Atropisomeric Properties of N-Acyl/ N-Sulfonyl 5 H-Dibenzo[ b, d]azepin-7(6 H)-ones

Article abstract of DOI:10.1021/acs.joc.1c00594

The stereochemistry of N-acyl/N-sulfonyl 5H-dibenzo[b,d]azepin-7(6H)-ones (I, II) was examined in detail by freezing the conformation with a methyl group at the C-4 of dibenzoazepine. Because the two axes (axis 1, axis 2) move together concertedly, I and

Full text of DOI:10.1021/acs.joc.1c00594

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Article
Atropisomeric Properties of N‑Acyl/N‑Sulfonyl
5H‑Dibenzo[b,d]azepin-7(6H)‑ones
Takuya Namba, Mayuno Hotta, Hidetsugu Tabata, Kosho Makino, Tetsuta Oshitari, Hideaki Natsugari,
and Hideyo Takahashi*
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ABSTRACT: The stereochemistry of N-acyl/N-sulfonyl 5H-dibenzo[b,d]-
azepin-7(6H)-ones (I, II) was examined in detail by freezing the conformation
with a methyl group at the C-4 of dibenzoazepine. Because the two axes (axis
1, axis 2) move together concertedly, I and II exist only as a pair of
enantiomers [(a1R, a2R) and (a1S, a2S)], which was confirmed by X-ray
analysis of IIBc. It was elucidated that the amide derivatives I exist in
equilibrium with the E/Z-amide (100:2−100:34), which means that the
exocyclic bond (axis 3) is not in concert with the endocyclic axes (axis 1, axis
2). For the preparation of 5H-dibenzo[b,d]azepin-7(6H)-one, the intra-
molecular Friedel−Crafts acylation of N-(1,1′)-biphenyl-2-yl-glycine derivatives was revisited. It was revealed that the electron-
withdrawing property of the amino-protective group was a key to the success of seven-membered cyclization.
(aS)/(aR) axial isomers6 derived from axes 1 and 2, and E/Z-
amide rotamers derived from axis 3. Similarly, the congener N-
sulfonyl derivatives (II) were considered to have atropisomeric
INTRODUCTION
Recently, we have been interested in the conformational
■
analysis of benzo-fused seven-membered-ring nitrogen hetero-
cycles, which are found as the scaffolds of many drugs.1 Our
continuing interest in the relationship between axial chirality
and biological activity2,3 prompted us to examine the N-acyl/
N-sulfonyl 5H-dibenzo[b,d]azepin-7(6H)-ones (I, II) (Figure
1), which were reported to have immunosuppressive effects by
properties caused by the biphenyl (axis 1) and Ar−N(SO2)
(axis 2).7 Their complex stereochemical structures are
considered to constitute a key core structure of the
immunosuppressive activity. Although the conformational
change, i.e., ring flip, in molecules without a methyl substituent
at the ortho position of the benzene ring (R1 = H) was
anticipated to be too rapid for isolation of the stereoisomers at
room temperature, molecules with 4-methyl (R1 = Me) were
expected to freeze the conformations so that relatively stable
stereoisomers could be separated. Such investigations should
reveal the active structure (eutomer) exerting the inhibitory
activity on the potassium channel (Kv1.3, IK-1) of T cell
activity. Herein we describe a study of the conformational
properties of the N-acyl/N-sulfonyl 5H-dibenzo[b,d]azepin-
7(6H)-ones nucleus (I, II), and preliminary results of the
blockade of the potassium channel. Through the synthesis, the
intramolecular Friedel−Crafts acylation as a crucial step to
provide the 5H-dibenzo[b,d]azepin-7(6H)-one nucleus was
revisited. It was shown that the electron-withdrawing effect of
the N-substituent of the amino acids affects the yield of
cyclized compounds.
Figure 1. N-Acyl 5H-dibenzo[b,d]azepin-7(6H)-ones (I) and N-
sulfonyl 5H-dibenzo[b,d]azepin-7(6H)-ones (II).
inhibiting the potassium channel (Kv1.3, IK-1) of T cells.4 The
Ca2+-dependent potassium channel IK-1 and the voltage-gated
potassium channel Kv1.3 in human T cells play a pivotal role
during cell proliferation. Thus, inhibitors of these channels
could be expected to be new drug candidates for treating
autoimmune diseases such as rheumatoid arthritis and multiple
sclerosis.5
The 5H-dibenzo[b,d]azepin-7(6H)-one moiety has dynamic
axial chirality based on the sp2−sp2 axis arising from the
biphenyl (axis 1). In addition, N-acylated derivatives (I) have
another axial chirality around the Ar−NC(O) (sp2−sp2) axis
(axis 2) and E/Z-amide rotamers based on the N−C(O)
axis (axis 3). Thus, N-acylated derivatives (I) should exist in
Received: March 12, 2021
Published: May 17, 2021
© 2021 The Authors. Published by
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https://doi.org/10.1021/acs.joc.1c00594
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ycarbonyl (1Ah) also provided N-acyl derivatives (IAg, IAh)
in good yields (Table 1, entries 7, 8). These results indicate
that the electron-withdrawing property of the amino-protecting
group is very important for this ring-closing reaction. Pleased
with this, we further examined the cyclization of 4-methyl-
substituted derivatives (1Bc−h). Despite the steric hindrance,
4-methyl-N-acyl/N-sulfonyl 5H-dibenzo[b,d]azepin-7(6H)-
ones (IIBc−h) were obtained in good yields (Table 1, entries
9−14).
Stereochemistry of N-Acyl-5H-Dibenzo[b,d]azepin-
7(6H)-ones. N-Acyl 5H-dibenzo[b,d]azepin-7(6H)-ones
(IA) (R1 = H) and (IB) (R1 = Me) should have chirality
based on the sp2−sp2 axis arising from the biphenyl (axis 1). In
addition, another axial chirality arising from the sp2−sp2 axis of
the benzene-amide bond (axis 2) should exist as well as E/Z-
amide diastereomers around the N−C(O) bond (axis 3). It
was therefore anticipated that IA and IB exist as complicated
stereoisomers. However, our preceding studies on this
dibenzoazepinone nucleus revealed that axes 1 and 2 move
concertedly to form the stable relative configuration.11 Thus,
we presumed that the configuration of the enantiomers should
be (a1R, a2R) and (a1S, a2S), respectively. Additionally, E/Z-
amide diastereomers around the N−C(O) bond (axis 3)
were assumed to exist. The conformational properties of IA
and IB are highlighted in Figure 2.
RESULTS AND DISCUSSION
■
Preparation of 5H-Dibenzo[b,d]azepin-7(6H)-ones.
For the preparation of 5H-dibenzo[b,d]azepin-7(6H)-one, we
intended to utilize the intramolecular Friedel−Crafts acylation
of N-(1,1′)-biphenyl-2-yl-glycine derivatives (1). The cycliza-
tion of the aryl amino acids appeared to be an obvious route.
According to the procedure reported in a previous paper,4 the
corresponding acid chlorides, prepared from N-(1,1′)-
biphenyl-2-yl-glycine using thionyl chloride, were treated
with anhydrous aluminum chloride. However, the reaction of
N-(1,1′)-biphenyl-2-yl-glycine derivatives with an N-acetyl
(1Aa), N-p-toluoyl (1Ab) provided complex mixtures (Table
1, entries 1, 2). Since further examination of the various
Table 1. Intramolecular Friedel−Crafts Acylation of Aryl
Amino Acids
Aryl amino
Entry
1
acid10
R1
H
X
Yield (%)
1Aa
Acetyl
 (Complex
mixture)
2
1Ab
H
p-Toluoyl
 (Complex
mixture)
3
4
5
6
7
8
9
10
11
12
13
14
1Ac
1Ad
1Ae
1Af
1Ag
1Ah
1Bc
1Bd
1Be
1Bf
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
p-Tosyl
Mesyl
o-Nosyl
p-Nosyl
Trifluoroacetyl
Methoxycarbonyl
p-Tosyl
Mesyl
o-Nosyl
IIAc 91
IIAd 86
IIAe 74
IIAf
IAg
IAh
69
97
84
IIBc 99
IIBd 72
IIBe 83
p-Nosyl
Trifluoroacetyl
Methoxycarbonyl
IIBf
IBg
IBh
83
99
96
1Bg
1Bh
reaction conditions was not rewarding, the pioneering work on
Friedel−Crafts cyclization of aryl amino acids8 was reviewed. It
was reported that Friedel−Crafts intramolecular acylation of
aryl amino acids has little hope of succeeding because it gave a
mixture of isoquinoline derivatives, oxazolonium halides, and
phenanthridine derivatives as major products. Among them,
Paterson and Procter reported that the N-p-tosylated aryl
amino acid reacted to give the desired cyclic compound,
although other N-acylated ones did not cyclize.9 In light of this,
we focused on the amino-protective groups of the electron-
withdrawing property and revisited the intramolecular
Friedel−Crafts acylation of aryl amino acids.
Figure 2. Conformational properties of N-acyl-5H-dibenzo[b,d]-
azepin-7(6H)-ones.
As expected, the cyclization of N-(1,1′)-biphenyl-2-yl-
glycine derivatives with an N-p-tosyl group (1Ac) provided
the corresponding 5H-dibenzo[b,d]azepin-7(6H)-one deriva-
tive (IIAc) in 91% yield (Table 1, entry 3). Similarly, N-mesyl
(1Ad), N-o-nosyl (1Ae), and N-p-nosyl (1Af) were feasible for
producing N-sulfonyl derivatives (IIAd−f) (Table 1, entries
4−6). Additionally, N-trifluoroacetyl (1Ag) and N-methox-
First, the conformational properties of IAg-h (R1 = H) in the
solution state were investigated precisely using 1H NMR
spectroscopy (Figure 3). Compounds IAg and IAh were
shown to exist as an equilibrium mixture of diastereomers in
solution (CDCl3) at the ratios 100:7 [Figure 3b] and 100:30
[Figure 3c], respectively. In each spectrum, one of the two
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1
Figure 3. H NMR spectra of IAa (a), IAg (b), and IAh (c).
Scheme 1. Preparation of IAa from IAg and Its E/Z-Amide Stereochemistry
diastereotopic H-6 proton resonances in the major amide
diastereomer is located at about 5.6 ppm (IAg) and 5.4 ppm
(IAh), each 1.5 ppm, 1.3 ppm downfield from its partner,
respectively. This downfield shift was also previously observed
by Hassner12a and Qadir et al.,12b who ascribed the
phenomenon to coplanarity between the exocyclic amide
carbonyl bond and the equatorial proton on the adjacent
carbon (C-6). Based on this anisotropic effect of the carbonyl
group, we presumed that both IAg and IAh exist in the E-
amide in preference to the Z-amide. It is clear that the two
endocyclic axes (axes 1 and 2) move together concertedly,
although the exocyclic axis (axis 3) does not move in concert
with them. Viewed in this light, it was assumed that the seven-
membered ring 5H-dibenzo[b,d]azepin-7(6H)-one exists only
as a pair of enantiomers [(a1R, a2R) and (a1S, a2S)] without the
presence of diastereomers [(a1R, a2S) and (a1S, a2R)].11
In need of solid evidence for the determination of the E/Z-
amide stereochemistry, investigation using NOE spectra
seemed promising. However, the trifluoroacetyl group in IAg
diastereomer is located at about 5.7 ppm, 1.7 ppm downfield
from its partner. Irradiation of the dominant CH3 resonance of
acetyl in the major amide diastereomer led to 2.65%
enhancement of the 4-H proton of benzene (Scheme 1).
Therefore, the preference of the E-amide in IAa was
determined. Based on this, the preference of the E-amide
observed in IAg and IAh was confirmed. It was also revealed
that IBg-h (R1 = Me) showing similar spectra (see Supporting
Information) preferred the E-amide to the Z-amide in solution
(Table 2).
Furthermore, the following computational studies were
carried out to study the conformational preferences of N-acyl
5H-dibenzo[b,d]azepin-7(6H)-ones of IAa, IAg, IAh, IBg, and
IBh. First, the conformational ensembles of IAa, IAg, IAh, IBg,
and IBh were generated from 2D chemical structures as the
initial structures for the density functional theory (DFT)
calculations. These conformations were generated and
optimized with the RDKit using the universal force field
(UFF) and clustered using a tolerance of 0.2 Å root-mean-
square deviation. For each conformer, the Hartree−Fock (HF)
calculations were carried out to obtain optimized geometries
and energies at the RHF/6-31G(d) levels. For each conformer
excluding atropisomers, DFT calculations were carried out to
obtain optimized geometries and energies at the RB3LYP/6-
31G(d) and the RmPW1PW91/6-311+G(d,p) levels. The
relative energy differences of the two conformers were
estimated on the basis of geometries fully optimized with
mPW1PW91/6-311+G(d,p) with energy calculations with the
1
was not observed in H NMR, and the methoxy carbonyl
group in IAh was inadequate because of the flexibility of the
−O−Me bond. Thus, the N-acetylated compound IAa was
prepared for this purpose from IAg through two steps
(hydrolysis and acetylation) (Scheme 1).
IAa as well as IAg−h was shown to exist as an equilibrium
mixture of E/Z-amide diastereomers in solution (CDCl3) at
the ratio 100:2 [Figure 3a]. Additionally, one of the two
diastereotopic H-6 proton resonances in the major amide
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enantiomer of IAh without the 4-methyl substituent (R1 = H)
was not separable at rt, IBh with the 4-methyl substituent (R1
= Me) was separable into the stable (a1R, a2R)- and (a1S, a2S)-
axial isomers, and the separated isomers showed a high energy
barrier to rotation (ΔG‡ = 116.0 kJ/mol). The physicochem-
ical properties of IBg and IBh are shown in Table 3. As
expected, the 4-methyl (R1 = Me) substituent was helpful to
freeze the conformations so that the relatively stable
stereoisomers could be separated.
