Experimental and theoretical rearrangement of N-acyl-2,2- dimethylaziridines in acidic medium

Article abstract of DOI:10.1007/s12039-015-1020-x

The acid isomerization of N-acyl-2,2-dimethylaziridines 1 in concentrated sulfuric acid at room temperature leads to oxazolines 2 but the neutral hydrolysis of 1 in pure water at room temperature leads to amidoalcohols 3. However, the use of aqueous solutions of H₂SO₄ at different concentrations at room temperature leads to a mixture of oxazolines 2, amidoalcohols 3 and allylamides 4 with yields depending on the acidity of the medium and the nature of the acyl group. A mechanism has been suggested to explain the formation of these three products. DFT calculations employing the Gaussian 09 program with DFT/B3LYP methods and 6-311++G(2d,2p) basis set were carried out which gave the most stable geometry as well as their atomic charge distributions of compounds 1-4. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-015-1020-x

c
J. Chem. Sci. Vol. 128, No. 2, February 2016, pp. 235–245. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-015-1020-x
Experimental and theoretical rearrangement of N-acyl-2,2-
dimethylaziridines in acidic medium
MADIHA KAMOUN MHIRIa, FIRAS ABOUMESSAADb, MOHAMED LOTFI EFRITa,
YOUSSEF ARFAOUIc,∗ and NÉJI BESBESb
aLaboratoire de Synthèse Organique et Hétérocyclique, Département de Chimie, Faculté des Sciences
de Tunis, Université Tunis El Manar, 2092, El Manar, Tunis, Tunisia
bLaboratoire Physicochimie de Matériaux Minéraux et leurs Applications, Centre National des Recherches
en Sciences des Matériaux, Technopole Borj Cédria, Soliman, 8027, Tunisia
cUnité Physico Chimie des Matériaux Condensés -UR11ES19 Département de Chimie Faculté des Sciences
de Tunis, Université Tunis El Manar, 2092, El Manar, Tunis, Tunisia
e-mail: arfaoui.youssef@gmail.com
MS received 9 July 2015; revised 2 November 2015; accepted 30 November 2015
Abstract. The acid isomerization of N-acyl-2,2-dimethylaziridines 1 in concentrated sulfuric acid at room
temperature leads to oxazolines 2 but the neutral hydrolysis of 1 in pure water at room temperature leads to
amidoalcohols 3. However, the use of aqueous solutions of H2SO4 at different concentrations at room tempera-
ture leads to a mixture of oxazolines 2, amidoalcohols 3 and allylamides 4 with yields depending on the acidity
of the medium and the nature of the acyl group. A mechanism has been suggested to explain the formation of
these three products. DFT calculations employing the Gaussian 09 program with DFT/B3LYP methods and 6-
311++G(2d,2p) basis set were carried out which gave the most stable geometry as well as their atomic charge
distributions of compounds 1-4.
Keywords. N-acylaziridine; hydrolysis; isomerization; DFT calculations.
ethanolysis in the presence of sodium perchlorate13 and
neutral hydrolysis14 of various N-activated aziridines
yielded the corresponding products by selective nucle-
ophilic attack of ethanol and water on the most substi-
tuted carbon.
In addition, we have studied the isomerization of N-
cinnamoyl-2,2-dimethylaziridine by concentrated sul-
furic acid which led to the corresponding oxazoline by
regiospecific ring opening on the C(Me)2 carbon side
of aziridine.15 However, Eastwood16 reported that the
treatment of isopropyl N-benzoyl-2-carboxylate with
the same Bronsted acid gives a mixture of two oxazo-
lines and two amidoalcohols resulting from the compet-
itive isomerization and hydrolysis reactions.
More recently, we investigated the reaction of
hydrated acid-activated clays with N-acyl-2,2-dimethy-
laziridines 1. A mixture of oxazolines, methallylamides
and amidoalcohols was formed and the yields closely
depended upon the aziridines 1.17,18
In order to improve the selectivity of the reaction
and to increase in the overall yield, we have now
studied the acid hydrolysis reaction of N-acyl-2,2-
dimethylaziridines.
1. Introduction
It is well-known that the aziridines derivatives exhibit
biological and pharmacological activities.1–4 Aziridines
can be also used to functionalize polymers5–8 by ring
opening of their heterocycles. The reactions of N-
acylaziridines with various thiols give the correspond-
ing amido sulfide products by an attack of the nucle-
ophile on the less substituted carbon of the heterocycle
are reported in literature.9 Moreover, N-acetylaziridine
is converted into the L-allothreonine, by ring opening
with Ac2O-Pyr on the C3 carbon side of aziridine.10
On the other hand, the synthesis of methylene amin-
odipeptides was obtained by competitive nucleophilic
attack of primary amines on the C2 and C3 carbons of
2(t-butoxycarbonyl methyl) aziridine derivatives.11
In our previous investigations, we have already
demonstrated that the N-aroylaziridines react with
sodium iodide in acetone to give a mixture of oxa-
zolines and allylamides. Such a reaction resulted
by the breaking of the C-N bonds.12 However, the
∗For correspondence
235

236
Madiha Kamoun Mhiri et al.
