Synthesis of Unexpected trans-meso Macrocycle from Novel Unsymmetrical Tetraphenylene

Article abstract of DOI:10.1055/s-0035-1561480

A highly unsymmetrical trisubstituted tetraphenylene was designed and synthesized as a novel superamolecular scaffold for an unexpected trans-meso tetraphenylene macrocycle, whose structure was unequivocally characterized by an X-ray crystallographic anal

Full text of DOI:10.1055/s-0035-1561480

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C.-L. Deng et al.
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Synthesis of Unexpected trans-meso Macrocycle from Novel
Unsymmetrical Tetraphenylene
Chun-Lin Denga
Sam C. K. Hauc
Xiao-Shui Penga,b
Henry N. C. Wong*a,b
a
Department of Chemistry & State Key Laboratory of Synthetic
Chemistry, The Chinese University of Hong Kong, Shatin, New
Territories, Hong Kong SAR, P. R. of China
hncwong@cuhk.edu.hk
b
Shenzhen Municipal Key Laboratory of Chemical Synthesis of Me-
dicinal Organic Molecules & Shenzhen Center of Novel Functional
Molecules, Shenzhen Research Institute, The Chinese University of
Hong Kong, No. 10, 2nd Yuexing Road, Shenzhen 518507, P. R. of
China
c
Department of Chemistry, Hong Kong Baptist University, Kowloon
Tong, Kowloon, Hong Kong SAR, P. R. of China
Received: 03.05.2016
Accepted after revision: 21.05.2016
Published online: 23.06.2016
DOI: 10.1055/s-0035-1561480; Art ID: st-2016-w0311-c
Abstract A highly unsymmetrical trisubstituted tetraphenylene was
designed and synthesized as a novel superamolecular scaffold for an
unexpected trans-meso tetraphenylene macrocycle, whose structure
was unequivocally characterized by an X-ray crystallographic analysis.
With the defined and electron-rich aromatic cavity, this macrocycle
could be further modified to be a potential host for organic cations with
biological interest.
Figure 1 Tetraphenylene
ever, versatile supramolecular scaffolds with rigid struc-
tures and specific properties, especially those in enantio-
merically pure forms, are still in great demand.
Key words tetraphenylene, nonplanar hydrocarbon, macrocycle,
host-guest chemistry, cation π interactions
Recently, through a palladium-catalyzed cross-coupling
reaction, we have successfully synthesized 2,11-dihydroxy-
Tetraphenylene is a rigid molecule featuring a saddle-
shaped scaffold in which all the benzene rings are alter-
nately oriented above and below the average plane of the
molecule (Figure 1). Although tetraphenylene is an achiral
molecule, the introduction of substitution groups reduces
4e
tetraphenylene as a novel supramolecular synthon. Its
perfect curvature provides the possibility of leading to the
construction of a new type of oxacalixarene analogues,
which can efficiently interact with fullerenes in the solu-
tion state. However, even if this module is very promising,
there are still some limitations in its further applications. In
the search for chiral hosts with much larger size of cavities
derived from tetraphenylene derivatives, we found that the
functional positions of tetraphenylenes are of vital impor-
tance. Eventually, based on the basic molecular modeling, a
highly unsymmetrical 2,7,10-trisubstituted tetraphenylene
1 shows potential to satisfy the aforementioned require-
ment (Figure 2).
Compound 1 possesses an O···O distance of 8.3 Å and a
bite angle of ca. 120° between the 2,10-disubstituted posi-
tions. From a geometrical point of view, these features are
ideal for the synthesis of larger macrocylces. Moreover, the
presence of additional functionality in the 7-position can
be used for further modification in order to extend relevant
applications and further developments. More importantly,
1
the D -symmetry of the parent tetraphenylene and there-
2d
fore substituted tetraphenylenes can be chiral. With the
nonplanar aromatic systems and inherent chirality, tetra-
phenylene derivatives and their optical antipodes have at-
tracted considerable attention not only for their fascinating
structure and theoretical interest, but also for their funda-
mental and prospective applications in constructing helical
2
2a,3
macrocyclic architectures, asymmetric catalysis,
molec-
4
5
6
ular recognition, molecular device, and materials science.
Over the past decades, macrocyclic chemistry is well
developed and many synthetic macrocycles with different
size of cavities, shapes, and binding properties were report-
ed. Various nonplanar hydrocarbon macrocyclic frame-
7
,8
works such as cyclotriveratrylene (CTV),
triben-
and iptycenes have contributed
to satisfactory performance of host-guest interaction. How-
9,10
11
zotriquinacene (TBTQ),
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B
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C.-L. Deng et al.
