Tandem transformations of tetrahydrobenzothieno[2,3-c]pyridines in the presence of activated alkynes

Article abstract of DOI:10.1016/j.tet.2010.09.098

The reactivity of some new tetrahydrothienopyridines towards activated alkynes was investigated. A novel cascade cleavage-spiroannulation process, leading to the formation of previously unreported derivatives of 1′H-spiro[1-benzothiophene-3,4′-pyridine] was discovered and studied.

Full text of DOI:10.1016/j.tet.2010.09.098

Tetrahedron 66 (2010) 9421e9430
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tandem transformations of tetrahydrobenzothieno[2,3-c]pyridines
in the presence of activated alkynes
,
a
a
a
Leonid G. Voskressensky a , Svetlana A. Kovaleva , Tatiana N. Borisova , Anna V. Listratova ,
*
Alexandr B. Eresko b, Valery S. Tolkunov b, Sergey V. Tolkunov b, Alexey V. Varlamov a
a Organic Chemistry Department of the Russian Peoples’ Friendship University, 6, Miklukho-Maklaia St., Moscow 117198, Russia
b L.M. Litvinenko Institute of Physical Organic and Coal Chemistry National Academy of Sciences of Ukraine, 70 R. Luxemburg St., Donetsk 83114, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 June 2010
Received in revised form 4 September 2010
Accepted 28 September 2010
The reactivity of some new tetrahydrothienopyridines towards activated alkynes was investigated.
A novel cascade cleavage-spiroannulation process, leading to the formation of previously unreported
derivatives of 10H-spiro[1-benzothiophene-3,40-pyridine] was discovered and studied.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Domino reactions
Spiroannulation
Ring expansion
Thienopyridine
Recyclization
1. Introduction
Domino reactions have emerged as powerful tools to allow the
rapid increase of molecular complexity. These processes avoid the
excessive handling and isolation of synthetic intermediates, gen-
erating less waste and thus, contribute towards ‘Green Chemis-
try’.1Domino reactions (also known as cascade or tandem) in which
multiple reactions are combined into one synthetic operation, have
been reported extensively in the literature and have already be-
come ‘state-of-the-art’ in synthetic organic chemistry.2
Our own research efforts have focused on developing a new
tandem reaction involving the Michael addition of the tertiary
N-atomin (hetero)annulatedpyrrolidines,3 piperidines4 orazepines5
to the triple bond of activated alkyne, followed by the nucleophilic
substitution (SN) reaction in the zwitter-ionic intermediate A
(Scheme 1).
The pathways for the further nucleophilic transformations of
the zwitter-ion A are presumably defined by the reactivity of the
anionic centre, the electronic effects of the substituent or the fused
aromatic system and the nature of the solvent. In aprotic solvents
tetrahydropyrrolopyridines produce pyrrolo[2,3-c]azocines 1, but
* Corresponding author. Tel./fax: þ7 495 955 0779; e-mail address: lvoskressensky@
Scheme 1.
sci.pfu.edu.ru (L.G. Voskressensky).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.098

9422
L.G. Voskressensky et al. / Tetrahedron 66 (2010) 9421e9430
in the case of methyl-substituted tetrahydropyridine fragment the
mixture of azocines and 3-vinylpyrroles 3 (the product of Hoffmann
degradation) is formed; tetrahydrocarbolines under the same
conditions smoothly form azocino[4,5-b] and [5,4-b]indoles 1. If the
reaction is carried out in methanol, the tandem transformation of
the tetrahydropyridine ring takes place and the formation of
alkoxyalkyl substituted pyrroles and indoles 2 occurs (Scheme 1).
Tetrahydroazepino[4,3-b]indoles under the action of activated
alkynes give azonino[5,6-b]indoles 4 in high yields both in aceto-
nitrile and in methanol. In the case of 4-hydroxymethyl dihy-
droisoindoles, a new recyclization takes place, providing access
towards phthalane derivatives 5.
The analysis of the data obtained earlier enabled us to consider
the transformation of the tetrahydropyridine ring as a domino
Michael addition-SN process. Based on this presumption we think
that electron effects and the annulation pattern of the fused frag-
ment would change the partial positive charge þ
d
1 appearing on C1
atom in the intermediate zwitter-ion A and would influence the
cleavage of C1eN bond thus determining the reaction pathway. It is
obvious that the steric effects of the substituents at C1- and N-atoms
would also affect the formation of the intermediate zwitter-ion A.
Thus, the elucidation of the reaction pathways requires taking
into account many parameters and makes the investigation of other
piperidine-containing substrates reactivity a justified task.
To get more information on the reaction scope and limitations,
we studied the transformations of tetrahydrothieno[2,3-c]pyri-
dines, condensed with benzene or oxopyrimidine rings under the
action of methyl propiolate (MP), acetyl acetylene, and dimethyl
acetylenedicarboxylate (DMAD).
Scheme 3.
2. Results and discussion
We have reported, that tetrahydrothieno[3,2-c]pyridines reac-
ted with dimethyl acetylenedicarboxylate (DMAD) or ethyl pro-
piolate in methanol or iso-propanol only under rather forcing
conditions (reflux, 4 days). Even so the target azocine derivatives
were not isolated. Two concurrent processes took place: the
cleavage of the tetrahydropyridine ring, leading to the formation of
3-methoxy(hydroxy) substituted thiophenes (6), or the elimination
of the benzyl fragment, producing N-dimethoxycarbonyl(ethoxy-
carbonyl)vinyl tetrahydrothieno[3,2-c]pyridines (7)6 (Scheme 2).
Scheme 4.
The present paper reports on new results of the tandem trans-
formations of tricyclic analogues of 11 in the reaction with activated
alkynes.
The annulation of a benzene ring to the thiophene moiety also
decreases the reactivity of thienopyridines in this reaction. Tetra-
hydrobenzothieno[2,3-c]pyridines 13a,b do not react with acti-
vated alkynes in methanol even under rather forcing reaction
conditions (several days at reflux). The use of aprotic solvents (THF,
nitromethane, acetonitrile) in the case of methyl propiolate or
acetyl acetylene did not allowed to isolate any product as well.
However in the case of the reaction of 13a,b with DMAD in aceto-
nitrile a really surprising productdspirotetrahydropyridyl annu-
lated benzothiophenesd14a, b were obtained9 (Scheme 5).
We presume, that the reaction proceeds via the intermediacy of
the zwitter-ion A, followed by the cleavage-recyclization sequence
to yield spiro compounds 14a, b. The structures were confirmed by
a complex of spectral data, including 1H, 13C NMR spectra (COSY,
HMBC experiments), mass- and IR-spectra.
Scheme 2.
Unlike tetrahydrothieno[3,2-c]pyridines 1,2,3-trimethylbenzo
[b]thieno[2,3-c]pyridines 8 reacted with activated alkynes (methyl
or ethyl propiolates, acetyl acetylene, DMAD) in methanol at rt
giving multi-component mixtures. The target tetrahydrobenzo[b]
thieno[3,2-d]azocines 9 were isolated in 2e9% yield, whereas the
main products of the reactions were 2-methoxyethyl substituted
benzo[b]thiophenes 10 resulting from the tandem cleavage of the
tetrahydropyridine ring under the action of methanol7 (Scheme 3).
At the same time 2-acetylaminotetrahydrothieno[2,3-c]pyri-
dines 11 are effectively converted into the target azocine de-
rivatives 12 under the action of activated alkynes both in methanol
or acetonitrile8 (Scheme 4).
The 1H NMR spectra of compounds 14a, b show characteristic
signals (doublets with 2J¼1.7 Hz) at 4e5 ppm fitting with the res-
onance of ]CH2 protons. The formation of spiropyridyl products in
the reaction of isosteric
b-carbolines with DMAD was reported
10
ꢀ
ꢀ
earlier by Gonzalez-Gomez et al.

L.G. Voskressensky et al. / Tetrahedron 66 (2010) 9421e9430
9423
Me
Y
N
Ar
S
15a-c
X
X
Me
Me
N
Y
N
X
+
OMe
Ar
Y
S
16a-g
S
Ar
Me
17a-g
X
N
Scheme 5.
N Me
Y
+
Y
S
The implementation of an aryl substituent in 1-position of the
benzothieno[2,3-c]pyridine skeleton changed both the activity and
transformation pathways of the thienopyridine system under the
action of alkynes. Compounds 15aec smoothly react with activated
acetylenes in methanol or acetonitrile (Scheme 6, Table 1).
Ar
X
S
Ar
19a-c
18a-d
Scheme 6.
Reactions of 1-phenyl- and 1-p-methoxyphenyl-derivatives 15a,
b with methyl propiolate in methanol proceed much faster com-
pared with the same reaction in the case of 1-p-nitrophenyl de-
rivative 15c. The reactions of 15aec with acetyl acetylene and
methyl propiolate lead to the formation of spiro[benzothieno-30,40-
piperidines] 18aed. In the case of methyl propiolate this trans-
formation is accompanied by the alternative reaction through the
intermediate ylide C, yielding the Stevens rearrangement
productsd1-aryl-1-vinyl-benzothienopyridines 19aec (Scheme 7).
The initially formed zwitter-ion A, most likely, partially exists in
the ‘opened’ form B, containing a benzhydryl-like cation, that facili-
tates ring expansion and spiroannulation processes, providing com-
pounds 16 and 18, respectively. The addition of a methanol molecule
to B yields substituted benzo[b]thiophenes 17aeg. The ability of
a 1-Ar radical to delocalize the negative charge on C-1 allows the
formation of the ylide intermediate C that undergoes the Stevens
rearrangement to give compounds 19aec. The spiro compounds
18aed are formed only as the (Z)-isomer. The structures of com-
pounds 18a (Fig. 1) and 16a (Fig. 2) were unambiguously elucidated
by means of X-ray analysis of their single crystals obtained by slow
evaporation of their methanol solution. Crystallographic data
(excluding structure factors) for compounds 18a and 16a have been
deposited with the Cambridge Crystallographic Data Centre [12,
Union Road, Cambridge CB2 1EZ, UK; tel.: þ44 1223 336 408; e-mail:
deposit@ccdc.cam.ac.uk] as supplementary publication numbers
CCDC 770393 and 770394, respectively. Those data can be obtained
free of charge at www.ccdc.cam.ac.uk/cont/retrieving.html.
