Microwave assisted synthesis of 3-benzazepin-2-ones as building blocks for 2,3-disubstituted tetrahydro-3-benzazepines

Article abstract of DOI:10.1016/j.tet.2012.01.052

Microwave assisted condensation of primary amines with keto acids 1a-c provided directly 3,4-disubstituted 1,3-dihydro-3-benzazepin-2-ones 2. Whereas small amine size, such as NH₃ afforded high yields of secondary lactams 2a, 2d, and 2g, primary amines with larger substituents in α-position led to lower yields of 2 or even to regioisomeric indanone derivatives 4. However, subsequent alkylation of 2a, 2d, and 2g with various alkyl halides provided the corresponding N-substituted 3-benzazepin-2-ones 2 in good yields. Hydrogenation of 2 followed by BH₃ reduction led to 3-benzazepines 9. 3-Benzyl-2-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (9c) reveals high σ₁ affinity and selectivity over σ₂ and NMDA receptors.

Full text of DOI:10.1016/j.tet.2012.01.052

Tetrahedron 68 (2012) 2687e2695
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Microwave assisted synthesis of 3-benzazepin-2-ones as building blocks for
2,3-disubstituted tetrahydro-3-benzazepines
a
a
a
b
a,
*
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Soumya Sarkar , Syed Masood Husain , Dirk Schepmann , Roland Frohlich , Bernhard Wunsch
a
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Institut fur Pharmazeutische und Medizinische Chemie der Westfalischen Wilhelms-Universitat Munster, Hittorfstraße 58-62, D-48149 Munster, Germany
Organisch-Chemisches Institut der Westfalischen Wilhelms-Universitat Munster, Correnstr. 40, D-48149 Munster, Germany
b
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a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave assisted condensation of primary amines with keto acids 1aec provided directly 3,4-
disubstituted 1,3-dihydro-3-benzazepin-2-ones 2. Whereas small amine size, such as NH3 afforded
high yields of secondary lactams 2a, 2d, and 2g, primary amines with larger substituents in a-position led
to lower yields of 2 or even to regioisomeric indanone derivatives 4. However, subsequent alkylation of
2a, 2d, and 2g with various alkyl halides provided the corresponding N-substituted 3-benzazepin-2-ones
2 in good yields. Hydrogenation of 2 followed by BH3 reduction led to 3-benzazepines 9. 3-Benzyl-2-
methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (9c) reveals high s1 affinity and selectivity over s2 and
NMDA receptors.
Received 9 December 2011
Received in revised form 16 January 2012
Accepted 17 January 2012
Available online 24 January 2012
Dedicated to Prof. Dr. Dr. h.c. Gottfried
Blaschke on occasion of his 75th birthday
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Keto acids
3-Benzazepin-2-ones
Indanones
Microwave irradiation
s
Affinity
X-ray structure
1. Introduction
antiamnesic,21 and analgesic activity21 and may also be used for
tumor imaging purposes.22
Seven-membered N-heterocycles, in particular tetrahydro-3-
benzazepines, have been extensively studied as dopamine re-
ceptor agonists and antagonists.1e3 Furthermore, several 3-
benzazepines have also been examined for pharmacological ef-
fects, which are not mediated by dopamine receptors.4e7 Some 3-
benzazepines have been shown to be active in animal models of
various neurological disorders including Parkinson’s disease8 and
Alzheimer’s disease.9
The seven-membered lactam 2 represents a versatile building
block for the synthesis of various 3-benzazepines 9, since it allows
the introduction of various substituents in almost all positions of
the N-containing heterocyclic part (position 1e5) of the ring system
(Fig. 1). Modifications of positions 2e4 are described in this man-
uscript, position 1 can be substituted by enolate chemistry as
shown for similar systems11e14 and position 5 can be modified by
enamide chemistry.
Recently, it was reported that differently substituted tetrahydro-
3-benzazepines interact with high affinity and selectivity with s1
receptors.10e14 The s1 receptor represents the best characterized
In the literature only few methods for the synthesis of 3-
benzazepin-2-ones of type 2 with an aldehydic/ketonic carbon at
position 4 (N/O-acetal, enamine) are described. Intra- or in-
termolecular condensation of various 2-(2-oxoalkyl)phenylacetic
acid derivatives with phenylglycinol led to 3-benzazepin-2-ones
subtype of the
s receptor family. It is well established as non-
opioid, non-phencyclidine but haloperidol sensitive receptor with
a characteristic ligand binding profile and a characteristic distri-
bution in the central nervous system (CNS) as well as in some pe-
ripheral tissues like kidney, liver, lung, and heart.15,16 Ligands for s1
receptors have a potential for the treatment of epileptic disorders,17
depression,18 and drug abuse.19 They also show neuroprotective,20
* Corresponding author. Tel.: þ49 251 8333311; fax: þ49 251 8332144; e-mail
Fig. 1. 3-Benzazepin-2-ones 2 as key building blocks for the synthesis of diversely
substituted tetrahydro-3-benzazepines.
€
address: wuensch@uni-muenster.de (B. Wunsch).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.052

2688
S. Sarkar et al. / Tetrahedron 68 (2012) 2687e2695
with an N/O-acetalic group in position 4.11e14 3-Benzazepinones of
C12
type
2 were regioselectively synthesized by intramolecular
hydroamidation of ortho-alkynylphenylacetamides.23 The synthesis
of N-unsubstituted 3-benzazepinones of type 2 was reported by
C1
C10
C2
condensation of -oxo acids with ammonium acetate in glacial
3
acetic acid.24 Furthermore, a 3-benzazepinone of type 2 was
formed as side product during the synthesis of fully conjugated
seven and eight membered heterocyclic systems.25
C11
C9
C8
Herein we wish to report the synthesis of both N-unsubstituted
and N-substituted 3-benzazepin-2-ones 2 under microwave irradi-
ation by direct combination of keto acids 1 and primary amines.
According toour strategyketo acids 1 provide all carbon atomsof the
final heterocyclic system and the remaining N-atom is coming from
ammonia or a primary amine (Fig.1). The resulting 3-benzazepin-2-
ones 2 are further developed into potent s1 ligands 9.
N3
C6
C4
C5
C7
O1
2. Synthesis
Fig. 2. X-ray crystal structure analysis of 2a.
