5
M. Synthesis 1986, 868-870. (e) Das, B.; Venkateswarlu, K.;
Krishnaiah, M.; Holla, H.; Majhi, A. Helv. Chim. Acta 2006, 89,
1417-1421. (f) Khan, A. T.; Ali, Md. A.; Goswami, P.;
Choudhury, L. H. J. Org. Chem. 2006, 71, 8961-8963. (g) Das, B.;
Srinivas, Y.; Holla, H.; Laxminarayana, K.; Narender, R.
Tetrahedron Lett. 2007, 48, 6681-6683. (h) Jiang, B.; Dou, Y.;
Xu, X.; Xu, M. Org. Lett. 2008, 10, 593-596. (i) Khan, A. T.;
Parvin, T.; Choudhury, L. H. J. Org. Chem. 2008, 73, 8398-8402.
33. Karki, M.; Magolan, J. J. Org. Chem. 2015, 80, 3701-3707.
34. Rezaei, N.; Sheikhi, E.; Rashidi Ranjbar, P. Synlett 2018, 29, 912-
917.
1,4-dihydropyridine-3,5-dicarboxylate (4g): White solid, yield:
0.360 g (92%); mp = 183–185 °C. MS (EI): m/z (%) = 391 (41)
[M+], 376 (19), 360 (11), 346 (2), 332 (32), 316 (7), 302 (3), 286
(2), 270 (2), 258 (2), 242 (2), 224 (100), 212 (2), 192 (15), 180
(2), 168 (22), 149 (15), 134 (7), 121 (7), 109 (8), 93 (4), 77 (11),
59 (10), 42 (6). 1H NMR (500.1 MHz, DMSO-d6): δ 2.28 (6H, s, 2
CH3), 3.58 (6H, s, 2 CO2CH3), 3.61 (3H. s, OCH3), 3.69 (6H, s, 2
OCH3), 4.86 (1H, s, ArCH), 6.41 (2H, d, s, CH), 8.89 (1H, s, NH).
13C NMR (125.8 MHz, DMSO-d6): δ 18.60 (CH3), 39.01 (ArCH),
51.10 (CO2CH3), 56.09 (OCH3), 60.31 (OCH3), 101.80 (NC=C),
104.55 (CH), 136.40, 143.82 (2C), 146.19 (NC=C), 152.95 (2C),
167.87 (2C=O). Diethyl 4-(3-hydroxyphenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (4h): Pale yellow solid, yield:
0.325 g (94%); mp = 196–198 °C. MS (EI): m/z (%) = 345 (30)
[M+], 330 (1), 316 (22), 300 (20), 288 (7), 272 (30), 256 (100),
244 (13), 232 (1), 224 (60), 213 (3), 206 (2), 196 (11), 184 (7),
178 (14), 168 (4), 158 (3), 150 (20), 144 (5), 135 (1), 128 (8), 122
(6), 115 (8), 106 (11), 93 (7), 84 (2), 77 (11), 65 (30), 53 (5), 42
(14). 1H NMR (500.1 MHz, DMSO-d6): δ 1.15 (6H, t, J = 7.1 Hz,
35. General procedure for the
preparation of
1,4-
dihydropyridines 4
A mixture of HBr (48% aq., 1 mmol) in DMSO (1 mL) was stirred
for 2 min at 75 °C. Then, benzylic alcohol (1 mmol), alkyl
acetoacetate (2 mmol), and ammonium hydroxide (1.5 mmol)
were added to the reaction mixture and stirring was continued at
75 °C for 2.5 h. The completion of reaction was followed by TLC.
After the reaction was complete, the reaction mixture was cooled
to ambient temperature, quenched by addition of water (2 mL),
and stirring was continued for 10 min at ambient temperature. The
resulting precipitate was filtered, washed with water, dried, and
recrystallized from ethanol to afford the pure product 4. Diethyl
2,6-dimethyl-4-(p-tolyl)-1,4-dihydropyridine-3,5-dicarboxylate
(4a): Yellow solid, yield: 0.323 g (94%); mp = 137–138 °C. MS
(EI): m/z (%) = 343 (21) [M+], 328 (2), 314 (21), 298 (19), 286
(9), 270 (41), 252 (100), 240 (8), 224 (52), 211 (3), 196 (88), 178
(16), 167 (6), 150 (23), 139 (4), 128 (7), 117 (2), 106 (11), 91
(24), 77 (8), 65 (24), 53 (6), 42 (20). 1H NMR (500.1 MHz,
acetone-d6): δ 1.20 (6H, t, J = 7.1 Hz, 2 OCH2CH3), 2.24 (3H, s,
PhCH3), 2.33 (6H, s, 2 CH3), 4.00–4.10 (4H, m, 2 OCH2CH3),
5.01 (1H, s, ArCH), 7.00 (2H, t, J = 7.9 Hz, CH), 7.18 (2H, t, J =
7.9 Hz, CH), 7.83 (1H, br s, NH). 13C NMR (125.8 MHz, acetone-
d6): δ 13.8 (CH3), 17.93 (OCH2CH3), 20.15 (ArCH3), 39.02
(ArCH), 58.93 (OCH2CH3), 103.16 (NC=C), 127.74 (C), 128.30
(CH), 134.96 (CH), 144.65 (C), 145.62 (NC=C), 167.14 (C=O).
