Br?nsted acid-promoted aziridination of electron-deficient olefins

Article abstract of DOI:10.1016/j.tet.2008.09.060

A combined theoretical and experimental approach was used to systematically study the Br?nsted acid-promoted aziridination of electron-deficient olefins. It was found that Br?nsted acid-promoted aziridination of electron-deficient olefins proceeded through the attack of the internal nitrogen of the azide to the terminal carbon of protonated olefin, which afforded an acyclic adduct that subsequently discharged N₂ to produce the aziridine ring. The basicity of the electron-deficient olefins is an important parameter to determine the efficiency of Br?nsted acid-promoted aziridination. More basic carbonyl compounds including vinyl ketones and acrylamides were predicted to be readily activated by Br?nsted acid such as TfOH, whereas less basic carbonyl compounds were predicted to be poor substrates. Significantly, all these theoretical predictions were demonstrated to be consistent with the experimental data. Furthermore, a systematic evaluation of TfOH-promoted aziridination of acrylamides was performed, which established a new, single-step method for the preparation of a number of aziridine-2-carboxamides.

Full text of DOI:10.1016/j.tet.2008.09.060

Tetrahedron 64 (2008) 11167–11174
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Brønsted acid-promoted aziridination of electron-deficient olefins
*
*
Juan Li, Yao Fu , Qing-Xiang Guo
Department of Chemistry, Joint Laboratory of Green Synthetic Chemistry, University of Science and Technology of China, Hefei 230026, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A combined theoretical and experimental approach was used to systematically study the Brønsted acid-
promoted aziridination of electron-deficient olefins. It was found that Brønsted acid-promoted aziridi-
nation of electron-deficient olefins proceeded through the attack of the internal nitrogen of the azide to
the terminal carbon of protonated olefin, which afforded an acyclic adduct that subsequently discharged
N2 to produce the aziridine ring. The basicity of the electron-deficient olefins is an important parameter
to determine the efficiency of Brønsted acid-promoted aziridination. More basic carbonyl compounds
including vinyl ketones and acrylamides were predicted to be readily activated by Brønsted acid such as
TfOH, whereas less basic carbonyl compounds were predicted to be poor substrates. Significantly, all
these theoretical predictions were demonstrated to be consistent with the experimental data. Further-
more, a systematic evaluation of TfOH-promoted aziridination of acrylamides was performed, which
established a new, single-step method for the preparation of a number of aziridine-2-carboxamides.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 25 July 2008
Received in revised form
17 September 2008
Accepted 19 September 2008
Available online 27 September 2008
1. Introduction
because of the difficulty encountered in the isolation of reaction
intermediates, it raises a serious question as to how the Brønsted
Organic azides are energy-rich and flexible intermediates that
present a broad range of chemical reactivity.1 The utilization of
these azides in organic synthesis has enjoyed considerable interest
over the past few decades, where they play the role of either
electrophile or nucleophile. Previous groundbreaking efforts of
Sharpless,2 Aube´,3 and several other groups have allowed the
synthesis of a variety of nitrogen-containing heterocycles from
organic azides. In particular, the [3þ2] cycloaddition reaction of
azides with olefins has been intensively studied for the preparation
of triazolines,4 which can be subsequently converted to syntheti-
cally more valuable intermediates, i.e., aziridines, through thermal5
or photochemical6 decomposition (Scheme 1). Nonetheless, a bot-
tleneck problem of this olefin aziridination method is that the
[3þ2] cycloaddition reaction tends to be extremely sluggish, which
may take weeks, or even months, at room temperature to get only
partial completion.7
To overcome the efficiency problem in the olefin aziridination
reaction, Johnston et al. reported in 2005 a highly interesting
finding that a Brønsted acid (namely, TfOH) could promote addition
of azides to electrophilic olefins, delivering the corresponding
aziridines in good yield under relatively mild, non-redox condi-
tions.8 The significance of this discovery is manifested by the fact
that olefin aziridination and subsequent ring-opening reactions can
form the basis for more complex target synthesis.9 Meanwhile,
acid accelerates the aziridination. In their study, Johnston et al.
proposed that the triazoline did not need to be an intermediate and
that rate acceleration and selective formation of the aziridine might
be explained by an unprecedented transition state (Scheme 1).8
However, since almost nothing has been known about the possible
occurrence of such a triangular transition state in the chemistry of
organic azides, more mechanistic examinations on this newly dis-
covered aziridination reaction remain necessary.
In the present study, we sought to study the mechanism of the
Brønsted acid-promoted olefin aziridination reaction using a com-
bined theoretical and experimental approach. Our major question
is how a Brønsted acid could dramatically accelerate the olefin
aziridination reaction. To answer this question, we carefully com-
pared the reaction pathway that involved the conventional
N2
R
N
N
N
N
thermal
EWG
R
EWG
Very sluggish
R
N3
+
EWG
δ
TfOH
R
N
H
δ
R
N2
O
N
R1
R'
EWG
H
(EWG = COR')
Very rapid
* Corresponding authors. Tel.: þ86 551 3607476; fax: þ86 551 3606689.
E-mail address: fuyao@ustc.edu.cn (Y. Fu).
Scheme 1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.060

11168
J. Li et al. / Tetrahedron 64 (2008) 11167–11174
triazoline intermediate with the one that involved the unusual
triangular transition state. In this way, we established the first
theoretical model that could interpret the experimental behavior
for the olefin aziridination reactions. To further corroborate our
theoretical model, we next examined the scope of Johnston’s azir-
idination reaction by considering the effects of substitution on the
azide and olefin substrates. To our satisfaction, we found that the
substituent effects predicted by the theoretical model were con-
sistent with the experimental results previously reported as well as
newly obtained by us, thereby providing further support for the
mechanism discussed in the present work. Furthermore, we sys-
tematically evaluated the efficiency of the Brønsted acid-promoted
aziridination reactions of acrylamides for the first time.
[3þ2] cycloaddition transition state for the formation of a pro-
tonated triazoline 6. Besides, we could not find the triangular
transition state (Scheme 1) proposed by Johnston et al.8 Nonethe-
less, we eventually discovered an interesting transition state (TS3)
where the internal nitrogen of the azide 1 attacked the terminal
carbon of protonated 3-butenone (3) nucleophilically. In this
transition state, the N–N–N angle (167.8ꢁ) remained close to 180ꢁ,
as opposed to 140.4ꢁ observed in the [3þ2] transition state TS1. The
IRC analysis from TS3 led to an acyclic adduct 7 (a zwiterionic in-
termediate) as a local minimum on the potential energy surface
(see Fig. 2). The solution-phase activation free energy associated
with TS3 was þ13.4 kcal/mol in acetonitrile from 1þ3. The forma-
tion of 7 in acetonitrile had a positive free energy of þ11.6 kcal/mol
calculated from 1þ3.
From intermediate 7, we next successfully located the transition
state (TS4) for the extrusion of nitrogen. The IRC analysis from this
transition state to the two associated minima, 7 and 9, indicated
that the nitrogen extrusion and the aziridine-ring formation took
place through a concerted process. The solution-phase activation
free energy associated with TS4 was þ11.3 kcal/mol in acetonitrile
from 7. The formation of 9 in acetonitrile had a large negative free
energy of ꢀ39.3 kcal/mol calculated from 1þ3. Finally, intermediate
9 should undergo a rapid proton exchange reaction with the me-
dium to produce the final product 8.
