Novel Bis(2-(5-((5-phenyl-1H-tetrazol-1-yl)methyl)-4H-1,2,4-triazol-3-yl)phenoxy)Alkanes: Synthesis and Characterization

Article abstract of DOI:10.1002/jhet.2211

In this study, 10 different substituted aromatic bis-benzaldehydes were synthesized by treating hydroxy benzaldehydes with various dihaloalkanes. Bis aldehydes 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j were treated with 2-(5-phenyl-1H-tetrazole-1-yl)acetohyd

Full text of DOI:10.1002/jhet.2211

Month 2014 Novel Bis(2-(5-((5-phenyl-1H-tetrazol-1-yl)methyl)-4H-1,2,4-triazol-3-yl)
phenoxy)Alkanes: Synthesis and Characterization
*
Aamer Saeed, Muhammad Qasim, and Majid Hussain
Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan
*
E-mail: aamersaeed@yahoo.com
Additional supporting information may be found in the online version of this article.
Received August 18, 2013
DOI 10.1002/jhet.2211
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
In this study, 10 different substituted aromatic bis-benzaldehydes were synthesized by treating hydroxy benz-
aldehydes with various dihaloalkanes. Bis aldehydes 5a–j were treated with 2-(5-phenyl-1H-tetrazole-1-yl)
acetohydrazide (4) in acidic medium and in the presence of ammonium acetate to yield a series of new isomeric
bis(2-(5-((5-phenyl-1H-tetrazol-1-yl)methyl)-4H-1,2,4-triazol-3-yl)phenoxy)alkanes (6a–j) in excellent to good
yield. The newly synthesized compounds were characterized by the available spectroscopic analysis.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
show intriguing spin-crossover properties for potential use
in molecular electronics, as information storage and
switching materials [17–19].
Keeping in view the immense biological importance of
these two nuclei and in continuation of our interest on the
synthesis of biologically active heterocycles [19,20],
herein, we describe the construction of molecules with
these biolabile rings together in a single molecular frame
work by molecular hybridization.
An azole is a class of five-membered nitrogen heterocy-
clic ring compounds, which have attained a valuable scope
over the last decade due its broad range of applications in
pharmaceutical, agrochemical, and material science.
Tetrazole, a subclass of azoles is such a unique nucleus,
which possesses both energetic and medicinal applications.
Polynitrogen compounds are used as a propellant [1,2] due
to their use for high-energy density materials (HEDM),
whose crucial characteristic from an energetic point of
view is the ratio between the energy released in a fragmen-
tation reaction and the specific weight. The formation of
nitrogen molecule only in such processes renders nitrogen
clusters as eco-caring HEDMs. In medicinal chemistry,
tetrazole derivatives are used as an antihypertensive [3],
antimycobacterial [4], anti-inflammatory [5], anticonvul-
sant [6], hypoglycemic [7], antibacterial [8], and antifungal
[9] agents.
On the other hand, 1,2,4-triazole is equally important
nucleus in competition with tetrazoles based on its applica-
tions. 1,2,4-Triazole ring with various pharmacological
effects has been reported as therapeutic agents. Com-
pounds bearing triazole moieties such as anastrozole,
vorozole, and letrozole appear to be very effective
aromatase inhibitors for preventing breast cancer. It
strongly interacts with the heme iron and aromatic substit-
uents in the active site of aromatase [10]. This nucleus not
only possesses antimicrobial [11], antitumor [12], antima-
larial [13], anti-inflammatory [14], and antifungal [15]
but also corrosion inhibitory [16] activities. Additionally,
substituted 1,2,4-triazoles also have attracted substantial
notice in coordination chemistry due to their rich and
versatile coordination properties. Their iron (II) complexes
RESULTS AND DISCUSSION
Synthesis of the easily accessible 2-(5-phenyl-1H-
tetrazole-1-yl)acetohydrazide was carried out according to
Scheme 1. Thus, 5-phenyl-1,2,3,4-tetrazole 1 was synthe-
sized by the cycloaddition reaction of benzonitrile with
sodium azide in the presence of zinc chloride as a
catalyst in aqueous medium. An improved synthesis of 2-
(5-phenyl-1H-tetrazole-1-yl)acetate (2) was achieved by
use of triethylamine and high dielectric solvent acetonitrile
followed by recrystallization from n-hexane. In FTIR, the
presence of vibrational stretching at 1756 cmÀ1 confirmed
the attachment of ester moiety. In 1H NMR, the two
protons singlet at 5.94 ppm was assigned to methylene
protons, whereas a three-proton singlet appeared at
3.75 ppm for ester methyl group. In 13C NMR spectrum,
the signal at 167.11 ppm was observed for ester carbonyl
carbon.
