The use of hydrazones for efficient mannich type coupling with aldehydes and
secondary amines
Valérie Atlan, Hugues Bienaymé, Laurent El Kaim* and Adinath Majee
Laboratoire Chimie et Procédés, Ecole Nationale Supérieure de Techniques Avancées, 32 Bd Victor, 75015 Paris,
France. E-mail: elkaim@ensta.fr
Received (in Cambridge, UK) 6th April 2000, Accepted 4th July 2000
Published on the Web 3rd August 2000
The Mannich reaction of hydrazones originally limited to the
coupling of hydrazones with formaldehyde has been ex-
tended to a large variety of aldehydes through appropriate
selection of experimental conditions; in conjunction with the
Japp–Klingmann reaction, this process provides an efficient
synthetic tool for the formation of carbon–carbon bonds.
The Mannich reaction is one of the most widely used reactions
for the formation of carbon–carbon bonds. In its initial form, it
implied the addition of aldehydes to ketones in the presence of
amines.1 The scope of the Mannich reaction was then extended
to the addition of different carbon nucleophiles such as nitro
compounds.2 The ease of deprotonation of monosubstituted
hydrazones 1 under basic conditions is dependent upon the
attached substituents. The resulting salt can be viewed as an aza-
substituted carbanion and as such may interact in a Mannich
reaction leading to carbon–carbon bond formation (Scheme 1).
Indeed in 1957, Keil and Ried3 reported such behavior but their
study revealed only modest synthetic potential as moderate to
good yields were only obtained with formaldehyde; furthermore
the hydrazones needed an electron withdrawing group (R1)
tethered to the carbonyl function. The potential of this reaction
has led us to perform a more extensive study and we were
delighted to find that different experimental conditions and the
appropriate selection of the amine permit the condensation of
hydrazones 1 with many different aldehydes 2 (Table 1,
Scheme 1) giving the new aminohydrazones 4 in good yields.
Most noteworthy are the good yields obtained with several
aliphatic aldehydes possessing a-hydrogens. For the latter,
competing aldol type reactions usually preclude their efficient
use in Mannich reactions.4 The first indication of success
probably came from the choice of N-benzylpiperazine as the
amine partner in this reaction. A net increase in yield is
observed in going from aliphatic amine to morpholine and
finally to N-benzylpiperazine. The reaction is best performed in
a concentrated toluene solution (2 M) at 80 °C with nearly
equimolar amounts of aldehyde (1.1 eq.) and amine (1.1 eq.).
The main drawback of this reaction is, as observed by Reid
and Keil,3 the need for an electron withdrawing group tethered
to the hydrazone functionality. This limitation on the starting
hydrazones is however deeply counter-balanced by their easy
access via the Japp–Klingmann reaction between b-ketoacids
and diazonium salts (Scheme 2).
Since the use of N-benzylpiperazine leads to good yields of
product, a clean way to displace this group becomes crucial for
the synthetic potential of this reaction. The chemistry of
azoalkenes brings us a possible answer to this problem:
treatment of hydrazone 4g in various alcohols with two
equivalents of 1,2-dibromoethane under reflux generates the
new ether 5 probably via an azoalkene trapping by the alcohol
(Scheme 3); hydrazone 4b behaves similarly. This substitution
Scheme 1
process needs an alcohol with a rather high boiling point (at
DOI: 10.1039/b002750m
Chem. Commun., 2000, 1585–1586
This journal is © The Royal Society of Chemistry 2000
1585
Atlan
