Allylic substitutions dimethyl malonate

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. 

The supported aqueous phase methodology was applied to the system Pd(OAc)2/5 TPPTS, a catalytic precursor for the Trost-Tsuji reaction. The characterization of the solid by 31P MAS NMR confirms the presence of Pd°(TPPTS)3 as the main surface species. The catalytic properties of the solid were tested for the allylic substitution of E-cinnamylethylcarbonate by different nucleophiles such as ethyl acetoacetate, dimethyl malonate, morpholine, phenol, and 2-mercapto-pyridine. The absence of palladium leaching was demonstrated, and having solved the problem of water leaching from the solid to the organic phase, the SAP-Pd catalyst was successfully recycled several times without loss in its activity. It was used in a continuous flow experiment which... 

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... 

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). 

Relatively subtle changes in the steric environment of the allyl termini result in substantial variations in regioselectivity, as shown in a series of ir-allyl ligands having a methyl at one terminus and either Pr", Bu or PH at the other terminus. This series varies from a 77 23 ratio favoring the less substituted terminus to >99 1 as the difference in group size increases, with dimethyl malonate as nucleophile (equation 207).399... 

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). 

Preliminary results suggest that ligands of type 3 are useful for Pd-catalyzed nucleophilic enantioselective substitution of allylic acetates by the sodium salt of dimethyl malonate. 

P-Menthylphosphetanes 77, in which an optical active dioxolane group is introduced at the a-position, have also provided asymmetric catalytic activity in the palladium-catalyzed allylic nucleophilic substitution of 1,3-diphenyl-propenyl acetate with the sodium salt of dimethyl malonate (Equation 12). 

Scheme 2 NHC/Pd-catalyzed allylic substitution with dimethyl malonate...

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. 

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 Tsuji-Trost ally lie substitution catalyzed by Pd complexes using CH-acidic nucleophiles can be performed in an ionic liquid of type 1 alone [30] as well as in a biphasic system [31]. In the latter case the use of trisulfonated triphenylphosphine (TPPTS) prevents the catalyst from leaching into the organic phase. In comparison with water as the catalyst-supporting phase, the ionic liquid system exhibits higher activity and selectivity. The enantio-selective version of the allylic substitution with dimethyl malonate can also be performed in ionic liquids with a homochiral ferrocenylphosphine as the ligand [32]. 

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). 

In addition, the formation of Pd black occurred readily during the reaction step hence, recovery of the ligands and their subsequent reuse following the addition of a fresh Pd source was attempted. Ligands 8, 10 and 11, when used in allylic substitutions with dimethyl malonate, were recovered in 76%, 68% and 84% yields, respectively, by evaporation of the organic solvent followed by extraction of the residue with FC-72 [37]. The same procedure allowed the quantitative recovery of 12 which was reused in a second run, affording the substitution product with 98% conversion and 92% ee [38]. 

Asymmetric palladium(0)-catalysed substitution of racemic allylic substrates with malonate and benzylamine as nucleophiles were performed using new enantiopure cyclic (3-iminophosphine ligands namely (2,6-dimethyl-phenyl)-( 1 -phenyl-2, 3,3a, 8a-tetrahydro- 1H-1 -phospha-cyclopenta[-a]inden-8-ylidene)-amines 1 (RP)... 

Activated methylene compounds such as dimethyl malonate have found substantial utility in palladium catalyzed allylic substitution reactions. Accordingly, the Krapcho decarboxylation is often used in conjunction with these reactions. As an example, the first total synthesis of enantiomerically pure (-)-wine lactone has utilized the sequence of reactions.27 First, the allylic substitution reaction of 2-cyclohexen-l-yl acetate (49) with alkali sodium dimethylmalonate yielded 51 with high enantioselectivity, as a result of the use of chiral phosphine ligand 50. The malonate was then subjected to Krapcho decarbomethoxylation using NaCl, H2O, and DMSO at 160 °C to yield 52. This reaction has been used similarly following the allylic substitution reaction with other malonate derivatives.28-30... 

Leitner and co-workers described Pd-catalyzed nucleophilic substitutions ofallylic substrates with different nucleophiles [27]. They used Pd2(dba)3 as the palladium source and phosphane 20 as perfluoro-tagged ligand [Eq. (5)]. Reaction between cinnamyl methyl carbonate (21) and various nucleophiles (Nu-H) were performed in a THF/C7FJ4 biphasic mixture. A decrease in conversion was observed only after the ninth run (with 5 mol% Pd complex). By reducing the amoimt of Pd complex to 1 mol%, five quantitative recyclings were possible. The standard protocol was also applied to the condensation of dimethyl malonate with allyl methyl carbonate, (2-vinyl)butyl carbonate, and cyclohex-2-enyl carbonate. In each case two recyclings were performed without any decrease in conversion. 

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