Darzen glycidic

Made by Shafaq Shaikh (Student of M.S Chemistry)

1. DARZEN CONDENSATION REACTION Made by Shafaq Shaikh M.Sc ( 1 st semester)

2. Contents Introduction Reaction Mechanism Conditions Examples Application Limitations

3. Introduction: DEFINITION : The formation of α , β -epoxy esters ( glycidic esters) from aldehydes and ketones and α -halo esters under basic conditions. HISTORY : The first report was published by E.Erlenmeyer . He described the condensation of benzaldehyde with ethyl chloroacetate in the presence of sodium metal. During the early 1900s G.Darzen developed and generalized the reaction and found that sodium ethoxide ( NaOEt ) was a very efficient condensing agent. Sodium amide and other bases such as N-ethyl-N-( tributylstannyl ) carbamate can also be used to bring about the Darzen condensation.   It is one of the most potential methodologies for the construction of α , β -epoxy carbonyl and its related compounds. T he base-induced addition of an α -halo ester to an aldehyde or ketone, provides a general route to glycidic acid derivatives.

4. Reaction: R 1 = alkyl,aryl ; X= Cl,Br,I ; R 2 = alkyl,aryl,H ; EWG=CO 2 R, CN, SO 2 R,CONR 2 , C(=O),C(=NR); R 3 = alkyl,aryl ; Y=O, NR; Base= Na, NaOEt , NaNH 2 , NaOH , K 2 CO 3 , NaOt -Bu; When Y=O and EWG= CO 2 R then the product is called glycidic ester.

5. Mechanism: 1 st Step Aldol reaction the base deprotonates the α -halo ester in a rate determining step and the resulting carbanion ( enolate ) attacks the carbonyl group of the reactant aldehyde or ketone . The resulting intermediate is a halohydrin .

6. 2 nd Step Epoxide ring formation Halohydrin undergoes SN i reaction to form the epoxide ring. The stereochemical outcome of the Darzen condensation is usually in favour of the trans glycidic derivatives. The stereochemical outcome is usually in favor of the trans glycidic deriavatives .

7. Conditions Aromatic aldehydes and ketones ,aliphatic ketones as well as α , β -unsaturated and cyclic ketones react smoothly and give good yields of the expected glycidic esters. Aliphatic aldehydes usually give lower yields, but the deprotonation of α -halo ester with a strong kinetic base prior to the addition of the aldehyde results in acceptable yields . α -halo sulfones , nitriles, ketones, ketimines , thiol esters, or amides can also be used to obtain corresponding glycidic derivatives. The stereochemistry of the product is determined by the initial enolate geometry and the steric requirement of the transition state. The selected reaction temperatures have been from many degrees below zero up to the boiling point of the solvent employed, depending on the nature of the reactants and catalyst . The solvent has been in many cases of the aprotic non-polar type, like anhydrous benzene or anhydrous ethyl ether, but ethyl alcohol and even aqueous dioxane have been used. The selection of the solvent has been determined in many cases by the nature of the condensing agent. For example, when sodium amide is used, anhydrous solvents of the inert type must be employed.

8. Condensing Agent As far as the condensing agent is concerned, sodium has been used in addition to sodium ethoxide or sodium amide. In the condensations with arylmethyl halides potassium carbonate has been preferred, and in those with phenacyl halides sodium hydroxide has been used with excellent results. It has been recently reported that sodium tert-butoxide gives good results in the condensations with esters of a- halogeno acids. The base employed has been either soluble in the medium, and the reaction carried out therefore under homogeneous conditions, or insoluble in it, as in the condensations with sodium amide.

9. The influence of the substituents T he study of condensations involving phenacyl halides (with p- nitrobenzaldehde ) describes substituents influence. p-nitro group in benzaldehyde accelerates the condensation with phenacyl chloride. The effect of the substituents on the rate of the condensation is due to their influence on the amount of nucleophilic character of the carbonyl group of the phenancyl halides an electron-releasing group will diminish the activity of the phenacyl halides the presence of an electron-attracting group like the nitro group in phenacyl halides has a very unfavorable influence.

10. Example 1 The Darzen condensation reaction invariably fails with aldehyde due to competing base-catalyzed self-condensation reaction. With LHMDS ( Lithium Hexamethyldisilazide ) as base, even acetaldehyde provide the desired glycidic ester product in the high yield.

