J.I. Olsen et al. / European Journal of Medicinal Chemistry 123 (2016) 155e160
159
(5.5 mL), and to the corresponding solution,1-azido-5-iodopentane
4.2.3. N-{5-[N0-(p-Methylphenyl)-selenoureido]pentyl}-1-
deoxynojirimycin (6c)
(0.66 g, 2.76 mmol) and K2CO3 (0.88 g, 6.4 mmol) were added, and
stirred at 80 ꢁC for 4.5 h. After that, the mixture was filtered and the
filtrate was concentrated in vacuo. The residue was purified by flash
chromatography (4:1 / 7:3 EtOAcꢀMeOH with 1% NH4OH) to
p-Methylyphenyl isoselenocyanate 16c (90 mg, 0.46 mmol) was
used. Column chromatography (1:3 MeOHꢀEtOAc) furnished 6c
(37 mg, 37%). [
a
]
26 ꢀ3 (c 1.06, CD3OD); 1H NMR (500 MHz, CD3OD)
D
afford 13 (0.26 g, 45% over two steps). [
a
]
26 ꢀ7 (c 0.84, MeOH); 1H
d 7.30e7.21 (m, 2H, AreH), 7.14e7.03 (m, 2H, AreH), 3.90e3.86 (m,
D
NMR (500 MHz, CD3OD)
d
3.95 (dd, 1H, J5,6a
¼
2.3 Hz,
2H, H-1a, H-1b), 3.67e3.61 (m, 2H, CH2), 3.50 (ddd, 1H, J4,5 ¼ 9.2 Hz,
J5,6a ¼ 4.9 Hz, J5,6b ¼ 10.6 Hz, H-5), 3.38 (t, 1H, J2,3 ¼ J3,4 ¼ 9.4 Hz, H-
3), 3.16 (dd, 1H, H-4), 3.06 (dd, 1H, J6a,6b ¼ 11.3 Hz, H-6a), 2.93e2.84
(m, 1H, CH2a pentyl), 2.72e2.61 (m, 1H, CH2b pentyl), 2.34 (s, 3H,
Me), 2.32e2.22 (m, 2H, H-2, H-6b), 1.68e1.53 (m, 4H, 2CH2),
J6a,6b ¼ 12.2 Hz, H-6a), 3.89 (dd, 1H, J5,6b ¼ 2.8 Hz, H-6b), 3.59e3.54
(m, 1H, H-2), 3.45 (t, 1H, J3,4 ¼ J4,5 ¼ 9.5 Hz, H-4), 3.34e3.31 (m, 2H,
CH2), 3.24 (t, 1H, H-3), 3.21e3.17 (m, 1H, H-1a), 3.09e3.02 (m, 1H,
CH2 pentyl), 2.88e2.82 (m, 1H, CH2 pentyl), 2.56e2.49 (m, 2H, H-
1b, H-5), 1.69e1.59 (m, 4H, 2CH2), 1.48e1.37 (m, 2H, CH2); 13C NMR
1.42e1.30 (m, 2H, CH2); 13C NMR (125.7 MHz, CD3OD)
d 138.1
(125.7 MHz, CD3OD)
d
79.5 (C-3), 70.7 (C-4), 69.5 (C-2), 67.5 (C-5),
(AreC), 131.3 (AreC), 130.2 (AreC), 126.5 (AreC), 80.3 (C-4), 71.6 (C-
3), 70.4 (C-5), 67.4 (C-2), 58.9 (C-1), 57.3 (C-6), 53.7 (CH2), 48.8
(CH2), 30.0 (CH2), 25.5 (CH2), 24.8 (CH2), 21.1 (CH3); HRESI-MS: m/z
calcd for C19H32N3O4Se ([MþH]þ): 446.1553, found: 446.1543.
57.7 (C-6), 56.5 (C-1), 53.7 (CH2), 52.3 (CH2), 29.6 (CH2), 25.4 (CH2),
24.5 (CH2); HRESI-MS m/z calcd for C11H23N4O4 ([MþH]þ):
275.1714, found: 275.1708.
Acknowledgements
4.2. General procedure for the synthesis of selenoureas 6aec
ꢀ
ꢀ
We thank the Direccion General de Investigacion of Spain
(CTQ2011-28417-C02-01, CEI10/00018), the Junta de Andalucía
(P11-CVI-7427, FQM134), the European Regional Development
Fund (FEDER), and the EU Research Potential (FP7-REGPOT-2012-
CT2012-31637-IMBRAIN), for financial support. J.I.O. and G.B.P.
also thank the Danish National Research Council (FNU) and the
To a solution of compound 13 (66 mg, 0.23 mmol) in MeOH
(10 mL) was added a catalytic amount of Raney-Ni. The mixture was
then stirred for 1 h under H2 atmosphere. After that it was filtered
through a Celite® pad and concentrated in vacuo to afford amine 14.
