An improved synthesis of substituted benzo[b]thiophenes using microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2004.11.005

An easy and high-yielding method for the synthesis of substituted benzo[b]thiophenes using microwave irradiation is described.

Full text of DOI:10.1016/j.tetlet.2004.11.005

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9645–9647
An improved synthesis of substituted benzo[b]thiophenes
using microwave irradiation
*
Daniel Allen, Owen Callaghan, Frederic L. Cordier, David R. Dobson, John R. Harris,
Terry M. Hotten, W. Martin Owton, Richard E. Rathmell and Virginia A. Wood
Lilly Research Centre, Eli Lilly and Company Ltd, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK
Received 17 August 2004; revised 25 October 2004; accepted 1 November 2004
Available online 11 November 2004
Abstract—An easy and high-yielding method for the synthesis of substituted benzo[b]thiophenes using microwave irradiation is
described.
ꢀ
2004 Elsevier Ltd. All rights reserved.
Benzo[b]thiophenes have always been of interest to
medicinal chemists and can be found in a number of
benzo[b]thiophenes 3. This route allows the preparation
of 4- or 6-substituted benzo[b]thiophenes, but has the
disadvantage that both reactions require high tempera-
tures, moderate to long reaction times and are low
yielding.
TM
marketed drugs such as Sertaconazole (Ginedermofix ),
TM
Zileuton (Leutrol ) and Raloxifene (Evista ).
TM
One of the classical syntheses of benzo[b]thiophenes
starts from commercially available thiophenols, reacting
with bromoacetaldehyde dimethyl acetal, followed by
cyclisation using strong acid. The reaction steps are
generally high yielding but when starting with 3-substi-
In this paper, we describe how both the cyclisation and
the subsequent decarboxylation were improved using
microwave technology.
tuted thiophenols the route gives a mixture of 4- and
1
Microwave technology has opened up new horizons for
chemists. It enables chemical reactions to be performed
very conveniently at high temperatures and, in most
cases, under pressure. Using conventional heating, the
energy must first be conducted through the walls of
the vessel containing the reactants, whereas microwaves
heat the contents directly, allowing the temperature to
rise much faster, so boosting reaction rates. Another
characteristic of microwaves is their ability to superheat
solvents to temperatures well in excess of their normal
boiling points; this is due to the even spread of heat
6
-substituted benzo[b]thiophenes. The regioisomers
are generally difficult to separate so necessitating the
application of an alternative route to access these substi-
tution patterns. One such method has been described
starting from commercially available benzaldehydes
2
(
Scheme 1). Benzaldehydes 1 can be reacted with
rhodanine and after hydrolysis with sodium hydroxide
afford, in good yields, the corresponding b-aryl-a-
mercaptoacrylic acids 2. The acids 2 can then be cyclised
and decarboxylated to give the corresponding
O
COOH
iii), iv)
i), ii)
H
R
R
R
SH
S
1
2
3
Scheme 1. (i) Rhodanine, AcOH; (ii) NaOH; (iii) cyclisation; (iv) decarboxylation.
Keywords: Benzothiophenes; Cyclisation; Decarboxylation; Microwave irradiation.
*
0
Corresponding author. Tel.: +44 1276 478 3120; fax: +44 1276 478 3525; e-mail: cordier_frederic@lilly.com
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.005

