A novel multicomponent reaction to synthesize substituted furo[3,2-c]chromenes via a Pd-catalyzed cascade process

Article abstract of DOI:10.1016/j.tetlet.2008.10.025

A novel one-pot three-component reaction for the synthesis of multisubstituted furo[3,2-c]chromenes using 3-(1-alkynyl)chromones, aryl iodides, and alcohols is developed via Pd-catalyzed cascade 1,4-addition and cyclization. This synthetic approach efficiently generates two C-O bonds and one C-C bond to construct diverse furo[3,2-c]chromenes structures.

Full text of DOI:10.1016/j.tetlet.2008.10.025

Tetrahedron Letters 49 (2008) 7364–7367
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Tetrahedron Letters
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A novel multicomponent reaction to synthesize substituted
furo[3,2-c]chromenes via a Pd-catalyzed cascade process
*
Lizhi Zhao, Gang Cheng, Youhong Hu
Shanghai Institute of Materia Medica, Chinese Academy of Science, 555 Zu Chong Zhi Road, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel one-pot three-component reaction for the synthesis of multisubstituted furo[3,2-c]chromenes
using 3-(1-alkynyl)chromones, aryl iodides, and alcohols is developed via Pd-catalyzed cascade 1,4-addi-
tion and cyclization. This synthetic approach efficiently generates two C–O bonds and one C–C bond to
construct diverse furo[3,2-c]chromenes structures.
Received 18 August 2008
Revised 29 September 2008
Accepted 7 October 2008
Available online 11 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
MCRs
Furo[3,2-c]chromenes
Pd-catalyzed
Cascade reaction
Domino and multicomponent reactions (MCRs) have attracted
great interest among synthetic chemists as powerful tools for the
rapid generation of molecular complexity and diversity.1 In partic-
ular, the use of transition metal-catalyzed domino reactions is now
recognized as an efficient synthetic strategy.2 Much attention has
been paid to the synthesis of highly substituted furans from 2-
(1-alkynyl)-2-alken-1-ones, including 3-(1-alkynyl)chromones, by
transition metal-catalyzed (using Au, Pt, or Cu catalysts)3 or elec-
trophilic cyclization4 (Scheme 1).
Recently, our group has reported a one-pot synthesis of fur-
ocoumarins through cascade addition–cyclization–oxidation using
3-(1-alkynyl)chromone as the starting material and water as the
nucleophile, in the presence of acid and without transition metal
mediation.5 We report herein a novel three-component reaction
for the synthesis of poly-substituted furo[3,2-c]chromenes via
Pd-catalyzed cascade addition and cyclization.
Larock and co-workers had previously mentioned that Pd(OAc)2
promoted the cyclization of 2-(1-alkynyl)-2-alken-1-ones in low
yield only, because of the facile reduction of Pd(II) to Pd(0) in the
presence of the alcohol.3a,4a We suspected that introducing aryl ha-
lide by oxidative addition of Pd(0) could generate the Pd(II) species
as a Lewis acid for 1,4-addition6 and the coordination reagent with
a triple bond for cyclization.7 In this plausible approach, the car-
bonyl group of chromone could be activated by the palladium(II),
which is formed in situ by oxidative addition of aryl halide with
Pd(0). The activated A induces 1,4-addition by nucleophilic attack
of the alcohol to generate intermediate B. Coordination of the triple
bond of B with ArPdX induces cyclization to give intermediate C,
which is followed by reductive elimination to furnish the product
D and regenerate the Pd(0) species. In the meantime, 3-(1-alky-
nyl)-chromone A could be directly cyclized to generate product
E. Recently, Xiao and Zhang also reported the similar mechanism
to generate tetrasubstituted furans by a Pd-catalyzed three-com-
ponent Michael addition/cyclization/cross-coupling reaction using
2-(1-alkynyl)-2-alken-1-ones, alcohols, and allyl chlorides.8
To test the feasibility of this possible mechanism, we started our
investigation of the three-component reaction using 3-phenyleth-
ynyl chromone (1a), p-iodotoluene (2a), and methanol (3a) under
different reaction conditions (Table 1). The reaction proceeded in
DMF at 45 °C for 16 h, using DIPEA as the base and Pd(PPh3)4 as
the catalyst, producing the desired compound 4a in 30% yield
and the direct cyclization product in 35% yield (entry 1). While
Pd2(dba)3 (5 mol %) was employed as the catalyst instead of
Pd(PPh3)4, the transformation was completed in 5 h in 37% yield
R3
R1
O
R3
O
E+
R1
Nu
E
NuH
R2
R2
E = H(cat. AuCl3); NuH= ROH, enol, ArH
E = I; NuH = ROH, RCOOH, H2O
E = PhSe; NuH = ROH
Scheme 1. Synthesis of highly substituted furans from 2-(1-alkynyl)-2-alken-1-
ones.
* Corresponding author. Tel.: +86 21 5080 5896; fax: +86 21 5050 5896.
E-mail address: yhhu@mail.shcnc.ac.cn (Y. Hu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.025

