Iodogen: A novel reagent for the oxidation of urazoles under heterogeneous conditions

Article abstract of DOI:10.1055/s-0029-1216902

Iodogen is employed as an efficient oxidizing agent for the conversion of urazoles and bis-urazoles into the corresponding 1,2,4-triazoles in good to excellent yields under mild heterogeneous conditions at room temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216902

PAPER
2729
Iodogen: A Novel Reagent for the Oxidation of Urazoles under Heterogeneous
Conditions
a
a
a
b
O
A
xidation of Urazo
h
les
U
sing Io
m
dogen ad Khoramabadi-zad,* Azam Shiri, Mohammad Ali Zolfigol, Shadpour Mallakpour
a
Faculty of Chemistry, Bu-Ali Sina University, P.O. Box 6517838683, Hamadan, Iran
b
Organic Polymer Chemistry Research Laboratory, College of Chemistry, Isfahan University of Technology, Isfahan 84156, Iran
Fax +98(31)18257407; E-mail: khoram@basu.ac.ir
Received 9 April 2009; revised 20 April 2009
and azo moieties in the molecule. They can undergo self-
17
Abstract: Iodogen is employed as an efficient oxidizing agent for
the conversion of urazoles and bis-urazoles into the corresponding
1,2,4-triazoles in good to excellent yields under mild heterogeneous
conditions at room temperature.
16
reactions leading to deazadimers and polymers.
Volanschi and coworkers have investigated the electro-
chemical behavior and redox reactivity of several 4-sub-
1
8
stituted 1,2,4-triazole-3,5-diones. TADs have been used
both as substrates and reagents in various organic reac-
Key words: iodogen, oxidations, chloroamides, glycolurils
19
tions including [2+2] cycloadditions, dehydrogena-
2
tion, electrophilic aromatic substitution, condensation
0
21
1
,3,4,6-Tetrachloro-3a,6a-diphenylglycoluril, also known
as iodogen (I), was first used by Fraker and Speck in 1978
22
of dicarbonyl compounds, and oxidation of alcohols to
1
6,23
aldehydes and ketones.
The varied reactivity of TADs
1
for the radioiodination of proteins and cell membranes,
2–6
and this procedure is still widely used for this purpose.
makes them interesting compounds, however, they can be
difficult to prepare and purify. It is interesting to note that
Iodogen (Figure 1) is a mild oxidizing agent and is as ef-
fective as enzymatic methods for the iodination of exter-
nally exposed residues, and is comparable with
chloramine-T for general protein iodination. In addition,
iodogen being a mild reagent results in limited oxidative
4-phenyl-3H-1,2,4-triazole-3,5-dione (2e) is an extremely
reactive dienophile and enophile.
24
All the known methods for the preparation of 1,2,4-tri-
azole-3,5-diones involve oxidation of the corresponding
urazoles. Although a number of reagents are available for
the efficient oxidation of urazoles into TADs, this trans-
formation is not straightforward due to their high sensitiv-
ity to the oxidizing agents and the reaction conditions. In
addition, most of the reported reagents produce by-prod-
ucts, which either decompose the sensitive 1,2,4-triazole-
7
–11
damage and retained cell viability.
O
Cl
Ph
Cl
Cl
N
N
N
N
Ph
3
,5-dione, or are difficult to remove from the reaction
Cl
product. Furthermore, the products are sensitive to light,
heat, alcohols, ethers, transition metals and several nu-
cleophiles. Another major drawback is the use of reagents
which are highly toxic or impose serious disposal prob-
O
I
Figure 1 The structure of iodogen (I)
25
lems, or both. The use of N-chloro- and N-bromo-con-
Di- and tetrachloroglycolurils were found to have good taining oxidizing agents have also been reported, but
bactericidal activity against test organisms. Chlorogly- without optimizing the reaction times or the amount of ox-
1
,12–15
26
colurils, prepared using chlorine gas,
generally have idizing agent required.
