Asymmetric synthesis of 3-substituted tetrahydro-2-benzazepines

Article abstract of DOI:10.1039/c5ob00731c

The enantiomerically and diastereomerically pure tricyclic oxazolidine cis-10 was prepared in a five step synthesis starting with 1-bromo-2-iodobenzene. Me₃SiCN and allylSiMe₃ reacted with cis-10 in the presence of TiCl₄ to form the nitrile (3S)-11 and the allyl derivative (3S)-12 with high diastereoselectivity. The hydrogenolytic removal of the chiral auxiliary failed, since the endocyclic benzyl-N-bond was cleaved simultaneously. Therefore the N-(hydroxyethyl)amide of (3S)-12 was transformed into the enamide 27, which was hydrolyzed to afford the secondary amide 28. The enamide strategy to remove the chiral auxiliary from (3S)-11 led to complete racemization due to fast deprotonation in α-position of the cyano moiety. Two pairs of enantiomers 30a-b/ent-30a-b with prototypical σ substituents at the N-atom were prepared. The low σ₁ affinity of the tetrahydro-2-benzazepines (ent-30b, K_i = 407 nM) is attributed to the short distance between the two lipophilic aromatic moieties.

Full text of DOI:10.1039/c5ob00731c

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Asymmetric synthesis of 3-substituted tetrahydro-
2-benzazepines†
Cite this: DOI: 10.1039/c5ob00731c
Matthias P. Quick,a Roland Fröhlich,b Dirk Schepmanna,c and Bernhard Wünsch*a,c
The enantiomerically and diastereomerically pure tricyclic oxazolidine cis-10 was prepared in a five step
synthesis starting with 1-bromo-2-iodobenzene. Me3SiCN and allylSiMe3 reacted with cis-10 in the pres-
ence of TiCl4 to form the nitrile (3S)-11 and the allyl derivative (3S)-12 with high diastereoselectivity. The
hydrogenolytic removal of the chiral auxiliary failed, since the endocyclic benzyl-N-bond was cleaved
simultaneously. Therefore the N-(hydroxyethyl)amide of (3S)-12 was transformed into the enamide 27,
which was hydrolyzed to afford the secondary amide 28. The enamide strategy to remove the chiral
auxiliary from (3S)-11 led to complete racemization due to fast deprotonation in α-position of the cyano
moiety. Two pairs of enantiomers 30a–b/ent-30a–b with prototypical σ substituents at the N-atom were
prepared. The low σ1 affinity of the tetrahydro-2-benzazepines (ent-30b, Ki = 407 nM) is attributed to the
short distance between the two lipophilic aromatic moieties.
Received 13th April 2015,
Accepted 19th May 2015
DOI: 10.1039/c5ob00731c
www.rsc.org/obc
1. Introduction
Tetrahydro-2-benzazepines can be regarded as regioisomers
(constitutional isomers) of tetrahydro-3-benzazepines and
ring homologs of tetrahydroisoquinolines. Both tetrahydro-3-
benzazepines1–7 and tetrahydroisoquinolines8,9 are found in
several pharmacologically active compounds and are therefore
regarded as privileged heterocycles. Despite its similarity to
these heterocycles, the tetrahydro-2-benzazepine ring system is
less abundant in pharmacologically active compounds. The
most prominent drug with a tetrahydro-2-benzazepine scaffold
is the natural product galantamine (Galanthus nivalis), which
inhibits the acetylcholine esterase and is therefore clinically
used for the treatment of Alzheimer’s disease.10,11 Very
recently we have reported on a novel synthetic approach to
racemic tetrahydro-2-benzazepines 1 which allows the intro-
duction of various substituents in 5-position12–14 (Fig. 1). In
particular, 5-benzyltetrahydro-2-benzazepines 1a with a linear
N-butyl moiety (Ki = 8.5 nM) and 1b with a N-(4-fluorobenzyl)
moiety (Ki = 7.1 nM) show high σ1 receptor affinity and selecti-
vity over the σ2 subtype.13
Fig. 1 Comparison of the envisaged 2-benzazepines 2 with regio-
isomeric 2-benzazepines
(position of R1) and 3-benzazepines
(position of ring N-atom), which show promising σ1 affinity.
1
3
The σ1 receptor represents a unique receptor, which differs
considerably from known mammalian ligand-gated ion
channel receptors, G-protein-coupled receptors, tyrosine
kinase receptors and nuclear receptors.15–18 σ1 receptor ago-
nists were reported to be beneficial for the treatment of Alzhei-
mer’s disease and depression. In contrast, σ1 antagonists
could be used for the treatment of pain, in particular, neuro-
pathic pain, schizophrenia, addiction (ethanol, cocaine, and
methamphetamine) and cancer.19–22 Although an X-ray crystal
structure is not yet available, a 3D homology model of the σ1
receptor protein was recently published.23 The intracellularly
located ligand binding site of the σ1 receptor was analyzed in
detail using this model.24 According to various pharmaco-
phore models, a protonated amino group flanked by two
hydrophobic moieties in defined distances is required for high
σ1 receptor affinity.25 Introduction of appropriate substituents
at the tetrahydro-2-benzazepine scaffold resulted in com-
aInstitut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-
Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
E-mail: wuensch@uni-muenster.de; Fax: +49-251-8332144; Tel: +49-251-8333311
bOrganisch-chemisches Institut der Westfälischen Wilhelms-Universität Münster,
Corrensstr. 40, D-48149 Münster, Germany
cCells-in-Motion Cluster of Excellence (EXC 1003 – CiM), Westfälische Wilhelms-
Universität Münster, Germany
†Electronic supplementary information (ESI) available. CCDC 1050885 and
1050886. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c5ob00731c
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Scheme 1 Plan for the synthesis of enantiomerically pure 3-substituted tetrahydro-2-benzazepines 2.
pounds that fit nicely into the reported pharmacophore azepines 2. The synthesis of the central tricyclic N/O-acetal has
models, explaining the high σ1 affinity of 1a and 1b.13
already been reported in a short communication34 (Scheme 1).
In addition to 1, tetrahydro-3-benzazepines 3, which are in
accordance with these pharmacophore models, also show very
high σ1 affinity.26,27 Recently we have reported a very short and
efficient asymmetric synthesis of tetrahydro-3-benzazepines 3,
which gave access to enantiomerically pure σ1 ligands of type
3.28,29 It was shown that the (R)-configured enantiomer (R)-3a
(Ki(σ1) = 3.2 nM) has four-fold higher σ1 affinity than the
(S)-configured enantiomer (S)-3a (Ki(σ1) = 12 nM). Both
enantiomers display high selectivity over the σ2 subtype.27
Since the tetrahydro-2-benzazepines 2 are regioisomers of
2-benzazepines 1 (position of the substituent R1) and 3-benz-
azepines 3 (position of the ring N-atom), which display promis-
ing σ1 affinity, the development of an asymmetric synthesis of
tetrahydro-2-benzazepines 2 with different substituents in
2- and 3-position was envisaged. Moreover, the σ1 and σ2
affinities of 2-benzazepines 2 with appropriate substituents R1
and R2 will be reported herein.
According to our plan, 1-bromo-2-iodobenzene (4) will be
converted into 2-bromophenylpropionaldehyde acetal 5. After
the introduction of a carboxylic acid, an enantiomerically pure
β-aminoalcohol will be used to establish the key tricyclic N/O-
acetal 6. The stereochemistry during the ring opening of the
cyclic N/O-acetal by different nucleophiles will be investigated.
After reductive removal of the N-bound chiral auxiliary, the
resulting secondary amines will be provided with substituents,
which give rise to high σ1 receptor affinity of the final 2-benz-
2. Synthesis
In the first step, Pd(OAc)2 catalyzed Heck reaction30 of
1-bromo-2-iodobenzene (4) with allyl alcohol31,32 afforded 3-(2-
bromophenyl)propionaldehyde upon coupling and subsequent
double bond isomerization.33 Treatment of the unpurified
aldehyde with ethylene glycol led to the ethylene acetal 7 in
75% yield over two reaction steps33–35 (Scheme 2). Bromine/
lithium exchange of 7 with n-BuLi at −78 °C and subsequent
trapping of the aryllithium intermediate with CO2 provided the
carboxylic acid 8, which was coupled with (R)-phenylglycinol to
form the amide 9. The highest yields of 9 were achieved using
the coupling agent EDC·HCl in the presence of 1-hydroxy-
benzotriazole (HOBt). Thus the corresponding ester consisting
of the acid 8 and HOBt could be isolated as side product.
Unexpectedly, the transformation of the hydroxyamide 9
into the tricyclic N/O-acetals 10 turned out to be very difficult.
Initial experiments with p-toluenesulfonic acid in protic or
aprotic solvents at low or high temperature did not yield the
expected tricyclic compounds 10. However, stirring a solution
of hydroxyamide 9 in CHCl3 and concentrated HCl at room
temperature for 16 h led to complete transformation of 9 into
the tricyclic N/O-acetals 10.34 Separation by flash chromato-
Scheme 2 Preparation of cis-10 and trans-10 as key intermediates for the asymmetric synthesis of 3-substituted tetrahydro-2-benzazepines.
Reagents and reaction conditions: (a) (1) H2CvCHCH2OH, Pd(OAc)2, NaHCO3, Et3BnNCl, DMF, 45 °C, 5.5 h; (2) ethylene glycol, TosOH, CHCl3,
reflux, 75% over two steps.35 (b) n-BuLi, THF, −80 °C, 10 min, then CO2, −78 °C, 75 min, 93%. (c) (R)-Phenylglycinol, EDC·HCl, HOBt, CH2Cl2, rt,
5.25 h, 74%. (d) CHCl3, HCl, rt, 16 h, cis-10 (76%), trans-10 (10%). The stereodescriptors cis and trans reflect the relative orientation of the methine
protons of the oxazolidine ring, i.e. the protons in 3- and 11a-position of the ring system.
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graphy provided cis-10 and trans-10 in 76% and 10% yields,
respectively.
The relative configuration of cis-10 and trans-10 was deter-
mined by NOE difference spectroscopy. At first the NOE experi-
ment was performed with cis-10. Irradiation at 5.22 ppm (3-H)
increased the signal at 5.27 ppm (11a-H). This nuclear Over-
hauser effect indicates cis-orientation of 3-H and 11a-H at the
five-membered oxazolidine ring. Since the absolute configur-
ation of the chiral center in 3-position is known from the start-
ing material (R)-phenylglycinol, (R)-configuration is attributed
to the newly formed center of chirality at 11a-position. The
same experiment performed with the diastereomer trans-10
did not increase the signal at 5.05 ppm (11a-H) after
irradiation at 5.47 ppm (3-H). These protons are on opposite
sides of the oxazolidine ring and therefore (S)-configuration is
attributed to the newly formed center of chirality in 11a-posi-
tion of trans-10.
Scheme 3 Stereoselective opening of the oxazolidine ring of cis-10.
Reagents and reaction conditions: (a) Me3SiCN, TiCl4, CH2Cl2, micro-
wave irradiation, 44% ((3S)-11, 19% ((3R)-11). (b) allylSiMe3, TiCl4, CH2Cl2,
microwave irradiation, 64% ((3S)-12, 5% ((3R)-12).
The stereoselective ring opening of bicyclic lactams pre-
pared by cyclocondensation of (R)-phenylglycinol and γ- or
δ-oxoalkanoic acids has been reported to result in enantio-
merically pure substituted pyrrolidine and piperidine deriva-
tives. For this purpose the bicyclic N/O-acetals were reacted
with different C-nucleophiles (e.g. Grignard reagents, cuprates,
and trimethylsilyl reagents) to produce substituted pyrrolidine
and piperidine derivatives. Activation of the bicyclic lactams
with a Lewis acid (e.g. TiCl4 and BF3) to form an N-acylimi-
nium intermediate often improved the conversion. Usually
this transformation resulted in high diastereoselectivities
(>9 : 1).36–41
Fig. 2 Crystal structure of compound (3S)-11. Thermal ellipsoids are
As described for bicyclic lactams the tricyclic lactam cis-10
(main diastereomer) was reacted with different C-nucleophiles.
However, reaction of cis-10 with Grignard reagents (PhMgBr,
MeMgBr, and EtMgBr) or cuprates (Me2CuCNLi2) at −78 °C to
+20 °C did not provide the corresponding alkylated products.
Moreover, the trimethylsilyl enol ether of acetophenone in the
presence of different Lewis acids (TiCl4, SnCl4, BF3, and OEt2)
did not transform cis-10 into the desired alkylated products.
Finally it was found that Me3SiCN and allylSiMe3 in the pres-
ence of a Lewis acid converted the tricyclic N/O-acetal cis-10
into the nitriles 11 and the allyl derivatives 12, respectively
(Scheme 3).
shown at the 15% probability level.
The reaction of cis-10 with Me3SiCN was carefully optimized
with respect to the Lewis acid (TiCl4, AlCl3, ZnCl2, BF3, OEt2,
and SnCl4), solvent (CH2Cl2 and THF), temperature (−78 °C to
+60 °C including microwave irradiation) and the stoichiometry
of the reagents. It turned out that the reaction of cis-10 with an
excess of Me3SiCN (15 equiv.) and TiCl4 (8 equiv.) in CH2Cl2
under microwave irradiation led to the best transformation
allowing the isolation of the diastereomeric nitriles (3S)-11
and (3R)-11 in 44% and 19% yields, respectively. A reduced
amount of Me3SiCN (3 equiv.) led to partial epimerization of
cis-10 to trans-10. Experiments with the analogous tin reagent
Bu3SnCN did not afford the nitriles 11.
Fig. 3 Crystal structure of compound (3R)-11. Thermal ellipsoids are
shown at the 15% probability level.
ation in 3-position of (3S)-11 (Fig. 2) and (R)-configuration in
3-position of (3R)-11 (Fig. 3). The elemental unit of both struc-
tures contains only one conformer. Both structures reveal
pseudoaxial orientation of the cyano moiety within the seven-
membered azepine ring due to the allylic strain of the lactam
group. However, the orientation of the 2-hydroxy-1-phenylethyl
After crystallization, X-ray crystal structure analyses of
the diastereomerically pure nitriles (3S)-11 and (3R)-11 were
recorded. The X-ray crystal structures clearly show (S)-configur-
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Scheme 4 Postulated mechanism of oxazolidine ring opening explaining the preferred formation of (3S)-configured products.
side chain at the N-atom differs in the structures of the diaster-
eomers. Whereas in (3S)-11 the phenyl moiety is oriented
towards the cyano moiety, in (3R)-11 it is oriented to the oppo-
site side.