Comparing the reaction free energy profiles (Fig. 3), we found
that pathway I had two high barriers to overcome, i.e., the forma-
tion of the triazoline intermediate (þ29.4 kcal/mol) and the ex-
trusion of nitrogen from the triazoline (þ30.4 kcal/mol). Because
the triazoline intermediate has a lower free energy than the
starting material, the observed kinetics should be mainly de-
termined by the second step with a barrier of þ30.4 kcal/mol. In
comparison, pathway II includes two relatively facile steps, i.e., the
formation of an acyclic adduct (þ13.4 kcal/mol) and the extrusion
of nitrogen (þ11.3 kcal/mol). Because all the intermediates before
the nitrogen extrusion step had higher energies than the starting
material, the observed kinetics should be determined by an overall
barrier of þ27.5 kcal/mol.
2. Results and discussion
2.1. General mechanism
To simplify the calculation, we firstly studied the reaction be-
tween azidomethane (1) and 3-butenone (2) to produce 1-(1-
methylaziridin-2-yl)ethanone (8) in acetonitrile solution (Fig. 1).
Two reaction pathways were considered to be different from each
other due to the presence or absence of TfOH. In the first pathway
under the neutral condition, a bimolecular collision between 1 and
2 might take place to produce either a cyclic adduct (4) or an acyclic
one (5). Through B3LYP/6-31þG(p,d) optimizations, it was found
that 5 was not a local minimum (i.e., 5 cannot be obtained through
the optimization). Thus we ruled out the possible involvement of 5
as an intermediate.
As to the triazoline intermediate 4, a classical [3þ2] cycload-
dition transition state (TS1) can be readily located (Fig. 2), where
3-butenone acted as a dipolarophile and azidomethane acted as
the dipole. The solution-phase activation free energy associated
with TS1 was þ29.4 kcal/mol in acetonitrile (Fig. 3). The formation
of 4 in acetonitrile had a negative free energy of ꢀ4.8 kcal/mol.
From 4, we then successfully located the transition state (TS2) for
the opening of triazoline through nitrogen extrusion to produce
the final product 8. The solution-phase activation free energy as-
sociated with the nitrogen extrusion step was þ30.4 kcal/mol in
acetonitrile.
Evidently, the difference between þ30.4 and þ27.5 kcal/mol by
ca. 3 kcal/mol means that pathway II should be faster than pathway
I by about 102 fold. This result is in good agreement with the ex-
perimental observations. On the basis of the above results, we can
finally draw the general mechanism for olefin aziridination under
the neutral or Brønsted acid-promoted condition, respectively
(Fig. 4).
For the second pathway under the acidic condition, it was found
that the protonation of 3-butenone by TfOH had a positive free
energy of þ4.6 kcal/mol in acetonitrile. Surprisingly, from 1 and
protonated 3-butenone (3) all attempts failed to locate the classical
N
N2
Path I
N
N
I
4
Me N3
1
O
O
N
N
N
2
II
TfOH
O
5
O
N
N
8
N
N
TfO-
(transition state
not found)
TfOH
TfO-
III
Me N3
1
6
O
H
O
3
H
N
N
N
N2
IV
OH
N
Path II
9
7
OH
Figure 1. Possible pathways for the reaction between azidomethane and 3-butenone.

J. Li et al. / Tetrahedron 64 (2008) 11167–11174
11169
1.167
1.140
167.8
1.133
1.269
1.240
140.4
99.2
106.5
108.6
2.121
2.201
1.472
3.179
1.403
2.322
1.483
2.050
104.5
1.389
2.275
93.4
1.404
90.7
1.466
106.2
1.384
1.489
1.321
1.516
1.231
1.516
1.229
TS1
TS2
TS3
1.127
119.3
1.128
1.266
3.310
1.803
116.7
113.8
1.582
1.441
1.386
1.473
1.481
1.492
1.330
TS4
7
Figure 2. Three-dimensional structures for TS1–TS4 and 7. The bond lengths directly involved in the reaction are given in angstrom.
2.2. Effects of substituents on azides
only slightly lower than that for azidobenzene (i.e., 28.7 kcal/mol),
whereas benzyl azide has an intermediate value, 28.2 kcal/mol.
The above calculations indicate that the effect of substitution on
the azide is not significant for the Brønsted acid-promoted olefin
aziridination reaction (1 kcal/mol difference in barrier means ca.
10-fold difference in rate). Noteworthy, Johnston et al. reported
yields of 93%, 79%, and 43% for the aziridination by adamantyl
azide, benzyl azide, and 1-azido-4-methoxybenzene, respectively.8
Thus, the experiments also showed that differently substituted
azides could be converted to the desired products under the same
reaction conditions, where alkyl azide was slightly more reactive
than benzyl azide and aryl azide.
Having studied the general mechanism for the Brønsted acid-
promoted olefin aziridination reaction, we then examined the ef-
fects of substituents on its efficiency. The results from such sub-
stituent effect studies may not only help us to understand the scope
of the reaction, but also test whether or not our proposed mecha-
nism is valid.
First, we fixed the olefin as 3-butenone. Three types of organic
azides, namely, azidomethane, azidobenzene, and benzyl azide,
were selected to represent alkyl, aryl, and benzylic azide, re-
spectively. It was found that for the formation of the olefin–azide
adduct through TS3, methyl azide had a much lower free energy
barrier than phenyl azide by about 8 kcal/mol (Fig. 5). This obser-
vation can be readily explained by the fact that the internal nitro-
gen of methyl azide is more nucleophilic than the internal nitrogen
of phenyl azide, presumably because of the better electron-donat-
ing ability of methyl group than that of phenyl. On the other hand,
the better electron-donating ability of the methyl group also makes
the extrusion of nitrogen from adduct 7 more difficult than the
phenyl case. Thus, the overall effect is that the free energy barrier
for the olefin aziridination by azidomethane (i.e., 27.5 kcal/mol) is
2.3. Effects of substituents on olefins
Johnston et al. reported the Brønsted acid-promoted addition of
organic azides to methyl vinyl ketone.8 It remains unclear whether
or not the other electron-deficient olefins (e.g., acrylate esters, ac-
rylonitriles, and acrylamides) can also participate in this reaction.
To solve this problem, we use theoretical method as discussed
above to model the reactions of benzyl azide with methyl acrylate,
acrylonitrile, and acrylamide in acetonitrile in the presence or ab-
sence of TfOH.
As to the reaction of benzyl azide with methyl acrylate, it is
found that the un-catalyzed reaction in the absence of TfOH has an
almost identical free energy profile as compared to the reaction of
3-butenone (pathway I in Fig. 6). The rate-limiting step is the
[3þ2] cycloaddition step to form the triazoline intermediate,
which has a free energy barrier of 31.3 kcal/mol (as compared to
30.4 kcal/mol for 3-butenone). On the other hand, we are very
surprised to find that the reaction of benzyl azide with methyl
acrylate in the presence of TfOH has a dramatically different free
energy profile as compared to the reaction of 3-butenone (path-
way II in Fig. 6). Firstly, it is found that the aziridination of methyl
acrylate in the presence of TfOH has a much higher free energy
barrier (i.e., 42.0 kcal/mol) as compared to that for 3-butenone
(i.e., 27.5 kcal/mol). Secondly, the aziridination of methyl acrylate
in the presence of TfOH actually has a much higher free energy
barrier (42.0 kcal/mol) than that in the absence of TfOH
(31.3 kcal/mol). This means that TfOH cannot promote the azir-
idination of methyl acrylate, despite the fact that methyl acrylate
is a typical electron-deficient olefin!
