Benzo[b]thiophen-3(2H)-one 1,1-dioxide-a versatile reagent in the synthesis of spiroheterocycles

Article abstract of DOI:10.1016/j.tet.2008.07.112

New applications of benzo[b]thiophen-3(2H)-one 1,1-dioxide have been investigated. The synthesis of a new heterocyclic system 3H,2′H-spiro[benzo[b]thieno[3,2-b]pyridine-3,2′-benzo[b]thiophene] is described and a mechanism for the cyclisation is proposed.

Full text of DOI:10.1016/j.tet.2008.07.112

Tetrahedron 64 (2008) 9947–9952
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Tetrahedron
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Benzo[b]thiophen-3(2H)-one 1,1-dioxideda versatile reagent in the synthesis
of spiroheterocycles
*
Brigita Cekavicus , Brigita Vigante, Edvards Liepinsh, Reinis Vilskersts, Arkadij Sobolev, Sergey Belyakov,
Aiva Plotniece, Kristaps Mekss, Gunars Duburs
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 May 2008
Received in revised form 16 July 2008
Accepted 31 July 2008
Available online 6 August 2008
New applications of benzo[b]thiophen-3(2H)-one 1,1-dioxide have been investigated. The synthesis of
a new heterocyclic system 3H,20H-spiro[benzo[b]thieno[3,2-b]pyridine-3,20-benzo[b]thiophene] is de-
scribed and a mechanism for the cyclisation is proposed.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Several synthetic methods for obtaining tetrahydropyridines
with geminal substituents have been already reported. Thus, under
Hantzsch reaction conditions an ester of p-nitrobenzoylacetic acid
with hexamethylenetetramine and ammonium acetate forms
a derivative of 3,3,5-tricarbonyl-1,2,3,4-tetrahydropyridine with
geminal substituents at position 3, instead of the corresponding
1,4-dihydropyridine derivative.1 Alternatively, the condensation of
ethyl benzoylacetate with 1,3,5-trimethylhexahydro-1,3,5-triazine
gives a tetrahydropyridine with geminal substituents at position 5
of the 1,4,5,6-tetrahydropyridine ring.2
The main task of our studies was to identify reaction conditions
directing the cyclisation of benzo[b]thiophen-3(2H)-one 1,1-di-
oxide
1 into the new sulfonyl group containing spirocyclic
heterocycles.
Benzo[b]thiophen-3(2H)-one 1,1-dioxide7 1 is a versatile re-
agent containing a sulfonyl group for the synthesis of polycyclic
pyridines. Previously, we have found that the compound 1, like 1,3-
indandione, undergoes cyclisation to 1,4-dihydrobenzothieno-[3,2-
b]-pyridine-5,5-dioxides.8 Compound 1 with aromatic aldehydes
easily forms 2-ylidene derivatives 6.9
Only a few types of spiroderivatives of fused tetrahydropyr-
idines have been previously synthesised. The cyclic b-diketone, 1,3-
1,5-Dicarbonyl derivatives 2 were obtained in the reaction of
compound 1 with aromatic aldehydes in ethanol/DMF mixture in
the presence of catalytic piperidine and acetic acid at reflux tem-
perature in 2 h (Scheme 1). In the case of 2a, the crystals obtained
from the reaction mixture were suitable for X-ray analysis.
We examined the internal Mannich reaction approach to gen-
erate 3,20-spiroderivatives 3 from 1,5-dicarbonyl derivatives 2.
Previously, the formation of spirocyclic derivatives was achieved
only from 3-aminocyclohex-2-enones5 and 1,3-indandiones.3 This
study disclosed the ability of aryl substituted 1,5-dicarbonyl com-
pounds 2a–c to undergo cyclisation into spirocycles 3a–c. The
condensation of derivatives 2a–c with hexamethylenetetramine in
acidic medium leads to the expected new heterocyclic spirosystems
3a–c, which might reasonably arise from an internal Mannich re-
action of compounds 2a–c due to the steric hindrance of the aryl
substituent. NMR spectroscopic studies have shown the existence
of chiral stereomers and meso forms of 1,5-dicarbonyl compounds
2a–c in the approximate ratio 2:1.
indandione, with formaldehyde and primary amines readily forms
2-spiroindan-1,3-diones.3 N-Monosubstituted 3-aminoindene-1-
ones with formaldehyde and free secondary amines also afford
spirocyclic indenopyridine derivatives instead of the expected bi-
cyclic Mannich products.4 The formation of spirocyclic derivatives
from 3-aminocyclohex-2-enones with formaldehyde was in-
vestigated in detail and a reaction mechanism was proposed.5,6 The
gem-dimethyl groups of the dimedone derivative directed the re-
action to give exclusively the spirocyclic compound formed by an
internal Mannich reaction. In the case of unsubstituted cyclo-
hexanedione enaminones mixtures of spirocyclic compounds and
acridinedione derivatives were formed.
