The first example of tetrahydrothieno[3,2-d]azocines synthesis

Article abstract of DOI:10.1016/j.tet.2008.08.034

A novel and efficient one-pot synthesis of thieno[3,2-d]azocines based on tamden transformation of tetrahydropyridine ring was elaborated.

Full text of DOI:10.1016/j.tet.2008.08.034

Tetrahedron 64 (2008) 10443–10452
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Tetrahedron
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The first example of tetrahydrothieno[3,2-d]azocines synthesis
*
Leonid G. Voskressensky , Anna V. Listratova, Tatiana N. Borisova, Svetlana A. Kovaleva,
Roman S. Borisov, Alexey V. Varlamov
Organic Chemistry Department, Russian Peoples Friendship University, 6, Miklukho-Maklaia Street, Moscow 117198, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 April 2008
Received in revised form 30 July 2008
Accepted 14 August 2008
Available online 16 August 2008
A novel and efficient one-pot synthesis of thieno[3,2-d]azocines based on tamden transformation of
tetrahydropyridine ring was elaborated.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
the cleavage of the tetrahydropyridine ring, leading to the forma-
tion of 3-methoxy(hydroxyl) substituted thiophenes (1), or the
Annulated azocines are of great interest to chemists as bioactive
compounds and models for stereochemistry and intermolecular
interactions in so called ‘medium rings’. Thienoazocines (as almost
all other members of this family) are not exhaustively studied most
likely due to the difficulties associated with their synthesis. The
majority of synthetic procedures described in the literature relate
to the synthesis of thieno- and bisthienoazocines where the het-
erocyclic fragment is fused with bicyclic[3.3.1]azanonane ring.1–3
However, some publications on the synthesis of other thienoazo-
cines are available. Thus hexahydrothieno[3,2-b]azocines can be
obtained by the cyclization of esters of 5-(3-aminothienyl-2)
valeric acid4 or by reactions of arylketones with the trimethylsilyl
ethers of enols.5 Hexahydrothieno[3,2-c]- and [2,3-c]azocines can
be synthesized via the Sommelet–Hauser rearrangement of qua-
ternary salts of thienyl-2 and thienyl-3-pyrrolidinium.6 To the best
of our knowledge, methods for the preparation of tetrahy-
drothieno[3,2-d]azocines have not been described in the literature
yet.
elimination of the benzyl fragment, producing N-dimethoxy-
carbonyl(ethoxycarbonyl)vinyl tetrahydrothieno[3,2-c]pyridines
(2)9 (Scheme 1).
Y
OMe
X
X
N
R1
Y
N
R
R1
S
2
S
1
R = Et, o-Cl-C6H4CH2; R1 = H, CHO
X = Y = CO2Me; X = H, Y = CO2Et
Scheme 1.
Unlike tetrahydrothieno[3,2-c]pyridines 1,2,3-trimethylbenzo[b]-
thieno[2,3-c]pyridines 3 reacted with activated alkynes (methyl or
ethyl propiolates, acetylacetylene, DMAD) in methanol at room
temperature giving multi-component mixtures. The target tetra-
hydrobenzo[b]thieno[3,2-d]azocines 4 were isolated in 2–9% yields
whereas the main products of the reactions were 2-methoxyethyl
substituted benzo[b]thiophenes 5 resulting from the tandem
cleavage of the tetrahydropyridine ring under the action of meth-
anol (Scheme 2).9
The formation of the multi-component mixtures and the con-
siderable quantity of substituted benzo[b]thiophenes 5 led us to
presume that in the intermediate zwetterion Adthe product of
Michael additiondthe C(1)–N bond cleavage takes place forming
the secondary carbonium cation B. Presumably methoxy group
facilitates such bond cleavage. The further transformations of the
cation B lead to the multi-component mixtures.
Recently, we have reported a new method for the preparation of
tetrahydropyrrolo[2,3-d]azocines7 and tetrahydroazocino[4,5-b]
and [5,4-b]indoles using tandem transformation of tetrahy-
dropyrrolo[3,2-c]pyridines, tetrahydro-b- and g
-carbolines8 under
the action of activated alkynes. Our attempts to apply this method to
tetrahydrothieno[3,2-c]pyridine and tetrahydrobenzo[b]thieno[2,3-
c]pyridine systems were unsuccessful. Tetrahydrothieno[3,2-c]pyr-
idines reacted with dimethyl acetylene dicarboxylate (DMAD) or
ethyl propiolate 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:
To check our presumptions we studied the transformations
of ethyl 2-acetylamino-3-ethoxycarbonyl-6-R-4,5,6,7-tetrahy-
drothieno[2,3-c]pyridines under the action of activated alkynes.
* Corresponding author. Tel.: þ7 495 955 07 44; fax: þ7 495 955 07 79.
E-mail address: lvoskressensky@sci.pfu.edu.ru (L.G. Voskressensky).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.034

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L.G. Voskressensky et al. / Tetrahedron 64 (2008) 10443–10452
Me
methyl propiolate, acetyl- and tosylacetylenes. In acetonitrile re-
Me
actions of thienopyridine 7d with methyl propiolate, acetylacety-
lene and DMAD required the excess of the reagent. Moreover in the
case of DMAD reflux was applied (Scheme 4, Table 1).
N
R
R
X
Y
S
Me
4
Y
R
R
N
N
X
Y
O
O
Y
X
Me
Me
Me
N
OEt
OEt
R
S
R
R
S
X
Me
N
Me
X
Y
NH
CF3
NH
O
O
Me
S
CF3
S
7a-d
8a-p
R
A
3
Scheme 4.
Y
X
Me
N
S
Table 1
Yields of thieno[3,2-d]azocines 8a–p
Y
X
Me
Me
N
R
R
Product
R
X
Y
Yield, %
Me
OMe
Me
8a
Me
H
COMe
45 (MeOH)
79 (MeCN)
44 (MeOH)
73 (MeCN)
73 (MeCN)
73 (MeCN)
53 (MeOH)
58 (MeCN)
70 (MeOH)
62 (MeCN)
87 (MeCN)
30 (MeOH)
35 (MeCN)
86 (MeOH)
88 (MeCN)
80 (MeOH)
83 (MeCN)
71 (MeCN)
14 (MeOH)
62 (MeCN)
40 (MeOH)
92 (MeCN)
74 (MeOH)
75 (MeCN)
92 (MeCN)
45 (MeOH)
68 (MeCN)
S
Me
8b
Me
H
CO2Me
R
5
R
B
8c
8d
8e
Me
Me
Et
H
p-Ts
CO2Me
COMe
Scheme 2.
CO2Me
H
8f
Et
H
CO2Me
2. Results and discussion
8g
8h
Et
Et
H
p-Ts
CO2Me
CO2Me
Thienopyridines 7 were obtained by the well-known Gewald
reaction10 starting from the appropriate 1-(alkyl)-piperidine-4-
ones and ethyl cyanoacetate followed by N-acetylation of the
intermediate NH-thienopyridines with acetic anhydride or
trifluoroacetic anhydride (Scheme 3).
8i
8j
i-Pr
i-Pr
H
H
COMe
CO2Me
8k
8l
i-Pr
i-Pr
H
p-Ts
CO2Me
CO2Me
O
8m
8n
Bn
Bn
H
H
COMe
O
OEt
NH2
CO2Et
CN
S, morpholine
EtOH
CO2Me
+
N
S
N
R
R
8o
8p
Bn
Bn
H
p-Ts
CO2Me
CO2Me
6a-d
(R1CO)2O
Et3N,
CH2Cl2
O
OEt
X-ray crystallographic analysis was carried out on a suitable
monocrystal of tetrahydrothieno[3,2-d]azocine 8n obtained by re-
crystallization from ethyl acetate by slow evaporation at room
temperature. The refined X-ray crystal structure of 8n is shown in
Figure 1.
The conformation of the eight-membered ring is a twisted boat
in which the C(4), C(3), C(9) and C(8) atoms are almost coplanar.
The N(1)–C(6) bond is shorter than the N(1)–C(5) (1.337 and
1.457 Å, respectively), denoting the presence of conjugation in the
enamine fragment. CCDC 696201 contains the supplementary
crystallographic data for this paper. These data can be obtained free
of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from
the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; tel.: þ44 1223 336 408; e-mail:
deposit@ccdc.cam.ac.uk].
NH
R1
N
S
O
R
7a-h
6a, 7a, 7e R = Me; 6b, 7b, 7f R = Et;
6c, 7c, 7g R = i-Pr; 6d, 7d, 7h R = Bn;
7a-d R1 = CF3; 7e-h R1 = Me
Scheme 3.
N-Triflouroacetyl substituted tetrahydrothienopyridines 7a–
d reacted with methyl propiolate, acetylacetylene, p-tosylacetylene
or DMAD smoothly at room temperature in methanol or in aceto-
nitrile to form tetrahydrothieno[3,2-d]azocines 8a–r. Usually, re-
actions carried out in methanol took less time to finish than in
acetonitrile. However, the use of acetonitrile as the solvent in-
creased the yields of the target azocine derivatives. Generally,
N-benzyl substituted thienopyridine 7d reacted with activated
alkynes slower than its N-alkyl analogues. The reactivity of thi-
enopyridines decreased in the row Me>Et>i-Pr>Bn (the only
exception was the reaction of thienopyridine 7d with acetylacety-
lene). As expected, DMAD proved to be less active alkyne than
Analogously 2-acetyl substituted tetrahydrothienopyridines 7e–
h under the action of acetylacetylene, methyl propiolate or DMAD
in acetonitrile produced thienoazocines 9a–h, j–l. The reaction of
thienopyridine 7g and DMAD yielded a multi-component reaction
mixture, which we failed to separate. The yields of thienoazocines
varied from 30 to 59% (Scheme 5).

L.G. Voskressensky et al. / Tetrahedron 64 (2008) 10443–10452
10445
Table 2
Yields of thieno[3,2–d]azocines 9a–l
Product
R
X
Y
Yield, %
9a
Me
H
COMe
31 (MeOH)
16 (MeCN)
12 (MeOH)
15 (MeCN)
3 (MeOH)
9b
9c
9d
9e
9f
Me
Me
Et
H
CO2Me
CO2Me
COMe
CO2Me
7 (MeCN)
H
56 (MeOH)
59 (MeCN)
60 (MeOH)
56 (MeCN)
58 (MeOH)
37 (MeCN)
52 (MeOH)
59 (MeCN)
81 (MeOH)
57 (MeCN)
Trace (MeOH)
d (MeCN)
64 (MeOH)
65 (MeCN)
37 (MeOH)
45 (MeCN)
30 (MeCN)
Et
H
CO2Me
CO2Me
COMe
Et
CO2Me
9g
9h
9i
i-Pr
i-Pr
i-Pr
Bn
Bn
Bn
H
H
CO2Me
CO2Me
COMe
CO2Me
H
9j
9k
9l
H
CO2Me
CO2Me
Figure 1.
CO2Me
O
OEt
Table 3
Yields of thiophenes 10a–c
R
X
N
NH
O
S
CH3
Product
R
X
Y
Yield, %
Y
10a
10b
10c
Me
i-Pr
i-Pr
CO2Me
H
CO2Me
CO2Me
COMe
CO2Me
22
19
49
9a-i
X
Y
X
MeCN
O
R
N
Y
5
X
OMe
4
R
To explore the reactivity of the synthesized compounds, thi-
enoazocine 11b was reduced by the action of NaCNBH3 in methanol
to the corresponding hexahydrothieno[3,2-d]azocine 12. The re-
actions of thienoazocine 11b with chloroacetyl chloride and
3-chlorophenylisocyanate gave N-substituted derivatives 13 and 14
(Scheme 6, Table 4).
