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DOI: 10.1055/s-0029-1217719
A Mild Protocol for the Efficient Synthesis of 5,6-Unsubstituted 1,4-Dihydropyridines
Publikationsverlauf
Publikationsdatum:
29. Juli 2009 (online)
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Abstract
Treatment of 6-alkoxy-1,4,5,6-tetrahydropyridines with neutral alumina (activity grade I) suspended in refluxing acetonitrile, afforded 1,4-dihydropyridines in excellent yields. This method allowed the efficient synthesis of 5,6-unsubstituted dihydropyridines, which are difficult to prepare by traditional methods, from acyclic and readily available precursors.
Key words
eliminations - heterocycles - dihydropyridines - cerium(IV) - Lewis acids
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References and Notes
General experimental procedure: To
a solution of a suitable primary amine (1.1 mmol) and β-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 α,β-unsaturated
aldehyde (1.1 mmol) in EtOH (3 mmol). The reaction mixture was stirred
at room temperature for 1 h, diluted with CH2Cl2
(15
mL) and washed with water (3 × 5 mL). The organic 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): δ = 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): δ = 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): δ = 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): δ = 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): δ = 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): δ = 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.