Copper-Catalyzed Synthesis of Furo[3,2- c ]coumarins and Dihydrofuro[3,2- c ]coumarins through a Propargylation/Alkyne Oxacyclization/Isomerization Cascade under Microwave Irradiation

Article abstract of DOI:10.1055/s-0035-1560500

A novel copper-catalyzed microwave-promoted propargylation/alkyne oxacyclization/isomerization cascade for the synthesis of 2-methylfuro[3,2-c]coumarins has been developed. This reaction provides furo[3,2-c]coumarins in moderate to good yields (≤82%) from

Full text of DOI:10.1055/s-0035-1560500

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Copper-Catalyzed Synthesis of Furo[3,2-c]coumarins and Dihy-
drofuro[3,2-c]coumarins through a Propargylation/Alkyne Oxacy-
clization/Isomerization Cascade under Microwave Irradiation
Xiao-Yan Zhanga,b
Li-Li Hub
Ze Shenb
Zhong-Zhu Chenb
Zhi-Gang Xub
Shi-Qiang Lib
Jian-Wu Xie*a
O
CuBr, DIPEA, DMSO
MW, 100 °C, 20 min
Ph
OH
O
O
O
OAc
80%
13 other examples (48–82%)
+
Ph
O
Hai-Lei Cui*b
O
Ph
a
CuBr, DIPEA, DCE
MW, 100 °C, 20 min
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials,
Department of Chemistry and Life Science, Zhejiang Normal University,
Jinhua 321004, P. R. of China
O
O
85%
xiejw@zjnu.cn
5 other examples (36–85%)
b
International Academy of Targeted Therapeutics and Innovation, Chongqing
University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing
402160, P. R. of China
cuihailei616@163.com
Received: 21.07.2015
Accepted after revision: 21.09.2015
Published online: 13.10.2015
search, a rapid, simple and efficient construction of struc-
turally diverse furo[3,2-c]coumarins is much desired.
DOI: 10.1055/s-0035-1560500; Art ID: st-2015-s0566-c
O
Abstract A novel copper-catalyzed microwave-promoted propargyl-
ation/alkyne oxacyclization/isomerization cascade for the synthesis of
2-methylfuro[3,2-c]coumarins has been developed. This reaction pro-
vides furo[3,2-c]coumarins in moderate to good yields (≤82%) from
readily available 4-hydroxycoumarins and terminal propargyl acetates
as starting materials. Interestingly, by changing the solvent from di-
methyl sulfoxide to 1,2-dichloroethane, the isomeric series of 2-meth-
ylene-2,3-dihydrofuro[3,2-c]coumarins were obtained in good to ac-
ceptable yields (≤85%).
O
O
neo-tanshinlactone
oxacyclization/isomerization
R3
Key words cascade reactions, coumarins, propargyl acetates, furo-
coumarins, cyclization
OH
O
O
OAc
R2
+
R2
R1
R1
The furo[3,2-c]coumarin (4H-furo[3,2-c]chromen-4-
one) framework occurs frequently in many medicinally im-
portant compounds with a wide variety of biological activi-
R3
O
O
O
propargylation
Scheme 1 Neo-tanshinlactone and a retrosynthetic analysis of its ana-
logues containing a furo[3,2-c]coumarin moiety
1,2
ties. For example, neo-tanshinlactone and its analogues,
which contain a furo[3,2-c]coumarin moiety, show selec-
tive cytotoxicity against two estrogen receptor-positive
breast cancer cell lines, MCF-7 and ZR-75-1 (Scheme 1).1
Consequently, the efficient construction of furo[3,2-c]cou-
marins from readily available starting materials has attract-
,2
Recently, a propargylation/alkyne oxacyclization/isom-
erization cascade, based on the activation of propargylic
alcohols and their derivatives by transition metals, has
emerged as a powerful tool for the assembly of heterocycles
that show potential applications in biomedical research.
