Stereochemistry of N-Benzoyl-5-substituted-1-benzazepines Revisited: Synthesis of the Conformationally Biased Derivatives and Revision of the Reported Structure

Article abstract of DOI:10.1021/acs.joc.5b02900

The syn (aR?,5R?) and anti (aS?,5R?) diastereomers of N-benzoyl-C5-substituted-1-benzazepines originating in the chiralities at C5 and the Ar-N(C=O) axis were first stereoselectively synthesized by biasing the conformation with a substituent at C6 and C9, respectively. Detailed examination of the stereochemistry (i.e., conformation and configuration) of these N-benzoyl-1-benzazepines by X-ray crystallographic analysis, VT NMR, and DFT calculations revealed new physicochemical aspects of these heterocycles including revision of the stereochemistry previously reported.

Full text of DOI:10.1021/acs.joc.5b02900

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Article
Stereochemistry of N-Benzoyl-5-substituted-1-benzazepines
Revisited: Synthesis of the Conformationally Biased
Derivatives and Revision of the Reported Structure
Hidetsugu Tabata, Tetsuya Yoneda, Tomohiko Tasaka, Shigekazu
Ito, Tetsuta Oshitari, Hideyo Takahashi, and Hideaki Natsugari
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02900 • Publication Date (Web): 21 Mar 2016
Downloaded from http://pubs.acs.org on March 26, 2016
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Stereochemistry of N-Benzoyl-5-substituted-1-
benzazepines Revisited: Synthesis of the
Conformationally Biased Derivatives and Revision of
the Reported Structure
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†
†
‡
§
†
Hidetsugu Tabata, Tetsuya Yoneda, Tomohiko Tasaka, Shigekazu Ito, Tetsuta Oshitari,
†
†,*
Hideyo Takahashi, and Hideaki Natsugari
†Faculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605,
Japan
‡Affinity Science Corporation, 1-11-1 Nishigotanda, Shinagawa-ku, Tokyo 141-0031, Japan
§Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo
Institute of Technology, Meguro-ku, Tokyo 152-8552, Japan
ABSTRACT: The syn (aR*,5R*) and anti (aS*,5R*) diastereomers of N-benzoyl-C5-
substituted-1-benzazepines originating in the chiralities at C5 and the Ar–N(C=O) axis were
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first stereoselectively synthesized by biasing the conformation with a substituent at C6 and C9,
respectively. Detailed examination of the stereochemistry (i.e., conformation and configuration)
of these N-benzoyl-1-benzazepines by X-ray crystallographic analysis, VT NMR, and DFT
calculations revealed new physicochemical aspects of these heterocycles including revision of
the stereochemistry previously reported.
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INTRODUCTION
The 1-benzazepine nucleus has been used as the core structure of various biologically active
1
molecules. In recent years, the vasopressin (VP) receptor ligands with the 1-benzazepine
2
3
nucleus (e.g., mozavaptan, tolvaptan ) (Figure 1) have been developed as agents for the
treatment of hyponatremia, congestive heart failure, etc.
Many of the vaptan class of drugs contain a preserved structure, i.e., a benzo-fused seven-
membered-ring nitrogen heterocycle (e.g., 1-benzazepine, 1,4-benzodiazepine) linked
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through N-1 to a substituted benzoyl group. In our previous papers, new VP receptor ligands
4
a
4b
with 1,5-benzodiazepine (1) and 1,5-benzothiazepine nuclei (2, 3) (Figure 1) were described
to reveal the importance of the stereochemistry around the seven-membered ring for exerting
their biological activity. In particular, the axial chirality (aS/aR) based on the Ar–N(C=O) (sp2–
2
5
sp ) axis was clarified to be crucial by freezing the conformation in molecules with an ortho
substituent (e.g., R = CH , Cl); the (aS) form was the eutomer (active enantiomer). Those studies
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also implied that, although often overlooked, such chirality may exist in the latent form in many
biologically active molecules, and the active form of the N-benzoyl-1-benzazepine-type VP
ligands (mozavaptan and tolvaptan) should also be (aS). In this regard, an understanding of the
stereochemistry of the N-acyl-1-benzazepines is important.
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axis
aS*
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+
N1
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N
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R
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O
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E
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anti
syn
1
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X
R
I a-d: X = CH3
II a-c: X = OH
III a-c: X = N(CH3)2
N
1
2
a: R = R = H
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b,d: R = H, R = Cl or CH
1
O
3
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c: R = CH R = H
3,
Z
(
R = H or CH3)
R
Figure 2. Anti/syn diastereomers originating in the (5R*) central chirality and (aR*)/(aS*) axial chirality
in E-N-benzoyl-1-benzazepines (Ia–d, IIa–c, and IIIa–c). For the E/Z-amide isomer, the Z isomer
1
shown in brackets was negligible in the H NMR spectrum.
Thus far, the pioneering conformational study on N-acyl-1-benzazepines by A. Hassner et al.,6
followed by the excellent analysis of N-benzoyl-5-methyl-1-benzazepine (Ia) by M. Qadir et
7
al. have been reported. Compound Ia possesses a stereogenic center at C5 in addition to the
8
chirality due to the axis at Ar–N(C=O). thus forming the anti and syn diastereomers; the
description “anti/syn” is used for the relative arrangement of the C5 substituent and the N-
benzoyl group, i.e., anti and syn denote the arrangement on the opposite (aS*,5R*) and the same
side (aR*,5R*), respectively (Figure 2). The reported structure of Ia, however, is interesting in
that Ia takes predominantly the syn form in solution with a ratio of syn/anti = 1:0.25 (by NMR
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analysis), whereas in the solid state (by X-ray crystal analysis) it takes the anti form,7,9 which
stimulated us to revisit the stereochemistry of Ia and related compounds (IIa, IIIa). This paper
deals with the detailed stereochemistry (conformation and configuration) of N-benzoyl-5-
substituted-1-benzazepines (I–III), including a revision of the stereochemistry of Ia in the
solution state previously reported.
