Enantioselective synthesis of a 2,2-disubstituted tetrahydro-3-benzazepine as Novel NMDA receptor antagonist

Article abstract of DOI:10.1515/znb-2010-0216

The tricyclic oxazolidines trans-4 and cis-4 were interconverted upon treatment with allyltrimethylsilane/TiCl₄. The oxazolidine trans-4 was diastereoselectively reacted with PhMgBr to yield the 4,4-disubstituted 3-benzazepinone 6, along with two side products. An X-ray crystal structure analysis of 6 proved the (R)-configuration of the stereogenic center C-4 and thus the retention of configuration. Reduction of 6 with AlCl ₃/LiAlH₄ (1/3) followed by hydrogenolysis with H ₂, Pd/C resulted in the formation of enantiomerically pure 2-methyl-2-phenyl-tetrahydro-3-benzazepine 11 which has a moderate affinity (K_i = 496 nM) to the PCP binding site of the NMDA receptor.

Full text of DOI:10.1515/znb-2010-0216

Enantioselective Synthesis of a 2,2-Disubstituted Tetrahydro-3-
benzazepine as Novel NMDA Receptor Antagonist
Syed Masood Husaina, Roland Fro¨hlichb, Dirk Schepmanna, and Bernhard Wu¨nscha
a Institut fu¨r Pharmazeutische und Medizinische Chemie der Westfa¨lischen Wilhelms-Universita¨t
Mu¨nster, Hittorfstraße 58 – 62, 48149 Mu¨nster, Germany
b Organisch-Chemisches Institut der Westfa¨lischen Wilhelms-Universita¨t Mu¨nster, Corrensstraße 40,
48149 Mu¨nster, Germany
Reprint requests to Prof. Dr. B. Wu¨nsch. Fax: +49-251-8332144. E-mail: wuensch@uni-muenster.de
Z. Naturforsch. 2010, 65b, 191 – 196; received September 22, 2009
The tricyclic oxazolidines trans-4 and cis-4 were interconverted upon treatment with allyltri-
methylsilane/TiCl4. The oxazolidine trans-4 was diastereoselectively reacted with PhMgBr to yield
the 4,4-disubstituted 3-benzazepinone 6, along with two side products. An X-ray crystal structure
analysis of 6 proved the (R)-configuration of the stereogenic center C-4 and thus the retention of
configuration. Reduction of 6 with AlCl3/LiAlH4 (1/3) followed by hydrogenolysis with H2, Pd/C
resulted in the formation of enantiomerically pure 2-methyl-2-phenyl-tetrahydro-3-benzazepine 11
which has a moderate affinity (Ki = 496 nM) to the PCP binding site of the NMDA receptor.
Key words: NMDA Antagonists, X-Ray Crystal Structure Analysis, Isomerization,
Asymmetric Synthesis, 2,2-Disubstituted Tetrahydro-3-benzazepines
Introduction
The NMDA receptor belongs to the group of
ionotropic glutamate receptors and is activated by N-
methyl-D-aspartate (NMDA). The ionotropic gluta-
mate receptors have in common substantial permeabil-
ity to both Na+ and K+ ions but differ in permeabil-
ity to Ca2+ ions. The NMDA receptor plays a funda-
mental role in excitatory neurotransmission in the cen-
tral nervous system (CNS) and affects plasticity, mem-
ory and learning, in addition to neuronal development.
The target of this project is specifically the phencycli-
dine (PCP) binding site, which is located within the
NMDA receptor-associated ion channel. Ligands inter-
acting with the PCP binding site block the influx of
Ca2+ ions and therefore function as NMDA receptor
antagonists [1, 2].
Modulators of glutamate receptors have been
the subject of intense research since they can be
used for the treatment of a wide variety of con-
ditions, ranging from acute ischemia and trauma,
to chronic neurodegenerative disorders such as
Huntington’s, Parkinson’s and Alzheimer’s diseases,
epilepsy, and HIV-associated dementia (HAD). More-
over, even psychiatric disorders have been pro-
posed to be amenable to glutamatergic modulation
[3, 4].