Herein, we describe the synthesis of a novel heterocyclic
system 3H,20H-spiro[benzo[b]thieno[3,2-b]pyridine-3,20-benzo[b]-
thiophene] from a
one 1,1-dioxide.
b-diketone analoguedbenzo[b]thiophen-3(2H)-
Investigation of the reaction course has demonstrated that the
reactivity of stereoisomers of 1,5-dicarbonyl derivatives 2a–c was
not affected by its configurational structure, since compounds 2a–c
rapidly disappeared from the reaction mixture. The putative
* Corresponding author. Tel.: þ371 67014928; fax: þ371 67550338.
E-mail address: arkady@osi.lv (B. Cekavicus).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.112

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B. Cekavicus et al. / Tetrahedron 64 (2008) 9947–9952
Scheme 1. Formation of 3,20-spirocycles 3a–c and dihydrodibenzothienopyridines 4a–
c from 1,5-dicarbonyl compounds 2a–c. Reagents and conditions: (a) RCHO, EtOH/DMF,
rt or reflux; (b) hexamethylenetetramine (HMTA), AcOH/DMF; (c) AcONH4, AcOH, re-
flux; (d) RCHO, AcONH4, AcOH, reflux; (e) 1,3,5-trimethylhexahydro-1,3,5-triazine,
AcOH, reflux; (f) MeI/NaH or Me2SO4/NaH; (g) RCHO, AcONH4, EtOH/AcOH, rt.
Scheme 2. Proposed mechanism for the formation of 3,20-spirocycles 3a–c from 1,5-
dicarbonyl compounds 2a–c and hexamethylenetetramine via internal Mannich
reaction.
mechanism of formation of spirocyclic derivatives from 3-amino-
cyclohex-2-enones with formaldehyde was proposed by Greenhill
et al.5,6 According to the authors the 3,20-spirocyclic compounds
might reasonably arise from an internal Mannich reaction. Possible
mechanism for the cyclocondensation of 1,5-dicarbonyl com-
pounds 2a–c and hexamethylenetetramine is shown in Scheme 2.
The unstable Mannich intermediate A gives the target spiro-
cycles 3a–c. On the other hand, compounds 2a–c in reaction with
ammonium acetate form the intermediate B. The intramolecular
addition of amino group to the carbonyl group (intermediate B)
furnishes dihydrodibenzothienopyridines 4a–c via Hantzsch type
cyclisation. Ring-opening–ring-closure rearrangements were pre-
viously described for transformation of 3,3,5-tricarbonyl-1,2,3,4-
tetrahydropyridines into pyridine derivatives with loss of formal-
dehyde.1 3,20-Spirocyclic derivatives were not rearranged to
compounds 4a–c in acidic media.
Alkylation of compound 3b required rather drastic conditions,
such as MeI/NaH and Me2SO4/NaH. Using this method, only a mix-
ture of alkylated and N–H products was obtained, where the
alkylated product 5b was the minor compound. The approach was
found to be inefficient for the preparation of N-alkylated
derivatives 5 via alkylation of 3,20-spirocycles 3. To avoid tedious
purification work, a better approach to N-alkylated derivative 5b
was developed, which involved condensation of 1,5-dicarbonyl
compound 2b and 1,3,5-trimethylhexahydro-1,3,5-triazine in acetic
acid.
The reaction of the compound 1 with aromatic aldehydes and
ammonium acetate in acetic acid under reflux led to dihy-
drodibenzothienopyridines 4a–c, alternatively, compounds 4a–c
can be obtained from 1,5-dicarbonyl derivatives 2a–c under similar
reaction conditions.
When reaction of compound 1 with 2-methoxybenzaldehyde
and ammonium acetate was performed in a mixture of ethanol and
acetic acid at rt only 2-arylidenebenzothiophene derivative 6b was
obtained instead of the expected product 4b.
Compound 2a consists of 2 diastereomers of meso typedsym-
metrical (achiral) one with C2 and C20 configurations equal (RR and
SS) and chiral one with C2 and C20 configurations different (RS and
SR). Both diastereomers give distinctly different 1H spectra (see
Section 4.2.1). Averaged coupling constant 3JH2–PhCHz7 Hz value in
achiral diastereomer probably indicates free rotation around C2–
3
PhCH bond. On contrary very distinct values of both JH2–PhCH and
3
0
JPhCH–H2 couplings points to serious sterical problems in the chiral
diastereomer 2a and rotations around C2–PhCH as well as around
PhCH–C20 are hindered.
The compound 2a gives salts due to moveable enol hydrogens
(Scheme 3). For the piperidinium salt of 2a, monocrystals were
obtained. X-ray structure analysis of the crystals shows the
formation of 2a anion and hindered rotation occurs in this case.

B. Cekavicus et al. / Tetrahedron 64 (2008) 9947–9952
9949
The X-ray structure of 2a is given in Supplementary data, as the
dimethylformamide solvate of 2a piperidinium salt.
O
S
O
S
O
O
H
O O
2a
Figure 2. The molecular structure of 5b.
