Two efficient cascade reactions to synthesize substituted furocoumarins

Article abstract of DOI:10.1021/jo800439y

(Chemical Equation Presented) We have developed two efficient one-pot reactions to generate furo[3,2-c]coumarins and chlorofuro[3,2-c]coumarins through addition/cyclization/oxidation and chlorination. One cascade addition/cyclization/oxidation sequence of

Full text of DOI:10.1021/jo800439y

SCHEME 1. Reported Addition and Cyclization of
2-(1-Alkynyl)-2-alken-1-ones
Two Efficient Cascade Reactions to Synthesize
Substituted Furocoumarins
Gang Cheng and Youhong Hu*
Shanghai Institute of Materia Medica, Chinese Academy of
Science, 555 Zu Chong Zhi Road, Shanghai 201203, China
SCHEME 2. Acid-Promoted Sequential One-Pot Reaction to
Synthesize Furocoumarins
yhhu@mail.shcnc.ac.cn
ReceiVed February 24, 2008
diversified furocoumarins. Herein, we report two approaches,
namely catalytic CuCl-promoted addition and cyclization of 1
together with oxygen as oxidant to form 4H-furo[3,2-c]chromen-
4-ones 2, and catalytic CuBr with CuCl2 as oxidant and
chlorinated reagent to produce 3-chloro-4H-furo[3,2-c]chromen-
4-ones 3 in a one-pot process.
The initial experiment was conducted by heating a mixture
of 3-alkynylchromone (1a), H2O (10 equiv), and CuCl (0.1
equiv) in DMF at 90 °C in an open flask. Furocoumarin (2a)
was successfully obtained in 71% yield (Table 1, entry 1). When
CuBr (0.1 equiv) was used instead of CuCl, the reaction gave
a similar result in 69% yield (Table 1, entry 2). By shortening
the reaction time to 2.5 h and lowering the reaction temperature
to 70-80 °C, the yield of 2a decreased (Table 1, entries 3-5).
By increasing the loading rate of the catalyst (CuCl used in
0.2, 0.5, and 1.0 equiv), the reaction was accelerated and the
yield of 2a was improved to 86%, 80%, and 96%, respectively
(Table 1, entries 6-8). However, there was no difference
performing the reaction in a pure oxygen atmosphere (Table 1,
entry 9). The use of other solvents such as dioxane, DMSO,
CH3CN, and toluene led to lower yields of the desired product
(Table 1, entries 10-13). The chloride product 3a was not
obtained in any of the investigations.
We examined the scope and limitations of this newly
developed domino approach under the optimized conditions
(Table 2). With electronic and steric variation (-R2) on the
acetylene moiety, the corresponding products were obtained in
good to moderate yields (Table 2, entries 1-5). Alkynes bearing
functional groups such as a cyanide or a tertiary alcohol (Table
2, entries 6-8) also gave the desired product in reasonable
yields. The alkyne with a TMS group only afforded desilylated
product 2j in 48% yield (Table 2, entry 9). However, electronic
effects on aromatic substitution of the chromone showed
equivocal results in the reaction. Substrate 1m with an electron-
We have developed two efficient one-pot reactions to
generate furo[3,2-c]coumarins and chlorofuro[3,2-c]cou-
marins through addition/cyclization/oxidation and chlorina-
tion. One cascade addition/cyclization/oxidation sequence of
1 with H2O in the presence of 20% CuCl as Lewis acid under
an air atmosphere generated the 2-substituted-4H-furo[3,2-
c]chromen-4-one 2. Another sequence in the presence of 10%
CuBr and excess CuCl2 as the oxidant afforded the 3-chloro-
2-substituted-4H-furo[3,2-c]chromen-4-one 3.
2-(1-Alkynyl)-2-alken-1-ones, which have three special func-
tional groups, are very attractive units because a C-O bond
and a remote carbon-nucleophile bond can be formed simul-
taneously. The groups of Larock, Oh, and Yamamoto have
independently reported Au-, Pt-, and Cu-catalyzed approaches
for the synthesis of highly substituted furans from this type of
universal intermediate.1 It has been suggested that a metal salt
can facilitate the reaction by its dual function as both a Lewis
acid to activate the carbonyl group and a coordination reagent
with alkynes (Scheme 1).
