Construction of Aromatic Multilayered Structures Based on the Conformational Properties of N,N’-Dimethylated Squaramide

Article abstract of DOI:10.1002/cplu.202000678

Squaramide is a highly rigid four-membered ring system bearing two carbonyl and two amino groups, and its derivatives have found applications in many fields. We synthesized several N,N’-dimethylated oligosquaramides linked via phenyl groups, and investigated their structures in the crystalline state and in solution. Compounds 1, 2 (bissquaramides), and 13 (trissquaramide) exist as folded structures in the crystalline state, in which the aromatic rings are located in a face-to-face position. In their multilayered structures, the benzene rings are more nearly parallel and are closer to each other, compared with those in N,N’-dimethylated oligoureas. Individual molecules of meta-connected compounds 2 and 13 show a helical structure with all-R or all-S axis chirality, but afford only racemic crystals. The NMR spectra indicated that these compounds retain well-ordered folded structures in solution. The unique steric and electronic properties of N,N’-dimethylated squaramide can provide access to novel functional aromatic multilayered and helical foldamers.

Full text of DOI:10.1002/cplu.202000678

Full Papers
doi.org/10.1002/cplu.202000678
ChemPlusChem
1
2
3
4
5
6
7
8
9
Construction of Aromatic Multilayered Structures Based on
the Conformational Properties of N,N’-Dimethylated
Squaramide
Maiko Arimura,[a] Kimiko Tanaka,[a] Midori Kanda,[a] Ko Urushibara,[a] Shinya Fujii,*[b]
Kosuke Katagiri,[c] Isao Azumaya,[d] Hiroyuki Kagechika,[b] and Aya Tanatani*[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
Squaramide is a highly rigid four-membered ring system
bearing two carbonyl and two amino groups, and its derivatives
have found applications in many fields. We synthesized several
N,N’-dimethylated oligosquaramides linked via phenyl groups,
and investigated their structures in the crystalline state and in
solution. Compounds 1, 2 (bissquaramides), and 13 (trissquar-
amide) exist as folded structures in the crystalline state, in
which the aromatic rings are located in a face-to-face position.
In their multilayered structures, the benzene rings are more
nearly parallel and are closer to each other, compared with
those in N,N’-dimethylated oligoureas. Individual molecules of
meta-connected compounds 2 and 13 show a helical structure
with all-R or all-S axis chirality, but afford only racemic crystals.
The NMR spectra indicated that these compounds retain well-
ordered folded structures in solution. The unique steric and
electronic properties of N,N’-dimethylated squaramide can
provide access to novel functional aromatic multilayered and
helical foldamers.
Introduction
also available as a bioisostere of urea or cyanoguanidine in
bioactive molecules.
Squaramide is an amino derivative of squaric acid, a four-
membered cyclic dibasic acid (Figure 1).[1] It is a key structure of
functional molecules in the fields of synthetic chemistry,[2]
supramolecular chemistry,[3] and medicinal chemistry[4] due to
its rigid structure and ability to form both ionic and hydrogen
bonds. Squaramide is a more effective cation acceptor than
urea, and in addition can act as an anion receptor, due to the
increased aromaticity of the 4-membered ring of squaramide
upon complex formation.[5,6] Thus, the squaramide skeleton
provides a versatile structural motif for molecular recognition or
in bifunctional organocatalysts for asymmetric synthesis. It is
The C–N bonds of squaramide have partial double-bond
character, like amide and urea bonds, and trans/cis isomerism
can occur. N,N’-Diarylsquaramides generally take (trans, trans)
form (Figure 2) both in the crystalline state and in solution.[7,8] In
this conformation, the formation of an intermolecular hydrogen
bond network between the carbonyl groups and hydrogen
Figure 1. Structures of squaric acid and squaramide.
[a] M. Arimura, K. Tanaka, M. Kanda, Dr. K. Urushibara, Prof. A. Tanatani
Department of Chemistry
Faculty of Science
Ochanomizu University
2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610 (Japan)
E-mail: tanatani.aya@ocha.ac.jp
[b] Assoc. Prof. S. Fujii, Prof. H. Kagechika
Institute of Biomaterials and Bioengineering
Tokyo Medical and Dental University (TMDU)
2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062 (Japan)
E-mail: fujiis.chem@tmd.ac.jp
[c] Assoc. Prof. K. Katagiri
Department of Chemistry
Faculty of Science and Engineering
Konan University
8-9-1 Okamoto, Higashinada, Kobe, Hyogo 658-8501 (Japan)
[d] Prof. I. Azumaya
Faculty of Pharmaceutical Sciences
Toho University
2-2-1 Miyama, Funabashi, Chiba 274-8510 (Japan)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cplu.202000678
Figure 2. Effects of N-methylation on conformations of aromatic squaramide,
amide and urea.
This article is part of a Special Collection on “Synthesis, Properties, and
Applications of Foldamers”.
ChemPlusChem 2021, 86, 198–205
198
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/cplu.202000678
ChemPlusChem
atoms on the nitrogen atoms results in the formation of a chain
structure in the crystal.[9] N,N’-Diarylsquaramides bearing ortho-
substituents on the aromatic rings also exist in the (trans, trans)
form; notably, they often show spontaneous chiral induction
upon crystallization, forming unique one-handed helical net-
work structures even though they contain no asymmetric
center.[10]
1
2
3
4
5
6
7
On the other hand, Muthyala et al. reported that N,N’-
dimethyl-N,N’-diphenylsquaramide exists in (cis, cis) form, in
which the two phenyl rings are located in a face-to-face
position (Figure 2).[8,11] Similar conformational characteristics are
observed in aromatic amides and ureas.[12,13] Thus, benzanilide
and N,N’-diphenylurea exist in trans forms, whereas their N-
methylated derivatives, N-methylbenzanilide and N,N’-dimethyl-
N,N’-diphenylurea, exist in cis forms. The cis conformational
preference of aromatic N-methylated (more generally N-
alkylated) amides and ureas is general, and can be utilized to
obtain aromatic foldamers with unique structures and func-
tions. In the case of aromatic N-methylated amides, the dihedral
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
Figure 3. Structures of the designed oligosquaramides 1–4.
