Asymmetric synthesis of enantiomerically pure 1,4-di- and 1,1,4-trisubstituted tetrahydro-1H-3-benzazepines

Article abstract of DOI:10.1016/j.tetasy.2011.07.027

A four step asymmetric synthesis of 1,4-di- and 1,1,4-trisubstituted enantiomerically pure tetrahydro-3-benzazepines is described. Tricyclic oxazolobenzazepinones trans-9 and cis-10 allow the introduction of different alkyl groups (methyl, ethyl, allyl) w

Full text of DOI:10.1016/j.tetasy.2011.07.027

Tetrahedron: Asymmetry 22 (2011) 1411–1422
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Asymmetric synthesis of enantiomerically pure 1,4-di-
and 1,1,4-trisubstituted tetrahydro-1H-3-benzazepines
⇑
Soumya Sarkar, Dirk Schepmann, Bernhard Wünsch
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Hittorfstraße 58-62, D-48149 Münster, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A four step asymmetric synthesis of 1,4-di- and 1,1,4-trisubstituted enantiomerically pure tetrahydro-3-
benzazepines is described. Tricyclic oxazolobenzazepinones trans-9 and cis-10 allow the introduction of
different alkyl groups (methyl, ethyl, allyl) with high diastereoselectivity (dr >99:1). The relative config-
uration of the new stereogenic center was determined by NOE experiments. Tricyclic lactams trans-9 and
cis-10 were also used for the introduction of two substituents and, moreover, the establishment of spiro-
cyclic rings. Reduction of the substitution products 11 and 12 with AlCl3/LiAlH4 (1:3) took place with
retention of configuration and the final hydrogenolytic removal of the N-(2-hydroxy-1-phenylethyl) res-
idue provided enantiomerically pure 1,4-di- and 1,1,4-trisubstituted tetrahydro-3-benzazepines 17 and
ent-17. In receptor binding studies with radioligands, the 3-benzazepines 17a–g and ent-17a–g did not
Received 20 June 2011
Accepted 25 July 2011
Available online 1 September 2011
show any interactions with r1, r2 or NMDA receptors.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
leading to neuronal cell death. Acute and chronic neurodegenerative
disorders including epilepsy, Alzheimer’s or Parkinson’s disease are
associated with increased activation of the NMDA receptor.19–21
The synthesis of 1-benzyltetrahydro-3-benzazepines 4 with
various substituents at the 4-position was accomplished by benzy-
lation of various tricyclic lactams of type 9 and 10.16,17 Herein we
report on the asymmetric synthesis of 4-methyltetrahydro-3-ben-
zazepines 5 bearing various substituents at the 1-position. (Fig. 1)
In particular, the stereocontrol of the small CH3 residue at the 11a-
position is investigated. An additional feature of this manuscript is
the stereoselective introduction of two substituents at the 1-
position.
The tetrahydro-3-benzazepine ring system is of interest from a
medicinal chemistry point of view, because it contains the phenyl-
ethylamine structural element, which is found in many natural
products and pharmacologically active compounds.1–3 Derivatives
with the 3-benzazepine scaffold are well known as agonists or
antagonists at dopamine D14,5 and dopamine D3 receptors.6 The 1-
phenyl derivative 1 (SCH-23390) represents a typical D1 receptor
antagonist7,8 (Fig. 1). Furthermore, 1-methyl-2,3,4,5-tetrahydro-
1H-3-benzazepine 2 has been described as a selective 5-HT2C recep-
tor agonist, which can be used for the treatment of obesity.9,10 It has
also been shown that compounds with the 3-benzazepine scaffold
are active in the animal models of various neurological disorders
including Parkinson’s disease11 and Alzheimer’s disease.12
2. Results and discussion
Recently, syntheses of racemic13 and enantiomerically pure
1-substituted 3-benzazepines 314,15 and enantiomerically pure 4-
substituted 1-benzyltetrahydro-3-benzazepines 416–18 were
reported (Fig. 1), which showed moderate to high affinity to the
phencyclidine (PCP) binding site of the NMDA receptor. The NMDA
receptor is one of the excitatory ionotropic glutamate receptors,
The asymmetric synthesis of differently substituted 3-benzaze-
pines 5 started from commercially available o-phenylenediacetic
acid 6, which was transformed into methyl keto acid 7 upon treat-
ment with an excess of MeLi22 (Scheme 1). Condensation of methyl
keto acid 7 with (R)-2-amino-2-phenylethanol 8 led to the diaste-
reomeric tricyclic lactams trans-9 and cis-10. The ratio of the dia-
stereomeric methyl derivatives trans-9 to cis-10 was almost
50:50.16–18 The trans- and cis-configured tricyclic lactams trans-9
and cis-10 were separated and exploited for the synthesis of enan-
tiomerically pure 3-benzazepines 17 with various substituents at
the 1-position.
which is activated by N-methyl-D-aspartate (NMDA). It controls
the penetration of Na+- and Ca2+-ions into the neuron by highly bal-
anced systems and plays a crucial role in important physiological
processes such as learning and memory. However, over-stimulation
of NMDA receptors results in an uncontrolled influx of Ca2+ ions
For the introduction of one substituent at the 6-position, the tri-
cyclic lactams trans-9 and cis-10 were deprotonated with 1.2 equiv
of LHMDS at ꢀ78 °C and the formed enolates were trapped with
⇑
Corresponding author. Tel.: +49 251 8333311; fax: +49 251 8332144.
E-mail address: wuensch@uni-muenster.de (B. Wünsch).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.07.027

1412
S. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1411–1422
5
4
NH
3
2
NH
1
R1
H3C
2
3
R2
CH3
Cl
5
1
4
5
1
4
3
2
3 NH
NH
N
CH3
2
HO
R2
R1
5
Ph
4
1
Figure 1. Development of differently substituted tetrahydro-3-benzazepines 5 from biologically active lead compounds.
alkyl halides at ꢀ78 °C to afford the monosubstituted tricyclic lac-
tams 11a–c and 12a–c, respectively. (Scheme 1, Table 1) All trans-
formations took place with high diastereoselectivity and produced
only one diastereomer according to GC–MS analysis (dr >99:1). The
high diastereoselectivity is in good agreement with the previously
observed high diastereoselectivity for the benzylation16,17 of trans-
9 and cis-10. The high diastereoselectivity was not limited to large
electrophiles such as benzyl bromide, since even very small elec-
trophiles such as methyl iodide or ethyl iodide led to high
diastereoselectivity.
The relative configuration of the alkylated products 11a–c and
12a–c and thus the absolute configuration of the newly formed
stereogenic center at the 6-position of the tricyclic system was
confirmed by NOE experiments. The NOE difference spectrum of
the methylated compound 12a showed an increase of the signal
at 3.79 ppm (6-H) after irradiation at 1.65 ppm (CH3) thus indicat-
ing a cis-arrangement of these groups and a (S)-configuration at C-
6. In the control experiment, irradiation at 3.79 ppm (6-H) led to an
increased signal at 1.65 ppm (CH3). Similarly, the configuration of
the newly formed stereogenic center of compounds 11a–c [(R)-
configuration] and 12b–c [(S)-configuration] was confirmed by
corresponding NOE experiments. The stereochemistry of the alkyl-
ated products 11a–c and 12a–c reveals that the CH3 moiety at C-
11a of trans-9 and cis-10 controls the attack to the electrophile,
which takes place exclusively from the opposite face to the C-11a
methyl moiety.
Next, two substituents were introduced at the 6-position of the
tricyclic systems. At first, the alkylation of trans-9 and cis-10 was
tried using 3 equiv of base LHMDS and methyl iodide at 0 °C. The
dimethyl derivatives 11d and 12d were isolated in 71% and 64%
yield, respectively. (Scheme 1, Table 1) Similar yields were ob-
tained with 5 equiv of the larger electrophile ethyl iodide, which
gave diethyl derivatives 11e and 12e.
Five- and six-membered spirocyclic ring systems were also syn-
thesized following the described strategy. Deprotonation of trans-9
and cis-10 with an excess of LHMDS and reaction of the formed
enolates with one equivalent of 1,4-diiodobutane or 1,5-diiodo-
pentane gave the spirocyclic 3-benzazepines 11f,g and 12f,g in
good yields (Scheme 1, Table 1).
For the introduction of two different substituents23,24 at the 6-
position, the monomethylated tricyclic lactam 11a was deproto-
nated with LHMDS and the enolate was reacted with different alkyl
halides. (Scheme 2) Initially, the reaction conditions (ꢀ78 °C,
3 equiv of LHMDS, 2 h, EtI) employed successfully for monoalkyla-
tion of trans-9 and cis-10 were unsuccessful in yielding the dialky-
lated product 13a. Increasing the reaction temperature to 0 °C did
not lead to the desired product 13a. However, performing the
deprotonation of 11a with 3 equiv of LHMDS at +25 °C and the sub-
sequent addition of an excess of ethyl iodide at ꢀ78 °C provided
the expected 6-ethyl-6-methyl derivative 13a together with the
hydroxylated product 14a (ratio 13a:14a = 80:20). A similar result
was obtained after alkylation of 11a with benzyl bromide using the
1
H3C
H3C
O
10
7
O
11
2
(c)
N
N
4
Ph
Ph
6
O
O
R2
R1
trans-9
11a-f
CH3
CO2H
CO2H
(a)
(b)
O
CO2H
7
+
H3C
O
H3C
O
6
(c)
N
N
Ph
Ph
O
O
R1
12a-f
R2
cis-10
Scheme 1. Reagents and conditions: (a) CH3Li (8 equiv), THF, 0 °C?20 °C, 24 h, 50%; (b) (R)-2-amino-2-phenylethanol 8, 120 °C toluene, reflux, 45% (trans-9), 42% (cis-10);
(c) LHMDS, RX; for further details of the reaction conditions see Table 1.

S. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1411–1422
1413
Table 1
Introduction of alkyl substituents at the 6-position of trans-9 and cis-10
Entry
Educt
Temp (°C)
RX
Equiv of RX
Product
R1
R2
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
trans-9
trans-9
trans-9
cis-10
cis-10
cis-10
trans-9
trans-9
cis-10
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
0
0
0
0
0
CH3I
C2H5I
Allyl-Br
CH3I
C2H5I
Allyl-Br
CH3I
C2H5I
CH3I
C2H5I
1.2
1.2
2.0
1.2
1.2
2.0
3.0
5.0
3.0
5.0
1.0
1.0
1.0
1.0
11a
11b
11c
12a
12b
12c
11d
11e
12d
12e
11f
CH3
C2H5
H2C@CHCH2
CH3
C2H5
H2C@CHCH2
CH3
C2H5
CH3
C2H5
H
H
H
H
H
H
CH3
C2H5
CH3
C2H5
45
48
66
47
53
64
71
63
64
71
48
51
54
47
cis-10
trans-9
trans-9
cis-10
I(CH2)4I
I(CH2)5I
I(CH2)4I
I(CH2)5I
(CH2)4
(CH2)5
(CH2)4
(CH2)5
0
0
0
11g
12f
12g
cis-10
H3C
H3C
O
N
H3C
O
O
1. LHMDS, 25 °C
2. R2X, -78 °C
+
N
N
Ph
Ph
Ph
R1
O
O
R2
O
R1
OH
14a-c
R1
13a-d
11a,b,h
Scheme 2.
Table 2
Introduction of two different substituents at the 6-position
Entry
Educt
R1
R2X
Products
R1
R2
Ratio 13:14a
Yield (%)
1
2
3
4
11a
11a
CH3
CH3
C2H5
CH2Ph
C2H5I
PhCH2Br
CH3I
13a,14a
CH3
CH3
C2H5
CH2Ph
C2H5
CH2Ph
CH3
80:20
60:40
0:100
0:100
32
60
30
35
13b,14a
(13c),14b
(13d),14c
11b
11h16
CH3I
CH3
a
The ratio of 13:14 was calculated by integration of the characteristic signals in the 1H NMR spectra of the unpurified products.
same reaction conditions. Again, the 6-benzyl-6-methyl substi-
tuted compound 13b was formed together with the hydroxylated
product 14a. In this case, the ratio of 13b:14a was 60:40 reflecting
the increased size of the electrophile benzyl bromide (Table 2). Due
to the same Rf values of 13a,b and 14a, it was not possible to purify
the products 13a,b by flash chromatography.
CH3
H
CH3
H
OH
Ph
(a)
(a)
(b)
N
NH
11a-g
R1
R2
R2
R1
All attempts to alkylate the ethyl and benzyl substituted tricy-
clic lactams 11b and 11h16,17 with methyl iodide led exclusively
to the hydroxylated products 14b and 14c, that is, the correspond-
ing dialkylated products were not formed (Scheme 2). It has been
shown that the additional oxygen atom of 14a–c does not originate
from O2 or moisture, since all reactions were conducted strictly un-
der N2 excluding air and water and were repeated at least twice.