Because the use of microwave irradiation frequently results
in efficient processes, clean reactions, and high yields in
synthetic chemistry, we aimed to combine the efficiency
of the cascade reaction with that of a microwave-assisted
process to develop rapid, simple, and efficient protocols for
4
3
ed much attention. Although several approaches have al-
5
,6
ready been developed for the synthesis of furo[3,2-c]cou-
marin analogues, these protocols have the drawbacks of
requiring multiple steps or expensive metal catalysts or of
tolerating a limited range of substituents. Given the poten-
tial applications of these compounds in drug-discovery re-
7
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the synthesis of medicinally important molecules. Inspired
by recent achievements, we surmised that microwave irra-
diation might be introduced into the synthesis of furocou-
marins by the propargylation/alkyne oxacyclization/isom-
erization cascade (Scheme 1). Here, we report a copper-cat-
rocoumarin or a dihydrofurocoumarin is possible in princi-
pal; we therefore conducted a screening of copper salts and
solvents. Other copper salts under the same conditions
gave lower yields of the desired furo[3,2-c]coumarin 3a
(entries 2–5). No improvement in the yield was achieved by
changing the solvent (entries 6–10). Interestingly, however,
the use of 1,2-dichloroethane gave the dihydrofurocouma-
rin 4a as the major product of the reaction. We reasoned
that it is because of the absence of the proton-transforming
enhancement observed in reactions with dimethyl sulfox-
ide as solvent (entry 1 versus entry 8). By using an excess of
the 4-hydroxycoumarin 1a and performing the reaction at a
higher concentration, we obtained improved yields, where-
as decreasing the catalyst loading had no significant influ-
ence on the yield (entries 11–13). An excess of the 4-hy-
droxycoumarin, a lower catalyst loading, and a higher con-
centration gave an improved yield (92%) of the
dihydrofurocoumarin 3a (entry 14). However, the yield of
dihydrofurocoumarin 3a was sensitive to both the reaction
5
alyzed
synthesis
of
furocoumarins
and
dihydrofurocoumarins from the corresponding 4-hydroxy-
coumarins and propargyl acetates under microwave irradi-
ation.
We chose 4-hydroxycoumarin (1a) and the propargylic
ester 2a as model substrates with copper(I) bromide as cat-
alyst in the presence of N,N-diisopropylethylamine in di-
methyl sulfoxide at 100 °C with microwave irradiation for
20 minutes as our initial conditions (Table 1). To our delight,
the desired product 3a and the isomeric 2-methylene-2,3-
dihydrofuro[3,2-c]coumarin 4a, bearing an exocyclic C=C
double bond, were detected by NMR spectroscopy in 74%
and 11% yield, respectively (Table 1, entry 1). This initial ex-
periment demonstrated that the transformation into a fu-
Table 1 Reaction Developmenta
OH
O
catalyst
solvent
MW
O
O
OAc
Ph
Ph
+
Ph
+
O
O
O
O
O
1a
2a
3a
4a
Entry
Catalyst
Solvent
Temp (°C)
Time (min)
Yieldb (%) of 3a
Yieldb (%) of 4a
1
2
3
4
5
6
7
8
9
CuBr
CuI
DMSO
DMSO
DMSO
DMSO
DMSO
MeOH
MeCN
DCE
100
100
100
100
100
100
100
100
100
100
100
100
100
100
120
100
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
30
74
57
52
49
44
15
51
16
6
11
<5
CuCl
<5
Cu(OTf)
2
<5
Cu(OAc)
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
2
·H
2
O
<5
60
30
74
1,4-dioxane
toluene
DMSO
DMSO
DMSO
DCE
48
1
1
1
1
1
1
1
0
12
82
81
91 (80)f
<5
73
1c
<5
2c,d
3c–e
4c–e
5c–e
6c–e
<5
<5
92 (85)f
22
DCE
40
58
DCE
24
a
b
c
d
e
f
Reaction conditions: (unless otherwise noted) 1a (0.2 mmol), 2a (0.2 mmol), DIPEA (1 equiv), catalyst (10 mol%), solvent (1.0 mL).
Determined by 1H NMR with CH
Br as internal standard.
a (1.2 equiv).
CuBr (5 mol%).
Concentration 0.4 M.
2
2
1
Isolated yield.
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time and the temperature, partly as a result of its isomeri-
zation into the furocoumarin 4a in the presence of a base
amenable to the use of a propargylic ester with an internal
alkyne group, as this type of substrate failed to give the
product 3o under the usual conditions. This suggests that
the formation of a copper–allenylidene complex is essential
(entries 15 and 16)
Having determined the optimized conditions (Table 1,
9
entry 13), we subjected various 4-hydroxycoumarins 1 to
the developed procedure. 4-Hydroxycoumarins 1 bearing
either an electron-withdrawing group (Br or Cl) or an elec-
tron-donating group (Me) in the 6-position gave the corre-
sponding furo[3,2-c]coumarins 3b–d in fair yield (54–60%).
for catalysis to occur.