Pathway I
Pathway II
TS1 (29.4)
TS4 (27.5)
TS2
(11.3)
(17.9)
(25.7)
TS3
29.4
7 (16.2)
(13.4)
(30.4)
1+3
(4.6)
1+2
4
(0.0)
(-4.8)
9
(-34.7)
8
(-39.8)
Reaction Coordination
Figure 3. Free energy profiles (in kcal/mol) for the two proposed pathways.

11170
J. Li et al. / Tetrahedron 64 (2008) 11167–11174
N
N
N
N
R'
N
N
R
R'
N
N
R
N
N
N
R'
R
O
R
R
O
R'
O
O
O
TfOH
R
TfO-
R
R'
N
N
N
N
N
N
N
N
R'
N
O
R
H
R'
O
H
R
H
OH
R
OH
R'
O
Figure 4. General mechanism for olefin aziridination under the neutral or Brønsted acid-promoted condition.
The above surprising observation requires an explanation. To this
Finally, for the reaction of benzyl azide with acrylamide, it is
found that the rate-limiting step in the absence of TfOH (pathway I
in Fig. 8) is the [3þ2] cycloaddition, which has a free energy barrier
of 32.7 kcal/mol. Interestingly, it is also found that the reaction of
benzyl azide with acrylamide in the presence of TfOH (pathway II in
Fig. 8) has a lower free energy barrier of 27.8 kcal/mol. These results
indicate that: (1) TfOH can promote the aziridination of acrylamide
byaccelerating the reaction byca.103- to 104-fold in rate (or 4.9 kcal/
mol in free energy barrier); (2) TfOH-promoted aziridination of
acrylamide (barrier¼27.8 kcal/mol) is only slightly slower than
TfOH-promoted aziridination of 3-butenone (barrier¼27.5 kcal/
mol). Noteworthy, the high reactivity of acrylamide as compared to
methyl acrylate and acrylonitrile can be readily attributed to the
good basicity of the amidyl carbonyl, whose protonation by TfOH in
acetonitrile has a negative free energy of ꢀ4.8 kcal/mol (Fig. 8).
Our above calculations show that Brønsted acid-promoted
aziridination of electron-deficient olefins has a dramatic de-
pendence on the substituents in the olefins. More basic carbonyl
compounds including vinyl ketones and acrylamides are easier to
be activated by the Brønsted acids, whereas less basic carbonyl
compounds including acrylate esters and acrylonitriles are not
good substrates in the reaction. To validate the theoretical pre-
dictions, we have examined the TfOH-promoted aziridination re-
actions of different electron-deficient olefins (Table 1). Through the
product analysis, we are able to identify the aziridine products for
all the olefin substrates. However, good yields are obtained only for
3-butenone and acrylamide,10 whereas the yields for acrylonitrile
end, we pay attention to the individual steps in pathway II of Fig-
ure 6. It is then recognized that the protonation of methyl acrylate in
acetonitrile by TfOH requires a free energy change of þ13.3 kcal/
mol, whereas the protonation of 3-butenone requires a free energy
change of þ4.6 kcal/mol. The ca. 9 kcal/mol difference in the pro-
tonation free energy means that methyl acrylate is much less basic
than 3-butenone (at their carbonyl oxygens). Because of the highly
unfavorable free energy cost in the protonation step, Brønsted acid
as strong as TfOH cannot promote the aziridination of methyl ac-
rylate in acetonitrile. A stronger Brønsted acid might be able to
promote this reaction, or the solvent should be re-optimized.
As to the reaction of benzyl azide with acrylonitrile, observa-
tions similar to the methyl acrylate case have been obtained for the
free energy profiles in the absence or presence of TfOH. For the
aziridination in the absence of TfOH (pathway I in Fig. 7), the rate-
limiting step is again the [3þ2] cycloaddition, which has a free
energy barrier of 31.3 kcal/mol. On the other hand, the reaction of
benzyl azide with acrylonitrile in the presence of TfOH (pathway II
in Fig. 7) has a much higher free energy barrier of 41.3 kcal/mol.
Thus, TfOH cannot promote the aziridination of acrylonitrile, de-
spite the fact that acrylonitrile is also a typical electron-deficient
olefin. The explanation of this observation is again associated with
the protonation free energy, which amounts to þ11.2 kcal/mol for
acrylonitrile (at its terminal nitrogen atom) as compared to
þ4.6 kcal/mol for 3-butenone.
1a, R=Me
(28.7)
(28.2)
(27.5)
ts4
30
1b, R=Bn
1c, R=Ph
ts3
7
50
20
10
TS4(42.0)
40
Pathway I
(9.2)
TS3(33.9)
Pathway II
7
TS2(28.6)
30
20
(32.8)
TS1 (31.3)
(20.5)
1+3
0
(31.3)
1+2
(31.3)
1+3
10
(13.3)
-10
-20
-30
-40
-50
1+2
0
4
(0.0)
(-2.7)
-10
-20
-30
-40
9
9
(-20.6)
8
Reaction between 1b + 2b
8
(-38.4)
Reaction Coordination
Reaction Coordination
Figure 6. Free energy profiles (in kcal/mol) for olefin aziridination between methyl
acrylate and benzyl azide in the absence (pathway I) or presence (pathway II) of TfOH
in acetonitrile.
Figure 5. Free energy profiles (in kcal/mol) for olefin aziridination by methyl, phenyl,
and benzyl azides under Brønsted acid-promoted condition.

J. Li et al. / Tetrahedron 64 (2008) 11167–11174
11171
Table 1
50
40
30
20
10
0
Brønsted acid-promoted aziridination of different electron-deficient olefinsa
TS4(41.3)
Pathway I
Entry
Olefin
Isolated yield (%)
(13.4)
7
Pathway II
TS3(31.5)
TS2
1
2
3
4
3-Butenone
Acrylamide
76 (79b)
72
TS1
(28.8)
(27.9)
(31.3)
(20.3)
Acrylonitrile
Methyl acrylate
10
20
(31.3)
1+3
29.8
(11.2)
a
General reaction conditions: organic azide (4.5 mmol), olefin (3.0 mmol), TfOH
(3.6 mmol), CH3CN (10 mL), 0 ꢁC to room temperature, 48 h.
1+2
4
b
(0.0)
(-1.0)
Yield previously reported in Ref. 8.
-10
-20
-30
-40
Table 2
9
Brønsted acid-promoted olefin aziridination of acrylamidesa
(-26.3)
Reaction between 1b + 2c
8
R3
R1
H
R3
N
R2
(-35.6)
H
N
TfOH
rt
0 °C
CH3CN, 48h
R4
+
R1 N3
N
R2
O
Reaction Coordination
O
R4
Figure 7. Free energy profiles (in kcal/mol) for olefin aziridination between acryloni-
trile and benzyl azide in the absence (pathway I) or presence (pathway II) of TfOH in
acetonitrile.