(silica gel, Petroleum ether / Ethyl ether: 20/80 for the
2. Experimental
compound 2, Ethyl ether/Ethyl acétate: 90/10 for the
compound 3, Petroleum ether /Ethyl ether: 50/40 for the
compound 4).
2.1 Materials, methods and instruments
The infrared spectra were recorded in CH2Cl2 on a
Bruker spectrometer IFS66V/S -IR 420 (between 400
2.3 Analytical data
1
and 4000 cm−1). The H NMR spectra were recorded
1
in CDCl3 on a Bruker AC spectrometer (300 MHz H
N-propanoyl-2,2-dimethylaziridine (1a). IR (CH2Cl2,
frequency). The 13C NMR spectra were recorded in
CDCl3 on a Bruker AC spectrometer (75 MHz 13C fre-
quency). Chemical shifts are reported in ppm from
internal TMS. Silica gel (70–230 mesh, Merck) was
used for the separation by column chromatography.
1
cm−1): ν (C=O) 1678. H NMR (300 MHz, CDCl3,
ppm): δ 1.15 (3H, q, J = 6 Hz, CH3), 1.35 (6H, s,
2CH3), 2.12 (2H, s, CH2N), 2.35 (2H, t, J = 6 Hz, CH2).
13C NMR (75 MHz, CDCl3, ppm): δ 9.32 (CH3), 23.06
(CH3), 30.92 (CH2), 36.82 (CH2N), 40.65 (Cq), 185.32
(C=O).
2.2 Synthesis
5,5-dimethyl-2-propyloxazoline (2a). IR: (CH2Cl2,
1
cm−1): ν (C=N) 1662. H NMR (300 MHz, CDCl3,
2.2a Synthesis of N-acylaziridines: N-acyl-2,2-di-
methylaziridines 1a-e were prepared from 2,2-
dimethylaziridine and various acyl chorides with an
excess of triethylamine in dry benzene according to
known procedures.19
ppm): δ 1.18 (3H, t, J = 6 Hz, CH3), 1.40 (6H, s,
2CH3), 2.28 (2H, q, J = 6 Hz, CH2), 3.55 (2H, s, CH2N).
13C NMR (75 MHz, CDCl3, ppm): δ 10.02 (CH3),
21.91 (CH2), 27.33 (2CH3), 66.43 (CH2N), 83.41 (Cq),
168.34 (C=N).
N-(2-hydroxy-2-methylpropyl)propylamide (3a). IR
(CH2Cl2, cm−1): ν (C=O) 1657, (NH) 3443, (OH)
2.2b Typical procedure of the rearrangement of N-
acylaziridines 1:
1
3585. H NMR (300 MHz, CDCl3, ppm): δ 1.12 (2H,
t, J = 6 Hz, CH2), 1.28 (6 H, s, 2CH3), 2.28 (2H,
q, J = 6 Hz, CH2), 2.56 (1H, s, OH), 3.27 (2H, s,
CH2N), 6.22 (1H, s, NH). 13C NMR (75 MHz, CDCl3,
ppm): δ 10.06 (CH3), 27.21 (2CH3), 29.59 (CH2), 50.36
(CH2N), 70.77 (Cq), 175.13 (C=O).
2.2b1 Reaction of conc. H2SO4 with N-acylaziridines
1: A cold 30 mL of conc. sulfuric acid was added to
2 mmol of aziridine 1 at a low temperature and then
stirred at room temperature for 2 h 30 min. The reaction
was quenched with 10% NaOH and the aqueous mix-
ture was extracted with ether (3×100 mL). The organic
extracts were combined, dried over anhydrous MgSO4,
filtered and concentrated to give oxazoline 2.
N-(2-methylprop-2-enyl)-propylamide (4a). IR
(CH2Cl2, cm−1): ν (C=C) 1648, (C=O) 1665, (NH)
3333, 3445. 1H NMR (300 MHz, CDCl3, ppm): δ 1.19
(3H, q, J = 6 Hz, CH3), 1.73 (3H, s, CH3), 2.28 (2H,
t, J = 6 Hz, CH2), 3.70 (2H, d, J = 6 Hz, CH2N) ;
4.83 (2H, s, CH2 =C), 5.84 (1H, s, NH). 13C NMR
(75 MHz, CDCl3, ppm): δ 10.01 (CH3), 20.34 (CH3),
29.74 (CH2), 44.95 (CH2N), 110.74 (CH2 =), 142.17
(C=), 173.80 (C=O).
