Synthesis of bis(benzoxazole) frameworks chiralized by planar chiral [2.2]Paracyclophane

Article abstract of DOI:10.1016/j.tetlet.2021.152871

In this study, a new class of chiral bis(benzoxazole) has been synthesized. The bis(benzoxazole) framework, which has an achiral structure was chiralized by a planar chiral [2.2]paracyclophane moiety. Both enantiomeric forms of the bis(benzoxazole) deriva

Full text of DOI:10.1016/j.tetlet.2021.152871

Tetrahedron Letters 67 (2021) 152871
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Synthesis of bis(benzoxazole) frameworks chiralized by planar chiral
[
2.2]Paracyclophane
⇑
Emrah Polat, Ozge Turbedaroglu, Murat Cakici
Faculty of Sciences, Department of Chemistry, Ataturk University, Erzurum 25240, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, a new class of chiral bis(benzoxazole) has been synthesized. The bis(benzoxazole) frame-
work, which has an achiral structure was chiralized by a planar chiral [2.2]paracyclophane moiety.
Both enantiomeric forms of the bis(benzoxazole) derivatives were successfully obtained in 99% ee.
Even though the starting material was not completely enantiomerically pure, enantiomeric enrichment
was afforded by the Horeau principle in the synthesis route.
Received 9 December 2020
Revised 15 January 2021
Accepted 21 January 2021
Available online 4 February 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Bis(benzoxazole)
[
2.2]Paracyclophane
Planar chirality
Horeau principle
Introduction
In this study, we report the synthesis of novel C
2
-symmetric bis
(
benzoxazole) derivatives that exhibit planar chirality by replacing
Chiral bis(oxazolines) are one of the most popular classes of
ligands used in coordination chemistry and asymmetric synthesis.
Many C -symmetric chiral oxazoline-based ligands have been syn-
2
the phenyl group with a [2.2]paracyclophane backbone to intro-
duce chirality (Fig. 2). Thus, we introduce a new type of planar chi-
ral Box- and Pybox-like bis(benzoxazole) ligands.
thesized and they are employed in a wide range of asymmetric
reactions [1–4]. These ligands consist of two oxazoline moieties
separated by a spacer unit, which is most commonly based on a
single carbon atom (Box) or a pyridine ring (PyBox). The chirality
in the box ligands is caused by two adjacent tetrahedral carbon
Result and discussion
This paper provides a concept for the design and synthesis of
novel C -symmetric bis(benzoxazole) ligands which are chiralized
2
by fusing the planar chiral [2.2]paracyclophane moiety.
3
atoms with sp hybridization in the oxazoline ring, which is avail-
able from enantiomerically pure amino alcohols [5].
Benzoxazoles are also an important class of heterocycle in
which an oxazole moiety is fused onto a benzene ring (Fig. 1). Ben-
zoxazole and their derivatives exhibit a broad spectrum of biolog-
ical activities [6] and are also used as brighteners [7],
photochromatic and fluorescent agents [8–9], and laser dyes [10–
The study was initiated with the synthesis of the optically pure
2
-aminophenol moiety, (S
phane (PC-CHO) was prepared with the Rieche formylation of
2.2]paracyclophane (PC). Resolution of the racemic 4-formyl[2.2]-
P
)-6 (Scheme 1). 4-Formyl[2.2]paracyclo-
[
paracyclophane (PC-CHO) was achieved as described in the litera-
ture [21] by converting the two enantiomers into their
1
1]. Box- and PyBox-like bis(benzoxazole) derivatives have been
synthesized and used in various applications [12–17]. However,
the achiral properties of the benzoxazole backbone caused by the
plane and symmetrical structure have restricted their chiral appli-
cations [18]. Due to their unique three-dimensional structural
properties, [2.2]paracyclophanes have important applications in
several areas such as asymmetric synthesis and material science
diastereomeric imines. (S
99% de after two crystallization steps. After hydrolyzing of
diastereomerically pure imine (S ,R)-4 over a column of silica,
Dakin oxidation of the (S )-PC-CHO resulted in (S )-4-hydroxy
2.2]paracyclophane ((S )-PC-OH) [22–23]. Synthesis of the ortho-
substituted planar chiral aminophenol derivative ((S )-6) was per-
formed according to the following synthetic steps [24]: MOM pro-
tection, ortho-directed metalation of MOM-protected (S )-PC-OH
P
,R)-4 was obtained in ca. 20% yield and
>
P
P
P
[
P
P
[
19–20].
P
with butyllithium, nucleophilic attack of the corresponding lithium
⇑
Corresponding author.
E-mail address: mcakici@atauni.edu.tr (M. Cakici).
derivative with p-toluenesulfonyl azide, and reduction of azido-
derivative (S )-5 with LiAlH .
P 4
https://doi.org/10.1016/j.tetlet.2021.152871
040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
0

