An efficient approach to functionalized benzo[ a ]xanthones through reactions of 2-methyl-3-(1-alkynyl)chromones with electron-deficient chromone-fused dienes

Article abstract of DOI:10.1021/ol101496w

An efficient tandem process was developed to synthesize diversified benzo[a]xanthones from 2-methyl-3-(1-alkynyl)chromones with electron-deficient chromone-fused dienes. This unusual reaction, involving multiple steps and not requiring the use of transition metal catalysts or an inert atmosphere, results in the formation of three new C-C bonds and one C-Obond.

Full text of DOI:10.1021/ol101496w

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3848-3851
An Efficient Approach to Functionalized
Benzo[a]xanthones through Reactions of
2-Methyl-3-(1-alkynyl)chromones with
Electron-Deficient Chromone-Fused
Dienes
Jian Gong, 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 July 4, 2010
ABSTRACT
An efficient tandem process was developed to synthesize diversified benzo[a]xanthones from 2-methyl-3-(1-alkynyl)chromones with electron-
deficient chromone-fused dienes. This unusual reaction, involving multiple steps and not requiring the use of transition metal catalysts or an
inert atmosphere, results in the formation of three new C-C bonds and one C-O bond.
The xanthone framework is ubiquitous in a wide variety of
naturally occurring and synthetic compounds that exhibit
important biological activity.1 Consequently, interest in the
development of efficient methods for the synthesis of
xanthones, bearing multiple and diverse substitution patterns,
has continued.2 Only a few synthetic routes for the prepara-
tion of benzo[a]xanthones have been described. One method,
involving visible light induced photooxidative cyclization of
(E)-2-styrylchromones,3 requires long time periods and takes
place in only modest yields. Other approaches employ harsh
conditions or multistep sequences to obtain this target in low
yields.4 Below, we describe the results of an investigation
that has led to the development of a facile and efficient
method for the synthesis of functionalized benzo[a]xanthones
that utilizes mild reaction conditions.
Tandem reactions, which employ easily prepared inter-
mediates containing multiple reactive sites, serve as attractive
methods to generate complex molecular architectures, espe-
cially those present in natural product skeletons.5 Our earlier
work in this area focused on the use of functionalized 3-(1-
alkynyl)chromones to generate diversified natural product-
(1) (a) Sousa, M. E.; Pinto, M. M. Curr. Med Chem. 2005, 12, 2447,
and references cited therein. (b) Palmer, B. D.; Henare, K.; Woon, S. T.;
Sutherland, R.; Reddy, C.; Wang, L. C.; Kieda, C.; Ching, L. M. J. Med.
Chem. 2007, 50, 3757.
(2) For recent studies, see: (a) Santos, C. M. M.; Silva, A. M. S.;
Cavaleiro, J. A. S. Eur. J. Org.Chem. 2009, 2642. (b) Xu, W. Z.; Huang,
Z. T.; Zheng, Q. Y. J. Org. Chem. 2008, 73, 5606. (c) Dang, A. T.; Miller,
D. O.; Dawe, L. N.; Bodwell, G. J. Org. Lett. 2008, 10, 233. (d) Swamy,
N. K.; Tatini, L. K.; Babu, J. M.; Annamalai, P.; Pal, M. Chem. Commun.
2007, 1035. (e) Zhao, J.; Yue, D.; Campo, M. A.; Larock, R. C. J. Am.
Chem. Soc. 2007, 129, 5288. (f) Zhao, J.; Larock, R. C. J. Org. Chem.
2007, 72, 583. (g) Mondal, M.; Puranik, V. G.; Argade, N. P. J. Org. Chem.
2006, 71, 4992. (h) Zhao, J.; Larock, R. C. Org. Lett. 2005, 7, 4273. (i)
Hauser, F. M.; Dorsch, W. A. Org. Lett. 2003, 5, 3753.
(3) Silva, A. M. S.; Pinto, D. C. G. A.; Tavares, H. R.; Cavaleiro, J. A. S.;
Jimeno, M. L.; Elguero, J. Eur. J. Org. Chem. 1998, 2031.
(4) (a) Brito, C. M.; Pinto, D. C. G. A.; Silva, A. M. S.; Silva, A. M. G.;
Tome, A. C.; Cavaleiro, J. A. S. Eur. J. Org. Chem. 2006, 2558. (b) Knight,
D. W.; Little, P. B. J. Chem. Soc., Perkin. Trans. 1 2001, 1771. (c) Gabbutt,
C. D.; Hepworth, J. D.; Heron, B. M.; Thomas, J. L. Tetrahedron Lett.
1998, 39, 881. (d) Horne, S. J. Org. Chem. 1990, 55, 4520. (e) Yokoe, I.;
Higuchi, K.; Shirataki, Y.; Komatsu, M. Chem. Pharm. Bull. 1981, 29, 2670.
10.1021/ol101496w  2010 American Chemical Society
Published on Web 08/12/2010

