Synthesis of 4-(thien-2-yl)-substituted coumarins through Lewis acid catalyzed Michael addition of thiophenes to 3-benzoylcoumarins followed by oxidation

Article abstract of DOI:10.1016/j.tetlet.2014.04.112

3-Benzoyl-4-(thien-2-yl)coumarins have been obtained in good yields according to the S_N^H addition-oxidation protocol, involving the diastereoselective addition of thiophenes at C-4 of 3-benzoylcoumarins under BBr₃ catalysi

Full text of DOI:10.1016/j.tetlet.2014.04.112

Accepted Manuscript
Synthesis of 4-(thien-2-yl)-substituted coumarins through Lewis acid catalyzed
Michael addition of thiophenes to 3-benzoylcoumarins followed by oxidation
Roman A. Irgashev, Arseny A. Karmatsky, Gennady L. Rusinov, Valery N.
Charushin
PII:
S0040-4039(14)00749-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.112
TETL 44574
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 March 2014
7 April 2014
30 April 2014
Please cite this article as: Irgashev, R.A., Karmatsky, A.A., Rusinov, G.L., Charushin, V.N., Synthesis of 4-(thien-2-
yl)-substituted coumarins through Lewis acid catalyzed Michael addition of thiophenes to 3-benzoylcoumarins
followed by oxidation, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.112
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Graphical abstract
_____________________________________________________________________________________
Synthesis of 4-(thien-2-yl)-substituted coumarins through Lewis acid catalyzed Michael addition of
thiophenes to 3-benzoylcoumarins followed by oxidation
Roman A. Irgashev*, Arseny A. Karmatsky, Gennady L. Rusinov, Valery N. Charushin
_____________________________________________________________________________________________________________________
∗
Corresponding author. Fax: +7 343 369 30 58;
e-mail: irgashev@ios.uran.ru

Synthesis of 4-(thien-2-yl)-substituted coumarins through Lewis acid
catalyzed Michael addition of thiophenes to 3-benzoylcoumarins followed by
oxidation
Roman A. Irgasheva,b,*, Arseny A. Karmatskya,b, Gennady L. Rusinova,b,
Valery N. Charushina,b
aI. Postovsky Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences, S. Kovalevskoy Str., 22,
Ekaterinburg, 620041, Russia; *Corresponding author: Fax: +7 343 369 30 58; e-mail: irgashev@ios.uran.ru
bUral Federal University named after the First President of Russia B. N. Yeltsin, Mira St. 19, Ekaterinburg,
620002, Russia
A B S T R A C T
H
3-Benzoyl-4-(thien-2-yl)coumarins have been obtained in good yields according to the SN
addition-oxidation protocol, involving the diastereoselective addition of thiophenes at C-4 of 3-
benzoylcoumarins under BBr3 catalysis, followed by oxidation of the intermediate 3,4-trans-3-
benzoyl-4-(thien-2-yl)-3,4-dihydrocoumarins with DDQ. This two-step procedure can be
H
regarded as nucleophilic substitution of hydrogen (SN ) on the heterocyclic ring of coumarins.
Keywords: Thiophenes, 3-Benzoylcoumarins, Lewis acid, Nucleophilic aromatic substitution of
hydrogen, Metal-free cross-coupling reactions, Oxidative coupling reactions, Direct
heteroarylation
Coumarins (2H-chromen-2-ones) belong to an important class of oxygen-containing
heterocycles, which are found widely in Nature, mostly in the plant kingdom. Both synthetic and
natural coumarins are known to exhibit a wide spectrum of pharmacological properties.1,2 Due to
their unique optical properties, coumarin derivatives have found wide application as basic
components of organic materials used in lasers, sensors, photosensitizers, light-emitting diodes
and fluorescent markers for biomedical imaging.3 In this respect, the practical value of coumarin
derivatives is incredibly high. This is the reason why research on modifying the structure of this
heterocyclic system has continued.
Coumarins 1, unsubstituted at C-4 and bearing an acceptor substituent at C-3, are easily
available: these heterocyclic compounds can be obtained by using the Perkin condensation of
salicylaldehydes with active methylene compounds, such as β-ketoesters or β-ketonitriles, under
basic conditions (Scheme 1). Due to the electron-deficient character of coumarins 1, the main
This paper is dedicated to Professor Oleg N. Chupakhin on the occasion of his 80th birthday.
2

