Aminolysis of 5-phenyl-2-tetrazolylacetic acid ethyl ester

Article abstract of DOI:10.1023/A:1011909127876

It was shown using 5-phenyl-2-tetrazolylacetic acid ethyl ester as an example that aminolysis is a competitive method of synthesizing primary amides. The efficiency of aminolysis by primary amines is linked to the basicity of the initial amine. Highly bas

Full text of DOI:10.1023/A:1011909127876

Chemistry of Heterocyclic Compounds, Vol. 37, No. 6, 2001
AMINOLYSIS OF 5-PHENYL-
2-TETRAZOLYLACETIC
ACID ETHYL ESTER
S. M. Putis, V. Yu. Zubarev, V. S. Poplavskii, and V. A. Ostrovskii
It was shown using 5-phenyl-2-tetrazolylacetic acid ethyl ester as an example that aminolysis is a
competitive method of synthesizing primary amides. The efficiency of aminolysis by primary amines is
linked to the basicity of the initial amine. Highly basic amines display more high reactivity independent
of the spatial structure of the substituent. Reaction of the investigated ester with secondary amines
occurs ambiguously.
Keywords: 5-phenyl-2-tetrazolylacetamides, 5-phenyl-2-tetrazolylacetic acid ethyl ester,
aminolysis.
The tetrazolylacetic acids are extremely attractive subjects in the chemistry of heterocyclic compounds.
They are considered as block reagents containing a tetrazole ring for the directed synthesis of biologically active
substances [1]. Methods of synthesizing tetrazolylacetic acids have been developed in fair detail [2,3]. The
acid–base properties of the isomeric tetrazolylacetic acids have been studied [4,5] and the electronic influence
of a tetrazole substituent on the acidity of the carboxyl group has been assessed quantitatively.
The amides of tetrazolylacetic acids are distinct and of significant interest as reagents for the directed
synthesis of biologically active compounds. For example, -lactam antibiotics of the cephalosporin series are
β
used widely (cefazolin and its analogs) and are derivatives of tetrazolylacetic acid amides.
There are practically no known methods for the convenient and universal synthesis of tetrazolylacetic
acid amides. Usually the reaction of difficultly accessible tetrazolylacetic acid halides with the appropriate
amine is used for this purpose [6]. We have suggested that aminolysis of tetrazolylacetic acid esters can be used
for this purpose. The reactions of 5-phenyltetrazolylacetic acid ethyl ester with primary and secondary amines
have been considered in the present work to check this hypothesis. Amines used for aminolysis were primary
amines of the simplest structure, ammonia, methylamine, and ethylamine, bifunctional primary amines,
hydrazine and ethylenediamine, and primary amines containing cyclic and frame substituents, cyclohexylamine
and 1-adamantylamine. Secondary amines involved in the aminolysis of 5-phenyl-2-tetrazolylacetic acid ethyl
ester were dimethylamine and diethylamine. The process of aminolysis was carried out in a medium of methanol
with a 1.5 to 10 fold molar excess in relation to tetrazolylacetic acid ester. An excess of ester 1 was taken to
provide efficient aminolysis with ethylenediamine.
__________________________________________________________________________________________
St. Petersburg State Technological Institute (Technical University), Saint Petersburg 198013, Russia;
e-mail: ostrovskii@mail.convey.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 759-762,
June, 2001. Original article submitted November 16, 2000.
698
0009-3122/01/3706-0698$25.00©2001 Plenum Publishing Corporation

TABLE 1. 1H and 13C NMR Spectra of the Amides 2-9 Synthesized
Com-
Chemical shifts of the 1H NMR signals, δ, ppm
Chemical shifts of the 13C NMR signals, δ, ppm
pound
C6H5
N(2)–CH2
NH
other signals
С=O
CN4
C6H5
N(2)–CH2
other signals
7.55-7.85
5.50
8.10
—
166.9
165.0
131.4; 130.1;
127.8; 127.2
55.5
—
2
3
4
5
6
7
7.55-8.08
7.50-8.03
7.50-8.05
7.55-8.05
7.55-8.05
5.45
5.48
5.90
5.50
5.50
9.65
8.45
—
4.80 (2H, s, NH2)
165.1
165.4
165.3
165.4
164.9
164.8
165.0
164.8
164.6
163.8
131.5; 130.1;
54.6
55.6
54.9
55.7
55.7
—
127.7; 127.2
2.68 (3H, s, СН3)
131.4; 130.1;
127.7; 127.2
26.6 (СН3)
2.87 (3H, s, СН3);
3.10 (3H, s, СН3)
131.4; 130.2;
36.8 (СН3);
36.1 (СН3)
127.8; 127.1
8.50
8.40
1.05 (3H, t, СН3);
131.5; 130.2;
127.7; 127.2
34.7 (СН2);
3.15 (2H, q, СН2)
15.3 (СН3)
1.25 (5Н, s, СН2);
1.70 (5Н, s, СН2);
2.47 (1Н, s, СН)
131.4; 130.1;
48.9 (4-СН2);
127.7; 127.2
33.1 (3-СН2);
26.0 (2-CH2); 25.2 (СН)
7.55-7.95
7.50-8.05
5.05
5.50
8.10
8.63
1.55 (6Н, s, СН2);
1.70 (6Н, s, СН2);
2.05 (3Н, s, СН)
167.0
165.3
164.1
165.0
131.0; 130.0;
128.4; 127.0
57.8
55.6
51.3 (Сquat);
8
36.0 (СН in Ad*);
29.2 (СН2 in Ad)
3.25 (4H, s, CON–СН2)
131.5; 130.1;
127.7; 127.2
39.2 (СON–CH2)
9
_______
* Ad = 1-adamantyl.

