Synthesis of novel selenium and tellurium-containing tetrazoles: A class of chalcogen compounds with antifungal activity

Article abstract of DOI:10.1016/j.tetlet.2012.04.040

We describe herein the synthesis and antifungal activity of new 5-arylchalcogenoalkyl-1H-tetrazoles 4. Arylchalcogenoalkyl-1H-tetrazoles 4 have been synthesized in high yields by reaction of arylchalcogenolate anions with chloronitriles 2, and subsequent

Full text of DOI:10.1016/j.tetlet.2012.04.040

Tetrahedron Letters 53 (2012) 3091–3094
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel selenium and tellurium-containing tetrazoles: a class
of chalcogen compounds with antifungal activity
Francieli M. Libero a, Maurício C. D. Xavier a, Francine N. Victoria b, Patrícia S. Nascente c,
a,
Lucielli Savegnago d, Gelson Perin a, , Diego Alves
⇑
⇑
a LASOL, CCQFA, Universidade Federal de Pelotas, UFPel, PO Box 354, 96010-900 Pelotas, RS, Brazil
b Faculdade de Agronomia Eliseu Maciel, DCTA, Universidade Federal de Pelotas, UFPel, Pelotas, RS, Brazil
c Instituto de Biologia, Universidade Federal de Pelotas, UFPel, Pelotas, RS, Brazil
d CDTec, Unidade Biotecnologia, Universidade Federal de Pelotas, UFPel, Pelotas, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe herein the synthesis and antifungal activity of new 5-arylchalcogenoalkyl-1H-tetrazoles 4.
Arylchalcogenoalkyl-1H-tetrazoles 4 have been synthesized in high yields by reaction of arylchalcogen-
olate anions with chloronitriles 2, and subsequent [2+3] cycloaddition of resulting arylchalcogenoalkyl-
nitriles 3 with sodium azide by zinc catalysis in aqueous solution. The obtained compound 4a was
screened for antifungal activity and presented inhibitory property against seven fungal strains. This
protocol is an efficient method to produce new selenium–nitrogen compounds with antifungal activity.
Ó 2012 Published by Elsevier Ltd.
Received 1 February 2012
Revised 4 April 2012
Accepted 5 April 2012
Available online 16 April 2012
Keywords:
Organochalcogen compounds
Nitriles
Cycloaddition
1H-Tetrazoles
Antifungal
Tetrazoles, classic nitrogen heterocyclic compounds,1 have
shown valuable properties in a wide range of applications, such
as in material sciences,2 catalysis,3 propellants,4 information
recording systems,5 explosives,6 and possible application in high-
energy chemistry.7 Tetrazole derivatives are well known com-
pounds with a high level of biological activity,8 such as antiviral,
antibacterial, antiallergic, anticonvulsant, anti-inflammatory prop-
erties, and use in pharmaceuticals as carboxylic acids isosteres.9 An
advantage of tetrazole derivatives over carboxylic acids is that they
are resistant to various biological metabolic degradation pathways,
conferring on the corresponding drug longer bioavailability.9 Usu-
ally, the most attractive way for the synthesis of 5-substituted 1H-
tetrazoles is [2+3] cycloaddition involves nitriles and azides (NaN3
and TMSN3).10 A variety of synthetic methods have been reported
in the literature using these reaction partners and the methodolo-
gies were performed in the presence of catalysts such as AlCl3,10a
BF3ÁOEt2,10b TBAF,10c Pd(PPh3)4,10d Zn/Al hydrotalcite,10e mesopor-
ous ZnS nanospheres,10f Cu–Zn alloy nanopowder,10g ZnO,10h
Cu2O10i and FeCl3–SiO2.10j However, some methods have little
drawbacks such as the use of toxic metals and strong Lewis acids
and harsh reaction conditions. To overcome these drawbacks,
Sharpless and co-workers described the synthesis of 1H-tetrazoles
by the addition of sodium azide to nitriles using zinc bromide in
water and this discovery facilitates the preparation of functional-
ized tetrazoles.11 Additionally, tetrazole rings were incorporated
in a large number of famous antihypertensive (Losartan, Valsartan,
and Irbesartan) and antifungal (TAK-456) agents (Fig. 1).12 There-
fore, remains the necessity for a deep study on the combinations
of substrates for the synthesis of more functionalized and complex
1H-tetrazoles.
