An expedient route to the azoles through oxidative desulfurization using iodine reagent

Article abstract of DOI:10.1016/j.tetlet.2012.10.114

A novel and expedient regioselective method for the synthesis of 5-aminotetrazoles and 3-amino-1,2,4-triazoles through oxidative desulfurization of corresponding 1,3-disubstituted thioureas has been discovered and optimized for the process conditions. The process is broadly applicable to structurally diverse 1,3-disubstituted thioureas.

Full text of DOI:10.1016/j.tetlet.2012.10.114

Tetrahedron Letters 54 (2013) 101–105
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Tetrahedron Letters
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An expedient route to the azoles through oxidative desulfurization using
iodine reagent
⇑
Nikhil C. Jadhav, Prashant B. Jagadhane, Kavitkumar N. Patel, Vikas N. Telvekar
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga, Mumbai 400 019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and expedient regioselective method for the synthesis of 5-aminotetrazoles and 3-amino-1,2,4-
triazoles through oxidative desulfurization of corresponding 1,3-disubstituted thioureas has been discov-
ered and optimized for the process conditions. The process is broadly applicable to structurally diverse
1,3-disubstituted thioureas.
Received 21 September 2012
Revised 23 October 2012
Accepted 25 October 2012
Available online 2 November 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Iodobenzene
OxoneÒ
Tetrazole
Triazole
Desulfurization
The synthesis of azoles has emerged as one of the most impor-
tant topic in the field of heterocyclic chemistry due to the fact that
azoles are the key features of pharmaceutical intermediates and
bioactive molecules.1,2 Among various azoles, aminotetrazole and
aminotriazole skeletons are vital synthetic motifs in organic and
medicinal chemistry.
Aminotetrazoles are the non-classical isosteric substituents of
carboxylic acid functional group thus they play a vital role in drug
discovery.3 Aminotetrazoles constitute a crucial part of many bio-
logically active pharmacophores and exhibit pharmaceutical activ-
ities such as antiviral,4 anti-allergic,5 and antibiotics.6
shown antiviral,7 antibacterial,8 anti-inflammatory,9 and anti-
fungal activities.10
Though some methods are available to synthesize aminotetraz-
oles and aminotriazoles, most of them have drawbacks like toxic
reagents, higher temperatures, and harsh reaction conditions.11
Thus novel reactions with metal-free conditions at ambient tem-
perature are highly desirable. Hypervalent iodine(III) reagents have
captivated organic chemists in recent years. Our lab has sparked
interest in development of novel and simple methodologies using
hypervalent iodine(III) reagents. Previously we have utilized this
reagent system for the construction of oxadiazole and thiadiazole
ring.12 We herein describe expedient routes to synthesize amino-
tetrazoles and aminotriazoles through oxidative desulfurization
using hypervalent iodine(III) reagent.
Aminotriazoles may serve as ‘urea mimics’ and thus, may be
exploited for the design of new bioactive compounds. They have
N
N
S
Iodobenzene/oxone/TEA/NaN3
room temperature
N
NH
2a
N
NH
1a
NH
Scheme 1. Synthesis of 5-aminotetrazoles from 1,3-disubstituted thioureas.
⇑
Corresponding author.
E-mail address: vikastelvekar@rediffmail.com (V.N. Telvekar).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.114

