Facile synthesis of benzobisimidazole and bibenzimidazole-based bisnitriles as potential precursors for DNA minor groove binders

Article abstract of DOI:10.1002/jhet.4353

The synthesis of bisnitrile derivatives of benzobisimidazole and bibenzimidazole in a good yield is described in detail for the first time. Nucleophilic substitution of 1,5-difluoro-2,4-dinitrobenzene using different amines produced the intermediate diami

Full text of DOI:10.1002/jhet.4353

Facile synthesis of Benzobisimidazole and Bibenzimidazole-based bisnitriles as potential
precursors for DNA minor groove binders.
Abdelbasset A. Farahat* a,b, Satori Iwamoto a, Michael Roche a, David W. Boykin c.
a Master of Pharmaceutical Sciences Program, California Northstate University, 9700 W. Taron
b
Dr., Elk Grove, California, 95757, Faculty of Pharmacy, Mansoura University, Mansoura,
Egypt 35516. c Chemistry Department, Georgia State University, Atlanta, GA, USA 30303.
* Corresponding author email: abdelbasset.farahat@cnsu.edu
Keywords
Benzobisimidazole, Bibenzimidazole, Bisnitriles, Suzuki coupling, DNA Minor groove.
Abstract
The synthesis of bisnitrile derivatives of benzobisimidazole and bibenzimidazole in a good yield
is described in detail for the first time. Nucleophilic substitution of 1,5-difluoro-2,4-
dinitrobenzene using different amines produced the intermediate diamines that were reduced
using sodium borohydride/Pd(C) to produce the tetramines. These tetramines were allowed to
couple with different aldehydes to produce the final benzimidazoles. In a different investigation,
these bisnitrile derivatives will be used to make benzimidazole diamidines that could be used as
potential mixed sequence minor groove binders.
Introduction
Benzobisimidazole and bibenzimidazole cores play an important role in the field of materials
chemistry. These cores can be used in solar cells [1], organometallic polymers [2], catalysts in
Suzuki reactions [3], and chemosensors for carbon dioxide [4]. While in the medicinal chemistry
field, only limited reports have appeared involving benzobisimidazole and bibenzimidazoles
cores which showed antitumor activity by inhibiting Topoisomerase II [5,6]. Heterocyclic
diamidines, which can effectively enter human cells, and bind specifically to AT base pairs in the
DNA duplex minor groove have been successfully used as nuclear and cell stains and as
therapeutic agents, mainly against infectious diseases, [7-13]. Expanding the DNA sequence
recognition ability of DNA minor groove binding diamidines to bind both AT and GC base pairs
could also expand their therapeutic targets and have an impact on many indications, such as
modulation of transcription factors biological activity [14,15]. Our group has considerable
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success in the design of mixed sequence binding compounds through making N-
alkylbenzimidazole thiophenes which are preorganized to fit the shape of the DNA minor groove
and H-bond to the NH of GC base pairs that projects into the minor groove [16-20] (figure 1). In
continuation of our effort to synthesize compounds that can specifically recognize GC base pairs,
we report here the facile synthesis of new N-alkyl-benzobisimidazole and N-alkyl-
bibenzimidazole-based bisnitrile intermediates to be used in a different investigation to
synthesize benzimidazole diamidines that can be used in our drug discovery projects.
Results and discussion
Scheme 1 outlines the synthesis of the formyl thiophenes 3 and 7. Compound 3 was made by
applying Suzuki coupling conditions between the bromo derivative 1 and the boronic acid
derivative 2. For the preparation of compound 7, we started by making the boronic ester 6 via
reaction of bis(pinacolato)diboron 4 with the bromo derivative 5. Suzuki coupling using
palladium (0) [21,22] was applied between the bromo compound 1 and the boronic ester 6 to
produce the formyl intermediate 7 in good yield.
