Enolate anions, addition reactions formation

The 1,4-addition of an enolate anion 1 to an o ,/3-unsaturated carbonyl compound 2, to yield a 1,5-dicarbonyl compound 3, is a powerful method for the formation of carbon-carbon bonds, and is called the Michael reaction or Michael addition The 1,4-addition to an o ,/3-unsaturated carbonyl substrate is also called a conjugate addition. Various other 1,4-additions are known, and sometimes referred to as Michael-like additions. 

When 2,2-dimethylpropanal is used to prepare the azomethine moiety, the corresponding azaallyl anion may be obtained when l,8-diazabicyclo[5.4.0]undec-7-ene/lithium bromide is used as base. The subsequent addition to various enones or methyl ( )-2-butenoate proceeds with anti selectivity, presumably via a chelated enolate. However, no reaction occurs when triethylamine is used as the base, whereas lithium diisopropylamide as the base leads to the formation of a cycloadduct, e.g., dimethyl 5-isopropyl-3-methyl-2,4-pyrrolidinedicarboxylate using methyl ( )-2-butenoate as the enone84 89,384. 

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... 

The Mannich reaction is best discussed via an example. A mixture of dimethylamine, formaldehyde and acetone under mild acidic conditions gives N,N-dimethyl-4-aminobutan-2-one. This is a two-stage process, beginning with the formation of an iminium cation from the amine and the more reactive of the two carbonyl compounds, in this case the aldehyde. This iminium cation then acts as the electrophile for addition of the nucleophile acetone. Now it would be nice if we could use the enolate anion as the nucleophile, as in the other reactions we have looked at, but under the mild acidic conditions we cannot have an anion, and the nucleophile must be portrayed as the enol tautomer of acetone. The addition is then unspectacular, and, after loss of a proton from the carbonyl, we are left with the product. 

The Claisen reaction may be visualized as initial formation of an enolate anion from one molecule of ester, followed by nucleophilic attack of this species on to the carbonyl group of a second molecule. The addition anion then loses ethoxide as leaving group, with reformation of the carbonyl group. 

The mechanistic steps can be deduced by inspection of structures and conditions. Enolate anion formation from diethyl malonate under basic conditions is indicated, and that this must attack the epoxide in an Sn2 reaction is implicated by the addition of the malonate moiety and disappearance of the epoxide. The subsequent ring formation follows logically from the addition anion, and is analogous to base hydrolysis of an ester. Ester hydrolysis followed by decarboxylation of the P-keto acid is then implicated by the acidic conditions and structural relationships. 

The addition of an enolate anion to C02 to form a (3-oxoacid represents one of the commonest means of incorporation of C02 into organic compounds. The reverse reaction of decarboxylation is a major mechanism of biochemical formation of C02. The equilibrium constants usually favor decarboxylation but the cleavage of ATP can be coupled to drive carboxylation when it is needed, e.g., in photosynthesis. 

In the case of cationic complexes with unsaturated macrocycles two molecules of nucleophile, such as ammonia, amines and alkoxides, add to carbon atoms of two inline groups. For example, the reaction of [Ni(Bzo[16]octaeneN4)](C104)2 (Table 106) with sodium methoxide or ethoxide yields the compounds (395),2860 while with secondary amines and diamines complexes of type (396) are obtained.28 1 The reaction of (396) with acetone at room temperature yields complex (397) where the enolate anion of acetone, MeC(0)CH2, replaces the diethylamide group (Scheme 58). 2862 The addition of molecules such as bis(2-hydroxyethyl)methylamine and bis(2-hydroxyethyl) sulfide, HOCH2CH2YCH2CH2OH (Y = NMe, S) results in the formation of derivatives which possess one more coordination site just above the plane of the macrocyclic donors (398).2863... 

The possibility of the enolate anion acting as if its charge were effectively concentrated on carbon or on oxygen was discussed previously in connection with aldol addition (Section 17-3B). However, the situation there was quite different from the one here, because aldol addition is easily reversible, whereas alkylation is not. Furthermore, while the aldol reaction involving C-O bond formation is unfavorable (AH° = + 20 kcal mole-1) compared to C-C bond formation (AHn = —4 kcal mole-1), both O- and C-alkylation of the anion have AH° < 0 (see Exercise 17-64). 

The reactions discussed in this chapter that depend on the formation of enolate anions (i.e., halogenation, aldol addition, and alkylation) often proceed smoothly and under milder conditions with 1,3-diketones than with monoketones. This is because the 1,3-diketones are stronger acids and therefore can form the enolate anions with weaker bases. The principal synthetic methods for preparing 1,3-dicarbonyl compounds will be discussed in Chapter 18. 

Introduction of a cyano group a to the carbonyl group of a ketone can be accomplished by prior formation of the enolate anion with LDA in THF and addition of this solution to p-TsCN at —78°C. The products are formed in moderate to high yields but the reaction is not applicable to methyl ketones. Treatment of TMSCH2N(Me)C=Nf-Bu with iec-butylhthium and R2C=0, followed by iodo-methane and NaOMe leads to the nitrile, R2CH-CN. ... 

Silyl enol ethers react with aldehydes in the presence of chiral boranes or other additives " to give aldols with good asymmetric induction (see the Mukaiyama aldol reaction in 16-35). Chiral boron enolates have been used. Since both new stereogenic centers are formed enantioselectively, this kind of process is called double asymmetric synthesis Where both the enolate derivative and substrate were achiral, carrying out the reaction in the presence of an optically active boron compound ° or a diamine coordinated with a tin compound ° gives the aldol product with excellent enantioselectivity for one stereoisomer. Formation of the magnesium enolate anion of a chiral amide, adds to aldehydes to give the alcohol enantioselectively. 

---