°
angle between the two phenyl groups is about 60 , and the N-
methylated oligoamides show dynamic helical structures in
solution.[12c] In N,N’-dimethylated ureas, the dihedral angle
°
between two phenyl groups is about 30 , and the N,N’-
dimethylated oligoureas form aromatic multilayered structures
both in the crystal and in solution.[13,14] Further, meta-connected
oligoureas showed well-ordered helical structures in the crystal,
based on all-R or all-S axis chirality of the PhÀ N bonds. The
equilibrium between the enantiomers is very fast, and the
introduction of an optically active substituent at the urea
nitrogen atoms induces handedness in the helical structure, as
revealed by the CD spectra.[15]
In comparison with development of the amide- or urea-
based foldamers, there are a few reports on the squaramide-
based foldamers.3 In the crystal structure of N,N’-dimethyl-N,N’-
diphenylsquaramide, the dihedral angle between the two
°
phenyl groups is about 15 , which is considerably smaller than
those of the folded cis-amides and (cis,cis)-ureas. Therefore, we
considered that the N,N’-dimethylsquaramide moiety could
serve a building block for a different type of aromatic multi-
layered and helical structure. To confirm this idea, we synthe-
sized N,N’-dimethylated oligosquaramides, and examined their
structures in solution and in the crystal.
Scheme 1. Synthesis of bissquaramides 1 and 2.
respectively. Finally, N-methylation using potassium tert-but-
oxide as a base afforded the target molecules 1 and 2.
Results and Discussion
Synthesis of trissquaramide 3 is illustrated in Scheme 2.
Reaction of diethyl squarate with one equivalent of aniline or
an excess of m-nitroaniline in the presence of zinc trifluorome-
thanesulfonate afforded the 1:1 adduct 9 or N,N’-diarylsquar-
amide 10, respectively. N-Methylation of 10, followed by
catalytic hydrogenation of the nitro group, gave 12, which was
reacted with 9 in ethanol to give trissquaramide 13. Finally, N-
methylation using sodium hydride as a base afforded the target
molecule 3, although the yield was low (11%).
We designed four oligomers, including para- and meta-
connected bissquaramides
1 and 2, and meta-connected
trissquaramide 3. For comparison, we also designed the hybrid
compound 4 bearing both N,N’-dimethylated squaramide and
urea moieties (Figure 3).
Synthesis of oligomers 1 and 2 is summarized in Scheme 1.
Diethyl squarate was reacted with one equivalent of N-meth-
ylaniline in the presence of zinc trifluoromethanesulfonate in
ethanol to afford the 1:1 adduct 6. The reaction of 6 with p- or
m-phenylenediamine was performed in a mixed solvent of
Synthesis of the squaramide-urea hybrid compound 4 is
summarized in Scheme 3. Reaction of diamine 12 with phenyl-
isocyanate afforded bisurea 14 in 83% yield, and N-methylation
°
toluene and DMF at 110 C to give bissquaramides 7 and 8,
ChemPlusChem 2021, 86, 198–205
www.chempluschem.org
199
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/cplu.202000678
ChemPlusChem
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
Scheme 2. Synthesis of bissquaramide 3.
solubility and multiple reaction sites of the starting materials 13
and 14.
Compounds 1 and 2 afforded good crystals for X-ray
crystallographic analysis, but unfortunately, we could not obtain
suitable crystals of compounds 3 and 4. Therefore, X-ray
crystallographic analysis was performed for compounds 1 and 2
(Table 1, Figure 4). Compound 1 crystallized in a monoclinic
system, space group P21/c, and included two molecules in the
unit cell. Compound 2 crystallized in a monoclinic system, space
group P21/c, and included four molecules of 2 and four
molecules of ethyl acetate in the unit cell. As expected, both
compounds showed aromatic multi-layered structures with all-
(cis, cis) squaramide moieties. The bond angles and bond
lengths at the squaramide moieties of 1 and 2 were essentially
the same as those of simple N,N’-diphenylsquaramide. The
bond length between nitrogen and carbon of the four-
membered ring is 1.33–1.35 Å, which indicates partial double
bond character of the N–C bonds, as in the case of amide and
Scheme 3. Synthesis of bissquaramide 4.
afforded the target molecule 4 in only 8% yield. The very low
yields of both compounds 3 and 4 are probably due to the low
Table 1. X-ray crystallographic data of compounds 1, 2, and 13.
1
2
13
recrystallization
solvent
formula
molecular weight
crystal system
space group
a [Å]
CH2Cl2-MeOH
AcOEt
DMF-MeOH
C30H26N4O4
506.55
Monoclinic
C30H26N4O4 ·(C4H8O2)
594.65
Monoclinic
C38H28N6O6 ·(C9H21N3O3)
883.95
Monoclinic
P21/c
P21/c
16.973(4)
9.000(2)
22.112(6)
110.508(4)
3163.8(14)
4
P21/c
9.9737(14)
8.9956(12)
14.462(2)
95.144(3)
1292.3(3)
2
14.922(3)
26.885(5)
11.388(2)
110.321(4)
4284.1(15)
4
b [Å]
c (Å]
°
β [ ]
V [Å3]
Z
R,
0.0573, 0.1379
0.1035, 0.2739
0.0497, 0.1014
Rw [I<2σ(I)]
R,
0.0980, 0.1588
2036188
0.1344, 0.2918
2036189
0.0986, 0.1171
2036190
Rw (all data)
CCDC
ChemPlusChem 2021, 86, 198–205
www.chempluschem.org
200
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/cplu.202000678
ChemPlusChem
1
2
3
4
5
6
7
8
9
Figure 4. Crystal structures of (a) 1 and (b) 2 in thermal ellipsoid model. The
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
Figure 5. Crystal structure of 13 in thermal ellipsoid model. The ellipsoids of
all nonhydrogen atoms are at 50% probability. (a) Top view. (b) Side view.