Therefore it was assumed that the oxygen atom of the new OH
group originates from the tricyclic lactam itself. Moreover, a simi-
lar oxidation was observed during the oxazolidine ring opening of
trans-9 with phenylmagnesium bromide.25 It can be concluded
that the introduction of a second different alkyl group at the 6-po-
sition of tricyclic lactams 11 and 12 is problematic due to low
yields, the formation of hydroxylated side products 14a–c and iso-
lation problems.
15a-g
17a-g
H
H
CH3
CH3
NH
OH
Ph
(b)
12a-g
N
R2
R2
R1
R1
16a-g
ent-17a-g
Scheme 3. Reagents and conditions: (a) AlCl3/LiAlH4 (1:3), THF; 0 °C or 70 °C, for
yields see Table 3; (b) H2 (1 atm), Pd/C, CH3OH, HCl, 4–6 h, for yields see Table 3.
ature of 70 °C, all reductions were performed at 0 °C. The AlH3
reductions took place with retention of configuration16–18 leading
to products 15a–g with an (R)-configuration and 16a–g with an
(S)-configuration at the 4-position of the 3-benzazepine ring
system, respectively. The retention of configuration can be ex-
plained by coordination of the Lewis acidic reducing agent AlH3
to the oxygen atom, opening of the oxazolidine ring and delivering
The conversion of mono- and dialkylated tricyclic lactams 11
and 12 into the corresponding 3-benzazepines required two suc-
cessive reduction steps (Scheme 3). At first, the oxazolidine moiety
and the lactam group were reduced by AlH3, which was generated
in situ upon mixing 1 equiv of AlCl3 and three equivalents of
26
LiAlH4 (Table 3). With the exception of the sterically demanding
diethyl derivatives 11e and 12e, which required a reaction temper-

1414
S. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1411–1422
Table 3
Reduction of 11 and 12 with AlCl3/LiAlH4 (1:3) and hydrogenolytic removal of the (R)-configured 2-hydroxy-1-phenylethyl residue
Entry
Educt
R1
R2
Producta
Yield (%)
Productb
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
11a
11b
11c
12a
12b
12c
11d
11e
12d
12e
11f
CH3
C2H5
H2C@CHCH2
CH3
C2H5
H2C@CHCH2
CH3
C2H5
CH3
C2H5
H
H
H
H
H
H
CH3
C2H5
CH3
C2H5
15a
15b
15c
16a
16b
16c
15d
15e
16d
16e
15f
55
82
75
60
80
72
71
85
69
73
75
60
70
69
17a
70
82
88
60
77
90
77
75
66
85
78
69
89
80
17b
17cc
ent-17a
ent-17b
ent-17cc
17d
17e
ent-17d
ent-17e
17f
17g
ent-17f
ent-17g
(CH2)4
(CH2)5
(CH2)4
(CH2)5
11g
12f
12g
15g
16f
16g
a
b
c
Product after reduction with AlCl3/LiAlH4 (1:3).
Product after hydrogenolysis.
For 17c and ent-17c, R1 = propyl.
one hydride from the same face as the departing oxygen atom. A
retention of configuration has been shown for other similar sys-
tems.16–18 The diastereomerically pure products 15 and 16 were
obtained in good yields (Table 3).
AlCl3/LiAlH4 1:3 led to the reductive opening of the oxazolidine
moiety and reduction of the lactam group. The final secondary
amines 17 and ent-17 were prepared by hydrogenolytic cleavage
of the N-(2-hydroxy-1-phenylethyl) moiety. The di- and trisubstit-
ued 3-benzazepines 17 and ent-17 did not show any significant
affinities to NMDA receptors (PCP site), or r1 and r2 receptors.
Finally the 2-hydroxy-1-phenylethyl residue (original chiral
auxiliary) at the 3-benzazepine N-atom of 15 and 16 had to be re-
moved. The hydrogenolytic removal (H2, Pd/C) of this group gave
high yields only, when 1 M HCl (1.5 mL) was added to the reaction
mixture (Scheme 3, Table 3). The diastereomeric 3-benzazepines
15 and 16 were transformed into enantiomeric 3-benzazepines
17 and ent-17 by removal of the (R)-configured N-residue. For
the allyl derivatives 15c and 16c, an additional hydrogenation of
the double bond took place leading to the corresponding propyl
derivatives 17c and ent-17c.
5. Experimental section
5.1. General
5.1.1. General methods and equipment
Unless otherwise mentioned, THF was dried with sodium/ben-
zophenone and was freshly distilled before use. Thin layer
chromatography (TLC): Silica Gel 60 F254 plates (Merck). Flash
In conclusion this strategy allows the synthesis of enantiomeri-
cally pure 1,4-disubstituted and 1,1,4-trisubstituted 3-benzaz-
epines in only four reaction steps starting from methyl keto acid 7.
chromatography (FC): Silica gel 60, 40–64 lm (Merck); parenthe-
ses include: diameter of the column, length of column, fraction
size, eluent, Rf value. IR: IR spectrophotometer 480Plus FT-ATR-IR
(Jasco). 1H NMR (400 MHz), 13C NMR (100 MHz): Mercury plus
400 spectrometer (Varian); d in ppm related to tetramethylsilane;
coupling constants are given with 0.5 Hz resolution. Where neces-
sary, the assignment of the signals in the 1H NMR and 13C NMR
spectra was performed using 1H–1H and 1H–13C COSY NMR spectra
as well as NOE (nuclear Overhauser effect) difference spectroscopy.
Optical rotations were determined with a Polarimeter 341 (Perkin
Elmer); length 1 dm, wavelength 589 nm (sodium D line); the unit
of the specific rotation [deg. mL dmꢀ1 gꢀ1] is omitted; concentra-
tion of the sample c [g/100 mL] and the solvents used are given
in brackets. MS: EI = electron impact, ESI = electro spray ionization:
MicroTof (Bruker Daltronics, Bremen), Calibration with sodium for-
mate clusters before measurement. Gas liquid chromatography
(GLC) was performed on a Shimadzu GC-17A gas chromatograph
equipped with an SE-54 capillary column (30 m ꢁ 0.32 mm,
3. Receptor binding studies
The affinities of the enantiomerically pure tetrahydro-3-benz-
azepines 17a–g and ent-17a–g toward NMDA receptors (PCP site),
r1 and r2 receptors were investigated in competitive receptor
binding studies. The affinity toward the PCP binding site of the
NMDA receptor was determined with the radioligand [3H]-(+)-
MK-801 and fresh pig brain cortex membrane preparations.15 In
the
[3H]-ditolylguanidine (
nea pig brains ( 1) and rat livers (
r
assays, the radioligands [3H]-(+)-pentazocine (
2) and membrane preparations from gui-
2) were used.27–30
r1) and
r
r
r
The 3-benzazepines 17a–g and ent-17a–g showed very low
affinities toward the PCP binding site of the NMDA receptor and
the r1 and r2 receptors. At a test compound concentration of
1 lM, the inhibition of radioligand binding was lower than 50%
indicating IC50 values greater than 1 lM.
0.25 lm film thickness) by CS-Chromatography Service using the
following program: N2 carrier gas, injection temperature 250 °C,
detector temperature 300 °C; temperature program: start temper-
ature 40 °C, heating rate 10 °C/min, end temperature 280 °C for
5 min.
4. Conclusion
In conclusion, enantiomerically pure 3-benzazepines 17a–g and
ent-17a–g were synthesized from tricyclic lactams trans-9 and cis-
10. After deprotonation with LHMDS both 6-mono- and 6,6-dialkyl
derivatives were obtained diastereoselectively. The configuration
of the newly formed stereogenic center at the 6-position of the tri-
cyclic lactams was confirmed by NOE experiments. The stepwise
introduction of two different alkyl substituents at the 6-position
was limited due to unexpected hydroxylation. Treatment with
5.1.2. General procedure A for the monoalkylation of tricyclic
lactams trans-9 and cis-10
Under N2 atmosphere, LHMDS (1 M in THF, 1.2 equiv) was
added to a cooled solution (ꢀ78 °C) of tricyclic lactam (1.0 equiv)
dissolved in THF (6 mL). After stirring for 1 h at ꢀ78 °C, alkyl halide
(1.2 equiv for methyl iodide and ethyl iodide and 2.0 equiv for ally
bromide) was added and the solution was further stirred for 3 h at

S. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1411–1422
1415
ꢀ78 °C. Completion of the transformation was confirmed by TLC.
5.2.2. (3R,6R,11aS)-6,11a-Dimethyl-3-phenyl-2,3,11,11a-
tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 11a
Saturated NaCl solution was added (10 mL) to hydrolyze the excess
of LHMDS and the mixture was extracted with EtOAc (3 ꢁ 10 mL).
The organic layer was washed with NaCl solution (10 mL) and
water (10 mL). The aqueous layer was reextracted with EtOAc
(2 ꢁ 10 mL). The combined organic layers were dried (Na2SO4), fil-
tered, the solvent was evaporated in vacuo and the residue was
purified by FC.
Following general procedure A, trans-9 (110 mg, 0.38 mmol)
was alkylated with methyl iodide (29 L, 0.46 mmol). The crude
l
product was purified by FC (d = 3 cm, l = 20 cm, V = 25 mL,
cyclohexane/EtOAc 8:2, Rf = 0.42 (cyclohexane/EtOAc 6:4)). Col-
orless liquid, yield 52 mg (45%). C20H21NO2 (307.4 g/mol). FT-IR
(ATR, film):
m
(cmꢀ1) = 2976 (aliphatic C–H), 1649 (C@O). 1H
NMR (CDCl3): d (ppm) = 1.48–154 (m, 6H, CH3/CH3), 3.35 (d,
J = 15.3 Hz, 1H, 11-H), 3.40 (d, J = 15.3 Hz, 1H, 11-H), 3.73 (dd,
J = 8.8/8.2 Hz, 1H, 2-H), 3.93 (q, J = 6.9 Hz, 1H, 6-H), 4.21 (t,
J = 8.8 Hz, 1H, 2-H), 5.03 (t, J = 8.4 Hz, 1H, 3-H), 7.08–7.26 (m,
9H, arom). 13C NMR (CDCl3): d (ppm) = 14.1 (1C, CH3), 27.1
(1C, CH3), 41.7 (1C, C-11), 44.6 (1C, C-6), 61.4 (1C, C-3), 69.0
(1C, C-2), 94.5 (1C, C-11a), 124.9,125.6, 127.2, 127.3, 128.1,
5.1.3. General procedure B for dialkylation of tricyclic lactams
trans-9 and cis-10
Under N2 atmosphere, LHMDS (1 M in THF, 3.0 equiv) was
added to a cooled solution (0 °C) of tricyclic lactam (1.0 equiv) dis-
solved in THF (6 mL). After stirring for 1 h at 0 °C, an excess of alkyl
halide (3.0 equiv for methyl iodide and 5.0 equiv for ethyl iodide)
was added. For the introduction of five and six membered spirocy-
clic rings 1,4-diiodobutane or 1,5-diiodopentane (1.0 equiv) was
added at 0 °C. The solution was stirred for a further 3 h at 0 °C.
Completion of the conversion was confirmed by TLC. Saturated
NaCl solution (10 mL) was then added and the mixture was ex-
tracted with EtOAc (3 ꢁ 10 mL). The organic layer was washed
with NaCl solution (10 mL) and water (10 mL) and the aqueous
layer was reextracted with EtOAc (2 ꢁ 10 mL). The combined or-
ganic layers were dried (Na2SO4), filtered, and the solvent was
evaporated in vacuo and the residue was purified by FC.
128.7, 130.3 (9C, Ph-CH), 133.9, 139.8, 140.7 (3C, Ph-C), 169.9
23
589
(1C, C@O). ½
a
ꢂ
¼ ꢀ154:4 (c 0.16, CH2Cl2). Exact mass (ESI):
m/z = calcd for C20H21NO2Na 330.1465, found 330.1467. Purity
(HPLC): 91.2% (tR = 20.07 min). GLC: tR = 16.9 min.
