Domino reactions of 2-methyl chromones containing an electron withdrawing group with chromone-fused dienes

Article abstract of DOI:10.1039/c1ob06613g

Domino reactions of 2-methyl substituted chromones containing an electron withdrawing group at the 3-position with chromone-fused dienes synthesized a diverse range of benzo[a]xanthones and complicated chromone derivatives. These multiple-step reactions r

Full text of DOI:10.1039/c1ob06613g

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2012, 10, 486
www.rsc.org/obc
COMMUNICATION
Domino reactions of 2-methyl chromones containing an electron withdrawing
group with chromone-fused dienes†
Jian Gong, Fuchun Xie, Wenming Ren, Hong Chen and Youhong Hu*
Received 21st September 2011, Accepted 20th October 2011
DOI: 10.1039/c1ob06613g
Domino reactions of 2-methyl substituted chromones con-
taining an electron withdrawing group at the 3-position
with chromone-fused dienes synthesized a diverse range of
benzo[a]xanthones and complicated chromone derivatives.
These multiple-step reactions result in either two or three
new C–C bonds without a transition metal catalyst or an
inert atmosphere.
Domino reactions that involve two or more bond-forming reac-
tions under identical conditions, allow the synthesis of complex
molecules from an easily prepared ingenious intermediate with
multiple reactive sites. The design of these reactions has gained
wide acceptance as an amazing modern synthetic strategy, due
Scheme 1 A proposed mechanism for the tandem reaction.
to an increase in synthetic efficiency by decreasing the number
of laboratory operations required for satisfactory yields.1 Our
group has been pursuing the diversified synthesis of complicated
with another pyrone ring-opening reaction to produce interme-
diate C, which could transform to D through an isomerisation.
The phenoxide center in D then attacks the carbonyl group
to give the intermediate E. The intermediate F, obtained from
dehydration of E, can undergo further 1,2-addition at the carbonyl
center to yield G. The subsequent elimination and pyrone ring
opening of G leads to the formation of benzo[a]xanthone 3a.
This cascade reaction involves multiple additions/ring open-
ings/eliminations and generates three new C–C bonds and one
C–O bond.
Initially, we investigated the cascade reaction of 1a and 2a
using DBU (1.0 equiv) as the base in THF with microwave
irradiation. To our delight, the target compound 3a was obtained
in 60% yield. Encouraged by this result, different solvents and
various equivalents of DBU were tested to improve the reaction
(Table 1). The reaction did not proceed well in common sol-
vents such as MeCN, DME, 1,4-dioxane, toluene, etc., giving
poor yields. When DMSO was used, the yield increased to
68%. Interestingly, upon doubling the number of equivalents of
DBU, the reaction proceeded efficiently in 10 min and the yield
increased significantly to 98% in THF and 91% in DMSO, respec-
tively.
natural-product-like scaffolds through cascade reactions based
on 3-(1-alkynyl)chromone2 and an electron-deficient chromone-
fused diene3 Significantly, we discovered that the methyl group
of 2-methyl chromone could be changed from its usual role as a
Michael acceptor4 to a nucleophile2c,3 to process different reac-
tions. Herein, we designed the 3-acetyl-2-methyl-4H-chromen-4-
one 1a with multiple reactive sites, including latent nucleophilic
(the methyl group at the 2-position) and electrophilic (COCH3)
centers, that could react with a Michael acceptor such as an
electron-deficient–chromone-fused diene, 2a,5 to initiate a new
cascade reaction for the efficient construction of substituted
benzo[a]xanthones.
The proposed reaction mechanism for the new tandem process
