Domino Vilsmeier-Haack/ring closure sequences: A facile synthesis of 3-chlorobenzo[b]thiophene-2-carbaldehydes

Article abstract of DOI:10.1016/j.tetlet.2011.05.046

Vilsmeier's reagent treatment of substituted diphenacyl sulfides or diphenacyl disulfides has led to the formation of a series of benzfused 3-chlorothiophene-2-carbaldehydes by a Domino Vilsmeier-Haack reaction/ring closure sequence, opening a new route for the synthesis of 3-chlorobenzo[b] thiophene-2-carbaldehydes and their benzfused analogues. A plausible mechanism has been proposed.

Full text of DOI:10.1016/j.tetlet.2011.05.046

Tetrahedron Letters 52 (2011) 3743–3746
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Domino Vilsmeier–Haack/ring closure sequences: a facile synthesis
of 3-chlorobenzo[b]thiophene-2-carbaldehydes
⇑
Nidhin Paul, Shanmugam Muthusubramanian
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 March 2011
Revised 9 May 2011
Accepted 11 May 2011
Available online 19 May 2011
Vilsmeier’s reagent treatment of substituted diphenacyl sulfides or diphenacyl disulfides has led to the
formation of a series of benzfused 3-chlorothiophene-2-carbaldehydes by a Domino Vilsmeier–Haack
reaction/ring closure sequence, opening a new route for the synthesis of 3-chlorobenzo[b]thiophene-2-
carbaldehydes and their benzfused analogues. A plausible mechanism has been proposed.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Benzo[b]thiophene
Vilsmeier–Haack reaction
Domino reaction
2-[(2-Oxo-2-arylethyl)sulfanyl]-1-aryl-1-
ethanones
Vilsmeier–Haack reaction has emerged as a popular tool for the
formylation and acylation of aromatic rings and construction of
heterocycles.1 This reaction, when carried out on active methylene
compounds, leads mainly to the formation of b-halo-carboxalde-
hyde derivatives, which are useful precursors in the construction
of different heterocyclic compounds by numerous transforma-
tions2 and thus the Vilsmeier–Haack procedure facilitates an easy
entry into various nitrogen- and oxygen-based heterocycles.3
Benzo[b]thiophene nucleus has attracted much attention as it is
present in various natural products.4 The benzo[b]thiophene skel-
eton was found to be present in several drug candidates.5,6 Sertaco-
nazole7 was recently approved as a topical anti-fungal agent and
zileuton8 is used for the chronic treatment of asthma. Mobam9 rep-
resents a potent insecticide which inhibits the enzyme acetyl cho-
linesterase. Many benzo[b]thiophene derivatives are well known
to exhibit a broad range of interesting biological activities, includ-
ing anti-inflammatory,10 antidepressive,11 antipsychotic,12 antivi-
ral,13 antiallergic,14 herpes virus inhibitors,15 prostaglandin or
dopamine receptor antagonists16 and tubulin polymerization
inhibitors.17 Thioindigo and its derivatives are benzothiophene
containing dyestuffs.18
of benzo[b]thiophene derivatives21–28 have been reported in the
literature.
This Letter describes the synthesis of 3-chlorobenzo [b]
thiophene-2-carbaldehyde and their derivatives from 2-[(2-oxo-
2-arylethyl)sulfanyl]-1-aryl-1-ethanones by a domino Vilsmeier–
Haack reaction/ring closure sequence (Scheme 1). The synthesised
3-chlorobenzo[b]thiophene-2-carbaldehydes can be used to gener-
ate pyridylbenzo[b]thiophene-2-carboxamide 4 and subsequently
benzo[b]thieno[2,3-c]naphthyridin-2-one 5, which act as antitu-
mour agents (Scheme 2).29
O
O
Cl
DMF/POCl3
S
Ar
Ar
Ar
0
80oC
2 Hrs
S
CHO
1a-h
2a-h
H3CO
H3C
3-Chlorobenzo[b]thiophene-2-carbaldehyde can be synthesized
by one-pot intramolecular cyclization of 2-[(carboxymethyl)
sulfanyl]benzoic acid under Vilsmeier–Haack condition19 and by
a two-step reduction/oxidation of 3-chlorobenzo[b]thiophene-2-
carboxylic acid.20 Many other synthetic protocols for construction
Cl
OCH3
1b
1c
1d
1e
1a
1f
1g
1h
⇑
Corresponding author. Tel.: +91 0452 2458246; fax: +91 0452 2459845.
E-mail address: muthumanian2001@yahoo.com (S. Muthusubramanian).
Scheme 1. Synthesis of 3-chlorobenzo[b]thiophene-2-carbaldehydes 2a–h.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.046

