Hydroxypropyl substituted nitrogen bridgehead fused cyanopyridines

Article abstract of DOI:10.1016/j.tet.2013.12.074

The reaction of 2-hetaryl-2-(tetrahydro-2-furanyliden)acetonitriles with substituted acetonitriles as C-nucleophiles has been investigated and the mechanism of the reaction has been suggested. A base promoted Michael addition of the substituted acetonitriles to 2-hetaryl-2-(tetrahydro-2-furanyliden) acetonitriles followed by ring transformations has provided novel convenient synthetic methods to nitrogen bridgehead fused cyanopyridines bearing hydroxypropyl side chain. The structures of obtained compounds have been established based on NMR spectroscopy investigation and X-ray diffraction data.

Full text of DOI:10.1016/j.tet.2013.12.074

Accepted Manuscript
Hydroxypropyl substituted nitrogen bridgehead fused cyanopyridines
Demyd S. Milokhov, Olga V. Khilya, Alexander V. Turov, Volodymyr V. Medviediev,
Oleg V. Shishkin, Yulian M. Volovenko
PII:
S0040-4020(13)01942-X
10.1016/j.tet.2013.12.074
TET 25158
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 October 2013
Revised Date: 12 December 2013
Accepted Date: 24 December 2013
Please cite this article as: Milokhov DS, Khilya OV, Turov AV, Medviediev VV, Shishkin OV, Volovenko
YM, Hydroxypropyl substituted nitrogen bridgehead fused cyanopyridines, Tetrahedron (2014), doi:
10.1016/j.tet.2013.12.074.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Hydroxypropyl substituted nitrogen
bridgehead fused cyanopyridines
Leave this area blank for abstract info.
Demyd S. Milokhova , Olga V. Khilyaa , Alexander V. Turova , Volodymyr V. Medviedievb , Oleg V. Shishkinb,
c and Yulian M. Volovenkoa
aChemistry Department, Taras Shevchenko National University of Kyiv, 64 Volodymyrska st., Kyiv 01601,
Ukraine
bSSI "Institute for Single Crystals", National Academy of Sciences of Ukraine, 60 Lenina ave., Kharkiv 61001,
Ukraine
cDepartment of Inorganic Chemistry, V. N. Karazin Kharkiv National University, 4 Svobody sq., Kharkiv 61202,
Ukraine
OH
OH
NC
O
NC
EWG
Y
NC
EWG
NH2
N
X
N
X
N
N
X = NH, S, NMe, CH=CH;
EWG = CN, SO2Me, Ar, Het; Y = NH, O

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Hydroxypropyl substituted nitrogen bridgehead fused cyanopyridines
Demyd S. Milokhova, *, Olga V. Khilyaa, , Alexander V. Turova , Volodymyr V. Medviedievb , Oleg V.
Shishkinb, c and Yulian M. Volovenkoa
aChemistry Department, Taras Shevchenko National University of Kyiv, 64 Volodymyrska st., Kyiv 01601, Ukraine
bSSI "Institute for Single Crystals", National Academy of Sciences of Ukraine, 60 Lenina ave., Kharkiv 61001, Ukraine
cDepartment of Inorganic Chemistry, V. N. Karazin Kharkiv National University, 4 Svobody sq., Kharkiv 61202, Ukraine
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The reaction of 2-hetaryl-2-(tetrahydro-2-furanyliden)acetonitriles with substituted acetonitriles
as C-nucleophiles has been investigated and the mechanism of the reaction has been suggested.
A base promoted Michael addition of the substituted acetonitriles to 2-hetaryl-2-(tetrahydro-2-
furanyliden)acetonitriles followed by ring transformations has provided novel convenient
synthetic methods to nitrogen bridgehead fused cyanopyridines bearing hydroxypropyl side
chain. The structures of obtained compounds have been established based on NMR spectroscopy
investigation and X-ray diffraction data.
Available online
Keywords:
Michael addition
2-Hetaryl-2-(tetrahydro-2-furanyliden)acetonitriles
Nucleophiles
2013 Elsevier Ltd. All rights reserved.
ω-Hydroxyalkylheterocycles
Fused pyridines
Hetarylacetonitriles
1. Introduction
Pyrido[1,2-a]benzimidazole scaffolds belong to fused pyridine
ring systems that have received a great deal of attention in the
past decade on account of their various biological activities
including antitumor (NSC 699944),1 antiviral,2 antimicrobial,3
4
antitubercular,3b,
antifungal (D11-2040)5 and antimalarial
activities (TDR86919).6 Cyanopyridobenzimidazole-based agents
displayed inhibitory activities of the cellular function of perforin
(PRF) protein as a potentially drugable target.7 The luminescent
properties of pyridobenzimidazole core have been highlighted, as
well.8 The synthesis of benzothiazole fused pyridines as a new
chemotype targeting the hepatitis C virus NS5B polymerase have
been recently reported (Figure 1).9
Syntheses of fused cyanopyridine rings containing
benzimidazole,1-8, 10 benzothiazole,9, 11 benzoxazole,12 imidazole,
pyrazol and triazole13 scaffolds have been described to date. The
main synthetic strategies to the fused pyridine ring system
mentioned above consist of utilizing hetarylacetonitrile
precursors
in:
Knoevenagel
reaction
followed
by
Figure 1. Biologically relevant fused cyanopyridines.
cyclocondensation, Michael addition to α,β-unsaturated nitriles,
and cyclocondensation with β-dicarbonyl compounds.
examples of such reagents are 3-functionalized acrylonitriles
incorporated into unsaturated heterocyclic ring which have been
shown to be valuable precursors in the synthesis of heterocyclic
systems.15
Developing novel synthons and efficient synthetic routes in
order to obtain designated heterocycles has always drawn
attention of organic chemists. Ring transformation reactions of
cyclic 1,3-dicarbonyl synthons have provided a convenient
2-Hetaryl-2-(tetrahydro-2-furanyliden)acetonitriles 3 represent
versatile building blocks in syntheses of ω-hydroxyalkyl
synthetic route to functionalized heterocycles.14 Important
———
Corresponding author. Tel.: +38-044-235-12-73; e-mail: demjd@yandex.ru (D.S. Milokhov), olgakh@univ.kiev.ua (O.V. Khilya)

2
Tetrahedron
fragment is found to be reactive towards N-nucleophiles with a
ACCEPTED MANUSCRIPT
following ring transformation.16 In this process the nucleophilic
substitution of the bridged heteroatom causes a disconnection of
the starting ring leading to
ω-hydroxyalkyl chain.17
Furanylidens 3 have already been utilized as cyclic 1,3-
a
dicarbonyl
heteroanalogs
in
the
synthesis
of ω-
hydroxyalkylheterocycles.18 As part of our ongoing research
concerning the synthetic utility of furanylidens 3 in heterocyclic
synthesis, it was considered of interest to study their reactions
Scheme 1. Synthesis of 2-hetaryl-2-(tetrahydro-2-furanyliden)acetonitriles 3.
substituted heterocycles due to the presence of 1,3-bielectrophilic
acrylonitrile fragment functionalized with unsaturated
heterocyclic ring and nucleophilic azaheterocyclic moiety. The
carbonyl group masked within the alkylidenetetrahydrofuran
with substituted acetonitriles as
functionalized fused cyanopyridines.
a novel route to the
Scheme 2. Synthesis of 1-amino- 7 and 1-iminocyanopyridines 8-10.
Table 1 Cyanopyridine derivatives 7–12 produced via Scheme 2 and 3
Products
1H NMR (δ)
Entry
Compd
Conditions
NH
Yield (%)
91
Mp (°C)
X
EWG
9-H
1
7a
-
CN
8.53
8.35
8.41
9.54
9.43
9.48
9.48
9.50
8.94
9.48b
9.05
8.53
8.62
9.50
8.48a
8.48a
6.76a
8.14
9.56
7.01
7.01
7.09
7.58
8.73
-
DMF, rt, 6 h
293-294
286-287
307-308
233-234
200-201
162-163
201-202
187-188
258-259
176-177
289-290
295-296
252-253
154-155
2
7b
-
SO2Me
DMF, 100 °C, 1 h
DMF, rt, 8 h
80
88
86
76
85
94
81
92
91
92
91
88
3
7c
-
Ph
4
8a
S
CN
Dioxane, rt, 2 h
Dioxane, reflux, 1 h
Dioxane, rt, 3 h
Dioxane, rt, 3 h
Dioxane, rt, 3 h
Dioxane, rt, 3 h
Dioxane, rt, 2 h
DMF, rt, 1 h
5
8b
S
SO2Me
6
8c
S
Ph
7
8d
S
3-Cl-C6H4
8
8e
S
4-OMe-C6H4
9
9a
NMe
CH=CH
S
CN
10
11
12
13
14
10a
11a
11b
11c
12a
CN
-
NH
NMe
S
-
-
DMF, rt, 2 h
-
-
DMF, rt, 1 h
CO2t-Bu
8.38
DMF, -10 – -5 °C, 4 h 53c (27)d
aThe signal of NH2 group protons.
bThe signal of 10-H proton.
cThe yield of crude product.
dThe yield of product after purification with column chromatography.
with γ-chlorobutanoyl chloride 2 according to the procedure
2. Results and discussion
published earlier (Scheme 1).19
2-Hetaryl-2-(tetrahydro-2-furanyliden)acetonitriles
3
have
been prepared via the two-step reaction of hetarylacetonitriles 1

3
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Scheme 3. Reaction of 2-hetaryl-2-(tetrahydro-2-furanyliden)acetonitriles 3a-c with cyanoacetate 5a,b.
