7 Experimental Procedures and Analytical Data
7.1 The Analytical Data for Starting Materials
Synthesis of (S)-2-Bromooctane [(S)-42ba]171
To the stirred solution of PPh3 (7.93 g, 30.2 mmol) in DCM (25 mL), Br2 (2.3 mL, 28 mmol) was added dropwise at 0 °C. After stirring for an additional 0.5 h at 0 °C, a solution of (R)-octan-2-ol (3.2 g, 25 mmol) and pyridine (2.3 mL, 28 mmol) in DCM (12 mL) was added dropwise at 0 °C, and the mixture was stirred for an additional 3 h at ambient temperature. The reaction mixture was concentrated in vacuo, the residue was vigorously stirred with n-hexane (50 mL), filtered and concentrated again. This operation was repeated twice. Column chromatography of the residue on silica gel (eluent n-hexane) yielded the product [(S)-42ba] (3.53 g, 73%) as a colorless liquid.
1H-NMR (300 MHz, CDCl3): δ = 4.14 (ddd, J = 8.1, 6.7, 5.3 Hz, 1H), 1.98-1.64 (m, 5H), 1.56-1.17 (m, 8H), 0.88 (t, J = 5.8 Hz, 3H).
13C-NMR (75 MHz, CDCl3): δ = 52.6 (CH), 41.8 (CH2), 32.3 (CH2), 29.2 (CH2), 28.3 (CH2), 27.0 (CH3), 23.2 (CH2), 14.6 (CH3).
[α23D] = +34.4° (MeOH).
MS (EI) m/z (relative intensity): 113 (26) [M–Br+], 71 (99), 57 (100), 43 (86).
HR-MS (ESI) m/z calculated for C8H17Br–H+: 191.0435; found: 191.0444.
The The analytical data are in accordance with those reported in the literature.192
Synthesis of 2-(4-Methoxyphenyl)pyridine (6ba)
192 Denton, R. M.; An, J.; Adeniran, B.; Blake, A. J.; Lewis, W.; Poulton, A. M. J. Org. Chem. 2011, 76, 6749–6767.
The general procedure A was followed using 1-bromo-4-methoxybenzene (15b) (6.3 mL, 50 mmol) and 2-chloropyridine 124a) (3.52 g, 34.0 mmol). Purification by column chromatography (n-hexane/EtOAc 5:1) followed by Kugelrohr distillation yielded 6ba (5.25 g, 94%) as a white solid.
M.p.: 53 - 54 °C [Lit.: 53 - 55 °C].193
HR-MS (EI): m/z calculated for C12H12NO+: 186.0919; found: 186.0915.
The analytical data are in accordance with those reported in the literature.193
Synthesis of 2-(4-Fluorophenyl)pyridine (6ca)
The general procedure A was followed using 1-bromo-4-fluorobenzene (15c) (8.79 g, 50.0 mmol) and 2-chloropyridine (124a) (3.39 g, 30.0 mmol). Purification by column chromatography (n-hexane/EtOAc 5:1) followed by Kugelrohr distillation yielded 6ca (3.88 g, 75%) as a white solid.
M.p.: 40 °C [Lit.: 38 - 39 °C].194
The analytical data are in accordance with those reported in the literature.194
193 Riggio, G.; Hopff, W.; Herbert, H.; Alfred, A.; Waser, P. G. Helv. Chim. Acta 1983, 66, 1039–1045.
194 Xu, J.; Cheng, G.; Su, D.; Liu, Y.; Wang, X.; Hu, Y. Chem. Eur. J. 2009, 13105–13110.
Synthesis of 2-(3-Fluorophenyl)pyridine (6da)
The general procedure A was followed using 1-bromo-3-flourobenzene (15d) (8.86 g, 51.0 mmol) and 2-chloropyridine (124a) (3.37 g, 30.0 mmol). Purification by column chromatography (n-hexane/EtOAc 5:1) followed by Kugelrohr distillation yielded 6da (3.43 g, 66%) as a colorless oil.
1H-NMR (300 MHz, CDCl3): = 8.68 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.79-7.63 (m, 4H), 7.41 (ddd, J = 8.2, 8.2, 6.0 Hz, 1H), 7.26 (ddd, JC–F = 6.7, 4.8, 1.5 Hz, 1H), 7.11 (ddd, J = 8.3, 2.6, 0.9 Hz, 1H).
