Heterocyclic synthesis using nitrilimines, part 12: Synthesis and bioactivity of 5-carboxymethylthio-1,2,4-triazoles

Article abstract of DOI:10.1080/00397910802603176

The reaction of 4-amino-5-phenyl-3,5-thiaaza-4-pentenoic acid 3 with various nitrilimines 2 led to the formation of substituted carboxymethylthio derivatives of 1,2,4-triazoles (4a-l) rather than the amino derivatives 5 or imidazole derivatives 6. The spe

Full text of DOI:10.1080/00397910802603176

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Heterocyclic Synthesis
Using Nitrilimines, Part 12:
Synthesis and Bioactivity of
5-Carboxymethylthio-1,2,4-
triazoles
Hany M. Dalloul a
a Faculty of Applied Science, Chemistry Department,
Alaqsa University of Gaza, Gaza, Palestine
Published online: 15 Apr 2009.
To cite this article: Hany M. Dalloul (2009) Heterocyclic Synthesis Using Nitrilimines,
Part 12: Synthesis and Bioactivity of 5-Carboxymethylthio-1,2,4-triazoles, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:10, 1847-1856
To link to this article: http://dx.doi.org/10.1080/00397910802603176
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Synthetic Communications1, 39: 1847–1856, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802603176
Heterocyclic Synthesis Using Nitrilimines,
Part 12: Synthesis and Bioactivity of
5-Carboxymethylthio-1,2,4-triazoles
Hany M. Dalloul
Faculty of Applied Science, Chemistry Department,
Alaqsa University of Gaza, Gaza, Palestine
Abstract: The reaction of 4-amino-5-phenyl-3,5-thiaaza-4-pentenoic acid 3 with
various nitrilimines 2 led to the formation of substituted carboxymethylthio deri-
vatives of 1,2,4-triazoles (4a–l) rather than the amino derivatives 5 or imidazole
derivatives 6. The spectral data of the synthesized compounds are in full agree-
ment with its molecular structure.
Keywords: 4-Amino-5-phenyl-3,5-thiaaza-4-pentenoic acid, 5-carboxymethylthio-
1,2,4-triazoles, cycloaddition, nitrilimines
INTRODUCTION
Nitrilimine is generally a 1,3-dipole for 1,3-dipolar cycloaddition
reactions, which have been employed in the synthesis of numerous
heterocycles.[1–6] However, it is known that the additions of nucleophilic
reagents such as amines to nitrilimines occur readily with high stereo-
specificity.[7] Recently, we have described an efficient one-pot synthesis
of substituted and spiro-1,2,4-triazoles utilizing available keto oximes,
hydrazones, and hydrazonoyl halides.[4–6] Quite recently, we synthesized
spiro-heterocycles containing triazole and thiazolidinone moieties
from the reaction of 2-phenylimino-1,3-thiazolidin-4-one with different
Received August 31, 2008.
Address correspondence to Hany M. Dalloul, Faculty of Applied Science,
Chemistry Department, Alaqsa University of Gaza, P. O. Box 4051, Gaza 76888,
Palestine via Israel. E-mail: hanydallool@yahoo.com
1847

1848
H. M. Dalloul
nitrilimines.[8] These triazoles and their heterocyclic derivatives have been
reportedly used as drugs and have considerable biological activities such
as analgesic, anthelmintic, antitubercular, antiviral, antifungal, plant-
growth regulating, anticancer, and antitumor activities.[9–14] As part of
our program aimed at developing new biologically active compounds,
in this work we report the synthesis of some new 1,2,4-triazole derivatives
from the reaction between C-substituted-N-arylnitrilimines (2a–l) and
4-amino-5-phenyl-3,5-thiaaza-4-pentenoic acid 3, which had been
unexplored in the literature.
RESULTS AND DISCUSSION
In the present work, we found that 4-amino-5-phenyl-3,5-thiaaza-4-
pentenoic acid 3 reacts readily with the nitrilimines 2, generated in situ
from the action of triethylamine onto hydrazonoyl halides 1, yielding
substituted carboxymethylthio derivatives of 1,2,4-triazoles (4a–l), which
were confirmed by their spectral data, rather than the amino derivatives
5. Also, imidazole derivatives 6 were not observed (Scheme 1).
The formation of compounds 4a–l is assumed to involve nucleophilic
addition adducts 7, which ultimately undergo intramolecular cyclization
Scheme 1. Synthetic pathway for compounds 4a–1.

