Soft carbon nucleophiles formation

Formation of a Tr-allylpalladium complex 29 takes place by the oxidative addition of allylic compounds, typically allylic esters, to Pd(0). The rr-allylpal-ladium complex is a resonance form of ir-allylpalladium and a coordinated tt-bond. TT-Allylpalladium complex formation involves inversion of stereochemistry, and the attack of the soft carbon nucleophile on the 7r-allylpalladium complex is also inversion, resulting in overall retention of the stereochemistry. On the other hand, the attack of hard carbon nucleophiles is retention, and hence Overall inversion takes place by the reaction of the hard carbon nucleophiles. 

TT-Aliylpalladium chloride reacts with a soft carbon nucleophile such as mal-onate and acetoacetate in DMSO as a coordinating solvent, and facile carbon-carbon bond formation takes place[l2,265], This reaction constitutes the basis of both stoichiometric and catalytic 7r-allylpalladium chemistry. Depending on the way in which 7r-allylpalladium complexes are prepared, the reaction becomes stoichiometric or catalytic. Preparation of the 7r-allylpalladium complexes 298 by the oxidative addition of Pd(0) to various allylic compounds (esters, carbonates etc.), and their reactions with nucleophiles, are catalytic, because Pd(0) is regenerated after the reaction with the nucleophile, and reacts again with allylic compounds. These catalytic reactions are treated in Chapter 4, Section 2. On the other hand, the preparation of the 7r-allyl complexes 299 from alkenes requires Pd(II) salts. The subsequent reaction with the nucleophile forms Pd(0). The whole process consumes Pd(ll), and ends as a stoichiometric process, because the in situ reoxidation of Pd(0) is hardly attainable. These stoichiometric reactions are treated in this section. 

In addition, a catalytic version of Tt-allylpalladium chemistry has been devel-oped[6,7]. Formation of the Tr-allylpalladium complexes by the oxidative addition of various allylic compounds to Pd(0) and subsequent reaction of the complex with soft carbon nucleophiles are the basis of catalytic allylation. After the reaction, Pd(0) is reformed, and undergoes oxidative addition to the allylic compounds again, making the reaction catalytic.-In addition to the soft carbon nucleophiles, hard carbon nucleophiles of organometallic compounds of main group metals are allylated with 7r-allylpalladium complexes. The reaction proceeds via transmetallation. These catalytic reactions are treated in this chapter. 

The stereochemistry of the Pd-catalyzed allylation of nucleophiles has been studied extensively[5,l8-20]. In the first step, 7r-allylpalladium complex formation by the attack of Pd(0) on an allylic part proceeds by inversion (anti attack). Then subsequent reaction of soft carbon nucleophiles, N- and 0-nucleophiles proceeds by inversion to give 1. Thus overall retention is observed. On the other hand, the reaction of hard carbon nucleophiles of organometallic compounds proceeds via transmetallation, which affords 2 by retention, and reductive elimination affords the final product 3. Thus the overall inversion is observed in this case[21,22]. 

Addition of MeMgl158 or PhLi160 to ir-allylpalladium complexes derived from methylenenoibomane exhibits selective C—C bond formation at die more hindered allyl terminus. Soft carbon nucleophiles with the same allyl species show the opposite regioselectivity (equation 252).158,160... 

An inherent difficulty in achieving high optical yields in ir-allylpalladium reactions is that with the soft carbon nucleophiles employed, attack occurs on the allyl ligand on the face opposite the palladium. This places the source of the chirality (the phosphine ligand) remote from where C—C bond formation is taking place. Despite these limitations, considerable success has been achieved in these reactions. 

Carbopalladation occurs with soft carbon nucleophiles. The PdCl2 complex of COD (100) is difficult to dissolve in organic solvents. However, when a heterogeneous mixture of the complex, malonate and Na2C03 in ether is stirred at room temperature, the new complex 101 is formed. This reaction is the first example of C—C bond formation and carbopalladation in the history of organopalladium chemistry. The double bond becomes electron deficient by the coordination of Pd(II), and attack of the carbon nucleophile becomes possible. The Pd-carbon n-bond in complex 101 is stabilized by coordination of the remaining alkene. The carbanion is generated by treatment of 101 with a base, and the cyclopropane 102 is formed by intramolecular nucleophilic attack. Overall, the cyclopropanation occurs by attack of the carbanion twice on the alkenic bond activated by Pd(II). The bicyclo[3.3.0]octane 103 was obtained by intermolecular attack of malonate on the complex 101 [11]. 

