The Synthesis of Two Regioisomeric Aldehydes with a Tetrahydrobenzo[ b ]thiophene Scaffold and Their Application in Solvent-Free Intramolecular 1,3-Dipolar Cycloaddition Reactions

Article abstract of DOI:10.1055/s-0035-1561428

The paper describes the synthesis of two regioisomeric 2-amino-3-formyl- and 3-amino-2-formyl-substituted derivatives of tetrahydrobenzo[b]thiophene and their subsequent thermally initiated reactions with secondary amines to give azomethine ylides that un

Full text of DOI:10.1055/s-0035-1561428

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
A
paper
Synthesis
L. Tenora et al.
Paper
The Synthesis of Two Regioisomeric Aldehydes with a Tetrahydro-
benzo[b]thiophene Scaffold and Their Application in Solvent-Free
Intramolecular 1,3-Dipolar Cycloaddition Reactions
L. Tenoraa
S. Mana
E. Van Den Bergeb
M. Potáček*a
a
Department of Chemistry, Masaryk University,
Kotlářská 2, 611 37 Brno, Czech Republic
potacek@chemi.muni.cz
Institute of Condensed Matter and Nanosciences,
b
Université catholique de Louvain, Place Louis Pasteur
1, box L4.01.02, 1348 Louvain-la-Neuve, Belgium
Received: 12.02.2016
Accepted after revision: 07.03.2016
Published online: 26.04.2016
O
NH2
OEt
OEt
NH2
DOI: 10.1055/s-0035-1561428; Art ID: ss-2016-t0108-op
S
S
Abstract The paper describes the synthesis of two regioisomeric 2-
amino-3-formyl- and 3-amino-2-formyl-substituted derivatives of tetra-
hydrobenzo[b]thiophene and their subsequent thermally initiated reac-
tions with secondary amines to give azomethine ylides that undergo in-
tramolecular 1,3-dipolar cycloadditions. In this way, two series of new
fused heterocyclic compounds with three stereogenic centers were
prepared. The compounds were identified and their structures were de-
termined.
O
A1
B1
Figure 1 Starting regioisomeric molecules A1 and B1
1
,3-Dipolar cycloaddition is a powerful tool for the syn-
thesis of five-membered heterocyclic compounds. For the
reaction, a dipole and a dipolarophile are required. Several
11
types of dipoles can enter into these cyclization reactions.
Key words dipolar cycloadditions, benzothiophenes, polycycles, het-
erocycles, azomethine ylides
In the case of a molecule that contains two assemblies of at-
oms, one acting as a dipole and the other as a dipolarophile,
it is possible to achieve intramolecular 1,3-dipolar cycload-
dition and, in this way, to form new fused rings. Such reac-
tions are characterized by high regio- and stereoselectivi-
ties. A frequently used method for preparing azomethine
ylide involves an aldehyde and an amino ester.
Fused heterocyclic compounds are known for their im-
portant biological properties and they are often used in
medicine as effective drugs. Studies have shown that the
substituted 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene
1,2
skeleton exhibits activity against cancer cells, as well as
3
antimicrobial activity. Derivatives of 2-amino-4,5,6,7-tet-
In our laboratory, we have experience in the application
of thermally initiated intramolecular 1,3-dipolar cycloaddi-
tion reactions and have published results concerning the
synthesis and stereoselectivity of fused heterocyclic com-
pounds, generally through the application of microwaves.
For example, we used this method to synthesize hexahy-
drochromeno[4,3-b]pyrroles (X = O) and hexahydropyrro-
rahydrobenzo[b]thiophene have recently been applied in
medicine as antidepressants and as useful agents for the
4
treatment of metabolic disorders (diabetes type II and obe-
5
sity). These activities are retained and even enhanced
when the skeleton is fused to other heterocyclic systems.6
Furthermore, it is interesting to note that the use of such
compounds in electroluminescent devices has also been
–9
2
12–15
lo[3,2-c]quinolines (X = NR ) (Scheme 1).
10
patented.
Whereas amino ester A1 is readily available by means of
the Gewald procedure,16 in which cyclohexanone reacts
with ethyl cyanoacetate and sulfur in the presence of a base
(usually pyridine), its regioisomer B1, with an amino group
in the 3-position, is not as easily prepared. There is little in-
formation available about its synthesis or the synthesis of
In this study, we decided to extend our synthesis of ben-
zothiophenes to more-complex structures for which the
starting molecules were regioisomeric substituted tetrahy-
drobenzo[b]thiophenes (Figure 1) and to apply 1,3-dipolar
cycloaddition.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
Synthesis
L. Tenora et al.
Paper
COOR2
white crystals in 82% yield (Scheme 3). Subsequently, the
ester group was reduced to an alcohol by treatment with
R1
R1
N
O
X
H
COOR2
LiAlH (95%) in diethyl ether at ~0 °C. The final preliminary
4
HN
H
step, before attempting the intramolecular dipolar cycload-
dition, was to oxidize the alcohol to an aldehyde. For this
oxidation, we tested Swern oxidation and oxidation with
PCC; the latter gave alcohol A4 in 58% yield. Both the tem-
perature of the reaction mixture and the method of reagent
addition were crucial in this reaction (see the experimental
section). The second regioisomer B1 was similarly convert-
ed into the corresponding aldehyde, except that the methyl
ester derivative was used instead of the ethyl ester. In the
final oxidizing step, PCC was the preferred oxidant (68%).
H
MW
X
X = O, NR3
Scheme 1 Microwave-initiated 1,3-dipolar cycloaddition to give hexa-
hydrochromeno[4,3-b]pyrroles or hexahydropyrrolo[3,2-c]quinolines
its derivatives. In the patent literature, Edwards et al. de-
scribe a method for the preparation of amino ester B1, but
8
they focus mainly on its properties and applications. De-
rivatives of B1 are potential nucleic acid antimetabolites,
and they have been used as modulators of histamine H4 re-
ceptors and for the treatment of disease states, disorders,
and conditions mediated by the receptors connected with
5
4
O
O
TsCl, pyridine
CH Cl , r.t.
3
6
OEt
NH2
OEt
2
2
7
8,9
S
80%
allergy-related diseases.
2
S
NH
Ts
1
However, when we used Edwards’s procedure, the yield
did not exceed 40%. We therefore developed a new im-
proved method for the synthesis of this scaffold, which we
A1
A2
Br
17
recently published. This new procedure also starts from
cyclohexanone, but proceeds according to Kuehne’s proto-
K2CO3, acetone, r.t.
82%
18
col. Details of this procedure are described in our pub-
OH
17
lished paper and our retrosynthetic approach is shown in
Scheme 2.
O
LiAlH4
OEt
Et2O, 0 °C
95%
S
N
NH2
S
N
N
N
Ts
O
Me
A4
A3
Ts
O
S
O
S
O
PCC
B1
CH2Cl2, r.t.
8%
O
5
Me
O
O
HN
+
N
S
N
Ts
A5
Scheme 2 Retrosynthetic approach to ester B1
Scheme 3 Overview of synthetic pathway to product A5
To achieve intramolecular 1,3-dipolar cycloaddition, we
needed an appropriate amino aldehyde with an allyl sub-
stituent in the β-position. Consequently, our previously
prepared β-amino esters A1 and B1 required further modi-
fication. First, the amino group was protected from further
reactions by the introduction of a tosyl group. Tosylation
with tosyl chloride in dichloromethane in the presence of
pyridine at room temperature for 24 hours gave, after crys-
tallization, a white product in 80% yield. The next step was
to introduce an allyl group onto the partially protected ami-
no group. Allylation with allyl bromide was conducted in
acetone in the presence of potassium carbonate. An excess
of allyl bromide (the total molar amount was three times
that of the starting molecule) was slowly added in several
portions over 24 hours to give the allyl derivative A3 as
Azomethine ylides were formed in situ from aldehydes
A5 (Scheme 4) and B5 (Scheme 5) with various N-substitut-
ed ethyl 2-aminoacetates C.
