Synthesis, structure, and reactions of (4-aryl-3-cyano-6-oxopiperidin-2-ylidene)malononitriles

Article abstract of DOI:10.1007/s10593-016-1918-3

[Figure not available: see fulltext.] The reaction of aromatic aldehydes with Meldrum's acid and malononitrile dimer in the presence of triethylamine led to the formation of (4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)malononitrile triethylammonium salts, which were converted upon acidification to (4-aryl-3-cyano-6-oxopiperidin-2-ylidene)malononitriles. The reaction of these compounds with thioglycolic acid anilide was observed to produce derivatives of 1,6-naphthyridine or thieno[2,3-h][1,6]naphthyridine, depending on the conditions. Structures of (3-cyano-6-oxo-4-phenylpiperidin-2-ylidene)malononitrile and its triethylammonium salt were studied by X-ray structural analysis.

Full text of DOI:10.1007/s10593-016-1918-3

DOI 10.1007/s10593-016-1918-3
Chemistry of Heterocyclic Compounds 2016, 52(7), 473–483
Synthesis, structure, and reactions
of (4-aryl-3-cyano-6-oxopiperidin-2-ylidene)malononitriles
Victor V. Dotsenko1*, Arif I. Ismiev2, Anastasiya N. Khrustaleva1, Konstantin A. Frolov1,
Sergey G. Krivokolysko1, Elena A. Chigorina3, Aleksey P. Snizhko1, Vladimir M. Gromenko1,
Ivan S. Bushmarinov4, Rizvan K. Askerov2, Tatyana M. Pekhtereva5, Sergey Yu. Suykov6,
Elena S. Papayanina7, Aleksandr V. Mazepa8, Abel M. Magerramov2
5 L. M. Litvinenko Institute of Physico-Organic Chemistry and
1
Kuban State University,
Coal Chemistry, 70 R. Luxemburg St., Donetsk 83114, Ukraine;
149 Stavropol'skaya St., Krasnodar 350040, Russia;
е-mail: infou_nmr@bigmir.net
е-mail: victor_dotsenko@bigmir.net
6 Institute of Organic Chemistry, National Academy of Sciences
of Ukraine, 5 Murmanska St., Kyiv 02660, Ukraine;
e-mail: sergel@ua.fm
2 Baku State University,
23 Academic Zahid Khalilov St., AZ 1148 Baku, AZ-1073/1,
Azerbaijan;
е-mail: arif_ismiev@mail.ru
7 University of Erlangen-Nuremberg, Institute of Organic
Chemistry II, 42 Henkestr., Erlangen 91054, Germany;
е-mail: infou_nmr@bigmir.net
3 Federal State Unitary Enterprise "State Scientific Research
Institute of Chemical Reagents and High Purity Chemical
Substances" (FSUE "IREA"), 3 Bogorodsky Val, Moscow
107076, Russia;
8 A. V. Bogatsky Physico-Chemical Institute, National Academy
of Sciences of Ukraine, 86 Lustdorfskaya Rd., Odessa 65080,
Ukraine;
e-mail: echigorina@mail.ru
4 A. N. Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences, 28 Vavilova St., Moscow 119991
V-334, Russia;
е-mail: almazepa@rambler.ru
е-mail: ib@ineos.ac.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(7), 473–483
Submitted May 28, 2016
Accepted July 11, 2016
O
H2N
CN CN
CN CN
CN
ArCHO
+
O
NH
–
CONHPh
Ar
Ar
NH2
CN
O
S
CN
NH
NH
Me
Me
Ar
N
Et3NH+
O
O
CN CN
O
O
H2N
The reaction of aromatic aldehydes with Meldrum's acid and malononitrile dimer in the presence of triethylamine led to the formation of
(4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)malononitrile triethylammonium salts, which were converted upon acidification to
(4-aryl-3-cyano-6-oxopiperidin-2-ylidene)malononitriles. The reaction of these compounds with thioglycolic acid anilide was observed
to produce derivatives of 1,6-naphthyridine or thieno[2,3-h][1,6]naphthyridine, depending on the conditions. Structures of (3-cyano-
6-oxo-4-phenylpiperidin-2-ylidene)malononitrile and its triethylammonium salt were studied by X-ray structural analysis.
Keywords: 2-aminoprop-1-ene-1,1,3-tricarbonitrile, Meldrum's acid, 1,6-naphthyridines, thieno[2,3-h][1,6]naphthyridines, cascade
heterocyclization, X-ray structural analysis.
Due to the presence of three electrophilic reactive sites,
(3-cyanopyridin-2(1H)-ylidene)malononitrile derivatives 1
have gained recognition as convenient reagents for various
cascade transformations and are quite often used for the
synthesis of heterocyclic compounds,1–8 especially
derivatives of 1,6-naphthyridine 26,9–15 (Scheme 1).
(3-Cyanopyridin-2(1H)-ylidene)malononitriles 1 can be
easily synthesized16–28 by cyclocondensation of various
1,3-biselectrophilic reagents with 2-aminoprop-1-ene-1,1,3-
tricarbonitrile (3) (malononitrile dimer) (the chemistry of
2-aminoprop-1-ene-1,1,3-tricarbonitrile has been covered
in review articles29–31).
Previously, we developed an original method for the
preparation of functionalized 1,2,3,4-tetrahydropyridin-
2-ones 4, based on a multicomponent reaction of aldehydes
with Meldrum's acid and chalcogenamides with activated
methylene groups, followed by cyclization of Michael
adducts 5 (Scheme 2).32–43
0009-3122/16/52(7)-0473©2016 Springer Science+Business Media New York
473

Chemistry of Heterocyclic Compounds 2016, 52(7), 473–483
Scheme 1
resulted in isolation and characterization of intermediates,
the respective Michael adducts 8а–d.
The sequence of reagent addition played a substantial
role in successful outcome of these reactions. Thus, the
tricyanobutadiene 9, separately prepared by in situ
condensation of dimer 3 with anisaldehyde, also gave
pyridine 7c in reaction with Meldrum's acid, but the
product yield (29%) was significantly lower than in the
case of the aforementioned method with a preliminary step
of aldehyde condensation with Meldrum's acid (Scheme 4).
A possible reason for the observed differences was the lower
electrophilicity of dienes 9 in Michael addition reactions,
compared to arylmethylidene derivatives of Meldrum's acid.
Scheme 4
O
3
+
ArCHO
O
Me
Me
1) Et3N, EtOH
, 1.5–2 h
CN CN
CN
O
O
Et3N
Ar
7c
EtOH
40–50°C, 10 min
25°C, 48 h
NH2
9

2) HCl
Ar = 4-MeOC6H4
While continuing research in this direction, we decided
The structures of compounds 6a,b and 7a–d were
studied by IR spectroscopy, 1Н and 13С NMR spectroscopy,
to study the reactivity of malononitrile dimer 3 under these
conditions. It was established that the reaction sequence of
Meldrum's acid with aromatic aldehydes and 2-aminoprop-
1-ene-1,1,3-tricarbonitrile (3) in the presence of Et3N in
alcohol, followed by refluxing, led to the formation of salts
6a,b, or else, after acidification of the reaction mixture,
provided (4-aryl-3-cyano-6-oxopiperidin-2-ylidene)malo-
nonitriles 7с,d (Scheme 3). Salts 6a,b were quantitatively
converted upon acidification to pyridines 7a,b. In contrast
to the reactions with chalcogenamides of cyanoacetic acid,
none of the experiments with malononitrile dimer 3
mass spectrometry, HPLC-MS and elemental analysis, and
1
X-ray structural analysis. Н NMR spectra of salts 6a,b
contained characteristic proton signals of the АВХ system:
a pair of double doublets (or multiplets) of 5-СН2 group at
2.43–2.53 ppm (cis protons) and 2.88–2.96 ppm (trans
protons), as well as an unresolved double doublet of the
4-CH group at 3.69–4.04 ppm. The structure of compounds
6a,b was confirmed by X-ray structural analysis of
(3-cyano-6-oxo-4-phenyl-1,4,5,6-tetrahydro-pyridin-2-yl)-
malononitrile triethylammonium salt (6а) (Fig. 1).