Entry
1
Azide
Amide
Compound Isolated yield (%)
NH2
N3
10
11
12
13
72
53
64
54
and methyl acrylate are considerably lower.11,12 These experiments
are consistent with our theoretical analyses.
O
H
N
N3
N3
N3
2
3
4
O
O
O
H
N
2.4. Brønsted acid-promoted aziridination of acrylamides
Johnston et al. reported the Brønsted acid-promoted reaction of
organic azides with methyl vinyl ketone and methyl acryl-
oyl(benzyl)carbamate.8 The former substrate gave aziridines as the
products, whereas the later substrate produced oxazolidine diones.
They have not studied the aziridination of acrylamides, which,
however, was predicted by the above calculations to be a relatively
facile reaction. Because this reaction can produce aziridine-2-car-
boxamides as highly interesting intermediates in organic synthesis
through their regio- and stereo-selective ring openings,13 we de-
cided to systematically evaluate this reaction in the present study.
Noteworthy, the previous syntheses of aziridine-2-carboxamides
normally required the preparation of the corresponding aziridine
esters or nitriles at first followed by their aminolysis or hydrolysis.14
Compared to the previous two-step methods, the current one-step
synthesis from readily available starting materials (organic azide
and acrylamides) is evidently an appealing approach.
H
N
C12H25
NH2
N3
N3
N3
N3
5
6
7
14
15
16
48
41
54
O
O
O
H
N
O
O
O
H
N
O
O
H
N
8
17
18
19
43
60
40
C12H25
NH2
n-C15H31
9
N3
Shown in Table 2 are the detailed isolated yields for the TfOH-
promoted reactions of various organic azides with different acryl-
amides affording aziridine-2-carboxamides as the mainproducts. It is
O
H
N
n-C15H31
10
N3
N3
N3
O
O
O
H
N
Pathway I
40
n-C15H31
n-C15H31
11
12
13
20
21
22
56
40
43
TS1 (32.7)
Pathway II
TS2 (28.9)
TS4 (27.8)
30
(23.7)
TS3
(2.7)
7
H
N
20
10
C12H25
NH2
32.7
(25.1)
(32.5)
N3
(28.6)
1+2
0
4
1+3
(0.0)
O
(-4.8)
(-4.8)
-10
-20
-30
-40
-50
N3
N3
N3
H
N
14
15
16
23
24
25
31
42
O
O
O
8
Reaction between 1b + 2d
H
N
9
(-37.3)
(-42.1)
Reaction Coordination
H
N
Figure 8. Free energy profiles (in kcal/mol) for olefin aziridination between acryl-
amide and benzyl azide in the absence (pathway I) or presence (pathway II) of TfOH in
acetonitrile.
40
C12H25
(continued on next page)

11172
J. Li et al. / Tetrahedron 64 (2008) 11167–11174
Table 2 (continued )
4. Experimental
Entry
Azide
Amide
NH2
Compound Isolated yield (%)
4.1. Theoretical method
N3
N3
N3
N3
17
26
27
28
29
d
59
47
50
56
0
All calculations were carried out with the Gaussian 03 suite of
programs.15 Density functional theory (DFT) calculations were
carried out using the B3LYP exchange-correlation functional, to-
gether with the standard 6-31þG(p,d) (for geometry optimization)
and 6-311þþG(d,p) (for single-point energy calculation) basis sets.
The potential energy surface was explored in detail to ensure that
all relevant stationary points were located and properly charac-
terized. Berny analytical gradient optimization routines were used
for the geometry optimization. The stationary points were char-
acterized by frequency calculations in order to verify that the
transition states had one and only one imaginary frequency. The
intrinsic reaction coordinate (IRC) path was traced to obtain and
check the energy profiles connecting each transition state to the
two associated minima of the proposed mechanism by using the
O
H
N
18
19
20
21
O
O
O
H
N
H
N
C12H25
NH2
N3
O
N3
NH2
´
second order Gonzalez–Schlegel integration method. Relative en-
22
d
0
thalpies ( H), entropies ( S), and free energies ( G) were calcu-
D
D
D
O
lated with the standard statistical thermodynamics at 298.15 K. The
solvent effects, modeled as a continuum medium, were considered
by performing single-point B3LYP/6-311þþG(d,p) calculations us-
ing the self-consistent reaction field (SCRF) based on the polariz-
able continuum model (PCM) of Tomasi’s group.16,17 Acetonitrile
was used as solvent. Note that a number of recent studies have
shown that it is sufficiently reliable to use the B3LYP method
augmented with appropriate basis sets to investigate the mecha-
nism of the [3þ2] cycloaddition reactions.18
a
General reaction conditions: organic azide (4.5 mmol), acrylamide (3.0 mmol),
TfOH (3.6 mmol), CH3CN (10 mL), 48 h.
found that both benzylic and normal alkyl azides can smoothly react
with unsubstituted acrylamides to give the desired products as white
solid in ca. 50–70% isolated yields (entries 1, 5, 9, 13, and 17).
Substituted acrylamides carrying substituents at the nitrogen atom
can also participate in the reaction, albeit with slightly lower yields
(ca. 30–60%). Furthermore, 2- or 3-substituted acrylamides cannot
afford the desired aziridine-2-carboxamides under the TfOH condi-
tions (entries 21 and 22). Noteworthy, the reported yields for TfOH-
promoted aziridination of 3-butenones were mostly around 70%,8
which are relatively higher than the yields for the aziridination of
acrylamides. A possible explanation is that acrylamides are more
reactive than 3-butenone toward some yet unclear side reactions
under the TfOH conditions, as we observe significant amounts of
highly polar byproduct mixtures in the aziridination of acrylamides.
4.2. Aziridination of acrylamides
4.2.1. Typical experimental procedure
A solution of the acrylamide (3.0 mmol) in acetonitrile (10 mL)
was cooled to 0 ꢁC and treated with triflic acid (3.6 mmol). Organic
azide (4.5 mmol) was then added in one portion and the reaction
mixture was allowed to stir for 48 h while attaining room tem-
perature. The reaction mixture was then diluted with ethyl acetate
and washed with 1 M aqueous NaOH. The organic layer was dried
over MgSO4 and concentrated. The residue was purified on a silica
gel column with petroleum ether/ethyl acetate as the eluent to
provide the desired product.
3. Conclusions
In the present work, we have utilized both the theoretical and
the experimental methods to systematically study the Brønsted
acid-promoted aziridination reaction of electron-deficient olefins.
We have the following major conclusions:
4.2.2. 1-Benzylaziridine-2-amide (10)
Prepared as a white solid. IR (KBr) 3405, 3207, 3031, 2926, 2853,
1671, 1636, 1498, 1450, 738, 697 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d
7.38–7.29 (m, 5H), 6.40 (br, 1H), 5.19 (br, 1H), 3.56 (d, J¼13.5 Hz,
(1) Brønsted acid-promoted aziridination reaction of electron-de-
ficient olefins does not undergo the classical [3þ2] cycloaddi-
tion mechanism. It proceeds through the attack of the internal
nitrogen of the azide to the terminal carbon of protonated
electron-deficient olefin, which affords an acyclic adduct that
subsequently discharges N2 to produce the aziridine ring.
