Synthetic methods ester condensations

The reaction of phosphorus pentasulfide with a-acylamino carbonyl compounds of type Ilia also yields thiazoles. Even more commonly, a mercaptoketone is condensed with a nitrile of type IVa or a-mercaptoacids or their esters with Schiff bases. This ring closure is limited to the thiazolidines. In the Va ring-closure type, /3-mercaptoalkylamines serve as the principal starting materials, and ethylformate is the reactant that supplies the carbon at the 2-position of the ring. These syntheses constitute the most important route for the preparation of many thiazolidines and 2-thiazohnes. In the Vb t3fpe of synthesis, one of the reactant supplies only the carbon at the 5-position of the resultant thiazole. Then in these latter years new modern synthetic methods of thiazole ring have been developed (see Section 7 also Refs. 515, 758, 807, 812, 822). 

Instead of a-halo esters, related reactants can be used e.g. the a-halo derivatives of ketones, nitriles, sulfones and A,A-disubstituted amides. The Darzens condensation is also of some importance as a synthetic method because a glycidic acid can be converted into the next higher homolog of the original aldehyde, or into a branched aldehyde (e.g. 5) if the original carbonyl substrate was a ketone ... 

The widely used synthetic method for the preparation of the title compounds involves the condensation of 2-aminopyridines with 1,3-bifunctional compounds (34) (/i-oxo esters, malonates, or 2-alkoxymethylene malonates)... 

The typical / -keto ester is ethyl acetoacetate (ethyl 3-oxo-butanoate). A retro-synthetic disconnection on this compound points to one of the most common methods for its synthesis, namely the Claisen ester condensation. 

This method, initiated by Marchesini in 1893 (i893G(24)65) (Scheme 177), consists of the condensation of an a-halocarbonyl compound with ammonium thiocarbamate (244 R2 = NH4) or its esters (244 R2 = alkyl). The reaction is carried out at low temperature in aqueous medium and then allowed to stand overnight. 2-Hydroxythiazoles (244 R2 = H) give 2-chlorothiazole derivatives almost quantitatively upon treatment with phosphorus oxychloride. This constitutes a convenient synthetic method for these compounds when the conversion of 2-amino- into 2-chloro-thiazole fails. 

Ring opening polymerization provides a synthetic method for introducing functional groups typical of condensation polymers into a polymer backbone, separated by varying lengths of methylenic units [Eq. (14)]. Typical functional groups include ethers, sulfides, esters, amides, double bonds, etc. 

Common synthetic methods for the preparation of cyclic 8-enamino esters are the condensation between a lactim ether and benzyl cyanoacetate followed by hydrogenolytic decarboxylation, or the imino ester carbon-carbon condensation with tert-butyl cyanoacetate followed by a trifluoroacetic acid treatment. The use of a thiolactam condensed with ethyl bromoacetate gives, after sulfur extrusion by triphenylphosphine, cyclic 8-enamino esters. Compared with these methods, the Meldrum s acid condensation followed by the monodecarboxylating transesterification described here is more convenient and practical. An extension of this procedure permits preparation of smaller... 

Classical /3-diketones can be obtained from the acylation of ketones by esters (Claisen condensation), in the presence of alkali-metal hydroxides, ethoxides, hydrides, or amides as condensing agents, to enhance the relatively low reactivity of the ester carbonyl group (Equation (l)).41 5 Other general synthetic methods have been described by Mehrotra.2... 

The enolates of other carbonyl compounds can be used in mixed aldol condensations. Extensive use has been made of the enolates of esters, thioesters, and amides. Of particular importance are several modified amides, such as those derived from oxazolidinones, that can be used as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, tin, and titanium derivatives have all been used. Because of their usefulness in aldol additions and other synthetic methods (see especially Section 6.4.2.3, Part B), there has been a good deal of interest in the factors that control the stereoselectivity of enolate formation from esters. For simple esters such as ethyl propanoate, the E-enolate is preferred under kinetic conditions using a strong base such as EDA in THE solution. Inclusion of a... 

Common synthetic methods for the preparation of cyclic B-enamino esters are the condensation between a lactim ether and benzyl cyanoacetate followed... 

A one-pot synthetic method for pyridines on a multigram scale was achieved from a condensation between 2 moles of a jS-keto ester and 1 mole of aldehyde under MWI using bentonite clay as a support and ammonium nitrate as the source of ammonia and oxidant. However, good yields of C-4 substituted pyridines 155 could only be obtained when the aldehydes were aliphatic, but only 5% yield of 155 (R = Ph) and 75% yield of 156 were obtained when benzaldehyde was used. A number of 1,3-dicarbonyl compounds including jS-keto esters were used as building blocks for the multicomponent Hantzsch synthesis (95T6511) whereby symmetrical 155 and 157 and nonsymmetrical pyridines 158 were synthesized (Scheme 32) (98TL1117). 

The unusual chiral (3-methoxy-y-amino acid dolaproine (Dap) is the most complex unit of dolastatin 52, which has a remarkable antineoplastic activity and is now in Phase II human cancer clinical trials. Many synthetic strategies such as aldol condensation and a cobalt-catalyzed Reformatsky reaction have been employed in its synthesis. Almeida and Coelho have demonstrated a stereoselective synthetic method for A-Boc-dolaproine (53) through a sequence of MBH reaction, a diastereoselective double bond hydrogenation and hydrolysis of the ester functional group (Scheme 5.8). ... 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

Among the compounds capable of forming enolates, the alkylation of ketones has been most widely studied and used synthetically. Similar reactions of esters, amides, and nitriles have also been developed. Alkylation of aldehyde enolates is not very common. One limitation is the fact that aldehydes are rapidly converted to aldol condensation products by base (see Chapter 2 for more discussion of this reaction). Only when the enolate can be rapidly and quantitatively formed is aldol condensation avoided. Success has been reported using potassium amide in liquid ammonia55 and potassium hydride in THF. Alkylation via enamines or enamine anions provides a more general method for alkylation of aldehydes. These reactions will be discussed in Section 1.9. 

In the second method (Scheme 26) a 3-oxo ester is synthesized from an acid chloride and 2,2-dimethyl-l,3-dioxane-4,6-dione. Then, reductive amination of the 3-oxo ester with a-methyl(phenyl)methylamine provides a 3-amino- 3-alkyl propionic acid ester. This compound is then converted into the corresponding aldehyde, which is condensed with an eno-late to afford the final product. A representative synthetic procedure of this method is given in detail. 

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