Linear polynuclear tetrazole-containing compounds

Article abstract of DOI:10.1007/s11178-005-0057-6

Linear polynuclear tetrazole-containing compounds were synthesized. Alkylation of 5-[ω-(5-phenyl-2-tetrazolyl)alkyl]tetrazoles with ethyl bromoacetate and chloroacetamide gave the corresponding esters and amides. Treatment of the latter with tetrachlorosilane-sodium azide afforded compounds containing three tetrazole rings linked through polymethylene bridges. Acid ionization constants of the products possessing an NH-tetrazole ring (pK _a = 2.9-3.2) and the corresponding carboxylic acids (pK _a = 2.9-3.1) in aqueous methanol were determined by potentiometric titration.

Full text of DOI:10.1007/s11178-005-0057-6

Russian Journal of Organic Chemistry, Vol. 40, No. 10, 2004, pp. 1532–1538. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 10, 2004,
pp. 1580–1586.
Original Russian Text Copyright © 2004 by Morozova, Komissarov, Esikov, Zubarev, Malin, Ostrovskii.
Linear Polynuclear Tetrazole-Containing Compounds
S. E. Morozova, A. V. Komissarov, K. A. Esikov, V. Yu. Zubarev,
A. A. Malin, and V. A. Ostrovskii
St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: ostrovskii@mail.convey.ru
Received March 29, 2004
Abstract—Linear polynuclear tetrazole-containing compounds were synthesized. Alkylation of 5-[ω-(5-
phenyl-2-tetrazolyl)alkyl]tetrazoles with ethyl bromoacetate and chloroacetamide gave the corresponding esters
and amides. Treatment of the latter with tetrachlorosilane–sodium azide afforded compounds containing three
tetrazole rings linked through polymethylene bridges. Acid ionization constants of the products possessing
an NH-tetrazole ring (pKa = 2.9–3.2) and the corresponding carboxylic acids (pKa = 2.9–3.1) in aqueous
methanol were determined by potentiometric titration.
In the recent years, much attention is given to
5-substituted tetrazoles and compounds possessing two
or more tetrazole rings. Polynuclear tetrazoles are
often difficult to obtain and explore. The series of such
compounds includes both branched molecules contain-
ing only several NH-tetrazole rings and linear struc-
tures consisting of 1,5- and 2,5-disubstituted and
NH-tetrazole rings. Polytetrazole derivatives may be
used in various fields. The synthesis of branched poly-
nuclear tetrazole-containing compounds (podands) was
reported previously. Their molecular structure and
physical properties suggest a strong complexing power
toward metal ions. Effecting filter materials for pro-
found purification of biological liquids from heavy
metals and radioactive elements have been developed
on the basis of some tetrazole podands [1, 2]. A pro-
mising line in this field of chemistry is the synthesis
of macrocyclic tetrazole-containing compounds, e.g.,
analogs of 12-crown-4 [3]. In addition, polytetrazole
fragments can be used as linkers in the design of
Scheme 1.
Ph
Ph
BrCH2COOEt
Et3N
O
N
N
N
N
N
N
+
OEt
N
N
N
N
N
N
(CH2)n
(CH2)n
N
N
N
N
OEt
O
Ph
IIa–IIc
IIIa–IIIc
N
N
N
N
N
N
(CH2)n
N
N
NH3 (aq.)
NH3 (aq.)
H
Ia–Ic
Ph
Ph
ClCH2CONH2
Et3N
O
N
N
N
N
N
N
+
NH2
N
N
N
N
N
N
(CH2)n
(CH2)n
N
N
N
N
NH2
O
IVa–IVc
Va–Vc
n = 1 (a), 2 (b), 3 (c).
1070-4280/04/4010-1532 © 2004 MAIK “Nauka/Interperiodica”

LINEAR POLYNUCLEAR TETRAZOLE-CONTAINING COMPOUNDS
1533
Scheme 2.
Ph
Ph
N
N
N
N
N
N
(1) NaOH; (2) HCl
N
N
N
N
N
N
(CH2)n
(CH2)n
VIa, VIc, VIIa–VIIc
COOH
N
N
N
N
N
COOEt
COOEt
COOH
IIa, IIc, IIIa–IIIc
Ph
Ph
70% H2SO4
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
IIb
VIb
oligonucleotide systems [4]. Search for efficient proce-
dures for the synthesis of new polynuclear tetrazoles
and study of their physical and chemical properties
seem to be important problems.
Va–Vc melt above 100°C (126–188°C) and that esters
IIa–IIc, IIIa, and IIIb are low-melting substances
(mp 58–95°C), fractional crystallization is more con-
venient to separate the isomeric amides. Oily ester IIIc
was separated from IIc by column chromatography.
Tetrazolylacetamides are used as starting com-
pounds for the preparation of linear polytetrazole-con-
taining systems. Primary carboxylic acid amides can
be converted into NH-tetrazoles by the action of tetra-
chlorosilane–sodium azide [5]. This approach may be
applied to various substrates, including those derived
from amino acids [6]. We have synthesized a series
of previously unknown 5-[ω-(5-phenyl-2-tetrazolyl)-
alkyl]-1(2)-tetrazolylacetic acids and their amides and
ethyl esters. The amides were converted into the corre-
sponding tritetrazoles by the action of SiCl4–NaN3.