ellipsoids of all nonhydrogen atoms are at 50% probability.
urea bonds. The dihedral angles between the terminal and
°
°
°
central benzene rings are both 12.3 for 1 and are 13.8 and
13.7 and 3.42 Å, respectively, which are similar values to those
°
22.3 for 2. The distances between the centers of the benzene
of compounds 1 and 2. The two terminal squaramide rings are
rings are both 3.43 Å for 1 and are 3.49 Å and 3.61 Å for 2.
These values are smaller than those of the corresponding N-
methylated bisurea 1513 (see structure in Table 2; dihedral angle
located on the same side and are nearly parallel with the
°
dihedral angle of 15.8 . This indicates that the folded structure
of N,N’-dimethyl-N,N’-diphenylsquaramide moiety could serve
as a linker to arrange two oligomers in a parallel orientation.
Indeed, we have obtained β-sheet-type oligoamides linked by
an N,N’-dimethyl-N,N’-diphenylsquaramide moiety.3e
°
42.7 , distance 4.01 Å). Thus, the N,N’-dimethylsquaramide
moiety can be used for construction of aromatic multi-layered
structures in which the benzene rings are located in a face-to-
face position, and the benzene rings take a more parallel
relationship than those in the corresponding N,N’-dimethylated
ureas. In the case of meta-connected bissquaramide 2, the axis
chirality is all-R or all-S in a single molecule, but the crystal is
racemic, containing both enantiomers in a 1:1 ratio.
Next, the structures of squaramides in solution were
1
examined by means of H NMR spectroscopy. Figure 6 shows
1
the aromatic region of the H NMR spectra of compound 2 and
the synthetic intermediate 8 in CDCl3. All aromatic protons of 2
were observed at higher field than the corresponding protons
of 8. In particular, the signal of the proton at the ortho position
to both nitrogen atoms on the central benzene ring is observed
at 5.74 ppm, higher than that of the corresponding proton of 8
by 1.44 ppm. Similar shifts of the aromatic protons to higher
field were observed in compound 1 as compared with 7.
We also conducted X-ray crystallographic analysis of the
synthetic intermediate 13 (Table 1, Figure 5). Compound 13
crystallized in a monoclinic system, space group P21/c, and
included four molecules and twelve molecules of DMF in the
unit cell. Eight of twelve molecules of DMF were connected to
NH of trissquaramide 13 by hydrogen-bonding. In the crystal
structure of 13, the central and terminal squaramides take (cis,
cis) and (trans, trans) forms, respectively. Individual molecules
are chiral (all-R or all-S) based on the axis of the N(Me)-C
(phenyl) bonds, but the crystal is racemic, containing both
enantiomers in a 1:1 ratio. The dihedral angle and center-to-
center distance between the two central benzene rings are
Next, the 1H NMR spectrum of compound 2 in DMSO-d6 was
compared with those of bissquaramide 16 without N-methyl
groups, and the corresponding bisurea derivatives 15 and 1712
with or without N-methyl groups, respectively. The signals of
the aromatic protons of both N-methylated compounds 2 and
15 were observed at higher field than those of compounds 16
and 17 (without N-methyl groups), which exist in linear (trans,
Table 2. Comparison of 1H NMR signals of 2 and 15–17 in DMSO-d6.
Compound
X
Chemical shift of aromatic protons [ppm]
H1
H2
H3
H4
H5
H6
2 (N-Me)
16 (N-H)
Δδ[a]
6.90
7.10
0.20
6.92
6.96
0.04
7.06
7.40
0.34
7.08
7.28
0.20
6.81
7.51
0.70
6.83
7.45
0.62
6.30
7.59
1.29
6.28
7.67
1.39
6.41
7.26
0.85
6.51
7.07
0.56
6.75
7.39
0.64
6.85
7.16
0.31
15 (N-Me)
17 (N-H)
Δδ[a]
[a] Δδ=δ (N-H compound)–δ (N-Me compound).
ChemPlusChem 2021, 86, 198–205
www.chempluschem.org
201
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/cplu.202000678
ChemPlusChem
183 K in the case of 2 (data not shown). Next, we examined the
1
2
3
4
5
6
7
8
helical properties of 2 by means of CD spectroscopy. No chiral
induction of 2 was seen upon addition of optically active
amines, such as (+)-boronylamine, (+)-cyclohexanediamine,
and (+)-2-amino-1-propanol. Further studies on the helical
properties of oligosquaramides are on-going, focusing on the
introduction of optically active substituents and the addition of
other chiral reagents.
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
Conclusion
Figure 6. Comparison of 1H NMR signals in the aromatic region of
compounds (a) 8 and (b) 2 in CDCl3.
We have designed and synthesized oligosquaramides 1–4,
based on the (cis, cis) conformational preference of N,N’-
dimethyl-N,N’-diphenylsquaramide. X-ray crystallographic stud-
ies showed that all the squaramide moieties of compounds 1, 2,
and 13 are in (cis, cis) form, and these compounds exist as
folded structures in which the aromatic rings are located in a
face-to-face position. The meta-connected compounds 2 and 13
took helical structures with all-R or all-S axis chirality, but
formed racemic crystals with a 1:1 ratio of the enantiomers.
These compounds also existed as well-ordered folded structures
in solution. Thus, the N,N’-dimethylsquaramide moiety is
expected to be a useful linker for construction of aromatic
multilayered structures, like the N,N’-dimethylurea moiety.
