Hexaphenolic Rigid Cages Prepared by Self-Organization of C 3v Tridentates

Article abstract of DOI:10.1021/acs.joc.7b03111

Coordination cages were composed by self-organization of rigid C_3v-symmetric heptaarene tridentates and Pd(II) precursors. The heptaarene framework involves one mesitylene, three phenol, and three pyridine moieties, which were connected by Suzu

Full text of DOI:10.1021/acs.joc.7b03111

Subscriber access provided by Stockholm University Library
Article
Hexaphenolic Rigid Cages Prepared by Self-Organization of C3v Tridentates
Hajime Abe, Daisuke Hashikawa, Takaya Minami, Kohei Ohtani,
Kentaro Masuda, Shinya Matsumoto, and Masahiko Inouye
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03111 • Publication Date (Web): 23 Feb 2018
Downloaded from http://pubs.acs.org on February 23, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
Hexaphenolic Rigid Cages Prepared by Self-Organization of C3v Tridentates
7
8
9
Hajime Abe,†* Daisuke Hashikawa,† Takaya Minami,‡ Kohei Ohtani,† Kentaro Masuda,† Shinya
Matsumoto,‡ and Masahiko Inouye†*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†Graduate School of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194
‡Graduate School of Environment and Information Sciences, Yokohama National University,
Yokohama, Kanagawa 240-8501
e-mail: abeh@pha.u-toyama.ac.jp
Abstract
Coordination cages were composed by self-organization of rigid C3v-symmetric heptaarene
tridentates and Pd(II) precursors. The heptaarene framework involves one mesitylene, three phenol,
and three pyridine moieties which were connected by Suzuki coupling reactions. The treatment of
the tridentates with Pd(dppp)(OTf)2 or Pd(en)(NO3)2 in a 2:3 molar ratio furnished coordination
cages, which was ascertained by crystallography, 1H NMR and DOSY measurements, and
ESI-TOFMS and UV-vis spectra. The cages have six phenolic hydroxy groups inside and were
expected to incorporate hydrogen-bonding guest molecules such as saccharides. CD and DOSY
measurements showed that octyl hexoside guests could be incorporated into the cage.
Introduction
Construction of cage-type structures has been one of most important projects in the field of
supramolecular chemistry. For this purpose, chemists occasionally utilize self-organization of
appropriate combinations of multidentate ligands with metal center precursors.1−4 The multidentate
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 23
1
2
3
4
5
6
7
8
ligands are usually designed to have rigidity by the use of sp2 and sp-type atoms. Thus, the resulting
cage-type complexes have provided interesting host spaces to recognize, stabilize, and manipulate
guest species.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Meanwhile, our group has so far developed host molecules for saccharide recognition from the
standpoint of host-guest chemistry. Among the host molecules, we have reported a C3v-symmetric
triphenolic compound 1,5 which showed satisfactory affinity for glycosides. The three hydroxy
groups of 1 are forced to direct to one side of the molecule because the rotation of the biaryl bonds is
inhibited by the methyl groups of the mesitylene center. Furthermore, Beletskiy and coworkers
revealed that 1 is effective as a multivalent acidic catalyst.6 Thus the fundamental framework of the
host 1 was found to be suitable for the structure of host molecules, and it is due to the rigidity and
C3v-symmetry to lower the entropic loss caused by host-guest association. We considered that this
framework can also be favorable as parts of self-organizing cage-type complexes.7 Tridental
heptaarene 2 was designed (Figure 1), in which three 4-pyridyl groups were introduced as a
coordinating group preserving the original rigidity and symmetry of 1. The ortho-positions of the
three phenol groups were considered to be suitable for electrophilic iodination followed by
Suzuki-Miyaura coupling. The tridentate 2 was expected to form a M3L2-cage-type complex 3 by the
addition of a metal center (M) precursor. Herein we describe the preparation of tridentate 2 and
construction of cage complex 3. The resulting cages were expected to have D3h or twisting D3
symmetry.2,3 Saccharide recognition by 3 was also studied to make use of the inwardly directed
phenolic hydroxy groups.
Figure 1. (left) Host molecules 1, (center) tridentates 2 and (right) formation of cage-type M3L2
complexes 3 by self-organization.
2
ACS Paragon Plus Environment

Page 3 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Results and Discussion
9
The tridentate 2 has three alkyl groups R to tune solubility, and here we synthesized methyl (2a) and
pentyl (2b) derivatives. The former was used to prepare crystals suitable for X-ray structure analyses,
and the latter was used to study properties in a solution phase.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The
methyl
derivative
2a
was
prepared
via
the
syn
conformer
of
2,4,6-tris(2-hydroxy-5-methylphenyl)mesitylene (1a) as an intermediate. The preparation of 1a
could be carried out in a similar way to the case of the pentyl analogue 1b we previously developed.5
In the route to 1b, the key steps were Suzuki-Miyaura coupling to construct the
2,4,6-tris(2-hydroxyphenyl)mesitylene structure and the thermal atropisomerization of the anti
conformer 6b-anti to a mixture with the syn isomer 6b-syn (Scheme 1).
Scheme 1. Key atropisomerization to prepare 1b (ref 5)
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 23
1
2
3
4
5
6
Scheme 2. Preparation of 1aa
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aDME = 1,2-dimethoxyethane.
Scheme 3. Preparation of tridentates 2a and 2b from 1a and 1ba
aNIS
=
N-iodosuccinimide,
dba
=
dibenzylideneacetone,
SPhos
=
2-(dicyclohexylphosphino)-2’,6’-dimethoxybiphenyl, TFA = trifluoroacetic acid.
4
ACS Paragon Plus Environment

Page 5 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
The preparation route to 2a was shown in Schemes 2 and 3. The Suzuki-Miyaura coupling of
2,4,6-triiodomesitylene5,8 (4) and 2-(methoxymethoxy)-5-methylbenzeneboronic acid9,10 (5a) gave
tetraarene product 6a-anti, conformational isomer of the required intermediate 6a-syn. When a
solution of 6a-anti in o-xylene was heated at 220 °C for 12 h, atropisomerization occurred and the
mixture reached the equilibrium mixture involving 6a-anti and 6a-syn in yields of 67% and 22%,
respectively. The conformers can be separated and purified easily by silica gel column
chromatography because the Rf value of 6a-syn is much smaller than that of 6a-anti. The MOM
groups of 6a-anti were detached by HCO2H, and once the product 1a was isolated as a solid, long
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
preservation at room temperature caused no isomerization to the anti conformer (checked by H
NMR) at least for a year.
Triiodide 7a could be obtained by triple iodination of 1a with N-iodosuccinimide (NIS) at the
ortho-positions of the three phenol units. Then the three hydroxy groups of 7a were protected again
with MOM groups to give 8a, and the Suzuki-Miyaura coupling of 8a with pyridine-4-boronic acid
gave MOM-protected tridentate 9a. Finally, the treatment of 9a with trifluoroacetic acid (TFA)
afforded the target tridentate 2a (Scheme 3).
The target 2b with pentyl groups was prepared from 4-pentylphenol through 1b.5 The synthetic route
from 1b to the target 2b could be carried out similarly to that from 1a to 2a as shown in Scheme 3.
With the target C3v-symmetric tridentates 2a and 2b in hands, we studied the construction of
cage-type M3L2 complexes such as 3a,b by the treatment with Pd(II) precursors (Scheme 4).
Mixtures of the tridentates and Pd(II) precursors were subjected to 1H NMR, DOSY, and
ESI-TOF-MS analyses in organic solutions, and X-ray crystallography of a single crystal.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 23
1
2
3
4
5
6
Scheme 4. Formation of 3a, 3b, and 3c from 2a and 2ba
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
adppp = 1,3-bis(diphenylphosphino)propane, en = ethylenediamine.
The coordination structure in a solid phase could be investigated by using the methyl-tridentate 2a.
Single crystals could be prepared from 2a and Pd(dppp)(OTf)2 (2:3) in a mixed solvent
1,4-dioxane/DMSO (Scheme 5). These colorless crystals were subjected to X-ray structure analyses
and the locations of Pd(II) centers and almost all atoms of 2a and dppp ligands could be determined
(Figure 2),11 whereas positions of solvent molecules and triflate anions were so ambiguous to specify
that the PLATON-SQUEEZE method was applied.12 The targeted cage framework could be assured
in the crystal phase by this analysis. The plane involving three Pd(II) centers was found to be the
symmetry plane of the crystal structure of the cage. The distances between oxygen atoms facing each
6
ACS Paragon Plus Environment