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RESULTS AND DISCUSSION
Synthesis of N-Benzoyl-5-substituted-1-benzazepines (I–III).
N-Benzoyl-5-substituted-1-benzazepines (Ia–d, IIa–c, and IIIa–c) were prepared from 5-
substituted N-benzoyl-1-benzazepines (6a, 6c, 8, and 13a–c) using procedures similar to those
previously reported2,3,7 as shown in Scheme 1 and 2, i.e., compounds Ia and Ic were prepared
by reduction of the corresponding 5-methylene derivatives (6a and 6c), respectively, and Ib and
Id were prepared by N-acylation of methyl-1-benzazepine (8), which was prepared from 7 by
7
reaction with MeMgBr followed by reduction with Et SiH (Scheme 1). Compounds IIa–c and
3
IIIa–c were prepared by reduction of 5-oxo-1-benzazepine derivatives (13a–c) with NaBH
4
and by reductive amination with NaBH
3
CN (or NaBH
4
) and CH
3
NH followed by N-
2
methylation, respectively (Scheme 2).2,3
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Computational Studies. To study the conformational preferences of the N-benzoyl-5-
substituted-1-benzazepines, the following computational studies were carried out. First, the
conformation ensembles of Ia, Ib, Ic, IIa, IIc, and IIIa were generated from 2D chemical
structures as the initial structures for the density functional theory (DFT) calculations. These
conformations were optimized within RDKit10 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)/DFT calculations were carried out to obtain optimized geometries and
energies at the RHF/6-31G(d,p), and RB3LYP/6-31G(d,p) and RB3LYP/6-311+G(d,p) levels.
For a set of stable conformers, the geometry optimizations and frequency analyses were carried
out at the RB3LYP/6-311+G(d,p) level. As a representative of the results obtained by these
computational studies, the selected conformers of Ia are illustrated below (in Figure 9).
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Stereochemistry of N-Benzoyl-5-methyl-1-benzazepines (Ia–d: X = CH
3
). In general, the N-
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benzoyl-5-substituted-1-benzazepines (I–III) theoretically have E/Z-amide isomers around
the N–C(=O) bond and (aS)/(aR)-axial isomers12 based on the Ar–N(C=O) (sp –sp ) axis
Figure 2), and thus four stereoisomers (conformers) may exist in the molecules. For the E/Z-
amide isomers, however, compounds I–III all exist predominantly in the E form, and the Z
2
2
(
1
13
isomer was negligible in the H NMR spectrum. Thus, compounds I–III exist only as a
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mixture of diastereomers (anti/syn isomers) originating in the two stereogenic elements at C5
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and the axis (Figure 2). The anti form and syn form possess the C5 substituent disposed in a
equatorial (eq.) and axial (ax.) orientation, respectively.
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Figures 3 and 4 show schematic drawings of the stereochemistry of I–III (a–c). First, the
conformation was examined in detail using 5-methyl derivatives Ia–d (X = CH ). In compound
3
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Ia, the ring inversion via rotation around the Ar–N(C=O) axis readily occurs to form
inseparable anti/syn diastereomers, whereas in Ib the rotation around the axis is restricted by
2
the ortho substituent (R ) to form separable anti/syn diastereomers (Figure 3). On the other
hand, in compound Ic (Figure 4), because of the steric hindrance caused by the C6 methyl group
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(allylic 1,3-strain), the C5 methyl group is confined so as to adopt a sterically less hindered
ax. orientation forming a syn isomer stereoselectively (Figure 4). The DFT calculation study of
Ic confirmed that the syn-chair structure exists as the lowest-energy conformer, e.g., more stable
by 15.5 kJ/mol than the anti-chair structure of Ic.
1
The H NMR spectra (in CDCl
3
, 296 K) of Ia, Ib, and Ic are shown in Figure 5. The spectrum
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of Ia is the same as that reported by M. Qadir et al., in which the diastereomers were observed
in a ratio of 1:0.25 [Figure 5 (a)].
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.35.2 5.1 5.0 4.9 4.8 4.7 4.6 4.5 4.4 4.3 4.2 4.1 4.0 3.9 3.8 3.7 3.6 3.5 3.4 3.3 3.2 3.1 3.0 2.9 2.8 2.7 2.6 2.5 2.4 2.3 2.2 2.1 2.0 1.9 1.8 1.7 1.6 1.5 1.4 1.3 1.2 1.1 1.0 0.9 0.8
X : parts per Million : Proton
1
3
The C NMR spectrum of Ia also exhibited the presence of the two isomers. The spectrum of
Ib before the separation procedure was that of a mixture of the diastereomers (ca. 1:0.06)
[
Figure 5 (b)], from which the minor isomer was successfully separated by preparative HPLC.
