L. D. Miranda et al.
SHORT COMMUNICATION
100 °C) for 10 min by using a CEM Discover microwave reactor.
Next, aliquots of DLP (0.2 equiv.) were added every 10 min (main-
taining microwave irradiation) until a total of 1.5 equiv. of the per-
oxide had been added. After completion of the reaction, the solvent
was evaporated under reduced pressure. The residue was taken up
in cold acetonitrile at 0 °C, leaving DLP undissolved. After fil-
tration and evaporation of the solvents under reduced pressure, the
crude product was purified by column chromatography on silica
gel to afford the desired product.
were obtained in moderate yields from the corresponding
xanthate 4d and coumarins 3a–3c. Furthermore, chromones
16–18 were obtained from the reaction of the piperidine-
derived xanthate 4e in moderate yields. In general, the re-
sults presented in Table 1 indicate that this xanthate-based
oxidative radical addition represents a convenient route to
the direct introduction of an alkyl functionality at C-3 of
the coumarin.
In the proposed mechanism (Scheme 2), the stabilized
benzyl radical 20 might be generated after the addition of
the radical 19 (generated by the action of DLP on xanthate
4)[14] to the coumarin system 3. In principle, if a stoichio-
metric quantity of DLP is present in the reaction medium,
the radical intermediate 20 might be oxidized to the benzyl
carbocation 21.[10,15] Deprotonation of 21 would restore the
double bond and finally produce the alkylated product. The
regiochemistry of this reaction is in accordance with pre-
vious results in the direct radical phosphonylation of flav-
ones and coumarins induced by manganese(III) acetate.[8a]
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental procedures, characterization data and 1H
NMR spectra.
Acknowledgments
Financial support from the Dirección General de Asuntos del Per-
sonal Académico (DGAPA) (PAPIIT-IN210413) is gratefully ac-
knowledged. We thank R. Patiño, A. Peña, R. Gabiño, E. Huerta,
I. Chavez, H. García-Rios, L. Velasco, J. Pérez, A. Toscano and
S. Hernandez-Ortega for technical support (Instituto de Química
UNAM).
[1] For a review on pharmacological activities, see: a) X.-M. Peng,
G. L. V. Damu, C.-H. Zhou, Curr. Pharm. Des. 2013, 19, 3884–
3930; b) P. Anand, B. Singh, N. Singh, Bioorg. Med. Chem.
2012, 20, 1175–1180; c) M. E. Riveiro, N. De Kimpe, A. Mog-
lioni, R. Vázquez, F. Monczor, C. Shayo, C. Davio, Curr. Med.
Chem. 2010, 17, 1325–1338; d) J. E. Sadler, Nature 2004, 427,
493–494; e) M. B. Rosenman, L. Baker, Y. Jing, D. Makenba-
eva, B. Meissner, T. A. Simon, D. Wiederkehr, S. Deitelzweig,
Curr. Med. Res. Opin. 2012, 28, 1407.
[2] a) V. P. Shibaev, Polym. Sci., Ser. A 2014, 56, 727–762; b) A. M.
Breul, M. D. Hager, U. S. Schubert, Chem. Soc. Rev. 2013, 42,
5366–407; c) V. F. Traven, A. V. Manaev, A. Y. Bochkov, T. A.
Chibisova, I. V. Ivanov, Russ. Chem. Bull. 2012, 61, 1342–1362;
d) V. F. Traven, A. Y. Bochkov, Heterocycl. Commun. 2013, 19,
219–238; e) Y. Song, Z. Chen, H. Li, Curr. Org. Chem. 2012,
16, 2690–2707; f) K. Tanaka, Molecules 2012, 17, 1408–1418;
g) M. V. Kulkarni, G. M. Kulkarni, C.-H. Lin, C.-M. Sun,
Curr. Med. Chem. 2006, 13, 2795–2818; h) H. E. Katerino-
poulos, Curr. Pharm. Des. 2004, 10, 3835–3852.
Scheme 2. Proposed mechanism for the oxidative radical addition.
[3] a) S. Sandhu, Y. Bansal, O. Silakari, G. Bansal, Bioorg. Med.
Chem. 2014, 22, 3806–3814; b) O. O. Ajani, O. C. Nwinyl, J.
Heterocycl. Chem. 2010, 47, 179–187; c) S. Rahmani-Nezhad,
L. Khosravani, M. Saeedi, K. Divsalar, L. Firoozpour, Y. Pour-
shojaei, Y. Sarrafi, H. Nadri, A. Moradi, M. Mahdavi, A.
Shafiee, A. Foroumadi, Synth. Commun. 2015, 45, 741–749.
[4] For recent literature, see: a) Y. Li, Z. Qi, H. Wang, X. Fu, C.
Duan, J. Org. Chem. 2012, 77, 2053–2057; b) C. E. Song, D.-
U. Jung, S. Y. Choung, E. J. Roh, S.-G. Lee, Angew. Chem. Int.
Ed. 2004, 43, 6183–6185; Angew. Chem. 2004, 116, 6309; c) Y.
Yamamoto, N. Kirai, Org. Lett. 2008, 10, 5513–5516; d) K. V.
Sashidhara, G. R. Palnati, S. R. Avula, A. Kumar, Synlett
2012, 23, 611–621; e) B. C. Ranu, R. Jana, Eur. J. Org. Chem.
2006, 3767–3770; f) H. S. P. Rao, S. Sivakumar, J. Org. Chem.
2006, 71, 8715–8723; g) C. Su, Z.-C. Chen, Q.-G. Zhen, Synthe-
sis 2003, 555–559; h) K. C. Majumdar, I. Ansary, S. Samanta,
B. Roy, Synlett 2011, 694–698; i) X. Mi, M. Huang, J. Zhang,
C. Wang, Y. Wu, Org. Lett. 2013, 15, 6266–6269.
Conclusions
We have described a convenient C-3 alkylation process
for the coumarin system. Mechanistically, the process in-
volves an intermolecular oxidative radical alkylation by
using a xanthate-based radical reaction. This method offers
the direct substitution of a C–H bond by an alkyl group,
under mild conditions with great selectivity. Additional re-
actions using polysubstituted coumarin substrates and
more complex xanthates are in progress in our laboratory;
these results will be published in due course.
Experimental Section
[5] a) W. Zhang, S. Yue, Y. Shen, H. Hu, Q. Meng, H. Wu, Y. Liu,
Org. Biomol. Chem. 2015, 13, 3602–3609; b) M. A. Zolfigol,
A. R. Moosavi-Zare, M. Zarei, C. R. Chim. 2014, 17, 1264–
1267; c) Liu, Y. Q. Sun, H. Zhang, Y. Huo, Y. Shi, H. Shi, W.
Guo, RSC Adv. 2014, 4, 64542–64550; d) R. Grigg, S. Whitney,
V. Sridharan, A. Keep, A. Derrick, Tetrahedron 2009, 65, 7468–
7473; e) F. Risitano, G. Grassi, F. Foti, C. Bilardo, Tetrahedron
Lett. 2001, 42, 3503–3505.
Typical Procedure for the Oxidative Radical Addition of Xanthates
to Coumarins: The coumarin substrate (1 equiv.) and the corre-
sponding xanthate (2 equiv.) were dissolved in toluene (0.5 m with
respect to the coumarin) in a microwave tube equipped with a stir
bar. The resulting solution was deaerated with a stream of argon
under ultrasonic agitation for 20 min. Then, 0.2 equiv. of DLP were
added, and the mixture was irradiated with microwaves (300 W,
4100
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