KOH-catalyzed regioselective ring openings of N-tosylaziridines with malonates in acetone

Article abstract of DOI:10.1016/j.molcata.2012.07.023

A simple and efficient method has been developed which describes KOH-oriented catalytic regioselective ring-opening reactions of various N-tosylaziridines with malonates. In the presence of 20 mol% KOH, most N-tosylaziridines can smoothly react with malonates to give the corresponding products in good to excellent yields (up to 99%) and with good to excellent regioselectivity under mild experimental conditions.

Full text of DOI:10.1016/j.molcata.2012.07.023

Journal of Molecular Catalysis A: Chemical 363–364 (2012) 446–450
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Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
KOH-catalyzed regioselective ring openings of N-tosylaziridines with malonates
in acetone
Xing Li∗, Jijuan Su, Honghong Chang, Gong Li, Yanwei Li, Wenlong Wei
Department of Chemistry and Chemical Engineering, Taiyuan University of Technology, 79 West Yingze Street, Taiyuan 030024, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient method has been developed which describes KOH-oriented catalytic regioselective
ring-opening reactions of various N-tosylaziridines with malonates. In the presence of 20 mol% KOH,
most N-tosylaziridines can smoothly react with malonates to give the corresponding products in good
to excellent yields (up to 99%) and with good to excellent regioselectivity under mild experimental
conditions.
Received 20 April 2012
Received in revised form 16 July 2012
Accepted 18 July 2012
Available online 27 July 2012
© 2012 Elsevier B.V. All rights reserved.
Keywords:
N-tosylaziridines
Ring-opening
Diethyl malonate
KOH
Catalyze
1. Introduction
with malonates 2 as an efficient catalyst in acetone for the prepara-
tion of ␥-amino acids precursor and the corresponding compounds.
␥-Amino acids are key structural motifs and widespread sub-
units prevalent in many biologically active compounds, such as
clinically used neurotransmission modulators [1–3]. Their syn-
thetic utility as well as interesting biological activities has led
many researchers to develop more interesting and efficient routes
toward their transformation [4–11]. In recent years, some attrac-
tive strategies for the stereoselective synthesis of ␥-amino acids
have been gradually reported. Among these routes, the methods
via stereoselective and enantioselective ring openings of meso-
aziridines with enolates are known as one of the most efficient
strategies and provide straightforward access to ␥-amino acids
[12–16]. Several reports and promoters such as inorganic base-
directed ring-opening reactions of aziridines with enolates as a
stoichiometric amount of promoter (See Scheme 1(a) and (b))
[11–14], have been observed for the ring openings of aziridines with
malonate, in which a plenty of inorganic base and lower tempera-
ture was needed and necessary that restrict their development. Up
to now, however, inorganic base-catalyzed ring-opening reactions
of N-tosylaziridines under mild conditions are still not observed
(See Scheme 1(c)). Herein, we wish to describe KOH-catalyzed
regioselective ring-opening reactions of various N-tosylaziridines 1
2. Experimental
1H NMR spectra were taken with a Bruker AVANCE III 600 MHz
NMR spectrometers. The chemical shifts are reported in ppm down-
field to the CDCl3 resonance (ı = 7.24). Spectra are reported as
follows: chemical shift (ı ppm), multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet), coupling constants (Hz), inte-
gration, and assignment. 13C NMR data were collected at 150 MHz
with complete proton decoupling. The chemical shifts are reported
in ppm downfield to the central CDCl3 resonance (ı = 77.23). Cou-
pling constants in 1H NMR spectra are given in Hz. High-resolution
mass spectra were performed on a micrOTOF-Q II instrument with
an ESI source. Melting points were measured with a RD-II melt-
ing point apparatus and are uncorrected. Unless otherwise noted,
Reagents obtained from commercial sources were used without
further purification. All solvents were purchased from commer-
cial sources and used with further purification. Deuterated solvents
were purchased from aladdin. Column chromatography was per-
formed on silica gel (200–300 mesh). All yields were referred to
isolated yields (average of two runs) of compounds.
Typical procedure for the ring-opening reactions. The mixture of
diethyl malonate 2a (304 ␮L, 2 mmol, 10 equiv.) and the powdered
KOH (2.3 mg, 20 mol%) in acetone (1.0 mL) was stirred in a test tube
under air atmosphere at 35 ◦C for 0.5 h. Subsequently, a solution
of N-tosylaziridine 1 (0.2 mmol) in acetone (0.5 mL) was added,
and the reaction mixture was stirred until N-tosylaziridine 1
∗
Corresponding author. Fax: +86 0351 6111165.
E-mail addresses: lixing@tyut.edu.cn, mh57600743@sina.com (X. Li).
1381-1169/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molcata.2012.07.023

