Efficient synthesis of 1-substituted-4-phenyl-1,4-dihydro-5H-tetrazole-5- thione and (1-Phenyl-1H-tetrazol-5-yl)thioacetyl derivatives

Article abstract of DOI:10.1002/hc.20353

A new and convenient synthesis of a variety of N- and S-substituted tetrazoles has been developed via azide and Mannich reaction methods. Compounds were characterized by elemental analysis, MALDI MS, and ¹H NMR data.

Full text of DOI:10.1002/hc.20353

Heteroatom Chemistry
Volume 18, Number 6, 2007
Efficient Synthesis of 1-Substituted-4-
phenyl-1, 4-dihydro-5H-tetrazole-5-thione
and (1-Phenyl-1H-tetrazol-5-yl)thioacetyl
Derivatives
Walid Fathalla1 and Ibrahim A. I. Ali2
1Department of Mathematical and Physical Sciences, Faculty of Engineering,
Suez Canal University, Port Said, Egypt
2Department of Chemistry, Faculty of Science, Suez Canal University, Ismailia, Egypt
Received 19 March 2006; revised 31 August 2006
inhibit prostoglandin synthesis and have significant
ABSTRACT: A new and convenient synthesis of
analgesic and anti-inflammatory activities [8–10].
a variety of N- and S-substituted tetrazoles has
been developed via azide and Mannich reaction
methods. Compounds were characterized by ele-
mental analysis, MALDI MS, and 1H NMR data.
ꢀ
C
2007 Wiley Periodicals, Inc. Heteroatom Chem 18:637–
643, 2007; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20353
INTRODUCTION
Substituted tetrazoles [1,2] are well known as an ex-
cellent nonclassical carboxylic acid bioisosteres in
biological molecules [3,4]. Recently, X-ray crystal
RESULTS AND DISCUSSION
In this study, we report an efficient synthesis of a
series of tetrazoles containing a variety of functional
methyl amino and acetamide moieties at positions 1
and 5, respectively, as represented in Schemes 1–3,
structure revealed that the tetrazolate moiety of sev-
eral nonpeptide antagonists was proved to form a
hydrogen bond with protonated lysine and histidine
at the active site of the angiotensin II receptor [3,5,6].
Waisser et al. [7] reported that substituted benzyl
sulfanyl group enhances the antimycobacterial ac-
tivity of 1-aryl-5-alkylsulfanyltetrazoles. Tiaramide I
and other benzothiazolone acetamides are shown to
for
a significant structure–activity relationship
study.
Our synthetic strategy is dependent on the
regioselective reactions of thioamides, which gives
S- and N-substituted derivatives [11–13]. Thus,
the reaction of 1 molar equivalent of the selected
1-phenyl-4,5-dihydro-1H-1,2,3,4-tetrazole-5-thione
(1) with 1 molar equivalent of secondary amines and
excess formaldehyde regioselectively gives a reason-
able amount of N-methyl amino tetrazole 2a–c. The
Correspondence to: Walid Fathalla; e-mail: walid399@yahoo.
com.
Present Address: 4-Suez Canal Authority street, P.O. box 41112,
Ismailia, Egypt.
c
ꢀ
2007 Wiley Periodicals, Inc.
637

638 Fathalla and Ali
N-substitution is due to strong Coulumbic attraction
between the hard part of the ambident nucleophile
and the electrophile [12]. However, treatment of
2 molar equivalents of tetrazole 1 with 1 molar
equivalent of piperazine and excess formaldehyde,
under the same reaction conditions, afforded bis
methyl amino piperazine 3.
S-alkylation reaction was favored because of an in-
teraction between the HOMO of the nucleophile and
the LUMO of the electrophile to produce the S-
attack [13]. Hydrazinolysis of 4 afforded hydrazide
5, which was subsequently converted into azide 6 by
treatment with NaNO2 and HCl mixture (Scheme 1).
The in situ generated azide 6 solution extracted
with ethyl acetate was used without isolation and
purification. One molar equivalent of the amine was
treated with 1 molar equivalent of the in situ gener-
ated ethyl acetate solution of azide 6 at −5◦C. A vari-
ety of S-substituted acetamides of tetrazoles 7a–c,
9, and 10a,b were obtained in moderate to good
yields. However, employing 1 molar equivalent of
the amine (piperazine and 1,6-diamino hexane) with
2 molar equivalents of the intermediate azide pro-
duced bistetrazoles derivatives 8 and 11, respectively
(Scheme 2). The long-chain derivatives 9–11 were
designed to increase the lipophilicity of the tetrazole
moiety, which is an important factor when design-
ing a drug molecule able to pass through the cell
membrane.
