3,7-Dichloro-2,6-di-(4,4′-butyl-amidino)benzo [2,1-b:4,5-b′]dithiophene dihydrochloride as potential anti-HIV agent

Article abstract of DOI:10.1081/SCC-100105671

The multistep synthesis of substituted diamidine of benzodithiophene structure as soluble salt is described. On this way was prepared the compound in title, 3,7-dichloro-2,6-di-(4,4′-n-butyl-amidino)benzo[2,1-b:4,5-b′] dithiophene dihydrochloride 6a. Prep

Full text of DOI:10.1081/SCC-100105671

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3,7-DICHLORO-2,6-DI-(4,4′-BUTYL-
AMIDINO)BENZO[2,1-b:4,5-b′]DITHIO-PHENE
DIHYDROCHLORIDE AS POTENTIAL ANTI-HIV AGENT
a
D. Pavliĉić & G. Karminski-Zamola b
a Department of Organic Chemistry Faculty of Chemical Engineering and Technology ,
University of Zagreb , Marulicev trg 20, Zagreb, 10000, Croatia
b Department of Organic Chemistry Faculty of Chemical Engineering and Technology ,
University of Zagreb , Marulicev trg 20, Zagreb, 10000, Croatia
Published online: 16 Aug 2006.
To cite this article: D. Pavliĉić & G. Karminski-Zamola (2001) 3,7-DICHLORO-2,6-DI-(4,4′-BUTYL-AMIDINO)BENZO[2,1-
b:4,5-b′]DITHIO-PHENE DIHYDROCHLORIDE AS POTENTIAL ANTI-HIV AGENT, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 31:19, 2997-3003, DOI: 10.1081/SCC-100105671
To link to this article: http://dx.doi.org/10.1081/SCC-100105671
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SYNTHETIC COMMUNICATIONS, 31(19), 2997–3003 (2001)
3,7-DICHLORO-2,6-DI-(4,40-BUTYL-
AMIDINO)BENZO[2,1-b:4,5-b0]DITHIO-
PHENE DIHYDROCHLORIDE AS
POTENTIAL ANTI-HIV AGENT
D. Pavlicic and G. Karminski-Zamola*
Department of Organic Chemistry Faculty of
Chemical Engineering and Technology,
University of Zagreb, Marulicev trg 20,
10000 Zagreb, Croatia
ABSTRACT
The multistep synthesis of substituted diamidine of benzo-
dithiophene structure as soluble salt is described. On this
way was prepared the compound in title; 3,7-dichloro-2,6-
di-(4,40-n-butyl-amidino)benzo[2,1-b:4,5-b0]dithiophene dihy-
drochloride 6a. Prepared compound could serve as new
intercalator on DNA in the HIV infection.
INTRODUCTION
There is a lot of articles describing the biological activity of diamidino
substituted heterocycles, specially in the recent time.1–5 A number of
aromatic diamidines have been shown to bind to the minor groove of
*Corresponding author.
2997
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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PAVLICIC AND KARMINSKI-ZAMOLA
DNA and to exhibit useful antimicrobial activities.6–9 A number of hypo-
thesis for the mode of antimicrobial action of aryl diamidines have been
proposed.10
Recently, amidino-substituted-diphenyl-furans have been demonstra-
ted diverse pharmacological activities. On one hand they show significant
antiproliferative activities against various tumor cell lines. On the other
hand, they display useful antimicrobial effects.2
Some carbamate analogues of 2,5-bis-(4-amidino-phenyl)furan are
synthesized and evaluated as prodrugs against Pneumocystis carini pneumo-
nia (PCP), (which is a leading cause of mortality and morbidity in patients
suffering from AIDS) (acquired immune deficiency syndrome), in the
immuno suppressed rat model.4 It was shown that they were more active
and less toxic than pentamidine for which was shown to inhibit DNA
topoisimerases from P. carini.11 Recently, 2-buten bridged diamidine analo-
gues of pentamidine were synthesized and in vitro examined as novel agents
to treat AIDS related infections against P. carini.5
RESULTS AND DISCUSSION
In continuation of our earlier work12,13 we prepared in multistep syn-
thesis the compound in title, for which we proposed its anti-HIV activity.
In consideration with its structure it could serve as intercalator or groove
binder of the DNA double helix.
In the first step of the reaction, it was prepared the mixture of
the diacid dichlorides 2a, 2b and 2c by heating overnight of E,E-1,4-phenyl-
ene-di-(2-ethenyl)-carboxylic acid with SOCl2 in the presence of the catalytic
amount of pyridine. Without the isolating of 2a from 2b and 2c, to
the mixture of diacid dichlorides was added equimolar amount of n-butyl-
amine in CH2Cl2 and the mixture was allowed to stir at room tem-
perature overnight. The mixture of amides 3a, 3b, and 3c was separated
by chromatography. The yields were as; 3a 78%, 3b 17% and 3c 5%.
In the next step of the reaction 3a reacts with SOCl2, and few drops
of DMF in CHCl3 and corresponding imidoyl chloride 4a was isolated
in the yield of the 95.2%. Without further purification 4a was used
in the next step of the reaction, saturating of 4a in CH2Cl2 with dry ammo-
nia gas at 0–5ꢀC. The yield on the corresponding diamidine 5a was
43.2%. In the last step of the reaction, free base of 5a was converted
into the salt by taking it up in the methanol saturated with HCl
and stirring. The disalt 6a was obtained in the yield of 8.5% and
1
was characterized by elemental analysis, H NMR spectra, and 13C NMR
spectra.

