The synthesis and microbiological activity of new 4-chloropyridin-2-yl derivatives

Article abstract of DOI:10.3987/COM-09-11696

Synthesis of 4-chloropicolinamidrazone derivatives starting from 4-chloropicolinamide is described. The desired compounds were formed by reactions of methyl 4-chloropicolinohydrazonamide or 4-chloro-N′-methylpicolinohydrazonamide with suitable counter partners (carbon disulfide, alkyl halides, aldehydes, ketones, carbohydrazonamides or isothiocyanates) or via 4-chloropicolinimidate, obtained by a convenient method from nitrile with catalytic amount of DBU. Selected products were screened for bacteriostatic and tuberculostatic activity.

Full text of DOI:10.3987/COM-09-11696

HETEROCYCLES, Vol. 78, No. 9, 2009
2217
HETEROCYCLES, Vol. 78, No. 9, 2009, pp. 2217 - 2231. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd March, 2009, Accepted, 23rd April, 2009, Published online, 23rd April, 2009.
DOI: 10.3987/COM-09-11696
THE SYNTHESIS AND MICROBIOLOGICAL ACTIVITY OF NEW
4-CHLOROPYRIDIN-2-YL DERIVATIVES
Agnieszka Bogdanowicz,*a Henryk Foks,a Anna Kędzia,b Ewa Kwapisz,b
Zofia Zwolska,c and Ewa Augustynowicz-Kopećc
a) Department of Organic Chemistry, Medical University of Gdańsk, Poland
E-mail address: miszke@amg.gda.pl
b) Department of Oral Microbiology, Medical University of Gdańsk, Poland
E-mail address: anak@amg.gda.pl
c) Department of Microbiology, Institute of Tuberculosis and Pulmonary Diseases,
Warsaw, Poland
Abstract – Synthesis of 4-chloropicolinamidrazone derivatives starting from
4-chloropicolinamide is described. The desired compounds were formed by
reactions
of
methyl
4-chloropicolinohydrazonamide
or
4-chloro-N'-methylpicolinohydrazonamide with suitable counter partners (carbon
disulfide, alkyl halides, aldehydes, ketones, carbohydrazonamides or
isothiocyanates) or via 4-chloropicolinimidate, obtained by a convenient method
from nitrile with catalytic amount of DBU. Selected products were screened for
bacteriostatic and tuberculostatic activity.
INTRODUCTION
Development of mycobacterial resistance to conventional drugs is one of the major difficulties in the
treatment of tuberculosis, and a major factor in increasing demand for new antituberculosis agents.
Looking for new structures with potential tuberculostatic activity, we pay attention to a recent report
suggesting that tuberculostatic activity of pyridin-2-yl-formamide thiosemicarbazones (A) is related to
their co-planarity1. The hypothesis prompted us to synthesis of new 2-substituted pyridine derivatives. To
increase probability that the prepared compounds will bear the desired activity, the pyridine ring was
connected with structural fragments witch have already been present in tuberculostatic compounds
namely: amidrazones (B),2 thiosemicarbazones (C), and thioureas (D)3 (Figure 1). Moreover some of
them fulfill the requirement of co-planarity with the pyridine moiety.

2218
HETEROCYCLES, Vol. 78, No. 9, 2009
H
N
H
H
N
NH2
H
N
N
R
N
H
R1
N
R2
S-
[A]
[B]
H
N
N
Me
S
S
O
N
H
Me
N
N
H
N
N
H
H
H
[D]
[C]
Figure 1
CHEMISTRY
A first set of compounds possessing the desired, outlined above structural characteristic, was prepared
from imidate 3, as the key intermediate. Starting 4-chloropicolinonitrile (2)4 was prepared, with one of
general metods, from amide 14 using a dehydrating agent (Scheme 1). Treatment of methanolic solution
of the nitrile (2) with catalytic amount of DBU resulted in formation of methyl 4-chloropicolinimidate (3).
The DBU catalyzed formation of imidates was the best for our compound, and seems to be a viable
alternative to the catalysis with alkali metal methanolate.5, 6 When sodium methanolate was used, chlorine
atom was converted to methoxy group. Reaction of the formed in situ imidate 3 with
4-phenylpiperazine-1-carbothiohydrazide and 4-phenylpiperazine-1-carbohydrazide gave amidrazones 4a
1
– 4b, respectively. H NMR spectra of the products demonstrated NH protons, as two-protons singlet at
6.28 (for 4a) and 6.58 (for 4b) and one-proton singlets at 8.58 (for 4a) and 8.60 (for 4b), which confirms
structures shown at Scheme 1. Analogous reaction of imidate 3 with benzenesulfonamide and
1
aminobenzenosulfonamide gave amidines 5a – 5b, respectively. H NMR spectra of the products
demonstrated NH protons, as two broad singlets at 8.29 and 8.92 (for 5a) and two broad singlets at 8.12
and 8.88 (for 5b), which confirms structures shown at Scheme 1.
Next group of compounds originated from amidrazone 6 as the key intermediate. The starting material
4-chloropicolinohydrazonamide (6) was prepared by reaction of nitrile 2 with hydrazine monohydrate.
Subsequently, it was reacted under various reaction conditions, with carbon disulfide. As expected,
reaction
of
6
with
carbon
disulfide
in
plane
methanol
gave
5-(4-chloropyridin-2-yl)-1,3,4-thiadiazole-2(3H)-thione (7). Two tautomers (7a and 7b) seem to be
possible for the compound, and the δ value 14.96 for the exchangeable proton suggested that it is
connected with nitrogen (7a).

HETEROCYCLES, Vol. 78, No. 9, 2009
2219
Cl
Cl
Cl
Cl
POCl3
DBU
a
NH2
NH
O
OMe
MeOH
N
C
N
CN
N
N
N
X
NH2
NH
1
2
3
4a, 4b
N
H2N
N
O
H2NO2S
SO2NH2
X=S, O
N
N
N
N
H2NHN
a:
Cl
N
Cl
S
H2NHN
NH
NH
N
O
O
S
HN
HN
S
O
O
NH2
5a
5b
Scheme 1. Products formed via imidate 3.
The conclusion was supported by IR (KBr), which demonstrated a strong absorption at 1235 cm-1, which
could correspond to C=S group. Thus, the reaction proceeded analogously as reported earlier7 for similar
compounds. The same reagent 6 but with addition of methyl iodide gave corresponding
S-methylthiadiazole derivative 8. Surprisingly, analogous condensation – alkylation reactions run in the
presence of equimolar amount of triethylamine (TEA), resulted in formation of linear dithiocarbazoic acid
monoesters 9a - c as the main products, while in the presence of excess of TEA, dithiocarbazoic acid
diesters 10a, b were obtained. Replacement of methyl iodide by 1,3-dibromopropane gave 1,3-dithiolane
derivative 11. Further, compound 6 was reacted with appropriate isothiocyanates to give N-methyl, allyl
and p-chlorophenyl thiosemicarbazides 12a - c (Scheme 2).
In the next step of the work, compounds with differently modified side chain in position 2 of the pyridine
moiety were obtained, by reactions of compound 6 with aldehydes, ketones and iminoesters (Scheme 3).
Reaction of 4-chloropicolinohydrazonamide (6) with 4-chlorobenzaldehyde, 5-nitrofuran-2-carbaldehyde,
5-nitrothiophene-2-carbaldehyde, 4-hydroxy-3-methoxybenzaldehyde or 4-(dimethylamino)benzaldehyde
gave corresponding condensation products 13a - e. Similarly, reaction with 1-(thiophen-2-yl)ethanone
gave 4-chloro-N'-[1-(thiophen-2-yl)ethylidene]picolinohydrazonamide (14). Reaction of amidrazone 6
with iminoesters lead initially, at room temperature, to corresponding carbimidates 15a, b, while heating
of the products in AcOH caused intramolecular cyclization to 1,2,4-triazole derivatives 16a, b.
Still another group of the required compounds originated from amidrazone 17, which itself was prepared
by reaction of nitrile 2 with methylhydrazine (Scheme 4). The compounds were prepared to check, by
comparison with products derived from 6, how methylation of the nitrogen atom will influence their

