Concise synthesis of 2-benzazepine derivatives and their biological activity

Article abstract of DOI:10.1021/jo300380z

Figure Persented: 2-Benzazepines, which are potentially good candidates for new drug therapies to treat skin wounds, were readily prepared from substituted cinnamylamide via an intramolecular Friedel-Crafts reaction. With few steps and effective reactions

Full text of DOI:10.1021/jo300380z

Article
pubs.acs.org/joc
Concise Synthesis of 2-Benzazepine Derivatives and Their Biological
Activity
Masahiro So,† Tomoko Kotake,† Kenji Matsuura,‡ Makoto Inui,*,‡ and Akio Kamimura*,†
†Department of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, Ube 755-8611, Japan
‡Department of Pharmacology, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan
S
* Supporting Information
ABSTRACT: 2-Benzazepines, which are potentially good candidates for new drug therapies to treat skin wounds, were readily
prepared from substituted cinnamylamide via an intramolecular Friedel−Crafts reaction. With few steps and effective reactions,
the procedure enables a rapid derivatization of 2-benzazepines. Moreover, optically active 4-substituted-2-benzazepines were
prepared from chiral α-substituted cinnamylamides, which were readily prepared by asymmetric α-alkylation of chiral cinnamyl
oxazolidinone amides. We have easily prepared a library of more than 20 derivatives and examined the biological activity of the
compounds.
an intramolecular Friedel−Crafts reaction and report the
synthesis of a library of 2-benzazepines using this facile
derivatization method. In addition, asymmetric 2-benzazepine
derivatives are examined with respect to their biological activity.
INTRODUCTION
■
Benzazepine possesses a 7-membered aza-heterocyclic ring-
fused aromatic unit, a framework that is often observed among
bioactive natural products and pharmaceuticals.1 For example,
paullones show cyclin-dependent kinase (CDK) inhibitory
activity and sirtuin 1 (SIRT1) inhibitory activity.1k−m 2-
Benzazepine derivatives have been investigated as mimics of
peptides containing the RGD motif, which is a well-known
antagonist of integrin-mediated adhesion and signal trans-
duction in cells.2 Syntheses of 2-benzazepine have been
performed by lactamization,3 transition metal-mediated cycliza-
tions such as the Heck reaction,4 and ring-closure metathesis
reaction.5 Most of these methods require several steps and the
use of precious and hazardous transition metal catalysts.
Therefore, a new transition metal-free methodology is desired
to synthesize 2-benzazepine derivatives.
Recently, we prepared and derivatized 2-benzazepines via the
7-endo selective radical cyclization of (o-bromobenzyl)-
methacrylamide6 and found that the 2-benzazepine derivatives
promoted epithelial cell migration without proliferation.7 Thus,
2-benzazepine derivatives are good candidates for new drug
therapies to treat skin wounds. Although radical cyclization
provides a convenient synthesis of 2-benzazepine derivatives, it
is usually very difficult to remove unwanted byproducts, derived
from tin hydride, from the crude reaction mixture. In addition,
tin compounds are usually toxic, and thus their use should be
avoided in the preparation of bioactive compounds. Therefore,
we initiated the development of a less toxic method to prepare
2-benzazepine derivatives. A new synthesis based on C−H
activation is fascinating because this approach can avoid the use
of precious transition metal catalysts as well as expensive aryl
halides. We assumed that an intramolecular Friedel−Crafts
reaction would be a good candidate for this purpose.8 In this
paper, we present a new method to prepare 2-benzazepines via
RESULTS AND DISCUSSION
■
We attempted the synthesis of 2-benzazepine derivatives using
commercially available 3,4-dimethoxyphenyl propionic acids.
Treatment of the acid with thionyl chloride followed by
methylamine resulted in the formation of the cyclization
precursor N-(methyl)-3-(3,4-dimethoxy)phenylpropionamides
1.9 An exposure of the compounds 1 to paraformaldehyde in
presence of trifluoroacetic acid gave the desired 2-benzazepines
2. Table 1 shows the results.
For example, 7,8-dimethoxy-2-benzazepine 2a was prepared
rapidly in 88% yield from 3-(3,4-dimethoxy)phenylpropionic
acid using the two-step sequence (entry 1). The isolated 2a
contained a single isomer and suggested that the cyclization
occurred in a highly regioselective manner. N-Ethyl-2-
benzazepine 2b was prepared in 92% yield (entry 2), while
N-isopropyl-2-benzazepine 2c was isolated in only 49% yield
(entry 3). Steric hindrance from the N-iPr group most probably
contributed to the lower yield of 2c. The cyclization from 3,4-
methylenedioxyphenyl propionic acid also progressed
smoothly, and the desired 2-benzazepines 2d−2f were obtained
in good yields (entries 4−6).
We examined the introduction of various alkyl groups at the
C4 position of the 4-unsubstituted-2-benzazepines 2 (Scheme
1). 4-Unsubstituted-2-benzazepines 2 underwent smooth
alkylation by treatment with LDA followed by various alkyl
halides, giving 3 and 4 in good yields. For example, the
Received: February 22, 2012
Published: March 30, 2012
© 2012 American Chemical Society
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The present cyclization depends on the methoxy substituents
on the aromatic ring. The formation of 2-benzazepines was
examined for monomethoxy substituted precursors (Scheme
2). Treatment of 4-methoxyphenylpropionic amide 5a, which
Table 1. Preparation of 4-Substituted-2-Benzazepines 2 via
an Intramolecular Friedel−Crafts Reaction
a
Scheme 2. Reaction of Different Methoxy-Substituted
Amides 5
b
entry
R1
R2
R3
2; yield (%)
1
2
3
4
5
6
Me
Me
Me
Me
Me
Me
Me
Et
2a; 88
2b; 92
2c; 49
2d; 72
2e; 83
2f; 87
iPr
Me
Et
−CH2−
−CH2−
−CH2−
nPr
a
Reagents and conditions: (i) SOCl2, THF, reflux, then R3NH2,
was prepared from the corresponding acid and amine, with
formalin and TFA failed to provide benzazepine 6a, whereas 3-
methoxyphenylpropionic amide 5b underwent the cyclization
to give 6b in 27% yield. The yield of 6b was improved to 34%
when the reaction was carried out at higher temperature. p-6b
was formed as the major isomer and the ratio between o-6b and
p-6b was 20:80.
These results clearly indicate that cyclization requires a
methoxy substituent in the para-position of the cyclized
aromatic carbon. When two electron-donating substituents
are on the benzene ring, cyclization occurs smoothly to afford
the desired 2-benzazepines in good yield. On the basis of these
results, we assume a reaction mechanism as depicted in Scheme
3. First, the iminium cation A is generated from the
b
NaHCO3, or R3NH2, EDCl; (ii) (CH2O)n, TFA, CH2Cl2. Isolated
yields.
methylation of N-methyl-2-benzazepine 2a gave N-methyl-4-
methyl-2-benzazepine 3a in 82% yield. We prepared 36
derivatives of 3 and 4 via this simple manipulation.
Scheme 1. C4 Alkylation of Benzazepines 2
Scheme 3. Plausible Reaction Mechanisms
propionamide and paraformaldehyde. The intermediate A
undergoes intramolecular Friedel−Crafts reaction via a
nucleophilic attack of the aromatic ring, thereby affording the
2-benzazepines in good yield (path A). This may be regarded as
a Pictet−Spengler reaction using amide derivatives.10 The
Pictet−Spengler reaction is usually applied to primary and
secondary amines, and amides are not commonly used for
intramolecular cyclization. Alternatively, 2-benzazepines can be
formed via intermolecular hydroxymethylation followed by
dehydration (path B); however, we have never detected any
intermediate benzyl alcohol B. Thus, we believe that the
Picktet−Spengler-type intramolecular Friedel−Crafts reaction
(path A) is the most possible mechanism for the reaction.
Although we achieved an effective construction of 2-
benzazepine derivatives from commercially available com-
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pounds under transition metal-free conditions, it was difficult to
obtain chiral 2-benzazepines using this method. To synthesize
chiral 2-benzazepine derivatives, the asymmetric alkylation of 4-
unsubstituted-2-benzazepines 2 is essential. However, asym-
metric alkylation reactions employing chiral additives such as
sparteine afforded only racemic products. Therefore, we
thought that the synthesis of chiral 4-substituted-2-benzaze-
pines via intramolecular Friedel−Crafts reaction of chiral
precursors should be practical, and specifically the asymmetric
alkylation of chiral oxazolidinone amides was attractive.
Therefore, the necessary chiral cyclization precursors were
prepared from 3,4-dimethoxyphenyl propionic acid 1.
Scheme 5. Preparation of (R)-4-Substituted-2-Benzazepines
(R)-3
a
The chiral oxazolidinones11 were introduced to 1 via the
usual method to give (S)-7 in 91% yield (Scheme 4).12 The
Scheme 4. Preparation of (S)-4-Substituted-2-Benzazepines
a
(S)-3
a
Reagents and conditions: (i) t-BuCOCl, Et3N, THF, −78 °C; (ii)
(R)-oxazolidinone, THF, −78 °C to rt; (iii) LDA, THF, −78 °C, then
R1X; (iv) LiOH, H2O2, THF−H2O, 0 °C to rt; (v) SOCl2, THF,
reflux; (vi) R2NH2; (vii) (CH2)n, TFA, CH2Cl2.
With 36 racemic and 18 optically active 2-benzazepines 3 in
hand, we next examined the biological activity of the 2-
benzazepine derivatives using an in vitro wound healing assay
with HaCat cells, derived from skin keratinocytes. Figure 1
shows typical results in the assay for racemic 2-benzazepines 3.
DMSO is a negative control that does not stimulate cell
migration, and the compound 10 is a positive control that
promotes cell migration.6 Cell migration was significantly
promoted when 30 μM of compounds 3g, 3h, and 3i were
employed in the assay. Their activities are as high as or slightly
a
Reagents and conditions: (i) t-BuCOCl, Et3N, THF, −78 °C; (ii)
(S)-oxazolidinone, THF, −78 °C to rt; (iii) LDA, THF, −78 °C, then
R1X; (iv) LiOH, H2O2, THF−H2O, 0 °C to rt; (v) SOCl2, THF,
reflux; (vi) R2NH2; (vii) (CH2)n, TFA, CH2Cl2.
following asymmetric alkylation was performed with various
alkyl halides and LDA in THF, thereby giving (S,S)-8 in 58−
71% yield.13 For example, the reaction of (S)-7 with benzyl
bromide provided (S,S)-8c in 71% yield with greater than 99%
diastereoselectivity. In this alkylation, bulky alkyl halides such as
benzyl bromide offered high diastereoselectivity. The obtained
alkylated products (S,S)-8 underwent hydrolysis in the
14
presence of LiOH and H2O2 to give the chiral carboxylic
acids (S)-9 in 87−93% yields without any significant loss in
enantiomeric excess. Intramolecular Friedel−Crafts reaction
was performed under the previously described conditions to
afford the desired chiral 2-benzazepines (S)-3 in 60−78%
isolated yield. Chiral HPLC analyses revealed that the
enantiomeric excesses of most of the products exceeded 90%,
and the optical purities obtained during alkylation were
maintained during the intramolecular Friedel−Crafts reaction.
A series of (R)-4-substituted-2-benzazepine (R)-3 were
prepared in good yields starting with the (R)-oxazolidinones
(Scheme 5). Importantly, all the reactions were performed via
simple and quick manipulations, and each compound was
prepared within a short period.
Figure 1. Effects of 2-benazepines 10 and 3 on the migration of HaCat
cells. The extent of cell migration into the wound area was determined
via an in vitro wound healing assay with the compound at 30 μM, and
it is expressed as a percentage of cell migration measured for cultures
incubated with DMSO (control). The data are means SEM for three
independent determinations. *P < 0.05, **P < 0.01 versus control.
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× 3). The organic phases were combined and dried with Na2SO4. After
filtration, the filtrate was concentrated using a rotary evaporator under
reduced pressure to give crude N-methyl-propanamide (0.681 g),
which was used without further purification. The N-methyl-
propanamide (0.536 g) was dissolved in CH2Cl2 (50 mL),
paraformaldehyde (0.332 g, 11.1 mmol), and trifluoroacetic acid
(1.85 mL, 24.2 mmol), and the reaction mixture was stirred at room
temperature for 24 h. Then saturated aqueous NaHCO3 (50 mL) was
added to the mixture, and the resulting solution was extracted with
CH2Cl2 (15 mL × 3). The organic phases were combined and dried
with Na2SO4. After filtration, the filtrate was concentrated using a
rotary evaporator under reduced pressure to give crude 2a, which was
purified by flash chromatography (silica gel/hexane then hexane/
EtOAc 1:3) to give 2a in 88% yield (two steps, 0.489 g, 2.08 mmol).
Pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 6.64 (s, 1 H), 6.57 (s,
1 H), 4.43 (s, 2 H), 3.87 (s, 3 H), 3.85 (s, 3 H), 3.10 (t, J = 6.6 Hz, 2
H), 3.05 (s, 3 H), 2.91 (t, J = 7.1 Hz, 2 H); 13C NMR (126 MHz,
CDCl3) δ 173.1, 147.9, 146.0, 129.0, 125.8, 112.9, 111.8, 55.4, 55.3,
53.3, 34.5, 32.9, 27.8; IR (neat) ν 3435, 2909, 1628, 1256 cm−1;
HRMS (ESI M + H) m/z 236.1294, calcd for C13H18NO3 236.1287.
The following compounds 2 were prepared in a similar manner.
2-Ethyl-7,8-dimethoxy-4,5-dihydro-1H-benzo[c]azepin-
3(2H)-one (2b). Yellow oil: 1H NMR (500 MHz, CDCl3) δ 6.63 (s, 1
H), 6.57 (s, 1 H), 4.42 (s, 2 H), 3.87 (s, 3 H), 3.85 (s, 3 H), 3.52 (q, J
= 7.1 Hz, 2 H), 3.10 (t, J = 6.9 Hz, 2 H), 2.89 (t, J = 6.9 Hz, 2 H), 1.10
(t, J = 7.2 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 172.3, 147.6,
145.9, 128.8, 126.3, 112.6, 111.3, 55.2, 55.0, 50.9, 41.7, 32.8, 27.7, 12.7;
IR (neat) ν 2934, 1632, 1518, 1204 cm−1; HRMS (ESI M + H) m/z
250.1443, calcd for C14H20NO3 250.1443.
higher than the compound 10. However, the activity was
sensitive to the steric size of the C4 substituent, and the
migration decreased when the C4 substituent became bulkier
than the butyl group.
Since the compounds 3 are racemic mixtures, we wondered
which enantiomer would promote cell migration. To answer
this question, we examined the effects of each enantiomer of 3g
on cell migration. Figure 2 shows the results. This figure clearly
2-Isopropyl-7,8-dimethoxy-4,5-dihydro-1H-benzo[c]azepin-
3(2H)-one (2c). Yellow oil: 1H NMR (500 MHz, CDCl3) δ 6.61 (s, 1
H), 6.56 (s, 1 H), 4.90 (dt, J = 13.6, 6.8 Hz, 1 H), 4.34 (s, 2 H), 3.87
(s, 3 H), 3.85 (s, 3 H), 3.10 (t, J = 6.7 Hz, 2 H), 2.90 (t, J = 6.7 Hz, 2
H), 1.09 (d, J = 6.8 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 173.2,
148.1, 146.5, 129.5, 127.3, 113.1, 111.6, 56.0, 55.7, 45.1, 44.5, 33.7,
28.5, 20.3; IR (neat) ν 2972, 1628, 1456, 1250 cm−1; HRMS (ESI M +
H) m/z 264.1598, calcd for C15H22NO3 264.1600.
Figure 2. Effects of the enantiomers of (S)-3g and (R)-3g on HaCat
cell migration. The extent of cell migration into the wound area was
determined with each enantiomer at 1−30 μM, and it is expressed as a
percentage of cell migration measured for cultures incubated with
DMSO (control). Data are means
SEM for three independent
determinations. *P < 0.05, **P < 0.01 versus control.
6-Methyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-c]-
indicated that both enantiomers are almost equally active.
Therefore, this biological activity is insensitive to the absolute
configuration at the C4 position of the 2-benzazepines.
1
azepin-7(6H)-one (2d). White solid: mp 150.0−151.0 °C; H NMR
(500 MHz, CDCl3) δ 6.62 (s, 1 H), 6.57 (s, 1 H), 5.93 (s, 2 H), 4.37
(s, 2 H), 3.05 (t, J = 6.8 Hz, 2 H), 3.04 (s, 3 H), 2.88 (t, J = 6.8 Hz, 2
H); 13C NMR (126 MHz, CDCl3) δ 173.3, 147.4, 145.5, 131.3, 127.5,
110.3, 109.0, 101.1, 54.0, 35.3, 33.8, 28.9; IR (CHCl3) ν 2903, 1643,
1503, 1227 cm−1; HRMS (ESI M + H) m/z 220.0973, calcd for
C12H14NO3 220.0974.