O
O
O
O
S
S
H
unconventional NOEs between (a) OCH3 and H40, and (b) H600 and
H2a (Fig. 1) that together with the long range coupling JH4–
4
HO OH
¼1.5 Hz allowed to define the pseudoaxial stereo orientation of
H2e
aromatic ring in position 4 of tetrahydropyridine ring. The relative
orientation of 30-CO and 10-SO2 substituents in position 3 were
tentatively assigned on the basis that there were no strong HMBC
cross peaks between H2e and H2a and carbonyl C30 as well as H4
and carbonyl C30. This indicates that the dihedral angles 1H4–C4–
C3–13C30, 1H2a–C2–C3–13C30 and 1H2e–C2–C3–13C30 all are close to
60ꢀ that defines the ‘up’ orientation of carbonyl C30 close to 4-(2-
methoxyphenyl) ring. This conclusion was confirmed by X-ray
analysis of the analogous compound 5b.
– H+
Piperidine
O
O
O
S
O
S
H
O
O
H
2a anion
For the confirmation of structure 5b, X-ray diffraction studies
werecarriedoutonmonocrystalsof5b. Figure2illustratesa diagram
of the molecule 5b giving the atomic numbering scheme followed in
the text. There are only a few examples of crystal structure of ben-
zothiophene dioxides in the literature. A search of the Cambridge
Structural Database10 (Version 5.28, November 2006) indicated that
there are only 24 entries of these compounds. The conformation of
the six-membered cycle of N1–C5–C1–C2–C3–C4 is near to the en-
velope. The deviation of atom C3 from the mean least-squares plane
of C4–N1–C5–C1–C2 equals to 0.641(4) Å. The intermolecular con-
tacts correspond to the sums of the van der Waals radii.
Scheme 3. Formation of 2a anion.
The structural elucidation of the new heterocyclic system,
3H,20H-spirocyclic compound 3, was mainly based on NMR spectra
and for compound 5b also on X-ray analysis data.
The determination of structure 3b was accomplished on the
basis of 2D-NMR 1H–1H and 1H–13C spectra recorded in DMSO-d6
solution. The comparison of 1H–1H TOCSY, 1H–1H DQF-COSY, 1H–13
C
HSQC and 1H–13C HMBC spectra led to the conclusion that the
structure of compound 3b corresponds to the one depicted in
Figure 1. The 1H and 13C chemical shifts given in Section 4 are in full
agreement with the proposed structure. 2D 1H–1H ROESY experi-
ment with mixing time 100 ms showed two important
3. Conclusions
The present study demonstrates the usefulness of sulfonyl
group containing 1,3-indandione analogue, benzo[b]thiophen-
3(2H)-one 1,1-dioxide, which with aromatic aldehydes easily forms
2,20-(arylmethylene)bis(benzo[b]thiophen-3(2H)-one) 1,1,10,10-tet-
raoxides and with aromatic aldehydes and ammonium acetate
forms 11-aryl-5,11-dihydrodi(benzo[b]thieno)[3,2-b:20,30-e]pyri-
dine 10,10,12,12-tetraoxides. We have performed the synthesis of a
novel heterocyclic system, 4-aryl-1,4-dihydro-3H,20H-spiro[benzo-
[b]thieno[3,2-b]pyridine-3,20-benzo[b]thiophen]-30-one 10,10,5,5-tet-
raoxides, from 2,20-(arylmethylene)bis(benzo[b]thiophen-3(2H)-
one) 1,1,10,10-tetraoxides and hexamethylenetetramine in the
internal Mannich reaction.
4. Experimental
4.1. General
All reagents were purchased from Aldrich, Acros, Fluka or Merck
and used without further purification. TLC was performed on
20ꢁ20 cm Silica gel TLC-PET F254 foils (Fluka). NMR spectra were
recorded with a Varian Mercury 200BB (200 MHz) or Bruker DMX-
Figure 1. Drawing of structure 3b. The 1H chemical shifts are given by the numbers
with regular type, and 13C ones with the numbers in bold and italics. Arrows indicate
the NOEs observed.

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B. Cekavicus et al. / Tetrahedron 64 (2008) 9947–9952
600 (600 MHz) spectrometer equipped with a cryoprobe in deu-
terated dimethylsulfoxide (DMSO-d6) solution at 25 ꢀC. Chemical
shifts are reported in parts per million relative to residual solvent
(relative intensity): 483 ([MþH]þ, 17). Anal. Calcd for C24H18O7S2: C,
59.74; H, 3.76; S, 13.29. Found: C, 59.73; H, 3.71; S, 13.37.