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Scheme 2 outlines the synthesis of the bisnitriles compounds 11 a-d and 13 a, b. Nucleophilic
displacement of the starting difluoro nitro derivative 1 with different amines in ethanol afforded
the amino substituted dinitro intermediates 9 a-c in good yield. We tried the reduction of the
dinitro compounds 9a-c using both catalytic hydrogenation and tin chloride in ethanol, but the
reactions were never complete presumably due to the insolubility of the starting dinitro
compounds, and the impure product could not be chromatographed due to high polarity. Finally,
we used sodium borohydride and Pd(C) in methanol/dichloromethane as a solvent to obtain the
intermediate tetraamines 10 a-c in good yield which were used directly in the next step without
further purification. These amines were coupled with different aldehydes and sodium
metabisulfite in DMSO to furnish the bisnitrile derivatives of benzobisimidazole 11 a-d and 13
a, b in a good yield [23,24].
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The synthesis of the dibenzimidazole dinitrile 19 is described in Scheme 3. We started with a
nucleophilic displacement of the fluoro derivative 14 by isopropylamine in ethanol to afford the
amine derivative 15. The boronic ester intermediate 16 was prepared by reaction of the starting
bromo compound 15 with bis(pinacolato)diboron using bis(triphenylphosphine)palladium
dichloride and potassium acetate in 1,4-dioxane. The former boronic ester underwent Suzuki
coupling with the bromo compound 15 to produce the bis nitro intermediate 17. With the aim of
saving one step, we tried to make the biphenyl nitro derivative 17 by homocoupling of the bromo
derivative 15 using hexabutylditin in toluene, but we never got a clean product. This nitro
compound 17 was successfully reduced using sodium borohydride and Pd(C) in
methanol/dichloromethane as a solvent to obtain the intermediate tetraamine 18 in good yield.
The bibenzimidazole bisnitrile 19 was prepared by coupling of the intermediate tetramine and 5-
formyl thiophene-2-carbonitrile using sodium metabisulfite in DMSO.
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Experimental.
All commercial reagents were used without purification. Melting points were determined on a
Mel-Temp 3.0 melting point apparatus and are uncorrected. TLC analysis was carried out on
1
silica gel 60 F254 precoated aluminum sheets using a UV light for detection. HNMR spectra
were recorded on a Bruker 400 MHz spectrometer using the indicated solvents, 13CNMR spectra
were recorded on a Bruker 200 MHz spectrometer using the indicated solvents. Mass spectra
were obtained from the Georgia State University Mass Spectrometry Laboratory, Atlanta, GA.
4-(5-Formylthiophen-2-yl)benzonitrile (3).
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K2CO3 (3.35 g, 25 mmol) in water (4 ml) and 4-cyanophenyl boronic acid (2.54 g, 17 mmol) in
methanol (4 ml) was added to a stirred solution of the bromo compound (2.86 g, 15 mmol) in
1,4-dioxane (15 mL) and the mixture was deaerated under nitrogen for 10 min.
Tetrakis(triphenylphosphine) palladium (0.727 g, 0.6 mmol) was added, and the reaction mixture
was vigorously stirred at 110 °C for 24 h and left to cool down. The formed solid was filtered,
washed with 1,4-dioxane then water, and dried. White solid, yield (81%, 2.58 g), mp 215-217
1
oC; HNMR (DMSO-d6, 400MHz) δ 9.95 (s, 1H, CHO), 8.06 (d, 1H, J= 4.00 Hz, Ar), 7.98 (d,
2H, J=8.80 Hz, Ar), 7.91 (d, 1H, J = 8.80 Hz, Ar), 7.88 (d, 1H, J= 4.00 Hz, Ar).
