Diversity oriented synthesis of benzoxanthene and benzochromene libraries via one-pot, three-component reactions and their anti-proliferative activity

Article abstract of DOI:10.1021/cc900143h

Libraries of benzoxanthenes, as well as of benzochromenes, were efficiently synthesized via one-pot, three-component reactions of 2-naphthol, aldehydes, and cyclic 1,3-diketones/malononitrile/ethyl cyanoacetate in the presence of catalytic amount of eerie

Full text of DOI:10.1021/cc900143h

20
J. Comb. Chem. 2010, 12, 20–24
Diversity Oriented Synthesis of Benzoxanthene and Benzochromene
Libraries via One-Pot, Three-Component Reactions and Their
Anti-proliferative Activity
Atul Kumar,*,† Siddharth Sharma,† Ram Awatar Maurya,† and Jayant Sarkar‡
Medicinal and Process Chemistry DiVision, and Drug Target DiscoVery and DeVelopment DiVision,
Central Drug Research Institute, CSIR, Lucknow, India
ReceiVed March 17, 2009
Libraries of benzoxanthenes, as well as of benzochromenes, were efficiently synthesized via one-pot, three-
component reactions of 2-naphthol, aldehydes, and cyclic 1,3-diketones/malononitrile/ethyl cyanoacetate in
the presence of catalytic amount of ceric ammonium nitrate (CAN) under solvent free conditions. The protocol
offers rapid synthesis of structurally diverse benzoxanthenes and benzochromenes for biologically screening.
All the synthesized compounds were evaluated for their anti-proliferative activity, and several compounds
were exhibiting promising anti-proliferative activity.
Design of highly efficient chemical reaction sequences that
synthesis of structurally diverse benzo(xanthenes)chromenes.
Thus, there is a need to develop general protocols for the
rapid and efficient synthesis of structurally diverse libraries
of benzo(xanthenes)chromenes.
Our initial experiments were focused on the one-pot, three-
component reaction of 2-naphthol, benzaldehyde, and dime-
done using different catalysts under solvent free conditions,
and the results are listed in Table 1 (Scheme 1).
It was found that ceric ammonium nitrate (CAN) showed
better catalytic activity among other catalysts such as FeCl3,
SnCl4, ZnCl2, and AlCl3. Although Ce(IV) derivatives are
normally employed as single-electron oxidants, the use of
the commercially available, inexpensive, and easily handled
CAN in carbon-carbon and carbon-heteroatom bond form-
ing reactions has recently attracted much attention,17 although
these studies are still in their early stages. As stated in a
recent review on the subject,17c the main current goal in this
area is the development of reactions that allow the use of
catalytic amounts of CAN.18 When 5 mol % CAN was used,
the reaction proceeded smoothly and gave the product 4a in
94% yield (Table 1, entry 6). Moreover, we found that the
yields were obviously affected by the amount of CAN loaded.
provide maximum structural complexity and diversity with
a minimum number of synthetic steps to assemble com-
pounds with interesting properties is a major challenge of
modern drug discovery.1 Recently, multicomponent reactions
have emerged as a highly valuable synthetic tool in the
context of modern drug discovery. The atom economy and
convergent character, the simplicity of a one-pot procedure,
the possible structural variations, the accessible complexity
of the molecules, and the very large number of accessible
compounds are among the described advantages of multi-
component reactions.2 Thus, they are perfectly amenable to
automation for combinatorial synthesis.3
Benzoxanthenes and benzochromenes are important classes
of biologically active heterocycles. Benzoxanthenes possess
analgesic,4 anti-inflammatory,5 antibacterial,6 and antiviral
activities.7 These compounds are being utilized as antagonists
for paralyzing action of zoxazolamine,8 and in photodynamic
therapy.9 Benzoxanthenes have also been employed as
dyes,10 pH sensitive fluorescent materials for visualization
of biomolecules,11 and in laser technologies.12 Many ben-
zoxanthene derivatives are potent nonpeptidic inhibitors of
recombinant human calpain I,13 and novel CCR1 receptor
antagonists.14 Benzochromenes are widely employed as
pigments, cosmetics, potential agrochemicals, and also as
components of many natural products.15
Table 1. Screening of Catalysts for One-Pot Condensation of
2-Naphthol, Benzaldehyde, and Dimedonea
entry catalyst catalyst (mol %) time (min)
yield (%)b
Several methods has been reported for the synthesis16 of
benzo(xanthenes)chromenes because of its enormous biologi-
cal and industrial importance. Most of reported procedures
describe the synthesis of only a narrow range of benzo(x-
anthenes)chromenes and also suffer from long reaction times
and harsh reaction conditions. A careful survey of literature
reveals that there is no general method available for the
1
2
3
4
5
6
7
8
none
120
30
30
30
30
30
30
30
30
30
<5
25
37
32
35
94
39
70
93
FeCl3
SnCl4
ZnCl2
AlCl3.
CAN
CAN
CAN
CAN
CAN
5
5
5
5
5
0.5
2
10
5
9
10c
94, 93, 94, 93, 92
a Reaction conditions: 2-naphthol (1.0 mmol), benzaldehyde (1.0
mmol), and 5,5-dimethylcyclohexane-1,3-dione (1.0 mmol), solvent free,
120 °C (oil bath). b Isolated yield. c Catalyst was reused five times after
drying.
* To whom correspondence should be addressed. E-mail: dratulsax@
gmail.com. Phone: 91-522-2612411. Fax: 91-522-2623405.
† Medicinal and Process Chemistry Division.
‡ Drug Target Discovery and Development Division.
10.1021/cc900143h  2010 American Chemical Society
Published on Web 12/02/2009

