A new enlargement methodology for the preparation of 2H-1- and 2H-3-benzazepin-2-one derivatives

Article abstract of DOI:10.1016/j.tet.2007.08.094

An investigation of the one-carbon homologation of some 1-tribromomethyl-isoquinoline and 2-tribromomethyl-quinoline derivatives was conducted. Under the influence of an aqueous solution of silver nitrate in the presence of a nucleophilic species (MeOH, H

Full text of DOI:10.1016/j.tet.2007.08.094

Tetrahedron 63 (2007) 11250–11259
A new enlargement methodology for the preparation
of 2H-1- and 2H-3-benzazepin-2-one derivatives
a
Ludivine Jean-Gerard, Mickael Pauvert, Sylvain Collet,
a,y
a,
*
ꢀ
€
Andre Guingant and Michel Evain
a,
b,z
*
ꢀ
a
´
´
´
Universite de Nantes, Nantes Atlantique Universites, CNRS, Faculte des Sciences et des Techniques, Laboratoire de Synthese
ꢁ
Organique (LSO), UMR CNRS 6513, 2, rue de la Houssinieꢁre—BP 92208—44322 Nantes Cedex 03, France
b
´
Institut des Materiaux Jean Rouxel, 2, rue de la Houssinieꢁre—BP 92208—44322 Nantes Cedex 03, France
Received 18 July 2007; revised 21 August 2007; accepted 29 August 2007
Available online 1 September 2007
Abstract—An investigation of the one-carbon homologation of some 1-tribromomethyl-isoquinoline and 2-tribromomethyl-quinoline deriv-
atives was conducted. Under the influence of an aqueous solution of silver nitrate in the presence of a nucleophilic species (MeOH, H2O,
EtNH2), these derivatives led to the respective expanded heterocycles, 2H-1- and 2H-3-benzazepin-2-one derivatives. A mechanism for
this novel ring enlargement involving initial formation of an aziridinium, and its subsequent opening to form a stabilized benzylic carbocation,
is proposed to explain the results.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Among the possible routes to a benzazepine structure, one
consists in ring enlargement of a six-membered ring pre-
cursor.8 This can be achieved either by insertion of a nitro-
gen atom in a carbacycle or by one-carbon homologation
of an azacycle. Regarding the second and less frequently
used approach, most of the reported examples rely on
the intermediary formation of an aziridine or a transient
aziridinium species9 as pictured in general terms in
Scheme 2 (X¼halogen, OCOR). This approach, however,
does not allow the direct formation of a benzazepinone
structure such as 1 or 2.10 We reasoned that if the exocy-
clic carbon involved in the enlargement process were tri-
ply activated (for instance, as in 3), the primary enlarged
species 5 would lead to a 1,3,4,5-tetrahydro-2H-3-benza-
zepin-2-one compound 6 after hydrolysis of its highly la-
bile N–CX2 moiety (Scheme 2, X¼halogen, PG is
a protecting group).11
Compounds characterized by a 1,3,4,5-tetrahydro-2H-1-
benzazepin-2-one structure or a 1,3,4,5-tetrahydro-2H-3-
benzazepin-2-one core structure (1 and 2, respectively)
have stimulated much synthetic effort due to their wide-
ranging pharmacological activities (Scheme 1). For in-
stance, compounds with a bicyclic core structure such as 1
have been shown to have activity against cyclin-dependent
kinases (CDKs)1 and the angiotensin-converting enzyme
(ACE).2 They also display activity as human growth hor-
mone (hGH) secretagogues,3 calcium channel blockers
(CCBs),4 and thrombin inhibitors.5 On the other hand, com-
pounds with core structure 2 have been reported to act as
specific bradycardic agents6 and g-secretase inhibitors.7
NH
In a retrosynthetic point of view (Scheme 3), the synthetic
precursor to 6 could be prepared by 1,2-addition of a trihalo-
methane anion to an iminium species, which in turn could be
prepared by quaternarization of the corresponding dihydro-
isoquinoline. Provided an additional reductive step is
accomplished (i.e., 7/6), an isoquinoline, rather than a di-
hydroisoquinoline species, is also a possible starting point to
reach a 1,3,4,5-tetrahydro-2H-3-benzazepin-2-one deriva-
tive. Of course, a compound such as 7 provides additional
synthetic possibilities by chemical manipulation of its
C4–C5 double bond. Finally, it is noteworthy that the above
general procedure, when applied to a dihydroquinoline or
N
H
O
O
1
2
Scheme 1.
Keywords: Ring enlargement; 2H-1- and 2H-3-benzazepin-2-one deriva-
tives.
* Corresponding authors. E-mail addresses: sylvain.collet@univ-nantes.fr;
andre.guingant@univ-nantes.fr
Present address: Atlanchim Laboratory, Pole Bio-Ouest, rue du Moulin de
y
ˆ
la Roussiere, 44800 Saint-Herblain, France.
ꢁ
All inquiries regarding X-ray diffraction should be directed to this author.
z
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.094

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L. Jean-Gerard et al. / Tetrahedron 63 (2007) 11250–11259
11251
X
X
n
n+1
N
R
X
N
N
R
R
breaking of this
C-N bond
x
or external
nucleophile (Nu:)
H2O
R
R
R
N
X
PG
N
PG
R
N
X
N
PG
PG
O
X
Nu
X
Nu
X
X
X
carbonyl precursor
3
5
4
6
Scheme 2.
a quinoline species, would be expected to lead to a 1,3,4,5-
tetrahydro-2H-1-benzazepin-2-one derivative.
to afford the tribromomethyl addition products 9 and 1115 in
good yields (Scheme 4).
On the basis of the importance of structures 1 and 2 in me-
dicinal chemistry and their presence in several natural prod-
ucts, there appeared to be a significant opportunity to study
the possibility of ring enlargement of quinoline and isoqui-
noline derivatives following the sequence shown in Scheme
3. The realization of this goal would offer an attractive po-
tential entry to a range of diverse 2H-1- and 2H-3-benzaze-
pin-2-ones whose preparation following known methods is
not always efficiently achieved. Herein, we describe our re-
alization of that objective and also report results that shed
light on some mechanistic aspects of these new ring expan-
sion reactions.
i
ii
N
N
Ph
N
Ph
Br
CBr3
8
9
iii
ii
N
N
Br
N
CBr3
Ph
Ph
10
11
Scheme 4. Reagents and conditions: (i) BnBr, MeOH, reflux, two weeks
(quantitative); (ii) CHBr3, aq NaOH [45 min (9), 2 h (11)] (9: 89%; 11:
80%); (iii) BnBr, MeOH, reflux, four days (71%).
With the key compounds 9 and 11 in hand, we initially ex-
amined the ability for 9 to lead to ring expansion and forma-
tion of a 1,3-dihydro-2H-3-benzazepin-2-one derivative.