signal (
d
(1H) 2.50 ppm,
d(
13C) 39.5 ppm). Two-dimensional spectra
4.2.3. 2,20-[(3-Nitrophenyl)methylene]bis(benzo[b]thiophen-3(2H)-
one) 1,1,10,10-tetraoxide (2c)
recorded included DQF-COSY, ROESY, TOCSY, sensitivity-enhanced
13C HSQC and 13C–1H HMBC. Pulsed-field gradients were used for
all 13C correlation spectra. 13C HMBC spectra were recorded with
coupling evolution delay for the generation of multiple-bond cor-
relations set to 62.5 ms. All 2D spectra were run with 4096ꢁ1024
points data matrix, giving s2max¼250 ms for 1H nucleus in acqui-
sition dimension and s1max¼200 ms for 1H or s1max¼50 ms for 13C
for indirect dimension. Prior to Fourier transform, the data matrix
was zero-filled twice and multiplication by shifted sine-bell win-
dow function applied. For 1H–13C HMBC the magnitude spectra
were calculated. Mass spectral data were determined on an Acquity
UPLC system (Waters) connected to a Q-TOF micro hybrid quad-
rupole time of flight mass spectrometer (Micromass) operating in
the ESI positive or negative ion mode on a Aquity UPLC BEH C18
Yield: 1.88 g (76%); white powder, mp 193–194 ꢀC; 1H NMR
(DMSO-d6, 200 MHz):
d
meso-2c: 4.50 (t, 1H, J¼6.6 Hz), 5.40 (d, 2H,
J¼6.2 Hz), 7.65–7.81 (m, 5H), 7.90–8.47 (m, 8H) and diastereomeric
mixture of RS-2c and SR-2c: 4.67 (dd, 1H, J¼11.0 and 2.9 Hz), 5.39 (d,
1H, J¼2.9 Hz), 5.78 (d,1H, J¼11.0 Hz), 7.65–7.81 (m, 5H), 7.90–8.47 (m,
8H); IR (Nujol): 1580 (C]C), 1730 (C]O) cmꢂ1. Anal. Calcd for
C23H15NO8S2: C, 55.53; H, 3.04; N, 2.82; S, 12.89. Found: C, 55.26; H,
2.97; N, 2.63; S, 13.23.
4.3. 4-Aryl-1,4-dihydro-3H,20H-spiro[benzo[b]thieno[3,2-
b]pyridine-3,20-benzo[b]thiophen]-30-one
10,10,5,5-tetraoxides (3a–c)
column (1.7
m
m, 2.1 mmꢁ50 mm) using a gradient elution with
General procedure. To a mixture of the appropriate 2,20-(aryl-
methylene)bis(benzo[b]thiophen-3(2H)-one) 1,1,10,10-tetraoxides
2a–c (1 mmol) in acetic acid (10 mL) and DMF (6 mL) hexamethyl-
enetetramine (0.42 g, 3 mmol) was added, and the reaction mixture
was heated under reflux with stirring for 24 h. After cooling the
mixture, the precipitated product was filtered off and crystallised
from a mixture of acetic acid and DMF.
acetonitrile/formic acid (0.1%) in water or Alliance HPLC system
(Waters) connected to a Micromass Quatro micro API mass spec-
trometer (Micromass) operating in the ESI positive ion mode on
a Symmetry HPLC C18 column (3.5
mm, 3.0 mmꢁ150 mm) with
a mobile phase of acetonitrile/DMF/heptafluorobutyric acid (0.5%)
in water (55:5:40 by volume). Melting points were determined on
a Boetius apparatus. Elemental analyses were determined on
a Carlo-Erba elemental analyser.
4.3.1. 4-Phenyl-1,4-dihydro-3H,20H-spiro[benzo[b]thieno[3,2-
b]pyridine-3,20-benzo[b]thiophen]-30-one 10,10,5,5-tetraoxide (3a)
Yield: 0.25 g (59%); grey powder, mp >300 ꢀC; 1H NMR (DMSO-
4.2. 2,20-(Arylmethylene)bis(benzo[b]thiophen-3(2H)-one)
1,1,10,10-tetraoxides (2a–c)
d6, 200 MHz):
d
3.86 (d, 1H, J¼13.9 Hz, overlap), 3.98 (dd, 1H, J¼2.9
and 13.9 Hz, overlap), 4.55 (s, 1H), 7.00–7.08 (m, 2H), 7.09–7.21 (m,
3H), 7.65 (dd, 1H, J¼7.3 and 8.1 Hz, overlap), 7.68 (dd, 1H, J¼7.3 and
8.1 Hz, overlap), 7.78 (d,1H, J¼6.6 Hz, overlap), 7.87 (d, 1H, J¼8.1 Hz,
overlap), 7.93 (d, 1H, J¼6.6 Hz, overlap), 8.00 (dd, 1H, J¼7.3 and
8.1 Hz, overlap), 8.14 (dd, 1H, J¼7.3 and 8.1 Hz, overlap), 8.28 (d, 1H,
J¼8.1 Hz, overlap), 8.63 (br d, 1H, J¼3.7 Hz); IR (Nujol): 1705 (C]O),
3300 (N–H) cmꢂ1; MS (þESI) m/z (relative intensity): 464 ([MþH]þ,
100), 486 ([MþNa]þ, 5). Anal. Calcd for C24H17NO5S2: C, 62.19; H,
3.70; N, 3.02; S, 13.83. Found: C, 61.72; H, 3.59; N, 3.06; S, 14.08.
