A new iodine catalyzed regioselective synthesis of xanthene synthons

Article abstract of DOI:10.1016/j.tetlet.2012.04.061

This Letter describes the iodine catalyzed one-pot regioselective synthesis of p-condensed xanthenes as our key point of transformation, which provides an efficient access to five skeletally diverse scaffolds in excellent yields.

Full text of DOI:10.1016/j.tetlet.2012.04.061

Tetrahedron Letters 53 (2012) 3281–3283
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Tetrahedron Letters
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A new iodine catalyzed regioselective synthesis of xanthene synthons q
Koneni V. Sashidhara a, , Abdhesh Kumar a, Ranga Prasad Dodda a, Bikash Kumar b
⇑
a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226 001, India
b Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli 229 010, India
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the iodine catalyzed one-pot regioselective synthesis of p-condensed xanthenes as
our key point of transformation, which provides an efficient access to five skeletally diverse scaffolds in
excellent yields.
Received 12 March 2012
Revised 11 April 2012
Accepted 15 April 2012
Available online 21 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Synthesis
Xanthenes
2-Hydroxyaromatic benzaldehydes
Regioselective
Diversity-oriented synthesis (DOS) has received much attention
lately as a tool for the exploration of the chemical space of molecu-
lar structures.1–4 The aim of DOS is to obtain collections of small
molecules as complex and diverse as possible. The screening of such
molecular libraries, searching for perturbing effects on disease
related biological pathways, may eventually lead to the identifica-
tion of therapeutic protein targets, which can be modulated by
small organic molecules. The development of effective strategies
in DOS is therefore very important in finding new pharmacological
targets.5–11
OH
R1
CHO
OH
OH
OH
R1
CHO
R2
R2
R1
a
R2
b
CHO
O
1a−d
2a−d
R1
R2 Yield (%)
3a
sec-Butyl
tert -Buty
iso-Propyl
Ethyl
sec-Butyl Br 82
tert -Buty Br 84
iso-Propyl Br 82
H
H
H
H
90
87
86
85
3a−h
3b
3c
3d
3e
3f
3g
3h
Ethyl
Br 80
Scheme 1. Synthesis of regioselective xanthenes (3a–h). Reagents and conditions: (a) (1) hexamethylenetetramine/TFA, 120 °C, 3 h, (2) 10% H2SO4, 90–100 °C, 2 h; (b) I2,
90–100 °C, 15 min.
q
Part X in the series, ‘Studies on Novel Synthetic Methodologies’.
⇑
Corresponding author. Tel.: +91 9919317940; fax: +91 522 2623405.
E-mail addresses: kv_sashidhara@cdri.res.in, sashidhar123@gmail.com (K.V. Sashidhara).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.061