2.2b2 Reaction of ultrapure water with N-acyla-
ziridines 1: A mixture of 2 mmol of aziridine 1, 2 mL
of ether and 10 mL of ultrapure water was stirred at
room temperature for 96 h. The mixture was extracted
with ether (3 × 100 mL). The organic extracts were
combined, dried over anhydrous MgSO4, filtered and
concentrated to give amidoalcohol 3.
N-benzyloyl-2,2-dimethylaziridine (1b). IR (CH2Cl2,
1
cm−1): ν (C=O) 1675. H NMR (300 MHz, CDCl3,
ppm): δ 1.20 (6H, s, 2CH3), 2.05 (2H, s, CH2N), 3.60
(2H, s, CH2Ph), 7.10-7.25 (5H, m, C6H5). 13C NMR (75
2.2b3 Reaction of N-acylaziridines 1 with a mixture of MHz, CDCl3, ppm): δ 23.69 (2CH3), 36.97 (CH2N),
water and sulfuric acid in different concentration: 41.35 (Cq), 45.22 (CH2Ph), 126.83 (C, Ph), 127.29 (2C,
cold solution of 9% or 48% H2SO4 by wt. in water was Ph), 128.62 (2C, Ph), 134.73 (Cq), 181.69 (C=O).
added to a mixture of 2 mmol of aziridine 1 in 2 mL of 2-benzyl-5,5-dimethyloxazoline (2b). IR (CH2Cl2,
A
1
ether at a low temperature and then stirred at room tem- cm−1): ν (C=N) 1659. H NMR (300 MHz, CDCl3,
perature for 96 h. The crude reaction was quenched with ppm): δ 1.28 (6H, s, 2CH3), 3.40 (2H, s, CH2Ph),
10% NaOH to neutral pH, and the aqueous mixture was 3.45 (2H, s, CH2N), 7.12-7.21 (5H, s, C6H5). 13C
extracted with ether (3 × 100 mL). The organic layers NMR (75 MHz, CDCl3, ppm): δ 27.83 (2CH3), 43.46
were combined, dried over anhydrous MgSO4, filtered (CH2Ph), 66.09 (CH2N), 84.20 (Cq), 126.82 (C, Ph),
and concentrated to give a mixture of compounds 2-4. 128.67 (2C, Ph), 129.10 (2C, Ph), 134.05 (Cq), 166.03
The products were purified by column chromatography (C=N).

Rearrangement of N-acyl-2,2- dimethylaziridines
237
s, NH), 7.16-8.10 (5H, m, C6H5). 13C NMR (75 MHz,
CDCl3, ppm): δ 27.32 (2CH3), 50.73 (CH2N), 70.95
(Cq), 126.91 (C, Ph), 128.43 (2C, Ph), 128.51 (2C, Ph),
131.55 (C, Ph), 134.60 (Cq), 168.55 (C=O).
N-(2-hydroxy-2-methylpropyl)-benzylamide (3b). IR
(CH2Cl2, cm−1): ν (C=O) 1655, (NH) 3440, (OH)
3580. 1H NMR (300 MHz, CDCl3, ppm): δ 1.10 (6H, s,
2CH3), 3.15 (2H, s, CH2N), 3.52 (2H, s, CH2Ph), 3.56
(1H, s, OH), 6.22 (1H, s, NH), 7.20-7.40 (5H, m, C6H5).
13C NMR (75 MHz, CDCl3, ppm): δ 27.05 (2CH3),
43.50 (CH2), 50.47 (CH2N), 70.51 (Cq), 126.14 (C, Ph),
128.24 (2C, Ph), 128.60 (2C, Ph), 141.73 (C=), 172.20
(C=O).
N-(2-hydroxy-2-methylpropyl)-benzamide (4c). IR
(CH2Cl2, cm−1): ν (C=C) 1635, (C=O) 1655, (NH)
1
3340, 3450. H NMR (300 MHz, CDCl3, ppm): δ
1.71 (3H, s, CH3), 3.89 (2H, s, CH2N), 4.79 (2H, s,
CH2 =C), 6.81 (1H, s, NH), 7.20-7.90 (5H, m, C6H5).
13C NMR (75 MHz, CDCl3, ppm): δ 20.32 (CH3), 45.37
(CH2N), 110.63 (CH2 =), 127.22 (2C, Ph), 128.03 (2C,
Ph), 131.66 (C, Ph), 137.74 (Cq), 141.94 (C=), 167.75
(C=O).