The elemental analysis together with MALDI MS
of both structures 2a–c and 3 agreed with the molec-
ular formula of these compounds. The MALDI of
1
2a gave 300.3 corresponding to (M + Na)+. The H
NMR spectra were used as a major tool in identifying
1
the N-substitution. Thus, H NMR spectra showed
a singlet at 5.33 ppm, characteristic for NCH2N,
and other peaks from secondary amine and tetrazole
moieties are also clearly shown in the Experimental
section.
The azide derivative 6 was proved to be highly
versatile intermediate, forming a variety of ace-
tamides. This extensive structure modification of the
selected tetrazole molecules 1 could affect the bio-
logical activity. The synthesis of tetrazole acetamides
via azide-coupling method is shown in Schemes 1–3.
The reaction of 1-phenyl-4,5-dihydro-1H-1,2,3,4-
tetraazole-5-thione (1) with chloroethyl acetate in
the presence of K2CO3 furnished the regioselective
S-alkylation reaction product 4 [13,14]. The expected
1
The H NMR spectra of the S-acylated deriva-
tives showed a singlet, typically associated with a
SCH2CO group appeared at 4.50 ppm for short-chain
derivatives 9, 7a–c, 8 and 4.06 ppm for long-chain
substituents 10a,b, and 11. The structure of hydroxy
SCHEME 1 Reagents and conditions: (i) CH2O, secondary amine, ethanol, 25◦C, 2 h; (ii) CH2O, piperazine, ethanol, 25◦C,
2 h; (iii) ClCH2COOC2H5, Et3N, EtOH, 85◦C, 6 h; (iv) NH2NH2·H2O, EtOH, 85◦C, 3 h; and (v) NaNO2, HCl, −5◦C, 30 min.
Heteroatom Chemistry DOI 10.1002/hc

Efficient Synthesis of N- and S-Substituted Tetrazoles 639
SCHEME 2 Reagents and conditions: (i) secondary amine, ethyl acetate, 25◦C, 24 h; (ii) piperazine, ethyl acetate, 25◦C,
24 h; (iii) 1-propanol amine, ethyl acetate, 25◦C, 24 h; (iv) 1,6-diamino hexane or 1-hexanol amine, ethyl acetate, 25◦C, 24 h;
(v) 1,6-diamino hexane, ethyl acetate, 25◦C, 24 h.
derivatives 9 and 10a was confirmed by measuring
the 1H NMR spectrum in CDCl3 and CDCl3/D2O. The
1H NMR spectrum of 9 in CDCl3 showed a quartet
at 3.42 ppm, while giving a triplet at 3.42 ppm in
CDCl3/D2O characteristic for NHCH2CH2. Further-
more, an exchangeable hydroxyl group appeared at
2.83 ppm. The structure of the bis derivatives 8 and
11 was simply deduced by comparing the inten-
sity of bi-nucleophilic amine residue to a tetrazole
thioacetyl moiety.
[17]. HOBt is widely used as an additive to decrease
racemization in the carbodiimide peptide coupling.
Our choice was azide coupling following Sahin et
al.’s method [18–20], which was reported to mini-
mize the degree of racemization in amino acid cou-
pling. Thus, azide 6 reacts with amino acid methyl
ester. HCl (Gly, Ala, Val, Leu, Meth) in the pres-
ence of Et3N afforded peptides 12a–e in good yield.
Hydrazinolysis of 12a,b afforded hydrazides 13a,b
(Scheme 3).
In addition, our next target was the elonga-
tion of the side chain at the thioacetyl group by
coupling with amino acid. It was designed to in-
crease the binding affinity of tetrazole moiety by
interacting with the receptor recognition sites. Sev-
eral coupling reagents were employed in the liter-
ature to introduce peptide bonds by the reaction
of acid derivatives with amino acid methyl ester.
Among those were 1-hydroxy-benzotriazole (HOBt)
[15,16] and N,N-dicyclohexylcarbodiimide (DCC)
The structure assignments of the amino acid
derivatives 12a–e were based on elemental analy-
sis, MALDI, and 1H NMR spectra. The MALDI spec-
tra of 12b gave 330.5 corresponding to (M + Na)+.
