Catalysis by molecular iodine: A rapid synthesis of 1,8-dioxo- octahydroxanthenes and their evaluation as potential anticancer agents

Article abstract of DOI:10.1016/j.bmcl.2012.01.126

Molecular iodine facilitated the reaction of 5,5-dimethyl-1,3- cyclohexanedione with aromatic aldehydes in iso-propanol affording a variety of 1,8-dioxo-octahydroxanthenes in high yields. Most of the compounds synthesized showed good anti-proliferative pr

Full text of DOI:10.1016/j.bmcl.2012.01.126

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2186–2191
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Catalysis by molecular iodine: A rapid synthesis of 1,8-dioxo-octahydroxanth-
enes and their evaluation as potential anticancer agents
Naveen Mulakayala a, P.V.N.S. Murthy b, D. Rambabu a,b, Madhu Aeluri a, Raju Adepu a,
G.R. Krishna c, C. Malla Reddy c, K.R.S. Prasad b, M. Chaitanya d, Chitta S. Kumar d,
a,
M.V. Basaveswara Rao e, , Manojit Pal
⇑
⇑
a Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Andhra Pradesh, India
b Department of Chemistry, K L University, Vaddeswaram Guntur 522 502, Andhra Pradesh, India
c Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata, West Bengal 741 252, India
d Department of Biochemistry, Sri Krishnadevaraya University, Anantapur 515 003, Andhra Pradesh, India
e Department of Chemistry, Krishna University, Machilipatnam 521 001, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Molecular iodine facilitated the reaction of 5,5-dimethyl-1,3-cyclohexanedione with aromatic aldehydes
in iso-propanol affording a variety of 1,8-dioxo-octahydroxanthenes in high yields. Most of the com-
pounds synthesized showed good anti-proliferative properties in vitro against three cancer cell lines and
9-(2-hydroxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione possessing
a 2-hydroxy phenyl group at C-9 position was found to be promising. Further structure elaboration of
the same compound and the crystal structure analysis and hydrogen bonding patterns of another
compound that is, 9-(4-methoxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8
(2H)-dione prepared by using this methodology is presented.
Received 25 December 2011
Revised 26 January 2012
Accepted 27 January 2012
Available online 7 February 2012
Keywords:
1,8-Dioxo-octahydroxanthene
5,5-Dimethyl-1,3-cyclohexanedione
Iodine
Ó 2012 Elsevier Ltd. All rights reserved.
Xanthene derivatives have attracted considerable interest
because of their various pharmacological properties such as anti-
bacterial, antiviral and anti-inflammatory activities.1,2 Apart from
their use as valuable synthetic precursors for many organic com-
pounds3 and dyes4 they also found uses in laser technologies,5a
and fluorescent materials for visualization of biomolecules.5b
While the cancer cell cytotoxicity of xanthene derivatives A
(Fig. 1) has been documented6a recently the anticancer properties
of their saturated analogs for example, 1,8-dioxo-octahydroxanth-
enes C designed via B (Fig. 1) has not been investigated earlier.
Moreover, in view of the fact that cancer is the second leading
cause of death6b worldwide there is a need for the identification
of new and more effective anticancer agents. This prompted us to
synthesize and assess the anticancer potential of 1,8-dioxo-
octahydroxanthenes in vitro.