N-(2-methylprop-2-enyl)-benzylamide (4b).
IR
(CH2Cl2, cm−1): ν (C=C) 1635, (C=O) 1655, (NH)
1
3445. H NMR (300 MHz, CDCl3, ppm): δ 1.70 (3H,
s, CH3), 3.55 (2H, s, CH2Ph), 3.76 (2H, s, CH2N),
4.75 (2H, s, CH2 =C), 6.15 (1H, s, NH), 7.15-7.32
(5H, m, C6H5). 13C NMR (75 MHz, CDCl3, ppm): δ
20.21 (CH3), 43.57 (CH2Ph), 44.90 (CH2N), 110.47
(CH2 =), 126.65 (C, Ph), 128.24 (2C, Ph), 127.39 (2C,
Ph), 134.82 (Cq), 141.73 (C=), 171.87 (C=O).
3. Results and Discussion
The rearrangements of N-acyl-2,2-dimethylaziridines
were carried out under three sets of conditions: a) pure
water, b) concentrated sulfuric acid and c) a range of
concentrations of aqueous sulfuric acid. The products
are oxazolines 2, amidoalcohols 3 or a mixture of 2, 3
and methallylamides 4 (table 1, scheme 1).
The second aspect of this study involves the effect of
the acyl groups on the outcome of the reaction. We treated
three N-acyl-2,2-dimethylaziridines substituted by alkyl
groups (ethyl and benzyl) as 1a, 1b and aryl group (phenyl)
as 1c with a mixture of water and sulfuric acid in diffe-
rent concentrations at room temperature for 96 h.
Such a treatment resulted in the formation of three
compounds 2, 3 and 4 and we conclude that the acid
hydrolysis of aziridines 1a-c with acidified water (39–
81%) is more efficient than the acid-activated clay (26–
38%) as previously reported.17,18 In addition, the reac-
tion of N-benzoyl-2,2-dimethylaziridine 1c with 9%
H2SO4 by wt. in water leads to a mixture of products
2c, 3c and 4c with a combined yield of 50% which is
N-benzoyl-2,2-dimethylaziridine (1c). IR (CH2Cl2,
1
cm−1): ν 1668 (C=O). H NMR (300 MHz, CDCl3,
ppm): δ 1.19 (6H, s, 2CH3), 2.20 (2H, s, CH2N), 7.05-
7.85 (5H, m, C6H5). 13C NMR (75 MHz, CDCl3, ppm):
δ 22.83 (2CH3), 36.62 (CH2N), 42.30 (C), 127.03 (2C,
Ph), 128.24 (2C, Ph), 131.85 (C, Ph), 134.56 (Cq),
178.00 (C=O).
5,5-dimethyl-2-phenyloxazoline (2c). IR (CH2Cl2,
1
cm−1): ν 1670 (C=N). H NMR (300 MHz, CDCl3,
ppm): δ 1.36 (6H, s, 2CH3), 3.60 (2H, s, CH2N), 7.16-
8.10 (5H, m, C6H5). 13C NMR (75 MHz, CDCl3, ppm):
δ 27.30 (2CH3), 66.82 (CH2N), 83.94 (Cq), 126.81 (2C,
Ph), 128.52 (2C, Ph), 129.17 (C, Ph), 134.12 (Cq),
166.56 (C=N).
N-(2-methylprop-2-enyl)-benzamide
(3c).
IR
(CH2Cl2, cm−1): ν (C=O) 1666, (NH) 3445, (OH)
3592. 1H NMR (300 MHz, CDCl3, ppm): δ 1.25 (6H, s,
2CH3), 3.32 (1H, s, OH), 3.40 (2H, s, CH2), 7.11 (1H,
Table 1. Transformation of N-acyl-2,2-dimethylazirines 1 by various H2SO4/H2O
mixtures into products 2, 3 and 4 at room temperature.
X% H2SO4 by
wt. in water
Entry
Aziridine
Total Yield (%)
2 (%)
3 (%)
4 (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
0
9
48
98
0
66
57
39
54
85
81
53
76
91
50
52
87
0
14
34
54
0
66
35
5
0
8
0
0
0
12
0
0
0
5
0
85
61
6
9
7
48
98
0
9
48
98
47
76
0
3
27
87
0
9
91
42
25
0
10
11
12
0
0

238
Madiha Kamoun Mhiri et al.
Me
OH
Me
Me
Me
1-4
R
Me
1) H2O/ H2SO4
2) NaOH/H2O
Me
Me
a
b
c
CH3-CH2
Ph-CH2
Ph
N
CH2
N
O
HN
R
+
HN
R
+
O
O
O
R
R
1
2
3
4
Scheme 1. Acid hydrolysis rearrangement of N-acyl-2,2-dimethylaziridines 1.
