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W. Qian et al. / Tetrahedron Letters 53 (2012) 271–274
product was observed with no cyclization product. The reaction mixture was
2H), 1.50 (t, J = 7.14 Hz, 3H), 1.02 (s, 9H); 13C NMR (100 MHz, CHLOROFORM-d)
d = 159.0, 153.7, 152.2, 141.3, 139.5, 129.2, 129.0, 127.1, 126.7, 125.8, 125.6,
118.0, 62.7, 43.3, 42.7, 30.3, 29.3, 14.2; HRMS (ESI): m/z [M+H]+ calcd for
heated at 70 °C for 2 h. After cooling, the solvent was evaporated and the
residue was submitted to flash column (DCM to DCM/ethyl acetate = 100:2 to
100:4 to 100:6) to give 5a (350 mg, 1.035 mmol, 52% yield) as an off-white
solid. 1H NMR (400 MHz, CHLOROFORM-d) d = 8.89 (s, 1 H), 8.53 (s, 1 H), 7.38
(d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 6.15 (s, 2H), 3.91 (s, 3H), 3.75 (s, 3H).
13C NMR (100 MHz, CHLOROFORM-d) d = 159.2, 154.4, 154.2, 134.7, 129.9,
129.0, 127.6, 126.4, 123.4, 119.2, 113.9, 55.3, 46.3, 41.8. HRMS (ESI): m/z
[M+H]+ calcd for C16H14N6O3: 339.1206; found: 339.1205.
C
22H24N6O4: 437.1927; found: 437.1914. 5j (white solid, 64% yield): 1H NMR
(400 MHz, CHLOROFORM-d) d = 9.07 (s, 1H), 7.58–7.44 (m, 5H), 5.28 (d,
J = 4.1 Hz, 2H), 4.69 (t, J = 5.1 Hz, 1H), 4.57 (q, J = 7.2 Hz, 2H), 3.37 (s, 6H), 1.49
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CHLOROFORM-d) d = 159.0, 154.2, 152.4,
141.2, 139.9, 129.1, 129.0, 127.0, 126.6, 125.7, 125.6, 117.9, 102.0, 62.6, 54.6,
44.0, 14.2; HRMS (ESI): m/z [M+H]+ calcd for C20H20N6O6: 441.1513; found:
441.1513. 5k (white solid, 73% yield): 1H NMR (400 MHz, CHLOROFORM-d) d
ppm 9.05 (s, 1H), 7.51–7.58 (m, 4H), 7.45–7.50 (m, 1H), 7.42 (d, J = 8.61 Hz,
2H), 6.79 (d, J = 8.60 Hz, 2H), 6.15 (br s, 2H), 4.56 (q, J = 7.04 Hz, 2H), 3.74 (s,
3H), 1.49 (t, J = 7.14 Hz, 3H); 13C NMR (100 MHz, CHLOROFORM-d) d = 159.4,
158.9, 154.1, 152.5, 141.2, 139.9, 130.4, 129.2, 129.1, 128.7, 127.2, 126.8, 125.7,
125.0, 118.3, 113.9, 62.7, 55.3, 46.6, 14.2; HRMS (ESI): m/z [M+H]+ calcd for
13. One-pot synthesis of 5k: A mixture of 1-phenyl-4,5-dichloro-6-pyridazone
(2.41 g, 10.0 mmol) and sodium azide (682.3 mg, 10.5 mmol) in 4 mL of DMF in
a 20 mL microwave vial was stirred at room temperature for 3 h to ensure
complete azide substitution. To this was added diethyl acetylenedicarboxylate
(5.10 g, 30.0 mmol) and the reaction vessel was sealed and heated at 90 °C for
3 h, then 100 °C for 2 h. After cooling to room temperature, 4-
methoxybenzylamine (3.9 ml, 30.0 mmol) was added dropwise (exothermic).