Carboxylic acids VIa, VIc, and VIIa–VIIc were
obtained by alkaline hydrolysis of the corresponding
esters and amides. Alkaline hydrolysis of ester IIb
gave 5-phenyltetrazole as the major product, presum-
ably as a result of retro-Michael reaction; therefore, it
was subjected to acid hydrolysis to obtain acid VIb
(Scheme 2). Treatment of amides IVa–IVc and Va–Vc
with the system tetrachlorosilane–sodium azide in
acetonitrile afforded tritetrazoles VIIIa–VIIIc and
IXa–IXc, respectively (Scheme 3). It should be noted
that the time necessary to complete the reaction with
the N1-isomers was longer by a factor of ~1.5 than
for the N2-isomers. Also, the reaction time appreciably
increased in going from compounds having three
methylene units to those possessing ethylene and
methylene bridging groups in the initial ditetrazole.
One tetrazole ring in initial ditetrazole derivatives
Ia–Ic contains an unsubstituted NH group [7]. It is
known that alkylation of NH-tetrazoles gives as a rule
mixtures of N1- and N2-substituted isomers [8]. Our
results showed that mixtures of isomeric tetrazolyl-
acetamides or ethyl tetrazolylacetates can be separated
by fractional crystallization more readily than mixtures
of analogous isomeric nitriles. By alkylation of
5-[ω-(5-phenyl-2-tetrazolyl)alkyl]tetrazoles with ethyl
bromoacetate and chloroacetamide in the presence of
triethylamine we obtained mixtures of the corre-
sponding isomeric esters IIa–IIc/IIIa–IIIc and amides
IVa–IVc/Va–Vc (Scheme 1). The isomers can be
separated by fractional crystallization from alcohol or
ether. Taking into account that amides IVa–IVc and
1
Some specific features were observed in the H
and 13C NMR spectra of the products. In going from
amides IV and V to the corresponding tritetrazoles, the
signal from the methylene protons neighboring to the
terminal tetrazole ring shifts downfield by almost
1 ppm. Presumably, the reason is a strong electron-
acceptor effect of the tetrazole ring. In the series of
ditetrazolylmethane derivatives (n = 1), the chemical
shifts of the CH2CO protons are similar for both
Scheme 3.
Ph
Ph
N
N
N
N
N
N
SiCl4, NaN3, MeCN
N
N
N
N
N
N
N
N
(CH2)n
(CH2)n
N
N
N
N
N
CONH2
N
H
IVa–IVc, Va–Vc
VIIIa–VIIIc, IXa–IXc
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004

MOROZOVA et al.
1534
Acidity constants (25°C) of compounds VI–IX
carboxylic acids and the corresponding NH-tetrazoles
differ insignificantly [11]. We determined the acidity
constants of tetrazolylacetic acids VI and VII and
NH-tetrazoles VIII and IX in aqueous methanol by
potentiometric titration (see table). It is seen that, in
keeping with the above stated, the pKa values of NH-
tetrazoles and the corresponding acids are very similar.
Moreover, there is almost no difference between the
pKa values of the respective N1- and N2-isomers. Fairly
strong acidity of the examined compounds is likely to
result from electron-acceptor effect of the ditetrazole
fragment.
Ph
Ph
N
N
N
N
N
N
N
N
N
N
N
N
(CH2)n
(CH2)n
R
N
N
R
N
N
VIa–VIc, VIIIa–VIIIc
VIIa–VIIc, IXa–IXc
VI, VII, R = HOCOCH2; VIII, IX, R = 5-tetrazolylmethyl.
NH acids OH acids
n
comp. no.
VIIIa
VIIIb
VIIIc
IXa
pKa
comp. no.
VIa
pKa
1
2
3
1
2
3
3.03±0.06
3.01±0.05
3.06±0.06
2.93±0.05
3.01±0.05
3.15±0.06
2.96±0.04
3.01±0.05
2.95±0.05
2.91±0.06
3.01±0.06
3.09±0.05
VIb
EXPERIMENTAL
VIc
Potentiometric measurements were performed using
a pH-121 potentiometer equipped with an ESL-43-07
glass electrode, an EVL-1M3 silver chloride electrode,
and a temperature-controlled cell (25°C). The titration
was carried out in 50% aqueous methanol which was
freed from carbon dioxide; a 0.1 N solution of sodium
hydroxide was used as titrant, and a 0.1 N solution of
sodium nitrate, as supporting electrolyte. The pKa
VIIa
VIIb
VIIc
IXb
IXc
regioisomers. By contrast, the chemical shifts of
protons in the bridging methylene group depend on
the position of the substituent in ring B (Scheme 4). In
the series of ethylene-bridged compounds (n = 2), the
position of substituent in ring B insignificantly affects
the chemical shift of the nearest CH2 protons, while
in compounds with a trimethylene bridge (n = 3) this
effect is much stronger.
1
values were calculated as described in [12]. The H
and 13C NMR spectra were recorded on a Bruker DPX-
300 spectrometer at 300 and 75 MHz, respectively,
using acetone-d6 as solvent and reference. The prog-
ress of reactions and the purity of products were
monitored by TLC on Kieselgel 60 F254 plates (Merck)
using CHCl3–MeOH (9:1 or 95:5) as eluent; spots
were visualized with UV light. All the products, except
for IIIc and VIb, were colorless crystalline substances.
Scheme 4.
