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L.M. Pardo et al. / Tetrahedron 66 (2010) 5811e5818
7.25e7.18 (m, 4H), 6.54e6.52 (m, 1H), 4.70 (d, J¼6.4, 2H), 2.73 (t,
1H); 13C NMR (CDCl3)
d (ppm) 194.8, 176.4, 164.4, 154.3, 137.4, 136.8,
J¼7.1, 2H), 2.49 (t, J¼7.0, 2H); 13C NMR (CDCl3)
d
(ppm) 171.1, 148.3,
124.9, 130.7, 129.3, 128.5, 128.0, 127.9, 123.1, 121.7, 114.3, 66.5, 60.6,
134.1, 133.5, 132.8, 132.6, 128.7, 128.5, 125.0, 89.1, 80.6, 41.3, 35.5,
55.6, 42.8, 29.2, 23.5; IR
n
(cmꢀ1) 3251, 1732, 1679, 1597; MS [Mþ1]
15.8; IR
n
(cmꢀ1) 3290, 1648, 1523; MS [Mþ1] m/z: 345 (34), 343
m/z: 352 (22, Mþ1ꢀCbz), 351 (100), 215 (84), 132 (33); HRMS calcd
(100), 325 (11), 301 (11), 295 (22); HRMS calcd for
for [C27H26N2O5$HþꢀCbz] 352.1323, found: 352.1387.
C18H1535ClN2O3$Hþ: 343.0849, found: 343.0851.
4.6.5. 5-(4-Methoxybenzoyl)-N-(2-nitrobenzyl)-2-pyrrolidinone
(25a). According to the typical procedure pyrrolidinone 25a was
obtained from 24a in 69% yield. It was purified by column chro-
matography (hexanes/EtOAc, 1/1) as a yellowish solid that was
triturated in hexanes: mp 55e58 ꢁC (hexanes); 1H NMR (CDCl3)
4.6. Typical procedure for the PIFA-mediated
heterocyclization
4.6.1. N-(3-N0-Benzyloxycarbonylaminopropyl)-5-(40-methoxy-
benzoyl)-2-pyrrolidinone (9a). A solution of alkynylamide 8a
(315 mg, 0.8 mmol) in CF3CH2OH (12 mL) was stirred at 0 ꢁC and
a solution of PIFA (526.8 mg, 1.2 mmol) in 6 mL of the same solvent
was added dropwise. The reaction mixture was stirred at that
temperature for 2 h. For the work up, aqueous Na2CO3 (10%) was
added and the mixture extracted with CH2Cl2 (3ꢂ20 mL). The
combined organic layers were washed with brine, dried over
Na2SO4, and the solvent evaporated. Purification of the crude by
flash chromatography (EtOAc) gave the desired product 9a as
a chromatographically pure yellowish oil (70%): 1H NMR (CDCl3)
d
(ppm) 7.88e7.82 (m, 3H), 7.59e7.57 (m, 2H), 7.48e7.38 (m, 1H),
6.92 (d, J¼8.8, 2H), 5.19e5.10 (m, 2H), 4.30 (d, J¼16.0, 1H), 3.84 (s,
3H), 2.52e2.33 (m, 3H), 2.09e1.97 (m, 1H); 13C NMR (CDCl3)
d
(ppm) 195.0, 176.2, 164.2, 148.7, 133.5, 132.0, 131.3, 130.7, 128.6,
126.9, 124.6, 114.2, 61.7, 55.6, 42.8, 29.0, 23.6; IR
n
(cmꢀ1) 1690,
1600, 1524; MS [Mþ1] m/z: 355 (100), 219 (62), 135 (13); HRMS
calcd for C19H18N2O5$Hþ: 355.1294, found: 355.1302.
