Redox-responsive conformational alteration of aromatic amides bearing N-quinonyl system

Article abstract of DOI:10.1016/j.tet.2012.04.114

Redox-induced conformational alteration of N-aryl-N-phenylamides, in which the N-aryl group consists of a hydroquinone-p-quinone system, was examined. The reduced form bearing a dihydroxyphenyl or dimethoxyphenyl group exists mainly in the E-form, whereas the oxidized form bearing a N-benzoquinone moiety takes the Z-form both in the crystal and in solution. This redox-induced conformational alteration is associated with a marked change in optical properties. This system appears to have suitable properties for use in external redox stimulus-responsive functional switching.

Full text of DOI:10.1016/j.tet.2012.04.114

Tetrahedron 68 (2012) 5346e5355
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Redox-responsive conformational alteration of aromatic amides bearing
N-quinonyl system
,
a
a
b
c
Iwao Okamoto a , Yusuke Takahashi , Mika Sawamura , Mio Matsumura , Hyuma Masu ,
*
Kosuke Katagiri d, Isao Azumaya d, Masanori Nishino a, Yukari Kohama a, Nobuyoshi Morita a,
Osamu Tamura a, Hiroyuki Kagechika e, Aya Tanatani b
,
*
a Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan
b Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan
c Chemical Analysis Center, Chiba University, Japan
d Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Kagawa, Japan
e Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 April 2012
Received in revised form 27 April 2012
Accepted 28 April 2012
Available online 3 May 2012
Redox-induced conformational alteration of N-aryl-N-phenylamides, in which the N-aryl group consists
of a hydroquinoneep-quinone system, was examined. The reduced form bearing a dihydroxyphenyl or
dimethoxyphenyl group exists mainly in the E-form, whereas the oxidized form bearing a N-benzo-
quinone moiety takes the Z-form both in the crystal and in solution. This redox-induced conformational
alteration is associated with a marked change in optical properties. This system appears to have suitable
properties for use in external redox stimulus-responsive functional switching.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Aromatic amide
Molecular switch
Molecular device
External stimulus responsive
Oxidation
Reduction
1. Introduction
and clinical applications.8,9 Various types of organic and inorganic
molecules with switching functions have been developed. Gener-
Regulation of three-dimensional structures and their dynamic
behaviors is important for the development of functional molecular
machines, such as molecular switches and molecular rotors. Mo-
lecular switches are defined as molecules that can be reversibly
interconverted between two or more stable states by some external
stimulus, such as light, electrical field, chemical reaction or in-
teraction with an analyte species. When the interconversion is
linked to some output, such molecules are potentially useful as
molecular devices in the fields of nanotechnology, analytical
chemistry, chemical biology, and so on.1e4 For example, photo-
ally, switching systems based on structural change of small organic
molecules, such as cyclization of 1,2-diarylethenes and isomeriza-
tion of azobenzenes, have sufficiently high energy barriers to allow
the two states to be clearly distinguished,10e12 although in-
terconversion between conformers with a rather small energy
barrier has also been used.13
We previously reported the unique conformational properties of
aromatic amides and their application to molecular switching
functions. We found that N-methylation, and more generally N-
alkylation, of secondary amides, such as benzanilide (1) causes
amide conformational alteration from Z- to E-form. For example, N-
methylbenzanilide (2) exists in the E-form in the crystal, and pre-
dominantly in the E-form in various solvents (Fig. 1a).14,15 Although
this alteration in solution is actually a change of the equilibrium
conformational ratio, it can be used for output switching.16,17 In
addition to conformational switching by means of chemical re-
action, some amide compounds alter their conformation in re-
sponse to a change of environmental conditions.18e23 For example,
the N,N-diarylacetamide 3 exists in the E-form (76.9%) in CD2Cl2,
chromic compounds exhibit
a light-driven reversible trans-
formation between two isomers, which have different absorption
spectra or other optical activities.5e7 Also, fluorescent sensors,
whose fluorescence properties change upon interacting or reacting
with an analyte, are used in both fundamental biological research
* Corresponding authors. E-mail addresses: iokamoto@ac.shoyaku.ac.jp (I. Oka-
moto), tanatani.aya@ocha.ac.jp (A. Tanatani).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.114

I. Okamoto et al. / Tetrahedron 68 (2012) 5346e5355
5347
to clarify the generality of the interconversion and to confirm the
switching mechanism.
O
O
CH3
N
2. Results and discussion
2.1. Syntheses
N-methylation
N
H
(a)
1
2
The N,N-diarylamino moieties of the simple amides 4ae6a serve
as both conformational switching and redox-active sites.25 How-
ever, the substituent on the acyl group may affect the switching
ability of the amide derivatives. To examine this possibility, we
designed and synthesized a series of N-phenyl-N-benzoquinonyl
amides 6bef of various carboxylic acids and the corresponding
reduced compounds (a series of 4 and 5), as shown in Scheme 1.
2,5-Dimethoxyaniline was coupled with bromobenzene in the
presence of Pd catalysts to afford N,N-diarylamine 7.33 Acylation of
7 with various acid chlorides gave N,N-diarylamides 4. Methyl
H
N
+ acid
O
O
N
N
(b)
H3C
H3C
+ base
3
N
O
H2N
OCH3
PhBr, Pd(0)
82%
HN
OCH3
N
OCH3
R2COCl
77-97%
R2
Fig. 1. (a) Conformational alteration of benzamide by N-methylation. (b) pH-
responsive conformational switching of N,N-diarylacetamide.
H3CO
H3CO
H3CO
4a-f
7
while the addition of TFA-d induces Z-structure (84.7%) as the
major conformer (Fig.1b).18 In this system, the electronic properties
of the aromatic rings are the key factor that determines the pre-
dominant conformation. Thus, E-conformational preference of ar-
omatic N-methylamides is at least partly due to the repulsive
O
N
a: R2 = CH3
O
b: R2 = C6H5
O
N
OH
c: R2 = C6F5
BBr3
R2
FeCl3
73-98%
O
R2
d: R2 = CHPh2
e: R2 = 2,4-dinitrobenzyl
f: R2 = CH2C6F5
18-77%
electrostatic interaction between the amide oxygen atom and the
p
HO
5a-f
Scheme 1. Synthesis of N,N-diarylamides 4e6.
electrons of the aromatic ring in the Z-conformer.24 In the case of
N,N-diarylacetamide, the more electron-rich aromatic ring is lo-
cated opposite the amide carbonyl group (E-conformer for 3).
Protonation of the amino group on the electron-rich aromatic ring
of 3 decreases the unfavorable interaction in the Z-conformer, and
causes conformational alteration.
6a-f
groups were removed to give hydroquinone derivatives 5, which
were oxidized with iron(III) chloride to give N-benzoquinonyla-
mides 6.
Building on these conformational properties of aromatic amides,
we recently reported another type of molecular switch, that is,
responsive to redox reaction (Fig. 2).25 In redox-based switching
systems, the redox-response group may be a metal complex26,27 or
a redox-active organic compound.28e32 In the latter case, the geo-
metrical change can be driven by a redox-active moiety. In the
present N,N-diarylacetamides (Fig. 2), the benzoquino-
neehydroquinone system is the redox-active moiety. Indeed, we
found that compounds 4a and 5a favor the E-conformation, in
which the electron-rich hydroquinone ring is located opposite the
carbonyl group. Oxidation reaction of 4a or 5a yielded 6a, in which
the benzoquinone ring, which is more electron-poor than the
phenyl group, is located at the same side as the carbonyl group.
Thus, reversible interconversion between 5a and 6a could be per-
formed electrochemically. In this study, we examined the redox-
driven switching properties of various N,N-diarylamides in order
2.2. Crystal structures
X-ray crystallographic analysis was conducted to establish the
crystal structures of these amides. Most of the amides gave
crystals suitable for X-ray analysis, except compound 4e. Among
them, 5b, 6c, and 6e afforded solvent-including crystals. The
crystal structures are summarized in Fig. 3. There is a common
structural feature in the crystals of 4, in that each amide bond
takes the E-form, in which the electron-rich dimethoxyphenyl
group is located opposite the carbonyl group. On the other hand,
N-benzoquinonylamides 6, except 6b, showed the Z-amide form
in the crystals.
