C-C bond cleavage of keto-aziridines; synthesis of oxazoles via regio-controlled ring expansion

Article abstract of DOI:10.3184/174751913X13843364573005

The ring expansion of keto-aziridines to the corresponding 2,5-diaryloxazoles in the presence of iodine in refluxing dimethyl sulfoxide, is described. A plausible mechanism for the synthesis of 2,5-diaryloxazoles is proposed.

Full text of DOI:10.3184/174751913X13843364573005

JOURNAL OF CHEMICAL RESEARCH 2013
DECEMBER, 745–747
RESEARCH PAPER 745
C–C bond cleavage of keto-aziridines; synthesis of oxazoles via regio-
controlled ring expansion
Heshmat Allah Samimi* and Soraya Entezami
Department of Chemistry, Faculty of Sciences, Shahrekord University, PO Box 115, Shahrekord, Iran
The ring expansion of keto-aziridines to the corresponding 2,5-diaryloxazoles in the presence of iodine in refluxing dimethyl
sulfoxide, is described. A plausible mechanism for the synthesis of 2,5-diaryloxazoles is proposed.
Keywords: keto-aziridine, ring expansion, oxazoles, iodine, regio-controlled reaction, C–C bond cleavage
The oxazole core is found in a diverse array of structures,
including biologically active agents such as anti-cancer,1 anti-
tubercular,2 antibacterial,3 anti-inflammatory4 and anti-HIV
agents,5. They are most commonly obtained by the Hantzsch
reaction.6 Other processes including aza-Wittig reactions,7
Schmidt rearrangements,8 Friedel–Crafts/Robinson–Gabriel
reactions,9 the cyclodehydration of β‑ketoamides,10 the use
of isocyanides,11 the dehydrogenation of oxazolines,12 cyclo-
isomerisation of N-propargyl amides13 and decomposition of
α‑diazoketones in nitriles,14 have also been developed for the
synthesis of oxazoles.
In addition, ring expansion of aziridines is an attractive
method for the preparation of a wide variety of five-membered
ring aza-heterocycles via a C–C or C–N bond cleavage.15,16
Ring-opening reaction of aziridines, predominantly involves
cleavage of the C–N bond of the ring,17–22 although a few
isomerisations are known in which the C–C bond of the ring
is broken.23–27
Despite numerous reports on the application of N-aryl,
N-alkyl or N-acyl aziridines in C–N or C–C bond cleavage,17–27
the synthesis of oxazoles from N-H aziridines by a C–C bond
cleavage has not yet been reported.
In continuation of our efforts in the development of the
chemistry of keto-aziridines,28–30 as well as the ring expansion
of keto-aziridines for the preparation of regio-isomers of trans-
oxazolines,31–34 we now report the C–C bond cleavage of N-H
aziridines and synthesis of the corresponding diaryloxazoles
in the presence of iodine. A similar role of iodine was also
reported by Padwa and co-workers.35
in some refluxing solvents. Treatment of 1a with iodine in
refluxing EtOH, DEG, DMAC, CH3CN or THF gave only a
trace amount 2,5-diphenyloxazole (14–38%) (Table 1, entries
7–11). However, the best result for the conversion of 2-benzoyl-
3-phenylaziridine 1a to 2,5-diphenyloxazole 3a was achieved
in the presence of iodine in refluxing DMSO (entry 12, 73%
yield). In another attempt, we examined treatment of 1a in
DMSO and in the presence of some other catalysts such as
ZnCl2, AlCl3, BF3.OEt2, but none of them gave a reasonable
yield of oxazole (Table 1, entries 13–15).
With the optimal reaction conditions in hand, the scope of the
ring expansion reaction of some keto-aziridines 1 was explored
by variation of substitution pattern, in the presence of iodine in
refluxing DMSO, and the results are summarised in Table 2.
1
All the products were characterised by H, 13C NMR and IR
spectra.
It is interesting to note that the yield of products is dependent
upon the substituents in the aryl groups. With a nitro group
(entries h and i) no oxazoles were obtained, instead both
aziridines gave 3-nitrobenzaldehyde upon treatment with
iodine.
Although the exact mechanism for this oxazole synthesis is
not clear, a proposed pathway for this synthesis is shown in
Scheme 1. First, iodine behaves as a Lewis acid to promote
C–C bond cleavage of the aziridine by coordinating with the
Table 1 Transformation of trans-2-benzoyl-3-phenylaziridine 1a to the
corresponding oxazole 3a under different conditions
trans-2-Aroyl-3-arylaziridines 1 were prepared following a
known synthetic procedure,32 by bromination of the appropriate
α,β‑unsaturated carbonyl compounds, followed by reaction
with ammonia solution (i.e. aqueous ammonia) in methanol at
room temperature.