Reaction of ester 2 with slight excess of hydrazine
hydrate in dry methanol at 45–50°C afforded the
acetohydrazide 3. In FTIR, the stretchings at 3132 (–NH)
and 3307 (–NH2) cmÀ1 confirmed the conversion of ester
into hydrazide. In 1H NMR spectrum, the singlet at
© 2014 HeteroCorporation

A. Saeed, M. Qasim, and M. Hussain
Vol 000
Scheme 1. Synthesis of 2-(5-Phenyl-1H-tetrazole-1-yl) acetohydrazide (3).
4.46 ppm was assigned to (NH2) and that at 9.65 ppm to
(–NH) proton, respectively. In 13C NMR spectrum, upfield
shift of carbonyl signal at 164.6 ppm confirmed conversion
of ester into hydrazide.
A variety of bis aldehydes were synthesized according to
route illustrated in Scheme 2. Anhydrous potassium
carbonate was used to abstract the acidic proton of differ-
ent isomeric hydroxybenzaldehydes 4a–j. The resulting
phenoxide ions were reacted with different dihaloalkanes
(n = 3,4,6) to afford a series of bis aldehydes 5a–j. In FTIR,
the absence of broad band of hydroxyl group and the
presence of stretching frequency at 1185 cmÀ1 confirmed
the formation of ether linkage, see Scheme 3.
Finally, the cyclization of 2-(5-phenyl-1H-tetrazole-1-
yl)acetohydrazide (3) with aromatic bis aldehydes 4a–j
was carried out in acidic medium in the presence of an
excess of ammonium acetate to furnish 6a–j. Mechanisti-
cally, the initial reaction of 3 with bis aldehydes 4a–j
may lead to the formation of Schiff bases. Subsequent at-
tack of the hydrazide moiety to the electrophilic carbon
of the Schiff bases followed by heterocyclization in the
presence of ammonia from ammonium acetate affords the
1,2,4-triazoles.
In FTIR, the absence of carbonyl stretching in all
synthesized compounds and the presence of absorption
in the region of 3428–3435 cmÀ1 attributed to N–H of
Scheme 2. Synthesis of 2,2′-(alkane-1,3-diylbis(oxy))dibenzaldehydes (5a–j).
Scheme 3. Bis(2-(5-((5-phenyl-1H-tetrazol-1-yl)methyl)-4H-1,2,4-triazol-3-yl)phenoxy)alkanes (6a–j).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Bis(2-(5-(phenyltetrazolyl)methyl)1,2,4-triazolyl)phenoxy)Alkanes
to get pure methyl 2-(5-phenyl-1H-tetrazole-1-yl)acetate. White
crystalline solid, yield: 88%; mp = 98–100°C:. IR (neat) cmÀ1
triazole ring confirms the functional group interconversion.
1HNMR reveals the presence of signal at 11–11.5 ppm and
the absence of signals of NH2 of hydrazide indicated the
formation of 4H-1,2,4-triazole. In 13C NMR spectrum,
the absence of characteristic signal of carbonyl carbon of
aldehydes at 210 ppm and the presence of signal at
158–165 ppm for carbons of triazole ring is another strong
evidence for the formation of 1,2,4-triazole. In GC-MS
spectral analysis, the molecular ion peak was observed
in almost all compounds. The base peak was observed
at m/z = 196.
:
1281 (N═N–N), 1547 (Ar–C═C), 1606 (C═N), 1756 (C═O),
1
2854 (CH3), 3067 (Ar–C–H); H-NMR (DMSO-d6, δ/ppm) 3.75
(s, 2H, CH3), 5.93 (s, 2H, CH2), 7.56–7.59 (m, 3H, Ar–H), δ
8.06–8.10 (m, 2H, Ar–H). 13C NMR (DMSO-d6, δ/ppm) 53.43,
53.83 (CH2C═O, OCH3), 126.85–131.28 (Ar), 164.85 (tetrazole
ring carbon), 167.11 (C═O).