Heterocyclic Synthesis Using Nitrilimines, Part 12
1849
Scheme 2. Suggested reaction mechanism.
to yield the phenylamino triazole intermediates 8, which cannot be
isolated or observed by thin-layer chromatography (TLC). The latter
intermediates afford the aromatic 1,2,4-triazole derivatives (4a–l) through
the elimination of an aniline molecule (Scheme 2). The purity of the
isolated compounds was checked by TLC in different solvents.
It is worth mentioning that the same nitrilimines 2 are found to react
with acetamidine, benzamidine, benzylthioformamidine, and acetaldox-
ime in cycloaddition processes to give 1,3,5-trisubstituted 1,2,4-triazoles
40a–l through elimination of ammonia or water molecules[15] (Scheme 3).
The structures of products 4a–l were elucidated on the basis of
analytical and spectral data. The physical properties and molecular ion
Scheme 3. Synthetic pathway compounds 40a–1.

1850
H. M. Dalloul
peaks are presented in the experimental part section. The infrared (IR)
spectra of these compounds exhibit characteristic absorption of a car-
boxylic acid group C¼O stretching at 1720–1730 cmꢀ1, and the bonded
O-H vibration at 2550–2500 cmꢀ1. Other absorptions were observed at
1640–1680 cmꢀ1 (Ar-C¼O), 1550–1620 cmꢀ1 (C¼C, C¼N), and 1220–
1240 cmꢀ1 (C-S). The 1H NMR spectra of compounds 4a–l show a signal
at 3.6–3.9 ppm for the methylene protons of the thioglycolic acid group.
In compounds 4a–c, the protons of the acetyl group resonate at about
2.5 ppm, whereas the signal at 8.8–8.9 ppm is attributed to the N-H of
the anilino group in compounds 4d–f. The 13C NMR spectra display the
characteristic signals of the suggested structures. The signal of the met-
hylene carbon of the thioglycolic acid resonates at about 37.7 ppm, and
the carboxylic carbon appears in the region 166–169 ppm. The signals
at about 154–152 ppm are attributed to C-3 and C-5 of the triazole ring.
This assignment is in good agreement with literature data for azo-
methine carbons in five membered heterocycles.[15] The 1H and 13C NMR
spectral data of the synthesized compounds are presented in the experi-
mental part.
In conclusion, it is clear that the aromaticity is the driving force for
the formation of aromatic 1,2,4-triazoles 4a–l.
Antimicrobial Activity
Most of the newly synthesized compounds 4a–l were tested for their anti-
bacterial and antifungal activity in vitro against bacterial strains such as
Escherichia coli, Staphylococcus aureus, Klebsiella spp., Proteus spp.,
Pseudomonas and Aspergillus flavus, and Candida albicans as fungi, and
employing the nutrient agar disc diffusion method[16] at 1–10 mg=ml in
N,N-dimethylformamide (DMF) by measuring the inhibition zone in
millimeters (mm). It is interesting to note that these aromatic triazoles
(4a–l) showed a weak degree of activity against tested bacteria and fungi
in comparison to DMF, which was used as the control. That may due to
lack of active substituted groups.
EXPERIMENTAL
All melting points were measured on an Electrothermal melting-point
apparatus and are uncorrected. The IR spectra were recorded in potas-
sium bromide discs on a Perkin-Elmer 237FT IR spectrophotometer.
1H and 13C NMR spectra were recorded in CDCl3 on Bruker AM 300-
MHz and Jeol LA-300 instruments at 21 ꢁC, using tetramethylsilane
(TMS) as an internal reference. Electron impact (EI) mass spectra were

