Dicarbonyl compounds dianions

The application of dianion chemistry in synthesis is not confined to 7-alkylation of p-dicarbonyl compounds. Dianions derived from p-keto sulfoxides can be alkylated at the 7 -carbon atom. Nitroalkanes can be deprotonated twice in the a-position to give dianions 7. In contrast to the monoanions, the dianions 7 give C-alkylated products in good yield (1.19). ... 

In the presence of a very strong base, such as an alkyllithium, sodium or potassium hydride, sodium or potassium amide, or LDA, 1,3-dicarbonyl compounds can be converted to their dianions by two sequential deprotonations.79 For example, reaction of benzoylacetone with sodium amide leads first to the enolate generated by deprotonation at the more acidic methylene group between the two carbonyl groups. A second equivalent of base deprotonates the benzyl methylene group to give a dienediolate. 

Alkylation of dianions occurs at the more basic carbon. This technique permits alkylation of 1,3-dicarbonyl compounds to be carried out cleanly at the less acidic position. Since, as discussed earlier, alkylation of the monoanion occurs at the carbon between the two carbonyl groups, the site of monoalkylation can be controlled by choice of the amount and nature of the base. A few examples of the formation and alkylation of dianions are collected in Scheme 1.7. In each case, alkylation occurs at the less stabilized anionic carbon. In Entry 3, the a-formyl substituent, which is removed after the alkylation, serves to direct the alkylation to the methyl-substituted carbon. Entry 6 is a step in the synthesis of artemisinin, an antimalarial component of a Chinese herbal medicine. The sulfoxide serves as an anion-stabilizing group and the dianion is alkylated at the less acidic a-position. Note that this reaction is also stereoselective for the trans isomer. The phenylsulfinyl group is removed reductively by aluminum. (See Section 5.6.2 for a discussion of this reaction.)... 

The process is assumed to take place by a chemoselective attack of the dianion 2-223 at the bromomethyl group of 2-221 and subsequent nucleophilic attack of the resultant monoanion 2-224 onto the epoxide moiety to give 2-225. Use of the sodium-lithium-salt 2-223 of the dicarbonyl compound 2-220, the reaction temperature as well as the Lewis acid LiC104, are crucial. The reaction seems to be quite general, since various 1,3-dicarbonyl compounds can be converted into the corresponding furans. 

Dianions or trianions derived from 1,3-dicarbonyl compounds react with nitroalkenes at low temperature to give the adduct, which undergoes a nitro-aldol type cyclization (Eq. 4.50).640... 

Alkylation reactions of dianions occur at the more basic carbon. This technique allows alkylation of 1,3-dicarbonyl compounds to be carried out cleanly at the less acidic position. Because, as discussed earlier, alkylation of the monoanion occurs at the carbon between the two carbonyl groups, the site of monoalkylation can be controlled by choice of the amount and nature of the base. A few examples of the formation and alkylation of dianions are collected in Scheme 1.8. 

Treatment of 1,3-dicarbonyl compounds with two equivalents of strong base can give a dianion that will react selectively with alkyl halides. For example, ethyl acetoacetate reacts first with NaH to form an enolate, and then with n-BuLi to form a dianion. This then adds i-Prl. 

Carbanions from hydrocarbons, nitriles, ketones, esters, TV./V-dialkyl acetamides and thioamides, and mono and dianions from (3-dicarbonyl compounds are some of the most common nucleophiles through which a new C-C bond can be formed. This C-C bond formation is also achieved by reaction with aromatic alkoxides. Among the nitrogen nucleophiles known to react are amide ions to form anilines however, the anions from aromatic amines, pyrroles, diazoles and triazoles, react with aromatic substrates to afford C-arylation. 

Dianions from (3 dicarbonyl compounds react quite well through the terminal carbon site, under irradiation [21,39]. Monoanions of (3-dicar-bonyl compounds do not react with 2-bromopyridine [40], 2-chloroquinoline... 

As previously indicated, monoanions of / -dicarbonyl compounds fail to react with phenyl halides however, the 1,3-dianions are suitable nucleophiles and react quite well through the terminal carbanion site185. 

The case of a-ketodianions needs to be discussed separately. These reagents can be obtained by double deprotonation of /3-dicarbonyl compounds. When NaH, then n-BuLi are employed, the resulting dianions react with aldehydes at the more basic site but with a weak reactivity at —78 °C120, depending on the structure of the dianion121. This regiose-lectivity is an obvious synthetic advantage since it permits the successive functionalization of both positions of the /3-dicarbonyl substrate. 

Finally, it was reported that dianions derived from dicarbonyl compounds react in a straightforward manner with dielectrophiles derived from oxalic acids, yielding interesting y-alkylidene butenolides or their aza counterparts. However, hydrolysis conditions are critical in the case of the aza derivatives600,601. 

As has been described, the parent monocarbollide-metal carbonyl piano-stool species 2-(CO)n-closo-2,1 -MCB,0II n] are now known for all of the metals M = Mo (12), W (13), Re (14), Fe (11), Ru (6), Os (8), and Ni (18). Evidence also exists for a dicarbonyl-platinum analogue of compound 18,20 and as mentioned earlier, the manganese analogue of 14 has also briefly been reported.3a A notable absence from this list, however, is any representative of the Group 9 metals. The carbonyl nitrosyl-cobalt complex 21 is very closely related to the hitherto unknown dicarbonyl-cobalt dianion [2,2-(CO)2-< 7<9.v<9-2,1 -CoCB10H 11]2 and this species remains an attractive synthetic target. 