Transferring the optimized conditions on the reaction of
cis-10 with allylSiMe3 led to the diastereomeric allyl derivatives
(3S)-12 and (3R)-12, which were separated by flash chromato-
graphy and isolated in 64% and 5% yield, respectively. The
main diastereomer (3S)-12 was crystallized from methanol
giving crystals suitable for X-ray crystal structure analysis.34
The elemental unit of (3S)-12 contains two conformers. In the
first conformer the allyl moiety adopts a pseudoaxial and in
the second conformer a pseudoequatorial orientation relative
to the benzazepine ring. In both conformers the phenyl moiety
Scheme 5 Removal of the chiral auxiliary from (3S)-11 by hydrogeno-
of the chiral auxiliary points towards the lipophilic allyl
moiety.
lysis. Reagents and reaction conditions: (a) LiAlH4, AlCl3, THF, 0 °C,
30 min. (b) 1,4-Diiodobutane, NaHCO3, CH3CN, reflux, 2 h, 49% (over
two steps). (c) H2 (1 bar), Pd/C, CH3OH, rt, 6 h. (d) 2-(3,4-Dichlorophe-
nyl)acetyl chloride, NEt3, rt, 48 h, 31% (over two steps). The enantiomer
ent-15 was prepared in the same manner starting from (S)-phenyl-
glycinol.
The reaction of cis-10 with both Me3SiCN and allylSiMe3 in
the presence of TiCl4 provided diastereoselectively the
(3S)-configured diastereomers (3S)-11 and (3S)-12 as main pro-
ducts. This diastereoselectivity is explained by attack of TiCl4
at the oxazolidine O-atom, opening the oxazolidine ring and
formation of chelate 13, in which TiCl4 is additionally co-
ordinated with the carbonyl O-atom (Scheme 4). In the chelate
13 the phenyl moiety of the chiral auxiliary is fixed below the
benzazepine ring plane shielding the Si-face at the C-atom of
the intermediate N-acyliminium ion 13. Thus the Re-face
attack of the nucleophiles Me3SiCN and allySiMe3 is favored,
leading predominantly to products with (3S)-configuration.34
In order to obtain enantiomerically pure products at the
end, the diastereomeric purity of the main diastereomers (3S)-
11 and (3S)-12 was determined by HPLC analysis. The
diastereomeric purity of both isolated compounds (3S)-11 and
(3S)-12 was greater than 99 : 1.
Next the main diastereomer (3S)-11 was reduced with AlH3,
which was generated by mixing three equivalents of LiAlH4
and one equivalent of AlCl3.42 Without purification the formed
primary amine 14 was alkylated with 1,4-diiodobutane to
afford the pyrrolidine 15 (Scheme 5). Stirring the pyrrolidine
15 under a H2 atmosphere in the presence of Pd/C not only
cleaved the exocyclic benzyl-N-bond but also the endocyclic
benzyl-N-bond resulting in the phenylpropylamine 16. The
structure of the very polar primary amine 16 was confirmed
after acylation with 2-(3,4-dichlorophenyl)acetyl chloride to
give the amide 17. The same result was obtained by transfer
hydrogenolysis of 15 using ammonium formate instead of H2.
Scheme 6 Removal of the chiral auxiliary from (3S)-11 by hydrolysis of
the enamide 19. Reagents and reaction conditions: (a) SOCl2, THF, 0 °C,
1 h, 64%. (b) DBU, THF, reflux, 1.5 h, 53%. (c) HCl, THF, reflux, 16 h, 76%
(racemic mixture). (d) LiAlH4, AlCl3, THF, 0 °C, 40 min; 2. PhCHvO,
NaBH(OAc)3, CH2Cl2, rt, 1 h, 36%.
Since the hydrogenolytic cleavage of the endocyclic benzyl-
N-bond appeared to be a general problem associated with the
2-benzazepine ring system, the chiral auxiliary should be
removed by hydrolysis of the enamide 19 43 (Scheme 6). Thus,
reaction of (3S)-11 with SOCl2 led to the chloride 18, which
yielded the enamide 19 upon treatment with DBU in refluxing
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the proton in α-position to the cyano moiety of 18 or 19
leading to racemization.
Next the allyl derivative (3S)-12 should be transformed into
enantiomerically pure tetrahydro-2-benzazepines. The tertiary
amine 22 was obtained by reduction of the lactam group of
(3S)-12 with AlH3. Reaction of the 2-benzazepine 22 with H2
and Pd/C in methanol again led to cleavage of the endocyclic
benzyl-N-bond (Scheme 7). According to LC-MS data the sec-
ondary amine 23 is the main product still bearing the
2-hydroxy-1-phenylethyl residue originating from the chiral
auxiliary. The same result was obtained upon hydrogenolysis
of the propyl derivative 25, which was prepared by hydrogen-
ation of the allyl moiety of (3S)-12 and subsequent AlH3
reduction.
Scheme 7 Attempts to remove the chiral auxiliary from the allyl deriva-
tive (3S)-12 hydrogenolytically. Reagents and reaction conditions: (a)
LiAlH4, AlCl3, THF, 0 °C, 30 min, rt, 30 min, 54%. (b) H2 (1 bar), Pd/C,
CH3OH, rt, 30 min, (c) H2 (5 bar), Pd/C, CH3OH, rt, 30 min, 99%. (d)
LiAlH4, AlCl3, THF, 0 °C, 1 h, 82%. The enantiomers ent-22 and ent-25
were prepared in the same manner starting from (S)-phenylglycinol.
It can be concluded that during hydrogenolysis the endo-
cyclic benzyl-N-bond of the prepared tetrahydro-2-benz-
azepines 15, 22 and 25 is at least as reactive as the exocyclic
benzyl-N-bond towards the chiral auxiliary.
The conversion of (3S)-12 into an enamide failed, probably
due to the reactivity of the allyl moiety in 3-position. Therefore
the propyl derivative 24 was reacted with SOCl2 to give the
chloro derivative 26, which was treated with LDA at −78 °C to
produce the enamide 27. In contrast to the cyano derivatives
18/19, the strong base LDA can be used in this case, since the
acidity of the proton at the center of chirality in 3-position is
very low. Hydrolysis of the enamide 27 with 20% HCl in
boiling Et2O led to the secondary amide 28 in 95% yield
(Scheme 8).
Finally the lactam 28 was reduced with AlH3 to afford the
secondary amine 29. During work-up the high volatility of the
amine 29 has to be taken into account; in particular, the
removal of the solvents has to be performed very carefully. In
the last step the secondary amine 29 was reductively alkylated
with benzaldehyde or cyclohexanecarbaldehyde and NaBH-
(OAc)3 to give the tertiary amines 30a and 30b. The benzyl and
cyclohexylmethyl moieties were selected, since potent σ1
ligands often contain these N-substituents.
THF. Then aqueous HCl in refluxing THF converted the
enamide 19 into the secondary lactam 20 (76% yield) together
with acetophenone. After selective AlH3 reduction of the nitrile
20, reductive alkylation of the resulting primary amine with
benzaldehyde and NaBH(OAc)3 provided the dibenzylamine
21. Reaction of 20 with AlH3 reduced chemoselectively the
cyano moiety but not the lactam function, which is probably
due to anion formation by fast deprotonation of the secondary
amide.
The dibenzylamine 21 was easily isolated in pure form and
subsequently its enantiomeric purity was analyzed. Recording
of the optical rotation even at different wavelengths led to a
specific rotation close to 0.0. A chiral HPLC showed two peaks
in the ratio 1 : 1 indicating complete racemization. Analyzing
the reaction sequence starting with (3S)-11 revealed that the
racemization took place during the reaction of the nitrile 18
with the base DBU. Obviously, the base DBU is able to remove
Scheme 8 Conversion of the propyl derivative 24 into the σ1 ligands 30. Reagents and reaction conditions: (a) SOCl2, THF, 0 °C, 0.5 h. (b) LDA, THF,
−78 °C, 1.5 h, 34% (over two steps). (c) HCl, H2O, Et2O, 38 °C, 4.5 h, 95%. (d) LiAlH4, AlCl3, THF, 0 °C, 1 h, 100%. (e) PhCHvO or C6H11CHvO, NaBH
(OAc)3, CH2Cl2, rt, 4–8 h, 31% (30a), 45% (30b). The enantiomers ent-30a and ent-30b were prepared in the same manner starting from
(S)-phenylglycinol.
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Compounds with a basic amino group should be tested κ-opioid receptors and the phencyclidine (PCP) and ifenprodil
pharmacologically. For this purpose the enantiomers ent-15, binding sites of the NMDA receptor was also included in this
ent-22, ent-25, ent-30a and ent-30b were prepared as described study. The affinity towards the above mentioned receptors was
above using (S)-phenylglycinol as a chiral auxiliary.
determined in competition experiments using radioligands
With the pairs of enantiomers 30a/ent-30a and 30b/ent-30b with high affinity and selectivity for the respective receptor.
in hand a chiral HPLC system was established to prove the The following radioligands were used: [3H]-(+)-pentazocine
enantiomeric purity of the ligands. One column alone did not (σ1),48,49 [3H]ditolylguanidine (σ2),48,49 [3H]-U-69593 (κ),50 [3H]-
lead to a sufficient separation of the enantiomers. Therefore, (+)-MK-801 (PCP binding site)51,52 and [3H]ifenprodil (ifen-
two columns, a Chiralcel OD® and a ChiralPak IB® column, prodil binding site).53,54 The results of the receptor binding
were employed sequentially. Since compounds 30 are rather studies are summarized in Table 1.
lipophilic,
a
rather lipophilic mobile phase (isohexane :
The basic tetrahydro-2-benzazepines show only very low
isopropanol 99 : 1) was used to achieve a separation of both affinity towards σ1, σ2 and κ-opioid receptors as well as the
pairs of enantiomers, allowing the determination of the ratio PCP and ifenprodil binding site of the NMDA receptor. There-
of enantiomers. Analysis of the products revealed the existence fore the reduction of the radioligand binding (in %) in the
of only small amounts of the corresponding enantiomers in presence of 1 µM of the test compound is given for most of the
the samples: 30a (13%), ent-30a (1.7%), 30b (3.6%), and ent- compounds. Since this value is below 50%, the IC50-value of
30b (2.5%). The benzyl derivative 30a was the first compound the test compounds is higher than 1 µM, indicating low inter-
of this series. For its preparation several conditions were actions. The only exception is the (S)-configured cyclohexyl-
explored until optimal conditions had been found. The par- methyl derivative ent-30b with a σ1 affinity of 407 nM.
ticular sample of 30a containing a rather high amount of its However, this σ1 affinity is also close to 1 µM indicating
enantiomer resulted from a non-optimized reaction sequence.
moderate σ1 affinity.
Pharmacophore models for σ1 and σ2 receptor ligands are
characterized by a basic amino group flanked by two lipophilic
moieties. The distances of these lipophilic moieties towards
the basic amino group differ considerably: the shorter distance
is in the range of 2.5–4 Å (σ1, σ2) and the longer distance in
the range of 6–10 Å (σ1) and 11.6–13.6 Å (σ2).25,55 In the case of
the tetrahydro-2-benzazepines of this work the distances of the
lipophilic phenyl moieties towards the central basic amino
3. Receptor affinity
The affinity of basic tetrahydro-2-benzazepines towards σ1 and
σ2 receptors was investigated. Since ligands for σ, κ-opioid and
NMDA receptors are often very similar differing only in an
N-substituent or the configuration,44–47 the affinity towards
Table 1 Affinities of tetrahydro-2-benzazepines towards various receptors
Ki SEMa (nM)
σ1
Compd
R1
R2
σ2
PCP
GluN2B
κ-Opioid
15
ent-15
22
ent-22
25
ent-25
30a
ent-30a
30b
ent-30b
(+)-Pentazocine
Haloperidol
Di-o-tolylguanidine
(+)-MK-801
Ifenprodil
CH2–pyr
CH2–pyr
PhCHCH2OH
PhCHCH2OH
PhCHCH2OH
PhCHCH2OH
PhCHCH2OH
PhCHCH2OH
CH2Ph
CH2Ph
CH2C6H11
CH2C6H11
28%
0%
0%
18%
9%
10%
2%
0%
11%
3%
0%
2%
33%
—
78 2.3
58 18
—
14%
26%
21%
21%
24%
40%
8%
11%
0%
0%
—
—
—
2.8 1.8
—
31%
24%
14%
0%
7%
0%
15%
18%
—
—
—
—
—
—
—
—
—
—
—
—
—
7.3 0.5
CH2CHvCH2
CH2CHvCH2
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
0%
27%
44%
17%
48%
48%
407 nM
5.7 2.2
6.3 1.6
89 29
—
8%
20%
23%
26%
—
—
—
—
10 0.7
—
—
—
—
—
Naloxone
—
a Most of the compounds of this series show rather low affinities. Therefore the radioligand displacement at a test compound concentration of
1 µM is given in %.
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group are identical and rather short (3.7 Å). It is postulated MicroTof (Bruker Daltonics, Bremen), calibration with sodium
that one distance is too short to bring the lipophilic substitu- formate clusters before measurement. Microwave apparatus:
ent into the corresponding binding pocket of the σ receptors. CEM Discover LabMate Synthesiser, single mode cavity;
The high σ1 affinity of the analogous tetrahydro-2-benz- Discover-PC-software (CEM Corporation, NC); reactions
azepines 1a and 1b (Fig. 1) is explained by the lipophilic were performed in glass vessels (capacity 10 mL) sealed with
benzyl moiety in 5-position occupying the more distal second the corresponding pressure adaptor; pressure was controlled
hydrophobic region of the σ1 receptor. The distance between using a piezo-electric pressure sensor; the temperature of the
the rather small allyl and propyl moieties in 3-position of the vessel contents was monitored using an external infrared
tetrahydro-2-benzazepines 22, 25 and 30 and the basic amino temperature control. Alternatively an 80 mL open vessel was
moiety appears to be too short to result in high binding used.
energy.