Fig. 1. Lead compound MK-801 (1) and tetrahydroisoqui-
noline 2 along with the desired tetrahydro-3-benzazepines 3.
The tetracyclic amine MK-801 (1) is a very po-
tent non-competitive NMDA receptor antagonist (Ki =
2.6 nM), which acts as an open channel blocker (Fig. 1)
[1, 4]. The formal cleavage of the C9a–C10 bond of
MK-801 results in tetrahydroisoquinolines 2, which
also interact with the PCP binding site. The NMDA
receptor affinities of the enantiomeric isoquinolines
(R)-2 and (S)-2 differ considerably with (S)-2 show-
ing high (Ki = 35.4 nM) and (R)-2 low affinity (Ki =
3.76 µM) [5].
c
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192
S. M. Husain et al. · Enantioselective Synthesis of a 2,2-Disubstituted Tetrahydro-3-benzazepine
In this work we aimed at synthesizing 2,2- the low yield, the allyl derivative 5 could not be iso-
disubstituted tetrahydro-3-benzazepines 3 with an ad- lated.
ditional methylene moiety in the heterocyclic ring sys-
This observation prompted us to study the intercon-
tem when compared with the isoquinolines 2. In partic- version reaction in more detail. Very recently we have
ular, tetrahydro-3-benzazepines 3 with the same con- shown that p-toluenesulfonic acid and trifluoroacetic
figuration at the C-2 stereocenter as the more potent
acid are not able to isomerize the diastereomers trans-4
enantiomer (S)-2 should be synthesized in order to get and cis-4 [8, 9]. Treatment of both diastereomers
novel ligands with high affinity towards the PCP bind- trans-4 and cis-4 with TiCl4, allyltrimethylsilane or tri-
ing site of the NMDA receptor.
ethylsilane alone also did not lead to any interconver-
sion. However, the reaction of the diastereomer cis-4
with allyltrimethylsilane (2 equiv.) and TiCl4 (1 equiv.)
led to isomerization, but without formation of any sub-
stitution product (trans-4 : cis-4 = 11 : 89). Obviously,
both TiCl4 and a silane are required for this isomeriza-
tion.
Since further products were not formed along with
cis-4, the isomerization reaction was further investi-
gated using cis-4 only. Prolongation of the reaction
time from 1 to 3 d led to a ratio of trans-4 : cis-4 of
38 : 62. Work-up of this mixture provided the diastere-
omer trans-4 in 35 % isolated yield. This isomerization
process allows the increase of the yield of the desired
stereoisomer and thus represents a considerable im-
provement of the asymmetric synthesis of tetrahydro-
3-benzazepines using tricyclic oxazolidines of type 4,
because the synthesis of 4 always affords 1 : 1 mixtures
of cis and trans diastereomers [8, 9].
In order to introduce carbon nucleophiles into the
tetrahydro-3-benzazepine scaffold, Grignard reagents
were tried [10]. For this purpose the tricyclic oxazo-
lidine trans-4 was reacted with 3 equivalents of Ph-
MgBr in THF at 0 ◦C (Scheme 2). This transformation
led to the 4,4-disubstituted tetrahydro-3-benzazepine 6
along with two side products, 7 and 8, which were sep-
arated by flash chromatography. The elimination prod-
uct 7 was isolated in 17 % yield and represented the
major product. The yield of the hydroxylated prod-
uct 8 (only one diastereomer) was 7.5 %, whereas the
desired tetrahydro-3-benzazepine derivative 6 was ob-
tained in only 6.5 % yield.
The C-2 stereocenter of 3 should be established by
stereoselective opening of the oxazolidines trans-4 and
cis-4 with carbon nucleophiles. The stereodescriptors
cis and trans define the relative configuration of the
higher ordered phenyl and benzyl residues or the lower
ordered proton and methyl moiety in the oxazolidine
ring [9]. In the literature [6], the opening of an oxazo-
lidine ring in a bicyclic system with two substituents
at the N/O-ketalic stereocenter by carbon nucleophiles
has not been reported so far.
