A concise synthesis of 3-arylated di- and tetrahydro-2 H-2-benzazepin-1- ones; A new synthetic approach to the homoprotoberberine framework

Article abstract of DOI:10.1055/s-0031-1290504

A variety of 3-arylated di- and tetrahydro-2H-2-benzazepin-1-ones were efficiently assembled through a sequence involving a Suzuki-Miyaura cross-coupling reaction with enol phosphates derived from the corresponding benzazepine-1,3-diones. This technique h

Full text of DOI:10.1055/s-0031-1290504

1410▌
PAPER
paper
A Concise Synthesis of 3-Arylated Di- and Tetrahydro-2H-2-benzazepin-1-
ones; A New Synthetic Approach to the Homoprotoberberine Framework
Stéphane Lebrun,a,b Axel Couture,*a,c Eric Deniau,a,b Pierre Grandclaudona,b
a
Université Lille Nord de France, 59000 Lille, France
Fax +33(3)20436309; E-Mail: axel.couture@univ-lille1.fr
b
USTL, Laboratoire de Chimie Organique Physique, EA CMF 4478, Bâtiment C3(2), 59655 Villeneuve d’Ascq Cedex, France
c
CNRS, UMR 8181 ‘UCCS’, Bâtiment C3(2), 59655 Villeneuve d’Ascq Cedex, France
Received: 13.12.2011; Accepted after revision: 14.02.2012
el technique to ensure the construction of the homoproto-
Abstract: A variety of 3-arylated di- and tetrahydro-2H-2-benz-
berberine skeleton. In the course of an ongoing program
azepin-1-ones were efficiently assembled through a sequence in-
devoted to the elaboration of structurally diversified ben-
volving a Suzuki–Miyaura cross-coupling reaction with enol
phosphates derived from the corresponding benzazepine-1,3-di-
zazepines, we recently reported a concise and flexible
ones. This technique has been further exploited for the construction synthesis of 2H-2-benzazepine-1,3-diones 3.12 This new
of the homoprotoberberine skeleton, which was readily accessed by
intramolecular carbocationic annulation reaction applied to a suit-
ably substituted precursor.
route, depicted in Scheme 1, was based upon the ultimate
creation of the alkene moiety embedded in the azahetero-
cyclic unit via an unprecedented ring-closing metathesis
(RCM) reaction applied to the easily accessible unsaturat-
Key words: fused-ring systems, metathesis, cross-coupling, enols,
ring closure
ed N-acyl-o-vinylbenzamides 2. We speculated that these
α,β-unsaturated oxobenzolactams 3 could serve a key role
as advanced intermediates prior to their conversion into 3-
The synthesis of benzo-fused azaheterocyclic compounds
is a topic of continuing interest because these ring systems
lie at the heart of a great variety of polyfunctionalized and
diversely functionalized models endowed with profound
chemotherapeutic properties.1 Benzazepines and the ma-
jor intermediates in their synthesis, that is the oxo deriva-
tives, at different oxidation levels fall into this category.
They are known to display potent inhibitory activity
against AchE and SERT,2 broncho-relaxing activity,3 and
to promote skin epithelial cell migration and wound heal-
ing.4 Many compounds of this class are also used as
antiarrhythmic5 and CNS agents,6 as inhibitors of PNMT,7
and are recommended for the treatment of stomach
disorders8 and hypoxia.9 Finally, some representatives
have been found to display anti-HIV activity10 and to treat
cardiovascular diseases, especially glaucoma and hyper-
tension.11 Due to the impressive range of exceptional bio-
activity of many of their derivatives, the chemistry of 2-
benzazepines has been the focus of new synthetic method-
ologies that may have generality for the construction of
multifarious substituted and functionalized models.1 In
particular the development of conceptually new synthetic
strategies for constructing a variety of 2-benzazepines
with an aryl appendage at C3 of the heterocyclic nucleus
constitutes an area of current interest.
arylbenzazepinones 11 and 12 as they possess the requi-
site structure and functional group location to be easily
converted into the targeted seven-membered compounds
through rather simple chemical manipulation. For this
purpose a variety of unsaturated oxobenzolactams 3a–d
were initially submitted to catalytic hydrogenation to pro-
vide excellent yield of saturated analogues 4a–d. We as-
sumed that these large seven-membered oxolactams
would possess the appropriate functionalities required for
the installation of an additional styrene unit through a pal-
ladium-mediated Suzuki–Miyaura cross-coupling reac-
tion. Since the pioneering work of Oshima et al.,13 who
coupled a series of vinyl phosphates with trialkylalumi-
num species in the presence of Pd(PPh3)4 catalyst, several
groups have used constitutionally diverse enol phosphates
in a variety of cross-coupling reactions.14 Whereas simple
N-alkylated amides proved not to be effective sub-
strates,14f the coupling reaction could however be per-
formed with models equipped with electron-withdrawing
groups on the nitrogen atom. The cyclic N-diacylated
models 4 developed in this study fulfill these stringent
structural criteria. Exposure of compounds 4a–d to potas-
sium hexamethyldisilazanide in tetrahydrofuran at –78 °C
provided the potassium enolate 5, which was intercepted
by reaction with diphenyl chlorophosphate followed by
standard work up to deliver the sensitive vinyl phosphates
6a–d that were used in the next step without further puri-
fication. A palladium-catalyzed Suzuki–Miyaura reaction
was subsequently applied under well-defined conditions.
