Isolation and characterization of atropisomers of seven-membered-ring benzolactams

Article abstract of DOI:10.1021/jo2008725

The atropisomeric properties of seven-membered-ring benzolactams (7a-c and 8a) [1,5-benzodiazepin-2-one (a), 1,5-benzothiazepin-4-one (b), and 1-benzazepin-2-one (c)] were examined. The atropisomers were isolated as the diastereomers with an (S)-phenethyl

Full text of DOI:10.1021/jo2008725

ARTICLE
pubs.acs.org/joc
Isolation and Characterization of Atropisomers of
Seven-Membered-Ring Benzolactams
Hidetsugu Tabata, Naoya Wada, Yuko Takada, Tetsuta Oshitari, Hideyo Takahashi, and Hideaki Natsugari*
School of Pharmaceutical Sciences, Teikyo University, 1091-1, Midori-ku, Sagamihara, Kanagawa 252-5195, Japan
S Supporting Information
b
ABSTRACT: The atropisomeric properties of seven-mem-
bered-ring benzolactams (7aꢀc and 8a) [1,5-benzodiazepin-
2-one (a), 1,5-benzothiazepin-4-one (b), and 1-benzazepin-2-
one (c)] were examined. The atropisomers were isolated as the
diastereomers with an (S)-phenethylamide moiety, which were
characterized by X-ray crystallography, and the barriers to their
interconversion were clarified.
’ INTRODUCTION
Seven-membered-ring benzolactams (I) (Figure 1) have been
used as the core structures of various biologically active mol-
ecules. Lofendazam (I: X = NH),1 diltiazem (I: X = S)2 and
benazepril (I: X = CH2)3 are the typical therapeutic agents
developed using these structures. Thus far, the conformation of
Figure 1. Seven-membered-ring benzolactams (I) and atropisomeric
these heterocycles has been extensively investigated to gain
structures A and B.
insight into the structures of these relatively flexible hetero-
cycles.4 In essence, the important point is that compound I
adopts chiral conformations because of an sp2ꢀsp2 axis at
ArꢀN(CdO) to form the atropisomeric structures A and B
(Figure 1)5 and the target molecules (receptors or enzymes) may
recognize A and B for biological activity. However, there has
been little discussion about the conformation from the viewpoint
of the atropisomerism.6
In our previous papers,7 we described the atropisomeric
properties of dibenzo[b,d]azepin-6-one (II:aꢀc), which is the
core structure of a γ-secretase inhibitor, LY-4115758 (Figure 2).
Compound II (aꢀc) was shown to exist as a racemate of the
atropisomers II-A and II-B with an activation free-energy barrier
to rotation (ΔGq) of 98ꢀ122 kJ/mol. X-ray analysis of the
Figure 2. Conformation and thermodynamic stability of the atropi-
enantiomers of IIc revealed the presence of two sp2ꢀsp2 axes of
somers of dibenzo[b,d]azepin-6-one (IIaꢀc: A, B).
ArꢀAr and ArꢀN(CdO), although they exist only as a pair of
enantiomers [A (a1R,a2S) and B (a1S,a2R)] without the presence
’ RESULTS AND DISCUSSION
of diastereomers [(a1R,a2R) and (a1S,a2S)]. We assumed that
this phenomenon occurred because the two axes move together
Synthesis of Seven-Membered-Ring Benzolactams. The
seven-membered-ring benzolactams (I) prepared are the 1,5-
benzodiazepin-2-ones (a series: X = NCH3), 1,5-benzothiazepin-
4-ones (b series: X = S), and 1-benzazepin-2-ones (c series: X =
like a gear. However, since the axial chirality at the arylꢀamide
bond has not been studied thoroughly9 compared with the
biphenyl chirality, this is often regarded merely as a consequence
CH2). The NH-lactams [1aꢀc (Y = H), 2aꢀc (Y = Cl)] were
of the biphenyl chirality and may not be fully confirmed. Herein
we report the conformation of the seven-membered-ring benzo-
lactams (I) to reveal and confirm the atropisomerism occurring
at the ArꢀN(CdO) axis.
prepared from the corresponding benzene precursors with
Received: April 30, 2011
Published: May 17, 2011
r
2011 American Chemical Society
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Scheme 1. Preparation of Seven-Membered-Ring Benzolactam Derivatives
methods, i.e., N-alkylation with methyl bromoacetate followed
by hydrolysis and amidation with (S)-phenethylamine
(Scheme 1). The intermediary compounds 4ꢀ6 are useful for
preparation of the biologically active molecules. The ortho-
substituent (Y = Cl, Ph) is introduced in the nuclei to provide
a higher rotation barrier for the axis, which may result in freezing
the conformation of the molecules.
Conformation of Seven-Membered-Ring Benzolactams
(1ꢀ6). First, the conformations of compounds 1ꢀ6 were
examined. The methylene protons of all the NH-lactams 1ꢀ3
(aꢀc) showed sharp signals with AA0XX0-type splitting patterns
in the 1H NMR spectra, reflecting the rapid ring-flipping includ-
ing the axis at arylꢀNH(CO) (Figure 3a for 3a). On the other
hand, compounds 4ꢀ6 which bear the N-methoxycarbonyl-
1
methyl moiety showed a different pattern in the H NMR
spectra. In compounds 4aꢀc, which are unsubstituted on the
benzene ring (Y = H), the methylene protons of the lactam ring
were observed as broad peaks without separation of the peaks of
the geminal protons, and the methylene protons of the N-
substituent also appeared as a broad signal (Figure 3b for 4a-
COOH). Attempted separation of the atropisomers of 4aꢀc at
room temperature using chiral HPLC failed. These results
suggest that the axial chirality caused by the ArꢀN(CdO)
(sp2ꢀsp2) axis is present, though the ring flipping occurs rather
fast at room temperature.13 In contrast, in the 1H NMR spectra
compounds of 5aꢀc (Y = Cl) and 6aꢀc (Y = Ph), all the
methylene protons of the lactam ring were observed as separated
sharp peaks (ABXY-type splitting) and the methylene protons of
the N-substituent as AB-quartet peaks (Figure 3c for 5a-COOH
and Figure 3d for 6a-COOH), which indicate that the rotation
around the ArꢀN(CdO) axis is restricted by the chloro and
phenyl groups to separate the protons as diastereotopic ones. The
upper field shift of the AB-quartet peaks in 6a-COOH compared
to those of 5a-COOH is obviously ascribed to the effect of the C9-
Figure 3. 1H NMR (400 MHz, CDCl3) spectra of 3a (a), 4a-COOH
(b), 5a-COOH (c), and 6a-COOH (d).
NHCH3, SH, and CH2 moieties, respectively, as shown in
Scheme 1. The compounds without a substituent at the ortho
position on the benzene ring (Y = H) (1aꢀc) are the known
compounds,10ꢀ12 and compounds 2aꢀc, which have a chloro
substituent at the ortho position (Y = Cl), were prepared
according to the modified methods reported for the synthesis
of 1aꢀc. It should be noted that the Beckmann rearrangement of
8-chloro-3,4-dihydronaphthalen-1-(2H)-one oxime with poly-
phosphoric acid (PPA) gave 9-chloro-1,3,4,5-tetrahydro-2H-1-
benzazepin-2-one (2c) and its regioisomer (1-one isomer) in a
ratio of 53:47, whose stereochemistry was determined by the 1H
NMR (chemical shift of the C3-methylene protons: δ 2.38 (t, J =
7.2 Hz, 2H) for 2c and 3.11 (br, 2H) for the isomer). Com-
pounds 3aꢀc with a phenyl group on the benzene ring were
prepared in good yields in the SuzukiꢀMiyaura reaction of 2aꢀc.
The benzolactams with N-substituents [R = CH2CO2CH3
(4ꢀ6) and CH2CONH(S)CH(CH3)Ph (7, 8)] were prepared
from the corresponding NH-lactams (1ꢀ3) using conventional
1
phenyl ring in 6a-COOH. As was expected from the H NMR
spectra, the atropisomers of 5aꢀc and 6aꢀc could be separated at
room temperature using chiral HPLC. Compound 5b (X = S, Y =
Cl) was subjected to X-ray structure analysis, which revealed that
the lactam ring takes a boatlike conformation and 5b exists as a
racemate in the crystals; the aR and aS14 atropisomers are present
in a unit cell (space group P21/n) (Figure 4).
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Figure 4. X-ray crystal structure of 5b (racemate): (aR)-form (left) and
(aS)-form (right) in a unit cell.
Figure 6. 1H NMR spectra of 7a-A (aR, S) (above) and 7a-B (aS, S)
(below).
Figure 5. X-ray crystal structures of 7a-A (aR, S) (left) and 7a-B (aS, S)
(right).