greater thermal stability than other known chloroamides
which makes them very useful as impregnating agents for
clothing. Furthermore, as they contain a high percentage
of active chlorine, they are useful as neutralizing agents or
as antivesicants for mustard gas and other vesicants. Chlo-
rinated glycolurils have been proposed as the source of
chlorine for swimming pool sanitation and sewage treat-
The stability of iodogen and simple work-up procedure
make it a safe and convenient source of chlorine in com-
parison to chlorine gas, which is a highly toxic oxidizing
agent. During the reaction, iodogen is transformed into an
environmentally benign and easily removable by-product
(diphenylglycoluril which is insoluble in dichloro-
methane). Despite its advantages, there has been limited
1
ment.
application of I in organic synthesis. We have thus inves-
-Substituted-1,2,4-triazole-3,5-diones (TADs) are well tigated iodogen as a mild reagent for the oxidation of ura-
4
known for their high reactivity in both thermal and photo- zoles 1 and bis-urazoles 3 under heterogeneous conditions
chemical reactions, due to the presence of both carbonyl (Scheme 1). Iodogen can be easily prepared from diphe-
2
7
nylglycoluril. The oxidation reactions are heterogeneous
as the solid substrates 1 and 3 are insoluble in the reaction
solvent (dichloromethane) whereas the products 2 and 4
are soluble in dichloromethane.
SYNTHESIS 2009, No. 16, pp 2729–2732
x
x.
x
x
.
2
0
0
9
Advanced online publication: 14.07.2009
DOI: 10.1055/s-0029-1216902; Art ID: Z06909SS
Georg Thieme Verlag Stuttgart · New York
©

2
730
A. Khoramabadi-zad et al.
PAPER
iodogen
diphenylglycoluril
chlorosuccinimide (V) failed (Figure 2). In the case of
N,N¢-dichlorophenobarbital (VI), urazoles were oxidized
into the corresponding 1,2,4-triazole-3,5-diones, howev-
er, we were unable to isolate the products due to their high
sensitivity.
H
N
R1
N
N
N
O
N
O
O
N
O
R2
CH2Cl2, r.t.
R2
2
1
Herein, we report a simple and inexpensive method for the
efficient oxidation of various urazoles 1 and bis-urazoles
3
into the corresponding 1,2,4-triazole-3,5-diones 2 and 4
under optimized heterogeneous conditions using iodogen
H
R1
N
N
N
N
(I) (Table 1).
iodogen
diphenylglycoluril
O
N
O
A plausible mechanism for this reaction involves in situ
generated chlorine cations acting as the oxidizing species.
Subsequent elimination of hydrogen chloride then yields
the 1,2,4-triazole-3,5-dione (Scheme 2).
O
O
N
O
O
R2
R2
O
N
O
CH2Cl2, r.t.
N
N
N
R1
N
N
H
4
3
H
H
N ••
H
Cl
N
Cl+
N
N
N N
– HCl
Scheme 1 Synthesis of 1,2,4-triazole-3,5-diones 2 and 4
– H+
O
N
O
O
N
O
O
N
O
R2
R2
R2
It should be noted that with the exception of iodogen as
the oxidizing agent, attempts to oxidize urazoles using
Scheme 2 A plausible mechanism for the iodogen-mediated oxida-
other active N-chloro reagents such as N-chlorosaccharin tion of urazoles or bis-urazoles into the corresponding 1,2,4-triazole-
3
,5-diones
(
II), chloramine-T (III), N-chlorophthalimide (IV) and N-
O
O
O
O
O
Cl
Cl
O
S
O
S
Cl
N
N
N
Cl
N–
Na+
N
Cl
N Cl
O
O
O
O
O
Ph
II
III
IV
V
VI
Figure 2 Structures of the N-chloro-based oxidizing agents II–VI
Table 1 Oxidation of Urazoles 1 and Bis-Urazoles 3 into the Corresponding 1,2,4-Triazole-3,5-diones 2 and 4 Using Iodogen
a
b
1
2
c
Iodogen (mmol) Time (h) Yield (%) Mp (°C)
Entry
Urazole Product
R
R
Found
Lit.
