Diethyl malonate, arylation

Aryl halides react too slowly to undergo substitution by the Sn2 mechanism with the sodium salt of diethyl malonate and so the phenyl substituent of phenobarbital cannot be introduced in the way that alkyl substituents can... 

Aryl lead tncarboxylates have been shown to be intermediates in two new routes to phenols, and to have considerable potential as reagents for the C-arylation of carbon acids which are more acidic than diethyl malonate. A... 

Palladium-Catalyzed Arylation of Enolates. Very substantial progress has been made in the use of Pd-catalyzed cross coupling for arylation of enolates and enolate equivalents. This reaction provides an important method for arylation of enolates, which is normally a difficult transformation to accomplish.171 A number of phosphine ligands have been found to promote these reactions. Bulky trialkyl phosphines such as /n. v-(/-butyl)phosphinc with a catalytic amount of Pd(OAc)2 results in phenylation of the enolates of aromatic ketones and diethyl malonate.172... 

Although most of the methods for the arylation of enolizable compounds so far developed rely on special phosphine ligands, there is a report of an unusually mild and efficient phosphine-free procedure for the arylation of diethyl malonate, the key to success of which is announced to be the use of a heterogeneous base. In this procedure all three halobenzenes, including PhCl, showed practically identical reactivity (49).198... 

Diethyl malonate was reacted with (het)aryl isothiocyanates in the presence of potassium hydroxide or sodium hydride in dioxane or THF at... 

The reaction of diethyl malonate and 2-aryl-4-methylthioquinazoline-3-oxides (1295) in boiling acetonitrile, in the presence of potassium tert-butoxide for 24 hr under nitrogen, afforded isoxazolo[2,3-c]quinazolines (1297, via 1296, in 57-61% yields (87SC1449). 

According to Thurston (702), the lower dibasic esters yield pure carbox5unonoguanamines so readily that this reaction is an excellent synthetic route, when confined to the lower esters. It has been apphed to 1-aryl- and alkyl-biguanides as usual, and to the alkali metal salts of half esters. The reaction involving diethyl malonate is represented below succinic acid esters (292, 699) react similarly. 

As the last example of C-C bond-formation reactions catalyzed by alkaline earth hydroxides, we mention the recently reported a-arylation of diethyl malonate in the presence of a palladium catalyst and a base in a separate phase 299). The arylation of carbonyl compounds is a carbon-carbon coupling reaction between an aryl halide and an enolate, which is usually catalyzed by palladium salts in the presence of an appropriate base (300,301). The arylation of diethyl malonate with bromobenzene (Scheme 48) was performed with tetrachloropalladate as the... 

Results Obtained in the Arylation of Diethyl Malonate with Bromobenzene Catalyzed by Na2PdCl4 and Various Solid Bases in a Batch Reactor (299)... 

The coupling of aryl halides and classical carbon nucleophiles, such as malonates, is also feasible in the presence of a properly selected palladium or copper catalyst. Diethyl malonate and 3-iodopyridine, for example, gave diethyl 2-(3 -pyridyl)malonate in 73% yield (7.84.), The optimal catalyst in this process consisted of copper(I) iodide and 2-hydroxylbiphenyl.106... 

The direct alkenylation of arylamines at the ortho position has been reported in reactions of o -chloroalkenylmagnesium chloride with N-lithioarylamines.22 Use of the CuI-L-proline catalyst system in DMSO has been found to be successful in promoting reactions of aryl iodides and bromides with activated methylene compounds, such as ethyl acetoacetate and diethyl malonate.23 The same catalyst in dioxane has been used in intramolecular cyclization of ene-carbamates leading to indoles or pyrrolo[2,3-cjpyridines.24... 

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. 

Highly substituted tetrahydrothiopyran 1,1-dioxides result from the Michael addition of diethyl malonate to the bis-styryl sulfones 459. On the basis of their NMR spectra, the aryl and aroyl substituents are equatorially disposed (Equation 149) <1999IJB376>. 

Phenylation and arylation have also been performed in bifunctional compounds such as malonates, /1-diketones and /1-ketoesters (Table 8.4). Diethyl malonate was arylated at room temperature affording mixtures of mono- and bis-arylated products, whereas isopropylidene malonate (Meldrum s acid) underwent bis arylation directly. Dimedone, the all carbon analogue of Meldrum s acid, was also mono-and bis-phenylated, with some concomitant O-phenylation [33], Generally, / -diketones show often ambident reactivity but the O-arylated product is normally the minor one an exception was noted in the triketone (PhCO)2CHCOPh which underwent mainly O-phenylation (68%) [33], Several dianions from /1-diketones have been arylated in high yields at the a-position, in a procedure superior to other methods [35]. 

Another important example leads to the preparation of diethyl phenylmalonate. This compound cannot be made by alkylation of diethyl malonate as aryl halides do not undergo nucleophilic substitution (Chapter 23). 