5.2. HPLC methods
5.2.1. Method 1: purity of compounds. Merck Hitachi
equipment; UV detector: L-7400; autosampler: L-7200; pump:
4. Conclusion
L-7100; degasser: L-7614; method A: column: LiChrospher® 60
Herein a novel asymmetric synthesis of enantiomerically pure RP-select B (5 µm), 250-4 mm cartridge; flow rate: 1.00 mL
3-substituted tetrahydro-2-benzazepines is reported. The key min−1; injection volume: 5.0 µL; detection λ = 210 nm; sol-
building block cis-10 was prepared stereoselectively in a five vents: A: water with 0.05% (v/v) trifluoroacetic acid; B: aceto-
step synthesis starting with 1-bromo-2-iodobenzene. The nitrile with 0.05% (v/v) trifluoroacetic acid: gradient elution
diastereoselective ring opening of the tricyclic oxazolidine cis- (A %): 0–4 min: 90%, 4–29 min: gradient from 90% to 0%,
10 with nucleophiles was investigated very carefully. Me3SiCN 29–31 min: 0%, 31–31.5 min: gradient from 0% to 90%,
and allylSiMe3 were found to open the oxazolidine ring in the 31.5–40 min: 90%.
presence of an excess of TiCl4. The reaction with allylSiMe3 led
5.2.2. Method 2: purity of compounds. The same appar-
to high diastereoselectivity (93 : 7), whereas moderate atus as that described for method 1, but with another gradient
a
diastereoselectivity (70 : 30) was observed with Me3SICN. The for the elution of the compounds, was used: solvents: A: water
removal of the chiral auxiliary turned out to be problematic with 0.05% (v/v) trifluoroacetic acid; B: acetonitrile with 0.05%
due to the fast hydrogenolytic cleavage of the endocyclic (v/v) trifluoroacetic acid: gradient elution (A %): 0–1 min: 80%,
benzyl-N-bond. Therefore the N-substituent was removed via a 1–22 min: gradient from 80% to 0%, 22–31 min: 0%,
three step enamide hydrolysis sequence. In receptor binding 31–31.5 min: gradient from 0% to 80%, 31.5–40 min: 80%.
studies with radioligands only the (S)-configured cyclohexyl-
5.2.3. Method 3: ratio of diastereomers (3S)-12 : (3R)-
methyl substituted 2-benzazepine ent-30b showed moderate σ1 12. Merck Hitachi equipment; UV-DAD detector: L-7455; rheo-
affinity (Ki = 407 nM). It is assumed that the second hydro- dyne 7125; pump: L6200A; data acquisition: HSM-software;
phobic pocket of the σ receptors cannot be addressed by the column: Daicel Chiralpak AD-H, 5 µm, 250 mm/4.6 mm; guard
3-substituted 2-benzazepines due to too short distances column: Daicel Chiralpak AD-H, 5 µm, 10 mm/4 mm; flow
between the lipophilic structural elements.
rate: 1.00 mL min−1; injection: volume: 7.0 µL; detection: λ =
210 nm; eluent: isohexane/isopropanol/ethanol = 80/8/12.
5.2.4. Method 4: preparative HPLC for the purification of
30b and ent-30b. Merck Hitachi equipment; UV detector:
L-7400; autosampler: L-7200; pump: L-6200A; data acquisition:
HSM-software; column: Phenomenex Gemini, 5 µm, C18, 110A,
5. Experimental part
5.1. General
Unless otherwise noted, moisture sensitive reactions were con- 250 mm/21.2 mm; guard column: Phenomenex Gemini, 5 µm,
ducted under dry nitrogen. THF was dried with sodium/benzo- C18, 110A, 50 mm/21.2 mm; flow rate: 9.99 mL min−1; injec-
phenone and was freshly distilled before use. Thin layer tion: volume: 180 µL (THF); detection λ = 210 nm; eluent:
chromatography (tlc): silica gel 60 F254 plates (Merck). Flash acetonitrile/water/NH3 conc. = 90/9.5/0.5.
chromatography (fc): silica gel 60, 40–64 µm (Merck); parenth-
5.2.5. Method 5: chiral HPLC to determine the enantio-
eses include: diameter of the column, length of column, frac- meric purity of dibenzylamine 21. Merck Hitachi equipment;
tion size, eluent, Rf value. Melting point: melting point UV-DAD detector: L-7455; rheodyne 7125; pump: L-6200A; data
apparatus SMP 3 (Stuart Scientific), uncorrected. IR: IR spectro- acquisition: HSM-software; column: Daicel Chiralpak AD-H,
photometer 480Plus FT-ATR-IR (Jasco). 1H NMR (400 MHz), 5 µm, 250 mm/4.6 mm; guard column: Daicel Chiralpak AD-H,
13C NMR (100 MHz): Mercury plus 400 spectrometer (Varian); 5 µm, 10 mm/4 mm; flow rate: 1.00 mL min−1; injection:
δ in ppm related to tetramethylsilane; coupling constants are volume: 5.0 µL; detection λ = 210 nm; eluent: isohexane/isopro-
given with 0.5 Hz resolution. Optical rotation: Polarimeter 341 panol = 9/1.
(PerkinElmer); 1.0 dm tube; concentration c in g per 100 mL;
5.2.6. Method 6: chiral HPLC to determine the enantio-
T = 20 °C; wavelength 589 nm (D-line of Na light); the unit of meric purity 2-benzazepines 30. Merck Hitachi equipment;
the specific rotation ([α]TD grad mL dm−1 g−1) is omitted for UV-DAD detector: L-7455; rheodyne 7125; pump: L-6200A; data
clarity. MS: EI = electron impact, ESI = electrospray ionization: acquisition: HSM-software; column 1: Daicel Chiralcel OD,
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10 µm, 250 mm/4.6 mm; guard column: Daicel Chiralpak IB, (R)-(−)-2-phenylglycinol (0.185 g, 1.35 mmol) was added.
5 µm, 10 mm/4 mm; column 2: Daicel Chiralpak IB, 5 µm, The reaction mixture was stirred at rt for 5.25 h and then
250 mm/4.6 mm; flow rate: 1.00 mL min−1; injection: volume: heated to reflux for 15 h. Under vigorous stirring the mixture
3.0 µL; detection λ = 210 nm; eluent: isohexane/isopropanol = was cooled down to rt, and then HCl (1 M) was added until
99/1.
no more precipitate was formed. The precipitate was filtered
off, washed thoroughly with CH2Cl2 and the layers of the
filtrate were separated. The organic layer was washed several
5.3. General procedures
5.3.1. General procedure 1: preparation of 0.67 M (AlH3) times with HCl and the precipitate was filtered off again. The
solution. Under N2, LiAlH4 (1 M, in THF, 5 mL) was trans- combined acidic aqueous layers were reextracted with CH2Cl2.
ferred into a dried Schlenk tube and cooled to 0 °C. HCl (2 M, The combined organic layers were washed several times
in Et2O, 2.5 mL) was added dropwise and the resulting clear with NaOH (2 M). The combined basic aqueous layers were
solution was stirred for 1 h at 0 °C.
reextracted with CH2Cl2 and then the combined organic
5.3.2. General procedure 2: preparation of 0.36 M (AlH3) layers were washed with brine (1×), dried (Na2SO4) and filtered.
solution. Under N2, AlCl3 (0.239 g, 1.80 mmol) was dissolved Silica gel was added and the solvent was removed under
in THF (14.5 mL) at 0 °C. LiAlH4 (1 M, in THF, 5.4 mL, reduced pressure. The residue was purified by fc (∅ = 3 cm, h =
5.4 mmol) was carefully added to the solution of AlCl3 under 14 cm, cyclohexane : ethyl acetate = 1 : 1, V = 14 mL, Rf = 0.31
stirring. The resulting clear solution was slowly brought to rt (cyclohexane : ethyl acetate
= 1 : 3)). Colorless solid, mp
and stirred for 20 min.
94.5 °C, 0.331 g (74%). C20H23NO4, Mr = 341.4. MS (EI): m/z
[%] = 341 (M, 8), 310 (M − CH2OH, 58), 117 (ArC3H5,
100), 73 (CH(OCH2)2, 87). 1H NMR (CDCl3): δ [ppm] =
5.4. Synthetic procedures
5.4.1 2-[2-(1,3-Dioxolan-2-yl)ethyl]benzoic acid (8). Under 1.93–2.07 (m, 2H, ArCH2CH2CH), 2.92 (t, J = 8.0 Hz, 2H,
N2, aryl bromide 7 (7.78 g, 30.27 mmol) was dissolved in THF ArCH2CH2CH), 3.05 (s, broad, 1H, CH2OH), 3.76–3.85 (m, 2H,
(151 mL) and cooled to −80 °C. n-BuLi (1.6 M in hexanes, CH(OCH2)2), 3.89–4.05 (m, 4H, CH(OCH2)2, CH2OH), 4.83 (t,
19.0 mL, 31.27 mmol) was added (1 mL min−1) and the result- J = 4.6 Hz, 1H, ArCH2CH2CH), 5.25–5.29 (m, 1H, NHCHPh),
ing clear solution was stirred for 10 min at −80 °C. CO2 gas 6.65 (d, 7.3 Hz, 1H, NH), 7.19–7.40 (m, 9H, Ar–H). IR (neat):
was dried carefully by bubbling through concentrated H2SO4
ν ] = 3291 (OH/NH), 1634 (OvCNHR, amide I),
[cm−1
before it was passed into the reaction mixture via a glass tube 1525 (OvCNHR, amide II). Specific rotation: [α]2D0 = −8.2
(inner diameter = 0.5 cm) for 75 min. It was essential to (c = 1.60; CH2Cl2). HPLC (method 1): tR = 15.58 min, purity
prevent plugging of the glass pipe and to install a Bunsen 96.1%.
valve! A colour change from yellow to red to colorless occurred
5.4.3 2-[2-(1,3-Dioxolan-2-yl)ethyl]-N-[(1S)-2-hydroxy-1-phenyl-
during this procedure. After removing the gas inlet, the reac- ethyl]benzamide (ent-9). As described for the synthesis of
tion mixture was brought to −5 °C and water was added until a amide 9, benzoic acid 8 (5.56 g, 25.0 mmol) was dissolved in
separation of layers occurred. Aqueous NaOH (2 M) was added CH2Cl2 (275 mL) and treated with HOBt·H2O (3.39 g,
until a pH value of 11–14 and the mixture was extracted with 25.0 mmol), EDC·HCl (4.79 g, 25 mmol) and (S)-(+)-2-phenyl-
Et2O to remove the starting material and byproducts. The glycinol (3.77 g, 27.5 mmol). After work-up, the residue was
benzoic acid 72 was precipitated from the aqueous layer by purified by fc (∅ = 8 cm, h = 10 cm, cyclohexane : ethyl acetate
addition of aqueous HCl (1 M). To prevent cleavage of the = 7 : 3, V = 65 mL, Rf = 0.31 (cyclohexane : ethyl acetate = 1 : 3)).
acetal, the amount of HCl was controlled. The aqueous layer Colorless solid, yield 6.9 g (80%). Specific rotation: [α]2D0 = +8.5
was extracted several times with Et2O, the combined organic (c = 0.62; CH2Cl2). HPLC (method 1): tR = 15.60 min, purity
layers were dried (Na2SO4) and the solvent and valeric acid 92.1%.
were removed under reduced pressure. Colourless solid, mp
5.4.4 (3R,11aR)-3-Phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo-
71–72 °C, yield 6.26 g (93%). C12H14O4, Mr = 222.2. MS (EI): [3,2-b][2]benzazepin-5(10H)-one (cis-10) and (3R,11aS)-3-
m/z [%] = 222 (M, 18), 177 (M − CO2, 24), 149 (M − CH- phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[3,2-b][2]benzazepin-5-
(OCH2)2, 100), 73 (CH(OCH2)2, 88). 1H NMR (CDCl3): δ [ppm] = (10H)-one (trans-10). HClconc. (8.39 g) was added to an ice-
1.93–1.98 (m, 2H, ArCH2CH2CH), 3.08–3.12 (m, 2H, ArCH2), cooled solution of benzamide 9 (5.03 g, 14.7 mmol) in CHCl3
3.73–3.99 (m, 4H, CH(OCH2)2), 4.88 (t, J = 4.9 Hz, 1H, (590 mL). The solution was vigorously stirred overnight at rt.
ArCH2CH2CH), 7.21–7.27 (m, 2H, Ar–H), 7.41 (t, J = 7.5 Hz, 1H, The reaction mixture was added to a saturated aqueous solu-
4-Harom), 7.98 (dd, J = 7.8/1.3 Hz, 1H, 6-Harom). A signal for the tion of NaHCO3. After the formation of CO2 had finished, the
CO2H proton is not seen in the spectrum. IR (neat): ν [cm−1] = aqueous layer was separated and extracted with CHCl3 (2×).
2985 (OH), 1675 (CvO). HPLC (method 1): tR = 14.26 min, The organic layer was washed with water (1×) and a saturated
purity 86.3%.
aqueous solution of NaCl resulting in a clear, colourless
5.4.2 2-[2-(1,3-Dioxolan-2-yl)ethyl]-N-[(1R)-2-hydroxy-1-phenyl- organic layer. The combined aqueous layers were reextracted
ethyl]benzamide (9). Under N2, benzoic acid 8 (0.300 g, with CHCl3. The combined organic layers were dried (Na2SO4),
1.35 mmol) was dissolved in CH2Cl2 (15 mL). HOBt·H2O filtered and the solvent was removed under reduced pressure.
(0.182 g, 1.35 mmol) and EDC·HCl (0.260 g, 1.35 mmol) The residue was purified by fc (∅ = 6 cm, h = 17, cyclohexane :
were added and the mixture was stirred for 5 min, and then ethyl acetate = 7 : 3, V = 30 mL).
