Transformations of 4,5,6,7-tetrahydrothieno[3,2-c]-and 1,2,3,4- tetrahydrobenzothieno[2,3-c]pyridines in reactions with alkynes activated by electron-withdrawing substituents

Article abstract of DOI:10.1007/s11172-007-0156-3

The transformations of tetrahydrothieno[3,2-c]-and tetrahydrobenzothieno[2, 3-c]pyridines in the reactions with acetylenedicarboxylic ester, alkyl propiolates, and acetylacetylene in alcohols were studied. Tetrahydrobenzothieno[3,2-d]azocines and 2-methoxyethyl-3-vinyl- aminoethylbenzothiophenes were synthesized.

Full text of DOI:10.1007/s11172-007-0156-3

Russian Chemical Bulletin, International Edition, Vol. 56, No. 5, pp. 1041—1048, May, 2007
1041
Transformations of 4,5,6,7ꢀtetrahydrothieno[3,2ꢀc]ꢀ and
1,2,3,4ꢀtetrahydrobenzothieno[2,3ꢀc]pyridines in reactions
with alkynes activated by electronꢀwithdrawing substituents
a
a
L. G. Voskressensky,a T. N. Borisova, A. V. Listratova,
ꢀ
E. A. Sorokina,a S. V. Tolkunov,b and A. V. Varlamova
аPeoples' Friendship University of Russia,
6 ul. MiklukhoꢀMaklaya, 117198 Moscow, Russian Federation.
Fax: +7 (495) 955 0779. Eꢀmail: lvoskressensky@sci.pfu.edu.ru
bL. M. Litvinenko Institute of Physicoorganic and Coal Chemistry, National Academy of Sciences of Ukraine,
70 ul. R. Lyuksemburg, 83114 Donetsk, Ukraine.
Еꢀmail: samit@skif.net
The transformations of tetrahydrothieno[3,2ꢀc]ꢀ and tetrahydrobenzothieno[2,3ꢀc]pyridines
in the reactions with acetylenedicarboxylic ester, alkyl propiolates, and acetylacetylene in
alcohols were studied. Tetrahydrobenzothieno[3,2ꢀd]azocines and 2ꢀmethoxyethylꢀ3ꢀvinylꢀ
aminoethylbenzothiophenes were synthesized.
Key words: tandem transformations, thienopyridines, benzothienopyridines, benzothienoꢀ
azocines, activated alkynes.
An interest in the development of procedures for the
synthesis of benzomorphanes and their heterocyclic anaꢀ
logs is associated with the presence of the azocine fragꢀ
ment in natural alkaloids.1 It is also known2 that bicyclic
azocines, viz., benzomorphanes, have analgesic activity.
Heterofused azocines remain virtually unknown.
spectively), were studied in the reactions with dimethyl
acetylenedicarboxylate (DMAD), ethylꢀ and methyl
propiolates, acetylacetylene, and propiolaldehyde.
Unlike tetrahydropyrrolo[3,2ꢀc]pyridines, thienoꢀ
pyridine 1 reacts with DMAD in methanol only upon
prolonged reflux. The expected 3ꢀmethoxymethylthioꢀ
phene 5 was isolated from the resulting multicomponent
mixture in 17% yield. The formation of the latter proꢀ
ceeds through the zwitterion A. The nucleophilic assisꢀ
tance of methanol through the formation of the transition
state B facilitates the C(4)—N bond cleavage (Scheme 1).
The reaction of thienopyridine 1 with DMAD in
boiling propanꢀ2ꢀol afforded Nꢀ(dimethoxycarbonylꢀ
vinyl)tetrahydrothieno[3,2ꢀc]pyridine 6 and a small
amount of 3ꢀhydroxymethylthiophene 7. This reaction
pathway is, apparently, attributed to steric hindrance to
the formation of the transition state B with propanꢀ2ꢀol,
resulting in debenzylation of the zwitterionic intermediꢀ
ate. Thiophene 7 is formed as a result of cleavage of the
tetrahydropyridine fragment due to the presence of a waꢀ
ter impurity in propanꢀ2ꢀol and elimination of the benzyl
fragment. The ability of thiophene to stabilize electronꢀ
deficient centers is much lower than that of pyrrole,9
which is responsible for low activity of thienopyridine 1 in
the reaction with DMAD.
Procedures for the synthesis of thienoazocines deꢀ
scribed in the literature are few in number and are based
on either the cleavage of dithienomorphanes and thienoꢀ
benzomorphanes3,4 or the Beckmann rearrangement of
benzothienocycloheptanone oximes.5,6 Recently, we
have demonstrated7,8 that tetrahydropyrrolo[3,2ꢀc]pyriꢀ
dines and their benzo analogs, viz., tetrahydroꢀβꢀ and
γꢀcarbolines, can be transformed into tetrahydropyrꢀ
rolo[2,3ꢀd]azocines and tetrahydroazocino[5,4ꢀb]ꢀ and
ꢀ[4,5ꢀb]indoles under the action of activated alkynes.
