Alkylation of dimethyl malonate

Initial C-perfluoroalkylation of p diketonesoccurs dunng thenUV irradiation in the presence of perfluoroalkyl iodides in liquid ammonia Pluorinated enami-noketones are obtained by subsequent ammonolysis of a difluoromethylene group and removal of the acetyl group [131] C-alkylation of dimethyl malonate takes... 

Both the regiochemistry and stereochemistry are influenced by reaction conditions. A striking example is a complete switch to 3-alkylation of dimethyl malonate... 

Scheme 4.24 Cinchona alkaloid derived phenyl selenides in Pd-catalyzed alkylation of dimethyl malonate with l,3-diphenyl-2-propenyl acetate.

Example 6.7 This example demonstrates the promoting effect of microwaves on an asymmetric catalytic reaction. Alkylation of dimethyl malonate carbanion is completed by a racemic allylic alcohol derivative in the presence of the complex of the Mo(III) ion with chiral bidentate nitrogen ligand VII. By this method, the key intermediate in the synthesis of the oral HfV inhibitor tipranavir was prepared in 95 % yield and 94 % e.e. (Scheme 6.11) [31]. Note that the racemic substrate is completely transformed into one enantiomer of the alkylated product revealing catalytic racemization of the non-reactive enantiomer ... 

Chiral phosphinous amides have been found to act as catalysts in enantio-selective allylic alkylation. Horoi has reported that the palladium-catalyzed reaction of ( )-l,3-diphenyl-2-propenyl acetate with the sodium enolate of dimethyl malonate in the presence of [PdCl(7i-allyl)]2 and the chiral ligands 45 gave 46 in 51-94% yields and up to 97% ee (Scheme 38). It is notorious that when the reaction is carried out with the chiral phosphinous amide (S)-45a, the product is also of (S) configuration, whereas by using (R)-45b the enantiomeric (R) product is obtained [165]. 

With the A-ring unit readily available, we directed our attention to the formation of the B-ring. At first, we duplicated the five step scheme reported in Sih s strigol synthesis involving 1) esterification of the acid 14, 2) allylic bromination with N-bromo 8 ucc i n imi d e (NBS) to 15, 3) condensation with the sodium salt of dimethyl malonate to 16, 4) alkylation with methyl bromoacetate to 17, and 5) acid catalyzed hydrolysis and decarboxylation to the acid 18. 

Volume 75 concludes with six procedures for the preparation of valuable building blocks. The first, 6,7-DIHYDROCYCLOPENTA-l,3-DIOXIN-5(4H)-ONE, serves as an effective /3-keto vinyl cation equivalent when subjected to reductive and alkylative 1,3-carbonyl transpositions. 3-CYCLOPENTENE-l-CARBOXYLIC ACID, the second procedure in this series, is prepared via the reaction of dimethyl malonate and cis-l,4-dichloro-2-butene, followed by hydrolysis and decarboxylation. The use of tetrahaloarenes as diaryne equivalents for the potential construction of molecular belts, collars, and strips is demonstrated with the preparation of anti- and syn-l,4,5,8-TETRAHYDROANTHRACENE 1,4 5,8-DIEPOXIDES. Also of potential interest to the organic materials community is 8,8-DICYANOHEPTAFULVENE, prepared by the condensation of cycloheptatrienylium tetrafluoroborate with bromomalononitrile. The preparation of 2-PHENYL-l-PYRROLINE, an important heterocycle for the synthesis of a variety of alkaloids and pyrroloisoquinoline antidepressants, illustrates the utility of the inexpensive N-vinylpyrrolidin-2-one as an effective 3-aminopropyl carbanion equivalent. The final preparation in Volume 75, cis-4a(S), 8a(R)-PERHYDRO-6(2H)-ISOQUINOLINONES, il lustrates the conversion of quinine via oxidative degradation to meroquinene esters that are subsequently cyclized to N-acylated cis-perhydroisoquinolones and as such represent attractive building blocks now readily available in the pool of chiral substrates. 

Allylic alkylationThis Pd(0) complex, in combination with a small quantity of bis(diphenylphosphino)ethane, is more effective than PdIPfQ.HOjL for alkylation of allylic acetates with the anion of dimethyl malonate. It also permits use of sodium cyclopentadienide as a nucleophile. 

Stereoselective allylic alkylations have been carried out with the aid of palladium catalysts. The 17-(Z)-ethylidene groups of steroids (obtained from the ketones by Wittig olefination) form n-allyl palladium complexes in the presence of copper(n) salts (B.M. Trost, 1974, 1976). Their alkylation with dimethyl malonate anions in the presence of 1,2-ethane-diylbis[diphenylphosphine] (— diphos) gives a reaction exclusively at the side chain and only the (20S) products. If one starts with the endocyclic 16,17 double bond and replaces an (S)-20-acetoxy group by using tetrakis(triphenylphospbine)palladium,the substitution occurs with complete retention of configuration, resulting from two complete inversions (B.M. Trost, 1976). 

Allylic alkylation. In general, allylic alkviation catalyzed by transition metals results from attack at the less substituted carbon atom of the ir-allyl intermediate. Deviation from this pattern is observed with some nucleo[ihilcs when Mo(CO)h is used as catalyst. For example, the anion of dimethyl malonate genei ated with 0,N-bis(trimethylsilyl)acctamidc (BSA) reacts with the allylic acetate 1 mainly by attack at the tertiary center to give 2. 