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N. C. Jadhav et al. / Tetrahedron Letters 54 (2013) 101–105
First, the method to synthesize 5-aminotetrazoles from corre-
observed in the absence of TEA. We next compared various sol-
vents such as MDC, ACN/water, ACN, and methanol. Superior re-
sults were observed with ACN/water affording 88% yield.
Subsequently, various 1,3-disubstituted thioureas were investi-
gated under the optimized conditions to study the scope of the sys-
tem (Table 1).13 The symmetrical thioureas containing electron
donating as well as electron withdrawing groups smoothly under-
went the reaction and produced corresponding products in moder-
ate to good yields. A noteworthy aspect is that the reaction was
regioselective in case of the unsymmetrical 1,3-disubstituted thio-
sponding 1,3-disubtituted thioureas via oxidative desulfurization
was developed using iodobenzene and oxoneÒ (Scheme 1).
For the initial study, 1,3-diphenylthiourea was chosen as a
model substrate to optimize the reaction conditions. To evaluate
the effect of the reagents’ concentration, reaction was carried out
with different combinations of iodobenzene, oxoneÒ, triethylamine
(TEA), and sodium azide at room temperature. The best result was
obtained when iodobenzene, oxoneÒ, TEA, and sodium azide were
used in 2, 3, 3, and 3 equiv, respectively. Very minor reaction was
Table 1
Synthesis of 5-aminotetrazoles from 1,3-disubstituted thioureasa
S
N
N
R1
R2 Iodobenzene/oxone®/TEA/NaN3
N
R1
N
NH
1a-f
NH
room temperature
NH
R2
2a-f
Sr. no.
Substrate
Productb
Yieldc (%)
N
N
N
N
N
NH
NH
NH
N
N
N
1
1a
88
2a
N
N
2
1b
75
2b
N
N
3
1c
80
2c
Br
N
N
N
NH
N
4
1d
85
2d
Br
N
N
H3C
N
NH
N
5
1e
78
2e

N. C. Jadhav et al. / Tetrahedron Letters 54 (2013) 101–105
103
Table 1 (continued)
Sr. no.
Substrate
Productb
Yieldc (%)
N
N
N
H2N
N
6
1f
72
2f
a
All reactions of 1,3-disubstituted thioureas (1 mmol) were performed at room temperature in the presence of iodobenzene
(2 equiv), oxoneÒ (3 equiv), TEA (3 equiv), and sodium azide (3 equiv) in ACN/water (1:1, v/v) (10 mL).
b
All previously reported products were identified by comparison of their NMR spectra, Mass spectra, and melting points with
literature data.
c
Isolated yields of analytically pure products.
N
N
S
Iodobenzene /Oxone /TEA /Formyl hydrazide
room temperature
NH
N
NH
NH
4a
3a
Scheme 2. Synthesis of 3-amino-1,2,4-triazoles from 1,3-disubstituted thioureas.
Table 2
Synthesis of 3-amino-1,2,4-triazoles from 1,3-disubstituted thioureasa
S
N
N
R2
N
R1
R2 Iodobenzene/oxone®/TEA/Formyl hydrazide
R1
NH
3a-f
NH
NH
4a-f
room temperature
Sr.no.
Substrate
Productb
Yieldc (%)
N
N
NH
N
1
3a
80
4a
Br
N
N
NH
N
2
3b
85
4b
Br
N
Cl
N
N
NH
3
3c
78
4c
Cl
(continued on next page)

