Synthesis of novel 5-aryl-1H-tetrazoles

Article abstract of DOI:10.1002/hc.20293

In this study phenylselenocyanate and some of its derivatives (o-Cl, p-Cl, p-Br, o-NO₂, p-NO₂, o-CH₃, p-CH₃, o-COOH, p-COOH, p-OCH₃ substituted) were synthesized (3a-3j). The synthesized compounds were converted to 5-aryl-1H-tetrazole (4a-4j), by Et ₃N · HCl-NaN₃ in toluene, which are a new series of phenylselanyl-1H-tetrazoles. The structure of all the presently synthesized compounds were confirmed using spectroscopic methods (FTIR, ¹H NMR, MS).

Full text of DOI:10.1002/hc.20293

Heteroatom Chemistry
Volume 18, Number 3, 2007
Synthesis of Novel 5-Aryl-1H-Tetrazoles
1
1
1
1
¨
Hamdi Ozkan, Serkan Yavuz, Ali Dis¸li, Yılmaz Yıldırır,
and Lemi Tu¨rker2
1Department of Chemistry, Faculty of Arts and Science, Gazi University, Teknikokullar, 06500,
Ankara, Turkey
2Department of Chemistry, Middle East Technical University, 06531, Ankara, Turkey
Received 3 August 2005; revised 10 December 2005
have found use especially in pharmaceuticals as
ABSTRACT: In this study phenylselenocyanate and
lipophilic spacers and carboxylic acid surrogates
some of its derivatives (o-Cl, p-Cl, p-Br, o-NO2,
[10], in explosives [11], and in photography. In addi-
p-NO2,o-CH3,p-CH3,o-COOH, p-COOH, p-OCH3 sub-
tion, tetrazoles are used in the synthesis of nitrogen-
stituted) were synthesized (3a–3j). The synthesized
containing heterocycles [12]. Tetrazole derivatives
compounds were converted to 5-aryl-1H-tetrazole
of fatty acid esters are known as substrates for N-
(4a–4j), by Et3N · HCl-NaN3 in toluene, which are a
myristoyl transferase and its respective coenzyme,
new series of phenylselanyl-1H-tetrazoles. The struc-
and show fungicidal and antiviral (including HIV)
ture of all the presently synthesized compounds
activities [13].
were confirmed using spectroscopic methods (FTIR,
In the field of heterocyclic synthesis, the chem-
1H NMR, MS).
2007 Wiley Periodicals, Inc. Het-
ꢀ
C
istry of tetrazoles in cycloaddition reactions has been
extensively investigated [14–16]. Huisgen et al. re-
ported that tetrazoles undergo ring cleavage, in high
boiling point solvent, to afford the corresponding ni-
trile imines through extrusion of a nitrogen molecule
[15]. The nitrile imines react with dipolarophiles by
[2ꢀ + 3ꢀ] cycloaddition to produce pyrazole deriva-
tives [16]. 1,2-Dehydrobenzene (o-benzyne) is an ex-
ample of a dienophilic aryne [17].
Le Blanc and Jursic have shown [18] that
5-alkyl(aryl)thiotetrazoles can be obtained in high
yields by the reaction of thiocyanates with sodium
azide under conditions of phase transfer catalysis in
the presence of hexadecyltrimethylammonium chlo-
ride (HDTMAC; see Scheme 1).
eroatom Chem 18:255–258, 2007; Published online in
Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20293
INTRODUCTION
Selenium is an element similar to sulfur in terms of
its chemical properties. Humans and animals need
selenium for various biological functions. Adult hu-
mans have to take 15 µg/kg selenium daily [1]. De-
ficiency of selenium in the human body may cause
cancer, subfertility, and heart diseases [2–5]. Also,
selenium and vitamin E have a role in the regu-
lation of the immune system and in the produc-
tion of testosterone hormones and sperma [6–8].
These activities in the body are usually performed
by organoselenium compounds.
Toluene-H2O
H
RS
HDTMAC
Tetrazoles are an increasingly popular function-
ality [9], with a wide range of applications. They
N
RSCN
NaN3
+
N
N
N
Correspondence to: Yılmaz Yıldırır; e-mail: yildirir@gazi.edu.tr.
2007 Wiley Periodicals, Inc.
SCHEME 1
c
ꢀ
255

¨
256 Ozkan et al.
RESULTS AND DISCUSSION
EXPERIMENTAL
In this study, novel selenium compounds were pre-
pared following the reaction sequences depicted in
Scheme 2 and were obtained in high yields (75–92%).
