Lithium perchlorate assisted one-pot three-component aminoalkylation of electron-rich aromatic compounds

Article abstract of DOI:10.1016/S0040-4039(01)01732-4

A one-pot, three-component, Mannich reaction of electron-rich aromatic compounds with in situ prepared iminium salts in 5 M ethereal lithium perchlorate gives good yields of aminoalkylated products at room temperature.

Full text of DOI:10.1016/S0040-4039(01)01732-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8111–8113
Lithium perchlorate assisted one-pot three-component
aminoalkylation of electron-rich aromatic compounds
Mohammad R. Saidi,* Najmoddin Azizi and M. Reza Naimi-Jamal
Department of Chemistry, Sharif University of Technology, PO Box 11345-9516, Tehran, Iran
Received 25 August 2001; accepted 14 September 2001
Abstract—A one-pot, three-component, Mannich reaction of electron-rich aromatic compounds with in situ prepared iminium
salts in 5 M ethereal lithium perchlorate gives good yields of aminoalkylated products at room temperature. © 2001 Elsevier
Science Ltd. All rights reserved.
The Mannich reaction has long been of great impor-
tance and a classical method for the aminoalkylation of
aldehydes, and has been one of the most important
basic reactions in organic chemistry for use in natural
product and pharmaceutical chemistry.1 The classical
Mannich reaction has limited applications, and many
attempts have been made to extend this reaction.2
Direct aminoalkylation has great interest in synthetic
organic chemistry and considerable importance for the
synthesis of drugs, pesticides and natural products.
Many methods of aminoalkylation of electron rich
aromatic compounds have been studied to date.
Katritzky and Risch have reported an improved
aminoalkylation of b-naphthol and phenol derivatives
with preformed iminium salts derived from aromatic
aldehydes, in a two-step sequence with 26–92% yields.3
Recently, we have reported the aminomethylation of
electron-rich aromatic compounds under solvent-free
conditions and the lithium perchlorate mediated, one-
pot, three-component aminoalkylation of aldehydes for
the preparation of a variety of amines and aminoesters,
as well as functionalized alkylamines.4
now wish to describe an efficient three-component and
one-pot method for aminoalkylation of electron-rich
aromatic compounds using aldehydes, (trimethyl-
silyl)dialkylamines, and an electron-rich aromatic com-
pound such as a- or b-naphthol, indole, N-methylin-
dole, coumarin or 6-hydroxyisoquinoline, at room
temperature in a concentrated solution of lithium per-
chlorate in diethyl ether. The reaction of b-naphthol
with in situ prepared iminium salts in a 5 M ethereal
lithium perchlorate solution gives good yields of
aminoalkylated aromatic and aliphatic compounds 1–
11 with moderate (in the case of aliphatic aldehydes) to
good yields. The yields appear to depend, not only on
the nucleophilicity of the electron-rich aromatic com-
pounds, but also on the reactivity of the iminium salt
and the starting aldehyde. The results are summarized
in Table 1. The aminoalkylation of 6-hydroxyisoquino-
line with a preformed iminium salt is shown in Scheme
1.
Experimental
General. LiClO4 (Fluka) was dried at 160°C and 10−1
Torr for 48 h. Ether was dried over Na/benzophenone
under argon. IR spectra were taken on a Mattson 1000
Unicam FTIR, 1H and 13C NMR spectra were recorded
on Bruker AC 80 instruments. All reactions were per-
formed under argon. Chemicals were purchased from
Fluka and used as received.
The preparation and purification of iminium salts in a
separate step, their hygroscopicity and susceptibility to
hydrolysis (with the exception of Eschenmoser’s salts),5
led us to develop an alternative method for the
aminoalkylation of electron-rich aromatic compounds.
In continuation of our current work on the lithium
perchlorate mediated aminoalkylation reaction,6 we
General procedure for the aminoalkylation of electron-
rich aromatic compounds
Keywords: aminoalkylation; Mannich reaction; lithium perchlorate;
electron-rich aromatic compounds.
The aldehyde (2 mmol) and 3 mL of 5 M LiClO4 in
diethyl ether were placed in a 50 mL flask under argon
* Corresponding author. Fax: 0098 21 601 2983; e-mail: saidi@
sharif.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01732-4

