Regioselective Synthesis of 4,7,12,15-Tetrasubstituted [2.2]Paracyclophanes: A Modular Route Involving Optical Resolution

Article abstract of DOI:10.1002/ejoc.202100762

A practical synthetic method for preparing bis-(para)-pseudo-ortho and bis-(para)-pseudo-meta type 4,7,12,15-tetrasubstituted [2.2]paracyclophanes is reported. Regioselective double Rieche formylation was successfully applied to the corresponding dibromo[2.2]paracyclophanes under slightly modified conditions. Aldehydes reacted in an unknown direction with Rieche formylation agents, dichloromethyl methyl ether and titanium(IV) tetrachloride, leading to the formation of benzal chlorides. Formylated products were obtained after hydrolysis of these benzal chloride derivatives. Optical resolution was performed with the diastereomer method and (R_P)-4,12-dibromo-7,15-diformyl[2.2]paracyclophane was successfully obtained in an enantiomerically pure form (99 % ee). Their synthetic utility is demonstrated with some exploratory transformations to access corresponding differently functionalized tetrasubstituted [2.2]paracyclophane derivatives.

Full text of DOI:10.1002/ejoc.202100762

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Regioselective Synthesis of 4,7,12,15-Tetrasubstituted
[2.2]Paracyclophanes: A Modular Route Involving Optical
Resolution
Authors: Fatmanur Biliz and Murat Cakici
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100762
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1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202100762
FULL PAPER
Regioselective Synthesis of 4,7,12,15-Tetrasubstituted
2.2]Paracyclophanes: A Modular Route Involving Optical
Resolution
[
[
a]
[a]
Fatmanur Biliz and Murat Cakici*
[
a]
F. Biliz, Dr. M. Cakici
Faculty of Science, Department of Chemistry,
Ataturk University, 25240 Erzurum, Turkey
Email: mcakici@atauni.edu.tr
https://avesis.atauni.edu.tr/mcakici
Supporting information for this article is given via a link at the end of the document.
Abstract: We report a practical synthetic method for preparing bis‐
para)-pseudo-ortho and bis-(para)-pseudo-meta type 4,7,12,15-
[2.2]paracyclophane derivatives,[12] which have received growing
attention as planar chiral scaffolds in the fields of polymer and
materials chemistry.[8a]
Given the many potential applications, it is important to develop
new synthetic strategies for regiocontrolled synthesis[13] and
(
tetrasubstituted [2.2]paracyclophanes. Regioselective double Rieche
formylation was successfully applied to the corresponding
dibromo[2.2]paracyclophanes under slightly modified conditions.
Aldehydes reacted in an unknown direction with Rieche formylation
agents, dichloromethyl methyl ether and titanium (IV) tetrachloride,
leading to the formation of benzal chlorides. Formylated products
were obtained after hydrolysis of these benzal chloride derivatives.
Optical resolution was performed with the diastereomer method and
optical
resolution
of
planar
chiral
tetrasubstituted
[
8a]
[2.2]paracyclophanes. In this article, we describe a practical
and efficient synthetic route for bis‐(para)‐pseudo‐ortho (1) and
bis‐(para)‐pseudo‐meta
[2.2]paracyclophanes
(2)
(Figure
type
1) from
tetrasubstituted
corresponding
(
R
P
)-
4,12-dibromo-7,15-diformyl[2.2]paracyclophane
was
dibromo[2.2]paracyclophanes. We also examined their optical
resolution and various functional group transformation to produce
successfully obtained in an enantiomerically pure form (99% ee).
Their synthetic utility is demonstrated with some exploratory
transformations to access corresponding differently functionalized
tetrasubstituted [2.2]paracyclophane derivatives.
synthetically
useful
planar
chiral
tetrasubstituted
[2.2]paracyclophane building blocks.
Introduction
Since the initial 1949 discovery of [2.2]paracyclophane (PCP),[1]
PCP and its derivatives have received a great deal of attention in
many fields of chemistry.[2] [2.2]Paracyclophane has an highly
strained three-dimensional structure of two facing benzene rings
that are linked in para position by a two-ethylene bridge. One of
the most impressive features of substituted PCPs is their planar
chirality capabilities, which offers novel opportunities in
asymmetric applications not possible with traditional forms of
chirality.[3]
Figure 1. Tetrasubstituted [2.2]paracyclophane building blocks used in this
study.
PCP backbone has a rigid three-dimensional structure, which
Because of their unique structural and electronic properties, PCP
derivatives have been explored for a wide range of applications,
including asymmetric synthesis and materials science.[3a] In
recent decades, many PCP-based planar chiral ligands and
catalysts have been developed and successfully employed for
various stereoselective processes.[4] Recently, the focus in
makes possible
polysubstituted
regiocontrolled
a
variety of different regioisomers for
[2.2]paracyclophanes.[12b]
Consequently,
tetrasubstituted
synthesis
of
[
2.2]paracyclophanes is often difficult. Bromo-substituted PCPs
are the starting point of many types of molecular architecture for
tetrasubstituted scaffolds.[14] One of the most common
approaches for the synthesis of bis‐(para)‐pseudo‐ortho and bis‐
[
2.2]paracyclophane chemistry has shifted and studies on
materials chemistry have come to the foreground.[
5]
(
para)‐pseudo‐meta type tetrasubstituted [2.2]paracyclophanes is
[
2.2]Paracyclophanes have been successfully employed as
based on the selective lithiation of tetrabromo-PCP 3 followed by
standard treatment with various electrophiles (Scheme 1).[15] This
planar chiral building blocks in various functional materials
6]
including
chiral
metal-organic
frameworks
(MOFs),[
method can often suffer from poor regioselectivity. Regioselective
electrophilic substitution of disubstituted [2.2]paracyclophanes is
a more advantageous approach for obtaining tetrasubstituted
optoelectronics,[ circularly polarized light emitting compounds,
7]
[8]
mesoporous polymers,[9] and supramolecular self-assembled
structures.[10] Although there are many studies on mono- and
disubstituted [2.2]paracyclophanes due to their well-known
chemistry,[11] relatively little is known about tetrasubstituted
2.2]paracyclophanes.[12b] This approach has been successfully
[
applied in the regioselective synthesis of tetrasubstituted
[16]
[
2.2]paracyclophane derivatives.
