A versatile synthesis of benzothieno-annelated 1,2-dihydropyridine and 1,2,3,4-tetrahydropyridine derivatives: The effect of the structure of benzothieno-annelated pyridinium salts on their reduction by sodium borohydride

Article abstract of DOI:10.1007/s00706-009-0222-7

Benzothieno[2,3-c]pyridinium and benzothieno[2,3-c]quinolinium salts were synthesized either by quaternization of benzothieno[2,3-c]pyridines, or recyclization of benzothieno[2,3-c]pyrylium salts with primary amines. One-pot synthesis of benzothieno[3,2-g

Full text of DOI:10.1007/s00706-009-0222-7

Monatsh Chem (2010) 141:35–43
DOI 10.1007/s00706-009-0222-7
ORIGINAL PAPER
A versatile synthesis of benzothieno-annelated
1,2-dihydropyridine and 1,2,3,4-tetrahydropyridine derivatives:
the effect of the structure of benzothieno-annelated pyridinium
salts on their reduction by sodium borohydride
•
Maksym A. Kryuchkov Roman I. Zubatyuk
•
•
Igor F. Perepichka Oleg V. Shishkin
•
Sergei V. Tolkunov
Received: 4 September 2009 / Accepted: 19 November 2009 / Published online: 8 December 2009
Ó Springer-Verlag 2009
Abstract Benzothieno[2,3-c]pyridinium and benzothie-
no[2,3-c]quinolinium salts were synthesized either by
quaternization of benzothieno[2,3-c]pyridines, or recycli-
zation of benzothieno[2,3-c]pyrylium salts with primary
amines. One-pot synthesis of benzothieno[3,2-g]indolizi-
nium salts from 1-(3-chloropropyl)-benzothieno[2,3-c]
pyrylium included consequent recyclization of the pyryli-
um core by ammonia into a pyridine intermediate and its
further intramolecular quaternization reaction. Depending
on the structure of benzothieno-annelated pyridinium salts,
their reaction with sodium borohydride in methanol results
in reduction of the pyridine core into tetrahydropyridine or
dihydropyridine derivatives. Whereas reduction of benzo-
thieno[2,3-c]pyridinium and benzothieno[3,2-g]indolizinium
salts readily yields benzothieno-annelated tetrahydropyri-
dines as a complex mixture of stereoisomers, reduction of
benzothieno[2,3-c]quinolinium salts results in dihydropyr-
idine derivatives. The structure of the latter, in particular,
was confirmed by single-crystal X-ray diffraction analysis.
Introduction
Natural b-carboline alkaloids, found in the seeds of
Peganum harmala (Scheme 1), are of special interest
because of their proven biological activity [1, 2]. Since
the 1980s b-carbolines have become an important
instrument in investigations of so called benzodiazepine
receptors (BDR) [3]. The latter are the sites of allosteric
regulation of c-aminobutyric acid (GABA) receptors
(Scheme 1).
High biological activity has also been demonstrated for
a number of benzothieno[2,3-c]pyridine derivatives, i.e.
S-isosters of b-carbolines [4]. Studies of biological activity
of benzothiophene analogs of harmine and harmaline as
monoamine oxidase (MAO) inhibitors in vitro showed that
the activity of the S-analog of harmine is similar to that of
harmine, and the S-analog of harmaline is even more
efficient than harmaline itself [5–7]. The sulfur analogs of
Peganum harmala alkaloids have higher solubility in lip-
ids, shorter biological half-life, and weaker tissue binding
than their nitrogen analogs [8, 9]. Tetrahydrobenzothie-
no[2,3-c]pyridine derivatives have been found to act as
appetite-depressing agents [10], analgesics [11], anxiolyt-
ics, and antidepressants [9, 12] (Scheme 2).
Keywords Pyrylium Á Benzothienopyridinium Á
Benzothienoquinolinium Á Benzothienoindolizinium Á
Alkylation Á Reduction
Among synthetic approaches to 1,2,3,4-tetrahydro
benzothieno[2,3-c]pyridines, the Pictet–Spengler cycliza-
tion of azomethines of 3-(2-aminoethyl)benzo[b]thiophenes
is a common and widely used method [4, 13]. Another
synthetic route includes Bischler–Napieralski cyclization
of 3-(2-acetylaminoethyl)benzo[b]thiophenes affording
3,4-dihydrobenzothieno[2,3-c]pyridines, which can then be
reduced into tetrahydro derivatives by sodium borohydride
or lithium aluminum hydride [14]. To the best of our
knowledge, N-substituted tetrahydrobenzothieno[2,3-c]
pyridines are directly inaccessible by these methods.
M. A. Kryuchkov (&) Á I. F. Perepichka Á S. V. Tolkunov
L. M. Litvinenko Institute of Physical Organic and Coal
Chemistry, National Academy of Sciences of Ukraine,
70 R. Luxemburg str., 83114 Donetsk, Ukraine
e-mail: maks_ne@yahoo.com
R. I. Zubatyuk Á O. V. Shishkin
Institute for Scintillation Materials,
National Academy of Sciences of Ukraine,
60 Lenina ave., 61001 Kharkiv, Ukraine
123

36
M. A. Kryuchkov et al.
R
R
N
N
O
O
CH3I
N
N
H
N
H
N
S
CH3CN
S
I
R
Harmine
Harmaline
R
1a, R = H
2a, R = H
2b, R = CH3
O
N
1b, R = CH3
HO
OH
Scheme 3
NH
However, application of this general alkylation proce-
dure to 3,3,6-trimethyl-1,2,3,4-tetrahydrobenzothieno[2,3-c]
quinolines 3a, 3b [16] did not lead to the expected salts 4a,
4b, when alkylated with methyl iodide in acetonitrile
under conditions similar to those for compounds 2a, 2b
(Scheme 4).
