MHz, DMSO-d6) δ 159.1, 157.5, 157.2, 156.9 (JC-F = 113.1 Hz),
152.6, 140.4, 135.2, 134.4, 130.7, 130.3, 127.3, 124.4, 123.7,
120.5*2 (JC-F = 8.5 Hz), 118.9, 117.7, 116.5*2 (JC-F = 23.2 Hz),
113.0, 105.2, 31.9, 30.6*3. HRMS (ESI) m/z: [M + H]+ Calcd for
C25H23FN4O3: 447.1827, Found: 447.1829.
125.8, 124.8, 124.2, 122.3, 118.4, 117.6 (JC-F = 180.3 Hz), 116.9,
113.4, 105.7, 32.4, 31.1*3. HRMS (ESI) m/z: [M + H]+ Calcd for
C25H23FN4O3: 447.1827, Found: 447.1829.
4.2.39.
(Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-
((Z)-3-(3-fluorophenoxy)benzylidene)piperazine-2,5-dione (6u).
4.2.34.
(Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-
Yield: 63.8%. Yellow solid. Mp: 238-240 C. 1H NMR (500 MHz,
DMSO-d6) δ 12.29 (d, J = 30.1 Hz, 2H), 10.16 (s, 1H), 7.85 (s,
1H), 7.51-7.36 (m, 2H), 7.32 (d, J = 7.7 Hz, 1H), 7.25 (s, 1H),
7.04-6.93 (m, 2H), 6.93-6.82 (m, 3H), 6.73 (s, 1H), 1.38 (s, 9H).
13C NMR (125 MHz, DMSO-d6) δ 164.3, 162.4, 158.9 (JC-F = 10.9
Hz), 158.0, 156.4 (JC-F = 57.8 Hz), 140.9, 135.9, 134.8, 131.7 (JC-
F = 9.9 Hz), 131.1, 130.9, 127.9, 125.8, 124.2, 120.5, 119.4, 114.5
(JC-F = 2.8 Hz), 113.40, 110.3 (JC-F = 20.9 Hz), 106.1 (JC-F = 24.6
Hz), 105.7, 32.4, 31.1*3. HRMS (ESI) m/z: [M + H]+ Calcd for
C25H23FN4O3: 447.1827, Found: 447.1827.
((Z)-3-((4-fluorophenyl)thio)benzylidene)piperazine-2,5-dione
(6p).
Yield: 10.9%. Yellow solid. Mp: 236-237 C. 1H NMR (500 MHz,
DMSO-d6) δ 12.29 (d, J = 35.0 Hz, 2H), 10.19 (s, 1H), 7.85 (s,
1H), 7.49 (dd, J = 7.9, 5.5 Hz, 2H), 7.41 (dd, J = 15.5, 7.3 Hz, 3H),
7.26 (t, J = 8.6 Hz, 2H), 7.16 (d, J = 6.5 Hz, 1H), 6.86 (s, 1H), 6.68
(s, 1H), 1.38 (s, 9H). 13C NMR (125 MHz, DMSO-d6) δ 162.8,
160.9, 156.8 (JC-F = 180.3 Hz), 140.4, 135.9, 134.6, 134.4, 134.0*2
(JC-F = 8.4 Hz), 130.7, 130.1, 129.8, 129.6, 129.1, 128.0, 127.4,
123.7, 116.7*2 (JC-F = 21.9 Hz), 112.8, 105.2, 31.9, 30.6*3. HRMS
(ESI) m/z: [M + H]+ Calcd for C25H23FN4O2S: 463.1599, Found:
463.1597.
4.2.40. (Z)-6-((Z)-benzylidene)-3-((5-(tert-butyl)-1H-imidazol-4-
yl)methylene)-1-methylpiperazine-2,5-dione (7a) and (Z)-6-((E)-
benzylidene)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-1-
methylpiperazine-2,5-dione (7b)
4.2.35.
(Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-
((Z)-3-phenoxybenzylidene)piperazine-2,5-dione (6q).
