2164
T. Utech et al. / European Journal of Medicinal Chemistry 46 (2011) 2157e2169
CH2eCH3), 1.22 (dq, J ¼ 12.8/2.4 Hz, 1H, 5-Heq), 1.66 (q, J ¼ 7.6 Hz,
2H, CH2eCH3), 1.59e1.73 (m, 1H, 5-Hax), 1.79e1.86 (m, 2H,
CH2eCH2eOtos), 2.45 (s, 3H, PheCH3), 3.78 (td, J ¼ 12.5/2.4 Hz, 1H,
6-Hax), 3.81 (ddd, J ¼ 12.5/5.4/1.8 Hz, 1H, 6-Heq), 3.76e3.87 (m, 1H,
4-Hax), 4.19 (dt, J ¼ 9.7/5.1 Hz, 1H, CH2eCH2eOtos), 4.38 (ddd,
J ¼ 9.7/7.6/6.3 Hz, 1H, CH2eCH2eOtos), 7.26e7.41 (m, 7H, Harom, 3-
HPhCH3 and 5-HPhCH3), 7.81 (d, J ¼ 8.2 Hz, 2H, 2-HPhCH3 and 6-
5.1.17. 2-(2,2-Diphenyl-1,3-dioxan-4-yl)-N-methylethan-1-amine
(22b)
Tosylate 18 (100 mg, 0.23 mmol) was dissolved in an ethanolic
solution of methylamine (8 M, 5 mL, 40 mmol) and the mixture was
heated to reflux for 12 h. After cooling down it was concentrated in
vacuo. The pale yellow residue was dissolved in CH2Cl2 (10 mL), the
mixture was washed with
a saturated solution of NaHCO3
HPhCH3). 1H NMR (C6D6):
d
(ppm) ¼ 0.52 (dq, J ¼ 12.2/2.1 Hz, 1H, 5-
(2 ꢃ10 mL), dried (MgSO4), filtered and concentrated in vacuo. The
residue was purified by fc (2 cm, 15 cm, CH2Cl2:MeOH ¼ 8:1, 2 mL,
Rf ¼ 0.16). Pale yellow oil, yield 28 mg (41%). C19H23NO2 (297.4).
HRMS: calcd. for C19H23NO2 297.1729; found 297.1728. MS (EI): m/z
Heq), 0.90 (t, J ¼ 7.3 Hz, 3H, CH2eCH3), 1.31 (qd, J ¼ 12.5/5.2 Hz, 1H,
5-Hax), 1.38e1.47 (m, 2H, CH2eCH2eOtos), 1.81 (s, 3H, PheCH3),
1.86 (q, J ¼ 7.3 Hz, 2H, CH2eCH3), 3.43 (td, J ¼ 11.5/2.7 Hz, 1H, 6-
Hax), 3.50e3.63 (m, 2H, 4-Hax and 6-Heq), 3.98 (dt, J ¼ 10.1/5.2 Hz,
1H, CH2eCH2eOtos), 4.34 (ddd, J ¼ 10.1/7.6/5.5 Hz, 1H,
CH2eCH2eOtos), 6.69 (d, J ¼ 7.9 Hz, 2H, 3-HPhCH3 and 5-HPhCH3),
7,13e7.18 (m, 1H, Harom), 7.31 (t, J ¼ 7.6 Hz, 2H, Harom), 7.44 (d,
J ¼ 7.1 Hz, 2H, Harom), 7.78 (d, J ¼ 8.2 Hz, 2H, 2-HPhCH3 and 6-HPhCH3).
(%) ¼ 297 [M, 1], 220 [MePh, 5], 115 [O(CH2)2CH(CH2)2NHCH3, 100],
~
105 [PhCO, 56]. IR (ATR, film):
n
(cmꢁ1) ¼ 3328 (NeH); 2953, 2875
(CeH), 2732 (NHCH3), 1098, 1020 (CeO), 768, 749 (ArCeH). 1H NMR
(CDCl3):
d
(ppm) ¼ 1.40 (dq, J ¼ 12.8/2.4 Hz, 1H, 5-Heq), 1.92 (dddd,
J ¼ 12.8/11.9/11.2/5.7 Hz, 1H, 5-Hax), 2.01e2.12 (m, 2H,
CH2eCH2eNHCH3), 2.63 (s, 3H, NHCH3), 3.04 (ddd, J ¼ 11.9/6.4/
5.5 Hz, 1H, CH2eCH2eNHCH3), 3.20 (ddd, J ¼ 11.9/6.1/5.5 Hz, 1H,
CH2eCH2eNHCH3), 3.99 (td, J ¼ 11.5/2.4 Hz, 1H, 6-Hax), 4.02e4.09
(m, 2H, 4-Hax and 6-Heq), 7.19e7.31 (m, 4H, Harom), 7.37e7.48 (m,
6H, Harom). A signal for the NH-proton is not seen in the spectrum.