Page 7 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
other were 0.594, 0.639, and 0.641 nm.
7
8
9
Scheme 5. Preparation of 3a from 2a and Pd(dppp)(OTf)2 in mixed solvent of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1,4-dioxane/DMSO
Figure 2. ORTEP diagrams for the crystal structure of 3a.a (left) Side view and (right) top view.
Details for conditions and parameters were described in Experimental and Supporting Information.
aORTEP plot shown with Gaussian ellipsoids at 50% probability level. Enlarged drawings are shown
in Figure S12.
Through the crystallography of 3a, the validity of the cage structure 3 could be demonstrated. Now
the coordination structure in a solution phase was studied by using the pentyl derivative 2b. A
solution of 2b (2.0 × 10−3 M) and Pd(dppp)(OTf)2 (dppp = 1,3-bis(diphenylphosphino)propane, 3.0
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 23
1
2
3
4
5
6
7
8
× 10−3 M) in a mixed solvent CDCl3/CD3OD (9:1 v/v) was subjected to H NMR measurements.
The solubility of 2b in only CDCl3 was not enough for NMR measurements, so that the mixed
solvent of CDCl3/CD3OD was applied here. As mentioned below, the coordinated species of 2b with
Pd(dppp)(OTf)2 showed good solubility in CDCl3. The spectrum of the solution was broadened but
very simple to suggest high symmetry of the resulting species (Figure 3). The signal of protons Ha
(marked as ) at the 2-positions of the pyridine rings shifted downfield probably because of the
coordination of the neighbor nitrogen atoms with Pd(II). On the other hand, the coordination caused
upfield shift to the signal of protons Hb () at the 3-positions most likely by the change of the
dihedral angle between the phenol and the pyridine rings. At the same time, anisotropic upfield shift
was also observed for the signal of protons Hc () at the 5-positions of the phenol rings. 31P NMR
measurement of the 2b/Pd(dppp)(OTf)2 mixture showed a single signal at  −5.87 ppm. The
chemical shift of the 31P NMR signal of Pd(dppp)(OTf)2 was  17.59 ppm, so it was supported that
the cage 3b formed here, in which all the six P atoms are equivalent as a result of the ligand
exchange from triflate to pyridine.
1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. 1H NMR spectra in CDCl3/CD3OD (9:1 v/v) of (a) Pd(dppp)(OTf)2, (b) a mixture of 2b +
Pd(dppp)(OTf)2 in a 2:3 molar ratio, and (c) 2b. The signals for pyridine (Ha () and Hb () in the
structure) and phenol units (Hc () and Hd ()) are marked with open and filled circles and
triangles. Conditions: [2b] = 2.0 × 10−3 M, [Pd(dppp)(OTf)2] = 3.0 × 10−3 M, CDCl3/CD3OD (9:1
v/v), 23 °C, 300 MHz.
8
ACS Paragon Plus Environment

Page 9 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
1
Figure S1 in Supporting Information shows the H NMR spectra of 2b/Pd(dppp)(OTf)2 mixtures in
9
different ratios of 2:3, 2:2, and 2:1 in CDCl3 ([2b] = 2.0 × 10−3 M). Although 2b by itself hardly
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
dissolved in chloroform, the addition of the Pd precursor made the solubility much better. The H
NMR spectra of 2:2 and 2:1 mixtures involve the signal sets of both 2b and the M3L2 complex 3b
independently on the 1H NMR time scale, and the 2:3 mixture showed only one set of the signals of
3b.
In the DOSY analysis of 3b by using a mixture of 2b (1.0 × 10−2 M) and Pd(dppp)(OTf)2 (1.5 × 10−2
M) in CDCl3, all of the C-H signals of 2b and dppp moieties could be assigned to one diffusion
constant D = 2.8 × 10−10 m2s−1 (Figure 4a). This finding indicated that 2b and dppp moieties were
involved in one species, and its Stokes radius was calculated as rs = 1.5 nm from a Stokes-Einstein
equation D = BT / 6  rs. The DOSY analyses of 2b was also carried out in DMSO-d6 and gave D
= 1.3 × 10−10 m2s−1 corresponding to rs = 1.7 nm.
Figure 4. DOSY spectra of (a) 3b (2b/Pd(dppp)(OTf)2 (2:3) mixture) in CDCl3, (b) 2b in DMSO-d6.
Conditions: [2b] = 1.0 × 10−2 M, [Pd(dppp)(OTf)2] = 1.5 × 10−2 M, 25 °C, 400 MHz.
ESI-TOF-MS measurements of 3b were carried out by using a 2:3 molar mixture of 2b and
Pd(dppp)(OTf)2 in CDCl3/MeOH (ca. 1:1). As shown in Figure 5, two kinds of molecular ions
corresponding to the Pd3L2 species, [(2b)2(Pd(dppp))3(TfO)4]2+ (= 3b
−
2TfO−) and
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 23
1
2
3
4
5
6
[(2b)2(Pd(dppp))3(TfO)5]+ (= 3b − TfO−), were observed.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 5. ESI-TOF-MS spectrum of a 2:3 molar mixture of 2b and Pd(dppp)(OTf)2. Sample: 2b (ca.
1 × 10−2 M) and Pd(dppp)(OTf)2 in CDCl3/MeOH (ca. 1:1).
UV-vis spectra were measured for solutions of 2b (1.6 × 10−4 M), Pd(dppp)(OTf)2 (2.3 × 10−3 M),
and 3b (a mixture of 2b (1.6 × 10−4 M) and Pd(dppp)(OTf)2 (2.3 × 10−4 M)) in CH2Cl2 (Figure 6).
The spectrum of 3b was much different from the sum spectrum of the spectra of 2b and the
Pd(dppp)(OTf)2 because of coordination.
10
ACS Paragon Plus Environment