In conclusion, we have synthesized 2-benzazepine derivatives
rapidly using an intramolecular Friedel−Crafts reaction that
conveniently provides racemic derivatives. The method is very
simple and useful because 2-benzazepines can be constructed in
two steps from commercially available 3,4-dimethoxyphenyl
propionic acid. It must be mentioned that all the steps are
performed without using transition metal catalysts or expensive
aryl halide reagents. The Friedel−Crafts reaction is also
applicable to the synthesis of asymmetric derivatives, and we
have prepared both enantiomers of 18 derivatives in sufficient
enantiomer excess. Further biological assays are underway in
our research group and will be reported in due course.
6-Ethyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-c]-
1
azepin-7(6H)-one (2e). White solid: mp 106.0−107.0 °C; H NMR
(500 MHz, CDCl3) δ 6.61 (s, 1 H), 6.58 (s, 1 H), 5.93 (s, 2 H), 4.36
(s, 2 H), 3.50 (q, J = 7.2 Hz, 2 H), 3.06 (t, J = 6.9 Hz, 2 H), 2.86 (t, J =
7.2 Hz, 2 H), 1.09 (t, J = 7.2 Hz, 3 H); 13C NMR (126 MHz, CDCl3)
δ 172.9, 147.4, 145.6, 131.3, 128.3, 110.3, 108.7, 101.2, 51.9, 42.7, 34.0,
29.0, 13.6; IR (CHCl3) ν 2901, 1640, 1487, 1233 cm−1: HRMS (ESI
M + H) m/z 234.1116, calcd for C13H16NO3 234.1130.
6-Propyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-c]-
1
azepin-7(6H)-one (2f). White solid: mp 108.0−109.0 °C; H NMR
EXPERIMENTAL SECTION
(500 MHz, CDCl3) δ 6.61 (s, 1 H), 6.56 (s, 1 H), 5.93 (s, 2 H), 4.36
(s, 2 H), 3.42 (t, J = 7.3 Hz, 2 H), 3.06 (t, J = 6.2 Hz, 2 H), 2.87 (dd, J
= 8.6, 5.1 Hz, 2 H), 1.60−1.41 (m, 2 H), 0.83 (t, J = 7.4 Hz, 3 H); 13C
NMR (126 MHz, CDCl3) δ 173.3, 147.3, 145.5, 131.2, 128.1, 110.3,
108.7, 101.1, 52.4, 49.6, 33.9, 29.1, 21.6, 11.3; IR (CHCl3) ν 2901,
1640, 1487, 1231 cm−1: HRMS (ESI M + H) m/z 248.1296, calcd for
C14H18NO3 248.1287.
■
Preparation of 7,8-Dimethoxy-2-methyl-4,5-dihydro-1H-
benzo[c]azepin-3(2H)-one (2a). Thionyl chloride (0.65 mL, 9.0
mmol) was added to a solution of 3-(3,4-dimethoxyphenyl)propanoic
acid (0.631 g, 3.00 mmol) in THF (30 mL) in a 100 mL round-
bottom flask, and the solution was heated at reflux for 4 h. The volatile
contents were then removed using a rotary evaporator under reduced
pressure. CH2Cl2 (30 mL) was added to the residue. A solution of
saturated aqueous NaHCO3 (10 mL) and aqueous MeNH2 (40%, 1.1
mL, 13 mmol, 4.2 equiv) were placed separately in a 100 mL three-
necked round-bottom flask and cooled at 0 °C. The CH2Cl2 solution,
containing propanoyl chloride, was added slowly to the aqueous
solution at 0 °C, and the reaction mixture was stirred for 1 h at 0 °C.
Saturated aqueous NaHCO3 (30 mL) was then added to the reaction
mixture, and the resulting solution was extracted with CH2Cl2 (15 mL
Preparation of 7,8-Dimethoxy-2,4-dimethyl-4,5-dihydro-1H-
benzo[c]azepin-3(2H)- one (3a). An LDA solution in THF (0.33
M, 2.6 mL, 0.86 mmol) was added to a solution of 2a (0.123 g, 0.524
mmol) in THF (2 mL) at −78 °C, and the mixture was stirred for 30
min at the same temperature. Iodomethane (0.28 mL, 4.5 mmol, 4.5
equiv) was then slowly added to the solution. The reaction mixture
was stirred for 2 h at the same temperature and then allowed to warm
to the room temperature for 30 min. Saturated aqueous NH4Cl (5
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mL) was added to the mixture, and THF was removed under reduced
pressure using a rotary evaporator. Saturated brine (20 mL) was then
added to the residue, and the resulting aqueous solution was extracted
with EtOAc (20 mL × 3). The organic phases were combined and
dried over Na2SO4. After filtration, the filtrate was concentrated under
reduced pressure. The oily residue was purified by flash chromatog-
raphy (silica gel/hexane then hexane/EtOAc 1:3), to give 3a in 82%
2-Ethyl-7,8-dimethoxy-4-methyl-4,5-dihydro-1H-benzo[c]-
1
azepin-3(2H)-one (3g). White solid: mp 125.0−125.5 °C; H NMR
(500 MHz, CDCl3) δ 6.59 (s, 1 H), 6.58 (s, 1 H), 5.10 (d, J = 16.4 Hz,
1 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.79 (d, J = 16.5 Hz, 1 H), 3.52 (q, J
= 7.1 Hz, 2 H), 3.46−3.27 (m, 1 H), 2.93 (dd, J = 17.1, 4.1 Hz, 1 H),
2.85 (dd, J = 16.9, 12.9 Hz, 1 H), 1.25 (d, J = 6.5 Hz, 3 H), 1.07 (t, J =
7.2 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 174.9, 148.2, 146.5,
129.6, 126.9, 113.3, 111.6, 56.0, 55.8, 51.4, 42.6, 37.7, 34.7, 17.5, 13.5;
IR (CHCl3) ν 2970, 2932, 1636, 1250 cm−1. Anal. Calcd. for
C15H21NO3: C, 68.42; H, 8.04; N, 5.32. Found: C, 68.25; H, 8.05; N,
5.26.
1
yield (0.107 g, 0.431 mmol). White solid: mp 168.0−168.6 °C; H
NMR (500 MHz, CDCl3) δ 6.60 (s, 1 H), 6.56 (s, 1 H), 5.17 (d, J =
16.3 Hz, 1 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.72 (d, J = 16.4 Hz, 1 H),
3.38 (tt, J = 12.7, 6.4 Hz, 1 H), 3.05 (s, 3 H), 2.95 (dd, J = 17.1, 4.1
Hz, 1 H), 2.84 (dd, J = 17.0, 13.0 Hz, 1 H), 1.25 (d, J = 6.5 Hz, 3 H);
13C NMR (126 MHz, CDCl3) δ 175.6, 148.4, 146.5, 129.7, 126.2,
113.5, 112.0, 56.1, 56.0, 53.7, 37.7, 35.3, 34.8, 17.6; IR (CHCl3) ν
2967, 1526, 1348, 1258 cm−1. Anal. Calcd. for C14H19NO3: C, 67.45;
H, 7.68; N, 5.62. Found: C, 67.27; H, 7.70; N, 5.60.
2,4-Diethyl-7,8-dimethoxy-4,5-dihydro-1H-benzo[c]azepin-
1
3(2H)-one (3h). White solid: mp 118.8−119.2 °C; H NMR (500
MHz, CDCl3) δ 6.60 (s, 1 H), 6.58 (s, 1 H), 5.12 (d, J = 16.4 Hz, 1
H), 3.86 (s, 3 H), 3.84 (s, 3 H), 3.80 (d, J = 16.5 Hz, 1 H), 3.62−3.43
(m, 2 H), 3.08 (ddd, J = 17.3, 9.7, 5.5 Hz, 1 H), 2.99 (dd, J = 17.0, 3.4
Hz, 1 H), 2.81 (dd, J = 16.9, 13.3 Hz, 1 H), 2.06−1.92 (m, 1 H),
1.50−1.36 (m, 1 H), 1.06 (t, J = 7.2 Hz, 3 H), 1.01 (t, J = 7.4 Hz, 3
H); 13C NMR (126 MHz, CDCl3) δ 174.3, 148.1, 146.4, 129.5, 126.9,
113.4, 111.6, 56.0, 55.8, 51.4, 42.4, 42.0, 35.5, 25.0, 13.5, 12.3; IR
(CHCl3) ν 2934, 1636, 1520, 1248 cm−1. Anal. Calcd. for C16H23NO3:
C, 69.29; H, 8.36; N, 5.05. Found: C, 69.20; H, 8.26; N, 5.01.
2-Ethyl-7,8-dimethoxy-4-propyl-4,5-dihydro-1H-benzo[c]-
The following compounds 3 were prepared in a similar manner.
2-Ethyl-7,8-dimethoxy-4-methyl-4,5-dihydro-1H-benzo[c]-
1
azepin-3(2H)-one (3b). Yellow solid: mp 89.5−90.0 °C; H NMR
(500 MHz, CDCl3) δ 6.60 (s, 1 H), 6.56 (s, 1 H), 5.19 (d, J = 16.3 Hz,
1 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.72 (d, J = 16.4 Hz, 1 H), 3.27−
3.06 (m, 1 H), 3.04 (s, 3 H), 3.00 (dd, J = 3.3, 16.1 Hz, 1 H), 2.79 (dd,
J = 13.4, 16.8 Hz, 1 H), 2.04−1.92 (m, 1 H), 1.50−1.37 (m, 1 H), 1.01
(t, J = 7.4 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 175.0, 148.3,
146.4, 129.6, 126.1, 113.6, 112.0, 56.0, 55.9, 53.5, 42.0, 35.6, 35.0, 25.1,
12.4; IR (CHCl3) ν 2936, 1643, 1522, 1261 cm−1; HRMS (ESI M +
H) m/z 264.1602, calcd for C15H22NO3 264.1600.
1
azepin-3(2H)-one (3i). Pale yellow solid: mp 107.8−108.3 °C; H
NMR (500 MHz, CDCl3) δ 6.59 (s, 1 H), 6.56 (s, 1 H), 5.11 (d, J =
16.4 Hz, 1 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 3.78 (d, J = 16.5 Hz, 1 H),
3.52 (q, J = 7.1 Hz, 2 H), 3.21−3.13 (m, 1 H), 2.97 (dd, J = 17.1, 3.5
Hz, 1 H), 2.82 (dd, J = 16.9, 13.3 Hz, 1 H), 1.96 (tdd, J = 10.1, 8.9, 5.6
Hz, 1 H), 1.52−1.26 (m, 3 H), 1.06 (t, J = 7.2 Hz, 3 H), 0.96 (t, J = 7.2
Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 174.4, 148.2, 146.5, 129.7,
127.0, 113.5, 111.6, 56.0, 55.8, 51.4, 42.5, 40.0, 35.9, 34.2, 20.9, 14.2,
13.6; IR (CHCl3) ν 2932, 1643, 1518, 1248 cm−1. Anal. Calcd. for
C17H25NO3: C, 70.07; H, 8.65; N, 4.81. Found: C, 69.94; H, 8.65; N,
4.72.
7,8-Dimethoxy-2-methyl-4-propyl-4,5-dihydro-1H-benzo[c]-
1
azepin-3(2H)-one (3c). Yellow solid: mp 88.4−88.9 °C; H NMR
(500 MHz, CDCl3) δ 6.60 (s, 1 H), 6.56 (s, 1 H), 5.19 (d, J = 16.3 Hz,
1 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.72 (d, J = 16.4 Hz, 1 H), 3.22 (dd,
J = 12.4, 7.1 Hz, 1 H), 3.03 (s, 3 H), 2.99 (dd, J = 17.2, 3.6 Hz, 1 H),
2.80 (dd, J = 13.5, 16.7 Hz, 1 H), 2.03−1.89 (m, 1 H), 1.55−1.27 (m,
3 H), 0.95 (t, J = 7.1 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 175.1,
148.4, 146.5, 129.7, 126.2, 113.6, 112.0, 56.1, 55.9, 53.6, 40.0, 35.9,
35.1, 34.3, 20.9, 14.3; IR (CHCl3) ν 2936, 1643, 1522, 1261 cm−1;
HRMS (ESI M + H) m/z 278.1765, calcd for C16H24NO3 278.1756.
4-Butyl-7,8-dimethoxy-2-methyl-4,5-dihydro-1H-benzo[c]-
azepin-3(2H)-one (3d). Yellow solid: mp 102.5−103.0 °C; 1H NMR
(500 MHz, CDCl3) δ 6.60 (s, 1 H), 6.56 (s, 1 H), 5.18 (d, J = 16.3 Hz,
1 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.71 (d, J = 16.4 Hz, 1 H), 3.20 (dd,
J = 12.3, 7.3 Hz, 1 H), 3.03 (s, 3 H), 2.99 (dd, J = 17.2, 3.8 Hz, 1 H),
2.80 (dd, J = 16.8, 13.4 Hz, 1 H), 2.14−1.83 (m, 1 H), 1.49−1.23 (m,
5 H), 0.92 (t, J = 6.9 Hz, 3 H); 13C NMR (68 MHz, CDCl3) δ 175.1,
148.6, 146.6, 129.8, 126.3, 113.8, 112.3, 55.9, 55.8, 53.4, 40.1, 35.8,
34.8, 31.7, 29.8, 22.7, 13.7; IR (CHCl3) ν 2953, 1651, 1522, 1256
cm−1. Anal. Calcd. for C17H25NO3: C, 70.07; H, 8.65; N, 4.81. Found:
C, 69.83; H, 8.57; N, 4.83.
4-Butyl-2-ethyl-7,8-dimethoxy-4,5-dihydro-1H-benzo[c]-
1
azepin-3(2H)-one (3j). White solid: mp 95.5−96.0 °C; H NMR
(500 MHz, CDCl3) δ 6.59 (s, 1 H), 6.56 (s, 1 H), 5.11 (d, J = 16.4 Hz,
1 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 3.78 (d, J = 16.5 Hz, 1 H), 3.52 (q, J
= 7.1 Hz, 2 H), 3.20−3.11 (m, 1 H), 2.98 (dd, J = 17.1, 3.4 Hz, 1 H),
2.82 (dd, J = 16.8, 13.3 Hz, 1 H), 2.15−1.82 (m, 1 H), 1.46−1.30 (m,
5 H), 1.06 (t, J = 7.1 Hz, 3 H), 0.92 (t, J = 6.9 Hz, 3 H); 13C NMR
(126 MHz, CDCl3) δ 174.33, 148.04, 146.32, 129.50, 126.84, 113.33,
111.51, 55.88, 55.69, 51.29, 42.33, 40.09, 35.77, 31.65, 29.86, 22.77,
13.92, 13.44; IR (CHCl3) ν 2932, 1640, 1520, 1254 cm−1. Anal. Calcd.
for C18H27NO3: C, 70.79; H, 8.91; N, 4.59. Found: C, 70.64; H, 8.99;
N, 4.60.
2-Ethyl-7,8-dimethoxy-4-pentyl-4,5-dihydro-1H-benzo[c]-
1
azepin-3(2H)-one (3k). White solid: mp 95.0−95.5 °C; H NMR
(500 MHz, CDCl3) δ 6.59 (s, 1 H), 6.56 (s, 1 H), 5.11 (d, J = 16.4 Hz,
1 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 3.78 (d, J = 16.5 Hz, 1 H), 3.52 (q, J
= 7.1 Hz, 2 H), 3.21−3.11 (m, 1 H), 2.97 (dd, J = 17.1, 3.4 Hz, 1 H),
2.82 (dd, J = 16.9, 13.3 Hz, 1 H), 1.96 (dq, J = 15.3, 7.5 Hz, 1 H),
1.41−1.19 (m, 7 H), 1.06 (t, J = 7.1 Hz, 3 H), 0.90 (t, J = 6.6 Hz, 3
H); 13C NMR (126 MHz, CDCl3) δ 174.6, 148.3, 146.6, 129.8, 127.1,
113.6, 111.7, 56.1, 55.9, 51.6, 42.6, 40.4, 36.0, 32.1, 32.1, 27.6, 22.7,
14.2, 13.7; IR (CHCl3) ν 2930, 1643, 1520, 1250 cm−1. Anal. Calcd.
for C19H29NO3: C, 71.44; H, 9.15; N, 4.38. Found: C, 71.18; H, 9.07;
N, 4.31.
