Synthesis of novel bithiophene-substituted heterocycles bearing carbonitrile groups

Article abstract of DOI:10.1080/00397910903537364

Symmetrical and unsymmetrical bithiophene-substituted heterocycles bearing carbonitriles including imidazo[1,2-a]pyridine, benzimidazole, and pyridine derivatives have been synthesized via different synthetic protocols. The bithiophene bis-imidazo[1,2-a]p

Full text of DOI:10.1080/00397910903537364

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Synthesis of Novel Bithiophene-
Substituted Heterocycles Bearing
Carbonitrile Groups
Mohamed A. Ismail a & David W. Boykin b
a Chemistry Department, Faculty of Science, Mansoura University,
Mansoura, Egypt
b Department of Chemistry, Georgia State University, Atlanta,
Georgia, USA
Version of record first published: 13 Jan 2011.
To cite this article: Mohamed A. Ismail & David W. Boykin (2011): Synthesis of Novel Bithiophene-
Substituted Heterocycles Bearing Carbonitrile Groups, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 41:3, 319-330
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Synthetic Communications1, 41: 319–330, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903537364
SYNTHESIS OF NOVEL BITHIOPHENE-SUBSTITUTED
HETEROCYCLES BEARING CARBONITRILE GROUPS
Mohamed A. Ismail1 and David W. Boykin2
1Chemistry Department, Faculty of Science, Mansoura University,
Mansoura, Egypt
2Department of Chemistry, Georgia State University, Atlanta, Georgia, USA
Symmetrical and unsymmetrical bithiophene-substituted heterocycles bearing carbonitriles
including imidazo[1,2-a]pyridine, benzimidazole, and pyridine derivatives have been
synthesized via different synthetic protocols. The bithiophene bis-imidazo[1,2-a]pyridine
derivatives 3a,b were achieved in three steps starting from 2-acetyl-5-bromothiophene.
Suzuki coupling reaction of 2a with 5-formylthiophen-2-ylboronic acid forms the formyl
derivative 5, which by condensation with 3,4-diaminobenzonitrile in the presence of sodium
bisulfite furnishes the unsymmetrical bithiophene derivative6. The bis-benzimidazole deriva-
tive 8 was obtained via hexabutylditin-mediated homocoupling of 5-bromothiophene-2-
carboxaldehyde, while the benzimidazole derivatives 12a,b were prepared via the formyl
derivatives 11a,b, a product of Velsmier formylation reaction of 10a,b. Two synthetic pro-
tocols for the aryl=hetaryl-2,20-bithiophene derivative 14 have also been presented. In
addition, the guanyl hydrazones of bithiophenes, 16 and 17, were prepared from bis(tri-
n-butylstannyl)-2,20-bithiophene through a Stille coupling reaction followed by a conden-
sation step.
Keywords: Bithiophene; formylation; Heck coupling; Stille coupling; Suzuki coupling
INTRODUCTION
Bi- and oligothiophenes have recently received increased attention because of
their wide applications as advanced materials.[1] They have been heavily investigated
as organic semiconductors, with particular application to thin-film transistors
(TFTs)[1b,c] and light-emitting devices (LEDs).[1d] Bithiophenes and their derivatives
are also important synthetic precursors for biologically active materials.[2]
Nitrile-containing compounds serve as precursors of diamidine-containing mole-
cules, which exhibit broad-spectrum antimicrobial activity, including effectiveness
against different protozoan diseases.[3–6] Moreover, bifuran diamidines I (Fig. 1)
and analogs showed specific recognition of G-quadruplex DNA.[7] Very recently,
the bithiophene diamidines of type II (Fig. 1) showed good activity against Trypano-
soma cruzi.[8] In this context and in continuation of our interest in preparing
Received October 13, 2009.
Address correspondence to Mohamed A. Ismail, Chemistry Department, College of Science, King
Faisal University, P.O. Box 380, Hofuf 31982, Saudi Arabia (current address). E-mail: ismail_158@
yahoo.com
319

320
M. A. ISMAIL AND D. W. BOYKIN
Figure 1. Bithiophene diamidines of type II.
biologically active diamidines, we recently reported an efficient homocoupling
approach to 5,50-diaryl-2,20-bichalcophenes of type I.[9] This route allows only the
synthesis of symmetrical analogs. Different triaryl=hetaryl systems of nitrile-
containing bichalcophenes also have been reported.[10] Given the promising proper-
ties of pyridines,[11] imidazo[1,2-a]pyridines,[12] and benzimidazoles,[13] we decided to
synthesize nitrile-containing bithiophenes of the aforementioned heterocycles.
Because of their activity against trypanosomes,[14] this report also described the
synthesis of two examples of guanyl hydrazones of a bithiophene derivative.
