Highly chemoselective addition of amines to epoxides in water

Article abstract of DOI:10.1021/ol051220q

(Chemical Equation Presented) Aminolysis of a variety of epoxides by aliphatic and aromatic amines in water, in the absence of any catalyst with high yields, is reported. β-Amino alcohols were formed under mild conditions with high selectivity and in excellent yields.

Full text of DOI:10.1021/ol051220q

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3649-3651
Highly Chemoselective Addition of
Amines to Epoxides in Water
Najmodin Azizi and Mohammad R. Saidi*
Department of Chemistry, Sharif UniVersity of Technology, P.O. Box 11465-9516,
Tehran, Iran
saidi@sharif.edu
Received May 24, 2005
ABSTRACT
Aminolysis of a variety of epoxides by aliphatic and aromatic amines in water, in the absence of any catalyst with high yields, is reported.
-Amino alcohols were formed under mild conditions with high selectivity and in excellent yields.
â
â-Amino alcohols are important organic compounds of
considerable use in medicinal chemistry, amino acids, and
chiral auxiliaries.1 One of the most practical and widely used
routes for the synthesis of these compounds is the direct
aminolysis of epoxides at elevated temperature with an
excess of amine.2 Recently, several methods using promoters
or catalysts in different organic solvents3 have been reported.
These include supercritical carbon dioxide (scCO2),4a mi-
crowave irradiation,4b hexafluoro-2-propanol,4c ionic liquid,4d
Bi(OTf)3 in water,4e and solvent-free conditions.4f,g
However, there are some limitations with these method-
ologies such as elevated temperatures, use of stoichiometric
or moisture-sensitive catalyst, and hazardous organic sol-
vents. By contrast, there is no report of the aminolysis of
epoxides in water without using any catalyst.4e
The preparation of â-amino alcohols in water is desirable,
since using water instead of an organic solvents has become
more important due to environmental considerations in recent
years.5
Herein, we wish to report the ring-opening of epoxides
with a variety of amines in water at room temperature.6
Treatment of epoxide 1 with 1.2 equiv of amine 2 resulted
in formation of the â-amino alcohol 3. The reactions were
(3) (a) Chini, M.; Crotti, P.; Macchia, F. Tetrahedron Lett. 1990, 31,
4661-4664. (b) Yamamoto, Y.; Asao, N.; Meguro, M.; Tsukade, N.;
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Commun. 1993, 1201-1203. (c) Meguro, M.; Asao, N.; Yamamoto, Y. J.
Chem. Soc., Perkin Trans. 1 1994, 2597-2601. (d) Sekar, G.; Singh, V.
K. J. Org. Chem. 1999, 64, 287-289. (e) Sagava, S.; Abe, H.; Hase, Y.;
Inaba, T. J. Org. Chem. 1999, 64, 4962-4965. (f) Curini, M.; Epifano, F.;
Marcotullio, M. C.; Rosati, O. Eur. J. Org. Chem. 2001, 4149-4152. (g)
Fagnou, K.; Lautens, M. Org. Lett. 2000, 2, 2319-2321. (h) Pacho’n, L.
D.; Gamez, P.; van Bassel, J. J. M.; Reedijk, J. Tetrahedron Lett. 2003,
44, 6025-6027. (i) Chakraborti, A. K.; Kondaskar, A. Tetrahedron Lett.
2003, 44, 8315-8319. (j) Zhao, P.-Q.; Xu, L.-W.; Xia, C.-G. Synlett 2004,
846-850. (k) Fan, R.-H.; Hou, X.-L. J. Org. Chem. 2003, 68, 726-730.
(l) Kamal, A.; Ramu, R.; Amerudin Azhar, M.; Ramesh Khanna, G. B.
Tetrahedron Lett. 2005, 46, 2675-2677. (m) Carree, F.; Gil, R.; Collin, J.
Tetrahedron Lett. 2004, 45, 7749-7751. (n) Sundrarajan, G.; Vijayakrishna,
K.; Varghese, B. Tetrahedron Lett. 2004, 45, 8253-8256. (o) Rodriquez,
J. R.; Navarro, A. Tetrahedron Lett. 2004, 45, 7495-7498.
(1) (a) Ager, D. J.; Prakash I.; Schaad, D. R. Chem. ReV. 1996, 96, 835-
876. (b) Bonini, C.; Righi, G. Synthesis 1994, 225-238. (c) Gehlert, D.
R.; Goldstein, D. J.; Hipskind, P. A. Ann. Rep. Med. Chem. 1999, 201-
210. (d) Corey, E. J.; Zhang, F. Angew. Chem., Int. Ed. 1999, 38, 1931-
1934. (e) Johannes, C. W.; Visser, M. S.; Weatherhead, G. S.; Hoveyda,
A. H. J. Am. Chem. Soc. 1998, 120, 8340-8347. (f) Chng, B. L.; Ganesan,
A. Bioorg. Med. Chem. Lett. 1997, 7, 1511-1514. (g) Bloom, J. D.; Dutia,
M. D.; Johnson, B. D.; Wissner, A.; Burns, M. G.; Largis, E. E.; Dolan, J.
A.; Claus, T. H. J. Med. Chem. 1992, 35, 3081-3084. (h) O’Brien, P.
Angew. Chem., Int. Ed. 1999, 38, 326-329. (i) Li, G.; Chang, H.-T.;
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ComprehensiVe Organic Synthesis; Mitsunobu, O., Winterfeldt, E., Ed.;
Pergamon: New York, 1996; Vol. 6, Part 1.3.4.1. (d) Crooks, P. A.;
Szyudler, R. Chem. Ind. (London) 1973, 1111-1112. (e) Deyrup, J. A.;
Moyer, C. L. J. Org. Chem. 1969, 34, 175-179. (f) Freifelder, M.; Stone,
G. R. J. Org. Chem. 1961, 26, 1477-1480. (g) Mousseron, M.; Jullien, J.;
Jolchine, Y. Bull. Soc. Chim. Fr. 1952, 757-766. (h) Lutz, R. E.; Freekand,
J. A.; Murphy, R. S. J. Am. Chem. Soc., 1948, 70, 2015-2023.
(4) (a) Surendra, K.; Krishnaveni, N. S.; Rao, K. R. Synlett 2005, 506-
510. (b) Mojtahedi, M. M.; Saidi, M. R.; Bolourtchian, M. J. Chem. Res.,
Synop. 1999, 128-129. (c) Das, U.; Crousse, B.; Kesavan, V.; Bonnet-
Delpon, D.; Be’gue’, J.-P. J. Org. Chem. 2000, 65, 6749-6751. (d) Yadav,
J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V. Tetrahedron Lett.
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10.1021/ol051220q CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/28/2005

