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doi.org/10.1002/cmdc.202100432
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was saponified according to general procedure D to afford 31
(60 mg, 0.19 mmol, 79%) as a brown oil without the need of any
purification. 1H-NMR (300 MHz, Methanol-d4) δ 7.84 (dt, J=7.9,
1.0 Hz, 1H), 7.26 (ddd, J=12.1, 8.1, 1.5 Hz, 1H), 7.10 (td, J=7.7,
1.8 Hz, 1H), 6.95 (td, J=8.0, 4.7 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.71–
6.64 (m, 2H), 2.52 (t, J=9.0 Hz, 2H), 1.65–1.49 (m, 2H), 1.37–1.24 (m,
6H), 0.88 (t, J=6.6 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 174.30,
156.45, 153.16, 143.80, 143.19, 133.45, 133.29, 128.59, 127.17,
124.07, 121.86, 120.51, 120.39, 119.98, 119.71, 118.26, 115.62, 36.04,
31.84, 31.46, 29.20, 22.76, 14.22; 19F-NMR (282 MHz, Methanol-d4) δ
À 118.95, À 118.96, À 118.98, À 118.99, À 119.00, À 119.02, À 119.03;
HRMS (ESI) [M+H]+ calcd for C19H22FNO2: 316.1707, found
316.1720; HPLC purity: 99%.
general procedure C. Purification by flash column chromatography
(hexanes/EtOAc 99:1 to 90:10) provided product 79 (93 mg,
1
0.28 mmol, 50%) as a yellow oil. H-NMR (300 MHz, CDCl3) δ 9.25
(s(br), 1H), 7.66 (dd, J=9.5, 3.1 Hz, 1H), 7.29–7.21 (m, 2H), 7.11–7.03
(m, 3H), 6.93 (d, J=7.6 Hz, 1H), 3.92 (s, 3H), 2.61 (t, J=9.0 Hz, 2H),
1.70–1.58 (m, 2H), 1.42–1.27 (m, 6H), 0.92 (t, J=6.7 Hz, 3H); 13C-NMR
(75 MHz, CDCl3) δ 168.11, 168.08, 155.87, 152.74, 144.85, 144.83,
144.61, 140.91, 129.31, 123.88, 122.39, 122.01, 121.71, 119.43,
117.00, 116.69, 115.91, 115.82, 112.24, 112.16, 52.08, 36.03, 31.85,
31.48, 29.12, 22.74, 14.21; 19F-NMR (282 MHz, CDCl3) δ À 126.87,
À 126.88, À 126.89, À 126.90, À 126.91, À 126.92, À 126.93, À 126.94.
5-Fluoro-2-((3-hexylphenyl)amino)benzoic acid (33). Saponifica-
tion of methyl 5-fluoro-2-((3-hexylphenyl)amino)benzoate 79
(74 mg, 0.22 mmol) was performed according to general procedure
D to afford 33 (66 mg, 0.21 mmol, 95%) as a yellow solid without
the need of any purification. 1H-NMR (300 MHz, Methanol-d4) δ 7.62
(dd, J=9.6, 3.1 Hz, 1H), 7.25–7.17 (m, 1H), 7.17 (dd, J=2.6, 2.0 Hz,
1H), 7.08 (ddd, J=9.3, 7.7, 3.1 Hz, 1H), 7.00–6.95 (m, 2H), 6.86 (d, J=
7.6 Hz, 1H), 2.55 (t, J=9.0 Hz, 2H), 1.64–1.52 (m, 2H), 1.33–1.26 (m,
6H), 0.88 (t, J=6.7 Hz, 3H); 13C-NMR (75 MHz, Methanol-d4) δ 170.68,
157.09, 153.98, 146.04, 145.59, 142.26, 130.29, 124.62, 122.88,
122.24, 120.02, 118.25, 116.75, 36.85, 32.86, 32.57, 30.03, 23.69,
Methyl 2-bromo-4-fluorobenzoate (76). Esterification of 2-bromo-
4-fluorobenzoic acid (2.00 g, 9.13 mmol) was performed according
to general procedure E to afford 76 (1.92 g, 8.25 mmol, 44%) as a
colorless oil without the need of any purification. 1H-NMR (300 MHz,
CDCl3) δ 7.89 (dd, J=8.7, 6.0 Hz, 1H), 7.43 (dd, J=8.3, 2.4 Hz, 1H),
7.09 (td, J=8.2, 2.5 Hz, 1H), 3.94 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ
165.66, 164.80, 163.10, 133.52, 133.46, 128.11, 128.09, 123.28,
123.21, 122.09, 121.93, 114.71, 114.57, 52.63; 19F-NMR (282 MHz,
CDCl3) δ À 105.73, À 105.75, À 105.76, À 105.78, À 105.78, À 105.81..