Studies of the characteristic features of these transformaꢀ
tions resulted in the development of an original procedure
for the synthesis of the aboveꢀmentioned fused azocines.
We expected that tetrahydrothieno[3,2ꢀc]ꢀ and tetraꢀ
hydrobenzothieno[2,3ꢀc]pyridines, which are analogs of
tetrahydropyrrolopyridines and carbolines, would be
transformed into thieno[2,3ꢀd]azocines and benzothieꢀ
no[3,2ꢀd]azocines, respectively, under the same reaction
conditions.
5ꢀ(oꢀChlorobenzyl)ꢀ4,5,6,7ꢀtetrahydrothieno[3,2ꢀc]ꢀ
pyridine (1) and its 2ꢀformyl derivative 2, as well as
1,2,3ꢀtrimethylꢀ and 1,2,3,5,8ꢀpentamethylꢀ1,2,3,4ꢀ
tetrahydrobenzo[b]thieno[2,3ꢀc]pyridines (3 and 4, reꢀ
2ꢀFormyltetrahydrothienopyridine 2 reacts with
DMAD in methanol and with ethyl propiolate in ethanol
already at room temperature for 6 and 4 days, respecꢀ
tively, to form multicomponent mixtures.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1003—1009, May, 2007.
1066ꢀ5285/07/5605ꢀ1041 © 2007 Springer Science+Business Media, Inc.

1042
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
Voskressensky et al.
Scheme 1
E = CO2Me
The reaction of formylthienopyridine 2 with DMAD
The reactions of tetrahydropyridines 3 and 4 with
afforded the debenzylation product (Nꢀdimethoxycarboꢀ
nylvinylꢀ2ꢀformylthienopyridine 8) and the cleavage prodꢀ
uct of the tetrahydropyridine ring (2ꢀformylꢀ3ꢀmethoxyꢀ
methylthiophene 9) in equal amounts (27 and 28%, reꢀ
spectively), whereas the reaction with ethyl propiolate
gave only 5ꢀformylꢀ2ꢀvinylthiophene 10, which is formed
as a result of the Hofmann cleavage of the tetrahydroꢀ
pyridine ring (Scheme 2).
DMAD, methyl propiolate, ethyl propiolate, and acetylꢀ
Scheme 3
Scheme 2
R = H (3), Me (4)
Comꢀ
R
X
Y
Comꢀ
R
R´
X
Y
pound
poundꢀ
11
12
13
14
15
16
17
H
H
H
CO2Me CO2Me 18
H
H
H
Me CO2Me CO2Me
CO2Me
COMe
H
H
19
20
Me CO2Me
Me COMe
H
H
Me CO2Me CO2Me 21 Me Me CO2Me CO2Me
Me CO2Et
Me CO2Me
Me COMe
H
H
H
22 Me Et
CO2Et
H
H
H
H
23 Me Me CO2Me
24 Me Me COMe
25 Me Me CHO
E = CO2Me

Transformations of tetrahydrothienopyridines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
1043
acetylene in methanol proceed at room temperature and
are completed in one day. In all cases, tetrahydroꢀ
benzothieno[3,2ꢀd]azocines 11—17 and 2ꢀmethoxyethylꢀ
3ꢀ(vinylaminopropyl)benzothiophenes 18—25 were isoꢀ
lated from the reaction mixtures in 2—9 and 22—50%
yields, respectively, after chromatographic separation
(Scheme 3, Table 1). The latter products, except for comꢀ
pound 22, were obtained as mixtures of diastereomers
(1H NMR spectroscopic data).
3 and 4, with methyl and ethyl propiolates in acetonitrile
produce exclusively azocino[5,4ꢀb]indoles in 35—70%
yields. The reactions of benzothienopyridines 3 and 4
with methyl propiolate and acetylacetylene at room temꢀ
perature give mixtures, from which 5ꢀmethoxycarbonylꢀ
substituted benzothienoazocines 12 and 16 and 5ꢀacetyl
derivative 17 were isolated chromatographically in 4—6%
yields.
Attempts to perform cyclization of 2ꢀmethoxyethylꢀ
substituted benzothiophenes 18—25 (by analogy with
methoxymethylꢀsubstituted indoles7) under the action
of Lewis acids (AlCl3, ZnCl2, TiCl4, or Et2O•BF3) to
prepare the corresponding benzothieno[3,2ꢀd]azocines
failed.W
The reactions of compounds 3 and 4 with propiolꢀ
aldehyde10 proceed with difficulty and are not brought to
completion even in the presence of a 10ꢀfold excess of
alkyne. In the case of benzothienopyridine 4, only
2ꢀmethoxyethylthiophene 25 was isolated from the reacꢀ
tion mixture in 47% yield.
