Synthesis of substituted benzothieno[3,2-c]isoquinolin-5(6H)-ones and their sulfinyl and sulfonyl derivatives

Article abstract of DOI:10.1007/s11172-014-0765-6

An approach to the synthesis of substituted benzothieno[3,2-c]isoquinolin-5(6H)-ones with good yields was suggested, which consists of the condensation of substituted 2-mercaptobenzo-nitriles with methyl 2-(chloromethyl)benzoate and subsequent treatment o

Full text of DOI:10.1007/s11172-014-0765-6

Russian Chemical Bulletin, International Edition, Vol. 63, No. 11, pp. 2478—2484, November, 2014
2478
Synthesis of substituted benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀones
and their sulfinyl and sulfonyl 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 (495) 952 5308. Eꢀmail: vek@ioc.ac.ru
An approach to the synthesis of substituted benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀones with
good yields was suggested, which consists of the condensation of substituted 2ꢀmercaptobenzoꢀ
nitriles with methyl 2ꢀ(chloromethyl)benzoate and subsequent treatment of the condensation
products obtained with potassium tertꢀbutoxide. The oxidation of the condensation products to
sulfoxides or sulfones and subsequent treatment of these compounds with potassium tertꢀbutꢀ
oxide led to substituted benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone 11ꢀoxides or substituted
benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone 11,11ꢀdioxides with good yields.
Key words: 2ꢀmercaptobenzonitriles, methyl 2ꢀ(chloromethyl)benzoate, potassium tertꢀ
butoxide, domino reactions, benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀones, benzothieno[3,2ꢀc]ꢀ
isoquinolinꢀ5(6H)ꢀone 11ꢀoxides, benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone 11,11ꢀdioxides.
Derivatives of fused isoquinolines attract attention due
benzyloxy]benzonitriles with potassium tertꢀbutoxide.5 We
suggested to use this synthetic approach for the preparaꢀ
tion of benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone derivaꢀ
tives, including those containing an oxidized sulfur atom.
Synthesis of substituted 2ꢀmercaptobenzonitriles.
2ꢀMercaptobenzonitrile 1a was obtained by the reaction
of 2ꢀnitrobenzonitrile with benzylmercaptane and subseꢀ
quent debenzylation of formed 2ꢀ(benzylthio)benzonitrile
upon treatment with anhydrous AlCl3 in benzene, as was
described in the work.6 Similarly, 2ꢀmercaptoꢀ4ꢀmethylꢀ
benzonitrile 1b was obtained from 4ꢀmethylꢀ2ꢀnitrobenꢀ
zonitrile (see Ref. 7). Unfortunately, the reaction of
4ꢀchloroꢀ2ꢀnitrobenzonitrile with benzylmercaptane led
to a poorly separable mixture of benzonitriles with benzꢀ
ylthio group at position 2 or 4. The reaction of 2ꢀbromoꢀ
4ꢀchlorobenzonitrile 2 with benzylmercaptane also led to
a mixture of benzonitriles.
To increase the selectivity of the substitution of haloꢀ
gen with benzylthio group, we suggested to use 2ꢀbromoꢀ
4ꢀchlorobenzamide (3) as the starting compound, which
was successfully obtained in good yield by the hydrolysis
of nitrile 2 with sulfuric acid at 85—90 C. The reaction of
amide 3 with benzylmercaptane, which was carried out in
the presence of K2CO3 in DMF at 80—85 C, proceeded
selectively and gave only 2ꢀ(benzylthio)ꢀ4ꢀchlorobenzꢀ
amide 4. Earlier, it was shown8 that the reaction of
2,4ꢀdinitrobenzamide with benzylmercaptane led to the
formation of a mixture of orthoꢀ and paraꢀsubstitution
products in the ratio of 9 : 1. In our case, the higher selecꢀ
tivity of substitution of the halogen was reached due to the
orthoꢀselectivity of the amide group and the easier substiꢀ
to their use as antitumor agents1,2 or as a medicine for
prevention and treatment of inflammatory and vascular
conditions.3
In continuation of our studies on the synthesis of fused
isoquinolines, in the present work we report the synthesis
of benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone derivatives.
Benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone was for the
first time synthesized in 9% yield by the reaction of diethyl
ꢀbromohomophthalate and 2ꢀmercaptobenzonitrile upon
treatment with K2CO3 in acetone.3 Relatively recently,
the authors of the work4 reported that they had successfulꢀ
ly obtained this compound in 95% yield by a sequential
addition to 1 equiv. of 2ꢀmercaptobenzonitrile of 1.1 equiv.
of potassium tertꢀbutoxide at 0 C, then 1 equiv. of methyl
2ꢀ(bromomethyl)benzoate at room temperature, and anꢀ
other 1.1 equiv. of potassium tertꢀbutoxide and heating of
the reaction mixture at 80 C for 1 h. Despite the latter
method gives high yields of the target product and can be
effected in one vessel, it also has serious disadvantages. In
particular, it cannot be used for the synthesis of benzoꢀ
thieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone derivatives containꢀ
ing an oxidized sulfur atom.
Earlier, we described the synthesis of benzofuro[3,2ꢀ
c]isoquinolinꢀ5(6H)ꢀones by the condensation reaction of
substituted salicylonitriles with methyl 2ꢀ(chloromethyl)ꢀ
benzoate upon treatment with K2CO3 and subsequent reꢀ
action of obtained substituted 2ꢀ[2ꢀ(methoxycarbonyl)ꢀ
* Dedicated to Academician of the Russian Academy of Sciences
Yu. N. Bubnov on the occasion of his 80th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2478—2484, November, 2014.
1066ꢀ5285/14/6311ꢀ2478 © 2014 Springer Science+Business Media, Inc.

Benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 11, November, 2014 2479
Scheme 1
Reagents and conditions: (a) H2SO4, 85—90 C, 1 h; (b) PhCH2SH (1 equiv.), K2CO3 (1.5 equiv.)/DMF, 80—85 C, 3 h; (c) POCl3,
CHCl3, reflux, 3 h; (d) AlCl3/C6H6, 20—25 C, 48 h.
Scheme 2
tution of the Br atom as compared to the Cl atom. The
dehydration of the amide group in compound 4 was carꢀ
ried out upon treatment with POCl3 in refluxing chloroꢀ
form to obtain the expected 2ꢀ(benzylthio)ꢀ4ꢀchloroꢀ
benzonitrile (5) in high yield. The bebenzylation of comꢀ
pound 5 upon treatment with AlCl3 in benzene gave
4ꢀchloroꢀ2ꢀmercaptobenzonitrile (1c) (Scheme 1).
Synthesis of substituted benzothieno[3,2ꢀc]isoquinolinꢀ
5(6H)ꢀones 8a—c. Initially, we attempted to synthesize
compounds 8a—c according to the procedure developed
for the synthesis of benzofuro[3,2ꢀc]isoquinolinꢀ5(6H)ꢀ
ones.5 Unfortunately, the reaction of thiols 1a—c with
methyl 2ꢀ(chloromethyl)benzoate 6 (see Ref. 9) in the
presence of K2CO3 in DMF gave substituted 2ꢀ[2ꢀ(methꢀ
oxycarbonyl)benzylthio]benzonitriles 7a—c in low or modꢀ
erate yields. At the same time, the reaction of compounds
1a—c and 6 in the presence of Et3N in refluxing CHCl3
gave compounds 7a—c in good or very good yields. The
reaction of sulfides 7a—c with potassium tertꢀbutoxide in
DMF led to the formation of substituted benzothieno[3,2ꢀc]ꢀ
isoquinolinꢀ5(6H)ꢀones 8a—c in high yield (Scheme 2).
Synthesis of benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone
derivatives containing an oxidized sulfur atom. The syntheꢀ
sis of benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀones 8a—c via
the intermediate compound 7a—c allowed us to obtain
new derivatives of heterocycles 8a—c, where the sulfur
atom can be modified to the sulfoxide or sulfone group.
Thus, the oxidation of sulfides 7a—c with 30% aqueous
H2O2 in a mixture of AcOH—CHCl3 at 50—55 C led to
the formation of sulfoxides 9a—c in good yields. The oxiꢀ
dation of sulfides 7a—c to sulfones 11a—c was carried out
upon treatment with KMnO4 in AcOH at 20—25 C to
obtain compounds 11a—c in very good yields. The reacꢀ
tion of sulfoxides 9a—c with potassium tertꢀbutoxide was
carried out under conditions described for sulfides 7a—c
to afford good yields of substituted benzothieno[3,2ꢀc]ꢀ
isoquinolinꢀ5(6H)ꢀone 11ꢀoxides 10a—c. Similar reacꢀ
tions of sulfones 11a—c with potassium tertꢀbutoxide led
to substituted benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone
11,11ꢀdioxides (Scheme 3).
Reagents and conditions: (a) 1.5 equiv. of Et3N, CHCl3, reflux,
40 min; (b) 1.1 equiv. of ButOK, DMF, 40 C, 30 min.
Comꢀ
R
Yield (%)
pound
7
8
a
b
c
H
Me
Cl
84
92
86
82
80
72
scopy, as well as by elemental analysis. The IR spectra of
compounds 7a—c, 9a—c, and 11a—c are characterized by
the presence of the absorption bands of the CN group in
the region 2220—2233 cm–1 and the ester C=O group in
the region 1708—1716 cm–1. The absorption bands of the
S=O group in compounds 9a—c are found in the region
1065—1076 cm–1. In compounds 11a—c, the SO2 group
has two absorption bands in the regions 1300—1329 and
1140—1157 cm–1. The 1H NMR spectra of 7a—c, 9a—c,
and 11a—c exhibit the signal for the protons of the ester
OMe group as a singlet in the region  3.67—3.84. The
The structures of compounds 7a—c—12a—c were conꢀ
firmed by IR spectroscopy, 1H and 13C NMR spectroꢀ

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Russ.Chem.Bull., Int.Ed., Vol. 63, No. 11, November, 2014
Kalugin and Shestopalov
Scheme 3
Comꢀ
pound
a
b
c
R
Yield (%)
Reagents and conditions: (a) 1.25 equiv. of 30% aqueous H2O2,
CHCl3—AcOH, 50—55 C, 4—6 h;
9
10
82
80
77
11
92
90
93
12
92
93
81
H
Me
Cl
67
70
66
(b) 1.6 equiv. of KMnO4, AcOH, 20—25 C, 40 min;
(c) ButOK, DMF, 40 C, 30 min.
1
signals for the OMe protons in the H NMR spectra of
sulfonyl group in heterocycles 12a—c has two absorption
7a—c are found in the range  3.81—3.84. The signals for
the protons of the CH2S group in compounds 7a—c are
found as a singlet at  4.66—4.74. The signals for the
protons of the CH2S(O) group in compounds 11a—c are
found as two doublets in the regions  4.74—4.83 and
4.87—4.93 with the spinꢀspin coupling constant of
J = 12.5 Hz. The signal for the protons of the CH2SO2
group in compounds 11a—c is found as a singlet in the
region  5.29—5.33. The 13C NMR spectra of compounds
7a—c, 9a—c, and 11a—c exhibit signals for the carbon
atoms of the ester OCH3 group at  52.01—52.24. The
signal for the carbon atom of the CN group has a chemical
shift of  116.05—117.01 for 7a—c, 114.05—114.94 for
9a—c, and 114.48—115.40 for 11a—c. The signal for the
carbon atom of the ester C=O group is observed at
 166.85—166.90 for 7a—c and 166.52—166.60 for comꢀ
pounds 9a—c and 11a—c. Sulfides 7a—c are characterꢀ
ized by the presence of the signal for the carbon atom of
the CH2S group at  35.22—35.49. In sulfoxides 9a—c,
the signal for the carbon atom of the CH2S(O) group is
observed at  57.70—58.14, whereas in sulfones 11a—c,
the signal for the carbon atom of the CH2SO2 group is
found at  57.80—57.94.
bands in the regions 1302—1304 and 1142—1148 cm–1
.
