Page 49 - Advanced Organic Chemistry Part B - Reactions & Synthesis

and tetramine were even more effective than HMPA in promoting reaction. 46 These 21
results, too, are presumably due to disaggregation of the enolate by the polyamines.
SECTION 1.2
OLi O Alkylation of Enolates
CH Ph
PhCH 2 Br 2
40 min, – 23°C

Additive (3eq) Yield (%)
none 6
HMPA 34
DMPU 3
NCH CH NMe
Me 2 2 2 2 6
NCH CH ) NMe
(Me 2 2 2 2 50
(Me NCH CH NCH ) 72
2
2
2
2 2
Me
Me N(CH CH N) CH CH NMe 2 33
2
2
2
3
2
2
Me
The reactivity of enolates is also affected by the metal counterion. For the most
+
+
commonly used ions the order of reactivity is Mg 2+ < Li < Na < K . The factors
+
that are responsible for this order are closely related to those described for solvents.
+
The smaller, harder Mg 2+ and Li cations are more tightly associated with the enolate
+
than are the Na and K ions. The tighter coordination decreases the reactivity of the
+
enolate and gives rise to more highly associated species.
1.2. Alkylation of Enolates 47
1.2.1. Alkylation of Highly Stabilized Enolates
Relatively acidic compounds such as malonate esters and -ketoesters were the
first class of compounds for which reliable conditions for carbanion alkylation were
developed. The alkylation of these relatively acidic compounds can be carried out in
alcohols as solvents using metal alkoxides as bases. The presence of two electron-
withdrawing substituents facilitates formation of the resulting enolate. Alkylation
occurs by an S 2 process, so the alkylating agent must be reactive toward nucleophilic
N
displacement. Primary halides and sulfonates, especially allylic and benzylic ones,
are the most reactive alkylating agents. Secondary systems react more slowly and
often give only moderate yields because of competing elimination. Tertiary halides
give only elimination products. Methylene groups can be dialkylated if sufficient base
and alkylating agent are used. Dialkylation can be an undesirable side reaction if
the monoalkyl derivative is the desired product. Sequential dialkylation using two
different alkyl groups is possible. Use of dihaloalkanes as alkylating reagents leads
to ring formation. The relative rates of cyclization for -haloalkyl malonate esters

46 M. Goto, K. Akimoto, K. Aoki, M. Shindo, and K. Koga, Chem. Pharm. Bull., 48, 1529 (2000).
47
For general reviews of enolate alkylation, see D. Caine, in Carbon-Carbon Bond Formation, Vol. 1,
R. L. Augustine, ed., Marcel Dekker, New York, 1979, Chap. 2; C. H. Heathcock, Modern Synthetic
Methods, 6, 1 (1992).