Results
The key intermediates trans-4 and cis-4 were pre-
pared by heating of 2-[2-(2-oxopropyl)phenyl]acetic
acid [7] with (R)-phenylglycinol in toluene [8].
At first the stereoselective introduction of an al-
lyl nucleophile at the N/O-ketalic stereocenter in po-
sition 11a was investigated (Scheme 1). For this
purpose, trans-4 was reacted with allyltrimethylsi-
lane (2 equiv.) and TiCl4 (1 equiv.). Only very low
amounts of the desired 4,4-disubstituted tetrahydro-
3-benzazepine 5 were detected by 1H-NMR spec-
troscopy. The reaction resulted in isomerization of
trans-4 into cis-4 (trans-4 : cis-4 = 90 : 10). Due to
In order to prove the configuration of the 4,4-
disubstituted tetrahydro-3-benzazepinederivative 6, an
X-ray crystal structure analysis was performed(Fig. 2).
Suitable crystals were obtained by recrystallization
from an n-hexane/CH2Cl2 mixture. The crystal struc-
ture of 6 clearly shows the (R)-configuration in posi-
tion 4 indicating that the nucleophilic attack had taken
place with retention of configuration.
Scheme 1. Interconversion of trans-4 and cis-4 upon treat-
ment with allyltrimethylsilane (2 equiv.) and TiCl4 (1 equiv.).
The formation of products 6 and 7 can be explained
by coordination of the magnesium atom of the Grig-
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S. M. Husain et al. · Enantioselective Synthesis of a 2,2-Disubstituted Tetrahydro-3-benzazepine
193
Scheme 2. Reaction of
trans-4 with three equi-
valents of PhMgBr and
transformation of 6 into
the enantiomerically pure
2,2-disubstituted tetrahy-
dro-3-benzazepine 11.
Table 1. Affinity of the 2,2-disubstituted tetrahydro-3-benz-
azepine 11 towards NMDA, σ1 and σ2 receptors.
Receptor
NMDA
σ1
Ki SEM (nM)
496 53
> 2000
σ2
134 13
yields the 4-methylene-substituted tetrahydro-3-benz-
azepine derivative 7. This side reaction together with
the sterically demanding N/O-ketalic substructure is
responsible for the low yields of the desired product 6.
Next, cis-4 was reacted with 3 equivalents of Ph-
MgBr. This reaction did not provide a 4,4-disubstituted
or a 4-methylene-substituted tetrahydro-3-benzazepine
derivative like 6 or 7. We assume that in the case of
cis-configuration both faces of the oxazolidine plane
are shielded by the phenyl moiety in position 3 (above
the ring plane) and the C-11a methyl moiety (below
the ring plane). Therefore, coordination of PhMgBr
with the oxazolidine ring O atom is inhibited result-
ing in fast deprotonation in α-position of the lactame
carbonyl moiety [11].
Fig. 2. Molecular structure of the 4,4-disubstituted tetra-
hydro-3-benzazepine 6 in the crystal.
The 4,4-disubstituted tetrahydro-3-benzazepine
derivative 6 was used to synthesize the enantiomeri-
cally pure 2,2-disubstituted tetrahydro-3-benzazepine
11 (Scheme 2). In the first step, the lactame 6 was
reduced with AlH3, which had been formed in situ by
mixing AlCl3 and LiAlH4 in the ratio 1 : 3 [12], to ob-
tain the N-substituted tetrahydro-3-benzazepine 10 in
69 % yield. Finally, the N-(2-hydroxy-1-phenylethyl)
protective group of 10 was removed by hydrogenolysis
(H2, Pd/C) to provide (2R)-11 in 67 % yield.
