Ethyl 2-[(Z)-2-(4-Cyanophenyl)-2-hydroxyvinyl]-4-(4-methoxyphenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate

Abstract

A one-pot, two-step method has been developed for the synthesis of ethyl 2-[(Z)-2-(4-cyanophenyl)-2-hydroxyvinyl]-4-(4-methoxyphenyl)-6-methyl-1,4-dihydro-pyrimidine-5-carboxylate, including a sulfide contraction step utilizing solution and solid phase synthesis.

Nonplanar 3,4-dihydropyrimidin-2(1H)-one derivatives (DHPMs) are attractive molecules for drug research because of their known multifaceted pharmacological profiles. Introduction of DHPMs resulted in the discovery of new kinds of calcium channel modulators [1], hepatitis B virus replication inhibitors [2], mitotic kinesin inhibitors [3] and α_1a-adrenergic receptor antagonists [4]. It seems to be reasonable that DHPMs are privileged structures for drug research and modifications around this motif are of considerable importance.

Due to our continuous efforts in search of new methods for modifying privileged hetreocycles, we report herein the synthesis of ethyl 2-[(Z)-2-(4-cyanophenyl)-2-hydroxyvinyl]-4-(4-methoxyphenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (3) from ethyl 4-(4-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1) in a one-pot, two-step synthesis (Scheme 1). The reaction sequence includes the S-alkylation of DHPM 1 by the α-bromoketone 2. The resulting intermediate undergoes in the presence of triphenylphosphine an Eschenmoser sulfide contraction to yield the desired product 3 [5]. Separation of the arising triphenylphosphine sulfide from the reaction mixture can be done by column chromatography, but is not an easy task. To prevent this costly separation procedure, we chose the application of polymer-bound triphenylphosphine. The reaction selectivity and yields of both phosphine agents are comparable. The presented synthetic method is well suited for a diversity-oriented synthesis strategy, using differently substituted Biginelli compounds and various α-bromoketones.

The title compound 3 has been fully characterized by ¹H- and ¹³C-NMR, IR, Raman and ESI-TOF MS analysis. It was observed that the ¹H NMR spectra of 3 show a duplicate set of some signals (approximately 3:1 ratio) due to different conformers of 3 in solution. No tautomeric form of 3 was observed in the NMR experiments. The ¹H NMR as well as the ¹³C NMR did not show appropriate signals for the expected aliphatic CH₂ group of a keto tautomer.

Experimental Procedure

To a suspension of ethyl 4-(4-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 1 (110 mg, 0.36 mmol, 1 equiv) in acetone (2 mL), powdered K₂CO₃ (75 mg, 0.54 mmol, 1.5 equiv) and 2-bromo-4`-cyanoacetophenone 2 (96 mg, 0.43 mmol, 1.2 equiv) were added subsequently. The reaction mixture was vigorously shaken at ambient temperature in a 4 mL capped glass vial, using an automatic shaker. A colour change of the solution from light yellow to dark brown took place. After shaking at ambient temperature under TLC monitoring (ethyl acatate/hexane 1:1, R_f: 0.3), complete conversion of 1 into the S-alkylated intermediate was observed after 30 min. Polymer-bound triphenylphosphine (0.54 mmol) (polystyrene, 2% DVB, 3 mmol/g, Fluka) was added in one portion, and the reaction temperature was raised to 80 ^oC. Shaking of the suspension was continued for additional 10 h to complete the sulfide contraction reaction. For work-up, the polymer was filtered off and washed with approx. 5 mL of ethyl acetate. The collected filtrates were concentrated under reduced pressure and subjected to flash chromatography (Silica-60, 0.06–0.20 mm, ethyl acetat/hexane 20% vol./vol.) to obtain pure viscous yellow product as an approx. 3:1 inseparable mixture of isomers in 65% (97 mg) yield.

HR-MS (ESI-Q-TOF) calcd. for C₂₄H₂₄N₃O₄ [MH]⁺: 418.1761 found [MH]⁺: 418.1769.

UV-Vis (CH₃CN), λ (nm): 374, 282, 244, 193.

IR (KBr, cm^-1): 2977 (C-H aromatic), 2227 (-C≡N), 1700 (C=O), 1630 (C=C), 1573, 1532, 1509, 1476, 1368, 1328, 1244, 1203, 1172, 1092, 1058, 1031.

Raman (powder, ATR, cm^-1): 2229, 1649, 1605, 1502, 1382, 1300, 1222, 1177, 1111, 872, 763.

¹H NMR (300 MHz, CDCl₃), δ (ppm): 1.13, 1.12 (t, 3H, J = 6.0 Hz, -OCH₂CH₃), 2.41, 2.33 (s, 3H, CH₃), 3.71, 3.68 (s, 3H, OCH₃), 4.03, 4.05 (q, 2H, J = 6.0 Hz, -OCH₂CH₃), 5.22 (s, 1H, CH), 5.28 (s, 1H, CH), 5.63, 5.38 (1H, D₂O exchangeable, OH), 6.77, 6.74 (d, 2H, J = 9.0 Hz, ArH), 7.17, 7.13 (d, 2H, J = 9.0 Hz, ArH), 7.58, 7.54 (d, 2H, J = 9.0 Hz, ArH), 7.76, 7.72 (d, 2H, J = 9.0 Hz, ArH), 12.72, 11.41 (br, 1H, D₂O exchangeable, N1-H). The second set of ¹H NMR signals (observed for the minor isomeric form) is italicized.

¹³C NMR (75 MHz, CDCl₃), δ (ppm): 14.2, 19.3, 52.8, 55.3, 60.3, 79.0, 103.7, 114.2, 118.6, 127.1, 128.0, 132.1, 135.8, 143.2, 144.3, 155.0, 159.5, 165.3, 183.9.