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doi.org/10.1002/cmdc.202000994
ChemMedChem
The organic layer was washed with sat. NaHCO3 solution (4×30 mL)
and dried over Na2SO4. The solvent was evaporated under reduced
pressure and the resultant crude product was purified by
centrifugal TLC (CH2Cl2) to give 13 as a white solid (222 mg, 98%).
1H NMR (500 MHz, CDCl3): δ=7.71 (br, 1H, NH), 7.50 (d, J=7.9 Hz,
2H, 2’-H, 6’-H), 7.29 (t, J=7.9 Hz, 2H, 3’-H, 5’-H), 7.09 (t, J=7.4 Hz,
1H, 4’-H), 3.70 (s, 3H, OCH3), 2.75 (t, J=6.5 Hz, 2H, 2-H or 3-H), 2.66
(t, J=6.5 Hz, 2H, 2-H or 3-H) ppm. 13C NMR (126 MHz, CDCl3): δ=
173.78 (C-1 or C-4), 169.84 (C-1 or C-4), 137.97 (C-1’), 129.07 (C-3’, C-
5’), 124.35 (C-4’), 119.90 (C-2’, C-6’), 52.12 (OCH3), 32.20 (C-2 or C-3),
29.36 (C-2 or C-3) ppm. HRMS (ESI): calcd. for C11H14NO3 [M+H]+
208.0968, found 208.0961. TLC (petroleum ether/EtOAc 7:3): Rf =
0.10.
MS (ESI): m/z=246.0 [M+H]+, 268.0 [M+Na]+. HRMS (ESI): calcd.
for C11H13N5O2 [M+H]+ 246.0986, found 246.0982. TLC (CH2Cl2/
MeOH 95:5): Rf =0.25. 18: H NMR (500 MHz, [D6]DMSO): δ=10.95
(s, 1H, NH), 9.05 (s, 1H, 5’’-H), 7.96 (d, J=8.8 Hz, 2H, 3’-H, 5’-H), 7.70
(d, J=8.8 Hz, 2H, 2’-H, 6’-H), 5.78 (s, 2H, 2-H), 2.53 (s, 3H, acetyl-CH3)
ppm. 13C NMR (126 MHz, [D6]DMSO): δ=196.53 (acetyl-C=O), 163.52
(C-1), 153.42 (C-5’’), 142.40 (C-1’), 132.34 (C-4’), 129.61 (C-3’, C-5’),
118.65 (C-2’, C-6’), 55.05 (C-2), 26.46 (acetyl-CH3) ppm. HRMS (ESI):
calcd. for C11H12N5O2 [M+H]+ 246.0986, found 246.0984. TLC
(CH2Cl2/MeOH 95:5): Rf =0.40.
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N-(4-Acetylphenyl)-2-(2H-tetrazol-5-yl)acetamide (19): A suspen-
sion of nitrile 23 (102 mg, 0.505 mmol), NaN3 (159 mg, 2.45 mmol)
and ZnBr2 (100 mg, 0.444 mmol) in iPrOH/water (1:3) was stirred
under reflux for 2 d. After cooling to RT, EtOAc (200 mL) was added,
and the organic layer was washed with HCl (0.2 m, 3×50 mL) and
brine (50 mL) and then dried over Na2SO4. The solvent was
evaporated under reduced pressure, and the resultant crude
product was purified by centrifugal TLC (CH2Cl2/MeOH 100:0!
N-(4-Acetylphenyl)-2-(1H-1,2,3-triazol-1-yl)acetamide (14): Alkyl
chloride 21 (60 mg, 0.28 mmol), NEt3 (90 μL, 0.65 mmol) and 1H-
1,2,3-triazole (20 μL, 0.34 mmol) were dissolved in DMF (10 mL) and
stirred at RT for 8 d. EtOAc (250 mL) was added, and the organic
layer was washed with water (5×30 mL) and brine (30 mL) and
then dried over Na2SO4. The solvent was evaporated under reduced
pressure, and the resultant crude product was purified by column
chromatography (CH2Cl2/MeOH 99:1) to give 14 as a white solid
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90:10) to give 19 as a white solid (41 mg, 33%). H NMR (500 MHz,
[D6]DMSO): δ=16.26 (br, 1H, 2’’-NH), 10.78 (s, 1H, NH(C=O)), 7.95 (d,
J=8.8 Hz, 2H, 3’-H, 5’-H), 7.72 (d, J=8.8 Hz, 2H, 2’-H, 6’-H), 4.20 (s,
2H, 2-H), 2.53 (s, 3H, acetyl-CH3) ppm. 13C NMR (126 MHz, [D6]
DMSO): δ=196.56 (acetyl-C=O), 165.73 (C-1), 150.82 (C-5’’, HMBC),
142.95 (C-1’), 132.11 (C-4’), 129.60 (C-3’, C-5’), 118.52 (C-2’, C-6’),
31.80 (C-2), 26.48 (acetyl-CH3) ppm. MS (ESI): m/z=246.0 [M+H]+.
