Nucleophiles malonate

Years earlier, Nicholas and Ladoulis had found another example of reactions catalyzed by Fe2(CO)9 127. They had shown that Fe2(CO)9 127 can be used as a catalyst for allylic alkylation of allylic acetates 129 by various malonate nucleophiles [109]. Although the regioselectivites were only moderately temperature-, solvent-, and substrate-dependent, further investigations concerned with the reaction mechanism and the catalytic species were undertaken [110]. Comparing stoichiometric reactions of cationic (ri -allyl)Fe(CO)4 and neutral (rj -crotyl ace-tate)Fe(CO)4 with different types of sodium malonates and the results of the Fe2(CO)9 127-catalyzed allylation they could show that these complexes are likely no reaction intermediates, because regioselectivites between stoichiometric and catalytic reactions differed. Examining the interaction of sodium dimethylmalonate 75 and Fe2(CO)9 127 they found some evidence for the involvement of a coordinated malonate species in the catalytic reactions. With an excess of malonate they... 

The first iridium catalysts for allylic substitution were published in 1997. Takeuchi showed that the combination of [fr(COD)Cl]2 and triphenylphosphite catalyzes the addition of malonate nucleophiles to the substituted terminus of t -allyliridium intermediates that are generated from allylic acetates. This selectivity for attack at the more substituted terminus gives rise to the branched allylic alkylation products (Fig. 4), rather than the linear products that had been formed by palladium-catalyzed allylic substitution reactions at that time [7]. The initial scope of iridium-catalyzed allylic substitution was also restricted to stabilized enolate nucleophiles, but it was quickly expanded to a wide range of other nucleophiles. 

Although most of these early reactions were conducted with allylic acetates, reactions of allylic carbonates, trifluoroacetates, and phosphates also occur. Sodium diethylmalonate also reacts with allylic alcohols in the presence of the iridium-triphenylphosphite catalyst. However, the alcohol itself does not act as a leaving group. Instead, transesterification occurs with one equivalent of malonate nucleophile to form a more labile ester leaving group. 

Although Helmchen et al. showed that asymmetric iridium-catalyzed allylic substitution could be achieved, the scope of the reactions catalyzed by iridium complexes of the PHOX ligands was limited. Thus, they evaluated reactions catalyzed by complexes generated from [lr(COD)Cl]2 and the dimethylamine-derived phosphoramidite monophos (Scheme 8) [45,51]. Although selectivity for the branched isomer from addition of malonate nucleophiles to allylic acetates was excellent, the highest enantiomeric excess obtained was 86%. This enantiomeric excess was obtained from a reaction of racemic branched allylic acetate. The enantiomeric excess was lower when linear allylic acetates were used. This system catalyzed addition of the hthium salts of A-benzyl sulfonamides to aUylic acetates, but the product of the reaction between this reagent and an alkyl-substituted linear aUylic acetate was formed with an enantiomeric excess of 13%. 

In the presence of thiourea catalyst 122, the authors converted various (hetero) aromatic and aliphatic trons-P-nitroalkenes with dimethyl malonate to the desired (S)-configured Michael adducts 1-8. The reaction occurred at low 122-loading (2-5 mol%) in toluene at -20 to 20 °C and furnished very good yields (88-95%) and ee values (75-99%) for the respective products (Scheme 6.120). The dependency of the catalytic efficiency and selectivity on both the presence of the (thio) urea functionality and the relative stereochemistry at the key stereogenic centers C8/C9 suggested bifunctional catalysis, that is, a quinuclidine-moiety-assisted generation of the deprotonated malonate nucleophile and its asymmetric addition to the (thio)urea-bound nitroalkene Michael acceptor [279]. 

Tomita and Endo have shown that three-component coupling of bisallene 163, aryl dihalide, and a malonate nucleophile takes place with a palladium catalyst. Arylpalladium species derived from the halide attacks the central carbon of allene to form a Tt-allylpalladium intermediate, which is then attacked by the malonate anion to form C-C... 

In step e, a tosylate is sucessfully displaced by an incoming malonate nucleophile with inversion of configuration. What is a potentially significant side-reaction when treating secondary tosylates with more basic nucleophiles ... 

In addition to cyclic allylic substrates, malonate nucleophiles have been used in reactions with both symmetrical" and unsymmetrical" acyclic systems, and with geminal dicarboxylates. Malonates and Meldrum s acid have also been used as nucleophiles in the desymmetrization of meso diesters. 

Although it probably did not involve a Heck reaction per se, Balme and co-workers employed an interesting tandem reaction in their construction of A 2) capnellene (147) (Scheme 6-26) [54J. Presumably vinyl iodide 144 undergoes initial oxidative addition with the palladium(O) catalyst to furnish a cr-alkenylpalladium(n) intermediate that is complexed to the pendant alkene. Intramolecular addition of the soft malonate nucleophile to this complex, from the opposite face, followed by reductive elimination, then provides tricycle... 

Another type of structure which has been examined are [RuCp]" complexes of 5-chloroindoles <88OM660>. These complexes undergo nucleophilic substitution by amine, alkoxide, thiolate and malonate nucleophiles (Scheme 133). 