Given the known halophile character of silver we thought
to trigger the aziridinium formation by exposure of 9 to an
aqueous solution of silver nitrate, hoping that the transient
species 12 would be prone to evolve as shown in Scheme
2. We were thus pleased to observe that, in accordance
with our expectations, a methanolic solution of the tribromo-
methyl derivative 9 led to the formation of the 2H-3-benza-
zepine-2-one 13 under the above conditions. The formation
of 13 can be accounted for by the mechanism shown in
Scheme 5 where methanol is the incoming nucleophile. It
is worth noting that the 2H-3-benzazepinone 14 could not
be detected in this experiment.
2. Results and discussion
Although trihalomethyl anions (X3Cꢀ, X¼Cl, Br) are
relatively good leaving groups, the negative charge being
stabilized by the three halogen atoms, examples of their
1,2-addition to aromatic iminium salts have already been re-
ported following different protocols.12 After several prelim-
inary experiments, it appeared to us that the most reliable
and efficient way to reach the key intermediates 9 and 11
was by applying the protocol reported by Duchardt and
€
12e
Krohnke.
Thus, after quaternarization of isoquinoline
and quinoline by treatment with benzyl bromide in methanol
at reflux, the resultant salts 813 and 10,14 vigorously stirred in
aqueous acetonitrile at 20 ꢁC, were sequentially treated with
bromoform and an aqueous solution of potassium hydroxide
X
X
R
N PG
R
R
R
+
N
X
N
N
PG
PG
X
O
Nu
1,2-addition
X
R
quaternarization
X
6
R
6
N PG
N
O
Nu
7
Scheme 3.

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L. Jean-Gerard et al. / Tetrahedron 63 (2007) 11250–11259
11252
aq AgNO3
MeOH
20 °C, 16h
Ph
Ph
Ph
N
N
9
N
Br
Br
O
Br
MeO
Br
R
MeOH
13 (R = OMe) (44%)
14 (R = OH)
12
Scheme 5.
path a
path b
OMe
b
MeOH
N
O
O
a
Ph
i
MeOH
Br
16
11
N
OMe
OMe
Br
Ph
ii
15
N
N
O
Ph
Ph
17
18
Scheme 6. Reagents and conditions: (i) 11 in methanol, aq AgNO3, 20 ꢁC, 3 h (50%); (ii) H2, 5% Pd/C, MeOH, 20 ꢁC (quantitative).
We next examined the behavior of 11 in the same experimen-
tal conditions as for 9. The problem is more complex in that
case because nucleophilic opening of the aziridinium
species 15 may take place at two distinct positions, i.e., at
carbon C2 or at carbon C4, to afford the 1,3-dihydro-2H-1-
benzazepin-2-one 16 or the 1,3-dihydro-2H-1-benzazepin-
2-one 17, respectively (Scheme 6).
Many examples of ring expansion of substituted pyrrolidines
via aziridinium species were shown to be stereospecific pro-
cesses.16 As pictured in general terms in Scheme 8, the reac-
tion proceeds through an internal displacement of a good
leaving group (Z) to generate an aziridinium salt that is sub-
sequently opened by the nucleophile present in the reaction
mixture (e.g., Zꢀ) following an SN2-type displacement
(Scheme 8). Because the stereochemical outcome for the re-
lated C6 to C7 enlargement is not yet known, we became
much interested to know if the opening of the aziridinium in-
termediary shown in Scheme 2 is, or is not, a stereoselective
process.
After being exposed to the action of AgNO3, a methanol so-
lution of the tribromo derivative 11 led to the formation of an
expanded heterocycle which was thought to be 17 rather than
16 on the basis of its NMR data. Its structure was finally fully
ascertained by comparison of its reduction product 18 with
an authentic sample prepared following a more conventional
route.11a Furthermore, when the whole sequence was per-
formed starting from lepidine (4-Me-quinoline), the 1,3-di-
hydro-2H-1-benzazepin-2-one 21 was identified as the sole
expanded product of the reaction. It thus appears that a meth-
yl substituent does not provide a sufficient steric bias to pre-
vent MeOH from approaching the benzylic carbon of the
transient aziridinium species (Scheme 7).
R1
R1
Z
Z
R1
H
H
H
H
Z
Z
N
R2
N
R2
N
R2
Z
Z
R1
R1
R1
N
R2
N
R2
N
R2
Me
N
Me
N
Me
N
i
ii
Scheme 8.
CBr3
We restricted our study to the example of the isoquinoline
enlargement and chose, as a model study, the chiral isoqui-
nolinium salt 22 whose synthesis had been already re-
ported17 from isoquinoline by application of the Zincke
reaction (Scheme 9).
Br
Ph
Ph
19
20
Me
N
Me OMe
MeOH
iii
MeOH
Br
When subjected to the action of bromoform in the presence
of aqueous KOH, salt 22 led to the formation of two dia-
stereomeric addition products, 23 and 24, which could be
routinely isolated in ca. 93% yield. The reaction was slightly
selective (ca. 3:1 ratio of diastereomers) and significant
amounts of the minor diastereomer could be obtained pure
by fractional crystallization from ether. The structure of
N
O
Br
Ph
Ph
21
Scheme 7. Reagents and conditions: (i) BnBr, MeOH, reflux, seven days
(74%); (ii) CHBr3, aq NaOH, 20 ꢁC (60%); (iii) aq AgNO3, MeOH,
20 ꢁC, 4 h (29%).

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L. Jean-Gerard et al. / Tetrahedron 63 (2007) 11250–11259
11253
The enlargement protocol was next applied to 24 and to a 3:1
mixture of diastereomers 23 and 24 to give, in each experi-
ment, a 1 to 1 ratio of enlarged diastereomers 25 and 26
(Scheme 10), which could be separated by flash chromato-
graphy only with difficulty.
i
NO2
ii
Ph
Me
N
N
N
Cl
Cl
H
H
NO2
22
To rule out the possibility that the above 1:1 mixture was the
result of an epimerization at C1, we submitted compound 9
in MeOD to the action of a solution of AgNO3 in D2O.19
The enlargement reaction took place without notable deute-
rium incorporation as judged from the 1H and 13C spectra of
the crude enlarged product 13. It thus appears that, in con-
trast to the stereochemical course of the C5 to C6 enlarge-
ment, opening of the transient aziridinium 27 does not take
place via an SN2-type displacement but merely involves its
prior dissociation into a benzylic carbocation species
(Scheme 11). By analogy we believe that such a mechanism
is also relevant to the transformation 9/13 (14). Although
not demonstrated, the formation of a transient benzylic
carbocation is also probably involved in the transformations
11/17 and 20/21.
iii
22
+
Ph
Me
Ph
Me
N
N
CBr3
23
H
CBr3
24
H
Scheme 9. Reagents and conditions: (i) 1-chloro-2,4-dinitrobenzene, ace-
tone, 60 ꢁC, 2 h (82%); (ii) (R)-1-phenylethylamine, n-BuOH, reflux, 15 h
(84%); (iii) CHBr3, aq NaOH, 20 ꢁC, 12 h (93%).