L. Zhao et al. / Tetrahedron Letters 49 (2008) 7364–7367
7365
Table 1
Effect of catalyst, solvent, and base on MCRa
I
O
Pd, base
O
+
+
MeOH
solvent, 45 o
C
O
O
O
1a
2a
3a
4a
Entry
Solvent
Base
Catalyst
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
MeCN
DCE
Toluene
DMF
DMF
DMF
DMF
DIPEA
DIPEA
Cs2CO3
Ag2CO3
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
Pd(PPh3)4
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3/PPh3
Pd2(dba)3/t-Bu3P
Pd(OAc)2/PPh3
PdCl2(MeCN)2
16
5
10
10
16
8
6
24
6
30
37
22
18
8
23
35
21
10
Trace
32
10
11
20
5
a
All reactions were carried out with 1a (0.20 mmol), 2a (0.22 mmol), methanol 3a (0.25 mL), base (0.8 mmol), and catalyst (0.02 mmol) in DMF (1 mL) at 45 °C for 5–24 h
under a nitrogen atmosphere.
b
Isolated yields.
Table 2
Three-component one-pot reaction for the synthesis of substituted furo[3,2-c]chromenesa
R1
O
O
R1
Pd2(dba)3 / DIPEA
DMF, 45 oC
R2
R2I
+
+
R3OH
O
O
R3
O
1
2
3
4
Entry
1
R1
R2
R3OH
Yieldb (%)
C6H5
MeOH
4a (31)
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
4b (66)
4c (33)
4d (25)
4e (34)
4f (62)
4g (55)
COOMe
OMe
S
S
4-MeO-C6H4
2b
4h (82)
(continued on next page)

7366
L. Zhao et al. / Tetrahedron Letters 49 (2008) 7364–7367
Table 2 (continued)
Entry
R1
R2
R3OH
Yieldb (%)
9
10
11
2-F-C6H4
4-CF3C6H4
(CH2)3CN
2b
2b
2b
MeOH
MeOH
MeOH
4i (64)
4j (55)
4k (57)
12
2b
MeOH
MeOH
4l (61)
OH
OH
13
2b
4m (45)
14
15
16
17
18
19
C(CH3)3
(CH2)4CH3
C6H5
C6H5
C6H5
2b
2b
2b
2b
2b
2b
MeOH
MeOH
i-PrOH
t-BuOH
BnOH
4n (49)
4o (55)
4p (45)
Complex
4q (48)
Complex
C6H5
p-NO2C6H5OH
a
Reaction conditions: 1 (0.2 mmol), 2 (0.22 mmol), and 3 (0.15 mL) in DMF (1.5 mL), using DIPEA (0.8 mmol) as the base and Pd2 (dba)3 (10 mol %) as the catalyst, at 45 °C
for 3–10 h.
b
Isolated yields.
(entry 2). Among organic bases such as Et3N and DBU and inor-
ganic bases such as K2CO3, Cs2CO3, and Ag2CO3, only DIPEA gave
the better result. After the different solvents were tested (entries
5–7), toluene exhibited the similar result as DMF. Surprisingly,
Pd species with the phosphine ligands decreased the reaction
efficiency (entries 8–10). The reported efficient catalyst PdCl2-
8
(MeCN)2 did not improve the yield significantly. Furthermore,
the additives such as Bu4NCl or LiCl or increasing the amount of
Pd2(dba)3 and p-iodotoluene did not effect the reaction.
Using the optimized conditions, we examined the scope of
three-component one-pot cascade reactions using various sub-
strates (Table 2). Among different aryl iodides, methyl 4-iodoben-
zoate 2b gave the desired product 4b in the best yield (66%, entry
2),9 which was obtained for X-ray crystal structure (Fig. 1).10 This
indicates that aryl iodides bearing electron-withdrawing groups
favor the cascade process due to the faster oxidative addition com-
pared with other iodides. Comparing with entry 1, the meta-substi-
Figure 1. X-ray crystal structure of 4b. Ellipsoid probability: 50%.
R1
O
Ar
ArX
Pd0Ln
O
O
R3
O
O
R1
D
R2PdX
R1
O
Pd
Pd(II)
Ar
O
O
O
R3
R1
O
C
A
R3OH
R1
R1
H
O
O
Pd
X
Ar
O
B
O
R3
O
O
R3
E
Scheme 2. Plausible mechanism for MCR.