NaHSO4ꢀSiO2,12 silica sulfuric acid,13 polyaniline p-toluenesulfo-
nate,14 PPA–SiO2,15 TiO2/SO4,2–16 Amberlyst-15,17 SbCl3/SiO2,18 or
Fe3+-montmorillonite.19 Among the other catalysts used include
trimethylsilylchloride,20 p-dodecylbenzenesulfonic acid,21,22 tri-
ethylbenzylammonium chloride23 or NH2SO3/SDS.24 Additionally,
the above condensation reaction can also be carried out in ionic li-
quid25 or ethylene glycol.26 However, some of these methodologies
suffer from disadvantages, such as low yields,14,15 prolonged reac-
tion time,8,12,21–23 harsh reaction conditions,7 and the requirement
of excess catalysts20 or special apparatus.22 Recently, iodine being
an inexpensive and commercially available reagent have attracted
considerable interest due to its non-hazardous nature and effi-
ciency in various organic transformations.27 Due to our continuing
interest in the use of iodine as a reagent or catalyst28 we have ob-
served that 5,5-dimethyl-1,3-cyclohexanedione (1) undergoes
smooth condensation with aromatic aldehydes (2) in the presence
of elemental iodine to give 1,8-dioxo-octahydroxanthene deriva-
tives (3) (Scheme 1) within short period of time. Herein we report
our preliminary results on the development of an iodine-mediated
simple and highly efficient method for synthesis of our target xan-
thene derivatives C (or 3) and their evaluation as potential antican-
cer agents. To the best of our knowledge synthesis of xanthenes
using such a methodology and their anticancer properties has
not been disclosed earlier.
One of the commonly used methods reported for the synthesis
of xanthene derivatives involved the condensation of aldehyde
with 1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione.
This reaction can be carried out in the presence of protonic acids7
or a range of Lewis acids such as InCl3ꢀ4H2O,8 FeCl3ꢀ8H2O,9
NaHSO4,10 or heterogeneous catalysts, such as Dowex-50W,11
⇑
Corresponding authors. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581.
E-mail address: manojitpal@rediffmail.com (M. Pal).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.01.126

N. Mulakayala et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2186–2191
2187
O
Ar
O
Ar
HO Ar
R1
R2
O
O
O
R
R
O
A
B
C
Fig. 1. Design of 1,8-dioxo-octahydroxanthenes (C) from the known cytotoxic xanthenes (A) as potential anticancer agents.
The reaction was carried out using a mixture of compound 1
(2.0 equiv) and aldehyde 2 (1.0 equiv) in the presence of iodine
(0.2 equiv) in i-propanol (3.0 mL) at 70–80 °C. The reaction pro-
ceeded smoothly and was completed within 20 min to give the
9-aryl substituted xanthenes derivatives 3 in good to excellent
yields (Table 1). A range of functionalized aromatic aldehydes
including mono and disubstituted derivatives were employed in
the present iodine-mediated condensation reaction. Both elec-
tron-donating groups for example, fluoro (entry 2), chloro (entry
3), bromo (entries 4, 10 and 11), methyl (entry 9), hydroxy (entries
5, 6, 10, 13 and 14) or methoxy (entries 8, 14 and 15) and electron-
withdrawing group for example, nitro (entries 7 and 12) present in
the aldehyde were well tolerated. All the 1,8-dioxo-octahydrox-
anthenes 3 prepared were well characterized by spectral (1H
NMR, IR and MS) data. The appearance of (i) a singlet in the region
4.6–4.8 d for C-9 proton and two singlets in the region 0.99–1.15 d
each for two methyl hydrogens in the 1H NMR spectra and (ii) IR
signals in the region 1680–1660 cmꢁ1 for carbonyl group charac-
terized the compound 3. Additionally, the molecular structure of
a representative compound for example, 3i was established unam-
biguously by single crystal X-ray diffraction (Fig. 2).29 Further, crys-
tal structure analysis was carried out to understand the packing
and/or hydrogen bonding patterns in crystal of these molecule
and results are summarized in the following section.
Compound 3i crystallizes in orthorhombic Pca2 (1) space group
with two molecules in the asymmetric unit (Z: 11 Z0: 0) (Fig. 3).
The two p-methoxyphenyl rings of the molecules in the asymmetric
unit are found to be not in coplanar with 3,3,6,6-tetramethyl-3,4,5
,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione. The torsion angles
of the p-methoxyphenyl ring with 3,3,6,6-tetramethyl-3,4,5,6,7,9-
hexahydro-1H-xanthene-1,8(2H)-dione are (C5–C6–C7–C18 76.9
(5), C18–C7–C8–C9 ꢁ78.0(4) and C42–C31–C32–C33 77.5(4) and
C29–C30–C31–C42 ꢁ77.9(5). The two molecules in the asymmetric
unit form same hydrogen bonding patterns in the crystal structure.
