A new synthetic route to unsymmetrical 9-arylxanthenes

Article abstract of DOI:10.1002/ejoc.200900676

A. facile and general three-step synthetic route towards unsymmetrical 9-arylxanthenes was developed. The reaction sequence involves nucleophilic substitution of commercially available 2-fluorobenzaldehydes with arenoxides, Grignard reaction of the resulting 2-arenoxybenzaldehydes with arylmagnesium bromides, followed by FeCl₃-catalyzed intramolecular diarylmethylation of the resulting carbinols, This strategy was extended to access symmetrical as well as unsymmetrical 9-arylthioxanthenes.

Full text of DOI:10.1002/ejoc.200900676

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900676
A New Synthetic Route to Unsymmetrical 9-Arylxanthenes[‡]
Sajal Kumar Das,[a] Ritesh Singh,[a] and Gautam Panda*[a]
Keywords: Fused-ring systems / Oxygen heterocycles / Arenes / Synthetic methods
A facile and general three-step synthetic route towards un- lecular diarylmethylation of the resulting carbinols. This
symmetrical 9-arylxanthenes was developed. The reaction
sequence involves nucleophilic substitution of commercially
available 2-fluorobenzaldehydes with arenoxides, Grignard
strategy was extended to access symmetrical as well as un-
symmetrical 9-arylthioxanthenes.
reaction of the resulting 2-arenoxybenzaldehydes with aryl- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
magnesium bromides, followed by FeCl3-catalyzed intramo-
Germany, 2009)
in laser technologies as a result of their useful spectroscopic
properties.[7] Oxidation of these compounds produce xanth-
ylium salts, which are also useful as dyes and fluorescent
materials.[8] For example, fluorescein and fluorone are
structurally related xanthene dyes (Figure 1). Fluorone de-
rivatives have found numerous applications such as in the
detection of a variety of metal ions,[9] sugars,[10] phosphoryl-
ated molecules,[11] HIV-1 nucleocapsid protein,[12] reactive
oxygen species,[13] in screening assays for mitochondrial per-
meability,[14] acetylcholinesterase inhibition,[15] and te-
lomerase inhibition.[16]
Introduction
Xanthenes and dibenzo[a,j]xanthenes have attracted con-
siderable attention over the years as a result of their wide
range of biological properties such as antiviral,[1] anti-in-
flammatory,[2] and antibacterial activities.[3] These com-
pounds have also been utilized as antagonists for paralyzing
action of zoxazolamine[4] and in photodynamic therapy
(PDT).[5] The flat, rigid structure of xanthenes has been
used to advantage as a linker for peptide synthesis and in
unnatural amino acids and related pharmaceutical precur-
sors.[6] More importantly, xanthenes and the related con-
densed ring system variants have also been used as dyes,
fluorescent materials for visualization of biomolecules, and
Results and Discussion
Over the past several years we have been involved in the
design, synthesis, and antitubercular and anticancer activi-
ties of various triarylmethanes (TRAMs).[17] In continua-
tion of our research program in this direction, we became
interested in synthesizing 9-arylxanthenes as conformation-
ally constrained analogues of TRAMs.
However, a literature survey revealed that the synthesis
of 9-arylxanthenes are known by three routes: (a) reaction
of xanthones with arylmagnesium halides (ArMgX) or aryl-
lithiums (ArLi) followed by subsequent conversion of the
resulting carbinols;[18] (b) condensation of β-naphthol with
aromatic aldehydes;[19] (c) coupling of arynes with aromatic
aldehydes.[20] However, only route (a) can permit the syn-
thesis unsymmetrical 9-arylxanthenes. Because substituted
xanthones are not commercially available, this method of
synthesizing unsymmetrical 9-arylxanthenes also requires
the synthesis of the starting xanthones, which, in turn, may
be a multistep process. Therefore, access to symmetrical as
well as unsymmetrical 9-arylxanthenes by a short and ef-
ficient method incorporating a wide range of substituent
patterns would further expand the scope of their applica-
tions in our ongoing research program.
Figure 1. Structures of some common xanthene dyes.
[‡] CDRI communication number 7732
[a] Medicinal and Process Chemistry Division, Central Drug
Research Institute,
Lucknow 226001, UP, India
Fax: +91-522-262-3405
E-mail: gautam.panda@gmail.com
gautam_panda@cdri.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900676.
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S. K. Das, R. Singh, G. Panda
SHORT COMMUNICATION
In 2005, we reported the synthesis of unsymmetrical tri- Table 1. Synthesis of 2-arenoxybenzaldehydes 11a–d.
substituted methanes (TRSMs) by intermolecular diaryl-
methylation of electron-rich arenes by using diaryl carbi-
nols as alkylating agents.[21] Accordingly, it was envisaged
that utilization of this diarylmethylation of electron-rich ar-
ene reaction could be applied to the synthesis of various
symmetrical as well as unsymmetrical 9-arylxanthenes 5 by
an intramolecular fashion in a diarylcarbinol 6 containing
a tethered arenoxy group (Scheme 1). Carbinol 6 could be
obtained by the Grignard reaction of aromatic halides with
2-arenoxybenzaldehydes 7.
Scheme 1. Retrosynthetic analysis of 9-arylxanthenes.
Table 2. Optimization studies for the synthesis 9-phenylxanthene.
Our study began with the synthesis of a series of four 2-
arenoxybenzaldehydes 11a–d by following a literature pro-
cedure that involved heating a solution of 2-fluorobenzalde-
hydes 8 or 9)[29] and aromatic hydroxy compounds 10a–c in
dry DMA at reflux in the presence of anhydrous K2CO3 as
a base (Table 1).[22] With 2-arenoxybenzaldehydes 11a–d in
