Zinc-catalyzed aminolysis of epoxides

Article abstract of DOI:10.1016/S0040-4039(03)01480-1

A series of amino alcohols has been prepared by a novel zinc-catalyzed nucleophilic opening of epoxide rings by amines.

Full text of DOI:10.1016/S0040-4039(03)01480-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6025–6027
Zinc-catalyzed aminolysis of epoxides
Laura Dura´n Pacho´n, Patrick Gamez, Jos J. M. van Brussel and Jan Reedijk*
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands
Received 14 May 2003; revised 4 June 2003; accepted 13 June 2003
Abstract—A series of amino alcohols has been prepared by a novel zinc-catalyzed nucleophilic opening of epoxide rings by
amines.
© 2003 Elsevier Ltd. All rights reserved.
Epoxides are an important class of synthons which
have found much use in synthetic organic chemistry.1–3
Thus, the nucleophilic ring opening of the oxirane ring
is often employed for the preparation of sophisticated
bioactive molecules.4 b-Amino alcohols5 were typically
obtained from opening of epoxides with an excess of
amines at elevated temperatures. Since very high tem-
peratures may be inappropriate for certain functional
groups, a variety of air-sensitive, expensive or specific
catalysts have been described in the literature to per-
form epoxide opening at room or low temperatures.6–10
However, it has been reported that aliphatic amines
failed to react with epoxides in the presence of cobalt,6
rhodium,9 or copper10 catalysts. The use of titanium
tetraisopropoxide allowed the aminolysis of epoxides by
to handle. Several amines and epoxides were employed
and the results are reported in Table 1.11,12
Three aminolyses of styrene oxide even led to total
conversions (entries 1–3). Furthermore, the ring open-
ings were highly regioselective with 3:4 ratios ranging
from 80:20 to 93:7. At this point, it should be men-
tioned that no reaction was observed between aniline
and styrene oxide in the absence of zinc(II) chloride.
Only 40% of b-amino alcohol was obtained when benz-
ylamine was used, probably because of a combination
of steric hindrance and its lower nucleophilicity (entry
4). This may also explain the poor regioselectivity
(59:41) of this addition. At first sight, the result
obtained with 2-(aminomethyl)pyridine was surprising
where no conversion of the epoxide could be detected
(entry 5). This may be due to co-ordination of the zinc
by the pyridine (see Fig. 1).
alkylamines in
a
pressure reactor.7 Finally, the
intramolecular aminolysis of epoxides catalyzed by
diethylaluminium chloride has been performed under
an argon atmosphere.8
Indeed, pyridine-containing ligands may be used in
order to fine-tune the properties of the zinc catalyst.
Furthermore, the utilization of chiral ligands may allow
the enantioselective opening of the oxiranes.
In this paper, a much more simple and effective cata-
lytic route for the synthesis of b-amino alcohols under
aerobic conditions is described. The reaction of both an
aliphatic or an aromatic amine with an epoxide, in the
presence of low-cost zinc(II) chloride as catalyst, leads
to the formation of the corresponding regioisomeric
b-amino alcohols 3 and 4 (Scheme 1).
The use of ethyl 3-phenylglycidate as the epoxide for
reaction with the same nucleophilic amines gave only
moderate yields, but with very high regioselectivities
(entries 6–8). The low reactivities observed may be due
to the chelating properties of ethyl 3-phenylglycidate
which reduce the activation of the oxirane ring by the
Typically, 5 mmol of the amine were reacted with 5
mmol of the epoxide in acetonitrile at 82°C under air
for 12 h. The nucleophilic addition is catalyzed by the
presence of 5 mol% zinc(II) chloride which is very easy
Keywords: ring opening; aminolysis; epoxide; zinc catalyst.
* Corresponding authors. Fax: (int.) +31-71-527-4671; e-mail:
reedijk@chem.leidenuniv.nl
Scheme 1. Zinc-catalyzed aminolysis of epoxides.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01480-1

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L. Dura´n Pacho´n et al. / Tetrahedron Letters 44 (2003) 6025–6027
Table 1. b-Aminoalcohols produced via Scheme 1
zinc catalyst (Fig. 2). The coordination of the carbonyl
group of the ester function probably decreases the
Lewis acidity of the zinc salt. This was confirmed by the
total conversion reached after a reaction time of 3 days
(entry 6), demonstrating the poorer catalytic activity of
the zinc complex.