In the case of hydroquinonylamides 5 the amide conformation
varied depending upon the acyl group; 5a, 5e, and 5f existed in the
E-form, whereas 5bed existed in the Z-form. In the crystals of these
hydroquinonylamides, the packing structures, especially formation
of intermolecular hydrogen bonding, strongly influenced the con-
formation of the amides. For example, in the crystal of 5a, which
takes E-form, the two hydroxyl groups form hydrogen bonds with
O
O
O
carbonyl groups of adjacent molecules, generating
a three-
N
OR1
N
O
dimensional network structure (Fig. 4). In the crystal of 5c, which
takes Z-form, the hydroxyl groups form intermolecular hydrogen
bonds with the carbonyl group or hydroxyl group, generating
a chain-type network structure (Fig. 5). These hydrogen bonding
network features, as well as other weak intermolecular in-
H3C
H3C
E-amide form
Z-amide form
R1O
4a: R1 = CH3
5a: R1 = H
6a
teractions, such as
pep interaction and CH/p interaction, would
Fig. 2. Redox-responsive conformational switching of N,N-diarylacetamide.
influence the conformation of each hydroquinonylamide.34e40

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I. Okamoto et al. / Tetrahedron 68 (2012) 5346e5355
Fig. 3. Thermal ellipsoid models of the crystal structures of amides 4e6. The ellipsoids are drawn at the 50% probability level, while isotropic hydrogen atoms are represented by
spheres of arbitrary size. Included solvent molecules (for 5b, 6c, and 6e) and disordered regions (5b and 5f) are omitted for clarity. For crystals including two conformers in their
asymmetric unit (4b, 5b, and 6d), representative conformers are shown.
The torsion angles around the amide bond and dihedral angles
between the amide plane and N-phenyl rings of N-aromatic rings
are listed in Table 1. Each amide bond is planar in the crystal, and
the torsion angles (deviation from planarity) are less than 20ꢀ. The
torsion angles of the amide bond in benzamides (4b, 5b, and 6b) are
somewhat larger than those of the other compounds. The two di-
hedral angles between the amide plane and N-aromatic rings in
each compound are large (65e80ꢀ for dimethoxyphenyl, 67e89ꢀ

I. Okamoto et al. / Tetrahedron 68 (2012) 5346e5355
5349
Table 1
Torsion and dihedral angles (ꢀ) around amide bonds
c
c
Amide jTorsion anglej
AreNeC]O
jTorsion anglej
PheNeC]O
Dihedral angle Dihedral angle
Ar-amide
Ph-amide
4a
5a
9.77(14)
2.05(14)
8.1(6)
18.6(2)
19.3(2)
9.1(3)
6.3(2)
8.8(2)
8.1(4)
7.9(3)
2.8(3)
19.7(2)
18.6(2)
16.3(2)
6.3(7)
2.4(2)
1.84(18)
5.8(3)
80.61(17)
88.72(16)
65.1(5)
72.2(2)
65.6(3)
78.4(3)
87.6(3)
72.5(3)
65.6(5)
74.58(19)
76.2(2)
69.5(3)
78.81(19)
81.63(17)
77.6(2)
72.2(2)
80.8(4)
70.5(4)
71.60(19)
71.9(2)
78.3(3)
60.8(2)
62.45(17)
80.09(16)
77.8(5)
45.8(2)
75.7(3)
57.1(3)
60.7(3)
56.3(3)
51.6(5)
36.45(19)
86.4(2)
89.1(3)
49.46(19)
61.29(17)
72.8(2)
73.2(2)
83.0(4)
70.5(4)
56.8(2)
77.2(3)
53.4(3)b
77.8(2)
6a
4ba
5ba
5.9(3)
17.7(3)
14.1(5)
13.98(15)
6.4(3)
6b
4c
5c
6c
2.4(4)
4d
5d
6da
2.18(16)
16.2(2)
6.3(3)
8.8(3)
3.3(3)
4.4(5)
9.73(16)
6.2(3)
0.8(2)
6.4(3)
1.1(2)
5.49(14)
4.77(19)
1.76(19)
3.1(5)
9.3(3)
5.4(2)
3.0(3)
6.0(4)
7.02(15)
5e
6e
4f
5fa
6f
a
The values for each conformer are indicated.
A value for major disordered phenyl ring is indicated.
The absolute values (0e90ꢀ) of the torsion angles are indicated.
b
c
analyses, the energy barrier for the rotation was roughly calculated
as 64 and 65 kJ/mol for 4a and 5a, respectively, and 39 kJ/mol for
6a.41 The barriers of other compounds whose two conformers were
observed are within the range from 45 to 74 kJ/mol (11e18 kcal/
mol), which is the general value for aromatic amides.42 The ratios of
E and Z-conformers were calculated from the integration values of
the 1H NMR spectra, and are summarized in Table 2.
Fig. 4. Hydrogen-bonded structure in the crystal of 5a. (a) Multiple hydrogen bonds
around one molecule and (b) 3D network structure. The molecules except the repre-
sentative one are colored in cyan. Hydrogen bonds are indicated by black dotted lines.
Acetamides 4a and 5a showed the E-form as the major con-
former (73% in CD2Cl2 at 213 K and 77% in CD3OD at 253 K, re-
spectively), while the oxidized form 6a showed the Z-form as the
major conformer (95% in CD2Cl2 at 178 K).25 Aromatic proton sig-
nals of the N-dimethoxyphenyl group or N-hydroquinonyl group in
the major conformer of 4b and 5b were shifted to higher field than
those in the minor conformer, though this was not the case in
acetamides 4a and 5a. This is considered to be the result of the
anisotropic effect of benzoyl group, as supported by the crystal
structure of 4b (Fig. 3) and the calculated optimized structures of
4b and 5b (Fig. 6). A similar tendency was also observed in per-
fluorophenyl derivatives 4c and 5c. The benzoyl group and per-
fluorobenzoyl group in the major conformers of the reduced forms
were placed on the same side as the dimethoxyphenyl or dihy-
droxyphenyl group on the amide nitrogen, that is, the major con-
formers could be assigned as E-form.
Oxidized form 6b showed only one set of signals, and two
conformers could not be distinguished even at 178 K. A NOE ex-
periment indicated that the two phenyl groups of 6b are located on
the same side of the amide bond (Fig. 7a). Further, o-protons of the
N-phenyl group of 6b were shifted to higher field as the tempera-
ture was lowered. These protons of 6c also showed a similar higher
field shift as the temperature was lowered, and the signals of 6c
showed peak broadening, followed by separation into two sets of
signals with a ratio of 87:13. The o-protons of the N-phenyl group of
the major conformer of 6c appeared at higher field than those of the
minor conformer. Therefore, benzoquinone derivatives 6b and 6c
exist predominantly in the Z-form. Thus, benzamide and per-
fluorobenzamide derivatives showed similar behavior to acetamide
derivatives, although the crystal structures of 5b, 5c, and 6b were
unexpected. The results are interesting, since our previous studies
showed that the electronic properties of aryl groups in N,N-diary-
lbenzamide derivatives have less effect on the amide conformation
Fig. 5. Hydrogen-bonded structure in the crystal of 5c. (a) Multiple hydrogen bonds
around one molecule and (b) 1D chain structures. The molecules except the repre-
sentative one are colored in cyan. Hydrogen bonds are indicated by black dotted lines.
for dihydroxylphenyl, 58e80ꢀ for benzoquinone, and 31e89ꢀ for
unsubstituted phenyl group). Generally, these dihedral angles of 5
were larger than those of the corresponding 4 and 6, at least partly
due to the presence of intermolecular hydrogen bonds.
