Conformational analysis of N-aryl-N-(2-azulenyl)acetamides

Article abstract of DOI:10.1016/j.tetlet.2018.09.053

Aromatic amides bearing 2-azulenyl group on the amide nitrogen were synthesized and their structures were investigated. The π-electron density of the N-aryl group was found to influence the cis-trans conformational preferences of these compounds in solution. X-ray crystallography revealed that the plane of the 2-azulenyl ring has a strong tendency to lie coplanar with the amide plane when the azulene group is located on the same side as the amide oxygen atom.

Full text of DOI:10.1016/j.tetlet.2018.09.053

Tetrahedron Letters xxx (2018) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Conformational analysis of N-aryl-N-(2-azulenyl)acetamides
⇑
Ai Ito, Takamasa Amaki, Ayako Ishii, Kazuo Fukuda, Ryu Yamasaki, Iwao Okamoto
Showa Pharmaceutical University, 3-3165, Higashi-Tamagawagakuen, Machida, Tokyo 195-8543, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Aromatic amides bearing 2-azulenyl group on the amide nitrogen were synthesized and their structures
were investigated. The -electron density of the N-aryl group was found to influence the cis-trans confor-
mational preferences of these compounds in solution. X-ray crystallography revealed that the plane of
the 2-azulenyl ring has a strong tendency to lie coplanar with the amide plane when the azulene group
is located on the same side as the amide oxygen atom.
Received 17 August 2018
Revised 12 September 2018
Accepted 20 September 2018
Available online xxxx
p
Ó 2018 Published by Elsevier Ltd.
Keywords:
Azulene
Amide conformational preference
Molecular switch
Although amides exist as cis and trans isomers because of the
partial double bond character of the CAN amide bond, the rotation
barrier of the CAN bond is low, and the isomers are usually in rapid
equilibrium at ambient temperature. Nevertheless, the conforma-
tional preference of amide compounds plays a key role in protein
folding [1–3], the bioactivities of pharmaceutical drugs, peptides
and proteins [4–6], and the catalytic activity of enzymes [7–9].
For example, the cis-trans isomerization of pSer/Thr-Pro motifs cat-
alyzed by Pin1 [protein interacting with NIMA (never in mitosis A)-
1] is involved in regulating a wide range of cellular processes [9].
We have previously shown that the conformational preference of
N,N-diaryl amides bearing six-membered aromatic rings, such as
of azulene has a zwitterionic character with a negatively charged
5-membered ring and a positively charged 7-membered ring that
enable Hückel aromatic stabilization of the structure. This means
that azulene has a relatively large dipole moment of m = 1.08 D
[22], whereas naphthalene has zero dipole moment. Azulene and
its derivatives have been widely applied in developing novel
advanced materials [24], such as conducting polymers [25,26],
optical materials [27,28], fluorescence switches [29,30], organic
field-effect transistors (OFETs) [31] and organic solar-cell materials
[32,33]. Furthermore, natural products and synthetic derivatives
bearing an azulene moiety, such as guaiazulene, possess interest-
ing bioactivities; e.g., anti-inflammatory [34], anti-ulcer [35,36],
anti-cancer [37] and other activities [38,39]. However, little infor-
mation is available about the conformational preferences of azu-
lenyl amides.
benzene and pyridine, is dependent on the relative
p-electron den-
sity of the N-aromatic moieties; i.e., the more -electron-rich N-
p
aryl group favors the trans position with respect to the amide oxy-
gen atom [10–13]. We also showed that some aromatic cis-amides
switch their conformation in response to external stimuli, such as
pH [14–17]. Further, in aromatic amides bearing N-thienyl group
Therefore, in this study, we aimed to explore the properties of
azulene-containing amide derivatives by synthesizing various N-
(2-azulenyl)acetamides and investigating their conformational
preferences in solution and in the solid state by means of NMR
and X-ray analysis. Our results indicate that the conformational
[18], although the
p-electron density influences the conforma-
tional preference, the size of the aromatic ring is also important.
Many kinds of aromatic groups can be used to build new functional
compounds incorporating amide structure [19,20], and here we
focused on azulene as a new type of N-aryl group for amides.