H
N
O
O
O
R
1
N
R
OEt
OEt
9
10
2
C
H
3
8
10c
3a
H
a R = Me
b R = Et
c R = Bn
d R = Bu
S
N
7
4
6S
N
Ts
5
A5
Ts
A6a–e
i
e R = Pr
Scheme 4 Summary of intramolecular 1,3-dipolar cycloaddition of al-
dehyde A5 with amino esters C and the formation of products A6a–e as
the only diastereoisomers (one enantiomer is depicted)
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

C
Synthesis
L. Tenora et al.
Paper
Ts
N
6
Ts
N
7
5
4
H
N
O
8
H
3a
10b
S
R
OEt
9
S
10
C
H
3
O
N
2
B5
a R = Me
b R = Et
c R = Bn
d R = Bu
e R = i-Pr
1
R
OEt
O
B6a–e
Scheme 5 Summary of intramolecular 1,3-dipolar cycloaddition of al-
dehyde B5 with amino esters C and the formation of products B6a–e as
the only diastereoisomers (one enantiomer is depicted)
First, we attempted to establish optimal conditions for
the reaction by varying the reaction temperature, the reac-
tion time, and the molar ratio of the two components. For
this optimization, ethyl (ethylamino)acetate (ethyl N-ethyl-
glycinate) was chosen as the reference amine. Reactions
were carried out in a preheated oil bath, and the tempera-
ture (140–200 °C), reaction time (5–90 min), and excess of
the secondary amine (1–2.5 mol) were varied. The progress
Figure 2 ORTEP diagram of the racemic compound A6b
tacks the electrophilic carbon atom of the aldehyde and, af-
ter water splits off, a 1,3-dipole azomethine ylide is formed
in situ. This enters into intramolecular 1,3-dipolar cycload-
dition to form two new heterocyclic systems.
1
of the reaction was monitored by both TLC and H NMR.
The following conditions were found to be optimal: tem-
perature, 160 °C; time, 30 min; and aldehyde/secondary
amine molar ratio, 1:2. Under these conditions, we ob-
served full conversion. Only with Ce (R = i-Pr) did a pro-
longed reaction time (60 min) and molar ratio of 1:2.5 have
to be used. The yields of products A6a–e and B6a–e are
summarized in Table 1. The multiplet of the allyl group (δ =
During the intramolecular 1,3-dipolar cycloaddition,
three stereogenic centers are created in positions 2, 3a, and
10c (Scheme 6). We might therefore expect the formation
of four racemic diastereoisomers. However, even when the
temperature of the reaction was varied, only one racemic
diastereomer was obtained. The NOESY spectrum suggest-
ed that the hydrogen atoms at the 10c- and 3a-positions are
oriented toward one side, and to the side opposite to the
hydrogen atom in the 2-position. This idea was supported
by the observation of the hydrogen atoms in the 3′ and 3′′
positions. NOESY interactions were observed only between
the hydrogen atoms in the 2 and 3′ positions and between
those in the 3′′ and 3a positions, which indicated opposite
orientations for the hydrogen atoms in the 2 and 3a posi-
tions. These conclusions were confirmed by X-ray crystal
structure analysis.20
3
.7 to 3.9 ppm) and the signal of the aldehyde group (δ =
1
9.90 ppm) in the H NMR spectrum were used as indicators
of the progress of the reaction. For structural assignments,
1
13
H and C NMR spectra were used, with confirmation by
D HSQC NMR. The structures of the tetracyclic products
2
were finally confirmed by an X-ray structure analysis of
A6b (Figure 2 and Supporting Information).
Table 1 1,3-Dipolar Cycloaddition Reaction with N-Substituted Ethyl
Aminoacetates C
In summary, two regioisomeric derivatives of aminotet-
rahydrobenzothiophenecarbaldehyde were prepared and
derivatized to permit subsequent formation of the corre-
sponding azomethine ylides. Under thermal initiation, the
aldehydes reacted with alkyl (alkylamino)acetates to give
azomethine ylides in situ; these azomethine ylides reacted
further to form new heterocyclic systems. Thus, by this re-
action, we prepared two new series of polycyclic systems
containing three stereogenic centers. Their structures, in-
cluding the stereochemical arrangement at the stereogenic
centers, were determined. We found that one racemic dia-
stereoisomer was obtained in each case. The configurations
of all three stereogenic centers in the molecule were the
same in both regioisomers.
R
Yield (%) of isomer A6 Yield (%) of isomer B6
a
b
c
Me
Et
79
91
88
86
75
68
77
70
83
74
Bn
Bu
i-Pr
d
e
The proposed mechanism for the formation of product
A6 is presented in Scheme 6. Cyclization to product B6 pro-
ceeds analogously. The nucleophilic secondary amine at-
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

D
Synthesis
L. Tenora et al.
Paper
O
O
O
HO
N
H
O
+
H
N
N
R
R
O
S
N
S
Ts
Ts
A5
–
H2O
O
O
N
R
N
O
R
O
S
S
N
N
Ts
Ts
O
O
R
1
N
H
9
7
10
2
H
3
a
3
8
1
0c
A6
H
S
6
4
N
5
Ts
Scheme 6 Plausible mechanism for the 1,3-dipolar cycloaddition of compound A5 and N-R substituted 2-amino ethyl acetate C (one enantiomer of
compound A6 is depicted).
ods and refined by full-matrix least-squares methods using the
SHELXTL program package. The hydrogen atoms were placed in cal-
culated idealized positions and refined as riding.
All chemicals were used as purchased. If necessary, solvents were
dried according to procedures reported in the literature.19 CH Cl was
21
2
2
distilled sequentially from anhyd CaCl and P O then stored over MS
2
2
5
(
3 Å). Et O was dried over Na anhydrous freshly distilled before use.
2
Pyridine was distilled from KOH and stored over MS (3 Å). PE for chro-
matography was fractionally distilled before use. The series of sec-
Ethyl 2-(Tosylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-car-
boxylate (A2)
13
ondary amines and both starting esters A1 and B1 were prepared
Compound A1 (10.0 g, 44.4 mmol, 1 equiv) was dissolved in distilled
16,17
according to the reported methods.
CH Cl (105 mL), and TsCl (13.1 g, 68.9 mmol, 1.6 equiv) and pyridine
2
2
Most of the reactions were carried out under a dry argon, and all re-
actions were monitored by TLC (Merck F254 silica gel). Column chro-
matography was performed on a Horizon HPFC system (Biotage, Up-
psala) with a FLASH Si 25+M cartridge. Melting points were measured
on an MPM HV2 instrument. FT-IR spectra were recorded on a Gene-
(5.89 g, 74.8 mmol, 1.7 equiv) were added. The mixture was stirred
for 24 h at r.t. under argon. H O (70 mL) was added, and the mixture
was stirred for a further 2 h. The organic phase was separated and the
aqueous phase was washed with CH Cl (3 × 10 mL). The combined
organic phases were dried (MgSO ) and concentrated. The crude red-
2
2
2
4
1
13
sis ATI (Mattson/Unicam) spectrometer. H and C NMR spectra were
recorded by using a Bruker Avance 300 spectrometer operating at fre-
brown solid was recrystallized from EtOH to give colorless crystals;
yield: 13.1 g (80%); mp 132–133 °C.
1
13
quencies of 300.13 MHz ( H) or 75.47 MHz ( C), with CDCl3 as the
IR (KBr): 1028, 1090, 1165, 1223, 1381, 1502, 1660, 2943, 3122, 3413,
solvent. TMS (δ = 0.00 ppm) or CHCl (δ = 7.27 ppm) served as inter-
–1
3
3475, 3548 cm .
1
nal standards for H NMR spectroscopy, and CDCl (δ = 77.23 ppm) for
C NMR spectroscopy. GC/MS data were obtained on a ThermoQuest
3
1
H NMR (300 MHz, CDCl ): δ = 1.33 (t, J = 7.1 Hz, 3 H, CH CH ), 1.69–
13
3
2
3
1
.78 (m, 4 H, H5 + H6), 2.41 (s, 3 H, C H CH ), 2.55–2.71 (m, 4 H, H4 +
6 4 3
Trace MS apparatus with EI ionization at 70 eV or on a Shimadzu
GCMS-QP2010 operated in EI mode at 70 eV. MS data were obtained
on a Fisons Instruments TRIO 1000 spectrometer at 70 eV in EI mode
and by thermal desorption. High-resolution mass spectra were re-
corded on a Q-Tof Micromass instrument operated in the positive ESI
H7), 4.26 (q, J = 7.1 Hz, 2 H, CH CH ), 7.27 (d, J = 8.6 Hz, 2 H, C H CH ),
2
3
6
4
3
7
.81 (d, J = 8.6 Hz, 2 H, C H CH ), 10.44 (br s, 1 H, NH).
6 4 3
13
C NMR (75 MHz, CDCl ): δ = 14.3 (CH CH ), 21.7 (C H CH ), 21.7 and
3
2
3
6
4
3
2
3.0 (CH -C5 + C6), 24.6 (CH -C4), 26.6 (CH -C7), 60.8 (CH CH ), 113.6
2 2 2 2 3
(
C), 126.8 (C), 127.5 and 129.9 (2 × 2 CH-C H CH ), 132.2 (C), 136.2
(CV = 30 V) mode. X-ray diffraction data were collected on a Kuma
6 4 3
(C), 144.4 (C), 148.1 (C), 166.0 (COOEt).