The synthesis of the 3-benzazepinones 2 started with keto acids
1, which are available by reaction of o-phenylenediacetic acid with
an excess of organolithium reagents26 Reaction of methyl keto acid
1a with benzylamine in refluxing toluene for 1 day led to the 3-
benzazepinone 2c in 20% yield together with some non-identified
products (Scheme 1). Increasing the amount of benzylamine up
to 10 equiv and the reaction time up to 3 days did not improve the
yield of 2c.
system are sp2-hybridized indicating a rather planar system. Due to
the tetrahedral structure of C-1, a deviation from coplanarity is only
observed around this carbon atom. The carbonyl moiety and the
adjacent N-atom are lying above the ring plane. This structure is
very similar to the structure of a comparable 3-benzazepine re-
ported recently by Liu and co-workers.23b
The table in Scheme 1 clearly indicates that the yields of the 3-
benzazepinones 2 decreased with increasing size of the amine
residue. The best yields (50e60 %) were obtained by reaction of
keto acids 1 with the very small amine NH3 (from NH4OAc), the
analogous condensations of 1 with methylamine and benzylamine
afforded considerably lower yields of the corresponding N-methyl
and N-benzyl derivatives. We assume that shielding of the N-atom
in the intermediates analogously to 3 inhibits the formation of
seven-membered lactams.
When using (S)-1-phenylethylamine bearing two substituents
in a-position of the amino moiety for the condensation with keto
acids 1a and 1b, the indanones (S)-4a and (S)-4b were isolated
instead of the expected 3-benzazepin-2-ones 2 (Scheme 2). Careful
analysis of the reaction mixtures did not provide any hints for the
presence of 3-benzazepinones. We assume that the electron rich
double bond of the enamine intermediate 3 reacted faster with the
carboxy group than the shielded amino moiety. An analogous
indanone derivative was also formed as side product during the
reaction of the sterically most demanding phenyl derivative 1c with
phenylglycinol.13
A similar observation was made during the reaction of o-phe-
nylenediacetic acid (5) with (R)-phenylglycinol, which provided
exclusively the 1-substituted indanone derivative (R)-7. Again a fast
reaction of the electron rich double bond of the intermediate ke-
tene-N/O-acetal 6 with the carboxy group is the reason for the
formation of the indanone (R)-7. Recrystallization of (R)-7 from
CH2Cl2/n-hexane led to crystals, which were suitable for an X-ray
crystal structure analysis (Fig. 3). This X-ray crystal structure
analysis proves the indanone structure of the product (R)-7 and,
moreover, the (E)-configuration of the exocyclic double bond
leading to an H-bond between the carbonyl moiety and the NH-
group. Due to similar chemical shifts in the 1H and 13C NMR spec-
tra of (S)-4a,b and (R)-7, we assume similar structures for (S)-4a and
(S)-4b, i.e. (Z)-configuration of the exocyclic double bond. The en-
antiomers (R)-4a,b and (S)-7 were synthesized in the same way
using (R)-1-phenylethylamine and (S)-phenylglycinol, respectively.
In order to improve the yields of N-substituted lactams, the
secondary lactams 2a, 2d, and 2g were alkylated with methyl io-
dide or benzyl bromide in the presence of concd KOH and tetra-
butylammonium iodide (Bu4NI) (Scheme 3).28 The differently
substituted dihydro-3-benzazepinones 2 were hydrogenated with
Scheme 1. Reagents and reaction conditions: (a) microwave irradiation, toluene,
120 ꢀC, 2e3 h, 150 W, 5 bar.
It has been shown that microwave irradiation often leads to
reduced reaction times (increased reaction rate) and improved
yields.27 Thus, the mixture of keto acid 1a and benzylamine in
toluene was irradiated by microwaves, which increased the yield of
the 3-benzazepinone 2c to 34%. Replacement of the solvent toluene
with DMF, THF or methanol did not lead to a further improvement
of the yield. Therefore, the optimized reaction conditions (micro-
wave irradiation, toluene) were applied on the transformation of
the three keto acids 1aec with NH4OAc, methylamine, and ben-
zylamine, respectively, which led to the expected 3-
benzazepinones 2aeg in yields of 26e60 %.
The NMR data of 2a (singlet at 6.15 ppm for 5-H; signals at 113.9
and 134.7 ppm for C-5 and C-4) show the presence of the C4eC5
double bond, which is further confirmed by recording an X-ray
crystal structure. Recrystallization of 2a with CH2Cl2/n-hexane
mixture led to crystals suitable for X-ray crystal structure analysis.
Moreover, the three-dimensional structure of the 3-benzazepinone
system is shown by the crystal structure (Fig. 2). With exception of
the sp3-hybridized carbon atom in 1-position, all atoms of the ring

S. Sarkar et al. / Tetrahedron 68 (2012) 2687e2695
2689
Scheme 2. Reagents and conditions: (a) microwave irradiation, toluene, 120 ꢀC, 2e3 h, 150 W, 5 bar, (S)-4a: 36%, (S)-4b: 25%. (b) toluene, 110 ꢀC, 3 days, 31%. The enantiomers (R)-
4a, (R)-4b and (S)-7 were prepared in the same manner.
O1
C2
C1
C9
C14
N1
C11
C3
C7
C10
O2
C13
C18
C4
C6
C15
C8
C5
C12
C16
C17
Fig. 3. X-ray crystal structure analysis of (R)-7 showing (E)-configuration of the exocyclic double bond.
H2 in the presence of Pd/C29 to afford the racemic tetrahydro-3-
BH3$THF complex30 to produce racemic 2,3-disubstituted tetrahy-
benzazepinoes 8 in 58e97 % yield. For the synthesis of potent s1
receptor ligands, which require a basic amino moiety and two hy-
drophobic regions,35,36 the lactam moiety of the N-benzyl
substituted 3-benzazepinones 8c, 8f, and 8i was reduced with
dro-3-benzazepines 9c, 9f, and 9i.
3. Receptor binding studies
The affinities of the 2,3-disubstituted tetrahydro-3-
benzazepines 9c, 9f, and 9i toward s1 and s2 receptors were in-
vestigated in competitive receptor binding studies. In the s1 assay
the radioligand [3H]-(þ)-pentazocine was used together with
membrane preparations from guinea pig brains as receptor mate-
rial. In the s2 assay rat liver preparations served as receptor ma-
terial. The non-selective radioligand [3H]-ditolylguanidine was
combined with (þ)-pentazocine to mask s1 receptors.31e34
The s1 receptor affinity of the racemic tetrahydro-3-
benzazepines 9c, 9f, and 9i decreases with increasing size of the
C-2 residue R1 (Table 1). Whereas the 3-benzazepine 9c containing
Table 1
Affinity of 2,3-disubtituted tetrahydro-3-benzazepines 9c, 9f, and 9i toward
s
receptors
Compd
R1
KiꢁSEM (nM)
s1
s2
9c
9f
9i
Me
Bu
Ph
12ꢁ5.6
437
1940
5.6ꢁ2.2
6.3ꢁ1.6
89ꢁ29
257
0%a
41%a
n.d.