The initial purpose of this research was to develop a new
method to synthesise oxazoles from the reaction of keto-
aziridines. Initial studies were aimed at finding optimal
conditions for the C–C bond cleavage of keto-aziridines. We
examined the reaction of 2-benzoyl-3-phenylaziridine (1 mmol)
in different solvents such as EtOH, DMSO (dimethyl sulfoxide),
DEG (diethylene glycol), DMAC (N,N-dimethylacetamide),
CH3CN or THF under reflux without any catalyst. However,
under these conditions a small amount of 2,5-diphenyloxazole
together with chalcone 2a were obtained (Table 1, entries 1–6).
The results are summarised in Table 1.
H
N
O
N
Conditions
+
Ph
Ph
Ph
Ph
O
O
Ph
Ph
2a
Time/h
1a
3a
Yield/%a
Entry
Conditionsb
2
0
24
22
12
0
3
0
8
36
5
0
0
38
14
19
41
18
73
21
24
9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
EtOH
DEG
DMAC
5
5
8
5
8
8
8
8
8
8
8
5
8
8
8
THF
CH3CN
DMSO
0
CH3CN/I2
THF/I2
EtOH/I2
DMAC/I2
DEG/I2
DMSO/I2
DMSO/ZnCl2
DMSO/BF3.OEt
DMSO/AlCl3
33
18
26
18
37
15
15
31
26
Further studies were aimed at exploring the effect of iodine
as a catalyst for the ring cleavage of the aziridines. Therefore,
we considered the possibility of ring expansion of 2-benzoyl-
3-phenylaziridine 1a in the presence of iodine as a catalyst
aIsolated yield after purification.
bAll reactions were performed in refluxing solvents.
* Correspondent. E-mail: samimi-h@sci.sku.ac.ir
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746 JOURNAL OF CHEMICAL RESEARCH 2013
Table 2 Synthesis of oxazoles 3 from the corresponding trans-2-aroyl-3-
arylaziridines 1
H
H
N
N
H
N
Ar1
Ar2
I2
H
CHO
Ar1
N
N
O
Ar1
DMSO/I2
Reflux
Ar2
DMSO/I2
Reflux
Ar1
Ar2
Ar1
Ar2
O
O
O
O
1
Ar2
NO2
C
B
Ar1=3-NO2 C6H4
3a-g
4h-i
I
1a-i
N
-HI
N
Entry
a
Ar1
Ar2
Time/h
6
5
6
4
5
8
6
10
10
Yield/%a
739,18
H
Ar1
Ar2
Ar2
O
C6H5
C6H5
O
Ar1
b
c
d
e
f
g
h
i
2-4-Cl2C6H3
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
C6H5
71
77
689
62
65
6618
0b
3
D
C6H5
Scheme 1 A proposed mechanism for synthesis of oxazoles from the
corresponding keto-aziridines.
2,4-Cl2C6H3
4-ClC6H4
4-MeOC6H4
3-NO2C6H4
3-NO2C6H4
C6H5
C6H5
4-ClC6H4
C6H5
presence of iodine in DMSO-H2O (1:1). The reaction afforded
3-nitrobenzaldehyde (39%) and a mixture of products.
In summary, we report an efficient and novel method for the
synthesis of 2,5-diaryloxazoles by C–C bond cleavage of trans-
2-benzoyl-3-arylaziridines in a completely regio-controlled
reaction in the presence of iodine in refluxing DMSO. The
synthesis of oxazoles from N-H aziridines by a C–C bond
cleavage has not been reported so far.
0b
aIsolated yield after purification.
b3-Nitrobenzaldehyde was obtained in low yields (9–11%).
nitrogen to give an intermediate B or C, Such coordination can
induce cleavage of the C–C bond of the strained aziridine ring.
In addition, the formation of ylide B or C can be envisioned
as being due to the presence of the electron-withdrawing
carbonyl group, which stabilises the carbanionic centre, and
3-aryl group which stabilises the benzylic cationic centre in the
azomethine ylide. The reaction then proceeds by ring closure to
a 2,3-dihydrooxazole D in the presence of iodine. Subsequent
elimination of HI gives the oxazole 3 (Scheme 1).
The intermediacy of this dipolar spices is supported by the
fact aziridine containing a nitro group (entries h and i), which
destabilises the carbocationic centre, did not give any oxazole.
According to the mechanism presented in Scheme 2 for the
conversion of the 3-(3-nitrophenyl)aziridines (entries h and i) to
aldehyde there are two possible routes. In route I, the aziridine
in the presence of iodine gives intermediate B which then
reacts with residual H2O in DMSO to produce intermediate F.