N
H
N
H
Norharmane-3-carboxylic acid
6-Hydroxy-1,2,3,4-
tetrahydro-norharmane
Scheme 1
Therefore, to afford pyridinium salts 4 we used another
approach, namely recyclization of pyrylium into pyridini-
um, using primary amines [17, 18]. We have previously
described a convenient synthesis of 1-oxo-3,3,6-trimethyl-
1,2,3,4-tetrahydrobenzothieno[2,3-c]pyrylium perchlorate
5 [16], which is a suitable starting material for the synthesis
of pyridinium salts 4. Heating 5 under reflux with one
equivalent of primary amine in 2-propanol resulted exclu-
sively in benzothieno[2,3-c]pyridinium salts 4c–4f in 60–
90% yields and no undesired 1-aminodibenzothiophene
derivatives [19] were detected (Scheme 5). This reaction
was successfully employed to gain access to not only N-
alkyl pyridinium salts 4c, 4d, but also N-aryl pyridinium
salts 4e, 4f, that are inaccessible by simple alkylation of
pyridines. A similar recyclization to obtain N-aryl pyridi-
nium salt 2c was previously described [19].
O
O
O
R
O
N
H
NH
NH
R
S
S
Appetite depressant
Anxiolytics
Scheme 2
Herewith we report the synthesis of 1,2,3-substituted
benzothieno[2,3-c]pyridinium salts and their reduction by
sodium borohydride in methanol. We demonstrate that,
depending on the substituents at the pyridine core, benzo-
thieno[2,3-c]pyridinium salts can undergo reduction to
1,2,3,4-tetrahydro- (9a–9c, 10) or 1,2-dihydrobenzothie-
no[2,3-c]pyridine derivatives (11c–11f). Surprisingly, in
the last case the keto-group is also left untouched.
We also prepared benzothieno[3,2-g]indolizinium salt 8
by tandem recyclization/quaternization [20] of pyrylium
perchlorate 7 with ammonia [21] (Scheme 6).
Our interest in indolizinium derivatives was particularly
stimulated by a recent report on novel alkaloids with a
pyrrolo[2,1-a]isoquinoline skeleton (Scheme 7) isolated
from Carduus crispus, which is used in Chinese folk
medicine for treatment of cold, stomach ache, and
Results and discussion
Synthetic and structural aspects
Three classes of benzothieno[2,3-c]pyridinium salts were
prepared in order to investigate their applicability in the
synthesis of tetrahydro derivatives and to determine how
structural changes in the pyridinium core affect the
reduction process. The desired pyridinium salts were
obtained either by alkylation of benzothieno[2,3-c]pyri-
dines, or by recyclization of benzothieno[2,3-c]pyrylium
derivatives. Thus, readily available 1,3-dialkyl-substituted
benzothieno[2,3-c]pyridines 1a, 1b [15] were successfully
alkylated with methyl iodide in acetonitrile affording
N-methyl derivatives 2a, 2b according to Scheme 3.
X
X
CH3I
N
N
S
S
CH3CN
I
3a, X = O
3b, X = H2
4a, X = O
4b, X = H2
Scheme 4
123

Synthesis of benzothieno-annelated hydropyridine derivatives
37
further reduction, and in some cases the reaction results in
1,2,5,6-tetrahydropyridines [27–30]. Studying the mecha-
nism of simple pyridinium ions reduction by sodium
borohydride, Lyle et al. demonstrated that transformation
of dihydropyridines into tetrahydropyridines involves their
protonation to form intermediates A and B (Scheme 8)
[31, 32].
O
O
RNH2
O
N
i-PrOH
R
ClO4
ClO4
S
S
4c, R = CH3CH2
5
4d, R = C6H5CH2,
4e, R = 4-CH3OC6H4
4f, R = 4-Br-C6H4
We found that benzothieno[2,3-c]pyridinium salts 2a–2c
and benzothieno[3,2-g]indolizinium salts 8 readily undergo
reduction to tetrahydro derivatives 9a–9c and 10, which
were obtained in 60–80% yields and isolated as hydro-
chlorides (Scheme 9).
Cl
Cl
PhNH2
ClO4
Compounds 9a–9c and 10 have two chiral carbon cen-
ters and are mixtures of four stereoisomers. It is known
that, in most cases, enantiomers can be distinguished in
NMR spectra only by using suitable enantiomeric dis-
crimination agents [33], but diastereomers might show up
O
N
ClO4
S
S
2c
6
Scheme 5
1
without special stereogenic treatment [34]. In our case, H
NMR spectra of 9a–9c and 10 enabled estimation of the
ratio between pairs of diastereomers in the obtained prod-
ucts. Thus, 9a and 9c are mixtures of two pairs of
diastereoisomers in 2:1 ratio, whereas in 9b the mixture is
in 1:1 ratio. The ratio could not be estimated for 10,
because the signals from pairs of diastereomers overlapped.
NH3
ClO4
Cl
O
N
Cl
i-PrOH
S
S
7
8
Scheme 6
N
R
O
O
O
BH4
BH4
HOR'
A
N
R
N
N
R
N
N
R
Cl
O
N
R
Crispine A
Crispine B
B
Scheme 7
Scheme 8
R1
rheumatism [22]. It was shown that crispine B has cyto-
toxic activity against some human-cancer lines in vitro.
