New amidino-benzimidazolyl thiophenes: Synthesis and photochemical synthesis

Article abstract of DOI:10.1002/hc.10126

The photochemical synthesis of amidino-benzimidazolyl thiophenes was discussed. The amidino-benzimidazolyl-substituted bis-1,2-(2-thienyl) ethenes and benzo[1,2-b:4,3-b′] dithiophenes were prepared by the condensation of amidino-substituted o-phenylene diamines with corresponding dialdehydes. The synthesized bis-cationic bis-amidino benzimidazolyl substituted diphenylfurans were found to inhibit HIV-1 infection.

Full text of DOI:10.1002/hc.10126

Heteroatom Chemistry
Volume 14, Number 3, 2003
New Amidino-Benzimidazolyl Thiophenes:
Synthesis and Photochemical Synthesis
Kristina Starcˇevic´,1 David W. Boykin,2
and Grace Karminski-Zamola1
1Department of Organic Chemistry, Faculty of Chemical Engineering and Technology,
University of Zagreb, 10000 Zagreb, Croatia
2Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University,
Atlanta, Georgia 30303-3083
Received 6 May 2002; revised 17 September 2002
stability [7,8]. A number of aromatic diamidines
ABSTRACT: New amidino-benzimidazolyl-substi-
have been shown to bind in minor groove on DNA
tuted bis-1,2-(2-thienyl)ethenes (4, 5, and 6) and
at AT-rich sites and to be affective against many
benzo[1,2-b:4,3-bꢀ]dithiophenes (8, 9, and 10) were
opportunistic organisms [9,10]. Several hypotheses
prepared by the condensation of amidino-substituted
have been proposed to explain the mode of action of
o-phenylene diamines with corresponding dialdehy-
these compounds. The factors important in minor
des (3 and 7). All prepared amidino-benzimidazolyl-
groove binding are hydrogen bonding, electrostatic
substituted compounds are of particular interest, be-
interactions, van der Waals interactions, and the
cause they can serve as intercalators or groove binders
radius of curvature of the observed molecule [11].
ꢁ
C
on DNA in anticancer therapy. 2003 Wiley Periodicals,
Amidinic compounds also showed antipara-
Inc. Heteroatom Chem 14:218–222, 2003; Published online
sitic activity [12]. Some dicationic amidino bis-
in Wiley InterScience (www.interscience.wiley.com). DOI
benzimidazoles were found to have potent fungi-
10.1002/hc.10126
cidal activity [13]. A series of amidino-substituted
carbazoles, furans, and benzimidazoles possess an-
timicrobial activity against a wide range of eukary-
otic pathogens and show inhibitory and fungicidal
activities against Candida albicans and Cryptococeus
INTRODUCTION
Amidino-benzimidazolyl-substituted heterocyclic
compounds are widely investigated on their bio-
logical activity [1–6]. The amidine groups at the
termini of the molecules seemed to contribute
significantly to the dications and the DNA complex
neoformans. Selected compounds were also found to
be active against Aspergillus fumigantus, Fusarium
solani, and Candida species other than C. albicans
[14].
Recently, synthesized bis-cationic bis-amidino
benzimidazolyl substituted diphenylfurans were
found to inhibit HIV-1 infection [15]. Wang found
that a series of an aromatic dication with an
amidine-phenyl-furan-benzimidazole-amidine stru-
cture could recognize specific sequences of DNA by
binding in the minor groove of DNA as a dimer [16].
Nguyen examined the influence of compound struc-
ture on affinity, sequence selectivity, and mode of
Correspondence to: Grace Karminski-Zamola; e-mail: gzamola@
pierre.fkit.hr.
Contract grant sponsor: Ministry of Science, Republic of
Croatia.
Contract grant number: 125005.
Contract grant sponsor: US-Croatian Project.
Contract grant number: JF 146.
2003 Wiley Periodicals, Inc.
c
ꢁ
218

New Amidino-Benzimidazolyl Thiophenes: Synthesis and Photochemical Synthesis 219
binding to DNA for unfused aromatic dications re-
lated to furamidine [17].
RESULTS AND DISCUSSION
The influence of the amidino and substituted
amidino groups in heterocyclic compounds, on the
biological activity, as well as well-known differ-
ent biological activities of a number of amidino-
substituted benzimidazoles, prompted us to synthe-
size new amidino-substituted heterocyclic systems
from the thiophene series [18,19].