Scheme 3. Mechanism for the formation of the 4,4-disubsti-
tuted tetrahydro-3-benzazepine 6 and the 4-methylene sub-
stituted 3-benzazepine 7.
nard reagent with the oxygen atom of the oxazoli-
dine moiety as shown in intermediate 9 (Scheme 3)
[10]. After coordination, the Ph group of PhMgBr can
act as a nucleophile as well as a base. The delivery
of the phenyl nucleophile from the same face as the
In competitive receptor binding studies with ra-
C–O bond results in the 4,4-disubstituted tetrahydro-3- dioligands [13], the (R)-2-methyl-2-phenyl-2,3,4,5-
benzazepine 6 and accounts for the observed retention tetrahydro-1H-3-benzazepine 11 revealed moderate
of configuration. In addition to the nucleophilic attack, affinity towards the PCP binding site of the NMDA
the coordinated phenyl moiety is able to remove a pro- receptor (Ki = 496 nM, Table 1). Compared with the
ton from the methyl moiety via a six-membered ring smaller homologous isoquinoline (S)-2 [5], which has
transition state. Subsequent oxazolidine ring opening the same stereochemistry as 11 [14], the affinity is
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194
S. M. Husain et al. · Enantioselective Synthesis of a 2,2-Disubstituted Tetrahydro-3-benzazepine
about 10-fold reduced. Obviously, increasing of the tosampler: L-7200; pump: L-7100; degasser: L-7614; col-
R
R
ꢀ
umn: LiChrospherꢀ 60 RP-select B (5 µm); LiCroCART
ring size by one methylene moiety results in lower-
ing of binding at the PCP binding site of the NMDA
receptor.
250-4 mm cartridge; flow rate: 1.000 mL min−1; injection
volume: 5.0 µL; detection at λ = 210 nm; solvents: A: wa-
ter with 0.05 % (v/v) trifluoroacetic acid; B: acetonitrile with
0.05 % (v/v) trifluoroacetic acid: gradient elution: (A%): 0 –
4 min: 90 %, 4 – 29 min: 90 % to 0 %, 29 – 31 min: 0 %, 31 –
31.5 min: 0 % to 90 %, 31.5 – 40 min: 90 %.
In addition to the NMDA receptor affinity the affin-
ity of the tetrahydro-3-benzazepine 11 towards σ1 and
σ2 receptors was investigated [15]. The compound did
not show any significant affinity to σ1 receptors (Ki >
2000 nM). However, a surprisingly high σ2 receptor
affinity (Ki = 134 nM) was observed, which even ex-
ceeds the NMDA receptor affinity. Nevertheless, 11
represents the starting point for the development of
novel potent NMDA receptor antagonists and σ2 re-
ceptor ligands.
In conclusion a method for the interconversion
of the diastereomeric tricyclic oxazolidines trans-4
and cis-4 has been developed, which increases the
overall yield of the desired diastereomer for subse-
quent asymmetric syntheses. Whereas the oxazoli-
dine trans-4 reacted with phenylmagnesium bromide
to form the 4,4-disubstituted tetrahydro-3-benzazepine
6, the corresponding cis-4 did not react to form a
phenyl addition product. Compound 6 was transformed
into the (R)-2-methyl-2-phenyl-2,3,4,5-tetrahydro-1H-
3-benzazepine 11, which revealed promising affinity to
the PCP binding site of the NMDA receptor and the σ2
receptor.
Conversion of cis-4 into trans-4
Under an atmosphere of N2 a solution of TiCl4 (4.5 mL
of 1.0 M in CH2Cl2; 4.5 mmol, 1 equiv.) was added via sy-
ringe to a stirred solution of allyltrimethylsilane (0.73 mL,
9.0 mmol, 2 equiv.) and oxazolidine cis-4 (1.32 mg,
4.5 mmol) in dry CH2Cl2 (24 mL) at r. t. The resulting so-
lution was stirred at r. t. for 3 d. Then it was cooled to
0
◦C and carefully quenched with saturated aqueous am-
monium chloride (20 mL). The resulting mixture was di-
luted with water (10 mL) and extracted with CH2Cl2 (3 ×
20 mL). The combined organic layers were washed with sat-
urated aqueous NaHCO3 (15 mL) and brine (15 mL), dried
(Na2SO4), and concentrated in vacuo to give 1.56 g of the
crude product. The product was purified by fc (3 cm, 1 =
20 cm, EtOAc/cyclohexane 10/90 to 40/60, 25 mL). trans-4
(Rf = 0.48, EtOAc/petroleum ether 50/50) and cis-4 (Rf =
0.14, EtOAc/petroleum ether 50/50) were isolated as color-
less solids [9] in yields of 462 mg (35 %) and 713 mg (54 %),
respectively.