N
O
3
Y
S
1
+
OEt
9a-i
2
OEt
S
MeOH
NH
NH
O
O
CH3
10a-c
7e-h
CH3
MeOH
X
R
N
O
R
N
X
OEt
Y
Me
N
O
Y
NH
O
S
X
CF3
OEt
S
O
S
Me
O
OEt
Y
N
OEt
NH2
NH
8a-d
NH
CH3
O
O
CH3
ethyl
Al2O3,
pH 10
S
12
A
B
E
acetate
Scheme 5.
O
The reactions of thienopyridines 7e–h with activated alkynes in
methanol led to the formation of the reaction mixtures containing
thienoazocines 9a–i and substituted thiophenesdproducts of the
cleavage of the tetrahydropyridine ring. Only thiophenes 10a–c
were isolated individually, the rest of them were registered by NMR
analysis of the reaction mixtures. In the case of reactions of thi-
enopyridines 7h with DMAD we failed to separate the reaction
mixture (Tables 2 and 3).
N-Trifluoroacetyl group in thienoazocines 8a–d was easily
removed by simply percolating their ethyl acetate solutions
through a pad of basic alumina oxide (pH¼10ꢀ0.5). The resulting
2-amino substituted thienoazocines 11a–d are of interest both as
synthons for the construction of more complex molecules con-
taining thienoazocine fragment and in view of their potential
bioactivity.
OEt
Me
X
O
N
Cl
NH2
S
11a-d
Cl
Y
OEt
S
Cl
O
O
H
N
m-Cl-C6H4NCO
O
OEt
Me
N
Me
N
E
13
NH
S
E
NH
O
14
E = CO2Me
Cl
Scheme 6.

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L.G. Voskressensky et al. / Tetrahedron 64 (2008) 10443–10452
Table 4
In the case of reactions with DMAD the resulting residue was pu-
rified by column chromatography with ethyl acetate/hexane (1:5)
Yields of thieno[3,2-d]azocines 11a–d
as eluent to yield thienoazocines 8d, h, l.
Product
X
Y
Yield, %
11a
11b
11c
11d
H
H
H
COMe
CO2Me
p-Ts
70
77
65
68
4.4.1. Ethyl 8-acetyl-6-methyl-2-[(trifluoroacetyl)amino]-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3-carboxylate (8a)
CO2Me
CO2Me
White powder mp 223–224 ꢁC (ethyl acetate/hexane). 1H NMR
(400 MHz, CDCl3):
d
¼9.56 (s, 1H, NHCOCF3), 7.25 (s, 1H, 7-H), 4.40
3. Conclusion
(q, 2H, J¼7.1 Hz, O–CH2–CH3), 4.07 (s, 2H, 9-CH2), 3.99–3.88 (m, 2H,
5-CH2), 3.38 (t, 2H, J¼5.4 Hz, 4-CH2), 3.10 (s, 3H, N–CH3), 2.18 (s, 3H,
COCH3), 1.42 (t, 3H, J¼7.1 Hz, O–CH2–CH3) ppm. 13C NMR (100 MHz,
We have elaborated a novel and original approach towards
thienoazocines starting from available tetrahydrothienopyridines.
Our method based on the tandem transformation of tetrahy-
dropyridine ring enables to obtain thienoazocines by the one-pot
procedure.
2
CDCl3):
d
¼191.6, 164.0, 153.1 (q, JC,F¼38 Hz), 153.0, 138.9, 131.7,
130.3, 119.5, 115.3 (q, 1JC,F¼287 Hz), 107.0, 61.0, 47.0, 43.8, 39.5, 30.3,
24.4, 21.0, 13.7 ppm. IR (KBr):
n
¼1732, 1656, 1642, 1585 cmꢃ1. EIMS
m/z (%): 404 (Mþ, 11), 361 (17), 315 (13), 287 (12), 272 (12), 260 (5),
202 (10), 178 (17), 160 (5), 136 (6), 112 (9), 94 (9), 82 (13), 69 (44), 57
(18), 44 (58), 43 (100), 42 (68). C17H19F3N2O4S (404.10): calcd C
50.49, H 4.74, N 6.93, O 15.83%; found: C 50.58, H 5.01, N 6.72, O
15.80%.
4. Experimental
4.1. General
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.
p-Tosylacetylene was synthesized by a literature procedure.11
Column chromatography was performed with aluminium oxide,
activated, neutral, Brockmann I purchased from ACROS ORGANICS.
1H and 13C NMR spectra were recorded in CDCl3 solutions or in
DMSO-d6, at 25 ꢁC, using a 400 MHz NMR spectrometer operating
at 400 and 100 MHz correspondingly, peak positions are given in
4.4.2. 3-Ethyl 8-methyl 6-methyl-2-[(trifluoroacetyl)amino]-
4,5,6,9-tetrahydrothieno[3,2-d]azocine-3,8-dicarboxylate (8b)
White powder mp 167–168 ꢁC (ethyl acetate/hexane). 1H NMR
(400 MHz, CDCl3):
d
¼12.17 (s, 1H, NHCOCF3), 7.43 (s, 1H, 7-H), 4.43
(q, 2H, J¼7.0 Hz, O–CH2–CH3), 4.02 (s, 2H, 9-CH2), 3.94–3.88 (m, 2H,
5-CH2), 3.71 (s, 3H, OCH3), 3.38 (t, 2H, J¼5.9 Hz, 4-CH2), 3.05 (s, 3H,
N–CH3), 1.45 (t, 3H, J¼7.0 Hz, O–CH2–CH3) ppm. 13C NMR (100 MHz,
2
CDCl3):
d
¼168.5, 164.0, 153.2 (q, JC,F¼38 Hz), 150.3, 139.0, 131.3,
130.3, 119.5, 115.2 (q, 1JC,F¼287 Hz), 92.5, 61.5, 50.6, 46.8, 43.7, 30.4,
23.4, 13.7 ppm. IR (KBr):
n
¼1715, 1700, 1616, 1567 cmꢃ1. EIMS m/z
parts per million (d) with tetramethylsilane used as the internal
(%): 420 (Mþ, 100), 405 (15), 389 (11), 361 (53), 330 (15), 315 (54),
293 (25), 284 (20), 272 (18), 260 (15), 247 (17), 221 (38), 202 (18),
190 (17), 178 (31), 162 (9), 152 (12), 128 (13), 121 (12), 96 (10), 82
(11), 69 (42), 59 (13), 44 (23), 42 (45). C17H19F3N2O5S (420.10): calcd
C 48.57, H 4.56, N 6.66, O 19.03%; found: C 48.71, H 4.52, N 6.84, O
18.94%.
standard. Mass-spectra were registered using ESI or EI techniques.
Vario Micro cube element analyzer was used to perform C, H, N, O
analyses.
4.2. General experimental procedure for the synthesis
of thienopyridines 7a–d
Trifluoroacetic anhydride (15 mmol) was added to a stirred so-
lution of thienopyridines 6a–d (10 mmol) and triethylamine
(15 mmol) in dry CH2Cl2 (50 mL). The reaction was stirred at room
temperature (TLC monitoring). The crude reaction mixture was
poured into water (50 mL) and extracted with CH2Cl2 (3ꢂ70 mL).
The solvent was evaporated under reduced pressure to give thie-
nopyridines 7a–d.
4.4.3. Ethyl 6-methyl-8-[(4-methylphenyl)sulphonyl]-2-
[(trifluoroacetyl)amino]-4,5,6,9-tetrahydrothieno[3,2-d]-
azocine-3-carboxylate (8c)
White powder mp 149–151 ꢁC (ethyl acetate/hexane). 1H NMR
(400 MHz, CDCl3):
d
¼9.72 (s, 1H, NHCOCF3), 7.67 (d, 2H, J¼8.1 Hz,
CH–Ar), 7.38 (s, 1H, 7-H), 7.27 (d, 2H, J¼8.1 Hz, CH–Ar), 4.37 (q, 2H,
J¼7.3 Hz, O–CH2–CH3), 3.82–3.77 (m, 2H, 5-CH2), 3.74 (s, 2H, 9-
CH2), 3.32 (t, 2H, J¼5.4 Hz, 4-CH2), 3.07 (s, 3H, N–CH3), 2.41 (s, 3H,
Ar–CH3), 1.39 (t, 3H, J¼7.3 Hz, O–CH2–CH3) ppm. 13C NMR
4.3. General experimental procedure for the synthesis
of thienopyridines 7e–h
2
(100 MHz, CDCl3):
d
¼164.3, 153.1 (q, JC,F¼38 Hz), 149.0, 140.5,
142.8, 140.0, 131.3, 130.0 (2C), 129.6, 127.3 (2C), 119.4, 115.8 (q,
1JC,F¼286 Hz), 99.9, 61.5, 47.4, 43.7, 31.0, 24.1, 21.3, 14.1 ppm. IR
Acetic anhydride (20 mmol) was added to a stirred solution of
thienopyridines 6a–d (10 mmol) and triethylamine (20 mmol) in
dry CH2Cl2 (50 mL). The reaction was stirred at room temperature
(TLC monitoring). The crude reaction mixture was poured into
water (50 mL) and extracted with CH2Cl2 (3ꢂ70 mL). The solvent
was evaporated under reduced pressure to give thienopyridines
7e–h.
(KBr):
n
¼1721,1665,1622,1563 cmꢃ1. EIMS m/z (%): 516 (Mþ, 8), 361
(83), 327 (7), 315 (33), 293 (10), 284 (12), 271 (6), 248 (7), 235 (5),
221 (13), 202 (27),189 (7),178 (12),146 (9),121 (7),107 (16), 91 (52),
80 (13), 69 (25), 65 (27), 58 (23), 51 (5), 44 (77), 42 (100), 34 (17).
C22H23F3N2O5S2 (516.10): calcd C 51.15, H 4.49, N 5.42, O 15.49%;
found: C 51.50, H 4.57, N 5.30, O 15.81%.
4.4. General experimental procedure for the synthesis
of thienoazocines 8a–l
4.4.4. 3-Ethyl 7,8-dimethyl 6-methyl-2-[(trifluoroacetyl)amino]-
4,5,6,9-tetrahydrothieno[3,2-d]azocine-3,7,8-tricarboxylate (8d)
White powder mp 135–137 ꢁC (ethyl acetate/hexane). Rf (20%
DMAD, methyl propiolate, acetyl- or p-tosylacetylene
(1.2 mmol) was added to a solution of one of the thienopyridines
7a–c (1 mmol) in methanol or acetonitrile (15 mL). The reaction
was stirred at 25 ꢁC (TLC monitoring). The solvent was evaporated
under reduced pressure. In the cases of reactions with methyl
propiolate, acetyl- or p-tosylacetylene the residue was recrystal-
lized (ethyl acetate/hexane) to give thienoazocines 8a–c, e–g, i–k.
