Synthesis of 5-aminopyrido[3′,2′:4,5]thieno[3,2-c]isoquinoline derivatives from 3-cyanopyridine-2(1H)-thiones and 2-(chloromethyl)benzamide

Article abstract of DOI:10.1007/s11172-018-2245-x

Substituted 5-aminopyrido[3′,2′:4,5]thieno[3,2-c]isoquinolines were synthesized by condensation of substituted 3-cyanopyridine-2(1H)-thiones with 2-(chloromethyl)benzamide and subsequent treatment of the condensation products with potassium tert-butoxide. Oxidation of the condensation products to sulfoxides and sulfones followed by treatment of these compounds with potassium tert-butoxide gives substituted 5-aminopyrido[3′,2′:4,5]thieno[3,2-c]isoquinoline 11-oxides and substituted 5-aminopyrido[3′,2′:4,5]thieno[3,2-c]isoquinoline 11,11-dioxides in good yields.

Full text of DOI:10.1007/s11172-018-2245-x

Russian Chemical Bulletin, International Edition, Vol. 67, No. 8, pp. 1492—1499, August, 2018
1492
Synthesis of 5-aminopyrido[3´,2´:4,5]thieno[3,2-c]isoquinoline derivatives from
3-cyanopyridine-2(1H)-thiones and 2-(chloromethyl)benzamide
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 (495) 952 5308. E-mail: vek@ioc.ac.ru
Substituted 5-aminopyrido[3´,2´:4,5]thieno[3,2-c]isoquinolines were synthesized by con-
densation of substituted 3-cyanopyridine-2(1H)-thiones with 2-(chloromethyl)benzamide and
subsequent treatment of the condensation products with potassium tert-butoxide. Oxidation of
the condensation products to sulfoxides and sulfones followed by treatment of these compounds
with potassium tert-butoxide gives substituted 5-aminopyrido[3´,2´:4,5]thieno[3,2-c]iso-
quinoline 11-oxides and substituted 5-aminopyrido[3´,2´:4,5]thieno[3,2-c]isoquinoline
11,11-dioxides in good yields.
Key words: 3-cyanopyridine-2(1H)-thiones, 2-(chloromethyl)benzamides, potassium tert-
butoxide, domino reactions, 5-aminopyrido[3´,2´:4,5]thieno[3,2-c]isoquinolines, 5-amino-
pyrido[3´,2´:4,5]thieno[3,2-c]isoquinoline 11-oxides, 5-aminopyrido[3´,2´:4,5]thieno[3,2-c]-
isoquinoline 11,11-dioxides.
Derivatives of fused isoquinolines are of practical inter-
est since they show different types of pharmacological
activities. Thus, indeno[1,2-c]isoquinolines are cytotoxic
and can be used for treating some types of cancer.1—3 Fused
isoquinolines may inhibit poly(ADP-ribose) synthetase
playing an essential role in the development of a number
of inflammatory diseases.4 For instance, derivatives of
indeno[1,2-c]isoquinolines, indolo[3,2-c]isoquinolines,
benzofuro[3,2-c]isoquinolines, and benzothieno[3,2-c]-
isoquinolines are capable of inhibiting this enzyme and
can be used for prophylaxis and treatment of arthritis,
diabetes, asthma, colitis, and cardiovascular diseases.5
Thieno[3,2-c]isoquinoline derivatives are found to inhibit
estrogen receptors and can be applied to treat inflammation
in atherosclerosis, myocardial infarction, heart failure,
inflammatory bowel diseases, and arthritis.6
Our studies on the synthesis of fused isoquinolines
result in the development of a general synthetic approach
to this type of heterocycles. This approach involves alkyl-
ation of the derivatives of benzoyl nitrile and nicotinoyl
nitrile bearing either the hydroxy or thiol group adjacent
to the nitrile moiety with 2-(chloromethyl)benzoic acid
derivatives followed by treatment of the resulting alkylation
products with potassium tert-butoxide. The structure of
the obtained fused isoquinolines depends on the nature
of 2-(chloromethyl)benzoic acid derivatives used in the
alkylation step. Thus, when the products obtained by
alkylation of salicylic acid nitrile, thiosalicylic acid nitrile,
3-cyanopyridine-2(1H)-ones, and 3-cyanopyridine-2(1H)-
thiones with 2-(chloromethyl)benzoate are treated with
potassium tert-butoxide, derivatives of benzofuro[3,2-c]-
isoquinoline-5(6H)-one,7 benzothieno[3,2-c]isoquino-
line-5(6H)-one,8 pyrido[3´,2´:4,5]furo[3,2-c]isoquino-
line-5(6H)-one,9 and pyrido[3´,2´:4,5]thieno[3,2-c]-
isoquinoline-5(6H)-one10 were synthesized via the
Thorpe—Ziegler  Thorpe—Guareschi domino reaction.
At the same time, when the products of alkylation of
salicylic acid nitriles, thiosalicylic acid nitriles, 3-cyano-
pyridine-2(1H)-ones, and 3-cyanopyridine-2(1H)-thiones
with 2-(chloromethyl)benzoyl nitrile are treated with
ButOK, derivatives of 5-aminobenzofuro[3,2-c]isoquino-
lines,7 5-aminobenzothieno[3,2-c]isoquinolines,11 and
5-aminopyrido[3´,2´:4,5]furo[3,2-c]isoquinoline9 were
prepared via the Thorpe—Ziegler  hetero-Thorpe—
Ziegler domino reaction. Similar types of the domino
reactions are well known.12 However, synthesis of fused
isoquinolines via the reaction sequence involving alkyl-
ation of benzoic acid nitriles and nicotinic acid nitriles
bearing either hydroxy or thiol group adjacent to the nitrile
moiety with 2-(chloromethyl)benzamide or its substituted
derivatives and subsequent treatment of the alkylation
products with ButOK has not been studied to date. The
present study is focused on the synthesis of pyrido-
[3´,2´:4,5]thieno[3,2-c]isoquinoline derivatives from
substituted 3-cyanopyridine-2(1H)-thiones and 2-(chloro-
methyl)benzamide.
Substituted 3-cyanopyridine-2(1H)-thiones 1a—d
react with 2-(chloromethyl)benzamide 2 in the presence
of Et3N in refluxing CHCl3 to give substituted 2-[(2-ami-
nocarbonylbenzyl)thio]-3-cyanopyridines 3a—d in good
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1492—1499, August, 2018.
1066-5285/18/6708-1492 © 2018 Springer Science+Business Media, Inc.

5-Aminopyrido[3´,2´:4,5]thieno[3,2-c]isoquinolines Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
1493
yields. Treatment of sulfides 3a—d with ButOK (1.5 equiv.)
in DMF results in substituted 5-aminopyrido[3´,2´:4,5]-
thieno[3,2-c]isoquinolines 4a—d in good yields (Scheme 1).
[3,2-c]isoquinolines bearing the oxidized sulfur atom by
oxidation of sulfides 3a—d to the corresponding sulfoxides
and sulfones and subsequent treatment of the obtained
derivatives with potassium tert-butoxide according to the
procedure described earlier for the derivatives of benzo-
thieno[3,2-c]isoquinolines8,11 and pyrido[3´,2´:4,5]thi-
eno[3,2-c]isoquinolines.10 Oxidation of sulfides 3a—d with
30% aqueous H2O2 in AcOH at 50—55 C for 3—4 h gives
sulfoxides 5a—d. Oxidation of sulfides 3a—d with KMnO4
in AcOH at room temperature leads to sulfones 7a—d
(Scheme 2).
Scheme 1
Treatment of sulfoxides 5a—d with ButOK under the
same conditions used for the reactions involving sulfides
3a—d gives the corresponding substituted 5-aminopyr-
ido[3´,2´:4,5]thieno[3,2-c]isoquinoline 11-oxides 6. It
should be noted that the yields of the target products
strongly depend on the substitution pattern of the starting
sulfoxides 5. Thus, alkyl-substituted sulfoxides 5a,b give
compounds 6a,b in good yields; while treatment of sulf-
oxide 5c bearing the phenyl group with ButOK produces
a large number of the side-products, therefore, target
product 6c was isolated in 27% yield only. The reaction of
sulfoxide 5d with potassium tert-butoxide leads only to
a mixture of the side products with heterocycle 4d being one
of the components of this mixture. In contrast, treatment
of sulfones 7a—d with ButOK in all cases gives substi-
tuted 5-aminopyrido[3´,2´:4,5]thieno[3,2-c]isoquinoline
11,11-dioxides 8a—d in good yields (see Scheme 2).
The structures of compounds 3a—d, 5a—d, and 7a—d
1, 3, 4: R1 = R3 = Me, R2 = H (a); R1 = H, R2 + R3 = (CH2)4 (b);
R1 = R3 = Ph, R2 = H (c); R1 = CF3, R2 = H, R3 = Ph (d)
1
were established by IR spectroscopy, H and 13C NMR
Reagents and conditions: i. Et3N (1.5 equiv.), DMF, 60—65 C,
40 min; ii. ButOK (1.5 equiv.), DMF, 70—75 C, 40 min.
spectroscopy, and confirmed by elemental analysis.