type of reaction they undergo is nucleophilic (Michael type) addition at C-4. However, the list of
reactions of coumarins 1 with aromatic (heteroaromatic) C-nucleophiles is limited by a few
examples of the Michael adduct formation. Indeed, the reactions of 3-alkoxycarbonyl substituted
coumarins with 3,5-dimethoxyphenol4 and indole,5 as well as nucleophilic addition of indole or
pyrrole at C-4 of 3-nitrocoumarin6 have resulted in the formation of 3,4-dihydrocoumarins 2-5,
respectively (Scheme 1).
EWG
X
H
O
(Het)Ar
O
H2C
EWG
O
EWG
O
(Hetero)arylation
O
R
R
R
Base
OH
No reports
1
X = CN, CO2Et
EWG = CN, NO2, CO2Alk, COAlk, COAr, CONR2
OMe
HN
HN
NH
MeO
OH
NO2
O
CO2Et
O
NO2
O
CO2Me
O
O
O
O
O
2
3
4
5
Scheme 1. The Perkin synthesis of 3-substituted coumarins 1.
Structures of the Michael adducts 2-5.
At present, there are no reports in the literature on metal-catalyzed or metal-free methods for the
direct (hetero)arylation of coumarins 1 at C-4 (Scheme 1).
It is worth noting that a very efficient approach for the direct functionalization of electron-
deficient azines (pyridines, pyrimidines, 1,2,4-triazines and their fused derivatives) is via
H
H
nucleophilic aromatic substitution of hydrogen (SN ).7,8 The two-step SN reactions usually
involve addition of nucleophiles to electron-deficient azines under acidic or basic catalysis,
H
followed by oxidation of the intermediate σH-adducts (Scheme 2). In particular, the SN
methodology provides access to a variety of nitrogen-containing heterocyclic compounds
through direct metal-free oxidative coupling of azines with electron-rich nucleophiles.
Scheme 2. Direct C-H functionalization of azines using the SNH methodology
3

In this Letter we report a convenient method for the preparation of 3-benzoyl-4-(thien-2-
yl)coumarins by nucleophilic aromatic substitution of hydrogen. This approach corresponds to
one of the principles of green chemistry, i.e., atom economy, since the direct C-H/C-H coupling
of 4-unsubstituted 3-benzoylcoumarins with thiophenes takes place.
The addition of 2-methylthiophene at C-4 of 3-benzoylcoumarin (6a) was first studied
under catalysis with various Lewis acids and CF3SO3H. 2-Methylthiophene was selected as the
model reagent, bearing one active nucleophilic center, namely C-5. The reaction of 6a with two
molar equivalents of 2-methylthiophene was carried out in dry dichloromethane at ambient
temperature for 24 hours to give 3-benzoyl-4-(5-methylthien-2-yl)-3,4-dihydrocoumarin (7a),
the yield of which varied depending on the catalyst used (Scheme 3, Table 1).
Me
S
Me
S
O
O
O
O
Ph
Ph
acid catalyst,
solvent,
24 h, RT
O
O
6a
7a
Scheme 3. Synthesis of 3,4-dihydrocoumarin 7a
Table 1. Reaction conditions and obtained yields of 3,4-dihydrocoumarin (7a)a
Entry
Acid catalyst
AlCl3
Solvent
CH2Cl2-THF (3:1)
CH2Cl2-THF (3:1)
CH2Cl2
CH2Cl2-THF (3:1)
CH2Cl2
Yield 7a (%)
40
1
2
3
4
5
6
7
6a/7ab
30
TiCl4
BF3•Et2O
SnCl4
6a/7ab
0 (dec.)
35
CF3SO3H
AlBr3
CH2Cl2
CH2Cl2
77
BBr3
a 1 mmol of 6a, 1.1 mmol of catalyst and 2 mmol of 2-methylthiophene were
bused
A mixture of 6a and 7a was obtained with a low conversion of the starting
compound
The formation of adduct 7a was achieved in a good yield (77%) when BBr3 was used as
the catalyst (Table 1, entry 7). The optimal reaction conditions for the addition of 2-
methylthiophene at C-4 of coumarin 6a were further applied to obtain 3,4-dihydro-coumarins
7b-e in 68−80% yields (Scheme 4, Table 2, entries 1-5).9 Unfortunately, the adducts of
coumarins 6 with thiophene or 2-bromothiophene were not formed under the above mentioned
reaction conditions. Nevertheless, the C-C coupling of these thiophenes with coumarins 6a,b,d
4