1
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European Journal of Organic Chemistry
10.1002/ejoc.202100762
FULL PAPER
formylating agents (TiCl
4
/DCME). Substrate rac-5 was completely
consumed in 20 h; however, benzal chloride derivative rac-6 was
unexpectedly obtained with a 91% yield.
In the literature,[ it has been suggested that benzal chlorides,
which can be seen as side products of Rieche formylation, occur
in a parallel pathway via dichloromethyl cation, a possible
intermediary in the DCME-Lewis acid interaction. However, this
result clearly shows that benzal chloride can also be formed from
aldehyde, which is the product of the formylation reaction, through
deoxygenative halogenation under Rieche conditions. Benzal
chloride formation proved to be effective only when reactions
were heated at 40 °C. To the best of our knowledge, there are no
published reports on the conversion of aldehydes to benzal
18]
4
chlorides with the formylating agents TiCl /DCME. Considering
Scheme
1.
Representative
synthetic
routes
to
tetrasubstituted
[
2.2]paracyclophanes.
the importance of developing new methods for the preparation of
benzal chlorides,[ this transformation might be synthetically
valuable for direct dichloromethyl functionalization of aryl
derivatives (formylation and dichlorination) or dichlorination of
aldehydes.
19]
Results and Discussion
When monoformylation product rac-5 was refluxed in CH
2 2
Cl with
In the present work, we focused on the para-regioselective double
formylation of dibromo[2.2]paracyclophanes. In our synthesis
strategy, regioselectivity was controlled by bromine atoms on the
a 4:16 formylating agent (TiCl /DCME) molar ratio for 20 h, a
4
second functionalization was achieved. However, instead of the
desired diformylation product (1), a mixture of benzal chloride
derivatives (7) were formed. This mixture was successfully
separated by column chromatography to give rac-7a and rac-7b
with yields of 31% and 57%, respectively.
[
2.2]paracyclophane backbone. Racemic pseudo-ortho- (rac-4a)
and pseudo-meta- (rac-4b) dibromo[2.2]paracyclophane
[12b, 17]
precursors were prepared as described in ref.
Supporting Information for details).
(see
It is important to note that the obtained benzal chlorides (7) form
the skeleton of the desired diformylation product 1. Hydrolysis of
rac-7a and rac-7b as a mixture, by refluxing in aqueous ethanol
First we examined a Rieche formylation of pseudo-ortho-
dibromo[2.2]paracyclophane (rac-4a) with various molar ratios of
TiCl
4
/dichloromethyl methyl ether (DCME) as formylating agents
:DCME of 1:4:2 in CH Cl at
(
80%, v/v), afforded the desired dialdehyde rac-1 at a 95% yield.
In fact, rac-1 was practically obtained by the initial preparation of
benzal chlorides (7) directly from rac-4a (4 equiv of TiCl , 16 equiv
of DCME, CH Cl , reflux, 48h) followed by hydrolysis of the crude
reaction mixture without any purification.
In a test reaction, rac-7b formed quantitatively from rac-1 by
refluxing in CH Cl with a 4:16 formylating agent (TiCl /DCME)
molar ratio for 5 h. This result supports that the TiCl /DCME pair
(
Scheme 2). For molar ratio 4a:TiCl
4
2
2
room temperature, para-directed monoformylation product rac-5
was obtained with a 95% yield. Many attempts were made to
prepare diformylation product rac-1, but a second formyl group
could not be introduced into the PCP framework with different
equivalents of the formylating agents (even in excess equivalents)
at room temperature. Reaction temperature was increased to
4
2
2
2
2
4
4
40 °C and Rieche conditions were applied for the monoformylated
acts as a deoxygenative halogenation agent for aldehydes as well
as formylation.
product rac-5 by refluxing in CH Cl with a 4:2 molar ratio of the
2
2
Scheme 2. Synthesis of racemic12-dibromo-7,15-diformyl[2.2]paracyclophane (rac-1) by regioselective double Rieche formylation.
2
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European Journal of Organic Chemistry
10.1002/ejoc.202100762
FULL PAPER
Scheme 3. Synthesis of bis-(para)-pseudo-meta type tetrasubstituted
Scheme 4. Optical resolution of rac-5 and synthesis of enantiomerically pure
(R )-4,12-dibromo-7,15-diformyl[2.2]paracyclophane ((R )-1).
P P
[
2.2]paracyclophane rac-2.
The same synthetic strategy was applied to pseudo-meta-
dibromo[2.2]paracyclophane (rac-4b) to achieve bis-(para)-
pseudo-meta type tetrasubstituted [2.2]paracyclophane rac-2
Thus, rac-5 was refluxed with 1.1 equivalent of (R)-
phenylethylamine (10) as a chiral resolving agent in toluene for
1
by
6 h. This led to a 1:1 mixture of the two diastereomers (confirmed
(
Scheme 3). First, the starting material rac-4b was treated with
1
H
P P
NMR), (R ,R)-11, and (S ,R)-11. The fractional
the formylating agents (TiCl /DCME) at a molar ratio of 4:2 at
4
crystallization of the diastereomeric imine mixture 11 from hexane
provided (-)-11, determined to be in the R -configuration in the
following step, with >99% de (26% yield) after two crystallization
steps. On the other hand, (S ,R)-11 was obtained from the first
room temperature to give the corresponding monoformylation
product rac-8 at a 76% yield. Then tetra‐functionalized PCP
derivatives rac-9a and rac-9b were obtained as mixtures in
different ratios from both rac-4b and rac-8 under the Rieche
conditions presented in Scheme 3.