Table 1. Reactions of Aliphatic Epoxides with Aliphatic
Amines in Water
carried out with a very simple procedure in water at room
temperature without adding any organic solvent or catalyst.
In some cases, the â-amino alcohols precipitated from the
solution and were separated by a simple filteration. Other-
wise, they were extracted from the aqueous solution by
diethyl ether.
To show the generality and scope of this new protocol,
structurally diverse amines were treated with various ep-
oxides. In general, the reaction rate of aminlolysis in water
depends on the structure of the epoxide and on the nucleo-
philicity of the amines. The results are summarized in (Tables
1 and 2). The data in Table 1 clearly show that the reaction
of aliphatic amines with different epoxides in water gives
the corresponding â-amino alcohols in high yield and in a
regioselective manner. The advantage of this procedure over
the reported methods is the formation of the â-amino alcohols
from attack at the terminal carbon of the epoxides (with the
exception of styrene oxide) as the only product.3,4 The
procedure of these reactions is very simple, and the yields
are generally high.8 To the best of our knowledge, these
results represent the highest regioselectivity reported to date
for nucleophilic ring opening of epoxide with amines.
(6) (a) Azizi, N.; Saidi, M. R. Organometallics 2004, 23, 1457-1458.
(b) Azizi, N.; Saidi, M. R. Tetrahedron 2004, 60, 383-387. (c) Azizi, N.;
Saidi, M. R. Eur. J. Org. Chem. 2003, 4630-4633. (d) Azizi, N.; Saidi,
M. R. J. Organomet. Chem. 2003, 688, 283-285. (e) Azizi, N.; Rajabi, F.;
Saidi, M. R. Tetrahedron Lett. 2004, 45, 9233-9236.
3650
Org. Lett., Vol. 7, No. 17, 2005

