3-Hetarylisocoumarins in the synthesis of 1-functionalized 3-hetarylisoquinolines

Article abstract of DOI:10.1007/s10593-020-02769-3

[Figure not available: see fulltext.] A convenient method was developed for the synthesis of novel isoquinolin-1(2H)-ones, 1-chloroisoquinolines, and 1-aminoisoquinolines with a heterocyclic substituent in position 3 via a recyclization of 3-hetarylisocoumarins with (NH₄)₂CO₃. 1-Aminoisoquinolines were efficiently obtained from corresponding 1-chloro-3-hetarylisoquinolines (obtained by interaction of isoquinolin-1(2H)-ones with POCl₃) and cyclic secondary amines (morpholine or 1-methylpiperazine). Literature data and preliminary results of biological assays allow to consider 1-amino-3-hetarylisoquinolines a promising family of anticancer compounds.

Full text of DOI:10.1007/s10593-020-02769-3

DOI 10.1007/s10593-020-02769-3
Chemistry of Heterocyclic Compounds 2020, 56(8), 1021–1029
3-Hetarylisocoumarins in the synthesis
of 1-functionalized 3-hetarylisoquinolines
Artem S. Konovalenko1, Oleh V. Shablykin1, Volodymyr S. Brovarets1,
Olga V. Shablykina1,2, Viktoriia S. Moskvina1,2*, Andriy V. Kozytskiy3
1 V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry,
National Academy of Sciences of Ukraine,
1 Murmanska St., Kyiv 02094, Ukraine; e-mail: brovarets@bpci.kiev.ua
2 Taras Shevchenko National University of Kyiv,
60 Volodymyrska St., Kyiv 01033, Ukraine; e-mail: v.moskvina@gmail.com
3 L. V. Pisarzhevskii Institute of Physical Chemistry,
National Academy of Sciences of Ukraine,
31 Nauky Ave., Kyiv 03028, Ukraine; e-mail: kozytskiy@ukr.net
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(8), 1021–1029
Submitted February 29, 2020
Accepted after revision April 17, 2020
A convenient method was developed for the synthesis of novel isoquinolin-1(2H)-ones, 1-chloroisoquinolines, and 1-aminoisoquinolines
with a heterocyclic substituent in position 3 via a recyclization of 3-hetarylisocoumarins with (NH4)2CO3. 1-Aminoisoquinolines were
efficiently obtained from corresponding 1-chloro-3-hetarylisoquinolines (obtained by interaction of isoquinolin-1(2H)-ones with POCl3)
and cyclic secondary amines (morpholine or 1-methylpiperazine). Literature data and preliminary results of biological assays allow to
consider 1-amino-3-hetarylisoquinolines a promising family of anticancer compounds.
Keywords: isocoumarin, isoquinoline, isoquinolin-1(2H)-ones, nitrogen-containing heterocycles, anticancer activity, recyclization.
Nitrogen-containing heterocycles are key components of
many bioactive natural products and potent drugs (Fig. 1),1
and for this reason they are assigned as privileged motifs in
drug development.2 The diverse functions of nitrogen-
containing compounds highly depend on their characteristic
structures, so the elaboration of N-heterocycles and the late-
stage modification of drug candidates with N-heterocycles
have emerged as an important strategy in organic synthetic
chemistry and drug discovery.3 The importance of nitrogen-
containing heterocycles in medicinal chemistry has
motivated many research groups to develop new and
efficient protocols for their synthesis.
exhibited antimicrobial activity,4 while compound 2 extracted
from seaweed Streptomyces sp.5 and compounds with general
formula 36 (Fig. 1) exhibits anticancer activity. The latter
compounds contain an interesting combination of a
heterocyclic substituent in position 3 and an amino group
in position 1.
Isoquinolones are an important family of N-hetero-
cycles, found in naturally occurring and synthetic small
molecules displaying diverse biological activities. Recently
more data has emerged about isoquinolines with aromatic
or heteroaromatic substituents in position 3 which have real-
world applications and have been of interest to us. For
instance, alkaloid of Hypecoum erectum corydamine 1
Figure 1. Compounds containing the isoquinoline motif.
0009-3122/20/56(8)-1021©2020 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2020, 56(8), 1021–1029
Isoquinolin-1-ones are often used as building blocks in
Other products depicted in Scheme 1 are interesting not
only for their potential practical usage, but also for further
synthetic transformations. For example, the chlorine atom
in position 1 of the isoquinoline ring could be easily
substituted with nucleophilic reagents, such as primary and
secondary amines. The previously mentioned 1-aminoiso-
quinolines 3 with anticancer activity (Fig. 1) were obtained
via this approach. The necessary isoquinolin-1(2H)-ones,
however, were synthesized by the condensation of o-methyl-
benzamides with heteroaromatic nitriles in the presence of
n-BuLi with low yields at this step.7 Such approach to a
certain degree limits the variability of possible heterocyclic
substituents.
Our previous research has demonstrated that various
3-hetarylisocoumarins can be easily obtained from readily
available reagents.16–19 The goal of this work was to
research the synthetic capabilities of isocoumarins as
source compounds for the straightforward synthesis of
3-hetaryl-substituted isoquinolin-1(2H)-ones, 1-chloro- and
1-aminoisoquinolines.
organic synthesis, and numerous approaches to their
synthesis have been developed.7 Compounds with a
substituent (methyl, benzyl) in position 1 dominate among
natural and synthetic isoquinolines, and the majority of
convenient approaches to construct the isoquinoline system
target primarily compounds of this type (e.g., one of
classical synthetic methods utilizes the Bischler–
Napieralski reaction with phenylethylamine8).
Over the several past decades catalysis with numerous
transition metals was used for the formation of isoquinolin-
1-ones. Recently, isoquinolin-1(2H)-one derivatives have
been synthesized from substituted benzamidines with aryl
alkynes using Ni(II),9 Rh(III),10 Pd/C catalysts.11 Also,
isoquinolinones have been synthesized via Co-catalyzed
ortho-C–H functionalization/annulation of arenes and
alkenes with alkynylsilanes.12 Furthermore, 1-halo- and
1-alkoxy-substituted isoquinolines were prepared via
Ru-catalyzed cyclization of substituted N-methoxy-
benzimidoyl halides with alkynes.13
Most of the aforementioned methods for the synthesis of
3-substituted isoquinolines have certain drawbacks, such as
the use of special or poorly accessible starting materials,
expensive catalysts, multistep procedures, photoactivation,
and harsh reaction conditions.
Therefore, with our goal being the creation of new
3-hetarylisoquinolines via convenient procedures and from
easily available reagents, we focused on the methodology by
Gabriel14 – the synthesis of 3-arylisoquinolines by the recycli-
zation of 1Н-isochromen-1-ones (isocoumarins) (Scheme 1).