To a solution of 60% NaH (8 mg, 0.30 mmol) in dry DMSO (2
mL), TMSOI (8 mg, 0.30 mmol) in dry DMSO (1 mL) solution
was added dropwise. Then, plinabulin (100 mg, 0.27 mmol) in dry
DMSO (1 mL) solution was added to the mixture dropwise. The
Yield: 43.8%. Yellow solid. Mp: 241-242 C. 1H NMR (500 MHz,
DMSO-d6) δ 12.29 (d, J = 33.3 Hz, 2H), 10.12 (s, 1H), 7.85 (s,
1H), 7.41 (q, J = 8.2 Hz, 3H), 7.28 (d, J = 7.6 Hz, 1H), 7.19 (s,
1H), 7.14 (t, J = 7.3 Hz, 1H), 7.07 (d, J = 8.0 Hz, 2H), 6.92 (d, J =
8.0 Hz, 1H), 6.85 (s, 1H), 6.72 (s, 1H), 1.38 (s, 9H). 13C NMR (125
MHz, DMSO-d6) δ 157.5, 156.6 (JC-F = 5.2 Hz), 156.2, 140.4,
135.2, 134.4, 130.7, 130.3, 130.0*2, 127.3, 124.5, 123.7, 123.4,
119.4*2, 118.5, 118.2, 113.1, 109.5, 105.2, 31.9, 30.6*3. HRMS
(ESI) m/z: [M + H]+ Calcd for C25H24N4O3: 429.1921, Found:
429.1922.
o
reaction was reacted at 80 C under microwave condition for 30
min. After the reaction was completed, the mixture was quenched
with water and extracted with EtOAc. The solvent was removed
under reduced pressure. The residue was purified by silica gel
column chromatography using petroleum ether/ethyl acetate (3:1)
to give yellow solid Compound 7a (16.0 mg, 0.05 mmol, 16.7%
yield) and yellow solid Compound 7b (20.0 mg, 0.06 mmol, 20.9%
1
yield), respectively. 7a: Mp: 211-213 C. H NMR (500 MHz,
4.2.36.
(Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-
DMSO-d6) δ 12.38 (s, 1H), 12.20 (s, 1H), 7.84 (s, 1H), 7.40 (t, J =
7.5 Hz, 2H), 7.33 (d, J = 7.1 Hz, 3H), 7.09 (s, 1H), 6.92 (s, 1H),
2.83 (s, 3H), 1.39 (s, 9H). 13C NMR (150 MHz, DMSO-d6) δ
159.0, 157.5, 140.4, 134.6, 134.4, 131.2, 130.7, 129.4, 128.1,
127.9, 123.5, 117.4, 105.9, 36.4, 31.9, 30.6. HRMS (ESI) m/z: [M
+ H]+ Calcd for C20H22N4O2: 351.1816, Found: 351.1817. 7b: Mp:
205-206 C. 1H NMR (500 MHz, DMSO-d6) δ 12.38 (s, 1H), 12.20
(s, 1H), 7.84 (s, 1H), 7.40 (t, J = 7.5 Hz, 2H), 7.33 (d, J = 7.1 Hz,
3H), 7.09 (s, 1H), 6.92 (s, 1H), 2.83 (s, 3H), 1.39 (s, 9H). 13C NMR
(125 MHz, DMSO-d6) δ 158.2, 154.7, 140.2, 135.2, 134.4, 132.6,
131.2*2, 130.8, 128.4*2, 124.8, 121.6, 121.2, 101.6, 54.4, 31.9,
30.6*3. HRMS (ESI) m/z: [M + H]+ Calcd for C20H22N4O2:
351.1816, Found: 351.1813.
((Z)-3-(4-methoxyphenoxy)benzylidene)piperazine-2,5-dione
(6r).
Yield: 37.8%. Yellow solid. Mp: 204-205 C. 1H NMR (500 MHz,
DMSO-d6) δ 12.29 (d, J = 35.0 Hz, 2H), 10.06 (s, 1H), 7.85 (s,
1H), 7.37 (t, J = 7.9 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.10 (s, 1H),
7.04 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.88-6.80 (m,
2H), 6.69 (s, 1H), 3.75 (s, 3H), 1.38 (s, 9H). 13C NMR (125 MHz,
DMSO-d6) δ 158.0, 157.5, 156.2, 155.6, 149.3, 140.4, 135.0,
134.4, 130.7, 130.1, 127.2, 123.7, 123.6, 120.6*2, 118.1, 116.8,
115.1*2, 113.2, 105.2, 55.4, 31.9, 30.6*3. HRMS (ESI) m/z: [M +
H]+ Calcd for C26H26N4O4: 459.2027, Found: 459.2030.