(þ)-Pentazocine
Haloperidol
Ditolylguanidine
78ꢁ2.3
57ꢁ18
Scheme 3. Reagents and conditions:(a) R2-X, KOH, Bu4NI, THF, 2 h (b) H2, 1 atm, Pd/C,
THF, 24e48 h (c) BH3$THF, THF, rt, 18 h.
n.d.¼not determined.
a
Inhibition (%) of the radioligand binding at a concentration of 1 mM.

2690
S. Sarkar et al. / Tetrahedron 68 (2012) 2687e2695
a small methyl substituent at position 2 shows high s1 affinity with
a Ki value of 12 nM, the 3-benzazepines 9f and 9i with larger
substituents at position 2 display moderate (Ki¼437 nM) and low
select B (5
jection volume: 5.0
m
m), 250e4 mm cartridge; flow rate: 1.00 mL/min; in-
m
L; detection at
l¼210 nm; solvents: A: water
with 0.05% (v/v) trifluoroacetic acid; B: acetonitrile with 0.05% (v/v)
trifluoroacetic acid: gradient elution: (A %): 0e4 min: 90%,
4e29 min: gradient from 90% to 0%, 29e31 min: 0%, 31e31.5 min:
gradient from 0% to 90%, 31.5e40 min: 90%. Microwave apparatus:
CEM Discover LabMate Synthesiser, single mode cavity; Discover-
PC-software (CEM Corporation, NC); reactions were performed in
glass vessels (capacity 10 mL) sealed with corresponding pressure
adapter; pressure was controlled using a piezo-electric pressure
sensor; temperature of the vessel contents was monitored by using
an external infrared temperature control.
s1 affinity (Ki¼1.9
mM), respectively.
According to the pharmacophore model of Glennon35,36
a s1
ligand should consist of a basic amino moiety flanked by two hy-
drophobic regions. The amino moiety can be either a secondary or
a tertiary amine. However, in case of a tertiary amine only small
residues are allowed as third substituent. The substituent at posi-
tion 2 of the 3-benzazepines 9 can be considered as the third
substituent defined in the Glennon model. In 9c this substituent is
rather small (CH3) and therefore the s1 affinity is high. As postu-
lated in the Glennon model larger substituents (butyl (9f), phenyl
(9i)) decrease or eliminate the interaction with s1 receptors.
A similar trend was observed for the s2 affinity of the 3-
benzazepines. Whereas 3-benzazepine 9c with the small 2-
methyl substituent displays moderate s2 affinity (Ki¼257 nM),
the benzazepines 9f and 9i did not compete remarkably with the
5.2. General procedures
5.2.1. General procedure A for the synthesis of N-unsubstituted 3-
benzazepin-2-ones 2. A mixture of keto acid 1 (1 equiv), NH4OAc
(2 equiv), and toluene was stirred under microwave irradiation
(150 W, 120 ꢀC, 5 bar pressure) for 2e3 h. The reaction mixture was
concentrated in vacuum and the residue was purified by fc.
radioligand up to a concentration of 1
benzazepine 9c can be considered as s1 selective ligand with
s1 s2 selectivity of 21.
Since some potent ligands also interact with the phencyclidine
mM. Nevertheless 3-
a
:
s
5.2.2. General procedure B for the synthesis of N-substituted 3-
benzazepin-2-ones 2. A mixture of keto acid 1 (1 equiv), methyl-
amine or benzylamine (2 equiv), and toluene was stirred under
microwave irradiation (150 W, 120 ꢀC, 5 bar pressure) for 2e3 h.
The reaction mixture was concentrated in vacuum and the residue
was purified by fc.
binding site of the NMDA receptor and vice versa37,38 the affinities
of the 3-benzazepines 9c, 9f, and 9i toward the NMDA receptor
were also determined.11 In competition experiments with the
radioligand (þ)-MK-801 the investigated 3-benzazepines did not
show any affinity to this receptor system.
4. Conclusion
5.2.3. General procedure C for N-alkylation of 2a, 2d, and
2g. Tetrabutylammonium iodide (0.5 equiv), concd KOH in H2O
(1.2 equiv), and alkyl halide (1.5 equiv) were added to benzazepi-
none 2 dissolved in THF (6 mL) and the mixture was stirred at rt for
2 h. Completion of the conversion was controlled by TLC. The re-
action mixture was washed with NaCl solution (10 mL) and water
(10 mL), the aqueous layer was extracted with EtOAc (3ꢄ10 mL), the
combined organic layers were dried (Na2SO4), filtered, the solvent
was evaporated in vacuum, and the residue was purified by fc.
The described microwave assisted reaction of keto acids 1 with
various primary amines allows the direct synthesis of diversely
substituted 3-benzazepin-2-ones 2. Transformations of keto acids 1
with primary amines bearing larger
a-substituents gave lower
yields or even led to indanone derivatives 4. Therefore, the sub-
sequent alkylation of secondary lactams 2a, 2d, and 2g with dif-
ferent alkyl halides represents an attractive alternative to obtain
the corresponding N-substituted 3-benzazepinones 2. The sec-
ondary lactams 2a, 2d, and 2g were available in 50e60 % yields
upon reaction of keto acids 1aec with NH4OAc. Catalytic hydro-
genation of 2 followed by BH3 reduction produced pharmacologi-
cally attractive tetrahydro-3-benzazepines 9. Preliminary receptor
binding studies revealed promising s1 receptor affinity of 9c
(Ki¼12 nM) stimulating the further exploitation of the 3-
benzazepine compound class as CNS receptor ligands.
5.2.4. General procedure D for the hydrogenation of 2. A mixture of
2 and Pd/C (100% by wt) in THF (5 mL) was stirred at rt under H2
atmosphere (balloon) for 24e48 h. The reaction mixture was fil-
tered through CeliteÒ bed and the solvent was removed under re-
duced pressure to obtain a residue, which was purified by fc.
5.2.5. General procedure E for reduction of lactams 8c, 8f, and
8i. Under N2 BH3$THF complex (2 equiv, 1 M in THF) was added to
lactam 8 (1 equiv) dissolved in THF (5 mL) and the mixture was
stirred at rt for 18 h. The reaction mixture was quenched with 1 M
NaOH (5 mL). The aqueous layer was extracted with EtOAc
(3ꢄ10 mL), the collected organic layers were dried (Na2SO4), con-
centrated under vacuum, and the residue was purified by fc.
