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A. Leite et al. / Tetrahedron 67 (2011) 4009e4016
4.2. Synthesis
resulting reaction mixturewasallowed to stiratroom temperature for
4 days. Upon filtration and removal of the solvent under reduced
pressure, the residue was purified by column chromatography using
a mixture of chloroform/methanol (6:4) as eluent to afford 1.87 g (65%
yield) of 2as awhite solid. (b) Using microwave irradiation: Amixtureof
3-benzyloxy-1-(30-carboxypropyl)-2-methyl-4-pyridinone (0.184 g,
0.64mmol, 2.3 equiv), DCC (0.138 g, 0.67mmol, 2.4 equiv), HOBt
(90.0mg, 0.67mmol, 2.4 equiv), 1,4-bis(3-aminopropyl)piperazine
(0.06mL, 0.28mmol)anddryDMF (20mL) was prepared and placed in
the cavity of a CEM microwave reactor using open vessel conditions.
The reaction vial was irradiated at 50 ꢀC (1 min ramp to 50 ꢀC and
30 min hold at 50 ꢀC, using 100 W maximum power). The reaction
mixturewas thenpurifiedbycolumnchromatographyusingamixture
of chloroform/methanol (6:4)as eluent to give 2(0.113 g, 55% yield).1H
3-Benzyloxy-2-methyl-4-pyrone and 3-benzyloxy-1-(30-car-
boxypropyl)-2-methyl-4-pyridinone was prepared as described in
the literature.14
4.3. Synthesis of 1,4-bis[(3-benzyloxy-2-methyl-4-
pyridinone)propyl]piperazine (1)
(a) Using standard conditions: To a mixture of 1,4-bis(3-amino-
propyl)piperazine (5.30 mL, 2.57 mmol), 3-benzyloxy-2-methyl-4-
pyrone (1.17 g, 5.41 mmol, 2.1 equiv), ethanol (100 mL) and water
(100 mL) was added dropwise a concentrated solution of NaOH
until pH 13. The resulting mixture was refluxed during 24 h. After
that time, the reaction mixture was concentrated in the rotative
evaporator until remove 100 mL of solvent. Subsequently,100 mL of
water was added and the pH was adjusted to 2 using HCl. The
aqueous layer was extracted three times with ethyl ether and the
organic layer was rejected. The pH of the aqueous layer was ad-
justed to 10 using a 20% solution of NaOH and it was extracted two
times with dichloromethane. The organic layer was dried over
anhydrous Na2SO4 and the solvent evaporated in vacuo to give
1.07 g (70% yield) of 1 as a white pallid solid. (b) Using microwave
NMR (400.15 MHz, DMSO-d6)
d
: 1.46 (4H, quintet, J 6.9 Hz, 2ꢃCH2),
2.15e2.35 (12H, m, 6ꢃCH2), 2.21 (6H, s, 2ꢃCH3), 2.46 (4H, t, J 6.8 Hz,
CH2), 2.98e3.05 (4H, m, CH2), 4.09 (4H, t, J 6.8 Hz, 2ꢃCH2), 5.00 (4H, s,
2ꢃCH2C6H5), 6.11 (2H, d, J 7.6 Hz, 2ꢃ5-H), 7.31e7.43 (10H, m,
2ꢃCH2C6H5), 7.51 (2H, d, J 7.6 Hz, 2ꢃ6-H), 7.96 (2H, t, J 5.4 Hz, 2ꢃNH)
ppm.
4.6. Synthesis of 1,4-bis[(N-propanamide-3-hydroxy-2-
irradiation: To
a mixture of 1,4-bis(3-aminopropyl)piperazine
methyl-4-pyridinone)propyl]piperazine (T2)
(2.65 mL, 1.29 mmol), 3-benzyloxy-2-methyl-4-pyrone (0.585 g,
2.71 mmol, 2.1 equiv), ethanol (50 mL) and water (50 mL) was
added dropwise a concentrated solution of NaOH until pH 13. The
resulting mixture was placed in the cavity of a CEM microwave
reactor using open vessel conditions. The reaction vial was irradi-
ated at 50 ꢀC (1 min ramp to 50 ꢀC and 30 min hold at 50 ꢀC, using
100 W maximum power). The reaction work-up was similar to the
described before affording 0.2517 g of compound 1 (33% yield). 1H
A 1 M solution of boron trichloride in dichloromethane (6 mL)
was droppedslowly into an ice-bath-cooled suspensionof solution of
2 (0.73 g, 1.00 mmol) in dry dichloromethane (50 mL), under argon
atmosphere. The mixturewas stirred at room temperature overnight.
Methanol (25 mL) was added to quench the reaction. After removalof
the solvent, the residue was precipitated with methanol/acetone to
afford the hydrochloride salt of T2 (0.55 g, 78% yield) as a white solid.
C, 45.97; N, 11.05; H, 6.78. C28H42N6O6$4HCl$2H2O requires C, 45.41;
NMR (400.15 MHz, DMSO-d6)
d: 1.71e1.75 (4H, m, 2ꢃCH2), 2.18 (6H,
N, 11.35; H 6.81%. 1H NMR (400.15 MHz, D2O)
d: 1.84e1.90 (4H, m,
s, 2ꢃCH3), 2.20e2.35 (8H, m, 4ꢃCH2-piperazine), 3.87 (4H, t, J
6.8 Hz, 2ꢃCH2), 5.02 (4H, s, 2ꢃCH2C6H5), 6.13 (2H, d, J 7.5 Hz, 2ꢃ5-
H), 7.29e7.40 (10H, m, 2ꢃCH2C6H5), 7.58 (2H, d, J 7.5 Hz, 2ꢃ6-H)
ppm.