However, the adjacent benzene rings in the multilayered
structures of oligosquaramides are more nearly parallel and are
located closer to each other, compared with those of oligour-
eas. In addition to the steric differences between aromatic
multilayers formed by oligosquaramides and oligoureas, there
are significant differences in the electronic properties of the
linkers. For example, squaramide is a more effective cation
acceptor than urea, and the four-membered ring of squaramide
has aromatic character. These properties of N,N’-dimethylated
squaramide are expected to be useful in the construction of
unique functional aromatic multilayered and helical foldamers.
trans) form. The chemical shift differences between 2 and 16
are larger than those between 15 and 17, especially for the
protons on the central benzene rings (H4–H6 in Table 2), which
indicates that the benzene rings of trissquaramide 2 are
arranged in a more compact layered structure than those of
bisurea 15, as was the case in the crystal structures.
1
The H NMR spectra of trissquaramides (3 vs 13) and hybrid
compounds (4 vs 14) were also compared (Table 3). In both
cases, fully N-methylated compounds 3 and 4 show the signals
of aromatic protons at higher field than those of the
corresponding partially N-methylated compounds 13 and 14.
The results, together with the crystal structures of 1, 2, and 13,
indicated that compounds 3 and 4 also took aromatic multi-
layered structures in solution. The folded structure of com-
pound 3 was confirmed by ROESY spectra (see the Supporting
Information), which indicated that the N-methyl groups on the
central squaramide moiety located near the terminal benzene
rings. The meta-connected compounds 2, 3, and 4 appeared to
take well-ordered helical structures in solution, like the crystal
structure of 2, although the conformers would be in rapid
1
equilibrium, as they could not be detected by H NMR even at
Table 3. Comparison of 1H NMR signals of 3, 4, 13, and 14.
Compound
X
Chemical shift of aromatic protons[a] [ppm]
H1
H2
H3
H4
H5
H6
H7
3 (N-Me)
13 (N-H)
Δδ[b]
6.89
7.11
0.22
6.95
7.02
0.07
7.06
7.38
0.32
7.06
7.27
0.21
6.80
7.48
0.68
6.78
7.43
0.65
6.28
7.22
0.94
6.17
7.10
0.93
6.68
6.84
0.16
6.49
6.77
0.28
6.15
6.98
0.83
6.80
6.94
0.14
6.40
6.56
0.16
6.31
6.47
0.16
4 (N-Me)
14 (N-H)
Δδ[b]
[a] Solvents: DMSO-d6 for 3 and 13, CD3OD for 4 and 14. [b] Δδ=δ (N-H compound)–δ (N-Me compound).
ChemPlusChem 2021, 86, 198–205
www.chempluschem.org
202
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/cplu.202000678
ChemPlusChem
Synthesis of Compound 1: Methyl iodide (3 ml, 0.05 mol) was
Experimental Section
1
2
3
4
5
6
7
8
9
added to a solution of 7 (96 mg, 0.20 mmol) and potassium tert-
butoxide (68 mg, 0.60 mmol) in dry DMF (4 mL). The mixture was
stirred at room temperature for 1 d. After evaporation, the residue
was extracted with methylene chloride and water. The organic layer
was washed with brine, dried over sodium sulfate, and evaporated.
The residue was purified by silica gel column chromatography
(methylene chloride : methanol=16:1) to give 1 (101 mg, quant).
General: All reagents were purchased from Sigma-Aldrich Chemical
Co., Wako pure Chemical Industries, Tokyo Kasei Kogyo Co., and
Kanto Kagaku Co., Inc. Silica Gel 60 N (spherical, neutral) and
Kieselgel 60 (230–400 mesh) for column chromatography were
1
purchased from Kanto Kagaku Co., Inc and Merck, respectively. H
and 13C NMR spectra were recorded on JEOL JNM-ECS400, JNM-
ECA500, and JNM-ECA600 spectrometers, and Bruker Avance 600
spectrometer. Mass spectral data were obtained on a Shimadzu
Biotech Axima CFRplus in the linear and reflectron modes using a
laser (λ=337 nm) and a Bruker Daltonics micro TOF-2focus in the
positive ion detection mode. X-ray crystallographic data were
collected on a Bruker SMART APEX II ULTRA diffractometer attached
with a CCD detector and graphite-monochromated MoKα (λ=
0.71073 Å) radiation. Data were corrected for absorption by the
multiscan semiemprical method implemented in SADABS and their
crystal structures were solved by intrinsic phasing method SHELXT
and refined by SHELXL. Full-matrix least-squares refinement was
performed on F2 for all unique reflections with anisotropic displace-
ment parameters for non-hydrogen atoms. All non-hydrogen atoms
were refined anisotropically. All hydrogen atoms were included as
their calculated positions.
1
1
Compound 1: H NMR H NMR (400 MHz,DMSO-d6) δ 7.05 (t, 4 H,
J=8 Hz), 6.89 (t, 2 H, J=8 Hz), 6,76 (d, 4 H, J=8 Hz), 6.51 (s, 4 H),
3.45 (s, 6 H), 3.38 (s, 6 H); 13C NMR (125 MHz, CDCl3) δ 186.67,
186.38, 167.76, 167.40, 142.49, 128.55, 124.33, 120.52, 116.73,
113.40, 38.04, 37.94; HRMS calcd for C30H26N4O4 [M+Na]+:
529.1836, Found: 529.1846.
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
Synthesis of Compound 2: Methyl iodide (7.5 ml, 0.12 mol) was
added to a solution of 8 (191 mg, 0.40 mmol) and potassium tert-
butoxide (136 mg, 1.21 mmol) in dry DMF (6 mL). The mixture was
stirred at room temperature for 1 d. After evaporation, the residue
was extracted with methylene chloride and water. The organic layer
was washed with brine, dried over sodium sulfate, and evaporated.
