Diethyl 2,6-Dimethyl,4-(1,1,1-trichloromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

In 1882, Hantzsch reported the first synthesis of dialkyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylates from a refluxing mixture of an aldehyde, a β-ketoester, and aqueous ammonium hydroxide in ethanol.[1] 1,4-dihydropyridines (1,4-DHPs) are well known as Ca⁺² channel blockers.[2,3]

Concentric H₂SO₄ (5 mL) was dropped on chloral hydrate (3 g) and 1,1,1-trichloroacetaldehyde was distilled at 98^oC.

Acetylacetone (4 mL, 40 mmol), freshly distilled 1,1,1-trichloroacetaldehyde (2.94 g, 20 mmol) and CH₃COONH₄ (1.44 g, 20 mmol) were dissolved in acetonitrile (15 mL). This mixture was added on [4] and refluxed for 3 h. The progress of the reaction was monitored by TLC analysis. After completion of the reaction, the resulting suspension was filtered and solid washed with acetonitrile (5 mL), solvent was evaporated. Residue was washed with water and extracted in CH₂Cl₂ (3x5 mL). The solution of CH₂Cl₂ was dried over anhydrous Na₂SO₄ and then filtered._. The solvent was removed under reduced pressure and pale yellow oil product in a good yield, 67.1 % (4.97 g).

UV λ_max (nm; ethyl alcohol) / ε (dm³.mol^-1.cm^-1): 392 / 6270

IR (KBr) (υ cm^-1): 3419 (N-H); 2984 (C=C); 1722 (C=C-C=O); 1031 (C-O); 818 (C-Cl).

¹H-NMR (400 MHz, CDCl₃): δ= 1.21 (t, 6H, -CH₃); 2.16 (s, 6H, -CH₃); 3.31 (s, 1H); 4.12 (q, 4H, methylenic).

¹³C-NMR (100 MHz, CDCl₃): δ= 29.8, 31.6, 58.5, 62.0, 81.7, 166.7, 169.0, 199.5.

Elemental Analysis: Calculated for C₁₄H₁₈ Cl₃NO₄: C, 45.37%; H, 4.89%; Cl, 28.69%; N, 3.78%. Found: C, 45.21%; H, 4.84%; Cl, 28.72%; N, 3.82%.