MeOH
–EtOH
HNR1R2
O
+
O
N
N
N
N
N
N
NR1R2
O
N
N
1
2–9
2 R1 = R2 = H; 3 R1 = H, R2 = NH2; 4 R1 = H, R2 = Me;
5 R1 = R2 = Me; 6 R1 = H, R2 = Et; 7 R1 = H, R2 = cyclo-C6H11;
1
2
8 R = H, R = 1-adamantyl;
N
N
O
N
N
9 R1 = H, R2 =
CH2CH2HN
All the primary amines investigated form the corresponding amide in good yield in the reaction. It is
interesting that the presence of a bulky substituent in the initial primary amine did not in practice inhibit the
aminolysis process. In the case of ethylenediamine, in spite of the significant difference in basicity of the amino
groups, aminolysis leads to the preparation of the disubstitution product.
A completely different picture was observed on aminolysis with certain secondary amines. The
appropriate secondary amide was formed by reaction of ester 1 with dimethylamine. Replacement of
dimethylamine by diethylamine leads to the formation of 5-phenyl-2-tetrazolylacetic acid methyl ester and
products of its further conversion.
It may be assumed that the aminolysis conditions proposed by us can be used for the synthesis of
primary amides of tetrazoleacetic acid of various structure. Other methods may turn out to be preferable for
secondary amides.
EXPERIMENTAL
1
The H and 13C NMR spectra of the compounds synthesized were recorded on a Bruker DPX 300
instrument in DMSO-d6 (300 MHz for 1H and 75 MHz for 13C), internal standard was TMS. The IR spectra were
obtained on a Perkin–Elmer Spectrum 1000 instrument in KBr disks. Melting points were determined on a type
PTP instrument with a heating rate of 1°/min in the melting range. A check on the progress of reactions was
effected by TLC on Merck Kieselgel 60F254 plates with visualization of spots in UV light. The initial substrate 1
was obtained by the procedure of [7].
General Procedure for Obtaining Amides 2-9. A methanolic or aqueous solution of amine was added
to a solution of substrate 1 (4.31 mmol) in methanol (40 ml) at 0-2°C. Amide numbers (molar ratio
amine : ester 1) are 2 (10), 3 (10), 4 (10), 5 (9), 6 (9.5), 7 (10), 8 (2), and 9 (0.3). At the end of the reaction
(check by TLC) the reaction solution was processed by procedure A or B. A. The precipitated solid was filtered
off and washed with distilled water (3 × 20 ml). B. The solvent was evaporated in vacuum, and the residue was
recrystallized from aqueous ethanol.
5-Phenyl-2-tetrazolylacetic Acid Amide (2). Amide 2 (0.5 g, 57%) of mp 185-186°C was obtained by
crystallization from 30% aqueous alcohol (A), Rf 0.17 (CHCl3–MeOH, 95 : 5). IR spectrum, , cm-1: 1405, 1270,
ν
1172, 1100 (tetrazole), 1448, 730 (C6H5), 1670 (C=O), 3314 (N–H), 2950, 1425 (CH2), 1373, 1072, 1047 (C–N).
Found, %: C 52.93; H 4.66; N 34.64. C9H9N5O. Calculated, %: C 53.20; H 4.46; N 34.47.
5-Phenyl-2-tetrazolylacetic Acid Hydrazide (3). Hydrazide 3 (0.91 g, 93%) of mp 207-208°C was
obtained by crystallization from 10% aqueous ethanol (A), Rf 0.15 (CHCl3–MeOH, 95 : 5). IR spectrum, , cm-1:
ν
1411, 1285, 1177, 1100 (tetrazole), 1448, 730 (C6H5), 1661 (C=O), 3314, 1551, 1529 (N–H), 2966, 2880 (CH2),
1379, 1072 1023, (C–N). Found, %: C 49.12; H 4.78; N 38.73. C9H10N6O. Calculated, %: C 49.54; H 4.62; N 38.51.
700

