384
M. Pieroni et al. / European Journal of Medicinal Chemistry 92 (2015) 377e386
Yield: 99%.
1H NMR (300 MHz-CDCl3) ẟ ¼ 1.38e1.43 (m, 1H), 1.73 (s, 1H),
2.13e2.17 (m, 1H), 2.45 (t, J ¼ 8.38 Hz, 1H), 3.19e3.51 (m, 4H), 5.87
(s, 1H), 7.17e7.28 (m, 5H).
1H NMR (400 MHz-CDCl3) ẟ ¼ 0.56 (t, J ¼ 5.6 Hz, 3H), 1.90 (s,
1H), 2.19 (d, J ¼ 4.08 Hz, 1H), 3.19 (s, 1H), 3.61 (t, J ¼ 6.6 Hz, 2H),
7.09e7.27 (m, 5H), 12.03 (s, 1H).
4.3.12. Tert-butyl (1-(hydroxymethyl)-2-phenylcyclopropyl)
carbamate (64)
4.3.9. 1-((tert-Butoxycarbonyl)amino)-2-
phenylcyclopropanecarboxylate (61)
A suspension of lithium aluminium hydride (745 mg; 20 mmol)
in dry THF (30 mL) was cooled to 0 ꢀC and ethyl 1-((tert-butox-
ycarbonyl)amino)-2-phenylcyclopropanecarboxylate 61 (1.5 g;
4.9 mmol) solubilized in dry THF (10 mL) was added under nitrogen
atmosphere. The reaction mixture was stirred at room temperature
until TLC showed the consumption of the limiting reagent, and then
a solution of NaOH 1 N (5 mL) was added and the organic phase
extracted with ethyl acetate (3 ꢃ 30 mL). The combined organic
layers were washed with brine, dried (Na2SO4) and concentrated
under reduced pressure to give a yellowish oil that is purified by
chromatography column eluting petroleum ethereethyl acetate
9:1, yielding the title compound as a yellowish oil.
Under nitrogen atmosphere, to a solution of 60 (3.064 g;
13 mmol) in anhydrous hexane (100 mL), diphenylphosphoryl
azide (3.12 mL; 14 mmol), triethylamine (2 mL; 15 mmol) and tert-
butanol (25 mL; 260 mmol) were added in this order and the
mixture was allowed to react at reflux. After 18 h, a solution of
Boc2O (4.28 g; 19 mmol) in dry hexane (5 mL) was added, and the
mixture was heated to reflux for additional 2 h. After cooling, the
solvent was evaporated under reduced pressure, and the residue
was taken up in ethyl acetate and washed with 5% citric acid
(3 ꢃ 15 mL), water (3 ꢃ 10 mL), and saturated NaHCO3 aqueous
solution (3 ꢃ 10 mL). The combined organic layers were washed
with brine, dried (Na2SO4) and concentrated under reduced pres-
sure to give a yellowish material that is purified by chromatography
column eluting petroleum ethereethyl acetate 9:1, yielding the
title compound as a white solid.
Yield: 89%.
1H NMR (300 MHz-CDCl3) ẟ ¼ 1.49 (s, 9H), 1.95 (q, J ¼ 5.36 Hz,
1H), 2.50 (t, J ¼ 7.35 Hz, 1H), 3.32 (d, J ¼ 11.82 Hz, 1H), 3.45 (d,
J ¼ 11.91 Hz, 1H), 3.66e3.84 (m, 2H) 5.38 (s, 1H), 7.22e7.35 (m, 5H).
Yield: 77%.
1H NMR (400 MHz-CDCl3) ẟ ¼ 0.85 (s, 3H), 1.51 (s, 9H),
1.61e1.66 (m, 1H), 2.17 (m, 1H), 2.83 (t, J ¼ 3.12 Hz, 1H), 3.81 (t,
J ¼ 3.8 Hz, 2H), 5.38 (s, 1H), 7.19e7.27 (m, 5H).