X. Li et al. / Journal of Molecular Catalysis A: Chemical 363–364 (2012) 446–450
447
O
Ts
R3
stoichiometric base
Lewis acid
(a)
N
(1)
R1
R2
CO2Et
CO2Et
stoichiometric
amount of base
(b)
Ts
R1
R3
N
(2)
(3)
+
R2
NHTs
CO2R4
R1
R2
R2 = CO2Et, COCH3 R4 = Me, Et
CO2Et
CO2Et
catalytic amount
R1
of base
(c)
R2
NHTs
Scheme 1. Inorganic base-promoted ring openings of N-tosylaziridines.
The effect of the amount of diethyl malonate 2a
was consumed fully as identified by TLC. The residue was then
purified by column chromatography on silica gel with the mixture
solvent of petroleum ether and ethyl acetate to afford the desired
product.
120
100
80
60
40
20
0
99
97
92
86
70
3. Results and discussion
Our investigation began with the ring-opening reaction of
N-tosylcyclohexylaziridine 1a with diethyl malonate 2a in the
presence of 10 mol% Cs2CO3 as the catalyst. The initial studies
were focused on finding the optimal solvent and catalyst. A series
of solvents were tested under air atmosphere at 35 ◦C and the
results are listed in Table 1. The reactivity was deeply depen-
dent on the solvent type. When this reaction was performed in
CH2Cl2 and DMSO, no corresponding product was attained (Table 1,
entries 1 and 2). THF and dioxane afforded the product with the
lower yields (Table 1, entries 3 and 4). CH3CN and DMF gave the
same yield of 44% (Table 1, entries 5 and 6). However, it was
noteworthy that the screening of solvents showed that acetone
exhibited the best performance and a 46% yield was obtained
(Table 1, entry 7).
The catalyst was also revealed to be an important parameter
for obtaining higher yield. Subsequently, a series of bases were
explored as catalysts. When Cs2CO3 was used, 46% yield was
obtained (Table 1, entry 7). In the case of other weak bases such
as NaHCO3 and CsF, worse results were observed (Table 1, entries
8 and 9). Although some strong bases such as NaH, LiOH and NaOH
provided lower yields (Table 1, entries 10–12), t-BuOK and CsOH
could give moderate yields (Table 1, entries 13 and 14). Noted that
KOH was found to be the most promising catalyst with 66% isolated
yield (Table 1, entry 15).
To further improve the yield, the effects of catalyst loading,
solvent dosage, reaction temperature and the amount of diethyl
malonate were examined. Unlike the solvent and catalyst which
exhibited a dramatic effect in this reaction, the use of different
catalyst loading, different solvent dosage, and different reaction
temperature indicated no or little effects on the reaction yield and
the results are listed in Table 2. Considering operational stability
and the yield comprehensively, 20 mol% KOH was used (Table 2,
entry 3 vs. 1 and 2) and the solvent dosage was chosen as 1.5 mL
(Table 2, entry 5 vs. 3 and 6). At last, 35 ◦C was utilized as reaction
temperature (Table 2, entry 5 vs. 7 and 8).
1.2(24h)
2(12h)
8(12h)
10(15h)
15(15h)
The amount of diethyl malonate 2a (equiv.)
Fig. 1. The effect of the amount of diethyl malonate 2a on the ring-opening reac-
tion (reaction conditions: N-tosylcyclohexylaziridine 1a (50 mg, 0.2 mmol), KOH
(2.3 mg, 0.04 mmol, 20 mol%) and acetone (1.0 mL) with specified conditions under
air atmosphere at 35 ◦C).
However, the amount of diethyl malonate evidently affected the
yield. There was a tendency that higher amount resulted in higher
yield (see Fig. 1). The yield reached to the highest value (99%) when
10 equiv. of diethyl malonate was adopted. Unfortunately, 15 equiv.
of diethyl malonate resulted in somewhat lower yield. In summary,
extensive screening showed that the optimized reaction conditions
were 0.2 mmol N-tosylaziridine and 10 equiv. of diethyl malonate
in the presence of 20 mol% KOH under air atmosphere in 1.5 mL
acetone at 35 ◦C.
NHTs
COMe
COOEt
COMe
KOH (20 mol%)
80oC, 8 h
(1)
COOEt
N
Ts
1.0 mL
3r
85% yield
COOMe
COOMe
NHTs
KOH (20 mol%)
80oC, 8 h
COOMe (2)
COOMe
N
Ts
10 equiv.
3s
97% yield
Scheme 2. Application of the ring opening.