As mentioned above, compounds 18a, b were isolated solely as
the (Z)-isomers, however, in the case of 1-p-nitrophenyl-tetrahy-
drobenzothieno[2,3-c]pyridine 15c, during the column chroma-
tography purification of the reaction mixtures (Al2O3, EtOAc/
Table 1
Compound
Alkyne
Solvent,
Time of
Product of reaction, yield, %
temperature
reaction
15a
Ar¼Ph
X¼Y¼CO2Me
MeOH, rt
MeOH, rt
MeOH, rt
MeCN, reflux
MeCN, rt
MeCN, rt
CH2Cl2, rt
MeOH, rt
MeOH, rt
25 h
20 h
17e, 90%
17a, 11%
17b, 11%
d
d
d
d
X¼H, Y¼CO2Me
X¼H, Y¼COMe
X¼Y¼CO2Me
16a, 81%
16d, 30%
18a, 5%
d
5 min
147 h
175 h
7 days
30 days
26 h
24 h
5 min
45 h
Multi-component mixture
X¼H, Y¼CO2Me
X¼H, Y¼COMe
X¼H, Y¼CO2Me
X¼Y¼CO2Me
16a, 63%
16d, 82%
16a, 62%
d
d
18a, 22%
18b, 15%
18a, 19%
d
trace
d
d
d
19a, 7%
d
15b
17f, 94%
Trace
17c, 48%
d
Ar¼p-OMeeC6H4
X¼H, Y¼CO2Me
X¼H, Y¼COMe
X¼Y¼CO2Me
16b, 83%
16e, 43%
16g, 32%
16b, 78%
16e, 89%
16b, 68%
d
d
d
MeOH, rt
d
d
MeCN, reflux
MeCN, reflux
MeCN, rt
d
d
X¼H, Y¼CO2Me
X¼H, Y¼COMe
X¼H, Y¼CO2Me
X¼Y¼CO2Me
11 h
d
d
d
11 days
20 days
10 days
3 days
16 h
257 h
158 h
92 h
d
d
d
CH2Cl2, rt
d
d
19b, 15%
15c
MeOH, 45 ꢀC
MeOH, 45 ꢀC
MeOH, 45 ꢀC
MeCN, reflux
MeCN, reflux
MeCN, reflux
17 g, 93%
d
d
d
d
d
Ar¼p-NO2-C6H4
X¼H, Y¼CO2Me
X¼H, Y¼COMe
X¼Y¼CO2Me
16c, 80%
16f, 53%
18c, 9%
18d, 16%
17d, 19%
Multi-component mixture
X¼H, Y¼CO2Me
X¼H, Y¼COMe
16c, 39%
16f, 56%
d
18c, 22%
18d, 29%
19c, 20%
d
d

9424
L.G. Voskressensky et al. / Tetrahedron 66 (2010) 9421e9430
Scheme 7.
Fig. 2. ORTEP plot of 16a with 50% probability ellipsoid.
quinoid structure A (Scheme 8). It was demonstrated, that the
isomerisation process is solvent-dependant, whereas the dissolu-
tion of (Z)-18c, d in ethyl acetate within 24 h leads to a 1:1 (E)/(Z)
18c, d mixture; however, the use of chloroform does not cause any
transformation. In contrast, (E)-18c, d, upon dissolution in CDCl3
are completely transformed into (Z)-18c, d within 2 weeks. The
latter was confirmed by the dynamic 1H NMR experiment (See
Supplementary data for details).
Fig. 1. ORTEP plot of 18a with 50% probability ellipsoid.
hexanes) ZeE isomerisation was observed and the corresponding
(E)-18c, d were isolated as well. The structures of both isomers
were elucidated based on 2D NOESY NMR experiments. We pre-
sume, that this isomerisation occurs via the intermediacy of the
Scheme 8.

L.G. Voskressensky et al. / Tetrahedron 66 (2010) 9421e9430
9425
3. Conclusion
H), 7.54 (2H, d, J 8.9 Hz, o-C6H4eNO2), 7.30 (d, 1H, J 7.4 Hz, 7-H), 7.20
(1H, dt, J 7.4, 1.1 Hz, 6-H), 7.12 (1H, dt, J 7.4, 1.1 Hz, 5-H), 7.02 (1H, dd,
J 7.4, 1.1 Hz, 4-H), 6.46 (1H, s, CHeAreNO2), 3.40 (3H, s, CO2Me),
3.30e3.37 (1H, m, 60-CH2), 3.09e3.15 (4H, m, 60-CH2, NeCH3), 2.08
(1H, ddd, J 13.7, 5.6, 3.9 Hz, 50-CH2), 1.95 (1H, ddd, J 13.7, 4.2, 9.4 Hz,
50-CH2); dC (100 MHz, CDCl3) 166.6, 155.2, 148.9, 145.9, 143.5, 136.0,
129.7, 128.6 (2C), 127.7, 125.4, 123.7 (2C), 123.0, 121.6, 117.0, 97.1,
56.4, 50.4, 43.3, 43.0, 38.1; m/z (LCMS) 409 [MþH]þ.
In summary, we have investigated the reactivity of some new
tetrahydrothienopyridines towards activated alkynes. A novel cas-
cade cleavage-spiroannulation process, leading to the formation of
previously unreported derivatives of 10H-spiro[1-benzothiophene-
3,40-pyridine] was found. Thework, aimed at the reaction conditions
optimization as well as at establishing its scope and limitations is
underway and will be reported in due course.
4.3. Experimental procedure for the synthesis of
benzothienoazocine 16c, spiro compound 18c and
benzothienopyridine 19c in acetonitrile
4. Experimental section
4.1. General
Methyl propiolate (0.711 mL, 8.0 mmol) was added to a solution
of benzothienopyridine 15c (250 mg, 0.8 mmol) in acetonitrile
(25 mL). The reaction mixture was heated at reflux for 158 h (TLC
monitoring). After completion the solvent was evaporated in vacuo.
The residue was purified by column chromatography (ethyl acetate/
hexane, 1:30) to give benzothienoazocine 16c (123 mg, 39%) as
a yellow solid, spiro compound 18c (69 mg, 22%) a yellow oil, and
benzothienopyridine 19c (63 mg, 20%) as a white solid.
All solvents were distilled and dried before use, DMAD, acetyl
acetylene and methyl propiolate were purchased from Acros
ORGANICS and were used without any additional purification. Col-
umn chromatography was performed with aluminium oxide, acti-
vated, neutral, Brockmann I purchased from ACROS ORGANIC or
Silicagel, 40e60
CDCl3 solutions, at 25ꢀC, using a 600 MHz NMR spectrometer, peak
positions are given in parts per million ( ) with tetramethylsilane
m
m, 60A. 1H and 13C NMR spectra were recorded in
d
used as the internal standard. Mass-spectra were registered using ESI
4.3.1. Methyl 3-methyl-6-(4-nitrophenyl)-1,2,3,6-tetrahydro[1]benzo-
thieno[3,2-d]azocine-5-carboxylate (16c). Purified by column chro-
matography (SiO2, chloroform/hexane, 1:4), yield 123 mg (39%).
or EI techniques. IR spectra were recorded with a PerkineElmer
Spectrum One instrument. Only noteworthy IR absorptions [cmꢁ1
]
are listed. Vario Micro cube element analyzer was used to perform C,
H, N analyses. Melting points were determined in capillary tube and
are uncorrected. 2-Methyl-1,2,3,4-tetrahydrobenzothieno[2,3-c]pyr-
idines 13a,b and 1-aryl-2-methyl-1,2,3,4-tetrahydrobenzothieno
[2,3-c]pyridines 15aec were prepared according to Ref. 11,12.
4.3.2. Methyl (2Z)-10-methyl-2-(4-nitrobenzylidene)-50,60-dihydro-
10H-spiro[1-benzothiophene-3,40-pyridine]-30-carboxylate
(18c). Purified by column chromatography (SiO2, chloroform/hex-
ane, 1:2), yield 69 mg (22%).
4.2. Experimental procedure for the synthesis of
benzothienoazocine 16c and spiro compound 18c in methanol
4.3.3. Methyl (2E)-3[2-methyl-1-(4-nitrophenyl)-1,2,3,4-tetrahydro
[1]benzothieno[2,3-c]pyridine-1-yl]acrylate (19c). Purified by col-
umn chromatography (SiO2, chloroform/hexane, 1:6), yield 63 mg,
(20%) as a white solid, mp 148e150 ꢀC (ethyl acetate/hexane);
[found: C, 64.7; H, 5.0; N, 6.8. C22H20N2O4S requires C, 64.69; H,
4.94; N, 6.86%]; Rf (sorbfil, 1:3, ethyl acetate/hexane) 0.70; nmax
Methyl propiolate (0.083 mL, 0.9 mmol) was added to a stirred
solution of benzothienopyridine 15c (250 mg, 0.8 mmol) in meth-
anol (25 mL) at 45 ꢀC. The temperature was maintained and the
stirring was continued for 3 days (TLC monitoring). After comple-
tion the solvent was evaporated in vacuo. The residue was purified
by column chromatography to give benzothienoazocine 16c
(251 mg, 80%) as a yellow solid and spiro compound 18c (28 mg, 9%)
as a yellow oil.
