(3R,11aR)-3-Phenyl-2,3,11,11a-tetrahydro-[1,3]oxazolo[3,2-b]-[2]benzazepin-5(10H)-one as a chiral building block for the asymmetric synthesis of 3-substituted 2-benzazepines

Article abstract of DOI:10.1016/j.tetasy.2010.03.019

A five-step synthesis of the chiral building block cis-2 is described. Key steps in the synthesis were a Heck reaction of 1-bromo-2-iodobenzene with allyl alcohol, the introduction of a carboxy group after Br/Li-exchange, and the diastereoselective format

Full text of DOI:10.1016/j.tetasy.2010.03.019

Tetrahedron: Asymmetry 21 (2010) 524–526
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
(3R,11aR)-3-Phenyl-2,3,11,11a-tetrahydro-[1,3]oxazolo[3,2-b]-[2]benzazepin-
5(10H)-one as a chiral building block for the asymmetric synthesis
of 3-substituted 2-benzazepines
Matthias P. Quick a, Roland Fröhlich b, Bernhard Wünsch a,
*
a Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Hittorfstraße 58-62, D-48149 Münster, Germany
b Organisch-Chemisches Institut der Westfälischen Wilhelms-Universität Münster, Corrensstr. 40, D-48149 Münster, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A five-step synthesis of the chiral building block cis-2 is described. Key steps in the synthesis were a Heck
reaction of 1-bromo-2-iodobenzene with allyl alcohol, the introduction of a carboxy group after Br/Li-
exchange, and the diastereoselective formation of the tricyclic oxazolidine system cis-2. Activation of
cis-2 with TiCl4 led to formation of a carbenium ion, which was attacked by allyltrimethylsilane exclu-
sively from the Re-face leading to the (3S)-configured 2-benzazepinone 8 in 65% yield. The configuration
of the new stereogenic center was determined by X-ray crystal structure analysis, which is the basis for
the proposed mechanism of this transformation. Enantiomerically pure 3-substituted 2-benzazepines
represent interesting drug candidates.
Received 20 January 2010
Accepted 11 March 2010
Available online 26 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
R
O
H
O
Enantiomerically pure bi- and tricyclic oxazolidines have been
widely used for the asymmetric synthesis of enantiomerically
pure N-heterocycles including pyrrolidines, piperidines, and
azepines.1–6 Very recently we have reported on the synthesis of
oxazolidine annulated 3-benzazepines of type 1. The diastereose-
lective alkylation of 1 and subsequent reductive degradation led
to enantiomerically pure 1-substituted 3-benzazepines with
N
N
Ph
O
O
Ph
1
2
Figure 1. Relationship between the new chiral building block
2 with a 2-
benzazepine substructure and the established building block 1 with a 3-benzaze-
pine substructure.
promising NMDA and
r receptor affinities (Fig. 1). Moreover,
compounds 1 with a residue in position 11a (e.g., R = CH3) could
be reduced or reacted with Grignard reagents to form enantio-
merically pure 2-mono- or 2,2-disubstituted 3-benzazepines,
respectively.7–12
2. Results and discussion
In the first approach (2-bromophenyl)propionaldehyde acetal 5
was prepared by homologation of 2-bromobenzaldehyde using a
Wittig reaction and subsequent hydrogenation of the double bond.
As reported in the literature, substantial debromination (5–10%)
occurred during hydrogenation,13 and the debrominated by-prod-
uct disturbed the subsequent reactions leading to decreased yields
after halogen/metal exchange.
