D. Dou et al. / Bioorg. Med. Chem. 19 (2011) 5749–5755
5753
the reaction mixture was warmed to 40 °C for 2 h. The solvent was
removed under vacuum and the residue was dissolved in 20 mL
ethyl acetate. The solvent was again removed under vacuum to give
compound 6 as a colorless oil (3.40 g; 100% yield). 1H NMR (CDCl3):
d 3.23–3.32 (m, 2H), 3.40–3.48 (m, 2H), 3.75 (s, 3H), 4.02 (s, 2H),
4.39 (s, 2H), 6.85–7.36 (m, 9H).
was taken up in ethyl acetate (50 mL), and water (40 mL) was
added. The two layers were separated and the organic layer was
washed with water (40 mL) and dried over anhydrous sodium sul-
fate. The drying agent was filtered off and the solvent was removed
to give pure compound 10 as a colorless oil (6.40 g; 100% yield). 1H
NMR (CDCl3): d 1.38 (s, 3H), 1.64 (t, J = 7.5 Hz, 2H), 2.66 (t, J = 7.0 Hz,
2H), 2.74 (t, J = 7.0 Hz, 2H), 3.78 (s, 2H), 6.82–7.35 (m, 9H).
5.2.6. 1-(2-Hydroxyethyl)-3-(3-phenoxybenzyl)imidazolidin-
2-one (7)
5.2.11. 2-(3-Phenoxybenzyl)-1,2,6-thiadiazinane 1,1-dioxide
(11a)
To a solution of compound 6 (1.70 g; 5 mmol) in 8 mL dry THF
was added dropwise a solution of 2 M LiBH4 (2.5 mL; 5 mmol), fol-
lowed by dropwise addition of absolute ethanol (15 mL). The reac-
tion mixture was stirred at room temperature overnight. The
reaction mixture was cooled in an ice bath and acidified with 5%
aqueous HCl to pH 4. The solvent was removed under vacuum
and the residue was taken up in ethyl acetate (85 mL) and washed
with brine (25 mL). The organic layer was dried over anhydrous so-
dium sulfate, filtered, and the solvent was removed under vacuum
to give compound 7 as a colorless oil (1.25 g; 80% yield). 1H NMR
(CDCl3): d 3.20–3.42 (m, 7H), 3.77 (t, J = 5.1 Hz, 2H), 4.35 (s, 2H),
6.85–7.36 (m, 9H).
To a refluxing solution of sulfamide (0.48 g; 5 mmol) in anhy-
drous pyridine (12 mL) was slowly added compound 10 (1.28 g;
5 mmol) over 1 h. The resulting reaction mixture was refluxed for
an additional 16 h. Pyridine was removed under vacuum, and the
residue was taken up in ethyl acetate (20 mL). The organic layer
was washed with 5% HCl (3 ꢁ 10 mL), brine (10 mL) and then dried
over anhydrous sodium sulfate. The drying agent was filtered off
and the solvent was removed, leaving a crude product which was
purified using flash chromatography (silica gel/ethyl acetate/hex-
anes) to give pure compound 11a as a white solid (1.45 g; 91%
yield), mp 94–96 °C. 1H NMR (CDCl3): d 1.60–1.71 (m, 2H), 3.20
(t, J = 5.6 Hz, 2H), 3.49 (q, J = 6.4 Hz, 2H), 4.19 (s, 2H), 4.57 (t,
J = 7.1 Hz, 1H), 6.88–7.38 (m, 9H). HRMS (ESI) calculated m/z for
5.2.7. 2-(2-Oxo-3-(3-phenoxybenzyl)imidazolidin-1-yl)ethyl
methanesulfonate (8)
C
16H19N2O3S [M+H]+ 319.1116; found 319.1129.
To a solution of compound 7 (1.25 g; 4 mmol) and triethylamine
(0.41 g; 4 mmol) in 10 mL dry methylene chloride was added
methanesulfonyl chloride (0.50 g; 4.3 mmol) at 0 °C. The reaction
mixture was allowed to warm to room temperature and stirred
overnight. Methylene chloride (10 mL) was added to the reaction
mixture and the resulting solution was washed with saturated so-
dium bicarbonate (2 ꢁ 20 mL). The organic layer was separated
and dried over anhydrous sodium sulfate. The drying agent was fil-
tered off and the solvent was removed to give compound 8 as a col-
orless oil (1.56 g; 100% yield). 1H NMR (CDCl3): d 3.02 (s, 3H), 3.25
(t, J = 7.6 Hz, 2H), 3.45 (t, J = 7.6 Hz, 2H), 3.58 (t, J = 4.8 Hz, 2H),
4.35–4.40 (m, 4H), 6.88–7.37 (m, 9H).
