7.62 (s, 1H), 7.56 (d, J = 7.1 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H),
7.43 (t, J = 5.1 Hz, 1H), 6.86 (s, 1H), 6.76 (s, 1H), 3.48 (t, J = 6.7
Hz, 2H), 3.43 (t, J = 6.4 Hz, 2H), 1.90 – 1.84 (m, 2H), 1.85 –
1.79 (m, 2H), 1.39 (s, 9H). 13C NMR (125 MHz, DMSO-d6) δ
167.9, 157.6, 156.2, 140.4, 137.5, 134.4, 133.2, 130.7, 130.5,
128.5, 127.6, 127.2, 126.5, 123.8, 113.2, 105.1, 48.9, 45.9, 31.9,
30.6, 25.9, 23.9. HRMS (ESI): Calcd for C24H28N5O3 [M+H]+
434.2187, found 434.2185.
d6) δ 12.60 (s, 1H), 10.57 (s, 1H), 8.74 (d, J = 4.3 Hz, 1H), 7.92
(td, J = 7.8, 1.8 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H),
7.63 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.49 (t, J = 7.7
Hz, 1H), 7.41 – 7.34 (m, 1H), 6.87 (s, 1H), 6.74 (s, 1H), 4.33 (t, J
= 7.6 Hz, 2H), 4.07 (t, J = 7.7 Hz, 2H), 2.32 – 2.21 (m, 2H). 13C
NMR (125 MHz, DMSO-d6) δ 168.5, 156.8, 156.7, 154.6, 148.5,
137.8, 133.5, 133.1, 131.7, 131.1, 128.1, 128.5, 127.3, 126.7,
126.5, 122.6, 114.8, 107.7, 52.9, 48.5, 15.5. HRMS (ESI): Calcd
for C21H19N4O3 [M+H]+ 375.1452, found 375.1451.
4.1.1.6 3-(piperidine-1-carbonyl)benzaldehyde (8c)
Yield: 93%. 1H NMR (500 MHz, CDCl3) δ 10.04 (s, 1H), 7.94
– 7.90 (m, 2H), 7.67 – 7.65 (m, 1H), 7.58 (t, J = 7.6 Hz, 1H),
3.73 (br s, 2H), 3.34 (br s, 2H), 1.70 – 1.63 (m, 6H). MS (ESI):
Calcd for C13H16NO2 [M+H]+ 218.12, found 218.24.
4.1.1.13 (3Z, 6Z)-3-(3-(piperidine-1-carbonyl) benzylidene)-6-
(pyridin-2-ylmethylene) piperazine-2,5-dione (9g)
Yield: 37%. Mp: 284.5-286.1oC. 1H NMR (500 MHz, DMSO-
d6) δ 12.60 (s, 1H), 10.53 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 7.91 (t,
J = 7.1 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 7.7 Hz,
1H), 7.52 – 7.45 (m, 2H), 7.41 – 7.36 (m, 1H), 7.31 (d, J = 7.5
Hz, 1H), 6.86 (s, 1H), 6.73 (s, 1H), 3.59 (br s, 2H), 3.34 (s, 2H),
1.70 – 1.20 (m, 6H). 13C NMR (125 MHz, CDCl3) δ 169.4, 157.1,
156.8, 154.7, 148.7, 137.9, 137.3, 133.4, 130.4, 129.7, 129.3,
127.3, 127.1, 126.7, 126.5, 122.6, 115.7, 110.1, 48.9, 43.4, 26.7,
24.7. HRMS (ESI): Calcd for C23H23N4O3 [M+H]+ 403.1765,
found 403.1763.