P
P
crystallization filtrate in ca. 70% de. The separation of
diastereomers was followed by the characteristic imine signals at
The synthesis of rac-2 was achieved by hydrolyzing obtained
benzal chlorides (9), either as pure or as crude mixture, in an
aqueous ethanol (80%, v/v) under reflux conditions. All
compounds were confirmed by mass spectrometry and NMR
spectroscopy including H NMR and 13C NMR. The spectral data
were in agreement with the desired structure.
P P
,R) and 8.29 ppm (R
,R) in the 1H NMR spectra.
8.30 (S
Subsequently, the resulting diastereomerically pure imine (R
1
P
,R)-
1 was hydrolyzed over silica gel during the chromatography and
P
purified to generate enantiopure (R )-5. The absolute
configuration of the resulting enantiomer was determined to be
1
(
(
R
S
P
), by comparison of its optical rotation with that of the known
)-enantiomer[23]. The enantiomeric purity of the obtained chiral
P
Aldehyde groups have many advantages in PCP chemistry such
as mild synthesis conditions, utility in many functional group
transformations, and being prepared as enantiopure through
various optical resolution methods. Due to the potential
asymmetric applications of tetrasubstituted PCPs, we
investigated their optical resolution through aldehyde functionality.
Currently, many resolution methods have been successfully
applied to access enantiomerically pure PCP derivatives,
including classical resolution methods,[20] chromatographic
separation on chiral stationary phases,[11b, 21] and catalytic kinetic
resolutions.[22] In an effort to achieve the optical resolution of rac-
P
product was >99%, confirmed by chiral HPLC analysis. (R )-5
was then subjected to the second Rieche formylation under
determined conditions to produce benzal chlorides (7).
Hydrolyzing of the crude benzal chloride products mixture by
heating in aqueous ethanol resulted in (R )-1. Unfortunately, the
P
optical resolution of rac-8 with the same method failed due to
unsuccessful crystallization attempts.
Further, the synthetic utility of prepared tetrasubstituted PCPs
was demonstrated by some useful functional group
transformations (Scheme 5). (R
carboxylic acid (R )-12 by treating it with potassium
permanganate at an 85% yield.
P
)-1 was oxidized into bis-
5, we successfully employed the classical resolution technique
P
involving diastereomeric imine formation (Scheme 4).
3
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European Journal of Organic Chemistry
10.1002/ejoc.202100762
FULL PAPER
Layer silica gel Chromatography) using Merck silica gel 60 F254 on
aluminum sheets. TLC plates were visualized under UV light (254 and 366
nm). Melting points were measured using a Gallenkamp apparatus and
are uncorrected. H NMR and 13C NMR spectra were recorded on a Varian
1
Mercury (400 MHz) or a Bruker Avance (400 MHz) spectrometer in CDCl
3
or DMSO-d using TMS as an internal standard. Chemical shifts were
6
expressed in parts per million (δ); multiplicities were described by the
following abbreviations: s (singlet), bs (broad singlet), d (doublet), dd
(
doublet of doublet), t (triplet), q (quartet), and m (multiplet); and coupling
constants values J were given in Hertz (Hz). High resolution mass spectra
HRMS) were obtained using an Agilent 6530 Accurate mass Q-ToF mass
(
spectrometer. Enantiomeric excesses were determined by HPLC analysis
using chiral column. Optical rotations were measured on a Bellingham +
Stanley, ADP220, 589 nm spectropolarimeter in
concentrations are given in g/100 mL.
a 1 dm tube;
Synthesis and Characterization
Scheme 5. Transformation of (R
P
)-1 to various synthetically useful
tetrasubstituted [2.2]paracyclophane building blocks.
4,12-Dibromo-7-formyl[2.2]paracyclophane (rac-5)
To a stirred solution of pseudo-ortho-dibromo[2.2]paracyclophane (rac-4a)
1.44 g, 3.90 mmol) in CH Cl (16 mL) were added a solution of TiCl (1.66
mL, 15.60 mmol) in CH Cl (2 mL) and dichloromethyl methyl ether (706
µL, 7.80 mmol) at 0 °C. The mixture was stirred at room temperature for
0 h, poured into ice and stirred for another 1 h. The two phases were
separated, and the aqueous layer was extracted with CH Cl (25 mL). The
combined organic phases were washed with saturated aqueous NaHCO
and brine, dried over Na SO and evaporated. The crude product was
purified by column chromatography eluting with hexane/EtOAc 9:1 to give
(
2
2
4
Bis-carboxylic acid (R
resulting in the corresponding planar chiral diamine derivative.