(KBr) 1722, 1640 cmꢁ1
; dH (400 MHz, CDCl3) 8.21 (2H, d, J 8.7 Hz, m-
C6H4eNO2), 7.74 (2H, d, 7.8 Hz, 5-H, 8-H), 7.64 (2H, d, J 8.7 Hz, o-
C6H4eNO2), 7.44 (1H, d, J 15.7 Hz, CH]CHeCO2Me), 7.37 (1H, t, J
7.8 Hz, 7-H), 7.29 (1H, t, J 7.8 Hz, 6-H), 5.85 (1H, d, J 15.7 Hz, CH]
CHeCO2Me), 3.77 (3H, s, OCH3), 3.11e3.00 (2H, m, 4-CH2),
2.97e2.89 (2H, m, 3-CH2), 2.34 (3H, s, NeCH3); dC (100 MHz, CDCl3)
166.0, 147.8, 145.7, 145.5, 140.0, 138.2, 130.0, 128.7, 127.5, 124.9,
124.4, 123.8 (3C), 122.4 (2C), 121.5, 61.3, 51.9, 46.8, 38.9, 24.3; m/z
(EI, 70 eV) 408 (27, Mþ), 392 (8), 377 (9), 340 (9), 323 (44), 306 (13),
286 (78), 267 (25), 258 (25), 223 (16), 213 (17) 188 (24), 160 (13),
128 (34), 117 (26), 103 (18), 76 (35), 59 (100), 42 (91).
4.2.1. Methyl 3-methyl-6-(4-nitrophenyl)-1,2,3,6-tetrahydro[1]benzo-
thieno[3,2-d]azocine-5-carboxylate (16c). Purified by column chro-
matography (SiO2, chloroform/hexane, 1:4), yield 251 mg, (80%) as
a yellow solid, mp 213e214 ꢀC (ethyl acetate/hexane); [found: C,
64.6; H, 5.0; N, 6.7. C22H20N2O4S requires C, 64.69; H, 4.94; N, 6.86%];
Rf (sorbfil, 1:3, ethyl acetate/hexane) 0.53; nmax (KBr) 1671,
1617 cmꢁ1
;
dH (400 MHz, CDCl3) 8.12 (2H, d, J 8.9 Hz, m-C6H4eNO2),
4.4. Experimental procedure for the synthesis of
benzothiophene 17g in methanol
7.82 (dd, 1H, J 7.2, 1.3 Hz, 8-H), 7.74 (1H, s, 4-H), 7.64 (1H, dd, J 7.2,
1.3 Hz, 11-H), 7.43e7.33 (4H, m, 9-H, 10-H, o-C6H4eNO2), 6.17 (1H, s,
6-H), 3.78 (3H, s, CO2Me), 3.72e3.64 (1H, m, 2-CH2), 3.34 (1H, ddd, J
17.5, 13.6, 4.4 Hz, 1-CH2), 3.03 (3H, s, NeCH3), 2.88 (1H, ddd, J 15.1,
4.4, 2.8 Hz, 2-CH2), 2.74 (1H, td, J 17.5, 2.8 Hz, 1-CH2); dC (100 MHz,
CDCl3) 170.3, 154.3, 152.3, 146.2, 141.7, 138.5, 138.1, 127.2 (2C), 127.1,
124.4, 124.2, 124.0 (2C), 122.2, 121.3, 95.2, 51.6, 48.6, 44.2, 41.9, 28.2;
m/z (LCMS) 409 [MþH]þ.
DMAD (0.147 mL, 1.2 mmol) was added to a stirred solution of
benzothienopyridine 15c (200 mg, 0.6 mmol) in methanol (20 mL)
at 45 ꢀC. The temperature was maintained and the stirring was
continued for 10 days (TLC monitoring). After completion the sol-
vent was evaporated in vacuo. The residue was purified by column
chromatography (Al2O3, ethyl acetate/hexane, 1:13) to give ben-
zothiophene 17g (267 mg, 93%) as a yellow oil.
4.2.2. Methyl (2Z)-10-methyl-2-(4-nitrobenzylidene)-50,60-dihydro-
10H-spiro[1-benzothiophene-3,40-pyridine]-30-carboxylate
(18c). Purified by column chromatography (SiO2, chloroform/hex-
ane, 1:2), yield 28 mg (9%) as a yellow oil; [found: C, 64.8; H, 4.9; N,
6.8. C22H20N2O4S requires C, 64.69; H, 4.94; N, 6.86%]; Rf (sorbfil,
4.4.1. Dimethyl
(2E)-2-[(2-{2-[methoxy(4-nitrophenyl)methyl]-1-
benzothien-3-yl}ethyl)(methyl)amino]but-2-enedioate (17g). Yield
267 mg (93%) as a yellow oil; [found: C, 60.3; H, 5.3; N, 5.7.
C25H26N2O7S requires C, 60.23; H, 5.26; N, 5.62%]; Rf (sorbfil, 1:3,
1:2, ethyl acetate/hexane) 0.45; nmax (KBr) 1679, 1614 cmꢁ1
;
dH
ethyl acetate/hexane) 0.54; nmax (KBr) 1739, 1693, 1578 cmꢁ1
;
dH
(400 MHz, CDCl3) 8.20 (2H, d, J 8.9 Hz, m-C6H4eNO2), 7.83 (1H, s, 20-
(600 MHz, CDCl3) 8.20 (2H, d, J 8.8 Hz, m-C6H4eNO2), 7.81 (1H, d, J

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L.G. Voskressensky et al. / Tetrahedron 66 (2010) 9421e9430
7.7 Hz, 7-H), 7.70e7.65 (3H, m, 4-H, o-C6H4eNO2), 7.41 (1H, d, J
7.7 Hz, 6-H), 7.35 (1H, d, J 7.7 Hz, 5-H), 5.79 (1H, s, CHeOCH3), 4.63
145.4, 143.3, 136.2, 128.6 (2C), 127.9, 125.7, 123.8 (2C), 123.1, 122.0,
117.3, 117.2, 56.5, 43.5, 43.4, 38.2, 26.3; m/z (LCMS) 393 [MþH]þ.
(1H, s,
CHeOCH3), 3.42e3.37 (2H, m,
b
0-CH), 3.89 (3H, s, CO2CH3), 3.67 (3H, s, CO2CH3), 3.47 (3H, s,
a
-CH2), 3.20e3.11 (2H, m,
b
-CH2),
4.6. Experimental procedure for the synthesis of
benzothienoazocine 16f and spiro compound 18d in
acetonitrile
2.71 (3H, s, NeCH3); dC (100 MHz, CDCl3) 167.9, 166.1, 154.2, 147.7,
140.9, 139.4, 139.2, 129.6, 127.8 (2C), 127.3, 125.0, 124.6, 123.8 (2C),
122.9, 121.3, 85.3, 78.6, 57.4, 53.1, 53.0, 50.8, 38.1, 26.0; m/z (LCMS)
499 [MþH]þ.
Acetylacetylene (0.329 mL, 4.2 mmol) was added to a solution of
benzothienopyridine 15c (200 mg, 0.6 mmol) in acetonitrile
(20 mL). The reaction mixture was heated at the reflux for 92 h (TLC
monitoring). After completion the solvent was evaporated in vacuo.
The residue was purified by column chromatography to give ben-
zothienoazocine 16f (136 mg, 56%) as a white solid and spiro
compound 18d (70 mg, 29%) as a yellow oil.
4.5. Experimental procedure for the synthesis of
benzothienoazicine 16f, spiro compound 18d and
benzothiophene 17d in methanol
Acetyl acetylene (0.057 mL, 0.7 mmol) was added to a stirred
solution of benzothienopyridine 15c (200 mg, 0.6 mmol) in meth-
anol (20 mL) at 45 ꢀC. The temperature was maintained and the
stirring was continued for 16 h (TLC monitoring). After completion
the solvent was evaporated in vacuo. The residue was purified by
column chromatography to give benzothienoazocine 16f (128 mg,
53%) as a white solid, spiro compound 18d (39 mg, 16%) as a yellow
oil and benzothiophene 17d (50 mg, 19%) as a yellow oil.
4.6.1. 1-[3-Methyl-6-(4-nitrophenyl)-1,2,3,6-tetrahydro[1]benzo-
thieno[3,2-d]azocin-5-yl]ethanone (16f). Purified by column chro-
matography (SiO2, chloroform), yield 136 mg, (56%) as a white solid,
mp 216e218 ꢀC (ethyl acetate/hexane).
4.6.2. 1-[(2Z)-10-Methyl-2-(4-nitrobenzylidene)-50,60-dihydro-10H-
spiro[1-benzothiophene-3,40-pyridin]-30-yl]ethanone (18d). Purified
by column chromatography (SiO2, chloroform), yield 70 mg, (29%)
as a yellow oil
4.5.1. 1-[3-Methyl-6-(4-nitrophenyl)-1,2,3,6-tetrahydro[1]benzo-
thieno[3,2-d]azocin-5-yl]ethanone (16f). Purified by column chro-
matography (SiO2, chloroform), yield 128 mg, (53%) as a white solid,
mp 216e218 ꢀC (ethyl acetate/hexane); [found: C, 67.4; H, 5.2; N,
7.1. C22H20N2O3S requires C, 67.33; H, 5.14; N, 7.14%]; Rf (sorbfil, 1:1,
4.7. Experimental procedure for the synthesis of
benzothienopyridine 17e in methanol
ethyl acetate/hexane) 0.40; nmax (KBr) 1635, 1572 cmꢁ1
; dH
(400 MHz, CDCl3) 8.10 (2H, d, J 8.9 Hz, m-C6H4eNO2), 7.81 (1H, d, J
7.4 Hz, 8-H), 7.64 (1H, d, J 7.4 Hz,11-H), 7.54 (1H, s, 4-H), 7.41 (1H, dt,
J 7.4, 1.2 Hz, 9-H), 7,37 (1H, dt, 7.4, J 1.2 Hz, 10-H), 7.24 (2H, dd, J 8.9,
1.2 Hz, o-C6H4eNO2), 6.54 (1H, s, 6-H), 3.79e3.71 (1H, m, 2-CH),
3.38 (1H, ddd, J 17.5, 13.7, 4.5 Hz, 1-CH), 3.10 (3H, s, NeCH3), 2.92
(1H, ddd, J 15.0, 4.5, 2.7 Hz, 2-CH), 2.77 (1H, td, J 17.5, 2.7 Hz, 1-CH),
2.38 (3H, s, COMe); dC (100 MHz, CDCl3) 193.9, 154.3, 154.2, 146.2,
141.6, 138.7, 138.3, 127.1 (2C), 124.4, 124.2, 124.0 (3C), 122.2, 121.2,
110.4, 48.8, 44.5, 39.6, 27.9, 24.8; m/z (LCMS) 393 [MþH]þ.