4.6.6. 5-Benzoyl-N-(2-nitrobenzyl)-2-pyrrolidinone (25b). Accord-
ing to the typical procedure pyrrolidinone 25b was obtained from
24b in 81% yield. It was purified as a yellowish oil by column
d
(ppm) 7.93 (d, J¼8.8, 2H), 7.33e7.26 (m, 5H), 6.97 (d, J¼8.8, 2H),
5.61 (m, 1H), 5.15e5.02 (m, 3H), 3.89 (s, 3H), 3.71e3.56 (m, 1H),
3.41e3.27 (m, 1H), 3.16e3.02 (m, 2H), 2.52e2.34 (m, 3H), 2.02e1.98
chromatography (EtOAc): 1H NMR (CDCl3)
d (ppm) 7.91e7.88 (m,
3H), 7.66e7.56 (m, 3H), 7.49e7.40 (m, 3H), 5.22e5.15 (m, 2H), 4.41
(m, 1H), 1.70e1.58 (m, 2H); 13C NMR (CDCl3)
d
(ppm) 195.4, 176.4,
164.3, 136.7, 130.7, 128.4, 128.0, 127.81, 114.3, 66.4, 61.8, 55.6, 39.3,
37.9, 29.5, 27.4, 23.8; IR
(cmꢀ1) 3332, 2938, 1685, 1599, 1512; MS
(d, J¼15.8, 1H), 2.50e2.43 (m, 3H), 2.05e2.02 (m, 1H); 13C NMR
(CDCl3)
d (ppm) 196.5, 176.2, 148.7, 133.9, 131.8, 134.0, 133.6, 131.3,
n
129.0, 128.6, 128.3, 124.7, 62.0, 42.7, 28.9, 23.4; IR n
(cmꢀ1) 1696,
[Mþ1] m/z: 304 (12, Mþ1ꢀCbz), 303 (79), 260 (28), 167 (100), 135
(17); HRMS calcd for [C23H26N2O5$HþꢀCbz] 304.1423, found:
304.1390.
1525; MS [Mþ1] m/z: 326 (20), 325 (100), 219 (86), 136 (18); HRMS
calcd for C18H16N2O4$Hþ: 325.1188, found: 325.1185.
4.6.7. 5-(4-Chlorobenzoyl)-N-(2-nitrobenzyl)-2-pyrrolidinone
(25c). According to the typical procedure pyrrolidinone 25a was
obtained from 24a in 57% yield. It was purified as a colorless oil by
4.6.2. N-(3-N0-Benzyloxycarbonylamino-2,2-dimethylpropyl)-5-(40-
methoxybenzoyl)-2-pyrrolidi-none (9b). According to the typical
procedure pyrrolidinone 9b was obtained from 8b in 89% yield. It
was purified by column chromatography (EtOAc) as a yellowish oil:
column chromatography (EtOAc): 1H NMR (CDCl3)
d (ppm)
7.88e7.80 (m, 3H), 7.66e7.56 (m, 2H), 7.43 (d, J¼8.6, 3H), 5.16e5.11
1H NMR (CDCl3)
d
(ppm) 7.93 (d, J¼8.8, 2H), 7.35e7.28 (m, 5H), 6.99
(m, 2H), 4.37 (d, J¼15.6, 1H), 2.45e2.41 (m, 3H), 2.00e1.98 (m, 1H);
(d, J¼8.8, 2H), 6.49e6.47 (m, 1H), 5.27 (d, J¼9.1, 1H), 5.11 (d, J¼12.3,
1H), 5.04 (d, J¼12.3, 1H), 3.89 (s, 3H), 3.76 (d, J¼14.8, 1H), 3.26e3.24
(m, 1H), 2.74e2.70 (m, 1H), 2.49e2.36 (m, 3H), 2.26 (d, J¼14.8, 1H),
2.06e1.99 (m, 1H), 0.92 (s, 3H), 0.86 (s, 3H); 13C NMR (CDCl3)
13C NMR (CDCl3)
d (ppm) 195.4, 175.9, 171.1, 148.8, 132.3, 131.8,
133.6, 131.9, 129.7, 129.3, 128.7, 124.6, 61.9, 42.5, 28.9, 23.3; IR
n
(cmꢀ1) 1697, 1524; MS [Mþ1] m/z: 361 (23), 360 (14), 359 (70),
219 (100), 136 (22); HRMS calcd for C18H1535ClN2O4$Hþ: 359.0799,
d
(ppm) 195.1, 177.7, 164.3, 157.2, 137.0, 130.7, 128.4, 127.9, 127.8,
found: 359.0798.
127.0, 114.3, 66.3, 64.3, 55.6, 50.3, 47.7, 37.2, 28.9, 24.7, 23.6; IR
n
(cmꢀ1) 3338, 2962, 1682, 1600; MS [Mþ1] m/z: 439 (1), 359 (10),
331 (100), 303 (11), 195 (47); HRMS calcd for C25H30N2O5$Hþ:
4.7. Typical procedure for the reductive amination
(method 1)
439.2233, found: 439.2249.