Therefore, an alternate strategy for the synthesis of 5 was fol-
lowed which avoided hydrogenation (Scheme 1). At first a Heck
reaction of 1-bromo-2-iodobenzene 3 with allyl alcohol and cata-
lytic amounts of Pd(OAc)2 was performed to provide phenylpropi-
onaldehyde 4.14 Acetalization of aldehyde 4 with ethylene glycol
led to ethylene acetal 5, without any side products, in 76% yield
over two steps. An exchange of the bromine atom of 5 with n-BuLi
at À80 °C and subsequent trapping of the resulting aryllithium
intermediate with CO2 led to the benzoic acid derivative 6 in 96%
In addition to 3-benzazepines, our interest has been focused on
the synthesis of enantiomerically pure 2-benzazepines, which are
regioisomers of 3-benzazepines (shift of the N-atom by one posi-
tion) or homologues of isoquinolines. Herein, we report on the
extension of the oxazolidine strategy with regards to the synthesis
of 3-substituted 2-benzazepines, which are expected to reveal
interesting pharmacological properties. In particular, the synthesis
of the enantiomerically pure central building block 2 is detailed,
which is structurally derived from the analogous 3-benzazepine
building block 1.
* Corresponding author. Tel.: +49 251 8333311; fax: +49 251 8332144.
E-mail address: wuensch@uni-muenster.de (B. Wünsch).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.019

M. P. Quick et al. / Tetrahedron: Asymmetry 21 (2010) 524–526
525
yield. After activation of the carboxy group of 6 with oxalyl chlo-
cis-2
(a)
ride, condensation with (R)-phenylglycinol proceeded to give
amide 7. The stereoselective formation of cis-configured tricyclic
oxazolidine cis-2 was achieved via the treatment of enantiomeri-
cally pure amide 7 with HCl saturated CHCl3 at room temperature.
In addition to the main product cis-2 (79% yield) small amounts of
the diastereomer trans-2 (7%) were isolated by flash chromatogra-
phy. The stereodescriptor cis refers to the relative orientation of the
protons in positions 3 and 11a in the oxazolidine moiety. The cis-
configuration of cis-2 was proven by NOE difference spectroscopy.
Having successfully established the stereoselective synthesis of
the chiral building block cis-2, its potential for the stereoselective
introduction of substituents at position 3 upon opening of the oxa-
zolidine ring was investigated. Treatment of cis-2 with allyltrimeth-
ylsilane and TiCl415 at 70 °C under microwave irradiation led to the
allyl-substituted 2-benzazepin-1-one 8 in 65% yield (Scheme 2).
According to 1H and 13C NMR spectroscopy as well as LC–MS inves-
tigations of the crude reaction product, only one product 8 was
formed indicating the excellent diastereoselectivity of this transfor-
mation. Variation of the reaction conditions (e.g., lower tempera-
ture, lack of microwave irradiation, prolonged reaction time) led
to considerably reduced yields of 8. Moreover, changing of the Le-
wis acid TiCl4 with other Lewis acids (e.g., BF3, AlCl3) or using more
reactive allyltrimethylstannane instead of allyltrimethylsilane did
not lead to any conversion. Obviously, the tricyclic system cis-2 is
very sensitive to the reaction conditions.
The NMR spectra of 8 recorded at room temperature only led to
very broad signals, which can be attributed to the slow conforma-
tional changes of the seven-membered 2-benzazepine ring. Record-
ing of the NMR spectra at 110 °C in nitrobenzene-d5 resulted in a
considerable improvement of the fine structure of the signals. How-
ever, careful interpretation of these NMR spectra did not allow an
unequivocal assignment of the absolute configuration of the new
stereogenic center of 8. Therefore, an X-ray crystal structure analy-
sis was performed. For this purpose 2-benzazepin-1-one 8 was
recrystallized from MeOH, which produced suitable crystals. The
X-ray crystal structure of 8 (Fig. 2) clearly demonstrates the (S)-
configuration at the 3-position of benzazepin-1-one 8.
H
N
OH
O
Ph
8
(c)
(b)
H
H
N
N
OH
OH
O
Ph
Ph
9
10
Scheme 2. Reagents and conditions: (a) allyltrimethylsilane 17 equiv, TiCl4 6 equiv,
CH2Cl2, 70 °C, 5 min (CEM-microwave), 65%; (b) H2, Pd/C, CH3OH, 5 bar, 30 min,
95%; (c) AlCl3 1.0 equiv, LiAlH4 3.0 equiv, THF, 0 °C, 0.5 h, 54%.