The final stage of the reaction depends on the pH.
Controlling the pH is very important in this stage
because the compounds obtained (usually organose-
lenium) decompose and form a precipitate of ele-
mental red selenium at a pH <5. The precipitation
of selenium causes both low yield and presence of
some impurities.
Substituted aryl amines and other chemicals were
obtained from Merck. All melting points were de-
termined in sealed capillaries and are uncorrected.
FTIR spectra were recorded on a Mattson 1000
1
spectrometer as KBr pellets. H NMR spectra were
recorded on a Varian Gemini 300 (300 MHz) NMR
spectrometer in DMSO-d6. Mass spectra measure-
ments were recorded on a Thermo Finnigan Trace
DSQ.
The structures of synthesized compounds
(phenylselanyl-1H-tetrazoles) were identified on the
basis of FTIR, 1H NMR, and MS spectral data. Spec-
tral values support the expected structures. The CN
bands observed in the IR spectra of 3a–j disappeared
in the IR spectra of 4a–j as expected. This could
be attributed to the conversion of CN groups into
the tetrazole ring. The characteristic NH absorp-
tion bands appeared between 3667 and 3100 cm−1
as broad bands due to the tautomeric structure of
tetrazoles and the N N bands appeared between
1515 and 1606 cm−1 and the Ar H band occurs at
3040 cm−1, approximately. In addition, in the 1H
NMR spectra of compounds 4c and 4d, a broad
signal was seen (between δ 4.7 and 6.9 due to NH
protons), which supports the proposed structures.
The signal of NH protons could not be seen in the
1H NMR spectra of other compounds because it was
recorded in DMSO. The MS spectra values were also
compatible with the expected values.
Typical Procedure
5-(4-Bromophenylselanyl)-1H-tetrazole (4c). 4-
Bromoaniline (1.74 g, 0.01 mol) and concentrated
HCl (2.7 mL, 0.04 mol) were mixed slowly. The 4-
bromoanilinium chloride was collected, air-dried,
and dissolved in 30 mL of absolute alcohol. The
stirred solution was cooled to –5 to 0◦C and diazo-
tized by careful dropwise addition (over a period of
30 min) of ethyl nitrite (1 mL, 0.006 mol). Both the
solution and ethyl nitrite (bp 17◦C) must be cold (–5
to 0◦C) during the addition. The syntheses of com-
pounds 2c and 3c were achieved according to the
procedure described in the literature [19]. For that
purpose, a solution of KSeCN (1.44 g, 0.01 mol) in
30 mL of absolute alcohol was added into the solu-
tion of the diazonium salt (2c) obtained previously.
The precipitate obtained was recrystallized from ab-
solute ethanol (mp for 3c: 70–71◦C; lit. mp for 3c:
70.5–71.5◦C [20]).
The prepared compounds containing both the
tetrazole ring and selenium are thought to be very
interesting because of the combination of tetrazole
and selenium used in the treatment of some dis-
eases. Also, we suggest that this novel synthetic route
can be used to prepare many new compounds that
can bind easily to different structures. These can be
important not only in the production of tetrazole-
containing drugs but also in the synthesis of complex
molecules.
Suspension of triethylammonium chloride
(1.37 g, 0.01 mol) in toluene (20 mL) was prepared
in a 250-mL two-necked flask equipped with a reflux
condenser. Then, sodium azide (0.65 g, 0.01 mol)
was slowly added portion-wise with stirring. A so-
lution of 4-bromophenylselenocyanate (3c) (2.61 g,
0.01 mol) in toluene (25 mL) was slowly added,
stirred for 5 min, and then heated to gentle reflux
for 8 h. After cooling the reaction mixture, distilled
water (20 mL) was added and the aqueous layer was
H
−
N2Cl
+
N
N
SeCN
NH2
Se
NaN3
.
1)
HCl
N
R
N
R
R
R
HCl
Et3N
2)
EtONO
KSeCN
−
N
2(g)
R'
R'
R'
R'
1
2
3
4
SCHEME 2 a) R = Cl, R’ = H; b) R = H, R’ = Cl; c) R = H, R’ = Br; d) R = CH3, R’ = H; e) R = H, R’ = CH3; f) R = NO2, R’ = H;
g) R = H, R’ = NO2; h) R = COOH, R’ = H; i) R = H, R’ = COOH; j) R = H, R’ = OCH3
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Novel 5-Aryl-1H-tetrazoles 257
separated. Then the toluene layer was washed with
water (3 × 5 mL) and aqueous extracts were col-
lected (light-brown colored). Then the aqueous layer
(pH 8) was cooled to 0–5◦C, acidified to pH 5.5 us-
ing dilute HCl while stirring for 10 min. The solid
precipitate formed was collected and washed with
water [21] (mp for 4c: 170–171◦C).
tomeric): 3660–3121; N N: 1606; C N: 1535; Ar H:
1
3056; Ar(C C): 1606, 1535; H NMR (DMSO-d6) +δH:
·
7.9 (d, 1H), 8.2 (d, 1H); MS for C7H5N5O2Se (M ):
269.