In this work, we prepared in a multistep syn-
thesis new amidino-benzimidazolyl-substituted
bis-1,2-(2-thienyl)ethenes 4, 5, and 6 and ami-
dino-benzimidazolyl-substituted benzo[1,2-b:4,3-bꢀ]-
dithiophenes 8, 9, and 10. In the first steps were
prepared amidino-substituted o-phenylene diamines
starting from acetamidobenzonitrile, which was
nitrated and hydrolyzed into 4-amino-3-nitrobenzo-
nitrile. Cyano group of the starting compound
reacted in the Pinner reaction in absolute EtOH
with dry HCl gas to give intermediate imidoesters.
Reaction of imidoester hydrochlorides with gaseous
ammonia, isopropylamine, or ethylenediamine in
dry EtOH and subsequent catalytic reduction gave
corresponding 4-amidino-substituted 1,2-phenylene
diamines [20].
SCHEME 1
These compounds are used later in the condensa-
tion with earlier prepared dialdehydes 3 and 7 [11].
Dialdehyde 3 was prepared in two ways. Starting
from 2-thiophenecarbaldehyde and 2-thienylacetic
acid by the condensation reaction in Ac2O and in
the presence of TEA, were prepared E- and Z-2,3-
di-(2-thienyl)acrylic acids 1a and 1b. The Z isomer
of 2,3-di-(2-thienyl)acrylic acid 1b was isolated from
the reaction mixture described earlier [21]. Com-
pound 1b was decarboxylated in quinoline and in the
presence of Cu powder into the Z-2-di-(2-thienyl)-
ethene 2b [22]. Compound 2b was also prepared by
the McMurry reaction in the mixture with E isomer
2a by treatment of thiophene-2-carbaldehyde with
a low-valent titanium reagent, prepared from tita-
nium(IV)chloride and zinc powder in boiling THF
[23]. Compound 2b was formylated into 1,2-di[(5-
formyl)2-thienyl]ethene (3) by Vilsmeier formyla-
tion [24]. Dialdehyde 3 was photochemically de-
hydrocyclized into 2,7-bis-formyl-benzo[1,2-b:4,3-bꢀ]
(7) by the reaction of photochemical dehydrogena-
tion described earlier [21]. Both dialdehydes 3
and 7 reacted later with earlier prepared amidino-
substituted phenylenediamines in the presence of
p-benzoquinone [6]. In this way were prepared
the dihydrochlorides 4–6 and 8–10 according to
Scheme 1.
EXPERIMENTAL
Instruments
Melting points were determined on a Kofler block
apparatus and are uncorrected. IR spectra were de-
termined with a Nicolet Magna 760 infrared spec-
trophotometer in KBr pellets. 1H NMR and 13C NMR
spectral data were determined using Bruker Avance
DPX 300 MHz NMR or Varian-Gemini 300 MHz
spectrometers with tetramethylsilane as an internal
standard. Elemental analyses were carried out in the
Microanalytical Laboratory at the Rugjer Boskovic
Institute.
E- and Z-2,3-Di-(2-thienyl)acrylic Acids
(1a and 1b)
Compounds 1a and 1b were prepared by a 45-min
heating of 2-thiophenecarbaldehyde (8.0 g, 70 mmol)
and 2-thiopheneacetic acid (10 g, 70 mmol) in tri-
ethylamine (10 ml), and acetic anhydride (10 ml).
After the reaction was completed, the mixture was
cooled, acidified with diluted hydrochloric acid (1:1),
and extracted with diethylether (350 ml). The or-
ganic layer was washed with water and the mixture

ˇ
220 Starcevic´, Boykin, and Karminski-Zamola
of acids 1a and 1b was extracted into 10% sodium
carbonate solution (1000 ml). The alkaline solution
of sodium salts of compounds 1a and 1b was boiled
with charcoal, filtered off, cooled, and acidified to
pH 5 with acetic acid. The precipitated Z isomer 1b
was filtered off and recrystallized from methanol. It
was obtained in a yield of 6.80 g (42%) as light yellow
crystals of mp 239–241◦C (lit [24] mp 240–241◦C).
