The synthesis of 3-cyano-2-(organylamino)thieno[3,2-c]isoquinoline derivatives

Article abstract of DOI:10.1007/s11172-019-2459-6

A method for the preparation of 3-cyano-2-(organylamino)thieno[3,2-c]isoquinoline derivatives has been developed. Alkylation of (2,2-dicyano-1-organylaminovinyl)thiolates with methyl 2-(chloromethyl)benzoate or N-substituted 2-(chloromethyl)benzamides with the subsequent treatment of the alkylation products with potassium tert-butoxide gave 3-cyano-2-(organylamino)thieno[3,2-c]isoquinolin-5(4H)-ones. In the case of utilization of (chloromethyl)benzonitrile in this synthesis, 5-amino-3-cyano-2-organylaminothieno[3,2-c]iso-quinolines were obtained.

Full text of DOI:10.1007/s11172-019-2459-6

Russian Chemical Bulletin, International Edition, Vol. 68, No. 3, pp. 588—596, March, 2019
588
The synthesis of 3-cyano-2-(organylamino)thieno[3,2-c]isoquinoline derivatives
V. E. Kalugin and A. M. Shestopalov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 952 5308. E-mail: vek@ioc.ac.ru
A method for the preparation of 3-cyano-2-(organylamino)thieno[3,2-c]isoquinoline de-
rivatives has been developed. Alkylation of (2,2-dicyano-1-organylaminovinyl)thiolates with
methyl 2-(chloromethyl)benzoate or N-substituted 2-(chloromethyl)benzamides with the sub-
sequent treatment of the alkylation products with potassium tert-butoxide gave 3-cyano-2-
(organylamino)thieno[3,2-c]isoquinolin-5(4H)-ones. In the case of utilization of (chloro-
methyl)benzonitrile in this synthesis, 5-amino-3-cyano-2-organylaminothieno[3,2-c]iso-
quinolines were obtained.
Key words: isothiocyanates, malononitrile, 2-(chloromethyl)benzoic acid derivatives, potas-
sium tert-butoxide, domino reactions, thieno[3,2-c]isoquinolines.
Derivatives of fused isoquinolines are of practical inter-
est due to their diverse pharmacological activity. For in-
stance, indeno[1,2-c]isoquinolines demonstrated a cyto-
toxic activity so they can be used to treat certain kinds of
cancer.1—3 The fused isoquinolines can act as inhibitors
of poly(ADP-ribose) synthetase, which plays an important
role in the development of many inflammatory diseases.4
Derivatives of indeno[1,2-c]isoquinolines, indolo[3,2-c]-
isoquinolines, benzofuro[3,2-c]isoquinolines, and benzo-
thieno[3,2-c]isoquinolines are such the inhibitors and can
be applied for the treatment and prevention of arthritides,
diabetes, asthma, colitis, and cardiovascular diseases.5
For the synthesis of fused isoquinolines, we have de-
veloped a versatile synthetic route consisting in the alkyl-
ation of oxygen- or sulfur-containing compounds bearing
a CN group at the adjacent carbon atom (2-cyanophenols,
2-cyanothiophenols, 3-cyanopyridin-2(1H)-ones, and
3-cyanopyridine-2(1H)-thiones) with methyl 2-(chloro-
methyl)benzoate or 2-(chloromethyl)benzonitrile and the
subsequent treatment of the alkylation products with
potassium tert-butoxide. Previously, we have successfully
applied this approach to prepare the derivatives of benzo-
furo[3,2-c]isoquinolines,6 benzothieno[3,2-c]isoquino-
lines,7,8 pyrido[3´,2´:4,5]furo[3,2-c]isoquinolines,9 and
pyrido[3´,2´:4,5]thieno[3,2-c]isoquinolines.10—12
In the present work, we decided to employ this synthetic
approach for building the thieno[3,2-c]isoquinoline hetero-
cyclic system. Compounds of this series may be of practi-
cal interest as pharmacological agents. In particular,
4-arylsulfonyl-4,5-dihydrothieno[3,2-c]isoquinolines ob-
tained from thieno[3,2-c]isoquinoline (1) have exhibited
an activity as the inhibitors of estrogen receptor and can
be employed for the treatment of inflammatory diseases
during atherosclerosis, myocardial infarction, cardiac
impairment, inflammatory bowel disorders and arthritis.13
To date, the multi-step synthesis of thieno[3,2-c]iso-
quinoline (1) from thiophene-3-carboxylic acid 2 is known
(Scheme 1).13
Scheme 1
Reagents and conditions: i. (PhO)2P(O)N3, Et3N, ButOH; ii. NBS; iii. 2-(HO)2BC6H4CHO, (dppf)PdCl2, NaHCO3; iv. HCl.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 0588—0596, March, 2019.
1066-5285/19/6803-0588 © 2019 Springer Science+Business Media, Inc.

Thieno[3,2-c]isoqunolines
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 3, March, 2019
589
At the same time, the known synthesis of substituted
thiophenes 3 consists in the alkylation of (2,2-dicyano-1-
organylaminovinyl)thiolates 4 with halides 5 contain-
ing the active methylene group and subsequent treat-
ment of the alkylation products 6 with a base.14—16
This treatment results in the Thorpe—Ziegler intramol-
ecular cyclization leading to tetrasubstituted thiophenes 3
(Scheme 2).
Results and Discussion
In our experiments, (2,2-dicyano-1-organylaminovi-
nyl)thiolates 4a—c were obtained in situ by the successive
addition of triethylamine (1.17 equiv.) and organyl thio-
cyanate 6a—c (1 equiv.) to the solution of malononitrile
in DMF. Methyl 2-(chloromethyl)benzoate (7) was then
added. The reaction was completed at room temperature
within ~20 h and resulted in alkylation products 8a—c in
good yields. Subsequent treatment of compounds 8a—c
with potassium tert-butoxide gave expected 3-cyano-2-
(organylamino)thieno[3,2-c]isoquinolin-5(H)-ones 9a—c
in good yields (Scheme 3).
Scheme 2
The mechanism for the interaction of compounds 8a—c
with potassium tert-butoxide is an example of the domino
reaction, which involves the formation of thiophene in-
termediates 10a—c at the first step via the Thorpe—Ziegler
reaction and their subsequent annelation into compounds
9a—c via the Guareschi—Thorpe reaction.
The alkylation of thiolates 4a—c with 2-(chloromethyl)-
benzonitrile 11 was carried out in a similar manner, and
alkylation products 12a—c were also obtained in good
yields (Scheme 4). Their subsequent treatment with potas-
sium tert-butoxide led to 5-amino-3-cyano-2-(organyl-
amino)thieno[3,2-c]isoquinolines 13a—c.
The mechanism of reaction of compounds 12a—c with
potassium tert-butoxide is an example of domino reaction
of another type. It involves the formation of thiophene
intermediates 14a—c at the first step via the Thorpe—
Ziegler reaction and their subsequent cyclization into
compounds 13a—c via the hetero Thorpe—Ziegler reaction.
The structure of starting compounds 8a—c and 12a—c,
as well as thieno[3,2-c]isoquinoline derivatives 9a—c and
One can see from this Scheme that (2,2-dicyano-1-
organylaminovinyl)thiolate contains the sulfur func-
tion that can easily be alkylated, and also the CN group
at the adjacent carbon atom and, consequently, meets
the requirements necessary for the synthesis of fused
isoquinolines. Therefore, it was interesting to investi-
gate the synthetic opportunity for the thieno[3,2-c]iso-
quinoline derivatives utilizing thiolates 4 and deriva-
tives of 2-(chloromethyl)benzoic acid as the starting
compounds.