After stirring at room temperature overnight, the reaction was completed. The
reaction mixture was dried under high vacuum to remove DMF and the residue
was submitted to flash column (DCM to DCM/ethyl acetate = 100:1 to 100:2 to
100:4) followed by recrystallization from hexanes to give 5k (3.43 g,
7.26 mmol, 73% yield) as a white solid. Compounds 5b–q were synthesized
in parallel in the similar procedures. 5b (off-white solid, 47% yield): 1H NMR
(400 MHz, CHLOROFORM-d) d = 8.91 (s, 1H), 7.41 (d, J = 8.6 Hz, 2H), 6.79 (d,
J = 8.8 Hz, 2H), 6.16 (br s, 2H), 4.55 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 3.75 (s, 3H),
1.48 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CHLOROFORM-d) d = 159.3, 158.9,
154.0, 152.5, 139.8, 130.2, 128.8, 126.7, 126.2, 124.0, 118.6, 113.9, 62.6, 55.2,
46.6, 41.8, 14.2; HRMS (ESI): m/z [M+H]+ calcd for C19H18N6O5: 411.1408;
found: 411.1426. 5c (off-white solid, 47% yield): 1H NMR (400 MHz,
CHLOROFORM-d) d ppm = 8.94 (s, 1H), 6.04 (m, 1H), 5.53 (d, J = 5.9 Hz, 2H),
5.35 (d, J = 17.0 Hz, 1H), 5.25 (d, J = 10.4 Hz, 1H), 4.56 (q, J = 7.24 Hz, 2H), 3.92
(s, 3H), 1.48 (t, J = 7.14 Hz, 3H); 13C NMR (100 MHz, CHLOROFORM-d) d = 159.0,
153.8, 152.0, 139.8, 132.3, 126.6, 126.2, 124.2, 119.1, 118.4, 62.6, 46.8, 41.7,
14.2; HRMS (ESI): m/z [M+H]+ calcd for C14H14N6O4: 331.1147; found:
331.1138. 5d (white solid, 47% yield): 1H NMR (400 MHz, CHLOROFORM-d)
d = 8.94 (s, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 4.98 (t, J = 8.0 Hz,
2H), 4.58 (q, J = 7.2 Hz, 2H), 3.93 (s, 3H), 3.07 (t, J = 8.4 Hz, 2H), 1.50 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CHLOROFORM-d) d = 159.0, 153.8, 152.3,
139.7, 136.7, 131.7, 131.0, 126.6, 126.2, 124.4, 120.7, 118.3, 62.7, 46.7, 41.8,
35.3, 14.3; HRMS (ESI): m/z [M+H]+ calcd for Br1C19H17N6O4: 473.0564; found:
473.0562. 5e (off-white solid, 46% yield): 1H NMR (400 MHz, CHLOROFORM-d)
d = 8.91 (s, 1H), 7.39 (d, J = 6.8 Hz, 2H), 7.32–7.17 (m, 3H), 6.20 (br s, 2H), 4.53
(q, J = 7.0 Hz, 2H), 3.90 (s, 3H), 1.47 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CHLOROFORM-d) d = 158.9, 153.9, 152.4, 139.9, 136.6, 128.6, 128.2, 127.8,
126.6, 126.2, 124.0, 118.6, 62.6, 47.2, 41.8, 14.2; HRMS (ESI): m/z [M+H]+ calcd
C
24H20N6O5: 473.1573; found: 473.1576. 5l (tan solid, 68% yield): 1H NMR
(400 MHz, CHLOROFORM-d) d = 9.14 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.76 (d,
J = 8.4 Hz, 2H), 5.07 (br s, 2H), 4.58 (q, J = 7.2 Hz, 2H), 3.60 (br s, 4H), 2.75 (br s,
