Molecules 2020, 25, 2078
8 of 11
118.57, 115.74, 114.29, 99.46, 95.10, 93.63, 80.15, 71.30, 56.95, 29.71, 28.24 (diastereotopic CH2); HRMS
(ESI-QTOF) m/z: [M + H]+ calcd for C16H14N2O3, 283.1077; found, 283.1035.
1-(8-cyano-7-(methoxymethoxy)quinolin-2-yl)but-3-yn-1-yl-methyl(2-(methylamino)ethyl)carbamate (
Carbonyldiimidazole (CDI) (240 mg, 1.49 mmol, 7 eq) was dissolved in CH2Cl2 (6 mL) and the solution
2
). 1,10-
was placed into an ice-bath. A solution of
1 (60 mg, 0.21 mmol, 1 eq) in CH2Cl2 (4 mL) was added
dropwise. The mixture was stirred at 0 ◦C for 1 h and then allowed to reach room temperature and
stirred until complete consumption of starting material (30 min, monitored by LC/MS). The reaction
was quenched with H2O (20 mL), the organic layer was separated and the aqueous layer was extracted
with CH2Cl2 (2
×
5 mL). The organic phases were combined in a round-bottomed flask, cooled by
placing the flask into an ice-bath and N,N’-dimethylethylenediamine (1.1 mL) was added dropwise.
The resulting mixture was stirred at 0 ◦C for 2 h, and then at room temperature for 1 h. The reaction
was then concentrated to dryness and the crude product was purified by column chromatography
1
(CH2Cl2/MeOH gradient) to yield
2
(48 mg, 0.12 mmol, 57%). H NMR (500 MHz, chloroform-d,
δ) 8.15
(d, J = 8.4 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.54 (m, 2H), 6.05 (t, J = 6.0 Hz, 1H), 5.45 (s, 2H), 3.64 (s, 1H,
N-H), 3.58 (s, 3H), 3.56–3.47 (m, 3H), 3.15–3.11 (m, 2H), 2.99 (m, 2H), 2.92 (m, 1H), 2.87 (q, J = 6.3 Hz, 1H),
2.51 (d, J = 31.9 Hz, 3H), 1.97 (d, J = 12.3 Hz, 1H). 13C NMR (126 MHz, chloroform-d,
δ) (rotamers) 162.19,
161.47, 155.95 (155.42), 148.10, 136.77, 133.63, 122.82, 119.08 (118.83), 115.74, 114.68, 99.64, 95.06, 79.86,
75.02, 70.76 (70.67), 56.88, 54.92 (54.01), 48.97 (48.36), 35.81 (35.73), 35.38 (34.89), 24.79. HRMS (ESI-QTOF)
m/z: [M + H]+ calcd for C21H24N4O4, 397.1870; found, 397.1818.
1-(8-cyano-7-(methoxymethoxy)quinolin-2-yl)but-3-yn-1-yl-(2-(2-chloro-N-methylacetamido)ethyl)(methyl)
carbamate (3). To a solution of 2 (48 mg, 0.12 mmol, 1 eq) in CH2Cl2 (5 mL), diisopropylethylamine
(0.04 mL, 0.24 mmol, 2 eq) was added dropwise and the mixture was cooled by placing the flask into an
ice-bath. A freshly prepared (by treatment of chloroacetic acid with thionyl chloride in CH2Cl2 at 0 ◦C)
1 M solution of chloroacetylchloride in CH2Cl2 (0.24 mL, 0.24 mmol, 2 eq) was added dropwise and the
resulting mixture was stirred at 0 ◦C for 2 h, and then at room temperature for 1 h. The reaction was
quenched with H2O (20 mL), extracted with CH2Cl2 (3
×
20 mL), dried over MgSO4, and concentrated
to dryness. The crude product was purified by column chromatography (hexanes/EtOAc gradient) to
1
yield
3
(41 mg, 0.09 mmol, 74%). H NMR (500 MHz, chloroform-d,
δ) 8.18 (d, J = 8.5 Hz, 1H), 7.99
(d, J = 9.2 Hz, 1H), 7.55 (dd, J = 9.4, 6.7 Hz, 2H), 6.11–5.98 (t, J = 9.8 Hz, 1H), 5.46 (s, 2H), 4.27–3.94
(m, 2H), 3.77–3.63 (m, 2H), 3.59 (s, 3H), 3.57–3.41 (m, 1H), 3.28–3.03 (m, 7H), 2.99 (d, J = 5.8 Hz, 2H),
2.09–1.93 (m, 1H). 13C NMR (126 MHz, chloroform-d,
δ) (rotamers) 166.78 (166.71), 162.27 (162.17),
161.70 (161.12), 155.76 (155.27), 148.27 (148.08), 136.79 (136.73), 133.63 (133.56), 122.95, 119.78 (118.50),
115.89 (115.73), 114.55, 99.83 (99.75), 95.07, 79.90 (79.61), 75.15, 70.76 (70.62), 56.90, 48.63, 46.79 (46.28,
46.20, 45.77), 41.52 (41.45, 41.00), 36.64 (35.98, 35.94), 35.55 (34.87), 24.88 (24.69). HRMS (ESI-QTOF) m/z:
[M + H]+ calcd for C23H25ClN4O5, 473.1586; found, 473.1539.
1-(8-cyano-7-hydroxyquinolin-2-yl)but-3-yn-1-yl-(2-(2-chloro-N-methylacetamido)ethyl)(methyl)carbamate (
4).
To a solution of (30 mg, 0.06 mmol, 1 eq) in CH2Cl2 (2 mL), H2O (0.1 mL) and trifluoroacetic acid
3
(0.4 mL) were added. The mixture was stirred at room temperature in the dark for 3 h. After reaction
completion (monitored by LC/MS) the mixture was concentrated to dryness and triturated multiple
1
times with THF, affording pure linker
4
(26 mg, 0.06 mmol, 99% yield). H NMR (500 MHz, chloroform-d,
δ
) 8.24 (d, J = 8.4 Hz, 0.5H, rotamer), 8.17 (d, J = 5.0 Hz, 0.5H, rotamer), 7.81 (dd, J = 18.4, 9.0 Hz, 1H),
7.37 (d, J = 8.3 Hz, 1H), 7.07 (d, J = 9.0 Hz, 0.5H, rotamer), 7.01 (d, J = 9.0 Hz, 0.5H, rotamer), 6.01
(bs, J = 6.4 Hz, 1H, OH), 5.94 (dd, J = 7.1, 4.5 Hz, 1H), 4.33–4.25 (m, 1H, rotamer), 4.17 (d, J = 4.4 Hz
1H, rotamer), 4.01–3.86 (m, 2H), 3.79–3.62 (m, 2H), 3.28 (m, 3H), 3.13–3.08 (m, 3H), 3.05–2.98 (m, 1H,
rotamer), 2.92 (ddd, J = 17.1, 7.1, 2.6 Hz, 1H, rotamer), 2.03 (m, 1H). 13C NMR (126 MHz, chloroform-d,
,
δ
) (rotamers) 168.54, 163.25, 160.42, 156.99, 147.08, 138.12 (137.86), 134.05 (133.88), 121.80, 118.62 (118.47),
116.20, 94.26 (93.88), 79.47 (78.97), 75.94, 71.17 (71.10), 46.47 (46.30), 46.09, 41.58 (40.85), 36.81 (36.00),
35.87 (34.84), 29.70, 25.36 (25.14). HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C21H21ClN4O4, 429.1324;
found, 429.1312.