2.3. Structures in solution
The 1H NMR spectra of most of the amides examined here gave
only one set of signals at room temperature. Lowering the tem-
perature caused peak broadening followed by separation of two
sets of signals, due to the E and Z-amide conformers. From these

5350
I. Okamoto et al. / Tetrahedron 68 (2012) 5346e5355
Table 2
Conformational analyses by 1H NMR measurement
Amide
Major
Ratio (%)
Temp (K)
Solvent
D
G0 (kJ/mol)a
(a)
(b)
(c)
(d)
4a
5a
6a
4b
5b
6b
4c
5c
6c
4d
5d
6d
4e
5e
6e
4f
E
E
Z
E
E
Z
E
E
Z
E
E
Z
E
E
Z
E
E
Z
73
77
95
72
72
d
213
253
178
193
223
d
CD2Cl2
CD3OD
CD2Cl2
CD2Cl2
CD3OD
CD2Cl2
CD2Cl2
CD3OD
CD2Cl2
CD2Cl2
CD3OD
CD2Cl2
CD2Cl2
CD3OD
CD2Cl2
CD2Cl2
CD3OD
CD2Cl2
ꢁ1.8
ꢁ2.5
þ4.4
ꢁ1.5
ꢁ1.8
66
81
87
80
83
d
303
233
193
213
213
d
ꢁ1.7
ꢁ2.8
þ3.1
ꢁ2.5
ꢁ2.8
78
80
d
213
213
d
ꢁ2.2
ꢁ2.5
79
90
d
213
213
d
ꢁ2.3
ꢁ3.9
5f
6f
a
D
G0¼ꢁRT ln([E]/[Z]).
(e)
Fig. 6. Anisotropic effect in closely facing aryl groups in (a) 4b (R1¼CH3) and (b) 5b
(R1¼H).43
Fig. 8. Time-dependent a
-proton signals in the 1H NMR spectrum of 5d at 213 K; (a)
0 min, (b) 10 min, (c) 50 min, (d) 70 min, (e) warmed to 303 K then cooled to 213 K again.
than those in N,N-diarylacetamide derivatives. The benzoquino-
neehydroquinone system appears to be effective for conforma-
tional switching in the benzamide skeleton.
could be assigned as the E-form. The 1H NMR spectrum at 178 K did
Next, we examined the conformations of
a-aryl acetamide de-
rivatives (series def). In diphenylacetamide derivative 4d, the
a
-
not show separate signals of the conformers of benzoquinone form
proton clearly showed different chemical shifts in the two con-
formers at 213 K:4.95 ppm in the major conformer, and 5.15 ppm in
6d, but the NOE correlation between the a-proton and N-phenyl
protons showed that 6d existed predominantly in the Z-form
the minor conformer. The anisotropic effect of the more
rich N-aryl group would be larger, causing a higher field shift of the
-proton, and therefore the diphenylacetyl group is located on the
p-electron-
(Fig. 7c).
a
-Monoarylacetamides showed similar behavior. The two a-
a
methylene protons in the major conformer of 4e gave non-
equivalent signals, whereas those in the minor conformer were
observed as equivalent (one signal). When 4e takes the E-form, in
which the dinitrophenyl group is located on the same side as the
dimethoxyphenyl group, rotation around CcarbonyleCmethylene bond
same side as the dimethoxyphenyl group in the major conformer.
This assignment was supported by a NOE experiment (Fig. 7b). The
structure of 5d in solution was determined by a more direct
method. In the normal 1H NMR spectrum at 213 K, there are two
a-
proton signals at 5.23 (major) and 5.17 ppm (minor). When the
crystal of 5d was dissolved in CD3OD at 213 K, and 1H NMR mea-
surement was immediately started at that temperature, the signal
at 5.17 ppm was observed predominantly in the early period of
measurement, and the signal at 5.23 ppm was hardly detectable. As
time passed at the same temperature, the signal at 5.23 ppm
appeared and became predominant (Fig. 8). Because the crystal
structure of 5d is the Z-form, the major conformer of 5d in solution
would be sterically restricted, and the
become nonequivalent. In the Z-amide form, there is little re-
striction of this rotation, and the -methylene protons should be
a-methylene protons would
a
equivalent (Fig. 9). From these considerations, the major conformer
of 4e could be assigned as E-form, and similarly 5e, 4f and 5f were
concluded to exist preferentially in the E-form. These assignments
were supported by measurement of the NMR spectrum of 4f im-
mediately after dissolving the crystals at low temperature, which
confirmed that the major conformer of 4f in CD2Cl2 was the E-form,
as observed in the crystal. In the cases of benzoquinone forms 6e
and 6f, one set of signals was observed at lower temperature, and
the predominant conformer was assigned as the Z-form by NOE
experiments (Fig. 10).
Thus, the major conformer of all the amide derivatives bearing
a dimethoxyphenyl (4) or dihydroxyphenyl group (5) is the E-form,
while the benzoquinone forms 6 predominantly exist in the Z-form.
These results indicate that conformational switching could occur
through conversion between benzoquinone and hydroquinone in
the N,N-diarylamide moiety, independently of the substituent on
the acyl group.
O
O
O
O
O
O
O
N
N
N
OCH3
H H
H H
H
H
1.4%
1.6%
OCH3
2.2%
1.9%
(a)
(b)
(c)
Fig. 7. Major conformers and NOE correlations of (a) 6b, (b) 4d, and (c) 6d.

I. Okamoto et al. / Tetrahedron 68 (2012) 5346e5355
5351
changes the functionality of only a small part of the molecule, in-
duces a conformational alteration of the whole molecule, and the
resulting change of intramolecular interaction is detectable as
a change in the optical properties of the molecule.
CH3
O
O
O
N
H
O
H
CH3
N
3. Conclusion
O2N
O
O
CH3
CH3
We report the redox-induced conformational alteration of the
N-phenyl-N-benzoquinonylamide system. The reduced form bear-
ing a dimethoxyphenyl or dihydroxyphenyl group exists mainly in
the E-form, while the oxidized form bearing a N-benzoquinone
moiety takes the Z-form, both in the crystal and predominantly in
solution. This conformational alteration is detectable as a change in
the optical properties of the molecule, and may have potential
application as a molecular switch. The presence of various sub-
stituents on the acyl part of N,N-diarylamides did not affect the
switching property, so it should be feasible to add functionality at
this site to generate other types of output of the switching system.
O2N
Z-form
O2N
NO2
E-form
Fig. 9. Restricted rotation in the major conformer of 4e and unrestricted rotation in the
minor conformer.
O
O
F
O
O
4. Experimental section
4.1. General
F
O
O
N
N
O2N
F
H
H
H
F
H
H
H
O2N
F
Melting points were determined by using a Yanaco melting
point apparatus MP-S3 and are uncorrected. Elemental analyses
were carried out on a Thermo Finnigan Flash EA1112, and antipy-
rine was used as a standard. 1H and 13C NMR spectra were recorded
on a JEOL AL-300, and chemical shifts are expressed in parts per
million relative to tetramethylsilane. 13C NMR signals of the pen-
tafluorophenyl group were not recorded. Low temperature 1H NMR
spectra were recorded on a JEOL AL-300 or Bruker AV-500. IR
spectra were recorded on a Shimadzu FTIR-8200A. UVevisible
spectra were recorded in a quartz cell on a JASCO V550-DS. Mass
spectra were measured on a JEOL MS700 or HX110. Silica gel [silica
(b)
(a)
2.2%
3.6%
Fig. 10. Major conformers and NOE correlations of (a) 6e and (b) 6f.
2.4. UVevisible absorption
Since the nature of the substituent on the acyl part of N,N-dia-
rylamides did not affect the switching property, it should be fea-
sible to add functionality related to the output of the switching
system at this site. As a first step, we examined the difference in
optical properties (UVevisible spectra) between the hydroquinone
form (5) and benzoquinone form (6), as shown in Fig. 11. For
acetamide (a series), the absorption of 5a at around 300 nm and at
220e280 nm decreased and increased, respectively, upon oxidation
to 6a. Similar changes were observed with diphenylacetamide (d
series) and perfluorophenyl derivative (f series). These changes are
gel 40e50 mm neutral (Kanto Chemical Co., Inc.)] was used for all
chromatographic procedures.
4.2. 2,5-Dimethoxy-N-phenylaniline (7)
A solution of bis(dibenzylideneacetone)palladium (60.0 mg,
0.10 mmol) and tri-tert-butylphosphine (34.0 mg, 0.17 mmol) in
4 mL of toluene was added to a mixture of bromobenzene (0.26 mL,
2.50 mmol), 2,5-dimethoxyaniline (386 mg, 2.50 mmol), and so-
dium tert-butoxide (268 mg, 2.75 mmol) in 2.5 mL of toluene. The
resulting mixture was heated at 100 ꢀC with stirring in a sealed
tube for 16 h, then cooled. The crude mixture was chromato-
graphed (AcOEt/n-hexane 1:30) to give 7 (473 mg, 82%). Pale brown
results
of
the
change
of
functionalities.