Ph
Ph
N
N
N
N
N
N
A
N
B
N
A
N
B
N
N
N
N
N
N
N
General procedure for the synthesis of ethyl
tetrazolylacetates IIa–IIc and IIIa–IIIc. Triethyl-
amine, 51.5 mmol, was added under stirring to a sus-
pension of 47 mmol of ditetrazole I in 70 ml of aceto-
nitrile. Ethyl bromoacetate, 51.5 mmol, was then
added, and the mixture was stirred for 5–6 h under
reflux. The solvent was removed under reduced pres-
sure, a 1:1 mixture of methylene chloride with water
was added to the residue, and the organic phase was
separated and washed in succession with two portions
of a 5% solution of Na2CO3, water, 2% hydrochloric
acid, and two portions of water. The solvent was
removed under reduced pressure, and the isomeric
products were separated by repeated crystallization
from ethanol or diethyl ether.
(CH2)n
(CH2)n
R
R
R = EtOCOCH2, NH2COCH2, HOCOCH2, HCN4CH2, n = 1–3.
Different regioisomers are characterized by dif-
ferent chemical shifts of the carbon atoms in the tetra-
zole rings [9]. The C5 signal in the 13C NMR spectra of
2,5-disubstituted tetrazoles appears at δC 160–165 ppm,
and the corresponding signal from 1,5-disubstituted
and NH-tetrazole rings is located at δC 150–155 ppm.
The 13C NMR spectra of the compounds synthesized in
the present work were in full agreement with the above
general relations.
The low toxicity and resistance to biochemical
decomposition are the main factors responsible for
successful application of tetrazole derivatives as isos-
teric analogs of carboxy group in molecular design of
medical agents [10]. It is important that pKa values of
Ethyl 5-(5-phenyl-2-tetrazolylmethyl)-1(2)-tetra-
zolyl acetates (IIa/IIIa). Yield 96% (mixture of
1
isomers), isomer ratio 1:1 (according to the H NMR
data). Isomer IIa: Yield 29%, mp 95°C (from Et2O).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004

LINEAR POLYNUCLEAR TETRAZOLE-CONTAINING COMPOUNDS
1535
1H NMR spectrum, δ, ppm: 1.21 t (3H, CH3, J =
7.3 Hz), 4.14 q (2H, OCH2, J = 7.3 Hz), 5.72 s (2H,
CH2CO), 6.55 s (2H, NCH2C), 7.50–7.60 m (3H,
Harom), 8.05–8.15 m (2H, Harom). 13C NMR spectrum,
δC, ppm: 14.2 (CH3); 45.7 (CH2CO); 49.4 (NCH2C);
63.2 (OCH2); 127.5, 128.0, 130.0, 131.6 (Carom), 151.0
(CH2CN); 166.3 (PhC); 166.6 (CO). Found, %:
C 49.28; H 4.42; N 36.01. C13H14N8O2. Calculated, %:
C 49.68; H 4.49; N 35.65. Isomer IIIa: Yield 37%,
Et2O). 1H NMR spectrum, δ, ppm: 1.22 t (3H, CH3, J =
7.3 Hz), 2.65 quint (2H, CH2CH2CH2, J = 7.3 Hz),
3.10 t (2H, NCH2CH2CH2C, J = 7.3 Hz), 4.20 q (2H,
OCH2, J = 7.3 Hz), 4.95 t (2H, NCH2CH2, J = 6.5 Hz),
5.44 s (2H, CH2CO), 7.50–7.60 m (3H, Harom), 8.10–
13
8.15 m (2H, Harom). C NMR spectrum, δC, ppm: 14.3
(CH3); 20.5 (NCH2CH2CH2C); 27.0 (CH2CH2CH2);
48.4 (CH2CO); 52.7 (NCH2CH2); 62.9 (OCH2); 127.4,
128.6, 129.8, 131.1 (Carom); 156.1 (NCH2CH2CH2C);
165.6 (PhC); 167.0 (CO). Found, %: C 52.86; H 5.78;
N 33.01. C15H18N8O2. Calculated, %: C 52.62; H 5.30;
N 32.73. Isomer IIIc: Yield 32%, oily substance.
1H NMR spectrum, δ, ppm: 1.25 t (3H, CH3, J =
7.3 Hz), 2.58 quint (2H, CH2CH2CH2, J = 7.3 Hz),
3.07 t (2H, NCH2CH2CH2C, J = 7.3 Hz), 4.23 q (2H,
OCH2, J = 7.3 Hz), 4.90 t (2H, NCH2CH2, J = 6.9 Hz),
5.61 s (2H, CH2CO), 7.45–7.60 m (3H, Harom), 8.10–
1
mp 58°C (from EtOH). H NMR spectrum, δ, ppm:
1.23 t (3H, CH3, J = 7.3 Hz), 4.23 q (2H, OCH2, J =
7.3 Hz), 5.73 s (2H, CH2CO), 6.40 s (2H, NCH2C),
7.50–7.55 m (3H, Harom), 8.10–8.15 m (2H, Harom).
13C NMR spectrum, δC, ppm: 14.2 (CH3); 48.3
(CH2CO); 54.3 (NCH2C); 62.9 (OCH2); 127.4, 128.1,
129.9, 131.3 (Carom); 161.3 (CH2CN), 166.0 (PhC),
166.2 (CO). Found, %: C 49.65; H 4.76; N 36.09.
C13H14N8O2. Calculated, %: C 49.68; H 4.49; N 35.65.