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OH
OH
unsymmetrical diiodobiphenyl 6. After protection of the
2
free hydroxyl with an isopropyl group, the desired biphenyl
1
7
was finally obtained in 89% yield for further Suzuki cross-
coupling reaction. It is noteworthy to point out that the re-
placement of methyl group with isopropyl group can be
able to meet all requirements of tolerance, solubility, and
stability, especially for the differentiation of methoxy and
isopropoxy groups for further selective deprotection. Final-
ly, compound 7 was successfully transformed to pinacol bo-
rate 8 in 33% yield.
7
R
R
10
OH
HO
1
'
chiral'
1
a: R = OTf
A Suzuki cross-coupling between 913 and 1014 led to bi-
phenyl 11 in 91%, as shown in Scheme 2. After removal of
the acetyl group and subsequent reduction in the presence
of Zn/AcOH, diamine 12 was finally obtained in 62% yield.
Moreover, making use of a similar diazotization conditions
for the synthesis of 5, diiodobiphenyl 13 was likewise pro-
duced in a moderate yield. Thus, we turn to the synthesis of
tetraphenylene 1a. With 8 and 13 in hand (Scheme 3), upon
Suzuki coupling conditions, two tetraphenylene isomers
14a and 14b were achieved as an inseparable mixture in
moderate yield. In order to purify tetraphenylenes 14a and
14b, the isopropyl group in compound 14 was selectively
Figure 2 The structure of 2,7,10-trisubstituted tetraphenylene
the unsymmetrical distribution of substituted sites could
make tetraphenylene 1 inherently chiral, which can be used
to synthesize novel chiral macrocyclic hosts through either
resolution of enantiomers or asymmetric synthesis. Accord-
2c,4e
ing to our own synthetic protocols,
the synthesis of
2,10-dihydroxytetraphenylene 1 could be achieved using a
Suzuki cross-coupling of unsymmetrical diiodobiphenyl
and diborate biphenyl partners.
As depicted in Scheme 1, commercially available aniline
2
was first converted into iodide 3, which was then allowed
removed with BCl . Although the resulting mixtures 15a
3
to undergo Ullmann dimerization to form 4 in good overall
yields. Then, subjection of 4 to catalytic hydrogenation led
to the formation of the relevant diamine in quantitative
yield, which could be used in the next step without further
purification. Deploying a known diazotization method,12
the diamine was subsequently converted into diiodide 5 in
a moderate yield, which was treated with one equivalent of
and 15b were still inseparable using column chromatogra-
phy, the free hydroxyl group and methoxyl group in com-
pounds 15 would afford a feasible access for the modifica-
tion of their polarities for further purification. To this end,
compound 15 was firstly treated with Tf O to give triflates
2
16. Without further purification, 16 was subsequently sub-
jected to BBr , affording column-separable tetraphenylenes
3
BBr to selectively remove one of methyl groups to form an
1a and 17 in acceptable yields.
3
OMe
OMe
OMe
HCl, NaNO2, 0 °C
1. Pd-C, H2, EtOAc, r.t.
NO2
Cu
then KI
1%
DMF, reflux
70%
NO2
2
. HCl, MeCN, NaNO2,
NO2
NO2
–10 °C; then KI, 0 °C to 80 °C
9
NH2
I
49% over 2 steps
OMe
2
3
4
OMe
OH
Oi-Pr
Oi-Pr
1
. n-BuLi
BBr3 (1equiv)
CH2Cl2
i-PrBr, K2CO3
2. B(OMe)3
I
I
I
I
I
I
B(Pin)
B(Pin)
DMF, 50 °C
3. 2 N HCl
4. pinacol,
toluene, reflux
33%
–78 °C to r.t.
89%
89%
OMe
OMe
OMe
O
OMe
B
8
5
6
7
B(Pin)=
O
Scheme 1 Synthesis of biphenyl 8
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C
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C.-L. Deng et al.
Cluster
OMe
OMe
OMe
NO2
1. 6 M HCl, MeOH,
reflux
B(OH)2
Pd(PPh3)4, CsF
DME, 70 °C
NO2
NH2
NH2
9
NHAc
2. Zn, AcOH, r.t.
I
62%
91%
NHAc
11
12
10
OMe
HCl, MeCN, NaNO2,
–
10 °C
I
I
then KI, 0 °C to 80 °C
8%
5
13
Scheme 2 Synthesis of biphenyl 13
The structures of these two compounds were confirmed
peptides through cation–π interaction and multiple nonco-
valent interactions. Therefore, we planned to prepare a
model host with racemic 1a for initial studies.