Figure 7. X-ray crystal structure of 7b-A (aR, S).
with those of 7a-B: H3a, H3b, H4a, H4b: δ (ppm) 2.34, 2.43, 2.70,
3.28 for 7a-A, and 2.39, 2.51, 2.94, 3.65 for 7a-B, respectively.
These data may easily be explained as due to the methylene
protons of the lactam ring of 7a-A locating over the benzene ring
in the phenethylamide moiety to appear at a higher field.
Similarly, compound 8a (Y = Ph) was obtained as a mixture of
the diastereomers in a ratio of A:B = 1:0.9, which were separated
by column chromatography (SiO2). The stereochemistry was
assigned on the basis of the chemical shifts of the methylene
protons as described above.
Compound 7b (X = S, Y = Cl) was obtained as a mixture of the
diastereomers in a ratio of 1:0.9, which were separated by
crystallization to afford 7b-A as crystals (yield 37%). From the
mother liquor, the isomer 7b-B (in 85% de) was obtained as an
oily substance. The stereochemistry was clarified by X-ray
structure analysis of 7b-A (Figure 7), which showed that the
thiazepinone ring takes a boatlike form similar to 7a; the
stereochemistry at the axis of 7b-A is aR,15 and hence, that of
7b-B was determined to be aS. The same tendency of the
chemical shifts of the methylene protons in the 1H NMR spectra
of 7b-A and B as those in 7a-A and B were observed, e.g., H2a:
δ (ppm) 3.15 for 7b-A, and 3.27 for 7b-B.16
Isolation and Structure Analysis of Atropisomers of Se-
ven-Membered-Ring Benzolactams (7aꢀc and 8a). For iso-
lation and characterization of the atropisomers, (S)-phenethylamide
derivatives of 5aꢀc and 6a (7aꢀc and 8a) (Y = Cl and Ph)
were prepared to separate the atropisomers as diastereomers
(Scheme 1).
Compound 7a (X = NCH3, Y = Cl) was obtained from 5a via
the carboxylic acid as a mixture of the diastereomers (A and B)
(80% yield) in a ratio of 1:0.7 (by 1H NMR), which were separated
on column chromatography using SiO2 to afford 7a-A and 7a-B as
crystals. Investigation of the reaction (amidation) using HPLC
showed that the ratio immediately after the reaction was 1:1,
indicating that the ratio of 1:0.7 is not the result of a kinetically
controlled reaction, but the result of equilibrium after thermo-
dynamic conversion.
Both isomers were subjected to X-ray structure analysis to
reveal that the benzolactam moiety exists in a boat-like form, and
the absolute stereochemistry at the axis is aR for 7a-A and aS for
7a-B (Figure 5).14,15 As shown in Figure 5, the isomers adopt
antipode forms at the benzolactam moiety, and the phenyl group
of the phenethylamide moiety of 7a-A locates anti to the benzene
ring of the benzolactam moiety (extended form), whereas that of
7a-B adopts the syn (folded form). The extended form seemed to
be thermodynamically more stable than the folded form to result
Compound 7c (X = CH2) was also obtained as a mixture of
diastereomers in a ratio of 1:0.8, which were separated by column
chromatography (SiO2) to afford 7c-A (yield 36%) and 7c-B
(yield 31%) as crystals. The stereochemistry was deduced by
comparing the chemical shifts of the methylene protons in the 1H
NMR spectra as discussed above, e.g., H3a, H3b: δ (ppm) 2.37,
2.84 for 7c-A, and 2.65, 3.44 for 7c-B.
1
in the preferred formation of 7a-A. In the H NMR spectra of
7a-A and 7a-B (Figure 6), the same coupling patterns of the ring
methylene protons were observed, which indicates that both
diastereomers have the same ring conformation (antipode form)
in solution (CDCl3). As shown in Figure 6, the 1H NMR spectra
are diagnostic for determining the stereochemistry. Thus, the
methylene protons of 7a-A appear in a higher field compared
Stereochemical Stability of Atropisomers of Seven-Mem-
bered-Ring Benzolactams (7aꢀc and 8a). The stereochemical
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Table 1. Separation of the Atropisomers (A and B) and Their Stereochemical Stability
compd (axial chiralitya)
mp (°C)
ΔGq kJ/mol
conditions for isomerizationb
equilibrium ratio (A:B)
7a-A (aR)
B (aS)
173ꢀ175
124ꢀ127
196ꢀ198
196ꢀ198
142ꢀ144
oilf
102.5
99.4
37 °C, 10 hc
37 °C, 8 h
50 °C, 14 hd
50 °C, 12 he
37 °C, 8 h
37 °C, 7 h
37 °C, 9 h
37 °C, 8 h
1:0.7
8a-A (aS)
B (aR)
106.9
105.8
100.8
99.2
1:0.9
1:0.9
1:0.8
7b-A (aR)
B (aS)
7c-A (aR)
52ꢀ54
78ꢀ80
101.9
B (aS)
99.8
a See ref 14. b To the equilibrium state in toluene. c At 50 °C, 2 h. d At 37 °C after 7 h, isomerized to 71% de. e At 37 °C after 7 h, isomerized to 60% de.
f 85% de.
stability of these separated diastereomers of 7aꢀc and 8a was next
examined at 37 °C (or 50 °C) in toluene. The activation
free energy barrier to rotation (ΔGq)17 and the conditions required
for isomerization to the equilibrium state are shown in Table 1. The
diastereomers7a-AandB showed ΔGq values of 102.5 and 99.4 kJ/
mol, respectively, which may reflect the equilibrium ratio of 1:0.7.
The higher stereochemical stability of 8a-A (106.9 kJ/mol)
compared with 7a-A (102.5 kJ/mol) is well explained because of
the steric bulkiness of phenyl vs Cl. The stability of benzolactams
7b (A/B) and 7c (A/B) was revealed to be almost the same as that
of 7a (A/B), which reached the equilibrium state at 37 °C for 7 to
10 h. Hereagain, the energybarrier to rotation of type A was shown
to be slightly higher than that of type B.
and 1,3,4,5-tetrahydro-2H-1-benzoazepin-2-one (1c)12 were prepared
according to the reported procedure, which were used for the prepara-
tion of the benzolactams with a chloro substituent at the ortho position
of the benzene ring (2a, 2b, and 2c) as described below.
9-Chloro-5-methyl-1,3,4,5-tetrahydro-2H-1,5-benzo-
diazepin-2-one (2a). (1) Concentrated H2SO4 (98%, 15 mL) was
added by portions to a mixture of 3-chloro-N-methyl-2-nitroaniline18
(5.75 g, 30.8 mmol) and acrylic acid (25 mL, 308 mmol) in H2O
(27 mL). The mixture was stirred at 80 °C for 5 h. After being cooled to
room temperature, the mixture was extracted with EtOAc. The extract
was washed with H2O and brine and dried. Removal of the solvent gave
yellow crystals which were collected and washed with i-Pr2O to afford
N-(3-chloro-2-nitrophenyl)-N-methyl-β-alanine (5.59 g, 70%): mp
1
126ꢀ129 °C; H NMR (400 MHz, CDCl3) δ 2.55 (t, J = 7.3 Hz,
2H), 2.77 (s, 3H), 3.34 (t, J = 7.3 Hz, 2H), 7.16 (dd, J = 0.9, 8.0 Hz, 1H),
7.17 (dd, J = 0.9, 8.3 Hz, 1H), 7.34 (dd, J = 8.0, 8.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 32.6, 42.3, 51.4, 121.1, 124.6, 125.8, 130.8, 145.6,
176.6; IR (KBr) 2966, 1714, 1594 cmꢀ1; HRMS (ESI) m/z calcd for
C10H10N2O4Cl 257.0335 (M ꢀ H)ꢀ, found 257.0349.
’ CONCLUSION
In conclusion, atropisomers of seven-membered-ring benzolac-
tams (I) (1,5-benzodiazepin-2-one, 1,5-benzothiazepin-4-one, and
1-benzazepin-2-one) were separated as diastereomers, and the
conformation was first clarified from the viewpoint of the atropi-
somerism. The axial chirality at the arylꢀamide bond is often
overlooked, although it exists in various forms as observed in the
dibenzo[b,d]azepin-6-ones (II). These results may support our
assumption that the two axial chiralities exist in II and move together
like a gear and may prove the relevance of the atropisomeric
structures of these heterocycles to the biological activity. We hope
that this work provides useful information for future drug design.
(2) To a stirred solution of N-(3-chloro-2-nitrophenyl)-N-methyl-
β-alanine (250 mg, 0.97 mmol) in 1,4-dioxane (2.4 mL) and H3PO4
(85%, 0.57 mL) was added Zn powder (474 mg, 7.25 mmol) by portions
at 80 °C. The mixture was refluxed for 5 h. After being cooled to room
temperature, the mixture was filtered. The filtrate was poured into
aq NaHCO3, and the aqueous mixture was extracted with EtOAc.
