Design and synthesis of condensed thienocoumarins by Suzuki-Miyaura reaction/lactonization tandem protocol

Article abstract of DOI:10.1016/j.tetlet.2012.10.096

A concise and efficient approach to a series of chromen-4-ones with fused thiophene ring has been developed using the Suzuki-Miyaura reaction of bromothiophene-2- and 3-carboxylates with 2-methoxyboronic acids and subsequent cyclization of prepared alkyl (2-methoxy)aryl thiophene-2- and 3-carboxylates under the action of BBr₃/KOtBu. Starting bromothiophenes are easily obtained from corresponding commercially available aminothiophenes by diazotization/bromination reaction.

Full text of DOI:10.1016/j.tetlet.2012.10.096

Tetrahedron Letters 53 (2012) 7135–7139
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Design and synthesis of condensed thienocoumarins by Suzuki–Miyaura
reaction/lactonization tandem protocol
Viktor O. Iaroshenko a,b, , Sajid Ali a, Satenik Mkrtchyan a, Ashot Gevorgyan a, Tariq Mahmood Babar a,
⇑
Volodymyr Semeniuchenko b, Zahid Hassan a, Alexander Villinger a, Peter Langer a,c
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b National Taras Shevchenko University, 62 Volodymyrska St., Kyiv 33 01033, Ukraine
c Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise and efficient approach to a series of chromen-4-ones with fused thiophene ring has been
developed using the Suzuki–Miyaura reaction of bromothiophene-2- and 3-carboxylates with 2-meth-
oxyboronic acids and subsequent cyclization of prepared alkyl (2-methoxy)aryl thiophene-2- and 3-car-
boxylates under the action of BBr3/KOtBu. Starting bromothiophenes are easily obtained from
corresponding commercially available aminothiophenes by diazotization/bromination reaction.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 23 July 2012
Revised 19 October 2012
Accepted 23 October 2012
Available online 30 October 2012
Keywords:
Thiophene
Coumarins
Suzuki–Miyaura coupling
Sandmeyer reaction
Lactonization
Heterocyclic systems containing an annulated coumarin moiety
are of considerable current interest as scaffolds which have found
major applications in medical chemistry. Coumarins (2H-1-benzo-
pyran-2-ones) are subunits of many natural products and occur in
a range of clinically used pharmaceuticals as well as in natural
products that have been isolated from a variety of plant sources1
and possess diverse bioactivities.2 On the other hand, the coumarin
framework is present in nonpeptidic HIV protease inhibitors,3
topoisomerase II,4 and tyrosine kinase5 inhibitors which are prom-
ising drug candidates. At the same time, coumarin derivatives have
found a wider application in material sciences, for example, due to
their optical properties.1 Annulated coumarins also show interest-
ing biological activities. For example furocoumarins can be found
in many natural products and exhibit antimicrobial and anticancer
activities.6
The coumestans, 6H-benzofuro[3,2-c]-[1]benzopyran-6-ones,
constitute a class of natural product analogues which have been
reported to possess diverse pharmacological properties, such as
phytoestrogenic, antibacterial, antifungal, antimyotoxic, and
phytoalexine effects.7 Coumarins annulated to a thiophene ring,
thieno[c]chromen-4-ones, have only been scarcely reported in the
literature so far. They are isosteres of 6H-benzo[c]chromen-6-ones
(coumestans) hence are of high importance for the design of new
pharmacologically active compounds.
The subject of the present study is to develop new and efficient
methods for the synthesis of thieno[c]chromen-4-ones. Based on a
retrosynthetic analysis of desired ring systems, we envisaged the
synthetic strategy depicted in Figure 1. The synthesis involves four
steps. First, the deaminative bromination of commercially avail-
able and inexpensive amines 1–3, second the Suzuki–Miyaura
reaction with ortho-methoxyphenylboronic acids, and, finally,
demethylation and lactonization.
To the best of our knowledge, this strategy has not been
previously applied to the synthesis of 4H-thieno[3,2-c]chromen-4-
ones, the main reason for that might be the synthetic accessibility
of the starting thiophenes 1–3 and related moieties. Coupled with
the Suzuki–Miyaura reaction the 4H-thieno[2,3-c]chromen-4-one
scaffold has been previously synthesized using ortho-hydrox-
yphenylboronic acid; however, this method suffers from the fact
that the synthesis of the starting boronic acid is in many cases diffi-
cult.8 Our laboratory had reported the synthesis of thieno[2,3-c:5,4-
c0]dichromene-6,8-dione from dimethyl 3,4-dibromothiophene-
2,5-dicarboxylate by the Suzuki–Miyaura reaction without further
exploration of this method concerning thienocoumarin synthesis.9
An important part of this Letter represents the synthesis of
fused benzo[b]benzothienocoumarins (6H-benzo[4,5]thieno[2,3-
c]chromen-6-ones). In fact the thiophene ring itself is a known
pharmacophore10 due to its isosterism to the benzene ring.11 The
⇑
Corresponding author. Fax: +49 (0)381 498 6412.
E-mail addresses:
viktor.iaroshenko@uni-rostock.de,
iva108@gmail.com
(V.O. Iaroshenko).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.096