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cis-10 (Rf = 0.25): colorless solid, mp 128 °C, yield 3.12 g (55–60 °C, 60 W, ramp 5 min, hold 1 min). The black reaction
(76%). C18H17NO2, Mr = 279.3. MS (EI): m/z [%] = 279 (M, 90), mixture was slowly transferred into a separation funnel filled
159 (M − PhCHCH2O, 10), 104 (PhCHCH2, 100). 1H NMR with cold water (50 mL). The aqueous layer was extracted
(CDCl3): δ [ppm] = 2.10–2.20 (m, 1H, ArCH2CH2CH), 2.27–2.38 several times with CH2Cl2. The organic layers where combined,
(tt, J = 12.3/6.9 Hz, 1H, ArCH2CH2CH), 2.67–2.76 (ddd, J = washed with water, dried (Na2SO4) and the solvent was
13.9/6.9/1.0 Hz, 1H, ArCH2CH2CH), 2.94–3.04 (m, 1H, removed under reduced pressure. The residue was purified by
ArCH2CH2CH), 3.94 (d, J = 8.8 Hz, 1H, OCH2CH), 4.40 (dd, J = fc (∅ = 4 cm, h = 15 cm, cyclohexane : ethyl acetate = 7 : 3, after
8.8/5.7 Hz, 1H, OCH2CH), 5.22 (d, J = 5.7 Hz, 1H, OCH2CH), cis-10 and (3R)-11 had eluted, cyclohexane : ethyl acetate = 1 : 3,
5.27 (dd, J = 9.5/5.7 Hz, 1H, ArCH2CH2CH), 7.12–7.16 (d, J = V = 25 mL).
7.4 Hz, 1H, 9-Harom., 7.17–7.34 (m, 7H, Ar–H), 7.49–7.53 (dd,
(3S)-11 (Rf = 0.06, cyclohexane : ethyl acetate = 7 : 3): color-
J = 7.6/1.3 Hz, 1H, 6-Harom.). 13C NMR (CDCl3): δ (ppm) = 29.4 less crystals, mp 164 °C, yield 0.291 g (44%). C19H18N2O2, Mr =
1
(C-10), 35.3 (C-11), 60.1 (C-3), 72.6 (C-2), 88.7 (C-11a), 126.2 306.4. MS (EI): m/z [%] = 306 (M, 2), 275 (M − CH2OH, 20). H
(C–Ar), 127.4 (C–Ar), 127.8 (C–Ar), 128.8 (C–Ar), 128.9 (C–Ar), NMR (CDCl3): δ [ppm] = 2.11–2.19 (m, 1H, ArCH2CH2CH),
131.4 (C–Ar), 136.3 (C–Arq), 137.6 (C–Arq), 140.9 (C–Arq), 166.0 2.53–2.60 (m, 1H, ArCH2CH2CH), 2.66 (dd, J = 13.8/6.2 Hz, 1H,
(CvO). IR (neat): ν [cm−1] = 1645 (OvCNR2). Specific rotation: ArCH2CH2CH), 2.94–3.02 (m, 2H, ArCH2CH2CH and
[α]2D0 = +100 (c = 1.00; CH2Cl2). HPLC (method 1): tR
18.20 min, purity 99.3%.
=
CHCH2OH), 4.07–4.13 (m, 1H, CHCH2OH), 4.28 (dd, J = 11.7/
4.4 Hz, 1H, CHCH2OH), 4.39 (dd, J = 11.7/1.8 Hz, 1H,
trans-10 (Rf = 0.40): pale yellow, viscous oil, yield 0.492 g ArCH2CH2CH), 6.12–6.20 (s, broad, 1H, CHCH2OH), 7.14–7.6
(10%). C18H17NO2, Mr = 279.3. MS (EI): m/z [%] = 279 (M, 100), (m, 1H, 6-Harom.), 7.28–7.47 (m, 7H, Ar–H), 7.74–7.77 (m, 1H,
1
120 (PhCHCH2O, 90), 104 (PhCHCH2, 86). H NMR (CDCl3): δ 9-Harom.). 13C NMR (CDCl3): δ (ppm) = 29.8 (C-4), 36.3 (C-5),
[ppm] = 2.25 (dddd, J = 13.0/9.3/7.9/1.4 Hz, 1H, ArCH2CH2CH), 60.6 (Ph–CHN), 73.0 (CH2OH), 89.1 (C-3), 118.2 (CN), 126.6 (C–
2.49 (tt, J = 12.7/6.2 Hz, 1H, ArCH2CH2CH), 2.75 (dd, J = 13.0/ Ar), 127.3 (C–Ar), 127.8 (C–Ar), 128.2 (C–Ar), 128.3 (C–Ar),
6.6 Hz, 1H, ArCH2CH2CH), 3.14 (td, 13.2/7.9 Hz, 1H, 128.3 (C–Ar), 128.7 (C–Ar), 129.0 (C–Ar), 129.1 (C–Ar), 129.2 (C–
ArCH2CH2CH), 4.21–4.27 (m, 2H, OCH2CH), 5.05 (dd, J = 9.3/ Ar), 129.3 (C–Ar), 129.4 (C–Ar), 129.6 (C–Ar), 129.7 (C–Ar),
5.7 Hz, 1H, ArCH2CH2CH), 5.47 (dd, J = 5.6/4.0 Hz, 1H, 129.8 (C–Ar), 130.0 (C–Ar), 130.2 (C–Ar), 131.8 (C–Ar), 132.3 (C–
OCH2CH), 7.18–7.40 (m, 7H, Ar–H), 7.49 (d, J = 8.1 Hz, 1H, Ar), 132.8 (C–Ar), 136.7 (C–Arq), 138.1 (C–Arq), 141.0 (C–Arq),
9-Harom.), 7.76 (d, J = 7.6 Hz, 1H, 6-Harom.). 13C NMR (CDCl3): δ 166.5 (CvO). IR (neat): ν [cm−1] = 2249 (CN), 1624 (OvCNR2).
(ppm) = 29.9 (C-10), 36.1 (C-11), 59.8 (C-3), 73.7 (C-2), 89.5 Specific rotation: [α]2D0 = −46 (c = 1.00; CH2Cl2). HPLC (method
(C-11a), 126.9 (C–Ar), 127.4 (C–Ar), 127.9 (C–Ar), 128.9 (C–Ar), 1): tR = 16.59, purity 99.7%.
129.3 (C–Ar), 129.6 (C–Ar), 131.8 (C–Ar), 135.0 (C–Arq), 138.9
(3R)-11 (Rf = 0.12, cyclohexane : ethyl acetate = 7 : 3): color-
(C–Arq), 140.6 (C–Arq), 168.1 (CvO). IR (neat): ν [cm−1] = 1645 less solid, mp 182–184 °C, yield 0.251 g (19%). C19H18N2O2, Mr
(OvCNR2). Specific rotation: [α]2D0 −164 (c = 0.14; CH2Cl2). = 306.4. MS (ESI): m/z [%] = 307 (M + H, 100). 1H NMR (CDCl3):
HPLC (method 1): tR = 18.90 min, purity 97.4%.
δ [ppm] = 1.57–1.69 (m, 1H, ArCH2CH2CH), 1.96 (tdd, J = 12.5/
5.4.5 (3S,11aS)-3-Phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo- 6.3/1.0 Hz, 1H, ArCH2CH2CH), 2.44 (s, 1H, CHCH2OH), 2.67
[3,2-b][2]benzazepin-5(10H)-one (ent-cis-10) and (3S,11aR)-3- (ddd, J = 13.8/6.3/1.6 Hz, 1H, ArCH2CH2CH), 2.91 (td, J = 13.7/
phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[3,2-b][2]benzazepin-5- 7.4 H, 1H, ArCH2CH2CH), 4.28–4.40 (m, 2H, CHCH2OH), 4.62
(10H)-one (ent-trans-10). As described for the synthesis of cis- (dd, J = 8.1/1.1 Hz, 1H, ArCH2CH2CH), 5.98 (t, J = 4.9 Hz, 1H,
10 and trans-10, benzamide ent-9 (5.023 g, 14.71 mmol) was CHCH2OH), 7.20 (m, 1H, ArH), 7.36–7.56 (m, 7H, ArH), 7.80
treated with HClconc. (8.39 g) in CHCl3 (588 mL). After work-up (d, J = 7.2/1.9 Hz, 1H, 9-Harom.). 13C NMR (CDCl3): δ (ppm) =
the residue was purified by fc (∅ = 5 cm, h = 17 cm, 29.3 (C-5), 35.6 (C-4), 43.9 (C-3), 58.8 (PhCHN), 62.5 (CH2OH),
cyclohexane : ethyl acetate = 7 : 3, V = 30 mL).
118.2 (CN), 128.3 (C–Ar), 128.6 (C–Ar), 128.8 (C–Ar), 129.3 (C–
ent-cis-10 (Rf = 0.25): colorless solid, yield 2.93 (71%). Ar), 130.2 (C–Ar), 132.5 (C–Ar), 134.8 (C–Arq), 136.3 (C–Arq),
Specific rotation: [α]2D0 = −103 (c = 1.00; CH2Cl2). HPLC 136.9 (C–Arq), 171.8 (CvO). IR (neat): ν [cm−1] = 2251 (–CN),
(method 2): tR = 15.85 min, purity 99.6%.
1639 (OvCNR2). Specific rotation: [α]2D0 = −17 (c = 0.10;
ent-trans-10 (Rf = 0.40): pale yellow, viscous oil, yield 0.216 g CH2Cl2). HPLC (method 1): tR = 16.95 min, purity 99.7%.
(6.3%). Specific rotation: [α]2D0 = +163 (c = 0.14; CH2Cl2). HPLC
(method 1): tR = 18.59 min, purity 98.7%.
5.4.7 (3R)-2-[(1S)-2-Hydroxy-1-phenylethyl]-1-oxo-2,3,4,5-
tetrahydro-1H-2-benzazepine-3-carbonitrile (ent-(3S)-11). As
5.4.6 (3S)-2-[(1R)-2-Hydroxy-1-phenylethyl]-1-oxo-2,3,4,5- described for the synthesis of (3S)-11/(3R)-11, ent-cis-10
tetrahydro-1H-2-benzazepine-3-carbonitrile ((3S)-11) and (3R)- (0.600 g, 2.15 mmol) was treated with Me3SiCN (4 mL, 3.16 g,
2-[(1R)-2-hydroxy-1-phenylethyl]-1-oxo-2,3,4,5-tetrahydro-1H- 31.0 mmol) and TiCl4 (1 M in CH2Cl2, 17 mL, 17.0 mmol) in
2-benzazepine-3-carbonitrile ((3R)-11). A solution of cis-10 CH2Cl2. After work-up, the residue was purified by fc (∅ =
(0.600 g, 2.15 mmol) in CH2Cl2 (17 mL) was transferred into 4 cm, h = 15 cm, cyclohexane : ethyl acetate = 7 : 3, V = 25 mL,
an 80 mL microwave reaction vessel and purged with N2. Rf
= 0.06 (cyclohexane : ethyl acetate = 7 : 3)). Colorless
Me3SiCN (4 mL, 3.16 g, 31 mmol) and TiCl4 (1 M in CH2Cl2, solid, yield 0.301 g (46%). Specific rotation: [α]2D0 = +45
17 mL, 17.0 mmol) were added. After purging again with N2, (c = 1.00; CH2Cl2). HPLC (method 2): tR = 13.28 min, purity
the vessel was sealed and reacted in the microwave apparatus 99.6%.
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5.4.8 (3S)-2-[(1R)-2-Hydroxy-1-phenylethyl]-3-(prop-2-en-1- 18.2 mmol) and TiCl4 (1 M in CH2Cl2, 6.4 mL, 6.4 mmol)
yl)-2,3,4,5-tetrahydro-2-benzazepin-1-one ((3S)-12) and (3R)-2- in CH2Cl2 (6 mL). After work-up, the residue was purified by fc
[(1R)-2-hydroxy-1-phenylethyl]-3-(prop-2-en-1-yl)-2,3,4,5-tetra- (∅ = 3 cm, h = 16 cm, hexane : ethyl acetate = 8 : 2, V = 25 mL,
hydro-2-benzazepin-1-one ((3R)-12).34 Under N2 cis-10 (0.30 g, Rf = 0.08 (cyclohexane : ethyl acetate = 7 : 3)). Colorless solid,
1.07 mmol) was dissolved in CH2Cl2 (6 mL). Me3Siallyl yield 0.202 g (59%). Specific rotation: [α]2D0 = −7.2 (c = 1.04;
(2.9 mL, 2.08 g, 18.2 mmol) and TiCl4 (1 M in CH2Cl2, 6.4 mL, CH2Cl2). HPLC (method 2): tR = 18.33 min, purity 99.3%.
6.4 mmol) were added. After purging with N2, the 80 mL-reac- HPLC (method 3): tR = 16.77 min, purity 99.8%. The diastereo-
tion vessel was sealed and reacted in the microwave apparatus mer ent-(3R)-12 was not isolated.
(70 °C, 80 W, ramp 5 min, hold 10 min). The dark orange
5.4.10 (2R)-2-[(3S)-3-(Aminomethyl)-2,3,4,5-tetrahydro-1H-2-
colored reaction mixture was slowly transferred into a separ- benzazepin-2-yl]-2-phenylethanol (14). A solution of nitrile
ation funnel filled with ice-cold water (50 mL). The layers were (3S)-11 (0.10 g, 0.326 mmol) in THF (2.6 mL) was added drop-
separated and the aqueous layer was extracted several times wise to a freshly prepared and cooled (0 °C) AlH3 solution
with CH2Cl2. The combined organic layers were washed with (0.67 M, 2.9 mL, 1.96 mmol, prepared according to general
water, dried (Na2SO4), filtered and the solvent was removed procedure 1) and the mixture was stirred for 30 min at 0 °C. A
under reduced pressure. The residue was purified by fc (∅ = few drops of a solution of glycerol/water (1/1) were added until
3 cm, h = 16 cm, n-hexane : ethyl acetate = 8 : 2, V = 25 mL).