The extract was washed with H2O and brine and dried. Removal
of the solvent gave colorless crystals that were collected and washed
1
with i-Pr2O to afford 2a (114 mg, 56%): mp 159ꢀ162 °C; H NMR
(400 MHz, CDCl3) δ 2.52 (t, J = 7.3 Hz, 2H), 2.84 (s, 3H), 3.54
(t, J = 7.3 Hz, 2H), 6.95 (dd, J = 1.7, 7.3 Hz, 1H), 7.07 (dd, J = 1.7, 8.0 Hz,
1H), 7.09 (dd, J = 7.3, 8.0 Hz, 1H), 7.22 (br, 1H); 13C NMR (100 MHz,
CDCl3) δ 33.7, 41.5, 58.2, 118.1, 122.7, 125.9, 126.1, 129.4, 144.0,
’ EXPERIMENTAL SECTION
The NH-lactams 5-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-
2-one (1a),10 2,3-dihydro-1,5-benzo[b][1,4]thiazepine-4(5H)-one(1b),11
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172.4; IR (KBr) 3178, 1680 cmꢀ1; HRMS (ESI) m/z calcd for
C10H12N2OCl 211.0633 (M þ H)þ, found 211.0632.
After being cooled to room temperature, the mixture was poured into
iceꢀwater. Pale yellow crystals separated were collected by filtration and
washed with H2O and hexane to afford 8-chloro-3,4-dihydronaphthalen-
1(2H)-one oxime (6.30 g, 92%): mp 159ꢀ161 °C; 1H NMR (400 MHz,
CDCl3) δ 1.79 (tt, J = 6.1, 6.8 Hz, 2H), 2.65 (t, J = 6.1 Hz, 2H), 2.87
(t, J = 6.8 Hz, 2H), 7.07 (dd, J = 0.7, 7.5 Hz, 1H), 7.14 (dd, J = 7.5, 8.0 Hz,
1H), 7.32 (dd, J = 0.7, 8.0 Hz, 1H), 9.30 (br, 1H); 13C NMR (100 MHz,
CDCl3) δ 21.0, 24.8, 31.0, 126.4, 128.8, 128.9, 129.5, 131.4, 143.8,
153.9; IR (KBr) 3231 cmꢀ1; HRMS (ESI) m/z calcd for C10H10ClNO
196.0524 (M þ H)þ, found 196.0524. The oxime thus obtained is the
sole isomer, whose stereochemistry is presumed to be (E).
5-Methyl-9-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzo-
diazepin-2-one (3a). To a stirred solution of 2a (594 mg, 2.82
mmol) in a mixture of N,N-dimethylacetamide (DMA) (17.1 mL) and
H2O (0.9 mL) were added tris(dibenzylideneacetone)dipalladium (0)
(Pd2(dba)3) (65 mg, 2.5 mol %), 2-dicyclohexcylphosphino-20,40,60-
triisopropylbiphenyl (Xphos) (81 mg, 6 mol %), and K2CO3 (779 mg,
5.64 mmol). After being stirred at 25 °C for 1 h under argon, the mixture
was treated with phenylboronic acid (1.03 g, 8.46 mmol) and stirred at
100 °C for 7 h under argon. After being cooled to room temperature, the
mixture was filtered through Celite. The filtrate was poured into H2O,
and the aqueous mixture was extracted with EtOAc. The extract was
washed with brine and dried. After removal of the solvent, the residue was
purified by column chromatography (silica gel, EtOAc/hexane = 1/3) to
(2) The mixture of the oxime (6.00 g, 30.6 mmol) and polypho-
sphoric acid (PPA) (104 g) was stirred at 95 °C for 1 h and then cooled
to room temperature. The mixture was poured into iceꢀwater and
extracted with EtOAc. The extract was washed successively with H2O,
saturated NaHCO3, and H2O and dried. Removal of the solvent gave a
white solid, which was purified by column chromatography (silica gel,
EtOAc/hexane = 1/4 to 1/1) to afford 2c (3.10 g, 52%) and 9-chloro-
2,3,4,5-tetrahydro-1H-2-benzoazepin-1-one (2c-regio isomer) (2.80 g,
1
afford 3a as colorless crystals (656 mg, 92%): mp 127ꢀ130 °C; H
NMR (400 MHz, CDCl3) δ 2.60 (t, J = 7.0 Hz, 2H), 2.88 (s, 3H), 3.56
(t, J = 7.0 Hz, 2H), 6.71 (br,1H), 6.98 (dd, J = 1.4, 7.5 Hz, 1H), 7.07 (dd,
J = 1.2, 8.0 Hz, 1H), 7.24 (dd, J = 7.3, 7.8 Hz, 1H), 7.30ꢀ7.32 (m, 2H),
7.35ꢀ7.39 (m, 1H), 7.41ꢀ7.45 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 33.9, 41.6, 58.5, 118.9, 123.8, 126.0, 127.8, 128.8, 129.2, 134.7, 137.9,
143.0, 172.9; IR (KBr) 3055, 1670 cmꢀ1; HRMS (ESI) m/z calcd for
C16H17N2O 253.1335 (M þ H)þ, found 253.1333.
1
47%) as colorless crystals. Data for 2c: mp 162ꢀ164 °C; H NMR
(400 MHz, CDCl3) δ 2.26 (quin, J = 6.8, 7.2 Hz, 2H), 2.38 (t, J = 7.2 Hz,
2H), 2.83 (t, J = 6.8 Hz, 2H), 7.08 (t, J = 7.8 Hz, 1H), 7.14 (dd, J = 1.4,
7.8 Hz, 1H), 7.22 (1H, b), 7.31 (dd, J = 1.4, 7.8 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 28.4, 30.8, 32.8, 125.8, 126.0, 127.8, 128.2, 134.8, 136.0,
173.7; IR (KBr) 3190, 1656 cmꢀ1; HRMS (ESI) m/z calcd for
C10H10ClNO 196.0524 (M þ H)þ, found 196.0524. Data for 2c-
6-Chloro-2,3-dihydro-1,5-benzo[b][1,4]thiazepine-4(5H)-
one (2b). To a stirred solution of 2-amino-3-chlorothiophenol19 (0.80 g,
5.0 mmol) in pyridine (6.0 mL) was added β-propiolactone (0.31 mL,
5.0 mmol) at 25 °C, and the mixture was stirred for 30 min. To the
mixture was added acetic anhydride (6.0 mL) dropwise over a period of
1 h with stirring. After being stirred at 5 °C for 14 h, the mixture was
concentrated. To the concentrate was added EtOAc, and the mixture
was washed successively with H2O, 2 N HCl, H2O, aq NaHCO3, and H2O
and dried. The organic layer was evaporated to afford 2b as colorless
1
regioisomer: mp 192ꢀ195 °C; H NMR (400 MHz, CDCl3) δ 1.96
(br, 2H), 2.83 (br, 2H), 3.11 (br, 2H), 6.51 (br, 1H), 7.10 (dd, J = 0.8, 7.8
Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.37 (dd, J = 0.8, 7.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 30.1, 30.3, 39.0, 126.7, 128.9, 131.0, 132.4,
132.9, 139.4, 169.5; IR (KBr) 3190, 1656 cmꢀ1; HRMS (ESI) m/z calcd
for C10H10ClNO 196.0524 (M þ H)þ, found 196.0526.
1
crystals (755 mg, 3.53 mmol, 71%): mp 168ꢀ170 °C; H NMR (400
9-Phenyl-1,3,4,5-tetrahydro-2H-1-benzoazepin-2-one (3c).
To a stirred solution of 2c (81 mg, 0.41 mmol) in a mixture of DMA
(2.8mL) andH2O (0.25 mL) were added Pd2(dba)3 (57mg, 0.060mmol),
Xphos (74 mg, 0.015 mmol), and K2CO3 (114 mg, 0.830 mmol). After
being stirred at 25 °C for 1 h under argon atmosphere, the mixture was
treated with phenylboronic acid (91 mg, 0.75 mmol) and stirred at 100 °C
for 50 h under argon atmosphere. After being cooled to room tempera-
ture, the mixture was filtered through Celite, and the filtrate was poured
into H2O. The aqueous mixture was extracted with EtOAc, and the extract
was washed with brine, dried, and evaporated. After removal of the
solvent, the residue was purified by column chromatography (silica gel,
EtOAc/hexane = 1/6) to afford 3c as a white solid (87 mg, 88%): mp
148ꢀ149 °C; 1H NMR (400 MHz, CDCl3) δ 2.29 (tt, J = 7.0, 7.3 Hz,
2H), 2.45 (t, J = 7.3 Hz, 2H), 2.84 (t, J = 7.0 Hz, 2H), 6.83 (br, 1H),
7.20ꢀ7.25 (m, 3H), 7.29ꢀ7.31 (m, 2H), 7.35ꢀ7.39 (m, 1H), 7.41ꢀ7.46
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 28.4, 30.6, 32.8, 125.5, 127.6,
128.6, 128.7, 128.9, 134.3, 134.6, 134.7, 137.7, 174.0; IR (KBr) 3054,
1664 cmꢀ1; HRMS (ESI) m/z calcd for C16H15NO238.1226 (M þ H)þ,
found 238.1237.
