Esters non-enolizable

Recently, Claisen rearrangement of allyl-vinyl ether prepared from glycal ester with Tebbe reagent was reported [91]. In contrast to the Ireland-Claisen rearrangement, in principle, a non-enolizable ester can be employed (O Scheme 63). This method was applied for the synthesis of C-disaccharide. 

An interesting solid-state synthesis of amides, using potassium fert-butoxide and accessible reagents, non-enolizable esters and amines, under the action of MW irradiation, has also been reported [93]. 

Varma RS, Naicker KP (1999) Solvent-free synthesis of amides from non-enolizable esters and amines using microwave irradiation. Tetrahedron Lett 40 6177... 

Acid derivatives that can be converted to amides include thiol acids (RCOSH), thiol esters (RCOSR), ° acyloxyboranes [RCOB(OR )2]. silicic esters [(RCOO)4Si], 1,1,1-trihalo ketones (RCOCXa), a-keto nitriles, acyl azides, and non-enolizable ketones (see the Haller-Bauer reaction 12-31). A polymer-bound acyl derivative was converted to an amide using tributylvinyl tin, trifluoroacetic acid, AsPh3, and a palladium catalyst. The source of amine in this reaction was the polymer itself, which was an amide resin. 

The alkaline hydrolysis of non-enolizable /J-keto esters has been recently investigated by Washburn and Cook (1986) who prepared a series of 4-nitrophenyl and phenyl 4-substituted 3-oxo-2,2-dimethylbutyrates [38],... 

The most used route to pyridines is called the Hantzsch synthesis. This uses a 1,3-dicarbonyl compound, frequently a 1,3-keto ester [ethyl ace-toacetate (ethyl 3-oxobutanoate)], and an aldehyde, which are heated together with ammonia (Scheme 2.18). At the end of the reaction the dihydropyridine is oxidized to the corresponding pyridine with nitric acid (or another oxidant such as Mn02). The normal Hantzsch procedure leads to symmetrical dihydropyridines. Two different 1,3-dicarbonyl compounds may not be used as two enoiate anions might form, giving mixed products when reacted with the aldehyde. The aldehyde itself should preferably be non-enolizable, otherwise the chance of aldoliza-tion exists, but with care this can be avoided. 

With diketene, intermediates of type (III) were isolated and subsequently cyclized under basic conditions following step (b). In the case of 3-oxo-carboxylic acid esters or 3-acyl Meldrum s acids, cyclization step (b) immediately follows reaction step (a), if a slight excess of amine is employed (85TH1 87TH1). Note that conversion of (III) to (V) involves the (IH)-enol (Table I cf. 75BSF2731). The relatively low yield in the case of malonic acid ester, as well as the failure of the reaction with the non-enolizable diphenyl phosphinylacetic ester and cyanoacetate, points to the participation of an enol structure of (III). 

A useful variation of this reaction involves lithium enolates derived from esters. - They react with imines derived from non-enolizable aldehydes to form -lactams (equations 44 and 45). ... 

If - instead of the usual polar ether - a non-polar solvent such as toluene, pentane, or dichloromethane is used as the reaction medium, clean conversion of a large variety (aromatic, aliphatic, non-enolizable, and enolizable) of esters to the corresponding trifluoromethyl ketones can be achieved [79] (Scheme 2.132). 

The stereochemistries were established at the stage of the ketones 38 - 40. The enolizable P-ketoester was m-fused compound 28, and the non-enolizable one (keto-form) was tram-fused compound 24. Reduction of the carbonyl group, mesylation or benzoylation, and then base treatment yielded the corresponding a,P-unsaturated ester in each case. Further reduction afforded the allyl alcohols 29 and 30 (Scheme 6). 

All ketones, aldehydes, and esters mentioned so far have had an a-carbon that can lead to an enol, which means that there was a hydrogen on that carbon that could be removed by base. When a ketone does not have such a proton (it is a non-enolizable ketone), treatment with strong base can lead to a C—C bond cleavage reaction. Discovered by Semmeler,52 Haller and Bauer developed the reaction illustrated by reaction of 63 with NaNH2 to give amide 65. Acyl addition of the amide anion to the carbonyl of the ketone led to 64, and loss of the anion Ph" gave the amide product. Workup protonates the anion to give, in this case, benzene. This... 

B.V. The Stobbe Condensation. When succinic ester derivatives (such as diethyl succinate, 215) are condensed with non-enolizable ketones or aldehydes in the presence of base, the initial condensation product is 216. The alkoxide reacts with the distal ester via acyl substitution to give a lactone intermediate (217). In the original version of this reaction, saponification of 217 gave the a-alkylidene monoester, 218. The reaction is not completely general and is limited to those a, co-diesters for which the Dieckmann condensation is not a... 

