Asymmetric synthesis of enantiomerically pure 2-substituted tetrahydro-3-benzazepines and their affinity to σ1 receptors

Article abstract of DOI:10.1021/jo900087e

A very short asymmetric synthesis of enantiomerically pure 2-substituted tetrahydro-3-benzazepines is described. First, 3-phenyl-2,3,11,11a-tetrahydro[1, 3]oxazolo[2,3-b][3] benzazepin-5(6H)-ones 3a-d and 4a-d were synthesized by condensation of 2-(2-oxoa

Full text of DOI:10.1021/jo900087e

Asymmetric Synthesis of Enantiomerically Pure 2-Substituted
Tetrahydro-3-benzazepines and Their Affinity to σ1 Receptors
Syed Masood Husain,† Roland Fro¨hlich,‡ Dirk Schepmann,† and Bernhard Wu¨nsch*,†
Institut fu¨r Pharmazeutische and Medizinische Chemie der Westfa¨lischen Wilhelms-UniVersita¨t Mu¨nster,
Hittorfstrasse 58-62, D-48149 Mu¨nster, Germany, and Organisch-Chemisches Institut der Westfa¨lischen
Wilhelms-UniVersita¨t Mu¨nster, Corrensstr. 40, D-48149 Mu¨nster, Germany
wuensch@uni-muenster.de
ReceiVed January 14, 2009
A very short asymmetric synthesis of enantiomerically pure 2-substituted tetrahydro-3-benzazepines is
described. First, 3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-ones 3a-d and
4a-d were synthesized by condensation of 2-(2-oxoalkyl)phenylacetic acids 1a-d with (R)-phenylglycinol
(2). With the exception of the 11a-phenyl derivatives 3d/4d (ratio 91:9), the ratio of the diastereomeric
11a-alkyl derivatives 3a-c/ 4a-c was almost 50:50. The configuration of the newly formed chiral center
in position 11a was proved by NOE experiments as well as X-ray crystal structure analysis. The reduction
of the oxazolo[2,3-b][3]benzazepin-5(6H)-ones trans-3 and cis-4 with AlCl3/LiAlH4 (1:3) took place
with retention of configuration and yielded 2,3-disubsituted tetrahydro-3-benzazepines 10 and11. In the
final step, removal of the N-(2-hydroxy-1-phenylethyl) residue from 10 and 11 by hydrogenolysis provided
four pairs of enantiomerically pure 2-substituted tetrahydro-3-benzazepines 12a-d and ent-12a-d, which
were tested for their σ1, σ2, and NMDA receptor affinities. The 2-butyl and the 2-phenyl derivatives 12c
and 12d show very high σ1 affinity with Ki values of 16 and 50 nM, respectively. The eudismic ratios are
greater than 50, reflecting highly stereoselective interaction with the σ1 receptor. Both σ1 ligands are
very selective against the σ2 subtype and the PCP binding site of the NMDA receptor.
Introduction
Seven-membered nitrogen heterocycles are constituents of a
number of compounds with interesting pharmacological pro-
perties.1-3 The tetrahydro-3-benzazepine ring system is of
particular interest from a medicinal chemistry viewpoint because
it contains the phenethylamine substructure, which is part of
several neurotransmitters (e.g., norepinephrine, dopamine) and
corresponding drugs (e.g., salbutamol, pergolide). During the
past 30 years, several tetrahydro-3-benzazepines, particularly
FIGURE 1. Pharmacologically interesting 3-benzazepines.
* To whom correspondence should be addressed. Tel: +49-251-8333311. Fax:
+49-251-8332144.
† Institut fu¨r Pharmazeutische and Medizinische Chemie.
‡ Organisch-Chemisches Institut.
1-aryl derivatives, have been developed as dopamine receptor
agonists and antagonists, e.g., fenoldopam and SCH-233903,4
(Figure 1). Very recently. 1-methyl-2,3,4,5-tetrahydro-1H-3-
(1) Kawase, M.; Saito, S.; Motohashi, N. Int. J. Antimicrob. Agents, 2000,
14, 193–201.
(2) Boros, T.; Hamilton, S. M.; Katz, B.; Kulanthaivel, P. J. Antibiot. 1994,
47, 1010–1015.
(3) Ladd, D. L.; Weinstock, J.; Wise, M.; Gessner, G. W.; Sawyer, J. L.;
Flaim, K. E. J. Med. Chem. 1986, 29, 1904–1912.
(4) Frishman, W. H. J. Clin. Pharmacol 1998, 38, 2–13.
2788 J. Org. Chem. 2009, 74, 2788–2793
10.1021/jo900087e CCC: $40.75 2009 American Chemical Society
Published on Web 03/06/2009

Asymmetric Synthesis of 2-Substituted Tetrahydro-3-benzazepines
SCHEME 1. Synthesis of Tricyclic Benzolactams trans-3
and cis-4a
benzazepines have been described as selective 5-HT2C receptor
agonists, which can be used for the treatment of obesity.5
Recently, high σ receptor affinity of enantiopure 1-substituted
3-benzazepines was reported from our group.6 This prompted
us to study binding of enantiopure 2-substituted 3-benzazepines
at σ receptors as viable targets. The σ receptors are well
established as a nonopioid, nonphencyclidine, and haloperidol-
sensitive receptor family with its own binding profile and a
characteristic distribution in the central nervous system (CNS)
and some peripheral tissues, like kidney, liver, lung, and heart.7,8
The class of σ receptors comprises two subtypes, termed σ1 and
σ2 receptors. The σ1 receptor plays an important role in several
physiological and pathophysiological processes. In particular,
σ1 antagonists can be used for the treatment of psychosis, and
they represent a new principle for the treatment of neuropathic
pain. Furthermore, σ ligands are investigated in clinical studies
for the treatment of depression, cocaine abuse, and epilepsy.9-11
The structures of σ1 ligands are quite diverse. In order to gain
more information about the σ1 binding site, it is necessary to
develop stereochemically defined, conformationally restricted
ligands with high σ1 affinity and high selectivity.