448
X. Li et al. / Journal of Molecular Catalysis A: Chemical 363–364 (2012) 446–450
Table 1
Screening of solvents and catalysts for the ring-opening reaction of N-tosylcyclohexylaziridine 1a with diethyl malonate 2a.a
NHTs
Cat* (base), 35 oC
COOEt
Ts
N
+
COOEt
COOEt
solvent, 24 h
COOEt
1a
2a
3a
Entry
Solvent
Catalyst
Yieldb [%]
1
2
3
4
5
6
7
8
CH2Cl2
DMSO
THF
Dioxane
CH3CN
DMF
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaHCO3
CsF
NaH
LiOH
NaOH
t-BuOK
CsOH
Trace
N.D.
16
22
44
44
46
N.D.
9
29
9
10
11
12
13
14
15
31
28
51
57
KOH
66
N.D., not detected.
a
Unless otherwise noted, all reactions were carried out with N-tosylcyclohexylaziridine 1a (50 mg, 0.2 mmol), diethyl malonate 2a (36 ␮L, 0.24 mmol, 1.2 equiv.), catalyst
(base, 0.02 mmol, 10 mol%) and solvent (1.0 mL) under air atmosphere at 35 ◦C for 24 h.
b
Isolated yield.
Under the optimized experimental conditions, the results of an
examination of the scope of the ring-opening reactions of a series
of N-tosylaziridines with diethyl malonate are presented in Table 3.
With regard to most aliphatic N-tosylaziridines, good to excellent
yields and high regioselectivity could be obtained (Table 3, entries
1–4). In terms of aromatic N-tosylaziridines, the electronic prop-
erties of the substituents on the aromatic ring of N-tosylaziridines
had an obvious influence on the yield. N-tosylaziridines bearing
electron-donating groups supplied better results than those with
electron-withdrawing groups (Table 3, entry 6 vs. 8 and entry 7
vs. 9). It was noteworthy that steric hindrance played an impor-
tant role on the yield which para-substituted N-tosylaziridines
afforded the corresponding products with higher yields than
ortho- and meta-substituted N-tosylaziridines (Table 3, entries
10, 12 and 13 vs. 6–9 and 11). At the same time, good to high
regioselectivity were attained about them. Unfortunately, the
meta-substituted N-tosylaziridine with nitro group ( NO2) gave
bad yield (Table 3, entry 16). In addition, aromatic N-tosylaziridines
with condensed-ring were also found to be suitable substrates
(Table 3, entries 14 and 15). Heteroaliphatic N-tosylazirdines
also provided good yield and regioselectivity (Table 3,
entry 17).
Furthermore, we explored the ring openings of N-
tosylcyclohexylaziridine 1a with ethyl acetoacetate and dimethyl
malonate for better understanding the generality of this method
in the presence of KOH under the optimum reaction conditions
(see Scheme 2). As for ethyl acetoacetate, 85% yield was obtained
in 1.0 mL of ethyl acetoacetate at 80 ◦C for 8 h (Scheme 2(1)).
About dimethyl malonate, the corresponding desired ring-opening
product 3s could be provided in 97% yield (Scheme 2(2)).
Table 2
Optimization of the other reaction conditions for the ring-opening reaction of N-tosylcyclohexylaziridine 1a with diethyl malonate 2a.a
NHTs
COOEt
KOH, T
Ts
N
+
COOEt
COOEt
acetone, t
COOEt
1a
2a
3a
Entry
Catalyst loading [mol%]
Solvent dosage[mL]
T [◦C]
Yieldb [%]
1
2
3
4
5
6
7
8
5
10
20
30
20
20
20
20
1.0
1.0
1.0
1.0
1.5
2.0
1.5
1.5
35
35
35
35
35
35
25
45
52
66
67
35
70
68
66
67
a
Unless otherwise noted, all reactions were carried out with N-tosylcyclohexylaziridine 1a (50 mg, 0.2 mmol) and diethyl malonate 2a (36 ␮L, 0.24 mmol, 1.2 equiv.) under
specified conditions for 24 h.
b
Isolated yield.