L. Zhao et al. / Tetrahedron Letters 49 (2008) 7364–7367
7367
tuted aryl iodide also gave the desired product 4e in the reasonable
References and notes
yield. Iodothiophenes such as 2-iodothiophene and 3-iodothio-
phene afforded the corresponding products 4f and 4g in 62% and
55% yields, respectively (entries 6 and 7).
1. (a) Wender, P. A. Chem. Rev. 1996, 96, 1; (b) Tietze, L. F.; Beifuss, U. Angew.
Chem., Int. Ed. Engl. 1993, 32, 131; (c) Armstrong, R. W.; Combsm, A. P.; Brown,
S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123; (d) Dömling, A.; Ugi, I. Angew.
Chem., Int. Ed. 2000, 39, 3168; (e) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879; (f)
Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957;
(g)Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH:
Weinheim, 2005; (h) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44,
1602.
2. (a) Tonogaki, K.; Itami, K.; Yoshida, J. J. Org. Chem. 2006, 8, 1419; (b) Lu, B. Z.;
Zhao, W.; Wei, H. X.; Dofour, M.; Farina, V.; Senanayake, C. H. Org. Lett. 2006, 8,
3271; (c) Bossharth, E.; Desbordes, P.; Monteiro, N.; Balme, G. Org. Lett. 2003, 5,
2441.
3. (a) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164; (b) Oh, C.
H.; Reddy, V. R.; Kim, A.; Kim, C. Y. Tetrahedron Lett. 2006, 47, 5307; (c) Patil, N.
T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2005, 70, 453.
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S. Org. Lett. 2005, 7, 4609; (c) Liu, X.; Pan, Z.; Shu, X.; Duan, X.; Kuabg, Y. Synlett
2006, 1962.
The arynyl moieties of chromones bearing different electronic
groups exhibit different reactivity. When R1 was the electron-
donating group p-methoxyl phenyl, the yield of 4h improved dra-
matically (82%, entry 8). However, when R1 was the electron-with-
drawing group (p-trifluoromethyl) phenyl, yield of 4j was
decreased to 55% (entry 10). These results suggest that the fast oxi-
dative addition of aryl iodide with the electron-withdrawing group
by Pd(0) and the higher electronic density of the alkyne groups
could stabilize the complex B (Scheme 2) to block the direct cy-
clized reaction in this process. Aliphatic ethynyls with hydroxy,
CN, or sterically hindering parts also gave the desired products in
moderate yields. The reaction of secondary alcohols i-PrOH and
BnOH with 1a and methyl 4-iodobenzoate 2b under the standard
condition proceeded smoothly, giving the corresponding products
4p and 4q in 45% and 48% yields, respectively (entries 16 and
18). However, tert-butyl alcohol and p-NO2C6H4OH gave a compli-
cated distribution of products each.
5. Cheng, G.; Hu, Y. Chem. Commun. 2007, 3285.
6. (a) Gaunt, M. J.; Spencer, J. B. Org. Lett. 2001, 3, 25; (b) Kobayashi, S.; Kakumoto,
K.; Sugiura, M. Org. Lett. 2002, 4, 1319; (c) Miller, K. J.; Kitagawa, T. T.;
Abu-Omar, M. M. Organometallics 2001, 20, 4403; (d) Takasu, K.; Nishida, N.;
Ihara, M. Synlett 2004, 1844; (e) Lin, Y.; Kao, J.; Chen, C. Org. Lett. 2007, 9,
5195.
7. (a) Hu, Y.; Nawoschik, K. J.; Liao, Y.; Ma, J.; Fathi, R.; Yang, Z. J. Org. Chem. 2004,
69, 2235; See the review for cyclization: (b) Balme, G.; Bouyssi, D.; Lomberget,
T.; Monteiro, N. Synthesis 2003, 211.
In conclusion, we have developed a novel three-component
one-pot cascade reaction for the synthesis of multisubstituted
furo[3,2-c]chromenes. This method rapidly increases the complex-
ity and diversity of furo[3,2-c]chromene structures. Further studies
of this methodology and biological evaluation of the compounds
are under investigation.
8. Xiao, Y.; Zhang, J. Angew. Chem., Int. Ed. 2008, 47, 1903.
9. Synthesis of 4b: To a stirred mixture of 3-(2-phenylethynyl)-4H-chromen-4-
one (50 mg, 0.20 mmol), methyl 4-iodobenzoate (57.6 mg, 0.22 mmol),
methanol (0.25 mL), and DIPEA (0.15 mL, 0.90 mmol) in dry DMF (1 mL) was
added Pd2(dba)3 (18.6 mg, 0.02 mmol) under a N2 balloon and the resulting
solution was heated at 45 °C for 5 h. Then it was quenched with water (10 mL)
and extracted with ethyl acetate (5 mL Â 3). The combined organic layers were
washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography to afford 54.3 mg of the
desired compound 4b (66% isolated yield) as a white solid. Mp 137–139 °C, 1H
NMR (CDCl3): d = 3.54 (s, 3H), 3.95 (s, 3H), 6.05 (s, 1H), 7.05–7.15 (m, 2H), 7.25–
7.35 (m, 4H), 7.50–7.60 (m, 4H), 7.67 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 8.1 Hz, 2H).
13C NMR (CDCl3): 52.2, 55.1, 97.3, 115.0, 115.6, 117.0, 119.6, 120.1, 122.0,
125.3, 126.4, 128.1, 128.3, 128.5, 128.9, 129.3, 130.1, 130.5, 134.7, 137.2, 143.3,
146.4, 149.8, 150.8, 166.8. HRMS calcd for C26H20O5 412.1311, found 412.1319.
10. Crystallographic data: 4b; CCDC 695854.
Acknowledgments
This work was supported by grants from Shanghai Commission
of Science and Technology (06PJ14112) and Chinese Academy of
Sciences (KSCX-2-YW-R-23).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.10.025.