Characteristic features of the IR spectra of these com-
pounds are the absorptions of the CN group at the
2212—2237 cm–1 and the amide group at 1650—1674 cm–1
It was interesting to study the possibility of synthesiz-
ing the derivatives of 5-aminopyrido[3´,2´:4,5]thieno-
Scheme 2
3, 5—8: R1 = R3 = Me, R2 = H (a); R1 = H, R2 + R3 = (CH2)4 (b); R1 = R3 = Ph, R2 = H (c); R1 = CF3, R2 = H, R3 = Ph (d)
Reagents and conditions: i. AcOH, 30% H2O2 (1.1 equiv.), 50—55 C, 3—4 h; ii. AcOH, KMnO4 (1.6 equiv.), 20—25 C, 40 min;
iii. ButOK (1.5 equiv.), DMF, 55—60 C, 1 h; iv. ButOK, DMF (1.5 equiv.), 55—60 C, 40 min.

1494 Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
Kalugin and Shestopalov
(C=O) and 3178—3478 cm–1 (NH2). The S=O groups of
sulfoxides 5a—d absorb at the 1037—1067 cm–1 range. In
the IR spectra of sulfones 7a—d, the SO2 group gives
two absorption bands at the ranges of 1310—1326 and
1132—1149 cm–1. In the 1H NMR spectra of compounds
3a—d, 5a—d, and 7a—d, the CONH2 amide group protons
resonate as two broadened singlets at H 7.27—7.42 and
7.67—7.96. 1H NMR spectra of sulfides 3a—d exhibit the
singlet signal of the CH2S protons at H 4.73—4.99. The
protons of the CH2S(O) moiety of sulfoxides 5a—d reso-
nate as two doublets at H 4.70—4.87 and 4.80—4.94 with
the spin-spin coupling constants of J = 11.7 Hz for 5b and
12.5 Hz for 5a and 5d. The protons of the CH2S(O) group
of sulfoxide 5c appear as a singlet at H 4.96. The singlets
of the CH2SO2 group protons of sulfones 7a—d were found
at H 5.37—5.65. In the 13C NMR spectra of compounds
3a—d, 5a—d, and 7a—d, the CN group carbon atoms
resonate at the C 110.83—115.57 range. 13C NMR spectra
of sulfides 3a—d show characteristic signals of the CH2S
group carbon atoms at C 31.00—32.12; the signals of the
CH2S(O) group carbon atoms of sulfoxides 5a—d are
observed at C 56.87—57.84, and the CH2SO2 group
carbon atoms of sulfones 7a—d resonate at C 53.77—
55.38. The carbon atoms of the CONH2 amide moieties
appear at the C 169.51—170.51 range. The 13C NMR
signals of the carbon atoms bonded to the amide groups
are of special interest. Thus, the signals of these carbons
are observed at C 135.60—136.29 for sulfides 3a—d, at
C 128.00—128.55 for sulfoxides 5a—d, and at C 125.77—
126.19 for sulfones 7a—d.
We believe that the reactions of sulfides 3, sulfoxides 5,
and sulfones 7 with potassium tert-butoxide follow the
same mechanism, namely, the domino reaction. On the
first step, the Thorpe—Ziegler reaction of compounds 3,
5, and 7 produces the corresponding benzothiophenic
intermediates 9, 10, and 11. Then these intermediates
undergo heterocyclization accompanied by the elimination
of the water molecule to give the target compounds 4, 6,
and 8 (Scheme 3).
Such a mechanism of the reaction of amides 3, 5, and
7 with ButOK allowed us to hope that the reaction of the
corresponding N-substituted amides with potassium tert-
butoxide would yield the derivatives of pyrido[3´,2´:4,5]-
thieno[3,2-c]isoquinolines bearing the 5-positioned N-sub-
stituted amino group.
To verify this assumption, we synthesized 4-[2-(chloro-
methyl)benzoyl]morpholine (12) by the reaction of
2-(chloromethyl)benzoyl chloride (13) with morpholine.
Alkylation of 3-cyanopyridine-2(1H)-thione 1a with
chloride 12 gives amide 14 in high yield. The reaction of
compound 14 with ButOK is accompanied by the side-
product formation; therefore, it was carried out under
milder conditions than the analogous reactions of com-
pound 3. Despite this precaution, the reaction produces
pyrido[3´,2´:4,5]thieno[3,2-c]isoquinoline derivative 15
bearing the 5-positioned morpholine moiety in 43% iso-
lated yield (Scheme 4).
In summary, we succeeded in the high-yield synthesis
of new 5-aminopyrido[3´,2´:4,5]thieno[3,2-c]isoquino-
lines by alkylation of substituted 3-cyanopyridine-2(1H)-
thiones with 2-(chloromethyl)benzamide followed by
treatment of the alkylation products with potassium tert-
butoxide. Oxidation of the alkylation products to the cor-
responding sulfoxides and sulfones and the subsequent
reaction of these compounds with ButOK give rise to
5-aminopyrido[3´,2´:4,5]thieno[3,2-c]isoquinoline de-
rivatives bearing the oxidized sulfur atom. Besides, we were
able to demonstrate that treatment of the product of al-
kylation of 3-cyanopyridine-2(1H)-thione with N-sub-
stituted 2-(chloromethyl)benzamide with potassium tert-
butoxide gives the derivative of pyrido[3´,2´:4,5]thi-
eno[3,2-c]isoquinolines bearing the 5-positioned N-sub-
stituted amino group.
IR spectra of the target products 4a—d, 6a—c, and
8a—d characterize by the presence of two or more absorp-
tion bands of the NH2 group at the 3227—3484 cm–1
range. The S=O groups of sulfoxides 6a—c absorb at the
1000—1015 cm–1 range. The sulfonyl groups of hetero-
cycles 8a—d give rise to two absorption bands at 1269—1292
and 1132—1152 cm–1 1H NMR spectra of compounds
.
4a—d, 6a—c, and 8a—d exhibit the broadened singlet
signal of the NH2 group protons at H 6.98—7.09 (4a—d),
7.36—7.96 (6a—c), and 6.89—8.25 (8a—d). 13C NMR
spectra of these compounds show signals of the CNH2
group carbon atoms at C 155.35—156.68 (4a—d), 158.58—
159.82 (6a—c), and 160.03—160.70 (8a—c).
Scheme 3
n = 0 (3, 4, 9), 1 (5, 6, 10), 2 (7, 8, 11 )

5-Aminopyrido[3´,2´:4,5]thieno[3,2-c]isoquinolines Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
1495
Scheme 4
Reagents and conditions: i. morpholine (1.1 equiv.), CHCl3, 0—25 C; ii. 1a, Et3N (1.5 equiv.), CHCl3, reflux, 1 ч; iii. ButOK
(1.5 equiv.), DMF, 20—25 C, 40 min.
: 19.57 (C(4)Me); 24.28 (C(6)Me); 31.09 (CH2S); 103.45
(C(3)py); 114.97 (CNpy); 120.25 (C(5)py); 127.14 (C(5)Bza); 127.84
(C(6)Bza); 129.70 (C(3)Bza); 130.76 (C(4)Bza); 135.77 (C(2)Bza);
136.28 (C(1)Bza); 152.44 (C(4)py); 160.94 (C(2)py); 161.32 (C(6)py);
170.32 (C=O).
Experimental
Melting points were measured with a Kofler apparatus. IR
spectra were recorded on a Specord M82 spectrometer in the
KBr pellets. 1H and 13C NMR spectra were run with a Bruker
Avance-300 instrument (working frequencies of 300 (1H) and
75 MHz (13C)) in DMSO-d6. The chemical shifts are given in
the  scale relative to SiMe4 as an internal standard. Notations
used in the description of the NMR spectra are as follows: Bza
is the benzamide moiety; py is the pyridine moiety, THQ is
5,6,7,8-tetrahydroquinoline; PTI is pyrido[3´,2´:4,5]thieno-
[3,2-c]isoquinoline; THTIQTQ is tetrahydroisoquinolino-
[3´,4´:4,5]thieno[2,3-b]quinoline. Elemental analysis was carried
out with a Perkin-Elmer 2400 CHN analyzer.
2-{[(2-Aminocarbonyl)benzyl]thio}-3-cyano-5,6,7,8-tetra-
hydroquinoline (3b). Yield 0.72 g (84%), colorless crystals, m.p.