Synthesis of Benzoxanthene and Benzochromene Libraries
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 21
Scheme 1
Scheme 2
Table 2. Solvent Effect on the Reaction of 2-Naphthol,
Benzaldehyde, and Dimedone Catalyzed by CAN
1) as well as with nitric acid. The above results showed that
CAN was essential in the reaction, and the best results were
obtained when the reaction was carried out with 5 mol % of
CAN under solvent free conditions at 120 °C.
yield (%)
temp (°C) time (min) 4a 5a
entry
solvent
1
2
3
4
5
6
acetonitrile
dichloromethane
tetrahydrofuran
methanol
ethanol
none
reflux
reflux
reflux
reflux
reflux
120
120
120
120
120
120
30
38 10
32
25 13
46 12
50 10
Then, we examined the effect solvents over the above
reaction. The results of Table 2 indicate that solvents affected
the efficiency of the reaction. Yields were poor in acetonitrile,
dichloromethane, and tetrahydrofuran (Table 2, entries 1-3).
Better yields were obtained in more polar solvents like
methanol and ethanol (Table 2, entry 4 and 5). However,
the best results were obtained under solvent free conditions
(Table 2, entry 6). In addition, 14-phenyl-14H-dibenzo[a-
,j]xanthene 5a was obtained as a side product in all solution
phase reactions (Scheme 2). On the other hand 5a were not
isolated under solvent free conditions.
5
94 not isolated
When 0.5 mol %, 2 mol % and 10 mol % of CAN were
used, the yields were 39%, 70%, and 93%, respectively
(Table 1, entries 7-9). Therefore, 5 mol % of CAN was
sufficient to push the reaction forward, and further increasing
the amount of CAN did not increase the yields. The catalytic
activity of the recycled CAN was also examined. CAN was
reused five times for the reaction without noticeable loss of
activity (Table 1, entry 10). In addition, no desired product
was detected in the absence of the catalyst (Table 1, entry
To study the generality of this protocol, a library of 12-
substituted-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-
ones was built using 2-naphthol, aldehydes, and cyclic 1,3-
Figure 1

22 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Kumar et al.
Scheme 3
to the formation compound 5. Reaction of malononitrile (6a)
or ethyl cyanoacetates (6b) with intermediate 8 yields
benzochromenes 7.
All the synthesized compounds were screened for their
anti-proliferative activity in human prostate cancer (DU-145),
breast cancer (MCF-7), cervical carcinoma (C-33A), lung
carcinoma (A 549), oral squamous cell carcinoma (KB),
control for general cytotoxicity (Vero) cancer cell lines. The
compounds which were showing activity below 50 µg/mL
are summarized in Table 3. Benzochromenes (4b, 4c, 4f, 4i,
4n, 7a, 7b, 7c, 7e, 7i, and 7k) were found more active in
comparison to benzoxanthenes (5b, 5f and 5j). Compounds
4i (6.7 µg/mL) and 7a (8.9 µg/mL) were most potent in
MCF-7, and showed more activity than the anti breast cancer
drug tamoxifen (10 µg/mL).
In conclusion, we have efficiently synthesized structurally
diverse libraries of benzoxanthenes and benzochromenes via
CAN catalyzed three-component reactions under solvent free
conditions. The advantages of this method include the use
of recyclable catalyst, high yields, simple workup procedure,
and easy isolation. All the synthesized compounds were
evaluated for anti-proliferative activities, and some of the
compounds exhibited significant activity in various cancer
cell lines.
dicarbonyl compounds (Figure 1). The diversity in the
benzoxanthene library was generated using aliphatic, electron
rich, as well as electron deficient, aromatic aldehydes,
cyclohexane-1,3-dione, 5,5-dimethylcyclohexane-1,3-dione,
and cyclopentane-1,3-dione.
It was observed that in the absence of cyclic 1,3-diketone,
the CAN catalyzed reaction of 2-naphthol and aldehyde under
solvent free conditions resulted to the formation of compound
5 in almost quantitative yield (Scheme 3, Figure 2).
Using malononitrile or ethyl cynoacetate as a third
component in the CAN mediated multicomponent reaction
of 2-naphthol and aldehydes, we synthesized a library of
benzochromes (Scheme 4, Figure 3).
The formation of benzoxanthenes and benzochromenes
could be explained by a proposed tentative mechanism
(Scheme 5). It was supposed that the reaction occurred via
the ortho-quinone methides intermediate 8, which was
formed by the nucleophilic addition of ꢀ-naphthol to alde-
hyde catalyzed with CAN. Subsequent attack of cyclic 1,3-
dicarbonyl compounds to the intermediate 8, afforded 9. Then
compounds 9 eliminated one molecule of H2O and afforded
compound 4.
General Procedure for the Synthesis of 12-Substituted-
9,10-dihydro-8H-benzo[a]xanthen-11(12H)-ones (4a-o).
In a 25 mL round-bottom flask, 2-naphthol (1 mmol), cyclic
1,3-diketone (1 mmol), aldehyde (1 mmol), and CAN (5 mol
%) were taken. The reaction mixture was heated at 120 °C
In the absence of cyclic 1,3-dicarbonyls the second
molecules of ꢀ-naphthol attacks to intermediate 8 leading
Figure 2. 14-Substituted-14H-dibenzo[a, j]xanthenes.
Scheme 4