C17
C18
C5
C12
C3
C2
C4
C6
C16
C13
C9
C15
C11
C7
C1
We next focused our attention on the possibility of using nu-
cleophiles other than methanol to promote, in association
with AgNO3, the C6 to C7 ring enlargement. In this regard,
the above reported examples of ring enlargement were also
studied in the presence of water and (or) ethylamine instead
of methanol. In a general manner, reactions were less effi-
cient in the presence of water, as compared to methanol,
and we only got a synthetically useful result with the tribro-
momethyl derivative 29, which was expanded to the 1,3,4,5-
tetrahydro-2H-3-benzazepin-2-one 30 in 71% yield
(Scheme 12).
N
C8
C14
Br2
C10
Br3
Br1
Figure 1. X-ray crystal structure of 24.
the minor diastereomer was firmly established as 24 by
X-ray analysis (Fig. 1) and, by inference, structure 23 was
thus attributed to the major diastereomer formed. The pre-
dominant formation of 23 may be accounted for by consid-
ering that the reactive conformation for 22 is the one that
minimizes allylic 1,3-strain18 (as shown in Scheme 9) and
wherein Br3Cꢀ is approaching the less congested face of
the iminium bond, i.e., the face opposite to the phenyl sub-
stituent of the attached chiral moiety.
The ring enlargement of 29 was also studied in the presence
of ethylamine in THF. We obtained results that greatly de-
pended on the reaction conditions (Scheme 13). Thus, if
the reaction was conducted in water or in a water/methanol
mixture, compounds 30 and 31 were isolated, respectively.
However, if the reaction was carried out in THF, the a-diketo
derivative 32 was the sole expanded compound isolated from
aq AgNO3
MeOH
24
Ph
Me
H
Ph
Me
H
N
+
N
23 + 24
(3:1 mixture)
O
O
aq AgNO3
MeOH
OMe
25
OMe
26
(dr : c.a. 1:1)
Scheme 10.
MeOH
H2O
N R*
Br
N R*
O
N
N
R*
R*
Br
CBr3
OMe
25 + 26
Br
Br
Ph
Me
24
27
R* =
H
Scheme 11.

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L. Jean-Gerard et al. / Tetrahedron 63 (2007) 11250–11259
11254
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
i
ii
iii
N
N
Ph
N
Ph
N
Ph
O
CBr3
OH
30
Br
28
29
Scheme 12. Reagents and conditions: (i) BnBr, toluene, reflux, 5 h (74%); (ii) CHBr3, aq NaOH, 20 ꢁC, 8 h (73%); (iii) aq AgNO3, ꢀ20 ꢁC to 20 ꢁC, 16 h (71%).
MeO
i
N
32 (X=O)
50% (X=O)
Ph
MeO
O
33 (X=NEt)
X
MeO
MeO
ii
30
N
Ph
75%
CBr3
MeO
MeO
iii
52%
29
N
31
Ph
O
OCH3
Scheme 13. Reagents and conditions: (i) 29 in THF, aq AgNO3, EtNH2 in THF, 20 ꢁC, 12 h; (ii) aq AgNO3, EtNH2 in THF, 20 ꢁC, 12 h; (iii) 29 in MeOH, aq
AgNO3, EtNH2 in THF, ꢀ20 ꢁC to 20 ꢁC, 12 h.
1
the crude mixture. Because traces of the corresponding im-
ine 33 were also detected when the reaction was carried
out at a lower temperature, we believed that 32 was derived
from 33 by hydrolysis. Interception of the transient carboca-
tion by ethylamine followed by oxidation of the CH–NHEt
moiety under the reaction conditions may explain the forma-
tion of imine 33.
Bruker Vector 22 spectrometer. H NMR spectra were re-
corded on a Bruker AC200 (or AC300) spectrometer at
200 MHz (respectively 300 MHz) or on a Bruker ARX400
spectrometer at 400 MHz. 13C NMR spectra were recorded
on a Bruker AC200 (or AC300) spectrometer at 50 MHz
(respectively 75 MHz) or on a Bruker ARX400 spectrometer
at 100 MHz. All NMR spectra used tetramethylsilane as the
internal standard and were run in deuteriated solvents. Ana-
lytical thin-layer chromatography (TLC) was performed on
silica gel aluminum plates precoated with a fluorescent indi-
cator (Merck 5735 Kieselgel 60 F254). Standard flash chro-
matography procedures were performed using 32–63 mm
silica gel (Merck Geduran SI 60 Art. 11567). Reactions
carried out under an inert atmosphere refer to the use of
argon or nitrogen. Diethyl ether, tetrahydrofuran (THF),
and toluene were dried by distilling from sodium and benzo-
phenone. Dichloromethane and acetonitrile were dried by
distillation from calcium hydride.
In summary, we have described a new procedure allowing
the C6 to C7 enlargement of quinoline and isoquinoline to
form 1,5-dihydro-2H-1-benzazepin-2-one and 1,3-dihydro-
2H-3-benzazepin-2-one structures, respectively, in fair to
good overall yields. The three-step sequence features a
quaternarization reaction, a tribromomethyl anion addition
and, as a key step, a silver-induced rearrangement. A rea-
sonable mechanism based on the formation of a transient
aziridinium species, its opening to form a stabilized benz-
ylic cation (at least with isoquinoline derivatives) followed
by its nucleophilic trapping with methanol (or water) has
been offered to account for the results. This new methodo-
logy should be complementary to conventional routes in
the preparation of 2H-1- and 2H-3-benzazepin-2-ones,
which proved to be useful structural patterns in medicinal
chemistry.
3.2. 2-Benzyl-isoquinolinium bromide 8
A solution of isoquinoline (2.5 mL, 21.0 mmol) in anhy-
drous methanol (25 mL) was treated with benzyl bromide
(2.50 mL, 23.1 mmol). The reaction was heated under reflux
with stirring for 14 days and then cooled to rt. The solvent
was removed in vacuo and the crude white solid was tritu-
rated in Et2O. The suspension was filtered and afforded the
desired isoquinolinium salt 8 as a white powder in quantita-
tive yield (6.3 g, 21.0 mmol). Mp (MeOH)¼112–113 ꢁC
(lit.13 mp¼108–110 ꢁC); 1H NMR (200 MHz, CDCl3)
d 11.05 (s, 1H), 8.91 (dd, 1H, J¼6.8, 1.2 Hz), 8.52 (d, 1H,
J¼8.2 Hz), 8.22 (d, 1H, J¼7.0 Hz), 8.05–7.85 (m, 2H),
7.80–7.65 (m, 3H), 7.20–7.10 (m, 3H), 6.28 (s, 2H); 13C
NMR (50 MHz, CDCl3) d 149.8, 137.1, 136.9, 134.4,
133.2, 131.0, 130.9, 129.6, 129.4 (2C), 129.3 (2C), 127.5,
127.0, 126.2, 63.5; IR (KBr) 3005, 1641, 1397, 1106,
722 cmꢀ1; EIMS m/z (%) 220 (2), 129 (76), 102 (19), 91
(100), 65 (15).
