Highly efficient regioselective ring openings of N-tosylaziridines to haloamines using ferric (III) halides

Article abstract of DOI:10.1016/j.cclet.2014.03.033

FeX₃ (X = Cl, Br) were found to be very effective reagents and powerful catalysts for regioselective ring openings of a variety of N-tosylaziridines with them to afford the corresponding β-haloamines in good to excellent yields with high regios

Full text of DOI:10.1016/j.cclet.2014.03.033

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CCLET-2919; No. of Pages 5
Chinese Chemical Letters xxx (2014) xxx–xxx
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Chinese Chemical Letters
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Original article
Highly efficient regioselective ring openings of N-tosylaziridines to
haloamines using ferric (III) halides
*
Xing Li, Zhi-Qin Sun, Hong-Hong Chang, Wen-Long Wei
Department of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, China
A R T I C L E I N F O
A B S T R A C T
Article history:
FeX3 (X = Cl, Br) were found to be very effective reagents and powerful catalysts for regioselective ring
Received 11 December 2013
Received in revised form 18 February 2014
Accepted 26 February 2014
Available online xxx
openings of a variety of N-tosylaziridines with them to afford the corresponding
b-haloamines in good to
excellent yields with high regioselectivity under mild conditions. At the same time, 13 new compounds
were obtained firstly. Moreover, the
with NaNO2 in moderate yield.
b-bromoamine prepared could be transferred into b-nitroamine
ß 2014 Wen-Long Wei. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
Keywords:
reserved.
Ring-opening
N-Tosylaziridine
Haloamine
Ferric (III) halide
Regioselectivity
1. Introduction
of aziridines still remains important and challenging. At the same
time, the discovery of novel catalysts and the development of new
Aziridines have been demonstrated to be valuable building
blocks in organic synthesis due to their reactivity and versatility
[1–9]. Their high ring strain energy endows them with high
reactivity and enables easy ring cleavage with various nucleo-
philes. The use of halides as nucleophiles leads to the formation of
methods that make use of mild experimental conditions and
readily available and inexpensive halides are highly desirable. Iron
is one of the most abundant metals on earth, and consequently one
of the most inexpensive and environmentally friendly ones to use.
Its salts are more practical catalysts compared to traditional Lewis
acids in several carbon-carbon bond forming reactions and have
found wide applications in organic synthesis [27,28]. Herein, we
will report a highly regioselective and efficient Fe(III) halide-
promoted ring-opening reactions of N-tosylaziridines with readily
b
-haloamines, which are versatile synthetic intermediates for the
synthesis of functional materials and biologically active com-
pounds. The direct conversion of aziridines into the corresponding
b
-haloamines has previously been reported with a variety of
halides. They are HCl [10–13], ZnX2 (X = Cl, Br, I) [14], MgBr2
[15,16], NaX (X = Br, I) [16], CeCl3ꢀ7H2O/NaI [17], indium trihalides
[18], LiX/Amb15 (X = Cl, Br, I) [19], BF3ꢀOEt2 as a fluorine source
[20], iodine/thiophenol [21], zirconyl chloride [22], PPh3/haloge-
nating agent [23], tetrabutylammonium halides in the presence of
available Fe(III) halides to give b-haloamines in good to excellent
yields with better substrate scope.
2. Experimental
b
-cyclodextrin [24], an activated DMF complex [25] and BF3ꢀOEt2/
tetraalkylammonium halides, respectively [26]. Although these
limited synthetic approaches have made significant progress and
provided some value in the past few years, most of these
methodologies suffer from disadvantages such as narrow substrate
scope, low regioselectivity, long reaction times, formation of other
inseparable regioisomers, and high temperature. Hence, the study
of efficient, highly regioselective and stereoselective ring openings
Typical procedure for the synthesis of chloroamines: A reaction
mixture of well-stirred N-tosylaziridine 1 (0.2 mmol) and FeCl3
(40 mol% or 50 mol%) in CH2Cl2 (2.5 mL) was stirred at the
specified temperature for a period of time under air atmosphere
(Scheme 1). After the reaction was completed, which was
monitored by TLC, the reaction mixture was concentrated under
vacuum, and the resultant crude mixture was purified by column
chromatography on silica gel with petroleum ether/ethyl acetate
to give the corresponding pure chloroamines 2 and 3.
The experimental procedure for the synthesis of bromoamines
is the same as that for the synthesis of chloroamines.
*
Corresponding author.
E-mail address: weiwenlong@tyut.edu.cn (W.-L. Wei).
http://dx.doi.org/10.1016/j.cclet.2014.03.033
1001-8417/ß 2014 Wen-Long Wei. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: X. Li, et al., Highly efficient regioselective ring openings of N-tosylaziridines to haloamines using ferric
(III) halides, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.033