Significantly, S-alkylation site (SCH2CO group)
was indicated as a singlet in the 1H NMR spec-
trum at 4.03 ppm for all amino acid derivatives
12a–e. The 1H NMR spectrum of methyl N-{[(1-
phenyl-1H-tetrazol-5-yl)thio]acetyl}alaninate (12b)
displayed multiplet resonance at δ 4.62–4.47 ppm
Heteroatom Chemistry DOI 10.1002/hc

640 Fathalla and Ali
SCHEME 3 (i) amino acid methyl ester hydrochloride, Et3N, ethyl acetate, 25◦C, 24 h; (ii) NH2NH2·H2O, EtOH, 85◦C, 3 h;
(iii) NaNO2, HCl, −5◦C, 30 min; (iv) glycine methyl ester hydrochloride, Et3N, ethyl acetate, 25◦C, 24 h.
characteristic for NHCH group, whereas a broad sig-
nal was observed at 7.48 ppm for a NH group. Addi-
tional evidence for the structure of glycine acetamide
derivative 12a was the dipeptide 14 formation via the
azide-coupling method as described above.
The starting compounds 1, 5 were prepared ac-
cording to the method described by Waisser et al.
[14].
Mannich Reaction
General Procedure. To the suspension of tetra-
zole 1 (1.78 g, 0.01 mol) in ethyl alcohol (30 mL,
absolute), formaldehyde (30%, 0.9 mL, 0.03 mol),
and the desired secondary amine (0.01 mol) were
added dropwise with stirring. The reaction mixture
was further stirred for 1–2 h at room temperature
and was concentrated under reduced pressure and
cooled. The solid obtained was filtered and crystal-
lized from ethyl alcohol.
CONCLUSION
In summary, we describe a simple, convenient, and
practical method for the extensive modification of
the structure of the selected 1-phenyl-4,5-dihydro-
1H-1,2,3,4-tetrazole-5-thione (1) regioselectively at
positions 1 and 5 via the azide-coupling method and
the Mannich reaction, respectively, with lipophilic
amines, secondary amines, and amino acids.
1-(Morpholin-4-yl-methyl)-4-phenyl-1,4-dihydro-
5H-tetrazole-5-thione (2a). (Amine = morpholine),
white powder (2.1 g, 76%), mp 154◦C. 1H NMR
(CDCl3): δ = 8.03–7.91 (m, 2H, Ar-H), 7.66–7.47 (m,
3H, Ar-H), 5.33 (s, 2H, CH2), 3.71 (t, 4H, J = 4.94
Hz, 2OCH2), 2.89 (t, 4H, J = 4.94 Hz, 2NCH2),
(MALDI, positive mode, matrix: DHB): m/z = 300.3
(M + Na)+. C12H15N5OS (277.3): C, 51.97; H, 5.45; N,
25.25; S, 11.56. Found: C, 51.76; H, 5.24; N, 25.12;
S, 11.43.
EXPERIMENTAL
Solvents were purified and dried in the usual way.
The boiling range of the petroleum ether used was
35–65◦C. Thin layer chromatography (TLC): silica
gel 60 F254 plastic plates (E. Merck, layer thickness
0.2 mm) detected by UV absorption. Melting points
were determined on a Bu¨chi 510 melting-point ap-
paratus, and the values are uncorrected. NMR spec-
tra were measured with Bruker AC 250 (250 MHz).
TMS (0.00 ppm) or the signal of the deuterated sol-
vent was used as internal standard. FAB-MS mod-
ified Finningan MAT 312/ AMD 5000 spectrome-
ter was used at 790 eV and T = 70 MALDI-MS, the
mass spectra were measured with a KRATOS Ana-
lytical Kompact spectrometer. Microanalyses were
performed at the Microanalytical Center, Chemistry
Department, Konstanz University, Germany.
1-Phenyl-4-(piperidin-1-yl-methyl)-1,4-dihydro-
5H-tetrazole-5-thione (2b). (Amine = piperidine),
white powder (1.8 g, 66%), mp 112◦C. 1H NMR
(CDCl3): δ = 8.01–7.84 (m, 2H, Ar-H), 7.65–7.44 (m,
3H, Ar-H), 5.32 (s, 2H, CH2), 2.78 (t, 4H, J= 5.1 Hz,
2NCH2), 1.69–1.54 (m, 4H, 2CH2), 1.47–1.32 (m, 2H,
CH2). (MALDI, positive mode, matrix: DHB): m/z =
298.4 (M + Na)+. C13H17N5S (275.4): C, 56.70; H,
Heteroatom Chemistry DOI 10.1002/hc

Efficient Synthesis of N- and S-Substituted Tetrazoles 641
6.22; N, 25.43; S, 11.64. Found: C, 56.64; H, 6.21; N,
25.33; S, 11.52.