Et2O/hexane) 0.78. 1H NMR (400 MHz, CDCl3):
d¼9.60 (s, 1H,
NHCOCF3), 4.41 (q, 2H, J¼7.1 Hz, O–CH2–CH3), 4.00 (s, 2H, 9-CH2),
3.84–3.81 (m, 2H, 5-CH2), 3.80 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.41
(t, 2H, J¼6.4 Hz, 4-CH2), 2.75 (s, 3H, N–CH3), 1.42 (t, 3H, J¼7.1 Hz, O–
CH2–CH3) ppm. 13C NMR (100 MHz, CDCl3):
d
¼167.6, 166.1, 163.9,
2
153.7, 153.1 (q, JC,F¼38 Hz), 139.8, 131.3, 129.6, 119.0, 115.3 (q,
1JC,F¼287 Hz), 95.9, 61.5, 52.2, 51.3, 50.1, 37.7, 27.4, 25.3,13.7 ppm. IR

L.G. Voskressensky et al. / Tetrahedron 64 (2008) 10443–10452
10447
(KBr):
n
¼1743, 1721, 1687, 1670, 1572 cmꢃ1. EIMS m/z (%): 478 (Mþ,
O–CH2–CH3), 3.97 (s, 2H, 9-CH2), 3.85 (t, 2H, J¼6.3 Hz, 5-CH2), 3.79
(s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.41 (t, 2H, J¼6.3 Hz, 4-CH2), 3.03
(q, 2H, J¼7.1 Hz, N–CH2–CH3), 1.41 (t, 3H, J¼7.1 Hz, O–CH2–CH3),
1.03 (t, 3H, J¼7.1 Hz, N–CH2–CH3) ppm. 13C NMR (100 MHz, CDCl3):
57), 419 (83), 389 (10), 373 (35), 359 (17), 345 (11), 341 (19), 323
(25), 313 (51), 293 (32), 272 (33), 260 (57), 247 (28), 234 (21), 221
(55), 202 (34), 190 (32), 185 (38), 178 (51), 162 (25), 152 (30), 136
(27), 126 (75), 116 (23), 103 (72), 102 (48), 100 (33), 82 (37), 72 (36),
69 (100), 59 (70), 57 (61), 45 (53), 43 (48). C19H21F3N2O7S (478.10):
calcd C 47.70, H 4.42, N 5.86, O 23.41%; found: C 47.74, H 4.49, N
5.75, O 23.50%.
d
¼169.7,164.7,163.8,153.4 (q, 2JC,F¼38 Hz),141.0,139.8,131.3,129.6,
119.0, 115.3 (q, 1JC,F¼287 Hz), 95.9, 61.7, 53.7, 51.7, 50.9, 45.8, 32.4,
24.6, 15.3, 14.2 ppm. IR (KBr):
n
¼1735, 1721, 1690, 1567 cmꢃ1. EIMS
m/z (%): 492 (Mþ, 60), 473 (5), 433 (100), 421 (10), 387 (19), 357
(11), 327 (12), 293 (15), 260 (20), 247 (8), 212 (6), 200 (11), 190 (9),
164 (6), 140 (19), 116 (31), 97 (8), 80 (16), 71 (57), 59 (40), 42 (36).
4.4.5. Ethyl 8-acetyl-6-ethyl-2-[(trifluoroacetyl)amino]-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3-carboxylate (8e)
C20H23F3N2O7S (492.12): calcd C 48.78, H 4.71, N 5.69, O 22.74%;
White powder mp 195–196 ꢁC (ethyl acetate/hexane). 1H NMR
found: C 48.70, H 5.02, N 5.45, O 23.02%.
(400 MHz, CDCl3):
d
¼9.68 (s, 1H, NHCOCF3), 7.27 (s, 1H, 7-H),
4.39 (q, 2H, J¼7.4 Hz, O–CH2–CH3), 4.07 (s, 2H, 9-CH2), 3.97–3.91
(m, 2H, 5-CH2), 3.36 (t, 2H, J¼5.6 Hz, 4-CH2), 3.27 (q, 2H,
J¼7.4 Hz, N–CH2–CH3), 2.18 (s, 3H, COCH3), 1.41 (t, 3H, J¼7.4 Hz,
4.4.9. Ethyl 8-acetyl-6-isopropyl-2-[(trifluoroacetyl)amino]-
4,5,6,9-tetrahydrothieno[3,2-d]azocine-3-carboxylate (8i)
White powder mp 180–181 ꢁC (ethyl acetate/hexane). 1H NMR
O–CH2–CH3), 1.23 (t, 3H, J¼7.4 Hz, N–CH2–CH3) ppm. 13C NMR
(400 MHz, CDCl3):
d
¼12.10 (s, 1H, NHCOCF3), 7.36 (s, 1H, 7-H), 4.40
2
(100 MHz, CDCl3):
d¼192.1, 164.5, 153.4 (q, JC,F¼38 Hz), 152.6,
(q, 2H, J¼7.3 Hz, O–CH2–CH3), 4.08 (s, 2H, 9-CH2), 3. 89–3. 96 (m,
2H, 5-CH2), 3.53–3.43 (m, 1H, –CH(CH3)2), 3.37 (t, 2H, J¼6.3 Hz, 4-
CH2), 2.20 (s, 3H, COCH3), 1.40 (t, 3H, J¼7.3 Hz, O–CH2–CH3), 1.25 (d,
1
139.5, 132.3, 130.9, 119.8, 115.5 (q, JC,F¼287 Hz), 107.7, 61.7, 51.7,
45.3, 32.1, 24.9, 21.6, 15.5, 14.1 ppm. IR (KBr):
n
¼1720, 1690,
1583 cmꢃ1. EIMS m/z (%): 418 (Mþ, 100), 389 (17), 375 (95), 347
(12), 329 (37), 301 (11), 272 (17), 247 (5), 221 (12), 202 (5), 178
(11), 160 (5), 96 (5), 69 (19), 58 (27), 43 (63). C18H21F3N2O4S
(418.12): calcd C 51.67, H 5.06, N 6.69, O 15.29%; found: C 51.74, H
5.19, N 6.72, O 15.35%.
6H, J¼6.5 Hz, –CH(CH3)2) ppm. 13C NMR (100 MHz, CDCl3):
¼191.8,
d
164.0, 153.1 (q, 2JC,F¼38 Hz), 150.9, 138.9, 131.8, 130.7, 119.3, 115.3 (q,
1JC,F¼287 Hz), 107.3, 61.0, 57.1, 42.5, 32.1, 24.5, 21.3, 21.2 (2C),
13.7 ppm. IR (KBr):
n
¼1725, 1659, 1576 cmꢃ1. EIMS m/z (%): 432
(Mþ, 51), 389 (80), 343 (19), 293 (7), 272 (10), 247 (5), 221 (6), 202
(5), 85 (12), 69 (15), 56 (8), 43 (100), 41 (12). C19H23F3N2O4S
(432.13): calcd C 52.77, H 5.36, N 6.48, O 14.80%; found: C 52.92, H
5.23, N 6.36, O 14.91%.
4.4.6. 3-Ethyl 8-methyl 6-ethyl-[(trifluoroacetyl)amino]-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3,8-dicarboxylate (8f)
Yellowish powder mp 134–135 ꢁC (ethyl acetate/hexane). 1H
NMR (400 MHz, CDCl3):
d
¼9.59 (s, 1H, NHCOCF3), 7.45 (s, 1H, 7-H),
4.4.10. 3-Ethyl 8-methyl 6-isopropyl-2-[(trifluoroacetyl)amino]-
4,5,6,9-tetrahydrothieno[3,2-d]azocine-3,8-dicarboxylate (8j)
White powder mp 148–150 ꢁC (ethyl acetate/hexane). 1H NMR
4.40 (q, 2H, J¼7.2 Hz, O–CH2–CH3), 3.99 (s, 2H, 9-CH2), 3.92–3.87
(m, 2H, 5-CH2), 3.68 (s, 3H, OCH3), 3.35 (t, 2H, J¼5.6 Hz, 4-CH2), 3.22
(q, 2H, J¼7.4 Hz, N–CH2–CH3), 1.41 (t, 3H, J¼7.2 Hz, O–CH2–CH3),
(400 MHz, CDCl3):
d
¼12.15 (s, 1H, NHCOCF3), 7.53 (s, 1H, 7-H), 4.39
1.20 (t, 3H, J¼7.4 Hz, N–CH2–CH3) ppm. 13C NMR (100 MHz, CDCl3):
(q, 2H, J¼7.3 Hz, O–CH2–CH3), 3.99 (s, 2H, 9-CH2), 3.89–3.84 (m, 2H,
5-CH2), 3.68 (s, 3H, OCH3), 3.49–3.39 (m, 1H, –CH(CH3)2), 3.35 (t,
2H, J¼5.3 Hz, 4-CH2), 1.40 (t, 3H, J¼7.3 Hz, O–CH2–CH3), 1.21 (d, 6H,
2
d
¼168.9, 164.5, 153.8 (q, JC,F¼38 Hz), 149.9, 139.5, 131.9, 130.9,
1
119.8, 115.6 (q, JC,F¼287 Hz), 93.2, 61.7, 51.5, 51.2, 45.7, 32.3, 24.1,
15.3, 14.2 ppm. IR (KBr):
n
¼1719, 1690, 1654, 1602 cmꢃ1. EIMS m/z
J¼6.5 Hz, –CH(CH3)2) ppm. 13C NMR (100 MHz, CDCl3):
¼168.5,
d
(%): 434 (Mþ, 34), 405 (10), 375 (25), 329 (45), 317 (5), 301 (11), 293
(28), 272 (13), 247 (7), 221 (25), 194 (6), 178 (12), 162 (5), 142 (17),
121 (7), 97 (11), 82 (16), 69 (100), 58 (77), 56 (96), 42 (45).
164.1, 153.2 (q, 2JC,F¼38 Hz), 147.9, 139.2, 131.5, 130.7, 119.3, 115.4 (q,
1JC,F¼287 Hz), 93.1, 61.0, 56.7, 50.6, 43.1, 32.1, 23.7, 21.4 (2C),
13.7 ppm. IR (KBr):
n
¼1723, 1663, 1605, 1565 cmꢃ1. EIMS m/z (%):
C
18H21F3N2O5S (434.11): calcd C 49.76, H 4.87, N 6.45, O 18.41%;
448 (Mþ, 43), 433 (8), 417 (12), 405 (31), 389 (78), 379 (5), 359 (11),
343 (26), 330 (13), 317 (5), 301 (21), 284 (32), 260 (23), 221 (11), 202
(7), 178 (11), 149 (13), 121 (8), 96 (11), 85 (27), 70 (31), 69 (29), 59
(28), 43 (100), 42 (27), 41 (47). C19H23F3N2O5S (448.13): calcd C
50.89, H 5.17, N 6.23, O 17.84%; found: C 50.74, H 5.29, N 6.35, O
17.90%.
found: C 49.64, H 4.69, N 6.42, O 18.50%.
4.4.7. Ethyl 6-ethyl-8-[(4-methylphenyl)sulphonyl]-2-
[(trifluoroacetyl)amino]-4,5,6,9-tetrahydrothieno[3,2-d]-
azocine-3-carboxylate (8g)
White crystals mp 145–147 ꢁC (ethyl acetate/hexane). 1H NMR
(400 MHz, CDCl3):
d
¼9.71 (s, 1H, NHCOCF3), 7.68 (d, 2H, J¼8.7 Hz,
4.4.11. Ethyl 6-isopropyl-[(4-methylphenyl)sulphonyl]-2-
[(trifluoroacetyl)amino]-4,5,6,9-tetrahydrothieno[3,2-d]-
azocine-3-carboxylate (8k)
CH–Ar), 7.44 (s, 1H, 7-H), 7.28 (d, 2H, J¼8.7 Hz, CH–Ar), 4.37 (q, 2H,
J¼7.3 Hz, O–CH2–CH3), 3.95–3.81 (m, 2H, 5-CH2), 3.75 (s, 2H, 9-
CH2), 3.32 (t, 2H, J¼5.6 Hz, 4-CH2), 3.25 (q, 2H, J¼7.2 Hz, N–CH2–
CH3), 2.42 (s, 3H, Ar–CH3), 1.39 (t, 3H, J¼7.3 Hz, O–CH2–CH3), 1.23 (t,
3H, J¼7.2 Hz, N–CH2–CH3) ppm. 13C NMR (100 MHz, CDCl3):
White powder mp 99–101 ꢁC (ethyl acetate/hexane). 1H NMR
(400 MHz, CDCl3):
d
¼9.71 (s, 1H, NHCOCF3), 7.67 (d, 2H, J¼8.0 Hz,
CH–Ar), 7.50 (s, 1H, 7-H), 7.28 (d, 2H, J¼8.0 Hz, CH–Ar), 4.36 (q, 2H,
J¼7.2 Hz, O–CH2–CH3), 3.83–3.77 (m, 2H, 5-CH2), 3.75 (s, 2H, 9-
CH2), 3.52–3.45 (m, 1H, –CH(CH3)2), 3.31 (t, 2H, J¼5.6 Hz, 4-CH2),
2.42 (s, 3H, Ar–CH3), 1.38 (t, 3H, J¼7.2 Hz, O–CH2–CH3), 1.24 (d, 6H,
d
¼164.4,153.8 (q, 2JC,F¼38 Hz),148.2,142.9,140.5,140.0,131.6,130.1
(2C), 129.8, 127.4 (2C), 119.3, 115.8 (q, 1JC,F¼287 Hz), 100.3, 61.6, 51.2,
45.3, 32.3, 24.2, 21.3, 15.2, 14.2 ppm. IR (KBr):
n
¼1724, 1659, 1623,
1562 cmꢃ1. EIMS m/z (%): 530 (Mþ, 10), 375 (100), 341 (8), 329 (32),
301 (7), 284 (13), 274 (6), 216 (9), 202 (70), 178 (5), 146 (5), 107 (7),
91 (25), 80 (5), 65 (10), 58 (27), 42 (7). C23H25F3N2O5S2 (530.12):
calcd C 52.06, H 4.75, N 5.28, O 15.08%; found: C 52.19, H 4.60, N
5.25, O 15.20%.
