Highly diastereoselective aminoalkylation of naphthols with chiral amines mediated by lithium perchlorate solution in diethyl ether

Article abstract of DOI:10.1016/S0957-4166(02)00863-7

One-pot, three-component, Mannich reaction of naphthols with in situ prepared imines in 5 M ethereal lithium perchlorate at room temperature affords the corresponding aminoalkylated products in high yields with high diastereoselectivities. The process is exemplified by the reaction of 2-naphthol with (R)-1-phenylethylamine and an aromatic aldehyde in concentrated ethereal lithium perchlorate solution, which affords a highly diastereoselective access to the requisite 2-aminoalkylated product.

Full text of DOI:10.1016/S0957-4166(02)00863-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 389–392
Highly diastereoselective aminoalkylation of naphthols with
chiral amines mediated by lithium perchlorate solution in
diethyl ether
Mohammad R. Saidi* and Najmoddin Azizi
Department of Chemistry, Sharif University of Technology, PO Box 11345-9516, Tehran, Iran
Received 8 November 2002; revised 11 December 2002; accepted 13 December 2002
Abstract—One-pot, three-component, Mannich reaction of naphthols with in situ prepared imines in 5 M ethereal lithium
perchlorate at room temperature affords the corresponding aminoalkylated products in high yields with high diastereoselectivities.
The process is exemplified by the reaction of 2-naphthol with (R)-1-phenylethylamine and an aromatic aldehyde in concentrated
ethereal lithium perchlorate solution, which affords a highly diastereoselective access to the requisite 2-aminoalkylated product.
© 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
New methods for the stereoselective aminoalkylation of
electron-rich aromatic compounds are currently of
great interest. Although a variety of methods for the
aminoalkylation of electron-rich aromatic compounds
are available,1,2 new direct approaches that are stereo-
selective and mild enough to allow the preparation of
single diastereoisomers are continuously attracting
interest.3
In concentrated ethereal lithium perchlorate solution,
aldehyde 1 and enantiopure (R)-1-phenylethylamine 2
(also readily available commercially as the (S) enan-
tiomer) produce the imine 3 as an intermediate at room
temperature. Upon addition of b-naphthol or a-naph-
thol to the reaction mixture, aminoalkylated products
4a–k were formed in moderate to high yields and with
diastereoselectivity (dr) from 75 to 99% (Tables 1 and
2).
The Mannich reaction is one of the most important
multi-component reactions in organic synthesis and
biosynthesis.4 In the course of this three-component
aminoalkylation of aldehydes, CꢀN and CꢀC single
bonds replace the CꢀO double bond.
When a mixture of aromatic aldehyde 1, (R)-1-
phenylethylamine, 2, and b-naphthol, in a molar ratio
of 1.0:1.5:1.0, was stirred under an argon atmosphere in
5 M ethereal lithium perchlorate solution at room
temperature for 4 h, the desired aminoalkylnaphthol
was produced in 20% yield. Reaction of a mixture of
Recently, we reported the lithium perchlorate-mediated,
one-pot three-component aminoalkylation of aromatic
or aliphatic aldehydes with (trimethylsilyl)alkylamines
and different nucleophiles, including electron-rich aro-
matic compounds.5 Herein we describe an efficient,
straightforward and diastereoselective method for the
aminoalkylation of naphthols with chiral amines medi-
ated by lithium perchlorate solution in diethyl ether.
aromatic
aldehyde
1,
(R)-(trimethylsilyl)-1-
(phenylethyl)amine and b-naphthol, in a molar ratio of
1.0:1.5:1.0, gave very similar results. When a mixture of
1, 2 and trimethylsilylchloride (TMSCl) in a molar ratio
of 1.0:1.5:0.5, respectively, were stirred for 15 min in
ethereal lithium perchlorate solution (4 mL, 5 M) at
room temperature under an argon atmosphere, pre-
sumably the imine 3, is formed. By addition of 1 equiv1
of b-naphthol into the reaction mixture and stirring at
room temperature for 6 h the 1-aminoalkyl-2-naphthol
was produced in >75% yield with a diastereomeric
purity of >99%, (Scheme 1, Table 1). The diastereo-
* Corresponding author. E-mail: saidi@sharif.edu
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00863-7