The residue was purified by silica gel column chromatography
(methylene chloride : methanol=16:1) to give 2 (122 mg, 60%).
Compound 2: 1H NMR (400 MHz, CDCl3) δ 7.00 (t, 4 H, J=8 Hz), 6.89
(t, 2 H, J= 8 Hz), 6.67 (t, 1 H, J=8 Hz), 6.57 (d, 4 H, J=8 Hz), 6.12
(dd, 2 H, J=8, 0.2 Hz), 5.75 (t, 1 H, J=2.4 Hz), 3.68 (s, 6 H), 3.50 (s, 6
H); 13C NMR (150 MHz, CDCl3) δ 168.11, 166.94, 143.02, 142.68,
129.07, 128.83, 125.27, 121.02, 116.67, 112.70, 39.03, 38.45, 27.87;
HRMS calcd for C30H26N4O4 [M+Na]+: 529.1843, Found: 529.1846.
Deposition Numbers: 2036188 (for 1), 2036189 (for 2, 2036190 (for
13) contain the supplementary crystallographic data for this paper.
These data are provided free of charge by the joint Cambridge
Crystallographic Data Centre and Fachinformationszentrum Karls-
ruhe Access Structures service www.ccdc.cam.ac.uk/structures.
Synthesis of Compound 6: N-Methylaniline (640 mg, 5.97 mmol)
was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5,
515 mg, 3.03 mmol) and zinc trifluoromethanesulfonate (113 mg,
Synthesis of Compound 9: A solution of 3,4-diethoxy-3-cyclo-
butene-1,2-dione (5, 2.043 g, 12.0 mmol) in ethanol (30 ml) and zinc
trifluoromethanesulfonate (851 mg, 2.34 mmol) were added to a
solution of aniline (1.100 g, 11.82 mmol) in ethanol (20 ml). The
mixture was stirred at room temperature for 2 days. The precip-
itates were removed by filtration. The filtrate was purified by silica
gel column chromatography (methylene chloride : methanol=
20:1) to give 9 (2.197 g, 86%). Compound 9: 1H NMR (600 MHz,
DMSO-d6) δ 10.76 (br s, 1 H), 7.35 (m, 4 H), 7.11 (m, 1 H), 4.77 (q, 2
H, J=7.2 Hz), 1.42 (t, 3 H, J=7.2 Hz); 13C NMR (125 MHz, DMSO-d6) δ
137.98, 129.08, 124.05, 119.61, 69.56, 15.67; HRMS calcd for
C12H11NO3 [M+Na]+: 240.0631, Found: 240.0631.
°
0.31 mmol) in dry ethanol (15 mL). The mixture was stirred at 45 C
for 19 h. After evaporation, methylene chloride and 2 N
hydrochloric acid were added to the residue. The organic layer was
washed with brine, dried over sodium sulfate, and evaporated to
1
give 6 (700 mg, quant). Compound 6: H NMR (400 MHz,CDCl3) δ
7.41 (t, 2 H, J=8 Hz), 7.30 (t, 1 H, J= 8 Hz), 7.17 (d, 2 H, J=8 Hz),
4.76 (br s, 2 H), 3.74 (br s, 3 H), 1.39 (br s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 184.51, 177.80, 141.57, 129.09, 127.11, 123.18, 69.98, 39.36,
15.93; HRMS calcd for C13H13NO3 [M+Na]+: 254.0787, Found:
254.0788.
Synthesis of Compound 10: A solution of m-nitroaniline (11.900 g,
86.16 mmol) in a mixture of toluene (95 ml) and DMF (5 ml) was
added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5,
6.980 g, 41.02 mmol) and zinc trifluoromethanesulfonate (3.083 g,
8.481 mmol) in a mixture of toluene (19 ml) and DMF (1 ml). The
Synthesis of Compound 7: 1,4-Phenylenediamine (33 mg,
0.31 mmol) was added to a solution of 6 (208 mg, 0.90 mmol) and
zinc trifluoromethanesulfonate (76 mg, 0.21 mmol) in a mixture of
dry toluene (1.9 mL) and DMA (0.1 mL). The mixture was stirred at
°
110 C for 1 d. The precipitates were corrected, washed with cooled
ethanol to give
(400 MHz,DMSO-d6) δ 9.14 (s, 2 H), 7.34 (m, 4 H), 7.18 (m, 6 H), 6.98
(s, 4 H), 3.67 (s, 6 H); 13C NMR (125 MHz, DMSO-d6) δ 184.97, 184.27,
166.88, 165.44, 141.78, 134.36, 128.82, 125.04. 121.48. 120.42, 38.36;
HRMS calcd for C28H22N4O4 [M+Na]+: 501.1528, Found: 501.1533.
°
mixture was stirred at 100 C for 1 d. The precipitates were
7
(127 mg, 85%). Compound 7: 1H NMR
collected, washed with methylene chloride/methanol to yield 10
(13.671 g, 94%). Compound 10: 1H NMR (600 MHz, DMSO-d6) δ
10.49 (br s, 2 H), 8.38 (s, 2 H), 7.91 (d, 2 H, J=7.2 Hz), 7.79 (d, 2 H,
J=8.4 Hz), 7.66 (t, 2 H, J=8.4, 7.8 Hz); 13C NMR (125 MHz, DMSO-d6)
δ 182.66, 165.96, 148.49, 130.74, 124.79, 117.51, 113.12, 99.52;
HRMS calcd for C16H9N4O6 [MÀ H]+: 353.0525, Found: 353.0528.