2-(1H-Tetrazol-5-ylselanyl)-benzoic acid (4h).
Yield: 83%; mp 164–165◦C; IR νmax (cm–1) (KBr):
N H (tautomeric): 3667–3300; N N: 1587; C N:
1518; Ar H: 3050, O-H: 3474, C O: 1657; Ar(C C):
1618, 1587, 1561; 1H NMR (DMSO-d6) δH: 8.3 (d, 1H),
5-(2-Chlorophenylselanyl)-1H-tetrazole (4a). Yield:
88%; mp 135–136◦C; IR νmax (cm–1) (KBr): N H (tau-
tomeric): 3602–3184; N N: 1587; C N: 1522; Ar H:
+
·
8.2 (d, 1H), 7.6 (m2H); MS for C8H6N4O2Se (M ):
271.66, (M+ – COOH): 22+4, (M+ – tetrazole): 200,
·
·
1
3045; Ar(C C): 1587, 1522, 1336; H NMR (DMSO-
(M+ – C2H2O2N4): 156, (M – Se – tetrazole): 121.
·
·
d6) δH: 6.9 (d, 1+H), 7.5 (m,+2H) 8.4 (d, 1H); MS for
·
·
C7H5N4ClSe (M ): 260, (M – tetrazole): 189.
4-(1H-Tetrazol-5-ylselanyl)-benzoic acid (4i).
Yield: 92%; mp 178–180◦C; IR νmax (cm–1) (KBr):
N H (tautomeric): 3667–3496; N N: 1592; C N:
1481; Ar H: 3045, O H: 3496, C O: 1689; Ar(C C):
5-(4-Chlorophenylselanyl)-1H-tetrazole (4b). Yield:
81%; mp 142–143◦C; IR νmax (cm (KBr): N H (tau-
tomeric): 3647–3223; N N: 1529; C N: 1478; Ar H:
1
1592, 1567, 1481; H NMR (DMSO-d6) δH: 7.6 (d,
1
3031; Ar(C C): 1631, 1529, 1478; H NMR (DMSO-
+
·
2H+)–7.9 (d, 2H), 12.9 (s, 1H); MS for C8H6N4O2Se
d6) 7.4 (d, 1H), 7.7 (d, 1H); MS for C7H5N4ClSe (M ):
+
(M ): 269.47, (M – tetrazole): 201 (M+ – Se –
tetrazole): 122.
·
·
·
+
260, (M+ – tetrazole): 190, (M – Se – tetrazole): 108.
·
·
5-(4-Bromophenylselanyl)-1H-tetrazole (4c). Yield:
90%; mp 170–171◦C; IR νmax (cm–1) (KBr): N H (tau-
tomeric): 3620–3190; N N: 1540; C N: 1465; Ar H:
5-(4-Methoxyphenylselanyl)-1H-tetrazole (4j).
Yield: 89%; mp 145–146◦C; IR νmax (cm–1) (KBr):
N H (tautomeric): 3647–3217; N N: 1592; C N:
1490; Ar H: 3031, C H: 2966; Ar(C C): 1592, 1490;
1H NMR (DMSO-d6) δH: 7.1 (d, +2H)–7.7 (d, 2H), 2.5
1
3032; Ar(C C): 1651, 1568, 1510; H NMR (CDCl3)
δH: 7.55 (d, 2H), 7.65 (d, 2H), 4.8–6.9 (broad, 1H);
+
+
·
·
MS for C7H5N4BrSe (M ): 304 (M – tetrazole): 235,
·
(s, 3H); MS for C8H6N4O2Se (M ): 256.
(M+ – Se – tetrazole): 156.