General procedure. Benzo[b]thiophen-3(2H)-one 1,1-dioxide 1
(1.82 g, 10 mmol) and the corresponding aldehyde (5.0 mmol) were
dissolved in the mixture of ethanol (50 mL) and DMF (5 mL) in the
presence of the catalytic amount of piperidine and acetic acid. The
mixture was heated under reflux with stirring for 2 h. After cooling
the white precipitate was filtered off and crystallised from ethanol/
DMF (2a,b) and acetic acid/DMF (2c).
4.2.1. 2,20-(Phenylmethylene)bis(benzo[b]thiophen-3(2H)-one)
1,1,10,10-tetraoxide (2a)
4.3.2. 4-(2-Methoxyphenyl)-1,4-dihydro-3H,20H-spiro-
[benzo[b]thieno[3,2-b]pyridine-3,20-benzo[b]thiophen]-30-
one 10,10,5,5-tetraoxide (3b)
Yield: 1.6 g (71%); white powder, mp 184–186 ꢀC; 1H NMR
(DMSO-d6, 600 MHz):
d
meso-2a: 4.31 (t, 1H, J¼7.2 Hz, PhCH), 5.23
Yield: 0.30 g (61%); white powder, mp >300 ꢀC; 1H NMR (DMSO-
(d, 2H, J¼7.2 Hz, H2, H20), 7.24 (t, 1H, J¼8.0 Hz, H400), 7.32 (t, 2H,
J¼8.0 Hz, H300, H500), 7.52 (d, 2H, J¼8.0 Hz, H200, H600), 7.80–8.20 (m,
8H, H4–H7 and H40–H70) and diastereomeric mixture of RS-2a and
SR-2a: 4.46 (dd, 1H, J¼11.2 and 2.2 Hz, PhCH), 5.17 (d, 1H, J¼2.2 Hz,
H200or H20), 5,64 (d, 1H, J¼11.2 Hz, H2 or H20), 7.31 (t, 1H, J¼8.0 Hz,
H4 ), 7.39 (t, 2H, J¼8.0 Hz, H300, H500), 7.54 (d, 2H, J¼8.0 Hz, H200,
H600), 7.80–8.20 (m, 8H, H4–H7 and H40–H70); IR (Nujol): 1587
(C]C), 1715 (C]O), 1731 (C]O) cmꢂ1; MS (þESI) m/z (relative in-
tensity): 453 ([MþH]þ, 15). Anal. Calcd for C23H16O6S2: C, 61.05; H,
3.56; S, 14.17. Found: C, 60.89; H, 3.50; S, 14.52.
d6, 600 MHz):
d
3.24 (s, 3H, OCH3), 3.67 (d, 1H, J¼14.4 Hz, H2a), 3.87
(ddd,1H, J¼1.5, 5.5 and 14.4 Hz, H2e), 4.89 (d,1H, J¼1.5 Hz, H4), 6.83
(d, 1H, J¼8.0 Hz, H300), 6.92 (t, 1H, J¼8.0 Hz, H500), 7.20 (dd, 1H, J¼2.0
and 8.0 Hz, H600), 7.27 (dt, 1H, J¼2.0 and 8.0 Hz, H400), 7.63 (t, 1H,
J¼8.0 Hz, H7), 7.72 (t, 1H, J¼8.0 Hz, H8), 7.74 (d, 1H, J¼8.0 Hz, H6),
7.92 (d, 1H, J¼8.0 Hz, H9), 7.95 (d, 1H, J¼8.0 Hz, H40), 7.98 (t, 1H,
J¼8.0 Hz, H50), 8.10 (dt,1H, J¼2.0 and 8.0 Hz, H60), 8.16 (dd,1H, J¼8.0
and 2.0 Hz, H70), 8.50 (br d, 1H, J¼5.5 Hz, NH); 13C NMR (DMSO-d6,
150 MHz):
d 33.4 (C4), 39.1 (C2), 54.4 (OCH3), 65.2 (C3), 97.8 (C4a),
108.8 (C300),119.3 (C6),119.4 (C500),120.2 (C9),120.9 (C70),123.0 (C40),
123.5 (C100), 126.6 (C9a), 128.4 (C400), 129.6 (C600), 130.0 (C7), 131.5
(C30a), 131.8 (C8), 133.9 (C50), 136.5 (C60), 138.8 (C5a), 142.5 (C9b),
142.6 (C70a), 155.1 (C200), 187.5 (C30); IR (Nujol): 1627, 1705 (C]O),
3300 (N–H) cmꢂ1; MS (þESI) m/z (relative intensity) 494 ([MþH]þ,
92), 516 ([MþNa]þ, 77). Anal. Calcd for C25H19NO6S2: C, 60.84; H,
3.88; N, 2.84; S, 12.99. Found: C, 60.67; H, 3.73; N, 2.81; S, 12.95.