Based on the literature data,18 the most frequently used
and, in our opinion, the most convenient and efficient
method for the recyclization of isocoumarin into isoquino-
linone is heating the source compound with NH3 in alcohol
solution. To maintain NH3 concentration at the temperature
optimal for this reaction (above 100°С) the heating must be
performed in a pressure tube or an autoclave. In addition, a
small number of procedures was developed for the
synthesis of isoquinolines where the reaction took place in
a sealed tube in THF,20 but no increase either in yield or in
the reaction rate was observed. There are several literature
examples of replacing NH3 with its derivatives – form-
Scheme 1. Synthesis of isoquinolines from isocoumarins
(literature data)
22
amide21 or AcONH4 in this recyclization, but the major
reason for this change was the ability to perform the
reaction at atmospheric pressure. Several examples of
successful recyclization of isocoumarin under the action of
concentrated NH3 under atmospheric pressure were
applicable to the molecules of specific structure: for
example, 8-nitro-substituted isocoumarins were transformed
into isoquinolinones when refluxed in MeO(CH2)2OH,23
and the condensed system of 1H-cyclopenta[c]isoquinoline-
3,5-(2H,4H)-dione was formed from a corresponding
isocoumarin when refluxed in formamide with a multifold
excess of NH3.24
The above considerations combined with the lack of
success in our attempts at the recyclization of the studied
3-hetarylcoumarins under atmospheric pressure in an
alcohol solution (no conversion) and the tendency of
starting compounds to decompose during the prolonged
heating in a strongly nucleophilic medium pushed us
toward using a classic procedure of heating in a sealed tube
to avoid the decomposition of the starting material. For a
more precise dosage of NH3, we decided to use its
synthetic equivalent, (NH4)2CO3.
Only the first stage of this transformation – the synthesis
of isoquinolin-1(2H)-ones – was subsequently actively
studied. For example, it was recently used for the counter
synthesis of the antiviral natural glucoside 4 (Scheme 2),
extracted from Іsatis tinctоria (dyer's weed).15
Scheme 2. Synthesis of 3-(furan-2-yl)-7-hydroxyisoquinolin-
1-(2H)-one from 3-(furan-2-yl)-7-hydroxy-1H-isochromen-1-one
(literature data)
The starting compounds 5a–g with thiazole, imidazo-
thiazole, and quinoxaline substituents in position 3 of
isocoumarin were synthesized from 3-(2-bromoacetyl)-
isocoumarin (6) (Scheme 3) using methods we have
developed earlier. When compounds 5a–g were heated in a
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Chemistry of Heterocyclic Compounds 2020, 56(8), 1021–1029
Scheme 3
Scheme 5
O
Cl
POCl3
NH
Het
N
, 10 h
66–78%
Het
7a–g
8a–g
X
N
HN
X
K2CO3, DMF
N
100 C, 10 h
60–81%
Het
9a–g (X = O)
10a–g (X = NMe)
much higher. Target compounds 9a–g, 10a–g were well
soluble in EtOAc which, of course, is a favorable factor for
further research of their biological activity and potential
uses.
Comprehensive physicochemical research has proven
the structures of synthesized compounds; data is presented
in the experimental part. Classification of multiplets in
1H NMR spectra of 3-substituted isocoumarins is straight-
forward due to characteristic signals – a singlet in position 4 of
the system and a doublet of the proton in position 8; the
latter is significantly shifted to the weak field because of
the carbonyl group's deshielding effect.
hydrothermal autoclave with 4 equiv of (NH4)2CO3 at 150°С
for 4 h (for compounds 5a–d) or 6 h (for compounds 5e–g),
a series of 3-hetaryl-substituted isoquinolin-1(2H)-ones 7a–g
(Scheme 4) were obtained. Lower temperatures or shorter
durations resulted in incomplete conversion.
The only significant change from isocoumarin to
isoquinolin-1(2H)-one is a noticeable shift of the singlet of
the proton in position 4 to the strong field. In order to
reliably correlate signals and identify spectral properties of
certain members of 1-chloro- and 1-aminoisoquinoline
derivative groups, additional NMR experiments were
performed: COSY, APT, and heteronuclear correlations
Scheme 4
1
1H–13C HMBC and H–13C HMQC. The consequence of
1-chloroisoquinoline system formation is the sharp shift of
isoquinoline ring signals to the weak field, especially
noticeable for the signals of isoquinoline ring protons at
positions 4 and 5 (Fig. 2).
The next type of compounds – 1-chloro-3-hetaryliso-
quinolines 8a–g – was synthesized by refluxing isoquinolin-
1(2H)-ones 7a–g in POCl3 (5 equiv); for most compounds,
the reaction took no longer than 10 h. Nucleophilic
substitution of the chlorine atom in compounds 8a–g with
an aliphatic amine fragment occurs when chloro derivatives
are heated with 3 equiv of a cyclic secondary amine
(morpholine or 1-methylpiperazine) in DMF with K2CO3 as
a base (Scheme 5). Under these conditions, it is possible to
obtain 1-aminoisoquinolines 9a–g and 10a–g with thiazole,
imidazothiazole, and quinoxaline substituents in position 3
of the isoquinoline system with average yields of around
70%.
It should be noted that while 1-chloroisoquinolines 8a–g, as
well as starting isocoumarins and isoquinolinones, are
poorly soluble even in solvents such as DMF or DMSO,
the solubility of their amino derivatives 9a–g, 10a–g is
Figure 2. NMR data of 1-chloroisoquinolines 8a,e (δ, ppm).
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Chemistry of Heterocyclic Compounds 2020, 56(8), 1021–1029
8.16
129.3
1-chloro-3-[2-(thiophen-2-yl)-1,3-thiazol-4-yl]isoquinoline
N
9.96
144.5
(8c) possess very low cytotoxicity and can only barely slow
down the growth of certain cell lines (average values of
cancer cell growth percentages were close to 100% at these
compounds concentration of 10–5 М). A more detailed
description of biological assays was published earlier.25
Notably, the comparison of this data with the published
research6 on the anticancer activity toward T47D cancer
cell lines (human ductal breast epithelial tumor cells),
DU145 (human prostate cancer cells), and HCT-15 (human
colorectal adenocarcinoma cells) has demonstrated that
compound 10с causes 50% decrease of cell growth in
smaller concentrations than most of thienylisoquinolines of
the general formula 3 (Fig. 1), and in some cases – in lower
concentrations than the reference medical compounds –
etoposide and doxorubicin. These results make the active
search of anticancer drugs among 1-amino-3-hetaryl-
isoquinolines a promising research direction.
To conclude, we have confirmed that the recyclization
of 3-hetarylisocoumarins by the reaction with ammonia is a
convenient approach to the synthesis of isoquinolin-1(2H)-
ones, 1-chloroisoquinolines, and 1-aminoisoquinolines
with a heterocyclic substituent in position 3, which allowed
us to significantly expand the list of presently known
compounds of this type.
