Ethyl acetoacetate anion

The first reaction stage is undoubtedly SN2 nucleophilic displacement of chlorine by the ethyl acetoacetate anion. Chlorine bond to carbon is weaker than that of fluorine. The resulting ethyl 5-fluoropentan-2-one-3-carboxylate subsequently cyclizes by an SNi reaction, displacing this time the fluorine atom [73]. 

After conversion to 19 (70% yield) via Nef reaction and ketalization, selective modification of the terminal olefin by reaction with LAH-TiCl4, quenching with I2, and displacement of the resulting terminal halogen with ethyl acetoacetate anion afforded 20 in 48% overall yield. Deacetylation with sodium ethoxide followed by deketalization under acidic conditions produced an 88% yield of keto ester 21. Seco acid 6 was then obtained (in 29% yield from 18) after reduction of the ketone and ester hydrolysis. Clearly, the significance of this... 

Six-membered ring heterocycles, for example N-2-pyridyl, N-6-methylpyridyl and N-4-pyridyl-2,6-dinitro-4-pyridones have been used with the ethyl acetoacetate anion in pyridine solution at 65-70 C during 5 hours for the synthesis of ethyl... 

The first step is the interaction of the basic catalyst with the ester to produce the carbanion (I) the carbanion so formed then attacks the carbonyl carbon of a second molecule of ester to produce the anion (II), which is converted to ethyl acetoacetate (II) by the ejection of an ethoxide ion. Finally (III) reacts with ethoxide ion to produce acetoacetic ester anion (IV). This and other anions are mesomeric thus (IV) may be written ... 

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

Ethyl acetoacetate is a stronger acid than ethanol and is quantitatively converted to its anion on treatment with sodium ethoxide in ethanol. 

The anion produced by proton abstraction from ethyl acetoacetate is nucleophilic. Adding an alkyl halide to a solution of the sodium salt of ethyl acetoacetate leads to alkylation of the a carbon. 

Anions of (3-keto esters are said to be synthetically equivalent to the enolates of ketones. The anion of ethyl acetoacetate is synthetically equivalent to the enolate of acetone, for example. The use of synthetically equivalent groups is a common tactic in synthetic organic chemistry. One of the skills that characterize the most creative practitioners of organic synthesis is an ability to recognize situations in which otherwise difficult transfonnations can be achieved through the use of synthetically equivalent reagents. 

The mechanism of the Feist-Benary reaction involves an aldol reaction followed by an intramolecular 0-alkylation and dehydration to yield the furan product. In the example below, ethyl acetoacetate (9) is deprotonated by the base (B) to yield anion 10 this carbanion reacts with chloroacetaldehyde (8) to furnish aldol adduct 11. Protonation of the alkoxide anion followed by deprotonation of the [i-dicarbonyl in 12 leads to... 

The condensation of arylsulfonyl acetonitriles 369a-c with 22a proceeds via addition of the in-situ formed anion 370 to the arylsulfonyl acetonitriles 369 to afford the dimers 371, in 69-94% yield, and hexamethyldisiloxane 7 [136]. Furthermore, y9-dicarbonyl compounds such as ethyl acetoacetate 372 a or ethyl benzoyl-acetate 372b are O-silylated by 22 a or 22 c to rather stable alkyl 3-O-trimethylsilyl-oxycrotonoate 373a and alkyl 3-0-trimethylsilyloxy-3-phenyl acrylate 373b [130]. Aliphatic nitro compounds such as nitromethane are O-trimethylsilylated and further transformed into oligomers [132] (cf Section 7.6) and are thus unsuitable reactants for silylation-C-substitutions (Scheme 4.50). 

A fourfold anionic domino process consistingofadominoMichael/aldol/Michael/ aldol process was used by Koo and coworkers for the synthesis of bicyclo[3.3.1]non-anes. They employed 2 equiv. of inexpensive ethyl acetoacetate and 1 equiv. of a simple a, 3-unsaturated aldehyde [290]. Differently substituted dihydroquinolines were assembled in a Michael/aldol/elimination/Friedel-Crafts-type alkylation protocol by the Wessel group [291]. An impressive approach in this field, namely the construction of the indole moiety 2-557, which represents the middle core of the man-zamines, has been published by Marko and coworkers [292]. Manzamine A (2-555) and B (2-556) are members of this unique family of indole alkaloids which were isolated from sponges of the genus Haliclona and Pelina (Scheme 2.126) [293]. 

Monoanions derived from nitroalkanes are more prone to alkylate on oxygen rather than on carbon in reactions with alkyl halides, as discussed in Section 5.1. Methods to circumvent O-alkylation of nitro compounds are presented in Sections 5.1 and 5.4, in which alkylation of the a.a-dianions of primary nitro compounds and radial reactions are described. Palladium-catalyzed alkylation of nitro compounds offers another useful method for C-alkylation of nitro compounds. Tsuj i and Trost have developed the carbon-carbon bond forming reactions using 7t-allyl Pd complexes. Various nucleophiles such as the anions derived from diethyl malonate or ethyl acetoacetate are employed for this transformation, as shown in Scheme 5.7. This process is now one of the most important tools for synthesis of complex compounds.6811-1 Nitro compounds can participate in palladium-catalyzed alkylation, both as alkylating agents (see Section 7.1.2) and nucleophiles. This section summarizes the C-alkylation of nitro compounds using transition metals. 