They also participated in weak Vander-Waal interactions through
the keto functional group, and are stabilized by methylene interac-
tions. These interactions propagated in 3D network packing as
shown in Figure 4.
intermediate E afforded the compound 3. It is mention worthy that
possible interaction of molecular iodine with carbonyl oxygen has
been indicated in the literature earlier.30 Moreover, the intermedi-
acy of compound E was supported by the fact that this compound
was isolated when the iodine-mediated reaction was carried out at
room temperature for 10 min. No cyclic product 3 was obtained even
after continuing the reaction for 12 h. However, the intermediate
E was converted to 3 when heated to reflux in isopropanol for
20 min in the presence of iodine.
To demonstrate the further scope of this reaction one of the
compound synthesized was used for further structure elaboration.
Thus, the compound 3e was propargylated31 using propargyl bro-
mide (Scheme 3) and the resulting alkyne 4 was then reacted with
p-iodophenol in the presence of (PPh3)2PdCl2 and CuI under a
Sonogashira condition.
Most of the xanthene derivatives synthesized for example, 3, 4
and 5 were tested for their anticancer properties in vitro. We eval-
uated our compounds for their anti-proliferative properties in vitro
against a number of cancer cell lines for example, human chronic
myeloid leukemia cells (K562), human colon carcinoma cells
(Colo-205), and human neuroblastoma cells (IMR32). The test com-
pounds were examined at various concentrations in a MTT (3-(4,
5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay
and the IC50 values obtained for each compounds are summarized
in Table 2. Harmine, a member of b-carboline family of compounds
showed cytotoxicity against HL60 and K562 cell lines32 was used
as a reference compound. While most of these compounds showed
inhibition of leukemia cell growth as reflected by their IC50 values
the good results however were obtained using compounds 3b, 3c,
3e, 3f, 3g, 3i, 3j, 3l, 3n, 3o, 4 and 5 (IC50 <50
lM, Table 2). Similarly,
except compounds 3i and 3k all other compounds (IC50 <50
lM,
Table 2) were found to be active against colon carcinoma cells
and except compounds 3c, 3h, 3i, 3k, 3l, 3m and 3o rest of the
compounds (IC50 <50
breast cancer cells. Overall, compound 3e possessing a 2-hydroxy
phenyl group at C-9 position was found to be promising (IC50
23–38 M, Table 2) and further functionalization of the 2-hydroxy
lM, Table 2) showed good activities against
ꢂ
l
phenyl ring (e.g., compounds 3f, 3j, 4 and 5) did not improve the
Mechanistically, the present iodine-mediated reaction seemed
to proceed via in situ generation of intermediate E that subse-
quently afforded the desired product 3 (Scheme 2). Thus (i)
aldol-type condensation between 1,3-cyclohexanedione (1) and
aldehyde (2) followed by (ii) intramolecular Michael addition
involving the hydroxyl group and enone moiety of the resulting
activity.
In conclusion, we have demonstrated the efficiency of molecu-
lar iodine as a catalyst for the preparation of 1,8-dioxo-octahydrox-
anthenes as potential anticancer agents. Both activated and
inactivated aromatic aldehydes participated well in the present
condensation reaction affording the expected products in high
yields. The advantages of the present method include (i) short reac-
tion time, (ii) operational simplicity and easy handling, (iii) func-
tional group tolerability, (iv) cleaner reaction products and (v)
does not involve the use of expensive and hazardous catalysts/
co-catalysts or reagents. The crystal structure analysis and hydro-
gen bonding patterns of one compound prepared by using this
methodology are presented. Most of the compounds synthesized
showed good anti-proliferative properties in vitro against three
cancer cell lines and the compound 3e possessing a 2-hydroxy phe-
nyl group at C-9 position was found to be promising. Overall, our
study suggests that 1,8-dioxo-octahydroxanthenes presented here
O
Ar
O
O
Iodine
ArCHO
+
O
O
i-propanol
70-80 °C
2
3
1
Scheme 1. Reaction of 5,5-dimethyl-1,3-cyclohexanedione (1) with aldehydes (2)
in the presence of molecular iodine.