was accomplished on refluxing the reagents with BBr3 in 1,2-dichloroethane (DCE) for one hour,
thus giving 3,4-dihydrocoumarins 7f-i (Scheme 4, Table 2, entries 6-9).10
Scheme 4. The synthesis of 3,4-dihydrocoumarins 7
Table 2. Yields and melting points of 3,4-dihydrocoumarins 7a
Entry
R1
H
H
H
H
R2
H
Br
Br
Cl
R3
H
H
Br
H
H
H
H
H
H
X
Me
Me
Me
Me
Me
H
Mp 7 (°C) Yield 7 (%)
Compounds 6 / 7
6a / 7a
1
2
3
4
5
6
7
8
9
161−162
207−208
157−158
190−191
147−148
144−145
157−158
191−192
184−185
77
70
80
73
68
69
84
63
59
6b / 7b
6c / 7c
6d / 7d
6e / 7e
benzo[f]
6a / 7f
H
H
H
H
H
H
6a / 7g
Br
6b / 7h
6d / 7i
Br
Cl
Br
H
a 3 mmol of 6, 3.3 mmol of BBr3 and 6 mmol of 2-methyl- or 2-bromothiophene or 30 mmol of thiophene
were used
It should be noted that the addition of thiophenes to coumarins 6 proceeds in a highly
diastereoselective manner and leads to the formation of the thermodynamically controlled
1
products, 3,4-trans-substituted dihydrocoumarins 7. No cis-isomers of 7 were detected in the H
NMR spectra of the crude reaction products. The NMR spectra of compounds 7 exhibited two
characteristic doublets for the H-3 and H-4 protons of the heterocyclic ring with 1H-1H coupling
constants of 6.0−6.9 Hz, which are in a good correlation with those (6.0−7.0 Hz) of the
corresponding signals in the 1H NMR spectra of 3,4-trans-3-benzoyl-4-aryl-3,4-
dihydrocoumarins.11 In addition, the structures of 3,4-dihydrocoumarins 7 were unequivocally
established by X-ray crystallographic analysis, performed on compound 7g (Figure 1).12
5