Heterocyclic Synthesis Using Nitrilimines, Part 12
1851
run on Finnigan MAT 8200 and 8400 mass spectrometers at 70 eV.
Elemental analyses were carried out at the microanalytical laboratory
at the University of Cairo, Giza, Egypt. Hydrazonoyl halides 1a–l were
prepared according to known literature procedures[7,17–21] and 4-amino-
5-phenyl-3,5-thiaaza-4-pentenoic acid 3 was purchased from BDH,
England, and used without further purification.
Synthesis of Compounds 4a–l
General Method
Triethylamine (3.0 g, 0.03 mol) in absolute tetrahydrofuran (THF) (10 ml)
was added dropwise to a stirred solution of hydrazonoyl halides 1a–l
(0.005 mol) and acid 3 (0.005 mol) in THF (50 ml) at room temperature.
Stirring was continued overnight, the solvent was evaporated in vacuo,
and the residual solid was washed with water to remove the triethylamine
salt. The crude solid product was collected and recrystallized from
aqueous ethanol (20 ml), affording the desired compounds.
The following compounds were prepared by this method.
(3-Acetyl-1-phenyl-1H-[1,2,4]triazol-5-Sulfanyl)-acetic Acid (4a)
Yield 1.02 g (74%); mp 176–178ꢁC (ethanol); IR: n ¼ 2525 (OH), 1720
(O-C¼O), 1670 (Ar-C¼O), 1224 (C-S) cmꢀ1
;
1H NMR: d ¼ 10.00 (s,
1H, OH), 7.66–7.09 (m, 5H, arom. H), 3.56 (s, 2H, CH2), 2.52 (s, 3H,
CH3) ppm; 13C NMR: d ¼ 195.1 (Ar-C¼O), 166.7 (O-C¼O), 156.3,
154.3 (C¼N), 136.2, 128.9, 125.5, 118.7 (4 arom. C), 37.8 (SCH2), 25.6
(CH3) ppm; MS: m=z ¼ 277 [Mþꢂ]. Analysis for C12H11N3O3S (277.30):
calcd. C, 51.98; H, 4.00; N, 15.15. Found: C, 52.22; H, 3.88; N, 15.02.
(3-Acetyl-1-(4-chlorophenyl)-1H-[1,2,4]triazol-5-sulfanyl)-acetic
Acid (4b)
Yield 1.23 g (79%); mp 181–183ꢁC (ethanol); IR: n ¼ 2520 (O-H), 1720
(O-C¼O), 1673 (Ar-C¼O), 1221 (C-S) cmꢀ1
;
1H NMR: d ¼ 10.00 (s,
1H, OH), 7.67–7.30 (m, 4H, arom. H), 3.55 (s, 2H, CH2), 2.55 (s, 3H,
CH3) ppm; 13C NMR: d ¼ 195.1 (Ar-C¼O), 166.6 (O-C¼O), 156.1,
154.0 (C¼N), 138.8, 129.8, 128.2, 125.6 (4 arom. C), 37.7 (SCH2), 25.6
(CH3) ppm; MS: m=z ¼ 311=313 [Mþ.]. Analysis for C12H10ClN3O3S
(311.75): calcd. C, 46.23; H, 3.23; N, 13.48. Found: C, 46.10; H, 3.12;
N, 13.60.