5.2.3. (3R,6R,11aS)-6-Ethyl-11a-methyl-3-phenyl-2,3,11,11a-
tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 11b
Following general procedure A, trans-9 (100 mg, 0.34 mmol)
was alkylated with ethyl iodide (0.68 mmol, 54 lL). The crude
product was purified by FC (d = 3 cm, l = 20 cm, V = 25 mL, cyclo-
hexane/EtOAc 85:15, Rf = 0.54 (cyclohexane/EtOAc 6:4)). Colorless
liquid, yield 52 mg (48%). C21H23NO2 (321.4 g/mol). FT-IR (ATR,
5.1.4. General procedure C for the reduction of tricyclic lactams
11 and 12 with AlCl3/LiAlH4
film):
m
(cmꢀ1) = 2963 (aliphatic C–H), 1653 (C@O). 1H NMR
Under N2 at 0 °C, dry THF (8 mL) was added to anhydrous
AlCl3 (1.02 mmol, 1.0 equiv). The resulting clear colorless solution
was stirred at 0 °C for 5 min. Then a solution of LiAlH4 (1 M in
THF, 3.05 mL, 3.05 mmol, 3.0 equiv) was added via syringe. The
resulting clear, colorless solution was allowed to warm to rt
and was stirred for 20 min to give a solution of alane (AlH3). A
solution of tricyclic lactam (1.02 mmol, 1.0 equiv) in dry THF
(8 mL) was added to the stirred, cooled (0 °C) solution of alane
in THF under N2. The resulting solution was stirred at 0 °C for
3 h and then warmed to rt over 30 min. For 6,6-disubstituted tri-
cyclic lactams, the reaction was carried out at a higher tempera-
ture and for a longer time (for 6,6-dimethyl derivatives: 0 °C,
overnight, and for 6,6-diethyl derivatives: 70 °C, overnight). The
resulting clear solution was cooled to 0 °C before 1 M HCl (only
few drops) was added carefully. 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 and brine
(15 mL), dried (Na2SO4), filtered, concentrated in vacuo and the
residue was purified by FC.
(CDCl3): d (ppm) = 0.95 (t, J = 7.3 Hz, 3H, CH2CH3), 1.52 (s, 3H,
CH3), 1.85–1.89 (m,1H, CH2CH3), 2.28–2.32 (m,1H, CH2CH3),
3.33 (d, J = 15.4 Hz, 1H, 11-H), 3.39 (d, J = 15.4 Hz, 1H, 11-H),
3.63 (t, J = 7.1 Hz, 1H, 6-H), 3.72 (dd, J = 8.8/8.2 Hz, 1H, 2-H),
4.23 (t, J = 8.8 Hz, 1H, 2-H), 5.06 (t, J = 8.4 Hz, 1H, 3-H), 7.01–
d (ppm) = 12.9 (1C,
CH2CH3), 21.6 (1C, CH3), 26.9 (1C, CH2CH3), 44.8 (1C, C-6), 49.9
(1C, C-11), 61.2 (1C, C-3), 69.0 (1C, C-2), 94.6 (1C, C-11a),
7.28 (m, 9H, arom). 13C NMR (CDCl3):
125.4, 125.7, 127.2, 127.3, 128.0, 128.7, 130.3 (9C, Ph-CH),
23
589
134.1, 138.9, 140.7 (3C, Ph-C), 169.3 (1C, C@O). ½
a
ꢂ
¼ ꢀ169:9
(c 0.14, CH2Cl2). Exact mass (ESI): m/z = calcd for C21H23NO2Na
344.1621, found 344.1614. Purity (HPLC): 99.2% (tR = 18.36 min).
GLC: tR = 17.2 min.
5.2.4. (3R,6R,11aS)-6-Allyl-11a-methyl-3-phenyl-2,3,11,11a-
tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 11c
Following general procedure A, trans-9 (91 mg, 0.31 mmol)
was alkylated with allyl bromide (0.62 mmol, 54 lL). The crude
product was purified by FC (d = 3 cm, l = 20 cm, V = 25 mL, cyclo-
hexane/EtOAc 85:15, Rf = 0.56 (cyclohexane/EtOAc 6:4)). Colorless
liquid, yield 68 mg (66%). C22H23NO2 (333.4 g/mol). FT-IR (ATR,
5.1.5. General procedure D for the hydrogenolysis of 15 and 16
A mixture of phenylethanol derivative 15 or 16, Pd/C (10% by
wt), methanol and 1 M HCl (1.5 mL) was stirred at rt under a H2
atmosphere (balloon) for 4–6 h. The reaction mixture was filtered
using a silica gel bed and the solvent was removed under re-
duced pressure to obtain a residue, which was dissolved in
CH2Cl2 (10 mL). The CH2Cl2 layer was washed with 1 M NaOH
(3 ꢁ 4 mL), which was extracted with CH2Cl2 (2ꢁ), dried
(Na2SO4), filtered, concentrated in vacuo, and the residue was
purified by FC.
film):
m
(cmꢀ1) = 2985 (aliphatic C–H), 1653 (C@O). 1H NMR
(CDCl3): d (ppm) = 1.54 (s, 3H, CH3). 2.55–2.69 (m, 1H, CH2–
CH@CH2), 2.96–3.08 (m, 1H, CH2–CH@CH2), 3.30 (d, J = 15.4 Hz,
1H, 11-H), 3.45 (d, J = 15.4 Hz, 1H, 11-H), 3.72 (dd, J = 8.8/
8.2 Hz, 1H, 2-H), 3.80–3.87 (m, 1H, 6-H), 4.22 (t, J = 8.8 Hz, 1H,
2-H), 4.95–5.11 (m, 3H, 3-H/CH2–CH@CH2), 5.76–5.91 (m, 1H,
CH2–CH@CH2), 7.01–7.32 (m, 9H, arom). 13C NMR (CDCl3): d
(ppm) = 26.9 (1C, CH3), 31.9 (1C, CH2–CH@CH2), 44.5 (1C, C-6),
47.2 (1C, C-11), 60.9 (1C, C-3), 68.8 (1C, C-2), 94.3 (1C, C-11a),
116.6 (1C, CH2–CH@CH2), 125.2, 125.3, 127.0, 127.2, 127.9,
5.2. Synthetic procedures
128.5, 130.2 (9C, Ph-CH), 133.8, 136.2, 138.0, 140.4 (4C, Ph-C/
23
5.2.1. Starting compounds
CH2–CH@CH2), 168.5 (1C, C@O). ½
a
ꢂ
¼ ꢀ210:0 (c 0.20, CH2Cl2).
589
The keto acid 7 was prepared as described in the literature.22
The synthesis of the diastereomeric tricyclic lactams trans-9 and
cis-10 was performed according to the literature.16,17
Exact mass (ESI): m/z = calcd for C22H23NO2Na 356.1621, found
356.1626.
Purity
(HPLC):
93.3%
(tR = 21.73 min).
GLC:
tR = 17.5 min.

1416
S. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1411–1422
5.2.5. (3R,11aS)-6,6,11a-Trimethyl-3-phenyl-2,3,11,11a-
tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 11d
Following general procedure B, trans-9 (41 mg, 0.14 mmol) was
5.2.8. (3R,11aS)-11a-Methyl-3-phenyl-2,3,11,11a-tetrahydro-
spiro[[1,3]oxazolo[2,3-b][3]benzazepine-6,10-cyclohexan]-5-
one 11g
dimethylated with an excess of methyl iodide (26
lL, 0.42 mmol).
Following general procedure B, trans-9 (60 mg, 0.21 mmol) was
The crude product was purified by FC (d = 3 cm, l = 20 cm,
V = 10 mL, cyclohexane/EtOAc 85:15, Rf = 0.62 (cyclohexane/EtOAc
6:4)). Colorless liquid, yield 31 mg (71%). C21H23NO2 (321.4 g/mol).
alkylated with 1,5-diiodopentane (31 lL, 0.21 mmol). The crude
product was purified by FC (d = 3 cm, l = 25 cm, V = 10 mL, cyclo-
hexane/EtOAc 85:15, Rf = 0.60 (cyclohexane/EtOAc 6:4)). Colorless
liquid, yield 38 mg (51%). C24H27NO2 (361.5 g/mol). FT-IR (ATR,
FT-IR (ATR, film):
m
(cmꢀ1) = 2972 (aliphatic C–H), 1631 (C@O). 1H
NMR (CDCl3): d (ppm) = 1.12 (s, 3H, CH3), 1.46 (s, 3H, CH3), 1.66 (s,
3H, CH3), 3.02 (d, J = 14.4 Hz, 1H, 11-H), 3.40 (d, J = 14.4 Hz, 1H, 11-
H), 3.73 (dd, J = 9.6/9.1 Hz, 1H, 2-H), 4.37 (dd, J = 8.8/8.4 Hz, 1H, 3-
H), 5.51 (dd, J = 9.6/8.4 Hz, 1H, 2-H), 7.05–7.42 (m, 9H, arom). 13C
NMR (CDCl3): d (ppm) = 23.6 (1C, CH3), 31.1 (1C, CH3), 31.7 (1C,
CH3), 47.1 (1C, C-11), 50.0 (1C, C-6), 62.6 (1C, C-3), 69.7 (1C, C-2),
95.6 (1C, C-11a), 125.9, 127.1, 127.5, 127.8, 128.0, 128.9, 131.3
film): m
(cmꢀ1) = 2926 (aliphatic C–H), 1637 (C@O). 1H NMR
(CDCl3): d (ppm) = 1.16–1.20 (m, 2H, CH2), 1.28 (s, 3H, CH3),
1.40–1.54 (m, 3H, CH2), 1.71–1.80 (m, 1H, CH2), 1.84–1.95 (m,
1H, CH2), 1.97–2.03 (m, 1H, CH2), 2.14–2.22 (m, 1H, CH2), 2.48–
2.59 (m, 1H, CH2), 3.28 (d, J = 15.4 Hz, 1H, 11-H), 3.42 (d,
J = 15.4 Hz, 1H, 11-H), 3.72 (t, J = 9.2 Hz, 1H, 2-H), 4.29 (t,
J = 8.6 Hz, 1H, 2-H), 5.40 (t, J = 8.9 Hz, 1H, 3-H), 6.97–7.51 (m, 9H,
arom). 13C NMR (CDCl3): d (ppm) = 23.2 (1C, CH3), 23.6, 24.7,
25.9 (3C, CH2CH2CH2CH2CH2), 36.2, 37.3 (2C, CH2-(CH2)3CH2),
47.1 (1C, C-11), 53.2 (1C, C-6), 62.5 (1C, C-3), 69.4 (1C, C-2), 95.6
(1C, C-11a), 126.2, 127.1, 127.4, 127.6, 127.7, 128.7, 129.4, 131.9
(9C, Ph-CH) 133.5 139.7, 143.6 (3C, Ph-C), 176.7 (1C, C@O).
23
589
½
a
C
ꢂ
¼ þ107:2 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for
21H23NO2Na 344.1621, found 344.1627. Purity (HPLC): 92.4%
(tR = 22.09 min).
(9C, Ph-CH), 134.4, 140.3, 142.2 (3C, Ph-C), 175.9 (1C, C@O).