As described for the preparation of 13d.HCl the hydrochloride 22b.
HCl was prepared from 22b (20 mg, 0.07 mmol). Colorless solid, mp
164 ꢀC, yield 10 mg (42%).
5.1.14. 4-(2-Azidoethyl)-2,2-diphenyl-1,3-dioxane (20)
A mixture of tosylate 18 (80 mg, 0.18 mmol) and NaN3 (113 mg,
1.8 mmol) in DMF (5 mL) was heated to reflux for 2 h. After cooling
downDMFwasevaporatedinvacuoandtheresiduewaspurifiedbyfc
(2 cm,15 cm, petroleum ether:EtOAc ¼ 7:3, 5 mL, Rf ¼ 0.60). Colorless
oil, yield 38 mg (69%). C18H19N3O2 (309.4). Anal. calcd. C 69.88, H 6.19,
N 13.60; found C 69.40, H 6.14, N 13.94. MS (EI): m/z (%) ¼ 309 [M,12],
~
232 [MePh, 100], 182 [(Ph)2CO, 31]. IR (ATR, film):
n
(cmꢁ1) ¼ 2951,
2875 (CeH), 2091 (N3), 1097, 1023 (CeO), 762, 746 (ArCeH). 1H NMR
5.1.18. 2-(2,2-Diphenyl-1,3-dioxan-4-yl)-N,N-dimethylethan-1-
amine (22c)
(CDCl3):
d
(ppm) ¼ 1.42 (dq, J ¼ 12.8/2.4 Hz, 1H, 5-Heq), 1.78 (dddd,
J ¼ 12.8/11.9/10.1/3.4 Hz,1H, 5-Hax),1.83e2.02(m, 2H, CH2eCH2eN3),
3.63 (t, J ¼ 7.2 Hz, 2H, eCH2eCH2eN3), 4.03 (td, J ¼ 11.3/2.4 Hz,1H, 6-
Hax), 4.05e4.13 (m, 2H, 4-Hax and 6-Heq), 7.17e7.32 (m, 4H, Harom),
7.38e7.62 (m, 4H, Harom), 7.80e7.83 (m, 2H, Harom).
Tosylate 18 (100 mg, 0.23 mmol) was dissolved in an ethanolic
solution of dimethylamine (5.6 M, 7 mL, 39.2 mmol) and the
mixture was heated to reflux for 4 h. After cooling down dime-
thylamine and ethanol were evaporated in vacuo. The yellow
residue was dissolved in CH2Cl2 (10 mL) and the mixture was
extracted with a saturated solution of NaHCO3 (2 ꢃ 10 mL). The
organic layer was dried over MgSO4, filtered and evaporated in
vacuo. The crude product was purified by fc (3 cm, 15 cm,
CH2Cl2:MeOH ¼ 8:1, 2 mL, Rf ¼ 0.21). Pale yellow oil, yield 57 mg
(80%). C20H25NO2 (311.4). HRMS: calcd. for C20H25NO2 311.1893;
found 311.1893. MS (EI): m/z (%) ¼ 311 [M, 1], 234 [MePh, 2], 176
5.1.15. trans-4-(2-Azidoethyl)-2-ethyl-2-phenyl-1,3-dioxane (21)
A mixture of tosylate 19 (43 mg, 0.26 mmol) and NaN3 (113 mg,
1.8 mmol) in DMF (5 mL) was heated to reflux for 2 h. After cooling
down DMF was evaporated in vacuo. The residue was purified by fc
(2 cm, 15 cm, petroleum ether:EtOAc ¼ 9:1, 5 mL, Rf ¼ 0.41). Color-
less oil, yield 45 mg (65%). C14H19N3O2 (261.3). HRMS (CI): calcd. for
C12H14N3O2 232.1084; found 232.1086. Anal. calcd. C 64.35, H 7.33,
N 16.08; found C 64.23, H 7.56, N 15.82. MS (CI): m/z (%) ¼ 262
[MePheCH2e N(CH3)2, 2],105 [PhCO, 31], 58 [eCH2eN(CH3)2, 100].