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M. Saidi, N. Azizi / Tetrahedron: Asymmetry 14 (2003) 389–392
Table 1. LiClO4-mediated stereoselective aminoalkylation of 2-naphthol with chiral amine
1
meric purity was determined by H NMR analysis of
the product. Completing the reaction over longer times
and under different conditions did not effect any
improvement in the yield of the 1-aminoalkyl-2-naph-
thol.
ethereal lithium perchlorate solution at room tempera-
ture under an argon atmosphere, gave the 2-
aminoalkyl-1-naphthol in 40% yield (Table 2, entries
1–3). In this case the dr was lower than for the b-
aminoalkylnaphthols. With isobutyraldehyde, low con-
version and dr was observed (20% yield with a
diastereomeric purity of 45–55%). When the pre-formed
imine 3 was used in a two-step process in ethereal
LiClO4 or with Lewis acids such as BF3-ether, ZnBr2 or
Addition of 1 equiv. of a-naphthol instead of b-naph-
thol into the mixture of 1, 2 and trimethylsilyl chloride
in a molar ratio of 1.0:1.5:0.5, respectively in 5 M
Scheme 1.

M. Saidi, N. Azizi / Tetrahedron: Asymmetry 14 (2003) 389–392
391
Table 2. LiClO4-mediated stereoselective aminoalkylation of 1-naphthol with chiral amine
Scheme 2.
AlCl3, the dr was not improved and the overall yields of
the aminoalkylated products 4 were lower in compari-
son with the one-pot reaction in the presence of TMSCl
(Scheme 2).
naphthol (2 mmol, 0.29 g) was added. Following the
1
progress of the reaction by TLC and H NMR, the
reaction mixture was stirred at room temperature for 6
h. 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 eluting with
petroleum ether/ethyl acetate. All compounds were
characterized on the basis of spectroscopic data (IR,
NMR, MS) by comparison with those reported in the
literature.3 The same procedure was used for the
diastereoselective aminoalkylation of 1-naphthol.
The structure of compounds 4a–k were confirmed by
their spectral data and were characterized by compari-
son of IR, NMR (1H and 13C) and MS spectra with
those reported in the literature.3
In summary, a one-pot, three-component diastereo-
selective aminoalkylation of 2-naphthol and 1-naphthol
has been achieved in good to moderate yields and with
very high to moderate selectivity.
3.2. Selected spectroscopic data for the major
diastereoisomers
3. Experimental
4a:3a 1H NMR (500 MHz, CDCl3): l 1.55 (d, J=6.8
Hz, 3H), 2.22 (br s, 1H), 3.95 (m, 1H), 5.51 (s, 1H),
7.22–7.80 (m, 16H), 13.80 (br s, 1H); 13C NMR (125
MHz, CDCl3): l 23.4 (CH3), 56.9 (CH), 60.6 (CH),
113.2, 120.4, 121.3, 122.7, 126.7, 127.7, 127.9, 128.1,
128.9, 129.0, 129.1, 129.3, 130.0, 130.1, 133.0, 141.9,
143.5, 157.7. IR (KBr), 3220, 1080, cm−1.
3.1. General procedure for diastereoselective aminoalkyl-
ation of 2-naphthol
A mixture of benzaldehyde (2 mmol, 0.21 g), (R)-(+)-1-
phenylethylamine (3 mmol, 0.36 g), and 5 M LiClO4 in
diethyl ether (4 mL) were placed in a 50 mL flask under
argon and stirred for 15 min at room temperature.
TMSCl (1 mmol) was added via a syringe. After the
addition of TMSCl, a white solid was formed. Then 2-
4c:3a 1H NMR (500 MHz, CDCl3): l 1.57 (d, J=6.9
Hz, 3H), 2.31 (br s, 1H), 3.91 (q, J=6.9 Hz, 1H), 5.94
(s, 3H), 7.13–8.25 (m, 15H), 13.65 (br s, 1H); 13C NMR

