Formation of 1,3,4-oxadiazolines and 1,3,4-oxadiazepines through acetylation of salicylic hydrazones

Article abstract of DOI:10.1016/j.tetlet.2014.12.037

A new series of 1,3,4-oxadiazolines and 1,3,4-oxadiazepines are prepared in a one-step reaction through cyclization of various N-benzylidene-2-hydroxybenzohydrazides. Cyclization in acetic anhydride yielded 1,3,4-oxadiazolines, while the reaction carried

Full text of DOI:10.1016/j.tetlet.2014.12.037

Tetrahedron Letters 56 (2015) 573–576
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Tetrahedron Letters
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Formation of 1,3,4-oxadiazolines and 1,3,4-oxadiazepines through
acetylation of salicylic hydrazones
Abeer A. Alhadi a,d, Rozana Othman b,d, Wageeh A. Yehye , Noorsaadah Abd Rahman
c
a,d,
⇑
a
Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
Department of Pharmacy, University of Malaya, 50603 Kuala Lumpur, Malaysia
b
c
Nanotechnology & Catalysis Research Centre, NANOCEN, University of Malaya, 50603 Kuala Lumpur, Malaysia
d
Drug Design and Development Group, University of Malaya, 50603 Kuala Lumpur, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 May 2014
Revised 25 November 2014
Accepted 9 December 2014
Available online 15 December 2014
A new series of 1,3,4-oxadiazolines and 1,3,4-oxadiazepines are prepared in a one-step reaction through
cyclization of various N-benzylidene-2-hydroxybenzohydrazides. Cyclization in acetic anhydride yielded
1,3,4-oxadiazolines, while the reaction carried out in acetic anhydride–acetic acid gave 1,3,4-oxadiaze-
pines, in some cases.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
1
1
,3,4-Oxadiazoline
,3,4-Oxadiazepine
Acetylation
Acid catalyzed
Oxadiazolines and oxadiazepines are important compounds for
both chemical and biological purposes.1 They have been used
extensively as synthons in various organic syntheses such as for
,2
3
the preparation of spiro-fused b-lactam oxadiazolines and of fused
oxadiazepines used as gamma secretase modulators for the treat-
ment of Alzheimer’s disease.4 In addition, oxadiazolines and oxa-
diazepines have been reported to exhibit diverse pharmacological
properties, which include antimicrobial, cytotoxic,7 antifungal,
5
6
8
and anticancer activities. Various aldehyde and ketone acyl hydra-
zones have been cyclized to give 3-acyl-1,3,4-oxadiazolines under
9
,10
acylating conditions.
However, there are only three reports on
acylhydrazones with a hydroxyl group at the ortho position of the
1
1
benzene ring being cyclized to give 3-acyl-1,3,4-oxadiazolines.
In the case of oxadiazepines, several methods have been reported
6
,12–14
for their synthesis, all of which are multi-step in nature.
For
example, El Badry and Taha reported that the diazotization of ethyl
-aminotetrazole-5-carboxylate in the presence of water resulted
in the formation of ethyl 1-hydroxytetrazole-5-carboxylate.
2
1
(
Scheme 1).
Scheme 1. El Badry and Taha’s work.2
Condensation of ethyl 1-hydroxytetrazole-5-carboxylate with
bromoacetone and/or phenacyl bromide in absolute ethanol in
the presence of anhydrous potassium carbonate provided acetyl-
oxy and 2-oxyacetophenone compounds, which were then reacted
with various 4-substituted anilines in the presence of acetic anhy-
dride/acetic acid to give 7-methyl(phenyl)-8-aryltetrazolo[1,5-b]-
6
1
,2,5-oxadiazepin-9-ones in three steps. Herein, we report a
novel, one-step intramolecular oxidative cyclization of a variety
1
5
⇑
Corresponding author. Tel.: +60 3 79674643; fax: +60 3 79674193.
E-mail address: noorsaadah@um.edu.my (N.A. Rahman).
of substituted benzaldehyde acylhydrazones 1 with a free hydro-
xyl group at the ortho position to give the oxadiazolines 2, which
http://dx.doi.org/10.1016/j.tetlet.2014.12.037
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0

