Electrophilic reactions soft carbon nucleophiles

Characteristic feateres of Pd-catalyzed reactions of allylic and propargylic electrophiles with soft carbon nucleophiles are smmnarized with typical examples in the following. 

Application of 7r-allylpalladium chemistry to organic synthesis has made remarkable progress[l]. As deseribed in Chapter 3, Seetion 3, Tt-allylpalladium complexes react with soft carbon nucleophiles such as maionates, /3-keto esters, and enamines in DMSO to form earbon-carbon bonds[2, 3], The characteristie feature of this reaction is that whereas organometallic reagents are eonsidered to be nucleophilic and react with electrophiles, typieally earbonyl eompounds, Tt-allylpalladium complexes are electrophilie and reaet with nucleophiles such as active methylene compounds, and Pd(0) is formed after the reaction. 

Catalytic reactions of allylic electrophiles with carbon or heteroatom nucleophiles to form the products of formal S 2 or S 2 substitutions (Equation 20.1) are called "catalytic allylic substitution reactions." Tliese reactions have become classic processes catalyzed by transition metal complexes and are often conducted in an asymmetric fashion. The aUylic electrophile is typically an allylic chloride, acetate, carbonate, or other t)q e of ester derived from an allylic alcohol. The nucleophile is most commonly a so-called soft nucleophile, such as the anion of a p-dicarbonyl compound, or it is a heteroatom nucleophile, such as an amine or the anion of an imide. The reactions with carbon nucleophiles are often called allylic alkylations. 

With this ability to control selectivity, palladium-catalyzed substitution chemistry was developed into an enantioselective process. In the early enantioselective reactions, a racemic or achiral allylic electrophile underwent substitution with a soft carbon nucleophile to... 

The [i-aUyl complexes can react with several types of nucleophiles, giving rise to the corresponding substitution products. O- and N-nucleophiles as well as soft carbon nucleophiles attack the t-allyl complex directly at the aUylic position, while hard C-nucleophiles react via transmetaUations [2c, 3]. If the nucleophihc attack occurs under an atmosphere of CO, insertion of CO can occur, yielding carbonyl compounds [4]. Alkenes and aUcynes can also insert into allyhnetal bonds, a protocol that is used preferentially for cycUzations [5]. Cyclizations can also occur, if the 7t-allylmetal complex contains an internal nucleophilic center. If the metalallyl complex acts as a nucleophile, direct coupling with aryl halides [6] or additions to electrophiles such as aldehydes, ketones, or imines are possible [7]. This review focuses on C-C coupling reactions via these tt-allyhnetal (or in some cases, a-allyhnetal) intermediates. 

The catalytic version of allylation of nucleophiles via 7r-allylpaUadium intermediates was discovered in 1970 using allylic esters and aUyl phenyl ethers as substrates (Scheme Formation of 7r-allylpaUadium complexes by oxidative addition of various allylic compounds to Pd(0) and subsequent reaction of electrophilic rr-allylpalladium complexes with soft carbon nucleophiles are the basis of the catalytic allylation. After the reaction, Pd(0) is regenerated, which undergoes oxidative addition to the allylic compounds again, making the whole reaction catalytic. The efficient catalytic cycle is ascribed to the characteristic feature that Pd(0) is more stable than Pd(II). Allylation of carbon nucleophiles with allyhc compounds via TT-allylpalladium complexes is called the Tsuji-Trost reaction. The reaction has wide synthetic applications, particularly for cyclization. " ... 

Evaluation of the only appropriate Fukui function is required for investigating an intramolecular reaction, as local softness is merely scaling of Fukui function (as shown in Equation 12.7), and does not alter the intramolecular reactivity trend. For this type, one needs to evaluate the proper Fukui functions (/+ or / ) for the different potential sites of the substrate. For example, the Fukui function values for the C and O atoms of H2CO, shown above, predicts that O atom should be the preferred site for an electrophilic attack, whereas C atom will be open to a nucleophilic attack. Atomic Fukui function for electrophilic attack (fc ) for the ring carbon atoms has been used to study the directing ability of substituents in electrophilic substitution reaction of monosubstituted benzene [23]. In some cases, it was shown that relative electrophilicity (f+/f ) or nucleophilicity (/ /f+) indices provide better intramolecular reactivity trend [23]. For example, basicity of substituted anilines could be explained successfully using relative nucleophilicity index ( / /f 1) [23]. Note however that these parameters are not able to differentiate the preferred site of protonation in benzene derivatives, determined from the absolute proton affinities [24],... 

For Pd-catalyzed cross-coupling reactions the organopalladium complex is generated from an organic electrophile RX and a Pd(0) complex in the presence of a carbon nucleophile. Not only organic halides but also sulfonium salts [38], iodonium salts [39], diazonium salts [40], or thiol esters (to yield acylpalladium complexes) [41] can be used as electrophiles. With allylic electrophiles (allyl halides, esters, or carbonates, or strained allylic ethers and related compounds) Pd-i73-jt-allyl complexes are formed these react as soft, electrophilic allylating reagents. 

The properties of dimethyl carbonate, (MeO)2CO, as an ambident electrophile have been investigated by analysis of the products of its reaction with various nucleophiles having different hard-soft character. Results were in good agreement with the Hard-Soft Acid-Base theory, hard nucleophiles attacking the hard C=0 group and soft nucleophiles the soft Me group (Scheme ll).37... 

