Dimethyl malonate, sodium

Allylic substitutions catalysed by palladium NHC complexes have been studied and the activity and selectivity of the catalysts compared to analogous Pd phosphine complexes. A simple catalytic system involves the generation of a Pd(NHC) catalyst in situ in THF, from Pdj(dba)j, imidazolium salt and Cs COj. This system showed very good activities for the substitution of the allylic acetates by the soft nucleophilic sodium dimethyl malonate (2.5 mol% Pdj(dba)3, 5 mol% IPr HCl, 0.1 equiv. C (CO ), THF, 50°C) (Scheme 2.22). Generation of the malonate nncleophile can also be carried out in situ from the dimethyhnalonate pro-nucleo-phile, in which case excess (2.1 equivalents) of Cs COj was used. The nature of the catalytic species, especially the number of IPr ligands on the metal is not clear. 

Based on the assumption that this reaction goes through Jt-allyl Mo intermediates (A and B), the result from either linear carbonate (L-C) or branched carbonate (B-C) should give exactly the same result if the equilibrium between A and B is much faster than nucleophilic addition of sodium dimethyl malonate to A or B (Curtain-Hammett) as shown in Scheme 2.17. 

This sequential substitution of the chloro and acetoxy groups makes the chloroacetates useful as building blocks. An example of the use of the chloroacetate 34 from isoprene for the synthesis of the Monarch butterfly pheromone is given in Scheme 737. Two different nucleophiles, sodium dimethyl malonate and sodium methyl acetoacetate, were employed in Pd(0)-catalyzed allylic substitutions. The transformation of 34 to 36 was also made... 

This work was repeated by several groups7 11 in the reaction of sodium dimethyl-malonate with methyl sorbate, Farmer and Metha9 observed small amounts of the 1,4-adduct besides the 1,6-addition product. Difficulties in conducting the transformations and analyzing the products are evident from reports on malonate additions to ethyl muconate12-14 depending on the reaction conditions, the expected 1,4-adduct (equation 4) or isomerization products formed by double bond displacement were isolated. Nucleophilic 1,4- and 1,6-addition reactions to 2,4-pentadienenitrile were also reported15-17. 

Only few examples have been reported so far on nucleophilic addition reactions to acceptor-substituted polyenes123,124,186 188. In 1933, Farmer and Martin186 examined the reaction of methyl 2,4,6-octatrienoate with sodium dimethyl malonate and isolated the 1,4-adduct as major product (equation 81). In contrast to this, 3,5,7-nonatrien-2-one and ethyl 2,4,6-octatrienoate react with organocuprates under 1,8-addition to provide the 4,6-dien-2-ones and 3,5-dienoates, respectively (equation 82)187. 

Ceric ammonium nitrate promoted oxidative addition of silyl enol ethers to 1,3-butadiene affords 1 1 mixtures of 4-(/J-oxoalkyl)-substituted 3-nitroxy-l-butene and l-nitroxy-2-butene27. Palladium(0)-catalyzed alkylation of the nitroxy isomeric mixture takes place through a common ij3 palladium complex which undergoes nucleophilic attack almost exclusively at the less substituted allylic carbon. Thus, oxidative addition of the silyl enol ether of 1-indanone to 1,3-butadiene followed by palladium-catalyzed substitution with sodium dimethyl malonate afforded 42% of a 19 1 mixture of methyl ( )-2-(methoxycarbonyl)-6-(l-oxo-2-indanyl)-4-hexenoate (5) and methyl 2-(methoxycarbonyl)-4-(l-oxo-2-indanyl)-3-vinylbutanoate (6), respectively (equation 12). 

In 1992, Legros and Fiaud found palladium-catalyzed benzyiic alkylation of naphthylmethyl and 1-naphthylethyl esters 103 with sodium dimethyl malonate 104 in dimethylformamide (DMF) to give the corresponding benzyiic alkylated products 105 in high yields (Equation (41)). " When trifluoroacetyl group is used as a leaving group of the ester partner, catalytic alkylation proceeds quite smoothly even at room temperature. In this reaction system, no reaction occurs with benzyiic acetates. 

Palladium acetate and triphenylphosphine generate the active tri- or tetrakis(triphenylphosphine)palladium(0) catalyst on addition of sodium dimethyl malonate. 

Sodium dimethyl malonate was prepared from equimolar amounts of sodium hydride and dimethyl malonate. 

Enantioselective allylic substitutions catalyzed by transition-metal complexes are a powerful method for constructing complex organic molecules [4f,55]. Palladium-based catalysts have often given excellent results. To expand the scope of the reaction, a new enantioselective allylic alkylation catalyzed by planar-chiral ruthenium complexes was developed [56]. For example, the reaction of l,3-diphenyl-2-propenyl ethyl carbonate with sodium dimethyl malonate in the presence of 5 mol% of a planar chiral (S)-ruthenium complex (Figure 5.3) at 20 °C for 6 h in THE resulted in the formation of the corresponding chiral allylic alkylated product of dimethyl 2-((2 )(lS)-l,3-diphenylprop-2-enyl)propane-l,3-dioate in 99% yield vsdth 96% e.e. (Eq. 5.33). 

Substitution reactions of allylic substrates with nucleophiles have been shown to be catalyzed by certain palladium complexes [2, 42], The catalytic cycle of the reactions involves Jt-allylpalladium as a key intermediate (Scheme 2-22). Oxidative addition of the allylic substrate to a palladium(o) species forms a rr-allylpal-ladium(n) complex, which undergoes attack of a nucleophile on the rr-allyl moiety to give an allylic substitution product. The substitution reactions proceed in an Sn or Sn- manner depending on catalysts, nucleophiles, and substituents on the substrates. Studies on the stereochemistry of the allylic substitution have revealed that soft carbon nucleophiles represented by sodium dimethyl malonate attack the TT-allyl carbon directly from the side opposite to the palladium (Scheme 2-23). 

The use of a stabilized carbanion as external nucleophile in the arylation or vinylation of conjugated dienes leads to a 1,4-addition of carbon atoms. This was first demonstrated by Dieck and co-workers [38] in 1983, who showed that l-bromo-2-methylpropene and sodium dimethyl malonate reacted with isoprene in the presence of a palladium catalyst to give 20 in moderate yield [Eq.(21)]. 

Table 7. Charge-Directed Palladium-Assisted Alkylation of Vinyl y-Rulyro-lactones with Sodium Dimethyl Malonate...

To a mixture of 715 mg (2.0 mmol) of dimethyl (/ra y-2-(phenylsulfonyl)-3-cyclohexen-l-yl]malonale, 22 mg (0.1 mmol) of Pd(OAc),. and 96 mg (0,24 mmol) of dppc in 3 mL of THF is added a solution of sodium dimethyl malonate, prepared from 818 mg (6.2 mmol) of dimethyl tnalonate and 180 mg (6.0 mmol) of Nall (80% in paraffin oil) in 8 mL of THF. The mixture is refluxed for 3.5 h under N,. After cooling to r.t., 10 mL of Et,0 and 5 mL sat. aq NaHCO, are added. The layers are separated and the aqueous layer is extracted with three 5-mL portions of F.t20. The combined organic layers are dried over Na,S04 and concentrated in vacuo, followed by filtration over silica gel (column 1 x 3 cm. FtOAc/hexane 1 1). Excess dimethyl malonate is removed by Kugelrohr distillation (100 C 1 Torrl and the crude product is purified by flash chromatography (silica gel. EtOAc/hexane 1 4) to give the product as a colorless oil yield 86% d.r. (transjcis) 87 13. For analytical purposes, the isomers are separated by preparative HPLC. 

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