RESULTS AND DISCUSSION
A three-step preparation of the symmetrical imidazo[1,2-a]pyridyl bithiophene
derivatives 3a,b starting from 2-acetyl-5-bromothiophene is described as outlined in
Scheme 1; thus, 2-acetyl-5-bromothiophene was brominated by using bromine in a
mixed solvent of dioxane=ether (1:2) to give compound 1 in 71% yield. A conden-
sation reaction of 6-aminonicotinonitrile or its methyl analog with 1 yielded the
bromothiophen-2-yl-imidazo[1,2-a]pyridine-6-carbonitriles 2a,b, which underwent
a Stille-type homocoupling reaction in the presence of hexabutylditin with a catalytic
amount of Pd(PPh3)4 (ꢀ2 mol%), using refluxing toluene as solvent to afford the
anticipated bithiophene derivatives 3a,b in 72 and 75% yields, respectively. On the
other hand, the unsymmetrical imidazo[1,2-a]pyridyl-benzimidazolyl bithiophene
derivative 6 was obtained in two steps utilizing Suzuki coupling reaction of 2a
with 5-formylthiophen-2-ylboronic acid to form the anticipated 2-(50-formyl-2,20-
bithiophen-5-yl)imidazo[1,2-a]pyridine-6-carbonitrile (5), which subsequently con-
densed with 3,4-diaminobenzonitrile in the presence of an equimolar ratio of sodium
bisulfite to give the desired dinitrile 6. An alternative synthesis of the formyl bithio-
phene derivative 5 was tried through a Stille coupling reaction of 2 with 2-tributyltin
thiophene, forming the product 4, followed by a Vilsmeier formylation reaction.
However, the last step gives an inseparable mixture that may be attributed to the
nucleophilic reactivity at C-3 of the imidazo[1,2-a]pyridine part of compound 4. This
is consistent with the reported literature.[15]
Scheme 2 outlines the preparation of 2-(2,20-bithiophene-5,50-diyl)-bis(1H-
benzo[d]imidazole-6-carbonitrile) (8) via hexabutylditin-mediated homocoupling of
5-bromothiophene-2-carboxaldehyde in the presence of catalytic Pd(PPh3)4 using
refluxing toluene as solvent at 90 ꢁC to form 5,50-diformyl-2,20-bithiophene (7).
Subsequent condensation of the diformyl 7 with 2 equivalents of 3,4-diaminobenzo-
nitrile in the presence of sodium bisulfite gave the desired bithiophene-substituted
benzimidazole 8.

BITHIOPHENE-SUBSTITUTED HETEROCYCLES
321
Scheme 1. Reagents and conditions: (i) Br2; (ii) EtOH, reflux; (iii) (Bu3Sn)2, Pd(PPh3)4; (iv) 2-tributyltin
thiophene, Pd(PPh3)4; (v) DMF-POCl3; (vi) 5-formylthiophen-2-ylboronic acid; (vii) 3,4-diaminobenzoni-
trile, sodium bisulfite, DMF, reflux.
The preparation of bithiophene-substituted benzimidazole derivatives 12a,b is
presented in Scheme 3. Thus, compound 12b was obtained in three steps starting
with the Stille coupling reaction of 5-(tri-n-butylstannyl)-2,20-bithiophene with
6-chloronicotinonitrile to form the anticipated 6-(2,20-bithiophen-5-yl)nicotinonitrile
(10b). A Vilsmeier formylation reaction of 10b furnished the formyl derivative 11b,
Scheme 2. Reagents and conditions: (i) toluene, (Bu3Sn)2, Pd(PPh3)4; (ii) 3,4-diaminobenzonitrile, sodium
bisulfite, DMF, reflux.

322
M. A. ISMAIL AND D. W. BOYKIN
Scheme 3. Reagents and conditions: (i) toluene, Pd(PPh3)4; (ii) DMF-POCl3; (iii) 3,4-diaminobenzonitrile,
sodium bisulfite, DMF, reflux; (iv) NBS, DMF; (v) 4-cyanophenylboronic acid, Pd(PPh3)4; (vi) 4-bromo-
benzonitrile, KOAc, Pd(PPh3)4, 125–135 ꢁC.
which, upon condensation with 3,4-diaminobenzonitrile in the presence of sodium
bisulfite, gave the desired dinitrile 12b. Two synthetic approaches for the synthesis
of 6-[50-(4-cyanophenyl)-2,20-bithiophen-5-yl]nicotinonitrile (14) are also presented
in Scheme 3. The first approach uses bromination of 10b with N-bromosuccinimide
in dimethylformamide (DMF) to furnish 6-(50-bromo-2,20-bithiophen-5-yl)nicotino-
nitrile (13) in 93% yield followed by Suzuki coupling of 13 with 4-cyanophenylboro-
nic acid to afford 14 in 69% yield. The second approach employs a Heck coupling
reaction directly from the reaction of compound 10b with 4-bromobenzonitrile to
afford 14 in 28% yield.