a Note: The stereodescriptors trans and cis define the relative configu-
ration in the oxazolidine ring: In 3 (4), the higher ranked substituents (Ph
and CH2aryl) are on opposite sides (the same side) of the oxazolidine ring
plane. In order to avoid confusion, the trans and cis assignment is maintained
for the d-series (R ) phenyl), although the hierarchy of the substituents is
changed according to CIP formalism.
we planned to use different keto acids 1a-d, which have been
prepared by reaction of o-phenylenediacetic acid with RLi.22
The condensation of the keto acids 1a-d with (R)-phenylgly-
cinol should give trans- and cis-configured tricyclic oxazo-
lidines, which should be exploited for the synthesis of enanti-
omerically pure 2-substituted tetrahydro-3-benzazepines.
In this work, a new strategy for the asymmetric synthesis of
enantiomerically pure 2-substituted 3-benzazepines is described
and the σ receptor affinity as well as the affinity to the PCP
binding site of the NMDA receptor of the resulting products is
detailed.
The asymmetric syntheses of substituted heterocycles by
Meyers et al. and Amat et al. make use of enantiomerically
pure oxazolidines. The intermediate bicyclic or tricyclic ox-
azolidines were synthesized by condensation of γ-, δ-, or ε-keto
acidswithachiralauxiliarysuchas(R)-or(S)-phenylglycinol.12-15
In particular, Amat et al. have used bicyclic oxazolidines for
the synthesis of diversely substituted piperidines and achieved
the synthesis of several natural occurring alkaloids.16-18 How-
ever, Meyers et al. make extensive use of chiral nonracemic
bicyclic and tricyclic lactams in the asymmetric synthesis of
several carbo- and heterocycles such as substituted naphthale-
nones, azepines, piperidines, and pyrrolidines.19-21
Results and Discussion
The trans- and cis-configured tricyclic benzolactams trans-3
and cis-4 represent the key intermediates in the planned
asymmetric synthesis of diversely substituted tetrahydro-3-
benzazepines. In order to synthesize the tricyclic benzolactams
3 and 4, a solution of keto acids 1a-d and (R)-phenylglycinol
(2) in toluene was heated to reflux for 3 days. These reaction
conditions produced pairs of trans- and cis-configured tricyclic
benzolactams trans-3a-d and cis-4a-d (Scheme 1).
The trans- and cis-configured diastereomers trans-3a-c and
cis-4a-c were separated and isolated by flash chromatography.
The configuration at the newly formed chiral center 11a was
determined by NOE experiments.
In order to show the success of the oxazolidine methodology
toward the synthesis of diversely substituted 3-benzazepines,
(5) Smith, B. M.; Smith, J. M.; Tsai, J. H.; Schultz, J. A.; Gilson, C. A.;
Estrada, S. A.; Chen, R. R.; Park, D. M.; Prieto, E. B.; Gallardo, C. S.; Sengupta,
D.; Thomsen, W. J.; Saldana, H. R.; Whelan, K. T.; Menzaghi, F.; Webb, R. R.;
Beeley, N. R. A. Bioorg. Med. Chem. Lett. 2005, 15, 1467–1470.
(6) Wirt, U.; Schepmann, D.; Wu¨nsch, B. Eur. J. Org. Chem. 2007, 46, 2–
475.
(7) Kaiser, C.; Pontecorvo, J.; Mewshaw, R. E. Neurotransm. 1991, 7, 1–5.
(8) Walker, J. M.; Rice, K. C. Pharmacol. ReV. 1990, 42, 353–402.
(9) Abou-Gharbia, M.; Ablordeppey, S. Y.; Glennon, R. A. In Annual Reports
in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press: San Diego, 1993,
Vol. 28, pp 1-10.
(10) Baeyens, J. M. PCT Int. Appl. 2006, WO 2006/010587 A1;Chem. Abstr.,
2006, 144, 121838.
(11) Hayashi, T.; Su, T.-P. CNS Drugs 2004, 18, 269–284.
(12) Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1992, 57, 1656–1662.
(13) Micouin, L.; Quirion, J. L.; Husson, H. P. Synth. Commun. 1996, 26,
1605–1611.
(14) Meyers, A. I.; Downing, S. V.; Weiser, M. J. J. Org. Chem. 2001, 66,
1413–1419.
(15) Wu¨nsch, T.; Meyers, A. I. J. Org. Chem. 1990, 55, 4233–4235.
(16) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org. Chem.
2003, 68, 1919–1928.
(17) Amat, M.; Pe´rez, M.; Minaglia, T.; Bosch, J. J. Org. Chem. 2008, 73,
6920–6923.