A key feature of furanylidens 3 is the presence of the carbonyl
group masked within the unsaturated heterocyclic ring which
undergoes a ring opening through the reaction with nucleophiles.
In this paper we have focused on the base-promoted ring
transformation reaction of furanylidens 3 with acetonitriles 4-6,
as C-nucleophiles. The synthetic approach allows obtaining fused
cyanopyridines 7–14 bearing hydroxypropyl side chain.
The formation of 7–10 is assumed to be initiated by Michael
addition of the carbanion generated in situ with NaH from
acetonitriles 4 to the acrylonitrile fragment of furanylidens 3
giving possible intermediate A. Then, intramolecular interaction
of heterocyclic nitrogen with the nitrile group of the acetonitrile
moiety proceeds and the subsequent disclosing of the
tetrahydrofuranyliden ring leads to 1-amino-
iminocyanopyridines 8–10 (Scheme 2, Table 1).
7
and 1-
Figure 2. Molecular structure of compound 10a according to X-ray
diffraction data with the atom numbering used in the crystallographic
analysis. Thermal ellipsoids are drawn at 50% probability level.
1
The structure of obtained compounds was confirmed by H
NMR, 13C NMR and FT-IR spectroscopy. Particularly, the
doublet of 9-H proton at 8.3–8.5 ppm (pyridobenzimidazoles)
and 9.4–9.5 ppm (pyridobenzothiazoles) shifted downfield due to
deshielding by magnetically anisotropic amino or imino groups
was a characteristic signal for each heterocycle that confirmed
the fused ring system formation. However, singlets of NH2 and
NH appear in the larger chemical shift range from 6.7 to 9.5 ppm
depending on the nature of the fused heterocycle and the
substitution pattern at the second position (Table 1). In the 13C
NMR spectra of the title compounds 7–10, the signal at around
96.1–69.1 ppm is assigned to carbon attached with carbonitrile
group while the carbon signal of CN appears at 117.6–114.2
ppm. IR spectra show the absorption in the range of 3548–3204
cm-1 corresponding to stretching vibrations of hydroxy, amino
and imino groups. The absorption of the nitrile group is observed
at 2225–2199 cm-1.
Figure 3. Molecular structure of compound 11c according to X-ray
diffraction data with the atom numbering used in the crystallographic
analysis. Thermal ellipsoids are drawn at 50% probability level.
The structure of 1-iminocyanopyridine 10a was confirmed by
X-ray diffraction (XRD) study (Figure 2). According to XRD
data the N1, C9-C14 pyridine ring adopts a sofa conformation
despite of presence of two weak intramolecular hydrogen bonds:
the C2-H2…N2 (H…N 2.21 Å, C-H…N 114°) and the N2-
H2N…π (H...X 2.64 Å, N-H…X 122o where X is a center of the
C15-N4 triple bond). The deviation of the C14 atom from mean
plane of remaining ring atoms is 0.314(7) Å.
butyl cyanoacetate 5b gave a mixture of products 11a and 12a
that were separated with column chromatography (Scheme 3).
The greatest amount of product 12a was isolated by performing
the reaction at low temperature. It should be noted that 1-
iminocyanopyridine 12a can be thermally rearranged into 1-
oxocyanopyridines 11 upon reflux in DMF (Scheme 3). The
reaction of furanylidens 3 with cyanoacetates 5 proceeds most
likely via the formation of Michael’s adduct B. The further
transformation of intermediate B could give 1-oxo- 11 and/or 1-
iminocyanopyridines 12 due to the presence of two non-
equivalent electrophilic centers in the final cyclization step.
The treatment of furanylidens 3 with ethyl cyanoacetate 5a
afforded 1-oxocyanopyridines 11. At the same time using tert-

4
Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 4. Reaction of 2-(benzothiazol-2-yl)-2-(tetrahydro-2-furanyliden)acetonitrile 3b with hetarylacetonitriles 6.
Table 1 Cyanopyridine derivatives 14 produced via Scheme 4
1H NMR (δ)
Entry
Compd
Yield (%)
Mp (°C)
225-226
197-198
9-H
NH
1
2
13a
9.54
9.67
8.03
89
90
13b
7.50
7.31
3
13c
9.57
83
199-200
4
5
6
13d
13e
13f
9.51
9.55
9.52
7.17
7.05
7.11
85
93
93
159-160
176-177
171-172
7
13g
9.56
7.45
86
197-198
The formation of 1-oxocyanopyridines 11 have been assumed
to be a thermodynamically controlled process on account of the
higher stability of 11 over that of 1-iminocyanopyridine 12 due to
the stronger conjugation between ring nitrogen and carbonyl
group.20 Nevertheless, the kinetically controlled product 1-
iminocyanopyridine 12a was obtained at low temperature when
cyanoacetate 5b containing a sterically hindered electrophilic
center of tert-butyloxycarbonyl group was employed.

5
NMR spectroscopy data of 12a revealed proton signal of tert-
butyl group at 1.6 ppm in H NMR as well as carbon signals at
slightly rotated with respect to the triazolopyridine bicycle: the
ACCEPTED MANUSCRIPT
1
C12-C8-C7-S1 and N5-C13-C14-C19 torsion angles are -
31.69(14)° and -11.28(16)°, respectively. The flattened
orientations of planar fragments are stabilized by the C-H…N
and C-H…S attractive interactions (H15…N4 2.64 Å, H19…N5
2.54 Å, H21A…S1 H…S 2.59 Å, van der Waals radii sums 21 are
2.66 Å and 3.01 Å, respectively) and by the N2-H2B...N1
intramolecular hydrogen bond (H…N 2.11 Å, N-H…N 128°).
The hydroxypropyl substituent at the C12 atom adopts trans
conformation and has approximately orthogonal orientation with
respect to the triazolopyridine fragment (the C12-C21-C22-C23,
C21-C22-C23-O1 and C8-C12-C21-C22 torsion angles are
155.10(10)°, 161.09(9)° and 110.02(12)°, respectively).
28.0 ppm and 81.5 ppm in 13C NMR. The characteristic signal of
9-H proton of 12a showed down field shift by 0.5 ppm compared
with that of 11a due to the increase of an anisotropic effect of the
imino group (Table 1). Moreover, the structure of 1-
oxocyanopyridine 11c was unambiguously confirmed by XRD-
study (Figure 3). According to XRD data the tricyclic fragment
of molecule 11c is planar. The hydroxypropyl substituent at the
C11 atom adopts all-trans conformation and has almost
orthogonal orientation with respect to the pyridinone ring (the
C11-C15-C16-C17, C15-C16-C17-O2 and C12-C11-C15-C16
torsion angles are 164.5(2)o, 169.3(2)o and 95.5(2)o,
respectively).
Hetaryl substituted 1-iminocyanopyridines 13a–g were
obtained according to the mechanism proposed above upon
treatment of 2-(benzothiazol-2-yl)-2-(tetrahydro-2-furanyliden)-
acetonitrile 3a with hetarylacetonitriles 6a–g. The structure
elucidation of derivatives 13a–g with 1H NMR data clearly
indicates the presence of AMRX spin system of
pyridobenzothiazole framework including characteristic signal of
9-H proton at 9.5–9.6 ppm and NH proton in the range of 7.0–8.0
ppm (Scheme 4, Table 2). The location of NH proton signal was
confirmed by exchange with D2O. Moreover, the structural
features of the compound 13b were clarified by COSY-90 and
one-dimensional NOE difference experiments. The NOE data
have indicated E-configuration of the imino group and non-
coplanar conformation of the two heterocyclic systems in
compound 13b (Figure 4).
Figure 5. Molecular structure of compound 14c according to X-ray
diffraction data with the atom numbering used in the crystallographic
analysis. Thermal ellipsoids are drawn at 50% probability level.
Thus, the study of the reaction of furanyliden 3a with
hetarylacetonitriles 6 revealed two reaction courses depending on
the nature of the heterocycle of the latter. Presented reactions
allow covalent combining of several pharmacophores which
include fused pyridine core, heterocyclic moiety and substituted
propyl side chain. It is noteworthy that all compounds obtained
7–14 exhibit fluorescence properties in organic solvents and in
the solid state, as well.