2188
N. Mulakayala et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2186–2191
Table 1
Preparation of 1,8-dioxo-octahydroxanthenes (3) using molecular iodinea
Entry
Aldehyde (2)
Time (min)
Product (3)
Yieldb (%)
Ref.
20
CHO
O
O
1
18
90
O
3a
F
CHO
F
O
O
O
2
19
93
8
O
3b
Cl
CHO
Cl
O
O
3
17
91
20
O
3c
Br
CHO
Br
O
O
4
18
93
20
O
3d
CHO
OH
OH
O
5
16
95
O
3e
HO
CHO
OH
OH
O
O
O
6
19
90
OH
O
3f
NO2
CHO
NO2
O
7
19
91
8
O
3g

N. Mulakayala et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2186–2191
2189
Table 1 (continued)
Entry
Aldehyde (2)
Time (min)
Product (3)
Yieldb (%)
Ref.
CHO
OH
OCH3
OH
O
O
OCH3
8
18
93
O
3h
OCH3
CHO
O
O
9
17
90
8
OCH3
O
3i
CHO
Br
O
OH
OH
O
Br
10
19
94
O
3j
CHO
Br
Br
O
O
11
16
91
8
O
3k
CHO
CHO
NO2
O
O
O
12
NO2
18
96
12
O
3l
OH
O
OH
13
19
95
15
O
3m
OH
CHO
OH
OCH3
O
OCH3
O
14
17
93
21
O
3n
(continued on next page)

2190
N. Mulakayala et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2186–2191
Table 1 (continued)
Entry
Aldehyde (2)
Time (min)
Product (3)
Yieldb (%)
Ref.
26
CHO
OCH3
OCH3
OCH3
OCH3
O
O
15
20
92
O
3o
a
All the reactions were carried out using compound 1 (2.0 equiv) and aldehyde 2 (1.0 equiv) in the presence of iodine (0.2 equiv) in i-propanol (3.0 mL) at 70–80 °C.
Isolated yield.
b
Fig. 2. ORTEP representation of the compound (3i) (Thermal ellipsoids are drawn at
50% probability level).
Fig. 4. (a) Showing the 3D packing patterns in compound (3i).
I
I
O
Ar
O
2
1
+
I2
OH OH
E
H2O + I2
O
Ar
O
O I
I-
3
OH2
Fig. 3. Showing the hydrogen bonding patterns in two molecules of asymmetric
unit in compound (3i).
Scheme 2. Proposed reaction mechanism for the iodine-mediated reaction of 1,3-
cyclohexanedione (1) with aldehyde (2).
OH
O
O
O
OH
Br
O
O
O
O
O
p-IC6H4OH
Pd(PPh3)2Cl2
CuI, Et3N
DMSO
K2CO3
DMF
O
O
O
3e
5
4
Scheme 3. Structural elaboration of compound 3e.

N. Mulakayala et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2186–2191
2191
Table 2
6. (a) Giri, R.; Goodell, J. R.; Xing, C.; Benoit, A.; Kaur, H.; Hiasa, H.; Ferguson, D. M.
Bioorg. Med. Chem. 2010, 18, 1456; (b) Parkin, D. M.; Bray, F.; Ferlay, J.; Pisani, P.
Cancer J. Clin. 2005, 55, 74.
7. Darviche, F.; Balalaie, S.; Chadegani, F.; Salehi, P. Synth. Commun. 2007, 37,
1059.
8. Fan, X.; Hu, X.; Zhang, X.; Wang, J. Can. J. Chem. 2005, 83, 16.
9. Fan, X.-S.; Li, Y.-Z.; Zhang, X.-Y.; Hu, X.-Y.; Wang, J.-J. Chin. J. Org. Chem. 2005,
25, 1482.