4.1.1.7 (3Z, 6Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl) methylene)-
6-(-3-(piperidine-1-carbonyl) benzylidene) piperazine-2,5-dione
(9c)
Yield: 74%. Mp: 188.0-190.0oC. 1H NMR (500 MHz, DMSO-
d6) δ 12.33 (s, 1H), 12.27 (s, 1H), 10.20 (s, 1H), 7.85 (s, 1H),
7.55 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 7.6
Hz, 1H), 6.86 (s, 1H), 6.75 (s, 1H), 3.59 (br s, 2H), 3.34 (s, 2H),
1.74 – 1.43 (m, 6H), 1.39 (s, 9H). 13C NMR (125 MHz, DMSO-
d6) δ 168.5, 157.6, 156.2, 140.4, 136.8, 134.4, 133.5, 130.7,
130.1, 128.7, 127.3, 127.1, 126.1, 123.8, 113.2, 105.2, 32.9, 30.6,
24.1. HRMS (ESI): Calcd for C25H30N5O3 [M+H]+ 448.2343,
found 448.2342.
4.1.1.14
(3Z,
6Z)-3-(3-(4-methylpiperazine-1-carbonyl)
benzylidene)-6-(pyridin-2-ylmethylene) piperazine-2,5-dione (9h)
Yield: 42%. Mp: 258.8-260.3oC. 1H NMR (500 MHz, CDCl3)
δ 12.88 (s, 1H), 8.67 (d, J = 4.65 Hz, 1H), 8.22 (s, 1H), 7.74 (t, J
= 7.7 Hz 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H),
7.43 (s, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H),
7.25 – 7.22 (m, 1H), 7.06 (s,1H), 6.77 (s,1H), 3.81 (s, 2H), 3.47
(s, 2H), 2.50 (s, 2H), 2.38 (s, 2H), 2.33 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 169.3, 157.1, 156.7, 154.7, 148.7, 137.4, 137.3,
133.5, 130.3, 129.8, 129.5, 127.5, 127.4, 126.8, 126.5, 115.5,
122.6, 110.2, 55.4, 54.8, 46.2. HRMS (ESI): Calcd for
C23H24N5O3 [M+H]+ 418.1874, found 418.1872.
4.1.1.8 3-(4-methylpiperazine-1-carbonyl)benzaldehyde (8d)
1
Yield: 73%. H NMR (500 MHz, DMSO-d6) δ 10.05 (s, 1H),
7.98 (dt, J = 7.4, 1.4 Hz, 1H), 7.90 (s, 1H), 7.72 (dt, J = 7.6, 1.5
Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 3.64 (s, 2H), 3.32 (br s, 2H),
2.42 – 2.23 (m, 4H), 2.20 (s, 3H). MS (ESI): Calcd for
C13H17N2O2 [M+H]+ 233.13, found 233.21.
4.1.1.9 (3Z, 6Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl) methylene)-
6-(-3-(4-methylpiperazine-1-carbonyl) benzylidene) piperazine-2,
5-dione (9d)
4.1.1.15 3-picolinoylbenzaldehyde (12a)
Step A: N-methoxy-N-methylpicolinamide
Yield: 68%. Mp: 214.0-216.0oC. 1H NMR (500 MHz, DMSO-
d6) δ 12.33 (s, 1H), 12.27 (s, 1H), 10.20 (s, 1H), 7.85 (s, 1H),
7.56 (d, J = 7.7 Hz, 1H), 7.48 – 7.45 (m, 2H), 7.30 (d, J = 7.5 Hz,
1H), 6.87 (s, 1H), 6.76 (s, 1H), 3.62 (s, 2H), 3.37 (s, 2H), 2.42 –
2.25 (m, 4H), 2.20 (s, 3H), 1.39 (s, 9H). 13C NMR (125 MHz,
DMSO-d6) δ 168.6, 157.6, 156.2, 140.4, 136.3, 134.4, 133.5,
130.7, 130.3, 128.8, 127.4, 127.3, 126.4, 123.8, 113.1, 105.2,
54.7, 45.6, 31.9, 30.6. HRMS (ESI): Calcd for C25H31N6O3
[M+H]+ 463.2452, found 463.2450.
To a solution picolinic acid (246 mg, 2 mmol) in CH3CN (10
mL) was added HOBT (270 mg, 2 mmol), EDCI (383.4 mg, 2
mmol) and N,O-dimethylhydroxylamine hydrochloride (293 mg,
3 mmol), NEt3 was added dropwise to the mixture. The reaction
o
was stirred at 25 C under a nitrogen atmosphere. After the
reaction was completed, the mixture was extracted with EtOAc.