(4R)-3-[(1R)-2-Hydroxy-1-phenylethyl]-4-methyl-4-phenyl-
1,3,4,5-tetrahydro-3-benzazepin-2-one (6), 3-[(1R)-2-hydr-
oxy-1-phenylethyl]-4-methylene-1,3,4,5-tetrahydro-3-benz-
azepin-2-one (7) and 1-hydroxy-3-[(1R)-2-hydroxy-1-phe-
nylethyl]-4-methylene-1,3,4,5-tetrahydro-3-benzazepin-2-
one (8)
Experimental Section
General
Unless otherwise mentioned, THF was dried with
sodium/benzophenone and was freshly distilled before use.
Thin layer chromatography (tlc): Silica gel 60 F254 plates
(Merck). Flash chromatography (fc): Silica gel 60, 40 –
64 µm (Merck); parentheses include: diameter of the col-
umn, height of silica gel bed, eluent, fraction size, Rf value.
Melting point: Melting point apparatus SMP 3 (Stuart Scien-
tific), uncorrected. Optical rotation: Polarimeter 341 (Perkin
Elmer); 1.0 dm tube; concentration c in g/100 mL; T =
20 ◦C; wavelength 589 nm (D line of Na light); unit of
A solution of trans-4 (405 mg, 1.38 mmol) in THF
(24 mL) was added via cannula t◦o a solution of PhMgBr
(1.0 M in THF, 4.14 mmol) at 0 C, and the mixture was
stirred at this temperature for 10 h and then at r. t. for 8 h.
The reaction was quenched by addition of a saturated NaCl
solution, and the mixture was extracted with EtOAc (3 ×
15 mL). The combined organic extracts were dried (Na2SO4)
and concentrated in vacuum. The residue (520 mg) was pu-
rified by fc (2 cm, 1 = 20 cm, EtOAc/cyclohexane 20/80 to
35/65, 15 mL).
[α] is grad mL dm−1
g
−1. MS: MAT GCQ (Thermo-
Finnigan); EI = electron impact, ESI = electro spray ioniza-
tion. HRMS: MicroTof (Bruker Daltronics, Bremen), Cali-
bration with sodium formate clusters before measurement.
IR: IR spectrophotometer 480Plus FT-ATR-IR (Jasco). 1H
6: Rf = 0.14, (EtOAc/cyclohexane 40/60), colorless solid,
20
yield 27 mg (6 %). [α]
= +7.6 (c = 1.05, CH2Cl2). –
589
NMR (400 MHz), 13C NMR (100 MHz): Mercury plus 400 1H NMR (CDCl3): δ = 1.74 (s, 3H, CH3), 3.03 (d, J =
spectrometer (Varian); δ in ppm relative to tetramethylsi- 15.0 Hz, 1H, 5-H), 3.61 (d, J = 15.0 Hz, 1H, 5-H), 3.96
lane; coupling constants are given in Hz with 0.5 Hz reso- (d, J = 15.4 Hz, 1H, 1-H), 3.97 – 4.05 (m, 3H, CH2OH,
lution. HPLC method for determination of the product pu- NCHPh), 4.32 (d, J = 15.2 Hz, 1H, 1-H), 6.82 – 6.84 (m,