Guanylhydrazones are normally included in the DNA minor-groove binding
category and have frequently been found to have activity against trypanosomes.[14]
Thus, the preparation of the guanylhydrazone derivative 16 involved the conden-
sation reaction between diformyl derivative 15, a Stille product of bis(tri-n-
butylstannyl)-2,20-bithiophene with 4-bromobenzaldehyde, and aminoguanidine
hydrochloride in the presence of Et3N. In a similar manner, compound 17 was
synthesized from the corresponding starting material. It should be noted that 4
equivalents of aminoguanidine or 2-hydrazino-2-imidazoline are necessary to drive
the reaction to completion to form guanylhydrazones.
In conclusion, we have described concise synthetic approaches for novel
bithiophene-substituted benzimidazole, imidazo[1,2-a]pyridine, and pyridine deriva-
tives. The use of these nitrile-containing heterocycles in the synthesis of diamidines
for biological evaluation will be reported in due course.

BITHIOPHENE-SUBSTITUTED HETEROCYCLES
323
Scheme 4. Reagents and conditions: (i) 4-bromobenzaldehyde, toluene, Pd(PPh3)4; (ii) aminoguanidine
hydrochloride=Et3N, EtOH; (iii) 2-hydrazino-2-imidazoline hydrobromide=Et3N, EtOH.
EXPERIMENTAL
General
Melting points were recorded using a Thomas-Hoover (Uni-Melt) capillary
melting-point apparatus and are uncorrected. Thin-layer chromatography (TLC)
analysis was carried out on silica-gel 60 F254 precoated aluminum sheets and detected
under ultraviolet (UV) light. Infrared (IR) spectra were recorded on a Mattson 5000
1
Fourier transform FT–IR spectrometer. H and 13C NMR spectra were recorded
employing a Varian Unity Plus 300 spectrometer at Georgia State University, and
chemical shifts (d) are in parts per million (ppm) relative to tetramethylsilane
(TMS) as internal standard. Mass spectra were recorded on a VG analytical 70-SE
spectrometer. Elemental analyses were obtained from Atlantic Microlab Inc.
(Norcross, GA) and are within ꢂ0.4 of the theoretical values. All chemicals and sol-
vents were purchased from Aldrich Co., Fisher Scientific, Frontier and Lancaster.
N-Bromosuccinimide (NBS) was recrystallized from nitromethane prior to use. All
solvents were reagent grade. 4-(2,20-Bithiophen-5-yl)benzonitrile[10] (10a), 5-(tri-n-
butylstannyl)-2,20-bithiophene[16]
,
were prepared according to the reported literature.
and bis(tri-n-butylstannyl)-2,20-bithiophene[17]
2-Bromo-1-(5-bromothiophen-2-yl)-ethanone (1)
Bromine (2.08 mL, 40 mmol) was added portionwise to a solution of 2-acetyl-5-
bromothiophene (8.20 g, 40 mmol) in 48 mL dioxane=ether (1:2) with cooling at
0–5 ꢁC and stirring over 1 h. The reaction mixture was further stirred with cooling.
After TLC indicated complete bromination, the reaction mixture was diluted with
ether (200 mL) and water (200 mL). The ethereal layer was separated, washed with

324
M. A. ISMAIL AND D. W. BOYKIN
1 M sodium bicarbonate aqueous solution, and dried over Na2SO4. The ether extract
was distilled off to afford 1 in 71% yield as a colorless sheet, mp 89–90 ꢁC (hexanes=
ether) (lit.[18] mp 90–91 ꢁC); IR (KBr) n 3083, 3000, 2952, 1670 (CO) cmꢃ1. 1H NMR
(CDCl3): d 4.28 (s, 2H), 7.14 (d, J ¼ 4.2 Hz, 1H), 7.54 (d, J ¼ 4.2 Hz, 1H). 13C NMR
(CDCl3): d 183.4, 142.1, 133.7, 131.5, 124.5, 29.6. MS (EI) m=e (rel. int.): 284, 286
(Mþ, 14, 7 bromine isotopes), 204 (2), 191 (100), 189 (92), 175 (7), 123 (4).
2-(5-Bromothiophen-2-yl)-imidazo[1,2-a]pyridine-6-carbonitrile (2a)
A mixture of 6-aminonicotinonitrile (1.19 g, 10 mmol) and 2-bromo-1-
(5-bromothiophen-2-yl)-ethanone (1) (2.84 g, 10 mmol) in ethanol (50 mL) was
heated at reflux for 24 h. The precipitated salt was filtered, suspended in water,
and neutralized with aqueous NaHCO3 solution. The free base precipitate was fil-
tered and dried to furnish 2a in 79% yield as an off-white solid, mp 249–250.5 ꢁC
(EtOH). IR (KBr) n 3089, 3048, 2225 (CN), 1625, 1573, 1529 cmꢃ1 1H NMR
.