1852
H. M. Dalloul
(3-Acetyl-1-(4-bromophenyl)-1H-[1,2,4]triazol-5-sulfanyl)-acetic
Acid (4c)
ꢁ
Yield 1.42 g (80%); mp 186–188 C (ethanol); IR: n ¼ 2525 (O-H), 1730
(O-C¼O), 1675 (Ar-C¼O), 1223 (C-S) cmꢀ1
;
1H NMR: d ¼ 10.00 (s,
1H, OH), 7.70–7.10 (m, 4H, arom. H), 3.56 (s, 2H, CH2), 2.56 (s, 3H,
CH3) ppm; 13C NMR: d ¼ 195.1 (Ar-C¼O), 166.7 (O-C¼O), 156.3,
154.3 (C¼N), 140.8, 131.8, 128.4, 116.8 (4 arom. C), 37.7 (SCH2), 25.6
(CH3) ppm; MS: m=z ¼ 356=358 [Mþꢂ]. Analysis for C12H10BrN3O3S
(356.20): calcd. C, 40.46; H, 2.83; N, 11.80. Found: C, 40.25; H, 3.95;
N, 11.67.
(1-Phenyl-3-phenylaminocarbonyl-1H-[1,2,4]triazol-5-sulfanyl)-acetic
Acid (4d)
Yield 1.27 g (72%); mp 166–168 ꢁC (ethanol); IR: n ¼ 3350 (PhN-H), 2530
(O-H), 1725 (O-C¼O), 1645 (Ar-C¼O), 1226 (C-S) cmꢀ1
;
1H NMR:
d ¼ 10.20 (s, 1H, OH), 8.80 (s, 1H, NH), 7.60–6.80 (m, 10H, arom. H),
3.9 (s, 2H, CH2) ppm; 13C NMR: d ¼ 166.9 (O-C¼O), 159.9 (Ar-C¼O),
156.3, 154.3 (C¼N), 142.2, 138.7, 137.5, 128.6, 129.9, 124.5, 121.0,
115.6 (8 arom. C), 37.7 (SCH2) ppm; MS: m=z ¼ 354 [Mþꢂ]. Analysis
for C17H14N4O3S (354.39): calcd. C, 57.62; H, 3.98; N, 15.81. Found:
C, 57.49; H, 4.10; N 15.98.
(1-(4-Methylphenyl)-3-phenylaminocarbonyl-1H-[1,2,4]triazol-5-
sulfanyl)-acetic Acid (4e)
Yield 1.29 g (70%); mp 196–198 ꢁC (ethanol); IR: n ¼ 3350 (PhN-H), 2525
(O-H), 1720 (O-C¼O), 1650 (Ar-C¼O), 1223 (C-S) cmꢀ1
;
1H NMR:
d ¼ 10.20 (s, 1H, OH), 8.90 (s, 1H, NH), 7.60–7.00 (m, 9H, arom. H),
3.7 (s, 2H, CH2), 2.36 (s, 3H, CH3) ppm; 13C NMR: d ¼ 167.1 (O-
C¼O), 159.8 (Ar-C¼O), 154.3, 152.8 (C¼N), 141.9, 139.7, 130.4, 129.8,
129.0, 128.6, 123.7, 120.6 (8 arom. C), 37.1 (SCH2), 21.2 (CH3) ppm;
MS: m=z ¼ 368 [Mþꢂ]. Analysis for C18H16N4O3S (368.42): calcd. C,
58.68; H, 3.38; N, 15.21. Found: C, 58.82; H, 3.50; N, 15.11.
(1-(4-Chlorophenyl)-3-phenylaminocarbonyl-1H-[1,2,4]triazol-5-
sulfanyl)-acetic Acid (4f)
Yield 1.50 g (77%); mp 186–188 ꢁC (ethanol); IR: n ¼ 3350 (PhN-H), 2530
(O-H), 1725 (O-C¼O), 1650 (Ar-C¼O), 1224 (C-S) cmꢀ1
;
1H NMR:
d ¼ 10.30 (s, 1H, OH), 8.90 (s, 1H, NH), 7.60–7.10 (m, 9H, arom. H),