23
589
½
a
C
ꢂ
¼ þ32:3 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for
5.2.6. (3R,11aS)-6,6-Diethyl-11a-methyl-3-phenyl-2,3,11,11a-
tetrahydro[1,3]oxazolo-[2,3-b][3]benzazepin-5(6H)-one 11e
Following general procedure B, trans-9 (100 mg, 0.34 mmol)
24H27NO2Na 384.1934, found 384.1936. Purity (HPLC): 99.7%
(tR = 22.92 min).
was diethylated with an excess of ethyl iodide (105 lL,
5.2.9. (3R,6S,11aR)-6,11a-Dimethyl-3-phenyl-2,3,11,11a-
tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 12a
Following general procedure A, cis-10 (83 mg, 0.28 mmol) was
1.70 mmol). The crude product was purified by FC (d = 3 cm,
l = 20 cm, V = 10 mL, cyclohexane/EtOAc 85:15, Rf = 0.63 (cyclohex-
ane/EtOAc 6:4)). Colorless liquid, yield 75 mg (63%). C23H27NO2
alkylated with methyl iodide (21 lL, 0.34 mmol). The crude prod-
(349.5 g/mol). FT-IR (ATR, film):
m
(cmꢀ1) = 2959 (aliphatic C–H),
uct was purified by FC (d = 3 cm, l = 20 cm, V = 25 mL, cyclohex-
ane/EtOAc 85:15, Rf = 0.31 (cyclohexane/EtOAc 6:4)). Colorless
liquid, yield 40 mg (47%). C20H21NO2 (307.4 g/mol). FT-IR (ATR,
1625 (C@O). 1H NMR (CDCl3): d (ppm) = 0.57 (t, J = 7.4 Hz, 3H,
CH2CH3), 0.62 (t, J = 7.4 Hz, 3H, CH2CH3), 1.31 (s, 3H, CH3), 1.34–
1.48 (m, 1H, CH2CH3), 1.94–2.04 (m, 1H, CH2CH3), 2.14–2.24 (m,
1H, CH2CH3), 2.35–2.45 (m, 1H, CH2CH3), 3.06 (d, J = 14.4 Hz, 1H,
11-H), 3.41 (d, J = 14.4 Hz, 1H, 11-H), 3.86 (t, J = 9.7 Hz, 1H, 2-H),
4.35–4.41 (m, 1H, 2-H), 5.48 (dd, J = 10.2/7.9, 1H, 3-H), 7.13–7.39
(m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 9.7 (1C, CH2CH3), 9.8
(1C, CH2CH3), 24.5 (1C, CH3), 36.2 (1C, CH2CH3), 38.4 (1C, CH2CH3),
48.1 (1C, C-11), 59.9 (1C, C-6), 64.0 (1C, C-3), 69.9 (1C, C-2), 95.5
(1C, C-11a), 126.8, 127.3, 127.7, 127.8, 128.5, 128.7, 131.2 (9C,
film):
m
(cmꢀ1) = 2927 (aliphatic C–H), 1655 (C@O). 1H NMR
(CDCl3): d (ppm) = 1.40 (d, J = 6.9 Hz, 3H, CH3), 1.65 (s, 3H, CH3),
3.35 (d, J = 15.5 Hz, 1H, 11-H), 3.49 (d, J = 15.5 Hz, 1H, 11-H), 3.64
(dd, J = 9.1/1.9 Hz, 1H, 2-H), 3.79 (q, J = 6.8 Hz, 1H, 6-H), 4.28 (dd,
J = 9.1/7.6 Hz, 1H, 2-H), 4.82 (dd, J = 7.6/1.8, 1H, 3-H), 6.37–6.41
(m, 2H, arom), 6.79–7.31 (m, 7H, arom). 13C NMR (CDCl3): d
(ppm) = 12.1 (1C, CH3), 27.1 (1C, CH3), 41.1 (1C, C-6), 45.2 (1C, C-
11), 60.1 (1C, C-3), 70.7 (1C, C-2), 94.2 (1C, C-11a), 124.6, 125.3,
Ph-CH), 135.7, 139.4, 139.9 (3C, Ph-C), 175.3 (1C, C@O).
127.1, 127.2, 127.4, 127.7, 128.3, 128.9, 130.2 (9C, Ph-CH), 135.0,
23
589
½
a
C
ꢂ
¼ þ120:5 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for
23
589
141.0, 142.1 (3C, Ph-C), 169.5 (1C, C@O). ½
a
ꢂ
¼ þ124:8 (c 0.16,
23H27NO2Na 372.1934, found 372.1933. Purity (HPLC): 96.9%
CH2Cl2). Exact mass (ESI): m/z = calcd for C20H21NO2Na 330.1465,
found 330.1462. Purity (HPLC): 92.7% (tR = 19.53 min). GLC:
tR = 16.5 min.
(tR = 22.48 min).
5.2.7. (3R,11aS)-11a-Methyl-3-phenyl-2,3,11,11a-tetrahydro-
spiro[[1,3]oxazolo[2,3-b][3]benzazepine-6,10-cyclopentan]-5-
one 11f
Following general procedure B, trans-9 (56 mg, 0.19 mmol)
was alkylated with 1,4-diodobutane (25 lL, 0.19 mmol). The
5.2.10. (3R,6S,11aR)-6-Ethyl-11a-methyl-3-phenyl-2,3,11,11a-
tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 12b
Following general procedure A, cis-10 (71 mg, 0.25 mmol) was
ethylated with EtI (0.50 mmol, 40 lL). The crude product was
purified by FC (d = 3 cm, l = 20 cm, V = 25 mL, cyclohexane/EtOAc
crude product was purified by FC (d = 3 cm, l = 25 cm,
V = 10 mL, cyclohexane/EtOAc 85:15, Rf = 0.59 (cyclohexane/
85:15, Rf = 0.40 (cyclohexane/EtOAc 6:4)). Colorless liquid, yield
EtOAc 6:4)). Colorless liquid, yield 32 mg (48%).
C23H25NO2
41 mg (53%).
C21H23NO2 (321.4 g/mol). FT-IR (ATR, film): m
(cmꢀ1) = 2954 (aliphatic C–
(cmꢀ1) = 2946 (aliphatic C–H), 1654 (C@O). 1H NMR (CDCl3): d
(ppm) = 1.00 (t, J = 7.3 Hz, 3H, CH2CH3), 1.71 (s, 3H, CH3), 1.75–
1.86 (m, 1H, CH2CH3), 2.15–2.27 (m, 1H, CH2CH3), 3.43 (d,
J = 15.4 Hz, 1H, 11-H), 3.52–3.60 (m, 2H, 11-H/6-H), 3.73 (dd,
J = 9.2/1.9 Hz, 1H, 2-H), 4.35 (dd, J = 9.1/7.6 Hz, 1H, 2-H), 4.90
(dd, J = 7.5/1.8 Hz, 1H, 3-H), 6.46–6.51 (m, 2H, arom), 6.91–7.37
(m, 7H, arom). 13C NMR (CDCl3): d (ppm) = 12.8 (1C, CH2CH3),
20.1 (1C, CH3), 26.3 (1C, CH2CH3), 45.3 (1C, C-6), 49.4 (1C, C-
11), 60.2 (1C, C-3), 70.7 (1C, C-2), 94.2 (1C, C-11a), 125.4,
(347.5 g/mol). FT-IR (ATR, film):
m
H), 1632 (C@O). 1H NMR (CDCl3): d (ppm) = 1.20 (s, 3H, CH3),
1.53–1.62 (m, 1H, CH2), 1.67–1.82 (m, 4H, CH2), 2.17–2.28 (m,
1H, CH2), 2.57–2.71 (m, 2H, CH2), 3.24 (d, J = 14.7 Hz, 1H, 11-
H), 3.43 (d, J = 14.7 Hz, 1H, 11-H), 3.73 (t, J = 8.9 Hz, 1H, 2-H),
4.34 (t, J = 8.7 Hz, 1H, 2-H), 5.45 (t, J = 8.8 Hz, 1H, 3-H), 7.01–
7.33 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 24.6 (1C, CH3),
26.1, 26.5 (2C, CH2–CH2CH2CH2), 40.1, 42.3 (2C, CH2–CH2CH2CH2),
46.1 (1C, C-11), 59.9 (1C, C-6), 62.3 (1C, C-3), 69.2 (1C, C-2), 95.2
(1C, C-11a), 125.6, 127.0, 127.3, 127.7, 127.9, 128.8, 131.5 (9C,
125.5, 127.1, 127.7, 128.3, 130.3 (9C, Ph-CH), 135.2, 140.2,
23
589
Ph-CH), 134.2, 140.5, 143.4 (3C, Ph-C), 175.1 (1C, C@O).
142.1 (3C, Ph-C), 168.9 (1C, C@O).
½
a
ꢂ
¼ þ120:6 (c 0.14,
23
589
½
a
C
ꢂ
¼ þ24:8 (c 0.12, CH2Cl2). Exact mass (ESI): m/z = calcd for
CH2Cl2). Exact mass (ESI): m/z = calcd for C21H23NO2Na
344.1621, found 344.1622. Purity (HPLC): 96.5% (tR = 18.27 min).
GLC: tR = 16.7 min.
23H25NO2Na 370.1778, found 370.1780. Purity (HPLC): 96.4%
(tR = 22.34 min).

S. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1411–1422
1417
5.2.11. (3R,6S,11aR)-6-Allyl-11a-methyl-3-phenyl-2,3,11,11a-
tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 12c
Following general procedure A, cis-10 (49 mg, 0.17 mmol) was
5.2.14. (3R,11aR)-11a-Methyl-3-phenyl-2,3,11,11a-tetrahydro-
spiro[[1,3]oxazolo[2,3-b][3]benzazepine-6,10-cyclopentan]-5-
one 12f
allylated with allyl bromide (0.34 mmol, 29
lL). The crude prod-
Following general procedure B, cis-10 (69 mg, 0.24 mmol) was
uct was purified by FC (d = 3 cm, l = 20 cm, V = 10 mL, cyclohex-
reacted with 1,4-diiodobutane (32 lL, 0.24 mmol). The crude prod-
ane/EtOAc 85:15, Rf = 0.43 (cyclohexane/EtOAc 6:4)). Colorless
uct was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclohexane/
oil, yield 36 mg (64%).
C22H23NO2 (333.4 g/mol). FT-IR (ATR,
EtOAc 85:15, Rf = 0.59 (cyclohexane/EtOAc 6:4)). Colorless liquid,
yield 44 mg (54%). C23H25NO2 (347.5 g/mol). FT-IR (ATR, film): m
film):
m
(cmꢀ1) = 2971 (aliphatic C–H), 1654 (C@O). 1H NMR
(CDCl3): d (ppm) = 1.65 (s, 3H, CH3), 2.47–2.51 (m, 1H, CH2–
CH@CH2), 2.87–2.91 (m, 1H, CH2–CH@CH2), 3.37 (d, J = 15.5 Hz,
1H, 11-H), 3.50 (d, J = 15.5 Hz, 1H, 11-H), 3.63–3.71 (m, 2H, 2-
H/6-H), 4.28 (dd, J = 9.1/7.6 Hz, 1H, 2-H), 4.82 (dd, J = 7.5/
1.7 Hz, 1H, 3-H), 4.96 (dd, J = 10.2/1.7 Hz, 1H, CH2–CH@CH2),
5.04 (dd, J = 17.2/1.7 Hz, 1H, CH2–CH@CH2), 5.76–5.91 (m, 1H,
CH2–CH@CH2), 6.39–7.32 (m, 9H, arom). 13C NMR (CDCl3): d
(ppm) = 25.2 (1C, CH3), 29.5 (1C, CH2–CH@CH2), 44.0 (1C, C-6),
45.8 (1C, C-11), 58.9 (1C, C-3), 69.4 (1C, C-2), 93.0 (1C, C-11a),
115.5 (1C, CH2–CH@CH2), 124.0, 124.1, 125.8, 126.0, 126.4,
(cmꢀ1) = 2921 (aliphatic C–H), 1617 (C@O). 1H NMR (CDCl3): d
(ppm) = 1.24 (s, 3H, CH3), 1.40–1.49 (m, 2H, CH2), 1.58–1.74 (m,
2H, CH2), 1.84–1.91 (m, 1H, CH2), 2.07–2.14 (m, 1H, CH2), 2.44–
2.47 (m, 1H, CH2), 2.74–2.81 (m, 1H, CH2), 3.43 (d, J = 14.9 Hz,
1H, 11-H), 3.84 (dd, J = 9.1/2.6 Hz, 1H, 2-H), 3.89 (d, J = 14.9 Hz,
1H, 11-H), 4.41 (dd, J = 9.1/7.9 Hz, 1H, 2-H), 4.99 (dd, J = 7.8/
2.6 Hz, 1H, 3-H), 7.08–7.33 (m, 9H, arom). 13C NMR (CDCl3): d
(ppm) = 24.3 (1C, CH3), 24.7, 34.7 (2C, CH2CH2CH2CH2), 40.3, 45.3
(2C, CH2CH2CH2CH2), 59.6 (1C, C-6), 62.1 (1C, C-3), 70.5 (1C, C-2),
94.4 (1C, C-11a), 126.1, 127.2, 127.3, 127.4, 127.7, 128.5, 132.1
127.0, 129.1 (9C, Ph-CH), 133.8, 135.3, 138.4, 140.7 (4C,
(9C, Ph-CH), 135.6, 142.9, 143.0 (3C, Ph-C), 171.5 (1C, C@O).
23
23
Ph-C/CH2–CH@CH2), 167.0 (1C, C@O). ½
aꢂ
¼ þ125:6 (c 0.16,
½
a
ꢂ
¼ ꢀ9:6 (c 0.24, CH2Cl2). Exact mass (ESI): m/z = calcd for
589
589
CH2Cl2). Exact mass (ESI): m/z = calcd for C22H23NO2Na
356.1621, found 356.1613. Purity (HPLC): 97.1% (tR = 19.08 min).
GLC: tR = 17.1 min.
C23H25NO2Na 370.1778, found 370.1774. Purity (HPLC): 94.8%
(tR = 22.01 min).