Azulene (C10H8) is a nonbenzenoid aromatic compound pos-
preference of N-(2-azulenyl)acetamides is dependent on the
p-
electron density of the N-aromatic moieties. Interestingly, N-(2-
azulenyl)acetamides tend to exist predominantly in the B-form,
in which the 2-azulenyl group is located on the same side as the
amide oxygen atom, in contrast to N,N-diaryl acetamides bearing
N-thienyl group [18].
2-Bromoazulene 4 was prepared via three steps from azulene 1
according to the reported procedures (Scheme 1) [40–42]. First, a
mixture of azulene 1, pin2B2, [IrCl(cod)]2 and 2,20-bipyridine
was refluxed in dry cyclohexane to give 2 (65% yield) together
with a small quantity of 20 (15%). Compound 2 was converted into
sessing 10 p-electrons, and its unique characteristics are well doc-
umented (Fig. 1) [21–23]. It is an isomer of naphthalene, but has
significantly different properties; e.g., naphthalene is colorless,
while azulene has a deep blue color [23]. In addition, the molecule
⇑
Corresponding author.
E-mail address: iokamaoto@ac.shoyaku.ac.jp (I. Okamoto).
https://doi.org/10.1016/j.tetlet.2018.09.053
0040-4039/Ó 2018 Published by Elsevier Ltd.
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2
A. Ito et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Fig. 1. Properties of azulene.
Fig. 2. Conformational preference of N-(2-azulenyl)acetamide 7a–7g.
on the opposite side and the same side as the amide oxygen atom,
respectively (Fig. 2).
The major conformer was assigned by means of NOE measure-
ments at low temperature. In the case of 7a, the major acetyl pro-
ton signal was correlated with only N-phenyl protons (Ph-2 and
Ph-6, 3.1%, Fig. 3 and Fig. S2), indicating that the major conformer
of 7a is the B-form in which the azulenyl group is located on the
same side as the amide oxygen atom (99% at 183 K, Table 1, entry
1).
Next, we investigated the conformational preferences of N-(2-
azulenyl)acetamides bearing an electron-withdrawing group on
the benzene ring, 7b–7d (fluoro series) and 7e–7g (nitro series)
(see Fig. 2). The temperature dependence of the 1H NMR spectra
and the NOE correlations of 7b–7g at 183 K are shown in the sup-
plementary data.
Major conformers and NOE correlations of 7a–7g are shown in
Fig. 3. In the cases of 7b–7d, the major acetyl proton signal was
correlated with the N-phenyl protons (7b, 3.3%; 7c, 2.5%), and
the minor acetyl proton signal was correlated with azulenyl pro-
tons (7b, 7.7%; 7c, 7.1%; 7d, 8.6%), respectively (Figs. S4, S6, S8).
These results indicated that the major conformers of 7b–7d are
in B-form.
In the cases of 7e and 7f bearing a mono-nitrophenyl group, the
major acetyl proton signal was correlated with N-phenyl protons
(7e, 3.4%; 7f, 3.7%) and the minor signal was correlated with azu-
lenyl protons (7e, 4.8%; 7f, 8.0%) (Figs. S10 and S12). But, in the
case of 7g bearing a dinitrophenyl group (para and ortho positions),
the major acetyl proton signal was correlated with the 1,3-position
azulene protons (7g, 1.7%) and the minor signal was correlated
with the 6-position N-phenyl proton (7g, 2.8%) (Fig. S14). These
results indicated that the major conformers of 7e and 7f are the
B-form, but the major conformer of 7g is the A-form.
Scheme 1. Synthesis of 2-bromoazulene (4).
2-hydroxyazulene 3 using hydrogen peroxide. Bromination of 3
using PBr3 gave 2-bromoazulene 4 (80% yield).
We synthesized N-(2-azulenyl)acetamides 7a–7g using 2-bro-
moazulene 4 as summarized in Scheme 2. First, compound 5 was
prepared from 4 and aniline in the presence of Pd2(dba)3 catalyst
and ( )-BINAP in 78% [43]. When compound 5 was reacted with
acetic anhydride, compound 8 was obtained in 75% yield as the
major product instead of 7a (Route A). Therefore, 7a–7g were pre-
pared from the corresponding amides 6a–6g with 2-bromoazulene
(4) by means of Cu-catalyzed coupling reaction [44] (Route B).