Scheme 3
4, 6, 8, 9, 10: R = Ph (a), Bn (b), Et (c)
Reagents and conditions: i. Et3N (1.17 equiv.), DMF, 20—25 °C, 30 min; ii. DMF, 20—25 °C, 20 h; iii. ButOK (1.5 equiv.), DMF,
70—75 °C, 2 h.

590
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 3, March, 2019
Kalugin and Shestopalov
Scheme 4
4, 6, 12, 13, 14: R = Ph (a), Bn (b), Et (c)
Reagents and conditions: i. Et3N (1.17 equiv.), DMF, 20—25 °C, 30 min; ii. DMF, 20—25 °C, 20 h; iii. ButOK (1.0 equiv.), DMF,
70—75 °C, 2 h.
13a—c, was confirmed by IR, 1H and 13C NMR spectro-
scopy, and also by elemental analysis. The IR spectra of
the starting compounds are characterized by the presence
of one or two absorption bands of the CN group in the
region of 2221—2201 cm–1 and that of the NH group in
the region of 3209—3317 cm–1. In addition, the IR spec-
tra of compounds 8a—c contain the absorption band for
the ester C=O group in the range of 1710—1715 cm–1. In
amino NH group, the amide NH group of compounds
9a—c, and the NH2 group of compounds 13a—c in the
range of 3487—3141 cm–1. In addition, compounds 9a—c
demonstrated the C=O absorption band in the interval of
1666—1637 cm–1. In the 1H NMR spectra of compounds
9a—c and 13a—c, the signal from the organylamino NH
proton appears as the broad singlet at δH = 8.41—10.80,
while the signal from the amide NH proton in compounds
9a—c is the broad singlet at δH = 11.95—11.98. The NH2
group in compounds 13a—c appears as the broad singlet
at δH = 7.01—7.08. The 13C NMR spectra of thieno[3,2-c]-
isoquinoline derivatives 9a—c and 13a—c contain the CN
signal at δC = 112.79—113.53 in the case of 9a—c and at
114.74—115.63 for 13a—c. The signal from the carbon atom
linked to the CN group is located at δC = 73.71—80.92.
The signal from the carbon atom linked to the organyl-
amino group appears at δC = 159.30—160.87 in the case
of phenylamino group and at 164.32—165.55 for the other
organylamino groups. In addition, the 13C NMR spectra
of compounds 9a—c contain the C=O signal in the range
of δC = 161.63—161.74. Spectra of compounds 13a—c
contain the signal from the carbon atom linked to the
amino group at δC = 157.05—157.19.
1
the H NMR spectra of starting compounds, the signal
from the protons of CH2S group appears as a singlet in the
region of δH = 4.53—4.64. The singlet of the NH group
was found in the range of δH = 9.06—10.96. Spectra of
compounds 8a—c contain singlets for the OCH3 group at
δH = 3.85. The 13C NMR spectra of starting compounds
contained the signals from the two CN groups in the in-
terval of δC = 113.32—116.83. Carbon atom between the
two CN groups resonted at 95.72—96.51, while that linked
to the organylamino group resonated at δC = 169.30—170.53
in the case of 8a—c and at 166.41—167.32 for 12a—c.
Spectra of all the starting compounds contain signal for
the CH2S group at δC of 35.53—36.86. In addition, the
spectra of compounds 10a—c contained the OCH3 signals
at δC = 52.25—52.30, C=O signals at 166.61—168.80, and
at 128.79—128.84 ppm-positioned signals for the carbon
atom linked to the ester group. Spectra of compounds
12a—c contained the signals at δC = 116.75—117.08 for the
CN group of benzonitrile moiety and at 111.57—111.73 for
the carbon atom bound to this CN group.
Finally, it was interesting to investigate the opportunity
of obtaining the thieno[3,2-c]isoquinoline derivatives
utilizing 2-(chloromethyl)benzamide12 as the starting
compound. However, it was not possible in this case to
isolate the alkylation products due to the side reactions.
Therefore, we decided to use N-substituted 2-(chloro-
methyl)benzamides 18a—c. Their synthesis is shown in
Scheme 5.
The IR spectra of thieno[3,2-c]isoquinoline derivatives
9a—c and 13a—c contain the absorption bands of the CN
group in the region of 2211—2193 cm–1. The important
feature of the IR spectra of compounds 9a—c and 13a—c
is the presence of several absorption bands of the organyl
Thiolates 4a,c were alkylated with halides 18a—c under
the same conditions described hereinbefore (Scheme 6).

Thieno[3,2-c]isoqunolines
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 3, March, 2019
591
Scheme 5
group adjacent to the carbonyl function at δH = 10.46—10.47.
The signals from the protons of the CH2S group appear
1
in the H NMR spectra as the singlet at δH = 4.53—4.57
in the case of amides 19c and 19d and at 4.27—4.37 for
the other amides. In the 13C NMR spectra of compounds
19a—f, the signals from the two CN groups are located at
δC = 113.54—116.89. The signal from the carbon atom
located between the two CN groups appears at δC
=
= 95.72—96.51 in the case of amides 19c and 19d and at
92.60—93.32 for the other amides. The CH2S signal at
δC = 34.32—35.15 is also characteristic. The amide C=O
signal is located at δC = 166.78—168.60, while that from
the carbon atom linked to the amide function is at
δC = 134.38—134.41 in the case of amides 19c,d and at
131.98—132.84 for the other amides.
The reaction of amides 19a—f with potassium tert-
butoxide was carried out under the conditions described
for compounds 8a—c. The reaction results are given in
Table 1, which shows that thieno[3,2-c]isoquinolin-5(4H)-
ones 9a,c were the only products of reactions.
The mechanism of transformation of compounds
18a—f under the action of potassium tert-butoxide is an
example of the third type of the domino reaction. It in-
volves the formation of thiophene intermediates 20a—f at
the first step via the Thorpe—Ziegler reaction and their
subsequent heterocyclization into compounds 9a,c via the
Guareschi—Thorpe reaction (see Scheme 6), while the
leaving particle is always an amine regardless of its struc-
ture or basicity. At this end, the reaction of potassium
tert-butoxide with the products of alkylation of 3-cyano-
pyridine-2(1H)-thiones with 2-(chloromethyl)benzamide
leads exclusively to 5-aminopyrido[3´,2´:4,5]thieno[3,2 -c]-
isoquinolines.12
17, 18: NR1R2 = NEt2 (a), NHPh (b), morpholin-4-yl (c)
Reagents and conditions: i. CCl4, 80 °C, 4 h; ii. CHCl3, 0—20 °C.
However, a longer time (3 days) was needed in this case
to complete the reaction.
Compounds 19a—f obtained in relatively good yields
were characterized by IR, 1H and 13C NMR spectroscopy,
and also by elemental analysis. The IR spectra of these
compounds are usually characterized by the presence of
two absorption bands of the CN group in the region of
2176—2211 cm–1. The C=O group exhibits its absorption
band about 1653 cm–1 in the case of amides 19c and 19d
and in the range of 1611—1594 cm–1 for the other amides.
The NH group usually appears as several absorption bands
in the interval of 3178—3478 cm–1. The 1H NMR spectra
of amides 19a—f contain the signal from the proton of
EtNH or PhNH group as the singlet at δH = 9.00—9.03
or 10.78—10.85, respectively. In addition, the spectra of
amides 19c and 19d contained also the singlet of the NH
Scheme 6
4, 6, 9: R3 = Ph (a), Et (c)
19, 20: NR1R2 = NEt3 (a, b), NHPh (c, d), morpholin-4-yl (e, f); R3 = Ph (a, c, e), Et (b, d, f)
Reagents and conditions: i. Et3N (1.17 equiv.), DMF, 20—25 °C, 30 min; ii. DMF, 20—25 °C, 72 h; iii. ButOK (1.5 equiv.), DMF,
70—75 °C, 2 h.