(3S)-12 (Rf = 0.08, cyclohexane : ethyl acetate 7 : 3): colorless ated, washed with Et2O, dissolved in NaOH (43%) and the
needles, mp 156 °C, yield 0.222 g (64%). C21H23NO2, Mr aqueous solution was extracted with Et2O. Filtrate and organic
the formation of H2 had ceased. The formed solid was separ-
=
321.4. MS (ESI): m/z [%] = 665 (2M + Na, 100), 322 (M + H, 10). extracts were combined, dried (K2CO3) and concentrated under
MS (EM): m/z = 322.1802 (calcd 322.1801 for C21H23NO2H+ reduced pressure. Without further purification the product
[M + H+]); m/z = 344.1621 (calcd 344.1621 for C21H23NO2Na was used for the synthesis of pyrrolidine 15. Orange colored
[M + Na+]; m/z = 665.3350 (calcd 665.3349 for (C21H23NO2)2Na+ liquid. C19H24N2O, Mr = 296.4. MS (EI): m/z [%] = 266 (M −
1
[2M + Na+]. 1H NMR (D5-nitrobenzene, 110 °C): δ [ppm] = CH2NH2, 63), 146 (2-benzazepine core, 100). H NMR (CDCl3):
1.14–1.24 (m, 2H, CH2CHvCH2), 1.46–1.57 (m, 1H, δ [ppm] = 1.79–1.84 (m, 1H, ArCH2CH2CH), 1.98–2.08 (m, 1H,
ArCH2CH2CH), 1.82–1.93 (m, 1H, ArCH2CH2CH), 2.29–2.38 ArCH2CH2CH), 2.76 (dd, J = 16.0/10.0 Hz, 1H, ArCH2CH2CH),
(m, 1H, ArCH2CH2CH), 2.39–2.40 (m, 1H, CH2OH), 2.63–2.73 2.88 (dd, J = 12.8/3.7 Hz, 1H, CHCH2NH2), 2.97–3.05 (m, 1H,
(m, 1H, ArCH2CH2CH), 3.16–3.24 (m, 1H, ArCH2CH2CH), ArCH2CH2CH), 3.14 (t, J = 11.5 Hz, 1H, CHCH2NH2), 3.4 (d, J =
3.88–3.93 (m, 1H, CHCH2OH), 3.96–4.07 (m, 2H, CHCH2OH 16.2 Hz, 1H, ArCH2N), 3.61–3.65 (m, 2H, PhCHCH2OH and
and CH2CHvCH2), 4.20 (d, J = 10.2 Hz, 1H, CH2CHvCH2), ArCH2CH2CH), 3.72 (t, J = 7.0 Hz, 2H, PhCHCH2OH), 4.15 (d,
4.58–4.65 (m, 1H, CH2CHvCH2), 5.54 (s, broad, 1H, J = 16.0 Hz, 1H, ArCH2N), 6.40 (d, J = 7.4 Hz, 1H 6-Harom),
CHCH2OH), 6.84–7.35 (m, 9H, Ar–H). The correct assignment 7.03–7.10 (m, 2H, Ar–H), 7.16–7.25 (m, 6H, Ar–H). Signals for
of the signals was performed by high temperature COSY the OH- and NH2-protons are not seen in the spectrum. 13C
experiments. IR (neat): ν [cm−1] = 3347 (OH), 1608 (OvCNR2), NMR (CDCl3): δ (ppm) = 29.0 (C-5), 32.0 (C-4), 42.7 (C-3), 48.1
916 (CvCH2). Specific rotation: [α]2D0 = +7.9 (c = 1.04; CH2Cl2). (CH2NH2), 57.9 (PhCHN), 63.6 (CH2OH), 65.8 (C-1), 125.8
HPLC (method 2): tR = 17.97 min, purity 99.6%. HPLC (C–Ar), 127.0 (C–Ar), 127.5 (C–Ar), 128.2 (C–Ar), 128.9 (C–Ar),
(method 3): tR = 10.66 min, purity 98.5%.
129.1 (C–Ar), 130.2 (C–Ar), 138.5 (C–Arq), 141.28 (C–Arq),
(3R)-12 (Rf = 0.10, cyclohexane : ethyl acetate 7 : 3): colorless 141.33 (C–Arq).
resin, yield 0.017 g (5%). C21H23NO2, Mr = 321.4. MS (ESI): m/z
[%] = 665 (2M + Na, 100), 344 (M + Na, 60). H NMR (D5-nitro- 2-benzazepin-2-yl]-2-phenylethanol (ent-14). As described for
5.4.11 (2S)-2-[(3R)-3-(Aminomethyl)-2,3,4,5-tetrahydro-1H-
1
benzene, 100 °C): δ [ppm] = 0.62–0.69 (m, 1H, ArCH2CH2CH), the synthesis of 14 a solution of nitrile ent-(3S)-11 (0.247 g,
0.74, −0.81 (m, 1H, ArCH2CH2CH), 0.83–0.91 (m, 1H, 0.806 mmol) in THF (6.45 mL) was treated with a freshly
CH2CHvCH2), 1.12–1.24 (m, 1H, CH2CHvCH2), 1.57–1.64 (m, prepared AlH3 solution (0.36 M, 16.1 mL, 5.80 mmol, general
1H, ArCH2CH2CH), 1.90–1.98 (m, 1H, ArCH2CH2CH), 2.38 (s, procedure 1). After work-up and removal of the solvent,
1H, CHCH2OH), 2.74–2.81 (m, 1H, ArCH2CH2CH), 3.47–3.55 the residue was directly used for the synthesis of pyrrolidine
(m, 2H, CHCH2OH), 3.94 (d,
CH2CHvCH2), 4.06 (d, J = 10.2 Hz, 1H, cis-CH2CHvCH2),
J
=
17.0 Hz, 1H, trans- ent-15.
5.4.12 (2R)-2-[(3S)-3-(Pyrrolidinomethyl)-2,3,4,5-tetrahydro-
4.71–4.82 (m, 1H, CH2CHvCH2), 5.14 (t, J = 6.4 Hz, 1H, 1H-2-benzazepin-2-yl]-2-phenylethanol (15). Primary amine 14
CHCH2OH), 6.22–6.33 (m, 1H, ArH), 6.44–6.55 (m 4H, ArH), was dissolved in acetonitrile (12 mL), and 1,4-diiodobutane
6.71 (m, 2H, ArH), 6.92 (m, 1H, ArH), 7.23 (s, 1H, ArH). IR (0.402 g, 1.3 mmol) and NaHCO3 (0.193 g, 2.3 mmol) were
(neat): ν [cm−1] = 3377 (O–H), 1611 (OvCNR2), 917 (CvCH2). added. The mixture was heated to reflux for 2 h and stirred
Specific rotation: [α]D20 = −20 (c = 0.29; CH2Cl2). HPLC (method overnight at rt. The solvent was reduced to half volume under
1): tR = 19.17 min, purity 91.9%.
reduced pressure. The mixture was acidified with 1 M HCl. By-
5.4.9 (3R)-2-[(1S)-2-Hydroxy-1-phenylethyl]-3-(prop-2-en-1-yl)- products and excess 1,4-diiodobutane were removed by extrac-
2,3,4,5-tetrahydro-2-benzazepin-1-one (ent-(3S)-12). As des- tion with Et2O. Treatment of the aqueous layer with 2 M NaOH
cribed for the synthesis of (3S)-12/(3R)-12, ent-cis-10 (0.30 g, led to a precipitate, which was extracted several times with
1.07 mmol) was treated with Me3Siallyl (2.9 mL, 2.08 g, Et2O. The organic layer was dried (Na2SO4) and concentrated
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under reduced pressure and the residue was purified by fc (∅ = the solvent was removed under reduced pressure. The residue
2 cm, h = 17 cm, cyclohexane : ethyl acetate : N,N-dimethyl- was purified twice by fc (∅ = 2 cm, h = 15 cm, cyclohexane :
ethanamine = 3 : 1 : 0.04, V = 14 mL, Rf = 0.50). Pale yellow ethyl acetate : dimethylethylamine = 1 : 6 : 0.04, V = 10 mL, Rf =
liquid, which solidified on cooling in the refrigerator, pale 0.30). Colorless oil, yield 18 mg (31%). C23H28Cl2N2O, Mr =
yellow solid, mp: 113–115 °C, yield 56 mg (49%, two steps 419.4. MS (EI): m/z [%] = 418 (M, 6), 84 (pyrrolidinomethyl,
from (3S)-11). C23H30N2O, Mr = 350.5. MS (EI): m/z [%] = 266 100). 1H NMR (CDCl3):
(M − pyrrolidinomethyl), 146 (2-benzazepine core, 100). MS ArCH2CH2CH, CH2N(CH2CH2)2),
δ
[ppm]
=
1.66–1.75 (m, 5H,
1.77–1.86 (m, 1H,
1
(ESI): m/z [%] = 351 (M + H, 100). H NMR (CDCl3): δ [ppm] = ArCH2CH2CH), 2.24 (s, 3H, ArCH3), 2.40–2.50 (m, 5H, CH2N-
1.77 (ddd, J = 14.4/9.1/2.2 Hz, 1H, ArCH2CH2CH), 1.82–1.86 (CH2CH2)2, ArCH2CH2CH), 2.55–2.62 (m, 3H, CH2N(CH2CH2)2,
(m, 4H, N(CH2CH2)2), 1.98 (dddd, J = 12.6/7.4/5.3/2.1 Hz, 1H, 3.50 (s, 2H, HNC(vO)CH2Ar), 3.96–4.05 (m, 1H,
ArCH2CH2CH), 2.33 (dd, J = 12.8/2.6 Hz, 1H, CHCH2N), ArCH2CH2CH), 5.85 (d, J = 6.7 Hz, 1H, HNC(vO)CH2Ar),
2.65–2.71 (m, 2H, N(CH2CH2)2), 2.75–2.78 (m, 2H, 7.06–7.15 (m, 5H, ArH), 7.39–7.41 (m, 2H, ArH). IR (neat):
N(CH2CH2)2), 2.83–2.92 (m, 3H, ArCH2CH2CH and CHCH2N), ν [cm−1] = 3284 (N–H), 1638 (OvCNHR, amide I), 1552
3.43–3.49 (m, 1H, ArCH2CH2CH), 3.57 (d, J = 16.8 Hz, 1H, (OvCNHR, amide II), 741 (Ar–Cl). HPLC (method 1): tR
ArCH2N), 3.68 (dd, J = 11.8/5.0 Hz, 1H, CHCH2OH), 3.75–3.77 18.56 min, purity 93.1%.
=
(m, 1H, CHCH2OH), 4.07 (dd, J = 11.8/3.5 Hz, 1H, CHCH2OH),
5.4.15 (3S)-2-[(1R)-2-Chloro-1-phenylethyl]-1-oxo-2,3,4,5-
4.18 (d, J = 16.8 Hz, 1H, ArCH2N), 6.40 (d, J = 7.5 Hz, 1H, tetrahydro-1H-2-benzazepine-3-carbonitrile (18). Under N2, a
9-Harom), 6.86 (td, J = 7.3/1.5 Hz, 1H, 8-Harom), 6.94–7.01 (m, solution of nitrile (3S)-11 (0.20 g, 0.653 mmol) in THF (12 mL)
2H, 6-Harom and 7-Harom), 7.06–7.11 (m, 5H, Ar–H). A signal for was cooled to 0 °C. A solution of SOCl2 (2 M in THF, 0.327 mL,
the OH proton is not seen in the spectrum. 13C NMR (CDCl3): 0.653 mmol) was added and the mixture was stirred at 0 °C for
δ (ppm) = 23.9 (C-3py, C-4py), 31.8 (C-5), 32.9 (C-4), 47.4 (C-3), 1 h. A saturated aqueous solution of NaHCO3 was added and
55.5 (C-2py, C-5py), 59.8 (PhCHN), 60.2 (CH2Npy), 63.6 (CH2OH), the mixture was stirred for 10 min. The solution was extracted
68.5 (C-1), 125.5 (C–Ar), 126.3 (C–Ar), 127.0 (C–Ar), 127.8 with ethyl acetate, and the combined organic layers were dried
(C–Ar), 128.7 (C–Ar), 129.3 (C–Ar), 129.4 (C–Ar), 139.9 (C–Arq), (Na2SO4), filtered and concentrated under reduced pressure.
140.4 (C–Arq), 141.8 (C–Arq). IR (neat): ν [cm−1] = 744 (1,2- The residue was purified by fc (∅ = 3 cm, h = 14 cm,
disubst. benzene). Specific rotation: [α]2D0 = −5.7 (c = 1.11; cyclohexane : ethyl acetate = 2 : 1, V = 14 mL, Rf = 0.38). Color-
CH2Cl2). HPLC (method 2): tR = 15.70 min, purity 99.5%.
less liquid, yield 0.135 g (64%). C19H17ClN2O, Mr = 324.8. MS
5.4.13 (2S)-2-[(3R)-3-(Pyrrolidinomethyl)-2,3,4,5-tetrahydro- (EM): m/z = 325.1090 (calcd 325.1102 for C19H1735ClN2OH+
1H-2-benzazepin-2-yl]-2-phenylethanol (ent-15). As described [M + H+]). 1H NMR (CDCl3): δ [ppm] = 2.22–2.31 (m, 1H,
for the synthesis of 15, primary amine ent-14 (0.806 mmol) ArCH2CH2CH), 2.53–2.60 (m, 1H, ArCH2CH2CH), 2.87–2.92
was treated with 1,4-diiodobutane (0.750 g, 2.42 mmol) and (m, 1H, ArCH2CH2CH), 3.13–3.21 (m, 1H, ArCH2CH2CH), 4.16
NaHCO3 (0.496 g, 5.90 mmol) in acetonitrile (32 mL). After (d, J = 5.5 Hz, 2H, NCHCH2Cl), 4.32 (dd, J = 7.6/2.7 Hz, 1H,
work-up, the residue was purified by fc (∅ = 3 cm, h = 15 cm, ArCH2CH2CH), 6.24–6.32 (m, broad, 1H, PhCHCH2Cl),
cyclohexane : ethyl
acetate : N,N-dimethylethanamine
=
7.20–7.22 (m, 1H, Ar–H), 7.32–7.49 (m, 7H, Ar–H), 7.79 (dd, J =
3 : 1 : 0.04, V = 14 mL, Rf = 0.50). A pale yellow liquid, which 7.4/1.6 Hz, 1H, 9-Harom.). 13C NMR (CDCl3): δ (ppm) = 29.3
solidified on cooling in the refrigerator, a pale yellow solid, (C-5), 35.9 (C-4), 43.8 (C-3), 53.6 (PhCHN), 59.0 (CH2Cl), 117.3
yield 0.127 g (45%, two steps from ent-(3S)-11). Specific (CN), 127.8 (C–Ar), 128.4 (C–Ar), 128.8 (C–Ar), 129.1 (C–Ar),
rotation: [α]2D0 = +5.8 (c = 1.11; CH2Cl2). HPLC (method 2): tR
14.95 min, purity 99.6%.