Concentrated hydrochloric acid was added to the fil-
trate and additional crystalline crops consisting of
the E isomer were filtered off. The yield of the E
isomer 1a was 1.67 g (7%), mp 174–175◦C (lit [24]
mp 174.5–175.5◦C).
in DMF (10 ml) by dropwise addition of (with stir-
ring and cooling) POCl3 (10 ml) in such a way that
the temperature of the reaction mixture did not ex-
ceed 10◦C. After complete addition, the mixture was
stirred for 30 min at room temperature, and then
heated at 90–95◦C for 45 min, cooled, and poured
into crushed ice (300 g), made weakly alkaline with
10% sodium hydroxide solution and left overnight
on ice. The gummy product was decanted, washed
with water, and recrystallized from methanol. The
yield was 2.77 g (72%), mp 205–208◦C. IR (cm−1)
1
(KBr): 1640 (CHO), 1660 (CHO). H NMR (CDCl3)
(δ ppm): 7.22 (d, J = 3.93 Hz, 1H, Hthioph.), 7.26 (s,
1H, Hethylenic), 7.69 (d, J = 3.93 Hz, 1H, Hthioph.), 9.94
(s, 1H, CHO). 13C NMR (δ ppm) (CDCl3): 124.6, 129.0,
138.5, 142.5, 149.8, 183.9. Anal. Calcd for C12H8O2S2:
C, 58.04; H, 3.25; S, 25.83. Found: C, 58.52; H, 3.48;
S, 26.12.
1,2-Di-(2-thienyl)ethene (2)
Method A. Decarboxylation of the correspond-
ing acid 1b (2.45 g, 10 mmol) was accomplished by
the method described earlier [22], by heating with
Cu powder (2.5 g) in quinoline (12.5 ml) (dried over
molecular sieves) for 1 h at boiling point. The re-
action mixture was transfered into ether (100 ml)
and washed with 10% hydrochloric acid (150 ml).
All ethereal extracts were collected, washed with wa-
ter, 10% hydrochloric acid, and then again with wa-
ter, and were dried over magnesium sulfate. The
ether was evaporated and the residue was recrys-
tallized from methanol. Yellow crystals were ob-
tained in a yield of 0.98 g (51.0%), mp 130–132◦C
1,2-Bis-{[5-(5-amidino-2-benzimidazolyl)]-
2-thienyl}ethene Dihydrochloride (4)
Compound 4 was prepared using the method de-
scribed earlier [6]. A mixture of compound 3 (0.50 g,
2 mmol), 3,4-diaminobenzamidine (0.6 g, 4 mmol),
and p-benzoquinone (0.43 g, 4 mmol) in absolute
EtOH (80 ml) was stirred at reflux for 4 h (under
nitrogen). The reaction mixture was cooled to room
temperature and precipitated dark crystals were fil-
tered off. The crude product was suspended in conc.
HCl, heated to boiling, and stirred overnight at room
temperature. Acetone was added to the solution.
Dark green crystals were filtered off and washed with
dry ether. The crystals of 4 were dissolved in water
and precipitated with acetone again, filtered off, and
dried. It was repeated a few times until the crystals
were analytically pure. It was obtained in a yield of
0.75 g (64%) dark crystals, mp >300◦C. IR (cm−1)
(KBr): 3372, 3067, 2927, 1672, 1625, 1578. 1H NMR
(δ ppm) (DMSO-d6): 9.3 (s, 4H, NH), 9.0 (s, 4H, NH),
8.13 (d, J = 3.65 Hz, 2H, Hthioph.), 8.05 (s, 2H, Harom.),
7.78 (d, J = 8.54 Hz, 2H, Harom.), 7.69 (d, J = 8.48 Hz,
1H, Harom.), 7.47 (d, J = 4.03 Hz, 1H, Hthioph.), 7.42 (s,
2H, Hethylenic). 13C NMR (δ ppm) (DMSO-d6): 165.9,
149.6, 144.9, 131.435, 129.5, 128.7, 122.7, 122.4,
121.6. Anal. Calcd for C26H22Cl2N8S2: C, 53.69; H,
3.81; N, 19.27. Found: C, 53.92; H, 3.59; N, 19.31.
1
(lit [25] mp 133–134◦C). H NMR (CDCl3) (δ ppm):
6.98 (1H, ABsyst., J = 5.05 and 3.65 Hz, Hthioph.), 7.03
(d, J = 3.65 Hz, 1H, Hthioph.), 7.05 (s, 1H, Hethylenic),
7.17 (d, J = 5.05 Hz, 1H, Hthioph.).
Method B. To
a
slurred solution of 2-
thiophenecarbaldehyde (5.6 g, 50 mmol) in THF
(100 ml) was added, dropwise and by stirring, tita-
nium(IV) chloride (6.5 ml) over a period of 30 min at
−18◦C. After stirring at this temperature for 30 min,
zinc powder (7.8 g) was added in small portions
over a period of 30 min. The mixture was stirred at
−18◦C for 30 min, warmed to room temperature,
and refluxed for 3.5 h. The reaction was quenched
by addition of ice water (100 ml) and the resulting
solid was collected by filtration and dried. The
solid was dissolved in methylene chloride (80 ml)
and the insoluble inorganic material was removed
by filtration. The filtrate was evaporated and the
residue was recrystallized from cyclohexane to give
4.70 g (98%) of pure E isomer 2a, mp 133–134◦C (lit
[23] mp 133–134◦C).