3744
N. Paul, S. Muthusubramanian / Tetrahedron Letters 52 (2011) 3743–3746
O
O
7.35, d,
J = 2.4 Hz
Cl
Cl
3.93, s, 3H
55.6
S
CH3
H
CHO
COCl
CH3
O
H
S
103.9
137.6
S
Cl
4
1a
Cl
H
O
3
2a
3a
7a
129.9
158.5
120.9
3
132.9
S
O
N
O
H
6
H
S
1
2
Cl
124.2
183.3
7
7.22, dd,
J = 9.0, 2.4 Hz
O
H
H
H
10.31, s, 1H
7.72, d,
J = 9.0 Hz
S
NH
S
HN
N
O
13
Fig. 2. Selected HMBCs and 1H, C NMR chemical shifts in 2e00.
4
5
Scheme 2. Retrosynthetic route for the antitumor agent 5.
correlation with C-7 at 124.2 ppm and HMBC contours with C-3a
at 137.6 and C-5 at 158.5 ppm. 2e0, which is the isomeric product
of 2e00, can be distinguished unambiguously from the latter from
its proton NMR spectrum. The structures of the benzo[b]thio-
phenes 2a–h were further confirmed by a single crystal X-ray crys-
tallographic study of 2g (Fig. 3).32
Initially,
2-[(2-oxo-2-arylethyl)sulfanyl]-1-aryl-1-ethanones
1a–h were treated with Vilsmeier reagent at 0 °C for 10 min. The
mixture quickly became viscous, but no products could be detected
by TLC. When the resulting mixture was heated at 80 °C for 2 h, the
reaction proceeded smoothly.30 The products, 2,3-disubstituted
benzo[b]thiophenes 2a–h were purified by column chromatogra-
phy (Scheme 1, Fig. 1). In the case of m-chloro and m-methoxy
substituted aryl systems, a mixture of products, 2d0, 2d00 and 2e0,
2e00, respectively, were obtained (Fig. 1). However, the reaction
seems to be regiospecific with 1g and 1h. In 1g, the 1 position of
naphthyl, and not 3 position, is involved in thiopohene ring forma-
tion. In 1h also, it is found that angular cyclisation is preferred over
linear cyclisation. No singlet appeared in the aryl region of the 1H
NMR spectrum of 2h, differentiating the compound from its regio
isomer.
The scope and generality of this methodology has been illus-
trated by carrying out the reaction with 1,5-diketones having
a-,b-naphthyl and 9H-fluorene rings (Scheme 1, 1f–h). Benzfused
benzothiophene systems, 1-chloronaphtho[2,1-b]thiophene-2-
carbaldehyde, 3-chloronaphtho[1,2-b]thiophene-2-carbaldehyde
and 3-chloro-10H-fluoreno[1,2-b]thiophene-2-carbaldehyde have
been obtained in good yields (Fig. 1).
A plausible mechanistic pathway for the formation of 3-chloro-
benzo[b]thiophene-2-carbaldehydes 2a–h can be explained by an
initial Vilsmeier–Haack reaction of 2-[(2-oxo-2-arylethyl)sulfa-
nyl]-1-aryl-1-ethanones (Scheme 3) to give functionalized chloro-
methyleneiminium salt intermediate 6. Though an electrophilic
attack by sulfur in the ortho position of the aryl ring33 or a con-
certed six electron ring closure34 could be advanced as the possible
routes to the ring closure, the route shown in Scheme 3 may be
credible, in which sulfide intermediate 9 is proposed. The subse-
quent cleavage of group X assisted by phosphorous oxychloride
can lead to the observed product. The recovery of 3-chloro-3-phe-
nyl-2-propenal from the reaction mixture, which may be obtained
by the reaction of acetophenone on Vilsmeier–Haack reagent,
supports the proposed mechanism. The fact that 2-naphthyl
substituted system undergoes ring closure exclusively in the
1-naphthyl position and also the 2-naphthyl system undergoes
reaction in a facile manner compared to 1-naphthyl system can
be explained by the relative stability of the cations 11, 12 and 13
(Fig. 4) expected in the proposed transformations.
The structures of benzo[b]thiophenes, 2 were established by 1H,
13C and 2D NMR spectral data as illustrated for a representative
1
example, 2e00. In the H NMR spectrum of 2e00(Fig. 2),31 the OCH3
protons appear as a three hydrogen singlet at 3.93 ppm and the
aldehyde proton as a one hydrogen singlet at 10.31 ppm, the
respective carbons appearing at 55.6 and 183.3 ppm. The doublet
at 7.35 ppm with a meta coupling of 2.4 Hz is assigned to H-4,
which is having
a C,H-COSY correlation with the signal at
103.9 ppm assignable to C-4. This hydrogen has HMBC contours
with carbon signals at 120.9, 129.9, 132.9 and 158.5 ppm ascrib-
able to C-6, C-3, C-7a and C-5, respectively (Fig. 2). The doublet
of doublet at 7.22 ppm (J = 9.0, 2.4 Hz) is assigned to H-6 and is
having C,H-COSY correlation with the signal at 120.9 ppm. It has
HMBC contours with carbon signals at 103.9, 132.9 and
158.5 ppm due to C-4, C-7a and C-5, respectively. The doublet at
7.72 ppm (J = 9.0 Hz) is assigned to H-7, which gives C,H-COSY
2-Mercapto-1-phenylethanone 14 on reaction with the Vilsme-
ier–Haack reagent (Scheme 4, Table 1) following the above
procedure yielded the same benzo[b]thiophenes 2. As the dimer
of 2-mercapto-1-phenylethanone 14, 2,20-disulfanediylbis(1-phe-
nylethanone) 15 under similar reaction conditions provides the
same product, it is proposed that the dimerisation occurs initially
in the case of 2-mercapto-1-phenylethanone and the remaining
Cl
Cl
Cl
Me
S
CHO MeO
S
CHO
S
CHO
2b
2c
2a
69%
Cl
72%
Cl
75%
Cl
Cl
Cl
MeO
S
CHO
S
CHO
S
CHO
S
CHO
OMe
2d''
2e''
38%
Cl
2e'
2d'
30%
32%
35%
Cl
Cl
Cl
S
CHO
S
CHO
S
CHO
2f
2g
74%
2h
60%
56%
Fig. 1. Structures and yields of 3-chlorobenzo[b]thiophene-2-carbaldehydes 2a–h.
Fig. 3. ORTEP diagram of 2g.