like scaffolds through employment of cascade reactions.6 At
the outset of the current effort, we envisaged that 2-methyl-
3-(1-alkynyl)chromones 1, possessing multiple reactive sites
including latent nuclephilic (the methyl group at the 2-posi-
tion) and electrophilic (the R,ꢀ-unsaturated system) centers,
could participate in a tandem process for the generation of
complex xanthones.6c In this process, electron-deficient
chromone-fused dienes 2 would play the role of double
Michael acceptors.7 It should be noted that these substances
are reported to participate in inverse-electron-demand
Diels-Alder reactions with special dienophiles to afford
xanthones.8 Moreover, we reasoned that 2 would be a
stronger electron acceptor than 1 and, as a result, it would
react with 1 through a new cascade reaction sequence to form
a novel complicated chromone-fused scaffold. The reaction
mechanism used as the foundation of the design of the new
tandem process is shown in Scheme 1. The pathway is
Table 1. Scope of Substrate 1a
Scheme 1. Proposed Reaction Mechanism
initiated by deprotonation of the methyl group of 1 by a base
to generate the corresponding carbanion, which would add
to the 2-position of 2a with concomitant pyrone ring-opening
to give intermediate 3b. Subsequently, the phenoxide center
in 3b undergoes tandem double Michael additions with
pyrone ring-opening to produce intermediate 3c, which could
tautomerize to generate either 3d or 3e. The phenoxide
Scheme 2. Tandem Reaction of 1a with 2a
a Reaction condition: 1 (0.2 mmol), 2a (0.2 mmol), DBU (0.2 mmol),
DMSO (1.5 mL), 120 °C, 10 min. b Isolated yield. c The reaction was
complicated and none of the desired product 4g was produced.
centers in 3d or 3e then promote a cyclization process with
the adjacent alkynyl or allene moiety, giving a carbanion of
Org. Lett., Vol. 12, No. 17, 2010
3849

3f, which could further undergo acyl substitution at the ester
center to yield 3h. The subsequent elimination and isomer-
ization of 3h leads to the formation of benzo[a]xanthone 4.
If successful, this cascade reaction would generate three new
C-C bonds and one C-O bond.
Table 2. Scope of Substrate 2a
To explore the feasibility of this process, we investigated
the cascade reaction of 1a with 2a using DBU as the base
and microwave irradiation conditions (Scheme 2). Impor-
tantly, this reaction yielded the desired product 4a in 71%
yield. Encouraged by this result, we probed the scope of this
tandem reaction by using various 2-methyl-3-(1-alkynyl)-
chromones 1 in reactions with 2a. Moderate to good yields
were obtained when the R2 group in 1 was aromatic (Table
1, entries 1-4). In addition, the desired products were formed
in reasonable yields (Table 1, entries 5 and 6) when R2 was
a nonsterically bulky alkyl group. However, when R2 was
sterically large (e.g., tert-butyl), the reaction was complicated
and none of the desired product 4g was produced (Table 1,
entry 7). A study of the electronic effects of substituents on
the aryl chromone ring showed that substrates containing
electron-withdrawing groups (Br, Cl, NO2) reacted to give
products in higher yields in contrast to the subtrates that
contained the electron-donating OMe group (Table 1, entries
9-12). It should be noted that the structure of 4h was
unambiguously assigned by using X-ray crystallographic
analysis (Figure 1).9
a Reaction condition: 1a (0.2 mmol), 2 (0.2 mmol) and DBU (0.2 mmol),
DMSO (1.5 mL), 120 °C, 10 min. b Isolated yield. c 5e1 was obtained as a
major product.10
2) than those involving substrates with sterically more
demanding substituents (Table 2, entries 3-6). Interestingly,
when the substituent on the chromone-fused diene is the
strong electron-withdrawing NO2 group (2f), the unexpected
product 5e1 was generated in 60% yield along with the
desired product 5e in 20% yield (Table 2, entry 5).10 The
structure of 5c was also assigned based on the results of
X-ray crystallographic analysis (Figure 1).9
Figure 1.
X-ray structures of 4h and 5c.9
Reaction of 1a with 2a, carried out in DMSO-d6 and D2O
leads to formation of [D]4a, which contains 76% deuterium
Studies of the tandem reaction were extended to include
various electron-deficient chromone-fused dienes (EWG )
CN, COMe, and various aryl carbonyl). In these processes,
the corresponding functionalized benzo[a]xanthones 5 were
produced in 46-75% yields. Reactions involving chromone-
fused dienes with less sterically hindered CN and COMe
groups lead to higher product yields (Table 2, entries 1 and
(5) For recent reviews, see: (a) Parsons, P. J.; Penkett, C. S.; Shell, A. J.
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.;
Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (d) Tietze, L. F.;
Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967. (e) Padwa, A. Pure
Appl. Chem. 2004, 76, 1933.
(6) (a) Zhao, L.; Xie, F.; Cheng, G.; Hu, Y. Angew. Chem., Int. Ed.
2009, 48, 6520. (b) Xie, F.; Pan, X.; Lin, S.; Hu, Y. Org. Biomol. Chem.
2010, 8, 1378. (c) Xie, F.; Chen, H.; Hu, Y. Org. Lett. 2010, 12, 3086.
3850
Org. Lett., Vol. 12, No. 17, 2010

