Oxidative cyclization of aldazines with bis(trifluoroacetoxy)iodobenzene

Article abstract of DOI:10.1016/j.tetlet.2005.02.067

Symmetrical and unsymmetrical aldazines are efficiently converted to 2,5-disubstituted-1,3,4-oxadiazoles by oxidation with bis(trifluoroacetoxy) iodobenzene (BTI).

Full text of DOI:10.1016/j.tetlet.2005.02.067

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2701–2704
Oxidative cyclization of aldazines with
bis(trifluoroacetoxy)iodobenzene
Zhenhua Shang, John Reiner, Junbiao Chang* and Kang Zhao*
College of Pharmaceuticals and Biotechnology, Tianjin University, Tianjin 300072, China
Received 8 October 2004; revised 26 January 2005; accepted 1 February 2005
Abstract—Symmetrical and unsymmetrical aldazines are efficiently converted to 2,5-disubstituted-1,3,4-oxadiazoles by oxidation
with bis(trifluoroacetoxy)iodobenzene (BTI).
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
methods are very useful for the preparation of large
quantities of materials due to the ready availability of
diacylhydrazines, hydrazides, and hydrazones as start-
ing materials, the reaction conditions tend to be harsh
and long reaction times are generally needed.
Symmetrical and unsymmetrical 1,3,4-oxadiazoles have
been reported to be biologically versatile compounds
displaying a variety of biological effects, which include
antiinflammatory,1 antifungal,2 antiparasitic,3 and anti-
microbial4 activities. In addition, they have been utilized
as bioisosteres of the carboxamide moiety in benzodiaze-
pine receptor agonists,5a muscarinic receptor ago-
nists,5b NK1 receptor antagonists,5c and Phe-Gly
peptidomimetics.5d Moreover, oxadiazole derivatives
have been widely used as electron conducting and hole
blocking materials in molecule-based as well as poly-
meric light-emitting devices (LEDs) due to the electron
deficient and favorable electron transport properties of
oxadiazole rings.6
An alternative route to 1,3,4-oxadiazoles 2 by oxidative
cyclization from the corresponding aldehyde N-acylhydr-
azones 3 proceeds with lead tetraacetate,15a lead(IV)
oxide,15b potassium permanganate,15c electro-chemical
methods,15d iodobenzene diacetate (IBD),15e or chlora-
mine T.15f The use of azines as oxidative cyclization pre-
cursors, however, is limited to a single example of Gillis
and Lamontagne who reported that benzalazine can be
oxidized to 2,5-diphenyl-1,3,4-oxadiazole with 2 equiv
of lead tetraacetate in benzene.16
The most common synthetic approach to 1,3,4-oxadiaz-
oles involves cyclodehydration of 1,2-diacylhydrazines 1
(Scheme 1). Typically, this reaction is carried out by
using thionyl chloride,7 phosphorous oxychloride,8
phosphorous pentoxide,9 triphenylphosphine,10 or trifluo-
romethane–sulfonic anhydride as the dehydrating
agent.11 Related preparations of oxadiazoles include
the reaction of hydrazides with ketenylidene triphenyl-
phosphorane,12 base promoted cyclization of trichloro-
acetyl hydrazones,13 and condensation of hydrazine
with 2-acyl-4,5-dichloropyrid-azin-3-ones in polyphos-
phoric acid (PPA) or BF3ÆOEt2.14 Although these
Herein we report that aldazines 4 react smoothly with
the organic iodine(III) reagent, bis(trifluoroacetoxy)iodo-
benzene (BTI), at room temperature to efficiently
afford 2,5-disubstituted 1,3,4-oxadiazoles 5 in good
yields (Scheme 2). Initial studies indicated that, among
the solvents that were surveyed, DMSO is the best sol-
vent for this oxidation (Table 1). Symmetrical and
unsymmetrical aldazines are oxidized to symmetrical
and unsymmetrical 1,3,4-oxadiazoles with equal facility
(Table 2). The use of DMSO as solvent and BTI as oxi-
dant gave good results in most of the cases examined
(products 5a–f, j, and k). When the aldazine 4 contains
a hydroxyl group (product 5g), the reaction proceeded
rapidly, but the yield was lower than for other examples.
Generally, molecules 4 with electron-donating moieties
on the aromatic rings (product 5e) gave better yields
and required shorter reaction times than those with
*
Corresponding authors. Tel.: +86 22 2740 4031; fax: +86 22 2789
0968; e-mail addresses: jbchang@public2.zz.ha.cn; combinology@
yahoo.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.067