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Kalugin and Shestopalov
Table 1. Transformations of compounds 19a—f*
(s, 1 H, NH). 13C NMR (DMSO-d6), δ: 36.17 (CH2S), 52.25
(OCH3), 97.63 (C(CN)2), 113.60 (CN), 116.22 (CN), 123.47
(CPh(2), CPh(6)), 126.50 (CPh(4)), 128.42 (CBz(5)), 128.84
(CBz(1)), 129.15 (CPh(3), CPh(5)), 130.89 (CBz(4)), 131.25
(CBz(6)), 132.64 (CBz(3)), 137.08 (CBz(2)), 138.22 (CPh(1)),
168.80 (C=O), 170.53 (=CNH).
Compound
R3
NR1R2
Product Yield (%)
19a
19b
19c
19d
19e
19f
Ph
Et
Ph
Et
Ph
Et
NEt2
NEt2
9а
9c
9а
9c
9a
9c
85
71
88
71
67
70
NHPh
Methyl 2-[(1-benzylamino-2,2-dicyanovinylthio)methyl]-
benzoate (8b). The yield was 0.66 g (61%), colorless crystals, m.p.
110 —111 °C (CHCl3—hexane). Found (%): C, 65.94; H, 4.81;
N, 11.71; S, 8.73. C20H17N3O2S. Calculated (%): C, 66.10;
H, 4.71; N, 11.56; S, 8.82. IR, ν/cm–1: 3251 (NH), 3085, 3026,
3005, 2221 (CN), 2211 (CN), 1710 (C=O), 1568, 1431, 1274,
NHPh
Morpholin-4-yl
Morpholin-4-yl
* Conditions: ButOK (1.5 equiv.), DMF, 70—75 °C, 2 h.
1
1132, 1080, 749, 712. H NMR (DMSO-d6), δ: 3.85 (s, 3 H,
OCH3); 4.62 (s, 2 H, CH2N); 4.66 (s, 2 H, CH2S); 7.20 (d, 2 H,
HPh(2), HPh(6), J = 6.6 Hz); 7.38—7.43 (m, 4 H, HPh(3), HPh(4),
HPh(5)P and HBz(3)); 7.48 (t, 1 H, HBz(5), J = 7.3 Hz); 7.58
(t, 1 H, HBz(4), J = 7.3 Hz); 7.92 (d, 1 H, HBz(6), J = 8.1 Hz); 9.58
(br.s, 1 H, NH). 13C NMR (DMSO-d6), δ: 36.86 (CH2S), 49.49
(PhCH2N), 52.23 (OCH3), 96.63 (C(CN)2), 115.38 (CN), 116.60
(CN), 127.34 (CPh(4)), 127.57 (CPh(3), CPh(5)), 128.43 (CBz(5)),
128.50 (CPh(2), CPh(6)), 128.79 (CBz(1)), 130.88 (CBz(4)), 131.26
(CBz(6)), 132.67 (CBz(3)), 136.62 (CPh(1)), 137.03 (CBz(2)),
166.61 (C=O), 170.33 (=CNH).
Methyl 2-[(2,2-dicyano-1-ethylaminovinylthio)methyl]benzo-
ate (8c). The yield was 0.61 g (56%), colorless crystals, m.p.
90—92 °C (CHCl3—hexane). Found (%): C, 59.93; H, 5.08;
N, 13.78; S, 10.50. C15H15N3O2S. Calculated (%): C, 59.78; H, 5.02;
N, 13.94; S, 10.64. IR, ν/cm–1: 3300 (NH), 2975, 2208 (CN),
1715 (C=O), 1568, 1443, 1381, 1271, 1239, 1131, 1082, 1042, 771,
715, 685. 1H NMR (DMSO-d6), δ: 1.11 (t, 3 H, CH3CH2N,
J = 7.3 Hz); 3.42 (q, 2 H, CH2N, J = 7.3 Hz); 3.86 (s, 3 H,
OCH3); 4.64 (s, 2 H, CH2S); 7.42—7.50 (m, 2 H, HBz(3),
HBz(5)); 7.60 (t, 1 H, HBz(4), J = 7.3 Hz); 7.91 (d, 1 H, HBz(6),
J = 7.6 Hz); 9.06 (br.s, 1 H, NH). 13C NMR (DMSO-d6), δ: 14.43
(CH3CH2N), 36.54 (CH2S), 41.76 (CH3CH2N), 52.30 (OCH3),
96.72 (C(CN)2), 115.74 (CN), 116.81 (CN), 128.43 (CBz(5)),
128.85 (CBz(1)), 130.88 (CBz(4)), 131.34 (CBz(6)), 132.66 (CBz(3)),
137.21 (CBz(2)), 166.67 (C=O), 169.30 (=CNH).
Therefore, we have developed an efficient method for
the preparation of new derivatives of the thieno[3,2-c]-
isoquinoline heterocyclic system via the alkylation of
(2,2-dicyano-1-organylaminovinyl)thiolates with ester,
nitrile, or amides of 2-(chloromethyl)benzoic acid followed
by treatment of the alkylation products with potassium
tert-butoxide.
Experimental
Melting points were measured on a Kofler plate. IR spectra
were recorded on a Specord M82 spectrometer in KBr pellets.
1H (300 MHz) and 13C (75 MHz) NMR spectra were recorded
on a Bruker AM-300 spectrometer in DMSO-d6 using SiMe4 as
an internal standard. In the NMR spectra of compounds 19c and
19d, designations 1-Ph and 2-Ph correspond to the N-phenyl-
amino and N-phenylamide groups, respectively. Elemental
analysis was carried out using a Perkin-Elmer 2400 CHN analyzer.
Synthesis of methyl 2-[(2,2-dicyano-1-organylaminovinylthio)-
methyl]benzoates 8a—c (general procedure). Triethylamine
(0.5 mL, 3.5 mmol) was added to a solution of malononitrile
(0.2 g, 3 mmol) in DMF (5 mL). After 10 min, isothiocyanate
6a—c (3 mmol) was added dropwise to the reaction mixture. The
mixture was stirred at room temperature for 30 min, methyl
2-(chloromethyl)benzoate 7 (0.56 g, 3 mmol)17 was added, and
the reaction mixture was stirred at 40—45 °C for 5 h and stored
for 16 h. The reaction mixture was poured into H2O (20 mL) and
extracted with CHCl3 (3×15 mL), the extract was washed with
H2O (3×15 mL) and dried over MgSO4, the solvent was evapo-
rated in vacuo, and the product was isolated by chromatography
on silica gel using CHCl3—hexane mixture (3 : 1) and CHCl3 as
the eluents. The eluate was evaporated, and the product was
crystallized from an appropriate solvent.
Methyl 2-[(2,2-dicyano-1-phenylaminovinylthio)methyl]-
benzoate (8a). The yield was 0.61 g (59%), colorless crystals, m.p.
