Synthesis and tuberculostatic activity of some 1,1-bis-methylthio-2-nitro- ethene derivatives

Article abstract of DOI:10.1080/104265090920921

1,1-bis-methylthio-2-nitro-ethene was used as a substrate to the syntheses of new heterocyclic compounds. In the reactions, with 1-phenylpiperazine - the corresponding diaminonitroethane 1, 1,3-diaminonitropropane, and 1,3-diaminonitropropanol - the nitro

Full text of DOI:10.1080/104265090920921

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Synthesis and Tuberculostatic
Activity of Some 1,1-Bis-
methylthio-2-nitro-ethene
Derivatives
Henryk Foks a , Danuta Pancechowska-Ksepko a ,
Mieczysław Janowiec b , Zofia Zwolska b & Ewa
Augustynowicz-Kopeé b
a Medical University of Gdańsk, Department of
Organic Chemistry , Gdańsk, Poland
b Institute of Tuberculosis and Pulmonary Diseases,
Department of Microbiology , Warsaw, Poland
Published online: 22 Aug 2006.
To cite this article: Henryk Foks , Danuta Pancechowska-Ksepko , Mieczysław
Janowiec , Zofia Zwolska & Ewa Augustynowicz-Kopeé (2005) Synthesis and
Tuberculostatic Activity of Some 1,1-Bis-methylthio-2-nitro-ethene Derivatives,
Phosphorus, Sulfur, and Silicon and the Related Elements, 180:10, 2291-2297, DOI:
10.1080/104265090920921
To link to this article: http://dx.doi.org/10.1080/104265090920921
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Phosphorus, Sulfur, and Silicon, 180:2291–2297, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090920921
Synthesis and Tuberculostatic Activity of Some
1,1-Bis-methylthio-2-nitro-ethene Derivatives
Henryk Foks
Danuta Pancechowska-Ksepko
Department of Organic Chemistry, Medical University of Gdan´sk,
Gdan´sk, Poland
ꢀ
Mieczyslꢀaw Janowiec
Zofia Zwolska
Ewa Augustynowicz-Kopec
´
Department of Microbiology, Institute of Tuberculosis and Pulmonary
Diseases, Warsaw, Poland
1,1-bis-methylthio-2-nitro-ethene was used as
a substrate to the syntheses
of new heterocyclic compounds. In the reactions, with 1-phenylpiperazine—
the corresponding diaminonitroethane 1, 1,3-diaminonitropropane, and 1,3-
diaminonitropropanol—the nitromethylenotetrahydropyrimidine derivatives
2
and were prepared, whereas, with o-phenylenediamine—2-nitromethyleno-
3
benzimidazole 4 were obtained. In the condensation reactions of compounds 2, 3,
and 4 with benzoyl isothiocyanate, the products 5, 6, and 7 were obtained, and
afterwards two of them, 5 and 6, were transformed into the isothiazolines 8 and 9.
1,1-bis-(4-phenylpiperazino)-2-nitroethane (1) was exposed to the action of phenyl
isothiocyanate and the derivative obtained (10) was transformed, in the reaction
with phenacylbromide, in to benzoylonitrothiophene 11. The diazo compounds 12,
13, and 14 were obtained in the reactions of nitromethylenotetrahydropyrimidines
2 and 3 and of 2-nitromethylenobenzimidazole 4 with benzenediazonium chloride.
The derivatives obtained were tested in vitro for their tuberculostatic activity. The
compounds 7 (MIC 8–32 µg/mL) and 14 (MIC 16–63 µg/mL) appeared to be the
most active compounds.
Keywords
1,1-Bis-methylthio-2-nitro-ethane; 1-phenylpiperazine; 1,3-diamines;
2-nitromethyleno-benzimidazoles; tuberculostatic
INTRODUCTION
The nitro ketene dithioacetals bearing different substituents have
been utilized in the synthesis of many heterocyclic compounds, such as
Received October 12, 2004; accepted October 14, 2004.
Address correspondence to Henryk Foks, Medical University of Gdan´sk, Department
of Organic Chemistry, Gdan´sk, Poland. E-mail: hfoks@farmacja.amg.gda.pl
2291