The ratio of diastereomers, which was formed during the
condensation of 1a-d with (R)-phenylglycinol, was determined
1
by interpretation of the H NMR spectra of the crude reaction
mixtures. Generally, 3-H of trans-configured benzolactams
3a-d gave characteristic triplets in the range 5.30-5.50 ppm
(J ) 8.0-8.9 Hz), whereas 3-H of the cis-configured benzolac-
tams 4a-d gave characteristic dd’s in the range 4.76-5.05 ppm
(J ) 7.5/2 Hz). The ratio of the diastereomeric tricyclic
benzolactams 3a-d:4a-d was determined by integration of
these characteristic 3-H signals. The results are summarized in
Table 1, which clearly indicate ratios of about 1:1 when using
a keto acid with an aliphatic residue at the keto group (1a-c).
In contrast to the reaction of alkyl keto acids 1a-c, the phenyl
keto acid 1d reacted with (R)-phenylglycinol (2) to form the
diastereomers trans-3d and cis-4d in the ratio 91:9 along with
a side product 5d causing a doublet at 5.60 ppm. The ratio of
the three compounds trans-3d, cis-4d, and 5d was 62:6:32, as
1
(18) Amat, M.; Llor, N.; Hidalgo, J.; Hernandez, A.; Bosch, J. Tetrahedron:
Asymmetry 1996, 7, 977–980.
(19) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503–9569.
(20) Meyers, A. I. J. Org. Chem. 2005, 70, 6137–6151.
(21) Munchhof, M. J.; Meyers, A. I. J. Org. Chem. 1995, 60, 7084–7085.
determined by integration of characteristic signals in the H
NMR spectrum of the crude reaction mixture.
(22) Husain, S. M.; Wu¨nsch, B. Synthesis 2008, 17, 2729–2732.
J. Org. Chem. Vol. 74, No. 7, 2009 2789

Husain et al.
TABLE 1. Ratio of trans- and cis-Configured Tricyclic
Benzolactams Formed by Condensation of 1a-d with 2
benzazepine ent-12d, the phenyl keto acid 1d was also reacted
with (S)-phenylglycinol (ent-2). In analogy with the transforma-
tion with (R)-phenylglycinol (2), trans- and cis-configured
diastereomers ent-3d and ent-4d were produced in a ratio of
90:10 using (S)-phenylglycinol, along with the indanone ent-
5d. The products ent-3d, ent-4d and ent-5d were purified and
isolated by flash chromatography in 46%, 2%, and 37% yield,
respectively.
trans/cis
ratio
R
3a/4a
3b/4b
3c/4c
3d/4d
52:48
52:48
54:46
91:9
Me
Et
n-Bu
Ph
ent-3d/ent-4d
90:10
Ph
The tricyclic benzolactams trans-3a-d, ent-3d, and cis-3a-c
were then reduced using alane (AlH3), which was formed in
situ from AlCl3/LiAlH4 (1:3). The reaction resulted in the
formation of two diastereomers 10 and 11. (Scheme 3) The
reduction of both diastereomers trans-3 and cis-4 led predomi-
nantly to the products with retention of configuration, respec-
tively. An X-ray crystal structure of the benzylated analogue
of 10a proves that the reduction with AlH3 had taken place with
retention of configuration at the original stereocenter C-11a.23
Since HPLC analysis with various achiral stationary phases
did not lead to a separation of the diastereomeric pairs 10/11,
the diastereomeric ratios were determined by a chiral HPLC
analysis, using CHIRALPAK AD-H column. With this HPLC
method it was possible to demonstrate that the flash chromato-
graphic purification led to a considerable improvement of the
diastereomeric ratios. Exemplarily, in case of the methyl
derivatives the diastereomeric ratios were increased from 93:7
to 98:2 (10a/11a) and from 89:11 to 99.5:0.5 (11a/10a). The
diastereomeric pairs 10b-d/11b-d were also separated by fc
and analyzed using the described chiral HPLC method (Table
2). Since the chromatographic behavior of the diastereomers
10 and 11 was quite similar, the complete separation resulted
in reduced yields. However, diastereomerically pure samples
were required for the synthesis of enantiomerically pure
2-substituted 3-benzazepines 12.
In the final step, 2-substituted 3-benzazepines 12 were
obtained by hydrogenolysis of compounds 10a-d, ent-10d, and
11a-c (Scheme 4). The removal of the 2-hydroxy-1-phenylethyl
moiety was performed with H2 and Pd/C as catalyst after
addition of a small amount of HCl. The compounds 12a-d and
ent-12a-d were obtained in 60-99% yields. However, the
3-benzazepines 12a and 12b with a small methyl or ethyl
substituent are rather volatile. So, it was difficult to remove the
solvent completely without dramatic loss of products.
The diastereomeric ratios determined for 10 and 11 are
identical to the enantiomeric ratios of the produced 2-substituted
tetrahydro-3-benzazpines 12. Thus, with exception of 12a and
12b (98:2), the 3-benzazepines 12 were isolated in almost
enantiomerically pure form (ee >99%) (Table 3).
SCHEME 2. Formation of the Diastereomeric Oxazolidines
3 and 4 and Indanone 5d
In order to unequivocally assign the configuration an X-ray
crystal structure analysis of the main diastereomer trans-3d was
performed. The third product 5d, which was formed in the
reaction of phenyl keto acid 1d with (R)-phenylglycinol, was
isolated in 32% yield. The structure of the indanone derivative
5d, which could not be assigned unequivocally using various
NMR spectroscopy techniques, was also identified by an X-ray
crystal structure analysis.