5. Experimental section
5.1. Chemistry, general
Flash chromatography (fc): Silica gel 60, 40e64
mm (Merck);
parentheses include: diameter of the column, length of column,
fraction size, eluent, Rf value. Melting point: melting point apparatus
SMP 3 (Stuart Scientific), uncorrected. IR: IR spectrophotometer
480Plus FT-ATR-IR (Jasco). 1H NMR (400 MHz), 13C NMR (100 MHz):
5.3. Synthetic procedures
5 . 3 .1. 4 - M e t h y l - 1, 3 - d i h y d r o - 3 - b e n z o a z e p i n - 2 - o n e
(2a).24b Following the general procedure A, methyl keto acid 1a
(500 mg, 2.6 mmol) and NH4OAc (401 mg, 5.2 mmol) were stirred in
toluene (15 mL) under microwave irradiation for 2 h. The crude
product was purified by fc (d¼3 cm, l¼20 cm, V¼20 mL, cyclohex-
ane/EtOAc 80:20, Rf¼0.22 (cyclohexane/EtOAc 60:40)). Colorless
solid, mp 173 ꢀC, yield 225 mg (50%). C11H11NO (173.2 g/mol). FT-IR
Mercury plus 400 spectrometer (Varian);
d in parts per million re-
lated to tetramethylsilane; coupling constants are given with 0.5 Hz
resolution. Optical rotation: Polarimeter 341 (PerkineElmer);
1.0 dm tube; concentration c in g/100 mL; T¼20 ꢀC; wavelength
589 nm (D-line of Na light); the unit of the specific rotation (½a DT
ꢂ
grad mL dmꢃ1
g
ꢃ1) is omitted for clarity. MS: EI¼electron impact,
ESI¼electro spray ionization: MicroTof (Bruker Daltronics, Bremen),
calibrationwith sodium formateclusters beforemeasurement. HPLC
method for determination of the product purity: Merck Hitachi
Equipment; UV detector: L-7400; autosampler: L-7200; pump: L-
7100; degasser: L-7614; Method A: column: LiChrospherÒ 60 RP-
(ATR, film):
(CDCl3):
n
(cmꢃ1)¼2970 (aliphatic CeH), 1672 (C]O). 1H NMR
d
(ppm)¼2.03 (d, J¼0.9 Hz, 3H, CH3), 3.42 (s, 2H,1-CH2), 6.15
(s, 1H, 5-H), 7.01e7.25 (m, 4H, arom), 7.70 (s, 1H, NeH). 13C NMR
(CDCl3):
(ppm)¼22.9 (1C, CH3), 43.1 (1C, C-1),113.9 (1C, C-5),127.0,
127.1, 127.9, 128.7 (4C, PheCH), 130.4, 133.4, 134.7 (3C, C-4/PheC),
d

S. Sarkar et al. / Tetrahedron 68 (2012) 2687e2695
2691
170.0 (1C, C]O). Exact mass (ESI): m/z¼calcd for C11H11NONa
196.0733, found 196.0739. Purity (HPLC): 99.9% (tR¼15.80 min).
For X-ray crystal structure analysis 2a was recrystallized from
CH2Cl2/n-hexane mixture. Formula C11H11NO, M¼173.21, colorless
3H, CH2CH2CH2CH3), 1.33e1.44 (m, 2H, CH2CH2CH2CH3), 1.52e1.61
(m, 2H, CH2CH2CH2CH3), 2.33 (t, J¼7.5 Hz, 2H, CH2CH2CH2CH3), 3.48
(s, 2H, 1-CH2), 6.24 (s, 1H, 5-H), 7.13e7.34 (m, 4H, arom), 7.68 (s, 1H,
NeH).13C NMR (CDCl3):
CH2CH2CH2CH3), 30.5
d
(ppm)¼14.1 (1C, CH2CH2CH2CH3), 22.3 (1C,
crystal 0.35ꢄ0.17ꢄ0.07 mm, a¼4.2358(1), b¼12.8115(3),
(1C, CH2CH2CH2CH3), 36.8 (1C,
3
c¼16.5005(5) A,
b
¼91.699(1) , V¼895.04(4) A , rcalcd¼1.285 g cmꢃ3
,
CH2CH2CH2CH3), 43.3 (1C, C-1), 113.9 (1C, C-5), 127.2, 127.4, 128.2,
128.9 (4C, PheCH),130.8,134.9,137.7(3C, C-4/PheC),170.5(1C, C]O).
Exact mass (ESI): m/z¼calcd for C14H17NOH 216.1383, found 216.1392.
Purity (HPLC): 90.9% (tR¼19.57 min).
ꢀ
ꢀ
ꢀ
m
¼0.083 mmꢃ1, empirical absorption correction (0.960 T 0.994),
ꢀ
Z¼4, monoclinic, space group P21/c (No. 14),
l
¼0.71073 A, T¼223 K,
u
and
4
scans, refined parameters, R¼0.065, wR2¼0.199, GOF 1.051,
ꢀꢃ3
max. residual electron density 0.37 (ꢃ0.25) e A . CCDC 832130.
5.3.2. 3,4-Dimethyl-1,3-dihydro-3-benzoazepin-2-one (2b).
5.3.5. 4-Butyl-3-methyl-1,3-dihydro-3-benzazepin-2-one (2e).23a
(a) Following the general procedure B, butyl keto acid 1b (62 mg,
0.26 mmol) was reacted with methylamine (2 M in THF, 0.26 mL,
0.52 mmol) in toluene (6 mL) under microwave irradiation for 2 h.
Work-up and fc purification provided colorless solid, yield 20 mg
(32%).
(a) Following the general procedure B, methyl keto acid 1a
(100 mg, 0.52 mmol) was reacted with methylamine (2 M in
THF, 0.52 mL, 1.04 mmol) in toluene (6 mL) under microwave
irradiation for 2 h. Work-up and fc purification provided col-
orless oil, yield 29 mg (30%).
(b) Following the general procedure C, 2d (54 mg, 0.25 mmol) was
(b) Following the general procedure C, secondary lactam 2a (50 mg,
methylated with methyl iodide (23 mL, 0.38 mmol), concd KOH
0.29 mmol) was N-methylated with methyl iodide (27
m
L,
(17 mg, 0.30 mmol), and Bu4NI (46 mg, 0.13 mmol). The crude
product was purified by fc (d¼2 cm, l¼15 cm, V¼10 mL, cy-
clohexane/EtOAc 80:20, Rf¼0.48 (cyclohexane/EtOAc 60:40)).