9646
D. Allen et al. / Tetrahedron Letters 45 (2004) 9645–9647
Table 1.
R1
R
1
COOH
I2
COOH
SH
Solvent
S
R2
R2
4
5
1
2
a
Entry
R
R
Solvent
DME
Power (W)
Temp (ꢁC)
Time (min)
Yield (%)
1
2
3
4
5
6
4-OMe
4-Me
4-Me
4-Me
4-F
5-F
H
300
400
400
300
300
400
120
180
160
160
160
180
25
8
67
80
77
Dioxane
DME
DME
6-Br
7-OMe
7-OMe
H
5
5
10
10
8
30
5
DME
Dioxane
30
83
6-Me
a
Isolated yields.
through the liquid, allowing it to reach a higher temper-
3
Table 2.
ature before bubbles form. This led us to believe that
microwave heating would improve both the cyclisation
and decarboxylation reactions.
R1
R1
decarboxylation
COOH
Initially, we focused on the cyclisation conditions. In
our hands, when the cyclisation of the b-aryl-a-merca-
ptoacrylic acid 4 was performed under the literature
conditions (iodine, dioxane, 110ꢁC), the yields were
S
S
R2
R2
2
1
2
R
R
Solvent
Power
W)
Temp Time
(ꢁC)
Yield
a
poor, requiring long reaction times and giving complex
reaction mixtures. The cyclisation under microwave
irradiation in a sealed vessel in a CEM MARS micro-
wave oven, at various continuous power and tempera-
ture settings, gave much improved yields with shorter
reaction times and cleaner product mixtures (Table
(
(min) (%)
b
6
-Cyano
-Cyano
H
H
Quinoline Conv.
Quinoline 600
215
200
60
45
52
93
6
a
Isolated yields.
Conv. = conventional heating (oil bath at 215ꢁC).
b
4
,5
1
). When a methoxy group was present in the 5-posi-
tion of the b-aryl-a-mercaptoacrylic acid 4, the cyclisa-
tion did not work as well but still afforded at least
Although the reaction was successful, the reaction mix-
ture was heterogenous and the work-up problematic. A
new homogenous method was developed and adapted
3
0% of desired product (entries 4 and 5).
9
using microwave heating, involving the use of an organ-
ic base (DBU) and a high boiling polar solvent (dimeth-
ylacetamide). The decarboxylation was carried out at
A more direct and amenable strategy to construct the
6
thienyl ring has been described (Scheme 2). This meth-
od is selective but depends on the commercial availabil-
ity of the starting o-fluorobenzaldehyde, or on its
synthesis via a fluorine directed ortho-lithiation. This
route is slightly longer, does not scale up very well and
still requires a decarboxylation.
2
MARS microwave reactor at 600Wcontinuous
00ꢁC for 1h in a sealed microwave vessel in a CEM
1
0
power. Results are presented in Table 3. This method
was very convenient as both base and solvent were easily
washed out.
The classical decarboxylation of benzo[b]thiophene-2-
carboxylic acids involves a copper-mediated reaction
in quinoline. We have demonstrated that the reaction
can be carried out directly on a 170mmol scale in a
All this chemistry was performed in a CEM MARS
microwave oven, which has a multimode cavity and is
therefore non-focused. This implies that the reactions
could be further optimised using a focused microwave
oven, which maximises the microwave irradiation in
the reaction mixture.
7
1
L round bottomed flask in a CEM MARS microwave
8
oven at 200ꢁC (Table 2).
In conclusion, the chemistry described provides an easy
and high-yielding method for the synthesis of substi-
tuted benzo[b]thiophenes using microwaves and in
particular novel reaction conditions for the decarboxyla-
tion reaction. Studies are currently underway to assess
the possibility that both the cyclisation and decarboxy-
lation reactions can take place in a Ôone-potÕ reaction
to further broaden the utility of this methodology. Our
results will be reported in due course.
O
R
R
R
i)
H
ii), iii)
COOH
S
F
F
6
7
8
Scheme 2. Reagents and conditions: (i) LDA, DMF, À78ꢁC; (ii) NEt
3
,
HSCH COOCH , DMSO; (iii) LiOH, THF, H O.
3
2
2

