Ring-opening reaction of aziridines with amines under the influence of dimethyl sulfoxide to dedicated to late Tomoko Kakinuma, past member in our laboratory

Article abstract of DOI:10.1016/j.tetlet.2016.05.044

The ring-opening reaction of various aziridines with amines proceeded at room temperature to afford the corresponding 1,2-diamines in good to excellent yields using only 3-5 equiv dimethyl sulfoxide (DMSO) to aziridines in hexane. This reaction can be performed with easy handling and proceeds under mild reaction conditions. Also a variety of amines are available as a nucleophile.

Full text of DOI:10.1016/j.tetlet.2016.05.044

Accepted Manuscript
Ring-opening reaction of aziridines with amines under the influence of dimethyl
sulfoxide
Toshihiro Isobe, Takeshi Oriyama
PII:
S0040-4039(16)30567-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.044
TETL 47663
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
11 March 2016
8 May 2016
12 May 2016
Please cite this article as: Isobe, T., Oriyama, T., Ring-opening reaction of aziridines with amines under the influence
of dimethyl sulfoxide, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.05.044
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Tetrahedron Letters
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Ring-opening reaction of aziridines with amines under the influence of dimethyl
sulfoxide
Toshihiro Isobe, Takeshi Oriyama∗
Department of Chemistry, Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito, Ibaraki 310-8512, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
The ring-opening reaction of various aziridines with amines proceeded at room temperature to
afford the corresponding 1,2-diamines in good to excellent yields using only 3–5 equiv dimethyl
sulfoxide (DMSO) to aziridines in hexane. This reaction can be performed with easy handling
and proceeds under mild reaction conditions. Also a variety of amines are available as a
nucleophile.
Received in revised form
Accepted
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Dimethyl sulfoxide
Molecular sieves
Aziridines
Amines
1
,2-Diamines
To dedicated to late Tomoko Kakinuma, past member in our
laboratory.
we undertook the ring-opening reaction of aziridines with amines
using DMSO and MS 4A.
Wu et al. already reported the ring-opening reaction of
5
i
aziridines with various nucleophiles in DMSO in 2006, but
there were still some issues to be resolved: (1) a large amount of
DMSO (2.0 mL to 0.25 mmol aziridines) is used; (2) heating
Aziridines are versatile intermediates in synthetic organic
1
chemistry. Many nucleophilic ring-opening reactions of
2
aziridines were reported. Using amines as a nucleophile in the
(
reactions are conducted at 60 °C) is needed; and (3) only
ring-opening reactions of aziridines, 1,2-diamines can be
obtained. Synthesizing 1,2-diamines efficiently is important
because their building blocks are contained in many biologically
and medicinally active compounds such as penicillins,
aromatic amines can be applied to this reaction. Here, we
describe that the ring-opening reaction of various aziridines with
aromatic and aliphatic amines proceeding by using only 3–5
equiv DMSO to aziridines at room temperature to afford the
corresponding 1,2-diamines in good to excellent yields.
3
oseltamivir, and other pharmaceuticals. Conventional methods
of inducing the ring-opening reactions of aziridines with amines
4
a
require a metal reagent such as Yb(OTf)
4e
3
,
Sn(OTf)
4g
5
2
or
Initially, we attempt the ring-opening reaction of aziridine 1a
8
(0.30 mmol), which is derived from cyclohexene with 1.2 equiv
4
b
4c, h
,
4d
4f
, TaCl
4i
Cu(OTf)
2
,
LiClO
4
InBr
3
,
LiNTf
2
,
BiCl
3
,
SmI
2
,
4
j
or sulfated zirconia. Green chemical methods were also reported,
but the examination of amines did not widely conducted in most
benzylamine 2a in DMSO (1 mL), in the presence of MS 4A
(100 mg). As expected, the corresponding 1,2-diamine is
obtained in 92% yield (Table 1, entry 1). We subsequently
examine the effect of solvents (entries 2–8). Other aprotic polar
solvents such as DMF and MeCN give the desired product in
lower yields in comparison with DMSO (entries 2 and 3). Using
MeOH as a solvent, we obtain the desired product in 45% yield
5
of those methods.
In recent years, dimethyl sulfoxide (DMSO) received renewed
6b, d, g
6a, c, e
6f, h
an oxidant, and a reactant
attention as a promoter,
of
efficient organic reactions. We also developed many novel
reactions using DMSO and molecular sieves (MS) 4A during the
7
course of our intensive work. For example, under the influence
of DMSO and MS 4A, the Knoevenagel reaction of N-
2 2
(entry 4). CH Cl , THF, and toluene are found to be ineffective
for this reaction (entries 5–7). To our surprise, in the case of a
hexane solvent, the corresponding product is obtained in 75%
yield (entry 8). The examination of the solvent reveals that
DMSO is suitable for this reaction and hexane also gives
comparatively good results.
7
tosylimines with active methylene compounds, the double
g
7
h
Michael addition of dithiols to acetylenic carbonyl compounds,
and the aza-Henry reaction of N-tosylimines with nitroalkanes
7
j
proceeded smoothly to produce the corresponding products
without a metal catalyst or base. Based on these investigations,
———
∗
Corresponding author. Tel.: +81-29-228-8368; fax: +81-29-228-8403; e-mail: takeshi.oriyama.sci@vc.ibaraki.ac.jp