Colorless solid, mp 58e59 ꢀC (mp 57e58 ꢀC23a), yield 40 mg
0.44 mmol), concd KOH (20 mg, 0.35 mmol), and Bu4NI (55 mg,
0.15 mmol). The crude product was purified by fc (d¼2 cm,
l¼15 cm, V¼10 mL, cyclohexane/EtOAc 80:20, Rf¼0.25 (cyclo-
hexane/EtOAc60:40)). Colorlessoil, yield 25 mg(46%). C12H13NO
(75%). C15H19NO (229.3 g/mol). FT-IR (ATR, film):
n
(cmꢃ1)¼
(ppm)¼
(187.2 g/mol). FT-IR (ATR, film):
n
(cmꢃ1)¼2962 (aliphatic CeH),
(ppm)¼2.14 (d, J¼1.1 Hz, 3H,
2955 (aliphatic CeH), 1655 (C]O). 1H NMR (CDCl3):
d
1655 (C]O). 1H NMR (CDCl3):
d
0.95 (t, J¼7.2 Hz, 3H, CH2CH2CH2CH3), 1.35e1.55 (m, 4H,
CH2CH2CH2CH3), 2.23e2.73 (m, 2H, CH2CH2CH2CH3), 3.04 (s,
3H, CH3), 3.44e3e65 (br s, 2H, 1-H), 6.46 (s, 1H, 5-H), 7.20e7.31
CH3), 3.01 (s, 3H, CH3), 3.45 (s, 2H, 1-CH2), 6.35 (s, 1H, 5-H),
7.10e7.24 (m, 4H, arom). 13C NMR (CDCl3):
d
(ppm)¼22.0 (1C,
CH3), 31.9 (1C, CH3), 43.1 (1C, C-1), 118.1 (1C, C-5), 126.7, 126.8,
128.1,128.2 (4C, PheCH),132.9,133.9,137.9 (3C, PheC/C-4) 169.3
(1C, C]O). Exact mass (ESI): m/z¼calcd for C12H13NOH 188.1075,
found 188.1118. Purity (HPLC): 95.6% (tR¼16.91 min).
(m, 4H, arom). 13C NMR (CDCl3):
d
(ppm)¼13.9 (1C,
CH2CH2CH2CH3), 22.2 (1C, CH2CH2CH2CH3), 30.5 (1C,
CH2CH2CH2CH3), 31.8 (1C, CH3), 35.1 (1C, CH2CH2CH2CH3), 43.0
(1C, C-1), 118.1 (1C, C-5), 126.9, 127.0, 128.1, 128.3 (4C, PheCH),
133.2, 133.8, 142.5 (3C, C-4/PheC), 169.7 (1C, C]O). Exact mass
(ESI): m/z¼calcd for C15H19NOH 230.1539, found 230.1562.
Purity (HPLC): 93.2% (tR¼20.65 min).
5.3.3. 3-Benzyl-4-methyl-1,3-dihydro-3-benzoazepin-2-one (2c).
(a) Following the general procedure B, methyl keto acid 1a (52 mg,
0.27 mmol) was reacted with benzylamine (59
mL, 0.54 mmol)
5.3.6. 3-Benzyl-4-butyl-1,3-dihydro-3-benzazepin-2-one (2f).
in toluene (6 mL) under microwave irradiation for 3 h. Work-up
and fc purification provided a colorless solid, yield 24 mg (34%).
(b) Following the general procedure C, secondary lactam 2a
(61 mg, 0.35 mmol) was N-benzylated with benzyl bromide
(a) Following the general procedure B, butyl keto acid 1b (50 mg,
0.21 mmol) was reacted with benzylamine (46 mL, 0.42 mmol)
in toluene (6 mL) under microwave irradiation for 3 h. Work-up
and fc purification provided colorless oil, yield 17 mg (26%).
(b) Following the general procedure C, 2d (38 mg, 0.18 mmol) was
(63 mL, 0.53 mmol), concd KOH (24 mg, 0.42 mmol), and Bu4NI
(65 mg, 0.18 mmol). The crude product was purified by fc
(d¼2 cm, l¼15 cm, V¼10 mL, cyclohexane/EtOAc 80:20, Rf¼0.42
(cyclohexane/EtOAc 60:40)). Colorless solid, mp 119 ꢀC, yield
reacted with benzyl bromide (32 mL, 0.27 mmol), concd KOH
(12 mg, 0.22 mmol), and Bu4NI (33 mg, 0.09 mmol). The crude
product was purified by fc (d¼2 cm, l¼15 cm, V¼10 mL, cy-
clohexane/EtOAc 80:20, Rf¼0.52 (cyclohexane/EtOAc 60:40)).
Colorless oil, yield 39 mg (73%). C21H23NO (305.4 g/mol). FT-IR
62 mg (67%). C18H17NO (263.3 g/mol). FT-IR (ATR, film):
n
(cmꢃ1)¼3029 (aromatic CeH), 1656 (C]O). 1H NMR (CDCl3):
d
(ppm)¼2.01 (d, J¼1.0 Hz, 3H, CH3), 3.55 (br s, 2H, 1-CH2), 4.63
(br s, 2H, NCH2Ph), 6.34 (s, 1H, 5-H), 6.76e6.81 (m, 2H, arom),
(ATR, film):
NMR (CDCl3):
n
(cmꢃ1)¼2956 (aliphatic CeH), 1659 (C]O). 1H
7.05e7.30 (m, 7H, arom). 13C NMR (CDCl3):
d
(ppm)¼22.2 (1C,
d
(ppm)¼0.91 (t, J¼7.2 Hz, 3H, CH2CH2CH2CH3),
CH3), 43.1 (1C, C-1), 46.9 (1C, NCH2Ph), 120.0 (1C, C-5), 126.8,
126.9, 127.1, 127.2, 128.3, 128.6 (9C, PheCH), 132.9, 134.0, 137.0,
137.3 (4C, PheC/C-4), 169.1 (1C, C]O). Exact mass (ESI): m/
z¼calcd for C18H17NONa 286.1202, found 286.1209. Purity
(HPLC): 90.0% (tR¼20.25 min).