d
26a
26a
26a
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
H
Me
1.0
0.5
0.45
0.5
0.5
0.5
0.5
1.0
0.5
0.5
1.0
2.0
2.5
0.66
1
100
100
89
92
96
91
94
90
96
95
93
87
98–99
97–98
54–55
40–42
95–97
d
H
Et
53–55
+
Na
H
n-Pr
c-Hex
Ph
41–44
2
6a
0.33
1
95–96
2
2
2
2
6a
6a
6a
6a
H
169–170
130–133
113–115
125–127
87–90
171–175
132–135
111–113
125–126
H
4-ClC H
6
1.5
1.25
2.5
1.25
0.58
2
4
1g
1h
1i
2g
2h
2i
H
3,4-Cl C H
2 6 3
H
4-O NC H
2 6 4
2
8
H
4-MeOC H
6
89–93
4
2
8
1
1
1
0
1
2
1j
2j
H
4-t-BuC H
6
122–127
144–150
183 (dec.)
122–126
145–150
4
+
26a
3a
3b
4a
4b
Na
H
(CH2)6
C H CH C H
4
2
6a
2.5
180–185 (dec.)
6
4
2
6
a
b
c
d
Reaction in CH Cl at r.t.
2
2
The products are known and their spectra and physical data are reported in the literature.
Yield of isolated product.
%
Conversion, as these compounds are very volatile.
Synthesis 2009, No. 16, 2729–2732 © Thieme Stuttgart · New York

PAPER
Oxidation of Urazoles Using Iodogen
C NMR (22.5 MHz, CDCl ): d = 25.5, 27.0, 41.1, 159.2.
2731
1
3
In conclusion, we have described iodogen (I) as a novel
reagent for the efficient and practical oxidation of ura-
zoles and bis-urazoles under heterogeneous conditions.
This system could be used for the oxidation of a range of
urazoles under mild and safe conditions.
3
Acknowledgment
The authors would like to thank Dr. Gholamabbas Chehardoli for
his kind assistance, and are grateful for financial support of this
work from Bu-Ali Sina University, Hamadan, Iran.
Chemicals were purchased from Fluka, Merck and Aldrich. Melting
points were measured using a Stuart Scientific SMP3 apparatus and
1
13
are uncorrected. The H NMR (90 MHz) and C NMR (22.5 MHz) References
spectra were recorded in CDCl using a Jeol FX90Q spectrometer.
3
(
(
(
(
1) Fraker, P. J.; Speck, J. C. Jr. Biochem. Biophys. Res.
Commun. 1978, 80, 849.
2) Weinmann, H.; Tilstam, U. Org. Process Res. Dev. 2002, 6,
The oxidation products were characterized by comparison of their
1
13
spectral (IR, H and C NMR) and physical data with authentic
2
6a,28
samples prepared by reported procedures.
data are provided for representative compounds.
NMR spectroscopic
384.
3) Kolvari, E.; Ghorbani-Choghamarani, A.; Salehi, P.; Shirini,
F.; Zolfigol, M. A. J. Iran Chem. Soc. 2007, 4, 126.
4) Hiegel, G. A.; Hogenauer, T. J.; Lewis, J. C. Synth.
Commun. 2005, 35, 2099.
4
-Phenyl-3H-1,2,4-triazole-3,5-dione (2e); Typical Procedure
A mixture of 4-phenylurazole (1e) (0.176 g, 1 mmol) and iodogen
I) (0.216 g, 0.5 mmol) in CH Cl (10 mL) was stirred at r.t. for 1 h.
(
2
2
(5) Luca, L. D.; Giacomelli, G. Synlett 2004, 2180.
(6) Biltz, H.; Behrens, O. Chem. Ber. 1910, 43, 1984.
(7) Williams, J. W. US Patent 2,649,389, 1953; Chem. Abstr.
1953, 48, 8267.
2
9
The reaction mixture was filtered and the solvent evaporated to
give 2e as a red, crystalline solid; yield: 0.167 g (96%).