208—210 C (DMF—MeOH). Found (%): C, 66.71; H, 5.37;
N, 12.92; S, 10.04. C18H17N3OS. Calculated (%): C, 66.85;
H, 5.30; N, 12.99; S, 9.91. IR, /cm–1: 3447, 3358, 3179 (NH2),
2938, 2223 (CN), 1650 (C=O), 1621, 1413, 1390. 1H NMR,
: 1.68—1.80 (m, 2 H, C(6)H2(THQ)); 1.82—1.90 (m, 2 H,
C(7)H2(THQ)); 2.69 (t, 2 H, C(5)H2(THQ), J = 5.9 Hz); 2.92 (t, 2 H,
C(8)H2(THQ), J = 5.9 Hz); 4.73 (s, 2 H, CH2S); 7.25—7.32
(m, 3 H, NH and H(3,5)Bza); 7.47—7.60 (m, 2 H, H(4,6)Bza);
7.81 (br.s, 1 H, NH); 7.85 (s, 1 H, H(5)py). 13C NMR, : 21.63
(C(6)THQ), 21.91 (C(7)THQ), 26.87 (C(5)THQ), 31.00 (CH2S),
32.29 (C(8)THQ), 102.90 (C(3)THQ), 115.81 (CNTHQ), 127.10
(C(5)Bza), 127.83 (C(6)Bza), 128.33 (C(4a)THQ), 129.67 (C(3)Bza),
130.78 (C(4)Bza), 135.73 (C(2)Bza), 136.39 (C(1)Bza), 141.74
(C(4)THQ), 157.23 (C(2)THQ), 161.47 (C(8a)THQ), 170.32 (C=O).
2-{[2-(Aminocarbonyl)benzyl]thio}-3-cyano-4,6-diphenyl-
pyridine (3c). Yield 0.97 g (78%), colorless crystals, m.p.
240—242 C (DMF—MeOH). Found (%): C, 74.17; H, 4.45;
N, 9.88; S, 7.45. C26H19N3OS. Calculated (%): C, 74.09;
H, 4.54; N, 9.97; S, 7.61. IR, /cm–1: 3368, 3184 (NH2), 2216 (CN),
1652 (C=O), 1620, 1568, 1528, 1368, 776. 1H NMR, : 4.98
(s, 2 H, CH2S); 7.30—7.40 (m, 2 H, H(3,5)Bza); 7.42 (br.s, 1 H,
NH); 7.52—7.67 (m, 8 H, H(3,4,5)6-Ph, H(3,4,5)4-Ph and
H(4,6)Bza); 7.70—7.78 (m, 2 H, H(2,6)4-Ph); 7.86—7.96 (m, 2 H,
H(5)py and NH); 8.32 (d, 2 H, H(2,6)6-Ph, J = 7.3 Hz). 13C
NMR, : 31.67 (CH2S), 102.51 (C(3)py), 115.58 (CNpy), 116.23
(C(5)py), 127.34 (C(5)Bza), 127.58 (C(3,5)6-Ph), 127.98 (C(6)Bza),
128.65 (C(3,5)4-Ph), 128.81 (C(2,6)4-Ph), 129.02 (C(2,6)6-Ph),
129.90 (C(3)Bza), 130.06 (C(4)4-Ph), 130.40 (C(4)6-Ph), 130.79
(C(4)Bza), 135.68 (C(2)Bza), 135.75 (C(1)Bza), 135.91 (C(1)4-Ph),
136.68 (C(1)6-Ph), 154.34 (C(4)py), 157.94 (C(6)py), 162.80 (C(2)py),
170.32 (C=O).
3-Cyanopyridine-2(1H)-thiones 1a,13 1b,14 1c,15 and 1d16
were synthesized by known procedures.
2-(Chloromethyl)benzamide (2). To H2SO4 (70 mL) heated
to 80—85 C, finely ground 2-(chloromethyl)benzonitrile (15.1 g,
0.1 mol) was added by portions. The reaction mixture was stirred
at 90 C for 1 h, cooled to room temperature and poured into
cold water (300 mL). The precipitated product was collected by
filtration, washed with cold water, and dried in air. Yield 13.2 g
(78%), colorless crystals, m.p.194—196 C (EtOH). Found (%):
C, 56.88; H, 4.62; N, 8.14; Cl, 20.74. C8H8ClNO. Calculated (%):
C, 56.65; H, 4.75; N, 8.26; Cl, 20.90. IR, /cm–1: 3381, 3189,
3037, 2924, 1680, 1647, 1618, 1577, 1446, 1392, 1082, 740.
1H NMR, : 4.90 (s, 2 H, CH2Cl); 7.27 (br.s, 1 H, NH); 7.39
(t, 1 H, H (5)Bza, J = 6.6 Hz); 7.42—7.50 (m, 2 H, H (3,4)Bza);
7.51 (br.s, 1 H, NH); 7.58 (d, 1 H, H (6)Bza, J = 7.3 Hz).
Synthesis of substituted 2-{[2-(aminocarbonyl)benzyl]thio}-
3-cyanopyridines 3a—d (general procedure). To a solution of
3-cyanopyridine-2(1H)-thione 1a—d (3 mmol) and 2-(chloro-
methyl)benzamide 2 (0.51 g, 3 mmol) in DMF (5 mL), Et3N
(0.6 mL, 4.2 mmol) was added. The reaction mixture was stirred
at 60—65 C for 40 min and poured into water (30 mL). The
precipitated solid was collected by filtration, washed with water,
dried in air, and crystallized from the appropriate solvent.
2-{[2-(Aminocarbonyl)benzyl]thio}-3-cyano-4,6-dimethyl-
pyridine (3a). Yield 0.72 g (81%), colorless crystals, m.p. 194—196 C
(DMF—MeOH). Found (%): C, 64.73; H, 5.16; N, 14.22;
S, 10.66. C16H15N3OS. Calculated (%): C, 64.62; H, 5.08;
N, 14.13; S, 10.78. IR, /cm–1: 3368, 3200 (NH2), 3068, 2212 (CN),
1652 (C=O), 1620, 1584, 1544, 1392, 1272. 1H NMR, : 2.37
(s, 3 H, C(4)Me); 2.54 (s, 3 H, C(6)Me); 4.74 (s, 2 H, CH2S);
7.08 (s, 1 H, H(5)py); 7.30—7.43 (m, 3 H, NH and H(3,5)Bza);
7.46—7.56 (m, 2 H, H(4,6)Bza); 7.87 (br.s, 1 H, NH). 13C NMR,
2-{[2-(Aminocarbonyl)benzyl]thio-3-cyano-4-(trifluorome-
thyl)-6-phenylpyridine (3d). Yield 0.92 g (75%), colorless crystals,
m.p. 210—212 C (MeOH). Found (%): C, 60.88; H, 3.51;
N, 9.96; S, 7.86. C21H14F3N3OS. Calculated (%): C, 61.01;
H, 3.41; N, 10.16; S, 7.75. IR, /cm–1: 3378, 3187 (NH2), 3090,
2230 (CN), 1654 (C=O), 1624, 1583, 1553, 1375, 1313, 1174, 1144.
1H NMR, : 4.99 (s, 2 H, CH2S); 7.28—7.42 (m, 3 H, NH and
H(3,5)Bza); 7.50—7.72 (m, 5 H, H(3,4,5)6-Ph and H(4,6)Bza);
7.96 (br.s, 1 H, NH); 8.23 (s, 1 H, H(5)py); 8.35 (d, 2 H, H(2,6)6-Ph
,

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Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
Kalugin and Shestopalov
J = 8.1 Hz). 13C NMR, : 32.12 (CH2S), 99.28 (C(3)py), 112.48
(q, C(5)py, J = 4.4 Hz); 112.84 (CNpy), 121.10 (q, CF3, JCF
= 275.3 Hz); 127.54 (C(5)Bza), 127.97 (C(3,5)6-Ph), 128.06 (C(6)Bza),
129.19 (C(2,6)6-Ph), 129.99 (C(3)Bza), 130.42 (C(4)6-Ph), 131.75
(C(4)Bza), 135.18 (C(2)Bza), 135.60 (C(1)Bza), 135.77 (C(1)6-Ph),
140.84 (q, C(4)py, J = 34.2 Hz); 159.70 (C(6)py), 164.52 (C(2)py),
170.23 (C=O).
Reaction of benzamides 3a—d with potassium tert-butoxide
(general procedure). To a solution of benzamide 3a—d (2 mmol)
in anhydrous DMF (5 mL), potassium tert-butoxide (0.34 g,
3 mmol) was added. The reaction mixture was stirred at 70—75 C
for 40 mim and poured into water (40 mL). The precipitate
formed was collected by filtration, dried in air, and crystallized
from the appropriate solvent.
(C(2,6)7-Ph), 129.70 (C(4)9-Ph), 130.37 (C(2,6)9-Ph), 131.45
(C(2)PTI), 132.01 (C(11b)PTI), 137.47 (C(1)7-Ph), 138.05 (C(1)9-Ph),
142.66 (C(7)PTI), 147.67 (C(6a)PTI), 154.43 (C(9)PTI), 155.35
(C(5)PTI), 161.73 (C(12a)PTI).