HO
Cl
O
OH
N
HN
N
N
N
HN
N
N
N
N
H
N
O
Losartan
Valsartan
HN
N
N
N
O
N
O
N
N
N
N
N
N
N
N
N
N
Irbesartan
TAK-456
⇑
Corresponding authors.
E-mail address: diego.alves@ufpel.edu.br (D. Alves).
Figure 1. Drugs containing tetrazolyl moiety in their structure.
0040-4039/$ - see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2012.04.040

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F. M. Libero et al. / Tetrahedron Letters 53 (2012) 3091–3094
In this way, organochalcogen compounds, specially containing
ment, TMSN3 was reacted with nitrile 3a using Cu2O (5 mol %) as
catalyst in a mixture of DMF/MeOH (9:1) at 100 °C, according to
the methodology described by Yamamoto.10i Under these condi-
tions, the desired product 4a was formed in 52% yield (Condition
B, Scheme 2). To our satisfaction, when the reaction of nitrile 3a
was performed with NaN3 using 1 equiv of ZnBr2 in H2O at
100 °C for 24 h,11a product 4a was achieved in 82% (Condition C,
Scheme 2). Unfortunately, when the ZnBr2 ratio was reduced from
1.0 to 0.5 equiv, a decrease in the yield of product 4a was observed
(Condition D, Scheme 2). After these experiments, we choose to
continue the synthesis of different 5-arylchalcogenoalkyl-1H-tet-
razoles 4, by the method developed by Sharpless and co-workers,
due to the fact that this protocol is safer and uses water as the sol-
vent (Condition C, Scheme 2).
Thus, before the synthesis of the corresponding 5-aryl-
chalcogenoalkyl-1H-tetrazoles 4, a variety of arylchalcogenoalkyl
nitriles 3b–m were synthesized by reactions with arylchalcogeno-
late anions with a range of chloronitriles 2 and the results are
shown in Table 1. In general, arylchalcogenoalkyl nitriles 3b–j de-
rived from different diaryl diselenides and chloronitriles 2 were
obtained in good yields (Table 1, entries 1–9). Extending this pro-
tocol to the synthesis of tellurium analogues, satisfactory yields of
desired aryltellanyl nitriles 3k–m were achieved (Table 1, entries
10–12).
selenium and tellurium, are attractive synthetic targets because
of their interesting biological activities13 and applicability in
organic reactions, well described in a great number of books and
reviews.14 Between these organochalcogen compounds, those
containing nitrogen atoms in their structure are a special class of
molecules and they have been employed in various organic trans-
formations, for instance, in asymmetric synthesis.15 Consequently,
the search for new and efficient methods for the synthesis of novel
nitrogen-functionalized organochalcogen compounds remains still
widely explored.
In this regard, selenium-containing tetrazoles were synthesized
by reaction of arylselanylcyanates with sodium azide affording the
corresponding products in good yields.16 This class of compounds
have a great importance since they combine the well known
applicability of the tetrazole group2–9 with that of the selenium
containing group.13–15 However, to the best of our knowledge,
the synthesis of organoselenium and tellurium-tetrazoles is scarce
and has not been well explored. In this sense, and due to our
interest correlated to preparation of nitrogen-functionalized
organochalcogen compounds,17 we describe herein the synthesis
of arylchalcogenoalkyl-1H tetrazoles 4 by [2+3] cycloaddition of
arylchalcogenoalkyl nitriles 3 with sodium azide by zinc catalysis
in aqueous solution (Scheme 1).