The structures of the resulting compounds were estabꢀ
lished by IR spectroscopy, 1H and 13C NMR spectroꢀ
scopy, mass spectrometry, and Xꢀray diffraction. The
It is known11 that the reactions of tetrahydroꢀβꢀ
carbolines, which are analogs of tetrahydrothienopyridines
Table 1. Yields, physicochemical characteristics, mass spectrometric data, and elemental analysis
data for benzothienoazocines 11—17 and 2ꢀalkoxyethylbenzothiophenes 18—25
Comꢀ Yield
M.p.*
/°C
MS,
m/z ([M]+)
Found
Calculated
Molecular
formula
(%)
poꢀ
(%)
und
C
H
N
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4.5
5.5
2
Oil
132—134
120—122
Oil
374**
315
64.58
64.32
68.32
68.54
72.53
72.20
66.03
65.81
70.31
70.55
70.23
69.93
73.58
73.35
62.38
62.20
66.02
65.68
68.42
68.85
63.58
63.72
68.70
68.45
66.95
67.17
70.01
70.15
69.90
69.53
6.00
6.21
7.01
6.71
6.84
7.07
6.52
6.78
7.42
7.61
7.00
7.34
7.29
7.69
6.80
6.71
6.95
7.29
7.68
7.60
7.43
7.21
8.45
8.24
7.56
7.78
8.39
8.13
7.98
7.88
3.40
3.75
4.35
4.44
4.52
4.68
3.46
3.49
4.01
3.92
4.15
4.08
4.24
4.28
3.30
3.45
4.20
4.03
4.42
4.23
3.42
3.23
3.59
3.47
3.82
3.73
4.12
3.90
4.18
4.05
C20H23NO4S
C18H21NO2S
C18H21NOS
C22H27NO4S
C21H27NO2S
C20H25NO2S
C20H25NOS
C21H27NO5S
C19H25NO3S
C19H25NO2S
C23H31NO5S
C23H33NO3S
C21H29NO3S
C21H29NO2S
C20H27NO2S
299
9
402**
357
4
110—111
196—198
234—236
80—82
Oil
4
343
6
327
50
25.5
29
35
22
39
33
47
405
348**
332**
433
Oil
114—116
Oil
404**
375
82—84
Oil
360**
345
98
* Hexane—AcOEt as the solvent.
** [M + H]+ (LCꢀMS data).

1044
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
Voskressensky et al.
Scheme 4
molecular structure of benzothienoazocine 16 is shown
in Fig. 1.
associated with elimination of the DMAD molecule and
retrodiene decomposition (Scheme 4).
The azocine ring adopts a boat conformation. The
C(7), C(13), C(10), and C(11) atoms lie in one plane,
whereas the N(1), C(8), C(9), and C(12) atoms are loꢀ
cated above this plane at distances of 0.41, 0.49, 1.49, and
0.51 Å, respectively. The methyl groups at the C(9) and
C(12) atoms are in syn orientations with respect to the
eightꢀmembered ring.
The major fragmentation pathway of alkoxyꢀ
ethylꢀsubstituted
benzothiophenes
18—25
inꢀ
volves elimination through βꢀcleavage of the
Me—CH=N+(Me)—C(Y)=CH(X) fragment, whose peak
has the maximum intensity. The main fragmentation
channel for the [M]+ ions of benzothienoazocines 11—17
is associated with the cleavage of the tetrahydroazocine
moiety, resulting in the fragment ions with the highest
intensity at m/z 174 (for azocines 11—13) and 202 (for
azocines 14—17). These compounds have, apparently,
the benzothiepinium structure (Scheme 5).
The IR spectra of compounds 11—24 show stretching
bands of the corresponding functional groups. For exꢀ
ample, these vibrations in the spectra of tetrahydroꢀ
thieno[3,2ꢀd]azocines 11 and 14 and alkoxyethylbenzoꢀ
thiophenes 18 and 21 are observed as two bands of the
ester groups at 1730—1736 and 1680—1686 cm–1, whereas
the corresponding vibrations in the spectra of derivaꢀ
tives 12, 15, 16, 19, 22, and 23 appear as one band
Scheme 5
at 1682—1665 cm–1
.
The absorption band at
1624—1687 cm–1 belongs to the COMe group (comꢀ
pounds 13, 17, 20, and 24); the band at 1650 cm–1, to the
aldehyde group (methoxyethylbenzothiophene 25). In
the spectra of compounds 11—24, the stretching viꢀ
brations of the double bond of the enamine fragment
(—CH=CH—NMe) appear at 1563—1630 cm–1
.
The 1H NMR spectra of benzothienoazocines 11—17
and substituted benzothiophenes 18—25 show signals for
all protons of the molecules with the corresponding chemiꢀ
cal shifts and spinꢀspin coupling constants (Tables 2
and 3). The 1H NMR spectra of azocines 12, 13, and
15—17 have a singlet for the H(4) proton at δ 7.40—7.56.
The 1H NMR spectra of diastereomers 18 and 21 are
characterized by two singlets for the vinyl proton (δ 4.62,
4.64 and δ 4.57, 4.59, respectively); the spectra of mixꢀ
tures of diastereomers of 19, 20, and 22—24, by two
doublets for the vinyl protons of each diastereomer at
δ 7.37—7.58 and 4.55—5.06. In the spectrum of comꢀ
pound 25, these signals appear as doublets at δ 6.78
and 6.94 and a multiplet at δ 5.14. The spinꢀspin coupling
constants (12.1—12.9 Hz) are indicative of the trans conꢀ
figuration of the enamine fragment.