Reduction of benzothieno-annelated pyridinium salts
2a–2c, 4c–4f, and 8 was carried out with fivefold excess of
sodium borohydride in methanol.
R1
R2
R2
1. NaBH4/MeOH
2. HCl
N
N
R
HCl
R
S
S
X
R1
R1
2a, R = CH3, R1 = R2 = H, X = I
2b, R = R1 = CH3, R2 = H, X = I
2c, R = C6H5, R1 = H, R2 = Cl, X = ClO4
9a, R = CH3, R1 = R2 = H
9b, R = R1 = CH3, R2 = H
It is known that reduction of pyridinium salts by sodium
borohydride results in a mixture of 1,2-dihydropyridines
and 1,4-dihydropyridines [23–26]. The ratio of the isomers
depends on the substituents in the pyridinium ring and the
conditions used. Quinolinium salts undergo similar reduc-
tion by NaBH4 to give a mixture of 1,2-dihydroquinolines
and 1,4-dihydroquinolines, and 1,2-dihydroisomers usually
predominate [27]. It should be noted that substituents at the
nitrogen and carbon atoms of the pyridine core affect
the stability of dihydropyridine derivatives towards
9c, R = C6H5, R1 = H, R2 = Cl
1. NaBH4/MeOH
2. HCl
HCl
N
N
Cl
S
S
10
8
Scheme 9
123

38
M. A. Kryuchkov et al.
O
O
NaBH4
CH3OH
N
N
R
ClO4
R
S
S
4c, R = CH3CH2
4d, R = C6H5CH2,
4e, R = 4-CH3OC6H4
4f, R = 4-Br-C6H4
11c, R = CH3CH2
11d, R = C6H5CH2,
11e, R = 4-CH3OC6H4
11f, R = 4-Br-C6H4
Scheme 10
Fig. 1 Molecular structure of compound 11f
For pyridinium salts 4c–4f the reduction proceeded
differently, affording exclusively dihydro derivatives 11c–
11f (Scheme 10). Even when a 20-fold excess of sodium
borohydride was used, no further reduction into tetrahydro
derivatives and/or reduction of the carbonyl group were
observed.
The 4-bromophenyl substituent is rotated relative to the
plane formed by the N(1) and linked atoms [C(9)–N(1)–
C(16)–C(17) torsion angle is 47.0(5)°] because of steric
factors (shortened intramolecular contacts C(21)ÁÁÁH(15B)
˚
˚
of 2.60 A, C(16)ÁÁÁH(15B) of 2.62 A, C(17)ÁÁÁH(9) of
˚
˚
Because 11c–11f have only one chiral center, two
enantiomers are not distinguished by NMR under condi-
tions that we used. 1H NMR spectra of compounds 11c–11f
contained only one signal from the proton on the chiral
carbon atom and one signal from the protons of the
neighboring methyl group.
2.72 A, and C(9)ÁÁÁH(17) of 2.81 A; van der Waals radii sum
˚
is 2.87 A [37]). This causes elongation of the N(1)–C(16)
˚
˚
bond up to 1.418(5) A and the mean value is 1.371 A [38].
The presence of a bulky substituent on the N(1) atom results
in axial orientation of the C(24) methyl group [the C(7)–
C(8)–C(9)–C(24) torsion angle is -81.9(5)°].
The increased stability of dihydro derivatives 11c–11f
towards further reduction into tetrahydro derivatives can be
rationalized on the basis of enaminoketone fragment for-
mation (and possibly because of steric hindrance). The
formation of such conjugated enaminoketone moiety also
causes a shift of the C=O absorption in the infrared spectra to
high frequencies (1,615 cm-1 for 11f) compared with that of
the initial pyridinium salt 4f (1,700 cm-1). Such a shift is
generally an indication of strongly conjugated carbonyl
groups [35] and, for example, the pyrazolone moiety (for-
mally containing the N–C=C–C=O fragment) was shown to
be stable in the reduction reaction with NaBH4 [36].
Some bond elongation is observed for the C(10)–C(11)
˚
and O(1)–C(12) bonds [1.376(6) and 1.238(5) A, and the
˚
mean values are 1.322 and 1.210 A], probably because of
strong conjugation within the N(1)–C(10)–C(11)-C(12)–
O(1) fragment.
The carbonyl group participates in the formation of the
intramolecular hydrogen bond C(5)–H(5)ÁÁÁO(1) (the HÁÁÁO
˚
distance is 2.32 A and the C–HÁÁÁO angle is 128°). In the
crystal, the molecules of 11f form infinite chains along
Single-crystal X-ray structure of 11f
Single-crystal X-ray diffraction analysis of compound 11f
provides confirmation that dihydropyridine derivatives are
formed. As seen from Fig. 1, molecule 11f is chiral. The
(R) configuration has been assigned to the chiral center, in
accordance with the Cahn–Ingold–Prelog rules.