δ = 8.23 (bs, 2H, NH2) 7.68–7.45 (m, 5H, Ar-H),
3.98 (s, 2H, SCH2); (MALDI, positive mode, matrix:
DHB): m/z = 273.3 (M + Na)+. C9H10N6OS (250.3):
C, 43.19; H, 4.03; N, 33.58; S, 12.81. Found: C, 43.12;
H, 3.84; N, 33.18; S, 12.69.
1-[(4-Methylpiperazin-1-yl)methyl]-4-phenyl-1,4-
dihydro-5H-tetrazole-5-thione (2c). (Amine = N-
methyl piperazine), white powder (2.5 g, 86%),
mp 139◦C. 1H NMR (CDCl3): δ = 8.01–7.86 (m,
2H, Ar-H), 7.62–7.35 (m, 3H, Ar-H), 5.33 (s, 2H,
CH2), 3.29–3.12 (m, 8H, 4CH2), 2.87 (s, 3H, CH3).
(MALDI, positive mode, matrix: DHB): m/z = 313.4
(M + Na)+. C13H18N6S (290.4): C, 53.77; H, 6.25; N,
28.94; S, 11.04. Found: C, 53.75; H, 6.24; N, 28.91;
S, 11.04.
[(1-Phenyl-1H-tetrazol-5-yl)thio] Acetyl Azide (6).
To a cold solution (∼ −5◦C) of hydrazide 5 (2.50 g,
0.01 mmol) in 1 N HCl solution (20 mL) and acetic
acid 96% (3 mL), 5 mL water solution of NaNO2
(1.38 g, 0.02 mmol) was added. The reaction mixture
was stirred at 0◦C for 30 min. The reaction mixture
was extracted three times with 30 mL ethyl acetate.
The combined yellow syrup extract was washed sev-
eral times with 3% solution of NaHCO3 and water till
it became neutral and was finally dried over Na2SO4.
The in situ generated azide 6 was used without fur-
ther isolation and purification.
1,1ꢁ -[Piperazine-1,4-diyl-bis-(methylene)]-bis-(4-
phenyl-1,4-dihydro-5H-tetrazole-5-thione)
(3). To
the suspension of tetrazole 1 (1.78 g, 0.01 mol) in
absolute ethyl alcohol (30 mL), formaldehyde (30%,
0.9 mL, 0.03 mol) and the desired secondary amine
(0.005 mol) were added dropwise with stirring. The
reaction mixture was further stirred for 2 h at room
temperature, concentrated under reduced pressure,
and cooled. The solid obtained was filtered and
crystallized from ethyl alcohol. White powder (3.1 g,
4-{[(1-Phenyl-1H-tetrazol-5-ptyl)thio]} Acetamide
Derivatives
General Procedure. To the previously prepared
cold ethyl acetate solution of azide 6 (from 0.01 mol
hydrazide), a solution of appropriate amines (0.01
mol) in ethyl acetate (20 mL) was added dropwise
with stirring. The reaction mixture was kept at −5◦C
for 12 h, then at room temperature for another 12 h.
The reaction mixture was washed with 0.5 N HCl,
water and 3% solution of NaHCO3 and dried over
Na2SO4. The solution was evaporated to dryness,
and the residue was recrystallized from ethyl ac-
etate/petroleum ether to give the desired product.
1
67%), mp 187◦C. H NMR (CDCl3): δ = 7.96–7.84
(m, 4H, Ar-H), 7.61–7.42 (m, 6H, Ar-H), 5.28 (s, 4H,
2CH2), 2.88 (s, 8H, 4CH2). (MALDI, positive mode,
matrix: DHB): m/z = 489.6 (M + Na)+. C20H22N10S2
(466.6): C, 51.48; H, 4.75; N, 30.02; S, 13.74. Found:
C, 51.46; H, 4.69; N, 29.99; S, 13.73.
Ethyl[(1-phenyl-1H-tetrazol-5-yl)thio] Acetate (4).
To a mixture of tetrazole 1 (1.78 g, 0.01 mol) and
K2CO3 (1.38 g, 0.01 mol) in dry acetone (30 mL),
ethyl chloroacetate (1.1 mL, 0.01 mol) was added.
The reaction mixture was heated under reflux for
6 h, filtered, then concentrated under reduced pres-
sure. The solid obtained was filtered and recrystal-
lized from ethyl alcohol. White powder (2.3 g, 88%),
4-{[(1-Phenyl-1H-tetrazol-5-yl)thio]acetyl} Mor-
pholine (7a). (Amine = morpholine), white powder
1
(2.8 g, 92%), mp 138◦C. H NMR (CDCl3): δ = 7.67–
7.52 (m, 5H, Ar-H), 4.49 (s, 2H, SCH2), 3.79–3.55
(m, 8H, 4CH2). (MALDI, positive mode, matrix:
DHB): m/z = 328.3 (M + Na)+. C13H15N5O2S (305.4):
C, 51.13; H, 4.95; N, 22.94; S, 10.50. Found: C, 51.12;
H, 4.95; N, 22.87; S, 10.49.