7,8-Dimethoxy-2-methyl-4-pentyl-4,5-dihydro-1H-benzo[c]-
azepin-3(2H)-one (3e). Yellow solid: mp 113.7−114.2 °C; 1H NMR
(500 MHz, CDCl3) δ 6.60 (s, 1 H), 6.56 (s, 1 H), 5.19 (d, J = 16.2 Hz,
1 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.71 (d, J = 15.8 Hz, 1 H), 3.20 (br,
1 H), 3.04 (s, 3 H), 2.99 (d, J = 16.9 Hz, 1 H), 2.80 (t, J = 14.9 Hz, 1
H), 2.17−1.76 (m, 1 H), 1.50−1.20 (m, 7 H), 1.00−0.77 (m, 3 H);
13C NMR (126 MHz, CDCl3) δ 175.2, 148.4, 146.4, 129.7, 126.1,
113.6, 112.0, 56.0, 55.9, 53.6, 40.2, 35.9, 35.1, 32.1, 32.0, 27.5, 22.6,
14.1; IR (CHCl3) ν 2953, 1651, 1522, 1252 cm−1. Anal. Calcd. for
C18H27NO3: C, 70.79; H, 8.91; N, 4.59. Found: C, 70.59; H, 8.85; N,
4.52.
4-Benzyl-2-ethyl-7,8-dimethoxy-4,5-dihydro-1H-benzo[c]-
1
azepin-3(2H)-one (3l). White solid: mp 181.5−182.0 °C; H NMR
4-Benzyl-7,8-dimethoxy-2-methyl-4,5-dihydro-1H-benzo[c]-
1
(500 MHz, CDCl3) δ 7.33−7.27 (m, 4 H), 7.21 (dd, J = 9.2, 4.3 Hz, 1
H), 6.54 (s, 1 H), 6.53 (s, 1 H), 5.09 (d, J = 16.4 Hz, 1 H), 3.85 (s, 3
H), 3.81 (s, 3 H), 3.77 (d, J = 16.5 Hz, 1 H), 3.62−3.40 (m, 3 H), 3.36
(dd, J = 14.0, 5.5 Hz, 1 H), 2.95 (dd, J = 17.0, 3.8 Hz, 1 H), 2.85 (dd, J
= 16.9, 13.1 Hz, 1 H), 2.69 (dd, J = 14.1, 8.3 Hz, 1 H), 1.07 (t, J = 7.1
Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 173.8, 148.1, 146.4, 140.1,
129.2, 129.1, 128.2, 126.7, 125.9, 113.4, 111.5, 55.9, 55.7, 51.3, 42.5,
41.9, 37.8, 34.7, 13.4; IR (CHCl3) ν 2930, 1638, 1520, 1248 cm−1.
Anal. Calcd. for C21H25NO3: C, 74.31; H, 7.42; N, 4.13. Found: C,
74.29; H, 7.38; N, 4.08.
azepin-3(2H)-one (3f). White solid: mp 162.5−163.0 °C; H NMR
(500 MHz,) δ 7.34−7.16 (m, 5 H), 6.54 (s, 1 H), 6.54 (s, 1 H), 5.16
(d, J = 16.3 Hz, 1 H), 3.85 (s, 3 H), 3.81 (s, 3 H), 3.70 (d, J = 16.4 Hz,
1 H), 3.54 (dq, J = 7.9, 5.4 Hz, 1 H), 3.35 (dd, J = 14.0, 5.8 Hz, 1 H),
3.05 (s, 3 H), 2.97 (dd, J = 17.0, 4.0 Hz, 1 H), 2.85 (dd, J = 16.9, 13.1
Hz, 1 H), 2.69 (dd, J = 14.0, 8.0 Hz, 1 H); 13C NMR (126 MHz,
CDCl3) δ 174.7, 148.4, 146.5, 140.2, 129.3, 128.4, 128.4, 126.2, 125.9,
113.6, 112.0, 56.1, 55.9, 53.6, 42.1, 38.0, 35.3, 34.9; IR (CHCl3) ν
2934, 1651, 1522, 1252 cm−1. Anal. Calcd. for C20H23NO3: C, 73.82;
H, 7.12; N, 4.30. Found: C, 74.12; H, 7.19; N, 4.33.
4021
dx.doi.org/10.1021/jo300380z | J. Org. Chem. 2012, 77, 4017−4028

The Journal of Organic Chemistry
Article
2-Isopropyl-7,8-dimethoxy-4-methyl-4,5-dihydro-1H-
benzo[c]azepin-3(2H)-one (3m). White solid: mp 103.5−104.0 °C;
1H NMR (500 MHz, CDCl3) δ 6.57 (s, 1 H), 6.56 (s, 1 H), 4.95 (m, J
6,8-Dimethyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]benzo-
[1,2-c]azepin-7(6H)-one (4a). White solid: mp 122.0−122.5 °C; 1H
NMR (500 MHz, CDCl3) δ 6.57 (s, 1 H), 6.55 (s, 1 H), 5.92 (s, 2 H),
5.07 (d, J = 16.2 Hz, 1 H), 3.70 (d, J = 16.3 Hz, 1 H), 3.35 (m, J = 6.3
Hz, 1 H), 3.03 (s, 3 H), 2.93 (dd, J = 17.1, 4.4 Hz, 1 H), 2.79 (dd, J =
17.1, 12.8 Hz, 1 H), 1.24 (d, J = 6.6 Hz, 3 H); 13C NMR (126 MHz,
CDCl3) δ 175.2, 147.2, 145.2, 131.0, 127.2, 110.3, 108.7, 101.0, 53.5,
37.9, 35.1, 34.9, 17.6; IR (CHCl3) 2899, 1645, 1227, 1028 cm−1. Anal.
Calcd. for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.74; H,
6.65; N, 5.88.
8-Ethyl-6-methyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]-
benzo[1,2-c]azepin-7(6H)-one (4b). Pale yellow solid: mp 102.5−
103.0 °C; 1H NMR (500 MHz, CDCl3) δ 6.58 (s, 1 H), 6.55 (s, 1 H),
5.92 (s, 2 H), 5.09 (d, J = 16.2 Hz, 1 H), 3.70 (d, J = 16.3 Hz, 1 H),
3.09 (td, J = 12.7, 5.5 Hz, 1 H), 3.02 (s, 3 H), 2.98 (dd, J = 16.9, 4.0
Hz, 1 H), 2.75 (dd, J = 17.0, 13.1 Hz, 1 H), 2.04−1.87 (m, 1 H),
1.54−1.33 (m, 1 H), 1.00 (t, J = 7.4 Hz, 3 H); 13C NMR (126 MHz,
CDCl3) δ 174.7, 147.2, 145.2, 131.0, 127.3, 110.4, 108.7, 101.0, 53.5,
42.2, 35.9, 34.9, 25.3, 12.3; IR (CHCl3) ν 2876, 1643, 1487, 1225
cm−1. Anal. Calcd. for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found:
C, 67.77; H, 7.06; N, 5.57.
6-Methyl-8-propyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]-
benzo[1,2-c]azepin-7(6H)-one (4c). Pale yellow oil: 1H NMR (500
MHz, CDCl3) δ 6.58 (s, 1 H), 6.55 (s, 1 H), 5.92 (s, 2 H), 5.09 (d, J =
16.2 Hz, 1 H), 3.71 (d, J = 16.3 Hz, 1 H), 3.25−3.15 (m, 1 H), 3.02 (s,
3 H), 2.96 (dd, J = 17.1, 4.3 Hz, 1 H), 2.76 (dd, J = 16.8, 12.9 Hz, 1
H), 2.04−1.85 (m, 1 H), 1.52−1.28 (m, 3 H), 0.95 (t, J = 7.1 Hz, 3
H); 13C NMR (126 MHz, CDCl3) δ 175.0, 147.3, 145.3 131.2, 127.4,
110.6, 108.8, 101.1, 53.7, 40.3, 36.3, 35.1, 34.5, 21.0, 14.3; IR (neat) ν
2930, 1647, 1487, 1236 cm−1; HRMS (ESI M + H) m/z 262.1456,
calcd for C15H20NO3 262.1443.
8-Butyl-6-methyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]-
benzo[1,2-c]azepin-7(6H)-one (4d). Pale yellow oil: 1H NMR (500
MHz, CDCl3) δ 6.58 (s, 1 H), 6.55 (s, 1 H), 5.92 (s, 2 H), 5.09 (d, J =
16.2 Hz, 1 H), 3.70 (d, J = 16.3 Hz, 1 H), 3.17 (m, J = 6.0 Hz, 1 H),
3.02 (s, 3 H), 2.97 (dd, J = 17.1, 4.3 Hz, 1 H), 2.76 (dd, J = 16.8, 12.9
Hz, 1 H), 2.01−1.88 (m, 1 H), 1.48−1.24 (m, 5 H), 0.92 (t, J = 7.0
Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 175.0, 147.3, 145.3, 131.2,
127.4, 110.6, 108.8, 101.1, 53.7, 40.5, 36.3, 35.1, 32.1, 30.1, 23.0, 14.1;
IR (neat) ν 2930, 1649, 1487, 1229 cm−1; HRMS (ESI M + H) m/z
276.1609, calcd for C16H22NO3 276.1600.
= 6.8 Hz, 1 H), 4.83 (d, J = 16.6 Hz, 1 H), 3.88 (d, J = 17.0 Hz, 1 H),
3.86 (s, 3 H), 3.84 (s, 3 H), 3.38−3.29 (m, 1 H), 2.94−2.84 (m, 2 H),
1.25 (d, J = 6.5 Hz, 3 H), 1.17 (d, J = 6.8 Hz, 3 H), 0.96 (d, J = 6.8 Hz,
3 H); 13C NMR (126 MHz, CDCl3) δ 174.8, 148.0, 146.4, 129.6,
127.5, 113.1, 111.3, 56.0, 55.7, 44.8, 44.3, 37.7, 34.8, 20.8, 20.0, 17.5;
IR (CHCl3) ν 2972, 1636, 1520, 1250 cm−1. Anal. Calcd. for
C16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.13; H, 8.47; N,
5.02.
4-Ethyl-2-isopropyl-7,8-dimethoxy-4,5-dihydro-1H-benzo-
[c]azepin-3(2H)-one (3n). White solid: mp 127.5−128.0 °C; 1H
NMR (500 MHz, CDCl3) δ 6.58 (s, 1 H), 6.56 (s, 1 H), 4.96 (m, J =
6.8 Hz, 1 H), 4.86 (d, J = 16.6 Hz, 1 H), 3.88 (d, J = 17.6 Hz, 1 H),
3.86 (s, 3 H), 3.84 (s, 3 H), 3.10−3.03 (m, 1 H), 2.97 (dd, J = 17.1, 2.9
Hz, 1 H), 2.82 (dd, J = 16.8, 13.5 Hz, 1 H), 2.08−1.91 (m, 1 H),
1.49−1.36 (m, 1 H), 1.17 (d, J = 6.8 Hz, 3 H), 1.01 (t, J = 7.4 Hz, 3
H), 0.95 (d, J = 6.8 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 174.2,
147.9, 146.4, 129.6, 127.5, 113.2, 111.3, 55.9, 55.7, 44.7, 44.1, 42.0,
35.5, 24.9, 20.8, 20.0, 12.3; IR (CHCl3) ν 2934, 1636, 1520, 1248
cm−1. Anal. Calcd. for C17H25NO3: C, 70.07; H, 8.65; N, 4.81. Found:
C, 69.75; H, 8.74; N, 4.82.
2-Isopropyl-7,8-dimethoxy-4-propyl-4,5-dihydro-1H-benzo-
[c]azepin-3(2H)-one (3o). White solid: mp 113.5−114.0 °C; 1H
NMR (500 MHz, CDCl3) δ 6.57 (s, 1 H), 6.56 (s, 1 H), 4.95 (m, J =
6.8 Hz, 1 H), 4.86 (d, J = 16.6 Hz, 1 H), 3.88 (d, J = 17.0 Hz, 1 H),
3.86 (s, 3H), 3.84 (s, 3 H), 3.22−3.08 (m, 1 H), 2.96 (dd, J = 17.0, 3.1
Hz, 1 H), 2.83 (dd, J = 16.8, 13.3 Hz, 1 H), 2.05−1.90 (m, 1 H),
1.50−1.30 (m, 3 H), 1.17 (d, J = 6.8 Hz, 3 H), 0.96 (dd, J = 8.2, 7.1
Hz, 6 H); 13C NMR (126 MHz, CDCl3) δ 174.4, 148.0, 146.5, 129.7,
127.6, 113.3, 111.4, 56.0, 55.8, 44.9, 44.3, 40.1, 35.9, 34.2, 20.9 (2C),
20.2, 14.3; IR (CHCl3) ν 2955, 1638, 1520, 1248 cm−1; HRMS (ESI
M + H) m/z 306.2069, calcd for C18H28NO3 306.2068.
4-Butyl-2-isopropyl-7,8-dimethoxy-4,5-dihydro-1H-benzo-
[c]azepin-3(2H)-one (3p). White solid: mp 99.3−99.8 °C; 1H NMR
(500 MHz, CDCl3) δ 6.57 (s, 1 H), 6.55 (s, 1 H), 4.96 (m, J = 6.8 Hz,
1 H), 4.85 (d, J = 16.6 Hz, 1 H), 3.88 (d, J = 16.4 Hz, 1 H), 3.86 (s, 3
H), 3.84 (s, 3 H), 3.17−3.10 (m, 1 H), 2.96 (dd, J = 17.1, 3.1 Hz, 1
H), 2.83 (dd, J = 16.9, 13.3 Hz, 1 H), 2.18−1.83 (m, 1 H), 1.54−1.32
(m, 5 H), 1.17 (d, J = 6.8 Hz, 3 H), 0.94 (d, J = 6.9 Hz, 3 H), 0.92 (t, J
= 7.0 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 174.4, 148.0, 146.4,
129.7, 127.6, 113.3, 111.4, 56.0, 55.7, 44.8, 44.2, 40.3, 35.9, 31.7, 30.0,
22.9, 20.8, 20.1, 14.0; IR (CHCl3) ν 2932, 1634, 1520, 1252 cm−1.
Anal. Calcd. for C19H29NO3: C, 71.44; H, 9.15; N, 4.38. Found: C,
71.33; H, 9.18; N, 4.34.
2-Isopropyl-7,8-dimethoxy-4-pentyl-4,5-dihydro-1H-benzo-
[c]azepin-3(2H)-one (3q). Pale yellow oil: 1H NMR (500 MHz,
CDCl3) δ 6.57 (s, 1 H), 6.55 (s, 1 H), 4.96 (m, J = 6.8 Hz, 1 H), 4.85
(d, J = 16.6 Hz, 1 H), 3.88 (d, J = 16.6 Hz, 1 H), 3.86 (s, 3 H), 3.84 (s,
3 H), 3.19−3.10 (m, 1 H), 2.96 (dd, J = 17.0, 3.1 Hz, 1 H), 2.83 (dd, J
= 16.8, 13.3 Hz, 1 H), 2.22−1.80 (m, 1 H), 1.48−1.23 (m, 7 H), 1.17
(d, J = 6.8 Hz, 3 H), 0.94 (d, J = 6.8 Hz, 3 H), 0.90 (t, J = 6.7 Hz, 3
H); 13C NMR (126 MHz, CDCl3) δ 174.4, 148.0, 146.4, 129.7, 127.6,
113.3, 111.4, 56.0, 55.7, 44.8, 44.2, 40.4, 35.9, 32.0, 32.0, 27.4, 22.5,
20.9, 20.1, 14.0; IR (neat) ν 2930, 1638, 1520, 1250 cm−1; HRMS
(ESI M + H) m/z 334.2389, calcd for C20H32NO3 334.2382.
4-Benzyl-2-isopropyl-7,8-dimethoxy-4,5-dhydro-1H-benzo-
[c]azepin-3(2H)-one (3r). White solid: mp 157.5−158.0 °C; 1H
NMR (500 MHz, CDCl3) δ 7.34−7.27 (m, 4 H), 7.24−7.16 (m, 1 H),
6.53 (s, 1 H), 6.50 (s, 1 H), 4.97 (dt, J = 13.6, 6.8 Hz, 1 H), 4.84 (d, J
= 16.6 Hz, 1 H), 3.87 (d, J = 16.8 Hz, 1 H), 3.84 (s, 3 H), 3.80 (s, 3
H), 3.48 (ddd, J = 13.0, 9.2, 4.8 Hz, 1 H), 3.37 (dd, J = 14.1, 5.2 Hz, 1
H), 3.00−2.78 (m, 2 H), 2.70 (dd, J = 14.1, 8.6 Hz, 1 H), 1.18 (d, J =
6.8 Hz, 3 H), 0.96 (d, J = 6.8 Hz, 3 H); 13C NMR (126 MHz, CDCl3)
δ 173.9, 147.9, 146.4, 140.2, 129.2, 129.2, 128.2, 127.4, 126.0, 113.3,
111.3, 55.9, 55.7, 44.8, 44.4, 42.0, 37.8, 34.6, 20.8, 20.0; IR (CHCl3) ν
2932, 1634, 1520, 1248 cm−1. Anal. Calcd. for C22H27NO3: C, 74.76;
H, 7.70; N, 3.96. Found: C, 74.59; H, 7.86; N, 3.90.