5-Amino-9-phenyl-7-(trifluoromethyl)pyrido[3΄,2΄:4,5]thieno-
[3,2-c]isoquinoline (4d). Yield 0.41 g (52%), yellow crystals, m.p.
227—230 C (CH2Cl2). Found (%): C, 63.58; H, 3.14; N, 10.51;
S, 8.03. C21H12F3N3S. Calculated (%): C, 63.79; H, 3.06;
N, 10.63; S, 8.11. IR, /cm–1: 3409, 3301, 3221, 1632, 1617, 1572,
1418, 1367, 1242, 1150, 1106, 769, 758, 706, 669. 1H NMR, :
7.06 (s, 2 H, NH2); 7.53—7.63 (m, 3 H, H(3,4,5)9-Ph); 7.73
(t, 1 H, H(3)PTI, J = 8.1 Hz); 7.88 (t, 1 H, H(2)PTI, J = 8.1 Hz);
=
8.04 (d, 1 H, H(1)PTI, J = 8.1 Hz); 8.31 (d, 2 H, H(2,6)9-Ph
J = 8.1 Hz); 8.33 (s, 1 H, H(8)PTI); 8.48 (d, 1 H, H(4)PTI
J = 8.1 Hz). 13C NMR, : 106.83 (C(11a)PTI), 113.62 (q, C(8)PTI
,
,
,
5-Amino-7,9-dimethylpyrido[3΄,2΄:4,5]thieno[3,2-c]isoquin-
oline (4a). Yield 0.44 g (79%), orange-yellow crystals, m.p.
278—280 C (DMF—MeOH). Found (%): C, 68.97; H, 4.88;
N, 15.17; S, 11.61. C16H13N3S. Calculated (%): C, 68.79; H, 4.69;
N, 15.04; S, 11.48. IR, /cm–1: 3472, 3436, 3328, 3224 (NH2),
1616, 1568, 1544, 1420, 1324, 756. 1H NMR, : 2.57 (s, 3 H,
C(7)Me); 3.02 (s, 3 H, C(9)Me); 6.98 (s, 2 H, NH2); 7.14 (s, 1 H,
J = 5.5 Hz); 117.68 (C(4a)PTI), 121.06 (C(6b)PTI), 121.80 (q, CF3,
JCF = 275.3 Hz); 124.13 (C(4)PTI), 125.41 (C(3)PTI), 127.11
(C(3,5)9-Ph), 127.42 (C(1)PTI), 129.03 (C(2,6)9-Ph), 130.08
(C(4)9-Ph), 131.34 (C(2)PTI), 131.47 (C(11b)PTI), 132.20 (q, C(7)PTI
,
J = 34.2 Hz); 136.92 (C(1)9-Ph), 140.78 (C(6a)PTI), 154.79
(C(9)PTI), 156.16 (C(5)PTI), 161.94 (C(10a)PTI).
H(8)PTI); 7.61 (t, 1 H, H(3)PTI, J = 7.3 Hz); 7.79 (t, 1 H, H(2)PTI
,
Synthesis of substituted 2-{[2-(aminocarbonyl)benzyl]sulfin-
yl}-3-cyanopyridines 5a—d (general procedure). To a stirred
suspension of compound 3a—d (3 mmol) in a mixture of AcOH
(10 mL) and CHCl3 (2 mL), 30% aqueous H2O2 (0.33 mL,
3.3 mmol) was added. The reaction mixture was stirred at 50—55 C
for 3—4 h (TLC monitoring) and cooled to room temperature.
Acetic acid was neutralized with a solution of Na2CO3. The
target product was extracted with CHCl3 (320 mL). The com-
bined organics were dried with MgSO4, filtered, and concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (gradient elution with hexane—CHCl3 (1 : 3),
then CHCl3) and subsequent crystallization from the appropriate
solvent.
2-{[2-(Aminocarbonyl)benzyl]sulfinyl}-3-cyano-4,6-dimethyl-
pyridine (5a). Yield 0.67 g (72%), colorless crystals, m.p.
196—198 C (acetone). Found (%): C, 61.53; H, 4.96; N, 13.27;
S, 10.38. C16H15N3O2S. Calculated (%): C, 61.32; H, 4.82;
N, 13.41; S, 10.23. IR, /cm–1: 3400, 3347, 3285, 3190 (NH2),
2927, 2219 (CN), 1673 (C=O), 1614, 1591, 1391, 1081, 1060
(S=O), 774. 1H NMR, : 2.46 (s, 3 H, C(4)Me); 2.57 (s, 3 H,
C(6)Me); 4.70 (d, 1 H, CH2S(O), J = 12.5 Hz); 4.80 (d, 1 H,
CH2S(O), J = 12.5 Hz); 7.14 (d, 1 H, H(3)Bza, J = 7.3 Hz);
7.30—7.40 (m, 3 H, H(4,5)Bza and NH); 7.50—7.58 (m, 2 H,
H(6)Bza and H(5)py); 7.71 (br.s, 1 H, NH). 13C NMR, : 19.59
(C(4)Me); 24.05 (C(6)Me); 57.04 (CH2S(O)), 106.26 (C(3)py),
112.89 (CNpy), 126.22 (C(5)py), 128.06 (C(5)Bza), 128.10
(C(6)Bza), 128.32 (C(1)Bza), 129.79 (C(3)Bza), 132.42 (C(4)Bza),
136.17 ((C(2)Bza), 153.59 (C(4)py), 162.15 (C(6)py), 163.76
(C(2)py), 169.56 (C=O).
J = 7.3 Hz); 7.90 (d, 1 H, H(1)PTI, J = 8.1 Hz); 8.39 (d, 1 H,
H(4)PTI, J = 7.3 Hz). 13C NMR, : 18.96 (C(7)Me); 23.81
(C(9)Me); 116.12 (C(11a)PTI), 116.91 (C(4a)PTI), 122.10 (C(8)PTI),
123.53 (C(4)PTI), 125.20 (C(6b)PTI), 125.38 (C(3)PTI), 126.49
(C(1)PTI), 131.16 (C(2)PTI), 132.07 (C(11b)PTI), 144.08 (C(7)PTI),
144.90 (C(6a)PTI), 156.03 (C(9)PTI), 156.50 (C(5)PTI), 159.85
(C(10a)PTI).
5-Amino-8,9,10,11-tetrahydroisoquinolino[3΄,4΄:4,5]thieno-
[2,3-b]quinoline (4b). Yield 0.45 g (74%), yellow crystals, m.p.
287—290 C (DMF—MeOH). Found (%): C, 70.63; H, 5.05;
N, 13.67; S, 10.61. C18H15N3S. Calculated (%): C, 70.79; H, 4.95;
N, 13.76; S, 10.50. IR, /cm–1: 3360, 3256 (NH2), 3144,
2928, 1644, 1616, 1568, 1528, 1424, 1320, 760. 1H NMR, :
1.70—1.90 (m, 4 H, C(9,10)H2(THIQTQ)); 2.85—3.02 (m, 4 H,
C(8,11)H2(THIQTQ)); 7.09 (s, 2 H, NH2); 7.60 (t, 1 H, H(3)THIQTQ
,
J = 7.3 Hz); 7.77 (t, 1 H, H(2)THIQTQ, J = 8.1 Hz); 7.86 (d, 1 H,
H(1)THIQTQ, J = 8.1 Hz); 8.06 (s, 1 H, H(7)THIQTQ); 8.39 (d, 1 H,
H(4)THIQTQ, J = 8.1 Hz). 13C NMR, : 22.38 (C(9)THIQTQ),
22.62 (C(10)THIQTQ), 28.39 (C(8)THIQTQ), 32.45 (C(11)THIQTQ),
116.72 (C(13a)THIQTQ), 117.80 (C(4a)THIQTQ), 123.59 (C(4)THIQTQ),
125.50 (C(3)THIQTQ), 126.48 (C(1)THIQTQ), 127.67
(C(6b)THIQTQ), 128.88 (C(7a)THIQTQ), 129.66 (C(7)THIQTQ),
131.26 (C(2)THIQTQ), 132.29 (C(13b)THIQTQ), 141.99
(C(6a)THIQTQ), 156.68 (C(5)THIQTQ), 156.99 (C(11a)THIQTQ),
157.18 (C(12a)THIQTQ).
5-Amino-7,9-diphenylpyrido[3΄,2´:4,5]thieno[3,2-c]isoquin-
oline (4c). Yield 0.58 g (72%), yellow crystals, m.p. 232—234 C
(DMF—MeOH). Found (%): C, 77.22; H, 4.28; N, 10.28;
S, 7.70. C26H17N3S. Calculated (%): C, 77.39; H, 4.25; N, 10.41;
S, 7.95. IR, /cm–1: 3408, 3376, 3240, 3216 (NH2), 3048, 1632,
1624, 1616, 1568, 1536, 1448, 1416, 1324, 752. 1H NMR, : 6.38
(s, 2 H, NH2); 7.45—7.60 (m, 6 H, H(3,4,5)9-Ph and H(3,4,5)7-Ph);
7.63 (t, 1 H, H(3)PTI, J = 8.1 Hz); 7.72—7.82 (m, 2 H, H(2,6)7-Ph);
7.83 (t, 1 H, H(2)PTI, J = 7.3 Hz); 7.88 (s, 1 H, H(8)PTI); 7.97
2-{[(2-Aminocarbonyl)benzyl]sulfinyl}-3-cyano-5,6,7,8-tetra-
hydroquinoline (5b). Yield 0.75 g (73%), colorless crystals, m.p.