1
mp 113◦C. H NMR (CDCl3): δ = 7.66–7.47 (m, 5H,
Ar-H), 4.31 (q, 2H, J = 6.9 Hz, OCH2), 4.26 (s, 2H,
SCH2), 1.29 (t, 3H, J = 7.1 Hz, CH3); (MALDI, pos-
itive mode, matrix: DHB): m/z = 287.3 (M + Na)+.
C11H12N4O2S (264.3): C, 49.99; H, 4.58; N, 21.20; S,
12.13. Found: C, 49.63; H, 4.37; N, 21.11; S, 11.94.
1-{[(1-Phenyl-1H-tetrazol-5-yl)thio]acetyl} Piperi-
dine (7b). (Amine = piperidine), white powder
1
(2.4 g, 79%), mp 73◦C. H NMR (CDCl3): δ = 7.67–
2-[(1-Phenyl-1H-tetrazol-5-yl)-thio]Acetohydrazide
(5) [14]. To a solution of the ester derivatives 4
(1.78 g, 0.01mol) in absolute ethyl alcohol (30 mL),
hydrazine hydrate (0.74 mL, 0.015 mol) was added
and the reaction mixture was heated under reflux for
3 h. The reaction mixture was cooled and evaporated
under reduced pressure till dried. The precipitated
residue was crystallized from ethyl alcohol. White
7.48 (m, 5H, Ar-H), 4.53 (s, 2H, SCH2), 3.68–3.46 (m,
4H, 2NCH2), 1.86–1.57 (m, 6H, 3CH2). (MALDI, pos-
itive mode, matrix: DHB): m/z = 326.4 (M + Na)+.
C14H17N5OS (303.4): C, 55.42; H, 5.65; N, 23.08; S,
10.57. Found: C, 55.41; H, 5.64; N, 23.08; S, 10.55.
1-Methyl-4-{[(1-phenyl-1H-tetrazol-5-yl)thio]
acetyl} Piperazine (7c). (Amine = N-methyl piper-
1
1
crystal (2.1 g, 69%), mp 164◦C. H NMR (CDCl3):
azine), white powder (2.2 g, 73%), mp 112◦C. H
Heteroatom Chemistry DOI 10.1002/hc

642 Fathalla and Ali
NMR (CDCl3): δ = 7.65–7.52 (m, 5H, Ar-H), 4.51
(s, 2H, CH2), 3.74–3.61 (m, 4H, 2NCH2), 2.51 (t,
2H, J = 4.94 Hz, CH2NCH3), 2.48 (t, 2H, J= 4.94
Hz, CH2NCH3), 2.34 (s, 3H, CH3) (MALDI, posi-
tive mode, matrix: DHB): m/z = 341.4 (M + Na)+.
C14H18N6OS (318.4): C, 52.81; H, 5.70; N, 26.39; S,
10.07. Found: C, 52.69; H, 5.63; N, 26.29; S, 10.01.
other 12 h. The reaction mixture was washed with
0.5 N HCl, water, and 3% solution of NaHCO3 and
dried over Na2SO4. The solution was evaporated to
dryness, and the residue was recrystallized by ethyl
acetate/petroleum ether to give the desired product.
1,4-Bis{[(1-phenyl-1H-tetrazol-5-yl)thio]acetyl}
piperazine (8). (Amine = piperazine), white pow-
1
N-(3-Hydroxypropyl)-2-[(1-phenyl-1H-tetrazol-5-
yl)thio] Acetamide (9). (1,3-Amino propanol), white
powder (1.9 g, 65%), mp 74◦C. 1H NMR (CDCl3): δ =
7.62–7.49 (m, 5H, Ar-H), 4.06 (s, 2H, SCH2), 3.76 (t,
1H, J = 7.1 Hz, NH), 3.64 (t, 2H, J = 7.1 Hz, OCH2),
3.42 (q, 2H, J = 7.1 Hz, NCH2), 2.82 (bs, 1H, OH),
1.78–1.66 (m, 2H, CH2), CDCl3/D2O, δ = 7.62–7.51
(m, 5H, Ar-H), 4.06 (s, 2H, SCH2), 3.64 (t, 2H,
J = 7.1 Hz, OCH2), 3.42 (t, 2H, J = 7.1 Hz, NCH2),
1.78–1.66 (m, 2H, CH2) (MALDI, positive mode,
matrix: DHB): m/z = 316.3 (M + Na)+. C12H15N5O2S
(293.3): C, 49.13; H, 5.15; N, 23.87; S, 10.93. Found:
C, C, 49.05; H, 5.12; N, 23.52; S, 10.79.
der (3.3 g, 63%), mp 95◦C. H NMR (CDCl3): δ =
7.65–7.52 (m, 10H, Ar-H), 4.48 (s, 4H, 2CH2), 3.92–
3.81 (m, 4H, 2NCH2), 3.75–3.63 (m, 4H, 2NCH2).