The mass spectra of all compounds have molecular
ion peaks corresponding to their molecular formulas.
The major fragmentation pathways of the [M]+ ions of
Nꢀdimethoxycarbonylꢀsubstituted compounds 6 and 8 are
C(15)
C(17)
C(16)
C(5)
C(8)
C(6)
C(4)
C(3)
C(9)
N(1)
C(10)
C(7)
C(13)
C(18)
C(2)
C(14)
C(11)
C(1)
S(1)
O(2)
C(12)
O(1)
Fig. 1. Molecular structure of benzothienoazocine 16.
To summarize, we demonstrated that the transformaꢀ
tions of fused tetrahydrothieno(benzothieno)pyridines in
the reactions with activated alkynes start with the addiꢀ
tion of the amine nitrogen atom at the triple bond and are
C(19)
C(20)

Transformations of tetrahydrothienopyridines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
1045
1
Table 2. H NMR spectra of benzothienoazocines 11—17
Comꢀ
poꢀ
und
δ (J/Hz)
C(1)H2
(dd)
H(2)
(m)
H(6)
(q)
C(2)Me C(6)Me
(d)
NMe
C(4)Y
(s)
C(5)X
C(8)R,
C(11)R
H(9),
H(10)
11
2.94 (J = 16.8,
J = 4.8); 3.20
(J = 16.8, J = 12.7)
2.93 (J = 16.9,
J = 3.2); 3.20
(J = 16.9, J = 12.7)
2.98 (J = 17.0,
J = 3.1); 3.29
(J = 17.0, J = 12.8)
3.16 (J = 16.9,
J = 4.7); 3.70
4.35
4.59
4.69
4.32
4.54
4.76
1.45
1.60
2.41
2.79
2.26
2.70
2.42
3.73
(OMe)
3.75 (s,
OMe)
7.76, 7.63
(both d,
J = 7.7)
7.73, 7.59
(both d,
J = 7.5)
7.61, 7.74 7.28—7.37
(both d,
J = 7.9)
7.35, 7.29
(both t,
J = 7.7)
7.35, 7.29
(both t,
(J = 7.2) (J = 6.4) (J = 7.2)
12
13
14
15
4.79
1.44
1.64
7.55
7.40
3.72
3.72 (s,
OMe)
(J = 7.3) (J = 6.6) (J = 7.3)
J = 7.5)
5.03
1.50
1.65
2.81 (s,
Me)
(J = 7.1) (J = 6.7) (J = 7.1)
(m)
4.81
1.42
1.60
3.76
2.44, 2.47
(both s, Me) (both d,
7.00, 6.95
(J = 7.2) (J = 6.4) (J = 7.2)
(OMe) (s, OMe)
(J = 16.9, J = 12.7)
3.20 (J = 16.9,
J = 2.9); 3.65
J = 7.3)
6.98, 6.19
4.85
1.38
1.65
7.56 1.29 (t, Me,
J = 7.1);
2.79, 2.76
(both s, Me) (both d,
(J = 7.2) (J = 6.6) (J = 7.2)
(J = 16.9, J = 12.7)
4.18 (q, CH2,
J = 7.1)
J = 7.3)
16
17
3.18 (J = 16.9,
J = 2.9); 3.65
(J = 16.9, J = 12.7)
3.21 (J = 16.7,
4.58
4.62
4.83
1.39
1.63
2.42
2.24
7.55
7.40
3.72 (s,
OMe)
2.79, 2.76
(both s, Me) (both d,
6.98, 6.92
(J = 7.2) (J = 6.6) (J = 7.2)
J = 7.3)
6.92, 6.97
5.05
1.43
1.62
2.81 (s,
Me)
2.85, 2.77
(both s, Me) (both d,
J = 2.9); 3.69
(J = 7.3) (J = 6.5) (J = 7.3)
(J = 16.7, J = 12.9)
J = 7.2)
of Sciences of Ukraine. The synthesis of these compounds will
be described elsewhere.*
common for such heterocyclic systems. The predomiꢀ
nance of a particular transformation pathway is, apparꢀ
ently, determined by the electronic properties of the
heterocyclic fragment.
5ꢀ(oꢀChlorobenzyl)ꢀ2ꢀformylꢀ4,5,6,7ꢀtetrahydrothieꢀ
no[3,2ꢀc]pyridine (2). Freshly distilled phosphorus oxychloride
(2.9 g, 19 mmol) was added dropwise to anhydrous DMF (5 mL,
64 mmol) cooled to –5 °C. After 50 min, the reaction mixture
was warmed to 20 °C, and a solution of thienopyridine 1 (0.5 g,
1.9 mmol) in anhydrous DMF (7 mL) was added. The reaction
was performed at ~20 °C for 7 h and at 60—65 °C for 9 h. The
course of the reaction was monitored by TLC. The reaction
mixture was made alkaline (pH 10) with a 20% NaOH solution
and extracted with diethyl ether (3×40 mL). The extract was
dried with magnesium sulfate. Then diethyl ether was distilled
off, and the residue was chromatographed. Formylthienopyridine
2 was obtained in a yield of 0.18 g (31%). Found (%): N, 4.83.
