4.2. General Procedures for the Preparation of Target Compounds
N–hydroxy–3–((2–oxo–2H–chromen–4–yl)amino)propanamide (10a). To a solution of hydroxyl amine hydrochloride (2.40 g, 34.8 mmol) in 10 mL MeOH, KOH (1.95 g, 34.8 mmol) was added. The reaction mixture was stirred for 10 min at 40 °C, and was then cooled to 0 °C and filtered. 3–((2–oxo–2H–chromen–4–yl)amino)propanoate methyl ester (320 mg, 1.1 mmol) was added to the filtrate followed by KOH (195 mg, 3.5 mmol), after which the reaction was stirred at room temperature for 30 min. The solvent was removed under reduced pressure, diluted with a saturated NH4Cl aqueous solution, and extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4. The resulting solution was evaporated under a reduced pressure and then purified by column chromatography [eluting with EtOAc followed by 10:1 CH2Cl2/MeOH] to give compound 10a (105 mg, 34.5% yield). 1H-NMR (600 MHz, DMSO-d6) δ 10.50 (brs, 1H), 8.81 (brs, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.76–7.75 (m, 1H), 7.59 (dd, J = 6.6, 6.0 Hz, 1H), 7.33–7.30 (m, 2H), 5.19 (s, 1H), 3.49–3.47 (m, 2H), 2.36 (t, J = 6.6 Hz, 2H). 13C-NMR (150 MHz, DMSO-d6) δ 166.90, 161.49, 153.06, 152.87, 131.92, 123.32, 122.38, 116.96, 114.40, 81.57, 40.04, 30.92. HRMS (ESI): calcd for [C12H12N2O4 + H] + 249.0870, found 249.0882. HPLC purity: 99.6%, tR = 2.2 min.
Compounds 10b–e, 11a–e and 12a,b were prepared according to the procedure described for the preparation of compound 10a.
N–hydroxy–6–((2–oxo–2H–chromen–4–yl)amino)hexanamide (10b) (31.4% yield). 1H-NMR (600 MHz, DMSO-d6) δ 10.37 (brs, 1H), 8.68 (brs, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.66–7.64 (m, 1H), 7.60–7.57 (m, 1H), 7.33–7.30 (m, 2H), 5.14 (s, 1H), 3.22 (q, J = 6.0 Hz, 2H), 1.97 (t, J = 7.8 Hz, 2H), 1.66–1.61 (m, 2H), 1.58–1.53 (m, 2H), 1.37–1.31 (m, 2H). 13C-NMR (150 MHz, DMSO-d6) δ 169.02, 161.58, 153.10, 153.08, 131.86, 123.26, 122.48, 116.95, 114.47, 81.16, 42.22, 32.23, 27.21, 26.19, 24.90. HR-MS (ESI): calcd for [C15H18N2O4 + H] + 291.1339, found 291.1344. HPLC purity: 99.8%, tR = 4.1 min.
N–hydroxy–6–((7–methoxy–2–oxo–2H–chromen–4–yl)amino)hexanamide (10c) (28.9% yield). 1H-NMR (600 MHz, DMSO-d6) δ 10.41 (brs, 1H), 8.68 (brs, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.68–7.66 (m, 1H), 6.89 (dd, J = 8.4, 2.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 4.98 (s, 1H), 3.83 (s, 3H), 3.20–3.15 (m, 2H), 1.96 (t, J = 7.8 Hz, 2H), 1.63–1.58 (m, 2H), 1.55–1.50 (m, 2H), 1.34–1.30 (m, 2H). 13C-NMR (150 MHz, DMSO-d6) δ 169.04, 162.09, 161.94, 154.86, 153.49, 123.93, 111.04, 107.66, 100.82, 79.13, 55.77, 42.11, 32.24, 27.33, 26.20, 24.93. HRMS (ESI): calcd for [C16H20N2O5 + H] + 321.1445, found 321.1450. HPLC purity: 99.5%, tR = 5.0 min.
N–hydroxy–7–((7–methoxy–2–oxo–2H–chromen–4–yl)amino)heptanamide (10d) (30.1% yield). 1H-NMR (600 MHz, DMSO-d6) δ 10.35 (brs, 1H), 8.67 (brs, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.54–7.52 (m, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.86–6.85 (m, 1H), 5.00 (s, 1H), 3.84 (s, 3H), 3.20–3.16 (m, 2H), 1.95 (t, J = 7.8 Hz, 2H), 1.63–1.58 (m, 2H), 1.52–1.48 (m, 2H), 1.37–1.32 (m, 2H), 1.31–1.28 (m, 2H). 13C-NMR (150 MHz, DMSO-d6) δ 169.07, 162.08, 161.88, 154.85, 153.43, 123.68, 111.05, 107.59, 100.82, 79.19, 55.74, 39.92, 32.21, 28.34, 27.46, 26.27, 25.05. HRMS (ESI): calcd for [C17H22N2O5 + H] + 335.1601, found 335.1607. HPLC purity: 99.1%, tR = 6.4 min.