(3-Chloro-4-cyanophenyl) boronic ester (6)
CH3COOK (4.10 g, 42 mmol), bis(binacolato)diboron (5.31 g, 20 mmol) and 4-bromo-2-
cholorobenzonitrile (3.00 g, 14 mmol) were stirred in a solution of 1,4-dioxane(25 mL), the
mixture was deaerated under nitrogen for 10 minutes. 1,1-bis(diphenylphosphino)ferrocene-
palladium(ii)dichloridedichloromethane (0.56 g, 0.7 mmol) was added and the reaction mixture
was vigorously stirred at 110 °C for 24 h and left to cool. The solvent was evaporated under
reduced pressure, the obtained solid was purified using column chromatography on silica gel,
o
and hexanes/ethyl acetate as an eluent. Colorless solid, yield (89%, 3.27 g), mp 98-99 C;
1HNMR (CDCl3, 400MHz) δ: 7.91 (s, 1H, Ar), 7.72-7.80 (m, 1H, Ar), 7.63-7.68 (m, 1H, Ar),
1.35 (s, 12H, 4CH3).
2-Chloro-4-(5-formylthiophen-2-yl) benzonitrile (7)
This compound was made by reaction between 5-bromothiophene-2-carbaldehyde and (3-chloro-
4-cyanophenyl) boronic ester by applying the Suzuki coupling conditions mentioned above.
White solid, yield (85 %). mp 151-152 oC; 1HNMR (DMSO-d6, 400MHz) δ 9.96 (s, 1H, CHO),
8.23 (d, 1H, J=1.60 Hz, Ar), 8.11 (d, 1H, J= 4.00 Hz, Ar), 8.06 (d, 1H, J=8.40 Hz, Ar), 8.01 (d,
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1H, J=4.00 Hz, Ar), 7.95 (dd, 1H, J = 1.20, 8.00 Hz, Ar); ESI-HRMS: m/z calculated for
C12H7ClNOS: 247.9931, found: 247.9896 (M+).
Synthesis of N1, N3-dialkyl-4,6-dinitrobenzene-1,3-diamine (9a-c).
Amines (80 mmol) were added to 1,5-difluoro-2,4-dinitrobenzene (4.08 g, 20 mmol) suspension
in ethanol (30 ml) and stirred at room temperature for 24 h. The precipitated yellow solid was
filtered and washed with cooled ethanol and dried.
N1, N3-Dimethyl-4,6-dinitrobenzene-1,3-diamine (9a).
Yellow solid (3.9 g 86 %), mp >250 oC dec. 1HNMR (DMSO-d6): δ 8.96 (br s, 1 H, Ar), 8.49 (s,
2 H, 2NH), 5.69 (s, 1 H, Ar), 2.99 (s, 6 H, 2 CH3); ESI-HRMS: m/z calculated for C8H10N4O4:
225.0624, found: 225.0627 (M+ - 1).
N1, N3-Diisopropyl-4,6-dinitrobenzene-1,3-diamine (9b).
Yellow solid (4.9 g 88 %), mp >250 oC dec. 1HNMR (DMSO-d6): δ 8.94 (s, 1 H, Ar), 8.07 (m, 2
H, 2NH), 5.86 (s, 1 H, Ar), 3.96 (m, 2 H, 2CH), 1.29 (d, J = 6 Hz, 12 H, 4 CH3); ESI-HRMS:
m/z calculated for C12H19N4O4: 283.1406, found: 283.1418 (M+ + 1).
N1, N3-Diisobutyl-4,6-dinitrobenzene-1,3-diamine (9c).
Yellow solid (5.2 g 84 %), mp >250 oC dec. 1HNMR (DMSO-d6): δ 8.89 (s, 1 H, Ar), 8.36 (m, 2
H, 2NH), 5.74 (s, 1 H, Ar), 3.96 (t, J = 6 Hz, 4 H, 2CH2), 1.97 (m, 2 H, 2CH), 0.97 (d, J = 6.8
Hz, 12 H, 4CH3); ESI-HRMS: m/z calculated for C14H22N4O4: 309.1563, found: 309.1567 (M+ -
1).
Synthesis of the tetraamines (10a-c).