(MALDI, positive mode, matrix: DHB): m/z = 545.6
(M + Na)+. C22H22N10O2S2 (522.6): C, 50.56; H, 4.24;
N, 26.80; S, 12.27. Found: C, 50.49 H, 4.21; N, 26.77;
S, 12.14.
N,Nꢁ -(Iminodihexane-6,1-diyl)bis{2-[(1-phenyl-
1H-tetrazol-5-yl)thio]acetamide} (11). (Amine
=
1,6-hexandiamine), white powder (2.8 g, 51%),
mp 145◦C. 1H NMR (CDCl3): δ = 7.63–7.49 (m,
8H, Ar-H), 7.28–7.12 (m, 3H, Ar-H, NH), 3.95
(s, 4H, 2SCH2), 3.26 (q, 4H, J = 7.0 Hz, 2NCH2),
1.59–1.43 (m, 8H, 2CH2), 1.38–1.20 (m, 8H, 2CH2),
(MALDI, positive mode, matrix: DHB): m/z = 575.7
(M + Na)+. C24H28N10O2S2(552.7): C, 52.16; H, 5.11;
N, 25.34; S, 11.60. Found: 52.13; H, 5.09; N, 25.28;
S, 11.59.
N-(6-Hydroxyhexyl)-2-[(1-phenyl-1H-tetrazol-5-yl)
thio] Acetamide (10a). (1,6-Aminohexanol), white
powder (2.8 g, 84%), mp 216◦C. CDCl3: δ = 7.59–7.48
(m, 5H, Ar-H), 7.18 (bs, 1H, NH), 4.04 (s, 2H, SCH2),
3.59 (t, 2H, J = 7.0 Hz, OCH2), 3.27 (q, 2H, J = 7.1
Hz, NCH2), 2.33 (bs, 1H, OH), 1.62–1.26 (m, 8H,
4CH2). CDCl3/D2O δ = 7.59–7.48 (m, 5H, Ar-H), 4.04
(s, 2H, SCH2), 3.59 (t, 2H, J = 7.1 Hz, OCH2), 3.27
(t, 2H, J = 7.1 Hz, NCH2), 1.78–1.66 (m, 2H, CH2),
(MALDI, positive mode, matrix: DHB): m/z = 358.4
(M + Na)+. C15H21N5O2S (335.4): C, 53.71; H, 6.31;
N, 20.88; S, 9.56. Found: C, 53.66; H, 6.31; N, 20.79;
S, 9.54.
Methyl N-{[(1-phenyl-1H-tetrazol-5-yl) thio]
acetyl} Amino Ester
General Procedure. To a recently generated
azide solution 6 in ethyl acetate (from 0.01 mol
hydrazide), appropriate amino ester hydrochloride
(0.01 mol) and triethyl amine (1 mL, 0.01 mol) was
added. The reaction mixture was kept at −5◦C for
12 h, and then at room temperature for another 12 h.
The reaction mixture was washed with 0.5 N HCl,
water, and 3% solution of NaHCO3 and dried over
Na2SO4. The solution was evaporated to dryness,
and the residue was recrystallized by ethyl acetate–
petroleum ether to give the desired product.
N-(6-Aminohexyl)-2-[(1-phenyl-1H-tetrazol-5-yl)
thio] Acetamide (10b). (1,6-Aminohexane), white
1
powder (2.3 g, 69%), mp 105◦C. H NMR (CDCl3):
δ = 7.63–7.52 (m, 5H, Ar-H), 7.16 (bs, 1H, NH),
3.92 (s, 2H, SCH2), 3.27 (q, 2H, J = 7.1 Hz, NCH2),
1.58–1.29 (m, 10H, 5CH2), (MALDI, positive mode,
matrix: DHB): m/z = 357.4. (M + Na)+. C15H22N6OS
(334.4): C, 53.87; H, 6.63; N, 25.13; S, 9.59. Found:
C, 53.81; H, 6.63; N, 25.06; S, 9.58.