1
The H NMR spectra of compounds 8a—c, 10a—c, and
12a—c exhibit the signal for the proton of the NH group as
a broad singlet at  11.80—12.91. In the 13C NMR specꢀ
tra, the signal for the carbon atom of the C=O group is
found at  161.70—161.75 for 8a—c and 162.57—164.01
for 10a—c and 12a—c.
We believe that the reactions of sulfides 7a—c, sulfꢀ
oxides 9a—c, and sulfones 11a—c with potassium tertꢀ
butoxide follow the same mechanism of a domino reacꢀ
tion, which includes the formation in the first step of the
corresponding benzothiophene intermediates 13a—c,
14a—c, and 15a—c by the Thorpe—Ziegler reaction and
their further annulation to compounds 8a—c, 10a—c, and
12a—c by the Thorpe—Guareschi reaction (Scheme 4).
In conclusion, we developed a simple and versatile
twoꢀstep method, which makes it possible to synthesize
benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone derivatives in
high yields. In the first step, the reaction of substituted
2ꢀmercaptobenzonitriles 1 with methyl 2ꢀ(chloromethyl)ꢀ
benzoate 6 leads to the intermediate esters 7, which by the
reaction with potassium tertꢀbutoxide are easily converted to
the corresponding benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀ
ones 8. The oxidation of compounds 7 to sulfoxides 9 or
sulfones 11 and subsequent reaction of these compounds
with potassium tertꢀbutoxide afforded earlier unknown
benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone 11ꢀoxides 10 or
benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone 11,11ꢀdioxides
12 containing an oxidized sulfur atom.
A characteristic feature of the IR spectra of compounds
8a—c, 10a—c, and 12a—c is the presence of the absorpꢀ
tion bands in the regions 3200—3064 cm–1 for the
NH group and 1645—1684 cm–1 for the C=O group. In
the IR spectra of heterocycles 10a—c, the absorption bands
of the S=O group are in the region 1007—1034 cm–1. The

Benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 11, November, 2014 2481
Scheme 4
n = 0 (7, 8, 13), 1 (9, 10, 14), 2 (11, 12, 15)
R = H (a), Me (b), Cl (c)
Calculated (%): C, 64.74; H, 3.88; Cl, 13.65; N, 5.39; S, 12.34.
IR, /cm–1: 3065, 2216 (CN); 1573, 1469, 1452, 1383, 1107,
823, 712. 1H NMR (CDCl3), : 4.24 (s, 2 H, CH2S); 7.23 (d, 1 H,
ArH, J = 8.1 Hz); 7.33 (m, 6 H, ArH); 7.53 (d, 1 H, ArH,
J = 8.1 Hz).
Experimental
IR spectra were recorded on a Specord M 80ꢀ2 spectrometer
in KBr pellets. 1H NMR spectra were recorded on a Bruker
AMꢀ300 spectrometer (300 MHz) in solutions in CDCl3 or
DMSOꢀd6. 13C NMR spectra were recorded on a Bruker AMꢀ300
spectrometer (75 MHz) in solution in DMSOꢀd6.
Synthesis of starting compounds. 2ꢀMercaptobenzonitriles
1a,4 1b,5 and methyl 2ꢀ(chloromethyl)benzoate 6 (see Ref. 9)
were obtained according to the procedures described in the litꢀ
erature.
4ꢀChloroꢀ2ꢀmercaptobenzonitrile (1c). Anhydrous AlCl3
(4.4 g, 33 mmol) was added to a solution of 2ꢀ(benzylthio)ꢀ4ꢀ
chlorobenzonitrile (6 g, 23 mmol) in benzene (60 mL). The
reaction mixture was stirred at room temperature for 48 h and
poured into crushed ice (80 g). The organic layer was separated
and sequentially washed with H2O (2×50 mL) and 5% aqueous
NaOH (2×40 mL). The alkaline solution was separated, acidiꢀ
fied with hydrochloric acid, the product was isolated by extracꢀ
tion with CHCl3 (3×30 mL). The extract was dried with Na2SO4,
the solvent was evaporated in vacuo, the product was crystallized
from a mixture of CHCl3—hexane to obtain compound 1c (3.1 g,
81%), m.p. 108—111 C. Found (%): C, 49.72; H, 2.27; Cl, 21.09;
N, 8.37; S, 19.07. C7H4ClNS. Calculated (%): C, 49.56; H, 2.38;
Cl, 20.90; N, 8.26; S, 18.90. IR, /cm–1: 3052, 2555, 2224 (CN);
1583, 1473, 1385, 1106, 820. 1H NMR (CDCl3), : 3.73 (s, 1 H,
SH); 7.26 (d, 1 H, ArH, J = 8.1 Hz); 7.48 (d, 1 H, ArH,
J = 8.1 Hz); 7.56 (s, 1 H, ArH).
Synthesis of sulfides 7a—c (general procedure). Triethylamine
(0.84 mL, 6 mmol) was added to a solution of thiophenol 1a—c
(4 mmol) and methyl 2ꢀ(chloromethyl)benzoate 6 (0.74 g,
4 mmol) in CHCl3 (5 mL). The reaction mixture was refluxed
for 40 min, the solvent was evaporated in vacuo and the product
was isolated by column chromatography (silica gel 60—80 mesh,
eluent hexane—CHCl3 = 3 : 2). The product obtained was crysꢀ
tallized from an appropriate solvent.