C15H14ClNOS. Calculated (%): N, 4.80. IR, ν/cm–1: 1700
(CHO). 1H NMR, δ: 2.89 (t, 2 H, C(6)H2, J = 5.3 Hz); 2.97 (t,
2 H, C(7)H2, J = 5.3 Hz); 3.65 (s, 2 H, C(4)H2); 4.40 (s, 2 H,
CH2Ar); 7.19—7.29 (m, 2 H, H arom.); 7.38 (dd, 1 H, H arom.,
J = 7.6 Hz, J = 1.5 Hz); 7.39 (s, 1 H, H(3)); 7.50 (dd, 1 H,
H arom., J = 7.3 Hz, J = 2.0 Hz); 9.79 (s, 1 H, CHO). MS, m/z:
291 [M]+ (for 35Cl).
Experimental
The IR spectra were recorded on an Infralum FTꢀ801
Fourierꢀtransform spectrometer in KBr pellets (for crystalline
compounds) or in films (for oils). The mass spectra were obꢀ
tained on Finnigan MAT 95XL and Hewlett—Packard MSꢀ5988
mass spectrometers using a direct inlet system; the ionizing voltꢀ
age was 70 eV. The ESI mass spectra were measured on an
Agilent 1100 series LC/MSD Trap System VL mass spectroꢀ
meter. The 1H NMR spectra were recorded on a Varian Unity
400 instrument (400 MHz) in CDCl3 with Me4Si as the internal
standard. The TLC analysis was performed on Silufol UVꢀ254
plates (visualization with iodine vapor). Column chromatograꢀ
phy was carried out on aluminum oxide (Brockmann activꢀ
ity 2; 60 mesh, Fluka) using an AcOEt—hexane mixture,
(1 : 10)—(1 : 50), as the eluent.
The yields, physicochemical characteristics, elemental analyꢀ
sis data, and spectroscopic characteristics of the compounds are
given in Tables 1—4.
5ꢀ(oꢀChlorobenzyl)ꢀ4,5,6,7ꢀtetrahydrothieno[3,2ꢀc]pyridine
(1) was isolated from the pharmaceutical Ticlid by the alkaline
treatment followed by extraction with diethyl ether. Compounds
3 and 4 were provided by the L. M. Litvinenko Institute of
Physicoorganic and Coal Chemistry of the National Academy
Reaction of 5ꢀ(oꢀchlorobenzyl)ꢀ4,5,6,7ꢀtetrahydrothieꢀ
no[3,2ꢀc]pyridine (1) with DMAD. A mixture of thienopyridine 1
(0.3 g, 1.1 mmol) and DMAD (0.19 g, 1.34 mmol) in anhydrous
MeOH or PriOH (10 mL) was refluxed for 4 days. The course of
the reaction was monitored by TLC. The solvent was distilled off
* S. V. Tolkunov, M. A. Kryuchkov, O. V. Shishkin, and R. I.
Zubatyuk, J. Heterocycl. Chem., 2007, in press.

1046
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
Voskressensky et al.
1
Table 3. H NMR spectra of 2ꢀalkoxyethylbenzothiophenes 18—25
Comꢀ
poꢀ
und
δ (J/Hz)
C(3)R
1´ꢀMe H(1´) OR´ C(1´)H2 2´ꢀMe H(2´) NMe C(4´)Y C(5´)X H(5´)
Z*
C(2)R
C(4)R C(7)R
H(5),
H(6)
18´ 1.57 (d, 4.72 3.26 3.03
J = 6.4) (m) (s, Me) (m)
18″ 1.54 (d, 4.72 3.27 3.03
J = 6.4) (m) (s, Me) (m)
19´ 1.54 (d, 4.72 3.27 3.02
J = 6.4) (m) (s, Me) (m)
19″ 1.57 (d, 4.72 3.29 3.02
J = 6.4) (m) (s, Me) (m)
20´ 1.54 (d, 4.73 3.28 3.04
J = 6.4) (m) (s, Me) (m)
20″ 1.57 (d, 4.73 3.29 3.04
J = 6.4) (m) (s, Me) (m)
21´ 1.53 (d, 4.64 3.23 3.09
J = 6.4) (m) (br.s, (m)
Me)
1.16 (d,
J = 6.6)
1.24 (d,
J = 6.7)
1.24 (d,
J = 7.1)
1.30 (d,
J = 6.4)
1.28 (d,
J = 6.6)
1.33 (d,
