Darzens condensation; Glycidic esters

Kirtikumar B. Jadhav ([email protected]),
A contribution from the Chakraborti Group, NIPER

Chemicals Used
p-Methoxy benzaldehyde, Methyl chloroacetate, Methanol [distilled from Na], Sodium metal

Procedure
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�s 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.

Data
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).

Lead Reference
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. �The Darzens Glycidic Ester Condensation� J. Org. Chem. 1969, 34, 3600-3604. 2. Tung, C.; Speziale, A.; Frazier, H. �The darzens condensation. II. Reaction of chloroacetamides with aromatic aldehydes.� J. Org. Chem. 1963, 28, 1514-1521.

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