2220
HETEROCYCLES, Vol. 78, No. 9, 2009
2
NH2-NH2
Cl
N
Cl
Cl
N
Cl
N
CS2, MeI
CS2
N
N
N
N
N
C
NH2
N
NH
S
N
S
NH2
S
7a
S
8
6
7b
SMe
SH
CS2
TEA
RX
CS2
TEA
CS2
TEA
RX
R-NCS
Br
Br
Cl
N
Cl
N
Cl
N
Cl
N
S
SR
S
S
N
N
N
N
R
C
N
H
SR
C
N
SR
C
N
S
C
N
H
N
H
NH2
NH2
NH2
NH2
9a, 9b, 9c
10a, 10b
11
12a, 12b, 12c
No
9a
9b
9c
10a 10b 12a
12b
12c
R
Me
Bu
Bn
Me Bn Me CH2CH=CH2 p-Cl-Ph
Scheme 2. Products formed via amidrazone 6.
Cl
N
Cl
N
H
Me
N
RCHO
MeCOR
6
N
C
N
R
C
N
R
NH2
13a-e
NH2
NH
R
14
MeO
Cl
Cl
N
NH2
R
AcOH
N
N
N
N
C
N
R
N
H
NH2
15a, b
16a, b
No
R
13a
13b
13c
13d
13e
14
15a, 16a 15b, 16b
N
Me
S
OH
Cl
N
N
NO2
NO2
Me
O
S
N
OMe
N
Scheme 3. Products formed via amidrazone 6.
tuberculostatic activity. Essentially, the obtained results were similar to those for demethylated derivative
6 (Scheme 2) except the reaction with isothiocyanatomethane, which gave in the same conditions
1,2,4-triazole 20 (Scheme 4).

HETEROCYCLES, Vol. 78, No. 9, 2009
2221
Cl
Cl
N
S
H2NNHMe
TEA, CS2, MeI
2
N
Me
N
N
17
C
N
H
C
N
SMe
NH2
NH2 Me
CS2
SCNMe
18
Cl
N
Cl
N
N
N
Me
N
S
Me
N
S
S
N
Me
19
20
Scheme 4. Products formed via 4-chloro-N'-methylpicolinohydrazonamide 17.
MICROBIOLOGICAL ACTIVITY
Antimicrobial activities of compounds were tested using the plate dilution technique in Brucella agar
supplemented with 5 % lamb blood,8 against 26 strains of anaerobic bacteria and agar dilution technique
with Miller-Hinton agar against 25 strains of aerobic bacteria (Table 1), isolated from the oral cavity,
respiratory system and abdominal cavity. The antibacterial activity of the tested compounds was also
performed against the following standard bacterial strains: Bacteroides fragilis ATCC 25285,
Fusobacterium nucleatum ATCC 25586, Peptostreptococcus anaerobius ATCC 27337,
Peptostreptococcus magnus ATCC 29328, Propionibacterium acnes ATCC 11827. Staphylococcus
aureus ATCC 25923, Enterococcus faecalis ATCC 29212, Klebsiella pneumonia ATCC 13883,
Acinetobacter baumannii ATCC 19606, Escherichia coli ATCC 25922 and Pseudomonas aeruginosa
ATCC 27853. The minimal inhibitory concentration (MIC) was defined as the lowest concentration of
derivative that inhibited growth of bacteria. Metronidazole and amikacin were used as the reference
substances. The investigation of susceptibility of aerobic and anaerobic bacteria to the compounds 2, 6,
9a, 13a – e, 14 are summarized in Table 1. The tested derivatives exhibited diversified activity against
aerobic and anaerobic bacteria. Compounds 9a (100 % of susceptible strains) and 13b (72 % of
susceptible strains) were found to be more active then the other compounds at concentrations in the range
from ≤ 6.2 to 100 µg/mL against the aerobes. The anaerobes were the most susceptible at concentrations
in the range from ≤ 6.2 to 100 µg/mL to derivatives 9a (50 %) and 2 (35 %). Compounds 13c – e and 14
did not exhibit any activity against aerobic and anaerobic bacteria.
Selected compounds 2 – 10b, 12a – 20 were tested for their tuberculostatic activity towards the standard
Mycobacterium tuberculosis H37Rv strain and two wild strains isolated from the tuberculotic patients: one
(Spec. 210) resistant to p-aminosalicylic acid (PAS), isonicotinic acid hydrazide (INH), etambutol (ETB)
and rifampicine (REP) and the other (Spec. 192) fully susceptible to the drugs administered. The

2222
HETEROCYCLES, Vol. 78, No. 9, 2009
tuberculostatic activity was determined in vitro by classical test tube method with Youman’s liquid
medium containing 10 % of bovine serum. In comparison with some of tuberculosis drugs: isonicotinic
acid hydrazide (MIC 0.5 µg/mL), viomycin (MIC 6.2 µg/mL), cycloserine (MIC 5 µg/mL) and
pyrazinamid (MIC 25 µg/mL), it was concluded that tested compounds showed no significant
tuberculostatic activity (MIC 25 – 100 µg/mL).
Table 1. Antibacterial Activity of tested compounds 2, 6, 9a, 13a – e, 14
MIC (µg/ mL)
Anaerobic bacteria
Compound no
2
6
9a
13a
13b
13c – e, 14
Metronidazole*
Gram positive:
Finegoldia magna (2)
Micromonas micros (3)
Actinomyces israelii (2)
Propionibacterium acnes(2)
Gram-negative:
≤ 0.4
≤ 0.4
3.1
≤ 6.2
50
50
100
≤ 6.2
50
25
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
50
25
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 100
100
Prevotella bivia (1)
≤ 0.4
≤ 0.4
≤ 0.4
≤ 0.4
≤ 0.4
≤ 0.4
1.6
100
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
100
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
Prevotella buccalis (2)
Prevotella intermedia (2)
Prevotella loescheii (1)
Porphyromonas saccharolytica (2)
Fusobacterium nucleatum (1)
Fusobacterium necrophorum (2)
Bacteroides fragilis (3)
Bacteroides ureolyticus (3)
Aerobic bacteria
≥ 200
≥ 200
≥ 200
100
100
100
≥ 200
50
100
≤ 0.4
6.2
≥ 200
≤ 6.2
≥ 200
Amikacin**
Gram positive:
≥ 200
≥ 200
≥ 200
≥ 200
≤ 6.2
≥ 200
≥ 200
25
25
≥ 200
≥ 200
Staphylococcus aureus (4)
Corynebacterium spp (2)
Gram-negative:
≤ 6.2
25
25
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
50
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
50
≥ 200
≥ 200
≥ 200
≥ 200
≥ 200
Klebsiella pneumoniae (3)
Acinetobacter baumannii (2)
Escherichia coli (6)
≤ 6.2
≤ 6.2
≤ 6.2
≤ 6.2
12.5
≤ 6.2
25
50
50
50
100
100
Pseudomonas aeruginosa (6)
Pseudomonas stutzeri (2)
50
*Metronidazole (Sigma)
**Amikacin sulfate salt (Sigma)
EXPERIMENTAL
Melting points were obtained with Boetius apparatus and are uncorrected. Elemental analyses for C, H, N
and S were performed on Carlo-Erba 1108 instrument. The IR spectra were taken using Mattson Satellite
spectrophotometer, and the 1H NMR spectra were obtained on Varian Gemini 200 MHz apparatus.