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Scheme.

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EXPERIMENTAL
Mps were determined on a Kofler hot stage microscope and are uncor-
rected. IR spectra were recorded on a Perkin–Elmer Model 257 spectro-
1
photometer in KBr discs H and 13C NMR spectra were recorded on a
Varian Gemini 300 (300 MHz) with TMS as internal standard in CDCl3
or DMSO-d6.
Synthesis of 3,7-Dichloro[1,2-b:4,5-b0]dithiophene-2,6-
dicarbonylchloride 2a/3-Chloro-6-(2-chlorocarbonyl-
ethenyl)benzo[b]thieno-2-carbonylchloride 2b and
1,4-Phenylene-di-(2-ethenyl)carboxylic Acid
Dicarbonylchloride 2c
The mixture of the compounds 2a, 2b and 2c was prepared by the
dropwise addition of thionyl chloride (30 mL, 0.42mol) into the stirred
mixture of E,E-1,4-phenylene-di-(2-ethenyl)carboxylic acid 1 (10.06 g,
0.046 mol) and pyridine (1 mL) at room temperature. The reaction mixture
was heated for 8 h at 140ꢀC. To the reaction mixture was added 80 mL of
toluene to remove successfully the excess of the thionye chloride under
reduced pressure. The remaining material was extracted with chloroform
(100 mL) to remove soluble by products. The obtained yellow crystals
8.47 g are the mixture of the products 2a, 2b and 2c. Without further separa-
tion, the mixture was used in the next step of the reaction.
Synthesis of 3,7-Dichloro[1,2-b:4,5-b0]dithiophene-2,6-di-
(n-butyl)carboxamide 3a/3-Chloro-6-(2-n-butylcarbamoyl-
ethenyl)-benzo[b]thieno-2-(n-butyl)carboxamide
3b and 1,4-Phenylene-di-(2-ethenyl)carboxylic Acid
Di-(n-butyl)carboxamide 3c
To the suspension of the mixture of 2a, 2b and 2c (2.00 g, 0.005 mol)
in dry dichloromethane was added n-butylamine (2.00 mL, 0.020 mol),
and stirred at room temperature 22 h. Excess of n-butylamine and solvent
was removed under reduced pressure and water was added. The obtained
solid was filtered off, washed with 10% HCl, than with 10%
NaHCO3. After drying the solid, which was the mixture of the products
3a, 3b and 3c was chromatographed on the silica gel column with the