J¼6.7 Hz, –CH(CH3)2) ppm. 13C NMR (100 MHz, CDCl3):
d
¼164.4,
2
153.5 (q, JC,F¼38 Hz), 146.8, 142.9, 140.4, 140.1, 131.7, 130.2 (2C),
1
129.7, 127.4 (2C), 119.3, 115.8 (q, JC,F¼287 Hz), 110.5, 61.6, 57.0,
43.4, 32.7, 24.3, 21.8 (2C), 21.3, 14.2 ppm. IR (KBr):
n
¼1720, 1670,
1609, 1565 cmꢃ1. EIMS m/z (%): 544 (Mþ, 10), 389 (100), 355 (6),
343 (20), 330 (5), 301 (17), 284 (17), 272 (12), 247 (5), 221 (8), 202
(11), 188 (5), 175 (7), 160 (5), 139 (7), 121 (5), 107 (8), 91 (27), 72
(15), 69 (14), 56 (12), 43 (38). C24H27F3N2O5S2 (544.13): calcd C
52.93, H 5.00, N 5.14, O 14.69%; found: C 53.07, H 4.89, N 5.35, O
14.58%.
4.4.8. 3-Ethyl 7,8-dimethyl 6-ethyl-2-[(trifluoroacetyl)amino]-
4,5,6,9-tetrahydrothieno[3,2-d]azocine-3,7,8-tricarboxylate (8h)
Yellowish viscous oil. Rf (15% Et2O/hexane) 0.61. 1H NMR
(400 MHz, CDCl3):
d
¼9.60 (s, 1H, NHCOCF3), 4.40 (q, 2H, J¼7.1 Hz,

10448
L.G. Voskressensky et al. / Tetrahedron 64 (2008) 10443–10452
2
4.4.12. 3-Ethyl 7,8-dimethyl 6-isopropyl-2-[(trifluoroacetyl)-
amino]-4,5,6,9-tetrahydrothieno[3,2-d]azocine-3,7,8-
tricarboxylate (8l)
115.8 (q, JC,F¼38 Hz), 140.8, 137.5, 132.0, 129.2, 128.8, 128.3, 127.8
(2C), 127.1, 126.9, 117.5, 115.3 (q, 1JC,F¼287 Hz), 98.0, 60.9, 55.3, 52.4,
51.5, 50.4, 28.2, 25.6, 13.6 ppm. IR (KBr):
n
¼1736, 1721, 1684,
White powder mp 145–147 ꢁC (ethyl acetate/hexane). Rf (15%
1569 cmꢃ1. EIMS m/z (%): 554 (Mþ, 5), 463 (25), 357 (5), 190 (7), 91
(100), 65 (13), 45 (12). C25H25F3N2O7S (554.13): calcd C 54.15, H
4.54, N 5.05, O 20.20%; found: C 54.29, H 4.72, N 5.01, O 20.12%.
Et2O/hexane) 0.82. 1H NMR (400 MHz, CDCl3):
d
¼9.56 (s, 1H,
NHCOCF3), 4.40 (q, 2H, J¼7.1 Hz, O–CH2–CH3), 3.82–3.79 (m, 5H,
OCH3 and 5-CH2), 3.66 (s, 3H, OCH3), 3.52–3.44 (m, 1H, –CH(CH3)2),
3.41 (t, 2H, J¼5.6 Hz, 4-CH2), 1.41 (t, 3H, J¼7.1 Hz, O–CH2–CH3), 1.15
4.6. General experimental procedure for the synthesis of
thienoazocines 8m, n in acetonitrile
(d, 6H, J¼6.7 Hz, –CH(CH3)2) ppm. 13C NMR (100 MHz, CDCl3):
2
d
¼167.6, 166.5, 164.0, 153.6, 153.2 (q, JC,F¼38 Hz), 139.8, 132.8,
130.0, 118.5, 115.4 (q, 1JC,F¼287 Hz), 97.0, 61.0, 52.5, 52.1, 51.2, 43.8,
Methyl propiolate or acetylacetylene (3 mmol) was added to
a solution of thienopyridine 7d (1 mmol) in acetonitrile (15 mL).
The reaction was stirred at 25 ꢁC (TLC monitoring). The solvent was
evaporated under reduced pressure. The residue was recrystallized
(ethyl acetate/hexane) to give thienoazocines 8m, n.
29.1, 25.3, 20.6 (2C), 13.7 ppm. IR (KBr):
n
¼1731, 1680, 1660,
1580 cmꢃ1. EIMS m/z (%): 506 (Mþ, 3), 410 (50), 367 (100), 351 (62),
321 (12), 289 (11), 261 (19), 43 (32). C21H25F3N2O7S (506.13): calcd
C 49.80, H 4.98, N 5.53, O 22.11%; found: C 49.74, H 5.26, N 5.75, O
22.47%.
4.5. General experimental procedure for the synthesis of
thienoazocines 8m, n, p in methanol
4.7. Experimental procedure for the synthesis of
thienoazocine 8o in acetonitrile
DMAD, methyl propiolate or acetylacetylene (1.2 mmol) was
added to a solution of thienopyridine 7d (1 mmol) in methanol
(15 mL). The reaction was stirred at 25 ꢁC (TLC monitoring). The
solvent was evaporated under reduced pressure, and the residue
was recrystallized (ethyl acetate/hexane) to give thienoazocines
8m–p.
p-Tosylacetylene (1.2 mmol) was added to a solution of thie-
nopyridine 7d (1 mmol) in acetonitrile (15 mL). The reaction was
stirred at 25 ꢁC (TLC monitoring). The solvent was evaporated un-
der reduced pressure, and the residue was recrystallized (ethyl
acetate/hexane) to give thienoazocine 8o.
4.8. Ethyl 6-benzyl-8-[(4-methylphenyl)sulphonyl]-2-
[(trifluoroacetyl)amino]-4,5,6,9-tetrahydrothieno[3,2-
d]azocine-3-carboxylate (8o)
4.5.1. Ethyl 8-acetyl-6-benzyl-2-[(trifluoroacetyl)amino]-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3-carboxylate (8m)
White powder mp 175–177 ꢁC (ethyl acetate/hexane). 1H NMR
(400 MHz, CDCl3):
d
¼12.18 (s, 1H, NHCOCF3), 7.47 (s, 1H, 7-H), 7.32–
White powder mp 213–214 ꢁC (ethyl acetate/hexane). 1H NMR
7.30 (m, 3H, CH–Ar), 7.13–7.12 (m, 2H, CH–Ar), 4.44 (s, 2H, CH2–Ar),
4.26 (q, 2H, J¼7.1 Hz, O–CH2–CH3), 4.13 (s, 2H, 9-CH2), 4.00–3.96 (m,
2H, 5-CH2), 3.13 (t, 2H, J¼6.1 Hz, 4-CH2), 2.25 (s, 3H, COCH3), 1.31 (t,
3H, J¼7.1 Hz, O–CH2–CH3) ppm. 13C NMR (100 MHz, CDCl3):
(400 MHz, CDCl3):
d
¼9.68 (s, 1H, NHCOCF3), 7.72 (d, 2H, J¼8.0 Hz,
CH–Ts), 7.33–7.29 (m, 5H, CH–Ar and CH–Ts), 7.10 (m, 2H, CH–Ar),
4.40 (s, 2H, Ar–CH2), 4.22 (q, 2H, J¼7.2 Hz, O–CH2–CH3), 3.81–3.77
(m, 4H, 5-CH2 and 9-CH2), 3.05 (t, 2H, J¼6.0 Hz, 4-CH2), 2.45 (s, 3H,
d
¼192.1,164.0,153.2 (q, 2JC,F¼38 Hz),153.1,139.5,138.0,131.6, 130.6,
Ar–CH3), 1.26 (t, 3H, J¼7.2 Hz, O–CH2–CH3) ppm. 13C NMR
1
128.3 (2C), 128.2, 127.4 (2C), 118.9, 115.4 (q, JC,F¼287 Hz), 107.8,
2
(100 MHz, CDCl3):
d
¼164.3, 153.3 (q, JC,F¼38 Hz), 149.3, 143.0,
60.8, 60.6, 46.5, 31.1, 24.5, 21.3, 13.6 ppm. IR (KBr):
n
¼1721, 1652,
1588 cmꢃ1. EIMS m/z (%): 480 (Mþ, 15), 437 (9), 389 (5), 91 (100), 65
(14), 43 (42). C23H23F3N2O4S (480.13): calcd C 57.49, H 4.82, N 5.83,
O 13.32%; found: C 57.74, H 4.79, N 5.75, O 13.50%.
140.4, 140.4, 138.4, 131.6, 130.1 (2C), 129.4, 128.8 (2C), 127.9, 127.8
(2C), 127.3 (2C), 119.0, 115.7 (q, 1JC,F¼287 Hz), 101.2, 61.4, 60.3, 46.8,
31.7, 24.2, 21.3, 14.0 ppm. IR (KBr):
n
¼1722, 1662, 1621, 1562 cmꢃ1
.
EIMS m/z (%): 592 (Mþ, 2), 272, 221 (6), 202 (10), 175 (7), 139 (11),
120 (10), 104 (7), 92 (100), 91 (17), 77 (7), 65 (47), 51 (6), 39 (15).
4.5.2. 3-Ethyl 8-methyl 6-benzyl-2-[(trifluoroacetyl)amino]-
4,5,6,9-tetrahydrothieno[3,2-d]azocine-3,8-dicarboxylate (8n)
White powder mp 157–159 ꢁC (ethyl acetate/hexane). 1H NMR
C28H27F3N2O5S2 (592.13): calcd C 56.74, H 4.59, N 4.73, O 13.50%;
found: C 56.56, H 4.50, N 4.75, O 13.33%.