Synthesis of Compound 8: 1,3-Phenylenediamine (111 mg,
1.03 mmol) was added to a solution of 6 (693 mg, 3.00 mmol) and
zinc trifluoromethanesulfonate (250 mg, 0.69 mmol) in a mixture of
dry toluene (5.5 mL) and DMA (0.4 mL). The mixture was stirred at
Synthesis of Compound 11: A suspension of sodium hydride (60%,
3.40 g, 85.0 mmol, washed with n-hexane twice) in DMF (30 mL)
was added to a solution of 10 (13.671 g, 38.589 mmol) in DMF
°
110 C for 1 d. The precipitates were corrected, washed with cooled
°
(170 mL) at 0 C. After stirring at room temperature for 10 min,
ethanol, and then purified by silica gel column chromatography
(methylene chloride : methanol=16:1) to give 8 (205 mg, 42%).
Compound 8: 1H NMR (400 MHz,CDCl3) δ 7.57 (t, 4 H, J=8 Hz), 7.48
(t, 1 H, J= 8 Hz), 7.25 (d, 4 H, J=8 Hz), 7.20 (s, 1 H), 7.10 (t, 1 H, J=
8 Hz), 6.75 (dd, 2 H, J=8, 0.2 Hz), 5.87 (br s, 2 H), 3.86 (s, 6 H); 13C
NMR (125 MHz, CDCl3) δ 185.09, 181.93, 166.29, 163.86, 140.81,
138.84, 130.42, 130.32, 128.46, 123.82, 113.94, 108.88, 39.94; HRMS
calcd for C28H21N4O4 [MÀ H]+: 477.1564, Found: 477.1568.
methyl iodide (40 mL) was added to the mixture. The reaction
mixture was stirred at room temperature for 1 d, and poured into
saturated ammonium chloride. The precipitates were collected by
filtration, and washed with methanol to yield 11 (10.912 g, 74%).
Compound 11: 1H NMR (600 MHz, DMSO-d6) δ 7.62 (d, 2 H, J=
7.5 Hz), 7.56 (s, 2 H), 7.31 (d, 2 H, J=7.5 Hz), 7.29 (t, 2 H, J=7.8 Hz),
3.69 (s, 6 H); 13C NMR (125 MHz, DMSO-d6) δ 187.18, 167.17, 147.60,
ChemPlusChem 2021, 86, 198–205
www.chempluschem.org
203
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/cplu.202000678
ChemPlusChem
1
143.32, 130.12, 126.17, 118.52, 114.88, 37.80; HRMS calcd for
8%). Compound 4: Colorless prisms; H NMR (600 MHz, CD3OD) δ
1
2
3
4
5
6
7
8
9
C18H14N4O6 [M+Na]+: 405.0799, Found: 405.0806.
7.06 (t, 4 H, J=8.4 Hz), 6.95 (t, 2 H, J=7.2 Hz), 6.80 (t, 2 H, J=
7.8 Hz), 6.78 (d, 4 H, J=7.8 Hz), 6.49 (d, 2 H, J=7.8 Hz), 6.31 (d, 2 H,
J=7.8 Hz), 6.17 (s, 2 H), 3.44 (s, 6 H), 3.12 (s, 6 H), 3.05 (s, 6 H); 13C
Synthesis of Compound 12: A mixture of 11 (2.115 g, 5.53 mmol)
and 10% Pd/C (215.2 mg) in dry DMF (55 mL) was stirred under H2
NMR (125 MHz, DMSO-d6)
δ 188.75, 169.53, 163.59, 147.48,
°
atmosphere at 60 C for 2 d. The reaction mixture was filtrated over
147.23,145.27, 131.13, 130.86, 127.72, 127.31, 124.39, 120.46,
120.15, 91.87, 80.32, 40.57, 40.39, 40.17, 31.59, 31.31; HRMS calcd
for C36H36N6O4 [M+Na]+: 639.2671, Found: 639.2690.
celite, and the filtrate was evaporated to give 12 (3.239 g, quant).
Compound 12: 1H NMR (600 MHz, DMSO-d6) δ 6.76 (t, 2 H, J=
8.4 Hz), 6.19 (d, 2 H, J=7.8 Hz), 6.12 (s, 2 H), 6.10 (d, 2 H, J=7.8 Hz),
5.02 (br s, 4 H), 3.37 (s, 6 H); 13C NMR (125 MHz, DMSO-d6) δ 185.99,
168.04, 149.07, 143.54, 128.93, 110.64, 108.21, 106.26, 38.14; HRMS
calcd for C18H18N4O2 [M+H]+: 323.1498, Found: 323.1503.
Acknowledgements
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
Synthesis of Compound 13: 9 (149 mg, 0.685 mmol) was added to
a solution of 12 (104 mg, 0.322 mmol) and zinc trifluoromethane-
sulfonate (22.7 mg, 0.062 mmol) in a mixture of toluene (7.6 ml)
This work was partly supported by JSPS KAKENHI Nos.17H03997
and 19 K22486 (SF), 16 K08318 (AT) and 17 J00036 (KU), and JSPS
Core-to-Core Program, A. Advanced Research Networks. AT grate-
fully acknowledges funding from The Sumitomo Foundation and
The Naito Foundation. KU is grateful for financial support from
JSPS Research Fellow for Young Scientists. A part of this research
is a Cooperative Research Project of the Research Center for
Biomedical Engineering.
°
and DMF (0.4 ml). The solution was stirred at 100 C for 3 d. After
evaporation, ethanol was added to the residue. The precipitates
were collected by filtration to yield 13 (198 mg, 0.298 mmol, 93%).
1
Compound 13: H NMR (600 MHz, DMSO-d6) δ 9.77 (br s, 2 H), 9.74
(br s, 2 H), 7.48 (d, 4 H, J=7.8 Hz), 7.38 (t, 4 H, J=7.8 Hz), 7.22 (s, 2
H), 7.11 (t, 2 H, J=7.8 Hz), 6.98 (t, 2 H, J=7.8 Hz), 6.84 (d, 2 H, J=
7.8 Hz), 6.56 (d, 2 H, J=8.1 Hz), 3.63 (s, 6 H); 13C NMR (125 MHz,
DMSO-d6) δ 186.45, 181.22, 167.22, 165.79, 164.93, 143.98, 140.68,
139.09, 138.38, 129.67, 129.37, 123.43, 118.61, 114.91, 113.69,
110.40, 37.97; HRMS calcd for C38H27N6O6 [MÀ H]+: 663.1992, Found:
663.2011.