KM-4 four-circle CCD diffractometer, and were corrected for Lorentz
and polarization effects. The structures were resolved by direct meth-
+
MS (EI, 70 eV): m/z (%) = 379 [M ] (90), 333 (15), 269 (20), 224 (100),
178 (80), 91 (60).
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E
Synthesis
L. Tenora et al.
Paper
Methyl 3-(Tosylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-
carboxylate (B2)
tion, and then allyl bromide (3.31 g, 27.4 mmol, 2 equiv) was added
dropwise. The suspension was stirred for 4 h at r.t. until no compound
B2 was detected by TLC (EtOAc–PE, 1:5). The mixture was filtered and
the solid residue was washed with acetone (20 mL). The solvent was
removed under reduced pressure and the crude yellow solid was re-
crystallized (EtOH) to give colorless crystals; yield 4.44 g (80%); mp
Compound B1 (5.00 g, 23.7 mmol, 1 equiv) was dissolved in distilled
CH Cl (50 mL) and then TsCl (6.77 g, 35.5 mmol, 1.5 equiv) and pyri-
2
2
dine (2.81 g, 35.5 mmol, 1.5 equiv) were added. The mixture was
stirred for 22 h at r.t. under argon. The starting ester was still detected
by TLC (CH Cl ) and therefore extra TsCl (4.51 g, 23.7 mmol, 1 equiv)
117–118 °C.
2
2
and pyridine (1.87 g, 23.7 mmol, 1 equiv) were added and the mix-
IR (KBr): 1074, 1115, 1161, 1259, 1342, 1446, 1464, 1552, 1597, 1718,
2854, 2943 cm .
–1
ture was stirred for a further 21 h. H O (35 mL) was then added and
2
the mixture was stirred for 2 h. The organic phase was separated, and
the aqueous phase was washed with CH Cl (3 × 10 mL). The com-
1
H NMR (300 MHz, CDCl ): δ = 1.65–1.90 (m, 4 H, H5 + H6), 2.41 (s, 3
3
2
2
H, C H CH ), 2.45–2.83 (m, 4 H, H4 + H7), 3.39 (s, 3 H, COOCH ), 4.01
6
4
3
3
bined organic phases were dried (MgSO ) and concentrated. The
4
(dd, J = 14.6, 8.3 Hz, 1 H, =CH ), 4.45 (dd, J = 14.6, 5.6 Hz, 1 H, =CH ),
2
2
crude brown solid was recrystallized (EtOH) to give a colorless solid;
yield: 5.80 g (67%); mp 114–116 °C.
5
.03 (d, J = 7.3 Hz, 2 H, CH CH), 5.88 (m, 1 H, CH CH), 7.25 (d, J = 8.2
2
2
Hz, 2 H, C H CH ), 7.60 (d, J = 8.2 Hz, 2 H, C H CH ).
6
4
3
6
4
3
IR (KBr): 1057, 1095, 1163, 1186, 1198, 1284, 1323, 1396, 1446, 1475,
13
C NMR (75 MHz, CDCl ): δ = 21.7 (C H CH ), 22.3 and 23.2 (CH -C5 +
3
6
4
3
2
–1
1560, 1595, 1680, 2931, 2953, 3153, 3190, 3207 cm .
C6), 24.7 (CH -C4), 26.0 (CH -C7), 51.6 (COOCH ), 54.5 (CH CH), 118.9
(=CH ), 125.1 (C), 127.9 and 129.5 (2 × 2CH-C H CH ), 134.1 (CH CH),
2
2
3
2
1
H NMR (300 MHz, CDCl ): δ = 1.74–1.77 and 1.86–1.90 (m, 4 H, H5 +
3
2
6
4
3
2
H6), 2.39 (s, 3 H, C H CH ), 2.74–2.83 (m, 4 H, H4 + H7), 3.54 (s, 3 H,
137.6 (C), 139.2 (C), 139.8 (C), 142.0 (C), 143.2 (C), 161.0 (COOMe).
6
4
3
COOCH ), 7.19 (d, J = 7.5 Hz, 2 H, C H CH ), 7.53 (d, J = 7.5 Hz, 2 H,
+
3
6
4
3
MS (EI, 70 eV): m/z (%) = 405 [M ] (<5), 250 (55), 218 (100), 210 (15),
1
C H CH ), 8.17 (br s, 1 H, NH).
6
4
3
90 (10), 162 (10), 91 (15), 65 (10).
13
C NMR (75 MHz, CDCl ): δ = 21.6 (C H CH ), 22.3 and 22.9 (CH -C5 +
3
6
4
3
2
C6), 24.9 (CH -C4), 26.0 (CH -C7), 51.7 (COOCH ), 116.8 (C), 127.6 and
2
2
3
N-Allyl-N-[3-(hydroxymethyl)-4,5,6,7-tetrahydro-1-benzothien-2-
yl]-4-toluenesulfonamide (A4)
1
29.1 (2 × 2CH-C H CH ), 135.1 (C), 135.4 (C), 140.6 (C), 143.5 (C),
6 4 3
143.9 (C), 163.1 (COOCH3).
LiAlH (0.95 g, 25.0 mmol, 1.05 equiv) was suspended in freshly dis-
4
+
MS (EI, 70 eV): m/z (%) = 365 [M ] (10), 210 (100), 196 (10), 178 (20),
54 (10), 91 (15), 65 (10).
tilled Et O (100 mL), and the mixture was cooled in an ice–salt bath to
2
1
0
°C. Compound A3 (10.0 g, 23.8 mmol, 1 equiv) was added gradually
in several portions, and the suspension was stirred at 0 °C under an
Ethyl 2-[Allyl(tosyl)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-
-carboxylate (A3)
inert atmosphere for 60 min, then warmed to r.t. Distilled H O (20
mL) was added dropwise to decompose excess reducing agent. The
organic phase was decanted, and the pasty residue was washed with
2
3
Ester A2 (10.0 g, 26.4 mmol, 1 equiv) was dissolved in acetone (120
Et O (3 × 15 mL). The organic phases were combined, dried (MgSO ),
mL). K CO (5.64 g, 40.8 mmol, 1.5 equiv) was added in a single por-
2
4
2
3
and concentrated in vacuo to give a white crystalline compound;
yield: 8.57 g (95%); mp 107–108 °C. This was used in the subsequent
step without purification.
tion, and then allyl bromide (4.62 g, 38.2 mmol, 1.4 equiv) was added
dropwise. The suspension was stirred for 24 h at r.t. while the reac-
tion was monitored by TLC (CH Cl ). After this time, the conversion to
2
2
product was incomplete, so a second portion of allyl bromide (4.62 g,
8.2 mmol, 1.4 equiv) was added and the mixture was stirred for a
IR (KBr): 1026, 1072, 1165, 1288, 1342, 1394, 1495, 1597, 2845, 2926,
2951, 3086, 3415, 3537 cm .
–1
3
further 16 h, after which the starting compound was completely con-
sumed. The mixture was filtered and the solid residue was washed
with acetone (20 mL). The solvent was removed under reduced pres-
sure and the crude orange solid was recrystallized from EtOH to give
colorless crystals; yield: 9.1 g (82%); mp 122–123 °C.
1
H NMR (300 MHz, CDCl ): δ = 1.54 (s, 2 H, CH OH), 1.73–1.83 (m, 4 H,
3
2
H5 + H6), 2.45 (s, 3 H, C H CH ), 2.56–2.80 (m, 4 H, H4 + H7), 4.05 (br
s, 1 H, CH OH), 4.43 (d, J = 5.9 Hz, 2 H, CH CH), 5.03–5.20 (m, 2 H,
=
7
6
4
3
2
2
CH ), 5.65–5.83 (m, 1 H, CH CH), 7.29 (d, J = 8.3 Hz, 2 H, C H CH ),
2
2
6
4
3
.65 (d, J = 8.3 Hz, 2 H, C H CH ).
6
4
3
IR (KBr): 1061, 1088, 1165, 1242, 1267, 1352, 1417, 1707, 2845, 2931,
13
C NMR (75 MHz, CDCl ): δ = 21.8 (C H CH ), 22.5 and 23.3 (CH -C5 +
3
6
4
3
2
–1
3089 cm .