5.2.15. (3R,11aR)-11a-Methyl-3-phenyl-2,3,11,11a-tetrahydro-
spiro[[1,3]oxazolo[2,3-b][3]benzazepine-6,10-cyclohexan]-5-
one 12g
Following general procedure B, cis-10 (45 mg, 0.15 mmol) was
reacted with 1,5-diiodopentane (21 lL, 0.15 mmol). The crude
5.2.12. (3R,11aR)-6,6,11a-Trimethyl-3-phenyl-2,3,11,11a-tetra-
hydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 12d
Following general procedure B, cis-10 (102 mg, 0.35 mmol) was
dimethylated with an excess of methyl iodide (65 lL, 1.05 mmol).
The crude product was purified by FC (d = 1 cm, l = 20 cm,
V = 10 mL, cyclohexane/EtOAc 85:15, Rf = 0.53 (cyclohexane/EtOAc
6:4)). Colorless oil, yield 38 mg (64%). C21H23NO2 (321.4 g/mol). FT-
product was purified by FC (d = 1 cm, l = 25 cm, V = 10 mL, cyclo-
hexane/EtOAc 85:15, Rf = 0.61 (cyclohexane/EtOAc 6:4)). Colorless
liquid, yield 25 mg (47%). C24H27NO2 (361.5 g/mol). FT-IR (ATR,
IR (ATR, film):
m
(cmꢀ1) = 2946 (aliphatic C–H), 1613 (C@O). 1H
film):
m
(cmꢀ1) = 2954 (aliphatic C–H), 1640 (C@O). 1H NMR
NMR (CDCl3): d (ppm) = 0.90 (s, 3H, CH3), 1.24 (s, 3H, CH3), 1.57
(s, 3H, CH3), 3.11 (d, J = 14.6 Hz, 1H, 11-H), 3.76 (dd, J = 9.1/
2.1 Hz, 1H, 2-H), 3.88 (d, J = 14.6 Hz, 1H, 11-H), 4.26 (dd, J = 9.1/
7.5 Hz, 1H, 2-H), 4.95 (dd, J = 7.4/2.1 Hz, 1H, 3-H), 7.01–7.39 (m,
9H, arom). 13C NMR (CDCl3): d (ppm) = 23.9 (1C, CH3), 27.4 (1C,
CH3), 31.6 (1C, CH3), 46.7 (1C, C-11), 49.3 (1C, C-6), 62.9 (1C, C-
3), 70.3 (1C, C-2), 93.8 (1C, C-11a), 126.1, 127.3, 127.4, 127.7,
(CDCl3): d (ppm) = 1.10 (s, 3H, CH3), 1.17–1.37 (m, 3H, CH2),
1.45–1.63 (m, 3H, CH2), 1.77–1.87 (m, 1H, CH2), 2.03–2.17 (m,
2H, CH2), 2.40–2.50 (m, 1H, CH2), 3.35 (d, J = 15.4 Hz, 1H, 11-
H), 3.74 (dd, J = 9.1/2.8 Hz, 1H, 2-H), 3.95 (d, J = 15.4 Hz, 1H,
11-H), 4.32 (dd, J = 9.1/7.9 Hz, 1H, 2-H), 4.96 (dd, J = 7.9/2.7 Hz,
1H, 3-H), 6.99–7.38 (m, 9H, arom). 13C NMR (CDCl3): d (ppm)
= 23.0, 23.3, 24.3, 26.0 (4C, CH3/CH2CH2CH2CH2CH2), 31.6, 36.4
(2C, CH2CH2CH2CH2CH2), 46.1 (1C, C-11), 51.8 (1C, C-6), 61.9
(1C, C-3), 70.1 (1C, C-2), 94.5 (1C, C-11a), 126.0, 127.0, 127.1,
127.8, 128.7, 132.3 (9C, Ph-CH), 134.9, 143.1, 143.7 (3C, Ph-C),
23
589
171.7 (1C, C@O). ½
aꢂ
¼ ꢀ64:5 (c 0.14, CH2Cl2). Exact mass (ESI):
m/z = calcd for C21H23NO2Na 344.1621, found 344.1621. Purity
128.3, 129.6, 132.8 (9C, Ph-CH), 135.7, 140.6, 142.9 (3C, Ph-C),
(HPLC): 94.3% (tR = 20.67 min).
23
589
172.4 (1C, C@O).
½
aꢂ
¼ ꢀ6:1 (c 0.10, CH2Cl2). Exact mass
(ESI): m/z = calcd for C24H27NO2Na 384.1934, found 384.1928.
5.2.13. (3R,11aR)-6,6-Diethyl-11a-methyl-3-phenyl-2,3,11,11a-
tetrahydro[1,3]oxazolo-[2,3-b][3]benazepin-5(6H)-one 12e
Following general procedure B, cis-10 (64 mg, 0.22 mmol) was
Purity (HPLC): 93.7% (tR = 22.85 min).
5.2.16. (R)-2-[(1R,4R)-1,4-Dimethyl-2,3,4,5-tetrahydro-1H-3-
benzazepin-3-yl]-2-phenylethanol 15a
diethylated with an excess of ethyl iodide (88 lL, 1.1 mmol). The
crude product was purified by FC (d = 1 cm, l = 20 cm, V = 10 mL,
cyclohexane/EtOAc 85:15, Rf = 0.59 (cyclohexane/EtOAc 6:4)). Col-
orless liquid, yield 54 mg (71%). C23H27NO2 (349.5 g/mol). FT-IR
Following general procedure C, 11a (47 mg, 0.15 mmol) was re-
duced with AlH3 and the product was purified by FC (d = 2 cm,
l = 20 cm, V = 15 mL, cyclohexane/EtOAc 90:10, Rf = 0.53 (cyclohex-
ane/EtOAc 6:4)). Colorless viscous oil, yield 24 mg (55%). C20H25NO
(ATR, film):
(CDCl3):
m
(cmꢀ1) = 2909 (aliphatic C-H), 1615 (C@O). 1H NMR
(ppm) = 0.28 (t, J = 7.4 Hz, 3H, CH2CH3), 0.74 (t,
d
(295.4 g/mol). FT-IR (ATR, film):
m
(cmꢀ1) = 3404 (w, OH), 2926 (w,
J = 7.4 Hz, 3H, CH2CH3), 1.19 (s, 3H, CH3), 1.22–1.32 (m, 1H,
CH2CH3), 2.05–2.20 (m, 2H, CH2CH3), 2.34–2.43 (m, 1H, CH2CH3),
3.20 (d, J = 14.6 Hz, 1H, 11-H), 3.75 (d, J = 14.6 Hz, 1H, 11-H), 3.90
(dd, J = 9.2/1.2 Hz, 1H, 2-H), 4.34 (dd, J = 9.1/6.6 Hz, 1H, 2-H), 5.09
(d, J = 6.1 Hz, 1H, 3-H), 7.06–7.30 (m, 6H, arom), 7.41–7.46 (m,
3H, arom). 13C NMR (CDCl3): d (ppm) = 9.4 (1C, CH2CH3), 10.9
(1C, CH2CH3), 24.8 (1C, CH3), 34.6 (1C, CH2CH3), 41.6 (1C, CH2CH3),
48.4 (1C, C-11), 60.6 (1C, C-6), 64.3 (1C, C-3), 70.0 (1C, C-2), 93.0
(1C, C-11a), 126.6, 126.7, 127.3, 127.7, 128.6, 129.1, 131.9 (9C,
aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.94 (d, J = 4.1 Hz, 3H,
CH3), 1.19 (d, J = 6.9 Hz, 3H, CH3), 2.28 (dd, J = 12.6/9.0 Hz, 1H, 2-
H), 2.43 (dd, J = 15.8/5.6 Hz, 1H, 5-H), 3.00–3.22 (m, 4H, 1-H/2-H/
4-H/5-H), 3.54 (dd, J = 9.3/3.6 Hz, 1H, CH2OH), 3.77–3.93 (m, 2H,
CH2OH/NCHPh), 6.93–7.30 (m, 9H, arom). A signal for the OH pro-
ton is not detected. 13C NMR (CDCl3): d (ppm) = 17.6 (1C, CH3), 19.5
(1C, CH3), 29.7 (1C, C-1), 40.7 (1C, C-5), 41.6 (1C, C-2), 51.5 (1C, C-
4), 60.6 (1C, CH2OH), 64.4 (1C, NCHPh), 125.9, 126.8, 127.7, 128.3,
128.4, 130.1 (9C, Ph-CH), 136.4, 137.9, 143.7 (3C, Ph-C).
Ph-CH), 135.8, 140.9, 143.6 (3C, Ph-C), 171.1 (1C, C@O).
23
23
½
a
ꢂ
¼ þ24:4 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for
½
a
ꢂ
¼ ꢀ79:7 (c 0.19, CH2Cl2). Exact mass (ESI): m/z = calcd for
589
589
C
20H25NOH 296.2009, found 296.2009. Purity (HPLC): 96.7%
C
23H27NO2Na 372.1934, found 372.1932. Purity (HPLC): 96.7%
(tR = 16.80 min).
(tR = 22.43 min).

1418
S. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1411–1422
5.2.17. (R)-2-[(1R,4R)-1-Ethyl-4-methyl-2,3,4,5-tetrahydro-1H-
3-benzazepin-3-yl]-2-phenylethanol 15b
(aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.52 (t, J = 7.4 Hz, 3H,
CH2CH3), 0.90 (t, J = 7.4 Hz, 3H, CH2CH3), 0.95 (d, J = 4.1 Hz, 3H,
CH3), 1.40–1.50 (m, 3H, CH2CH3/CH2OH), 1.62–1.66 (m, 1H,
CH2CH3), 1.98–2.02 (m, 1H, CH2CH3), 2.34–2.38 (m, 2H, 2-H/5-H),
2.86–2.90 (m, 1H, 4-H), 3.20–3.24 (m, 2H, 2-H/5-H), 3.55–3.58
(m, 1H, CH2OH), 3.75–3.79 (m, 1H, CH2OH), 3.86–3.90 (m, 1H,
NCHPh), 6.88–7.34 (m, 9H, arom). 13C NMR (CDCl3): d (ppm)
= 8.8 (1C, CH3), 8.9 (2C, 2 ꢁ CH2CH3), 28.9 (1C, CH2CH3), 29.9 (1C,
CH2CH3), 41.9 (1C, C-1), 47.2 (1C, C-5), 52.6 (1C, C-2), 54.2 (1C, C-
4), 61.0 (1C, CH2OH), 64.7 (1C, NCHPh), 125.8, 126.4, 127.9,
Following general procedure C, 11b (35 mg; 0.11 mmol) was re-
duced with AlH3 and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.54 (cyclohex-
ane/EtOAc 6:4)). Colorless viscous oil, yield 27 mg (82%). C21H27NO
(309.4 g/mol). FT-IR (ATR, film):
m
(cmꢀ1) = 3445 (OH), 2927 (ali-
phatic C–H). 1H NMR (CDCl3): d (ppm) = 0.83–0.98 (m, 6H,
CH2CH3/CH3), 1.52–1.68 (m, 2H, CH2CH3), 2.33–2.61 (m, 3H, 2-H/
5-H/CH2OH), 2.82–2.98 (m, 1H, 1-H), 3.06–3.27 (m, 3H, 2-H/4-H/
5-H), 3.62–3.66 (m, 1H, CH2OH), 3.79–3.90 (m, 2H, CH2OH/NCHPh),
6.89–7.31 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 12.3 (1C,
CH2CH3), 12.6 (1C, CH3), 21.3 (1C, CH2CH3), 26.7 (1C, C-1), 41.5
(1C, C-5), 44.6 (1C, C-2), 49.7 (1C, C-4), 60.7 (1C, CH2OH), 68.8
128.1, 128.5, 128.8 (9C, Ph-CH), 131.9, 144.3 (3C, Ph-C).
23
589
½
a
C
ꢂ
¼ þ18:6 (c 0.20, CH2Cl2). Exact mass (ESI): m/z = calcd for
23H31NOH 338.2478, found 338.2474. Purity (HPLC): 95.8%
(tR = 19.14 min).