4.2.37.
(Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-
4.2.41.
(Z)-8-benzylidene-1-(tert-butyl)-8,9-dihydro-5H-
((Z)-3-(4-nitrophenoxy)benzylidene)piperazine-2,5-dione (6s).
imidazo[1,5-c]pyrazino[2,1-f]pyrimidine-7,10-dione (7c).
Yield: 25.1%. Yellow solid. Mp: 155-157 C. 1H NMR (500 MHz,
DMSO-d6) δ 12.39-12.14 (m, 1H), 8.32-8.22 (m, 2H), 7.84 (s, 1H),
7.51 (t, J = 7.9 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 1.9
Hz, 1H), 7.20 (d, J = 9.1 Hz, 2H), 7.11 (dd, J = 8.2, 2.3 Hz, 1H),
6.85 (s, 1H), 6.75 (s, 1H), 1.37 (s, 9H). 13C NMR (125 MHz,
DMSO-d6) δ 163.3, 158.1, 156.6, 154.8, 142.7, 140.9, 136.3,
134.8, 131.2, 131.1, 128.0, 127.0, 126.6*2, 124.2, 121.4, 120.4,
117.9*2, 113.1, 105.7, 32.4, 31.1*3. HRMS (ESI) m/z: [M + H]+
Calcd for C25H23N5O5: 474.1772, Found: 474.1774.
To a solution of plinabulin (100 mg, 0.30 mmol) in dry THF (2
mL), 60% NaH (48 mg, 1.19 mmol) was added. And the solution
o
was stirred at 25 C for 30 min. Then intermediate 31 (389 mg,
1.19 mmol) in dry THF (3 mL) solution was added dropwise the
mixture. Subsequently, the solution was stirred at 25 oC for 12 h.
After the reaction was completed, the mixture was quenched with
water and extracted with EtOAc. The solvent was removed under
reduced pressure. The residue was purified by silica gel column
chromatography using petroleum ether/ethyl acetate (2:1) to give
yellow solid Compound 7c (27.0 mg, 0.08 mmol, 26.0% yield).
Mp: 191-193 C. 1H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1H),
7.87 (s, 1H), 7.54 (d, J = 7.5 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.33
(t, J = 7.3 Hz, 1H), 7.02 (s, 1H), 6.85 (s, 1H), 5.92 (s, 2H), 1.33 (s,
9H). 13C NMR (125 MHz, DMSO-d6) δ 156.3, 155.9, 135.8, 133.0,
131.7, 131.5, 129.4*2, 128.7*2, 128.3, 125.8, 122.3, 118.0, 115.8,
104.8, 65.0, 53.8, 33.5, 30.6*3. HRMS (ESI) m/z: [M + H]+ Calcd
for C20H20N4O2: 349.1659, Found: 349.1664.
4.2.38.
(Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-
((Z)-3-(2-fluorophenoxy)benzylidene)piperazine-2,5-dione (6t).
Yield: 53.5%. Yellow solid. Mp: 206-207 C. 1H NMR (500 MHz,
DMSO-d6) δ 12.29 (d, J = 32.2 Hz, 2H), 10.12 (s, 1H), 7.85 (s,
1H), 7.40 (q, J = 8.6, 8.2 Hz, 2H), 7.33-7.14 (m, 5H), 6.87 (d, J =
16.5 Hz, 2H), 6.71 (s, 1H), 1.38 (s, 9H).13C NMR (125 MHz,
DMSO-d6) δ 158.0, 157.2, 156.6, 153.9 (JC-F = 244.6 Hz), 143.3
(JC-F = 11.2 Hz), 140.9, 135.7, 134.8, 131.1, 130.7, 127.8, 125.9,