C6), 24.2 (CH -C4), 25.4 (CH -C7), 56.0 and 56.1 (CH OH, CH CH),
120.1 (=CH ), 128.6 and 129.8 (2 × 2CH-C H CH ), 132.3 (CH CH),
2
2
2
2
1
H NMR (300 MHz, CDCl ): δ = 1.31 (t, J = 7.1 Hz, 3 H, CH CH ), 1.70–
3
2
3
2
6
4
3
2
1
.79 (m, 4 H, H5 + H6), 2.42 (s, 3 H, C H CH ), 2.60–2.85 (m, 4 H, H4 +
133.7 (C), 134.0 (C), 134.3 (C), 135.6 (C), 140.7 (C), 144.4 (C).
6
4
3
H7), 4.11 (q, J = 7.1 Hz, 2 H, CH CH ), 4.22 (d, J = 8.3 Hz, 2 H, CH CH),
+
2
3
2
MS (EI, 70 eV): m/z (%) = 377 [M ] (20), 222 (75), 194 (100), 91 (45), 41
5
.10–5.18 (m, 2 H, =CH ), 5.80–5.95 (m, 1 H, CH CH), 7.27 (d, J = 8.3
2
2
(50).
Hz, 2 H, C H CH ), 7.65 (d, J = 8.3 Hz, 2 H, C H CH ).
6
4
3
6
4
3
1
3
C NMR (75 MHz, CDCl ): δ = 14.2 (CH CH ), 21.7 (C H CH ), 22.6 and
3
2
3
6
4
3
N-Allyl-N-[2-(hydroxymethyl)-4,5,6,7-tetrahydro-1-benzothien-3-
yl]-4-toluenesulfonamide (B4)
2
2.9 (CH -C5 + C6), 25.3 (CH -C4), 25.9 (CH -C7), 55.9 (CH CH), 60.7
2 2 2 2
(
CH CH ), 119.3 (=CH ), 128.0 and 129.6 (2 × 2CH-C H CH ), 130.7 (C),
2 3 2 6 4 3
LiAlH4 (0.52 g, 13.6 mmol, 1.1 equiv) was suspended in freshly dis-
1
1
33.0 (CH CH), 134.5 (C), 135.6 (C), 136.5 (C), 141.4 (C), 143.7 (C),
63.0 (COOEt).
2
tilled Et O (50 mL), and the mixture was cooled in an ice–salt bath to
2
0
°C. A suspension of compound B3 (5.00 g, 12.3 mmol, 1 equiv) in
+
MS (EI, 70 eV): m/z (%) = 419 [M ] (10), 264 (95), 218 (100), 91 (50).
Et O (25 mL) was added by syringe, and the mixture was stirred at
2
0
°C under an inert atmosphere for 60 min, then warmed to r.t. (1.5
Methyl 3-[Allyl(tosyl)amino]-4,5,6,7-tetrahydrobenzo[b]thio-
h). Distilled H O (10 mL) was added dropwise to decompose excess
2
phene-2-carboxylate (B3)
reducing agent. The organic phase was decanted and the pasty resi-
due was washed with Et O (3 × 10 mL). The organic fractions were
Compound B2 (5.00 g, 13.7 mmol, 1 equiv) was dissolved in acetone
2
(
60 mL). K CO (3.78 g, 27.4 mmol, 2 equiv) was added in a single por-
2 3
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

F
Synthesis
L. Tenora et al.
Paper
combined, dried (MgSO ), and concentrated in vacuo to give a color-
less oily compound; yield: 3.91 g (84%). The crude product was used
in the subsequent step without purification.
IR (KBr): 1045, 1090, 1109, 1165, 1240, 1350, 1410, 1464, 1543, 1595,
1660, 2858, 2937 cm .
4
–1
1
H NMR (300 MHz, CDCl ): δ = 1.58–1.91 (m, 4 H, H5 + H6), 2.14–2.37
3
IR (neat): 1028, 1095, 1159, 1336, 1408, 1444, 1489, 1595, 2856,
(m, 2 H, H4), 2.44 (s, 3 H, C H CH ), 2.76–2.80 (m, 2 H, H7), 4.08 (dd,
6
4
3
–1
2929, 3438, 3523 cm
.
J = 14.4, 7.0 Hz, 1 H, =CH ), 4.25 (dd, J = 14.4, 6.7 Hz, 1 H, =CH ), 5.04–
2
2
1
5.12 (m, 2 H, CH
2
CH), 5.72–5.86 (m, 1 H, CH
2
CH), 7.30 (d, J = 8.2 Hz, 2
H NMR (300 MHz, CDCl ): δ = 1.20–1.98 (m, 6 H, H4 + H5 + H6), 2.43
3
H, C H CH ), 7.60 (d, J = 8.2 Hz, 2 H, C H CH ), 9.18 (s, 1 H, HC=O).
(
(
(
(
s, 3 H, C H CH ), 2.63–2.67 (m, 2 H, H7), 3.06 (br s, 1 H, CH OH), 3.71
dd, J = 14.5, 7.8 Hz, 1 H, =CH ), 4.35 (d, J = 10.7 Hz, 1 H, CH OH), 4.43
dd, J = 14.5, 5.0 Hz, 1 H, =CH ), 4.71 (d, J = 13.0 Hz, 1 H, CH OH), 5.07
d, J = 8.0 Hz, 2 H, CH CH), 5.80 (m, 1 H, CH CH), 7.28 (d, J = 8.2 Hz, 2
6
4
3
6
4
3
6
4
3
2
13
C NMR (75 MHz, CDCl ): δ = 21.8 (C H CH ), 22.1 and 22.9 (CH -C5 +
3 6 4 3 2
2
2
C6), 24.1 (CH -C4), 26.5 (CH -C7), 54.7 (CH CH), 120.3 (=CH ), 127.5
2
2
2 2 2 2
and 130.1 (2 × 2CH-C H CH ), 132.5 (CH CH), 136.3 (C), 137.2 (C),
6 4 3 2
2
2
H, C H CH ), 7.58 (d, J = 8.2 Hz, 2 H, C H CH ).
137.4 (C), 141.7 (C), 144.5 (C), 146.9 (C), 182.1 (HC=O).
6
4
3
6
4
3
13
+
C NMR (75 MHz, CDCl ): δ = 21.7 (C H CH ), 22.4 and 23.3 (CH -C5 +
MS (EI, 70 eV): m/z (%) = 375 (M ,<5), 220 (100), 192 (40), 178 (25),
3
6
4
3
2
C6), 24.0 (CH -C4), 25.5 (CH -C7), 53.3 (CH CH), 56.8 (CH OH), 119.2
159 (15), 91 (15).
2
2
2
2
(
=CH ), 127.4 and 129.8 (2 × 2CH–C H CH ), 131.3 (C), 132.6 (C), 133.2
2
6
4
3
(
CH CH), 135.3 (C), 137.1 (C), 139.9 (C), 144.0 (C).
2
Ethyl (2R*,3aR*,10cR*)-5-Tosyl-2,3,3a,4,5,7,8,9,10,10c-decahydro-
1H-[1]benzothieno[2,3-b]pyrrolo[2,3-d]pyridine-2-carboxylates
A6a–e and Ethyl (2R*,3aR*,10bR*)-5-Tosyl-2,3,3a,4,5,6,7,8,9,10b-
decahydro-1H-[1]benzothieno[3,2-b]pyrrolo[2,3-d]pyridine-2-
carboxylates B6a–e; General Procedure
+
MS (EI, 70 eV): m/z (%) = 377 [M ] (5), 221 (45), 204 (100), 194 (65),
1
78 (10), 166 (50), 153 (45), 125 (20), 91 (35), 79 (10), 65 (15).
N-Allyl-N-(3-formyl-4,5,6,7-tetrahydro-1-benzothien-2-yl)-4-tol-
uenesulfonamide (A5)
Aldehyde A5 or B5 (200 mg, 0.53 mmol, 1 equiv) and the appropriate
secondary amine C (Ca–d; 1.07 mmol, 2 equiv; Ce; 1.32 mmol, 2.5
equiv) were mixed in a test tube and stirred in a preheated oil bath
PCC (8.56 g, 39.7 mmol, 1.5 equiv) was dissolved in CH Cl (70 mL),
and the orange mixture was stirred under argon while a solution of
compound A4 (10.0 g, 26.5 mmol, 1 equiv) in CH Cl (30 mL) was add-
2
2
(
(
160 °C) under argon while the reaction was monitored by TLC
CH Cl ). Heating was stopped when the aldehyde was consumed. The
2
2
ed by syringe over a few seconds. The solution, which became black
within a few minutes, was stirred for 2 h while the reaction was mon-
itored by TLC (CH Cl ). When the starting material was no longer de-
2
2
products were purified by column chromatography.