7136
V. O. Iaroshenko et al. / Tetrahedron Letters 53 (2012) 7135–7139
Table 1
Compounds 7, 8, and 9a
R
R
MeO
Structure
%
Structure
%
Br
a)
b)
Het
OR
Het
Het
O
OR
O
O
O
78
78
c)
OMe
thieno[c]cumarines
OMe
Cl
S
S
O
7a
O
O
7b
O
NH2
NH2
OEt
O
OMe
S
NH2
S
OMe
1
O
S
2
3
79
80
OMe
OMe
S
Figure 1. Retrosynthetic analysis: (a) formation of the coumarin ring by lacton-
S
7d
ization; (b) Suzuki reaction; (c) deaminative bromination.
O
7c
OMe
F3C
NH2
Br
i
OMe
OMe
77
82
74
85
65
83
86%
S
S
OMe
OMe
O
O
1
O
S
S
4
O
7e
O
7f
O
S
OEt
OEt
Br
i
NH2
83%
OMe
OEt
S
S
S
O
7h
2
OMe
5
S
Br
NH2
7g
O
O
i
CN
O
O
ii
MeO
O
OMe
OMe
80%
S
OMe
S
NO2
OMe
6
3
F
S
Scheme 1. Reagents and conditions: (i): tert-butyl-nitrite, CuBr2, CH3CN, 2 h, rt,
10% aq HCl; (ii) HSCH2CO2Me, KOH, DMF, 0 °C, 1 h.
OMe
OEt
8a
S
7i
O
O
OEt
R
R
80
82
79
70
S
S
B(OH)2
8b
8d
8c
8e
4
5
OMe
OEt
i
O
O
S
OEt
OEt
O
7
R
O
S
S
R
Cl
B(OH)2
O
O
i
S
OEt
OEt
8
R
R
85
60
75
79
CF3
S
S
8g
B(OH)2
i
O
8f
6
O
O
S
OMe
OEt
OEt
OMe
OMe
OMe
9
S
Scheme 2. Reagents and conditions: (i) ArB(OH)2 (1.2 equiv), Pd(PPh3)4 (5 mol %),
K3PO4 (1.5 equiv), 1,4-dioxane, 90 °C, 4 h.
S
S
8h
8i
Cl
pharmacological profile of benzothiophenes (selective modulation
of estrogen receptor,12 antifungal activity,13 HIV protease inhibi-
tion,14 influence on neural protein folding,15 regulation of bone
morphogenetic protein,16) and the usefulness of arylated benzothi-
ophenes in the field of electronics10a,17 inspired us to prepare these
compounds.
O
88
71
O
S
OMe
9a
S
OMe
9b