J = 6.6)
1.24 (d,
J = 6.9)
3.82 2.83
(m) (s)
3.82 2.80
(m) (s)
3.72 2.70
(m) (s)
3.72 2.72
(m) (s)
3.80 2.74
(m) (s)
3.80 2.76
(m) (s)
3.72 2.83
(m) (s)
3.61 (s, 3.61 (s,
OMe) OMe)
3.62 (s, 3.62 (s,
4.64
(s)
4.62
(s)
7.64 (d, 7.83 (d, 7.31—7.40 1.86 : 1
J = 7.9) J = 7.8) (m)
7.60 (d, 7.83 (d, 7.31—7.40
J = 7.6) J = 7.8) (m)
OMe)
7.50 (d,
OMe)
3.65
4.55 (d, 7.61 (d, 7.83 (d, 7.34—7.39 1.22 : 1
(m)
4.57 (d, 7.61 (d, 7.83 (d, 7.34—7.39
J = 12.8) (s, Me) J = 12.8) J = 7.8) J = 7.8) (m)
7.46 (d, 2.01 5.04 (d, 7.61 (d, 7.61 (d, 7.32—7.40 1 : 1
J = 12.7) (s, Me) J = 12.7) J = 7.6) J = 7.6) (m)
7.54 (d, 2.04 5.06 (d, 7.83 (d, 7.83 (d, 7.32—7.40
J = 12.7) (s, Me) J = 12.7) J = 7.9) J = 7.9) (m)
2.66 (s, 6.97—7.03 1.5 : 1
Me) (m)
J = 12.8) (s, Me) J = 12.8) J = 7.8) J = 7.8)
7.58 (d, 3.66
3.57 (s, 3.31 (s,
OMe) OMe)
4.59
(s)
2.49
(br.s,
Me)
2.49
(br.s,
Me)
2.68
(s)
21″ 1.55 (d, 4.64 3.23 3.09
J = 6.4) (m) (br.s, (m)
Me)
22 1.24 (d, 4.78 1.28 3.17
J = 6.5) (q, (m, Me); (m)
J = 3.42 (m,
1.30 (d,
J = 6.7)
3.72 2.79
(m) (s)
3.57 (s, 3.31 (s,
4.57
(s)
2.79 (s, 6.97—7.03
OMe)
OMe)
Me)
(m)
1.20 (d,
J = 6.3)
3.58 2.49
(m) (s)
7.49
(d, J =
1.34 (t,
Me,
4.59
(d,
J =
2.68
(s)
7.00, 7.04 —**
(both d,
12.9) J = 7.4);
J = 7.7)
6.3) CH2Me)
4.11 (q, 12.9)
CH2Me,
J = 7.4)
23´ 1.32 (d, 4.70 3.28 3.17
J = 6.7) (m) (s, Me) (m)
23″ 1.25 (d, 4.70 3.29 3.17
J = 6.7) (m) (s, Me) (m)
1.52 (d,
J = 6.2)
1.56 (d,
J = 6.4)
1.27 (d,
J = 6.3)
1.33 (d,
J = 6.5)
1.35 (d,
J = 6.7)
1.40 (d,
J = 6.8)
3.60 2.50
(m) (s)
3.60 2.50
(m) (s)
3.64 2.48
(m) (br.s) J = 12.3) (s, Me)
3.64 2.48 7.49 (d, 2.01
(m) (br.s) J = 12.1) (s, Me)
7.43 (d, 3.64 (s, 4.55 (d,
2.70
2.70
(br.s)
2.70
(br.s)
2.68
(br.s)
2.68
(br.s)
2.78
7.00 (d, 6.7 : 1
J = 7.3)
7.05 (d,
J = 7.3)
7.01 (d, 1.5 : 1
J = 7.3)
J = 12.9) OMe) J = 12.9) (br.s)
7.34 (d, 3.65 (s, 4.57 (d, 2.70
J = 12.9) OMe) J = 12.8) (br.s)
24´
1.54 4.67 3.27 3.17
(m) (m) (s, Me) (m)
1.54 4.67 3.30 3.17
(m) (m) (s, Me) (m)
7.37 (d,
2.01
5.04
(m)
5.04
(m)
5.14
(m)
5.14
(m)
2.68
(br.s)
2.68
(br.s)
2.69
(br.s)
2.69
(br.s)
24″
7.05 (d,
J = 7.5)
25´ 1.54 (d, 4.63 3.29 3.18
J = 6.2) (m) (s, Me) (m)
25″ 1.55 (d, 4.63 3.26 3.18
J = 6.4) (m) (s, Me) (m)
3.69 2.50
(m) (s)
3.69 2.50
(m) (s)
6.94
(m)
6.78
(m)
8.96 (s,
CHO)
8.91 (s,
CHO)
7.05
(m)
7.05
(m)
1.5 : 1
(br.s)
2.78
(br.s)
* The ratio between the major (singly primed) and minor (doubly primed) diastereomers.
** One diastereomer.
in vacuo, and the residue was chromatographed. The reaction in
methanol produced dimethyl (E)ꢀ2ꢀ[Nꢀ(oꢀchlorobenzyl)ꢀ2ꢀ(3ꢀ
methoxymethylthiophenꢀ2ꢀyl)ethyl]aminobutꢀ2ꢀeneꢀ1,4ꢀdioate
(5). The reaction in propanꢀ2ꢀol afforded dimethyl
(E)ꢀ2ꢀ(4,5,6,7ꢀtetrahydrothieno[3,2ꢀc]pyridinꢀ5ꢀyl)butꢀ2ꢀeneꢀ
1,4ꢀdioate (6) and dimethyl (E)ꢀ2ꢀ[2ꢀ(3ꢀhydroxymethylthiophenꢀ
2ꢀyl)ethyl]aminobutꢀ2ꢀeneꢀ1,4ꢀdioate (7).
