RSC Advances
PAPER
A versatile synthesis of bis[2-
(29-hydroxylphenyl)benzoxazole] derivatives as zinc
sensors3
Junfeng Wang and Yi Pang*
A versatile synthetic route has been developed to prepare 2, 5-bis(benzoxazole-2-yl)benzene-1,4-diol
derivatives 2. Although one of the derivatives (2b) has recently been shown to exhibit an excellent
response to Zn2+ cations, the low yielding synthetic route will likely prevent its wide application. This report
describes an improved synthetic procedure to obtain 2, thereby making this class of compounds available
for biologically relevant studies. An effective synthesis has been developed for 2-aminophenol derivative 6,
Received 5th March 2013,
Accepted 12th April 2013
which bears
a carboxylate group in the desired position. The strategy allows construction of
DOI: 10.1039/c3ra41080c
bis(benzoxazole) compound 5, where the built-in ester group can be easily converted to either a
hydroxymethyl or a bromomethyl group to introduce the zinc-chelating ligand.
One of the essential components in bis(HBO) sensor 2b is
the di-2-picolylamine (DPA) group, which is used to selectively
Introduction
In recent years, fluorescent sensors have emerged as useful
tools for molecular imaging.1 Among the optical imaging
technologies, near infrared (NIR) fluorescence (700-1000 nm)
has received immense attention owing to its low absorption
and autofluorescence from organisms and tissues in the NIR
spectral range.2 The attractive features of NIR fluorescence
dyes include minimized background interference, improved
tissue depth penetration and image sensitivity,3–5 which
enables the detection of molecular activity for in vivo
applications.6 An ideal NIR probe should exhibit a large
Stokes shift, in order to minimize interference between
excitation and emission signals. Additionally, a desirable NIR
probe should be integrated with a suitable chemical event that
can generate a large optical response when responding to a
specific analyte of interest.2 Our recent studies show that 2,
bind the zinc cation to trigger the subsequent NIR emission
from the zinc complex 3b.9 In the previous report, bromina-
tion of the methyl group (on benzoxazole A of compound 1)
was the bottleneck for the synthesis of bis(HBO) system due to
the low yield (12.1%). In addition, bromination via a radical
mechanism makes it a synthetic challenge to include any
primary or secondary alkyl groups on benzoxazole B, which
hampers the study of substitution effects on the optical
properties. In order to overcome the drawback of the existing
approach, we decided to explore the alternative routes to
introduce the DPA group. Herein, we report a versatile and
efficient synthesis of the bis(HBO) system, which not only
provides bis(HBO) 2a and 2b, but also new derivatives.
In the previous design, the low yield of bromination step
was introduced at the late stage of synthesis. Part of the
problem is that functionalization of the Ar–CH3 moiety is
difficult. In the new molecular design, benzoxazole fragment A
of bis(HBO) 4 includes a more reactive benzylic hydroxy group,
which could be transformed to DPA group in high yield. The
synthetic design is based on the following knowledge: (a)
bromination and tosylation of benzylic hydroxyl group can be
accomplished in more than 90% yield;10,11 (b) replacement of
Br or OTs with a chelating group, such as DPA, has also been
reported in up to 99% yield.10,11 As shown in Scheme 1, the
efficient synthesis is dependent on the construction of key
intermediate 4, which could be obtained by reduction of ester
5 or direct coupling between 8 and 7.
5-bis(benzoxazole-2-yl)benzene-1,4-diol derivatives
2
[2,5-
bis(HBO)] can exhibit a remarkable optical response upon
zinc binding, giving the turn-on emission in both the visible
(at y550 nm) and NIR regions (at y750 nm).7–9 The
fluorescence properties of the sensor appear to be quite
sensitive to the substituents present on benzoxazole moiety B
(Fig. 1). Although sensor 2b exhibits better performance than
2a,9 the current synthetic route to 2 suffers from low yields
(total yield ,1%). It is, therefore, highly desirable to develop
an efficient synthesis of 2, in order to facilitate its application
in various studies.
Department of Chemistry & Maurice Morton Institute of Polymer Science, University
of Akron, Akron, OH 44325, U.S.A. E-mail: yp5@uakron.edu; Tel: +1-330-972-8263
Our initial attention was directed to the synthesis of
2-aminophenol derivatives 6 and 8 (Scheme 2). First, direct
nitration of 9 with nitric acid failed to produce the desired
Electronic supplementary information (ESI) available. See DOI: 10.1039/
3
c3ra41080c
This journal is ß The Royal Society of Chemistry 2013
RSC Adv.