Scheme 2
Scheme 3
CN CN
CN
–
Ar
CN
NH2
NC
Ar
ArCHO
NH
CN CN
CN
–CO2
–Me2CO
Et3NH+
Et3NH+
O
O
Et3N
Ar
CN
O
CN
CN
CN
HCl
+
O
EtOH, 
1–3 h
–O
6a,b
O
NH
EtOH
Me
Me
H2N
O
O
O
O
6c d
,
3
Me Me
7a–d
–CO2
–Me2CO
8a–d
a Ar = Ph, b Ar = 2-ClC6H4, c Ar = 4-MeOC6H4, d Ar = 3,4-(MeO) C6H4
2
474

Chemistry of Heterocyclic Compounds 2016, 52(7), 473–483
Figure 1. The molecular structure of salt 6а with atoms
represented by thermal vibration ellipsoids of 50% probability.
Figure 2. The molecular structure of (3-cyano-6-oxo-4-phenyl-
piperidin-2-ylidene)malononitrile 7а with atoms represented by
thermal vibration ellipsoids of 50% probability.
The structural features of compounds 7a,b were more
interesting. X-ray structural analysis data obtained for
monocrystal of compound 7а indicated a structure
corresponding to (3-cyanopiperidin-2-ylidene)malono-
nitrile in crystalline state (Fig. 2). Powder X-ray diffraction
analysis of compound 7а also confirmed that the main
product was the dicyanomethylidene tautomer. The main
peaks observed in the powder diffractogram agreed with
the monocrystal diffraction data. The Rietveld refinement
performed for the monocrystal structure of compound 7а
by using powder diffraction data showed that the sample
was monophasic, with the main phase content of 99 1%.
Scheme 5
1
At the same time, according to Н and 13С NMR data,
compounds 7 existed in solution phase as a mixture of
prototropic tautomers 7-А and 7-В (Scheme 5), while no
signals of the possible dicyanomethyl tautomer 7-С were
observed. It should be noted that compound 7а, previously
obtained12 by a reaction of 5-cyano-6-methoxy-3,4-
dihydropyridin-2(1Н)-one with malononitrile, has been
reported to exist exclusively in the form of tautomer 7-А
(Scheme 5). Besides the data of monocrystal X-ray
structural analysis and powder X-ray diffraction, the
structure of compounds 7a–d was confirmed by IR
spectroscopy, elemental analysis, HPLC-MS analysis, as
well as NMR dataset (APT and DEPT-135 13C, COSY,
NOESY, EXSY, 1H–13C HSQC, and 1H–13C HMBC).
In our case, the existence of compounds 7a–d in
solution phase as tautomers 7-А and 7-В was confirmed by
doubling of the characteristic pattern of proton signals,
pointing to the same spin system topology (Fig. 3), as well
as dynamic equilibrium between two forms, as established
by EXSY NMR experiment (Fig. 4, with matching phases
of diagonal peaks and cross peaks).
The ratio of lactam 7-А and lactim 7-В tautomers in the
mixtures varied from ~4:1 to ~2:1 and mainly depended on
the solvent and structure of compound 7. The tautomer
ratio could be determined from the integrated intensities of
1Н NMR signals, where the signals were assigned to
specific tautomers based on the analysis of NH and OH
proton signals. The spectrum of compound 7а (see the
Supplementary information file) contained two proton
signals in the interval of 8.81–9.07 ppm with combined
integral corresponding to ~1Н. According to 1H–13C HSQC
and EXSY NMR data, these signals belonged to
heteronuclear protons and were involved in a dynamic
equilibrium. The signal at 8.81 ppm was narrower,
probably belonging to amide NH proton of the main
tautomer 7а-А, while a very broad signal with a maximum
at 9.07 ppm was assigned to ОH proton of the minor
tautomer 7а-В. The assignment of NMR signals for
475

Chemistry of Heterocyclic Compounds 2016, 52(7), 473–483
Figure 4. Part of EXSY NMR spectrum of compound 7а, with
signals of protons at the С-3 atom shown. The antiphase
components are plotted with gray lines, main peaks and cross
peaks having a matching phase are plotted with black lines.
Figure 3. Part of 1Н–1Н COSY NMR spectrum of (3-cyano-6-oxo-
4-phenylpiperidin-2-ylidene)malononitrile (7а).
compound 7а was based on the analysis of NMR dataset
1
including APT and DEPT-135 13C, H–13C HSQC, and
1H–13C HMBC experiments (Fig. 5, Table 1).
An interesting NMR spectral feature of compounds
7c,d in DMSO-d6 solution was the altered character and
doubling of the number of aromatic proton signals, while
the integrated intensity of these signals still corresponded
to one set of Н Ar protons. The probable reason for this
was the rotation of aromatic substituent to various
conformations. The same samples in СCl4–DMSO-d6
solution gave the usual NMR spectral features.
Some properties of the obtained compounds were
studied, such as the reaction with thioglycolic acid anilide
(10) (Scheme 6). The reaction of (3-cyanopiperidin-2-yl-
idene)malononitriles 7a,c,d with anilide 10 in refluxing
alcohol in the presence of ~2.7 equiv of Et3N proceeded
through an attack by RS– anion at one of the nitrile groups
of the =C(CN)2 moiety. The initial cascade cyclization
products were 1,6-naphthyridines 11a,c,d, which under the
reaction conditions partially underwent intramolecular
Thorpe–Ziegler cyclization, forming the expected thieno-
[2,3-h][1,6]naphthyridines 12a,c,d.
Figure 5. 1Н–13С HMBC correlations for the tautomers of
compound 7a.
Table 1. The main 1H–13C HSQC and 1H–13C HMBC correlations
observed for tautomers of compound 7a
2D NMR correlations,
1Н NMR chemical shifts,
δ, ppm
1H–13C
HSQC
1H–13C
HMBC
δ, ppm
7а-А (major tautomer)
The extent of the cascade process and the ratio of
naphthyridines 11a,c,d and thienonaphthyridines 12a,c,d in
the mixture under these conditions obviously depended on
the structure of aryl substituent and the solubility of
products (Table 2).