13C-NMR (75 MHz, CDCl3): = 163.3 (d, JC–F = 245 Hz, Cq), 156.0 (d, JC–F = 3 Hz, Cq), 149.7 (CH), 141.7 (d, JC–F = 8 Hz, Cq), 136.8 (CH), 130.2 (d, JC–F = 8 Hz, CH), 122.6 (CH), 122.4 (d, JC–F = 3 Hz, CH), 120.5 (CH), 115.7 (d,JC–F = 21 Hz, CH), 113.8 (d,JC–F = 23 Hz, CH).
MS (EI) m/z (relative intensity): 173 (100) [M+], 154 (11), 146 (15), 125 (8), 120 (9), 75 (7).
HR-MS (EI): m/z calculated for C11H8FN+: 173.0641; found: 173.0642.
The analytical data are in accordance with those reported in the literature.172
Synthesis of 4-Methyl-2-(o-tolyl)pyridine (6eb)
The general procedure A was followed using 1-bromo-2-methylbenzene (15e) (1.05 g, 6.30 mmol) and 2-bromo-4-methylpyridine (124b) (0.59 g, 3.30 mmol). Purification by column chromatography (n-hexane/EtOAc 5:1) followed by Kugelrohr distillation yielded 6eb (0.53 g, 88%) as a colorless oil.
1H-NMR (300 MHz, CDCl3): δ = 8.54 (dd, J = 5.1, 0.8 Hz, 1H), 7.41-7.34 (m, 1H), 7.30-7.23 (m, 3H), 7.23-7.18 (m, 1H), 7.07 (ddd, J = 5.0, 1.7, 0.8 Hz, 1H), 2.40 (s, 3H), 2.36 (s, 3H).
13C-NMR (75 MHz, CDCl3): δ = 160.1 (Cq), 149.1 (CH), 147.3 (Cq), 140.7 (Cq), 135.9 (Cq), 130.8 (CH), 129.7 (CH), 128.3 (CH), 125.9 (CH), 125.1 (CH), 122.8 (CH), 21.3 (CH3), 20.4 (CH3).
MS (EI) m/z (relative intensity): 183 (62) [M+], 167 (100), 152 (19), 115 (10), 89 (15).
HR-MS (EI) m/z calculated for C13H13N+: 183.1048; found: 183.1047.
The analytical data are in accordance with those reported in the literature.195
Synthesis of 2-(2,4-Dimethoxyphenyl)pyridine (6fa)
The general procedure A was followed using 1-bromo-2,4-dimethoxybenzene (15f) (1.89 g, 8.70 mmol) and 2-chloropyridine (124a) (0.69 g, 6.10 mmol). Purification by column chromatography (n-hexane/EtOAc 1:1) followed by Kugelrohr distillation yielded 6fa (0.91 g, 69%) as a colorless oil.
1H-NMR (300 MHz, CDCl3): δ = 8.66 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.92-7.72 (m, 2H), 7.66 (ddd, J = 8.1, 7.4, 1.9 Hz, 1H), 7.15 (ddd, J = 7.4, 4.9, 1.2 Hz, 1H), 6.62 (dd, J = 8.5, 2.4 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H).
13C-NMR (75 MHz, CDCl3): δ = 161.0 (Cq), 157.8 (Cq), 155.5 (Cq), 148.9 (CH), 135.3 (CH), 131.7 (CH), 124.4 (CH), 121.8 (Cq), 120.8 (CH), 104.9 (CH), 98.6 (CH), 55.3 (CH3), 55.2 (CH3).
MS (EI) m/z (relative intensity): 214 (100) [M-H+], 200 (14), 185 (47), 170 (47), 142 (53), 80 (30).
HR-MS (EI) m/z calculated for C13H13NO2-H+: 214.0868; found: 214.0867.
The analytical data are in accordance with those reported in the literature.196
Synthesis of 2-(4-Fluoro-2-methoxyphenyl)pyridine (6ga)
The general procedure A was followed using 1-bromo-4-flouro-2-methoxybenzene (15g) (2.06 g, 10.0 mmol) and 2-chloropyridine (124a) (1.14 g, 9.90 mmol). Purification by column chromatography (n-hexane/EtOAc 1:1) followed by Kugelrohr distillation yielded 6ga (0.67 g, 33%) as a colorless oil.
