Page 64 - Advanced Organic Chemistry Part B - Reactions & Synthesis

36 1.2.4. Generation and Alkylation of Dianions

CHAPTER 1 In the presence of a very strong base, such as an alkyllithium, sodium or potassium
Alkylation of Enolates hydride, sodium or potassium amide, or LDA, 1,3-dicarbonyl compounds can be
79
and Other Carbon converted to their dianions by two sequential deprotonations. For example, reaction of
Nucleophiles
benzoylacetone with sodium amide leads first to the enolate generated by deprotonation
at the more acidic methylene group between the two carbonyl groups. A second
equivalent of base deprotonates the benzyl methylene group to give a dienediolate.
–
+
O O Li O – O Li + PhCHCH 3 O O
2 NaNH 2
PhCH CCH CCH 3 PhCH C CH C CH 3 Cl PhCHCCH CCH 3
2
2
2
PhCHCH 3
Ref. 80
Alkylation of dianions occurs at the more basic carbon. This technique permits
alkylation of 1,3-dicarbonyl compounds to be carried out cleanly at the less acidic
position. Since, as discussed earlier, alkylation of the monoanion occurs at the carbon
between the two carbonyl groups, the site of monoalkylation can be controlled by
choice of the amount and nature of the base. A few examples of the formation and
alkylation of dianions are collected in Scheme 1.7. In each case, alkylation occurs
at the less stabilized anionic carbon. In Entry 3, the -formyl substituent, which is
removed after the alkylation, serves to direct the alkylation to the methyl-substituted
carbon. Entry 6 is a step in the synthesis of artemisinin, an antimalarial component
of a Chinese herbal medicine. The sulfoxide serves as an anion-stabilizing group and
the dianion is alkylated at the less acidic -position. Note that this reaction is also
stereoselective for the trans isomer. The phenylsulfinyl group is removed reductively
by aluminum. (See Section 5.6.2 for a discussion of this reaction.)

1.2.5. Intramolecular Alkylation of Enolates

There are many examples of formation of three- through seven-membered rings by
intramolecular enolate alkylation. The reactions depend on attainment of a TS having an
approximately linear arrangement of the nucleophilic carbon, the electrophilic carbon,
and the leaving group. Since the HOMO of the enolate is involved, the approach
2
must be approximately perpendicular to the enolate. 81 In intramolecular alkylation,
these stereoelectronic restrictions on the direction of approach of the electrophile
to the enolate become important. Baldwin has summarized the general principles
that govern the energetics of intramolecular ring-closure reactions. 82 Analysis of the
stereochemistry of intramolecular enolate alkylation requires consideration of both the
direction of approach and enolate conformation. The intramolecular alkylation reaction
83
of 7 gives exclusively 8, having the cis ring juncture. The alkylation probably occurs
through a TS like F. The TS geometry permits the electrons of the enolate to achieve
an approximately colinear alignment with the sulfonate leaving group. The TS G for
79
For reviews, see (a) T. M. Harris and C. M. Harris, Org. React., 17, 155 (1969); E. M. Kaiser, J. D. Petty,
and P. L. A. Knutson, Synthesis, 509 (1977); C. M. Thompson and D. L. C. Green, Tetrahedron, 47,
4223 (1991); C. M. Thompson, Dianion Chemistry in Organic Synthesis, CRC Press, Boca Raton, FL,
1994.
80 D. M. von Schriltz, K. G. Hampton, and C. R. Hauser, J. Org. Chem., 34, 2509 (1969).
81
J. E. Baldwin and L. I. Kruse, J. Chem. Soc., Chem. Commun., 233 (1977).
82 J. E. Baldwin, R. C. Thomas, L. I. Kruse, and L. Silberman, J. Org. Chem., 42, 3846 (1977).
83 J. M. Conia and F. Rouessac, Tetrahedron, 16, 45 (1961).