DMAD (0.132 mL, 1.1 mmol) was added to a stirred solution of
benzothienopyridine 15a (250 mg, 0.9 mmol) in methanol (20 mL).
The stirring was continued for 25 h (TLC monitoring). After com-
pletion the solvent was evaporated in vacuo. The residue was pu-
rified by column chromatography (Al2O3, ethyl acetate/hexane,
1:40) to give benzothienopyridine 17e (367 mg, 90%) as a white oil.
4.7.1. Dimethyl (2E)-2-[2-{2-[methoxy(phenyl) methyl]-1-benzo-
thien-3-yl}ethyl(methyl)amino]but-2-enedioate (17e). Purified by
column chromatography (Al2O3, ethyl acetate/hexane, 1:40), yield
367 mg (90%) as a white oil; [found: C, 66.3; H, 6.0; N, 3.1.
C25H27NO5S requires C, 66.20; H, 6.00; N, 3.09%]; Rf (sorbfil, ethyl
4.5.2. (3E)-4-[(2-{2-[Methoxy(4-nitrophenyl)methyl]-1-benzothien-
3-yl}ethyl)(methyl)amino]but-3-en-2one (17d). Purified by column
chromatography (SiO2, 0.2% methanol/chloroform), yield 50 mg,
(19%) as a yellow oil; [found: C, 65.1; H, 5.8; N, 6.6. C23H24N2O4S
requires C, 65.07; H, 5.70; N, 6.60%]; Rf (sorbfil, ethyl acetate) 0.20;
acetate/hexane, 1:2) 0.53; nmax (KBr) 1740, 1693, 1578 cmꢁ1
; dH
(400 MHz, CDCl3) 7.80 (1H, d, J 7.9 Hz, 7-H), 7.69 (1H, d, J 7.9 Hz, 4-
H), 7.47 (2H, dd, J 8.7,1.1 Hz, 5-H, 6-H), 7.40e7.30 (5H, m, C6H5), 5.65
nmax (KBr) 1655, 1603, 1564 cmꢁ1
;
dH (400 MHz, CDCl3) 8.22 (2H, d, J
8.7 Hz, m-C6H4eNO2), 7.81 (1H, d, J 7.7 Hz, 7-H), 7.67 (1H, d, J 7.7 Hz,
4-H), 7.61 (2H, d, J 8.7 Hz, o-C6H4eNO2), 7.46 (1H, d, J 13.2 Hz,
0-H),
7.44e7.39 (1H, m, 6-H), 7.38e7.34 (1H, m, 5-H), 5.68 (1H, s,
CHeOCH3), 5.10 (1H, d, J 13.2 Hz,
0-H), 3.47 (3H, s, CHeOCH3), 3.42
(2H, t, J 7.4 Hz, -CH2), 3.14e3.10 (2H, m, -CH2), 2.78 (3H, br s,
(1H, s, CHeOCH3), 4.63 (1H, s,
s, CO2CH3), 3.44 (3H, s, CHeOCH3), 3.27e3.08 (4H, m,
b
0-CH), 3.91 (3H, s, CO2CH3), 3.67 (3H,
a
-CH2 and b-
a
CH2), 2.66 (3H, s, NeCH3); dC (100 MHz, CDCl3) 168.1, 166.1, 154.4,
142.7, 140.6, 139.7, 139.3, 128.7 (2C), 128.5, 128.3, 127.3 (2C), 124.5,
124.3, 122.7, 121.3, 84.9, 80.0, 57.2, 53.0, 52.8, 50.8, 37.9, 25.9; m/z
(EI, 70 eV) 453 (4, Mþ), 188 (9), 186 (100), 82 (14).
b
b
a
NeCH3), 2.09 (3H, s, COCH3); dC (100 MHz, CDCl3) 195.2, 151.3 (2C),
147.7, 147.6, 140.4, 139.3, 139.2, 127.7 (2C), 125.1, 124.6, 123.8 (2C),
122.9, 121.3, 97.4, 78.8, 57.5, 57.0, 36.2, 28.4, 27.1; m/z (LCMS) 425
[MþH]þ.
4.8. Experimental procedure for the synthesis of
benzotheinoazocine 16a, spiro compound 18a and
benzothiophene 17a in methanol
4.5.3. 1-[(2Z)-10-Methyl-2-(4-nitrobenzylidene)-50,60-dihydro-10H-
spiro[1-benzothiophene-3,40-pyridin]-30-yl]ethanone (18d). Purified
by column chromatography (SiO2, chloroform), yield 39 mg, (16%)
as a yellow oil; [found: C, 67.4; H, 5.2; N, 7.1. C22H20N2O3S requires
C, 67.33; H, 5.14; N, 7.14%]; Rf (sorbfil, ethyl acetate) 0.29; nmax (KBr)
Methyl propiolate (0.095 mL, 1.1 mmol) was added to a stirred
solution of benzothienopyridine 15a (250 mg, 0.9 mmol) in
methanol (25 mL). The stirring was continued for 20 h (TLC mon-
itoring). After completion the solvent was evaporated in vacuo. The
residue was purified by column chromatography to give benzo-
thienoazocine 16a (263 mg, 81%) as a white solid, spiro compound
18a (16 mg, 5%) as a white solid and benzothiophene 17a (39 mg,
11%) as a white solid.
1690, 1584 cmꢁ1
; dH (400 MHz, CDCl3) 8.21 (2H, d, J 8.6 Hz, m-
C6H4eNO2), 7.83 (1H, s, 20-H), 7.53 (d, 2H, J 8.6 Hz, o-C6H4eNO2),
7.32 (1H, d, J 7.7 Hz, 7-H), 7.24e7.21 (1H, m, 6-H), 7.13 (1H, t, J 7.5 Hz,
5-H), 7.00 (1H, d, J 7.5 Hz, 4-H), 6.41 (1H, s, CHeAreNO2), 3.36 (1H,
ddd, J 13.4, 9.3, 4.0 Hz, 60-CH2), 3.20e3.12 (4H, m, 60-CH2, NeCH3),
2.12e2.06 (1H, m, 50-CH2), 1.97 (1H, ddd, J 13.4, 4.0, 9.3 Hz, 50-CH2),
1.83 (3H, s, COCH3); dC (100 MHz, CDCl3) 194.4, 154.8, 149.7, 145.6,
4.8.1. Methyl 3-methyl-6-phenyl-1,2,3,6-tetrahydro[1]benzothieno
[3,2-d]azocine-5-carboxylate (16a). Purified by column chroma-
tography (Al2O3, ethyl acetate/hexane, 1:50), yield 263 mg (81%) as

L.G. Voskressensky et al. / Tetrahedron 66 (2010) 9421e9430
9427
a white solid, mp 208e210 ꢀC (ethyl acetate/hexane); [found: C, 72.6;
H, 5.9; N, 3.9. C22H21NO2S requires C, 72.70; H, 5.82; N, 3.85%]; Rf
column chromatography (Al2O3, ethyl acetate/hexane, 1:45), yield
73 mg (22%) as a white solid, mp 174e176 ꢀC (ethyl acetate/hexane).
(sorbfil, ethyl acetate/hexane, 1:3) 0.42; nmax (KBr) 1665, 1616 cmꢁ1
;
dH (400 MHz, CDCl3) 7.80 (1H, d, J 7.6 Hz, 8-H), 7.71 (1H, s, 4-H), 7.61
(1H, d, J 7.6 Hz,11-H), 7.38 (1H, dt, J 7.6,1.2 Hz, 9-H), 7.33 (1H, dt, J 7.6,
1.2 Hz, 10-H), 7.28e7.24 (2H, m, 6-Ph), 7.18e7.13 (3H, m, 6-Ph), 6.12
(1H, s, 6-H), 3.75 (3H, s, CO2CH3), 3.95e3.88 (1H, m, 2-CH2), 3.29 (1H,
ddd, J 17.5, 13.5, 4.4 Hz, 1-CH2), 3.00 (3H, s, NeCH3), 2.81 (1H, ddd, J
15.0, 4.4, 2.8 Hz, 2-CH2), 2.72 (1H, td, J 17.5, 2.8 Hz, 1-CH2); dC
(100 MHz, CDCl3) 170.7, 152.1, 146.9, 142.1, 140.4, 138.3, 128.8 (2C),
126.8,126.3, (2C),125.9,124.0,123.9,122.2,121.3, 96.4, 51.5, 48.8, 44.2,
41.6, 28.4; m/z (EI, 70 eV) 363 (87, Mþ), 306 (31), 304 (50), 273 (13),
261 (16), 234 (14), 216 (10), 202 (15), 184 (10), 160 (76), 152 (9), 140
(16), 128 (9), 115 (18), 91 (9), 77 (10), 59 (65), 42 (100).
4.10. Experimental procedure for the synthesis of
benzothienoazocine 16a, spiro compound 18a and
benzothienopyridine 19a in dichloromethane
Methyl propiolate (0.196 mL, 2.2 mmol) was added to a stirred
solution of benzothienopyridine 15a (250 mg, 0.9 mmol) in CH2Cl2
(25 mL). The stirring was continued for 30 days (TLC monitoring).
After completion the solvent was evaporated in vacuo. The residue
was purified by column chromatography to give benzothienoazo-
cine 16a (201 mg, 62%) as a white solid, spiro compound 18a
(62 mg, 19%) as a white solid and benzothienopyridine 19a (23 mg,
7%) as a white oil.
4.8.2. Methyl (2Z)-2-benzylidene-10-methyl-50,60-dihydro-10H-spiro
[1-benzothiophene-3,40-pyridine]-30-carboxylate (18a). Purified by
column chromatography (Al2O3, ethyl acetate/hexane, 1:45), yield
16 mg (5%) as a white solid, mp 174e176 ꢀC (ethyl acetate/hexane);
[found: C, 72.7;H, 5.7; N, 3.9. C22H21NO2S requires C, 72.70; H, 5.82; N,
3.85%]; Rf (sorbfil, ethyl acetate/hexane, 1:3) 0.27; nmax (KBr) 1687,
4.10.1. Methyl 3-methyl-6-phenyl-1,2,3,6-tetrahydro[1]benzothieno
[3,2-d]azocine-5-carboxylate (16a). Purified by column chroma-
tography (Al2O3, ethyl acetate/hexane, 1:50), yield 201 mg (62%) as
a white solid, mp 208e210 ꢀC (ethyl acetate/hexane).