Table 2. E/Z Equilibrium Ratio and Energy Differences of
1
IAa, IAg, IAh, IBg, and IBh Based on H NMR and DFT
Calculation13
Table 3. Optical Rotation of the Atropisomers [(+) and
(−)] and Their Stereochemical Stability
Energy difference (kJ/mol)
Calculated
E/Z ratio (1H NMR Experimental
(DFT)
ΔG298
R1
R2
at 296 K in CDCl3)
ΔGTc
IAa
IAg
IAh
IBg
IBh
H
H
H
Me
Me
Me
100:2
100:7
100:30
100:17
100:34
9.7
6.7
3.0
4.4
2.7
10.3
7.2
2.8
3.5
3.0
CF3
MeO
CF3
MeO
a
Unfortunately, each E/Z-amide of N-acyl 5H-dibenzo[b,d]azepin-
7(6H)-ones (IAa, IAg-h, IBg-h) was not separated by HPLC at rt.
RmPW1PW91/6-311+G(d,p) in the SCRF/IEFPCM model
in CHCl3.13 Zero-point energy (ZPE) correction was made on
the basis of the frequency calculation with the RmPW1PW91/
6-311+G(d,p). The results are shown in Table 2. As a
representative result obtained in those computational studies,
the selected conformers of the E/Z-amide of IAa are illustrated
in Figure 4. Others are shown in the Supporting Information.
a
[α]D
ΔG‡
b
X
(+)
(−)
(kJ/mol)
IBg
IBh
COCF3
COOMe +145.8 as
94.7% ee
+12.2 as 99.5% ee −12.1 as 99.9% ee
124.8
116.0
−146.8 as
94.8% ee
IIBc
IIBd
IIBe
IIBf
p-Tosyl
Mesyl
o-Nosyl
p-Nosyl
+64.9 as 96.1% ee −65.8 as 96.8% ee
+89.8 as 97.0% ee −90.8 as 98.7% ee
+61.5 as 99.8% ee −61.1 as 99.8% ee
+27.2 as 98.5% ee −27.9 as 99.8% ee
127.5
126.3
131.6
131.6
a
In CHCl3 and for each concentration (c), see the Experimental
b
Section. Conditions required for determination of ΔG‡ in toluene at
80 °C.
Figure 4. Conformers of IAa with the (a1S, a2S) stereochemistry and
free energy difference (ΔG298) calculated by the DFT method.
Stereochemistry of N-Sulfonyl-5H-dibenzo[b,d]-
azepin-7(6H)-ones. The stereochemistry of the N-sulfonyl
derivatives (IIA/B) was investigated next, and a general
picture of the conformational property is shown in Figure 5.
Although the sulfonamide group is an important functional
moiety observed in various biologically active compounds, its
physicochemical properties are not as well understood as those
of the amide group. Similar to N-acyl derivatives (IA/B), N-
It was confirmed that N-acyl 5H-dibenzo[b,d]azepin-7(6H)-
ones exist in the stable relative configuration of a pair of
enantiomers [(a1R, a2R) and (a1S, a2S)] without the presence
of diastereomers [(a1R, a2S) and (a1S, a2R)]. Additionally, in
each case, the E-amide was preferred, although the energy
difference between the E-amide and Z-amide was less than
10.3 kJ/mol.
Then we investigated the physicochemical properties of
(a1R, a2R)- and (a1S, a2S)-axial isomers. As mentioned above,
methylene protons (H-6) in these compounds were observed
as diastereotopic, meaning the presence of axial chirality. In
IAg (R1 = H), however, the ring inversion via rotation around
the axis was too rapid for separation of the axial isomers at rt,
and thus IAg was not separated by chiral HPLC. On the other
hand, compound IBg with a 4-methyl substituent (R1 = Me)
was conformationally frozen and separable into the stable (a1R,
a2R)- and (a1S, a2S)-isomers, and the separated isomers
showed a high energy barrier to rotation (ΔG‡ = 124.8 kJ/
mol).14 Next, N-methoxycarbonyl 5H-dibenzo[b,d]azepin-
7(6H)-one (IAh) and its 4-methyl derivative (IBh) were
investigated, and similar results were obtained. While each
Figure 5. Conformational property of N-sulfonyl-5H-dibenzo[b,d]-
azepin-7(6H)-ones.
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sulfonyl derivatives (IIA/B) should have chirality based on the
sp2−sp2 axis arising from the biphenyl (axis 1). In addition,
another axial chirality arising from the benzene−sulfonamide
bond should exist. Our studies have recently revealed that the
atropisomeric property of the sulfonamide group is caused by
the Ar−N(SO2) axis (axis 2).7a,15 The planarity of the N−SO2
arises from both the nitrogen atom possessing an sp2-like
nature and the double-bond character between the S−N bond.
As well as N-acyl derivatives (IA/B), it was anticipated that
axes 1 and 2 would move together concertedly to form the
stable relative configuration of (a1R*, a2R*). Thus, the
configuration of the enantiomers was presumed to be (a1R,
a2R) and (a1S, a2S), respectively.
In order to elucidate how axes 1 and 2 move together
concertedly to form the stable relative configuration, N-tosyl
5H-dibenzo[b,d]azepin-7(6H)-one (IIAc) (R1 = H) and its 4-
methyl derivative (R1 = Me) (IIBc) were examined. In the 1H
NMR (CDCl3) spectra of IIAc and IIBc, they exist as a single
compound, and each methylene proton (6-H) was observed as
a separated sharp peak, which indicates the presence of
chirality. The atropisomers of (IIAc) (R1 = H) were
inseparable by chiral HPLC because the ring inversion via
rotation around the axis was too rapid for separation at rt. In
contrast, those of IIBc (R1 = Me) were sufficiently stable to be
separated and isolated with chiral HPLC at rt; the separated
isomers showed a high energy barrier to rotation (ΔG‡ = 127.5
kJ/mol). Each isomer has opposite [α]D values: that with
shorter retention time in HPLC at 96.8% ee showed [α]D
−65.8 (c 0.23, CHCl3) and that with a longer retention time in
HPLC at 96.1% ee showed [α]D +64.9 (c 0.21, CHCl3),
confirming that they are enantiomers. As well as N-tosyl 5H-
dibenzo[b,d]azepin-7(6H)-one (IIAc) (R1 = H), the atro-
pisomers of other N-sulfonyl derivatives (IIAd−f) (R1 = H)
were inseparable by chiral HPLC. On the other hand, the
presence of the atropisomers of the corresponding 4-methyl
derivative (IIBc−f) (R1 = Me) was confirmed by isolating each
isomer by chiral HPLC. The separated isomers showed a high
energy barrier to rotation (IIBd: ΔG‡ = 126.3 kJ/mol, IIBe:
ΔG‡ = 131.6 kJ/mol, IIBf: ΔG‡ = 131.6 kJ/mol). The
physicochemical properties of IIBc−f are shown in Table 3. It
is noteworthy that compounds IIBe and IIBf with the most
electron-withdrawing nosyl group showed the highest energy
barrier to rotation.
Figure 6. X-ray crystal structure of IIBc. The structure with the (a1R,
a2R) stereochemistry was extracted from the CIF data of the
racemates.
O) is on the amide (>N−CO) plane and the N−C bond has
a double-bond character due to the resonance, the double-
bond character of the N−S bond without the planarity of
sulfonamide (>N−SO) is interesting. It was also found that
the seven-membered ring exists in a boat-like form, the
benzene ring of the tosyl moiety locates over the benzene ring
of biphenyl (folded form), and they are nearly parallel to each
other.
Blockade of Potassium Channel Kv1.3. We next
conducted a preliminary investigation of the blockade of the
potassium channel. Considering the level of activity on Kv1.3
of IIAc (IC50 5.8 μM),4 blocking activity on the voltage-gated
potassium channel Kv1.3 with 4-aminopyridine as a positive
control was tested for IIBc using patch-clamp technology
(Table 4). IIBc in racemic form showed a moderate level of
Table 4. Blocking Activity of IIBc at 10 μM (Racemate and
Atropisomers)
a
% Inhibition
IIBc
(+)-IIBc
(−)-IIBc
4-Aminopyridine
63
14
43
19
b
a
% inhibition values shown are the means of duplicate measurements.
At 100 μM.
b
Fortunately, a single crystal for the X-ray crystal structure
analysis of IIBc (racemate) was obtained, in which IIBc
possessed the stable relative configuration of (aR, aR) and (aS,
aS) as expected in a unit cell (Figure 6). It was revealed that
axial chirality caused by the Ar−N(SO2) axis (axis 2), which
showed a rather high energy barrier (ΔG‡ = 126.3−131.6 kJ/
mol), moves concertedly with the axis at the biphenyl (axis 1)
to form the stable relative configuration of (aR*, aR*) without
the presence of diastereomers (aR*, aS*). Such a high energy
barrier might be due to the planarity of the nitrogen atom.16
The sum of angles around the nitrogen atom in the >N−SO2
moiety is 359.2°, indicating the sp2-like nature of the nitrogen
atom. In addition, the bond length between N−S (0.16 nm)
suggests the double-bond character of the N−S bond. While
these data imply that the > N−S moiety forms a plane, it was
found that the SO2 moiety locates so as to interweave with the
N−SO2 axis: dihedral angles ∠O1−S−N−C6 and ∠O2−S−
N−C4a were −44.90° and +12.64°, respectively. The
important point to note is that the sulfonyl (SO) bond is
not on the >N−S plane. Considering that the carbonyl (C
inhibitory activity of 63% at 10 μM when the channel was in
the closed state. Hence, the separated enantiomers of (+)-IIBc
and (−)-IIBc were subjected to the binding assay to examine
the difference in potency between the enantiomers. Although
the enantiomers and the racemate exhibited similar levels of
affinity (within a 4.5-fold difference), (−)-IIBc showed more
potent affinity than (+)-IIBc.
CONCLUSION
■
The efficient synthesis of N-acyl/N-sulfonyl 5H-dibenzo[b,d]-
azepin-7(6H)-ones and the physicochemical properties of N-
acyl/N-sulfonyl 5H-dibenzo[b,d]azepin-7(6H)-ones were elu-
cidated. Improvement of the Friedel−Crafts acylation of N-
(1,1′)-biphenyl-2-yl-glycine derivatives17 was achieved by the
introduction of the amino-protective groups with electron-
1
withdrawing properties. H NMR revealed that N-acyl 5H-
dibenzo[b,d]azepin-7(6H)-ones exist in E-amide in preference
to Z-amide in solution, which was also supported by DFT
calculations. The equilibration of the amide diastereomer
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129.0, 128.5, 128.1, 51.2, 22.2; IR (ATR) 2873, 1716, 1608 cm−1;
HRMS (ESI-TOF) m/z calcd for C16H15NO3Na 292.0944 (M+Na)+,
found 292.0951.
means that the exocyclic bond (axis 3) is not in concert with
the endocyclic axes (axis 1, axis 2). Additionally, stable
atropisomers [(a1R, a2R) and (a1S, a2S)] of 4-methyl
derivatives of N-acyl-5H-dibenzo[b,d]azepin-7(6H)-ones were
isolated. Similarly, the atropisomers of 4-methyl derivatives of
N-sulfonyl 5H-dibenzo[b,d]azepin-7(6H)-ones were isolated.
The separated isomers showed a high energy barrier to
rotation (ΔG‡ = 116.0−131.6 kJ/mol), and X-ray crystal
structure analysis of the racemate of 4-methyl-5-tosyl-5,6-
dihydro-7H-dibenzo[b,d]azepin-7-one showed that it pos-
sessed the stable relative configuration of (a1R, a2R) and
(a1S, a2S) in a unit cell. It was revealed that axial chirality
caused by the Ar−N(SO2) axis moves together concertedly
with the axis at the biphenyl to form the stable relative
configuration of (a1R*, a2R*). The preliminary results on the
difference between the atropisomers of N-sulfonyl 5H-
dibenzo[b,d]azepin-7(6H)-ones in the potency of potassium
channel Kv1.3 blockade might be a clue for the design of
potassium channel inhibitors. More detailed investigation
through the structure−activity relationship (SAR) study of
N-acyl/N-sulfonyl 5H-dibenzo[b,d]azepin-7(6H)-ones is
under consideration.
N-([1,1′-Biphenyl]-2-yl)-N-(4-methylbenzoyl)glycine (1Ab). Com-
pound 1Ab was prepared according to a similar procedure as
described for the preparation of 1Aa from S2a. Colorless crystal
1
(900.0 mg, 62%), mp 147−149 °C: H NMR (600 MHz, CDCl3) δ
7.37−7.34 (m, 4H), 7.31 (ddd, 2H, J = 7.8, 7.8, 3.0 Hz), 7.26 (ddd,
1H, J = 7.2, 7.2, 1.8 Hz), 7.15 (dd, 2H, J = 7.2, 1.2 Hz), 7.05 (d, 2H, J
= 8.4 Hz), 6.90 (d, 2H, J = 8.4 Hz), 4.78 (d, 1H, J = 17.4 Hz), 3.76
(d, 1H, J = 17.4 Hz), 2.27 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 173.6, 170.7, 141.2, 140.8, 138.4, 138.3, 131.4, 131.2, 129.6,
129.3, 128.9, 128.7, 128.4, 128.3, 127.9, 53.0, 21.5; IR (ATR) 2827,
1716, 1607 cm−1; HRMS (ESI-TOF) m/z calcd for C22H20NO3
346.1438 (M+H)+, found 346.1439.
N-([1,1′-Biphenyl]-2-yl)-N-(2,2,2-trifluoroacetyl)glycine (1Ag).
The benzyl ester of S2g (141.0 mg, 0.34 mmol) was dissolved in
EXPERIMENTAL SECTION
■
General Information. All reagents were purchased from
commercial suppliers and used as received. Reaction mixtures were
stirred magnetically, and the reactions were monitored by thin-layer
chromatography (TLC) on precoated silica gel plates. For the
reactions that require heating, an oil bath was used. Column
chromatography was performed using silica gel (45−60 μm). For
recrystallizaton, crude products were dissolved in AcOEt/diisopropyl
ether/hexane, and the precipitated crystals were collected. Extracted
solutions were dried over anhydrous Na2SO4. Solvents were
evaporated under reduced pressure. NMR spectra were recorded on
THF/MeOH (5.0 mL), and 10% palladium on activated carbon (14.1
mg, 10% w/w) was added at rt for 18 h under a hydrogen atmosphere.