13
8.15 m (2H, Harom). C NMR spectrum, δC, ppm: 14.3
(CH3); 22.9 (NCH2CH2CH2C); 28.0 (CH2CH2CH2);
52.9 (CH2CO); 53.9 (NCH2CH2); 62.8 (OCH2); 127.4,
128.6, 129.8, 131.1 (Carom); 165.6 (PhC), 166.4
(NCH2CH2CH2C), 166.6 (CO). Found, %: C 53.02;
H 5.77; N 33.22. C15H18N8O2. Calculated, %: C 52.62;
H 5.30; N 32.73.
Ethyl 5-[2-(5-phenyl-2-tetrazolyl)ethyl]-1(2)-
tetrazolylacetates (IIb/IIIb). Yield 84% (mixture of
isomers), isomer ratio 1:1 (1H NMR). Isomer IIb:
1
Yield 31%, mp 67°C (from Et2O). H NMR spectrum,
δ, ppm: 1.25 t (3H, CH3, J = 7.1 Hz), 3.84 t (2H,
NCH2CH2C, J = 7.1 Hz), 4.23 q (2H, OCH2, J =
7.1 Hz), 5.29 t (2H, NCH2CH2C, J = 7.1 Hz), 5.33 s
(2H, CH2CO), 7.50–7.55 m (3H, Harom), 8.05–8.15 m
General procedure for the synthesis of tetra-
zolylacetamides IVa–IVc and Va–Vc. a. Triethyl-
amine, 20 mmol, was added to a suspension of
13 mmol of ditetrazole Ia–Ic in 50 ml of acetonitrile,
and 20 mmol of chloroacetamide was added to the
resulting solution. The mixture was stirred for 8–15 h
under reflux, the solvent was removed under reduced
pressure, and a 1:1 mixture of ethyl acetate with water
was added to the residue. The organic phase was
separated and washed in succession with two portions
of a 5% solution of Na2CO3, water, 2% hydrochloric
acid, and two portions of water. The solvent was
removed under reduced pressure, and the isomeric
products were separated by repeated crystallization
from ethanol or diethyl ether.
13
(2H, Harom). C NMR spectrum, δC, ppm: 14.9 (CH3);
23.5 (NCH2CH2C); 48.5 (CH2CO); 50.6 (NCH2CH2C);
63.0 (OCH2); 127.3, 128.4, 129.8, 131.2 (Carom), 154.0
(CH2CH2C); 165.6 (PhC); 166.9 (CO). Found, %:
C 50.99; H 5.08; N 34.10. C14H16N8O2. Calculated, %:
C 51.21; H 4.91; N 34.13. Isomer IIIb: Yield 24%,
1
mp 70°C (from EtOH). H NMR spectrum, δ, ppm:
1.22 t (3H, CH3, J = 7.1 Hz), 3.76 t (2H, NCH2CH2C,
J = 6.9 Hz), 4.20 q (2H, OCH2, J = 7.1 Hz), 5.22 t (2H,
NCH2CH2, J = 6.9 Hz), 5.60 s (2H, CH2CO), 7.50–
7.55 m (3H, Harom), 8.05–8.15 m (2H, Harom). 13C NMR
spectrum, δC, ppm: 14.3 (CH3); 26.0 (NCH2CH2C);
51.6 (CH2CO); 53.9 (NCH2CH2); 62.8 (OCH2); 127.3,
128.5, 129.8, 131.1 (Carom); 163.9 (CH2CH2C); 165.5
(PhC); 166.4 (CO). Found, %: C 50.85; H 4.85;
N 33.86. C14H16N8O2. Calculated, %: C 51.21; H 4.91;
N 34.13.
b. Ethyl ester IIa–IIc or IIIa–IIIc, 16 mmol, was
dissolved in 40 ml of ethanol, 160 mmol of 25%
aqueous ammonia was added, the mixture was heated
for 0.5 h at 60–70°C and cooled, and the precipitate
was filtered off.
Ethyl 5-[3-(5-phenyl-2-tetrazolyl)propyl]-1(2)-
tetrazolylacetates (IIc/IIIc). Yield 91% (mixture of
isomers), isomer ratio 1:1 (1H NMR). A part of
N1-isomer IIc was isolated by crystallization from
ethanol. The remaining isomer mixture was separated
by column chromatography on silica gel using chloro-
form as eluent. Isomer IIc: Yield 39%, mp 68°C (from
5-(5-Phenyl-2-tetrazolylmethyl)-1-tetrazolylacet-
amide (IVa). Yield 73% (b), mp 188°C (frm EtOH).
1H NMR spectrum, δ, ppm: 5.56 s (2H, CH2CO),
6.49 s (2H, NCH2C), 7.01 br.s (1H, CONH2), 7.50–
7.60 m (4H, Harom, CONH2), 8.05–8.15 m (2H, Harom).
13C NMR spectrum, δC, ppm: 46.1 (CH2CO); 50.3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004

MOROZOVA et al.
1536
(NCH2C); 127.5, 128.0, 129.9, 131.4 (Carom); 151.3
(NCH2C); 166.1 (PhC); 166.9 (CO). Found, %:
C 46.76; H 4.56; N 44.49. C11H11N9O. Calculated, %:
C 46.31; H 3.89; N 44.19.