4.2.2. 2,20-[(2-Methoxyphenyl)methylene]bis(benzo[b]thiophen-
3(2H)-one) 1,1,10,10-tetraoxide (2b)
Yield: 2.04 g (84%); white powder, mp 204 ꢀC; 1H NMR (DMSO-
d6, 200 MHz):
d
meso-2b: 3.83 (s, 3H, overlap), 4.63 (t,1H, J¼5.9 Hz),
5.24 (d, 2H, J¼5.9 Hz, overlap), 7.03 (t,1H, J¼8.1 Hz, overlap), 7.34 (t,
1H, J¼8.1 Hz, overlap), 7.54–7.74 (m, 2H), 7.87–8.25 (m, 8H) and
diastereomeric mixture of RS-2b and SR-2b: 3.78 (s, 3H, overlap),
4.82 (dd, 1H, J¼2.2 and 11.7 Hz), 5.13 (d, 1H, J¼2.2 Hz, overlap), 5.77
(d, 1H, J¼11.7 Hz), 7.07 (t, 1H, J¼8.1 Hz, overlap), 7.38 (t, 1H,
J¼8.1 Hz, overlap), 7.54–7.74 (m, 2H), 7.87–8.25 (m, 8H); IR (Nujol):
1580 (C]C), 1720 (C]O), 1730 (C]O) cmꢂ1; MS (þESI) m/z
4.3.3. 4-(3-Nitrophenyl)-1,4-dihydro-3H,20H-spiro[benzo-
[b]thieno[3,2-b]pyridine-3,20-benzo[b]thiophen]-30-one
10,10,5,5-tetraoxide (3c)
Yield: 0.11 g (22%); pale yellow powder, mp >300 ꢀC; 1H NMR
(DMSO-d6, 200 MHz):
d
3.81 (d, 1H, J¼14.7 Hz), 4.05 (dd, 1H, J¼2.9

B. Cekavicus et al. / Tetrahedron 64 (2008) 9947–9952
9951
and 14.7 Hz), 4.94 (s, 1H), 7.59 (dd, 1H, J¼7.3 and 7.3 Hz, overlap),
4.4.5. 11-(2-Methoxyphenyl)-5,11-dihydrodi(benzo[b]thieno)[3,2-
7.62–7.76 (m, 2H overlap), 7.80 (d, 2H, J¼7.3 Hz, overlap), 7.87–8.02
(m, 4H, overlap), 8.18–8.21 (m, 2H), 8.27 (d,1H, J¼7.3 Hz), 8.78 (br d,
1H, J¼4.4 Hz); IR (Nujol): 1720, 1735 (C]O), 3280 (N–H) cmꢂ1; MS
(ꢂESI) m/z (relative intensity): 507 ([MꢂH]þ, 100), 508 ([Mþ]þ, 35).
Anal. Calcd for C24H16N2O7S2: C, 56.69; H, 3.17; N, 5.51; S, 12.61.
Found: C, 56.59; H, 2.77; N, 5.27; S, 12.49.
b:20,30-e]pyridine 10,10,12,12-tetraoxide (4b)
Yield: 0.40 g (86%). The 1H NMR spectrum is in accordance with
the one described in Section 4.4.2 for compound 4b obtained by
method A.
4.4.6. 11-(3-Nitrophenyl)-5,11-dihydrodi(benzo[b]thieno)[3,2-
b:20,30-e]pyridine 10,10,12,12-tetraoxide (4c)
Yield: 0.42 g (88%). The 1H NMR spectrum is in accordance with
the one described in Section 4.4.3 for compound 4c obtained by
method A.
4.4. 11-Aryl-5,11-dihydrodi(benzo[b]thieno)[3,2-b:20,30-
e]pyridine 10,10,12,12-tetraoxides (4a–c)
General procedure. Method A: a solution of benzo[b]thiophen-
3(2H)-one 1,1-dioxide 1 (0.46 g, 2.5 mmol), the corresponding al-
dehyde (2.5 mmol) and ammonium acetate (0.77 g, 10 mmol) in
glacial acetic acid was stirred under reflux for 6 h. After cooling the
mixture, the pale yellow precipitate was filtered off and crystallised
from acetic acid/DMF or washed with hot AcOH/DMF (for 4c) to
give the compounds 4a–c.
4.5. 4-(2-Methoxyphenyl)-1-methyl-1,4-dihydro-2H,30H-
spiro[benzo[b]thieno[3,2-b]pyridine-3,20-benzo[b]thiophen]-
30-one 10,10,5,5-tetraoxide (5b)
Method A: to a solution of 3b (0.25 g, 0.5 mmol) in DMF (2 mL)
wasaddedNaH(0.06 g,1 mmol). Thereactionmixturewasstirredfor
30 min at rt, after which MeI (0.13 mL, 2 mmol) was added and the
mixture was stirred for another 1.5 h at 50 ꢀC. The reaction mixture
was diluted with water and the precipitated product was filtered off
to give a mixture of 5b and 3b (0.11 g).1H NMR (DMSO-d6, 200 MHz):
4.4.1. 11-Phenyl-5,11-dihydrodi(benzo[b]thieno)[3,2-b:20,30-
e]pyridine 10,10,12,12-tetraoxide (4a)
Yield: 0.46 g (85%); white powder, mp >300 ꢀC; 1H NMR
d
(major peaks) 3.25 (s, 3H, N–CH3) and 8.62 (br d,1H, J¼5.5 Hz, NH).