127—128 °C (CHCl3—hexane). Found (%): C, 65.53; H, 4.41;
N, 12.18; S, 9.07. C19H15N3O2S. Calculated (%): C, 65.31;
H, 4.33; N, 12.03; S, 9.18. IR, ν/cm–1: 3263 (NH), 3039, 3020,
2210 (CN), 2201 (CN), 1708 (C=O), 1597, 1500, 1446, 1294,
1277, 1081, 713, 700. 1H NMR (DMSO-d6), δ: 3.85 (s, 3 H,
OCH3); 4.59 (s, 2 H, CH2S); 7.13 (d, 2 H, HPh(2), HPh(6),
J = 8.1 Hz); 7.26 (t, 1 H, HPh (4), J = 7.3 Hz); 7.40 (m, 3 H, HPh(3),
HPh(5) and HBz(3))*; 7.48 (t, 1 H, HBz(5), J = 7.3 Hz); 7.57
(t, 1 H, HBz(4), J = 7.3 Hz); 7.93 (d, 1 H, HBz(6), J = 7.3 Hz); 10.85
Synthesis of 3-cyano-2-(organylamino)thieno[3,2-c]isoquinol-
in-5(4H)-ones 9a—c (general procedure). Potassium tert-butoxide
(0.34 g, 3 mmol) was added to a solution of compound 8a—c
(2 mmol) in anhydrous DMF (3 mL). The reaction mixture was
stirred at 70—75 °C for 2 h and poured into H2O (20 mL). The
resulting solution was acidified with AcOH. The precipitated
crystals were filtered off, washed with H2O, dried, and recrystal-
lized from an appropriate solvent.
3-Cyano-2-(phenylamino)thieno[3,2-c]isoquinolin-5(4H)-one
(9a). The yield was 0.5 g (78%), brown crystals, m.p. 310—312 °C
(decomp.) (DMF—MeOH). Found (%): C, 68.23; H, 3.57;
N, 13.16; S, 10.17. C18H11N3OS. Calculated (%): C, 68.12; H, 3.49;
N, 13.24; S, 10.10. IR, ν/cm–1: 3449, 3183, 3147, 3094 (NH),
3054, 3010, 2211 (CN), 1666 (C=O), 1610, 1601, 1543, 1462,
1
1425, 1179, 745, 689. H NMR (DMSO-d6), δ: 7.19 (m, 1 H,
HPh(4)); 7.32—7.45 (m, 5 H, HTIQ(7)** and HPh(2), HPh(3),
HPh(5), HPh(6)); 7.48 (d, 1 H, HTIQ(9), J = 8.1 Hz); 7.68 (t, 1 H,
HTIQ(8), J = 7.3 Hz); 8.22 (d, 1 H, HTIQ(6), J = 8.1 Hz); 10.80
(br.s, 1 H, PhNH); 11.98 (br.s, 1 H, C(O)NH). 13C NMR
(DMSO-d6), δ: 80.92 (CTIQ(3)), 99.86 (CTIQ(9b)), 112.89
(CN), 120.43 (CPh(2), CPh(6)), 121.20 (CTIQ(7)), 122.75
* Bz is the moiety of benzoic acid.
** TIQ is the thienoisoquinoline moiety.

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Russ. Chem. Bull., Int. Ed., Vol. 68, No. 3, March, 2019
593
(CTIQ(5a)), 124.52 (CTIQ(6)), 125.18 (CPh(4)), 127.97 (CTIQ(9)),
129.57 (CPh(3), CPh(5)), 132.57 (CTIQ(9a)), 133.20 (CTIQ(8)),
136.58 (CTIQ(3a)), 140.77(CPh(1)), 160.87 (CTIQ(2)), 161.63
(CTIQ(5)).
HBzn(3), HBzn(5))*; 7.72 (t, 1 H, HBzn(4), J = 7.3 Hz); 7.87
(d, 1 H, HBzn(6), J = 7.3 Hz); 10.96 (s, 1 H, NH). 13C NMR
(DMSO-d6), δ: 35.53 (CH2S), 97.30 (C(CN)2), 111.73 (CBzn(1)),
113.32 (CN), 115.83 (CN), 116.90 (CNBzn), 123.54 (CPh(2),
CPh(6)), 126.67 (CPh(4)), 128.83 (CBzn(5)), 129.15 (CPh(3),
CPh(5)), 130.18 (CBzn(4)), 133.47 (CBzn(6)), 133.53 (CBzn(3)),
138.00 (CPh(1)), 139.43 (CBzn(2)), 167.21 (=CNH).
2-Benzylamino-3-cyanothieno[3,2-c]isoquinolin-5(4H)-one
(9b). The yield was 0.46 g (73%), orange crystals, m.p. 278—281 °C
(decomp.) (DMF—MeOH). Found (%): C, 68.69; H, 4.04;
N, 12.51; S, 9.75. C19H13N3OS. Calculated (%): C, 68.86;
H, 3.95; N, 12.68; S, 9.67. IR, ν/cm–1: 3281 (NH), 3087, 3062,
3033, 2978, 2944, 2866, 2210 (CN), 1650 (C=O), 1609, 1561,
[(Benzylamino)(2-cyanobenzylthio)methylidene]malononitrile
(12b). The yield was 0.58 g (58%), colorless crystals, m.p.
132—133 °C (CHCl3—hexane). Found (%): C, 68.87; H, 4.18;
N, 16.82; S, 9.79. C19H14N4S. Calculated (%): C, 69.07; H, 4.27;
N, 16.96; S, 9.70. IR, ν/cm–1: 3266 (NH), 3066, 2214 (CN),
2201 (CN), 1572, 1556, 1453, 1342, 1312, 776, 745, 694. 1H NMR
(DMSO-d6), δ: 4.55 (s, 2 H, CH2S); 4.65 (s, 2 H, CH2N); 7.17
(d, 2 H, HPh(2), HPh(6), J = 7.3 Hz); 7.34 (m, 3 H, HPh(3),
HPh(4), HPh(5)); 7.55 (t, 2 H, HBzn(3), HBzn(5), J = 7.3 Hz);
7.71 (t, 1 H, HBzn(4), J = 7.3 Hz); 7.88 (d, 1 H, HBzn(6), J = 7.6 Hz);
9.70 (br.s, 1 H, NH). 13C NMR (DMSO-d6), δ: 36.16 (CH2S),
49.45, 96.57 (C(CN)2), 111.57 (CBzn(1)), 114.86 (CN), 116.26
(CN), 116.75 (CNBzn), 127.17 (CPh(3), CPh(5)), 127.42 (CPh(4)),
128.34 (CBzn(5)), 128.67 (CPh(2), CPh(6)), 130.07 (CBzn(4)),
133.25 (CBzn(6)), 133.32 (CBzn(3)), 136.29 (CPh(1)), 139.12
(CBzn(2)), 168.41 (=CNH).
[(2-Cyanobenzylthio)(ethylamino)methylidene]malononitrile
(12c). The yield was 0.5 g (62%), colorless crystals, m.p.
105—107 °C (CHCl3—hexane). Found (%): C, 62.89; H, 4.62;
N, 20.73; S, 12.08. C14H12N4S. Calculated (%): C, 62.67; H, 4.51;
N, 20.88; S, 11.95. IR, ν/cm–1: 3317 (NH), 3073, 2979, 2209
(CN), 1562, 1413, 1374, 1237, 1067, 1044, 777, 760, 661. 1H NMR
(DMSO-d6), δ: 1.11 (t, 3 H, CH3CH2N, J = 7.3 Hz); 3.45 (q, 2 H,
CH3CH2N, J = 7.3 Hz); 4.53 (s, 2 H, CH2S); 7.53 (t, 1 H,
HBzn(5), J = 7.3 Hz); 7.58 (d, 1 H, HBzn(3), J = 8.1 Hz); 7.73
(t, 1 H, HBzn(4), J = 7.3 Hz); 7.88 (d, 1 H, HBzn(6), J = 8.1 Hz);
9.20 (br.s, 1 H, NH). 13C NMR (DMSO-d6), δ: 14.38 (CH3CH2N),
36.04 (SCH2), 41.81 (CH3CH2N), 96.52 (C(CN)2), 111.68
(CBzn(1)), 115.61 (CN), 116.42 (CN), 117.08 (CNBzn), 128.88
(CBzn(5)), 130.38 (CBzn(4)), 133.43 (CBzn(6)), 133.54 (CBzn(3)),
139.64 (CBzn(2)), 167.32 (=CNH).