The formation of equal amounts of two diastereomers in case
of Me, Et, and n-Bu derivatives can be explained on the basis
of the reaction mechanism proposed by Meyers et al.14 (Scheme
2). Accordingly, the existence of an equilibrium between trans-
and cis-configured oxazolidines trans-8a-c and cis-9a-c, which
were formed by the loss of one water molecule, and the equally
stable tricyclic products trans-3a-c and cis-4a-c resulted in
the observed diastereomeric ratios of 1:1. In the case of phenyl
derivatives, the 91:9 ratio of trans-3d/cis-4d can be explained
by stabilizing π/π-interactions of the cis-oriented phenyl rings
in positions 2 and 4 of the trans-configured intermediate trans-
8d. This stabilizing effect shifts the equilibrium to trans-8d and
finally leads to the higher amount of trans-3d.
Receptor Affinity
The formation of indanone 5d was explained on the basis of
an imine-enamine tautomerism. In the enamine tautomer 7d,
the double bond is stabilized by two phenyl groups, which are
shifting the imine (6d)-enamine (7d) equilibrium on the
enamine side. The enamine 7d is able to attack the carboxy
group and provide the indanone 5d.
The condensation of phenyl keto acid 1d with (R)-phenylg-
lycinol (2) provided stereoselectively the trans-configured
diastereomer trans-3d with (R)-configuration at position 11a in
44% yield. However, the diastereomer cis-4d with (S)-config-
uration at position 11a was only formed in low amounts.
Considering the importance of the (11aS)-configured tricyclic
benzolactam cis-4d for the synthesis of the enantiomeric
The affinity of enantiomerically pure 2-substituted 3-benz-
azepines 12a-d and ent-12a-d to σ1 and σ2 receptors as well
as the PCP binding site of the NMDA receptor was determined
in receptor-binding studies.
In the σ assays, the radioligands [3H]-(+)-pentazocine (σ1)
and [3H]-ditolylguanidine (σ2) and membrane preparations from
guinea pig brains (σ1) and rat livers (σ2) were used.6,24,25 In
addition to σ receptor binding, the affinity toward NMDA
(23) Husain, S. M.; Fro¨hlich, R.; Wu¨nsch, B. Tetrahedron: Asymmetry 2008,
19, 1613–1616.
(24) De-Haven-Hudkins, D. L.; Fleissner, L. C.; Ford-Rice, F. Y. Eur.
J. Pharmacol.Mol. Pharmacol. Sect 1992, 227, 371–378.
(25) Mach, R. H.; Smith, C. H.; Childers, S. R. Life Sci. 1995, 57, 57–62.
2790 J. Org. Chem. Vol. 74, No. 7, 2009

Asymmetric Synthesis of 2-Substituted Tetrahydro-3-benzazepines
SCHEME 3. Reduction of trans- and cis-Configured Tricyclic Benzolactams with AlH3
TABLE 2. Diastereomeric Ratios and Yields of the Reduced Products 10a-d, ent-10d, and 11a-c after fc Purification
R
diastereomers
ratio
yield of 10 (%)
diastereomers
ratio
yield of 11 (%)
Me
Et
n-Bu
Ph
10a/11a
10b/11b
10c/11c
10d/11d
98:2
98:2
99.7:0.3
99.4:0.6
99.7:0.3
36
41
45
55
45
10a/11a
10b/11b
10c/11c
0.5:99.5
0.2:99.8
0.3:99.7
51
32
47
Ph
ent-10d/ent-11d
TABLE 3. Yields, Enantiomeric Excess, and Specific Optical Rotation of 2-Substituted 3-Benzazepines 12a-d and Their Enantiomers
ent-12a-d
R
compound
yield (%)
eeb (%)
specific rotation
compd
yield (%)
eeb (%)
specific rotation
Mea
12a
12b
12c
12d
88
77
92
60
96
96
99.4
98.8
+12.6
+28.9
+36.7
+52.7
ent-12a
ent-12b
ent-12b
ent-12d
73
83
94
80
99.0
99.6
99.4
99.4
-11.8
-32.8
-37.4
-54.9
Eta
n-Bu
Ph
a Volatile compounds! b The ee values are derived from the ratio of the diastereomers 10/11.
TABLE 4. Affinity of Enantiomerically Pure 2-Substituted
3-Benzazepines toward σ1, σ2, and NMDA Receptors
SCHEME 4. Hydrogenolysis of the Reduced Products
Ki ( SEM [nM]
compd
R
σ1
3670
σ2
NMDA
12a
Me
3053
9%a
1040
5%a
40%a
48%a
15%a
35%a
20%b
0%a
ent-12a
299 ( 114
12b
Et
36%a
ent-12b
40%a
12c
n-Bu
Ph
16 ( 1.4
879 ( 49
50 ( 34.8
3025 ( 1020
ent-12c
2062
616
12d
32%a
8%a
a
ent-12d
0%
427 ( 109
(+)-pentazocine
haloperidol
ditolylguanidine
(S)-ketamin
(+)-MK-801
4.2 ( 1.1
3.9 ( 1.5
61 ( 18
78 ( 2.3
42 ( 17
receptors was also included in this study because some potent
σ1 antagonists also interact with NMDA receptors. The affinity
for the PCP binding site of the NMDA receptor was determined
in competition experiments using the radioligand [3H]-(+)-MK-
801.6 Fresh pig brain cortex membrane preparations were
employed as receptor material.
