Synthesis of tri-arylated cyclotriveratrilenes with ortho- and meta-extended functionality

Article abstract of DOI:10.1016/j.tetlet.2015.12.030

Aromatic nucleophilic substitution reaction between cyclotriguaiacylene and ortho- or meta-functionalized fluoroarenes affords a series of ortho- or meta-extended cyclotriveratrilene (CTV) cavitands. Further transformation of the functional groups into NH

Full text of DOI:10.1016/j.tetlet.2015.12.030

Tetrahedron Letters 57 (2016) 233–236
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of tri-arylated cyclotriveratrilenes with ortho- and
meta-extended functionality
Kouhei Ito a, Michael P. Schramm b, Mao Kanaura a, Masataka Ide a, Naoki Endo a, Tetsuo Iwasawa a,
⇑
a Department of Materials Chemistry, Faculty of Science and Technology, Ryukoku University, Otsu, Shiga 520-2194, Japan
b Department of Chemistry and Biochemistry, California State University Long Beach, 1250 Bellflower Blvd., Long Beach, CA 90840, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Aromatic nucleophilic substitution reaction between cyclotriguaiacylene and ortho- or meta-functional-
ized fluoroarenes affords a series of ortho- or meta-extended cyclotriveratrilene (CTV) cavitands. Further
transformation of the functional groups into NH and/or OH moieties has been demonstrated. This enabled
us to prepare an amphoteric water-soluble cavitand bearing anilino-NH2 and phenolic-OH substituents.
In addition, one molecular structure was successfully determined by crystallographic analysis, which
suggests an extended/flattened structure. We propose that vase-shaped conformations with inwardly
directed functional groups will soon be possible with the CTV scaffold.
Received 28 October 2015
Revised 26 November 2015
Accepted 7 December 2015
Available online 8 December 2015
Keywords:
Cyclotriguaiacylene
Supramolecular capsule
Cyclotriveratrilene
Water-soluble cavitand
Introverted functionality
Ó 2015 Elsevier Ltd. All rights reserved.
Natural receptors like enzymes have functional groups oriented
inwardly for molecular recognition.1,2 Amino acid functional
groups converge to create reactive sites inside the hydrophobic
pockets, and part of the pockets remains open so that guests can
sample the space, enter and leave. Thus they serve as well-
organized chemical cavity for performing biological operations,
and most assemblies operate in aqueous media.3 Inspired by these,
chemists have quested for syntheses of artificial cavitands bearing
functional groups inside chemical spaces, and water-soluble cavi-
tands.4,5 For example, Rebek group has invented a type of inwardly
functionalized resorcin[4]arene-based cavitands, and water-
soluble cavitands. The former provides a reactive site which con-
verges onto the concave surface, and the latter hydrophobic space
in water.6 Those cavitands have been employed as a tool of
chemical reactions for understanding facets of bio-relevant phe-
nomena.7–9
During this past decade, our group has focused on the novel
synthesis of inwardly functionalized cavitands which are derived
from a platform of triquinoxaline-spanned resorcin[4]arene. The
template is a rigid scaffold so that functional groups of dialkylsi-
lanes,10 allylsilanes,11 pyridine N-oxide12 point to the cavity;
hence, the functionalized cavitands enabled us to find unique
supramolecular effects in terms of reactivity and encapsulation.
From the viewpoint of rigid macromolecular terminals, a threefold
symmetrical Cyclotriveratrilene (CTV)13 also has intrinsically been
fixed hollow like at the tapered end of resorcin[4]arenes.14 The CTV
macrocycle has been deployed as a hemicryptophane-based cap-
sule with functional groups in its interior pocket;15,16 for example,
Makita and Ogawa prepared a Zinc(II)-induced hemicryptophane
that enhanced chemical catalysis as compared to model com-
plexes.17 One of key features of Makita and Ogawa’s capsule would
exist in the shape of ‘para-extended’ hemicryptophane which is
derived from
a
reaction between para-fluorobenzene and
cyclotriguaiacylene 1 (Scheme 1). The usage of para-substituted
fluorobenzene extended its cavity and provided the capsule with
a rigid framework. Despite such an attractive achievement as a
capsule, CTV has never been developed as an inwardly functional-
ized cavitand. To do so, ‘meta-extended’ or ‘ortho-extended’ CTV
architectures could be effective, because as modelling suggests
the functional groups can point internally (Scheme 2). We
envisioned several applications. With ortho- or meta-positioned
functional groups the potential to bind a central metal could
position a reactive site inside the cavity.10–12 Alternatively, the
tri-functional groups can converge inwardly to recognize a guest
molecule selectively. To the best of our knowledge, few examples
of such a type of CTV-cavity have been reported so far.18 Perhaps
owing to perceived steric hindrance in ‘meta-and ortho-extended’
CTV they haven’t been pursued. Indeed ‘para-extended’ CTV has
been reported by Pochini in 2004.19
We present a synthetic study to prepare ‘meta- and/or ortho-
extended’ CTV-cavitands. First, three molecules of ortho- and/or
⇑
Corresponding author. Tel.: +81 77 543 7461; fax: +81 77 543 7483.
E-mail address: iwasawa@rins.ryukoku.ac.jp (T. Iwasawa).
http://dx.doi.org/10.1016/j.tetlet.2015.12.030
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