Methyl 2ꢀ{[(2ꢀcyanophenyl)thio]methyl}benzoate (7a). The
yield was 84%, m.p. 81—83 C (CHCl3—hexane). Found (%):
C, 68.07; H, 4.53; N, 5.05; S, 11.19. C16H13NO2S. Calculatꢀ
ed (%): C, 67.82; H, 4.62; N, 4.94; S, 11.31. IR, /cm–1: 3063,
3020, 2953, 2223 (CN); 1718 (C=O); 1577, 1435, 1266, 1080,
758. 1H NMR (DMSOꢀd6), : 3.82 (s, 3 H, OMe); 4.67 (s, 2 H,
SCH2); 7.40 (m, 3 H, ArH); 7.50 (t, 1 H, ArH, J = 7.3 Hz); 7.59
(m, 2 H, ArH); 7.78 (d, 1 H, ArH, J = 7.3 Hz); 7.84 (d, 1 H,
ArH, J = 7.3 Hz). 13C NMR (DMSOꢀd6), : 35.59 (SCH2);
52.16 (OMe); 112.53, 116.80 (CN); 126.98, 127.87, 129.25,
130.04, 130.61, 131.19, 132.24, 133.48, 133.75, 137.64, 140.02,
166.90 (C=O).
2ꢀBromoꢀ4ꢀchlorobenzamide (3). A mixture of 2ꢀbromoꢀ4ꢀ
chlorobenzonitrile 2 (10.84 g, 50 mmol) (see Ref. 10) and H2SO4
(40 mL) was stirred at 85—90 C for 1 h, then cooled to room
temperature and poured into iceꢀcold H2O (300 mL). The preꢀ
cipitated product was filtered off, washed with H2O, and dried.
The yield was 10.6 g (90%), m.p. 177—178 C (EtOH). Found (%):
C, 36.07; H, 2.01; Br, 33.82; Cl, 15.02; N, 6.11. C7H5BrClNO.
Calculated (%): C, 35.86; H, 2.15; Br, 34.08, Cl, 15.12; N, 5.97.
IR, /cm–1: 3377, 3186 (NH); 3075, 1651 (C=O); 1620, 1583,
1396, 1103, 1038, 834, 814. 1H NMR (CDCl3), : 6.03 (br.s, 1 H,
NH); 6.14 (br.s, 1 H, NH); 7.38 (d, 1 H, ArH, J = 7.3 Hz); 7.64
(m, 2 H, ArH).
2ꢀ(Benzylthio)ꢀ4ꢀchlorobenzamide (4). Anhydrous K2CO3
(8.2 g, 60 mmol) was added to a solution of 2ꢀbromoꢀ4ꢀchloroꢀ
benzamide (9.4 g, 40 mmol) and benzylmercaptane (5 g, 41 mmol)
in DMF (50 mL). The reaction mixture was stirred at 80—85 C
for 3 h and then poured into H2O (150 mL). The precipitated
product was filtered off, washed with H2O, dried, and crystalꢀ
lized from MeOH to obtain compound 4 (9.1 g, 82%), m.p.
140—142 C. Found (%): C, 60.71; H, 4.44; Cl, 12.64; N, 4.97;
S, 11.65. C14H12ClNOS. Calculated (%): C, 60.54; H, 4.35;
Cl, 12.76; N, 5.04; S, 11.54. IR, /cm–1: 3374, 3186 (NH); 1644
(C=O); 1577, 1397, 1104, 822. 1H NMR (CDCl3), : 4.12
(s, 2 H, CH2S); 6.23 (br.s, 1 H, NH); 6.53 (br.s, 1 H, NH); 7.26
(m, 6 H, ArH); 7.37 (s, 1 H, ArH); 7.64 (d, 1 H, ArH, J = 8.8 Hz).
2ꢀ(Benzylthio)ꢀ4ꢀchlorobenzonitrile (5). A solution of
2ꢀ(benzylthio)ꢀ4ꢀchlorobenzamide (8.9 g, 32 mmol) and POCl3
(3.7 g, 25 mmol) in CHCl3 (50 mL) was refluxed for 3 h, cooled
to room temperature, and poured into H2O (150 mL). The orꢀ
ganic layer was separated, several times washed with H2O, and
dried with MgSO4. The solvent was evaporated in vacuo and the
product was purified by column chromatography (silica gel
60—80 mesh, eluent hexane—CHCl3 = 1 : 1). The yield was
6.6 g (80%), m.p. 108—110 C (CHCl3—hexane). Found (%):
C, 64.52; H, 3.95; Cl, 13.47; N, 5.51; S, 12.18. C14H10ClNS.
Methyl 2ꢀ{[(2ꢀcyanoꢀ5ꢀmethylphenyl)thio]methyl}benzoate
(7b). The yield was 92%, m.p. 62—64 C (CHCl3—hexane).
Found (%): C, 68.77; H, 5.01; N, 4.85; S 10.92. C17H15NO2S.
Calculated (%): C, 68.66; H, 5.08; N, 4.71; S, 10.78. IR, /cm–1
:
3050, 2966, 2220 (CN); 1708 (C=O); 1595, 1431, 1269, 1079,

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Russ.Chem.Bull., Int.Ed., Vol. 63, No. 11, November, 2014
Kalugin and Shestopalov
709. 1H NMR (DMSOꢀd6), : 2.34 (s, 3 H, ArMe); 3.81 (s, 3 H,
OMe); 4.66 (s, 2 H, SCH2); 7.19 (d, 1 H, ArH, J = 7.3 Hz); 7.39
(m, 2 H, ArH); 7.43 (s, 1 H, ArH); 7.51 (t, 1 H, ArH, J = 7.3 Hz);
7.65 (d, 1 H, ArH, J = 8.1 Hz); 7.84 (d, 1 H, ArH, J = 7.3 Hz).