142.2
141.7
130.6 7.86
131.1 7.90
8.14
8.60
129.6
114.4
145.1
7.78 128.3
7.68 131.1
138.7
121.6
150.8
129.3
8.16
N
N
125.9
8.18
160.8
9g
N
1H–13C HMBC
COSY
3.50
51.9
66.7 3.92
O
8.17
117.6
7.75
129.7
S
N
7.18
128.9
161.7
8.01
128.5
8.02
111.9
136.8
155.8
128.1
7.72
7.68 130.7
138.8
120.9
143.4
S
127.0
7.56
N
125.8
8.04
160.8
10c
N
51.1 3.42
55.0 2.60
Experimental
N
1H, 13C NMR spectra, APT spectra, and 2D experiments
(COSY, 1H–13C HMBC, 1H–13C HMQC) of obtained products
were recorded on a Bruker Avance 500 spectrometer (500
and 126 MHz, respectively) in DMSO-d6 and CF3CO2D
solutions with TMS as internal standard. Mass spectra were
recorded on an Agilent 1100 LCMSD SL instrument
(atmospheric pressure chemical ionization (APCI)) and
HP 5890 Series II GC with HP 5972 MSD instrument
(electron impact ionization (EI)). Elemental analyses were
performed at the Analytical Laboratory of the Institute of
Organic Chemistry of NAS of Ukraine on a vario MICRO
cube instrument, their results were found to be in good
agreement ( 0.4%) with the calculated values. Melting
points were measured on an automated melting point
system OptiMelt MPA100. The reaction progress was
monitored by the TLC on Merck Silica gel 60 F254. In
correlations of 1H NMR spectra, the protons of iso-
coumarin and its derived isoquinoline ring are designated
as H; atoms of a substituent in position 3 of the main
system as Н'; if the 3-heterocycle contains an additional
(hetero)aromatic substituent, its protons are marked as Н''.
3-Hetaryl-1H-isochromen-1-ones 5a–g were obtained
from 3-(2-bromoacetyl)-1H-isochromen-1-one 6 (0.01 mol)
according to the method described in literature.16
46.2 2.29
Figure 3. NMR data of 1-aminoisoquinolines 9g and 10с (δ, ppm).
The proton in position 4 of the isoquinoline system of
1-aminoisoquinolines 9, 10 is deshielded, and the
difference in chemical shifts of protons in positions 5 and 8
(Fig. 3) is as insignificant as it is in 1-chloro derivatives
(Fig. 2), whereas it is around 0.5 ppm for corresponding
isocoumarins and isoquinolinones.
Preliminary biological study of some of the synthesized
compounds confirmed the starting hypothesis of anticancer
activity being inherent for 1-aminoisoquinolines, with the
type of amine substituent significantly influencing the
activity. For example, 1-(morpholin-4-yl)-3-[2-(thiophen-
2-yl)-1,3-thiazol-4-yl]isoquinoline (9c) is sufficiently effi-
cient against several cancer types: melanomas MALME-3M
(cancer cell growth according to one dose assay of the
compound in concentration of 10–5 М – 0.6%) and UACC-257
(17.3%), breast MDA-MB-468 (5.8%), and colon COLO 205
(20.5%) cell lines. 1-(4-Methylpiperazin-1-yl)-3-[2-(thiophen-
2-yl)-1,3-thiazol-4-yl]isoquinoline (10c) stops the growth
of the majority of the studied cell lines; this compound is even
lethal, in particular, for the COLO 205 (–51.1%), HCC-2998
(–38.2%; GI50 1.72 µM, TGI 3.40 µM, LC50 6.75 µM), and
HT29 (–27.3%; GI50 1.66 µM, TGI 3.41 µM, LC50 7.00 µM)
colon cancer lines. Isoquinoline 10c was also effective
against the melanoma line M14 (–44.9%; GI50 1.87 µM,
TGI 3.71 µM, LC50 7.34 µM) and the K-562 leukemia line
(–35.9%; GI50 2.16 µM, TGI 4.92 µM, LC50 >100.0 µM).
At the same time, the starting isocoumarin 5c and 3-[2-(thio-
phen-2-yl)-1,3-thiazol-4-yl]isoquinolin-1(2H)-one (7c) and
Physical and spectral properties of compounds 5a,b,f16
and 5e,g17 are found in previous papers.
3-[2-(Thiophen-2-yl)-1,3-thiazol-4-yl]-1H-isochromen-
1-one (5c). Yield 2.24 g (72%), white solid, mp 200–201°C.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.22 (1H,
dd, J = 4.9, J = 3.8, H-4''); 7.46 (1H, s, H-4); 7.62 (1H, td,
J = 8.0, J = 4.3, H-7); 7.79 (1H, dd, J = 3.8, J = 0.8, H-5'');
7.81 (1H, dd, J = 4.9, J = 0.8, H-3''); 7.86–7.88 (2H, m,
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Chemistry of Heterocyclic Compounds 2020, 56(8), 1021–1029
H-5,6); 8.12 (1H, s, H-5'); 8.18 (1H, d, J = 8.0, Н-8).
(CF3CO2D), δ, ppm: 113.6; 118.3; 122.1; 124.3; 125.4;
126.8; 128.0; 130.2; 130.8; 134.8; 136.1; 137.1; 137.3;
138.8; 164.9; 168.1. Mass spectrum (EI, 70 eV), m/z (Irel, %):
310 [M]+ (100). Found, %: C 61.72; H 3.41; N 8.92;
S 20.63. C16H10N2OS2. Calculated, %: C 61.91; H 3.25;
N 9.03; S 20.66.
3-[2-(Pyridin-4-yl)-1,3-thiazol-4-yl]isoquinolin-1(2H)-
one (7d). Yield 735 mg (75%), yellow solid, mp 337–338°C.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.44 (1Н,
s, Н-4); 7.49–7.55 (1Н, m, Н-7); 7.71–7.80 (2Н, m, Н-5,6);
8.00–8.06 (2Н, m, H-3'',5''); 8.20–8.26 (1Н, m, Н-8); 8.63
(1Н, br. s, H-5'); 8.74–8.79 (2H, m, H-2'',6''); 11.38 (1Н,
br. s, NН). 13C NMR spectrum (CF3CO2D), δ, ppm: 109.2;
118.6; 121.0; 121.9; 124.6; 125.6; 127.9; 128.4; 134.2;
137.0; 139.8; 147.5; 148.1; 159.1; 161.4. Mass spectrum
(EI, 70 eV), m/z (Irel, %): 305 [M]+ (100). Found, %:
C 66.71; H 3.71; N 13.57; S 10.48. C17H11N3OS.
Calculated, %: C 66.87; H 3.63; N 13.76; S 10.50.
13C NMR spectrum (DMSO-d6), δ, ppm: 103.5; 118.6;
120.6; 127.5; 128.9; 129.0; 129.2; 129.4; 130.2; 135.8;
136.2; 137.3; 147.8; 148.8; 161.3; 162.6. Mass spectrum
(EI, 70 eV), m/z (Irel, %): 311 [M]+ (100). Found, %:
C 61.78; H 2.83; N 4.46; S 20.64. C16H9NO2S2. Calculated, %:
C 61.72; H 2.91; N 4.50; S 20.59.