195 Ackermann, L.; Potukuchi, H. K.; Kapdi, A. R.; Schulzke, C. Chem. Eur. J. 2010, 16, 3300–3303.
196 (a) Maeyama, K. Rec. Res. Dev. Org. Chem. 2003, 7, 43–51; (b) Terashima, M. Chem. Pharm. Bull. 1985, 33, 1009–1015.
1H-NMR (300 MHz, CDCl3): δ = 8.67 (ddd, J = 4.9, 1.9, 1.0 Hz, 1H), 7.79-7.72 (m, 2H), 7.67 (ddd, J = 8.0, 7.4, 1.9 Hz, 1H), 7.18 (ddd, J = 7.4, 4.9, 1.3 Hz, 1H), 6.85-6.55 (m, 2H), 3.83 (s, 3H).
13C-NMR (126 MHz, CDCl3): δ = 164.0 (d, JC-F = 248 Hz, Cq), 158.2 (d, JC-F = 10 Hz, Cq), 155.3 (Cq), 149.5 (CH), 135.8 (CH), 132.4 (d, JC-F = 10 Hz, CH), 125.3 (d, JC-F = 3 Hz, Cq), 124.9 (CH), 121.7 (CH), 107.6 (d, JC-F = 21 Hz, CH), 99.5 (d, JC-F = 26 Hz, CH), 55.9 (CH3).
19F-NMR (282 MHz, CDCl3): δ = -109.40 - 111.63 (m).
HR-MS (ESI) m/z calculated for C12H10FNO+H+: 204.0819; found: 204.0824.
Synthesis of N,N-Dimethyl-3-(pyridin-2-yl)aniline (6ha)
The general procedure A was followed using 3-bromo-N,N-dimethylaniline (15h) (5.00 g, 25.0 mmol) and 2-chloropyridine (124a) (2.24 g, 19.8 mmol). Purification by column chromatography (n-hexane/EtOAc 9:1) followed by Kugelrohr distillation yielded 6ha (2.92 g, 74%) as yellow oil.
1H-NMR (300 MHz, CDCl3): δ = 8.77-8.54 (m, 1H), 7.81-7.68 (m, 2H), 7.45 (dd, J = 2.7, 1.6 Hz, 1H), 7.39-7.17 (m, 3H), 6.84 (ddd, J = 8.0, 2.7, 1.2 Hz, 1H), 3.04 (s, 6H).
13C-NMR (75 MHz, CDCl3): δ = 158.5 (Cq), 151.5 (Cq), 149.6 (CH), 140.3 (Cq), 137.5 (CH), 130.0 (CH), 122.6 (CH), 121.6 (CH), 116.2 (CH), 114.2 (CH), 111.9 (CH), 41.4 (CH3).
MS (EI) m/z (relative intensity): 198 (100) [M+], 183 (72), 168 (12), 154 (38), 127 (14), 91 (14), 43 (15).
HR-MS (EI) m/z calculated for C13H14N2-H+: 197.1079; found: 197.1081.
The analytical data were in accordance with those reported in the literature.197
Synthesis of 2-(4-tert-Butylphenyl)pyridine (6ia)
197 Yoshikai, N.; Asako, S.; Yamakawa, T.; Ilies, L.; Nakamura, E. Chem. Asian J. 2011, 6, 3059–3065.
The general procedure A was followed using 1-bromo-4-tert-butylbenzene (15i) (5.40 g, 25.3 mmol) and 2-chloropyridine (124a) (2.34 g, 20.7 mmol). Purification by column chromatography (n-hexane/EtOAc 9:1) followed by Kugelrohr distillation yielded 6ia (3.3 g, 75%) as a colorless oil.
1H-NMR (300 MHz, CDCl3): δ = 8.68 (dt, J = 4.9, 1.4 Hz, 1H), 8.00-7.83 (m, 2H), 7.78-7.64 (m, 2H), 7.58-7.41 (m, 2H), 7.21 (ddd, J = 5.8, 4.9, 2.7 Hz, 1H), 1.36 (s, 9H).
13C-NMR (75 MHz, CDCl3): δ = 157.6 (Cq), 152.3 (Cq), 149.7 (CH), 136.8 (CH), 136.7 (Cq), 126.7 (2xCH), 125.9 (CH), 121.9 (CH), 120.5 (CH), 34.8 (Cq), 31.5 (CH3).
