Regioselective synthesis of N-β-hydroxyethylaziridines by the ring-opening reaction of epoxides with aziridine generated in situ

Article abstract of DOI:10.1021/ol0529703

Biologically important N-β-hydroxyethylaziridine intermediates were conveniently prepared by regioselective ring-opening reactions of diversely substituted epoxides. Ethyleneimine generated in situ under basic conditions from β-chloroethylamine was used a

Full text of DOI:10.1021/ol0529703

ORGANIC
LETTERS
2
006
Vol. 8, No. 6
085-1087
Regioselective Synthesis of
N- -Hydroxyethylaziridines by the
Ring-Opening Reaction of Epoxides with
Aziridine Generated in Situ
1
â
Ha Young Kim, Arindam Talukdar, and Mark Cushman*
Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue
Cancer Center, School of Pharmacy and Pharmaceutical Sciences, Purdue UniVersity,
West Lafayette, Indiana 47907
cushman@pharmacy.purdue.edu
Received December 8, 2005
ABSTRACT
Biologically important N-â-hydroxyethylaziridine intermediates were conveniently prepared by regioselective ring-opening reactions of diversely
substituted epoxides. Ethyleneimine generated in situ under basic conditions from
â-chloroethylamine was used as a nucleophile to open the
epoxides in an aqueous environment.
Aziridines are recognized as some of the most versatile
synthetic intermediates in organic synthesis and for their
importance in nitrogen-containing biologically active com-
compounds and imines, and â-amino alcohol derivatives via
2
,3
intramolecular cyclization reactions. Although ethylene-
imine is a direct source of substituted aziridines, its use is
limited by its severe acute toxicity, explosion hazard,
decomposition during storage, and instability toward violent
1
pounds. Furthermore, N-â-hydroxyethylaziridines are one
of the key types of precursors in the synthesis of natural
and unnatural amino acids, â-blockers, and â-amino alcohols.
Due to their significant position in synthetic organic chem-
istry, diverse synthetic methodologies have been reported
for the preparation of aziridines.2 Generally, aziridines are
prepared from diazoacetates via ylide intermediates, olefins,
direct conversion of epoxides, methylene transfer to carbonyl
4
polymerization.
The purpose of the present investigation was to synthesize
N-â-hydroxyethylaziridines by ring opening of epoxides with
ethyleneimine generated in situ from â-chloroethylamine. If
successful, this would avoid the toxicity and polymerization
problems associated with the direct use of ethyleneimine.4
Additional advantages of this approach include employment
of a limited number of steps, safety, and exploitation of the
,3
(1) (a) Martindale. The Extraphamacopoeic, 29th ed.; The Pharmaceutical
Press: London, 1989; p 6314. (b) Heel, R. C. Drugs 1979, 71, 425. (c)
Schubert, J.; Schwesinger, R.; Prinzbach, H. Angew. Chem., Int. Ed. Engl.
5
desirable properties of water as a solvent.
1
984, 23, 167. (d) Hu, X. E. Tetrahedron 2004, 60, 2701. (e) Mueller, P.;
Benzyl (S)-(+)-glycidyl ether (Scheme 1) was tested to
determine optimal reaction conditions for subsequent use in
the ring-opening reactions of diverse epoxide substrates
(Table 1). The epoxide was heated at 90 °C with 3.0 or 2.0
equiv (entries 1 and 2) of 2-chloroethylamine hydrochloride
Fruit, C. Chem. ReV. 2003, 103, 2905. (e) Kim, B. M.; Bae, S. J.; So, S.
M.; Yoo, H. T.; Chang, S. K.; Lee, J. H.; Kang, J. S. Org. Lett. 2001, 3,
2
439.
2) (a) Concell o´ n, J. M.; Riego, E.; Rivero, I. A.; Ochoa, A. J. Org.
Chem. 2004, 69, 6244. (b) Doyle, M. P.; Hu, W.; Timmons, D. Org. Lett.
(
2
1
001, 3, 933. (c) Baird, C. P.; Taylor, P. C. J. Chem. Soc., Perkin Trans.
1998, 3399. (d) Yamauchi, Y.; Kawate, T.; Katagiri, T.; Uneyama, K.
Tetrahedron 2003, 59, 9839. (e) Tanner, D.; Groth, T. Tetrahedron 1997,
5
2
3, 16139. (f) Tsuchiya, Y.; Kumamoto, T.; Ishikawa, T. J. Org. Chem.
004, 69, 8504.
(4) (a) Wystrach, V. P.; Kaiser, D. W.; Schaefer, F. C. J. Am. Chem.
Soc. 1955, 77, 5915. (b) Wystrach, V. P.; Kaiser, D. W.; Schaefer, F. C. J.
Am. Chem. Soc. 1956, 78, 1263.
(3) (a) Osborn, H. M. I.; Sweeney, J. Tetrahedron: Asymmetry 1997,
1
8, 1693. (b) Atkinson, R. S. Tetrahedron 1999, 55, 1519. (c) Xu, J.
(5) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275.
Tetrahedron: Asymmetry 2002, 13, 1129.
1
0.1021/ol0529703 CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/24/2006

