Synthesis and conformational analysis of N-aryl-N-(3-thienyl)acetamides

Article abstract of DOI:10.1016/j.tetlet.2018.05.037

The cis-trans conformational equilibrium of amides is of interest because it can be used to control functional activity. Here, we designed and synthesized a series of N-(3-thienyl)amides in order to study the factors affecting their conformational equilibrium. NMR studies showed that the major conformer of N-methyl-N-(3-thienyl)amide in solution is the E-form (cis form), as is the case for N-methylacetamide. For N-aryl-N-(3-thienyl)amides bearing an N-phenyl moiety, the major conformers differ depending on not only the relative π-electron density of the N-aryl moiety, but also its size. X-ray analysis showed that their solid-state conformational preferences were similar to those in solution.

Full text of DOI:10.1016/j.tetlet.2018.05.037

Tetrahedron Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and conformational analysis of N-aryl-N-(3-thienyl)
acetamides
⇑
Ai Ito, Yuki Asami, Marino Asato, Kazuo Fukuda, Ryu Yamasaki, Iwao Okamoto
Showa Pharmaceutical University, 3-3165, Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The cis-trans conformational equilibrium of amides is of interest because it can be used to control func-
tional activity. Here, we designed and synthesized a series of N-(3-thienyl)amides in order to study the
factors affecting their conformational equilibrium. NMR studies showed that the major conformer of
N-methyl-N-(3-thienyl)amide in solution is the E-form (cis form), as is the case for N-methylacetamide.
For N-aryl-N-(3-thienyl)amides bearing an N-phenyl moiety, the major conformers differ depending on
Received 13 April 2018
Revised 11 May 2018
Accepted 15 May 2018
Available online xxxx
not only the relative
their solid-state conformational preferences were similar to those in solution.
Ó 2018 Published by Elsevier Ltd.
p-electron density of the N-aryl moiety, but also its size. X-ray analysis showed that
Keywords:
Aromatic amide
Thiophene
Cis-trans equilibrium
Introduction
p-electron-rich N-aryl group is preferentially located trans to the
amide oxygen atom.14–16 This effect is important in sterical
structure of N-aryl amides, and is useful to design or control the
structure of those amides.17 We speculated that if the conforma-
tional preference of N,N-diarylamides is influenced by electronic
repulsion between the carbonyl and the aryl groups, it should be
also influenced by the size of the aromatic ring. Here, we aimed
to test this idea.
Amide is a key structure in peptides and proteins and an impor-
tant building block for pharmaceutical drugs. The amide bond has
a partial double bond character, and so amides can exist in a cis–
trans conformational equilibrium. The conformational preference
of amides is an important issue because it can be utilized to control
the functional activity of bioactive compounds,1–3 analogously
with other external stimulus switches.4,5 For example, tamibaro-
ten, which has activity against acute promyelocytic leukaemia
(APL),6 exists in trans amide form, but N-methylation of the amide
nitrogen switches the conformational preference from trans to cis
amide and renders the compound inactive.1 It is a general trend
that secondary amides such as benzanilide takes trans-amide form,
while N-methylbenzanilide favors cis-amide form both in the solid
state and in solution.7,8 In order to investigate the factors
underlying these properties, we have synthesized various aromatic
cis-amides, and we reported that some of them switch their confor-
mation in response to external stimuli, such as pH.9–12 One reason
for the cis conformational preference associated with N-methyla-
tion is considered to be the effect of electronic repulsion between
Thiophene is a heterocyclic five-membered aromatic ring and
has a higher
p
-electron density than benzene.18–20 Thiophene is
an important structural component of pharmaceuticals, natural
products, synthetic devices and materials. For example, duloxetine
is used to treat depression,21 and pyrantel is an antiparasitic.22 In
addition, oligo- and polythiophene derivatives have been widely
applied in optoelectronic devices and sensors.23–25 However, little
information is available about the conformational preferences of
thienyl amides.