V. O. Iaroshenko et al. / Tetrahedron Letters 53 (2012) 7135–7139
7137
Table 2
Table 1 (continued)
Synthesis of compounds 10–15a
Structure
%
Structure
%
Structure
%
Structure
%
CF3
MeO
79
88
O
78
86
O
O
OMe
S
S
S
OMe
9c
S
OMe
9d
9f
O
13a
O
10a
OMe
F
MeO
MeO
F
O
74
84
OMe
O
80
79
S
OMe
9e
S
O
S
10b
O
OMe
S
13b
O
O
a
Yields of isolated products.
Cl
O
MeO
Cl
OMe
R
85
75
S
R
S
MeO
MeO
O
10c
R
13c
B(OH)2
HO
OMe
MeO
4
O
ii
S
i
OMe
OMe
S
13
O
10
O
R
78
75
77
76
80
81
O
S
O
O
O
MeO
MeO
O
OEt
10d
S
13d
HO
R
R
B(OH)2
O
5
ii
S
MeO
S
i
14
MeO
R
11
MeO
R
O
OMe
R
O
OMe
S
S
O
10e
O
O
13e
B(OH)2
O
MeO
6
ii
O
S
i
S
OMe
MeO
OH
15
12
O
S
13f
Scheme 3. Reagents and conditions: (i): ArB(OH)2 (1.2 equiv), Pd(PPh3)4 (5 mol %),
K3PO4 (1.5 equiv), 1,4-dioxane, 90 °C, 4h; (ii): (a) BBr3, CH2Cl2, (b) KOtBu, H2O.
OMe
O
O
S
10f
We have earlier reported the synthesis of biaryl lactones by a
combination of the Suzuki–Miyaura reaction of various alkyl 2-trif-
luoromethylsulfonyloxy-salicylates with ortho-methoxyphenylbo-
ronic acids and subsequent BBr3-mediated demethylation and
lactonization.18 Snieckus et al. reported the combination of the di-
rected ortho metalation with the Suzuki–Miyaura reaction and
subsequent lactonization.19
With our concept in hand, we have started the investigation of
the synthesis of thieno[c]coumarins. The synthesis of compounds
4–6 was achieved starting from 1 to 3 by a deamination/bromina-
tion reaction (Scheme 1). This transformation swiftly took place in
acetonitrile using tert-butyl nitrite as the diazotization agent and
copper bromide as the source of halogen.
As a next step, we have tested the Suzuki–Miyaura C–C coupling
of obtained compounds with the set of commercially available aro-
matic and heteroaromatic boronic acids. The reaction of 4–6, car-
ried out in 1,4-dioxane under reflux and using Pd(PPh3)4 as the
catalyst and potassium phosphate as the base, afforded products
7–9 in excellent yields (Scheme 2, Table 1).
Inspired by these successful results next we have switched on
the development of the preparative synthetic methods toward con-
densed thienocoumarins following the proposed retrosynthetic
analysis (Fig. 1). The reaction of 4–6 with ortho-methoxyphenylbo-
O
O
OEt
79
77
80
71
83
85
82
75
S
S
14a
14b
MeO
OEt
11a
O
O
O
F
S
S
F
MeO
OEt
11b
11c
O
O
O
O
Cl
S
S
Cl
14c
14d
MeO
OEt
O
O
OH
S
S
MeO
OMe
11d
(continued on next page)

7138
V. O. Iaroshenko et al. / Tetrahedron Letters 53 (2012) 7135–7139
Table 2 (continued)
Structure
%
Structure
%
O
O
O
OEt
OMe
74
75
S
S
OH
14e
MeO
OEt
11e
11f
O
O
O
MeO
82
86
79
S
S
HO
14f
MeO
Figure 3. Molecular structure of compound 15a.
MeO
O
synthetic strategy starting from readily available amino-thio-
phenes via diazotization–bromination/Suzuki–Miyaura reaction/
KOtBu induced lactonization. The scope and limitation of the meth-
od were extensively studied and the structures of two products
O
74
80
O
S
S
15a
S
OMe
Cl
12a
Cl
were unambiguously confirmed by
diffraction.
a single crystal X-ray
MeO
O
70
O
Supplementary data
S
OMe
O
12b
15b
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.10.
096.
a
Yields of isolated products.
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22. Crystallographic data (excluding structure factors) for the structures 13c and
15a reported in this Letter have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no. 866896 and
no. 866897 and can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 (1223)336033; e-mail:
deposit@ccdc.cam.ac.uk, or via www.ccdc.cam.ac.uk/data_request/cif.