2
2
O
tected, the mixture was diluted with Et O (200 mL). The black solid
residue was washed with additional Et O (2 × 15 mL). The organic
phases were combined, filtered through a layer of Florisil (10 cm),
and concentrated under reduced pressure. The crude product was re-
crystallized (EtOH) to give a white solid; yield: 5.79 g (58%); mp 102–
2
R
1
O
2
9
10
2
N
H
3
8
10c
3a
H
7
4
S
103 °C.
6
5 N
Ts
IR (KBr): 1088, 1165, 1228, 1309, 1352, 1414, 1485, 1597, 1680, 2754,
–1
2837, 2941, 3089 cm
.
Figure 3 A6a–e
1
H NMR (300 MHz, CDCl ): δ = 1.70–2.00 (m, 4 H, H5 + H6), 2.46 (s, 3
3
H, C H CH ), 2.64–2.85 (m, 4 H, H4 + H7), 4.14 (d, J = 5.8 Hz, 2 H,
Ethyl (2R*,3aR*,10cR*)-1-Methyl-5-tosyl-2,3,3a,4,5,7,8,9,10,10c-
decahydro-1H-[1]benzothieno[2,3-b]pyrrolo[2,3-d]pyridine-2-
carboxylate (A6a)
6
4
3
CH CH), 5.05–5.30 (m, 2 H, =CH ), 5.70–5.90 (m, 1 H, CH CH), 7.33 (d,
2
2
2
J = 8.1 Hz, 2 H, C H CH ), 7.64 (d, J = 8.1 Hz, 2 H, C H CH ), 9.90 (s, 1 H,
6
4
3
6
4
3
HC=O).
Prepared by the general method using ethyl (methylamino)acetate
1
3
(Ca; 125 mg), and purified by column chromatography(PE–EtOAc,
C NMR (75 MHz, CDCl ): δ = 21.7 (C H CH ), 22.3 and 22.8 (CH -C5 +
3
6
4
3
2
4:1) to give a colorless crystalline solid; yield: 200 mg (79%); mp 140–
41 °C.
C6), 25.3 (CH -C4), 25.6 (CH -C7), 56.6 (CH CH), 121.0 (=CH ), 128.5
and 129.9 (2 × 2CH-C H CH ), 131.6 (CH CH) 133.9 (C), 134.0 (C),
2
2
2
2
1
6
4
3
2
1
35.8 (C), 137.7 (C), 144.8 (C), 149.3 (C), 186.1 (HC=O).
IR (KBr): 1030, 1090, 1161, 1184, 1294, 1352, 1446, 1591, 1729, 2852,
2940, 2976 cm .
–1
+
MS (EI, 70 eV): m/z (%) = 375 [M ] (<5), 220 (100), 192 (65), 178 (55),
91 (70), 41 (70).
1
H NMR (300 MHz, CDCl ): δ = 1.26 (t, J = 7.2 Hz, 3 H, CH CH ), 1.52–
3 2 3
1
.97 (m, 6 H, H8 + H9 + H3a + 1H in H3), 2.02–2.14 (m, 1 H, H3), 2.29
), 2.38 (s, 3 H, C CH ) 2.41–2.49 (m, 2 H, H10), 2.63–
2.74 (m, 2 H, H7), 3.30 (dd, J = 12.8, 11.1 Hz, 1 H, H4), 3.56 (dd, J = 8.7,
.4 Hz, 1 H, H2), 3.79 (d, J = 5.0 Hz, 1 H, H10c), 3.89 (dd, J = 12.8, 4.6
N-Allyl-N-(2-formyl-4,5,6,7-tetrahydro-1-benzothien-3-yl)-4-tol-
uenesulfonamide (B5)
(s, 3 H, NCH
3
6
H
4
3
4
Compound B4 (5.00 g, 13.2 mmol, 1 equiv) was dissolved in distilled
Hz, 1 H, H4), 4.14 (q, J = 7.2 Hz, 2 H, CH CH ), 7.23 (d, J = 8.1 Hz, 2 H,
CH Cl (35 mL), and PCC (4.28 g, 19.9 mmol, 1.5 equiv) was added in
2
3
2
2
C H CH ), 7.68 (d, J = 8.1 Hz, 2 H, C H CH ).
several portions. The dark-red mixture was stirred under argon for 2
h while the reaction was monitored by TLC (CH Cl ). When conver-
6
4
3
6
4
3
13
2
2
C NMR (75 MHz, CDCl ): δ = 14.3 (CH CH ), 21.5 (C H CH ), 22.8 and
3
2
3
6
4
3
sion was complete, Et O (100 mL) was added. The black solid residue
23.4 (C8 + C9), 24.4 and 24.9 (C7 + C10), 31.2 (C3), 34.6 (C3a), 35.8
2
in the flask was washed with Et O (2 × 10 mL), and the organic phases
(NCH ), 49.4 (C4), 55.6 (C10c), 60.2 (CH CH ), 63.5 (C2), 122.4 (C ),
2
3
2
3
Ar
were combined, filtered through Florisil (10 cm), and concentrated
under reduced pressure. The crude product was recrystallized (EtOH)
to give a colorless solid; yield: 3.38 g (68%); mp 109–110 °C.
127.2 (2 × CH-C H CH ), 127.8 (C), 129.6 (2 × CH-C H CH ), 132.5 (C),
6 4 3 6 4 3
134.9 (C), 135.2 (C), 143.9 (C), 174.0 (COOEt).
HRMS (EI): m/z [M + H]+ calcd for C24H31N O S +: 475.1725; found:
2
4 2
475.1712.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

G
Synthesis
L. Tenora et al.
Paper
Ethyl (2R*,3aR*,10cR*)-1-Ethyl-5-tosyl-2,3,3a,4,5,7,8,9,10,10c-
decahydro-1H-[1]benzothieno[2,3-b]pyrrolo[2,3-d]pyridine-2-
carboxylate (A6b)
1H NMR (300 MHz, CDCl ):
δ
=
0.69 (t,
J = 7.2 Hz, 3 H,
3
NCH CH CH CH ), 0.88–1.10 (m, 2 H, NCH CH CH CH ), 1.10–1.21 (m,
2
2
2
3
2
2
2
3
2 H, NCH CH CH CH ), 1.25 (t, J = 7.1 Hz, 3 H, CH CH ), 1.56–1.94 (m,
2
2
2
3
2
3
6
H, H8 + H9 + H3a + 1H in H3), 2.00–2.11 (m, 1 H, H3), 2.38 (s, 3 H,
Prepared by the general method using ethyl (ethylamino)acetate (Cb;
C H CH ) 2.38–2.58 (m, 4 H, H10 + NCH CH CH CH ), 2.68 (t, J = 5.9
140 mg), and purified by column chromatography (PE–EtOAc, 4:1) to
6
4
3
2
2
2
3
Hz, 2 H, H7), 3.20 (dd, J = 12.3, 10.0 Hz, 1 H, 1H in H4), 3.67 (dd, J = 9.0,
.2 Hz, 1 H, H2), 3.86 (d, J = 4.3 Hz, 1 H, H10c), 3.88 (dd, J = 11.0, 4.7
give a colorless crystalline solid; yield: 234 mg (91%); mp 111–113 °C.
4
IR (KBr): 1026, 1092, 1167, 1354, 1448, 1495, 1726, 2848, 2933 cm–1
.
Hz, 1 H, 1H in H4), 4.13 (dq, J = 7.1, 1.6 Hz, 2 H, CH CH ), 7.24 (d, J =
8.3 Hz, 2 H, C H CH ), 7.70 (d, J = 8.3 Hz, 2 H, C H CH ).
2
3
1
H NMR (300 MHz, CDCl ): δ = 0.84 (t, J = 7.1 Hz, 3 H, NCH CH ), 1.25
3
2
3
6
4
3
6
4
3
(
t, J = 7.1 Hz, 3 H, CH CH ), 1.54–1.96 (m, 6 H, H8 + H9 + H3a + 1H
2 3
13
C NMR (75 MHz, CDCl ): δ = 13.7 (NCH CH CH CH ), 14.3 (CH CH ),
3
2
2
2
3
2
3
in H3), 2.00–2.11 (m, 1 H, H3), 2.38 (s, 3 H, C H CH ), 2.40–2.46 (m, 2
6
4
3
20.1 (NCH CH CH CH ), 21.5 (C H CH ), 22.7 and 23.5 (C8 + C9), 24.3
2 2 2 3 6 4 3
H, H10), 2.47–2.61 (m, 2 H, NCH CH ), 2.68 (td, J = 5.4, 2.9 Hz, 2 H,
2
3
and 24.8 (C7 + C10), 30.6 (NCH CH CH CH ), 31.0 (C3), 34.3 (C3a),
2
2
2
3
H7), 3.27 (dd, J = 12.6, 11.3 Hz, 1 H, H4), 3.71 (dd, J = 9.1, 3.9 Hz, 1 H,
H2), 3.86 (d, J = 4.7 Hz, 1 H, H10c), 3.88 (dd, J = 12.6, 4.6 Hz, 1 H, H4),
47.3 (NCH CH CH CH ), 49.0 (C4), 55.4 (C10c), 59.3 (C2), 60.1
2 2 2 3
(
CH CH ), 122.1 (C), 127.3 (2 × CH–C H CH ), 127.5 (C), 129.6 (2 × CH–
2
3
6
4
3
4
.13 (dq, J = 7.1, 2.1 Hz, 2 H, CH CH ), 7.23 (d, J = 8.2 Hz, 2 H, C H CH ),
2
3
6
4
3
C H CH ), 132.7 (C), 134.6 (C), 134.8 (C), 143.9 (C), 174.4 (COOEt).