1613 cmꢁ1
;
dH (400 MHz, CDCl3) 7.82 (1H, s, 20-H), 7.42 (2H, d, J 7.7 Hz,
4.10.2. Methyl (2Z)-2-benzylidene-10-methyl-50,60-dihydro-10H-spiro
[1-benzothiophene-3,40-pyridine]-30-carboxylate (18a). Purified by
column chromatography (Al2O3, ethyl acetate/hexane, 1:45), yield
62 mg (19%) as a white solid, mp 174e176 ꢀC (ethyl acetate/hexane).
C6H5), 7.36 (2H, t, J 7.7 Hz, C6H5), 7.27e7.24 (1H, m, 7-H), 7.20 (1H, d, J
7.7 Hz, C6H5), 7.16 (1H, dt, J 7.5,1.2 Hz, 6-H), 7.07 (1H, dt, J 7.5, 1.2 Hz, 5-
H), 6.99 (1H, dd, J 7.5, 1.2 Hz, 4-H), 6.40 (1H, s, CHeAr), 3.41e3.35 (4H,
m, 60-CH2, CO2CH3), 3.10 (3H, s, NeCH3), 3.05 (1H, td, J 12.8, 4.5 Hz, 60-
CH2), 2.09 (1H, ddd, J 13.6, 4.5, 3.8 Hz, 50-CH2), 1.90 (1H, ddd, J 13.6,
10.5, 4.5 Hz, 50-CH2); dC (100 MHz, CDCl3) 167.1, 148.9, 148.2, 146.1,
137.0, 136.9, 128.4 (2C), 128.3 (2C), 127.3, 126.2, 124.9, 122.8, 121.4,
119.5, 97.4, 55.5, 50.4, 43.3, 42.9, 37.7; m/z (EI, 70 eV) 363 (18, Mþ), 306
(12), 304 (10), 272 (15), 247 (9), 91 (11), 77 (12), 59 (100), 42 (72).
4.10.3. Methyl (2E)-3-(2-methyl-1-phenyl-1,2,3,4-tetrahydro[1]ben-
zothieno[2,3-c]pyridine-1-yl)acrylate (19a). Purified by column
chromatography (Al2O3, ethyl acetate/hexane, 1:45), yield 23 mg
(7%) as a white oil; [found: C, 72.6; H, 5.9; N, 3.9. C22H21NO2S re-
quires C, 72.70; H, 5.82; N, 3.85%]; Rf (sorbfil, ethyl acetate/hexane,
1:3) 0.85; nmax (KBr) 1721, 1647 cmꢁ1
; dH (400 MHz, CDCl3)
4.8.3. Methyl (2E)-3-[(2-{2-[methoxy(phenyl) methyl]-1-benzothien-
3-yl}ethyl)(methyl)amino] acrylate (17a). Purified by column chro-
matography (Al2O3, ethyl acetate/hexane, 1:40), yield 39 mg (11%)
as a white solid, mp 82e83 ꢀC (ethyl acetate/hexane); [found: C,
69.8; H, 6.5; N, 3.6. C23H25NO3S requires C, 69.84; H, 6.37; N, 3.54%];
Rf (sorbfil, ethyl acetate/hexane, 1:3) 0.26; nmax (KBr) 1663,
7.65e7.63 (2H, m, 5H, 8H), 7.52 (2H, d, J 7.2 Hz, 6H, 7H), 7.50 (1H, d, J
15.9 Hz, CH]CHeCO2Me), 7.39e7.31 (4H, m, 1-Ph), 7.28e7.25 (1H,
m, 1-Ph), 5.82 (1H, d, J 15.9 Hz, CH]CHeCO2Me), 3.77 (3H, s,
CO2CH3), 3.10e3.00 (2H, m, 4-CH2), 2.96e2.87 (2H, m, 3-CH2), 2.35
(3H, s, NeCH3); dC (100 MHz, CDCl3) 166.4, 147.9, 143.7, 140.5, 140.1,
138.6, 129.2, 128.4 (2C), 128.0, 127.7 (2C), 126.0, 124.3, 124.0, 122.3,
121.1, 61.1, 51.6, 46.7, 38.9, 24.4; m/z (EI, 70 eV) 363 (10, Mþ), 286
(47), 278 (15), 261 (11), 77 (35), 59 (32), 42 (100).
1613 cmꢁ1
d, J 7.9 Hz, 4-H), 7.47e7.40 (4H, m, Ph,
6-H), 7.35e7.30 (2H, m, Ph), 5.59 (1H, s, CHeOCH3), 4.60 (1H, d, J
12.8 Hz,
0-CH), 3.70 (3H, s, CO2CH3), 3.44 (3H, s, CHeOCH3),
3.26e3.19 (1H, m, -CH2), 3.12e3.01 (3H, m, -CH2 and -CH2), 2.70
;
dH (400 MHz, CDCl3) 7.81 (1H, d, J 7.9 Hz, 7-H), 7.62 (1H,
a
0-CH), 7.39e7.36 (2H, m, 5-H,
b
4.11. Experimental procedure for the synthesis of
benzothienoazocine 16d and benzothiophene 17b in methanol
b
a
b
(3H, s, NeCH3); dC (100 MHz, CDCl3) 169.9, 151.9, 142.6, 140.5, 139.6,
139.2, 132.6, 128.7 (2C), 128.4, 127.3 (2C), 124.4, 124.2, 122.7, 121.0,
84.8, 80.3, 57.4, 55.3, 50.6, 40.9, 26.3; m/z (LCMS) 396 [MþH]þ.
Acetylacetylene (0.084 mL, 1.1 mmol) was added to a stirred
solution of benzothienopyridine 15a (250 mg, 0.9 mmol) in
methanol (25 mL). The stirring was continued for 5 min (TLC
monitoring). After completion the solvent was evaporated in vacuo.
The residue was purified by column chromatography to give ben-
zothienoazocine 16d (94 mg, 30%) as a white solid and benzo-
thiophene 17b (203 mg, 60%) as a white oil.
4.9. Experimental procedure for the synthesis of
benzothienoazocine 16a and spiro compounds 18a in
acetonitrile
Methyl propiolate (0.800 mL, 9.0 mmol) was added to a solution
of benzothienopyridine 15a (250 mg, 0.9 mmol) in acetonitrile
(25 mL). The reaction mixture was heated at reflux for 175 h (TLC
monitoring). After completion the solvent was evaporated in vacuo.
The residue was purified by column chromatography to give ben-
zothienoazocine 16a (205 mg, 63%) as a white solid and spiro
compound 18a (73 mg, 22%) as a white solid.
4.11.1. 1-(3-Methyl-6-phenyl-1,2,3,6-tetrahydro [1]benzothieno[3,2-
d]azocin-5-yl)ehtanone (16d). Purified by column chromatography
(Al2O3, ethyl acetate/hexane,1:15), 94 mg (30%) as a white solid, mp
203e205 ꢀC (ethyl acetate/hexane); [found: C, 76.1; H, 6.2; N, 4.0.
C22H21NOS requires C, 76.04; H, 6.09; N, 4.03%]; Rf (sorbfil, ethyl
acetate/hexane, 1:2) 0.48; nmax (KBr) 1630, 1580, 1575 cmꢁ1
; dH
(400 MHz, CDCl3) 7.80 (1H, d, J 7.5 Hz, 8-H), 7.62 (1H, d, J 7.5 Hz, 11-
H), 7.51 (1H, s, 4-H), 7.38 (1H, dt, J 7.5, 1.2 Hz, 9-H), 7.33 (1H, dt, J 7.5,
1.2 Hz, 10-H), 7.24 (2H, t, J 7.9 Hz, o-6-Ph), 7.14 (1H, t, J 7.9 Hz, p-6-
Ph), 7.08 (2H, d, J 7.9 Hz, m-6-Ph), 6.47 (1H, s, 6-H), 4.04e3.96 (1H,
m, 2-CH2), 3.32 (1H, ddd, J 17.1, 13.6, 4.5 Hz, 1-CH2), 3.06 (3H, s,
NeCH3), 2.85 (1H, ddd, J 15.0, 4.5, 2.7 Hz, 2-CH2), 2.74 (1H, td, J 17.1,
2.7 Hz, 1-CH2), 2.37 (3H, s, COMe); dC (100 MHz, CDCl3) 194.2, 154.1,
146.6, 142.0, 140.5, 138.4, 128.8 (2C), 126.8, 126.2 (2C), 125.7, 124.0,
4.9.1. Methyl 3-methyl-6-phenyl-1,2,3,6-tetrahydro[1]benzothieno
[3,2-d]azocine-5-carboxylate (16a). Purified by column chroma-
tography (Al2O3, ethyl acetate/hexane, 1:50), yield 205 mg (63%) as
a white solid, mp 208e210 ꢀC (ethyl acetate/hexane).
4.9.2. Methyl (2Z)-2-benzylidene-10-methyl-50,60-dihydro-10H-spiro
[1-benzothiophene-3,40-pyridine]-30-carboxylate (18a). Purified by

9428
L.G. Voskressensky et al. / Tetrahedron 66 (2010) 9421e9430
123.9, 122.2, 121.1, 111.4, 48.9, 44.6, 39.5, 28.1, 25.1; m/z (EI, 70 eV)
5.89; N, 3.56%]; Rf (sorbfil, ethyl acetate/hexane, 1:3) 0.41; nmax
(KBr) 1667, 1612 cmꢁ1
dH (400 MHz, CDCl3) 7.80 (1H, d, J 7.3 Hz,
347 (8, Mþ), 304 (5), 43 (100).