The dihydropyridine ring adopts a conformation which is
intermediate between sofa and twist-boat. The C(8)–C(7)–
C(11)–C(10) and N(1)–C(10)–C(11)–C(7) torsion angles
are -24.0(5) and 14.5(6)°. The C(9) and N(1) atoms deviate
from the mean plane of the other atoms of the ring by -0.540
˚
and 0.116 A, respectively. The conformation of the cyclo-
hexenone ring can be described as distorted sofa. The C(10),
C(11), C(12), C(13), and C(15) atoms are coplanar within
Fig. 2 Crystal packing of compound 11f, hydrogen atoms are
omitted for clarity
˚
0.04 A and the C(14) atom lies at 0.65 A from this plane.
˚
123

Synthesis of benzothieno-annelated hydropyridine derivatives
39
the (010) direction through the BrÁÁÁp interactions (Fig. 2):
the distance between Br(1) and the center of C(16)ÁÁÁC(21)
methyl iodide (7.5 mmol) was added and the solution was
heated under reflux for 24 h. The precipitate formed was
isolated by filtration, washed successively with acetone and
diethyl ether, and dried. The crude product was recrystal-
lized from methanol.
˚
ring is 3.69 A, close to the van der Waals radii sum (3.68 A).
˚
Conclusions
1,2,3-Trimethyl[1]benzothieno[2,3-c]pyridinium
iodide (2a, C14H14INS)
This compound was obtained in 70% yield as yellowish
In conclusion, benzothieno[2,3-c]pyridinium salts 2a–2c,
4c–4f and benzothieno[3,2-g]indolizinium salts 8 are con-
venient intermediates for synthesis of 1,2,3-substituted
benzothieno-annelated heterocyclic systems with dihydro-
pyridine and tetrahydropyridine moieties. We have shown
that, depending on the structure of benzothieno-annelated
pyridinium salts, their reaction with sodium borohydride in
methanol results in reduction of the pyridine core into
tetrahydropyridine or dihydropyridine rings. Reduction of
pyridinium (2a–2c) and indolizinium salts (8) readily gives
corresponding benzothieno-annelated tetrahydropyridines
in good yields. Reduction of 4c–4f, which contain cyclo-
hexanone fragments attached to the pyridine ring, leads to
dihydropyridine derivatives 11c–11f. The single-crystal
X-ray diffraction analysis of 11f also confirms that the
carbonyl group is not reduced. Studies of biological
activity of the synthesized compounds are in progress and
will be reported elsewhere.
1
needles. M.p.: 258–259 °C; H NMR (200 MHz, DMSO-
d6): d = 2.96 (3H, s, 3-CH3), 3.05 (3H, s, 1-CH3), 4.24
(3H, s, N-CH3), 7.71 (1H, t, J = 8.0 Hz, 6-H), 7.84 (1H, t,
J = 8.0 Hz, 7-H), 8.24 (1H, d, J = 8.0 Hz, 5-H), 8.62 (1H,
d, J = 8.0 Hz, 8-H), 8.84 (1H, s, 4-H) ppm.
1,2,3,5,8-Pentamethyl[1]benzothieno[2,3-c]pyridinium
iodide (2b, C16H18INS)
This compound was obtained in 85% yield as yellow–green
1
crystals. M.p.: 260–262 °C; H NMR (200 MHz, DMSO-
d6): d = 2.59 (3H, s, 3-CH3), 2.93 (3H, s, 1-CH3), 2.98
(3H, s, 5-CH3), 3.12 (3H, s, 8-CH3), 4.23 (3H, s, N-CH3),
7.44 (1H, d, J = 7.6 Hz, 6-H), 7.59 (1H, d, J = 7.6 Hz,
7-H), 8.63 (1H, s, 4-H) ppm.
General procedure for preparation of
[1]benzothieno[2,3-c]quinolinium perchlorates 4c–4f
To a stirred suspension of 0.7 g 5 (1.8 mmol) in 10 cm3 2-
propanol, one equivalent of the corresponding amine was
added and the mixture was heated under reflux for 3 h. The
precipitate formed was isolated by filtration, washed suc-
cessively with 2-propanol, acetone, and diethyl ether,
dried, and recrystallized from acetic acid.
Experimental
Melting points were determined in non-sealed capillaries
using a Bellstone apparatus. The infrared spectra were
recorded on a Specord IR-75 spectrometer from KBr pel-
lets. The 1H NMR spectra were recorded on Varian Gemini
200 (200 MHz), Bruker Avance 400 (400 MHz), and
Bruker DRX 500 (500 MHz) NMR instruments, using
TMS as an internal standard; assignments of protons were
5-Ethyl-1,2,3,4-tetrahydro-3,3,6-trimethyl-1-oxo[1]
benzothieno[2,3-c]quinolinium perchlorate
(4c, C20H22ClNO5S)
This compound was obtained in 62% yield as a yellow
1
powder. M.p.: 225–226 °C; H NMR (200 MHz, DMSO-
1
based on H–1H COSY NMR spectra. Mass spectra were
acquired on HP 59980B and Micromass Autospec instru-
ments, operating in electron-impact mode at 70 eV. CHNS
elemental analyses were performed using a Fisons AE1108
analyzer and the results were found to be in good agree-
ment ( 0.25%) with the calculated values.
d6): d = 1.22 (6H, s, 3,3-CH3), 1.55 (3H, t, J = 7.0 Hz,
CH3CH2), 2.91 (2H, s, 2-CH2), 3.24 (3H, s, 6-CH3), 3.46
(2H, s, 4-CH2), 4.81 (2H, q, J = 7.0 Hz, CH3CH2), 7.63
(1H, t, J = 8.0 Hz, 10-H), 7.87 (1H, t, J = 8.0 Hz, 9-H),
8.32 (1H, d, J = 8.0 Hz, 11-H), 8.72 (1H, d, J = 8.0 Hz,
8-H) ppm.
