Atom-economical chemoselective synthesis of furocoumarins via cascade palladium catalyzed oxidative alkoxylation of 4-oxohydrocoumarins and alkenes

Article abstract of DOI:10.1039/c4ra15732j

A novel and efficient procedure for the synthesis of furo[3,2-c] coumarins fromreadily available 4-oxohydrocoumarins and alkenes in the presence of a catalytic amount of Pd(CF₃COO)₂ has been developed. Atom-economical characteristics and mild conditions of this method are in accord with the concept of modern green chemistry.

Full text of DOI:10.1039/c4ra15732j

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Atom-economical chemoselective synthesis of
furocoumarins via cascade palladium catalyzed
oxidative alkoxylation of 4-oxohydrocoumarins
and alkenes†
Cite this: RSC Adv., 2015, 5, 4972
Received 25th October 2014
Accepted 10th December 2014
*
Xian-chun Tan,‡ Hai-yuan Zhao,‡ Ying-ming Pan, Na Wu, Heng-shan Wang
DOI: 10.1039/c4ra15732j
*
and Zhen-feng Chen
www.rsc.org/advances
A novel and efficient procedure for the synthesis of furo[3,2-c] cyclisation of 4-hydroxycoumarin and haloketones to synthe-
coumarins from readily available 4-oxohydrocoumarins and alkenes in size furo[3,2-c]coumarin derivatives.5 Chen developed an effi-
the presence of a catalytic amount of Pd(CF3COO)2 has been devel- cient synthetic method via Michael–Oxa-Michael–aromatization
oped. Atom-economical characteristics and mild conditions of this protocol of nitroallylic acetates with 1,3-dicarbonyls mediated
method are in accord with the concept of modern green chemistry.
by base.6 Lin group employed phosphorus zwitterions with acid
chloride in a one-step procedure to approach furo[3,2-c]
coumarins.7 However, these methods require special materials,
harsh reaction conditions, long reaction times or involving
multistep synthetic operations, and all of them are not atom-
economical (Scheme 1a). Therefore, an atom-economical,
straightforward, convenient, and high regioselective route to
synthesize furocoumarins with basic chemical materials is still
highly attractive. To the best of our knowledge, the palladium-
catalyzed synthesis of furo[3,2-c]coumarins directly from
simple alkenes and 4-oxohydrocoumarins has not been repor-
ted so far. As a result of development on the transition-metal-
catalyzed C–H functionalization of alkenes in our group,8
herein, we developed a Pd(CF3COO)2 catalyzed aerobic oxidative
alkoxylation of 4-oxohydrocoumarins and alkenes in a cascade
sequence to afford the desired furocoumarins in good yields
(Scheme 1b).
Coumarins are important structural units in several natural
products, and feature widely in biologically active compounds.1
Among them, furocoumarins are a structural motif found in
numerous pharmaceutically active compounds (Fig. 1). Neo-
tanshinlactone2 and Coumestrol3 exhibit high anti-tumor
tissue-type as well as anti-breast cancer cell line selectivity.
Pyrazolyl furocoumarin4 showed good in vitro antifungal
activity.
For this reason, considerable efforts have been expended to
develop the synthetic methods of furocoumarins. Sameh and
Risitano groups applied respectively a tandem O-alkylation/
Fig. 1 Bioactive furocoumarin analogues.
Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources
(Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences
of Guangxi Normal University, Guilin 541004, People's Republic of China. E-mail:
panym2013@hotmail.com; chenzfubc@yahoo.com; Fax: +86-773-5803930; Tel: +86-
773-5846279
† Electronic supplementary information (ESI) available: General experimental
procedures, and spectral data, NMR spectra and high resolution mass spectra
for all compounds. See DOI: 10.1039/c4ra15732j
‡ These authors contributed equally to this work.
Scheme 1 Different approaches to furocoumarins and our work.
4972 | RSC Adv., 2015, 5, 4972–4975
This journal is © The Royal Society of Chemistry 2015