(400 MHz, CDCl3):
d
¼12.20 (s, 1H, NHCOCF3), 7.63 (s,1H, 7-H), 7.27–
7.25 (m, 3H, CH–Ar), 7.10–7.08 (m, 2H, CH–Ar), 4.36 (s, 2H, CH2–Ar),
4.23 (q, 2H, J¼7.1 Hz, O–CH2–CH3), 4.02 (s, 2H, 9-CH2), 3.91–3.86
(m, 5-CH2), 3.72 (s, 3H, OCH3), 3.06 (t, 2H, J¼5.8 Hz, 4-CH2), 1.27 (t,
3H, J¼7.1 Hz, O–CH2–CH3) ppm. 13C NMR (100 MHz, CDCl3):
4.9. Experimental procedure for the synthesis of
thienoazocine 8p in acetonitrile
DMAD (3 mmol) was added to a solution of thienopyridine 7d
(1 mmol) in acetonitrile (15 mL). The reaction mixture was heated
to reflux (TLC monitoring). The solvent was evaporated under re-
duced pressure. The resulting residue was purified by column
chromatography with ethyl acetate/hexane (1:1) as eluent to give
thienoazocine 8p.
d
¼168.6,164.0,153.1 (q, 2JC,F¼38 Hz),150.5,139.5,138.1,131.3,130.7,
128.3 (2C), 127.3, 127.2 (2C), 119.0, 115.4 (q, 1JC,F¼287 Hz), 93.7, 60.9,
60.4, 50.7, 46.5, 31.2, 23.6, 13.6 ppm. IR (KBr):
n¼1721, 1676, 1660,
1589 cmꢃ1. EIMS m/z (%): 496 (Mþ, 3), 132 (5), 91 (100), 65 (13), 42
(5). C23H23F3N2O5S (496.13): calcd C 55.64, H 4.67, N 5.64, O 16.11%;
found: C 55.79, H 4.69, N 5.78, O 16.37%.
4.5.3. 3-Ethyl 7,8-dimethyl 6-benzyl-2-[(trifluoroacetyl)amino]-
4,5,6,9-tetrahydrothieno[3,2-d]azocine-3,7,8-tricarboxylate (8p)
White powder mp 136–138 ꢁC (ethyl acetate/hexane). Rf (20%
4.10. General experimental procedure for the synthesis of
thienoazocines 9a–c in acetonitrile
Et2O/hexane) 0.65. 1H NMR (400 MHz, CDCl3):
d
¼12.17 (s, 1H,
To a stirred solution of thienopyridine 7e (1 mmol) in acetoni-
trile (15 mL) at 25 ꢁC methyl propiolate, acetylacetylene or DMAD
(1.2 mmol) was added and the stirring was continued (TLC moni-
toring). The solvent was removed evaporated under reduced
pressure, the resulting residue was purified by column
chromatography.
NHCOCF3), 7.20–7.11 (m, 3H, CH–Ar), 7.06–7.04 (m, 2H, CH–Ar), 4.23
(q, 2H, J¼7.1 Hz, O–CH2–CH3), 4.13 (s, 2H, Ar–CH2), 3.99 (s, 2H, 9-
CH2), 3.84 (t, 2H, J¼6.5 Hz, 5-CH2), 3.79 (s, 3H, OCH3), 3.75 (s, 3H,
OCH3), 3.14 (t, 2H, J¼6.5 Hz, 4-CH2), 1.34 (t, 3H, J¼7.1 Hz, O–CH2–
CH3) ppm. 13C NMR (100 MHz, CDCl3):
d¼167.7, 166.5, 163.9, 153.6,

L.G. Voskressensky et al. / Tetrahedron 64 (2008) 10443–10452
10449
4.10.1. Ethyl 8-acetyl-(acetylamino)-6-methyl-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3-carboxylate (9a)
4.35 (q, 2H, J¼7.2 Hz, O–CH2–CH3), 4.03 (s, 2H, 9-CH2), 3.96–3.89
(m, 2H, 5-CH2), 3.34 (t, 2H, J¼6.0 Hz, 4-CH2), 3.26 (q, 2H, J¼7.1 Hz,
N–CH2–CH3), 2.22 (s, 3H, COCH3), 2.19 (s, 3H, COCH3), 1.40 (t, 3H,
Eluent ethyl acetate/hexane (3:1). White powder mp 148–
150 ꢁC (ethyl acetate/hexane). Rf (10% Et2O/hexane) 0.43. 1H NMR
J¼7.2 Hz, O–CH2–CH3), 1.23 (t, 3H, J¼7.1 Hz, N–CH2–CH3) ppm. 13
C
(400 MHz, CDCl3):
d
¼11.18 (s, 1H, NHCOCH3), 7.25 (s, 1H, 7-H), 4.36
NMR (100 MHz, CDCl3):
d
¼193.3, 166.9, 166.3, 151.5, 147.4, 128.6,
(q, 2H, J¼7.1 Hz, O–CH2–CH3), 4.03 (s, 2H, 9-CH2), 3.94–3.88 (m, 2H,
5-CH2), 3.35 (t, 2H, J¼5.8 Hz, 4-CH2), 3.09 (s, 3H, N–CH3), 2.23 (s,
3H, COCH3), 2.19 (s, 3H, COCH3), 1.41 (t, 3H, J¼7.1 Hz, O–CH2–
128.4, 112.8, 109.0, 60.7, 51.9, 46.0, 32.4, 24.9, 23.7, 22.1, 15.0,
14.5 ppm. IR (KBr):
n
¼1683, 1654, 1630, 1585 cmꢃ1. EIMS m/z (%):
364 (Mþ, 12), 321 (13), 293 (5), 125 (5), 58 (20), 43 (100).
CH3) ppm. 13C NMR (100 MHz, CDCl3):
d
¼191.5, 167.0, 164.4, 152.37,
C18H24N2O4S (364.15): calcd C 59.32, H 6.64, N 7.69, O 17.56%;
found: C 59.54, H 6.69, N 7.55, O 17.32%.
144.4, 128.6, 128.1, 113.7, 107.8, 60.3, 47.3, 43.8, 30.6, 24.4, 23.0, 21.0,
14.0 ppm. IR (KBr):
n
¼1732, 1686, 1655, 1570 cmꢃ1. EIMS m/z (%):
350 (Mþ, 36), 307 (47), 293 (12), 279 (10), 265 (21), 251 (16), 239
(17), 233 (10), 219 (27), 206 (8), 197 (15), 191 (17), 176 (240), 164
(18),149 (15),136 (13),125 (33),112 (98), 94 (12), 82 (17), 77 (10), 70
(32), 60 (18), 43 (100). C17H22N2O4S (350.13): calcd C 58.27, H 6.33,
N 7.99, O 18.26%; found: C 58.34, H 6.49, N 7.75, O 18.00%.
4.11.2. 3-Ethyl 8-methyl 2-(acetylamino)-6-ethyl-4,5,6,9-
tetrahdyrothieno[3,2-d]azocine-3,8-dicarboxylate (9e)
White powder mp 175–177 ꢁC (ethyl acetate/hexane). 1H NMR
(400 MHz, CDCl3):
d
¼11.19 (s, 1H, NHCOCH3), 7.46 (s, 1H, 7-H), 4.36
(q, 2H, J¼7.0 Hz, O–CH2–CH3), 3.95 (s, 2H, 9-CH2), 3.91–3.85 (m, 2H,
5-CH2), 3.68 (s, 3H, OCH3), 3.32 (t, 2H, J¼6.0 Hz, 4-CH2), 3.22 (q, 2H,
J¼7.2 Hz, N–CH2–CH3), 2.24 (s, 3H, COCH3), 1.40 (t, 3H, J¼7.0 Hz, O–
CH2–CH3), 1.19 (t, 3H, J¼7.2 Hz, N–CH2–CH3) ppm. 13C NMR
4.10.2. 3-Ethyl 8-methyl 2-(acetylamino)-6-methyl-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3,8-dicarboxylate (9b)
Eluent ethyl acetate/hexane (1:7). White powder mp 172–174 ꢁC
(100 MHz, CDCl3):
d
¼168.6, 167.0, 164.6, 149.2, 144.4, 128.9, 128.0,
(ethyl acetate/hexane). Rf (10% Et2O/hexane) 0.54. 1H NMR
113.7, 93.7, 60.3, 51.2, 50.4, 45.5, 32.0, 23.3, 23.0, 14.7, 14.0 ppm. IR
(400 MHz, CDCl3):
d
¼11.20 (s, 1H, NHCOCH3), 7.41 (s, 1H, 7-H), 4.37
(KBr):
n
¼1717, 1676, 1594 cmꢃ1. EIMS m/z (%): 380 (Mþ, 87), 351
(q, 2H, J¼7.1 Hz, O–CH2–CH3), 3.95 (s, 2H, 9-CH2), 3.89–3.84 (m, 2H,
5-CH2), 3.68 (s, 3H, OCH3), 3.33 (t, 2H, J¼5.8 Hz, 4-CH2), 3.03 (s, 3H,
N–CH3), 2.24 (s, 3H, COCH3), 1.41 (t, 3H, J¼7.1 Hz, O–CH2–CH3) ppm.
(53), 321 (100), 293 (12), 281 (23), 275 (37), 267 (14), 247 (9), 239
(43), 233 (27), 220 (12), 197 (24), 176 (17), 164 (16), 136 (7), 125 (24),
121 (6), 59 (5), 58 (11). C18H24N2O5S (380.14): calcd C 56.82, H 6.36,
N 7.36, O 21.03%; found: C 56.74, H 6.49, N 7.38, O 21.20%.
13C NMR (100 MHz, CDCl3):
d¼169.8,166.9,166.3,150.5,147.3,128.5,
128.3, 113.0, 94.6, 60.7, 51.2, 47.9, 44.1, 31.5, 23.9, 23.7, 14.4 ppm. IR
(KBr):
n
¼1685, 1660, 1587, 1526 cmꢃ1. EIMS m/z (%): 366 (Mþ, 100),
4.11.3. 3-Ethyl 7,8-dimethyl 2-(acetylamino)-6-ethyl-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3,7,8-tricarboxylate (9f)
White powder mp 145–146 ꢁC (ethyl acetate/hexane). Rf (15%
351 (20), 335 (19), 323 (22), 307 (73), 281 (22), 276 (17), 267 (20), 261
(49), 239 (38), 234 (19), 220 (17), 219 (42),197 (29),195 (18),176 (21),
164 (18), 125 (26), 43 (22). C17H22N2O5S (366.12): calcd C 55.72, H
6.05, N 7.64, O 21.83%; found: C 55.49, H 6.09, N 7.42, O 21.89%.
Et2O/hexane) 0.77. 1H NMR (400 MHz, CDCl3):
d
¼11.18 (s, 1H,
NHCOCH3), 4.36 (q, 2H, J¼7.1 Hz, O–CH2–CH3), 3.93 (s, 2H, 9-CH2),
3.86 (t, 2H, J¼5.9 Hz, 5-CH2), 3.79 (s, 3H, OCH3), 3.68 (s, 3H, OCH3),
3.37 (t, 2H, J¼5.9 Hz, 4-CH2), 3.03 (q, 2H, J¼7.2 Hz, N–CH2–CH3),
2.22 (s, 3H, N–CH3), 1.40 (t, 3H, J¼7.1 Hz, O–CH2–CH3), 1.02 (t, 3H,
4.10.3. 3-Ethyl 7,8-dimethyl 2-(acetylamino)-6-methyl-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3,7,8-tricarboxylate (9c)
Eluent ethyl acetate/hexane (1:5). White powder mp 147–149 ꢁC
J¼7.2 Hz, N–CH2–CH3) ppm. 13C NMR (100 MHz, CDCl3):
¼168.5,
d
(ethyl acetate/hexane). Rf (10% Et2O/hexane) 0.49.1H NMR (400 MHz,
167.4, 167.0, 166.2, 153.7, 147.7, 129.9, 126.7, 112.2, 98.6, 60.8, 52.5,
CDCl3):
d
¼11.19 (s,1H, NHCOCH3), 4.37 (q, 2H, J¼7.2 Hz, O–CH2–CH3),
51.7, 49.2, 46.2, 29.3, 25.9, 23.7, 14.5, 14.4 ppm. IR (KBr):
n
¼1736,
3.95 (s, 2H, 9-CH2), 3.84–3.79 (m, 5H, OCH3 and 5-CH2), 3.70 (s, 3H,
OCH3), 3.38 (t, 2H, J¼6.5 Hz, 4-CH2), 2.74 (s, 3H, N–CH3), 2.25 (s, 3H,
COCH3), 1.41 (t, 3H, J¼7.2 Hz, O–CH2–CH3) ppm. 13C NMR (100 MHz,
1682, 1671, 1560 cmꢃ1. EIMS m/z (%): 438 (Mþ, 27), 407 (7), 380 (17),
379 (100), 367 (27), 349 (11), 333 (16), 319 (11), 276 (12), 261 (8),
239 (10), 234 (8), 198 (6), 197 (8), 164 (11), 128 (5), 125 (12), 117 (5),
59 (6), 43 (24). C20H26N2O7S (438.15): calcd C 54.78, H 5.98, N 6.39,
O 25.54%; found: C 54.64, H 6.19, N 6.25, O 25.61%.