=
129.5 (C–Ar), 130.1 (C–Ar), 132.6 (C–Ar), 135.1 (C–Arq), 135.9
(C–Arq), 136.5 (C–Arq), 171.3 (CvO). IR (neat): ν [cm−1] = 1646
5.4.14 (S)-2-(3,4-Dichlorophenyl)-N-(1-(pyrrolidin-1-yl)-4- (OvCNR2), a signal for the CN group is not seen.
(o-tolyl)butan-2-yl)acetamide (17). A mixture of pyrrolidine 15 5.4.16 ( )-1-Oxo-2-(1-phenylvinyl)-2,3,4,5-tetrahydro-1H-2-
(48 mg, 0.137 mmol), MeOH (1.5 mL) and Pd/C (10%, 17 mg) benzazepine-3-carbonitrile (19). Under N2, DBU (0.32 mL,
was stirred under a H2 atmosphere (1 bar) at 0 °C for 6 h. After 2.1 mmol) was added to a solution of chloride 18 (0.135 g,
addition of 1 M HCl (1.5 mL), hydrogenation was continued 0.412 mmol) in THF (6.5 mL). The reaction mixture was
overnight, then conc. HCl (1 drop) was added and the reaction heated to reflux for 1.5 h, and then stirred at rt for 10 min.
mixture was stirred for an additional 32 h under H2. The cata- A sufficient amount of silica gel was added and the solvent
lyst was filtered off. The mixture was alkalized with NaOH and was removed under reduced pressure. The residue was purified
extracted several times with Et2O. The combined organic layers by fc (∅ = 3 cm, h = 17 cm, cyclohexane : ethyl acetate = 2 : 1,
were dried (Na2SO4), filtered, the solvent was removed under V = 14 mL, Rf = 0.19). Colorless viscous oil, yield 65 mg (53%).
reduced pressure and the residue (16, 33 mg) was dissolved in C19H16N2O, Mr = 288.3. MS (EM): m/z = 289.1335 (calcd
CH2Cl2. After cooling to 0 °C in an ice-bath, 3,4-dichlorophenyl- 289.1335 for C19H16N2OH+ [M + H+]); m/z = 335.1754 (calcd
+
acetyl chloride (0.1 mL) and NEt3 (0.1 mL) were added. The 335.1754 for C19H16N2OC2H5OH2 [M + 2H+]). 1H NMR
mixture was slowly brought to rt and stirred at rt for 48 h. (CDCl3): δ [ppm] = 2.33 (dddd, J = 13.8/8.6/7.1/5.1 Hz, 1H,
NaOH was added and the mixture was extracted several times ArCH2CH2CH), 2.51 (dtd,
J
=
12.7/7.2/5.2 Hz, 1H,
with CH2Cl2. The combined organic layers were washed with ArCH2CH2CH), 2.85–2.99 (m, 1H, ArCH2CH2CH), 3.02–3.19
saturated aqueous NaCl solution, dried (Na2SO4), filtered and (m, 1H, ArCH2CH2CH), 4.57 (dd,
J
=
6.7/5.1 Hz, 1H,
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ArCH2CH2CH), 5.38 (d, J = 0.9 Hz, 1H, CvCH2), 5.80 (d, J = (td, J = 13.0/7.7 Hz, 1H, ArCH2CH2CH), 3.23–3.31 (m, 3H,
0.9 Hz, 1H, CvCH2), 7.18–7.21 (m, 1H, Ar–H), 7.27–7.48 (m, N(CH2Ph)2, ArCH2CH2CH), 3.70 (d, 13.3 Hz, 2H,
J
=
7H, Ar–H), 7.73 (dd, J = 7.4/1.6 Hz, 1H, 9-Harom.). IR (neat): N(CH2Ph)2), 5.97 (d, J = 2.7 Hz, 1H, CONHR), 7.13 (d, J =
ν [cm−1] = 1643 (OvCNR2), a signal for the CN group is not 7.2 Hz, 1H, ArH), 7.23–7.38 (m, 12H, ArH), 7.68 (dd, J = 7.5/
observed.
1.4 Hz, 1H, ArH). IR (neat): ν [cm−1] = 1653 (OvCNHR). HPLC
5.4.17 ( )-1-Oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-3-carbo- (method 1): tR = 17.19 min, purity 97.1%. HPLC (method 5):
nitrile (20). 1 M HCl (5 mL) and HClconc. (7 drops) were tR = 10.64 min, 48.5% (enantiomer 1) and tR = 12.31 min,
added to a solution of enamide 19 (65 mg, 0.22 mmol) in THF 48.5% (enantiomer 2).
(5 mL). The mixture was heated to reflux overnight, HClconc.
5.4.19 (2R)-2-Phenyl-2-[(3S)-3-(prop-2-en-1-yl)-2,3,4,5-tetra-
(10 drops) was added and the mixture was heated to reflux for hydro-1H-2-benzazepin-2-yl]ethanol (22). Under N2, a solution
an additional 18 h. The mixture was poured into a saturated of AlH3 (0.36 M in THF, 1.9 mL, 0.68 mmol, freshly prepared
solution of aqueous NaHCO3, the mixture was extracted with according to general procedure 2) was cooled to 0 °C. With a
ethyl acetate, the combined organic layers were dried (Na2SO4), cannula, a solution of allylbenzazepinone (3S)-12 (70 mg,
filtered and the solvent was removed under reduced pressure. 0.218 mmol) in THF (1.8 mL) was slowly transferred into the
The residue was purified by fc, which was performed with a solution of AlH3. The mixture was stirred at 0 °C for 0.5 h and
gradient (∅ = 2 cm, h = 16 cm, cyclohexane : ethyl acetate = at rt for 0.5 h. 1 M NaOH (2 mL) was added, and the precipi-
2 : 1) until acetophenone had been eluted, then cyclohexane : tate was removed and washed carefully with Et2O. The layers
ethyl acetate = 1 : 2, V = 14 mL, Rf = 0.25 (cyclohexane : ethyl were separated and the aqueous layer was washed several
acetate = 1 : 2). A pale yellow liquid, yield 31 mg (76%). times with Et2O. The combined organic layers were dried
C11H10N2O, Mr = 186.2. MS (EM): m/z = 187.0866 (calcd (Na2SO4), filtered and the solvent was removed under reduced
187.0869 for C11H10N2OH+ [M + H+]); m/z = 395.1478 (calcd pressure. The residue was purified by fc (∅ = 1 cm, h = 15 cm,
1
395.1478 for (C11H10N2O)2Na+ [2M + Na+]). H NMR (CDCl3): δ cyclohexane : ethyl acetate = 8 : 2, V = 7 mL, Rf = 0.42). Colorless
[ppm] = 2.25–2.46 (m, 2H, ArCH2CH2CH), 2.75–3.07 (m, 2H, oil, yield 36 mg (54%). C21H25NO, Mr = 307.4. MS (EM): m/z =
1
ArCH2CH2CH), 4.21 (dt, J = 9.0/6.4 Hz, 1H, ArCH2CH2CH), see enantiomer ent-22. H NMR (CDCl3): δ [ppm] = 1.70–1.77
6.47–6.60 (s, broad, 1H, CONH), 7.15–7.17 (m, 1H, 6-Harom.), (m, 1H, ArCH2CH2CH), 1.98–2.06 (m, 1H, ArCH2CH2CH),
7.32–7.45 (m, 2H, 7-Harom., 8-Harom.), 7.68 (dd, J = 7.5/1.5 Hz, 2.39 (dt, J = 14.1/7.1 Hz, 1H, CH2CHvCH2), 2.62–2.74
1H, 9-Harom.). IR (neat): ν [cm−1] = 3210 (NH), 2247 (CN), 1655 (m, 2H, ArCH2CH2CH, CH2CHvCH2), 3.10–3.17 (m, 1H,
(CONHR).
ArCH2CH2CH), 3.37–3.41 (m, 2H, ArCH2N, ArCH2CH2CH),
5.4.18 ( )-3-(N,N-Dibenzylaminomethyl)-2,3,4,5-tetrahydro- 3.66–3.71 (m, 2H, NCHCH2OH, NCHCH2OH), 3.82–3.88 (m,
2-benzazepin-1-one (21). Under N2, a solution of nitrile 20 1H, NCHCH2OH), 4.19 (d, J = 15.7 Hz, 1H, ArCH2N), 5.11–5.17
(68 mg, 0.365 mmol) in THF (2.9 mL) was added to a cooled (m, 2H, CH2CHvCH2), 5.98 (ddt, J = 17.2/10.1/7.1 Hz, 1H,
(0 °C) freshly prepared solution of AlH3 (0.67 M, 3.0 mL, CH2CHvCH2), 6.51 (d, J = 7.3 Hz, 1H, ArH), 6.94–7.00 (m, 1H,
2.01 mmol, prepared according to general procedure 1) and ArH), 7.10–7.11 (m, 2H, ArH), 7.23–7.35 (m, 5H, ArH). A signal
the mixture was stirred for 40 min at 0 °C. A solution of gly- for the OH-proton is not seen in the spectrum. 13C NMR
cerol in water (1 : 1) was added dropwise until the evolution of (CDCl3): δ (ppm) = 28.9 (CH2CHvCH2), 29.1 (C-5), 36.9 (C-4),
H2 had ceased. The precipitate was filtered off, suspended in 49.3 (C-3), 57.3 (PhCHN), 64.1 (C-1), 64.7 (CH2OH), 116.6
THF (1 mL), heated to reflux and filtered off. This procedure (CHvCH2), 125.7 (C–Ar), 127.1 (C–Ar), 127.6 (C–Ar), 127.7
was repeated twice. The combined filtrates were dried (C–Ar), 128.5 (C–Ar), 128.9 (C–Ar), 128.9 (C–Ar), 129.0 (C–Ar),
(Na2SO4), filtered and the solvent was removed under reduced 129.1 (C–Ar), 130.0 (C–Ar), 136.9 (CHvCH2), 139.4 (C–Arq),
pressure at high vacuum yielding 63 mg of crude primary 140.7 (C–Arq), 142.7 (C–Arq). IR (neat): ν [cm−1] = see enantio-
amine. The crude primary amine was dissolved in CH2Cl2 mer ent-22. Specific rotation: [α]2D0 = −17 (c = 0.60; CH2Cl2).
(75 mL). Under N2, benzaldehyde (0.116 g, 1.09 mmol) and HPLC (method 2): tR = 13.53 min, purity 97.8%.
NaBH(OAc)3 (0.273 g, 1.29 mmol) were added and the mixture
5.4.20 (2S)-2-Phenyl-2-[(3R)-3-(prop-2-en-1-yl)-2,3,4,5-tetra-
was stirred at rt for 1 h. Under ice-cooling 1 M HCl was added, hydro-1H-2-benzazepin-2-yl]ethanol (ent-22). As described for
and the mixture was stirred at rt for 10 min. Then 2 M NaOH the synthesis of 22, allylbenzazepinone ent-(3S)-12 (0.10 g,
was added, the layers were separated and the aqueous layer 0.31 mmol) in THF (2.5 mL) was treated with a freshly pre-
was extracted with CH2Cl2. The combined organic layers were pared solution of AlH3 (0.67 M in THF, 1.4 mL, 0.94 mmol,
dried (Na2SO4), filtered, concentrated in vacuo and the residue general procedure 1). The mixture was stirred at 0 °C for 0.5 h
was purified by fc (∅ = 3 cm, h = 17 cm, cyclohexane : ethyl and at rt for 0.5 h. A solution of glycerol in water (1 : 1) was
acetate = 3 : 1, V = 14 mL, Rf = 0.12). Pale yellow oil, yield 48 mg added dropwise, until the evolution of H2 gas had ceased. The
(36%, two steps from nitrile 20). C25H26N2O, Mr = 370.5. MS precipitate was filtered off, suspended in THF (1 mL), heated
(EM): m/z = 371.2196 (calcd 371.2118 for C25H26N2OH+ [M + to reflux and filtered off. This procedure was repeated twice.
H+]). 1H NMR (CDCl3):
δ [ppm] = 1.57–1.63 (m, 1H, The solvent of the combined filtrates was removed under
ArCH2CH2CH), 1.83–1.52 (m, 1H, ArCH2CH2CH), 2.40 (dd, J = reduced pressure. The residue was dissolved in CH2Cl2,
13.0/4.4 Hz, 1H, CHCH2NR2), 2.56 (dd, J = 13.0/10.5 Hz, 1H, washed with 2 M NaOH, dried (Na2SO4), filtered and the
CHCH2NR2), 2.64 (dd, 13.6/6.2 Hz, 1H, ArCH2CH2CH), 2.93 solvent was removed under reduced pressure. The residue was
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purified by fc (∅ = 2 cm, h = 16 cm, cyclohexane : ethyl acetate 1H, NCHCH2OH), 4.17 (d, J = 15.6 Hz, 1H, ArCH2N), 6.47 (d,
= 9 : 1, V = 14 mL, Rf = 0.20). Colorless oil, yield 66 mg (69%). J = 7.3 Hz, 1H, ArH)), 6.94–6.98 (m, 1H, ArH), 7.10–7.12 (m,
C21H25NO, Mr = 307.4. MS (EM): m/z = 308.2003 (calcd 2H, ArH), 7.24–7.36 (m, 5H, ArH). A signal for the OH-proton
308.2009 for C21H25NOH+ [M + H+]). IR (neat): ν [cm−1] = 3854 is not seen in the spectrum. 13C NMR (CDCl3): δ (ppm) = 14.6
(O–H), 1638 (C–Harom.), 1491 (C–Harom.). Specific rotation: (CH2CH2CH3), 20.1 (CH2CH2CH3), 28.8 (C-5), 31.0
[α]2D0 = +16 (c = 0.72; CH2Cl2). HPLC (method 1): tR
15.97 min, purity 99.7%.