203—205 C (acetone). Found (%): C, 63.84; H, 5.17; N, 12.25;
S, 9.40. C18H17N3O2S. Calculated (%): C, 63.70; H, 5.05;
N, 12.38; S, 9.45. IR, /cm–1: 3393, 3309, 3255, 3206 (NH2),
2942, 2229 (CN), 1658 (C=O), 1617, 1384, 1047, 1037 (S=O),
1023, 778. 1H NMR, : 1.70—1.80 (m, 2 H, C(6)H2(THQ));
(d, 1 H, H(1)PTI, J = 8.1 Hz); 8.25 (d, 2 H, H(2,6)9-Ph
,
J = 8.1 Hz); 8.37 (d, 1 H, H(4)PTI, J = 8.1 Hz). 13C NMR, :
117.64 (C(4a)PTI), 117.87 (C(11a)PTI), 119.21 (C(8)PTI), 124.04
(C(4)PTI), 124.59 (C(6b)PTI), 125.50 (C(3)PTI), 127.12 (C(1)PTI),
127.19 (C(3,5)9-Ph), 127.58 (C(3,5)7-Ph), 128.64 (C(4)7-Ph), 129.14
1.80—1.90 (m, 2 H, C(7)H2(THQ)); 2.82 (t, 2 H, C(5)H2(THQ),
J = 5.9 Hz); 2.92 (t, 2 H, C(8)H2(THQ), J = 5.9 Hz); 4.70 (d, 1 H,
CH2S(O), J = 11.7 Hz); 4.82 (d, 1 H, CH2S(O), J = 11.7 Hz);
7.12—7.22 (m, 1 H, H(3)Bza); 7.27 (br.s, 1 H, NH); 7.36 (m, 2 H,

5-Aminopyrido[3´,2´:4,5]thieno[3,2-c]isoquinolines Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
1497
H(4,5)Bza); 7.52 (d, 1 H, H(6)Bza, J = 7.3 Hz); 7.63 (br.s, 1 H,
NH); 8.05 (s, 1 H, H(4)py). 13C NMR, : 21.21 (C(6)THQ), 21.70
(C(7)THQ), 27.54 (C(5)THQ), 32.12 (C(8)THQ), 56.87 (CH2S(O)),
105.16 (C(3)THQ), 114.03 (CNTHQ), 128.00 (C(1)Bza), 128.10
(C(5)Bza), 128.23 (C(6)Bza), 129.80 (C(3)Bza), 132.52 (C(4)Bza),
135.29 (C(2)Bza), 136.13 (C(4a)THQ), 143.01 (C(4)THQ), 160.32
(C(2)THQ), 162.33 (C(8a)THQ), 169.51 (C=O).
NH). 13C NMR, : 20.09 (C(4)Me); 23.95 (C(6)Me); 53.77
(CH2SO2), 104.96 (C(3)py), 112.72 (CNpy), 125.77 (C(1)Bza),
127.94 (C(5)py), 128.25 (C(5)Bza), 128.52 (C(6)Bza), 129.79
(C(3)Bza), 133.44 (C(4)Bza), 137.14 (C(2)Bza), 154.88 (C(4)py),
157.05 (C(2)py), 161.72 (C(6)py), 169.84 (C=O).
2-{[(2-Aminocarbonyl]benzyl]sulfonyl}-3-cyano-5,6,7,8-tetra-
hydroisoquinoline (7b). Yield 0.75 g (71%), colorless crystals, m.p.
241—243 C (DMF—MeOH). Found (%): C, 60.70; H, 4.71;
N, 11.77; S, 9.11. C18H17N3O3S. Calculated (%): C, 60.83;
H, 4.82; N, 11.82; S, 9.02. IR, /cm–1: 3432, 3338, 3290, 3209
(NH2), 2950, 2232 (CN), 1669 (C=O), 1579, 1335, 1310 (SO2),
1300, 1138 (SO2), 782, 739. 1H NMR, : 1.70—1.80 (m, 2 H,
C(6)H2(THQ)); 1.82—1.92 (m, 2 H, C(7)H2(THQ)); 2.85 (t, 2 H,
C(5)H2(THQ), J = 5.9 Hz); 2.96 (t, 2 H, C(8)H2(THQ), J = 5.9 Hz);
5.37 (s, 2 H, CH2SO2); 7.27 (br.s, 1 H, NH); 7.37—7.49 (m, 3 H,
H(3,4,5)Bza); 7.51 (d, 1 H, H(6)Bza, J = 6.6 Hz); 7.67 (br.s, 1 H,
NH); 8.20 (s, 1 H, H(5)py). 13C NMR, : 20.99 (C(6)THQ), 21.56
(C(7)THQ), 27.64 (C(5)THQ), 31.99 (C(8)THQ), 54.12 (CH2SO2),
104.35 (C(3)py), 114.02 (CNpy), 125.95 (C(1)Bza), 128.20 (C(5)Bza),
128.47 (C(6)Bza), 129.83 (C(3)Bza), 133.45 (C(4)Bza), 136.87
(C(4a)THQ), 137.60 (C(2)Bza), 143.99 (C(4)THQ), 153.39 (C(2)THQ),
162.08 (C(8a)THQ), 169.66 (C=O).
2-{[2-(Aminocarbonyl)benzyl]sulfonyl}-3-cyano-4,6-diphen-
ylpyridine (7c). Yield 0.98 g (72%), colorless crystals, m.p.
240—242 C (MeOH). Found (%): C, 69.03; H, 4.17; N, 9.18;
S, 7.14. C26H19N3O3S. Calculated (%): C, 68.86; H, 4.22; N, 9.27;
S, 7.07. IR, ν/cm–1: 3463, 3332, 3281, 3202 (NH2), 3067, 2227
(CN), 1664 (C=O), 1585, 1575, 1386, 1320 (SO2), 1142 (SO2),
782, 756. 1H NMR, : 5.65 (s, 2 H, CH2SO2); 7.33 (br.s, 1 H,
NH); 7.43—7.68 (m, 10 H, H(3,4,5,6)Bza, H(3,4,5)6-Ph and
H(3,4,5)4-Ph); 7.70—7.78 (m, 2 H, H(2,6)4-Ph); 7.84 (br.s, 1 H,
NH); 8.31 (d, 2 H, H(2,6)6-Ph, J = 6.6 Hz); 8.47 (s, 1 H, H(5)py).
13C NMR, : 54.52 (CH2SO2), 104.02 (Cpy(3)), 113.86 (CNpy),
124.17 (C(5)py), 126.19 (C(1)Bza), 128.57 (C(3,5)6-Ph), 128.93
(C(5)Bza), 129.18 (C(6)Bza), 129.30 (C(3,5)4-Ph), 129.67 (C(2,6)4-Ph),
129.72 (C(2,6)6-Ph), 130.43 (C(4)4-Ph), 130.82 (C(4)6-Ph), 132.06
(C(3)Bza), 134.09 (C(4)Bza), 135.75 (C(1)4-Ph), 135.84 (C(1)6-Ph),
137.80 (C(2)Bza), 157.34 (C(4)py), 158.38 (C(6)py), 159.55 (C(2)py),
170.51 (C=O).
2-{[2-(Aminocarbonyl)benzyl]sulfinyl}-3-cyano-4,6-diphen-
ylpyridine (5c). Yield 0.68 g (52%), colorless crystals, m.p.
247—249 C (DMF—MeOH). Found (%): C, 71.55; H, 4.48;
N, 9.49; S, 7.25. C26H19N3O2S. Calculated (%): C, 71.38; H, 4.38;
N, 9.60; S, 7.33. IR, /cm–1: 3478, 3396, 3291, 3239, 3178 (NH2),
3066, 2223 (CN), 1670 (C=O), 1583, 1574, 1368, 1083, 1067
(S=O), 1058, 701. 1H NMR, : 4.94 (s, 2 H, CH2S(O)); 7.20—7.28
(m, 1 H, H(3)Bza); 7.34—7.45 (m, 2 H, NH and H(5)Bza);
7.48—7.68 (m, 9 H, H(4,6)Bza, H(3,4,5)6-Ph, H(3,4,5)4-Ph and
NH); 7.70—7.78 (m, 2 H, H(2,6)4-Ph); 8.22—8.32 (m, 3 H,
H(2,6)6-Ph and H(5)py). 13C NMR, : 57.53 (CH2S(O)), 105.22
(C(3)py), 113.56 (CNpy), 122.03 (C(5)py), 127.89 (C(3,5)6-Ph),
128.17 (C(5)Bza), 128.29 (C(6)Bza), 128.55 (C(1)Bza), 128.79
(C(3,5)4-Ph), 128.95 (C(2,6)4-Ph), 128.98 (C(2,6)6-Ph), 129.96
(C(4)4-Ph), 130.18 (C(4)6-Ph), 131.16 (C(3)Bza), 132.45 (C(4)Bza),
135.19 (C(2)Bza), 135.93 (C(1)4-Ph), 136.07 (C(1)6-Ph), 155.05
(C(4)py), 158.69 (C(6)py), 165.38 (C(2)py), 169.60 (C=O).
