Ketones, reaction with NaOEt

Problem 15.64 Isopropyl chloride is treated with triphenylphosphine (Ph P) and then with NaOEt. CH3CHO is added to the reaction product to give a compound, C,H, . When C5H, is treated with diborane and then CrO, a ketone is obtained. Give the structural formula for C,H, and the name of the ketone. d... 

An important application of the Reformatsky reaction is the conversion of P-hydroxy esters to a, P-unsaturated esters. Acid-catalyzed dehydration usually leads to a mixture of a, P- and P, y-unsaturated esters. However, conversion of the initially formed p-hydroxy esters to their corresponding acetates by treatment with acetyl chloride, followed by base-catalyzed dehydration with NaOEt, produces conjugated esters in high purity. This sequence of reactions provides an alternative route to the Homer-Wads worth-Emmons olefmation of ketones (see Chapter 8). 

When acetone reacts with NaOEt in ethanol to form enolate anion 27, it is a reversible acid-base reaction. Therefore, unreacted ketone or aldehyde always remains in the reaction, and this fact allows self-condensation to occur. Is it possible to choose a base that will generate the enolate anion, but the equilibrium is pushed far to the right (toward the enolate anion product) If such a base is available, self-condensation is much less of a problem, which is particularly important for mixed aldol condensation reactions. As chemists experimented to find such a base, it was discovered that amide bases (RaNr), derived from secondary amines (R2NH) accomplished this goal. 

What does all of this mean The reaction of 2-pentanone with LDA in THF at -78°C constitutes typical kinetic control conditions. Therefore, formation of the kinetic enolate and subsequent reaction with benzaldehyde to give 34 is predictable based on the kinetic versus thermodynamic control arguments. In various experiments, the reaction with an unsymmetrical ketone under what are termed thermodynamic conditions leads to products derived from the more substituted (thermodynamic) enolate anion. Thermodynamic control conditions typically use a base such as sodium methoxide or sodium amide in an alcohol solvent at reflux. The yields of this reaction are not always good, as when 2-butanone (37) reacts with NaOEt in ethanol for 1 day. Self-condensation at the more substituted carbon occurs to give the dehydrated aldol product 38 in 14% yield. Note that the second step uses aqueous acid and, under these conditions, elimination of water occurs. 

Aqueous acid workup of 92 gives the alcohol, 93. With malonic ester derivatives, loss of water to form 94 occurs very easily, with dilute acid or with gentle heating because the C=C unit is conjugated to two carbonyl groups, facilitating dehydration. Although it is possible to isolate 83, it is more usually difficult. The enolate anion of malonate esters also reacts with ketones and may be condensed with other esters in acyl substitution reactions. When 90 is treated with NaOEt in ethanol and then with ethyl butanoate, the final product after mild hydrolysis is a keto-diester, 95. 

A variation of the malonic ester synthetic uses a P-keto ester such as 116. In Section 22.7.1, the Claisen condensation generated P-keto esters via acyl substitution that employed ester enolate anions. When 116 is converted to the enolate anion with NaOEt in ethanol, reaction with benzyl bromide gives the alkylation product 117. When 117 is saponified, the product is P-keto acid 118, and decarboxylation via heating leads to 4-phenyl-2-butanone, 119. This reaction sequence converts a P-keto ester, available from the ester precursors, to a substituted ketone in what is known as the acetoacetic acid synthesis. Both the malonic ester synthesis and the acetoacetic acid synthesis employ enolate alkylation reactions to build larger molecules from smaller ones, and they are quite useful in synthesis. 

The cyclobutanone (255) reacted with acid to furnish the keto-acid (259). Upon esterification, ketalization and reduction, (259) was converted to the alcohol (260). Mesylation of the alcohol (260) and then treatment of the mesylate with NaN3 in DMSO provided the azide (261). The azide (261) was then transformed to the urethane (262) by reduction and ethyl chloroformate reaction. The urethane (262) was deketalized by acid, nitrosated by N204—NaOAc and decomposed by NaOEt—EtOH to give the ketone (263) 89). The ketone (263) served as a starting material for the synthesis of veatchine (264)90). 

NaOEt in Et0H-Et20 at -10 °C at this temperature the polymerization of MVK is slow and the reaction stops at the 3-hydroxy ketone, which is then dehydrated with oxalic acid, " or... 

The various steps in the overall sequence will here be considered individually, but only briefly, and no attempt will be made to indicate the scope of the WEH procedure which, as has already been indicated, has been widely reviewed. The aldol condensation which leads to the ions 154 is considered to be essentially reversible, a feature which has been observed in the reactions between diethyl (prop-2-enyl)phosphonate anion and aromatic aldehy-des Reversibility has also been demonstrated in a variety of other reactions that include crossover experiments, based on the system from benzaldehyde and 153 (Z = CN or COOMe) into which a more electrophilic aldehyde is added this results in the incorporation of the latter into products in such a way that the dissociation of the phospho-nate-benzaldehyde adduct must have occurred The addition of an aldehyde to a deuterium-labelled adduct in the presence of NaOEt-EtOH affords a mixture of labelled and unlabelled alkenes in the ratio of ca 1 1. The product (158) from the interaction of HO (Na2C03 in Et0H-H20) and a dialkyl (a-cyanoethenyl)phosphonate decomposes into the expected alkene, but also dissociates into a carbonyl compound together with a carbanion the latter can then be trapped by the addition of a different aldehyde or ketone (Scheme 30) ... 

This reaction was first reported by Aston and Greenburg in 1940. It is the transformation of Qf-haloketone into ester along with the migration of one of the alkyl (or aryl) moieties in this ketone to the of-position of another moiety when the or-haloketone is treated with alkali alkoxide (e.g., NaOEt, NaOMe). In many cases, this rearrangement is used to prepare the esters of tertiary of-carbon. 

With respect to this sequence of observed reactions, experimental evidence shows that 21 reacts with the base (NaOEt) to form an enolate anion, and the nucleophilic carbon atom of that enolate anion attacks the carbonyl of a second aldehyde to give the alkoxide of 22. This is a normal acyl addition reaction, and the nucleophile is the a-carbon of the enolate anion. Treatment of this initial alkoxide product with aqueous acid under mild conditions simply generates alcohol 22, as with all other acyl addition reactions (see Chapter 18). Product 22 is called an alilol or an aldolate. The reaction of an aldehyde or a ketone with a base generates an aldol product. Vigorous acid hydrolysis led to protonation of the OH unit in 22 by the strong acid (to form an oxonium ion), which eliminated a molecule of water (dehydration) to give the alkene unit in 23. 

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