3. Experimental procedures
3.1. General methods
Melting points were determined using a Stuart Scientific
SMP3 Tottoli apparatus. Microanalysis was carried out at
ꢀ
the ‘Services de Microanalyses de l’Universite de Chatenay
Malabry—France’. HRMS was carried out at the ‘Centre
ꢀ
regional de mesures physiques de l’Ouest, Rennes—France’
or at the ‘Centre commun de spectrometrie de masse-Uni-
ꢀ
ꢀ
versite Claude Bernard Lyon 1, Villeurbanne—France’. IR
spectra were recorded neat or as KBr pellets on an IRTF

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L. Jean-Gerard et al. / Tetrahedron 63 (2007) 11250–11259
11255
3.3. 2-Benzyl-1-tribromomethyl-1,2-dihydro-isoquino-
line 9
(9); CIMS m/z 470 (M+H)+; HRMS (LSIMS) m/z calcd for
C17H15NBr3 (M+H+) 469.8755, found 469.876.
To a solution of the isoquinolinium salt 8 (500 mg,
1.66 mmol) in acetonitrile/water (1:1, 6 mL) were succes-
sively added bromoform (193 mL, 2.16 mmol) and an aque-
ous solution of KOH (1 mL, 115 mg, 2.05 mmol). The
reaction mixture was vigorously stirred for 45 min. The re-
sulting precipitate was filtered, rinsed with water, and dried
under high vacuum to afford the desired compound 9 as a yel-
low solid in 89% yield (700 mg, 1.48 mmol). Mp (MeCN/
3.6. 3-Benzyl-1-methoxy-1,3-dihydro-benzo[b]azepin-2-
one 13
An aqueous solution of silver nitrate (1 mL, 540 mg,
3.18 mmol) was added to a solution of the compound 9
(500 mg, 1.06 mmol) in MeOH (10 mL) cooled at ꢀ20 ꢁC.
The reaction was then stirred in the dark for 16 h while the
temperature was allowed to rise to rt. The insoluble salts
were filtered off through Celite, rinsed with CH2Cl2, and
the filtrate was concentrated in vacuo. The crude product
was diluted with CH2Cl2 (30 mL) and washed with water
(2ꢂ20 mL) and brine (1ꢂ20 mL). The organic layer was
dried (MgSO4) and filtered. The solvent was removed in
vacuo and the crude product was purified by silica gel chro-
matography (eluting with EtOAc/petroleum ether: 40:60) to
afford the desired compound 13 as a yellow oil in 44% yield
1
H2O)¼101–102 ꢁC; H NMR (400 MHz, CDCl3) d 7.46
(d, 1H, J¼7.6 Hz), 7.33 (td, 1H, J¼7.6, 1.2 Hz), 7.10–7.20
(m, 5H), 6.90–7.0 (m, 2H), 6.38 (dd, 1H, J¼7.2, 0.8 Hz),
5.74 (d, 1H, J¼7.2 Hz), 5.23 (s, 1H), 4.77 and 4.97 (AB sys-
tem, 2H, J¼16.0 Hz); 13C NMR (100 MHz, CDCl3) d 138.4,
134.8, 134.4, 131.1, 129.0, 128.8 (2C), 127.6, 126.9 (2C),
125.1, 124.1, 121.9, 103.6, 77.5, 62.3, 59.8; IR (KBr)
1623, 1487, 1368, 1155, 770, 601, 549 cmꢀ1; EIMS m/z
(%) 220 (87), 173 (8), 129 (12), 91 (100), 65 (11). Anal.
Calcd for C17H14NBr3: C, 43.26; H, 2.99; N, 2.97. Found:
C, 43.26; H, 2.98; N, 2.95%.
1
(130 mg, 0.46 mmol). H NMR (200 MHz, CDCl3) d 7.65
(d, 1H, J¼7.6 Hz), 7.44 (td, 1H, J¼1.4, 7.6 Hz), 7.35–7.20
(m, 5H), 7.15–7.05 (m, 2H), 6.45 (d, 1H, J¼9.2 Hz), 6.25
(d, 1H, J¼9.2 Hz), 4.87 and 4.71 (AB system, 2H,
J¼15.0 Hz), 4.45 (br s, 1H), 3.59 (s, 3H); 13C NMR
(50 MHz, CDCl3) d 166.9, 136.6, 133.7, 131.2, 129.0,
128.7 (2C), 128.4, 127.8 (2C), 127.7, 127.4, 127.0, 124.3,
117.3, 81.1, 58.3, 50.8; IR (neat) 1678, 1496, 1455, 1397,
3.4. 1-Benzyl-quinolinium bromide 10
A solution of quinoline (2.7 mL, 19.4 mmol) in anhydrous
methanol (30 mL) was treated with benzyl bromide
(2.6 mL, 21.3 mmol). The reaction was heated under reflux
with stirring for seven days and then cooled to rt. The solvent
was removed in vacuo and the crude white solid was tritu-
rated in CH2Cl2. The suspension was filtered and the opera-
tion was repeated twice to afford the desired quinolinium salt
10 as a white powder in 71% yield (4.2 g, 14.0 mmol). Mp
(CH2Cl2)¼183–184 ꢁC (lit.20 mp¼188 ꢁC); 1H NMR
(300 MHz, CDCl3) d 10.57 (d, 1H, J¼5.8 Hz), 9.25 (d,
1H, J¼8.4 Hz), 8.57 (d, 1H, J¼8.2 Hz), 8.37 (d, 1H,
J¼8.0 Hz), 8.20 (t, 1H, J¼8.4 Hz), 8.11 (dd, 1H, J¼8.0,
8.2 Hz), 7.88 (t, 1H, J¼8.0 Hz), 7.50–7.40 (m, 2H), 7.30–
7.15 (m, 3H), 6.71 (s, 2H); 13C NMR (75 MHz, CDCl3)
d 150.5, 147.9, 138.0, 136.2, 132.8, 130.9, 130.3, 130.2,
129.4, 129.2, 127.6, 122.3, 119.5, 60.9; IR (KBr) 1529,
ꢃ
1211, 1127, 785 cmꢀ1; EIMS m/z (%) 279 (42, M+ ), 264
(9), 220 (19), 91 (100), 65 (18); HRMS (EI) m/z calcd for
ꢃ
C18H17NO2 (M+ ) 279.1259, found 279.127.
3.7. 1-Benzyl-5-methoxy-1,5-dihydro-benzo[b]azepin-2-
one 17
An aqueous solution of silver nitrate (1 mL, 680 mg,
3.99 mmol) was added to a solution of the compound 10
(630 mg, 1.33 mmol) in MeOH (10 mL). The reaction was
then stirred in the dark for 3 h. The insoluble salts were fil-
tered off through Celite, rinsed with EtOAc, and the filtrate
was concentrated in vacuo. The crude product was diluted
with EtOAc (20 mL) and washed with water (2ꢂ20 mL)
and brine (1ꢂ20 mL). The organic layer was dried (MgSO4)
and filtered. The solvent was removed in vacuo and the crude
product was purified by silica gel chromatography (eluting
with EtOAc/petroleum ether: 50:50) to afford the desired
compound 17 as a yellow oil in 50% yield (185 mg,
774, 765, 718 cmꢀ1
.
