3
16. Miura, T.; Tagashira, J.; Sekimoto, R.; Ishida, R.; Aoki, H.;
Ohgiya. T. 2012, US 2012/0225896 A1.
20. Representative procedure for the preparation of 4-aminopyrones
7a-7f:
17. Defant, A.; Mancini, I. Tetrahedron, 2013, 69, 4586- 4590.
18. Experimental procedure for the synthesis of 6-methyl-2-oxo-2H-
pyran-4-yl 4-methylbenzenesulfonate (2) (96%) colorless solid: 4-
Hydroxy-6-methyl-2H-pyran-2-one (triacetic acid lactone, 1)
(0.63 g, 5 mmol) and tosyl chloride (0.955 g, 5 mmol) was
dissolved in CH2Cl2 (37.5 mL). Triethylamine (2.05 mL, 15
mmol) was added and the reaction mixture was left stirring at rt.
overnight (23 h). CH2Cl2 (50 mL) was added and the organic
phase was washed with water (25 mL) and brine (25 mL). The
organic phase was dried over MgSO4. After concentration in
vacuo the crude product was purified by column chromatography
using hexane/ethyl acetate (4:1) as eluent to afford the desired
product.11 Rf = 0.18 (silica gel, hexanes/EtOAc 3:1); 1H NMR
(300 MHz, Chloroform-d) δ = 7.82 (d, 2H), 7.37 (d, 2H), 6.00 (s,
1H), 5.80 (s, 1H), 2.45 (s, 3H), 2.23 (s, 3H) ppm.
19. Representative procedure for the preparation of pyridones 6a-6g:
A mixture of triacetic acid lactone (1) (0.5 g, 3.96 mmoL, 1 eq)
and primary amine (4.35 mmoL, 1.1 eq) in water (2.5 mL) was
heated to 100 0C overnight. After completion of the reaction (TLC
monitoring), the reaction mixture was cooled down and the
precipitate was filtered and washed with ethyl acetate and dried
under vacuum to obtain the desired product.12
Method A: A mixture of 6-methyl-2-oxo-2H-pyran-4-yl 4-
methylbenzenesulfonate (2) (0.08 g, 0.3 mmoL, 1 eq) and amine
(0.66 mmoL, 2.2 eq) in ethanol (4 mL) was stirred at rt. overnight.
After completion of the reaction (TLC monitoring), solvent was
evaporated. The crude compound was purified by preparative thin
layer chromatography (EtOAc/dichloromethane) to afford the
desired product. Method B: A mixture of triacetic acid lactone (1)
(0.17 g, 1.4 mmoL, 1 eq) and amine (1.54 mmoL, 1.1 eq) in water
(1.5-2 mL) was stirred at rt. overnight. After completion of the
reaction (TLC monitoring), solvent was evaporated. The crude
compound was purified by preparative thin layer chromatography
(EtOAc/dichloromethane) to afford the desired product.
4-(ethylamino)-6-methyl-2H-pyran-2-one (7a) (Method A: 51%,
Method B: 83%) Colorless liquid: Rf
= 0.11 (silica gel,
1
CH2Cl2/EtOAc 1:1); H NMR (300 MHz, Methanol-d4) δ = 5.92
(s, 1H), 5.72 (s, 1H), 3.32 (m, 2H), 2.39 (s, 3H), 1.24 (t, 3H) ppm;
13C NMR (126 MHz, Methanol-d4) δ = 163.68, 157.62, 152.78,
97.77, 89.99, 35.12, 27.46, 16.60 ppm; LRMS (ESI-QTOF) calcd
for C8H12NO2 [M + H]+ 154.0868, found 154.0871.
4-(butylamino)-6-methyl-2H-pyran-2-one (7b) (Method A: 82%,
Method B: 44%) White solid: mp >260 0C; Rf = 0.24 (silica gel,
CH2Cl2/EtOAc 1:1); 1H NMR (300 MHz, Methanol-d4) δ = 5.75
(s, 1H), 4.86 (s, 1H), 2.93 (m, 2H), 1.64 (m, 2H), 1.41 (m, 2H),
0.93 (t, 3H) ppm; 13C NMR (126 MHz, Methanol-d4) δ = 160.55,
160.06, 154.39, 102.35, 85.08, 42.10, 37.52, 18.34, 18.01, 11.06
1-ethyl-4-hydroxy-6-methylpyridin-2(1H)-one (6a) (79%) Light
0
6
brown solid: mp 240-242 C (Lit. 247 0C) ; Rf = 0.16 (silica gel,
1
CH2Cl2/EtOAc 1:1); H NMR (300 MHz, Methanol-d4) δ = 5.92
(d, 1H), 5.72 (d, 1H), 4.05 (q, 2H), 2.39 (s, 3H), 1.24 (t, 3H) ppm;
13C NMR (126 MHz, Methanol-d4) δ = 165.74, 164.21, 145.70,
100.64 (2C), 37.09, 17.14, 11.18 ppm; LRMS (ESI-QTOF) calcd
for C8H12NO2 [M + H]+ 154.0868, found 154.0872.
ppm; LRMS (ESI-QTOF) calcd for C10H16NO2 [M +
H]+
182.1181, found 181.1176.