For this purpose the vinyl phosphates 6a–d, a suitably
(un)substituted aromatic boronic acid 7–9, aqueous sodi-
um carbonate, and a few drops of ethanol were refluxed in
tetrahydrofuran. Under these conditions the benzoenelac-
tams 11a–d were isolated in very satisfactory yields
In this report, we wish to enrich the repertoire of these
synthetic approaches by the assembly of an array of 3-ar-
ylated di- and tetrahydro-2H-2-benzazepin-1-ones 11 and
12, respectively. The synthetic potential of this new route
has been further emphasized by the development of a nov-
SYNTHESIS 2012, 44, 1410–1416
Advanced online publication: 16.03.2012
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DOI: 10.1055/s-0031-1290504; Art ID: SS-2011-Z1150-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
A Concise Synthesis of 3-Arylated Di- and Tetrahydro-2H-2-benzazepin-1-ones
1411
1. NaH, THF
r.t., 30 min
Grubbs'
nd generation
(5 mol%)
2.
COCl
O
O
2
O
R3
R3
R3
R1
R2
R1
R2
N
R1
R2
N
N
H
–78 °C to r.t., 5 h
48–70%
toluene, reflux, 5 h
O
O
69–81%
1a–e
2a–e
3a–e
R3
O
O
O
Cl
O
R3
H2, Pd/C
EtOH, r.t.
12 h
KHMDS
THF
–78 °C
R3
R1
R2
P
R1
R2
R1
R2
N
N
N
PhO
OPh
O
O
O
O
89–95%
P
OPh
K
PhO
4a–e
5
6a–e
O
O
Na2CO3, H2O
ArB(OH)2 7–10
Pd(PPh3)4
H2, Pd/C
EtOH, r.t.
12 h
R3
R3
R4
R4
R1
R2
R1
R2
N
N
R5
R5
72–87%
R6
R6
11a–e
12a–e
for 12e: R4 = H;
1 = R2 = R5 = R6 = OMe
3 = CH2-CH(OMe)2
R
O
O
R
HCOONH4
Pd/C, MeOH
reflux, 3 h
AcOH then H2SO4
r.t., 1 h
MeO
MeO
MeO
B
N
N
A
OMe
OMe
OMe
OMe
88%
81%
MeO
13
14
Scheme 1
(Scheme 1). Ensuing catalytic hydrogenation of the ole- due to the lack of general synthetic methods for their elab-
finic double bond delivered the corresponding tetrahydro- oration.2a,15
benzazepinones 12a–d.
At this stage we surmised that the technique developed for
A representative series of compounds prepared by this the assembly of the arylated benzazepinone template with
method are presented in Table 1 where it can be seen that the capacity to incorporate additional substituents or func-
this simple procedure affords fairly good yields of the tar- tionalities could pave the way for the construction of
geted (un)saturated models 11a–d and 12a–d. It is worthy structurally more sophisticated compounds. In particular
of note that, in contrast to the saturated models, the use of the homoprotoberberine framework could be accessed
benzazepines with unsaturation in the azaheterocycle ring through a carbocationic process applied to a model struc-
has few synthetic and biological applications probably turally related to 12 and further equipped with a dialkoxy-
ethyl appendage on the lactam nitrogen.
Table 1 2-Benzazepine-1,3-diones 3, Dihydro-2-benzazepine-1,3-diones 4, Dihydro-2-benzazepin-1-ones 11, and Tetrahydro-2-benzazepin-
1-ones 12 Prepared
3, 4,
2-Benzazepine-1,3-diones 3 and 4
Boronic acid 7–10
2-Benzazepin-1-ones 11, 12
R1
R2
R3
R4
R5
R6
11, 12
Yield (%)
7–10
Yield (%)
3
4
11
12
7512
6912
8112
7212
a
b
c
H
H
H
H
H
H
Me
Bn
Pr
95
90
92
90
89
7
H
OMe
H
H
87
78
72
85
78
90
88
94
88
85
8
H
H
9
OMe
H
OMe
H
OMe
H
d
e
OMe OMe Me
8
OMe OMe CH2CH(OMe)2 74
10
H
OMe
OMe
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1410–1416

1412
S. Lebrun et al.
PAPER
1H NMR (300 MHz, CDCl3): δ = 3.43 (s, 6 H, 2 OCH3), 3.59 (t,
J = 5.5 Hz, 2 H, NCH2), 3.90 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3),
4.51 (d, J = 5.3 Hz, 1 H, OCHO), 5.32 (d, J = 10.8 Hz, 1 H, Hvinyl),
5.61 (d, J = 17.4 Hz, 1 H, Hvinyl), 6.05 (br s, 1 H, NH), 6.98 (s, 1 H,
Harom), 7.02 (dd, J = 10.8, 17.9 Hz, 1 H, Hvinyl), 7.07 (s, 1 H, Harom).