2702
Z. Shang et al. / Tetrahedron Letters 46 (2005) 2701–2704
O
H
N
H
N N
O
Oxidative
cyclization
R'
N
R'
R
N
R
N
H
R
Dehydration
R'
O
O
R
1
3
2
Scheme 1.
N N
N
R'
R
N
A proposal for the reaction mechanism is shown in
Scheme 3. The imine moiety of 4 can be oxidized to nitre-
nium ion 6 (Scheme 3), which in turn may react with the
trifluoroacetate counter ion to afford after elimination of
iodobenzene and trifluoroacetic acid, iminoanhydride 8.
This intermediate can then cyclize to 10, which after reac-
tion with a second equivalent of BTI, and elimination of
iodobenzene, trifluoroacetic acid, and rearrangement
byproduct 15 (pathway A) or trifluoroacetic anhydride
(pathway B), would give the product 5. When the reac-
tion is carried out in DMSO, pathway A may be pre-
ferred; pathway B may operate in non-nucleophilic
solvents. In support of pathway B, trifluoroacetic anhy-
dride formation was indirectly studied by adding 3,4,5-
trimethoxy-phenylamine to the reaction mixture result-
ing in the formation of 2,2,2-trifluoro-N-(3,4,5-trimeth-
oxy-phenyl)-acetamide (unreported results).
R'
O
5
4
Scheme 2.
electron-withdrawing moieties (product 5h) possibly due
to resonance stabilization by the methoxy group on the
proposed nitrenium ion intermediate (Scheme 3). The
reaction also proceeded well with heteroaromatic ald-
azines such as furfuralazine (product 5f) and 2-furfural-
p-tolylazine (product 5k) to yield the oxadiazoles in
69% and 80%, respectively. Substrates such as 4,40-di-
bromobenzalazine, 4,40-dinitrobenzalazine, and 2,20,4,40-
tetrachlorobenzalazine failed to cyclize probably due to
their poor solubility in DMSO. Isobutyraldehyde and
propionaldehyde azine derivatives also failed to give
the oxadiazole products.
The reported method of preparing 2,5-diaryl-1,3,4-oxa-
diazoles is operationally simple, rapid, and gives
good yields. As the reaction conditions are extremely
mild, it could be a generally useful method for the syn-
thesis of a wide variety of oxadiazole containing
compounds.
Commercially available BTI is commonly used as an
efficient oxidizing reagent in organic synthesis. Many
applications of BTI have been reported17 a reflection
both of its mild reactivity along with a low side-product
profile. In the current report, similar advantages of this
reagent, mild reactivity and cleanly prepared products,
were observed. A related oxidant, iodobenzene diacetate
has been used to convert an aldazine to an aldehyde
dimethylacetal in alcohol;18 however, a change of sol-
vent from alcohol to CHCl3 in this reaction did not yield
any oxidative cyclization product even after 12 h at
room temperature (unreported results).
2. General procedure
A dried round-bottomed flask was charged with ald-
azine (0.5 mmol),19 bis(trifluoroacetoxy)iodobenzene
(BTI, 1.1 mmol), and anhydrous DMSO (10 mL). This
Table 1. Solvent effect on oxidation of benzalazine with BTI
Solvents
DMSO
CHCl3
CH2Cl2
THF
Dioxane
MeCN
Reaction time (min)
Yield (%)
5
69
90
40
100
35
240
—
300
—
30
20
Table 2. Oxidative cyclization of aldazines with bis(trifluoroacetoxy)iodobenzene
Product
R
R0
Reaction time (min)
Isolated Yield (%)
5a
5b
5c
5d
5e
5f
Ph
Ph
p-MeC6H4
5
10
10
13
35
4
69
83
71
77
85
65
49
53
68
76
80
p-MeC6H4
p-MeOC6H4
o-MeOC6H4
3,4-(MeO)2C6H3
2-Furyl
p-MeOC6H4
o-MeOC6H4
3,4-(MeO)2C6H3
2-Furyl
5g
5h
5i
p-OHC6H4
4,5-(MeO)2-2-nitroC6H2
Ph
p-OHC6H4
4,5-(MeO)2-2-nitroC6H2
p-MeOC6H4
p-MeOC6H4
2-Furyl
3
65
10
7
5j
5k
p-MeC6H4
p-MeC6H4
6