5
74
A. A. Alhadi et al. / Tetrahedron Letters 56 (2015) 573–576
OH
H
Table 1
N
O
Structures and yields of synthesized compounds 3a–i
N
Ar
7
OAc
O
N N
OH
H
0
A
O
C
-80
c
2
c 2
°
1
O
h
N
O
0
A
°
N
Ar
Ac O
120-130 °C
Ar
3
2
1
C
-
,
0
1
2
1
O
1
3
OAc
O
OH
O
N N
Ac O
20-130 °C
2
Producta
Yieldc (%)
1
Entry
1
Ar
Ar
Ar
N N
OAc
3
O
2
O
O
Cl
Cl
N N
78
Scheme 2. Synthesis of 1,3,4-oxadiazoline derivatives 3.
O
3
3
a
OAc
were isolated and characterized. Acetylation of the oxadiazoline 2
1
6–18
O
N N
led to the formation of 1,3,4-oxadiazoline derivatives 3
as
O
O
shown in Scheme 2. Thus, reactions of substituted benzaldehyde
acylhydrazones 1 in acetic anhydride at 120–130 °C resulted in
the cyclized products 3 (Scheme 2). The reactions proceeded
smoothly with no side products being observed under these
2
3
4
5
6
70
70
65
60
58
O
b
OAc
1
5,19
conditions.
F3CO
O
N N
OCF3
Under these acylation conditions, compounds 1a–i, possessing
either electron-donating or electron-withdrawing substituents on
1
6–18,20
the aryl ring cyclized to give 1,3,4-oxadiazolines 3a–i
5
in
O
1
8
3cb
3d
8–85% yields (Table 1). The presence of an electron-withdraw-
ing substituent on the phenyl ring tended to give better yields with
the best yield being obtained with a nitro substituent, and the low-
est with a tert-butyl substituent.17,18 This is to be expected since a
OAc
S
O
N N
S
strong electron-withdrawing group such as NO
2
on the aryl ring
O
would enhance the electrophilicity of the iminium carbon, while
1
8
an electron-donating group would decrease the electrophilicity.
OAc
In some cases, when the cyclization reactions of 1 were carried
out at 50–60 °C in acetic anhydride/acetic acid solution, 1,3,4-oxa-
diazepines 4 were obtained instead of 1,3,4-oxadiazolines 3
O
N N
1
8,20,21
(
Scheme 3).
Table 2 summarizes the products of the cyclization reactions of
compound 1 using the Ac O–AcOH conditions. Presumably, the
acidic conditions influenced the reaction to form the seven-mem-
O
3
e
2
OAc
O
N N
1
8,20,21
bered oxadiazepines.
We have proposed two pathways leading to the formation of
oxadiazolines 3 (Scheme 4). One pathway involves acetylation of
the free hydroxyl group on the benzene ring to form 5, which then
undergoes intramolecular oxidative cyclization to form 3 (Pathway
A). An alternative pathway involves intramolecular oxidative cycli-
zation of 1 to first produce 2a and 2b, followed by acylation of the
phenol to form 3 (Pathway B).
However, since we isolated only the oxadiazolines 2a and 2b
with a free ortho phenolic group and no product 5 from this reac-
tion, we concluded that the cyclization occurred through pathway
B. Compounds 2a and 2b (Scheme 4), then underwent acetylation
to produce 3a and 3b.
It has been well established that compound 1 can undergo
keto–enol tautomerisation as shown in Scheme 5.
We propose that the mechanism for the oxidative cyclization
reactions leading to 2a and 2b involves attack of the enolic oxygen
of the enol tautomer on the azomethine imine moiety as shown in
Scheme 6.
O
3f
OAc
O N
O
N N
2
NO2
OAc
Ph
7
8
9
85
70
75
O
3
3
3
g
OAc
O
AcO
N
N
O
hb
OAc
O
N N
In the case of the seven-membered oxadiazepines, we propose
that the reaction occurs via nucleophilic attack of the phenolic oxy-
gen on the iminium carbon as shown in Scheme 7. Here, the imin-
O
id
b
d
Structure was confirmed by X-ray crystallography.
This compound was previously reported in Ref. 11 along with a crystal structure,
ium carbon acts as a carbonyl analogue and participates in an
intramolecular nucleophilic addition reaction1
9,22
with the ortho
but without any data.
phenolic group. Subsequently, the oxadiazepine underwent acety-
lation to give only the diacetylated product 4 (Scheme 7).
a
All products were identified by ATIR, NMR, and EI-HRMS analyses.
c
Isolated yield after recrystallization.