13C NMR (DMSOꢀd6), : 21.15 (ArMe); 35.45 (SCH2); 52.14
(OMe); 109.47, 117.01 (CN); 127.70, 127.83, 129.30, 130.41,
130.53, 131.28, 132.20, 133.48, 137.66, 139.76, 144.21,
166.89 (C=O).
Methyl 2ꢀ{[(5ꢀchloroꢀ2ꢀcyanophenyl)thio]methyl}benzoate
(7c). The yield was 86%, m.p. 86—88 C (MeOH). Found (%):
C, 60.26; H, 3.89; N, 4.47; Cl, 11.30; S, 10.21. C16H12ClNO2S.
Calculated (%): C, 60.47; H, 3.81; N, 4.41; Cl, 11.16; S, 10.09.
IR, /cm–1: 3091, 2950, 2225 (CN); 1717 (C=O); 1576, 1432,
1263, 1103, 1078, 826, 814. 1H NMR (DMSOꢀd6), : 3.83 (s, 3 H,
OCH3); 4.74 (s, 2 H, SCH2); 7.39 (m, 4 H, ArH); 7.64 (s, 1 H,
ArH); 7.80 (d, 1 H, ArH, J = 8.8 Hz); 7.86 (d, 1 H, ArH, J = 7.3 Hz).
13C NMR (DMSOꢀd6), : 35.22 (SCH2); 52.21 (OMe); 110.55,
116.05 (CN); 126.88, 128.05, 128.77, 129.30, 130.65, 131.30,
132.34, 135.17, 137.13, 138.63, 142.77, 166.85 (C=O).
Synthesis of substituted benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀ
ones 8a—c (general procedure). Potassium tertꢀbutoxide (0.37 g,
3.3 mmol) was added to a solution of compound 6a—c (3 mmol)
in DMF (3 mL). The reaction mixture was stirred at 40 C for
30 min and then poured into H2O (30 mL). The mixture obꢀ
tained was diluted with AcOH (0.5 mL) and after a while the
crystals formed were filtered off, washed with H2O, dried, and
recrystallized from an appropriate solvent.
Benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone (8a). The yield was
82%, m.p. > 350 C (DMF—MeOH). Found (%): C, 71.84; H, 3.75;
N, 5.69; S, 12.54. C15H9NOS. Calculated (%): C, 71.69; H, 3.61;
N, 5.57; S, 12.76. IR, /cm–1: 3173, 3112 (NH); 3054, 2921,
2875, 2822, 1654 (C=O); 1609, 1380, 1331, 886, 751. 1H NMR
(DMSOꢀd6), : 7.49 (m, 2 H); 7.59 (t, 1 H, J = 6.6 Hz); 7.80
(m, 2 H); 8.04 (m, 1 H); 8.35 (d, 1 H, J = 7.3 Hz); 8.45 (m, 1 H);
12.44 (s, 1 H, NH). 13C NMR (DMSOꢀd6), : 113.98, 121.70,
123.28, 123.55, 124.91, 124.97, 126.73, 127.25, 128.23, 130.02,
132.53, 133.03, 133.38, 137.30, 161.73 (C=O).
9ꢀMethylbenzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone (8b). The
yield was 80%, m.p. 338—340 C (DMF—MeOH). Found (%):
C, 72.62; H, 4.26; N, 5.15; S, 12.22. C16H11NOS. Calculatꢀ
ed (%): C, 72.43; H, 4.18; N, 5.28; S, 12.08. IR, /cm–1: 3169,
3128 (NH); 3053, 2922, 2881, 2835, 1645 (C=O); 1611, 1339,
813, 759. 1H NMR (DMSOꢀd6), : 2.46 (s, 3 H, ArMe); 7.31
(d, 1 H, J = 8.1 Hz); 7.57 (t, 1 H, J = 7.3 Hz); 7.76 (t, 1 H,
J = 7.3 Hz); 7.81 (m, 2 H); 8.32 (m, 2 H); 12.43 (s, 1 H, NH).
13C NMR (DMSOꢀd6), : 21.17 (ArMe); 112.98, 121.37, 123.03,
123.15, 124.65, 126.46, 126.88, 127.82, 128.17, 132.51, 133.16,
133.27, 136.66, 137.59, 161.75 (C=O).
9ꢀChlorobenzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone (8c). The
yield was 72%, m.p. > 350 C (DMF—MeOH). Found (%):
C, 62.87; H, 2.91; Cl, 12.60; N, 4.78; S, 11.39. C15H8ClNOS.
Calculated (%): C, 63.05; H, 2.82; Cl, 12.41; N, 4.90; S, 11.22.
IR, /cm–1: 3176 (NH); 3072, 2936, 2870, 1656 (C=O); 1608,
1556, 1472, 1452, 1324, 1136, 888, 852, 756. 1H NMR (DMSOꢀd6),
: 7.53 (d, 1 H, J = 8.1 Hz); 7.60 (t, 1 H, J = 7.3 Hz); 7.79 (m, 2 H);
8.19 (s, 1 H); 8.34 (d, 1 H, J = 7.3 Hz); 8.43 (d, 1 H, J = 7.3 Hz);
11.80 (s, 1 H, NH). 13C NMR (DMSOꢀd6), : 114.20, 121.50,
122.80, 123.18, 124.71, 125.14, 126.38, 126.84, 127.03, 127.98,
128.84, 131.10, 132.60, 132.95, 161.70 (C=O).
a solution of sulfide 7a—c (4 mmol) in CHCl3 (5 mL). The
reaction mixture was stirred at 50—55 C for 4—6 h (TLC moniꢀ
toring), then poured into 15% aqueous Na2CO3 (30 mL), and
the product was extracted with CHCl3 (3×15 mL). The extract
was dried with Na2SO4 and filtered, the solvent was evaporated
in vacuo, and the product was isolated by column chromatography
(silica gel 60—80 mesh, eluent CHCl3, CHCl3—acetone = 3 : 1).