MHz, CDCl3) δ 2.64 (t, J = 6.9 Hz, 2H), 3.45 (t, J = 6.9 Hz, 2H), 7.10
(t, J = 7.9 Hz, 1H), 7.30(s, 1H), 7.42 (dd, J = 1.4, 7.9 Hz, 1H), 7.51 (dd,
J = 1.4, 7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 33.7, 34.5, 126.6,
127.2, 128.6, 130.3, 134.1, 138.8, 172.2; IR (KBr) 3112, 1672 cmꢀ1
;
HRMS (ESI) m/z calcd for C9H8ClNOS 214.0080 (M þ H)þ, found
214.0088.
2,3-Dihydro-6-phenyl-1,5-benzo[b][1,4]thiazepine-4(5H)-
one (3b). To a stirred solution of 2b (106 mg, 0.5 mmol) in a mixture of
DMA (3.0 mL) and H2O (0.16 mL) were added Pd2(dba) (46 mg, 10
mol %), Xphos (57 mg, 24 mol %), and K2CO3 (138 mg, 1.0 mmol).
After being stirred at room temperature for 1 h under argon atmosphere,
the mixture was treated with phenylboronic acid (487 mg, 4.0 mmol)
and stirred at 100 °C for 7 h under argon atmosphere. After being cooled
to room temperature, the mixture was filtered through Celite. The
filtrate was poured into H2O. The aqueous mixture was extracted with
EtOAc, and the extract was washed with H2O and dried. After removal of
the solvent, the oily residue was purified by column chromatography
(silica gel, EtOAc/hexane = 1:3) to give 3b as colorless crystals (123 mg,
97%): mp 175ꢀ177 °C; 1H NMR (400 MHz, CDCl3) δ 2.74 (t, J = 6.8
Hz, 2H), 3.48 (t, J = 6.8 Hz, 2H), 6.86 (br, 1H), 7.23 (t,
J = 7.5 Hz, 1H), 7.28ꢀ7.34 (m, 3H), 7.36ꢀ7.47 (m, 3H), 7.63 (dd, J
= 1.4, 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 33.7, 34.3, 100.5,
126.2, 127.2, 128.1, 128.9, 129.0, 131.1, 134.7, 135.9, 138.6, 172.4; IR
(KBr) 2918, 1674 cmꢀ1; HRMS (ESI) m/z calcd for C15H13NOS
256.0791 (M þ H)þ, found 256.0793.
Preparation of Methyl (1,5-Benzodiazepin-1-yl)acetates
4a, 5a, and 6a: Methyl (5-methyl-2-oxo-2,3,4,5-tetrahydro-
1H-1,5-benzodiazepin-1-yl)acetate (4a). To a solution of 1a10
(1.00 g, 5.67 mmol) in DMF (16 mL) was added NaH (60%, 681 mg, 17
mmol) at ꢀ20 °C, and the mixture was stirred at ꢀ20 °C for 15 min.
Then methyl bromoacetate (2.7 mL, 28.4 mmol) was added to the
mixture, and stirring was continued at ꢀ20 °C for 2.5 h. After being
warmed to room temperature, the mixture was poured into H2O. The
aqueous mixture was extracted with EtOAc, and the combined organic
layer was washed with H2O and dried. After removal of the solvent, the
residue was purified by column chromatography (silica gel, EtOAc/
9-Chloro-1,3,4,5-tetrahydro-2H-1-benzoazepin-2-one (2c)
and 2c-Regioisomer via the Beckmann Rearrangement of
8-Chloro-3,4-dihydronaphthalen-1(2H)-one Oxime. (1) A
mixture of 8-chloro-3,4-dihydro-1(2H)-naphthalenone20 (6.30 g,
34.9 mmol), hydroxylamine hydrochloride (7.20 g, 104 mmol), sodium
acetate (8.64 g, 105 mmol), and EtOH (350 mL) was refluxed for 1.5 h.
1
dichloromethane =1:5) to give 4a as a colorless oil (1.26 g, 89%): H
NMR (400 MHz, CDCl3) δ 2.52 (tꢀbr, J = 6.8 Hz, 2H), 2.81 (s, 3H),
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3.43 (br, 2H), 3.80 (s, 3H), 4.41 (br, 2H), 7.01ꢀ7.06 (m, 2H), 7.14 (dd,
J = 1.4, 7.8 Hz, 1H), 7.22 (ddd, J = 1.4, 7.8, 8.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 34.0, 41.0, 50.9, 52.4, 58.7, 119.3, 122.3, 122.8,
137.5, 143.2, 170.0, 172.3; IR (neat) 3489, 1752, 1676 cmꢀ1; HRMS
(ESI) m/z calcd for C13H17N2O3 249.1234 (M þ H)þ, found 249.1235.
Compounds 5a and 6a were prepared from the corresponding 1,5-
benzodiazepinones (2a, 3a) according to a similar procedure described
for the preparation of 4a from 1a.
Preparation of Methyl (1-Benzoazepinyl)acetate: 4c, 5c,
and 6c. Compounds 4c, 5c, and 6c were prepared from the corre-
sponding 1-benzoazepinones (1c,12 2c, 3c) according to a similar
procedure described for the preparation of 4a from 1a.
Methyl (2-oxo-2,3,4,5-tetrahydro-1H-1-benzoazepin-
1-yl)acetate (4c): white solid (93%); mp 79ꢀ80 °C; 1H NMR (400
MHz, CDCl3) δ 2.20 (br, 2H), 2.35 (br-t, J = 6.8 Hz, 2H), 2.92 (br, 2H),
3.74 (s, 3H), 4.51 (s, 2H), 7.11ꢀ7.22 (m, 3H), 7.25ꢀ7.29 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ28.8, 29.8, 32.8, 49.8, 52.2, 122.0, 126.4, 127.4,
129.4, 135.8, 142.2, 169.6, 173.2; IR (KBr) 2954, 1746, 1672 cmꢀ1; HRMS
(ESI) m/z calcd for C13H15NO3 234.1125 (M þ H)þ, found 234.1125.
Methyl (9-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzoa-
zepin-1-yl)acetate (5c): white solid (90%); mp 92ꢀ94 °C; 1H
NMR (400 MHz, CDCl3) δ 1.88ꢀ1.98 (m, 1H), 2.22ꢀ2.44 (m, 3H),
2.65 (dd, J = 6.5, 13.4 Hz, 1H), 3.48ꢀ3.72 (m, 1H), 3.69 (s, 3H), 4.11 (d,
J = 17.3 Hz, 1H), 4.88 (d, J = 17.3 Hz, 1H), 7.14ꢀ7.20 (m, 2H), 7.34
(dd, J = 2.1, 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 28.3, 29.7,
32.2, 49.3, 52.0, 127.9, 128.3, 128.7, 129.0, 138.7, 140.0, 169.5, 173.5; IR
(KBr) 2950, 1742, 1673 cmꢀ1; HRMS (ESI) m/z calcd for
C13H14NO3Cl 290.0554 (M þ Na)þ, found 290.0554.
Methyl (9-chloro-5-methyl-2-oxo-2,3,4,5-tetrahydro-1H-
1,5-benzodiazepin-1-yl)acetate (5a): colorless oil (97%); 1H
NMR (400 MHz, CDCl3) δ 2.39 (ddd, J = 1.2, 5.6, 12.9 Hz, 1H),
2.57 (ddd, J = 7.0, 12.9, 13.1 Hz, 1H), 2.84 (s, 3H), 3.09 (ddd, J = 1.2, 7.0,
10.0 Hz, 1H), 3.70 (s, 3H), 3.74 (ddd, J = 5.6, 10.0, 13.1 Hz, 1H,), 4.24
(d, J = 17.0 Hz, 1H), 4.53 (d, J = 17.0 Hz, 1H), 7.00 (dd, J = 1.4, 8.0 Hz,
1H), 7.12 (dd, J = 1.4, 8.0 Hz, 1H), 7.19 (dd, J = 8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 33.6, 41.1, 49.6, 52.0, 58.2, 118.2, 124.4, 128.2,
130.4, 133.9, 146.6, 168.6, 173.1; IR (neat) 3355, 1750, 1681 cmꢀ1
;
HRMS (ESI) m/z calcd for C13H16N2O3Cl 283.0844 (M þ H)þ, found
283.0830.