Benzothieno[2,3-c]pyridines1a, 1b [15], benzothieno[2,3-
c]pyridinium perchlorate 2c [19], benzothieno[2,3-c]quino-
lines 3a, 3b [16], benzothieno[2,3-c]pyrylium perchlorates 5
[16] and 6 [19], and benzothieno[3,2-g]indolizinium chloride
8 [21] were obtained as reported elsewhere.
1,2,3,4-Tetrahydro-3,3,6-trimethyl-1-oxo-5-
(phenylmethyl)-[1]benzothieno[2,3-c]quinolinium
perchlorate (4d, C25H24ClNO5S)
This compound was obtained in 75% yield as a yellow
1
General procedure for preparation of
[1]benzothieno[2,3-c]pyridinium iodides 2a, 2b
powder. M.p.: 247–248 °C; H NMR (200 MHz, DMSO-
d6): d = 1.07 (6H, s, 3,3-CH3), 3.15 (3H, s, 6-CH3), 3.23
(2H, s, 2-CH2), 3.31 (2H, s, 4-CH2), 6.14 (2H, s,
C6H5CH2), 7.11–7.29 (2H, m, 2,6-Ph), 7.30–7.55 (3H, m,
3,4,5-Ph), 7.67 (1H, t, J = 7.0 Hz, 10-H), 7.91 (1H, t,
To a solution of benzothieno[2,3-c]pyridine 1a, 1b
(1.5 mmol) in 10 cm3 acetonitrile a fivefold excess of
123

40
M. A. Kryuchkov et al.
J = 7.0 Hz, 9-H), 8.36 (1H, dd, J = 7.5 Hz, 2.2 Hz,
11-H), 8.79 (1H, dd, J = 7.5 Hz, 2.2 Hz, 8-H) ppm.
and, finally, the solution obtained was heated under reflux
for 3 h. The solution was concentrated by evaporation,
diluted with a large amount of water to dissolve the inor-
ganic compounds, and the oily product was extracted with
3 9 20 cm3 CHCl3. Chloroform was removed under
reduced pressure, the residue was dissolved in 10 cm3
acetone, and 0.2 cm3 (2 mmol) of conc. HCl was added.
The precipitate was isolated by filtration, washed succes-
sively with dry acetone and diethyl ether, and dried. The
crude product was recrystallized from methanol.
1,2,3,4-Tetrahydro-5-(4-methoxyphenyl)-3,3,6-trimethyl-1-
oxo[1]benzothieno[2,3-c]quinolinium perchlorate
(4e, C25H24ClNO6S)
This compound was obtained in 60% yield as a yellow
1
powder. M.p.: 259–260 °C; H NMR (200 MHz, DMSO-
d6): d = 1.11 (6H, s, 3,3-CH3), 2.75 (3H, s, 6-CH3), 2.82
(2H, s, 2-CH2), 2.91 (2H, s, 4-CH2), 3.95 (3H, s, OCH3),
7.35 (2H, d, J = 8.0 Hz, 2,6-Ph), 7.63 (2H, d, J = 8.0 Hz,
3,5-Ph), 7.74 (1H, t, J = 8.0 Hz, 10-H), 7.96 (1H, t,
J = 8.0 Hz, 9-H), 8.44 (1H, d, J = 8.0 Hz, 11-H), 8.91
(1H, d, J = 8.0 Hz, 8-H) ppm.
1,2,3,4-Tetrahydro-1,2,3-trimethyl[1]benzothieno
[2,3-c]pyridine hydrochloride (9a, C14H18ClNS)
This compound was obtained from salt 2a in 60 % yield as
light-yellow crystals. M.p.: 195–197 °C. According to its
1H NMR spectrum, this product is a mixture of two pairs of
5-(4-Bromophenyl)-1,2,3,4-tetrahydro-3,3,6-trimethyl-1-
oxo[1]benzothieno[2,3-c]quinolinium perchlorate
(4f, C24H21BrClNO5S)
1
diastereoisomers in 2:1 ratio (accordingly, two sets of H
NMR shifts are given in parentheses; the first set is for the
major isomer). 1H NMR (500 MHz, DMSO-d6):
d = [(1.66, d, J = 6.7 Hz) and (1.56, d, J = 6.7 Hz),
3H, 3-CH3], [(1.80, d, J = 6.7 Hz) and (1.90, d,
J = 6.7 Hz), 3H, 1-CH3], [(2.54, d, J = 4.8 Hz) and
(2.97, d, J = 4.8 Hz), 3H, N-CH3], 2.78–2.90 (1H, m, 4-
CH2), 3.11–3.22 (1H, m, 4-CH2), [(3.99–4.11, m) and
(3.65–3.74, m), 1H, 3-CH], [(5.04–5.12, m) and (4.68–
4.75, m), 1H, 1-CH], 7.33–7.45 (2H, m, 5,6-H), 7.68 (1H,
d, J = 8.0 Hz, 8-H), 7.87 (1H, t, J = 8.0 Hz, 7-H),
[(12.98, br s) and (12.57, br s), 1H, N?-H] ppm; 13C
NMR (125 MHz, CDCl3): d = 19.91, 32.77, 33.35, 35.85,
55.63, 58.03, 123.91, 126.54, 126.96, 128.22, 129.19,
131.32, 138.61, 139.34 ppm; MS (EI, 70 eV): m/z = 231
(M?), 216 (M?-CH3).