In our recent paper, we demonstrated that using CH3SO3H
as acid, water as nucleophile, and CuCl2 as oxidant, a sequential
one-pot reaction of 1 through addition/cyclization/oxidation
(Scheme 2),2 formed furocoumarins 2, which can be found in
many natural products and exhibits potent biological activity.3
On the basis of these results, we commenced our program to
develop a more convenient one-pot cascade process to construct
(3) (a) Donnelly, D. M. X.; Boland, G. M. Nat. Prod. Rep. 1998, 241. (b)
Miski, M.; Jakupovic, J. Phytochemistry 1990, 29, 1995. (c) Schuster, N.;
Christiansen, C.; Jakupovic, J.; Mungai, M. Phytochemistry 1993, 34, 1179. (d)
Wang, X.; Bastow, K. F.; Sun, C.; Lin, Y.; Yu, H.; Don, M.; Wu, T.; Nakamura,
S.; Lee, K. J. Med. Chem. 2004, 47, 5816. (e) Grese, T.; Pennington, L. D.;
Sluka, J. P.; Adrian, M. D.; Cole, H. W.; Fuson, T. R.; Magee, D. E.; Phillips,
D. L.; Rowley, E. R.; Shetler, P. K.; Short, L. L.; Venugopalan, M.; Yang, N. N.;
Sato, M.; Glasebrook, A. L.; Bryant, H. U. J. Med. Chem. 1998, 41, 1272. (f)
Zhao, L.; Brinton, R. D. J. Med. Chem. 2005, 48, 3463.
(1) (a) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126,
11164. (b) Oh, C. H.; Reddy, V. R.; Kim, A.; Rhim, C. Y. Tetrahedron Lett.
2006, 47, 5307. (c) Patil, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2005,
70, 4531. (d) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285. (e) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W.
Org. Lett. 2001, 3, 3769.
(2) Cheng, G.; Hu, Y. Chem. Commun. 2007, 3285.
4732 J. Org. Chem. 2008, 73, 4732–4735
10.1021/jo800439y CCC: $40.75 2008 American Chemical Society
Published on Web 05/28/2008

TABLE 1. Optimization of the CuCl-Catalyzed Cascade Reaction
SCHEME 3. The Cascade Reaction with Subsequent
Chlorination or Elimination
a
of 1a with H2O and O2
entry
solvent
catalyst
temp, time
yield ([%)
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
THF
10% CuCl
10% CuBr
10% CuCl
10% CuBr
10% CuCl
20% CuCl
50% CuCl
100% CuCl
10% CuCl
10% CuCl
10% CuCl
10% CuCl
10% CuCl
90 °C, 20 h
90 °C, 20 h
90 °C, 2.5 h
90 °C, 2.5 h
70-80 °C, 20 h
90 °C, 10 h
90 °C, 10 h
90 °C, 10 h
90 °C, 20 h
reflux, 10 h
reflux, 10 h
reflux, 10 h
reflux, 10 h
71
69
53
41
44
86
80
96
71b
46
8
of CuCl2 to 4.2 equiv, the yield of 3a was improved with less
directly cyclized product 2a (Table 3, entry 2). Without the acid,
the desired product 3a was also obtained in low yield (Table 3,
entry 3). Comparing the different catalysts (CH3SO3H, CuCl,
and CuBr), CuBr is the most efficient, giving 3a in 70% yield
(Table 3, entry 6). The reason for the varying efficiencies of
CuCl and CuBr is not clear at present.1c Reducing the reaction
temperature to 75 °C was more beneficial, generating 3a in 84%
yield (Table 3, entry 7). However, with CuBr2 as the brominating
reagent and oxidant, the reaction gave complicated products
(Table 3, entry 8). After testing other solvents, DMF was judged
the best in the cascade addition-cyclization-oxidation-
chlorination.
9
10
11
12
13
toluene
dioxane
low
low
a Reaction was carried out on a 0.2 mmol scale and 0.04 mL of H2O
in 1 mL of solvent in an open flask and heated for the specified time.
b The reaction was performed under an oxygen atmosphere.