Synthesis of 2-(5-Phenyl-1H-tetrazole-1-yl)acetohydrazide
(3). To a solution of tetrazole-ester (2) (0.218 g, 1.0 mmol) in
10 mL of dry distilled methanol was added hydrazine hydrate
(2 mmol). The reaction mixture was stirred at room temperature
for 12 h. The reaction was monitored by TLC. The precipitates
obtained were filtered, washed with methanol to obtain
tetrazole-hydrazide (3). White crystalline solid, yield: 89%;
mp = 212°C:. IR (neat) cmÀ1: 1280 (N═N–N), 1549 (Ar-C═C),
1608 (C═N), 1659 (C═O), 3057 (Ar–C–H), 3132 (N–H), 3307
CONCLUSION
In the present study, the molecular hybridization of
triazole and tetrazole followed by their connection via
phenoxy ether linkage leading to symmetrical molecules
with four rings has been carried out. The new scaffold
incorporates biologically important pharmacophores in a
single molecular frame work, and the possibility of
introduction of different substituents in the aromatic ring
as well as variable spacer chain length indicates their
potential diversity leading to molecules for use in
drug discovery.
1
(NH2); H-NMR (DMSO-d6, δ/ppm) 4.46 (s, 2H, NH2), 5.45 (s,
2H, CH2), 7.55–7.61 (m, 3H, Ar–H), 8.05–8.08 (m, 2H, Ar–H),
9.65 (s, 1H, NH), 13C NMR (DMSO-d6, δ/ppm) 54.14
(CH2C═O), 126.78–131.12 (Ar), 163.99 (tetrazole ring carbon),
164.62 (C═O).
General procedure for the synthesis of bis aldehydes
(5a–j).
Suitable substituted hydroxybenzaldehydes (4a–j)
(0.2 mmol) were refluxed with different dihaloalkanes
(0.1 mmol) using anhydrous potassium carbonate (0.1 mmol) in
dry acetone for 4–5 h. The completion of reaction was checked
by TLC. On completion, the reaction mixture was filtered and
the residue was washed with dry hot acetone. Filtrate was
evaporated to afford pure crystalline products (5a–j) in each
case in 80–86% yields.
EXPERIMENTAL
Melting points were recorded using a digital Gallenkamp
(SANYO, Loughborough, UK) model MPD BM 3.5 apparatus
and were uncorrected. 1H and 13C NMR spectra were determined
in CDCl3 at 300 and 75 MHz, respectively, using Bruker AM-300
spectrophotometer (Billerica, Middlesex, MA, USA). FT-IR
spectra were recorded using Rad Excalibur FTS 3000 MX
spectrophotometer (Madison, WI, USA). Mass spectra (EI, 70 eV)
were recorded on a GC–MS instrument (Agilent Technologies 1200
series, Santa Clara, CA, USA), and elemental analyses were carried
out with a LECO-183 CHNS analyzer (LECO Corporation, St Joseph,
MI, USA).
2,2′-(Propane-1,3-diylbis(oxy))dibenzaldehyde (5a).
IR
(neat) cmÀ1: 1553 (Ar–C═C), 1725 (C═O), 3052 (Ar–C–H),
2903 (CH2); 1H-NMR (DMSO-d6, δ/ppm) 2.18–2.27 (m, 2H,
CH2), 4.02 (t, J = 11.93Hz, 4H, CH2), 7.23–8.28 (m, 8H, Ar–H),
9.13 (s, 1H, CHO).
2,2′-(Butane-1,4-diylbis(oxy))dibenzaldehyde (5b).
IR
(neat) cmÀ1: 1561 (Ar–C═C), 1734 (C═O), 3098 (Ar–C–H),
2909 (CH2); 1H-NMR (DMSO-d6, δ/ppm) 1.53–1.69 (m, 4H,
CH2), 4.32–4.41 (t, J = 11.82 Hz, 4H, CH2), 6.23 (s, 4H, CH2),
7.21–8.34 (m, 8H, Ar–H), 9.76 (s, 1H, CHO).
2,2′-(Hexane-1,6-diylbis(oxy))dibenzaldehyde (5c).
IR
Synthesis of 5-phenyl tetrazole (1). 5-Phenyl tetrazole was
synthesized by a one of the most convenient routes reported by
Sharpless et al. [21]..A mixture of sodium azide (3 mmol),
benzonitrile (2 mmol), and zinc (II) chloride (3 mmol) was
suspended in H2O (16 mL). The reaction mixture was heated
under reflux for 15 h. After consumption of nitriles, the mixture
was cooled at room temperature and filtered. In continuation of
(neat) cmÀ1:1575 (Ar–C═C), 1745 (C═O), 3043 (Ar–C–H),
2921 (CH2); 1H-NMR (DMSO-d6, δ/ppm) 1.32–1.64 (m, 8H,
CH2), 4.01–4.12 (t, J = 11.67 Hz, 4H, CH2), 7.32–8.76 (m, 8H,
Ar–H), 9.53 (s, 2H, CHO).