The mixture was filtered and washed with 1 M HCl aq. and brine. The
filtrate was dried and concentrated under reduced pressure. The
concentrate was purified by recrystallization to afford 1Ag as colorless
1
crystals (116.0 mg, 99%), mp 190−191 °C: H NMR (600 MHz,
CDCl3) δ 7.56 (d, 1H, J = 7.2 Hz), 7.49 (ddd, 1H, J = 7.2, 7.2, 1.2
Hz), 7.45−7.38 (m, 5H), 7.27 (dd, 2H, J = 6.6, 1.8 Hz), 4.37 (d, 1H, J
= 17.4 Hz), 3.42 (d, 1H, J = 17.4 Hz); 13C{1H} NMR (150 MHz,
1
a spectrometer at 600 MHz for H NMR and at 150 MHz for 13C
NMR at 296 K unless otherwise stated. Tetramethylsilane (TMS) (δ
0.00) or residual internal CHCl3 (δ 7.26) was used as an internal
reference for the 1H spectroscopy measurements of samples in
CDCl3. TMS (δ 0.00) or residual internal CHCl3 (δ 77.16) was used
as an internal reference for the 13C spectroscopy measurements of
samples in CDCl3. Coupling constants (J) are reported in hertz (Hz).
Splitting patterns are abbreviated as follows: singlet (s); doublet (d);
triplet (t); quartet (q); multiplet (m); and broad (br). The high-
resolution mass spectra (HRMS) were recorded using an ESI/TOF,
APCI/TOF, or EI-MS mass spectrometer. IR spectra were recorded
on an FT-IR spectrometer equipped with ATR (Diamond). Melting
points were recorded on a melting point apparatus and are
uncorrected. The chemical structures of S1−S10 were shown in the
Supporting Information.
2
CDCl3) δ 171.8, 158.2 (C−F, JC−F = 37.6 Hz), 139.3, 137.9, 136.9,
1
131.6, 130.0, 129.7, 129.1, 128.7, 128.6, 128,4, 116.3 (C−F, JC−F
=
289.0 Hz), 52.1; IR (ATR) 2929, 1732, 1693 cm−1; HRMS (ESI-
TOF) m/z calcd for C16H12F3NO3Na 322.0697 (M+Na)+, found
322.0702.
N-([1,1′-Biphenyl]-2-yl)-N-(methoxycarbonyl)glycine (1Ah).
Compound 1Ah was prepared according to a similar procedure as
N-([1,1′-Biphenyl]-2-yl)-N-acetylglycine (1Aa). NaOH aq (930
μL, 9.30 mmol) was added to a stirred solution of methyl ester S2a
described for the preparation of 1Aa from S2a, purified by
recrystallization. Colorless crystal (331.0 mg, 70%), mp 138−140
1
°C: H NMR (600 MHz, CDCl3) δ 7.50 (dt, 1H, J = 6.6, 1.8 Hz),
7.42−7.33 (m, 7H), 7.28−7.26 (m, 1H), 4.34 (d, 1H, J = 18.0 Hz),
3.64 (s, 3H), 3.40 (d, 1H, J = 18.0 Hz); 13C{1H} NMR (150 MHz,
CDCl3) δ 174.6, 156.8, 139.4, 139.0, 138.9, 130.9, 129.7, 128.8, 128.6,
128.5, 128.4, 127.8, 53.5, 51.6; IR (ATR) 3070, 1770, 1664 cm−1;
HRMS (ESI-TOF) m/z calcd for C16H15NO4Na 308.0893 (M+Na)+,
found 308.0908.
General Procedure of Intramolecular Friedel−Crafts Acyla-
tion. 5-(2,2,2-Trifluoroacetyl)-5,6-dihydro-7H-dibenzo[b,d]azepin-
7-one (IAg). 1Ag (1.00 g, 3.09 mmol) was dissolved in SOCl2
(7.00 mL, 0.5 M) at reflux for 1 h under an argon atmosphere. The
mixture was concentrated under reduced pressure. The concentrate
was dissolved in CH2Cl2 (20.0 mL) at −78 °C under an argon
atmosphere, and aluminum chloride (1.98 g, 14.8 mmol) was added.
After being stirred at rt for 1 h, the mixture was treated with 1 M HCl
(1.05 g, 3.70 mmol) in MeOH (7.4 mL) at rt under an argon
atmosphere. After stirring for 2 h, the mixture was treated with HCl
and extracted with ethyl acetate. The extract was washed with 1 M
HCl aq. and brine, dried, and concentrated. The concentrate was
purified by recrystallization. Colorless crystal (800.0 mg, 80%), mp
1
173−174 °C: H NMR (600 MHz, CDCl3) δ 7.55 (d, 1H, J = 8.4
Hz), 7.44−7.36 (m, 6H), 7.25−7.24 (m, 2H), 4.52 (d, 1H, J = 17.4
Hz), 3.38 (d, 1H, J = 17.4 Hz), 1.95 (s, 3H); 13C{1H} NMR (150
MHz, CDCl3) δ 172.8, 172.2, 140.3, 139.4, 138.4, 131.5, 129.8, 129.2,
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Article
concentrate was purified by recrystallization to afford 1Bg as colorless
1
crystals (334.2 mg, 52%), mp 168−169 °C: H NMR (600 MHz,
CDCl3) δ 7.42−7.38 (m, 2H), 7.38−7.34 (m, 2H), 7.30 (d, 1H, J =
6.0 Hz), 7.19−7.18 (m, 3H), 4.06 (d, 1H, J = 17.2 Hz), 3.62 (d, 1H, J
= 17.2 Hz), 2.46 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ171.6,
2
158.5 (C−F, JC−F = 37.6 Hz), 141.0, 138.6, 137.2, 137.0, 130.1,
1
129.4, 129.3, 129.2, 128.9, 128.8, 128.4, 128.2, 116.1 (C−F, JC−F
=
aq. and extracted with ethyl acetate. The extract was washed with 1 M
HCl aq., 1 M NaHCO3 aq., and brine, dried, and concentrated. The
concentrate was purified by column chromatography (silica gel,
hexane/EtOAc = 4:1) to afford IAg as colorless crystals (914.0 mg,
97%), mp 95−96 °C: 1H NMR (600 MHz, CDCl3) E-isomer: δ 7.79
(dd, 1H, J = 8.4, 1.8 Hz), 7.68 (ddd, 1H, J = 7.5, 7.5, 1.2 Hz), 7.60−
7.58 (m, 2H), 7.53−7.49 (m, 3H), 7.43 (d, 1H, J = 7.8 Hz), 5.56 (d,
1H, J = 18.6 Hz), 4.11 (d, 1H, J = 18.6 Hz); Z-isomer: δ 7.79 (dd,
1H, J = 8.4, 1.8 Hz), 7.68 (ddd, 1H, J = 7.5, 7.5, 1.2 Hz), 7.60−7.58
(m, 2H), 7.53−7.49 (m, 3H), 7.43 (d, 1H, J = 7.8 Hz), 5.07 (d, 1H, J
= 21.0, 1.8 Hz), 4.37 (d, 1H, J = 21.0, 1.8 Hz); 13C{1H} NMR (150
287.6 Hz), 53.8, 18.3; IR (ATR) 2948, 1740, 1692 cm−1; HRMS
(ESI-TOF) m/z calcd for C17H14F3NO3Na 360.0818 (M+Na)+,
found 360.0826.
N-(Methoxycarbonyl)-N-(3-methyl-[1,1′-biphenyl]-2-yl)glycine
(1Bh). Compound 1Bh was prepared according to a similar procedure
2
MHz, CDCl3) E-isomer: δ 200.9, 156.8 (C−F, JC−F = 37.6 Hz),
138.5, 136.7, 136.5, 135.4, 133.9, 130.9, 130,9 129.9, 129.8, 129.7,
as described for the preparation of 1Aa from S2a. Colorless crystal
1
1
129.3, 127.6, 116.1 (C−F, JC−F = 289.0 Hz), 62.3; IR (ATR) 1695,
(232.5 mg, 99%), mp 179−180 °C: H NMR (600 MHz, CDCl3) δ
1678 cm−1; HRMS (ESI-TOF) m/z calcd for C15H9F3N 350.0646 (M
+HCOO)−, found 350.0652.
7.42−7.39 (m, 2H), 7.35 (ddd, 1H, J = 7.2, 7.2, 1.2 Hz), 7.28 (dd,
1H, J = 7.8, 7.8 Hz), 7.26−7.23 (m, 1H), 7.22 (dd, 2H, J = 9.0, 1.8
Hz), 7.18 (dd, 1H, J = 6.6, 1.8 Hz), 3.88 (d, 1H, J = 17.7 Hz), 3.78 (s,
3H), 3.33 (d, 1H, J = 17.7 Hz), 2.40 (s, 3H); 13C{1H} NMR (150
MHz, CDCl3) δ 172.9, 157.1, 139.6, 139.3, 138.0, 137.8, 130.4, 128.8,
128.7, 128.6, 128.5, 128.3, 128.0, 127.7, 53.6, 52.1, 18.2; IR (ATR)
3061, 1755, 1670 cm−1; HRMS (ESI-TOF) m/z calcd for
C17H17NO4Na 322.1050 (M+Na)+, found 332.1051.
Methyl 7-Oxo-6,7-dihydro-5H-dibenzo[b,d]azepine-5-carboxy-
late (IAh). Compound IAh was prepared according to a similar
4-Methyl-5-(2,2,2-trifluoroacetyl)-5,6-dihydro-7H-dibenzo[b,d]-
azepin-7-one (IBg). Compound IBg was prepared according to a
procedure as described for the preparation of IAg from 1Ag. Colorless
crystal (31.5 mg, 84%), mp 130−131 °C: 1H NMR (600 MHz,
CDCl3) E-isomer: δ 7.81 (d, 1H, J = 7.8 Hz), 7.65 (dd, 1H, J = 7.2,
7.2 Hz), 7.59−7.52 (m, 2H), 7.50−7.43 (m, 3H), 7.34 (d, 1H, J = 6.6
Hz), 5.36 (d, 1H, J = 18.6 Hz), 4.09 (d, 1H, J = 18.6 Hz), 3.55 (s,
3H); Z-isomer: δ 7.81 (d, 1H, J = 7.8 Hz), 7.65 (dd, 1H, J = 7.2, 7.2
Hz), 7.59−7.52 (m, 2H), 7.50−7.43 (m, 3H), 7.34 (d, 1H, J = 6.6
Hz), 5.14 (d, 1H, J = 19.2 Hz), 4.10 (d, 1H, J = 19.2 Hz), 3.67 (s,
3H); 13C{1H} NMR (150 MHz, CDCl3) E-isomer: δ 203.8, 155.9,
139.0, 137.7, 137.3, 136.4, 133.4, 130.7, 129.9, 129.8, 129.6, 129.2,
128.6, 128.0, 62.6, 53.5; IR (ATR) 1699, 1686 cm−1; HRMS (ESI-
TOF) m/z calcd for C16H13NO3Na 297.0788 (M+Na)+, found
290.0792.
similar procedure as described for the preparation of IAg from 1Ag.
Colorless crystal (37.4 mg, 99%), mp 84−85 °C: 1H NMR (600
MHz, CDCl3) E-isomer: δ 7.73 (dd, 1H, J = 7.8, 1.8 Hz), 7.66 (ddd,
1H, J = 7.6, 7.6, 1.6 Hz), 7.52−7.45 (m, 3H), 7.38 (dd, 2H, J = 6.4,
6.4 Hz), 5.50 (d, 1H, J = 18.0 Hz), 3.99 (d, 1H, J = 18.0 Hz), 2.37 (s,
3H); Z-isomer: δ 7.73 (dd, 1H, J = 7.8, 1.8 Hz), 7.66 (ddd, 1H, J =
7.6, 7.6, 1.6 Hz), 7.52−7.45 (m, 3H), 7.38 (dd, 2H, J = 6.4, 6.4 Hz),
5.07 (d, 1H, J = 19.6, 1.8 Hz), 4.26 (d, 1H, J = 19.6, 1.8 Hz), 2.30 (s,
3H); 13C{1H} NMR (150 MHz, CDCl3) E-isomer: δ 201.3, 157.4
N-(3-Methyl-[1,1′-biphenyl]-2-yl)-N-(2,2,2-trifluoroacetyl)glycine
(1Bg). K2CO3 (265.9 mg, 1.92 mmol) was added to a stirred solution
2
(C−F, JC−F = 111.2 Hz), 139.3, 136.9, 136.1, 135.4, 135.2, 133.7,
1
131.5, 130.6, 129.7, 129.5, 129.2, 128.5, 115.8 (C−F, JC−F = 865.5
2
Hz), 61.6, 17.6; Z-isomer: δ 200.5, 155.6 (C−F, JC−F = 37.6 Hz),
137.1, 137.0, 136.8, 135.1, 134.8, 134.1, 131.7, 130.1, 129.7, 129.2,
1
129.0, 128.9, 116.2 (C−F, JC−F = 289.0 Hz), 61.8, 17.4; IR (ATR)
1700, 1686 cm−1; HRMS (ESI-TOF) m/z calcd for C17H11F3NO2
318.0747 (M−H)−, found 318.0743. Separation of atropisomers.