Conflict of Interest
Synthesis of Compound 3: A suspension of sodium hydride (60%,
21 mg, 0.535 mmol, washed with n-hexane twice) in DMF (2 mL)
was added to a solution of 13 (74 mg, 0.111 mmol) in DMF (3 mL)
The authors declare no conflict of interest.
°
at 0 C. After stirring at room temperature for 10 min, methyl iodide
Keywords: conformation analysis
structures · oligomers · squaramides
·
foldamers
·
helical
(1 mL) was added to the mixture, and the reaction mixture was
stirred at room temperature for 1 d. Saturated ammonium chloride
was added the mixture, and extracted with methylene chloride. The
organic layer was dried over sodium sulfate, and evaporated. The
residue was purified by PTLC (methylene chloride : methanol=
[1] a) R. I. Storer, C. Aciro, L. H. Jones, Chem. Soc. Rev. 2011, 40, 2330–2346;
b) J. Alemán, A. Parra, H. Jiang, K. A. Jørgensen, Chem. Eur. J. 2011, 17,
6890–6899.
1
20:1) to give 3 (8.8 mg, 0.012 mmol, 11%). Compound 3: H NMR
(600 MHz, CDCl3) δ 6.98 (t, 4 H, J=7.8 Hz), 6.86 (t, 2 H, J=7.8 Hz),
6.68 (t, 2 H, J=7.8 Hz), 6.58 (d, 4 H, J=7.2 Hz), 6.15 (d, 2 H, J=
7.8 Hz), 6.10 (d, 2 H, J=7.8 Hz), 5.81 (s, 2 H), 3.65 (s, 6 H), 3.44 (s, 6
H), 3.31 (s, 6 H); 13C NMR (125 MHz, CDCl3) δ 187.15, 186.67, 186.33,
168.53, 167.48, 166.70, 143.06, 142.82, 142.57, 129.37, 128.99,
125.65, 121.27, 116.84, 116.41, 112.58, 39.17, 38.67, 38.39, 29.73;
HRMS calcd for C42H36N6O4 [M+Na]+: 743.2588, Found: 743.2589
[2] a) H. H. Zou, J. Hu, J. Zhang, J.-S. You, D. Ma, D. Lü, R.-G. Xie, Mol. Catal.
A 2005, 242, 57–61; b) J. P. Malerich, K. Hagihara, V. H. Rawal, J. Am.
Chem. Soc. 2008, 130, 14416–14417; c) Y. Zhu, J. P. Malerich, V. H. Rawal
Angew. Chem. Int. Ed. 2010, 49, 153–156; Angew. Chem. 2010, 122, 157–
160; Angew. Chem. 2010, 122, 157–160; d) H. Jiang, M. W. Paixâo, D.
Monge, K. A. Jørgensen, J. Am. Chem. Soc. 2010, 132, 2775–2783.
[3] a) S. Tomas, R. Prohens, G. Deslongchamps, P. Ballester, A. Costa, Angew.
Chem. Int. Ed. 1999, 38, 2208–2211; Angew. Chem. 1999, 111, 2346–
2349; b) M. N. Piña, C. Rotger, B. Soberats, P. Ballester, P. M. Deya, A.
Costa, Chem. Commun. 2007, 963–965; c) R. Prohens, A. Portell, X.
Alcobe, Cryst. Growth Des. 2012, 12, 4548–4553; d) S. Park, J. Uchida, K.
Urushibara, H. Kagechika, T. Kato, A. Tanatani, Chem. Lett. 2018, 47, 601–
604; e) J. Atcher, A. Nagai, P. Mayer, V. Maurizot, A. Tanatani, I. Huc,
Chem. Commun. 2019, 55, 10392–10395.
[4] a) J. A. Butera, M. M. Antane, S. A. Antane, T. M. Argentieri, C. Freeden,
R. F. Graceffa, B. H. Hirth, D. Jenkins, J. R. Lennox, E. Matelan, N. W.
Norton, D. Quagliato, J. H. Sheldon, W. Spinelli, D. Warga, A. Wojdan, M.
Woods, J. Med. Chem. 2000, 43, 1187–1202; b) J. A. Burera, M. M. Antane,
S. A. Antane, T. M. Argentieri, C. Freeden, R. F. Graceffa, B. H. Hirth, D.
Jenkins, J. R. Lennox, E. Matelan, N. W. Norton, D. Quagliato, J. H.
Sheldon, W. Spinelli, D. Warga, A. Wojdan, M. Woods, Bioorg. Med.
Chem. Lett. 2007, 17, 1713–1717; c) J. Charton, B. P. Déprez, R. F. Déprez-
Poulain, Bioorg. Med. Chem. Lett. 2008, 18, 4968–4971; d) M. P. Dwyer, P.
Biju, Curr. Top. Med. Chem. 2010, 10, 1339–1350.