In this study, we focused on the conformational preferences
of N,N-diarylamides bearing thiophene. To avoid the dominant
effect of chalcogen-bonding interaction in N-(2-thienyl)amides
and related compounds,26–29 we designed and synthesized vari-
ous N-(3-thienyl)amides 3a-3f without an intramolecular SÁ Á ÁO
interaction and investigated their conformational preferences in
solution and in the solid state by means of NMR and X-ray
analysis.
the carbonyl lone pair and the aryl p
-electrons.13 From this point of
view, we have investigated the conformational preference in
N,N-diaryl type amides bearing six-membered aromatic rings, such
as benzene and pyridine. Our results indicate that the conforma-
tional preference of N,N-diarylamides is dependent on the relative
p-electron densities of the N-aromatic parts; that is, the more
Results and discussion
⇑
We synthesized N-(3-thienyl)acetamides 3a-3f as summarized
in Scheme 1. The acetamide derivatives 2a-2c are commercially
Corresponding author.
E-mail address: iokamoto@ac.shoyaku.ac.jp (I. Okamoto).
https://doi.org/10.1016/j.tetlet.2018.05.037
0040-4039/Ó 2018 Published by Elsevier Ltd.
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2
A. Ito et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Scheme 1. Synthesis of N-arylacetamides.
available. The other acetamide derivatives 2d-2f were prepared by
acetylation of the corresponding amines 1d-1f (method A).30
Compound 3a was prepared from N-methylacetamide 2a with
3-bromothiophene in the presence of CuI catalyst and N,N’-
dimethylethylenediamine in 52% yield (method B).31 Compounds
3b-3e were prepared from the corresponding amides 2b-2e with
3-bromothiophene in the presence of CuI catalyst and trans-1,2-
diaminocyclohexane in 35–91% yield (method C).31 When N-(4-
nitrophenyl)acetamide 2f was reacted with 3-bromothiophene in
method C, N-(4-nitrophenyl)-3-thiophenamine 4 was unexpect-
edly obtained in 40% yield as a major product instead of 3f.
Therefore, 3f was prepared from 4 in acetic anhydride with
Cu(BF4)2Á6H2O catalyst in 74% yield (method A). We also synthe-
sized N,N-diphenyl type amide 5 from 2f using method B, for
comparison of conformational behavior.
Fig. 1. Conformational preferences of N-(3-thienyl)acetamides 3a-3f.
To investigate the conformational preference of N-(3-thienyl)
acetamides 3a-3f in solution, we examined the temperature
dependence of the 1H NMR spectra of these amides. The 1H NMR
spectra of 3a-3f in CD2Cl2 showed one set of signals at 303 K, but
at lower temperature these peaks were broadened and separated
into two sets of signals, due to the E-form and Z-form amide con-
formers (Figs. S1, S3, S5, S7, S9, S11). Here, E-form and Z-form refer
to the conformers in which the 3-thienyl group is located on the
opposite side and the same side as the amide oxygen atom, respec-
tively (Fig. 1). The major conformers of 3a-3f were assigned by
means of NOE measurements at low temperature. In the case of
3a at 223 K, the major signal of acetyl protons was correlated with
only thienyl protons (Th-2; 3.4% and Th-4; 2.3%), and the minor
signal of acetyl protons and N-methyl protons were correlated
with each other (Fig. S2). Therefore, the major conformer of 3a is
E-form, in which the thienyl group is located at the opposite side
from the amide oxygen atom (Fig. 2). In the case of 3b at 213 K,
the major signal of acetyl protons was correlated with only phenyl
protons (Ph-2 and Ph-6, 5.3%), and the minor signal of acetyl
Fig. 2. Major conformers and NOE correlations of 3a-3f.
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A. Ito et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
protons was correlated with thienyl protons (Th-2; 5.5%, Th-4;
3.3%) (Fig. S4). Similarly, in the cases of 3c and 3d, the major signal
of acetyl protons was correlated with only phenyl protons (3c, Ph-2
and Ph-6, 5.8% at 183 K; 3d, Ph-2 and Ph-6: 7.5%, Ph-3 and Ph-5:
2.6% at 253 K, see Figs. S6 and S8). These results indicated that
the major conformers of 3b-3d are the Z-form (Fig. 2). On the other
hand, in the cases of 3e and 3f, acetyl protons were correlated with
only thienyl protons (3e, Th-2; 5.1% and Th-4; 4.1% at 213 K; 3f,
Th-2; 6.5% and Th-4; 3.8% at 203 K, see Figs. S10 and S12). These
results indicated that the major conformers of 3e-3f are the E-form
(Fig. 2).