383 ( 41
2.9 ( 0.6
a Inhibition of the radioligand binding at a concentration of 1 µM.
b Inhibition of the radioligand binding at a concentration of 10 µM.
With exception of ent-12a, both enantiomers of the 3-ben-
zazepines with small substituents (Me, Et) in position 2 (12a
and 12b) show very low σ1 affinity (Ki > 3000 nM). However,
the enantiomers 12c and 12d with a butyl or phenyl substituent
show high σ1 receptor affinity with Ki values of 16 and 50 nM,
respectively. The corresponding enantiomers ent-12c and ent-
12d display only low σ1 affinity indicating high eudismic ratios
of greater than 50 for both enantiomeric pairs. The σ1 receptor
shows a clear preference at least for the butyl and phenyl
substituted 3-benzazepines with a definite orientation of the
2-substituent ((2R) for 12c and (2S) for 12d).
the hydrophobic interactions are too small to produce consider-
able free energy during binding to the σ1 receptor protein.
The affinity of the 3-benzazepines 12 toward σ2 receptors is
considerably lower compared with their affinities to σ1 receptors,
indicating high σ1/σ2 selectivity. Only the phenyl derivatives
12d and ent-12d possess moderate σ2 affinity. Since both
enantiomers have almost the same Ki values, the eudismic ratio
is almost one. It should be noted that the receptor selectivity is
dramatically influenced by the stereochemistry. Whereas the
enantiomer 12d predominantly interacts with the σ1 receptor,
the enantiomer ent-12d prefers the σ2 subtype.
The high σ1 affinity of 12c and 12d may be due to the
presence of the long hydrophobic butyl chain or the large phenyl
ring, which fill up the hydrophobic pocket of the σ1 receptor.
In case of the smaller methyl and ethyl groups of 12a and 12b,
The affinity of all 3-benzazepines 12 and ent-12 toward the
PCP binding site of the NMDA receptor is very low. At a
concentration of 1 µM, the inhibition of radioligand binding is
lower than 50% indicating IC50 values greater than 1 µM. In
J. Org. Chem. Vol. 74, No. 7, 2009 2791

Husain et al.
(3R,11aS)-11a-Methyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]ox-
azolo[2,3-b][3]benzazepin-5(6H)-one (trans-3a) and (3R,11aR)-
11a-Methyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-
b][3]benzazepin-5(6H)-one (cis-4a). Following general procedure
A for the synthesis of tricyclic benzolactams, the keto acid 1a (766
mg, 3.98 mmol) and (R)-phenylglycinol (2, 546.1 mg, 3.98 mmol)
were heated to reflux in toluene (40 mL) for 3 d to obtain 1459 mg
particular the 2-butyl- and 2-phenyl-3-benzazepines 12c and 12d
represent potent σ1 ligands with high selectivity toward the σ2
receptor and the PCP binding site of the NMDA receptor.
Conclusion
A general procedure for the synthesis of chiral nonracemic
tricyclic benzolactams was established, which was used suc-
cessfully for the synthesis of enantiopure 2-substituted 3-benz-
azepines in only two reductive steps (AlH3; H2, Pd/C). A series
of four enantiomeric pairs 12a-d and ent-12a-d was synthesized
according to the new method. Receptor binding studies revealed
that the butyl and the phenyl derivatives 12c and 12d bind with
high affinity to σ1 receptors. Compounds 12c and 12d show
high eudismic ratios (>50) and high selectivity over the σ2
subtype and the PCP binding site of the NMDA receptor.
1
of crude product. The H NMR spectrum of the residue shows
signals for the diastereomers 3a and 4a in a ratio 50:50. The
diastereomers 3a and 4a were separated by flash chromatography
(L 5 cm, l ) 25 cm, V ) 30 mL, EtOAc/cyclohexane 10:90 to
40:60) and were further purified by recrystallization (CH2Cl2/n-
hexane). trans-3a: Rf ) 0.48 (petroleum ether/EtOAc 50:50);
colorless solid; yield 479 mg (41%); mp 141-143 °C; [R]20
)
589
-56.3 (c ) 0.54, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.32 (s,
3H, CH3), 3.24 (d, J ) 14.7 Hz, 1H, 11-H), 3.51 (d, J ) 14.7 Hz,
1H, 11-H), 3.89 (t, J ) 8.8 Hz, 1H, 2-H), 3.96 (m, 2H, 6-H), 4.48
(t, J ) 8.6 Hz, 1H, 2-H), 5.44 (t, J ) 8.0 Hz, 1H, 3-H), 7.15 (d, J
) 7.4 Hz, 2H, arom), 7.20-7.32 (m, 7H, arom); 13C NMR (100
MHz, CDCl3) δ 25.4 (1C, CH3), 43.4 (1C, C-11), 44.2 (1C, C-6),
60.9 (1C, C-2), 69.2 (1C, C-3), 94.5 (1C, C-11a), 125.6, 127.3,
127.9, 128.0, 129.6, 130.3 (9C, Ph-CH) 133.9, 134.6, 140.6, (3C,
Ph-C), 167.1 (1C, CdO); FT-IR (ATR, film) ν˜ (cm-1) 3027 (w,
arom C-H), 2985, 2883 (w, aliph C-H), 1635 (s, carbonyl CdO);
MS (EI) m/z 293 [M, 6], 251 [M - COCH2, 24], 160 [M -
(COCH2, C7H7), 72], 120 [PhCHCH2O, 100]; HPLC purity 92.8%,
tR ) 20.81 min; HRMS calcd for C19H19NO2H 294.1489, found
294.1485. cis-4a: Rf ) 0.14 (petroleum ether/EtOAc 50:50);
Experimental Section
General Methods. The keto acids 1a-d were prepared by
reaction of o-phenylenediacetic acid with organolithium reagents.