This compound was obtained in 89% yield as a yellow
1
powder. M.p.: 290–291 °C; H NMR (200 MHz, DMSO-
d6): d = 1.08 (6H, s, 3,3-CH3), 2.74 (3H, s, 6-CH3), 2.80
(2H, s, 2-CH2), 2.89 (2H, s, 4-CH2), 7.63–7.78 (3H, m, 2,6-
Ph, 10-H), 7.88–8.11 (3H, m, 3,5-Ph, 9-H), 8.42 (1H, d,
J = 8.4 Hz, 11-H), 8.89 (1H, d, J = 8.4 Hz, 8-H) ppm; IR
(KBr): m = 3,400, 2,943, 2,363, 2,333, 1,700, 1,595,
1,100 cm-1
.
1-(3-Chloropropyl)-3-phenyl[1]benzothieno[2,3-c]pyryli-
um perchlorate (7, C20H16Cl2O5S)
This compound was prepared by following the procedure
similar one described previously [21]. To a solution of
1.5 g 2-(3-benzo[b]thienyl)-1-phenylethanone (6.0 mmol)
in 10 cm3 dichloroethane, 0.67 cm3 4-chlorobutyryl chlo-
ride (6.0 mmol) and 0.80 g anhydrous AlCl3 (6.0 mmol)
were added with stirring at 10 °C. After stirring for 3 h at
r.t., 0.60 cm3 70% HClO4 (6.0 mmol) was added dropwise.
The precipitate was isolated by filtration, washed succes-
sively with aqueous isopropanol, isopropanol, and diethyl
ether, and dried to afford 1.58 g (60%) product as an
1,2,3,4-Tetrahydro-1,2,3,5,8-pentamethyl[1]
benzothieno[2,3-c]pyridine (9b, C16H21NS)
This compound was obtained from salt 2b in 72 % yield as
yellow crystals. M.p.: 175–177 °C. 9b was then converted
into the base for further characterization. To achieve this, it
was dissolved in warm water and excess NaHCO3 was
added. The milk-like solution formed was extracted with
diethyl ether (3 9 20 cm3), organic extracts were dried
over MgSO4, the solvent was then evaporated, and the
residue was dried in vacuo to afford the base of 9b as a
1
orange powder. M.p.: 212–213 °C; H NMR (200 MHz,
CDCl3): d = 2.71 (2H, m, CH2CH2CH2Cl), 3.81 (4H, t,
J = 6.0 Hz, CH2CH2CH2Cl), 7.63–7.81 (3H, m, 3,4,5-Ph),
7.86 (1H, t, J = 8.0 Hz, 6-H), 8.06 (1H, t, J = 8.0 Hz,
7-H), 8.14–8.30 (3H, m, 5-H, 2,6-Ph), 8.70 (1H, d,
J = 8.0 Hz, 8-H), 8.94 (1H, s, 4-H) ppm.
1
light-yellow oil. According to its H NMR spectrum, 9b is
a mixture of two pairs of diastereoisomers in 1:1 ratio
(accordingly, two sets of 1H NMR shifts are given in
1
General procedure for sodium borohydride reduction
of compounds 2a–2c and 8
parentheses). H NMR (500 MHz, CDCl3): d = [(1.24, d,
J = 6.8 Hz) and (1.35, d, J = 6.8 Hz), 3H, 3-CH3], [(1.55,
d, J = 6.8 Hz) and (1.60, d, J = 6.8 Hz), 3H, 1-CH3],
[(2.34, s) and (2.44, s), 3H, 5-CH3], 2.49 (3H, s, 8-CH3),
2.70 (3H, d, J = 3.6 Hz, N-CH3), [(2.81–2.96, m) and
(3.28–3.40, m), 2H, 4-CH2], 3.03–3.22 (1H, m, 3-CH),
3.88–4.04 (1H, m, 1-CH), 6.97 (1H, d, J = 7.4 Hz, 6-H),
7.01 (1H, d, J = 7.4 Hz, 7-H) ppm; 13C NMR (125 MHz,
To a stirred suspension of benzothieno[2,3-c]pyridinium
salt 2a–2c or 8 (2 mmol) in 10 cm3 methanol a fivefold
excess of sodium borohydride was added with care at room
temperature, avoiding intense evolution of hydrogen.
During the addition of NaBH4 the pyridinium salt dissolved
123

Synthesis of benzothieno-annelated hydropyridine derivatives
41
CDCl3): d = 19.88, 20.46, 20.81, 31.98, 33.05, 34.68,
55.77, 58.53, 123.70, 126.73, 126.76, 128.61, 129.29,
130.52, 133.71, 139.94 ppm; MS (EI, 70 eV): m/z = 259
(M?), 244 (M?-CH3).
precipitate was isolated by filtration, washed with water,
dried, and recrystallized from 10:1 2-propanol–water.