Initially, our studies were focused on the synthesis of 2-(phe-
nylselanyl)acetonitrile 3a,18 the starting material for the synthesis
of the desired 5-(phenylselanylmethyl)-1H-tetrazole 4a. Thus, phe-
nylselenolate anion, generated in situ by the reaction of diphenyl
diselenide 1a with NaBH4/EtOH, reacted with chloroacetonitrile
at room temperature, affording compound 3a in excellent yield
(Scheme 2).18a
Next, the synthesized arylchalcogenoalkyl nitriles 3b–m (0.5
mmol) were reacted with NaN3 (0.5 mmol) and ZnBr2 (0.5 mmol)
in H2O at 100 °C for 24 h to produce arylchalcogenoalkyl-1H-tetra-
Table 1
Arylchalcogenoalkyl nitriles 3b–m synthesizeda
After that, we turned our attention to the application of obtained
2-(phenylselanyl)acetonitrile 3a in the synthesis of 5-(phenylsela-
nyl-methyl)-1H-tetrazole 4a. The synthesis of compound 4a is sig-
nificant since their carboxylic acid analogues and derivatives were
synthesized and shown interesting biological activities.19 Thus,
some experiments were performed to synthesize compound 4a in
satisfactory yield (Scheme 2).
Recently, Das et al. developed the synthesis of 5-substituted
1H-tetrazoles by treatment of organic nitriles with NaN3 in the
presence of catalytic amount of iodine in DMF at 120 °C.20 Applying
these reaction conditions to nitrile 3a, arylselanyl-tetrazole 4a was
obtained in 60% yield (Condition A, Scheme 2). In other experi-
ArYYAr (1)
NaBH4
X
CN
ArY
CN
THF/EtOH
8 h, r.t., N2
n
(2)
n
(3)
Entry
1
Product (3) (yield)
Entry
7
Product (3) (yield)
Se CN
Se
CN
3b (98%)
3h (77%)
O
Se CN
2
3
8
9
Se CN
3i (75%)
3c (99%)
H
N
Cl
N
NaN3, ZnBr2
H2O, reflux
24 h, air
N
CN
ArY
CN
ArY
Se
N
Se CN
n
n
(4)
(3)
3d (91%)
3j (73%)
n = 1, 2, 3
Y = Se, Te
F3C
S
Se CN
Te CN
4
5
6
10
11
12
Scheme 1. General scheme of the reaction.
3k (85%)
3e (89%)
H
CN
Se CN
(1a)
reaction
conditions
N
N
PhSeSePh
NaBH4
Te
N
Cl
CN
(2a)
PhSe
CN
PhSe
3f (88%)
N
3l (81%)
THF/EtOH
8 h, r.t., N2
(3a)
92%
(4a)
CN
Se
Te
CN
o
Condition A:
Condition B:
Condition C:
Condition D:
NaN3, I2 (1 mol%), DMF at 120 C (60%)
o
TMSN3, Cu2O (5 mol%), DMF/MeOH at 100 C (52%)
3g (73%)
3m (82%)
o
NaN3, ZnBr2 (1 eq.), H2O at 100 C (82%)
a
o
Reactions are performed in the presence of diaryl dichalcogenides 1 (1.0 mmol),
chloronitriles 2 (2.0 mmol), and NaBH4 (3.0 mmol) in EtOH (15 mL) and THF (5 mL)
NaN3, ZnBr2 (0.5 eq.), H2O at 100 C (35%)
at room temperature for 8 h in nitrogen atmosphere.
Scheme 2. Optimization of synthesis of 5-(phenylselanyl-methyl)-1H-tetrazole 4a.

F. M. Libero et al. / Tetrahedron Letters 53 (2012) 3091–3094
3093
Table 2
Table 2 (continued)
Arylchalcogenoalkyl-1H-tetrazoles 4b–m synthesizeda
Entry
Product (4)
Isolated yieldb (%)
H
N
N
H
N
NaN3, ZnBr2
H2O, reflux
24 h, air
N
ArY
CN
ArY
N
Te
n
n
N
13
65
N
(3)
(4)
N
4m
Entry
1
Product (4)
Isolated yieldb (%)
a
Reactions are performed in the presence of arylchalcogenoalkyl nitriles
(0.5 mmol), NaN3 (0.5 mmol), and ZnBr2 (0.5 mmol) in H2O at 100 °C for 24 h in
3
H
N
open atmosphere.
Se
b
N
82
Yields are given for isolated products.