Thieno[2,3-h][1,6]naphthyridines are a relatively new
type of polyheterocyclic compounds, with only a few
examples of synthesis reported.44–46 It should also be noted
that our proposed approach of using cascade reactions has
not been previously applied to the synthesis of analogous
thienoazines47–50 or sulfur-containing naphthyridine
derivatives.51–55
2.82 (dd, 5-СН(cis));
3.15 (dd, 5-СН(trans))
3.85–3.91 (m, 4-СН)
32.6
36.0 (C-4); 36.3 (C-3); 136.4
(C-1 Ph); 168.1 (C=O)
36.0 32.6 (C-5); 36.3 (C-3); 113.2 (CN);
127.4 (C Ph); 136.4 (C-1 Ph);
160.5 (C-2); 168.1 (C=O)
36.3 32.6 (C-5); 36.0 (C-4); 62.7
(C=C(CN)2); 113.2 (C≡N);
4.63 (d, 3-СН)
136.4 (C-1 Ph); 160.5 (C-2)
7а-B (minor tautomer)
2.88 (dd, 5-СН(cis));
3.04 (dd, 5-СН(trans))
3.85–3.91 (m, 4-СН)
35.0 35.3 (C-3); 38.7 (C-4); 137.2
(C-1 Ph); 167.7 (C-6)
38.7 35.0 (C-5); 35.3 (C-3); 114.7 (CN);
137.2 (C-1 Ph); 160.5 (С-2);
167.7 (C-6)
35.3 35.0 (C-5); 38.7 (C-4); 63.8
(C=C(CN)2); 114.7 (C≡N);
137.2 (C-1 Ph); 160.5 (C-2)
In order to optimize and increase the yield of the target
1,2,3,4-tetrahydrothieno[2,3-h][1,6]naphthyridines 12a–c,
various options of basic catalysis were examined. For
4.83 (d, 3-СН)
476

Chemistry of Heterocyclic Compounds 2016, 52(7), 473–483
Scheme 6
Table 2. The products of reactions between (3-cyanopiperidin-2-yl-
idene)malononitriles 7a,c,d and thioglycolic acid anilide 10
Experimental
IR spectra of compounds 6a,b, 7а were recorded on an
Infraspek FSM-1201 FT-IR spectrophotometer in KBr
pellets, the spectra of other compounds were recorded on
an IKS-29 spectrometer in Nujol. 1Н, 13С and APT 13C NMR
spectra of compounds 6a,b, 7a,c,d, 11d were acquired on a
Bruker DRX-500 instrument (500 and 125 MHz,
respectively) in DMSO-d6, with TMS as internal standard.
1Н, 13С, and DEPT-135 13C NMR spectra of compounds
Total
yield
Ratio of
Starting
material
Reaction
time, h
Ar
reaction products
11+12, % 11 : 12 (method)
Ph
4.5
5
68
~2:5 (1Н NMR,)
7a
7c
~1:4 (HPLC)
4-MeOC6H4
57
~5:2 (1Н NMR)
~2:1 (HPLC )
3,4-(MeO)2C6H3
4
64
>95:traces (1Н NMR)
7d
1
7a–c, 12a·HCl, 12a–c, as well as the NOESY, H–13C
100:0 (HPLC)
1
1
COSY, H–13C HSQC, and H–13C HMBC NMR experi-
ments for compound 7а were acquired on a Bruker Avance II
400 instrument (400 MHz for Н nuclei, 100 MHz for 13С
1
example, refluxing the trinitrile 7а with thioglycolic acid ani-
lide (10) in the presence of a large excess of Et3N (10 equiv),
followed by treatment with an excess of HCl gave thieno-
naphthyridine hydrochloride 12а in 58% yield (Scheme 7).
Substitution of the organic base with 10% aqueous KОН
solution gave good results, increasing the yields of thieno-
[2,3-h][1,6]naphthyridines 12а–с from trinitriles 7а,с or
from salt 6b to 75–84%. The mixtures of compounds 11а,с
and 12а,с described above were converted nearly
quantitatively to compounds 12a,c upon heating with KOH
in EtOH.
Thus, we have investigated the reaction of malononitrile
dimer with aromatic aldehydes and Meldrum's acid,
developed methods for the preparation of triethylammonium
salts of (4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridin-
2-yl)malononitriles and (4-aryl-3-cyano-6-oxopiperidin-
2-ylidene)malononitriles, performed detailed characteriza-
tion of product structure, including X-ray crystallography
studies. The obtained dicyanomethylidene derivatives
participated in a previously unreported cascade reaction
with thioglycolic acid anilide, leading to the formation of
relatively little known thieno[2,3-h][1,6]naphthyridine
derivatives.
nuclei) in DMSO-d6 (compounds 12а,с) or in ~1:2 СCl4–
DMSO-d6 (the rest of the compounds), with TMS as
internal standard. Signals of the major tautomer are
1
denoted with one asterisk (*) in Н and 13С NMR spectra,
while the signals of the minor tautomer are denoted with
two asterisks (**). Those 13С NMR signals observed in
antiphase are labeled in italics. Mass spectra were recorded
on an МХ1321 spectrometer by using a system for direct
introduction of samples at 200°С ionization chamber
temperature and EI ionization (70 eV). HPLC-MS analysis
was performed on an Agilent 1100 Series chromatograph
with diode matrix (215, 254, and 265 nm) and mass
selective (Aligent LC/MSD SL) detectors, ionization by
atmospheric pressure electrospray (ES-API). Elemental
analysis was performed on a Carlo-Erba 1106 Analyzer.
Melting points were determined on a Kofler bench and
were not corrected. Powder X-ray diffractogram of
compound 7а was recorded on
a
DRON-4-07
diffractometer. Purity of the obtained compounds was
controlled by TLC on Silufol UV-254 plates, eluent 1:1
acetone–hexane, visualization with iodine vapor or under
UV light.
2-Aminoprop-1-ene-1,1,3-tricarbonitrile (3) was obtained
by dimerization of malononitrile in the presence of KОН in
EtOH according to the procedure described by Mittelbach.56
2,2-Dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) was
obtained by a published procedure.57 Thioglycolic acid
anilide (10) is a commercially available reagent.
Scheme 7
Preparation of (4-aryl-3-cyano-6-oxo-1,4,5,6-tetra-
hydropyridin-2-yl)malononitrile triethylammonium salts
6а,b and (4-aryl-3-cyano-6-oxopiperidin-2-ylidene)-
malononitriles 7a–d (General method). A 250-ml round
bottom flask was charged with Meldrum's acid (6.0 g,
477

Chemistry of Heterocyclic Compounds 2016, 52(7), 473–483
41.6 mmol), EtOH (50 ml), aromatic aldehyde (42 mmol),
129.7 (C Ar); 132.3 (C Ar); 138.7 (C Ar); 151.6 (C-2);
168.4 (C=O). Mass spectrum (EI, 70 eV), m/z (Irel, %): 296
[М–Et3N]+ (17), 254 [М–Et3N–СН2СО]+ (21), 219 (14), 165
(65), 139 (13), 137 (12), 101 [Et3N]+ (32), 86 [Et3N–СН3]+
(100), 58 (37), 45 (16). Mass spectrum, m/z (ES-API): 102.2
[Et3NH+], 295.0, 297.0 [М–Et3NH]–. Found, %: C 63.34;
H 6.22; N 17.72. C21H24ClN5O. Calculated, %: C 63.39;
H 6.08; N 17.60.
and 6 drops of Et3N. The mixture was stirred until
complete dissolution of the starting reagents (5–10 min).
Precipitation of condensation product may occur during
this time. The mixture was treated with additional EtOH
(20 ml), malononitrile dimer 3 (5.5 g, 41.6 mmol), and
Et3N (8.7 ml, 62.4 mmol, 1.5 equiv). The obtained solution
was refluxed for 1–3 h, evaporated to a syrup consistency,
cooled, treated with acetone (20 ml) and EtOH (5 ml). In
the case of Ar = Ph and 2-ClC6H4, the crystalline
precipitate of salt 6а,b was filtered off after 48 h, washed
with cold acetone and petroleum ether. The filtrate
obtained after separation of the salt was vigorously stirred
and cooled while adding a mixture of alcohol and concd.
HCl to рН 2. The yellow precipitated product was filtered
off after 4 h, washed with EtOH and petroleum ether,
giving compounds 7а,b.
