Aqueous ring opening of N-tosylaziridine with aniline derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.02.076

A series of N-(p-X-phenyl)-N'-(p-toluenesulfonyl)1,2-ethylenediamines compounds, TsN(H)CH₂CH₂N(H)PhX, were synthesized by the uncatalyzed ring opening reaction of N-tosylaziridine with p-X-aniline derivatives in pure water at 50 °C. No solvolysis product was observed and the only side product was that of a subsequent ring opening reactions of N-tosylaziridine with the product anilines leading to substituted diethylenetriamines, XPhN(CH₂CH₂NTs)₂.

Full text of DOI:10.1016/j.tetlet.2012.02.076

Tetrahedron Letters 53 (2012) 2288–2291
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Tetrahedron Letters
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Aqueous ring opening of N-tosylaziridine with aniline derivatives
⇑
Mengping Zhu, Bahram Moasser
Department of Chemistry, Georgetown University, 37th and O Streets, NW, Washington, DC 20057, United States
a r t i c l e i n f o
a b s t r a c t
A series of N-(p-X-phenyl)-N0-(p-toluenesulfonyl)1,2-ethylenediamines compounds, TsN(H)CH2CH2N(H)PhX,
were synthesized by the uncatalyzed ring opening reaction of N-tosylaziridine with p-X-aniline derivatives
in pure water at 50 °C. No solvolysis product was observed and the only side product was that of a
subsequent ring opening reactions of N-tosylaziridine with the product anilines leading to substituted die-
thylenetriamines, XPhN(CH2CH2NTs)2.
Article history:
Received 4 August 2011
Revised 15 February 2012
Accepted 16 February 2012
Available online 23 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Catalysis
Aziridine
Aqueous
Ring opening
On water
Nucleophilic ring opening of aziridines with oxygen and nitro-
gen nucleophiles is a versatile reaction for the synthesis of 1,2-ami-
noalcohols and 1,2-diamines.1 Our interest in this class of reaction
stemmed from our desire to prepare the ligand series 3a–j
(Fig. 1) for the study of the electronic effects on the rate of
complete conversion at reasonable time as determined by TLC.
After cooling to room temperature, 2 mL of ethyl acetate was
added and vigorously shaken. The organic layer was dried under
rotary evaporation. A portion of the residue was dissolved in
0.7 mL CDCl3 together with (4.26 lL, 0.05 mmol) 1,4-dioxane as
RuH(g
6-arene)(L2)-catalyzed transfer hydrogenation of ketones
an NMR internal standard. The conversion and selectivity values
were determined based on the integrations of NMR peaks. For lar-
ger scale syntheses the ethyl acetate layer was washed with brine,
dried with MgSO4, and then concentrated to brown liquid under
vacuum. The crude products were recrystallized from ethyl acetate
and hexane.
Table 1 shows the results of the uncatalyzed reaction of ten ani-
line derivatives with N-tosylaziridine in water. There is no solvol-
ysis product detected with any of the anilines. The only other
products were N0-aryl, N,N-bis(tosyl)diethylenetriamines, 4a–j,
formed from a second nucleophilic attack of 3a–j on 1. The identity
of 4a–j was confirmed by their mass spectrum and 1H NMR which
are more consistent with the nucleophilic attack of the arylamine,
not tosylamide, on a second molecule of 1, leading to the symmet-
ric XPhN(CH2CH2NTs)2. Characterization data for compounds 3a–j,
PhN(CH2CH2NTs)2, as well as, kinetic data for the reactions of 1
with 2a–j can be found in the Supplementary data.
There is a trade-off between conversion and selectivity with
electronic character of the substituents. For strongly electron
donating groups the reaction is completed in 30 min with moder-
ate yields. Mildly electron withdrawing substituents diminish the
conversion but increase selectivity. Strongly electron withdrawing
substituents suppress the conversion but maintain reasonable
selectivity. We would expect better yields at longer reaction times.
The reaction of 4-(diemethylamino)aniline with 1 at 50 °C resulted
(where L2 is the monobasic form of 3a–j). To synthesize 3a–j we
initially explored the reaction of anilines with N-tosylaziridine
(1) in organic solvents, but these gave mixed results. Here, we re-
port a simple and practical synthesis of 3a–j by the ring opening
reaction of 1 with aniline derivatives 2a–j in pure water at 50 °C
(Fig. 1).
Qu and co-workers2 have demonstrated that the uncatalyzed
ring opening of epoxides and aziridines with water (solvolysis) or
external nucleophiles proceeded well in water at 60 °C. Interest-
ingly, with external nucleophiles the solvolysis product was com-
pletely suppressed. The amine nucleophiles employed by Qu
et al. were aniline, benzylamine, and sodium azide. Based on these
results we suspected our synthesis would be effective with acti-
vated nitrogen nucleophiles, but the weaker nucleophiles would
not be able to compete with solvolysis. To our surprise, the reac-
tion in water is not only effective for electron releasing anilines
but also for electron withdrawing ones. Thus, we synthesized the
complete ligand series, 3a–j, by the uncatalyzed reaction of the
para-substituted anilines with N-tosylaziridine in water at 50 °C.
In a typical experiment, aniline (9.1 lL, 0.1 mmol) was added to
a suspension of N-tosylaziridine (9.9 mg, 0.05 mmol) in 1 mL of
distilled water and stirred at 50 °C. All reactions were followed to
⇑
Corresponding author. Tel.: +1 202 687 5937; fax: +1 202 687 6209.
E-mail address: bm276@georgetown.edu (B. Moasser).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.076