CDCl3):
d
¼169.8, 166.9, 166.3, 165.8, 150.2, 146.9, 128.2, 127.3, 112.4,
97.2, 60.7, 56.3, 51.2, 48.2, 44.4, 31.8, 23.8, 23.5, 14.2 ppm. IR (KBr):
n
¼1735, 1680, 1667, 1569 cmꢃ1. EIMS m/z (%): 424 (Mþ, 35), 367 (45),
366(20), 365(100), 364(31), 333 (15), 325 (23), 321(16), 319 (33), 305
(16), 277 (28), 276 (19), 259 (16), 234 (16), 217 (17),186 (73),164 (16),
125 (18), 82 (18), 43 (28). C19H24N2O7S (424.13): calcd C 53.76, H 5.70,
N 6.60, O 26.38%; found: C 53.44, H 5.49, N 6.75, O 26.17%.
4.11.4. Ethyl 8-acetyl-2-(acetylamino)-6-isopropyl-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3-carboxylate (9g)
White powder mp 146–147 ꢁC (ethyl acetate/hexane). 1H NMR
(400 MHz, CDCl3):
d
¼10.60 (s, 1H, NHCOCH3), 7.37 (s, 1H, 7-H), 4.35
(q, 2H, J¼7.2 Hz, O–CH2–CH3), 4.02 (s, 2H, 9-CH2), 3.92–3.85 (m, 2H,
5-CH2), 3.51–3.44 (m, 1H, CH(CH3)2), 3.33 (t, 2H, J¼5.6 Hz, 4-CH2),
2.22 (s, 3H, COCH3), 2.19 (s, 3H, COCH3), 1.39 (t, 3H, J¼7.2 Hz, O–
CH2–CH3), 1.24 (d, 6H, J¼6.7 Hz, CH(CH3)2) ppm. 13C NMR
4.11. General experimental procedure for the synthesis of
thienoazocines 9d–h in acetonitrile
To a stirred solution of thienopyridines 7f, g (1 mmol) in ace-
tonitrile (15 mL) at 25 ꢁC methyl propiolate, acetylacetylene or
DMAD (1.2 mmol) was added and stirring was continued (TLC
monitoring). The solvent was evaporated under reduced pressure.
In the cases of reactions with methyl propiolate or acetylacetylene
the resulting residue was recrystallized with ethyl acetate/hexane
to give thienoazocines 9d, e, g, h. In the case of reactions with
DMAD the residue was purified by column chromatography with
ethyl acetate/hexane (1:7) as eluent to give thienoazocines 9f, i.
(100 MHz, CDCl3):
d
¼192.2, 167.6, 165.0, 151.2, 144.7, 129.3, 128.5,
113.7, 108.2, 60.8, 57.5, 43.1, 32.8, 25.0, 23.5, 21.7 (2C), 21.5,
14.4 ppm. IR (KBr):
n
¼1686, 1655, 1617, 1587 cmꢃ1. EIMS m/z (%):
378 (Mþ, 32), 363 (5), 289 (6), 265 (5), 176 (6), 125 (7), 72 (8), 56
(11), 43 (100). C19H26N2O4S (378.16): calcd C 60.29, H 6.92, N 7.40, O
16.91%; found: C 60.34, H 6.89, N 7.25, O 17.02%.
4.11.5. 3-Ethyl 8-methyl 2-(acetylamino)-6-isopropyl-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3,8-dicarboxylate (9h)
White powder mp 140–141 ꢁC (ethyl acetate/hexane). 1H NMR
4.11.1. Ethyl 8-acetyl-2-(acetylamino)-6-ethyl-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3-carboxylate (9d)
(400 MHz, CDCl3):
d
¼10.59 (s, 1H, NHCOCH3), 7.53 (s, 1H, 7-H), 4.34
(q, 2H, J¼7.2 Hz, O–CH2–CH3), 3.94 (s, 2H, 9-CH2), 3.88–3.80 (m, 2H,
5-CH2), 3.67 (s, 3H, OCH3), 3.48–3.40 (m, 1H, CH(CH3)2), 3.32 (t, 2H,
J¼5.6 Hz, 4-CH2), 2.23 (s, 3H, COCH3), 1.20 (d, 6H, J¼6.7 Hz,
Yellowish powder mp 167–169 ꢁC (ethyl acetate/hexane). 1H
NMR (400 MHz, CDCl3):
d¼10.6 (s, 1H, NHCOCH3), 7.29 (s, 1H, 7-H),

10450
L.G. Voskressensky et al. / Tetrahedron 64 (2008) 10443–10452
CH(CH3)2) ppm. 13C NMR (100 MHz, CDCl3):
d
¼169.1, 167.7, 165.1,
C25H28N2O7S (500.16): calcd C 59.99, H 5.64, N 5.60, O 22.37%;
found: C 59.87, H 5.72, N 5.39, O 22.06%.
148.3, 144.7, 128.4, 128.2, 113.9, 93.7, 60.9, 57.1, 51.1, 43.5, 32.9, 23.8,
23.5, 21.9 (2C), 14.4 ppm. IR (KBr):
n
¼1693, 1670, 1653, 1605 cmꢃ1
.
EIMS m/z (%): 394 (Mþ, 6), 335 (5), 125 (7), 43 (100). C19H26N2O5S
(394.16): calcd C 57.85, H 6.64, N 7.10, O 20.28%; found: C 57.78, H
6.59, N 7.16, O 20.17%.
4.13. General experimental procedure for the synthesis of
thienoazocines 9a, b, d–h, j, k and substituted thiophenes
10a–c
4.12. General experimental procedure for the synthesis of
thienoazocines 9j–l in acetonitrile
To a stirred solution of thienopyridines 7e–h (1 mmol) in
methanol (15 mL) at 25 ꢁC DMAD, methyl propiolate or acetylace-
tylene (1.2 mmol) was added and stirring was continued (TLC
monitoring). Methanol was evaporated under reduced pressure
and the resulting residue was purified using column chromatog-
raphy providing compounds 9a–c, 10a (for 7e), 9d–f (for 7f), 9g, h,
10b, c (for 7g). In the case of thienopyridine 7h after the evapora-
tion of the solvent thienoazocines 9j, k were recrystallized from the
reaction mixtures with ethyl acetate/hexane.
To a stirred solution of thienopyridine 7h (1 mmol) in acetoni-
trile (15 mL) at 25 ꢁC methyl propiolate, acetylacetylene or DMAD
(2 mmol) was added and stirring was continued (TLC monitoring).
The solvent was evaporated under reduced pressure and the
resulting residue was recrystallized with ethyl acetate/hexane to
give thienoazocines 9j, k. In the case of DMAD the residue was
purified by column chromatography with ethyl acetate/hexane
(1:5) as eluent to give thienoazocine 9l.
4.13.1. Dimethyl (2E)-2-[{2-[5-(acetylamino)-4-(ethoxycarbonyl)-
2-(methoxymethyl)-3-thienyl]ethyl}(methyl)amino]but-2-
enedioate (10a)
4.12.1. Ethyl 8-acetyl-2-(acetylamino)-6-benzyl-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3-carboxylate (9j)
White powder mp 130–132 ꢁC (ethyl acetate/hexane). 1H NMR
White powder mp 182–184 ꢁC (ethyl acetate/hexane). 1H NMR
(400 MHz, CDCl3):
d
¼11.29 (s, 1H, NHCOCH3), 4.67 (s, 1H, ]CH),
(400 MHz, CDCl3):
d
¼10.57 (s, 1H, NH–COCH3), 7.44 (s, 1H, 7-H),
4.49–4.42 (m, 4H, O–CH2–CH3 and CH2–OCH3), 3.94 (s, 3H, OCH3),
3.65 (s, 3H, OCH3), 3.39 (s, 3H, CH2–OCH3), 3.34–3.19 (m, 2H, 5-
CH2), 3.13–3.08 (m, 2H, 4-CH2), 2.77 (s, 3H, N–CH3), 2.28 (s, 3H,
COCH3), 1.42 (t, 3H, J¼7.0 Hz, O–CH2–CH3) ppm. 13C NMR (100 MHz,
7.29–7.27 (m, 3H, CH–Ar), 7.11–7.09 (m, 2H, CH–Ar), 4.41 (s, 2H,
Ar–CH2), 4.18 (q, 2H, J¼7.1 Hz, O–CH2–CH3), 4.06 (s, 2H, 9-CH2),
3.96–3.89 (m, 2H, 5-CH2), 3.07 (t, 2H, J¼5.6 Hz, 4-CH2), 2.24 (s,
3H, COCH3), 2.22 (s, 3H, COCH3), 1.25 (t, 3H, J¼7.1 Hz, O–CH2–
CDCl3):
d
¼167.3, 166.5, 164.3, 149.6, 143.8, 139.6, 133.7, 127.4, 113.3,
CH3) ppm. 13C NMR (100 MHz, CDCl3):
d¼192.1, 167.0, 164.5, 152.9,
86.7, 68.1, 61.4, 57.8, 54.7, 52.3, 51.4, 38.5, 29.7, 23.5, 14.1 ppm. IR
144.6, 138.0, 128.7 (2C), 128.3, 128.0 (2C), 127.4, 127.3, 113.5, 108.4,
60.6, 60.1, 46.6, 31.3, 24.5, 23.0, 21.1, 13.9 ppm. IR (KBr):
(KBr):
n
¼1736, 1694, 1663, 1565 cmꢃ1. EIMS m/z (%): 456 (Mþ, 3),
n
¼1684,
397 (9), 252 (8), 187 (9), 186 (100), 158 (5), 82 (16), 45 (6).
1651, 1588 cmꢃ1. EIMS m/z (%): 426 (Mþ, 12), 383 (9), 335 (14),
293 (8), 265 (10), 247 (7), 239 (11), 218 (5), 188 (6), 176 (5), 120
(9), 106 (5), 91 (100), 65 (13), 43 (59). C23H26N2O4S (426.16): calcd
C 64.77, H 6.14, N 6.57, O 15.00%; found: C 64.64, H 6.09, N 6.75, O
15.07%.
C20H28N2O8S (456.16): calcd C 52.62, H 6.18, N 6.14, O 28.04%;
found: C 52.44, H 6.29, N 6.05, O 28.29%.