(3-Cyano-6-oxo-4-phenylpiperidin-2-ylidene)malono-
nitrile (7а). Yield 1.20 g (11%, when filtrate was acidified
after separation of salt 6а) or 4.97 g (46%, when salt 6а
was not isolated prior to acidification), yellow crystals, mp
212–214°С (MeOH) (mp 251–253°С12). IR spectrum, ν,
cm–1: 3420, 3216, 3137 (N–H), 2250, 2225, 2167 (С≡N),
1
1717 (C=O). H NMR spectrum (500 MHz, DMSO-d6), δ,
ppm (J, Hz) (~3:1 ratio of tautomers 7а-А and 7а-В): 2.83–
2
2.90 (1H, m, 5-CH(cis)); 3.04** (0.25Н, dd, J = 16.5,
In the rest of the cases the obtained acetone-alcohol
solution was treated by dropwise addition of an excess of
1:1 concd. HCl solution in EtOH to рН 2. The obtained
suspension was stirred for 3–4 h, the product was filtered
off, washed with EtOH and petroleum ether, giving
compounds 7с,d.
3J = 9.3, 5-CH(trans)); 3.19–3.25* (0.75Н, m (unresolved
dd), 5-CH(trans)); 3.91–3.93 (1Н, m, 4-CH); 4.79–4.81*
(0.75Н, m, 3-CH); 4.97** (0.25Н, d, 3J = 7.8, 3-CH); 7.19–
7.44 (5Н, m, H Ph); 8.81* (0.75Н, s, NH); 9.07** (0.25Н,
1
very br. s, ОH). H NMR spectrum (400 MHz, СCl4–
DMSO-d6), δ, ppm (J, Hz) (~4:1 ratio of tautomers 7а-А and
2
(3-Cyano-6-oxo-4-phenyl-1,4,5,6-tetrahydropyridin-
2-yl)malononitrile triethylammonium salt (6а). Yield
9.75 g (64%), pale-yellow crystals, mp 130–132°С. IR
spectrum, ν, cm–1: 3411, 3220, 3155 (N–H), 2187, 2165,
7а-В): 2.82* (0.8Н, br. dd, J = 17.1, 3J = 3.0, 5-CH(cis));
2
2.88** (0.2Н, dd, J = 17.1, 3J = 4.4, 5-CH(cis)); 3.04**
2
(0.2Н, br. dd, J = 17.1, 3J = 8.1, 5-CH(trans)); 3.15*
2
(0.8Н, br. dd, J = 17.1, 3J = 14.2, 5-CH(trans)); 3.85–3.91
1
2133 (С≡N), 1707 (C=O). H NMR spectrum (500 MHz,
(1Н, m, 4-CH); 4.63* (0.8Н, br. d, 3J = 4.0, 3-CH); 4.83**
(0.2Н, d, 3J = 7.1, 3-CH); 7.32–7.44 (5Н, m, H Ph). Signals
of protons bonded to heteroatoms were not observed due to
deuterium exchange. APT 13С NMR spectrum (125 MHz,
DMSO-d6), δ, ppm: 32.6 (C-5); 35.3 (CН); 35.7 (СН); 36.3
(СН); 68.0 (=C(CN)2); 111.1 (CN); 111.3 (CN); 112.9
(CN); 113.8 (CN); 120.9 (CN); 121.3 (CN); 126.8 (CH
Ph); 127.2 (CH Ph); 127.6 (CH Ph); 128.2 (CH Ph); 128.5
(CH Ph); 128.8 (CH Ph); 129.0 (CH Ph); 136.7 (С-1 Ph);
161.2 (C-2); 161.5 (C-2); 168.4 (C-6); 168.9 (C-6). 13С
NMR spectrum (100 MHz, CCl4–DMSO-d6), δ, ppm: 32.9*
(C-5); 35.0** (C-5); 35.3** (C-3); 36.0* (C-4); 36.3*
(C-3); 38.7** (C-4); 62.7* (=C(CN)2); 63.8** (=C(CN)2);
110.6* (=C(CN)2); 111.9** (=C(CN)2); 112.3* (=C(CN)2);
113.2* (3-CN); 114.7** (3-CN); 127.0** (C-2,6 Ph);
127.4* (C-2,6 Ph); 128.0** (C-4 Ph); 128.1* (C-4 Ph);
128.6* (C-3,5 Ph); 128.8** (C-3,5 Ph); 136.4* (С-1 Ph);
137.2** (C-1 Ph); 160.5* (С-2); 167.7** (C-6); 168.1*
(C-6). 13С NMR DEPT-135 spectrum (100 MHz, CCl4–
DMSO-d6), δ, ppm: 32.4; 34.6; 34.9; 35.6; 35.8; 38.2;
126.5; 127.0; 127.5; 127.6; 128.1; 128.3. Mass spectrum
(EI, 70 eV), m/z (Irel, %): 262 [М]+ (27), 220 [М–СН2С(О)]+
(67), 131 [PhCHСНС(О)]+ (100), 105 (33), 103 (35), 77
(22), 52 (15). Mass spectrum, m/z (ES-API): 261.0 [М–H]–.
Found, %: C 68.64; H 3.92; N 21.38. C15H10N4O.
Calculated, %: C 68.69; H 3.84; N 21.36.
3
DMSO-d6), δ, ppm (J, Hz): 1.16 (9H, t, J = 7.1,
N(СН2СН3)3); 2.49–2.53 (1Н, m, 5-CH(cis)) (partial
2
overlap with the DMSO signal); 2.88 (1Н, dd, J = 16.2,
3J = 6.9, 5-CH(trans)); 3.08 (6Н, q, J = 7.1, (СН2СН3)3);
3
3.69–3.71 (1Н, m (unresolved dd), 4-CH); 7.18–7.23 (3Н,
m, H Ph); 7.29–7.32 (2Н, m, H Ph); 8.81–8.82 (2H, m, NH,
NH+). APT 13C NMR spectrum (125 MHz, DMSO-d6), δ,
ppm (J, Hz): 8.6 (N(СН2СН3)3); 30.7 ((NC)2C–); 39.1
(C-5); 39.1 (C-4); 45.8 (N(СН2СН3)3); 68.0 (C-3); 120.9
(3-CN); 121.3 ((NC)2C–); 126.7 (C-3,4,5 Ph); 128.4 (C-2,6
Ph); 142.5 (C-1 Ph); 150.4 (C-2); 168.9 (C=O). Mass
spectrum, m/z (ES-API): 102.2 [Et3NH]+, 261.1 [М–Et3NH]–.
Found, %: C 69.20; H 7.07; N 19.32. C21H25N5O.
Calculated, %: C 69.40; H 6.93; N 19.27.
[4-(2-chlorophenyl)-3-cyano-6-oxo-1,4,5,6-tetrahydro-
pyridin-2-yl]malononitrile triethylammonium salt (6b).
Yield 12.10 g (73%), pale-yellow fine crystalline powder,
mp 184–186°С. IR spectrum, ν, cm–1: 3434, 3390, 3201,
3143 (N–H), 2190, 2165, 2144 (С≡N), 1711 (C=O).
1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz):
3
1.16 (9H, t, J = 7.1, N(СН2СН3)3); 2.43–2.49 (1Н, m,
5-CH(cis)) (partial overlap with the DMSO signal); 2.96
2
(1Н, dd, J = 16.2, 3J = 6.9, 5-CH(trans)); 3.08 (6Н, q,
3J = 7.1, N(СН2СН3)33); 4.02–4.04 (1Н, m (unresolved dd),
4-CH); 7.18 (1Н, d, J = 7.1, H Ar); 7.27–7.30 (1Н, m,
3
H Ar); 7.33–7.36 (1Н, m, H Ar); 7.45 (1Н, d, J = 7.7,
[4-(2-Chlorophenyl)-3-cyano-6-oxopiperidin-2-ylidene]-
malononitrile (7b). Yield 0.70 g (6%, when filtrate was
acidified after separation of salt 6b) or 8.65 g (70%, when
salt 6b was not isolated prior to acidification), pale-yellow
powder, mp 284–286°С (EtOH). IR spectrum, ν, cm–1:
3447, 3228 (N–H), 2265, 2235 (С≡N), 1722 (C=O).