rity: Merck Hitachi Equipment; UV detector: L-7400; au- 2H, arom. CH), 6.93 (d, J = 7.3 Hz, 1H, arom. CH), 7.00 –
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S. M. Husain et al. · Enantioselective Synthesis of a 2,2-Disubstituted Tetrahydro-3-benzazepine
195
7.12 (m, 7H, arom. CH), 7.19 – 7.34 (m, 4H, arom. CH). – for 3 h and then warmed to r. t. over 30 min. The result-
◦
13C NMR (CDCl3): δ = 26.8 (1C, CH3), 45.1 (1C, 1-C), 48.6 ing clear solution was cooled to 0 C and then quenched
(1C, 5-C), 66.9 (1C, NCHPh), 67.8 (1C, CH2OH), 67.9 (1C, by careful addition of 1 M HCl (only few drops). The re-
4-C), 126.4, 126.6, 127.7, 127.7, 128.0, 128.1, 128.5, 128.5, sulting slurry was diluted with water (10 mL) and extracted
129.8 (10C, Ph-CH), 134.43, 135.11, 138.4, 143.8 (4C, Ph- with CH2Cl2 (3 × 5 mL). The combined organic layers were
C), 171.7 (1C, CO). – IR: ν = 3402 (w, OH), 3056, 3033 washed with 1 M NaOH and brine (10 mL). The combined or-
(w, arom. C-H), 2982, 2930 (m, aliph. C-H), 1617 (s, C=O) ganic layers were dried (Na2SO4), filtered, and concentrated
cm−1. – HRMS (ESI): m/z = 372.1972 (calcd. 372.1958 in vacuo. The residue (20 mg) was purified by fc (1 cm,
for C25H25NO2H, [M+H]+). – HPLC: Purity 95.6 %, tR
=
l = 24 cm, EtOAc/petroleum ether 5/95, 10 mL, Rf = 0.51
20.19 min.
(EtOAc/cyclohexane 40/60)). Colorless liquid, yield 14 mg
20
(69 %). – [α]
= −48.6 (c = 0.5, CH2Cl2). – 1H NMR
7: Rf = 0.16, (EtOAc/cyclohexane 40/60), colorless solid,
yield 68 mg (17 %). – H NMR (CDCl3): δ = 3.03 (d, J =
589
1
(CDCl3): δ = 1.49 (s, 3H, CH3), 2.68 (d, J = 14.2 Hz, 1H,
1-H), 2.92 (ddd, J = 14.6/6.9/3.5 Hz, 1H, 5-H), 3.15 (ddd, J =
13.6/8.5/3.8 Hz, 1H, 4-H), 3.25 (ddd, J = 14.4/8.4/3.6 Hz,
1H, 5-H), 3.43 (ddd, J = 13.8/7.0/3.7 Hz, 1H, 5-H), 3.51 (d,
J = 14.2 Hz, 1H, 1-H), 3.74 – 3.81 (m, 2H, CH2OH), 3.92
(dt, J = 10.1/6.1 Hz, 1H, NCHPh), 6.14 (d, J = 7.3 Hz, 1H,
arom. CH), 7.09 – 7.25 (m, 11H, arom. CH), 7.40 (dd, J =
7.6/2.0 Hz, 2H, arom. CH). A signal for an OH proton could
not be detected. – 13C NMR (CDCl3): δ = 20.7 (1C, CH3),
37.3 (1C, 5-C), 42.9 (1C, 1-C), 51.6 (1C, 4-C), 63.6 (1C,
2-C), 64.0 (1C, CH2OH), 64.2 (1C, NCHPh), 126.22, 126.6,
126.7, 126.8, 127.9, 128.2, 128.3, 128.7, 130.6 (14C, PhCH),
138.5, 141.1, 141.6, 148.6 (4C, Ph-C). – IR: ν = 3417
(w, OH), 3056, 3026 (w, arom. CH), 2923, 2857 (w, aliph.
