Synthesis of 3-arylcoumarins via Suzuki-cross-coupling reactions of 3-chlorocoumarin

Article abstract of DOI:10.1016/j.tetlet.2011.01.048

A convenient and innovative protocol for an efficient synthesis of different substituted 3-arylcoumarins is reported. The developed synthetic route involves a Pd-catalyzed cross-coupling reaction using a catalytic complex Pd-salen. Under these conditions a series of different substituted boronic acids have been successfully coupled to a coumarin halide to afford novel coumarins in good yields.

Full text of DOI:10.1016/j.tetlet.2011.01.048

Tetrahedron Letters 52 (2011) 1225–1227
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 3-arylcoumarins via Suzuki-cross-coupling reactions
of 3-chlorocoumarin
Maria Joao Matos a,b, , Saleta Vazquez-Rodriguez a, Fernanda Borges b, Lourdes Santana a, Eugenio Uriarte a
⇑
a Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
b CIQUP/Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient, new, and effective protocol for a rapid synthesis of different substituted 3-arylcoumarins is
reported. The developed synthetic route involves Pd-catalyzed cross-coupling reaction, using a catalytic
complex Pd-salen. Under these conditions, a series of different substituted boronic acids have been suc-
cessfully reacted with a coumarin halide to afford the coupling products in good yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 15 November 2010
Revised 5 January 2011
Accepted 12 January 2011
Available online 18 January 2011
Keywords:
3-Arylcoumarins
Suzuki reaction
3-Chlorocoumarin
N,N0-Bis(salicylidene)-ethylenediamino-
palladium catalyst
Coumarins are an important class of benzopyrones that are
found in the vegetable kingdom, either in free or combined state.1
They occupy an important place in the realm of natural products
and synthetic organic chemistry. The diverse biological and phar-
maceutical properties of natural and synthetic coumarins as anti-
oxidants,2 anti-HIV,3 anticancer,4 vasorelaxants5 or enzymatic
inhibitors6 are well-known.1 In the last few years our research
group has been engaged in the synthesis of new biologically active
coumarins. In particular, the 3-phenylcoumarin’s scaffold has been
the focal point of our most recent studies. In fact we have demon-
strated that some 3-phenylcoumarins play an important role in the
monoamino oxidase (MAO) enzymatic inhibition.7–9 Accordingly,
the interesting application potential of the 3-arylcoumarins in
the Health Sciences promotes their preparation as an interesting
topic in synthetic organic chemistry.
Two different strategies can be used to obtain the phenylcouma-
rins. One is the construction of the coumarin nucleus by condensa-
tion–cyclization-type reactions. Wittig,10 Pechmann,5,7,11,12
Perkin8,9,13–17 or Knoevenagel18,19 reactions are some of the syn-
theticroutesfrequentlydescribedtoprepare3-arylcoumarins, start-
ing from phenols or aromatic carbonyl compounds. The classical
Perkin condensation is perhaps the most direct and simple method
known for the preparation of 3-arylcoumarins.16 Although this
method is often used, it has some drawbacks such as the application
of strong acids and high temperatures and sometimes the request of
multi-step reactions.