(1C, NCHPh), 125.2, 125.8, 126.4, 127.6, 128.2, 128.5, 130.4 (9C,
23
589
Ph-CH), 138.1, 142.4 (3C, Ph-C). ½
aꢂ
¼ þ28:3 (c 0.10, CH2Cl2). Ex-
5.2.21. (R)-2-[(R)-4-Methyl-2,3,4,5-tetrahydrospiro[[3]benzaz-
epin-1,10-cyclopentan]-3-yl]-2-phenylethanol 15f
act mass (ESI): m/z = calcd for C21H27NOH 310.2165, found
310.2167. Purity (HPLC): 93.1% (tR = 17.32 min).
Following general procedure C, 11f (40 mg; 0.12 mmol) was re-
duced with AlH3 and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.56 (cyclohex-
ane/EtOAc 6:4)). Colorless viscous oil, yield 29 mg (75%). C23H29NO
5.2.18. (R)-2-[(1R,4R)-1-Allyl-4-methyl-2,3,4,5-tetrahydro-1H-3-
benzazepin-3-yl]-2-phenylethanol 15c
Following general procedure C, 11c (30 mg; 0.09 mmol) was re-
duced with AlH3 and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.58 (cyclohex-
ane/EtOAc 6:4)). Colorless viscous oil, yield 22 mg (75%). C22H27NO
(335.5 g/mol). FT-IR (ATR, film): m
(cmꢀ1) = 3423 (OH), 2952 (ali-
phatic C–H). 1H NMR (CDCl3): d (ppm) = 0.66 (d, J = 6.3 Hz, 3H,
CH3), 1.40–2.16 (m, 8H, CH2), 2.41–2.75 (m, 4H, 2-H/4-H/5-H/
CH2OH), 3.24–3.39 (m, 2H, 2-H/5-H), 3.59–3.62 (m, 1H, CH2OH),
3.68–3.80 (m, 2H, CH2OH/NCHPh), 6.84–7.26 (m, 9H, arom). 13C
(321.5 g/mol). FT-IR (ATR, film):
m
(cmꢀ1) = 3441 (OH), 2924 (ali-
phatic C–H). 1H NMR (CDCl3): d (ppm) = 0.90 (d, J = 4.1 Hz, 3H,
CH3), 1.24 (s, 1H, CH2OH), 2.32–2.56 (m, 4H, CH2–CH@CH2/2-H/5-
H), 3.00–3.14 (m, 1H, 1-H), 3.15–3.33 (m, 3H, 2-H/4-H/5-H),
3.56–3.68 (m, 1H, CH2OH), 3.87–4.00 (m, 2H, CH2OH/NCHPh),
4.96–5.19 (m, 2H, CH2–CH@CH2), 5.69–5.99 (m, 1H, CH2–CH@CH2),
6.89–7.34 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 17.5 (1C,
CH3), 38.6 (1C, CH2–CH@CH2), 42.0 (1C, C-1), 46.8 (1C, C-5), 49.8
(1C, C-2), 51.8 (1C, C-4), 61.0 (1C, CH2OH), 64.7 (1C, NCHPh),
116.7 (1C, CH2–CH@CH2), 126.2, 126.8, 127.9, 128.5, 128.6, 130.6
NMR (CDCl3): d (ppm) = 13.9 (1C, CH3), 24.1, 24.6 (2C,
CH2CH2CH2CH2), 36.4, 38.8 (2C, CH2CH2CH2CH2), 43.7 (1C, C-1),
52.8 (1C, C-5), 53.2 (1C, C-2), 55.2 (1C, C-4), 62.7 (1C, CH2OH),
70.3 (1C, NCHPh), 125.7, 126.2, 126.5, 127.8, 128.6, 129.0 (9C,
23
589
Ph-CH), 131.5, 138.2, 147.4 (3C, Ph-C). ½
a
ꢂ
¼ þ17:4 (c 0.14,
CH2Cl2). Exact mass (ESI): m/z = calcd for C23H29NOH 336.2322,
found 336.2324. Purity (HPLC): 93.7% (tR = 18.19 min).
5.2.22. (R)-2-[(R)-4-Methyl-2,3,4,5-tetrahydrospiro[[3]benzaz-
epin-1,10-cyclohexan]-3-yl]-2-phenylethanol 15g
(9C, Ph-CH), 136.8, 138.2, 142.3 (4C, Ph-C/CH2–CH@CH2).
23
589
½
a
C
ꢂ
¼ þ38:8 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for
Following general procedure C, 11g (53 mg; 0.15 mmol) was re-
duced with AlH3 and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.58 (cyclohex-
ane/EtOAc 6:4)). Colorless viscous oil, yield 30 mg (60%). C24H31NO
22H27NOH 322.2165, found 322.2162. Purity (HPLC): 96.9%
(tR = 17.59 min).
5.2.19. (R)-2-[(R)-1,1,4-Trimethyl-2,3,4,5-tetrahydro-1H-3-benz-
azepin-3-yl]-2-phenylethanol 15d
(349.5 g/mol) FT-IR (ATR, film): m
(cmꢀ1) = 3428 (OH), 2924 (ali-
phatic C–H). 1H NMR (CDCl3): d (ppm) = 0.96 (d, J = 3.5 Hz, 3H,
CH3), 1.10–1.32 (m, 4H, CH2), 1.39 (s, 1H, CH2OH), 1.51–1.85 (m,
5H, CH2), 1.89–2.08 (m,1H, CH2), 2.28–2.45 (m, 2H, 2-H/5-H),
3.04–3.20 (m, 2H, 2-H/4-H), 3.26 (dd, J = 14.8/6.4 Hz, 1H, 5-H),
3.51 (dd, J = 10.4/4.6 Hz, 1H, CH2OH), 3.70–3.76 (m, 1H, NCHPh),
3.89 (dd, J = 10.6/4.5 Hz, 1H, CH2OH), 6.86–7.40 (m, 9H, arom).
13C NMR (CDCl3): d (ppm) = 18.4 (1C, CH3), 22.6, 22.9, 23.4, 24.5,
25.8 (5C, CH2), 41.1 (1C, C-1), 43.5 (1C, C-5), 50.9 (1C, C-2), 53.7
(1C, C-4), 60.7 (1C, CH2OH), 62.3 (1C, NCHPh), 125.6, 125.7,
Following general procedure C, 11d (22 mg; 0.07 mmol) was re-
duced with AlH3 and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.64 (cyclohex-
ane/EtOAc 6:4)). Colorless viscous oil, yield 15 mg (71%). C21H27NO
(309.4 g/mol). FT-IR (ATR, film):
m
(cm-1) = 3441 (OH), 2962 (ali-
phatic C–H). 1H NMR (CDCl3): d (ppm) = 0.98 (d, J = 4.1 Hz, 3H,
CH3), 1.12 (s, 3H, CH3), 1.41 (s, 3H, CH3), 2.36 (d, J = 13.1 Hz, 1H,
5-H), 2.59–2.70 (m, 2H, 2-H/5-H), 3.19–3.31 (m, 2H, 2-H/4-H),
3.51–3.61 (m, 1H, CH2OH), 3.78–3.91 (m, 2H, CH2OH/NCHPh),
7.13 (m, 9H, arom). 13C NMR (CDCl3): d (ppm) = 19.1 (1C, CH3),
25.8 (1C, CH3), 30.9 (1C, CH3), 41.6 (1C, C-1), 53.6 (1C,C-5), 58.0
(1C, C-2), 61.0 (1C, C-4), 64.6 (1C, CH2OH), 68.2 (1C, NCHPh),
126.0, 127.8, 128.4, 128.6 (9C, Ph-CH), 131.4, 137.4, 147.6 (3C,
23
589
Ph-C). ½
aꢂ
¼ þ2:2 (c 0.30, CH2Cl2). Exact mass (ESI): m/z = calcd
for C24H31NOH 350.2478, found 350.2498. Purity (HPLC): 93.2%
(tR = 18.56 min).
125.9, 127.1, 127.2, 127.9, 128.5, 128.8, 131.7 (9C, Ph-CH), 135.2,
23
137.6, 146.8 (3C, Ph-C). [
a
]
589 = +2.2 (c 0.14, CH2Cl2). Exact mass
5.2.23. (R)-2-[(1S,4S)-1,4-Dimethyl-2,3,4,5-tetrahydro-1H-3-
benzazepin-3-yl]-2-phenylethanol 16a
(ESI): m/z = calcd for C21H27NOH 310.2165, found 310.2161. Purity
(HPLC): 94.9% (tR = 15.15 min).
Following general procedure C, 12a (37 mg; 0.12 mmol) was re-
duced with AlH3 and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.52 (cyclohex-
ane/EtOAc 6:4)). Colorless viscous oil, yield 21 mg (60%). C20H25NO
5.2.20. (R)-2-[(R)-1,1-Diethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-
benzazepin-3-yl]-2-phenylethanol 15e
Following general procedure C, 11e (25 mg; 0.07 mmol) was re-
duced with AlH3 and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.60 (cyclohex-
ane/EtOAc 6:4)). Colorless viscous oil, yield 20 mg (85%). C23H31NO
(295.4 g/mol). FT-IR (ATR, film): m
(cmꢀ1) = 3427 (OH), 2926 (ali-
phatic C–H). 1H NMR (CDCl3): d (ppm) = 0.86 (d, J = 4.1 Hz, 3H,
CH3), 1.39 (d, J = 7.0 Hz, 3H, CH3), 2.49 (s, 1H, CH2OH), 2.66 (dd,
J = 14.4/7.4 Hz, 1H, 2-H), 2.88 (dd, J = 12.3/5.2 Hz, 1H, 5-H), 2.89–
3.09 (m, 1H, 1-H), 3.12–3.44 (m, 3H, 2-H/4-H/5-H), 3.65–3.77 (m,
(337.4 g/mol). FT-IR (ATR, film):
m
(cmꢀ1) = 3454 (OH), 2962

S. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1411–1422
1419
3H, CH2OH/NCHPh), 7.10–7.34 (m, 9H, arom). 13C NMR (CDCl3): d
(ppm) = 17.4 (2C, CH3), 29.9 (1C, C-1), 43.6 (1C, C-5), 47.3 (1C, C-
2), 57.0 (1C, C-4), 61.3 (1C, CH2OH), 71.0 (1C, NCHPh), 126.6,
5.2.27. (R)-2-[(S)-1,1-Diethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-
benzazepin-3-yl]-2-phenylethanol 16e
Following general procedure C, 12e (42 mg; 0.12 mmol) was re-
duced with AlH3 and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.56 (cyclohex-
ane/EtOAc 6:4)). Colorless viscous oil, yield 29 mg (73%). C23H31NO
126.9, 127.8, 128.5, 128.8 (9C, Ph-CH), 138.0, 139.7 (3C, Ph-C).
23
589
½
a
C
ꢂ
¼ ꢀ12:3 (c 0.16, CH2Cl2). Exact mass (ESI): m/z = calcd for
20H25NOH 296.2009, found 296.2005. Purity (HPLC): 97.9%
(tR = 16.23 min).
(337.4 g/mol). FT-IR (ATR, film): m
(cmꢀ1) = 3441 (OH), 2963 (ali-
phatic C–H). 1H NMR (CDCl3): d (ppm) = 0.52 (t, J = 7.4 Hz, 3H,
CH2CH3), 0.71 (t, J = 7.4 Hz, 3H, CH2CH3), 0.77 (d, J = 6.1 Hz, 3H,
CH3), 1.38 (m, 1H, CH2CH3), 1.50–1.61 (m, 1H, CH2CH3), 1.70–
1.84 (m, 1H, CH2CH3), 1.92–2.17 (m, 1H, CH2CH3), 1.95–2.05 (m,
1H, CH2OH), 2.46–2.51 (m, 1H, 5-H), 2.60 (d, J = 14.2 Hz, 1H, 2-
H), 3.00–3.35 (m, 3H, 2-H/4-H/5-H), 3.55–3.65 (m, 1H, CH2OH),
3.69–3.86 (m, 2H, CH2OH/NCHPh), 6.86–7.30 (m, 9H, arom). 13C
NMR (CDCl3): d (ppm) = 8.6 (1C, CH2CH3), 8.8 (2C, CH2CH3/CH3),
29.9 (1C, CH2CH3), 30.5 (1C, CH2CH3), 47.0 (1C, C-1), 51.9 (1C, C-
5), 55.4 (1C, C-2), 62.4 (2C, C-4/CH2OH), 70.4 (1C, NCHPh), 126.0,
5.2.24. (R)-2-[(1S,4S)-1-Ethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-
benzazepin-3-yl]-2-phenylethanol 16b
Following general procedure C, 12b (57 mg; 0.18 mmol) was re-
duced with AlH3 and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.56 (cyclohex-
ane/EtOAc 6:4)). Colorless viscous oil, yield 44 mg (80%). C21H27NO
(309.4 g/mol). FT-IR (ATR, film):
m
(cmꢀ1) = 3447 (OH), 2960 (ali-
phatic C–H). 1H NMR (CDCl3): d (ppm) = 0.78–0.92 (m, 6H, CH3/
CH2CH3). 1.67–1.80 (m, 1H, CH2CH3), 1.89–2.01 (m, 2H, CH2CH3/
CH2OH), 2.39–2.79 (m, 3H, 1-H/2-H/5-H), 2.80–2.90 (m, 1H, 4-H),
3.11–3.52 (m, 3H, CH2OH/2-H/5-H), 3.55–3.86 (m, 2H, CH2OH/
NCHPh), 6.96–7.40 (m, 9H, arom). 13C NMR (CDCl3): d (ppm)
= 13.1 (2C, CH3/CH2CH3), 24.4 (1C, CH2CH3), 43.9 (1C, C-1), 45.9
(2C, C-2/C-5), 57.0 (1C, C-4), 61.6 (1C, CH2OH), 71.3 (1C, NCHPh),
126.3, 127.8, 128.2, 128.5, 128.9 (9C, Ph-CH), 132.05, 138.0, 144.3
23
589
(3C, Ph-C). ½
aꢂ
¼ ꢀ14:6 (c 0.24, CH2Cl2). Exact mass (ESI): m/
z = calcd for C23H31NOH 338.2478, found 338.2466. Purity (HPLC):
97.7% (tR = 18.21 min).