L. Dura´n Pacho´n et al. / Tetrahedron Letters 44 (2003) 6025–6027
6027
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3. Ghosh, A. K.; Wang, Y. J. Org. Chem. 1999, 64, 2789–
2795.
4. Yamaguchi, T.; Harada, N.; Ozaki, K.; Hashiyama, T.
Tetrahedron Lett. 1998, 39, 5575–5578.
5. Chang, B. L.; Ganesan, A. Bioorg. Med. Chem. Lett.
1997, 7, 1511–1514.
Figure 1. Likely coordination of 2-(aminomethyl)pyridine to
zinc.
6. De, A.; Ghosh, S.; Iqbal, J. Tetrahedon Lett. 1997, 38,
8379–8382 (CoCl2).
7. Yadav, J. S.; Bandyopadhyay, A.; Reddy, B. V. S. Tetra-
hedron Lett. 2001, 42, 6385–6388 [Ti(OiPr)4].
8. Hatakeyama, S.; Matsumoto, H.; Fukuyama, H.;
Mukugi, Y.; Irie, H. J. Org. Chem. 1997, 62, 2275–2279
(Et2AlCl).
Figure 2. Chelating ability of ethyl 3-phenylglycidate
9. Fagnou, K.; Lautens, M. Org. Lett. 2000, 2, 2319–2321
{[Rh(CO)2Cl]2}.
10. Sekar, G.; Singh, V. K. J. Org. Chem. 1999, 64, 287–289
[Cu(OTf)2 and Sn(OTf)2].
Finally, three aminolyses were performed on an
aliphatic epoxide, namely cyclohexene oxide (entries
9–11). Good yields were achieved (53–76%), taking into
account that aliphatic epoxides are less reactive than
the aromatic ones. In addition, the aminolysis of cyclo-
hexene oxide by aniline was achieved using other zinc
salts as catalysts, i.e. zinc(II) bromide and zinc(II)
perchlorate under the same experimental conditions
(Table 1, entry 9). ZnBr2 led to 71% conversion while
85% of the epoxide was opened with Zn(ClO4)2. Fur-
ther investigations are currently in progress to improve
these catalytic activities.
11. General procedure: A mixture of the epoxide (5 mmol),
the amine (5 mmol), 2-bromotoluene (5 mmol, 855 mg;
internal GC standard), and zinc chloride (0.25 mmol, 34
mg) in acetonitrile (20 mL) was stirred under reflux under
air for 12 h. After this reaction time, the reaction mixture
was filtered under reduced pressure over a small quantity
of silica. The filtrate was concentrated in vacuo and
1
analyzed by GC and H NMR.
12. 3a: l 3.74 (dd, J=11.0, 7.8 Hz, 1H), 3.92 (dd, J=11.0,
4.4 Hz, 1H), 4.52 (dd, J=7.8, 4.4 Hz, 1H), 6.5–7.5 (m,
10H) ppm; 3b: l 3.5–3.9 (m, 2H), 3.45 (dd, J=6.7, 4.1
Hz, 1H), 6.9–7.4 (m, 9H) ppm; 3c: l 0.95 (t, J=7.0 Hz,
6H), 1.2–1.4 (m, 8H), 3.78 (dd, J=11.0, 7.7 Hz, 1H), 3.90
(dd, J=10.8, 4.7 Hz, 1H), 4.52 (dd, J=7.7, 4.7 Hz, 1H),
6.7–7.2 (m, 5H) ppm; 3d: l 3.55 (dd, J=10.6, 8.6 Hz,
1H), 3.59 (d, J=12.9 Hz, 1H), 3.7 (dd, J=10.6, 4.3 Hz,
1H), 3.77 (d, J=12.9 Hz, 1H), 3.82 (d, J=4.3 Hz, 1H),
7.0–7.6 (m, 10H) ppm; 3e: l 1.16 (t, J=9.0 Hz, 3H),
3.8–4.1(m, 3H), 4.2 (q, J=9.0 Hz, 2H), 4.65 (d, J=6.8
Hz, 1H), 6.9–7.5 (m, 10H) ppm; 3f: l 0.91 (t, J=7.0 Hz,
6H), 1.10–1.4 (m, 7H), 2.2–2.4 (m, 4H), 3.45 (d, J=13.8
Hz, 1H), 4.09 (d, J=13.8 Hz, 1H), 4.18 (q, J=9.0 Hz,
2H), 4.65 (d, J=11 Hz, 1H), 7.28–7.40 (m, 5H) ppm; 3g:
l 1.15 (t, J=8.9 Hz, 3H), 3.35 (d, J=13.9 Hz, 1H), 3.9
(d, J=13.9 Hz, 1H), 4.11 (d, J=6.7 Hz, 1H), 4.22 (q,
J=8.9 Hz, 2H), 4.85 (br s, 1H), 7.25–7.43 (m, 10H) ppm;
trans-3h: l 1.0 (m, 1H), 1.34 (m, 3H), 1.76 (m, 2H), 2.1
(m, 2H), 2.80 (ddd, J=10.6, 9.8, 3.8 Hz, 1H), 3.3 (ddd,
J=9.9, 9.8, 4.6 Hz, 1H), 6.75 (m, 3H), 7.1 (m, 2H) ppm;
trans-3i: l 0.90 (t, J=7.2 Hz, 6H), 1.1–1.4 (m, 7H),
1.6–1.8 (m, 4H), 2.12 (m, 1H), 2.2–2.4 (m, 4H), 3.31 (m,
1H), 4.07 (s, 1H) ppm; trans-3j: l 1.08 (m, 1H), 1.34 (m,
3H), 1.40 (s, 2H), 1.79 (m, 2H), 2.1 (m, 2H), 2.85 (ddd,
J=10.4, 9.7, 3.8 Hz, 1H), 3.3 (ddd, J=9.9, 9.7, 4.5 Hz,
1H), 7.06 (m, 5H) ppm.
In summary, a simple and regioselective zinc-catalyzed
aminolysis of aromatic or aliphatic epoxides performed
under air is reported with good to very high yields. The
use of 2-(aminomethyl)pyridine as the nucleophilic
amine showed the possibility of catalyzing the ring
opening by a zinc/pyridine-containing ligand complex.
Consequently, the reaction involving bipyridine-derived
ligands is currently under investigation and the result-
ing fine-tuning of the catalyst is expected to allow
optimization of the activity, especially in the case of
ethyl 3-phenylglycidate. Furthermore, enantioselective
zinc-catalyzed aminolysis is now being studied.
Acknowledgements
Financial support from COST Action D21/003/2001
and the Dutch National Research School Combination
Catalysis (HRSMC and NIOK) is gratefully
acknowledged.
References
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hedron Lett. 1997, 38, 861–864.