Diethyl 4-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate (4e): Yellow solid, yield: 0.335 g (93%); mp =
160–162°C. MS (EI): m/z (%) = 359 (40) [M+],344 (3), 330 (48),
314 (23), 302 (11), 286 (82), 271 (3), 252 (100), 240 (7), 224 (58),
213 (6), 196 (87), 178 (14), 167 (7), 150 (25), 139 (2), 128 (8),
117( 2), 106 (10), 92 (16), 77 (29), 64 (10), 53 (4), 42 (17). 1H
NMR (500.1 MHz, acetone-d6): δ 1.20 (6H, t, J = 7.1, Hz, 2
OCH2CH3), 2.07 (3H, s, 2 CH3), 3.73 (3H, s, OCH3), 4.00–4.11
(4H, m, OCH2CH3), 4.98 (1H, s, ArCH), 6.76 (2H, d, J = 8.6 Hz,
2CH), 7.20 (2H, d, J = 8.6 Hz, 2CH), 7.83 (1H, br s, NH). 13C
NMR (125.8 MHz, acetone-d6): δ 13.88 (CH3), 17.88 (OCH2CH3),
38.50 (ArCH), 54.42 (OCH3), 58.91 (OCH2CH3), 103.27 (NC=C),
113.02, 128.78 (2 CH), 140.68 (C), 144.43 (NC=C), 158.02 (C),
167.17 (C=O). Dimethyl 2,6-dimethyl-4-(3,4,5-trimethoxyphenyl)-
2
OCH2CH3), 2.26 (6H, s, 2 CH3), 3.81–4.26 (4H, m, 2
OCH2CH3), 4.82 (1H, s, ArCH), 6.49 (1H, d, J = 8.2 Hz, CH),
6.59 (1H, s, CH), 6.60 (1H, d, J = 7.8 Hz, CH), 6.97 (1H, t, J = 7.8
Hz, CH), 8.75 (1H, s, NH), 9.09 (1H, s, OH). 13C NMR (125.8
MHz, DMSO-d6):
δ 14.64 (CH3), 18.67 (OCH2CH3), 39.11
(ArCH), 59.41 (OCH2CH3), 102.29 (NC=C), 113.27 (C), 114.83,
118.49, 129.01 (3CH), 145.52 (NC=C), 149.86 (C), 157.41 (CH),
167.50 (C=O). Dimethyl 4-(3-bromophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (4k): White solid, yield: 0.366
g (96%); mp = 192–194 °C. MS (EI): m/z (%) = 381 (11) [M+
81Br], 379 (12) [M+ 79Br], 364 (8), 348 (11), 334 (1), 320 (14), 304
(1), 290 (3), 268 (2), 254 (1), 241 (4), 224 (100), 209 (10), 192
(23), 180 (11), 165 (12), 149 (16), 134 (14), 121 (6), 104 (8), 90
(5), 76 (17), 59 (13), 42 (11). 1H NMR (500.1 MHz, DMSO-d6): δ
2.27 (6H, s, 2 CH3), 3.56 (6H, s, 2 CO2CH3), 4.87 (1H, s, ArCH),
7.14 (1H, d, J = 7.6 Hz, CH), 7.19 (1H, t, J = 7.7 Hz, CH), 7.25
(1H, s, CH), 7.31 (1H, d, J= 7.6 Hz, 1H), 8.97 (1H, s, NH). 13C
NMR (125.8 MHz, DMSO-d6): δ 18.70 (2CH3), 39.10 (ArCH),
51.21 (CO2CH3), 101.46 (NC=C), 121.83 (C), 126.59, 129.37,
130.09, 130.83 (4CH), 146.61 (NC=C), 150.86 (C), 167.61 (C=O).
36. (a) Yadav, D. K.; Patel, R.; Srivastava, V. P.; Watal, G.; Yadav, L.
D. S. Chin. J. Chem. 2011, 29, 118-122. (b) Suresh, Kumar, D.;
Sandhu, J. S. Synth. Commun. 2009, 39, 1957-1965. (c) Eynde, J.
J. V.; Delfosse, F., Mayence, A.; Van Haverbeke, Y. Tetrahedron,
1995, 51, 6511-6516. (d) Ghosh, S.; Saikh, F.; Das, J.; Pramanik,
A. K. Tetrahedron Lett. 2013, 54, 58-62.
37. Olah, G. A.; Vankar, Y. D.; Arvanaghi, M.; Surya Prakash, G.
Synthesis 1979, 720-721.
Metal-free oxidative C-C coupling
HBr/DMSO system as a simple and
available coupling reagent
Novel modification for Hantzsch 1,4-
dihyropyridine synthesis
One-pot method without any isolation step