N
N
4a
Table 3
H
Evaluation of the antifungal activity of compound 4a against the fungal strainsa
N
Se
N
2
3
71
72
N
Fungal strain
Minimum inhibitory concentration (
lM)
N
4b
Compound 4a
Fluconazole
O
C. albicans
C. lipolytica
C. parapsilosis
C. laurentii
T. asahii
104.2 36.2
156.25 62.5⁄
166.72 72.2
250 0⁄
62.5
31.25
0
0
H
N
52.1 18.0
62.5
83.3 36.1
62.5
166.6 72.0
Se
N
0
N
N
125
0
4c
C. guilhermondi
C. globosa
125.0 0⁄
0
Cl
187.5 72.2
H
a
The values were analyzed by one-way ANOVA followed by the Newman–Keuls
N
Se
4
5
83
86
N
multiple comparison test, each value is expressed as the mean standard deviation.
The tests were performed three times in duplicate. Asterisks represent significant
effects (⁄p <0.05) compared with fluconazole, for each strain.
N
N
4d
H
N
F3C
Se
N
N
zoles 4b–m.21 The results disclosed in Table 2 reveal that our proto-
col worked well for a variety of substituted compounds 3, affording
good yields of the desired selenium and tellurium-tetrazoles. In a
general way, the reactions are a little sensitive to the electronic ef-
fect of the aromatic ring in the arylselenium moiety. For example,
arylselenium nitriles containing electron-withdrawing group
(EWG) gave a slightly higher yield than those bearing electron-
donating group (EDG) (Table 2, entries 4,5 vs. 2,3). When the reac-
tion was performed with 2-thienylselanyl acetonitrile 3f, the
respective selenium tetrazole 4f was obtained in 84% yield (Table
2, entry 6). Extending the scope of obtained selenium-tetrazoles, dif-
ferent phenylselanylalkyl nitriles 3g–j furnished the corresponding
tetrazoles 4g–j in satisfactory yields (Table 2, entries 7–10).
Additionally, the possibility of synthesis of tellurium-tetrazoles
was investigated and phenyltellanylalkyl nitriles 3k–m were effi-
ciently cyclized with NaN3 to phenyltellanylalkyl-1H-tetrazoles
4k, 4l, and 4m in 75%, 74%, and 65% yield, respectively (Table 2, en-
tries 11–13).
Finally, according to the literature, tetrazole derivatives are well
known compounds with an antifungal activity.8 Research and
development of potent and effective antimicrobial agents repre-
sent one of the most important advances in therapeutics, not only
in the control of serious infections, but also in the prevention and
treatment of some infectious complications. Over the past decade,
fungal infections have become an important complication and a
major cause of morbidity and mortality in immunocompromised
individuals.22 Thus, the antifungal activity23 of synthesized 5-(phe-
nylselanylmethyl)-1H-tetrazole 4a was evaluated using seven fun-
gal strains, and the results are shown in Table 3.
N
4e
H
N
S
Se
N
6
7
84
71
N
N
4f
H
N
N
N
N
Se
4g
H
N
Se
N
8
61
73
74
N
N
4h
H
N
Se
N
N
9
N
4i
H
N
N
N
N
10
Se
4j
H
N
Te
N
N
11
12
75
74
N
To evaluate the potential of compound 4a as an antifungal agent
we compared the results obtained with fluconazole, a known anti-
fungal drug, using statistical analysis (one-way ANOVA). The re-
sults show that the minimum inhibitory concentration of
4k
H
N
N
N
N
Te
4l

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F. M. Libero et al. / Tetrahedron Letters 53 (2012) 3091–3094
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fluconazole was not different when compared with compound 4a
for Candida albicans, Candida globosa, Thrichosporum asahii, and
Candida parapsilosis. Based on this, it is possible to conclude that
the effect of compound 4a is comparable with an active antifungal
drug largely used for the treatment of fungal infections. On the
other hand, the minimum inhibitory concentration of fluconazole
was different when compared with compound 4a for Candida
lipolytica, Cryptococcus laurntii, and Candida guilhermondi. Thus,
our results are a contribution to the research about the develop-
ment of new antifungal drugs, and compound 4a evaluated shows
good results when compared to fluconazole.