Because both dihydrofurans10 and coumarins11 are com-
mon moieties in natural products and act as important pre-
cursors in synthetic chemistry, we also attempted to syn-
thesize dihydrofuro[3,2-c]coumarins, combining both moi-
7-Bromo-4-hydroxycoumarin gave a lower yield of product
eties.1
2,13
From our studies on the optimized conditions
3
e, whereas 7-methoxy-4-hydroxycoumarin gave a good
(Table 1, entry 14), we surmised that replacing dimethyl
sulfoxide as a solvent with 1,2-dichloroethane might give
the corresponding 2-methylenedihydrofuro[3,2-c]couma-
rin products. This hypothesis turned out to be correct, and
product 4a–e were obtained in moderate to good yields
(Scheme 3). A 4-hydroxycoumarin bearing an electron-
withdrawing group gave compound 4c in a lower yield as a
result of an isomerization side reaction. However, dihydro-
furo[3,2-c]coumarin 4f was not obtained under the current
reaction conditions because of the formation of the isomer-
ized product 3m.14 Compound 4g was not obtained with
1,2-dichloroethane as solvent, but the use of dimethyl sulf-
oxide as the solvent did give the desired product.
yield of 3f, indicating that an electron-donating group is
beneficial for the reaction. 4-Hydroxybenzo[h]coumarin
also gave the expected product 3g in 64% yield. We then ex-
amined the scope of the reaction with respect to the prop-
argyl acetate 2 (Scheme 2). Reactions with aryl propargylic
esters proceeded smoothly to give the desired products 3h–
l in moderate to good yields (61–70%). The substituents on
the aryl ring had little effect on the yield. A hetaryl-substi-
tuted propargylic ester gave the corresponding furo[3,2-c]-
coumarin 3m in good yield. A trace of product 3n was de-
tected in the case of an alkylated propargylic ester, which
8
showed poor reactivity. The reaction did not seem to be
CuBr, DIPEA, DMSO
MW, 100 °C, 20 min
1
+
2
3
O
O
O
O
Ph
Br
Ph
Cl
Ph
Ph
O
O
O
O
O
O
O
O
3a 80%
3b 54%
3c 60%
3d 57%
O
O
O
O
Ph
Ph
Ph
Cl
O
O
O
O
Br
O
O
MeO
O
O
3e 48%
3f 80%
3g 64%a
3h 63%
F
OMe
O
O
O
O
OMe
O
O
O
O
O
O
O
O
3i 61%
3j 63%
3k 62%
3l 70%
Ph
Ph
O
O
O
O
O
O
O
O
O
O
3m 82%
3n trace
3o (not detected)
Scheme 2 Scope of the copper-catalyzed microwaved-promoted process for the construction of furo[3,2-c]coumarins. Reagents and conditions: 1 (0.48
mmol), 2 (0.4 mmol), DIPEA (0.4 mmol), CuBr (5 mol%), DMSO (1.0 mL), microwave irradiation, 100 °C, 20 min. The reported yields are isolated yields.
a
Irradiated for 30 minutes.
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CuBr, DIPEA, DCE
MW, 100 °C, 20 min
1
+
2
4
O
O
O
O
Br
Ph
Ph
Ph
O
O
O
O
MeO
O
O
O
O
4d 64%a
4a 85%
4b 68%
4c 36%
O
O
O
O
OMe
O
O
O
O
O
O
4g 41%b
4e 82%
4f (not detected)
Scheme 3 Synthesis of dihydrofuro[3,2-c]coumarins. Reagents and conditions: 1 (0.48 mmol), 2 (0.4 mmol), DIPEA (0.4 mmol), CuBr (5 mol%), DCE
a
b
(
1.0 mL), microwave irradiation, 100 °C, 20 min. The reported yields are the isolated yields. Irradiated for 40 min. In DMSO at 150 °C with CuBr (20
mol%).
In conclusion, we have developed a novel copper-cata-
Liu, Y.-N.; Wu, P.-C.; Bastow, K. F.; Morris-Natschke, S. L.; Brossi,
A.; Lang, J.-Y.; Hsu, J. L.; Hung, M.-C.; Lee, K.-H. J. Med. Chem.
lyzed microwaved-promoted process for the construction
of furo[3,2-c]coumarins from 4-hydroxycoumarins and ter-
minal propargyl acetates in moderate to good yields
through a propargylation/alkyne oxacyclization/isomeriza-
2
010, 53, 2299.