HETEROCYCLES, Vol. 78, No. 9, 2009
2223
4-Chloropicolinonitrile (2)
4-Chloropicolinamide (1) (5.0 g, 32 mmol) was susspended in dry dioxane (30 mL) and POCl3 (5 mL,
53.6 mmol) was added. The mixture was refluxed for 1.5 h and then the solution was evaporated. Ice (20
g) was added to the residue, and the precipitated solid was collected by filtration and crystallized from
H2O to give 4-chloropicolinonitrile (2) (2.21 g, 50 %) as colorless solid, mp 80 – 82 °C (83 – 84 °C).5 1H
NMR (CDCl3) δ 7.56 (1H, dd, J1 = 1.9 Hz, J2 = 5.4 Hz), 7.73 (1H, d, J = 1.9 Hz), 8.64 (1H, d, J = 5.4
Hz); IR (KBr) ν 3086, 2240, 1570, 1547, 1461, 1381, 847, 465 cm-1.
4-Chloro-N'-(4-phenylpiperazine-1-carbonothioyl)picolinohydrazonamide (4a)
4-Chloropicolinonitrile (2) (0.511 g, 4 mmol) was dissolved in anhydrous MeOH (10 mL) containing
DBU (0.2 mL), as
a
catalyst. The mixture was refluxed for 10 min. Next
4-phenylpiperazine-1-carbothiohydrazide (0.944 g, 4 mmol) was added, and reflux was continued for 1
min and the mixture was left at rt for 5 h. The reaction mixture was acidified with acetic acid (0.3 mL),
the
product
was
filtered
off
and
crystallized
from
dioxane
to
give
4-chloro-N'-(4-phenylpiperazine-1-carbonothioyl)picolinohydrazonamide (4a) (0.78 g, 52 %) as a yellow
1
crystals, mp 160 – 163 °C. H NMR (CDCl3) δ 3.28 (4H, m), 4.18 (4H, m), 6.86 (2H, s), 6.95 (5H, m),
7.41 (1H, dd, J1 = 2.0 Hz, J2 = 5.3 Hz), 7.98 (1H, d, J = 2.0 Hz), 8. 54 (1H, d, J = 5.3 Hz), 8.58 (1H, s);
IR (KBr) ν 3388, 3269, 2923, 1599, 1340, 1227, 1017, 758 cm-1; Anal. Calcd for C17H19ClN6S: C, 54.46;
H, 5.11; N, 22.42; S, 8.55. Found: C, 54.32; H, 5.09; N, 22.39; S, 8.53.
4-Chloro-N'-(4-phenylpiperazine-1-carbonyl)picolinohydrazonamide (4b)
4-Chloropicolinonitrile (2) (0.249 g, 1.8 mmol) was dissolved in anhydrous MeOH (5 mL) containing
DBU (0.1 mL), as a catalyst. The mixture was refluxed for 10 min and then cooled.
4-Phenylpiperazine-1-carbohydrazide (0.396 g, 1.8 mmol) was added and the mixture was stirred at rt for
2 h. The reaction mixture was acidified with acetic acid, the obtained solid was filtered off, and
crystallized from MeOH to give 4-chloro-N'-(4-phenylpiperazine-1-carbonyl)picolinohydrazonamide (4b)
(0.312 g, 50 %) as a yellow crystals, mp 296 – 298 °C. 1H NMR (DMSO–d6) δ 3.17 (4H, d, J = 5.1 Hz),
3.57 (4H, d, J = 5.1 Hz), 6.58 (2H, s), 6.80 – 7.27 (5H, m), 7.56 (1H, dd, J1 = 2.1 Hz, J2 = 5.3 Hz), 8.02
(1H, d, J = 2.1 Hz), 8.53 (1H, d, J = 5.3 Hz), 8.60 (1H, s); IR (KBr) ν 3430, 3333, 3232, 2814, 1631,
1539, 1425, 1229, 1156, 999, 761 cm-1. Anal. Calcd for C17H19ClN6O: C, 56.90; H, 5.34; N, 23.42.
Found: C, 56.79; H, 5.32; N, 23.40.
4-Chloro-N'-(phenylsulfonyl)picolinimidamide (5a)
4-Chloropicolinonitrile (2) (0.277 g, 2 mmol) was dissolved in anhydrous MeOH (5 mL) containing DBU
(0.2 mL), as a catalyst. The mixture was refluxed for 10 min, then the benzenosulfonamide (0.309 g, 1.8
mmol) was added, and the mixture was refluxed for 10 h. The reaction was cooled to rt, and the precipitated

