Synthesis and acidity of 5-phenyltetrazol-2-ylalkanoic acids and the corresponding 5-(5-phenyltetrazol-2-ylalkyl)tetrazoles

Article abstract of DOI:10.1023/A:1020933900167

We have obtained 5-phenyltetrazol-2-ylalkanoic acids and their derivatives containing terminal nitrile, amide, and tetrazol-5-yl groups. Tetrazolylalkanoic acids with two (pK_a 4.93) and three (pK_a 5.45) bridging methylene groups are

Full text of DOI:10.1023/A:1020933900167

Chemistry of Heterocyclic Compounds, Vol. 38, No. 8, 2002
SYNTHESIS AND ACIDITY OF
5-PHENYLTETRAZOL-2-YLALKANOIC
ACIDS AND THE CORRESPONDING
5-(5-PHENYLTETRAZOL-2-YLALKYL)TETRAZOLES
K. A. Esikov, V. Yu. Zubarev, E. V. Bezklubnaya, A. A. Malin, and V. A. Ostrovskii
We have obtained 5-phenyltetrazol-2-ylalkanoic acids and their derivatives containing terminal nitrile,
amide, and tetrazol-5-yl groups. Tetrazolylalkanoic acids with two (pKa 4.93) and three (pKa 5.45)
bridging methylene groups are weaker acids than the corresponding ditetrazoles (pKa 4.68 and 5.29
respectively). However, the acidity of 5-phenyltetrazol-2-ylacetic acid (pKa 3.12), is higher than acidity
of the corresponding ditetrazole (pKa 3.27).
Keywords: ditetrazoles, tetrazoles, tetrazolylalkanoic acids, acidity.
In medicinal chemistry, the NH-unsubstituted tetrazole ring is considered as a metabolically stable
substitute for carboxyl group. Recently in synthesis of novel biologically active substances, considerable
attention has been paid to tetrazol-5-ylalkyl synthons [1]. The 5-(tetrazol-5-yl)amyl radical has been used in the
molecular design of a modified AMP deaminase inhibitor (1) [2]. Recently a new potential inhibitor of
thymidylate synthetases, ZD 9331, containing 2-(tetrazol-2-yl)ethyl substituent has been synthesized [3], so
methods are being actively developed for directed synthesis of biologically active compounds containing
tetrazol-5-ylalkyl moiety [4].
H
N
F
O
N
N
N
O
O
N
N
OH
N
HO
N
HN
N
N
N
H
H
N
N
H
1
N
N
ZD 9331
In this work, we have synthesized and studied 5-phenyltetrazol-2-ylalkanoic acids and their derivatives
containing terminal nitrile, amide, and tetrazol-5-yl groups.
Alkylation of NH-unsubstituted tetrazoles by various electrophilic agents is widely used for synthesis of
disubstituted tetrazoles [5]. We used this reaction for synthesis of nitriles and amides of tetrazolylalkanoic acids.
__________________________________________________________________________________________
St. Petersburg State Technological Institute (Technical University), St. Petersburg 198013, Russia;
e-mail: kirill_esikov@mail.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1127-1132,
August, 2002. Original article submitted April 3, 2002.
986
0009-3122/02/3808-0986$27.00©2002 Plenum Publishing Corporation

Nitriles of 5-phenyltetrazol-2-ylalkanoic acids 2b,c and amide of 5-phenyltetrazol-2-ylacetic acid (3a)
were obtained by alkylation of 5-phenyltetrazole (4) by acrylonitrile in the presence of triethylamine (Michael's
method) or by nitriles or amides of the corresponding haloalkanoic acids.
In all cases, we observed formation of two regioisomers: N(1)- and N(2)-disubstituted tetrazoles. The
N(2)-isomers were isolated from the mixture by fractional crystallization.
Ph
Ph
H
N
N
N
CH2=CHCN
+
N
N
N
N
4
CN
N
2b
Ph
Ph
N
N
N
N
4
+
ClCH2CONH2
4
BrCH2CH2CH2CN
+
N
N
CONH2
CN
N
N
2c
3a
Amides of 5-phenyltetrazol-2-ylpropionic (3b) and 5-phenyltetrazol-2-ylbutanoic (3c) acids were
obtained by reaction of the corresponding nitriles 2b,c with conc. H2SO4.
Ph
Ph
N
N
H2SO4
H2SO4
N
N
2b
2c
N
N
CONH2
CONH2
N
N
3c
3b
When amide 3a and nitrile 2c were treated with an aqueous solution of NaOH followed by acidification,
we obtained the corresponding 5-phenyltetrazol-2-ylalkanoic acids 5a and 5c in good yield. At the same time,
our attempts to obtain acids 5b by base hydrolysis of nitrile 2b were unsuccessful: instead of the expected
carboxylic acid, we isolated tetrazole 4. It was shown earlier that on cleavage of 1-(β-cyanoethyl)-5R-tetrazoles
in alkaline medium, the corresponding NH-unsubstituted 5-R-tetrazoles were formed [6, 7]. A similar process
probably also occurs under similar conditions in the case of 2-(β-cyanoethyl)-5R-tetrazoles. At the same time,
the target compound 5b could be synthesized by treatment of nitrile 2b with 75% H2SO4.
1. NaOH
2. HCl
4
Ph
1. NaOH
2. HCl
2b
Ph
N
N
3a
H2SO4 (75%)
N
N
COOH
N
N
N
5a
COOH
N
5b
1. NaOH
2. HCl
Ph
N
N
2c
N
COOH
N
5c
987