If the enolate of a carboxylic ester is formed at room temperature then selfcondensation of the ester results. This reaction is known as the Claisen condensation and gives a p-keto ester product. A variety of bases including EDA, sodium hydride or sodium alkoxides can be used and the reaction may be driven to completion by the deprotonation of the product, to give the anion of the P-keto ester (p.Sra 11). The Claisen condensation reaction works best when the two ester groups are the same, to give the self-condensation product (1.59), or when one of the ester groups is non-enoUzable. The reaction is less useful in cases where two different enolizable esters are used, as a mixture of up to four p-keto ester products is normally obtained. The product P-keto esters are useful in synthesis as they readily undergo alkylation and decarboxylation reactions (see Section 1.1.1). 

An alternative method for the formation of an a,(3-unsaturated carbonyl compound is the elimination of an initially formed Mannich product. The procedure is particularly effective for the formation of (3,(3-bis(unsubstituted) a, -unsaturated carbonyl compounds. The Mannich product 11 can be formed in the presence of a secondary amine and a non-enolizable aldehyde such as formaldehyde (2.12). The Mannich reaction is a useful carbon-carbon bond-forming reaction and the products have found application in the synthesis of, in particular, alkaloid ring systems. The Mannich product may eliminate under the reaction conditions, or can be alkylated to form the quaternary ammonium salt in order to induce elimination. A convenient variation of this method is the use of Eschenmoser s salt, H2C=NMe2 X. For example, Nicolaou s synthesis of hemibrevetoxin B used this salt in order to introduce the required methylene unit a- to the aldehyde 12 (2.13). The same transformation with the corresponding methyl ester, which is less acidic, requires prior enolization with a strong base (e.g. NaN(SiMe3)2) and subsequent quatemization of the tertiary amine with iodomethane and elimination using DBU. 

The MBH reactions of non-enolizable a-diketones precursors (Figure 1.4) with the activated olefins, e.g. acrolein, methyl acrylate and acrylonitrile, have been investigated systematically. The reaction of 3,3,5,5-tetramethyl-cyclopentane-l,2-dione (162) with acrolein and acrylonitrile, but not methyl acrylate, afforded the mono-a-hydroxyalkylation products in high yields. Other nonenolizable a-diketones, such as camphorquinone (159), homo-adamantane-2,3-dione (160) and bicyclo[ 3.3.2]decane-9,10-dione (161) reacted only with acrylonitrile, probably due to the hindered nature of the a-dicarbonyl compounds and the difference in steric demand between nitrile and ester. 

The combination, CH2=CHCH2MgBr-LiNR2, has been found useful in converting non- or slowly enolizable esters or carboxamides into 2-propenyl ketones. 

The modification of the Peterson reaction using an N-trimethylsilylamide anion instead of an a-silyl carbanion offers a promising route to the corresponding imines. Treatment of N-(p-tolyl)-N-trimethylsilylamide anion with carbonyl compounds yields the corresponding ketimines [400]. In particular, LiHMDS has been utilized for the preparation of N-trimethylsilylimines, which are useful as masked imine derivatives in the synthesis of yS-lactam antibiotics [401-407]. Reactions of LiHMDS with non-enolizable aldehydes, enolizable aldehydes, ketones, a diketone, and a-keto esters give the respective imines (Scheme 2.153) [408-413]. Chloro-trimethylsilane is added to convert the generated lithium trimethylsilanolate into hexamethyldisiloxane. 

Two different carboxylic esters, the first enolizable and having low DF and the second non-enolizable and having high DF, have been immobilized in the same 2% cross-linked polystyrene and cross-condensed in 85% yield (vs, 20% in solution) as shown in Scheme 27. When each of the esters was bound to a different support, and the two supported esters were treated with tri-phenylmethyllithium in one flask at the same time, only the starting carboxylic acids were recovered, indicating that no condensation occurs in solution. 

There are severd drawbacks for this otherwise simple reaction. One of the shortcomings is its impractical slow rate, often requiring two or more weeks for completion. Also, the yields are inconsistent. In addition, die reaction is not applicable to p-substituted alkenes mid is limited to only a few clasps of activated ketones, such as a-keto esters (9,10), perfluoroalkyl ketones (11), and non-enolizable 1,2-diketones (12), For example, only 7% conversion occurs when acetone is reacted with n-butyl acrylate at 120 C in 4-6 d and aralkyl ketones fail to react even under high pressure (2). 

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