CH) cm−1. – HRMS (ESI): m/z = 358.2166 (calcd. 358.2156
18 Hz, 1H, 5-H), 3.54 (dd, J = 15.9/11.7 Hz, 2H, 5-H/1-H),
3.99 (d, J = 13.8 Hz, 1H, 1-H), 4.04 (dd, J = 9.9/4.9 Hz,
1H, CH2OH), 4.16 (t, J = 10.4 Hz, 1H, CH2OH), 5.00
(d, J = 1.0 Hz, 1H, =CH2), 5.18 (s, 1H, =CH2), 5.54 (dd,
J = 9.5/5.1 Hz, 1H, NCHPh), 6.78 (d, J = 6.6 Hz, 1H,
arom. CH), 7.05 – 7.21 (m, 8H, arom. CH). – 13C NMR
(CDCl3): δ = 39.3 (1C, 5-C), 41.9 (1C, 1-C), 60.9 (1C,
NCHPh), 62.1 (1C, CH2OH), 115.6 (1C, =CH2), 121.8,
125.6, 126.3, 127.1, 127.4, 127.5, 128.6, 129.5 (9C, Ph-CH),
130.9, 133.7, 136.0 (3C, Ph-C), 144.1 (1C, 4-C), 171.4
(1C, CO). – IR: ν = 3390 (w, OH), 2923 (w, arom. C-H),
1632 (s, C=O) cm−1. – C19H19NO2 (293.4). – MS (ESI):
m/z (%) = 294 (100) [M+H]+. – HPLC: Purity 82.3 %,
tR = 19.67 min.
8: Rf = 0.26, (EtOAc/cyclohexane 40/60), pale-yellow
solid, yield 32 mg (7.5 %). – 1H NMR (CDCl3): δ = 3.69
(d, J = 18.6 Hz, 1H, 5-H), 3.85 (d, J = 18.5 Hz, 1H, 5-H),
4.04 (m, 2H, OH/CH2OH), 4.21 (dd, J = 11.8/9.4 Hz, 1H,
CH2OH), 4.76 (d, J = 2.4 Hz, 1H, =CH2), 5.25 (d, J =
2.3 Hz, 1H, =CH2), 5.44 (dd, J = 9.3/4.9 Hz, 1H, NCHPh),
5.78 (d, J = 4.6 Hz, 1H, 1-H), 6.94 (d, J = 7.4 Hz, 1H,
arom. CH), 7.15 – 7.26 (m, 7H, arom. CH), 7.78 (1H, J =
7.8 Hz, 1H, arom. CH). – 13C NMR (CDCl3): δ = 40.2 (1C,
5-C), 62.8 (1C, CH2OH), 65.3 (1C, NCHPh), 68.4 (1C, 1-C),
117.4 (1C, =CH2), 124.4, 127.1, 127.9, 128.0, 128.4, 128.8,
129.5 (9C, Ph-CH), 132.6, 137.6, 143.8 (3C, Ph-C), 136.8
(1C, 4-C), 173.7 (1C, CO). – IR: ν = 3403 (w, OH), 3054,
3032 (w, arom. C-H), 2984 (m, aliph. C-H), 1619 (s, C=O)
cm−1. C19H19NO3 (309.4). – MS (ESI): m/z (%) = 310 (100)
[M+H]+.
for C25H27NOH, [M+H]+). – HPLC: purity 75.96 %, tR
=
18.75 min.