1.21e1.51 (m, 4H, CH2CH2CH2CH3), 2.10e2.57 (m, 2H,
CH2CH2CH2CH3), 3.36e3.83 (m, br, 2H. 1-CH2), 4.16e4.38 (m,
br, 1H, NCH2Ph), 5.30e5.52 (m, br, 1H, NCH2Ph), 6.45 (s, 1H, 5-
H), 6.79e6.85 (m, 2H, arom), 7.10e7.40 (m, 7H, arom). 13C NMR
(CDCl3):
d
(ppm)¼13.8 (1C, CH2CH2CH2CH3), 22.3 (1C,
CH2CH2CH2CH3), 30.5 (1C, CH2CH2CH2CH3), 34.8 (1C,
CH2CH2CH2CH3), 43.0 (1C, C-1), 46.6 (1C, NCH2Ph),120.3 (1C, C-
5), 126.8, 126.9, 127.0, 128.1, 128.2, 128.4, 128.9 (9C, PheCH),
133.2, 133.8, 137.3, 141.4 (4C, C-4/PheC), 169.8 (1C, C]O). Exact
mass (ESI): m/z¼calcd for C21H23NONa 328.1672, found
328.1675. Purity (HPLC): 90.1% (tR¼22.71 min).
5.3.4. 4-Butyl-1,3-dihydro-3-benzoazepin-2-one (2d).23a Following
the general procedure A, a mixture of butyl keto acid 1b (113 mg,
0.48 mmol), NH4OAc (74 mg, 0.96 mmol), and toluene (10 mL) was
stirred under microwave irradiation for 2 h. The crude product was
purified by fc (d¼3 cm, l¼15 cm, V¼20 mL, cyclohexane/EtOAc 80:20,
Rf¼0.39 (cyclohexane/EtOAc 60:40)). Colorless solid, yield 58 mg
(56%). C14H17NO (215.3 g/mol). FT-IR (ATR, film):
iphatic CeH),1665(C]O).1H NMR (CDCl3):
n
(cmꢃ1)¼2975 (al-
5.3.7. 4-Phenyl-1,3-dihydro-3-benzazepin-2-one
(2g). Following
d
(ppm)¼0.94(t, J¼7.3 Hz,
the general procedure A, mixture of phenyl keto acid 1c (270 mg,

2692
S. Sarkar et al. / Tetrahedron 68 (2012) 2687e2695
1.06 mmol), NH4OAc (164 mg, 2.12 mmol), and toluene (10 mL) was
stirred under microwave irradiation for 3 h. The crude product was
purified by fc (d¼3 cm, l¼20 cm, V¼20 mL, cyclohexane/EtOAc
80:20, Rf¼0.33 (cyclohexane/EtOAc 60:40)). Colorless solid, mp
159 ꢀC, yield 150 mg (60%). C16H13NO (235.3 g/mol). FT-IR (ATR,
(43 mL, 0.34 mmol) in toluene (6 mL) under microwave irradia-
tion for 2 h. Pale yellow solid, mp 156e158 ꢀC, yield 20 mg (41%).
23
½
a
ꢂ
ꢃ153.0 (c 0.12, CH2Cl2). Exact mass (ESI): m/z¼calcd for
589
C19H19NONa 300.1359, found 300.1355. Purity (HPLC): 96.5%
(tR¼21.49 min).
film):
n
(cmꢃ1)¼2934 (aliphatic CeH),1652 (C]O). 1H NMR (CDCl3):
d
(ppm)¼3.63 (s, 2H, 1-CH2), 6.83 (s, 1H, 5-H), 7.28e7.49 (m, 7H,
5.3.12. (Z)-1-{1-[(S)-(1-Phenylethyl)amino]pentylidene}indan-2-one
[(S)-4b]. Following the general procedure A, butyl keto acid 1b
(49 mg, 0.21 mmol), (S)-1-phenylethylamine (52 mL, 0.42 mmol),
arom), 7.59e7.69 (m, 3H, arom/NeH). 13C NMR (CDCl3):
d
(ppm)¼
43.0 (1C, C-1), 115.2 (1C, C-5), 126.5, 127.2, 127.7, 128.7, 128.9, 129.0,
129.3 (9C, PheCH), 131.6, 134.5, 136.7, 137.5 (4C, C-4/PheC), 170.3
(1C, C]O). Exact mass (ESI): m/z¼calcd for C16H3NOH 236.1075,
found 236.1111. Purity (HPLC): 92.8% (tR¼19.09 min).
and toluene (6 mL) was stirred under microwave irradiation
(150 MW, 120 ꢀC) for 2 h. The crude product was purified by flash
chromatography (d¼3 cm, l¼20 cm, V¼20 mL, cyclohexane/EtOAc
85:15, Rf¼0.57 (cyclohexane/EtOAc 60:40)). Pale yellow solid, mp
76e78 ꢀC, yield 16 mg (25%). C22H25NO (319.4 g/mol). FT-IR (ATR,
5.3.8. 3-Methyl-4-phenyl-1,3-dihydro-3-benzazepin-2-one
Following the general procedure C, 2g (32 mg, 0.14 mmol) was
methylatedwithmethyliodide(13 L,0.21mmol), concdKOH(10mg,
(2h).
film):
n
(cmꢃ1)¼2960 (aliphatic CeH),1624 (C]O). 1H NMR (CDCl3):
m
d
(ppm)¼0.84 (t, J¼7.1 Hz, 3H, CH3), 1.22e1.50 (m, 4H,
0.18 mmol), and Bu4NI (26 mg, 0.07 mmol). The crude product was
purified by fc (d¼2 cm, l¼10 cm, V¼10 mL, cyclohexane/EtOAc 80:20,
Rf¼0.39 (cyclohexane/EtOAc 60:40)). Colorless solid, mp 138 ꢀC (mp
138e139 ꢀC23), yield27mg(79%). C17H15NO(249.3g/mol). FT-IR (ATR,
CH2CH2CH2CH3), 1.56 (d, J¼6.8 Hz, 3H, CH3), 2.35e2.58 (m, 2H,
CH2CH2CH2CH3), 3.39 (s, 2H, 1-CH2), 4.77 (‘quint’, J¼7.1 Hz,
NCHCH3Ph), 6.87e7.30 (m, 9H, arom), 11.77 (br s, 1H, NH). 13C NMR
(CDCl3):
CH2CH2CH2CH3),
d
(ppm)¼13.7 (1C, CH3), 22.9 (1C, CH3), 24.9 (1C,
film):
n
(cmꢃ1)¼2968 (aliphatic CeH), 1654 (C]O). 1H NMR (CDCl3):
28.5 (1C, CH2CH2CH2CH3), 28.7 (1C,
d
(ppm)¼2.80 (s, 3H, CH3), 3.37e3.75 (m, 2H,1-CH2), 6.74 (s,1H, 5-H),
CH2CH2CH2CH3), 42.6 (1C, C-3), 52.8 (1C, NCHCH3Ph), 106.4 (1C, C-
1), 118.2, 122.6, 124.3, 125.6, 126.9, 127.4, 128.9 (9C, PheCH), 133.9,
7.16e7.45 (m, 9H, arom). 13C NMR (CDCl3):
d
(ppm)¼35.1 (1C, CH3),
43.0 (1C, C-1), 120.2 (1C, C-5), 127.0, 127.4, 127.5, 128.4, 128.7, 128.9
(9C,PheCH),133.6,133.7,137.8,143.3(4C,C-4/PheC),169.8(1C,C]O).