2224
HETEROCYCLES, Vol. 78, No. 9, 2009
solid was filtered off and washed with water. The product was crystallized from MeOH to give
4-chloro-N'-(phenylsulfonyl)picolinimidamide (5a) (0.235 g, 40 %) as colorless crystals, mp 119 –
121 °C. 1H NMR (CDCl3) δ 7.58 – 7.67 (3H, m), 7.85 (1H, dd, J1 = 1.9 Hz, J2 = 5.3 Hz), 8.00 (2H, d, J =
7.3 Hz), 8.10 (1H, d, J = 1.9 Hz), 8.29 (1H, bs), 8.68 (1H, d, J = 5.3 Hz), 8.92 (1H, bs); IR (KBr) ν 3418,
3311, 1618, 1574, 1285, 1142, 1084, 791, 590 cm-1. Anal. Calcd for C12H10ClN3O2S: C, 48.73; H, 3.41; N,
14.21; S, 10.84. Found: C, 48.61; H, 3.40; 14.19; S, 10.81.
N'-(4-aminophenylsulfonyl)-4-chloropicolinimidamide (5b)
4-Chloropicolinonitrile (2) (0.257 g, 1.85 mmol) was dissolved in anhydrous MeOH (5 mL) containing
DBU (0.1 mL), as a catalyst. The mixture was refluxed for 10 min. Then 4-aminobenzenosulfonamide
(0.287 g, 1.67 mmol) was added and the mixture was refluxed for 1.5 h. After cooling down the
precipitated
solid
was
filtered
off
and
crystallized
from
EtOH
to
give
N'-(4-aminophenylsulfonyl)-4-chloropicolinimidamide (5b) (0.197 g, 34 %) as a bright solid, mp 206 -
209 °C. 1H NMR (DMSO-d6) δ 5.96 (2H, s), 6.58 (2H, d, J = 8.7 Hz), 7.59 (2H, d, J = 8.7 Hz), 7.81 (1H,
dd, J1 = 1.9 Hz, J2 = 5.3 Hz), 8.04 (1H, d, J = 1.9 Hz), 8.12 (1H, bs), 8.65 (1H, d, J = 5.3 Hz), 8.88 (1H,
bs); IR (KBr) ν 3447, 3423, 3336, 1613, 1589, 1503, 1429, 1265, 1140,1084, 791, 572 cm-1. Anal. Calcd
for C12H11ClN4O2S: C, 46.38; H, 3.57; N, 18.03; S, 10.32. Found: C, 46.30; H, 3.56; N, 17.99; S, 10.29.
4-Chloropicolinohydrazonamide (6)
A mixture of 4-chloropicolinonitrile (2) (1.385 g, 10 mmol) and hydrazine monohydrate (5 mL, 103
mmol) in MeOH (20 mL) was heated under reflux for 30 min and the solvent was evaporated. The residue
was diluted with benzene (10 mL) and evaporated again. Ice (10 g) was added to the residue, the formed
solid was filtered off and crystallized from MeOH to give 4-chloropicolinohydrazonamide (6) (1.15 g,
67 %) as a yellow solid, mp 107 – 109 °C. 1H NMR (CDCl3) δ 4.67 (2H, bs), 5.22 (2H, s), 7.29 (1H, s),
8.06 (1H,s), 8.41 (1H, d, J = 5.4 Hz); IR (KBr) ν 3439, 3330, 3203,1655, 1625,1550, 1577, 1345, 882,
724 cm-1. Anal. Calcd for C6H7ClN4: C, 42.24; H, 4.14; N, 32.84. Found: C, 42.18; H, 4.12; N, 32.79.
5-(4-Chloropyridin-2-yl)-1,3,4-thiadiazole-2(3H)-thione (7)
4-Chloropicolinohydrazonamide (6) (0.511 g, 3 mmol) was dissolved in MeOH (5 mL) and on cooling CS2
(1 mL, 16.5 mmol) was added. The mixture was left at rt for 24 h. Ice (20 g) was added to the reaction
mixture and the precipitated solid was filtered off and crystallized from MeOH to give
5-(4-chloropyridin-2-yl)-1,3,4-thiadiazole-2-thiol (7) (0.24 g, 35 %) as a yellow solid, mp 175 – 177 °C. 1H
NMR (DMSO–d6) δ 7.66 (1H, dd, J1 = 2.0 Hz, J2 = 5.7 Hz), 8.08 (1H, d, J = 2.0 Hz), 8.62 (1H, d, J = 5.7
Hz), 14.96 (1H, s); IR (KBr) ν 3088, 2994, 2890, 1574, 1471, 1401, 1294, 1235, 1073, 782, 728 cm-1. Anal.
Calcd for C7H4ClN3S2: C, 36.60; H, 1.76; N, 18.29; S, 27.92. Found: C, 36.54; 1.75; N, 18.25; S, 27.88.
2-(4-Chloropyridin-2-yl)-5-(methylthio)-1,3,4-thiadiazole (8)

HETEROCYCLES, Vol. 78, No. 9, 2009
2225
4-Chloropicolinohydrazonamide (6) (0.511 g, 3 mmol) was dissolved in anhydrous MeOH (10 mL). On
cooling, CS2 (1 ml, 16.5 mmol) and MeI (0.24 mL, 3.9 mmol) were added, and the mixture was stirred at
rt for 1 h. The precipitated solid was filtered off and crystallized from MeOH:H2O (1:1) to give
2-(4-chloropyridin-2-yl)-5-(methylthio)-1,3,4-thiadiazole (8) (0.42 g, 57 %) as colorless crystals, mp 122
– 123 °C. 1H NMR (CDCl3) δ 2.85 (3H, s), 7.36 (1H, dd, J1 = 2.0 Hz, J2 = 5,4 Hz), 8.32 (1H, d, J = 2.0
Hz), 8.53 (1H, d, J = 5.4 Hz); IR (KBr) ν 1577, 1554, 1396, 1360, 1082, 834, 739 cm-1. Anal. Calcd for
C8H6ClN3S2: C, 39.42; H, 2.48; N, 17.24; S, 26.31. Found: C, 39.37; H, 2.47; N, 17.20; S, 26.27.
General method for synthesis of compounds 9a-c
A solution of 4-chloropicolinohydrazonamide (6) (0.852 g, 5 mmol) in MeOH (15 mL) containing 0.83
mL of triethylamine (6 mmol) was cooled to 0 ºC and then CS2 (0.36 mL, 6 mmol) was added, and the
mixture was stirred at rt for 1 h. Next, iodomethane (5 mmol) (for compound 9a), buthyl iodid (5 mmol)
(for 9b), (chloromethyl)benzene (5 mmol) (for 9c) was added, and the mixture was stirred at rt for 2 h.
The precipitated solid was filtered off and crystallized.
Methyl 2-[amino(4-chloropyridin-2-yl)methylene]hydrazinecarbodithioate (9a)
The crude product was crystallized from MeOH to give yellow solid (89 %), mp 159 – 160 °C. 1H NMR
(Acetone) δ 2.56 (3H, s), 6.99 (2H, s), 7.59 (1H, dd, J1 = 2.1 Hz, J2 = 5.1 Hz), 8.22 (1H, d, J = 2.1 Hz),
8.57 (1H, d, J = 5.1 Hz), 10.93 (1H, s); IR (KBr) ν 3384, 3280, 2911, 1665, 1577, 1365, 1317, 1002, 958,
741 cm-1. Anal. Calcd for C8H9ClN4S2: C, 36.85; H, 3.48; N, 21.49; S, 24.59. Found: C, 36.79; H, 3.46; N,
21.44; S, 24.54.
Butyl 2-[amino(4-chloropyridin-2-yl)methylene]hydrazinecarbodithioate (9b)
1
The crude product was crystallized from EtOH to give yellow solid (32 %), mp 121 – 122 °C. H NMR
(Acetone) δ 0.95 (3H, s), 1.45 (2H, m), 1.67 (2H, m), 3.25 (2H, t, J = 7.2 Hz), 6.99 (2H, s), 7.58 (1H, dd,
J1 = 2.0 Hz, J2 = 5.5 Hz), 8.22 (1H, d, J = 2.0 Hz), 8.57 (1H, d, J = 5.5 Hz), 10.83 (1H, s); IR (KBr) ν
3404, 3311, 2957, 1661, 1508, 1366, 1318, 994, 737 cm-1. Anal. Calcd for C11H15ClN4S2: C, 43.63; H,
4.99; N, 18.50; S, 21.18. Found: C, 43.56; H, 4.97; N, 18.45; S, 21.14.
Benzyl 2-[amino(4-chloropyridin-2-yl)methylene]hydrazinecarbodithioate (9c)
The crude product was crystallized from MeOH to give yellow solid (38 %), mp 218 – 221 °C. 1H NMR
(CDCl3) δ 4.34 (2H, s), 7.06 - 7.98 (9H, m), 8.45 (1H, d, J = 4.9 Hz), 9.74 (1H, s); IR (KBr) ν 3434, 3323,
2923, 1660, 1574, 1469, 1361, 1312, 1241, 1068, 1000, 831, 735, 693, 473 cm-1. Anal. Calcd for
C14H13ClN4S2: C, 49.92; H, 3.89; N, 16.63; S, 19.04. Found: C, 49.79; H, 3.87; N, 16.59; S, 18.98.
Dimethyl amino(4-chloropyridin-2-yl)methylenecarbonohydrazonodithioate (10a)
A solution of 4-chloropicolinohydrazonamide (6) (0.852 g, 5 mmol) and triethylamine (1.66 mL, 11.5
mmol) in MeOH (10 mL) was cooled to 0 ºC and then CS2 (0.3 mL, 5 mmol) was added, and the mixture