D. Allen et al. / Tetrahedron Letters 45 (2004) 9645–9647
9647
Table 3.
and hexane and allowed to dry overnight to give 6-meth-
oxybenzo[b]thiophene (3.19g, 83%). H NMR data were
consistent with that published in the literature.
. Gallagher, P. T.; Rathmell, R. E.; Fagan, M. A.; PCT Int.
Appl., CODEN: PIXXD2 WO 2002094262 A1 20021128,
1
1
2
a
Entry
R
R
Yield (%)
1
2
11
11
11
11
11
1
2
3
4
5
6
7
8
9
3-CF
3-CF
3-CF
3-CF
3-CF
4-F
3
3
3
3
3
H
75
65
62
78
78
87
100
91
100
91
87
100
95
92
54
85
70
49
65
83
80
87
70
5
5-Br
5-Cl
5-CN
6-Br
H
2
002.
6
7
8
. Bridges, A. J.; Lee, A.; Maduakor, E. C.; Schwartz, C. E.
Tetrahedron Lett. 1992, 33, 7499–7502.
. Zambias, R. A.; Hammond, M. L. Synth. Commun. 1991,
4-Cl
4-Br
H
2
1, 959–964.
H
. Decarboxylation conditions using Cu/quinoline in a
microwave oven: A 1L two-necked round bottomed flask,
equipped with a magnetic stirrer bar, was charged with
4-Me
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4-CF
6-F
3
H
H
6
1
-cyano-benzo[b]thiophene-2-carboxylic acid (34.6g,
70mmol), quinoline (420mL) and copper bronze powder
6-Cl
6-Br
7-F
H
H
(
4.2g, 66mmol). The flask was attached to a gas bubbler
H
and the temperature probe from the CEM MARS
microwave oven inserted through a gas tight septum and
heated for 45min at 600W(100%) at 200 ꢁC. As 170–
4-F
4-F
6-F
6-Br
7-OMe
6-Br
5-F
6-F
6-F
6-Br
7-OMe
4-F
1
80ꢁC was reached degassing through the bubbler was
4-Cl
4-Br
4-Br
4-Me
4-Me
4-Me
evident. The mixture was cooled to room temperature and
then slowly poured onto ice/concd HCl with stirring. The
mixture was extracted with diethyl ether (4 · 100mL) and
the combined extracts were then washed with 5M HCl and
dried (MgSO ). The crude products were purified by
4
chromatography on silica (400g) eluting with ether/hexane
1:4) to give benzo[b]thiophene-6-carbonitrile as a cream
a
(
solid (25.3g, 93%). H NMR (CDCl
(
Isolated yields.
1
3
, 300MHz): d 8.2
1H, s), 7.9 (1H, d, J = 8.3Hz), 7.7 (1H, d, J = 5.65Hz),
Acknowledgements
7.6 (1H, dd, J = 1.01 and 7.28Hz), 7.4 (1H, d,
J = 5.65Hz).
The assistance of Dr. Lesley Walton in proofreading this
paper is gratefully acknowledged.
9
. Urquhart, M. W. J. Unpublished results.
10. Typical decarboxylation conditions using DBU/DMA in a
microwave oven: mixture of 3-(trifluorometh-
A
yl)benzo[b]thiophene-2-carboxylic acid (3.12g, 12.7mmol)
and DBU (8g, 52.5mmol) in DMA (20mL) was heated in
a sealed vessel in a microwave reactor (600W) for 1h.
After cooling to room temperature the mixture was
poured into 1N HCl and the product extracted into ethyl
acetate. The organic phase was collected, dried (MgSO4),
filtered and concentrated under reduced pressure. The
crude product was passed through a pad of silica eluting
with hexane/ethyl acetate (19:1) to give 3-(trifluoro-
methyl)-benzo[b]thiophene (1.92g, 9.5mmol) in 75% yield.
References and notes
1
2
3
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89–892.
. Weisburg, J. H.; Weisburg, E. K. Clin. Pharmacol. Ther.
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CEM (Microwave Technology) Ltd, website
www.cemsynthesis.com.
. Typical cyclisation conditions in the microwave oven:
8
1
1
4
H NMR data were consistent with those published in the
1
1
(
2Z)-2-Mercapto-3-(4-methylphenyl)-2-propenoic
3.88g, 20mmol) was placed in a microwave vessel and
acid
literature. Note: Readers should be aware that this
reaction develops pressure due to release of carbon
dioxide, and this should be taken into account when
performing this transformation.
(
taken up in dioxane (30mL). Iodine (7.32g, 30mmol) was
added. The vessel was sealed and heated to 180ꢁC for
min at 400Win a CEM MARS microwave oven. The
mixture was then allowed to cool down to room temper-
ature and poured into saturated aqueous sodium bisulfite.
The resulting pink solid was filtered off, washed with water
8
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