1
13
16
by H NMR and C NMR spectroscopy, as well as by high-
15
resolution mass spectrometry. Thus, the designed racemic
,7,10-trisubstituted tetraphenylene 1a was successfully
prepared.
Since the three-dimensional tetraphenylene scaffolds in
2
As demonstrated in Scheme 4, compound 1a underwent
cyanation to give 18 in 51% yield according to a well-estab-
lished method.2b The cyano group is crucial for further
modification. Next, compound 18 was converted into dibro-
mo compound 19 in 70%, which was subsequently allowed
to react with one equivalent of 18 in the presence of a large
excess of Cs CO in MeCN, furnishing the dimeric product
compound 1a may provide a macrocyclic rigid and pocket-
like conformation, we reason that the covalent linkage of
two building blocks could mimic the biological aromatic
cavity efficiently bound to posttranslationally methylated
2
3
i-PrO
R1
HO
R1
Pd(dppf)2Cl2, K2CO3
BBr3
8
+ 13
DME–H2O, 80 °C
0%
CH2Cl2, –85 °C
9%
2
9
R2
R2
MeO
MeO
4a, R1 = H, R2 = OMe
4b, R1 = OMe, R2 = H
1
2
1
1
15a, R = H, R = OMe
1
2
15b, R = OMe, R = H
TfO
R1
TfO
TfO
OH
Tf2O, pyridine
CH2Cl2, 0 °C to r.t.
5%
BBr3
+
CH2Cl2
78 °C to r.t.
–
8
R2
MeO
HO
OH
HO
1
2
1a, 48%
1
1
6a, R = H, R = OMe
17, 47%
1
2
6b, R = OMe, R = H
Scheme 3 Synthesis of 1a
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D
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C.-L. Deng et al.
Cluster
TfO
OH
NC
O
OH
NC
Br
Pd(PPh3)4, Zn(CN)2
DMF, 150 °C
1%
BrCH2CH2Br
Cs2CO3, acetone
70%
5
HO
HO
O
1a
18
19
Br
NC
+
18
Cs2CO3
O
MeCN, reflux
O
O
other dimeric isomers
O
23%
CN
trans-meso-20, 10%
Scheme 4 Synthesis of 20
2
0 with some unconfirmed dimeric isomers in 33% overall
as illustrated in Figure 4 (b). Based on the crystal structure,
the calculated electrostatic potential surface of dimer sug-
gested that the defined cavity with aromatic walls was elec-
tron-rich (Figure 4, c). It seems reasonable to assume that
20 could efficiently host electron-deficient organic cations.
17
yield. These isomers were not easy to purify using column
chromatography, probably due to their asymmetry and the
inherent chirality of the tetraphenylene subunit. However,
to our delight, a single dimeric isomer 20 was obtained
with a yield of 10% employing column chromatography. The
isolated pure dimeric isomer 20 was fully characterized by
1
13
H NMR, C NMR, and HRMS spectra.
Gratifyingly, the single crystal of the dimeric isomer 20
was obtained by slow evaporation of an ethyl acetate solu-
18
tion of 20. The ORTEP drawing structure of the dimeric
isomer 20 in Figure 3 unequivocally indicated that the iso-
lated dimeric cyclic isomer 20 was the trans-dimer in meso
form of R,R,S,S.
Figure 4 (a) Cavity size; (b) illustration of solvent molecules interact-
ing with 20 via hydrogen bonding; (c) the electrostatic potential sur-
face calculated at PM6 level of theory, Spartan ’14, Wavefunction Inc.
Figure 3 ORTEP drawing of 20 showing thermal ellipsoids at the 40%
probability level, solvent molecular and hydrogen atoms were omitted
for clarity
It is worth mentioning that 20 cannot be directly uti-
lized to investigate binding events with methylated pep-
tides because of its bad solubility in biological relevant
solution such as water or DMSO. Nevertheless, from the
synthetic point of view, the cyano group in 20 could be fac-
ilely transformed into carboxylates or further functional-
ized with glycoside, which would provide good solubility in
aqueous medium.
The crystal structure of 20 adopted a highly symmetric
and parallelogram-shaped structure in solid state. Solvent
ethyl acetate was co-crystallized in the lattice and interact-
ed with the dimeric ring compound through two weak C–
H···O bond (dC–H···O=2.55, 2.64 Å, respectively). The cavity
size was found to be ca. 7.9 Å in width and 7.1 Å in height,
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

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C.-L. Deng et al.
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In summary, through a palladium-catalyzed Suzuki cou-
pling reaction, we have synthesized a highly unsymmetrical
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could be obtained without enantiomeric resolution of 1a.