is shown in Scheme 1. The reaction is initiated by deprotonation
of the 2-methyl group of 1a by a base (e.g., DBU) to generate
the corresponding carbanion, which can attack the 2-position
of 2a generating intermediate A with concomitant pyrone ring-
opening to give intermediate B. Subsequently, the phenoxide
center in B undergoes tandem double Michael additions along
State Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Science, 555 Zu Chong Zhi Road, Shanghai,
201203, China. E-mail: yhhu@mail.shcnc.ac.cn; Fax: +86-21-5080-5896;
Tel: +86-21-5080-5896
This tandem reaction was extended to include various electron-
deficient–chromone-fused dienes 2 with moderate to excellent
yields. (Table 2). The yield was only 65% when the phenyl ring
was replaced by a methyl group (Table 2, entry 1). It was noted
that substitution on both the chromone ring and the aromatic ring
† Electronic supplementary information (ESI) available: Synthesis and 1H
and 13C NMR spectra of compounds 3 and 4. CCDC reference numbers
814417. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1ob06613g
486 | Org. Biomol. Chem., 2012, 10, 486–489
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
Table 1 Optimization of the tandem reaction of 1a and 2aa
Entry
Base (equiv)
Solvent
T (◦C)
t (min)
Yield (%)b
1
2
3
4
5
6
7
8
DBU (1.0)
DBU (1.0)
DBU (1.0)
DBU (1.0)
DBU (1.0)
DBU (2.0)
DBU (1.0)
DBU (2.0)
THF
MeCN
DME
1,4-dioxane
toluene
THF
DMSO
DMSO
100
100
100
100
100
100
100
100
10
10
10
10
10
10
10
10
60
43
0c
30
34
98
68
91
a General conditions: 1a (0.2 mmol), 2a (0.2 mmol) and DBU in solvent (2 mL) heated in a microwave reactor at 100 ◦C for 10 min. b Isolated yield.
c Reaction was complicated and no product was detected.
affected the yields. When substitution consisted of an electron-
donating group (Table 2, entries 2 and 3), only moderate yields
were given. However, when an electron-withdrawing group was
used (Table 2, entries 5, 6 and 8), the reactions gave excellent
yields. The structure of 3e was unambiguously established by X-
ray crystal structure analysis (Fig. 1).6
intermediate F stage did not proceed with further cyclization but
directly eliminated the hydrogen in the presence of a base along
with opening of the pyrone ring to generate the final product 4
(Scheme 3). To verify this hypothesis, substrates 2l, 2m, 2n were
investigated using this protocol. Products 4c, 4d and 4e with the
same core structure were obtained in reasonable yields (Table 3,
entries 3–5).
Scheme 3 A proposed mechanism for the products 4.
Fig. 1 X-ray crystal structure of 3e. Ellipsoid probability: 50%.
When substrate 1a was changed to 1b or 1c, the reactions in
the presence of DBU or EtONa as the base gave complicated
products. After changing to Et3N as the base, the desired
products 4f and 4g without further cyclization were separated
in 70 and 71% yields, respectively (Scheme 4). When employing
In addition, reaction of 1a with 2a, carried out in DMSO-
d6 and D2O leads to the formation of [D]3a with distinct
deuterium incorporation at specific aryl ring positions (Scheme
2). These 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.
Scheme 2 Deuterium labeling experiment in the reaction of 1a with 2a.
When substrates 2 were changed from a ketone to an ester or
nitrile under standard conditions, the reactions became compli-
cated. After screening the reaction conditions by using different
bases and solvents, the EtONa/EtOH system was chosen to
obtain products 4a and 4b in 51 and 72% yield, respectively
(Table 3, entries 1–2). The result shows that the reaction at the
Scheme 4 Reaction of other 2-methyl chromones with EWGs at the 3
position with 2i.
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 486–489 | 487
©

