P.S.G. Nunes et al.
Bioorganic Chemistry 113 (2021) 104982
described protocols, are briefly reported in the supplementary
information.
found: 471.1599.
General procedure A – To a microwave flask containing a magnetic
stirring bar, sodium ascorbate (0.2 eq.) diluted with DMF (100 µL) was
added followed by CuSO4 (0.05 eq., 1 mol.Lꢀ 1 in water). The reaction
mixture was stirred for 5 min and then the alkyne derivative (6a-c, 1.1
eq.) and azido derivative (7–13, 1 eq.), both diluted in DMF, were
added. The reaction mixture was microwaved with 100 W, 80 ◦C for
5–10 min. The crude reaction was poured in EtOAc and extracted with
brine. The organic phase was concentrated and purified by flash chro-
matography (EtOAc/MeOH 5%).
4.1.5. N-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-6,7-
dimethoxyquinazolin-4-amine (21b)
Yield: 72% (51 mg, 0.13 mmol). 1H NMR (300 MHz, CDCl3) δH
(ppm): 8.53 (1H, s, H-7), 7.65 (1H, s, H-12), 7.38 (3H, dd, J 5.0 Hz, J 1.8
Hz, H-Ar), 7.28 (2H, d, J 7.7 Hz, H-Ar), 7.15 (1H, s, H-3), 7.03 (2H, s, H-
6, H-9), 5.50 (2H, s, H-13), 4.89 (2H, d, J 5.4 Hz, H-10), 3.99 (3H, s, H-
20), 3.79 (3H, s, H-21).13C NMR (75 MHz, CDCl3) δC (ppm): 158.1 (C-2),
154.4 (C-8), 153.8 (C-7), 149.0 (C-1), 146.5 (C-4), 134.5 (C-14), 129.3
(C-15, C-16), 129.0 (C-19), 128.2 (C-17, C-18), 122.9 (C-12), 107.5 (C-
3), 100.1 (C-6), 56.3 (C-21), 56.2 (C-20), 54.5 (C-13), 36.3 (C-10).
HRMS (ES+): m/z [M+H]+ calculated for C20H21N6O+2 : 377.1721,
found: 377.1719.
4.1.1. N-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4-amine
(21a)
Yield: 67% (53 mg, 0.17 mmol). 1H NMR (300 MHz, DMSOd6) δH
(ppm): 8.77 (1H, t, J 5.6 Hz, H-9), 8.44 (1H, s, H-7), 8.20 (1H, d, J 7.8
Hz, H-3), 8.02 (1H, s, H-12), 7.79–7.60 (2H, m, H-2, H-6), 7.47 (1H, ddd,
J 8.2 Hz, J 6.9 Hz, J 1.3 Hz, H-1), 7.36–7.21 (5H, m, H-Ar), 5.49 (2H, s,
H-13), 4.75 (2H, d, J 5.7 Hz, H-10). 13C NMR (75 MHz, DMSOd6) δC
(ppm): 159.2 (C-8), 155.0 (C-7), 149.1 (C-4), 145.2 (C-11), 136.2 (C-14),
132.7 (C-2), 128.7 (C-17, C-18), 128.1 (C-19), 128.0 (C-15, C-16), 127.5
(C-6), 125.8 (C-1), 123.3 (C-12), 122.7 (C-3), 115.0 (C-5), 52.7 (C-13),
36.0 (C-10). HRMS (ES+): m/z [M+H]+ calculated for C18H17N+6 :
317.1509, found: 317.1508.
4.1.6. 6,7-dimethoxy-N-{[1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl]methyl}
quinazolin-4-amine (22b)
Yield: 45% (36 mg, 0.08 mmol). 1H NMR (300 MHz, DMSOd6) δH
(ppm): 8.49 (2H, t, J 5.4 Hz, H-7, H-9), 8.22 (2H, d, J 8.5 Hz, H-17, H-
18), 8.14 (1H, s, H-12), 7.63 (1H, s, H-6), 7.51 (2H, d, J 8.6 Hz, H-17, H-
18), 7.12 (1H, s, H-3), 5.73 (2H, s, H-13), 4.79 (2H, d, J 5.4 Hz. H-10),
3.89 (3H, s, H-20), 3.86 (3H, s, H-21).13C NMR (126 MHz, DMSOd6) δC
(ppm): 157.9 (C-2), 153.8 (C-8), 153.2 (C-7), 148.3 (C-1), 147.2 (C-19),
145.6 (C-14), 143.4 (C-4), 129.0 (C-17, C-18), 123.8 (C-15, C-16), 123.6
(C-12), 107.0 (C-3), 102.0 (C-6), 55.9 (C-20), 55.6 (C-21), 51.7 (C-13),
35.7 (C-10). HRMS (ES+): m/z [M+H]+ calculated for C20H20N7O+4 :
422.1577, found: 422.1574.