(2) The basicity of the electron-deficient olefins is an important
parameter to determine the efficiency of Brønsted acid-pro-
moted aziridination. More basic carbonyl compounds including
vinyl ketones and acrylamides are predicted to be readily acti-
vated by Brønsted acid as strong as TfOH, whereas less basic
carbonyl compounds including acrylate esters and acrylonitriles
are predicted to be poor substrates under the TfOH conditions.
(3) The theoretical predictions are consistent with all the available
experimental results previously reported or newly obtained in
the present study. In particular, our systematic evaluation of
TfOH-promoted aziridination of acrylamides establishes a new,
single-step method for the preparation of a number of azir-
idine-2-carboxamides from acrylamides and organic azides.
1H), 3.50 (d, J¼13.5 Hz, 1H), 2.18 (dd, J¼7.2, 2.7 Hz, 1H), 2.06 (d,
J¼2.7 Hz, 1H), 1.80 (d, J¼7.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) ppm
173.7, 138.0, 128.6, 128.0, 127.6, 63.1, 39.0, 35.3; HRMS (EI) exact
mass calcd for C10H12N2O [M]þ 176.0950, found 176.0938.
4.2.3. 1-Benzylaziridine-2-(N-phenyl)amide (11)
Prepared as a white solid. IR (KBr) 3435, 3286, 3134, 3059, 2933,
2844, 1661, 1601, 1539, 1499, 1444, 1310, 754, 721, 692 cmꢀ1 1H
;
NMR (300 MHz, CDCl3)
d
8.36 (br, 1H), 7.50 (d, J¼7.5 Hz, 2H), 7.40–
7.25 (m, 7H), 7.08 (t, J¼7.3 Hz, 1H), 3.66 (d, J¼13.3 Hz, 1H), 3.55 (d,
J¼13.3 Hz, 1H), 2.34 (dd, J¼6.9, 3.0 Hz, 1H), 2.11 (d, J¼3.0 Hz, 1H),
1.88 (d, J¼6.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) ppm 168.3, 137.6,
137.4, 128.9, 128.6, 128.0, 127.6, 124.1, 119.5, 62.7, 39.4, 35.2; HRMS
(EI) exact mass calcd for C16H16N2O [M]þ 252.1263, found 252.1256.
4.2.4. 1-Benzylaziridine-2-(N-cyclohexyl)amide (12)
Prepared as a white solid. IR (KBr) 3274, 3086, 3030, 2926, 2851,
1648, 1558, 1448, 1424, 1267, 1026, 733, 696 cmꢀ1
;
1H NMR
(300 MHz, CDCl3)
d 7.37–7.28 (m, 5H), 6.41 (br, 1H), 3.69–3.66 (m,

J. Li et al. / Tetrahedron 64 (2008) 11167–11174
11173
1H), 3.56 (d, J¼13.5 Hz, 1H), 3.47 (d, J¼13.5 Hz, 1H), 2.17 (dd, J¼6.9,
3.0 Hz, 1H), 1.93 (d, J¼3.0 Hz, 1H), 1.86–1.81 (m, 2H), 1.75 (d,
J¼6.9 Hz, 1H), 1.69–1.56 (m, 2H), 1.36–1.06 (m, 6H); 13C NMR
(75 MHz, CDCl3) ppm 169.3, 138.0, 128.5, 127.9, 127.4, 62.9, 47.3,
39.3, 35.2, 32.9, 25.5, 24.7; HRMS (EI) exact mass calcd for
C16H22N2O [M]þ 258.1732, found 258.1736.
(m, 24H), 0.87 (t, J¼6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) ppm 174.1,
60.0, 38.9, 35.3, 32.0, 29.8, 29.7, 29.6, 29.5, 27.4, 22.8, 14.2; HRMS (EI)
exact mass calcd for C19H38N2O [M]þ 310.2984, found 310.2979.
4.2.11. 1-n-Hexadecylaziridine-2-(N-phenyl)amide (19)
Prepared as a white solid. IR (KBr) 3432, 3250, 3197, 3139, 3080,
2919, 2850, 1658, 1603, 1550, 1501, 1468, 1444, 1315, 753, 721,
4.2.5. 1-Benzylaziridine-2-(N-n-dodecyl)amide (13)
690 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 8.36 (br, 1H), 7.51 (d,
Prepared as a white solid. IR (KBr) 3427, 3299, 3061, 2920, 2851,
J¼7.8 Hz, 2H), 7.32–7.24 (m, 2H), 7.06 (t, J¼7.3 Hz, 1H), 2.44–2.29
(m, 2H), 2.09 (dd, J¼6.9, 2.8 Hz, 1H), 1.98 (d, J¼2.8 Hz, 1H), 1.67 (d,
J¼6.9 Hz, 1H), 1.61–1.53 (m, 4H), 1.29–1.20 (m, 24H), 0.86 (t,
J¼6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) ppm 168.8, 137.6, 129.0,
124.1, 119.4, 59.6, 39.5, 35.3, 32.0, 29.8, 29.7, 29.6, 29.5, 29.4, 27.4,
22.7, 14.2; HRMS (EI) exact mass calcd for C25H42N2O [M]þ
386.3297, found 386.3304.
1645, 1549, 1466, 726, 697 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.37–
7.32 (m, 5H), 6.53 (br, 1H), 3.55 (d, J¼13.5 Hz, 1H), 3.49 (d,
J¼13.5 Hz, 1H), 3.23–3.12 (m, 2H), 2.21 (dd, J¼6.7, 2.8 Hz, 1H), 1.95
(d, J¼2.8 Hz, 1H), 1.77 (d, J¼6.7 Hz, 1H), 1.45–1.43 (m, 2H), 1.31–1.20
(m, 18H), 0.88 (t, J¼6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) ppm
170.3, 138.1, 128.6, 128.1, 127.6, 63.1, 39.3, 38.9, 35.3, 32.0, 29.7, 29.6,
29.4, 26.9, 22.8, 14.2; HRMS (EI) exact mass calcd for C22H36N2O
[M]þ 344.2828, found 344.2819.
4.2.12. 1-n-Hexadecylaziridine-2-(N-cyclohexyl)amide (20)
Prepared as a white solid. IR (KBr) 3277, 3088, 2923, 2843, 1651,
4.2.6. 1-(p-Methoxybenzyl)aziridine-2-amide (14)
1559, 1469 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 6.41–6.39 (br, 1H),
Prepared as a white solid. IR (KBr) 3405, 3206, 2933, 2842, 1632,
3.72–3.68 (m, 1H), 2.37–2.30 (m, 1H), 2.26–2.20 (m, 1H), 1.95 (dd,
J¼6.7, 2.8 Hz,1H),1.90–1.86 (m,1H),1.80–1.76 (m, 2H),1.69–1.62 (m,
2H),1.56–1.42 (m, 5H),1.25–1.05 (m, 30H), 0.87 (t, J¼6.4 Hz, 3H); 13C
NMR (75 MHz, CDCl3) ppm 169.9, 59.9, 47.3, 39.3, 35.3, 33.1, 32.0,
29.8, 29.7, 29.6, 29.5, 27.4, 25.6, 24.9, 24.8, 22.8,14.2; HRMS (EI) exact
mass calcd for C25H48N2O [M]þ 392.3767, found 392.3772.