3. Conclusion
To conclude, the present investigation has resulted in the
single-step synthesis of the nitrogen bridgehead fused
cyanopyridines bearing hydroxypropyl side chain. The 2-hetaryl-
2-(tetrahydro-2-furanyliden)acetonitriles have been proved to be
a versatile building blocks in the heterocyclic synthesis.
4. Experimental
Figure 4. Molecular structure of compound 13b according to NMR
spectroscopy data. The NOE data are given as a percentage increase in
integrated intensity on the irradiation of the corresponding proton signal.
4.1. X-Ray diffraction study of compounds 11c and 14c
Intensities of reflections were measured on an automatic
«Xcalibur 3» diffractometer (graphite monochromated MoKα
radiation, CCD-detector ω scaning). All structures were solved
by direct method using SHELX97 package.22 Positions of the
hydrogen atoms were located from electron density difference
maps and refined by “riding” model with Uiso = nUeq of carrier
non-hydrogen atom (n = 1.5 for methyl group and n = 1.2 for
other hydrogen atoms). Structures were refined by full-matrix
least-squares method against F2 in anisotropic approximation for
non-hydrogen atoms. Final atomic coordinates, geometrical
parameters and crystallographic data have been deposited with
the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ, UK (fax: +44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk). CCDC deposition numbers for
structures 10a, 11c and 14c are 975165, 919951 and 954181,
respectively. These data can be obtained free of charge from the
At the same time, the interaction of furanyliden 3a with 1H-
azahetarylacetonitriles 6h–j in the presence of two equivalents of
sodium hydride afforded the benzothiazolyl substituted
aminocyanopyridines 14a–c in good yields. It should be outlined
that a different (1- or 2-fold) excess of sodium hydride has an
effect only on the reaction rate, but not on the reaction course. In
this case, 1H-azahetarylacetonitriles 6h–j represent C,N-
binucleophiles which react with 1,3-bielectrophilic acrylonitrile
fragment of furanyliden 3a giving rise to amino products 14a–c
(Scheme 4). 1H NMR data of compounds 14a–c showed the
presence of NH2 group signal at 7.8–8.2 ppm.
The structure of aminotriazolo[1,5-a]pyridine 14c was
unequivocally confirmed by XRD-study (Figure 5). According to
XRD data the benzothiazole fragment and the benzene ring are

6
Tetrahedron
ACCEPTED MANUSCRIPT
Cambridge
Crystallographic
Data
Centre
via
4.3.2.
1-Amino-3-(3-hydroxypropyl)-2-
www.ccdc.cam.ac.uk/products/csd/request/.
(methylsulfonyl)pyrido[1,2-a]benzimidazole-4-carbonitrile (7b).
White solid (from DMF); mp 286-287 °C; yield: 0.55 g (80%).
IR (KBr): 3389, 3289, 3204, 2225, 1631, 1610, 1578, 1529,
Crystal data for 10a at 296K: (C18H14N4O, Mr = 302.33), a =
7.299(7) Å, b = 7.907(8) Å, c = 12.384(12) Å, α = 91.08(2)°, β =
96.004(19)°, γ = 95.10(2)°,V = 707.6(12) Å3, space group P-1, Z
= 2, Dc = 1.419 g/sm-3, ꢀ(MoKα) = 0.092 mm-1, F(000) = 316.
1305, 1138 cm-1. H NMR (400 MHz, DMSO-d6): δ = 1.83 (m,
1
2H, 2-CH2), 3.13 (t, J = 7.8 Hz, 2H, 1-CH2), 3.40 (s, 3H, Me),
3.52 (t, J = 6.6 Hz, 2H, 3-CH2), 4.66 (s, 1H, OH), 7.37 (t, J = 7.8
Hz, 1Н, 8-Н), 7.54 (t, J = 7.8 Hz, 1Н, 7-Н), 7.82 (d, J = 7.8 Hz,
1Н, 6-Н), 8.35 (d, J = 7.8 Hz, 1Н, 9-Н), 8.48 (s, 2H, NH2). 13C
NMR (100 MHz, DMSO-d6): δ = 31.2, 35.0, 46.1, 61.4, 88.3,
101.7, 115.5, 116.2, 119.7, 122.2, 127.2, 129.6, 145.5, 147.5,
150.9, 155.0. Anal. Calcd for C16H16N4O3S: C, 55.80; H, 4.68; N,
16.27; S, 9.31. Found: C, 55.93; H, 4.75; N, 16.16; S, 9.36.
5267 reflections measured up to 2θmax= 50.0°, 2482 unique (Rint
=
0.1451) which were used in all calculations. Refinement was
converged at wR2=0.2203 (all data), R1=0.0961 (1122 reflections
with I>2σ(I)), GoF=1.03.
Crystal data for 11c at 293K: (C17H14N4O2, Mr = 306.32), a =
11.1646(10) Å, b = 7.6032(7) Å, c = 17.5915(11) Å, β =
103.652(7)°, V = 1451.1(2) Å3, space group P21/n, Z = 4, Dc =
1.402 g/sm-3, ꢀ(MoKα) = 0.096 mm-1, F(000) = 640. 11123
4.3.3.
1-Amino-3-(3-hydroxypropyl)-2-phenylpyrido[1,2-
reflections measured up to 2θmax= 52.0°, 2835 unique (Rint
=
a]benzimidazole-4-carbonitrile (7c). White solid (from DMF);
0.0435) which were used in all calculations. Refinement was
converged at wR2=0.1394 (all data), R1=0.0498 (2039 reflections
with I>2σ(I)), GoF=1.03.
mp 307-308 °C; yield: 0.60 g (88%). IR (KBr): 3448, 3304,
3214, 2219, 1637, 1614, 1031, 738 cm-1. H NMR (400 MHz,
1
DMSO-d6): δ = 1.55 (m, 2H, 2-CH2), 2.54 (t, J = 7.8 Hz, 2H, 1-
CH2), 3.21 (m, 2H, 3-CH2), 4.46 (t, J = 5.1 Hz, 1H, OH), 6.76 (s,
2H, NH2), 7.29 (t, J = 8.1 Hz, 1Н, 8-Н), 7.39 (d, J = 7.1 Hz, 2Н,
2,6-НPh), 7.52-7.57 (m, 4Н, 7-Н and 3,4,5-НPh), 7.81 (d, J = 8.1
Hz, 1Н, 6-Н), 8.41 (d, J = 8.1 Hz, 1Н, 9-Н). 13C NMR (100
MHz, DMSO-d6): δ = 30.1, 33.2, 60.9, 84.2, 106.6, 115.4, 117.3,
118.4, 120.1, 126.1, 128.6, 128.9, 129.7, 131.9, 133.8, 145.3,
147.7, 148.5, 153.7. Anal. Calcd for C21H18N4O: C, 73.67; H,
5.30; N, 16.36. Found: C, 73.62; H, 5.34; N, 16.42.
Crystal data for 14c at 100K: (C23H18N6OS, Mr = 426.49), a =
9.9292(14) Å, b = 10.6658(14) Å, c = 11.1010(14) Å, α =
113.885(4)°, β = 110.271(4)°, γ = 98.065(4)°, V = 952.9(2) Å3,
space group P-1, Z = 2, Dc = 1.486 g/sm-3, ꢀ(MoKα) = 0.201 mm-
1, F(000) = 444. 49039 reflections measured up to 2θmax= 30.0°,
5549 unique (Rint = 0.0326) which were used in all calculations.
Refinement was converged at wR2=0.1008 (all data), R1=0.0376
(4837 reflections with I>2σ(I)), GoF=1.05.
4.2. General
4.4. General procedure for the preparation of compounds 8–
10
Melting points were determined by using a Kofler-type hot
stage microscope (Boetius VEB Analytik) and are corrected. H
1
To a stirred solution of the corresponding acetonitrile 4a–e
(3.0 mmol) in anhydrous dioxane (15 mL), NaH (0.07 g, 3.0
mmol) was added and left at rt for 30 min. Then the
corresponding furanilidene 3b–d (2.0 mmol) was added and the
reaction mixture was stirred at rt for 2–3 h (at reflux for 1 h in the
case of (methylsulfonyl)acetonitrile 4b). After the reaction was
complete (TLC monitoring), the reaction mixture was diluted
with H2O (100 mL) and acidified with HCl to pH = 7.0–7.5. The
precipitated crude product was filtered off, washed with water,
dried and recrystallized from appropriate solvent.
NMR spectra were recorded at 400 MHz on a Varian Mercury-
400 spectrometer. Chemical shifts (δ) were given in ppm
downfield from the internal standard TMS. The J values were
given in Hz. 13C NMR spectra were recorded at 100 MHz on the
same instruments. The IR spectra were obtained with a FTIR
Spectrometer Perkin Elmer BX II with KBr pellets. Elemental
analyses were performed on a CHNOS elementar vario MICRO
Cube analyzer. The reaction progress was monitored by TLC on
Merck 60 F254 silica gel plates using CHCl3-MeOH (9:1) system
as the eluent.
