Aminoalkylation with aldehydes mediated by solid lithium perchlorate

Article abstract of DOI:10.1007/s00706-003-0093-2

The solid LiClO₄-mediated one-pot reaction of aldehydes with secondary amines and C nucleophiles afforded the corresponding aminoalkylation products in high yields. Unlike the previous reported procedure, the aminoalkylation of aldehyde was achieved in the presence of only 0.5 equivalents of solid lithium perchlorate in dichloromethane as the solvent with good to high yields at room temperature. Springer-Verlag 2003.

Full text of DOI:10.1007/s00706-003-0093-2

Monatshefte f€ur Chemie 135, 309–312 (2004)
DOI 10.1007/s00706-003-0093-2
Aminoalkylation with Aldehydes
Mediated by Solid Lithium Perchlorate
Ã
Mohammad R. Saidi and Mohammad Nazari
Department of Chemistry, Sharif University of Technology, P.O. Box 11365-9516,
Tehran, Iran
Received May 27, 2003; accepted (revised) June 24, 2003
Published online November 20, 2003 # Springer-Verlag 2003
Summary. The solid LiClO4-mediated one-pot reaction of aldehydes with secondary amines and C
nucleophiles afforded the corresponding aminoalkylation products in high yields. Unlike the previous
reported procedure, the aminoalkylation of aldehyde was achieved in the presence of only 0.5 equiva-
lents of solid lithium perchlorate in dichloromethane as the solvent with good to high yields at room
temperature.
Keywords. Aminoalkylation; Aldehyde; Solid Lithium Perchlorate; Mannich reaction.
Introduction
Direct aminoalkylation is interesting for synthetic organic chemistry and it has
considerable importance for the synthesis of drugs, pesticides, and natural pro-
ducts. Dialkylamino esters and amines are widely used for their antispasmodic
activity, as topical anesthetic, amongst other pharmaceutical uses, and as plant
growth promoters [1–4]. The Mannich reaction is one of the most important multi-
component reactions in organic synthesis and biosynthesis [5]. The classical
Mannich reaction is an aminoalkylation with formaldehydes involving three-
components, an aldehyde, a secondary amine, and compounds with an active CH
[6a]. Although, ꢀ-aminoketones (Mannich bases) can be obtained in good yields,
the classical reaction has limited applications. Many attempts have been made to
extend the Mannich reaction [6b]. In this context, Mannich products can be pre-
pared by the addition of nucleophiles to the benzotriazole 1 or titanium derivatives
of type 2 [7, 8], as well as addition of nucleophiles to in situ prepared iminium salts
3 from trimethylsilyldimethyl amine and an aldehyde in a concentrated ethereal
LiClO4 solution (LPDE) [9]. We have reported several transformations of the
iminium salt 3 to different organic compounds on a 2 mmol scale (ca. 2.1 g solid
LiClO4 for each run) [10].
Ã
Corresponding author. E-mail: saidi@sharif.edu

310
M. R. Saidi and M. Nazari
Formulae 1
Although LPDE is a convenient medium to carry out reactions under neutral
condition, drying lithium perchlorate and preparation of its concentrated solution in
diethyl ether (ca. 5.0 M) is one disadvantage of this medium. On the other hand,
due to the current challenge for developing easy to handle synthetic systems and in
continuation of our interest on the applications of lithium perchlorate for various
organic transformation, we herein describe a simple, general, and efficient protocol
for the aminoalkylation with aldehydes with different types of nucleophiles using
only about 0.08 g of solid LiClO4, in a small amount of CH2Cl2.
Results and Discussion
Treatment of 1 equivalent of an aldehyde with 1.5 equivalents of a secondary
amine and a nucleophile in the presence of about 0.5 equivalents of solid LiClO4
produces the expected aminoalkylated product in high yield after a short time at
room temperature (Scheme 1).
Several aldehydes, secondary amines, and nucleophiles were examined accord-
ing to this procedure. The reaction time is different for each reaction due to the
nucleophilicity of each nucleophile (Table 1). The aminoalkylation reaction did not
occur without using solid LiClO4. The three components coupling reactions pre-
ceeded smoothly and the corresponding aminoalkylated products were isolated in
good to high yields with no by-products. In most cases the pure products were
isolated without any further purification. The reaction can also proceed with 2-
methylpropanal (an enolizable aldehyde) in relatively good yield. All compounds
are known and they were characterized on the basis of their spectroscopic data (IR,
NMR, MS) and by comparison with data reported in Ref. [10].
In conclusion we have presented a practical, efficient, and simple method for
aminoalkylation with aldehydes using a small amount of solid lithium perchlorate
(about 0.5 equiv.) in dichloromethane.
Scheme 1

Aminoalkylation with Aldehydes Mediated by LiClO4
311
Table 1. Aminoalkylation of aldehydes with different nucleophiles mediated by solid LiClO4
a
b
Isolated yields; In this case 0.12 g of LiClO4 were used

312
M. R. Saidi and M. Nazari: Aminoalkylation with Aldehydes Mediated by LiClO4
Experimental
NMR spectra were recorded on a Bruker ACF 500, IR spectra with a Perkin Elmer 1600 FTIR
spectrometer. Column chromatography was performed on silica gel, Merck grade 60. CH2Cl2 was
distilled before use. All reactions were performed under Ar. Anhydrous LiClO4 and other chemicals
were from Fluka or Merck. All compounds were characterized on the basis of spectroscopic data (IR,
NMR, MS) and by comparison with data reported in Ref. [10].
General Procedure for the Aminoalkylation with Aldehydes Mediated by Solid LiClO4
Lithium perchlorate (0.75 mmol, 0.08g) was added to 5 cm3 of dry CH2Cl2. After 2 min of stirring,
2 mmol of aldehyde were added and the mixture was stirred at rt for 5 min. A secondary amine
(3.0mmol) was added and the solution was stirred until the iminium salt was formed after about
5 min stirring at rt. Then 3 mmol of a nucleophile were added and the reaction mixture was stirred at rt
for an appropriate time as indicated in Table 1 (In case of 7a, 7b, and 7g, 4 mmol of nucleophile were
added). After the reaction was completed, 10 cm3 of CH2Cl2 and 20cm3 of H2O were added and the
organic layer was separated. The filtrate was washed with H2O. The organic phase was separated, dried
over MgSO4, and the solvent was removed using a rotary evaporator. Further purification was carried
out by column chromatography on basic alumina eluting with petroleum ether=ethyl acetate or by
recrystalization. For products 7h–7o no purification was needed, and the pure products were isolated
after usual work up.
Acknowledgments
We thank ‘‘Volkswagen-Stiftung, Federal Republic of Germany’’ for financial support to purchase
equipments and chemicals.
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