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X. Li et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
R2
Table 1
NHTs
Cl
Cl
R2
R1
R2
R1
FeCl3 (40 or 50 mol%)
CH2Cl2 (2.5 mL), 25 o
1 (0.2 mmol)
Screening of reaction conditions for ring openings of N-tosylcyclohexylaziridine 1a
with anhydrous chloride source.a
N-Ts
+
C
NHTs
R1
Cl
chloride
NTs
3
2
solvent
NHTs
Scheme 1. Ring openings of N-tosylaziridines 1 with FeCl3.
1a
2a
Entry Chloride Solvent T (8C)
Amount of Solvent t (h) Yield
source
chloride
(equiv.)
dosage
(mL)
(%)b
Br
NO2
65 oC, DMSO
1
2
AlCl3
MgCl2
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
CH2Cl2
CH2Cl2
CH2Cl2
THF
25
25
25
25
25
35
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.5
1.5
2.5
12
16
Trace
75
NaNO2
NHTs
NHTs
3
0.5
81
4a
6a
4
12
12
N.D.c
N.D.
83
5
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Scheme 2. Nucleophile substitution of 4a with NaNO2.
6
0.5
7
Reflux 2.0
0.5
0.5
0.5
1.5
7.5
3
86
8
25
25
25
25
25
25
25
1.5
1.0
0.5
0.4
0.4
0.4
0.5
89
9
92
10
11
12
13
14
94
Typical procedure for the synthesis of 6a: A mixture of
b-
93
bromoamine 4a (0.2 mmol) and NaNO2 (0.3 mmol, 1.5 equiv.) in
DMSO (1.2 mL) was stirred under air atmosphere at 65 8C for 4 h
(Scheme 2). After the complete conversion monitored by TLC, the
reaction mixture was diluted with water (10 mL) and extracted
with ether (2 ꢁ 15 mL). The combined organic layers were dried
over anhydrous Na2SO4, concentrated in vacuum and the resulting
product was purified by column chromatography on silica gel
(200–300 mesh, ethyl acetate/petroleum ether, 1:4) to afford pure
6a.
94
5
88
1.5
98
a
Unless otherwise noted, all reactions were performed with N-tosylcyclohex-
ylaziridine 1a (0.2 mmol) under specified conditions.
b
Isolated yields after column chromatographic purification.
c
N.D. = not detected.
The physical and spectral data and spectra of 1H NMR, 13C NMR
and HRMS of all products are given in Supporting information.
reaction worked equally well with both aliphatic and aromatic N-
tosylaziridines, and the corresponding products were provided in
good to excellent yields with high regioselectivity (Table 2). The
important feature of the reaction is its high regioselectivity. Both
cyclic and acyclic alkenes-derived aliphatic N-tosylaziridines
proceeded smoothly with FeCl3 and FeBr3 affording only one
regioisomer 2 or 4, respectively, in excellent yields, and the
formation of the other regioisomers 3 or 5 was not observed
(Table 2, entries 1–4). The ring opening reactions of cyclic N-
tosylaziridines were completely anti-stereoselective, giving only
the trans isomers. Acyclic terminal N-tosylaziridines gave high
regioselectivity with the formation of only one product, which
demonstrates the predominant attack of the nucleophile at the
less hindered terminal carbon [17,18]. In terms of mono-
substituted aromatic N-tosylaziridines, neither the electronic
properties of the substituents on the aromatic ring nor the steric
hindrance had obvious influence on the yields. Except for 1n
which gave two isomers with high regioselectivity (94/6) about
FeBr3, other N-tosylaziridines provided the single regioisomer 3 or
5 by nucleophilic attack of the halide ion (FeCl3 and FeBr3) at the
benzylic position, and up to 99% yields were obtained within 0.5 h
(Table 2, entries 5–12). It was possible that electronic factors
predominated over the steric factors in this process. In addition,
moderate yields and high regioselectivity could also be obtained
with condensed-ring N-tosylaziridines (Table 2, entries 13–14).
Unfortunately, it can be seen that disubstituted aromatic N-
tosylaziridines provided the two regioisomer products in good
yields with bad regioselectivity due to the effect of spatial
structure and the fact that the regioisomers could not be
separated by column chromatography on silica gel (Table 2,
entries 15,16).
3. Results and discussion
Initially, our aim was to identify the best halides through
screening metal halides in terms of the ring openings of N-
tosylaziridines [29], and we began our research by choosing N-
tosylcyclohexylaziridine 1a as the model substrate. Subsequently,
a series of halides was screened under air atmosphere at room
temperature, and the results are summarized in Table 1. When
AlCl3 was used, the trace amount of product was detected (Table 1,
entry 1). Compared with MgCl2 (75%), FeCl3 provided a better
result (81%) (Table 1, entry 3). So, FeCl3 was selected as a better
nucleophile that also served as an excellent catalyst for the ring
openings.
Then, a series of experimental parameters was examined.
Different solvents such as CH2Cl2, THF and CH3CN were screened.
No product was detected when this reaction was performed in THF
or CH3CN (Table 1, entries 4,5). CH2Cl2 was identified as the best
solvent for this reaction (Table 1, entry 3). The investigation of the
temperature indicated that room temperature was suitable
(Table 1, entry 3 vs. 6, 7). Subsequently, the screening of the
amount of FeCl3 was carried out. 81% yield was obtained when
2.0 equiv. of FeCl3 was adopted (Table 1, entry 3). Decreasing the
amount of FeCl3 from 2.0 to 0.5 equiv. can dramatically increase
the yield to 94% (Table 1, entry 10). Further improvement of the
yield was not observed by using 0.4 equiv of FeCl3 (Table 1, entry
11). Besides, it was found that the reaction time can be reduced by
increasing the solvent dosages from 2.0 to 2.5 mL (Table 1, entry 12
vs. 11). At last, extensive screening showed the optimal reaction
conditions were 0.2 mmol N-tosylcyclohexylaziridine 1a and
50 mol% FeCl3 in 2.5 mL CH2Cl2 under air atmosphere at room
temperature for 1.5 h (Table 1, entry 14).
Br-substituted organic compounds have versatile applications
in organic synthesis. Some new functional groups can be smoothly
introduced by nucleophilic substitution of
a bromo group.
Furthermore, we examined the substitution reactions of the
b
-
haloamines obtained through the ring openings of N-tosylazir-
idines. The Br group in the product 4a could be conveniently
substituted by the nitro group (-NO2) using NaNO2, and the desired
product 6a was obtained in 55% yield (see Scheme 2).
Having established the optimal conditions of this ring-opening
reaction, we turned to a survey of the substrate scope and
generality of this method. Similarly, FeCl3 and FeBr3 reacted well
to give the corresponding chloro and bromo amines, and this
Please cite this article in press as: X. Li, et al., Highly efficient regioselective ring openings of N-tosylaziridines to haloamines using ferric
(III) halides, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.033

