2252
S. Maiti, J. C. Menéndez
LETTER
(15 mL) and washed with water (3 × 5 mL). The organic
see: Simon, C.; Constantieux, T.; Rodríguez, J. Eur. J. Org.
Chem. 2004, 4957.
layer was dried over anhydrous Na2SO4 and concentrated to
dryness. The crude residue was dissolved in MeCN (10 mL)
and neutral, grade I activity Al2O3 (5 g) was added. The
suspension was heated under reflux for the time specified in
Table 2. After completion of the reaction (verified by NMR),
the mixture was diluted with CH2Cl2 and filtered through a
layer of Celite, which was thoroughly washed with boiling
CH2Cl2 (50 mL, in several portions). The organic layer was
washed with water (5 mL), dried over anhydrous Na2SO4
and concentrated to dryness. The crude residue was purified
by column chromatography on neutral Al2O3 (EtOAc–
petroleum ether, 98:2 containing 1% Et3N). Characterization
data for representative compounds 2 are given below.
Ethyl 1-Butyl-2-methyl-1,4-dihydropyridine-3-
carboxylate (2a). Colorless viscous liquid. IR (neat, NaCl):
2960, 2932, 2874, 1681, 1567, 1233, 1178, 1145, 1073 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.92 (t, J = 7.2 Hz, 3 H),
1.23 (t, J = 7.1 Hz, 3 H), 1.29–1.38 (m, 2 H), 1.44–1.56 (m,
2 H), 2.31 (s, 3 H), 3.1 (d, J = 3.5 Hz, 2 H), 3.2 (t, J = 7.2 Hz,
2 H), 4.05–4.13 (m, 2 H), 4.68–4.75 (m, 1 H), 5.67 (d,
J = 7.9 Hz, 1 H). 13C NMR (62.9 MHz, CDCl3): d = 14.3,
14.9, 15.8, 20.3, 24.9, 32.7, 50.2, 59.6, 94.9, 104.2, 130.9,
150.9, 169.6. Anal. Calcd for C13H21NO2 (223.3): C, 69.92;
H, 9.48; N, 6.27; Found: C, 69.65; H, 9.23; N, 6.12.
Ethyl 1-Butyl-2,4-dimethyl-1,4-dihydropyridine-3-
carboxylate (2e). Colorless viscous liquid. IR (neat, NaCl):
2958, 2930, 2872, 1684, 1560, 1232, 1177, 1137, 1088
cm–1. 1H NMR (250 MHz, CDCl3): d = 0.92–0.98 (m, 6 H),
1.27 (t, J = 6.4 Hz, 3 H), 1.33–1.42 (m, 2 H), 1.48–1.59 (m,
2 H), 2.38 (s, 3 H), 3.11–3.23 (m, 1 H), 3.32–3.52 (m, 2 H),
4.07–4.20 (m, 2 H), 4.87 (dd, J = 7.4, 6.2 Hz, 1 H), 5.81 (d,
J = 7.4 Hz, 1 H). 13C NMR (62.9 MHz, CDCl3): d = 14.3,
14.9, 16.0, 20.2, 25.3, 28.5, 32.8, 50.2, 59.5, 101.0, 109.2,
129.6, 149.3, 169.7. Anal. Calcd for C14H23NO2 (237.3): C,
70.85; H, 9.77; N, 5.90. Found: C, 70.57; H, 9.50; N, 6.00.
Ethyl 1-Butyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-
carboxylate (2k). Light-yellow viscous liquid. IR (neat,
NaCl): 2959, 2872, 1682, 1557, 1393, 1230, 1178, 1145,
1078 cm–1. 1H NMR (250 MHz, CDCl3): d = 0.99 (t, J = 7.3
Hz, 3 H), 1.13 (t, J = 7.1 Hz, 3 H), 1.31–1.46 (m, 2 H), 1.55–
1.68 (m, 2 H), 2.49 (s, 3 H), 3.21–3.32 (m, 1 H), 3.44–3.56
(m, 1 H), 3.99 (q, J = 7.1 Hz, 2 H), 4.60 (d, J = 5.6 Hz, 1 H),
4.96 (dd, J = 5.6, 7.5 Hz, 1 H), 5.91 (d, J = 7.6 Hz, 1 H),
7.15–7.55 (m, 5 H). 13C NMR (62.9 MHz, CDCl3): d = 14.3,
14.7, 16.2, 20.1, 32.7, 40.5, 50.4, 59.5, 99.9, 108.2, 126.3,
127.7 (2 × C), 128.6 (2 × C), 129.3, 149.1, 149.7, 169.6.