Synthesis of 5-amino-3-cyano-2-(organylamino)thieno[3,2-c]-
isoquinolines 13a—c (general procedure). Potassium tert-butoxide
(0.23 g, 2 mmol) was added to a solution of compound 12a—c
(2 mmol) in anhydrous DMF (3 mL). The reaction mixture was
stirred at 70—75 °C for 2 h and poured into H2O (20 mL). The
precipitated crystals were filtered off, washed with H2O, dried,
and recrystallized from an appropriate solvent.
5-Amino-3-cyano-2-(phenylamino)thieno[3,2-c]isoquinoline
(13a). The yield was 0.44 g (70%), brown crystals, m.p.
256—258 °C (MeOH—DMF). Found (%): C, 68.58; H, 3.91;
N, 17.65; S, 10.07. C18H12N4S. Calculated (%): C, 68.33; H, 3.82;
N, 17.71; S, 10.13. IR, ν/cm–1: 3469, 3317 (NH2), 3178, 3151
(NH), 2958, 2201 (CN), 1686, 1649, 1616, 1599, 1558, 1541,
1496, 1372, 1297, 747, 699. 1H NMR (DMSO-d6), δ: 7.08—7.20
(m, 3 H, NH2 and HPh(4)); 7.32—7.50 (m, 5 H, HTIQ(7) and
HPh(2), HPh(3), HPh(5), HPh(6)); 7.60—7.70 (m, 2 H, HTIQ(8),
HTIQ(9)); 8.26 (d, 1 H, HTIQ(6), J = 8.1 Hz); 10.06 (s, 1 H,
PhNH). 13C NMR (DMSO-d6), δ: 79.12 (CTIQ(3)), 105.05
(CTIQ(9b)), 115.04 (CTIQ(5a)), 115.63 (CN), 119.89 (CPh(2),
CPh(6)), 121.64 (CTIQ(7)), 123.86 (CTIQ(6)), 124.47 (CPh(4)),
1
1541, 1363, 1334, 917, 758, 696. H NMR (DMSO-d6), δ: 4.51
(s, 2 H, CH2N); 7.25—7.47 (m, 7 H, HTIQ(7), HTIQ(9) and Ph);
7.64 (t, 1 H, HTIQ(8), J = 7.3 Hz); 8.15 (d, 1 H, HTIQ(6), J = 8.1 Hz);
9.02 (br.s, 1 H, BnNH); 11.98 (br.s, 1 H, C(O)NH). 13C NMR
(DMSO-d6), δ: 49.91 (CH2N), 74.60 (CTIQ(3)), 98.22 (CTIQ(9b)),
113.53 (CN), 120.65 (CTIQ(7)), 122.06 (CTIQ(5a)), 124.40
(CTIQ(6)), 127.37 (CPh(3), CPh(5)), 127.40 (CPh(4)), 127.97
(CTIQ(9)), 128.51 (CPh(2), CPh(6)), 132.82 (CTIQ(9a)), 133.15
(CTIQ(8)), 136.61 (CTIQ(3a)), 137.02 (CPh(1)), 161.67 (CTIQ(5)),
165.55 (CTIQ(2)).
3-Cyano-2-(ethylamino)thieno[3,2-c]isoquinolin-5(4H)-one
(9c). The yield was 0.47 g (87%), greenish brown crystals, m.p.
298—300 °C (decomp.) (DMF—MeOH). Found (%): C, 62.63;
H, 4.18; N, 15.67; S, 11.74. C14H11N3OS. Calculated (%):
C, 62.44; H, 4.12; N, 15.60; S, 11.90. IR, ν/cm–1: 3399, 3273 (NH),
3061, 2973, 2931, 2867, 2766, 2199 (CN), 1637 (C=O), 1608,
1559, 1542, 1477, 1397, 1334, 1142, 900, 757. 1H NMR (DMSO-d6),
δ: 1.25 (t, 3 H, CH3CH2N, J = 7.0 Hz); 3.32 (q, 2 H, CH3CH2N,
J = 6.6 Hz); 7.33 (t, 1 H, HTIQ(7), J = 7.3 Hz), 7.42 (d, 1 H,
HTIQ(9), J = 8.1 Hz); 7.66 (t, 1 H, HTIQ(8), J = 6.6 Hz); 8.15
(d, 1 H, HTIQ(6), J = 7.3 Hz); 8.41 (br.s, 1 H, EtNH); 11.95 (br.s,
1 H, C(O)NH). 13C NMR (DMSO-d6), δ: 13.82 (CH3CH2N),
41.95 (CH3CH2N), 73.76 (CTIQ(3)), 97.32 (CTIQ(9b)), 113.75
(CN), 120.66 (CTIQ(7)), 121.98 (CTIQ(5a)), 124.30 (CTIQ(6)),
128.01 (CTIQ(9)), 132.98 (CTIQ(9a)), 133.58 (CTIQ(8)), 136.68
(CTIQ(3a)), 161.74 (CTIQ(5)), 165.50 (CTIQ(2)).
Synthesis of [(2-cyanobenzylthio)(organylamino)methylidene]-
malononitriles 12a—c (general procedure). Triethylamine (0.5 mL,
3.5 mmol) was added to a solution of malononitrile (0.2 g,
3 mmol) in DMF (10 mL). After 10 min, isothiocyanate 6a—c
(3 mmol) was added dropwise to the reaction mixture. The
mixture was stirred at room temperature for 30 min, 2-(chloro-
methyl)benzonitrile 11 (0.45 g, 3 mmol)18 was then added,
and the reaction mixture was stirred at 40—45 °C for 3 h
and stored for 16 h. The reaction mixture was poured into
H2O (40 mL) and extracted with CHCl3 (3×20 mL), the ex-
tract was washed with H2O (3×30 mL) and dried over MgSO4,
the solvent was evaporated in vacuo, and the product was iso-
lated by chromatography on silica gel using CHCl3—hexane
mixture (3 : 1) and CHCl3 as the eluents. The eluate was evapo-
rated, and the product was crystallized from an appropriate
solvent.
[(2-Cyanobenzylthio)(phenylamino)methylidene]malononitrile
(12a). The yield was 0.56 g (59%), colorless crystals, m.p.
142.5—143 °C (CHCl3—hexane). Found (%): C, 68.55; H, 3.71;
N, 17.86; S, 10.19. C18H12N4S. Calculated (%): C, 68.33; H, 3.82;
N, 17.71; S, 10.13. IR, ν/cm–1: 3209 (NH), 3061, 2941, 2218
(CN), 1596, 1553, 1462, 1404, 1356, 1249, 764, 756, 694.
1H NMR (DMSO-d6), δ: 4.61 (s, 2 H, CH2S); 7.10 (d, 2 H,
H
Ph(2), HPh(6), J = 7.6 Hz); 7.26 (t, 1 H, HPh(4), J = 7.3 Hz);
* Bzn is the benzonitrile moiety.