4.4.1.
3-(3-Hydroxypropyl)-1-imino-1H-pyrido[2,1-
4.3. General procedure for the preparation of compounds 7
b][1,3]benzothiazole-2,4-dicarbonitrile (8a). Yellow solid (from
dioxane); mp 233-234 °C; yield: 0.53 g (86%). IR (KBr): 3422,
To a stirred solution of the corresponding acetonitrile 4a–c
(3.0 mmol) in anhydrous DMF (10 mL), NaH (0.07 g, 3.0 mmol)
was added and left at rt for 20 min. Then furanilidene 3b (0.45 g,
2.0 mmol) was added and the reaction mixture was stirred at rt
1
3301, 2208, 1610, 1501, 1020, 762 cm-1. H NMR (400 MHz,
DMSO-d6): δ = 1.83 (m, 2H, 2-CH2), 2.78 (t, J = 7.6 Hz, 2H, 1-
CH2), 3.55 (m, 2H, 3-CH2), 4.54 (t, J = 4.6 Hz, 1H, OH), 7.54
(m, 2Н, 7,8-H), 8.10 (d, J = 7.3 Hz, 1Н, 6-Н), 8.14 (s, 1H, NH),
9.54 (d, J = 8.1 Hz, 1Н, 9-Н). 13C NMR (100 MHz, DMSO-d6): δ
= 31.2, 32.3, 60.6, 82.6, 96.1, 114.7, 114.8, 121.6, 122.9, 125.3,
127.2, 127.4, 139.1, 154.6, 155.2, 160.5. Anal. Calcd for
C16H12N4OS: C, 62.32; H, 3.92; N, 18.17; S, 10.40. Found: C,
62.12; H, 4.03; N, 18.19; S, 10.52.
for 6–8
h
(at 100 °C for
1
h
in the case of
(methylsulfonyl)acetonitrile 4b). After the reaction was complete
(TLC monitoring), the reaction mixture was diluted with H2O
(100 mL) and acidified with HCl to pH = 7.0–7.5. The
precipitated crude product was filtered off, washed with water,
dried and recrystallized from appropriate solvent.
4.4.2.
3-(3-Hydroxypropyl)-1-imino-2-(methylsulfonyl)-1H-
4.3.1.
1-Amino-3-(3-hydroxypropyl)pyrido[1,2-
pyrido[2,1-b][1,3]benzothiazole-4-carbonitrile (8b). Yellow
solid (from dioxane); mp 200-201 °C; yield: 0.55 g (76%). IR
(KBr): 3548, 3355, 2207, 1601, 1481, 1121, 1056 cm-1. 1H NMR
(400 MHz, DMSO-d6): δ = 1.78 (m, 2H, 2-CH2), 2.98 (t, J = 7.8
Hz, 2H, 1-CH2), 3.30 (s, 3H, Me), 3.50 (t, J = 6.6 Hz, 2H, 3-
CH2), 4.65 (br s, 1H, OH), 7.59 (m, 2Н, 7,8-H), 8.14 (d, J = 7.3
Hz, 1Н, 6-Н), 9.43 (d, J = 7.6 Hz, 1Н, 9-Н), 9.56 (s, 1H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 29.9, 33.8, 44.0, 61.0, 82.5,
116.4, 116.5, 121.4, 123.3, 125.4, 127.2, 127.4, 139.6, 153.1,
153.2, 161.3. Anal. Calcd for C16H15N3O3S2: C, 53.17; H, 4.18;
N, 11.63; S, 17.74. Found: C, 53.05; H, 4.19; N, 11.57; S, 17.65.
a]benzimidazole-2,4-dicarbonitrile (7a). White solid (from
DMF); mp 293-294 °C; yield: 0.53 g (91%). IR (KBr): 3394,
1
3329, 3213, 2211, 1644, 1618, 1585, 1561, 1055, 761 cm-1. H
NMR (400 MHz, DMSO-d6): δ = 1.86 (m, 2H, 2-CH2), 2.94 (t, J
= 7.9 Hz, 2H, 1-CH2), 3.56 (m, 2H, 3-CH2), 4.50 (t, J = 4.6 Hz,
1H, OH), 7.33 (t, J = 7.9 Hz, 1Н, 8-Н), 7.51 (t, J = 7.9 Hz, 1Н, 7-
Н), 7.75 (d, J = 7.9 Hz, 1Н, 6-Н), 8.48 (br s, 2H, NH2), 8.53 (d, J
= 7.9 Hz, 1Н, 9-Н). 13C NMR (100 MHz, DMSO-d6): δ = 31.5,
33.3, 61.1, 77.2, 86.7, 115.2, 115.3, 115.8, 119.3, 122.1, 126.7,
128.8, 145.2, 147.7, 152.5, 155.7. Anal. Calcd for C16H13N5O: C,
65.97; H, 4.50; N, 24.04. Found: C, 65.68; H, 4.38; N, 24.27.

7
4.4.3. 3-(3-Hydroxypropyl)-1-imino-2-phenyl-1H-pyrido[2,1-
b][1,3]benzothiazole-4-carbonitrile (8c). Yellow solid (from
isopropanol); mp 162-163 °C; yield: 0.61 g (85%). IR (KBr):
Hz, 1Н, 6-Н), 8.73 (s, 1H, NH), 9.48 (d, J = 8.5 Hz, 1H, 10-H).
ACCEPTED MANUSCRIPT
13C NMR (100 MHz, DMSO-d6): δ = 31.4, 32.3, 60.5, 90.6, 95.8,
114.2, 114.8, 119.6, 120.6, 126.4, 128.4, 129.6, 130.7, 134.4,
139.8, 148.4, 155.9, 158.6. Anal. Calcd for C18H14N4O: C, 71.51;
H, 4.67; N, 18.53. Found: C, 71.37; H, 4.75; N, 18.41.
1
3401, 3308, 2200, 1611, 1594, 1525, 1054, 756 cm-1. H NMR
(400 MHz, DMSO-d6): δ = 1.60 (m, 2H, 2-CH2), 2.24 (t, J = 7.8
Hz, 2H, 1-CH2), 3.25 (m, 2H, 3-CH2), 4.20 (t, J = 5.0 Hz, 1H,
OH), 7.01 (s, 1H, NH), 7.21 (d, J = 7.3 Hz, 2H, 2,6-HAr), 7.44
(m, 2Н, 7,8-H), 7.48 (t, J = 7.3 Hz, 1H, 4-HAr), 7.54 (t, J = 7.3
Hz, 2H, 3,5-HAr), 7.92 (dd, J = 5.6, 3.2 Hz, 1Н, 6-Н), 9.48 (dd, J
= 5.6, 3.7 Hz, 1Н, 9-Н). 13C NMR (100 MHz, DMSO-d6): δ =
29.4, 32.7, 60.9, 82.1, 116.7, 121.5, 122.3, 124.5, 125.0, 126.3,
126.6, 128.7, 129.7 (2C), 130.4 (2C), 134.6, 139.8, 140.6, 155.3,
159.6. Anal. Calcd for C21H17N3OS: C, 70.17; H, 4.77; N, 11.69;
S, 8.92. Found: C, 70.08; H, 4.73; N, 11.61; S, 8.80.
4.5. General procedure for the preparation of compounds 11
To a stirred solution of ethyl cyanoacetate 5a (0.32 mL, 3.0
mmol) in anhydrous DMF (10 mL), NaH (0.07 g, 3.0 mmol) was
added and left at rt for 20 min. Then the corresponding
furanilidene 3a–c (2.0 mmol) was added and the reaction mixture
was stirred at 25 ºC for 1–2 h. After the reaction was complete
(TLC monitoring), the reaction mixture was diluted with H2O
(100 mL) and acidified with HCl to pH = 7.0–7.5. The
precipitated crude product was filtered off, washed with water,
dried and recrystallized from appropriate solvent.
4.4.4. 2-(3-Chlorophenyl)-3-(3-hydroxypropyl)-1-imino-1H-
pyrido[2,1-b][1,3]benzothiazole-4-carbonitrile (8d). Yellow
solid (from isopropanol); mp 201-202 °C; yield: 0.74 g (94%). IR
4.5.1.