Pentanedione (acac) and related jS-dicarbonyl compounds are an extremely important class of hgands that have been studied widely for many years. In general, jS-dicarbonyl compounds exist as mixtures of tautomeric keto and enol forms (equation 15). These compounds are usually easily deprotonated to form monoanions, which form the basis for a large class of coordination compounds, encompassing vir-tuaUy every element. In addition, coordination compounds of the dianions and trianions of jS-diketones have been observed, as well as complexes of the neutral molecules. ... 

The cyclization of the dianions of some 1,3-dicarbonyl compounds with l-bromo-2-chloroethane led to the generation of a number of 2-alkylidenetetrahydrofurans with good regio- and... 

Molander et al. have reported on the dianionic [4 + 3] annulation reaction of 1,4-dicarbonyl compounds with 3-iodo-2-[(trimethylsilyl)methyl]propene (4a X = I, Y = CHiSiMea) x)moted by tin(II) fluoride The extraordinary efficiency of ttiis novel stereoselective seven-member ring forming process, coupled with the simplicity of the procedure, promises to provide an expedient route to innumerable cyclic organic molecules (Scheme 9). 

Enolate ions derived from /3-dicarbonyl compounds are unreactive toward 2-chloroquinoline even under photolytic conditions.10 However, the dilithium salt of benzoylacetone does react by an SrnI mechanism with 2-chloroquinoline. The less substituted carbon atom of the dianion is the nucleophilic site 43 forms.109 ... 

The l,3-bis(trimethylsililoxy)butadienes 130-132, as the equivalent of methyl acetoacetate dianion, constitute the three-carbon fragments with two nucleophilic sites (equation 110). Condensation of 130-132 with various equivalents of -dicarbonyl compounds and titanium(IV) chloride gives substituted methyl salicylates. The differential reactivity of the electrophiles which increases in the order conjugated position of enone > ketone > monothioacetal, acetal and of 130-132 (4-position > 2-position) ensures complete regioselectivity in this combination of two three-carbon units to form phenols such as 133 and 134 °° °. ... 

Michael addition of the dianions derived from -dicarbonyl compounds facilitated yet another annulation - Michael addition of a dianion then intramolecular aldol condensation (Scheme 6.89) [112]. Complexation of ATPH with trans-chal-cone (112) in CH2CI2 at -78 °C, followed by treatment with the dianion of methyl acetoacetate gave, after quenching with aqueous HCl, bicyclic product 113 in a nearly quantitative yield. This system can be used for elaboration of the bicyclo [3,5,l]undecane ring system in 114, as can be found in the backbones of terpenoids and the taxol family. 

Dicarbonyl compounds may be converted into dianions, which react with electrophiles at the more basic site. Huckin and Weiler found that 3-keto ester dianions undergo aldol addition reactions at the more basic methyl position (equation 32). The lithium/sodium dianion shows surprisingly weak reactivity, giving the aldol in only 11% yield after 1 h at -78 °C In contrast, the lithium enolates of simple ketones and esters, which should be much less basic than the 3-keto ester dianion, react with aldehydes to give nearly quantitative yields of aldols in THF in seconds at -78 °C. ° Seebach and Meyer also studied this reaction, and obtained the oxolactone (equation 33). Simple diastereoselection in the reaction of 3-keto ester dianions has also been studied (vide infra). 

Cyclocondensation of dianions of p-dicarbonyl compounds 35 with nitriles offers a possibility for the formation of asymmetrically 2,6-disubstituted 4-pyridones 36, e.g. ... 

Alkylation of a 1,3-dicarbonyl compound at a flanking methyl or methylene group instead of at the doubly activated C-2 position does not usually take place to any significant extent. It can be accomplished selectively and in good yield, however, by way of the corresponding dianion, itself prepared from the dicarbonyl compound and two equivalents of a suitable strong base. For example, 2,4-pentanedione 2 is converted into 2,4-nonanedione by reaction at the more-reactive, less-resonance-stabilized carbanion (1.17). ... 

The monoanions of 1,3-dicarbonyl compounds react smoothly with the cis-oriented epoxy triflate 1 to give the intermediate I which, after further base treatment, leads to a dihydrofuran system [20] (Scheme 7). After treatment of 1 with dianions of 1,3-dicarbonyl compounds, tetrahydrofurylidine formation is observed under kinetic conditions [20] (Scheme 7). 

In the presence of a very strong base, such as amide ion or an organolithium reagent, it is possible to convert dicarbonyl compounds to their dianions. Subsequent alkylation of such dianions leads to alkylation at the more strongly basic enolate site, rather than at the carbon atom between the two carbonyl carbons. The more acidic methylene group activated by two carbonyl substituents is the preferred site in the monoanion, as discussed earlier. The ability to determine the site of monoalkylation by choice of the amount and nature of the basic catalyst has significantly expanded the synthetic utility of enolate alkylations. Scheme 1.7 gives some examples of formation and alkylation of dianions. 

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