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The spectrum of the separated minor isomer of Ib [Figure 5 (c)] was measured at low
temperature (253 K), since its relative instability prompts isomerization into the major isomer
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at rt. Very importantly, compound Ic exhibited H NMR signals [Figure 5 (d)] similar to those
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of the minor forms of Ia and Ib. From these H NMR analyses, it is clear that the structural
features of the major isomer of Ia is similar to those of the major isomer of Ib, and the minor
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isomer of Ia has the structural features similar to those of the minor isomer of Ib [Figure 5 (c)]
and compound Ic [Figure 5 (d)]. Through detailed inspection of the 2D-NMR spectra (NOESY,
COSY, and HMQC) the stereochemistry of Ib (major isomer) and Ic in solution was deduced
to be E-anti and E-syn, respectively. The E-anti form of Ib (major isomer) was supported by
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the H NMR spectrum, in which the vicinal couplings ( J) observed for 5-H proton (δ 3.36–
3
5ax
3.43 ppm) are consistent with the axial orientation of the proton: the J values (Hz), 3.4 (H ,
4
eq
5ax
4ax
H ) and 10.3 (H , H ), correspond well with the values estimated from the torsion angles
5
ax
4eq
obtained from the X-ray crystal structure, i.e., the torsion angles: ∠H -C5-C4-H = 50 ° and
H5ax-C5-C4-H = 180 °.14
4ax
∠
Furthermore, the diagnostic data for supporting the E-anti structure of Ib (major) in solution
were obtained by the nuclear Overhauser enhanced differential spectroscopy (NOEDS) of the
major isomer of N-p-toluoyl analogue of Ib (Id) (Figure 7),15 i.e., NOE enhancement and
correlation were observed between the 5-CH protons and 6-H proton, and between 5-H proton
3
eq
ax
and 2’-H (in Ar), 4-H , and 3-H protons as shown in Figure 7, indicating the anti structure
with the 5-CH
3
group in an equatorial orientation and 5-H proton in an axial one.
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Table 1. Anti/syn equilibrium ratio of Ia–c measured by H NMR, energy difference calculated
from the equilibrium ratio and by DFT calculation, and energy barrier
Energy difference (kJ/mol) a
experimental calculated (DFT)
anti : syn ratio
( H NMR in
Energy barrier
R1
H
R2
H
1
experimental
(∆G‡ kJ/mol)
CDCl
3
at 296 K
)
∆GTC
∆G298
: 0.25b
69.5 (Tc = 383 K)c
(63.4)d
1
3.4
(3.8)d
4.0
(5.0)d,e
Ia
(
1 : 0.25 at 298 K)d
H
Cl
H
1 : 0.06f
7.2
5.9
NAg
Ib
Ic
h
i
NAg
CH
3
– :
1
–
15.5
a
b
Comparison between the anti and syn isomers with the chair-like form. Almost the same ratio was
c
1
observed in CD
3
OD and DMSO-d . Estimated from the coalescence VT H NMR spectra measured in
: Tc = coalescence temperature. Data in Ref 7. By molecular mechanics calculation. The
6
d
e
f
DMSO-d
6
g
h
1
ratio in CD
spectrum. Not determined.
2
Cl
2
was 1:0.08. NA: not analyzed. The anti isomer was not confirmed in the H NMR
i
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The deduced structures of Ib (major) and Ic were also obtained by the X-ray crystal
analysis, as shown in Figure 6. It is noteworthy that the lowest-energy conformers of Ib (E-
anti-chair) and Ic (E-syn-chair) obtained by the DFT calculations coincide with the X-ray
crystal structures. Thus, the stereochemistry of the major and minor isomers of Ia in both
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solid and solution state was unambiguously assigned to be anti and syn, respectively, and
7
these results clearly indicate that the previously reported structure of the major diastereomer
of Ia in solution state (syn) was misassigned.9
‡
The activation free energy barrier to rotation (∆G ) between the anti/syn isomers of Ia was
1
1
estimated using variable-temperature H NMR (VT H NMR) in DMSO-d (see Figure S3 in
6
‡
16
the Supporting Information); the coalescence spectra yielded a ∆G value of ca. 69.5 kJ/mol
(
Table 1). The energy difference (∆G) between the anti/syn isomers was calculated by DFT to
be 4.0 kJ/mol, which is in good agreement with the experimental value of 3.4 kJ/mol [calculated
from the equilibrium ratio (1:0.25)] (Table 1).
1
Furthermore, very unexpectedly, the VT H NMR study of Ia at lower temperatures (243 K
to 183 K in CD
2
Cl ) unveiled another interesting conformational aspect of N-benzoyl-5-methyl-
2
1
-benzazepines (Figure 8, Table 2): by lowering the temperature, each diastereotopic methylene
proton signal in the major anti isomer of Ia split into paired signals
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5.25.1 5.0 4.9 4.8 4.7 4.6 4.5 4.4 4.3 4.2 4.1 4.0 3.9 3.8 3.7 3.6 3.5 3.4 3.3 3.2 3.1 3.0 2.9 2.8 2.7 2.6 2.5 2.4 2.3 2.2 2.1 2.0 1.9 1.8 1.7 1.6 1.5 1.4 1.3 1.2 1.1 1.0 0.9 0.8
X : parts per Million : Proton
1
Table 2. Chair/boat equilibrium in Ia
–
c measured by H NMR and energy difference
Energy difference (kJ/mol)
experimental calculated (DFT)
Energy barrier
(∆G kJ/mol)
(Tc = 223 K)b
40.4
chair:boat ratio
‡
a
at 183 K
∆G
TC
∆G298
Ia (for aR*, S*)c
Ib (for aR*, S*)d
1 : 0.3
1.7
2.4
3.6
1 : 0.2
4.0
9.1
40.6
NAh
Ic (aS*, S*)e
f
g
1 :
–
–
a
d
1
. bTc = coalescence temperature. cThe major anti isomer of Ia.
Measured by H NMR in CD
2
Cl
2
e
f
g
The major anti isomer of Ib. Syn form. The boat form was not confirmed. Not determined.
hNA: not analyzed.