104
N. C. Jadhav et al. / Tetrahedron Letters 54 (2013) 101–105
Table 2 (continued)
Sr.no.
Substrate
Productb
Yieldc (%)
H3CO
N
N
NH
N
4
3d
75
4d
OCH3
N
N
NH
N
5
3e
68
4e
Br
H CO
3
N
N
N
NH
6
3f
70
4f
a
All reactions of 1,3-disubstituted thioureas (1 mmol) were performed at room temperature in the presence of iodobenzene
(2 equiv), oxoneÒ (4 equiv), TEA (3 equiv), and formyl hydrazide (3 equiv) in methanol (10 mL).
b
All previously reported products were identified by comparison of their NMR spectra, Mass spectra, and melting points with
literature data.
c
Isolated yields of analytically pure products.
ureas. The amine having lower pKa was attached to the ring nitro-
gen and the amine having higher pKa contributed to exocyclic ami-
no group.
Acknowledgments
N.C.J. and K.N.P. acknowledge the University Grant Commission
(UGC) India and P.B.J. thanks the Rajiv Gandhi National Fellowship
(RGNF) for financial support.
Subsequently, we extended this study to prepare 3-amino-
1,2,4-triazoles using 1,3-disubstituted thioureas with formyl
hydrazide (Scheme 2). The reaction was first explored in previ-
ously affirmed condition, however the result was unsatisfactory.
Thus, reaction parameters such as stoichiometry of reagents, con-
centration, time, and temperature were studied using 1,3-diphen-
ylthiourea as the model substrate for optimization of the process.
Optimization afforded 2 equivalence of iodobenzene, 4 equiva-
lence of oxoneÒ, 3 equivalence of TEA, and formyl hydrazide as
the best combination of reagents for this transformation. Examin-
ations of various solvents confirmed the use of methanol as
solvent.
References and notes
1. Upadhayaya, R. S.; Jain, S.; Sinha, N.; Kishore, N.; Chandra, R.; Arora, S. K. Eur. J.
Med. Chem. 2004, 39, 579.
2. Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson, A. L.; Pierce, M. E.;
Price, W. A.; Santella, J. B.; Wells, G. J.; Wexler, R. R. J. Med. Chem. 1991, 34,
2525.
3. Yella, R.; Khatun, N.; Rout, S.; Patel, B. K. Org. Biomol. Chem. 2011, 9, 3235.
4. Poonian, M. S.; Nowoswiat, E. F.; Blount, J. F.; Kramer, M. J. J. Med. Chem. 1976,
19, 1017.
5. Ford, R. E.; Knowles, P.; Lunt, E.; Marshall, S. M.; Penrose, A. J.; Ramsden, C. A.;
Summers, A. J. H.; Walker, J. L.; Wright, D. E. J. Med. Chem. 1986, 29, 538.
6. Andrus, A.; Partridge, B.; Heck, J. V.; Christensen, B. G. Tetrahedron Lett. 1984,
25, 911.
In this case also with unsymmetrical 1,3-disubstituted thio-
ureas, the product formed having lower pKa amine get attached
to the ring nitrogen and amine having higher pKa contributed to
exocyclic amino group.
7. De Clercq, E. J. Clin. Virol. 2004, 30, 115.
8. Papakonstantinou-Garoufalias, S.; Pouli, N.; Marakos, P.; Chytyroglou-Ladas, A.
Farmaco 2002, 57, 973.
As summarized in Table 2, various substrates of 1,3-disubsti-
tuted thioureas were subjected to optimized conditions.14
In summary, we have successfully developed a novel, simple,
and highly efficient regioselective method for the synthesis of
aminotetrazoles and aminotriazoles from corresponding 1,3-
disubstituted thioureas. The procedure is broadly applicable to
1,3-disubstituted thioureas containing electron-rich as well as
electron-deficient functional groups.
9. Navidpour, L.; Shadnia, H.; Shafaroodi, H.; Amini, M.; Dehpour, A. R.; Shafiee, A.
Bioorg. Med. Chem. 1976, 2007, 15.
10. Lebouvier, N.; Giraud, F.; Corbin, T.; Na, Y. M.; Le Baut, G.; Marchand, P.; Le
Borgne, M. Tetrahedron Lett. 2006, 47, 6479.
11. Katritzky, A. R.; Rogovoy, B. V.; Kovalenko, K. V. J. Org. Chem. 2003, 68, 4941.
and references cited therein.
12. Patel, K. N.; Jadhav, N. C.; Jagadhane, P. B.; Telvekar, V. N. Synlett 2012, 23, 1970.
13. Typical experimental procedure to synthesize 5-aminotetrazoles: A mixture of
iodobenzene (2 equiv) and OxoneÒ (3 equiv) in ACN/water was stirred at rt for
20 min followed by the addition of TEA (3 equiv) and substrate (1 equiv) and

N. C. Jadhav et al. / Tetrahedron Letters 54 (2013) 101–105
105
after 5 min NaN3 was added at rt and stirred for 3 h. The reaction mixture was
diluted with H2O and then extracted twice with EtOAc. The organic layer was
washed successively with 10% NaHCO3 (2 Â 20 mL) and H2O (2 Â 20 mL) and
dried over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure to give the crude product. The product was purified using silica gel
column chromatography (20% EtOAc–hexane).
20 min followed by the addition of TEA (3 equiv) and substrate (1 equiv) and
after 5 min formyl hydrazide (3 equiv) was added at rt and stirred for 3 h. The
reaction mixture was diluted with H2O and then extracted twice with EtOAc.
The organic layer was washed successively with 10% NaHCO3 (2 Â 20 mL)and
H2O (2 Â 20 mL) and dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure to give the crude product. The product was purified
using silica gel column chromatography (20% EtOAc–hexane).
14. Typical experimental procedure to synthesize 3-amino-1,2,4-triazoles: A mixture
of iodobenzene (2 equiv) and OxoneÒ (4 equiv) in methanol was stirred at rt for