4.1.2. N-{[1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl] methyl} quinazolin-4-
amine (22a)
Yield: 42% (38 mg, 0.10 mmol). 1H NMR (500 MHz, DMSOd6) δH
(ppm): 8.84 (1H, t, H-9), 8.50 (1H, s, H-7), 8.25 (1H, d, J 8.3 Hz, H-3),
8.21 (2H, d, J 8.7 Hz, H-17, H-18), 8.15 (1H, s, H-12), 7.77 (1H, t, J 7.6
Hz, H-2), 7.70 (1H, d, J 8.3 Hz, H-6), 7.54–7.48 (3H, m, H-1, H-15, H-
16), 5.73 (2H, s, H-13), 4.82 (4H, d, J 5.6 Hz, H-10). 13C NMR (126 MHz,
DMSOd6) δC (ppm): 159.1 (C-8), 154.9 (C-7), 149.0 (C-4), 147.2 (C-19),
145.3 (C-11), 143.4 (C-14), 132.5 (C-2), 128.9 (C-15, C-16), 127.4 (C-6),
125.6 (C-1), 123.7 (C-17, C-18), 123.6 (C-12), 122.6, (C-3), 114.9 (C-5),
51.7 (C-13), 35.9 (C-10). HRMS (ES+): m/z [M+H]+ calculated for
4.1.7. 6-(benzyloxy)-7-methoxy-N-{[1-(4-nitrobenzyl)-1H-1,2,3-triazol-
4-yl]methyl} quinazolin-4-amine (22c)
A mixture of CuSO4 (0.45 mg, 0.003 mmol, 5 mol%), 1,10-phenan-
troline monohydrate (0.5 mg, 0.003 mmol, 5 mol%), and sodium
ascorbate (11 mg, 0.06 mmol) in EtOH:H2O [2:1 (v/v), 1 mL], was
stirred for 5 min at room temperature. Subsequently the compounds 4-
amino-[N- (propynyl)]-6-benzyloxy-7-methoxy-quinazoline (6c) (19.7
mg, 0.06 mmol) and 1-(azidomethyl)-4-nitro-benzene (8) (10 mg, 0.06
mmol) diluted in EtOH:H2O [2:1 (v/v); 1 mL] were added to the reaction
mixture, which was stirred for 18 h at room temperature. After, the
reaction mixture was concentrated in vacuo and purified by silica gel
column chromatography [EtOAc: MeOH (9.5:0.5)]. The compound 22c
was obtained in quantitative yield (28 mg, 0.06 mmol).1H NMR (300
MHz, DMSOd6) δH (ppm): δ 8.49 (1H, d, J 5.5 Hz, H-9), 8.39 (1H, s, H-7),
8.22 (2H, d, J 8.8 Hz, H-17, H-18), 8.15 (1H, s, H-12), 7.81 (1H, s, H-6),
7.55–7.47 (4H, m, H-15, H-16, H-22, H-26), 7.46–7.32 (3H, m, H-23, H-
24, H-25), 7.13 (1H, s, H-3), 5.74 (2H, s, H-13), 5.13 (2H, s, H-21), 4.81
C
18H16N7O+2 : 362.1360, found: 362.1360.
4.1.3. N-{[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]methyl}quinazolin-
4-amine (23a)
Yield: 53% (17 mg, 0.049 mmol). 1H NMR (400 MHz, CDCl3) δH
(ppm): 8.65 (1H, s, H-7), 7.86–7.76 (2H, m,H-3, H-6), 7.72 (1H, t, J 8.3
Hz, H-2), 7.55 (1H, s, H-12), 7.43 (1H, t, J 8.2 Hz, H-1), 7.27–7.21 (2H,
m, H-15, H-16), 6.97 (1H, sl, H-9), 6.91–6.87 (2H, m, H-17, H-18), 5.45
(2H, s, H-13), 4.90 (2H, d, J 5.0 Hz, H-10), 3.80 (3H, s, H-20). 13C NMR
(101 MHz, CDCl3) δC (ppm): 160.2 (C-8), 159.3 (C-19), 155.0 (C-7),
149.1 (C-4), 144.9 (C-11), 132.9 (C-2), 129.8 (C-15, C-16), 128.3 (C-3),
126.4 (C-1), 126.5 (C-14), 122.3 (C-12), 121.1 (C-6), 115.1 (C-5), 114.7
(C-17, C-18), 55.5 (C-20), 54.0 (C-13), 36.6 (C-10). HRMS (ES+): m/z
[M+H]+ calculated for C19H19N6O+: 347.1615, found: 347.1616.