5-Phenyl-2-tetrazolylacetic Acid N-Methylamide (4). Amide 4 (0.36 g, 37%) of mp 163-164°C was
obtained by crystallization from 20% aqueous ethanol (A), Rf 0.35 (CHCl3–MeOH, 95 : 5). IR spectrum, , cm-1:
ν
1404,1278, 1163, 1101 (tetrazole), 1449, 731 (C6H5), 1660 (C=O), 3303, 1578, 1528 (N–H), 2964, 2888 (CH2),
1388, 1073, 1025 (C–N). Found, %: C 55.65; H 5.57; N 32.26. C10H11N5O. Calculated, %: C 55.29; H 5.10;
N 32.24.
5-Phenyl-2-tetrazolylacetic Acid N,N-Dimethylamide (5). Amide 5 (0.65 g, 65%) of mp 133-134°C
was obtained by crystallization from 10% aqueous ethanol (B), Rf 0.36 (CHCl3–MeOH, 95 : 5). IR spectrum,
, cm-1: 1401, 1283, 1180, 1130 (tetrazole), 1451, 735 (C6H5), 1662 (C=O), 2969, 2933 (CH2), 1378, 1071, 1029
ν
(C–N). Found, %: C 56.95; H 5.97; N 30.06. C11H13N5O. Calculated, %: C 57.13; H 5.67; N 30.28.
5-Phenyl-2-tetrazolylacetic Acid N-Ethylamide (6). Amide 6 (0.86 g, 86%) of mp 151-152°C was
obtained by crystallization from 25% aqueous ethanol (A), Rf 0.45 (CHCl3–MeOH, 95 : 5). IR spectrum, , cm-1:
ν
1406, 1277, 1173, 1102 (tetrazole), 1447, 729 (C6H5), 1660 (C=O), 3287, 1560, 1527 (N–H), 2954, 2882 (CH2),
1381, 1070, 1022 (C–N). Found, %: C 57.69; H 6.01; N 30.67. C11H13N5O. Calculated, %: C 57.13; H 5.67;
N 30.28.
5-Phenyl-2-tetrazolylacetic Acid N-Cyclohexylamide (7). Amide 7 (0.71 g, 58%) of mp 173-174°C
was obtained by crystallization from 50% aqueous ethanol (B), Rf 0.62 (CHCl3–MeOH, 95 : 5). IR spectrum,
, cm-1: 1421, 1279, 1171, 1091 (tetrazole), 1447, 728 (C6H5), 1654 (C=O), 3291, 1556, 1528 (N–H), 2938,
ν
2851 (CH2), 1371, 1072, 1024 (C–N). Found, %: C 63.64; H 6.72; N 24.97. C15H19N5O. Calculated, %: C 63.14;
H 6.71; N 24.54.
5-Phenyl-2-tetrazolylacetic Acid N-1-Adamantylamide (8). Amide 8 (0.91 g, 54%) of mp 263-264°C
was obtained by crystallization from 20% aqueous ethanol (B), Rf 0.15 (CHCl3–MeOH, 9 : 1). IR spectrum,
, cm-1: 1418, 1279, 1177, 1110 (tetrazole), 1452, 730 (C6H5), 1632 (C=O), 1562, 1529 (N–H), 3006, 2935,
ν
2912, 2853 (CH2 and CH), 1073, 1026 (C–N). Found, %: C 66.98; H 6.83; N 20.23. C19H23N50. Calculated, %:
C 67.63; H 6.87; N 20.76.
N,N'-Bis(5-phenyl-2-tetrazolylmethylcarbonyl)-1,2-diaminoethane (9). Amide 9 (0.83 g, 44%) of
mp 255-256°C was obtained by crystallization from 40% aqueous ethanol (A), Rf 0.55 (CHCl3–MeOH, 9 : 1). IR
spectrum, , cm-1: 1415, 1284, 1194, 1104 (tetrazole), 1449, 728 (C6H5), 1664 (C=O), 3296, 1576, 1528 (N–H),
ν
2953, 2875 (CH2), 1364, 1072, 1027 (C–N). Found, %: C 55.77; H 4.44; N 32.61. C20H20N10O2. Calculated, %:
C 55.55; H 4.66; N 32.39.
The work was carried out with the financial support of the International Scientific Fund (grant r99-468)
and the Fund for the Administration of St. Petersburg (grants M2000-2.5D-572 and M2000-2.5P-573).
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