For
2,4-
dinitrophenylacetamide (e series), the absorption of benzoqui-
none form 6e at 220e280 nm was significantly weaker than that of
the corresponding hydroquinone form 5e. The reason for this dif-
ference is unclear, but may be related at least in part to the in-
teraction between the electron-poor 2,4-dinitrophenyl group and
N-aryl groups. The results suggest that redox reaction, which
oil; 1H NMR (300 MHz, CDCl3)
d
7.29 (2H, t, J¼8.4 Hz), 7.17 (2H, d,
0.2
0.1
J¼8.4 Hz), 6.96 (1H, t, J¼8.4 Hz), 6.90 (1H, d, J¼2.8 Hz), 6.78 (1H, d,
J¼8.6 Hz), 6.35 (1H, dd, J¼8.6, 2.9 Hz), 3.85 (3H, s), 3.73 (3H, s); m/z
(EI) 229; HRMS (EI): Mþ, found 229.1114. C14H15NO2 requires
229.1103.
0
4.3. N-(2,5-Dimethoxyphenyl)-N-phenylacetamide (4a)
a
Abs
Δ
A mixture of 7 (303 mg, 1.32 mmol) and 3.8 mL of acetic an-
hydride (39.7 mmol) was heated at 85 ꢀC for 22 h. The volatiles
were removed under reduced pressure, and the residue was flash-
chromatographed (AcOEt/n-hexane 1:4 then AcOEt) to afford
358 mg (99%) of amide 4a. Mp 98e101 ꢀC; Anal. Found: C, 70.83; H,
6.47; N, 5.10. C16H17NO3 requires C, 70.83; H, 6.32; N, 5.16%; nmax
-0.1
d
e
-0.2
f
-0.3
(KBr) 1665, 1512, 1223, 1038 cmꢁ1; 1H NMR (300 MHz, CDCl3)
(3H, br s), 7.17 (2H, br m), 6.87 (3H, br m), 3.82 (3H, s), 3.74 (3H, s),
2.01 (3H, s); 13C NMR (75 MHz, DMSO-d6, 120 ꢀC)
168.6, 153.3,
d
7.31
220
250
300
Wavelength [nm]
350
400
d
Fig. 11. Difference in UVevisible absorption between hydroquinone (5) and benzo-
quinone (6) derivatives. Spectra were measured at the concentration of 0.017 mmol/L
149.2, 142.5, 132.3, 127.8, 125.8, 125.2, 115.6, 114.0, 113.7, 55.8, 55.3,
in ethanol.
DAbs¼Abs(6)ꢁAbs(5).
21.6; m/z (EI) 271.

5352
I. Okamoto et al. / Tetrahedron 68 (2012) 5346e5355
4.4. N-(2,5-Dimethoxyphenyl)-N-phenylbenzamide (4b)
149.4, 148.8, 146.6, 142.1, 137.8, 135.2, 130.6, 129.6, 128.6, 127.2,
126.0, 119.7, 115.9, 114.9, 113.7, 56.1, 55.5, 39.2; m/z (EI) 437.
To a suspension of sodium hydride (55% in oil, 173 mg,
3.97 mmol, washed with hexane) in tetrahydrofuran, a solution of 7
(910 mg, 3.97 mmol) in tetrahydrofuran was added. The mixture
was stirred for 15 min, then benzoyl chloride (0.67 mL, 5.70 mmol)
was added. The resulting mixture was heated at 60 ꢀC for 18 h and
extracted with AcOEt. The organic solution was washed with brine
and dried over MgSO4. Volatiles were removed under reduced
pressure, and the residue was flash-chromatographed (AcOEt/n-
hexane 1:8) to afford 1.23 g (93%) of amide 4b. Mp 90.0e93.0 ꢀC;
Anal. Found: C, 75.44; H, 6.03; N, 4.14. C21H19NO3 requires C, 75.66;
H, 5.74; N, 4.26%; nmax (KBr) 1663, 1504, 1238, 1047 cmꢁ1; 1H NMR
4.8. N-(2,5-Dimethoxyphenyl)-2-(pentafluorophenyl)-N-
phenylacetamide (4f)
A mixture of pentafluoroacetic acid (27.6 mg, 0.122 mmol) and
SOCl2 (0.2 mL, 1.03 mmol) was heated at reflux for 14 h. Volatiles
were removed under reduced pressure, and a solution of 7
(29.0 mg, 0.127 mmol) in toluene (1.0 mL) was added. The mixture
was heated at reflux for 4 h, then cooled. A small amount of water
was added, and the resulting mixture was extracted with AcOEt.
The organic layer was washed with satd NaHCO3 aqueous, water
and brine, and dried over Na2SO4. Volatiles were removed under
reduced pressure, and the residue was flash-chromatographed
(chloroform) to afford 45.1 mg (85%) of amide 4f. Mp
120.5e121.0 ꢀC; Anal. Found: C, 60.24; H, 3.81; N, 3.24. C22H16NO3F5
requires C, 60.42; H, 3.69; N, 3.20%; nmax (KBr) 2964, 2937, 2841,
(300 MHz, CDCl3)
d
7.48 (2H, m), 7.20 (8H, m), 6.74 (3H, m), 3.69
171.3, 154.3, 149.8,
(3H, s), 3.62 (3H, s); 13C NMR (75 MHz, CD2Cl2)
d
144.1, 137.1, 133.7, 130.2, 129.1, 128.9, 127.9, 127.0, 126.3, 116.1, 113.9,
113.5, 56.3, 56.1; m/z (EI) 333.
4.5. 2,3,4,5,6-Pentafluoro-N-(2,5-dimethoxyphenyl)-N-
phenylbenzamide (4c)
1670, 1352, 1117 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.58e7.10 (5H,
m), 7.04e6.71 (3H, m), 3.89 (E3H, s), 3.83 (Z3H, s), 3.77 (E3H, s), 3.73
13
(Z3H, s), 3.70e3.56 (2H, m); C NMR (75 MHz, DMSO-d6, 120 ꢀC)
The amide 4c was obtained in the same manner as described for
4b in quantitative yield. Mp 80.0e82.0 ꢀC; Anal. Found: C, 59.53; H,
3.54; N, 3.17. C21H14NO3F5 requires C, 59.58; H, 3.33; N, 3.31%; nmax
d
166.2, 153.4, 149.0, 141.9, 130.9, 128.1, 125.7 (overlapped), 115.4,
114.6, 113.7, 55.7, 55.3, 28.1; m/z (EI) 437.
(KBr) 1684, 1506, 1272,1043 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.30
(E5HþZ5H, m), 6.97 (Z1H, d, J¼8.6 Hz), 6.88 (Z2H, m), 6.82 (E1H, s),
6.78 (E1H, dd, J¼8.9, 3.0 Hz), 6.72 (E1H, d, J¼9.9 Hz), 3.88 (Z3H, s),
3.76 (Z3H, s), 3.73 (E3H, s), 3.69 (E3H, s); 13C NMR (75 MHz, DMSO-
4.9. N-(2,5-Dihydroxyphenyl)-N-phenylacetamide (5a)
To a solution of 4a (840 mg, 3.10 mmol) in 30 mL of dry
dichloromethane, 9.56 mL of 1.0 M boron tribromide solution in
dichloromethane was added, and the mixture was stirred for 19 h.
Water (1 mL) was added and the resulting mixture was stirred for
5 min, then poured into 100 mL of water. The aqueous layer was
extracted with ethyl acetate. The combined organic layer was
washed with brine and dried over magnesium sulfate. After re-
moval of the solvent under reduced pressure, the residue was flash-
chromatographed (AcOEt/n-hexane 3:1) to afford 581 mg of amide
5a (77%). Mp 166e167 ꢀC; Anal. Found: C, 68.97; H, 5.15; N, 5.53.