View Article Online
Table 2 Tandem reaction of 1a with various electron-deficient–
chromone-fused dienes 2a
Table 3 Extension of the tandem reactiona
Entry
1
Substrate 2
Product 3
Yield (%)b
51
Entry
1
Substrate 2
Product 3
Yield (%)b
65
2
3
72
75
2
3
70
67
4
5
74
79
4
5
82
90
a General conditions: 1a (0.2 mmol), 2a (0.2 mmol) and EtONa (0.2 mmol)
in EtOH (2 mL) heated in an oil bath at 80 ◦C for 1 h. b Isolated yield.
6
7
8
92
80
93c
access to functionalized benzo[a]xanthones and novel chromone
derivatives. Obviously, this study found unusual tandem processes
that generate a diverse range of natural-like products from similar
intermediates that involve multiple reactions, without the necessity
for a transition metal and inert atmosphere. Further applications
of these chromone substrates to construct interesting complicated
molecules and their biological study are under investigation.
Acknowledgements
This work was supported by grants from Major Projects in
National Science and Technology, “Creation of major new drugs”
(No. 2009ZX09301-001) and the National Natural Science Foun-
dation of China (30873142).
a General conditions: 1a (0.2 mmol), 2a (0.2 mmol)◦and DBU (0.4 mmol) in
THF (2 mL) heated in a microwave reactor at 100 C for 10 min. b Isolated
yield. c DBU, DMSO, 100 ◦C, 1 h. (THF is replaced by DMSO for good
solubility of substrates 2i.).
Notes and references
1 For recent reviews, see: (a) P. J. Parsons, C. S. Penkett and A. J. Shell,
Chem. Rev., 1996, 96, 195; (b) K. C. Nicolaou, T. Montagnon and S. A.
Snyder, Chem. Commun., 2003, 551; (c) K. C. Nicolaou, D. J. Edmonds
and P. G. Bulger, Angew. Chem., Int. Ed., 2006, 45, 7134; (d) L. F. Tietze
and N. Rackelmann, Pure Appl. Chem., 2004, 76, 1967; (e) A. Padwa,
Pure Appl. Chem., 2004, 76, 1933 and references cited therein.
2 (a) L. Zhao, F. Xie, G. Cheng and Y. Hu, Angew. Chem., Int. Ed., 2009,
48, 6520; (b) F. Xie, X. Pan, S. Lin and Y. Hu, Org. Biomol. Chem., 2010,
8, 1378; (c) F. Xie, H. Chen and Y. Hu, Org. Lett., 2010, 12, 3086; (d) Y.
Liu, L. Huang, F. Xie and Y. Hu, J. Org. Chem., 2010, 75, 6304.
2-methyl-4-oxo-4H-chromene-3-carbonitrile 1d in the reaction,
the product 3j was obtained in 62% yield after optimizing
the conditions. This reaction is then followed by the reaction
mechanism illustrated in Scheme 1 due to the NH2 group being a
stronger nucleophile.
3 J. Gong, F. Xie, H. Chen and Y. Hu, Org. Lett., 2010, 12, 3848.
4 (a) G. P. Ellis, In Comprehensive Heterocyclic Chemistry, A. R. Katritzky,
C. W. Rees, ed; Elsevier Science Ltd., 1997, Vol. 3, pp 675–705; (b) V. S.
Jamode and A. S. Kale, Asian J. Chem., 2006, 18, 3197; (c) J. Quiroga, J.
Portilla, R. Abonia, B. Insuasty, M. Nogueras and J. Cobo, Tetrahedron
In summary, we have developed efficient base-promoted domino
reactions of 2-methyl chromones with electron withdrawing
groups at the 3-position armed with latent nucleophilic and
electrophilic centers. These mild tandem reactions provide efficient
488 | Org. Biomol. Chem., 2012, 10, 486–489
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
Lett., 2008, 49, 6254; (d) E. Budzisz, M. Miernicka, I. Lorenz, P. Mayer,
E. Balcerczak, U. Krajewska and M. Rozalski, Eur. J. Med. Chem., 2010,
45, 2613.
5 (a) C. M. Brito, D. C. G. A. Pinto, A. M. S. Silva, A. M. G. Silva, A. C.
Tome and J. A. S. Cavaleiro, Eur. J. Org. Chem., 2006, 2558; (b) D. W.
Knight and P. B. Little, J. Chem. Soc., Perkin Trans. 1, 2001, 1771; (c) C.
D. Gabbutt, J. D. Hepworth, B. M. Heron and J. L. Thomas, Tetrahedron
Lett., 1998, 39, 881; (d) S. Horne, J. Org. Chem., 1990, 55, 4520; (e) I.
Yokoe, K. Higuchi, Y. Shirataki and M. Komatsu, Chem. Pharm. Bull.,
1981, 29, 2670; (f) A. M. S. Silva, D. C. G. A. Pinto, H. R. Tavares, J.
A. S. Cavaleiro, M. L. Jimeno and J. Elguero, Eur. J. Org. Chem., 1998,
2031.
6 CCDC 814417 (3e) contains the supplementary crystallographic data
for this paper (see the ESI†).
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 486–489 | 489
©