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showing the appearance of two new conformers (with a ratio of 1:0.3), although that in the
1
7
minor syn isomer of Ia apparently did not show any change (Figure 8). The energy barrier
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‡
(
∆G ) between the split conformers estimated by VT NMR was 40.4 kJ/mol (Tc = 223 K in
CD
2
Cl ). The energy difference (∆G) between the conformers was 1.7 kJ/mol (calculated from
2
the equilibrium ratio at 183 K). Compound Ib (major anti isomer) also exhibited two
conformers in NMR at lower temperatures (see Figure S6 in the Supporting Information),
1
7
whereas compound Ic (syn form) apparently did not show any change in the spectrum. The
appearance of the two conformers from the anti isomers (major isomers of Ia and Ib) at lower
temperatures was unanticipated, since thus far the anti isomer is believed to take a chair form.6,7
The conformers observed at lower temperatures were most probably chair and boat forms, and
thus the signals appearing in the NMR spectrum at rt may be the population-weighted average
ones between the chair and boat forms (in brackets in Figure 3). In addition, it is noteworthy
that, in the X-ray crystallographic analysis of Ib (Figure 6), two independent molecules
[
Molecule I (chair) and Molecule II (boat)] are present in a unit cell, which may support the
assumption.
The relatively small energy difference (∆G) between the chair and boat forms in the anti
isomers calculated by DFT is also consistent with this phenomenon: ∆G298 value, 3.6 kJ/mol
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Figure 9. Four selected conformers of Ia (E-amide isomer) and the free energy difference (∆G298) as
calculated by the DFT method.
for Ia; and 4.0 kJ/mol for Ib (Table 2, Figure 9). In contrast, in the syn isomers of Ia–Ic, large
energy differences between the chair and boat forms were calculated, i.e., the ∆G298 values
(kJ/mol) calculated by DFT were 9.2, 7.3, and 9.1 for Ia, Ib, and Ic, respectively. The reason
1
why the syn isomers apparently did not show any change at lower temperatures in the H NMR
spectrum may be the large energy differences between the conformers.17
Stereochemistry of 5-Hydroxy- and 5-(N,N-Dimethylamino)-N-(p-toluoyl)-1-benzazepines
[
IIa–c: X = OH and IIIa–c: X = N(CH
3
2
) ]. Next, the stereochemistry of the N-benzoyl-1-
benzazepines with 5-hydroxy (IIa–c) and 5-N,N-dimethylamino (IIIa–c) groups (see Figures
3, 4 and Table 3) was examined. Compounds IIa–c and IIIa–c are the basic structure of
3
2
tolvaptan and mozavaptan (see Figure 1), respectively. The anti/syn stereochemistry of these
drugs has previously received little attention and has not been analyzed, although the E/Z-amide
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18
2
isomer has been discussed (i.e., the E isomer is predominant). In essence, IIa–c and IIIa–c
showed structural features similar to those of Ia–c. The anti/syn stereochemistry of IIa–c and
IIIa–c in the solution state was determined by the 2D-NMR spectra (NOESY, COSY, and
HMQC). Similarly to Ia–c, the anti form is predominant in IIa,b and IIIa,b, and only the syn
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form is observed in IIc and IIIc. The H NMR spectra of a–c-series of compounds are compared
as shown in Figures S1 and S2 (in the Supporting Information). The X-ray crystallographic
structures of IIc and IIIa are shown in Figure 6, in which IIc revealed a syn-chair (ax. OH)
form as expected, whereas that of IIIa unexpectedly showed a boat form with the N(CH
)
3 2
group in anti (eq.) form. The anti/syn ratio, energy barrier, and energy difference for IIa–c and
IIIa–c are summarized in Table 3 (cf., Table 1 for Ia–c).
For the anti/syn ratio of IIa–c and IIIa–c in the solution state, it is interesting to note that, in
1
2
the a-series (R = R = H) of compounds (IIa and IIIa), the syn proportion increased compared
with that of Ia (anti/syn ratio: 1:0.25). i.e., the anti/syn ratio of IIa is 1:0.30, and that of IIIa is
1
:0.43–1:0.82 (Tables 3). The increase in the syn isomer in IIa and IIIa may be explained by
the steric bulk of the substituent, which confers a labile nature due to the steric repulsion
between C6-H and C5-substituent to increase the syn isomer with the substituent in
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1
Table 3. Anti/syn equilibrium ratio of IIa–c and IIIa–c measured by H NMR, energy difference
calculated from the equilibrium ratio and by DFT calculation, and energy barrier
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anti : syn ratio
Energy difference ( kJ/mol)
experimental calculated (DFT)
Energy barrier
experimental
(∆G‡ kJ/mol)
1
X
R1
R2
( H NMR
at 296 K)a
1 : 0.30b
∆GTC
∆G298
68.8 (Tc = 333 K)c
IIa
IIb
IIc
OH
OH
OH
H
H
H
3.0
4.2
4.7
NAd
10.8
NAd
CH
3
1 : 0.15
e
f
NAd
CH
3
H
–
: 1
–
1 : 0.82
0.5
1.8
2.1
2.1
4.5
1
: 0.50 in CD
2
3
Cl
2
71.0 (Tc = 353 K)c
IIIa N(CH
3
)
2
H
H
3.4
1 : 0.43 in CD
OD
1
: 0.43 in THF-d
8
NAd
NAd
IIIb N(CH
3
3
)
)
2
2
H
CH
3
1 : 0.16
e
f
NAd
NAd
IIIc N(CH
CH
3
H
–
: 1
–
a
b
In DMSO-d
6
unless otherwise stated. Almost the same ratio was observed in CDCl
3
, CD
2
Cl
2
, and
: Tc =
c
1
CD
3
OD. Estimated from the coalescence VT H NMR spectra measured in DMSO-d
coalescence temperature. NA: not analyzed. The anti form was not confirmed. Not determined.