MS (EI) m/z (relative intensity): 211 (24) [M+], 196 (100), 181 (10), 168 (11).
HR-MS (ESI) m/z calculated for C15H17N+: 211.1361; found: 211.1363.
The analytical data are in accordance with those reported in the literature.198
Synthesis of 2-(2,3,4,5,6-Pentadeuterophenyl)pyridin ([D5]-6aa)
The general procedure A was followed using 1-bromo-2,3,4,5,6-pentadeuterobenzene ([D5]-15a) (2.32 g, 14.3 mmol) and 2-chloropyridine (124a) (1.21 g, 10.7 mmol). Purification by column chromatography (n-hexane/EtOAc 5:1) followed by Kugelrohr distillation yielded [D5]-6aa (1.1 g, 64%) as a colorless oil.
1H-NMR (300 MHz, CDCl3): = 8.70 (ddd, J = 4.8, 1.4, 0.3, Hz, 1 H), 7.80-7.71 (m, 2 H), 7.25-7.21 (m, 1H).
13C-NMR (75 MHz, CDCl3): = 156.9 (Cq), 149.2 (CH), 138.8 (Cq), 136.3 (CH), 128.0 (t, JC-D = 25 Hz, Cq), 127.8 (t, JC-D = 25 Hz, CD), 126.1 (t, JC-D = 25 Hz, CD), 121.7 (CH), 120.1 (CH).
HR-MS (EI) m/z calculated for C11H4D5N+: 161.1127; found: 161.1122.
The analytical data were in accordance with those reported in the literature.199
198 Kobayashi, O.; Uraguchi, D.; Yamakawa, T. Org. Lett. 2009, 11, 2679–2682.
199 Kozhushkov, S. I.; Yufit, D. S.; Ackermann, L. Org. Lett. 2008, 10, 3409–3412.
Synthesis of 4-(Pyridin-2-yl)pyrimidin-2-amine (127a)200
A solution of guanidinine nitrate b (3.14 g, 25.0 mmol) in abs. EtOH (20 mL) was added to a stirred solution of pyridylpropenone a (3.5 g, 20.0 mmol) in boiling abs. EtOH (30 mL) and stirring was continued for 20 min. To this mixture Na (0.9 g, 40 mmol) in EtOH (20 mL) was added and the reaction mixture stirred at 80 °C for 16 h. The solution was allowed to cool to ambient temperature and the precipitate was removed by filtration followed by concentration of the filtrate under reduced pressure. After purification by column chromatography (EtOAc/DCM 95:5) the product 127a (1.72 g, 50%) was isolated as a yellow solid.
M.r.: 133 - 134 °C [Lit: 132 - 137 °C].200
1H-NMR (300 MHz, CDCl3): δ = 8.69 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.43 (d, J = 5.1 Hz, 1H), 8.31 (dt, J = 7.9, 1.1 Hz, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.62 (d, J = 5.2 Hz, 1H), 7.35 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 5.35 (s, 2H).
13C-NMR (75 MHz, CDCl3): δ = 164.2 (Cq), 163.3 (Cq), 159.5 (CH), 154.5 (Cq), 149.6 (CH), 137.0 (CH), 125.2 (CH), 121.6 (CH), 108.2 (CH).
MS (EI) m/z (relative intensity): 172 (100) [M+], 145 (12), 131 (10), 103 (19), 79 (21).
HR-MS (EI) m/z calculated for C9H8N4+
: 172.0749; found: 172.0746.
The analytical data are in accordance with those reported in the literature.200
Synthesis of N-Methyl-4-(pyridin-2-yl)-pyrimidin-2-amine (127b) & N,N-Dimethyl-4-(pyridin-2-yl)-pyrimidin-2-amine (127c)
200 D’Amora, A.; Fanfoni, L.; o ula, D.; Guidolin, .; Zangrando, .; Felluga, F.; Gladiali, .; Benedetti, F.;
Milani, B. Organometallics 2010, 29, 4472–4485.
To a stirred solution of 127a (1.7 g, 10 mmol) in dry THF (50 mL) was added NaH (1.0 g, 25 mmol) in one portion. The reaction mixture was stirred for 8 h at ambient temperature. MeI (1.6 mL, 25 mmol) was added dropwise and the solution was stirred over night. After addition of aq. NH4Cl-solution (50 mL) and separation of the organic layer, the aq. layer was extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with H2O (50 mL) and brine (50 mL) and then dried over anhydrous Na2SO4. After filtration and evaporation, column chromatography and Kugelrohr distillation gave 127b (0.48 g, 24%) and 127c (0.79 g, 43%) as yellow oils.
