Efficient construction of a 3 C -xanthone-linked 3 C -chromone scaffold by novel double michael additions and cyclizations

Article abstract of DOI:10.1021/ol101100d

A novel base-promoted cascade reaction of 2-methyl-3-(1-alkynyl)chromones to produce a 3C-xanthone-linked 3C-chromone scaffold has been developed. This tandem process involves multiple reactions such as Michael additions/ cyclizations under mild conditions without a transition metal catalyst and inert atmosphere.

Full text of DOI:10.1021/ol101100d

ORGANIC
LETTERS
2010
Vol. 12, No. 13
3086-3089
Efficient Construction of a
3C-Xanthone-Linked 3C-Chromone
Scaffold by Novel Double Michael
Additions and Cyclizations
Fuchun Xie, Hong Chen, and Youhong Hu*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Science, 555 Zu Chong Zhi Road, Shanghai 201203, China
yhhu@mail.shcnc.ac.cn
Received May 13, 2010
ABSTRACT
A novel base-promoted cascade reaction of 2-methyl-3-(1-alkynyl)chromones to produce a 3C-xanthone-linked 3C-chromone scaffold has
been developed. This tandem process involves multiple reactions such as Michael additions/cyclizations under mild conditions without a
transition metal catalyst and inert atmosphere.
Tandem reactions that involve the production of multiple C-C
bonds in a single manipulation provide an efficient way to
construct complex molecules from readily available materials.1
The design of a tandem reaction from an easily prepared
ingenious intermediate with multiple reactive sites to generate
complex molecular architectures is significant and attractive,
especially for the synthesis of natural product skeletons.2 Our
group has been pursuing the diversified synthesis of natural-
product-like scaffolds through cascade reactions based on 3-(1-
alkynyl)chromone intermediates.3 The chromone moiety is well-
known as a Michael receptor.4 However, the reactivity of the
methyl group of chromone at the 2-position has rarely been
investigated. Only a few reports have mentioned that the methyl
group of 2-methyl chromone could be used in aldol condensa-
tions with electrophiles (such as aromatic aldehydes, dimethyl-
formamide dimethyl acetal, diethyl oxalate, and 4-nitrosodim-
ethylanilines) under basic conditions.5 We envisioned that the
(1) For recent reviews, see: (a) Tietze, L. F. Chem. ReV. 1996, 96, 115.
(b) Eilbracht, P.; Barfacker, L.; Buss, C.; Hollmann, C.; Kitsos-Rzychon,
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ReV. 1999, 99, 3329. (c) Ajamian, A.; Gleason, J. L. Angew. Chem., Int.
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G. C. Chem. ReV. 2005, 105, 1001. (e) Enders, D.; Grondal, C.; Huttl, M. R.
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(h) Gorobets, E. V. M.; Mansur, S.; Valeev, F. A. Russ. Chem. ReV. 2000,
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(3) (a) Cheng, G.; Hu, Y. Chem. Commun. 2007, 3285. (b) Cheng, G.;
Hu, Y. J. Org. Chem. 2008, 73, 4732. (c) Zhao, L.; Cheng, G.; Hu, Y.
Tetrahedron Lett. 2008, 49, 7364. (d) Zhao, L.; Xie, F.; Cheng, G.; Hu, Y.
Angew. Chem., Int. Ed. 2009, 48, 6520. (e) Xie, F.; Pan, X.; Lin, S.; Hu,
Y. Org. Biomol. Chem. 2010, 8, 1378.
(4) For recent examples, see: (a) Ibrahim, M. A. ArkiVoc 2008, 192. (b)
Sosnovskikh, V.; Irgashev, R.; Moshkin, V.; Kodess, M. Russ. Chem. Bull.
2008, 57, 2146. (c) Sosnovskikh, V. Y.; Irgashev, R. A.; Kodess, M. I.
Tetrahedron 2008, 64, 2997. (d) Sosnovskikh, V. Y.; Moshkin, V. S.;
Kodess, M. I. Tetrahedron 2008, 64, 7877. (e) Sosnovskikh, V. Y.; Moshkin,
V. S.; Irgashev, R. A. Tetrahedron Lett. 2006, 47, 8543. (f) Lin, Y. D.;
Kao, J. Q.; Chen, C. T. Org. Lett. 2007, 9, 5195. (g) Shokol, T.; Turov, V.;
Semeniuchenko, V.; Krivokhizha, N.; Khilya, V. Chem. Heterocycl. Compd.
2006, 42, 500. (h) Gasparova, R.; Lacova, M. Molecules 2005, 10, 937.
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Chem. ReV. 1996, 96, 195. (b) Nicolaou, K. C.; Montagnon, T.; Snyder,
S. A. Chem. Commun. 2003, 551. (c) Nicolaou, K. C.; Edmonds, D. J.;
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10.1021/ol101100d  2010 American Chemical Society
Published on Web 06/10/2010