We believe that these results will be helpful for the design
and construction of other unique supramolecular architec-
tures. On the other hand, our continued work towards fur-
ther modifications and recognition ability of dimeric hosts
for organic cations are under way in our laboratories.
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1
Acknowledgment
This work was supported by an Area of Excellence Scheme estab-
lished under the Research Grants Council of the Hong Kong SAR, Chi-
na (Project No. AoE/P-03/08), as well as a grant to the State Key
Laboratory of Synthetic Chemistry from the Innovation and Technolo-
gy Commission, and the Research Grants Council of Hong Kong (CRF
C4030-14G) and Faculty of Science, The Chinese University of Hong
Kong (Scheme I). Grants from the National Natural Science Founda-
tion of China (NSFC No. 21272199), The Chinese Academy of Scienc-
es–Croucher Foundation Funding Scheme for Joint Laboratories, the
Shenzhen Science and Technology Innovation Committee for the Mu-
nicipal Key Laboratory Scheme (ZDSY20130401150914965), and the
Shenzhen Basic Research Program (JCYJ20140425184428455) are
also gratefully acknowledged.
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10) For recent examples, see: (a) Bredenkötter, B.; Grzywa, M.;
Alaghemandi, M.; Schmid, R.; Herrebout, W.; Bultinck, P.;
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561480.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
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(
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C.-L. Deng et al.
Cluster
(
17) Experimental Procedure for the Synthesis of 20
119.0, 116.8, 116.3, 113.7, 113.0, 111.3, 67.3. ESI-MS: m/z = 797
+
+
Under an argon atmosphere, a mixture of 18 (13 mg, 0.035
mmol), 19 (20 mg, 0.035 mmol), and Cs CO (114 mg, 0.35
[M + Na] . ESI-HRMS: m/z calcd for C54H34N O Na [M + Na] :
2 4
797.2411; found: 797.2401.
2
3
–2
mmol) in dry MeCN (10 M, 4 mL) was stirred at 90 °C for 48 h.
The mixture was cooled to room temperature, and the solvent
was removed. The crude residue was dissolved in a mixture of
CH Cl and water. The organic layer was separated, washed with
(18) X-ray Crystallographic Data for 20
C54H34N O , M = 774.88, monoclinic, P2(1)/c, a = 10.7287(5) Å,
2
4
b = 23.4747(11) Å, c = 10.5235(5) Å, α = 90°, β = 106.5140(10)°,
3
–3
γ = 90°, T = 173(2) K, V = 2541.0(2) A , Z = 2, ρ (mg mm ):
2
2
calc
–1
water and then brine, dried over Na SO , and concentrated
1.243, absorption coefficient = 0.082 mm , F(000) = 1000,
crystal size: 0.50 × 0.40 × 0.30 mm, 2θ range for data collection:
1.73 to 25.25°, reflections collected: 58557, independent reflec-
2
4
under reduced pressure. The crude product was purified by
column chromatography over silica gel (10 g, eluting with PE–
CH Cl , 5:2) to give the product 20 (3 mg, 10%) as a white solid.
tions: 4601 [R(int)
=
0.0229], data/restraints/parameters:
2
2
1
2
R = 0.21 (PE–CH Cl , 5:2); mp >250 °C. H NMR (400 MHz, CD -
4601/0/325, goodness-of-fit on F : 1.075, final R indexes [I > =
2σ (I)]: R1 = 0.0432, wR2 = 0.1261, final R indexes [all data]: R1
= 0.0478, wR2 = 0.1323, largest diff. peak and hole: 0.405 and –
f
2
2
2
Cl ): δ = 7.55 (dd, J = 8.0, 1.7 Hz, 2 H), 7.38 (d, J = 1.8 Hz, 2 H),
2
7
1
.29–7.24 (m, 6 H), 7.16 (dd, J = 7.4, 1.7 Hz, 2 H), 7.07–6.97 (m,
0 H), 6.61 (d, J = 2.4 Hz, 2 H), 6.57 (d, J = 2.4 Hz, 2 H), 4.48–4.44
–3
0.342 e A . CCDC-1476587 contains the supplementary crys-
tallographic data for 20. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
13
(
m, 4 H), 4.30 (br s, 4 H). C NMR (100 MHz, CD Cl ): δ = 158.2,
2 2
1
1
57.7, 146.3, 143.2, 142.9, 141.3, 140.8, 140.6, 134.8, 133.3,
32.9, 131.3, 130.8, 130.3, 130.2, 129.4, 129.4, 128.1, 127.6,
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F