Pd (C) (0.2 g) was added to a suspension of the nitro compound 2a-c (4 mmol) in a deaerated
mixture of dichloromethane/methanol (3/1, 60 ml), sodium borohydride (0.45 gm, 12 mmol) was
added, and the reaction mixture was stirred for 4 h at room temperature. The reaction mixture
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was filtered, and the filtrate was concentrated under reduced pressure, the formed residue was
dissolved in acetone (50 ml) and filtered. The filtrate was evaporated under reduced pressure and
dried under vacuum at room temperature and used directly in the next step without further
characterization.
Synthesis of the bisnitriles (11a-d and 13 a,b).
Sodium metabisulphite (1.14 g, 6 mmol) was added to a solution of the tetraamines 10a-c (3
mmol) and the appropriate aldehydes (6 mmol) in DMSO (10 mL) and the mixture was heated at
o
150 C for 30 min. The reaction mixture was poured into water, filtered, and dried. Purification
was by crystallization from DMF and then acetone.
4,4'-((1,7-Dimethyl-1,7-dihydrobenzo[1,2-d:4,5-d']diimidazole-2,6-diyl)bis(thiophene-5,2-
diyl))dibenzonitrile (11a).
o
Greenish solid (1.12 g, 68 %), mp > 300 C; 1HNMR (DMSO-d6): δ 7.99 (m, 4 H, Ar), 7.93 (m,
5 H, Ar), 7.91 (m, 5 H, Ar), 4.15 (s, 6H, 2CH3); ESI-HRMS: m/z calculated for C32H21N6S2:
553.1264, found: 553.1272 (M+ + 1).
4,4'-((1,7-Diisopropyl-1,7-dihydrobenzo[1,2-d:4,5-d']diimidazole-2,6-diyl)bis(thiophene-5,2-
diyl))dibenzonitrile (11b).
o
Greenish solid (1.07 g, 59 %), mp > 300 C; 1HNMR (DMSO-d6): δ 8.03 (m, 4 H, Ar), 7.97 (m,
6 H, Ar), 7.54 (d, J = 3.2 Hz, 2 H, Ar), 7.37 (d, J = 3.2 Hz, 2 H, Ar), 5.42 (t, J = 6.8 Hz, 2 H,
2NH), 1.78 (d, J = 6.8 Hz, 12 H, 4CH3); ESI-HRMS: m/z calculated for C36H28N6S2: 609.1895,
found: 609.1901 (M+ + 1).
4,4'-((1,7-Diisobutyl-1,7-dihydrobenzo[1,2-d:4,5-d']diimidazole-2,6-diyl)bis(thiophene-5,2-
diyl))dibenzonitrile (11c).
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Yellow solid (1.16 g, 61 %), mp > 300 oC; 1HNMR (DMSO-d6): δ 7.97 (d, J = 8.4 Hz, 4 H, Ar),
7.91 (d, J = 8.4 Hz, 4 H, Ar), 7.88 (br s, 2 H, Ar), 7.84 (d, J = 4 Hz, 2 H, Ar), 7.79 (d, J = 4 Hz, 2
H, Ar), 4.47 (d, J = 6.8 Hz, 4 H, 2CH2), 2.52 (m, 2 H, 2CH), 0.93 (d, J = 6.8 Hz, 12 H, 4CH3);
13CNMR (DMSO-d6): δ 147.2, 146.4, 143.6, 141.3, 140.1, 137.8, 135.9, 135.1, 133.7, 129.0,
127.9, 127.4, 126.6, 110.7; ESI-HRMS: m/z calculated for C38H33N6S2: 637.2208, found:
637.2217 (M+ + 1).
4,4'-((1,7-Diisopropyl-1,7-dihydrobenzo[1,2-d:4,5-d']diimidazole-2,6-diyl)bis(thiophene-5,2-
diyl))bis(2-chlorobenzonitrile) (11d).