C14H13NO3 requires C, 69.12; H, 5.39; N, 5.76%; nmax (KBr) 3323,
d6, 150 ꢀC)
d 157.0,153.0, 148.8,140.6, 129.6, 128.1,126.5, 125.4, 115.1,
114.9, 113.5, 55.5, 55.3; m/z (EI) 423.
4.6. N-(2,5-Dimethoxyphenyl)-2,2,N-triphenylacetamide (4d)
A mixture of 7 (56.0 mg, 0.245 mmol), toluene (2.4 mL) and
diphenylacetyl chloride (76.0 mg, 0.318 mmol) was heated at reflux
for 19 h, then cooled, poured into water and extracted with
dichloromethane. The organic layer was washed with water and
dried over Na2SO4. Volatiles were removed under reduced pres-
sure, and the residue was flash-chromatographed (diethyl ether/n-
hexane 1:2) to afford 93.8 mg (90%) of amide 4d. Mp
151.0e152.0 ꢀC; Anal. Found: C, 79.14; H, 5.81; N, 3.13. C28H25NO3
requires C, 79.41; H, 5.95; N, 3.31%; nmax (KBr) 3065, 3007, 2833,
1614, 1512 cmꢁ1
8.91 (1H, br s), 7.14 (5H, m), 6.69 (3H, m), 1.90 (3H, s); 13C NMR
(75 MHz, DMSO-d6, 120 ꢀC)
168.8, 149.8, 145.4, 142.8, 130.4, 127.7,
; d 9.30 (1H, br s),
1H NMR (300 MHz, DMSO-d6)
d
125.6, 124.8, 117.0, 115.6, 115.5, 21.8; m/z (EI) 243.
Compounds 5bef were prepared in the same manner as de-
scribed for 5a.
1672, 1500, 1350 cmꢁ1 1H NMR (300 MHz, DMSO-d6, 120 ꢀC)
;
d
7.34e7.14 (15H, m), 7.05 (1H, d, J¼9.2 Hz), 6.92 (1H, dd, J¼9.0 Hz)
6.59 (1H, d, J¼2.9 Hz), 5.03 (1H, s), 3.66 (3H, s), 3.60 (3H, s); 13C
NMR (75 MHz, DMSO-d6, 150 ꢀC)
d 170.4, 153.0, 149.0, 142.2, 139.1,
131.4, 127.8, 127.7, 127.1, 125.9, 125.6, 125.4, 115.6, 114.4, 113.4, 55.3,
55.2, 54.0; m/z (EI) 423.
4.10. N-(2,5-Dihydroxyphenyl)-N-phenylbenzamide (5b)
Mp 114.0e115.0 ꢀC. nmax (KBr) 3300, 1636, 1510 cmꢁ1 1H NMR
;
4.7. N-(2,5-Dimethoxyphenyl)-2-(2,4-dinitrophenyl)-N-
phenylacetamide (4e)
(300 MHz, CDCl3) d 7.40 (2H, m), 7.24 (6H, m), 7.10 (2H, m), 6.95 (1H,
d, J¼8.6 Hz), 6.67 (1H, dd, J¼8.8, 2.9 Hz), 6.36 (1H, d, J¼2.9 Hz); 13C
NMR (75 MHz, DMSO-d6)
d 169.8, 149.8, 145.6, 143.5, 136.8, 130.8,
A mixture of 7 (500 mg, 2.18 mmol), chloroform (5.0 mL) and
2,4-dinitrophenylacetyl chloride (651 mg, 2.66 mmol) was heated
at 50 ꢀC for 21 h, then allowed to cool. A small amount of water was
added, followed by further chloroform. The organic solution was
washed with water and dried over Na2SO4. Volatiles were removed
under reduced pressure, and the residue was flash-
chromatographed (diethyl ether/n-hexane 5:2) to afford 717 mg
(77%) of amide 4e. Mp 150.5e151.0 ꢀC; Anal. Found: C, 60.17; H,
4.16; N, 9.35. C22H19N3O7 requires C, 60.41; H, 4.38; N, 9.61%; nmax
129.6, 128.5, 128.0, 127.4, 126.4, 125.6, 116.9, 116.1, 115.5; m/z (EI)
305; HRMS (EI): Mþ, found 305.1046. C19H15NO3 requires 305.1052.
4.11. 2,3,4,5,6-Pentafluoro-N-(2,5-dihydroxyphenyl)-N-
phenylbenzamide (5c)
Mp 111.0e114.0 ꢀC. nmax (KBr) 3265, 1663, 1504 cmꢁ1
(300 MHz, DMSO-d6, 120 ꢀC)
;
1H NMR
7.53 (2H, t, J¼7.0 Hz), 7.43 (1H, t,
d
(KBr) 1663, 1535,1508, 1348 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
8.91
J¼7.3 Hz), 7.37 (2H, d, J¼7.0 Hz), 7.21 (1H, d, J¼8.8 Hz), 6.61 (1H, dd,
(1H, d, J¼2.2 Hz), 8.38 (1H, dd, J¼8.4, 2.4 Hz), 7.56 (1H, d, J¼8.4 Hz),
7.50e7.12 (5H, m), 7.04e6.71 (3H, m), 4.20 (E1H, d, J¼16.3 Hz), 4.10
(Z2H, s), 3.91 (E3H, s), 3.91 (E1H, d, J¼16.3 Hz), 3.82 (Z3H, s), 3.78
J¼8.8, 2.7 Hz), 6.30 (1H, d, J¼2.7 Hz); 13C NMR (75 MHz, DMSO-d6)
d
158.9, 155.5, 146.2, 140.8, 134.2, 129.6, 128.6, 128.1, 121.8, 113.7,
112.0; m/z (EI) 395; HRMS (EI): Mþ, found 395.0589. C19H10NO3F5
(E3H, s), 3.73 (Z3H, s); 13C NMR (75 MHz, DMSO-d6)
d
168.1, 153.4,
requires 395.0581.

I. Okamoto et al. / Tetrahedron 68 (2012) 5346e5355
5353
4.12. N-(2,5-Dihydroxyphenyl)-2,2,N-triphenylacetamide (5d)
Mp 100.5e101.5 ꢀC. nmax (KBr) 1636, 1501, 1366 cmꢁ1 1H NMR
4.17. 2,3,4,5,6-Pentafluoro-N-(3,6-dioxocyclohexa-1,4-dien-1-
yl)-N-phenylbenzamide (6c)
;
(300 MHz, DMSO-d6) 9.57 (E1H, s), 9.02 (Z1H, s), 8.79 (E1H, s),
d
Mp 128.0e129.0 ꢀC; nmax (KBr) 1692, 1668 cmꢁ1 1H NMR
;
8.78 (Z1H, s), 7.41e7.09 (15H, m), 6.87 (E1H, d, J¼8.8 Hz), 6.63 (1H,
(300 MHz, CDCl3)
d
7.34 (3H, m), 7.30 (2H, d, J¼9.6 Hz), 6.92 (1H, d,
dd, J¼8.8, 2.9 Hz), 6.53 (Z2H, m), 6.10 (1H, d, J¼2.9 Hz), 5.10 (E1H, s),
J¼10.3 Hz), 6.80 (1H, dd, J¼10.3, 2.4 Hz), 6.52 (1H, d, J¼2.5 Hz); 13C
13
5.08 (Z1H, s); C NMR (75 MHz, DMSO-d6, 120 ꢀC)