3-[2-(Pyridin-4-yl)-1,3-thiazol-4-yl]-1H-isochromen-
1-one (5d). Yield 2.33 g (76%), red-yellow solid, mp 263–
1
264°C. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
7.62–7.67 (2H, m, H-4,7); 7.83 (1H, d, J = 7.6, H-5); 7.90
(1H, t, J = 7.6, H-6); 8.21 (1H, d, J = 7.6, H-8); 8.30 (2H,
br. d, J = 5.6, H-3'',5''); 8.46 (1H, s, H-5'); 8.92 (2H, d,
J = 5.6, H-2'',6''). 13C NMR spectrum (DMSO-d6), δ, ppm:
106.0; 119.1; 122.9; 123.5; 126.9; 129.3; 129.6; 136.7;
137.3; 141.7; 147.1; 149.6; 150.7; 161.1; 166.4. Mass
spectrum (EI, 70 eV), m/z (Irel, %): 306 [M]+ (100). Found, %:
C 66.56; H 3.21; N 9.19; S 10.32. C17H10N2O2S.
Calculated, %: C 66.65; H 3.29; N 9.14; S 10.47.
3-(Imidazo[2,1-b][1,3]thiazol-6-yl)isoquinolin-1(2H)-
one (7e). Yield 618 mg (72%), white solid, mp 265–266°C.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.16 (1Н,
s, Н-4); 7.32 (1H, d, J = 4.4, H-2'); 7.40–7.47 (1H, m,
H-7); 7.63–7.71 (2H, m, H-5,6); 8.04 (1H, d, J = 4.4, H-3');
8.18 (1Н, d, J = 8.0, Н-8); 8.52 (1H, s, H-5'); 11.18 (1Н,
br. s, NН). 13C NMR spectrum (CF3CO2D), δ, ppm: 113.1;
113.9; 119.7; 122.1; 122.9; 125.0; 127.7; 128.7; 131.3;
132.8; 136.9; 138.4; 150.3; 165.9. Mass spectrum (EI, 70 eV),
m/z (Irel, %): 267 [M]+ (100). Found, %: C 62.85; H 3.27;
N 15.67; S 11.86. C14H9N3OS. Calculated, %: C 62.91;
H 3.39; N 15.72; S 11.99.
Synthesis of 3-hetarylisoquinolin-1(2H)-ones 7a–g
(General method). A mixture of isocoumarin 5a–g
(3.21 mmol) and (NH4)2CO3 (1.23 g, 12.84 mmol, 4 equiv)
in abs. EtOH (15 ml) was heated in a hydrothermal
autoclave at 150°C and stirred for 4–6 h. When the mixture
was cooled, a precipitate was formed, which was filtered
off and washed with H2O. The obtained product was
purified by crystallization from EtOH–DMF, 1:1.
3-(2-Methyl-1,3-thiazol-4-yl)isoquinolin-1(2H)-one (7a).
Yield 530 mg (69%), white solid, mp 215–217°C. 1H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 2.73 (3H, s, CH3);
7.31 (1Н, s, Н-4); 7.48 (1Н, t, J = 7.3, Н-7); 7.70 (1Н, t,
J = 7.3, Н-6); 7.76 (1Н, d, J = 7.8, H-5); 8.19 (1Н, d,
J = 7.8, Н-8); 8.31 (1Н, s, H-5'); 11.38 (1Н, br. s, NН).
13C NMR spectrum (CF3CO2D), δ, ppm: 15.1; 113.0;
120.0; 124.3; 126.8; 128.1; 130.8; 136.0; 137.2; 139.1;
176.5; one signal in the weak field overlaps with the
solvent signals. Mass spectrum (EI, 70 eV), m/z (Irel, %):
242 [M]+ (100). Found, %: C 64.37; H 4.11; N 11.65;
S 13.35. C13H10N2OS. Calculated, %: C 64.44; H 4.16;
N 11.56; S 13.23.
3-(2-Phenyl-1,3-thiazol-4-yl)isoquinolin-1(2H)-one (7b).
Yield 742 mg (76%), white solid, mp 300–301°C. 1H NMR
spectrum (CF3CO2D), δ, ppm (J, Hz): 8.57 (2H, t, J = 7.6,
H-3'',5''); 8.67–8.75 (3H, m, H-4,7,4''); 8.83 (1H, d, J = 7.8,
H-5); 8.88–8.92 (1H, t, J = 7.8, H-6); 8.95 (2H, d, J = 7.6,
H-2'',6''); 9.34 (1H, s, H-5'); 9.39 (1Н, d, J = 8.1, Н-8).
13C NMR spectrum (CF3CO2D), δ, ppm: 114.8; 121.1;
123.0; 124.9; 125.3; 127.6; 128.4; 128.9; 131.1; 131.7;
136.8; 137.0; 138.2; 140.6; 165.7; 176.7. Mass spectrum
(EI, 70 eV), m/z (Irel, %): 304 [M]+ (100). Found, %: C 71.11;
H 3.83; N 9.12; S 10.61. C18H12N2OS. Calculated, %:
C 71.03; H 3.97; N 9.20; S 10.53.
3-[2-(Thiophen-2-yl)-1,3-thiazol-4-yl]isoquinolin-1(2H)-
one (7c). Yield 787 mg (79%), yellow solid, mp 225–226°C.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.21 (1Н,
br. t, J = 4.2, H-4''); 7.34 (1Н, s, Н-4); 7.52 (1Н, t, J = 7.6,
Н-7); 7.73 (1Н, t, J = 7.6, Н-6); 7.77 (1Н, d, J = 3.4, H-5'');
7.75–7.84 (2Н, m, Н-5,3''); 8.22 (1Н, d, J = 8.2, Н-8); 8.44
(1Н, s, H-5'); 11.42 (1Н, br. s, NН). 13C NMR spectrum
3-(Quinoxalin-2-yl)isoquinolin-1(2H)-one (7f). Yield
1
570 mg (65%), yellow solid, mp 256–257°C. H NMR
spectrum (CF3CO2D), δ, ppm (J, Hz): 7.46 (1H, s, H-4);
7.53–7.63 (1H, m, H-7); 7.68–7.76 (2H, m, H-5',8'); 7.76–
7.87 (2H, m, H-6,7); 8.07–8.17 (2H, m, H-6',7'); 8.48 (1Н,
d, J = 8.1, Н-8); 9.45 (1H, d, J = 1.6, H-3'); 10.34 (1Н,
br. s, NН). 13C NMR spectrum (CF3CO2D), δ, ppm: 115.6;
121.4; 128.1; 129.6; 129.7; 131.4 (2C); 132.4; 134.4;
136.7; 136.9; 138.0; 138.3; 145.8; 146.5; signals in the
weak field overlap with the solvent signals. Mass spectrum (EI,
70 eV), m/z (Irel, %): 273 [M]+ (100). Found, %: C 74.66;
H 4.12; N 15.31. C17H11N3O. Calculated, %: C 74.71;
H 4.06; N 15.38.