;
8-H) 7.72 (1H, s, 4-H), 7.62 (1H, d, J 7.3 Hz, 11-H), 7.38 (1H, dt, J
7.3, 1.2 Hz, 9-H), 7.33 (1H, dt, J 7.3, 1.2 Hz, 10-H), 7.09 (2H, dd, J
8.8, 1.2 Hz, o-PheOCH3), 6.81 (2H, d, J 8.8 Hz, m-PheOCH3), 6.06
(1H, s, 6-H), 4.03e3.95 (1H, m, 2-CH2), 3.77 (3H, s, COCH3), 3.76
(3H, s, OCH3), 3.30 (1H, ddd, J 4.4, 13.5, 17.4 Hz, 1-CH2), 3.01 (3H,
s, NeCH3), 2.83 (1H, ddd, J 14.9, 4.4, 2.8 Hz, 2-CH2), 2.72 (1H, td, J
17.4, 2.8 Hz, 1-CH2); dC (100 MHz, CDCl3) 170.7, 157.8, 152.2, 142.1,
140.7, 139.1, 138.2, 127.3 (2C), 126.7, 123.9 (2C), 122.1, 121.2, 114.1
(2C), 96.5, 55.3, 51.5, 48.9, 44.1, 41.0, 28.3; m/z (EI, 70 eV) 393 (62,
Mþ), 362 (11), 336 (63), 334 (66), 330 (16), 319 (14), 303 (20), 291
(24), 277 (33), 272 (19), 258 (20), 247 (21), 234 (27), 232 (37), 226
(24), 220 (23), 202 (23), 200 (25), 184 (20), 171 (28), 160 (100),
145 (23), 140 (48), 128 (22), 121 (56), 115 (35), 91 (11), 77 (15), 58
(37), 44 (23), 42 (93).
4.11.2. (3E)-4-[(2-{2-[Methoxy(phenyl)methyl]-1-benzothien-3-yl}
ethyl)(methyl)amino]but-3-en-2-one (17b). Purified by column
chromatography (Al2O3, ethyl acetate/hexane, 1:15), 94 mg (30%) as
a white oil; [found: C, 72.9; H, 6.7; N, 3.7. C23H25NO2S requires C,
72.79; H, 6.64; N, 3.69%]; Rf (sorbfil, ethyl acetate/hexane, 1:2) 0.21;
nmax (KBr) 1655, 1602, 1563 cmꢁ1
;
dH (400 MHz, CDCl3) 7.82 (1H, d, J
8.1 Hz, 7-H), 7.62 (1H, d, J 8.1 Hz, 4-H), 7.46e7.31 (8H, m, Ph, 5-H, 6-
H and
0-CHeAc), 5.58 (1H, s, CHeOCH3), 5.07 (1H, d, J 13.2 Hz, a0
CH), 3.44 (3H, s, CHeOCH3), 3.32e3.23 (1H, m, -CH2), 3.13e3.03
(3H, m, -CH2 and -CH2), 2.73 (3H, br s, NeCH3), 2.09 (3H, s,
b
-
b
a
b
COCH3); dC (100 MHz, CDCl3) 195.3, 151.6 (2C), 142.7, 140.5, 139.7,
139.2, 128.8 (2C), 128.5, 127.3 (2C), 124.5, 124.3, 122.8, 121.8, 97.4,
80.3, 57.3, 56.6, 36.2, 28.2, 27.1; m/z (LCMS) 380 [MþH]þ.
4.12. Experimental procedure for the synthesis of
benzothienoazocine 16d and spiro compound 18b in
acetonitrile
4.14. Experimental procedure for the synthesis of
benzothienoazocine 16b in acetonitrile
Methyl propiolate (0.356 mL, 4.0 mmol) was added to a solution
of benzothienopyridine 15b (250 mg, 0.8 mmol) in acetonitrile
(25 mL). The reaction mixture was heated at reflux for 11 h (TLC
monitoring). After completion the solvent was evaporated in vacuo.
The residue was purified by column chromatography (ethyl acetate/
hexane, 1:50) to give benzothienoazocine 16b (247 mg, 78%) as
a white solid.
Acetylacetylene (0.129 mL, 1.8 mmol) was added to a stirred
solution of benzothienopyridine 15a (250 mg, 0.9 mmol) in ace-
tonitrile (25 mL). The stirring was continued for 7 days (TLC mon-
itoring). After completion the solvent was evaporated in vacuo. The
residue was purified by column chromatography to give benzo-
thienoazocine 16d (255 mg, 82%) as a white solid and spiro com-
pound 18b (48 mg, 15%) as a yellow oil.
4.14.1. Methyl 6-(4-methoxyphenyl)-3-methyl-1,2,3,6-tetrahydro[1]
benzothieno[3,2-d]azocine-5-carboxylate (16b). Purified by column
chromatography (Al2O3, ethyl acetate/hexane, 1:50), 247 mg (78%)
as a white solid, mp 177e178 ꢀC (ethyl acetate/hexane).
4.12.1. 1-(3-Methyl-6-phenyl-1,2,3,6-tetrahydro [1]benzothieno[3,2-
d]azocin-5-yl)ehtanone (16d). Purified by column chromatography
(Al2O3, ethyl acetate/hexane, 1:15), 255 mg (82%) as a white solid,
mp 203e205 ꢀC (ethyl acetate/hexane).
4.12.2. 1[(2Z)-2-Benzylidene-10-methyl-50,60-dihydro-10H-spiro[1-
benzothiophene-3,40-pyridin]-30-yl]ethanone (18b). Purified by col-
umn chromatography (Al2O3, ethyl acetate/hexane, 1:5), yield
48 mg (15%) as a yellow oil; [found: C, 76.1; H, 6.2; N, 4.0.
C22H21NOS requires C, 76.08; H, 6.09; N, 4.03%]; Rf (sorbfil, ethyl
4.15. Experimental procedure for the synthesis of
benzothienoazocine 16b and benzothienopyridine 19b in
dichloromethane
Methyl propiolate (0.356 mL, 4.0 mmol) was added to a stirred
solution of benzothienopyridine 15b (250 mg, 0.8 mmol) in ace-
tonitrile (25 mL). The stirring was continued for 20 days (TLC
monitoring). After completion the solvent was evaporated in
vacuo. The residue was purified by column chromatography (ethyl
acetate/hexane, 1:50) to give benzothienoazocine 16b (216 mg,
68%) as a white solid and benzothienopyridine 19b (45 mg, 15%) as
a white oil.
acetate/hexane, 1:3) 0.28; nmax (KBr) 1594 cmꢁ1
; dH (400 MHz,
CDCl3) 7.89 (1H, s, 20-H), 7.40e7.39 (2H, m, 4-H, 7-H), 7.37e7.35 (2H,
m, 5-H, 6-H), 7.29e7.28 (1H, m, Ph), 7.23e7.18 (2H, m, Ph), 7.09 (1H,
td, J 7.5, 1.0 Hz, Ph), 7.01 (1H, d, J 7.5 Hz, Ph), 6.40 (1H, s, CHeAr),
3.39e3.34 (1H, m, 60-CH2), 3.15 (3H, s, NeCH3), 3.06 (1H, td, J 13.0,
4.3 Hz, 60-CH2), 2.10 (1H, ddd, J 13.8, 4.3, 3.7 Hz, 50-CH2), 1.91 (1H,
ddd, J 13.8, 10.6, 4.3 Hz, 50-CH2), 1.69 (3H, s, COCH3); dC (100 MHz,
CDCl3) 195.0, 149.3, 147.6, 145.7, 137.2, 136.6, 128.3 (2C), 128.2 (2C),
127.7, 126.5, 125.3, 123.2, 121.9, 120.4, 97.6, 56.0, 43.5, 43.2, 37.9,
27.2; m/z (LCMS) 348 [MþH]þ.
4.15.1. Methyl 6-(4-methoxyphenyl)-3-methyl-1,2,3,6-tetrahydro[1]
benzothieno[3,2-d]azocine-5-carboxylate (16b). Purified by column
chromatography (Al2O3, ethyl acetate/hexane, 1:50), 216 mg (68%)
as a white solid, mp 177e178 ꢀC (ethyl acetate/hexane).
4.13. Experimental procedure for the synthesis of
benzotheinoazocine 16b in methanol
4.15.2. Methyl
(2E)-3-[2-methyl-1-(4-methoxyphenyl)-2-methyl-
Methyl propiolate (0.087 mL, 1.0 mmol) was added to a stirred
solution of benzothienopyridine 15b (250 mg, 0.8 mmol) in ace-
tonitrile (25 mL). The stirring was continued for 24 h (TLC moni-
toring). After completion the solvent was evaporated in vacuo. The
residue was purified by column chromatography (ethyl acetate/
hexane, 1:50) to give benzothienoazocine 16b (263 mg, 83%) as
a white solid.
1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine-1-yl]acrylate
(19b). Purified by column chromatography (Al2O3, ethyl acetate/
hexane,1:50), 216 mg (68%) as a white oil; [found: C, 70.3; H, 6.0; N,
3.6. C23H23NO3S requires C, 70.20; H, 5.89; N, 3.56%]; Rf (sorbfil,
ethyl acetate/hexane, 1:3) 0.85; nmax (KBr) 1721, 1647 cmꢁ1
; dH
(400 MHz, CDCl3) 7.65e7.61 (2H, m, CHeAr), 7.47 (1H, d, J 15.8 Hz,
CH]CHeCO2Me), 7.41 (2H, d, J 8.9 Hz, o-C6H4eOCH3), 7.36e7.32
(1H, m, 7-H), 7.28e7.24 (1H, m, 6-H), 6.88 (2H, d, J 8.9 Hz, m-
C6H4eOCH3), 5.81 (1H, d, J 15.8 Hz, CH]CHeCO2Me), 3.81 (3H, s,
OCH3), 3.76 (3H, s, CO2CH3), 3.07e2.99 (2H, m, 4-CH2), 2.97e2.84
(2H, m, 3-CH2), 2.33 (3H, s, NeCH3); dC (100 MHz, CDCl3) 166.5,
159.2, 148.2, 141.0, 140.1, 138.6, 135.7, 129.1, 128.9 (2C), 125.8, 124.3,
123.9, 122.3, 121.1, 113.7 (2C), 66.6, 55.2, 51.6, 46.8, 38.8, 24.4; m/z
4.13.1. Methyl 6-(4-methoxyphenyl)-3-methyl-1,2,3,6-tetrahydro[1]
benzothieno[3,2-d]azocine-5-carboxylate (16b). Purified by column
chromatography (Al2O3, ethyl acetate/hexane, 1:50), 263 mg
(83%) as a white solid, mp 177e178 ꢀC (ethyl acetate/hexane);
[found: C, 70.1; H, 6.0; N, 3.7. C23H23NO3S requires C, 70.20; H,

L.G. Voskressensky et al. / Tetrahedron 66 (2010) 9421e9430
9429
(EI, 70 eV) 393 (10, Mþ), 308 (25), 286 (20), 259 (9), 92 (11), 77 (25),
59 (53), 42 (100).
benzothienoazocine 16e (104 mg, 43%) as a white solid and ben-
zothiophene 17c (123 mg, 48%) as a white oil.
