Page 175 - Advanced Organic Chemistry Part B - Reactions & Synthesis

2.2.3. Amine-Catalyzed Condensation Reactions 147
Iminium ions are intermediates in a group of reactions that form , -unsaturated SECTION 2.2
compounds having structures corresponding to those formed by mixed aldol addition Addition Reactions of
followed by dehydration. These reactions are catalyzed by amines or buffer systems Imines and Iminium Ions
containing an amine and an acid and are referred to as Knoevenagel condensations. 211
The reactive electrophile is probably the protonated form of the imine, since it is a
more reactive electrophile than the corresponding carbonyl compound. 212

H + H +
ArCH NC H ArCHNHC H ArCH NHC H ArCH CHNO 2
4 9
4 9
4 9
–
CH NO 2 CH NO 2 H CHNO 2
2
2
The carbon nucleophiles in amine-catalyzed reaction conditions are usually rather
acidic compounds containing two EWG substituents. Malonate esters, cyanoacetate
esters, and cyanoacetamide are examples of compounds that undergo condensation
reactions under Knoevenagel conditions. 213 Nitroalkanes are also effective as nucle-
ophilic reactants. The single nitro group activates the -hydrogens enough to permit
deprotonation under the weakly basic conditions. A relatively acidic proton in the
nucleophile is important for two reasons. First, it permits weak bases, such as amines,
to provide a sufficient concentration of the enolate for reaction. An acidic proton
also facilitates the elimination step that drives the reaction to completion. Usually the
product that is isolated is the , -unsaturated derivative of the original adduct.
B
H R
CO R CO 2
2
R C C R C C
2
2
CN
X CN
X = OH or NR 2
Malonic acid or cyanoacetic acid can also be used as the nucleophile. With malonic
acid or cyanoacetic acid as reactants, the products usually undergo decarboxylation.
This may occur as a concerted fragmentation of the adduct. 214
X
O
R C CHCO H
2
2
RCR + CH (CO H) 2 R C CHCO 2 H
2
2
2
C O
X = OH or NR 2 – O
Decarboxylative condensations of this type are sometimes carried out in pyridine,
which cannot form an imine intermediate, but has been shown to catalyze the
decarboxylation of arylidene malonic acids. 215 The decarboxylation occurs by
concerted decomposition of the adduct of pyridine to the , -unsaturated diacid.
211 G. Jones, Org. React., 15, 204 (1967); R. L. Reeves, in The Chemistry of the Carbonyl Group, S. Patai,
ed., Interscience, New York, 1966, pp. 593–599.
212
T. I. Crowell and D. W. Peck, J. Am. Chem. Soc., 75, 1075 (1953).
213 A. C. Cope, C. M. Hofmann, C. Wyckoff, and E. Hardenbergh, J. Am. Chem. Soc., 63, 3452 (1941).
214 E. J. Corey, J. Am. Chem. Soc., 74, 5897 (1952).
215
E. J. Corey and G. Fraenkel, J. Am. Chem. Soc., 75, 1168 (1953).