4.3.13. 2-Bromo-N-(1-(hydroxymethyl)-2-phenylcyclopropyl)
acetamide (65)
Trifluoroacetic acid (2 mL) was added dropwise at 0 ꢀC to a
solution
of
ethyl
1-((tert-butoxycarbonyl)amino)-2-
4.3.10. Ethyl1-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-
phenylcyclopropanecarboxylate (62)
phenylcyclopropanecarboxylate 64 (1.027 g; 3.9 mmol) in
dichloromethane (8 mL). After stirring at room temperature for 1 h,
a solution of NaOH 1 N (3 mL) was added to the reaction mixture,
and the organic layers were separated, washed with brine, dried
over Na2SO4 and evaporated under reduced pressure. To a solution
To a solution of ethyl 61 (1.5 g; 4.91 mmol) in dichloromethane
(12 mL), trifluoroacetic acid (3 mL) was added dropwise at 0 ꢀC. The
solution, turned dark red, was stirred at room temperature for
1 h and then a solution of NaOH 1 M (10 mL) was added, and the
organic layers separated, washed with brine, dried over Na2SO4 and
evaporated under reduced pressure. The colourless product ob-
tained after treatment was solubilized in dichloromethane (5 mL)
of the residue and triethylamine (940
dichloromethane (25 mL) at 0 ꢀC, a solution of bromoacetylchloride
(509 l; 6.12 mmol) in dichloromethane (10 mL) was added drop-
mL; 6.07 mmol) in anhydrous
m
wise. The reaction mixture was stirred until consumption of the
limiting reagent, as determined by TLC. The reaction mixture was
then treated with HCl 1 N (3 mL), and the organic layers separated,
washed with brine, dried over Na2SO4 and evaporated under
reduced pressure, to give a crude material that is purified through
flash chromatography eluting dichloromethaneemethanol 97:3,
yielding 65 as a pale yellow oil. Yield: 34%. 1H NMR (400 MHz-
CDCl3) ẟ ¼ 1.35e1.49 (m, 2H), 1.99 (s, 2H), 2.75 (q, J ¼ 7.52 Hz, 1H),
3.41e3.52 (m, 1H), 4.11 (s, 2H), 7.18 (s, 1H), 7.25e7.34 (m, 5H).
and added dropwise to
a
solution of the N-Boc-2-
aminoacetaldehyde (272 mg; 1.71 mmol) in dichloromethane
(5 mL) at room temperature. After 15 min, sodium triacetoxybor-
ohydride (906 mg; 4.26 mmol) was added in one portion and the
reaction mixture was stirred at room temperature until the TLC
showed the complete consumption of the amine. The solvent was
evaporated under reduced pressure and the residue was taken up
in ethyl acetate and washed with water (3 ꢃ 10 mL), brine and dried
over Na2SO4. After evaporation of the solvent, the crude material
was purified through a chromatography column eluting petroleum
ethereethyl acetate 6:4 to yield the title compound as a pale yellow
oil.
4.3.14. 1-Phenyl-7-oxa-4-azaspiro[2.5]octan-5-one (66)
under nitrogen atmosphere, to a suspension of NaH (904 mg;
1.15 mmol) in dry THF (25 mL) at 0 ꢀC, 2-bromo-N-(1-(hydrox-
ymethyl)-2-phenylcyclopropyl)acetamide 65 (311 mg; 1.15 mmol),
solubilized in dry THF (5 mL), was added dropwise. The mixture
was stirred at the same temperature for 2 h and then poured into
ice water, and extracted with ethyl acetate (3 ꢃ 10 mL). The com-
bined organic layers were washed with brine, dried (Na2SO4) and
concentrated under reduced pressure to give a yellowish oil that is
purified by chromatography column eluting petroleum ethereethyl
acetate 8:2, yielding compound 66 as a pale yellow oil. Yield: 98%.
1H NMR (300 MHz-CDCl3) ẟ ¼ 1.38e1.43 (m, 1H), 2.13e2.17 (m,
1H), 2.45 (t, J ¼ 8.38 Hz, 1H), 3.19e3.51 (m, 4H), 5.87 (s, 1H),
7.17e7.28 (m, 5H).
Yield: 42%.
1H NMR (400 MHz-CDCl3) ẟ ¼ 0.75 (t, J ¼ 7. 08 Hz, 3H),
1.43e1.45 (m, 11H), 1.95 (q, J ¼ 5.36 Hz, 1H), 2.64 (t, J ¼ 8.52 Hz, 1H),
2.81e2.92 (m, 2H), 3.16e3.25 (m, 2H), 3.69e3.78 (m, 2H), 5.08 (s,
1H), 7.18e7.28 (m, 5H).
4.3.11. 1-Phenyl-4,7-diazaspiro[2.5]octan-8-one (63)
To a solution of compound 62 (240 mg; 0.68 mmol) in
dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL) was added
dropwise at 0 ꢀC and the mixture was allowed to stir at room
temperature for 1 h. A solution of KOH 10% (10 mL) was added
dropwise to the reaction flask in an ice bath, and the stirring is
continued for additional 2 h. The precipitated obtained is collected,
and purified through flash chromatography column eluting
dichloromethaneemethanol 95:5 to yield the title compound as
light pink solid.
4.3.15. (E)-3-(4-Chlorophenyl)-2-phenyl-prop-2-enoic acid (67)
A solution of 4-Cl-benzaldehyde (2.0 g, 14.23 mmol), phenyl-
acetic acid (1.9 g, 14.23 mmol) and triethylamine (2.0 mL,
14.23 mmol) in acetic anhydride (10 mL) was stirred at 90 ꢀC. After
6 h of heating the reaction was cooled to 25 ꢀC. Diethyl ether
Yield: 54%.