Figure 2. Evolution of the yield of the compounds 2b, 3b
and 4b based on X% H2SO4 by wt. in water.
Figure 1. Evolution of the yield of the compounds 2a, 3a
and 4a based on X% H2SO4 by wt. in water.
much higher than the one obtained by the acid activated
clay (30% yield).
This outcome prompted us to extend this type of
acid hydrolysis reaction of N-acylaziridines 1 (table 1
and figures 1–3). The selectivity was observed when
we used ultrapure water and/or concentrated sulfuric
acid to give respectively amidoalcohols 3 (entries 1, 5
and 9) and oxazolines 2 (entries 4, 8 and 12). We also
found that the N-benzoylaziridine 1c is more reactive
than the N-propanoylaziridine 1a and N-phenylacetyl
aziridines 1b. These experimental results revealed that
the mesomeric effect of aroyl group has an important
influence in the progress of these reactions.
Figure 3. Evolution of the yield of the compounds 2c, 3c
and 4c based on X% H2SO4 by wt. in water.
Furthermore, when the concentration of the solution
was equal to a value of 9% H2SO4 by wt. in water, we
obtained a mixture of oxazolines 2a-c, amidoalcohols
3a-c and methallylamides 4a-c (entries 2, 6 and 10).
Besides, these results also revealed that the increase
in acidity of aqueous solution from 9% to 48%
The formation of methallylamide 4a-c in aqueous H2SO4 by wt. leads to a considerable increase
solution at room temperature in 96 hours was totally in the yield of oxazolines 2 (entries 2,6,10 vs
unexpected. In fact, we have already demonstrated that 3,7,11). We suggested then that amidoalcohols 3
methallylamides 4 can be obtained by thermolysis of and methallylamides 4 are rearranged into oxazo-
N-acyl-2,2-dimethylaziridines 1 at 110◦C in toluene for lines 2 in these conditions. In fact, Fanta obtained
48 h.20
2-paranitrophenyl-5,5-dimethyloxazoline by the treat-
We also noted that the dehydration of alcohols to ment of N-methallylparanitrobenzamide with concen-
alkenes is usually very hard under condition at high trated sulfuric acid at room temperature and confirmed
temperature. The amidoalcohols 3 can then result by by our research.21,22 In our study, we obtained oxazo-
rearrangement of the aziridines 1 in aqueous acid line 2a by treatment of the amidoalcohol 4a with 48%
solutions.
H2SO4 by wt. in water under the same conditions.23

Rearrangement of N-acyl-2,2- dimethylaziridines
239
The structures of these products 1-4 were already
On the other hand, several experimental and theoreti-
confirmed by IR, H NMR and 13C NMR and also by cal works focused on the determination of the structures
comparing its authentic samples.19
of aziridines and the study of the reactivity of these
Similarly, we followed the evolution of product for- heterocycles.26–30
1
mation based on the X% H2SO4 by wt. in water. The
DFT quantum chemical calculations of structures and
analysis of the curves presented in figures 1–3 reveals energies were carried out with the aid of GAUSSIAN
that the allylamides 4a-c were formed with low yields 09 set of programs.29 Geometrical parameters of the
and at low concentrations and then disappear starting reactants and products for the studied reactions
from 48% of the total weight and that there are two were fully optimized at the hybrid density func-
critical points at 21% and 29% in yields. We found tional B3LYP30,31 level using the 6-311++G(2d,2p)
that these products 2a, 2b and 3a, 3b were obtained basis.
using 21% and 24% H2SO4 by wt. in water. However,
A good agreement is obtained between the experi-
the replacement of ethyl and benzyl groups by phenyl mental and the theoretical results. The results show that
group stabilizes the aziridine 1c and that requires a dou- the two carbons of methyl groups carried by the C2
ble concentration of 48% H2SO4 by wt. in water to form carbon of aziridines 1 have atomic charges higher than
the products 2c and 3c (27 and 25% yields).
those of C2 and C3 (tables 2–4, entries 1-3).
Table 2. Evolution of atomic charges (a.u.) of selected atoms of compounds 1a, 2a,
3a and 4a.
Entry Atom
1
2
3
4
5
6
7
8
9
CH3
CH3
CH2
C-Me
N
−0.6
−0.6
0.1
−0.6
−0.6
−0.2
0.3
−0.6
−0.6
−0.2
0.3
−0.6
−0.6
−0.2
−0.2
0.0
−0.5
−0.5
−0.6
C-O
−0.6
C=O
C=O
C=N
C=N
−0.6
−0.7
−0.6
0.7
0.7
0.8
0.6
−0.5
10
Table 3. Evolution of atomic charges (a.u.) of selected atoms of compounds 1b, 2b, 3b and 4b.