13C NMR (75 MHz, CDCl3): δ = 41.4 (CH2), 54.4 (2 OCH3), 55.9
(OCH3), 56.0 (OCH3), 102.5 (OCHO), 108.7 (CH), 110.7 (CH),
115.5 (CH2), 127.5 (Cq), 129.3 (Cq), 134.6 (CH), 148.6 (Cq), 150.4
(Cq), 168.8 (C=O).
Homoprotoberberines as exemplified by compound 14
are a group of alkaloids that exhibit antimalarial and anti-
bacterial properties16 and current synthetic routes are in-
variably multistep procedures with low overall yields.16,17
Most available synthetic methods rely upon the ultimate
creation of the seven-membered heterocyclic unit A from
adequately substituted 1-phenylethylisoquinoline deriva-
tives. Curiously, studies aimed at the alternative creation
of the six-membered nucleus B are rather scarce.18 The
first facet of the synthesis of the polyalkoxylated model
study 14 was the elaboration of the polyenic compound
2e, which was easily obtained from a readily available
precursor 1e. RCM reaction under the well-defined condi-
tions spared the acetal function and the benzazepinedione
3e was obtained in excellent yield (Table 1). Subsequent
catalytic hydrogenation delivered the tetrahydrobenzaze-
pinone 4e candidate for the planned installation of the ad-
ditional styrene unit. Deprotonation, capture with
diphenyl chlorophosphate and Suzuki–Miyaura coupling
with aromatic boronic acid 10 proceeded uneventfully to
afford the dihydrobenzazepinone 11e in fairly good yield.
Hydrogenation followed by treatment of resulting 12e
with acetic acid in the presence of sulfuric acid gave regi-
oselective cyclization of the opened model and formation
of the endocyclic aromatic enelactam 13. With this com-
pound in hand, we were one reaction away from the ho-
moprotoberberine exemplary representative 14, which
was readily obtained by ultimate reduction of the N–C=C
unit embedded in the annulated compound.
Anal. Calcd for C15H21NO5 (295.34): C, 61.00; H, 7.17; N, 4.74.
Found: C, 60.87; H, 7.02; N, 4.69.
N-Acryloyl-N-(2,2-dimethoxyethyl)-4,5-dimethoxy-2-vinyl-
benzamide (2e)
Oil; yield: 755 mg (48%).
1H NMR (300 MHz, CDCl3): δ = 3.37 (s, 6 H, 2 OCH3), 3.86 (s, 3
H, OCH3), 3.92 (d, J = 5.7 Hz, 2 H, NCH2), 3.96 (s, 3 H, OCH3),
4.75 (t, J = 5.7 Hz, 1 H, OCHO), 5.30 (d, J = 10.9 Hz, 1 H, Hvinyl),
5.49 (dd, J = 4.2, 7.3 Hz, 1 H, Hvinyl), 5.65 (d, J = 17.2 Hz, 1 H,
H
vinyl), 6.18–6.23 (m, 2 H, Hvinyl.), 6.89 (s, 1 H, Harom), 6.98 (dd,
J = 6.4, 17.2 Hz, 1 H, Hvinyl), 7.03 (s, 1 H, Harom).
13C NMR (75 MHz, CDCl3): δ = 47.0 (CH2), 54.4 (2 OCH3), 56.0
(OCH3), 56.1 (OCH3), 101.9 (OCHO), 108.4 (CH), 111.5 (CH),
116.2 (CH2), 126.7 (Cq), 128.3 (CH2), 130.3 (CH), 131.6 (Cq), 133.3
(CH), 148.5 (Cq), 151.6 (Cq), 169.3 (C=O), 172.7 (C=O).
Anal. Calcd for C18H23NO6 (349.39): C, 61.88; H, 6.64; N, 4.01.
Found: C, 61.67; H, 6.82; N, 4.18.
2-(2,2-Dimethoxyethyl)-7,8-dimethoxy-2-benzazepine-1,3-di-
one (3e)
Oil; yield: 357 mg (74%).
1H NMR (300 MHz, CDCl3): δ = 3.38 (s, 6 H, 2 OCH3), 3.99 (s, 3
H, OCH3), 4.00 (s, 3 H, OCH3), 4.38 (d, J = 5.4 Hz, 2 H, NCH2),
4.76 (t, J = 5.4 Hz, 1 H, OCHO), 6.39 (d, J = 12.5 Hz, 1 H, Hvinyl),
6.80 (s, 1 H, Harom), 6.97 (d, J = 12.5 Hz, 1 H, Hvinyl), 7.83 (s, 1 H,
In conclusion we have completed a new conceptual ap-
proach to the synthesis of a variety of di- and tetrahydro-
benzazepin-1-ones. This new methodology which hinges
upon the initial construction of a benzazepinedione tem-
plate on reliance with RCM reaction reveals the utility of
phosphoryl enamides as effective, synthetically useful
substrates for the installation of a styrene unit in the lac-
tam framework. The synthetic potential of this technique
has been further emphasized by the assembly of the ho-
moprotoberberine ring system, and we believe that this
work demonstrates a general new methodology for the
preparation of structurally related naturally occurring al-
kaloids and bioactive congeners as well.