4.13.2. Ethyl 2-(acetylamino)-4-(2-{isopropyl[(1E)-3-oxobut-
1-en-1-yl]amino}ethyl)-5-(methoxymethyl)thiophene-3-
carboxylate (10b)
4.12.2. 3-Ethyl 8-methyl 2-(acetylamino)-6-benzyl-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3,8-dicarboxylate (9k)
White powder mp 160–162 ꢁC (ethyl acetate/hexane). 1H NMR
Yellow viscous oil. 1H NMR (400 MHz, CDCl3):
d¼7.62 (d, 1H,
J¼12.4 Hz, N–CH]), 5.30 (d, 1H, J¼12.4 Hz, ]CH–COCH3), 4.43–
4.42 (m, 4H, O–CH2–CH3 and CH2–OCH3), 3.37 (s, 3H, OCH3), 3.34–
3.28 (m, 3H, 5-CH2 and –CH(CH3)2), 3.11–3.03 (m, 2H, 4-CH2), 2.28
(s, 3H, COCH3), 2.12 (s, 3H, COCH3), 1.45 (t, 3H, J¼7.0 Hz, O–CH2–
CH3), 1.15 (d, 6H, J¼6.0 Hz, –CH(CH3)2) ppm. 13C NMR (100 MHz,
(400 MHz, CDCl3):
d
¼10.55 (s, 1H, NH–COCH3), 7.62 (s, 1H, 7-H),
7.26–7.25 (m, 3H, CH–Ar), 7.10–7.09 (m, 2H, CH–Ar), 4.35 (s, 2H,
Ar–CH2), 4.17 (q, 2H, J¼7.1 Hz, O–CH2–CH3), 3.97 (s, 2H, 9-CH2),
3.88–3.81 (m, 2H, 5-CH2), 3.70 (s, 3H, OCH3), 3.05–3.02 (m, 2H, 4-
CH2), 2.24 (s, 3H, COCH3), 1.24 (t, 3H, J¼7.1 Hz, O–CH2–CH3) ppm.
DMSO-d6):
d
¼192.7, 167.3, 164.3, 148.6, 147.4, 132.6, 126.8, 112.3,
96.9, 66.0, 60.7, 57.4, 54.0, 47.9, 27.3, 25.9, 23.1, 20.8 (2C), 14.0 ppm.
13C NMR (100 MHz, CDCl3):
d¼168.6, 166.9, 164.5, 150.3, 129.0,
IR (KBr):
n
¼1738, 1707, 1620 cmꢃ1. EIMS m/z (%): 410 (Mþ, 18), 396
128.5, 128.3 (2C), 127.7, 127.3, 127.2 (2C), 127.1, 113.7, 94.4, 60.4,
60.2, 50.5, 46.7, 31.4, 23.4, 23.0, 13.8 ppm. IR (KBr):
(7), 395 (38), 335 (5), 283 (5), 268 (5), 241 (50),141 (9),140 (100), 98
(49), 80 (15), 70 (5), 56 (10), 55 (6), 43 (42), 41 (5). C20H30N2O5S
(410.19): calcd C 58.51, H 7.37, N 6.82, O 19.49%; found: C 58.44, H
7.49, N 6.75, O 19.30%.
n
¼1730, 1687,
1667, 1614 cmꢃ1. EIMS m/z (%): 442 (Mþ, 17), 383 (9), 351 (35),
309 (6), 265 (7), 239 (15), 204 (13), 197 (10), 190 (6), 176 (5), 132
(12), 125 (10), 106 (7), 91 (100), 65 (10), 43 (37). C23H26N2O5S
(442.16): calcd C 62.42, H 5.92, N 6.33, O 18.08%; found: C 62.34,
H 5.84, N 6.25, O 18.24%.
4.13.3. Dimethyl (2E)-2-[{2-[5-(acetylamino)-4-(ethoxycarbonyl)-
2-(methoxymethyl)-3-thienyl]ethyl}(isopropyl)amino]but-2-
enedioate (10c)
4.12.3. 3-Ethyl 7,8-dimethyl 2-(acetylamino)-6-benzyl-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3,7,8-tricarboxylate (9l)
Yellow viscous oil. 1H NMR (400 MHz, CDCl3):
d
¼10.44 (s, 1H,
NH), 4.84 (s, 1H, ]CH), 4.50 (q, 2H, J¼7.2 Hz, O–CH2–CH3), 4.46 (s,
2H, CH2–OCH3), 3.93 (s, 3H, OCH3), 3.65 (s, 3H, CH2–OCH3), 3.57–
3.51 (m, 1H, –CH(CH3)2), 3.38 (s, 3H, OCH3), 3.25–3.21 (m, 2H, 5-
CH2), 3.13–3.10 (m, 2H, 4-CH2), 2.28 (s, 3H, N–CH3), 1.41 (t, 3H,
J¼7.2 Hz, O–CH2–CH3), 1.06 (d, 6H, J¼6.7 Hz, –CH(CH3)2) ppm. 13C
Viscous yellow oil. Rf (20% Et2O/hexane) 0.59. 1H NMR
(400 MHz, CDCl3):
d
¼10.58 (s, 1H, NH–COCH3), 7.19–7.12 (m, 3H,
CH–Ar), 7.09–7.05 (m, 2H, CH–Ar), 4.18 (q, 2H, J¼7.2 Hz, O–CH2–
CH3), 4.13 (s, 2H, Ar–CH2), 3.94 (s, 2H, 9-CH2), 3.81 (t, 2H, J¼6.4 Hz,
5-CH2), 3.76 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.09 (t, 2H, J¼6.4 Hz,
4-CH2), 2.27 (s, 3H, COCH3), 1.31 (t, 3H, J¼7.2 Hz, O–CH2–CH3) ppm.
NMR (100 MHz, CDCl3):
146.8, 139.9, 120.2, 86.3, 63.6, 56.9, 53.1, 46.7 (2C), 43.7, 35.7, 20.3,
d
¼190.9, 189.6, 188.6, 187.9, 173.5, 168.0,
13C NMR (100 MHz, CDCl3):
d
¼167.8,167.0,166.5,164.3,153.3,145.4,
11.9, 10.1, 6.3 (2C) ppm. IR (KBr):
n
¼1737, 1867, 1655, 1578 cmꢃ1
.
133.3, 130.4, 127.8 (2C), 127.2 (2C), 127.0, 125.5, 112.8, 99.0, 60.1,
EIMS m/z (%): 484 (Mþ, 5), 425 (6), 215 (10), 214 (100), 172 (12),
164 (5), 140 (28), 112 (8), 43 (6). C22H32N2O8S (484.19): calcd C
54.53, H 6.66, N 5.78, O 26.41%; found: C 54.35, H 6.48, N 5.65, O
26.17%.
55.2, 52.1, 51.3, 50.2, 28.3, 25.6, 23.1, 13.9 ppm. IR (KBr):
n
¼1736,
1687, 1654, 1564 cmꢃ1. EIMS m/z (%): 500 (Mþ, 5), 409 (25), 349 (7),
303 (5), 261 (6), 190 (7), 125 (8), 91 (100), 65 (14), 59 (7), 43 (55).

L.G. Voskressensky et al. / Tetrahedron 64 (2008) 10443–10452
10451
4.14. General procedure for the synthesis of thienoazocines
11a–d
(100 MHz, DMSO-d6):
115.5, 105.0, 97.2, 58.8, 51.9, 50.9, 50.7, 37.7, 28.3, 25.5, 14.3 ppm. IR
d
¼167.8, 166.3, 164.6, 162.0, 153.3, 130.7,
(KBr):
n
¼3475, 3351, 1739, 1689, 1659, 1600 cmꢃ1. EIMS m/z (%): 382
To the stirred solution of thienoazocines 8a–d (1 g) alkaline
(Mþ, 75), 351 (8), 335 (6), 325 (67), 323 (100), 307 (8), 293 (21), 277
(53), 263 (14), 245 (16), 234 (27), 217 (21), 210 (13),197 (14),189 (6),
175 (9), 164 (21), 152 (7), 136 (10), 125 (27), 116 (9), 103 (6), 82 (7),
72 (6), 65 (5), 59 (12), 42 (27), 39 (10). C17H22N2O6S (382.12): calcd
C 53.39, H 5.80, N 7.33, O 25.10%; found: C 53.24, H 5.74, N 7.25, O
25.26%.
alumina oxide (pH¼10ꢀ0.5) (30 g) was added, the stirring was
continued at 25 ꢁC (TLC monitoring). The reaction mixture was
filtrated and washed with ethyl acetate. The filtrate was gathered
and the solvent was evaporated under reduced pressure to give
thienoazocines 11a–d.
4.14.1. Ethyl 8-acetyl-2-amino-6-methyl-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3-carboxylate (11a)
4.15. Experimental procedure for the synthesis
of thienoazocine 12
White powder mp 239–241 ꢁC (ethyl acetate/hexane). 1H NMR
(400 MHz, CDCl3):
d
¼7.27 (s, 1H, 7-H), 5.90 (s, 2H, NH2), 4.28 (q, 2H,
J¼7.1 Hz, O–CH2–CH3), 3.91–3.84 (m, 4H, 5-CH2 and 9-CH2), 3.29 (t,
2H, J¼5.6 Hz, 4-CH2), 3.10 (s, 3H, N–CH3), 2.19 (s, 3H, COCH3),1.35 (t,
3H, J¼7.1 Hz, O–CH2–CH3) ppm. 13C NMR (100 MHz, DMSO-d6):
NaCNBH3 (98 mg, 1.55 mmol) and a few drops of acetic acid, as
a catalyst, were added to a solution of thienoazocine 11a (250 mg,
0.77 mmol) in methanol (20 mL). The reaction mixture was heated
at reflux (TLC monitoring). The solvent was evaporated under re-
duced pressure. Water (15 mL) was added to the residue and the pH
was adjusted to 8–9 (Na2CO3). The resulting solution was extracted
with ether (3ꢂ25 mL). The solvent was evaporated under reduced
pressure to give hexahydrothienoazocine 12 (216 mg, 86%).
d
¼191.6, 164.7, 161.3, 152.6, 129.5, 117.8, 108.2, 105.4, 58.7, 47.5, 43.7,
31.1, 24.3, 21.2, 14.3 ppm. IR (KBr):
n
¼3387, 3281, 1732, 1666,
1573 cmꢃ1. EIMS m/z (%): 308 (Mþ, 63), 293 (5), 279 (5), 265 (36),
251 (17), 237 (10), 229 (7), 219 (39), 208 (13), 197 (10), 191 (23), 176
(29), 164 (15), 151 (7), 136 (9), 125 (31), 110 (6), 94 (6), 82 (12), 77
(7), 66 (11), 53 (7), 44 (68), 43 (100), 42 (62). C15H20N2O3S (308.12):
calcd C 58.42, H 6.54, N 9.08, O 15.56%; found: C 58.34, H 6.49, N
8.79, O 15.40%.
4.15.1. 3-Ethyl 8-methyl 2-amino-6-methyl-4,5,6,7,8,9-
hexahydrothieno[3,2-d]azocine-3,8-dicarboxylate (12)
Yellowish viscous oil. 1H NMR (400 MHz, CDCl3):
d
¼5.92 (s, 2H,
4.14.2. 3-Ethyl 8-methyl 2-amino-6-methyl-4,5,6,9-
NH2), 4.27 (q, 2H, J¼7.1 Hz, O–CH2–CH3), 3.71 (s, 3H, OCH3), 3.15–
3.03 (m, 2H, 7-CH2), 2.90–2.85 (m, 2H, 9-CH2), 2.80–2.75 (m, 1H, 4-
CH2), 2.72–2.66 (m, 1H, 5-CH2), 2.61–2.54 (m, 3H, 4-CH2 and 8-CH),
2.38 (s, 3H, N–CH3), 1.33 (t, 3H, J¼7.1 Hz, O–CH2–CH3) ppm. 13C
tetrahydrothieno[3,2-d]azocine-3,8-dicarboxylate (11b)
White crystals mp 156–158 ꢁC (ethyl acetate/hexane). 1H NMR
(400 MHz, CDCl3):
d
¼7.40 (s, 1H, 7-H), 5.83 (s, 2H, NH2), 4.28 (q, 2H,
J¼7.2 Hz, O–CH2–CH3), 3.83–3.79 (m, 4H, 5-CH2 and 9-CH2), 3.66 (s,
3H, OCH3), 3.27 (t, 2H, J¼6.0 Hz, 4-CH2), 3.02 (s, 3H, N–CH3), 1.35 (t,
3H, J¼7.2 Hz, O–CH2–CH3) ppm. 13C NMR (100 MHz, CDCl3):
NMR (100 MHz, CDCl3):
d
¼174.3, 165.9, 161.9, 135.0, 117.1, 106.3,
59.6, 59.3, 56.4, 51.7, 48.1, 47.1, 29.3, 26.8, 14.5 ppm. IR (KBr):
n
¼3434, 3330, 1730, 1665 cmꢃ1. EIMS m/z (%): 326 (Mþ, 85), 293
d
¼170.0, 165.7, 161.0, 150.6, 130.0, 119.2, 107.4, 94.5, 59.6, 51.2, 47.9,
(27), 247 (29), 240 (54), 239 (100), 224 (21), 211 (39), 210 (44), 198
(36), 197 (67), 194 (21), 193 (22), 180 (20), 178 (23), 164 (30), 152
(18), 125 (26), 109 (44), 58 (25), 43 (23). C15H22N2O4S (326.13):
calcd C 55.19, H 6.79, N 8.58, O 19.61%; found: C 55.34, H 6.87, N
8.25, O 19.52%.