Z. Shang et al. / Tetrahedron Letters 46 (2005) 2701–2704
2703
CF COO
Ph
CF COO
Ph
3
3
-PhI
I
N
I
N
N
R'
CF CO
3
2
R
N
R'
R'
-CF CO H
PhI(OCOCF )
3
2
3 2
R
N
R
N
OCOCF
R
7
3
4
6
R
Ph
R'
N
R
R
N
COCF
R'
3
N
COCF
PhI(OCOCF )
N
N
H
3
N
3 2
I
N
COCF
O
3
O
N
O
- CF CO
O
O
CF
3
2
3
H
CF
3
O
R'
R'
+
O
10
11
9
8
R
R
N
N
- CF CO H
O
S
3
2
N
N N
O
S
O
O
O
CF
S
N
-PhI
3
CF
R
R'
3
CF
O
O
5
3
Pathway A
O
R'
O
R'
13
12
CF CO
3
2
Pathway B
CF CO
3
2
R
N
N N
O
O
O
OCOCF
3
+
R
R'
O
N
CF COOH
S
CF
3
CF
3
3
-(CF CO) O
3
2
15
O
R'
5
14
Scheme 3.
mixture was stirred at room temperature (above 30 °C)
and monitored by TLC. When the reaction was com-
plete, purification of the product directly by flash chro-
matography (silica gel, ethyl acetate–petroleum ether)
afforded 2,5-disubstituted 1,3,4-oxadiazoles as solids.
(d, 4H, J = 8.8 Hz), 7.90–7.92 (d, 4H, J = 8.8 Hz),
10.25 (s, 2H) >340 °C (lit.8b mp 350 °C).
Acknowledgements
1H NMR (400 MHz, CDCl3) compound 5a: 7.51–8.14
(m, 10H), 137–138 °C (lit.8b mp 138 °C; lit.14 mp 132–
133 °C); 5b: 2.41 (s, 6H), 7.29–7.31 (d, 4H, J = 8.0 Hz),
7.98–8.00 (d, 4H, J = 8.0 Hz) 179–180 °C (lit.8b mp
175 °C; lit.15c mp 187 °C in ethanol); 5c: 3.86 (s, 6H),
6.99–7.01 (m, 4H), 8.02–8.05 (dd, 4H, J = 1.6 Hz,
J = 7.2 Hz) 159–161 °C (lit.8b mp 161.5 °C); compound
5d: 3.95 (s, 6H), 7.03–7.07 (m, 4H), 7.45–7.49 (m, 2H),
7.97–7.99 (dd, 2H, J = 1.6 Hz, J = 1.6 Hz) 115–116 °C
(lit.8b 99.5 °C); 5e: 3.95 (s, 6H), 3.98 (s, 6H), 6.96 (d,
2H, J = 8.4 Hz), 7.63–7.68 (m, 4H) 13C NMR 56.0,
56.2, 109.5, 111.1, 116.6, 120.3, 149.4, 151.9, 164.2;
179–181 °C; compound 5f: 6.59–6.60 (dd, 2H,
J = 1.6 Hz, J = 3.6 Hz), 7.21–7.22 (dd, 2H, J = 0.8 Hz,
J = 3.6 Hz), 7.64–7.65 (dd, 2H, J = 0.8 Hz, J = 1.6 Hz)
143–144 °C (lit.14 mp 136–138 °C); compound 5h: 3.84
(s, 6H), 3.90 (s, 6H), 7.38 (s, 2H), 7.65 (s, 2H); 13C
NMR 56.4, 56.4, 62.8, 108.2, 111.0, 132.3, 139.8,
148.0, 153.9; 205–207 °C; compound 5i: 3.86 (s, 3H),
6.99–7.02 (dd, 2H, J = 2.0 Hz, J = 2.8 Hz), 7.49–7.52
(m, 3H), 8.04–8.06 (dd, 2H, J = 2.0 Hz, J = 2.8 Hz),
8.09–8.11 (m, 2H) 148–149 °C (lit.15b mp 150 °C); com-
pound 5j: 2.41 (s, 3H), 3.86 (s, 3H), 6.99–7.02 (m, 2H),
7.29–7.31 (d, 2H, J = 8.0 Hz), 7.97–7.99 (d, 2H,
J = 8.4 Hz), 8.03–8.06 (m, 2H) 148–150 °C (lit.15c mp
150 °C in methanol); compound 5k: 2.40 (s, 3H), 6.58–
6.60 (m, 1H), 7.18–7.19 (d, 1H, J = 3.6 Hz), 7.28–7.30
(d, 2H, J = 8.4 Hz), 7.63–7.64 (m, 1H), 7.96–7.98 (d,
K.Z. acknowledges the Outstanding Young Scholarship
from NSFC (#30125043), the Basic Research Project
(#2002CCA01500) of the MOST and the Cheung Kong
Scholars Programme for financial support.
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