3,3′-(Ethane-1,2-diylbis(oxy))dibenzaldehyde (5d).
IR
(neat) cmÀ1: 1563 (Ar–C═C), 1774 (C═O), 3093 (Ar–C–H),
2903 (CH2); 1H-NMR (DMSO-d6, δ/ppm) 4.31–4.42 (t,
J = 11.73 Hz, 4H, CH2), 7.65–8.89 (m, 8H, Ar–H), 9.74 (s, 2H,
CHO).
workup, the solid residue was treated with 3 N HCl (4 mL) to
17
afford pure product. White solid, yield: 78%; mp = 216°C
;
1H-NMR (DMSO-d6, δ/ppm) 7.59–7.62 (m, 3H, Ar–H), 8.02–8.06
(m, 2H, Ar–H), 13C NMR (DMSO-d6, δ/ppm) 124.55–131.73
(Ar), 155.79 (tetrazole ring carbon).
3,3′-(Butane-1,4-diylbis(oxy))dibenzaldehyde (5e).
IR
(neat) cmÀ1:1541 (Ar–C═C), 1723 (C═O), 3052 (Ar–C–H),
2906 (CH2); 1H-NMR (DMSO-d6, δ/ppm) 1.63–1.73 (m, 4H,
CH2), 4.32–4.63 (t, J = 11.82 Hz, 4H, CH2), 7.34–8.89 (m, 8H,
Ar–H), 9.78 (s, 1H, CHO).
Synthesis of methyl 2-(5-phenyl-1H-tetrazole-1-yl)acetate
(2).
Methyl chloroacetate was refluxed (0.523 mL, 6 mmol) in
15mL of acetonitrile. Then a stirred mixture of 5-phenyl tetrazole
(1) (0.438g, 3 mmol), triethylamine (1.674mL, 12mmol), and
acetonitrile (25 mL) was added dropwise. The reaction mixture
was heated on oil bath for 2 h keeping the temperature 82°C.
The reaction was monitored by TLC. Acetonitrile was removed
under reduced pressure and product was recrystallized in n-hexane
3,3′-(Hexane-1,6-diylbis(oxy))dibenzaldehyde (5f).
IR
(neat) cmÀ1: 1585 (Ar–C═C), 1745 (C═O), 3081 (Ar–C–H),
2907 (CH2); 1H-NMR (DMSO-d6, δ/ppm) 1.51–1.62 (m, 8H,
CH2), 4.20–4.32 (t, J = 11.74 Hz, 4H, CH2), 7.22–8.95 (m, 8H,
Ar–H), 9.62 (s, 2H, CHO).
Journal of Heterocyclic Chemistry
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A. Saeed, M. Qasim, and M. Hussain
Vol 000
4,4′-(Propane-1,3-diylbis(oxy))dibenzaldehyde (5g).
IR
4H, –OCH2), 6.11 (s, 2H, CH2), 6.69–8.45 (m, 18H, Ar–H), 11.96
(s, 2H, NH), 13C NMR (DMSO-d6, δ/ppm) 25.59, 29.08 (2CH2),
54.36 (NCH2N), 68.30 (OCH2), 113.17–141.23 (Ar), 157.68,
164.58 (triazole ring carbons), 166.50 (tetrazole ring carbon). MS,
m/z (%): 720 [M]+ (69), 196 (100), 315 (43), 399 (67), 518 (23).
1,2-Bis(3-(5-((5-phenyl-1H-tetrazol-1-yl)methyl)-4H-1,2,4-
triazol-3-yl)phenoxy)ethane (6d). Yield: 68%; mp = 265–270°C:
Anal. Calcd for C34H28N14O2: C, 61.44; H, 4.25; N, 29.50; Found
C, 61.45; H, 4.28; N, 29.52; IR (neat) cmÀ1: 3431 (N–H), 3152
(NCH), 3043 (ArCH), 1627 (C═N), 1563 (–N═N), 1123 (C–N),
1H-NMR (DMSO-d6, δ/ppm) 4.10 (4H, –OCH2), 6.13 (s, 2H,
CH2), 7.09–8.55 (m, 18H, Ar–H), 11.96 (s, 2H, NH), 13C NMR
(DMSO-d6, δ/ppm) 54.36 (NCH2N), 68.38 (OCH2), 113.25–142.23
(Ar), 157.78, 164.58 (triazole ring carbons), 166.50 (tetrazole
ring carbon). MS, m/z (%): 664 [M]+ (75), 196 (100), 315 (27),
343 (41), 462 (66).