employment of the nucleophilic methyl group and the R,ꢀ-
unsaturated system of 2-methylchromones with a triple bond
under basic conditions could initiate a new cascade reaction to
produce a 3C-xanthone-linked 3C-chromone skeleton.
The proposed reaction is shown in Scheme 1. First, the
methyl group of 1 could be deprotonated by a base, such as
DBU, to generate the corresponding carbanion, which attacks
at the 2-position of a second molecule with pyrone ring
opening to give intermediate 3. Subsequently, phenol ion 3
undergoes a cyclization with the adjacent alkynyl bond,
which is followed by a second Michael addition with pyrone
ring opening to produce intermediate 4, which can be
isomerized to intermediate 5a or 5b.The phenol ion 5a or
5b could also undergo a second cyclization with the adjacent
alkynyl bond or allene and isomerize to afford product 2.
Significantly, from the easily prepared 2-methyl-3-(1-alky-
nyl)chromones, the formation of two new C-C bonds and
C-O bonds could be efficiently created accompanying
double ring openings and closings.
Figure 1. Unique bioactive natural products with a 3C-xanthone-
linked 3C-chromone substructure.
through an intermolecular Diels-Alder cycloaddition be-
tween two molecules of the precursor.8 Herein, we report
an efficient, novel cascade reaction for constructing this
interesting framework rapidly under microwave irradiation
in good to excellent yields.
Table 1. Optimization of Reaction Conditionsa
Scheme 1. Plausible Reaction Mechanism
entry base (equiv)
solvent
THF
acetonitrile
DME
dioxane
toluene
DMF
DMSO
DMSO
DMSO
temp (°C) t (min) yieldb (%)
1c
2c
3c
4c
5c
6c
7
DBU (2.0)
DBU (2.0)
DBU (2.0)
DBU (2.0)
DBU (2.0)
DBU (2.0)
DBU (2.0)
DBU (1.0)
DBU (0.5)
120
120
120
120
120
120
120
120
120
10
10
10
10
10
10
10
10
10
<30
<30
<30
<30
<30
<30
50d
90d
85d
8
9c
a General conditions: 1a (0.4 mmol) and DBU in solvent (1.5 mL) heated
in a microwave reactor at 120 °C for 10 min. b Yield was evaluated by
TLC. c With 1a recovered. d Isolated yield.
3C-Xanthone-linked 3C-chromone with an axial chirality
as a core structure was found in the fascinating unique natural
products vinaxanthone, (RR)-2′-methoxyvinaxanthone, and
chaetocyclinone C (Figure 1) from penicillium,6 which
exhibited important biological activity.7 Only the Tatsuta
group has reported a biomimetic synthesis of vinaxanthone
Initially, we investigated the cascade dimeric reaction of
1a with DBU (2 equiv) as base in THF at 50 °C for 24 h
under oil-bath heating conditions. The desired product 2a
was obtained with slow transformation. Therefore, we
decided to apply this tandem process under microwave
irradiation (Table 1). The reaction did not proceed well in
most common solvents such as THF, DME, toluene, DMF,
etc., giving less than 30% yield of 2a with abundant 1a
recovered (Table 1, entries 1-6). To our delight, when the
solvent was changed to DMSO, 1a was consumed completely
to afford 2a in 50% yield (Table 1, entry 7). Employing DBU
as 1.0 equiv, the reaction proceeded smoothly in 10 min and
the yield increased significantly to 90% (Table 1, entry 8).
(5) (a) Santos, C. M. M.; Silva, A. M. S.; Cavaleiro, J. A. S. Eur. J.
Org. Chem. 2009, 2642. (b) Santos, C. M. M.; Silva, A. M. S.; Cavaleiro,
J. A. S. Synlett 2005, 3095. (c) Venkateswara Rao, K. Ind. Eng. Chem.
Res. 2002, 41, 3333. (d) Alonso, R.; Brossi, A. Tetrahedron Lett. 1988,
29, 735. (e) Ghosh, C. K.; Bhattacharyya, S.; Patra, A. J. Chem. Soc., Perkin
Trans. 1 1999, 3005. (f) Sami, S. M.; Sayed, A. A.; Ibrahim, S. S. Egypt.
J. Chem. 1981, 23, 337. (g) El-Shaaer, M. H.; Lacova, P. Z. M.; Matulova,
M. Collect. Czech. Chem. Commun. 1994, 59, 1673.
(6) (a) Aoki, M.; Itezono, Y.; Shirai, H.; Nakayama, N.; Sakai, A.;
Tanaka, Y.; Yamaguchi, A.; Shimma, N.; Yokose, K.; Seto, H. Tetrahedron
Lett. 1991, 32, 4737. (b) Wrigley, S. K.; Latif, M. A.; Gibson, T. M.;
Chicarelli-Robinson, M.; Williams, D. H. Pure Appl. Chem. 1994, 66, 2383.
(c) Lo¨sgen, S.; Schlo¨rke, O.; Meindl, K.; Herbst-Irmer, R.; Zeeck, A. Eur.
J. Org. Chem. 2007, 2191. (d) Rezanka, T.; Rezanka, P.; Sigler, K. J. Nat.
Prod. 2008, 71, 820.
(7) (a) Kumagai, K.; Hosotani, N.; Kikuchi, K.; Kimura, T.; Saji, I. J.
Antibiot. 2003, 56, 610. (b) Zheng, C. J.; Sohn, M. J.; Kim, W. G. J.
Antimicrob. Chemother. 2009, 63, 949.
(8) Tatsuta, K.; Kasai, S.; Amano, Y.; Yamaguchi, T.; Seki, M.;
Hosokawa, S. Chem. Lett. 2007, 36, 10.
Org. Lett., Vol. 12, No. 13, 2010
3087

