Electrophilic Centers Other than Carbon

Reactions of nitrogen and carbon nucleophiles have been found to proceed exclusively at an exocyclic C-l electrophilic center rather than at C-2 or C-4 of the coumarin ring for compounds such as 285 (Scheme 36). Though the yields are somewhat low, it was reported that no other products were observed other than those from C-l attack <2004SC3409>. 

Note that the reaction at the phosphorus atom is postulated to occur by an SN2 (no intermediate formed) rather than by an addition mechanism such as we encountered with carboxylic acid derivatives (Kirby and Warren, 1967). As we learned in Section 13.2, for attack at a saturated carbon atom, OH- is a better nucleophile than H20 by about a factor of 104 (Table 13.2). Toward phosphorus, which is a harder electrophilic center (see Box 13.1), however, the relative nucleophilicity increases dramatically. For triphenyl phosphate, for example, OH- is about 108 times stronger than H20 as a nucleophile (Barnard et al., 1961). Note that in the case of triphenyl phosphate, no substitution may occur at the carbon bound to the oxygen of the alcohol moiety, and therefore, neutral hydrolysis is much less important as compared to the other cases (see /NB values in Table 13.12). Consequently, the base-catalyzed reaction generally occurs at the phosphorus atom leading to the dissociation of the alcohol moiety that is the best leaving group (P-0 cleavage), as is illustrated by the reaction of parathion with OH ... 

The complexes generated by oxidative addition of haloarenes and haloalkenes to palladium(O) are electrophilic at the metal-substituted center, and can therefore react with carbon nucleophiles other than alkenes, especially with enolate and homoenolate ions to form new C—C bonds [176, 177]. 

It is often very useful to be able to alkylate a readily available chiral a-hetero-substitut-ed carboxylic acid in an enantiospecific manner, as a means of using the chiral center and at the same time building-up the rest of the target carbon skeleton. Such a reaction has been devised by Seebach and coworkers524. In this process a-hydroxy- and a-mercaptocar-boxylic acids were first reacted with pivaldehyde, to produce a 1,3-dioxolanone or 1,3-oxathiolanone. This was followed by reaction with base and alkylation by an alkyl halide and subsequent hydrolysis to regenerate the hydroxyl or mercapto group (equation 70). The product was obtained in greater than 95% ee. Similar reactions with other electrophiles were also successful. 

The classical example of the selective activation of a reaction site in a substrate with more than one reactive center is acetoacetic ester 168 (Scheme 2.80). Its reactive form is the enolate 169, which reacts with a variety of electrophiles selectively at the central carbon atom. A subsequent hydrolysis and decarboxylation of the product 170 leads to the formation of ketone 171. The structure of 171 corresponds to the coupling of the electrophile with the carbanion 172, or, in other words, with deprotonated acetone. Thus acetoacetic ester is actually employed in this sequence as a synthetic equivalent to 172. 

This implies that the other elementary steps in cycle B (Scheme 1), i.e., Pd-carbomethoxy formation and protonolysis of the palladium-alkenyl species, must even be considerably faster than the observed overall high reaction rate. A high rate of Pd-carbomethoxy formation (at equilibrium) could be expected for the strongly electrophilic metal center. However, the latter step, protonolysis of the Pd-alkenyl bond in l-palladium-2-carbomethoxypropene and 2-palladium-1-car-bomethoxypropene, respectively, is expected to be a slow reaction, because the proton has to overcome a relatively high barrier of (electrostatic) repulsion by the cationic palladium center on its way to the palladium-carbon bond. 

Where do mercuration reactions fit into this picture A mercurinium ion has both similarities and differences, as compared with the intermediates that have been described for other electrophilic additions. The electrophile in oxymercuration reactions, +HgX or Hg +, is a soft Lewis acid and polarizes the TT-electrons of an alkene to the extent that a three-center two-electron bond is formed between mercury and the two carbons of the double bond. However, there is also back bonding from Hg +(i orbitals to the alkene tt orbital. There is weaker bridging in the mercurinium ion than in the three-center four-electron bonding of the bromonium ion. 

The ease of adduct formation depends largely on the electron density on the N atom of the imine and the electrophilicity of the center carbon atom of the isocyanate. Most reactive are persubstituted guanidines and amidines on one side and aryl isocyanates with electron withdrawing substituents on the other side. The initial attack occurs on the more nucleophilic center. Delocalization of the developing charges favors intermolecular [2-I-2-I-2] cycloaddition over intramolecular [2-1-2] cycloaddition or the exchange reaction. When a hydrogen shift can occur, the intramolecular isocyanate induced enurea reaction is faster than the intermolecular [2-I-2-I-2] cycloaddition reaction. Thermodynamically controlled equilibria are established above 100 °C and the thermodynamically more stable reaction product is isolated. 

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