The organic layer was washed with brine and was dried over
anhydrous sodium sulfate (Na2SO4). Then solvent was removed
under reduced pressure. The residue was purified by silica gel
column chromatography using petroleum ether–ethyl acetate
4.1.1.10 3-(morpholine-4-carbonyl)benzaldehyde (8e)
1
Yield: 59%. 1H NMR (500 MHz, CDCl3) δ 10.05 (s, 1H), 7.95
(dt, J = 7.6, 1.3 Hz, 1H), 7.92 (s, 1H), 7.69 (dt, J = 7.6, 1.4 Hz,
1H), 7.62 (t, J = 7.6 Hz, 1H), 3.89 – 3.39 (m, 8H). MS (ESI):
Calcd for C12H14NO3 [M+H]+ 220.10, found 220.21.
(10:1) to give compound (235 mg, 70% yield). H NMR (500
MHz, DMSO-d6) δ 8.60 (d, J = 4.2 Hz, 1H), 7.91 (t, J = 7.6 Hz,
1H), 7.58 (br s, 1H), 7.51 – 7.47 (m, 1H), 3.65 (s, 3H), 3.27 (s,
3H). MS (ESI): m/z = 167.24 [M+H]+.
Step B: (3-(1, 3-dioxolan-2-yl) phenyl)(pyridin-2-yl)methanone
(11a)
4.1.1.11
(3Z,
6Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)
methylene)-6-(-3-(morpholine-4-carbonyl)
benzylidene)
According to the procedure described for the synthesis of 12d
(Step A) Yield: 26%. 1H NMR (500 MHz,DMSO-d6) δ 8.73 (d, J
= 3.9 Hz, 1H), 8.08 (t, J = 7.7 Hz, 1H), 8.03 – 7.96 (m, 3H), 7.73
(d, J = 7.6 Hz, 1H), 7.70 – 7.66 (m, 1H), 7.57 (t, J = 7.6 Hz, 1H),
5.82 (s,1H) 4.08 – 4.02 (m, 2H), 4.01 – 3.94 (m, 2H). MS (ESI):
m/z = 256.34 [M+H]+.
piperazine-2,5-dione (9e)
Yield: 76%. Mp: 182.0-184.0oC. 1H NMR (500 MHz, DMSO-
d6) δ 12.32 (s, 1H), 12.26 (s, 1H), 10.19 (s, 1H), 7.85 (s, 1H),
7.57 (d, J = 7.7 Hz, 1H), 7.52 (s, 1H), 7.47 (t, J = 7.7 Hz, 1H),
7.33 (d, J = 7.6 Hz, 1H), 6.86 (s, 1H), 6.75 (s, 1H), 3.70 – 3.40
(m, 8H), 1.39 (s, 9H). 13C NMR (125 MHz, DMSO-d6) δ 168.7,
157.6, 156.2, 140.4, 135.9, 134.4, 133.5, 130.7, 130.4, 128.8,
127.5, 127.4, 126.5, 123.8, 113.1, 105.2, 66.1, 31.9, 30.6. HRMS
(ESI): Calcd for C24H28N5 O4 [M+H]+ 450.2136, found 450.2133.
Step C:
According to the procedure described for the synthesis of 12d
(Step C) Yield: 78%. 1H NMR (500 MHz, DMSO-d6) δ 10.11 (s,
1H), 8.75 (d, J = 4.3 Hz, 1H), 8.48 (s, 1H), 8.30 (d, J = 7.7 Hz,
1H), 8.19 (d, J = 7.5 Hz, 1H), 8.12 – 8.07 (m,2H), 7.79 (t, J = 7.6
Hz, 1H), 7.72 (t, J = 5.5 Hz, 1H). MS (ESI): Calcd for
4.1.1.12 (3Z, 6Z)-3-(3-(azetidine-1-carbonyl) benzylidene)-6-
(pyridin-2-ylmethylene) piperazine-2,5-dione (9f)
Yield: 52%. Mp: 273.8-274.4oC. 1H NMR (500 MHz, DMSO-