6-Methyl-8-pentyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]-
benzo[1,2-c]azepin-7(6H)-one (4e). Pale yellow solid: mp 66.0−
66.5 °C; 1H NMR (500 MHz, CDCl3) δ 6.58 (s, 1 H), 6.55 (s, 1 H),
5.92 (s, 2 H), 5.09 (d, J = 16.2 Hz, 1 H), 3.69 (d, J = 16.3 Hz, 1 H),
3.22−3.12 (m, 1 H), 3.01 (s, 3 H), 2.97 (dd, J = 17.1, 4.3 Hz, 1 H),
2.76 (dd, J = 16.8, 12.9 Hz, 1 H), 2.04−1.80 (m, 1 H), 1.46−1.24 (m,
7 H), 0.89 (t, J = 6.5 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 174.9,
147.2, 145.3, 131.1, 127.3, 110.5, 108.7, 101.0, 53.5, 40.5, 36.3, 35.0,
32.3, 32.0, 27.5, 22.6, 14.1; IR (CHCl3) ν 2926, 1647, 1487, 1225
cm−1; HRMS (ESI M + H) m/z 290.1762, calcd for C17H24NO3
290.1756.
8-Benzyl-6-methyl-8,9-dihydro-5H-[1,3]dioxolo-
1
[4′,5′:4,5benzo[1,2-c]azepin-7(6H)-one (4f). Pale yellow oil: H
NMR (500 MHz, CDCl3) δ 7.36−7.26 (m, 4 H), 7.24−7.16 (m, 1 H),
6.53 (s, 2 H), 5.90 (d, J = 3.2 Hz, 2 H),5.06 (d, J = 16.3 Hz, 1 H), 3.67
(d, J = 16.4 Hz, 1 H), 3.54−3.45 (m, 1 H), 3.33 (dd, J = 13.9, 5.9 Hz, 1
H), 3.03 (s, 3 H), 2.94 (dd, J = 17.0, 4.2 Hz, 1 H), 2.81 (dd, J = 17.0,
13.0 Hz, 1 H), 2.67 (dd, J = 14.0, 7.9 Hz, 1 H); 13C NMR (126 MHz,
CDCl3) δ 174.3, 147.2, 145.3, 140.1, 130.6, 129.2, 128.3, 127.1, 126.1,
110.5, 108.7, 101.0, 53.5, 42.3, 38.0, 35.2, 35.1; IR (neat) ν 2891, 1645,
1487, 1231 cm−1: HRMS (ESI M + H) m/z 310.1436, calcd for
C19H20NO3 310.1443.
6-Ethyl-8-methyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]-
benzo[1,2-c]azepin-7(6H)-one (4g). White solid: mp 160.4−160.8
°C; 1H NMR (500 MHz, CDCl3) δ 6.57 (s, 1 H), 6.56 (s, 1 H), 5.92
(s, 2 H), 5.02 (d, J = 16.4 Hz, 1 H), 3.76 (d, J = 16.4 Hz, 1 H), 3.63−
3.38 (m, 2 H), 3.38−3.15 (m, 1 H), 2.91 (dd, J = 17.1, 4.2 Hz, 1 H),
2.81 (dd, J = 17.0, 12.9 Hz, 1 H), 1.23 (d, J = 6.5 Hz, 3 H), 1.06 (t, J =
7.2 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 174.7, 147.0, 145.3,
130.9, 128.0, 110.2, 108.3, 101.0, 51.4, 42.5, 38.0, 34.8, 17.6, 13.5; IR
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(CHCl3) ν 2899, 1647, 1476, 1233 cm−1. Anal. Calcd. for C14H17NO3:
C, 68.00; H, 6.93; N, 5.66. Found: C, 67.82; H, 7.02; N, 5.72.
6,8-Diethyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-
c]azepin-7(6H)-one (4h). Yellow solid: mp 88.5−89.0 °C; 1H NMR
(500 MHz, CDCl3) δ 6.57 (s, 1 H), 6.56 (s, 1 H), 5.92 (s, 2 H), 5.03
(d, J = 16.4 Hz, 1 H), 3.77 (d, J = 16.4 Hz, 1 H), 3.50 (m, J = 7.1 Hz, 2
H), 3.05 (m, J = 6.3 Hz, 1 H), 2.96 (dd, J = 17.1, 3.7 Hz, 1 H), 2.77
(dd, J = 16.9, 13.2 Hz, 1 H), 2.04−1.88 (m, 1 H), 1.51−1.34 (m, 1 H),
1.06 (t, J = 7.2 Hz, 3 H), 1.00 (t, J = 7.4 Hz, 3 H); 13C NMR (126
MHz, CDCl3) δ 174.1, 147.0, 145.3, 131.0, 128.1, 110.4, 108.4, 101.0,
51.4, 42.4, 42.2, 35.9, 25.2, 13.6, 12.3; IR (CHCl3) ν 2930, 1641, 1487,
1223 cm−1. Anal. Calcd. for C15H19NO3: C, 68.94; H, 7.33; N, 5.36.
Found: C, 68.73; H, 7.41; N, 5.31.
6-Ethyl-8-propyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]-
benzo[1,2-c]azepin-7(6H)-one (4i). Yellow oil: 1H NMR (500
MHz, CDCl3) δ 6.57 (s, 1 H), 6.56 (s, 1 H), 5.92 (s, 2 H), 5.03 (d, J =
16.4 Hz, 1 H), 3.77 (d, J = 16.4 Hz, 1 H), 3.50 (m, J = 6.9 Hz, 2 H),
3.15 (m, J = 5.9 Hz, 1 H), 2.94 (dd, J = 17.0, 3.8 Hz, 1 H), 2.78 (dd, J
= 17.0, 13.1 Hz, 1 H), 2.08−1.88 (m, 1 H), 1.49−1.29 (m, 3 H), 1.06
(t, J = 7.2 Hz, 3 H), 0.95 (t, J = 7.2 Hz, 3 H); 13C NMR (126 MHz,
CDCl3) δ 174.3, 147.1, 145.3, 131.0, 128.1, 110.4, 108.4, 101.0, 51.5,
42.5, 40.2, 36.2, 34.3, 20.9, 14.2, 13.6; IR (neat) ν 2932, 1643, 1485,
1234 cm−1; HRMS (ESI M + H) m/z 276.1599, calcd for C16H22NO3
276.1600.
8-Butyl-6-ethyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]benzo-
[1,2-c]azepin-7(6H)-one (4j). Yellow oil: 1H NMR (500 MHz,
CDCl3) δ 6.57 (s, 1 H), 6.56 (s, 1 H), 5.92 (s, 2 H), 5.03 (d, J = 16.4
Hz, 1 H), 3.76 (d, J = 16.4 Hz, 1 H), 3.50 (m, J = 7.0 Hz, 2 H), 3.18−
3.08 (m, 1 H), 2.95 (dd, J = 17.1, 3.8 Hz, 1 H), 2.78 (dd, J = 17.0, 13.2
Hz, 1 H), 2.00−1.90 (m, 1 H), 1.46−1.28 (m, 5 H), 1.06 (t, J = 7.2
Hz, 3 H), 0.92 (t, J = 7.0 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ
174.4, 147.1, 145.3, 131.1, 128.1, 110.4, 108.4, 101.0, 51.5, 42.5, 40.5,
36.3, 31.9, 30.0, 22.9, 14.1, 13.6; IR (neat) ν 2957, 1649, 1489, 1233
cm−1; HRMS (ESI M + H) m/z 290.1769, calcd for C17H24NO3
290.1756.
6-Ethyl-8-pentyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]-
benzo[1,2-c]azepin-7(6H)-one (4k). Yellow oil: 1H NMR (500
MHz, CDCl3) δ 6.57 (s, 1 H), 6.56 (s, 1 H), 5.92 (s, 2 H), 5.03 (d, J =
16.4 Hz, 1 H), 3.76 (d, J = 16.4 Hz, 1 H), 3.50 (m, J = 7.1 Hz, 2 H),
3.20−3.04 (m, 1 H), 2.94 (dd, J = 17.1, 3.8 Hz, 1 H), 2.78 (dd, J =
17.0, 13.1 Hz, 1 H), 1.98−1.90 (m, 1 H), 1.45−1.28 (m, 7 H), 1.05 (t,
J = 7.2 Hz, 3 H), 0.89 (t, J = 6.6 Hz, 3 H); 13C NMR (126 MHz,
CDCl3) δ 174.3, 147.1, 145.3, 131.1, 128.1, 110.4, 108.4, 101.0, 51.5,
42.5, 40.5, 36.2, 32.2, 32.0, 27.5, 22.6, 14.1, 13.6; IR (neat) ν 2928,
1645, 1487, 1231 cm−1; HRMS (ESI M + H) m/z 304.1931, calcd for
C18H26NO3 304.1913.
MHz, CDCl3) δ 6.56 (s, 1 H), 6.55 (s, 1 H), 5.91 (s, 2 H), 5.04 (d, J =
16.4 Hz, 1 H), 3.74 (d, J = 16.5 Hz, 1 H), 3.50 (dt, J = 13.5, 7.4 Hz, 1
H), 3.33 (dt, J = 13.7, 7.1 Hz, 1 H), 3.12−3.00 (m, 1 H), 2.95 (dd, J =
17.0, 3.6 Hz, 1 H), 2.77 (dd, J = 17.0, 13.2 Hz, 1 H), 2.03−1.89 (m, 1
H), 1.55−1.35 (m, 3 H), 1.00 (t, J = 7.4 Hz, 3 H), 0.80 (t, J = 7.4 Hz, 3
H); 13C NMR (126 MHz, CDCl3) δ 174.5, 147.0, 145.3, 130.9, 128.0,
110.3, 108.4, 101.0, 51.8, 49.3, 42.2, 36.0, 25.2, 21.6, 12.3, 11.2; IR
(neat) ν 2874, 1643, 1487, 1244 cm−1; HRMS (ESI M + H) m/z
276.1610, calcd for C16H22NO3 276.1600.
6,8-Dipropyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]benzo-
[1,2-c]azepin-7(6H)-one (4o). Yellow oil: 1H NMR (500 MHz,
CDCl3) δ 6.57 (s, 1 H), 6.54 (s, 1 H), 5.92 (d, J = 1.5 Hz, 2 H), 5.04
(d, J = 16.4 Hz, 1 H), 3.74 (d, J = 16.4 Hz, 1 H), 3.49 (dt, J = 13.7, 7.4
Hz, 1 H), 3.34 (dt, J = 13.7, 7.1 Hz, 1 H), 3.18−3.13 (m, 1 H), 2.94
(dd, J = 17.1, 3.7 Hz, 1 H), 2.79 (dd, J = 17.0, 13.1 Hz, 1 H), 1.99−
1.90 (m, 1 H), 1.51−1.43 (m, 5 H), 0.95 (t, J = 7.2 Hz, 3 H), 0.80 (t, J
= 7.4 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 174.6, 147.0, 145.3,
131.0, 128.0, 110.3, 108.4, 101.0, 51.8, 49.3, 40.1, 36.3, 34.3, 21.6, 20.9,
14.2, 11.2; IR (neat) ν 2957, 1645, 1487, 1235 cm−1; HRMS (ESI M +
H) m/z 290.1754, calcd for C17H24NO3 290.1756.
8-Butyl-6-propyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]-
benzo[1,2-c]azepin-7(6H)-one (4p). Yellow oil: 1H NMR (500
MHz, CDCl3) δ 6.57 (s, 1 H), 6.54 (s, 1 H), 5.92 (d, J = 1.2 Hz, 2 H),
5.04 (d, J = 16.4 Hz, 1 H), 3.74 (d, J = 16.5 Hz, 1 H), 3.50 (dt, J =
14.9, 7.5 Hz, 1 H), 3.33 (dt, J = 13.8, 7.1 Hz, 1 H), 3.18−3.10 (m, 1
H), 2.95 (dd, J = 17.1, 3.7 Hz, 1 H), 2.79 (dd, J = 17.0, 13.2 Hz, 1 H),
1.98−1.92 (m, 1 H), 1.51−1.29 (m, 7 H), 0.92 (t, J = 7.0 Hz, 3 H),
0.80 (t, J = 7.4 Hz, 3 H); 13C NMR (126 MHz,) δ 174.5, 147.0, 145.2,
130.9, 128.0, 110.3, 108.4, 100.9, 51.8, 49.3, 40.3, 36.3, 31.9, 29.9, 22.8,
21.6, 14.0, 11.1; IR (neat) ν 2928, 1643, 1487, 1229 cm−1; HRMS
(ESI M + H) m/z 304.1923, calcd for C18H26NO3 304.1913.
8-Pentyl-6-propyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]-
benzo[1,2-c]azepin-7(6H)-one (4q). Pale yellow oil: 1H NMR (500
MHz, CDCl3) δ 6.57 (s, 1 H), 6.54 (s, 1 H), 5.92 (d, J = 1.3 Hz, 2 H),
5.04 (d, J = 16.3 Hz, 1 H), 3.74 (d, J = 16.4 Hz, 1 H), 3.50 (dt, J =
13.7, 7.5 Hz, 1 H), 3.33 (dt, J = 13.7, 7.1 Hz, 1 H), 3.21−3.02 (m, 1
H), 2.94 (dd, J = 17.1, 3.7 Hz, 1 H), 2.78 (dd, J = 17.0, 13.2 Hz, 1 H),
2.05−1.75 (m, 1 H), 1.51−1.29 (m, 9 H), 0.89 (t, J = 6.6 Hz, 3 H),
0.80 (t, J = 7.4 Hz, 3 H); 13C NMR (126 MHz,) δ 174.6, 147.0, 145.2,
131.0, 128.0, 110.3, 108.4, 101.0, 51.8, 49.3, 40.4, 36.3, 32.1, 32.0, 27.4,
22.6, 21.6, 14.1, 11.2; IR (neat) ν 2926, 1645, 1487, 1227 cm−1;
HRMS (ESI M + H) m/z 318.2069, calcd for C19H28NO3 318.2069.
8-Benzyl-6-propyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]-
benzo[1,2-c]azepin-7(6H)-one (4r). Yellow solid: mp 103.5−104.0
1
°C; H NMR (500 MHz, CDCl3) δ 7.34−7.27 (m, 4 H), 7.25−7.15
(m, 1 H), 6.52 (s, 1 H), 6.52 (s, 1 H), 5.90 (s, 1 H), 5.89 (s, 1 H), 5.02
(d, J = 16.4 Hz, 1 H), 3.72 (d, J = 16.5 Hz, 1 H), 3.55 (dt, J = 13.7, 7.6
Hz, 1 H), 3.51−3.42 (m, 1 H), 3.34 (dd, J = 14.2, 5.6 Hz, 2 H), 3.29
(dd, J = 13.7, 6.9 Hz, 1 H), 2.93 (dd, J = 17.1, 3.9 Hz, 1 H), 2.83 (dd, J
= 17.0, 12.9 Hz, 1 H), 2.67 (dd, J = 14.0, 8.0 Hz, 1 H), 1.47 (m, J = 7.3
Hz, 2 H), 0.80 (t, J = 7.4 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ
174.0, 146.9, 145.2, 140.1, 130.4, 129.2, 128.2, 127.8, 126.0, 110.3,
108.3, 100.9, 51.7, 49.5, 42.2, 37.9, 35.2, 21.5, 11.1; IR (CHCl3) ν
2928, 1643, 1487, 1231 cm−1. Anal. Calcd. for C21H23NO3: C, 74.75;
H, 6.87; N, 4.15. Found: C, 74.46; H, 6.96; N, 4.08.