Page 11 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 6. UV-vis spectra in CH2Cl2 of (black solid) 2b (1.6 × 10−4 M), (blue) Pd(dppp)(OTf)2 (2.3 ×
10−4 M), (black broken) the sum spectrum of these two spectra, and (red) 3b, a mixture of 2b (1.6 ×
10−4 M) and Pd(dppp)(OTf)2 (2.3 × 10−4 M). Conditions: CH2Cl2, 23 °C, path length = 1 mm.
The concentration dependence was studied for the UV-vis spectrum of 3b generated from a mixture
2b/Pd(dppp)(OTf)2 (2:3) in CH2Cl2 at a concentration range of [3b] = 6.3 × 10−4 to 3.9 × 10−5
M
(Figure S2). The plots for the absorbance at 283 and 327 nm obeyed linear laws, and no meaningful
concentration dependence was observed for molar absorptivity. Thus, the coordinative organization
of 2b and Pd(II) was strong enough, and no decomposition of the cage framework of 3b occurred in
that concentration range for the study of guest recognition abilities of the cage as mentioned below.
As well as Pd(dppp)(OTf)2, another kind of precursor Pd(en)(NO3)2 (en = ethylenediamine) was
applied.1d The construction of Pd3L2-type cage complex 3c (Scheme 4) was assured in DMSO-d6 on
the basis of 1H NMR and DOSY analyses in a manner similar to the case of 3b (Figures S3 and S4).
Solubility of 3c in apolar solvents such as chloroform and dichloromethane was not enough to
carried out further studies.
A DFT calculation was carried out to study the structure of Pd3L2 cage after the coordination of 2b
and Pd(II) (2:3), and an optimized structure could be obtained as shown in Figure S5 in the
Supporting Information. The distances between opposite pairs of terminal carbons of pentyl groups
were in the range of 2.96−2.82 nm from the structure, which is approximately twice of the Stokes
radius rs calculated from the DOSY analysis mentioned above (Figure 4). In this structure the
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 23
1
2
3
4
5
6
7
8
distances between oxygen atoms facing each other were 0.559, 0.559, and 0.555 nm, slightly short
but not so different from those measured in the X-ray structure of 3a in Figure 2.
9
Molecular recognition targeting glycosides has been one of the important topics in host-guest
chemistry.13−16 The triphenolic compound 1 was originally developed as a host device for saccharide
recognition. Here host ability by the cage complex 3b was also studied by the use of a series of octyl
hexosides, octyl - and -D-glucopyranoside (-Glc and -Glc), octyl - and -D-mannopyranoside
(-Man and -Man), octyl -D-galactopyranoside (-Gal), and octyl -D-fructopyranoside (-Fru)
(Figure S6).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
First, solutions of the cage 3b, generated from a mixtures of 2b (2.0 × 10−3 M) and Pd(dppp)(OTf)2
1
(3.0 × 10−3 M) in CDCl3 with and without -Glc (1.0 × 10−3 M) were prepared and their H NMR
spectra were compared with the 1H NMR spectrum of -Glc (1.0 × 10−3 M) in CDCl3 (Figure 7).

Figure 7. Change of chemical shifts of 1H NMR signals of -glucoside guest. 1H NMR spectra of (a)
3b, (b) 3b + -Glc, and (c) -Glc. Host 3b was prepared from 2b and Pd/(dppp)(OTf)2 (2:3). Mark
“a” indicate the signals of anomeric proton of -Glc. Conditions: 2b (2.0 × 10−3 M), Pd(dppp)(OTf)2
(3.0 × 10−3 M), -Glc (1.0 × 10−3 M),CDCl3, 300 MHz, 23˚C
The signals of C-H protons of -Glc broadened and moved upfield in the presence of 3b. These
changes would be rationalized as anisotropic effects receiving from the cage framework of 3b. Also
other kinds of hexosides received broadening and anisotropic effects from 3b (Figure S7 in the
12
ACS Paragon Plus Environment

Page 13 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Supporting Information). A similar type of upfield shifts for C-H signals of the saccharide guests
have been observed for our tetraarene host molecules triphenolic 1b5 and triresorcinolic one.17 The
9
1
addition order of the substrates was irrelevant to the product, for example, when two H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
samples were prepared in different addition orders, 2b → Pd(dppp)(OTf)2 → -Glc and -Glc →
1
Pd(dppp)(OTf)2 → 2b, the spectra were observed to be identical (Figure S8). H NMR spectra of
mixtures of 3b and -Glc in various ratios showed averaged broad signals, and signals of caged and
free guests did not separate (Figure S9). These findings indicated that the guest can easily go in and
out of the cage at room temperature. During the titration experiment (see below), no meaningful
time-dependence was observed in CD measurements.
DOSY analyses of the cage 3b, generated from a mixture of 2b (1.0 × 10−2 M) and Pd(dppp)(OTf)2
(1.5 × 10−2 M), were carried out again in the presence of -Glc (5.0 × 10−3 M). The signals of all the
C-H protons not only 3b but also -Glc could be attributed to a single diffusion constant D = 2.8 ×
10−10 m2s−1 (Figure 8a). This D value was same as that of 3b in the absence of -Glc (D = 2.8 ×
10−10 m2s−1, Figure 4a), so the cage framework was hardly deformed by the addition of the guest. On
the other hand, a solution of solely -Glc (5.0 × 10−3 M) in CDCl3 showed a much bigger diffusion
constant D = 7.0 × 10−10 m2s−1 (Figure 8b), indicating that the guest -Glc molecules were
incorporated in the cage framework of 3b.
Figure 8. DOSY spectra of (a) 3b (2b/Pd(dppp)(OTf)2 (2:3) mixture) in CDCl3 in the presence of
-Glc, and (b) -Glc in CDCl3. Conditions: 2b (1.0 × 10−2 M), Pd(dppp)(OTf)2 (1.5 × 10−2 M),
-Glc (5.0 × 10−3 M), 25 °C, 400 MHz.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 23
1
2
3
4
5
6
7
8
9
The UV-vis spectrum of 3b scarcely changed in the presence of -Glc as a guest (Figure S10).
When the M3L2 cage 3 is incorporating the guest hexoside, chirality can be induced on its framework
by twisting or distortion of the cage. The CD measurements were carried out for 3b (1.5 × 10−4 M),
generated from the mixture of 2b (3.0 × 10−4 M) and Pd(dppp)(OTf)2 (4.5 × 10−4 M), in the presence
of octyl hexosides (1.5 × 10−4 M). The spectra were summarized in Figure 9A and it was found that
three kinds of guest -Glc, -Gal, and -Man induced Cotton effects at the absorptive range of the
cage.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 9. (a) CD spectra of mixtures of 3b with octyl hexosides. Conditions: 2b (3.0 ×10−4 M),
Pd(dppp)(OTf)2 (4.5 × 10−4 M), octyl hexoside (1.5 × 10−4 M), CH2Cl2, 25 °C, path length = 1 mm.
(b) The titration curve from CD spectrum of 3b at 345 nm by the addition of -Man. The line is the
fitted curve assuming 1:1 binding. The corresponding CD spectra were shown in Figure S11.
Conditions: 2b (6.0 × 10−4 M), Pd(dppp)(OTf)2 (9.0 × 10−4 M), -Man (0 to 1.2 × 10−3 M), CH2Cl2,
25 ˚C, path length = 1 mm.
Among the hexoside guests, -Man induced the strongest Cotton effect around 300 − 350 nm
(Figure 9A, blue solid line). A titration experiment was carried out by using -Man as a titrant in
CH2Cl2. The spectral changes were shown in Figure S11, and the association constant assuming 1:1
binding was obtained as Ka = 1.9 × 104 mol L−1 from the titration curve plotting the CD change at
345 nm (Figure 9B). This Ka value was slightly stronger than that between 1b and -Man we
reported previously (Ka = 1.5 × 104 mol L−1).5 Allosteric effect seemed to be limited among the six
14
ACS Paragon Plus Environment