CHIRALPAK IA (1.0 cmϕ × 25 cm): eluent, 30% 2-propanol in
hexane; flow rate, 0.5 mL/min; temperature, 25 °C; detection, 254
nm; former peak, retention time = 9.4 min; [α]D20 +12.2 as 99.5% ee
(c 0.15, CHCl3); latter peak, retention time = 13.8 min; [α]D20 −12.1
as 99.9% ee (c 0.35, CHCl3).
of amide S5g (358.0 mg, 1.28 mmol) in DMF (2.6 mL) at rt under an
argon atmosphere and treated with benzyl bromoacetate (181.0 μL,
1.15 mmol) for 2 days. The reaction mixture was poured into water
and extracted with ethyl acetate. The extract was washed with brine,
dried, and concentrated. The concentrate was dissolved in CH2Cl2,
and TFAA (537.6 μL, 3.84 mmol) was added at 0 °C under an argon
atmosphere for 1 h. The mixture was treated with 1 M HCl aq. and
extracted with ethyl acetate. The extract was washed with 1 M HCl
aq., 1 M NaHCO3 aq., and brine, dried, and concentrated. The
concentrate was purified by column chromatography (silica gel,
hexane/ethyl acetate = 4:1) to afford benzyl ester as a crude crystal
(506.0 mg, 1.50 mmol). Benzyl ester was dissolved in THF/MeOH
(7.5 mL), and 10% palladium on activated carbon (50.6 mg, 10% w/
w) was added at rt for 18 h under a hydrogen atmosphere. The
mixture was filtered and washed with 1 M HCl aq. and brine. The
filtrate was dried and concentrated under reduced pressure. The
Methyl 4-Methyl-7-oxo-6,7-dihydro-5H-dibenzo[b,d]azepine-5-
carboxylate (IBh). Compound IBh was prepared according to a
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Article
similar procedure as described for the preparation of IAg from 1Ag.
Colorless crystal (32.3 mg, 96%), mp 116−118 °C: H NMR (600
(m, 1H), 7.69 (ddd, 1H, J = 7.2, 7.2, 1.8 Hz), 7.64 (dd, 1H, J = 7.2,
7.2 Hz), 7.56 (d, 1H, J = 7.8 Hz), 7.43 (dd, 1H, J = 8.4, 8.4 Hz), 7.39
(ddd, 1H, J = 8.4, 8.4, 1.8 Hz), 7.31−7.27 (m, 3H), 7.14−7.15 (m,
2H), 3.60 (br, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 172.6,
148.0, 141.9, 138.3, 136.8, 135.2, 134.1, 133.8, 131.9, 131.8, 131.7,
129.5, 128.8, 128.6, 128.4, 127.8, 126.1, 125.4, 124.6, 53.0; IR (ATR)
3276, 1758, 1539, 1349, 1334, 1121 cm−1; HRMS (ESI-TOF) m/z
calcd for C20H16N2O6SNa 435.0621 (M+Na)+, found 435.0625.
N-([1,1′-Biphenyl]-2-yl)-N-(4-nitrobenzenesulfonyl)glycine (1Af).
Compound 1Af was prepared according to a similar procedure as
1
MHz, CDCl3) E-isomer: δ 7.77 (dd, 1H, J = 8.4, 1.2 Hz), 7.63 (ddd,
1H, J = 7.8, 7.8, 1.2 Hz), 7.50−7.45 (m, 2H), 7.40−7.35 (m, 2H),
7.34−7.31 (m, 1H), 5.31 (d, 1H, J = 18.6 Hz), 3.98 (d, 1H, J = 18.6
Hz), 3.52 (s, 3H), 2.30 (s, 3H); Z-isomer: δ 7.77 (dd, 1H, J = 8.4, 1.2
Hz), 7.63 (ddd, 1H, J = 7.8, 7.8, 1.2 Hz), 7.50−7.45 (m, 2H), 7.39−
7.35 (m, 2H), 7.34−7.30 (m, 1H), 5.08 (d, 1H, J = 18.6 Hz), 4.00 (d,
1H, J = 18.6 Hz), 3.63 (s, 3H), 2.34 (s, 3H); 13C{1H} NMR (150
MHz, CDCl3) E-isomer: δ 204.2, 155.8, 138.4, 137.7, 136.4, 136.0,
134.7, 133.2, 131.1, 129.7, 129.6, 129.1, 128.6, 128.5, 61.7, 53.5, 17.7;
IR (ATR) 1705, 1678 cm−1; HRMS (ESI-TOF) m/z calcd for
C17H15NO3SK 320.0684 (M+K)+, found 320.0685. Separation of
atropisomers. CHIRALPAK IA (1.0 cmϕ × 25 cm): eluent, 30% 2-
propanol in hexane; flow rate, 0.5 mL/min; temperature, 25 °C;
20
detection, 254 nm; former peak, retention time = 10.3 min; [α]D
+145.8 as 94.7% ee (c 0.07, CHCl3); latter peak, retention time = 15.0
20
min; [α]D −146.8 as 94.8% ee (c 0.06, CHCl3).
N-([1,1′-Biphenyl]-2-yl)-N-tosylglycine (1Ac). NaOH aq. (200.0
μL, 0.50 mmol) was added to a stirred solution of methyl ester S10c
described for the preparation of 1Ac from S10c. Colorless crystal
(249.6 mg, 85%), mp 179−181 °C: H NMR (600 MHz, CDCl3) δ
1
8.25 (ddd, 2H, J = 8.4, 2.4, 2.4 Hz), 7.87 (dd, 2H, J = 8.4, 2.4 Hz),
7.44 (ddd, 1H, J = 6.6, 6.6, 2.4 Hz), 7.40−7.32 (m, 6H), 7.31−7.29
(m, 2H), 4.42 (br, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 173.0,
150.2, 146.1, 141.7, 138.3, 136.4, 132.2, 130.6, 129.7, 129.4, 128.9,
128.7, 128.6, 128.1, 124.1, 52.7; IR (ATR) 3318, 1774, 1528, 1338,
1307, 1138 cm−1; HRMS (ESI-TOF) m/z calcd for C20H16N2O6SNa
435.0621 (M+Na)+, found 435.0626.
5-Tosyl-5,6-dihydro-7H-dibenzo[b,d]azepin-7-one (IIAc). Com-
pound IIAc was prepared according to a similar procedure as
(116.0 mg, 0.29 mmol) in MeOH (4.0 mL) at rt under an argon
atmosphere. After stirring for 2 h, the mixture was treated with HCl
and extracted with ethyl acetate. The extract was washed with 1 M
HCl aq. and brine, dried, and concentrated. The concentrate was
purified by recrystallization to afford 1Ac as colorless crystals (159.7
mg, 84%), mp 193−194 °C: 1H NMR (600 MHz, CDCl3) δ 7.62 (d,
2H, J = 8.4 Hz), 7.38−7.35 (m, 5H), 7.32−7.26 (m, 6H), 3.99 (br,
2H), 2.44 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 173.2, 144.0,
141.4, 138.7, 137.4, 137.1, 131.8, 130.7, 129.6, 129.1, 128.9, 128.5,
128.2, 127.9, 52.0, 21.7; IR (ATR) 3200, 1743, 1327, 1140 cm−1;
HRMS (ESI-TOF) m/z calcd for C21H19NO4SNa 404.0927 (M
+Na)+, found 404.0936.
described for the preparation of IAg from 1Ag. Colorless crystal (33.0
1
mg, 91%), mp 124−125 °C: H NMR (600 MHz, CDCl3) δ 7.64−
7.61 (m, 1H), 7.52 (dd, 1H, J = 8.4, 1.6 Hz), 7.49−7.45 (m, 2H),
7.42−7.39 (m, 2H), 7.27 (ddd, 1H, J = 7.8, 7.8, 1.2 Hz), 7.17 (d, 2H,
J = 7.8 Hz), 7.04 (d, 1H, J = 6.6 Hz), 6.84 (d, 2H, J = 7.8 Hz), 5.27
(d, 1H, J = 19.2 Hz), 4.38 (d, 1H, J = 19.2 Hz), 2.26 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 203.0, 143.1, 139.2, 137.5,
N-([1,1′-Biphenyl]-2-yl)-N-(methylsulfonyl)glycine (1Ad). Com-
pound 1Ad was prepared according to a similar procedure as
137.1, 137.0, 136.2, 133.0, 130.9, 130.8, 130.2, 130.0, 129.9, 129.5,
129.4, 127.9, 126.8, 63.7, 21.5; IR (ATR) 1675, 1335, 1155 cm−1;
HRMS (ESI-TOF) m/z calcd for C21H17NO3SNa 386.0821 (M
+Na)+, found 386.0822.
5-(Methylsulfonyl)-5,6-dihydro-7H-dibenzo[b,d]azepin-7-one
(IIAd). Compound IIAd was prepared according to a similar
described for the preparation of 1Ac from S10c. Colorless crystal
(186.0 mg, 70%), mp 100−101 °C: H NMR (600 MHz, CDCl3) δ
1
7.63−7.62 (m, 1H), 7.51 (dd, 2H, J = 7.2, 1.8 Hz), 7.46−7.39 (m,
6H), 4.01 (br, 2H), 3.15 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3)
δ 174.1, 141.6, 138.6, 137.4, 132.1, 129.9, 129.3, 129.2, 128.7, 128.1,
52.1, 42.6; IR (ATR) 3365, 1706, 1323, 1142 cm−1; HRMS (ESI-
TOF) m/z calcd for C15H15NO4SNa 328.0614 (M+Na)+, found
328.0622.
N-([1,1′-Biphenyl]-2-yl)-N-(2-nitrobenzenesulfonyl)glycine (1Ae).
Compound 1Ae was prepared according to a similar procedure as
procedure as described for the preparation of IAg from 1Ag.
Colorless crystal (32.0 mg, 86%), mp 170−171 °C: H NMR (600
1
MHz, CDCl3) δ 7.83 (d, 1H, J = 7.2 Hz), 7.71 (ddd, 1H, J = 7.6, 7.6,
1.2 Hz), 7.61−7.57 (m, 2H), 7.56−7.53 (m, 3H), 7.51−7.48 (m, 1H),
5.19 (d, 1H, J = 19.8 Hz), 4.36 (d, 1H, J = 19.8 Hz), 2.41 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 203.3, 139.1, 137.6, 136.8,
136.5, 133.9, 130.9, 130.6, 130.4, 130.3, 130.2, 129.8, 129.0, 64.0,
40.5; IR (ATR) 1686, 1337, 1153 cm−1; HRMS (ESI-TOF) m/z
calcd for C15H13NO3SK 326.0248 (M+K)+, found 326.0252.
5-[(2-Nitrophenyl)sulfonyl]-5,6-dihydro-7H-dibenzo[b,d]-
vazepin-7-one (IIAe). Compound IIAe was prepared according to a
similar procedure as described for the preparation of IAg from 1Ag.
described for the preparation of 1Ac from S10c. Colorless crystal
(163.0 mg, 66%), mp 120−121 °C: H NMR (600 MHz, CDCl3) δ
8.27 (dd, 1H, J = 8.4, 8.4 Hz), 7.87 (d, 1H, J = 7.8 Hz), 7.76−7.73
1
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7.41−7.36 (m, 5H), 7.31−7.29 (m, 2H), 7.17−7.14 (m, 1H), 4.42 (d,
1H, J = 18.0 Hz), 4.03 (d, 1H, J = 18.0 Hz), 2.75 (s, 3H), 2.54 (s,
3H); 13C{1H} NMR (150 MHz, CDCl3) δ 173.5, 142.7, 139.9, 139.3,
138.4, 131.4, 129.8, 129.7, 128.7, 128.2, 127.9, 53.3, 42.2, 19.9; IR
(ATR) 3020, 1758, 1327, 1138 cm−1; HRMS (ESI-TOF) m/z calcd
for C16H17NO4SNa 342.0771 (M+Na)+, found 342.0774.
N-(3-Methyl-[1,1′-biphenyl]-2-yl)-N-([2-nitrophenyl]sulfonyl)-
glycine (1Be). Compound 1Be was prepared according to a similar
1
Colorless crystal (28.6 mg, 74%), mp 194−195 °C: H NMR (600
MHz, CDCl3) δ 7.62−7.58 (m, 2H), 7.54 (ddd, 1H, J = 7.8, 7.8, 1.8
Hz), 7.50 (ddd, 1H, J = 7.6, 7.6, 1.2 Hz), 7.44−7.39 (m, 3H), 7.32
(dd, 1H, J = 7.8, 7.8 Hz), 7.28−7.25 (m, 2H), 7.18 (dd, 1H, J = 7.2,
7.2 Hz), 7.01 (d, 1H, J = 7.2 Hz), 5.43 (d, 1H, J = 19.6 Hz), 4.46 (d,
1H, J = 19.6 Hz); 13C{1H} NMR (150 MHz, CDCl3) δ 202.6, 146.9,
139.5, 137.0, 136.5, 135.9, 133.5, 133.0, 132.9, 131.6, 131.2, 131.0,
130.8, 130.7, 130.1, 128.9, 128.3, 128.2, 124.1, 64.7; IR (ATR) 1688,
1541, 1362, 1297, 1166 cm−1; HRMS (ESI-TOF) m/z calcd for
C20H14N2O5SNa 417.0516 (M+Na)+, found 417.0522.
procedure as described for the preparation of 1Ac from S10c.
Colorless crystal (150.5 mg, 68%), mp 199−201 °C: H NMR (600
1
5-[(4-Nitrophenyl)sulfonyl]-5,6-dihydro-7H-dibenzo[b,d]azepin-
7-one (IIAf). Compound IIAf was prepared according to a similar
MHz, CDCl3) δ 7.70 (d, 1H, J = 7.8 Hz), 7.66 (dd, 1H, J = 7.8, 7.8
Hz), 7.55−7.52 (m, 2H), 7.32−7.28 (m, 3H), 7.23 (dd, 2H, J = 7.8,
7.8 Hz), 7.16 (d, 2H, J = 7.8 Hz), 7.06 (d, 1H, J = 7.2 Hz), 4.52 (d,
1H, J = 18.0 Hz), 4.16 (d, 1H, J = 18.0 Hz), 2.41 (s, 3H); 13C{1H}
NMR (150 MHz, CDCl3) δ 171.1, 148.5, 143.5, 140.1, 139.6, 136.4,
133.9, 133.7, 132.0, 131.7, 131.6, 130.3, 129.5, 129.0, 128.1, 127.7,
124.3, 54.2, 20.3; IR (ATR) 3028, 1708, 1543, 1366, 1364, 1166
cm−1; HRMS (ESI-TOF) m/z calcd for C21H18N2O6SNa 449.0778
(M+Na)+, found 449.0781.