N. Paul, S. Muthusubramanian / Tetrahedron Letters 52 (2011) 3743–3746
3745
OH
O
Cl
Cl
S
POCl3
R
R
R
R
Me
N
Me
Me
DMF
OPOCl2
S
X
6
S
N
Me
1
X
7
-
X = ArCOCH2
Cl
Cl
Cl
POCl3
R
Me
N
Me
R
H2O
R
Me
N
Me
C
2
S
Me
N
S
H
S
X
X
8
Me
9
10
POCl3
Scheme 3. Plausible mechanism for formation of 3-chloro benzo[b] thiophene-2-carbaldehydes 2.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.046.
13
12
11
References and notes
Fig. 4. Structures of cations from 1e and 1f.
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O
SH
Ar
Cl
DMF/POCl3
14a-c
0-80 o
2 h
C
or
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CHO
O
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2a, 2b and 2g
S
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Ar
Ar
15a,c
Scheme 4. Synthesis of 3-chlorobenzo[b]thiophene-2-carbaldehydes from 2,20-
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Synthesis of 2a, 2b and 2g
Entry
Ar
Compound
Yield from 14a (%)
Yield from 15a (%)
69
—
72
a
b
c
C6H5
4-MeC6H4
2-Naphthyl
2a
2b
2g
43
40
45
b
a
Yield after purification by column.
Reaction not performed.
b
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pathway is expected to be the same as explained above for 2-[(2-
oxo-2-arylethyl)sulfanyl]-1-aryl-1-ethanones 1. It must be added
that ArCOCH2SAr does not undergo this reaction yielding
benzothiophene.
In conclusion, the use of the Vilsmeier–Haack conditions has
permitted us to develop a fast method for the construction of
benzo[b]thiophene derivatives. This methodology opens a new
route to the synthesis of 3-chlorobenzo[b]thiophene-2-carbalde-
hydes, 1-chloronaphtho[2,1-b]thiophene-2-carbaldehyde, 3-chlo-
ronaphtho[1,2-b]thiophene-2-carbaldehyde and 3-chloro-10H-
fluoreno[1,2-b]thiophene-2-carbaldehyde
via
the
domino
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Acknowledgements
The authors thank DST, New Delhi for assistance under the IRH-
PA program for the NMR facility and one of the authors (N.P.)
thanks UGC, New Delhi for fellowship.

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30. Typical procedure for synthesis of 2a–h: 2-[(2-oxo-2-arylethyl)sulfanyl]-1-aryl-
1-ethanone (0.1 mol) was dissolved in dry DMF (7 ml) and the solution was
cooled to 0 °C. To this cold solution POCl3 (0.5 mol) was added drop wise and
allowed stirring for 10 min. The temperature was increased to 80 °C and after
completion of reaction (monitored by TLC) the mixture was poured into ice
cold sodium acetate (0.2 mol) solution and the solid was filtered out and
purified by column chromatography using ethyl acetate/petroleum ether
mixture (3:1 v/v) to to yield pure 2a–h.
31. 3-Chloro-5-methoxybenzo[b]thiophene-2-carbaldehyde
(2e00).
Isolated
as
colorless solid; yield: 38%, mp 140–141 °C; 1H NMR (300 MHz, CDCl3) dH:
3.93 (s, 3H, OCH3), 7.22 (dd, 1H, J = 9.0, 2.4 Hz, Ar–H), 7.35 (d, 1H, J = 2.4 Hz, Ar–
H), 7.72 (d, 1H, J = 9.0 Hz, Ar–H), 10.31 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3)
dC: 55.7, 104.0, 121.0, 124.2, 130.0, 132.9, 136.1, 137.6, 158.5, 183.3. Anal.
Calcd for C10H7ClO2S: C, 52.99; H, 3.11%. Found C, 52.94; H, 3.05.
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