14.43; 19F-NMR (282 MHz, Methanol-d4)
À 129.01, À 129.01, À 129.02, À 129.03, À 129.04, À 129.06; HRMS (ESI)
[M+H]+ calcd for C19H22FNO2: 316.1707, found 316.1718; HPLC
purity: >99%.
δ
À 128.98, À 129.00,
Methyl 4-fluoro-2-((3-hexylphenyl)amino)benzoate (77). 3-Hexyla-
niline 68 (121 mg, 0.68 mmol) was reacted with 76 according to
general procedure C. Purification by flash column chromatography
(hexanes/EtOAc 95:5) provided product 77 (211 mg, 0.64 mmol,
1
94%) as a yellow oil. H-NMR (300 MHz, CDCl3) δ 9.65 (s(br), 1H),
Methyl 2-bromo-6-fluorobenzoate (80). Esterification of 2-bromo-
6-fluorobenzoic acid (300 mg, 1.4 mmol) was performed according
to general procedure E to afford 80 (140 mg, 0.6 mmol, 43%) as a
colorless oil without the need of any purification. 1H-NMR (300 MHz,
CDCl3) δ 7.38 (dd, J=8.1, 0.7 Hz, 1H), 7.30–7.20 (m, 1H), 7.11–7.02
(m, 1H), 3.96 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ 164.43, 161.34,
157.97, 132.11, 131.99, 128.71, 128.67, 124.78, 124.51, 120.39,
120.34, 115.17, 114.89, 53.11; 19F-NMR (282 MHz, CDCl3) δ À 111.50,
À 111.52, À 111.54, À 111.56.
7.98 (dd, J=9.0, 6.8 Hz, 1H), 7.29 (td, J=7.4, 1.3 Hz, 1H), 7.11–7.06
(m, 2H), 6.99 (d, J=7.6 Hz, 1H), 6.87 (dd, J=12.2, 2.5 Hz, 1H), 6.45–
6.37 (m, 1H), 3.91 (s, 3H), 2.67–2.59 (t, J=7.5 Hz, 2H), 1.71–1.58 (m,
2H), 1.41–1.30 (m, 6H), 0.96–0.88 (m, 3H); 13C-NMR (75 MHz, CDCl3) δ
168.61, 168.42, 165.28, 150.89, 150.73, 144.73, 139.85, 134.38,
134.23, 129.40, 124.84, 123.54, 120.62, 107.96, 104.73, 104.43,
100.07, 99.72, 51.84, 35.99, 31.85, 31.46, 29.10, 22.73, 14.21; 19F-NMR
(282 MHz, CDCl3) δ À 103.31, À 103.32, À 103.34, À 103.34, À 103.35,
À 103.36, À 103.37, À 103.38, À 103.39, À 103.41, À 103.41.