N-(3-Methyl-[1,1′-biphenyl]-2-yl)-N-([4-nitrophenyl]sulfonyl)-
glycine (1Bf). Compound 1Bf was prepared according to a similar
procedure as described for the preparation of IAg from 1Ag. Colorless
crystal (386.4 mg, 69%), mp 168−169 °C: H NMR (600 MHz,
1
CDCl3) δ 7.84 (ddd, 2H, J = 9.0, 2.4, 2.4 Hz), 7.71−7.69 (m, 1H),
7.55−7.51 (m, 3H), 7.43−7.40 (m, 3H), 7.34 (ddd, 1H, J = 7.2, 7.2,
1.8 Hz), 7.27 (ddd, 1H, J = 7.2, 7.2, 1.8 Hz), 6.96 (d, 1H, J = 7.2 Hz),
5.33 (d, 1H, J = 19.2 Hz), 4.45 (d, 1H, J = 19.2 Hz); 13C{1H} NMR
(150 MHz, CDCl3) δ 201.5, 149.8, 145.2, 138.8, 137.1, 136.0, 135.9,
133.4, 131.1, 131.0, 130.7, 130.4, 130.2, 129.6, 128.5, 127.9, 123.8,
64.0; IR (ATR) 1686, 1523, 1357, 1348, 1171 cm−1; HRMS (APCI-
TOF) m/z calcd for C22H20NO4S 394.0551 (M−H)−, found
393.0552.
procedure as described for the preparation of 1Ac from S10c.
Colorless crystal (235.4 mg, 77%), mp 185−187 °C: H NMR (600
1
N-(3-Methyl-[1,1′-biphenyl]-2-yl)-N-tosylglycine (1Bc). Com-
MHz, CDCl3) δ 8.14 (ddd, 2H, J = 9.0, 2.4, 2.4 Hz), 7.78 (ddd, 2H, J
= 9.0, 2.4, 2.4 Hz), 7.33−7.28 (m, 3H), 7.22 (dd, 2H, J = 7.8, 7.8 Hz),
7.19 (dd, 2H, J = 7.8, 1.2 Hz), 7.09 (dd, 1H, J = 6.6, 1.8 Hz), 4.29 (d,
2H, J = 1.8 Hz), 2.37 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ
171.7, 150.1, 145.6, 143.1, 139.8, 139.4, 136.7, 131.6, 130.3, 129.5,
129.2, 128.0, 127.7, 123.8, 53.9, 20.1; IR (ATR) 3318, 1775, 1528,
1339, 1307, 1138 cm−1; HRMS (ESI-TOF) m/z calcd for
C21H17N2O6S 425.0813 (M−H)−, found 425.0812.
pound 1Bc was prepared according to a similar procedure as
4-Methyl-5-tosyl-5,6-dihydro-7H-dibenzo[b,d]azepin-7-one
(IIBc). Compound IIBc was prepared according to a similar procedure
described for the preparation of 1Ac from S10c. Colorless crystal
1
(195.0 mg, 93%), mp 208−210 °C: H NMR (600 MHz, CDCl3) δ
7.56 (d, 2H, J = 8.4 Hz), 7.33−7.30 (m, 1H), 7.29−7.26 (m, 3H),
7.25−7.22 (m, 5H), 7.09 (dd, 1H, J = 7.8, 2.4 Hz), 4.11 (d, 1H, J =
17.6 Hz), 3.97 (d, 1H, J = 17.6 Hz), 2.44 (s, 3H), 2.23 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 171.1, 144.2, 143.4, 139.7,
139.5, 137.0, 136.5, 131.3, 130.0, 129.7, 129.6, 128.6, 128.3, 128.0,
127.6, 53.4, 21.7, 20.0; IR (ATR) 3201, 1730, 1337, 1151 cm−1;
HRMS (ESI-TOF) m/z calcd for C22H21NO4SNa 418.1084 (M
+Na)+, found 418.1086.
as described for the preparation of IAg from 1Ag. Colorless crystal
(25.3 mg, 99%), mp 159−160 °C: H NMR (600 MHz, CDCl3) δ
1
N-(3-Methyl-[1,1′-biphenyl]-2-yl)-N-(methylsulfonyl)glycine
(1Bd). Compound 1Bd was prepared according to a similar procedure
7.42−7.36 (m, 3H), 7.27 (d, 1H, J = 1.8 Hz), 7.23−7.16 (m, 5H),
6.83 (d, 2H, J = 7.8 Hz), 5.12 (d, 1H, J = 19.6 Hz), 4.31 (d, 1H, J =
19.6 Hz), 2.57 (s, 3H), 2.28 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 203.3, 142.9, 140.1, 140.0, 138.3, 137.5, 136.4, 136.2, 133.0,
131.9, 130.0, 129.8, 129.5, 129.3, 129.0, 127.8, 126.9, 63.0, 21.5, 19.3;
IR (ATR) 1682, 1344, 1161 cm−1; HRMS (ESI-TOF) m/z calcd for
C22H19NO3SNa 400.0978 (M+Na)+, found 400.0980. Separation of
atropisomers. CHIRALPAK IB (1.0 cmϕ × 25 cm): eluent, 30% 2-
propanol in hexane; flow rate, 0.3 mL/min; temperature, 25 °C;
as described for the preparation of 1Ac from S10c. Colorless crystal
1
20
(192.9 mg, 86%), mp 162−165 °C: H NMR (600 MHz, CDCl3) δ
detection, 254 nm; former peak, retention time = 24.1 min; [α]D
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−65.8 as 96.8% ee (c 0.23, CHCl3); latter peak, retention time = 28.5
139.5, 138.0, 136.1, 135.2, 133.4, 132.4, 130.4, 130.1, 129.4, 129.1,
128.4, 128.1, 124.0, 63.3, 19.2; IR (ATR) 1683, 1523, 1351, 1351,
1166 cm−1; HRMS (ESI-TOF) m/z calcd for C21H17N2O5S 409.0853
(M+H)+, found 409.0853. Separation of atropisomers. CHIRALPAK
IA (1.0 cmϕ × 25 cm): eluent, 30% 2-propanol in hexane; flow rate,
0.5 mL/min; temperature, 25 °C; detection, 254 nm; former peak,
retention time = 22.5 min; [α]D20 +27.2 as 98.5% ee (c 0.34, CHCl3);
latter peak, retention time = 30.1 min; [α]D −27.9 as 99.8% ee (c
0.07, CHCl3).
20
min; [α]D +64.9 as 96.1% ee (c 0.21, CHCl3).
4-Methyl-5-(methylsulfonyl)-5,6-dihydro-7H-dibenzo[b,d]-
azepin-7-one (IIBd). Compound IIBd was prepared according to a
5,6-Dihydro-7H-dibenzo[b,d]azepin-7-one (2). K2CO3 (45.2 mg,
0.32 mmol) was added to a stirred solution of IAg (50.0 mg, 0.16
similar procedure as described for the preparation of IAg from 1Ag.
1
Colorless crystal (28.0 mg, 72%), mp 177−178 °C: H NMR (600
MHz, CDCl3) δ 7.76 (dd, 1H, J = 8.4, 1.6 Hz), 7.70 (ddd, 1H, J = 7.8,
7.8, 1.2 Hz), 7.59 (dd, 1H, J = 7.8, 1.2 Hz), 7.52 (dd, 1H, J = 7.6, 7.6
Hz), 7.42 (dd, 1H, J = 7.8, 7.8 Hz), 7.39−7.35 (m, 2H), 5.08 (d, 1H, J
= 20.0 Hz), 4.32 (d, 1H, J = 20.0 Hz), 2.52 (s, 3H), 2.28 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 203.6, 139.9, 139.8, 138.4,
136.9, 135.6, 133.9, 132.2, 130.2, 130.1, 129.5, 129.0, 128.8, 63.6,
40.5, 19.1; IR (ATR) 1683, 1337, 1151 cm−1; HRMS (ESI-TOF) m/z
calcd for C16H15NO3SNa 324.0665 (M+Na)+, found 324.0665.
Separation of atropisomers. CHIRALPAK IA (1.0 cmϕ × 25 cm):
eluent, 30% 2-propanol in hexane; flow rate, 0.5 mL/min;
temperature, 25 °C; detection, 254 nm; former peak, retention time
mmol) in MeOH/H2O = 5:1 (1.6 mL) at reflux under an argon
atmosphere. After being stirred at reflux for 30 min, the mixture was
treated with 1 M NaHCO3 aq. and brine, dried, and concentrated.
The concentrate was purified by column chromatography (silica gel,
hexane/ethyl acetate = 4:1) to afford 2 as yellow oil (33.0 mg, 99%):
1H NMR (600 MHz, CDCl3) δ 7.94 (dd, 1H, J = 7.8, 1.2 Hz), 7.63
(ddd, 1H, J = 7.8, 7.8, 1.2 Hz), 7.59 (dd, 1H, J = 7.2, 1.2 Hz), 7.50
(dd, 1H, J = 7.2, 1.8 Hz), 7.44 (ddd, 1H, J = 7.2, 7.2, 1.2 Hz), 7.31
(ddd, 1H, J = 7.2, 7.2, 1.2 Hz), 7.22 (ddd, 1H, J = 7.2, 7.2, 1.2 Hz),
7.02 (dd, 1H, J = 7.8, 1.2 Hz), 4.16 (s, 2H); 13C{1H} NMR (150
MHz, CDCl3) δ 204.3, 147.5, 138.8, 136.9, 133.0, 132.6, 130.8, 130.5,
129.6, 129.5, 127.7, 124.6, 121.1, 63.8; IR (ATR) 3335, 1665 cm−1;
HRMS (ESI-TOF) m/z: calcd for C14H12NO 210.0913 (M+H)+,
found 210.0914.
20
= 30.0 min; [α]D +89.8 as 97.0% ee (c 0.23, CHCl3),; latter peak,
retention time = 34.9 min; [α]D20 −90.8 as 98.7% ee (c 0.27, CHCl3).
4-Methyl-5-([2-nitrophenyl]sulfonyl)-5,6-dihydro-7H-dibenzo-
[b,d]azepin-7-one (IIBe). Compound IIBe was prepared according to
5-Acetyl-5,6-dihydro-7H-dibenzo[b,d]azepin-7-one (IAa). Acetyl
chloride (30.7 μL, 0.43 mmol) and pyridine (47.7 μL, 0.58 mmol)
a similar procedure as described for the preparation of IAg from 1Ag.
1
Colorless crystal (61.0 mg, 83%), mp 185−187 °C: H NMR (600
MHz, CDCl3) δ 7.49 (dd, 1H, J = 7.2, 1.2 Hz), 7.45−7.39 (m, 4H),
7.32 (ddd, 1H, J = 7.8, 7.8, 1.2 Hz), 7.27 (dd, 1H, J = 8.4, 1.8 Hz),
7.24−7.21 (m, 2H), 7.12−7.09 (m, 2H), 5.40 (d, 1H, J = 19.8 Hz),
4.36 (d, 1H, J = 19.8 Hz), 2.51 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 202.8, 147.0, 140.2, 139.9, 137.3, 137.1, 135.0, 133.6, 133.4,
132.8, 132.2, 131.7, 131.2, 130.4, 129.7, 129.2, 128.9, 128.1, 124.1,
64.1, 19.0; IR (ATR) 1688, 1533, 1356, 1356, 1166 cm−1; HRMS
(ESI-TOF) m/z calcd for C21H17N2O5S 409.0853 (M+H)+, found
409.0856. Separation of atropisomers. CHIRALPAK IA (1.0 cmϕ ×
25 cm): eluent, 30% 2-propanol in hexane; flow rate, 0.5 mL/min;
temperature, 25 °C; detection, 254 nm; former peak, retention time =
were added to a stirred solution of 2 (60.5 mg, 0.29 mmol) in THF (3
mL) at 0 °C under an argon atmosphere. The mixture was stirred at rt
for 1.5 h, poured into aqueous HCl, and extracted with ethyl acetate.
The organic phase was washed with 1 M HCl aq., 1 M NaHCO3 aq.,
and brine, then dried, and concentrated. The residue was purified by
column chromatography (silica gel, hexane/EtOAc = 1:2) to afford
1
IAa as colorless crystals (24.0 mg, 33%), mp 126−127 °C: H NMR
(600 MHz, CDCl3); E-isomer: δ 7.77 (d, 1H, J = 6.6 Hz), 7.65 (ddd,
1H, J = 7.2, 7.2, 1.2 Hz), 7.60 (dd, 1H, J = 7.2, 1.2 Hz), 7.53 (ddd,
1H, J = 8.4, 8.4, 1.8 Hz), 7.50−7.47 (m, 3H), 7.36 (dd, 1H, J = 7.8,
1.8 Hz), 5.71 (d, 1H, J = 18.6 Hz), 3.95 (d, 1H, J = 18.6 Hz), 1.79 (s,
3H); Z-isomer: δ 7.77 (d, 1H, J = 6.6 Hz), 7.65 (ddd, 1H, J = 7.2, 7.2,
1.2 Hz), 7.60 (dd, 1H, J = 7.2, 1.2 Hz), 7.53 (ddd, 1H, J = 8.4, 8.4, 1.8
Hz), 7.50−7.47 (m, 3H), 7.36 (dd, 1H, J = 7.8, 1.8 Hz), 4.88 (d, 1H, J
= 19.6 Hz), 4.34 (d, 1H, J = 19.6 Hz), 1.79 (s, 3H); 13C{1H} NMR
(150 MHz, CDCl3) δ 203.5, 170.2, 140.1, 138.2, 136.5, 136.4, 133.2,
130.8, 129.9, 129.8, 129.7, 129.2, 128.9, 127.6, 60.7, 21.9; IR (ATR)
1667, 1596 cm−1; HRMS (ESI-TOF) m/z calcd for C16H14NO2
252.1019 (M+H)+, found 252.1020.
20
19.1 min; [α]D +61.5 as 99.8% ee (c 0.55, CHCl3); latter peak,
retention time = 26.2 min; [α]D20 −61.1 as 99.8% ee (c 0.90, CHCl3).