6
d
e
f
the axial position. The high proportion of the syn isomer (anti/syn = 1:0.82) of IIIa in DMSO-
d was unexpected, because the ratios for Ia and IIa were unchanged regardless of the solvent
6
used, and the energy difference (∆G) between the anti and syn forms in IIIa obtained by DFT
calculation was 3.4 kJ/mol. This unexpected ratio observed in IIIa may be caused by
stabilization of the syn form in DMSO, although the mechanism of the solvent effect is not clear
1
2
at present. On the other hand, similar to Ib and Ic, the b-series (R = H, R = CH
3
) of compounds
1
2
(
IIb and IIIb) predominantly formed the anti isomer, and the c-series (R = CH
3
, R = H) of
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compounds (IIc and IIIc) existed only as the syn isomer. The DFT calculation study of IIc also
supported the hypothesis that the syn-chair structure exists as the most stable conformer, i.e.,
more stable by 10.8 kJ/mol than the anti-chair structure.
0
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0
CONCLUSION
The syn and anti diastereomers of N-benzoyl-5-substituted-1-benzazepines (I–III) was first
prepared stereoselectively by biasing the conformation with a substituent at C6 (for Ic–IIIc)
and C9 (for Ib–IIIb), respectively, and the stereochemistry of I–III was examined in detail to
reveal new physicochemical aspects of these heterocycles including revision of the previously
reported stereochemistry of Ia in the solution state. The results may not only shed light on the
active form of the vaptan class of VP ligands (e.g., mozavaptan and tolvaptan), but also may
provide useful information for future drug design when these heterocycles are used as the
scaffold.
EXPERIMENTAL SECTION
General experimental procedure.
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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) with precoated silica gel plates. Column chromatography was
10
11
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60
performed using silica gel (45‒60 μm). Extracted solutions were dried over anhydrous MgSO
4
or Na
2
SO . Solvents were evaporated under reduced pressure. NMR spectra were recorded on
4
1
13
a spectrometer at 400 MHz or 600 MHz for H NMR, and 100 MHz or 150 MHz for C NMR
at 296 K unless otherwise stated. Chemical shifts are given in parts per million (ppm) downfield
from tetramethylsilane as an internal standard, and 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 mass spectrometer. IR spectra were recorded on a FT-IR spectrometer equipped
with ATR (Diamond). Melting points were recorded on a melting point apparatus and are
uncorrected.
1
-Benzoyl-5-methyl-2,3,4,5-tetrahydro-1H-1-benzazepine (Ia). Compound Ia was prepared
7
7
according to the procedure previously reported. Colorless crystals: mp 88–89 °C (lit. mp 87.8–
1
8
8.6 °C). The spectroscopic data of Ia was identical to those of the compound reported. The H
NMR spectrum in CDCl
3
is shown in Figure 5, which indicates that the anti/syn ratio is 1:0.25:
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1H NMR (CDCl
, 600 MHz) anti (equatorial)-isomer (= reportedly axial-isomer): δ 1.30–
7
3
4
a
3e
1
.37 (m, 1H, H ), 1.46 (d, J = 7.6 Hz, 3H, CH
3
), 1.64–1.72 (m, 1H, H ), 1.92–2.06 (m, 2H,
0
1
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3
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0
1
2
3
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7
8
9
0
3
a
4e
2a
5a
H and H ), 3.00–3.08 (m, 1H, H ), 3.24–3.32 (m, 1H, H ), 4.67 (ddd, J = 3.4, 6.9, 13.1 Hz,
2
e
1
H, H ), 6.62 (d, J = 7.6 Hz, 1H, Ar-H), 6.90 (t, J = 7.6 Hz, 1H, Ar-H), 7.09–7.31 (m, 7H, Ar-
7
H). syn (axial)-isomer (= reportedly equatorial-isomer): δ 1.51 (d, J = 6.9 Hz, 3H, 5-CH
3
),
3
e
4a
4e
3a
1.76–1.84 (m, 2H, H and H ), 1.92–2.06 (m, 1H, H ), 2.23–2.35 (m, 1H, H ), 2.66–2.75 (m,
2
a
5e
2e
1H, H ), 3.17–3.26 (m, 1H, H ), 5.14 (m, 1H, H ), 6.54 (d, J = 7.6 Hz, 1H, Ar-H), 6.85 (dt, J
=
1.3, 7.6 Hz, 1H, Ar-H),7.07 (t, J = 7.6 Hz, 1H, Ar-H), other aromatic protons overlapped by
13
resonances of the anti-isomer; C NMR (CDCl
3
, 150 MHz) anti-isomer: δ 20.0 (CH ), 27.0
3
(
C-3), 34.4 (C-4), 34.8 (C-5), 47.0 (C-2), 125.3 (Ar-C), 126.6 (Ar-C), 127.3 (Ar-C), 127.7 (Ar-
C), 128.1 (Ar-C), 128.5 (Ar-C), 129.5 (Ar-C), 136.2 (Ar-C), 141.9 (Ar-C), 142.6 (Ar-C), 169.5
(
CO). syn-isomer; δ 18.7 (CH
27.1 (Ar-C), 127.5 (Ar-C), 128.9 (Ar-C), 129.4 (Ar-C), 129.5 (Ar-C), 130.6 (Ar-C), 136.2 (Ar-
C), 142.1 (Ar-C), 143.0 (Ar-C), carbonyl peak not observed.