Page 15 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
hydroxy groups of 3b and those of the hexoside guest.
7
8
9
In conclusion, L2M3-type cage complexes 3a-c could be constructed by the use of rigid
C3v-symmetric tridentates 2 with Pd(II) precursors. The formation of the cage structures could be
ascertained on the basis of 1H NMR, DOSY, ESI-TOF-MS analyses, and X-ray crystallography. The
cage 3b was found to incorporate octyl glycosides as guests with displaying Cotton effects. The CD
titration showed that association between 3b and octyl -mannoside was slightly stronger than that
using the triphenolic parent 1b. We are now looking for guests incorporated tightly within cages 3
much efficiently to utilize the cage as a host molecule and a solubilizing agent.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
General.
1H, 13C, and 31P NMR spectra were recorded on a Varian Gemini 300, a JEOL ECX-400P, and a
JEOL ECA500II spectrometers using tetramethylsilane (TMS) and H3PO4 as internal references.
ESI-HRMS analyses were carried out on a JEOL JMS-T100LC mass spectrometer. IR spectra were
measured with a JASCO FT/IR-460plus spectrometer. Melting points were determined with a
Yanako MP-500D and not corrected. THF was distilled from sodium benzophenone ketyl before use.
Other commercially available reagents and solvents were used without further purification.
anti-1,3,5-Tris(2-hydroxy-5-pentylphenyl)-2,4,6-trimethylbenzene (1b)5 and 2,4,6-triiodomesitylene
(4)5,8 were prepared according to the procedures in the literature.
2-(Methoxymethoxy)-5-methylbenzeneboronic acid (5a).
To a solution of 4-(methoxymethoxy)toluene (17.5 g, 115 mmol) in THF (320 mL) was added
n-BuLi (2.6 M in hexane, 49 mL, 127 mmol) at 0 °C. The mixture was stirred at that temperature for
2 h, then B(Oi-Pr)3 (32 g, 172 mmol) was added in one portion to the mixture, which was
additionally stirred for 1 h, being allowed to room temperature. The reaction mixture was quenched
with a saturated aqueous NH4Cl solution and stirred for 1 h at room temperature. The resulting
mixture was extracted with AcOEt (50 mL × 3), and the combined organic layer was washed with
brine and dried over MgSO4, and concentrated by a rotary evaporator. The resulting residue was
1
washed with hexane (50 mL × 3) to give 5a (14 g, 62%) as a colorless solid. H and 13C NMR
spectra of this product matched with those reported by Naruta and coworkers.10 Mp 80 − 83 °C; IR
(KBr) νmax 3349, 3008, 2958, 2927, 2911, 2826, 1491 cm−1; 1H NMR (300 MHz, CDCl3) δ 2.31 (3 H,
s), 3.50 (3 H, s), 5.26 (2 H, s), 6.78 (2 H, s), 7.02 (1 H, d, J = 8.4 Hz), 7.21 (1 H, d, J = 8.4 Hz), 7.67
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 23
1
2
3
4
5
6
(1 H, s). 13C NMR (75 MHz, CDCl3) δ 20.1, 56.4, 94.6, 113.2, 131.3, 133.1, 137.0, 160.1; HRMS
7
8
(ESI-TOF) m/z: [M + 2MeOH − 2H2O + Na]+ Calcd for C11H17BNaO4 247.1118; Found 247.1126.
9
anti-1,3,5-Tris(2-(methoxymethoxy)-5-methylphenyl)-2,4,6-trimethylbenzene
(6a-anti).
A
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
mixture of 5 (8.0 g, 41 mmol), 2,4,6-triiodomesitylene5,8 (4, 4.06 g, 8.2 mmol), Pd(PPh3)4 (565 mg,
0.49 mmol), and Ba(OH)2·8H2O (23.3 g, 82 mmol), 1,2-dimethoxyethane (200 mL), and water (30
mL) was stirred under reflux for 24 h. The resulting mixture was concentrated and subjected to silica
gel column chromatography (eluent: hexane/CH2Cl2 = 4:1) to afford 6a-anti (4.1 g, 88%) as a
1
colorless solid. Mp 178−179 °C; IR (KBr) νmax 2952, 2924, 2824, 1497 cm−1; H NMR (300 MHz,
CDCl3) δ 1.73 (9 H, s), 2.31 (9 H, s), 3.30 (6 H, s), 3.35 (3 H, s), 4.98 (4 H, s), 5.06 (2 H, s), 6.90 (1
H, s), 6.97 (2 H, s), 7.06−7.10 (6 H, m); 13C NMR (75 MHz, CDCl3) δ 18.8, 18.9, 20.7, 55.7, 94.8,
95.2, 115.5, 116.1, 128.4, 131.2, 131.5, 131.65, 131.70, 131.8, 132.2, 133.6, 135.4, 135.5, 152.0,
152.2; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C36H42NaO6 593.2879; Found 593.2897.
syn-1,3,5-Tris(2-(methoxymethoxy)-5-methylphenyl)-2,4,6-trimethylbenzene (6a-syn). Thermal
atropisomerization of 6a-anti. A solution of 6a-anti (4.7 g, 8.3 mmol) in o-xylene (20 mL) was set
in an autoclave reactor and stirred at 220 °C for 12 h. The resulting solution was concentrated by a
rotary evaporator and subjected to silica gel column chromatography (eluent: CH2Cl2) to collect
recovered 6a-anti (3.18 g, 67%) and 6a-syn (1.05 g, 22%) as a colorless solid. Mp 151−154 °C; IR
1
(KBr) νmax 2923, 2822, 1497 cm−1; H NMR (300 MHz, CDCl3) δ 1.75 (9 H, s), 2.32 (9 H, s), 3.27
(9 H, s), 4.91 (6 H, s), 6.98 (3 H, s), 7.02−7.11 (6 H, m); 13C NMR (75 MHz, CDCl3) δ 18.9, 20.8,
55.7, 95.3, 116.3, 128.4, 131.7, 132.3, 133.8, 135.6, 151.9; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C36H42NaO6 593.2879; Found 593.2895.
syn-1,3,5-Tris(2-hydroxy-5-methylphenyl)-2,4,6-trimethylbenzene (1a).
A mixture of 6a-syn (107 mg, 0.19 mmol), HCO2H (3 mL), and CH2Cl2 (5 mL) was stirred for 20 h
at room temperature. The resulting mixture was concentrated by a rotary evaporator and subjected to
silica gel column chromatography (eluent: CH2Cl2/MeOH = 100:1) to give 1a (62 mg, 76%) as a
1
colorless solid. Mp 302 °C (dec); IR (KBr) νmax 3419 (br), 3018, 2922, 2863, 1496 cm−1; H NMR
(300 MHz, CDCl3) δ 1.72 (9 H, s), 2.29 (9 H, s), 6.19 (3 H, br s), 6.72 (3 H, d, J = 8.1 Hz), 6.89 (3 H,
s), 6.99 (3 H, d, J = 7.8 Hz); 13C NMR (75 MHz, CDCl3) δ 18.3, 20.7, 115.3, 127.5, 129.0, 129.9,
130.4, 134.9, 136.7, 150.1; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C30H30NaO3 461.2093;
Found 461.2082.
syn-1,3,5-Tris(2-hydroxy-3-iodo-5-methylphenyl)-2,4,6-trimethylbenzene (7a).
16
ACS Paragon Plus Environment