(DMSO-d6): d 7.28 (d, J ¼ 4.2 Hz, 1H), 7.49–7.55 (m, 2H), 7.72 (d, J ¼ 9.6 Hz,
1H), 8.42 (s, 1H), 9.33 (s, 1H). 13C NMR (DMSO-d6): d 143.8, 140.5, 138.2,
133.9, 131.4, 125.2, 125.1, 117.0, 116.7, 111.6, 109.4, 97.3. MS (EI) m=e (rel. int.):
303, 305 (Mþ, 54, 52 bromine isotopes), 224 (100), 180 (30). Anal. calcd. for
C12H6BrN3S: C, 47.38; H, 1.99; N, 13.81. Found. C, 47.61; H, 2.10; N, 13.64.
2-(5-Bromothiophen-2-yl)-8-methylimidazo[1,2-a]pyridine-6-
carbonitrile (2b)
The same procedure described for preparation of 2a was used starting with
6-amino-5-methylnicotinonitrile instead of 6-aminonicotinonitrile. Yield 68% as
off-white needles, mp 213–214.5 ꢁC. IR (KBr) n 3100, 3083, 2925, 2223 (CN),
1
1643, 1617 cmꢃ1. H NMR (DMSO-d6): d 2.46 (s, 3H), 7.21 (d, J ¼ 3.6 Hz, 1H),
7.28 (s, 1H), 7.40 (d, J ¼ 3.6 Hz, 1H), 8.31 (s, 1H), 9.09 (s, 1H). 13C NMR
(DMSO-d6): d 144.4, 139.8, 138.3, 131.4, 131.1, 127.1, 124.8, 122.9, 116.7, 111.2,
109.8, 97.1, 15.9. MS (ESI) m=e (rel. int.): d 318, 320 (Mþ þ 1, 100, 96 bromine iso-
topes). Anal. calcd. for C13H8BrN3S: C, 49.07; H, 2.53; N, 13.21. Found. C, 49.40;
H, 2.69; N, 13.02.
2,2’-(2,2’-Bithiophene-5,5’-diyl)-bis(imidazo[1,2-a]pyridine-6-
carbonitrile) (3a)
Hexa-n-butylditin (2.9 g, 5 mmol) was added to a solution of 2a (1.52 g,
5 mmol) and tetrakis(triphenylphosphine) palladium (100 mg, 0.085 mmol) in toluene
(40 mL). The reaction mixture was heated under N2 at 120 ꢁC for 6 h, then cooled,
and the precipitate was filtered and washed with hexanes. Recrystallization from
DMF gave compound 3a in 72% as a dark-green powder, mp > 320 ꢁC. IR (KBr)
1
n 3083, 3050, 2225 (CN), 1629, 1567 cmꢃ1. H NMR (DMSO-d6): d 7.36–7.69 (m,
8H), 8.37 (s, 2H), 9.23 (s, 2H). MS (ESI) m=e (rel. int.): 448 (Mþ, 13), 449
(Mþ þ 1, 87), 409 (24), 320 (100). High-resolution mass calcd. for C24H13N6S2:
449.0643. Observed: 449.0641. Anal. calcd. for C24H12N6S2: C, 64.27; H, 2.70.
Found. C, 63.94; H, 2.81.

BITHIOPHENE-SUBSTITUTED HETEROCYCLES
325
2,2’-(2,2’-Bithiophene-5,5’-diyl)-bis(8-methylimidazo[1,2-a]pyridine-
6-carbonitrile) (3b)
The same procedure described for preparation of 3a was used starting with 2b.
Yield 75% as a dark-green powder, mp 304–306 ꢁC. IR (KBr) n 3072, 2954, 2921,
2225 (CN), 1623, 1573 cmꢃ1
.
1H NMR (DMSO-d6): d 2.54 (s, 6H, 2 ꢄ CH3),
7.27–7.54 (m, 6H), 8.33 (s, 2H), 9.07 (s, 2H). MS (ESI) m=e (rel. int.): 477
(Mþ þ 1, 33), 478 (Mþ þ 2, 10), 452 (22), 409 (58), 331 (100). High-resolution mass
calcd. for C26H17N6S2: 477.0956. Observed: 477.0967. Anal. calcd. for
C26H16N6S2: C, 65.53; H, 3.38. Found. C, 65.22; H, 3.19.
2-(2,2’-Bithiophen-5-yl)imidazo[1,2-a]pyridine-6-carbonitrile (4)
A mixture of 2a (3.03 g, 10 mmol), 2-tri-n-butyltin thiophene (3.72 g,
10 mmol), and tetrakis(triphenylphosphine) palladium (200 mg) in dry dioxane
(50 mL) was heated under nitrogen at 100–110 ꢁC for 24 h. The solvent was eva-
porated under reduced pressure, and the resulting residue was dissolved in ethyl
acetate. This solution was passed through celite to remove Pd. The solution was
evaporated, and the residue was chromatographed on silica gel using hexanes=
EtOAc (3:7) as an eluent to furnish compound 4 in 76% yield as a pale yellow
solid, mp 219–220.5 ꢁC. 1H NMR (DMSO-d6): d 7.08–7.11 (m, 1H), 7.27–7.34
(m, 2H), 7.43–7.54 (m, 3H), 7.68 (d, J ¼ 9.6 Hz, 1H), 8.35 (s, 1H), 9.24 (s, 1H).