2
Tetrahedron
a
Table 1. Screening of solvents
The effect of additives is subsequently investigated (Table 3).
When the reaction is conducted without an additive, the
corresponding 1,2-diamine is obtained in 94% yield (entry 1).
NHTs
NHBn
MS 4A
Solvent, rt, 24 h
NTs
+
BnNH2
2
Adding 100 µL H O, the yield decreases (entry 2). Adding 100
mg MS 4A gives a higher yield (entry 3). We speculate that MS
remove a trace amount of water in the reaction mixture to prevent
a loss of Lewis basicity of DMSO. Therefore, it is better to
perform the reaction in absolute dehydrated conditions in the
presence of a dehydrating reagent. Then, the reaction is
performed testing various dehydrating reagents (entries 4–9). MS
1a
2a
3aa
b
Yield (%)
Entry
Solvent
1
2
3
4
5
6
7
8
DMSO
DMF
92
71
54
45
28
22
6
®
4A, 5A, Drierite , and Na SO give the desired product in the
2
4
same yield; however, we choose MS 4A as it gives the most
7
reliable results in our many reported reactions. An examination
MeCN
MeOH
of the MS 4A amount added (entries 10–13) indicates that 50 mg
MS 4A is the most suitable for the reaction as it gives the highest
yield. Additionally, when the reaction is performed without
hexane, the desired compound is also obtained in 96% yield
CH
2
Cl
2
THF
toluene
hexane
(
entry 14). According to this result, we believe that the higher
75
substrate concentration in DMSO accelerates the reaction. Taking
the experimental convenience into consideration, we use hexane
as a solvent for further investigations.
a
Reactions were carried out using an aziridine 1a (0.30 mmol) and
benzylamine 2a (0.36 mmol) in solvent (1 mL) in the presence of MS 4A
(
100 mg).
b
Isolated yield of purified product.
a
Table 3. Screening of additives
NHTs
DMSO, Additive
In our previous work on the double Michael addition of
NTs
+
BnNH2
7h
dithiols to acetylenic carbonyl compounds, we found that the
reaction proceeded similarly by using only 5 equiv DMSO to
substrates in hexane in place of using DMSO as a solvent (2 mL
to 0.30 mmol substrates). Therefore, we expect that the amount
of DMSO can be reduced by using hexane as a solvent. Thus, we
investigate the equivalent of DMSO to aziridine in hexane (Table
hexane, rt, 24 h
NHBn
3aa
1
a
2a
b
Yield (%)
Entry
Additive
1
2
3
4
5
6
7
8
9
none
O (100 µL)
94
77
96
94
96
92
96
91
96
95
98
95
91
2
). Fortunately, when reducing DMSO from 1 mL to 107 µL (5
H
2
equiv to aziridine), the desired 1,2-diamine is obtained in 96%
yield (entry 2). We obtain the same result by reducing DMSO
down to 3 equiv (entry 3), whereas the yields decreases when we
use less than 3 equiv DMSO (entries 4–8). From the above
results, 3 equiv is considered the adequate amount of DMSO.
MS 4A (100 mg)
MS 3A (100 mg)
MS 5A (100 mg)
MS 13X (100 mg)
®
Drierite (100 mg)
a
Table 2. Screening of the amount of DMSO
MgSO (100 mg)
4
NHTs
Na SO (100 mg)
4
2
DMSO, MS 4A
NTs
+
BnNH2
1
1
1
1
1
0
1
2
3
4
MS 4A (70 mg)
MS 4A (50 mg)
MS 4A (30 mg)
MS 4A (10 mg)
MS 4A (50 mg)
hexane, rt, 24 h
NHBn
3aa
1a
2a
b
Yield (%)
Entry
DMSO
1
2
3
4
5
6
7
8
47 equiv, 1 mL
5 equiv, 107 µL
3 equiv, 64 µL
2 equiv, 43 µL
1 equiv, 21 µL
0.5 equiv, 11 µL
0.1 equiv, 2 µL
0 equiv
92
96
96
94
86
84
75
75
c
96
a
Reactions were carried out using an aziridine 1a (0.30 mmol) and
benzylamine 2a (0.36 mmol) in hexane (1 mL) in the presence of DMSO
(
0.90 mmol).
b
Isolated yield of purified product.
Reaction was carried out without hexane.
c
The scope of the present study is to investigate this reaction
9
using various amines, as shown in Scheme 1. The reaction with
various aliphatic and aromatic amines as nucleophiles is
successful. Not only primary amines but also secondary cyclic
amines are applicable nucleophiles among aliphatic amines (3aa–
3ao), although the reaction with diethylamine or
diisopropylamine gives no desired product. Using 5 equiv DMSO
and extending the reaction time, the corresponding 1,2-diamines
a
Reactions were carried out using an aziridine 1a (0.30 mmol) and
benzylamine 2a (0.36 mmol) in hexane (1 mL) in the presence of MS 4A
(
100 mg).
b
Isolated yield of purified product.