3) (a) Cadierno, V.; Díez, J.; Gimeno, J.; Nebra, N. J. Org. Chem.
008, 73, 5852. (b) Lee, C.-J.; Jang, Y.-J.; Wu, Z.-Z.; Lin, W. Org.
(
2
Lett. 2012, 14, 1906. (c) Zhang, W. L.; Yue, S. N.; Shen, Y. M.; Hu,
H. Y.; Meng, Q.-H.; Wu, H.; Liu, Y. Org. Biomol. Chem. 2015, 13,
3602. (d) Cheng, G.; Hu, Y. J. Org. Chem. 2008, 73, 4732.
(e) Huang, W.; Wang, J.; Shen, Q.; Zhou, X. Tetrahedron 2007, 63,
11636. (f) Ponra, S.; Gohain, M.; van Tonder, J. H.;
Bezuidenhoudt, B. C. B. Synlett 2015, 26, 745.
15
tion cascade. By using 1,2-dichloromethane as the solvent
instead of dimethyl sulfoxide, a range of 2-methylenedihy-
drofuro[3,2-c]coumarins could be obtained as the major
16
products. The extension of the strategy to the synthesis of
other analogues and its application in biomedical research
are currently ongoing in our laboratory.
(
4) For reviews on cascade reactions, see: (a) Grondal, C.; Jeanty,
M.; Enders, D. Nat. Chem. 2010, 2, 167. (b) Yu, X.; Wang, W. Org.
Biomol. Chem. 2008, 6, 2037. (c) Enders, D.; Grondal, C.; Hüttl,
M. R. M. Angew. Chem. Int. Ed. 2007, 46, 1570. (d) Walji, A. M.;
MacMillan, D. W. C. Synlett 2007, 1477. (e) Nicolaou, K. C.;
Edmonds, D. J.; Bulger, P. G. Angew. Chem. Int. Ed. 2006, 45,
Acknowledgment
We are grateful for the support provided for this study by the National
Science Foundation of China (21502013), the Scientific and Techno-
logical Research Program of the Chongqing Municipal Education
Commission (KJ1501111), and Chongqing University of Arts and Sci-
ences. We thank Ms. Han-Zhao Liu for performing the LC/MS analysis
7134.
(
5) For reviews on propargylation, see: (a) Ding, C.-H.; Hou, X.-L.
Chem. Rev. 2011, 111, 1914. (b) Miyake, Y.; Uemura, S.;
Nishibayashi, Y. ChemCatChem 2009, 1, 342. (c) Detz, R. J.;
Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2009,
6263. (d) Nishibayashi, Y. Synthesis 2012, 44, 489. (e) Zhang, D.-
Y.; Hu, X.-P. Tetrahedron Lett. 2015, 56, 283. (f) Hu, X.-H.; Liu, Z.-
T.; Shao, L.; Hu, X.-P. Synthesis 2015, 47, 913.
Supporting Information
Supporting information for this article is available online at
(6) For selected examples on the synthesis of furan derivatives by
using propargylation/cycloisomerization strategy, see:
a) Cadierno, V.; Gimeno, J.; Nebra, N. Adv. Synth. Catal. 2007,
http://dx.doi.org/10.1055/s-0035-1560500.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
a
(
349, 382. (b) Yoshida, M.; Ohno, S.; Shishido, K. Chem. Eur. J.
References and Notes
2012, 18, 1604. (c) Pan, Y.-m.; Zhao, S.-y.; Ji, W.-h.; Zhang, Z.-p.
J. Comb. Chem. 2009, 11, 103. (d) Zhan, Z.-p.; Cai, X.-b.; Wang, S.-
p.; Yu, J.-l.; Liu, H.-j.; Cui, Y.-y. J. Org. Chem. 2007, 72, 9838.
(1) (a) Lee, K.-H. J. Nat. Prod. 2010, 73, 500. (b) Boland, G. M.;
Donnelly, D. M. X. Nat. Prod. Rep. 1998, 15, 241.
(e) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7, 3925.