5-[3-(5-Phenyl-2-tetrazolyl)propyl]-2-tetrazolyl-
acetamide (Vc). Yield 85% (b), mp 124°C (from
1
EtOH). H NMR spectrum, δ, ppm: 2.57 quint (2H,
CH2CH2CH2, J = 7.3 Hz), 3.05 t (2H, NCH2CH2CH2C,
J = 7.3 Hz), 4.91 t (2H, NCH2CH2CH2, J = 6.9 Hz),
5.41 s (2H, CH2CO), 6.82 br.s and 7.21 br.s (1H each,
5-[2-(5-Phenyl-2-tetrazolyl)ethyl]-1-tetrazolyl-
acetamide (IVb). Yield 79% (b), mp 160°C (from
1
CONH2), 7.50–7.55 m (3H, Harom), 8.10–8.15 m (2H,
EtOH). H NMR spectrum, δ, ppm: 3.80 t (2H,
13
H
arom). C NMR spectrum, δC, ppm: 23.0 (NCH2CH2-
NCH2CH2C, J = 7.3 Hz), 5.28 t (2H, NCH2CH2C, J =
7.3 Hz), 5.37 s (2H, CH2CO), 6.97 br.s and 7.43 br.s
(1H each, CONH2), 7.50–7.55 m (3H, Harom), 8.05–
CH2C); 28.1 (CH2CH2CH2); 53.0 (CH2CO); 55.1
(NCH2CH2CH2); 127.4, 128.6, 129.9, 131.1 (Carom);
165.6 (PhC); 166.2 (NCH2CH2CH2C); 167.2 (CO).
Found, %: C 50.24; H 4.87; N 40.53. C13H15N9O. Cal-
culated, %: C 49.83; H 4.83; N 40.23.
13
8.15 m (2H, Harom). C NMR spectrum, δC, ppm: 23.8
(NCH2CH2C); 49.5 (CH2CO), 50.8 (NCH2CH2C);
127.4, 128.5, 129.9, 131.2 (Carom); 154.2 (NCH2CH2C);
165.6 (PhC); 167.2 (CONH2). Found, %: C 47.88;
H 4.51; N 42.49. C12H13N9O. Calculated, %: C 48.16;
H 4.38; N 42.12.
5-(5-Phenyl-2-tetrazolylmethyl)-1-tetrazolyl-
acetic acid (VIa). Ester IIa, 3.4 g (11 mmol), was dis-
solved on heating in 40 ml (1.3 g, 32 mol) of aqueous
sodium hydroxide. The solution was heated for 0.5 h at
70°C, cooled, and acidified to pH 1–2 with hydro-
chloric acid. The precipitate was filtered off and
recrystallized from 70% aqueous alcohol. Yield 2.4 g
5-[3-(5-Phenyl-2-tetrazolyl)propyl]-1-tetrazolyl-
acetamide (IVc). Yield 81% (b), mp 126°C (from
1
EtOH). H NMR spectrum, δ, ppm: 2.65 quint (2H,
CH2CH2CH2, J = 7.3 Hz), 3.08 t (2H, NCH2CH2CH2C,
J = 7.3 Hz), 4.95 t (2H, NCH2CH2, J = 6.5 Hz), 5.27 s
(2H, CH2CO), 6.86 br.s and 7.35 br.s (1H each,
1
(78%), mp 153°C (from EtOH). H NMR spectrum,
δ, ppm: 5.71 s (2H, CH2CO), 5.79 br.s (1H, COOH),
CONH2), 7.50–7.55 m (3H, Harom), 8.10–8.15 m (2H,
6.56 s (2H, NCH2C), 7.50–7.60 m (3H, Harom), 8.05–
13
13
H
arom). C NMR spectrum, δC, ppm: 20.8 (NCH2CH2-
8.15 m (2H, Harom). C NMR spectrum, δC, ppm: 45.7
CH2C); 27.0 (CH2CH2CH2); 49.3 (CH2CO); 52.9
(NCH2CH2CH2); 127.4, 128.6, 129.9, 131.1 (Carom);
156.3 (NCH2CH2CH2C); 165.6 (PhC); 166.6 (CO).
Found, %: C 49.46; H 4.37; N 41.25. C13H15N9O. Cal-
culated, %: C 49.83; H 4.83; N 40.23.
(CH2CO); 49.2 (NCH2C); 127.5, 127.9, 129.9, 131.5
(Carom); 151.0 (NCH2C); 166.2 (PhC); 167.4 (CO).
Found, %: C 46.36; H 3.71; N 39.35. C11H10N8O2. Cal-
culated, %: C 46.16; H 3.52; N 39.15.
5-[2-(5-Phenyl-2-tetrazolyl)ethyl]-1-tetrazolyl-
acetic acid (VIb). Ester IIb, 1.0 g (3 mmol), was
added to 20 ml of 70% sulfuric acid, the mixture was
heated for 1 h at 70°C, poured into 300 ml of water,
and cooled, and the precipitate was filtered off and
recrystallized from 40% ethanol. Yield 1.7 g (76%),
5-(5-Phenyl-2-tetrazolylmethyl)-2-tetrazolylacet-
amide (Va). Yield 84% (b), mp 170°C (from EtOH).
1H NMR spectrum, δ, ppm: 5.52 s (2H, CH2CO),
6.34 s (2H, NCH2C), 6.89 br.s and 7.32 br.s (1H each,
CONH2), 7.50–7.60 m (3H, Harom), 8.05–8.15 m (2H,
H
arom). 13C NMR spectrum, δC, ppm: 48.3 (CH2CO);
1
mp 172°C (from EtOH). H NMR spectrum, δ, ppm:
55.5 (NCH2C); 127.4, 128.2, 129.9, 131.4 (Carom);
161.1 (NCH2C); 166.0 (PhC); 166.3 (CO). Found, %:
C 46.13; H 4.11; N 44.48. C11H11N9O. Calculated, %:
C 46.31; H 3.89; N 44.19.