d
170.7, 149.6,
NMR (75 MHz, CDCl3) d 186.5, 180.4, 158.8, 147.1, 139.2, 136.4, 136.3,
145.3, 142.6, 139.4, 129.6, 128.1, 127.8, 127.2, 126.0, 125.8, 125.3,
116.7, 116.0, 115.6, 53.9; m/z (EI) 395; HRMS (EI): Mþ, found
395.1528. C26H21NO3 requires 395.1521.
130.7, 130.1, 129.6, 127.5; m/z (EI) 303; HRMS (EI): Mþ, found
393.0423. C19H8NO3F5 requires 393.0424.
4.18. N-(3,6-Dioxocyclohexa-1,4-dien-1-yl)-2,2,N-
triphenylacetamide (6d)
4.13. N-(2,5-Dihydroxyphenyl)-2-(2,4-dinitrophenyl)-N-
phenylacetamide (5e)
Mp 145.0e148.0 ꢀC; nmax (KBr) 1663, 1491, 1379 cmꢁ1
;
1H NMR
(300 MHz, CD2Cl2) 7.44e7.18 (13H, m), 7.15e7.08 (2H, m), 6.86
d
Mp 153.0 ꢀC. nmax (KBr) 1649, 1535, 1348 cmꢁ1
;
1H NMR
(1H, d, J¼10.1 Hz), 6.71 (1H, dd, J¼10.2, 2.5 Hz), 6.36 (1H, d,
(300 MHz, DMSO-d6) 9.55 (Z1H, s), 9.02 (Z1H, s), 8.85 (E2H, s),
d
J¼2.6 Hz), 5.05 (1H, s); 13C NMR (75 MHz, CDCl3)
d 186.8, 181.3,
8.73 (1H, d, J¼2.6 Hz), 8.46 (1H, dd, J¼8.4, 2.6 Hz), 7.77 (1H, d,
J¼8.43 Hz), 7.70e7.08 (5H, m), 6.98e6.43 (3H, m), 4.20 (E1H, d,
J¼17.2 Hz), 4.11 (Z2H, s), 3.99 (E1H, d, J¼16.9 Hz); 13C NMR (75 MHz,
172.8, 149.1, 140.3, 138.6, 136.5, 136.2, 130.1, 130.0, 129.2, 129.0,
128.7, 128.5, 127.3, 55.2; m/z (EI) 393; HRMS (EI): Mþ, found
393.1369. C26H19NO3 requires 393.1365.
CD3OD)
d 171.5, 152.2, 150.5, 148.6, 147.8, 143.9, 139.5, 136.3, 130.9,
129.9, 128.2, 127.7, 127.5, 121.2, 118.7, 118.2, 117.0, 41.1; m/z (EI) 409;
4.19. N-(3,6-Dioxocyclohexa-1,4-dien-1-yl)-2-(2,4-
dinitrophenyl)-N-phenylacetamide (6e)
HRMS (EI): Mþ, found 409.0906. C20H15N3O7 requires 409.0910.
4.14. N-(2,5-Dihydroxyphenyl)-2-(pentafluorophenyl)-N-
phenylacetamide (5f)
Mp 85.0e87.0 ꢀC; nmax (KBr) 1668, 1535, 1348 cmꢁ1
(300 MHz, CDCl3)
;
1H NMR
d
8.93 (1H, d, J¼2.2 Hz), 8.42 (1H, dd, J¼8.4,
2.2 Hz), 7.60 (1H, d, J¼8.4 Hz), 7.58e7.42 (5H, m), 6.85 (1H, d,
Mp 167.5e169.0 ꢀC. nmax (KBr) 1670, 1523, 1508, 1352, 1230,
J¼10.3 Hz), 6.74 (1H, dd, J¼10.3, 2.2 Hz), 6.52 (1H, d, J¼2.2 Hz), 4.11
1128 cmꢁ1
;
1H NMR (300 MHz, CD3OD)
d
7.66e7.15 (5H, m), 6.85
(2H, s); 13C NMR (75 MHz, CDCl3)
d 186.7, 181.2, 168.8, 148.8, 148.0,
(1H, d, J¼8.8 Hz), 6.71 (1H, dd, J¼8.8, 2.6 Hz), 6.64 (1H, d, J¼2.9 Hz),
147.4, 140.0, 136.8, 136.4, 136.3, 134.8, 130.648, 130.591, 129.7, 128.4,
127.3, 120.6, 40.4; m/z (EI) 407; HRMS (EI): Mþ, found 407.0769.
C20H13N3O7 requires 407.0753.
3.90 (1H, d, J¼16.9 Hz), 3.78 (1H, d, J¼16.1 Hz); 13C NMR (75 MHz,
DMSO-d6, 120 ꢀC)
d 166.3, 150.0, 145.5, 142.2, 128.9, 127.9, 125.5,
125.3, 117.2, 116.1, 115.3, 28.1; m/z (EI) 409; HRMS (EI): Mþ, found
409.0753. C20H12NO3F5 requires 409.0737.
4.20. N-(3,6-Dioxocyclohexa-1,4-dien-1-yl)-2-
(pentafluorophenyl)-N-phenylacetamide (6f)
4.15. N-(3,6-Dioxocyclohexa-1,4-dien-1-yl)-N-
phenylbenzamide (6a)
Mp 149.0e151.0 ꢀC; nmax (KBr) 3055, 1701, 1655, 1599, 1529,
1508, 1254, 1124 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 7.51 (3H, m),
7.39 (2H, m), 6.87 (1H, d, J¼10.3 Hz), 6.74 (1H, dd, J¼10.3, 2.6 Hz),
A solution of 5a (40 mg, 0.16 mmol), 0.1 mL of 2 M hydrochloric
acid, and iron (III) chloride (77.8 mg, 0.48 mmol) in 20 mL of
methanol was stirred at ambient temperature for 1 h, then poured
into water. The aqueous mixture was extracted with ethyl acetate.
The organic layer was dried over magnesium sulfate, the solvent
was removed under reduced pressure, and the residue was flash-
chromatographed (AcOEt/n-hexane 1:2) to afford 27 mg (70%) of
amide 6a. Mp 145e149 ꢀC; Anal. Found: C, 69.48; H, 4.90; N, 5.87.
C14H11NO3 requires C, 69.70; H, 4.60; N, 5.81%; nmax (KBr) 1684,
6.45 (1H, d, J¼2.6 Hz), 3.67 (2H, s); 13C NMR (75 MHz, CD2Cl2)
d
186.7, 181.0, 167.8, 148.0, 140.0, 136.2, 136.1, 130.4, 130.3, 129.3,
128.1, 28.5; m/z (EI) 407; HRMS (EI): Mþ, found 407.0570.
C20H10NO3F5 requires 407.0581.
4.21. Single-crystal X-ray crystallography
New crystallographic data were collected on a CCD diffractom-
ꢀ
eter with Mo K
a
(l
¼0.71073 A) radiation. Data collections for al-
1654 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.44 (3H, m), 7.27 (2H, m),
most compounds were carried out at room temperature or low
temperature (90e273 K) using liquid nitrogen. For crystal of 6b,
which is very thin plate, a data collection was carried out at 15 K
using liquid helium. All of the crystal structures were solved by
direct methods with SHELXS-97 and refined with full-matrix least-
squares SHELXL-97.44 All non-hydrogen atoms were refined an-
isotropically. Hydrogen atoms of the amides were included at their
calculated positions. Crystallographic data are summarized below
(for published data, only CCDC deposit numbers are given).25
Compound 4a: CCDC-635794.
6.88 (1H, d, J¼10.3 Hz), 6.74 (1H, dd, J¼10.3 Hz), 6.37 (1H, d,
J¼2.4 Hz), 2.06 (3H, s); 13C NMR (75 MHz, CDCl3)
d 187.0, 181.4,
171.2, 149.1, 141.1, 136.5, 136.2, 130.2, 129.8, 129.0, 128.0, 22.7; m/z
(EI) 241.
Compounds 6bef were prepared in the same manner as de-
scribed for 6a.
4.16. N-(3,6-Dioxocyclohexa-1,4-dien-1-yl)-N-
phenylbenzamide (6b)
Compound 4b: recrystallized from AcOEt/n-hexane. C21H19NO3,
Mp 131.0e133.0 ꢀC; nmax (KBr) 1684, 1655 cmꢁ1
;
1H NMR
Mr¼333.37, triclinic, Pꢁ1, a¼9.584(1), b¼11.199(1), c¼18.362(2) A,
ꢀ
3
ꢀ
ꢀ
(300 MHz, CDCl3) 7.60 (2H, m), 7.31 (6H, m), 7.08 (2H, m), 6.86
d
a
¼101.791(2),
b
¼96.568(2),
g
¼109.903(2) , V¼1777.4(4) A , Z¼4,
(1H, d, J¼9.7 Hz), 6.75 (1H, dd, J¼10.3, 2.6 Hz), 6.22 (1H, d,
Dcalcd¼1.246 Mg mꢁ3, 2qmax¼54.96ꢀ, T¼273 K, 10,547 reflections
J¼2.4 Hz); 13C NMR (75 MHz, CD2Cl2)
d
187.2, 182.1, 171.3, 150.9,
measured, 6855 unique (Rint¼0.026),
m
¼0.083 mme1. The final R1
142.3, 137.0, 136.4, 134.8, 132.0, 130.2, 129.9, 128.6, 128.1, 128.0,
127.5; m/z (EI) 303; HRMS (EI): Mþ, found 303.0927. C19H13NO3
requires 303.0895.
and wR2 were 0.0479 and 0.0732 (I>2s(I)). CCDC-869639.