nitrogen and the carbinol carbon appeared at lower field as
doublets of doublets at δ 2.25 (dd, J ) 4.8 and 12.0 Hz, 1
H) and at δ 2.40 (dd, J ) 6.9 and 12.0 Hz, 1 H). The basic
pattern of four separate signals observed for the aziridine
protons did not change on conversion of the product to its
TMS ether. This indicates that intramolecular hydrogen
bonding between the hydroxyl group and the aziridine
nitrogen is not responsible for the observation of four separate
signals for the aziridine protons.
Scheme 1
and excess aqueous sodium hydroxide to afford the substi-
tuted N-â-hydroxyethylaziridine (Scheme 1) as the major
product in 67% and 60% yields, respectively.
The reaction mechanism likely involves in situ formation
of ethyleneimine, which then participates in the regioselective
ring opening reaction of the epoxide to produce the â-N-
hydroxyethylaziridine product. As can be seen in Table 1,
the use of excess sodium hydroxide relative to 2-chloro-
ethylamine hydrochloride afforded the desired product,
whereas the use of equimolar amounts of sodium hydroxide
and 2-chloroethylamine hydrochloride resulted in only a trace
amount of the aziridine product detected by TLC (entry 3).
Two equivalents of base are required, one to deprotonate
the starting material and one to neutralize the hydrochloric
acid generated in the aziridine ring closure reaction (Scheme
2). As expected, the product was optically active, producing
Table 1. Optimization Reactions with 2-Chloroethylamine
Hydrochloride in Aqueous Dioxane Solution or in Organic
Solventsa
2
-chloroethyl-
amine
b
hydrochloride
(equiv)
NaOH or
base (equiv)
yield
(%)
entry
solvent (°C)
1
2
3
4
5
6
7
8
3.0
NaOH (6.0) water/dioxane (90) 67
c
2.0
NaOH (4.0) water/dioxane (90) 60
1.5
NaOH (1.5) water/dioxane (90) trace
NaOH (2.1) water/dioxane (90) 43
NaOH (3.0) water/dioxane (90) 22
1.05
d
1.5
2.0
2.0
2.0
Et
Et
3
N (4.0)
N (4.0)
water/dioxane (100) trace
3
DMF (90 to 100)
20
not
t-BuOH (4.0) THF (70)
Scheme 2
e
e
detected
not
detected
9
2.0
NaH (4.0) DMSO (70)
a
Each reaction mixture was stirred for 12 h at 90 °C. b Reaction yield
refers to the pure products isolated after flash column chromatography.
c
d
Reaction was performed with 0.1 equiv of NaI additive. 2-Bromoeth-
e
ylamine hydrochloride was used instead of 2-chloroethylamine. No desired
product was obtained.
The use of 2-bromoethylamine hydrochloride instead of
-chloroethylamine hydrochloride (entry 5) did not improve
an optical rotation [R]23
compares favorably with the [R]
value of the substituted (R)-N-â-hydroxyethylaziridine ob-
tained from the reaction of its enantiomer, (-)-benzyl (R)-
glycidyl ether, following the same reaction procedure
outlined in Scheme 1.
) -11.9 (c 1, CHCl
), which
) +11.9 (c 1, CHCl
2
D
3
2
3
D
3
)
the yield. The best result was obtained from a mixed solvent
system prepared from equal volumes of dioxane and aqueous
sodium hydroxide. Reactions in organic solvents with bases
such as triethylamine or potassium tert-butoxide or sodium
hydride provided poor yields or no detectable product. In
general, it was necessary to include dioxane in the solvent
because of the limited solubility of the epoxide in water.
The ring opening reaction of epoxides using substrates with
different substituents was examined next, employing the
optimal reaction conditions determined from the study
reported in Table 1. The reaction of p-chlorostyrene epoxide
(entry 2, Table 2) provided the N-â-hydroxyethylaziridine
product in higher yield (83%) than was obtained with the
styrene substrate (65%, entry 3).
1
6
The H NMR spectrum of the substituted N-â-hydroxy-
ethylaziridine obtained as described in Scheme 1 exhibited
separate signals for each of the four aziridine protons as well
as the two protons of the methylene group located between
the nitrogen and the carbinol carbon. Two upfield aziridine
protons occurred as doublets of doublets at δ 1.16 (dd, J )
In the case of epoxides fused to carbocyclic rings (entries
3
.9 and 7.5 Hz, 1 H) and 1.23 (dd, J ) 3.9 and 7.5 Hz, 1
H), while two lower field aziridine protons appeared as
apparent triplets at 1.74 (dd, J ) 3.9, 5.7 Hz, 1 H) and 1.78
dd, J ) 3.9, 5.8 Hz, 1 H). There was no apparent geminal
coupling of the aziridine protons. On the other hand, the two
protons on the methylene groups located between the
4
and 5), the results were similar to each other regardless of
the difference in ring size. The C -symmetric substrate trans-
2
stilbene oxide (entry 6) provided the aziridine product in 65%
yield, close to that of the two epoxides fused to carbocycles.
Similarly, the ring-opening reactions of two epoxides sub-
stituted with straight hydrocarbon chains (entries 7 and 8)
afforded yields that were similar to the others. The formation
of byproducts was generally low (<5%). In some cases,
epoxide hydrolysis products were detected.
(
1
1
(
6) The H NMR spectrum was obtained using CDCl3. H and 13C NMR
spectra and mass and elemental analysis data are available in the Supporting
Information.
1086
Org. Lett., Vol. 8, No. 6, 2006