Heterocyclic Synthesis Using Nitrilimines, Part 12
1853
3.90 (s, 2H, CH2) ppm; 13C NMR: d ¼ 167.1 (O-C¼O), 159.9 (Ar-C¼O),
154.6, 152.5 (C¼N), 141.3, 138.9, 130.3, 128.7, 128.5, 124.3, 123.3, 120.2
(8 arom. C), 37.7 (SCH2) ppm; MS: m=z ¼ 388=390 [Mþꢂ]. Analysis for
C17H13ClN4O3S (388.84): calcd. C, 52.51; H, 3.37; N, 14.41. Found: C,
52.37; H, 3.45; N, 14.33.
(3-(2-Naphthoyl)-1-phenyl-1H-[1,2,4]triazol-5-sulfanyl)-acetic
Acid (4 g)
ꢁ
Yield 1.48 g (76%); mp 213–215 C (ethanol); IR: n ¼ 2530 (O-H), 1725
(O-C¼O), 1620 (Ar-C¼O), 1229 (C-S) cmꢀ1
;
1H NMR: d ¼ 10.40 (s,
1H, OH), 8.90–7.20 (m, 12H, arom. H), 3.80 (s, 2H, CH2) ppm; 13C
NMR: d ¼ 182.1 (Ar-C¼O), 169.1 (O-C¼O), 153.6, 152.2 (C¼N),
141.5, 135.4, 132.7, 132.4, 132.2, 129.9, 128.9, 128.5, 127.6, 127.1,
126.5, 125.5, 120.8, 115.4 (14 arom. C), 37.7 (SCH2) ppm; MS: m=z ¼ 389
[Mþꢂ]. Analysis for C21H15N3O3S (389.44): calcd. C, 64.77; H, 3.88; N,
10.79. Found: C, 64.91; H, 4.02; N, 10.68.
(1-(4-Methylphenyl)-3-(2-naphthoyl)-1H-[1,2,4]triazol-5-sulfanyl)-
acetic Acid (4 h)
Yield 1.43 g (71%); mp 196–198ꢁC (ethanol); IR: n ¼ 2525 (O-H), 1730
(O-C¼O), 1630 (Ar-C¼O), 1226 (C-S) cmꢀ1
;
1H NMR: d ¼ 10.30 (s,
1H, OH), 8.90–7.26 (m, 11H, arom. H), 3.84 (s, 2H, CH2), 2.40 (s, 3H,
CH3) ppm; 13C NMR: d ¼ 182.0 (Ar-C¼O), 169.1 (O-C¼O), 153.6,
152.8 (C¼N), 142.1, 135.4, 132.9, 132.6, 132.4, 129.9, 128.9, 128.5,
128.1, 127.9, 127.7, 126.6, 125.5, 121.0 (14 arom. C), 37.7 (SCH2),
21.4 (CH3) ppm; MS: m=z ¼ 403 [Mþꢂ]. Analysis for C22H17N3O3S
(403.46): calcd. C, 65.49; H, 4.25; N, 10.41. Found: C, 65.35; H, 4.13;
N, 10.35.
(1-(4-Chlorophenyl)-3-(2-naphthoyl)-1H-[1,2,4]triazol-5-sulfanyl)-
acetic Acid (4i)
ꢁ
Yield 1.65 g (78%); mp 221–223 C (ethanol); IR: n ¼ 2530 (O-H), 1725
(O-C¼O), 1625 (Ar-C¼O), 1228 (C-S) cmꢀ1
;
1H NMR: d ¼ 10.50 (s,
1H, OH), 8.90–7.30 (m, 11H, arom. H), 3.90 (s, 2H, CH2) ppm; 13C
NMR: d ¼ 182.1 (Ar-C¼O), 169.1 (O-C¼O), 153.9, 152.9 (C¼N),
141.6, 135.6, 132.3, 133.0, 132.7, 130.0, 128.9, 128.5, 128.0, 127.9,
127.7, 126.6, 125.6, 120.9 (14 arom. C), 37.7 (SCH2) ppm; MS:
m=z ¼ 423=425 [Mþꢂ]. Analysis for C21H14ClN3O3S (423.88): calcd. C,
59.51; H, 3.33; N, 9.91. Found: C, 59.66; H, 3.45; N, 10.05.