The method is being described in literature.22
General Procedure A for the Synthesis of Tricyclic Benzolac-
tams (Oxazolo-3-benzazepinones). A solution of keto acid (3.98
mmol, 1 equiv) and (R)-phenylglycinol (3.98 mmol, 1 equiv) in
toluene (40 mL) was heated to reflux for 3 d. Then the mixture
was cooled and concentrated in vacuum, and the residue was
dissolved in EtOAc (50 mL). The solution was washed with 1 M
NaOH (3 × 15 mL), the aqueous layer was extracted three times
with EtOAc, the combined EtOAc layers were washed with 1 M
HCl (3 × 15 mL), the HCl layers were extracted three times with
EtOAc, and the combined EtOAc layers were washed with a
saturated NaHCO3 solution, dried (Na2SO4), and concentrated in
colorless solid; yield 362.4 mg (31%); mp 99-101 °C; [R]20
)
589
+137 (c ) 0.57, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.55 (s,
3H, CH3), 3.31 (d, J ) 15.4 Hz, 1H, 11-H), 3.45 (d, J ) 14.9 Hz,
1H, 6-H), 3.53 (d, J ) 15.4 Hz, 1H, 11-H),3.76 (dd, J ) 9.0/ 2.0
Hz, 1H, 2-H), 3.79 (d, J ) 14.8 Hz, 1H, 6-H), 4.34 (dd, J ) 9.0/
7.7 Hz, 1H, 2-H), 4.93 (dd, J ) 7.4/1.4 Hz, 1H, 3-H), 6.71 (d, J )
7.0 Hz, 2H, arom), 6.97-7.26 (m, 7H, arom); 13C NMR (100 MHz,
CDCl3) δ 25.8 (1C, CH3), 43.4 (1C, C-11), 44.8 (1C, C-6), 60.3
(1C, C-2), 70.7 (1C, C-3), 94.0 (1C, C-11a), 125.7, 127.3, 127.6,
127.7, 128.4, 129.3, 130.3 (9C, Ph-CH), 134.5, 135.5, 141.9 (3C,
Ph-C), 167.2 (1C, CdO). FT-IR (ATR, Film): ν˜ (cm-1) ) 3028
(w, arom. C-H), 2979 (w, aliph C-H), 1652 (s, carbonyl CdO);
MS (EI) m/z 293 [M, 8], 251 [M - COCH2, 24], 160 [M -
(COCH2, C7H7), 65], 120 [PhCHCH2O, 100]; HPLC purity 99.5%,
tR ) 20.07 min; HRMS calcd for C19H19NO2H 294.1489, found
294.1489.
1
vacuum. The H NMR spectrum of the residue was recorded in
order to determine the ratio of the two diastereomers. The two
diastereomers were separated by flash chromatography and were
further purified by recrystallization (CH2Cl2/n-hexane) if necessary.
General Procedure B for the Reduction of Tricyclic Ben-
zolactams Using Alane (AlH3). At 0 °C, dry THF (8 mL) was
added to anhydrous AlCl3 (1.02 mmol, 1 equiv) under nitrogen
atmosphere. The resulting clear colorless solution was allowed to
stir at 0 °C for 5 min. Then a solution of LiAlH4 (1.0 M in THF,
3.05 mmol, 3 equiv) was added via syringe. The resulting clear,
colorless solution was allowed to warm to room temperature and
was stirred for 20 min to give a solution of alane (AlH3).
A solution of tricyclic benzolactam (1.02 mmol, 1 equiv) in dry
THF (8 mL) was added to the stirred, cooled (0 °C) solution of
alane in dry THF under nitrogen atmosphere. The resulting solution
was stirred at 0 °C for 3 h and then warmed to room temperature
over 30 min. The resulting clear solution was recooled to 0 °C and
then quenched by careful addition of 1 M HCl (only few drops).
The resulting slurry was diluted with water (10 mL) and extracted
with CH2Cl2 (3 × 15 mL). The combined organic layers were
washed with 1 M NaOH (back-extracted with CH2Cl2 (15 mL))
and washed with brine (15 mL). The combined organic layer was
dried (Na2SO4), filtered, and concentrated in vacuum to provide
thecrudeproduct,whichwasfurtherpurifiedbyflashchromatography.
General Procedure C for the Hydrogenolysis. A mixture of
phenylethanol derivative and Pd/C (10% by wt) in methanol and
1 M HCl (1.5 mL) was stirred at room temperature under a H2
atmosphere (balloon) for 4-6 h. The reaction mixture was
filtered using a silica bed, and the solvent 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), which
was back-extracted with CH2Cl2 (2×). The combined organic
layers were dried (Na2SO4), filtered, and concentrated in vacuo
(at max 30 °C) to provide an oily liquid which was purified by
flash chromatography.