Figure 1. Mercury13 representation of the X-ray crystal structure of 7g.
Thermal ellipsoids at 50% probability.
Oxidation of 3,4-dihydrocoumarins 7 was the final step to complete the functionalization
H
of 3-benzoylcoumarins 6 at C-4 via the SN methodology. Several oxidizing agents (N-bromo-
succinimide or SO2Cl2/pyridine-CH2Cl2 at RT; chloranil or DDQ/1,4-dioxane at reflux) were
tested for this purpose, while 3,4-dihydrocoumarin 7a was chosen as a model compound to find
the optimum oxidation conditions. The reactions of 7a with N-bromosuccinimide or SO2Cl2 led
to decomposition of compound 7a. The use of DDQ for the oxidation of 7a proved to be
successful and 4-substituted 3-benzoylcoumarin 8a was obtained in 69% yield. Coumarin 8a was
also obtained in the case of oxidation with chloranil, but the conversion of the starting material
7a was rather poor and the yield of the target product was only 17%. The best reaction
conditions for the oxidation of 7a with DDQ were applied for the preparation of coumarins 8b-e
(Scheme 5, Table 3).14
X
X
S
S
O
O
O
O
R1
R1
DDQ
Ph
Ph
1,4-dioxane, , 10 h
O
O
R2
R2
8a-e
7a-c,g,i
Scheme 5. Oxidation of 3,4-dihydrocoumarins 7
Table 3. Yields and melting points of coumarins 8
Entry Compounds 7 / 8
X
R1
H
R2
H
Mp 8 (°C)
162−163
179−180
183−184
153−154
191−192
Yield 8 (%)
1
2
3
4
5
7a / 8a
7b / 8b
7c / 8c
7g / 8d
7i / 8e
Me
Me
Me
Br
69
65
79
87
78
Br
Br
H
H
Br
H
H
Cl
H
6

It is worth noting that the reaction conditions found for the oxidation of 3,4-
dihydrocoumarins 7 with DDQ are far from perfect, and they need to be improved as low
conversions of the starting 3,4-dihydrocoumarins were observed with compounds 7d-f,h.
The range of coumarins 8 can be expanded through modification of 4-(5-bromothien-2-yl)
substituted 3-benzoylcoumarins by means of cross-coupling reactions. Indeed, 4-[5-
(het)arylthien-2-yl]-3-benzoylcoumarins 8f,g were prepared from coumarin 8d via the Suzuki
and Stille cross-coupling reactions with phenylboronic acid and 2-(tributylstannyl)thiophene,
respectively (Scheme 6).
Scheme 6. Cross-coupling reactions of coumarin 8d
4-(Thien-2-yl)-substituted 3-benzoylcoumarins 8 can be regarded as structural analogs of 3-
aroylchromones 9 and 10, which upon irradiation with UV light are transformed irreversibly into
fluorescent derivatives of fused chromones 11 and 12 (Scheme 7).
Scheme 7. UV-transformation of 3-aroylchromones 9 and 10
Due to this ability 3-aroylchromones, compounds 9 and 10 are used as components of materials
for multilayer optical discs of ultra-high information capacity.15 In this respect, 3-
benzoylcoumarins 8 can also be considered as promising compounds for the development of
photosensitive materials.
7