Harom).
13C NMR (75 MHz, CDCl3): δ = 46.3 (CH2), 53.8 (2 OCH3), 56.2
(OCH3), 56.3 (OCH3), 101.5 (OCHO), 113.0 (CH), 115.5 (CH),
124.3 (CH), 126.5 (Cq), 126.8 (Cq), 138.0 (CH), 150.6 (Cq), 152.2
(Cq), 165.7 (C=O), 167.1 (C=O).
Anal. Calcd for C16H19NO6 (321.33): C, 59.81; H, 5.96; N, 4.36.
Found: C, 60.08; H, 5.77; N, 4.46.
4,5-Dihydro-2-benzazepine-1,3-diones 4a–e; General
Procedure
A soln of benzazepine-1,3-dione 3a–e (2 mmol) in EtOH (20 mL)
was stirred with Pd/C (10%, 20 mg) at r.t. under H2 (1 atm) until
TLC indicated complete consumption of the starting material (12
h). The mixture was filtered through a pad of Celite, which was fur-
ther eluted with EtOH (30 mL) and CH2Cl2 (30 mL). The combined
filtrate was evaporated under reduce pressure, and the resulting
crude product was purified by flash column chromatography (silica
gel, EtOAc–hexanes, 50:50) to afford the dihydrobenzazepine-1,3-
diones 4a–e as pale yellow oils (Table 2).
All solvents were dried and distilled according to standard proce-
dures. Dry glassware was obtained by oven-drying and assembly
under dry argon. The glassware was equipped with rubber septa and
reagent transfer was performed by syringe techniques. For flash
chromatography, Merck silica gel 60 (40–63 μm; 230–400 mesh
ASTM) was used. The melting points were obtained on a Reichert-
Thermopan apparatus and are not corrected. Elemental analyses
were obtained using a Carlo-Erba CHNS-11110 equipment. NMR
spectra were recorded on a Bruker AM 300 (300 MHz and 75 MHz,
for 1H, and 13C), CDCl3 as solvent, TMS as internal standard.
3-Arylated Dihydro-2-benzazepin-1-ones 11a–e; General
Procedure
A 0.5 M soln of KHMDS in toluene (3 mL, 1.5 mmol) was added
dropwise to a stirred soln of benzazepine-1,3-dione 4a–e (1 mmol)
and diphenyl chlorophosphate (0.31 mL, 1.5 mmol) in anhyd THF
(15 mL) at –78 °C under argon. After stirring for 30 min at –78 °C,
H2O (10 mL) was added and the mixture was extracted with Et2O (2
× 30 mL). The combined organic layers were dried (MgSO4) and
concentrated under vacuum to afford the intermediate vinyl phos-
phates 6a–e as yellow oils that were then used in the coupling step
without further purification.
Compounds 1a–e, 2a–e, 3a–e were prepared according to reported
procedures.12
N-(2,2-Dimethoxyethyl)-4,5-dimethoxy-2-vinylbenzamide (1e)
Colorless crystals (hexane–toluene); yield: 4.31 g (73%); mp 101–
102 °C.
Synthesis 2012, 44, 1410–1416
© Georg Thieme Verlag Stuttgart · New York

PAPER
A Concise Synthesis of 3-Arylated Di- and Tetrahydro-2H-2-benzazepin-1-ones
1413
A 2 M aq Na2CO3 soln (1 mL, 2 mmol), Pd(PPh3)4 (58 mg, 5 mol%),
and aromatic boronic acid 7–10 (1.5 mmol) were added under argon
to a stirred soln of crude 6a–e (1 mmol) in THF (10 mL). The mix-
ture was refluxed for 2 h, then diluted with H2O (10 mL) and ex-
tracted with Et2O (3 × 15 mL). The combined organic layers were
dried (MgSO4) and concentrated under vacuum to give orange oils.
Purification by flash column chromatography (EtOAc–hexanes,
40:60) afforded 3-arylated dihydro-2-benzazepin-1-ones 11a–e as
pale yellow oils (Table 2).
13C NMR (75 MHz, CDCl3): δ = 29.9 (CH2), 39.3 (CH2), 55.9
(NCH), 56.0 (2 OCH3), 56.1 (2 OCH3), 108.1 (CH), 108.5 (CH),
109.1 (CH), 111.2 (CH), 111.8 (CH), 121.9 (CH), 122.9 (Cq), 124.8
(Cq), 126.8 (Cq), 131.6 (Cq), 147.9 (Cq), 148.0 (Cq), 148.3 (Cq),
151.4 (Cq), 168.6 (C=O).
Anal. Calcd for C22H23NO5 (381.43): C, 69.28; H, 6.08; N, 3.67.
Found: C, 69.14; H, 6.28; N, 3.49.