Protonation of the amino function will generate a good leaving
group (a protonated hemi-aminal) from which elimination of
the aldehyde can now occur. Whereas in route II, It can be
deduced that the electron-withdrawing nitro-group destabilises
the carbocationic centre in intermediate B, which is less likely
to be formed. However, the aziridine in the presence of iodine
reacts with H2O faster than an intramolecular reaction to afford
intermediate F, which gives the aldehyde via a C–N bond
cleavage.
Experimental
All yields refer to isolated products after purification by column
chromatography or distillation in vacuum. Products were
characterised by IR, 1H NMR and 13C NMR spectra, TLC and
melting points. NMR spectra were recorded on a Bruker AMX-400
spectrometer (1H at 400 MHz and 13C at 100 MHz) in CDCl3 with
chemical shift values in ppm downfield from TMS. IR spectra were
recorded on a JASCO, FT/IR-6300 spectrophotometer. All solvents
used were dried and distilled according to standard procedures.
Synthesis of oxazoles 3a–g from the corresponding keto-aziridines 1a–g;
general procedure
Iodine (0.24 g, 1 mmol) was added to a solution of the keto-aziridine
(1.0 mmol) in DMSO (15 mL) and the mixture was stirred at reflux for
4–8 h. The progress of the reaction was monitored by TLC (EtOAc-
hexane: 1:4). After completion of the reaction, EtOAc (15 mL) and
water (15 mL) was added to the mixture. The organic layer was
separated and rinsed twice with water and dried with anhydrous
Na2SO4. Evaporation of the solvent under reduced pressure and
subsequent purification of the residue by column chromatography
(silica gel, EtOAc-hexane: 1:4) provided the 2,5-diaryloxazoles 3 (62–
77%) (Table 2).
5-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)oxazole (3b): Yellow solid,
m.p. 136–139 °C; H NMR (400 MHz, CDCl3): δ 7.94 (d, J=8.5 Hz,
1H), 7.65 (d, J=8.7 Hz, 2H), 7.49 (d, J=2.1 Hz, 1H), 7.44 (s, 1H), 7.36
1
To further investigate the proposed mechanism we examined
the reaction of 2-benzoyl-3-(3-nitrophenyl)aziridine in the
H
N
Ar1
Ar2
I2
O
H
H
N
H
H
N
H2O
I
B
N
e
t
Ar1
u
or
Ar1
o
O
Ar1
R
Ar2
I2
H
Ar2
Ar2
O
O
OH
N
1
I2
OH2
R
F
Ar1
o
O
u
F
t
e
I
I
Ar2
H2O
Ar1CHO
Scheme 2 A proposed mechanism for the conversion of aziridines containing nitro groups (entries h and i) to the corresponding aldehydes.
JCR1302091_FINAL.indd 746
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JOURNAL OF CHEMICAL RESEARCH 2013 747
(d, J=8.7 Hz, 2H), 7.30 (dd, J=8.5, 2.1 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 161.3, 151.5, 136.4, 135.6, 134.1, 131.7, 129.5, 129.7, 128.5,
128.9, 127.7, 125.6, 123.1. Anal. Calcd for C15H8Cl3NO: C, 55.50; H, 2.48;
N, 4.32. Found: C, 55.56; H, 2.47; N, 4.22%.
3
4
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127 °C; H NMR (400 MHz, CDCl3): δ 7.94 (d, J=8.60 Hz, 2H), 7.66
6
7
(d, J=8.57 Hz, 2H), 7.37 (d, J=8.60 Hz, 2H), 7.35 (s, 1H), 7.32 (d,
J=8.60 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 160.4, 150.5, 136.6,
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C15H9Cl2NO: C, 62.09; H, 3.13; N, 4.83. Found: C, 62.13; H, 3.16; N,
4.84%.
2-(2,4-Dichlorophenyl)-5-phenyloxazole (3e): Yellow solid, m.p.
90–92 °C; IR (KBr): νmax /cm–1 3064, 1662, 1590, 1482, 1101, 867, 828,
756, 685; 1H NMR (400 MHz, CDCl3): δ 7.32–7.26 (m, 1H), 7.38–7.33 (m,
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130.0, 129.2, 129.1, 129.0, 127.4, 124.6, 124.5, 123.8, 121.2. Anal. Calcd
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4.78%.
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1
102 °C; IR (KBr): νmax /cm–1 3064, 2993, 1656, 1586, 821, 756, 691; H
NMR (400 MHz, CDCl3): δ 8.11 (d, J=7.50, 2H), 7.84–7.62 (m, 3H),
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We thank the Research Council of Shahrekord University for
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Received 29 July 2013; accepted 23 September 2013
Paper 1302091 doi: 10.3184/174751913X13843364573005
Published online: 6 December 2013
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