(2R)-2-Methyl-2-phenyl-2,3,4,5-tetrahydro-1H-3-benz-
azepine (11)
A mixture of 10 (13 mg, 0.036 mmol) and Pd/C (10 % by
wt) in methanol (1.5 mL) and 1 M HCl (0.5 mL) was stirred
at r. t. under an H2 atmosphere (balloon) for 6 h. The reac-
tion mixture was filtered using a silica gel bed, and the sol-
vent was removed under reduced pressure to obtain a residue,
which was dissolved in CH2Cl2 (10 mL) and washed with
1 M NaOH (3 × 4 mL). The combined organic layers were
dried (Na2SO4), filtered and concentrated in vacuo to pro-
vide an oil (10 mg); fc (1 cm, 1 = 20 cm, EtOAc/petroleum
ether/NH3 40/59.5/0.5, 10 mL, Rf = 0.33). Colorless liquid,
1
yield 5.8 mg (67 %). – H NMR (CDCl3): δ = 1.23 (s, 3H,
CH3), 2.75 – 2.81 (m, 1H, 5-H), 2.88 – 2.98 (m, 3H, 5-H/4-
H), 3.01 (d, J = 14.2 Hz, 1H, 1-H), 3.40 (d, J = 14.1 H, 1H,
1-H), 6.98 – 7.01 (m, 1H, arom. CH), 7.06 (d, J = 3.1 Hz,
(2R)-2-[(2R)-2-Methyl-2-phenyl-2,3,4,5-tetrahydro-1H-3-
benzazepin-3-yl]-2-phenylethanol (10)
◦
Under N2 at 0 C dry THF (2mL) was added to anhy- 2H, arom. CH), 7.14 (t, J = 7.4 Hz, 1H, arom. CH), 7.27
drous AlCl3 (7.8 mg, 0.059 mmol, 1 equiv.) and stirred for (t, J = 7.7 Hz, 2H, arom. CH), 7.52 (dd, J = 8.4/1.0 Hz,
5 min. Then a solution of LiAlH4 (0.17 mL, 1.0 M in THF, 2H, arom. CH). A signal for the NH proton could not be
0.177 mmol; 3 equiv.) was added via syringe. The resulting detected. – 13C NMR (CDCl3): δ = 29.9 (1C, CH3), 38.0
clear, colorless solution was allowed to warm to r. t. and was (1C, 5-C), 42.1 (1C, 1-C), 48.9 (1C, 4-C), 57.2 (1C, 2-C),
stirred for 20 min to give a solution of alane (AlH3). A so- 126.2, 126.3, 126.5, 126.7, 128.5, 130.8 (9C, Ph-CH), 138.6,
lution of 6 (22 mg, 0.059 mmol) in dry THF (2 mL) was 141.1 (3C, Ph-C). – IR: ν = 3063, 3026 (w, arom. CH), 2923
added at 0 C. The resulting solution was stirred at 0 C (w, aliph. CH) cm−1. – HRMS (ESI): m/z = 283.160 (calcd.
◦
◦
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196
S. M. Husain et al. · Enantioselective Synthesis of a 2,2-Disubstituted Tetrahydro-3-benzazepine
238.1590 for C17H19NH, [M+H]+). – HPLC: purity 98.1 %, tron density 0.16 / −0.16 e A−3, Flack parameter −0.3(4).
˚
tR = 15.49 min.
Hydrogen atoms were calculated and refined as riding atoms.
The data set was collected with a Nonius KappaCCD diffrac-
tometer. Programs used: data collection: COLLECT [16], data
reduction: DENZO-SMN [17], absorption correction: DENZO
[18], structure solution: SHELXS-97 [19], structure refine-
ment: SHELXL-97 [20], graphics: SCHAKAL [21].
CCDC 718245 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge via www.ccdc.cam.ac.uk/data request/cif.
X-Ray crystal structure analysis of 6
Empirical formula C25H25NO2, M = 371.46, colorless
crystal 0.25 × 0.15 × 0.05 mm3, monoclinic, space group
˚
=
P21 (no. 4), a = 9◦.1779(3), b = 10.6325(4), c = 11.5696(5) A,
3
˚
β = 109.838(2) , V = 1062.01(7) A , Z = 2, ρcalc
1.16 g cm−3, µ = 0.6 mm−1, empirical absorption correction
˚
(0.870 ≤ T ≤ 0.972), CuKα radiation, λ = 1.54178 A, T =
Acknowledgement
293(2) K, ω and φ scans, 6934 reflections collected ( h, k,
l), [(sinθ)/λ] = 0.60 A−1, 2379 independent (Rint = 0.051)
˚
We wish to thank the NRW Graduate School of Chem-
istry for a stipend, which was funded by the Government of
the State Nordrhein-Westfalen and the DAAD.
and 1999 observed reflections [I ≥ 2 σ(I)], 255 refined pa-
rameters, R = 0.050, wR2 = 0.132, max. / min. residual elec-
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