(R)-2-[(R)-2-Methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-
2-phenylethanol (10a). Following general procedure B for reduc-
tion with AlH3, trans-3a (300 mg, 1.02 mmol) was reduced with
AlH3 to give 318 mg of the crude product. The product was purified
by column chromatography (EtOAc/cyclohexane 15:85) and ana-
lyzed for dr: colorless oil; yield 192.8 mg (66.7%); chiral HPLC
(n-hex/i-pro 98:2) ratio of 10a/11a ) 93: 7, tR(10a) ) 14.64, tR(11a)
) 16.26. After second column: L ) 2 cm, l ) 45 cm, V ) 100
mL, petroleum ether/EtOAc 95:5. After all columns: yield 104.1
mg (36%); ratio 10a/11a ) 98:2; [R]20 ) -48.2 (c ) 0.79,
589
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 0.81 (d, J ) 6.6 Hz, 3H,
CH3), 2.68 (dd, J ) 14.6/6.5 Hz, 1H, 1-H), 2.72-2.83 (m, 2H,
4-H/5-H), 2.98-3.09 (m, 2H, 4-H/5-H), 3.20-3.26 (m, 2H, 1-H/
2-H), 3.78 (dd, J ) 10.5/4.8 Hz, 1H, CH2OH), 3.95 (dd, J ) 10.4/
7.9 Hz, 1H, CH2OH), 4.02 (dd, J ) 7.8/4.8 Hz, 1H, NCHPh),
7.00-7.06 (m, 4H, arom), 7.28-7.36 (m, 5H, arom, asignal for
OH proton could not be detected; 13C NMR (100 MHz, CDCl3) δ
16.1 (1C, CH3), 37.0 (1C, C-5), 43.5 (1C, C-1), 45.6 (1C, C-4),
51.9 (1C, C-2), 61.5 (1C, CH2OH), 67.0 (1C, NCHPh), 126.4, 126.6,
128.0, 128.5, 128.7, 128.8, 130.1 (9C, Ph-CH), 139.0, 139.2, 141.2
(3C, Ph-C). FT-IR (ATR, film): ν˜ (cm-1) ) 3431 (w, O-H), 3062
(w, arom C-H), 3024 (w, arom C-H), 2928 (w, aliph C-H); MS
(EI) m/z 282 [MH+, 2], 251 [MH - (CH2OH), 100], 91 [C7H7,
21]; HPLC purity 97.4%, tR ) 17.20 min; HRMS calcd for
C19H23NOH: 282.1852, found 282.1861.
2792 J. Org. Chem. Vol. 74, No. 7, 2009

Asymmetric Synthesis of 2-Substituted Tetrahydro-3-benzazepines
(R)-2-[(S)-2-Methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-
2-phenylethanol (11a). Following general procedure B for reduc-
tion with AlH3, cis-4a (300 mg, 1.02 mmol) was reduced with AlH3
to give 328 mg of the crude product. The product was purified by
flash chromatography (EtOAc/cyclohexane 15:85) and analyzed for
dr: colorless oil; yield 228 mg (79%); chiral HPLC (n-hex/i-pro
98:2): ratio of 11a/10a ) 89:11, tR(10a) ) 14.64, tR(11a) ) 16.26.
After the first column (2 cm × 20 cm): cyclohexane/EtOAc 85:15.
After the second column (L ) 2 cm, l ) 45 cm, V ) 100 mL,
petroleum ether/EtOAc 95:5): yield 180.2 mg (62.6%), ratio of 11a/
10a ) 99.5:0.5; [R]20589 ) +5.0 (c ) 0.74, CH2Cl2); 1H NMR (400
MHz, CDCl3) δ 0.70 (d, J ) 6.7 Hz, 3H, CH3), 2.63 (dd, J )
14.4/6.3 Hz, 1H, 1-H), 2.69-2.76 (m, 2H, 4-H, 5-H), 3.02-3.08
(m, 2H, 4-H, 5-H), 3.34 (dd, J ) 14.4/2.6 Hz, 1H, 1-H), 3.39-3.46
(m, 1H, 2-H), 3.66 (dd, J ) 10.8/5.3 Hz, 1H, CH2OH), 3.84 (dd,
J ) 10.8/8.3 Hz, 1H, CH2OH), 3.98 (dd, J ) 8.2/5.3 Hz, 1H,
NCHPh), 7.02-7.15 (m, 4H, arom), 7.28-7.34 (m, 5H, arom), a
signal for OH proton could not be detected; 13C NMR (100 MHz,
CDCl3) δ 14.1 (1C, CH3), 37.2 (1C, C-5), 42.2 (1C, C-4), 43.5
(1C, C-1), 54.9 (1C, C-2), 62.2 (1C, CH2OH), 70.1 (1C, NCHPh),
126.4, 126.5, 127.9, 128.7, 128.8, 128.9, 130.2 (9C, Ph-CH), 139.0,
140.3, 141.4 (3C, Ph-C); FT-IR (ATR, film) ν˜ (cm-1) ) 3414 (b,
alcoholic OH), 3058, 3020 (w, arom C-H), 2962, 2927 (w, aliph
C-H); MS (EI) m/z 282 [MH+, 0.6], 250 [M - CH2OH, 100], 91
[C7H7, 15]; HPLC purity 98%, tR ) 17.20 min; HRMS calcd for
C19H23NOH 282.1852, found 282.1862.
(R)-2-Methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (12a). Fol-
lowing general procedure C for hydrogenolysis, 10a (97.7 mg, 0.34
mmol) was stirred under H2 to yield 80 mg of a crude yellow oil.