To a solution of crude 14 (56 mg, 0.23 mmol) in dry MeOH (10 mL)
was added the corresponding isoselenocyanate 16aec (0.46 mmol),
and the reaction was stirred at rt and in the dark for 24 h. Con-
centration to dryness and purification by column chromatography
using the eluant indicated in each case afforded selenoureas 6aec.
ꢀ
Obra Social La Caixa-Fundacion Caja Canarias, respectively, for the
award of predoctoral grants. We would also like to thank the Ser-
ꢀ
vicio de Resonancia Magnetica Nuclear, CITIUS (University of Sev-
ille) for the performance of NMR experiments.
4.2.1. N-{5-[N0-(p-Bromophenyl)selenoureido]pentyl}-1-
deoxynojirimycin (6a)
Appendix A. Supplementary data
p-Bromophenyl isoselenocyanate 16a (120 mg, 0.46 mmol) was
Supplementary data related to this article can be found at http://
used. Column chromatography (1:3 MeOHꢀEtOAc) furnished 6a:
25
75 mg, 66%. [
a
]
D
ꢀ8 (c 0.51, CH3OH); 1H NMR (500 MHz, CD3OD)
d
7.54 (m, 2H AreH), 7.22 (m, 2H, AreH), 3.89 (m, 2H, H-1a, H-1b),
References
3.70e3.63 (m, 2H, CH2 pentyl), 3.55e3.47 (m, 1H, H-5), 3.42e3.37
(t, 1H, J2,3 ¼ J3,4 ¼ 9.2 Hz, H-3), 3.17 (t, 1H, J4,5 ¼ 9.1 Hz, H-4),
3.11e3.05 (m, 1H, H-6a), 2.97e2.87 (m, 1H, CH2a pentyl), 2.74e2.65
(m, 1H, CH2b pentyl), 2.39e2.23 (m, 2H, H-2, H-6b), 1.72e1.52 (m,
4H, 2CH2), 1.43e1.31 (m, 2H, CH2); 13C NMR (125.7 MHz, CD3OD)
ꢀ
ꢀ
d
180.1 (CSe), 138.5 (AreC), 133.6 (AreC), 128.0 (AreC), 120.4
(AreC), 80.2 (C-4), 71.5 (C-3), 70.3 (C-5), 67.4 (C-2), 58.8 (C-1), 57.3
(C-6), 53.7 (CH2), 48.5 (CH2), 29.9 (CH2), 25.5 (CH2), 24.8 (CH2);
HRESI-MS: m/z calcd for C18H29BrN3O4Se ([MþH]þ): 510.0501,
found: 510.0485.
ꢀ
ꢀ
ꢀ
4.2.2. N-{5-[N0-(p-Methoxyphenyl)-selenoureido]pentyl}-1-
deoxynojirimycin (6b)
p-Methoxyphenyl isoselenocyanate 16b (98 mg, 0.46 mmol)
was used. Column chromatography (1:3 / 3:7 MeOHꢀEtOAc)
26
furnished 6b: 54 mg, 52%. [
(500 MHz, CD3OD)
a]
ꢀ7 (c 0.46, CH3OH); 1H NMR
D
d 7.16e7.13 (m, 2H, AreH), 7.00e6.94 (m, 2H,
AreH), 3.90e3.86 (m, 2H, H-1a, H-1b), 3.81 (s, 3H, OMe) 3.65e3.61
(m, 2H, CH2), 3.50 (ddd, 1H, J4,5 ¼ 9.2 Hz, J5,6a ¼ 4.9 Hz,
J5,6b ¼ 10.6 Hz, H-5), 3.38 (t, 2H, J2,3 ¼ J3,4 ¼ 9.4 Hz, H-3), 3.16 (dd,
1H, H-4), 3.06 (dd, 1H, J6a,6b ¼ 11.3 Hz, H-6a), 2.92e2.83 (m, 1H,
CH2a pentyl), 2.71e2.62 (m, 1H, CH2b pentyl), 2.32e2.22 (m, 2H, H-
2, H-6b), 1.66e1.54 (m, 4H, 2CH2), 1.36e1.27 (m, 2H, CH2); 13C NMR
(125.7 MHz, CD3OD) d 179.2 (CSe), 160.2 (AreC), 131.2 (AreC), 128.5
(AreC), 116.0 (AreC), 80.3 (C-4), 71.7 (C-3), 70.4 (C-5), 67.4 (C-2),
59.0 (C-1), 57.4 (C-6), 56.0 (OMe), 53.7 (CH2), 48.5 (CH2), 30.1 (CH2),
25.5 (CH2), 24.8 (CH2); HRESI-MS: m/z calcd for C19H32N3O5Se
([MþH]þ): 462.1502, found: 462.1489.