8112
M. R. Saidi et al. / Tetrahedron Letters 42 (2001) 8111–8113
Table 1. LiClO4-mediated aminoalkylation of electron-rich aromatic compounds
and stirred for 5 min. The (trimethylsilyl)dialkylamine
(3 mmol) was added via a syringe. After 30 min, an
electron-rich aromatic compound, such as b-naphthol
(2 mmol), was added and the mixture was stirred at
room temperature for a given time (Table 1), then
water (20 mL) and dichloromethane (20 mL) were
added. The organic phase was separated, dried over
MgSO4, and the solvent was removed using a rotary
evaporator. The crude product was further purified by
column chromatography on basic alumina and was
Scheme 1.

M. R. Saidi et al. / Tetrahedron Letters 42 (2001) 8111–8113
8113
characterized by comparison of IR and NMR (1H and
13C) spectra with those of an authentic sample. Yields
refer to pure isolated products.
Synthesis; Wiley: UK, 1995; Vol. 4, p. 2582; (b) Tramon-
tini, M.; Angiolini, L. Tetrahedron 1990, 46, 1791–1837.
2. (a) Heaney, H. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 2, p. 953; (b) Loh, T.-P.; Wei, L.-L. Tetrahedron Lett.
1998, 39, 323–326; (c) Katritzky, A. R.; Fan, W.-Q.; Long,
Q.-H. Synthesis 1993, 229–232.
Caution: Although we did not have an accident using
lithium perchlorate (LiClO4), it is advisable to dry
lithium perchlorate in a hood behind a lab-shield.
3. (a) Grumbach, H.-J.; Arend, M.; Risch, N. Synthesis 1996,
883–887; (b) Katritzky, A. R.; Abdel-Fattah, A. A. A.;
Tymoshenko, D. O.; Belyakov, S. A.; Ghiviriga, I.; Steel,
P. J. J. Org. Chem. 1999, 64, 6071–6075; (c) Sharifi, A.;
Mirzaei, M.; Naimi-Jamal, M. R. Monatsh. Chem. 2001,
132, 875–880.
In conclusion, a mild, one-pot and fast, aminoalkyla-
tion of b-naphthol, 2,4-dimethyl-phenol, 6-hydroxyiso-
quinoline or 7-hydroxycoumarin with in situ prepared
iminium salts at rt has been achieved in good to
moderate yields. The reaction time was 1–6 h.
4. (a) Saidi, M. R.; Hydari, A.; Ipaktschi, J. Chem. Ber. 1994,
127, 1761–1764; (b) Saidi, M. R.; Khalaji, H. R.; Ipak-
tschi, J. J. Chem. Soc., Perkin Trans. 1 1997, 1983–1986;
(c) Saidi, M. R.; Khalaji, H. R. J. Chem. Res. (S) 1997,
340–341; (d) Mojtahedi, M. M.; Sharifi, A.; Mohsenzadeh,
F.; Saidi, M. R. Synth. Commun. 2000, 30, 69–72.
5. Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int.
Ed. Engl. 1998, 37, 1044–1070.
6. (a) Naimi-Jamal, M. R.; Mojtahedi, M. M.; Ipaktschi, J.;
Saidi, M. R. J. Chem. Soc., Perkin Trans. 1 1999, 3709–
3711; (b) Naimi-Jamal, M. R.; Ipaktschi, J.; Saidi, M. R.
Eur. J. Org. Chem. 2000, 1735–1739; (c) Saidi, M. R.;
Azizi, N.; Zali-Boinee, H. Tetrahedron 2001, 57, 6829–
6832.
Acknowledgements
We thank ‘Volkswagen-Stiftung, Federal Republic of
Germany’ for financial support towards the purchase of
chemicals and equipment. M.R.S. thanks the Ministry
of Science, Research and Technology of Iran for partial
financial support.
References
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