An alternative strategy consists in the direct 3-arylation of the
coumarin scaffold by metal cross-coupling reactions. In recent
years, palladium-catalyzed coupling reactions have been develop-
ing into a versatile and efficient method for the C–C bond forma-
tion. Suzuki20,21 and Stille have described simple synthetic routes
to obtain C–C liaisons throughout the coupling arylboronic or
organotin compounds with organic halides catalyzed by a palla-
dium-complex. In these reactions, Pd complexes are used as cata-
lysts in which the ligands are P and/or N lone pairs donors or
active Pd complexes are generated in situ.22 In the first case, some
of these ligands are expensive, toxic, and sensitive to air and a ma-
jor challenge lies in the separation of product from the expensive
catalyst, much to the dismay of large-scale producers.22 Ionic liq-
uids,23 free of organic solvent systems or phase-transfer catalysts24
have been used to provide a green alternative chemistry to the
conventional organic methodologies, but they are not devoid of
toxicity. In turn, phosphine ligands25 had played an important role
in C–C bond formation, in homogeneous reaction medium. Several
efforts have been made in order to discover air and moisture-stable
palladium ligands.25 However, these ligands are air- and moisture-
sensitive and the P–C bond degradation frequently occurs at ele-
vated temperature.26 The degradation of the catalyst strongly af-
fects conversion and selectivity of the derivatives.27 So, different
methods using phosphine-free ligands have been explored for
application in this kind of reactions.28
Because of its versatility, palladium catalyzed coupling reac-
tions were widely used to synthesize different arylcoumarins.
The arylation in 4-position of the coumarin nucleus is usually
achieved by arylation of 4-hydroxycoumarins with arylboronic
⇑
Corresponding author.
E-mail address: mariacmatos@gmail.com (M.J. Matos).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.048

1226
M. J. Matos et al. / Tetrahedron Letters 52 (2011) 1225–1227
R
reaction using 3-chlorocoumarin to afford 3-arylcoumarins has
never been described. This constraint encourages us to explore this
synthetic strategy. Accordingly, preliminary experiments were done
to examine the effect of various ligands for Pd-based coupling.42,43
The most promising one was N,N0-bis(salicylidene)-ethylenediami-
no-palladium (salen-Pd). In fact, Pd(OAc)2-salen couple in presence
of a Na2CO3 in DMF/H2O (1:1) was found to be an efficient catalytic
system to obtain a variety of 3-arylcoumarin derivatives (Scheme
1).40 As coumarins are sensitive substrates to alkaline conditions,
and may result in the cleavage of the lactone ring, the solvent, and
base for the coupling reaction were carefully studied. To optimize
the reaction the influence of the palladium source in the catalytic
activity was also performed. Pd(OAc)2 was found to be the best op-
tion.40 After reaction optimization, the influence of the Pd-salen
complex in the Suzuki reaction involving cross-coupling of a couma-
rin halide and different arylboronic acids was investigated. The Su-
zuki reaction developed herein was found to be effective when
using arylboronic acids with a variety of functional groups. Further-
more the reaction works with iodo-, bromo- or chloro-coumarin
substrates. Different reaction times are required for each coumarin
halide type. Although it is well-known that in Suzuki reaction the
chloride derivatives are less reactive than the bromide or the iodide
ones, the use of the 3-chlorocoumarin as starting material in the
reaction is related with its commercial availability. The synthesis
of 3-iodocoumarin and 3-bromocoumarin involves the introduction
of other synthetic steps in the overall reaction.
Comparing the synthetic route herein proposed with the classic
one, previously reported by us,7,8 one can verify that both are easy
and not too expensive methodologies. The main advantage of this
new synthetic approach is that it can afford 3-arylcoumarins with
different substitution patterns. By means of the traditional meth-
odology, hydroxyl and nitro derivatives could not be obtained
and/or purified. The reaction was not clean and the obtained crude
product was a complex mixture with several sub-products and the
purification process was worthless. The reaction versatility is the
main advantage of this synthetic strategy comparing to the classic
Perkin reaction. Compounds 4–744–46 and 1047 are exclusively pre-
pared by the Suzuki methodology while compounds 1–3, 8, and 9
can be prepared by both methods (Table 1).48–50 The proposed syn-
thetic strategy operates from micro- to macro-scale and avoids the
formation of undesired sub-products. The palladium complex can
be easily and almost totally recuperated at the end of the process.
The catalyst is recovered from the reaction mixture when the prod-
uct is purified by flash chromatography and it is ready to be reused.
This subject has great interest because of the toxicity and the cost
of palladium complexes.