3.85 t (2H, NCH2CH2C, J = 7.3 Hz), 5.29 t (2H,
NCH2CH2C, J = 7.3 Hz), 5.53 s (2H, CH2CO), 7.50–
7.55 m (3H, Harom), 8.05–8.15 m (2H, Harom), 8.80 br.s
(1H, COOH). 13C NMR spectrum, δC, ppm: 23.5
(NCH2CH2C); 48.3 (CH2CO); 50.6 (NCH2CH2C);
127.3, 128.4, 129.8, 131.2 (Carom); 154.0 (NCH2CH2C);
165.6 (PhC); 167.7 (CO). Found, %: C 48.42; H 4.39;
N 37.63. C12H12N8O2. Calculated, %: C 48.00; H 4.03;
N 37.32.
5-[2-(5-Phenyl-2-tetrazolyl)ethyl]-2-tetrazolyl-
acetamide (Vb). Yield 85% (b), mp 161°C (from
1
EtOH). H NMR spectrum, δ, ppm: 3.74 t (2H,
NCH2CH2C, J = 7.3 Hz), 5.20 t (2H, NCH2CH2C, J =
7.3 Hz), 5.41 s (2H, CH2CO), 6.78 br.s and 7.12 br.s
(1H each, CONH2), 7.50–7.55 m (3H, Harom), 8.05–
13
5-[3-(5-Phenyl-2-tetrazolyl)propyl]-1-tetrazolyl-
acetic acid (VIc) was synthesized as described above
for acid VIa. Yield 92%, mp 129°C (from EtOH).
1H NMR spectrum, δ, ppm: 2.66 quint (2H, CH2CH2-
CH2, J = 7.3 Hz), 3.13 t (2H, NCH2CH2CH2C, J =
7.3 Hz), 4.95 t (2H, NCH2CH2CH2, J = 6.5 Hz), 5.45 s
8.15 m (2H, Harom). C NMR spectrum, δC, ppm: 26.1
(NCH2CH2C); 51.7 (CH2CO); 55.2 (NCH2CH2C);
127.4, 128.6, 129.9, 131.1 (Carom); 163.8 (NCH2CH2C);
165.6 (PhC); 166.6 (CO). Found, %: C 48.33; H 4.78;
N 42.20. C12H13N9O. Calculated, %: C 48.16; H 4.38;
N 42.12.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004

LINEAR POLYNUCLEAR TETRAZOLE-CONTAINING COMPOUNDS
1537
acetonitrile, 21 mmol of sodium azide, and 21 mmol of
tetrachlorosilane in 20 ml of acetonitrile. The mixture
was heated for 6–7 h under reflux and analyzed by
TLC for the initial amide. If necessary, additional
amounts of the reactants (5.2 mmol of NaN3 and
5.2 mmol of SiCl4) were added. This procedure was
repeated every 6 h until the initial amide disappeared
completely. The mixture was then poured in small
portions under stirring into a solution of sodium
carbonate, maintaining the pH value above 7. The
precipitate of silicic acid was filtered off, charcoal was
added to the filtrate, and the mixture was stirred for
0.5 h and filtered. A solution of sodium nitrite was
added to the filtrate, and the mixture was slowly
acidified to pH 1–2 by adding hydrochloric acid. The
solution was cooled, and the precipitate was filtered
off and recrystallized from ethanol.
(2H, CH2CO), 7.50–7.55 m (3H, Harom), 8.10–8.15 m
(2H, Harom), 11.74 br.s (1H, COOH). 13C NMR
spectrum, δC, ppm: 20.5 (NCH2CH2CH2C); 27.0
(CH2CH2CH2); 48.1 (CH2CO); 52.7 (NCH2CH2CH2);
127.3, 128.5, 129.8, 131.1 (Carom); 156.1 (NCH2CH2-
CH2C); 165.6 (PhC); 167.8 (COOH). Found, %:
C 49.36; H 4.27; N 36.00. C13H14N8O2. Calculated, %:
C 49.68; H 4.49; N 35.65.
5-(5-Phenyl-2-tetrazolylmethyl)-2-tetrazolyl-
acetic acid (VIIa) was synthesized as described above
for acid VIa. Yield 93%, mp 154°C (from EtOH).
1H NMR spectrum, δ, ppm: 5.73 s (2H, CH2CO),
6.39 s (2H, NCH2C), 7.50–7.60 m (3H, Harom), 8.05–
13
8.15 m (2H, Harom), 11.83 br.s (1H, COOH). C NMR
spectrum, δC, ppm: 48.3 (CH2CO); 54.1 (NCH2C);
127.4, 128.1, 129.9, 131.3 (Carom); 161.2 (NCH2C);
166.0 (PhC); 167.0 (CO). Found, %: C 45.94; H 3.45;
N 39.44. C11H10N8O2. Calculated, %: C 46.16; H 3.52;
N 39.15.
5-(5-Phenyl-2-tetrazolylmethyl)-1-(5-tetrazolyl-
methyl)tetrazole (VIIIa). Reaction time 89 h. Yield
1
68%, mp 87°C (from EtOH). H NMR spectrum, δ,
5-[2-(5-Phenyl-2-tetrazolyl)ethyl]-2-tetrazolyl-
acetic acid (VIIb) was synthesized as described above
for acid VIa. Yield 91%, mp 146°C (from EtOH).