View Article Online
Communication
RSC Advances
In order to identify the optimal reaction conditions, 4- obtained in higher yields from electron rich alkenes than that
oxohydrocoumarin 1a with styrene 2a were chosen as model from electron poor alkenes. The position of substituent on
substrates. Initially, the reaction of 1a (0.5 mmol) and 2a (0.5 benzene ring seemed to have little inuence on the product
mmol) in the presence of 20 mol% Pd(CF3COO)2 in PhCl at yield (Table 2, entry 3ac). Terminal alkenes bearing polycyclic
ꢀ
90 C for 4 h gave the furo[3,2-c]coumarins 3aa in 81% yield aromatic substituent, such as 2-vinylnaphthalene led to the
(Table 1, entry 1). In addition, in the presence of other cata- corresponding 2-naphthalen-furo[3,2-c]coumarin 3ah in 75%
lysts such as Sc(OTf)3, Y(OTf)3, Cu(OAc)2, Rh(OH)3, InCl3 and yield (Table 2, entry 3ah). Additionally, the reaction of the
AuBr3, most of the starting material 1a was recovered (Table
1, entries 2–7). When other palladium catalysts such as
Pd3(dba)2, PdCl2 and Pd(OAc)2 were used, the yield of 3aa
Table 2 Synthesis of substituted furo[3,2-c]coumarins from 4-oxo-
dramatically decreased to 45À69% (Table 1, entries 8À10).
Further optimization suggested that solvents also had a
strong effect on this process (Table 1, entries 11À15). The
reactions were obviously restrained when they were per-
formed in DMSO, DMF and DCE (Table 1, entries 11–13). The
reactions in PhCH3 and 1,4-dioxane yielded 60% and 40% of
1a, respectively (Table 1, entries 14 and 15). Hence, it was
concluded that the best conditions involved 20 mol%
hydrocoumarins and alkenesa
ꢀ
Pd(CF3COO)2 in PhCl at 90 C.
With the above optimized conditions in hand, the scope of
the substrates was investigated. Typical results are shown in
Table 2. To our delight, catalyzed by Pd(CF3COO)2, both aryl-
substituted internal alkenes and terminal alkenes produced
high yields of furo[3,2-c]coumarins under the optimized
conditions. Terminal alkenes with differents substituted
groups such as Me, OMe, F, Cl and OCOCH3, all reacted
smoothly afforded the target products in high yields (Table 2,
entries 3ab–3ag). In general, the desired products could be
Table 1 Optimization of the formation of substituted furo[3,2-c]
coumarinsa
Entry
Catalyst
Solvent
Yieldb (%)
1
2
Pd(CF3COO)2
Sc(OTf)3
PhCl
PhCl
81
0
3
Y(OTf)3
PhCl
0
4
5
Cu(OAc)2
Rh(OH)3
PhCl
PhCl
0
0
6
InCl3
PhCl
0
7
AuBr3
PhCl
0
8
9
Pd3(dba)2
PdCl2
Pd(OAc)2
Pd(CF3COO)2
Pd(CF3COO)2
Pd(CF3COO)2
Pd(CF3COO)2
Pd(CF3COO)2
PhCl
PhCl
PhCl
DMSO
DMF
DCE
PhCH3
1,4-Dioxane
45
30
69
20
0
25
60
40
10
11
12
13
14
15
a
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), catalyst (20 mol%),
Reactions conditions: 0.5 mmol of 1 and 0.5 mmol of 2 in the presence
solvent (2 mL), 90 ꢀC, 4 h. b Isolated yield of the pure product based on of 20 mol% of Pd(CF3COO)2, 2 mL of PhCl at 90 ꢀC for 4 h. Isolated
1a.
yields.
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 4972–4975 | 4973