5-Ethyl-3,4,5,6-tetrahydro-3,3,6-trimethyl[1]benzothie-
no[2,3-c]quinolin-1(2H)-one (11c, C20H23NOS)
6-Chloro-1,2,3,4-tetrahydro-1,3-dimethyl-2-phenyl[1]
benzothieno[2,3-c]pyridine hydrochloride
(9c, C19H19Cl2NS)
This compound was obtained from salt 4c in 78% yield as
white crystals. M.p.: 186–187 °C; 1H NMR (400 MHz,
CDCl3): d = 1.15 (3H, s, 3-CH3), 1.16 (3H, s, 3-CH3), 1.26
(3H, t, J = 7.1 Hz, CH3CH2), 1.39 (3H, d, J = 6.3 Hz,
6-CH3), 2.24 (1H, d, J = 16.2 Hz, 4-CH2), 2.30 (1H, d,
J = 16.2 Hz, 4-CH2), 2.46 (1H, d, J = 16.6 Hz, 2-CH2),
2.57 (1H, d, J = 16.6 Hz, 2-CH2), 3.39–3.48 (1H, m,
CH3CHH), 3.59–3.68 (1H, m, CH3CHH), 4.86 (1H, q,
J = 6.4 Hz, 6-H), 7.16–7.25 (2H, m, 9,10-H), 7.69 (1H,
dd, J = 8.7 Hz, 1.9 Hz, 11-H), 8.13 (1H, dd, J = 8.7 Hz,
1.9 Hz, 8-H) ppm; 13C NMR (100 MHz, CDCl3):
d = 15.32, 20.14, 27.67, 29.65, 31.81, 41.05, 44.99,
50.45, 55.99, 107.44, 122.02, 123.80, 123.87, 126.65,
126.87, 128.50, 136.54, 139.55, 157.51, 190.50 ppm; MS
(EI, 70 eV): m/z = 325 (M?), 310 (M?-CH3).
This compound was obtained from salt 2c in 52% yield as
1
yellowish crystals. M.p.: 204–206 °C. According to its H
NMR spectrum, this product is a mixture of two stereo-
1
isomers in 2:1 ratio (accordingly, two sets of H NMR
shifts are given in parentheses; the first set is for the major
isomer). 1H NMR (500 MHz, DMSO-d6): d = 1.25 (3H, d,
J = 6.0 Hz, 3-CH3), 1.56 (3H, d, J = 6.0 Hz, 1-CH3),
3.21–3.74 (2H, m, CH2), [(4.28–4.44, m) and (4.07–4.20,
m), 1H, 3-CH], [(5.23–5.39, m) and (5.00–5.14, m), 1H,
1-CH], [(7.37, d, J = 8.5 Hz) and (7.32, d, J = 8.5 Hz),
1H, 8-H], 7.41–7.66 (5H, m, Ph), [(7.77, s) and (7.68, s),
1H, 5-H], [(7.90, d, J = 8.5 Hz) and (7.85, d, J = 8.5 Hz),
1H, 7-H], 14.45 (1H, br s, N?-H) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 18.05, 23.18, 24.90, 29.47,
38.45, 120.93, 121.14, 123.70, 124.29, 124.40, 125.02,
127.00, 129.77, 130.01, 136.53, 136.73, 138.99 ppm; MS
(EI, 70 eV): m/z = 327 (M?), 312 (M?-CH3).
3,4,5,6-Tetrahydro-3,3,6-trimethyl-5-(phenyl-
methyl)[1]benzothieno[2,3-c]quinolin-1(2H)-one
(11d, C25H25NOS)
This compound was obtained from salt 4d in 63% yield as
white crystals. M.p.: 171–173 °C; 1H NMR (400 MHz,
CDCl3): d = 1.04 (3H, s, 3-CH3), 1.12 (3H, s, 3-CH3), 1.40
(3H, d, J = 6.4 Hz, 6-CH3), 2.29 (2H, s, 4-CH2), 2.47 (1H,
d, J = 16.9 Hz, 2-CH2), 2.57 (1H, d, J = 16.9 Hz, 2-CH2),
4.61 (1H, d, J = 16.8 Hz, C6H5CHH), 4.83 (1H, q,
J = 6.4 Hz, 6-H), 4.95 (1H, d, J = 16.8 Hz, C6H5CHH),
7.15 (2H, d, J = 7.6 Hz, 2,6-Ph), 7.18–7.34 (5H, m, 9,10-
H, 3,4,5-Ph), 7.70 (1H, d, J = 8.0 Hz, 11-H), 8.18 (1H, d,
J = 8.0 Hz, 8-H) ppm; 13C NMR (100 MHz, CDCl3):
d = 21.09, 28.05, 28.59, 32.84, 43.02, 51.35, 53.48, 58.71,
108.19, 114.61, 122.09, 123.85, 126.11, 126.51, 127.02,
127.89, 128.94, 129.13, 136.36, 136.62, 139.76, 157.52,
191.08 ppm; MS (EI, 70 eV): m/z = 387 (M?), 372
(M?-CH3).
1,2,3,5,6,11b-Hexahydro-5-phenyl[1]benzothieno
[3,2-g]indolizine hydrochloride (10, C20H20ClNS)
This compound was obtained from salt 8 in 81% yield as
rose crystals. M.p.: 299–301 °C; 1H NMR (400 MHz,
DMSO-d6): d = 1.88–2.29 (3H, m, 6-CHH, 2-CH2), 2.58–
2.72 (1H, m, 6-CHH), 2.89–3.07 (1H, m, 1-CHH), 3.33–
3.46 (3H, m, 1-CHH, 3-CH2), 4.67–4.83 (1H, m, 11b-CH),
5.02–5.18 (1H, m, 5-CH), 7.39–7.61 (5H, m, 3,4,5-Ph, 8,9-
H), 7.75–7.84 (1H, dd, J = 8.6 Hz, 2.5 Hz, 7-H), 7.87–
7.96 (2H, d, J = 7.1 Hz, 2,6-Ph), 7.99–8.09 (1H, dd,
J = 8.6 Hz, 2.5 Hz, 10-H), 12.74 (1H, br s, N?-H) ppm;
13C NMR (100 MHz, DMSO-d6): d = 22.00, 30.06, 30.42,
51.39, 60.87, 62.26, 121.74, 122.72, 124.73, 125.02,
127.56, 128.63, 129.06, 129.24, 131.58, 135.73, 137.00,
138.27 ppm; MS (EI, 70 eV): m/z = 305 (M?), 228
(M?-C6H5).