3-(6,7-Dimethylquinoxalin-2-yl)isoquinolin-1(2H)-one
(7g). Yield 677 mg (70%), yellow solid, mp 301–302°C.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 2.50
(overlaps with DMSO signal, 2CH3); 7.61 (1Н, t, J = 7.6, Н-7);
7.78–7.87 (3H, m, H-4–6); 7.91 (1H, s, H-5'(8')); 7.98 (1H,
s, H-8'(5')); 8.29 (1Н, d, J = 7.6, Н-8); 9.58 (1H, s, H-3');
10.73 (1Н, br. s, NН). 13C NMR spectrum (CF3CO2D), δ, ppm:
18.1; 18.5; 112.9; 117.8; 122.1; 126.0; 126.7; 127.5; 128.0;
129.6; 129.9; 130.2; 135.0; 136.6; 143.1; 143.2; 148.4;
151.1; 163.5. Mass spectrum (EI, 70 eV), m/z (Irel, %): 301
[M]+ (100). Found, %: C 75.56; H 5.10; N 14.19.
C19H15N3O. Calculated, %: C 75.73; H 5.02; N 13.94.
Synthesis of 1-chloro-3-hetarylisoquinolines 8a–g
(General method). A mixture of compound 7a–g (2.54 mmol)
and POCl3 (2.4 ml, 25.4 mmol, 10 equiv) was boiled with
stirring for 10 h. The reaction mixture was cooled to room
1025

Chemistry of Heterocyclic Compounds 2020, 56(8), 1021–1029
temperature, poured onto ice (15 g), and NaHCO3 was
8.34 (1H, s, H-4). 13C NMR spectrum (DMSO-d6), δ, ppm:
112.8; 114.3; 115.2; 120.6; 125.5; 126.2; 128.2; 129.0;
132.4; 138.8; 145.9; 146.3; 150.3; 150.4. Mass spectrum
(APCI), m/z (Irel, %): 286 [M+H]+ (100). Found, %:
C 58.60; H 2.97; Cl 12.25; N 14.92; S 10.98. C14H8ClN3S.
Calculated, %: C 58.85; H 2.82; Cl 12.41; N 14.71;
S 11.22.
2-(1-Chloroisoquinolin-3-yl)quinoxaline (8f). Yield
526 mg (71%), white solid, mp 203–204°C. 1H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 7.88–7.96 (3H, m,
H-7,6',7'); 7.98 (1H, t, J = 6.8, H-6); 8.17 (1H, d, J = 7.7,
H-5); 8.20 (1H, d, J = 7.1, H-8); 8.36 (2H, d, J = 8.1,
H-5',8'); 9.03 (1H, s, H-4); 9.84 (1H, s, H-3'). 13С NMR
spectrum (CF3CO2D), δ, ppm: 123.2; 125.3; 127.7; 129.4;
130.3; 130.6; 133.3; 135.6; 135.8; 136.3; 137.0; 138.0;
140.2; 140.3; 144.0; 144.3; 154.7. Mass spectrum (APCI), m/z
(Irel, %): 292 [M+H]+ (100). Found, %: C 69.87; H 3.36;
Cl 12.08; N 14.32. C17H10ClN3. Calculated, %: C 69.99;
H 3.46; Cl 12.15; N 14.40.
2-(1-Chloroisoquinolin-3-yl)-6,7-dimethylquinoxaline
(8g). Yield 601 mg (74%), yellow solid, mp 204–205°C.
1H NMR spectrum, δ, ppm (J, Hz): 2.50 (overlaps with
DMSO signal, 2CH3); 7.88–7.93 (2H, m, H-7,5'(8')); 7.93–
8.00 (2H, m, H-6,8'(5')); 8.32–8.38 (2H, m, H-5,8); 8.97
(1H, s, H-4); 9.73 (1H, s, H-3'). 13С NMR spectrum
(CF3CO2D), δ, ppm: 20.1; 20.7; 120.6; 124.7; 127.5; 129.3;
129.4; 130.4; 130.6; 132.9; 135.5; 135.8; 140.3; 140.6;
143.0; 144.4; 151.3; 154.4; 154.8. Mass spectrum (APCI),
m/z (Irel, %): 320 [M+H]+ (100). Found, %: C 71.41; H 4.49;
Cl 11.18; N 13.19. C19H14ClN3. Calculated, %: C 71.36;
H 4.41; Cl 11.09; N 13.14.
added to the neutral reaction medium. The aqueous
solution was extracted with EtOAc; the organic phase was
dried over Na2SO4, the solution was evaporated, and a
spectrally pure product was obtained.
1-Chloro-3-(2-methyl-1,3-thiazol-4-yl)isoquinoline (8a).
Yield 503 mg (76%), white solid, mp 139–140°C. 1H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 2.76 (3H, s, CH3);
7.78 (1Н, t, J = 7.6, Н-7); 7.87 (1Н, t, J = 7.6, Н-6); 8.10
(1Н, br. s, H-5'); 8.18 (1Н, d, J = 8.2, Н-5); 8.25 (1Н, d,
J = 8.4, Н-8); 8.46 (1Н, s, Н-4). 13С NMR spectrum
(DMSO-d6), δ, ppm: 19.5; 117.3; 118.5; 125.8; 126.2;
128.6; 129.6; 132.5; 138.8; 145.5; 150.7; 153.1; 167.1.
Mass spectrum (APCI), m/z (Irel, %): 261 [M+H]+ (100).
Found, %: C 59.62; H 3.36; Cl 13.44; N 10.53; S 12.06.
C13H9ClN2S. Calculated, %: C 59.88; H 3.48; Cl 13.60;
N 10.74; S 12.30.
1-Chloro-3-(2-phenyl-1,3-thiazol-4-yl)isoquinoline (8b).
Yield 580 mg (71%), white solid, mp 160–161°C. 1H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 7.50–7.58 (3H, m,
H-3''–5''); 7.80 (1Н, t, J = 7.2, Н-7); 7.88 (1Н, t, J = 7.2,
Н-6); 8.07 (2H, d, J = 6.1, H-2'',6''); 8.21 (1Н, d, J = 8.0,
Н-5); 8.27 (1Н, d, J = 8.0, Н-8); 8.32 (1Н, s, H-5'); 8.62
(1Н, s, Н-4). 13С NMR spectrum (DMSO-d6), δ, ppm:
117.6; 119.2; 125.9; 126.2; 126.8; 128.6; 129.7; 131.1;
132.6; 133.2; 138.7; 145.2; 150.8; 154.4; 168.3. Mass
spectrum (APCI), m/z (Irel, %): 323 [M+H]+ (100). Found, %:
C 67.12; H 3.25; Cl 10.78; N 8.74; S 10.06. C18H11ClN2S.
Calculated, %: C 66.97; H 3.43; Cl 10.98; N 8.68; S 9.93.