4-Methyl-5-([4-nitrophenyl]sulfonyl)-5,6-dihydro-7H-dibenzo-
[b,d]azepin-7-one (IIBf). Compound IIBf was prepared according to
Preparation of Starting Materials (1Aa−h, 1Bc−h). N-Acyl-/
sulfonyl-(1,1′)-biphenyl-2-yl-glycines 1Aa−j, 1Be−j were prepared in
accordance with the method reported in a previous paper.4 The
characterization of the intermediates S1a, S1b, S1g, S1h, S2a, S2b,
S2g, S2h, S3, S4, S5g, S5h, S6h, S7c, S7d, S7e, S7f, S8c, S8d, S8e,
S8f, S9c, S9d, S9e, S9f, S10c, S10d, S10e, and S10f are described in
the Experimental Section. The reaction schemes are described in the
Supporting Information.
a similar procedure as described for the preparation of IAg from 1Ag.
Colorless crystal (77.2 mg, 83%), mp 184−186 °C: H NMR (600
1
MHz, CDCl3) δ 7.85 (ddd, 2H, J = 8.4, 2.4, 2.4 Hz), 7.47 (ddd, 2H, J
= 9.0, 2.4, 2.4 Hz), 7.42 (d, 2H, J = 4.8 Hz), 7.36 (ddd, 1H, J = 7.6,
7.6, 1.2 Hz), 7.31 (dd, 1H, J = 7.8, 1.2 Hz), 7.22 (dd, 1H, J = 4.6, 4.6
Hz), 7.17 (ddd, 1H, J = 7.6, 7.6, 1.2 Hz), 7.11 (dd, 1H, J = 7.8, 1.2
Hz), 5.19 (d, 1H, J = 19.8 Hz), 4.38 (d, 1H, J = 19.8 Hz), 2.61 (s,
3H); 13C{1H} NMR (150 MHz, CDCl3) δ 201.8, 149.7, 145.6, 140.1.
N-([1,1′-Biphenyl]-2-yl)acetamide (S1a). Acetyl chloride (2.33
mL, 33 mmol) and pyridine (3.67 mL, 45 mmol) were added to a
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1H, J = 7.2, 1.2 Hz), 7.13 (ddd, 1H, J = 7.4, 7.4, 1.2 Hz), 3.71 (s, 3H),
6.66 (br, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 154.1, 138.2,
134.9, 131.5, 130.3, 129.4, 129.3, 128.6, 128.1, 123.5, 119.7, 52.4; IR
(ATR) 3412, 1729 cm−1; HRMS (ESI-TOF) m/z calcd for
C14H14NO2 228.1019 (M+H)+, found 228.1010.
Methyl N-([1,1′-Biphenyl]-2-yl)-N-acetylglycinate (S2a). Sodium
hydride (60% oil) (1.5 mg, 37.5 mmol) was added to a stirred
stirred solution of 2-aminobiphenyl (5.02 g, 30 mmol) in THF (30
mL) at 0 °C under an argon atmosphere. After stirring at rt for 30
min, the mixture was treated with 1 M HCl aq. and extracted with
ethyl acetate. The extract was washed with 1 M HCl aq., 1 M
NaHCO3 aq., and brine, dried, and concentrated. The concentrate
was purified by column chromatography (silica gel, hexane/ethyl
acetate = 1:1) to afford S1a as colorless crystals (5.47 g, 87%), mp
1
108−110 °C: H NMR (600 MHz, CDCl3) δ 8.26 (d, 1H, J = 8.4
solution of S1a (5.30 g, 25.0 mmol) in DMF (50.0 mL) at 0 °C under
an argon atmosphere. After stirring at rt for 20 min, the mixture was
cooled to 0 °C and treated with methyl bromoacetate (3.46 mL, 37.5
mmol). After being stirred at rt for 1 h, the mixture was treated with 1
M HCl aq. and extracted with ethyl acetate. The extract was washed
with 1 M HCl aq., 1 M NaHCO3 aq., and brine, dried, and
concentrated. The concentrate was purified by column chromatog-
raphy (silica gel, hexane/EtOAc = 1:2) to afford S2a as colorless
crystals (7.76 g, 99%), mp 112−114 °C: 1H NMR (600 MHz,
CDCl3) δ 7.59 (dd, 1H, J = 7.8, 1.8 Hz), 7.44−7.39 (m, 5H), 7.38−
7.35 (m, 1H), 7.27−7.25 (m, 2H), 4.54 (d, 1H, J = 17.4 Hz), 3.68 (s,
3H), 3.30 (d, 1H, J = 17.4 Hz), 1.96 (s, 3H); 13C{1H} NMR (150
MHz, CDCl3) δ 171.3, 169.7, 140.5, 139.5, 138.5, 131.4, 130.1, 129.0,
128.9, 128.6, 128.0, 52.2, 50.7, 22.3; IR (ATR) 1749, 1658 cm−1;
HRMS (ESI-TOF) m/z calcd for C17H17NO3Na 306.1101 (M+Na)+,
found 306.1107.
Hz), 7.49 (dd, 1H, J = 7.6, 7.6 Hz), 7.42 (dd, 1H, J = 7.2, 7.2 Hz),
7.38−7.36 (m, 3H), 7.24 (d, 1H, J = 7.8 Hz), 7.18 (dd, 1H J = 7.6, 7.6
Hz), 7.13 (br, 1H), 2.02 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3)
δ 168.4, 138.3, 134.8, 132.3, 130.2, 129.4, 129.2, 128.6, 128.1, 124.5,
121.8, 24.7; IR (ATR) 3287, 1659 cm−1; HRMS (ESI-TOF) m/z
calcd for C14H14NO 212.1070 (M+H)+, found 212.1074.
N-([1,1′-Biphenyl]-2-yl)-4-methylbenzamide (S1b). Compound
S1b was prepared according to a similar procedure as described for
the preparation of S1a from 2-aminobiphenyl. Colorless crystal (6.81
g, 96%), mp 95−96 °C: 1H NMR (600 MHz, CDCl3) δ 8.55 (d, 1H, J
= 8.4 Hz), 7.97 (br, 1H), 7.52−7.48 (m, 4H), 7.45−7.42 (m, 4H),
7.30 (dd, 1H, J = 7.8, 1.2 Hz), 7.21 (ddd, 1H, J = 7.2, 7.2, 1.2 Hz),
7.19 (d, 2H, J = 7.8 Hz), 2.37 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 165.1, 142.4, 138.3, 135.2, 132.3, 132.1, 130.1, 129.5, 129.4,
128.8, 128.3, 127.0, 124.3, 121.2, 21.6; IR (ATR) 3311, 1709 cm−1;
HRMS (ESI-TOF) m/z calcd for C20H18NO 288.1383 (M+H)+,
found 288.1391.
Methyl N-([1,1′-Biphenyl]-2-yl)-N-(4-methylbenzoyl)glycinate
(S2b). Compound S2b was prepared according to a similar procedure
N-([1,1′-Biphenyl]-2-yl)-2,2,2-trifluoroacetamide (S1g). TFAA
as described for the preparation of S2a from S1a. Colorless crystal
(3.03 g, 82%), mp 99−100 °C: 1H NMR (600 MHz, CDCl3) δ 7.39−
7.34 (m, 4H), 7.31 (d, 2H, J = 4.2 Hz), 7.25−7.23 (m, 1H), 7.21 (dd,
2H, J = 7.8, 1.2 Hz), 7.09 (d, 2H, J = 8.4 Hz), 6.91 (d, 2H, J = 7.8
Hz), 4.78 (d, 1H, J = 17.4 Hz), 3.74 (s, 3H), 3.65 (d, 1H, J = 17.4
Hz), 2.27 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 170.2, 169.9,
141.5, 140.5, 138.5, 138.1, 131.6, 131.3, 129.9, 129.2, 128.9, 128.7,
128.5, 128.3, 128.1, 127.8, 52.5, 52.3, 21.5; IR (ATR) 1604, 1607
cm−1; HRMS (ESI-TOF) m/z calcd for C23H22NO3 360.1594 (M
+H)+, found 360.1594.
(168.0 μL, 1.20 mmol) was added to a solution of 2-aminobiphenyl
(169.0 mg, 1.00 mmol) in CH2Cl2 (5.00 mL) at 0 °C. After stirring at
rt for 20 min, the mixture was treated with 1 M HCl aq. and extracted
with ethyl acetate. The extract was washed with 1 M HCl aq., 1 M
NaHCO3 aq., and brine, dried, and concentrated. The concentrate
was purified by recrystallization to afford S1g as colorless crystals
(263.0 mg, 99%), mp 88−89 °C: 1H NMR (600 MHz, CDCl3) δ 8.29
(d, 1H, J = 8.4 Hz), 7.99 (br, 1H), 7.53−7.51 (m, 2H), 7.47−7.43
(m, 2H), 7.37−7.29 (m, 4H); 13C{1H} NMR (150 MHz, CDCl3) δ
Benzyl N-([1,1′-Biphenyl]-2-yl)-N-(2,2,2-trifluoroacetyl)glycinate
(S2g). K2CO3 (124.4 mg, 0.90 mmol) was added to a stirred solution
2
154.7 (C−F, JC−F = 37.6 Hz), 136.9, 133.3, 132.3, 130.5, 129.6,
129.2, 128.9, 128.8, 126.4, 121.5, 115.8 (C−F, 1JC−F = 289.0 Hz); IR
(ATR) 3244, 1709 cm−1; HRMS (ESI-TOF) m/z calcd for
C14H9F3NO 264.0642 (M−H)−, found 264.0639.
of S1g (159.0 mg, 0.60 mmol) in DMF (1.0 mL) at rt under an argon
atmosphere and treated with benzyl bromoacetate (75.0 μL, 0.8
mmol) for 2 days. The reaction mixture was poured into water and
extracted with ethyl acetate. The extract was washed with brine, dried,
and concentrated. The concentrate was dissolved in CH2Cl2, and
TFAA (252.0 μL, 1.80 mmol) was added at 0 °C under an argon
atmosphere for 1 h. The mixture was treated with 1 M HCl aq. and
extracted with ethyl acetate. The extract was washed with 1 M HCl
aq., 1 M NaHCO3 aq., and brine, dried, and concentrated. The
concentrate was purified by column chromatography (silica gel,
hexane/ethyl acetate = 4:1) to afford S2g as colorless crystals (149.0
Methyl [1,1′-Biphenyl]-2-ylcarbamate (S1h). Compound S1h was
prepared according to a similar procedure as described for the
preparation of S1a from 2-aminobiphenyl. Colorless crystal (421.3
1
1
mg, 93%), mp 56−57 °C: H NMR (600 MHz, CDCl3) δ 8.14 (br,
mg, 82%), mp 82−83 °C: H NMR (600 MHz, CDCl3) δ 7.54 (d,
1H), 7.48 (dd, 2H, J = 7.8, 7.8 Hz), 7.42−7.34 (m, 4H), 7.22 (dd,
1H, J = 8.4 Hz), 7.48 (ddd, 1H, J = 7.6, 7.6, 1.2 Hz), 7.43−7.33 (m,
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8H), 7.29−7.27 (m, 4H), 5.14 (d, 1H, J = 12.4 Hz), 5.09 (d, 1H, J =
12.4 Hz), 4.41 (d, 1H, J = 17.1 Hz), 3.41 (d, 1H, J = 17.1 Hz);
2
13C{1H} NMR (150 MHz, CDCl3) δ 167.2, 158.1 (C−F, JC−F
=
5
36.1 Hz), 139.3, 137.9, 137.1, 135.0, 131.5, 129.9 (C−F, JC−F = 5.8
Hz), 129.1, 128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 117.3 (C−
F, 1JC−F = 576.5 Hz), 67.6, 52.5; IR (ATR) 1754, 1698 cm−1; HRMS
(ESI-TOF) m/z calcd for C23H18F3NO3Na 436.1131 (M+Na)+,
found 436.1133.
as described for the preparation of S1g from 2-aminobiphenyl.
1
Colorless crystal (285.0 mg, 99%), mp 152−153 °C: H NMR (600
Methyl N-([1,1′-Biphenyl]-2-yl)-N-(methoxycarbonyl)glycinate
MHz, CDCl3) δ 7.42−7.35 (m, 3H), 7.33 (d, 1H, J = 4.2 Hz), 7.29
(d, 1H, J = 7.2 Hz), 7.26−7.24 (m, 2H), 7.22 (dd, 1H, J = 7.2, 1.2
Hz), 2.29 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 156.0 (C−F,
2JC−F = 37.6 Hz), 139.9, 138.5, 136.4, 130.5, 129.6, 128.8, 128.7,
(S2h). Compound S2h was prepared according to a similar procedure
1
128.4, 128.1, 116.0 (C−F, JC−F = 289.0 Hz), 18.4; IR (ATR) 3253,
1680 cm−1; HRMS (ESI-TOF) m/z calcd for C15H11F3NO 278.0798
(M−H)−, found 278.0795.