Entry Atom
1
2
3
4
5
6
7
8
9
10
CH3
CH3
CH2
C-Me
N
−0.6
−0.6
0.1
−0.6
−0.6
−0.2
0.3
−0.6
−0.6
−0.2
0.3
−0.6
−0.6
−0.2
−0.2
0.0
−0.5
−0.5
−0.5
C-O
−0.6
C=O
C=O
C=N
C=N
−0.6
−0.7
−0.6
0.7
0.7
0.8
0.6
−0.5

240
Madiha Kamoun Mhiri et al.
Table 4. Evolution of atomic charges (a.u.) of selected atoms of compounds 1c, 2c, 3c and
4c.
Entry Atom
1
2
3
4
5
6
7
8
9
CH3
CH3
CH2
C-Me
N
−0.6
−0.6
0.2
−0.6
−0.6
−0.2
0.3
−0.6
−0.6
−0.2
0.3
−0.6
−0.6
−0.2
−0.1
0.0
−0.5
−0.5
−0.6
C-O
−0.6
C=O
C=O
C=N
C=N
−0.6
−0.7
−0.5
0.7
0.7
0.7
0.6
−0.5
10
G°(Kcal/mol)
G°(Kcal/mol)
Me
Me
Me
OH
Me
5
Me
N
H2O
+
HN
Et
Me
N
5
O
O
Et
1a
3a
-0.026
O
0
Et
0.00
1a
0
0.00
-5
-5
Me
Me
Me
Figure 4. Energetic profile of hydrolysis of N-propanoyl-
2,2-dimethylaziridine 1a.
CH2
HN
Et
-10
N
O
O
4a
-14.1
Et
2a
-15
-20
In the case of reagents 1, we noticed that the atomic
charge of oxygen is far superior to that of nitrogen
(tables 2–4, entries 5,7). Consequently, we conclude
that the oxygen site is more basic than the nitrogen one.
However, the nitrogen site is more nucleophilic site than
the oxygen site, the protonation of the aziridine occurs
on the nitrogen atom. We have also observed a very
important difference in charge density between oxygen
-16.6
Figure 5. Energetic profile of isomerization of N-pro-
panoyl-2,2-dimethylaziridine 1a.
and nitrogen when comparing the atomic charges of 4 was very unstable in acidic medium and instantly
C=O and C=N groups of compounds 1-4 (tables 2–4, transformed into its corresponding oxazoline 2 isomer.
entries 9, 10).
We conclude that the kinetic behavior of the acid
All results are presented in figures 4–9 where we hydrolysis of aziridines 1a-c depends closely on the
have plotted the energies of the reactant and products. nature of acyl group carried by the heterocycle.
A good agreement is obtained between the experimen-
Several mechanisms in acidity media were proposed
tal and the theoretical. Figures 4, 6 and 8 showed that to explain the formation of the mixture of three products
the transformation of N-acylaziridine 1a-c into amidoa- 2, 3 and 4 from N-acyl-2,2-dimethylaziridine 1.
cohol 3a-c. The formation of amidoalcohol 3 took place
Firstly, we have proposed “a push pull” mech-
at low sulfuric acid concentration (9% wt.), while at anism to explain the formation of amidoalcohol
higher concentration (48% wt.) the reaction afforded 3 by neutral hydrolysis of the N-acylaziridines 1
oxazoline 2 and allylamide 4. The latter compound (scheme 2). That it is a facile formation of a hydrogen

Rearrangement of N-acyl-2,2- dimethylaziridines
241
G°(Kcal/mol)
G°(Kcal/mol)
Me
Me
OH
Me
Me
OH
Me
Me
5
5
Me
Me
N
N
H2O
H2O
+
+
HN
HN
Ph
O
O
O
O
PhCH2
Ph
1b
PhCH2
1c
3b
-0.032
3c
-0.030
0
0
0.00
0.00
-5
-5
Figure 6. Energetic profile of hydrolysis of N-phenyl-
acetyl-2,2-dimethylaziridine 1b.
Figure 8. Energetic profile of hydrolysis of N-benzoyl-
2,2-dimethylaziridine 1c.
G°(Kcal/mol)
G°(Kcal/mol)
Me
Me
Me
Me
5
N
5
N
O
O
PhCH2
Ph
1b
0.00
1c
0.00
0
0
Me
Me
Me
-5
-5
Me
Me
CH2
Me
HN
Ph
N
O
O
Ph
-10
CH2
N
O
-10
-15
4c
-10.9
HN
2c
O
PhCH2
PhH2
-11.8
4b
-15.3
-15
-20
2b
-16.0
Figure 9. Energetic profile of isomerization of N-benzoyl-
2,2-dimethylaziridine 1c.