Exact mass(ESI): m/z¼calcd for C17H15NOH 250.1226 found 250.1296.
Purity (HPLC): 96.6% (tR¼20.41 min).
142.2, 144.5 (3C, PheC), 164.0 (1C, C]CCH2CH2CH2CH3), 202.6 (1C,
23
C]O).
½
a
ꢂ
þ154.6 (c 0.15, CH2Cl2). Exact mass (ESI): m/
589
z¼calculated for C19H19NONa 342.1828, found 342.1834. Purity
(HPLC): 75.9% (tR¼24.12 min).
5.3.9. 3-Benzyl-4-phenyl-1,3-dihydro-3-benzoazepin-2-one
5.3.13. (Z)-1-{1-[(R)-(1-Phenylethyl)amino]pentylidene}indan-2-one
(2i). Following the general procedure C, 2g (35 mg, 0.15 mmol) was
[(R)-4b]. Following the general procedure B, butyl keto acid 1b
reacted with benzyl bromide (27
mL 0.23 mmol), concd KOH (10 mg,
(46 mg, 0.20 mmol), (R)-1-phenylethylamine (52 mL, 0.40 mmol),
0.18 mmol), and Bu4NI (29 mg, 0.08 mmol). The crude product was
purified by fc (d¼2 cm, l¼10 cm, V¼10 mL, cyclohexane/EtOAc
80:20, Rf¼0.44 (cyclohexane/EtOAc 60:40)). Colorless solid, mp
98 ꢀC, yield 40 mg (83%). C23H19NO (325.4 g/mol). FT-IR (ATR, film):
and toluene (6 mL) were stirred under microwave irradiation for
2 h. The crude product was purified by fc (d¼3 cm, l¼20 cm,
V¼20 mL, cyclohexane/EtOAc 85:15, Rf¼0.57 (cyclohexane/EtOAc
23
60:40)). Pale yellow solid, mp 76e78 ꢀC, yield 17 mg (27%). ½
ꢂ
a
589
n
(cmꢃ1)¼3026 (aliphatic CeH), 1659 (C]O). 1H NMR (CDCl3):
(ppm)¼3.45e3.94 (m, 3H, 1-CH2/NCH2Ph), 5.28e5.42 (m, 1H,
ꢃ151.5 (c 0.17, CH2Cl2). Exact mass (ESI): m/z¼calcd for C19H19NONa
342.1828, found 342.1842. Purity (HPLC): 80.0% (tR¼24.08 min).
d
NCH2Ph), 6.44e6.49 (m, 2H, arom), 6.70 (s, 1H, 5-H), 6.86e7.00 (m,
3H, arom), 7.12e7.38 (m, 9H, arom). 13C NMR (CDCl3):
d
(ppm)¼43.0
5.3.14. (R,E)-1-(4-Phenyloxazolidin-2-ylidene)indan-2-one
[(R)-
(1C, C-1), 48.6 (1C, NCH2Ph), 122.7 (1C, C-5), 126.8, 127.1, 127.2,
127.3, 127.6, 127.9, 128.3, 128.6, 128.7, 128.9 (14C, PheCH), 133.5,
133.8, 136.9, 137.6, 142.2 (5C, C-4/PheC), 169.8 (1C, C]O). Exact
mass (ESI): m/z¼calcd for C23H19NOH 326.1545 found 326.1575.
Purity (HPLC): 90.8% (tR¼22.33 min).
7]. A solution of o-phenylenediacetic acid (5, 300 mg, 1.54 mmol)
and (R)-phenylglycinol (211 mg, 1.54 mmol) in toluene (40 mL) was
heated to reflux for 3 days. Then the mixture was cooled, concen-
trated in vacuum, and the residue was dissolved in EtOAc (50 mL).
The solution was washed with 1 M NaOH (3ꢄ15 mL), the aqueous
layer was extracted thrice with EtOAc and the combined EtOAc
layers were washed with 1 M HCl (3ꢄ15 mL). The organic layer was
dried (Na2SO4), concentrated in vacuo, and the residue was purified
by fc (d¼2 cm, l¼25 cm, V¼25 mL, cyclohexane/EtOAc 80:20,
Rf¼0.33 (petroleum ether/EtOAc 1:1). The product was further pu-
rified by recrystallization (CH2Cl2/n-hexane). Colorless solid, mp
173e175 ꢀC, yield 133 mg (31%). C18H15NO2 (277.3 g/mol)). FT-IR
5.3.10. (Z)-1-{1-[(S)-(1-Phenylethyl)amino]ethylidene}indan-2-one
[(S)-4a]. Following the general procedure B, methyl keto acid 1a
(39 mg, 0.20 mmol) was reacted with (S)-1-phenylethylamine
(52 mL, 0.40 mmol) in toluene (6 mL) under microwave irradiation
for 2 h. The crude product was purified by fc (d¼3 cm, l¼20 cm,
V¼20 mL, cyclohexane/EtOAc 85:15, Rf¼0.47 (cyclohexane/EtOAc
60:40)). Pale yellow solid, mp 156e168 ꢀC, yield 20 mg (36%).