3.5. 1-Benzyl-2-(tribromomethyl)-1,2-dihydroquinoline
11
To a solution of the quinolinium salt 10 (500 mg,
1.67 mmol) in acetonitrile/water (1:1, 6 mL) were succes-
sively added bromoform (179 mL, 2.0 mmol) and an aqueous
solution of KOH (1 mL, 102.4 mg). The reaction mixture
was vigorously stirred for 2 h producing a biphasic mixture.
The more dense layer was separated and directly purified by
silica gel chromatography (eluting with EtOAc/petroleum
ether: 20:80) to afford the desired compound 11 as a yellow
oil in 80% yield (630 mg, 1.34 mmol). 1H NMR (300 MHz,
CDCl3) d 7.25–7.05 (m, 7H), 6.97 (d, 1H, J¼9.6 Hz), 6.88
(d, 1H, J¼8.0 Hz), 6.27 (dt, 1H, J¼1.0, 8.0 Hz), 6.23 (dd,
1H, J¼5.8, 9.6 Hz), 5.34 and 5.02 (AB system, 2H,
J¼16.6 Hz), 4.81 (dd, 1H, J¼1.0, 5.8 Hz); 13C NMR
(75 MHz, CDCl3) d 143.4, 137.9, 130.8, 129.4, 128.7
(2C), 127.4, 127.3, 127.1 (2C), 123.6, 118.7, 118.4, 115.8,
75.4, 60.9, 59.8; IR (neat) 3028, 2923, 1636, 1600, 1488,
590 cmꢀ1; EIMS m/z (%) 220 (69), 129 (8), 91 (100), 65
1
0.66 mmol). H NMR (200 MHz, CDCl3) d 7.45–7.05 (m,
9H), 6.51 (dd, 1H, J¼4.0, 11.2 Hz), 5.84 (d, 1H,
J¼11.2 Hz), 5.40 and 5.08 (AB system, 2H, J¼15.2 Hz),
4.82 (br s, 1H), 3.40 (s, 3H); 13C NMR (50 MHz, CDCl3)
d 166.5, 146.1, 138.4, 138.3, 137.7, 128.5 (2C), 127.5
(2C), 127.4, 127.3, 125.7, 123.1, 122.6, 121.1, 77.2, 57.7,
52.4; IR (KBr) 1659, 1615, 1595, 1488, 1382 cmꢀ1; EIMS
ꢃ
m/z (%) 279 (8, M+ ), 264 (19), 246 (30), 91 (100), 65
(18); HRMS (FAB) m/z calcd for C18H18NO2 (M+H+)
280.1338, found 280.134.
3.8. 1-Benzyl-5-methoxy-1,3,4,5-tetrahydro-benzo[b]-
azepin-2-one 18
To a solution of the compound 17 (180 mg, 0.64 mmol) in
anhydrous MeOH (5 mL) was added 30 mg of Pd/C (5%).

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L. Jean-Gerard et al. / Tetrahedron 63 (2007) 11250–11259
11256
The suspension was stirred under a hydrogen atmosphere for
15 h. The reaction mixture was then filtered through Celite
and concentrated to afford the title compound 18 as a white
solid in quantitative yield (180.0 mg, 0.64 mmol). Mp
filtered off through Celite, rinsed with CH2Cl2, and the
filtrate was concentrated in vacuo. The crude product was
diluted with CH2Cl2 (5 mL) and washed with water
(2ꢂ5 mL) and brine (1ꢂ5 mL). The organic layer was dried
(MgSO4) and filtered. The solvent was removed in vacuo
and the crude product was purified by silica gel chromato-
graphy (eluting with EtOAc/petroleum ether: 3:7) to afford
the desired compound 21 as a colorless oil in 29% yield
1
(CH2Cl2)¼69–70 ꢁC; H NMR (200 MHz, CDCl3) d 7.35–
7.10 (m, 9H), 5.37 and 4.63 (AB system, 2H, J¼14.4 Hz),
4.01 (dd, 1H, J¼6.8, 10.4 Hz), 3.06 (s, 3H), 2.65–2.45 (m,
1H), 2.35–2.15 (m, 2H), 1.90–1.70 (m, 1H); 13C NMR
(50 MHz, CDCl3) d 172.6, 140.5, 137.6, 135.9, 128.6
(2C), 128.5 (2C), 128.1, 127.5, 126.7, 124.6, 123.3, 77.5,
57.6, 51.3, 35.4, 31.8; IR (neat) 2980, 1667, 1601, 1456,
1
(11 mg, 0.04 mmol). H NMR (300 MHz, CDCl3) d 7.29–
7.14 (m, 9H), 6.48 (d, 1H, J¼11.1 Hz), 6.01 (d, 1H,
J¼11.1 Hz), 5.10 and 5.37 (AB system, 2H, J¼15.5 Hz),
3.09 (s, 3H), 1.64 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 166.7, 147.3, 140.3, 139.3, 137.8, 128.7 (2C), 128.2,
127.6 (2C), 127.2, 125.2 (2C), 123.6 (2C), 76.4, 53.9,
51.0, 21.6; IR (neat) >3000, 1661, 1612 cmꢀ1; EIMS m/z
ꢃ
740 cmꢀ1; EIMS m/z (%) 281 (24, M+ ), 253 (10), 221
(15), 194 (58), 130 (100), 91 (90), 77 (11), 65 (22), 51 (4);
HRMS (FAB) m/z calcd for C18H20NO2 (M+H)+ 282.1494,
found 282.149. Anal. Calcd for C18H19NO2: C, 76.84; H,
6.81; N, 4.98. Found: C, 76.66; H, 6.96; N, 4.84%.
ꢃ
(%) 293 (2, M+ ), 278 (8), 261 (6), 170 (10), 91 (100);
ꢃ
HRMS (EI) m/z calcd for C19H19NO2 (M+ ) 293.1416, found
293.140.
3.9. 1-Benzyl-4-methylquinolinium bromide 19
Benzyl bromide (1.1 mL, 9.2 mmol) was added to a solution
of lepidine (1 mL, 7.6 mmol) in anhydrous methanol
(12 mL). The reaction was heated under reflux with stirring
for seven days and then cooled to rt. The solvent was re-
moved in vacuo and the crude white solid was triturated in
CH2Cl2. The suspension was filtered and the operation was
repeated twice to afford the desired salt 19 as a white powder
in 74% yield (1.7 g, 5.4 mmol). Mp (CH3OH)¼179–180 ꢁC
(lit.21 mp¼181–182 ꢁC); 1H NMR (300 MHz, CDCl3) d 9.39
(d, 1H, J¼6.0 Hz), 8.58 (d, 1H, J¼8.5 Hz), 8.46 (d, 1H,
J¼8.5 Hz), 8.16 (t, 1H, J¼8.5 Hz), 8.07 (d, 1H,
J¼6.0 Hz), 8.02 (t, 1H, J¼8.5 Hz), 7.42–7.33 (m, 5H),
3.11 (s, 3H); 13C NMR (75 MHz, CDCl3) d 161.8, 149.8,
139.0, 136.6, 134.8, 131.2, 130.7, 130.6 (2C), 130.3, 128.4
(3C), 124.1, 120.8, 61.8, 20.5.