3
), 24.1 (C-3), 32.3 (C-4), 40.9 (C-5), 48.4 (C-2), 126.7 (Ar-C),
1
9
-chloro-5-methyl-2,3,4,5-tetrahydro-1H-1-benzazepine (8). To a stirred solution of 9-
3
chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (7) (150 mg, 0.77 mmol) in THF (11 mL)
at 25 °C under an atmosphere of argon was added methyl magnesium iodide (1 M in THF, 3
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mL, 3.08 mmol). The mixture was stirred at 25 °C for 6 h, and evaporated. To the residue was
added saturated NH Cl (aq), and the mixture was extracted with diethyl ether. The extract was
4
10
11
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13
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17
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washed with brine, dried, and concentrated to give 9-chloro-5-hydroxy-5-methyl-2,3,4,5-
tetrahydro-1H-1-benzazepine, which was used in the next reaction without further purification.
To the crude product (109 mg) were added TFA (0.4 mL, 5.0 mmol) and Et SiH (0.8 mL, 5.0
3
mmol). After being stirred at 25 °C for 4 h, the mixture was treated with saturated NaHCO
3
(aq), and then extracted with ethyl acetate. The extract was washed with brine, dried, and
concentrated. The concentrate was purified by column chromatography on silica gel
1
(
hexane/ethyl acetate = 20:1) to give 8 as a colorless oil (102 mg, 0.52 mmol, 68%): H NMR
(
CDCl
.95 (m, 1H), 3.05–3.13 (m, 3H), 4.51 (br, 1H), 6.75 (t, J = 7.6 Hz, 1H), 7.04 (dd, J = 1.4, 7.6
Hz, 1H), 7.16 (dd, J = 1.4, 8.3 Hz, 1H); 13C NMR (CDCl
, 150 MHz)
3
, 600 MHz) δ 1.31 (d, J = 7.6 Hz, 3H), 1.53–1.60 (m, 1H), 1.72–1.80 (m, 2H), 1.87–
1
3
δ 19.6, 27.5, 33.5, 38.7, 48.1, 120.7, 124.1, 126.7, 127.0, 138.9, 145.8; IR(ATR) 778, 1138,
-1
+
1
273, 3473 cm ; HRMS (ESI) m/z calcd for C11H14NCl 196.0888 (M+H) , found 196.0888.
1
-Benzoyl-9-chloro-5-mthyl-2,3,4,5-tetrahydro-1H-1-benzazepine (Ib). To a stirred
solution of 8 (50 mg, 0.26 mmol) in THF (3 mL) at 0 °C under an atmosphere of argon was
added sodium hydride (60% in oil) (15 mg, 0.38 mmol). The mixture was stirred at 25 °C for
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
24
3
0 min, cooled to 0 °C, and treated with benzoyl chloride (0.09 mL, 0.77 mmol). After being
stirred at 25 °C for 3 h, the mixture was treated with H O, extracted with ethyl acetate. The
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
extract was washed with brine, dried, and concentrated. The concentrate was purified by
column chromatography on silica gel (hexane/ethyl acetate = 10:1) to afford Ib as a white
powder (74 mg, 0.25 mmol, 95%). Signals of a mixture of anti/syn (= 1:0.06) diastereomers
1
13
1
were observed in the H NMR and C NMR spectra; anti isomer (major isomer), H NMR
4
a
(600 MHz, CDCl ) δ 1.28–1.35 (m, J = 4.1, 9.6, 10.3, 13.6 Hz, 1H, H ), 1.46 (d, J = 6.9 Hz,
3
3
e
3
6
=
H, 5-CH ), 1.59–1.66 (m, J = 3.4, 4.1, 6.9, 6.9, 14.1 Hz, 1H, H ), 1.92–1.99 (m, J = 3.4, 4.1,
3
4
e
3a
.9, 13.6 Hz, 1H, H ), 2.00–2.09 (m, J = 4.1, 4.1, 9.6, 9.6, 14.1 Hz, 1H, H ), 2.91–2.99 (m, J
2a
5a
3.4, 9.6, 13,2 Hz, 1H, H ), 3.36–3.43 (m, J = 3.4, 6.9, 10.3 Hz, 1H, H ), 4.64–4.70 (m, J =
2e
4
.1, 6.9, 13.2 Hz, 1H, H ), 7.04 (dd, J = 1.4, 8.3 Hz, 1H, Ar-H), 7.10–7.16 (m, 2H, Ar-H),
.19–7.25 (m, 3H, Ar-H), 7.48 (t, J = 8.3 Hz, 1H, Ar-H), 8.11 (dd, J = 1.4, 7.6 Hz, 1H, Ar-H)
7
(see, Tables S1–3 in the Supporting Information for the detailed analysis of the methylene
1
13
protons by H NMR) ; C NMR (150 MHz, CDCl
3
) δ 20.1, 26.9, 34.3, 35.3, 45.9, 123.6,
1
27.3, 127.5, 127.9, 128.7, 129.8, 132.2, 136.0, 139.7, 145.2, 169.3; syn isomer (minor
1
isomer) H NMR (600 MHz, CDCl ) δ 1.53 (d, J = 7.6 Hz, 3H), 1.69–1.84 (m, 2H), 1.94–
3
2.00 (m, 1H), 2.27–2.36 (m, 1H), 2.66, (t, J = 12.4 Hz, 1H), 3.20–3.28 (m, 1H), 5.07 (d, J =
12.4 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.08–7.16 (m, 3H), 7.20 (d, J = 6.9 Hz, 1H), 7.26–7.29
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1
(
m, 1H), 7.64 (t, J = 7.6 Hz, 2H) [the H NMR spectral data of the syn (minor) isomer
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
described above are those assigned using the separated syn isomer (isolated as a colorless oil)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
at 253K.]; C NMR (150 MHz, CDCl ) δ 20.3, 29.4, 33.8, 34.9, 49.3, 123.7, 126.5, 126.8,
3
-1
1
27.1, 127.7, 128.5, 128.8, 129.6, 136.4, 145.4, 170.5; IR(ATR) 1643 cm ; HRMS (ESI) m/z
+
calcd for C18H18NOCl 300.1150 (M+H) , found 300.1150. The anti/syn isomers of Ib were
separable by HPLC. The separation condition is as follows: CHIRALPAK IA (1.0 cmɸ × 25
cm); Eluent, hexane/ethanol (19 /1); Flow rate, 2.0 mL/min; Temperature, 23 ºC; Detection,
2
54 nm. Minor peak: retention time = 16.0 min, 18.7 min; Major peak: retention time = 20.5
min, 21.9 min. The two minor peaks (= the same diastereomer) were collected by HPLC using
1
the chiral column and combined to subject to the H NMR analysis [Figure 5 (c)]. Crystals
suitable for X-ray crysatallography were obtained by recrystallization of the anti/syn (=
1
:0.06) mixture from hexane/ethyl acetate.