(127b)
The analytical data are in accordance with those reported in the literature.201
Synthesis of 1-(6-Bromopyridin-3-yl)ethanone (124z)
To a stirred solution of 2,5-dibromopyridine (10.6 g, 44.7 mmol) in dry Et2O (200 mL) at -78 °C was added dropwise a solution of t-BuLi (1.6 M, 29 mL, 45 mmol) in n-pentane over 10 min. After 30 min of stirring at -78 °C, DMA (5.2 mL, 50 mmol) was added and stirring continued for 1.5 h. The resulting mixture was warmed to ambient temperature and poured into water (50 mL). The organic phase was washed with water (2 × 30 mL). The aqueous layer was extracted with Et2O (3 × 30 mL). The combined organic layers were dried over Na2SO4. Removal of the solvent under reduced pressure gave a yellow solid (4.1 g, 46%), which was used without further purification.
M.r.: 127 - 128 °C [Lit.: 127 - 128 °C].
1H-NMR (300 MHz, CDCl3): δ = 8.89 (d, J = 2.5 Hz, 1H), 8.07 (dd, J = 8.3, 2.5 Hz, 1H), 7.76-7.52 (m, 1H), 2.62 (s, 3H).
13C-NMR (75 MHz, CDCl3): δ = 195.7 (Cq), 150.5 (CH), 147.1 (Cq), 137.8 (CH), 131.6 (Cq), 128.7 (CH), 26.9 (CH3).
MS (EI) m/z (relative intensity): 199 (35) [M+], 185 (100), 157 (48), 91 (43), 72 (39).
HR-MS (EI) m/z calculated for C7H6BrNO+: 198.9633; found: 198.9633.
The analytical data are in accordance with those reported in the literature.202
Synthesis of 1-(6-Phenylpyridin-3-yl)ethanone (6ze)
201 Muller, K.; Schubert, A.; Jozak, T.; Ahrens-Botzong, A.; Schnemann, V.; Thiel, W. R. Chem. Cat. Chem 2011, 3, 887–892.
202 El-Deeb, I.M.; Lee, S. H. Bioorg. Med. Chem. 2010, 18, 3860–3874.
Pd(OAc)2 (80 mg, 0.35 mmol), PPh3 (0.08 g, 0.25 mmol), aq. solution of K2CO3 (2.0 M, 16 mL, 32 mmol) and distilled water (32 mL) were added to a degassed solution of 5-acetyl-6-bromopyridine (124z) (4.2 g, 21 mmol) and phenylboronic acid (52e) (3.22 g, 27.0 mmol) in 1-propanol (50 mL), and the mixture was refluxed over night. After cooling to ambient temperature, distilled water (50 mL) was added and the mixture was extracted with EtOAc (2 x 50 mL). The organic layer was dried over anhydrous Na2SO4, and the solvent was evaporated to give the crude ketone, which was purified by recrystallisation from MeOH/DCM to give 6ze (1.9 g, 46%) as colorless plates.
M.p.: 119 °C [Lit.: 119 - 120 °C].
1H-NMR (300 MHz, CDCl3): δ = 9.23 (dd, J = 2.3, 0.9 Hz, 1H), 8.29 (dd, J = 8.4, 2.3 Hz, 1H), 8.10-8.02 (m, 2H), 7.84 (dd, J = 8.4, 0.9 Hz, 1H), 7.59-7.43 (m, 3H), 2.66 (s, 3H).
13C-NMR (75 MHz, CDCl3): δ = 197.0 (Cq), 161.5 (Cq), 150.7 (CH), 138.7 (Cq), 136.9 (CH), 131.2 (Cq), 130.6 (CH), 129.5 (2xCH), 127.9 (2xCH), 120.7 (CH), 27.3 (CH3).
MS (EI) m/z (relative intensity): 197 (68) [M+], 182 (100), 154 (45), 127 (50), 77 (23), 43 (29).
HR-MS (EI) m/z calculated for C13H11NO+: 197.0841; found: 197.0837.