7.39 (t, 2 H, HPh(3), HPh(5), J = 7.5 Hz); 7.50—7.60 (m, 2 H,

594
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 3, March, 2019
Kalugin and Shestopalov
125.36 (CTIQ(9)), 129.46 (CPh(3), CPh(5)), 131.14 (CTIQ(8)),
131.74 (CTIQ(9a)), 141.12 (CPh(1)), 148.02 (CTIQ(3a)), 157.19
(CTIQ(5)), 159.30 (CTIQ(2)).
3.08 (q, 2 H, CH3CH2N, J = 6.6 Hz); 3.51 (q, 2 H, CH3CH2N,
J = 6.6 Hz); 4.71 (s, 2 H, CH2Cl); 7.31 (t, 1 H, HBza(5),
J = 8.1 Hz)*; 7.40—7.48 (m, 2 H, HBza(3), HBza(4)); 7.58 (d, 1 H,
HBza(6), J = 8.1 Hz).
5-Amino-2-benzylamino-3-cyanothieno[3,2-c]isoquinoline
(13b). The yield was 0.48 g (73%), orange crystals, m.p.
262—265 °C (decomp.) (DMF). Found (%): C, 69.22; H, 4.34;
N, 16.83; S, 9.77. C19H14N4S. Calculated (%): C, 69.07; H, 4.27;
N, 16.96; S, 9.70. IR, ν/cm–1: 3464, 3316 (NH2), 3228 (NH),
3064, 3024, 2945, 2193 (CN), 1652, 1620, 1540, 1504, 1439,
2-Chloromethyl-N-phenylbenzamide (18b). The yield was
3.13 g (85%), colorless crystals, m.p. 105—107 °C (MeOH).
Found (%): C, 68.57; H, 5.04; N, 5.81; Cl, 14.31. C14H12ClNO.
Calculated (%): C, 68.44; H, 4.92; N, 5.70; Cl, 14.43. IR, ν/cm–1
:
3261 (NH), 3234, 3196, 3133, 3070, 2969, 1638 (C=O), 1596, 1544,
1
1
1424, 1348, 912, 748, 743, 697. H NMR (DMSO-d6), δ: 4.55
1491, 1443, 1434, 1329, 1271, 793, 697. H NMR (DMSO-d6),
(d, 2 H, CH2N, J = 5.9 Hz); 7.03 (br.s, 2 H, NH2); 7.32 (t, 1 H,
HTIQ(7), J = 7.3 Hz), 7.36—7.47 (m, 5 H, Ph); 7.50 (d, 1 H,
HTIQ(9), J = 8.8 Hz); 7.61 (t, 1 H, HTIQ(8), J = 7.3 Hz); 8.21
(d, 1 H, HTIQ(6), J = 8.1 Hz); 8.81 (t, 1 H, BnNH, J = 8.8 Hz).
13C NMR (DMSO-d6), δ: 49.59 (CH2N), 79.40 (CTIQ(3)), 103.08
(CTIQ(9b)), 114.84 (CN), 116.23 (CTIQ(5a)), 121.17 (CTIQ(7)),
123.63 (CTIQ(6)), 125.38 (CTIQ(9)), 127.34 (CPh(4)), 127.37
(CPh(3), CPh(5)), 128.52 (CPh(2), CPh(6)), 131.04 (CTIQ(8)),
131.84 (CTIQ(9a)), 136.62 (CPh(1)), 149.00 (CTIQ(3a)), 157.11
(CTIQ(5)), 164.49 (CTIQ(2)).
5-Amino-3-cyano-2-(ethylamino)thieno[3,2-c]isoquinoline
(13c). The yield was 0.43 g (80%), greenish brown crystals, m.p.
280—283 °C (decomp.) (DMF). Found (%): C, 62.55; H, 4.59;
N, 21.02; S, 11.79. C14H12N4S. Calculated (%): C, 62.67; H, 4.51;
N, 20.88; S, 11.95. IR, ν/cm–1: 3487, 3320 (NH2), 3188, 3141
(NH), 2969, 2929, 2201 (CN), 1650,1617, 1579, 1561, 1549, 1502,
1431, 1350, 748. 1H NMR (DMSO-d6), δ: 1.26 (t, 3 H, CH3CH2N,
J = 7.3 Hz); 3.33 (q, 2 H, CH3CH2N, J = 7.3 Hz); 7.01 (s, 2 H,
NH2); 7.34 (t, 1 H, HTIQ(7), J = 7.3 Hz); 7.53 (d, 1 H, HTIQ(9),
J = 8.1 Hz); 7.62 (t, 1 H, HTIQ(8), J = 7.3 Hz); 8.18 (br.s, 1 H,
EtNH); 8.21 (d, 1 H, HTIQ(6), J = 8.1 Hz). 13C NMR (DMSO-d6),
δ: 14.18 (CH3CH2N), 41.46 (CH3CH2N), 78.46 (CTIQ(5)), 102.68
(CTIQ(9b)), 114.74 (CN), 116.14 (CTIQ(5a)), 121.12 (CTIQ(7)),
123.45 (CTIQ(6)), 125.37 (CTIQ(9)), 130.97 (CTIQ(8)), 131.91
(CTIQ(9a)), 149.25 (CTIQ(3a)), 157.05 (CTIQ(5)), 164.32 (CTIQ(2)).
Synthesis of 2-(chloromethyl)benzoyl chloride 16. Sulfuryl
chloride (9.7 g, 72 mmol) and azobisisobutyronitrile (0.25 g,
1.5 mmol) were added to a solution of 2-methylbenzoyl chloride 15
(9.3 g, 60 mmol) in CCl4 (20 mL). The reaction mixture was
refluxed for 4 h, cooled, and filtered. The solvent was evapo-
rated in vacuo, and the residue was distilled. Acid chloride 16 was
isolated in the yield of 9.8 g (87%), b.p. 172—174 °C (36 Torr)
(cf. Ref. 19: 135 °C (14 Torr)).
δ: 4.98 (s, 2 H, CH2Cl); 7.11 (t, 1 H, HPh(4), J = 7.3 Hz);
7.30—7.43 (m, 3 H, HPh(3), HPh(5) and H(5)Bza); 7.51 (t, 1 H,
HBza(4), J = 7.3 Hz), 7.56—7.64 (m, 2 H, HBza(3), HBza(6));
7.76 (d, 2 H, HPh(2), HPh(6), J = 8.1 Hz); 10.46 (s, 1 H, NH).
4-[2-(Chloromethyl)benzoyl]morpholine (18c). The yield was
2.95 g (82%), viscous oil. Found (%): C, 60.32; H, 5.97; N, 5.73;
Cl, 14.71. C12H14ClNO2. Calculated (%): C, 60.13; H, 5.89;
N, 5.84; Cl, 14.89. IR, ν/cm–1: 3479, 3255, 3060, 2967, 2920,
2856, 1633 (C=O), 1456, 1279, 1259, 1114, 1019, 846, 775, 741,
680. 1H NMR (DMSO-d6), δ: 3.16 (t, 2 H, CH2N, J = 4.4 Hz);
3.53 (t, 2 H, CH2N, J = 4.4 Hz); 3.66 (t, 4 H, CH2OCH2,
J = 4.4 Hz); 4.63—4.86 (m, 2 H, CH2Cl); 7.32 (t, 1 H, HBza(5),
J = 6.6 Hz); 7.40—7.50 (m, 2 H, HBza(3), HBza(4)); 7.47 (d, 1 H,
HBza(6), J = 6.6 Hz).