234
K. Ito et al. / Tetrahedron Letters 57 (2016) 233–236
and yielded 6 in 60% and 7 in 75%. This SNAr for ortho-extended
CTV compounds except the preparation of 5 is readily amenable
to multi gram-scale (entry 1).
The substituents at ortho-positions of 2–4 were readily con-
verted into electron-donating groups as NH2 and OH (Scheme 3).
For the reduction of nitro 2 to aniline 8, conventional hydrogena-
19
tion utilizing NH2NH2 and/or gaseous H2 in the presence of cat-
alytic amount of Pd/C were tried; however, both reactions were
very sluggish.21 Finally, addition of NH4OAc turned out to acceler-
ate and complete the reduction within 1 h to give 8 (Scheme 3a).22
Furthermore this conversion can provide a one-pot protocol for
mono-alkylation of 8 to synthesize 9: an appropriate amount of
CH3CN was sequentially added to the reaction mixture of 8. Careful
addition of CH3CN and TLC monitoring readily furnished 9 in mod-
erate 50% yield. Reduction of 3 needed with LiAlH4 (6 equiv)
yielded 10 in 55% Scheme 3b. For Scheme 3c, while the solvent of
CH2Cl2/ethanol scarcely dissolved the aldehyde 4, prolonged reac-
tion time completed the reduction by NaBH4 in 86% yield of 11
with giving colourless solution state. For Scheme 3d, Dakin oxida-
tion of 4 proceeded as a overnight reaction, and followed by
hydrolysis to afford 12 in 50% yield. The solubility of 8–12 in
organic solvents was drastically improved compared to the parent
2–4.
Scheme 1. Synthesis of ‘para-extended’ cyclotriveratrilenes.
Crystals of benzyl alcohol 11 were obtained by slow diffusion of
a solution of compounds in CH2Cl2/CH3CN.23 The X-ray crystal
structure analysis shows ortho-positioned moieties of CH2OH are
randomly floating and doesn’t form intra-molecular hydrogen
bonds between OH and OCH3 (Fig. 1a). Instead from the view point
of head-to-head arrangement in crystal lattice (Fig. 1b), one mole-
cule makes a pair with another through one hydrogen bonding
between mutual two CH2OH groups, and embraces partner’s one
phenyl moiety. This indicates pi-donor ability of three phenyl rings
of CTV skeleton 11 attracts the counter phenyl moiety.
Scheme 2. Representation of (a) ‘meta-extended’ or (b) ‘ortho-extended’
cyclotriveratrilenes for embodiment of inwardly functionalized CTV-cavitands.
meta-substituted fluoroarenes reacted with three phenolic OH of
triguaiacylene 1; then, further transformations of the ortho- and/
or meta-positioned substituents produced newly extended CTV
functionalized with amino or hydroxy groups. These studies
enabled us to characterize an extended solid-state structure and
to provide a molecular design of novel water-soluble amino-phe-
nol cavitand.
Nucleophilic aromatic substituent reactions (SNAr) in DMF with
K2CO3 were performed between 120 and ortho-substituted fluo-
roarenes (Table 1). For entries 1–3, electron-withdrawing groups
of NO2, CN, and CHO facilitated the SNAr reactions, giving CTV ana-
logues 2, 3, and 4 in from 81% to 93% yield. Compared to SNAr uti-
lizing para-substituted fluorobenzenes reported by Pochini in
2004,19 ortho-substituted fluorobenzenes have similar reactivity.
However, for entry 4, methyl ester group that is less electron-with-
drawing was not an efficient reaction partner, only yielding 19% of
5 even with prolonged heating. For entries 5 and 6, nitriles fluo-
ropyridines reacted with 1 under a more mild heating of 90 °C,
Table 1
Reaction of 1 with ortho-substituted fluoroarenes
Entry
X
X0
R
Temp (°C) Time (h) Product % yielda
1
2
3
4
5
6
C
C
C
C
N
C
C
C
C
C
C
N
NO2
CN
CHO
CO2CH3 150
CN
CN
150
150
150
4
4
2.5
24
2
2
3
4
5
6
7
93 (2.37 g)
81 (2.32 g)
91 (2.62 g)
19 (461 mg)
60 (1.52 g)
75 (1.66 g)
90
90
5
Scheme 3. Synthesis of ortho-functionalized CTV derivatives; (a) anilines 8 and 9,
(b) benzylamine 10, (c) benzylalcohol 11, and (d) phenol 12.
a
Actual formations in parenthesis.