N–hydroxy–8–((7–methoxy–2–oxo–2H–chromen–4–yl)amino)octanamide (10e) (25.4% yield). 1H-NMR (600 MHz, DMSO-d6) δ 10.35 (brs, 1H), 8.67 (brs, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.53–7.51 (m, 1H), 6.91 (dd, J = 8.4, 2.4 Hz, 1H), 6.88–6.85 (m, 1H), 5.00 (s, 1H), 3.84 (s, 3H), 3.20–3.18 (m, 2H), 1.94 (t, J = 7.2 Hz, 2H), 1.62–1.59 (m, 2H), 1.50–1.48 (m, 2H), 1.34–1.30 (m, 4H), 1.26–1.23 (m, 2H). 13C-NMR (150 MHz, DMSO-d6) δ 168.97, 162.08, 161.87, 154.85, 153.42, 123.66, 111.06, 107.59, 100.83, 79.19, 55.74, 39.92, 32.18, 28.55, 28.48, 27.56, 26.47, 25.06. HRMS (ESI): calcd for [C18H24N2O5 + H]+ 349.1758, found 349.1747. HPLC purity: 99.4%, tR = 8.0 min.
N–hydroxy–5–((7–methoxy–2–oxo–2H–chromen–4–yl)oxy)pentanamide (11a) (31.2% yield). 1H-NMR (600 MHz, CD3OD) δ 7.78 (d, J = 8.4 Hz, 1H), 6.93 (dd, J = 8.4, 2.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 5.65 (s, 1H), 4.21 (t, J = 6.6 Hz, 2H), 3.88 (s, 3H), 2.20 (t, J = 7.2 Hz, 2H), 1.94–1.90 (m, 2H), 1.88–1.84 (m, 2H). 13C-NMR (150 MHz, CD3OD) δ 172.48, 168.23, 165.97, 165.16, 156.42, 125.35, 113.63, 110.05, 101.40, 88.40, 70.28, 56.41, 33.21, 29.04, 23.23. HRMS (ESI): calcd for [C15H17NO6 + H] + 308.1129, found 308.1122. HPLC purity: 98.9%, tR = 5.8 min.
N–hydroxy–6–((7–methoxy–2–oxo–2H–chromen–4–yl)oxy)hexanamide (11b) (41.6% yield). 1H-NMR (600 MHz, DMSO-d6) δ 10.36 (brs, 1H), 8.69 (brs, 1H), 7.69 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 8.4, 2.4 Hz, 1H), 5.73 (s, 1H), 4.18 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 1.99 (t, J = 7.2 Hz, 2H), 1.83–1.78 (m, 2H), 1.61–1.56 (m, 2H), 1.46–1.42 (m, 2H). 13C-NMR (150 MHz, DMSO-d6) δ 168.96, 165.40, 162.88, 162.10, 154.63, 123.93, 112.19, 108.35, 100.53, 87.88, 69.20, 55.92, 32.14, 27.17, 25.03, 24.77. HRMS (ESI): calcd for [C16H19NO6 + H] + 322.1285, found 322.1285. HPLC purity: 99.2%, tR = 7.1 min.
N–hydroxy–7–((7–methoxy–2–oxo–2H–chromen–4–yl)oxy)heptanamide (11c) (39.7% yield). 1H-NMR (600 MHz, CD3OD) δ 7.77 (d, J = 8.4 Hz, 1H), 6.95 (dd, J = 8.4, 2.4 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 5.66 (s, 1H), 4.21 (t, J = 6.6 Hz, 2H), 3.89 (s, 3H), 2.12 (t, J = 7.2 Hz, 2H), 1.94–1.90 (m, 2H), 1.70–1.65 (m, 2H), 1.59–1.54 (m, 2H), 1.47–1.42 (m, 2H). 13C-NMR (150 MHz, CD3OD) δ 168.34, 166.04, 165.17, 156.44, 125.31, 113.65, 110.11, 101.44, 88.33, 70.76, 56.42, 33.64, 29.76, 29.47, 26.72, 26.62. HRMS (ESI): calcd for [C17H21NO6 + H] + 336.1442, found 336.1433. HPLC purity: 96.9%, tR = 18.8 min.