Flash chromatography (L ) 1 cm, l ) 25 cm, V ) 10 mL, EtOAc/
petroleum ether/NH3 79.5:20:0.5) of the crude product gave a
colorless liquid, yield 49 mg (88%), Rf ) 0.26 (EtOAc/MeOH/
NH3 30:69:1): [R]20589 ) +12.6 (c ) 0.2, CH2Cl2); 1H NMR (400
MHz, CDCl3) δ 1.18 (d, J ) 6.1 Hz, 3H, CH3), 2.72-2.91 (m,
5H, 1-H/2-H/4-H/5-H), 3.01 (ddd, J ) 14.7/10.6/1.9 Hz, 1H, 4-H),
3.23 (ddd, J ) 12.9/6.5/2.90 Hz, 1H, 5-H), 7.06-7.13 (m, 4H, Ph-
CH), asignal for NH proton could not be detected; 13C NMR (100
MHz, CDCl3) δ 24.0 (1C, CH3), 39.3 (1C, C-5), 46.7 (1C, C-1),
47.8 (1C, C-4), 53.5 (1C, C-2), 126.4, 126.4, 129.3, 129.8 (4C,
Ph-CH), 140.8, 142.4 (2C, Ph-C); FT-IR (ATR, film) ν˜ (cm-1) 3305
(w, NH), 3147, 3015 (w, arom C-H), 2965, 2929, 2897, 2821 (w,
aliph C-H); MS (EI) m/z 162 [MH+,100], 146 [M - CH3, 90],
115 [Ph-C3H5, 38]; HRMS calcd for C11H15NH 162.1277, found
162.1274; HPLC purity 99.1%, tR ) 11.79 min.
(R)-2-Ethyl-2,3,4,5-tetrahydro-1H-3-benzoazepine (12b). Fol-
lowing general procedure C for hydrogenolysis, 10b (126 mg, 0.42
mmol) was stirred under H2 to give a colorless liquid: yield 58.4
mg (77%); Rf ) 0.26 (EtOAc/MeOH/NH3 30:69:1); [R]20
)
589
+28.9 (c ) 0.58, CH2Cl2); HRMS calcd for C12H17NH 176.1434,
found 176.1446; HPLC purity 99.1%, tR ) 11.79 min.
(S)-2-Ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine (ent-12b). Fol-
lowing general procedure C for hydrogenolysis, 11b (109 mg, 0.36
mmol) was stirred under H2 to afford a colorless liquid: yield 54
mg (83%); [R]20589 ) -32.8 (c ) 0.76, CH2Cl2); HRMS calcd for
C12H17NH 176.1434, found 176.1458; HPLC purity 99.1%, tR
11.79 min.
)
(R)-2-Butyl-2,3,4,5-tetrahydro-1H-3-benzazepine (12c). Fol-
lowing general procedure C for hydrogenolysis, 10c (77 mg, 0.24
mmol) was stirred under H2 to give a pale yellow liquid: yield 44.8
mg (92%), Rf ) 0.12 (EtOAc/petroleum ether/NH3 80:19.5:0.5);
[R]20 ) +36.7 (c ) 0.72, CH2Cl2); HRMS calcd for C14H21NH
589
204.1747, found 204.1756; HPLC purity 97.2%, tR ) 16.51 min.
(S)-2-Butyl-2,3,4,5-tetrahydro-1H-3-benzazepine (ent-12c). Fol-
lowing general procedure C for hydrogenolysis, 11c (106 mg, 0.33
mmol) was stirred under H2 to afford a colorless liquid: yield 63.1
mg (94.7%); [R]20289 ) -37.4 (c ) 0.7, CH2Cl2); HRMS calcd for
C14H21NH 204.1747, found 204.1760; HPLC purity 98.5%, tR
16.46 min.
)
(S)-2-Phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (12d). Fol-
lowing general procedure C for hydrogenolysis, 10d (79.6 mg, 0.23
mmol) was stirred under H2 to produce a colorless liquid: yield 44
mg (85%); Rf ) 0.39 (EtOAc/petroleum ether/NH3 40:59.5:0.5);
[R]20 ) +34.7 (c ) 0.89, CH2Cl2); HRMS calcd for C16H17NH
589
224.1434, found 224.1436; HPLC purity 98%, tR ) 16.45 min.
(R)-2-Phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (ent-12d).
Following general procedure C for hydrogenolysis, ent-10d (52 mg,
0.15 mmol) was stirred under H2 to afford a colorless liquid: yield
27 mg (80%); [R]20589 ) -54.9 (c ) 0.49, CH2Cl2); HRMS calcd
for C16H17NH 224.1434, found 224.1425; HPLC purity 98.3%, tR
) 16.47 min.
Acknowledgment. We thank the NRW Graduate School of
Chemistry for a stipend, which is funded by the Government
of the State Nordrhein-Westfalen and the DAAD.
Supporting Information Available: 1H and 13C spectra and
crystallographic data (CIF) are available along with a description
of chiral HPLC methods and receptor binding studies. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(S)-2-Methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (ent-12a).
Following general procedure C for hydrogenolysis, 11a (36 mg,
0.13 mmol) was stirred under H2 to afford a colorless liquid: yield
15.5 mg (73%); [R]20289 ) -11.8 (c ) 0.3, CH2Cl2); HRMS calcd
for C11H15NH 162.1277, found 162.1276; HPLC purity 98.6%, tR
) 11.95 min.
JO900087E
J. Org. Chem. Vol. 74, No. 7, 2009 2793