(2) (a) Wang, X.; Bastow, K. F.; Sun, C.-M.; Lin, Y.-L.; Yu, H.-J.; Don,
M.-J.; Wu, T.-S.; Nakamura, S.; Lee, K.-H. J. Med. Chem. 2004, 47,
(f) Sanz, R.; Miguel, D.; Martínez, A.; Álvarez-Gutiérrez, J. M.;
Rodríguez, F. Org. Lett. 2007, 9, 727. (g) Feng, X.; Tan, Z.; Chen,
D.; Shen, Y.; Cuo, C.-C.; Xiang, J.; Zhu, C. Tetrahedron Lett. 2008,
5
816. (b) Wang, X.; Nakagawa-Goto, K.; Bastow, K. F.; Don, M.-
J.; Lin, Y.-L.; Wu, T.-S.; Lee, K.-H. J. Med. Chem. 2006, 49, 5631.
c) Dong, Y.; Shi, Q.; Liu, Y.-N.; Wang, X.; Bastow, K. F.; Lee, K.-H.
49, 4110.
(
(
7) For reviews, see: (a) Larhed, M.; Moberg, C.; Hallberg, A. Acc.
Chem. Res. 2002, 35, 717. (b) Roberts, B. A.; Strauss, C. R. Acc.
Chem. Res. 2005, 38, 653. (c) Lew, A.; Krutzik, P. O.; Hart, M. E.;
J. Med. Chem. 2009, 52, 3586. (d) Dong, Y.; Shi, Q.; Pai, H.-C.;
Peng, C.-Y.; Pan, S.-L.; Teng, C.-M.; Nakagawa-Goto, K.; Yu, D.;
©
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2
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Synlett
X.-Y. Zhang et al.
Cluster
Chamberlin, A. R. J. Comb. Chem. 2002, 4, 95. (d) Lidström, P.;
Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225.
(15) Furo[3,2-c]coumarins 3; General Procedure
A mixture of 4-hydroxycoumarin 1 (0.48 mmol, 1.2 equiv),
propargyl acetate 2 (0.40 mmol, 1.0 equiv), DIPEA (0.40 mmol,
1.0 eq), CuBr (0.02 mmol, 5 mol%), and DMSO (1 mL) was stirred
at r.t. for 30 s and then heated at 100 °C for 20 min by micro-
wave irradiation. The mixture was then cooled to r.t., the reac-
(e) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199.
(
8) Higher temperatures and greater catalyst loadings led to the
formation of dihydrofuro[3,2-c]coumarin 4g in 41% yield (see
Scheme 3).
(9) (a) Shiner, V. J.; Wilson, J. W. J. Am. Chem. Soc. 1962, 84, 2402.
tion was quenched with sat. aq NH Cl, and the mixture was
4
(b) Imada, Y.; Yuasa, M.; Nakamura, I.; Murahashi, S.-I. J. Org.
extracted with CH Cl . The organic layers were combined,
2
2
Chem. 1994, 59, 2282.
washed with brine, dried (Na SO ), filtered, and concentrated in
2
4
(
(
10) For a review, see: Lipshutz, B. H. Chem. Rev. 1986, 86, 795.
11) For a review, see: Musa, M. A.; Cooperwood, J. S.; Khan, O. F.
Curr. Med. Chem. 2008, 15, 2664.
vacuo. Purification by a flash chromatography (silica gel,
hexane–EtOAc) gave the desired product 3.
(16) 2-Methylene-2,3-dihydrofuro[3,2-c]coumarins 4; General
Procedure
(
12) For a recent example of an asymmetric synthesis of dihydrofu-
rans from propargylic esters, see: Zhu, F.-L.; Wang, Y.-H.; Zhang,
D.-Y.; Xu, J.; Hu, X.-P. Angew. Chem. Int. Ed. 2014, 53, 10223.
13) For studies on the synthesis of dihydrofuro[3,2-c]coumarins by
the Xie group, see: (a) Xie, J.-W.; Li, P.; Wang, T.; Zhou, F.-T. Tet-
rahedron Lett. 2011, 52, 2379. (b) Fan, L.-P.; Li, P.; Li, X.-S.; Xu,
D.-C.; Ge, M.-M.; Zhu, W.-D.; Xie, J.-W. J. Org. Chem. 2010, 75,
A mixture of 4-hydroxycoumarin 1 (0.48 mmol, 1.2 equiv),
propargyl acetate 2 (0.40 mmol, 1.0 equiv), DIPEA (0.40 mmol,
1.0 equiv), CuBr (0.02 mmol, 5 mol%), and DCE (1 mL) was
stirred at r.t. for 30 s and then heated at 100 °C for 20 min by
microwave irradiation. The mixture was cooled to r.t. and
directly purified by flash chromatography (silica gel, hexane–
EtOAc) to give the desired product 4.
(
8716.
(14) In this case, the isomerized product 3m was isolated in 91%
yield.
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