4-(isopropylamino)-6-methyl-2H-pyran-2-one (7c) (Method A:
0
65%, Method B: 69%) White solid: mp >260 C; Rf = 0.13 (silica
1
4-hydroxy-1-isobutyl-6-methylpyridin-2(1H)-one (6b) (56%) Light
gel, CH2Cl2/EtOAc 1:1); H NMR (300 MHz, Methanol-d4) δ =
0
brown solid: mp 173-175 C; Rf = 0.35 (silica gel, CH2Cl2/EtOAc
5.76 (s, 1H), 5.21 (s, 1H), 3.63 (m, 1H), 2.13 (s, 3H), 1.20 (d, 6H)
ppm; 13C NMR (126 MHz, Methanol-d4) δ = 165.87, 158.99,
156.69, 97.95, 76.32, 41.94, 19.01 (2C), 16.63 ppm; LRMS (ESI-
QTOF) calcd for C9H14NO2 [M + H]+ 168.1025, found 168.1030.
4-(benzylamino)-6-methyl-2H-pyran-2-one (7d) (Method A: 32%)
1:1); 1H NMR (300 MHz, Methanol-d4) δ = 5.92 (d, 1H), 5.73 (d,
1H), 3.85 (d, 2H), 2.37 (s, 3H), 2.26-2.05 (m, 1H), 1.04-0.80 (m,
6H) ppm; 13C NMR (126 MHz, Methanol-d4) δ = 165.41, 164.67,
146.18, 100.54, 94.73, 48.51, 26.18, 17.90, 17.20 (2C) ppm;
LRMS (ESI-QTOF) calcd for C10H16NO2 [M + H]+ 182.1181,
found 182.1191.
0
White solid: mp 126-130 C; Rf = 0.43 (silica gel, CH2Cl2/EtOAc
1:1); 1H NMR (300 MHz, Methanol-d4) δ = 7.41 – 7.17 (m, 5H),
5.90 (s, 1H), 4.94 (s, 1H), 4.33 (d, 2H), 2.15 (s, 3H) ppm; LRMS
(ESI-QTOF) calcd for C13H14NO2 [M + H]+ 216.1025, found
216.1034. 13C NMR data agreed with the literature.17
1-benzyl-4-hydroxy-6-methylpyridin-2(1H)-one (6c) (20%) White
solid: mp 219-220 0C (Lit. 217 0C) 6; Rf = 0.30 (silica gel,
CH2Cl2/EtOAc 1:1); 1H NMR (300 MHz, Methanol-d4) δ = 7.33
(m, 2H), 7.27 (m, 1H), 7.11 (m, 2H), 5.97 (d, 1H), 5.82 (d, 1H),
5.32 (s, 2H), 2.25 (s, 3H) ppm; LRMS (ESI-QTOF) calcd for
C13H14NO2 [M + H]+ 216.1025, found 216.1040. 13C NMR data
agreed with the literature.14
1-(benzo[1,3]dioxol-5-ylmethyl)-4-hydroxy-6-methylpyridin-
2(1H)-one (6d) (80%): mp 206-209 0C; Rf = 0.30 (silica gel,
CH2Cl2/EtOAc 1:1); 1H NMR (300 MHz, Chloroform-d) δ = 6.76
(s, 1H), 6.72 (d, 1H), 6.69 (d, 1H), 5.94 (s, 2H), 5.92 (d, 1H), 5.68
(d, 1H), 5.13 (s, 2H), 2.15 (s, 3H) ppm; 13C NMR (126 MHz,
DMSO-d6) δ = 163.85, 155.28, 147.80, 146.57, 145.65, 133.25,
120.72, 108.65, 108.58, 101.35, 101.30, 99.40, 45.55, 20.37 ppm;
LRMS (ESI-QTOF) calcd for C14H14NO4 [M + H]+ 260.0923,
found 260.0932.
4-hydroxy-1-(4-methoxybenzyl)-6-methylpyridin-2(1H)-one (6e)
(48%) White solid: mp 221-225 0C; Rf = 0.24 (silica gel,
CH2Cl2/EtOAc 1:1); 1H NMR (300 MHz, Methanol-d4) δ = 7.27
(d, 2H), 7.07 (d, 2H), 5.86 (d, 1H), 5.50 (d, 1H), 5.19 (s, 2H), 3.77
(s, 3H), 2.20 (s, 3H) ppm; LRMS (ESI-QTOF) calcd for
C14H16NO3 [M + H]+ 246.1130, found 246.1142. 13C NMR data
agreed with the literature.15
4-(diethylamino)-6-methyl-2H-pyran-2-one (7e) (Method A: 95%,
Method B: 47%) Yellow solid: mp 96-98 0C; Rf = 0.30 (silica gel,
CH2Cl2/EtOAc 1:1); 1H NMR (300 MHz, Methanol-d4) δ = 5.80
(d, 1H), 4.99 (d, 1H), 3.41 (q, 4H), 2.21 (s, 3H), 1.19 (t, 6H) ppm;
13C NMR (126 MHz, Methanol-d4) δ = 165.56, 160.24, 156.37,
94.74, 77.67, 42.67 (2C), 17.09 (2C), 16.63 ppm; LRMS (ESI-
QTOF) calcd for C10H16NO2 [M + H]+ 182.1181, found 182.1189.