2,3,10,11-Tetramethoxy-5,13,14,14a-tetrahydro-6H-isoqui-
no[2,1-b][2]benzazepin-8-one (14)
Tetrahydro-2-benzazepin-1-ones 12a–e; General Procedure
By following the previously described procedure used for the hy-
drogenation of 3a–e. Purification by flash column chromatography
(silica gel, EtOAc–hexanes, 40:60) furnished the tetrahydrobenz-
azepinones 12a–e as pale yellow oils (12a,e) or pale yellow solids
(12b–d) which were further recrystallized (hexane–toluene) (Table
2).
A solution of HCOONH4 (160 mg, 2.5 mmol) in H2O (2 mL) was
slowly added to a stirred soln of 13 (0.5 mmol) in MeOH (10 mL)
with Pd/C (10%, 10 mg). The mixture was refluxed for 3 h then fil-
tered hot through Celite. H2O (10 mL) was added and the soln was
extracted with CH2Cl2 (3 × 20 mL). The combined organic layers
were dried (MgSO4) and concentrated under vacuum to give an oily
product. Purification by flash chromatography (EtOAc–hexanes,
50:50) delivered homoprotoberberine 14 as colorless solid, which
was recrystallized (hexane–toluene); yield: 169 mg (88%); mp 145–
146 °C.
1H NMR (300 MHz, CDCl3): δ = 1.98–2.22 (m, 2 H, CH2), 2.59 (dd,
J = 6.3, 13.8 Hz, 1 H, CH2), 2.82 (t, J = 5.6 Hz, 2 H, CH2), 2.85–
3.03 (m, 1 H, CH2), 3.72 (s, 3 H, OCH3), 3.75–3.84 (m, 2 H, NCH2),
3.81 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 4.41
(dd, J = 5.3, 12.3 Hz, 1 H, NCH), 6.42 (s, 1 H, Harom), 6.64 (s, 2 H,
2,3,10,11-Tetramethoxy-14,14a-dihydro-13H-isoquino[2,1-
b][2]benzazepin-8-one (13)
H2SO4 (95–98%, 10 mL) was added dropwise to a soln of acetal 12e
(0.5 mmol) in glacial AcOH (6 mL). The mixture was stirred at r.t.
for 0.5 h then made neutral by slow addition of 30% aq NH4OH.
The soln was extracted with CH2Cl2 (2 × 30 mL), dried (Na2SO4),
and concentration under vacuum to give the enelactam 13 as a col-
orless solid, which was recrystallized (hexane–toluene); yield: 154
mg (81%); mp 124–125 °C.
Harom), 7.19 (s, 1 H, Harom).
1H NMR (300 MHz, CDCl3): δ = 2.33–2.42 (m, 1 H, CH2), 2.65 (dd,
J = 6.9, 13.9 Hz, 1 H, CH2), 2.81–2.93 (m, 1 H, CH2), 3.80 (s, 3 H,
OCH3), 3.82–3.86 (m, 1 H, CH2), 3.88 (s, 3 H, OCH3), 3.92 (s, 3 H,
OCH3), 3.97 (s, 3 H, OCH3), 4.76 (dd, J = 4.9, 12.6 Hz, 1 H, NCH),
5.85 (d, J = 7.9 Hz, 1 H, Hvinyl.), 6.44 (s, 1 H, Harom), 6.62 (s, 1 H,
13C NMR (75 MHz, CDCl3): δ = 28.6 (CH2), 30.6 (CH2), 39.7
(CH2), 40.1 (CH2), 55.6 (NCH), 55.9 (2 OCH3), 56.0 (OCH3), 56.05
(OCH3), 109.2 (CH), 111.2 (CH), 111.25 (CH), 111.8 (CH), 127.3
(Cq), 127.9 (Cq), 128.0 (Cq), 130.9 (Cq), 147.7 (Cq), 147.8 (Cq),
147.9 (Cq), 150.7 (Cq), 170.7 (C=O).
Harom), 6.72 (s, 1 H, Harom), 7.18 (d, J = 7.9 Hz, 1 H, Hvinyl), 7.26 (s,
Anal. Calcd for C22H25NO5 (383.45): C, 68.91; H, 6.57; N, 3.65.
Found: C, 70.05; H, 6.35; N, 3.48.