E. Polat, O. Turbedaroglu and M. Cakici
Tetrahedron Letters 67 (2021) 152871
plete the conversion. Later, unconsumed (S
the purification step via column chromatography.
P P
After deprotection of the (S ,S )-8 with HCl, (S ,S )-9 was
P
)-6 was recovered in
P
P
refluxed with methanesulfonic acid in 1,4-dioxane for 8 h, which
resulted in the desired planar chiral [2.2]paracyclophane-based
P P P P
bis(benzoxazole) derivative (S ,S )-1. The structure of (S ,S )-1
1
13
was characterized by H NMR, C NMR, IR, and HRMS spectra. Chi-
ral HPLC analysis showed that the enantiomeric purity was >99%
ee.
The same strategy was also followed to synthesize the methy-
lene bridged bis(benzoxazole) derivative (S ,S )-2. First, the start-
P P
ing material dimethylmalonic acid was treated with oxalyl
chloride in the presence of N,N-dimethylformamide to give corre-
sponding acyl chloride 10. Bis(benzoxazole) (S
with high yields as a result of the amidation of acyl chloride 10
with (S )-6, removal of the MOM protecting group, and ring closure
to form benzoxazole (Scheme 3). The structure of the methylene
bridged bis(benzoxazole) (S ,S )-2 was also confirmed by mass
spectrometry, IR, and NMR spectroscopy including H NMR and
P P
,S )-2 was obtained
Fig. 1. Typical bis(oxazoline) and bis(benzoxazole) structures.
P
P
P
1
1
3
C NMR. The spectral data were in agreement with the desired
structure.
We planned to synthesize the other enantiomer of the bis(ben-
zoxazole) 1 as well. However, after crystallization of the diastere-
omeric imine mixture of 4, only the (S ,R)-4 isomer could be
obtained in pure form. To the best of our knowledge, (R ,R)-4 iso-
mer remains waste product in the crystallization filtrate
Scheme 1).
We found that (R
P
P
a
Fig. 2. Structures of planar chiral bis(benzoxazole) in this study.
(
P
,R)-4 can be obtained up to 90–95% de by re-
We tried different methods to form a benzoxazole structure and
found that a direct ring closure after removing the MOM group was
not a suitable method. As a synthesis strategy, we decided to fol-
crystallization of the (R )-isomer rich filtrate remaining from first
P
crystallization of the diastereomeric mixture of 4 (Scheme 4).
Actually, this enantiomeric purity is not sufficient for an asym-
metric synthesis. However, we thought that the enantiomeric
excess of the product in the amidation step would increase by
removing of the minor enantiomer through the statistical forma-
tion of diastereomeric forms of 8 (the Horeau principle) [25]. To
low the amidation of (S
P
)-6, MOM-deprotection, and ring closure
steps.
The amidation of (S
P
)-6 with 2,6-pyridinedicarbonyl dichloride
(
7) as a linker was investigated under various reaction conditions
(
data not given). The optimum reaction conditions are shown in
test this idea, (Rp)-6, obtained from (R ,R)-4 under the described
P
Scheme 2. 2,6-Pyridinedicarbonyl dichloride (7), which is obtained
from 2,6-pyridinedicarboxylic acid by treatment of SOCl , was
reacted with (S )-6 in presence of NEt . The corresponding diamide
,S )-8 was obtained with a 96% yield. In this reaction, a little
excess of (S )-6, which is synthetically valuable, was used to com-
procedure in 90% ee, was reacted with 2,6-pyridinedicarbonyl
dichloride (7). The H NMR spectrum of the crude product showed
1
2
P
3
the presence of two diamide 8 diastereomers at a 92:8 ratio. The
resulting diastereomeric mixture was successfully separated by
column chromatography to give (R ,R )-8 and (R ,S )-8 (meso) with
(S
P P
P
P
P
P P
P
Scheme 1. Synthesis of 2-aminophenol moiety, (S )-6.
2

E. Polat, O. Turbedaroglu and M. Cakici
Tetrahedron Letters 67 (2021) 152871
P P
Scheme 2. Synthesis of the planar chiral bis(benzoxazole) (S ,S )-1.
P P
Scheme 3. Synthesis of the methylene bridged bis(benzoxazole) (S ,S )-2.
increased to 99% ee (determined by Chiral HPLC). (R
cessfully obtained with the ring closure after removal of the MOM
group. All the spectral data of the (R ,R )-1 were in agreement with
)-isomer sample (Scheme 5).
P P
,R )-1 was suc-
P
P
P P
those of the (S ,S
Conclusion
Benzoxazole units with planes of symmetry are achiral. This
study introduces chirality into the framework of bis(benzoxazole)
with a [2.2]paracyclophane fragment and developed a new family
of Box- and PyBox-like ligands that may be useful in asymmetric
synthesis and heterocyclic chemistry. We have also demonstrated
the synthetic utility of the Horeau principle in the synthesis strat-
egy to obtain the (R
,S )-isomers 1 and 2, subjecting (R
a waste scalemic mixture of crystallization filtrate, to the same
synthesis route resulted in 99% ee of (R ,R )-1. Studies on the appli-
P
)-isomer derivative. Besides the synthesis of
(S
P
P
P
)-6 (90% ee), obtained from
P
P
cations of new bis (benzoxazole) derivatives are in progress.
P
Scheme 4. Synthesis of (R )-6 (in 90–95% ee).
Declaration of Competing Interest
yields of 90% and 9%, respectively. Separation of these two
diastereomers effectively removed the minor (S )-enantiomer from
the major (R )-enantiomer and the enantiopurity of the (R ,R )-8
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
P
P
P
P
3

E. Polat, O. Turbedaroglu and M. Cakici
Tetrahedron Letters 67 (2021) 152871
P P
Scheme 5. Synthesis of the (R ,R )-isomer of 1 by the Horeau principle.
[
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The authors thank The Scientific and Technological Research
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