Compound 5. The yield was 0.08 g (16.6%), yellow oil.
Found (%): N, 3.22. C21H24ClNO5S. Calculated (%): N, 3.20.
MS (LCꢀMS), m/z: 438 [M + H]+ (for 35Cl).
4.25 (s, 2 H, C(4)H2); 4.85 (s, 1 H, CH=); 6.75 (d, H(3), J =
5.2 Hz); 7.15 (d, 1 H, H(2), J = 5.2 Hz). MS, m/z: 281 [M]+
(for 35Cl).
Compound 7. The yield was 0.02 г (6%), yellow oil.
Found (%): N, 4.63. C13H17NO5S. Calculated (%): N, 4.68.
1H NMR, δ: 2.90 and 3.50 (both t, 2 H each, CH2, J = 5.3 Hz);
3.60 and 4.00 (both s, 3 H each, MeO); 4.25 (s, 2 H, CH2OH);
4.83 (s, 1 H, CH=); 6.78 (d, 1 H, H(4)); 7.14 (d, 1 H, H(5)).
MS, m/z: 299 [M]+ (for 35Cl).
Reaction of 5ꢀ(oꢀchlorobenzyl)ꢀ2ꢀformylꢀ4,5,6,7ꢀtetrahydroꢀ
thieno[3,2ꢀc]pyridine (2) with DMAD and ethyl propiolate.
Acetylenedicarboxylic ester (0.1 g, 0.7 mmol) or ethyl propiolate
(0.68 g, 0.7 mmol) was added to a solution of formylthienoꢀ
pyridine 2 (0.17 g, 0.58 mmol) in anhydrous MeOH or EtOH
Compound 6. The yield was 0.06 g (18%), yellow oil.
Found (%): N, 4.93. C13H15NO4S. Calculated (%): N, 4.98.
1H NMR, δ: 2.92 (t, 2 H, C(6)H2, J = 5.6 Hz); 3.50 (t, 2 H,
C(7)H2, J = 5.6 Hz); 3.65 and 3.95 (both s, 3 H each, MeO);

Transformations of tetrahydrothienopyridines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
1047
Table 4. 13C NMR of compounds 16, 18—20, 24, and 25 (in
CDCl3)
4.75 (d, 1 H, CH=, J = 13.1 Hz); 5.39 (d, 1 H, CH2=, J =
10.7 Hz); 5.76 (d, 1 H, CH2=, J = 17.1 Hz); 6.65 (dd, 1 H,
CH=, J = 10.1 Hz, J = 17.1 Hz); 7.40 (s, 1 H, H(4)); 7.75 (d,
1 H, CH=, J = 13.1 Hz); 9.78 (s, 1 H, CHO). MS, m/z: 389 [M]+
(for 35Cl).
Comꢀ
pound
δ
Reactions of tetrahydrobenzothieno[2,3ꢀc]pyridines 3 and 4
with activated alkynes (general procedure). Activated alkyne
(1 mmol, 0.14 g of DMAD, 0.084 g of methyl propiolate, 0.068 g
of acetylacetylene, or 0.054 g of propiolaldehyde) was added to a
solution of compound 3 (0.2 g, 0.84 mmol) or compound 4
(0.22g, 0.84 mmol) in anhydrous MeOH (5 mL). The reaction
with ethyl propiolate was carried out in anhydrous EtOH. The
reaction mixture was stirred for 20—24 h. The course of the
reaction was monitored by TLC. Methanol (ethanol) was
evaporated in vacuo, and the residue was chromatographed.
Benzothienoazocines 11—17 and 2ꢀalkoxyethylbenzothiophenes
18—25 were successively eluted. The yields, physicochemical
constants, and elemental analysis data for compounds 11—25
are given in Table 1; the 1H NMR spectroscopic data for
benzothienoazocines 11—17, in Table 2; the 1H NMR spectroꢀ
scopic data for benzothiophenes 18—25, in Table 3; the
13C NMR spectroscopic data for compounds 16, 18—20, 24,
and 25, in Table 4.