3.12. (D)-2-[(1R)-1-Phenethyl]isoquinolinium chloride
22
To a solution of 2-(2,4-dinitrophenyl)isoquinolinium chlo-
ride17 (5 g, 15 mmol) in n-BuOH (100 mL) was added
(+)-(1R)-1-phenylethylamine (1.83 g, 15 mmol), and this
mixture was heated under reflux for 15 h. Removal of sol-
vent under reduced pressure left a gum, which was dissolved
in water and filtered. The aqueous phase was collected, basi-
fied with a few drops of concentrated ammonia, and washed
twice with AcOEt in order to remove the remaining 2,4-di-
nitrophenylamine and the excess of phenylethylamine.
Evaporation of water and subsequent filtration through
a small column of silica gel (eluting with CH2Cl2/MeOH:
4:1) gave salt 22 as a pale pink gum in 84% yield (3.4 g,
12.6 mmol). The spectroscopic data correspond to the one
described in the literature.17a
3.10. 1-Benzyl-2-(tribromomethyl)-1,2-dihydro-4-methyl-
quinoline 20
3.13. (S/R)-1-(Tribromoethyl)-1,2-dihydro-2-[(R)-1-
phenylethyl]isoquinoline 23 and 24
To a solution of the salt 19 (100 mg, 0.32 mmol) in acetoni-
trile/water (1:1, 1.2 mL) were successfully added, at 0 ꢁC
and in the dark, bromoform (86 mL, 0.96 mmol) and an
aqueous solution of KOH (540 mL, 52.1 mg, 0.93 mmol).
The reaction was stopped when the reaction mixture turned
green. The mixture was then extracted with CH2Cl2
(2ꢂ10 mL), washed with water (1ꢂ10 mL) and with brine
(1ꢂ10 mL). The organic layer was dried (MgSO4) and fil-
tered. The solvent was removed in vacuo and the crude prod-
uct was purified by silica gel chromatography (eluting
with EtOAc/petroleum ether: 70:30) to afford the desired
compound 20 as a colored oil in 60% yield (93 mg,
To a solution of the isoquinolinium salt 22 (280 mg,
1.0 mmol) in acetonitrile/water (1:1, 4.5 mL) were succes-
sively added bromoform (280 mL, 3.1 mmol) and an aqueous
solution of KOH (2.2 mL, 169 mg, 3.0 mmol). The reaction
mixture was vigorously stirred for 12 h producing a biphasic
mixture. The more dense layer was then diluted in EtOAc
(10 mL) and washed with water (2ꢂ5 mL) and brine
(1ꢂ5 mL). The organic layer was then dried (MgSO4) and
concentrated invacuo to afford the two desired diastereomers
23 and 24 (3:1 ratio) as yellow crystals in 93% yield (470 mg,
0.97 mmol). A subsequent fractional crystallization in Et2O
under a nitrogen flow permitted the isolation of each diaste-
reomer. Compound 23: 1H NMR (300 MHz, CDCl3) d 7.72
(d, 2H, J¼7.2 Hz), 7.63 (d, 1H, J¼7.3 Hz), 7.45–7.32 (m,
4H), 7.22 (td, 1H, J¼1.3, 7.6 Hz), 7.10 (d, 1H, J¼7.7 Hz),
6.04 (d, 1H, J¼7.5 Hz), 5.75 (d, 1H, J¼7.5 Hz), 5.36 (s,
1H), 5.03 (q, 1H, J¼6.6 Hz), 1.38 (d, 3H, J¼6.6 Hz). Com-
1
0.19 mmol). H NMR (300 MHz, CDCl3) d 6.70–7.40 (m,
9H), 6.09 (d, 1H, J¼6.1 Hz), 5.03 and 5.34 (AB system,
2H, J¼16.4 Hz), 4.74 (d, 1H, J¼6.1 Hz), 2.23 (s, 3H). The
high instability of this compound only permitted the obten-
tion of the 1H NMR spectra.
3.11. 1-Benzyl-5-methoxy-5-methyl-1H-benzo[b]azepin-
2(5H)-one 21
1
pound 24: H NMR (300 MHz, CDCl3) d 7.30–7.34 (m,
2H), 7.11–7.14 (m, 3H), 7.08–7.11 (m, 2H), 6.95–6.98 (m,
2H), 6.80 (d, 1H, J¼7.4 Hz), 5.85 (d, 1H, J¼7.5 Hz), 5.11
(s, 1H), 5.09 (q, 1H, J¼7.0 Hz), 1.80 (d, 3H, J¼7.0 Hz).
The high instability of these compounds only permitted the
obtention of the 1H NMR spectra.
An aqueous solution of silver nitrate (110 mL, 66.1 mg,
0.39 mmol) was added to a solution of the compound 20
(63 mg, 0.13 mmol) in MeOH (1.1 mL). The reaction was
then stirred in the dark for 4 h. The insoluble salts were

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L. Jean-Gerard et al. / Tetrahedron 63 (2007) 11250–11259
11257
3.14. 1-Methoxy-3-[(R)-1-phenylethyl]-1H-benzo[d]-
azepin-2(3H)-ones 25 and 26
stirred for 8 h. The resulting precipitate was filtered, rinsed
with water, and dried under high vacuum to afford the de-
sired compound 29 as a white solid in 73% yield (2.4 mg,
4.50 mmol). Mp (CH3CN/H2O)¼198–199 ꢁC; 1H NMR
(300 MHz, CDCl3) d 7.50–7.20 (m, 6H), 6.67 (s, 1H), 4.60
(s, 1H), 4.52 and 3.90 (d, 2H, J¼13.7 Hz), 3.90 (s, 6H),
3.50–3.35 (m, 1H), 3.30–3.15 (m, 1H), 2.70–2.55 (m, 1H),
2.45–2.30 (m, 1H); 13C NMR (75 MHz, CDCl3) d 149.2,
146.4, 138.9, 131.0, 128.6, 128.5, 127.3, 123.0, 115.8,
111.1, 79.0, 63.5, 61.8, 56.3, 55.9, 47.3, 27.7; IR (KBr)
2943, 1517, 1277, 700 cmꢀ1; CIMS m/z 532 (M+H+), 452,
374, 282; HRMS (CI+) m/z calcd for C19H21NO2 Br3
(M+H+) 531.9123, found 531.912.