13C NMR (DMSO-d6): d 143.9, 141.1, 136.6, 136.2, 135.1, 133.8, 128.3, 125.7,
125.5, 125.1, 124.8, 124.1, 116.9, 109.5, 97.1. MS (EI) m=e (rel. int.): 307 (Mþ,
100), 308 (Mþ þ 1, 23), 274 (5), 262 (5), 131 (13). High-resolution mass calcd.
for C16H9N3S2: 307.0237. Observed: 307.0234. Anal. calcd. for C16H9N3S2:
C, 62.52; H, 2.95. Found. C, 62.60; H, 3.01.
2-(5’-Formyl-2,2’-bithiophen-5-yl)imidazo[1,2-a]pyridine-
6-carbonitrile (5)
To a stirred solution of 2a (1.51 g, 5 mmol), and tetrakis(triphenylphosphine)
palladium (200 mg) in toluene (10 mL) under a nitrogen atmosphere, 10 mL of a
1 M aqueous solution of NaHCO3 were added, followed by 5-formylthiophen-2-
ylboronic acid (936 mg, 6 mmol) in 5 mL of methanol. The vigorously stirred mix-
ture was warmed to 80 ꢁC for 16 h. The solvent was evaporated, and the precipi-
tate was partitioned between methylene chloride (300 mL) and aqueous solution
containing 5 mL of concentrated ammonia. The organic layer was dried (Na2SO4)
and then concentrated to dryness under reduced pressure to afford 5 in 61% yield
as a brown-yellow solid, mp 268–270 ꢁC (DMF). IR (KBr) n 3137, 3081, 2227
(CN), 1650 (CO), 1573 cmꢃ1 1H NMR (DMSO-d6): d 7.46–7.69 (m, 6H), 8.43
.
(s, 1H), 9.26 (s, 1H), 9.87 (s, 1H). 13C NMR (DMSO-d6): d 183.2, 145.1,
143.8, 141.2, 140.5, 138.5, 138.0, 134.9, 133.7, 127.5, 125.8, 125.1, 124.9, 116.9,
116.5, 110.0, 97.2. MS (EI) m=e (rel. int.): 335 (Mþ, 100), 307 (12), 262 (28).
Anal. calcd. for C17H9N3OS2: C, 60.88; H, 2.70; N, 12.53. Found. C, 60.75;
H, 2.73; N, 12.67.

326
M. A. ISMAIL AND D. W. BOYKIN
2-{5’-(6-Cyanoimidazo[1,2-a]pyridin-2-yl)-2,2’-bithiophen-5-yl}-1H-
benzimidazole-6-carbonitrile (6)
A solution of 5 (670 mg, 2 mmol), 3,4-diaminobenzonitrile (267 mg, 2 mmol),
and sodium bisulfite (261 mg, 2.5 mmol) in 10 mL DMF was allowed to reflux over-
night. After cooling, the reaction mixture was poured onto water. The solid was col-
lected by filtration and washed with aqueous sodium bicarbonate (2.5%) and water
to furnish 3a in 77% yield as a brown solid, mp > 320 ꢁC (DMF). IR (KBr) n 3353
1
(NH), 3083, 2962, 2221 (CN), 1619, 1567 cmꢃ1. H NMR (DMSO-d6): d 7.45–7.85
(m, 8H), 8.04 (s, 1H), 8.41 (s, 1H), 9.26 (s, 1H), 13.30 (s, 1H, NH). MS (ESI) m=e
(rel. int.); 449 (Mþ þ 1, 60), 413 (30), 365 (32), 331 (100). High-resolution mass calcd.
for C24H13N6S2: 449.0643. Observed: 449.0641. Anal. calcd. for C24H12N6S2:
C, 64.27; H, 2.70. Found. C, 64.05; H, 2.79.
2,2’-Bithiophene-5,5’-dicarboxaldehyde (7)
The same procedure described for preparation of 3a was used starting with
5-bromothiophene-2-carboxaldehyde (the temperature of the reaction maintained
at 90 ꢁC). Yield 70% as a golden solid, mp 212.5–214 ꢁC (lit.[19] mp 215–217 ꢁC;
1
lit.[20] mp 185–195 ꢁC). IR (KBr) n 3100, 1654 (CO), 1538, 1436 cmꢃ1. H NMR
(DMSO-d6): d 7.73 (d, J ¼ 3.9 Hz, 2H), 8.02 (d, J ¼ 3.9 Hz, 2H), 9.93 (s, 2H). 13C
NMR (DMSO-d6): d 184.3, 143.5, 143.4, 138.9, 127.9. MS (EI) m=e (rel. int.): 222
(Mþ, 100), 193 (18), 149 (32).