2292
H. Foks et al.
pyrrole, pyrimidine, pyridazine, triazole, thiazole, pyridine, thiophene,
and isoxazole derivatives.1 They also served as useful precursors for
aminonitroethene derivatives which exhibited various biological ac-
tivities, including gastroprotective2 secretion and inhibition, antacid,
antiulcer,3 antifungal, and antibacterial,4,5 inhibition of the histamine
H2 receptor6 activities.
CHEMISTRY
In the present work, an attempt at obtaining the new heterocyclic
compounds of potentially tuberculostatic activity was made. 1,1-
bis-methylthio-2-nitro-ethene, obtained from nitromethane and car-
bon disulphide according to the method described by Gomperer and
Schaefer,7 was used as a substrate. This compound reacted with 1-
phenyl-piperazine and diphenylpiperazinonitroethen 1 was obtained
in good yield (Scheme 1). The nitromethylenotetrahydropyrimidine
derivatives 2 and 3 were produced from the starting compound and
1,3-diaminopropane as well as 1,3-diamino-2-propanol. Under the same
conditions, upon heating the equimolar amounts of the substrates,
1,1-bis-methylthio-2-nitroethene and o-phenylenediamine in ethanol,
2-nitromethylenobenzimidazole 4 was produced.8 The compounds 2, 3,
and 4 reacted with benzoyl isothiocyanate to form, after several hours of
heating in acetone, the benzoylthioamide derivatives 5, 6, and 7. Two
SCHEME 1

1,1-BIS-methylthio-2-nitro-ethene Derivatives
2293
of them, 5 and 6, were oxidized with hydrogen peroxide in an acidic
medium to the isothiazoline derivatives 8 and 9 by analogy to the reac-
tions reported earlier.9−13
1,1-bis-(4-phenylpiperazino)-2-nitro-ethene 1 reacted with phenyl
isothiocyanate, while refluxing in dioxane, which gave compound 10. It
transformed in the next step into the benzoylnitrothiophene derivative
11.
The nucleophilic character of the carbon atom next to the nitro group
in compounds 2 and 3 was utilized in the reactions with benzenediazo-
nium chloride, which produced diazo compounds 12 and 13. The reac-
tion with nitro-methylenobenzimidazole 4, conducted analogically, gave
the diazo derivative 14.
PHARMACOLOGICAL TESTS
The compounds obtained were tested for their tuberculostatic activity
towards the mycobacterium tuberculosis H37Rv strain and two strains
isolated from the tuberculotic patients: one was resistant to the Ison-
icotinic Acid Hydrazide (INH), Ethambutol (ETB), and Rifampycine
(RFP); the other was fully susceptible to the drugs administered.
Tuberculostatic activity was tested in vitro by the classical test tube
method with Yoiman’s liquid medium containing 10% of bovine serum.
The Minimum Inhibiting Concentration (MIC) values were within
8–500 µg/mL. The most active compounds 7 (MIC 8–32 µg/mL)
and 14 (MIC 16–63 µg/mL) were tested in a complex way with
the following standard strains (Table I): Myc. H37Rv—human strain;
TABLE I Tuberculostatic Activity of Compounds 7
and 14
Compound
Mycobacterium
strains
7 (MIC)
14 (MIC)
H37Rv
An5
8
32
63
32
63
250
32
63
500
250
250
16
250
32
125
63
500
125
250
250
500
500
Kansasii
Scrophulaceum
Intracellurae
Fortuitum
Kirchbarg
Wells
Smegmatis
607
Phlei