Methyl N-{[(1-phenyl-1H-tetrazol-5-yl)thio]acetyl}
Glycinate (12a). (Amino acid = glycine), white pow-
1
der (2.3 g, 68%), mp 87◦C. H NMR (CDCl3): δ =
7.63–7.43 (m, 6H, Ar-H, NH), 4.08 (s, 2H, SCH2),
4.03 (s, 2H, NHCH2), 3.72 (s, 3H, OCH3), (MALDI,
positive mode, matrix: DHB): m/z = 330.3 (M + Na)+.
C12H13N5O3S (307.3): C, 46.90; H, 4.26; N, 22.79; S,
10.43. Found: C, 46.89; H, 4.24; N, 22.78; S, 10.41.
N,Nꢁ-(Alkyldiamino)bis{2-[(1-phenyl-1H-tetrazol-
5-yl)thio]acetamide}
General Procedure. To a recently generated
azide solution 6 in ethyl acetate (from 0.01 mol
hydrazide), a solution of the appropriate diamine
(0.005 mol) in ethyl acetate (20 mL) was added drop-
wise with stirring. The reaction mixture was kept at
−5◦C for 12 h, then at room temperature for an-
Methyl N-{[(1-phenyl-1H-tetrazol-5-yl)thio]acetyl}
Alaninate (12b). (Amino acid = L-alanine), white
1
powder (2.5 g, 78%), mp 67◦C. H NMR (CDCl3):
Heteroatom Chemistry DOI 10.1002/hc

Efficient Synthesis of N- and S-Substituted Tetrazoles 643
δ = 7.58–7.53 (m, 5H, Ar-H), 7.48 (bs, 1H, NH), 4.62–
4.47 (m, 1H, CHCH3), 4.03 (s, 2H, SCH2), 3.71 (s, 3H,
OCH3), 1.42 (d, 3H, J = 12.0 Hz, CHCH3), (MALDI,
positive mode, matrix: DHB): m/z = 344.3 (M + Na)+.
C13H15N5O3S (321.4): C, 48.59; H, 4.70 N, 21.79; S,
9.98. Found: C, 48.56; H, 4.68 N, 21.73; S, 9.90.
NHCH), 3.49 (bs, 2H, NH2), 1.29–1.16. (m, 3H,
CHCH3), (MALDI, positive mode, matrix: DHB): m/z
= 344.4 (M + Na)+. C12H15N7O2S (321.4): C, 44.85;
H, 4.70 N, 30.51; S, 9.98. Found: C, 44.61; H, 4.63 N,
30.49; S, 9.87.
Methyl N-{[(1-phenyl-1H-tetrazol-5-yl)thio]acetyl}
Glycylglycinate (14). White powder (2.7 g, 74%), mp
150◦C. 1H NMR (CDCl3): δ = 7.70 (bs, 1H, NH), 7.58–
7.53 (m, 5H, Ar-H), 7.33 (bs, 1H, NH), 4.14–4.08 (m,
4H, 2NHCH2), 4.01 (s, 2H, SCH2), 3.71 (s, 3H, OCH3),
(MALDI, positive mode, matrix: DHB): m/z = 387.4
(M + Na)+. C14H16N6O4S (364.4): C, 46.15; H, 4.43 N,
23.06; S, 8.80. Found: C, 46.13; H, 4.37 N, 23.04; S,
8.78.
Methyl N-{[(1-phenyl-1H-tetrazol-5-yl)thio]acetyl}
Valinate (12c). (Amino acid = L-valine), white pow-
1
der (1.9 g, 55%), mp 59◦C. H NMR (CDCl3): δ =
7.63–7.58 (m, 5H, Ar-H), 7.50 (bs, 1H, NH), 4.59–
4.48 (m, 1H, NHCH), 4.04 (s, 2H, SCH2), 3.72 (s, 3H,
OCH3), 2.29–2.12 (m, 1H, CHCH3), 0.95–0.82 (m, 6H,
2CH3), (MALDI, positive mode, matrix: DHB): m/z =
372.4 (M + Na)+. C15H19N5O3S (349.4): C, 51.56; H,
5.48 N, 20.04; S, 9.18. Found: C, 51.56; H, 5.47 N,
20.02; S, 9.17.
REFERENCES
Methyl N-{[(1-phenyl-1H-tetrazol-5-yl)thio]acetyl}
Leucinate (12d). (Amino acid = L-leucine), white
[1] Thornber, C. W. Chem Soc Rev 1979, 8, 563–580.
[2] Butler, R. N. In Comprehensive Heterocyclic Chem-
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(Eds.); Pergamon: Oxford, 1996; Vol. 4, p. 621.
