3.18 (m, 1H), 3.10
(s, 1H), 3.02-2.85 (m, 2H), 2.53-2.47 (m, 1H), 2.40-2.33 (m,
1H), 2.13-2.00 (m, 1H), 1.83-1.78 (m, 1H), 1.70 (br s, 2H),
1.52-1.34 (m, 6H); 13C NMR (CDCl3) δ 165.2, 146.4, 146.0,
138.6, 137.6, 135.9, 135.1, 135.0, 132.4, 129.6, 128.5, 126.2,
125.9, 60.0, 49.9, 47.6, 46.9, 46.4, 45.9, 42.6, 42.1, 36.7, 36.6,
11.3; IR (KBr) 3448, 2923, 2851, 2364, 1718, 1648, 1458 cm-1
;
CI MS m/z 377 (M + H)+, 329, 311. The 1H NMR spectrum
was consistent with a 1:1 mixture of the exo and endo
structures.
31.2, 30.8, 15.0, 14.9; IR (KBr) 3413, 2977, 1670, 1455 cm-1
;
CI MS m/z 338 (M + H)+, 292, 272. The 1H NMR spectrum
was consistent with a 1:1 mixture of the exo and endo
structures.
1,3-Dip r op yl-3,9-d ih yd r o-9-ben zyl-8-exo-[2-n or bor n -5-
en yl]-1H-p u r in e-2,6-d ion e (2a ) a n d 1,3-Dip r op yl-3,9-d i-
h yd r o-9-ben zyl-8-en d o-[2-n or bor n -5-en yl]-1H-p u r in e-2,6-
d ion e (2b). A mixture of 1-bromopropane (1.4 mL, 15 mmol),
potassium carbonate (2.1 g, 15 mmol), and 16 (1:1 exo/endo
mixture, 2.9 g, 7.7 mmol) in anhydrous N,N-dimethylforma-
mide (50 mL) was heated at 70 °C under nitrogen and stirred
for 2.5 h. The mixture was cooled to room temperature and
diluted with ether (300 mL). This solution was washed with
water (2 × 100 mL) and brine (1 × 100 mL) and dried (MgSO4).
The solvent was removed under reduced pressure to produce
crude 2 as a yellow oil. The NMR spectrum of this crude
residue was consistent with the proposed structures as a 1:1
mixture of exo and endo 2-norbornenyl epimers. This oil was
then purified by flash column chromatography on silica gel,
eluting with ethyl acetate/hexanes (4:6), to first produce the
exo isomer 2a as a colorless oil, which crystallized to a white
solid upon standing (1.6 g, 50% yield): mp (DSC) 119 °C; TLC
Rf (50% ethyl acetate/hexanes) ) 0.64; 1H NMR (CDCl3) δ
7.33-7.29 (m, 3H), 7.18-7.15 (m, 2H), 6.15-6.13 (m, 1H),
6.12-6.01 (m, 1H), 5.25 (q, 2H, J ) 22.9 Hz), 4.36 (t, 2H, J )
6.5 Hz), 4.08 (t, 2H, J ) 9.1 Hz), 2.93 (s, 1H), 2.65 (s, 1H),
2.58-2.54 (m, 1H), 2.36-2.29 (m, 1H), 1.93 (d, 1H, J ) 8.5
Hz), 1.82 (q, 2H, J ) 7.2 Hz), 1.71 (q, 2H, J ) 7.5 Hz), 1.41-
1.30 (m, 2H), 1.04 (t, 3H, J ) 7.5 Hz), 0.96 (t, 3H, J ) 7.5 Hz);
An alternative, nonchromatographic method for purification
was carried out on a small scale. A 1 g sample of the crude
reaction residue (after removal of the reaction solvent) was
filtered through a plug of silica gel, eluting with methanol/
methylene chloride (1:19, 150 mL). The solvent was removed
under reduced pressure, and the residue was dissolved in 2 N
HCl solution (100 mL). This acid solution was washed with
ether (2 × 100 mL), and the aqueous layer was made basic
with 2 N NaOH solution (110 mL). The precipitate was
collected by vacuum filtration, washed with water (50 mL),
and dried overnight (30 mmHg vacuum, 60 °C) to produce 3
as a white powder. The 1H NMR spectrum was identical to
the spectrum obtained from the chromatographic purification.
E t h yl 5-[[(n -P r op yla m in o)ca r bon yl]a m in o]-2-[2-n or -
bor n -5-en yl]-1-ben zyl-1H-im idazole-4-car boxylate (15, 1:1
Exo/En d o Mixtu r e). n-Propyl isocyanate (5.4 mL, 58 mmol)
was added to a solution of 3 (1:1 exo/endo mixture, 6.5 g, 19
mmol) and triethylamine (8.1 mL, 58 mmol) in anhydrous
toluene (80 mL) under nitrogen, and the reaction mixture was
heated at reflux to stir for 18 h. The mixture was cooled to
room temperature, and the solvent was removed under re-
duced pressure. The residue was charged with ether (100 mL),