H Ar); 8.83 (1H, very br. s, NH+); 9.00 (1Н, s, NH). APT
13C NMR spectrum (125 MHz, DMSO-d6), δ, ppm (J, Hz):
8.6 (N(СН2СН3)3); 31.2 ((NC)2C–); 36.7 (C-4); 37.6 (C-5);
47.8 (N(СН2СН3)3); 66.1 (C-3); 120.5 (3-CN); 121.1
((N≡C)2C–); 127.5 (C Ar); 128.1 (C Ar); 128.8 (C Ar);
478

Chemistry of Heterocyclic Compounds 2016, 52(7), 473–483
1H NMR spectrum (400 MHz, СCl4–DMSO-d6), δ, ppm
114.8** (CN); 128.0** (C-2,6 Ar); 128.1* (C-1 Ar);
128.5* (C-2,6 Ar); 128.8** (C-1 Ar); 158.9** (C-4 Ar);
159.0* (C-4 Ar); 160.6* (C-2); 167.8** (C-6); 168.2*
(C-6). 13С NMR DEPT-135 spectrum (100 MHz, CCl4–
DMSO-d6), δ, ppm: 32.6* (C-5); 34.8** (C-5); 34.9* (C-3);
35.1** (C-3); 36.1* (C-4); 37.5** (C-4); 54.4* (OCH3);
113.5* (C-3,5 Ar); 113.7** (C-3,5 Ar); 127.7* (C-2,6 Ar);
128.1** (C-2,6 Ar). Mass spectrum, m/z (ES-API): 293.2
[M+H]+, 310.2 [M+NH3]+, 315.0 [M+Na]+, 291.2 [М–H]–.
Found, %: C 65.63; H 4.28; N 19.22. C16H12N4O2.
Calculated, %: C 65.75; H 4.14; N 19.17.
(J, Hz) (~4:1 ratio of tautomers 7b-А and 7b-В): 2.80*
2
(0.8Н, br. d (unresolved dd), J = 15.3, 5-CH(cis)); 2.96**
2
(0.2Н, dd, J = 14.4, 3J = 4.5, 5-CH(cis)); 3.32* (0.8Н,
2
pseudo t (unresolved dd), J = 15.3, 5-CH(trans)); 3.44**
2
(0.2Н, br. dd, J = 14.4, 3J = 7.3, 5-CH(trans)); 4.21–4.24
(1Н, m, 4-CH); 4.50* (0.8Н, m, 3-CH); 4.94** (0.2Н, d,
3J = 7.6, 3-CH); 7.21–7.49 (4Н, m, H Ar); 8.36* (0.6Н,
br. s, NH). The NH proton signal had lower intensity due to
partial deuterium exchange, the ОН proton signal was not
observed. 13С NMR spectrum (100 MHz, CCl4–DMSO-d6),
δ, ppm: 32.6* (C-5); 33.7* (C-3); 34.2* (C-4); 35.0**
(C-5); 36.2** (C-3); 36.9** (C-4); 62.9* (=C(CN)2); 65.6*
(=C(CN)2); 110.4* (CN); 110.9** (CN); 111.9** (CN);
112.2* (CN); 112.7* (CN); 112.8** (CN); 127.6* (C Ar);
127.9** (C Ar); 128.2** (C Ar); 128.4* (C Ar); 129.1**
(C Ar); 129.6** (C Ar); 129.7* (C Ar); 129.9* (C Ar);
132.6** (C Ar); 133.2* (C Ar); 133.4* (C Ar); 134.8**
(C Ar); 159.6* (C-2); 160.6** (C-2); 167.5** (C-6);
167.9* (C-6). 13С NMR DEPT-135 spectrum (100 MHz,
CCl4–DMSO-d6), δ, ppm: 32.0; 33.2; 33.7; 35.0; 35.7;
36.5; 126.9; 127.2; 127.4; 127.9; 128.9; 129.1; 129.2;
129.4. Mass spectrum (EI, 70 eV), m/z (Irel, %): 296 [М]+
(21), 254 [М–СН2СО]+ (36), 219 (24), 165 [ArCHСНСО]+
(100), 139 [ArCHСН2]+ (18), 103 (17), 101 (15), 77 (11),
52 (11). Found, %: C 60.54; H 3.18; N 18.78. C15H9ClN4O.
Calculated, %: C 60.72; H 3.06; N 18.88.
[3-Cyano-4-(3,4-dimethoxyphenyl)-6-oxopiperidin-
2-ylidene]malononitrile (7d). Yield 11.82 g (88%), pale-
yellow fine crystalline powder, mp 238–240°С (acetone).
IR spectrum, ν, cm–1: 3451, 3208 (N–H), 2265, 2218
(С≡N), 1722 (C=O). 1H NMR spectrum (500 MHz,
DMSO-d6), δ, ppm (J, Hz) (~2:1 ratio of tautomers 7d-А
and 7d-В): 2.78–2.83 (1H, m, 5-CH(cis)); 3.02–3.09**
(0.33Н, m, 5-CH(trans)); 3.19–3.25* (0.66Н, m, 5-CH
(trans)); 3.63–3.83 (7Н, m, 4-CH, 2OCH3); 4.77–4.78*
3
(0.66Н, m, 3-CH); 4.97** (0.33Н, d, J = 6.6, 3-CH); 6.66
3
(0.5Н, d, J = 7.7, H Ar); 6.80 (0.5Н, br. s, H Ar); 6.86
3
(0.5Н, d, J = 7.7, H Ar); 6.94–7.01 (1Н, m, H Ar); 7.06
(0.5Н, br. s, H Ar); 8.82* (0.5Н, br. s, NH); 12.29** (0.2Н,
very br. s, OH). Signals of protons bonded to heteroatoms
were not observed due to deuterium exchange. APT
13С NMR spectrum (125 MHz, DMSO-d6), δ, ppm: 32.9*
(C-5); 35.3** (C-5); 35.5* (C-3); 36.5* (C-4); 38.4**
(C-3); 38.8** (C-4); 55.54* (OCH3); 55.57* (OCH3);
55.62** (OCH3); 55.63** (OCH3); 61.88* (=C(CN)2);
61.92** (=C(CN)2); 111.2* (CN); 111.4** (CH Ar);
111.8* (CH Ar); 112.2** (CN); 113.0* (CN); 113.9* (CN);
114.0** (CN); 118.6** (CH Ar); 119.2** (CH Ar); 119.5*
(CH Ar); 120.7* (CH Ar); 129.0* (C-1 Ar); 129.6** (C-1
Ar); 148.3** (C Ar); 148.7* (C Ar); 149.7* (C Ar); 150.3*
(C Ar); 161.3* (C-2); 168.6** (C-6); 169.1* (C-6). Mass
spectrum, m/z (ES-API): 340.2 [M+NH4]+, 321.2 [М–H]–.
Found, %: C 63.30; H 4.51; N 17.32. C17H14N4O3.
Calculated, %: C 63.35; H 4.38; N 17.38.