2226
HETEROCYCLES, Vol. 78, No. 9, 2009
was stirred at rt for 0.5 h. Iodomethane (0.62 mL, 10 mmol) was added, and the mixture was stirred at rt
for 2 h. The solvent was evaporated and diethyl eter (30 mL) was added to the residue. The precipitated
solid
was
filtered
off
and
crystallized
from
EtOH
to
give
dimethyl
amino(4-chloropyridin-2-yl)methylenecarbonohydrazonodithioate (10a) (1.09 g, 79 %) as a yellow solid,
mp 101 – 103 °C. 1H NMR (CDCl3) δ 2.55 (3H, s), 2.59 (3H, s), 6.15 (2H, s), 7.34 (1H, dd, J1 = 1.9 Hz,
J2 = 5.3Hz), 8.35 (1H, s), 8.46 (1H, d, J = 5.3Hz); IR (KBr) ν 3469, 3359, 1613, 1548, 1460, 1345, 1035,
944, 745 cm-1. Anal. Calcd for C9H11ClN4S2: C, 39.34; H, 4.03; N, 20.39; S, 23.34. Found: C, 39.29; H,
4,02; N, 20.35; S, 23.30.
Dibenzyl amino(4-chloropyridin-2-yl)methylenecarbonohydrazonodithioate (10b)
A solution of 4-chloropicolinohydrazonamide (6) (0.341 g, 2 mmol) and triethylamine (0.84 mL, 6 mmol)
in MeOH (10 mL) was cooled to 0 ºC and then CS2 (0.18 mL, 3 mmol) was added. The mixture was
stirred at rt for 1 h. Next, benzyl chloride (0.46 mL, 4 mmol) was added and the mixture was stirred at rt
for 24 h. The formed precipitate was filtered off and crystallized from MeOH:H2O (1:1) to give dibenzyl
amino(4-chloropyridin-2-yl)methylenecarbonohydrazonodithioate (10b) (0.28 g, 33 %) as a yellow solid,
1
mp 83 – 84 °C. H NMR (CDCl3) δ 4.31 (2H, s), 4.42 (2H, s), 5.95 (2H, s), 7.31 – 7.45 (10H, m), 7.47
(1H, d, J = 2.1 Hz), 8.26 (1H, d, J = 2.1 Hz), 8.44 (1H, d, J = 5.4 Hz); ); IR (KBr) ν 3456, 3365, 1616,
1548, 1461, 1416, 1348, 1239, 1011, 742, 696 cm-1. Anal. Calcd for C21H19ClN4S2: C, 59.07; H, 4.49; N,
13.12; S, 15.02, Found: C, 58.94; H, 4.47; N, 13.08; S, 14.99.
4-Chloro-N'-(1,3-dithian-2-ylidene)picolinohydrazonamide (11)
A solution of 4-chloropicolinohydrazonamide (6) (0.511 g ,3 mmol) and triethylamine (1.05 mL, 7.5
mmol) in MeOH (10 mL) was cooled to 0 ºC and then CS2 (0.27 mL, 4.5 mmol) was added. The mixture
was stirred at rt for 1 h. Next, 1,3-dibromopropane (0.36 mL, 3.6 mmol) was added, and the mixture was
stirred at rt for 3 h. The mixture was neutralized with diluted acetic acid and extracted with
dichloromethane (3 x 30 mL). The organic layer was dried over anhydrous MgSO4 (2 g) for 12 h and
evaporated give 4-chloro-N'-(1,3-dithian-2-ylidene)picolinohydrazonamide (11) (0.27 g, 31 %) as a
yellow solid, mp 166 – 169 °C. 1H NMR (CDCl3) δ 2.48 (2H, m), 3.23 (2H, m), 3.74 (2H, t, J = 5.2 Hz),
6.31 (2H, s), 7.41 (1H, dd, J1 = 3.3 Hz, J2 = 5.1 Hz), 8.36 (1H, s), 8.47 (1H, d, J = 5.1 Hz); IR (KBr) ν
3437, 3307, 2937, 2677, 2491, 1627, 1574, 1433, 1170, 1036, 952 cm-1. Anal. Calcd for C10H11ClN4S2: C,
41.88; H, 3.87; N, 19.53; S, 22.36. Found: C, 41.81; H, 3.86; N, 19.49; S, 22.32.
General method for compounds 12a-c
A solution of 4-chloropicolinohydrazonamide (6) (0.511 g, 3 mmol) in dry dioxane (5 mL) was treated with
isothiocyanatomethane (0.22 g, 3 mmol) (for 12a), allyl isothiocyanate (0.291 mL, 3 mmol) (for 12b) and