C20
C4
C6
C5
C18
C7
C19
C5A
C3
C8
C10
C13
N2
C12
C9A
C9
C14
C15
C1
O1
C11
O11
C17
C16
Figure 2. X-ray crystal structure analysis of 8.
The (S)-configuration at the 3-position of 8 confirms the
retention of configuration during the ring opening of cis-2 with
allyltrimethylsilane and TiCl4. Therefore, the following mecha-
nism16 for the allylation of 8 is proposed: TiCl4 first opens the oxa-
zolidine ring. Coordination of TiCl4 with the original O-atom of the
oxazolidine ring and the O-atom of the carbonyl moiety brings the
phenyl moiety ‘under’ the 2-benzazepine plane, thus shielding the
Si-face of the carbenium ion, which results in exclusive attack of
allyltrimethylsilane from the Re-face. (Scheme 3)
The allyl moiety of 8 was reduced with H2 in the presence of Pd/
C to give the propyl derivative 9 in 95% yield. Even at a pressure of
5 bar, the (2-hydroxy-1-phenylethyl) residue on the N-atom of 8
was not cleaved. Reduction of the lactam moiety of 8 proceeded
O
O
I
CHO
(b)
(a)
(c)
O
O
Br
Br
Br
CO2H
3
4
5
6
O
H
H
O
(d)
O
(e)
O
H
N
N
N
OH
O
O
Ph
O
Ph
Ph
7
cis-2
trans-2
Scheme 1. Reagents and conditions: (a) 1-bromo-2-iodobenzene 1.0 equiv, allyl alcohol 3.0 equiv, NaHCO3 2.5 equiv, BnEt3NCl 1 equiv, Pd(OAc)2 0.02 equiv, DMF, 45 °C, 6 h;
(b) p-TolSO3H, 0.2 equiv, ethylene glycol 1.8 equiv, CHCl3 reflux (Dean–Stark trap), 76%; (c) n-BuLi 1.05 equiv, CO2 gas, THF, À80 °C, 1.4 h, 96%; (d) (1) oxalyl chloride
1.2 equiv, DMF catalytic, Et2O; (2) (R)-phenylglycinol 1 equiv, NaOHaq 9 equiv, CH2Cl2, 45%; (e) HClconcd catalytic, CHCl3, 79% (cis-2), 7% (trans-2).

526
M. P. Quick et al. / Tetrahedron: Asymmetry 21 (2010) 524–526
SiMe3
H
TiCl4
O
8
N
N
O
O
O
Cl4Ti
cis-2
Scheme 3. Proposed mechanism for the stereoselective transfer of the allyl group at C-3 of the 2-benzazepine ring.
with AlH3, which was formed in situ by mixing LiAlH4 and AlCl3 in
a 1:3 ratio.17 The 3-allyl-substituted 2-benzazepine 10 was iso-
lated in 54% yield.
absorption correction (0.731 6 T 6 0.976), Z = 8, orthorhombic,
space group P212121 (No. 19), k = 1.54178 Å, T = 223(2) K, and u
scans, 44474 reflections collected ( h, k, l), [(sinh)/k] = 0.60 ÅÀ1
6268 independent (Rint = 0.081) and 5307 observed reflections
[I P 2
(I)], 436 refined parameters, R = 0.044, wR2 = 0.112, Flack
x
,
r
3. Conclusion
parameter 0.0(2), max. (min.) residual electron density 0.19
(À0.14) e ÅÀ3, hydrogen atoms calculated and refined as riding
atoms, two almost identical molecules in the asymmetric unit.
Data set was collected with a Nonius KappaCCD diffractometer.