1,2-Bis-{[5-(5-N-isopropylamidino-2-
benzimidazolyl)]-2-thienyl}ethene
Dihydrochloride (5)
1,2-Di-[5-formyl-2-(2-thienyl)]ethene (3)
Compound 5 was prepared using the method de-
scribed for the preparation of 4, from 3 (0.3 g,
1.2 mmol), 3,4-diamino-N-isopropylbenzamidine
Compound 3 was prepared by the Vilsmeier reac-
tion described earlier [24] from 2b (3.00 g, 24 mmol)

New Amidino-Benzimidazolyl Thiophenes: Synthesis and Photochemical Synthesis 221
(0.46 g, 2.43 mmol), and p-benzoquinone (0.26 g,
3,4-diaminobenzamidine (0.61 g, 4.1 mmol), and
p-benzoquinone (0.44 g, 4.1 mmol) in absolute
EtOH (80 ml). It was obtained in a yield of
0.6 g (45.0%) dark green crystals, mp >300◦C.
IR (cm−1) (KBr): 3340, 3076, 2924, 2852, 1673,
1624. 1H NMR (δ ppm) (DMSO-d6): 9.39 (s, 4H,
NH), 9.06 (s, 4H, NH), 8.83 (s, 2H, Hthioph.), 8.23
(s, 2H, Harom.), 8.18 (s, 2H, Hethylenic), 7.87 (d, J =
8.55 Hz, 2H, Harom.), 7.74 (dd, J = 8.55, 1.65 Hz,
2H, Harom.). 13C NMR (δ ppm) (DMSO-d6): 169.1,
149.8, 137.8, 134.8, 134.02, 122.5, 121.8, 120.8. Anal.
Calcd for C26H20N8S2Cl2: C, 53.84; H, 3.45; N, 19.30;
Cl, 12.23. Found: C, 53.85; H, 3.62; N, 19.06; Cl,
12.3.
2.42 mmol) in absolute EtOH (80 ml). It was ob-
tained in a yield of 0.31 g (38%) dark green crys-
tals, mp >300◦C. IR (cm−1) (KBr): 3415, 3255, 3089,
1673, 1627, 1575. 1H NMR (δ ppm) (DMSO-d6): 9.53
(s, 2H, NH), 9.39 (s, 2H, NH), 8.97 (s, 2H, NH), 8.01
(s, 2H, Harom.), 7.98 (d, J = 3.47 Hz, 2H, Hthioph.), 7.76
(d, J = 8.42 Hz, 2H, Harom.), 7.56 (d, J = 8.36 Hz, 2H,
Harom.), 7.45 (d, J = 3.47 Hz, 2H, Hthioph.), 7.40 (s, 2H,
H
ethylenic), 4.10–4.06 (m, 2H, CH), 1.31 (d, J = 6.23
Hz, 12H, CH3). 13C NMR (δ ppm) (DMSO-d6): 163.7,
149.6, 148.9, 140.7, 137.9, 133.2, 130.9, 129.01, 125.6,
125.2, 124.3, 116.4, 116.4, 47.7, 22.9. Anal calcd for
C32H34N8S2Cl2: C, 57.73; H, 5.12; N, 16.82. Found: C,
57.56; H, 5.38; N, 16.43.