[3-Cyano-4-(4-methoxyphenyl)-6-oxopiperidin-2-ylidene]-
malononitrile (7с). Yield 10.26 g (84%), pale-yellow fine
crystalline powder, mp 246–248°С (acetone). IR spectrum,
ν, cm–1: 3375, 3222 (N–H), 2265, 2229 (С≡N), 1730
1
(C=O). H NMR spectrum (500 MHz, DMSO-d6), δ, ppm
(J, Hz) (~3:1 ratio of tautomers 7с-А and 7с-В): 2.79–2.82
2
(1H, m, 5-CH(cis)); 3.00** (0.25Н, dd, J = 16.5, 3J = 8.8,
5-CH(trans)); 3.15–3.21* (0.75Н, m (unresolved dd), 5-CH
(trans)); 3.64–3.85 (4Н, m, 4-CH, ОСН3); 4.72–4.75*
(0.75Н, m, 3-СН); 4.90** (0.25Н, d, 3J = 7.7, 3-СН); 6.86*
3
(0.75Н, d, J = 7.1, H Ar); 6.95–7.00 (1.25Н, m, H Ar);
7.09* (0.75Н, d, 3J = 7.1, H Ar); 7.28** (0.25Н, d, 3J = 6.6,
H Ar); 7.50–7.40 (1Н, m, H Ar); 8.77* (0.50Н, br. s, NH).
The NH proton signal had lower intensity due to partial
deuterium exchange, the ОН proton signal was not
Reaction
of
2-amino-4-(4-methoxyphenyl)buta-
1,3-diene-1,1,3-tricarbonitrile (9) with Meldrum's acid.
A mixture of malononitrile dimer 3 (1.00 g, 7.57 mmol),
anisaldehyde (0.92 ml, 7.57 mmol), and EtOH (15 ml) was
treated with Et3N (0.20 ml, 1.44 mmol) and heated at 40–
50°С until homogeneous. The obtained solution was stirred
at this temperature for 10 min and left for 48 h at 25°С.
The obtained suspension, containing yellow crystalline
precipitate of butadiene 9, was treated with Meldrum's acid
(1.15 g, 8.00 mmol) and Et3N (1.40 ml, 10.00 mmol). The
obtained solution was refluxed for 1.5–2 h, cooled, and
treated with an excess of 1:1 concd. HCl in EtOH to рН 2.
The obtained suspension was stirred for 3–4 h, the yellow
product was filtered off, washed with EtOH and petroleum
ether, and recrystallized from a 1:1 mixture of MeOH–
Me2CO, giving compound 7с. Yield 0.70 g (29%), creme-
colored fine crystalline powder. The spectral characteristics
of the product were identical to those given above.
1
observed. H NMR spectrum (400 MHz, СCl4–DMSO-d6),
δ, ppm (J, Hz) (~4:1 ratio of tautomers 7с-А and 7с-В):
2
2.77* (0.8Н, br. d, J = 16.6, 5-CH(cis)); 2.85** (0.2Н, dd,
2J = 17.2, 3J = 4.1, 5-CH(cis)); 3.01** (0.2Н, br. dd,
2J = 17.2, 3J = 8.1, 5-CH(trans)); 3.08–3.16* (0.8Н, m
(unresolved dd), 5-CH(trans)); 3.77** (0.6Н, s, OCH3);
3.78* (2.4Н, s, OCH3); 3.82–3.84 (1Н, m, 4-CH); 4.57–
3
4.59* (0.8Н, m, 3-CH); 4.79** (0.2Н, d, J = 7.1, 3-CH);
6.88–6.92 (2H, m, H Ar); 7.25** (0.4Н, d, 3J = 8.1, H Ar);
3
7.33* (1.6Н, d, J = 8.1, H Ar); 12.26 (0.6Н, very br. s,
OH, NH). Signals of protons bonded to heteroatoms were
not observed due to deuterium exchange. 13С NMR
spectrum (100 MHz, CCl4–DMSO-d6), δ, ppm: 33.0*
(C-5); 35.1** (C-5); 35.3* (C-3); 35.5** (C-3); 36.5*
(C-4); 37.9** (C-4); 54.8* (MeO); 62.4* (=C(CN)2);
110.5* (CN); 111.9** (CN); 112.4* (CN); 113.2* (CN);
113.8* (C-3,5 Ar); 114.0** (C-3,5 Ar); 114.6** (CN);
Reactions of (3-cyanopiperidin-2-ylidene)malono-
nitriles 7a,c,d with thioglycolic acid anilide (10) in the
479

Chemistry of Heterocyclic Compounds 2016, 52(7), 473–483
presence of Et3N. A mixture of trinitrile 7a,c,d (2.70 mmol)
and thioglycolic acid anilide 10 (320 mg, 1.91 mmol) in
96% EtOH (10 ml) was treated with an excess of Et3N (2.6 ml,
19 mmol). The obtained yellow solution was stirred and
refluxed. Precipitation of a crystalline product started after
approximately 1 h. The mixture was refluxed for 3 h,
cooled, and treated with an excess of concd. HCl to рН 2.
The reaction mixture was maintained for 8 h, the
precipitated product was filtered off, washed with cold
acetone, and dried. Yield 515 mg (58%), pinkish-colored
powder, decomp. temp. >300°С. The product gave positive
tests for chloride ion (Beilstein test, AgNO3), while the
mass spectral signals at m/z 36–38 were characteristic of
hydrochlorides. IR spectrum, ν, cm–1: 3345 (N–H), 1695 sh.,
1682 (C=O). 1H NMR spectrum (400 MHz, ССl4–DMSO-d6),
and anilide 10 (0.68 g, 4.05 mmol, 1.5 equiv) in 96% EtOH
(10–12 ml) was treated with Et3N (1.0 ml, 7.20 mmol). The
obtained solution was stirred and refluxed for the duration
indicated in Table 2. Rapid precipitation started after 1.5–
2.5 h, the mixture was cooled, the precipitate was filtered
off after 2–3 h, washed with EtOH and petroleum ether.
The product was naphthyridine 11d, or mixtures of
naphthyridines and thienonaphthyridines 11а+12а and
11с+12с. The product yields and ratios are indicated in
Table 2. Mixtures of compounds 11 and 12 are separable
by silica gel column chromatography, eluting with acetone.
2-[(5-Amino-8-cyano-2-oxo-4-phenyl-1,2,3,4-tetrahydro-
1,6-naphthyridin-7-yl)sulfanyl]-N-phenylacetamide (11а)
and 5,9-diamino-2-oxo-N,4-diphenyl-1,2,3,4-tetrahydro-
thieno[2,3-h][1,6]naphthyridine-8-carboxamide (12а).
Total yield 0.78 g (68%), pale-yellow fine crystalline
powder. Ratio of 11а:12а ~2:5 (1Н NMR) or ~1:4 (HPLC).
1Н, APT 13С NMR and HPLC-MS data for the mixture are
provided in the Supplementary information file.
2
δ, ppm (J, Hz): 2.75 (1H, br. d (unresolved dd), J = 15.7,
2
3-СН(cis)); 3.19 (1Н, dd, J = 15.7, 3J = 6.3, 3-СН(trans));
4.53–4.54 (1H, m, 4-СН); 7.05–7.08 (1Н, m, H Ph); 7.18–
7.31 (7Н, m, H Ph); 7.66 (2H, d, 3J = 7.6, H Ph); 9.53 (1H,
br. s, NH); 9.92 (1H, very br. s, NH). The signals of
protonated 5-NH2 and 9-NH2 amino groups were identified
as a very broad signal at 7.00–7.70 ppm. 13С NMR
spectrum (100 MHz, CCl4–DMSO-d6), δ, ppm: 33.8 (C-3);
37.5 (C-4); 97.8 (C-4a); 100.6 (C Ar); 108.8 (C Ar); 120.7
(С Ph); 122.8 (С Ph); 126.7 (С Ph); 126.9 (С Ph); 127.7
(С Ph); 128.3 (С Ph); 138.7 (С-1 Ph); 138.9 (С-1 Ph);
145.6 (С Ar); 147.2 (С Ar); 147.7 (С Ar); 152.9 (С Ar);
162.7 (CONH); 168.0 (CONH). 13С NMR DEPT-135
spectrum (100 MHz, CCl4–DMSO-d6), δ, ppm: 33.9 (C-3);
37.6 (C-4); 120.9 (СH Ph); 123.2 (СH Ph); 126.8 (СH Ph);
126.9 (СH Ph); 128.1 (СH Ph); 128.4 (СH Ph). Mass
spectrum (EI, 70 eV), m/z (Irel, %): 429 [М–HCl]+ (9), 336
[М–HCl–PhNH2]+ (15), 220 (8), 131 (11), 93 (22), 77 [Ph]+
(9), 56 (14), 39 (39), 38 (58), 37 [HCl]+ (100), 36 (38).