6
4
3
7
.69 (d, J = 8.2 Hz, 2 H, C H CH ).
6
4
3
HRMS (EI): m/z [M + H]+ calcd for C27H37N O S2+: 517.2195; found:
13
2
4
C NMR (75 MHz, CDCl ): δ = 14.1 (NCH CH ), 14.3 (CH CH ),
3
2
3
2
3
517.2192.
2
1.5(C H CH ), 22.7 and 23.5 (C8 + C9), 24.4 and 24.8 (C7 + C10), 31.0
6 4 3
(
6
C3), 34.3 (C3a), 42.2 (NCH CH ), 49.3 (C4), 55.6 (C10c), 59.3 (C2),
2 3
Ethyl (2R*,3aR*,10cR*)-1-Isopropyl-5-tosyl-2,3,3a,4,5,7,8,9,10,10c-
decahydro-1H-[1]benzothieno[2,3-b]pyrrolo[2,3-d]pyridine-2-
carboxylate (A6e)
0.1 (CH CH ), 122.5 (C), 127.3 (2 × CH–C H CH ), 127.7 (C), 129.6 (2 ×
2
3
6
4
3
CH–C H CH ), 132.7 (C), 134.9 (C), 135.0 (C), 143.9 (C), 174.3 (COOEt).
HRMS (EI): m/z [M + H]+ calcd for C25H33N O S2+: 489.1882; found:
4
6
4
3
2
4
Prepared by the general method using ethyl (isopropylamino)acetate
89.1873.
(
Ce; 194 mg), and purified by column chromatography (PE–EtOAc,
4
1
:1) to give a yellowish crystalline solid; yield: 201 mg (75%); mp
02–104 °C.
Ethyl (2R*,3aR*,10cR*)-1-Benzyl-5-tosyl-2,3,3a,4,5,7,8,9,10,10c-
decahydro-1H-[1]benzothieno[2,3-b]pyrrolo[2,3-d]pyridine-2-
carboxylate (A6c)
IR (KBr): 1005, 1030, 1088, 1167, 1282, 1354, 1448, 1500, 1597, 1732,
–1
2866, 2933 cm .
Prepared by the general method using ethyl (benzylamino)acetate
1
H NMR (300 MHz, CDCl ): δ = 0.60 (d, J = 6.6 Hz, 3 H, NCH(CH ) ),
(
Cc; 206 mg), and purified by column chromatography (PE–EtOAc,
3
3 2
0
1
2
.93 (d, J = 6.6 Hz, 3 H, NCH(CH ) ), 1.26 (t, J = 7.1 Hz, 3 H, CH CH ),
.60–2.09 (m, 7 H, H8 + H9 + H3a + H3), 2.38 (s, 3 H, C H CH ) 2.40–
.55 (m, 2 H, H10), 2.65–2.73 (m, 2 H, H7), 2.99 [sept, J = 6.6 Hz, 1 H,
4
1
:1) to give a colorless crystalline solid; yield: 258 mg (88%); mp 128–
29 °C.
3
2
2
3
6
4
3
IR (KBr): 1005, 1025, 1088, 1124, 1167, 1294, 1354, 1450, 1498, 1595,
NCH(CH ) ], 3.16 (dd, J = 12.3, 10.0 Hz, 1 H, 1H in H4), 3.75 (dd, J =
–1
3 2
1
724, 2845, 2933 cm .
22.6, 3.9 Hz, 1 H, 1H in H4), 3.75 (dd, J = 4.4, 1.8 Hz, 1 H, H2), 4.11 (q,
1
H NMR (300 MHz, CDCl ): δ = 1.19 (t, J = 7.1 Hz, 3 H, CH CH ), 1.64–
3
2
3
J = 7.1 Hz, 2 H, CH CH ), 4.21 (d, J = 4.5 Hz, 1 H, H10c), 7.24 (d, J = 8.2
Hz, 2 H, C H CH ), 7.73 (d, J = 8.2 Hz, 2 H, C H CH ).
6 4 3 6 4 3
2
3
2
.09 (m, 7 H, H8 + H9 + H3a + H3), 2.44 (s, 3 H, C H CH ) 2.45–2.55 (m,
6 4 3
2
H, H10), 2.62–2.73 (m, 2 H, H7), 3.28 (dd, J = 12.3, 10.0 Hz, 1 H, 1H in
13
C NMR (75 MHz, CDCl ): δ = 14.3 (CH CH ), 21.1 [NCH(CH ) ], 21.8
3
2
3
3 2
H4), 3.35 (dd, J = 9.3, 3.9 Hz, 1 H, H2), 3.73 (d, J = 2.7 Hz, 2 H,
NCH C H ), 3.97 (dd, J = 12.1, 4.4 Hz, 1 H, 1H in H4), 4.04–4.11 (m, 3 H,
(C H CH ), 22.9 and 23.7 (C8 + C9), 24.6 and 24.8 (C7 + C10), 32.4 (C3),
6 4 3
2
6
5
35.5 (C3a), 46.1 [NCH(CH ) ], 49.1 (C4), 54.6 (C10c), 56.1 (C2), 60.5
3 2
H10c, CH CH ), 6.84–6.93 (m, 2 H, NCH C H ), 7.10–7.18 (m, 3 H,
2
3
2
6
5
(
CH CH ), 123.3 (C), 127.5 (2 × CH–C H CH ), 128.0 (C), 129.8 (2 × CH–
2
3
6
4
3
NCH C H ) 7.29 (d, J = 8.2 Hz, 2 H, C H CH ), 7.77 (d, J = 8.2 Hz, 2 H,
2
6
5
6
4
3
C H CH ), 133.1 (C), 134.8 (C), 135.1 (C), 144.1 (C), 177.8 (COOEt).
6
4
3
C H CH ).
6
4
3
HRMS (EI): m/z [M + H]+ calcd for C26H35N O S2+: 503.2038; found:
13
2
4
C NMR (75 MHz, CDCl ): δ = 14.4 (CH CH ), 21.8 (C H CH ), 22.9 and
3
2
3
6
4
3
503.2039.
23.6 (C8 + C9), 24.5 and 24.9 (C7 + C10), 31.4 (C3), 34.5 (C3a), 49.1
(
1
1
C4), 51.8 (NCH C H ), 55.4 (C10c), 58.7 (C2), 60.3 (CH CH ), 121.7 (C),
27.0 (CH-NCH C H ), 127.7 (2 × CH–C H CH ), 128.0 (C), 128.2 and
2 6 5 6 4 3
2
6
5
2
3
7
9
6
Ts
N
5
28.4 (2 × 2 CH–NCH C H ), 129.9 (2 × CH–C H CH ), 132.8 (C), 134.6
8
4
2
6
5
6
4
3
(C), 135.4 (C), 139.4 (C), 144.2 (C), 174.3 (COOEt).
H
10b
3a
HRMS (EI): m/z [M + H]+ calcd for C30H35N O S2+: 551.2038; found:
5
10 S
2
4
3
H
51.2055.
N
2
R 1
O
Ethyl (2R*,3aR*,10cR*)-1-Butyl-5-tosyl-2,3,3a,4,5,7,8,9,10,10c-
decahydro-1H-[1]benzothieno[2,3-b]pyrrolo[2,3-d]pyridine-2-
carboxylate (A6d)
O
Figure 4 B6a–e
Prepared by the general method using ethyl (butylamino)acetate (Cd;
Ethyl (2R*,3aR*,10bR*)-1-Methyl-5-tosyl-2,3,3a,4,5,6,7,8,9,10b-
decahydro-1H-[1]benzothieno[3,2-b]pyrrolo[2,3-d]pyridine-2-
carboxylate (B6a)
170 mg), and purified by column chromatography (PE–EtOAc, 4:1) to
give a colorless crystalline solid; yield: 237 mg (86%); mp 71–73 °C.