(neat) cmÀ1: 1543 (Ar–C═C), 1767 (C═O), 3061 (Ar–C–H),
2903 (CH2); 1H-NMR (DMSO-d6, δ/ppm) 2.06–2.17 (m, 2H,
CH2), 4.01 (t, J = 11.86 Hz, 4H, CH2), 7.15–8.34 (m, 8H, Ar–H),
9.32 (s, 1H, CHO).
4,4′-(Butane-1,4-diylbis(oxy))dibenzaldehyde (5h).
IR
(neat) cmÀ1:1556 (Ar–C═C), 1727 (C═O), 3067 (Ar–C–H),
2901 (CH2); 1H-NMR (DMSO-d6, δ/ppm) 1.61–1.71 (m, 4H,
CH2), 4.21–4.67 (t, J = 11.82 Hz, 4H, CH2), 7.21–8.34 (m, 8H,
Ar–H), 9.72 (s, 1H, CHO).
4,4′-(Hexane-1,6-diylbis(oxy))dibenzaldehyde (5i).
IR
(neat) cmÀ1: 1563 (Ar–C═C), 1732 (C═O), 3054 (Ar–C–H),
2904 (CH2); 1H-NMR (DMSO-d6, δ/ppm) 1.48–1.57 (m, 8H,
CH2), 4.19–4.24 (t, J = 11.74 Hz, 4H, CH2), 7.10–8.76 (m, 8H,
Ar–H), 9.45 (s, 2H, CHO).
4-((6-(4-Formyl-2-methoxyphenoxy)hexyl)oxy)-2-methoxy-
benzaldehyde (5j).
IR (neat) cmÀ1: 1535 (Ar–C═C), 1756
1,4-Bis(3-(5-((5-phenyl-1H-tetrazol-1-yl)methyl)-4H-1,2,4-
triazol-3-yl)phenoxy)butane (6e). Yield: 79%; mp = 285–289°C:
Anal. Calcd for C36H32N14O2: C, 61.44; H, 4.25; N, 29.50; Found C,
61.45; H, 4.28; N, 29.52; IR (neat) cmÀ1: 3431 (N–H), 3152 (NCH),
(C═O), 3082 (Ar–C–H), 2911 (CH2); 1H-NMR (DMSO-d6,
δ/ppm) 1.43–1.64 (m, 8H, CH2), 3.32 (s, 6H, OCH3), 4.75–4.89
(t, J = 11.81 Hz, 4H, CH2), 6.81–8.72 (m, 6H, Ar–H), 7.83 (s, 2H,
CHO).
1
3043 (ArCH), 1627 (C═N), 1563 (–N═N), 1123 (C–N), H-NMR
General procedure for the synthesis of bis(2-(5-((5-phenyl-
1H-tetrazol-1-yl)methyl)-4H-1,2,4-triazol-3-yl)phenoxy)alkanes
(DMSO-d6, δ/ppm) 1.98 (m, 4H, CH2), 4.15 (t, J = 11.2 Hz,
4H, –OCH2), 6.1 (s, 4H, NCH2N), 7.29–8.68 (m, 18H, Ar–H),
11.99 (s, 2H, NH), 13C NMR (DMSO-d6, δ/ppm) 25.95 (CH2),
54.34 (NCH2N), 68.17 (OCH2), 113.10–141.15 (Ar), 157.60,
164.59 (triazole ring carbons), 166.50 (tetrazole ring carbon). MS,
m/z (%): 692 [M]+ (75), 196 (100), 315 (27), 343 (41), 462 (66).
1,6-Bis(3-(5-((5-phenyl-1H-tetrazol-1-yl)methyl)-4H-1,2,4-
triazol-3-yl)phenoxy)hexane (6f). Yield: 58%; mp = 320–324°C:
Anal. Calcd for C38H36N14O2: C, 61.44; H, 4.25; N, 29.50; Found
C, 61.45; H, 4.28; N, 29.52; IR (neat)cmÀ1: 3431 (N–H), 3152
(NCH), 3043 (ArCH), 1627 (C═N), 1563 (–N═N), 1123 (C–N),
1H-NMR (DMSO-d6, δ/ppm) 1.58–1.94 (m, 8H, CH2), 4.15 (t,
J = 10.70 Hz, 4H, –OCH2), 6.11 (s, 2H, CH2), 6.69–8.45 (m, 18H,
Ar–H), 11.96 (s, 2H, NH), 13C NMR (DMSO-d6, δ/ppm) 27.59,
30.08 (2CH2), 54.36 (NCH2N), 69.30 (OCH2), 113.17–141.43
(Ar), 157.7, 164.6 (triazole ring carbons), 166.59 (tetrazole ring
carbon). MS, m/z (%): 720 [M]+ (75), 196 (100), 315 (27), 343
(41), 462 (66).
