Page 212 - Advanced Organic Chemistry Part B - Reactions & Synthesis

184 When the EWG is a carbonyl group, there can be competition with 1,2-addition, which
is especially likely for aldehydes but can also occur with ketones. With successively less
CHAPTER 2
reactive carbonyl groups, 1,4-addition becomes more favorable. Highly reactive, hard
Reactions of Carbon nucleophiles tend to favor 1,2-addition and the reaction is irreversible if the nucleophile
Nucleophiles with
Carbonyl Compounds is a poor leaving group. For example with organometallic reagents, 1,2-addition is
usually observed and it is irreversible because there is no tendency to expel an alkyl
anion. Section 2.6.5 considers some exceptions in which organometallic reagents are
added in the 1,4-manner. With less basic nucleophiles, the 1,2-addition is more easily
reversible and the 1,4-addition product is usually more stable.

O R O – – O O O – R O
RC C CHCH CR″ RC CR 2 + R′CH CHCR″ R′CH CHC C CR

R R′ R″ R
1,4-addition 1,2-addition

Retrosynthetically, there are inherently two possible approaches to the products
of conjugate addition as represented below, where Y and Z represent two different
anion-stabilizing groups.

H
– –
2
Y CHR 1 + CH 2 C Z Y CH CH 2 C Z Y C CH 2 + R CH Z
R 2 R 1 R 2 R 1

When a catalytic amount of base is used, the most effective nucleophiles are enolates
derived from relatively acidic compounds such as -ketoesters or malonate esters.
The adduct anions are more basic than the nucleophile and are protonated under the
reaction conditions.

– O H O R S–H
+ R EWG O R
X Z EWG X – X EWG
Z
less basic more basic Z

Scheme 2.23 provides some examples of conjugate addition reactions. Entry 1
illustrates the tendency for reaction to proceed through the more stable enolate. Entries
2 to 5 are typical examples of addition of doubly stabilized enolates to electrophilic
alkenes. Entries 6 to 8 are cases of addition of nitroalkanes. Nitroalkanes are compa-
rable in acidity to -ketoesters (see Table 1.1) and are often excellent nucleophiles
for conjugate addition. Note that in Entry 8 fluoride ion is used as the base. Entry 9
is a case of adding a zinc enolate (Reformatsky reagent) to a nitroalkene. Entry 10
shows an enamine as the carbon nucleophile. All of these reactions were done under
equilibrating conditions.
The fluoride ion is an effective catalyst for conjugate additions involving relatively
acidic carbon nucleophiles. 292 The reactions can be done in the presence of excess

292
J. H. Clark, Chem. Rev., 80, 429 (1980).