K. Ito et al. / Tetrahedron Letters 57 (2016) 233–236
235
Scheme 4. Synthesis of meta-functionalized CTV derivatives; (a) aniline 14, and (b)
amphoteric CTV 15.
Scheme 3a was successfully applicable to give 14 in 47% yield
(Scheme 4a). Then we envisioned synthesis of water-soluble CTV
15 that possesses amphoteric substructures of –NH2 and –OH.
The demethylation step of 13 needed heat condition at 90 °C to
give the corresponding phenol in moderate 50% yield, and the
following reduction step smoothly proceeded in the presence of
NH4OAc, and purification by simple reprecipitation from EtOAc/
Hexane yielded 15 in 82% (Scheme 4b).24 Thus, the water-soluble
15 is endowed with basic NH2 and acidic OH at the upper rim of
the CTV skeleton. With these results we predict future application
of 15 may provide a unique hydrophobic concave shape in aqueous
media.25
With a viable protocol in hand for the preparation of ortho- and
meta-extended CTV, we have explored possibility for binding with
a transition metal like representation in Scheme 2. Not only transi-
tion metal-sources of Mo and Ti but also nonmetal precursors of
Boron, Aluminium, Silicon, and Phosphorus were attempted to
react with ortho-extended 9–11, and meta-extended 14: however,
at this time, desired complexes were not observed while the start-
ing CTV compounds were consumed on TLC monitoring. Some
were found but not isolated successfully, owing to the thermody-
namically unstable condition caused by steric hindrance.
In summary, the successful arrangement of NH and OH groups,
placed at ortho- and/or meta-positions of extended aromatic rings,
affords a new architecture for CTV derivatives. The new CTV arche-
types are prepared with the aim of inward orientation of functional
groups towards the CTV concave surface; actually crystallographic
analysis shows the possibility that such functionalities converge to
create reactive and interactive sites inside the hydrophobic hollow.
Such an inwardly directed functional group of the CTV cavitand
will be a form of synthetic receptor, which can provide a ligand
to make a complex with transition metals and can serve as a host
to recognize guest species. While we envisioned so, this goal has
not yet materialized. Nevertheless an interesting class of com-
pounds was made for future study. Towards the goal of synthetic
receptors based on these ortho- and/or meta-extended CTV cavi-
tands, further synthetic developments are ongoing and will be
reported in due course.
Figure 1. ORTEP drawing of 11 with thermal ellipsoids at the 50% probability level,
and hydrogen atoms are omitted for clarity; (a) perspective view showing the one
disordered acetonitrile molecule residing nearby a benzyl alcohol moiety, and (b)
head-to-head arrangement in the crystal lattice (the acetonitrile is omitted for ease
of view).
Next, SNAr reaction of 1 with meta-substituted fluorobenzenes
was demonstrated (Table 2). For entry 1, 1-fluoro-3-nitrobenzene
needed overnight to complete the reaction, and purification of
recrystallization from propionitrile yielded 1.57 g of desired nitro
13 in 51% yield. For entries 2 and 3, the starting 1-fluoro-3-
cyanobenzene or 1-fluoro-3-formylbenzene disappeared on TLC
monitoring; however, the crude products resulted in complicated
mixtures. Further transformation of nitro 13 was attested in
Scheme 4, and mono-alkylation procedure of ortho-version 2 in
Table 2
Reaction of 1 with meta-substituted fluorobenzene
Acknowledgments
We thank the Japan Society of the Promotion of Science
Invitation Fellowships for Research in Japan (Long-term, L-15528,
M.P.S). The authors thank Dr. Toshiyuki Iwai and Dr. Takatoshi
Ito for assistance with HRMS. Prof. Dr. Ken-ichi Yamada,
Prof. Dr. Yosuke Yamaoka, and Prof. Dr. Kiyosei Takasu are grate-
fully thanked for gentle assistance in crystallographic analysis.
Entry
R
Product
% yielda
1
2
3
NO2
CN
CHO
13
—
—
51 (1.57 g)
—
—
a
Actual formations in parentheses.

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K. Ito et al. / Tetrahedron Letters 57 (2016) 233–236
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23. CCDC-1400888 (foe 11) contains the supplementary crystallographic data for
this Letter. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Triclinic, space group P-1, colourless, a = 8.736(6) Å, b = 15.859(5) Å,
c = 16.012(14) Å,
a
= 115°, b = 102°,
c
= 94°, V = 1931(3) Å3, Z = 2, T = 93 K,
R1 = 0.0434, wR2 = 0.1620,
Dcalcd = 1.321 g cm–3
,
l
(Mo-K ,
a
) = 0.742 mm–1
GOF = 1.107.
24. Opposite order of the transformation that is the first reduction and the second
demethylation didn’t work well.
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2377.