Compound 4c: recrystallized from AcOEt/n-hexane. C21H14F5NO3,
Mr¼423.33, monoclinic, P21/c, a¼9.0044(12), b¼10.9394(14),

5354
I. Okamoto et al. / Tetrahedron 68 (2012) 5346e5355
3
ꢀ
ꢀ
c¼18.914(3)
A,
b
¼93.304(2)ꢀ,
V¼1859.9(4)
A ,
Z¼4,
Z¼8, Dcalcd¼1.325 Mg mꢁ3, 2qmax¼54.62ꢀ, T¼100 K, 19,436 re-
Dcalcd¼1.512 Mg mꢁ3, 2qmax¼55.10ꢀ, T¼150 K, 10,966 reflections
flections measured, 7960 unique (Rint¼0.0393),
m
¼0.087 mme1. The
measured, 4253 unique (Rint¼0.0374),
m
¼0.134 mme1. The final R1
final R1 and wR2 were 0.0476 and 0.1262 (I>2s(I)). CCDC-869650.
and wR2 were 0.0437 and 0.1101 (I>2
s
(I)). CCDC-869640.
Compound 6e: recrystallized from AcOEt/toluene. C27H21N3O7,
ꢀ
Compound 4d: recrystallized from chloroform/n-hexane.
Mr¼499.47, triclinic, Pꢁ1, a¼6.580(3), b¼8.029(4), c¼23.044(10) A,
3
ꢀ
ꢀ
C28H25NO3, Mr¼423.49, monoclinic, P21/c, a¼16.1190(17),
a
¼81.488(7),
b
¼88.252(7),
g
¼73.314(6) , V¼1153.3(9) A , Z¼2,
3
ꢀ
ꢀ
ꢀ
b¼8.8009(9), c¼17.6258(19) A,
b
¼115.7900(10) , V¼2251.4(4) A ,
Dcalcd¼1.438 Mg mꢁ3, 2qmax¼56.94ꢀ, T¼90 K, 6751 reflections
Z¼4, Dcalcd¼1.249 Mg mꢁ3, 2qmax¼54.54ꢀ, T¼150 K, 10,923 re-
measured, 5012 unique (Rint¼0.0335),
m
¼0.106 mme1. The final R1
flections measured, 4597 unique (Rint¼0.0343),
m
¼0.081 mme1. The
and wR2 were 0.0790 and 0.1810 (I>2s(I)). CCDC-869651.
final R1 and wR2 were 0.0465 and 0.1049 (I>2
s
(I)). CCDC-869641.
Compound 6f: recrystallized from methanol. C20H10F5NO3,
Mr¼407.29, orthorhombic, Pna21, a¼9.6646(9), b¼26.929(3),
Compound 4f: recrystallized from toluene. C22H16F5NO3,
3
ꢀ
Mr¼437.36, triclinic, Pꢁ1, a¼7.193(3), b¼11.214(4), c¼12.293(4) A,
c¼6.5950(6) A, V¼1716.4(3) A , Z¼4, Dcalcd¼1.576 Mg mꢁ3
,
ꢀ
ꢀ
3
ꢀ
ꢀ
a¼97.388(4),
b
¼99.773(4),
g
¼93.336(4) , V¼965.7(6) A , Z¼2,
2
qmax¼54.08ꢀ, T¼90 K, 8139 reflections measured, 3404 unique
Dcalcd¼1.504 Mg mꢁ3, 2qmax¼53.88ꢀ, T¼120 K, 4604 reflections
(Rint¼0.0213),
m
¼0.142 mme1. The final R1 and wR2 were 0.0291 and
measured, 3573 unique (Rint¼0.0137),
and wR2 were 0.0449 and 0.1196 (I>2
Compound 5a: CCDC-635795.
m
¼0.132 mme1. The final R1
0.0679 (I>2s(I)). CCDC-869652.
s
(I)). CCDC-869642.
Acknowledgements
Compound
5b:
recrystallized
from
toluene.
C19H15NO3$0.5(C7H8), Mr¼351.39, triclinic, Pꢁ1, a¼11.575(9),
This work was supported by Grant-in-Aid for Scientific Research
from the Japan Society for the Promotion of Science.
ꢀ
b¼15.082(12), c¼16.349(13) A,
a¼93.366(10),
b
¼98.056(10),
3
g
¼101.046(9)ꢀ, V¼2763(4) A , Z¼6, Dcalcd¼1.267 Mg mꢁ3
,
ꢀ
2
qmax¼54.44ꢀ, T¼120 K,13,889 reflections measured,10,635 unique
Supplementary data
(Rint¼0.0179),
m
¼0.084 mme1. The final R1 and wR2 were 0.0562
and 0.1449 (I>2
s
(I)). CCDC-869643.
Supplementary data are available in PDF format: additional
UVevisible absorption spectra, 1H NMR and 13C NMR spectra.
Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tet.2012.04.114.
Compound 5c: recrystallized from AcOEt/dichloromethane.
C19H10F5NO3, Mr¼395.28, triclinic, Pꢁ1, a¼7.1522(9), b¼8.724(1),
ꢀ
c¼14.973(2) A,
a
¼83.843(2),
b¼83.825(2),
g
¼68.696(2)ꢀ,
V¼863.0(2) A , Z¼2, Dcalcd¼1.521 Mg mꢁ3, 2qmax¼55.08ꢀ, T¼273 K,
3
ꢀ
5160 reflections measured, 3387 unique (Rint¼0.021),
References and notes
m
¼0.139 mme1. The final R1 and wR2 were 0.0451 and 0.0682
1. Feringa, B. L.; Browne, W.R. Eds; Molecular Switches Wiley-VCH: Weinheim,
Germany, 2011.
2. Balzani, V.; Credi, A.; Venturi, M. Molecular Devices and Machines; Wiley-VCH:
Weinheim, Germany, 2004.
3. Ballardini, R.; Balzani, V.; Credi, A.; Gandolfi, M. T.; Venturi, M. Acc. Chem. Res.
2001, 34, 445e455.
4. Feringa, B. L.; van Delden, R. A.; Koumura, N.; Geertsema, E. M. Chem. Rev. 2000,
100, 1789e1816.
(I>2s(I)). CCDC-869644.
Compound 5d: recrystallized from chloroform. C26H21NO3,
Mr¼395.44, monoclinic, P21, a¼10.3289(9), b¼7.7588(7),
3
ꢀ
c¼12.1287(10) A,
b
¼94.4440(10)ꢀ, V¼969.07(15) A , Z¼2,
ꢀ
Dcalcd¼1.355 Mg mꢁ3, 2qmax¼54.22ꢀ, T¼150 K, 4823 reflections
measured, 3524 unique (Rint¼0.0127),
m
¼0.089 mme1. The final R1
and wR2 were 0.0299 and 0.0675 (I>2
s
(I)). CCDC-869645.
5. Brown, G. H. Photochromism; Wiley-Interscience: New York, NY, 1971.
€
6. Durr, H.; Bouas-Laurent, H. Photochromism: Molecules and Systems; Elsevier:
Compound 5e: recrystallized from AcOEt/chloroform.
C20H15N3O7, Mr¼409.35, hexagonal, Rꢁ3, a¼b¼22.5515(14),
Amsterdam, 1990.
7. Irie, M. Chem. Rev. 2000, 100, 1683e1684.
8. Kobayashi, H.; Ogawa, M.; Alford, R.; Choyke, P. L.; Urano, Y. Chem. Rev. 2010,
110, 2620e2640.
9. Tsien, R. Y. In Fluorescent and Photochemical Probes of Dynamic Biochemical
Signals inside Living Cells; Czarnik, A. W., Ed.; American Chemical Society:
Washington, DC, 1993; pp 130e146.