Preparation of 3-(4-Methoxyphenyl)-N-methylpropanamide
(5a). EDCI (2.063 g, 30.6 mmol) was added to a solution of 3-(4-
methoxyphenyl)propionic acid (1.814 g, 10.06 mmol) and methyl-
amine hydrochloride (2.06 g, 10.6 mmol) in CH2Cl2 (40 mL) at room
temperature. Et3N (6.25 mL, 45.1 mmol) was then added to the
solution, and the reaction mixture was stirred at room temperature for
6 h. Aqueous HCl (1 M, 100 mL) was added to the reaction mixture,
and the organic phase was separated. The aqueous phase was extracted
with CH2Cl2 (40 mL × 3). The organic phases were combined and
dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo,
and the residue was purified by flash chromatography (silica gel/
hexane then hexane/EtOAc 7:1 to 1:3) to give 5a in 41% yield (804.6
mg, 4.16 mmol). White solid: mp 87.5−88.0 °C;1H NMR (500 MHz,
CDCl3) δ 7.11 (dd, J = 8.8, 2.3 Hz, 2 H), 6.82 (d, J = 8.7 Hz, 2 H),
5.31 (s, 1 H), 3.78 (s, 3 H), 2.90 (t, J = 7.7 Hz, 2 H), 2.76 (d, J = 4.9
8-Benzyl-6-ethyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]-
1
benzo[1,2-c]azepin-7(6H)-one (4l). Pale yellow oil: H NMR (500
MHz, CDCl3) δ 7.37−7.23 (m, 4 H), 7.23−7.13 (m, 1 H), 6.52 (s, 1
H), 6.49 (s, 1 H), 5.86 (d, J = 5.0 Hz, 2 H), 4.97 (d, J = 16.4 Hz, 1 H),
3.72 (d, J = 16.5 Hz, 1 H), 3.56 (dq, J = 14.3, 7.2 Hz, 1 H), 3.49−3.39
(m, 2 H), 3.33 (dd, J = 14.0, 5.5 Hz, 1 H), 2.90 (dd, J = 17.0, 4.0 Hz, 1
H), 2.80 (dd, J = 16.9, 13.0 Hz, 1 H), 2.67 (dd, J = 14.0, 8.1 Hz, 1 H),
1.05 (t, J = 7.2 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 173.8, 147.1,
145.3, 140.1, 130.6, 129.3, 128.3, 127.9, 126.1, 110.4, 108.3, 101.0,
51.4, 42.7, 42.3, 37.9, 35.1, 13.5; IR (neat) ν 2889, 1641, 1487, 1233
cm−1; HRMS (ESI M + H) m/z 324.1617, calcd for C20H22NO3
324.1600.
8-Methyl-6-propyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]-
benzo[1,2-c]azepin-7(6H)-one (4m). White solid: mp 139.0−139.5
°C; 1H NMR (500 MHz, CDCl3) δ 6.56 (s, 1 H), 6.55 (s, 1 H), 5.92
(s, 2 H), 5.03 (d, J = 16.3 Hz, 1 H), 3.74 (d, J = 16.4 Hz, 1 H), 3.58−
3.46 (m, 1 H), 3.40−3.26 (m, 2 H), 2.91 (dd, J = 17.1, 4.1 Hz, 1 H),
2.82 (dd, J = 17.1, 12.8 Hz, 1 H), 1.54−1.41 (m, 2 H), 1.23 (d, J = 6.5
Hz, 3 H), 0.81 (t, J = 7.4 Hz, 3 H); 13C NMR (126 MHz,) δ 175.0,
147.0, 145.3, 130.9, 127.9, 110.2, 108.4, 101.0, 51.9, 49.5, 38.1, 34.8,
21.6, 17.6, 11.2; IR (CHCl3) ν 2930, 1643, 1485, 1229 cm−1. Anal.
Calcd. for C15H19NO3: C, 68.94; H, 7.33; N, 5.36. Found: C, 68.61; H,
7.33; N, 5.40.
8-Ethyl-6-propyl-8,9-dihydro-5H-[1,3]dioxolo[4′,5′:4,5]-
benzo[1,2-c]azepin-7(6H)-one (4n). Pale yellow oil: 1H NMR (500
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Hz, 3 H), 2.42 (t, J = 8.8 Hz, 2 H); 13C NMR (126 MHz, CDCl3) δ
172.9, 158.1, 133.0, 129.4, 114.0, 55.4, 38.9, 31.0, 26.4; HRMS (FAB
M + H) m/z 194.1177, calcd for C11H16NO2 194.1181.
C21H23NO5: C, 68.28; H, 6.28; N, 3.79. Found: C, 68.19; H, 6.38;
N, 3.77.
R-7 was prepared in a similar manner.
(R)-4-Benzyl-3-(3-(3,4-dimethoxyphenyl)propanoyl)-
oxazolidin-2-one (R-7). White solid: mp 91.5−92.0 °C; [α]D −47.3°
(c = 0.99, CHCl3); the enantiomeric purity was determined by HPLC
analysis (230 nm, 40 °C) tR 35.2 min (major); tR 38.2 min (minor)
[CHIRALPAK IC (2.1 mm × 250 mm) (from Daicel Chemical Ind.,
Compound 5b was prepared in a similar manner.
3-(3-Methoxyphenyl)-N-methylpropanamide (5b). Colorless
1
oil: H NMR (500 MHz, CDCl3) δ 7.20 (dd, J = 8.9, 7.5 Hz, 1 H),
6.78 (d, J = 7.5 Hz, 1 H), 6.76−6.72 (m, 2 H), 5.36 (s, 1 H), 3.78 (s, 3
H), 2.94 (t, J = 7.8 Hz, 2 H), 2.77 (d, J = 4.9 Hz, 2 H), 2.45 (d, J = 7.8
Hz, 2 H); 13C NMR (126 MHz, CDCl3) δ 172.9, 158.1, 133.0, 129.4,
114.0, 55.4, 38.9, 31.0, 26.4; HRMS (FAB M + H) m/z 194.1175,
calcd for C11H16NO2 194.1181.
Preparation of 6b. Paraformaldehyde (0.0653 g, 2.17 mmol) and
TFA (0.41 mL, 5.4 mmol) were added to a solution of 3-(3-
methoxyphenyl)-N-methylpropanamide 5b (0.103 g, 0.531 mmol) in
ClCH2CH2Cl (11 mL) at room temperature, and the reaction mixture
was stirred at room temperature for 4 h. Saturated aqueous NaHCO3
(15 mL) was then added, and the resulting biphasic mixture was
extracted with CH2Cl2 (3 × 50 mL). The organic phases were
combined and dried over Na2SO4. After filtration, the filtrate was
concentrated using a rotary evaporator, and the residue was purified by
flash chromatography (silica gel/hexane then hexane/EtOAc 3:1 to
1:3) to give 6b in 34% yield (0.0373 g, 0.182 mmol). o-6b and p-6b
were separated by preparative recycle HPLC apparatus.
1
Ltd.) hexane/i-PrOH, 85/15, 1.00 mL/min] as >99% ee; H NMR
(500 MHz, CDCl3) δ 7.35−7.26 (m, 3 H), 7.17 (d, J = 6.8 Hz, 2 H),
6.84−6.79 (m, 3 H), 4.67 (ddd, J = 12.9, 7.0, 3.4 Hz, 1 H), 4.19 (dd, J
= 9.2, 7.0 Hz, 1 H), 4.15 (dd, J = 9.0, 3.3 Hz, 1 H), 3.88 (s, 3 H), 3.86
(s, 3 H), 3.36−3.17 (m, 3 H), 3.00 (dd, J = 14.1, 6.7 Hz, 1 H), 2.95
(dd, J = 14.0, 7.0 Hz, 1 H), 2.75 (dd, J = 13.4, 9.5 Hz, 1 H); 13C NMR
(126 MHz, CDCl3) δ 172.5, 153. 4, 148.9, 147.5, 135.2, 133.1, 129.4,
128.9, 127.4, 120.5, 111.9, 111.3, 66.2, 55.9, 55.9, 55.1, 37.8, 37.3, 30.0;
IR (CHCl3) ν 2936, 1778, 1258, 1028 cm−1. Anal. Calcd. for
C21H23NO5: C, 68.28; H, 6.28; N, 3.79. Found: C, 68.02; H, 6.37; N,
3.81.
(S)-4-Benzyl-3-((S)-3-(3,4-dimethoxyphenyl)-2-
methylpropanoyl)oxazolidin-2-one (S,S-8a). Under a nitrogen
atmosphere, LDA (1.0 M, 5.5 mL, 5.5 mmoL) was added slowly to a
solution of (S)-7 (1.853 g, 5.016 mmol) in THF (50 mL) at −78 °C,
and the reaction mixture was then stirred at the same temperature for
30 min. Iodomethane (1.40 mL, 22.5 mmol) was added to the reaction
mixture, and the resulting solution was stirred at −78 °C for 2 h and
then at room temperature for 30 min. Saturated aqueous NH4Cl (20
mL) was added to the reaction mixture. THF was removed under
reduced pressure. Saturated brine (20 mL) was then added to the
residue, and the resulting aqueous solution was extracted with EtOAc
(50 mL × 3). The organic phases were combined, dried over Na2SO4,
and filtered. The filtrate was concentrated under reduced pressure.
The residue was purified by flash chromatography (silica gel/hexane
then hexane/EtOAc 4:1) to afford S,S-8a in 69% yield (1.334 g, 3.480
mmol). Colorless oil: [α]D +103.7° (c = 1.01, CHCl3); HPLC analysis
indicated diastereomeric ratio was 96/4; 1H NMR (500 MHz, CDCl3)
δ 7.36−7.28 (m, 3 H), 7.20 (d, J = 6.9 Hz, 2 H), 6.79−6.75 (m, 3 H),
4.52 (dddd, J = 9.9, 7.7, 3.2, 2.4 Hz, 1 H), 4.15−4.05 (m, 2 H), 3.99 (t,
J = 8.4 Hz, 1 H), 3.87 (s, 3 H), 3.85 (s, 3 H), 3.24 (dd, J = 13.3, 3.3
Hz, 1 H), 2.98 (dd, J = 13.4, 7.8 Hz, 1 H), 2.75 (dd, J = 13.4, 9.6 Hz, 1
H), 2.65 (dd, J = 13.4, 7.3 Hz, 1 H), 1.25 (d, J = 6.8 Hz, 3 H); 13C
NMR (126 MHz, CDCl3) δ 176.3, 152.9, 148.5, 147.3, 135.1, 131.6,
129.2, 128.7, 127.1, 120.9, 112.0, 110.8, 65.8, 55.6, 55.8, 55.1, 39.4,
39.3, 37.6, 16.8; IR (neat) ν 2934, 1773, 1694, 1234, 1026, 727 cm−1;
HRMS (ESI M + H) m/z 384.1808, calcd for C22H26NO5 384.1811.
Other compounds 8 were prepared in a similar manner.
9-Methoxy-2-methyl-4,5-dihydro-1H-benzo[c]azepin-3(2H)-
one (o-6b). Pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.16 (t, J
= 8.0 Hz, 1 H), 6.75 (d, J = 7.7 Hz, 1 H), 6.72 (d, J = 8.2 Hz, 1 H),
4.64 (s, 2 H), 3.82 (s, 3 H), 3.12 (t, J = 6.9 Hz, 2 H), 3.03 (s, 3 H),
2.88 (t, J = 6.9 Hz, 2 H); 13C NMR (126 MHz, CDCl3) δ 173.9, 156.3,
140.0, 128.4, 123.9, 122.4, 108.1, 55.8, 44.7, 35.8, 34.0, 29.1; HRMS
(FAB M + H) m/z 206.1189, calcd for C12H16NO2 206.1181.
7-Methoxy-2-methyl-4,5-dihydro-1H-benzo[c]azepin-3(2H)-
1
one (p-6b). White solid: mp 107.0−107.5 °C; H NMR (500 MHz,
CDCl3) δ 7.00 (d, J = 8.2 Hz, 1 H), 6.69 (d, J = 2.5 Hz, 1 H), 6.67 (dd,
J = 8.2, 2.7 Hz, 1 H), 4.43 (s, 2 H), 3.78 (s, 3 H), 3.14 (t, J = 6.5 Hz, 2
H), 3.04 (s, 3 H), 2.91 (t, J = 6.5 Hz, 2 H); 13C NMR (126 MHz,
CDCl3) δ 173.5, 159.4, 139.1, 130.1, 126.7, 115.7, 111.4, 55.8, 53.9,
35.2, 33.6, 29.1; HRMS (ESI M + H) m/z 206.1177, calcd for
C12H16NO2 206.1181.
(S)-4-Benzyl-3-(3-(3,4-dimethoxyphenyl)propanoyl)-
oxazolidin-2-one (S-7). Et3N (1.66 mL, 11.9 mmol) and pivaloyl
chloride (1.28 mL, 10.4 mmol) were added to a solution of 3-(3,4-
dimethoxyphenyl)propanoic acid (2.102 g, 9.999 mmol) in THF (50
mL) at −78 °C, and the reaction mixture was stirred at the same
temperature for 1 h. LDA (1.0 M, 12.0 mL) was slowly added to a
solution of (S)-4-benzyloxazolidin-2-one (1.952 g, 11.0 mmol) in THF
(50 mL) at −78 °C. The former reaction mixture was then transferred
via a cannula to the latter solution at −78 °C, and the resulting mixture
was stirred at the same temperature for 1 h and then at room
temperature for 24 h. Saturated aqueous NH4Cl (20 mL) was added to
the reaction mixture. THF was removed using a rotary evaporator
under reduced pressure. Saturated aqueous NaHCO3 (50 mL) was
added to the residue. The resulting mixture was extracted with EtOAc
(50 mL × 3). The organic phases were combined, dried over Na2SO4,
and filtered. The filtrate was then concentrated under reduced
pressure, and the residue was purified by flash chromatography (silica
gel/hexane then hexane/EtOAc 3:1) to afford S-7 in 91% yield (3.361
g, 9.099 mmol). White solid: mp 91.5−92.0 °C; [α]D +47.8° (c = 0.99,
CHCl3); the enantiomeric purity was determined by HPLC analysis
(230 nm, 40 °C) tR 37.0 min (major); tR 34.9 min (minor)
[CHIRALPAK IC (2.1 mm × 250 mm) (from Daicel Chemical Ind.,
(R)-4-Benzyl-3-((R)-3-(3,4-dimethoxyphenyl)-2-
methylpropanoyl)oxazolidin-2-one (R,R-8a). Pale yellow oil: [α]D
−87.9° (c = 3.28, CHCl3); HPLC analysis indicated diastereomeric
1
ratio was 96/4; H NMR (500 MHz, CDCl3) δ 7.37−7.26 (m, 3 H),
7.20 (d, J = 6.9 Hz, 2 H), 6.81−6.73 (m, 3 H), 4.52 (dddd, J = 9.8, 7.7,
3.3, 2.5 Hz, 1 H), 4.13−4.08 (m, 2 H), 4.03−3.95 (t, J = 8.4 Hz, 1 H),
3.87 (s, 3 H), 3.85 (s, 3 H), 3.24 (dd, J = 13.4, 3.3 Hz, 1 H), 2.98 (dd,
J = 13.4, 7.8 Hz, 1 H), 2.75 (dd, J = 13.4, 9.6 Hz, 1 H), 2.65 (dd, J =
13.4, 7.3 Hz, 1 H), 1.25 (d, J = 6.8 Hz, 3 H); 13C NMR (126 MHz,
CDCl3) δ 176.5, 153.1, 148.6, 147.5, 135.2, 131.8, 129.4, 128.9, 127.3,
121.1, 112.2, 110.9, 66.0, 55.8, 55.8, 55.4, 39.6, 39.5, 37.8, 17.0; IR
(neat) ν 2932, 1775, 1695, 1236, 729 cm−1; HRMS (ESI M + H) m/z
384.1825, calcd for C22H26NO5 384.1811.
