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A. Thaqi et al. / European Journal of Medicinal Chemistry 45 (2010) 1717–1723
5.2.2.7. cis-5-Benzyl-2-hexyltetrahydro-2H,3aH-pyrrolo[3,4-c]pyrrole-
1,3-dione (9p). A mixture of anhydride 5 (100 mg, 0.43 mmol) and
n-octylamine (61 mg, 0.47 mmol) in anhydrous toluene (0.6 mL)
was reacted for 10 min as described in the general microwave
procedure. Work-up as described afforded a residue which was
subjected to column chromatography (silica gel, 49.5:49.5:1 v/v
ethyl acetate/hexane/triethyl amine) to afford 9p as a yellow oil
and was then concentrated under reduced pressure to leave a solid
which was washed with ether (5 mL) and then dried under reduced
pressure to afford 10n as a white solid (HCl salt) (248 mg, 88%), mp
202–204 ꢀC. 1H NMR (D2O):
d
¼ 0.98 (3H, t, J ¼ 7.4 Hz), 1.34–1.43
(2H, sext, J ¼ 7.4 Hz), 1.62 (2H, p, J ¼ 7.5 Hz), 3.59 (2H, t, J ¼ 7.4 Hz),
3.72–3.78 (2H, m), 3.88 (2H, d, J ¼ 10.9 Hz), 3.92–3.97 (m, 2H,
2 ꢃ CH); 13C NMR (D2O):
d
¼ 6.9, 13.6, 22.8, 33.6, 37.6, 41.3, 173.0;
(121 mg, 79%). 1H NMR (CDCl3):
d
¼ 0.85–0.90 (3H, m), 1.27–1.30
HRMS (ESIþ) m/z calcd for C10H17N2O2 (Mþ) 197.1289, found
(10H, m), 1.54–1.63 (2H, m), 2.32–2.42 (2H, m), 3.10–3.16 (2H, m),
197.1290.
3.27 (2H, d, J ¼ 10.0 Hz), 3.50 (2H, t, J ¼ 7.2 Hz), 3.57 (2H, s);
7.17–7.33 (m, 5H); 13C NMR (CDCl3):
d
¼ 14.2, 22.7, 26.8, 27.7, 29.3,
5.2.2.11. cis-2-Hexyl tetrahydro-2H, 3aH-pyrrolo[3,4-c]pyrrole-1,3-
dione (10o). A mixture of Boc-6 (362 mg, 1.5 mmol) and n-hexyl-
amine (220 mg, 1.7 mmol) in anhydrous toluene (1.5 mL) was
reacted for 14 min as described in the general microwave proce-
dure. Work-up as described afforded a residue which was passed
through a plug (silica gel, ethyl acetate) to afford Boc-10o as a clear
29.3, 31.9, 39.2, 44.5, 56.4, 58.5, 127.3, 128.4, 128.5, 138.0, 170.5;
HRMS (ESIþ) m/z calcd for C21H31N2O2 (M þ H)þ requires 343.2386,
found 343.2377.
5.2.2.8. cis-5-Benzyl-2-octyltetrahydro-2H,3aH-pyrrolo[3,4-c]pyrrole-
1,3-dione (9o). A mixture of anhydride 5 (100 mg, 0.43 mmol) and
n-hexylamine (48 mg, 0.47 mmol) in anhydrous toluene (0.6 mL)
was reacted for 10 min as described in the general procedure.
Work-up as described afforded a residue which was subjected to
column chromatography (silica gel, ethyl acetate) to afford 9o as
oil (472 mg, 97%). 1H NMR (CDCl3):
d
¼ 0.77 (3H, s, J ¼ 6.8 Hz), 1.17
(6H, m),1.33 (9H, s),1.41–1.48 (2H, m), 3.20–3.26 (2H, m), 3.32–3.43
(4H, m), 3.86 (2H, d, J ¼ 12.1 Hz); 13C NMR (CDCl3):
d
¼ 13.9, 22.4,
26.2, 27.4, 27.4, 31.2, 39.2, 44.2, 48.0, 80.4, 154.0, 177.9.
