1.3-Dicarbonyl leaving groups

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... 

In those cases, where conjugated 1,3-dicarbonyl compounds have a leaving group in the p-position, reaction with a 5(4//)-oxazolone occurs via an addition-elimination reaction sequence to give, after cyclization, pyran-2-ones 165... 

Azine approach. Cyclization of the oxime (48) (73G219) corresponds to a common method for the preparation of isoxazoles, viz. the reaction between 1,3-dicarbonyl compounds and hydroxylamine. Similarly a cyano group reacts with hydroxylamine to form an N-hydroxyamidine which can be cyclized to an isoxazole if the vicinal carbon is activated and carries a leaving group. The 5-cyanopyrimidine (49) perhaps behaves unexpectedly in that it is a trichloromethyl substituent which is the leaving group in the cyclization (79JHC11-09). This behavior may be attributed to its location in the activated pyrimidine 4-position. 

Like aldol reactions, the addition of enolates to esters is reversible. 1,3-Dicarbonyl compounds that cannot be deprotonated cleave readily to give two simple carbonyl compounds under basic conditions. The cleavage occurs by addition-elimination, and an enolate acts as a leaving group. 

These allyl cation complexes 229 are electrophilic and react with a variety of nucleophiles, most notably with the stabilised enolates of P-dicarbonyl compounds such as malonates. The immediate product is again a Jt-complex of Pd(0) 230 but there is now no leaving group so the Pd(0) drops off and is available for a second cycle of reactions. Though the reaction strictly requires Pd(0), the more convenient Pd(II) compounds are often used with phosphine ligands. Reduction to Pd(0) occurs either because the phosphine is a reducing agent or by oxypalladation and p-elimination. 

The retrosynthesis of pyrylium ions (Fig. 6.2) is based on the ring-opening reaction by hydroxide ions (see p 224) and leads to 1,5-dicarbonyl compounds 20-22. From these starting materials the synthesis of pyrylium ions can occur by cyclocondensation, their oxidation level is brought about by removal of a hydride ion or of a suitable leaving group ... 

Ambient nucleophiles ( S-diketones or jS-ketoesters) are known to attack always by the more basic y-carbon atom. A difficulty, frequently encountered in intramolecular alkylation of S-dicarbonyl compounds, is the concurrent formation of both C- and 0-alkylated products. It is, however, normally possible to direct the alkylation toward carbon or oxygen by proper selection of (1) the solvent, (2) the enolate counter ion, and (3) the leaving group. 

The 1,3-dicarbonyl unit has been shown to be an excellent leaving group in 5 1 reactions catalysed by FeCl3. °" The catalysis is thought to occur when the iron coordinates with the two carbonyl oxygens before the ionization step. These reactions proceed via either a free carbenium ion or a carbenium ion-pair intermediate, which is consumed in a second reaction with a nucleophile such as C(3) of 5-bromoindole. Yields of these alkylation reaetions range from 73 to 99%. 

The a-protons of p-dicarbonyl compounds are highly acidic (pKg about 13). Sodium hydride is a strong base, lodobutane is a good electrophile, since iodide is a good leaving group and its electronegativity polarises the carbon-iodine bond. 

The self-aldol reaction of aldehydes and ketones gives either P-hydroxy carbonyl or a,P-unsaturated carbonyl products. When the same reaction mechanism is applied to esters, the reaction is called the Claisen condensation. Like the aldol reaction, the Claisen condensation involves the attack of an enolate (or enol) nucleophile on a carbonyl electrophile. However, subsequent elimination of the leaving group creates a P-keto ester product. If this 1,3-dicarbonyl pattern is present in a TM, it is an indication that the TM might be the product of a Claisen condensation, and a Claisen disconnection will be one option for retrosynthesis. 

The title compound also exhibits affinity for /3-dicarbonyl compounds, enabling their use as leaving groups in retro-Claisen reactions (eq 29) or cyclopropane-1,1-diester ring openings. ... 

Trifluoroacetamidine (585) is most widely used for the principal synthesis of pyrimidines. Compound 585 can be prepared from ethyl trifluoroacetate by ammo-nolysis, followed by dehydration with P2O5 and reaction with ammonia (Scheme 124) [335,336]. Amidine 585 has been introduced into reaction with various p-dicarbonyl compounds and their synthetic equivalents (Table 27), including p-ketoesters (Entries 1-6), in particular p-ketopyruvates (Entry 3) and a-alkoxymethylene-p-ketoesters (Entries 4-6), p-enaminocarbonyl compounds (Entries 7-9), malonic acid derivatives (Entry 10), fluorinated p-diketones (Entry 11), vinamidinium salts (Entry 12), a,p-unsaturated nitriles with leaving group at p position (Entries 13-15) and other bis-electrophiles (Entries 16, 17). Usually, the reaction gives moderate yields of the target 2-CF3-pyrimidines (ca. 50 %). 

Vinylcyclopropanes react with nonacarbonyldiiron under formation of allylic (1,2,3,5-1) -pentenediyl)Fe(CO)3 compounds. " Instead of treatment with nonacarbonyldiiron, the leaving group bearing alkenes can also be subjected to reaction with the nucleophilic iron(-II) species K[Fe(CO)3NO]. Reaction of this ferrate with ( )- and (Z -2-butenylmesylate leads stereoselectively to anti- and 5y -dicarbonyl(l-methyl-Ti -2-propenyl)nitrosyliron, respectively (Scheme 4-79). 

Compounds whose structures are similar to (3-dicarbonyl compounds also have active hydrogens. These compounds have a CH2 sandwiched between two electron-withdrawing groups, some examples of which are in Figure 15-21. The loss of a hydrogen ion from the sandwiched carbon leaves an anion, which can then behave as a nucleophile similar to other nucleophiles seen in this chapter. 

In contrast, /3-dicarbonyl compounds such as malonic ester and acetoacetic ester are more acidic than alcohols. They are completely deprotonated by alkoxides, and the resulting enolates are easily alkylated and acylated. At the end of the synthesis, one of the carbonyl groups can be removed by decarboxylation, leaving a compound that is difficult or impossible to make by direct alkylation or acylation of a simple ester. 

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