2-{[2-(Aminocarbonyl)benzyl]sulfinyl}-3-cyano-4-trifluoro-
methyl-6-phenylpyridine (5d). Yield 1.03 g (80%), colorless
crystals, m.p. 213—216 C (acetone—hexane). Found (%): C, 58.92;
H, 3.41; N, 9.63; S, 7.36. C21H14F3N3O2S. Calculated (%):
C, 58.74; H, 3.29; N, 9.79; S, 7.47. IR, /cm–1: 3395, 3286, 3239,
3178 (NH2), 3066, 2230 (CN), 1674 (C=O), 1583, 1574, 1368,
1061 (S=O), 1058, 701. 1H NMR, : 4.87 (d, 1 H, CH2S(O),
J = 12.5 Hz); 4.94 (d, 1 H, CH2S(O), J = 12.5 Hz); 7.22—7.30
(m, 1 H, H(3)Bza); 7.33—7.45 (m, 3 H, H(4,5)Bza and NH);
7.52—7.67 (m, 4 H, H(6)Bza and H(3,4,5)6-Ph); 7.79 (br.s, 1 H,
NH); 8.24 (d, 2 H, H(2,6)6-Ph, J = 6.6 Hz); 8.61 (s, 1 H, H(5)py).
13C NMR, : 57.84 (CH2S(O)), 102.49 (C(3)py), 110.73 (CNpy),
118.43 (q, C(5)py, J = 4.4 Hz); 121.32 (q, CF3, JCF
=
= 275.3 Hz); 128.14 (C(5)Bza), 128.22 (C(1)Bza), 128.22 (C(3,5)6-Ph),
128.29 (C(6)Bza), 129.11 (C(2,6)6-Ph), 129.95 (C(4)6-Ph), 132.05
(C(3)Bza), 132.64 (C(4)Bza), 134.91 (C(2)Bza), 135.81 (C(1)6-Ph),
141.45 (q, C(4)py, J = 33.2 Hz); 160.12 (C(6)py), 167.15 (C(2)py),
169.54 (C=O).
2-{[2-(Aminocarbonyl)benzyl]sulfonyl}-3-cyano-4-trifluoro-
methyl-6-phenylpyridine (7d). Yield 1 g (75%), colorless crystals,
m.p. 230—232 C (MeOH). Found (%): C, 56.77; H, 3.11;
N, 9.31; S, 7.08. C21H14F3N3O3S. Calculated (%): C, 56.63;
H, 3.17; N, 9.43; S, 7.20. IR, /cm–1: 3477, 3331, 3280, 3196,
3184 (NH2), 3076, 2237 (CN), 1665 (C=O), 1590, 1429, 1380,
1326 (SO2), 1269, 1189, 1149 (SO2), 779. 1H NMR, : 5.55 (s, 2 H,
CH2SO2); 7.27 (br.s, 1 H, NH); 7.42—7.68 (m, 7 H, H(3,4,5,6)Bza
Synthesis of substituted 2-{[2-(aminocarbonyl)benzyl]sulfon-
yl}-3-cyanopyridines 7a—d (general procedure). To a stirred solu-
tion or suspension of benzamide 3a—d (3 mmol) in AcOH
(12—15 mL), finely ground KMnO4 (0.76 g, 4.8 mmol) was
added at such a rate to maintain the reaction temperature at
20—25 C. The mixture was stirred for 40 min, decolorized by
addition of a Na2SO3 solution, and poured into water (50 mL).
The precipitated product was collected by filtration, washed with
water, dried in air, and crystallized from the appropriate solvent.
2-{[2-(Aminocarbonyl)benzyl]sulfonyl}-3-cyano-4,6-dimeth-
ylpyridine (7a). Yield 0.47 g (48%), colorless crystals, m.p.
230—232 C (DMF—MeOH). Found (%): C, 58.23; H, 4.71; N, 12.82;
S, 9.61. C16H15N3O3S. Calculated (%): C, 58.35; H, 4.59;
N, 12.76; S, 9.73. IR, /cm–1: 3429, 3296, 3183 (NH2), 3013,
2959, 2237 (CN), 1670, 1662 (C=O), 1609, 1592, 1381, 1311
(SO2), 1300, 1148, 1132 (SO2), 879, 778. 1H NMR, : 2.52 (s, 3 H,
C(4)Me); 2.61 (s, 3 H, C(6)Me); 5.42 (s, 2 H, CH2SO2); 7.31
(br.s, 1 H, NH); 7.40—7.48 (m, 3 H, H(3,4,5)Bza); 7.52
(d, 1 H, H(6)Bza, J = 6.6 Hz); 7.72 (s, 1 H, H(5)py); 7.75 (br.s, 1 H,
and H(3,4,5)6-Ph); 7.79 (br.s, 1 H, NH); 8.25 (d, 2 H, H(2,6)6-Ph
,
J = 6.6 Hz); 8.76 (s, 1 H, H(5)py). 13C NMR, : 55.38 (CH2SO2),
101.67 (C(3)py), 111.70 (CNpy), 120.97 (q, C(5)py, J = 5.5 Hz),
121.78 (q, CF3, JCF = 277.6 Hz); 126.06 (C(1)Bza), 128.87 (C(5)Bza),
128.92 (C(3,5)6-Ph), 129.33 (C(6)Bza), 129.78 (C(2,6)6-Ph), 130.57
(C(4)6-Ph), 132.97 (C(3)Bza), 134.12 (C(4)Bza), 134.93 (C(1)6-Ph),
137.35 (C(2)Bza), 143.25 (q, C(4)py, J = 33.2 Hz); 160.00 (C(2)py),
160.43 (C(6)py), 170.34 (C=O).
Synthesis of substituted 5-aminopyrido[3΄,2΄:4,5]thieno[3,2-c]-
isoquinoline oxides 6a—d (general procedure). To a solution of
benzamide 5a—d (2 mmol) in anhydrous DMF (4 mL), potas-
sium tert-butoxide (0.34 g, 3 mmol) was added. The reaction
mixture was stirred at 55—60 C for 50 min and poured into
water (20 mL). The products were extracted with CHCl3 (315 mL).

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Kalugin and Shestopalov
The combined organic layers were washed with water (320 mL),
dried with MgSO4, and concentrated. The target products were
purified by silica gel column chromatography (elution with
CHCl3) and subsequent crystallization from appropriate solvent.
Chromatographic purification of the products obtained by the
reaction of benzamide 5d with ButOK gives also 0.1 g (13%) of
compound 4d.
5-Amino-7,9-dimethylpyrido[3΄,2΄:4,5]thieno[3,2-c]isoquin-
oline 11-oxide (6a). Yield 0.44 g (75%), yellow crystals, m.p.
272—274 C (DMF—MeOH). Found (%): C, 64.81; H, 4.36;
N, 14.12; S, 10.97. C16H13N3OS. Calculated (%): C, 65.07;
H, 4.44; N, 14.23; S, 10.85. IR, /cm–1: 3344, 3240 (NH2), 3168,
2920, 1632, 1616, 1592, 1568, 1544, 1504, 1420, 1368, 1000 (S=O),
968, 752. 1H NMR, : 2.51 (s, 3 H, C(7)Me); 2.82 (s, 3 H, C(9)Me);
7.23 (s, 1 H, H(8)PTI); 7.55 (t, 1 H, H(3)PTI, J = 7.3 Hz); 7.78
(t, 1 H, H(2)PTI, J = 7.3 Hz); 7.81 (s, 2 H, NH2); 7.97 (d, 1 H,
H(1)PTI, J = 8.1 Hz); 8.31 (d, 1 H, H(4)PTI, J = 8.1 Hz). 13C
NMR, : 18.48 (C(7)Me); 23.53 (C(9)Me); 116.10 (C(4a)PTI),
118.91 (C(11a)PTI), 122.43 (C(4)PTI), 125.47 (C(3)PTI), 126.53
(C(6b)PTI), 126.76 (C(1)PTI), 128.26 (C(8)PTI), 132.51 (C(2)PTI),
133.83 (C(11b)PTI), 146.01 (C(6a)PTI), 151.20 (C(7)PTI), 158.58
(C(5)PTI), 160.75 (C(9)PTI), 166.06 (C(10a)PTI).