Methyl 2-fluoro-6-((3-hexylphenyl)amino)benzoate (81). 3-Hexyla-
niline 68 (100 mg, 0.56 mmol) was reacted with 80 according to
general procedure C. Purification by flash column chromatography
(hexanes/EtOAc 99:1 to 90:10) provided product 81 (162 mg,
4-Fluoro-2-((3-hexylphenyl)amino)benzoic acid (32). Saponifica-
tion of methyl 4-fluoro-2-((3-hexylphenyl)amino)benzoate 77
(200 mg, 0.61 mmol) was performed according to general proce-
dure D to afford 32 (95 mg, 0.30 mmol, 49%) as a yellow solid
1
0.49 mmol, 88%) as a yellow oil. H-NMR (300 MHz, CDCl3) δ 9.09
1
without the need of any purification. H-NMR (300 MHz, CDCl3) δ
(s(br), 1H), 7.28–7.14 (m, 2H), 7.06–7.01 (m, 2H), 6.98 (d, J=8.6 Hz,
1H), 6.93 (d, J=7.6 Hz, 1H), 6.46 (ddd, J=11.2, 8.1, 1.0 Hz, 1H), 3.94
(s, 3H), 2.59 (t, J=9.0 Hz, 2H), 1.65–1.58 (m, 2H), 1.37–1.27 (m, 6H),
0.93–0.86 (t, J=6.6 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 167.86,
165.14, 161.75, 149.02, 144.64, 140.54, 133.87, 129.32, 124.27,
122.86, 119.96, 110.12, 105.22, 52.28, 36.02, 31.85, 31.48, 29.12,
9.43 (s(br), 1H), 8.04 (dd, J=8.7, 6.9 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H),
7.12–7.05 (m, 2H), 7.01 (d, J=7.6 Hz, 1H), 6.80 (dd, J=12.1, 2.2 Hz,
1H), 6.48–6.38 (m, 1H), 2.68–2.56 (t, J=7.5 Hz, 2H), 1.71–1.55 (m,
2H), 1.41–1.24 (m, 6H), 0.89 (t, J=6.6 Hz, 3H); 13C-NMR (75 MHz,
CDCl3) δ 172.87, 169.39, 166.04, 151.91, 151.75, 144.91, 139.47,
135.57, 135.41, 129.52, 125.38, 124.10, 121.23, 105.21, 104.90,
100.18, 99.83, 36.01, 31.86, 31.50, 29.13, 22.75, 14.24; 19F-NMR
(282 MHz, CDCl3) δ À 101.57, À 101.59, À 101.61, À 101.63, À 101.66;
HRMS (ESI) [M+H]+ calcd for C19H22FNO2: 316.1707, found
316.1722; HPLC purity: >99%.
22.75, 14.23; 19F-NMR (282 MHz, CDCl3)
À 105.87, À 105.89.
δ
À 105.83, À 105.85,
2-Fluoro-6-((3-hexylphenyl)amino)benzoic
acid (34=LM98).
Methyl 2-fluoro-6-((3-hexylphenyl)amino)benzoate 81 (100 mg,
0.30 mmol) was saponified according to general procedure D to
afford 34 (LM98) (57 mg, 0.18 mmol, 60%) as a brown solid without
the need of any purification. 1H-NMR (300 MHz, Methanol-d4) δ
7.25–7.11 (m, 2H), 6.99–6.85 (m, 4H), 6.43 (ddd, J=11.2, 8.1, 0.7 Hz,
1H), 2.57–2.49 (t, J=7.5 Hz, 2H), 1.56 (quint, J=7.6 Hz, 2H), 1.33–
1.23 (m, 6H), 0.86 (t, J=6.6 Hz, 3H); 13C-NMR (75 MHz, Methanol-d4)
δ 169.79, 166.44, 163.06, 150.11, 150.05, 145.55, 141.87, 134.66,
134.51, 130.27, 124.98, 123.36, 120.56, 110.85, 110.81, 105.94,
105.62, 104.96, 104.77, 36.80, 32.83, 32.52, 30.00, 23.66, 14.44; 19F-
Methyl 2-bromo-5-fluorobenzoate (78). Esterification of 2-bromo-
5-fluorobenzoic acid (300 mg, 1.37 mmol) was performed according
to general procedure E to afford 78 (262 mg, 1.13 mmol, 82%) as a
colorless oil without the need of any purification. 1H-NMR (300 MHz,
CDCl3) δ 7.60 (dt, J=7.9, 2.5 Hz, 1H), 7.51 (dt, J=8.7, 2.9 Hz, 1H),
7.10–7.00 (m, 1H), 3.93 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ 165.47,
163.06, 159.76, 135.97, 135.87, 133.56, 133.46, 120.23, 119.93,
118.79, 118.46, 116.19, 116.15, 52.82; 19F-NMR (282 MHz, CDCl3) δ
À 113.95, À 113.96, À 113.97, À 113.98, À 113.99, À 113.99, À 114.00,
À 114.02.
NMR (282 MHz, Methanol-d4)
δ
À 107.32, À 107.34, À 107.36,
À 107.38; HRMS (ESI) [M+H]+ calcd for C19H22FNO2: 316.1707, found
316.1722; HPLC purity: >99%.
Methyl 5-fluoro-2-((3-hexylphenyl)amino)benzoate (79). 3-Hexyla-
niline 68 (100 mg, 0.56 mmol) was reacted with 78 according to
ChemMedChem 2021, 16, 1–22
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