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X. Li et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
3
Table 2
Regioselective ring openings of various N-tosylaziridines with anhydrous FeX3.a
R2
R1
NHTs
X
X
R2
R1
R2
R1
FeX3 (40 or 50 mol%)
CH2Cl2 (2.5 mL), 25 oC
+
N-Ts
.
NHTs
3 X= Cl
5 X= Br
2 X= Cl
X= Br
1
4
Entry
N-tosylaziridine 1
X = Cl
Productb
X = Br
Time (min)
90
Yield (%)c
98
Productb
Time (min)
135
Yield (%)c
98
Cl
NHTs
Br
1
1a
NTs
2a
2b
2c
2d
3e
3f
4a
4b
4c
–
NHTs
Cl
Br
2
3
1b
1c
1d
1e
1f
480
480
270
10
20
20
15
10
25
5
94
91
93
93d
85
96
90
84
95d
79
86
135
135
–
96
90
–
NTs
NHTs
NHTs
Cl
Br
4
4
4
NTs
NHTs
NHTs
Cl
4
12
12
NTs
NHTs
NHTs
Cl
NHTs
Br
NTs
5d
5e
5f
10
20
40
25
20
25
30
20
89
90
96
91
84
84
89
91
NHTs
Br
NHTs
NTs
6e
Cl
Br
Br
Br
NHTs
Br
NHTs
Cl
Cl
Cl
Cl
NTs
7e
1g
1h
1i
3g
5g
5h
5i
NHTs
Br
NHTs
NTs
NTs
Cl
8e
3hCl
Cl
Cl
NHTs
Cl
NHTs
Br
9e
3i
Cl
Cl
Cl
NHTs
Br
NHTs
Cl
CH3
CH3
CH3
NTs
10d
11e
12e
1j
3j
5j
NHTs
Cl
NHTs
Br
NTs
H3C
H C
1k
1l
3k
5kH3C
3
NHTs
Cl
NHTs
Br
NTs
H3CO
3lH3CO
10
5lH3CO
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(III) halides, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.033

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X. Li et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
Table 2 (Continued )
Entry
N-tosylaziridine 1
X = Cl
X = Br
Productb
Time (min)
5
Yield (%)c
19
Productb
Time (min)
15
Yield (%)c
46
NHTs
Br
NHTs
Cl
NHTs
13e
1m
3m
3n
5m
NHTs
NHTs
Cl
NTs
14e
1n
15
67
5n
4n
15
70f
Br
Br
(5n:4n = 94:6)
NHTs
15e
1o
3o
2o
30
89
–
–
–
(3o:2o = 59:41)g
16e
1p
3p
2p
30
86
–
–
–
(3p:2p = 64:36)g
a
Unless otherwise noted, all reactions were performed with N-tosylaziridines 1 (0.2 mmol) and 50 mol.% anhydrous FeX3 (X = Cl or Br) under air atmosphere in CH2Cl2
(2.5 mL) at 25 8C.
b
Products 2 and 4 were formed through terminal attack and products 3 and 5 were formed through internal attack.
c
Isolated yield after column chromatographic purification.
d
40 mol% anhydrous FeX3 and 0 8C were adopted.
40 mol% anhydrous FeX3 was used about all aromatic N-tosylaziridines.
e
f
Combined yield of isolated 4n and 5n.
The ratio was determined by 1H NMR spectrum.
g
4. Conclusion
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2014.03.033.
Please cite this article in press as: X. Li, et al., Highly efficient regioselective ring openings of N-tosylaziridines to haloamines using ferric
(III) halides, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.033

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Please cite this article in press as: X. Li, et al., Highly efficient regioselective ring openings of N-tosylaziridines to haloamines using ferric
(III) halides, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.033