Page 17 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
To a mixture of 1a (400 mg, 0.91 mmol) and p-toluenesulfonic acid (52 mg, 0.27 mmol) in MeOH (5
mL) was added N-iodosuccinimide (NIS) (677 mg, 3.0 mmol) and the mixture was stirred for 1 h at
room temperature. After that a 10% aqueous solution of Na2S2O3 (5 mL) was added to the reaction
mixture, which was stirred until that the color of iodine faded. The resulting mixture was extracted
with CH2Cl2 (10 mL × 2), and the combined organic layer was dried over MgSO4, concentrated by a
rotary evaporator, and subjected to silica gel column chromatography (eluent: CH2Cl2) to give 7a
(390 mg, 52%) as a colorless solid. Mp 282 °C (dec); IR (KBr) νmax 3368 (br), 3013, 2918, 2859,
1458 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.74 (9 H, s), 2.28 (9 H, s), 6.29 (3 H, br s), 6.86 (3 H, s),
7.53 (3 H, s); 13C NMR (75 MHz, CDCl3) δ 18.5, 20.1, 84.6, 126.8, 130.7, 131.8, 134.9, 136.6,
138.2, 149.7; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C30H27I3NaO3 838.8992; Found
838.8965.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
syn-1,3,5-Tris(2-hydroxy-3-iodo-5-pentylphenyl)-2,4,6-trimethylbenzene (7b).
To a mixture of 1b5 (230 mg, 0.38 mmol) and p-toluenesulfonic acid (5.7 mg, 0.03 mmol) in CH2Cl2
(20 ml) was added N-iodosuccinimide (NIS) (22 mg, 0.11 mmol) and the mixture was stirred for 1 h
at room temperature. After that a 10% aqueous solution of Na2S2O3 (10 mL) was added to the
reaction mixture, which was stirred until that the color of iodine faded. The resulting mixture was
extracted with CH2Cl2 (10 mL × 2), and the combined organic layer was dried over MgSO4,
concentrated by a rotary evaporator, and subjected to silica gel column chromatography (eluent:
CH2Cl2) to give 7b (240 mg, 59%) as a colorless solid. Mp 154−157 °C; IR (KBr) νmax 3570, 3468,
1
3360, 2953, 2927, 2855, 1460 cm−1; H NMR (300 MHz, CDCl3) δ 0.87 (9 H, t, J = 6.9 Hz),
1.26−1.31 (12 H, m), 1.55−1.61 (6 H, m), 1.75 (9 H, s), 2.52 (6 H, t, J = 7.8 Hz), 6.24 (3 H, br s),
6.88 (3 H, s), 7.52 (3 H, s); 13C NMR (75 MHz, CDCl3) δ 14.1, 18.4, 22.5, 31.2, 31.3, 34.5, 84.8,
126.7, 135.0, 136.6, 135.0, 137.0, 137.5, 149.8; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C42H51I3NaO3 ([M + Na]+) 1007.0870; Found 1007.0909.
syn-1,3,5-Tris(2-(methoxymethoxy)-3-iodo-5-methylphenyl)-2,4,6-trimethylbenzene (8a). To a
suspension of NaH (47 mg, 1.2 mmol; commercial 55% dispersion was washed thoroughly with
hexane before use) in THF (7 mL) were subsequently added a solution of 7a (247 mg, 0.3 mmol) in
THF (5 mL) and chloromethyl methyl ether (0.11 mg, 1.36 mmol) at 0 °C. After the mixture was
stirred at 0 °C for 3 h, to the mixture were added a saturated aqueous NaHCO3 solution (5 mL) and
AcOEt (10 mL), and the organic layer was separated and concentrated by a rotary evaporator. Water
(10 mL) was added to the resulting residue and extracted with AcOEt (5 mL × 2), and the combined
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 23
1
2
3
4
5
6
7
8
AcOEt extract was washed with water (5 mL) and a saturated aqueous NaHCO3 solution (5 mL)
subsequently, dried over Na2SO4, and concentrated by a rotary evaporator. The resulting residue was
subjected to silica gel column chromatography (eluent: hexane/CH2Cl2 = 1:1) to give 8a (246 mg,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
86%) as a colorless solid. Mp 234−236 °C; IR (KBr) νmax 2991, 2921, 2825, 1450, 1436 cm−1; H
NMR (300 MHz, CDCl3) δ 1.79 (9 H, s), 2.28 (9 H, s), 3.51 (9 H, s), 4.60 (6 H, s), 6.88 (3 H, s),
7.64 (3 H, s); 13C NMR (75 MHz, CDCl3) δ 19.2, 20.3, 58.3, 93.0, 98.2, 132.4, 134.2, 134.3, 135.4,
136.2, 139.0, 151.4; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C36H39I3NaO6 970.9778; Found
970.9813.
syn-1,3,5-Tris(2-(methoxymethoxy)-3-iodo-5-pentylphenyl)-2,4,6-trimethylbenzene (8b). To a
suspension of NaH (49 mg, 1.2 mmol; commercial 55% dispersion was washed thoroughly with
hexane before use) in THF (5 mL) were subsequently added a solution of 7b (300 mg, 0.31 mmol) in
THF (5 mL) and chloromethyl methyl ether (110 mg, 1.4 mmol) at 0 °C. After the mixture was
stirred at 0 °C for 5 h, to the mixture were added a saturated aqueous NaHCO3 solution (10 mL) and
AcOEt (15 mL), and the organic layer was separated and concentrated by a rotary evaporator. Water
(30 mL) was added to the resulting residue and extracted with AcOEt (15 mL × 2), and the combined
AcOEt extract was washed with water (15 mL) and a saturated aqueous NaHCO3 solution (15 mL)
subsequently, dried over Na2SO4, and concentrated by a rotary evaporator. The resulting residue was
subjected to silica gel column chromatography (eluent: hexane/CH2Cl2 = 1:1) to give 8b (261 mg,
76%) as a dilute yellow oil. IR (NaCl) νmax 2955, 2927, 2856, 1454 cm−1; H NMR (300 MHz,
1
CDCl3) δ 0.86 (9 H, t, J = 6.6 Hz), 1.25−1.30 (12 H, m), 1.55−1.61 (6 H, m), 1.80 (9 H, s), 2.53 (6 H,
t, J = 7.5 Hz), 3.52 (9 H, s), 4.60 (6 H, s), 6.89 (3 H, s), 7.63 (3 H, s); 13C NMR (75 MHz, CDCl3) δ
14.1, 19.1, 22.5, 31.0, 31.3, 34.7, 58.3, 93.1, 98.3, 131.8, 134.1, 134.4, 136.3, 138.4, 140.5, 151.5;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C48H63I3NaO6 1139.1656; Found 1139.1666.
syn-1,3,5-Tris(2-(methoxymethoxy)-3-(4-pyridyl)-5-methylphenyl)-2,4,6-trimethylbenzene (9a).
A mixture of triiodide 8a (86 mg, 0.091 mmol), 4-pyridineboronic acid (56 mg, 0.45 mmol), K2CO3
(125
mg,
0.91
mmol),
Pd2(dba)3‧CHCl3
(11
mg,
0.009
mmol),
and
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (17 mg, 0.036 mmol), 1,2-dimethoxyethane (8
mL), and water (1.5 mL) was stirred under reflux for 20 h. The resulting mixture was concentrated
and subjected to silica gel column chromatography (eluent: CH2Cl2/MeOH = 40:1 to 20:1) to give 9a
(55 mg, 76%) as a colorless solid. Mp 133−136 °C; IR (KBr) νmax 3022, 2925, 2836, 1598 cm−1; 1H
NMR (300 MHz, CDCl3) δ 1.98 (9 H, s), 2.41 (9 H, s), 2.76 (9 H, s), 4.33 (6 H, s), 7.05 (3 H, s),
18
ACS Paragon Plus Environment