3-(3-Hydroxypropyl)-1-oxo-1H-pyrido[2,1-
b][1,3]benzothiazole-2,4-dicarbonitrile (11a). Pale yellow solid
1
(KBr): 3529, 3305, 2199, 1609, 1587, 1523, 1062, 758 cm-1. H
NMR (400 MHz, DMSO-d6): δ = 1.59 (m, 2H, 2-CH2), 2.25 (t, J
= 7.6 Hz, 2H, 1-CH2), 3.29 (m, 2H, 3-CH2), 4.21 (t, J = 5.2 Hz,
1H, OH), 7.01 (s, 1H, NH), 7.17 (d, J = 7.8 Hz, 1H, 6-HAr), 7.23
(s, 1H, 2-HAr), 7.44 (m, 2Н, 7,8-H), 7.49 (d, J = 7.8 Hz, 1H, 4-
HAr), 7.55 (t, J = 7.8 Hz, 1H, 5-HAr), 7.92 (J = 5.6, 3.2 Hz, 1Н, 6-
Н), 9.48 (dd, J = 5.6, 3.4 Hz, 1Н, 9-Н). 13C NMR (100 MHz,
DMSO-d6): δ = 29.4, 32.6, 60.8, 82.0, 116.5, 121.5, 122.4, 122.9,
125.0, 126.4, 126.6, 128.9, 129.1, 130.3, 131.4, 134.8, 136.6,
139.8, 141.2, 155.8, 159.1. Anal. Calcd for C21H16ClN3OS: C,
64.03; H, 4.09; N, 10.67; S, 8.14. Found: C, 64.10; H, 4.14; N,
10.63; S, 8.08.
(from DMF); mp 289-290 °C; yield: 0.57 g (92%). IR (KBr):
1
3438, 2219, 1671, 1495, 1060, 770 cm-1. H NMR (400 MHz,
DMSO-d6): δ = 1.87 (m, 2H, 2-CH2), 2.94 (t, J = 7.9 Hz, 2H, 1-
CH2), 3.57 (t, J = 6.1 Hz, 2H, 3-CH2), 4.54 (br s, 1H, OH), 7.67
(m, 2Н, 7,8-Н), 8.20 (d, J = 7.9 Hz, 1Н, 6-Н), 9.05 (d, J = 7.9 Hz,
1Н, 9-Н). 13C NMR (100 MHz, DMSO-d6): δ = 31.6, 32.8, 60.7,
86.8, 96.9, 115.1, 115.4, 120.1, 124.3, 126.1, 128.7 (2C), 138.6,
158.9, 161.1, 164.9. Anal. Calcd for C16H11N3O2S: C, 62.12; H,
3.58; N, 13.58; S, 10.37. Found: C, 62.20; H, 3.62; N, 13.57; S,
10.31.
4.5.2.
3-(3-Hydroxypropyl)-1-oxo-1,5-dihydropyrido[1,2-
4.4.5. 3-(3-Hydroxypropyl)-1-imino-2-(4-(methyloxy)phenyl)-
1H-pyrido[2,1-b][1,3]benzothiazole-4-carbonitrile (8e). Yellow
solid (from ethanol); mp 187-188 °C; yield: 0.63 g (81%). IR
a]benzimidazole-2,4-dicarbonitrile (11b). White solid (from
DMF); mp 295-296 °C; yield: 0.53 g (91%). IR (KBr): 3425,
1
2216, 1665, 1609, 1535, 1029, 757 cm-1. H NMR (400 MHz,
1
(KBr): 3483, 3300, 2207, 1596, 1525, 1249, 1027, 756 cm-1. H
DMSO-d6): δ = 1.86 (m, 2H, 2-CH2), 2.89 (t, J = 7.6 Hz, 2H, 1-
CH2), 3.57 (t, J = 6.1 Hz, 2H, 3-CH2), 4.55 (br s, 1H, OH), 7.41
(t, J = 7.8 Hz, 1Н, 8-Н), 7.53 (t, J = 7.8 Hz, 1Н, 7-Н), 7.59 (d, J
= 7.8 Hz, 1Н, 6-Н), 8.53 (d, J = 7.8 Hz, 1Н, 9-Н), 14.45 (br s,
1H, 5-NH). 13C NMR (100 MHz, DMSO-d6): δ = 31.8, 33.2,
61.0, 73.6, 89.1, 112.7, 114.8, 115.9, 116.8, 124.2, 127.6, 128.0,
131.9, 146.7, 157.4, 162.4. Anal. Calcd for C16H12N4O2: C,
65.75; H, 4.14; N, 19.17. Found: C, 65.68; H, 4.21; N, 19.25.
NMR (400 MHz, DMSO-d6): δ = 1.60 (m, 2H, 2-CH2), 2.26 (t, J
= 7.8 Hz, 2H, 1-CH2), 3.29 (m, 2H, 3-CH2), 3.85 (s, 3H, OMe),
4.21 (t, J = 4.8 Hz, 1H, OH), 7.05 (d, J = 8.4 Hz, 2H, 3,5-HAr),
7.09 (s, 1H, NH), 7.13 (d, J = 8.4 Hz, 2H, 2,6-HAr), 7.44 (m, 2Н,
7,8-H), 7.92 (m, 1Н, 6-Н), 9.50 (m, 1Н, 9-Н). 13C NMR (100
MHz, DMSO-d6): δ = 29.7, 33.1, 55.5, 61.2, 82.4, 115.5 (2C),
117.0, 121.8, 122.6, 124.6, 125.3, 126.5, 126.6, 126.8, 131.8
(2C), 140.1, 141.1, 155.4, 159.8, 160.2. Anal. Calcd for
C22H19N3O2S: C, 67.84; H, 4.92; N, 10.79; S, 8.23. Found: C,
67.70; H, 4.76; N, 10.65; S, 8.28.
4.5.3.
3-(3-Hydroxypropyl)-5-methyl-1-oxo-1,5-
(11c).
dihydropyrido[1,2-a]benzimidazole-2,4-dicarbonitrile
White solid (from buthanol); mp 252-253 °C; yield: 0.54 g
(88%). IR (KBr): 3492, 2217, 1655, 1587, 1532, 1049, 768 cm-1.
1H NMR (400 MHz, DMSO-d6): δ = 1.85 (m, 2H, 2-CH2), 2.92
(t, J = 7.6 Hz, 2H, 1-CH2), 3.57 (t, J = 6.1 Hz, 2H, 3-CH2), 4.20
(s, 3Н, NMe), 4.50 (s, 1H, OH), 7.49 (t, J = 7.6 Hz, 1Н, 8-Н),
7.63 (t, J = 7.6 Hz, 1Н, 7-Н), 7.83 (d, J = 7.6 Hz, 1Н, 6-Н), 8.62
(d, J = 7.6 Hz, 1Н, 9-Н). 13C NMR (100 MHz, DMSO-d6): δ =
31.6, 31.8, 32.8, 60.7, 73.4, 89.0, 111.2, 115.5, 115.8, 116.3,
124.8, 126.4, 127.6, 133.0, 145.1, 157.2, 162.9. Anal. Calcd for
C17H14N4O2: C, 66.66; H, 4.61; N, 18.29. Found: C, 66.79; H,
4.62; N, 18.11.
4.4.6.
3-(3-Hydroxypropyl)-1-imino-5-methyl-1,5-
(9a).
dihydropyrido[1,2-a]benzimidazole-2,4-dicarbonitrile
White solid (from buthanol); mp 258-259 °C; yield: 0.56 g
(92%). IR (KBr): 3506, 3313, 2207, 1618, 1598, 1576, 1532,
1071, 786 cm-1. H NMR (400 MHz, DMSO-d6): δ = 1.85 (m,
1
2H, 2-CH2), 2.78 (t, J = 7.9 Hz, 2H, 1-CH2), 3.54 (m, 2H, 3-
CH2), 4.12 (s, 3Н, NMe), 4.49 (t, J = 5.2 Hz, 1H, OH), 7.40 (t, J
= 7.9 Hz, 1Н, 8-Н), 7.53 (t, J = 7.9 Hz, 1Н, 7-Н), 7.58 (s, 1H,
NH), 7.70 (d, J = 7.9 Hz, 1Н, 6-Н), 8.94 (d, J = 7.9 Hz, 1Н, 9-Н).
13C NMR (100 MHz, DMSO-d6): δ = 31.8, 32.0, 33.0, 61.1, 69.1,
88.2, 110.7, 116.7, 116.8, 118.2, 124.5, 126.9, 127.7, 133.5,
145.7, 153.5, 158.6. Anal. Calcd for C17H15N5O: C, 66.87; H,
4.95; N, 22.94. Found: C, 66.60; H, 5.06; N, 22.81.
4.6. General procedure for the preparation of tert-butyl 4-
cyano-3-(3-hydroxypropyl)-1-imino-1H-pyrido[2,1-
b][1,3]benzothiazole-2-carboxylate 12a
4.4.7.