HETEROCYCLES, Vol. 78, No. 9, 2009
2227
1-chloro-4-isothiocyanatobenzene (0.508 g, 3 mmol) (for 12c) and heated under reflux for 15 min. The
reaction mixture was then cooled and poured into petroleum ether (30 mL). The product was filtered off
and crystallized from MeOH:H2O (2:1) or dioxane (12c).
2-[Amino(4-chloropyridin-2-yl)methylene]-N-methylhydrazinecarbothioamide (12a)
Reaction with isothiocyanatomethane. Product 12a was isolated as a yellow solid (0.31g, 42 %), mp 175
– 177 °C. 1H NMR (DMSO–d6) δ 3.02 (3H, d, J = 4.6 Hz), 6.92 (2H, s), 7.56 (1H, dd, J1 = 2.1 Hz, J2 =
5.4 Hz), 8.42 (1H, d, J = 4.6 Hz), 8.53 (1H, d, J = 5.4 Hz), 8.62 (1H, d, J = 2.1 Hz), 10.07 (1H, s); IR
(KBr) ν 3440, 3405, 3351, 3279, 3175, 1656, 1550, 1430, 1259, 1070, 711 cm-1. Anal. Calcd for
C8H10ClN5S: C, 39.43; H, 4.14; N, 28.74; S, 13.16. Found: C, 39.38; H, 4.13; N, 28.69; S, 13.13.
N-Allyl-2-[amino(4-chloropyridin-2-yl)methylene]hydrazinecarbothioamide (12b)
Reaction with allyl isothiocyanate. Product 12b was isolated as a yellow solid (0.66 g, 82 %), mp 158 –
160 oC. 1H NMR (CDCl3) δ 4.43 (2H, s), 5.24 (1H, s), 5.32 (1H, d, J = 15.6 Hz), 6.00 (1H, s), 6.44 (2H,
s), 7.35 (1H, s), 7.59 (1H, s), 8.06 (1H, s), 8.45 (1H, s), 9.81 (1H, s); IR (KBr) ν 3423, 3365, 3269, 1655,
1575, 1541, 1431, 1295, 1222, 828, 714 cm-1. Anal. Calcd for C10H12ClN5S: C, 44.52; H, 4.48; N, 25.96;
S, 11.89. Found: C, 44.46; H, 4.46; N, 25.90; S, 11.85.
2-[Amino(4-chloropyridin-2-yl)methylene]-N-(4-chlorophenyl)hydrazinecarbothioamide (12c)
Reaction with 1-chloro-4-isothiocyanatobenzene. Product 12c was isolated as a white solid (0.20 g, 20 %),
mp 164 – 166 °C. 1H NMR (DMSO–d6) δ 7.14 (2H, s), 7.42 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 8.3 Hz),
7.59 (1H, d, J = 5.3 Hz), 8.54 (1H, d, J = 5.3 Hz), 8.77 (1H, s), 10.03 (1H, s), 10.50 (1H, s); IR (KBr) ν
3401, 3281, 3229, 2968, 1665, 1577, 1533, 1467, 1334, 1200, 1090, 828, 721 cm-1. Anal. Calcd for
C13H11Cl2N5S: C, 45.89; H, 3.26; N, 20.58; S, 9.42. Found: C, 45.79; H, 3.25; N, 20.52; S, 9.39.
General procedure for compound 13a-e
A solution of 4-chloropicolinohydrazonamide (6) (0.341 g, 2 mmol) in MeOH (5 mL) was treated with
4-chlorobenzaldehyde (0.281 g, 2 mmol) (for 13a), 5-nitrofuran-2-carbaldehyde (0.282 g, 2 mmol) (for
13b), 5-nitrothiophene-2-carbaldehyde (0.314 g, 2 mmol) (for 13c), 4-hydroxy-3-methoxybenzaldehyde
(0.304 g, 2 mmol) (for 13d) or 4-(dimethylamino)benzaldehyde (0.298 g, 2 mmol) (for 13e) and stirred at
rt for 1h. The product was filtered off and crystallized from MeOH to give compounds 13a-e,
respectively.
4-Chloro-N'-(4-chlorobenzylidene)picolinohydrazonamide (13a)
Reaction with 4-chlorobenzaldehyde. Product 13a was isolated as a yellow solid (0.304 g, 52 %), mp 132 –
134 ºC. 1H NMR (DMSO–d6) δ 7.17 (1H, s), 7.32 (1H, s), 7.51 (2H, d, J = 7.8 Hz), 7.71 (1H, d, J = 4.8 Hz),
7.98 (2H, d, J = 7.8 Hz), 8.23 (1H, s), 8.50 (1H, s), 8.65 (1H, d, J = 4.8 Hz); IR (KBr) ν 3491,

2228
HETEROCYCLES, Vol. 78, No. 9, 2009
3375,1623,1548, 1464, 1327, 1087, 1011, 836, 732 cm-1. Anal. Calcd for C13H10Cl2N4: C, 53.26; H, 3.44;
N, 19.11. Found: C, 53.13; H, 3.43; N, 19.08.
4-Chloro-N'-[(5-nitrofuran-2-yl)methylene]picolinohydrazonamide (13b)
Reaction with 5-nitrofuran-2-carbaldehyde. Produkt 13b was isolated as a red solid (0.4 g, 68 %), mp 174
– 177 ºC. 1H NMR (DMSO–d6) δ 7.43 (1H, d, J = 3.9 Hz), 7.59 (2H, bs), 7.74 (1H, dd, J1 = 1.9 Hz, J2 =
5.4 Hz), 7.84 (1H, d, J = 3.9 Hz), 8.24 (1H, d, J = 1.9 Hz), 8.41 (1H, s), 8.67 (1H, d, J = 5.4 Hz); IR
(KBr) ν 3474, 3348, 1624, 1551, 1467, 1347, 1252, 1179, 1008, 735 cm-1. Anal. Calcd for C11H8ClN5O3:
C, 44.99; H, 2.75; N, 23.85. Fund: C, 44.87; H, 2.74; N, 23.79.
4-Chloro-N'-[(5-nitrothiophen-2-yl)methylene]picolinohydrazonamide (13c)
Reaction with 5-nitrothiophene-2-carbaldehyde. Product 13c was isolated as a yellow solid (0.276 g, 45 %),
mp 218 – 220 oC. 1H NMR (CDCl3) δ 7.03 (1H, s), 7.04 (1H, s), 7.29 (1H, d, J = 3.6 Hz), 7.47 (1H, dd, J1
= 5.1 Hz, J2 = 1.9 Hz), 7.94 (1H, d, J = 1.9 Hz); 8.08 (1H, s); 8.54 (1H, d, J = 3.6 Hz); 8.56 (1H, d, J =
1.9 Hz); IR (KBr) ν 3454, 3356, 1614, 1551, 1486, 1337, 1205, 1060, 814, 733, 708 cm-1. Anal. Calcd for
C11H8ClN5O2S: C, 42.66, H, 2.60; N, 22.61; S, 10.35. Found: C, 42.59; H, 2.59; N, 22.56; S, 10.32.
4-Chloro-N'-(4-hydroxy-3-methoxybenzylidene)picolinohydrazonamide (13d)
Reaction with 4-hydroxy-3-methoxybenzaldehyde. Product 13d was isolated as a yellow solid (0.438 g,
74 %), mp 130 – 131 oC. 1H NMR (DMSO–d6) δ 3.85 (3H, s); 6.79 (1H, d, J = 7.8 Hz); 7.05 (2H, s); 7.17
(1H, d, J = 7.8 Hz); 7.62 (1H, s); 7.66 (1H, d, J = 5.1 Hz); 8.20 (1H, s); 8.36 (1H, s); 8.61 (1H, d, J = 5.1
Hz); 9.49 (1H, s); IR (KBr) ν 3476, 3362, 1621, 1521, 1465, 1285, 1117, 1032, 854, 728, 501 cm-1. Anal.
Calcd for C14H13ClN4O2: C, 55.18; H, 4.30; N, 18.39. Found: C, 55.04; H, 4.28; N, 18.35.
4-Chloro-N'-[4-(dimethylamino)benzylidene]picolinohydrazonamide (13e)
Reaction with 4-(dimethylamino)benzaldehyde. Product 13e was isolated as a yellow solid (0.168 g,
28 %), mp 149 – 151 oC. 1H NMR (DMSO–d6) δ 2.97 (6H, s); 6.71 (2H, d, J = 8.5 Hz); 6.88 (2H, s); 7.64
(1H, d, J = 3.3 Hz); 7.69 (2H, d, J = 8.5 Hz); 8.20 (1H, s); 8.36 (1H, s); 8.61 (1H, d, J = 5.4 Hz); IR
(KBr) ν 3494, 3376, 1604, 1546, 1369, 1175, 812, 728, 587 cm-1. Anal. Calcd for C15H16ClN5: C, 59.70;
H, 5.34; N, 23.21. Found: C, 59.64; H, 5.32; N, 23.17.
4-Chloro-N'-[1-(thiophen-2-yl)ethylidene]picolinohydrazonamide (14)
A solution of 4-chloropicolinohydrazonamide (6) (0.341 g, 2 mmol) in MeOH (10 mL) containing 1 mL
of acetic acid, as a catalyst, was treated with 1-(thiophen-2-yl)ethanone (0.252 g, 2 mmol). The mixture
was left at rt for 1 h. The formed precipitate was filtered off, and crystallized from MeOH to give
4-chloro-N'-[1-(thiophen-2-yl)ethylidene]picolinohydrazonamide (14) as a yellow solid (0.456 g, 82 %),
mp 167 – 169 oC. 1H NMR (DMSO–d6) δ 2.52 (3H, s); 7.04 (2H, bs); 7.15 (1H, t, J = 4.8 Hz); 7.63 (1H, d,
J = 3.4 Hz); 7.71 (1H, dd, J1 = 5.3 Hz, J2 = 1.4 Hz); 7.85 (1H, d, J = 4.8 Hz); 8.45 (1H, d, J = 1.4 Hz); 8.66