1-Chloro-3-[2-(thiophen-2-yl)-1,3-thiazol-4-yl]iso-
quinoline (8c). Yield 626 mg (75%), white solid, mp 181–
1
182°C. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
Synthesis of 3-hetaryl-1-(morpholin-4-yl)isoquinolines
9a–g and 3-hetaryl-1-(4-methylpiperazin-1-yl)isoquinolines
10a–g (General method). The corresponding amine
(morpholine or 1-methylpiperazine, 2.85 mmol, 1.5 equiv)
and K2CO3 (0.79 g, 5.7 mmol, 3 equiv) were added to a
solution of compound 8a–g (1.90 mmol) in DMF (5 ml),
and the resulting mixture was heated with stirring at 100°C
for 10 h. The reaction mixture was cooled to room tempe-
rature, filtered from inorganic residue, and the solvent was
evaporated. EtOAc (15 ml) was added to the residue, the
mixture was heated and filtered from the residue. The clear
solution was kept at –10°C until yellow crystals were
formed, which were filtered off, washed with cold EtOAc
to give a spectrally pure product. The filtrate after crystalli-
zation still contains a significant portion of the target
product, so the solvent was evaporated and the residue was
recrystallized from EtOAc (10 ml).
7.22 (1Н, dd, J = 4.7, J = 3.9, H-4''); 7.74–7.76 (3Н, m,
Н-7,3'',5''); 7.91 (1Н, t, J = 7.4, Н-6); 8.26 (1Н, d, J = 8.2,
Н-5); 8.28 (1Н, s, H-5'); 8.30 (1Н, d, J = 8.2, Н-8); 8.51
(1Н, s, Н-4). 13C NMR spectrum (DMSO-d6), δ, ppm:
117.4; 118.7; 126.0; 126.2; 128.4; 128.7; 129.0; 129.8
(2C); 132.6; 136.7; 138.7; 145.0; 150.8; 153.9; 162.3. Mass
spectrum (APCI), m/z (Irel, %): 329 [M+H]+ (100). Found, %:
C 58.34; H 2.88; Cl 10.77; N 8.37; S 19.30. C16H9ClN2S2.
Calculated, %: C 58.44; H 2.76; Cl 10.78; N 8.52; S 19.50.
1-Chloro-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]isoquinoline
(8d). Yield 542 mg (66%), light-brown solid, mp 217–218°C.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.80 (1Н, t,
J = 7.5, Н-7); 7.90 (1Н, t, J = 7.5, Н-6); 8.02 (2H, br. d, J = 4.2,
H-3'',5''); 8.21 (1Н, d, J = 7.8, Н-5); 8.28 (1Н, d, J = 7.8,
Н-8); 8.49 (1Н, s, Н-5'); 8.65 (1Н, s, Н-4); 8.75 (2H, br. d,
J = 4.2, H-2'',6''). 13C NMR spectrum (DMSO-d6), δ, ppm:
117.8; 120.6; 121.1; 126.1; 126.3; 128.7; 129.9; 132.7;
138.7; 139.8; 144.9; 150.9; 151.3; 155.0; 165.7. Mass
spectrum (APCI), m/z (Irel, %): 324 [M+H]+ (100). Found, %:
C 63.20; H 3.19; Cl 11.08; N 12.82; S 9.76. C17H10ClN3S.
Calculated, %: C 63.06; H 3.11; Cl 10.95; N 12.98; S 9.90.
1-Chloro-3-(imidazo[2,1-b][1,3]thiazol-6-yl)isoquinoline
(8e). Yield 566 mg (78%), white solid, mp 227–228°C.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.31 (1H,
d, J = 4.3, H-2'); 7.73 (1Н, t, J = 7.6, Н-7); 7.84 (1Н, t,
J = 7.6, Н-6); 7.93 (1H, d, J = 4.3, H-3'); 8.10 (1Н, d,
J = 8.2, Н-5); 8.22 (1Н, d, J = 8.4, Н-8); 8.32 (1H, s, H-5');
3-(2-Methyl-1,3-thiazol-4-yl)-1-(morpholin-4-yl)iso-
quinoline (9a). Yield 456 mg (77%), white solid, mp 165–
1
166°C. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
2.75 (3H, s, 2'-CH3); 3.40 (4H, br. t, J = 3.8, CH2NCH2);
3.89 (4H, br. t, J = 3.8, CH2OCH2); 7.57 (1H, t, J = 7.6,
H-7); 7.70 (1H, t, J = 7.6, H-6); 7.99 (1H, d, J = 8.1, H-5);
8.04 (2H, s, H-4,5'); 8.10 (1H, d, J = 8.4, H-8). 13C NMR
spectrum (DMSO-d6), δ, ppm: 19.5; 51.9; 66.7; 112.2;
117.0; 120.7; 125.8; 126.9; 128.4; 130.7; 139.0; 144.0;
155.1; 160.8; 166.4. Mass spectrum (APCI), m/z (Irel, %):
312 [M+H]+ (100). Found, %: C 65.66; H 5.57; N 13.39;
1026

Chemistry of Heterocyclic Compounds 2020, 56(8), 1021–1029
S 10.37. C17H17N3OS. Calculated, %: C 65.57; H 5.50;
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 3.49–3.55
(4H, m, CH2NCH2); 3.91–3.97 (4H, m, CH2OCH2); 7.69
(1H, t, J = 7.4, H-7); 7.79 (1H, t, J = 7.4, H-6); 7.84–7.94
(2H, m, H-6',7'); 8.12–8.22 (4H, m, H-5,8,5',8'); 8.60 (1H,
s, H-4); 9.96 (1H, s, H-3'). 13C NMR spectrum (DMSO-d6),
δ, ppm: 52.0; 66.7; 114.5; 121.6; 126.0; 128.3; 129.2;
129.5; 129.6; 130.6; 131.1; 131.2; 138.8; 141.8; 142.3;
144.5; 150.8; 160.8. Mass spectrum (APCI), m/z (Irel, %):
343 [M+H]+ (100). Found, %: C 73.41; H 5.46; N 16.49.
C21H18N4O. Calculated, %: C 73.67; H 5.30; N 16.36.
6,7-Dimethyl-2-[1-(morpholin-4-yl)isoquinolin-3-yl]-
quinoxaline (9g). Yield 422 mg (60%), yellow solid,
N 13.49; S 10.30.
1-(Morpholin-4-yl)-3-(2-phenyl-1,3-thiazol-4-yl)iso-
quinoline (9b). Yield 497 mg (70%), light-yellow solid,
1
mp 169–170°C. H NMR spectrum, δ, ppm (J, Hz): 3.37–
3.48 (4H, m, CH2NCH2); 3.85–3.94 (4H, m, CH2OCH2);
7.50–7.63 (4H, m, H-7,3''–5''); 7.72 (1Н, t, J = 7.3, Н-6);
8.03 (1Н, d, J = 8.0, Н-5); 8.08 (2H, d, J = 6.6, H-2'',6'');
8.12 (1Н, d, J = 8.2, Н-8); 8.20 (1H, s, H-4(5')); 8.27 (1H,
s, H-5'(4)). 13C NMR spectrum (DMSO-d6), δ, ppm: 51.9;
66.6; 112.4; 117.7; 120.8; 125.8; 126.7; 127.0; 128.4;
129.7; 130.7; 130.8; 133.5; 138.9; 143.7; 156.5; 160.7;
167.7. Mass spectrum (APCI), m/z (Irel, %): 374 [M+H]+
(100). Found, %: C 70.71; H 5.21; N 11.29; S 8.66.
