Darzens condensation; Glycidic esters
SyntheticPage 225 (2005)
Submitted 10th May 2005, published 11th May 2005
Kirtikumar B. Jadhav (firstname.lastname@example.org),
A contribution from the Chakraborti Group, NIPER
p-Methoxy benzaldehyde, Methyl chloroacetate, Methanol [distilled from Na], Sodium metal
To a solution of 5.1g (0.22 gram-atoms) of Na in 90mL of anhydrous MeOH, chilled to -10ºC in an ice bath, a solution of 20g (0.15 moles) of 4-Methoxy benzaldehyde and 23.9g (0.22 moles) of Methyl chloroacetate was added dropwise over a period of 3h, during which time the reaction mixture was vigorously stirred and finally the whole became a white paste. After the addition was completed, the mixture was stirred at -5ºC for 2h and then at room temperature for 3h. The mixture was poured into ice-water (350mL) containing AcOH (2mL); the precipitated white solid was filtered, washed with cold water and dried in a dessicator. The crude glycidate weighed 23g (75%). It was recrystallized from MeOH to give pure Methyl glycidate. Author's Comments
It抯 imperative to maintain inert (N2) atmosphere throughout the course of reaction. The glycidic ester is an important key intermediate in the synthesis of Diltiazem ?a Ca2+ Channel blocker. The diastereomeric mixture obtained can further be purified by enzymatic methods in order to gain access to diltiazem.
Melting range: 68-69ºC. 1H NMR (300MHz, CDCl3): 7.21 (2H, d, J = 8.6Hz), 6.89 (2H, d, J = 8.6Hz), 4.05 (1H, m*), 3.51 (1H, m*), 3.82 (3H, s), 3.80 (3H, s). [* = as the reaction yields inseparable mixture of cis- and trans-glycidic ester, well resolved doublets for epoxide CH
protons were not obtained]. APCI MS: 208.9 (M+1). FT-IR (KBr, thin plate, ): 3020.2 cm-1 (w, sp2 C-H str), 2954.4 cm-1 (w, asymm. sp3 C-H str), 2837.7 cm-1 (w, symm. sp3 C-H str), 1728.3 cm-1 (vs, ester C=O str), 1613.8 - 1437 cm-1 (m, aro. skeletal C=C vibrations), 1311.7 cm-1 (m), 1294.0 cm-1 (m, symm str of epoxide), 1251.5 cm-1 (s, asymm. Ar-O-C str), 1179.0 cm-1 (w), 1029.4 cm-1 (s, symm Ar-O-C str), 856.1 cm-1 (w), 840.4 cm-1 (m, para subst. oop bend), 800.3 cm-1 (w), 774.2 cm-1( w).
1. Ban, Y.; Oishi, T. Chem. Pharm. Bull., 1958, 6, 574-576. 2. Crotti, P.; Ferretti, M; Macchia, F. J. Org. Chem. 1986, 51, 2759-2766. Other References
1. Bachelor, F.; Bansal, R. 慣he Darzens Glycidic Ester
Condensation?J. Org. Chem. 1969, 34, 3600-3604. 2. Tung, C.; Speziale, A.; Frazier, H. 慣he darzens condensation. II. Reaction of chloroacetamides with aromatic aldehydes.?J. Org. Chem. 1963, 28, 1514-1521.