Another procedure utilizes oxides of nitrogen. An example is the oxidation of diethyl malonate to diethyl oxomalonate, CO(COjCjH5)j, with nitrous anhydride (76%). Synthesis of alkyl aryl a-diketones has been accomplished under similar conditions (30-40%). ... 

The halogenopurines react with many other nucleophiles including hydrazines, hydrox-ylamine and alkoxyamines, sulfonic acids and thiocyanates, and compounds with active methylene groups such as diethyl malonate furnish appropriate purine derivatives which offer valuable routes to alkyl and substituted alkyl derivatives. Also aryl groups have been substituted for halogen using aryllithiums (63N224). 

Cyclization reactions via coupling of an aryl group and a stabilized carbon nucleophile to the 1,4-positions of a diene were reported by Grigg and Sridharan [40]. The reaction proceeds via a spirocyclic jr-allyl intermediate. Diethyl malonate and dicyanomethane were used as the stabilized carbon nucleophiles. In one example, spirocyclic compound 21 was obtained from 18 in 60% yield [Eq.(25)]. 

Under the classical conditions (pyridine, CHCI3, room temperature or 40-60 C), diethyl malonate did not react with aryllead triacetates and the a-methyl and a-phenyl derivatives reacted slowly to give poor yields (-25%) of the corresponding a-aryl a-substituted malonic acid diesters. Moderate to good yields were obtained by reacting the sodium salt of substituted malonic esters with aryllead triacetates in THF in the presence of pyridine, but the sodium salt of diethyl malonate again failed to react. 

The general approach can be enlarged and conditions for condensation made milder by the use of further-activated esters, thus condensation with methyl nitroacetate produces 3-nitro-coumarins, condensations with Wittig ylides " allow orffto-hydroxyaryl ketones to be used ° and the use of diethyl malonate (or malonic acid ) (a 3-ester can be removed by hydrolysis and decarboxylation ), malononitrile, ethyl trifluo-roacetoacetate, or substituted acetonitriles in a Knoevenagel condensation, produces coumarins with a 3-ester, 3-trifluoroacetyl, " 3-cyano, or 3-alkyl or -aryl substituent. Condensation with IV-acetylglycine generates 3-acetylamino-coumarins. ... 

An interesting method for the simultaneous formation of two C—C bonds is represented by the regio- and stereoselective arylation of 1,4-cyclohexadiene with iodobenzene and diethyl malonate. After oxidative insertion of palladium(O) into the aryl - iodine bond the arylpalladium species generated adds syn to a double bond and a subsequent syn palladium migration forms a ttK-woTt-allylpalladium intermediate. The palladium is displaced with inversion by the soft carbanion to produce the /ran.v-cy cl oh ex en e derivative 4 in high yield26, at the same time regenerating an active palladium(O) catalyst for the next catalytic cycle. 

Arylazo sulfides (389) behave as arylating agents in an Srn photostimulated process involving the conjugate bases (390) of malononitrile, ethyl cyanoacetate, diethyl malonate and ethyl acetoacetate and provide access to synthetically strategic substrates (391). The effectiveness of the arylation depends on the electrophilicity of the aryl radicals (392) and on the HOMO energy of the... 

Under ordinary conditions, aryl or alkenyl halides do not react with enolate anions, although reaction can occur with aryl halides bearing strongly electronegative substituents in the ortho and para positions. 2,4-Dinitrochlorobenzene, for example, with ethyl cyanoacetate gives ethyl (2,4-dinitrophenyl)cyanoacetate (90%) by an addition-elimination pathway. Unactivated aryl halides may react with enolates under more vigorous conditions, particularly sodium amide in liquid ammonia. Under these conditions, the reaction of bromobenzene with diethyl-malonate, for example, takes place by an elimination-addition sequence in which benzyne is an intermediate (1.8). 

The first milder method for this transformation, developed by Buchwald and Hennessy in 2002 [66], employed CuI/2-phenylphenol as a catalytic system to perform the arylation of diethyl malonates. The reaction worked well at 70 °C, but for some substrates such as isopropylidene malonate, l,3desired products were observed. In addition, only aryl iodides were compatible with these reaction conditions. 

CuI/L-proUne (LI) was proved to be a quite efficient catalytic system for this coupling. The reaction proceeded smoothly in DMSO at 40-50°C in the presence of CS2CO3 (Table 9.14, entry 1) [67]. Both aryl iodides and bromides were suitable substrates. A wide range of activated methylene compounds, including ethyl ace-toacetate, ethyl benzoyl acetate, and diethyl malonate were compatible with these reaction conditions. This catalytic system could also be used for the arylation of aryl iodides with acetylacetone and ethyl cyanoacetate (entry 2) [68]. Recently, it was found that 2-picoUnic acid (L4) could lead to the arylation of aryl iodides and diethyl malonate worked at room temperature (entry 3) [69]. For hindered substrates or aryl bromides, higher reaction temperatures were still required. Additionally, Chxn-Py-Al (L16) was revealed to accelerate the Cul-catalyzed coupling of iodobenzene with diethyl malonate, ethyl cyanoacetate and malononitrile (entry 4) [26],... 

---