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[6] Goldgur, Y.; Craigie, R.; Cohen, G. H.; Fujiwara, T.;
Yoshinaga, T.; Fujishita, T.; Sugimoto, H.; Endo, T.;
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1
powder (2.2 g, 61%), mp 51◦C. H NMR (CDCl3): δ
= 7.63–7.53 (m, 5H, Ar-H), 7.36 (bs, 1H, NH), 4.63–
4.51 (m, 1H, NHCH), 4.08 (s, 2H, SCH2), 3.74 (s, 3H,
OCH3), 1.68–1.52 (m, 2H, CHCH2), 1.80–1.26 (m, 1H,
CHCH3), 1.03–0.84 (m, 6H, 2CH3), (MALDI, posi-
tive mode, matrix: DHB): m/z = 386.4 (M + Na)+.
C16H21N5O3S (363.4): C, 52.88; H, 5.82 N, 19.27; S,
8.82. Found: C, 52.86; H, 5.82 N, 19.24; S, 8.80.
Methyl N-{[(1-phenyl-1H-tetrazol-5-yl)thio]acetyl}
Methioninate (12e). (Amino acid = L-methionine),
yellow oil (2.0 g, 53%), 1H NMR (CDCl3): δ = 7.68 (bs,
1H, NH), 7.61–7.45 (m, 5H, Ar-H), 4.76–4.64 (m, 1H,
NHCH), 4.08 (s, 2H, SCH2), 3.71 (s, 3H, OCH3), 2.51
(t, 2H, J = 7.1 Hz, SCH2), 1.92–2.22 (m, 5H, SCH3,
CH2CH), (MALDI, positive mode, matrix: DHB): m/z
= 404.5 (M + Na)+. C15H19N5O3S2 (381.5): C, 47.23;
H, 5.02 N, 18.36; S, 16.81. Found: C, 47.18; H, 4.85
N, 18.26; S, 16.79.
[9] C¸ akir, B.; Dogruer, D.; Yesilada, E.; Sahin, M .F. J
Fac Pharm Gazi 1997, 14, 92–98.
¨
[10] Dogruer, D.; Unlu¨, S.; Yesilada, E.; Sahin, M. F.
Farmaco 1997, 52, 745–750.
[11] El-Tamany, S. H.; Abd El-Fattah, M.; Ibrahim, A. I.;
Salem, M. E. J Indian Chem Soc 1997, 74, 772–776.
ˇ
[12] Fathalla, W.; Cajan, M.; Pazdera, P. Molecules 2000,
5, 1210–1223.
ˇ
N2-{[(1-Phenyl-1H-tetrazol-5-yl)thio]acetyl} Gly-
cine Hydrazide (13a). (Amino acid = glycine), white
powder (2.8 g, 91%), mp 189◦C. 1H NMR (CDCl3): δ =
9.05 (bs, 1H, NH), 8.60 (bs, 1H, NH), 7.63–7.55 (m,
5H, Ar-H), 4.24 (s, 2H, SCH2), 3.66 (bs, 2H, NH2),
3.33–3.23 (m, 2H, NHCH2), (MALDI, positive mode,
matrix: DHB): m/z = 330.3 (M + Na)+. C11H13N7O2S
(307.3): C, 42.99; H, 4.26 N, 31.90; S, 10.43. Found:
42.85; H, 4.19 N, 31.87; S, 10.38.
[13] Fathalla, W.; Cajan, M.; Pazdera, P. Molecules 2001,
6, 557–573.
[14] Waisser, K.; Vanzura, J.; Hrabalek, A.; Vinsova, J.;
Gresak, S. Collect Czech Chem Commun 1991, 56,
2389–2394.
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Trans I 1981, 2982–2990, references therein.
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256, 8963–8969.
¨
[18] Sahin, G.; Palaska, E.; Ekizoglu, M.; Ozalp, M.
Farmaco 2002, 57, 539–542.
N2-{[(1-Phenyl-1H-tetrazol-5-yl)thio]acetyl} Ala-
nine Hydrazide (13b). (Amino acid = L-alanine),
white powder (2.6 g, 80%), mp 163◦C. 1H NMR
(CDCl3): δ = 9.18 (bs, 1H, NH), 8.66 (bs, 1H, NH),
7.71–7.57 (m, 5H, Ar-H), 4.31–4.15 (s, 3H, SCH2,
[19] Ali, I. A. I.; Al-Masoudi, I. A.; Saeed, B., Al-Masoudi,
N. A.; La Colla, P. Heteroatom Chem 2005, 16, 148–
155.
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Saeed, B.; La Colla, P. Heteroatom Chem 2005, 16,
576–586.
Heteroatom Chemistry DOI 10.1002/hc