M. Zhu, B. Moasser / Tetrahedron Letters 53 (2012) 2288–2291
2289
Figure 1. The aqueous ring opening reaction of 1 with 2a–j.
in 100% conversion in 30 min and produced diamine and at least
five different oligomers from multiple ring opening reactions.
The reactions producing 3a–f are kinetically second order;
whereas, the reactions forming 3g–j are zero order. For 3a–f a
kinetic model for the two consecutive second order reactions
shown in Figure 1 was developed in terms of the concentration
of one substrate, 1, which is common to both steps. The rate pro-
files for 3a–f were fitted to this kinetic expression in order to esti-
mate the observed rate constants. The exact values of k1 and k2 are
not readily obtained by this method; however, because both reac-
tions in Figure 1 involve the nucleophilic attack of the aniline nitro-
gen para to the substituent, we believe that the observed rate
constants accurately reflect the relative reactivity of the aniline
derivatives. The rate profiles for 3g–j were linear from which an
observed rate constant was directly calculated. The details of the
analysis are given in the Supplementary data.
substituent. This implies a lack of localized positive charge accu-
mulation on the aniline nitrogen with advancing C–N bond forma-
tion. The second order kinetics, the large and negative
q, and the
lack of linear correlation with r+ values can be interpreted in
two ways.
First, the charge formation at the aniline nitrogen is more stabi-
lized by the water shell than it is by the para-substituent. In an
extreme of this scenario the organized water cluster surrounding
the aziridine-aniline reacting pair can place a hydroxide in close
proximity of the aniline. The evolution of charge on the aniline
nitrogen is then attenuated by concomitant deprotonation of ani-
line with hydroxide. The ion product (Kw) for pure water increases
rapidly with temperature, leading to higher [H+] and [OHꢀ].3
Therefore, high temperature water can contribute to acid or base
catalysis. Conversely, an acid catalyzed mechanism in which the
aziridine nitrogen is protonated is possible. In this instance, the
lack of resonance contribution from the aniline para-substituents
A Hammett correlation on the reactant series of 2a–f was per-
formed and the results are shown in Figure 2. A reaction constant
(non-linear fit with
Ph)N–C bond formation and C–N(Ts) bond cleavage. Indeed, Qu
r
+) may be explained by synchronous (p-X-
of
q
= ꢀ1.4 was found which implies extensive C–N bond forma-
tion in the transition state. However, when the rate data are plot-
ted against Brown–Okamoto r+ constants there is significant
curvature, especially with the strongly electron releasing methoxy
Table 1
Summary of reactions of 1 with 2a–j at 50 °C
Product
X
Time
(h)
Conversiona
(%)
Selectivityb
(%)
Yield
(%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
OCH3
OCH2CH3 0.5
CH3
H
F
0.5
100
100
100
100
88
84
96
82
70
54
66
68
66
86
90
85
78
91
67
54
66
68
66
76
76
82
64
64
40
0.5
1.0
1.0
1.0
6.0
6.0
6.0
16
Cl
CF3
COCH3
CN
NO2
3j
60
a
r) and Brown–Okamoto (r
+) correlations for the reactions of 1
Based on 1.
Based on 3.
Figure 2. Hammett (
with 2a–f.
b