IR (KBr): 1011, 1028, 1090, 1165, 1292, 1356, 1450, 1498, 1726, 2860,
Prepared by the general method using ethyl (methylamino)acetate
–1
2929 cm .
(
Ca; 125 mg), and purified by column chromatography (PE–EtOAc,
6
1
:1) to give a yellowish crystalline solid; yield: 172 mg (68%); mp
32–134 °C.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

H
Synthesis
L. Tenora et al.
Paper
1
3
IR (KBr): 1030, 1092, 1167, 1261, 1335, 1352, 1448, 1599, 1728, 2798,
C NMR (75 MHz, CDCl ): δ = 14.5 (CH CH ), 21.8 (C H CH ), 22.9 and
3
2
3
6
4
3
2
812, 2858, 2937, 2985 cm–1
.
23.6 (C7 + C8), 25.4 and 25.7 (C6 + C9), 34.0 (C3), 36.7 (C3a), 52.2 (C4),
54.1 (NCH ), 58.1 (C10b), 60.2 (CH CH ), 61.9 (C2), 127.4 (CH–
NCH C H ), 127.9 (2 × CH–C H CH ), 128.4 and 128.9 (2 × 2 CH–
NCH C H ), 129.8 (2 × CH–C H CH ), 132.2 (C), 132.5 (C), 133.2 (C),
1
1
2
C
6
H
5
2
3
H NMR (300 MHz, CDCl ): δ = 1.24 (t, J = 7.1 Hz, 3 H, CH CH ), 1.47–
3
2
3
1
.60 and 1.76–2.07 (m, 6 H, H7 + H8 + H3), 2.44 (s, 3 H, C H CH ), 2.56
2
6
5
6
4
3
6
4
3
(
s, 3 H, NCH ), 2.65–3.01 (m, 6 H, H6 + H9 + H2 + H3a + 1H in H4), 3.27
2
6
5
6
4
3
3
33.3 (C), 136.6 (C), 138.7 (C), 144.1 (C), 173.4 (COOEt).
(d, J = 8.7 Hz, 1 H, H10b), 3.65 (d, J = 7.9 Hz, 1 H, H2), 4.07 (dd, J = 6.1,
+
1
2.7 Hz, 1 H, 1H in H4), 4.11 (q, J = 7.0 Hz, 2 H, CH CH ), 7.24 (d, J = 8.0
MS: m/z (%) = 551 (M , <5), 477 (75), 395 (10), 322 (15), 321 (55), 231
2
3
Hz, 2 H, C H CH ), 7.53 (d, J = 8.0 Hz, 2 H, C H CH ).
(30), 190 (10), 91 (100).
6
4
3
6
4
3
13
HRMS (EI): m/z [M + H]+ calcd for C30H35N O S2+: 551.2038; found:
C NMR (75 MHz, CDCl ): δ = 14.6 (CH CH ), 21.8 (C H CH ), 23.0 and
3
2
3
6
4
3
2
4
2
3.6 (C7 + C8), 25.6 and 25.7 (C6 + C9), 33.1 (C3), 35.9 (NCH ), 37.2
551.2033.
3
(
C3a), 52.0 (C4), 58.8 (C10b), 60.3 (CH CH ), 66.4 (C2), 127.9 and
2 3
1
29.8 (2 × 2CH–C H CH ), 130.1 (C), 132.5 (C), 133.4 (C), 133.5 (C),
6 4 3
Ethyl (2R*,3aR*,10bR*)-1-Butyl-5-tosyl-2,3,3a,4,5,6,7,8,9,10b-deca-
hydro-1H-[1]benzothieno[3,2-b]pyrrolo[2,3-d]pyridine-2-carbox-
ylate (B6d)
136.7 (C), 144.0 (C), 173.3 (COOEt).
+
MS: m/z (%) = 474 (M , <5), 401 (80), 319 (10), 245 (100), 231 (10),
1
90 (15), 91 (15), 57 (15).
Prepared by the general method using ethyl (butylamino)acetate (Cd;
170 mg), and purified by column chromatography (PE–EtOAc, 5:1) to
give a yellowish crystalline solid; yield: 228 mg (83%); mp 136–
HRMS (EI): m/z [M + H]+ calcd for C24H31N O S +: 475.1725; found:
2
4 2
475.1741.
138 °C.
Ethyl (2R*,3aR*,10bR*)-1-Ethyl-5-tosyl-2,3,3a,4,5,6,7,8,9,10b-deca-
hydro-1H-[1]benzothieno[3,2-b]pyrrolo[2,3-d]pyridine-2-carbox-
ylate (B6b)
IR (KBr): 1034, 1092, 1120, 1167, 1313, 1338, 1352, 1446, 1597, 1732,
–1
2858, 2933, 2958, 2980 cm
.
1H NMR (300 MHz, CDCl ):
δ
=
0.90 (t,
J = 7.0 Hz, 3 H,
3
Prepared by the general method using ethyl (ethylamino)acetate (Cb;
NCH CH CH CH ), 1.21 (t, J = 7.1 Hz, 3 H, CH CH ), 1.25–1.69 and
2
2
2
3
2
3
140 mg), and purified by column chromatography (PE–EtOAc, 5:1) to
1.74–2.00 (m, 10 H, H7 + H8 + H3 + NCH CH CH CH + NCH CH CH -
2 2 2 3 2 2 2
give a colorless crystalline solid; yield: 200 mg (77%); mp 147–149 °C.
CH ), 2.42 (s, 3 H, C H CH ), 2.44–3.05 (m, 8 H, H6 + H9 + H3a + 1H in
3
6
4
3
IR (KBr): 1028, 1099, 1169, 1342, 1450, 1599, 1730, 2846, 2945 cm–1
H4 + NCH
2
CH
2
CH
2
CH ), 3.18 (d, J = 9.2 Hz, 1 H, H10b), 3.76 (d, J = 7.7
3
.
Hz, 1 H, H2), 4.03–4.16 (m, 3 H, 1H in H4 + CH CH ), 7.24 (d, J = 8.2 Hz,
2
3
1
H NMR (300 MHz, CDCl ): δ = 1.08 (t, J = 7.2 Hz, 3 H, NCH CH ), 1.21
3
2
3
2
H, C H CH ), 7.54 (d, J = 8.2 Hz, 2 H, C H CH ).
6
4
3
6
4
3
(
t, J = 7.1 Hz, 3 H, CH CH ), 1.41–1.58 and 1.73–2.00 (m, 6 H, H7 + H8 +
2 3
13
C NMR (75 MHz, CDCl ): δ = 14.2 (NCH CH CH CH ), 14.6 (CH CH ),
H3), 2.42 (s, 3 H, C H CH ), 2.44–2.96 (m, 7 H, H6 + H9 + 1H in
3
2
2
2
3
2
3
6
4
3
2
0.8 (NCH CH CH CH ), 21.7 (C H CH ), 23.0 and 23.6 (C7 + C8), 25.3
NCH CH + H3a + 1H in H4), 3.11 (dd, J = 12.5, 7.5 Hz, 1 H, NCH CH ),
2 2 2 3 6 4 3
2
3
2
3
and 25.7 (C6 + C9), 30.8 (NCH CH CH CH ), 33.8 (C3), 36.3 (C3a), 50.3
3.20 (d, J = 9.2 Hz, 1 H, H10b), 3.80 (d, J = 7.7 Hz, 1 H, H2), 4.03–4.14
2
2
2
3
(
NCH CH CH CH ), 52.2 (C4), 58.6 (C10b), 60.2 (CH CH ), 62.5 (C2),
(
m, 3 H, 1H in H4 + CH CH ), 7.24 (d, J = 8.2 Hz, 2 H, C H CH ), 7.54 (d,
2
2
2
3
2
3
2
3
6
4
3
1
1
27.9 and 129.7 (2 × 2CH–C H CH ), 132.0 (C), 132.5 (C), 133.1 (C),
6 4 3
33.3 (C), 136.6 (C), 144.0 (C), 173.5 (COOEt).
J = 8.2 Hz, 2 H, C H CH ).