(a)
Cl
Cl
O
O
O
O
O
1 - 9
(a)
1:
R = H
N
61 %
58 %
56 %
64 %
65 %
55 %
59 %
63 %
61 %
2: R = p-OMe
3: R = m-OMe
4: R = m-OH
5:
6:
R = p-NO2
R = m-NO2
7: R = m-NH2
8: R = p-Me
9: R = p-Cl
O
10
60 %
Scheme 1. Synthesis of 3-arylcoumarin derivatives. Reagents and conditions: (a) 3-
chlorocoumarin (1.0 equiv), phenylboronic acid/2-chloro-5-pyridineboronic acid
(1.25 equiv), sodium carbonate (2.0 equiv), palladium complex (0.5 mol %), DMF/
H2O (1:1), 110 °C, 120–180 min.
acids via C–OH bond activation.29 Accordingly, the 4-hydroxy
group is converted in pseudohalides, such as triflates or tosylates
which are used instead of halides in a coupling reaction with aryl-
boronic acids (via a Suzuki type reaction). In other cases, the aryl
substituents have been successfully incorporated in 4-position of
the hydroxycoumarin using organostannanes30 or organozinc com-
pounds31 under Stille or Negishi conditions, respectively.
However, the formation of the aryl C–C bond using coumarin as
starting material is till now an uncommon subject.32,33 To our
knowledge, few papers have been published so far concerning the
3-arylation of coumarin nucleus by direct coupling under Suzuki
conditions: in all these cases, the halide was 3-bromocoumarin.
And the catalysts were the classic palladium acetate (Pd(OAc)2), tet-
rakis(triphenylphosphine)palladium (0) Pd(PPh3)434,35, and [1,10-
bis(diphenylphosphino)ferrocene]palladium(II)
dichloride.36,37
Salen ligand has been found to be a highly active catalyst for the Su-
zuki reaction performed with aryl iodides, bromides, and chlorides,
giving excellent yields, in a short reaction time.38,39 Salen ligand is a
bright yellow solid, soluble in polar organic solvents, and effective in
C–C bond forming reactions with high selectivity. This symmetrical
palladium(II) complex was a product of the reaction of the Salen li-
gand with palladium acetate (for 20 h at room temperature) in a
good yield. This complex promotes a catalytic activity in a low con-
centration (0.5 mol %).40 Noteworthy to mention that Salen is a che-
lating ligand generally used in coordination chemistry and
homogeneous catalysis.41
Although significant advances have been performed in the metal-
catalyzed synthesis, the palladium-catalyzed cross-coupling
In conclusion, a novel and versatile route for the synthesis of 3-
arylcoumarins is proposed. The palladium cross-coupling reaction
can be applied to obtain a series of different functionalized deriv-
atives. In addition, we have shown that N,N0-bis(salicylidene)-eth-
ylenediamino-palladium proved to be a good catalyst for the
Suzuki reaction of heterocyclic activated chlorides with arylbo-
ronic acids, under aerobic conditions. This methodology is an effi-
cient synthetic route for obtaining different 3-arylcoumarins.
Table 1
Synthesis of 3-arylcoumarins (1–10) by Perkin reaction and/or via Suzuki-cross-
coupling reaction
Compounds
Perkin reactiona
Time (min) Yield (%)
Suzuki reactionb
Time (min) Yield (%)
1
2
3
4
5
6
7
8
9
10
1440
1440
1440
⁄
60
65
68
⁄
120
120
120
180
160
160
160
120
140
140
61
58
56
64
65
55
59
63
61
60
Acknowledgments
⁄
⁄
The authors thank the Spanish Ministry (PS0900501) and Xunta
da Galicia (INCITE09E2R203035ES and PGIDIT09CSA030203PR) for
the financial support. M.J.M. thanks Fundação de Ciência e Tecno-
logia for the SFRH/BD/61262/2009 scholarship.
⁄
⁄
⁄
⁄
1440
2160
⁄
70
63
⁄
References and notes
*
Compounds 4–7 and 10 are exclusively prepared by the Suzuki methodology.
a
Conditions: phenylacetic acids, DCC, DMSO, 110 °C, 24–36 h.
b
1. Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Curr. Med. Chem.
2005, 12, 887–916.
Reactions with 3-chlorocoumarin. Compound 1 was synthesized using 3-bro-
mocoumarin—reaction time: 100 min; yield: 70%.

M. J. Matos et al. / Tetrahedron Letters 52 (2011) 1225–1227
1227
2. Kontogiorgis, C.; Hadjipavlou-Litina, D. J. Enzyme Inhib. Med. Chem. 2003, 18,
36. Guo, H.-M.; Tanaka, F. J. Org. Chem. 2009, 74, 2417–2424.
63–69.
37. Zhang, L.; Meng, T.; Fan, R.; Wu, J. J. Org. Chem. 2007, 72, 7279–7286.
3. Spino, C.; Dodier, M.; Sotheeswaran, S. Bioorg. Med. Chem. Lett. 1998, 8, 3475–
3478.
4. Kempen, I.; Papapostolou, D.; Thierry, N.; Pochet, L.; Counerotte, S.; Masereel,
B.; Foidart, J. M.; Reboud-Ravaux, M. J.; Noel, A.; Pirotte, B. Br. J. Cancer 2003, 88,
1111–1118.
5. Vilar, S.; Quezada, E.; Santana, L.; Uriarte, E.; Yanez, M.; Fraiz, N.; Alcaide, C.;
Cano, E.; Orallo, F. Bioorg. Med. Chem. Lett. 2006, 16, 257–261.
6. Quezada, E.; Delogu, G.; Picciau, C.; Santana, L.; Podda, G.; Borges, F.; Garcia-
Moraes, V.; Vina, D.; Orallo, F. Molecules 2010, 15, 270–279.
7. Santana, L.; González-Díaz, H.; Quezada, E.; Uriarte, E.; Yáñez, M.; Viña, D.;
Orallo, F. J. Med. Chem. 2008, 51, 6740–6751.
8. Matos, M. J.; Viña, D.; Quezada, E.; Picciau, C.; Delogu, G.; Orallo, F.; Santana, L.;
Uriarte, E. Bioorg. Med. Chem. Lett. 2009, 19, 3268–3270.
9. Matos, M. J.; Viña, D.; Picciau, C.; Orallo, F.; Santana, L.; Uriarte, E. Bioorg. Med.
Chem. Lett. 2009, 19, 5053–5055.
38. Miller, K. J.; Baag, J. H.; Abu-Omar, M. M. Inorg. Chem. 1999, 38, 4510–4514.
39. Audisio, D.; Messaoudi, S.; Peyrat, J. F.; Alami, M. Tetrahedron Lett. 2007, 48,
6928–6932.
40. Borhade, S. R.; Waghmode, S. B. Tetrahedron Lett. 2008, 49, 3423–3429.
41. Bahkerad, M.; Keivanloo, A.; Bahramian, B.; Hashemi, M. Tetrahedron Lett. 2009,
50, 1557–1559.
42. Crociani, B.; Antonaroli, S.; Burattini, M.; Benetollo, F.; Scrivanti, A.; Bertoldini,
M. J. Organomet. Chem. 2008, 693, 3932–3938.
43. Blug, M.; Guibert, C.; Le Goff, X.; Mézailles, N. Chem. Commun. 2009, 2, 201–
203.
44. Leitao, A.; Andricopulo, A. D.; Oliva, G.; Pupo, M. T.; de Marchi, A. A.; Vieira, P.
C.; da Silva, M. F.; Ferreira, V. F.; de Souza, M. C.; Sa, M. M.; Moraes, V.;
Montanari, C. A. Bioorg. Med. Chem. Lett. 2004, 14, 2199–2204.
45. Mashraqui, S. H.; Vashi, D.; Mistry, H. D. Synth. Commun. 2004, 34, 3129–3134.
46. General method to prepare 3-arylcoumarins: To
a 20 mL two neck round-
10. Mali, R. S.; Joshi, P. P. Synth. Commun. 2001, 31, 2753–2767.
11. Ming, Y.; Boykin, D. W. Heterocycles 1987, 26, 3229–3231.
12. Hans, N.; Singhi, M.; Sharma, V.; Grover, S. K. Indian J. Chem., Sect B 1996, 11,
1159–1162.
13. Khiri, C.; Ladhar, F.; El Gharbi, R.; Le Bigot, Y. Synth. Commun. 1999, 29, 1451–
1461.
14. Mohanty, S.; Makrandi, J. K.; Grove, S. K. Indian J. Chem., Sect B 1989, 28B, 766–
769.
15. Langmuir, M. E.; Yang, J. R.; Moussa, A. M.; Laura, R.; Lecompte, K. A.
Tetrahedron Lett. 1995, 36, 3989–3992.
16. Mashraqui, S.; Vashi, D.; Mistry, H. D. Synth. Commun. 2004, 34, 3129–3134.
17. Kabeya, L. M.; de Marchi, A. A.; Kanashiro, A.; Lopes, N. P.; da Silva, C. H. Bioorg.
Med. Chem. 2007, 15, 1516–1524.
18. Bogdal, D. J. Chem. Res. (S) 1998, 468–469.
19. Mali, R. S.; Tilve, S. G. Synth. Commun. 1990, 20, 1781–1791.
20. Suzuki, A. J. Organomet. Chem. 2002, 653, 83–90.
21. Wang, J.; Meng, F.; Zhang, L. Organometallics 2009, 28, 2334–2337.
22. Cobert, J. P.; Mignani, G. Chem. Rev. 2006, 106, 2651–2710.
23. Dupont, J.; de Souza, R. F.; Suarez, A. Z. Chem. Rev. 2002, 102, 3667–3691.
24. Paetzold, E.; Oehme, G. J. Mol. Catal. A: Chem. 2000, 152, 69–76.
25. Genet, J. P.; Savignac, M. J. Organomet. Chem. 1999, 576, 305–317.
26. Safin, D. A.; Babashkina, M. G. Catal. Lett. 2009, 130, 679–682.
27. Mingji, D.; Liang, B.; Wang, C.; You, Z.; Xiang, J.; Dog, G.; Chen, J.; Yang, Z. Adv.
Synth. Catal. 2004, 346, 1669–1673.
28. Farina, V. Adv. Synth. Catal. 2004, 346, 1553–1582.
29. Luo, Y.; Wu, J. Tetrahedron Lett. 2009, 50, 2103–2105.
30. Schio, L.; Chatreaux, F.; Klich, M. Tetrahedron Lett. 2000, 41, 1543–1547.
31. Wu, J.; Liao, Y.; Yang, Z. J. Org. Chem. 2001, 66, 3642–3645.
32. Nemeryuk, M. P.; Dimitrova, V. D.; Sedov, A. L.; Anisimova, O. S.; Traven, V. F.
Chem. Heterocycl. Compd. 2002, 38, 249–250.
bottomed flask was added a solution of 3-chlorocoumarin (0.83 mmol), aryl
boronic acid (1.04 mmol), Na2CO3 (1.66 mmol), and Pd-salen complex
(0.5 mol %) in DMF/H2O (1:1). The reaction mixture was heated at 110 °C for
120–180 min. The reaction was monitored by chromatography. After the
completion of the reaction, the mixture was extracted with ethyl acetate
(3 ꢀ 20 mL). The organic extracts were dried over anhydrous sodium sulphate,
filtrated, and the solvent was evaporated under vacuum. The obtained crude
product was purified by column chromatography (hexane/ethyl acetate 9:1) to
give the coumarins (1–9). 3-(30-Nitrophenyl)coumarin (6): yellow solid, yield
55%; mp 252–3 °C. 1H NMR (CDCl3): d = 7.17–7.22 (m, 2H, H-7, H-8), 7.39–7.48
(m, 3H, H-5, H-6, H-50), 7.52–7.54 (m, 1H, H-60), 7.60–7.71 (m, 2H, H-4, H-40),
8.44 (s, 1H, H-20). 13C NMR (CDCl3): d = 110.0, 114.2, 116.7, 117.6, 119.3, 122.8,
125.5, 128.5, 131.1, 132.6, 132.7, 141.4, 149.1, 152.8, 158.6. MS: m/z (%) = 268
(26), 267 (M+, 100), 239 (24), 221 (38), 193 (17) 165 (52), 164 (16), 163 (19),
139 (12), 82 (11). Anal. calcd. for C15H9NO4 (267.24): C, 67.42; H, 3.39. Found:
C, 67.38; H, 3.36. 3-(30-aminophenyl)coumarin (7): white solid, yield 59%; mp
154–5 °C. 1H NMR (CDCl3): d = 4.12 (s, 2H, –NH2), 7.27–7.38 (m, 4H, H-20, H-40,
H-60, H-8), 7.47 (dd, 2H, H-6, H-7, J = 7.74, J = 1.31), 7.53–7.58 (m, 2H, H-5, H-
50), 7.88 (s, 1H, H-4). 13C NMR (CDCl3): d = 116.8, 118.8, 122.4, 125.0, 125.2,
127.2, 127.8, 128.7, 131.9, 133.3, 140.1, 152.6, 155.2, 157.3, 158.8. MS: m/z
(%) = 239 (10), 238 (19), 237 (M+, 100), 182 (36), 181 (12), 152 (50), 124 (18),
89 (45), 63 (28), 62 (18). Anal. calcd. for C15H11NO2 (237.25): C, 75.94; H, 4.67.
Found: C, 76.00; H, 4.72.
47. 3-(40-Chloropyridin-30-yl)coumarin (10): white solid, yield 60%; mp 234–5 °C.
1H NMR (CDCl3): d = 7.32–7.37 (m, 2H, H-50, H-8), 7.46 (d, 2H, H-6, H-7,
J = 7.51), 7.52–7.58 (m, 2H, H-5, H-60), 7.88 (s, 1H, H-4), 8.58 (s, 1H, H-20). 13C
NMR (CDCl3): d = 116.8, 118.8, 122.3, 124.7, 125.0, 125.2, 127.2, 131.8, 137.0,
140.0, 147.7, 149.6, 152.7, 157.3. MS: m/z (%) = 260 (5), 259 (32), 258 (15), 257
(M+, 100), 223 (18), 182 (34), 152 (44) 123 (13), 89 (40), 85 (23), 71 (30), 63
(18), 57 (35). Anal. calcd. for C14H8ClNO2 (257.57): C, 65.26; H, 3.13. Found: C,
65.24; H, 3.10.
33. Martins, S.; Branco, P. S.; de la Torre, M. C.; Sierra, M. A.; Pereira, A. Synlett
2010, 19, 2918–2922.
34. Schiedel, M.-S.; Briehn, C. A.; Bauerle, P. Angew. Chem., Int. Ed. 2001, 40, 4677–
4680.
48. Castaneda, F. Rendiconti Istituto Superiore di Sanita (Italian Edition) 1964, 27, 99.
49. Sabitha, G.; Rao, A. V. Synth. Commun. 1987, 17, 341–354.
50. Archer, J. F.; Grimshaw, J. J. Chem. Soc., Sect B: Phys. Org. 1969, 3, 266–270.
35. Chen, L.; Hu, T.-S.; Yao, Z.-J. Eur. J. Org. Chem. 2008, 36, 6175–6182.