2H), 2.55 (br s, 4H), 1.50 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CHLOROFORM-
d) d = 158.9, 154.0, 152.3, 143.8, 139.8, 131.1 (q, J = 34 Hz), 127.9, 126.5, 126.3
(q, J = 3 Hz), 126.2, 125.7, 123.6 (q, J = 271 Hz), 117.9, 67.1, 62.7, 57.7, 53.9,
42.3, 14.2; HRMS (ESI): m/z [M+H]+ calcd for C23F3H22N7O5: 534.1703; found:
534.1717. 5m (white solid, 46% yield): 1H NMR (400 MHz, CHLOROFORM-d)
d = 8.87 (s, 1H), 7.38–7.21 (m, 2H), 7.06 (t, J = 8.8 Hz, 1H), 5.58 (s, 2H), 5.17 (t,
J = 7.1 Hz, 2H), 4.55 (q, J = 7.2 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 2.88 (t, J = 7.1 Hz,
2H), 1.47 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CHLOROFORM-d) d = 170.9, 162.3 (d, J = 250 Hz), 159.0, 153.9, 152.3, 139.7,
136.2 (d, J = 4 Hz), 130.7 (d, J = 10 Hz), 126.5, 125.6 (d, J = 4 Hz), 124.5, 120.9 (d,
J = 8 Hz), 118.1, 114.5, 114.2, 62.6, 60.9, 47.1 (d, J = 3 Hz), 41.4, 33.8, 14.2, 14.1;
HRMS (ESI): m/z [M+H]+ calcd for C22Cl1F1H20N6O6: 519.1186; found:
519.1199. 5n (off-white solid, 42% yield): 1H NMR (400 MHz, CHLOROFORM-
d) d = 8.97 (s, 1H), 7.40–7.28 (m, 2H), 7.14–7.06 (m, 2H), 5.52 (s, 2H), 5.27 (t,
J = 5.4 Hz, 2H), 4.55 (q, J = 7.0 Hz, 2H), 3.67 (t, J = 5.4 Hz, 2H), 3.25 (s, 3H), 1.48
(t, J = 7.1 Hz, 3H); HRMS (ESI): m/z [M+H]+ calcd for C20F1H19N6O5: 443.1470;
found: 443.1470. 5o (white solid, 64% yield): 1H NMR (400 MHz,
CHLOROFORM-d) d = 8.98 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz,
2H), 5.73 (d, J = 2.3 Hz, 2H), 5.41 (s, 2H), 4.55 (q, J = 7.0 Hz, 2H), 2.27 (t,
J = 2.3 Hz, 1H), 1.48 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CHLOROFORM-d)
d = 158.8, 153.5, 151.5, 140.1, 134.6, 133.5, 130.5, 129.0, 126.7, 126.4, 123.7,
118.6, 78.0, 72.8, 62.8, 56.2, 34.4, 14.2; HRMS (ESI): m/z [M+H]+ calcd for
C
20Cl1H15N6O4: 439.0914; found: 439.0903. 5p (pale-yellow film, 44% yield):
1H NMR (400 MHz, CHLOROFORM-d) d = 7.61 (d, J = 7.8 Hz, 2H), 7.50 (t,
J = 7.6 Hz, 2H), 7.43, (s, 1H), 7.45–7.39 (m, 1H), 6.84 (s, 1H), 4.49 (q,
J = 7.0 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H), 1.32 (t,
J = 6.7 Hz, 2H), 1.09 (s, 9H); 13C NMR (100 MHz, CHLOROFORM-d) d = 159.4,
157.7, 157.6, 141.6, 139.7, 139.6, 138.1, 134.3, 128.9, 128.6, 125.4, 107.8, 63.4,
62.2, 54.2, 30.1, 14.2, 13.9; HRMS (ESI): m/z [M+H]+ calcd for C22H26N6O5:
455.2032; found: 455.2043. 5q (yellow film, 48% yield): 1H NMR (400 MHz,
CHLOROFORM-d) d ppm = 7.25 (s, 1H), 7.11–7.19 (m, 3H), 6.75–6.84 (m, 3H),
4.41–4.51 (m, 2H), 4.05–4.20 (m, 3H), 3.83 (s, 3H), 1.45 (t, J = 8 Hz, 3H), 1.43 (d,
J = 8 Hz, 3H), 1.20 (t, J = 7.14 Hz, 3H); HRMS (ESI): m/z [M+H]+ calcd for