)-13 was synthesized following established procedures: a four-
step reaction sequence where only the final product needs
purification. Under Dakin oxidation condition, (R )-1 was
converted into the corresponding dihydroxy-PCP derivative,
which was isolated as methyl ether ((R )-14) at a 59% yield after
I and K CO
P
)-12 underwent Curtius rearrangement,
2
2
(R
P
2
2
2
P
3
2
4
P
4
9
,12-dibromo-7-formyl[2.2]paracyclophane (rac-5) (1.47 g, 3.70 mmol,
5%) as a white solid. R
=0.26 (Hexane/EtOAc 19:1); m.p. 88-90°C; 1
) δ=9.90 (s, 1H), 7.31 (s, 1H), 7.15 (d, J = 1.5 Hz,
H), 7.03 (s, 1H), 6.44 (dd, J = 7.9, 1.5 Hz, 1H), 6.41 (d, J = 7.9 Hz, 1H),
3.87 (dd, J = 13.0, 9.9 Hz, 1H), 3.52 – 3.42 (m, 2H), 3.14 – 3.01 (m, 3H),
treating the crude product with CH
3
2
3
.
f
H
NMR (400 MHz, CDCl
1
3
Conclusion
2
1
3
3
.95 – 2.82 (m, 2H); 13C NMR (100 MHz, CDCl
40.1, 138.8, 137.9, 136.3, 135.4, 134.0, 133.1, 132.9, 131.1, 126.9, 35.9,
3
) δ=191.0, 144.2, 141.2,
In conclusion, we have developed an alternative and efficient
preparation method for bis‐(para)-pseudo‐ortho and bis‐(para)-
pseudo‐meta type tetrasubstituted [2.2]paracyclophanes. The
5.5, 32.3, 30.5; HRMS (APCI-TOF) m/z: Calcd for C17H15Br
2
O [M+H]+
92.9484, found 392.9461.
corresponding
dibromo[2.2]paracyclophanes
underwent
4,12-Dibromo-7-(dichloromethyl)[2.2]paracyclophane (rac-6)
regioselective double Rieche formylation under the modified
conditions. We found that a reaction temperature of about 40 °C
is required for the second formylation. Unexpectedly, the resulting
aldehyde converted into benzal chloride under Rieche conditions
and a higher temperature. Further investigations are currently in
progress on this new finding, which may be synthetically useful
for the deoxydichlorination of aldehydes. The desired aldehyde
derivatives can be easily obtained by hydrolysis of the resulting
benzal chlorides. As an example of the enantiomeric separation,
optical resolution of rac-5 was successfully performed with the
To a stirred solution of 4,12-dibromo-7-formyl[2.2]paracyclophane (rac-5)
0.185 g, 0.47 mmol) in CH Cl (4 mL) were added a solution of TiCl (200
µL, 1,88 mmol) in CH Cl (1 mL) and dichloromethyl methyl ether (851 µL,
.4 mmol) at 0 °C. The mixture was refluxed with stirring at 40 °C for 7 h,
poured into ice and stirred for another 1 h. The two phases were separated,
and the aqueous layer was extracted with CH Cl (15 mL). The combined
organic phases were washed with saturated aqueous NaHCO and brine,
dried over Na SO and evaporated. The crude product was purified by
(
2
2
4
2
2
9
2
2
3
2
4
column chromatography eluting with hexane/EtOAc 19:1 to give
corresponding benzal chloride rac-6 (0.195 g, 0.43 mmol, 91%) as a white
1
solid. R
f
=0.65 (Hexane/EtOAc 19:1); m.p. 160-162°C; H NMR (400 MHz,
diastereomeric imine formation to give (R
9% ee. We also demonstrated some synthetic applications of
)-1 to obtain valuable substituted PCPs. Regarding bromo-
P P
)-5 and then (R )-1 in
CDCl
3
) δ=7.24 (d, J = 1.9 Hz, 1H), 7.18 (s, 1H), 7.00 (s, 1H), 6.75 (s, 1H),
.72 (d, J = 7.8 Hz, 1H), 6.44 (dd, J = 7.8, 1.9 Hz, 1H), 3.52 – 3.40 (m, 2H),
.26 (dd, J = 14.0, 10.0 Hz, 1H), 3.15 – 3.01 (m, 3H), 2.94 – 2.78 (m, 2H);
) δ=141.4, 140.4, 138.0, 137.6, 137.2, 134.6,
33.3, 133.0, 132.7, 131.6, 128.7, 126.5, 69.5, 35.6, 35.4, 32.2, 30.2;
9
(R
P
6
3
substituents, their ability to be applied for many different
transformations will make 1 and 2 attractive planar chiral building
blocks in PCP chemistry. Further studies on their applications in
the synthesis of new functional materials are in progress in our
laboratory.
1
3C NMR (100 MHz, CDCl
3
1
Cl [M–Cl]+ 410.9145, found
HRMS (ESI-TOF) m/z: Calcd for C17H14Br
2
410.9121.
Benzal chloride derivatives rac-7a and rac-7b
To a stirred solution of 4,12-dibromo-7-formyl[2.2]paracyclophane (rac-5)
Experimental Section
2 2 4
(0.729 g, 1.85 mmol) in CH Cl (12 mL) were added a solution of TiCl (789
µL, 7,40 mmol) in CH Cl (3 mL) and dichloromethyl methyl ether (2,68 mL,
2
2
General
29.6 mmol) at 0 °C. The mixture was refluxed with stirring at 40 °C for 20
h, poured into ice and stirred for another 1 h. The two phases were
separated, and the aqueous layer was extracted with CH
combined organic phases were washed with saturated aqueous NaHCO
2 2
Cl (15 mL). The
All reagents and solvents were purchased from commercial sources and
used without further purification. Reactions were monitored by TLC (Thin
3
4
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European Journal of Organic Chemistry
10.1002/ejoc.202100762
FULL PAPER
and brine, dried over Na
2
SO
4
and evaporated. The remaining residue was
combined organic phases were washed with saturated aqueous NaHCO
3
purified by column chromatography eluting with hexane/EtOAc 19:1 to give
2 4
and brine, dried over Na SO and evaporated. The remaining residue was
benzal chloride derivatives rac-7a (0.277 g, 0.58 mmol, 31%) and rac-7b
purified by column chromatography eluting with hexane/EtOAc 39:1 to give
benzal chloride derivatives rac- 9a (0.029 g, 0.06 mmol, 12%) and rac-9b
(0.207 g, 0.39 mmol, 78%). The resulting products were used in the next
step as a mixture.