1 H, Harom).
Table 2 Physical and Spectroscopic Data of 2-Benzazepine-1,3-diones 4a–e and 2-Benzazepin-1-ones 11a–e, 12a–e Prepared
Producta
1H NMR (CDCl3–TMS): δ, J (Hz)
13C NMR (CDCl3–TMS): δ
Mp (°C)
oil
4a
2.93–3.11 (m, 4 H, 2 CH2), 3.40 (s, 3 H, NCH3), 7.19 (d,
J = 7.2, 1 H, Harom), 7.33–7.48 (m, 2 H, Harom), 8.03 (d,
28.8 (CH2), 32.3 (NCH3), 40.0 (CH2), 127.3
(CH), 127.5 (CH), 132.2 (Cq), 132.7 (CH), 133.1
(CH), 140.4 (Cq), 168.6 (C=O), 175.6 (C=O)
J = 7.7, 1 H, Harom
)
4b
oil
3.03 (s, 4 H, 2 CH2), 5.26 (s, 2 H, NCH2Ph), 7.17 (d, J = 8.1, 28.7 (CH2), 40.3 (CH2), 47.7 (NCH2Ph), 127.2
1 H, Harom), 7.25–7.48 (m, 7 H, Harom), 7.96 (d, J = 7.8, 1 H, (CH), 127.3 (CH), 127.4 (CH), 128.2 (2 CH),
128.4 (2 CH), 132.6 (CH), 132.7 (Cq), 133.0
(CH), 137.9 (Cq), 140.1 (Cq), 168.5 (C=O), 175.1
(C=O)
Harom
)
4c
oil
oil
0.95 (t, J = 7.4, 3 H, CH3), 1.68 (q, J = 7.4, 2 H, CH2), 2.95 11.5 (CH3), 21.5 (CH2), 28.7 (CH2), 40.4 (CH2),
(m, 4 H, 2 CH2), 3.93–3.99 (m, 2 H, NCH2), 7.14 (d, J = 6.7, 46.6 (NCH2), 127.2 (CH), 127.3 (CH), 132.4
1 H, Harom), 7.25–7.42 (m, 2 H, Harom), 7.95 (d, J = 7.3, 1 H, (CH), 132.8 (CH), 133.0 (Cq), 140.0 (Cq), 168.5
Harom
)
(C=O), 175.3 (C=O)
4d
2.93–3.05 (m, 4 H, 2 CH2), 3.36 (s, 3 H, NCH3), 3.93 (s, 3 H, 28.7 (CH2), 32.4 (NCH3), 39.5 (CH2), 56.1 (2
OCH3), 3.95 (s, 3 H, OCH3), 6.62 (s, 1 H, Harom), 7.64 (s, 1 H, OCH3), 110.1 (CH), 115.7 (CH), 123.7 (Cq),
Harom
)
135.4 (Cq), 147.7 (Cq), 152.3 (Cq), 167.1 (C=O),
167.9 (C=O)
© Georg Thieme Verlag Stuttgart · New York
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Table 2 Physical and Spectroscopic Data of 2-Benzazepine-1,3-diones 4a–e and 2-Benzazepin-1-ones 11a–e, 12a–e Prepared (continued)
Producta
1H NMR (CDCl3–TMS): δ, J (Hz)
13C NMR (CDCl3–TMS): δ
Mp (°C)
oil
4e
2.98–3.05 (m, 4 H, 2 CH2), 3.34 (s, 6 H, 2 OCH3), 3.92 (s, 3 28.4 (CH2), 40.0 (CH2), 44.5 (CH2), 53.6 (2
H, OCH3), 3.94 (s, 3 H, OCH3), 4.25 (d, J = 5.6, 2 H, NCH2), OCH3), 56.0 (OCH3), 56.1 (OCH3), 101.4
4.69 (t, J = 5.6, 1 H, OCHO), 6.63 (s, 1 H, Harom), 7.57 (s, 1 (OCHO), 110.0 (CH), 115.3 (CH), 123.9 (Cq),
H, Harom
)
135.1 (Cq), 147.7 (Cq), 152.2 (Cq), 167.8 (C=O),
175.1 (C=O)
11a
11b
oil
3.00–3.12 (m, 1 H, CH2), 3.17 (s, 3 H, NCH3), 3.56–3.64 (m, 31.7 (CH2), 34.3 (NCH3), 58.5 (OCH3), 113.6 (2
1 H, CH2), 3.82 (s, 3 H, OCH3), 5.90 (t, J = 7.5, 1 H, Hvinyl), CH), 122.3 (CH), 127.1 (CH), 128.5 (CH), 128.7
(CH), 129.1 (Cq), 129.9 (2 CH), 130.5 (CH),
135.4 (Cq), 136.3 (Cq), 137.8 (Cq), 159.5 (Cq),
169.9 (C=O)
6.87 (d, J = 8.7, 2 H, Harom), 7.11 (d, J = 8.0, 1 H, Harom), 7.22
(d, J = 8.7, 2 H, Harom), 7.29–7.36 (m, 2 H, Harom), 7.93 (dd,
J = 1.7, 7.5, 1 H, Harom
)
78–79 °C
2.99 (dd, J = 8.0, 13.2, 1 H, CH2), 3.44 (dd, J = 7.0, 13.2, 1 31.6 (CH2), 49.5 (NCH2Ph), 115.5 (CH), 124.3
H, CH2), 4.07 (d, J = 14.2, 1 H, NCH2Ph), 5.82 (d, J = 14.2, (CH), 125.9 (CH), 127.0 (2 CH), 127.5 (CH),