~
IR (ATR, film):
n
(cmꢁ1) ¼ 2947, 2869 (CeH), 2815, 2763 (N(CH3)2),
[MHþ, 100], 232 [MeC2H5, 40], 184 [MePh, 6], 105 [PhCO, 1]. IR
1097, 1025 (CeO), 760, 745 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼
~
(ATR, film):
n
(cmꢁ1) ¼ 2973, 2876 (CeH), 2093 (N3), 1090, 1025
1.41 (dq, J ¼ 12.8/2.4 Hz, 1H, 5-Heq), 1.75 (dtd, J ¼ 12.8/11.9/2.4 Hz,
1H, 5-Hax), 1.82e1.98 (m, 2H, CH2eCH2eN(CH3)2), 2.34 (s, 6H, N
(CH3)2), 2.58 (ddd, J ¼ 11.9/9.1/6.1 Hz, 1H, CH2eCH2eN(CH3)2), 2.68
(ddd, J ¼ 11.9/9.4/5.5 Hz, 1H, CH2eCH2eN(CH3)2), 3.99 (td, J ¼ 11.3/
2.4 Hz, 1H, 6-Hax), 4.03e4.16 (m, 2H, 4-Hax and 6-Heq), 7.15e7.30
(m, 4H, Harom), 7.35e7.41 (m, 2H, Harom), 7.49e7.54 (m, 4H, Harom).
As described for the preparation of 13d.HCl the hydrochloride 22c.
HCl was prepared from 22c (57 mg, 0.20 mmol). Colorless solid, mp
94 ꢀC, yield 46 mg (65%).
(CeO), 756, 745 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 0.78 (t,
J ¼ 7.4 Hz, 3H, CH2eCH3), 1.26 (dq, J ¼ 12.8/2.4 Hz, 1H, 5-Heq),
1.67e1.86 (m, 3H, 5-Hax and CH2eCH2eN3), 1.72 (q, J ¼ 7.4 Hz, 2H,
CH2eCH3), 3.50e3.53 (m, 2H, CH2eCH2eN3), 3.77 (td, J ¼ 11.6/
2.7 Hz, 1H, 6-Hax), 3.75e3.82 (m, 1H, 4-Hax), 3.85 (ddd, J ¼ 11.6/5.5/
1.8 Hz, 1H, 6-Heq), 7.24e7.41 (m, 5H, Harom).
5.1.16. 2-(2,2-Diphenyl-1,3-dioxan-4-yl)ethan-1-amine (22a)
A mixture of azide 20 (85 mg, 0.2 mmol) and Pd/C (51 mg, 5%) in
EtOAc (3 mL) was stirred under a H2 atmosphere (balloon) for 12 h
at rt. The mixture was filtered over CeliteÒ and the filtrate was
concentrated in vacuo. Pale yellow oil, yield 52 mg (82%).
C18H21NO2 (283.4). HRMS: calcd. for C18H21NO2 283.1578; found
283.1572. MS (EI): m/z (%) ¼ 283 [M, 5], 239 [MeCH2CH2NH2, 4],
5.1.19. N-Benzyl-2-(2,2-diphenyl-1,3-dioxan-4-yl)ethan-1-amine
(22d)
A mixture of tosylate 18 (200 mg, 0.45 mmol) and freshly
distilled benzylamine (0.10 mL, 0.9 mmol) in toluene (5 mL) was
heated to reflux for 5 h. After cooling down excess of benzylamine
and toluene was evaporated in vacuo. The yellow residue was dis-
solved in CH2Cl2 (10 mL) and the mixture was extracted with
a saturated solution of NaHCO3 (2 ꢃ 10 mL). The organic layer was
dried over MgSO4, filtered and concentrated in vacuo. The residue
was purified by fc (2 cm, 15 cm, EtOAc, 5 mL, Rf ¼ 0.22). Pale yellow
oil, yield 110 mg (65%). C25H27NO2 (373.5). Anal. calcd. C 80.39, H
7.29, N 3.75; found C 79.90, H 7.08, N 3.56. MS (EI): m/z (%) ¼ 373 [M,
þ
~
206 [M ePh, 36], 105 [PhCO, 100]. IR (ATR, film):
n
(cmꢁ1) ¼ 3420
(NeH); 2928, 2855 (CeH); 1728 (NeH); 1096, 1024 (CeO); 749, 712
(ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 1.39 (dq, J ¼ 12.8/2.1 Hz,1H, 5-
Heq), 1.66 (dddd, J ¼ 12.7/11.2/10.3/3.6 Hz, 1H, 5-Hax), 1.73 (s broad,
2H, eNH2), 1.82e1.98 (m, 2H, CH2eCH2eNH2), 2.98 (dt, J ¼ 12.5/
7.3 Hz, 1H, CH2eCH2eNH2), 3.05 (ddd, J ¼ 12.5/7.9/6.1 Hz, 1H,
CH2eCH2eNH2), 3.95e4.09 (m, 2H, 4-Hax and 6-Heq), 4.02 (td,
J ¼ 11.3/2.1 Hz, 1H, 6-Hax), 7.18e7.30 (m, 4H, Harom), 7.36e7.41 (m,
2H, Harom), 7.49e7.54 (m, 4H, Harom).
5], 296 [MePh, 9], 191 [Oe(CH2)2eCHe(CH2)2eNHeBn, 90] 105
~
[PhCO, 75], 91 [tropylium, 100]. IR (ATR, film):
n
(cmꢁ1) ¼ 3325