hand, we turned our attention for the next steps. Thus, ini-
tially 2-phenoxybenzaldehyde 11a was treated with freshly
prepared phenylmagnesium bromide to get carbinol 12a in
very high yield (see the scheme for Table 3). It was sub-
sequently chosen as a model substrate for the investigation
of the intramolecular diarylmethylation reaction leading to
9-phenylxanthene. In view of the use of a catalytic amount
of concentrated H2SO4 in our previous work on the synthe-
sis of unsymmetrical TRSMs,[21] we first examined the cy-
clization of alcohol 12a in the presence of concentrated
[a] Isolated yield of 13a after silica gel column chromatography.
H2SO4 (Table 2, Entry 1). Thus, a solution of 12a in dry
benzene was heated at reflux for 30 min to afford 9-aryl-
xanthene 13a (75% yield). Similarly, the use of some other and intramolecular hydroamination and hydroalkoxylation
well-known Friedel–Crafts protic and Lewis acid catalysts of alkenes.[27] Also owing to the toxic nature of benzene,[28]
such as anhydrous AlCl3, Sc(OTf)3, and TfOH in the above we chose dichloromethane (DCM) as the reaction medium.
reaction was also effective under suitable reaction condi-
On the basis of these facts and the above optimization
tions. Also, it was found that 12a could be transformed into results, we then turned our attention to explore the scope
13a in high yield by treating a solution of 12a in dry of FeCl3-catalyzed diarylmethylation of electron-rich arenes
CH2Cl2 at room temperature with the use of FeCl3 (10 mol- with various diarylcarbinols containing tethered arenoxy
%).
groups. Towards that objective, a series of carbinols 12b–x
It appeared that the high stabilization of the diarylmethyl was first synthesized by the addition of various freshly pre-
carbocation made the cyclization reaction very effective. pared arylmagnesium bromides on 11a–d (Table 3). All the
However, although the above intramolecular diarylmethyl- reactions were very high yielding (90–96%). Next, treat-
ation of electron-rich arenes could be done by using a wide ment of the resulting carbinols with FeCl3 (10 mol-%) in
range of Lewis and Brønsted acid catalysts, we were inter- dry CH2Cl2 at room temperature furnished the correspond-
ested to do the reaction using less-expensive anhydrous ing 9-arylxanthenes 13b–x in high yields (Table 3). The re-
FeCl3, which has already been used in alkylation of elec- action was amenable to a variety of aromatic rings for the
tron-rich arenes with aromatic aldehydes,[23] arylation of synthesis of unsymmetrical 9-arylxanthenes. The reaction
benzyl alcohols and benzyl carboxylates,[24] hydroarylation sequence shown in Table 3 involves several salient features:
of styrenes,[25] benzylation of 1,3-dicarbonyl compounds,[26] (a) the diverse collection of 9-arylxanthenes demonstrates
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A New Synthetic Route to Unsymmetrical 9-Arylxanthenes
Table 3. Synthesis of 9-arylxanthenes 13b–x.
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S. K. Das, R. Singh, G. Panda
SHORT COMMUNICATION
the potential to utilize any 2-arenoxybenzaldehyde as a Towards that objective, 2-arylsulfanylbenzaldehydes 14a,b
common precursor to a library of 9-arylxanthenes; (b) were first synthesized by essentially following the similar
many of the products obtained would not be readily access- strategy as that described for 2-arenoxybenzaldehydes 11a–
ible by conventional routes; (c) reaction of 2-arenoxy het- d (Scheme 2).
eroarene-1-aldehydes with heteroarylmagenesium halides or
Subsequently, treatment of freshly prepared arylmagne-
heteroaryllithiums (other than 2-thienylmagnesium bro- sium bromides with 14a,b furnished carbinols 15a–f in high
mide) remains unexplored; thus one or more heterocycles yields. Next, treatment of the resulting carbinols with FeCl3
should be easily incorporated into the 9-arylxanthene sys- (10 mol-%) in dry CH2Cl2 at room temperature furnished
tem if so desired; (d) high-yielding access to these com- the corresponding 9-arylthioxanthenes 16a–f in high yields
pounds is only made possible by the mild reaction condi- (Table 4). In this case, symmetrical, as well as unsymmetri-
tions employed; (e) symmetrical, as well as unsymmetrical, cal, 9-arylthioxanthenes could be synthesized depending on
9-arylxanthenes could be synthesized.
the choice of the starting aldehydes and Grignard reagents.
Next, with the goal of accessing the 9-arylthioxanthenes
products, the propensity of FeCl3-catalyzed diarylmethyl-
ation of electron-rich arenes with various diarylcarbinols
containing a tethered arylsulfanyl group was investigated.
Conclusions
In conclusion, we have demonstrated a new synthetic
route of 9-arylxanthenes and 9-arylthioxanthenes by FeCl3-
catalyzed diarylmethylation of electron-rich arenes. The re-
action was driven by cationic activation of diaryl carbinols
by FeCl3 (10 mol-%). Our synthetic strategy could allow
significant variation of all aryl rings of symmetrical and
unsymmetrical 9-arylxanthenes, which were not easily avail-
able.
Scheme 2. Synthesis of 2-arylsulfanylbenzaldehydes 14a,b.
Table 4. Synthesis of 9-arylthioxanthenes 16a–f.
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures and analytical data of se-
lected compounds.
Acknowledgments
This work was supported by the Department of Science and Tech-
nology (DST), India. S.K.D and R.S thank the Council of Scien-
tific and Industrial Research (CSIR), India for research fellowships.
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Received: June 18, 2009
Published Online: August 20, 2009
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