(S)-4-Benzyl-3-((S)-2-(3,4-dimethoxybenzyl)pent-4-enoyl)-
oxazolidin-2-one (S,S-8b). Pale yellow oil: [α]D +107.3° (c = 0.98,
1
1
Ltd.) hexane/i-PrOH, 85/15, 1.00 mL/min] as >99% ee; H NMR
CHCl3); HPLC analysis indicated diastereomeric ratio was 99/1; H
(500 MHz, CDCl3) δ 7.36−7.24 (m, 3 H), 7.17 (d, J = 6.9 Hz, 2 H),
6.83−6.78 (m, 3 H), 4.67 (ddd, J = 12.9, 6.9, 3.4 Hz, 1 H), 4.19 (dd, J
= 9.1, 6.5 Hz, 1 H), 4.16 (dd, J = 9.1, 3.4 Hz, 1 H), 3.89 (s, 3 H), 3.86
(s, 3 H), 3.34−3.19 (m, 3 H), 3.01 (dd, J = 13.8 Hz, 6.4 Hz, 1 H), 2.93
(dd, J = 13.8, 6.7 Hz, 1 H), 2.75 (dd, J = 13.4, 9.5 Hz, 1 H); 13C NMR
(126 MHz, CDCl3) δ 172.4, 153.4, 148.8, 147.4, 135.1, 133.0, 129.4,
128.9, 127.3, 120.4, 111.9, 111.2, 66.1, 55.9, 55.8, 55.0, 37.7, 37.3, 29.9;
IR (CHCl3) ν 2936, 1643, 907, 725 cm−1. Anal. Calcd. for
NMR (500 MHz, CDCl3) δ 7.35−7.27 (m, 3 H), 7.19 (d, J = 6.9 Hz, 2
H), 6.80−6.70 (m, 3 H), 5.92−5.80 (m, 1 H), 5.13 (dq, J = 17.0, 1.5
Hz, 1 H), 5.08 (ddd, J = 11.1, 1.9, 0.9 Hz, 1 H), 4.46 (dddd, J = 10.0,
7.7, 3.3, 2.4 Hz, 1 H), 4.39−4.29 (m, 1 H), 4.03 (dd, J = 9.0, 2.4 Hz, 1
H), 3.87 (s, 3 H), 3.86 (dd, J = 9.3, 6.9 Hz, 1 H), 3.84 (s, 3 H), 3.23
(dd, J = 13.3, 3.3 Hz, 1 H), 2.90 (dd, J = 13.5, 8.9 Hz, 1 H), 2.78 (dd, J
= 13.5, 6.5 Hz, 1 H), 2.65 (dd, J = 13.4, 9.9 Hz, 1 H), 2.60−2.50 (m, 1
H), 2.40−2.31 (m, 1 H); 13C NMR (126 MHz, CDCl3) δ 175.3,
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Article
153.1, 148.6, 147.5, 135.3, 135.1, 131.4, 129.4, 128.8, 127.2, 121.0,
117.3, 112.1, 110.9, 65.8, 55.8, 55.8, 55.4, 43.9, 38.0, 37.9, 36.3; IR
(neat) ν 2934, 1775, 1236, 1028 cm−1; HRMS (ESI M + H) m/z
410.1968, calcd for C24H28NO5 410.1967.
41.5, 39.0, 16.5; IR (neat) ν 3650−3450, 2938, 1705, 1261, 905 cm−1;
HRMS (ESI M − H) m/z 223.0969, calcd for C12H15O4 223.0970.
Other compounds 9 were prepared in a similar manner.
(R)-3-(3,4-Dimethoxyphenyl)-2-methylpropanoic Acid (R-
9a). Pale yellow oil: [α]D −18.8° (c = 2.54, CHCl3); the enantiomeric
purity was determined by HPLC analysis (230 nm, 40 °C) tR 24.4 min
(major); tR 15.7 min (minor) [CHIRALPAK IC (2.1 mm × 250 mm)
(from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 80/20, 1.00 mL/
min] as 92% ee; 1H NMR (500 MHz, CDCl3) δ 6.81−6.69 (m, 3 H),
3.86 (s, 6 H), 3.01 (m, J = 6.9 Hz, 1 H), 2.73 (dd, J = 14.1, 7.0 Hz, 1
H), 2.62 (dd, J = 13.6, 7.9 Hz, 1 H), 1.17 (d, J = 6.9 Hz, 3 H); 13C
NMR (126 MHz, CDCl3) δ 182.5, 148.8, 147.6, 131.6, 121.0, 112.2,
111.2, 55.8, 55.7, 41.5, 38.9, 16.5; IR (neat) ν 3600−3000, 2936, 1703,
1514, 1260, 1140 cm−1; HRMS (ESI M − H) m/z 223.0968, calcd for
C12H15O4 223.0970.
(R)-4-Benzyl-3-((R)-2-(3,4-dimethoxybenzyl)pent-4-enoyl)-
oxazolidin-2-one (R,R-8b). Pale yellow oil: [α]D −105.5° (c= 1.05,
1
CHCl3); HPLC analysis indicated diastereomeric ratio was 99/1; H
NMR (500 MHz, CDCl3) δ 7.35−7.24 (m, 3 H), 7.19 (d, J = 7.0 Hz, 2
H), 6.82−6.69 (m, 3 H), 5.86 (ddt, J = 17.1, 10.1, 7.0 Hz, 1 H), 5.13
(d, J = 17.1 Hz, 1 H), 5.08 (d, J = 10.2 Hz, 1 H), 4.49−4.43 (m, 1 H),
4.36−4.30 (m, 1 H), 4.03 (dd, J = 9.0, 2.3 Hz, 1 H), 3.86 (s, 1 H), 3.86
(dd, J = 9.3, 6.9 Hz, 1 H), 3.83 (s, 1 H), 3.23 (dd, J = 13.4, 3.1 Hz, 1
H), 2.90 (dd, J = 13.5, 8.9 Hz, 1 H), 2.78 (dd, J = 13.5, 6.5 Hz, 1 H),
2.65 (dd, J = 13.3, 9.9 Hz, 1 H), 2.58−2.51 (m, 1 H), 2.38−2.33 (m, 1
H); 13C NMR (126 MHz,) δ 175.5, 153.2, 148.7, 147.6, 135.4, 135.2,
131.5, 129.5, 129.0, 127.4, 121.1, 117.4, 112.2, 111.0, 65.9, 55.9, 55.9,
55.6, 44.0, 38.1, 38.1, 36.4; IR (neat) ν 2916, 1775, 1695, 1516, 1236
cm−1; HRMS (ESI M + H) m/z 410.1960, calcd for C24H28NO5
410.1967.
(S)-4-Benzyl-3-((S)-2-benzyl-3-(3,4-dimethoxyphenyl)-
propanoyl)oxazolidin-2-one (S,S-8c). Pale yellow oil: [α]D +85.7°
(c = 0.97, CHCl3); HPLC analysis indicated diastereomeric ratio was
>99/1; 1H NMR (500 MHz, CDCl3) δ 7.30−7.18 (m, 8 H), 6.94 (dd,
J = 7.0, 2.4 Hz, 2 H), 6.81−6.73 (m, 3 H), 4.70−4.62 (m, 1 H), 4.44−
4.38 (m, 1 H), 3.93 (dd, J = 9.0, 2.5 Hz, 1 H), 3.86 (s, 3 H), 3.83 (s, 3
H), 3.81 (t, J = 7.7 Hz, 1 H), 3.11 (dd, J = 13.4, 9.1 Hz, 1 H), 2.95 (dd,
J = 13.5, 8.9 Hz, 1 H), 2.90 (dd, J = 14.6, 3.3 Hz, 1 H), 2.87 (dd, J =
13.4, 6.0 Hz, 1 H), 2.80 (dd, J = 13.4, 6.6 Hz, 1 H), 2.42 (dd, J = 13.5,
9.1 Hz, 1 H); 13C NMR (126 MHz, CDCl3) δ 175.2, 152.8, 148.6,
147.5, 138.9, 134.9, 131.2, 129.3, 129.2, 128.7, 128.3, 127.1, 126.4,
121.0, 112.0, 110.9, 65.5, 55.8, 55.7, 54.9, 46.1, 38.4, 38.1, 37.4; IR
(neat) ν 2946, 1775, 1236, 1028 cm−1; HRMS (ESI M + H) m/z
460.2097, calcd for C28H30NO5 460.2124.
(R)-4-Benzyl-3-((R)-2-benzyl-3-(3,4-dimethoxyphenyl)-
propanoyl)oxazolidin-2-one (R,R-8c). Pale yellow oil: [α]D −86.9°
(c = 1.16, CHCl3); HPLC analysis indicated diastereomeric ratio was
>99/1; 1H NMR (500 MHz, CDCl3) δ 7.31−7.18 (m, 8 H), 6.94 (dd,
J = 6.9, 2.5 Hz, 2 H), 6.81−6.71 (m, 3 H), 4.66 (tt, J = 8.9, 6.3 Hz, 1
H), 4.44−4.39 (m, 1 H), 3.93 (dd, J = 9.0, 2.4 Hz, 1 H), 3.86 (s, 3 H),
3.84 (s, 3 H), 3.81 (d, J = 8.6 Hz, 1 H), 3.11 (dd, J = 13.4, 9.2 Hz, 1
H), 2.95 (dd, J = 13.3, 8.7 Hz, 2 H), 2.91 (dd, J = 13.2, 3.1 Hz, 1 H),
2.87 (dd, J = 13.4, 6.0 Hz, 1 H), 2.80 (dd, J = 13.4, 6.6 Hz, 1 H), 2.42
(dd, J = 13.5, 9.1 Hz, 1 H); 13C NMR (126 MHz, CDCl3) δ 175.4,
152.9, 148.7, 147.5, 138.9, 135.0, 131.3, 129.3, 129.3, 128.8, 128.4,
127.2, 126.5, 121.0, 112.1, 110.9, 65.6, 55.9, 55.8, 55.0, 46.2, 38.5, 38.2,
37.5; IR (neat) ν 2936, 1775, 1260, 1028 cm−1; HRMS (ESI M + H)
m/z 460.2108, calcd for C28H30NO5 460.2124.
Preparation of (S)-3-(3,4-Dimethoxyphenyl)-2-methylpropa-
noic Acid (S-9a). H2O2 (30% in water, 0.40 mL, 3.9 mmol) and
LiOH (0.025 g, 1.04 mmol) in water (1 mL) were added to a solution
of (S,S)-8a (0.154 g, 0.400 mmol) in THF (3 mL) at 0 °C. The
reaction mixture was allowed to warm to room temperature and then
stirred for 4 h. Aqueous 30% Na2S2O3 (2 mL) was added slowly to the
mixture at 0 °C, and THF was removed using a rotary evaporator
under reduced pressure. 3 N HCl aq (10 mL) was added to the
residue, and the aqueous mixture was extracted with EtOAc (20 mL ×
3). The organic phases were combined, dried over Na2SO4, and
filtered. The filtrate was then concentrated under reduced pressure,
and the crude product was purified by flash chromatography (silica
gel/hexane then hexane/EtOAc 1:1) to give S-9a in 87% yield (0.078
g, 0.35 mmol). Pale yellow oil: [α]D +14.8° (c = 2.23, CHCl3); the
enantiomeric purity was determined by HPLC analysis (230 nm, 40
°C) tR 23.2 min (major); tR 16.8 min (minor) [CHIRALPAK IC (2.1
mm × 250 mm) (from Daicel Chemical Ind., Ltd.) hexane/i-PrOH,
80/20, 1.00 mL/min] as 92% ee; 1H NMR (500 MHz, CDCl3) δ 6.79
(d, J = 8.1 Hz, 1 H), 6.73 (dd, J = 10.9, 2.7 Hz, 2 H), 3.86 (s, 6 H),
3.01 (dd, J = 13.6, 6.7 Hz, 1 H), 2.74 (m, J = 7.0 Hz, 1 H), 2.63 (dd, J
= 13.6, 7.8 Hz, 1 H), 1.18 (d, J = 6.9 Hz, 3 H); 13C NMR (126 MHz,
CDCl3) δ 182.4, 148.8, 147.6, 131.6, 121.0, 112.2, 111.2, 55.9, 55.8,
(S)-2-(3,4-Dimethoxybenzyl)pent-4-enoic Acid (S-9b). Pale
yellow oil: [α]D +23.5° (c = 1.11, CHCl3); the enantiomeric purity was
determined by HPLC analysis (230 nm, 40 °C) tR 22.8 min (major);
tR 14.2 min (minor) [CHIRALPAK IC (2.1 mm × 250 mm) (from
Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 80/20, 1.00 mL/min] as
1
97% ee.; H NMR (500 MHz, CDCl3) δ 6.78 (d, J = 8.1 Hz, 1 H),
6.74−6.71 (m, 2 H), 5.79 (ddt, J = 17.1, 10.1, 7.0 Hz, 1 H), 5.13−5.05
(m, 2 H), 3.85 (s, 6 H), 2.93 (td, J = 10.2, 4.9 Hz, 1 H), 2.84−2.68 (m,
2 H), 2.42−2.26 (m, 2 H); 13C NMR (126 MHz, CDCl3) δ 181.1,
148.7, 147.5, 134.8, 131.3, 120.9, 117.4, 112.1, 111.1, 55.8, 55.7, 47.2,
36.9, 35.6; IR (neat) 3400−3000, 2936, 1705, 1260, 1140 cm−1;
HRMS (ESI M − H) m/z 249.1132, calcd for C14H17O4 249.1127.
(R)-2-(3,4-Dimethoxybenzyl)pent-4-enoic Acid (R-9b). Pale
yellow oil: [α]D −16.5° (c = 1.03, CHCl3); the enantiomeric purity
was determined by HPLC analysis (230 nm, 40 °C) tR 12.3 min
(major); tR 24.5 min (minor) [CHIRALPAK IC (2.1 mm × 250 mm)
(from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 80/20, 1.00 mL/
min] as 98% ee; 1H NMR (500 MHz, CDCl3) δ 6.79 (d, J = 8.1 Hz, 1
H), 6.76−6.68 (m, 2 H), 5.79 (ddt, J = 17.1, 10.2, 7.0 Hz, 1 H), 5.16−
5.04 (m, 2 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 2.98−2.90 (m, 1 H), 2.79−
2.72 (m, 2 H), 2.41−2.26 (m, 2 H); 13C NMR (126 MHz, CDCl3) δ
180.9, 148.6, 147.5, 134.8, 131.2, 120.8, 117.3, 112.0, 111.0, 55.7, 55.6,
47.1, 36.9, 35.5; IR (neat) ν 3400−3000, 2936, 1732, 1705, 1236
cm−1; HRMS (ESI M − H) m/z 249.1130, calcd for C14H17O4
249.1127.
(S)-2-Benzyl-3-(3,4-dimethoxyphenyl)propanoic Acid (S-9c).
Pale yellow oil: [α]D +5.8° (c = 1.17, CHCl3); the enantiomeric purity
was determined by HPLC analysis (230 nm, 40 °C) tR 27.7 min
(major); tR 33.6 min (minor) [CHIRALPAK IC (2.1 mm × 250 mm)
(from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 82/18, 0.70 mL/
min] as >99% ee; 1H NMR (500 MHz, CDCl3) δ 7.31−7.15 (m, 5 H),
6.77 (d, J = 8.2 Hz, 1 H), 6.71 (dd, J = 8.1, 2.0 Hz, 1 H), 6.67 (d, J =
1.9 Hz, 1 H), 3.85 (s, 3 H), 3.83 (s, 3 H), 3.11−2.90 (m, 3 H), 2.88−
2.64 (m, 2 H); 13C NMR (126 MHz, CDCl3) δ 181.0, 148.8, 147.7,
138.8, 131.3, 128.9, 128.5, 126.5, 120.9, 112.1, 111.3, 55.8, 55.8, 49.4,
37.6, 37.4; IR (neat) 3300, 3000, 2936, 1705, 1260, 727 cm−1; HRMS
(ESI M − H) m/z 299.1294, calcd for C18H19O4 299.1283.
(R)-2-Benzyl-3-(3,4-dimethoxyphenyl)propanoic Acid (R-9c).
Colorless oil: [α]D −6.2° (c = 0.98, CHCl3); the enantiomeric purity
was determined by HPLC analysis (230 nm, 40 °C) tR 31.4 min
(major); tR 28.4 min (minor) [CHIRALPAK IC (2.1 mm × 250 mm)
(from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 82/18, 0.70 mL/
min] as >99% ee; 1H NMR (500 MHz, CDCl3) δ 7.31−7.15 (m, 5 H),
6.77 (d, J = 8.2 Hz, 1 H), 6.71 (dd, J = 8.1, 2.0 Hz, 1 H), 6.67 (d, J =
1.9 Hz, 1 H), 3.85 (s, 3 H), 3.83 (s, 3 H), 2.97−2.93 (m, 3 H), 2.84−
2.74 (m, 2 H); 13C NMR (126 MHz, CDCl3) δ 181.0, 148.8, 147.6,
138.8, 131.2, 128.9, 128.5, 126.5, 120.9, 112.1, 111.2, 55.8, 55.8, 49.4,
37.6, 37.4; IR (neat) ν 3500−3000, 2936, 1705, 1260, 1028 cm−1;
HRMS (ESI M − H) m/z 299.1299, calcd for C18H19O4 299.1283.
Preparation of (S)-7,8-Dimethoxy-2,4-dimethyl-4,5-dihydro-
1H-benzo[c]azepin-3(2H)-one (S-3a). A solution of 9a (0.116 g,
0.516 mmol) and SOCl2 (0.11 mL, 1.5 mmol) in THF (5 mL) was
heated at reflux for 4 h. THF and excess amounts of SOCl2 were then
evaporated under reduced pressure. CH2Cl2 (5 mL) was added to the
residue, and this solution was added slowly to a biphasic mixture of
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Article
CH2Cl2 (3 mL), saturated aqueous NaHCO3 (3 mL), and an aqueous
solution of MeNH2 (40%, 0.20 mL, 2.3 mmol) at 0 °C. This reaction
mixture was stirred for 2 h. Saturated aqueous NaHCO3 (5 mL) was
added to the mixture, and the reaction mixture was extracted with
CH2Cl2 (10 mL × 3). The organic phases were combined, dried over
Na2SO4, and filtered. The filtrate was then concentrated under reduced
pressure to give N-methyl-propanamide (0.127 g), which was used for
the next step without further purification.
