Page 75 - Advanced Organic Chemistry Part B - Reactions & Synthesis

The nucleophilicity of the -carbon atoms permits enamines to be used synthetically 47
for alkylation reactions.
SECTION 1.3
R O R The Nitrogen Analogs of
.. + H O Enols and Enolates:
2
R' 2 N C CR 2 CH 2 X R' N C C CH R" R C C CH 2 R" Enamines
2
2
and Imine Anions
R R" R R R
The enamines derived from cyclohexanones are of particular interest. The pyrrol-
idine enamine is most frequently used for synthetic applications. The enamine mixture
formed from pyrrolidine and 2-methylcyclohexanone is predominantly isomer 17. 106 A
steric effect is responsible for this preference. Conjugation between the nitrogen atom
and the orbitals of the double bond favors coplanarity of the bonds that are darkened
in the structures. In isomer 17 the methyl group adopts a quasi-axial conformation to
avoid steric interaction with the amine substituents. 107 A serious nonbonded repulsion
(A 1 3 strain) in 18 destabilizes this isomer.

steric
H H H H
repulsion
H N H H N H H
H H H C H
C H H
H
17 18

Owing to the predominance of the less-substituted enamine, alkylations occur primarily
at the less-substituted -carbon. Synthetic advantage can be taken of this selec-
tivity to prepare 2,6-disubstituted cyclohexanones. The iminium ions resulting from
C-alkylation are hydrolyzed in the workup procedure.

+ +
N N H O
2
2
2
CH 3 + ICH CH CCH 3 CH 3 CH CH CCH 3 CH 3 CH CH CCH 3
CO C(CH ) CO C(CH ) CO H
2
3 3
3 3
2
2
52%
Ref. 108
Alkylation of enamines requires relatively reactive alkylating agents for good
results. Methyl iodide, allyl and benzyl halides, -halo esters, -halo ethers, and -halo
ketones are the most successful alkylating agents. The use of enamines for selective
alkylation has largely been supplanted by the methods for kinetic enolate formation
described in Section 1.2.
Some enamine alkylation reactions are shown in Scheme 1.10. Entries 1 and 2 are
typical alkylations using reactive halides. In Entries 3 and 4, the halides are secondary
with -carbonyl substituents. Entry 5 involves an unactivated primary bromide and
the yield is modest. The reaction in Entry 6 involves introduction of two groups. This
106
W. D. Gurowitz and M. A. Joseph, J. Org. Chem., 32, 3289 (1967).
107 F. Johnson, L. G. Duquette, A. Whitehead, and L. C. Dorman, Tetrahedron, 30, 3241 (1974); K. Muller,
F. Previdoli, and H. Desilvestro, Helv. Chim. Acta, 64, 2497 (1981); J. E. Anderson, D. Casarini, and
L. Lunazzi, Tetrahedron Lett., 25, 3141 (1988).
108
P. L. Stotter and K. A. Hill, J. Am. Chem. Soc., 96, 6524 (1974).