6
4
3
13
C NMR (75 MHz, CDCl ): δ = 13.8 (NCH CH ), 14.6 (CH CH ), 21.8
3
2
3
2
3
+
MS: m/z (%) = 516 (M ,<5), 443 (100), 361 (10), 287 (80), 231 (20), 190
(
C H CH ), 22.9 and 23.6 (C7 + C8), 25.3 and 25.7 (C6 + C9), 33.7 (C3),
6 4 3
(15), 91 (10).
3
6.2 (C3a), 44.6 (NCH CH ), 52.2 (C4), 58.4 (C10b), 60.2 (CH CH ), 62.1
2
3
2
3
(
C2), 127.9 and 129.7 (2 × 2CH–C H CH ), 131.8 (C), 132.5 (C), 133.2
HRMS (EI): m/z [M + H]+ calcd for C27H37N O S2+: 517.2195; found:
6 4 3
2
4
(C), 133.3 (C), 136.5 (C), 144.0 (C), 173.4 (COOEt).
517.2176.
+
MS: m/z (%) = 488 (M , <5), 411 (99), 333 (10), 259 (100), 231 (15),
190 (10), 91 (10), 56 (10).
Ethyl (2R*,3aR*,10bR*)-1-Isopropyl-5-tosyl-2,3,3a,4,5,6,7,8,9,10b-
decahydro-1H-[1]benzothieno[3,2-b]pyrrolo[2,3-d]pyridine-2-
carboxylate (B6e)
HRMS (EI): m/z [M + H]+ calcd for C25H33N O S +: 489.1882; found:
2
4 2
489.1876.
Prepared by the general method using ethyl (isopropylamino)acetate
(
6
1
Ce; 155 mg), and purified by column chromatography (PE–EtOAc,
:1) to give a yellow crystalline solid; yield: 198 mg (74%); mp 144–
46 °C.
Ethyl (2R*,3aR*,10bR*)-1-Benzyl-5-tosyl-2,3,3a,4,5,6,7,8,9,10b-
decahydro-1H-[1]benzothieno[3,2-b]pyrrolo[2,3-d]pyridine-2-
carboxylate (B6c)
IR (KBr): 1030, 1092, 1165, 1360, 1456, 1599, 1730, 2852, 2929, 2976
Prepared by the general method using ethyl (benzylamino)acetate
–1
cm
.
(
Cc; 206 mg), and purified by column chromatography (PE–EtOAc,
1
1
1
2:1) to give a colorless crystalline solid; yield: 205 mg (70%); mp
68–170 °C.
H NMR (300 MHz, CDCl ): δ = 0.89 [d, J = 6.6 Hz, 3 H, NCH(CH ) ],
3 3 2
1.08 [d, J = 6.6 Hz, 3 H, NCH(CH ) ], 1.26 (t, J = 7.1 Hz, 3 H, CH CH ),
3
2
2
3
IR (KBr): 1028, 1088, 1165, 1344, 1448, 1604, 1728, 2850, 2935 cm–1
1.33–1.58 and 1.78–1.94 (m, 6 H, H7 + H8 + H3), 2.42 (s, 3 H,
.
C H CH ), 2.50–2.92 (m, 6 H, H6 + H9 + H3a + 1H in H4), 3.12 (d, J = 7.8
6
4
3
1
H NMR (300 MHz, CDCl ): δ = 1.19 (t, J = 7.1 Hz, 3 H, CH CH ), 1.36–
3
2
3
Hz, 1 H, H10b), 3.36 [d, J = 6.4 Hz, 1 H, NCH(CH ) ], 3.75 (d, J = 7.5 Hz,
3
2
1
.66 and 1.74–2.02 (m, 6 H, H7 + H8 + H3), 2.45 (s, 3 H, C H CH ),
6 4 3
1
H, H2), 4.01–4.20 (m, 3 H, 1H in H4 + CH CH ), 7.25 (d, J = 8.2 Hz, 2
2 3
2.51–3.02 (m, 6 H, H6 + H9 + H3a + 1H in H4), 3.40–3.45 (m, 2 H, H2,
H, C H CH ), 7.57 (d, J = 8.2 Hz, 2 H, C H CH ).
6
4
3
6
4
3
H10b), 3.61 (d, J = 13.6 Hz, 1 H, NCH C H ), 4.01–4.16 (m, 3 H, 1H in
2
6
5
13
C NMR (75 MHz, CDCl ): δ = 14.3 (CH CH ), 18.4 [NCH(CH ) ], 21.7
H4 + CH CH ), 4.34 (d, J = 13.6 Hz, 1 H, NCH C H ), 7.17–7.30 (m, 7 H,
3
2
3
3 2
2
3
2
6
5
(
C H CH ), 22.3 [NCH(CH ) ], 22.9 and 23.6 (C7 + C8), 25.1 and 25.7
C H CH , NCH C H ), 7.57 (d, J = 8.3 Hz, 2 H, C H CH ).
6 4 3 3 2
6
4
3
2
6
5
6
4
3
(
C6 + C9), 34.9 (C3), 37.8 (C3a), 48.5 [NCH(CH ) ], 51.7 (C4), 55.0
3
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

I
Synthesis
L. Tenora et al.
Paper
(
1
C10b), 60.5 (2C, C2 + CH CH ), 127.9 and 129.7 (2 × 2CH–C H CH ),
32.7 (C), 132.9 (C), 133.3 (C), 133.7 (C), 136.6 (C), 144.0 (C), 175.8
(6) Gryshenko, A. A.; Bdzhola, V. G.; Balanda, A. O.; Briukhovetska,
N. V.; Kotey, I. M.; Golub, A. G.; Ruban, T. P.; Lukash, L. L.;
Yarmoluk, S. M. Bioorg. Med. Chem. 2015, 23, 2287.
(7) Ye, F.; Chen, D.; Yu, S.; Wang, Y.; Wang, Y.; Chen, L.; Song, X.;
Xie, Z.; Liang, G.; Li, X.; Liu, Z.; Lin, D. CN 105017277, 2015.
2
3
6
4
3
(
COOEt).
MS: m/z (%) = 502 (M , <5), 429 (100), 273 (95), 231 (55), 203 (10),
90 (15), 91 (25), 70 (25).
HRMS (EI): m/z [M + H]+ calcd for C26H35N O S2+: 503.2038; found:
+
1
(
8) Edwards, J. P.; Neff, D. K.; Smith, D. M.; Venable, J. D. US
0090075970, 2009; Chem. Abstr. 2009, 150, 329838
2
4
2
5
03.2033.
(9) Butini, S.; Fattorusso, C.; Gemma, S.; Sanna Coccone, S.;
Borriello, M. WO 2008031888, 2008.
(
10) (a) Kim, B.-K.; Lee, S.-S.; Shin, C.-J.; Jung, S.-H.; Kwon, O.-H.;
Kim, Y.-K.; Kim, C.-W.; Kim, H.-S.; Seo, J.-H.; Yu, E.-S.; Choi, B. K.;
Hwang, K. Y. WO 2015105313, 2015. (b) Kim, B.-K.; Jung, H.-K.;
Han, S.-J.; Kwon, O.-H.; Kim, Y.-K.; Kim, C.-W.; Kim, H.-S.; Seo, J.-
H.; Shin, C.-J.; Yu, E.-S.; Choi, B. K.; Hwang, K. Y. WO
Acknowledgment
The authors are grateful to Masaryk University for its institutional
support of this research. Our thanks also go to Marek Nečas for help
with the X-ray crystal structure analysis of the prepared compounds.
2015105315, 2016.
(
11) (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Vol. 1;
Padwa, A., Ed.; Wiley: New York, 1984. (b) Padwa, A. Angew.
Chem., Int. Ed. Engl. 1976, 15, 123. (c) Harwood, L.; Vickers, R. J.
In Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products.; Padwa, A.; Pearson,
W. H., Eds.; Wiley: New York, 2003, Chap. 3, 169.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561428.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(
(
(
(
(
(
12) Pospíšil, J.; Potáček, M. Eur. J. Org. Chem. 2004, 710.
13) Pospíšil, J.; Potáček, M. Tetrahedron 2007, 63, 337.
14) Pospíšil, J.; Potáček, M. Heterocycles 2004, 63, 1165.
15) Neuschl, M.; Bogdal, D.; Potáček, M. Molecules 2007, 12, 49.
16) Gewald, K.; Schinke, E.; Böttcher, H. Chem. Ber. 1966, 99, 94.
17) Tenora, L.; Buchlovič, M.; Man, S.; Potáček, M. Tetrahedron Lett.
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(
(
(
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20) CCDC 1436220 (A6b), 1436221 (A6c), 1436222 (B6b), and
1
436223 (B6c) contain the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
21) SHELXTL, Version 5.10; Bruker AXS: Madison (WI, USA), 1997.
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(
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I