3-(3-Hydroxypropyl)-1-imino-1H-pyrido[1,2-
To a stirred solution of tert-butyl cyanoacetate 5b (0.43 mL,
3.0 mmol) in anhydrous DMF (15 mL), NaH (0.07 g, 3.0 mmol)
was added and left at rt for 20 min. A mixture was cooled to -10
ºC and furanilidene 3a (0.48 g, 2.0 mmol) was added upon
stirring. Then the reaction mixture was stirred for 4 h while
maintaining internal temperature in the range of -10 – -5 ºC. The
reaction mixture was diluted with H2O (100 mL) and acidified
a]quinoline-2,4-dicarbonitrile (10a). Red solid (from DMF); mp
176-177 °C; yield: 0.55 g (91%). IR (KBr): 3488, 3260, 2206,
1
1634, 1614, 1519, 1469, 1054, 764 cm-1. H NMR (400 MHz,
DMSO-d6): δ = 1.81 (m, 2H, 2-CH2), 2.76 (t, J = 7.8 Hz, 2H, 1-
CH2), 3.56 (m, 2H, 3-CH2), 4.50 (t, J = 5.1 Hz, 1H, OH), 7.50 (d,
J = 8.5 Hz, 1H, 5-Н), 7.55 (t, J = 7.6 Hz, 1H, 8-Н), 7.61 (t, J =
8.5 Hz, 1H, 9-Н), 7.85 (d, J = 7.6 Hz, 1H, 7-Н), 8.11 (d, J = 8.5

8
Tetrahedron
with HCl to pH = 7.0–7.5. The precipitated crude product was
C, 70.22; H, 4.42; N, 13.65; S, 7.81. Found: C, 70.30; H, 4.35; N,
ACCEPTED MANUSCRIPT
filtered off and dried giving a mixture of compounds 12a and 11a
in a molar ratio 2:1 (0.59 g). The crude product was washed with
benzene (2 × 25 mL). The combined organic washings were
concentrated under vacuum and subjected to column
chromatography on silica gel using benzene:ethyl acetate (5:1) as
eluent to provide pure compound 12a. Yellow solid; mp 154-155
°C; yield: 0.21 g (27%). IR (KBr): 3448, 3333, 2935, 2205, 1701,
1606, 1521, 1147, 758. 1H NMR (400 MHz, DMSO-d6): δ = 1.58
(s, 9H, t-Bu), 1.75 (m, 2H, 2-CH2), 2.63 (t, J = 7.8 Hz, 2H, 1-
CH2), 3.51 (m, 2H, 3-CH2), 4.71 (t, J = 4.9 Hz, 1H, OH), 7.55
(m, 2Н, 7,8-H), 8.09 (m, 1Н, 6-Н), 8.38 (s, 1H, NH), 9.50 (m,
1Н, 9-Н). 13C NMR (100 MHz, DMSO-d6): δ = 28.0, 29.9, 32.8,
60.9, 81.5, 83.5, 115.3, 116.6, 121.3, 123.0, 125.2, 126.8, 127.1,
139.6, 145.8, 155.5, 158.5, 165.1. Anal. Calcd for C20H21N3O3S:
C, 62.64; H, 5.52; N, 10.96; S, 8.36. Found: C, 62.73; H, 5.46; N,
10.88; S, 8.20.
13.56; S, 7.73.
4.8.3.
2-(1-(Difluoromethyl)-1H-benzimidazol-2-yl)-3-(3-
hydroxypropyl)-1-imino-1H-pyrido[2,1-b][1,3]benzothiazole-4-
carbonitrile (13c). Yellow solid (from isopropanol); mp 199-200
°C; yield: 0.74 g (83%). IR (KBr): 3388, 3333, 2202, 1610, 1530,
1354, 1047, 757 cm-1. H NMR (400 MHz, DMSO-d6): δ = 1.65
1
(m, 1H, 2a-CH2), 1.75 (m, 1H, 2b-CH2), 2.15 (m, 1H, 3a-CH2),
2.53 (m, 1H, 3b-CH2), 3.32 (m, 2H, 1-CH2), 4.31 (t, J = 4.9 Hz,
1H, OH), 7.31 (s, 1H, NH), 7.43 (m, 2H, 5,6-HHet), 7.53 (m, 2Н,
7,8-H), 7.74 (t, J = 56.9 Hz, 1H, CHF2), 7.78 (d, J = 7.6 Hz, 1H,
7-HHet), 7.84 (d, J = 7.6 Hz, 1H, 4-HHet), 8.03 (m, 1Н, 6-Н), 9.57
(m, 1Н, 9-Н). 13C NMR (100 MHz, DMSO-d6): δ = 29.9, 32.5,
60.9, 82.5, 110.3 (1JCF = 246 Hz), 111.6, 112.9, 116.6, 120.9,
122.0, 122.8, 124.4, 125.3, 125.4, 126.9, 127.2, 131.6, 140.1,
143.8, 145.5, 148.3, 157.7, 159.1. Anal. Calcd for C23H17F2N5OS:
C, 61.46; H, 3.81; N, 15.58; S, 7.13. Found: C, 61.22; H, 3.72; N,
15.50; S, 7.08.
4.7. Transformation of compound 12a to 11a
4.8.4. 3-(3-Hydroxypropyl)-1-imino-2-(1-methyl-1H-imidazol-
2-yl)-1H-pyrido[2,1-b][1,3]benzothiazole-4-carbonitrile (13d).
Yellow solid (from propanol); mp 235 °C; yield: 0.62 g (85%).
A solution of compound 12a (0.08 g, 0.2 mmol) in DMF (5
mL) was refluxed for 20 min. Solvent was removed by
evaporation in vacuo giving compound 11a in near quantitative
yield (0.06 g). Compound characterizations are given above.
1
IR (KBr): 3393, 3324, 2201, 1609, 1530, 1051, 764 cm-1. H
NMR (400 MHz, DMSO-d6): δ = 1.55 (m, 1H, 2a-CH2), 1.65 (m,
1H, 2b-CH2), 2.06 (m, 1H, 3a-CH2), 2.44 (m, 1H, 3b-CH2), 3.35
(m, 2H, 1-CH2), 3.48 (s, 3H, NMe), 4.70 (t, J = 5.1 Hz, 1H, OH),
7.13 (m, 1H, 5-HHet), 7.17 (s, 1H, NH), 7.39 (m, 1H, 4-HHet), 7.53
(m, 2Н, 7,8-H), 8.09 (m, 1Н, 6-Н), 9.51 (m, 1Н, 9-Н). 13C NMR
(100 MHz, DMSO-d6): δ = 29.6, 32.4, 33.2, 60.8, 81.8, 114.1,
117.4, 121.5, 123.3, 123.3, 125.6, 127.1, 127.4, 129.3, 140.0,
140.8, 146.3, 158.3, 158.5. Anal. Calcd for C19H17N5OS: C,
62.79; H, 4.71; N, 19.27; S, 8.82. Found: C, 62.68; H, 4.77; N,
19.11; S, 8.89.
4.8. General procedure for the preparation of compounds 13
To a stirred solution of corresponding hetarylacetonitrile 6a–g
(2.3 mmol) in anhydrous dioxane (20 mL), NaH (0.05 g, 3.0
mmol) was added and left at rt for 10 min. Then furanilidene 3a
(0.48 g, 2.0 mmol) was added and the reaction mixture was
stirred at rt for 1–2 h. After the reaction was complete (TLC
monitoring), the reaction mixture was diluted with H2O (100 mL)
and acidified with HCl to pH = 7.0–7.5. The precipitated crude
product was filtered off, washed with water, dried and
recrystallized from appropriate solvent.
4.8.5.
3-(3-Hydroxypropyl)-1-imino-2-(1-(2,2,2-
trifluoroethyl)-1H-imidazol-2-yl)-1H-pyrido[2,1-
4.8.1. 2-(1,3-Benzothiazol-2-yl)-3-(3-hydroxypropyl)-1-imino-
b][1,3]benzothiazole-4-carbonitrile (13e). Yellow solid (from
dioxane); mp 176-177 °C; yield: 0.80 g (93%). IR (KBr): 3330,
1H-pyrido[2,1-b][1,3]benzothiazole-4-carbonitrile
(13a).
Yellow solid (from buthanol); mp 225-226 °C; yield: 0.74 g
(89%). IR (KBr): 3384, 3321, 2204, 1604, 1523, 1055, 761 cm-1.
1H NMR (400 MHz, DMSO-d6): δ = 1.81 (m, 2H, 2-CH2), 2.56
(t, J = 7.6 Hz, 2H, 1-CH2), 3.40 (m, 2H, 3-CH2), 4.28 (t, J = 4.6
Hz, 1H, OH), 7.50 (m, 2Н, 7,8-H), 7.53 (t, J = 7.8 Hz, 1Н, 5-
HHet), 7.58 (t, J = 7.8 Hz, 1H, 6-HHet), 8.00 (m, 1Н, 6-Н), 8.03 (s,
1H, NH), 8.10 (d, J = 7.8 Hz, 1H, 7-HHet), 8.14 (d, J = 7.8 Hz,
1H, 4-HHet), 9.54 (m, 1Н, 9-Н). 13C NMR (100 MHz, DMSO-d6):
δ = 29.8, 33.2, 61.0, 82.0, 115.7, 117.0, 121.4, 123.0, 123.2,
123.9, 125.5, 126.5, 127.1 (2C), 127.3, 136.3, 139.8, 145.6,
153.5, 157.0, 158.5, 161.9. Anal. Calcd for C22H16N4OS2: C,
63.44; H, 3.87; N, 13.45; S, 15.40. Found: C, 63.38; H, 4.00; N,
13.58; S, 15.26.