N–hydroxy–8–((7–methoxy–2–oxo–2H–chromen–4–yl)oxy)octanamide (11d) (45.8% yield). 1H-NMR (600 MHz, CD3OD) δ 7.75 (d, J = 8.4 Hz, 1H), 6.94 (dd, J = 8.4, 2.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 5.65 (s, 1H), 4.20 (t, J = 6.6 Hz, 2H), 3.89 (s, 3H), 2.10 (t, J = 7.2 Hz, 2H), 1.92–1.89 (m, 2H), 1.67–1.62 (m, 2H), 1.58–1.52 (m, 2H), 1.46–1.43 (m, 2H), 1.40–1.37 (m, 2H). 13C-NMR (150 MHz, CD3OD) δ 172.98, 168.33, 166.04, 165.15, 156.41, 125.27, 113.63, 110.10, 101.44, 88.32, 70.84, 56.42, 33.72, 29.99, 29.98, 29.54, 26.89, 26.65. HRMS (ESI): calcd for [C18H23NO6 + H] + 350.1598, found 350.1596. HPLC purity: 99.2%, tR = 10.3 min.
N–hydroxy–9–((7–methoxy–2–oxo–2H–chromen–4–yl)oxy)nonanamide (11e) (42.3% yield). 1H-NMR (600 MHz, DMSO-d6) δ 10.33 (brs, 1H), 8.66 (brs, 1H), 7.69 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.4 Hz, 1H), 5.73 (s, 1H), 4.18 (t, J = 6.6 Hz, 2H), 3.85 (s, 3H), 1.94 (t, J = 7.2 Hz, 2H), 1.81–1.79 (m, 2H), 1.50–1.47 (m, 2H), 1.46–1.43 (m, 2H), 1.35–1.32 (m, 2H), 1.30–1.26 (m, 2H), 1.26–1.22 (m, 2H). 13C-NMR (150 MHz, DMSO-d6) δ 169.07, 165.41, 162.87, 162.09, 154.62, 123.89, 112.20, 108.36, 100.54, 87.85, 69.29, 55.91, 32.23, 28.64, 28.56, 28.52, 27.95, 25.38, 25.08. HRMS (ESI): calcd for [C19H25NO6 + H] + 364.1755, found 364.1761. HPLC purity: 99.0%, tR = 18.7 min.
N–hydroxy–8–((2–oxo–2H–chromen–7–yl)oxy)octanamide (12a) (37.6% yield). 1H-NMR (600 MHz, DMSO-d6) δ 10.34 (brs, 1H), 8.67 (brs, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.4, 2.4 Hz, 1H), 6.28 (d, J = 9.0 Hz, 1H), 4.06 (t, J = 6.6 Hz, 2H), 1.94 (t, J = 7.2 Hz, 2H), 1.74–1.71 (m, 2H), 1.51–1.48 (m, 2H), 1.42–1.39 (m, 2H), 1.33–1.29 (m, 2H), 1.28–1.24 (m, 2H). 13C-NMR (150 MHz, DMSO-d6) δ 169.08, 161.88, 160.32, 155.42, 144.35, 129.46, 112.71, 112.36, 112.22, 101.10, 68.25, 32.22, 28.49, 28.40, 28.38, 25.31, 25.04. HRMS (ESI): calcd for [C17H21NO5 + H] + 320.1492, found 320.1488. HPLC purity: 99.1%, tR = 8.9 min.
N–hydroxy–8–((4–methyl–2–oxo–2H–chromen–7–yl)oxy)octanamide (12b) (33.2% yield). 1H-NMR (600 MHz, DMSO-d6) δ 10.33 (brs, 1H), 8.66 (brs, 1H), 7.67 (d, J = 9.0 Hz, 1H), 6.96–6.94 (m, 2H), 6.20 (s, 1H), 4.07 (t, J = 6.6 Hz, 2H), 2.40 (s, 3H), 1.94 (t, J = 7.2 Hz, 2H), 1.75–1.70 (m, 2H), 1.52–1.47 (m, 2H), 1.43–1.38 (m, 2H), 1.35–1.30 (m, 2H), 1.28–1.23 (m, 2H). 13C-NMR (150 MHz, DMSO-d6) δ169.09, 161.79, 160.19, 154.77, 153.45, 126.44, 112.99, 112.43, 111.04, 101.12, 68.23, 32.22, 28.50, 28.41, 28.39, 25.32, 25.04, 18.13. HRMS (ESI): calcd for [C18H23NO5 + H] + 334.1649, found 334.1637. HPLC purity: 98.8%, tR = 10.3 min.
Compounds
10a–
e and
11a–
e have been published in patent no. CN 108658915A (Oct 16, 2018) [
37].