Synthesis of N-substituted 2-[(2,2-dicyano-1-organylamino-
vinylthio)methyl]benzamides 19a—f (general procedure). Tri-
ethylamine (0.5 mL, 3.5 mmol) was added to a solution of
malononitrile (0.2 g, 3 mmol) in DMF (5 mL). After 10 min,
isothiocyanate 6a,c (3 mmol) was added dropwise to the reaction
mixture. The mixture was stirred at room temperature for 30 min,
N-substituted 2-(chloromethyl)benzamide 18a—f (3 mmol) was
then added, and the reaction mixture was stirred at 40—45 °C
for 2 h and stored for 3 days. The mixture was poured into H2O
(40 mL) and extracted with CHCl3 (3×20 mL), the extract was
washed with H2O (3×30 mL) and dried over MgSO4, the solvent
was evaporated, and the product was isolated by chromatography
on silica gel using CHCl3 and CHCl3—acetone mixture (4 : 1)
as the eluents. The eluate was evaporated, and the product was
crystallized from an appropriate solvent.
2-[(2,2-Dicyano-1-phenylaminovinylthio)methyl]-N,N-di-
ethylbenzamide (19a). The yield was 0.6 g (51%), colorless crys-
tals, m.p. 125—127 °C (CHCl3—hexane). Found (%): C, 67.83;
H, 5.59; N, 14.51; S, 8.33. C22H22N4OS. Calculated (%):
C, 67.67; H, 5.68; N, 14.35; S, 8.21. IR, ν/cm–1: 3440, 3171, 3119
(NH), 3029, 3004, 2968, 2968, 2930, 2210 (CN), 1605, 1593,
1510, 1484, 1464, 1449, 1317, 781, 754, 735. 1H NMR (DMSO-d6),
δ: 1.11 (t, 3 H, CH3CH2N, J = 7.0 Hz); 1.17 (t, 3 H, CH3CH2N,
J = 7.0 Hz); 3.07 (q, 2 H, CH3CH2N, J = 7.0 Hz); 3.45 (q, 2 H,
CH3CH2N, J = 6.6 Hz); 4.27 (s, 2 H, CH2S); 7.17 (d, 2 H,
HPh(2), HPh(6), J = 8.1 Hz); 7.27 (t, 2 H, HPh(3), HPh(5),
J = 8.1 Hz); 7.36—7.46 (m, 5 H, HBza(3), HBza(4), HBza(5),
HBza(6) and HPh(4)); 10.85 (s, 1 H, NH). 13C NMR (DMSO-d6),
δ: 12.51 (CH3CH2N), 13.85 (CH3CH2N), 34.43 (CH2S), 38.35
(CH3CH2N), 42.83 (CH3CH2N), 93.32 (C(CN)2), 113.58 (CN),
116.06 (CN), 123.66 (CPh(2), CPh(6)), 125.80 (CBza(5)), 126.59
(CPh(4)), 128.00 (CBza(6)), 129.13 (CBza(4)), 129.18 (CPh(3),
CPh(5)), 130.21 (CBza(3)), 131.98 (CBza(2)), 136.95 (CBza(1)),
138.22 (CPh(1)), 168.47 (C=O), 168.90 (=CNH).
Synthesis of N-substituted 2-(chloromethyl)benzamides 18a—c
(general procedure). A solution of the corresponding amine
17a—c (30 mmol) in CHCl3 (20 mL) was added dropwise at
0—5 °C to a stirred solution of 2-(chloromethyl)benzoyl chloride
16 (2.84 g, 15 mmol) in CHCl3 (20 mL). The reaction mixture
was stirred at this temperature for 30 min, warmed to room
temperature, and poured into H2O (60 mL). The organic layer
was separated, washed with H2O (2×30 mL), and dried over
MgSO4. The solvent was evaporated in vacuo. Compounds 18a,c
were purified by chromatography on silica gel using CHCl3—
hexane mixture (3 : 1) and CHCl3 as the eluents, while compound
18b was crystallized from MeOH.
2-Chloromethyl-N,N-diethylbenzamide (18a). The yield was
2.7 g (80%), oil. Found (%): C, 63.64; H, 7.01; N, 6.28; Cl, 15.53.
C12H16ClNO. Calculated (%): C, 63.85; H, 7.14; N, 6.21;
Cl, 15.71. IR, ν/cm–1: 2973, 2935, 2875, 1631 (C=O), 1459, 1431,
1
1290, 1082, 771, 679. H NMR (DMSO-d6), δ: 1.04 (t, 3 H,
* Bza is the benzamide moiety.
CH3CH2N, J = 7.0 Hz); 1.18 (t, 3 H, CH3CH2N, J = 7.0 Hz);

Thieno[3,2-c]isoqunolines
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 3, March, 2019
595
2-[(2,2-Dicyano-1-ethylaminovinylthio)methyl]-N,N-diethyl-
benzamide (19b). The yield was 0.58 g (57%), colorless crystals,
m.p. 142—144 °C (CHCl3—hexane). Found (%): C, 62.96;
H, 6.55; N, 16.44; S, 9.29. C18H22N4OS. Calculated (%):
C, 63.13; H, 6.48; N, 16.36; S, 9.36. IR, ν/cm–1: 3423, 3168
(NH), 2973, 2835, 2872, 2209 (CN), 2200 (CN), 1594 (C=O),
H, 5.06; N, 13.69; S, 7.89. C22H20N4O2S. Calculated (%):
C, 65.33; H, 4.98; N, 13.85; S, 7.93. IR, ν/cm–1: 3429, 3137 (NH),
3058, 2973, 2921, 2850, 2206 (CN), 2184 (CN), 1611 (C=O),
1
1592, 1495, 1445, 1276, 1261, 1115, 1021, 762, 695. H NMR
(DMSO-d6), δ: 3.16 (t, 2 H, CH2N, J = 4.4 Hz); 3.48 (t, 2 H,
CH2N, J = 4.4 Hz); 3.66 (t, 4 H, CH2OCH2, J = 4.4 Hz); 4.33
(s, 2 H, CH2S); 7.16 (t, 2 H, H1-Ph(2), H1-Ph(6), J = 7.3 Hz);
7.22—7.34 (m, 2 H, H1-Ph(4) and H Bza (3)); 7.35—7.50 (m, 5 H,
H1-Ph(3), H1-Ph(5) and HBza(4), HBza(5), HBza(6)); 10.84
(s, 1 H, NH). 13C NMR (DMSO-d6), δ: 34.54 (SCH2), 41.67
(CH2N), 47.24 (CH2N), 65.88 (CH2OCH2), 93.18 (C(CN)2),
113.54 (CN), 116.23 (CN), 123.65 (CPh(2), CPh(6)), 126.53
(CPh(4)), 126.88(CBza(5)), 128.02 (CBza(6)), 129.19 (CPh(3),
CPh(5)), 129.53 (CBza(4)), 130.34 (CBza(3)), 132.87 (CBza(2)),
135.44 (CBza(1)), 138.25 (CPh(1)), 167.62 (C=O), 168.81 (=CNH).
{(Ethylamino)[2-(morpholin-4-ylcarbonyl)benzylthio]meth-
ylidene}malononitrile (19f). The yield was 0.62 g (58%), colorless
crystals, m.p. 152—154 °C (MeOH). Found (%): C, 60.77;
H, 5.79; N, 15.81; S, 8.87. C18H20N4O2S. Calculated (%):
C, 60.65; H, 5.66; N, 15.72; S, 8.99. IR, ν/cm–1: 3436, 3413,
3186 (NH), 2987, 2977, 2965, 2860, 2204 (CN), 2193 (CN), 1608
(C=O), 1596, 1562, 1531, 1460, 1440, 1279, 1114, 783, 747.