6-methyl-4-(phenylamino)-2H-pyran-2-one (7f) (Method A: 55%)
0
White solid: mp 192-195 C (Lit. 195-196 0C) 13; Rf = 0.43 (silica
gel, CH2Cl2/EtOAc 1:1); 1H NMR (300 MHz, Acetone-d6) δ =
7.48 – 7.36 (m, 2H), 7.32 – 7.14 (m, 3H), 5.95 (d, 1H), 5.27 (d,
1H), 2.14 (s, 3H) ppm; 13C NMR (126 MHz, Methanol-d4) δ =
165.54, 160.18, 156.21, 141.31, 127.65 (2C), 123.91, 121.73 (2C),
97.47, 79.47, 16.84 ppm; LRMS (ESI-QTOF) calcd for
C12H12NO2 [M + H]+ 202.0868, found 202.0879.
21. Experimental procedure for the preparation of 4,4'-(piperazine-
1,4-diyl)bis(6-methyl-2H-pyran-2-one) (8) (Method A: 21%,
Method B: 54%) white solid : Method A: A mixture of 6-methyl-
2-oxo-2H-pyran-4-yl 4-methylbenzenesulfonate (2) (0.1 g, 0.36
mmoL, 2 eq) and piperazine (0.18 mmoL, 1 eq) in ethanol (8 mL)
was stirred at rt. overnight. After completion of the reaction (TLC
monitoring), solvent was evaporated. The crude compound was
4-hydroxy-6-methyl-1-(3,4,5-trimethoxybenzyl)pyridin-2(1H)-one
0
(6f) (69%) Light yellow solid: mp 251-255 C; Rf = 0.11 (silica
gel, CH2Cl2/EtOAc 1:1); 1H NMR (300 MHz, Methanol-d4) δ =
6.43 (s, 2H), 5.97 (d, 1H), 5.82 (d, 1H), 5.26 (s, 2H), 3.80 (s, 6H),
3.76 (s, 3H), 2.29 (s, 3H) ppm; 13C NMR (126 MHz, Methanol-d4)
δ = 163.37, 159.92, 151.91, 132.02 (2C), 131.43, 115.89, 101.54
(2C), 100.73, 94.46, 58.12, 53.55 (2C), 45.61, 17.52 ppm; LRMS
(ESI-QTOF) calcd for C16H20NO5 [M + H]+ 306.1341, found
306.1347.
purified
by
preparative
thin
layer
chromatography
(EtOAc/dichloromethane) to afford the desired product. Method
B: A mixture of triacetic acid lactone (1) (0.15 g, 1.2 mmoL, 2 eq)
and piperazine (0.6 mmoL, 1 eq) in water (1.5 mL) was stirred at
rt. overnight. After completion of the reaction (TLC monitoring),
solvent was evaporated. The crude compound was purified by
preparative thin layer chromatography (EtOAc/dichloromethane)
to afford the desired product: Rf = 0.13 (silica gel, CH2Cl2/EtOAc
7:1); 1H NMR (300 MHz, Methanol-d4) δ = 5.77 (s, 2H), 4.86 (s,
2H), 3.11 (s, 8H), 2.14 (s, 6H) ppm; 13C NMR (400 MHz,
Methanol-d4) δ = 179.72 (2C), 169.40 (2C), 161.39 (2C), 105.51
(2C), 87.39 (2C), 42.94 (4C), 18.22 (2C) ppm; LRMS (ESI-
QTOF) calcd for C16H19N2O4 [M + H]+ 303.1345, found 303.1347.
22. Experimental procedure for the preparation of 4,4',4'',4'''-
(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis(6-
4-hydroxy-6-methyl-1-phenethylpyridin-2(1H)-one (6g) (29%)
0
6
White solid: mp 244-247 C (Lit. 252 0C) ; Rf = 0.34 (silica gel,
CH2Cl2/EtOAc 1:1); 1H NMR (300 MHz, Methanol-d4) δ = 7.35-
7.14 (m, 5H), 5.85 (d, 1H), 5.77 (d, 1H), 4.17 (t, 2H), 2.97 (t, 2H),
2.12 (s, 3H) ppm; LRMS (ESI-QTOF) calcd for C14H16NO2 [M +
H]+ 230.1181, found 230.1173. NMR data agreed with the
literature.16