44.2, 31.8, 23.9, 14.6 ppm. IR (KBr):
n
¼3400, 3297, 1666, 1619,
1589 cmꢃ1. EIMS m/z (%): 324 (Mþ, 57), 309 (11), 293 (13), 281 (7),
265 (32), 248 (5), 234 (15), 219 (35), 210 (10), 204 (6), 197 (23), 191
(14), 176 (22), 164 (32), 151 (15), 139 (12), 125 (64), 110 (16), 105 (7),
96 (16), 91 (12), 82 (13), 66 (17), 53 (14), 43 (53), 42 (100), 39 (22).
C
15H20N2O4S (324.11): calcd C 55.54, H 6.21, N 8.64, O 19.73%;
found: C 55.38, H 6.39, N 8.78, O 19.59%.
4.16. Experimental procedure for the synthesis
of thienoazocine 13
4.14.3. Ethyl 2-amino-6-methyl-8-[(4-methylphenyl)sulphonyl]-
4,5,6,9-tetrahydrothieno[3,2-d]azocine-3-carboxylate (11c)
White powder mp 231–233 ꢁC (ethyl acetate/hexane). 1H NMR
To a stirred solution of thienoazocine 11a (250 mg, 0.77 mmol)
dry CH2Cl2 (20 mL) triethylamine (0.13 mL, 0.93 mmol) and
chloroacetyl chloride (0.07 mL, 0.93 mmol) were added, the stirring
was continued (TCL monitoring). The reaction mixture was poured
into water (20 mL) and was extracted with CH2Cl2 (3ꢂ20 mL). The
solvent was evaporated under reduced pressure to give thieno-
azocine 13 (261 mg, 84%).
(400 MHz, CDCl3):
d
¼7.67 (d, 2H, J¼8.1 Hz, CH–Ar), 7.38 (s, 1H, 7-H),
7.25 (d, 2H, J¼8.1 Hz, CH–Ar), 5.73 (s, 2H, NH2), 4.26 (q, 2H,
J¼7.3 Hz, O–CH2–CH3), 3.76–3.73 (m, 2H, 5-CH2), 3.58 (s, 2H, 9-
CH2), 3.25 (t, 2H, J¼5.6 Hz, 4-CH2), 3.06 (s, 3H, N–CH3), 2.42 (s, 3H,
Ar–CH3), 1.34 (t, 3H, J¼7.3 Hz, O–CH2–CH3) ppm. 13C NMR
(100 MHz, DMSO-d6):
d¼164.6, 161.6, 148.5, 141.8, 140.9, 130.5,
129.3 (2C), 126.5 (2C), 115.2, 105.3, 100.9, 58.7, 47.4, 43.2, 31.4, 23.8,
20.8, 14.2 ppm. IR (KBr):
4.16.1. 3-Ethyl 8-methyl 2-[(chloroacetyl)amino]-6-methyl-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3,8-dicarboxylate (13)
n
¼3416, 3319, 1657, 1631, 1584 cmꢃ1. EIMS
m/z (%): 420 (Mþ, 11), 265 (36), 247 (8), 237 (9), 219 (34), 191 (14),
175 (18), 164 (5), 149 (6), 125 (17), 104 (6), 91 (31), 82 (7), 77 (8), 65
(18), 51 (7), 44 (43), 43 (100), 42 (71), 39 (19). C20H24N2O4S2
(420.12): calcd C 57.12, H 5.75, N 6.66, O 15.22%; found: C 57.24, H
5.67, N 6.77, O 15.44%.
White powder mp 201–203 ꢁC (ethyl acetate). 1H NMR
(400 MHz, CDCl3):
d
¼9.81 (s, 1H, NH), 7.40 (s, 1H, 7-H), 4.41 (q, 2H,
J¼7.1 Hz, O–CH2–CH3), 4.24 (s, 2H, CH2–CO), 3.97 (s, 2H, 9-CH2),
3.90–3.85 (m, 2H, 5-CH2), 3.68 (s, 3H, OCH3), 3.38–3.34 (m, 2H, 4-
CH2), 3.03 (s, 3H, N–CH3), 1.41 (t, 3H, J¼7.1 Hz, O–CH2–CH3) ppm.
13C NMR (100 MHz, DMSO-d6):
d¼168.5, 164.4, 163.7, 150.1, 143.3,
4.14.4. 3-Ethyl 7,8-dimethyl 2-amino-6-methyl-4,5,6,9-
tetrahydrothieno[3,2-d]azocine-3,7,8-tricarboxylate (11d)
White powder mp 146–148 ꢁC (ethyl acetate/hexane). 1H NMR
129.4, 128.9, 115.3, 93.7, 60.6, 50.4, 47.4, 43.5, 42.4, 30.7, 23.4,
13.9 ppm. IR (KBr):
n
¼1663, 1615, 1598 cmꢃ1. EIMS m/z (%): 400
(Mþ, 16), 341 (17), 310 (6), 295 (9), 273 (15), 219 (6), 194 (12), 176
(7), 166 (11), 151 (6), 136 (5), 125 (7), 108 (5), 94 (6), 77 (47), 65 (6),
59 (13), 49 (43), 43 (46), 42 (100). C17H21ClN2O5S (400.09): calcd C
50.93, H 5.28, N 6.99, O 19.96%; found: C 50.88, H 5.24, N 7.13, O
19.88%.
(400 MHz, CDCl3):
d
¼5.88 (s, 2H, NH2), 4.28 (q, 2H, J¼7.1 Hz, O–
CH2–CH3), 3.81 (s, 3H, OCH3), 3.80 (s, 2H, 9-CH2), 3.75 (t, 2H,
J¼6.2 Hz, 5-CH2), 3.67 (s, 3H, OCH3), 3.31 (t, 2H, J¼6.2 Hz, 4-CH2),
2.74 (s, 3H, N–CH3),1.35 (t, 3H, J¼7.1 Hz, O–CH2–CH3) ppm. 13C NMR

10452
L.G. Voskressensky et al. / Tetrahedron 64 (2008) 10443–10452
4.17. Experimental procedure for the synthesis of
thienoazocine 14
245 (17), 235 (16), 234 (15), 220 (10), 219 (35), 218 (12), 217 (12),
202 (10), 197 (15), 191 (13), 190 (11), 178 (12), 176 (18), 164 (18), 162
(11), 155 (29), 154 (11), 153 (100), 151 (12), 127 (26), 126 (12), 125
(63), 100 (18), 90 (27), 72 (13), 63 (14), 44 (12), 42 (16).
To a stirred solution of thienoazocine 11a (300 mg, 0.93 mmol)
in dry CH2Cl2 (20 mL) triethylamine (0.38 mL, 2.78 mmol) and
3-chlorophenylisocyanate (0.34 mL, 2.78 mmol) were added and
the stirring was continued (TLC monitoring). The reaction mixture
was poured into water (25 mL) and extracted CH2Cl2 (3ꢂ25 mL).
The solvent was evaporated under reduced pressure to give thi-
enoazocine 14 (326 mg, 74%).
C22H24ClN3O5S (477.11): calcd C 55.28, H 5.06, N 8.79, O 16.74%;
found: C 55.34, H 4.89, N 8.85, O 16.81%.
Acknowledgements
Authors thank the Russian Foundation for Basic Research for
financial support (grant # 07-03-12029-ofi).
4.17.1. 3-Ethyl 8-methyl 2-({[(3-chlorophenyl)amino]-
carbonyl}amino)-6-methyl-4,5,6,9-tetrahydrothieno-
[3,2-d]azocine-3,8-dicarboxylate (14)
References and notes
White powder mp 211–213 ꢁC (ethyl acetate). 1H NMR
1. Faltz, H.; Liebscher, J. Synlett 1998, 1355.
2. Maffrand, J. P.; Lucas, M. Heterocycles 1980, 14, 325.
(400 MHz, CDCl3):
d
¼10.81 (s, 1H, NH), 7.58 (s, 1H, NH), 7.40 (s, 1H,
3. Alvarez, M.; Bosch, J.; Gramados, R.; Lopez, F. J. Heterocycl. Chem. 1978, 15, 193.
4. Confalone, P. N.; Pizzolato, G.; Ushkokovic, M. R. Helv. Chim. Acta. 1976, 59, 104.
5. Lee, J. S.; Lee, D. J.; Kim, B. S.; Kim, K. J. Chem. Soc., Perkin Trans. 1 2001, 21, 2774.
6. Cotelle, P.; Hasiak, B.; Barbry, D.; Couturier, D. Synth. Commun. 1987, 17, 935.
7. Voskressensky, L. G.; Borisova, Y. N.; Vorob’eva, T. A.; Chernyshev, A. I.; Varla-
mov, A. V. Russ. Chem. Bull., Int. Ed. 2005, 54, 2594.
8. Voskressensky, L. G.; Borisova, T. N.; Kulikova, L. N.; Varlamov, A. V.; Catto, M.;
Altomare, C.; Carotti, A. Eur. J. Org. Chem. 2004, 3128.
9. Voskressensky, L. G.; Borisova, T. N.; Listratova, A. V.; Sorokina, E. A.; Tolkunov,
S. V.; Varlamov, A. V. Russ. Chem. Bull., Int. Ed. 2007, 56, 1041.
7-H), 7.28–7.15 (m, 2H, CH–Ar), 7.06 (d, 1H, J¼7.6 Hz, CH–Ar), 7.04
(s, 1H, CH–Ar), 4.32 (q, 2H, J¼7.1 Hz, O–CH2–CH3), 3.97 (s, 2H, 9-
CH2), 3.86–3.85 (m, 2H, 5-CH2), 3.68 (s, 3H, OCH3), 3.30 (t, 2H,
J¼5.5 Hz, 4-CH2), 3.01 (s, 3H, N–CH3), 1.36 (t, 3H, J¼7.1 Hz, O–CH2–
CH3) ppm. 13C NMR (100 MHz, DMSO-d6):
d¼168.6, 165.2, 151.1,
150.1, 147.5, 140.7, 133.3, 130.2, 128.4, 126.9, 122.2, 118.3, 117.1, 112.0,
93.9, 60.1, 50.3, 47.5, 43.6, 30.9, 23.3, 14.0 ppm. IR (KBr):
n
¼1701,
1658, 1611, 1595, 1525 cmꢃ1. EIMS m/z (%): 477 (Mþ, 15), 350 (19),
10. Gewald, K.; Schinke, E.; Boticher, H. Chem. Ber. 1965, 99, 94.
11. Waykole, L.; Paquette, L. A. Org. Synth. 1989, 67, 149.
324 (30), 293 (11), 291 (27), 281 (12), 267 (15), 265 (21), 263 (13),