The analytical data are in accordance with those reported in the literature.202
Synthesis of 1-(6-Phenylpyridin-3-yl)ethanol (125b)
NaBH4 (0.4 g , 10.6 mmol) was added portionwise to a stirred solution of 6xe (1.8 g, 9.1 mmol) in EtOH (10 mL). The reaction mixture was stirred at ambient temperature for 2 h. After evaporation the remaining residue was washed with brine (10 mL) and extracted with DCM (2 x 25 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. After evaporation of the solvent 125xe could be isolated quantitatively as a yellow oil and was used without further purification.
1H-NMR (300 MHz, CDCl3): δ = 8.53 (d, J = 2.2 Hz, 1H), 8.01-7.81 (m, 2H), 7.70 (dd, J = 8.3, 2.2 Hz, 1H), 7.61 (dd, J = 8.2, 0.8 Hz, 1H), 7.49-7.32 (m, 3H), 4.88 (q, J = 6.6 Hz, 1H), 3.62 (s, 1H), 1.48 (d, J = 6.6 Hz, 3H).
13C-NMR (75 MHz, CDCl3): δ = 156.6 (Cq), 147.3 (CH), 139.8 (Cq), 139.1 (CH), 134.2 (CH), 129.0 (CH), 128.8 (CH), 127.0 (CH), 120.6 (CH), 67.7 (CH), 25.2 (CH3).
MS (EI) m/z (relative intensity): 199 (45) [M+], 184 (100), 156 (52), 127 (10), 78 (11), 43 (11).
HR-MS (EI) m/z calculated for C13H13NO+: 199.0997; found: 199.0992.
Synthesis of 5-(1-Methoxyethyl)-2-phenylpyridine (126b)
To a stirred solution of the respective alcohol 125xe (1.6 g, 8.0 mmol) in dry THF (25 mL) NaH (0.55 g of a 60% suspension in mineral oil, 13.5 mmol) was added in one portion. The reaction mixture was stirred for 8 h at ambient temperature. MeI (0.85 mL, 13.5 mmol) was added dropwise and the solution was stirred over night. After addition of aq. NH4Cl-solution (30 mL) and separation of the organic layer, the aq. layer was extracted with EtOAc (2 x 30 mL). The combined organic phase was washed with H2O (30 mL) and brine (30 mL) and was dried over anhydrous Na2SO4. Filtration, evaporation, column chromatography (n-hexane/EtOAc 3:2) and Kugelrohr distillation gave 126b (1.7 g, 99%) as a yellow oil.
1H-NMR (300 MHz, CDCl3): δ = 8.61 (dd, J = 1.6 Hz, 1H), 8.07-7.91 (m, 2H), 7.73 (d, J = 1.6 Hz, 2H), 7.53-7.36 (m, 3H), 4.39 (q, J = 6.5 Hz, 1H), 3.27 (s, 3H), 1.50 (d, J = 6.5 Hz, 3H).
13C-NMR (75 MHz, CDCl3): δ = 157.1 (Cq), 148.3 (CH), 139.3 (Cq), 137.2 (Cq), 134.7 (CH), 129.0 (CH), 128.9 (CH), 127.0 (CH), 120.6 (CH), 77.3 (CH), 56.7 (CH3), 23.7 (CH3).
MS (EI) m/z (relative intensity): 213 (20) [M+], 198 (100), 182 (37), 154 (12), 127 (12), 43 (13).
HR-MS (EI) m/z calculated for C14H15NO+: 213.1154; found: 213.1159.
Synthesis of Methyl-4-(pyridin-2-yl)-benzoate (6pa)203
203 Deshmukh, M.; Patil, S.; Banerjee, K.; Oulkar, D.; Shripanavar, D. Der Pharmacia Lettre 2011, 3, 264–266.
To a solution of 4-(pyridin-2-yl)benzoic acid (6ra) (0.80 g, 4.0 mmol) in MeOH (5.0 mL) conc. H2SO4
(0.25 mL) was added and the reaction mixture was stirred at 70 °C for an additional 7 h. After completion of the reaction, the mixture was cooled to ambient temperature and neutralized with aq.
NaHCO3 (25 mL). The remaining residue was extracted with chloroform (2 50 mL). The solvent was removed under reduced pressure to give 6pa (0.39 g, 46%) as an off-white solid.