126.4, 127.8, 128.5, 128.9 (9C, Ph-CH), 139.7 (3C, Ph-C).
5.2.28. (R)-2-[(S)-4-Methyl-2,3,4,5-tetrahydrospiro[[3]benzaz-
epin-1,10-cyclopentan]-3-yl]-2-phenylethanol 16f
23
½
a
ꢂ
¼ ꢀ18:7 (c 0.16, CH2Cl2). Exact mass (ESI): m/z = calcd for
589
C21H27NOH 310.2165, found 310.2168. Purity (HPLC): 94.7%
Following general procedure C, 12f (24 mg; 0.07 mmol) was re-
duced with AlH3 and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.56 (cyclohex-
ane/EtOAc 6:4)). Colorless viscous oil, yield 16 mg (70%). C23H29NO
(tR = 16.93 min).
5.2.25. (R)-2-[(1S,4S)-1-Allyl-4-methyl-2,3,4,5-tetrahydro-1H-3-
benzazepin-3-yl]-2-phenylethanol 16c
(335.5 g/mol). FT-IR (ATR, film):
m
(cmꢀ1) = 3423 (OH), 2925 (ali-
phatic C–H). 1H NMR (CDCl3): d (ppm) = 0.88 (d, J = 6.1 Hz, 3H,
CH3), 1.18 (s, 1H, CH2OH), 1.55–1.95 (m, 7H, CH2), 2.04–2.16 (m,
1H, CH2), 2.41–2.55 (m, 2H, 2-H/5-H), 2.76 (d, J = 14.3 Hz, 1H, 2-
H), 3.08–3.29 (m, 2H, 4-H/5-H), 3.52–3.64 (m, 1H, CH2OH), 3.75–
3.94 (m, 2H, CH2OH/NCHPh), 6.84–7.33 (m, 9H, arom). 13C NMR
(CDCl3): d (ppm) = 17.8 (1C, CH3), 24.4, 24.5 (2C, CH2CH2CH2CH2),
38.9, 39.8 (2C, CH2CH2CH2CH2), 42.2 (1C, C-1), 53.2 (1C, C-5),
53.6 (1C, C-2), 55.6 (1C, C-4), 61.0 (1C, CH2OH), 64.9 (1C, NCHPh),
Following general procedure C, 12c (31 mg; 0.09 mmol) was re-
duced with AlH3, and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.53 (cyclohex-
ane/EtOAc 6:4)). Colorless viscous oil, yield 20 mg (72%). C22H27NO
(321.5 g/mol). FT-IR (ATR, film):
m
(cmꢀ1) = 3441 (OH), 2925 (ali-
phatic C–H). 1H NMR (CDCl3): d (ppm) = 0.73 (d, J = 4.1 Hz, 3H,
CH3), 2.33–2.48 (m, 2H, CH2–CH@CH2), 2.51–2.71 (m, 3H, 2-H/5-
H/CH2OH), 2.75–2.93 (m, 2H, 2-H/5-H), 3.02–3.46 (m, 3H, 1-H/4-
H/CH2OH), 3.48–3.77 (m, 2H, NCHPh/CH2OH), 4.90 (d, J = 10.1 Hz,
1H, CH2–CH@CH2), 4.99 (d, J = 17.3 Hz, 1H, CH2–CH@CH2), 5.68
(m, 1H, CH2–CH@CH2), 6.79–7.50 (m, 9H, arom). 13C NMR (CDCl3):
d (ppm) = 29.9 (1C, CH3), 36.0 (1C, CH2–CH@CH2), 43.7 (1C, C-5),
45.9 (1C, C-1/C-2), 56.8 (1C, C-4), 61.6 (1C, CH2OH), 71.2 (1C,
NCHPh), 116.2 (1C, CH2–CH@CH2), 126.6, 127.8, 128.5, 128.6,
125.7, 126.2, 126.6, 127.7, 128.4 (9C, Ph-CH), 131.3, 136.6, 146.9
23
589
(3C, Ph-C). ½
aꢂ
¼ ꢀ24:7 (c 0.20, CH2Cl2). Exact mass (ESI): m/
z = calcd for C23H29NOH 336.2322, found 336.2327. Purity (HPLC):
90.4% (tR = 18.23 min).
5.2.29. (R)-2-[(S)-4-Methyl-2,3,4,5-tetrahydrospiro[[3]benzaz-
epin-1,10-cyclohexan]-3-yl]-2-phenylethanol 16g
Following general procedure C, 12g (44 mg; 0.12 mmol) was re-
duced with AlH3 and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.57 (cyclohex-
ane/EtOAc 6:4)). Colorless viscous oil, yield 29 mg (69%). C24H31NO
128.9 (9C, Ph-CH), 137.3, 139.7 (4C, Ph-C/CH2–CH@CH2).
23
589
½
a
C
ꢂ
¼ ꢀ3:6 (c 0.15, CH2Cl2). Exact mass (ESI): m/z = calcd for
22H27NOH 322.2165, found 322.2159. Purity (HPLC): 93.9%
(tR = 17.28 min).
(349.5 g/mol). FT-IR (ATR, film):
m
(cmꢀ1) = 3441 (OH), 2923 (ali-
phatic C–H). 1H NMR (CDCl3): d (ppm) = 0.85 (d, J = 5.9 Hz, 3H,
CH3), 1.09–1.90 (m, 11H, CH2/CH2OH), 2.31–3.24 (m, 5H, 2-H/4-
H/5-H), 3.48–3.82 (m, 3H, CH2OH/NCHPh), 6.88–7.39 (m, 9H,
arom). 13C NMR (CDCl3): d (ppm) = 16.3 (1C, CH3), 22.7, 22.9,
26.2 (3C, CH2CH2CH2CH2CH2), 27.2, 30.4 (2C, CH2(CH2)3CH2), 35.8
(2C, C-1/C-5), 43.8 (1C, C-2), 53.7 (1C, C-4), 62.9 (1C, CH2OH),
5.2.26. (R)-2-[(S)-1,1,4-Trimethyl-2,3,4,5-tetrahydro-1H-3-benz-
azepin-3-yl]-2-phenylethanol 16d
Following general procedure C, 12d (48 mg; 0.15 mmol) was re-
duced with AlH3, which was purified by FC (d = 1 cm, l = 25 cm,
V = 10 mL, cyclohexane/EtOAc 90:10, Rf = 0.60 (cyclohexane/EtOAc
6:4)). Colorless viscous oil, yield 31 mg (69%). C21H27NO (309.4 g/
mol). FT-IR (ATR, film):
m
(cmꢀ1) = 3441 (OH), 2960 (aliphatic C–
69.1 (1C, NCHPh), 126.3, 127.1, 127.7, 128.5, 128.9, 131.1 (9C,
H). 1H NMR (CDCl3): d (ppm) = 0.71 (d, J = 6.4 Hz, 3H, CH3), 1.22
(s, 3H, CH3), 1.28 (s, 3H, CH3), 2.59–2.98 (m, 4H, 2-H/4-H/5-H/
CH2OH), 3.28–3.45 (m, 2H, 2-H/5-H), 3.53–3.64 (m, 1H, CH2OH),
3.77–3.97 (m, 2H, CH2OH/NCHPh), 6.85–7.32 (m, 9H, arom). 13C
NMR (CDCl3): d (ppm) = 15.1 (1C, CH3), 30.4, 30.9 (2C, 2 ꢁ CH3),
41.2 (1C, C-1), 55.9 (1C, C-5), 58.0 (1C, C-2), 61.0 (1C, C-4), 62.4
23
589
Ph-CH), 138.0, 140.4, 147.7 (3C, Ph-C). ½
aꢂ
¼ ꢀ10:6 (c 0.25,
CH2Cl2). Exact mass (ESI): m/z = calcd for C24H31NOH 350.2478,
found 350.2482. Purity (HPLC): 90.5% (tR = 19.02 min).
5.2.30. (1R,4R)-1,4-Dimethyl-2,3,4,5-tetrahydro-1H-3-benzaz-
epine 17a
According to general procedure D, 15a (40 mg, 0.14 mmol)
was hydrogenated and the product was purified by FC
(d = 1 cm, l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-
dimethylethanamine 50:49.5:0.5, Rf = 0.19 (EtOAc/petroleum
(1C, CH2OH), 70.1 (1C, NCHPh), 126.3, 126.9, 127.8, 128.5, 128.9
23
589
(9C, Ph-CH), 131.7, 137.4, 147.1 (3C, Ph-C). ½
a
ꢂ
¼ ꢀ10:2 (c 0.14,
CH2Cl2). Exact mass (ESI): m/z = calcd for C21H27NOH 310.2165,
found 310.2161. Purity (HPLC): 96.6% (tR = 16.35 min).

1420
S. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1411–1422
ether/N,N-dimethylethanamine 70:29.5:0.5)). Colorless viscous
(m, 3H, CH2CH2CH3/NH), 1.68–1.87 (m, 2H, CH2CH2CH3), 2.50
(dd, J = 13.2/8.3 Hz, 1H, 5-H), 2.70–2.91 (m, 4H, 1-H/2-H/4-H/5-
H), 3.10 (dd, J = 13.2/2.8 Hz, 1H, 2-H), 6.95–7.14 (m, 4H, arom).
13C NMR (CDCl3): d (ppm) = 14.7 (1C, CH2CH2CH3), 21.2 (1C, CH3),
29.9 (1C, CH2CH2CH3), 34.5 (1C, CH2CH2CH3), 45.1 (2C, C-2/C-5),
oil, yield 16 mg (70%). C12H17N (175.3 g/mol). FT-IR (ATR, film):
m
(cm-1) = 3264 (w, N–H), 2930 (aliphatic C–H). 1H NMR (CDCl3):
d (ppm) = 1.18 (d, J = 6.3 Hz, 3H, CH3), 1.33 (d, J = 7.2 Hz, 3H,
CH3), 1.98 (s, 1H, NH), 2.58 (dd, J = 13.0/9.0 Hz, 1H, 2-H), 2.73
(d, J = 14.1 Hz, 1H, 5-H), 2.76–2.84 (m, 1H, 4-H), 2.93 (dd,
J = 14.0/9.1 Hz, 1H, 5-H), 3.06 (dd, J = 13.0/1.8 Hz, 1H, 2-H),
3.08–3.19 (m, 1H, 1-H), 7.05–7.15 (m, 2H, arom), 7.19 (d,
J = 3.7 Hz, 2H, arom). 13C NMR (CDCl3): d (ppm) = 18.4 (1C,
CH3), 24.0 (1C, CH3), 29.9 (1C, C-1), 40.0 (1C, C-5), 46.4 (1C, C-
47.2 (1C, C-1), 52.3 (1C, C-4), 126.0, 126.4, 130.0 (4C, Ph-CH)
23
589
140.0, 144.8 (2C, Ph-C). ½
aꢂ
¼ þ16:8 (c 0.19, CH2Cl2). Exact mass
(ESI): m/z = calcd for C14H21NH 204.1747, found 204.1739. Purity
(HPLC): 96.8% (tR = 15.23 min).
2), 52.8 (1C, C-4), 124.8, 126.1, 126.5, 129.7 (4C, Ph-CH), 140.7,
145.6 (2C, Ph-C). [a] 589 = +8.6 (c 0.14, CH2Cl2). Exact mass
5.2.35. (1S,4S)-4-Methyl-1-propyl-2,3,4,5-tetrahydro-1H-3-
benzazepine ent-17c
23
(ESI): m/z = calcd for C12H17NH 176.1434, found 176.1430. Purity
(HPLC): 99.2% (tR = 11.96 min).