340—342 C (DMF—MeOH). Found (%): C, 61.88; H, 4.16;
N, 13.50; S, 10.21. C16H13N3O2S. Calculated (%): C, 61.72; H, 4.21;
N, 13.50; S, 10.30. IR, /cm–1: 3472, 3416, 3376 (NH2), 2928,
1616, 1544, 1504, 1424, 1280 (SO2), 1152 (SO2), 1116, 752.
1H NMR, : 2.57 (s, 3 H, C(7)Me); 2.91 (s, 3 H, C(9)Me); 7.43
(s, 1 H, H(8)PTI); 7.64 (t, 1 H, H(3)PTI, J = 8.1 Hz); 7.86—7.93
(m, 2 H, H(1,2)PTI); 8.18 (s, 2 H, NH2); 8.41 (d, 1 H, H(4)PTI
,
J = 8.8 Hz). 13C NMR, : 19.38 (C(7)Me); 23.56 (C(9)Me);
111.63 (C(11a)PTI), 115.77 (C(4a)PTI), 121.73 (C(4)PTI), 122.35
(C(6b)PTI), 125.69 (C(3)PTI), 127.43 (C(1)PTI), 129.84 (C(11b)PTI),
129.87 (C(8)PTI), 133.25 (C(2)PTI), 146.72 (C(6a)PTI), 147.05
(C(7)PTI), 157.56 (C(10a)PTI), 160.03 (C(5)PTI), 161.46 (C(9)PTI).
5-Amino-8,9,10,11-tetrahydroisoquinolino[3΄,4΄:4,5]thieno-
[2,3-b]quinoline 13,13-dioxide (8b). Yield 0.49 g (72%), light
yellow crystals, m.p. 322—324 C (DMF—MeOH). Found (%):
C, 64.31; H, 4.39; N, 12.33; S, 9.61. C18H15N3O2S. Calculat-
ed (%): C, 64.08; H, 4.48; N, 12.45; S, 9.50. IR, /cm–1: 3456,
3408, 3320, 3248 (NH2), 3216, 2952, 1640, 1624, 1616, 1584,
1564, 1544, 1512, 1432, 1384, 1292 (SO2), 1136 (SO2), 1024,
768. 1H NMR, : 1.70—1.80 (m, 2 H, C(9)H2(THIQTQ));
1.82—1.92 (m, 2 H, C(10)H2(THIQTQ)); 2.86—3.00 (m, 4 H,
C(8,11)H2(THIQTQ)); 7.65 (t, 1 H, H(3)THIQTQ, J = 8.1 Hz);
7.87—7.93 (m, 2 H, H(1,2)THIQTQ); 7.96 (s, 1 H, H(8)THIQTQ);
8.25 (br.s, 2 H, NH2); 8.44 (d, 1 H, H(4)THIQTQ, J = 8.8 Hz).
13C NMR, : 21.75 (C(9)(THIQTQ)); 22.21 (C(10)(THIQTQ)); 28.79
(C(8)(THIQTQ)); 32.26 (C(11)(THIQTQ)); 112.49 (C(13a)THIQTQ),
116.75 (C(4a)THIQTQ), 121.74 (C(4)THIQTQ), 124.94 (C(6b)THIQTQ),
125.84 (C(3)THIQTQ), 127.53 (C(1)THIQTQ), 129.83 (C(13b)THIQTQ),
130.51 (C(7)THIQTQ), 133.36 (C(2)THIQTQ), 137.81 (C(7a)THIQTQ),
144.80 (C(6a)THIQTQ), 154.81 (C(12a)THIQTQ), 160.12 (C(5)THIQTQ),
162.01 (C(11a)THIQTQ).
5-Amino-8,9,10,11-tetrahydroisoquinolino[3΄,4΄:4,5]thieno-
[2,3-b]quinoline 13-oxide (6b). Yield 0.45 g (70%), yellow crys-
tals, m.p. 288—290 C (DMF—MeOH). Found (%): C, 67.45;
H, 4.77; N, 12.88; S, 9.83. C18H15N3OS. Calculated (%): C, 67.27;
H, 4.70; N, 13.07; S, 9.98. IR, /cm–1: 3328, 3264, 3216 (NH2),
2920, 2952, 1640, 1616, 1568, 1536, 1504, 1432, 1388, 1000
(S=O), 768. 1H NMR, : 1.70—1.80 (m, 2 H, C(9)H2(THIQTQ));
1.80—1.90 (m, 2 H, C(10)H2(THIQTQ)); 2.83—2.98 (m, 4 H,
C(8,11)H2(THIQTQ)); 7.58 (t, 1 H, H(3)THIQTQ, J = 8.1 Hz);
7.76—7.83 (m, 2 H, H(2,7)THIQTQ), 7.95 (s, 2 H, NH2);
5-Amino-7,9-diphenylpyrido[3΄,2΄:4,5]thieno[3,2-c]isoquin-
oline 11,11-dioxide (8c). Yield 0.67 g (77%), yellow crystals, m.p.
336—338 C (DMF—MeOH). Found (%): C, 71.61; H, 4.04;
N, 9.76; S, 7.25. C26H17N3O2S. Calculated (%): C, 71.71; H, 3.95;
N, 9.65; S, 7.36. IR, /cm–1: 3472, 3432, 3376 (NH2), 1616,
1600, 1592, 1584, 1576, 1544, 1424, 1284 (SO2), 1132 (SO2), 760.
1H NMR, : 7.45—7.60 (m, 6 H, H(3,4,5)9-Ph and H(3,4,5)7-Ph);
7.65 (t, 1 H, H(3)PTI, J = 8.1 Hz); 7.68 (br.s, 2 H, NH2);
7.70—7.78 (m, 2 H, H(2,6)7-Ph); 7.93 (t, 1 H, H(2)PTI, J = 7.3 Hz);
8.00 (d, 1 H, H(1)PTI, J = 8.1 Hz); 8.12 (s, 1 H, H(8)PTI);
8.00 (d, 1 H, H(1)THIQTQ, J = 8.1 Hz); 8.44 (d, 1 H, H(4)THIQTQ
,
J = 8.8 Hz). 13C NMR, : 21.91 (C(9)(THIQTQ)); 22.34
(C(10)(THIQTQ)); 28.58 (C(8)(THIQTQ)); 32.18 (C(11)(THIQTQ));
117.02 (C(4a)THIQTQ), 119.86 (C(13a)THIQTQ), 122.49 (C(4)THIQTQ),
125.59 (C(3)THIQTQ), 126.86 (C(1)THIQTQ), 129.33 (C(6b)THIQTQ),
130.54 (C(7)THIQTQ), 132.62 (C(2)THIQTQ), 133.76 (C(13b)THIQTQ),
135.82 (C(7a)THIQTQ), 149.04 (C(6a)THIQTQ), 158.73 (C(5)THIQTQ),
161.31 (C(11a)THIQTQ), 163.14 (C(12a)THIQTQ).
5-Amino-7,9-diphenylpyrido[3΄,2΄:4,5]thieno[3,2-c]isoquin-
oline 11-oxide (6c). Yield 0.23 g (27%), yellow crystals, m.p.
182—186 C (DMF—MeOH). Found (%): C, 74.58; H, 4.01;
N, 9.91; S, 7.77. C26H17N3OS. Calculated (%): C, 74.44; H, 4.08;
N, 10.02; S, 7.64. IR, /cm–1: 3444, 3426, 3319 (NH2), 3207,
3057, 2906, 1640, 1615, 1588, 1576, 1542, 1502, 1417, 1359, 1027,
1015 (S=O), 759, 696. 1H NMR, : 7.36 (br.s, 1 H, NH2);
7.51—7.63 (m, 7 H, H(3,4,5)9-Ph, H(3,4,5)7-Ph and H(3)PTI);
7.74—7.81 (m, 2 H, H(2,6)7-Ph); 7.85 (t, 1 H, H(2)PTI, J = 7.3 Hz);
8.05 (s, 1 H, H(8)PTI); 8.11 (d, 1 H, H(1)PTI, J = 7.3 Hz);
8.26—8.34 (m, 2 H, H(2,6)9-Ph); 8.38 (d, 1 H, H(4)PTI, J = 7.3 Hz).
13C NMR, : 116.62 (C(4a)PTI), 120.10 (C(11a)PTI), 122.59
(C(4)PTI), 124.61 (C(8)PTI), 125.40 (C(3)PTI), 126.30 (C(6b)PTI),
126.89 (C(1)PTI), 127.00 (C(3,5)9-Ph), 127.52 (C(3,5)7-Ph), 128.84
(C(4)7-Ph), 128.94 (C(2,6)7-Ph), 129.97 (C(4)9-Ph), 130.05
(C(2,6)9-Ph), 132.33 (C(2)PTI), 133.63 (C(11b)PTI), 136.07 (C(1)7-Ph),
136.80 (C(1)9-Ph); 148.09 (C(6a)PTI), 149.69 (C(7)PTI), 155.94
(C(9)PTI), 159.82 (C(5)PTI), 168.12 (C(10a)PTI).