1H NMR spectrum, δ, ppm: 3.76 t (2H, NCH2CH2C,
J = 7.1 Hz), 5.22 t (2H, NCH2CH2C, J = 7.1 Hz),
5.61 s (2H, CH2CO), 7.50–7.55 m (3H, Harom), 8.05–
ppm: 6.01 br.s (1H, NH), 6.48 s (2H, CH2CNH), 6.68 s
(2H, NCH2C), 7.50–7.55 m (3H, Harom), 8.00–8.10 m
(2H, Harom). 13C NMR spectrum, δC, ppm: 42.8
(NCH2C); 45.7 (CH2CNH); 127.5, 127.8, 129.9, 131.5
(Carom); 150.8 (NCH2C); 155.4 (CH2CNH); 166.2 (PhC).
Found, %: C 42.24; H 3.06; N 53.73. C11H10N12. Cal-
culated, %: C 42.58; H 3.25; N 54.17.
13
8.15 m (2H, Harom), 11.91 br.s (1H, COOH). C NMR
spectrum, δC, ppm: 26.0 (NCH2CH2C); 51.6 (CH2CO);
53.7 (NCH2CH2C); 127.4, 128.5, 129.8, 131.1 (Carom);
163.9 (NCH2CH2C); 165.5 (PhC); 167.2 (CO). Found,
%: C 48.35; H 4.08; N 37.78. C12H12N8O2. Calculated,
%: C 48.00; H 4.03; N 37.32.
5-[2-(5-Phenyl-2-tetrazolyl)ethyl]-1-(5-tetrazolyl-
methyl)tetrazole (VIIIb). Reaction time 80 h. The
product contained an admixture of 5-phenyltetrazole
which was removed by recrystallization from ethanol.
1
Yield 33%, mp 135°C (from EtOH). H NMR spec-
5-[3-(5-Phenyl-2-tetrazolyl)propyl]-2-tetrazolyl-
acetic acid (VIIc) was synthesized as described above
for acid VIa. Yield 94%, mp 58°C (from EtOH).
1H NMR spectrum, δ, ppm: 2.58 quint (2H, CH2CH2-
CH2, J = 7.3 Hz), 3.08 t (2H, NCH2CH2CH2C, J =
7.3 Hz), 4.89 t (2H, NCH2CH2CH2C, J = 6.9 Hz),
5.62 s (2H, CH2CO), 7.50–7.55 m (3H, Harom),
7.74 br.s (1H, COOH), 8.10–8.15 m (2H, Harom).
13C NMR spectrum, δC, ppm: 22.8 (NCH2CH2CH2C);
27.9 (CH2CH2CH2); 52.9 (CH2CO); 53.7 (NCH2CH2-
CH2C); 127.3, 128.4, 129.7, 131.0 (Carom); 165.4
(PhC); 166.2 (NCH2CH2CH2C); 167.3 (CO). Found,
%: C 49.86; H 5.20; N 35.31. C13H14N8O2. Calculated,
%: C 49.68; H 4.49; N 35.65.
trum, δ, ppm: 4.01 t (2H, NCH2CH2C, J = 7.3 Hz),
5.35 t (2H, NCH2CH2C, J = 7.3 Hz), 6.28 s (2H,
NCH2C), 7.50–7.55 m (3H, Harom), 8.05–8.10 m (2H,
H
arom), 15.31 br.s (1H, NH). 13C NMR spectrum,
δC, ppm: 23.7 (NCH2CH2C); 41.6 (NCH2C); 50.5
(NCH2CH2C); 127.3, 128.3, 129.8, 131.1 (Carom);
155.3 (NCH2C); 153.8 (NCH2CH2C); 165.5 (PhC).
Found, %: C 44.64; H 3.83; N 51.92. C12H12N12. Cal-
culated, %: C 44.44; H 3.73; N 51.83.
5-[3-(5-Phenyl-2-tetrazolyl)propyl]-1-(5-tetra-
zolylmethyl)tetrazole (VIIIc). Reaction time 34 h.
1
Yield 62%, mp 128°C (from EtOH). H NMR spec-
trum, δ, ppm: 2.69 quint (2H, CH2CH2CH2, J =
7.3 Hz), 3.27 t (2H, NCH2CH2CH2C, J = 7.3 Hz),
4.97 t (2H, NCH2CH2CH2, J = 6.5 Hz), 6.19 s (2H,
NCH2C), 7.50–7.55 m (3H, Harom), 8.05–8.15 m (2H,
General procedure for the synthesis of tritetra-
zoles VIIIa–VIIIc and IXa–IXc. A reactor equipped
with a reflux condenser (capped with a drying tube),
stirrer, and thermometer was charged under stirring
with 10.5 mmol of amide IVa–IVc or Va–Vc, 50 ml of
H
arom), 14.07 br.s (1H, NH). 13C NMR spectrum, δC,
ppm: 20.7 (NCH2CH2CH2C); 26.8 (CH2CH2CH2);
41.5 (NCH2C); 52.7 (NCH2CH2CH2C); 127.3, 128.5,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004

MOROZOVA et al.
1538
129.8, 131.1 (Carom); 155.3 (NCH2C); 155.8 (NCH2-
CH2CH2C); 165.5 (PhC). Found, %: C 45.88; H 4.07;
N 49.95. C13H14N12. Calculated, %: C 46.15; H 4.17;
N 49.68.
N 49.98. C13H14N12. Calculated, %: C 46.15; H 4.17;
N 49.68.