3282
K. V. Sashidhara et al. / Tetrahedron Letters 53 (2012) 3281–3283
molecules like coumarins, chalcones, Schiff0 base, arylcoumarins,
OH
O
and dioxocine analogs, using inexpensive starting materials.
The route followed for the preparation of regioselective xan-
thene and their further diversification are illustrated in Scheme 1.
The Duff reaction on 2-sec-butylphenol (1a) gave compound 5-sec-
butyl-4-hydroxyisophthalaldehyde (2a) which on condensation
with b-naphthol in the presence of catalytic amounts of iodine22
furnished para-selective dibenzoxanthenes (3a) exclusively in
90% yield. A likely explanation as to why the 5-sec-butyl-4-hydrox-
yisophthalaldehyde condenses so selectively with b-naphthol in
the presence of iodine (mild lewis acid) is that, the reactive benze-
noid forms are favored over the unreactive quinoid forms. Further-
2
1
3
H
6
12
4
6
11
10
HMBC
7
5
4
13
5
H
C
9
3
O
2
8
1
Figure 1. Selected 1H–13C HMBC correlations of compound 3a.
more, the presence of the hydroxyl group
a to the aldehyde will
better stabilize (intramolecular H-bonding) the benzenoid rather
than the quinoid form. Similar results were obtained, when other
dialdehydes (2a–d) were condensed with b-naphthols to form
their corresponding regioselective xanthenes (3b–h). To the best
of our knowledge this is the first report of regioselective synthesis
of xanthenes from aromatic dicarbaldehydes.
The structure elucidation of the versatile intermediate xanthene
3a was done as follows. The ESI-mass spectrum gave a molecular
ion at m/z 459 indicated the formation of the required product
3a. In the IR spectrum of compound 3a exhibited absorption band
of carbonyl at 1639 cmꢀ1 and aromatic C–H stretch at 3057 cmꢀ1
indicating the presence of aromatic skeleton. The 1H NMR spec-
trum of the product in addition to other signals showed signals
Xanthenes are tricyclic dibenzopyrans with diverse pharmaco-
logical activities, such as antibacterials,12 antivirals,13 anti-
inflammatories,14 and find application even in photodynamic ther-
apy.15,16 Further, these compounds also have wide application in
industries, such as dyes in laser technology17 and for the fluorescent
materials for visualization of biomolecules.18 In addition many xan-
thene derivatives have shown anticancer activity.19,20 However, the
development of therapeutic agents that take advantage of this un-
ique heterocyclic structure has been limited.
Considering the above valid points and our ongoing efforts on
oxygenated heterocycles,21 herein we report an efficient approach
for regioselective synthesis of xanthenes and their further diversity
oriented protocol for the synthesis of pharmaceutically important
OH
O
O
O
O
O
R3
R4
R4
5a
5b
Yield (%)
H
Cl
64
63
66
O
5a−d
5c CH3
5d OCH3 65
4a−c
b
a
R3
Yield (%)
87
82
OH
O
O
R5
4a
CH3
N
H
H
4b OCH3
4c OC2H5 83
c
e
O
O
3a
O
O
O
6a-c
d
R5
Yield (%)
84
87
6a
OCH3
Ethyl
O
6b Phenyl
6c 4-methyl phenyl 85
O
O
8
91 %
O
7
94 %
Scheme 2. Synthesis of substituted xanthenes of 3a. Reagents and conditions: (a) R3COCH2COOC2H5, or CH2(COR3)2, EtOH or MeOH, piperidine, reflux, 30 min; (b) 10% KOH,
p-R4C6H4COCH3, EtOH, reflux, 4–5 h; (c) R5-NH2, PTSA, EtOH, reflux, 1 h; (d) p-CH3OC6H4CH2COOH, cyanuric chloride, N-methyl morpholine, DMF, 110 °C, 50 min; (e)
epichlorohydrin, Et3N, reflux, 75 min.

