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D ow nl oa de d B y: [C D L Jo ur na ls A cc ou nt ] A t: 01 :2 4 10 S ep te m be r 2 00 7 SYNTHETIC COMMUNICATIONS, 1 4 ( 2 ) , 121-125 (1984) AN IMPROVED PROCEDURE FOR THE SYNTHESIS OF GLYCIDIC ESTERS R . Della Pergola and P. D i Battista ("1 Montefluos S.p.A. - Centro Ricerche e Sviluppo - Via Bonfa- dini, 148 - 20138 Milano - ltaly ABSTRACT - Aromatic and aliphatic aldehydes and ketones readily undergo Darzens condensation on reaction with NaH and chloroacetate in CH CN. 3 The Darzens reaction gives glycidic es ters (&,P-epoxyesters) by reaction with d-haloesters in the presence of base on aldehydes and ketones. Although several different experimental procedures a re available none appears to be devoid of drawbacks. While aromatic aldehydes and ketones react fairly well in alcohol in the presence of alkoxide, aliphatic aldehydes, in particular those with 9-hydrogen atoms, react rather poorly. lective base such a s LiN(SiMe 3 2 care must taken in the temperature control since the intermediate carbanion undergoes extensive decomposition above -78°C. A very se- in THF gives high yields but ('1 To whom correspondence should be addressed. Copyright 0 1984 by Marcel Dekker, Inc. 121 0039-791 1/84/14024112 1 % 3 . S O / O D ow nl oa de d B y: [C D L Jo ur na ls A cc ou nt ] A t: 01 :2 4 10 S ep te m be r 2 00 7 122 DELLA PERGOLA AND DI BATTISTA Furthermore, d-bromo esters are needed, instead readily available a(-chloro esters. Recently, the tion has been carried out in DMF with X CO and 2 3 of the more Darzens reac- catalytic a- mounts of tetraalkyl ammonium salts. However, low yields are obtained for the conversion of unbranched aldehydes and ketones and long reaction times are required, even in the most favoura- ble cases.3 We wish to communicate results obtained using a procedure of wider scope which, in addition to being fast and simple, gives good yields with all types of carbonyl compounds. We have found that the Darzens reaction can be carried outcon- veniently in CH CN using NaH as a base. Keeping the temper- ature at 60"C, quantitative conversions are obtained in 1-2 hours and the yields are satisfactory for all the carbonyl compounds examined. Onlyfew examples of the use of NaH are known for this reaction. Speziale and Frazier report that acetone and cy- clohexanone are smoothly converted into their glycidic deriva- tives in hexane and in the presence of N c ~ H . ~ In ethyl ether, benzaldehyde and ethyl chloroacetate give the glycidic ester with NaH, but Ph-CH=CClCO Et is also present as a by prod- 2 uct. To our knowledge acetonitrile has never been chosen as a solvent for the Darzens condensation, probably because of the acidity of its protons. Following the idea that a polar solvent should stabilize the inter- mediate carbanion and should enhance the selectivity, we oper- ated in CH CN and proved that under the conditions described herein the reaction proceeds rapidly and without any interfer- ence of the conjugate base of the solvent. The temperature of the reaction should be kept at 60° C , since below this tempera- ture the reaction is slow and the NaH does not react completely after every addition, while hydrogen evolves too vigorously i f 3 3 D ow nl oa de d B y: [C D L Jo ur na ls A cc ou nt ] A t: 01 :2 4 10 S ep te m be r 2 00 7 SYNTHESIS OF GLYCIDIC ESTERS 123 TABLE Data for the NaH promoted Darzens reaction in CH CN of car- 3 with ethyl chloroacetate bony1 compounds Carbonyl compound CH 1 3 CH -CH-CHO 3 n-C H -CHO 5 11 Ph-CHO 3 Ph-CO-CH 0 WbCH 3 3 CH3 1 CH3 Yield ("> cis/trans b.p. Refa (torr) - 76 50/50 81 (12) 3 70 25/75 101-104 1 (0.2) 76 - 100-102 2 (3) 76 45/55 89-93 8 (0.1) 7 4 - 98-100 7 (0.02) ("1 Determined on distilled products, at least 95% pure on G.L.C. analyses. D ow nl oa de d B y: [C D L Jo ur na ls A cc ou nt ] A t: 01 :2 4 10 S ep te m be r 2 00 7 124 DELLA PERGOLA AND DI BATTISTA the temperature is allowed to increase. Above 65'C, the reac- tion is faster, but sometimes darkening of the solution is ob- served and slightly lower yields a re obtained. After the end of the addition, a short period of reflux results in disappearance of the last traces of carbonyl compound. The reaction was monitored by G. L.C., and the ratio of the iso- m e r s could be easily determined. Their actual geometry was con- firmed by NMR spectroscopy. No special effort was devoted to find experimental conditions which would give a stereoselectivity of the reaction higher than described herein, 2 EXPERIMENTAL All reagents were freshly distilled before use. Acetonitrile (Analar grade) was used without further purification. NaH was used as an 80% dispersion in vaseline oil. Boiling points a r e un- corrected. G . L. C. analyses were performed on a Carlo Erba Fractovap 4200 gas chromatograph equipped with a 1 m, 4 mm 0 glass column packed with 10% Supelco SP 1000 on 100 / 120 Chromosorb W AW. Typical Procedure. A 1 1, four necked flask was purged with nitrogen and heated to remove moisture. Ethyl a- chloroacetate (0.55 moll and the carbonyl compound (0.5 moll w e r e added under vigorous mechanical stirring to CH3CN (4.50 ml). The mixture was heated at 60'C and NaH (0.55 moll was added as a solid in small portions, with care be- ing taken to prevent the temperature from rising above 65°C. These additions lasted about 1.5 hours. At the end of the addi- tion, the mixture was stirred until no more hydrogen was evolved and was then refluxed for 0.5 hour. The solvent was removed by distillation through a short Vigreux column. The residue was D ow nl oa de d B y: [C D L Jo ur na ls A cc ou nt ] A t: 01 :2 4 10 S ep te m be r 2 00 7 SYNTHESIS OF GLYCIDIC ESTERS 125 taken up with water (150 ml) and CH2C12 (150 ml). The organic layer was separated and the aqueous solution was extracted with CH C1 (3 x 70 ml). The organic phases were collected, dried (Na2S0 1, and evaporated. The brown residue was distilled 5 vacuo using a 25 cm Vigreux column. 2 2 4 REFERENCES 1) Newmann, M. S . and Magerlin, B. J . ; Org. Reactions, 1949, 5, 413. 2) Borch, R.F.; Tetrahedron x., 1972, 36, 3761. 3) Gladiali, S. and Soccolini, F . ; Synth. Comm., 1982, 12, 355. 4) Speziale, A. J . and Frazier, H.W.; 1. Org. Chem., 1961, - 26, 3170. 5) Field, L . and Carlile,C.G.; 1. Org. Czm., 1961, 3, 3176. 6) Roux-Schmitt, M.C. , Seyden-Penne, J. and Wolfe, S.; Tetrahedron, 1972, 2 8 , 4965. 7) Sankyo, Ger. Offen., 204748; _I_- Chem. Abstr., 1971, 74, 126849e. 81 Allen, C.F.H. and Van Allan, J . ; Org. Synth. Coll. Vol. 111, 727. - 9) Sisido, K . , Torii, S. and Kawanisi; J. Org. Chem., 1964, 2, 904.