HETEROCYCLES, Vol. 78, No. 9, 2009
2229
(1H, d, J = 5.3 Hz); IR (KBr) ν 3438, 3311, 1613, 1548, 1466, 1417, 1294, 1018, 832, 717 cm-1. Anal. Calcd
for C12H11ClN4S: C, 51.70; H, 3.98; N, 20.10; S, 11.50. Found: C, 51.61; H, 3.96; N, 20.05; S, 11.47.
N'-[Amino(4-chloropyridin-2-yl)methylene]pyrimidine-2-carbohydrazonamide (15a)
A solution of pyrimidine-2-carbonitrile (0.525 g, 5 mmol) and triethylamine (0.5 mL) in MeOH (10 mL),
was refluxed for 2 h. Next, the solvent was evaporated, and MeOH (5 mL) followed by
4-chloropicolinohydrazonamide (6) (0.852 g, 5 mmol) and acetic acid (0.2 mL) were added to the residue.
The mixture was stirred for 5 min, and the formed precipitate was filtered off and crystallized from
MeOH/H2O (1:1) to give N'-[amino(4-chloropyridin-2-yl)methylene]pyrimidine-2-carbohydrazonamide
o
1
(15a) (0.497 g, 35 %) as a yellow crystals, mp 188 – 190 C. H NMR (DMSO–d6) δ 6.39 (2H, s); 6.52
(2H, s); 7.31 (2H, m); 8.39 (1H, d, J = 1.9 Hz); 8.46 (1H, d, J = 5.4 Hz); 8.84 (2H, d, J = 4.8 Hz); IR
(KBr) ν 3296, 1611, 1547, 1443, 1349, 1038, 817, 639 cm-1. Anal. Calcd for C11H10ClN7: C, 47.92; H,
3.66; N, 35.56. Found: C, 47.82; H, 3.65; N, 35.49.
N'-[Amino(4-chloropyridin-2-yl)methylene]pyrazine-2-carbohydrazonamide (15b)
Methyl pyrazine-2-carbimidate (0.274 g,
2
mmol) was added to
a
solution of
4-chloropicolinohydrazonamide (6) (0.341 g, 2 mmol) and acetic acid (o.1 mL) in MeOH (10 mL) and the
mixture was stirred at rt for 5 min. The formed solid was filtered off and crystallized from EtOH to give
N'-[amino(4-chloropyridin-2-yl)methylene]pyrazine-2-carbohydrazonamide (15b) (0.418 g, 76 %) as a
yellow crystals, mp 255 – 257 oC. 1H NMR (DMSO–d6) δ 7.45 (2H, s), 8.54 - 8.70 (6H, m), 9.65 (2H, s);
IR (KBr) ν 3400, 3293, 1605, 1548, 1464, 1425, 1020, 714 cm-1. Anal. Calcd for C11H10ClN7: C, 47.92;
H, 3.66; N, 35.56. Found: C, 47.81; H, 3.65; N, 35.48.
General method for compounds 16a and 16b.
A solution of 1 mmol of N'-[amino(4-chloropyridin-2-yl)methylene]pyrimidine-2-carbohydrazonamide
(15a) or N'-[amino(4-chloropyridin-2-yl)methylene]pyrazine-2-carbohydrazonamide (15b) in glacial
acetic acid (3 mL) was refluxed for 1 h. The reaction mixture was then cooled and poured into cold water.
The formed solid product was filtered off, and crystallized from MeOH/H2O (2:1) to give compounds 16a
and 16b, respectively.
2-[5-(4-Chloropyridin-2-yl)-4H-1,2,4-triazol-3-yl]pyrimidine (16a)
Reaction with methyl pyrimidine-2-carbimidate. Product 16a was isolated as colorless solid (0.219 g,
o
1
85 %), mp 204 – 205 C. H NMR (DMSO–d6) δ 7.62 (2H, m), 8.20 (1H, s), 8.71 (1H, d, J = 5.4 Hz),
9.01 (2H, d, J = 4.8 Hz), 11.25 (1H, s); IR (KBr) ν 3444, 1565, 1452, 1396, 1210, 1152, 789, 754 cm-1.
Anal. Calcd for C11H7ClN6: C, 51.08; H, 2.73; N, 32.49. Found: C, 50.96; H, 2.72; N, 32.41.
2-[5-(4-chloropyridin-2-yl)-4H-1,2,4-triazol-3-yl]pyrazine (16b)