H
In conclusion, we have shown for the first time that the SN methodology is an efficient
approach for the direct heteroarylation of 4-unsubstituted coumarins. A convenient metal-free
method for the synthesis of 3-benzoyl-4-(thien-2-yl)coumarins has been developed through the
addition of thiophenes at C-4 of 3-benzoylcoumarins under BBr3 catalysis, followed by oxidation
of the 3,4-dihydrocoumarins with DDQ to give 4-(thien-2-yl)-substituted 3-benzoylcoumarins,
which are of interest as potential optical materials. Further studies on the photochemical
properties of these coumarins and optimization of the second synthetic step are in progress.
Acknowledgments
This work was supported by the Ural Division of the Russian Academy of Sciences (Grants №
12-P-3-1014, 12-P-3-1030, 12-T-3-1025 and 12-T-3-1031), the Russian Foundation for Basic
Research (research projects No. 13-03-12434-ofi_m2, 13-03-96049-r_ural_a, 14-03-01017_A,
14-03-00479_A), and the Scientific Council of the President of the Russian Federation (grant
МК-3043.2014.3).
References and notes
1. O'Kennedy, R.; Thornes, R. D. Coumarins, Biology, Applications and Mode of Action, John
Wiley and Sons, Chichester, 1997.
2. (a) Mahmoud, Z. F.; Sarg, T. M.; Amer, M. E.; Khafagy, S. M. Pharmazie 1983, 38, 486; (b)
Spino, C.; Dodier, M.; Sotheeswaran, S. Bioorg. Med. Chem. Lett., 1998, 8, 3475; (c) Sardari, S.;
Mori, Y.; Horita, K.; Micetich, R. G.; Nishibe, S.; Daneshtalab, M. Bioorg. Med. Chem. 1999, 7,
1933; (d) Reutrakul, V.; Leewanich, P.; Tuchinda, P.; Pohmakotr, M.; Jaipetch, T. Sophasan, S.;
Santisuk, T. Planta Med. 2003, 69, 1048; (e) Kontogiorgis, C.; Litina, D. H. J. Enzyme Inhib.
Med. Chem. 2003, 18, 63; (f) Shen, Q.; Peng, Q.; Shao, J.; Liu, X.; Huang, Z.; Pu, X.; Ma, L.; Li,
Y.-M.; Chan, A. S. C.; Gu, L. Eur. J. Med. Chem. 2005, 40, 1307.
3. (a) Lee, K. S.; Kim, H. J.; Kim, G. H.; Shin, I.; Hong, J. I. Org. Lett. 2008, 10, 49; (b) Zhao,
Y.; Zheng, Q.; Dakin, K.; Xu, K.; Martinez, M. L.; Li, W.-H. J. Am. Chem. Soc. 2004, 126,
4653; (c) Woodroofe, C. C.; Won, A. C.; Lippard, S. J. Inorg. Chem. 2005, 44, 3112; (d) Hara,
K.; Wang, Z. S.; Sato, T.; Furube, A.; Katoh, R.; Sugihara, H.; Dan-Oh, Y.; Kasada, C.; Shinpo,
A.; Suga, S. J. Phys. Chem. Sect. B 2005, 109, 15476; (e) Hara, K.; Sato, T.; Katoh, R.; Furube,
A.; Ohga, Y.; Shinpo, A.; Suga, S.; Sayama, K.; Sugihara, H.; Arakawa, H. J. Phys. Chem. B
2003, 107, 597.
4. Duan, S.; Jana, R.; Tunge, J. A. J. Org. Chem. 2009, 74, 4612.
8