128.4 (2 CH), 128.7 (2 CH), 128.8 (2 CH), 129.5
(CH), 131.1 (CH), 131.5 (CH), 133.2 (Cq), 133.6
(Cq), 138.0 (Cq), 140.8 (Cq), 144.3 (Cq), 170.1
(C=O)
1 H, NCH2Ph), 6.06 (t, J = 7.5, 1 H, Hvinyl), 6.85–6.93 (m, 1
H, Harom), 7.03–7.12 (m, 1 H, Harom), 7.22–7.43 (m, 11 H,
Harom), 7.98–8.02 (m, 1 H, Harom
)
11c
134–135 °C 0.93 (t, J = 7.3, 3 H, CH3), 1.53–1.71 (m, 2 H, CH2), 2.92– 11.6 (CH3), 22.1 (CH2), 31.7 (CH2), 48.1
3.01 (m, 1 H, CH2), 3.13 (dd, J = 8.0, 13.2, 1 H, CH2), 3.64 (NCH2), 56.3 (2 OCH3), 60.9 (OCH3), 103.9 (2
(dd, J = 6.9, 12.9, 1 H, NCH2), 3.84 (s, 6 H, 2 OCH3), 3.95 (s, CH), 122.9 (CH), 125.7 (CH), 126.8 (CH), 131.0
(CH), 131.1 (CH), 132.6 (Cq), 133.7 (Cq), 141.2
(Cq), 144.1 (Cq), 153.3 (2 Cq), 153.4 (Cq), 169.7
(C=O)
3 H, OCH3), 4.41–4.52 (m, 1 H, NCH2), 6.05 (t, J = 7.6, 1 H,
Hvinyl), 6.48 (s, 2 H, Harom), 7.10 (d, J = 6.9, 1 H, Harom), 7.29–
7.39 (m, 2 H, Harom), 7.94 (dd, J = 1.6, 7.7, 1 H, Harom
)
11d
11e
89–90 °C
2.98–3.05 (m, 1 H, CH2), 3.26 (s, 3 H, NCH3), 3.61–3.68 (m, 31.6 (CH2), 34.5 (NCH3), 56.0 (2 OCH3), 111.6
1 H, CH2), 3.94 (s, 3 H, OCH3), 3.97 (s, 3 H, OCH3), 6.01 (t, (CH), 116.3 (CH), 125.8 (CH), 126.8 (2 CH),
128.5 (CH), 128.7 (2 CH), 128.9 (Cq), 134.1 (Cq),
134.6 (Cq), 135.8 (Cq), 147.3 (Cq), 153.1 (Cq),
169.5 (C=O)
J = 7.5, 1 H, Hvinyl), 6.66 (s, 1 H, Harom), 7.15–7.21 (m, 2 H,
Harom), 7.32–7.41 (m, 3 H, Harom), 7.60 (s, 1 H, Harom
)
oil
2.93–3.11 (m, 2 H, CH2), 3.27 (s, 3 H, OCH3), 3.35 (s, 3 H, 31.1 (CH2), 47.2 (NCH2), 53.4 (OCH3), 53.5
OCH3), 3.69 (dd, J = 6.9, 13.1, 1 H, NCH2), 3.89 (s, 6 H, 2 (OCH3), 55.9 (OCH3), 55.95 (OCH3), 56.1 (2
OCH3), 3.90 (s, 3 H, OCH3), 3.91 (s, 3 H, OCH3), 4.57 (dd, OCH3), 101.1 (OCHO), 108.8 (CH), 109.7 (CH),
J = 4.6, 13.8, 1 H, NCH2), 4.71 (t, J = 5.6, 1 H, OCHO), 6.00 111.0 (CH), 113.5 (CH), 119.7 (CH), 121.8 (CH),
124.9 (Cq), 129.2 (Cq), 138.4 (Cq), 141.0 (Cq),
147.5 (Cq), 149.0 (Cq), 149.3 (Cq), 152.4 (Cq),
169.6 (C=O)
(t, J = 7.5, 1 H, Hvinyl), 6.59 (s, 1 H, Harom), 6.73 (s, 1 H, Harom),
6.79 (d, J = 8.3, 1 H, Harom), 6.85 (d, J = 8.3, 1 H, Harom), 7.47
(s, 1 H, Harom
)
12a
12b
oil
oil
2.05–2.21 (m, 1 H, CH2), 2.52–2.58 (m, 1 H, CH2), 2.68 (s, 3 29.3 (NCH3), 30.4 (CH2), 31.6 (CH2), 55.3
H, NCH3), 2.81–3.03 (m, 2 H, CH2), 3.82 (s, 3 H, OCH3),
4.68 (dd, J = 4.3, 12.8, 1 H, NCH), 6.89 (d, J = 8.7, 2 H,
(NCH), 58.8 (OCH3), 113.9 (2 CH), 127.2 (CH),
128.3 (CH), 128.4 (CH), 128.9 (Cq), 129.8 (2
CH), 130.8 (CH), 136.5 (Cq), 137.4 (Cq), 159.3
(Cq), 171.1 (C=O)
Harom), 7.18 (d, J = 8.7, 2 H, Harom), 7.31–7.39 (m, 3 H, Harom),
7.73–7.80 (m, 1 H, Harom
)
2.12–2.21 (m, 1 H, CH2), 2.53–2.65 (m, 1 H, CH2), 2.75–2.84 29.3 (CH2), 34.2 (CH2), 49.6 (NCH2Ph), 63.2
(m, 2 H, CH2), 4.35 (d, J = 14.6, 1 H, NCH2Ph), 4.78 (dd, (NCH), 115.4 (CH), 120.4 (CH), 127.5 (Cq),