TABLE 2. Scope of the Cu(I)-Catalyzed Reaction of 1 with H2O
and O2 To Construct Furocoumarinsa
We applied the optimized conditions to synthesize a series
of substituted 3-chloro-4H-furo[3,2-c]chromen-4-ones 3 (Table
4). With electronic and steric variation (-R2) on the acetylene
moiety, 3-alkynyl-4H-chromen-4-ones smoothly underwent
reaction to give the corresponding products in good to moderate
yields (Table 4, entries 1-6). Only an electron-withdrawing
group on the aromatic ring of alkyne 1d gave the corresponding
product 3d in 57% yield (Table 4, entry 3). When R2 is TMS,
the reaction only afforded the dichloride product 3j in 40% yield
(Table 4, entry 7). Substrates with a substituent of CH3 or Cl at
the 6-position of the chromone (R1) reacted well to give 3k
and 3l. With an electron-donating group (R1 ) OMe), the
reaction gave the desired product 3m in 47% yield along with
the chlorinated product of 3m at the 8-position in 20% yield
(Table 4, entry 10). The substrate with an electron-withdrawing
group (R1 ) NO2) afforded the desired product 3n in 35% yield
at a higher temperature (Table 4, entry 11).
entry
R1
R2
product
yield (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
CH3
Cl
CH3O
NO2
4-CH3-C6H4
4-CH3O-C6H4
4-CF3-C6H4
-(CH2)4CH3
-C(CH3)3
-(CH2)3CN
-C(CH3)2OH
-C(CH2)5OH
-Si(CH3)3
-C6H5
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
81
73
73
78
77
69
55
56
48b
74
72
45
46c
9
10
11
12
13
-C6H5
-C6H5
-C6H5
Interestingly, substrates 1h and 1i bearing an R-hydroxyl
group on the acetylene moiety generated products 3h and 3i,
which were chlorinated at the carbon adjacent to the hydroxy
group, together with elimination products 4h and 4i (Scheme
3. It is clear that the further chlorination in this cascade reaction
is connected with the hydroxy group. This process may involve
C-H activation by the SET transformation.4 A mechanistic
study of this reaction is under way.
On the basis of the above results, the mechanisms of the two
cascade reactions are proposed (Figure 1). In the two processes,
Cu(I) acting as a Lewis acid activates the carbonyl group and
promotes a 1,4-addition of H2O to the carbon-carbon double
bond. In path A, Cu(I) could be coordinated with the alkynyl
moiety of B to induce the cyclization, which is followed by the
protonation of the resulting organocopper intermediate C to
a Conditions: A mixture of 0.2 mmol of 3-alkynylchromone, H2O
(11.0 equiv) and 20 mol % of CuCl in 1 mL of DMF was heated at 90
b
°C. R2 ) H. c The reaction was heated to 90 °C for 10 h, and then to
120 °C for 10 h.
donating group (R1 ) OMe) at the 6-position of the chromone
gave the desired product 2m in 45% yield (Table 2, entry 12),
and substrate 1n with an electron-withdrawing group (R1 )
NO2) at the 6-position of the chromone afforded the corre-
sponding product 2n in 46% yield at 120 °C (Table 2, entry
13).
Our recent paper2 reported that a mixture of 1a, CH3SO3H
(1.5 equiv), CuCl2 (2.1 equiv), and 0.02 mL of H2O in DMF at
90 °C in a one-pot process gave 3-chloro-2-phenyl-4H-furo[3,2-
c]chromen-4-one 3a (40%) and 2a (35%), respectively (Table
3, entry 1). To improve the yield of 3a for developing a coupling
reaction to produce the diversified furocoumarins scaffold,
optimization of this cascade addition-cyclization-chlorination-
oxidation was further investigated. By increasing the amount
(4) (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790. (b) Sheldon, R. A.; Kochi, J. K. Metal-Catalyzed Oxidations
of Organic Compounds; Academic Press: New York, 1981; pp 7-8. (c) Zhang,
Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2007, 9, 3813.