5. (а) Ye, M.; Yang, Y.; Tang, Y.; Sun, X.; Ma, Z.; Qin, W. Synlett 2006, 1240; (b) Tan, F.; Li,
F.; Zhang, X.-X.; Wang, X.-F.; Cheng, H.-G.; Chen, J.-R.; Xiao, W.-J. Tetrahedron 2011, 67,
446.
6. Nickerson, D. M.; Mattson, A. E. Chem. Eur. J. 2012, 18, 8310.
7. For reviews, see: (a) Chupakhin, O. N.; Charushin, V. N.; van der Plas, H. C. Nucleophilic
Aromatic Substitution of Hydrogen, Academic Press: San Diego, NY, 1994; (b) Charushin, V.
N.; Chupakhin, O. N. Pure Appl. Chem. 2004, 76, 1621; (c) Charushin, V. N.; Chupakhin, O. N.
Mendeleev Commun. 2007, 17, 249; (d) Makosza, M.; Wojciechowski, K. Chem. Rev., 2004,
104, 2631; (e) Makosza, M. Chem. Soc. Rev. 2010, 39, 2855.
8. (a) Verbitskiy, E. V.; Cheprakova, E. M.; Slepukhin, P. A.; Kodess, M. I.; Ezhikova, M. A.;
Pervova, M. G.; Rusinov, G. L.; Chupakhin, O. N.; Charushin, V. N. Tetrahedron 2012, 68,
5445; (b) Verbitskiy, E. V.; Rusinov, G. L.; Charushin, V. N.; Chupakhin, O. N.; Cheprakova, E.
M.; Slepukhin, P. A.; Pervova, M. G.; Ezhikova, M. A.; Kodess, M. I. Eur. J. Org. Chem. 2012,
2012, 6612.
9. General procedure for the synthesis of 4-(5-methylthien-2-yl)-substituted 3-benzoyl-3,4-
dihydrocoumarins 7a-e: BBr3 (0.32 ml, 3.3 mmol) and 2-methylthiophene (0.58 ml, 6 mmol)
were added to a solution of an appropriate 3-benzoylcoumarin 6 (3 mmol) in dry CH2Cl2 (30 ml)
and the resulting solution was stirred at room temperature for 24 h. The mixture was treated with
H2O (30 ml) and stirred for 2 h. The organic layer was separated and then filtered through a
silica gel pad. The filtrate was concentrated under reduced pressure and the residue was
recrystallized from EtOH/CH2Cl2 affording the target product 7.
10. General procedure for the synthesis of 4-(thien-2-yl)-substituted 3-benzoyl-3,4-
dihydrocoumarins 7f-i: BBr3 (0.32 ml, 3.3 mmol), thiophene (2.37 ml, 30 mmol) or 2-
bromothiophene (0.58 ml, 6 mmol) were added to a solution of the appropriate 3-
benzoylcoumarin 6 (3 mmol) in dry (CH2Cl)2 (30 ml) and the resulting solution was stirred at
reflux for 1 h. The mixture was treated with H2O (30 ml) and stirred for 2 h. The organic layer
was separated and then filtered through a silica gel pad. The filtrate was concentrated under
reduced pressure and the residue recrystallized from EtOH/CH2Cl2, thus affording the target
product 7. The analytical data for 3,4-dihydrocoumarins 7a-i are available in the Supplementary
information.
11. Liang, D.; Wang, M.; Bekturhun, B.; Xiong, B.; Liua, Q. Adv. Synth. Catal. 2010, 352, 1593.
12. Crystal data for 7g: Yellow crystals 0.4×0.2×0.15 mm, θ < 26.38o, 12968 reflections were
collected, 3518 independent reflections (Rint 0.0493), completeness 99.6%. Crystal is
monoclinic, space group P2(1)/c, a= 5.4868(5) Å, b= 13.9319(13) Å, c= 22.588(3) Å, α= 90.00o,
β= 92.261(9)o, γ= 90.00o, µ= 2.520 mm-1. The SHELXTL program16 was used for solution and
9

structure refinement. Refinement and the final R indices: R1= 0.0337 [I>2σ(I)], wR2= 0.0444
[I>2σ(I)], R1= 0.1042 (all data), wR2= 0.0473 (all data), S= 1.001. Deposition number CCDC
985930 contains the supplementary crystallographic data for this structure. These data can be
obtained free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
13. Mercury 3.1, available from http://www.ccdc.cam.ac.uk/mercury/
14. General procedure for the synthesis of 4-(thien-2-yl)-substituted 3-benzoylcoumarins 8a-e: A
solution of 3,4-dihydrocoumarin 7 (1.5 mmol) and DDQ (0.68 g, 3 mmol) in 1,4-dioxane (15 ml)
was heated at reflux for 10 h. After cooling, the mixture was filtered through Al2O3 and the
residue washed with CH2Cl2. The filtrate was concentrated under reduced pressure and the
residue was recrystallized from EtOH/CH2Cl2, thus affording coumarins 8. The analytical data
for coumarins 8a-e are available in the Supplementary information.
15. (a) Barachevsky, V. A.; Strokach, Y. P.; Puankov, Y. A.; Kobeleva, O. I.; Valova, T. M.;
Levchenko, K. S.; Yarovenko, V. N.; Krayushkin, M. M. ARKIVOC 2009, (ix), 70; (b)
Krayushkin, M. M.; Levchenko, K. S.; Yarovenko, V. N.; Zavarzin, I. V.; Barachevsky, V. A.;
Puankov, Y. A.; Valova, T. M.; Kobeleva, O. I. ARKIVOC 2009, (ix), 269.
16. Sheldrick, G. M. Acta Cryst. Sect. A. 2008, 64, 112.
10