Figure 7. Energetic profile of isomerization of N-phenyl-
acetyl-2,2-dimethylaziridine 1b.
bond between the first water molecule and the oxygen
The treatment of N-acyl-2,2-dimethylaziridine 1 with
of the amide group or bond of aziridine 1 to give the aqueous acidic solution (9% and 48% by weight), can
intermediate I. The regiospecific nucleophilic attack of be explained as follows: the first step is the formation
the second water molecule happens on the C2 carbon, of the aziridinium ion IV and second step is obtaining
best suited with a positive partial charge, which is the carbocation V (scheme 4). The last intermediate V
stabilized by the density effects of the methyl groups. undergoes the competition between hydrolysis and rear-
The oxonium intermediate II leads to the amidoalco- rangement. Indeed, the rearrangement is performed by
hol 3 after proton exchange and rearrangement of the the migration of the hydrogen from the methyl group
intermediate III (scheme 2).
on the oxygen of amide on a transition state TS1, to
Furthermore, the use of concentrated sulfuric acid give the intermediate VII (figure 4, path a). The latter
favors the oxophilic reaction of the substrate 1 to lead VII will undergo either the intramolecular cyclization
to N-protonated IV (scheme 3). This intermediate IV to give the oxazoline 2 through the transition state TS2
undergoes the heterolytic cleavage of the C2-N bond and the intermediate oxazolinium IV (scheme 4, path c)
to give the more stable tertiary carbocation V. The or undergo proton exchange for allylamide 4 (scheme 4,
ring closure of V, by nucleophilic attack of oxygen on path d). Furthermore, solvation of the intermediate V
this tertiary carbocation, forms the oxazoline 2 via the with two molecules of water leads to the transition
intermediate VI.
state TS3 which will be transformed into amidoalcool 3

242
Madiha Kamoun Mhiri et al.
by proton exchange of the intermediate IX (scheme 4, results of these IRC show that rearrangement through
path b).
two transition states TS1a (9.02 kcal mol−1) and TS2a
For a good understanding of the acid hydrolysis (20.86 kcal mol−1).
process of these heterocycles 1, we focused our
The analysis of the energetic plots are shown in
study on the reactivity of the N-propanoyl-2,2-dime- figures 5 and 10 and the mechanism is shown in
thylaziridine 1a in acidic medium. In the first step of scheme 4 which reveal that the methallylamide 4a is
this theoretical study, we carried out the geometry opti- the kinetic product, whereas the oxazoline 2a is the
mization calculations, the molecular structure starting thermodynamic product.
from the carbocation Va and moving along the coor-
In the second step, we followed the rearrangement
dinate of the reaction until the oxazolinium IVa. The of this intermediate Va into the amidium IX by the
H
H
O
Me
Me
OH
Me
Me
.
.
Me
Me
Me
Me
Me
.
.
Me
H
.
.
.
O
2H2O
+
-
..
.
.
N
N
N
R
.
HN
R
OH
N
.
H
.
-H2O
.
.
O
OH
.
.
O
H
O
O
O
R
R
.
R
H
1
I
II
III
3
Scheme 2. Mechanism proposed of the neutral hydrolysis of N-acylaziridine 1.
Me
Me
Me
Me
Me
Me
Me
Me
Me
+
H+
Me
+
+
HN
N
HN
N
O
HN
R
O
- H +
O
O
O
R
R
R
R
1
IV
V
VI
2
Scheme 3. Mechanism proposed of the acid isomerization of N-acylaziridine 1.
2.93A°
Me
CH2
.
+.
.
.
.
.
2.97A°
VI
2
H
.
HN
.
.
- H +
Me
.
.
Me
O
1.26A°
c
d
CH2
.
+.
.
.
.
H
R
+
.
.
.
.
.
1.47 A°
HN
HN
.
.
.
.
O
TS2
OH
a
1.23A°
R
R
Me
Me
1.56 A°
TS1
VII
+
4
- H +
IV
HN
R
O
V
Me
Me
Me
Me
H
Me
H
.
Me
.
.
.
+
b
O
H
+
HN
O
OH
.
3
O
HN
HN
H
.
.
-H3O+
H
.
H
.
.
.
.
. . .
.
.
.
2H2O
H
O
O
H
O
O
O
R
R
H
R
H
H
IX
VIII
TS3
Scheme 4. Proposed competitive rearrangements of the acid hydrolysis of N-acylaziridine 1.