J. Org. Chem. Vol. 73, No. 12, 2008 4733

TABLE 3. Optimization of Addition-Cyclization-Oxidation-Chlorination for 1a
yield (%)
entry
solvent
catalyst
cupric salt
temp (°C)
3a
2a
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3SO3H (1.5 equiv)
CH3SO3H (1.5 equiv)
CuCl2 (2.1 equiv)
CuCl2 (4.2 equiv)
CuCl2 (4.2 equiv)
CuCl2 (4.2 equiv)
CuCl2 (4.2 equiv)
CuCl2 (4.2 equiv)
CuCl2 (4.2 equiv)
CuBr2 (4.2 equiv)
90
90
90
90
90
90
75
75
40
59
54
62
48
70
84
35
19
14
18
17
9
CH3SO3H (0.1 equiv)
CuCl (0.1 equiv)
CuBr (0.1 equiv)
CuBr (0.1 equiv
CuBr (0.1 equiv)
4
complex
9
10
CH3CN
acetone
CuBr (0.1 equiv)
CuBr (0.1 equiv)
CuCl2 (4.2 equiv)
CuCl2 (4.2 equiv)
reflux
reflux
15
0
0
0
TABLE 4. Domino Addition-Cyclization-Oxidation-
Chlorination To Construct Substituted 3-Chloro-4H-
furo[3,2-c]chromen-4-ones 3a
and promotes the cyclization to release CuCl even though Cu(I)
exists in the reaction.
A further application for chlorofurochromenones was initially
tested by a Suzuki reaction (Scheme 4). After testing several
reaction conditions, only P(t-Bu)3 as ligand gave a satisfactory
result because 3b is an inactive substrate.
In summary, we have developed two efficient one-pot cascade
reactions to generate substituted furocoumarins. One cascade
addition/cyclization/oxidation of 1 with H2O in the presence of
20% CuCl as Lewis acid under an air atmosphere generated
2-substituted 4H-furo[3,2-c]chromen-4-one. Another reaction in
the presence of 10% CuBr and excess CuCl2 as the oxidant
afforded 3-chloro-2-substituted-4H-furo[3,2-c]chromen-4-one.
Comparing the two tandem processes, Cu(I) did not transform
to Cu(II) as oxidant under the first reaction conditions because
the chloride product was not obtained. CuCl2 could be a stronger
coordination reagent with the triple bond of 2-(1-alkynyl)-2-
entry
R1
R2
product
yield (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
CH3
Cl
CH3O
NO2
4-CH3-C6H4
4-CH3O-C6H4
4-CF3-C6H4
-(CH2)4CH3
-C(CH3)3
-(CH2)3CN
-Si(CH3)3
-C6H5
3b
3c
3d
3e
3f
3g
3j
3k
3l
3m
3n
77
86
57
75
76
73
40b
70
65
47
35c
9
10
11
-C6H5
-C6H5
-C6H5
a Conditions: 0.1 equiv of CuBr, 4.2 equiv of CuCl2, and 10 equiv of
b
H2O, 75 °C, 10 h. R2 ) Cl. c A mixture of 1n (0.20 mmol), CuBr
(0.02 mmol), CuCl2 (0.84 mmol), and H2O (2.2 mmol) in DMF (1 mL)
was heated at 90 °C for 10 h, then heated to 110 °C for an additional
20 h.
SCHEME 4. Suzuki Coupling Reaction of 3b
afford lactol D with simultaneous regeneration of the Cu(I)
catalyst.1c Lactol D is oxidized to lactone E by O2 in an open-
flask reaction. In this process, Cu(I) was not transformed to
Cu(II) as oxidant because chlorofurocoumarins were not ob-
served as byproduct. In path B, CuCl2 could be employed as
the chlorination reagent and oxidant as well because alkenes
and alkynes can be halogenated by CuCl2.5 Compared with path
A, CuCl2 has a stronger association with the triple bond of B
FIGURE 1. The proposed mechanisms of the two cascade pro-
cesses.
(5) (a) Ma, S.; Wu, S. J. Org. Chem. 1999, 64, 9314. (b) Lu, W.-D.; Wu,
M.-J. Tetrahedron 2007, 63, 356.