(tt, J = 13.0, 6.5 Hz, 1 H), 2.93 (dd, J = 17.1, 4.0 Hz, 1 H), 2.86 (dd, J
= 17.1, 12.5 Hz, 1 H), 1.25 (d, J = 6.5 Hz, 3 H), 1.07 (t, J = 7.2 Hz, 3
H); 13C NMR (126 MHz, CDCl3) δ 175.0, 148.3, 146.6, 129.7, 126.9,
113.3, 111.6, 56.1, 55.9, 51.6, 42.7, 37.8, 34.8, 17.6, 13.6; IR (CHCl3) ν
2970, 1645, 1522, 1252 cm−1. Anal. Calcd. for C15H21NO3: C, 68.42;
H, 8.04; N, 5.32. Found: C, 68.09; H, 8.05; N, 5.28.
(S)-7,8-Dimethoxy-4-methyl-2-propyl-4,5-dihydro-1H-
benzo[c]azepin-3(2H)-one (S-3s). Pale yellow oil: [α]D +91.4° (c =
0.98, CHCl3); the enantiomeric purity was determined by HPLC
analysis (230 nm, 40 °C) tR 11.5 min (major); tR 14.0 min (minor)
[CHIRALPAK AD (2.1 mm × 250 mm) (from Daicel Chemical Ind.,
Ltd.) hexane/i-PrOH, 94/6, 1.00 mL/min] as 91% ee; 1H NMR (500
MHz, CDCl3) δ 6.59 (s, 1 H), 6.55 (s, 1 H), 5.11 (d, J = 16.3 Hz, 1
H), 3.86 (s, 3 H), 3.84 (s, 3H), 3.77 (d, J = 16.5 Hz, 1 H), 3.53−3.47
(m, 1 H), 3.41−3.31 (m, 2 H), 2.93 (dd, J = 16.9, 4.5 Hz, 1 H), 2.86
(dd, J = 17.1, 12.5 Hz, 1 H), 1.53−1.44 (m, 2 H), 1.25 (d, J = 6.5 Hz, 3
H), 0.81 (t, J = 7.4 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 174.8,
147.8, 146.1, 129.2, 126.5, 113.0, 111.4, 55.6, 55.4, 51.5, 49.1, 37.3,
34.3, 21.2, 17.1, 10.8; IR (neat) ν 2934, 1641, 1196, 907 cm−1; HRMS
(ESI M + H) m/z 278.1762, calcd for C16H24NO3 278.1756.
(R)-7,8-Dimethoxy-4-methyl-2-propyl-4,5-dihydro-1H-
benzo[c]azepin-3(2H)-one (R-3s). Pale yellow oil: [α]D −91.2° (c =
1.02, CHCl3); the enantiomeric purity was determined by HPLC
analysis (230 nm, 40 °C) tR 13.6 min (major); tR 11.0 min (minor)
[CHIRALPAK AD (2.1 mm × 250 mm) (from Daicel Chemical Ind.,
Ltd.) hexane/i-PrOH, 94/6, 1.00 mL/min] as 89% ee; 1H NMR (500
MHz, CDCl3) δ 6.59 (s, 1 H), 6.55 (s, 1 H), 5.11 (d, J = 16.3 Hz, 1
H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.77 (d, J = 16.5 Hz, 1 H), 3.53−3.47
(m, 1 H), 3.41−3.32 (m, 2 H), 2.93 (dd, J = 17.0, 4.2 Hz, 1 H), 2.86
(dd, J = 17.1, 12.5 Hz, 1 H), 1.54−1.44 (m, 1 H), 1.25 (d, J = 6.5 Hz, 3
H), 0.81 (t, J = 7.4 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 175.2,
148.0, 146.3, 129.4, 126.6, 113.1, 111.5, 55.8, 55.7, 51.7, 49.4, 37.5,
34.5, 21.4, 17.3, 11.0; IR (neat) ν 2933, 1640, 1520, 1196 cm−1;
HRMS (ESI M + H) m/z 278.1758, calcd for C16H24NO3 278.1756.
(S)-4-Allyl-7,8-dimethoxy-2-methyl-4,5-dihydro-1H-benzo-
[c]azepin-3(2H)-one (S-3t). White solid: mp 123.5−124.0 °C; [α]D
+93.9° (c = 1.09, CHCl3); the enantiomeric purity was determined by
HPLC analysis (230 nm, 40 °C) tR 11.0 min (major); tR 12.7 min
(minor) [CHIRALPAK AD (2.1 mm × 250 mm) (from Daicel
Chemical Ind., Ltd.) hexane/i-PrOH, 90/10, 1.00 mL/min] as 97% ee;
1H NMR (500 MHz, CDCl3) δ 6.61 (s, 1 H), 6.56 (s, 1 H), 5.95−5.85
(m, 1 H), 5.20−5.11 (m, 2 H), 5.07 (d, J = 10.2 Hz, 1 H), 3.87 (s, 3
H), 3.84 (s, 3 H), 3.73 (d, J = 16.4 Hz, 1 H), 3.29 (ddd, J = 12.9, 11.4,
6.7 Hz, 1 H), 3.05 (s, 3 H), 3.01 (dd, J = 17.0, 3.8 Hz, 1 H), 2.79 (dd, J
= 17.0, 13.2 Hz, 1 H), 2.75−2.68 (m, 1 H), 2.22−2.15 (m, 1 H); 13C
NMR (126 MHz, CDCl3) δ 174.2, 148.1, 146.2, 136.4, 129.0, 125.8,
116.3, 113.3, 111.8, 55.7, 55.6, 53.2, 39.6, 36.0, 34.8, 34.7; IR (CHCl3)
ν 2936, 1643, 1252, 909 cm−1. Anal. Calcd. for C16H21NO3: C, 69.79;
H, 7.69; N, 5.09. Found: C, 69.51; H, 7.82; N, 5.03.
(R)-4-Allyl-7,8-dimethoxy-2-methyl-4,5-dihydro-1H-benzo-
[c]azepin-3(2H)-one (R-3t). White solid: mp 123.5−124.0 °C; [α]D
−92.5° (c = 2.81, CHCl3); the enantiomeric purity was determined by
HPLC analysis (230 nm, 40 °C) tR 13.1 min (major); tR 11.3 min
(minor) [CHIRALPAK AD (2.1 mm × 250 mm) (from Daicel
Chemical Ind., Ltd.) hexane/i-PrOH, 90/10, 1.00 mL/min] as 96% ee;
1H NMR (500 MHz, CDCl3) δ 6.61 (s, 1 H), 6.56 (s, 1 H), 5.90
(dddd, J = 17.2, 10.2, 8.2, 5.7 Hz, 1 H), 5.18 (d, J = 17.0 Hz, 1 H), 5.14
(d, J = 18.5 Hz, 1 H), 5.08 (d, J = 10.1 Hz, 1 H), 3.87 (s, 3 H), 3.84 (s,
3 H), 3.73 (d, J = 16.4 Hz, 1 H), 3.29 (ddd, J = 13.2, 11.2, 6.7 Hz, 1
H), 3.05 (s, 3 H), 3.01 (dd, J = 17.0, 4.1 Hz, 1 H), 2.79 (dd, J = 17.1,
13.2 Hz, 1 H), 2.75−2.68 (m, 1 H), 2.22−2.15 (m, 1 H); 13C NMR
(126 MHz, CDCl3) δ 174.5, 148.3, 146.4, 136.6, 129.3, 126.0, 116.6,
113.5, 111.9, 56.0, 55.8, 53.5, 39.9, 36.2, 35.1, 35.0; IR (CHCl3) ν
2936, 1643, 1252, 1206 cm−1; HRMS (ESI M + H) m/z 276.1605,
calcd for C16H22NO3 276.1600.
(S)-4-Allyl-2-ethyl-7,8-dimethoxy-4,5-dihydro-1H-benzo[c]-
azepin-3(2H)-one (S-3u). Colorless oil: [α]D +89.1° (c = 1.08,
CHCl3); the enantiomeric purity was determined by HPLC analysis
(230 nm, 40 °C) tR 9.2 min (major); tR 10.6 min (minor)
[CHIRALPAK AD (2.1 mm × 250 mm) (from Daicel Chemical
A solution of N-methyl-propanamide (0.091 g) paraformaldehyde
(0.047 g, 1.58 mmol), and trifluoroacetic acid (0.3 mL, 3.9 mmol) in
CH2Cl2 (8 mL) was stirred at room temperature for 18 h. Saturated
aqueous NaHCO3 (20 mL) was then added to the reaction mixture,
and the resulting biphasic mixture was extracted with CH2Cl2 (10 mL
× 3). The organic phases were combined, dried over Na2SO4, and
filtered. The filtrate was then concentrated under reduced pressure,
and the residue was purified by flash chromatography (silica gel/
hexane then hexane/EtOAc 1:3) to give S-3a in 62% yield (0.058 g,
0.23 mmol). White solid: mp 197.5−198.0 °C; [α]D +100.7° (c = 1.01,
CHCl3); the enantiomeric purity was determined by HPLC analysis
(230 nm, 40 °C) tR 18.6 min (major); tR 16.7 min (minor)
[CHIRALPAK IC (2.1 mm × 250 mm) (from Daicel Chemical Ind.,
Ltd.) hexane/i-PrOH, 60/40, 1.00 mL/min] as 90% ee; 1H NMR (500
MHz, CDCl3) δ 6.60 (s, 1 H), 6.56 (s, 1 H), 5.17 (d, J = 16.3 Hz, 1
H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.72 (d, J = 16.4 Hz, 1 H), 3.45−3.34
(m, 1 H), 3.05 (s, 3 H), 2.95 (dd, J = 17.1, 4.1 Hz, 1 H), 2.84 (dd, J =
17.1, 13.0 Hz, 1 H), 1.25 (d, J = 6.5 Hz, 3 H); 13C NMR (126 MHz,
CDCl3) δ 175.6, 148.4, 146.5, 129.7, 126.2, 113.5, 111.9, 56.1, 56.0,
53.7, 37.7, 35.3, 34.8, 17.6; IR (CHCl3) ν 2930, 1647, 1524, 1256,
1107 cm−1. Anal. Calcd. for C14H19NO3: C, 67.45; H, 7.68; N, 5.62.
Found: C, 67.24; H, 7.71; N, 5.66.
Other optically active compounds 3 were prepared in a similar
manner.
(R)-7,8-Dimethoxy-2,4-dimethyl-4,5-dihydro-1H-benzo[c]-
azepin-3(2H)-one (R-3a). White solid: mp 197.5−198.0 °C; [α]D
−122.2° (c = 1.07, CHCl3); the enantiomeric purity was determined
by HPLC analysis (230 nm, 40 °C) tR 16.6 min (major); tR 18.5 min
(minor) [CHIRALPAK IC (2.1 mm × 250 mm) (from Daicel
Chemical Ind., Ltd.) hexane/i-PrOH, 60/40, 1.00 mL/min] as 88% ee;
1H NMR (500 MHz, CDCl3) δ 6.60 (s, 1 H), 6.56 (s, 1 H), 5.17 (d, J
= 16.3 Hz, 1 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.72 (d, J = 16.4 Hz, 1
H), 3.38 (tt, J = 12.9, 6.4 Hz, 1 H), 3.05 (s, 3 H), 2.95 (dd, J = 17.0,
3.9 Hz, 1 H), 2.84 (dd, J = 17.1, 12.9 Hz, 1 H), 1.25 (d, J = 6.5 Hz, 3
H); 13C NMR (126 MHz, CDCl3) δ 175.6, 148.4, 146.5, 129.7, 126.2,
113.5, 111.9, 56.1, 56.0, 53.7, 37.8, 35.3, 34.8, 17.6; IR (CHCl3) ν
2930, 1647, 1524, 1256, 1211 cm−1. Anal. Calcd. for C14H19NO3: C,
67.45; H, 7.68; N, 5.62. Found: C, 67.27; H, 7.70; N, 5.63.
(S)-2-ethyl-7,8-Dimethoxy-4-methyl-4,5-dihydro-1H-benzo-
[c]azepin-3(2H)-one (S-3g). White solid: mp 132.7−133.2 °C; [α]D
+103.7° (c = 1.15, CHCl3); the enantiomeric purity was determined
by HPLC analysis (230 nm, 40 °C) tR 9.7 min (major); tR 11.4 min
(minor) [CHIRALPAK IC (2.1 mm × 250 mm) (from Daicel
Chemical Ind., Ltd.) hexane/i-PrOH, 92/8, 1.00 mL/min] as 89% ee;
1H NMR (500 MHz, CDCl3) δ 6.59 (s, 1 H), 6.56 (s, 1 H), 5.10 (d, J
= 16.3 Hz, 1 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.79 (d, J = 16.5 Hz, 1
H), 3.54 (dd, J = 7.1, 2.0 Hz, 1 H), 3.51 (dd, J = 7.1, 1.9 Hz, 1 H), 3.35
(tt, J = 12.8, 6.5 Hz, 1 H), 2.93 (dd, J = 17.1, 4.2 Hz, 1 H), 2.86 (dd, J
= 17.0, 12.7 Hz, 1 H), 1.25 (d, J = 6.5 Hz, 3 H), 1.07 (t, J = 7.2 Hz, 3
H); 13C NMR (126 MHz, CDCl3) δ 175.1, 148.3, 146.6, 129.7, 126.9,
113.4, 111.6, 56.1, 56.0, 51.6, 42.7, 37.8, 34.8, 17.6, 13.7; IR (CHCl3) ν
2972, 1643, 1520, 1462, 1252, 1202, 743 cm−1; HRMS (ESI M + H)
m/z 264.1598, calcd for C15H22NO3 264.1600.
(R)-2-Ethyl-7,8-dimethoxy-4-methyl-4,5-dihydro-1H-benzo-
[c]azepin-3(2H)-one (R-3g). White solid: mp 132.7−133.2 °C; [α]D
−116.0° (c = 0.98, CHCl3); the enantiomeric purity was determined
by HPLC analysis (230 nm, 40 °C) tR 11.6 min (major); tR 9.8 min
(minor) [CHIRALPAK IC (2.1 mm × 250 mm) (from Daicel
Chemical Ind., Ltd.) hexane/i-PrOH, 92/8, 1.00 mL/min] as 89% ee;
1H NMR (500 MHz, CDCl3) δ 6.59 (s, 1 H), 6.56 (s, 1 H), 5.10 (d, J
= 16.4 Hz, 1 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.79 (d, J = 16.5 Hz, 1
H), 3.54 (dd, J = 7.2, 2.1 Hz, 1 H), 3.51 (dd, J = 7.1, 2.1 Hz, 1 H), 3.35
4026
dx.doi.org/10.1021/jo300380z | J. Org. Chem. 2012, 77, 4017−4028

The Journal of Organic Chemistry
Article
1
Ind., Ltd.) hexane/i-PrOH, 92/8, 1.00 mL/min] as 97% ee; H NMR
(500 MHz, CDCl3) δ 6.60 (s, 1 H), 6.56 (s, 1 H), 5.90 (dddd, J = 16.0,
10.1, 8.2, 5.7 Hz, 1 H), 5.17−5.05 (m, 3 H), 3.86 (s, 3 H), 3.84 (s, 3
H), 3.80 (d, J = 16.5 Hz, 1 H), 3.52 (q, J = 7.1 Hz, 2 H), 3.25 (dt, J =
17.5, 6.7 Hz, 1 H), 3.01 (dd, J = 17.1, 3.3 Hz, 1 H), 2.80 (dd, J = 17.0,
13.3 Hz, 1 H), 2.75−2.67 (m, 1 H), 2.23−2.14 (m, 1 H), 1.07 (t, J =
7.2 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 173.9, 148.1, 146.4,
136.5, 129.2, 126.7, 116.4, 113.3, 111.5, 55.9, 55.7, 51.3, 42.4, 39.8,
36.0, 34.8, 13.4; IR (neat) ν 2934, 1640, 1120, 909 cm−1; HRMS (ESI
M + H) m/z 290.1774, calcd for C17H24NO3 290.1756.
129.1, 128.2, 126.0, 125.9, 113.5, 111.9, 55.9, 55.7, 53.4, 41.9, 37.8,
35.0, 34.8; IR (neat) ν 2936, 1645, 1252, 1207 cm−1; HRMS (ESI M +
H) m/z 326.1764, calcd for C20H24NO3 326.1756.