Methyl (5-methyl-2-oxo-9-phenyl-2,3,4,5-tetrahydro-1H-
1,5-benzodiazepin-1-yl)acetate (6a): colorless crystals (82%);
Methyl (2-oxo-9-phenyl-2,3,4,5-tetrahydro-1H-1-benzoa-
1
1
mp 157ꢀ159 °C; H NMR (400 MHz, CDCl3) δ 2.49 (dd, J = 5.3,
zepin-1-yl) acetate (6c): hite solid (97%); mp 150ꢀ153 °C; H
12.7 Hz, 1H), 2.84 (ddd, J = 7.3, 12.7, 13.1 Hz, 1H), 2.90 (s, 3H), 3.18
(d, J = 17.0 Hz, 1H), 3.20 (dd, J = 7.3, 10.0 Hz, 1H), 3.52 (s, 3H), 3.81
(ddd, J = 5.3, 10.0, 13.1 Hz, 1H), 4.15 (d, J = 17.0 Hz, 1H), 7.04 (dd, J =
1.4, 7.5 Hz, 1H), 7.09 (dd, J = 0.9, 8.3 Hz, 1H), 7.31ꢀ7.37 (m, 4H),
7.40ꢀ7.43 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 34.1, 41.1, 49.4,
51.7, 58.2, 118.7, 125.0, 127.7, 127.9, 128.4, 128.9, 134.0, 136.6, 139.0,
145.4, 168.6, 173.5; IR (KBr) 2949, 1737, 1669 cmꢀ1; HRMS (ESI) m/z
calcd for C19H21N2O3 325.1547 (M þ H)þ, found 325.1531.
Preparation of Methyl (1,5-Benzothiazepinyl)acetate: 4b,
5b, and 6b. Compounds 4b, 5b, and 6b were prepared from the
corresponding 1,5-benzothiazepinones (1b,11 2b, 3b) according to a
similar procedure described for the preparation of 4a from 1a.
Methyl (3,4-dihydro-4-oxo-1,5-benzothiazepin-5(2H)-
yl)acetate (4b): colorless oil (97%); 1H NMR (600 MHz, CDCl3) δ
2.65 (br, 2H), 3.40 (br, 2H), 3.80 (s, 3H), 4.00 (br, 1H), 4.90 (br, 1H),
7.22 (ddd, J = 1.3, 7.4, 7.4 Hz, 1H), 7.33 (dd, J = 1.3, 7.4 Hz, 1H), 7.41
(ddd, J = 1.6, 7.4, 7.4 Hz, 1H), 7.62 (dd, J = 1.6, 7.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 33.8, 34.1, 51.0, 52.4, 123.6, 127.2, 127.7, 130.7,
135.7, 146.8, 169.7, 171.7; IR (neat) 2953, 1750, 1672 cmꢀ1; HRMS
(ESI) m/z calcd for C12H13NO3S 252. 0685 (M þ H)þ, found
252.0694.
NMR (400 MHz, CDCl3) δ 1.99ꢀ2.09 (m, 1H), 2.41ꢀ2.49 (m, 2H),
2.53ꢀ2.59 (m, 1H), 2.69 (dd, J = 6.3, 13.4 Hz, 1H), 3.11 (d, J = 17.3 Hz,
1H), 3.59 (s, 3H), 3.70 (ddd, J = 6.8, 7.0, 13.4 Hz, 1H), 4.17
(d, J = 17.3 Hz, 1H), 7.23 (dd, J = 2.6, 6.5 Hz, 1H), 7.27ꢀ7.32
(m, 4H), 7.34ꢀ7.38 (m, 1H), 7.41ꢀ7.45 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 28.5, 29.7, 32.7, 49.6, 51.8, 127.5, 127.7, 128.2, 128.7,
129.0, 129.7, 136.0, 138.1, 138.9, 139.0, 169.4, 174.0; IR (KBr) 2952,
1755, 1666 cmꢀ1; HRMS (ESI) m/z calcd for C19H19NO3 332.1257
(M þ Na)þ, found 332.1272.
2-(9-Chloro-5-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1,5-
benzodiazepin-1-yl)-N-[(1S)-1-phenylethyl]acetamide (7a)
and the Atropisomers 7a-A and 7a-B. 1) To a solution of 5a
(1.00 g, 3.54 mmol) in MeOH (10 mL) was added 1 N NaOH aq
(30 mL). After being stirred at 25 °C for 2 h, the mixture was acidified
with 2 N HCl and extracted with EtOAc. The extract was dried and
concentrated to afford 9-chloro-5-methyl-2-oxo-2,3,4,5-tetrahydro-1H-
1,5-benzodiazepin-1-yl)acetic acid (5a-CO2H) as a white solid (662 mg,
70%): mp 145ꢀ147 °C; 1H NMR (400 MHz, CDCl3) δ 2.47 (ddd, J =
0.9, 6.1, 13.1 Hz, 1H), 2.54 (ddd, J = 7.3, 12.4, 13.1 Hz, 1H), 2.89 (s,
3H), 3.06 (ddd, J = 0.9, 7.3, 10.5 Hz, 1H), 3.78 (ddd, J = 6.1, 10.5, 12.4
Hz, 1H), 4.01 (d, J = 17.0 Hz, 1H), 5.06 (d, J = 17.0 Hz, 1H), 7.20 (dd,
J = 2.6, 6.5 Hz, 1H), 7.37ꢀ7.42 (m, 2H), 12.43 (br, 1H); 13C NMR (100
MHz, CDCl3) δ 32.9, 40.6, 50.1, 58.9, 118.5, 127.6, 129.8, 130.4, 134.4,
144.6, 169.1, 172.2; IR (KBr) 3334, 1750, 1683 cmꢀ1; HRMS (ESI) m/z
calcd for 269.0687 C12H14N2O3Cl (M þ H)þ, found 269.0679.
(2) To a solution of5a-CO2H (150 mg, 0.558 mmol) in THF(4.5 mL)
were added N-hydroxybenzotriazole (HOBt) (82.9 mg, 0.614 mmol),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (321 mg, 1.67
mmol), and (S)-(ꢀ)-1-phenethylamine ((S)-PEA) (0.36 mL, 2.8
mmol). The mixture was stirred at 25 °C for 3 h. After removal of the
solvent, the residue was poured into aq NaHCO3. The aqueous solution
was extracted with EtOAc, and the extract was washed successively with
aq NaHCO3, H2O, dilute HCl, and H2O and dried. Removal of the
solvent gave a mixture of the diastereomers 7a-A and 7a-B (ratio 1: 0.67
determined by 1H NMR) as a white foam (166 mg, 80%). The mixture
was separated and purified by column chromatography (silica gel, EtOAc/
hexane = 1:2) to give 7a-A (aR,S) (isolated yield: 69 mg, 34%) and 7a-B
Methyl (6-chloro-3,4-dihydro-4-oxo-1,5-benzothiazepin-
1
5(2H)-yl)acetate (5b): colorless crystals (98%); mp 93ꢀ96 °C; H
NMR (400 MHz, CDCl3) δ 2.54 (ddd, J = 7.6, 12.4, 12.6 Hz, 1H), 2.67
(ddd, J = 1.8, 6.0, 12.6 Hz, 1H), 3.29ꢀ3.41 (m, 2H), 3.73 (s, 3H), 4.29
(d, J = 16.8 Hz, 1H), 4.54 (d, J = 16.8 Hz, 1H), 7.22 (dd, J = 7.5, 8.0 Hz,
1H), 7.49 (dd, J = 1.2, 8.0 Hz, 1H), 7.59 (dd, J = 1.2, 7.5 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 33.4, 33.9, 49.4, 52.0, 128.5, 129.9, 131.8,
132.1, 134.7, 168.2, 172.1; IR (KBr) 2951, 1761, 1735 cmꢀ1; HRMS (ESI)
m/z calcd for C12H12NO3SCl 308.0119 (M þ Na)þ, found 308.0107.
This compound was subjected to X-ray crystallographic analysis.
Methyl (3,4-dihydro-4-oxo-6-phenyl-1,5-benzothiazepin-
5(2H)-yl)acetate (6b): white solid (76%); mp 136ꢀ138 °C; 1H NMR
(400 MHz, CDCl3) δ 2.76 (ddd, J = 1.9, 6.3, 12.4 Hz, 1H), 2.84 (ddd,
J = 7.0, 12.4, 12.4 Hz, 1H), 3.23 (d, J = 16.8 Hz, 1H), 3.39 (ddd, J = 6.3,
12.4, 12.4 Hz, 1H), 3.47 (ddd, J = 1.9, 7.0, 12.4 Hz, 1H), 3.55 (s, 3H),
4.16 (d, J= 16.8 Hz, 1H), 7.29ꢀ7.46 (m, 7H), 7.66 (dd, J = 1.7, 7.5 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 33.7, 33.8, 49.5, 51.7, 127.9, 128.1, 128.1,
129.1, 130.7, 132.3, 135.1, 137.5, 138.3, 168.3, 172.5; IR (KBr) 2957,
1737, 1670 cmꢀ1; HRMS (ESI) m/z calcd for C18H17NO3S 328.1002
(M þ H)þ, found 328.1000.