4.6.3. N-[(2-N0-Benzyloxycarbonylaminomethyl)phenyl]-5-(40-me-
thoxybenzoyl)-2-pyrrolidinone (15). According to the typical pro-
cedure pyrrolidinone 15 was obtained from 14 in 39% yield. It was
purified by column chromatography (hexanes/EtOAc, 1/1) as a pale
4.7.1. Synthesis of 1-(4-methoxyphenyl)-octahydro-pyrrolo[1,2-a]
[1,4]diazepin-7-one (10a). A solution of pyrrolidinone 9a (246 mg,
0.6 mmol) in 6 mL of MeOH and 0.5 mL of HCl (1 M) was hydro-
genated (70 psi) in the presence of Pd/C overnight. The catalyst was
filtered through Celite and the solution treated with 15 mL of an
aqueous solution of Na2CO3 (20%). The mixture was extracted with
CH2Cl2 (3ꢂ15 mL), the combined organic extracts were dried with
Na2SO4, and the solvent evaporated under vacuum. The resulting oil
was purified by column chromatography (MeOH) to afford dia-
zepinone 10a as a colorless oil (48%) as an inseparable mixture of
both diastereoisomers. Reported data is given for the both of them:
brown oil: 1H NMR (CDCl3)
d
(ppm) 7.87 (d, J¼8.6, 2H), 7.49 (br s,
1H), 7.37e7.22 (m, 8H), 6.91 (d, J¼8.8, 2H), 5.69e5.65 (m, 1H), 5.13
(s, 2H), 4.56e4.54 (m, 2H), 3.84 (s, 3H), 2.52e2.23 (m, 3H),
2.15e2.07 (m, 1H); 13C NMR (CDCl3)
d (ppm) 195.1, 164.3, 156.8,
136.8, 136.1, 127.0, 130.8, 128.5, 128.3, 128.1, 128.0, 114.2, 66.6, 64.9,
55.6, 41.4, 30.1, 24.5; IR
n
(cmꢀ1) 3354, 1693, 1599; MS [Mþ1] m/z:
459 (6), 351 (17), 323 (20), 308 (100), 215 (63),135 (11); HRMS calcd
for C27H26N2O5$Hþ: 459.1920, found: 459.1900.
1H NMR (CDCl3)
d
(ppm) 7.27 (d, J¼8.8, 2H), 7.21 (d, J¼8.5, 2H),
6.88e6.82 (m, 4H), 5.08 (br s, 1H), 4.60 (d, J¼6.7, 1H), 3.84e3.79 (m,
1H), 3.82e3.79 (m, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.73e3.69 (m, 1H),
3.63e3,56 (m, 1H), 3.48e3.35 (m, 2H), 2.93e2.87 (m, 1H),
2.84e2.79 (m,1H), 2.77e2.70 (m, 2H), 2.39e2.32 (m, 2H), 2.18e2.10
(m, 2H), 2.10e2.00 (m, 1H), 1.99e1.85 (m, 3H), 1.82e1.73 (m, 1H),
4.6.4. N-[(2-N0-Benzyloxycarbonylamino)benzyl]-5-(40-methoxy-
benzoyl)-2-pyrrolidinone (20). According to the typical procedure
pyrrolidinone 20 was obtained from 19 in 65% yield. It was purified
by column chromatography (hexanes/EtOAc, 1/1) as a yellowish oil:
1H NMR (CDCl3)
d
(ppm) 8.90 (s, 1H), 8.02 (d, J¼8.1, 1H), 7.86 (d,
1.71e1.64 (m, 1H), 1.63e1.55 (m, 2H); 13C NMR (CDCl3)
d (ppm)
J¼8.7, 2H), 7.46e7.26 (m, 6H), 6.97e6.89 (m, 4H), 5.22 (s, 2H),
5.03e4.98 (m, 3H), 3.87 (s, 3H), 2.52e2.28 (m, 3H), 2.02e1.88 (m,
176.6, 176.1, 158.8, 158.5, 133.1, 133.8, 127.7, 127.0, 114.0, 113.7, 75.6,
71.2, 65.7, 63.6, 55.2, 40.6, 39.9, 39.2, 38.3, 30.5, 30.1, 29.5, 21.0, 17.7;