Rearrangement of N-acyl-2,2- dimethylaziridines
243
G°(Kcal/mol)
Me
Me
CH2
15
10
.
+.
.
.
.
.
.
.
CH2
.
.
H
.
+.
HN
.
.
.
.
.
.
O
.
H
.
HN
.
.
.
.
O
TS1a
Et
Me
Me
TS2a
Et
9.02
+
7.93
HN
Et
5
O
Va
0.00
0
Me
-5
+
HN
OH
VIIa
-12.93
Et
-10
-15
-20
Me
Me
+
HN
O
R
IVa
-30
-35
-32.27
Figure 10. Energetic profile for paths a, c and d of rearrangement of the intermediate Va.
G°(Kcal/mol)
Me
Me
25
.
.
.
.
O
.
H
.
HN
Et
H
.
.
.
.
.
O
H
O
20
15
H
TS3a
17.63
10
5
Me
H
Me
Me
Me
+
HN
OH
+
O
HN
Et
H
. . .
2 H O
H
O
+
2
O
Et
IXa
0.94
Va
0
0.00
-5
Figure 11. Energetic profile for path b of rearrangement of the intermediate Va.

244
Madiha Kamoun Mhiri et al.
Me
Me
H+
+
Me
CH2
HN
R
HN
O
O
Me
Me
Me
Me
O
R
4
V
N
O
+
HN
H+
H
H
+
O
OH
R
Me
R
Me
Me
VI
2
H+
Me
HN
HN
O
-H2O
O
R
R
3
II
Scheme 5. Mechanism of acid transformation of amidoalcohol 3 and allylamide 4 into oxazoline 2.
5. Chena P C, Wanga S C, Hwanga J Z, Yehb J T, Huangd
C Y and K N Chena 2010 J. Chin. Chem. Soc. 57 901
6. Benrabah D, Mouzali M, Sanchez J Y and Lemoigne F
1990 Eur. Polym. J. 26 1061
7. Stewart I C, Lee C C, Bergman R G and Toste F D 2005
J. Am. Chem. Soc. 127 17616
8. Wu J, Hou X-L and Dai L-X 2001 J. Chem. Soc., Perkin
Trans. 1 1314
9. Cardillo G, Gentilucci L, Tolomelli A and Tomasini C
1988 J. Org. Chem. 63 3458
calculation of the IRC (figure 11). The results show
that this reaction involves a transition state TS3a
(17.63 kcal mol−1).
On the other hand, we have found that increasing the
concentration of sulfuric acid causes the transforma-
tion of amidoalcool 3 and allylamide 4 into oxazoline
2 (table 1). We proposed then the following mechanism
(scheme 5).
10. Alcaide A and Llebaria A 2012 Tetrahedron Lett. 53
2137
4. Conclusions
11. Thierry J and Servajean V 2004 Tetrahedron Lett. 45
821
12. Besbes N 1998 Tetrahedron Lett. 39 4275
13. Buchhlolz B and Stamm H 1988 Isr. J. Chem. 27 17
14. Besbes N 1999 Tetrahedron Lett 40 6569
15. Besbes N 2001 Bull. Pol. Ac. Sc. Chem. 49 313
16. Easwood F W, Perlmutter P and Yang Q 1997 J. Chem.
Soc. Perkin Trans. 1 35
17. Besbes N, Jellali H, Pale P, Efrit M L and Srasra E 2010
Phosphorus, Sulfur Silicon Relat. Elem. 185 883
18. Besbes N, Jellali H, Pale P, Srasra E and Efrit M L 2010
C. R. Chim. 13 358
In conclusion, this work illustrates complementarities
between theoretical study and chemical reactions to
determine the mechanism of formation of the com-
pounds 2, 3 and 4. The evolution of the yields of
oxazolines 2, amidoalcohols 3 and methallylamides
4 closely depended on both the acidity of the reac-
tion medium and the nature of the acyl group of 2,2-
dimethylaziridines 1.
19. Besbes N, Ayed T, Pale P and Tangour B 2008 C. R.
Chimie 11 1283
20. Fanta P E, Smat R J, Piecz L F and Clemens 1966 J.
Org. Chem. 31 3113
21. Fanta P E and Walsh E N 1966 J. Org. Chem. 31 59
22. Arfaoui Y, Besbes N, Kamoun Mhiri M, Efrit M L
and Srasra E 2011 Symposium International de Chimie
Hétérocyclique Octobre, Fès, Maroc 26
Supplementary Information (SI)
1H and 13C NMR spectra of representative molecules
are available at www.ias.ac.in/chemsci.
23. Park G, Kim S C and Kang H Y 2005 Bull. Korean
Chem. Soc. 26 1339
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