4.16. Experimental procedure for the synthesis
benzothiophene 17f in methanol
4.18.1. 1-[6-(4-Methoxyphenyl)-3-methyl-1,2,3,6-tetrahydro[1]ben-
zothieno[3,2-d]azocin-5-yl]ethanone (16e). Purified by column
chromatography (Al2O3, ethyl acetate/hexane, 1:13), 104 mg (43%)
as a white solid, mp 227e229 ꢀC (ethyl acetate/hexane); [found: C,
73.3; H, 6.2; N, 3.7. C23H23NO2S requires C, 73.18; H, 6.14; N, 3.71%];
Rf (sorbfil, ethyl acetate/hexane, 1:1) 0.40; nmax (KBr) 1614,
DMAD (0.095 mL, 0.8 mmol) was added to a stirred solution of
benzothienopyridine 15b (200 mg, 0.6 mmol) in acetonitrile
(20 mL). The stirring was continued for 26 h (TLC monitoring). After
completion the solvent was evaporated in vacuo. The residue was
purified by column chromatography (ethyl acetate/hexane, 1:13) to
give benzothiophene 17f (294 mg, 94%) as a white oil.
1578 cmꢁ1
; dH (400 MHz, CDCl3) 7.79 (1H, d, J 7.6 Hz, 8-H), 7.62 (1H,
d, J 7.6 Hz,11-H), 7.52 (1H, s, 4-H), 7.38 (1H, dt, J 7.6,1.1 Hz, 9-H), 7.33
(1H, dt, J 7.6, 1.1 Hz, 10-H), 6.99 (2H, d, J 8.3 Hz, o-C6H4eOCH3), 6.78
(2H, d, J 8.3 Hz, m-C6H4eOCH3), 6.36 (1H, s, 6-H), 4.07e4.05 (1H, m,
2-CH2), 3.76 (3H, s, eAreOCH3), 3.32 (1H, ddd, J 17.3, 13.4, 4.3 Hz, 1-
CH2), 3.07 (3H, s, NeCH3), 2.86 (1H, ddd, J 15.0, 4.5, 2.7 Hz, 2-CH2),
2.74 (1H, td, J 17.3, 2.7 Hz, 1-CH2), 2.36 (3H, s, COMe); dC (100 MHz,
CDCl3) 194.1, 157.7, 154.1, 141.9, 140.8, 138.7, 138.2, 127.1 (2C), 126.7,
123.9, 123.8, 122.1, 121.0, 114.1 (2C), 111.5, 55.2, 49.0, 44.4, 38.8, 28.0,
25.1; m/z (EI, 70 eV) 377 (1, Mþ), 235 (10), 202 (23),155 (14), 92 (14),
77 (24), 58 (15), 42 (100).
4.16.1. Dimethyl (2E)-2-[(2-{2-[methoxy(4-methoxyphenyl)methyl]-
1-benzothien-3-yl}ethyl)(methyl)amino]but-2-enedioate
(17f). Purified by column chromatography (Al2O3, ethyl acetate/
hexane, 1:13), 294 mg (94%) as a white oil; [found: C, 64.7; H, 6.1; N,
2.9. C26H29NO6S requires C, 64.58; H, 6.04; N, 2.90%]; Rf (sorbfil,
ethyl acetate/hexane,1:2) 0.45; nmax (KBr) 1737,1687,1585 cmꢁ1
; dH
(400 MHz, CDCl3) 7.80 (1H, d, J 7.8 Hz, 7-H), 7.68 (1H, d, J 7.8 Hz,
4-H), 7.39 (2H, d, J 8.7 Hz, o-C6H4eOCH3), 7.31 (2H, t, J 7.8 Hz, 5-H,
6-H), 6.89 (2H, d, J 8.7 Hz, m-C6H4eOCH3), 5.60 (1H, s, CHeOCH3),
4.18.2. (3E)-4-[(2-{2-[Methoxy(4-methoxyphenyl)methyl]-1-benzo-
thieno-3-yl}ethyl)(methyl)amino]but-3-en-2-one (17c). Purified by
column chromatography (Al2O3, ethyl acetate/hexane, 1:5), 123 mg
(48%)asawhiteoil;[found:C,70.3;H, 6.7;N,3.4.C24H27NO3Srequires
C, 70.39; H, 6.65; N, 3.42%]; Rf (sorbfil, ethyl acetate/hexane,1:1) 0.18;
4.62 (1H, s,
(3H, s, OCH3), 3.42 (3H, s, CHeOCH3), 3.31e3.03 (4H, m,
-CH2), 2.66 (3H, s, NeCH3); dC (100 MHz, CDCl3) 168.0,166.0,159.6,
b
0-CH), 3.91 (3H, s, CO2CH3), 3.80 (3H, s, CO2CH3), 3.67
a
-CH2 and
b
154.3, 143.1, 139.7, 139.1, 132.6, 128.6 (2C), 128.1, 124.3, 124.2, 122.6,
121.1, 114.0 (2C), 84.8, 79.6, 57.0, 55.2, 52.9, 52.7, 50.7, 37.9, 25.8; m/z
(LCMS) 484 [MþH]þ.
nmax (KBr) 1656,1609 cmꢁ1
7-H), 7.61 (1H, d, J 7.6 Hz, 4-H), 7.41 (1H, d, J 12.7 Hz,
(4H, m, 5-H, 6-H, o-C6H4eOCH3), 6.91 (2H, d, J 8.7 Hz, m-C6H4eOCH3),
5.53 (1H, s, CHeOCH3), 5.07 (1H, d, J 13.4 Hz,
0-CH), 3.80 (3H, s,
AreOCH3), 3.41 (3H, s, CHeOCH3), 3.28 (1H, ddd, J 5.9, 9.0,13.0 Hz,
CH2), 3.15e3.00(3H, m, -CH2 and -CH2), 2.73(3H, brs, NeCH3), 2.09
;
dH (400 MHz, CDCl3) 7.81 (1H, d, J 7.6 Hz,
a
0-CH), 7.39e7.29
4.17. Experimental procedure for the synthesis of
benzotheinoazocine 16g in acetonitrile
b
b-
a
b
DMAD (0.736 mL, 6.0 mmol) was added to a stirred solution of
benzothienopyridine 15b (200 mg, 0.6 mmol) in acetonitrile
(20 mL). The stirring was continued for 35 days (TLC monitoring).
After completion the solvent was evaporated in vacuo. The residue
was purified by column chromatography (ethyl acetate/hexane,
1:7) to give benzothienoazocine 16g (93 mg, 32%) as a white oil.
(3H, s, COCH3); dC (100 MHz, CDCl3) 195.3, 159.6, 151.7, 151.6, 143.1,
139.6,139.1,132.5,128.6(2C),124.3,124.2,122.7,120.8,114.0 (2C), 97.3,
79.8, 57.0, 56.7, 55.3, 35.8, 38.0, 27.0; m/z (LCMS) 410 [MþH]þ.
4.19. Experimental procedure for the synthesis of
benzothienoazocine 16e in acetonitrile
4.17.1. Dimethyl 6-(4-methoxyphenyl)-3-methyl-1,2,3,6-tetrahydro
[1]benzothieno[3,2-d]azocine-4,5-dicarboxylate (16g). Purified by
column chromatography (Al2O3, ethyl acetate/hexane, 1:7), 93 mg
(32%) as a white oil; [found: C, 66.5; H, 5.7; N, 3.2. C25H25NO5S re-
quires C, 66.50; H, 5.58; N, 3.10%]; Rf (sorbfil, ethyl acetate/hexane,
Acetylacetylene (0.094 mL, 1.2 mmol) was added to a stirred so-
lution of benzothienopyridine 15b (200 mg, 0.6 mmol) in acetonitrile
(20 mL). The stirring was continued for 11 days (TLC monitoring).
After completion the solvent was evaporated in vacuo. The residue
was purified by column chromatography (ethyl acetate/hexane,1:13)
to give benzothienoazocine 16e (217 mg, 89%) as a white solid.
1:2) 0.51; nmax (KBr) 1738,1683,1561 cmꢁ1
; dH (400 MHz, CDCl3) 7.84
(1H, dd, J 7.1, 1.3 Hz, 8-H), 7.64 (1H, dd, J 7.1, 1.3 Hz, 11-H), 7.41e7.33
(2H, m, 9-H,10-H), 7.05 (2H, dd, J 8.8,1.1 Hz, o-C6H4eOCH3), 6.80 (2H,
d, J 8.8 Hz, m-C6H4eOCH3), 6.11 (1H, s, 6-H), 3.88e3.84 (1H, m, 2-
CH2), 3.81 (3H, s, CO2CH3), 3.77 (3H, s, CO2CH3), 3.75 (3H, s, OCH3),
3.32 (1H, ddd, J 16.7, 13.5, 6.2 Hz, 1-CH2), 3.05 (1H, ddd, J 14.8, 6.2,
1.3 Hz, 2-CH2), 2.67 (3H, s, NeCH3), 2.46 (1H, ddd, J 16.7, 4.4,1.3 Hz,1-
CH2); dC (100 MHz, CDCl3) 169.4, 167.1, 158.0, 155.8, 141.5, 138.9,
138.7, 136.8, 127.7, 127.3 (2C), 124.0, 123.9, 122.3, 120.8, 114.0 (2C),
99.5, 55.2, 52.7, 52.5, 51.9, 43.2, 37.8, 25.9; m/z (EI, 70 eV) 451 (1, Mþ),
393 (15), 362 (11), 334 (15), 308 (33), 306 (16), 291 (11), 286 (24), 276
(9), 258 (12), 247 (11), 221 (11), 202 (13),185 (18),150 (10), 92 (13), 77
(29), 59 (65), 44 (33), 42 (100).