a
Scheme 1. Ring-opening reaction of aziridines with various amines
NHTs
DMSO, MS 4A
hexane, rt
1
2
NTs
+
R R NH
1
NR R2
1
a
2
3
NHTs
NHTs
NHTs
NHTs
NHTs
NHBn
N
H
N
H
N
H
N
H
OMe
3aa, 98%
3ab, 94%
3ac, 79%
3ad, 65%
3ae, 69%
NHTs
N
NHTs
NHTs
NHTs
NHTs
OH
N
H
N
N
H
N
H
N
H
3af, 91%
3ag, 73%
3ah, 75%
3ai, 35%
3aj, 86%
NHTs
N
NHTs
N
NHTs
N
NHTs
N
NHTs
N
O
N
3ak, 91%
3al, 100%
3am, 98%
3an, 95%
3ao, 94%
NHTs
NH
NHTs
NHTs
NHTs
NHTs
NHPh
N
H
N
H
N
H
OMe
3
ap, 59% (81%)b
3aq, 91%b
3ar, 54%b
3as, 13%b
3at, 94%b
NHTs
NHTs
NHTs
NHTs
NHTs
N
N
H
N
H
N
N
H
OH
N
H
Cl
H
N
au, 93%b
3av, 78%b, c (91%)c, d
3aw, 56%b
3ax, 46%b
3ay, 28%b
3
a
Reactions were carried out using an aziridine 1a (0.30 mmol) and an amine 2 (0.36 mmol) in hexane (1 mL) in the presence of DMSO (0.90 mmol) and MS 4A
50 mg) for 24 h. Yield of isolated product after chromatographic purification is shown.
(
b
5
equiv DMSO were used and reaction was performed for 48 h.
c
Yield of isolated product after recrystallization.
d
Reactions were carried out using an aziridine 1a (5.0 mmol, 1.3 g) and an amine 2v (5.0 mmol, 0.55 g) in hexane (10 mL) in the presence of DMSO (25 mmol,
.8 mL) and MS 4A (800 mg) for 48 h.
1
are obtained in practical yields when aromatic amines as employed as a nucleophile (3ap–3ay). The reaction of aziridine with
steric-hindered or electron-deficient amines gives the corresponding 1,2-diamines in lower yields (3ai, 3ar, 3as, and 3aw). 4-
Nitroaniline and ethyl 4-aminobenzoate do not give the desired compounds. Aromatic secondary amines such as N-methylaniline,
1,2,3,4-tetrahydroquinoline, and carbazole are also checked in this reaction system, but the corresponding products are not obtained.
A successful result is obtained from a gram-scale reaction using 1.0 equiv amine to aziridine (3av).

3
We further evaluate the ring-opening reaction of a variety of aziridines with benzylamine 2a and aniline 2p, as summarized in
Scheme 2. Cyclopentene-derived aziridine is also suitable in
Scheme 2. Ring-opening reaction of various aziridines with
a
amines
R1
R2
R1
R2
NHR3
NHR4
DMSO, MS 4A
hexane, rt, 24 h
NR3
+
4
R NH2
1
2
3
NHTs
NHR4
NHTs
NHR4
4
4
3
aa, R = Bn, 98%
4
3ba, R = Bn, 72%
4
3
ap, R = Ph, 59%
3bp, R = Ph, 25%
Ph
Ph
NHTs
NHR4
Ph
NHTs
Ph
4
R HN
4
4
3
ca, R = Bn, 5%
cp, R4 = Ph, 0%
3da, R = Bn, 96%
4
3
3dp, R = Ph, 47%
Ph
NHR4
NHTs
Ph
NHTs
NHR4
ea + 3ea', R = Bn, 97%, 36:64 drb
4
3
3
ep + 3ep', R = Ph, 95%, 15:85 drc
4
NHR4
NHTs
NHTs
NHR4
fa + 3fa', R = Bn, 87%, 25:75 drb
4
3
3
fp + 3fp', R4 = Ph, 90%, 3:97 drc
Cl
Cl
NHTs
NHR4
NHTs
NHR4
ga + 3ga', R = Bn, 90%, 46:54 drb
4
3
3
gp + 3gp', R = Ph, 81%, 9:91 drc
4
Bn
NHTs
NHR4
NHTs
Ph
NHBz
NHBn
HO
4
R HN
3
3
ha, R4 = Bn, 76%
3ia, R4 = Bn, 87%
3ip, R = Ph, 76%d
3ja, 53%
4
4
hp, R = Ph, 50%