X. Li et al. / Journal of Molecular Catalysis A: Chemical 363–364 (2012) 446–450
449
Table 3
Substrate scope of the ring-opening reactions of N-tosylaziridine 1 with diethyl malonate 2a.a
COOEt
COOEt
NHTs
R1
R2
NHTs
COOEt
COOEt
R1
R2
COOEt
COOEt
KOH (20 mol%)
acetone, 35oC
R1
R2
N
Ts
+
+
1
2a
3
4
Entry
N-tosylaziridine
Product
t [h]
Yieldb [%]
cRatio 3:4
COOEt
CH
COOEt
N-Ts
NHTs
COOEt
CH
1
3a
16
99
–
COOEt
N-Ts
NHTs
NHTs
NHTs
2
3
4
3b
3c
3d
56
24
53
94
85
82
–
–
–
COOEt
N-Ts
C
4
COOEt
H
4
COOEt
N-Ts
N-Ts
C
12
COOEt
H
12
COOEt
CH
EtOOC
NHTs
5d
4e
37
92
11:89
COOEt
N-Ts
CH
Me
EtOOC
NHTs
Me
6
7
4f
37
37
80
84
–
–
COOEt
N-Ts
Me
CH
EtOOC
Me
NHTs
4g
N-Ts
COOEt
CH
Cl
EtOOC
NHTs
8d
4h
4i
20
20
73
77
19:81
Cl
COOEt
N-Ts
N-Ts
Cl
CH
CH
EtOOC
Cl
NHTs
9
–
COOEt
EtOOC
NHTs
10d
11d
4j
21
47
89
65
14:86
7:93
Cl
Cl
COOEt
N-Ts
N-Ts
CH
MeO
EtOOC
MeO
NHTs
4k
COOEt
CH
EtOOC
NHTs
12d
4l
27
20
91
96
17:83
Br
Br
COOEt
N-Ts
CH
EtOOC
NHTs
O2N
O2N
13
4m
–

450
X. Li et al. / Journal of Molecular Catalysis A: Chemical 363–364 (2012) 446–450
Table 3 (Continued)
COOEt
R1
R2
NHTs
COOEt
COOEt
R1
COOEt
COOEt
KOH (20 mol%)
acetone, 35oC
R1
R2
N
Ts
+
COOEt
NHTs
+
R2
1
2a
3
4
Entry
N-tosylaziridine
Product
t [h]
Yieldb [%]
cRatio 3:4
COOEt
N-Ts
CH
EtOOC
NHTs
14
4n
21
73
–
N-Ts
COOEt
CH
EtOOC
NHTs
15
16
4o
4p
36
20
72
–
COOEt
N-Ts
CH
O2N
EtOOC
O2N
NHTs
Trace
COOEt
COOEt
NH-Ts
N-Ts
s
s
17
3q
21
83
95:5
a
Unless otherwise specified, all reactions were carried out with N-tosylaziridine 1 (0.2 mmol), diethyl malonate 2a (304 ␮L, 2 mmol, 10 equiv.), catalyst (KOH, 2.3 mg,
20 mol%) and acetone (1.5 mL) under air atmosphere at 35 ◦C for the identified time.
b
Isolated yield.
Combined yield of isolated 3 and 4.
c
d
These compounds gave two isomer products that could not be separated by column chromatography and HPLC, and their ratios were determined by 1H NMR.
4. Conclusions
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friendly reagent, is found to be an excellent base catalyst for the
ring-opening reactions of N-tosylaziridines with diethyl malonate
under mild conditions in acetone. Wide substrate scope, mild con-
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Appendix A. Supplementary data
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found, in the online version, at http://dx.doi.org/10.1016/j.molcata.
2012.07.023.
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