8.22—8.30 (m, 2 H, H(2,6)9-Ph); 8.43 (d, 1 H, H(4)PTI
,
J = 8.1 Hz). 13C NMR, : 112.47 (C(11a)PTI), 116.34 (C(4a)PTI),
122.00 (C(4)PTI), 122.36 (C(6b)PTI), 124.82 (C(8)PTI), 125.73
(C(3)PTI), 126.32 (C(4)7-Ph), 127.30 (C(3,5)9-Ph), 127.76 (C(1)PTI),
127.82 (C(3,5)7-Ph), 129.31 (C(2,6)7-Ph), 129.79 (C(11b)PTI),
130.19 (C(2,6)9-Ph), 130.68 (C(4)9-Ph), 133.32 (C(2)PTI), 136.28
(C(1)7-Ph), 136.44 (C(1)9-Ph), 145.80 (C(7)PTI), 148.79 (C(6a)PTI),
157.36 (C(9)PTI), 159.09 (C(10a)PTI), 160.70 (C(5)PTI).
5-Amino-7-trifluoromethyl-9-phenylpyrido[3΄,2΄:4,5]thieno-
[3,2-c]isoquinoline 11,11-dioxide (8d). Yield 0.67 g (78%), yellow
crystals, m.p. > 350 C (CHCl3—MeOH). Found (%): C, 58.83;
H, 2.97; N, 9.96; S, 7.43. C21H12F3N3O2S. Calculated (%):
C, 59.02; H, 2.83; N, 9.83; S, 7.50. IR, /cm–1: 3405, 3308 (NH2),
3069, 2928, 1689, 1619, 1555, 1510, 1473, 1434, 1269 (SO2), 1152
(SO2), 1108, 871, 767, 757, 689. 1H NMR, : 6.89 (br.s, 2 H,
NH2); 7.40—7.53 (m, 4 H, H(3,4,5)9-Ph and H(3)PTI); 7.74
(t, 1 H, H(2)PTI, J = 7.3 Hz); 7.81 (d, 1 H, H(1)PTI, J = 7.3 Hz);
7.99 (d, 2 H, H(2,6)9-Ph, J= 8.1 Hz); 8.27 (d, 1 H, H(4)PTI, J = 7.3 Hz);
8.30 (s, 1 H, H(8)PTI).
Substituted 5-aminopyrido[3΄,2΄:4,5]thieno[3,2-c]isoquino-
line dioxides 8a—d were synthesized similarly to compounds 4a—d.
5-Amino-7,9-dimethylpyrido[3΄,2΄:4,5]thieno[3,2-c]isoquin-
oline 11,11-dioxide (8a). Yield 0.51 g (82%), yellow crystals, m.p.
2-(Chloromethyl)benzoyl chloride (13). To a solution of
o-toluoyl chloride (9.3 g, 60 mmol) in CCl4 (20 mL), sulfuryl

5-Aminopyrido[3´,2´:4,5]thieno[3,2-c]isoquinolines Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
1499
chloride (9.7 g, 72 mmol) and diazoisobutyronitrile (0.25 g,
1.5 mmol) were added. The reaction mixture was refluxed for 4 h,
cooled down, filtered, and concentrated in vacuo. Vacuum distil-
lation of the residue afforded 9.8 g (87%) of chloride 13, b.p.
172—174 C (36 Torr) (cf. Ref. 17: b.p. 135 C (14 Torr)).
CHCl3) afforded 0.22 g (43%) of compound 15, yellow crystals,
m.p. 226—228 C (DMF). Found (%): C, 68.89; H, 5.43;
N, 12.13; S, 9.05. C20H19N3OS. Calculated (%): C, 68.74;
H, 5.48; N, 12.02; S, 9.17. IR, /cm–1: 3064, 3052, 2957, 2915,
2851, 2837, 1582, 1563, 1396, 1367, 1265, 1247, 1118, 1021, 897,
763. 1H NMR, : 2.60 (s, 3 H, C(4)Me); 3.00 (s, 3 H, C(6)Me);
3.45 (t, 4 H, CH2NCH2, J = 4.4 Hz); 3.94 (t, 4 H, CH2OCH2,
4-[2-(Chloromethyl)benzoyl]morpholine (12). To a stirred
solution of 2-(chloromethyl)benzoyl chloride 13 (2.84 g, 15 mmol)
in CHCl3 (20 mL), a solution of morpholine (2.78 g, 32 mmol)
in CHCl3 (20 mL) was added dropwise at 0—5 C. The reaction
mixture was stirred at this temperature for 30 min and after warm-
ing up to room temperature was poured into water (60 mL). The
organic layer was separated, washed with water (2×30 mL), dried
with MgSO4, and the solvent was removed in vacuo. Purification
of the residue by silica gel column chromatography afforded 2.95 g
(82%) of compound 12, 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, 14.79. IR, /cm–1: 3479, 3255, 3060, 2967,
2920, 2856, 1633 (C=O), 1456, 1279, 1259, 1114, 1019, 846, 775,
741, 680. 1H NMR, : 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);
4.66—4.86 (m, 2 H, CH2Cl); 7.32 (t, 1 H, H(5)Bza, J = 6.6 Hz);
7.34—7.42 (m, 2 H, H(3,4)Bza); 7.47 (d, 1 H, H(6)Bza, J = 6.6 Hz).
3-Cyano-4,6-dimethyl-2-{[2-(4-morpholinocarbonyl)benzyl]-
thio}pyridine (14). To a suspension of pyridinethione 1a (1.64 g,
10 mmol) in CHCl3 (15 mL), Et3N (1.5 mL, 15 mmol) and
amide 12 (2.4 g, 10 mmol) were added. The reaction mixture was
refluxed for 1 h, cooled down, washed with water (220 mL),
and dried with MgSO4. Removal of the solvent in vacuo and
purification of the residue by silica gel column chromatography
(elution with CHCl3) afforded 3.1 g (84%) of amide 14, colorless
crystals, m.p. 158—160 C (MeOH). Found (%): C, 65.49;
H, 5.82; N, 11.38; S, 8.61. C20H21N3O2S. Calculated (%):
C, 65.37; H, 5.76; N, 11.44; S, 8.72. IR, /cm–1: 2969, 2920,
2861, 1622 (C=O), 1582, 1445, 1434, 1275, 1112, 1013, 781.
1H NMR, : 2.40 (s, 3 H, C(4)Me); 2.53 (s, 3 H, C(6)Me); 3.19
(t, 2 H, CH2N, J = 4.4 Hz); 3.56 (t, 2 H, CH2N, J = 4.4 Hz);
3.62 (t, 4 H, CH2OCH2, J = 4.4 Hz); 4.55 (s, 2 H, CH2S); 7.13
(s, 1 H, H(5)py); 7.29 (t, 1 H, H(5)Bza, J = 6.6 Hz); 7.30—7.40
(m, 2 H, H(2,3)Bza); 7.55 (d, 1 H, H(4)Bza, J = 7.3 Hz). 13C
NMR, : 19.58 (C(4)Me); 24.26 (C(6)Me); 30.69 (CH2S), 41.51
(CH2N), 47.28 (CH2N), 65.82 (CH2OCH2), 103.42 (C(3)py),
114.88 (CNpy), 120.58 (C(5)py), 126.51 (C(5)Bza), 127.40 (C(6)Bza),
129.00 (C(3)Bza), 130.68 (C(4)Bza), 134.50 (C(2)Bza), 135.65 (C(1)Bza),
152.56 (C(4)py), 160.01 (C(2)py), 161.44 (C(6)py), 168.02 (C=O).
7,9-Dimethyl-5-(morpholin-4-yl)pyrido[3´,2´:4,5]thieno[3,2-c]-
isoquinoline (15). To a solution of compound 14 (0.55 g, 1.5 mmol)
in DMF (3 mL), ButOK (0.25 g, 2.23 mmol) was added. The
reaction mixture was stirred at room temperature for 40 min,
poured into water (15 mL), and extracted with CHCl3. The or-
ganic layer was washed with water (220 mL) and dried with
MgSO4. Removal of the solvent in vacuo and purification of
the residue by silica gel column chromatography (elution with
J = 4.4 Hz); 7.19 (s, 1 H, H(8)PTI); 7.71 (t, 1 H, H(3)PTI
,
J = 8.1 Hz); 7.86 (t, 1 H, H(2)PTI, J = 8.1 Hz); 8.03 (d, 1 H,
H(1)PTI, J = 8.8 Hz); 8.28 (d, 1 H, H(4)PTI, J = 8.1 Hz).
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Received September 13, 2017;
in revised form May 7, 2018;
accepted May 11, 2018