HRMS (ESI): calcd. for C11H12N5O2 [M+H]+ 246.0986, found
246.0980. TLC (CH2Cl2/MeOH/HCOOH 94:5:1): Rf =0.50.
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(17 mg, 25%). H NMR (500 MHz, [D6]DMSO): δ=10.83 (s, 1H, NH),
8.17 (d, J=0.9 Hz, 1H, 5’’-H), 7.96 (d, J=8.8 Hz, 2H, 3’-H, 5’-H), 7.77
(d, J=0.8 Hz, 1H, 4’’-H), 7.72 (d, J=8.8 Hz, 2H, 2’-H, 6’-H), 5.41 (s, 2H,
2-H), 2.53 (s, 3H, acetyl-CH3) ppm. 13C NMR (126 MHz, [D6]DMSO):
δ=196.52 (acetyl-C=O), 164.96 (C-1), 142.69 (C-1’), 133.15 (C-4’’),
132.15 (C-4’), 129.61 (C-3’, C-5’), 126.55 (C-5’’), 118.53 (C-2’, C-6’),
52.04 (C-2), 26.45 (acetyl-CH3) ppm. MS (ESI): m/z=245.0 [M+H]+.
HRMS (ESI): calcd. for C12H13N4O2 [M+H]+ 245.1033, found
245.1030. TLC (CH2Cl2/MeOH 95:5): Rf =0.15.
N-(4-Acetylphenyl)-2-(1H-imidazol-4-yl)acetamide (20): 2-(1H-imi-
dazol-4-yl)acetic acid hydrochloride (180 mg, 1.11 mmol), HBTU
(430 mg, 1.13 mmol) and DIPEA (140 μL, 0.823 mmol) were dis-
solved in DMF (5 mL). After 5 min stirring at RT, p-aminoacetophe-
none (101 mg, 0.747 mmol) was added, and the reaction mixture
was stirred at RT for 27 h. EtOAc (200 mL) was added, and the
organic layer was washed with NaHCO3 solution (1.0 m, 3×50 mL)
and brine (50 mL) and then dried over Na2SO4. The solvent was
evaporated under reduced pressure, and the resultant crude
product was purified by column chromatography (CH2Cl2/MeOH/
NEt3 90:5:5) to give 20 as a white solid (70 mg, 39%). 1H NMR
(500 MHz, [D6]DMSO): δ=11.95 (br, 1H, 1’’-NH), 10.44 (s, 1H,
NH(C=O)), 7.92 (d, J=8.8 Hz, 2H, 3’-H, 5’-H), 7.73 (d, J=8.8 Hz, 2H,
2’-H, 6’-H), 7.58 (d, J=1.0 Hz, 1H, imidazole-H), 6.94 (s, 1H,
imidazole-H), 3.61 (s, 2H, 2-H), 2.52 (s, 3H, acetyl-CH3) ppm. 13C NMR
(126 MHz, [D6]DMSO): δ=196.46 (acetyl-C=O), 169.29 (C-1), 143.57
(C-1’), 134.95 (imidazole-C), 131.60 (C-4’), 129.47 (C-3’, C-5’), 118.25
(C-2’, C-6’), 35.87 (C-2), 26.40 (acetyl-CH3) ppm (due to poor
relaxation, two imidazole-carbon nuclei could not be observed, but
the respective hydrogen nuclei were found in the 1H NMR
spectrum). HRMS (ESI): calcd. for C13H14N3O2 [M+H]+ 244.1081,
found 244.1077. TLC (CH2Cl2/MeOH/NEt3 85:10:5): Rf =0.25.
N-(4-Acetylphenyl)-2-(1H-imidazol-1-yl)acetamide (15): General
procedure GP1 with 1H-imidazole (41 mg, 0.60 mmol) and alkyl
iodide 22 (156 mg, 0.515 mmol) to give 15 as a white solid (47 mg,
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38%). H NMR (500 MHz, [D6]DMSO): δ=10.65 (s, 1H, NH), 7.95 (d,
J=8.8 Hz, 2H, 3’-H, 5’-H), 7.72 (d, J=8.8 Hz, 2H, 2’-H, 6’-H), 7.64 (s,
1H, 2’’-H), 7.17 (t, J=1.9 Hz, 1H, 5’’-H), 6.90 (t, J=0.9 Hz, 1H, 4’’-H),
4.96 (s, 2H, 2-H), 2.53 (s, 3H, acetyl-CH3) ppm. 13C NMR (126 MHz,
[D6]DMSO): δ=196.50 (acetyl-C=O), 166.43 (C-1), 142.93 (C-1’),
138.35 (C-2’’), 131.93 (C-4’), 129.59 (C-3’, C-5’), 127.92 (C-4’’), 120.76
(C-5’’), 118.39 (C-2’, C-6’), 49.18 (C-2), 26.43 (acetyl-CH3) ppm. HRMS
(ESI): calcd. for C13H14N3O2 [M+H]+ 244.1081, found 244.1078. TLC
(CH2Cl2/MeOH 9:1): Rf =0.20.