Methyl (3-Methyl-[1,1′-biphenyl]-2-yl)carbamate (S5h). Com-
pound S5h was prepared according to a similar procedure as
described for the preparation of S2a from S1a. Colorless crystal
1
(492.0 mg, 89%), mp 65−66 °C: H NMR (600 MHz, CDCl3) δ
7.55−7.53 (m, 1H), 7.42−7.40 (m, 2H), 7.39−7.34 (m, 4H), 7.28
(dd, 2H, J = 7.2, 1.2 Hz), 4.33 (d, 1H, J = 18.0 Hz), 3.69 (s, 3H), 3.65
(s, 3H), 3.35 (d, 1H, J = 18.0 Hz); 13C{1H} NMR (150 MHz,
CDCl3) δ 170.1, 156.7, 139.4, 139.2, 139.0, 130.8, 130.4, 129.9, 128.8,
128.7, 128.5, 128.4, 128.2, 127.7, 53.4, 52.2, 51.6; IR (ATR) 1754,
1698 cm−1; HRMS (ESI-TOF) m/z calcd for C17H17NO4Na
322.1050 (M+Na)+, found 322.1055.
described for the preparation of S1a. Colorless crystal (195.0 mg,
82%), mp 124−125 °C: H NMR (600 MHz, CDCl3) δ 7.43−7.40
1
3-Methyl-2-nitro-(1,1′)-biphenyl (S3). K2CO3 (1279.8 mg, 9.26
(m, 2H), 7.36−7.33 (m, 2H), 7.32 (dd, 2H, J = 8.4, 1.2 Hz), 7.25−
7.24 (m, 1H), 7.18−7.17 (m, 1H), 5.95 (br, 1H), 3.67 (s, 3H), 2.35
(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 139.8, 139.7, 136.8,
136.7, 132.5, 130.3, 129.0, 128.5, 128.2, 127.5, 127.3, 52.7, 18.6; IR
(ATR) 3228, 1706 cm−1; HRMS (ESI-TOF) m/z calcd for
C15H16NO2 242.1176 (M+H)+, found 242.1176.
mmol) and Pd(PPh3)4 (250 mg) were added to a stirred solution of
Methyl N-(Methoxycarbonyl)-N-(3-methyl-[1,1′-biphenyl]-2-yl)-
glycinate (S6h). Compound S6h was prepared according to a similar
3-bromo-2-nitrotoluene (1.00 g, 4.63 mmol) and phenylboronic acid
(839.9 mg, 6.94 mmol) in DMF/H2O = 5:1 (46.0 mL) at reflux under
an argon atmosphere. After being stirred at reflux for 16 h, the mixture
was treated with 1 M HCl aq. and extracted with ethyl acetate. The
extract was washed with 1 M HCl aq. and brine, dried, and
concentrated. The concentrate was purified by column chromatog-
raphy (silica gel, hexane/CH2Cl2 = 2:1) to afford S3 as colorless
crystals (990.2 mg, 99%), mp 74−75 °C: 1H NMR (600 MHz,
CDCl3) δ 7.44−7.39 (m, 4H), 7.36−7.35 (m, 2H), 7.30 (d, 1H, J =
7.2 Hz), 7.26 (d, 1H, J = 8.4 Hz), 2.39 (s, 3H); 13C{1H} NMR (150
MHz, CDCl3) δ 151.0, 136.9, 134.5, 130.4, 130.1, 129.8, 128.9, 128.8,
128.6, 128.2, 17.6; IR (ATR) 1522, 1370 cm−1; HRMS (EI-MS) m/z
calcd for C13H11NO2 213.0790 (M+), found 213.0791.
procedure as described for the preparation of S2a. Colorless crystal
(246.0 mg, 99%), mp 160−162 °C: H NMR (600 MHz, CDCl3) δ
1
7.42−7.39 (m, 2H), 7.37−7.34 (m, 1H), 7.31−7.25 (m, 2H), 7.24−
7.23 (m, 2H), 7.18 (dd, 1H, J = 6.0, 2.4 Hz), 3.91 (d, 1H, J = 17.1
Hz), 3.79 (s, 3H), 3.62 (s, 3H), 3.24 (d, 1H, J = 17.1 Hz), 2.49 (s,
3H); 13C{1H} NMR (150 MHz, CDCl3) δ 169.7, 156.8, 139.7, 139.6,
138.4, 138.3, 130.5, 128.9, 128.5, 128.4, 128.0, 127.7, 53.6, 52.1, 52.0,
18.3; IR (ATR) 1755, 1705 cm−1; HRMS (ESI-TOF) m/z calcd for
C18H19NO4Na 336.1206 (M+Na)+, found 336.1209.
3-Methyl-2-amino-(1,1′)biphenyl (S4). S3 (935.5 mg, 4.39 mmol)
was dissolved in THF/MeOH = 1:1 (10.0 mL), and 10% palladium
N-([1,1′-Biphenyl]-2-yl)-4-methylbenzenesulfonamide (S7c). p-
Tosyl choloride (270.0 mg, 1.41 mmol) was added to a solution of
on activated carbon (93.5 mg, 10% w/w) and hydrogen were added
and stirred at rt for 19 h. The mixture was filtered, and the filtrate was
washed with water and brine, dried, and concentrated under reduced
pressure. The concentrate was purified by recrystallization to provide
S4 (800.3 mg, 99%), mp 64−65 °C: 1H NMR (600 MHz, CDCl3) δ
7.46−7.43 (m, 4H), 7.36−7.34 (m, 1H), 7.07 (d, 1H, J = 6.6 Hz),
7.01 (dd, 1H, J = 7.8, 1.2 Hz), 6.77 (dd, 1H, J = 7.8, 7.8 Hz), 3.74 (br,
2H), 2.23 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 141.7, 140.0,
129.8, 129.4, 129.0, 128.4, 127.7, 127.3, 122.6, 118.3, 18.1; IR (ATR)
3376, 3457 cm−1; HRMS (ESI-TOF) m/z calcd for C13H14N
184.1121 (M+H)+, found 184.1128.
2-aminobiphenyl (200.0 mg, 1.18 mmol) in pyridine (10.0 mL) at 0
°C. After stirring at rt for 23 h, the mixture was treated with 1 M HCl
aq. and extracted with ethyl acetate. The extract was washed with 1 M
HCl aq., 1 M NaHCO3 aq., and brine, dried, and concentrated. The
concentrate was purified by column chromatography (silica gel,
hexane/EtOAc = 4:1) to afford S7c as colorless crystals (243.1 mg,
64%), mp 92−93 °C: 1H NMR (600 MHz, CDCl3) δ 7.71(d, 1H, J =
8.4 Hz), 7.47 (d, 2H, J = 8.4 Hz), 7.38−7.31 (m, 4H), 7.19 (d, 2H, J
= 8.4 Hz), 7.14 (ddd, 1H, J = 7.6, 7.6, 1.2 Hz), 7.10 (dd, 1H, J = 7.2,
1.8 Hz), 6.86 (dd, 2H, J = 7.2, 1.8 Hz), 6.58 (br, 1H), 2.40 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 144.0, 137.4, 136.3, 134.0,
2,2,2-Trifluoro-N-(3-methyl-[1,1′-biphenyl]-2-yl)acetamide
(S5g). Compound S5g was prepared according to a similar procedure
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133.9, 130.4, 129.7, 129.2, 129.0, 128.8, 128.2, 127.3, 125.0, 121.5,
21.7; IR (ATR) 3245, 1328, 1158 cm−1; HRMS (ESI-TOF) m/z
calcd for C19H17NO2SNa 346.0872 (M+Na)+, found 346.0872.
N-([1,1′-Biphenyl]-2-yl)methanesulfonamide (S7d). Compound
S7d was prepared according to a similar procedure as described for
solution of S7c (218.0 mg, 0.67 mmol) in DMF (5.0 mL) at 0 °C
under an argon atmosphere. The mixture was stirred at rt for 20 min,
then cooled to 0 °C and treated with methyl bromoacetate (93.0 μL,
1.00 mmol). After stirring at rt for 1 h, the mixture was treated with 1
M HCl aq. and extracted with ethyl acetate. The extract was washed
with 1 M HCl aq., 1 M NaHCO3 aq., and brine, dried, and
concentrated. The concentrate was purified by column chromatog-
raphy (silica gel, hexane/EtOAc = 4:1) to afford S8c as colorless
1
crystal (212.0 mg, 80%), mp 103−104 °C: H NMR (600 MHz,
CDCl3) δ 7.66 (ddd, 2H, J = 8.4, 2.4, 1.8 Hz), 7.39−7.35 (m, 7H),
7.32 (dd, 1H, J = 7.8, 1.8 Hz), 7.29 (dd, 2H, J = 8.4, 1.8 Hz), 7.27−
7.26 (m, 1H), 3.98 (br, 2H), 3.52 (s, 3H), 2.46 (s, 3H); 13C{1H}
NMR (150 MHz, CDCl3) δ 169.5, 143.8, 141.4, 138.8, 138.0, 137.3,
131.8, 130.6, 129.5, 129.2, 128.8, 128.5, 128.2, 128.1, 127.8, 52.1,
52.1, 21.8; IR (ATR) 1740, 1332, 1155 cm−1; HRMS (ESI-TOF) m/z
calcd for C22H21NO4SNa 418.1084 (M+Na)+, found 418.1098.
Methyl N-([1,1′-Biphenyl]-2-yl)-N-(methylsulfonyl)glycinate
(S8d). Compound S8d was prepared according to a similar procedure
the preparation of S7c from 2-aminobiphenyl. Colorless crystal (225.0
mg, 91%), mp 62−63 °C: H NMR (600 MHz, CDCl3) δ 7.67 (d,
1
1H, J = 7.8 Hz), 7.50 (dd, 2H, J = 7.2, 7.2 Hz), 7.44 (ddd, 1H, J = 7.8,
7.8, 1.8 Hz), 7.39 (ddd, 1H, J = 8.4, 8.4, 1.8 Hz), 7.33−7.32 (m, 2H),
7.28 (dd, 1H, J = 7.2, 1.8 Hz), 7.23 (ddd, 1H, J = 7.8, 7.8, 1.8 Hz),
6.49 (br, 1H), 2.87 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ
137.5, 134.1, 133.4, 130.9, 129.6, 129.1, 128.6, 125.0, 120.1, 39.8; IR
(ATR) 3252, 1317, 1144 cm−1; HRMS (ESI-TOF) m/z calcd for
C13H12NO2S 246.0594 (M−H)−, found 246.0600.
N-([1,1′-Biphenyl]-2-yl)-2-nitrobenzenesulfonamide (S7e). Com-
pound S7e was prepared according to a similar procedure as
as described for the preparation of S8c from S7c. Colorless crystal
1
(280.0 mg, 99%), mp 110−111 °C: H NMR (600 MHz, CDCl3) δ
7.66 (dd, 1H, J = 7.8, 1.2 Hz), 7.53 (d, 2H, J = 6.6 Hz), 7.45 (dd, 2H,
J = 7.2, 7.2 Hz), 7.44−7.38 (m, 4H), 3.96 (br, 2H), 3.66 (s, 3H), 3.23
(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 170.4, 141.7, 138.7,
137.6, 132.0, 129.8, 129.2, 129.1, 128.6, 128.0, 52.4, 52.3, 42.7; IR
(ATR) 1753, 1330, 1548 cm−1; HRMS (ESI-TOF) m/z calcd for
C16H17NO4SNa 342.0771 (M+Na)+, found 342.0776.
described for the preparation of S7c from 2-aminobiphenyl. Colorless
crystal (284.5 mg, 80%), mp 101−102 °C: H NMR (600 MHz,
1
CDCl3) δ 7.75 (dd, 1H, J = 7.2, 1.2 Hz), 7.71 (d, 2H, J = 8.4 Hz),
7.67 (ddd, 1H, J = 7.8, 7.8, 1.2 Hz), 7.65 (br, 1H), 7.59 (ddd, 1H, J =
7.8, 7.8, 1.8 Hz), 7.40 (ddd, 1H, J = 7.8, 7.8, 1.2 Hz), 7.28−7.27 (m,
1H), 7.25−7.21 (m, 3H), 7.13 (dd, 1H, J = 7.8, 1.8 Hz), 6.86 (dd,
2H, J = 8.4, 1.8 Hz); 13C{1H} NMR (150 MHz, CDCl3) δ 147.6,
137.5, 136.4, 133.6, 133.4, 133.1, 132.7, 131.0, 130.4, 129.0, 128.9,
128.7, 128.1, 126.4, 125.8, 125.3; IR (ATR) 3326, 1533, 1391, 1359,
1176 cm−1; HRMS (ESI-TOF) m/z calcd for C18H14N2O4SNa
377.0566 (M+Na)+, found 377.0567.
Methyl N-([1,1′-Biphenyl]-2-yl)-N-([2-nitrophenyl]sulfonyl)-
glycinate (S8e). Compound S8e was prepared according to a similar
N-([1,1′-Biphenyl]-2-yl)-4-nitrobenzenesulfonamide (S7f). Com-
pound S7f was prepared according to a similar procedure as described
procedure as described for the preparation of S8c from S7c. Colorless
crystal (303.0 mg, 96%), mp 122−123 °C: H NMR (600 MHz,
1
CDCl3) δ 7.90 (dd, 1H, J = 7.8, 1.8 Hz), 7.78 (dd, 1H, J = 7.8, 1.2
Hz), 7.69 (ddd, 1H, J = 7.2, 7.2, 1.2 Hz), 7.65 (ddd, 1H, J = 7.8, 7.8,
1.2 Hz), 7.56 (dd, 1H, J = 7.8, 1.2 Hz), 7.43 (ddd, 1H, J = 7.2, 7.2, 1.8
Hz), 7.39 (ddd, 1H, J = 7.2, 7.2, 1.8 Hz), 7.31−7.27 (m, 4H), 7.18−
7.17 (m, 2H), 4.20 (br, 2H), 3,63 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 169.7, 148.1, 141.9, 138.4, 136.9, 134.3, 133.7, 131.9, 131.9,
131.8, 131.7, 129.4, 128.8, 128.5, 128.4, 127.7, 124.5, 53.3, 52.3; IR
(ATR) 1755, 1547, 1373, 1361, 1170 cm−1; HRMS (ESI-TOF) m/z
calcd for C21H18N2O6SNa 499.0778 (M+Na)+, found 499.0785.
Methyl N-([1,1′-Biphenyl]-2-yl)-N-([4-nitrophenyl]sulfonyl)-
glycinate (S8f). Compound S8f was prepared according to a similar
for the preparation of S7c from 2-aminobiphenyl. Colorless crystal
(329.6 mg, 93%), mp 143−144 °C: H NMR (600 MHz, CDCl3) δ
1
8.17 (dt, 2H, J = 8.4, 1.8, Hz), 7.71 (dd, 1H, J = 7.8, 1.2 Hz), 7.64 (dt,
2H, J = 9.0, 1.8, Hz), 7.40−7.37 (m, 2H), 7.33 (dd, 2H, J = 7.2, 7.2
Hz), 7.24 (ddd, 1H, J = 7.8, 7.8, 1.2 Hz), 7,14 (dd, 1H, J = 7.8, 1.8
Hz), 6.82 (dd, 2H, J = 7.2, 1.8 Hz), 6.80 (br, 1H); 13C{1H} NMR
(150 MHz, CDCl3) δ 150.3, 144.7, 137.1, 135.1, 132.5, 130.6, 129.4,
129.1, 128.7, 128.5, 126.4, 124.2, 123.1; IR (ATR) 3267, 1523, 1400,
1347, 1165 cm−1; HRMS (ESI-TOF) m/z calcd for C18H13N2O4S
353.0602 (M−H)−, found 353.0600.