In order to investigate the conformational preference of N-(2-
azuleny)acetamides 7 in solution, we first examined the tempera-
ture dependence of the 1H NMR spectra of 7a bearing a phenyl
group. The 1H NMR spectra of 7a in CD2Cl2 showed one set of sig-
nals at 303 K, but at lower temperature these peaks were broad-
ened and separated into two sets of signals, due to the A-form
and B-form amide conformers (Fig. S1). Here, A-form and B-form
refer to the conformers in which the 2-azulenyl group is located
Scheme 2. Synthesis of N-(2-azulenyl)acetamides 7a–7g.
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A. Ito et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
Fig. 3. Major conformers and NOE correlations of 7a–7g.
Table 1
Conformational preference of N-(2-azulenyl)acetamides 7a–7g in CD2Cl2 at 183 K.
Entry
Amidea
R
Major form
Ratio (%)b
D
G° (kcal/mol)c
1
2
3
4
5
6
7
7a
7b
7c
7d
7e
7f
phenyl
B
B
B
B
B
B
A
99
93
85
67
80
82
89
ꢀ1.67
ꢀ0.94
ꢀ0.63
ꢀ0.26
ꢀ0.50
ꢀ0.55
+0.76
3,4,5-trifluorophenyl
2,3,4,5-tetrafluorophenyl
2,3,4,5,6-pentafluorophenyl
4-nitrophenyl
2-nitrophenyl
2,4-dinitrophenyl
7 g
a
b
c
See Fig. 2.
The ratio at 183 K was determined by 1H NMR measurement.
D
G° = ꢀRT ln ([B-form]/[A-form]).
These assignments were supported by the observed anisotropic
183 K is 89% (Table 1, entry 7). These results suggest that the con-
formational preferences of these amides are dependent on the p-
effects (Fig. S15). For example, the Az-4 and Az-8 proton peaks of
the major conformers of 7a–7f were shifted to higher field than
those of the minor conformers owing to the carbonyl group,
whereas the Az-4 and Az-8 proton peaks of the major conformer
of 7g were shifted to lower field than those of the minor conformer.
In addition, the acetyl signals of the major conformers of 7a–7f
appeared at higher field than those of the corresponding minor
conformers. On the other hand, the acetyl signal of the major con-
former of 7g appeared at lower field than that of the corresponding
minor conformer. This is reasonable, because benzene and azulene
should have different effects on the acetyl signals. A similar phe-
nomenon was reported for N-aryl-N-(2-thienyl)acetamides [18].
Conformation ratios of 7b–7g are summarized in Table 1. In the
cases of 7b-7d bearing tri-, tetra- and penta-fluoro benzene deriva-
tives, the ratios of the B-form conformers at 183 K are 93% (7b,
3,4,5-triFPh), 85% (7c, 2,3,4,5-tetraFPh) and 67% (7d, 2,3,4,5,6-pen-
taFPh), respectively (Table 1, entries 2–4). In the cases of 7e (4-
NO2Ph) and 7f (2-NO2Ph), the major conformers are also B-form,
and the ratios of B-form conformers at 183 K are almost the same;
80% (7e) and 82% (7f) (Table 1, entries 5 and 6). On the other hand,
in the case of 7g (2,4-diNO2Ph), the ratio of the A-form conformer at
electron density of the N-phenyl group. In the case of 7b–7d, as
the number of fluoro groups on the benzene ring increases, the
ratio of major B-form conformer decreases. Likewise, in the case
of 7e–7g containing nitrobenzene, the ratio of A-form increases
as the p-electron density of the N-phenyl group decreases.