The intermediate enolate formed in a Michael reaction normally undergoes protonation to give the ketone product. However, in the presence of an aldehyde, a Michael/Aldol cascade can occur. Using the racemic Michael acceptor (11.41), Shibasaki has demonstrated an enantioselective and diastereoselective Michael/Aldol cascade involving the malonate nucleophile (11.42) and the aldehyde (11.43). The process also involves a kinetic resolution of the starting material. Not only is this a remarkable example of several aspects of stereoselectivity, the product (11.44) is a useful prostaglandin precursor. 

FIGURE 6 The reaction studied by computational methods and the calculated structure of malonate nucleophile 71K. 

While the two DPT methods produced some minor differences in energy, both led to the same conclusions. Quahtatively, the concave face (endo approach) of malonate nucleophile 70 appeared to be more sterically crowded than the convex face (exo approach) due to the cyclohexenone ring being roughly perpendicular to the plane formed by the metal-coordinated malonate anion (71-K). This analysis confirmed that our initial hypothesis with respect to which face is more sterically accessible was not flawed. It also confirms that the observed stereoselectivity is likely due to a confluence of factors, rather than a pure steric influence. 

Cyclobutylidene derivatives have been regio- and stereoselec-tively reduced to substituted vinyl cyclobutanes with Pd(dba)2 and sodium formate. Heteroaryl benzylic acetates (including 2° acetates) undergo Pd-catalyzed benzylic nucleophilic substitution with malonate nucleophiles. Cyclobutanone O-benzoyloximes have been converted to a variety of nitrile derivatives using Pd(dba)2 in combination with chelating phosphines (eq 27). ... 

On the other hand, imidazolidines 53a and 53c have also been successfully employed in this reaction, showing a similar behavior to that observed in the same reaction with malonate nucleophiles and with 53c appearing as the most efficient catalyst (Scheme 3.21). ° The use of differently substituted nitroalkenes was also evaluated but diastereoselectivities still remained rather low, obtaining... 

The use of carbanionic nucleophiles in the Mizoroki-Heck cyclization-/ -allyl nucleophilic trapping sequence allowed for streamlined access to the triquinane core common to various members of the capnellene family of natural products. For example, Shibasaki and coworkers obtained diquinane 57 in 77% yield and 87% ee by Mizoroki-Heck cy-clization of trienyl triflate 47 in the presence of malonate nucleophile 56 Scheme 16.14). It is notable that two new C-C bonds and three stereocentres are generated in this reaction. Eleven additional steps were used to convert intermediate 57 to ( )-A ( Ecapnellene (58). This first catalytic asymmetric total synthesis ( )-A d2). j pjjgjjgjjg achieved in 19 steps and 20% overall yield from commercially available materials. A related approach has recently been employed to prepare intermediates en route to capnellenols 53 and 54 (Scheme 16.12) [41]. 

Nucleophilic attack of stabilized carbon nucleophiles on coordinated olefins is also known. Hegedus developed the alkylation of olefins shown in Equation 11.31. The (olefin)palladium(II) chloride complexes did not react with malonate nucleophiles, but the triethylamine adduct does react with this carbon nucleophile to provide the alkylation product. This reaction has recently been incorporated into a catalytic alkylation of olefins by Widenhoefer. - Intramolecular reaction of the 1,3-dicarbonyl compounds with pendant olefins in the presence of (GHjCNl PdCl occurs to generate cyclic products containing a new C-C bond (Equation 11.32). Some intermolecular reactions with ethylene and propylene have also been developed by this group. Deuterium labeling studies (Equation 11.32) have shown that the addition occurs by external attack on the coordinated olefin. ... 

A variant on this approach is to incorporate the enantiotopic alkenes into a five-membered ring such as a cyclopentadiene. 3-Hydride elimination is then obviated, as a if-allyl complex 5.130 is formed after insertion, which may be intercepted by an added nucleophile, such as acetate (Scheme 5.39). Other nucleophiles, including carbon nucleophiles can also be used to intercept the tt -allyl intermediate (see Section 9.2.9). This chemistry was used in a synthesis of capnellene 5.137 (Scheme 5.40). The T]p-allyl intermediate 5.130 was intercepted with a functionalized malonate nucleophile 5.132. The malonate was used to construct the third five-membered ring of the natural product while one ester group was removed by Krapcho... 

Inversion during formation of the Ti -allyl complex is not always observed. For the tricyclic compound 9.119, the endo face is sterically blocked, and only the exo face is accessible (Scheme 9.37). It was observed that only the exo isomer reacted with a malonate nucleophile in the presence of a molybdenum catalyst. ... 

The development of a highly enantioselective catalytic asymmetric conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes is described, as is its use in the synthesis of the selective endothelin A antagonist ABT-546. Employing 4 mol% of a bis(oxazoline)-Mg(OTf)2 complex with 5.5 mol% of an amine co-catalyst, the product nitroketone is obtained in 88% ee, with good yields. Particularly important to the reaction is the water content. While water is necessary during the generation of the catalyst, the water must then be removed in order to maximize selectivity and reactivity. The scope of the reaction has been extended to other ketoester and malonate nucleophiles, as well as other nitroolefins. 

Cyclopropanes are obtained by the electrolysis of a mixture of activated alkenes and a malonate nucleophile (Scheme 1.14) [22]. Electrolysis is also useful for one-pot cyclopropanation from an aromatic aldehyde, malononitrile, and a malonate ester [23]. 

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