1515, 1461, 1443, 1340, 1257, 1029, 819 cmꢀ1 1H NMR (300 MHz,
;
CDCl3)
d
7.23 (d, J¼8.4 Hz, 2H), 6.87 (d, J¼8.4 Hz, 2H), 6.38 (br, 1H),
5.26 (br, 1H), 3.80 (s, 3H), 3.49 (d, J¼12.9 Hz, 1H), 3.43 (d, J¼12.9 Hz,
1H), 2.16–2.14 (m, 1H), 2.02 (d, J¼2.7 Hz, 1H), 1.78 (d, J¼7.2 Hz, 1H);
13C NMR (75 MHz, CDCl3) ppm 173.8, 159.0, 130.0, 129.3, 114.0, 62.5,
55.3, 38.8, 35.1; HRMS (EI) exact mass calcd for C11H14N2O2 [M]þ
206.1055, found 206.1051.
4.2.13. 1-n-Hexadecylaziridine-2-(N-n-dodecyl)amide (21)
Prepared as a white solid. IR (KBr) 3428, 3282, 2956, 2918, 2849,
4.2.7. 1-(p-Methoxybenzyl)aziridine-2-(N-phenyl)amide (15)
1645, 1553, 1469 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 6.50 (br, 1H),
Prepared as a white solid. IR (KBr) 3431, 3288, 3134, 3062, 2926,
3.22–3.13 (m, 2H), 2.35–2.24 (m, 3H), 1.99–1.98 (m, 1H), 1.84–1.83
(m, 1H), 1.58–1.45 (m, 6H), 1.31–1.20 (m, 42H), 0.87 (t, J¼6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3) ppm 170.7, 59.9, 39.2, 38.9, 35.3,
32.0, 29.8, 29.7, 29.6, 29.4, 27.4, 26.9, 22.8, 14.2; HRMS (EI) exact
mass calcd for C31H62N2O [M]þ 478.4862, found 478.4861.
2840, 1662, 1604, 1513, 1443, 1311, 1248, 1032, 823, 755, 692 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
8.37 (br, 1H), 7.49 (d, J¼8.1 Hz, 2H),
7.32–7.25 (m, 4H), 7.07 (t, J¼7.2 Hz, 1H), 6.89 (d, J¼8.4 Hz, 2H), 3.80
(s, 3H), 3.58 (d, J¼12.9 Hz, 1H), 3.50 (d, J¼12.9 Hz, 1H), 2.33–2.31
(m, 1H), 2.08 (d, J¼2.7 Hz, 1H), 1.88–1.85 (m, J¼7.2 Hz, 1H); 13C NMR
(75 MHz, CDCl3) ppm 168.5, 159.3, 137.5, 129.9, 129.5, 129.1, 124.3,
119.6, 114.2, 62.3, 55.4, 39.5, 35.3; HRMS (EI) exact mass calcd for
C17H18N2O2 [M]þ 282.1368, found 282.1370.
4.2.14. 1-(2-Naphthalenemethyl)aziridine-2-amide (22)
Prepared as a white solid. IR (KBr) 3398, 3201, 2923, 1640, 1510,
1441, 799, 771 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
8.17 (d, J¼7.8 Hz,
1H), 7.89–7.86 (m, 1H), 7.83–7.80 (m, 1H), 7.57–7.42 (m, 4H), 6.34
(br, 1H), 5.36 (br, 1H), 3.96 (s, 2H), 2.25 (dd, J¼6.9, 3.0 Hz, 1H), 2.09
(d, J¼3.0 Hz, 1H), 1.87 (d, J¼6.9 Hz, 1H); 13C NMR (75 MHz, CDCl3)
ppm 173.8, 133.8, 133.7, 131.6, 128.8, 128.4, 126.3, 126.0, 125.9, 125.5,
123.8, 61.2, 39.1, 35.7; HRMS (EI) exact mass calcd for C14H14N2O
[M]þ 226.1106, found 226.1104.
4.2.8. 1-(p-Methoxybenzyl)aziridine-2-(N-cyclohexyl)amide (16)
Prepared as a white solid. IR (KBr) 3277, 3087, 2931, 2851, 1647,
1613, 1557, 1512, 1251, 1026, 811 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d
7.23 (d, J¼8.5 Hz, 2H), 6.87 (d, J¼8.5 Hz, 2H), 6.42–6.39 (br, 1H),
3.81 (s, 3H), 3.73–3.68 (m, 1H), 3.50 (d, J¼13.2 Hz, 1H), 3.39 (d,
J¼13.2 Hz, 1H), 2.15 (dd, J¼6.9, 3.0 Hz, 1H), 1.90 (d, J¼3.0 Hz, 1H),
1.87–1.80 (m, 2H), 1.74 (d, J¼6.9 Hz, 1H), 1.68–1.56 (m, 2H), 1.39–
1.05 (m, 6H); 13C NMR (75 MHz, CDCl3) ppm 169.5, 159.0, 130.2,
129.2, 113.9, 62.4, 55.3, 47.4, 39.2, 35.2, 33.0, 25.5, 24.8; HRMS (EI)
exact mass calcd for C17H24N2O2 [M]þ 288.1838, found 288.1838.
4.2.15. 1-(2-Naphthalenemethyl)aziridine-2-(N-phenyl)amide (23)
Prepared as a white solid. IR (KBr) 3430, 3265, 3134, 3064, 2959,
2924, 2851, 1664, 1599, 1542, 1499, 1444, 1308, 1260, 797, 779, 755,
691 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 8.32 (br, 1H), 8.29 (d,
J¼8.7 Hz, 1H), 7.90 (d, J¼8.1 Hz, 1H), 7.84–7.81 (m, 1H), 7.62–7.50
(m, 3H), 7.44–7.43 (m, 2H), 7.38–7.32 (m, 2H), 7.28–7.22 (m, 1H),
7.04 (t, J¼7.5 Hz, 1H), 4.12 (d, J¼13.5 Hz, 1H), 3.96 (d, J¼13.5 Hz, 1H),
2.40 (dd, J¼7.0, 2.8 Hz, 1H), 2.17 (d, J¼2.8 Hz, 1H), 1.97 (d, J¼7.0 Hz,
1H); 13C NMR (75 MHz, CDCl3) ppm 168.4, 137.4, 134.0, 133.5, 131.7,
129.1, 129.0, 128.7, 126.4, 126.3, 126.0, 125.5, 124.2, 123.9, 119.5, 61.0,
39.5, 35.9; HRMS (EI) exact mass calcd for C20H18N2O [M]þ
302.1419, found 302.1412.