(0.560 g, 1.05 mmol, 57%). The resulting products were used in the next
step as a mixture.
Benzal chloride rac-7a: R
1H NMR (400 MHz, CDCl
f
=0.35 (Hexane/EtOAc 19:1); m.p. 114-117 °C;
) δ=9.77 (s, 1H), 7.36 (s, 1H), 7.19 – 7.14 (m,
1
3
Benzal chloride rac-9a: R
f
=0.31 (Hexane/EtOAc 19:1); m.p. 139-141°C; H
2
(
(
H), 6.87 (s, 1H), 6.71 (s, 1H), 3.96 (dd, J = 12.4, 9.4 Hz, 1H), 3.58 – 3.35
m, 2H), 3.32 (dd, J = 14.0, 9.9 Hz, 1H), 3.16 – 2.89 (m, 4H); 13C NMR
100 MHz, CDCl ) δ=191.6, 143.6, 140.6, 138.9, 137.8, 137.2, 136.8,
35.6, 135.5, 134.5, 132.6, 131.4, 128.8, 69.0, 34.9, 34.9, 30.7, 30.0;
NMR (400 MHz, CDCl
3
) δ=9.88 (s, 1H), 7.66 (s, 1H), 7.44 (s, 1H), 6.94 (s,
1H), 6.76 (s, 1H), 6.44 (s, 1H), 4.08 (dd, J = 12.9, 9.7 Hz, 1H), 3.46 – 3.30
(m, 3H), 3.27 – 3.17 (m, 1H), 3.15 – 3.06 (m, 1H), 3.03 – 2.93 (m, 1H),
2.88 – 2.078 (m, 1H); 13C NMR (100 MHz, CDCl
3
1
3
) δ=191.9, 142.2, 140.1,
+
HRMS (APCI-TOF) m/z: Calcd for C18
2
H14Br ClO [M–Cl] 438.9094, found
140.0, 137.8, 137.5, 137.4, 137.1, 135.4, 135.3, 133.4, 129.1, 128.9, 68.8,
4
38.9095.
33.1, 32.8, 32.7, 31.8; HRMS (APCI-TOF) m/z: Calcd for C18
H
15Br
2
Cl
2
O
+
[M+H] 474.8861 found 474.8860.
Benzal chloride rac-7b: R
f
=0.54 (Hexane/EtOAc 19:1); m.p. 207-209 °C;
) δ=7.32 (s, 2H), 7.01 (s, 2H), 6.60 (s, 2H), 3.49
3.38 (m, 4H), 3.13 (ddd, J = 13.5, 9.9, 7.7 Hz, 2H), 2.97 (ddd, J = 13.5,
.9, 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl
) δ=138.9, 138.4, 136.5, 134.9,
1H NMR (400 MHz, CDCl
Benzal chloride rac-9b: R
=0.44 (Hexane/EtOAc 19:1); m.p. 168-170°C;
3
f
–
9
1
1H NMR (400 MHz, CDCl
3
) δ=7.51 (s, 2H), 6.81 (s, 2H), 6.73 (s, 2H), 3.52
3
– 3.40 (m, 2H), 3.39 – 3.27 (m, 2H), 3.23 – 3.10 (m, 2H), 2.99 – 2.85 (m,
2H); 13C NMR (100 MHz, CDCl
) δ=140.2, 136.6, 136.5, 136.3, 129.1,
30.9, 128.5, 69.6, 34.9, 30.2; HRMS (APCI-TOF) m/z: Calcd for
3
+
C
18
H14Br
2
Cl
3
[M–Cl] 492.8522, found 492.8517.
128.8, 69.1, 32.6, 32.1; HRMS (ESI-TOF) m/z: Calcd for C18
Cl] 492.8522, found 492.8515.
H14Br
2
Cl
3
[M–
+
4,12-Dibromo-7,15-diformyl[2.2]paracyclophane (rac-1)
4
,15-Dibromo-7,12-diformyl[2.2]paracyclophane (rac-2)
The mixture of rac-7a and rac-7b (0.837 g, 1.63 mmol) from previous step
was dissolved in 25 mL of EtOH/H O (5:1) and the resulting solution was
refluxed for 2 h. After completion of the reaction (by monitoring TLC), the
solvent was evaporated under reduced pressure. The residue was taken
2
The mixture of rac-9a and rac-9b (0.236 g, 0.45 mmol) from previous step
was dissolved in 15 mL of EtOH/H O (5:1) and the resulting solution was
refluxed for 2 h. After completion of the reaction (by monitoring TLC), the
solvent was evaporated under reduced pressure. The residue was taken
up in CH
aqueous phase was extracted with CH
organic phases were dried over Na SO and concentrated under reduced
pressure. The crude product was purified on silica gel column using
hexane/EtOAc, (9:1) to afford 4,12-dibromo-7,15-
2
up in CH
aqueous phase was extracted with CH
organic phases were dried over Na SO and concentrated under reduced
pressure. The crude product was purified on silica gel column using
hexane/EtOAc, (9:1) to afford 4,12-dibromo-7,15-
2
Cl
2
(20mL) and the solution washed with water (20 mL). The
2
Cl (20mL) and the combined
2
2
Cl
2
(20mL) and the solution washed with water (20 mL). The
2
4
2
Cl (20mL) and the combined
2
2
4
formyl[2.2]paracyclophane (rac-1) (0.654 g, 1.55 mmol, 95%) as a white
1
solid. R
f
=0.15 (Hexane/EtOAc 19:1); m.p. 202-205 °C; H NMR (400 MHz,
formyl[2.2]paracyclophane (rac-2) (0.172 g, 0.41 mmol, 91%) as a white
1
CDCl
–
3
) δ=9.79 (s, 2H), 7.27 (s, 2H), 6.88 (s, 2H), 4.00 – 3.87 (m, 2H), 3.55
3.41 (m, 2H), 3.13 – 2.94 (m, 4H); 13C NMR (100 MHz, CDCl
) δ=191.4,
solid. R
CDCl
– 3.32 (m, 2H), 3.24 – 3.10 (m, 2H), 2.97 – 2.83 (m, 2H); 13C NMR (100
f
=0.24 (Hexane/EtOAc 19:1); m.p. 177-179 °C; H NMR (400 MHz,
3
3
) δ=9.90 (s, 2H), 7.58 (s, 2H), 6.60 (s, 2H), 4.11 – 3.98 (m, 2H), 3.45
1
43.6, 140.3, 137.6, 136.1, 135.6, 133.2, 35.2, 30.7; HRMS (APCI-TOF)
+
m/z: Calcd for C18
H15Br
O
2 2
[M+H] 420.9433, found 420.9420.