2294
H. Foks et al.
Myc. An5—cattle strain; Myc. kansasii—photochromogenic strain;
Myc. scrofulaceum—scotochromogenic strain; Myc. intracellulare—
nonchromogenic strain; Myc. fortuitum—quick-growing strain from IV
group according to Runyn; Myc. kirchberg—bird-strain; Myc. wells—
rodents’ strain; and from quick-growing saprophytic strains, Myc. smeg-
matic, Myc. 607 and Myc. phlei.
EXPERIMENTAL
Melting points were determined with the Reichert apparatus and are
1
uncorrected. The H NMR spectra were taken with a Varian Gemini
200 spectrometer. Reaction yields and the physical constants of the
compounds obtained are given in Table II. The results of elemental
analysis for C and H for all of the compounds that were obtained were
in good agreement with the data calculated.
1,1-Bis(4-phenyl-piperazin-1-yl)-2-nitro-ethene (1)
1,1-bis-methylthio-2-nitroethene (5 mmole) dissolved in ethanol
(15 mL) was refluxed with 1-phenylpiperazine (10 mmole) for
1 h. On cooling down, the precipitate of compound 1 was filtered
off.
2-(Nitromethylene)hexahydropyrimidine (2),
2-(Nitromethylene)hexahydropyrimidin-5-ol (3),
and 2-Nitromethyl-1H-benzimidazole (4)
1,1-bis-methylthio-2-nitroethene (10 mmole) that was dissolved in
ethanol (20 mL) was refluxed with 1,3-diaminopropane; 1,3-diamino-
2-propanol; or o-phenylenodiamine, respectively, (10 mmole) for 1 h.
Methyl mercaptan was evolved intensely when heating. On cooling
down, the products precipitated and were filtered off.
N-[2-Nitro-2-(tetrahydro-pyrimidin-2-ylidene)-thioacetyl]-
benzamide (5), N[2-(5-hy-droxy-tetrahydro-pyrimidin-2-
ylidene)-2-nitro-thioacetyl]-benzamide (6), N-2-(1H-
benzimidazol-2-yl)-2-nitro-thioacetylbenzamide (7)
Compound 2, 3, or 4 (5 mmole), respectively, dissolved in anhydrous
acetone (10 mL) and was refluxed with benzoyl isothiocyanate (5 mmole)
for 3 h. On cooling down, the coloured precipitates of compounds 5, 6,
or 7 were filtered off.

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H. Foks et al.
N-(3-Nitro-4,5,6,7-tetrahydro-isothiazolo[2,3-a]pyrimidin-2-
ylidene)-benzamide (8), N-(6-hydroxy-3-nitro-4,5,6,7-
tetrahydro-isothiazolo[2,3-a]pyrimidin-2-ylidene)-
benzamide (9)
Compound 5 or 6 (2.5 mmole) that was dissolved in ethanol (20 mL) was
treated with concentrated HCl (0.25 mL) and then treated with 30%
H2O2 (0.6 mL) and refluxed 0.5 h. The solution was decolorized while
heating and upon cooling down the compounds 8 or 9 precipitated.
3,3-Bis-(4-phenyl-piperazin-1-yl)-2-nitro-N-phenyl-
thioacrylamide (10)
Compound 1 (2.5 mmole) dissolved in anhydrous dioxane (10 mL) was
refluxed with phenyl isothiocyanate (2.5 mmole) for 2 h. The solvent
was then evaporated, the oily residue was treated with ethyl ether, and
the precipitated compound 10 was filtered off.
[4-Nitro-5-phenylamino-3-(4-phenylpiperazin-1-yl)-thiophen-2-
yl]-phenyl-methanone (11)
Compound 10 (2 mmole) and phenacylbromide (2 mmole) were dissolved
in ethanol (15 mL) and refluxed for 2 h. On cooling down, the precipi-
tated compound 11 was filtered off.
[Nitro-(tetrahydro-pyrimidin-2-ylidene)-methyl]-phenyl-
diazene (12), 2-(Nitro-phenyl-azomethylene)-hexahydro-
pyrimidin-5-ol (13), [(1H-benzoimidazol-2-yl)-nitro-methyl]-
phenyl-diazene (14)
Compound 2, 3, or 4, (10 mmole) respectively, that was dissolved in
a solution of dimethylformamide (15 mL) and ethanol (30 mL) was
treated with sodium acetate (1.25 g) and was dissolved in water (5 mL).
The solution of a diazonium salt was prepared separately from aniline
(0.91 mL), water (2.5 mL), concentrated HCl (2.5 mL), and NaNO2 (1 g)
in water (5 mL). This solution was added dropwise to the reaction mix-
ture and stirred for 0.5 h at ambient temperature. The precipitate 12,
13, or 14 was filtered off.
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