A. A. Alhadi et al. / Tetrahedron Letters 56 (2015) 573–576
575
Table 2 (continued)
OH
NH
Producta
Yieldc (%)
Entry
Ar
N
Ar
O
OAc
1
O N
2
Ac O/AcOH
O
N
2
5
N
70
5
0-60 °C, 1 h
O
3
NO2
g
OAc
O
O
OAc
F3CO
OCF3
O
O
N
N
O
N N
6
7
N
65
65
O
Ar
N
or
O
Ar
3c
O
OAc
O
4
3
O
O
Scheme 3. Synthesis of 1,3,4-oxadiazepines 4 and 1,3,4-oxadiazolines 3.
N
N
O
3
b
Table 2
OAc
Structures and yields of compounds 4a,d,e,f and 3b,c,g,h, i
AcO
O
N N
OAc
O
N N
OAc
8
9
63
70
Ar
O
3
h
OH
O
3
b,c,g,h,i
OAc
NH
Ac O, AcOH
2
N
Ar
O
N N
Ph
50-60 °C, 1 h
O
O
O
N
N
1a-i
O
O
3
i
O
Ar
b
Structure was confirmed by X-ray crystallography.
All products were identified by ATIR, NMR, and EI-HRMS analyses.
Isolated yield after recrystallization.
4
a,d,e,f
a
c
Producta
Yieldc (%)
Entry
Ar
O
O
O
Cl
N
N
O
O
OH
1
63
NH
N
Cl
S
X
O
4
4
4
4
ab
1
A
Pathway A
OAc
Pathway B
O
C
7
c
c 2
°
0
2
O
O
-
8
A
0
O
8
0
-
°
C
S
N
N
0
7
OH
O
NH
N
2
3
4
O
75
66
55
X
N
C
X
N
O
O
5
2O
°
c
0
2a and 2b
db
A
3
1
-
0
OAc
2
O
1
O
O
N N
X
N
N
O
O
a X= Cl
O
O
b X= OCH
3
3
a and 3b
eb
Scheme 4. Proposed pathways for the cyclization of 1.
O
O
N
N
OH
H
OH
N
OH
O
N
O
N
Ar
N
Ar
f
Scheme 5. Tautomerisation of compound 1.

5
76
A. A. Alhadi et al. / Tetrahedron Letters 56 (2015) 573–576
OH
H
OH
References and notes
N
N
O
N
OH
Ar
N
Ar
1.
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Greenlee, W.; Cohen-Williams, M.; Hyde, L.; Song, L.; Zhang, L.; Chu, I.; Huang,
X. Bioorg. Med. Chem. Lett. 2013, 23, 466–471.
OAc
N
OH N
N
O
NAc
Ar
Ar
Ac O
2
O
H
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Scheme 6. A plausible mechanism for the formation of compounds 3a–i.
9.
Somogyi, L. J. Heterocycl. Chem. 2007, 44, 1235–1246.
O
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O
H
N
O
H
N
N
Ar
Ar
N
H
- H
NH
NH
H
OH
OH
HO
1
Ar
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O
O
2617–2620.
NH
NH
N
15. General procedure for the synthesis of hydrazones 1a–i: 2-
Hydroxybenzohydrazide (0.30 g, 2 mmol) and different para-substituted
benzaldehyde derivatives (0.2 g, 2 mmol) were refluxed in EtOH (20 ml) for
2
Ac O
2
N
O
O
O
Ar
Ar
4
5
h. The solvent was removed by evaporation and the resulting products were
obtained as white solids (1a,c–i) or as a yellow solid (1b).
16. General procedure for synthesis of oxadiazoline analogs (Table 1): A mixture of
Scheme 7. A plausible mechanism for the formation of compounds 4.
hydrazone 1a–i (1.58 mmol) in Ac
stirring. The solution was cooled and then poured onto crushed ice and stirred
vigorously. A precipitate formed which was washed with distilled H O to
remove the Ac O. The obtained solid was further purified by crystallization
from an appropriate solvent.
2
O (6 ml) was refluxed for 2 h under vigorous
2
2
In summary, 1,3,4-oxadiazolines containing an acetoxy group at
the ortho position of the benzene ring were prepared in one-step,
via intramolecular oxidative cyclization of acylhydrazones in acetic
anhydride, which serves both as a reactant and the solvent. How-
ever, 1,3,4-oxadiazolines or 1,3,4-oxadiazepines were obtained in
some cases, when the reactions were carried out under acid-cata-
lyzed conditions.
17. Most products were found to be homogeneous by TLC and 400 MHz NMR
analyses, but when necessary, heterogeneous products were readily purified
by silica gel column chromatography using hexane/CHCl
8. See Supplementary data for complete experimental details.
19. Jiang, L.; Chen, Y.-C. Catal. Sci. Tech. 2011, 1, 354–365.
3
as the eluent.
1
20. Crystallographic data for compounds 3c, 3h, 4a, 4d and 4e have been deposited
at the Cambridge Crystallographic Data Centre, with the deposition numbers
9
63045, 963044, 963041, 963043 and 963042, respectively.
1. General procedure for the synthesis of oxadiazepine derivatives (Table 2):
Compounds 4a,f,e,d were obtained from the reaction of Ac O (6 ml) with
2
Acknowledgments
2
hydrazones 1a,f,e,d (2 mmol) in the presence of AcOH (6 ml), and the resulting
solution was stirred vigorously for 1 h at 50–60 °C. A precipitate formed which
was washed with distilled H O to remove the Ac O. The obtained solid was
The authors acknowledge support from the University of
Malaya under the UMRG: RG056/11BIO and UMRG program
RP002/2012.
2
2
further purified by crystallization from an appropriate solvent.
22. Dewick, P. M. Essentials of Organic Chemistry: For Students of Pharmacy,
Medicinal Chemistry and Biological Chemistry; Wiley: Chichester, 2006; pp
369–370.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.12.037.