Methyl N-([1,1′-Biphenyl]-2-yl)-N-tosylglycinate (S8c). Sodium
hydride (60% oil) (80.0 mg, 2.01 mmol) was added to a stirred
procedure as described for the preparation of S8c from S7c. Colorless
1
crystal (334.0 mg, 91%), mp 149−150 °C: H NMR (600 MHz,
CDCl3) δ 8.30 (dt, 2H, J = 9.0, 2.4 Hz), 7.92 (dt, 2H, J = 9.0, 1.8 Hz),
7.44−7.39 (m, 6H), 7.36 (d, 1H, J = 7.2 Hz), 7.30 (dd, 2H, J = 4.8,
1.8 Hz), 4.13 (br, 2H), 3.59 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 169.3, 150.2, 146.4, 141.8, 138.4, 136.6, 132.2, 130.4, 129.6,
129.0, 128.6, 128.5, 128.0, 124.0, 52.9, 52.4; IR (ATR) 1760, 1525,
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1341, 1313, 1163 cm−1; HRMS (ESI-TOF) m/z calcd for
C21H19N2O6S 427.0958 (M+H)+, found 427.0973.
= 7.8 Hz), 6.80 (d, 2H, J = 8.4 Hz), 6.67 (br, 1H), 2.62 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 149.8, 143.3, 140.7, 139.8,
4-Methyl-N-(3-methyl-[1,1′-biphenyl]-2-yl)benzenesulfonamide
138.9, 131.3, 130.0, 128.9, 128.7, 128.6, 128.5, 128.1, 127.3, 124.0,
20.1; IR (ATR) 3259, 1525, 1351, 1310, 1154 cm−1; HRMS (ESI-
TOF) m/z calcd for C19H15N2O4S 367.0758 (M−H)−, found
367.0750.
(S9c). Compound S9c was prepared according to a similar procedure
Methyl N-(3-Methyl-[1,1′-biphenyl]-2-yl)-N-tosylglycinate
(S10c). Compound S10c was prepared according to a similar
as described for the preparation of S7c from 2-aminobiphenyl.
1
Colorless crystal (303.9 mg, 90%), mp 114−116 °C: H NMR (600
MHz, CDCl3) δ 7.29 (d, 1H, J = 7.8 Hz), 7.22−7.18 (m, 2H), 7.14
(dd, 2H, J = 7.2, 7.2 Hz), 7.09 (d, 2H, J = 7.8 Hz), 6.97 (d, 3H, J =
7.8 Hz), 6.78 (dd, 2H, J = 7.2, 1.2 Hz), 6.52 (br, 1H), 2.56 (s, 3H),
2.38 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 143.0, 140.6,
139.1, 139.0, 136.7, 131.2, 131.1, 129.5, 128.5, 128.4, 127.6, 127.0,
21.6, 20.1; IR (ATR) 3294, 1331, 1162 cm−1; HRMS (ESI-TOF) m/z
calcd for C20H19NO2SNa 360.1029 (M+Na)+, found 360.1029.
N-(3-Methyl-[1,1′-biphenyl]-2-yl)methanesulfonamide (S9d).
Compound S9d was prepared according to a similar procedure as
procedure as described for the preparation of S8c from S7c. Colorless
crystal (234.1 mg, 66%), mp 118−120 °C: H NMR (600 MHz,
1
CDCl3) δ 7.57 (d, 2H, J = 8.4 Hz), 7.33−7.30 (m, 1H), 7.28−7.25
(m, 6H), 7.21 (d, 2H, J = 8.2 Hz), 7.08−7.06 (m, 1H), 4.17 (d, 1H, J
= 17.2 Hz), 3.81 (d, 1H, J = 17.2 Hz), 3.54 (s, 3H), 2.43 (s, 3H), 2.37
(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 169.2, 143.6, 142.9,
140.2, 139.9, 137.5, 137.4, 131.2, 129.9, 129.6, 129.4, 128.3, 128.2,
127.9, 127.5, 53.2, 52.1, 21.7, 20.3; IR (ATR) 1766, 1335, 1158 cm−1;
HRMS (ESI-TOF) m/z calcd for C23H24NO4S 410.1421 (M+H)+,
found 410.1424.
Methyl N-(3-Methyl-[1,1′-biphenyl]-2-yl)-N-(methylsulfonyl)-
glycinate (S10d). Compound S10d was prepared according to a
described for the preparation of S7c from 2-aminobiphenyl. Colorless
crystal (216.5 mg, 83%), mp 95−96 °C: 1H NMR (600 MHz,
CDCl3) δ 7.47−7.44 (m, 2H), 7.41−7.36 (m, 3H), 7.32−7.29 (m,
2H), 7.22−7.19 (m, 1H), 6.05 (br, 1H), 2.53 (s, 3H), 2.21 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 141.0, 139.9, 139.0, 131.7,
130.9, 129.7, 128.8, 128.7, 128.3, 127.8, 41.2, 19.8; IR (ATR) 3244,
1314, 1145 cm−1; HRMS (ESI-TOF) m/z calcd for C14H15NO2SNa
284.0716 (M+Na)+, found 284.0719.
similar procedure as described for the preparation of S8c from S7c.
Colorless crystal (243.4 mg, 91%), mp 108−109 °C: H NMR (600
1
N-(3-Methyl-[1,1′-biphenyl]-2-yl)-2-nitrobenzenesulfonamide
MHz, CDCl3) δ 7.44−7.35 (m, 5H), 7.30−7.27 (m, 2H), 7.15−7.13
(m, 1H), 4.31 (d, 1H, J = 18.0 Hz), 3.97 (d, 1H, J = 18.0 Hz), 3.68 (s,
3H), 2.80 (s, 3H), 2.55 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ
169.6, 142.7, 140.0, 139.2, 138.6, 131.3, 129.8, 129.6, 128.5, 128.2,
127.8, 53.5, 52.3, 42.4, 19.9; IR (ATR) 1756, 1327, 1139 cm−1;
HRMS (ESI-TOF) m/z calcd for C17H19NO4SNa 356.0927 (M
+Na)+, found 356.0927.
(S9e). Compound S9e was prepared according to a similar procedure
Methyl N-(3-Methyl-[1,1′-biphenyl]-2-yl)-N-([2-nitrophenyl]-
sulfonyl)glycinate (S10e). Compound S10e was prepared according
as described for the preparation of S7c from 2-aminobiphenyl.
Colorless crystal (206.6 mg, 47%), mp 135−137 °C: H NMR (600
1
MHz, CDCl3) δ 7.66 (dd, 1H, J = 8.4, 1.2 Hz), 7.59−7.54 (m, 3H),
7.51 (ddd, 1H, J = 7.8, 7.8, 1.2 Hz), 7.34 (d, 1H, 7.2 Hz), 7.29−7.26
(m, 1H), 7.03−6.97 (m, 3H), 6.91 (dd, 2H, 7.8, 2.4 Hz), 2.61 (s,
3H); 13C{1H} NMR (150 MHz, CDCl3) δ 146.7, 140.9, 140.0, 138.9,
135.2, 133.1, 132.9, 131.5, 130.9, 130.6, 128.8, 128.5, 128.3, 128.2,
127.1, 126.1, 20.0; IR (ATR) 3386, 1532, 1385, 1328, 1162 cm−1;
HRMS (ESI-TOF) m/z calcd for C29H16N2O4SNa 391.0723 (M
+Na)+, found 391.0723.
to a similar procedure as described for the preparation of S8c from
S7c. Colorless crystal (332.0 mg, 84%), mp 138−139 °C: H NMR
1
N-(3-Methyl-[1,1′-biphenyl]-2-yl)-4-nitrobenzenesulfonamide
(600 MHz, CDCl3) δ 7.73 (dd, 1H, J = 9.0, 1.8 Hz), 7.65 (ddd, 1H, J
= 7.6, 7.6, 1.2 Hz), 7.54−7.51 (m, 2H), 7.34−7.27 (m, 3H), 7.23 (dd,
2H, J = 7.6, 7.6 Hz), 7.17 (d, 2H, J = 6.6 Hz), 7.07−7.04 (m, 1H),
4.48 (d, 1H, J = 18.0 Hz), 4.08 (d, 1H, J = 18.0 Hz), 3.64 (s, 3H),
2.45 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 169.1, 148.5,
143.4, 140.2, 139.7, 136.5, 134.0, 133.7, 132.0, 131.6, 130.2, 129.5,
128.8, 128.0, 127.6, 124.2, 54.4, 52.3, 20.3; IR (ATR) 1771, 1548,
1374, 1346, 1199 cm−1; HRMS (ESI-TOF) m/z calcd for
C22H20N2O6SNa 463.0934 (M+Na)+, found 463.0935.
(S9f). Compound S9f was prepared according to a similar procedure
as described for the preparation of S7c from 2-aminobiphenyl.
Methyl N-(3-Methyl-[1,1′-biphenyl]-2-yl)-N-([4-nitrophenyl)-
sulfonyl)glycinate (S10f). Compound S10f was prepared according
to a similar procedure as described for the preparation of S8c from
1
Colorless crystal (315.7 mg, 86%), mp 148−151 °C: H NMR (600
MHz, CDCl3) δ 7.95 (dd, 2H, J = 8.4, 1.2 Hz), 7.38 (dd, 2H, J = 8.4,
1.8 Hz), 7.34 (d, 1H, J = 8.4 Hz), 7.28 (dd, 1H, J = 8.4, 8.4 Hz), 7.18
(dd, 1H, J = 7.8, 7.8 Hz), 7.09 (dd, 2H, J = 7.2, 7.2 Hz), 7.00 (d, 1H, J
1
S7c. Colorless crystal (324.4 mg, 87%), mp 153−156 °C: H NMR
(600 MHz, CDCl3) δ 8.16 (dd, 2H, J = 8.4, 2.4 Hz), 7.80 (dd, 2H, J =
7576
https://doi.org/10.1021/acs.joc.1c00594
J. Org. Chem. 2021, 86, 7563−7578

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Tetsuta Oshitari − Faculty of Pharma Sciences, Teikyo
University, Itabashi-ku, Tokyo 173-8605, Japan
Hideaki Natsugari − Graduate School of Pharmaceutical
Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-
0033, Japan; orcid.org/0000-0002-6442-1598
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00594
Notes
9.0, 1.8 Hz), 7.32−7.27 (m, 3H), 7.24 (dd, 2H, J = 7.2, 7.2 Hz), 7.19
(dd, 2H, J = 6.6, 1.8 Hz), 7.09 (dd, 1H, J = 7.2, 1.8 Hz), 4.27 (d, 1H, J
= 17.4 Hz), 4.22 (d, 1H, J = 17.4 Hz), 3.65 (s, 3H), 2.36 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 168.8, 150.0, 145.9, 143.1,
139.8, 139.5, 136.9, 131.5, 130.2, 129.5, 129.0, 128.0, 127.6, 123.7,
54.3, 52.4, 20.0; IR (ATR) 1759, 1524, 1349, 1314, 1158 cm−1;
HRMS (ESI-TOF) m/z calcd for C22H20N2O6SNa 463.0934 (M
+Na)+, found 463.0934.
Measurement of the Blocking Activity on the Voltage-
Gated Potassium Channel Kv1.3. The assays were performed
under the conditions described below. The parameters measured the
maximum outward current evoked on stepping to 0 mV from the
holding potential. The peak current amplitude was calculated before
and after compound addition, and the amount of block was assessed
by dividing the test compound current amplitude by the control
current amplitude. Test compounds are the mean hKv1.3 current
amplitude collected in the presence of test compound at each
concentration, and the control is the mean hKv1.3 current amplitude
collected for the last 15 s of the control. All data were filtered for seal
quality, seal drop, and current amplitude.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by a Grant-in-Aid for
Scientific Research (C) (19K06980) from the Japan Society
for the Promotion of Science. H.T. is grateful for financial
support from the Hoansha Foundation.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00594.
■
sı
1
Reaction schemes to prepare 1A−h and 1Bc−h; H
NMR spectra of IBg and IBh; Chiral HPLC charts of
IBg, IBh, IIBc, IIBd, IIBe, IIBf; Stereochemical stability
of the enantiomers of IBg, IBh, IIBc, IIBd, IIBe, IIBf;
NOE spectrum of IAa; ORTEP drawing of IIBc; DFT
calculation study; 1H-, 13C-, and 2D-NMR (COSY,
HMBC for IAa) spectra (PDF)
Accession Codes
CCDC 2057747 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
■
Hideyo Takahashi − Faculty of Pharmaceutical Sciences,
Tokyo University of Science, Noda-shi, Chiba 278-8510,
Japan; orcid.org/0000-0001-5965-3987; Email: hide-
tak@rs.tus.ac.jp
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C.; Feurle, J.; Tasler, S.; Prutting, S.; Kuras, Z.; Visan, V.; Grissmer, S.
̈
Authors
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Takuya Namba − Faculty of Pharmaceutical Sciences, Tokyo
University of Science, Noda-shi, Chiba 278-8510, Japan
Mayuno Hotta − Faculty of Pharmaceutical Sciences, Tokyo
University of Science, Noda-shi, Chiba 278-8510, Japan
Hidetsugu Tabata − Faculty of Pharma Sciences, Teikyo
University, Itabashi-ku, Tokyo 173-8605, Japan
Kosho Makino − Faculty of Pharmaceutical Sciences, Tokyo
University of Science, Noda-shi, Chiba 278-8510, Japan
7577
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J. Org. Chem. 2021, 86, 7563−7578

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pubs.acs.org/joc
Article
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