2230
HETEROCYCLES, Vol. 78, No. 9, 2009
Reaction with methyl pyrazine-2-carbimidate. Product 16b was isolated as colorless solid (0.229 g, 89 %),
mp 217 – 219 oC. 1H NMR (DMSO–d6) δ 6.92 (1H, m), 7.61 (1H, s), 8.41 (1H, d, J = 5.2 Hz), 8.74 (2H,
m), 9.32 (1H, m), 11.15 (1H, s); IR (KBr) ν 3435, 1633, 1556, 1380, 1160, 1019, 788, 763 cm-1. Anal.
Calcd for C11H7ClN6: C, 51.08; H, 2.73; N, 32.49. Found: C, 51.01; H, 2.72; N, 32.43.
4-Chloro-N'-methylpicolinohydrazonamide (17)
A mixture of 4-chloropicolinonitrile (0.415 g, 3 mmol) and methyl hydrazine (0.32 mL, 6 mmol) in
MeOH (3 mL) was refluxed for 30 min and the solvent was evaporated. The residue was diluted with
benzene (10 mL), and evaporated again. Ice (10 g) was added to the residue, the product was filtered off
and crystallized from benzene: petroleum ether (1:10) to give 4-chloro-N'-methylpicolinohydrazonamide
(17) (0.26 g, 47 %) as a yellow crystals, mp 102 – 104 °C. 1H NMR (CDCl3) δ 3.01 (3H, s), 5.15 (2H, s),
7.25 (1H, dd, J1 = 1.9 Hz, J2 = 5.3 Hz), 7.28 (1H, s), 8.12 (1H, d, J = 1.9 Hz), 8.39 (1H, d, J = 5.3 Hz); IR
(KBr) ν 3326, 3206, 1648, 1574, 1548, 1475, 1346, 1071, 829, 735 cm-1. Anal. Calcd for C7H9ClN4: C,
45.54; H, 4.91; N, 30.35. Found: C, 45.46; H, 4.89; N, 30.29.
Methyl 2-[amino(4-chloropyridin-2-yl)methylene]-1-methylhydrazinecarbodithioate (18)
A solution of 4-chloro-N'-methylpicolinohydrazonamide (17) (0.554 g, 3 mmol) and triethylamine (0.5
mL, 3.6 mmol) in MeOH (15 mL) was cooled to 0 ºC and then CS2 (0.22 mL, 3.6 mmol) was added. The
reaction mixture was stirred at rt for 1.5 h. Next, iodomethane (0.19 mL, 3 mmol) was added and the
mixture was stirred at rt for next 1 h. The solvent was evaporated and petroleum ether (20 mL) was added
to the residue. The precipitated solid was filtered off and crystallized from MeOH:H2O (3:2) to give
methyl 2-[amino(4-chloropyridin-2-yl)methylene]-1-methylhydrazinecarbodithioate (18) (0.230 g, 28 %)
as a yellow solid, mp 175 – 177 °C. 1H NMR (CDCl3) δ 2.55 (3H, s), 3.73 (3H, s), 6.15 (2H, s), 7.47 (1H,
dd, J1 = 2.1 Hz, J2 = 5.2 Hz), 8.37 (1H, d, J = 2.1 Hz), 8.53 (1H, d, J = 5.2 Hz); IR (KBr) ν 3409, 3294,
2917, 1629, 1575, 1368, 1100, 987, 740 cm-1. Anal. Calcd for C9H11ClN4S2: C, 39.34; H, 4.03; N, 20.39;
S, 23.34. Found: C, 39.28; H, 4.01; N, 20.34; S, 23.28.
5-(4-Chloropyridin-2-yl)-3-methyl-1,3,4-thiadiazole-2(3H)-thione (19)
A solution of 4-chloro-N'-methylpicolinohydrazonamide (17) (0.554 g, 3 mmol) in MeOH (5 mL) was
cooled to 0 ºC and then CS2 (1 mL, 16.5 mmol) was added. The reaction mixture was left at rt for 12 h.
The solid product was filtered off and crystallized from EtOH:H2O (4:1) to give
5-(4-chloropyridin-2-yl)-3-methyl-1,3, 4-thiadiazole-2(3H)-thione (19) (0.432 g, 59 %) as a yellow crystals,
mp 181 – 183 °C. 1H NMR (CDCl3) δ 3.97 (3H, s), 7.38 (1H, dd, J1 = 2.0 Hz, J2 = 5.4 Hz), 8.01 (1H, d, J =
2.0 Hz), 8.51 (1H, d, J = 5.4 Hz); IR (KBr) ν 3056, 1572, 1404, 1295, 1135, 1101, 757 cm-1. Anal. Calcd
for C8H6ClN3S2: C, 39.42; H, 2.48; N, 17.24; S, 26.31. Found: C, 39.33; H, 2.47; N, 17.20; S, 26.26.
3-(4-Chloropyridin-2-yl)-1,4-dimethyl-1H-1,2,4-triazole-5(4H)-thione (20)

HETEROCYCLES, Vol. 78, No. 9, 2009
2231
Method A:
A solution of 4-chloro-N'-methylpicolinohydrazonamide (17) (0.369 g, 2 mmol) in dry dioxane (5 mL)
was treated with isothiocyanatomethane (0.15 g, 2 mmol) and refluxed for 15 min. The reaction mixture
was then cooled and poured into petroleum ether (30 mL). The product was filtered off and crystallized
from H2O to give 3-(4-chloropyridin-2-yl)-1,4-dimethyl-1H-1,2,4-triazole-5(4H)-thione (20) (0.147 g,
31 %) as a yellow solid, mp 169 – 170 °C.
Method B:
Isothiocyanatomethane
(0.15
g,
2
mmol)
was
added
to
a
solution
of
4-chloro-N'-methylpicolinohydrazonamide (17) (0.369 g, 2 mmol) in MeOH (5 mL), and the mixture was
stirred at rt for 1 h. Next, the solvent was evaporated and ice (20 g) was added to the residue. The
precipitate
was
filtered
off
and
crystallized
from
MeOH:H2O
(1:1)
to
give
3-(4-chloropyridin-2-yl)-1,4-dimethyl-1H-1,2,4-triazole-5(4H)-thione (20) (0.25 g, 52 %) as a yellow
solid, mp 169 – 170 °C. 1H NMR (CDCl3) δ 3.91 (3H, s), 4.06 (3H, s), 7.41 (1H, dd, J1 = 2.0 Hz, J2 = 5.4
Hz), 8.05 (1H, d, J = 2.0 Hz), 8.57 (1H, d, J = 5.4 Hz); IR (KBr) ν 3054, 1576, 1480, 1364, 1162, 1343,
767 cm-1. Anal. Calcd for C9H9ClN4S: C, 44.91; H, 3.77; N, 23.28; S, 13.32. Found: C, 44.82; H, 3.76; N,
23.22; S, 13.29.
REFERENCES
1. A. Olczak, M. L. Glowka, J. Golka, M. Szczesio, J. Bojarska, K. Kozlowska, H. Foks, and C.
Orlewska, J. Mol. Struct., 2007, 830, 171.
2. D. Ranft, G. Lehwark-Yvetot, K.-J. Schaper, and A. Buge, Arch. Pharm., 1997, 330, 169.
3. L. Doub, L. M. Richardson, D. R. Herbst, M. L. Black, O. L. Stevenson, L. L. Bambas, G. P.
Youmans, and A. S. Youmans, J. Am. Chem. Soc., 1958, 80, 2205.
4. D. Varlet, E. Fourmaintraux, P. Depreux, and D. Lesieur, Heterocycles, 2000, 53, 797.
5. C. M. Tice and L. M. Bryman, Tetrahedron, 2001, 57, 2689.
6. D.-K. Kim, J. Kim, and H.-J. Park, Bioorg. Med. Chem., 2004, 12, 2013.
7. S. Kubota, Y. Koida, T. Kossaka, and O. Kinino, Chem. Pharm. Bull., 1970, 18, 1696.
8. A. Balows, H. J. Hausler, K. L. Herrmann, H. D. Isenberg, and H. J. Shadomy: Manual of Clinical
Microbiology (5th ed). Am. Soc. Microbiol., Washington, 1991.