Dicarbonyl compounds malonates

In contrast, when pentan-2,4-dione was allowed to react with 3a under similar conditions, chelated pentan-2,4-dionato complex 9 was obtained in which one of four phosphorus atoms of the framework is dissociated. This result of the unique reaction was confirmed by the X-ray structure analysis of the complex 9. Although the explanation of these results obtained for two types of )9-dicarbonyl compounds, malonate and pentan-2,4-dione, is not straightforward at present, the difference in the steric congestion between two dicarbonyl compounds seems to be responsible. 

Starting from oxygen-linked 1,3-dicarbonyl compounds (malonates or acetoacetates), Tietze and co-workers have demonstrated an allylic substitution at the a-position of varions snbstrates (aUyl acetates, carbonates, and chlorides). Under the conditions employed, bisalkylation was observed in all cases. Since the acetoacetates could be alkylated by hard electrophiles at the y-position, a broad spectrum of compounds might be obtained. The cleavage from the resin was performed using DIBAL-H to obtain the corresponding diols (Scheme 24). 

Most of the reactions of ester enolates described so far have centered on stabilized eno lates derived from 1 3 dicarbonyl compounds such as diethyl malonate and ethyl ace toacetate Although the synthetic value of these and related stabilized enolates is clear chemists have long been interested m extending the usefulness of nonstabilized enolates derived from simple esters Consider the deprotonation of an ester as represented by the acid—base reaction... 

Although the antithyroid activity of compounds incorporating an enolizable thioamide function was discussed earlier, this activity was in fact first found in the pyrimidine series. The simplest compound to show this activity, methylthiouracil (80) (shown in both enol and keto forms), is prepared quite simply by condensation of ethyl acetoacetate with thiourea.Further work in this series shows that better activity was obtained by incorporation of a lipophilic side chain. Preparation of the required dicarbonyl compound starts with acylation of the magnesium enolate of the unsyrametrically esterified malonate, 81, with butyryl chlo-... 

Hermann and colleagues218,219 found that treatment of ketene thioacetal monoxides 172 and 173, with enamines, sodium malonates, /J-dicarbonyl compounds and lithio-... 

Reaction of 1,3-dicarbonyl compounds with IVJV-dimethylformamide dimethyl acetal followed by malonamide in the presence of sodium hydride gives 5,6-disubstituted 1,2-dihydro-2-oxopyridine-3-carboxamides, whereas reaction of the intermediate enamines with cyanothioacetamide or cyanoacetamide in the presence of piperidine provides 2-thioxopyridine-3-carboxamides and 4,5-disubstituted l,2-dihydro-2-oxopyridine-3-carboxamides, respectively <95S923>. P-Enaminonitriles 14 react with p-ketoesters and alkyl malonates, in the presence of stoichiometric amounts of tin(IV) chloride, to afford 4-aminopyiidines 15 and 4-amino-2-pyridones 16 <95T(51)12277>. 

Example The lactone (8>, needed for a natural product synthesis, might be made from (6) via epoxide (7) and so a synthesis for (6) was required. Wittlg disconnection reveals a 1,5-dicarbonyl compound (9), best made by Michael addition of a substituted malonate (11) to enone (10). The enone was made by the simple but reliable Grignard route rather than risking a Mannich reaction of unknown regloselectivity. 

We must now disconnect the 1,4-relationship in (3 and there are many possibilities here. Disconnection the central bond is possible, e.g. to give (31) and malonate, or cyanide could be added to (35), The bt-s probably to use an available 1,4-dicarbonyl compound such as (37). 

In a similar way, carbocycles having a quaternary center could be obtained from acyclic unsaturated 1,3-dicarbonyl compounds [206]. Other combinations are the domino hydroformylation/Wittig olefmation/hydrogenation described by Breit and coworkers [207]. The same group also developed the useful domino hydroformyla-tion/Knoevenagel/hydrogenation/decarboxylation process (Scheme 6/2.14) [208] a typical example is the reaction of 6/2-66 in the presence of a monoester of malonic acid to give 6/2-67 in 41 % yield in a syn anti-ratio of 96 4. Compounds 6/2-68 and 6/2-69 can be assumed as intermediates. 

Microwave-mediated transesterification of commercially available neat poly(styr-ene-co-allyl alcohol) with ethyl 3-oxobutanoate, ethyl 3-phenyl-3-oxopropanoate, and diethyl malonate provided the desired polymer-supported /i-dicarbonyl compounds (Scheme 12.18) [65]. Multigram quantities of these interesting building blocks for heterocycle synthesis were obtained simply by exposing the neat mixture of reagents to microwave irradiation in a domestic microwave oven for 10 min. 