Note that reaction (a) involves the attack of the soft P atom at the soft carbon atom as predicted by the simple SHAB rule, but reactions (b) and (c) involve the soft atom attacking the hard centres C=0 and P=0 to give products contrary to the general principle (and also in opposition to Pauling s adjacent charge rule (16)). Finally reaction (d) involves the harder nucleophilic atom O attacking the soft electrophile. 

We should compare the S reaction at silicon with the S 2 reaction at carbon. There are some iportant differences. Alkyl halides are soft electrophiles but silyl halides are hard electrophiles. Alkyl halides react only very slowly with fluoride ion but silyl halides react more rapidly with fluoride [than with any other nucleophile. The best nucleophiles for saturated carbon are neutral and/or based on elements down the periodic table (S, Se, I). The best nucleophiles for silicon are charged and based on highly electronegative atoms (chiefly F, Cl, and O). A familiar example is the reaction of enolates at carbon with alkyl halides but at oxygen with silyl chlorides (Chapter 21). 

Just as there is no single measure of acidity and basicity, there is no single measure of nucleophilicity and electrophilicity—the rank order of nucleophiles changes when the reference electrophile changes. A hard nucleophile like a fluoride ion reacts fast with a silyl ether in an SN2 reaction at the silicon atom, which is relatively hard, but a soft nucleophile like triethylamine does not. In contrast, triethylamine reacts with methyl iodide in an SN2 reaction at a carbon atom, but fluoride ion does not. These examples, which are all equilibria, are governed by... 

Among the various carbon-carbon and carbon-hetero atom bond forming reactions promoted or catalyzed by transition metals, allylic substitution via electrophilic n-allyl-complexes is of utmost importance. Studies focused on the synthetic potential of alkyl or aryl substituted ( n3-allyl)Fe(CO)4 1+) complexes have shown that nucleophilic attack by soft carbon and hetero atom nucleophiles preferentially proceeds regioselectively at the less or syn-substituted allyl terminus.4 Additionally, polar effects on the regioselectivity of this reaction caused by electron-withdrawing functionalities (e.g., CO2R, CONR2) have been examined by the... 

The sequential trans-addition of a carbon nucleophile and a carbon electrophile across an arene double bond in (arene)Cr(CO)3 was first reported in 1983 [35]. Since then this methodology has undergone extensive development, with recent efforts mainly directed towards enantioenriched products [36]. Anionic (cy-clohexadienyl)Cr(CO)3 complexes are very soft nucleophiles and this places restrictions on the electrophiles that can be used in this sequence. Specifically these reactions are successful when carbanion dissociation from the intermediate anionic cyclohexadienyl complex is slow compared to the reaction with the carbon electrophile. The sequential addition is usually carried out as a one-pot reaction and the proposed reaction sequence is that shown in Scheme 11. In contrast to the nucleophile addition/protonation sequence, products form with excellent 1,2-regioselectivity. It is likely that this is due to an irreversible transfer of the acyl, allyl, or propargyl group to one of the two termini of the cyclohexadienyl ligand. 

Because of the qualitative nature of the HSAB model, it tells us nothing about the absolute value of kinetic rate constants. The usefulness of the HSAB model arises from its ability to predict the relative reactivities of nucleophiles with various substrates. For example, C-O cleavage of dimethyl phosphates results from nucleophilic attack at carbon, a soft electrophilic site (carbonium ions are soft electrophiles), whereas cleavage of the P-O bond results from nucleophilic attack at the phosphorus atom (P-O), a hard electrophilic site. Accordingly, reaction of dimethyl phosphate with a soft nucleophile, such as sulfide, would expect to occur mainly at the soft carbon center, resulting in C-O cleavage (2.79). On the other hand, nucleophilic attack by a hard nucleophile, such as hydroxide ion, is expected to occur predominantly at the hard phosphorus center (2.80). 

A-Carbethoxyaziridine is an ambident electrophile with soft ring carbon sites and a hard carbonyl group. The HSAB principle may be applied to account for its reaction with a variety of nucleophilic agents (89). 

Enantiosdective allyic substitution processes have been developed over the course of 30 years. Initial observations of the reactions of nucleophiles with paUadium-allyl complexes led to the observation of catalytic substitutions of aUylic ethers and esters, and then catalytic enantioselective aUylic substitutions. The use of catalysts based on ottier metals has led to reactions that occur with complementary regiochemistry. Moreover, flie scope of the reactions has expanded to include heteroatom and unstabilized carbon nucleophiles. Suitable electrophiles for these reactions indude allyhc esters of various types, allyhc ethers, aUylic alcohols, and aUylic halides. Enantioselective reactions can be conducted with monoesters or by selection for deavage of one of two equivalent esters. The mechanism of these reactions occurs by initial oxidative addition to form a metal-aUyl complex. The second step involves nudeophilic attadc on ttie aUyl ligand for reaction of "soft" nudeophiles or inner-sphere reductive eUmination for reactions of "hard" nudeophiles. The external nudeophilic attack typicaUy occurs by reaction of the nudeophile with a cationic aUyl complex at the face opposite to that to which Uie metal is bound. Exceptions indude reactions of certain molybdenum-aUyl complexes. Dissociation of product then regenerates the starting catalyst. Because of the diversity of the classes of these reactions, aUylic substitution—in particular asymmetric aUylic substitution—has been used to prepare a wide variety of natural products. 

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