An aqueous solution of silver nitrate (660 mL, 356.4 mg,
2.1 mmol) was added to a solution of the compound 23
(400 mg, 0.82 mmol) in anhydrous MeOH (8.0 mL). The re-
action was then stirred in the dark for 16 h. The insoluble
salts were filtered off through Celite, rinsed with CH2Cl2,
and the filtrate was concentrated in vacuo. The crude product
was diluted with CH2Cl2 (20 mL) and washed with water
(2ꢂ10 mL) and brine (1ꢂ10 mL). The organic layer was
dried (MgSO4) and filtered. The solvent was removed in va-
cuo and the crude product was purified by silica gel chroma-
tography (eluting with EtOAc/petroleum ether: 10:90) to
afford a 1:1 mixture of the diastereomers 25 and 26 as a yel-
low oil in 34% yield (82 mg, 0.28 mmol). First diastereo-
mer: 1H NMR (300 MHz, CDCl3) d 7.62 (d, 1H,
J¼7.9 Hz), 7.46 (t, 1H, J¼7.3 Hz), 7.31 (t, 1H, J¼7.3 Hz),
7.20 (m, 5H), 7.02 (br s, 1H), 6.40 (d, 1H, J¼9.3 Hz), 6.18
(d, 1H, J¼9.0 Hz), 6.06 (q, 1H, J¼7.03 Hz), 4.47 (br s,
1H), 3.56 (s, 3H), 1.67 (d, 3H, J¼6.9 Hz); 13C NMR
(75 MHz, CDCl3) d 166.9, 140.5, 133.6, 131.4, 128.8
(2C), 128.5 (3C), 127.3 (2C), 127.0 (2C), 125.3, 117.8,
81.0, 58.2, 52.3, 17.2; IR (neat) 1670 cmꢀ1; EIMS m/z (%)
3.17. 3-Benzyl-4,5-dihydro-1-hydroxy-7,8-dimethoxy-
1H-benzo[d]azepin-2(3H)-one 30
An aqueous solution of silver nitrate (1 mL, 280 mg,
1.68 mmol) was added to a solution of the compound 29
(300 mg, 0.56 mmol) in acetonitrile/water (2:8, 10 mL)
cooled to ꢀ20 ꢁC. The reaction was then stirred in the
dark for 16 h while the temperature was allowed to rise to
rt. The insoluble salts were filtered off through Celite, rinsed
with CH2Cl2, and the filtrate was concentrated in vacuo. The
crude product was diluted with CH2Cl2 (30 mL) and washed
with water (2ꢂ20 mL) and brine (1ꢂ20 mL). The organic
layer was dried (MgSO4) and filtered. The solvent was re-
moved in vacuo and the crude product was purified by silica
gel chromatography (eluting with EtOAc/petroleum ether:
7:3) to afford the title compound as a yellow solid in 71%
yield (130 mg, 0.40 mmol). Mp (AcOEt/hexanes)¼131–
ꢃ
293 (18, M+ ), 189 (28), 105 (100), 77 (37); HRMS (EI)
ꢃ
m/z calcd for C19H19NO2 (M+ ) 293.1416, found 293.141.
Second diastereomer: H NMR (300 MHz, CDCl3) d 7.1–
1
7.7 (m, 9H), 6.47 (d, 1H, J¼9.4 Hz), 6.11 (q, 1H,
J¼7.1 Hz), 6.01 (d, 1H, J¼9.2 Hz), 4.34 (br s, 1H), 3.62
(s, 3H), 1.38 (d, 3H, J¼7.0 Hz); 13C NMR (75 MHz,
CDCl3) d 166.5, 139.7, 135.1, 133.9, 130.0, 128.8 (2C),
128.3, 127.9, 127.7 (2C), 127.3, 126.9, 125.2, 118.4, 80.8,
58.4, 51.8, 17.8.
1
132 ꢁC; H NMR (300 MHz, CDCl3) d 7.40 (s, 1H), 7.35–
7.15 (m, 5H), 6.49 (s, 1H), 5.76 (d, 1H, J¼5.8 Hz), 4.84
and 4.53 (AB system, 2H, J¼14.8 Hz), 4.55 (d, 1H,
J¼5.8 Hz), 4.10–3.90 (m, 1H), 3.91 (s, 3H), 3.82 (s, 3H),
3.40–3.25 (m, 1H), 3.10–2.75 (m, 2H); 13C NMR
(75 MHz, CDCl3) d 173.6, 148.1, 147.7, 136.6, 128.8
(2C), 128.6, 128.1 (2C), 127.9, 125.5, 112.9, 108.3, 67.9,
56.0 (2C), 50.9, 45.2, 31.4; IR (KBr) 3405, 1656, 1513,
3.15. 2-Benzyl-6,7-dimethoxy-3,4-dihydro-isoquinoli-
nium bromide 28
A solution of 6,7-dimethoxy-3,4-dihydro-isoquinoline22
(1.6 g, 8.4 mmol) in anhydrous toluene (32 mL) was treated
with benzyl bromide (2 mL, 16.7 mmol). The reaction was
heated under reflux with stirring for 5 h. The resulting sus-
pension was filtered and the precipitate was washed with an-
hydrous diethyl ether. The crude solid was dissolved in
a minimal amount of methanol and Et2O was added drop-
wise leading to precipitation of the product. The product
was then filtered, collected to afford the desired pure
compound 28 as yellow crystals in 74% yield (2.3 g,
6.3 mmol). Mp (CH3OH/Et2O)¼192–195 ꢁC (lit.23
mp¼186–188 ꢁC); 1H NMR (300 MHz, CD3OD) d 10.3 (s,
1H), 7.67 (s, 1H), 7.58 (m, 2H), 7.36 (m, 3H), 6.84
(s, 1H), 5.50 (s, 2H), 3.91–3.98 (m, 2H), 3.98 (s, 3H), 3.91
(s, 3H), 3.18 (t, 2H, J¼8.2 Hz); 13C NMR (75 MHz, CDCl3)
d 164.9, 157.6, 148.8, 132.1, 131.4, 129.6, 129.5 (2C), 129.4
(2C), 117.2, 115.9, 110.7, 63.1, 56.8, 56.6, 47.4, 25.6.
ꢃ
1261, 1119 cmꢀ1; EIMS m/z (%) 327 (36, M+ ), 297 (43),
206 (24), 91 (100), 77 (9), 65 (12); HRMS (EI) m/z calcd
ꢃ
for C19H21NO4 (M+ ) 327.1471, found 327.147.
3.18. 3-Benzyl-4,5-dihydro-1,7,8-trimethoxy-1H-
benzo[d]azepin-2(3H)-one 31
An aqueous solution of silver nitrate (1 mL, 280 mg,
1.68 mmol) was added to a solution of the compound 29
(300 mg, 0.56 mmol) in MeOH (10 mL) cooled to ꢀ20 ꢁC.