=
(CH2CH2CH3), 34.4 (C-4), 49.3 (C-3), 56.3 (PhCHN), 64.3
(CH2OH), 64.4 (C-1), 125.5 (C–Ar), 127.0 (C–Ar), 127.6 (C–Ar),
5.4.21 (3R)-2-[(1R)-2-Hydroxy-1-phenylethyl]-3-propyl-2,3,4,5- 128.5 (C–Ar), 128.8 (C–Ar), 128.8 (C–Ar), 130.1 (C–Ar), 139.5 (C–
tetrahydro-2-benzazepin-1-one (24). A mixture of allylbenz- Arq), 141.0 (C–Arq), 143.0 (C–Arq). IR (neat): ν [cm−1] = 3452
azepinone (3S)-12 (0.10 g, 0.31 mmol), CH3OH (12 mL) and (O–H), 2927 (C–H), 1600 (C–Harom.), 1491 (C–Harom.). Specific
Pd/C (10%, 10 mg) was shaken under a H2 atmosphere (5 bar) rotation: [α]2D0 = −24 (c = 0.68; CH2Cl2). HPLC (method 1): tR
=
at rt for 30 min. The mixture was filtered and the solvent was 17.79 min, purity 99.4%.
removed under reduced pressure. Colorless solid, mp 161 °C,
5.4.24 (2S)-2-Phenyl-2-[(3S)-3-propyl-2,3,4,5-tetrahydro-1H-2-
yield 0.101 g (99%). C21H25NO2, Mr = 323.4 MS (ESI): m/z [%] = benzazepin-2-yl]ethanol (ent-25). As described for the syn-
324 (M + H, 17), 346 (M + Na, 100), 669 (2 M + Na, 12). 1H thesis of 25, propylbenzazepinone ent-24 (0.10 g, 31 mmol)
NMR (D5-nitrobenzene, 100 °C): δ [ppm] = 0.01–0.04 (m, 3H, was dissolved in THF (2.5 mL) and treated with a freshly pre-
CH3), 0.30–0.42 (m, 2H, CH2CH2CH3), 0.58–0.63 (m, 2H, pared solution of AlH3 (0.67 M, 1.39 mL, 0.93 mmol, general
CH2CH2CH3), 1.60–1.62 (m, 1H, ArCH2CH2CH), 1.69 (s, 1H, procedure 1). After work-up, the residue was purified by fc (∅ =
CHCH2OH), 1.92–1.97 (m, 1H, ArCH2CH2CH), 2.48–2.52 2 cm, h = 15 cm, cyclohexane : ethyl acetate = 9 : 1, V = 14 mL,
(m, 1H, ArCH2CH2CH), 2.72–2.79 (m, 1H, ArCH2CH2CH), Rf = 0.36). Colorless oil, yield 66 mg (68%). Specific rotation:
3.19–3.22 (m, 1H, ArCH2CH2CH), 4.02–4.05 (m, 1H, [α]2D0 = +24 (c = 1.07; CH2Cl2). HPLC (method 1): tR
CHCH2OH), 4.12–4.18 (m, 1H, CHCH2OH), 5.50–5.58 (s, 17.32 min, purity 99.5%.
=
broad, 1H, CHCH2OH), 6.79–7.47 (m, 9H, Ar–H). IR (neat): ν
[cm−1] = 3356 (OH), 1619 (OvCNR2). Specific rotation: [α]D20
+11 (c = 1.00; CH2Cl2). HPLC (method 1): tR = 20.11 min, purity SOCl2 (0.023 mL, 0.31 mmol) was added to a solution of 24
98.4%. (50 mg, 0.154 mmol) in THF (3 mL) at 0 °C. The mixture was
5.4.25 (3R)-2-[(1R)-2-Chloro-1-phenylethyl]-3-propyl-2,3,4,5-
=
tetrahydro-2-benzazepin-1-one (26). Under N2, freshly distilled
5.4.22 (3S)-2-[(1S)-2-Hydroxy-1-phenylethyl]-3-propyl-2,3,4,5- stirred at 0 °C for 0.5 h. The solvent and excess SOCl2 were
tetrahydro-2-benzazepin-1-one (ent-24). As described for the removed at rt under reduced pressure. As the colorless liquid
synthesis of 24, allylbenzazepinone ent-(3S)-12 (0.57 g, was very unstable, the unpurified product was immediately
1.78 mmol) was reduced with H2 (5 bar) in the presence of Pd/ used in the next step. C21H24ClNO, Mr = 341.9. MS (EM): m/z =
C (10%, 57 mg) in MeOH (27 mL). After work-up, purification 364.1439 (calcd 364.1439 for C21H2435ClNONa+ [M + Na+]).
of the residue was not necessary. Colorless solid, yield 0.556 g
(95%). Specific rotation: [α]2D0 = −10 (c = 1.00; CH2Cl2). HPLC tetrahydro-1H-2-benzazepin-1-one (ent-26). As described for
(method 1): tR = 19.35 min, purity 99.2%. the synthesis of 26, ent-24 (0.200 g, 0.62 mmol) was treated
5.4.26 (3S)-2-[(1S)-2-Chloro-1-phenylethyl]-3-propyl-2,3,4,5-
5.4.23 (2R)-2-Phenyl-2-[(3R)-3-propyl-2,3,4,5-tetrahydro-1H-2- with freshly distilled SOCl2 (0.093 mL, 1.24 mmol) in THF
benzazepin-2-yl]ethanol (25). Under N2, a solution of propyl- (12 mL). After removal of the solvent and SOCl2, the colorless
benzazepinone 24 (90 mg, 0.278 mmol) in THF (2.22 mL) was liquid was immediately used in the next step.
added to a freshly prepared solution of AlH3 (0.67 M, 1.25 mL,
5.4.27 (3R)-2-(1-Phenylvinyl)-3-propyl-2,3,4,5-tetrahydro-2-
0.83 mmol, general procedure 1) at 0 °C and the mixture was benzazepin-1-one (27). At −78 °C a freshly prepared solution
stirred for 1 h at 0 °C. A solution of glycerol in water (1 : 1) was of LDA (0.57 M in THF/n-hexane, 1.25 mL, 0.71 mmol) was
added dropwise until the evolution of H2 had ceased. The pre- added slowly to
a solution of unpurified 26 (50 mg,
cipitate was filtered off, suspended in THF (1 mL), heated to 0.154 mmol) in THF (1.5 mL). The mixture was stirred at
reflux and filtered off. This procedure was repeated twice. The −78 °C for 1.5 h. The black reaction mixture was poured into
solvent of the combined filtrates was removed under reduced water and the aqueous layer was extracted several times with
pressure. The residue was dissolved in Et2O, the solution was Et2O. The combined organic layers were washed with saturated
washed with 2 M NaOH, dried (Na2SO4), and filtered and the aqueous NaCl solution, dried (Na2SO4), and filtered, silica gel
solvent was removed under reduced pressure. The residue was was added and the solvent was removed under reduced
purified by fc (∅ = 2 cm, h = 15 cm, cyclohexane : ethyl acetate pressure. The residue was purified by fc (∅ = 2 cm, h = 17 cm,
= 9 : 1, V = 7 mL, Rf = 0.36). Colorless oil, yield 71 mg (82%). cyclohexane : ethyl acetate = 6 : 1, V = 12 mL, Rf = 0.16
C21H27NO, Mr = 309.4. MS (EM): m/z = 310.2165 (calcd (cyclohexane : ethyl acetate = 4 : 1). Pale yellow oil, yield 16 mg
310.2165 for C21H27NOH+ [M + H+]). 1H NMR (CDCl3): δ [ppm] (34%, two steps from 24). C21H23NO, Mr = 305.4 MS (EM): m/z
= 1.01 (t, J = 7.1 Hz, 3H, CH2CH2CH3), 1.45–1.69 (m, 4H, = 306.1852 (calcd 306.1852 for C21H23NOH+ [M + H+]); m/z =
CH2CH2CH3, ArCH2CH2CH), 1.95–2.04 (m, 2H, CH2CH2CH3, 328.1672 (calcd 328.1617 for C21H23NONa+ [M + Na+]). 1H
ArCH2CH2CH), 2.61 (m, 1H, ArCH2CH2CH), 3.16 (m, 1H, NMR (CDCl3): δ [ppm] = 0.68 (t, J = 7.3 Hz, 3H, CH2CH2CH3),
ArCH2CH2CH), 3.28–3.32 (m, 2H, ArCH2CH2CH, ArCH2N), 0.97–1.52 (m, 4H, CH2CH2CH3), 1.83–1.95 (m, 1H,
3.66–3.70 (m, 2H, NCHCH2OH), NCHCH2OH), 3.79–3.85 (m, ArCH2CH2CH), 2.07 (dddd, J = 13.5/11.7/ 6.8/5.0 Hz, 1H,
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ArCH2CH2CH), 2.82 (ddd,
ArCH2CH2CH), 3.07 (ddd,
J
J
=
=
13.7/6.9/2.4 Hz, 1H, stirred at 0 °C for 1 h. The ice bath was removed, and the
13.6/11.1/7.6 Hz, 1H, mixture was stirred overnight at rt. A mixture of ethylene
ArCH2CH2CH), 3.58–3.69 (m, 1H, ArCH2CH2CH), 5.28 (s, 1H, glycol : water (1 : 1) was added dropwise until evolution of H2
CvCH2), 5.87 (s, 1H, CvCH2), 7.16 (dd, J = 7.0/1.5 Hz, 1H, gas had ceased. The precipitate was filtered off, suspended in
ArH), 7.27–7.43 (m, 5H, ArH), 7.50–7.55 (m, 2H, ArH), 7.70 (dd, THF (1 mL), heated to reflux and filtered off. This procedure
J = 6.8/2.1 Hz, 1H, 9-Harom.). IR (neat): ν [cm−1] = 2957 (C–H), was repeated twice. The combined filtrates were evaporated
1646 (CONR2). HPLC (method 1): tR = 21.76 min, purity 99.3%. with gentle heating. The residue was dissolved in CH2Cl2,
5.4.28 (3S)-2-(1-Phenylvinyl)-3-propyl-2,3,4,5-tetrahydro-2- washed with 2 M NaOH dried (Na2SO4), filtered and the solvent
benzazepin-1-one (ent-27). As described for the synthesis of was removed under vacuum with gentle heating. (Caution! The
27, unpurified ent-26 (0.212 g, 0.62 mmol) was treated with a product 29 is volatile.) Colorless oil, yield 31 mg (100%)
1
freshly prepared solution of LiTMP (0.56 M in THF/hexanes, C13H19N, Mr = 189.3. MS (ESI): m/z [%] = 190 (M + H, 100). H
5.56 mL, 3.1 mmol) in THF (6.5 mL) for 40 min. After work-up, NMR (CDCl3): δ [ppm] = 0.92 (t, J = 6.9 Hz, 3H, CH2CH2CH3),
the residue was purified by fc (∅ = 3 cm, h = 10 cm, hexane : 1.24 (qd, J = 12.2/1.6 Hz, 1H, ArCH2CH2CH), 1.34–1.44 (m, 4H,
ethyl acetate = 5 : 1, V = 14 mL, Rf = 0.40 (cyclohexane : ethyl CH2CH2CH3), 1.96 (ddt, J = 13.7/7.0/2.1 Hz, 1H, ArCH2CH2CH),
acetate = 7 : 3). Colorless oil, yield 0.148 g (78%, two steps from 2.82 (ddd, J = 14.6/6.9/1.6 Hz, 1H, ArCH2CH2CH), 2.86–2.92
ent-24).
(m, 1H, ArCH2CH2CH), 3.01 (ddd, J = 14.1/12.2/1.6 Hz, 1H,
5.4.29 (3R)-3-Propyl-2,3,4,5-tetrahydro-2-benzazepin-1-one ArCH2CH2CH), 3.83 (d, J = 14.6 Hz, 1H, ArCH2N), 3.91 (d, J =
(28). 20% HCl (0.5 mL) was added to a solution of enamide 27 14.5 Hz, 1H, ArCH2N), 7.03–7.08 (m, 4H, ArH). IR (neat):
(16 mg, 0.05 mmol) in Et2O (0.75 mL). The mixture was heated ν [cm−1] = 2923 (C–H), 1492 (C–Harom.), 747 (1,2-disubst.
to reflux for 4.5 h and then poured into a saturated aqueous benzene).
NaHCO3 solution. The mixture was extracted with Et2O (3×).
5.4.32 (3S)-3-Propyl-2,3,4,5-tetrahydro-1H-2-benzazepine
The combined organic layers were dried (Na2SO4) and filtered, (ent-29). As described for the synthesis of 29, ent-28 (30 mg,
silica gel was added and the solvent was removed under 0.148 mmol) was treated with a freshly prepared AlH3 solution
reduced pressure. The residue was purified by fc (∅ = 2 cm, h = (0.67 M, 1.33 mL, 0.891 mmol, general procedure 1) in THF
15 cm, cyclohexane : ethyl acetate = 2 : 1, V = 10 mL, Rf = 0.13). (1.5 mL) for 30 min. After work-up and careful evaporation of
Colorless solid, yield 10 mg (95%). C13H17NO, Mr = 203.3. MS the solvent under reduced pressure, the residue was directly
(EM): m/z = 226.1202 (calcd 226.1202 for C13H17NONa+ [M + used for the next step. Pale yellow oil, yield 25 mg.