(R)-4-Benzyl-7,8-dimethoxy-2-methyl-4,5-dihydro-1H-
benzo[c]azepin-3(2H)-one (R-3f). Colorless oil: [α]D −138.4° (c =
0.99, CHCl3); the enantiomeric purity was determined by HPLC
analysis (230 nm, 40 °C) tR 30.0 min (major); tR 38.5 min (minor)
[CHIRALPAK ID (2.1 mm × 250 mm) (from Daicel Chemical Ind.,
Ltd.) hexane/i-PrOH, 80/20, 1.00 mL/min] as 96% ee; 1H NMR (500
MHz, CDCl3) δ 7.33−7.26 (m, 4 H), 7.25−7.17 (m, 1 H), 6.54 (s, 1
H), 6.53 (s, 1 H), 5.16 (d, J = 16.3 Hz, 1 H), 3.85 (s, 3 H), 3.81 (s, 3
H), 3.70 (d, J = 16.4 Hz, 1 H), 3.61−3.47 (m, 1 H), 3.36 (dd, J = 14.0,
5.8 Hz, 1 H), 3.05 (s, 3 H), 2.97 (dd, J = 17.0, 4.1 Hz, 1 H), 2.85 (dd, J
= 17.1, 13.1 Hz, 1 H), 2.69 (dd, J = 14.0, 8.0 Hz, 1 H); 13C NMR (126
MHz,) δ 174.4, 148.2, 146.3, 140.1, 129.1, 129.1, 128.2, 126.0, 125.9,
113.5, 111.9, 55.9, 55.7, 53.4, 41.9, 37.8, 35.0, 34.8; IR (neat) ν 2936,
1643, 1252, 909 cm−1; HRMS (ESI M + H) m/z 326.1754, calcd for
C20H24NO3 326.1756.
(S)-4-Benzyl-2-ethyl-7,8-dimethoxy-4,5-dihydro-1H-benzo-
[c]azepin-3(2H)-one (S-3l). Pale yellow oil: [α]D +122.5° (c = 1.01,
CHCl3); the enantiomeric purity was determined by HPLC analysis
(230 nm, 40 °C) tR 32.8 min (major); tR 29.0 min (minor)
[CHIRALPAK IC (2.1 mm × 250 mm) (from Daicel Chemical Ind.,
Ltd.) hexane/i-PrOH, 80/20, 1.00 mL/min] as 98% ee; 1H NMR (500
MHz, CDCl3) δ 7.35−7.27 (m, 4 H), 7.24−7.15 (m, 1 H), 6.54 (s, 1
H), 6.53 (s, 1 H), 5.09 (d, J = 16.4 Hz, 1 H), 3.85 (s, 3 H), 3.80 (s, 3
H), 3.77 (d, J = 16.5 Hz, 1 H), 3.59−3.45 (m, 3 H), 3.36 (dd, J = 14.0,
5.5 Hz, 1 H), 2.95 (dd, J = 17.0, 3.8 Hz, 1 H), 2.85 (dd, J = 16.9, 13.0
Hz, 1 H), 2.69 (dd, J = 14.1, 8.3 Hz, 1 H), 1.07 (t, J = 7.2 Hz, 3 H);
13C NMR (126 MHz, CDCl3) δ 174.0, 148.1, 146.4, 140.1, 129.2,
(R)-4-Allyl-2-ethyl-7,8-dimethoxy-4,5-dihydro-1H-benzo[c]-
azepin-3(2H)-one (R-3u). Colorless oil: [α]D −87.7° (c = 3.09,
CHCl3); the enantiomeric purity was determined by HPLC analysis
(230 nm, 40 °C) tR 11.4 min (major); tR 9.7 min (minor)
[CHIRALPAK AD (2.1 mm × 250 mm) (from Daicel Chemical
1
Ind., Ltd.) hexane/i-PrOH, 92/8, 1.00 mL/min] as 94% ee; H NMR
(500 MHz, CDCl3) δ 6.60 (s, 1 H), 6.56 (s, 1 H), 5.90 (dddd, J = 17.1,
10.1, 8.2, 5.7 Hz, 1 H), 5.17−5.05 (m, 3 H), 3.86 (s, 3 H), 3.84 (s, 3
H), 3.80 (d, J = 16.5 Hz, 1 H), 3.53 (q, J = 7.2 Hz, 2 H), 3.25 (dtd, J =
11.0, 6.8, 4.1 Hz, 1 H), 3.02 (dd, J = 17.0, 3.3 Hz, 1 H), 2.80 (dd, J =
17.1, 13.2 Hz, 1 H), 2.71 (dtt, J = 14.6, 6.0, 1.5 Hz, 1 H), 2.19 (dt, J =
14.6, 7.8 Hz, 1 H), 1.07 (t, J = 7.2 Hz, 3 H); 13C NMR (126 MHz,
CDCl3) δ 174.0, 148.2, 146.5, 136.8, 129.4, 126.8, 116.6, 113.4, 111.6,
56.0, 55.8, 51.5, 42.6, 39.9, 36.2, 35.0, 13.5; IR (neat) ν 2934, 1640,
1200, 912 cm−1; HRMS (ESI M + H) m/z 290.1755, calcd for
C17H24NO3 290.1756.
(S)-4-Allyl-7,8-dimethoxy-2-propyl-4,5-dihydro-1H-benzo-
[c]azepin-3(2H)-one (S-3v). Pale yellow oil: [α]D +72.5° (c = 1.69,
CHCl3); the enantiomeric purity was determined by HPLC analysis
(230 nm, 40 °C) tR 10.7 min (major); tR 12.6 min (minor)
[CHIRALPAK AD (2.1 mm × 250 mm) (from Daicel Chemical Ind.,
Ltd.) hexane/i-PrOH, 94/6, 1.00 mL/min] as 96% ee; 1H NMR (500
MHz, CDCl3) δ 6.60 (s, 1 H), 6.55 (s, 1 H), 5.95−5.85 (m, 1 H), 5.13
(d, J = 18.3 Hz, 1 H), 5.11 (d, J = 16.4 Hz, 1 H), 5.07 (d, J = 10.1 Hz,
1 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 3.78 (d, J = 16.5 Hz, 1 H), 3.54−
3.46 (m, 1 H), 3.41−3.33 (m, 1 H), 3.26 (ddd, J = 13.0, 10.9, 6.6 Hz, 1
H), 3.01 (dd, J = 17.1, 3.2 Hz, 1 H), 2.81 (dd, J = 17.0, 13.3 Hz, 1 H),
2.76−2.67 (m, 1 H), 2.22−2.14 (m, 1 H), 1.53−1.44 (m, 2 H), 0.81 (t,
J = 7.4 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 174.1, 148.0, 146.3,
136.4, 129.1, 126.5, 116.3, 113.2, 111.5, 55.7, 55.5, 51.6, 49.2, 39.7,
35.9, 34.7, 21.3, 10.9; IR (neat) ν 2936, 1643, 907, 725 cm−1; HRMS
(ESI M + H) m/z 304.1927, calcd for C18H26NO3 304.1913.
(R)-4-Allyl-7,8-dimethoxy-2-propyl-4,5-dihydro-1H-benzo-
[c]azepin-3(2H)-one (R-3v). Pale yellow oil: [α]D −75.2° (c = 1.04,
CHCl3); the enantiomeric purity was determined by HPLC analysis
(230 nm, 40 °C) tR 12.3 min (major); tR 10.4 min (minor)
[CHIRALPAK AD (2.1 mm × 250 mm) (from Daicel Chemical Ind.,
Ltd.) hexane/i-PrOH, 94/6, 1.00 mL/min] as 96% ee; 1H NMR (500
MHz, CDCl3) δ 6.60 (s, 1 H), 6.55 (s, 1 H), 5.94−5.85 (m, 1 H), 5.13
(dd, J = 17.1, 1.1 Hz, 1 H), 5.11 (d, J = 16.4 Hz, 1 H), 5.07 (d, J = 10.2
Hz, 1 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 3.78 (d, J = 16.5 Hz, 1 H),
3.54−3.46 (m, 1 H), 3.41−3.34 (m, 1 H), 3.26 (ddd, J = 13.0, 10.9, 6.7
Hz, 1 H), 3.01 (dd, J = 17.1, 3.3 Hz, 1 H), 2.81 (dd, J = 17.0, 13.3 Hz,
1 H), 2.75−2.68 (m, 1 H), 2.22−2.14 (m, 1 H), 1.53−1.44 (m, 1 H),
0.81 (t, J = 7.4 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 174.2, 148.0,
146.3, 136.5, 129.1, 126.5, 116.3, 113.2, 111.5, 55.8, 55.6, 51.6, 49.3,
39.7, 35.9, 34.8, 21.3, 10.9; IR (neat) ν 2934, 1641, 1196, 910 cm−1;
HRMS (ESI M + H) m/z 304.1921, calcd for C18H26NO3 304.1913.
(S)-4-Benzyl-7,8-dimethoxy-2-methyl-4,5-dihydro-1H-
benzo[c]azepin-3(2H)-one (S-3f). Colorless oil: [α]D +140.1° (c =
1.01, CHCl3); the enantiomeric purity was determined by HPLC
analysis (230 nm, 40 °C) tR 29.5 min (major); tR 38.9 min (minor)
[CHIRALPAK ID (2.1 mm × 250 mm) (from Daicel Chemical Ind.,
Ltd.) hexane/i-PrOH, 80/20, 1.00 mL/min] as 94% ee; 1H NMR (500
MHz, CDCl3) δ 7.34−7.26 (m, 4 H), 7.25−7.15 (m, 1 H), 6.54 (s, 1
H), 6.53 (s, 1 H), 5.16 (d, J = 16.3 Hz, 1 H), 3.85 (s, 3 H), 3.81 (s, 3
H), 3.70 (d, J = 16.4 Hz, 1 H), 3.54 (dq, J = 7.7, 5.5 Hz, 1 H), 3.35
(dd, J = 14.0, 5.8 Hz, 1 H), 3.05 (s, 3 H), 2.97 (dd, J = 17.0, 4.0 Hz, 1
H), 2.85 (dd, J = 16.8, 13.2 Hz, 1 H), 2.68 (dd, J = 14.0, 8.0 Hz, 1 H);
13C NMR (126 MHz, CDCl3) δ 174.4, 148.2, 146.3, 140.1, 129.2,
129.1, 128.2, 126.7, 126.0, 113.4, 111.5, 55.9, 55.7, 51.4, 42.6, 42.0,
37.8, 34.7, 13.4; IR (neat) ν 2934, 1643, 1200, 909 cm−1; HRMS (ESI
M + H) m/z 340.1912, calcd for C21H26NO3 340.1913.
(R)-4-Benzyl-2-ethyl-7,8-dimethoxy-4,5-dihydro-1H-benzo-
[c]azepin-3(2H)-one (R-3l). Pale yellow oil: [α]D −140.5° (c = 0.95,
CHCl3); the enantiomeric purity was determined by HPLC analysis
(230 nm, 40 °C) tR 29.0 min (major); tR 33.0 min (minor)
[CHIRALPAK IC (2.1 mm × 250 mm) (from Daicel Chemical Ind.,
Ltd.) hexane/i-PrOH, 80/20, 1.00 mL/min] as 98% ee; 1H NMR (500
MHz, CDCl3) δ 7.33−7.26 (m, 4 H), 7.24−7.17 (m, 1 H), 6.54 (s, 1
H), 6.53 (s, 1 H), 5.09 (d, J = 16.4 Hz, 1 H), 3.85 (s, 3 H), 3.81 (s, 3
H), 3.77 (d, J = 16.5 Hz, 1 H), 3.60−3.45 (m, 3 H), 3.36 (dd, J = 14.0,
5.6 Hz, 1 H), 2.95 (dd, J = 17.1, 3.4 Hz, 1 H), 2.85 (dd, J = 16.9, 12.9
Hz, 1 H), 2.69 (dd, J = 14.1, 8.3 Hz, 1 H), 1.07 (t, J = 7.2 Hz, 3 H);
13C NMR (126 MHz, CDCl3) δ 173.9, 148.1, 146.4, 140.1, 129.2,
129.1, 128.2, 126.7, 126.0, 113.5, 111.6, 55.9, 55.7, 51.3, 42.6, 42.0,
37.8, 34.7, 13.4; IR (neat) ν 2934, 1641, 1200, 909 cm−1; HRMS (ESI
M + H) m/z 340.1911, calcd for C21H26NO3 340.1913.
(S)-4-Benzyl-7,8-dimethoxy-2-propyl-4,5-dihydro-1H-benzo-
[c]azepin-3(2H)-one (S-3w). Pale yellow oil: [α]D +122.1° (c = 1.03,
CHCl3); the enantiomeric purity was determined by HPLC analysis
(230 nm, 40 °C) tR 27.4 min (major); tR 23.5 min (minor)
[CHIRALPAK IC (2.1 mm × 250 mm) (from Daicel Chemical Ind.,
Ltd.) hexane/i-PrOH, 80/20, 1.00 mL/min] as 98% ee; 1H NMR (500
MHz, CDCl3) δ 7.32−7.27 (m, 4 H), 7.24−7.16 (m, 1 H), 6.53 (s, 2
H), 5.11 (d, J = 16.4 Hz, 1 H), 3.85 (s, 3 H), 3.81 (s, 3 H), 3.75 (d, J =
16.5 Hz, 1 H), 3.58−3.45 (m, 2 H), 3.39−3.30 (m, 2 H), 2.95 (dd, J =
17.0, 3.6 Hz, 1 H), 2.86 (dd, J = 16.7, 13.2 Hz, 1 H), 2.69 (dd, J = 14.0,
8.1 Hz, 1 H), 1.53−1.43 (m, 1 H), 0.80 (t, J = 7.4 Hz, 3 H); 13C NMR
(126 MHz, CDCl3) δ 174.0, 147.9, 146.2, 139.9, 128.9, 128.8, 128.0,
126.4, 125.7, 113.2, 111.4, 55.7, 55.4, 51.5, 49.2, 41.7, 37.6, 34.6, 21.3,
10.9; IR (neat) ν 2936, 1645, 907, 725 cm−1; HRMS (ESI M + H) m/
z 354.2043, calcd for C22H28NO3 354.2069.
(R)-4-Benzyl-7,8-dimethoxy-2-propyl-4,5-dihydro-1H-
benzo[c]azepin-3(2H)-one (R-3w). Pale yellow oil: [α]D −125.5° (c
= 1.04, CHCl3); the enantiomeric purity was determined by HPLC
analysis (230 nm, 40 °C) tR 23.5 min (major); tR 27.8 min (minor)
[CHIRALPAK IC (2.1 mm × 250 mm) (from Daicel Chemical Ind.,
Ltd.) hexane/i-PrOH, 80/20, 1.00 mL/min] as 99% ee; 1H NMR (500
MHz, CDCl3) δ 7.33−7.26 (m, 4 H), 7.24−7.16 (m, 1 H), 6.53 (s, 2
4027
dx.doi.org/10.1021/jo300380z | J. Org. Chem. 2012, 77, 4017−4028

The Journal of Organic Chemistry
Article
H), 5.11 (d, J = 16.3 Hz, 1 H), 3.85 (s, 3 H), 3.81 (s, 3 H), 3.75 (d, J =
16.5 Hz, 1 H), 3.57−3.45 (m, 2 H), 3.39−3.31 (m, 1 H), 2.95 (dd, J =
17.1, 3.4 Hz, 1 H), 2.86 (dd, J = 17.0, 12.9 Hz, 1 H), 2.68 (dd, J = 14.1,
8.1 Hz, 1 H), 1.48 (h, J = 7.4 Hz, 2 H), 0.80 (t, J = 7.4 Hz, 3 H); 13C
NMR (126 MHz, CDCl3) δ 174.0, 147.9, 146.2, 140.0, 129.0, 128.9,
128.0, 126.5, 125.7, 113.2, 111.5, 55.7, 55.5, 51.5, 49.3, 41.8, 37.6, 34.6,
21.3, 10.9; IR (neat) ν 2936, 1643, 907, 725 cm−1; HRMS (ESI M +
H) m/z 354.2089, calcd for C22H28NO3 354.2069.
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In Vitro Wound Healing Assay. HaCat cells (2.5 × 104 per well)
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with Dulbecco’s modified Eagle’s medium (DMEM), the cells were
incubated for 24 h at 5% CO2 and 37 °C with DMEM, containing
various concentrations (0−30 μM) of compounds (final DMSO
concentration of 0.1%). The cells were photographed immediately
after wounding, the wounded area was marked on the base of the plate,
and the same field was photographed again after incubation for 18 h.
The migration of the cells into the wound area was then evaluated.
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ASSOCIATED CONTENT
* Supporting Information
Spectroscopic charts for compounds 2−9. This material is
■
S
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: ak10@yamaguchi-u.ac.jp, minui@yamaguchi-u.ac.jp.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to Yamaguchi University for financial
aid by the YU Strategic Program for Fostering Research
Activities (2010−2011).
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