Programs used: data collection COLLECT (Nonius, B.V. 1998), data
reduction Denzo-SMN,18 absorption correction Denzo,19 structure
The tricyclic oxazolidine cis-2 represents an interesting new
chiral building block for the synthesis of enantiomerically pure
3-substituted 2-benzazepines. The carefully optimized synthesis
of cis-2 comprises five reaction steps including the diastereoselec-
tive intramolecular formation of the tricyclic oxazolidine ring sys-
tem from 7. Ring opening of the oxazolidine ring of cis-2 with
allyltrimethylsilane and TiCl4 exclusively took place from the Re-
face leading to 2-benzazepines with (S)-configuration in position 3.
solution SHELXS-97,20 structure refinement SHELXL-97,21 graphics
22
SCHAKAL
.
CCDC 742207 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: (internat.) +44(1223)336 033, E-mail: deposit@ccdc.
cam.ac.uk].
4. Experimental
4.1. Synthesis of (3S)-3-allyl-2-[(1R)-2-hydroxy-1-phenylethyl]-
2,3,4,5-tetrahydro-2-benzazepin-1-one 8
Acknowledgments
Under N2, tricyclic oxazolidine cis-2 (300 mg, 1.07 mmol) was
dissolved in CH2Cl2 (6 mL). Allyltrimethylsilane (2.9 mL,
18.2 mmol) and TiCl4 (6.4 mL, 6.4 mmol) were added carefully to
the solution. After microwave irradiation (CEM Discover LabMate
Microwave, ramp 5 min, run 5 min, P = 80 W, T = 70 °C), the mix-
ture was poured into water and extracted with CH2Cl2. The organic
layers were dried over Na2SO4, and filtered, after which silica gel
was added and the solvent was removed under reduced pressure.
The residue was purified by flash chromatography (hexane/ethyl
acetate = 8/2). Colorless needles, mp 156 °C, yield 223 mg (65%).
C21H23NO2 (Mr = 321.4). MS (ESI): m/z (%) = 665 (2M+Na, 100), 322
(M+H, 10). HRMS (ESI): m/z = calcd for C21H23NO2H+ 322.1801,
found 322.1802; m/z = calcd for C21H23NO2Na+ 344. 1621, found
344.1621; m/z = calcd for (C21H23NO2)2Na+ 665.3349, found
665.3350. 1H NMR (nitrobenzene-d5, 110 °C): d (ppm) = 1.18–1.22
(m, broad, 2H, CH2CH@CH2), 1.50–154 (m, broad, 1H, ArCH2CH2),
1.84–1.88 (m, broad, 1H, ArCH2CH2), 2.34–2.38 (m, broad, 1H,
ArCH2), 2.64–2.68 (m, broad, 1H, ArCH2), 3.19–3.22 (m, broad, 1 H,
ArCH2CH2CH), 3.88–3.93 (m, broad, 1H, CHCH2OH), 3.96–4.07 (m,
broad, 2H, CHCH2OH, CH@CH2), 4.20 (d, J = 10.2 Hz, 1H, CH@CH2),
4.659–4.63 (m broad, 1H, CH@CH2), 5.52–5.56 (s, broad, 1H,
CHCH2OH), 6.84–7.35 (m, 9H, Ar-H). The correct assignment of the
signals was accomplished by high temperature COSY experiments.
This work was performed within the framework of the Interna-
tional Research Training Group ‘Complex Functional Systems in Chem-
istry: Design, Synthesis and Applications’ in collaboration with
Nagoya University. Financial support of the IRTG Münster-Nagoya
and of this project by the Deutsche Forschungsgemeinschaft is grate-
fully acknowledged.
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IR (neat):
m
(cmÀ1) = 3347 (OH), 1608 (CONR2), 916 (C@CH2). Spe-
cific rotation: [a]D = +7.9 (c 1.04, CHCl2). Purity by HPLC: 99.6%
(tR = 18 min).
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Formula C21H23NO2, M = 321.40, light colorless crystal 0.55 Â
0.20 Â 0.04 mm, a = 8.7429(3), b = 17.4383(6), c = 23. 1886(10) Å,
V = 3535.4(2) Å3,
q , l
calcd = 1.208 g cmÀ3 = 0.607 mmÀ1, empirical