5-Phenyl-2-(tetrazol-5-ylmethyl)-tetrazole (6a) was synthesized from amide 3a, using a promising
azidation system tetrachlorosilane–sodium azide, which can be used for synthesis of both NH-unsubstituted
tetrazoles and 1,5-disubstituted tetrazoles from carboxylic acid amides [8].
Ph
N
NaN3, SiCl4
N
N
HN
3a
N
N
6a
N
N
1-(5-Phenyltetrazol-2-yl)-2-(tetrazol-5-yl)ethane (6b) and 1-(5-phenyltetrazol-2-yl)-3-(tetrazol-5-
yl)propane (6c) were synthesized by 1,3-dipolar cycloaddition of dimethylammonium azide to nitriles 2b and 2c
respectively at 110°C in DMA. Advantages of this azidation agent have been considered earlier in [9]. As a
result of azidation of nitrile 2b, along with the expected tetrazole 6b we detected tetrazole 4, which probably is
formed upon thermal decomposition of the starting nitrile. In order to eliminate this side reaction, the process
was conducted under relatively mild conditions (3 h, 90°C). In contrast to nitrile 2b, harsher conditions are
required for conversion of nitrile 2c to the corresponding tetrazole 6c (33 h, 110°C).
NaN3,
Me2NH2Cl
Ph
Ph
N
NaN3,
Me2NH2Cl
N
N
N
N
N
N
2c
N
H
N
N
N
N
2b
N
H
N
N
6c
N
6b
One reason why the tetrazole ring can be used in medicinal chemistry as an analog of the carboxyl group
is their similar acid properties. Accordingly, it is of interest to compare the acidity of the synthesized carboxylic
acids 5a-c and tetrazoles 6a-c.
In this work, we used potentiometric titration to determine the acid constants for the synthesized
tetrazolylalkanoic acids and the corresponding NH-unsubstituted ditetrazoles (Table 1).
The data obtained allow us to see a trend toward a decrease in acidity as the number of bridging
methylene groups increases, which is due to weakening of the inductive acceptor effect of the 5-phenyltetrazol-
2-yl substituent.
Interesting results come from comparing the acid constants found. ω-(5-Phenyltetrazol-2-yl)alkanoic
acids 5b,c, with two and three bridging methylene groups, are weaker acids than the corresponding ditetrazoles
6b,c. However, the acidity of tetrazolylacetic acid 5a, containing only one methylene bridging group, has a
slightly higher acidity than the corresponding tetrazole 6a.
TABLE 1. Acidity of Compounds 5a-c and 6a-c (50% methanol, 25°C)
Compound
pKa
Compound
pKa
3.12 ± 0.05*
4.93 ± 0.04
5.45 ± 0.03
3.27 ± 0.03
4.68 ± 0.02
5.29 ± 0.03
5a
5b
5c
6a
6b
6c
_______
* pKa 3.31 (50% ethanol, 25°C) [10].
988

EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on a Bruker DPX-300 spectrometer (300 and 75 MHz
respectively); the solvent and internal standard was acetone-d6. Potentiometric titration was carried out in 50%
MeOH at 25°C; the titrant was NaOH solution (0.1 mol/l), the supporting electrolyte was NaNO3 solution
(0.1 mol/l). The constants were calculated by the method [11]. The course of the reactions and the purity of the
compounds obtained were monitored by TLC on Merck Kieselgel 60 F254 plates in the system CHCl3–MeOH,
9:1, visualization in UV light.
2-(2-Cyanoethyl)-5-phenyltetrazole (2b). Et3N (20.2 g, 0.2 mol) was added with stirring to suspension
of tetrazole 4 (28.9 g, 0.2 mol) in MeCN (100 ml), acrylonitrile (15.9 g, 0.3 mol) was added to the homogeneous
solution obtained and the reaction mass was held for 3 days at room temperature. MeCN was distilled off, the
remaining viscous oil was dissolved in CH2Cl2 and washed twice with 5% Na2CO3 solution, water, 2% HCl
solution, and twice more with water. CH2Cl2 was distilled off, the oil obtained crystallized after some time.
After recrystallization from 70% aqueous ethanol, we obtained 23.1 g (58%) of nitrile 2b, free of the N(1) isomer
1
(monitored by TLC); mp 56°C (mp 55-57°C [11]). H NMR spectrum, δ, ppm, J (Hz): 3.40 (2H, t, J = 6.4,
13
CH2CN); 5.14 (2H, t, J = 6.4, CH2CH2CN); 7.51-7.59 (3H, m, Ph); 8.10-8.19 (2H, m, Ph). C NMR spectrum,
δ, ppm: 18.6 (CH2CN); 49.5 (CH2CH2CN); 117.6 (CN); 127.4, 128.2, 129.9, 131.3 (Ph); 165.9 (CN4).
Found, %: C 60.35; H 4.88; N 35.09. C10H9N5. Calculated, %: C 60.29; H 4.55; N 35.15.
2-(3-Cyanopropyl)-5-phenyltetrazole (2c). Et3N (10.1 g, 0.1 mol) was added with stirring to
suspension of tetrazole 4 (14.5 g, 0.1 mol) in MeCN (50 ml), γ-bromobutyronitrile (14.8 g, 0.1 mol) was added
to the homogeneous solution obtained and the reaction mass was held for 1 day at room temperature.
Triethylammonium bromide precipitate formed was filtered out, MeCN was distilled off, the remaining viscous
oil was dissolved in CH2Cl2 and washed in a separatory funnel twice with 5% Na2CO3 solution, water, 2% HCl
solution, and twice more with water. CH2Cl2 was distilled off, the oil obtained was recrystallized from ethanol
3-4 times until a pure substance was formed (monitored by TLC). Obtained 9.6 g (45%) of nitrile 2c, free of the
1
N(1) isomer; mp 36-37°C. H NMR spectrum, δ, ppm, J (Hz): 2.46 (2H, q, J = 6.8, CH2CH2CN); 2.69 (2H, t,
J = 7.1, CH2CN); 4.90 (2H, t, J = 6.6, CH2CH2CH2CN); 7.49-7.58 (3H, m, Ph); 8.09-8.18 (2H, m, Ph). 13C NMR
spectrum, δ, ppm: 14.8 (CH2CN); 26.0 (CH2CH2CN); 52.2 (CH2CH2CH2CN); 119.5 (CN); 127.3, 128.4, 129.8,
131.1 (Ph); 165.6 (CN4). Found, %: C 62.15; H 5.11; N 33.05. C11H11N5. Calculated, %: C 61.96; H 5.20;
N 32.84.
5-Phenyltetrazol-2-ylethanoic Acid Amide (3a). Et3N (10.1 g, 0.1 mol) was added with stirring to
suspension of tetrazole 4 (14.5 g, 0.1 mol) in MeCN (50 ml), ClCH2CONH2 (9.4 g, 0.1 mol) was added to the
homogenous solution obtained and the reaction mass was held for 1 day at room temperature. The
triethylammonium chloride precipitate formed was filtered out, MeCN was distilled off, the residue was
dissolved in CH2Cl2 and washed twice with 5% Na2CO3 solution, water, 2% HCl solution, and twice more with
water. CH2Cl2 was distilled off, the residue was recrystallized from 50% ethanol. Obtained 13.8 g (68%) of
amide 3a, free of the N(1) isomer (monitored by TLC); mp 188°C (mp 187°C [12] and 186-186.5°C [13]).
1H NMR spectrum, δ, ppm: 5.54 (2H, s, CH2); 6.92 and 7.33 (2H, two br. s, CONH2); 7.50-7.58 (3H, m, Ph);
13
8.09-8.18 (2H, m, Ph). C NMR spectrum, δ, ppm: 55.4 (CH2); 127.4, 128.5, 129.9, 131.2 (Ph); 165.7 (CN4);
166.8 (CONH2). Found, %: C 53.09; H 4.52; N 34.76. C9H9H5O. Calculated, %: C 53.20; H 4.46; N 34.46.
5-Phenyltetrazol-2-ylpropanoic Acid Amide (3b). Nitrile 2b (10.2 g, 0.05 mol) was added to conc.
H2SO4 (50 ml), stirred until completely dissolved, and the reaction mass was held for 1 day at ~20°C. Then the
mixture was added to water (500 ml) in small portions with stirring. The precipitate formed was filtered out and
recrystallized from 50% ethanol. Obtained 9.6 g (88%) of amide 3b; mp 126-127°C (mp 131-132°C [13] and
1
132°C [12]). H NMR spectrum, δ, ppm, J (Hz): 3.07 (2H, t, J = 6.8, CH2CONH2); 4.97 (2H, t, J = 7.0,
CH2CH2CONH2); 6.44 and 7.03 (2H, two br. s, CONH2); 7.49-7.57 (3H, m, Ph); 8.06-8.16 (2H, m, Ph).
989