MHz, CDCl
3
) δ=191.4, 143.8, 139.9, 138.6, 135.5, 134.7, 133.6, 32.9,
+
32.8; HRMS (APCI-TOF) m/z: Calcd for C18
H15Br
O
2 2
[M+H] 420.9433,
found 420.9431.
4,15-Dibromo-7-formyl[2.2]paracyclophane (rac-8)
To a stirred solution of pseudo-meta-dibromo[2.2]paracyclophane (rac-4b)
Optical
Resolution
of
racemic
4,12-dibromo-7-
(
1.15 g, 3.14 mmol) in CH Cl (16 mL) were added a solution of TiCl (1.34
mL, 12.56 mmol) in CH Cl (2 mL) and dichloromethyl methyl ether (568
µL, 6.28 mmol) at 0 °C. The mixture was stirred at room temperature for
0 h, poured into ice and stirred for another 1 h. The two phases were
separated, and the aqueous layer was extracted with CH Cl (25 mL). The
combined organic phases were washed with saturated aqueous NaHCO
and brine, dried over Na SO and evaporated. The crude product was
purified by column chromatography eluting with hexane/EtOAc 4:1 to give
2
2
4
formyl[2.2]paracyclophane (rac-5)
2
2
rac-4,12-dibromo-7-formyl[2.2]paracyclophane (rac-5) (1.48 g, 3.76 mmol)
and (R)-phenylethylamine (10) (5.02 g, 4.14 mmol) were heated under
reflux in toluene (50 mL). The progress of the reaction was monitored by
1H NMR spectroscopy. After 16 h, the solvent was evaporated and the
crude product 11 (mixture of diastereoisomers) recrystallized twice from
2
2
2
3
2
4
hexane (10 mL, then 5 mL) giving imine (R
P
,R)-11 (de: >99%, calculated
,R) and 8.29 (R ,R) ppm
P P
,R) and 7.01 (R ,R) ppm). Yield: 0.49 g (0.99 mmol, 26%);
1
4
,15-dibromo-7-formyl[2.2]paracyclophane (rac-8) (0.940 g, 2.39 mmol,
by H NMR considering the resonance at 8.30 (S
P
P
1
76%) as a white solid. R
f
=0.42 (Hexane/EtOAc 19:1); m.p. 135-138°C; H
or 7.06 (S
(R ,R)-11; m.p. 135-138°C; [α] = –287 (c=0.54, in CH
MHz, CDCl
2
0
1
NMR (400 MHz, CDCl
3
) δ=9.87 (s, 1H), 7.60 (s, 1H), 7.12 (d, J = 7.8 Hz,
P
2
Cl
2
); H NMR (400
D
1
4
3
1
1
3
3
H), 6.72 (s, 1H), 6.52 (dd, J = 7.8, 1.8 Hz, 1H), 6.48 (d, J = 1.8 Hz, 1H),
3
) δ=8.29 (s, 1H), 7.46 (d, J = 7.7 Hz, 2H), 7.37 (t, J = 7.7 Hz,
.07 (dd, J = 13.0, 10.0 Hz, 1H), 3.40 – 3.30 (m, 2H), 3.23 – 3.13 (m, 2H),
.13 – 3.02 (m, 1H), 2.95 (ddd, J = 13.0, 10.1, 7.1 Hz, 1H), 2.76 (ddd, J =
2H), 7.30 – 7.23 (m, 1H), 7.21 (s, 1H), 7.15 (d, J = 1.8 Hz, 1H), 7.01 (s,
1H), 6.48 – 6.36 (m, 2H), 4.55 (q, J = 6.6 Hz, 1H), 3.73 (dd, J = 13.2, 9.8
Hz, 1H), 3.46 – 3.29 (m, 2H), 3.12 – 2.96 (m, 3H), 2.88 – 2.76 (m, 1H),
2.72 – 2.59 (m, 1H), 1.66 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl
δ=157.7, 145.1, 141.8, 141.3, 139.2, 138.8, 136.1, 135.4, 134.6, 133.0,
3.0, 10.1, 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl
3
) δ=191.7, 143.5, 141.5,
40.2, 139.9, 138.8, 136.0, 135.5, 135.0, 133.8, 130.8, 130.7, 127.4, 34.0,
3
)
3.4, 33.4, 33.0; HRMS (APCI-TOF) m/z: Calcd for C17
H15Br
2
O [M+H]+
92.9484, found 392.9481.