Table 2. Scope of the Reactiona
Table 3. Scope of the Reactiona
a Reaction conditions: 1 (0.2 mmol), 1′ (0.2 mmol), DBU (1.0 equiv),
DMSO (1.5 mL), 120 °C, 10 min. b Isolated yields. c The reaction was
carried out at 130 °C.
Lowering the amount of DBU (0.5 equiv), the yield
decreased slightly to 85% with less 1a recovered (Table 1,
entry 9). These results show that this tandem process can be
catalyzed by the base and transformed completely only in
DMSO.
Various 2-methyl-3-(1-alkynyl)chromones 1 were used to
extend the scope of this reaction under the optimized
conditions. Good to excellent yields were obtained when R1
was an aromatic group on the acetylene moiety (Table 2,
entries 1-4). When R1 was an aliphatic chain, the reaction
also gave good yields (Table 2, entries 5 and 6). Substitution
with a sterically hindering group (tert-butyl) afforded the
desired product 2g1 in a 14% yield, along with 2g2 in a 57%
yield (Table 2, entry 7).9 When R1 was a trimethylsilyl group,
the desilylated product 2h was obtained in a 63% yield (Table
2, entry 8). In addition, reactions with various substituents
on the aryl ring of the 2-methyl-3-(1-alkynyl)chromones
a Reaction conditions: 1 (0.4 mmol), DBU (1.0 equiv), DMSO (1.5 mL),
120 °C, 10 min. b Isolated yields. c The reaction was carried out on a 0.6
mmol scale at 140 °C.
3088
Org. Lett., Vol. 12, No. 13, 2010

Interestingly, the reaction of 1e with an aliphatic chain and
1′a gave the desired product 2′f (Table 3, entry 6). When
the R3 groups of 1′ were an aliphatic chain, the cross-dimeric
reaction failed to give just the self-dimeric product. In
addition, substituents on the aryl ring of 1 had no effect on
the cross-dimerization reaction (Table 3, entries 7 and 8).
The deuterium labeling experiment of 1a with D2O
produced [D]2a with 70% deuterium incorporation on the
aryl ring and 75% at the methyl and methylene moieties,
respectively. Those results indicate that the methylene and
the methyl of intermediates could be exchanged with D2O
quickly because of the ready formation of the corresponding
carbanion under basic conditions.
In conclusion, we have discovered a novel base-promoted
cascade reaction to produce the 3C-xanthone-linked 3C-
Figure 2. X-ray structure of 2k.10
proceeded smoothly in good yields (Table 2, entries 9-13).
The structures of 2h and 2k were further confirmed by X-ray
crystal structure analysis (Figure 2).10
Scheme 2. Deuterium Labeling Experiment of 1a
According to the proposed mechanism, we expected that
3-(1-alkynyl)chromones without a sterically hindering methyl
group could be better Michael acceptors than 2-methyl-3-
(1-alkynyl)chromones and preferred to undergo the cross-
cascade process. To our delight, the cross dimerization of
1a and 1′a did afford the desired product 2′a in 71% yield
along with two self-dimeric byproducts of 1a and 1′a (Table
3, entry 1).3e The cross reaction of 1 and 1′ gave good yields
when R1 or R3 were aromatic groups (Table 3, entries 2-5).
chromone scaffold. The products were unambiguously
established using X-ray crystal structure analysis. This
unusual tandem process involves multiple reactions without
the necessity for a transition metal and inert atmosphere.
Further application of 1 and 1′ to generate novel natural-
product-like compounds and biological evaluation of the
novel compounds is ongoing in our laboratory.
(9) The formation of 2g2 can be explained as follows. The phenol ion
3g firstly undergoes a cyclization; however, the further Michael addition is
unfavorable because of the steric effect of the tert-butyl group. The major
intermediate 4g2 isomerizes into 5g2, the methyl group of which is then
deprotonated by base and undergoes a cyclization and isomerization to give
product 2g2.
Acknowledgment. This work was supported by grants
from Major Projects in National Science and Technology,
“Creation of major new drugs” (No.2009ZX09301-001) and
National Natural Science Foundation of China (30873142).
Supporting Information Available: Experimental pro-
cedures and 1H NMR and 13C NMR spectra for compounds
in Tables 2 and 3. This material is available free of charge
via the Internet at http://pubs.acs.org.
(10) CCDC 764693 (2h) and 768701 (2k) contain the supplementary
crystallographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
OL101100D
Org. Lett., Vol. 12, No. 13, 2010
3089