1
2206, 1610, 1536, 1265, 1169, 754 cm-1. H NMR (400 MHz,
DMSO-d6): δ = 1.74 (m, 2H, 2-CH2), 1.99 (m, 1H, 3a-CH2), 2.42
(m, 1H, 3b-CH2), 3.36 (m, 2H, 1-CH2), 4.55 (t, J = 5.4 Hz, 1H,
OH), 4.68 (m, 1H, Ha-CH2-CF3), 4.78 (m, 1H, Hb-CH2-CF3), 7.05
(s, 1H, NH), 7.20 (d, J = 1.0 Hz, 1H, 5-HHet), 7.41 (d, J = 1.0 Hz,
1H, 4-HHet), 7.49 (m, 2Н, 7,8-H), 7.98 (m, 1Н, 6-Н), 9.55 (m, 1Н,
9-Н). 13C NMR (100 MHz, DMSO-d6): δ = 29.9, 32.5, 46.5 (2JCF
= 46 Hz), 60.9, 81.8, 112.7, 117.4, 121.6, 123.0, 123.2, 124.2
(1JCF = 278 Hz), 125.5, 127.1, 127.4, 130.3, 140.1, 141.8, 147.4,
158.6, 158.6. Anal. Calcd for C20H16F3N5OS: C, 55.68; H, 3.74;
N, 16.23; S, 7.43. Found: C, 55.45; H, 3.66; N, 16.08; S, 7.31.
4.8.6. 3-(3-Hydroxypropyl)-1-imino-2-(1-(phenylmethyl)-1H-
imidazol-2-yl)-1H-pyrido[2,1-b][1,3]benzothiazole-4-
4.8.2.
3-(3-Hydroxypropyl)-1-imino-2-quinolin-2-yl-1H-
carbonitrile (13f). Yellow solid (from isopropanol); mp 171-172
°C; yield: 0.82 g (93%). IR (KBr): 3448, 3321, 2199, 1612, 1532,
pyrido[2,1-b][1,3]benzothiazole-4-carbonitrile (13b). Yellow
solid (from dioxane); mp 197-198 °C; yield: 0.74 g (90%). IR
1
1274, 1057, 754 cm-1. H NMR (400 MHz, DMSO-d6): δ = 1.62
1
(KBr): 3423, 3322, 2201, 1612, 1522, 1058, 757 cm-1. H NMR
(m, 1H, 2a-CH2), 1.72 (m, 1H, 2b-CH2), 1.91 (m, 1H, 3a-CH2),
2.23 (m, 1H, 3b-CH2), 3.32 (m, 2H, 1-CH2), 4.67 (t, J = 5.4 Hz,
1H, OH), 4.93 (d, J = 14.9 Hz, 1H, Ha-CH2-Ph), 5.07 (d, J = 14.9
Hz, 1H, Hb-CH2-Ph), 7.11 (m, 3H, 2,6-HPh and NH), 7.17 (s, 1H,
5-HHet), 7.23 (m, 3H, 3,4,5-HPh), 7.46 (s, 1H, 4-HHet), 7.55 (m,
2Н, 7,8-H), 7.99 (m, 1Н, 6-Н), 9.52 (m, 1Н, 9-Н). 13C NMR (100
MHz, DMSO-d6): δ = 29.6, 32.2, 50.3, 60.4, 82.0, 114.2, 116.7,
121.8, 122.1, 122.7, 125.4, 126.8, 127.0, 128.2, 128.3 (2C), 128.9
(2C), 129.4, 136.8, 140.0, 140.7, 146.7, 157.8, 158.3. Anal.
Calcd for C25H21N5OS: C, 68.32; H, 4.82; N, 15.93; S, 7.30.
Found: C, 68.15; H, 4.97; N, 15.73; S, 7.19.
(400 MHz, DMSO-d6 / toluene-d8): δ = 1.88 (m, 2H, 2-CH2),
2.43 (t, J = 7.9 Hz, 2H, 1-CH2), 3.39 (m, 2H, 3-CH2), 4.68 (t, J =
5.1 Hz, 1H, OH), 7.52 (m, 2H, 7,8-H), 7.58 (d, J = 8.3 Hz, 1H, 3-
Н
Het), 7.69 (t, J = 8.0 Hz, 1H, 6-НHet), 7.74 (s, 1H, NH), 7.83 (t, J
= 8.0 Hz, 1H, 7-НHet), 8.03 (m, 1Н, 6-Н), 8.08 (d, J = 8.0 Hz, 1H,
5-HHet), 8.20 (d, J = 8.0 Hz, 1H, 8-HHet), 8.53 (d, J = 8.3 Hz, 1H,
4-HHet), 9.67 (m, 1Н, 9-Н). 13C NMR (100 MHz, DMSO-d6): δ =
29.1, 32.5, 60.7, 81.7, 117.2, 121.2, 123.0, 123.3, 123.8, 125.1,
126.7, 127.0, 127.3, 127.5, 128.4, 129.2, 130.3, 138.1, 139.8,
141.9, 148.3, 154.7, 156.6, 158.4. Anal. Calcd for C24H18N4OS:

9
4.8.7. 3-(3-Hydroxypropyl)-1-imino-2-(6,7,8,9-tetrahydro-5H-
[1,2,4]triazolo[4,3-a]azepin-3-yl)-1H-pyrido[2,1-
NMR (100 MHz, DMSO-d6): δ = 30.4, 34.2, 61.2, 84.5, 100.1,
ACCEPTED MANUSCRIPT
115.8, 122.5, 123.9, 126.1, 126.6, 128.0 (2C), 129.1 (2C), 130.6,
130.9, 136.9, 146.1, 151.8, 153.3, 153.5, 161.2, 164.5; Anal.
Calcd for C23H18N6OS: C, 64.77; H, 4.25; N, 19.70; S, 7.52.
Found: C, 64.67; H, 4.31; N, 19.58; S, 7.48.
b][1,3]benzothiazole-4-carbonitrile (13g). Yellow solid (from
isopropanol); mp 197-198 °C; yield: 0.72 g (86%). IR (KBr):
1
3424, 3355, 2939, 2200, 1610, 1528, 1059, 775 cm-1. H NMR
(400 MHz, DMSO-d6): δ = 1.62-1.80 (m, 6H, 2-CH2 and 7,8-
HHet), 1.88 (m, 2Н, 6-HHet), 2.14 (m, 1H, 3a-CH2), 2.46 (m, 1H,
3b-CH2), 3.02 (m, 2Н, 9-HHet), 3.36 (m, 2H, 1-CH2), 3.80 (m, 2Н,
5-HHet), 4.48 (t, J = 4.9 Hz, 1H, OH), 7.45 (s, 1H, NH), 7.49 (m,
2Н, 7,8-H), 7.99 (m, 1Н, 6-Н), 9.56 (m, 1Н, 9-Н). 13C NMR (100
MHz, DMSO-d6): δ = 25.5, 26.9, 28.6, 29.6, 30.6, 32.8, 45.3,
60.8, 81.8, 110.8, 117.3, 121.7, 123.4, 125.6, 127.2, 127.5, 140.1,
147.5, 148.5, 157.7, 158.3, 159.1. Anal. Calcd for C22H22N6OS:
C, 63.14; H, 5.30; N, 20.08; S, 7.66. Found: C, 63.19; H, 5.39; N,
20.94; S, 7.57.
4.10. Preparation of compound 2-(quinolin-2-yl)-2-
(tetrahydro-2-furanyliden)acetonitrile 3d
Compound 3d was obtained according to the procedure
published earlier.19 White solid (from ethanol); mp 148-149°C;
yield: 2.05 g (87%). IR (KBr): 2212, 1603, 1205, 828 cm-1. H
1
NMR (400 MHz, DMSO-d6): δ = 2.25 (m, 2H, 4-CH2), 3.24 (t, J
= 7.8 Hz, 2H, 3-CH2), 4.68 (t, J = 6.8 Hz, 2H, 5-CH2), 7.49 (t, J =
8.1 Hz, 1H, 7-НHet), 7.68 (t, J = 8.1 Hz, 1H, 6-НHet), 7.84 (d, J =
8.1 Hz, 1H, 5-HHet), 7.97 (d, J = 8.1 Hz, 1H, 8-HHet), 8.00 (d, J =
8.8 Hz, 1H, 3-HHet), 8.19 (d, J = 8.8 Hz, 1H, 4-HHet). 13C NMR
(100 MHz, DMSO-d6): δ = 23.4, 34.1, 77.4, 88.7, 119.2, 120.5,
126.4, 126.7, 127.9, 129.3, 129.9, 136.5, 147.8, 152.4, 176.8.