3
c¼20.773(3) A, V¼9149.3(14) A , Z¼18, Dcalcd¼1.337 Mg mꢁ3
,
ꢀ
ꢀ
2
qmax¼54.36ꢀ, T¼150 K, 15,219 reflections measured, 4201 unique
(Rint¼0.0476),
m
¼0.103 mme1. The final R1 and wR2 were 0.0712 and
0.2346 (I>2s(I)). CCDC-869646.
10. Feringa, B. L. Acc. Chem. Res. 2001, 34, 504e513.
11. Balzani, V.; Credi, A.; Raymo, F. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2000, 39,
3348e3391.
Compound 5f: recrystallized from AcOEt/dichloromethane/n-
hexane. C20H12F5NO3, Mr¼409.31, triclinic, Pꢁ1, a¼8.4196(10),
ꢀ
b¼13.4776(16), c¼17.081(2) A,
a
¼82.6400(10),
b
¼76.9940(10),
12. Irie, M. Chem. Rev. 2000, 100, 1683e1890.
3
ꢀ
13. Kay, E. R.; Leigh, D. A.; Zerbetto, F. Angew. Chem., Int. Ed. 2007, 46, 72e191.
14. Itai, A.; Toriumi, Y.; Tomioka, N.; Kagechika, H.; Azumaya, I.; Shudo, K. Tetra-
hedron Lett. 1989, 30, 6177e6180.
15. Azumaya, I.; Kagechika, H.; Fujiwara, Y.; Itoh, M.; Yamaguchi, K.; Shudo, K. J. Am.
Chem. Soc. 1991, 113, 2833e2838.
16. Kagechika, H. Curr. Med. Chem. 2002, 9, 591e608.
17. Kagechika, H.; Himi, T.; Kawachi, E.; Shudo, K. J. Med. Chem. 1989, 32,
2292e2296.
18. Yamasaki, R.; Tanatani, A.; Azumaya, I.; Saito, S.; Yamaguchi, K.; Kagechika, H.
Org. Lett. 2003, 5, 1265e1267.
19. Yamasaki, R.; Tanatani, A.; Azumaya, I.; Masu, H.; Yamaguchi, K.; Kagechika, H.
Cryst. Growth Des. 2006, 6, 2007e2010.
g
¼88.3220(10)ꢀ, V¼1873.0(4) A , Z¼4, Dcalcd¼1.452 Mg mꢁ3
,
2
qmax¼54.30ꢀ, T¼120 K, 9331 reflections measured, 7146 unique
(Rint¼0.0150),
m
¼0.131 mme1. The final R1 and wR2 were 0.0545 and
0.1363 (I>2
s
(I)). CCDC-869647.
Compound 6a: CCDC-635796.
Compound 6b: recrystallized from AcOEt/n-hexane. C19H13NO3,
Mr¼303.30, orthorhombic, Pca21, a¼9.034(5), b¼17.635(10),
3
c¼9.248(6) A, V¼1473.3(15) A , Z¼4, Dcalcd¼1.367 Mg mꢁ3
,
ꢀ
ꢀ
2
qmax¼52.44ꢀ, T¼15 K, 5958 reflections measured, 2696 unique
(Rint¼0.0694),
m
¼0.093 mme1. The final R1 and wR2 were 0.0689
20. Okamoto, I.; Nabeta, M.; Yamamoto, M.; Mikami, M.; Takeya, T.; Tamura, O.
Tetrahedron Lett. 2006, 47, 7143e7146.
and 0.1643 (I>2s(I)). CCDC-869648.
21. Okamoto, I.; Nabeta, M.; Hayakawa, Y.; Morita, N.; Takeya, T.; Masu, H.; Azu-
maya, I.; Tamura, O. J. Am. Chem. Soc. 2007, 129, 1892e1893.
22. Okamoto, I.; Nabeta, M.; Minami, T.; Nakashima, A.; Morita, N.; Takeya, T.;
Masu, H.; Azumaya, I.; Tamura, O. Tetrahedron Lett. 2007, 48, 573e577.
23. Okamoto, I.; Terashima, M.; Masu, H.; Nabeta, M.; Ono, K.; Morita, N.; Katagiri,
K.; Azumaya, I.; Tamura, O. Tetrahedron 2011, 67, 8536e8543.
24. Saito, S.; Toriumi, Y.; Tomioka, N.; Itai, A. J. Org. Chem. 1995, 60, 4715e4720.
25. Okamoto, I.; Yamasaki, R.; Sawamura, M.; Kato, T.; Nagayama, N.; Takeya, T.;
Tamura, O.; Masu, H.; Azumaya, I.; Yamaguchi, K.; Kagechika, H.; Tanatani, A.
Org. Lett. 2007, 9, 5545e5547.
Compound 6c: recrystallized from dichloromethane/n-hexane.
C19H8F5NO3$0.33(O), Mr¼398.60, hexagonal, Rꢁ3, a¼b¼36.382(5),
3
c¼6.7101(11) A, V¼7691.7(19) A , Z¼18, Dcalcd¼1.549 Mg mꢁ3
,
ꢀ
ꢀ
2
qmax¼55.00ꢀ, T¼300 K, 14,088 reflections measured, 3866 unique
(Rint¼0.0699),
m
¼0.142 mme1. The final R1 and wR2 were 0.0536
and 0.1449 (I>2s(I)). CCDC-869649.
Compound 6d: recrystallized from dichloromethane/ether.
C26H19NO3,
b¼22.128(2), c¼16.7037(16) A,
Mr¼393.42,
monoclinic,
P21,
a¼11.2320(11),
26. Zahn, S.; Canary, J. W. Science 2000, 288, 1404e1407.
27. Zhang, J.; Canary, J. W. Org. Lett. 2006, 8, 3907e3910.
3
ꢀ
ꢀ
ꢀ
b
¼108.2400(10) , V¼3943.0(7) A ,

I. Okamoto et al. / Tetrahedron 68 (2012) 5346e5355
5355
28. Westermeier, C.; Gallmeier, H.-C.; Komma, M.; Daub, J. Chem. Commun. 1999,
2427e2428.
36. Desiraju, G.; Steiner, T. The Weak Hydrogen Bond: In Structural Chemistry and
Biology; Oxford University: Oxford, 2001.
29. Nishida, J.; Suzuki, T.; Ohkita, M.; Tsuji, T. Angew. Chem., Int. Ed. 2001, 40,
3251e3254.
37. Nishio, M. CrystEngComm 2004, 6, 130e158.
38. Desiraju, G. R. Acc. Chem. Res. 1991, 24, 290e296.
30. Gomar-Nadal, E.; Veciana, J.; Rovira, C.; Amabilino, D. B. Adv. Mater. (Weinheim,
Ger.) 2005, 17, 2095e2098.
31. Fukui, M.; Mori, T.; Inoue, Y.; Rathore, R. Org. Lett. 2007, 9, 3977e3980.
32. Iordache, A.; Oltean, M.; Milet, A.; Thomas, F.; Baptiste, B.; Saint-Aman, E.;
Bucher, C. J. Am. Chem. Soc. 2012, 134, 2653e2671.
33. Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2003, 68,
2861e2873.
39. Steiner, T. New J. Chem. 1998, 22, 1099e1103.
40. Taylor, R.; Kennard, O. J. Am. Chem. Soc. 1982, 104, 5063e5070.
41. The rotational barrier of the amide bond was calculated by the following
equation:
D
Gz¼4.57 Tc (9.97þlog(Tc/Dn)); Oki, M. Applications of Dynamic NMR
Spectroscopy to Organic Chemistry; VCH: Weinheim, Germany, 1985.
42. Greenberg, A.; Breneman, C. M.; Liebman, J. F. The Amide Linkage; Wiley-In-
terscience: New York, NY, 2003.
34. Steiner, T. Crystallogr. Rev. 1996, 6, 1e51.
43. Structures are optimized by the calculation using Spartan ’04, B3LYP/6e31G*.
35. Nishio, M.; Hirota, M.; Umezawa, Y. The CH/
p
Interaction, Evidence, Nature and
44.
A
short history of SHELX. Sheldrick, G. M. Acta Crystallogr. 2008, A64,
Consequences; Wiley-VCH: New York, NY, 1998.
112e122.