Another substituted derivative of BINAP was used by Lemaire et al. [109]. The ammonium salt catalysts (7 and 8, Fig. 41.10) were prepared in situ from the bro-mohydrates and [Ru( /3-2-methylallyl)2(/72-COD)], and immobilized in several ionic liquids. By comparative studies of the hydrogenation of ethyl acetoacetate, the best results were obtained with imidazolium- and pyridinium-containing ionic liquids. No significant ee was observed with the phosphonium salt. This observation was attributed to problems of solubility and to the ability of complexation for the phosphonium ion. From the anionic side, use of the [BF4] anion appeared superior compared to [PF6] and [(CF3S02)2N]A... 

The proportion of the /rans-O-alkylated product [101] increases in the order no ligand < 18-crown-6 < [2.2.2]-cryptand. This difference was attributed to the fact that the enolate anion in a crown-ether complex is still capable of interacting with the cation, which stabilizes conformation [96]. For the cryptate, however, cation-anion interactions are less likely and electrostatic repulsion will force the anion to adopt conformation [99], which is the same as that of the free anion in DMSO. This explanation was substantiated by the fact that the anion was found to have structure [96] in the solid state of the potassium acetoacetate complex of 18-crown-6 (Cambillau et al., 1978). Using 23Na NMR, Cornelis et al. (1978) have recently concluded that the active nucleophilic species is the ion pair formed between 18-crown-6 and sodium ethyl acetoacetate, in which Na+ is co-ordinated to both the anion and the ligand. 

However, the reaction is not quite that simple, and to understand and utilize the Claisen reaction we have to consider pAT values again. Loss of ethoxide from the addition anion is not really favourable, since ethoxide is not a particularly good leaving group. This is because ethoxide is a strong base, the conjugate base of a weak acid (see Section 6.1.4). So far then, the reaction will be reversible. What makes it actually proceed further is the fact that ethoxide is a strong base, and able to ionize acids. The ethyl acetoacetate prodnct is a 1,3-dicarbonyl componnd and has relatively acidic protons on the methylene between the two carbonyls (see Section 10.1). With... 

The same viewpoint can taken for the ester function in a P-ketoester such as ethyl acetoacetate. Again, acidity of the a-protons is increased because there are two carbonyl groups, and generation of an enolate anion is facilitated. Although mono- or... 

The nucleophile will be the enolate anion from ethyl acetoacetate, which attacks the P-carbon of the electrophile, generating an addition complex that then acquires a proton at the a-position with restoration of the carbonyl group. The product is a 8-ketoester with an ester side-chain that has a... 

When ethyl acetoacetate was employed instead of diethyl malonate in a similar solid-state reaction, dihydrofuran-fused Cgo derivative 47 was obtained in 22% yield (49% based on consumed Cgo). Again, the initially formed anion is supposed to be oxidized by oxygen to the corresponding radical, which undergoes intramolecular cyclization with release of a hydrogen radical as shown in Scheme 22 [52]. 

Active methylene anions also displace the 5-halogen substituent for example, the 5-chloro derivative (152) (X = Cl) reacts with the sodium salt of ethyl acetoacetate to give (90) (R = Et) which is readily hydrolyzed and decarboxylated (Scheme 22) <82M793>. The 5-chloro substituent in (152) (X = Cl) is also readily displaced by the lithium enolate of 3-(methoxycarbonyl)quinuclidine (153) to give (154) which on hydrolysis with sodium hydroxide and then decarboxylation with hydrochloric... 

The enolate anion attacks the carbonyl carbon of a second molecule of ester and gives a P-ketoester. Thus, the Claisen condensation is a nucleophilic acyl substitution reaction. Eor example, two molecules of ethyl acetate condense together to form the enolate of ethyl acetoacetate, which upon addition of an acid produces ethyl acetoacetate (P-ketoester). 

Nucleophilic attack of the enolate anion to the carhonyl carhon of another ethyl acetate gives an alkoxide tetrahedral intermediate. The resulting alkoxide reforms the carhonyl group hy ejecting the ethoxide anion. This ethoxide anion deprotonates the a-hydrogen, and produces a new enolate anion of the resulting condensed product, which is protonated in the next step upon acidification during work-up and yields the ethyl acetoacetate. 

The carboxylation reaction (Scheme 13) nicely illustrates the advantage of using the hindered azobenzenes azobenzene is itself carboxylated under the reaction conditions used whereas the di-r-butyl compound is too hindered and acts only as a probase. Entry 8 is an example of both condensation (of ethyl acetate to ethyl acetoacetate) and subsequent alkylation. Yields are often high and the reaction conditions are usually convenient. The electrogenerated bases are effectively produced in either dimethylformamide or acetonitrile in the latter case the cyanomethyl anion must also be present but this does not seem to interfere with alkylation reactions. 

Both l,3-oxazin-4-ones and -2,4-diones are attacked by nucleophiles at C-2. Enolate anions, for example, yield open-chain intermediates initially, but these normally ring-close again to form pyridones <80H(14)1333>. Certainly this is the case when sodium ethoxide in ethanol is employed to generate the enolate thus diones (35) react with ethyl acetoacetate... 

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