Anal. Calcd for C19H25NO2 (299.4): C, 76.22; H, 8.42; N,
4.68. Found: C, 75.98; H, 8.31; N, 4.23.
(14) For some dihydropyridine syntheses not directly related to
the Hantzsch reaction, see: (a) Geirsson, J. K. F.;
Johannesdottir, J. F. J. Org. Chem. 1996, 61, 7320.
(b) Evdokimov, N. M.; Magedov, I. V.; Kireev, A. S.;
Kornienko, A. Org. Lett. 2006, 6, 899. (c) Sridharan, V.;
Perumal, P. T.; Avendaño, C.; Menéndez, J. C. Tetrahedron
2007, 63, 4407; for organocatalyzed versions of the same
reaction, see references 14g and 14h. (d) Bartoli, G.;
Babiuch, K.; Bosco, M.; Carlone, A.; Galzerano, P.;
Melchiorre, P.; Sambri, L. Synlett 2007, 2897. (e)Singh,L.;
Singh Ishar, M. P.; Elango, M.; Subramanian, V.; Gupta, V.;
Kanwal, V. P. J. Org. Chem. 2008, 73, 2224. (f) Li, M.;
Zuo, Z.; Wen, L.; Wang, S. J. Comb. Chem. 2008, 10, 436.
(g) Franke, P. T.; Johansen, R. L.; Bertelsen, S.; Jørgensen,
K. A. Chem. Asian J. 2008, 3, 216. (h) Kumar, A.; Maurya,
R. A. Tetrahedron 2008, 64, 3477.
(15) For some recent improvements of the Hantzsch
dihydropyridine synthesis, see: (a) Vanden Eynde, J. J.;
Mayence, A. Molecules 2003, 8, 381. (b) Kidwai, M.;
Mohan, R. Can. J. Chem. 2004, 82, 427. (c) Sharma, G. V.
M.; Reddy, K. L.; Lakshmi, P. S.; Krishna, P. R. Synthesis
2006, 55. (d) Kumar, A.; Maurya, R. A. Tetrahedron 2007,
63, 1946. (e) Wang, S.-X.; Li, Z.-Y.; Zhang, J.-C.; Li, J.-T.
Ultrason. Sonochem. 2008, 15, 677. (f) Arumugan, P.;
Perumal, P. T. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 2008, 47, 1084.
(16) For some recent examples of the use of this strategy, see:
(a) Carranco, I.; Díaz, J. L.; Jiménez, O.; Lavilla, R.
Tetrahedron Lett. 2003, 44, 8449. (b) Lavilla, R.;Bernabeu,
M. C.; Carranco, I.; Díaz, J. L. Org. Lett. 2003, 5, 717.
(c) Lavilla, R.; Carranco, I.; Díaz, J. L.; Bernabeu, M. C.
Mol. Diversity 2003, 6, 171. (d) Jiménez, O.; de la Rosa, G.;
Lavilla, R. Angew. Chem. Int. Ed. 2005, 44, 6521.
(e) Masdeu, C.; Gómez, E.; Williams, N. A. O.; Lavilla, R.
Angew. Chem. Int. Ed. 2007, 46, 3043.
(17) See, for instance: (a) Zhu, X. Q.; Zhao, B. J.; Cheng, J. P.
J. Org. Chem. 2000, 65, 8158. (b) Zhu, X. Q.; Wang, H. Y.;
Wang, J. S.; Liu, Y. C. J. Org. Chem. 2001, 66, 344.
(18) Sridharan, V.; Maiti, S.; Menéndez, J. C. Chem. Eur. J.
2009, 15, 4565.
(19) General experimental procedure: To a solution of a suitable
primary amine (1.1 mmol) and b-keto ester (1 mmol) in
anhydrous MeCN (5 mL) was added CAN (5 mol%). The
solution was stirred at room temperature for 30 minutes. To
this solution was added a suitable a,b-unsaturated aldehyde
(1.1 mmol) in EtOH (3 mmol). The reaction mixture was
stirred at room temperature for 1 h, diluted with CH2Cl2
Synlett 2009, No. 14, 2249–2252 © Thieme Stuttgart · New York