Page 50 - Advanced Organic Chemistry Part B - Reactions & Synthesis

22 are 650,000:1:6500:5 for formation of three-, four-, five-, and six-membered rings,
respectively. 48 (See Section 4.3 of Part A to review the effect of ring size on S 2
N
CHAPTER 1
reactions.)
Alkylation of Enolates Some examples of alkylation reactions involving relatively acidic carbon acids
and Other Carbon
Nucleophiles are shown in Scheme 1.3. Entries 1 to 4 are typical examples using sodium ethoxide as
the base. Entry 5 is similar, but employs sodium hydride as the base. The synthesis of
diethyl cyclobutanedicarboxylate in Entry 6 illustrates ring formation by intramolecular
alkylation reactions. Additional examples of intramolecular alkylation are considered
in Section 1.2.5. Note also the stereoselectivity in Entry 7, where the existing branched
substituent leads to a trans orientation of the methyl group.
The 2-substituted -ketoesters (Entries 1, 4, 5, and 7) and malonic ester (Entries
2 and 6) prepared by the methods illustrated in Scheme 1.3 are useful for the synthesis

Scheme 1.3. Alkylation of Enolates Stabilized by Two Functional Groups

NaOEt
a
1 CH COCH CO C H + CH (CH ) Br CH COCHCO C H
2
3
3
2 2 5
2 3
2 2 5
3
(CH ) CH 3
2 3
b
2 CH (CO C H ) + Cl NaOEt CHCO C H ) 69 – 72%
2 2 5 2
2
2 2 5 2
K CO 3 61%
2
c
3 CH COCH COCH + CH I CH COCHCOCH 3
2
3
3
3
3
CH 3 75 – 77%
NaOEt
d
4 CH COCH CO C H + ClCH CO C H CH COCHCO C H
2 2 5
2 2 5
2
2 2 5
3
3
2
CH CO C H
2 2 5
2
O O 56 – 62%
5 e NaH
CH CO CH
CO 2 2 3
3 + BrCH (CH ) CO C H DMF
2 2 5
2 5
2
CH (CH ) CO C H
2 5
2
2 2 5
85% on 1-mol scale
CO C H
NaOEt 2 2 5
6 f CH (CO C H ) + BrCH CH CH Cl CO C H
2 2 5
2
2 2 5 2
2
2
2
53 – 55%
O
O CO 2 CH 3
7 g CH K CO 3
2
CO 2 3 CH 3
CH I
3
CH
CH 3 3 90%
a. C. S. Marvel and F. D. Hager, Org. Synth., I, 248 (1941).
b. R. B. Moffett, Org. Synth., IV, 291 (1963).
c. A. W. Johnson, E. Markham, and R. Price, Org. Synth., 42, 75 (1962).
d. H. Adkins, N. Isbell, and B. Wojcik, Org. Synth., II, 262 (1943).
e. K. F. Bernardy, J. F. Poletto, J. Nocera, P. Miranda, R. E. Schaub, and M. J. Weiss, J. Org. Chem., 45,
4702 (1980).
f. R. P. Mariella and R. Raube, Org. Synth., IV, 288 (1963).
g. D. F. Taber and S. C. Malcom, J. Org. Chem., 66, 944 (2001).
48
A. C. Knipe and C. J. Stirling, J. Chem. Soc. B, 67 (1968); For a discussion of factors that affect
intramolecular alkylation of enolates, see J. Janjatovic and Z. Majerski, J. Org. Chem., 45, 4892 (1980).