These assignments of the major conformers of 3b-3f were sup-
ported by the anisotropic effect (Fig. S15). For example, the Th-4
proton peaks of the major conformers of 3b-3d were shifted to
higher field than those of the minor conformers owing to the car-
bonyl group, whereas the Th-4 proton peaks of the major conform-
ers of 3e and 3f were shifted to lower field than those of the minor
conformers. In addition, acetyl signals of the major conformers of
3b-3d appeared at higher field than those of the corresponding
minor conformers. On the other hand, acetyl signals of the major
conformers of 3e and 3f appeared at lower field than those of the
corresponding minor conformers. It is reasonable because geomet-
rically different two aromatic rings, benzene and thiophene, should
have different effect on higher field shift of acetyl signals.
Therefore, we next investigated the crystal structures of these
amides using X-ray crystallographic analysis. Compounds 3a and
3e were obtained as oils, but 3b-3d and 3f crystallized as prisms.
Their crystal structures are shown in Fig. 3. Compound 3b bearing
a phenyl group takes the Z-form as well as two disordered confor-
mations. Compounds 3c and 3d exist in Z-form, while 3f exists in E-
form. Thus, conformational preferences in the solid state were
essentially the same as those in solution. Table 2 shows the torsion
angles around the amide bond and dihedral angles between the
amide plane and the N-thienyl and N-phenyl groups in 3b-3d
and 3f. The torsion angles are less than 6°, and each amide bond
is planar in the crystal.
In the N,N-diphenylacetamide derivatives we reported before,
the dihedral angles between the amide plane and the phenyl rings
in the crystal are much larger (ca. 60–89°), that is, the two N-phe-
nyl rings are nearly perpendicular to the amide plane. For example,
in N-(3,5-dihydroxyphenyl)-N-phenylacetamide, the dihedral
angles between the amide plane and phenyl ring are 88.7° for dihy-
droxyphenyl and 80.1° for the unsubstituted phenyl group.15
Conformational ratios of 3a-3f are summarized in Table 1. The
major conformer of 3a bearing a methyl group is the E-form (90%
at 223 K, Table 1, entry 1), as in the case for most N-methylated
secondary amides.1,7 In the case of 3b bearing a phenyl group,
the major conformer is the Z-form, with the N-phenyl group
located opposite the amide oxygen atom (68% at 213 K, Table 1,
entry 2). In the cases of 3c and 3d containing an electron-donating
group on the phenyl group, the major conformer is also the Z-form:
the ratios of Z-form conformer are 72% (3c, 183 K) and 78% (3d,
253 K) (Table 1, entries 3 and 4). On the other hand, in the cases
Z-form
3ba
Z-form
Z-form
3c
3d
of 3e and 3f containing a p-electron-poor phenyl group, the major
conformer is the E-form (3e; 74%, 213 K, 3f; 87%, 203 K, see Table 1,
entries 5 and 6). These results indicate that the conformational
preferences of these amides are dependent on the relative
tron densities of the two N-aromatic parts. In the cases of 3b-3d,
the Z-form ratio increases as the -electron density of N-phenyl
group increases. On the other hand, in the cases of 3e and 3f con-
taining a -electron-poor phenyl group, the N-thienyl group is
p-elec-
p
p
located opposite the amide oxygen atom. These results are essen-
tially in accordance with previous findings.14–16
Benzene is considered to have a lower p-electron density in the
E-form
ring than thiophene.18,32 However, the major conformer of 3b
bearing a phenyl group is Z-form, and this cannot be explained in
Z-form
3f
5
terms of the
p-electron density of N-aryl groups, in contrast to
the other N,N-diarylamides.14–16 These results suggested that the
effect of thiophene on amide structure is similar to, but not exactly
the same as that of the benzene ring.
Fig. 3. The crystal structures of N-(3-thienyl)acetamides 3b-3d, 3f and N-(4-
nitrophenyl)-N-phenylacetamide 5. aTwo other disordered conformations were
observed: one was assigned as predominantly E-form (ca. 77%) and the other as
predominantly Z-form (ca. 85%).
Table 1
Conformational preference of 3a-3f in CD2Cl2.