1,3-Bis(4-(5-((5-phenyl-1H-tetrazol-1-yl)methyl)-4H-1,2,4-
triazol-3-yl)phenoxy)propane (6g). Yield: 68%; mp = 245–248°C:
Anal. Calcd for C35H30N14O2: C, 61.94; H, 4.46; N, 28.89; Found
C, 61.96; H, 4.48; N, 28.91; IR (neat) cmÀ1: 3427 (N–H), 3154
(NCH), 3043 (ArCH), 1626 (C═N), 1572 (–N═N), 1125 (C–N).
1H-NMR (DMSO-d6, δ/ppm) 2.28 (m, 2H, CH2), 4.30 (t,
J=10.8 Hz, 4H, –OCH2), 6.1 (s, 4H, NCH2N), 7.01–8.63 (m,
18H, Ar–H), 11.88 (s, 2H, NH), 13C NMR (DMSO-d6, δ/ppm)
29.21 (CH2), 54.33 (NCH2N), 66.92 (OCH2), 115.31–145.22
(Ar), 160.4, 164.6 (triazole ring carbons), 166.4 (tetrazole ring
carbon). MS, m/z (%): 678 [M]+ (69), 196 (100), 315 (22), 357
(43), 476 (73).
(6a–j).
About 0.2 mol of 2-(5-phenyl-1H-tetrazol-1-yl)
acetohydrazide (3) and 0.1 mol of bisaldehydes (5a–j) was
dissolved in glacial acetic acid followed by the addition of a pinch
of ammonium acetate, and resulting mixture was stirred for 24h at
room temperature. The reaction mixture was then neutralized with
liquid ammonia solution, and the resulting precipitates were
filtered and then washed with excess of water to obtain the pure
product (6a–j) in 58–88% yields.
1,3-Bis(2-(5-((5-phenyl-1H-tetrazol-1-yl)methyl)-4H-1,2,4-
triazol-3-yl)phenoxy)propane (6a). Yield: 78%; mp = 275–280°C:
Anal. Calcd for C35H30N14O2: C, 61.94; H, 4.46; N, 28.89;
Found C, 61.95; H, 4.47; N, 28.90; IR (neat) cmÀ1: 3430
(N–H), 3161 (NCH), 3053 (ArCH), 1631 (C═N), 1567 (–N═N),
1131 (C–N), 1H-NMR (DMSO-d6, δ/ppm) 2.28 (m, 2H, CH2),
4.30 (t, J= 10.8 Hz, 4H, –OCH2), 6.1 (s, 4H, NCH2N), 7.01–8.63
(m, 18H, Ar–H), 11.96 (s, 2H, NH), 13C NMR (DMSO-d6, δ/ppm)
29.21 (CH2), 54.33 (NCH2N), 65.16 (OCH2), 113.15–141.28 (Ar),
157.46, 164.59 (triazole ring carbons), 166.47 (tetrazole ring
carbon). MS, m/z (%): 678 [M]+ (69), 196 (100), 315 (32), 357
(44), 476 (64).
1,4-Bis(2-(5-((5-phenyl-1H-tetrazol-1-yl)methyl)-4H-1,2,4-
triazol-3-yl)phenoxy)butane (6b). Yield: 68%; mp = 292–297°C:
Anal. Calcd for C36H32N14O2: C, 63.32; H, 5.03; N, 27.21; Found
C, 63.36; H, 5.06; N, 27.22; IR (neat) cmÀ1: 3428 (N–H), 3154
(NCH), 3043 (ArCH), 1623 (C═N), 1571 (–N═N), 1122 (C–N),
1H-NMR (DMSO-d6, δ/ppm) 1.56–1.84 (m, 8H, CH2), 4.10
(t, J = 10.50 Hz, 4H, –OCH2), 6.11 (s, 2H, CH2), 6.69–8.45
(m, 18H, Ar–H), 11.96 (s, 2H, NH), 13C NMR (DMSO-d6,
δ/ppm) 25.59, 29.08 (2CH2), 54.36 (NCH2N), 68.30 (OCH2),
113.17–141.23 (Ar), 157.68, 164.58 (triazole ring carbons),
166.50 (tetrazole ring carbon). MS, m/z (%): 692 [M]+ (69),
196 (100), 315 (43), 399 (67), 518 (23).