Yellow solid (1.11 g, 55 %), mp > 300 oC; 1HNMR (DMSO-d6): δ 8.20 (br s, 2 H, Ar), 8.02 (m,
5 H, Ar), 7.97 (br s, 1 H, Ar), 7.89 (d, J = 8.4 Hz, 2 H, Ar), 7.74 (d, J = 3.6 Hz, 2 H, Ar), 5.26 (t,
J = 6.8 Hz, 2 H, 2CH), 1.78 (d, J = 6.4 Hz, 12 H, 4CH3); ESI-HRMS: m/z calculated for
C36H27Cl2N6S2: 677.1110, found: 677.1123 (M+ + 1).
5,5'-(1,7-Diisopropyl-1,7-dihydrobenzo[1,2-d:4,5-d']diimidazole-2,6-diyl)bis(thiophene-2-
carbonitrile) (13a).
o
1
Yellow solid (0.98 g, 72 %), mp > 300 C; HNMR (DMSO-d6): δ 8.12 (d, J = 4 Hz, 2 H, Ar),
8.00 (br s, 1 H, Ar), 7.93 (br s, 1 H, Ar), 7.73 (d, J = 4 Hz, 2 H, Ar), 5.17 (m, 2 H, 2CH), 1.74 (d,
J = 6.8 Hz, 12 H, 4CH3); ESI-HRMS: m/z calculated for C24H21N6S2: 457.1269, found: 457.1264
(M+ + 1).
5,5'-(1,7-Diisobutyl-1,7-dihydrobenzo[1,2-d:4,5-d']diimidazole-2,6-diyl)bis(thiophene-2-
carbonitrile) (13b).
o
1
Yellow solid (0.99 g, 68 %), mp > 300 C; HNMR (DMSO-d6): δ 8.09 (d, J = 4 Hz, 2 H, Ar),
8.01 (br s, 1 H, Ar), 7.94 (br s, 1 H, Ar), 7.86 (d, J = 4 Hz, 2 H, Ar), 4.46 (d, J = 7.2 Hz, 4 H,
13
2CH2), 2.13 (m, 2 H, 2CH), 0.88 (d, J = 6.4 Hz, 12 H, 4CH3); CNMR (DMSO-d6): δ 146.1,
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140.9, 140.7, 140.1, 136.3, 127.7, 114.5, 110.3, 108.0, 92.6 ;ESI-HRMS: m/z calculated for
C26H25N6S2: 485.1582, found: 485.1594 (M+ + 1).
4-Bromo-N-isopropyl-2-nitroaniline (15).
Isopropylmine (2.36 g, 40 mmol) was added to 4-bromo-1-fluoro-2-nitrobenzene (4.4 g, 20
mmol) in ethanol (20 ml) and stirred at room temperature for 24 h. The reaction mixture was
evaporated under reduced pressure. The product was filtered, washed with cold ethanol, and
o
1
dried. Orange solid (3.67 g, 72 %), mp 97-98 C; HNMR (DMSO-d6): δ 8.15 (br s, 1 H, Ar),
7.88 (d, J = 7.2 Hz, 1 H, Ar), 7.64 (d, J = 9.2 Hz, 1 H), 7.08 (d, J = 9.2 Hz, 1 H, NH), 3.92 (m, 1
H, CH), 1.25 (d, J = 6 Hz, 6 H, 2CH3); ESI-HRMS: m/z calculated for C9H12BrN2O2: 259.077,
found: 259.066 (M+ + 1).
N-Isopropyl-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (16).
Potassium acetate (5.88 g, 60 mmol) and bis(pinacolato)diboron (7.59 gm, 30 mmol) were added
to a stirred solution of the bromo compound 6 (5.18 gm, 20 mmol) in 1,4-dioxane (60 mL) and
the mixture was deaerated under nitrogen for 20 min. Dichlorobis(triphenylphosphine)palladium
(0.56 g, 0.8 mmol) was added and the reaction mixture was vigorously stirred at 100 °C for 12 h
under nitrogen. The solvent was evaporated under reduced pressure and the formed residue was
purified using column chromatography on silica gel, and hexanes/ethyl acetate as an eluent.