C22H19N3OS. Calculated, %: C 70.75; H 5.13; N 11.25;
S 8.58.
1
mp 116–117°C. H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 2.50 (overlaps with DMSO signal, 2CH3); 3.50
(overlaps with H2O signal, CH2NCH2); 3.86–3.92 (4H, m,
CH2OCH2); 7.65 (1H, t, J = 7.6, H-7); 7.75 (1H, t, J = 7.6,
H-6); 7.88 (1H, s, H-5'(8')); 7.92 (1H, s, H-8'(5')); 8.12
(1Н, d, J = 8.2, H-5); 8.16 (1Н, d, J = 8.6, H-8); 8.52 (1H,
s, H-4); 9.83 (1H, s, H-3'). 13C NMR spectrum (CF3CO2D),
δ, ppm: 20.1; 20.6; 51.9; 66.5; 118.2; 120.4; 130.6; 121.5;
128.6; 129.5; 129.6; 131.4; 132.6; 132.9; 138.1; 139.6;
143.7; 144.7; 151.1; 154.1; 158.3. Mass spectrum (APCI),
m/z (Irel, %): 371 [M+H]+ (100). Found, %: C 74.63;
H 5.67; N 15.19. C23H22N4O. Calculated, %: C 74.57;
H 5.99; N 15.12.
1-(4-Methylpiperazin-1-yl)-3-(2-methyl-1,3-thiazol-4-yl)-
isoquinoline (10a). Yield 395 mg (64%), white solid,
mp 159–160°C. 1H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 2.30 (3Н, s, NCH3); 2.58–2.65 (4H, m, CH2N(CH3)
CH2); 2.75 (3H, s, 2'-CH3); 3.38–3.46 (4H, m, CH2NCH2);
7.56 (1H, t, J = 7.4, H-7); 7.68 (1H, t, J = 7.4, H-6); 7.97
(1H, d, J = 8.0, H-5); 8.01 (1H, s, H-4(5')); 8.02 (1H, s,
H-5'(4)); 8.04 (1H, d, J = 8.4, H-8). 13C NMR spectrum
(DMSO-d6), δ, ppm: 19.5; 46.4; 51.2; 55.2; 111.9; 117.0;
120.8; 125.8; 126.8; 128.4; 130.6; 139.0; 144.0; 155.3; 160.9;
166.4. Mass spectrum (APCI), m/z (Irel, %): 325 [M+H]+
(100). Found, %: C 66.70; H 6.27; N 17.36; S 9.98.
C18H20N4S. Calculated, %: C 66.64; H 6.21; N 17.27; S 9.88.
1-(4-Methylpiperazin-1-yl)-3-(2-phenyl-1,3-thiazol-4-yl)-
isoquinoline (10b). Yield 455 mg (62%), light-yellow
solid, mp 129–130°C. 1H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 2.50 (3Н, s, NCH3); 2.79–3.00 (4H, m,
CH2N(CH3)CH2); 3.45–3.57 (4Н, m, CH2NCH2); 7.49–
7.60 (4H, m, H-7,3''–5''); 7.70 (1Н, t, J = 7.5, H-6); 8.01
(1Н, d, J = 8.1, H-5); 8.03–8.08 (3H, m, H-8,2'',6''); 8.17
(1Н, s, Н-4); 8.25 (1Н, s, Н-5'). 13C NMR spectrum
(DMSO-d6), δ, ppm: 46.3; 51.2; 55.1; 112.0; 117.8; 120.9;
125.8; 126.7; 126.9; 128.4; 129.7; 130.7; 130.9; 133.5;
138.9; 143.7; 156.6; 160.9; 167.8. Mass spectrum (APCI),
m/z (Irel, %): 387 [M+H]+ (100). Found, %: C 71.41;
H 5.79; N 14.58; S 8.21. C23H22N4S. Calculated, %:
C 71.47; H 5.74; N 14.50; S 8.29.
1-(Morpholin-4-yl)-3-[2-(thiophen-2-yl)-1,3-thiazol-4-
yl]isoquinoline (9c). Yield 548 mg (76%), light-yellow
solid, mp 180–181°С. 1H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 3.43 (4H, br. t, J = 4.6, CH2NCH2); 3.90
(4Н, br. t, J = 4.6, CH2OCH2); 7.22 (1Н, dd, J = 5.0,
J = 3.5, H-4''); 7.60 (1Н, t, J = 7.6, H-7); 7.72 (1Н, t,
J = 7.6, H-6); 7.76 (1Н, d, J = 3.5, H-5''); 7.78 (1Н, d, J = 5.0,
H-3''); 8.02–8.10 (2Н, m, Н-4,5); 8.12 (1Н, d, J = 8.6, Н-8);
8.22 (1Н, s, Н-5'). 13C NMR spectrum (DMSO-d6), δ, ppm:
51.9; 66.7; 112.3; 117.4; 120.9; 125.9; 127.1; 128.1; 128.6;
129.0; 129.5; 130.8; 137.0; 138.9; 143.5; 155.9; 160.8;
161.7. Mass spectrum (APCI), m/z (Irel, %): 380 [M+H]+
(100). Found, %: C 63.37; H 4.59; N 11.15; S 16.97.
C20H17N3OS2. Calculated, %: C 63.30; H 4.52; N 11.07;
S 16.90.
1-(Morpholin-4-yl)-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-
isoquinoline (9d). Yield 533 mg (75%), light-brown solid,
1
mp 193–194°C. H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 3.39–3.48 (4H, m, CH2NCH2); 3.85–3.95 (4H, m,
CH2OCH2); 7.60 (1H, t, J = 7.0, H-7); 7.72 (1H, t, J = 7.0,
H-6); 7.96–8.06 (3H, m, H-5,3'',5''); 8.12 (1H, d, J = 8.0,
H-8); 8.20 (1H, s, H-4(5')); 8.41 (1H, s, H-5'(4)); 8.71–8.80
(2H, m, H-2'',6''). 13C NMR spectrum (DMSO-d6), δ, ppm:
51.9; 66.7; 112.6; 120.0; 120.6; 121.0; 125.9; 127.3; 128.6;
130.9; 139.0; 140.0; 143.4; 151.3; 157.1; 160.9; 165.3.
Mass spectrum (APCI), m/z (Irel, %): 375 [M+H]+ (100).
Found, %: C 67.51; H 4.84; N 15.05; S 8.43. C21H18N4OS.
Calculated, %: C 67.36; H 4.85; N 14.96; S 8.56.