N-(2-Bromo-6-methylphenyl)-N-(pent-4-en-1-yl)benzamide (5c). To a solution of N-(2-
bromo-3-methylphenyl)benzamide (4c)18 (538 mg, 1.85 mmol) in THF (15 mL) was added
sodium hydride (60% in oil) (84 mg, 2.11 mmol) at 0 °C under an atmosphere of argon. After
the mixture was stirred at 25 °C for 1 h, and pent-4-enyl tosylate (371 mg, 1.54 mmol) was
added. After being stirred at 25 °C for 8 h, the mixture was treated with H O, and extracted
2
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6
26
with ethyl acetate. The extract was washed with brine, dried, and concentrated. The concentrate
was purified by column chromatography on silica gel (hexane/ethyl acetate = 20/1) to afford 5c
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
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5
6
7
8
9
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
(
515 mg, 93%) as a colorless oil: H NMR (600 MHz, CDCl
3
) δ 1.61–1.69 (m, 1H), 1.81–1.88
(
m, 1H), 2.06–2.17 (m, 2H), 2.37 (s, 3H), 3.38–3.43 (m, 1H), 4.23–4.28 (m, 1H), 4.95 (d, J =
9.6 Hz, 1H), 5.01 (d, J = 17.1 Hz, 1H), 5.77–5.84 (m, 1H), 6.89 (d, J = 7.5 Hz, 1H), 7.02–7.04
1
3
(m, 2H), 7.12 (t, J = 7.5 Hz, 2H), 7.18–7.20 (m, 1H), 7.31 (d, J = 7.5 Hz, 2H); C NMR (150
MHz, CDCl ) δ 23.9, 26.5, 31.3, 48.9, 115.0, 126.0, 127.2, 127.6, 127.9, 129.2, 129.5, 129.8,
3
–
1
1
36.3, 137.9, 140.3, 142.2, 170.6; IR (ATR) 1652 cm ; HRMS (ESI) m/z calcd for
+
C
19
H20NOBr 380.0620 (M+Na) , found 380.0622.
1
-Benzoyl-6-methyl-5-methylene-2,3,4,5-tetrahydro-1H-1-benzazepine (6c). To
a
suspension of Pd (OAc)
2
(12.7 mg, 5 mol%) in DMF (5 mL) were added PPh (59.5 mg, 20
3
mol%), LiCl (52.9 mg, 1.25 mmol), and Et N (0.32 mL, 2.27 mmol) under an atmosphere of
3
argon. After the mixture was stirred at 25 °C for 15 min, a solution of N-(2-bromo-6-
methylphenyl)-N-(pent-4-en-1-yl)benzamide (5c) (409 mg, 1.14 mmol) in DMF (3 mL) was
added to the mixture. After being stirred at 130 °C for 20 h, the mixture was cooled to rt and
filtered through Celite. The filtrate was washed with H O, brine and dried, and concentrated.
2
The concentrate was purified by column chromatography on silica gel (hexane/ethyl acetate =
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1
8
:1) to give 6c as colorless crystals (247 mg, 79%): mp 90–92 °C: H NMR (600 MHz, CDCl
3
)
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
δ 1.85–1.91 (m, 1H), 2.01–2.06 (m, 1H), 2.22 (ddd, J = 3.4, 11.0, 13.0 Hz, 1H), 2.33 (s, 3H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
.68–2.70 (m, 1H), 2.94 (ddd, J = 2.7, 11.0, 11.6 Hz, 1H), 4.85 (ddd, J = 3.4, 13.0, 13.6 Hz,
H), 5.04 (d, J = 1.3 Hz, 1H), 5.48 (br, 1H), 6.48 (d, J = 7.5 Hz, 1H), 6.81 (t, J = 7.5 Hz, 1H),
1
7.03 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.19 (t, J = 7.5 Hz,
1
3
1H), 7.24 (d, J = 7.5 Hz, 2H); C NMR (150 MHz, CDCl
3
) δ 20.4, 29.0, 34.7, 47.2, 116.5,
125.8, 126.9, 127.5, 127.9, 129.2, 129.2, 135.9, 136.5, 139.9, 147.0, 169.5; IR (ATR) 2918,
–
1
+
1
639 cm ; HRMS (ESI) m/z calcd for C19H19NO 278.1539 (M+H) , found 278.1540.
