Stabilized carbon nucleophiles activation

In its original form, the Michael addition consisted on the addition of diethyl malonate across the double bond of ethyl cinnamate in the presence of sodium ethoxide to afford a substituted pentanedioic acid ester. Currently, all reactions that involve a 1,4-addition of stabilized carbon nucleophiles to activated 7i-systems are known as Michael additions. Among the various reactants, enolates derived from p-dicarbonyl compounds are substrates of choice due to their easy deprotonation under mild conditions. Recently, Michael addition-based MCRs emerged as highly potential methodologies for the synthesis of polysubstituted heterocycles in the five- to seven-membered series. 

The Mannich reaction is the prototype of carbon-carbon bond forming reactions that involve the addition of resonance-stabilized carbon nucleophiles to iminium salts and imines. In its original and most widely recognized form, the Mannich reaction consists of three components (i) ammonia, a primary amine, or a secondary amine (ii) a nonenolizable aldehyde, usually formaldehyde and (iii) an active... 

The majority of cases (Table 1) involve activation of the diene by complexation to Pd(II) and Pt(II) centers. However, other metal-diene complexes have been examined including Ni(II), Ir(I), and Mn(I) complexes. Cationic or neutral complexes are used in the nucleophilic addition reactions. The most common nucleophiles employed are oxygen or nitrogen bases (hydroxide, alkoxides, carboxylates, amines) or stabilized carbon nucleophiles (malonate, j8-diketonates). The dienes employed include 1,5-cyc-looctadiene, norbomadiene, dicyclopentadiene, 4-vinylcyclohexene, 7-(alkylidene)nor-bornene and endo-4-vinylnorbornene. 

In addition to solvolysis and nitrenium ion formation, Af-aLkoxy-A-chloroamides (2) also undergo bimolecular reactions with nucleophiles at nitrogen. Not only is the configuration destabilized by the anomeric effect, it also parallels that of a-halo ketones, where halogen on an sp carbon is activated towards reactions by the adjacent carbonyl. This rate-enhancing effect on 8 /2 processes at carbon is well-known, and has been attributed to conjugation of the p-orbital on carbon with the carbonyl jr-bond in the S 2 transition state stabilization of ionic character at the central carbon as outlined by Pross as weU as electrostatic attraction to the carbonyl carbon. The transition states are also affected by the nature of the nucleophile. ... 

Subsequent to CO2 association in the hydrophobic pocket, the chemistry of turnover requires the intimate participation of zinc. The role of zinc is to promote a water molecule as a potent nucleophile, and this is a role which the zinc of carbonic anhydrase II shares with the metal ion of the zinc proteases (discussed in the next section). In fact, the zinc of carbonic anhydrase II promotes the ionization of its bound water so that the active enzyme is in the zinc-hydroxide form (Coleman, 1967 Lindskog and Coleman, 1973 Silverman and Lindskog, 1988). Studies of small-molecule complexes yield effective models of the carbonic anhydrase active site which are catalytically active in zinc-hydroxide forms (Woolley, 1975). In addition to its role in promoting a nucleophilic water molecule, the zinc of carbonic anhydrase II is a classical electrophilic catalyst that is, it stabilizes the developing negative charge of the transition state and product bicarbonate anion. This role does not require the inner-sphere interaction of zinc with the substrate C=0 in a precatalytic complex. 

The intramolecular addition of carbon nucleophiles to alkenes has received comparatively little attention relative to heterocyclization reactions. The first examples of Pd-catalyzed oxidative carbocyclization reactions were described by Backvall and coworkers [164-166]. Conjugaled dienes with appended al-lyl silane and stabilized carbanion nucleophiles undergo 1,4-carbochlorination (Eq. 36) and carboacetoxylation (Eq. 37), respectively. The former reaction employs BQ as the stoichiometric oxidant, whereas the latter uses O2. The authors do not describe efforts to use molecular oxygen in the reaction with allyl silanes however, BQ was cited as being imsuccessful in the reaction with stabihzed car-banions. Benzoquinone is known to activate Ti-allyl-Pd intermediates toward nucleophilic attack (see below. Sect. 4.4). In the absence of BQ, -hydride eUm-ination occurs to form diene 43 in competition with attack of acetate on the intermediate jr-allyl-Pd" species to form the 1,4-addition product 44. 

Regio- and diastereoselective rhodium-catalyzed tandem allylic alkylation of 71 with stabilized carbon and heteroatom nucleophiles 72 followed by the PK annulation by the same catalyst was described by Evans and co-workers. Alkylation of an optically active allylic alcohol carbonate 71 proceeds in a regio- and stereospecific manner successfully at 30 °C by 7r-acidic Rh(i) catalysts (Equation (41)). The resultant product then undergoes the PKR with the aid of the pre-existing catalyst under GO pressure at elevated temperature. ... 

Many newer methods for generating cyclohexane derivatives from carbohydrates still depend on the intramolecular attack of nucleophilic carbon species at electrophilic centers, and the range of options is now extensive. Thus, the nucleophiles may be carb-anions stabilized by carbonyl, phosphonate, nitro, or dithio groups, and they may bond to carbonyl carbon atoms, or to those that carry appropriate leaving groups or are contained in epoxide rings, or as jj-centers of a,p-unsaturated carbonyl systems. Otherwise, the nucleophilic activity at the 7-centers of allylsilanes or a-positions of vinyl silanes may be used to react with electrophilic carbon atoms. 

This acts as an electron sink to stabilize the formation of a negative charge on one of the a carbons (equation 2.35). After tautomerization to form the enamine, the methylene carbon is activated as a nucleophile. 

Once complexed to palladium(II), the alkene is generally activated towards nucleophilic attack, with nucleophiles ranging from chloride to phenyllithium undergoing reaction. The reaction is, however, quite sensitive to conditions and displacement of the alkene by the nucleophile (path a) or oxidative destruction of the nucleophile can become an important competing reaction. Nucleophilic attack occurs predominately to exclusively at the more-substituted position of the alkene (the position best able to stabilize positive charge) and from the face opposite the metal (trans attack, path b) to produce a new carbon-nucleophile bond and a new carbon-metal bond. This newly formed a-alkylmetal complex (2) is... 

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]. 

With two activating substituents, as in the ester 4.159, conjugate reduction (and conjugate addition of carbon nucleophiles) is fast and almost always observed with any nucleophile.390 The stability of the conjugated enolate product 4.160, and Coulombic and frontier orbital factors, all readily explain this observation. 

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