Synthesis of Compound 14: A solution of 12 (36 mg, 0.112 mmol)
in THF (5 ml) was added to a solution of phenyl isocyanate (21 mg,
0.175 mmol) in THF (1 ml). The mixture was stirred at room
temperature for 1 d. After evaporation, the residue was washed by
ethyl acetate to yield 14 (52 mg, 83%). Compound 14: 1H NMR
(600 MHz, DMSO-d6) δ 8.66 (br s, 2 H), 8.63 (br s, 2 H), 7.45 (d, 4 H,
J=6.0 Hz), 7.26 (t, 4 H, J=6.0 Hz), 7.11 (s, 2 H), 6.96 (t, 2 H, J=
6.0 Hz), 6.92 (t, 2 H, J=6.0 Hz), 6.79 (d, 2 H, J=6.0 Hz), 6.46 (d, 2 H,
J=1.2 Hz), 3.82 (s, 6H); 13C NMR (125 MHz, DMSO-d6) δ 186.53,
152.62, 143.42, 140.15, 139.77, 129.09, 122.25, 119.08, 118.57,
116.70, 114.20, 113.51, 110.58, 105.68; HRMS calcd for C32H28N6O4
[M+Na]+: 583.2061, Found: 583.2064.
Synthesis of Compound 4: A suspension of sodium hydride (60%,
13 mg, 0.32 mmol, washed with n-hexane twice) in DMF (1 mL) was
added to a solution of 14 (35 mg, 0.062 mmol) in DMF (2 mL) at
[5] V. Amendola, G. Bergamaschi, M. Boiocchi, L. Fabbrizzi, M. Milani, Chem.
Eur. J. 2010, 16, 4368–4380.
°
0 C. After stirring at room temperature for 10 min, methyl iodide
[6] a) S. Tomas, R. Prohens, M. Vega, M. C. Rotger, P. M. Deya, P. Ballester, A.
Costa, J. Org. Chem. 1996, 61, 9394–9401; b) R. Prohens, S. Tomas, J.
Morey, P. M. Deya, P. Ballester, A. Costa, Tetrahedron Lett. 1998, 39,
1063–1066; c) D. Quiñonero, A. Frontera, G. A. Suner, J. Morey, A. Costa,
P. Ballester, P. M. Deya, Chem. Phys. Lett. 2000, 326, 247–254; d) D.
Quiñonero, R. Prohens, C. Garau, A. Frontera, P. Ballester, A. Costa, P. M.
Deya, Chem. Phys. Lett. 2002, 351, 115–120; e) C. Garau, A. Frontera, P.
(0.2 mL) was added to the mixture, and the reaction mixture was
stirred at room temperature for 3 d. Saturated ammonium chrolide
was added to the mixture, and extracted with methylene chloride.
The organic layer was dried over sodium sulfate, and evaporated.
The residue was purified by PTLC (ethyl acetate) to give 4 (3 mg,
ChemPlusChem 2021, 86, 198–205
www.chempluschem.org
204
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/cplu.202000678
ChemPlusChem
Ballester, D. Quiñonero, A. Costa, P. M. Deya, Eur. J. Org. Chem. 2005,
179–183.
6442; c) A. Tanatani, A. Yokoyama, I. Azumaya, Y. Takakura, C. Mitsui, M.
Shiro, M. Uchiyama, A. Muranaka, N. Kobayashi, T. Yokozawa, J. Am.
Chem. Soc. 2005, 127, 8553–8561.
1
2
3
4
5
6
7
8
9
[7] Carlos E. Silva, He'lio F. Dos Santos, Nivaldo L. Speziali, Renata Diniz,
Luiz Fernando C. de Oliveira, J. Phys. Chem. A 2010, 114, 10097–10109.
[8] R. S. Muthyala, G. Subramaniam, L. Todaro, Org. Lett. 2004, 6, 4663–
4665.
[9] a) C. Rotger, B. Soberats, D. Quiñonero, A. Frontera, P. Ballester, J. Benet-
Buchholz, P. M. Deya, A. Costa, Eur. J. Org. Chem. 2008, 1864–1868; b) A.
Prtell, R. Barbas, D. Braga, M. Polito, C. Puigjaner, R. Prohens,
CrystEngComm 2009, 11, 52–54; c) A. Rostami, A. Colin, X. Y. Li, M. G.
Chudzinski, A. J. Lough, M. S. Taylor, J. Org. Chem. 2010, 75, 3983–
3992A.
[10] M. Kanda, K. Urushibara, S. Park, S. Fujii, H. Masu, K. Katagiri, I. Azumaya,
H. Kagechika, H. A. Tanatani, Tetrahedron 2019, 75, 2771–2777.
[11] V. Ramalingam, N. Bhagirath, R. S. Muthyala, J. Org. Chem. 2007, 72,
3976–3979.
[13] a) K. Yamaguchi, G. Matsumura, H. Kagechika, I. Azumaya, Y. Ito, A. Itai,
K. Shudo, J. Am. Chem. Soc. 1991, 113, 5474–5475; b) A. Tanatani, H.
Kagechika, I. Azumaya, F. Fukutomi, Y. Ito, K. Yamaguchi, K. Shudo,
Tetrahedron Lett. 1997, 38, 4425–4428.
[14] a) J. Clayden, L. Lemiègre, M. Helliwell, J. Org. Chem. 2007, 72, 2302–
2308; b) J. Clayden, L. Lemiègre, G. A. Morris, M. Pickworth, T. J. Snape,
L. H. Jones, J. Am. Chem. Soc. 2008, 130, 15193–15202.
[15] M. Kudo, T. Hanashima, A. Muranaka, H. Sato, M. Uchiyama, I. Azumaya,
T. Hirano, H. Kagechika, A. Tanatani, J. Org. Chem. 2009, 74, 8154–8163.
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
[12] a) H. Kagechika, T. Himi, E. Kawachi, Y. Hashimoto, K. Shudo, J. Med.
Chem. 1989, 32, 2292–2296; b) A. Tanatani, K. Yamaguchi, I. Azumaya, R.
Fukutomi, K. Shudo, H. Kagechika, J. Am. Chem. Soc. 1998, 120, 6433–
Manuscript received: October 13, 2020
Revised manuscript received: January 12, 2021
Accepted manuscript online: January 20, 2021
ChemPlusChem 2021, 86, 198–205
www.chempluschem.org
205
© 2021 Wiley-VCH GmbH