N-(4-Acetylphenyl)-2-(1H-1,2,4-triazol-1-yl)acetamide (16): General
procedure GP1 with 1H-1,2,4-triazol (46 mg, 0.67 mmol) and alkyl
iodide 22 (165 mg, 0.545 mmol) to give 16 as a slightly orange solid
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(87 mg, 65%). H NMR (500 MHz, [D6]DMSO): δ=10.76 (s, 1H, NH),
8.56 (s, 1H, 5’’-H), 8.01 (s, 1H, 3’’-H), 7.95 (d, J=8.8 Hz, 2H, 3’-H, 5’-
H), 7.71 (d, J=8.8 Hz, 2H, 2’-H, 6’-H), 5.19 (s, 2H, 2-H), 2.53 (s, 3H,
acetyl-CH3) ppm. 13C NMR (126 MHz, [D6]DMSO): δ=196.58 (acetyl-
C=O), 165.26 (C-1), 151.47 (C-3’’), 145.69 (C-5’’), 142.73 (C-1’), 132.16
(C-4’), 129.66 (C-3’, C-5’), 118.55 (C-2’, C-6’), 51.85 (C-2), 26.51
(acetyl-CH3) ppm. MS (ESI): m/z=245.0 [M+H]+. HRMS (ESI): calcd.
for C12H13N4O2 [M+H]+ 245.1033, found 245.1030. TLC (CH2Cl2/
MeOH 95:5): Rf =0.10.
N-(4-Acetylphenyl)-2-chloroacetamide (21): p-Aminoacetophe-
none (1.00 g, 7.41 mmol) and DIPEA (1.40 mL, 8.18 mmol) were
dissolved in THF (5 mL). Chloroacetyl chloride (650 μL, 8.16 mmol)
was added dropwise, and the reaction mixture was stirred at RT for
20 min. The reaction was quenched by addition of MeOH (15 mL).
The mixture was then diluted with EtOAc (200 mL), washed with
HCl (0.2 m, 3×30 mL) and sat. NaHCO3 solution (3×30 mL) and
then dried over Na2SO4. The solvent was evaporated under reduced
N-(4-Acetylphenyl)-2-(1H-tetrazol-1-yl)acetamide (17) and N-(4-
acetylphenyl)-2-(2H-tetrazol-2-yl)acetamide (18): General proce-
dure GP1 with 1H-tetrazole (27 mg, 0.39 mmol) and alkyl iodide 22
(101 mg, 0.333 mmol) to give 17 as a white solid (28 mg, 34%) and
18 as a white solid (26 mg, 32%). 17: 1H NMR (500 MHz, [D6]DMSO):
δ=10.90 (s, 1H, NH), 9.43 (s, 1H, 5’’-H), 7.96 (d, J=8.8 Hz, 2H, 3’-H,
5’-H), 7.71 (d, J=8.8 Hz, 2H, 2’-H, 6’-H), 5.54 (s, 2H, 2-H), 2.53 (s, 3H,
acetyl-CH3) ppm. 13C NMR (126 MHz, [D6]DMSO): δ=196.55 (acetyl-
C=O), 164.14 (C-1), 145.26 (C-5’’), 142.50 (C-1’), 132.27 (C-4’), 129.64
(C-3’, C-5’), 118.59 (C-2’, C-6’), 50.14 (C-2), 26.46 (acetyl-CH3) ppm.
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pressure to give 21 as a slightly green solid (1.54 g, 98%). H NMR
(500 MHz, CDCl3): δ=8.41 (s, 1H, NH), 7.98 (d, J=8.7 Hz, 2H, 3’-H, 5’-
H), 7.68 (d, J=8.7 Hz, 2H, 2’-H, 6’-H), 4.22 (s, 2H, 2-H), 2.59 (s, 3H,
acetyl-CH3) ppm. 13C NMR (126 MHz, CDCl3): δ=196.95 (acetyl-C=O),
164.14 (C-1), 141.00 (C-1’), 133.90 (C-4’), 129.89 (C-3’, C-5’), 119.39
(C-2’, C-6’), 42.99 (C-2), 26.61 (acetyl-CH3) ppm. HRMS (ESI): calcd.
for C10H11ClNO2 [M+H]+ 212.0473, found 212.0466. TLC (CH2Cl2/
MeOH 95:5): Rf =0.55.
ChemMedChem 2021, 16, 1257–1267
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