11. Example 2 + LDA,THF,HMPA, Hexane cyclopentanone lactone α - bromoester α , β -epoxy ester

12. Example 3 The reaction occurs in two steps. 1 st Step aldol reaction of a halocarbon and an aldehyde. 2 nd Step an intramolecular nucleophilic substitution. The negatively charged oxygen attacks the carbon with the halogen , forming the epoxide. Chlorine is used as the halogen because it is an excellent leaving group. Also in this experiment, benzyltriethylammonium chloride is used as a catalyst.

13. Example 4

14. Example 5

15. Synthetic Application No. 1 In the laboratory of P.G. Steel, a five-step synthesis of (±)- epiasarinin from piperonal was developed. The key steps in the sequence involved the Darzens condensation, alkenyl epoxide- dihydrofuran rearrangement and a Lewis acid mediated cyclization. The desired vinyl epoxide intermediate was prepared by treating the solution of (E )- methyl-4bromocrotonate and piperonal with LDA, then quenching the reaction mixture with mild acid (NH4Cl).

16. Synthetic Application No. 2 A. Schwartz et al. synthesized several calcium channel blockers of the diltiazem group enantioselectively by using an auxiliary-induced asymmetric Darzens glycidic ester condensation. The condensation of p- anisaldehyde with an enantiopure α- chloro ester afforded a pair of diastereomeric glycidic esters that possessed significantly different solubility. The major product was crystallized directly from the reaction mixture in 54% yield and in essentially enantiopure form. This major glycidic ester was then converted to diltiazem in a few more steps.

17. Synthetic Application No. 3 The halohydrin mixture from acetophenone and t-butyl chloroacetate was prepared by the method of Munch-Peterson and treated with potassium t- butoxide in the presence of p- nitrobenzaldehyde . The glycidic esters from this reaction were analyzed by gas phase chromatography and found to consist of 87% product from direct cyclization and 13% glycidic ester from p- nitrobenzaldehyde .

18. Synthetic Application No. 4 Zimmer- man when he treated ethyl 2-chloro-3-hydroxy-2 , 3- diphenylpropionate with potassium t- butoxide in the presence of m- nitrobenzaldehyde . There was isolated only the glycidic ester resulting from the m- nitrobenzaldehyde .

19. Synthetic Application No. 5 `a sterically controlled reaction favored by Cromwell and Setterquist the important factor is the conformation of the halohydrin anion leading to cyclization. In their work the condensation between benzaldehyde and phenacyl bromide gave predominantly the trans isomer. 1 2

20. They suggest that the configurationally unfavorable threo isomer 1 fails to cyclize to 2 but instead reverses to the reactants and then re-forms the more favorable erythro isomer 3 which can then readily cyclize to give the trans- glycidic ester 4. 4 3 A mechanism based on electronic repulsion between the oxyanion and the halogen atom has been proposed by Dahn and Loewe. It is their suggestion that the halogen atom and the carbonyl oxygen which is developing a negative charge be trans coplanar in the transition state leading to the halohydrin oxy anion. The remaining groups would orient themselves to give the most favorable conformation. These would correspond to the conformations 1 and 3 where 3 would be the most favored conformation.

21. Synthetic Application No. 5 Highly Enantioselective Darzens Reaction of a Camphor-Derived Sulfonium Amide to Give Glycidic Amides and Their Applications in Synthesis V. K. Aggarwal, G. Hynd , W. Picoul , J.-L. Vasse ,  J. Am. Chem. Soc. ,  2002 , A camphor-derived amide-stabilized ylide reacts with aldehydes at -50°C in ethanol to give glycidic amides in one step with up to 99% ee and complete diastereoselectivity . Further transformations of epoxyamides were investigated.

22. Limitation The Darzen condensation is a well-established method for the synthesis of glycidic esters. Unfortunate, the method fails for acetaldehyde and monosubstituted acetaldehyde derivatives presumably due to competing base-catalyzed self-condensations of the aldehydes. Our need for a convenient route to ester & for a synthesis currently under investigation prompted the development of an alternate synthesis based on prior generation of the α - haloester anion. A desirable feature that a reaction must fulfill to be suitable for a kinetic study is a high yield in the sole reaction product. Unfortunately, such yields are uncommon in the Darzens condensation . Consequently , for that purpose it was necessary to find a homogeneous high-yield reaction. The hydroxyl-ion-cat- alyzed condensations of phenacyl chloride with benzaldehyde and of p- methoxyphenacyl chloride with p- nitrobenzaldehyde , in aqueous dioxane , give yields close to the theoretical values.