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dichloromethane : methanol (40:1). First was eluated 3a. The yield of the
white crystals of 3a was 0.843 g (78.0%) mp 219–223ꢀC. IR (cmÀ1) (KBr):
3721–3380 (NH), 2958–2864 (CH2), 1644 (CONH). 1H NMR (CDCl3),
d: 7.80 (s, 2H, NH), 7.17 (s, 2H, Harom.), 3.55 (AB, J1 ¼ 6.67, J2 ¼ 6.41 Hz,
4H, CH2), 1.61–1.73 (m, 4H, CH2), 1.38–1.56 (m, 4H, CH2), 1.00 (t,
J ¼ 7.43 Hz, 6H, CH3). 13C NMR (CDCl3), d: 160.25, 136.01, 133.90,
39.90, 31.26 ppm. (Found: C, 52.20; H, 4.56; N, 6.33, C20H22Cl2N2O2S2,
requires C, 52.51; H, 4.85; N, 6.12%).
The yield of the white crystals of 3b was 0.184 g (17%) mp 224–226ꢀC.
IR (cmÀ1) (KBr): 3295 (NH), 2958–2872 (CH2), 1652(CONH), 1632(C ¼C).
1H NMR (CDCl3), d: 7.91 (s, 1H, Harom.), 7.80 (d, J ¼ 8.47 Hz, 1H, Harom.),
7.71 (d, J ¼ 15.38 Hz, Hethen.), 7.59 (d, J ¼ 8.46 Hz, Harom.), 7.14 (s, 1H, NH),
6.52(d, J ¼ 15.38 Hz, 1H, Hethen.), 5.87 (s, 1H, NH), 3.52(AB J ¼ 6.93,
1
J2 ¼ 6.67 Hz, 2H, CH2), 3.42(AB J ¼ 6.92, J2 ¼ 6.67 Hz, 2H, CH2),
1
1.72–1.53 (m, 4H, CH2), 1.50–1.37 (m, 4H, CH2), 1.01–0.93 (m, 6H, CH3).
13C NMR (CDCl3), d: 165.40, 160.72, 138.42, 137.96, 137.34, 135.24, 134.62,
125.27, 124.78, 124.00, 123.75, 39.26, 32.09, 31.84, 20.48, 20.44, 14.54 ppm.
(Found: C, 60.92; H, 6.47; N, 7.00, C20H25ClN2O2S, requires C, 61.13;
H, 6.41; N, 7.13%). The last was elueted 3c in the yield of 0.054 g
(5%) mp 285–287ꢀC. IR (cmÀ1) (KBr): 3290 (NH), 2959–2871 (CH2), 1651
1
(CONH), 1619 (C¼C). H NMR (DMSO-d6), d: 8.13 (s, 2H, NH), 7.60 (s,
4H, Harom.), 7.42(d, J ¼ 15.79 Hz, 2H, Hethen.), 6.67 (d, J ¼ 15.77 Hz, 2H,
H
ethen.), 3.20 (AB, J1 ¼ 6.42, J2 ¼ 6.83 Hz, 4H, CH2), 1.49–1.41 (m, 4H,
CH2), 1.37–1.29 (m, 4H, CH2), 0.91 (t, J ¼ 7.22 Hz, 6H, CH3). 13C NMR
(CDCl3), d: 164.79, 137.74, 135.99, 128.12, 123.09, 31.35, 19.74, 3.79 ppm.
(Found: C, 73.27; H, 8.32; N, 8.27, C20H28N2O2, requires C, 73.14; H,
8.59; N, 8.53%).
Synthesis of 3,7-Dichloro[1,2-b:4,5-b0]dithiophene-
2,6-di-(n-butyl)-imidoylchloride 4a
To a suspension of 3a (1.12g, 0.0024 mol) in dry CHCl (40 mL)
3
and thionylchloride (1 mL, 0.014 mol) was added a few drops of N,N-
dimethylformamide and the mixture was allowed to reflux for 30 h. The
solution was filtered hot and the filtrate was distilled under reduced pressure
and the solid trituated with dry hexane (40 mL) on the reflux 30 min. The
solution was left on ice 24 h, and the crystals filtered off and dried
under vacuum at 40ꢀC to yield 1.13 g (95.2%) yellow crystals of di-imidoyl
chloride which was used directly in the next step without further
characterization.