1-Benzoyl-5,6-dimethyl-2,3,4,5-tetrahydro-1H-1-benzazepine (Ic). To a solution of 6c (193
mg, 0.697 mmol) in ethanol (6 mL) was added 10% Pd/C (139 mg). The susupension was stirred
at 25 °C under a hydrogen atmosphere for 20 h. The mixture was then filtered through a thin
pad of Celite, which was washed with ethyl acetate. The collected filtrate was evaporated, and
the residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 8:1)
1
to afford Ic as colorless crystals (128 mg, 65%): mp 76–78 °C; in the H NMR spectrum, signals
1
due to the syn diastereomer were observed and those of the anti isomer were negligible; H
3
NMR (600 MHz, CDCl ) δ 1.45 (d, J = 7.5 Hz, 3H), 1.74–1.77 (m, 2H), 1.95–1.99 (m, 1H),
2
.23–2.31 (m, 1H), 2.41 (s, 3H), 2.69–2.73 (m, 1H), 3.58–3.63 (m, 1H), 5.07–5.11 (m, 1H),
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2
2
2
2
2
2
2
3
3
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3
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3
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5
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28
6
2
1
1
.42 (d, J = 8.2 Hz, 1H), 6.73 (dd, J = 7.5, 8.2 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 7.11–7.14 (m,
1
3
H), 7.20–7.24 (m, 3H); C NMR (150 MHz, CDCl
3
) δ 17.3, 21.1, 23.9, 31.8, 33.1, 48.4, 125.9,
0
1
2
3
4
5
6
7
8
9
0
1
2
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8
9
0
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4
5
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8
9
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6
7
8
9
0
27.4(x2), 127.6, 128.9(x2), 129.3, 129.4, 135.8, 136.7, 140.5, 143.4, 168.5. IR (ATR) 2938,
–
1
+
633 cm ; HRMS (ESI) m/z calcd for C19H21NO 302.1515 (M+Na) , found 302.1520.
1
-Benzoyl-6-chloro-5-methyl-2,3,4,5-tetrahydro-1H-1-benzazepine (Id). Sodium hydride
(
60% in oil) (8.3 mg, 0.21 mmol) was added to a stirred solution of 8 (20.3 mg, 0.104 mmol)
in THF (1 mL) at 0 °C under an atmosphere of argon. The mixture was stirred at 25 °C for 30
min, cooled to 0 °C, and treated with p-toluoyl chloride (41 µL, 0.31 mmol). After being stirred
at 25 °C for 9 h, the mixture was treated with H O and then extracted with ethyl acetate. The
2
extract was washed with brine, dried, and concentrated. The concentrate was purified by column
chromatography on silica gel (hexane/ethyl acetate = 10:1) to afford Id as pale yellow crystals
(
28.9 mg, 89%): mp 121–123 °C; Signals of a mixture of anti/syn (= 1:0.07) diastereomers were
1
13
1
observed in the H NMR and C NMR spectra; anti isomer (major isomer), H NMR (600
MHz, CDCl
3
) δ 1.26–1.35 (m,1H), 1.45 (d, J = 6.8 Hz, 3H), 1.56–1.65 (m, 1H), 1.91–2.08 (m,
H), 2.24 (s, 3H), 2.93 (ddd, J = 2.7, 9.1, 12.8 Hz, 1H), 3.38 (ddq, J = 3.2, 6.8, 13.7 Hz, 1H),
.66 (ddd, J = 3.6, 6.8, 12.8 Hz, 1H), 6.91 (d, J = 7.8 Hz, 2H), 7.05 (dd, J = 1.3, 7.8 Hz, 1H),
2
4
7
1
3
.12 (d, J = 7.8 Hz, 2H), 7.15 (t, J = 7.8 Hz, 1H), 7.24 (dd, J = 1.3, 7.8 Hz, 1H); C NMR (150
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MHz, CDCl
3
) δ 20.0, 21.3, 26.8, 34.2, 35.2, 45.8, 126.8, 127.8, 127.9, 127.9, 128.5, 129.1,
1
30.1, 132.2, 133.0, 139.8, 139.9, 145.1, 169.4; syn isomer (minor isomer) (only the
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
distinguishable peaks are described), H NMR (600 MHz, CDCl
3
) δ 1.05 (d, J = 7.7 Hz, 0.21H),
2
.25 (s, 0.21H), 2.58–2.66 (m, 0.07H), 3.21–3.25 (m, 0.07H), 5.05–5.09 (m, 0.07H), 7.36–7.38
1
3
(m, 0.07H), 7.52 (d, J = 8.2 Hz, 0.14H); C NMR (150 MHz, CDCl
3
) δ 20.2, 21.7, 23.7, 32.2,
41.0, 47.5, 49.2, 126.8, 127.7, 128.3, 128.8, 129.0, 129.1, 132.4, 143.3, 144.3, 170.8; IR (ATR)
–
1
+
2933, 1644 cm ; HRMS (ESI) m/z calcd for C19H21NO 336.1126 (M+Na) found 336.1131.
5-Oxo-2,3,4,5-tetrahydro-1-p-toluenesulfonyl-1H-1-benzazepine (11a) and 5-oxo-2,3,4,5-
tetrahydro-1H-1-benzazepine (12a). Compound 11a was prepared according to the reported
1
9
method shown in Scheme 2 starting from methyl 2-(N-p-toluenesulfonyl)aminobenzote (9a).
Removal of the p-toluenesulfonyl group with polyphosphric acid (PPA) afforded 12a.19
Methyl 3-Methyl-2-(N-p-toluenesulfonyl)aminobenzoate (9b). To a solution of methyl 2-
amino-3-methylbenzote (3.14 g, 19 mmol) in pyridine (20 mL) was added p-TsCl (4.3 g, 22.8
mmol). After being stirred at 25 °C for 18 h, the mixture was poured into ice-water. The
resultant precipitates were collected by filtration. The solid obtained was dissolved in CH
2
Cl ,
2
and the solution was washed with dil. HCl, H O, dried, and evaporated. The residue was
2
purified by recrystallization (CH
2
Cl /hexane) to give 9b as white solids (5.81 g, 95%): mp
2
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