1H NMR (DMSO-d6), δ: 1.13 (t, 3 H, CH3CH2N, J = 7.0 Hz);
3.23 (t, 2 H, CH2N, J = 4.4 Hz); 3.50 (q, 2 H, CH3CH2N,
J = 7.3 Hz); 3.56 (t, 2 H, CH2N, J = 4.4 Hz); 3.68 (t, 4 H,
CH2OCH2, J = 4.4 Hz); 4.37 (s, 2 H, CH2S); 7.32 (d, 1 H,
HBza(3), J = 7.3 Hz); 7.36—7.50 (m, 3 H, HBza(4), HBza(5),
HBza(6)); 9.03 (br.s, 1 H, NH). 13C NMR (DMSO-d6), δ: 14.38
(CH3CH2N), 34.54 (CH2S), 41.69 (CH2N), 41.82 (CH3CH2N),
47.30 (CH2N), 65.93 (CH2OCH2), 92.82 (C(CN)2), 115.77 (CN),
116.85 (CN), 126.83 (CBza(5)), 128.06 (CBza(6)), 129.56 (CBza(4)),
130.53 (CBza(3)), 132.84 (CBza(2)), 135.42 (CBza(1)), 167.72
(C=O), 168.97 (=CNH).
1
1557, 1522, 1461, 1440, 1363, 1297, 1260, 777, 748. H NMR
(DMSO-d6), δ: 1.05 (t, 3 H, CH3CH2NH, J = 7.0 Hz); 1.12
(t, 3 H, CH3CH2N, J = 7.0 Hz); 1.18 (t, 3 H, CH3CH2N,
J = 7.0 Hz); 3.11 (q, 2 H, CH3CH2N, J = 6.6 Hz); 3.42—3.55
(m, 4 H, CH3CH2N and CH3CH2NH); 4.32 (s, 2 H, CH2S);
7.28 (d, 1 H, HBza(3), J = 7.3 Hz); 7.35—7.52 (m, 3 H, HBza(4),
HBza(5), HBza(6)); 9.02 (br.s, 1 H, NH). 13C NMR (DMSO-d6),
δ: 12.45 (CH3CH2N), 13.70 (CH3CH2N), 14.39 (CH3CH2NH),
34.45 (CH2S), 38.37 (CH3CH2N), 41.76 (CH3CH2NH), 42.84
(CH3CH2N), 92.60 (C(CN)2), 113.60 (CN), 116.00 (CN), 125.89
(CBza(5)), 128.04 (CBza(6)), 129.21 (CBza(4)), 130.37 (CBza(3)),
132.02 (CBza(2)), 136.92 (CBza(1)), 168.60 (C=O), 169.21
(=CNH).
2-[(2,2-Dicyano-1-phenylaminovinylthio)methyl]-N-phenyl-
benzamide (19c). The yield was 0.66 g (55%), colorless crystals,
m.p. 184—186 °C (MeOH). Found (%): C, 70.41; H, 4.53;
N, 13.57; S, 7.74. C24H18N4OS. Calculated (%): C, 70.22;
H, 4.42; N, 13.65; S, 7.81. IR, ν/cm–1: 3291 (NH), 3106, 3059,
2961, 2926, 2210 (CN), 2176 (CN), 1653 (C=O), 1599, 1533,
1500, 1442, 1323, 1301, 1278, 766, 750, 695. 1H NMR (DMSO-d6),
δ: 4.53 (s, 2 H, CH2S); 7.08—7.16 (m, 3 H, H2-Ph(4) and
H1-Ph(2), H1-Ph(6)); 7.21 (t, 1 H, H1-Ph(4), J = 7.3 Hz);
7.30—7.40 (m, 4 H, H1-Ph(3), H1-Ph(5) and H2-Ph(3), H2-Ph(5));
7.45—7.55 (m, 3 H, HBza(3), HBza(4), HBza(5)); 7.64 (d, 1 H,
HBza(6), J = 6.6 Hz); 7.74 (d, 2 H, H2-Ph(2), H2-Ph(6), J = 8.1 Hz);
10.46 (s, 1 H, NH); 10.78 (s, 1 H, NH). 13C NMR (DMSO-d6),
δ: 35.05 (SCH2), 96.51 (C(CN)2), 113.72 (CN), 116.13 (CN),
120.28 (C2-Ph(2), C2-Ph(6)), 123.69 (C1-Ph(2), C1-Ph(6)), 123.82
(C2-Ph(4)), 126.48 (C1-Ph(4)), 128.03 (CBza(5)), 128.44 (CBza(6)),
128.53 (C1-Ph(3), C1-Ph(5)), 129.11 (C2-Ph(3), C2-Ph(5)), 130.51
(CBza(4)), 130.69 (CBza(3)), 134.41 (CBza(2)), 135.96 (CBza(1)),
138.31 (C1-Ph(1)), 138.96 (C2-Ph(1)), 166.78 (C=O), 169.33
(=CNH).
Reaction of N-substituted 2-[(2,2-dicyano-1-organylamino-
vinylthio)methyl])benzamides 19a—f with potassium tert-butoxide
(general procedure). The reaction of amides 19a—f with potas-
sium tert-butoxide was carried out according to the procedure
described for compounds 8a—c. The reaction results are given
in Table 1.
2-[(2,2-Dicyano-1-ethylaminovinylthio)methyl]-N-phenyl-
benzamide (19d). The yield was 0.68 g (62%), colorless crystals,
m.p. 170—172 °C (MeOH). Found (%): C, 66.13; H, 5.07;
N, 15.39; S, 8.91. C20H18N4OS. Calculated (%): C, 66.28;
H, 5.01; N, 15.46; S, 8.85. IR, ν/cm–1: 3308, 3188 (NH), 3043,
3105, 2992, 2932, 2211 (CN), 2185 (CN), 1654 (C=O), 1602,
1543, 1500, 1440, 1330, 1290, 898, 751, 705, 897. 1H NMR
(DMSO-d6), δ: 1.07 (t, 3 H, CH3CH2N, J = 7.3 Hz); 3.40 (q, 2 H,
CH3CH2N, J = 7.3 Hz); 4.57 (s, 2 H, CH2S); 7.12 (t, 1 H,
H2-Ph(4), J = 7.3 Hz), 7.36 (t, 2 H, H2-Ph(3), H2-Ph(5), J = 8.1 Hz),
7.44—7.57 (m, 3 H, HBza(3), HBza(4), HBza(5)); 7.64 (d, 1 H,
HBza(6), J = 6.6 Hz); 7.75 (d, 2 H, H2-Ph(2), H2-Ph(6), J = 8.1 Hz);
9.00 (br.s, 1 H, NH); 10.47 (s, 1 H, NH). 13C NMR (DMSO-d6),
δ: 14.40 (CH3CH2N), 35.15 (SCH2), 41.75 (CH3CH2N), 95.72
(C(CN)2), 115.85 (CN), 116.89 (CN), 120.15 (CPh(2), CPh(6)),
123.84 (CPh(4)), 128.04 (CBza(5)), 128.32 (CBza(6)), 128.56
(CPh(3), CPh(5)), 130.50 (CBza(4)), 130.72 (CBza(3)), 134.38
(CBza(2)), 136.04 (CBza(1)), 138.96 (CPh(1)), 166.92 (C=O),
169.57 (=CNH).
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Received June 26, 2018;
in revised form November 21, 2018;
accepted December 3, 2018