(aS,S) (isolated yield: 45 mg, 22%). 7a-A (aR,S): colorless crystals; mp
1
173ꢀ175 °C; [R]21 þ111.2 (c 0.30, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 1.37 (d, J = 6.8 Hz, 3H), 2.19 (s, 3H), 2.34 (dd, J = 5.9, 12.9
Hz, 1H), 2.43 (ddd, J = 5.9, 7.3, 12.9 Hz, 1H), 2.70 (dd, J = 7.3, 10.3 Hz,
1H), 3.28 (ddd, J = 5.9, 10.3, 12.9 Hz, 1H), 4.02 (d, J = 17.3 Hz, 1H),
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4.91 (d, J = 17.3 Hz, 1H), 5.17 (quin, J = 6.8 Hz, 1H), 6.99 (t, J = 4.6 Hz,
1H), 7.26ꢀ7.27 (m, 3H), 7.38ꢀ7.40 (m, 4H), 8.30 (br-d, J = 6.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 20.2, 33.2, 40.2, 47.1, 51.9, 58.5,
118.1, 126.5, 127.2, 128.4, 128.9, 129.9, 134.3, 142.6, 145.4, 167.3, 171.8;
IR (KBr) 3236, 1685, 1664 cmꢀ1; HRMS (ESI) m/z calcd for
C20H23N3O2Cl 372.1473 (M þ H)þ, found 372.1454. 7a-B (aS,S):
colorless crystals; mp 124ꢀ127 °C; [R]21D ꢀ44.9 (c 0.30, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 1.51 (d, J = 7.1 Hz, 3H), 2.25 (s, 3H), 2.39
(dd, J = 5.6, 12.9 Hz, 1H), 2.51 (ddd, J = 5.6 7.3, 12.9 Hz, 1H), 2.94 (dd, J
= 7.3, 10.5 Hz, 1H), 3.65 (ddd, J = 5.6, 10.5, 12.9 Hz, 1H), 4.08 (d, J =
17.3 Hz, 1H), 4.98 (d, J = 17.3 Hz, 1H), 5.15 (quin, J = 7.1 Hz, 1H), 6.92
(dd, J = 4.6, 8.8 Hz, 1H), 7.03ꢀ7.06 (m, 2H), 7.17ꢀ7.22 (m, 2H),
7.26ꢀ7.27 (m, 3H), 8.08 (br-d, J = 7.1 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 21.0, 33.3, 40.3, 47.5, 51.2, 59.2, 118.0, 126.2, 126.5, 127.0,
128.3, 128.8, 129.8, 133.9, 143.0, 145.4, 167.2, 171.8; IR (KBr) 3246,
1682, 1670 cmꢀ1; HRMS (ESI) m/z calcd for C20H23N3O2Cl 372.1473
(M þ H)þ, found 372.1454.
according to a similar procedure described for the preparation of 7a
from 5a.
(9-Chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-
yl)acetic acid (5c-CO2H): white solid (90%); mp 143ꢀ145 °C; 1H
NMR (400 MHz, CDCl3) δ1.88ꢀ1.97(m, 1H),2.21ꢀ2.42(m, 3H), 2.62
(dd, J=6.5, 13.6 Hz, 1H),3.57 (ddd, J= 7.3, 13.4, 13.6 Hz, 1H), 4.17 (d, J=
17.5 Hz, 1H), 4.83 (d, J = 17.5 Hz, 1H), 7.14 (dd, J = 1.7, 7.5 Hz, 1H), 7.19
(dd, J = 7.5, 7.8 Hz, 1H), 7.35 (dd, J = 1.7, 7.8 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 28.3, 29.8, 32.1, 49.5, 128.0, 128.5, 128.7, 129.0, 138.5,
139.8, 173.0, 174.1; IR (KBr) 2944, 1745, 1624 cmꢀ1; HRMS (ESI) m/z
calcd for C12H12NO3Cl 276.0398 (M þ Na)þ, found 276.0397.
2-(9-Chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzoazepin-
1-yl)-N-[(1S)-1-phenylethyl]acetamide (7c). The mixture (with a
ratio of 1:0.8 determined by 1H NMR) of the diastereomers of 7c-A and
7c-B was obtained as a white foam (yield 87%). The foam was
chromatographed on SiO2 to separate the diastereomers 7c-A (aR,S)
and 7c-B (aS,S). 7c-A (aR,S): colorless crystals (isolated yield: 36%); mp
52ꢀ54 °C; [R]24D ꢀ19.1 (c 0.2, MeOH); 1H NMR (400 MHz, CDCl3)
δ 1.47 (d, J = 7.0 Hz, 3H), 1.78ꢀ1.84 (m, 1H), 2.09ꢀ2.30 (m, 3H), 2.37
(dd, J = 7.3, 10.3 Hz, 1H), 2.84 (ddd, J = 5.9, 10.3, 12.9 Hz, 1H), 3.97
(d, J = 14.9 Hz, 1H), 4.69 (d, J = 14.9 Hz, 1H), 5.08 (quin, J = 7.0 Hz,
1H), 6.73 (br-d, J = 7.6 Hz, 1H), 7.05 (dd, J = 1.2, 7.5 Hz, 1H), 7.15 (t, J =
7.5 Hz, 1H), 7.23ꢀ7.35 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 22.0,
28.3, 29.5, 32.2, 48.8, 52.2, 125.9, 126.0, 127.1, 127.6, 128.3, 128.4, 128.4,
128.7, 128.9, 138.8, 139.3, 142.8, 167.1, 174.3; IR (KBr) 3306, 2931,
1656 cmꢀ1; HRMS (ESI) m/z calcd for C20H21N2O2Cl 379.1184
(M þ Na)þ, found 379.1181. 7c-B (aS,S): colorless crystals (isolated
2-(6-Chloro-3,4-dihydro-4-oxo-1H-1,5-benzothiazepin-1-
yl)-N-[(1S)-1-phenylethyl]acetamide (7b) and the Atropi-
somers 7b-A and 7b-B. Compounds 7b was prepared from the
corresponding acetate (5b) via the carboxylic acid (5b-CO2H) accord-
ing to a similar procedure described for the preparation of 7a from 5a.
(6-Chloro-3,4-dihydro-4-oxo-1H-1,5-benzothiazepin-1-yl)-
acetic acid (5b-CO2H): white solid (88%); mp144ꢀ146 °C; 1H NMR
(600 MHz, DMSO-d6) δ 2.41 (ddd, J = 7.3, 12.8, 12.8 Hz, 1H), 2.51 (ddd,
J = 1.1, 6.2, 12.8 Hz, 1H), 3.21 (ddd, J = 6.2, 11.7, 12.8 Hz, 1H), 3.33 (ddd,
J = 1.1, 7.3, 11.7 Hz, 1H), 4.13 (d, J = 17.2 Hz, 1H), 4.17 (d, J = 17.2 Hz,
1H), 7.34 (dd, J = 7.6, 8.4 Hz, 1H), 7.61 (dd, J = 1.4, 7.6 Hz, 1H), 7.64 (dd,
J = 1.4, 8.4 Hz, 1H), 12.4 (br, 1H); 13C NMR (150 MHz, d-DMSO)
δ 32.9, 33.5, 49.3, 128.9, 129.1, 131.2, 132.0, 134.7, 142.9, 168.5, 171.6;
IR (KBr) 2918, 1747, 1632 cmꢀ1; HRMS (ESI) m/z calcd for
C11H10NO3SCl 293.9962 (M þ Na)þ, found 293.9947.
yield: 31%); mp 78ꢀ80 °C; [R]24 ꢀ217.4 (c 0.2, MeOH); 1H NMR
D
(400 MHz, CDCl3) δ 1.53 (d, J = 7.0 Hz, 3H), 1.88ꢀ1.97 (m, 1H),
2.21ꢀ2.42 (m, 3H), 2.65 (dd, J = 7.3, 10.5 Hz, 1H), 3.44 (ddd, J = 5.6,
10.5, 12.9 Hz, 1H), 3.99 (d, J = 15.1 Hz, 1H), 4.61 (d, J = 15.1 Hz, 1H),
5.09 (quin, J = 7.0 Hz, 1H), 6.47 (br-d, J = 7.6 Hz, 1H), 7.12 (dd, J = 1.4,
7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.22ꢀ7.35 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 21.9, 28.4, 29.9, 32.3, 49.0, 52.4, 126.0, 127.2,
127.8, 125.5, 128.8, 128.9, 139.1, 139.5, 142.9, 167.4, 174.3; IR (KBr)
3309, 2942, 1654 cmꢀ1; HRMS (ESI) m/z calcd for C20H21N2O2Cl
357.1364 (M þ H)þ, found 357.1370.