13C NMR spectrum, δ, ppm: 34.7 (CH2CONH2); 50.0 (CH2CH2CONH2); 127.3, 128.7, 129.9, 131.1 (Ph); 165.4
(CN4); 171.3 (CONH2). Found, %: C 55.65; H 5.51; N 32.58. C10H11N5O. Calculated, %: C 55.29; H 5.10;
N 32.24.
5-Phenyltetrazol-2-ylbutanoic Acid Amide (3c) was obtained similarly to amide 3b from nitrile 2c.
Yield 67%; mp 148-149°C. 1H NMR spectrum, δ, ppm, J (Hz): 2.26-2.38 (4H, m, CH2CH2CONH2; 4.80 (2H, t,
J = 6.7, CH2CH2CH2CONH2); 6.25 and 6.82 (2H, two br. s, CONH2); 7.50-7.58 (3H, m, Ph); 8.09-8.17 (2H, m,
Ph). 13C NMR spectrum δ, ppm: 25.8 (CH2CONH2); 32.0 (CH2CH2CONH2); 53.3 (CH2CH2CH2CONH2); 127.4,
128.7, 129.9, 131.1 (Ph); 165.5 (CN4); 173.7 (CONH2). Found, %: C 57.38; H 5.39; N 30.48, C11H13N5O.
Calculated, %: C 57.13; H 5.67; N 30.28.
5-Phenyltetrazol-2-ylethanoic Acid (5a). Amide 3a (10.2 g, 0.05 mol) was added to solution of NaOH
(6.0 g, 0.15 mol) in water (50 ml). The mixture obtained was boiled with stirring until the precipitate was
completely dissolved (~3 h), then it was added to water (150 ml) and acidified with HCl to pH ~2. The
precipitate was filtered off and recrystallized from water. Obtained 9.5 g (93%) of acid 5a; mp 184°C
(mp 184-186°C [14] and 186-187°C [15]). 1H NMR spectrum, δ, ppm: 5.75 (2H, s, CH2); 7.50-7.58 (3H, m, Ph);
13
8.11-8.20 (2H, m, Ph); 11.72 (1H, br. s, COOH). C NMR spectrum, δ, ppm: 53.9 (CH2); 127.4, 128.2, 129.9,
131.3 (Ph); 165.8 (CN4); 167.3 (COOH). Found, %: C 53.08; H 4.28; N 27.54. C9H8N4O2. Calculated, %:
C 52.94; H 3.95; N 27.44.
5-Phenyltetrazol-2-ylpropanoic Acid (5b). Nitrile 2b (12.6 g, 0.063 mol) was added to 70% H2SO4
(50 ml). The mixture was stirred for 3 h with heating (85°C) and added to water (500 ml). The precipitate was
filtered off and recrystallized from 50% ethanol. Obtained 7.6 g (55%) of acid 5b; mp 127-128°C (mp 128°C
1
[16] and 128-129°C [14]). H NMR spectrum, δ, ppm, J (Hz): 3.23 (2H, t, J = 6.6, CH2COOH); 5.00 (2H, t,
13
J = 6.6, CH2CH2COOH); 7.50-7.58 (3H, m, Ph); 8.08-8.17 (2H, m, Ph); 11.11 (1H, br. s, COOH). C NMR
spectrum, δ, ppm: 33.2 (CH2COOH); 49.6 (CH2CH2COOH); 127.3, 128.6, 129.9, 131.1 (Ph); 165.4 (CN4);
171.5 (COOH). Found, %: C 55.26; H 4.86; N 25.97. C10H10N4O2. Calculated, %: C 55.04; H 4.62; N 25.68.
5-Phenyltetrazol-2-ylbutanoic Acid (5c). Nitrile 2c (5.9 g, 0.028 mol) was added to solution of NaOH
(3.3 g, 0.084 mol) in water (50 ml). The mixture obtained was heated with stirring for 7 h, then added to water