Na+]); m/z = 429.2512 (calcd 429.2513 for (C13H17NO)2Na+ [2M
5.4.33 (3R)-2-Benzyl-3-propyl-2,3,4,5-tetrahydro-1H-2-benz-
+ Na+]). 1H NMR (CDCl3): δ [ppm] = 0.88 (t, J = 7.2 Hz, 3H, azepine (30a). Under N2, a solution of the unpurified second-
CH2CH2CH3), 1.29–1.55 (m, 4H, CH2CH2CH3), 1.79–1.87 (m, ary amine 29 (35 mg, 0.185 mmol), benzaldehyde (65 mg,
1H, ArCH2CH2CH), 1.97 (tdd,
J = 12.2/6.6/5.4 Hz, 1H, 0.611 mmol) and NaBH(OAc)3 (0.153 g, 0.722 mmol) in CH2Cl2
ArCH2CH2CH), 2.70 (dd, 13.6/6.6 Hz, 1H, ArCH2CH2CH), 3.00 (3 mL) was stirred. After stirring for 4 h at rt an additional
(td, J = 13.0/8.0 Hz, 1H, ArCH2CH2CH), 3.09–3.19 (m, 1H, amount of NaBH(OAc)3 (40 mg) was added and the mixture
ArCH2CH2CH), 5.82 (s, 1H, NH), 7.18 (d, J = 7.3 Hz, 1H, ArH), was stirred for an additional 18 h. After addition of 1 M HCl,
7.30–7.42 (m, 2H, ArH), 7.70 (dd, J = 7.5/1.3 Hz, 1H, ArH). the mixture was stirred at rt for 10 min. Then 2 M NaOH was
13C NMR (CDCl3):
δ (ppm) = 14.0 (CH2CH2CH3), 19.6 added, the layers were separated and the aqueous layer was
(CH2CH2CH3), 30.8 (C-5), 36.9 (C-4), 37.3 (CH2CH2CH3)), 51.1 extracted with CH2Cl2. The combined organic layers were dried
(C-3), 127.1 (C–Ar), 128.7 (C–Ar), 128.8 (C–Ar), 131.3 (C–Ar), (Na2SO4), filtered, concentrated in vacuo and the residue was
135.3 (C–Arq), 138.9 (C–Arq), 172.7 (CvO). IR (neat): ν [cm−1] = purified by fc (∅ = 2 cm, h = 18 cm, cyclohexane : ethyl acetate
3192 (N–H), 1652 (OvCNHR). Specific rotation: [α]2D0 = −180 = 18 : 1, V = 14 mL, Rf = 0.4). Colorless oil, yield 16 mg (31%).
1
(c = 1.01; CH2Cl2). HPLC (method 1): tR = 17.93 min, purity C20H25N, Mr = 279.4. MS (ESI): m/z [%] = 280 (M + H, 100). H
84.1%.
NMR (CDCl3): δ [ppm] = 0.88 (t, J = 7.2 Hz, 3H, CH2CH2CH3),
5.4.30 (3S)-3-Propyl-2,3,4,5-tetrahydro-2-benzazepin-1-one 1.31–1.43 (m, 2H, CH2CH2CH3), 1.44–1.56 (m, 2H,
(ent-28). As described for the synthesis of 28, ent-27 (0.148 g, ArCH2CH2CH, CH2CH2CH3), 1.66–1.77 (m, 2H, ArCH2CH2CH,
0.485 mmol) was treated with 20% HCl (5 mL) in Et2O (7 mL) CH2CH2CH3), 2.73–2.79 (m. 1H, ArCH2CH2CH), 2.87–2.95 (m,
for 2 h. After work-up, the residue was purified by fc (∅ = 1H, ArCH2CH2CH), 2.97–3.03 (m, 1H, ArCH2CH2CH), 3.08 (d,
2 cm, h = 15 cm, hexane : ethyl acetate = 8 : 2, V = 14 mL, Rf = J = 13.8 Hz, 1H, 1-H), 3.52 (d, J = 13.8 Hz, 1H, 1-H), 3.70 (d, J =
0.12). Pale yellow oil, yield 30 mg (30%). MS (EM): m/z = 15.0 Hz, 1H, NCH2Ph), 3.90 (d, J = 15.1 Hz, 1H, NCH2Ph), 6.71
204.1409 (calcd 204.1383 for C13H17NOH+ [M + H+]). Specific (d, J = 7.3 Hz, 1H, ArH), 6.96–7.02 (m, 1H, ArH), 7.08–7.09 (m,
rotation: [α]2D0 = +200 (c = 1.00; CH2Cl2). HPLC (method 1): tR = 2H, ArH), 7.14–7.25 (m, 5H, ArH). 13C NMR (CDCl3): δ (ppm) =
17.45 min, purity 99.3%.
14.43 (CH2CH2CH3)), 20.2 (CH2CH2CH3)), 28.4 (C-5), 34.5
5.4.31 (3R)-3-Propyl-2,3,4,5-tetrahydro-1H-2-benzazepine (29). (C-4), 36.7 (CH2CH2CH3), 51.1 (C-3), 55.1 (PhCH2), 65.2 (C-1),
Under N2, a freshly prepared AlH3 solution (0.67 M, 1.3 mL, 125.6 (C–Ar), 126.7 (C–Ar), 127.1 (C–Ar), 128.2 (C–Ar), 128.9
0.87 mmol, prepared according to general procedure 1) was (C–Ar), 128.9 (C–Ar), 130.5 (C–Ar), 139.5 (C–Arq), 140.2 (C–Arq),
added in a cooled (0 °C) solution of lactam 28 (28 mg, 143.1 (C–Arq). IR (neat):
0.138 mmol) in THF (1.4 mL) and the reaction mixture was (C–Harom.), 1493 (C–Harom.). Specific rotation: [α]2D0 = +30 (c =
ν ] = 2922 (C–H), 1602
[cm−1
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0.63; CH2Cl2). HPLC (method 1): tR = 18.25 min, purity 98.2%. 5.5. X-ray crystal structure analysis
HPLC (method 6): tR = 7.78 min, ratio of enantiomers
5.5.1. General. Data sets were collected with a Nonius
KappaCCD diffractometer. Programmes used: data collection,
COLLECT (R. W. W. Hooft, Bruker AXS, 2008, Delft, The
Netherlands); data reduction Denzo-SMN;56 absorption correc-
tion, Denzo;57 structure solution SHELXS-97;58 structure
refinement SHELXL-9759 and graphics, XP (Bruker AXS, 2000).
Thermal ellipsoids are shown with 15% probability, R-values
are given for observed reflections, and wR2 values are given for
all reflections.
86.8 : 13.2.
5.4.34 (3S)-2-Benzyl-3-propyl-2,3,4,5-tetrahydro-1H-2-benz-
azepine (ent-30a). As described for the synthesis of 30a,
unpurified secondary amine ent-29 (25 mg, 0.132 mmol) was
treated with benzaldehyde (46 mg, 0.436 mmol), NaBH(OAc)3
(0.109 g, 0.515 mmol) in CH2Cl2 (2.5 mL). After 3 h, a further
amount of NaBH(OAc)3 (40 mg) was added. The mixture was
stirred for 6.5 h. After work-up, the residue was purified by
fc (∅ = 2 cm, h = 18 cm, n-hexane : ethyl acetate = 18 : 1, V =
14 mL, Rf = 0.30). Colorless oil, yield 15.6 mg (43%). Specific
5.5.2. X-ray
crystal
structure of
(3S)-11. Formula
C19H18N2O2, M = 306.35, colorless crystal, 0.37 × 0.07 ×
0.05 mm, a = 7.9192(2), b = 14.3040(9), c = 14.6004(9) Å, V =
1653.9(2) Å3, ρcalc = 1.230 g cm−3, μ = 0.647 mm−1, empirical
absorption correction (0.795 ≤ T ≤ 0.968), Z = 4, orthorhombic,
space group P212121 (no. 19), λ = 1.54178 Å, T = 223(2) K, ω and
φ scans, 6802 reflections collected ( h, k, l) [(sin θ)/λ] =
0.60 Å−1, 2771 independent (Rint = 0.035) and 2607 observed
reflections [I > 2σ(I)], 209 refined parameters, R = 0.039, wR2 =
rotation: [α]2D0 = −34 (c = 0.53; CH2Cl2). HPLC (method 1): tR
17.71 min, purity 98.7%. HPLC (method 6): tR = 8.07 min, ratio
of enantiomers 98.3 : 1.7.
=
5.4.35 (3R)-2-(Cyclohexylmethyl)-3-propyl-2,3,4,5-tetrahydro-
1H-2-benzazepine (30b). Under N2, a solution of the unpuri-
fied secondary amine 29 (31 mg, 0.164 mmol), cyclohexanecarb-
aldehyde (61 mg, 0.54 mmol) and NaBH(OAc)3 (0.136 g,
0.64 mmol) in CH2Cl2 (3 mL) was stirred The mixture was
stirred at rt for 8 h. After addition of 1 M HCl, the mixture was
stirred at rt for 10 min. Then 2 M NaOH was added, the layers
were separated and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were dried (Na2SO4), fil-
tered, and concentrated in vacuo and the residue was purified
by preparative HPLC (method 4): tR = 53.3 min to 63.2 min.
Colorless oil, yield 21 mg (45%). C20H31N, Mr = 285.5. MS
(EM): m/z = 286.2521 (calcd 286.2529 for C20H31NH+ [M + H+]).
1H NMR (CDCl3): δ [ppm] = 0.62–0.73 (m, 2H, Cy), 0.87 (t, J =
7.2 Hz, 3H, CH2CH2CH3), 1.01–1.68 (m, 14H, Cy, CH2CH2CH3,
ArCH2CH2CH), 1.71–1.89 (m, 2H, NCH2Cy, CH2), 1.93–2.06 (m,
1H, NCH2Cy), 2.62–2.77 (m, 1H, ArCH2CH2CH), 2.80–2.93 (m,
2H, ArCH2CH2CH), 3.71 (d, J = 15.4 Hz, 1H, ArCH2N), 4.03 (d,
J = 15.2 Hz, 1H, ArCH2N), 7.01–7.06 (m, 4H, ArH). 13C NMR
(CDCl3): δ (ppm) = 14.5 (CH2CH2CH3), 20.4 (CH2CH2CH3)),
26.5 (Ccyclohex.), 26.6 (Ccyclohex.), 27.2 (Ccyclohex.), 28.1 (C-5), 31.9
(Ccyclohex.), 32.1 (Ccyclohex.), 34.5 (Ccyclohex.), 35.5 (C-4), 36.8
(CH2CH2CH3), 54.0 (CH2Cyclohex.), 56.0 (C-3), 65.9 (C-1), 125.7
(C–Ar), 127.0 (C–Ar), 129.0 (C–Ar), 130.1 (C–Ar), 140.1 (C–Arq),
0.102, max. (min.) residual electron density 0.11 (−0.13) e Å−3
,
the hydrogen atoms were calculated and refined as riding
atoms. Flack parameter: −0.0(3). CCDC 1050885.
5.5.3. X-ray crystal structure of (3R)-11. Formula
C19H18N2O2, M = 306.35, colorless crystal, 0.47 × 0.07 ×
0.02 mm, a = 7.4874(6), b = 7.3181(4), c = 15.1101(13) Å, β =
103.139(5)°, V = 806.3(1) Å3, ρcalc = 1.262 g cm−3, μ =
0.663 mm−1, empirical absorption correction (0.745 ≤ T ≤
0.986), Z = 2, monoclinic, space group P21 (no. 4), λ =
1.54178 Å, T = 223(2) K, ω and φ scans, 4431 reflections col-
lected ( h, k, l) [(sin θ)/λ] = 0.59 Å−1, 2009 independent (Rint
= 0.041) and 1805 observed reflections [I > 2σ(I)], 209 refined
parameters, R = 0.045, wR2 = 0.116, max. (min.) residual elec-
tron density 0.29 (−0.17) e Å−3, the hydrogen atoms were calcu-
lated and refined as riding atoms. Flack parameter: −0.2(4).
CCDC 1050886.
5.6. Receptor binding studies
5.6.1. Affinity towards the σ1 receptor. The affinity towards
the σ1 receptor was recorded as described in ref. 48 and 49.
5.6.2. Affinity towards the σ2 receptor. The affinity towards
the σ2 receptor was recorded as described in ref. 48 and 49.
5.6.3. Affinity towards the κ-opioid receptor. The affinity
towards the κ-opioid receptor was recorded as described in ref.
50.
143.1 (C–Arq). IR (neat):
(C–Harom.), 752 (1,2 disubst. benzene). Specific rotation: [α]D20
+21 (c = 0.64; CH2Cl2). HPLC (method 1): tR = 20.06 min, purity
99.8%. HPLC (method 6): tR = 6.95 min, ratio of enantiomers
96.4 : 3.6.
ν ] = 2918 (C–H), 1491
[cm−1
=
5.4.36 (3S)-2-(Cyclohexylmethyl)-3-propyl-2,3,4,5-tetrahydro-
1H-2-benzazepine (ent-30b). As described for the synthesis of
30b, unpurified secondary amine ent-29 (17 mg, 0.09 mmol)
was treated with cyclohexanecarbaldehyde (33 mg, 0.30 mmol)
and NaBH(OAc)3 (78 mg, 0.35 mmol) in CH2Cl2 (2 mL). After
2.5 h, an additional amount of NaBH(OAc)3 (31 mg) was
added. The mixture was stirred at rt for 6 h. After work-up, the
5.6.4. Affinity towards the PCP binding site of the NMDA
receptor. The affinity towards the PCP binding site of the
NMDA receptor was recorded as described in ref. 51 and 52.
5.6.5. Affinity towards the ifenprodil binding site of the
NMDA receptor. The affinity towards the ifenprodil binding
site of the NMDA receptor was recorded as described in ref. 53
and 54.
residue was purified by preparative HPLC (method 4): tR
=
54.1 min to 67.6 min. Colorless oil, yield 16 mg (62%). Specific
Acknowledgements
rotation: [α]2D0 = −22 (c = 0.53; CH2Cl2). HPLC (method 1): tR
=
19.57 min, purity 99.7%. HPLC (method 6): tR = 7.13 min, ratio This work was performed within the framework of the Inter-
of enantiomers 97.5 : 2.5.
national Research Training Group ‘Complex Functional
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Organic & Biomolecular Chemistry
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