Table 2. Regioselective Ring Opening of Epoxides with
Ethyleneimine Generated in Situ in the Same Reaction Pota,b
Scheme 3
the conditions previously reported for the synthesis of
aziridine from 2-choroethylamine in aqueous sodium hy-
4
droxide. Furthermore, the 65% yield reported for entry 3
(Table 2) is comparable to the 48% yield reported for the
reaction of aziridine with styrene epoxide in aqueous solution
8
at 100 °C.
In cases for which regioisomeric reaction products are
possible, only one regioisomer was isolated as evidenced by
1
the H NMR spectral data. The observed regioisomers were
consistently derived from nucleophilic attack of the aziridine
nitrogen atom on the less-substituted carbon atom of the
epoxide. It is possible that small amounts of the other
regioisomers might have formed but were removed during
purification of the product.
In conclusion, we have established a regioselective ring
opening reaction of epoxides to yield â-hydroxy aziridines
by in situ generation of ethyleneimine using a mixed solvent
system of aqueous sodium hydroxide and 1,4-dioxane. The
formation of ethyleneimine likely occurs prior to ring opening
of epoxide. This protocol offers the advantage of avoiding
the use of ethyleneimine as a starting material in the synthesis
8
,9
of N-â-hydroxyethylaziridines.
a
Reactions proceeded in a 1:2:4 molar ratio of epoxide/2-chloroethyl-
amine hydrochloride/NaOH. A stock solution of sodium hydroxide was
prepared by dissolving 40 g of NaOH in 60 mL of water. Typically, the
Acknowledgment. This work was made possible by the
National Institutes of Health (NIH) through support by RCE
Award U54 AI57153 and RO1 Grant GM51469. This
research was conducted in a facility constructed with support
from Research Facilities Improvement Program Grant Num-
ber C06-14499 from the National Center for Research
Resources of the National Institutes of Health. We thank Prof.
Philip L. Fuchs, Department of Chemistry, Purdue Univer-
sity, for insightful discussions and suggestions during this
study.
b
reaction mixture was heated at 90 °C for 12 h in a 1:1 volume ratio of
c
water/1,4-dioxane. Reaction yield refers to the isolated pure products
d
obtained after flash column chromatography. Reaction proceeded in a 1:3:6
molar ratio of epoxide/2-chloroethylamine/NaOH.
A comparison experiment7 was conducted with pure
ethyleneimine and benzyl (S)-(+)-glycidyl ether using the
optimal reaction condition (Scheme 3). The expected ring-
opened product displayed the same NMR spectrum as the
substance obtained as described in the Scheme 2. In this
reaction, the yield after purification was 69%, similar to those
listed in Table 2. This result is consistent with the mecha-
nistic pathway involving formation of aziridine from 2-chlo-
roethylamine prior to nucleophilic ring opening of the
epoxide. The formation of aziridine from 2-chloroethylamine
in the reaction mixtures studied here is also consistent with
Supporting Information Available: Spectral data for all
compounds along with detailed experimental procedures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0529703
(8) Funke, A.; Benoit, G. Bull. Soc. Chim. Fr. 1953, 1021.
(
9) (a) Rooney, C. S.; Stuart, R. S.; Watson, B. K.; Williams, H. W. R.
(
7) The reaction was carried out in a 1:2:4 molar ratio of epoxide/
Can. J. Chem. 1974, 53, 2279. (b) Webb, P.; Threadgill, M. D. J. Labelled
Compd. Radiopharm. 1990, 28, 257. (c) Sova, A. N.; Sal’nikova, S. I.;
Gella, I. M.; Aliev, A. E.; Kostyanovsky, R. G. Khim.-Farm. Zh. 1989, 23,
1088. (d) Naylor, M. A.; Stephens, M. A.; Cole, S.; Threadgill, M. D.;
Stratford, I. J.; O’Neill, P.; Fielden, E. M.; Adams, G. E. J. Med. Chem.
1990, 33, 2508.
ethyleneimine/NaOH with heating at 90 °C for 12 h in a mixed solvent
system of water and 1,4-dioxane (1:1). Total water volume, including water
volume used in aqueous NaOH solution, was adjusted to the same solvent
volume of 1,4-dioxane used in the reaction. A stock solution of sodium
hydroxide was prepared by dissolving 40 g of NaOH in 60 mL of water.
Org. Lett., Vol. 8, No. 6, 2006
1087