The isolated product was crystallized from an appropriate solvent.
Methyl 2ꢀ{[(2ꢀcyanophenyl)sulfinyl]methyl}benzoate (9a).
The yield was 67%, m.p. 66—68 C (diethyl ether—hexane).
Found (%): C, 64.38; H, 4.29; N, 4.75; S, 10.87. C16H13NO3S.
Calculated (%): C, 64.20; H, 4.38; N, 4.68; S, 10.71. IR, /cm–1
:
3065, 2225 (CN); 1709 (C=O); 1576, 1431, 1268, 1071, 1065
(S=O); 1042, 764. 1H NMR (DMSOꢀd6), : 3.70 (s, 3 H, OMe);
4.76 (d, 1 H, S(O)CH2, J = 12.5 Hz); 4.93 (d, 1 H, S(O)CH2,
J = 12.5 Hz); 7.05 (d, 1 H, ArH, J = 6.6 Hz); 7.45 (m, 3 H, ArH);
7.69 (t, 1 H, ArH, J = 7.3 Hz); 7.80 (m, 2 H, ArH); 7.93 (d, 1 H,
ArH, J = 7.3 Hz). 13C NMR (DMSOꢀd6), : 52.03 (OMe); 57.99
(S(O)CH2); 108.85, 114.75 (CN); 125.38, 128.56, 128.86, 130.04,
130.34, 131.83, 131.88, 133.41, 133.82, 145.96, 166.54 (C=O).
Methyl 2ꢀ{[(2ꢀcyanoꢀ5ꢀmethylphenyl)sulfinyl]methyl}benzoꢀ
ate (9b). The yield was 70%, m.p. 86—89 C (diethyl ether).
Found (%): C, 65.08; H, 4.75; N, 4.57; S, 10.34. C17H15NO3S.
Calculated (%): C, 65.16; H, 4.82; N, 4.47; S, 10.23. IR, /cm–1
:
3064, 3035, 2953, 2222 (CN); 1712 (C=O); 1597, 1432,
1290, 1278, 1079, 1067 (S=O); 1041, 839, 776, 717. 1H NMR
(DMSOꢀd6), : 2.34 (s, 3 H, ArMe); 3.70 (s, 3 H, OMe); 4.74
(d, 1 H, S(O)CH2, J = 12.5 Hz); 4.87 (d, 1 H, S(O)CH2,
J = 12.5 Hz); 7.04 (d, 1 H, ArH, J = 6.6 Hz); 7.21 (s, 1 H, ArH);
7.48 (m, 3 H, ArH); 7.80 (m, 2 H, ArH). 13C NMR (DMSOꢀd6),
: 21.25 (ArMe); 52.01 (OMe); 58.17 (S(O)CH2); 105.83, 114.94
(CN); 125.74, 128.51, 128.91, 130.11, 130.25, 131.78, 132.40,
133.24, 133.43, 144.86, 145.74, 166.52 (C=O).
Methyl 2ꢀ{[(5ꢀchloroꢀ2ꢀcyanophenyl)sulfinyl]methyl}benzoꢀ
ate (9c). The yield was 66%, m.p. 92—94 C (diethyl ether—
hexane); Found (%): C, 57.48; H, 3.71; N, 4.26; Cl, 10.75;
S, 9.51. C16H12ClNO3S. Calculated (%): C, 57.57; H, 3.62;
N, 4.20; Cl, 10.62; S, 9.60. IR, /cm–1: 3092, 3016, 2948, 2232
(CN); 1712 (C=O); 1576, 1436, 1268, 1100, 1076 (S=O); 1040,
836, 764, 716. 1H NMR (DMSOꢀd6), : 3.72 (s, 3 H, OMe); 4.83
(d, 1 H, S(O)CH2, J = 12.5 Hz); 4.93 (d, 1 H, S(O)CH2,
J = 12.5 Hz); 7.08 (d, 1 H, ArH, J = 6.6 Hz); 7.27 (s, 1 H, ArH);
7.49 (m, 2 H, ArH); 7.81 (m, 2 H, ArH); 7.98 (d, 1 H, ArH,
J = 8.1 Hz). 13C NMR (DMSOꢀd6), : 52.07 (OMe); 57.70
(S(O)CH2); 107.63, 114.07 (CN); 125.28, 128.40, 128.71,
130.05, 130.33, 131.86, 131.97, 133.55, 135.09, 139.20, 148.32,
166.52 (C=O).
Synthesis of sulfones 11a—c (general procedure). Powdered
KMnO4 (1 g, 6.3 mmol) was added to a stirred mixture of sulfide
7a—c (4 mmol) and AcOH (15—20 mL) at such a rate that to
keep the temperature of the reaction mixture within 20—25 C.
The mixture was stirred for another 40 min, discolored by the
addition of aqueous Na2SO3, then poured into H2O (70 mL).
The product was extracted with CHCl3 (3×15 mL). The extract
was dried with Na2SO4 and filtered, the solvent was evaporated
in vacuo and the product was crystallized from an appropriate
solvent.
Methyl 2ꢀ{[(2ꢀcyanophenyl)sulfonyl]methyl}benzoate (11a).