2,2’-(2,2’-Bithiophen-5,5’-diyl)-bis(1H-benzimidazole-6-carbonitrile) (8)
The same procedure described for the preparation of 6 was used, employing
dialdehyde derivative 7 (1 equiv) and 3,4-diaminobenzonitrile (2 equiv). Yield 75%
as a brown powder, mp > 320 ꢁC (DMF). IR (KBr) n 3455 (NH), 3089, 2215
(CN), 1614, 1563 cmꢃ1 1H NMR (DMSO-d6): d 7.31–7.71 (m, 6H), 7.88 (d,
.
J ¼ 3.9 Hz, 2H), 8.08 (s, 2H), 13.70 (br s, 2H, 2NH). MS (EI) m=e (rel. int.): 448
(Mþ, 100), 321 (38). Anal. calcd. for C24H12N6S2: C, 64.27; H, 2.70; N, 18.74.
Found. C, 63.90; H, 2.85; N, 18.46.
6-(2,2’-Bithiophen-5-yl)nicotinonitrile (10b)
Adopting the same procedure used for the preparation of 4, a Stille coupling
reaction was performed using 6-chloronicotinonitrile and 5-(tri-n-butylstannyl)-2,20-
bithiophene to yield the cyano derivative 10b in 85% yield as a yelꢃlo1w solid; mp
176–177 ꢁC (EtOH). IR (KBr) n 2217 (CN), 1639, 1583, 1513 cm
.
1H NMR
(DMSO-d6): d 7.10–7.14 (m, 1H), 7.40 (d, J ¼ 3.9 Hz, 1H), 7.45 (d, J ¼ 3.9 Hz,
1H), 7.59 (dd, J ¼ 5.1, 1.2 Hz, 1H), 7.95 (d, J ¼ 3.9 Hz, 1H), 8.11 (d, J ¼ 8.4 Hz,
1H), 8.28 (dd, J ¼ 8.4, 2.1 Hz, 1H), 8.92 (d, J ¼ 2.1 Hz, 1H). 13C NMR (DMSO-
d6): d 154.3, 152.6, 141.13, 141.08, 140.5, 136.0, 129.4, 128.6, 126.7, 125.4, 125.3,
118.4, 117.3, 106.4. Anal. calcd. for C14H8N2S2: C, 62.66; H, 3.00; N, 10.44. Found.
C, 62.57; H, 2.97; N, 10.45.

BITHIOPHENE-SUBSTITUTED HETEROCYCLES
327
4-(5’-Formyl-2,2’-bithiophen-5-yl)benzonitrile (11a)
Freshly distilled DMF (4.2 mL) was stirred in an ice bath with dropwise
addition of POCl3 (14 mL), followed by a suspension of compound 10a (1.86 g,
7 mmol) in methylene chloride (12 mL). The reaction mixture was stirred under heat-
ing at 85–95 ꢁC for 6 h. The solvent was distilled off under reduced pressure, then
poured onto ice water, and the solid was collected by filtration and washed with
aqueous sodium bicarbonate (2.5%) and water to furnish 11a in 81% yield as a
golden solid, mp 197–198 ꢁC (EtOH). IR (KBr) n 3095, 2921, 2223 (CN), 1654
(CO), 1600 cmꢃ1
.
1H NMR (DMSO-d6): d 7.59 (d, J ¼ 3.3 Hz, 1H), 7.66 (d,
J ¼ 3.9 Hz, 1H), 7.79 (d, J ¼ 3.9 Hz, 1H), 7.87 (s, 4H), 8.00 (d, J ¼ 3.3 Hz, 1H),
9.88 (s, 1H). 13C NMR (DMSO-d6): d 184.0, 144.7, 142.5, 141.8, 139.2, 137.1,
136.5, 133.2, 128.5, 127.8, 126.0, 125.8, 110.2, 99.5. MS (EI) m=e (rel. int.): 295
(Mþ, 100), 267 (8), 222 (29). High-resolution mass calcd. for C16H9NOS2:
295.0125. Observed: 295.0126. Anal. Calcd for C16H9NOS2: C, 65.06; H, 3.07.
Found. C, 65.15; H, 3.13.
6-(5’-Formyl-2,2’-bithiophen-5-yl)nicotinonitrile (11b)
The same procedure described for preparation of 11a was used starting with
10b. Yield 77% as a golden solid, mp 258–259.5 ꢁC. IR (KBr) n 3085, 3050, 2794,
2223 (CN), 1656 (CO), 1587, 1515 cmꢃ1. 1H NMR (DMSO-d6): d 7.65 (d, J ¼ 3.9 Hz,
Hz, 1H), 7.68 (d, J ¼ 3.9 Hz, 1H), 8.00 (d, J ¼ 3.9 Hz, 1H), 8.03 (d, J ¼ 3.9 Hz, 1H),
8.16 (d, J ¼ 8.4 Hz, 1H), 8.31 (dd, J ¼ 8.4, 2.1 Hz, 1H), 8.95 (d, J ¼ 2.1 Hz, 1H), 9.90
(s, 1H). Anal. calcd. for C15H8N2OS2: C, 60.79; H, 2.72; N, 9.45. Found. C, 60.60; H,
2.82; N, 9.23.