1
H NMR (90 MHz, CDCl ): d = 7.5 (s, 5 H, ArH).
3
1
3
(8) Adkins, H. B. US Patent 2,654,763, 1953; Chem. Abstr.
953, 48, 10778.
9) Slezak, F. B.; Hirsch, A.; Rosen, I. J. Org. Chem. 1960, 25,
60.
10) Slezak, F. B.; Bluestone, H.; Magee, T. A.; Wotiz, J. H.
J. Org. Chem. 1962, 27, 2181.
C NMR (22.5 MHz, CDCl ): d = 124.3, 129.6, 129.9, 158.0.
3
1
(
4-Methyl-3H-1,2,4-triazole-3,5-dione (2a)
Pink crystals.
6
(
1
H NMR (90 MHz, CDCl ): d = 3.3 (s, 3 H, CH ).
3
3
(
11) (a) Zettler, T. T. US Patent 3,252,901, 1966; Chem. Abstr.
1966, 65, 6922. (b) Horvath, R. J.; Parsons, C. G.; Zettler, T.
T. US Patent 3,445,383, 1969; Chem. Abstr. 1969, 70,
4-Ethyl-3H-1,2,4-triazole-3,5-dione (2b)
Pink crystals.
1
H NMR (90 MHz, CDCl ): d = 1.3 (t, J = 7.0 Hz, 3 H, CH ), 3.7 (q,
3
109008.
(12) Unak, T.; Akgun, Z.; Yildirim, Y.; Dumanb, Y.; Erenel, G.
3
J = 7.0 Hz, 2 H, CH2).
Appl. Radiat. Isot. 2001, 54, 749.
13) Yuan, H.; Luo, J.; Field, S.; Weissleder, R.; Cantley, L.;
Josephson, L. Bioconjugate Chem. 2005, 16, 669.
14) Safavy, A.; Georg, G. I.; Velde, D. V.; Raisch, K. P.; Safavy,
K.; Carpenter, M.; Wang, W.; Bonner, J. A.; Khazaeli, M.
B.; Buchsbaum, D. J. Bioconjugate Chem. 2004, 15, 1264.
1
3
C NMR (22.5 MHz, CDCl ): d = 12.7, 36.7, 159.2.
3
(
(
4-(4-Chlorophenyl)-3H-1,2,4-triazole-3,5-dione (2f)
Red crystals.
1
H NMR (90 MHz, CDCl ): d = 7.4 (s, 4 H, ArH).
3
1
3
(15) Cook, J.; Pratt, R.; Lilien, J. Biochemistry 1984, 23, 899.
C NMR (22.5 MHz, CDCl ): d = 125.1, 128.1, 130.3, 135.6,
3
(16) Borhani, D. W.; Greene, F. D. J. Org. Chem. 1986, 51, 1563.
17) Pirkle, W. H.; Stickler, J. C. J. Am. Chem. Soc. 1970, 92,
1
57.8.
(
7
497.
4
-(4-Nitrophenyl)-3H-1,2,4-triazole-3,5-dione (2h)
Red crystals.
(
18) Alstanei, A.-M.; Hornoiu, C.; Aycard, J.-P.; Carles, M.;
Volanschi, E. J. Electroanal. Chem. 2003, 542, 13; and
references therein.
(19) (a) Hall, J. H.; Krishnan, G. J. Org. Chem. 1984, 49, 2498.
(b) Hall, J. H.; Jones, M. L. J. Org. Chem. 1983, 48, 822.
1
H NMR (90 MHz, CDCl ): d = 7.9–8.4 (m, 4 H, ArH).
3
1
3
C NMR (22.5 MHz, CDCl ): d = 124.0, 125.4, 135.1, 147.7,
3
57.8.
1
(
102, 6384.
c) Seymour, G. A.; Green, F. D. J. Am. Chem. Soc. 1980,
4-(4-Methoxyphenyl)-3H-1,2,4-triazole-3,5-dione (2i)
Dark-red crystals.