10. Ma, J.-J.; Li, J.-C.; Tang, R.-X.; Zhou, X.; Wu, Q.-H.; Wang, C.; Zhang, M.-M.; Li, Q.
Chin. J. Org. Chem. 2007, 27, 640.
11. Shakibaei, G. I.; Mirzaei, P.; Bazgir, A. Appl. Catal., A 2007, 325, 188.
12. Das, B.; Thirupathi, P.; Reddy, K. R.; Ravikanth, B.; Nagarapu, L. Catal. Commun.
2007, 8, 535.
13. Seyyedhamzeh, M.; Mirzaei, P.; Bazgir, A. Dyes Pigm. 2008, 86, 836.
14. John, A.; Yadav, P. J. P.; Palaniappan, S. J. Mol. Catal. A: Chem. 2006, 248, 121.
15. Kantevari, S.; Bantu, R.; Nagarapu, L. J. Mol. Catal. A: Chem. 2007, 269, 53.
16. Jin, T.-S.; Zhang, J.-S.; Wang, A.-Q.; Li, T.-S. Synth. Commun. 2005, 35, 2339.
17. Das, B.; Thirupathi, P.; Mahender, I.; Reddy, V. S.; Rao, Y. K. J. Mol. Catal. A:
Chem. 2006, 247, 233.
18. Zhang, Z.-H.; Liu, Y.-H. Catal. Commun. 2008, 9, 1715.
19. Song, G.; Wang, B.; Luo, H.; Yang, L. Catal. Commun. 2007, 8, 673.
20. Kantevari, S.; Bantu, R.; Nagarapu, L. Arkivoc 2006, xvi, 136.
21. Jin, T.-S.; Zhang, J.-S.; Xiao, J.-C.; Wang, A.-Q.; Li, T.-S. Synlett 2004, 866.
22. Jin, T.-S.; Zhang, J.-S.; Xiao, J.-C.; Wang, A.-Q.; Li, T.-S. Ultrason. Sonochem. 2006,
13, 220.
Cytotoxic properties of compounds 3, 4 and 5 against various cancer cell lines
a,b
Compound
IC50
(lM)
K562
Colo-205
IMR32
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
4
56
35
44
59
23
36
46
55
49
37
74
47
56
49
45
34
28
32
39
30
42
42
38
28
38
41
>100
29
>100
37
41
32
33
28
30
26
45
42
55
49
23
41
49
62
53
46
>100
52
63
45
56
42
35
38
5
Harmine
23. Shi, D.-Q.; Zhuang, Q.-Y.; Chen, J.; Wang, X.-S.; Tu, S.-J.; Hu, H.-W. Chin. J. Org.
Chem. 2003, 23, 694.
a
IC50 represent the concentration of compound that causes a 50% growth inhi-
24. Jin, T.-S.; Zhang, J.-S.; Wang, A.-Q.; Zhang, F.-S. Chin. J. Org. Chem. 2005, 25, 335.
25. Ma, J.-J.; Zhou, X.; Zhang, X.-H.; Wang, C.; Wang, Z.; Li, J.-C.; Li, Q. Aust. J. Chem.
2007, 60, 146.
bition to untreated cells using the MTT assay.
b
Data represent the mean values of three independent determinations.
26. Tu, S.-J.; Zhou, J.-F.; Lu, Z.-S.; Deng, X.; Shi, D.-Q.; Wang, S.-H. Synth. Commun.
2002, 32, 3063.
27. For selected references, see: (a) Yadav, J. S.; Reddy, B. V. S.; Hashim, S. R. J.
have medicinal value and the basic framework of this class of het-
erocycles could be an attractive template for the identification of
novel and potential anticancer agents.
Chem. Soc., Perkin Trans.