2,7-Bis-[(5-N-isopropylamidino)-2-
benzimidazolyl]-benzo[1,2-b:4,3-bꢀ]dithiophene
Dihydrochloride (9)
1,2-Bis-{[5-(5-imidazolinyl)-2-benzimidazolyl)]-
2-thienyl}ethene Dihydrochloride (6)
Compound 6 was prepared in the way described for
the preparation of 4, from 3 (0.22 g, 0.9 mmol), 4-[N-
(2-imidazolinyl)]-1,2-phenylene-diamine (0.5 g, 1.8
mmol), and p-benzoquinone (0.18 g, 1.8 mmol) in
absolute EtOH (80 ml). It was obtained in a yield
of 0.15 g (39%) dark green crystals mp >300◦C. IR
Compound 9 was prepared in the way descri-
bed for the preparation of 5, from 7 (0.87 g,
3.5 mmol), 3,4-diamino-N-isopropylbenzamidine
(1.35 g, 7.06 mmol), and p-benzoquinone (0.76 g,
7.06 mmol) in absolute EtOH (50 ml). It was ob-
tained in a yield of 1.64 g (70.0%) green cystals, mp
>300◦C. IR (cm−1) (KBr): 3363, 3073, 2978, 1667,
1626. 1H NMR (δ ppm) (DMSO-d6): 9.57 (s, 2H, NH),
9.42 (s, 2H, NH), 8.99 (s, 2H, NH), 8.83 (s, 2H,
Hthioph.), 8.21 (s, 2H, Harom.), 8.16 (s, 2H, Hethylenic), 7.88
(d, J = 8.48 Hz, 2H, Harom.), 7.60 (d, J = 8.75 Hz, 2H,
Harom.), 4.1–4.09 (m, 2H, CH), 1.32 (d, J = 6.3 Hz,
12H, CH3). 13C NMR (δ ppm) (DMSO-d6): 162.2,
149.3, 137.6, 134.6, 133.7, 123.1, 122.6, 122.4, 120.6,
44.9, 21.2. Anal. Calcd for C32H32N8S2Cl2·3H2O: C,
53.50; H, 5.29; N, 15.60. Found: C, 53.72; H, 5.06; N,
15.79.
1
(cm−1) (KBr): 3390, 3120, 2976, 1606. H NMR (δ
ppm) (DMSO-d6): 10.59 (s, 4H, NH), 8.31 (s, 2H,
Harom.), 8.0 (d, J = 3.55 Hz, 2H, Hthioph.), 7.84 (d, J =
8.45 Hz, 2H, Harom.), 7.79 (d, J = 8.37 Hz, 2H, Harom.),
7.45 (d, J = 3.8 Hz, 2H, Hthioph.), 7.39 (s, 2H, Hethylenic),
4.03 (s, 8H, CH2). Anal. Calcd for C30H26Cl2N8S2: C,
56.87; H, 4.10; N, 17.68. Found: C, 56.61; H, 3.95; N,
17.35.
2,7-Bis-formyl-benzo[1,2-b:4,3-bꢀ]dithiophene (7)
Compound 7 was prepared from 3 (0.3 g, 1.2 mmol),
which was dissolved in toluene (300 ml) and irradi-
ated with 400 W high-pressure mercury arch lamp
during 5 h. J2 (0.1 g) was added into the solution and
the air was bubbled through. The solvent was evapo-
rated and the residue recrystallized from methanol.
It was obtained in a yield of 0.19 g (63.8%) dark yel-
low crystals, mp 243–247◦C. IR (cm−1) (KBr): 1668,
2,7-Bis-[(5-imidazolinyl)-2-benzimidazolyl]-
benzo[1,2-b:4,3-bꢀ]dithiophene Dihydrochloride
(10)
Compound 10 was prepared in the way described for
the preparation of 6, from 7 (0.21 g, 0.85 mmol), 4-
[N-(2-imidazolinyl)]-1,2-phenylene-diamine (0.5 g,
1.7 mmol), and p-benzoquinone (0.18 g, 1.7 mmol)
in absolute EtOH (80 ml). It was obtained in a yield
of 0.45 g (83.0%) dark green crystals, mp >300◦C.
1
1508, 1224. H NMR (δ ppm) (DMSO-d6): 10.22 (s,
2H, CHO), 9.02 (s, 2H, Hthioph.), 8.32 (s, 2H, Harom.).
13C NMR (δ ppm) (DMSO-d6): 186.0, 144.02, 140.2,
135.2, 133.2, 123.6. Anal. Calcd for C12H6O2S2: C,
58.54; H, 2.44. Found: C, 58.31; H, 2.38.
1
IR (cm−1) (KBr): 3407, 3118, 2970, 1605. H NMR
(δ ppm) (DMSO-d6): 14.5 (s, 2H, NH), 10.53 (s, 4H,
NH), 8.79 (s, 2H, Hthioph.), 8.39 (s, 2H, Harom.), 8.20
(s, 2H, Hethylenic), 7.91–7.88 (m, 4H, Harom.), 4.06 (s,
8H, CH2). Anal. Calcd for C30H24N8S2Cl2·2H2O: C,
53.97; H, 4.23; N, 16.17. Found: C, 54.05; H, 4.20; N,
15.98.
2,7-Bis-[(5-amidino)-2-benzimidazolyl]-benzo-
[1,2-b:4,3-bꢀ]dithiophene Dihydrochloride (8)
Compound 8 was prepared in the way described
for the preparation of 4, from 7 (0.5 g, 2.3 mmol),

ˇ
222 Starcevic´, Boykin, and Karminski-Zamola
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