2290
M. Zhu, B. Moasser / Tetrahedron Letters 53 (2012) 2288–2291
et al. have also proposed that the increased [H+] at higher temper-
atures may be responsible for the water-catalyzed ring opening of
epoxides and aziridines.
Table 2
Summary of reactions of 1 with 2a–j at 25 °C
Product
X
Time
(h)
Conversiona
(%)
Selectivityb
(%)
Yield
(%)
Second, the curvature in the Brown–Okamoto plot may be ex-
plained by the formation of a donor-acceptor complex between
the electron deficient aryl ring of the N-tosylaziridine and the elec-
3a
3b
3c
3d
3e
3f
3g
3h
3i
OCH3
OCH2CH3 20
CH3
H
F
20
98
100
98
97
92
85
36
6
94
73
78
69
96
98
100
100
100
0
92
73
76
67
88
83
36
6
r
+, such
20
20
20
20
20
20
20
20
tron rich aryl rings of the anilines with large and negative
as, 2a and 2b. The charge in the transition state is thereby delocal-
ized within the aryl rings of the reacting adduct. This interpreta-
tion is made with caution and would be limited to electron poor
aryl aziridines. Unfortunately, with our data the two mechanisms
involving specific base catalysis or adduct formation are kinetically
indistinguishable from an unassisted nucleophilic reaction.
Although we do not yet have a detailed mechanism for this
reaction, we believe that water plays an important role in the rate
and selectivity. There are examples of catalyzed aqueous ring
opening reactions of aziridines and epoxides.4 Qu et al.2 have dem-
onstrated the uncatalyzed reaction of electron rich aziridines (R
group on nitrogen = H, alkyl, aryl) and epoxides in hot water. Under
their conditions the reactions may proceed by an SN2 mechanism
that is proton-assisted due to the increased [H+] of water at ele-
vated temperatures. Interestingly, Saidi5 had previously reported
the uncatalyzed ring opening of aziridines and epoxides at room
temperature, albeit with longer reaction times. The unassisted ring
opening of aziridines bearing electron deficient nitrogen (R = CO2R,
SO2R and COR) is known in organic solvents but typically requires
higher temperatures and longer reaction times6 (the times are im-
proved with base or use of microwave radiation7). Our unassisted
aqueous ring opening reactions are faster than those reported in
organic solvents. Based on the fit with second order kinetics and
the influence of substituent parameters we propose that the ring
opening reactions of 3a–f are specific base catalyzed due to the ele-
vated [OHꢀ] at 50 °C.
The situation with 3g–j is mechanistically distinct. Our rate
expression (in terms of [1]) for 3a–f has no limiting cases where
it takes the form of a zero order equation. The significantly lowered
rate constant and the different kinetics point to a different mecha-
nism for 3g–j, perhaps one in which the physical interaction of 2g–
j with water is even more critical to the chemical reactivity.
For our studies we did not vary the aniline to aziridine ratio to
probe the effect of nucleophile stoichiometry on product selectiv-
ity. The 2:1 nucleophile/electrophile ratio is typical of ring opening
reactions of aziridine in water.2,8 In organic solvents the stoichiom-
etry ranges from 1:19 to 4:110 and there does not seem to be a pat-
tern in the product yield. In contrast to these studies that use of
substituted aziridines, we employ the parent (unsubstituted) N-
tosylaziridine which is perhaps most prone to multiple addition
reactions. However, we anticipate the effect of reactant stoichiom-
etry on product selectivity to be very complex. Kinetic expression
for a system of consecutive second order reactions, such as the
reaction scheme in Figure 1, have been obtained11 that describe
the time-dependency of the product selectivity as a function of
the ratio of the rate constants for the competing reactions (k1/k2).
These expressions can be used for non-stoichiometric reactant con-
centrations;11c however, the initial reactant ratio can only affect
the time during and the reaction when the optimum selectivity
is achieved. Furthermore, optimal selectivity may not correspond
to high conversions. A complete analysis of this problem requires
a rigorous kinetic study that is beyond the scope of this Letter.
Moreover, even if increasing the aniline/aziridine ratio leads to in-
creased selectivity for mono-addition product for a 1 h reaction at
50 °C, that increase in yield comes at the expense of lower atom
economy (excess reactant) resulting in an overall less efficient
synthesis.
Cl
CF3
COCH3
CN
18
0
18
0
3j
NO2
a
Based on 1.
Based on 3.
b
at 25 °C. However, the conversions were lower at this temperature,
especially for the more electron withdrawing anilines, and the reac-
tion time was increased considerably. Increasing the temperature
to 75 °C led to unpredictable results and irregular trends in conver-
sion and selectivity relative to the reactions at 50 °C. It appears that
the best yields are obtained at 25 °C for electron rich anilines and at
50 °C for electron poor anilines.
Interestingly, N-tosylaziridine is insoluble in water at room
temperature but becomes more soluble at 50 °C. At the same tem-
perature, the 0.1 mM aniline derivatives are water soluble. There is
a growing interest in the aqueous phase reactions of substrates
that are insoluble in water but show rate accelerations relative to
organic solvents. These ‘on water’ reactions that do not form a
homogeneous phase have been investigated12 and reviewed.13 In
our case, water is the catalyst for activation of the aniline nucleo-
philes toward ring opening of aziridines In fact, this activation is
powerful enough that with the strongly electron donating 4-
dimethylamino group multiple subsequent ring opening reactions
are promoted, forming several oligomers in addition to the initial
diamine. This is supportive of an enhanced nucleophilic property
of the anilines for ‘on water’ reactions.
In summary, we have synthesized a series of N-(p-X-phenyl)-N0-
(p-toluenesulfonyl)1,2-ethylenediamine derivatives, 3a–j, by the
unassisted ring opening reaction of N-tosylaziridine with anilines
in water at 50 °C. This is a practical synthesis that works well for
both electron donating and electron withdrawing substituents.
The work-up of the reaction is simple and the procedure is amena-
ble to large-scale synthesis. The use of water as a solvent makes
this a green chemical synthesis alternative to traditional methods.
In addition to its environmental benefits, we believe that the reac-
tion is in fact accelerated by water.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.076.
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