(20) (a) Mallakpour, S. E.; Butler, G. B. J. Polym. Sci., Part A:
Polym. Chem. 1989, 27, 217. (b) Mallakpour, S. E.; Butler,
G. B. J. Polym. Sci., Part A: Polym. Chem. 1989, 27, 125.
1
H NMR (90 MHz, CDCl ): d = 3.9 (s, 3 H, OCH ), 7.0–7.4 (m, 4
3
3
H, ArH).
(c) Mallakpour, S. E.; Butler, G. B. J. Polym. Sci., Part A:
Polym. Chem. 1987, 25, 2781.
1
3
C NMR (22.5 MHz, CDCl ): d = 55.6, 115.2, 125.6, 126.0, 158.0,
3
1
60.2.
(
(
21) Klindert, T.; Seitz, G. Synth. Commun. 1996, 26, 2587.
22) Wilson, R. M.; Chantarasiri, N. J. Am. Chem. Soc. 1991,
4-(4-tert-Butylphenyl)-3H-1,2,4-triazole-3,5-dione (2j)
Red crystals.
1
13, 2301.
(
(
(
23) Cookson, R. C.; Stevens, I. D. R.; Watts, C. T. Chem.
Commun. 1966, 744.
24) Mallakpour, S. E.; Butler, G. B.; Aghabozorg, H.; Palenik,
G. J. Macromolecules 1985, 18, 342.
25) (a) Read, G.; Richardson, N. R. J. Chem. Soc., Perkin Trans.
1
H NMR (90 MHz, CDCl ): d = 1.3 (s, 9 H, CH ), 7.2–7.5 (m, 4 H,
3
3
ArH).
4,4¢-Hexane-1,6-diylbis(3H-1,2,4-triazole-3,5-dione) (4a)
Pink crystals.
1
1996, 167. (b) Arya, V. P.; Shenoy, S. Indian J. Chem.,
Sect. B: Org. Chem. Incl. Med. Chem. 1976, 14, 883.
c) Warnho, H.; Wald, K. Org. Prep. Proced. Int. 1975, 7,
1
H NMR (90 MHz, CDCl ): d = 1.3–1.6 (m, 8 H), 3.6 (t, J = 7.0 Hz,
3
(
4
H).
Synthesis 2009, No. 16, 2729–2732 © Thieme Stuttgart · New York

2
732
A. Khoramabadi-zad et al.
PAPER
251. (d) Mallakpour, S. E. J. Chem. Educ. 1992, 69, 238.
(27) Khoramabadi A., Shiri A. unpublished results.
(
4
e) Mallakpour, S. E.; Zolfigol, M. A. J. Sci. I. R. Iran 1993,
, 199.
26) (a) Zolfigol, M. A.; Gorbani-Vaghei, R.; Mallakpour, S.;
(28) Zolfigol, M. A.; Chehardoli, G.; Ghaemi, E.; Madrakian, E.;
Zare, R.; Azadbakht, T.; Niknam, K.; Mallakpour, S.
Monatsh. Chem. 2008, 139, 261.
(
Chehardoli, G.; Ghorbani Choghamarani, A.; Hosein Yazdi,
A. Synthesis 2006, 1631. (b) Zolfigol, M. A.; Nasr-Isfahani,
H.; Mallakpour, S.; Safaiee, M. Synlett 2005, 761.
(29) As the product 4-substituted-3H-1,2,4-triazole-3,5-diones
are very volatile, it is important that the temperature be
maintained below 50 °C during evaporation of the solvent to
prevent loss of material.
(
c) Zolfigol, M. A.; Madrakian, E.; Ghaemi, E.; Mallakpour,
S. Synlett 2002, 1633. (d) Zolfigol, M. A.; Bagherzadeh, M.;
Chehardoli, G.; Mallakpour, S.; Mamaghani, M. J. Chem.
Res. 2001, 390.
Synthesis 2009, No. 16, 2729–2732 © Thieme Stuttgart · New York