4.2.9. 1-(p-Methoxybenzyl)aziridine-2-(N-n-dodecyl)amide (17)
Prepared as a white solid. IR (KBr) 3425, 3301, 2955, 2919, 2849,
1645, 1615, 1549, 1515, 1467, 1252, 1034, 828 cmꢀ1 1H NMR
;
(300 MHz, CDCl3)
d
7.23 (d, J¼8.4 Hz, 2H), 6.87 (d, J¼8.4 Hz, 2H),
6.49 (br, 1H), 3.80 (s, 3H), 3.47 (d, J¼13.2 Hz, 1H), 3.41 (d, J¼13.2 Hz,
1H), 3.18 (d, J¼6.9 Hz, 1H), 3.13 (d, J¼6.9 Hz, 1H), 2.18 (dd, J¼6.9,
3.0 Hz, 1H), 1.91 (d, J¼3.0 Hz, 1H), 1.74 (d, J¼6.9 Hz, 1H), 1.44–1.42
(m, 2H), 1.31–1.20 (m, 18H), 0.88 (t, J¼6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3) ppm 170.4, 159.1, 130.2, 129.4, 114.0, 62.6, 55.4,
39.3, 38.9, 35.3, 32.0, 29.7, 29.6, 29.4, 26.9, 22.8, 14.2; HRMS (EI)
exact mass calcd for C23H38N2O2 [M]þ 374.2933, found 374.2936.
4.2.16. 1-(2-Naphthalenemethyl)aziridine-2-(N-cyclohexyl)-
amide (24)
Prepared as a white solid. IR (KBr) 3282, 3061, 2930, 2852, 1648,
1553, 1445, 1269, 1256, 1013, 776, 687 cmꢀ1 1H NMR (300 MHz,
;
4.2.10. 1-n-Hexadecylaziridine-2-amide (18)
CDCl3)
d
8.21 (d, J¼8.7 Hz, 1H), 7.89–7.86 (m, 1H), 7.82–7.79 (m, 1H),
Prepared as a white solid. IR (KBr) 3380, 3171, 2918, 2850, 1667,
7.55–7.50 (m, 2H), 7.43–7.41 (m, 2H), 6.42–6.40 (br, 1H), 4.03 (d,
J¼13.6 Hz, 1H), 3.88 (d, J¼13.6 Hz, 1H), 3.67–3.56 (m, 1H), 2.23 (dd,
J¼6.9, 3.0 Hz, 1H), 1.99 (d, J¼3.0 Hz, 1H), 1.84 (d, J¼6.9 Hz, 1H),
1628, 1467 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
6.37 (br, 1H), 5.19 (br,
1H), 2.35–2.26(m, 2H),1.95–1.93(m, 2H),1.65–1.49(m, 5H),1.30–1.20

11174
J. Li et al. / Tetrahedron 64 (2008) 11167–11174
1.74–1.49 (m, 4H), 1.32–0.94 (m, 6H); 13C NMR (75 MHz, CDCl3)
ppm 169.3, 133.8, 133.7, 131.6, 128.7, 128.3, 126.1, 126.0, 125.8, 125.4,
123.8, 61.0, 47.0, 39.2, 35.9, 32.6, 25.5, 24.4; HRMS (EI) exact mass
calcd for C20H24N2O [M]þ 308.1889, found 308.1886.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.09.060.
4.2.17. 1-(2-Naphthalenemethyl)aziridine-2-(N-n-dodecyl)-
amide (25)
References and notes
Prepared as a white solid. IR (KBr) 3317, 3055, 2923, 2851, 1653,
1531, 1464, 796, 772 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 8.18 (d,
1. Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44,
5188.
2. (a) Demko, Z. P.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2113; (b) Wang,
Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.; Finn, M. G. J. Am. Chem.
Soc. 2003, 125, 3192.
3. (a) Milligan, G. L.; Mossman, C. J.; Aube, J. J. Am. Chem. Soc. 1995, 117, 10449;
(b) Desai, P.; Schildknegt, K.; Agrios, K. A.; Mossman, C.; Milligan, G. L.; Aube´,
J. J. Am. Chem. Soc. 2000, 122, 7226; (c) Wrobleski, A.; Aube, J. J. Org. Chem.
2001, 66, 886.
J¼8.1 Hz, 1H), 7.88–7.85 (m, 1H), 7.81–7.78 (m, 1H), 7.54–7.40 (m,
4H), 6.44 (br, 1H), 4.00 (d, J¼13.5 Hz, 1H), 3.87 (d, J¼13.5 Hz, 1H),
3.15–3.02 (m, 2H), 2.25 (dd, J¼6.9, 3.0 Hz,1H),1.98 (d, J¼3.0 Hz,1H),
1.83 (d, J¼6.9 Hz, 1H), 1.30–1.11 (m, 20H), 0.87 (t, J¼6.3 Hz, 3H); 13C
NMR (75 MHz, CDCl3) ppm 170.1, 133.8, 131.6, 128.7, 128.3, 126.1,
126.0, 125.8, 125.4, 123.8, 61.1, 39.3, 38.7, 35.7, 31.9, 29.7, 29.6, 29.5,
29.4, 29.2, 26.7, 22.7, 14.1; HRMS (EI) exact mass calcd for
C26H38N2O [M]þ 394.2984, found 394.2987.
´
´
4. Scheiner, P.; Schomaker, J. H.; Deming, S.; Libbey, W. J.; Nowack, G. P. J. Am.
Chem. Soc. 1965, 87, 306.
5. (a) Huisgen, R.; Szeimies, G.; Mobius, L. Chem. Ber. 1966, 99, 475; (b) Broeckx,
W.; Overbergh, N.; Samyn, C.; Smets, G.; L’Abbe, G. Tetrahedron 1971, 27, 3527;
(c) Schultz, A. G.; McMahon, W. G. J. Org. Chem. 1984, 49, 1676; (d) Sha, C.-K.;
Ouyang, S.-L.; Hsieh, D.-Y.; Chang, R.-C.; Chang, S.-C. J. Org. Chem. 1986, 51, 1490;
(e) Molander, G. A.; Bibeau, C. T. Tetrahedron Lett. 2002, 43, 5385.
4.2.18. 1-Phenethylaziridine-2-amide (26)
Prepared as a white solid. IR (KBr) 3300, 3153, 3028, 2940, 2891,
2847, 1689, 1633, 1497, 1433, 1340, 732, 700 cmꢀ1
;
1H NMR
6. (a) Allemann, S.; Vogel, P. Synthesis 1991, 923; (b) Dahl, R. S.; Finney, N. S. J. Am.
Chem. Soc. 2004, 126, 8356.
(300 MHz, CDCl3)
d 7.32–7.19 (m, 5H), 6.27 (br, 1H), 5.51 (br, 1H),
2.87 (t, J¼6.8 Hz, 2H), 2.71–2.63 (m, 1H), 2.55–2.47 (m, 1H), 1.95–
1.93 (m, 2H), 1.59 (d, J¼6.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) ppm
174.0, 139.5, 128.7, 128.4, 126.3, 61.1, 38.8, 36.0, 35.0; HRMS (EI)
exact mass calcd for C11H14N2O [M]þ 190.1106, found 190.1113.
7. Anderson, G. T.; Henry, J. R.; Weinreb, S. M. J. Org. Chem. 1991, 56, 6946.
8. Mahoney, J. M.; Smith, C. R.; Johnston, J. N. J. Am. Chem. Soc. 2005, 127, 1354.
9. (a) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247; (b) Graham, M. A.; Wadsworth,
A. H.; Thornton-Pett, M.; Rayner, C. M. Chem. Commun. 2001, 966.
10. Thermal reaction between acrylamides and alkyl azides at room temperature
could afford triazolines but not aziridines in the absence of TfOH. See: Yang,
C.-H.; Shen, H.-J.; Wang, R.-H.; Wang, J.-C. J. Chin. Chem. Soc. 2002, 49, 95.