(2H, d, J 5.4 Hz, H-10), 3.89 (3H, s, H-20).13C NMR (75 MHz, DMSOd6
)
δC (ppm): 158.1 (C-8), 154.0 (C-2), 153.5 (C-7), 147.4 (C-1), 147.2 (C-
4), 146.1 (C-19), 145.6 (C-14), 143.6 (C-27), 136.4 (C-11), 129.1 (C-15,
C-16), 128.6 (C-23, C-25), 128.3 (C-22, C-26), 128.2 (C-24), 123.9 (C-
17, C-18), 123.8 (C-12), 108.5 (C-5), 107.1 (C-3), 103.3 (C-6), 70.4 (C-
21), 55.8 (C-20), 51.8 (C-13), 35.8 (C-10).HRMS (ES+): m/z [M+H]+
calculated for C26H24N7O+4 498.1884, found: 498.1881.
4.1.4. N-{[1-(2-((phenylsulfonyl)methyl]benzyl}-[(1H-1,2,3-triazol-4-yl)
methyl] quinazolin-4-amine (25a)
Yield: 65% (16 mg, 0.034 mmol). 1H NMR (500 MHz, DMSOd6) δH
(ppm): 8.81 (1H, t, J 5.6 Hz, H-9), 8.47 (1H, s, H-7), 8.22 (1H, d, J 8.2
Hz, H-3), 8.00 (1H, s, H-12), 7.79 (2H, d, J 8.1 Hz, H-22, H-26), 7.75
(2H, t, J 7.5 Hz, H-23, H-25), 7.69 (1H, d, J 8.3 Hz, H-6), 7.62 (2H, t, J
7.8 Hz, H-2, H-24), 7.50 (1H, t, J 7.6 Hz, H-1), 7.31 (1H, t, J 7.5 Hz, H-
19), 7.23 (1H, d, J 7.6 Hz, H-17), 7.08 (2H, t, J 7.3 Hz, H-16, H-18), 5.60
(2H, s, H-13), 4.91 (2H, s, H-20), 4.78 (2H, d, J 5.6 Hz, H-10). 13C NMR
(126 MHz; DMSOd6) δC (ppm): 159.1 (C-8), 154.9 (C-7), 149.0 (C-4),
145.3 (C-11), 138.4 (C-15), 136.5 (C-14), 134.1 (C-24), 133.0 (C-16),
132.6 (C-2), 129.3 (C-23, C-25), 129.2 (C-17), 128.8 (C-18), 128.1 (C-
22, C-26), 128.0 (C-19), 127.4 (C-6), 126.6 (C-21), 125.7 (C-1), 123.4
(C-12), 122.7 (C-3), 114.9 (C-5), 57.8 (C-20), 49.9 (C-13), 35.9 (C-10).
HRMS (ES+): m/z [M+H]+ calculated for C25H23N6O2S+: 471.1598,
4.1.8. 7-methoxy-4-{[1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl]
methylamino}quinazolin-6-ol (22d)
A solution of compound 22c (10 mg, 0.02 mmol) in TFA (110 μL) was
refluxed for 50 min. After cooling to room temperature the mixture was
poured into ice. The solvent was removed in vacuo and the crude
product was purified by filtration over Discovery® DSC-18 SPE cartridge
(H2O:MeOH). Yield: 55% (4.5 mg, 0.01 mmol). 1H NMR (300 MHz,
CD3OD) δH (ppm): 8.64 (1H, s, H-7), 8.23 (2H, d, J 8.8 Hz, H-17, H-18),
8.12 (1H, s, H-12), 7.59 (1H, s, H-3), 7.51 (2H, d, J 8.8 Hz, H-15, H-16),
7.16 (1H, s, H-6), 5.74 (2H, s, H-13), 5.04 (2H, s, H-10), 4.08 (3H, s, H-
21). 13C NMR (101 MHz, CD3OD) δC (ppm): 161.2 (C-8), 157.6 (C-2),
150.4 (C-1), 149.4 (C-7), 149.3 (C-4), 143.9 (C-19), 134.9 (C-11), 130.0
(C-15, C-16), 125.3 (C-12), 125.0 (C-17, C-18), 109.0 (C-5), 107.3 (C-3),
9