Anal. Calcd for C15H12N2O: C, 76.25; H, 5.12; N, 11.86. Found:
C, 76.37; H, 5.19; N, 11.88.
4.9. General procedure for the preparation of compounds 14
To
a
stirred
solution
of
corresponding
1H-azahetarylacetonitrile 6h–j (2.3 mmol) in anhydrous DMF
(15 mL), NaH (0.05 g, 3.0 mmol) was added and left at rt for 10
min. Then furanilidene 3a (0.48 g, 2.0 mmol) was added and the
reaction mixture was stirred at rt for 6–8 h. After the reaction was
complete (TLC monitoring), the reaction mixture was diluted
with H2O (100 mL) and acidified with HCl to pH = 7.0–7.5. The
precipitated crude product was filtered off, washed with water,
dried and recrystallized from appropriate solvent.
References and notes
1. (a) Refaat, H. M. Med. Chem. Res. 2012, 21, 1253; (b) Badawey,
E. A. M.; Kappe, T. Eur. J. Med. Chem. 1999, 34, 663; (c) El-
Hawash, S. A. M.; Badawey, E. A. M.; Kappe, T. Pharmazie
1999, 54, 341; (d) Badawey, E.; Kappe, T. Eur. J. Med. Chem.
1995, 30, 327.
2. Kotovskaya, S. K.; Baskakova, Z. M; Charushin, V. N;
Chupakhin, O. N.; Belanov, E. F.; Bormotov, N. I.; Balakhnin, S.
M.; Serova, O. A. Pharm. Chem. J. 2005, 39, 574.
3. (a) Jardosh, H. H.; Sangani, C. B.; Patel, M. P.; Patel, R. G. Chin.
Chem. Lett. 2013, 24, 123; (b) Sangani, C. B.; Jardosh, H. H.;
Patel, M. P.; Patel, R. G. Med. Chem. Res. 2013, 22, 3035.
4. Pieroni, M.; Tipparaju, S. K.; Kozikowski, A. P.; Lun, S.; Bishai,
W. R.; Song, Y.; Sturm, A. W. ChemMedChem 2011, 6, 334.
5. (a) Takeshita, H.; Watanabe, J.; Kawakami, K.; Takahashi, H.;
Takemura, M.; Kimura, Y.; Kitamura, A.; Someya, K.; Nakajima,
R. Bioorg. Med. Chem. Lett. 2010, 20, 3893; (b) Kitamura, A.;
Someya, K.; Hata, M.; Nakajima, R.; Takemura, M. Antimicrob.
Agents Chemother. 2009, 53, 670; (c) Kitamura, A.; Higuchi, S.;
Hata, M.; Kawakami, K.; Yoshida, K.; Namba, K.; Nakajima, R.
Antimicrob. Agents Chemother. 2009, 53, 3963.
4.9.1.
5-Amino-6-(1,3-benzothiazol-2-yl)-7-(3-
hydroxypropyl)imidazo[1,2-a]pyridine-8-carbonitrile (14a). Pale
yellow solid (from DMF / acetonitrile); mp 236-237 °C; yield:
0.50 g (72%). IR (KBr): 3367, 3145, 2212, 1656, 1545, 1049,
1
703 cm-1. H NMR (400 MHz, DMSO-d6): δ = 1.65 (m, 2H, 2-
CH2), 2.68 (t, J = 7.8 Hz, 2H, 1-CH2), 3.25 (q, J = 5.5 Hz, 2H, 3-
CH2), 4.44 (t, J = 5.5 Hz, 1H, OH), 7.53 (t, J = 7.8 Hz, 1Н, 5-
НHet), 7.59 (t, J = 7.8 Hz, 1H, 6-НHet), 7.64 (s, 1Н, 2-Н), 7.80 (s,
2H, NH2), 8.15 (d, J = 7.8 Hz, 1H, 7-НHet), 8.20 (m, 2Н, 3-Н and
4-НHet). 13C NMR (100 MHz, DMSO-d6): δ = 29.7, 33.8, 60.8,
85.4, 97.0, 110.8, 116.8, 122.6, 123.6, 125.9, 126.5, 134.2, 136.9,
144.2, 145.0, 149.3, 153.4, 161.9. Anal. Calcd for C18H15N5OS:
C, 61.87; H, 4.33; N, 20.04; S, 9.18. Found: C, 61.80; H, 4.38; N,
20.01; S, 9.13.
6. Ndakala, A. J.; Gessner, R. K.; Gitari, P. W.; October, N.; White,
K. L.; Hudson, A.; Fakorede, F.; Shackleford, D. M.; Kaiser, M.;
Yeates, C.; Charman, S. A.; Chibale, K. J. Med. Chem. 2011, 54,
4581.
7. Lyons, D. M.; Huttunen, K. M.; Browne, K. A.; Ciccone, A.;
Trapani, J. A.; Denny, W. A.; Spicer, J. A. Bioorg. Med. Chem.
2011, 19, 4091.
4.9.2.
1-Amino-2-(1,3-benzothiazol-2-yl)-3-(3-
hydroxypropyl)pyrido[1,2-a]benzimidazole-4-carbonitrile (14b).
White solid (from DMF); mp 279-280 °C; yield: 0.67 g (84%).
IR (KBr): 3420, 3313, 3217, 2219, 1642, 1547, 1026, 760 cm-1.
1H NMR (400 MHz, DMSO-d6): δ = 1.80 (m, 2H, 2-CH2), 2.88
(t, J = 7.8 Hz, 2H, 1-CH2), 3.39 (m, 2H, 3-CH2), 4.28 (t, J = 4.6
Hz, 1H, OH), 7.31 (t, J = 7.8 Hz, 1Н, 8-Н), 7.52 (m, 2Н, 7-Н and
5-НHet), 7.58 (t, J = 7.6 Hz, 1H, 6-НHet), 7.82 (d, J = 7.8 Hz, 1Н,
6-Н), 7.90 (s, 2H, NH2), 8.08 (d, J = 7.6 Hz, 1H, 7-НHet), 8.13 (d,
J = 7.6 Hz, 1H, 4-НHet), 8.47 (d, J = 7.8 Hz, 1Н, 9-Н). 13C NMR
(100 MHz, DMSO-d6): δ = 30.2, 33.6, 60.8, 84.8, 98.1, 115.4,
116.8, 118.7, 120.8, 122.5, 123.5, 125.9, 126.4, 126.5, 128.9,
137.0, 145.2, 148.4, 149.0, 153.3, 153.9, 161.8. Anal. Calcd for
C22H17N5OS: C, 66.15; H, 4.29; N, 17.53; S, 8.03. Found: C,
66.04; H, 4.36; N, 17.60; S, 7.99.
8.
(a) Sabnis, R. W.; Rangnekar, D. W. J. Heterocycl. Chem. 1990,
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4.9.3.
5-Amino-6-(1,3-benzothiazol-2-yl)-7-(3-
hydroxypropyl)-2-phenyl[1,2,4]triazolo[1,5-a]pyridine-8-
carbonitrile (14c). White solid (from DMF / acetonitrile); mp
231-232 °C; yield: 0.74 g (87%); IR (KBr): 3394, 3329, 3136,
1
2216, 1633, 1560, 1049, 763 cm-1; H NMR (400 MHz, DMSO-
d6): δ = 1.72 (m, 2H, 2-CH2), 2.74 (t, J = 7.8 Hz, 2H, 1-CH2),
3.32 (m, 2H, 3-CH2), 4.48 (t, J = 5.1 Hz, 1H, OH), 7.52-7.62 (m,
5Н, 3,4,5-Ph and 5,6-НHet), 8.16 (d, J = 8.1 Hz, 1Н, 7-НHet), 8.22
(d, J = 8.1 Hz, 1Н, 4-НHet), 8.27 (m, 4H, 2,6-Ph and NH2); 13C

10
Tetrahedron
12. Rida, S. M.; Ashour, F. A.; El-Hawash, S. A. M.; ElSemary,
ACCEPTED MANUSCRIPT
M. M.; Badr, M. H.; Shalaby, M. A. Eur. J. Med. Chem. 2005, 40,
949.
13. Kuroyanagi, J.; Kanai, K.; Sugimoto, Y.; Fujisawa, T.; Suzuki, T.;
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2012, 44, 895; (c) Bonacorso, H. G.; Porte, L. M. F.; Paim, G. R.;
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Souza, A.; Echevarria, A.; Brondani, P. B.; Flores, D. C.;
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