In its original form, the Michael addition consisted on the addition of diethyl malonate across the double bond of ethyl cinnamate in the presence of sodium ethoxide to afford a substituted pentanedioic acid ester. Currently, all reactions that involve a 1,4-addition of stabilized carbon nucleophiles to activated 7i-systems are known as Michael additions. Among the various reactants, enolates derived from p-dicarbonyl compounds are substrates of choice due to their easy deprotonation under mild conditions. Recently, Michael addition-based MCRs emerged as highly potential methodologies for the synthesis of polysubstituted heterocycles in the five- to seven-membered series. 

The disulfide dimers of 2-aminothiophenols have also been used in the syntheses of benzothiazines. In this case, nitrogen acts as a nucleophile and sulfur as an electrophile. Reagents that have nucleophilic carbons adjacent to an electrophilic carbon can be reacted with these disulfides. Examples include a,(3-unsaturated esters that undergo conjugate addition followed by enolate addition to sulfur (Equation 86) <1983J(P1)567>, and 1,3-dicarbonyl compounds such as ethyl acetoacetate <2005AXEo2716> and dimethyl malonate <2006ARK(xv)68> (Scheme 63). 

Table I illustrates this synthesis in schematic form. The first column lists all functions A and B of the 1,3-dicarbonyl compounds or their equivalents that are used to introduce certain substituents R and R" into positions 5 and 7 e.g., unsubstituted TP is formed by malondialdehyde, the 5,7-dione by diethyl malonate, and the 5,7-diamine by malonitrile. Unsymmetrical C3-synthons with different A and B moieties may form two isomeric TPs in which R and R" interchange their positions. The direction of attack depends on both synthon structure and reaction conditions.

Magnesium enolates derived from /S-dicarbonyl compounds can be easily obtained by metallation with l-PrMgBr. A stable cyclic chelate is obtained. As example, the magnesium enolate of mixed malonate is shown in equation 48. 

Table 5 Reductive Cyclization of Oximino Malonates and Related Compounds with /3-Dicarbonyl Compounds...

Dicarbonyl compounds (ethyl acetoacetate and diethyl malonate) have been added to indene in a cerium(rV) ammonium nitrate-mediated addition.119 Similar additions have been observed for ring-substituted styrenes.120... 

Generally, there is no limitation in the 1,3-dicarbonyl compound used. However, several types of these substances are not stable, such as malone dialdehydes or formyl acetic acid. In such cases, l,l,l-trichloro-4-oxo-butanone 96 is an appropriate substitute, since the trichloromethylcarbonyl moiety can easily be transformed into a carboxylic acid ester after the reaction by treatment with an alcohol and a... 

The arylation of ethyl acetoacetate, ethyl benzoylacetate, and diethyl malonate under the catalysis of CuI/L-proline in DMSO has been performed at 40-50 °C in the presence of CS2CO3 to provide the 2-aryl-1,3-dicarbonyl compounds in good yields.38 Both aryl iodides and aryl bromides are compatible with these reaction conditions. 

A highly enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroalkenes has been reported that employs a newly developed Ni(II)-(bis)diamine-based catalyst (174). The reaction scope includes substituted and unsubstituted malonates, /3-keto esters, and nitroalkenes bearing aromatic and aliphatic residues.202... 

The extra ester group is not normally added to the preformed ketone as ethyl acetoacetate 41 is available and the diester is available diethyl malonate 59. If it is necessary to make the 1,3-dicarbonyl compound, this can be done by methods described in chapters 19 and 20. The carboxylic acid 56 can be disconnected at the branchpoint to an alkyl halide and the synthon 58 that could be realised as the anion of diethyl malonate 59 or the lithium enolate of ethyl acetate. 

Attempts to react enol(ate)s of esters with aliphatic aldehydes are doomed as the aldehyde will simply condense with itself. If the ester is replaced by a malonate 60, there is so much enol(ate) from the (5-dicarbonyl compound that the reaction is good. This style of aldol reaction is often called a Knoevenagel reaction10 and needs only a buffered mixture of amine and carboxylic acid. The enol reacts with the aldehyde 61 in the usual way and enolisation of the product 62 usually means that dehydration occurs under the conditions of the reaction. 

Dicarbonyl compounds, such as malonate derivatives, can also be classified under two categories. As well as reacting simply as a three-atom bis-electrophilic fragment (as in the synthesis of barbiturate 10.25 (page 77), an alternative reactivity is available. Condensation (by nucleophilic attack) of the active methylene carbon and electrophilic reaction at just one of the carbonyl groups is a two-atom nucleophilic/electrophilic profile, as seen in the preparation of coumarin 9.16. 

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