2ꢃCH2), 2.54 (6H, s, 2ꢃCH3), 2.79 (4H, t, J 6.8 Hz, 2ꢃCH2), 3.15e3.22
(8H, m, 4ꢃCH2), 3.55e3.65 (8H, m, 4ꢃCH2-piperazine), 4.56 (4H, t, J
6.8 Hz, 2ꢃCH2), 7.04 (2H, d, J 7.2 Hz, 2ꢃ5-H), 7.97 (2H, d, J 7.2 Hz, 2ꢃ6-
H) ppm. 13C NMR (100.63 MHz, D2O)
d: 12.3 (CH3), 23.4 (CH2), 35.5
4.4. Synthesis of 1,4-bis[(3-hydroxy-2-methyl-4-pyridinone)
propyl]piperazine (T1)
(CH2), 36.1 (CH2), 48.7 (CH2-piperazine), 52.4 (CH2), 54.5 (CH2), 111.0
(C-5), 138.7 (C-6), 142.3 (C-2), 142.7 (C-3), 159.1 (C-4), 171.8 (C]O)
ppm. MS (FAB) m/z: 559 [(MþH)ꢁ4HCl]þ.
A 1 M solution of boron trichloride in dichloromethane (16 mL)
was dropped slowly into an ice-bath-cooled suspension of 1 (1.60 g,
2.68 mmol) in dry dichloromethane (100 mL), under argon atmo-
sphere. The mixture was stirred at room temperature overnight.
Methanol (50 mL) was added to quench the reaction. After removal
of the solvent in vacuo, the residue was precipitated with methanol/
acetone to afford the hydrochloride salt of T1 (1.13 g, 75% yield) as
a white solid. C, 40.75; N, 8.54; H, 7.12. C22H32N4O4$4HCl$5H2O re-
4.7. Synthesis of 1,2-bis(N-propanamide-3-benzyloxy-2-
methyl-4-pyridinone)benzene 3
(a) Using standard conditions: A mixture of 3-benzyloxy-1-(30-
carboxypropyl)-2-methyl-4-pyridinone
(0.92 g,
3.19 mmol,
2.3 equiv), DCC (0.69 g, 3.33 mmol, 2.4 equiv), HOBt (0.45 g,
3.33 mmol, 2.4 equiv) and dry DMF (20 mL) was stirred at room
temperature, under argon atmosphere, for 30 min. After that time,
1,2-diaminobenzene (0.15 g, 1.39 mmol) was added and the
resulting reaction mixture was allowed to stir at room temperature
for 3 days. Upon filtration and removal of the solvent under reduced
pressure, the residue was purified by flash chromatography using
a mixture of chloroform/methanol/ethyl acetate (17:2:1) as eluent
to afford 3 (0.31 g, 34% yield) as a white solid. (b) Using microwave
quires C, 40.50; N, 8.59; H, 7.11%. 1H NMR (400.15 MHz, D2O)
d:
2.18e2.22 (4H, m, 2ꢃCH2), 2.47 (6H, s, 2ꢃCH3), 3.21e3.26 (4H, m,
2ꢃCH2), 3.47e3.56 (8H, m, 4ꢃCH2-piperazine), 4.31 (4H, t, J 7.6 Hz,
2ꢃCH2), 6.70(2H, d, J 6.8 Hz, 2ꢃ5-H), 7.93 (2H, d, J 6.8 Hz, 2ꢃ6-H).13
C
NMR (100.63 MHz, D2O) d: 12.3 (CH3), 24.4 (CH2), 49.1 (CH2-piper-
azine), 53.0 (CH2), 53.2 (CH2),111.3 (C-5),138.5 (C-6),142.3 and 142.9
(C-2 and C-3), 159.1 (C-4). MS (FAB) m/z: 417 [(MþH)ꢁ4HCl]þ.
4.5. Synthesis of 1,4-bis[(N-propanamide-3-benzyloxy-2-
irradiation: A
mixture of 3-benzyloxy-1-(30-carboxypropyl)-2-
methyl-4-pyridinone)propyl]piperazine (2)
methyl-4-pyridinone (0.184 g, 0.64 mmol, 2.3 equiv), DCC (0.138 g,
0.67 mmol, 2.4 equiv), HOBt (90.0 mg, 0.67 mmol, 2.4 equiv), 1,2-
diaminobenzene (30.0 mg, 0.28 mmol) and dry DMA (4 mL) was
placed in a 10 mL reaction vial, which was then closed under argon
atmosphere and placed in the cavity of a CEM microwave reactor.
The reaction vial was irradiated at 50 ꢀC (1 min ramp to 50 ꢀC and
30 min hold at 50 ꢀC, using 100 W maximum power). The reaction
mixture was then purified by flash chromatography (chloroform/
(a) Using standard conditions: A mixture of 3-benzyloxy-1-(30-car-
boxypropyl)-2-methyl-4-pyridinone (2.57 g, 8.94 mmol, 2.3 equiv),
DCC (1.92 g, 9.33 mmol, 2.4 equiv), HOBt (1.26 g, 9.33 mmol,
2.4 equiv) and dry DMF (80 mL) was stirred at room temperature,
under argon atmosphere, for 30 min. After that time, 1,4-bis(3-ami-
nopropyl)piperazine (0.80 mL, 3.89 mmol) was added and the