4734 J. Org. Chem. Vol. 73, No. 12, 2008

Procedure B: Synthesis of 3-Chloro-4H-furo[3,2-c]chromen-4-
ones by the CuBr-Cascade Reaction of 1 with H2O and CuCl2. A
solution of substrate 1 (3-alkynyl-chromone, 0.2 mmol), CuBr (2.9
mg, 0.02 mmol), CuCl2 (113.4 mg, 0.84 mmol), and H2O (0.04
mL, 2.2 mmol) in DMF (1 mL) was heated at 90 °C for 10-20 h.
Next the reaction mixture was cooled to room temperature and
diluted with ethyl acetate (30 mL). The organic layer was washed
with water (3 × 30 mL) and brine (10 mL) and then dried over
Na2SO4. Upon removal of the solvent, the residue was purified by
column chromatography to afford the corresponding 3-chloro-4H-
furo[3,2-c]chromen-4-ones.
3-Chloro-2-p-tolyl-4H-furo[3,2-c]chromen-4-one (3b). With 1b
as substrate, procedure B was followed and the product was purified
by flash chromatography (silica gel, 2:1 petroleum ether/CH2Cl2)
to afford 48 mg of 3b (77%) as a white solid: mp 169-171 °C; 1H
NMR (CDCl3) δ 7.91 (m, 3H), 7.53 (t, J ) 8.0 Hz, 1H), 7.42 (d,
J ) 8.0 Hz, 1H), 7.37 (t, J ) 8.0 Hz, 1H), 7.28 (t, J ) 8.4 Hz,
2H), 2.41 (s, 3H); 13C NMR (CDCl3) δ 156.17, 155.02, 152.41,
149.94, 139.57, 131.06, 129.38, 125.37, 124.83, 124.62, 120.64,
117.16, 112.04, 110.01, 109.27, 21.37; MS (EI) m/z 310 (M+ (35Cl),
100), 312 (33); HRMS calcd for C18H11ClO3 (35Cl) 310.0397, found
310.0389.
alken-1-one than CuCl because the major product was the
chloride at the 3-position under the second reaction conditions.
Further applications of these methods and the biological
activities of these compounds are currently being investigated
in our laboratory.
Experimental Section
Procedure A: Synthesis of 4H-Furo[3,2-c]chromen-4-ones by
CuCl-Catalyzed Cascade Reaction of 1 with H2O and O2. A
solution of substrate 1 (3-alkynyl-chromone, 0.2 mmol), CuCl (4.0
mg, 0.04 mmol), and H2O (0.04 mL, 2.2 mmol) in DMF (1 mL)
was heated at 90 °C for 10-20 h. Then the reaction mixture was
cooled to room temperature and diluted with ethyl acetate (30 mL).
The organic layer was washed with water (3 × 30 mL) and brine
(10 mL) and then dried over Na2SO4. Upon removal of the solvent,
the residue was purified by column chromatography to afford
corresponding 4H-furo[3,2-c]chromen-4-ones.
2-p-Tolyl-4H-furo[3,2-c]chromen-4-one (2b)4. With 1b as
substrate, procedure A was followed then the product was purified
by flash chromatography (silica gel, 6:1 petroleum ether/ethyl
acetate) to afford 45 mg of 2b (81%) as a white solid: mp 205-206
°C; 1H NMR (CDCl3) δ 7.95 (dd, J ) 7.8, 1.4 Hz, 1H), 7.70 (d, J
) 8.0 Hz, 2H), 7.52 (td, J ) 7.7, 1.4 Hz, 1H), 7.45 (dd, J ) 7.7,
1.4 Hz, 1H), 7.37 (td, J ) 7.7, 1.4 Hz, 1H), 7.27 (d, J ) 8.0 Hz,
2H), 7.11 (s, 1H), 2.41 (s, 3H); 13C NMR (CDCl3) δ ) 158.22,
156.83, 156.51, 152.47, 139.28, 130.38, 129.63, 126.16, 124.47,
124.43, 120.68, 117.28, 112.75, 112.47, 101.81, 21.36; MS (EI)
m/z 276 (M+, 100). Anal. Calcd for C18H12O3: C 78.25, H 4.38.
Found: C 77.92, H 4.38.
Acknowledgment. The Hundred Talent Project of the
Chinese Academy of Sciences supported this work.
Supporting Information Available: Experimental proce-
dures and spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO800439Y
J. Org. Chem. Vol. 73, No. 12, 2008 4735