(DMSO-d6, 200 MHz): d 5.21 (s, 1H), 7.29–7.33 (m, 3H), 7.45 (dd, 2H,
Method B: to a solution of 3b (0.25 g, 0.5 mmol) in HMPA (2 mL)
J¼1.5 and 7.4 Hz), 7.71 (dd, 2H, J¼7.5 and 7.5 Hz), 7.89 (dd, 2H, J¼7.5
and 7.5 Hz, overlap), 7.89 (d, 2H, J¼7.5 Hz, overlap), 8.33 (d, 2H,
J¼7.5 Hz), 10.55 (br s, 1H); IR (Nujol): 1654 (C]C), 3399 (N–
H) cmꢂ1; MS (þESI) m/z (relative intensity) 434 ([MþH]þ, 10). Anal.
Calcd for C23H15NO4S2: C, 63.72; H, 3.49; N, 3.23; S, 14.79. Found: C,
63.59; H, 3.51; N, 3.21; S, 14.61.
was added NaH (0.06 g, 1 mmol). The reaction mixture was stirred
for 30 min at rt, after which Me2SO4 (0.15 mL, 2 mmol) was added
and the mixture was stirred for another 30 min at 50 ꢀC. The re-
action mixture was diluted with water and the precipitated product
was filtered off to give a mixture of 5b and 3b (0.12 g).
Method C: methylamine solution in water (40 wt %, 4 mL,
46.2 mmol) and formaldehyde solution in water (37 wt %, 4 mL,
55.2 mmol) were mixed at ꢂ18 ꢀC and kept in a refrigerator for 3 h.
The resulting water solution containing 1,3,5-trimethylhexahydro-
1,3,5-triazine (8 mL, ca.15.4 mmol) was added to a suspension of 2b
(0.48 g, 1 mmol) in glacial acetic acid (20 mL) at rt. After being
stirred at reflux for 2 h, the resulting mixture was diluted with
water and extracted with CHCl3. The extract was washed succes-
sively with water and brine, and then dried over MgSO4. After re-
moval of solvents in vacuum the residue was crystallised from
methanol giving 5b as a yellow powder (0.21 g, 42%), mp >300 ꢀC.
4.4.2. 11-(2-Methoxyphenyl)-5,11-dihydrodi(benzo[b]thieno)[3,2-
b:20,30-e]pyridine 10,10,12,12-tetraoxide (4b)
Yield: 0.48 g (82%); white powder, mp >300 ꢀC; 1H NMR
(DMSO-d6, 200 MHz):
d
3.81 (s, 3H), 5.60 (s, 1H), 6.86 (dd, 1H, J¼7.3
and 7.3 Hz), 6.98 (d, 1H, J¼7.3 Hz), 7.22 (ddd, 1H, J¼1.5, 7.3 and
7.3 Hz), 7.33 (dd, 1H, J¼1.5 and 7.3 Hz), 7.68 (dd, 2H, J¼7.3 and
7.3 Hz, overlap), 7.84 (dd, 2H, J¼7.3 and 7.3 Hz, overlap), 7.87 (d, 2H,
J¼7.3 Hz, overlap), 8.28 (d, 2H, J¼7.3 Hz), 10.41 (br s, 1H); IR (Nujol):
1665 (C]C), 3360 (N–H) cmꢂ1. Anal. Calcd for C24H17NO5S2: C,
62.19; H, 3.70; N, 3.03; S, 13.84. Found: C, 61.91; H, 3.67; N, 2.99; S,
13.72.
1H NMR (DMSO-d6, 200 MHz):
d 3.20 (s, 3H), 3.58 (s, 3H), 3.83 (dd,
2H, J¼3.7 and 1.5 Hz), 4.85 (s, 1H), 6.85 (d, 1H, J¼8.1 Hz), 6.92 (dd,
1H, J¼8.1 and 7.4 Hz), 7.26 (d, 1H, J¼7.3 Hz, overlap), 7.29 (ddd, 1H,
J¼1.5, 6.6 and 7.3 Hz, overlap), 7.70 (dd, 1H, J¼6.6 and 7.3 Hz,
overlap), 7.72 (d, 1H, J¼6.6 Hz, overlap), 7.83 (d, 1H, J¼5.9 Hz), 7.99
(ddd, 1H, J¼1.5, 5.9 and 8.1 Hz, overlap), 8.00 (d, 1H, J¼5.9 Hz,
overlap), 8.17–8.09 (m, 2H), 8.23 (d, 1H, J¼7.3 Hz); IR (Nujol): 1630,
1710 (C]O) cmꢂ1; MS (þESI) m/z (relative intensity): 508 ([MþH]þ,
100), 530 ([MþNa]þ, 18). Anal. Calcd for C26H21NO6S2: C, 61.52; H,
4.17; N, 2.76; S, 12.63. Found: C, 61.53; H, 3.93; N, 2.47; S, 12.49.