M.p.: 99 °C [Lit.: 98 - 99 °C].204
The analytical data are in accordance with those reported in the literature.204
Synthesis of 4-(Pyridin-2-yl)benzoic acid (6ra)
A solution of 2-p-tolylpyridine (6oa) (1.99 g, 11.8 mmol) and pyridine (5.9 mL) in water (30 mL) was heated at 100 °C. KMnO4 (5.88 g, 37.2 mmol) was added in one portion and the reaction mixture was stirred at 100 °C for an additional 5 h. After cooling to ambient temperature, the solution was filtered and the filtrate acidified with conc. aq. HCl to pH 5. Filtration and evaporation yielded 6ra (0.94 g, 40%) as a white solid.
M.p.: 241 °C. [Lit.: 236–238 °C].205
1H-NMR (300 MHz, DMSO-d6): δ = 12.96 (s, 1H), 8.71 (d, J = 4.7 Hz, 1H), 8.49-7.65 (m, 6H), 7.41 (dd, J
= 6.1, 6.1 Hz, 1H).
204 Nunez, A.; Sanchez, A.; Burgos, C.; Alvarez-Builla, J. Tetrahedron 2004, 60, 6217–6224.
205 Bailey, T. R. Tetrahedron Lett. 1986, 27, 4407–4410.
13C-NMR (75 MHz, DMSO-d6): δ = 167.0 (Cq), 154.7 (Cq), 149.5 (CH), 142.3 (Cq), 137.5 (CH), 131.1 (Cq), 129.6 (CH), 126.6 (CH), 123.3 (CH), 120.9 (CH).
MS (EI) m/z (relative intensity): 199 (100) [M+], 182 (46), 154 (70), 127 (24).
HR-MS (EI) m/z calculated for C12H9NO2+
: 199.0633; found: 199.0637.
The analytical data were in accordance with those reported in the literature.206
Synthesis of (E)-N-[1-(4-Fluorophenyl)ethylidene]-4-methoxyaniline (121a)
The general procedure B was followed using 4-fluoroacetophenone (0.71 g, 5.1 mmol) and anisidine (0.77 g, 6.3 mmol) in PhMe (25 mL). Purification by column chromatography (n-hexane) yielded 121a (0.75 g, 60%) as a yellow solid.
M.r.: 75 - 81 °C.
1H-NMR (300 MHz, CDCl3): δ = 7.97-7.92 (m, 2H), 7.09 (d, J = 8.6 Hz, 2H), 6.89 (dd, J = 9.0, 2.4 Hz, 2H), 6.73 (ddd, J = 9.0, 2.4,2.4 Hz, 2H), 3.80 (s, 3H), 2.22 (s, 3H).
13C-NMR (75 MHz, CDCl3): δ = 164.3 (Cq), 164.1 (d, JC-F = 259 Hz, Cq), 155.9 (Cq), 144.5 (Cq), 135.8 (Cq), 129.1 (d, JC-F = 9 Hz, CH), 120.7 (CH), 115.1 (d, JC-F = 20 Hz, CH), 114.2 (CH), 55.5 (CH3), 17.3 (CH3).
19F-NMR (282 MHz, CDCl3): δ = - 110.7 - -110.8 (m).
IR (ATR):
~
= 3389, 2988, 2945, 2902, 2831, 1716, 1506, 1363, 1028, 840, 813, 729, 567cm-1. MS (EI) m/z (relative intensity): 243 (68) [M+], 228 (100), 213 (5), 185 (5), 77 (5).HR-MS (ESI) m/z calculated for C15H14FNO+H+: 244.1132; found: 244.1133.
Synthesis of (E)-N-[1-(3-Fluorophenyl)ethylidene]-4-methoxyaniline (121b)
206 Gong, Y.; Pauls, H. W. Synlett 2000, 829–831.
The general procedure B was followed using 3-fluoroacetophenone (0.65 g, 4.7 mmol) and anisidine (0.79 g, 6.4 mmol) in PhMe (25 mL). Purification by column chromatography (n-hexane) yielded 121b (0.71 g, 62%) as a yellow oil.
HR-MS (ESI) m/z calculated for C15H14FNO+H+: 244.1138; found: 244.1133.