131.2, 128.7, 128.6, 127.1, 126.8, 126.7, 70.8, 35.6, 35.3, 32.4, 30.7, 25.1.
Benzal chloride derivatives rac-9a and rac-9b
(S
P
,R)-11 was obtained from the first crystallization filtrate with about 70%
de
To a stirred solution of 4,15-dibromo-7-formyl[2.2]paracyclophane (rac-8)
0.197 g, 0.50 mmol) in CH Cl (5 mL) were added a solution of TiCl (213
µL, 2,00 mmol) in CH Cl (1 mL) and dichloromethyl methyl ether (724 µL,
.00 mmol) at 0 °C. The mixture was refluxed with stirring at 40 °C for 20
h, poured into ice and stirred for another 1 h. The two phases were
separated, and the aqueous layer was extracted with CH Cl (15 mL). The
(
2
2
4
P P
(R )-4,12-Dibromo-7-formyl[2.2]paracyclophane ((R )-5)
2
2
8
(
R
P
,R)-11 (0.49 g, 0.99 mmol) was hydrolyzed and separated on silica gel
column by eluting with CH Cl (R )-4,12-Dibromo-7-
formyl[2.2]paracyclophane ((R )-5) (382 mg, 0.97 mmol, 98%) was
2
2
.
P
2
2
P
5
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202100762
FULL PAPER
2
0
obtained as a white solid. [α] = –193 (c=0.58, in CH
2
Cl
2
); ee: >99%;
water, 0.5 mmol). After stirring at room temperature for 4 d, the reaction
D
HPLC conditions: 9.8 min (R), 10.8 min (S). Chiralcel OD-H column, n-
hexane/i-PrOH 95:05, 1 mL/min flow rate, 254 nm.
mixture was concentrated in vacuo, diluted with CH
washed with water (10 mL). The aqueous phase was extracted with CH
10mL). The combined organic phases were dried over Na SO
concentrated under reduced pressure. The resulting
2
Cl
2
(10 mL) and
Cl
and
2
2
(
2
4
(
R
P
)-4,12-Dibromo-7,15-diformyl[2.2]paracyclophane ((R
P
)-1)
dihydroxy[2.2]paracyclophane derivative was used for the next reaction
without purification. The crude product was dissolved in acetone (5 mL),
(
R
P
)-1 was prepared from (R )-5 by following the same procedure as
P
20
described in the synthesis of (rac)-5. [α] = –157 (c 1.0, CH
spectral data were in agreement with (rac)-5
2
Cl
2
). All the
D
and K
added to the solution. The reaction mixture was stirred at reflux
temperature under N atmosphere for 20 h. The cooled mixture was
2 3
CO (276 mg, 2 mmol) and iodomethane (70 mg, 0.5 mmol) were
2
(
R
P
)-4,12-Dibromo-7,15-dicarboxy[2.2]paracyclophane ((R
P
)-1)
filtrated, and the filtrate was evaporated under reduced pressure. The
residue was purified on silica gel column using hexane/EtOAc, (9:1) to
To a stirred solution of (R
(R )-1) (0.296 g, 0.70 mmol) in acetone (3 mL), a solution of potassium
permanganate (0.553 g, 3,50 mmol) in H O (3 mL) was added dropwise
P
)-4,12-dibromo-7,15-formyl[2.2]paracyclophane
afford (R
Hexane/EtOAc 19:1); m.p. 127-129 °C; [α]D = –45 (c=0.5, in CHCl
NMR (400 MHz, CDCl
P f
)-14 (25 mg, 0.059 mmol, 59%) as a white solid. R =0.45
(
P
20
); 1
(
3
H
2
3
) δ=7.07 (s, 2H), 6.16 (s, 2H), 3.69 (s, 6H), 3.29 –
.11 (m, 4H), 2.88 – 2.71 (m, 4H); 13C NMR (100 MHz, CDCl
) δ=158.0,
and the mixture was refluxed for 2 h. After cooling to room temperature,
the suspension was filtered and washed with water (3 mL). Aqueous layer
was acidified to pH 1 by the addition of hydrochloric acid. The precipitate
3
1
3
41.3, 134.7, 128.6, 117.6, 116.0, 55.7, 34.3, 28.1; HRMS (APCI-TOF)
+
m/z: Calcd for C18H19Br
O
2 2
[M+H] 424.9746, found 424.9734.
was separated by filtration and after washing with CH Cl
2
2
(1 mL) and water
(3
mL) dried on air to yield pure (R )-4,12-dibromo-7,15-
P
dicarboxy[2.2]paracyclophane ((R
P
)-12) (0.274 g, 0.60 mmol, 85%) as a
20
1
white solid. m.p. 186-187°C; [α] = +167 (c=0.3, in DMSO); H NMR (400
Acknowledgements
D
MHz, DMSO-d
6
) δ=12.91 (bs, 2H), 7.18 (s, 2H), 7.15 (s, 2H), 3.82 (dd, J =
2.1, 9.4 Hz, 2H), 3.24 (dd, J = 12.8, 9.2 Hz, 2H), 3.10 – 2.97 (m, 2H), 2.97
2.85 (m, 2H); 13C NMR (100 MHz, DMSO-d
) δ=167.0, 143.4, 139.0,
1
–
1
This work was partially supported by Atatürk University (Projects
FAD-2017-6107 and FAD-2019-7025).
6
35.1, 134.5, 131.0, 129.9, 34.3, 32.0; HRMS (ESI-TOF) m/z: Calcd for
+
18
C H14Br
2
NaO
4
[M+Na] 474.9151, found 474.9144.