3-(Imidazo[2,1-b][1,3]thiazol-6-yl)-1-(morpholin-4-yl)-
isoquinoline (9e). Yield 435 mg (68%), light-yellow solid,
1
mp 169–170°C. H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 3.45–3.52 (4H, m, CH2NCH2); 3.83–3.90 (4H, m,
CH2OCH2); 7.26 (1H, d, J = 2.6, H-2'); 7.50 (1H, t, J = 7.5,
H-7); 7.66 (1H, t, J = 7.5, H-6); 7.90 (1H, s, H-4); 7.91–
7.94 (2H, m, H-5,3'); 8.06 (1Н, d, J = 8.2, H-8); 8.26 (1H,
s, H-5'). 13C NMR spectrum (DMSO-d6), δ, ppm: 51.9;
66.6; 110.1; 112.2; 113.6; 120.4; 120.5; 125.7; 126.3;
128.0; 130.6; 139.0; 144.6; 147.8; 159.8; 160.6. Mass
spectrum, m/z (Irel, %): 337 [M+H]+ (100) Found, %:
C 64.41; H 4.86; N 16.51; S 9.62. C18H16N4OS. Calculated, %:
C 64.27; H 4.79; N 16.65; S 9.53.
1-(4-Methylpiperazin-1-yl)-3-[2-(thiophen-2-yl)-1,3-
thiazol-4-yl]isoquinoline (10c). Yield 522 mg (70%), yellow
solid, mp 118–119°C. 1H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 2.29 (3Н, s, NCH3); 2.54–2.66 (4H, m,
CH2N(CH3)CH2); 3.38–3.46 (4Н, m, CH2NCH2); 7.18 (1Н,
br. t, J = 4.5, H-4''); 7.56 (1Н, t, J = 7.6, H-7); 7.68 (1Н, t,
J = 7.6, H-6); 7.72 (1Н, br. s, H-5''); 7.75 (1Н, d, J = 4.3,
2-[1-(Morpholin-4-yl)isoquinolin-3-yl]quinoxaline (9f).
Yield 449 mg (69%), light-brown solid, mp 170–171°C.
1027

Chemistry of Heterocyclic Compounds 2020, 56(8), 1021–1029
H-3''); 8.00–8.06 (3Н, m, Н-4,5,8); 8.17 (1Н, s, Н-5').
19.4; 20.0; 43.9; 48.3; 53.5; 119.7; 120.9; 128.9; 129.1;
130.4; 130.9; 131.9; 132.9; 138.1; 139.3; 142.8; 144.1;
150.6; 153.8; 157.7; signals in the weak field overlap with
the solvent signals. Mass spectrum (APCI), m/z (Irel, %):
384 [M+H]+ (100). Found, %: C 75.11; H 6.52; N 18.32.
C24H25N5. Calculated, %: C 75.17; H 6.57; N 18.26.
13C NMR spectrum (DMSO-d6), δ, ppm: 46.2; 51.1 (2C);
55.0 (2C); 111.9; 117.6; 120.9; 125.8; 127.0; 128.1; 128.5;
128.9; 129.7; 130.7; 136.8; 138.8; 143.4; 155.8; 160.8;
161.7. Mass spectrum (APCI), m/z (Irel, %): 393 [M+H]+
(100). Found, %: C 64.19; H 5.19; N 14.34; S 16.39.
C21H20N4S2. Calculated, %: C 64.26; H 5.14; N 14.27;
S 16.33.
In vitro anticancer screening of the synthesized
compounds. The synthesized compounds were screened at
the National Cancer Institute (NCI), Bethesda, Maryland,
U.S.A., within the Developmental Therapeutic Program.26
The full NCI 60 cell panel engaged a total of 60 different
human tumor cell lines derived from nine cancer types. The
single-dose assay established the percentage of cancel cell
growth inhibition at 10 µM concentrations of studied
compounds. The five-dose multiple assay (0.01, 0.1, 1, 10,
and 100 µM) established the GI50 (growth inhibitory
activity, corresponds to the concentration of the compound
causing 50% decrease in net cell growth) parameters, TGI
value (cytostatic activity, corresponds to the concentration
of the compound resulting in total growth inhibition), and
LC50 value (cytotoxic activity – concentration of the
compound causing net 50% loss of initial cells).
1-(4-Methylpiperazin-1-yl)-3-[2-(pyridin-4-yl)-1,3-
thiazol-4-yl]isoquinoline (10d). Yield 596 mg (81%), light-
1
brown solid, mp 179–180°C. H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 2.29 (3Н, s, NCH3); 2.54–2.67 (4H, m,
CH2N(CH3)CH2); 3.38–3.49 (4H, m, CH2NCH2); 7.58 (1H,
t, J = 7.3, H-7); 7.71 (1H, t, J = 7.1, H-6); 7.94–8.03 (3H,
m, H-5,3'',5''); 8.06 (1H, d, J = 8.0, H-8); 8.16 (1H, s, H-4(5'));
8.38 (1H, s, H-5'(4)); 8.75 (2H, d, J = 4.2, H-2'',6'').
13C NMR spectrum (DMSO-d6), δ, ppm: 46.3; 51.2; 55.1;
112.2; 119.8; 120.5; 120.9; 125.8; 127.1; 128.4; 130.8;
138.9; 140.0; 143.4; 151.2; 157.1; 160.9; 165.1. Mass
spectrum (APCI), m/z (Irel, %): 388 [M+H]+ (100). Found,
%: C 68.26; H 5.53; N 18.15; S 8.34. C22H21N5S.
Calculated, %: C 68.19; H 5.46; N 18.07; S 8.27.
3-(Imidazo[2,1-b][1,3]thiazol-6-yl)-1-(4-methylpiperazin-
1-yl)isoquinoline (10e). Yield 485 mg (73%), light-yellow
solid, mp 171–172°C. 1H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 2.28 (3Н, s, NCH3); 2.56–2.64 (4H, m,
CH2N(CH3)CH2); 3.36–3.45 (4Н, m, CH2NCH2); 7.23–
7.27 (1H, m, H-2'); 7.50 (1H, t, J = 7.5, H-7); 7.64 (1H, t,
J = 7.5, H-6); 7.86 (1H, s, H-4); 7.89 (1Н, d, J = 8.0, H-5);
7.91–7.95 (1H, m, H-3'); 8.01 (1Н, d, J = 8.4, H-8); 8.24
(1H, s, H-5'). 13C NMR spectrum (DMSO-d6), δ, ppm:
46.4; 51.2; 55.2; 109.9; 112.2; 113.6; 120.5; 120.7; 125.8;
126.2; 128.0; 130.5; 139.0; 144.6; 147.9; 149.8; 160.8.
Mass spectrum (APCI), m/z (Irel, %): 350 [M+H]+ (100).
Found, %: C 65.37; H 5.41; N 20.11; S 9.12. C19H19N5S.
Calculated, %: C 65.30; H 5.48; N 20.04; S 9.17.
We would like to thank US Public Health Service and
National Cancer Institute, U.S.A., for in vitro evaluation of
anticancer activity (providing the NCI-60 cell testing)
within the framework of Developmental Therapeutic
Program and Enamine Ltd. for the material and technical
support.
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186°C. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
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default.htm
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