1,4-Bis(4-(5-((5-phenyl-1H-tetrazol-1-yl)methyl)-4H-1,2,4-
triazol-3-yl)phenoxy)butane (6h). Yield: 69%; mp = 272–276°C:
Anal. Calcd for C36H32N14O2: C, 62.42; H, 4.66; N, 28.31; Found
C, 62.39; H, 4.54; N, 28.29; IR (neat) cmÀ1: 3429 (N–H), 3159
(NCH), 3049 (ArCH), 1628 (C═N), 1568 (–N═N), 1127 (C–N),
1H-NMR (DMSO-d6, δ/ppm) 1.85 (m, 4H, CH2), 4.20 (t,
J = 11.6 Hz, 4H, –OCH2), 6.1 (s, 4H, NCH2N), 7.56–8.48 (m,
18H, Ar–H), 11.99 (s, 2H, NH), 13C NMR (DMSO-d6, δ/ppm)
25.95 (CH2), 54.54 (NCH2N), 68.37 (OCH2), 113.58–141.65
(Ar), 157.60, 164.59 (triazole ring carbons), 166.55 (tetrazole ring
1,6-Bis(2-(5-((5-phenyl-1H-tetrazol-1-yl)methyl)-4H-1,2,4-
triazol-3-yl)phenoxy)hexane (6c). Yield: 72%; mp = 310–314°C:
Anal. Calcd for C38H36N14O2: C, 63.32; H, 5.03; N, 27.21; Found C,
63.36; H, 5.06; N, 27.22; IR (neat) cmÀ1: 3428 (N–H), 3154 (NCH),
1
3043 (ArCH), 1623 (C═N), 1571 (–N═N), 1122 (C–N), H-NMR
(DMSO-d6, δ/ppm) 1.56–1.84 (m, 8H, CH2), 4.10 (t, J= 10.50 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Bis(2-(5-(phenyltetrazolyl)methyl)1,2,4-triazolyl)phenoxy)Alkanes
carbon). MS, m/z (%): 692 [M]+ (69), 196 (100), 315 (78), 371 (33),
490 (24).
[4] Tukulula, M.; Sharma, R.; Meurillon, R.; Mahajan, A.; Naran,
A.; Warner, D.; Huang, J.; Mekonnen, B.; Chibale, K. Med Chem Lett
2013, 4, 128.
1,6-Bis(4-(5-((5-phenyl-1H-tetrazol-1-yl)methyl)-4H-1,2,4-
triazol-3-yl)phenoxy)hexane (6i). Yield: 58%; mp= 302–306°C:
Anal. Calcd for C38H36N14O2: C, 63.32; H, 5.03; N, 27.21; Found
C, 63.33; H, 5.04; N, 27.39; IR (neat) cmÀ1: 3431 (N–H), 3150
(NCH), 3060 (ArCH), 1628 (C═N), 1561 (-N═N), 1124 (C–N).
1H-NMR (DMSO-d6, δ/ppm) 1.76, 1.84 (m, 8H, CH2), 4.16 (t,
J = 10.54 Hz, 4H, –OCH2), 6.11 (s, 2H, CH2), 6.69–8.65 (m,
18H, Ar-H), 11.96 (s, 2H, NH), 13C NMR (DMSO-d6, δ/ppm)
26.59, 29.88 (2x CH2), 54.96 (NCH2N), 68.30 (OCH2), 113.17–
141.23 (Ar), 158.68, 164.78 (triazole ring carbons), 166.58
(tetrazole ring carbon): 720 [M]+ (69), 196 (100), 315 (50), 399
(62), 518 (31).
[5] Bepary, S.; Das, B. K.; Bachar, S. C.; Kundu, J. K.;
Rouf, A. S. S.; Datta, B. K. Pak J Pharm Sci 2008, 21, 295.
[6] Sun, X.; Wei, C.; Deng, X.; Sun, Z. Pharma Rep 2010, 62, 273.
[7] Gao, Y. L.; Zhao, G. L.; Liu, W.; Shao, H.; Wang, Y. L.;
Xu, W. R.; Tang, L. D.; Wang, J. W. Indian J Chem 2010, 49B, 1499.
[8] Varadaraji, D.; Suban, S. S.; Ramasamy, V. R.;
Kubendiran, K.; Raguraman, J. S. K. G.; Nalilu, S. K.; Pati, H. N. Org
Commun 2010, 3, 45.