for C18H16N6O4: 381.1303; found: 381.1311. 5f (off-white solid, 48% yield): 1
H
NMR (400 MHz, CHLOROFORM-d) d = 9.08 (s, 1H), 7.64–7.44 (m, 5H), 4.57 (d,
J = 7.2 Hz, 2H), 4.19 (s, 3H), 1.50 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CHLOROFORM-d) d = 159.0, 154.4, 152.5, 141.1, 139.6, 129.2, 127.2, 126.6,
125.7, 125.67, 117.9, 62.7, 33.3, 14.2; HRMS (ESI): m/z [M+H]+ calcd for
C
17H14N6O4: 367.1147; found: 367.1145. 5g (off-white solid, 61% yield): 1H
NMR (400 MHz, CHLOROFORM-d) d = 9.10 (s, 1H), 7.57–7.52 (m, 4H), 7.51–7.45
(m, 1H), 4.84 (d, J = 7.0 Hz, 2H), 4.57 (q, J = 7.2 Hz, 2H), 2.28–2.05 (m, 1H), 1.50
(t, J = 7.1 Hz, 3H), 0.96 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz, CHLOROFORM-d)
d = 159.0, 154.0, 152.4, 141.3, 139.8, 129.2, 129.1, 127.2, 126.6, 125.8, 125.6,
118.0, 62.6, 50.9, 29.5, 19.7, 14.2; HRMS (ESI): m/z [M+H]+ calcd for
C
21H24N6O5: 441.1876; found: 441.1865.
14. Synthesis of 10: To a solution of 5k (47.2 mg, 0.100 mmol) in 2 mL of MeOH/
DCM 1:1 was added isobutylamine (49.6 l, 0.500 mmol). After stirring at
l
room temperature for 24 h, the solvents were evaporated and the residue was
submitted to flash column (DCM to DCM/ethyl acetate = 100: 2 to 100:4 to
100:6 to 10:1) to give 10 (35 mg, 0.070 mmol, 70% yield) as a white solid. 1H
NMR (400 MHz, CHLOROFORM-d) d = 9.57 (t, J = 5.0 Hz, 1H), 9.12 (s, 1H), 7.61–
7.46 (m, 5 H), 7.41 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.21 (br s, 2H),
3.77 (s, 3H), 3.42 (t, J = 6.3 Hz, 2H), 2.00 (quind, J = 6.7, 13.4 Hz, 1H), 1.05 (d,
J = 6.7 Hz, 6H). 13C NMR (100 MHz, CHLOROFORM-d) d = 159.6, 157.2, 155.9,
154.0, 142.8, 141.1, 130.3, 129.3, 129.2, 128.2, 127.2, 125.7, 124.1, 123.9, 119.4,
114.1, 55.3, 47.3, 47.1, 28.4, 20.3. HRMS (ESI): m/z [M+H]+ calcd for
C
20H20N6O4: 409.1615; found: 409.1616. 5h (off-white solid, 67% yield): 1H
NMR (400 MHz, CHLOROFORM-d) d ppm = 9.09 (s, 1H), 7.53–7.57 (m, 4H),
7.46–7.51 (m, 1H), 4.86 (d, J = 5.28 Hz, 2H), 4.57 (q, J = 7.0 Hz, 2H), 1.54–1.91
(m, 7H), 1.50 (t, J = 7.1 Hz, 3H), 1.15 (d, J = 7.8 Hz, 4H); 13C NMR (100 MHz,
CHLOROFORM-d) d = 159.0, 154.0, 152.4, 141.3, 139.8, 129.3, 129.2, 127.2,
126.6, 125.8, 125.7, 118.0, 62.7, 50.0, 38.6, 30.2, 26.2, 25.8, 14.3; HRMS (ESI):
m/z [M+H]+ calcd for C23H24N6O4: 449.1927; found: 449.1931. 5i (off-white
solid, 63% yield): 1H NMR (400 MHz, CHLOROFORM-d) d ppm = 9.07 (s, 1H),
7.45–7.59 (m, 5H), 4.85–4.96 (m, 2H), 4.57 (q, J = 7.24 Hz, 2H), 1.64–1.76 (m,
C
26H25N7O4: 500.2046; found: 500.2047.