The analytical data are in accordance with those reported in the literature.207
Synthesis of (E)-4-Methoxy-N-[1-(3-methoxyphenyl)-ethylidene]aniline (121c)
The general procedure B was followed using 3-methoxyacetophenone (0.76 g, 5.1 mmol) and anisidine (0.79 g, 6.4 mmol) in PhMe (25 mL). Purification by column chromatography (n-hexane) yielded 121c (0.91 g, 70%) as an orange oil.
1H-NMR (300 MHz, CDCl3): δ = 7.65-7.55 (m, 1H), 7.50-7.46 (m, 1H), 7.32 (dd, J = 8.0, 8.0 Hz, 1H),
The analytical data were in accordance with those reported in the literature.208
207 Lee, P. S.; Fujita, T.; Yoshikai, N. J. Am. Chem. Soc. 2011, 133, 17283–17295.
208 Moessner, C.; Bolm, C. Angew. Chem. Int. Ed. 2005, 44, 7564–7567.
Synthesis of (E)-N-[1-(3-Chlorophenyl)-ethylidene]-4-methoxyaniline (121d)
The general procedure B was followed using 3-chloroacetophenone (1.54 g, 10.0 mmol) and anisidine (1.55 g, 12.5 mmol) in PhMe (25 mL). Purification by column chromatography (n-hexane) yielded 121d (1.45 g, 56%) as a yellow solid.
M.r.: 66 °C [Lit.: 64 - 65 °C].
1H-NMR (300 MHz, CDCl3) δ = 7.97 (dd, J = 2.9, 2.3 Hz, 1H), 7.82 (ddd, J = 8.0, 1.7, 1.7 Hz, 1H), 7.49-7.30 (m, 2H), 6.95-6.85 (m, 2H), 6.82-6.63 (m, 2H), 3.82 (s, 3H), 2.24 (s, 3H).
13C-NMR (75 MHz, CDCl3) δ = 164.4 (Cq), 156.2 (Cq), 144.3 (Cq), 141.6 (Cq), 134.6 (Cq), 130.3 (CH), 129.6 (CH), 127.4 (CH), 125.3 (CH), 120.8 (CH), 114.4 (CH), 55.5 (CH3), 17.4 (CH3).
MS (EI) m/z (relative intensity): 259 (53) [M+], 244 (100), 148 (15), 92 (15), 64 (13), 43 (40).
HR-MS (EI) m/z calculated for C15H14ClNO+: 259.0764; found: 259.0755.
The analytical data are in accordance with those reported in the literature.209
Synthesis of (E)-4-Methoxy-N-(1-m-tolylethylidene)aniline (121e)
General procedure B was followed using 3-methylacetophenone (0.70 g, 5.2 mmol) and anisidine (0.78 g, 6.3 mmol) in PhMe (25 mL). Purification by column chromatography (n-hexane) yielded 121e (0.59 g, 47%) as a yellow solid.
M.p.: 59 - 61 °C. [Lit.: 60 - 62 °C].210
1H-NMR (300 MHz, CDCl3): δ = 7.84 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.37-7.21 (m, 2H), 6.90 (ddd, J = 9.3, 2.2, 2.2 Hz, 2H), 6.77 (ddd, J = 9.3, 2.2, 2.2 Hz, 2H), 3.78 (s, 3H), 2.41 (s, 3H), 2.23 (s, 3H).
209 Yoshikai, N.; Matsumoto, A.; Norinder, J.; Nakamura, E. Angew. Chem. Int. Ed. 2009, 48, 2925–2928.
210 Chen, F.; Ding, Z.; He, Y.; Qin, J.; Wang, T.; Fan, Q.-H. Tetrahedron 2012, 68, 5248–5257.
13C-NMR (75 MHz, CDCl3): δ = 165.5 (Cq), 155.6 (Cq), 144.5 (Cq), 139.4 (Cq), 137.6 (Cq), 130.8 (CH), 127.9 (CH), 127.3 (CH), 124.1 (CH), 120.5 (CH), 113.9 (CH), 55.2 (CH3), 21.3 (CH3), 17.2 (CH3).
IR (ATR):
~
= 2983, 2926, 2839, 1668, 1504, 1284, 1237, 1054, 1036, 840, 754, 695 cm-1. MS (EI) m/z (relative intensity): 239 (50) [M+], 224 (100), 148 (10), 92 (12), 77 (16), 64 (13).HR-MS (ESI) m/z calculated for C16H17NO+H+: 240.1383; found: 240.1383.
The analytical data were in accordance with those reported in the literature.210