The novel tandem process proceeds by way of a multistep
pathway involving sequential Michael addition/cyclization/
1,2-addition/elimination. Further applications of 2-methyl-
3-(1-alkynyl)chromones in processes leading to the genera-
tion of interesting natural product-like and biologically active
benzo[a]xanthones are under investigation.
Scheme 3
.
Deuterium Labeling Experiment in the Reaction of
1a with 2a
Acknowledgment. This work was supported by grants
from Major Projects in National Science and Technology,
“Creation of major new drugs” (No. 2009ZX09501-010).
Supporting Information Available: Experimental pro-
cedures and 1H NMR and 13C NMR spectra for compounds
in Tables 1 and 2. This material is available free of charge
via the Internet at http://pubs.acs.org.
incorporation at a single aryl ring position (Scheme 3). This
result indicates that the methyl protons in 1a exchange
rapidly with D2O through reversible formation of the
corresponding carbanion under the basic conditions employed
in this process.
OL101496W
In conclusion, this investigation has led to the development
of a novel tandem process for the preparation of various
benzo[a]xanthones starting with 2-methyl-3-(1-alkynyl)-
chromones and electron-deficient chromone-fused dienes.
(10) Proposed mechanism for formation of 5e1:
(7) (a) Levai, A.; Silva, A. M. S.; Pinto, D. C. G. A.; Cavaleiro, J. A. S.;
Alkorta, I.; Elguero, J.; Jekoe, J. Eur. J. Org. Chem. 2004, 4672. (b)
Siddiqui, Z. N.; Asad, M.; Praveen, S. Med. Chem. Res. 2008, 17, 318. (c)
Singh, G.; Singh, G.; Ishar, M. P. S. HelV. Chim. Acta 2003, 86, 169. (d)
Levai, A.; Jekoe, J. J. Heterocycl. Chem. 2004, 41, 439. (e) Levai, A.; Jeko,
J. J. Heterocycl. Chem. 2002, 39, 1333. (f) Bodwell, G. J.; Hawco, K. M.;
da Silva, R. P. Synlett 2003, 2, 179. (g) Abass, M.; Abdel-Megid, M.;
Hassan, M. Synth. Commun. 2007, 37, 329. (h) To´th, G.; Simon, A.; Gondos,
T.; Le´vai, A.; Jeko¨, J.; Andra´si, F. Magn. Reson. Chem. 2006, 44, 856.
(8) (a) Dang, A. T.; Miller, D. O.; Dawe, L. N.; Bodwell, G. J. Org.
Lett. 2008, 10, 233. (b) Tatsuta, K.; Kasai, S.; Amano, Y.; Yamaguchi, T.;
Seki, M.; Hosokawa, S. Chem. Lett. 2007, 36, 10.
(9) CCDC 776163 (4h) and 776162 (5c) contain the supplementary
crystallographic data for this paper. The crystallographic coordinates have
been deposited with the Cambridge Crystallographic Data Centre; deposition
nos. 776163 and 776162. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre, 12 Union Rd., Cambridge
CB2 1EZ, UK or via www.ccdc.cam.ac.uk/data_request/cif.
Reaction at the NO2 group, which is a strong electron-withdrawing group
activated methylene moiety in intermediate 3i, which competes with that
of the phenoxide ion through aldol condensation with the carbonyl group
to give 5e1.
Org. Lett., Vol. 12, No. 17, 2010
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