[9] Malik, M. A.; Al-Thabaiti, S. A.; Malik, M. A. Int J Mol Sci
2012, 13, 1080.
[10] Sharma, J.; Ahmad, S.; Alam, M. S. J. Chem Pharm Res 2012,
4, 5157.
[11] Bayrak, H.; Demirbas, A.; Bektas, H.; Karaoglu, S. E.;
Demirbas, N. Turk J Chem 2010, 34, 835.
[12] Hou, Y. P.; Sun, J.; Pang, Z. H.; Lv, P. C.; Li, D. D.; Yan, L.;
Zhang, H. J.; Zheng, E. X.; Zhao, J.; Zhu, H. L. Bioorg Med Chem 2011,
19, 5948.
[13] Guantai, E. M.; Ncokazi, K.; Egan, T. J.; Gut, J.; Rosenthal,
P. J.; Smith, P. J.; Chibale, K. Bioorg Med Chem 2010, 18, 8243.
[14] Abdel Megeed, A. M.; Abdel-Rahman, H. M.; Alkaramany,
G. E. S.; El-Gendy, M. A. Eur J Med Chem 2009, 44, 117.
[15] Xu, J.; Cao, Y.; Zhang, J.; Yu, S.; Zou, Y.; Chai, X.; Wu, Q.;
Zhang, D.; Jiang, Y.; Sun, Q. Eur J Med Chem 2011, 46, 3142.
[16] Zarrouk, A.; Hammouti, B.; Al-Deyab, S. S.; Salghi, R.;
Zarrok, H.; Jama, C.; Bentiss, F. Int J Electrochem Sci 2012, 7, 5997.
[17] Habibi, D.; Nasrollahzadeh, M.; Faraji, A. R.; Bayat, Y.
Tetrahedron 2010, 66, 3866.
1,6-Bis(2-methoxy-4-(5-((5-phenyl-1H-tetrazol-1-yl)methyl)-
4H-1,2,4-triazol-3-yl)phenoxy) hexane (6j).
Yield: 88%;
mp = 331–336°C: Anal. Calcd for C40H40N14O4: C, 61.53; H,
5.16; N, 25.11; Found C, 61.56; H, 5.18; N, 25.13; IR
(neat) cmÀ1: 3432 (N–H), 3149 (NCH), 3048 (ArCH), 1629
(C═N), 1565 (–N═N), 1126 (C–N), 1H-NMR (DMSO-d6,
δ/ppm) 1.48, 1.76 (m, 8H, CH2), 3.79 (–OMe), 4.01 (t,
J = 11.4Hz, 4H, –OCH2), 6.14 (s, 2H, CH2), 6.99–8.09 (m, 18H,
Ar–H), 11.87 (s, 2H, NH), 13C NMR (DMSO-d6, δ/ppm) 25.72,
29.06 (2CH2), 54.44 (NCH2N), 56.04 (–OMe), 68.61 (OCH2),
109.35–149.67 (Ar), 150.68, 164.60 (triazole ring carbons),
166.43 (tetrazole ring carbon). MS, m/z (%): 780 [M]+ (69), 196
(100), 345 (59), 429 (74), 578 (41).
[18] Zhu, D. R.; Xu, Y.; Yu, Z.; Guo, Z. J.; Sang, H.; Liu, T.;
You, X. Z. Chem Mater 2002, 14, 838.
[19] Kitchen, J. A.; Brooker, S. Coord Chem Rev 2008, 252, 2072.
[20] a)Saeed, A.; Mahesar, P. A. Tetrahedron 2014, 70, 1401 b)
Saeed, A.; Arif, M.; Irfan, M.; Bolte, M. Turkish J Chem 2013, 37, 383.
c)Ali, A.; Saeed, A.; Naeem, A.; Shahid, M.; Bolte, M.; Iqbal, J. Med
Chem Comm 2012, 3, 1428 d)Saeed, A.; Masoudi, N. A.; Ahmed, A.
A.; Pannecouque, C. Z. Naturforsch 2011, 66b, 512.
[21] Demko, Z. P.; Sharpless, K. B. Angew Chem Int Ed 2002,
41, 2110.
REFERENCES AND NOTES
[1] Fischer, N.; Izsak, D.; Klapctke, M. T.; Stierstorfer, J. Eur J
Chem 2013, 19, 8948.
[2] Klapotke, T. M.; Piercey, D. G. Inorg Chem 2011, 50, 2732.
[3] Rao, S. N.; Babu, K. S. Org Commun 2011, 4, 105.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet