Short synthesis of cytotoxic 4-arylcoumarins

Article abstract of DOI:10.1080/00397910500501235

A short synthesis of cytotoxic 4-arylcoumarins via condensation of phenols with cinnamic acids in the presence of CF₃COOH, followed by dehydrogenation with DDQ, is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910500501235

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Short Synthesis of Cytotoxic 4‐Arylcoumarins
Eleonora Rizzi a , Sabrina Dallavalle a , Lucio Merlini a , Graziella Pratesi b &
Franco Zunino b
a Dipartimento di Scienze Molecolari Agroalimentari , Università di Milano ,
Milan, Italy
b Unità di Farmacologia Preclinica , Istituto Nazionale per lo Studio e la Cura
dei Tumori , Milan, Italy
Published online: 16 Aug 2006.
To cite this article: Eleonora Rizzi , Sabrina Dallavalle , Lucio Merlini , Graziella Pratesi & Franco Zunino
(2006) Short Synthesis of Cytotoxic 4‐Arylcoumarins, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 36:8, 1117-1122, DOI: 10.1080/00397910500501235
To link to this article: http://dx.doi.org/10.1080/00397910500501235
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Synthetic Communicationsw, 36: 1117–1122, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500501235
Short Synthesis of Cytotoxic
4-Arylcoumarins
Eleonora Rizzi, Sabrina Dallavalle, and Lucio Merlini
`
Dipartimento di Scienze Molecolari Agroalimentari, Universita di
Milano, Milan, Italy
Graziella Pratesi and Franco Zunino
Unita di Farmacologia Preclinica, Istituto Nazionale per lo Studio e la
Cura dei Tumori, Milan, Italy
`
Abstract: A short synthesis of cytotoxic 4-arylcoumarins via condensation of phenols
with cinnamic acids in the presence of CF3COOH, followed by dehydrogenation with
DDQ, is described.
Keywords: Arylcoumarins, cytotoxic activity, DDQ, dehydrogenation
In a recent paper Bailly et al.[1] reported on the cytotoxic activity of some
4-arylcoumarins, in particular with hydroxy and methoxy substituents, as
analogues of combretastatins. These compounds were prepared from an
appropriate 4-hydroxycoumarin, via triflation followed by Suzuki arylation
with a benzyl-protected substituted arylboronic acid or via Stille coupling.
We report here on a shorter synthesis of some examples of this class of
compounds, which takes advantage of a direct synthesis of 3,4-dihydro-4-aryl-
coumarins via an acid-catalyzed condensation of cinnamic acids with phenols,
followed by dehydrogenation with 2,3-dichloro-5,6-dicyano-p-benzoquinone
(DDQ).
The condensation of phenols with cinnamic acids to give 4-aryl-3,4-dihy-
drocoumarins was first reported by Liebermann and Hartmann[2] and later
exploited in a variety of acid conditions.[3] In our case, condensation of
Received in the U.K. May 23, 2005
Address correspondence to Lucio Merlini, Dipartimento di Scienze Molecolari
`
Agroalimentari, Universita di Milano, Via Celoria 2, I 20133, Milan, Italy.
Tel.: þ39 0250316812; Fax: þ39 0250316801; E-mail: lucio.merlini@unimi.it
1117

1118
E. Rizzi et al.
phenols 1 with cinnamic acids 2 in the presence of trifluoroacetic acid at room
temperature or reflux gave the expected 3,4-dihydrocoumarins 3 in good
yields. These conditions, experienced for the first time by Chaturvedi and
Mulchandani[4] (who, however, unfortunately assigned the wrong structure
of benzo[b]furan-2-ones to the compounds obtained) are particularly
favorable for the intermolecular dihydroarylation when the cinnamic acid
has an electron-donating substituent, particularly a 4-methoxy group. This
has been now clearly established on a number of examples by Li et al.[5]
whose paper appeared when this work was already in a final stage.
The dihydrocoumarins 3 so obtained were dehydrogenated with DDQ in
dioxane at reflux or room temperature to the arylcoumarins 4 with yields
ranging from 30 to 86% (Scheme 1). There are examples in the literature of
dehydrogenation of 4-aryl-3,4-dihydrocoumarins with Pd[6] and S,[7] but to
our knowledge DDQ was never used for this purpose. This reagent has the
advantage of simplicity of experimental conditions, as described later. Only
when the starting compounds 1 or 2 contained a free OH group did this
have to be protected as an acetate prior to the DDQ treatment, followed by
hydrolysis with K2CO3 in methanol.
Scheme 1. Yields of the preparation and cytotoxic activity (IC50, mM) of
4-arylcoumarins 4. a: CF3COOH, rt or reflux; b: DDQ in dioxane, rt or reflux.

Short Synthesis of Cytotoxic 4-Arylcoumarins
1119
The cytotoxic activity of some of these compounds against the CEM
human leukemia cell line was recently reported by Bailly et al.[1] We tested
the prepared compounds against a solid tumor cell line, the human non-
small lung carcinoma cell line H460. The results are comparable with those
reported by Bailly et al.[1] (Scheme 1). that is, they confirmed the importance
of the 3-hydroxy-4-methoxyphenyl substitution for the cytotoxic activity.
EXPERIMENTAL
Synthesis of 4-Aryl-3,4-dihydrocoumarins
A solution of the appropriate phenol 1 (1.1 mmol) and the appropriate
cinnamic acid 2 (1 mmol) in 4 mL of CF3COOH was stirred at room tempera-
ture (3c, 3e, 3f, 3g) or refluxed (3a) to a complete disappearance of the
cinnamic acid. After elimination of CF3COOH in vacuo, the crude product
was purified by flash column chromatography on silica gel (hexane/EtOAc
6 : 4 or 8 : 2) to give compound 3. Analytical data for compounds 3a,[8]
3b,[3] 3c,[8] 3f [9] were in agreement with those reported in the literature.
Synthesis of 3d
A solution of 110 mg (0.33 mmol) of 3e and 41 mg (0.5 mmol) of AcONa in
1 mL of acetic anhydride was refluxed for 16 h and left at room temperature
overnight. After evaporation of acetic anhydride, the slurry was added with
ethyl acetate. The organic layer was washed with water (3 ꢀ 10 mL) and
brine (3 ꢀ 10 mL), dried, and evaporated to obtain 118 mg of a white solid.
1
Yield 95%, mp 157–1588C, H NMR (CDCl3) d: 2.27 (3H, s, Ac), 2.96
(1H, d, H-3, J ¼ 6.10 Hz), 2.97 (1H, d, H-3, J ¼ 3.05 Hz), 3.74 (3H, s,
-OCH3), 3.76 (3H, s, -OCH3), 3.80 (3H, s, -OCH3), 4.48 (1H, dd, H-4,
J ¼ 3.05 Hz, J ¼ 6.10 Hz), 6.25 (1H, d, 1Ar, J ¼ 2.24 Hz), 6.29 (1H, d,
1Ar, J ¼ 2.24 Hz), 6.80 (1H, d, 1Ar, J ¼ 2.24 Hz), 6.82 (1H, d, 1Ar,
J ¼ 8.54 Hz), 6.91 (1H, dd, 1Ar, J ¼ 2.24 Hz, J¼ 8.54 Hz). EIMS m/z: 372
(Mþ, 35%), 330 (100), 287 (30).
Compound 3e
1
Mp 176–1788C; H NMR (CDCl3) d: 2.95 (1H, d, H-3, J ¼ 5.29 Hz), 2.96
(1H, d, H-3, J ¼ 3.46 Hz), 3.80 (3H, s, OCH3), 3.81 (3H, s, OCH3), 3.82
(3H, s, OCH3), 4.46 (1H, dd, H-4, J ¼ 3.46 Hz, J ¼ 5.29 Hz), 6.25 (1H, d,
1Ar, J ¼ 2.24 Hz), 6.30 (1H, d, 1Ar, J ¼ 2.24 Hz), 6.54 (1H, dd, 1Ar,
J ¼ 2.24 Hz, J ¼ 8.14 Hz), 6.68 (1H, d, 1Ar, J ¼ 2.24 Hz), 6.72 (1H, d,
1Ar, J ¼ 8.14 Hz). EIMS m/z: 330 (Mþ, 100%), 287 (45), 271 (20).

1120
E. Rizzi et al.
Compound 3g
Mp 93–958C; 1H NMR (CDCl3) d: 2.96 (1H, d, H-3, J ¼ 7.44 Hz), 2.99 (1H,
d, H-3, J ¼ 5.95 Hz), 3.79 (3H, s, OCH3), 3.86 (3H, s, OCH3), 4.18 (1H, dd,
H-4, J ¼ 5.95 Hz, J ¼ 7.44 Hz), 5.60 (1H, s, -OH), 6.60 (1H, dd, 1Ar,
J ¼ 2.61 Hz, J ¼ 8.19 Hz), 6.63 (1H, dd, 1Ar, J ¼ 2.61 Hz, J¼ 8.19 Hz),
6.66 (1H, d, 1Ar, J ¼ 2.61 Hz), 6.71 (1H, d, 1Ar, J ¼ 2.61 Hz), 6.79 (1H, d,
1Ar, J ¼ 8.19 Hz), 6.88 (1H, d, 1Ar, J ¼ 8.19 Hz). 13C NMR (CDCl3) d:
37.42, 39.49, 55.40, 55.97, 102.44, 110.71, 110.91, 113.64, 117.76, 118.95,
128.89, 133.91, 145.97, 152.36, 159.91, 167.74.
Synthesis of 4-Arylcoumarins
DDQ (1.5 mmol) was added to a solution of compound 3 (1 mmol) in 4.5 mL
of dioxane. The mixture was stirred at room temperature (4a, 4c, 4g) or
refluxed (4d, 4f) until of the starting material completely disappeared (TLC
toluene/EtOAc 9 : 1). After elimination of dioxane in vacuo, the crude
product was washed with a solution of Na2S2O3 (3 ꢀ 15 mL) and with
saturated NaCl solution (3 ꢀ 15 mL) and was purified by flash column chromato-
graphy on silica gel (hexane EtOAc 6:4 or 8:2) to give compound 4. Analytical
data of compounds 4a[10] 4b,[11] 4c,[12] 4d,[13] 4e,[14] and 4f[15] were in
agreement with those reported in the literature.
Synthesis of 4b
A mixture of 4a (0.15 g, 0.53 mmol) and pyridine hydrochloride (0.307 g,
2.66 mmol) was placed in a round-bottom flask and subjected to microwave
(MW) irradiation at 210 W for 24 min (6ꢀ4 pulses).[16] After complete
conversion, a solution of HCl 2 N was added, and the resulting suspension
was stirred at room temperature for 1 h. Then the aqueous phase was
extracted with ethyl acetate. The organic layer was washed with a solution
of NaHCO3 (3 ꢀ 25 mL) and water (3 ꢀ 25 mL), dried, and evaporated to
afford an orange oil. Purification by flash column chromatography on silica
gel (eluent: toluene/ethyl acetate 3 : 1) afforded 4b as a yellow solid
(87 mg). Yield: 64%, mp 2358C.
Synthesis of 4e
A 10% aqueous solution of K2CO3 (0.5 mL) was slowly dropped into a
solution of 30 mg of 4d (0.081 mmol) in 1 mL of CH3CN/MeOH 1 : 1. The
reaction mixture was stirred for 2 h at room temperature, then concentrated
in vacuo, acidified with HCl 2 N, and extracted with ethyl acetate

Short Synthesis of Cytotoxic 4-Arylcoumarins
1121
(4 ꢀ 20 mL). The organic layers were dried and evaporated to afford 15 mg of
the title compound.[14]
Synthesis of 4g
Compound 4g was obtained using the procedure reported for 4e; mp 169–
1
1718C; H NMR (CDCl3) d: 3.87 (3H, s, OCH3), 3.97 (3H, s, OCH3), 5.50
(1H, s, OH), 6.18 (1H, s, H-3), 6.85 (1H, dd, 1Ar, J ¼ 2.23 Hz,
J ¼ 8.93 Hz), 6.87 (1H, d, 1Ar, J¼ 2.23 Hz), 6.95–7.05 (3H, m, 3Ar), 7.48
(1H, d, 1Ar, J ¼ 8.93 Hz).
ACKNOWLEDGMENTS
`
We are indebted to Ministero dell’Universita e Ricerca (MIUR) (Cofin 2003
and Fondo Incentivazione Ricerca di Base (FIRB) 2001 projects) for
financial support.
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