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Synthesis of 3,7-Dichloro[1,2-b:4,5-b0]dithiophene-
2,6-di-(n-butyl)amidine 5a
The solution of di-imidoyl chloride 4a (1.5 g, 0.003 mol) in dry CH2Cl2
(45 mL) was saturated with dry ammonia at 0–5ꢀC. The mixture was
stirred at room temperature for 24 h and the solvent was removed under
reduced pressure. The residue was treated with ice water and the pH of
the slurry was adjusted to a value of 10 by adding 2M NaOH. The result-
ing solid was filtered, washed with water and dried under vacuum. The
obtained orange crystals of the base were recrystallized from CH2Cl2 : dioxane
(1:1). The yield was 0.5 g (43.2%) mp 199–202ꢀC. IR (cmÀ1) (KBr): 3417
1
(NH), 2959–2872 (CH), 1668 (C¼N). H NMR (DMSO-d6), d: 7.84 (s, 2H,
H
arom.), 7.00–6.25 (m, 4H, NH), 3.15 (AB, J1 ¼ 6.89, J2 ¼ 6.67 Hz, 4H, CH2),
1.61–1.54 (m, 4H, CH2), 1.47–1.37 (m, 4H, CH2), 0.95 (t, J ¼ 7.27 Hz,
6H, CH3). 13C NMR (CDCl3), d: 150.07, 135.52, 135.04, 130.18, 119.80,
117.13, 32.30, 20.31, 14.03 ppm. (Found: C, 52.29; H, 5.03; N, 12.05,
C20H24Cl2N4S2, requires, C, 52.74; H, 5.31; N, 12.30%).
Synthesis of 3,7-Dichloro[1,2-b:4,5-b0]dithiophene-
2,6-di-(n-butyl)amidine Dihydrochloride 6a
The free base 5a was converted into the salt by dissolving 0.67 g
(0.0015 mol) in absolute methanol (60 mL). Dry HCl gas was bubbled
through the solution at 0–5ꢀC for 1 h. The solution was stirred at room
temperature for 24 h. After reducing the solvent volume (1/3) under reduced
pressure, additionofdry ether (200 mL) caused precipitation ofthe pale yellow
salt, which was filtered, washed with ether, dissolved once more in methanol
and precipitated with ether, crystals filtered off and dried under vacuum to
yield0.46 g (58.5%) dihydrochloride 6amp 223–228ꢀC. IR (cmÀ1) (KBr): 3417
1
(NH), 2959–2872 (CH), 1668 (C¼N). H NMR (DMSO-d6), d: 10.60–9.94
(m, 4H, NH), 8.20 (s, 2H, Harom.), 1.72–1.62 (m, 4H, CH2), 1.53–1.38 (m,
4H, CH2), 0.95 (t, J ¼ 7.29 Hz, 6H, CH3). 13C NMR (DMSO-d6), d: 155.26,
135.10, 131.61, 124.45, 121.81, 43.34, 29.36, 19.59, 13.70 (Found: C, 45.013;
H, 4.59; N, 10.37, C20H26Cl4N4S2, requires C, 45.46; H, 4.96, N, 10.60%).
ACKNOWLEDGMENT
The authors wish to express their gratitude to the Ministry of Science
of the Republic of Croatia (scientific project no. 125005) for the financial
support of this research.

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Received in the UK September 26, 2000

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