Keywords: Benzal chlorides • Chiral resolution • Cyclophanes •
Planar chirality • Rieche formylation
(
R
P
)-4,12-Diamino-7,15-dibromo[2.2]paracyclophane ((R
P
)-13)
(
0
R
P
)-4,12-dibromo-7,15-dicarboxy[2.2]paracyclophane ((R
. Two drops of DMF were added,
then the mixture was refluxed for 1 h. Excess SOCl was removed under
P
)-12) (0.275 g
[
[
1]
2]
C. J. Brown, A. C. Farthing, Nature 1949, 164, 915-916.
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.585 mmol) was dissolved in 5 mL SOCl
2
2
reduced pressure to give the corresponding acyl chloride (0.285 g, 0.580
mmol, 99%). Without any further purification the corresponding acyl
chloride was used in the next step. The crude acyl chloride was dissolved
in acetone (20 mL) and the mixture was cooled to 0 °C. To this cooled
mixture was added a solution of NaN
at 0 °C for 1 h. The reaction mixture was then diluted with H
extracted with diethyl ether (3x20 mL). The combined organic phases were
dried over MgSO and concentrated under reduced pressure. The
corresponding acyl azide (0.277 g, 0.550 mmol, 95%) was obtained as a
white solid and used without further purification. H NMR (400 MHz, CDCl
δ=7.24 (s, 2H), 7.17 (s, 2H), 3.99 – 3.92 (m, 2H), 3.46 – 3.31 (m, 2H), 3.13
–
[3]
3
2
in H O (10mL) dropwise and stirred
[
4]
2
O (10mL) and
4
1
3
)
[
5]
2.93 (m, 4H); 13C NMR (100 MHz, CDCl
35.1, 132.9, 130.3, 34.8, 32.4. Toluene (8 mL) was added to the obtained
3
) δ=172.0, 144.7, 140.0, 135.8,
1
acyl azide, and the solution was refluxed for 1 h. The solvent was
[6]
[7]
[8]
M. Cakici, Z. G. Gu, M. Nieger, J. Burck, L. Heinke, S.
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evaporated under reduced pressure and the almost pure isocyanate
1
(
0.237 g, 0.530 mmol, 96%) was obtained as a white solid. H NMR (400
6430-6437.
3
MHz, CDCl ) δ=7.18 (s, 2H), 6.54 (s, 2H), 3.36 – 3.29 (m, 2H), 3.17 – 3.10
m, 2H), 2.95 – 2.82 (m, 4H); 13C NMR (100 MHz, CDCl
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J Am Chem Soc 2014, 136, 3350-3353; b) M. Gon, Y.
Morisaki, Y. Chujo, Eur. J. Org. Chem. 2015, 2015, 7756-
(
3
) δ=140.7, 135.5,
135.0, 133.3, 128.6, 128.5, 123.6, 33.8, 29.6. The obtained isocyanate
was dissolved in EtOH (15 mL) and the solution was refluxed for 2 h.
Aqueous potassium hydroxide solution (5 mL, 20%) was added and further
continued reflux for 45 h. The reaction mixture was cooled to room
temperature and poured into 30 mL of ice-cold potassium hydroxide
solution (20%). The precipitated off-white solid was collected by filtration,
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P
washed with water and air-dried to give (R )-4,12-diamino-7,15-
dibromo[2.2]paracyclophane ((R )-13) (0.170 g, 0.430 mmol, 81%). The
P
2
0
overall yield for the four-step sequence was 74%. m.p. 151-153°C; [α]
=
D
1
–
82 (c=0.33, in CH
2
Cl
2
); H NMR (400 MHz, CDCl
3
) δ=6.98 (s, 2H), 6.25
s, 2H), 3.44 (bs, 4H), 3.21 – 3.05 (m, 2H), 2.94 – 2.74 (m, 6H); 3C NMR
1
(
(
100 MHz, CDCl
3
) δ=144.6, 139.5, 134.7, 125.8, 118.4, 115.3, 32.7, 29.1;
[M+H]+ 394.9753, found
HRMS (ESI-TOF) m/z: Calcd for C16
2 2
H17Br N
7, 232-238; e) J. Anhäuser, A. Lützen, M. Engeser,
394.9745.
ChemPlusChem 2020, 85, 2528-2533; f) J. Anhäuser, R.
Puttreddy, L. Glanz, A. Schneider, M. Engeser, K.
Rissanen, A. Lützen, Chem. Eur. J. 2019, 25, 12294-
(
R
P
)-4,12-Dibromo-7,15-dimethoxy[2.2]paracyclophane ((R
P
)-14)
1
2297; g) Y. Lorenz, J. Anhäuser, A. Lützen, M. Engeser,
To a stirred solution of (R
P
)-1 (42 mg, 0.1 mmol) in 3 mL of CH
2
Cl
2
/MeOH
J. Am. Soc. Mass Spectrom. 2019, 30, 2007-2013; h) G.
Meyer-Eppler, F. Topić, G. Schnakenburg, K. Rissanen, A.
(1:1) were added concentrated H
2
SO (1 drop) and H (30 µL, 50% in
4
2 2
O
6
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202100762
FULL PAPER
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7
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European Journal of Organic Chemistry
10.1002/ejoc.202100762
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Regioselective preparation of tetrasubstituted [2.2]paracyclophanes, which are useful planar chiral building blocks for various
functional materials, is a difficult task. We report a new efficient synthetic route for obtaining bis-(para)-pseudo-ortho and bis-(para)-
pseudo-meta type tetrasubstituted [2.2]paracyclophanes. We evaluate the optical resolution and some useful transformations.
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