·
5-(2-Methylphenylselanyl)-1H-tetrazole (4d). Yield:
92%; mp 136–138◦C; IR νmax(cm–1) (KBr): N H (tau-
tomeric): 3667–3127; N N: 1515; C N: 1478; Ar H:
3037, C H: 2915; Ar(C C): 1515, 1478; 1H NMR
(CDCl3) δH: 7.5 (m, 4H), 4.7–6.3 (broad, 1H), 2.6 (s,
REFERENCES
[1] Rayman, M. P. Br Med J 2000, 356, 233–241.
[2] Rayman, M. P. Br Med J 1997, 314, 387–388.
[3] Chen, X.; Yang, G.; Chen, J.; Chen, X.; Wen, Z.; Ge,
K. Biol Trace Elem Res 1980, 2, 91–107.
[4] Schrauzer, G. N.; White, D. A.; Schneider, C. J.
Bioinorg Chem 1976, 6(3), 265–270.
+
·
+
·
3H); MS for C8H8N4Se (M ): 240, (M – tetrazole):
170, (M+ – Se – tetrazole): 91.
·
[5] Glatre, E.; Thomassen, Y. T. Int F Epidemiol 1989,
18(1), 45–49.
5-(4-Methylphenylselanyl)-1H-tetrazole (4e). Yield:
79%; mp 150–152◦C; IR νmax(cm–1) (KBr): N H (tau-
tomeric): 3621–3275; N N: 1525; C N: 1496; Ar H:
3031, C H: 2838; Ar(C C): 1515, 1496; 1H NMR
(DMSO-d6) δH: 7.2 (d, 2H), 7.7 (d, 2H), 2.4+(s, 3H);
[6] Bronzetti, G.; Cini, M.; Andreoli, E. Mutat Res 2001,
496, 105–115.
[7] Oldereid, N. B.; Thomassen, Y.; Purvis, K. Hum Re-
prod 1998, 13, 2172–2176.
[8] Kendall, N. R.; McMuller, S.; Gren, A.; Rodway, R. G.
Animal Reprod Sci 2000, 62, 277–228
[9] Butler, N. P. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R.; Rees, C. W.; Scriven,
E. F. (Eds); Pergamon: Oxford, UK, 1996; Vol. 4.
[10] Herr, R. J. Bioorg Med Chem 2002, 10, 3379–3393.
[11] Mohan, V. K.; Tang, B. T. J Chem Phys 1983, 79,
4271–4278.
[12] Koldobskii, G. I.; Ostrovskii, V. A. Usp Khim 1994,
63(10), 847–865.
[13] Moderhack, D. J. Prakt Chem/Chem-Ztg 1998, 340,
687–709.
MS for C8H8N4Se (M+ – tetrazole):170, (M – Se –
tetrazole): 91.
·
·
5-(2-Nitrophenylselanyl)-1H-tetrazole (4f). Yield:
78%; mp 180–181◦C; IR νmax (cm–1) (KBr): N H (tau-
tomeric): 3672–3300; N N: 1599; C N: 1515; Ar H:
1
3095; Ar(C C): 1599, 1580, 1515; H NMR (DMSO-
d6) δH: 6.8 (d, 1H), 7.7 (m, 2H), 8.5 (d, 1H); MS for
+
·
C7H5N5O2Se (M ): 271.
[14] Demko, Z. P.; Sharpless, K. B. Angew Chem, Int Ed
Engl 2002, 41, 2113–2116.
[15] Huisgen, R.; Sauer, J.; Sturm, H. J.; Markgraf, H.
Chem Ber 1960, 93, 2106–2124.
5-(4-Nitrophenylselanyl)-1H-tetrazole (4g). Yield:
75%; mp 154–155◦C; IR νmax (cm–1) (KBr): N H (tau-
Heteroatom Chemistry DOI 10.1002/hc

¨
258 Ozkan et al.
¨
[16] Bryce, M. R.; Vernon, J. M. Adv Heterocycl Chem
1981, 28, 183–229.
[19] Ozkan, H.; Dis¸li, A.; Yıldırır, Y. Org Prep Proc Int
2004, 36, 161–163.
[17] Ashraf, A. A.; Raafat, M. S. Tetrahedron Lett 2005,
46, 2679–2682.
[20] Challenger, F.; Peters, A. T.; Halevy, J. J Chem Soc
[Abstracts] 1926, 1648–1655.
[18] Le Blanc, B. W.; Jursic, B. S. Synth Commun 1998,
28, 3591–3599.
[21] Srinvas, K.; Snehalatha Nair, C. K.; Ramesh, S.; Pard-
hasaradhi, M. Org Prep Proc Int 2004, 36, 69–71.
Heteroatom Chemistry DOI 10.1002/hc