K. V. Sashidhara et al. / Tetrahedron Letters 53 (2012) 3281–3283
3283
at d 11.04 and 9.58 belonging to the hydroxyl and latter to a free
References and notes
aldehyde, respectively. The 13C NMR spectrum in addition to other
signals, showed diagnostic signal at d 196.9 (CHO) revealed that
the product had aldehydic group. In the HMBC spectrum, C-2 (d
158.0) gave correlations with protons present at d 3.05, 7.23,
7.73, 11.04, and also at d 9.58; this was only possible if the free
aldehyde is at ortho position. This indicated that the condensation
involved the aldehyde at para position (Scheme 1). Through HMBC
we investigated further and found that proton at C-14 (d 6.42) gave
correlation with C-4 (d 130.8), and C-6 (134.3). Finally, aldehydic
proton (d 9.58) gave correlation with C-1 (d 120.5), C-2 (d 158.0),
and C-6 (d 134.3). Thus, the final analysis with all the spectral data
led to structure as 3a. Selected HMBC correlations of compound 3a
are shown in Figure 1.
With an efficient route to the regioselective synthesis of xanth-
enes in hand, its diversification was undertaken to afford various
analogs in a straightforward way in excellent yields (Scheme 2).
Thus, subsequent diversification on 3a was accomplished by apply-
ing the Knoevenagel condensation, catalyzed by piperidine, result-
ing in the formation of its coumarin derivatives (4a–c).
Alternatively, compound 3a on Claisen–Schmidt reaction23 with
different acetophenones in refluxing ethanol, in the presence of a
10% KOH furnished chalcones (5a–d). In all the chalcones synthe-
sized the trans double bond (on the basis of coupling constant)
was obtained exclusively. The low yields of chalcones obtained
may be due to the combined effects of steric hindrance and the
low reactivity of ortho-aldehyde which is involved in hydrogen
bonding with the adjacent hydroxyl group. Furthermore, the com-
pound 3a on reaction with different amines in ethanol in the pres-
ence of catalytic amount of PTSA cleanly furnished its Schiff base
(6a–c) derivatives that existed in keto-enamine form in high
yields.24 The formation of 3-arylcoumarin (7) was demonstrated
by the reaction of 3a with 4-methoxyphenylacetic acid in the pres-
ence of cyanuric chloride in excellent yield.21b Similarly, dioxocine
(8) was derived by reaction of 3a with epichlorohydrin using tri-
ethylamine as catalyst.21d All compounds were characterized using
1H NMR, 13C NMR, 2D NMR, mass spectrometry, and IR spectros-
copy. The purity of these compounds was ascertained by TLC and
spectral analysis25 (please refer to Supplementary data).
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In summary, we describe a simple and efficient method for the
synthesis of regioselective xanthene and their further diversifica-
tion. The advantage of this method is the ease of modification of
each unit and their combination with another pharmacophore as
potential pharmacological agents. This transformation could be of
immense importance to medicinal chemists using appropriate
templates to generate an interesting library of substituted
xanthenes.
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25. Synthesis of 3-sec-butyl-5-(14H-dibenzo[a,j]xanthene-14-yl)-2-hydroxybenz
aldehyde (3a): 5-sec-butyl-4-hydroxyisonaphthaldehyde (2 g, 9.708 mmol)
and naphthalen-2-ol (2.796 g, 19.4 mmol) in the presence of iodine as
catalyst, was heated at 90–95 °C for 15–30 min. The reaction was monitored
by TLC to establish completion. The remaining I2 was removed by washing
with satd aq Na2S2O3. The mixture was then extracted by chloroform
(3 ꢁ 50 mL). The combined organic layers were dried on Na2SO4, filtered, and
concentrated to dryness under reduced pressure. The crude product was
purified over column chromatography (100–200 mesh) to furnish compound
3a. White solid, yield: 90%; mp 125–127 °C; IR (KBr): 3394, 3057, 1639,
Acknowledgements
Authors acknowledge the SAIF division for providing the spec-
troscopic and analytical data. We are also thankful to Dr. T.K. Cha-
kraborty (Director, CDRI) for his constant support and
encouragement. A.K. and R.P.D. are thankful to the CSIR, New Delhi,
India for financial support. This is the CSIR-CDRI communication
number 8230.
1046 cmꢀ1 1HNMR (CDCl3, 300 MHz): d 11.03 (s, 1H), 9.58 (s, 1H), 8.28 (d,
;
J = 8.4 Hz, 2H), 7.81–7.73 (m, 5H), 7.56–7.51 (m, 2H), 7.47–7.36 (m, 4H), 7.24–
7.21 (m, 1H), 6.40 (s, 1H), 3.09–2.97 (m, 1H), 1.67–1.49 (m, 2H), 1.14 (d,
J = 6.9 Hz, 3H), 0.73 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 196.9, 158.0,
148.8, 136.7, 135.3, 134.3, 131.4, 131.3, 130.8, 129.2, 129.1, 126.9, 124.5, 122.6,
122.5, 120.5, 118.1, 116.9, 37.4, 32.9, 29.3, 20.2, 11.9; ESI-MS (m/z): 459
(M+H)+. Anal. Calcd C32H26O3: C, 83.82; H, 5.72. Found C, 83.96; H, 5.57.
Supplementary data
Supplementary data (Spectral data of all the compounds) asso-
ciated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.04.061.