Page 19 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
7.16 (3 H, s), 7.52 (6 H, d, J = 5.7 Hz), 8.64 (6 H, d, J = 4.2 Hz); 13C NMR (75 MHz, CDCl3) δ 19.4,
20.9, 56.7, 98.3, 124.6, 130.0, 132.6, 133.5, 134.0, 134.3, 135.1, 136.3, 147.1, 149.1, 149.2; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C51H52N3O6 802.3856; Found 802.3864.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
syn-1,3,5-Tris(2-(methoxymethoxy)-3-(4-pyridyl)-5-pentyllphenyl)-2,4,6-trimethylbenzene (9b).
A mixture of triiodide 8b (224 mg, 0.21 mmol), 4-pyridineboronic acid (154 mg, 1.25 mmol),
K2CO3 (288 mg, 2.1 mmol), Pd2(dba)3‧CHCl3 (11 mg, 0.011 mmol), and
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (17 mg, 0.042 mmol), 1,2-dimethoxyethane (6
mL), and water (1 mL) was stirred under reflux for 20 h. The resulting mixture was concentrated by
a rotary evaporator and subjected to silica gel column chromatography (eluent: CH2Cl2/MeOH =
80:1 to 20:1) to give 9b (148 mg, 73%) as a colorless viscous oil. IR (KBr) νmax 2954, 2926, 2855,
1
1598, 1455 cm−1; H NMR (300 MHz, CDCl3) δ 0.89 (9 H, t, J = 6.6 Hz), 1.30−1.37 (12 H, m),
1.64−1.69 (6 H, m), 1.99 (9 H, s), 2.66 (6 H, t, J = 7.5 Hz), 2.77 (9 H, s), 4.34 (6 H, s), 7.08 (3 H, s),
7.16 (3 H, s), 7.53 (6 H, br s), 8.65 (6 H, br s); 13C NMR (75 MHz, CDCl3) δ 14.1, 19.3, 22.6, 31.2,
31.4, 35.2, 56.7, 98.3, 124.6, 129.3, 132.0, 133.5, 134.4, 135.0, 136.1, 139.1, 147.1, 149.2; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C63H76N3O6 970.5734; Found 970.5761.
syn-1,3,5-Tris(2-hydroxy-3-(4-pyridyl)-5-methylphenyl)-2,4,6-trimethylbenzene (2a). A mixture
of trifluoroacetic acid (3 mL) and 9b (300 mg, 0.37 mmol) in toluene (5 mL) was stirred at 90 °C for
2 h . The resulting mixture was concentrated by a rotary evaporator and treated with a saturated
aqueous NaHCO3 solution (20 mL). The mixture was extracted with CH2Cl2/MeOH = 10 : 1 (20 mL
× 2), and the combined organic layer was dried over MgSO4, and concentrated by a rotary evaporator,
and subjected to silica gel column chromatography (eluent: CH2Cl2/MeOH = 20:1 → 15:1) to give
2a (195 mg, 78%) as a colorless solid. Mp 275 °C (dec); IR (KBr) νmax 3362 (br), 3023, 2923, 2863,
1604 cm−1; 1H NMR (300 MHz, CDCl3/CD3OD = 9 : 1) δ 1.85 (9 H, s), 2.39 (9 H, s), 7.03 (3 H, s),
7.16 (3 H, s), 7.62 (6 H, d, J = 6.0 Hz), 8.46 (6 H, d, J = 5.1 Hz); 13C NMR (75 MHz,
CDCl3/CD3OD = 9 : 1) δ 18.2, 20.3, 124.3, 125.3, 129.0, 129.7, 130.0, 131.0, 134.8, 136.6, 147.5,
147.8, 148.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C45H40N3O3 670.3070; Found 670.3075.
syn-1,3,5-Tris(2-hydroxy-3-(4-pyridyl)-5-pentylphenyl)-2,4,6-trimethylbenzene (2b). A mixture
of trifluoroacetic acid (2 mL) and 9b (148 mg, 0.15 mmol) in toluene (3 mL) was stirred at 90 °C for
2 h . The resulting mixture was concentrated by a rotary evaporator and treated with a saturated
aqueous NaHCO3 solution (10 mL). The mixture was extracted with CH2Cl2 / MeOH = 10 : 1 (10
mL × 2), and the combined organic layer was dried over MgSO4, and concentrated by a rotary
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 23
1
2
3
4
5
6
7
8
evaporator, and subjected to silica gel column chromatography (eluent: CH2Cl2/MeOH = 20:1 to
15:1) to give 2b (107 mg, 84%) as a colorless solid. Mp 242−245°C; IR (KBr) νmax 3384 (br),
2955, 2927, 2856, 1604 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 0.84 (9 H, t, J = 6.6 Hz), 1.27−1.31
(12 H, m), 1.57−1.62 (6 H, m), 1.75 (9 H, s), 2.60 (6 H, t, J = 7.8 Hz), 6.99 (3 H, s), 7.23 (3 H, s),
7.25 (3 H, s), 7.64 (6 H, d, J = 5.7 Hz), 8.57 (6 H, br s); 13C NMR (75 MHz, DMSO-d6) δ 14.0, 18.3,
22.0, 30.80, 30.84, 34.2, 123.9, 124.7, 127.9, 129.1, 130.0, 134.2, 134.5, 136.3, 146.0, 148.5, 149.0;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C57H64N3O3 838.4948; Found 838.4952.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Cage Complex 3b; {2(2b)‧3[Pd(dppp)]}6+‧6(TfO−). Typical Procedure to prepare a H NMR
sample.
To a CDCl3 (1.0 mL) solution of Pd(dppp)(OTf)2 (2.45 mg, 0.0030 mmol) was added tridentate
1
ligand 2b (1.68 mg, 0.0020 mmol) and the mixture was stirred for 15 min at room temperature. H
NMR spectrum of this CDCl3 solution suggested that L2M3-type coordination cage formed
1
quantitatively. H NMR (300 MHz, CDCl3) δ 0.87 (9 H, t, J = 6.9 Hz), 1.23−1.37 (24 H, m),
1.59−1.64 (12 H, m), 1.80 (18 H, s), 2.25 (6 H, br s), 2.57 (6 H, t, J = 7.5 Hz), 3.26 (12 H, br s), 6.58
(6 H, s), 6.94 (6 H, s), 7.54−7.10 (60 H, br s), 7.72 (12H, br s), 8.87 (12H, br s); 13C NMR (75 MHz,
CDCl3) δ 14.0 17.7, 18.4, 22.5, 31.05, 31.17, 34.9, 68.0, 123.9, 126.4, 128.8, 129.3, 130.6, 131.19,
131.44, 132.9, 133.9, 134.9, 136.6, 149.1, 149.8; 31P NMR (400 MHz, CDCl3) δ −5.87 (s). HRMS
(ESI-TOF): m/z [(2b)2‧(Pd(dppp)3(OTf)5]+ Calcd for 3977.9058; Found 3977.8846.
X-ray Crystallography of 3a.
To a suspension of 2a and Pd(dppp)(OTf)2 (2:3 molar ratio) in 1,4-dioxane was slowly added DMSO
until the mixture became homogeneous. Single crystals of 3a appeared as blocks according to slow
vaporization of dioxane during standing at room temperature.
The diffraction data for the single crystal of 3a were collected at 123 K under a nitrogen atmosphere
on a Rigaku XtaLAB P200 diffractometer using graphite-monochromated Cu-Kα radiation (λ=
1.54187 Å) and data reduction was performed using CrysAlisPro.18 The structure of 3a was solved
by direct methods using SHELXT19 and refined by full-matrix least-squares methods based on F2
using SHELXL.20 There were found residual peaks based on solvent molecules and triflate anions
inside the cage structure. However, residual peaks could not be assigned to any molecules due to
heavy disorder including triflate anions. We then refined these peaks using the SQUEEZE
procedure12 implemented into PLATON software and the analysis was converged. All non-hydrogen
atoms were anisotropically refined and the hydrogen atoms were refined with the riding model.
20
ACS Paragon Plus Environment