Found, %: C 59.42; H 4.54; N 15.09. C23H19N5O2S·HCl.
Calculated, %: C 59.29; H 4.33; N 15.03.
2-{[5-Amino-8-cyano-4-(4-methoxyphenyl)-2-oxo-
1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl]sulfanyl}-N-phe-
nylacetamide (11с) and 5,9-diamino-4-(4-methoxy-
phenyl)-2-oxo-N-phenyl-1,2,3,4-tetrahydrothieno[2,3-h]-
[1,6]naphthyridine-8-carboxamide (12с). Total yield
0.72 g (57%), pale-yellow fine crystalline powder. Ratio of
1
11с:12с was ~5:2 (1Н NMR) or ~2:1 (HPLC). Н NMR,
APT 13С NMR spectra, and HPLC-MS analysis data for the
mixture are provided in the Supplementary information
file.
2-{[5-Amino-8-cyano-4-(3,4-dimethoxyphenyl)-2-oxo-
1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl]sulfanyl}-N-phe-
nylacetamide (11d). Yield 839 mg (64%), beige fine
crystalline powder, readily soluble in acetone. The purity
according to HPLC-MS data was ~100%. The product
contained ~5% impurity of the isomeric thieno-
Reaction of compounds 6b and 7a,c with thioglycolic
acid anilide (10) in the presence of KOH. A mixture of
trinitrile 7a,c (1.90 mmol) or salt 6b (500 mg, 1.26 mmol)
and an equimolar amount of anilide 10 in 96% EtOH (10 ml)
was treated with an excess of 10% aqueous KOH solution
(1.0 ml, 1.95 mmol, ~1.5 equiv). The obtained yellow
solution was stirred and refluxed for 3–5 h, possibly
accompanied by the formation of precipitate. The mixture
was treated with excess of АсОН, maintained for 24 h, the
precipitate was filtered off and washed with EtOH. The
reaction products were purified by refluxing with АсОН,
cooled, the precipitate was filtered off and and dried at
100°С. Thienonaphthyridines 12а–с were obtained as beige
or yellow powders.
1
1
naphthyridine 12d according to H NMR data. H NMR
spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz): 2.61 (1H,
2
br. d (unresolved dd), J = 15.9, 3-СН(cis)); 3.04 (1Н, dd,
2J = 15.9, 3J = 6.6, 3-СН(trans)); 3.67 (3Н, s, OCH3); 3.69
2
(3H, s, OCH3); 4.05 (2H, АВ system, J = 14.3, SCH2);
3
4.19–4.20 (1H, m, 4-СН); 6.45 (1Н, d, J = 7.7, H Ar);
3
6.79 (1Н, d, J = 7.7, H Ar); 6.83 (1H, s, H Ar); 6.92 (2H,
br. s, NH2); 7.02–7.06 (1H, m, H Ph); 7.27–7.30 (2H, m,
H Ph); 7.55 (2H, d, 3J = 7.1, H Ph); 10.04 (1H, br. s, NH);
10.20 (1H, br. s, NH). APT 13С NMR spectrum (125 MHz,
DMSO-d6), δ, ppm: 33.9 (C-3); 34.1 (C-4); 38.5 (SCH2);
55.4 (OCH3); 55.5 (OCH3); 82.0 (C-8); 98.9 (C-4a); 111.5
(CH Ar); 111.8 (CH Ar); 114.8 (CN); 118.0 (CH Ar);
119.2 (C-2,6 Ph); 123.5 (C-4 Ph); 128.7 (C-3,5 Ph); 132.7
(C-Ar); 138.8 (C-1 Ph); 147.7 (C–OMe); 147.9 (C–OMe);
148.8 (C-8a); 157.7 (C-5(7)); 160.0 (С-7(5)); 166.5
(СONH); 169.3 (CONH). Mass spectrum (ES-API), m/z:
490.2 [M+H]+, 488.0 [М–H]–. Found, %: C 61.28; H 4.84;
N 14.29. C25H23N5O4S. Calculated, %: C 61.34; H 4.74;
N 14.31.
5,9-Diamino-2-oxo-N,4-diphenyl-1,2,3,4-tetrahydro-
thieno[2,3-h][1,6]naphthyridine-8-carboxamide (12а).
Yield 610 mg (75%), beige powder, decomp. temp. >300°С.
IR spectrum, ν, cm–1: 3311, 3151 (N–H), 1695 (C=O).
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz):
2.76 (1H, br. d (unresolved dd), 2J = 15.7, 3-СН(cis)); 3.21
2
(1Н, dd, J = 15.7, 3J = 6.7, 3-СН(trans)); 4.60–4.61 (1H,
5,9-Diamino-2-oxo-N,4-diphenyl-1,2,3,4-tetrahydro-
thieno[2,3-h][1,6]naphthyridine-8-carboxamide hydrochlo-
ride (12а·HCl). A mixture of trinitrile 7а (500 mg, 1.90 mmol)
m, 4-СН); 7.04–7.08 (1Н, m, H Ph); 7.20–7.32 (7Н, m,
3
H Ph); 7.68 (2H, d, J = 8.1, H Ph); 9.64 (1H, br. s, NH);
10.01 (1H, very br. s, NH). The signals of 5-NH2 and
480

Chemistry of Heterocyclic Compounds 2016, 52(7), 473–483
9-NH2 amino groups were observed as a very broad peak at
(OСН3); 113.8 (СH Ar); 121.0 (СH Ph); 123.4 (СH Ph);
127.9 (СH Ar); 128.2 (СH Ph). Mass spectrum (EI, 70 eV),
m/z (Irel, %): 459 [М]+ (48), 367 [М–PhNH]+ (100), 340
(10), 161 (12), 119 (12), 93 [PhNH2]+ (30). Found, %:
C 62.51; H 4.78; N 15.20. C24H21N5O3S. Calculated, %:
C 62.73; H 4.61; N 15.24.
7.20–8.70 ppm. 13С NMR spectrum (100 MHz, DMSO-d6),
δ, ppm: 34.0 (C-3); 37.8 (C-4); 97.0 (C-4a); 101.3 (C-Ar);
108.7 (C-Ar); 120.2 (С Ph); 123.5 (С Ph); 127.1 (С Ph);
127.2 (С Ph); 128.4 (С Ph); 128.7 (С Ph); 138.8 (С-1 Ph);
139.3 (С-1 Ph); 145.2 (С Ar); 148.1 (С Ar); 150.1 (С Ar);
153.9 (С Ar); 163.4 (CONH); 169.0 (CONH). 13С NMR
DEPT-135 spectrum (100 MHz, DMSO-d6), δ, ppm: 33.8
(C-4); 37.5 (C-3); 121.0 (СH Ph); 123.2 (СH Ph); 126.8
(СH Ph); 127.0 (СH Ph); 128.1 (СH Ph); 128.4 (СH Ph).
Found, %: C 64.08; H 4.59; N 16.10. C23H19N5O2S.
Calculated, %: C 64.32; H 4.46; N 16.31.
X-ray structural analysis of compounds 6а and 7a.