2-[5’-(4-Cyanophenyl)-2,2’-bithiophen-5-yl]-1H-
benzimidazole-6-carbonitrile (12a)
The same procedure described for preparation of 6 was used starting with 11a.
Yield 74% as a brown powder, mp 320–322 ꢁC (DMF). IR (KBr) n 3415 (NH), 3075,
2221 (CN), 1596, 1577, 1536 cmꢃ1.1H NMR (DMSO-d6): d 7.52–7.61 (m, 3H),
7.70–7.88 (m, 6H), 7.97–8.08 (m, 2H), 13.40 (s, 1H, NH). 13C NMR (DMSO-d6):
d 149.0, 141.1, 139.5, 138.8, 137.2, 136.9, 133.1, 130.7, 130.2, 130.0, 127.6, 126.9,
126.2, 125.8, 125.2, 120.0, 119.8, 118.7, 115.4, 109.9, 104.4. MS (EI) m=e (rel. int.):
408 (Mþ, 100). High-resolution mass calcd. for C23H12N4S2: 408.0503. Observed:
408.0519. Anal. calcd. for C23H12N4S2: C, 67.62; H, 2.96. Found. C, 67.30; H, 3.07.
2-[5’-(5-Cyanopyridin-2-yl)-2,2’-bithiophen-5-yl]-1H-
benzimidazole-6-carbonitrile (12b)
The same procedure described for preparation of 6 was used starting with 11b.
Yield 70% as a brown powder, mp > 320 ꢁC (DMF). IR (KBr) n 3097, 2223 (CN),
1658, 1621, 1587 cmꢃ1 1H NMR (DMSO-d6): d 7.50–7.57 (m, 3H), 7.71 (d,
.
J ¼ 8.1 Hz, 1H), 7.89 (d, J ¼ 3.9 Hz, 1H), 7.97 (d, J ¼ 3.9 Hz, 1H), 8.04 (s, 1H),
8.10 (d, J ¼ 8.4 Hz, 1H), 8.27 (dd, J ¼ 8.4, 2.1 Hz, 1H), 8.93 (d, J ¼ 2.1 Hz, 1H)

328
M. A. ISMAIL AND D. W. BOYKIN
13.65 (s, 1H, NH). MS (EI) m=e (rel. int.): 409 (Mþ, 100), 376 (4), 320 (10). High-
resolution mass calcd. for C22H11N5S2: 409.0456. Observed: 409.0464. Anal. calcd.
for C22H11N5S2: C, 64.53; H, 2.71. Found: C, 64.21; H, 2.86.
6-(5’-Bromo-2,2’-bithiophen-5-yl)nicotinonitrile (13)
NBS (1.78 g, 10 mmol) was added portionwise to a solution of 10b (2.67 g,
10 mmol) in DMF (30 mL) with stirring. The reaction mixture was stirred overnight,
then poured onto cold water. The precipitate that formed was collected, washed with
water, and dried to give 13 in 93% yield as a yellow solid, mp 209–210 ꢁC. IR (KBr) n
1
3077, 3045, 2229 (CN), 1641, 1585, 1550 cmꢃ1. H NMR (DMSO-d6): d 7.26–7.33
(m, 2H), 7.43 (d, J ¼ 4.2 Hz, 1H), 7.98 (d, J ¼ 4.2 Hz, 1H), 8.15 (d, J ¼ 8.4 Hz,
1H), 8.31 (dd, J ¼ 8.4, 2.1 Hz, 1H), 8.93 (d, J ¼ 2.1 Hz, 1H). 13C NMR (DMSO-
d6): d 150.1, 148.6, 137.8, 136.6, 135.6, 133.7, 127.9, 125.3, 122.0, 121.8, 114.5,
113.2, 107.5, 102.6. MS (EI) m=e (rel. int.): 346, 348 (Mþ, 100, 95 bromine isotopes),
267 (13), 223 (40). High-resolution mass calcd. for C14H7BrN2S2: 345.9234.
Observed: 345.9234. Anal. calcd. for C14H7BrN2S2: C, 48.42; H, 2.03. Found. C,
48.29; H, 2.01.