Page 21 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Acknowledgment.
9
This study was supported by JSPS KAKENHI Grant Numbers; JP17H05360 (HA, Coordination
Asymmetry) and JP24350066 (HA). The authors thank Dr. Hiroyasu Sato (Rigaku Corporation) for
his support in X-ray measurement. This work was supported by JSPS Core-to-Core Program, B.
Asia-Africa Science Platforms.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supporting Information.
Figures S1−S12, crystallographic data for 3a, and 1H and 13C NMR data for 5a and new compounds.
X-ray data in CIF format for 3a. These materials are available free of charge via the Internet at
http://pubs.acs.org.
References and Notes
1. Recent reviews of molecular cages formed by coordinative self-organization: (a) Yoshizawa, M.;
Fujita, M. Bull. Chem. Soc. Jpn. 2010, 83, 609−618. (b) Yoshizawa, M.; Klosterman, J. K.; Fujita, M.
Angew. Chem., Int. Ed. 2009, 48, 3418−3438. (c) Klosterman, J. K.; Yamauchi, Y.; Fujita, M. Chem.
Soc. Rev. 2009, 38, 1714−1725. (d) Fujita, M. Chem. Soc. Rev. 1998, 27, 417−425. (e) Rebek, J. Jr.
Angew. Chem., Int. Ed. 2005, 44, 2068−2078. (f) Hof, F.; Craig, S. L.; Nuckolls, C.; Rebek, J., Jr.
Angew. Chem., Int. Ed. 2002, 41, 1488−1508. (g) Zarra, S.; Wood, D. M.; Roberts, D. A.; Nitschke, J.
R. Chem. Soc. Rev. 2015, 44, 419−432. (h) Smulders, M. M. J.; Riddell, I. A.; Browne, C.; Nitschke,
J. R. Chem. Soc. Rev. 2013, 42, 1728−1754. (i) Bloch, W. M.; Clever, G. H. Chem. Commun. 2017,
53, 8506−8516. (j) Han, M.; Engelhard, D. M.; Clever, G. H. Chem. Soc. Rev. 2014, 43, 1848−1860.
(k) Yoshizawa, M.; Yamashina, M. Chem. Lett. 2017, 46, 163−171. (l) Ward, M. D.; Raithby, P. R.
Chem. Soc. Rev. 2013, 42, 1619−1636. (m) Dalgarno, S. J.; Power, N. P.; Atwood, J. L.; Coord.
Chem. Rev. 2008, 252, 825−841. (n) Schmuck, C. Angew. Chem., Int. Ed. 2007, 46, 5830−5833. (o)
Fiedler, D.; Leung, D. H.; Bergman, R. G.; Raymond, K. N. Acc. Chem. Res. 2005, 38, 349−358.
2. For examples of cage compounds with D3h symmetry, see: Catalano, V. J.; Bennett, B. L.; Yson, R.
L.; Noll, B. C. J. Am. Chem. Soc. 2000, 122, 10056−10062. See also references cited in refs 1a and
1c.
3. For examples of cage compounds with D3 symmetry, see: (a) Akine, S.; Miyashita, M.;
Nabeshima, T. J. Am. Chem. Soc. 2017, 139, 4631−4634. (b) Miguez-Lago, S.; Cid, M. M.;
Alonso-Gomez, J. L. Eur. J. Org. Chem. 2016, 5716−5721. (c) Traore, T.; Delacour, L.;
Garcia-Argote, S.; Berthault, P.; Cintrat, J.-C.; Rousseau, B. Org. Lett. 2010, 12, 960−962. (d) Glaser,
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 23
1
2
3
4
5
6
7
R. Chirality 2008, 20, 910−918. (e) Westcott, A.; Fisher, J.; Harding, L. P.; Rizkallah, P.; Hardie, M.
J. J. Am. Chem. Soc. 2008, 130, 2950−2951.
8
9
4. For recent examples of self-organized cage hosts to recognize guest molecules, see: (a) Imamura,
T.; Maehara, T.; Sekiya, R.; Haino, T. Chem.–Eur. J. 2016, 22, 3250−3254. (b) Yamada, H.; Ikeda,
T.; Mizuta, T.; Haino, T. Org. Lett. 2012, 14, 4510−4513. (c) Haino, T.; Kobayashi, M.; Fukazawa, Y.
Chem.−Eur. J. 2006, 12, 3310−3319. (d) Kobayashi, K.; Yamanaka, M. Chem. Soc. Rev. 2015, 44,
449−466. (e) Yamanaka, M.; Kobayashi, K. Asian J. Org. Chem. 2013, 2, 276−289. (f) Yamanaka,
M.; Kawaharada, M.; Nito, Y.; Takaya, H.; Kobayashi, K. J. Am. Chem. Soc. 2011, 133,
16650−16656. (g) Nishimura, N.; Kobayashi, K. J. Org. Chem. 2010, 75, 6079−6085. (h) Nishimura,
N.; Yoza, K.; Kobayashi, K. J. Am. Chem. Soc. 2010, 132, 777−790. (i) Kitagawa, H.; Kobori, Y.;
Yamanaka, M.; Yoza, K.; Kobayashi, K. Proc. Nat. Acad. Sci. U.S.A. 2009, 106, 10444−10448. (j)
Kobayashi, K.; Kitagawa, R.; Yamada, Y.; Yamanaka, M.; Suematsu, T.; Sei, Y.; Yamaguchi, K. J.
Org. Chem. 2007, 72, 3242−3246. (k) Yamanaka, M.; Yamada, Y.; Sei, Y.; Yamaguchi, K.;
Kobayashi, K. J. Am. Chem. Soc. 2006, 128, 1531−1539. (l) Mastalerz, M. Angew. Chem., Int. Ed.
2010, 49, 5042−5053. (m) Schmitt, A.; Chatelet, B.; Padula, D.; Di Bari, L.; Dutasta, J.-P.; Martinez,
A. New J. Chem. 2015, 39, 1749−1753. See also references cited in refs 1a, 1n, and 1o.
5. Abe, H.; Aoyagi, Y.; Inouye, M. Org. Lett. 2005, 7, 59−61.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6. Beletskiy, E. V.; Schmidt, J.; Wang, X.-B.; Kass, S. R. J. Am. Chem. Soc. 2012, 134,
18534−18537.
7. Recently, Chen and coworkers reported the construction and application of a cage molecule based
on 1 by dynamic covalent chemistry. See Chen, H.-Y.; Gou, M.; Wang, J.-B. Chem. Commun. 2017,
53, 3524−3526.
8. Ohshiro, N.; Takei, F.; Onitsuka K.; Takahashi, S. J. Organomet. Chem. 1998, 569, 195−202. See
also: Suzuki, H. Organic Syntheses, Coll. Vol. 6, pp 700; Wiley, 1988.
9. The boronic acid 5a is a known compound and has been prepared by Br-Li exchange of
2-bromo-1-(methoxymethoxy)-4-methylbenzene and trapping with B(OMe)3. For example, see ref
10. We generated the lithio intermediate by ortho-lithiation from 4-(methoxymethoxy)toluene and it
was trapped with B(OPr-i)3. See the Experimental Section.
10. Liu, J.-G.; Naruta, Y.; Tani, F. Chem. – Eur. J. 2007, 13, 6365−6378.
11. The locations of the hydrogen atoms of six OH groups were acquired by calculation.
12. Spek, A. L. Acta Cryst. 2015, C71, 9–18.
13. For selected reviews for saccharide recognition by synthetic host molecules, see: (a) Miron, C.
E.; Petitjean, A. ChemBioChem 2015, 16, 365−379. (b) Mazik, M. RSC Adv. 2012, 2, 2630−2642. (c)
Jin, S.; Cheng, Y.; Reid, S.; Li, M.; Wang, B. Med. Res. Rev. 2010, 30, 171−257. (d) Penadés, S. Ed.
Host–Guest Chemistry: Mimetic Approaches to Study Carbohydrate Recognition. Topics in Current
Chemistry, Vol. 218; Springer, 2002. (e) Davis, A. P. Org. Biomol. Chem. 2009, 7, 3629−3638. (f)
22
ACS Paragon Plus Environment