(400 ml) and acidified with HCl to pH ~2. The precipitate was filtered out and recrystallized from 50% ethanol.
1
Obtained 6.1 g (94%) of acid 5c; mp 86°C (mp 81°C [16]). H NMR spectrum, δ, ppm, J (Hz): 2.34 (2H, q,
J = 6.8, CH2CH2COOH); 2.50 (2H, t, J = 7.1, CH2COOH); 4.84 (2H, t, J = 6.8, CH2CH2CH2CN); 7.50-7.58 (3H,
13
m, Ph); 8.09-8.18 (2H, m, Ph); 10.75 (1H, br. s, COOH). C NMR spectrum, δ, ppm: 25.3 (CH2COOH); 30.7
(CH2CH2COOH); 53.0 (CH2CH2CH2COOH); 127.4, 128.7, 129.9, 131.1 (Ph); 165.6 (CN4); 173.7 (COOH).
Found, %: C 56.50; H 5.64; N 23.93. C11H12N4O2. Calculated, %: C 56.89; H 5.21; N 24.12.
5-Phenyl-2-(tetrazol-5-ylmethyl)tetrazole (6a) was obtained by the procedure [8]; mp 145°C.
1H NMR spectrum, ppm: 6.51 (2H, s, CH2); 7.48-7.56 (3H, m, Ph); 8.06-8.15 (2H, m, Ph); 14.69 (1H, br. s,
CN4H). 13C NMR spectrum, δ, ppm: 47.2 (CH2); 127.4, 127.9, 129.8, 131.4 (Ph); 154.4 (CN4H); 166.1 (PhCN4).
Found, %: C 47.43; H 3.67; N 49.41. C9H8N8. Calculated, %: C 47.37; H 3.53; N 49.10.
1-(5-Phenyltetrazol-2-yl)-2-(tetrazol-5-yl)ethane (6b). Nitrile 2b (10.0 g, 0.05 mol), NaN3 (3.6 g,
0.055 mol), Me2NH2Cl (4.5 g, 0.055 mol), and DMF (70 ml) were stirred for 3 h at 90-95°C. NaCl precipitate
formed was filtered off, DMF was distilled off, the residue was dissolved in water (50 ml) and acidified with
HCl to pH ~2. The precipitate was filtered off and recrystallized from 50% ethanol. Obtained 10.7 g (88%) of
tetrazole 6b; mp 153°C. 1H NMR spectrum, δ, ppm, J (Hz): 3.87 (2H, t, J = 6.8, CH2CN4H); 5.27 (2H, t, J = 6.8,
13
CH2CH2CN4H); 7.49-7.57 (3H, m, Ph); 8.03-8.13 (2H, m, Ph); 15.13 (1H, br. s, CN4H). C NMR spectrum,
δ, ppm: 24.4 (CH2CN4H); 51.3 (CH2CH2CN4H); 127.3, 128.3, 129.8, 131.2 (Ph); 154.6 (CN4H); 165.6 (PhCN4).
Found, %: C 49.05; H 4.29; N 46.55. C10H10N8. Calculated, %: C 49.58; H 4.16; N 46.26.
990

1-(5-Phenyltetrazol-2-yl)-3-(tetrazol-5-yl)propane (6c) was obtained similarly to tetrazole 6b from
1
nitrile 2c (held for 33 h at 110°C). Yield 75%; mp 146°C. H NMR spectrum, δ, ppm, J (Hz): 2.63 (2H, q,
J = 7.1, CH2CH2CN4H); 3.17 (2H, t, J = 7.7, CH2CN4H); 4.93 (2H, t, J = 7.0, CH2CH2CH2CN4H); 7.49-7.57
13
(3H, m, Ph); 8.07-8.16 (2H, m, Ph); 14.97 (1H, br. s, CN4H). C NMR spectrum, δ, ppm: 21.1. (CH2CN4H);
27.5 (CH2CH2CN4H); 52.8 (CH2CH2CH2CN4H); 127.3, 128.5, 129.8, 131.1 (Ph); 156.2 (CN4H); 165.6 (PhCN4).
Found, %: C 51.79; H 4.87; N 43.90. C11H12N8. Calculated, %: C 51.56; H 4.72; N 43.72.
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