Synthesis of Benzoxanthene and Benzochromene Libraries
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 23
Figure 3. 3-Amino-1-substituted-1H-benzo[f]chromenes.
Scheme 5
for 30 min under solvent free conditions. The reaction was
followed by TLC monitoring. After completion, ethyl acetate
was added to the reaction mixture and was shaken well to
dissolve all organic compounds. Then it was filtered to
remove CAN. The filtrate was concentrated, and the crude
product was purified by silica-gel column chromatography
to yield pure compounds.
General Procedure for the Synthesis of 14-Substituted-
14H-dibenzo[a, j]xanthenes (5a-n). In a 25 mL round-
bottom flask, aldehyde (1 mmol), 2-naphthol (2 mmol), and
CAN (5 mol %) were taken. The reaction mixture was stirred
at 120 °C under solvent-free conditions for 30 min. After
completion, the reaction mixture was cooled to room
temperature, and ethyl acetate was added and shaken well
to dissolve all organic components, then filtered to remove
CAN. The filtrate was concentrated and purified by silica
gel column chromatography.
General Procedure for the Synthesis of 3-Amino-1-
substituted-1H-benzo[f]chromenes (7a-k). In a 25 mL
round-bottom flask, aldehyde (1 mmol), 2-naphthol (1 mmol),
malononitrile/ethyl cynoacetate (1 mmol), and CAN (5 mol
%) were taken. The reaction mixture was stirred at 120 °C
under solvent-free conditions for 30 min. After completion,
the reaction mixture was cooled to room temperature, and
ethyl acetate was added and shaken well to dissolve all
organic components, then filtered to remove CAN. The
filtrate was concentrated and purified by silica gel column
chromatography.

24 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Kumar et al.
Table 3. Inhibition of Proliferation of the Synthesized Librarya
IC50 (µg/mL)
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compounds
DU 145
MCF-7
C-33A
A 549
KB
Vero
4b
4c
4f
12.5
14.3
8.0
18.1
19.8
11.7
6.7
23.3
21.1
37.8
21.9
8.9
12.2
22.1
15.7
14.2
16.7
8.2
14.7
9.9
13.7
12.6
6.1
27.7
32.8
16.3
36.8
23.2
8.3
4.0
17.6
6.7
8.9
5.2
18.2
5.7
4i
11.3
26.7
19.0
21.7
25.6
13.3
10.0
16.7
18.6
12.4
17.4
17.7
19.2
36.6
38.6
28.6
14.6
10.5
19.7
15.0
27.1
11.9
21.8
16.9
18.5
11.7
16.3
7.6
15.2
21.6
14.2
19.6
12.9
4n
5b
5f
13.3
38.6
41.9
29.7
12.5
8.1
14.0
11.7
18.9
19.6
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5j
7a
7b
7c
7e
7i
5.4
18.9
22.5
10.2
12.9
7k
a All the synthesized compounds were tested against these cell lines
but had an IC50 value superior to 50 µg/mL.
Acknowledgment. S.S. and R.A.M. are thankful to CSIR,
New Delhi, for financial support. The authors also acknowl-
edge SAIF-CDRI for providing spectral and analytical data.
Supporting Information Available. Detailed experimen-
tal procedures and compound characterization data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
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CC900143H