2-(6-Chloro-3,4-dihydro-4-oxo-1H-1,5-benzothiazepin-1-
yl)-N-[(1S)-1-phenylethyl]acetamide (7b). The mixture (with a
ratio of 1:0.9 determined by 1H NMR) of the diastereomers of 7b-A and
7b-B was obtained as a colorless foam (yield 99%). The foam was treated
with Et2O to separate the diastereomers 7b-A (aR,S) and 7b-B (aS,S).
The diastereomer 7b-A was obtained as colorless crystals (isolated yield:
37%), and the diastereomer 7b-B wasobtainedfromthe motherliquor asa
colorless oily substance (isolated yield: 40% in a 85% de (B:A = 5.6:1)).
7b-A (aR,S): colorless crystals; mp 142ꢀ144 °C; [R]25D ꢀ107.8 (c 0.1,
MeOH); 1H NMR (400 MHz, CDCl3) δ 1.45 (d, J = 7.2 Hz, 3H), 2.46
(ddd, J = 7.2, 12.8, 12.8 Hz, 1H), 2.64 (ddd, J = 1.2, 5.6, 12.8 Hz, 1H),
3.15 (ddd, J = 5.6, 12.8, 12.8 Hz, 1H), 3.35 (ddd, J = 1.2, 7.2, 12.8 Hz,
1H), 4.07 (d, J = 16.6 Hz, 1H), 4.84 (d, J = 16.6 Hz, 1H), 5.11 (quin,
J = 7.2 Hz, 1H), 7.25ꢀ7.30 (m, 2H), 7.33ꢀ7.36 (m, 4H), 7.55 (dd,
J = 1.2, 8.2 Hz, 1H), 7.59 (dd, J = 1.2, 7.6 Hz, 1H), 7.90 (br-d, J = 7.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 21.7, 33.1, 34.1, 48.9, 52.8, 126.2,
127.1, 128.4, 129.2, 132.8, 134.5, 166.5, 171.6; IR (KBr) 3305,
1673 cmꢀ1; HRMS (ESI) m/z calcd for C19H19N2O2SCl 397.0748
2-(5-Methyl-2-oxo-9-phenyl-2,3,4,5-tetrahydro-1H-1,5-
benzodiazepin-1-yl)-N-[(1S)-1-phenylethyl]acetamide (8a)
and the Atropisomers 8a-A and 8a-B. Compound 8a was pre-
pared from the corresponding acetate (6a) via the carboxylic acid (6a-CO2H)
according to a similar procedure described for the preparation of 7a from 5a.
(5-Methyl-2-oxo-9-phenyl-2,3,4,5-tetrahydro-1H-1,5-ben-
zodiazepin-1-yl)acetic acid (6a-CO2H): white solid (94%); mp
179ꢀ183 °C; 1H NMR (400 MHz, CDCl3) δ 2.57 (dd, J = 5.6, 12.9 Hz,
1H), 2.82 (ddd, J = 7.3, 12.7, 12.9 Hz, 1H), 2.92 (s, 3H), 3.08 (d, J = 18.0
Hz, 1H), 3.14 (dd, J = 7.3, 10.5 Hz, 1H), 3.82 (ddd, J = 5.6, 10.5, 12.7 Hz,
1H), 4.49 (d, J = 18.0 Hz, 1H), 7.25 (dd, J = 1.2, 8.0 Hz, 1H), 7.30ꢀ7.35
(m, 3H), 7.39ꢀ7.47 (m, 3H), 7.50 (dd, J = 7.8, 8.0 Hz, 1H), 12.5 (br,
1H); 13C NMR (100 MHz, CDCl3) δ 33.2, 40.6, 50.1, 59.0, 118.8, 128.1,
128.3, 128.5, 129.1, 129.5, 134.5, 136.9, 137.8, 143.1, 169.4, 172.8; IR
(KBr) 3491, 1739, 1679 cmꢀ1; HRMS (ESI) m/z calcd for C18H19N2O3
311.1390 (M þ H)þ, found 311.1387.
(M þ Na)þ, found 397.0751. 7b-B (aS,S) (85% de): colorless oil; [R]25
D
þ21.099 (c 0.1, MeOH); 1H NMR (400 MHz, CDCl3) δ 1.52 (d, J = 7.2
Hz, 3H), 2.46 (ddd, J = 7.4, 12.8, 12.8 Hz, 1H), 2.65 (ddd, J = 1.6, 6.1,
12.8 Hz, 1H), 3.27 (ddd, J = 6.1, 12.8, 12.8, 1H), 3.37 (ddd, J = 1.6, 7.4,
12.8 Hz, 1H), 4.07 (d, J = 16.6 Hz, 1H), 4.89 (d, J = 16.6 Hz, 1H), 5.10
(quin, J = 7.2 Hz, 1H), 7.18ꢀ7.35 (m, 6H), 7.52 (dd, J = 0.6, 8.4 Hz,
2H), 7.83 (br-d, 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.7, 33.2,
34.1, 49.0, 52.3, 126.2, 128.3, 129.0, 130.3, 130.4, 132.7, 134.4, 142.3,
142.9, 166.3, 171.6; IR (neat) 3316, 1680 cmꢀ1; HRMS (ESI) m/z calcd
for C19H19N2O2SCl 397.0748 (M þ Na)þ, found 397.0747.
2-(5-Methyl-2-oxo-9-phenyl-2,3,4,5-tetrahydro-1H-1,5-
benzodiazepin-1-yl)-N-[(1S)-1-phenylethyl]acetamide (8a).
1
The mixture (with a ratio of 1:0.89 determined by H NMR) of the
diastereomers of 8a-A and 8a-B was obtained as a colorless form (yield
89%), which was chromatographed on SiO2 to separate the diastereo-
mers 8a-A (aS,S) and 8a-B (aR,S). 8a-A (aS,S): colorless crystals
(isolated yield: 39%); mp 196ꢀ198 °C; [R]21D þ51.5 (c 0.30, CHCl3);
1H NMR (400 MHz, CDCl3) δ 1.34 (d, J = 6.8 Hz, 3H), 2.22 (s, 3H),
2.47 (dd, J = 5.3, 12.9 Hz, 1H), 2.75 (ddd, J = 5.3, 7.5, 12.9 Hz, 1H), 2.87
(dd, J = 7.5, 10.0 Hz, 1H), 3.08 (d, J = 17.3 Hz, 1H), 3.37 (ddd, J = 5.3,
10.0, 12.9 Hz, 1H), 4.22 (d, J = 17.3 Hz, 1H), 5.09 (quin, J = 6.8 Hz, 1H),
2-(9-Chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzoaze-
pin-1-yl)-N-[(1S)-1-phenylethyl]acetamide (7c) and the
Atropisomers (7c-A and 7c-B). Compounds 7c was prepared from
the corresponding acetate (5c) via the carboxylic acid (5c-CO2H)
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The Journal of Organic Chemistry
ARTICLE
7.06 (dd, J = 1.2, 8.0 Hz, 1H), 7.21 (dd, J = 1.4, 7.8 Hz, 1H), 7.27ꢀ7.30
(m, 1H), 7.33ꢀ7.46 (m, 10H), 8.33 (br-d, J = 7.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 20.3, 33.7, 40.3, 47.1, 52.2, 58.6, 118.4, 126.4,
127.1, 128.1, 128.2, 128.4, 128.5, 129.2, 134.4, 137.1, 138.0, 142.7, 144.0,
167.5, 172.4; IR (KBr) 3246, 1676 cmꢀ1; HRMS (ESI) m/z calcd for
C26H28N3O2 414.2176 (M þ H)þ, found 414.2171. 8a-B (aR,S): colorless
and 1H NMR spectra of the temperature dependent analysis for
4c. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
crystals (isolated yield: 39%); mp 196ꢀ198 °C; [R]21 ꢀ46.2 (c 0.30,
Corresponding Author
*E-mail: natsu@pharm.teikyo-u.ac.jp.
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 1.47 (d, J = 7.3 Hz, 3H), 2.34
(s, 3H), 2.51 (dd, J = 5.3, 12.9 Hz, 1H), 2.82 (ddd, J = 5.3, 7.5, 12.9 Hz, 1H),
3.05 (dd, J= 7.5, 10.0 Hz, 1H), 3.07 (d, J = 17.3 Hz, 1H), 3.72 (ddd, J = 5.3,
10.0, 12.9 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 5.08 (quin, J = 7.3 Hz, 1H),
6.99ꢀ7.01(m, 3H), 7.17ꢀ7.22 (m, 4H), 7.33ꢀ7.45 (m, 6H), 8.10 (br-d, J =
7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ21.2,33.8,40.6,47.4,51.5, 59.3,
118.4, 126.1, 126.9, 127.1, 128.1, 128.2, 128.3, 128.4, 129.2, 134.0, 137.1,
138.0, 143.1, 144.0, 167.3, 172.5. IR (KBr) 3275, 1678 cmꢀ1; HRMS
(ESI) m/z calcd for C26H28N3O2 414.2176 (M þ H)þ, found 414.2171.