J = 4.5, 12.4, 1 H, NCH), 5.02 (d, J = 14.6, 1 H, NCH2Ph), 128.0 (CH), 128.4 (2 CH), 128.7 (2 CH), 128.9
(CH), 129.5 (2 CH), 129.6 (2 CH), 129.8 (CH),
133.0 (Cq), 134.7 (Cq), 134.9 (CH), 139.6 (Cq),
174.1 (C=O)
6.95–7.13 (m, 4 H, Harom), 7.17–7.29 (m, 7 H, Harom), 7.38–
7.55 (m, 2 H, Harom), 7.81 (d, J = 7.3, 1 H, Harom
)
Synthesis 2012, 44, 1410–1416
© Georg Thieme Verlag Stuttgart · New York

PAPER
A Concise Synthesis of 3-Arylated Di- and Tetrahydro-2H-2-benzazepin-1-ones
1415
Table 2 Physical and Spectroscopic Data of 2-Benzazepine-1,3-diones 4a–e and 2-Benzazepin-1-ones 11a–e, 12a–e Prepared (continued)
Producta
1H NMR (CDCl3–TMS): δ, J (Hz)
13C NMR (CDCl3–TMS): δ
Mp (°C)
oil
12c
0.81 (t, J = 7.3, 3 H, CH3), 1.45–1.63 (m, 2 H, CH2), 2.03– 11.8 (CH3), 23.2 (CH2), 30.3 (CH2), 33.6 (CH2),
2.09 (m, 1 H, CH2), 2.58–2.66 (m, 1 H, CH2), 2.74–2.96 (m, 45.0 (CH2), 56.3 (2 OCH3), 59.9 (OCH3), 60.3
3 H, CH2, NCH2), 3.63–3.68 (m, 1 H, NCH2), 3.82 (s, 6 H, 2 (NCH), 106.0 (2 CH), 127.2 (CH), 128.1 (CH),
128.6 (CH), 130.8 (CH), 132.7 (Cq), 136.6 (Cq),
137.3 (Cq), 144.2 (Cq), 153.2 (2 Cq), 170.9 (C=O)
OCH3), 3.94 (s, 3 H, OCH3), 4.65 (dd, J = 4.7, 12.3, 1 H,
NCH), 6.46 (s, 2 H, Harom), 7.11–7.18 (d, J = 7.2, 1 H, Harom),
7.27–7.38 (m, 2 H, Harom), 7.73 (d, J = 7.4, 1 H, Harom
)
12d
12e
oil
oil
2.07–2.15 (m, 1 H, CH2), 2.48–2.54 (m, 1 H, CH2), 2.73 (s, 3 29.5 (NCH3), 30.6 (CH2), 31.5 (CH2), 55.5
H, NCH3), 2.89–3.12 (m, 2 H, CH2), 3.91 (s, 3 H, OCH3), (NCH), 56.0 (2 OCH3), 113.6 (CH), 115.9 (CH),
3.95 (s, 3 H, OCH3), 4.76 (dd, J = 4.7, 12.5, 1 H, NCH), 6.64 127.4 (2 CH), 128.2 (CH), 128.5 (2 CH), 128.9
(Cq), 133.5 (Cq), 134.4 (Cq), 148.6 (Cq), 153.3
(Cq), 171.3 (C=O)
(s, 1 H, Harom), 7.10–7.16 (m, 2 H, Harom), 7.31–7.40 (m, 3 H,
Harom), 7.59 (s, 1 H, Harom
)
2.08–2.19 (m, 1 H, CH2), 2.51–2.57 (m, 1 H, CH2), 2.80–2.98 30.1 (CH2), 34.2 (CH2), 45.8 (NCH2), 53.5
(m, 2 H, CH2), 3.20 (s, 3 H, OCH3), 3.29 (s, 3 H, OCH3), 3.79 (OCH3), 53.6 (OCH3), 55.9 (OCH3), 56.0
(dd, J = 7.0, 13.0, 1 H, NCH2), 3.85 (s, 6 H, 2 OCH3), 3.87 (s, (OCH3), 56.1 (2 OCH3), 60.5 (NCH), 100.8
6 H, 2 OCH3), 4.52 (dd, J = 4.6, 13.1, 1 H, NCH2), 4.65–4.72 (OCHO), 108.7 (CH), 110.7 (CH), 111.6 (CH),
113.9 (CH), 121.9 (CH), 128.6 (Cq), 130.5 (Cq),
136.1 (Cq), 147.2 (Cq), 148.8 (Cq), 149.5 (Cq),
152.5 (Cq), 171.1 (C=O)
(m, 2 H, OCHO, NCH), 6.61 (s, 1 H, Harom), 6.68–6.85 (m, 3
H, Harom), 7.25 (s, 1 H, Harom
)
a Satisfactory microanalyses obtained: C ± 0.29, H ± 0.25, N ± 0.29.
(4) Ishibashi, H.; Kobayashi, T.; Nakashima, S.; Tamura, O.
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Acknowledgment
This research was supported by the CNRS and by MENESR. The
authors are grateful to M. Dubois for technical assistance.
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Synthesis 2012, 44, 1410–1416
© Georg Thieme Verlag Stuttgart · New York