Crystals of compound 6а (C21H25N5O, M 363.46) were
monoclinic, space group P21/n; at T 296 K: a 15.4817(5),
b 8.1208(3), c 16.1815(5) Å; β 3.7160(10)°; V 2030.12(12) Å3;
Z 4; dcalc 1.189 g/cm3; F(000) 776; μ 0.076 mm–1. The unit
cell parameters and intensities of 20804 reflections (4443
independent reflections, Rint 0.0211) were measured on a
Bruker APEX II CCD automated three-circle
diffractometer (λMoKα radiation, graphite monochro-
mator, ω- and φ-scanning, 2θmax 54°). The structure was
solved by direct methods and refined with full matrix
method of least squares by F2 in anisotropic approximation
for non-hydrogen atoms. The position of Н atom involved
in hydrogen bonding was found from differential synthesis
of electron density and refined in isotropic approximation.
The coordinates of other hydrogen atoms were calculated
geometrically and refined according to the "rider" model.
The final probability factors were R1 0.0737 for 3458
independent reflections with I > 2σ(I) and wR2 0.2224 for
all independent reflections. All calculations were
performed by using the SHELXTL software suite.58 The
complete crystallographic dataset for compound 6a was
deposited at the Cambridge Crystallographic Data Center
(deposit CCDC 978371).
Crystals of compound 7а (C15H10N4O, M 262.27) were
monoclinic, space group P21/c; at T 296 K: a 11.2643(5),
b 16.6323(7), c 6.9332(3) Å; β 96.9710(10)°; V 1289.34(10) Å3;
Z 4; dcalc 1.351 g/cm3; F(000) 544; μ 0.090 mm–1. The unit
cell parameters and intensities of 14501 reflections (3112
independent reflections, Rint 0.0200) were measured on a
Bruker APEX II CCD automated three-circle
diffractometer (λMoKα radiation, graphite monochromator,
ω- and φ-scanning, 2θmax 56°). The structure was solved by
direct methods and refined with full matrix method of least
squares by F2 in anisotropic approximation for non-
hydrogen atoms. The position of Н atom involved in
hydrogen bonding was found from differential synthesis of
electron density and refined in isotropic approximation.
The coordinates of other hydrogen atoms were calculated
geometrically and refined according to the "rider" model.
The final probability factors were R1 0.0438 for 2544
independent reflections with I > 2σ(I) and wR2 0.1182 for
all independent reflections. All calculations were
performed by using the SHELXTL software suite.58 The
complete crystallographic dataset for compound 7a was
deposited at the Cambridge Crystallographic Data Center
(deposit CCDC 978217).
5,9-Diamino-4-(2-chlorophenyl)-2-oxo-N-phenyl-1,2,3,4-
tetrahydrothieno[2,3-h][1,6]naphthyridine-8-carboxamide
(12b). Yield 485 mg (80%), light-yellow powder, decomp.
temp. >300°С. IR spectrum, ν, cm–1: 3413, 2290 (N–H),
1712 (C=O). 1H NMR spectrum (400 MHz, ССl4–DMSO-d6),
2
δ, ppm (J, Hz): 2.75 (1H, br. d (unresolved dd), J = 15.4,
2
3-СН(cis)); 3.06 (1Н, dd, J = 15.4, 3J = 6.1, 3-СН(trans));
4.57–4.59 (1H, m, 4-СН); 6.78–6.79 (1Н, m, H Ar); 6.98–
7.00 (1Н, m, H Ar); 7.16–7.24 (4Н, m, H Ar); 7.45–7.46
(1Н, m, H Ar); 7.64–7.65 (2Н, m, H Ar); 9.08 (1H, br. s,
CONH); 9.65 (1H, very br. s, CONH). The signals of
5-NH2 and 9-NH2 amino groups were observed as a very
broad peak at 5.20–6.20 ppm. 13С NMR spectrum (100 MHz,
CCl4–DMSO-d6), δ, ppm: 33.2 (C-4); 36.2 (C-3); 99.0
(C-4a); 107.8 (C-8); 121.0 (СH Ph); 122.9 (С Ar); 127.4
(С Ar); 127.7 (С Ar); 128.1 (СH Ph); 129.0 (С Ar); 130.1
(С Ar); 133.3 (С Ar); 136.6 (С Ar); 139.1 (С Ar); 143.3
(С Ar); 148.5 (С Ar); 157.2 (С Ar); 159.6 (С Ar); 163.9
(CONH); 168.3 (CONH). 13С NMR DEPT-135 spectrum
(100 MHz, CCl4–DMSO-d6), δ, ppm: 33.0 (C-4); 35.9
(C-3); 120.7 (СH Ph); 122.7 (СH Ar); 127.1 (СH Ar); 127.5
(СH Ar); 127.8 (СH Ph); 128.7 (СH Ar); 129.9 (СH Ar).
Mass spectrum (EI, 70 eV), m/z (Irel, %): 465 [М(37Cl)]+
(22), 463 [М(35Cl)]+ (53), 373 [М(37Cl)–PhNH2]+ (33), 371
[М(35Cl)–PhNH]+ (100), 93 [PhNH2]+ (12), 46 (31), 44
(28). Found, %: C 59.40; H 4.02; N 15.12. C23H18ClN5O2S.
Calculated, %: C 59.54; H 3.91; N 15.10.
5,9-Diamino-4-(4-methoxyphenyl)-2-oxo-N-phenyl-
1,2,3,4-tetrahydrothieno[2,3-h][1,6]naphthyridine-8-carb-
oxamide (12с). Yield 735 mg (84%), yellow powder, decomp.
temp. >300°С. IR spectrum, ν, cm–1: 3348, 3162 (N–H),
1
1709 (C=O). H NMR spectrum (400 MHz, DMSO-d6), δ,
2
ppm (J, Hz): 2.72 (1H, br. d (unresolved dd), J = 15.7,
2
3-СН(cis)); 3.16 (1Н, dd, J = 15.7, 3J = 6.3, 3-СН(trans));
3.69 (3Н, s, OСН3); 4.52–4.53 (1H, m, 4-СН); 6.85 (2Н, d,
3J = 8.1, H Ar); 7.05–7.12 (3Н, m, H Ph); 7.29–7.33 (2Н,
3
m, H Ph); 7.66 (2Н, d, J = 8.1, H Ar); 9.69 (1H, br. s,
CONH); 9.99 (1H, very br. s, CONH). The signals of
5-NH2 and 9-NH2 amino groups were observed as a very
broad peak at 5.50–6.50 ppm. 13С NMR spectrum (100 MHz,
DMSO-d6), δ, ppm: 33.3 (C-4); 37.9 (C-3); 55.1 (OСН3);
97.1 (C-4a); 101.8 (C Ar); 108.8 (C-8); 114.1 (CH Ar);
121.3 (СH Ph); 123.6 (СH Ar); 128.2 (СH Ar); 128.5 (СH
Ar); 131.0 (С Ar); 138.8 (С Ar); 145.2 (С Ar); 148.1
(С Ar); 149.4 (С Ar); 153.6 (С Ar); 158.5 (С Ar); 163.3
(CONH); 169.2 (CONH). 13С NMR DEPT-135 spectrum
(100 MHz, DMSO-d6), δ, ppm: 33.0 (C-4); 37.7 (C-3); 54.9
The Supplementary Iiformation file containing spectra
of compounds, as well as the X-ray crystallographic data
for compounds 6a, 7а, is available at http://
link.springer.com/journal/10593.
481

Chemistry of Heterocyclic Compounds 2016, 52(7), 473–483
Shvekhgeimer, M.-G. A., Ed.; VINITI: Moscow, 1991, Vol. 20
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