The reaction was then stirred in the dark for 16 h while the
temperature was allowed to rise to rt. The insoluble salts
were filtered off through Celite, rinsed with CH2Cl2, and
the filtrate was concentrated in vacuo. The crude product
was diluted with CH2Cl2 (30 mL) and washed with water
(2ꢂ20 mL) and brine (1ꢂ20 mL). The organic layer was
dried (MgSO4) and filtered. The solvent was removed in va-
cuo and the crude product was purified by silica gel chroma-
tography (eluting with EtOAc/petroleum ether: 30:70) to
afford the title compound as a yellow oil in 52% yield
(99.4 mg, 0.29 mmol). 1H NMR (300 MHz, CDCl3)
d 7.34–7.25 (m, 5H), 6.95 (s, 1H), 6.52 (s, 1H), 5.02 (s,
1H), 4.76 and 4.58 (AB system, 2H, J¼14.7 Hz), 4.26–
4.32 (m, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.55 (s, 3H),
3.16. 2-Benzyl-6,7-dimethoxy-1-tribromomehyl-1,2,3,4-
tetrahydro-isoquinoline 29
The isoquinolinium salt 28 (2.2 g, 6.17 mmol) was dissolved
in acetonitrile/water (1:1, 23 mL). A subsequent addition of
bromoform (0.6 mL, 1.87 g, 7.4 mmol) and an aqueous solu-
tion of KOH (3.8 mL, 381 mg, 6.8 mmol) led to the forma-
tion of a precipitate. The reaction mixture was vigorously

´
L. Jean-Gerard et al. / Tetrahedron 63 (2007) 11250–11259
11258
3.48–3.41 (m, 1H), 2.94–2.81 (m, 2H); 13C NMR (75 MHz,
CDCl3) d 170.9, 149.2, 147.4, 137.6, 129.1, 128.7 (2C),
128.3 (2C), 127.6, 125.0, 113.5 (2C), 85.6, 57.8, 56.1,
56.0, 50.4, 43.7, 32.4; IR (KBr) 2933, 1653, 1517, 1456,
graphite-monochromatized
Mo
K-L2,3
radiation
˚
(l¼0.71073 A). Data were corrected for Lorentz-polariza-
tion effects and absorption corrections applied using
a Gaussian integration. The structure was solved with the
SIR2004 direct methods24 and subsequent calculations
were carried out with the JANA2006 program package.25
All non-hydrogen atoms were refined anisotropically and
hydrogen atoms were introduced with geometrical con-
straints and riding atomic displacement parameters. The
absolute configuration was unambiguously determined by
refining the inversion twin ratio.
ꢃ
1251 cmꢀ1; EIMS m/z (%) 341 (65, M+ ), 309 (17), 282
(36), 250 (79), 177 (35), 91 (100); HRMS (EI) m/z calcd
ꢃ
for C20H23NO4 (M+ ) 341.1627, found 341.163.
3.19. 3-Benzyl-4,5-dihydro-7,8-dimethoxy-3H-benzo-
[d]azepine-1,2-dione 32
An aqueous solution of silver nitrate (132 mL, 185 mg,
1.1 mmol) and a solution of EtNH2 in THF (2 M, 1.9 mL,
3.7 mmol) were added to a solution of the compound 29
(200 mg, 0.37 mmol) in anhydrous THF (6 mL). The reac-
tion was then stirred in the dark for 16 h. The insoluble salts
were filtered off through Celite, rinsed with CH2Cl2, and the
filtrate was concentrated in vacuo. The crude product was
diluted with CH2Cl2 (20 mL) and washed with water
(2ꢂ15 mL) and brine (1ꢂ15 mL). The organic layer was
dried (MgSO4) and filtered. The solvent was removed in va-
cuo and the crude product was purified by silica gel chroma-
tography (eluting with EtOAc/petroleum ether: 1:1) to afford
the title compound 32 as yellow crystals in 50% yield
(60 mg, 0.185 mmol). Mp (AcOEt/hexanes)¼221–222 ꢁC;
1H NMR (300 MHz, CDCl3) d 7.31–7.20 (m, 6H), 6.52 (s,
1H), 4.65 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.57 (m, 2H),
2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) d 193.1, 167.3,
153.4, 148.2, 136.3, 135.6, 128.9 (2C), 128.6 (2C), 128.1,
126.7, 112.1 (2C), 56.1 (2C), 49.3, 45.5, 31.5; IR (KBr)
3100–2850, 1677, 1653, 1258 cmꢀ1; CIMS m/z 343
CCDC 651575 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Crystal data for 24: C18H16Br3N, Mr¼486, monoclinic,
˚
P21, a¼13.4635(5), b¼6.1104(3), c¼11.2325(6) A, b¼
108.267(4), V¼877.50(7) A , Z¼2, rcalcd¼1.83894 g cmꢀ3
,
3
˚
m¼6.892 mmꢀ1, F(000)¼472, colorless needle, 0.32ꢂ
0.08ꢂ0.06 mm3, 2qmax¼60ꢁ, T¼298 K, 20,995 reflections,
4563 unique (99% completeness), Rint¼0.064, 198 parame-
ters, GOF¼1.64, wR2¼0.0969, R¼0.0397 for 3957 reflec-
tions with I>2s(I).
Acknowledgements
We thank Dr. Virginie Dupont for preliminary experiments.
ꢀ
We also thank the CNRS, the ‘Region Pays de la Loire’ and
the ‘Ministere de l’Education Nationale’ for financial sup-
ꢃ
[(M+18)+]; HRMS (EI) m/z calcd for C19H19NO4 (M+ )
ꢁ
325.1314, found 325.132.
port.
3.20. 3-Benzyl-1-(ethylimino)-4,5-dihydro-7,8-di-
methoxy-1H-benzo[d]azepin-2(3H)-one 33
References and notes
An aqueous solution of silver nitrate (132 mL, 185 mg,
1.1 mmol) and a solution of EtNH2 in THF (2 M, 1.9 mL,
3.7 mmol) were added to a solution of the compound 29
(200 mg, 0.37 mmol) in anhydrous THF (6 mL) cooled to
ꢀ20 ꢁC. The reaction was then stirred in the dark for 72 h
while the temperature was allowed to warm up to rt. The in-
soluble salts were filtered off through Celite, rinsed with
CH2Cl2, and the filtrate was concentrated in vacuo. The
crude product was diluted with CH2Cl2 (15 mL) and washed
with water (2ꢂ15 mL) and brine (1ꢂ15 mL). The organic
layer was dried (MgSO4) and filtered. The solvent was re-
moved in vacuo and the crude product was purified by silica
gel chromatography (eluting with EtOAc/petroleum ether:
3:2) to afford the title compound 33 as a colorless oil in
3.2% yield (4.2 mg, 0.012 mmol). 1H NMR (300 MHz,
CDCl3) d 7.37–7.19 (m, 6H), 6.61 (s, 1H), 4.68 (s, 2H),
3.93 (s, 3H), 3.90 (s, 3H), 3.51 (m, 2H), 3.23 (q, 2H,
J¼7.2 Hz), 2.95 (m, 2H), 1.12 (t, 3H, J¼7.2 Hz).
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