A mixture of Boc-10o (472 mg, 1.45 mmol) in aqueous HCl (2 M,
2 mL) and methanol (40 mL) was stirred and heated at reflux for 3
h. The resulting mixture was allowed cool to ambient temperature
and was then concentrated under reduced pressure to leave solid
which was washed with cold ethyl acetate (5 mL) and then dried
under reduced pressure to afford 10o as a white solid (HCl salt)
a gold oil (89 mg, 66%). 1H NMR (CDCl3):
1.29–1.30 (6H, m), 1.55–1.62 (2H, m), 2.32–2.39 (2H, m), 3.08–3.17
d
¼ 0.89 (3H, t, J ¼ 6.4 Hz),
(2H, m), 3.27 (2H, d, J ¼ 10.0 Hz), 3.50 (2H, t, J ¼ 7.2 Hz), 3.56 (2H,
s), 7.16–7.32 (5H, m); 13C NMR (CDCl3):
31.5, 39.2, 44.5, 56.5, 58.5, 127.4, 128.5, 128.5, 138.0, 179.5; HRMS
(ESIþ) m/z calcd for C19H27N2O2 (M þ H)þ 315.2073, found
315.2070.
d
¼ 14.2, 22.6, 26.5, 27.7,
(359 mg, 95%), mp 219–223 ꢀC. 1H NMR (D2O):
d
¼ 0.94 (3H, m),1.37
(6H, m), 1.64 (2H, p, J ¼ 6.5 Hz), 3.58 (2H, t, J ¼ 7.4 Hz), 3.71–3.76
(2H, m), 3.87 (2H, d, J ¼ 12.0 Hz), 3.91–3.95 (2H, m); 13C NMR (D2O):
5.2.2.9. (3aR,6aS)-2-propyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-
dione (10m). Boc-6 (362 mg, 1.5 mmol) and n-propylamine
(100 mg, 1.70 mmol) in anhydrous toluene (1.5 mL) was reacted for
14 min as described in the general microwave procedure. Work-up
as described afforded a residue which was passed through a plug
(silica gel, ethyl acetate) to afford Boc-10m as a clear oil (363 mg,
d
¼ 7.4, 15.9, 19.9, 20.6, 24.6, 33.9, 37.6, 41.3, 172.9; HRMS (ESIþ) m/z
calcd for C12H21N2O2 (M þ H)þ requires 225.1603, found 225.1601.
5.2.2.12. cis-2-Octyl tetrahydro-2H, 3aH-pyrrolo[3,4-c]pyrrole-1,3-
dione (10p). A mixture of Boc-6 (169 mg, 0.7 mmol) and n-octyl-
amine (100 mg, 0.77 mmol) in anhydrous toluene (1.0 mL) was
reacted for 14 min as described in the general microwave proce-
dure. Work-up as described afforded a residue which was passed
through a plug (silica gel, 2:1 v/v, hexane/ethyl acetate) to afford
86%). 1H NMR (CDCl3):
d
¼ 0.80 (3H, t, J ¼ 7.4 Hz), 1.36 (9H, s), 1.52
(2H, sext, J ¼ 7.4 Hz), 3.26–3.29 (2H, m), 3.38–3.45 (4H , m), 3.88–
3.91 (2H, d, J ¼ 12.1 Hz); 13C NMR (CDCl3):
¼ 11.1, 20.9, 28.3, 40.8,
d
44.3, 48.1, 80.6, 154.0, 178.0.
Boc-10p as a clear oil (199 mg, 80%). 1H NMR (CDCl3):
d
¼ 0.85–0.89
A mixture of Boc-10m (412 mg, 1.39 mmol) in aqueous HCl (2 M,
2 mL) and methanol (40 mL) was stirred and heated at reflux for 3h.
The resulting mixture was allowed cool to ambient temperature
and was then concentrated under reduced pressure to leave a tan
solid which was washed with ethyl acetate (5 mL) and then dried
under reduced pressure to afford 10m as a cream solid (HCl salt)
(3H, m), 1.26 (10H, m), 1.43 (9H, s), 1.55 (2H, m), 3.30–3.34 (2H, m),
3.42–3.55 (4H, m), 3.93–3.97 (2H, d, J ¼ 12.0 Hz); 13C NMR (CDCl3):
d
¼ 14.0, 22.6, 26.6, 27.5, 28.3, 29.0, 29.1, 31.7, 39.2, 44.2, 48.1, 80.4,
154.0, 177.9.