Yellow solid (4.2 g, 70 %), mp 142-143 oC. 1HNMR (DMSO-d6): δ 8.35 (s, 1 H, Ar), 8.04 (d, J =
7.2 Hz, 1 H, Ar), 7.69 (d, J = 8.4 Hz, 1 H, Ar), 7.06 (d, J = 8.4 Hz, 1 H, NH), 3.95 (d, J = 6.4 Hz,
1 H, CH), 1.28 (s, 12 H, 4CH3), 1.26 (s, 6 H, 2CH3).
N4,N4'-Diisopropyl-3,3'-dinitro-[1,1'-biphenyl]-4,4'-diamine (17).
K2CO3 (2.76 g, 20 mmol) in water (5 ml) and the boronic ester 7 (3.36 gm, 11 mmol) methanol
(10 ml) were added to a stirred solution of the bromo compound 6 (2.59 gm, 10 mmol) in 1,4-
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dioxane (30 mL) and the mixture was deaerated under nitrogen for 20 min.
Tetrakis(triphenylphosphine) palladium (0.46 g, 0.4 mmol) was added and the reaction mixture
was vigorously stirred at 100 °C for 12 h. The solvent was evaporated under reduced pressure,
the solid was partitioned between ethyl acetate (200 mL) and 2 M aqueous Na2CO3 (25 mL)
containing 5 mL of concentrated ammonia, to remove palladium residues, then washed with
water, passed through celite to remove the catalyst, dried (sodium sulfate) and evaporated. The
product was purified using column chromatography on silica gel, and hexanes/ethyl acetate as an
eluent.
o
1
Yellow solid (2.61, 73 %), mp > 250 C. dec. HNMR (DMSO-d6): δ 8.25 (br s, 2 H, Ar), 7.93
(d, J = 8.4 Hz, 2 H, Ar), 7.88 (m, 2 H, Ar), 7.18 (d, J = 8.4 Hz, 2 H, 2NH), 3.99 (m, 2 H, 2CH),
1.29 (d, J = 6 Hz, 12 H, 4CH3); ESI-HRMS: m/z calculated for C18H23N4O4: 359.1719, found:
359.1713 (M+ + 1).
N4,N4'-diisopropyl-[1,1'-biphenyl]-3,3',4,4'-tetraamine (18).
This compound was prepared using the sodium borohydride method mentioned above starting
from the bis-nitro compound 17, and was used in the next step without further characterization.
5,5'-(1,1'-diisopropyl-1H,1'H-[5,5'-bibenzo[d]imidazole]-2,2'-diyl)bis(thiophene-2-
carbonitrile) (19).
This compound was prepared using sodium metabisulphite method mentioned above starting
from the tetraamine 18 and 5-formylthiophene-2-carbonitrile in DMSO.
Yellow solid (69 %), mp > 300 oC. 1HNMR (DMSO-d6): δ 8.11 (d, J = 4 Hz, 2 H, Ar), 8.02 (br s,
2 H, Ar), 7.93 (d, J = 8.4 Hz, 2 H, Ar), 7.74 (d, J = 4 Hz, 2 H, Ar), 7.66 (d, J = 8.4 Hz, 2 H, Ar),
5.12 (d, J = 6.8 Hz, 2 H, 2CH), 1.69 (d, J = 6.8 Hz, 12 H, 4CH3); 13CNMR (DMSO-d6): δ 145.5,
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144.3, 140.3, 140.0, 136.0, 133.8, 128.9, 123.5, 118.2, 114.4, 114.1, 110.7;ESI-HRMS: m/z
calculated for C30H25N6S2: 533.1582, found: 533.1606 (M+ + 1).
Conclusion.
Two new series of N-alkyl-Benzobisimidazole and N-alkyl-bibenzimidazole-based bisnitrile
intermediates were prepared in a facile way for the first time. In a different investigation these
bisnitriles intermediates will be converted to dicationic diamidines that are designed to bind
selectively and strongly to mixed base-pair sequences in the DNA minor groove. These
compounds could be the starting point for development of antileukemic drugs.
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