1854
H. M. Dalloul
(3-Benzoyl-1-(4-chlorophenyl)-1H-[1,2,4]triazol-5-sulfanyl)-acetic
Acid (4j)
ꢁ
Yield 1.25 g (67%); mp 200–202 C (ethanol); IR: n ¼ 2520 (O-H), 1720
(O-C¼O), 1650 (Ar-C¼O), 1231 (C-S) cmꢀ1
;
1H NMR: d ¼ 10.20
(s, 1H, OH), 8.40–6.90 (m, 9H, arom. H), 3.75 (s, 2H, CH2) ppm; 13C
NMR: d ¼ 182.3 (Ar-C¼O), 168.9 (O-C¼O), 154.1, 153.1 (C¼N),
141.0, 135.5, 133.2, 132.8, 129.3, 127.9, 127.3, 115.5 (8 arom. C), 37.8
(SCH2) ppm; MS: m=z ¼ 373=375 [Mþꢂ]. Analysis for C17H12ClN3O3S
(373.82): calcd. C, 54.62; H, 3.24; N, 11.24. Found: C, 54.80; H, 3.15;
N, 11.10.
(1-(4-Chlorophenyl)-3-(2-furoyl)-1H-[1,2,4]triazol-5-sulfanyl)-acetic
Acid (4k)
ꢁ
Yield 1.25 g (69%); mp 177–179 C (ethanol); IR: n ¼ 2530 (O-H), 1725
(O-C¼O), 1660 (Ar-C¼O), 1236 (C-S) cmꢀ1
;
1H NMR: d ¼ 10.30
(s, 1H, OH), 8.30–7.16 (m, 7H, arom. H), 3.70 (s, 2H, CH2) ppm; 13C
NMR: d ¼ 173.6 (Ar-C¼O), 167.8 (O-C¼O), 154.40, 152.2 (C¼N),
142.1, 138.5, 135.5, 135.0, 129.2, 128.6, 127.8, 120.9 (8 arom. C), 37.7
(SCH2) ppm; MS: m=z ¼ 363=365 [Mþꢂ]. Analysis for C15H10ClN3O4S
(363.78): calcd. C, 49.53; H, 2.77; N, 11.55. Found: C, 49.40; H, 2.85;
N, 11.63.
(1-(4-Chlorophenyl)-3-(2-thenoyl)-1H-[1,2,4]triazol-5-sulfanyl)-
acetic Acid (4l)
Yield 1.33 g (70%); mp 156–158ꢁC (ethanol); IR: n ¼ 2525 (O-H), 1720
1
(O-C¼O), 1660 (Ar-C¼O), 1233 (C-S) cmꢀ1; H NMR: d ¼ 10.10 (s, 1H,
OH), 8.30–7.10 (m, 7H, arom. H), 3.72 (s, 2H, CH2) ppm; 13C NMR:
d ¼ 174.2 (Ar-C¼O), 167.9 (O-C¼O), 153.5, 152.6 (C¼N), 142.2, 138.5,
135.3, 134.8, 129.2, 128.4, 128.0, 120.8 (8 arom. C), 37.7 (SCH2) ppm;
MS m=z ¼ 379=381 [Mþ.]. Analysis for C15H10ClN3O3S2 (379.85): calcd.
C, 47.43; H, 2.65; N, 11.06. Found: C, 47.36; H, 2.72; N, 10.95.
ACKNOWLEDGMENT
The author thanks the Ministry of Higher Education for financial sup-
port and Dr. A. S. Abu Samaha for providing the antimicrobial testing
facility for the synthesized compounds.

Heterocyclic Synthesis Using Nitrilimines, Part 12
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