16
19.5, 19.7, 23.0, 24.9, 34.2, 34.4, 51.2, 54.2, 96.8,
98.5, 114.8, 123.7, 127.8, 129.1, 130.1, 138.4, 140.1,
140.9, 154.0, 170.2
18.1 (18.2), 23.8 (23.9), 30.6 (30.5), 31.3, 50.7, 52.7
(52.5), 56.3, 56.7 (56.4), 73.0 (73.1), 84.5 (84.5),
121.3 (121.2), 122.7 (122.8), 124.1, 124.4, 128.1,
138.8 (138.9), 139.5, 145.1 (145.0), 154.6,
165.8 (165.9), 167.9
11.1 (13.9), 22.6 (23.6), 28.6 (30.4), 38.7, 50.5, 56.4,
68.1, 73.0, 84.7, 121.1, 122.9, 124.4 (124.1), 128.5,
128.7 (130.8), 132.4, 138.9, 139.4, 144.9 (150.4),
167.7 (169.8)
19.3, 23.5, 23.6, 29.5 (29.4), 32.7 (32.6), 56.3 (56.5),
61.8 (61.7), 73.1 (73.0), 97.0, 121.1, 122.8 (122.7),
124.0, 124.4 (124.3), 128.2 (128.0), 138.8 (138.7),
139.2 (139.1), 144.7 (144.9), 150.0 (149.9), 195.2
18.9, 19.9, 21.4 (21.5), 23.6 (23.3), 28.2 (28.1), 29.6,
34.0 (33.7), 56.2 (56.6), 63.4, 72.9 (73.3), 97.5, 124.5
(124.3), 128.1, 129.6 (129.8), 130.1 (130.4), 137.1,
139.9 (138.8), 144.2, 145.0, 150.2, 195.2
18
19
20
24
25
Xꢀray diffraction study of compound 16. Xꢀray diffraction
data were collected on an Enraf—Nonius CADꢀ4 diffractoꢀ
meter (MoꢀKα radiation, β filter, ω/2θꢀscanning technique,
1.68° < θ < 25.23°) from a crystal of compound 16 of dimenꢀ
sions 0.56×0.21×0.20 mm. The crystals are monoclinic: a =
6.1639(1) Å, b = 18.704(4) Å, c = 15.867(3) Å, β = 93.31(3)°,
10.9, 14.1, 23.0, 28.9, 33.4, 38.7, 63.5, 68.1, 73.5,
102.0, 124.6, 128.1, 128.1, 129.3, 132.5, 137.0,
140.1, 144.2, 145.3, 189.4
V = 1826.0(6) Å3, space group P2(1)/c, Z = 4, dcalc
=
Note. The chemical shifts for the minor isomer are given in
parentheses; in other cases, the signals of diastereomers are
identical.
1.249 g cm–3, µ = 0.189 mm–1, T = 293 K. The intensities of
3286 independent reflections were measured. The structure was
solved by direct methods using the SHELXSꢀ97 program packꢀ
age12 and refined anisotropically by the fullꢀmatrix leastꢀsquares
method using the SHELXLꢀ97 program package.13 The final
structure refinement was carried out based on all F 2 to
wR2 = 0.0920, R1 = 0.0339, S = 0.873.
(10 mL), respectively. The reaction mixture was stirred at ~20 °C
for 4—7 days. The course of the reaction was monitored by
TLC. The solvent was evaporated in vacuo, and the residue was
chromatographed. The reaction with DMAD produced dimethyl
(E)ꢀ2ꢀ(2ꢀformylꢀ4,5,6,7ꢀtetrahydrothieno[3,2ꢀc]pyridinꢀ5ꢀ
yl)butꢀ2ꢀeneꢀ1,4ꢀdioate (8) and dimethyl (Е)ꢀ2ꢀ{Nꢀoꢀchloroꢀ
benzylꢀ2ꢀ[(5ꢀformylꢀ3ꢀmethoxymethylthiophenꢀ2ꢀyl)ethyl]amiꢀ
no}butꢀ2ꢀeneꢀ1,4ꢀdioate (9). The reaction with ethyl propiolate
afforded ethyl (Е)ꢀ3ꢀ[Nꢀoꢀchlorobenzylꢀ2ꢀ(5ꢀformylꢀ2ꢀvinylthioꢀ
phenꢀ3ꢀylmethyl)amino]acrylate (10).
Compound 8. The yield was 0.06 g (27%), yellow oil.
Found (%): N, 4.58. C14H15NO5S. Calculated (%): N, 4.53.
1H NMR, δ: 2.99 and 3.50 (both t, 2 H each, CH2, J = 5.6 Hz);
3.65 and 3.96 (both s, 3 H each, MeO); 4.27 (s, 2 H, CH2); 4.86
(s, 1 H, CH=); 7.42 (s, 1 H, H(3)); 9.83 (s, 1 H, CHO).
MS (LCꢀMS), m/z: 310 [M + H]+.
This study was financially supported by the Russian
Foundation for Basic Research (Project Nos 05ꢀ03ꢀ32211
and 05ꢀ03ꢀ08419).
References
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Compound 9. The yield was 0.91 g (28%), yellow oil.
Found (%): N, 2.93. C22H24ClNO6S. Calculated (%): N, 3.01.
1H NMR, δ: 3.15 (t, 2 H, CH2, J = 5.3 Hz); 3.35 (s, 3 H, MeO);
3.55 (t, 2 H, CH2, J = 5.3 Hz); 3.61 and 3.95 (both s, 3 H each,
MeO); 4.35 (s, 2 H, CH2OMe); 4.40 (s, 2 H, CH2Ar); 4.85 (s,
1 H, CH=); 7.10—7.50 (m, 4 H, H arom.); 7.61 (s, 1 H, H(4));
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Received July 10, 2006;
in revised form March 21, 2007