Boc-10p (508 mg, 1.5 mmol) in aqueous HCl (2 M, 2 mL) and
methanol (40 mL) was stirred and heated at reflux for 3 h. The
resulting mixture was allowed cool to ambient temperature and
was the concentrated under reduced pressure to leave an oily solid
which was triturated with ethyl acetate to afford 10p as a yellow
(248 mg, 88%), mp 206–208 ꢀC. 1H NMR (400 MHz, D2O):
d
¼ 0.87
(3H, t, J ¼ 7.4 Hz), 1.52–1.61 (2H, m), 3.46 (2H, t, J ¼ 7.4 Hz), 3.61–
3.69 (4H, m), 3.80 (2H, dd, J ¼ 13.1 and 0.6 Hz), 3.84–3.89 (2H, m);
13C NMR (100 MHz, D2O):
d
¼ 10.6, 20.2, 41.3, 43.5, 47.2, 178.9;
solid (HCl salt) (375 mg, 87%). 1H NMR (D2O):
d
¼ 0.92–1.00 (3H, br
HRMS (ESIþ) m/z calcd for C9H15N2O2 (M þ H)þ requires 183.1134,
m), 1.38 (10H, br s), 1.64 (2H, br p, J ¼ 6.9 Hz), 3.58 (2H, t, J ¼ 7.4 Hz),
found 183.1131.
3.71–3.80 (2H, m), 3.86–3.97 (4H, br m); 13C NMR (D2O):
d
¼ 12.4,
21.1, 25.2, 25.6, 27.3, 27.4, 30.1, 38.8, 42.5, 46.3, 177.7; HRMS (ESIþ)
m/z calcd for C14H25N2O2 (M þ H)þ requires 253.1916, found
253.1919.
5.2.2.10. cis-2-propyl-tetrahydro-2H, 3aH-pyrrolo[3,4-c]pyrrole-1,3-
dione (10n). A mixture of Boc-6 (362 mg, 1.5 mmol) and n-butyl-
amine (124 mg, 1.70 mmol) in anhydrous toluene (1.5 mL) was
reacted for 14 min as described in the general microwave proce-
dure. Work-up as described afforded a residue which was passed
through a plug (silica gel, ethyl acetate) to afford Boc-10n as a gold
5.2.2.13. cis-5-Butyltetrahydro-5H-thieno[3,4-c]pyrrole-4,6-dione
(11n). A mixture of anhydride 4 (43 mg, 0.27 mmol) and n-butyl-
amine (22 mg, 0.30 mmol) in anhydrous toluene (0.5 mL) was reacted
for14 minasdescribed inthe generalmicrowave procedure. Work-up
as described afforded a residue which was subjected to column
chromatography (silica gel, 1:3 v/v ethyl acetate/hexane). The rele-
vant fractions were visualised with I2, then combined and concen-
trated under reduced pressure to afford 11n as a clear oil (122 mg,
oil (412 mg, 93%). 1H NMR (CDCl3):
d
¼ 0.91 (3H, t, J ¼ 7.4 Hz), 1.28
(2H, sext, J ¼ 7.4 Hz), 1.43 (9H, s), 1.49–1.59 (2H, m), 3.27–3.34 (2H,
m), 3.44–3.52 (4H, m), 3.96 (2H, d J ¼ 11.9 Hz); 13C NMR (CDCl3):
d
¼ 13.6, 193.9, 28.3, 29.6, 39.0, 44.2, 48.1, 80.5, 154.0, 178.0.
A mixture of Boc-10n (412 mg, 1.39 mmol) in aqueous HCl (2 M,
2 mL) and methanol (40 mL) was stirred and heated at reflux for 3h.
The resulting mixture was allowed cool to ambient temperature
91%). 1H NMR (CDCl3):
1.60 (2H, m), 2.98–3.08 (2H, m), 3.32 (2H, d, J ¼ 12.7 Hz), 3.41–3.48
d
0.92(3H, t, J¼ 7.3Hz),1.22–1.37 (2H, m),1.50–