View Article Online
RSC Advances
Communication
internal alkenes 2i and 2j with 4-oxohydrocoumarin 1a also
gave the desired products 3ai and 3aj in 83% and 80% yields,
respectively (Table 2, entries 3ai and 3aj). Unfortunately,
when the aliphatic alkene was used, the reaction failed to
afford the desired product (Table 2, entry 3ak). Moreover,
oxohydrocoumarin bearing substituent such as 6-methoxy-4-
hydroxycoumarin and 7-methyl-4-hydroxycoumarin were
found to afford the desired products in 82–84% yields (Table
2, entries 3ba-3ci).
Surprisingly, the reaction of 4-oxohydrocoumarin 1a
with different methacrylates 4 failed to afford the desired
products but gave unexpected product 3al in high yields
(Scheme 2).
To explore the possible reaction pathway, isotope deuterium-
labeled styrene 2a–d was used to react with 4-oxohy-
ꢀ
drocoumarin 1a in PhCl at 90 C for 4 h. The substituted furo
[3,2-c]coumarin 3aa–d was obtained in 79% yield. Over 96% of
deuterium was incorporated in the product (Scheme 3).
On the basis of the mechanism of previous reports9 and our
results, a plausible mechanism is provided in Scheme 4. a-
Palladation of 1,3-ketone ester can provide A, followed by
styrene coordination and Heck insertion to B. Reductive elimi-
nation to produce dihydro-furocoumarin D, which has been
detected and isolated in our experiment. Finally, oxidative
aromatization under air affords the desired product furo-
coumarins. Isolated dihydro-furocoumarin D reacted in the
optimized conditions for another 2 h to afford the nal furo[3,2-
c]coumarin 3aa in 95% yield (Scheme 5).
Scheme 4 Possible reaction mechanism.
Scheme 5 Isolated intermediate D and oxidation of D.
In summary, we have developed an efficient synthetic
method to synthesis furo[3,2-c]coumarins from readily
available 4-oxohydrocoumarins and alkenes. This opera-
tionally simple method gives a rapid access to the furo[3,2-c]
coumarins. Atom-economical characteristics and mild
conditions of the method are in accord with the concept of
modern green chemistry.
Experimental section
1H and 13C NMR spectra were measured on a Bruker Avance 500
MHz NMR spectrometer with CDCl3 as solvent and recorded in
ppm relative to an internal tetramethylsilane standard. General
chemicals were purchased from commercial suppliers and used
without further purication.
General experimental procedure for synthesis of furo[3,2-c]
coumarins
The mixture of 4-hydroxycoumarin 1 (0.5 mmol), alkenes 2 (0.5
mmol) and Pd(CF3COO)2 (0.1 mmol) in PhCl (2 mL) was stirred
at 90 ꢀC for 4 h. The progress of the reaction was monitored by
thin-layer chromatography. Upon completion, the mixture was
then cooled and evaporated under reduced pressure. The target
product 3 was puried by ash chromatography on silica gel
using a mixture of ethyl acetate and petroleum ether.
Scheme 2 Synthesis of 2-methyl-furo[3,2-c]coumarin 3al from 4-
hydroxycoumarin 1a and methacrylates 4.
Acknowledgements
We thank Ministry of Education of China (IRT1225), the
National Natural Science Foundation of China (21362002,
41465009 and 81260472), Guangxi Natural Science Foundation
of China (2014GXNSFDA118007), State Key Laboratory Cultiva-
tion Base for the Chemistry and Molecular Engineering of
Medicinal Resources, Ministry of Science and Technology of
China (CMEMR2014-A02, CMEMR2014-A04, CMEMR2012-A20
Scheme 3 Deuterium labeling experiment.
4974 | RSC Adv., 2015, 5, 4972–4975
This journal is © The Royal Society of Chemistry 2015

View Article Online
Communication
RSC Advances
and CMEMR2013-C01), Key Project of Guangxi Department of 5 (a) A. Sehemi, G. Abdullah, E. Gogary and R. Sameh, Chin. J.
Education (2013ZD006), and Bagui Scholar Program.
Chem., 2012, 30, 316; (b) F. Risitano, G. Grassi, F. Foti and
C. Bilardo, Tetrahedron Lett., 2001, 42, 3503.
6 W. Y. Huang, Y. C. Chen and K. Chen, Chem.–Asian J., 2012, 7,
688.
Notes and references
1 (a) L. Santana, E. Uriarte, F. Roleira, N. Milhazes and
F. Borges, Curr. Med. Chem., 2004, 11, 3239; (b) F. Borges,
F. Roleira, N. Milhazes, L. Santana and E. Uriarte, Curr.
Med. Chem., 2005, 12, 887; (c) B. M. Trost and F. Tost, J. Am.
Chem. Soc., 1996, 118, 6305.
2 X. H. Wang, K. F. Bastow, C. M. Sun, Y. L. Lin, H. J. Yu,
M. J. Don, T. S. Wu, S. Nakamura and K. H. Lee, J. Med.
Chem., 2004, 47, 5816.
7 C. Lee, Y. Jang, Z. Wu and W. Lin, Org. Lett., 2012, 14, 1906.
8 (a) P. Liu, J. L. Liu, H.-S. Wang, Y.-M. Pan, H. Liang and
Z. F. Chen, Chem. Commun., 2014, 50, 4795; (b) P. Liu,
H. S. Wang, Y. M. Pan, W. L. Dai, H. Liang and Z. F. Chen,
Chem. Commun., 2013, 49, 5295; (c) Q. Wu, P. Liu,
Y. M. Pan, Y. L. Xu and H. S. Wang, RSC Adv., 2012, 2,
10167; (d) G. B. Huang, X. Wang, Y. M. Pan, H. S. Wang,
G. Y. Yao and Y. Zhang, J. Org. Chem., 2013, 78, 2742.
9 U. Sharma, T. Naveen, A. Maji, S. Manna and D. Maiti, Angew.
Chem., Int. Ed., 2013, 52, 12669.
3 G. A. Kraus and N. Zhang, J. Org. Chem., 2000, 65, 5644.
4 S. Bondock, W. Khalifa and A. A. Fadda, Eur. J. Med. Chem.,
2011, 46, 2555.
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 4972–4975 | 4975