Claisen condensation alkylation

Sodium amide is a dehydrating agent. It is used in preparing sodium cyanide and hydrazine, and in many organic synthetic reactions such as Claisen condensations, alkylations of ketones and nitriles, and in ammonoly-sis reactions. 

USE In Claisen condensations, alkylation of nitriles and ketones, synthesis of ethynyl compds, acetylenic carbinols. 

Pyridine, 4-methoxy-3-styryl-photoelectron spectroscopy, 2, 137 Pyridine, 2-methyI-alkylation, 2, 176 amination, 2, 233, 236 carboxylation, 2, 53 chlorination, 2, 201, 331 Claisen condensation, 2, 51 methiodide... 

Ethyl ethoxalylpropionate has been prepared by the Claisen condensation of ethyl oxalate with ethyl propionate as above, and by the alkylation of ethyl ethoxalylacetate. ... 

The thenyl cyanides are of great importance for the preparation of thiophene derivatives. Because of the acidifying effects of both the thienyl and of the cyano groups, carbanions are easily obtained through the reaction with sodamide or sodium ethoxide, which can be alkylated with halides, carbethoxylated with ethyl carbonate, or acylated by Claisen condensation with ethyl... 

In the presence of strong bases, carbonyl compounds form enolate ions, which may be employed as nucleophilic reagents to attack alkyl halides or other suitably electron-deficient substrates giving carbon-carbon bonds. (The aldol and Claisen condensations... 

A fi-keto-bis-a-amino acid derivative 267 is a common precursor in these syntheses (Scheme 57), obtained by asymmetric Schollkopf alkylation <1994TL4091>, by Claisen condensation of glutamic acid precursors <1997TL6483, 1998JOC5937>, or by hydrogenation of bis-a,/3-unsaturated amino acid derivatives <2001TL3159>. 

Lithium amide is used in synthesis of histamine and analgesic drugs. The compound also is used in many organic synthetic reactions including alkylation of ketones and nitriles, Claisen condensation, and in synthesis of antioxidants and acetylenic compounds. 

The aniline nitrogen is then converted to the para-toluenesulfonamide (4-3). Reaction of this intermediate with ethyl co-chlorobutyrate in the presence of potassium carbonate then gives the alkylation product (4-4). Potassium tert-butoxide-catalyzed Claisen condensation of this diester leads to azepinone (4-5) as a mixture of methyl and ethyl esters resulting from alternate cyclization routes. A strong acid leads to the transient keto-acid, which then decarboxylates the toluensulfonyl group is lost under reaction conditions as well as affording the benzazepinone (4-6). This last intermediate is then acylated with the benzoyl chloride (4-7) to afford amide (4-8). 

The above reactions have been illustrated for 2- and 4-alkylpyridines. They generally fail if no heteroatom is a or 7, as in 3-alkylpyridines and 5-alkylpyrimidines. a- and [3-Alkyl groups in pyridine A-oxides are somewhat more reactive than those on the corresponding pyridines. In addition to the reactions already mentioned, 2-picoline 1-oxide undergoes Claisen condensation with ethyl oxalate to yield the pyruvic ester (630) (for the conversion of alkyl substituents in A-oxides into CH,OAc groups see Section 3.2.3.12.5.iv). 

Alkyl 3-oxobutanoic esters react with concentrated alkali by a different path to reverse the Claisen condensation ... 

C-H activation-Cope rearrangement, 10, 177 Claisen condensation equivalent, 10, 174 Claisen rearrangement equivalent, 10, 176 enolate alkylation equivalent, 10, 171 Mannich reaction equivalent, 10, 174 as strategic reaction, 10, 171 intermolecular C-H insertion, C-H activation-Cope rearrangement as strategic reaction, 10, 178... 

The mixed Claisen condensation ensures that only mono-alkylation of the lactone carbonyl group occurs. 

Two sequential thio-Claisen condensations convert dialkyl ketones into thiopyran-4-ones in a rapid, high-yielding process. Initial reaction with an aromatic dithioester produces an a, 3-unsaturated ketone which, after alkylation at sulfur, undergoes reaction with a second dithioester and cyclization to the substituted thiopyranone follows (Scheme 200) <1993JOC3042>. 

The reaction of 2-methyl-4-carbethoxyoxazole (114) with ethyl acetate under basic conditions had been reported to result in the product of alkylation on the methyl group of 124 which was thought to exist in the enol form 125 (49). On reinvestigation of the reaction it was revealed that the product was actually that of Claisen condensation (126) which existed in the enol form 127 (75). The close... 

Thus Sn2 alkylation occurs on the carbon atom, whereas a-chloroethers, well known to react by an SnI mechanism, undergo O-alkylation as predicted by the SHAB principle. Both reactions are kinetically controlled, and bond formation is not far advanced in the transition state. Acylating agents (which have a hard electrophilic carbon atom) however, give the C-acylated product in the Claisen condensation. 

In Chapter 28 you will meet the reaction of an ester with its own enolate the Claisen condensation. This reaction can be an irritating side-reaction in the chemistry of lithium ester enolates when alkylation is desired, and again it can be avoided only if the ester is converted entirely to its enolate under conditions where the Claisen condensation is slow. A good way of stopping this happening is to add the ester to the solution of LDA (and not the LDA to the ester) so that there is never excess ester for the enolate to react with. 

Unfortunately neither reaction will work The black route requires a controlled condensation between two different enolizable esters—a recipe for a mixture of products. The simple alkylation route above removes the need for control. The green route requires a condensation between an unsymmetrical ketone and diethyl carbonate. This condensation will work all right, but not to give this product. As you saw on p. 730, Claisen condensations prefer to give the less substituted dicarbonyl compound, and condensation would occur at the methyl group of the ketone on the right to give the other unsymmetrical keto-ester. 

Chlorosulfites, see Alkyl chlorosulfites ChugacT reaction, 42 Claisen condensation, of aromatic aldehydes, 53 of esters, 345... 

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