This study was performed under financial support
by the Ministry of Education of the Russian Federation
(project no. T02-09.3-3222) and by the Integratsiya
Federal Program for State Support and Integration
of Education and Fundamental Science (project
no. I0667).
5-(5-Phenyl-2-tetrazolylmethyl)-2-(5-tetrazolyl-
methyl)tetrazole (IXa). Reaction time 45 h. Yield
1
73%, mp 125°C (from EtOH). H NMR spectrum, δ,
ppm: 6.37 s (2H, NCH2C), 6.48 s (2H, CH2CNH),
7.50–7.55 m (3H, Harom), 8.05–8.15 m (2H, Harom),
14.90 br.s (1H, NH). 13C NMR spectrum, δC, ppm:
47.5 (CH2CNH); 48.2 (NCH2C); 127.4, 128.0, 129.9,
131.3 (Carom); 154.5 (CH2CNH); 161.6 (NCH2C);
166.0 (PhC). Found, %: C 42.42; H 2.93; N 54.46.
C11H10N12. Calculated, %: C 42.58; H 3.25; N 54.17.
REFERENCES
1. Zubarev, V.Yu. and Ostrovskii, V.A., Khim. Geterotsikl.
Soedin., 2000, p. 867.
2. Zubarev, V.Yu., Bezklubnaya, E.V., Pyartman, A.K.,
Trifonov, R.E., and Ostrovskii, V.A., Khim. Geterotsikl.
Soedin., 2003, p. 1496.
5-[2-(5-Phenyl-2-tetrazolyl)ethyl]-2-(5-tetrazolyl-
methyl)tetrazole (IXb). Reaction time 65 h. Yield
1
3. Zubarev, V.Yu., Trifonov, R.E., Filichev, V.V., Ostrov-
skii, V.A., Abell, A.D., and Edmonds, M.K., J. Chem.
Soc., Perkin Trans. 2, 2001, p. 417.
64%, mp 144°C (from EtOH). H NMR spectrum, δ,
ppm: 3.74 t (2H, NCH2CH2C, J = 7.3 Hz), 5.19 t (2H,
NCH2CH2C, J = 7.3 Hz), 6.35 s (2H, NCH2C), 7.50–
7.55 m (3H, Harom), 8.05–8.10 m (2H, Harom), 15.53 br.s
4. Filichev, V.V., Jasko, M.V., Malin, A.A., Zubarev, V.Yu.,
and Ostrovskii, V.A., Tetrahedron Lett., 2002, vol. 43,
p. 1901.
13
(1H, NH). C NMR spectrum, δC, ppm: 26.0 (NCH2-
CH2C); 47.0 (NCH2C); 51.5 (NCH2CH2C); 127.4,
128.5, 129.8, 131.1 (Carom); 154.4 (NCH2C); 164.4
(NCH2CH2C); 165.5 (PhC). Found, %: C 44.78;
H 3.94; N 52.12. C12H12N12. Calculated, %: C 44.44;
H 3.73; N 51.83.
5. El-Ahl, A.-A.S., Elmorsy, S.S., Elbeheery, A.H., and
Amer, F.A., Tetrahedron Lett., 1997, vol. 38, p. 1257.
6. Esikov, K.A., Morozova, S.E., Malin, A.A., and Ostrov-
skii, V.A., Russ. J. Org. Chem., 2002, vol. 38, p. 1370.
7. Esikov, K.A., Zubarev, V.Yu., Bezklubnaya, E.V., Ma-
lin, A.A., and Ostrovskii, V.A., Khim. Geterotsikl.
Soedin., 2002, p. 1127.
5-[3-(5-Phenyl-2-tetrazolyl)propyl]-2-(5-tetra-
zolylmethyl)tetrazole (IXc). Reaction time 21 h.
1
Yield 59%, mp 121°C (from EtOH). H NMR spec-
8. Koldobskii, G.I. and Ostrovskii, V.A., Usp. Khim., 1994,
trum, δ, ppm: 2.56 quint (2H, CH2CH2CH2, J =
7.3 Hz), 3.05 t (2H, NCH2CH2CH2C, J = 7.3 Hz),
4.89 t (2H, NCH2CH2CH2C, J = 6.9 Hz), 6.39 s (2H,
NCH2C), 7.45–7.55 m (3H, Harom), 8.05–8.15 m (2H,
Harom), 15.01 br.s (1H, NH). 13C NMR spectrum, δC,
ppm: 22.9 (NCH2CH2CH2C); 27.8 (CH2CH2CH2);
46.9 (NCH2C); 52.9 (NCH2CH2CH2); 127.3, 128.4,
129.7, 131.0 (Carom); 154.3 (NCH2C); 165.5 (PhC);
166.7 (NCH2CH2CH2C). Found, %: C 46.47; H 3.90;
vol. 63, p. 847.
9. Butler, R.N., Comprehensive Heterocyclic Chemistry II,
Katritzky, A.R., Rees, C.W., and Scriven, E.F.V., Eds.,
Oxford: Pergamon, 1996, vol. 4, pp. 621, 905.
10. Herr, R.J., Bioorg. Med. Chem., 2002, vol. 10, p. 3379.
11. Koldobskii, G.I., Ostrovskii, V.A., and Gidaspov, B.V.,
Khim. Geterotsikl. Soedin., 1980, p. 867.
12. Albert, A. and Serjeant, E., Ionization Constants of
Acids and Bases, London: Methuen, 1962.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004