In summary, we have demonstrated the efficient synthesis of
novel selenium and tellurium containing tetrazoles. The corre-
sponding 5-arylchalcogenoalkyl-1H-tetrazoles were synthesized
in high yields by 1,3-dipolar cycloaddition of arylchalcogenoalkyl-
nitriles with sodium azide by zinc catalysis in aqueous solution.
The obtained compound 4a was screened for antifungal activity
and presented good results on inhibition of T. asahii and C. lipolyti-
ca. This protocol is an efficient method to produce new selenium-
nitrogen compounds with antifungal activity. Studies regarding
evaluation of antifungal activity of the 5-arylchalcogenoalkyl-1H-
tetrazoles synthesized are ongoing in our lab.
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Acknowledgments
We are grateful to CAPES, CNPq, FINEP, and FAPERGS for the
financial support.
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To
a
5 mL round-bottomed flask was added the corresponding
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bromide (0.5 mmol), and 2 mL of H2O. The reaction mixture was refluxed for
24 h under vigorous stirring. After this time, HCl (2 M, 3 mL) and ethyl acetate
(15 mL) were added, and vigorous stirring was continued until no solid was
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organic layers were dried with MgSO4 and evaporated under reduced pressure.
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hexane/ethyl acetate as eluent and recrystallized if necessary.
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Höfner, G.; Wanner, K. T. Bioorg. Med. Chem. 2011, 19, 6492; (g) Upadhayaya, R.
S.; Jain, S.; Sinha, N.; Kishore, N.; Chandra, R.; Arora, S. K. Eur. J. Med. Chem.
2004, 39, 579; (h) Kumar, C. N. S. S.; Parida, D. K.; Santhoshi, A.; Kota, A. K.;
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Selected spectral and analytical data for 5-(phenylselanylmethyl)-1H-tetrazole
(4a): Yield: 0.097 g (82%); white solid; mp: 78–79 °C. MS: m/z (rel. int.) 242
(M+2, 10), 240 (M, 57), 172 (10), 157 (57), 118 (38), 91 (48), 77 (100), 55 (86).
IR (KBr):
m = 3356, 2997, 2852, 2713, 2609, 1653, 1558, 1473, 1433, 1369, 1255,
1209, 1051, 1020, 839, 742, 694 cmÀ1 1H NMR (400 MHz, CDCl3): d = 7.47–
.
7.44 (m, 2H), 7.29–7.24 (m, 3H), 4.3 (s, 2H). 13C NMR (100 MHz, CDCl3):
d = 156.09, 134.12, 129.54, 128.59, 127.77, 16.74. HRMS: m/z calculated mass
to C8H8N4Se+H+: 239.9914; found: 239.9915.
22. Turan-Zitouni, G.; Kaplanciki, Z. A.; Yildiz, M. T.; Chevallet, P.; Kaya, D. Eur. J.
Med. Chem. 2005, 40, 607.
23. Minimum
inhibitory
concentration
(MIC)—Microdilution
assay:
Recommendations of National Committee for Clinical Laboratory Standards
(NCCLS) (2002, M27-A2) were mostly used to measure the minimum
inhibitory concentration (MIC) values. Compound 4a was diluted on
dimethyl sulfoxide (DMSO) tested in concentrations ranging from 500 to
0.85
lM, in triplicate in each assay, and the assays were repeated three times
in their entirety to confirm the results. Compound 4a (100
l
L) was serially
diluted by 50% with the medium RPMI 1640 (with glutamine and phenol red
without bicarbonate) buffered in MOPS (3-(N-morfolin)propanosulfonic acid)
in 96 well microtiter plates, and 100 lL of fungal culture was added to each
well. The MIC was recorded as the lowest concentration of the tested drug that
inhibited the fungal growth.
9. (a) Singh, H.; Chawla, A. S.; Kapoor, V. K.; Paul, D.; Malhotra, R. K. Prog. Med.
Chem. 1980, 17, 151; (b) Hert, R. J. Bioorg. Med. Chem. 2002, 10, 3379.
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Kumar, A.; Narayanan, R.; Shechter, H. J. Org. Chem. 1996, 61, 4462; (c)
Amantini, D.; Beleggia, R.; Fringuelli, F.; Pizzo, F.; Vaccoro, L. J. Org. Chem. 2004,
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