Page 23 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Walker, D. B.; Joshi, G.; Davis, A. P. Cell. Mol. Life Sci. 2009, 66, 3177−3191. (g) Mazik, M. Chem.
Soc. Rev. 2009, 38, 935−956. (h) Davis, A. P.; Wareham, R. S. Angew. Chem., Int. Ed. 1999, 38,
2978−2996. (i) Zhang, D.-W.; Zhao, X.; Li, Z.-T. Acc. Chem. Res. 2014, 47, 1961−1970.
14. For recent examples for saccharide recognition in host molecules of cage structures, see: (a) Rios,
P.; Mooibroek, T. J.; Carter, T. S.; Williams, C.; Wilson, M. R.; Crump, M. P.; Davis, A. P. Chem. Sci.
2017, 8, 4056−4061. (b) Mooibroek, T. J.; Crump, M. P.; Davis, A. P. Org. Biomol. Chem. 2016, 14,
1930−1933. (c) Rios, R.; Carter, T. S.; Mooibroek, T. J.; Crump, M. P.; Lisbjerg, M.; Pittelkow, M.;
Supekar, N. T.; Boons, G.-J.; Davis, A. P. Angew. Chem., Int. Ed. 2016, 55, 3387−3392. (d)
Mooibroek, T. J.; Casas-Solvas, J. M.; Harniman, R. L.; Renney, C. M.; Carter, T. S.; Crump, M. P.;
Davis, A. P. Nat. Chem. 2016, 8, 69−74. (e) Destecroix, H.; Renney, C. M.; Mooibroek, T. J.; Carter,
T. S.; Stewart, P. F. N.; Crump, M. P.; Davis, A. P. Angew. Chem., Int. Ed. 2015, 54, 2057−2061. (f)
Yamashina, M.; Akita, M.; Hasegawa, T.; Hayashi, S.; Yoshizawa, M. Sci. Adv. 2017, 3, e1701126.
(g) Zhang, D.; Mulatier, J.-C.; Cochrane, J. R.; Guy, L.; Gao, G.; Dutasta, J.-P.; Martinez, A. Chem.
− Eur. J. 2016, 22, 8038−8042.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15. For recent examples for saccharide recognition in host molecules of cage-like structures, see: (a)
Amrhein, F.; Lippe, J.; Mazik, M. Org. Biomol. Chem. 2016, 14, 10648−10659. (b) Lippe, J.;
Seichter, W.; Mazik, M. Org. Biomol. Chem. 2015, 13, 11622−11632. (c) Lippe, J.; Mazik, M. J. Org.
Chem. 2015, 80, 1427−1439. (d) Chandramouli, N.; Ferrand, Y.; Lautrette, G.; Kauffmann, B.;
Mackereth, C. D.; Laguerre, M.; Dubreuil, D.; Huc, I. Nat. Chem. 2015, 7, 334−341. (e) Mandal, P.
K.; Kauffmann, B.; Destecroix, H.; Ferrand, Y.; Davis, A. P.; Huc, I. Chem. Commun. 2016, 52,
9355−9358.
16. For selected examples from our works, see: (a) Ohishi, Y.; Abe, H.; Inouye, M. Eur. J. Org.
Chem. 2017, 6975−6979. (b) Hirokane, S.; Takashima, S.; Abe, H.; Inouye, M. Eur. J. Org. Chem.
2017, 726−733. (c) Abe, H.; Yoneda, T.; Ohishi, Y.; Inouye, M. Chem. − Eur. J. 2016, 22,
18944−18952. (d) Ohishi, Y.; Abe, H.; Inouye, M. Chem. − Eur. J. 2015, 21, 16504−16511. (e) Abe,
H.; Chida, Y.; Kurokawa, H.; Inouye, M. J. Org. Chem. 2011, 133, 3366−3371. (f) Waki, M.; Abe,
H.; Inouye, M. Chem. − Eur. J. 2006, 12, 7639−7647. (g) Inouye, M.; Waki, M.; Abe, H. J. Am.
Chem. Soc. 2004, 126, 2022−2027.
17. Abe, H.; Horii, A.; Matsumoto, S.; Shiro, M.; Inouye, M. Org. Lett. 2008, 10, 2685−2688.
18. CrysAlisPro: Data Collection and Processing Software, Rigaku Corporation (2015). Tokyo
196-8666, Japan.
19. SHELXT Version 2014/5: Sheldrick, G. M. Acta Cryst. 2014, A70, C1437.
20. SHELXL Version 2014/7: Sheldrick, G. M. Acta Cryst. 2008, A64, 112.
23
ACS Paragon Plus Environment