5.2.12. 1-(3-Phenoxybenzyl)tetrahydropyrimidin-2(1H)-one (11b)
To solution of compound 10 (0.52 g; 2 mmol) in dry 1,4-dioxane
(12 mL) was added a solution of N,N0-carbonyldiimidazole (0.40 g;
2.48 mmol) in 2 mL dry 1,4-dioxane. The reaction mixture was stir-
red at room temperature for 18 h. The solvent was removed and
the residue was taken up in ethyl acetate (20 mL). The organic
layer was washed with 5% HCl (3 ꢁ 10 mL), brine (10 mL) and dried
over anhydrous sodium sulfate. The drying agent was filtered off
and the solvent was removed to give a solid. The crude product
was washed with 20 mL diethyl ether to give pure compound
11b as a white solid (0.32 g; 57% yield), mp 91–93 °C. 1H NMR
(CDCl3): d 1.80–1.92 (m, 2H), 3.19 (t, J = 5.1 Hz, 2H), 3.30 (t,
J = 4.8 Hz, 2H), 4.53 (s, 2H), 6.80–7.40 (m, 9H). HRMS (ESI) calcu-
lated m/z for C17H19N2O2 [M+H]+ 283.1447; found 283.1429.
5.2.8. 1-(2-Morpholinoethyl)-3-(3-phenoxybenzyl)imidazolidin-
2-one (9a)
A mixture of compound 8 (0.86 g; 2.2 mmol), morpholine
(0.19 g; 2.2 mmol) and NaHCO3 (1.0 g; 12 mmol) in 10 mL 95% eth-
anol was refluxed overnight. The solvent was removed and the res-
idue was taken up in ethyl acetate (30 mL) and water (30 mL). The
organic layer was separated, washed with 30 mL brine and then
dried over anhydrous sodium sulfate. The drying agent was filtered
off and the solvent was removed to give pure compound 9a as a
white solid (0.65 g; 78% yield), mp 66–68 °C. 1H NMR (CDCl3): d
2.43–2.54 (m, 6H), 3.17–3.23 (m, 2H), 3.32–3.41 (m, 4H), 3.70 (t,
J = 4.9 Hz, 4H), 4.36 (s, 2H), 6.86–7.37 (m, 9H). HRMS (ESI) calcu-
lated m/z C22H28N3O3 [M+H]+ 382.2131; found 382.2151.
5.2.13. 1-(Azidomethyl)-3-phenoxybenzene (13)
A solution of m-(phenoxy)toluene (3.68 g; 20 mmol) in 45 mL
CCl4 was treated with N-bromosuccinimide (5.34 g; 30 mmol)
and azo-bis(isobutyronitrile) (15 mg) and the reaction mixture
was refluxed for 3 h. The solution was allowed to cool to room tem-
perature and then placed in an ice bath. A white precipitate formed
which was filtered off and the filtrate was evaporated, leaving pure
compound 1 as a yellow oil (4.5 g; 86% yield). 1H NMR (CDCl3): d
4.4 (s, 2H), 6.9–7.41 (m, 9H). This was used in the next step. To so-
dium azide (3.25 g; 50 mmol) in dry DMSO (80 mL) was added
compound 12 (4.5 g; 17.1 mmol) and the reaction mixture was
stirred overnight at room temperature. The reaction mixture was
cooled in an ice bath and quenched with water (50 mL). The aque-
ous layer was extracted with ethyl ether (3 ꢁ 30 mL). The com-
bined ethyl ether extracts were washed with water (2 ꢁ 20 mL)
and dried over anhydrous sodium sulfate. The solvent was re-
moved, leaving a crude product which was purified using flash
chromatography (silica gel/methylene chloride/hexanes) to give
compound 13 as a colorless oil (3.31 g; 60% yield). 1H NMR (CDCl3):
d 4.25 (s, 2H), 6.07–7.45 (m, 9H).
5.2.9. 3,30-(2,20-(Piperazine-1,4-diyl)bis(ethane-2,1-diyl))bis(1-
(3-phenoxybenzyl)imidazo-lidin-2-one) (9b)
Compound 9b was prepared using a similar procedure as that
used for making compound 9a using piperazine. Colorless oil (55%
yield). 1H NMR (CDCl3): d 2.40–2.60 (m, 12H), 3.12–3.21 (m, 4H),
3.28–3.43 (m, 8H), 4.34 (s, 4H), 6.82–7.37 (m, 18H). HRMS (ESI) cal-
culated m/z C40H47N6O4 [M+H]+ 675.3659; found 675.3645.
5.2.10. N1-(3-Phenoxybenzyl)propane-1,3-diamine (10)
To a solution of 1,3-diaminopropane (7.4 g; 100 mmol) in 65 mL
methanol kept in an ice bath was added 3-(phenoxy)benzaldehyde
(4.95 g; 25 mmol) in small portions. After the addition, sodium
borohydride (0.94 g; 25 mmol) was added slowly in small portions
at 0 °C. The reaction was allowed to warm to room temperature
overnight with stirring. The solvent was removed and the residue
5.2.14. 2-(1-(3-Phenoxybenzyl)-1H-1,2,3-triazol-4-yl)propan-2-
ol (14a)
To compound 13 (2.02 g; 9 mmol) was added 2-methyl-3-bu-
tyn-2-ol (0.76 g; 9 mmol), t-butyl alcohol (20 mL), water (20 mL),
sodium ascorbate (0.3 g; 1.5 mmol), and CuSO4ꢂ5H2O (60 mg).