The palladium catalyst generally used is Pd(PPhj)4, which can be formed in situ from Pd(OAc)2 and PPhj. The most often used allylic substrates are those having an ester or a carbonate as a leaving group, although -OPO(OR)2, -OPh, -Cl, or -Br will also work. Soft nucleophiles of the malonate-type generally give the best results for carbon-carbon bond formation. The reaction is usually in eversible and thus proceeds under kinetic control. Other soft carbon nucleophiles are anions from nitromethane, enolates, and enamines. 

Aryllead, vinyllead, and alk-l-ynyllead tricarboxylates behave as aryl, vinyl and alkynyl cation equivalents to react with a variety of nucleophiles, especially soft carbon nucleophiles such as T -dicarbonyl compounds, phenols, and nitroalkanes. In these reactions, unique regioselectivity is obtained in which there is a preference for the generation of quaternary carbon centers. This aspect of reactivity has been put to use in a number of natural product syntheses and can result in the formation of highly hindered structures. 

Predominant formation of the C-benzylated product can be understood by considering the soft carbon nucleophile attacking the benzyl carbon of the oxosulfonium trilluoromethane sulfonate, with diphenyl sulfoxide acting as a soft leaving group. The reaction also proceeds smoothly with various other substituted benzyl alcohols with moderate to good yields. Sodium enolates derived from esters, a-cyano esters, a-aromatic and aliphatic ketones can also be benzylated with consistent high yields. 

The reaction of 7r-allylpalladium chloride with malonate and acetoacetate as soft carbon nucleophiles to give allytmalonate and allylacetoacetate, discovered by this author in 1965, is the first example of the carbon-carbon bond formation mediated by a Pd complex (Scheme In addition to the allylation of malonate, the reaction of cyclohexanone enamine with 7r-allylpalladium chloride gave 2-aUylcyclohexanone after hydrolysis. The discovery of the allylation of nucleohphiles with 7r-allylpalladium chloride means the birth of TT-allylpalladium chemistry, which has developed as a remarkably useful synthetic method. 

Pd-catalyzed reactions of allylic esters such as aUyl acetates, carbonates, and phosphates with soft carbon nucleophiles such as malonate esters are useful for carbon-carbon bond formation (Sects. V.2.1.1-V.2.1.5). hi this section, Pd-catalyzed substitution reactions of nitrogen-containing allylic derivatives such as allylic amines, ammonium salts, tosylim-ides, and nitro compounds are described (Scheme 1). The allylic derivatives of other group 15 atoms have never been used as allyl unit source in Pd-catalyzed alkylation reactions so far. 

Transition metal-catalyzed allylic alkylation is generally considered to involve mechanistically four fundamental steps as shown in Scheme 1 coordination, oxidative addition, ligand exchange, and reductive elimination. A key step of the catalytic cycle is an initial formation of a (7r-allyl)metal complex and its reactivity. The soft carbon-centered nucleophiles, defined as those derived from conjugate acids whose pAj, < 25, usually attack the allyl ligand from the opposite side... 

A quite useful resin in nucleophilic carbon-carbon bond formation reactions is the carboxylic resin (5). The soft metal from the nucleophile is... 

Since its discovery by Tsuji [15,16] and catalytic expansion by Hata [17] and Atkins [18], allylic substitution has become the most popular palladium-catalyzed method for carbon-carbon bond formation along with crosscoupling reactions. However, the first report using NHC in this transformation only appeared recently [19]. An imidazolium salt with a bulky substituent on the nitrogen atoms, IPr HC1, was found to be a suitable ligand for allylic substitution with soft nucleophiles (Scheme 2). Pd2(dba)3 as palladium source and Cs2C03 as base completed the catalyst system. 

Soft nucleophiles (Nu) generally give the best results so, for carbon-carbon bond formation, stabilized enolates such as malonates are best, but for C-X (X = O, N, S) bond formation the reaction is successful with alkoxides, amines, cyanide, and thioalkoxides. This example shows an amine attacking outside the ring probably because the alkene prefers to be inside the ring. 

The Michael-type addition, a nucleophilic addition of an anion to the carbon-carbon double bond of an a,(3-unsaturated ketone, aldehyde, nitrile, nitro, sulphonyl, or carboxylic acid derivative, provides a powerful tool for carbon-carbon bond formation. The reaction is most successful with relatively nonbasic ( soft ) nucleophiles such as thiols, cyanide, primary and secondary amines, and P-dicarbonyl compounds. There is often a competition between direct attack on the carbonyl carbon (1,2-addition) and conjugate addition (1,4-addition) when the substrate is an a,(3-unsaturated carbonyl compound. 

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