1 2000, 3025; (b) Yadav, J. S.; Reddy, B. V. S.;
Premalatha, K.; Swamy, T. Tetrahedron Lett. 2005, 46, 2687; (c) Kumar, H. M. S.;
Reddy, B. V. S.; Reddy, E. J.; Yadav, J. S. Chem. Lett. 1999, 857; (d) Yadav, J. S.;
Reddy, B. V. S.; Rao, C. V.; Chand, P. K.; Prasad, A. R. Synlett 2001, 1638; (e) Wu,
J.; Xia, H.-G.; Gao, K. Org. Biomol. Chem. 2006, 4, 126; (f) Varla, R.; Nuvula, S.;
Adapa, S. R. J. Org. Chem. 2006, 71, 8283; For a review, see: (g) Mphahlele, M. J.
Molecules 2009, 14, 4814.
Acknowledgements
28. (a) Barange, D. K.; Batchu, V. R.; Gorja, D.; Pattabiraman, V. R.; Tatini, L. K.;
Babu, J. M.; Pal, M. Tetrahedron 2007, 63, 1775; (b) Venkataraman, S.; Barabge,
D. K.; Pal, M. Tetrahedron Lett. 2006, 47, 7317; (c) Pal, M.; Subramanian, V.;
Parasuraman, K.; Yeleswarapu, K. R. Tetrahedron 2003, 59, 9563.
The authors thank management of Institute of Life Sciences for
continuous encouragement and support.
29. Crystal data of 3i: Molecular formula = C24H28O4, Formula weight = 380.20,
Crystal system = Orthorhombic, space group = Pca2(1), a = 14.145(8) Å,
b = 15.162(9) Å, c = 20.708(14) Å, V = 4441.6(5) Å3, T = 296(2) K, Z = 11,
Supplementary data
Dc = 1.678 Mg mꢁ3
,
l
(Mo-K
a
) = 2.11 mmꢁ1
,
32,863 reflections measured,
(I)],
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2012.01.126.
4394 independent reflections, 3712 observed reflections [I >2.0
r
R1_obs = 0.045, Goodness of fit = 1.042. Crystallographic data (excluding
structure factors) for 3i have been deposited with the Cambridge
Crystallographic Data Center as supplementary publication number CCDC
858071.
References and notes
1. Jonathan, R. D.; Srinivas, K. R.; Glen, E. B. Eur. J. Med. Chem. 1988, 23, 111.
2. (a) Robak, J.; Gryglewski, R. J. Pol. J. Pharmacol. 1996, 48, 555; (b) Wang, H. K.;
Morris-Natschke, S. L.; Lee, K. H. Med. Res. Rev. 1997, 17, 367; (c) Rukavishnikov,
A. V.; Smith, M. P.; Birrell, G. B.; Keana, J. F. W.; Griffith, O. H. Tetrahedron Lett.
1998, 39, 6637.
3. Shchekotikhin, Y. M.; Nikolaeva, T. G. Chem. Heterocycl. Compd. 2006, 42, 28.
4. Hilderbrand, S. A.; Weissleder, R. Tetrahedron Lett. 2007, 48, 4383.
5. (a) Pohlers, G.; Scaiano, J. C. Chem. Mater. 1997, 9, 3222; (b) Knight, C. G.;
Stephens, T. Biochem. J. 1989, 258, 683.
30. (a) Wang, Y.-h.; Li, L.; Chen, X.-s. Chem. Res. Chin. Univ. 2008, 24, 520.
doi:10.1016/S1005-9040(08)60109-9; (b) Bandgar, B. P.; Shaikh, K. A.
Tetrahedron Lett. 1959, 2003, 44.
31. Hans, R. H.; Guantai, E. M.; Lategan, C.; Smith, P. J.; Wan, B.; Franzblau, S. G.;
Gut, J.; Rosenthal, P. J.; Chibale, K. Bioorg. Med. Chem. Lett. 2010, 20, 942.
32. Jahaniani, F.; Ebrahimi, S. A.; Rahbar-Roshandel, N.; Mahmoudian, M.
Phytochemistry 2005, 66, 1581.