3,4,5,6-Tetrahydro-5-(4-methoxyphenyl)-3,3,6-tri-
methyl[1]benzothieno[2,3-c]quinolin-1(2H)-one
(11e, C25H25NO2S)
This compound was obtained from salt 4e in 69% yield as
white crystals. M.p.: 173–174 °C; 1H NMR (400 MHz,
CDCl3): d = 1.05 (3H, s, 3-CH3), 1.07 (3H, s, 3-CH3), 1.53
(3H, d, J = 6.4 Hz, 6-CH3), 2.18 (1H, d, J = 16.8 Hz,
2-CH2), 2.24–2.31 (2H, m, 4-CH2), 2.38 (1H, d,
J = 16.8 Hz, 2-CH2), 3.84 (3H, s, OCH3), 5.00 (1H, q,
J = 6.5 Hz, 6-H), 6.95 (2H, d, J = 9.0 Hz, 2,6-Ph), 7.19
(2H, d, J = 8.5 Hz, 3,5-Ph), 7.21–7.29 (2H, m, 9,10-H),
7.72 (1H, d, J = 8.0 Hz, 11-H), 8.16 (1H, d, J = 8.0 Hz,
8-H) ppm; 13C NMR (100 MHz, CDCl3): d = 20.99,
27.95, 28.65, 32.52, 43.01, 51.28, 55.86, 58.88, 109.63,
General procedure for sodium borohydride reduction
of compounds 4c–4f
To a suspension of the pyridinium salt 4c–4f (3 mmol) in
10 cm3 methanol, 20-fold excess of sodium borohydride
was added with care at room temperature, avoiding intense
evolution of hydrogen. During addition of NaBH4 the
pyridinium salt dissolved and, finally, the solution formed
was heated under reflux for 3 h. The solution was con-
centrated and diluted with a large amount of water. The
123

42
M. A. Kryuchkov et al.
114.83, 122.08, 123.83, 123.94, 126.01, 126.75, 128.47,
129.55, 136.36, 136.45, 139.52, 156.98, 158.82,
192.00 ppm; IR (KBr): m = 3,441, 3,053, 2,954, 2,867,
2,833, 1,617, 1,562, 1,537, 1,455, 1,424, 1,378, 1,365,
1,295, 1,272, 1,248, 1,172, 1,102, 1,076, 1,061,
1,033 cm-1; MS (EI, 70 eV): m/z = 403 (M?), 388
(M?-CH3).
structure was established according to Flack parameter
value 0.00(1).
Tables of atomic coordinates, bond lengths and angles,
anisotropic displacement parameters, hydrogen coordi-
nates, and isotropic displacement parameters have been
deposited at the Cambridge Crystallographic Data Centre,
CCDC No. 267307. These data can be obtained free of
charge from the CCDC via http://www.ccdc.cam.ac.uk/
data_request/cif.
5-(4-Bromophenyl)-3,4,5,6-tetrahydro-3,3,6-tri-
methyl[1]benzothieno[2,3-c]quinolin-1(2H)-one
(11f, C24H22BrNOS)
This compound was obtained from salt 4f in 75% yield as
light-brown crystals. M.p.: 209–211 °C; 1H NMR
(400 MHz, CDCl3): d = 1.07 (3H, s, 3-CH3), 1.11 (3H,
s, 3-CH3), 1.55 (3H, d, J = 6.5 Hz, 6-CH3), 2.17 (1H, d,
J = 16.4 Hz, 4-CH2), 2.30 (1H, d, J = 16.0 Hz, 2-CH2),
2.47 (1H, d, J = 16.4 Hz, 4-CH2), 2.51 (1H, d,
J = 16.0 Hz, 2-CH2), 5.09 (1H, q, J = 6.5 Hz, 6-H),
7.18–7.30 (4H, m, 3,5-Ph, 9,10-H), 7.56 (2H, d,
J = 8.5 Hz, 2,6-Ph), 7.73 (1H, d, J = 8.0 Hz, 11-H),
8.11 (1H, d, J = 8.0 Hz, 8-H) ppm; 13C NMR (100 MHz,
CDCl3): d = 21.12, 28.15, 28.30, 33.24, 43.03, 51.56,
58.49, 111.90, 120.62, 122.15, 123.98, 124.06, 125.63,
126.55, 127.95, 130.12, 132.79, 136.19, 139.41, 142.71,
155.16, 192.73 ppm; IR (KBr): m = 3,400, 2,920, 2,850,
2,320, 2,350, 1,615, 1,505, 1,480, 1,400, 1,390, 1,360,
1,270, 1,250, 1,180, 1,140, 1,095, 1,075, 1,005 cm-1; MS
(EI, 70 eV): m/z = 451 (M?, 79Br), 453 (M?, 81Br), 436
(M?-CH3, 79Br), 438 (M?-CH3, 81Br).
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Crystals suitable for single-crystal X-ray analysis
were grown in a closed vial from a toluene–n-hexane
mixture (1:2). Crystals of 11f are monoclinic, C24H22
˚
˚
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3
˚
˚
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452.40, Z = 2, space group P21, dcalc = 1.467 g/cm3,
l(MoKa) = 2.123 mm-1
,
F(000) = 464. Unit cell
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Synthesis of benzothieno-annelated hydropyridine derivatives
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123