6-[5’-(4-Cyanophenyl)-2,2’-bithiophen-5-yl]nicotinonitrile (14)
Method A. Adopting the same procedure used for the preparation of 5, a
Suzuki coupling reaction was performed using 13 and 4-cyanophenylboronic acid
to yield 14 in 69% yield as a brick-red solid, mp 307–309.5 ꢁC (DMF). IR (KBr) n
1
3062, 2225 (CN), 1635, 1587 cmꢃ1. H NMR (DMSO-d6): d 7.45–7.57 (m, 3H),
7.70–7.93 (m, 5H), 8.08–8.25 (m, 2H), 8.91 (s, 1H). MS (EI) m=e (rel. int.): 369
(Mþ, 100). High-resolution mass calcd. for C21H11N3S2: 369.0394. Observed:
369.0382. Anal. calcd. for C21H11N3S2: C, 68.27; H, 3.00. Found. C, 67.88; H, 3.12.
Method B. A mixture of compound 10b (1.34 g, 5 mmol), 4-bromobenzoni-
trile (925 mg, 5 mmol), tetrakis(triphenylphosphine) palladium (200 mg), and potass-
ium acetate (2.5 g, 25 mmol) in dry DMF (20 mL) was heated under nitrogen at
130–135 ꢁC overnight. The reaction mixture then poured onto cold water. The pre-
cipitate that formed was collected and recrystallized from DMF to afford compound
14 in 28% yield.
4,4’-(2,2’-Bithiophen-5,5’-diyl)dibenzaldehyde (15)
Adopting the same procedure used for the preparation of 4, a Stille coupling
reaction was performed using 4-bromobenzaldehyde (2 equiv) and bis(tri-n-
butylstannyl)-2,20-bithiophene (1 equiv) to yield 15 in 82% yield as a green-yellow
solid; mp 244–246 ꢁC (DMF). IR (KBr) n 3100, 3062, 2861, 1694 (CHO), 1598,
1
1563 cmꢃ1. H NMR (DMSO-d6): d 7.47 (d, J ¼ 3.6 Hz, 2H), 7.71 (d, J ¼ 3.6 Hz,
2H), 7.89 (d, J ¼ 7.5 Hz, 4H), 7.95 (d, J ¼ 7.5 Hz, 4H), 10.01 (s, 2H). MS (EI) m=e
(rel. int.): 374 (Mþ, 100), 346 (87). High-resolution mass calcd. for C22H14O2S2:
374.0435. Observed: 374.0412. Anal. calcd. for C22H14O2S2: C, 70.56; H, 3.77.
Found. C, 70.75; H, 3.63.

BITHIOPHENE-SUBSTITUTED HETEROCYCLES
329
N-[4,4’-(2,2’-Bithiophen-5,5’-diyl)dibenzylidene]-N’-amidino
Hydrazine (16)
A mixture of 15 (374 mg, 1 mmol), aminoguanidine hydrochloride (440 mg,
4 mmol), and triethylamine (4 mmol) in absolute ethanol (40 mL) was heated at
reflux overnight. The formed precipitate was filtered, washedꢁwith water, and dried
to give 16 in 65% yield as a brown-yellow solid, mp > 320 C (DMF=EtOH). IR
1
(KBr) n 3432, 3365, 3342 (NH, NH2), 3070, 1687, 1598 cmꢃ1. H NMR (DMSO-
d6): d 5.53 (br s, 4H), 5.95 (br s, 4H), 7.37 (d, J ¼ 4.2 Hz, 2H), 7.53 (d, J ¼ 4.2 Hz,
2H), 7.62 (d, J ¼ 8.4 Hz, 4H), 7.71 (d, J ¼ 8.4 Hz, 4H), 7.98 (s, 2H). Anal. calcd.
for C24H22N8S2: C, 59.24; H, 4.56; N, 23.03. Found: C, 59.50; H, 4.60; N, 22.73.
N-[4,4’-(2,2’-Bithiophen-5,5’-diyl)dibenzylidene]-N’-(4,5-dihydro-1H-
imidazol-2-yl) Hydrazine (17)
The same procedure described for 16 was used, employing 2-hydrazino-2-
imidazoline hydrobromide iꢁnstead of aminoguanidine hydrochloride. Yield 69% as
an orange solid, mp > 320 C. IR (KBr) n 3430 (NH), 3143, 3066, 2923, 2883,
2829, 1635, 1573, 1544 cmꢃ1 1H NMR (DMSO-d6): d 3.44 (s, 8H), 6.23 (br s,
.
2H), 6.61 (br s, 2H), 7.34 (d, J ¼ 3.9 Hz, 2H), 7.49 (d, J ¼ 3.9 Hz, 2H), 7.63 (d,
J ¼ 8.4 Hz, 4H), 7.71 (d, J ¼ 8.4 Hz, 4H), 8.00 (s, 2H). Anal. calcd. for
C28H26N8S2: C, 62.43; H, 4.86; N, 20.80. Found: C, 62.09; H, 4.87; N, 20.94.
ACKNOWLEDGMENTS
This work was supported by the Bill and Melinda Gates Foundation and by
National Institute of Health Grant AI46365.
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