Page 52 - Advanced Organic Chemistry Part B - Reactions & Synthesis

24 as the synthetic equivalent of acetone. Entries 2 and 3 show synthesis of carboxylic
acids via the malonate ester route. Entry 4 is an example of a nitrile synthesis, starting
CHAPTER 1
with ethyl cyanoacetate as the carbon nucleophile. The cyano group also facilitates
Alkylation of Enolates decarboxylation. Entry 5 illustrates an alternative decarboxylation procedure in which
and Other Carbon
Nucleophiles lithium iodide is used to cleave the -ketoester by nucleophilic demethylation.
It is also possible to use the dilithium derivative of acetoacetic acid as the synthetic
equivalent of acetone enolate. 49 In this case, the hydrolysis step is unnecessary and
decarboxylation can be done directly on the alkylation product.

O O – Li + O
2n-BuLi + 1) R X
–
CH CCH CO H CH C CHCO Li CH 3 CCH R
3
2
2
3
2
2
2) H +
(–CO )
2
Similarly, the dilithium dianion of monoethyl malonate is easily alkylated and the
product decarboxylates after acidification. 50
1) 25°C, 2 h
n-C H Br + LiCHCO Li CH (CH ) CO H
2 4
2
4 9
2
3
2) 68°C, 18 h
CO C H 80%
2 2 5
(–CO )
2
1.2.2. Alkylation of Ketone Enolates
The preparation of ketones and ester from -dicarbonyl enolates has largely
been supplanted by procedures based on selective enolate formation. These proce-
dures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis
and decarboxylation of keto ester intermediates. The development of conditions for
stoichiometric formation of both kinetically and thermodynamically controlled enolates
has permitted the extensive use of enolate alkylation reactions in multistep synthesis of
complex molecules. One aspect of the alkylation reaction that is crucial in many cases
is the stereoselectivity. The alkylation has a stereoelectronic preference for approach
of the electrophile perpendicular to the plane of the enolate, because the electrons
are involved in bond formation. A major factor in determining the stereoselectivity
of ketone enolate alkylations is the difference in steric hindrance on the two faces
of the enolate. The electrophile approaches from the less hindered of the two faces
and the degree of stereoselectivity depends on the steric differentiation. Numerous
examples of such effects have been observed. 51 In ketone and ester enolates that are
exocyclic to a conformationally biased cyclohexane ring there is a small preference for

49 R. A. Kjonaas and D. D. Patel, Tetrahedron Lett., 25, 5467 (1984).
50 J. E. McMurry and J. H. Musser, J. Org. Chem., 40, 2556 (1975).
51
For reviews, see D. A. Evans, in Asymmetric Synthesis, Vol. 3, J. D. Morrison, ed., Academic Press,
New York, 1984, Chap. 1; D. Caine, in Carbon-Carbon Bond Formation, R. L. Augustine, ed., Marcel
Dekker, New York, 1979, Chap. 2.