Stability Stabilized nucleophiles

This section deals with reactions that correspond to Pathway C, defined earlier (p. 64), that lead to formation of alkenes. The reactions discussed include those of phosphorus-stabilized nucleophiles (Wittig and related reactions), a a-silyl (Peterson reaction) and a-sulfonyl (Julia olefination) with aldehydes and ketones. These important rections can be used to convert a carbonyl group to an alkene by reaction with a carbon nucleophile. In each case, the addition step is followed by an elimination. 

The use of strongly stabilized nucleophiles, for example, of [(EtO)2P(0)CHX] Li+ 58a-d, where X is a powerful EWG group, such as Me02C, CN, S02Me, or P(O) (OEt)2, in the conjugated addition with a-nitroolefins gives rise to more complex processes (201b) (Scheme 3.58). 

Besides the allylation reactions, imines can also undergo enol silyl ether addition as with carbonyl compounds. Carbon-carbon bond formation involving the addition of resonance-stabilized nucleophiles such as enols and enolates or enol ethers to iminium salt or imine can be referred to as a Mannich reaction, and this is one of the most important classes of reactions in organic synthesis.104... 

Scheme 7. The simplest type of enantioselective allylic alkylation which occurs on treatment of an allylic substrate with a metal derivative, together with a stabilized nucleophile (R = H, alkyl or aryl X" = leaving group [M] = metal catalyst Nu" = nucleophile L = coordinating atom).

Elimination reactions (Figure 5.7) often result in the formation of carbon-carbon double bonds, isomerizations involve intramolecular shifts of hydrogen atoms to change the position of a double bond, as in the aldose-ketose isomerization involving an enediolate anion intermediate, while rearrangements break and reform carbon-carbon bonds, as illustrated for the side-chain displacement involved in the biosynthesis of the branched chain amino acids valine and isoleucine. Finally, we have reactions that involve generation of resonance-stabilized nucleophilic carbanions (enolate anions), followed by their addition to an electrophilic carbon (such as the carbonyl carbon atoms... 

Dimethylpyrimido[4,5-f]pyridazine-5,7-dione 23 and its derivatives undergo attack at both C-3 and C-4. Under conditions of kinetic control, addition occurs preferentially at the more electron-deficient C, whereas thermodynamic control conditions, or the use of bulkier nucleophiles, favor addition at the less hindered position 3. This duality is illustrated by the addition of Grignard and organolithium reagents to C of 3-chloro analogue 24 (Equation 9), whereas stabilized nucleophiles such as the anion of nitromethane add at C-3 (Scheme 10) <2000CHE975>. Displacement of the 3-chloride occurs also upon treatment of 24 with amines (Equation 10) <2000CHE1213>. 

Isonitriles 6, formed by dehydration of 6-(formylamino)penicillanates, can be alkylated by stabilized nucleophiles such as (bromomethyl)benzene and methyl 2-bromoacetate (see Table 2)8-9. In this case alkylation also takes place preferentially from the least hindered a-side of the enolate8,9. The corresponding cephalosporin isonitriles decompose on attempted alkylation8. 

Displacement of allylic gem -diacetates.1 In the presence of Pd(dppe)22 as catalyst and 0,N-bis(trimethylsilyl)acetamide as base, one acetoxy group of an allylic gem-diacetate can be displaced by a stabilized nucleophile. 

Stabilized Nucleophiles with Electron Deficient Alkenes and Alkynes... 

The addition of stabilized nucleophiles to activated ir-systems is one of the oldest and most useful constructive methods in organic synthesis, dating back more than a hundred years. In 1887 Michael, after whom the most well-known example of this reaction was named, published the first of a series of papers on this reaction describing the addition of the sodium salt of both diethyl malonate (1) and ethyl ace-toacetate (2) to ethyl cinnamate (3) to give the products (4) and (5), respectively (equation 1).1 This Mi-... 

These early results paved the way for a myriad of applications of this process in organic synthesis, as described in detail in this chapter. It should be pointed out that only additions of stabilized nucleophiles are included here, with the addition of reactive nucleophiles (organolithiums, Grignards, cuprates, etc.), Lewis acid promoted additions and asymmetric nucleophilic additions, among others, being covered in Chapters 1.3 and 1.5, respectively, in this volume. 

The literally thousands of examples involving the addition of stabilized nucleophiles to activated alkenes and alkynes have spawned many reviews over the years. The Michael reaction has been discussed in detail several times7 and reviews on other related topics, such as annulation8 and Mannich base meth-iodides,9 have also appeared, as have several reviews on nucleophilic additions to activated alkynes.10... 

The addition of stabilized nucleophiles—both carbon and heteronucleophiles—to activated alkynes has been used far less often in organic synthesis than the corresponding addition to activated alkenes. Since several excellent reviews on nucleophilic additions to alkynes appeared in the 1960s and 1970s,10 this section includes only a few representative examples from the early literature and some more recent applications. 

The addition of stabilized nucleophiles to activated ir-systems is one of the most widely used constructive methods in organic synthesis. This chapter has provided a selective overview of this still burgeoning area where further progress continues, especially in the area of stereocontrol. 

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