Very recently, Ikariya reported chiral amido ruthenium complex-catalyzed asymmetric Michael addition of dimethyl malonate with conjugate enones using Ru[(i ,i )-TsDPEN](>7 -arene) ((R,R)-TsDPEN = (lR,2R)-N-(p-toluenesulfonyl)-l,2-di-phenylethylenediamine) [84], The reaction of cyclopentenone with dimethyl malonate gave the corresponding /3-alkylation product in 99% yield with 97% e.e. (Eq. 9.60). For this mthenium-catalyzed asymmetric Michael addition, the Bronsted basicity of the amido ligand is responsible for the excellent catalytic activity. 

Allylic and dienyl sulfones have been prepared by conjugate addition to 1,3-dienes ". Phenylsulfonyhnercuration of conjugated dienes gives mercury adducts which can be treated with base to afford phenylsulfonyldienes. 2-(Phenylsulfonyl)-l,3-dienes can be stereo- and regioselectively functionalized via Michael addition of nucleophiles to give allylic sulfones. A key intermediate in the synthesis of a Monarch butterfly pheromone 4 was prepared by BackvaU and Juntunen by alkylation and subsequent palladium-catalyzed substitution of the allylic sulfone formed by Michael addition of dimethyl malonate to 2-(phenylsulfonyl)-l,3-butadiene (equation 10). 

An interesting approach to develop an asymmetric allylic alkylation catalyst by using a peptide-based phosphine hgand was examined by Gilbertson (Scheme 3.70) [135]. Phosphine-sulfide amino acid 211 was incorporated into a peptide sequence on a polymer support After reduchon of the phosphine sulfide to phosphine, the polymer-supported pephde sequence having phosphine-(support-Gly-Pps-D-Ala-Pro-Pps-D-Ala-Ac) was prepared. The complex of the peptide with Pd was uhhzed for the asymmetric addition of dimethyl malonate 202 to 3-acetoxycy-clopentene 212 to give 213 in 59% yield and 66% ee. 

It was observed that the rate of palladium-catalyzed allylic alkylation in water was drastically enhanced when the reaction was performed in the presence of surfactants [15]. Enantioselectivity up to 92% was obtained in the reaction of dimethyl malonate with l,3-diphenyl-2-propenyl acetate when a chiral ligand such as Binap was used in the presence of cetyltrimethylammonium hydrogen sulfate (Eq. 6) [16]-... 

A closely related methodology (route c) involves the dianion from a diketone (R = Me) with the anion of dimethyl malonate (R = Me) (ref.25). The bis-trimethylsilyl ether from methyl acetoacetate has been interacted with the ketalised acid chloride shown (R = CgH ) to furnish the methoxy carbonyl derivative of olivetol (route d) (ref.26). It was also found that pentane-2,4-dione with dimethyl malonate in the presence of sodium hydride afforded methyl orsellinate (ref.26). In a biomimetic approach (route e) a tetraketone has been enzymically cyclised to give the corresponding orsellinic acid (R=H, R = alkyl) (ref. 27). 

The stereochemical course of alkylation was investigated by reaction of the 4-f-butyl derivative (4) of (1) with the anion of dimethyl malonate with TOT... 

When using PPh3, separation or solvent extraction of the products from the ionic phase is not feasible. However, when the hydrophilic phosphine P(w-C6H4S03Na)3 was used, the IL could be recovered and recycled three times without losing activity in the alkylation by dimethyl malonate. 

This asymmetric transformation includes neither racemization nor epimerization. Both enantiomeric substrates, S, and Sj, are converted to a single enantiomeric intermediate I having two diastereotopic reaction sites through the interaction with a chiral catalyst or reagent. The selectivity is determined only by the rate ratio in the two reaction pathways to Pj and Pj, while the rate of formation of I from Sf, and Sj and their equilibrium affect only the overall rate of the reaction Scheme 5.54 shows a typical example [143]. A chiral Pd complex reacts with racemic 2-cyclohexenyl acetate to form a chiral tr-allyl intermediate, in which the stereogeruc centre of the substrate is lost The reaction with a lithium salt of dimethyl malonate gives the alkylated malonate in 91% yield and 98% ee. 

Addition is usually the main process and products are isolated in good yields. In one particular case reported in 1997, the nonstereoselective 1,2-aIkylation of dimethyl malonate on the monoepoxide derived from cM-l,2-dihydroxy catechol has been explained by electronic and steric effects of the bulky side chain dioxolane ring. One can say that almost every vinyl epoxide is a good electrophile for Pd-catalyzed alkylations. The possible variation around the metal center and the tolerance toward aqueous or organic solvents extend the long list of nucleophiles available for C—C bond formation. 

Complexation of alkenes to iron carbonyl fragments increases the electrophilicity of the alkene, owing to the electron-withdrawing ability of the carbonyl ligands. The anion of dimethyl malonate will attack the iron tetracarbonyl complex of methyl acrylate 6.295 (Scheme 6.113). " The resulting anion 6.296 is obviously related to the intermediates involved in the reactions of Collman s reagent (Section 4.5.1). Thus, carbonylation and addition of an alkyl halide results in acylation. 

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