The yield was 92%, m.p. 126—128 C (MeOH). Found (%):
C, 60.86; H, 4.10; N, 4.39; S, 10.05. C16H13NO4S. Calculated (%):
C, 60.94; H, 4.16; N, 4.44; S, 10.17. IR, /cm–1: 3096, 3014,
Synthesis of sulfoxides 9a—c (general procedure). Acetic acid
(3 mL) and 30% aqueous H2O2 (0.5 mL, 5 mmol) were added to

Benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 11, November, 2014 2483
2951, 2233 (CN); 1719 (C=O); 1436, 1326 (SO2); 1300 (SO2);
1157 (SO2); 1119, 768. 1H NMR (DMSOꢀd6), : 3.67 (s, 3 H,
OMe); 5.33 (s, 2 H, SO2CH2); 7.38 (d, 1 H, ArH, J = 7.3 Hz);
7.50 (t, 1 H, ArH, J = 7.3 Hz); 7.58 (t, 1 H, ArH, J = 7.3 Hz);
7.67 (d, 1 H, ArH, J = 7.3 Hz); 7.79 (d, 1 H, ArH, J = 8.1 Hz);
7.88 (m, 2 H, ArH); 8.12 (d, 1 H, ArH, J = 7.3 Hz). 13C NMR
(DMSOꢀd6), : 52.14 (OMe); 57.80 (SO2CH2); 110.95, 115.25
(CN); 127.90, 129.23, 130.37, 130.48, 130.82, 132.27, 133.61,
133.91, 134.56, 135.85, 139.06, 166.56 (C=O).
N, 4.98; S, 11.40. IR, /cm–1: 3177, 3127 (NH); 3029, 2925,
2865, 1667 (C=O); 1614, 1478, 1366, 1135, 1058, 1034 (S=O);
836, 764. 1H NMR (DMSOꢀd6), : 2.46 (s, 3 H, CH3); 7.51
(d, 1 H, J = 7.3 Hz); 7.58 (t, 1 H, J = 7.3 Hz); 7.84 (t, 1 H,
J = 7.3 Hz); 7.88 (s, 1 H); 7.95 (d, 1 H, J = 7.3 Hz); 8.14 (d, 1 H,
J = 6.6 Hz); 8.28 (d, 1 H, J = 7.3 Hz); 12.52 (s, 1 H, NH).
13C NMR (DMSOꢀd6), : 20.99 (ArMe); 117.01, 122.22, 122.35,
124.58, 127.26, 127.49, 128.15, 128,54, 132.82, 133.19, 133.78,
140.47, 141.34, 145.56, 162.67 (C=O).
Methyl 2ꢀ{[(2ꢀcyanoꢀ5ꢀmethylphenyl)sulfonyl]methyl}benzoꢀ
ate (11b). The yield was 90%, m.p. 160—162 C (PriOH).
Found (%): C, 62.12; H, 4.48; N, 4.32; S, 9.65. C17H15NO4S.
9ꢀChlorobenzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone 11ꢀoxide
(10c). The yield was 77%, m.p. > 340 C (DMF—MeOH).
Found (%): C, 59.82; H, 2.77; Cl, 11.64; N, 4.70; S, 10.53.
Calculated (%): C, 61.99; H, 4.59; N, 4.25; S, 9.73. IR, /cm–1
3024, 2956, 2232 (CN); 1712 (C=O); 1600, 1436, 1324 (SO2);
1300 (SO2); 1272, 1152 (SO2); 1140, 1120, 836, 736, 716.
1H NMR (DMSOꢀd6), : 2.38 (s, 3 H, ArMe); 3.68 (s, 3 H, OMe);
5.29 (s, 2 H, SO2CH2); 7.37 (d, 1 H, ArH, J = 7.3 Hz); 7.52
(m, 2 H, ArH); 7.58 (t, 1 H, ArH, J = 7.3 Hz); 7.71 (d, 1 H, ArH,
J = 7.3 Hz); 7.80 (d, 1 H, ArH, J = 8.1 Hz); 7.98 (d, 1 H, ArH,
J = 7.3 Hz). 13C NMR (DMSOꢀd6), : 20.92 (ArMe); 52.13
(OMe); 57.94 (SO2CH2); 107.96, 115.40 (CN); 127.91, 129.20,
130.45, 130.51, 131.18, 132.23, 133.89, 134.85, 135.65, 138.93,
144.73, 166.59 (C=O).
Methyl 2ꢀ{[(5ꢀchloroꢀ2ꢀcyanophenyl)sulfonyl]methyl}benzoꢀ
ate (11c). The yield was 93%, m.p. 130—132 C (MeOH).
Found (%): C, 55.18; H, 3.35; N, 4.11; Cl, 10.30; S, 9.28.
C16H12ClNO4S. Calculated (%): C, 54.94; H, 3.46; N, 4.00; Cl,
10.14; S, 9.17. IR, /cm–1: 3104, 3078, 2990, 2936, 2231 (CN);
1723 (C=O); 1583, 1448, 1329 (SO2); 1267, 1169, 1150 (SO2);
1124, 1075, 845, 779. 1H NMR (DMSOꢀd6), : 3.70 (s, 3 H,
OMe); 5.37 (s, 2 H, SO2CH2); 7.40 (d, 1 H, ArH, J = 7.3 Hz);
7.57 (m, 2 H, ArH); 7.61 (s, 1 H, ArH); 7.83 (d, 1 H, ArH,
J = 6.6 Hz); 8.04 (d, 1 H, ArH, J = 8.1 Hz); 8.16 (d, 1 H, ArH,
J = 8.8 Hz). 13C NMR (DMSOꢀd6), : 52.24 (OMe); 57.99
(SO2CH2); 109.83, 114,48 (CN); 127.62, 129.46, 130.45,
130.63, 132.43, 134.00, 134.61, 137.44, 138.58, 140.82, 147.43,
166.60 (C=O).
:
C15H8ClNO2S. Calculated (%): C, 59.71; H, 2.67; Cl, 11.75;
N, 4.64; S, 10.62. IR, /cm–1: 3200, 3135 (NH); 3075, 3017,
2937, 2855, 2800, 1684 (C=O); 1613, 1475, 1443, 1134, 1097,
1009 (S=O); 991, 834, 759. 1H NMR (DMSOꢀd6), : 7.60 (m, 1 H);
7.82 (m, 2 H); 7.86 (m, 1 H); 8.21 (s, 1 H); 8.27 (m, 2 H); 12.42
(s, 1 H, NH). 13C NMR (DMSOꢀd6), : 118.00, 122.39, 123.96,
124.81, 127.29, 127.67, 128.21, 130.37, 132.52, 132.91, 133.84,
135.42 139.90, 147.26, 162.78 (C=O).
Benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone 11,11ꢀdioxide (12a).
The yield was 92%, m.p.> 350 C (DMF—MeOH). Found (%):
C, 63.72; H, 3.31; N, 4.82; S, 11.22. C15H9NO3S. Calculatꢀ
ed (%): C, 63.59; H, 3.20; N, 4.94; S, 11.32. IR, /cm–1: 3190
(NH); 3064, 2926, 2859, 1650 (C=O); 1605, 1478, 1307 (SO2);
1167, 1148 (SO2); 760. 1H NMR (DMSOꢀd6), : 7.68 (t, 1 H,
J = 7.3 Hz); 7.77 (t, 1 H, J = 7.3 Hz); 7.86 (m, 2 H); 7.94 (t, 1 H,
J = 8.1 Hz); 8.04 (d, 1 H, J = 7.3 Hz); 8.35 (d, 2 H, J = 8.1 Hz);
12.91 (s, 1 H, NH). 13C NMR (DMSOꢀd6), : 112.13, 123.03,
123.34, 124.30, 126.46, 127.66, 129.70, 129.95, 130.44, 133.69,
135.67, 135.77, 139.30, 140.32, 164.01 (C=O).
9ꢀMethylbenzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone 11,11ꢀdiꢀ
oxide (12b). The yield was 93%, m.p. > 350 C (DMF—MeOH).
Found (%): C, 64.74; H, 3.59; N, 4.55; S, 10.96. C16H11NO3S.
Calculated (%): C, 64.63; H, 3.73; N, 4.71; S, 10.78. IR, /cm–1
:
3189, 3136 (NH); 3064, 3038, 2925, 2868, 1664 (C=O); 1640,
1605, 1482, 1302 (SO2); 1144 (SO2); 763. 1H NMR (DMSOꢀd6),
: 2.48 (s, 3 H, ArMe); 7.64 (m, 2 H); 7.87 (m, 3 H); 8.22
(d, 1 H, J = 7.3 Hz); 8.31 (d, 1 H, J = 8.1 Hz); 12.86 (s, 1 H,
NH). 13C NMR (DMSOꢀd6), : 21.56 (ArMe); 110.70, 122.22,
122.43, 123.12, 124.19, 125.30, 128.41, 128.98, 129.75, 130.41,
134.69, 134.91, 139.76, 143.66, 163.23 (C=O).
9ꢀChlorobenzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone 11,11ꢀdiꢀ
oxide (12c). The yield was 81%, m.p. > 350 C (DMF—MeOH).
Found (%): C, 56.55; H, 2.46; Cl, 10.90; N, 4.33; S, 9.87.
C15H8ClNO3S. Calculated (%): C, 56.70; H, 2.54; Cl, 11.16;
N, 4.41; S, 10.09. IR, /cm–1: 3193 (NH); 3081, 3070, 3037,
2934, 2870, 1657 (C=O); 1625, 1605, 1479, 1304 (SO2); 1234,
1167, 1142 (SO2); 765. 1H NMR (DMSOꢀd6), : 7.68 (m, 1 H);
7.85 (m, 1 H); 7.93 (m, 2 H); 8.31 (m, 3 H); 11.80 (s, 1 H, NH).
13C NMR (DMSOꢀd6), : 112.54, 121.76, 122.02, 122.62, 124.28,
124.85, 125.25, 128.24, 128.43, 128.82, 134.05, 134.22, 136.94,
140.41, 162.57 (C=O).
Synthesis of substituted benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀ
one 11ꢀoxides 10a—c and benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀ
one 11,11ꢀdioxides 12a—c (general procedure). Potassium tertꢀ
butoxide (0.37 g, 3.3 mmol) was added to a solution of sulfoxide
9a—c or sulfone 11a—c (3 mmol) in DMF (3 mL). The reaction
mixture was stirred at 40 C for 30 min, then poured into H2O
(30 mL), followed by the addition of AcOH (0.5 mL). After
a while, the crystals formed were filtered off, washed with H2O,
dried, and recrystallized from an appropriate solvent.
Benzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone 11ꢀoxide (10a).
The yield was 82%, m.p. 297—299 C (DMF—MeOH).
Found (%): C, 67.28; H, 3.48; N, 5.12; S, 12.14. C15H9NO2S.
Calculated (%): C, 67.40; H, 3.39; N, 5.24; S, 11.99. IR, /cm–1
:
3196, 3135 (NH); 3072, 2928, 2858, 1679 (C=O); 1612, 1475,
1137, 1058, 1007 (S=O); 753. 1H NMR (DMSOꢀd6), : 7.61
(t, 1 H, J = 7.3 Hz); 7.67 (t, 1 H, J = 8.1 Hz); 7.74 (t, 1 H,
J = 7.3 Hz); 7.87 (t, 1 H, J = 7.3 Hz); 7.99 (d, 1 H, J = 7.3 Hz);
8.09 (d, 1 H, J = 7.3 Hz); 8.30 (m, 2 H); 12.69 (s, 1 H, NH).
13C NMR (DMSOꢀd6), : 117.79, 122.44, 122.63, 124.84, 127.06,
127.59, 128.20, 130.77, 131.24, 132.52, 133.07, 133.89, 140.31,
145.39, 162.68 (C=O).
9ꢀMethylbenzothieno[3,2ꢀc]isoquinolinꢀ5(6H)ꢀone 11ꢀoxide
(10b). The yield was 80%, m.p. 327—330 C (decomp.)
(DMF—MeOH). Found (%): C, 68.52; H, 4.03; N, 5.07;
S, 11.23. C16H11NO2S. Calculated (%): C, 68.31; H, 3.94;
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Received March 5, 2014;
in revised form July 22, 2014