4.19.1. 1-[6-(4-Methoxyphenyl)-3-methyl-1,2,3,6-tetrahydro[1]benzo-
thieno[3,2-d]azocin-5-yl]ethanone (16e). Purified by column chro-
matography (Al2O3, ethyl acetate/hexane, 1:13), 217 mg (89%) as
a white solid, mp 227e229 ꢀC (ethyl acetate/hexane).
4.20. Experimental procedure for the synthesis of spiro
compound (E)-18c
Spiro compound (Z)-18c (50 mg, 0.1 mmol) was dissolved in ethyl
acetate (10 mL) at rt. After1 h the solvent was evaporated. The residue
was triturated with 10 mL of diethyl ether. The yellow precipitate was
filtered-off to give (E)-18c (12 mg, 24%). According to the NMR data
the mother liquor contained 2:1 mixture of (E)-18c and (Z)-18c.
4.18. Experimental procedure for the synthesis
benzothienoazocine 16e and benzothiophene 17c in methanol
4.20.1. Methyl (2E)-10-methyl-2-(4-nitrobenzylidene)-50,60-dihydro-
10H-spiro[1-benzothiophene-3,40-pyridine]-30-carboxylate (E-18c). A
yellow solid mp 203e202 ꢀC (ethyl acetate/hexane); [found: C, 64.7;
H, 4.9; N, 6.9. C22H20N2O4S requires C, 64.69; H, 4.94; N, 6.86%]; Rf
Acetylacetylene (0.061 mL, 0.8 mmol) was added to a stirred
solution of benzothienopyridine 15b (200 mg, 0.6 mmol) in ace-
tonitrile (20 mL). The stirring was continued for 5 min (TLC mon-
itoring). After completion the solvent was evaporated in vacuo. The
residue was purified by column chromatography to give
(sorbfil,1:3, ethyl acetate/hexane) 0.40; nmax (KBr) 1674, 1614 cmꢁ1
;
dH (400 MHz, CDCl3) 8.07 (2H, d, J 8.9 Hz, m-C6H4eNO2), 7.37 (2H, d, J

9430
L.G. Voskressensky et al. / Tetrahedron 66 (2010) 9421e9430
8.9 Hz, o-C6H4eNO2), 7.31 (1H, s, 20-H), 7.21e7.15 (m, 2H, 4-H, 7-H),
7.04 (1H, dt, J 7.3, 1.7 Hz, 6-H), 6.83 (1H, d, 7.3 Hz, 5-H), 6.58 (1H, s,
CHeAreNO2), 3.38 (3H, s, CO2Me), 3.25e3.17 (1H, m, 60-CH2), 3.07
(1H, ddd, J 13.0, 4.9, 3.6 Hz, 60-CH2), 3.03 (3H, s, NeCH3), 2.40 (1H,
ddd, J 13.9,11.6, 4.9 Hz, 50-CH2), 2.01 (1H, td, J 13.9, 3.6 Hz, 50-CH2); dC
(100 MHz, CDCl3) 166.0, 154.5, 149.0, 147.7, 143.4, 129.8 (2C), 128.7,
127.9, 124.5, 123.9, 123.8, 122.8 (2C), 121.2, 117.4, 117.2, 51.9, 50.5,
44.0, 43.0, 35.0; m/z (EI, 70 eV) 408 (10, Mþ), 349 (20), 281 (20), 272
(90), 259 (150), 240 (35), 226 (15), 213 (44), 207 (62), 200 (26), 171
(24), 127 (26), 89 (23), 59 (65), 44 (87), 36 (100).
by column chromatography (Al2O3, ethyl acetate/hexane, 1:1), yield
38 mg, (76%) as a yellow oil.
Acknowledgements
Authors gratefully acknowledge the Center for collective use
(CPK) of the PFUR for the registration of NMR spectra.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.09.098. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
4.21. Experimental procedure for the synthesis of spiro
compound (E)-18d
Spiro compound (Z)-18d (50 mg, 0.1 mmol) was dissolved in
ethyl acetate (10 mL) at rt. After 1 h the solvent was evaporated. The
residue was purified by column chromatography to give spiro
compound (E)-18d (8 mg, 16%) as a yellow solid and spiro com-
pound (Z)-18d (38 mg, 76%) as a yellow oil.
References and notes
1. Swift, M. D.; Donaldson, A.; Sutherland, A. Tetrahedron Lett. 2009, 50,
3241e3244.
2. For selected general reviews on domino and related reactions, see: (a) Wasilke,
J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. Coord. Chem. Rev. 2005, 105, 1001e1020;
(b) Tietze, L. F. Chem. Rev. 1996, 96, 115e136; (c) Parsons, P. J.; Penkett, C. S.;
Shell, A. J. Chem. Rev. 1996, 96, 195e206; (d) Nicolaou, K. C.; Montagnon, T.;
Snyder, S. A. Chem. Commun. 2003, 551e564; (e) Bunce, R. A. Tetrahedron 1995,
51, 13103e13159; (f) Pellissier, H. Tetrahedron 2006, 62, 1619e1665; (g)
Pellissier, H. Tetrahedron 2006, 62, 2143e2173; (h) Nicolaou, K. C.; Edmonds, D.
J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134e7186; (i) Trost, B. M.
Science 1991, 254, 1471e1477.
3. Voskressenky, L. G.; Kulikova, L. N.; Kleimenov, A.; Guranova, N.; Borisova, T. N.;
Varlamov, A. V. Tetrahedron Lett. 2009, 50, 4851e4853.
4. Voskressenky, L. G.; Borisova, T. N.; Kulikova, L. N.; Varlamov, A. V.; Catto, M.;
Altomare, C.; Carotti, A. Eur. J. Org. Chem. 2004, 3128e3135.
4.21.1. 1-[(2E)-10-Methyl-2-(4-nitrobenzylidene)-50,60-dihydro-10H-
spiro[1-benzothiophene-3,40-pyridin]-30-yl]ethanone (E-18d). Purified
by column chromatography (Al2O3, ethyl acetate/hexane, 1:1), yield
8 mg, (16%) as a yellow solid, mp 207e208ꢀC (ethyl acetate/hexane);
[found: C, 67.3; H, 5.1; N, 7.1. C22H20N2O3S requires C, 67.33; H, 5.14; N,
7.14%]; Rf (sorbfil, ethyl acetate/hexane, 1:1) 0.58; nmax (KBr) 1691,
1582 cmꢁ1
; dH (400 MHz, CDCl3) 8.07 (2H, d, J 8.7 Hz, m-C6H4eNO2),
7.35 (d, 2H, J 8.7 Hz, o-C6H4eNO2), 7.22 (1H, s, 20-H), 7.21 (1H, dd, J 7.5,
1.2 Hz, 7-H), 7.16 (1H, dt, J 7.5,1.2 Hz, 6-H), 7.01 (1H, dt, J 7.5, 1.2 Hz, 5-
H), 6.75 (1H, dd, J 7.5, 1.2 Hz, 4-H), 6.52 (1H, s, C]CHeAreNO2),
3.28e3.21 (1H, m, 60-CH2), 3.16e3.11 (4H, m, 60-CH2, NeCH3), 2.42
(1H, ddd, J 13.8, 11.7, 5.0 Hz, 50-CH2), 2.03 (1H, dt, J 13.8, 3.5 Hz, 50-
CH2), 1.73 (3H, s, COCH3); dC (100 MHz, CDCl3) 191.3, 154.8, 148.4,
147.5, 145.6, 143.4, 136.0, 129.8 (2C), 127.8, 124.5, 123.4, 122.6 (2C),
121.2, 116.7 (2C), 51.9, 44.1, 43.4, 40.1, 34.9; m/z (EI, 70 eV) 392 (30,
Mþ), 350 (100), 335 (15), 304 (10), 293 (34), 276 (25), 260 (21), 256
(24), 247 (30), 243 (44), 229 (77), 215 (25), 213 (50), 200 (50),198 (61),
184 (19), 171 (34), 149 (13), 134 (10), 127 (15), 115 (17), 101 (22), 96
(27), 94 (25), 91 (37), 81 (20), 68 (17), 59 (53), 57 (90), 53 (65), 44 (65).
5. Voskressensky, L. G.; Akbulatov, S. V.; Borisova, T. N.; Varlamov, A. V. Tetrahe-
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6. Voskressensky, L. G.; Borisova, T. N.; Listratova, A. V.; Sorokina, E. A.; Tolkunov,
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8. Voskressensky, L. G.; Listratova, A. V.; Borisova, T. N.; Kovaleva, S. A.; Borisov, R. S.;
Varlamov, A. V. Tetrahedron 2008, 64, 10443e10452.
9. Voskressensky, L. G.; Kovaleva, S. A.; Borisova, T. N.; Listratova, A. V.; Tolkunov,
V. S.; Eresko, A. B.; Tolkunov, S. V.; Varlamov, A. V. Chem. Heterocycl. Compd.
2010, 3, 949e952.
ꢀ
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10. Gonzalez-Gomez, A.; Dominguez, G. D.; Perez-Castells, J. Tetrahedron 2009, 65,
3378e3391.
11. Campaigne, E.; Homfeld, E. J. Heterocycl. Chem. 1979, 16, 1321e1324.
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8, 1013e1016.
4.21.2. 1-[(2Z)-10-Methyl-2-(4-nitrobenzylidene)-50,60-dihydro-10H-
spiro[1-benzothiophene-3,40-pyridin]-30-yl]ethanone (Z-18d). Purified