Table 2. Reaction of Styrene Oxide with Amines in Water
entry
amine
aniline
p-isopropylaniline
PhCH2NH2
n-BuNH2
tert-BuNH2
diallylamine
sec-BuNH2
cyclohexylamine
piperidine
yield (%)
ratio A:B
entry
amine
yield (T)
ratioa A:B
1
2
3
4
5
6
7
8
9
97
94
88
94
92
90
86
92
96
96
96:4
11
12
13
14
15
16
17
18
19
pyrrolidine
Et2NH
93
92
35:65
24:76
90:10
70:30
25:75
8:92
30:70
21:79
20:80
35:65
10:90
Et2NHb
Et2NHc
Et2NHd
Et2NHe
Et2NHf
Et2NHg
Et2NHh
0.0
0.0
0.0
0.0
50
45:55
0.0
0.0
10
morpholine
a Regioselectivity was determined by NMR spectra. b CH2Cl2. c CH3CN. d Hexane. e Toluene. f Ethanol. g Diethyl ether. h Solvent-free.
Additions of aromatic amines such as aniline and 4-ni-
troaniline to alkyl epoxides are sluggish and give very low
yields with the exception of styrene oxide. Therefore, the
low reactivity of aromatic amines such as aniline shows the
chemoselectivity in the addition of aliphatic amines to
epoxides with this method. To show the chemoselectivity,
cyclohexene oxide was treated with the mixture of aniline
and piperidine. Analysis of the mixture after 10 h shows that
only piperidine reacted with cyclohexene oxide (Scheme 1).
A as the major regioisomer, by nucleophilic attack at the
benzylic carbon. In the case of aliphatic amines, preferential
attack occurs at the terminal carbon, and the major product
is regioisomer B (Table 2). For the sake of comparison,
opening reactions of styrene oxide with diethylamine were
carried out in the classic way in different organic solvents
and under solvent-free conditions at room temperature. In
common organic solvents (CH2Cl2, CH3CN, toluene, and
hexane) under solvent-free conditions and without using a
catalyst, the reaction does not take place after 2 days.
However, in the case of protic solvents such as ethanol, the
reaction gives up to 50% of the product after 1 day.
The role of the water as reaction medium is still not clear.
Hydrophobic and hydrogen bonding interactions and polarity
are the main factors that influence the reactivity and
selectivity of the process. We propose an SN2 mechanism
for these processes by comparison of the reaction conditions
with those reported in the literature.7 We are currently
investigating the mechanism of the reaction of styrene oxide
in aqueous medium.
Scheme 1. Chemoselective Addition of Aliphatic Amines in
the Presence of Aromatic Amines
Aniline and p-isopropylaniline react with styrene oxide and
give high yields of the corresponding â-amino alcohols.
On the other hand, treatment of styrene oxide with different
aromatic, aliphatic, and hindered amines gives a mixture of
two regioisomers, A and B, in high yields (Table 2).
Aminolysis of styrene oxide with aromatic amines afforded
In summary, we have demonstrated an economical and
practical method for the synthesis of a wide range of â-amino
alcohols under mild conditions in water. In light of its
operational simplicity, simple purification procedure, high
yields, complete regioselectivity (except styrene oxide),
ability to proceed without a catalyst, and environmentally
friendly conditions, this protocol is superior to the existing
methods.
(7) Amantini, D.; Fringuelli, F.; Piermatti, O.; Torttoioli, S.; Vaccaro,
L. ArkiVoc 2002, 293-311.
(8) General Procedure for the Synthesis of â-Amino Alcohols. An
epoxide (5 mmol) and water (2 mL) were placed in a test tube equipped
with a magnetic stirrer. Then, an amine (6 mmol) was added in one portion,
and the test tube was kept at room temperature under vigorous magnetic
stirring for 5-24 h. The reaction was monitored with TLC. Then, water (2
mL) was added, and the organic materials were extracted with diethyl ether
(2 × 10 mL). The organic layer was separated and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure to give the
â-amino alcohols in the almost pure form. The crude product was analyzed
by GC and 1H and 13C NMR. In some cases, further purification was carried
out by short-column chromatography on silica gel (ethyl acetate/petroleum
ether).
Acknowledgment. We are grateful to the Research
Council of Sharif University of Technology for financial
support.
Supporting Information Available: General experimen-
tal procedure for opening the epoxide ring in water and
1
copies of H NMR and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL051220Q
Org. Lett., Vol. 7, No. 17, 2005
3651