Entry
Amidea
R
Major form
Ratio
(%)b
Temp
(K)
DG°
(kcal/mol)c
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
Methyl
Phenyl
4-methylphenyl
4-methoxyphenyl
2,3,4,5-tetrafluorophenyl
4-nitrophenyl
E
Z
Z
Z
E
E
90
68
72
78
74
87
223
213
183
253
213
203
+0.97
-0.32
-0.34
-0.64
+0.44
+0.77
a
b
c
See Fig. 1.
The ratio was determined by 1H NMR measurement.
G° = ÀRT ln ([Z-form]/[E-form]).
D
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4
A. Ito et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Table 2
Torsion and dihedral angles (°) around amide bonds of N-(3-thienyl) acetamides 3b-3d, 3f and N-(4-nitrophenyl)-N-phenylacetamide 5.
Amide
Amide-form
Torsion anglea(°)
Dihedral angle(°)
ArANAC@O
Ar-amide
3b
3c
3d
3f
5
Z
Z
Z
E
Z
1.65 (Thb)
1.34 (Th)
1.15 (Th)
3.89 (Th)
12.26 (Th)
5.74 (Ph)
24.14 (Thb)
24.01 (Th)
31.28 (Th)
73.08 (Th)
68.80 (Ph)
87.42 (Ph)
1.76 (4-MePh)
0.23 (4-MeOPh)
1.41 (4-NO2Ph)
7.65 (4-NO2Ph)
81.53 (4-MePh)
82.66 (4-MeOPh)
59.02 (4-NO2Ph)
42.05 (4-NO2Ph)
a
The absolute values (0–90°) of the torsion angles are indicated.
Th is the 3-thienyl group.
b
the solid-state structure, as shown in Fig. 3. Compound 5 exists
in Z-form, which is consistent with the preference in solution.
The dihedral angles of the N-phenyl moieties were similar to those
in 3f (Table 2).
Fig. 4 compares the conformational preferences of 3f and 5 in
CD2Cl2 at 203 K. In both major conformations, 4-nitrophenyl group
is located on the same side as the amide oxygen atom, though the
ratio of 3f (87%, see Table 1 entry 6) is less than that of 5 (91%). This
may reflect the repulsion between the aromatic moiety and the
carbonyl group. That is, although the relative
p-electron density
of the thiophene to the N-(4-nitrophenyl) moiety of 3f can be con-
sidered as larger than that of the benzene of 5, the electronic repul-
sion between the carbonyl oxygen and thiophene of 3f is less than
that between the carbonyl and benzene of 5. Considering from
crystal structures, one reason of this difference can be the dihedral
angles (Ar-amide) of N-phenyl and N-thienyl groups, thiophene
ring tends to be placed at smaller dihedral angle form amide place
than benzene ring, when cis to oxygen.
In conclusion, we designed and synthesized a series of N-(3-
thienyl)acetamides 3a-3f and investigated their conformational
preferences in solution and in the solid state. Our results indicate
that the conformational preferences of these amides are dependent
Fig. 4. Conformational preferences of 3f and 5 in CD2Cl2 at 203 K.
on not only the relative
p-electron densities of the N-aromatic
moieties, but also on the size of the aromatic ring on the nitrogen
atom. These findings should be helpful in the design of novel aro-
matic amide structures, and may offer opportunities for functional
switching.
In the case of 3b (partially Z-form), and 3c-3d (Z-form), the thio-
phene ring, which is located on the same side as the amide oxygen
atom, is nearly parallel to the amide plane: the dihedral angles
between the amide plane and N-thienyl ring are 24.1° (3b), 24.0°
(3c), and 31.3° (3d). In contrast, the N-phenyl ring of 3b-3d is
nearly perpendicular to the amide plane: the dihedral angles are
87.4° (3b), 81.5° (3c), and 82.7° (3d).
On the other hand, in the case of 3f (E-form), both the phenyl
ring and thiophene ring are placed at large torsion angles from
the amide plane, as in the case of N,N-diphenylacetamide deriva-
tives15: the dihedral angles between the amide plane and N-thienyl
ring (73.1°) and between the amide plane and N-phenyl ring
(59.0°) are close to perpendicular to the amide plane. These crystal
structures indicated that the N-thienyl moiety has a different steric
character from the N-phenyl group, that is, it tends to lie parallel to
amide plane when cis to oxygen, and is twisted in the trans
position.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2018.05.037.
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