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M. Saidi, N. Azizi / Tetrahedron: Asymmetry 14 (2003) 389–392
(125 MHz, CDCl3): 23.6 (CH3), 57.9 (CH), 60.1 (CH),
112.4, 120.1, 121.2, 123.7, 127.2, 127.4, 128.4, 128.8,
129.3, 129.7, 130.5, 132.6, 134.4, 142.9, 142.6, 149.0,
158.0. IR (KBr), 3283, 1210, cm−1.
Chem., Int. Ed. 1998, 37, 1044; (c) 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.
2. (a) Sharifi, A.; Mirzaei, M.; Naimi-Jamal, M. R. Monatsh.
Chem. 2001, 132, 875; (b) Saidi, M. R.; Azizi, N.; Naimi-
Jamal, M. R. Tetrahedron Lett. 2001, 42, 8111.
3. (a) Cimarelli, C.; Mazzanti, A.; Palmieri, G.; Volpini, E. J.
Org. Chem. 2001, 66, 4759; (b) Chi, K.-W.; Ahn, Y.-S.;
Shim, K. T.; Park, T. N.; Ahn, J. S. Bull. Korean Chem.
Soc. 1999, 20, 937; (c) Palmieri, G. Tetrahedron: Asymme-
try 2000, 11, 3361; (d) Palmieri, G. Eur. J. Org. Chem.
1999, 805; (e) Cimarelli, C.; Palmieri, G. Tetrahedron 1998,
54, 15711; (f) Zhang, L.-C. Org. Lett. 2001, 3, 2733; (g)
Cardellicchio, C.; Ciecarella, G.; Naso, F.; Perna, F.;
Tortorreka, P. Tetrahedron 1999, 55, 14685.
4. (a) Encyclopedia of Reagents for Organic Synthesis; Paqett,
L. A., Ed.; Wiley: UK, 1995; Vol. 4, p. 2582; (b) Tramon-
tini, M.; Angiolini, L. Tetrahedron 1990, 46, 1791; (c)
Heaney, H. In Comprehensive Organic Synthesis; Trost, B.
M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol.
2, pp. 953–957; (d) Loh, T.-P.; Wei, L.-L. Tetrahedron
Lett. 1998, 39, 323; (e) Katritzky, A. R.; Fan, W.-Q.;
Long, Q.-H. Synthesis 1993, 229.
5. (a) Saidi, M. R.; Khalaji, H. R.; Ipaktschi, J. J. Chem.
Soc., Perkin Trans. 1 1997, 1983; (b) Saidi, M. R.; Khalaji,
H. R. J. Chem. Res. (S) 1997, 340; (c) Naimi-Jamal, M.
R.; Mojtahedi, M. M.; Ipaktschi, J.; Saidi, M. R. J. Chem.
Soc., Perkin Trans. 1 1999, 3709; (d) Naimi-Jamal, M. R.;
Ipaktschi, J.; Saidi, M. R. Eur. J. Org. Chem. 2000, 1735;
(e) Saidi, M. R.; Azizi, N.; Zali-Boinee, H. Tetrahedron
2001, 57, 6829; (f) Saidi, M. R.; Azizi, N. Synlett 2002,
1347.
4k:3a 1H NMR (500 MHz, CDCl3): l 1.54 (d, J=6.8
Hz, 3H), 2.32 (br s, 1H), 3.94 (q, J=6.8 Hz, 1H), 4.85
(s, 1H), 7.04–7.89 (m, 16H), 12.90 (br s, 1H); 13C NMR
(125 MHz, CDCl3): l 23.8 (CH3), 56.8 (CH), 65.6
(CH), 116.1, 118.4, 119.3, 120.9, 123.3, 125.3, 126.7,
127.2, 127.8, 128.1, 128.3, 129.4, 129.6, 134.3, 142.8,
143.7, 149.0, 154.9. IR (KBr), 3380, 1095, cm−1.
Caution: Although we did not have any accidents while
using LiClO4, it is advisable to dry lithium perchlorate
in a fume hood using a suitable lab-shield.
Acknowledgements
We are grateful to the Ministry of Science, Research
and Technology for financial support. We also thank
‘Volkswagen-Stiftung, Federal Republic of Germany’
for financial support towards the purchase of equip-
ment and chemicals.
References
1. (a) Grumbach, H.-J.; Arend, M.; Risch, N. Synthesis 1996,
883; (b) Arend, M.; Westermann, B.; Risch, N. Angew.