According to general procedure D, 16c (36 mg, 0.17 mmol) was
hydrogenated and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethan-
amine 50:49.5:0.5, Rf = 0.18 (EtOAc/petroleum ether/N,N-dimethy-
5.2.31. (1S,4S)-1,4-Dimethyl-2,3,4,5-tetrahydro-1H-3-benzaz-
epine ent-17a
According to general procedure D, 16a (18 mg, 0.06 mmol) was
hydrogenated and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethan-
amine 50:49.5:0.5, Rf = 0.19 (EtOAc/petroleum ether/N,N-dimethy-
lethanamine 70:29.5:0.5)). Colorless viscous oil, yield 10 mg (90%).
23
589
½
aꢂ
¼ ꢀ16:4 (c 0.16, CH2Cl2). Exact mass (ESI): m/z = calcd for
C14H21NH 204.1747, found 204.1763. Purity (HPLC): 97.3%
(tR = 14.95 min).
lethanamine 70:29.5:0.5)). Colorless viscous oil, yield 6 mg (60%).
5.2.36. (R)-1,1,4-Trimethyl-2,3,4,5-tetrahydro-1H-3-benzaz-
epine 17d
23
½
a
ꢂ
¼ ꢀ8:8 (c 0.11, CH2Cl2). Exact mass (ESI): m/z = calcd for
589
C12H17NH 176.1434, found 176.1433. Purity (HPLC): 95.6%
According to general procedure D, 15d (22 mg, 0.07 mmol) was
hydrogenated and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethan-
amine 50:49.5:0.5, Rf = 0.28 (EtOAc/petroleum ether/N,N-dimethy-
lethanamine 70:29.5:0.5)). Colorless viscous oil, yield 10 mg (77%).
(tR = 12.15 min).
5.2.32. (1R,4R)-1-Ethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-
benzazepine 17b
According to general procedure D, 15b (18 mg, 0.06 mmol) was
hydrogenated and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethan-
amine 50:49.5:0.5, Rf = 0.21 (EtOAc/petroleum ether/N,N-dimethy-
lethanamine 70:29.5:0.5)). Colorless viscous oil, yield 9 mg (82%).
C
13H19N (189.3 g/mol). FT-IR (ATR, film):
m
(cmꢀ1) = 3340 (N–H),
(ppm) = 1.18 (d,
2925 (aliphatic C–H). 1H NMR (CDCl3):
d
J = 6.4 Hz, 3H, CH3), 1.35 (s, 6H, CH3), 1.80 (s, 1H, NH), 2.79 (d,
J = 14.8 Hz, 1H, 5-H), 2.87 (d, J = 13.8 Hz, 1H, 2-H), 2.91–2.99 (m,
2H, 2-H/4-H), 3.10 (dd, J = 14.8/9.5 Hz, 1H, 5-H), 7.04 (d,
J = 7.4 Hz, 1H, arom), 7.06–7.12 (m, 1H, arom), 7.17 (t, J = 7.5 Hz,
1H, arom), 7.35 (d, J = 7.8 Hz, 1H, arom). 13C NMR (CDCl3): d
(ppm) = 23.9 (1C, CH3), 26.5 (1C, CH3), 29.7 (1C, CH3), 41.4 (1C, C-
C
13H19N (189.3 g/mol). FT-IR (ATR, film): m
(cmꢀ1) = 3302 (N–H),
2923 (w, aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.97 (t,
J = 7.3 Hz, 3H, CH2CH3), 1.08 (d, J = 6.1 Hz, 3H, CH3), 1.50–1.61 (m,
1H, CH2CH3), 1.75–1.98 (m, 2H, CH2CH3/NH), 2.50 (dd, J = 12.8/
8.5 Hz, 1H, 5-H), 2.77–2.96 (m, 4H, 1-H/2-H/4-H/5-H), 3.12 (dd,
J = 13.2/2.5 Hz, 1H, 2-H), 7.00–7.24 (m, 4H, arom). 13C NMR
(CDCl3): d (ppm) = 12.8 (1C, CH2CH3), 22.9 (1C, CH3), 24.9 (1C,
1), 47.4 (1C, C-5), 53.4 (1C, C-4), 59.5 (1C, C-2), 126.2, 126.5,
23
589
131.8 (4C, Ph-CH), 139.5, 148.1 (2C, Ph-C). ½
aꢂ
¼ þ8:9 (c 0.10,
CH2Cl2). Exact mass (ESI): m/z = calcd for C13H19NH 190.1590,
found 190.1594. Purity (HPLC): 98.0% (tR = 12.56 min).
CH2CH3), 29.9 (1C, C-1), 45.1 (1C, C-5), 47.9 (1C, C-2), 52.4 (1C, C-
23
589
4), 126.0, 126.5, 130.0 (4C, Ph-CH), 144.7 (2C, Ph-C). ½
aꢂ
¼ þ8:8
5.2.37. (S)-1,1,4-Trimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine
ent-17d
(c 0.17, CH2Cl2). Exact mass (ESI): m/z = calcd for C13H19NH
190.1601, found 190.1589. Purity (HPLC): 95.7% (tR = 13.45 min).
According to general procedure D, 16d (48 mg, 0.16 mmol) was
hydrogenated and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethan-
amine 50:49.5:0.5, Rf = 0.28 (EtOAc/petroleum ether/N,N-dimethyl-
5.2.33. (1S,4S)-1-Ethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-
benzazepine ent-17b
According to general procedure D, 16b (42 mg, 0.14 mmol) was
hydrogenated and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethan-
amine 50:49.5:0.5, Rf = 0.21 (EtOAc/petroleum ether/N,N-dimethy-
ethanamine 70:29.5:0.5)). Colorless viscous oil, yield 19 mg (66%).
23
½
a
ꢂ
¼ ꢀ8:3 (c 0.14, CH2Cl2). Exact mass (ESI): m/z = calcd for
589
C13H19NH 190.1590, found 190.1582. Purity (HPLC): 98.2%
(tR = 13.67 min).
lethanamine 70:29.5:0.5)). Colorless viscous oil, yield 20 mg (77%).
23
589
½
a
C
ꢂ
¼ ꢀ8:9 (c 0.15, CH2Cl2). Exact mass (ESI): m/z = calcd for
5.2.38. (R)-1,1-Diethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-benz-
azepine 17e
13H19NH 190.1601, found 190.1590. Purity (HPLC): 97.7%
(tR = 13.11 min).
According to general procedure D, 15e (12 mg, 0.04 mmol) was
hydrogenated and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethan-
amine 50:49.5:0.5, Rf = 0.28 (EtOAc/petroleum ether/N,N-dimethy-
lethanamine 70:29.5:0.5)). Colorless viscous oil, yield 6 mg (75%).
5.2.34. (1R,4R)-4-Methyl-1-propyl-2,3,4,5-tetrahydro-1H-3-
benzazepine 17c
According to the general procedure D, 15c (26 mg, 0.08 mmol)
was hydrogenated and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethan-
amine 50:49.5:0.5, Rf = 0.18 (EtOAc/petroleum ether/N,N-dimethy-
lethanamine 70:29.5:0.5)). Colorless viscous oil, yield 15 mg (88%).
C
15H23N (217.4). FT-IR (ATR, film): m
(cmꢀ1) = 3315 (N–H), 2925
(aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.73 (t, J = 7.5 Hz, 3H,
CH2CH3), 0.86 (t, J = 7.4 Hz, 3H, CH2CH3), 1.11 (d, J = 6.4 Hz, 3H,
CH3), 1.50–1.63 (m, 2H, CH2CH3/NH), 1.64–1.79 (m, 2H, CH2CH3),
1.84–1.95 (m, 1H, CH2CH3), 2.82–2.95 (m, 3H, 2-H/5-H), 3.00–
3.10 (m, 2H, 4-H/5-H), 7.04 (d, J = 7.2 Hz, 1H, arom), 7.10 (td,
J = 7.3/1.4 Hz, 1H, arom), 7.15–7.27 (m, 2H, arom). 13C NMR
C
14H21N (203.3 g/mol). FT-IR (ATR, film): m
(cmꢀ1) = 3289 (N–H),
2923 (w, aliphatic C–H). 1H NMR (CDCl3): d (ppm) = 0.90 (t,
J = 7.3 Hz, 3H, CH2CH2CH3), 1.07 (d, J = 6.3 Hz, 3H, CH3), 1.28–1.57

S. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1411–1422
1421
(CDCl3): d (ppm) = 8.8 (1C, CH2CH3), 8.9 (1C, CH2CH3), 22.8 (1C,
CH3), 31.2 (1C, CH2CH3), 32.2 (1C, CH2CH3), 44.9 (1C, C-1), 47.8
C-1), 53.6 (1C, C-2), 126.0, 126.2, 126.5, 132.1 (4C, Ph-CH), 139.6,
23
149.3 (2C, Ph-C). ½
a
ꢂ
¼ þ12:0 (c 0.16, CH2Cl2). Exact mass (ESI):
589
(1C, C-5), 52.8 (1C, C-4), 54.5 (1C, C-2), 126.0, 126.2, 129.0, 132.2
m/z = calcd for C16H23NH 230.1903, found 230.1893. Purity (HPLC):
23
589
(4C, Ph-CH), 139.1, 143.7 (2C, Ph-C). ½
a
C
ꢂ
¼ þ4:1 (c 0.10, CH2Cl2).
98.4% (tR = 15.92 min).
Exact mass (ESI): m/z = calcd for
15H23NH 218.1903, found
218.1894. Purity (HPLC): 97.4% (tR = 15.56 min).
5.2.43. (S)-3-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepine-
1,10-cyclohexane] ent-17g
5.2.39. (S)-1,1-Diethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-
benzazepine ent-17e
According to general procedure D, 16e (21 mg, 0.06 mmol) was
hydrogenated and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethan-
amine 50:49.5:0.5, Rf = 0.31 (EtOAc/petroleum ether/N,N-dimethy-
According to the general procedure D, 16g (22 mg, 0.06 mmol)
was hydrogenated and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethan-
amine 50:49.5:0.5, Rf = 0.36 (EtOAc/petroleum ether/N,N-dimethyl-
ethanamine 70:29.5:0.5)). Colorless viscous oil, yield 11 mg
23
589
(80%). ½
aꢂ
¼ ꢀ14:7 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd
lethanamine 70:29.5:0.5)). Colorless viscous oil, yield 11 mg (85%).
for C16H23NH 230.1903, found 230.1893. Purity (HPLC): 95.0%
23
589
½
a
C
ꢂ
¼ ꢀ4:8 (c 0.10, CH2Cl2). Exact mass (ESI): m/z = calcd for
(tR = 16.08 min).
15H23NH 218.1903, found 218.1944. Purity (HPLC): 99.6%
(tR = 15.50 min).
5.3. Receptor binding studies
5.2.40. (R)-3-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepine-
1,10-cyclopentane] 17f
The NMDA receptor affinity was determined according to the
literature.15 The r1 and r2 receptor affinities were recorded
according to the literature.27–30
According to general procedure D, 15f (14 mg, 0.04 mmol) was
hydrogenated and the product was purified by FC (d = 1 cm,
l = 25 cm, V = 10 mL, EtOAc/petroleum ether/N,N-dimethylethan-
amine 50:49.5:0.5, Rf = 0.33 (EtOAc/petroleum ether/N,N-dimethy-
lethanamine 70:29.5:0.5)). Colorless viscous oil, yield 7 mg (78%).
Acknowledgments
We wish to thank the NRW Graduate School of Chemistry
(2008–11) for a stipend, which was funded by the Government
of the State Nordrhein-Westfalen and the Westfälische Wil-
helms-Universität Münster.
C
15H21N (215.3 g/mol). FT-IR (ATR, film):
m
(cmꢀ1) = 3378 (N–H),
(ppm) = 1.17 (d,
2934 (aliphatic C–H). 1H NMR (CDCl3):
d
J = 6.4 Hz, 3H, CH3), 1.58–1.94 (m, 6H, CH2), 2.13–2.23 (m, 1H,
CH2), 2.27–2.38 (m, 1H, CH2), 2.70 (d, J = 14.6 Hz, 1H, 5-H), 2.79–
2.93 (m, 3H, 2-H/4-H), 3.11 (dd, J = 14.6/9.6 Hz, 1H, 5-H), 7.01–
7.32 (m, 4H, arom). A signal for the NH proton is not detected.
13C NMR (CDCl3): d (ppm) = 23.7 (1C, CH3), 23.9, 24.3 (2C,
CH2CH2CH2CH2), 34.5, 37.2 (2C, CH2CH2CH2CH2), 47.3 (1C, C-5),
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589
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23
589
½
a
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¼ ꢀ23:0 (c 0.14, CH2Cl2). Exact mass (ESI): m/z = calcd for
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