Next, we conducted X-ray crystallographic analysis of 7a and
7e–7g (see Supplementary data). The crystal structures are illus-
trated in Fig 4. The three conformers of 7a and 7e all exist in the
B-form. In addition, the two conformers of 7f both take the B-form
in the crystal. Thus, the conformational preferences of 7a, 7e and 7f
in the crystal were the same as those in solution. On the other
hand, 7g bearing a 2,4-dinitrophenyl group exists in B-form in
the crystal; that is, its conformational preference in the crystal is
different from that in solution. This may be because intermolecular
aromatic interaction stabilizes the B-form in the crystal, that is, the
2,4-dinitrophenyl group is placed with its edge close to the face of
the azulene moiety, and this edge-to-face interaction affects the
structure in the crystal (see Supplementary data).
The amide torsion angle and dihedral angle between the amide
plane and the N-(2-azulenyl) and N-phenyl groups in 7a and 7e–g
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4
A. Ito et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Fig. 4. Crystal structures of 7a and 7e–7g. #The crystal contains several conformers: 7a (three types); 7f (two types).
Table 2
Torsion and dihedral angles (°) around amide bonds of N-(2-azulenyl)acetamides 7a and 7e–7g.
Amide
Amide-form
Torsion anglea (°)
Dihedral angle (°)
RANAC@O
R-amide
7a
B
B
B
B
B
B
B
4.43 (Azb)
6.43 (Az)
9.59 (Az)
8.47 (Az)
0.78 (Az)
7.15 (Az)
0.02 (Az)
4.64 (Ph)
2.08 (Ph)
14.39 (Ph)
7.57 (4-NO2Ph)
3.12 (2-NO2Ph)
3.21 (2-NO2Ph)
1.84 (2,4-diNO2Ph)
5.61 (Azb)
17.57 (Az)
35.77 (Az)
32.77 (Az)
8.24 (Az)
8.40 (Az)
1.22 (Az)
87.69 (Ph)
86.79 (Ph)
66.59 (Ph)
72.04 (4-NO2Ph)
76.70 (2-NO2Ph)
82.07 (2-NO2Ph)
83.62 (2,4-diNO2Ph)
7e
7f
7 g
a
The absolute values (0–90°) of the torsion angles are indicated.
Az is the 2-azulenyl group.
b
are shown in Table 2. The torsion angles are less than 15°, and each
amide bond is planar in the crystal. In the cases of 7a, 7e–g, the
azulene ring, which is located on the same side as the amide oxy-
gen atom, is coplanar with the amide plane: the dihedral angles
between the amide plane and N-azulenyl ring are 5.6°, 17.6° and
35.8° (7a), 33° (7e), 8.2° and 8.4° (7f), and 1.2° (7g). On the other
hand, the N-phenyl ring, which is located on the opposite side to
the amide oxygen atom, is nearly perpendicular to the amide plane
with dihedral angles of 66-88°. Recently, we reported that in N-
aryl-N-(3-thienyl)acetamides, the thiophene ring tends to lie at a
smaller dihedral angle from the amide plane than the benzene ring,
when it is cis to oxygen. For example, in the case of N,N-dipheny-
lacetamides, the dihedral angles between the amide plane and the
phenyl ring are ca. 60–89° in the crystal [12]. On the other hand, in
N-phenyl-N-(3-thienyl)acetamide, the dihedral angle between the
amide plane and N-thienyl ring is 24.1° in the crystal [18]. There-
fore, the azulene ring in N-aryl-N-(2-azulenyl)acetamides shows
a similar tendency to the thiophene ring in N-aryl-N-(3-thienyl)ac-
etamides, as described above. In addition, the azulene ring tends to
be more nearly coplanar with the amide plane than does the thio-
phene ring in the solid state. Thus, the 2-azulenyl group on amide
nitrogen tends to favor the amide plane, and the conformational
preference of these amides in solution can be regarded as a result
of this steric feature of the N-azulenyl group. That is, although the
p-electron density of the five-membered ring of azulene may be
greater than that of benzene, the electronic repulsion between car-
bonyl oxygen and N-2-azulene part is less severe than that
between carbonyl oxygen and the N-phenyl moiety (Fig. 5).
In conclusion, we synthesized 7a–7g and investigated their con-
formations in solution and in the solid state by means of NMR and
X-ray crystallographic analysis. Our results are essentially consis-
tent with previous findings showing that the conformational pref-
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A. Ito et al. / Tetrahedron Letters xxx (2018) xxx–xxx
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