4.4.3. 11-(3-Nitrophenyl)-5,11-dihydrodi(benzo[b]thieno)[3,2-
b:20,30-e]pyridine 10,10,12,12-tetraoxide (4c)
Yield: 0.52 g (87%); white powder, mp >300 ꢀC; 1H NMR
(DMSO-d6, 200 MHz):
d
5.55 (s, 1H), 7.71 (dd, 2H, J¼7.3 and 7.3 Hz),
7.88 (dd, 2H, J¼7.3 and 7.3 Hz, overlap), 7.87 (dd, 1H, J¼7.3 and
7.3 Hz, overlap), 7.90 (d, 2H, J¼7.3 Hz, overlap), 8.02 (d, 1H,
J¼7.3 Hz), 8.16 (dd, 1H, J¼2.2 and 7.3 Hz), 8.34 (d, 2H, J¼7.3 Hz,
overlap), 8.36 (s, 1H, overlap), 10.68 (br s, 1H); IR (Nujol): 1663
(C]C), 3281 (N–H) cmꢂ1. Anal. Calcd for C23H14N2O6S2: C, 57.74; H,
2.95; N, 5.86; S, 13.41. Found: C, 54.45; H, 2.85; N, 5.72; S, 12.98.
Method B: to a mixture of the appropriate 2,20-(arylmethyle-
4.6. Crystal data for compounds 5b and 2a
Calculations were carried out with the complexes of pro-
grams.11,12 For crystallographic data, see Cambridge Crystallo-
graphic Data Centre as Supplementary Publication Numbers CCDC
602189 and 684658.
ne)bis(benzo[b]thiophen-3(2H)-one)
1,1,10,10-tetraoxide
2a–c
(1 mmol) in glacial acetic acid (20 mL), ammonium acetate (0.77 g,
10 mmol) was added and the reaction mixture was stirred under
reflux for 6 h. After cooling the mixture, the precipitated product
was filtered off and crystallised from acetic acid/DMF (for 4a,b) or
washed with hot AcOH/DMF (for 4c) to give the compounds 4a–c.
4.7. 2-[1-(2-Methoxyphenyl)-methylidene]-
benzo[b]thiophen-3(2H)-one-1,1-dioxide (6b)
4.4.4. 11-Phenyl-5,11-dihydrodi(benzo[b]thieno)[3,2-b:20,30-
e]pyridine 10,10,12,12-tetraoxide (4a)
A solution of benzo[b]thiophen-3(2H)-one 1,1-dioxide 1 (0.46 g,
2.5 mmol), 2-methoxybenzaldehyde (0.38 g, 2.5 mmol) and ammo-
nium acetate (0.39 g, 5 mmol) in ethanol (30 mL) and glacial acetic
acid (10 mL) was stirred for 48 h. The yellow precipitate was filtered
off and crystallised from acetic acid to give 6b as bright yellow
Yield: 0.39 g (90%). The 1H NMR spectrum is in accordance with
the one described in Section 4.4.1 for compound 4a obtained by
method A.

9952
B. Cekavicus et al. / Tetrahedron 64 (2008) 9947–9952
crystals (0.53 g, 70%), mp 174 ꢀC. 1H NMR (DMSO-d6, 200 MHz):
References and notes
d
3.90 (s, 3H), 8.00 (dd, 1H, J¼6.8 and 8.8 Hz, overlap), 8.12 (d, 2H,
1. Chekavichus, B. S.; Sausin, A. E.; Zolotoyabko, R. M.; Liepin’sh, E. E.; Mazheika,
I. B.; Dubur, G. Ya. Chem. Heterocycl. Compd. (Engl. Transl.) 1986, 22, 410–414.
2. Darnbrough, G.; Knowles, P.; O’Connor, S. P.; Tierney, F. J. Tetrahedron 1986, 42,
2339–2344.
3. Morhle, H.; Dornbrack, S.; Novak, H. I. Monatsh. Chem. 1981, 112, 1417–1423.
4. Morhle, H.; Novak, H. I. Z. Naturforsch. 1982, 37b, 669–674.
5. Greenhill, J. V. J. Chem. Soc. C 1971, 2699–2703.
J¼8.8 Hz, overlap), 8.14 (s,1H, overlap), 8.18–8.26 (m, 5H); IR (Nujol):
1610, 1660, 1690 (C]O) cmꢂ1; MS: 300 [M]þ. Anal. Calcd for
C
16H12O4S:C,63.99;H, 4.03;S,10.68.Found:C,63.57;H, 3.91;S,10.50.
Acknowledgements
6. Chaaban, I.; Greenhill, J. V.; Akhtar, P. J. Chem. Soc., Perkin Trans. 1 1979, 1593–
1596.
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This research work was supported by Grants 05.1780 and
05.1790 of the Latvian Council of Science. We are indebted to Dr. S.
Grinberga for the mass spectral analyses and to Mrs. E. Sarule for
the elemental analyses.
10. Allen, F. H. Acta Crystallogr. 2002, B58, 380–388.
11. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.; Polidori,
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University of Go¨ttingen: Go¨ttingen, Germany, 1997.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.07.112.