Single-Crystal X-ray Analysis. All measurements were made on a
RIGAKU RAXIS RAPID imaging plate area detector with graphite-
monochromated Cu KR radiation. The data were collected at a
temperature of ꢀ100 °C. The structure was solved by direct method
SIR92 and expanded using Fourier techniques. The non-hydrogen
atoms were refined anisotropically. All calculations were performed
using Crystal Structure (Crystal Structure 3.8) crystallographic software
package. Typical crystal data are as follows.
’ ACKNOWLEDGMENT
We thank Sagami Chemical Research Center for X-ray
analysis. This work was supported in part by a Grant-in-Aid for
Scientific Research (C) (21590124) and a Grant-in-Aid for
Young Scientists (B) (21790025) from the Japan Society for
the Promotion of Sciences.
’ REFERENCES
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B. M. J. Med. Chem. 1985, 28, 1511–1516.
Cryatal Data for 5b. C12H12O3NClS: mp 93ꢀ96 °C; Mr = 285.74,
Cu KR (λ = 1.54187 Å), monoclinic, P21/n, colorless prism 0.60 ꢁ
0.50 ꢁ 0.30 mm, crystal dimensions a = 9.31754(17) Å, b = 11.0378(2) Å,
c = 24.8795(5) Å, R = 90°, β = 91.2800(7)°, γ = 90°, T = 173 K, Z = 8, V =
(4) For studies on conformation including the atropisomeric prop-
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somerism between A and B due to an sp2ꢀsp2 axis at ArꢀN(CdO) may
play a key role.
(6) For review articles on axial chirality and atropisomerism, see: (a)
Clayden, J. Tetrahedron 2004, 60, 4335 in Tetrahedron Symposia-in-
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Takahashi, H.; Natsugari, H. J. Org. Chem. 2010, 75, 5984–5993.
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J. Pharmacol. Exp. Ther. 2004, 309, 49–55. (b) Fuwa, H.; Okamura, Y.;
Morohashi, Y.; Tomita, T.; Iwatsubo, T.; Kan, T.; Fukuyama, T.;
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Mitchell, D.; Carr, M. A.; Stout, J. R.; Belvo, M. D. Tetrahedron:
Asymmetry 2009, 20, 1262–1266.
2558.10(8) Å3, Dcalc = 1.484 gcmꢀ3, μCu KR = 41.854 cmꢀ1, F000
1184.00, GOF = 1.227, Rint = 0.058, R1 = 0.0468, wR2 = 0.1304.
=
Crystal Data for 7a-A (aR,S). C20H22O2N3Cl: mp 173ꢀ175 °C,
Mr = 371.87, Cu KR (λ = 1.54187 Å), orthorhombic, P212121, colorless
prism 0.50 ꢁ 0.40 ꢁ 0.20 mm, crystal dimensions a = 8.18197(15) Å, b =
12.6373(2) Å, c = 17.1203(3) Å, R = 90°, β = 90°, γ = 90°, T = 173 K, Z =
4, V = 1875.71(6) Å3, Dcalc = 1.315 gcmꢀ3, μCu KR = 19.565 cmꢀ1
,
F000 = 784.00, GOF = 0.648, Rint = 0.136, R1 = 0.0471, wR2 = 0.1054,
Flack parameter = 0.04(6).
Crystal Data for 7a-B (aS,S). C20H22O2N3Cl: mp 124ꢀ127 °C,
Mr = 371.87, Cu KR (λ = 1.54187 Å), orthorhombic, P212121, colorless
prism 0.25 ꢁ 0.20 ꢁ 0.10 mm, crystal dimensions a = 8.18197(15) Å, b =
8.69418(16) Å, c = 26.3682(5) Å, R = 90°, β = 90°, γ = 90°, T = 173 K,
Z = 4, V = 1875.71(6) Å3, Dcalc = 1.317 gcmꢀ3, μCu KR = 19.583 cmꢀ1
,
F000 = 784.00, GOF = 0.737, Rint = 0.040, R1 = 0.0286, wR2 = 0.0660,
Flack parameter = 0.003(14).
Crystal Data for 7b-A (aR,S). C19H19O2N2ClS: mp 142ꢀ144 °C,
Mr = 374.88, Cu KR (λ = 1.54187 Å), monoclinic, P21, colorless prism
0.60 ꢁ 0.40 ꢁ 0.40 mm, crystal dimensions a = 8.3785(4) Å, b =
12.3205(4) Å, c = 8.5550(3) Å, R = 90°, β = 90.842(3)°, γ = 90°, T = 173
K, Z = 2, V = 1875.71(6) Å3, Dcalc = 1.3410 gcmꢀ3, μCu KR =
31.449 cmꢀ1, F000 = 392.00, GOF = 0.737, Rint = 0.045, R1 = 0.0385,
wR2 = 0.0906, Flack parameter = 0.00(2)
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35, 477–483. (b) Natsugari, H.; Ikeura, Y.; Kamo, I.; Ishimaru, T.;
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T. J. Med. Chem. 1999, 42, 3982–3993. (c) Albert, J. S.; Aharony, D.;
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Shenvi, A.; Sherwood, S.; Warwick, P. J.; Russell, K. J. Med. Chem. 2002,
45, 3972–3983. (d) Guile, S. D.; Bantick, J. R.; Cooper, M. E.; Donald,
D. K.; Eyssade, C.; Ingall, A. H.; Lewis, R. J.; Martin, B. P.; Mohammed,
R. T.; Potter, T. J.; Reynolds, R. H.; St-Gallay, S. A.; Wright, A. D. J. Med.
Chem. 2007, 50, 254–263. (e) Welch, C. J.; Biba, M.; Pye, P.; Angelaud,
Stereochemical (Thermodynamic) Stability of Diastereo-
meric Atropisomers (A/B of 7aꢀc and 8a). The ΔGq value was
determined on the basis of the time-dependent conversion rate (% de)
estimated from chiral or nonchiral HPLC analysis of a solution of the
diastereomeric atropisomers (A and B) after the compounds were
allowed to stand at designated temperatures.17
’ ASSOCIATED CONTENT
S
Supporting Information. General experimental proce-
b
dure, H NMR and 13C NMR spectra for new compounds,
1
figures of thermal isomerization rate of enantiomers of 7aꢀc and
8a, X-ray data (CIF) for compounds 5b, 7a-A, 7a-B, and 7b-A,
5130
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ARTICLE
R.; Egbertson, M. J. Chromatogr. B 2008, 875, 118–121. (f) Porter, J.;
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Hutchinson, B.; Trevitt, G.; Turner, J.; Edwards, C.; Watkins, C.; Davis,
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Takahashi, H; Wakamatsu, S.; Tabata, H; Oshitari, T.; Harada, A.; Inoue,
K.; Natsugari, H. Org. Lett. 2011, 13, 760–763. (h) Tabata, H;
Nakagomi, J.; Morizono, D.; Oshitari, T.; Takahashi, H.; Natsugari, H.
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(10) Hussenether, T.; H€ubner, H.; Gmeiner, P.; Trosch€utz, R.
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1996, 26, 3443–3452.
(13) Temperature dependent 1H NMR analysis was conducted for
compound 4c (X = CH2, Y = H) to reveal that 4c exists as a racemate of
the atropisomers at ꢀ40 °C in CDCl3. The activation free-energy barrier
to rotation (ΔGq) value estimated from this analysis was ca. 56 kJ/mol.
See the Supporting Information.
(14) Note that the definition of the axial chirality (aS and aR) leads to
reversed stereochemical designations between 5, 7 (Y = Cl) and 6, 8 (Y =
Ph) according to the priority rule. The terms aS and aR (chiral axis
nomenclature) correspond to P and M (helix nomenclature), respectively.
(15) The absolute stereochemistry was determined based on the
Flack parameter (Cu KR radiation was used for the measurement).
(16) Note that the numbering H2 of 7b corresponds to H4 of 7a/7c
according to the numbering rule.
(17) For determination of the ΔGq value, see: Petit, M.; Lapierre,
A. J. B.; Curran, D. P. J. Am. Chem. Soc. 2005, 127, 14994–14995.
(18) White, W. N.; Klink, J. R. J. Org. Chem. 1977, 42, 166–169.
(19) Gupta, R. R.; Ojha, K. G.; Kumar, M. J. Heterocycl. Chem. 1980,
17, 1325–1327.
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M. E. J. Org. Chem. 2003, 68, 10195–10198.
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