a
Reactions were carried out using an aziridine 1 (0.30 mmol) and an amine 2 (0.36 mmol) in hexane (1 mL) in the presence of DMSO (0.90 mmol) and
MS 4A (50 mg). Yield of isolated product after chromatographic purification
is shown.
b
Ratio of regioisomers was determined by isolated yield of each product.
c
1
Ratio of regioisomers was determined by H NMR analysis of the mixture.
d
Yield of isolated product after recrystallization.
these reaction conditions (3ba and 3bp), but treatment of aziridines derived from cycloheptene and cyclooctene does not produce
the corresponding compounds. The reaction of aziridines prepared from trans-stilbene is successful, whereas cis-stilbene-derived
aziridine is not a suitable substrate (3ca, 3cp, 3da, and 3dp). Using aziridines derived from styrenes, the ring-opening reactions
occur in a regioselective manner with preferential attack at the benzylic carbon (3ea, 3ep, 3fa, 3fp, 3ga, and 3gp). Only one
regioisomer is obtained in 50%–87% yields when the reactions are conducted with aziridines prepared from allylbenzene and
cinnamyl alcohol, which has a free hydroxy group (3ha, 3hp, 3ia, and 3ip). When the reaction is performed with N-Bz aziridine, the
desired compound is obtained in 53% yield (3ja). Cyclohexene-derived aziridines which have N-Boc, N-Ph, and N-Bn protecting
groups are inert for this reaction with no product forming.
In conclusion, a simple and convenient method for the ring-opening reaction of aziridines with amines is developed. This
reaction has the following synthetic advantages: (1) in contrast to conventional methods, the present reaction does not need a metal
reagent or heating; (2) a wide range of aziridines can be employed; (3) not only aromatic amines but also aliphatic amines are
available as a nucleophile; (4) the reaction can be performed with easy handling and proceeds smoothly under mild reaction
conditions; and (5) only 3–5 equiv DMSO to aziridines are needed to complete the reaction. Mechanistic studies and the application
of DMSO-promoted benign reactions in other efficient reactions are currently being assessed in our laboratory.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas ‘Advanced Molecular Transformations of
Carbon Resources’ from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Supplementary data
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4

5
8
.
Aziridines were prepared according to the procedure reported in references: (a) Ando, T.; Kano, D.; Minakata, S.; Ryu, I.; Komatsu, M.
Tetrahedron 1998, 54, 13485; (b) Thakur, V. V.; Sudalai, A. Tetrahedron 2003, 44, 989.
9
.
Dehydrated DMSO was purchased from Wako Pure Chemical Industries, Ltd. and used without further purification. Typical experimental
procedure is as follows: benzylamine 2a (39 µL, 0.36 mmol) and DMSO (64 µL, 0.90 mmol) were added to a solution of 7-tosyl-7-aza-
bicyclo[4.1.0]heptane 1a (75.8 mg, 0.30 mmol) in hexane (1 mL) in the presence of MS 4A (50 mg) at room temperature under argon
atmosphere. The resultant mixture was stirred for 24 h at room temperature, and the reaction was quenched with water. The organic materials
2 4
were extracted with AcOEt, washed with brine, and dried over Na SO . trans-N-(2-(Benzylamino)cyclohexyl)-4-methylbenzenesulfonamide 3aa
(105.9 mg, 98%) was isolated by thin layer chromatography on silica gel.

Graphical Abstract
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Ring-opening reaction of aziridines with
amines under the influence of dimethyl
sulfoxide
Leave this area blank for abstract info.
Toshihiro Isobe, Takeshi Oriyama*
DMSO (3–5 equiv)
MS 4A (50 mg)
R1
R1 NHR3
NR3
4
5
+
R R NH
R2
hexane (1 mL), rt, 24–48 h
Mild Reaction Conditions
R2 NR R5
4
0
.30 mmol
1.2 equiv
up to 100%

7
Highlights
•
•
•
Only 3–5 equiv DMSO to aziridines are needed to complete the reaction.
The reaction can be performed with easy handling and proceeds at room temperature.
A variety of amines are available as a nucleophile.