11. The aziridine products (at fairly low yields) from methyl acrylate and acrylo-
nitrile may not come from the TfOH-promoted pathway. They may be gener-
ated from the thermal [3þ2] cycloaddition between the azide and the olefin
followed by nitrogen extrusion. See Ref. 7 for more information.
12. Noteworthy, Aube et al. recently reported that Lewis acids activate the reaction
between enones and azide derivatives along a domino reaction path, the first
step corresponds to a [3þ2] cycloaddition to afford 1,2,3-triazolines, followed
by a ring contraction process to obtain the final enaminone product. See: (a)
Reddy, D. S.; Judd, W. R.; Aube´, J. Org. Lett. 2003, 5, 3899; (b) Castillo, R.; Andres,
J.; Domingo, L. R. Eur. J. Org. Chem. 2005, 4705.
4.2.19. 1-Phenethylaziridine-2-(N-phenyl)amide (27)
Prepared as a white solid. IR (KBr) 3324, 3060, 3028, 2929, 2840,
1682, 1595, 1525, 1496, 1442, 1311, 757, 696, 640 cmꢀ1 1H NMR
;
(300 MHz, CDCl3)
d
8.26 (br, 1H), 7.46 (d, J¼7.8 Hz, 2H), 7.36–7.22
(m, 7H), 7.08 (t, J¼7.2 Hz, 1H), 2.94–2.82 (m, 3H), 2.57–2.51 (m, 1H),
2.11 (dd, J¼6.9, 3.0 Hz, 1H), 1.98 (d, J¼3.0 Hz, 1H), 1.70 (d, J¼6.9 Hz,
1H); 13C NMR (75 MHz, CDCl3) ppm 168.5, 139.5, 137.5, 129.0, 128.8,
128.6, 126.5, 124.1, 119.4, 60.7, 39.5, 36.0, 35.3; HRMS (EI) exact
mass calcd for C17H18N2O [M]þ 266.1419, found 266.1422.
13. Moran-Ramallal, R.; Liz, R.; Gotor, V. Org. Lett. 2007, 9, 521.
14. (a) Lambert, C.; Viehe, H. G. Tetrahedron Lett. 1985, 26, 4439; (b) Galonic, D. P.;
Ide, N. D.; van der Donk, W. A.; Gin, D. Y. J. Am. Chem. Soc. 2005, 127, 7359; (c)
Wang, J.-Y.; Wang, D.-X.; Zheng, Q.-Y.; Huang, Z.-T.; Wang, M.-X. J. Org. Chem.
2007, 72, 2040.
4.2.20. 1-Phenethylaziridine-2-(N-cyclohexyl)amide (28)
Prepared as a white solid. IR (KBr) 3431, 3272, 3088, 3025, 2920,
2851, 1647, 1559, 1449, 1270, 750, 695 cmꢀ1 1H NMR (300 MHz,
;
15. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J.
V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
Revision A.1; Gaussian: Pittsburgh, PA, 2003.
CDCl3)d7.32–7.19(m, 5H), 6.32–6.29(br,1H), 3.72–3.66(m,1H), 2.86–
2.76 (m, 3H), 2.45–2.35 (m, 1H), 2.17 (dd, J¼6.9, 3.0 Hz, 1H), 1.79 (d,
J¼3.0 Hz, 1H), 1.77–1.62 (m, 4H), 1.57 (d, J¼6.9 Hz, 1H), 1.35–1.31 (m,
3H), 1.16–0.98 (m, 3H); 13C NMR (75 MHz, CDCl3) ppm 169.4, 139.5,
128.6, 128.3, 126.2, 60.9, 47.2, 39.1, 35.9, 35.1, 32.9, 25.4, 24.7; HRMS
(EI) exact mass calcd for C17H24N2O [M]þ 272.1889, found 272.1885.
4.2.21. 1-Phenethylaziridine-2-(N-n-dodecyl)amide (29)
Prepared as awhite solid. IR (KBr) 3281, 3063, 2921, 2851,1644,1550,
1466, 699 cmꢀ1;1H NMR (300 MHz, CDCl3)
d7.32–7.18 (m, 5H), 6.39 (br,
1H), 3.18–3.11 (m, 2H), 2.88–2.83 (m, 2H), 2.72–2.70 (m, 1H), 2.47–2.43
(m, 1H), 1.99 (dd, J¼6.9, 3.0 Hz, 1H), 1.82 (d, J¼3.0 Hz, 1H), 1.57 (d,
J¼6.9 Hz, 1H), 1.46–1.41 (m, 2H), 1.31–1.20 (m, 18H), 0.88 (t, J¼6.6 Hz,
3H); 13CNMR(75 MHz,CDCl3) ppm 170.3,139.5,128.7,128.4,126.3, 61.0,
39.1, 38.8, 36.0, 35.1, 31.9, 29.6, 29.5, 29.3, 26.8, 22.7, 14.1; HRMS (EI)
exact mass calcd for C23H38N2O [M]þ 358.2984, found 358.2982.
16. (a) Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995; (b) Cossi, M.; Rega, N.;
Scalmani, G.; Barone, V. J. Comput. Chem. 2003, 24, 669; (c) Tomasi, J.; Mennucci,
B.; Cammi, R. Chem. Rev. 2005, 105, 2999.
17. (a) Fu, Y.; Liu, L.; Li, R.-Q.; Liu, R.; Guo, Q.-X. J. Am. Chem. Soc. 2004, 126, 814; (b)
Fu, Y.; Liu, L.; Yu, H.-Z.; Wang, Y.-M.; Guo, Q.-X. J. Am. Chem. Soc. 2005, 127, 7227.
18. (a) Luft, J. A. R.; Meleson, K.; Houk, K. N. Org. Lett. 2007, 9, 555; (b) Lin, X.-J.; Xu,
W.-R.; Wu, J.; Liu, C.-B. Acta Chim. Sinica 2007, 65, 930; (c) Diev, V. V.; Kostikov,
R. R.; Gleiter, R.; Molchanov, A. P. J. Org. Chem. 2006, 71, 4066; (d) Yan, X.-X.;
Peng, Q.; Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew. Chem., Int.
Ed. 2006, 45, 1979; (e) Domingo, L. R.; Picher, M. T.; Arroyo, P.; Saez, J. A. J. Org.
Chem. 2006, 71, 9319; (f) Ponti, A.; Molteni, G. Chem.dEur. J. 2006, 12, 1156; (g)
Domingo, L. R.; Arno, M.; Merino, P.; Tejero, T. Eur. J. Org. Chem. 2006, 15, 3464;
(h) Lu, X.-H.; Yu, H.-B.; Xu, Y.-H.; Wu, W.-R. Chin. J. Chem. 2006, 24, 307; (i) Polo,
V.; Andres, J.; Castillo, R.; Berski, S.; Silvi, B. Chem.dEur. J. 2004, 10, 5165; (j)
Domingo, L. R.; Picher, M. T. Tetrahedron 2004, 60, 5053.
Acknowledgements
This work was supported by the National Basic Research Pro-
gram of China (2007CB210205) and the National Natural Science
Foundation of China (Grant nos. 20602034 and 90713009).