(ATR, film):
n
(cmꢃ1)¼3211 (w, NeH), 3065, 3033 (w, arom CeH),
C19H19NO (277.4 g/mol). FT-IR (ATR, film):
n
(cmꢃ1)¼2970 (aliphatic
1658 (s, C]O). 1H NMR (CDCl3):
d
(ppm)¼3.46 (s, 2H, 3-H), 4.45 (dd,
CeH), 1627 (C]O). 1H NMR (CDCl3):
d
(ppm)¼1.64 (d, J¼6.8 Hz, 3H,
J¼8.7/6.7 Hz, 1H, 5-H oxaz.), 4.96 (t, J¼8.7 Hz, 1H, 5-H oxaz.), 5.16
(dd, J¼8.6/6.8 Hz,1H, 4-H oxaz.), 7.02 (m,1H, arom), 7.21 (t, J¼7.6 Hz,
2H, arom), 7.31e7.44 (m, 6H, arom), 9.50 (br s, 1H, NH). 13C NMR
CH3), 2.23 (s, 3H, CH3), 3.48 (s, 2H, 3-CH2), 4.86 (‘quint’, J¼6.8 Hz,1H,
NCHCH3Ph), 6.94e7.40 (m, 9H, arom), 11.70 (br s, 1H, NH). 13C NMR
(CDCl3):
d
(ppm)¼16.7 (1C, CH3), 24.9 (1C, CH3), 42.8 (1C, C-3), 53.4
(CDCl3):
d
(ppm)¼42.8 (1C, C-3), 58.3 (1C, C-5 oxaz.), 76.2 (1C, C-4
(1C, NCHCH3Ph), 107.5 (1C, C-1), 118.9, 122.9, 124.6, 125.7, 126.9,
oxaz), 91.0 (1C, C-1),118.6, 122.5, 124.5, 126.9, 127.3, 128.8, 129.5 (9C,
127.6, 129.2 (9C, PheCH), 134.1, 142.9, 144.3 (3C, PheC), 160.1 (1C,
PheCH),133.2,141.1,141.9 (3C, PheC),163.6 (1C, C-2 oxaz),199.8 (1C,
23
20
C]CCH3), 202.1 (1C, C]O). ½
a
ꢂ
þ150.0 (c 0.13, CH2Cl2). Exact mass
C]O). ½
a
ꢂ
ꢃ87.8 (c 1.84, CH2Cl2). MS (EI): m/z (%)¼277 [M, 100],
589
589
(ESI): m/z¼calcd for C19H19NONa 300.1359, found 300.1354. Purity
(HPLC): 84.6% (tR¼21.81 min).
157 [MꢃPhCHCH2O, 68]. Purity (HPLC): 99.2%, tR¼21.74 min.
For X-ray crystal structure analysis (R)-7 was recrystallized from
CH2Cl2/n-hexane mixture. Formula C18H15NO2, M¼277.31, colorless
5.3.11. (Z)-1-{1-[(R)-(1-Phenylethyl)amino]ethylidene}indan-2-one
[(R)-4a]. Following the general procedure B, methyl keto acid 1a
(33 mg, 0.17 mmol) was reacted with (R)-1-phenylethylamine
crystal
0.18ꢄ0.15ꢄ0.06
mm,
a¼22.845(1),
b¼5.296(1),
3
¼133.63(1) , V¼1400.9(3) A , rcalcd¼1.315 g cmꢃ3
,
ꢀ
ꢀ
ꢀ
c¼15.997(1) A,
b
m
¼0.086 mmꢃ1, empirical absorption correction (0.985 T 0.995),

S. Sarkar et al. / Tetrahedron 68 (2012) 2687e2695
2693
ꢀ
Z¼4, monoclinic, space group C2 (No. 5),
l
¼0.71073 A, T¼223 K,
u
2.90 (dd, J¼15.8/10.5 Hz, 1H, 5-H), 3.02 (dd, J¼15.8/3.3 Hz, 1H, 5-H),
3.56 (d, J¼15.2 Hz, 1H, 1-H), 3.59e3.68 (m, 1H, 4-H), 3.92 (d,
and
4
scans, refined parameters, R¼0.050, wR2¼0.110, GOF 1.054,
Flack parameter 0.8(18), max. residual electron density 0.22
J¼15.2 Hz, 1H, 1-H), 5.59 (br s, 1H, NH), 6.92e7.23 (m, 4H, arom). 13
C
ꢀꢃ3
(ꢃ0.18) e A . CCDC 857523.
NMR (CDCl3):
d
(ppm)¼14.2 (1C, CH2CH2CH2CH3), 22.7 (1C,
CH2CH2CH2CH3),
28.1
(1C,
CH2CH2CH2CH3),
36.6
(1C,
5.3.15. (S,E)-1-(4-Phenyloxazolidin-2-ylidene)indan-2-one (S-7). As
described for the synthesis of (R)-7, o-phenylenediacetic acid (5,
CH2CH2CH2CH3), 38.8 (1C, C-5), 42.8 (1C, C-1), 53.2 (1C, C-4), 127.2,
127.5, 129.9, 130.1 (4C, PheCH), 132.7, 136.7 (2C, PheC), 172.3 (1C,
C]O). Exact mass (ESI): m/z¼calcd for C14H19NOH 218.1539, found
218.1570. Purity (HPLC): 90.3% (tR¼19.17 min).
300 mg, 1.54 mmol) and (S)-phenylglycinol (211 mg, 1.54 mmol)
20
589
were heated to reflux. Colorless solid, yield 149 mg (35%). ½
a
ꢂ
þ93.3 (c 0.86, CH2Cl2). Purity (HPLC): 98.5%, tR¼21.74 min.
5.3.20. 4-Butyl-3-methyl-1,3,4,5-tetrahydro-3-benzazepin-2-one
(8e). Following to the general procedure D, 2e (40 mg, 0.17 mmol)
was hydrogenated and the crude product was purified by fc
(d¼2 cm, l¼10 cm, V¼10 mL, cyclohexane/EtOAc 80:20, Rf¼0.21
(cyclohexane/EtOAc 60:40)). Colorless oil, yield 28 mg (69%).
5.3.16. 4-Methyl-1,3,4,5-tetrahydro-3-benzazepin-2-one
(8a). Following the general procedure D, 2a (30 mg, 0.17 mmol) was
hydrogenated and the crude product was purified by fc (d¼2 cm,
l¼10 cm, V¼10 mL, cyclohexane/EtOAc 80:20, Rf¼0.10 (cyclohexane/
EtOAc 60:40)). Colorless oil, yield 21 mg (70%). C11H13NO (175.2 g/
C15H21NO (231.3 g/mol). FT-IR (ATR, film):
n
(cmꢃ1)¼2960 (aliphatic
mol). FT-IR (ATR, film):
n
(cmꢃ1)¼2950 (aliphatic CeH), 1670 (C]O).
CeH), 1648 (C]O). 1H NMR (CDCl3):
d
(ppm)¼0.86 (t, J¼6.9 Hz, 3H,
1H NMR (CDCl3):
d
(ppm)¼1.20 (d, J¼6.3 Hz, 3H, CH3), 2.90 (dd,
CH2CH2CH2CH3), 1.21e1.35 (m, 4H, CH2CH2CH2CH3), 1.38e1.70 (m,
2H, CH2CH2CH2CH3), 2.81 (s, 3H, CH3), 2.96e3.02 (m, 2H, 5-H),
3.62e3.76 (m, 2H, 1-H/4-H), 3.94 (d, J¼15.3 Hz, 1H, 1-H), 7.03e7.16
J¼15.8/10.3 Hz, 1H, 5-H), 3.03 (dd, J¼15.8/3.3 Hz, 1H, 5-H), 3.58 (d,
J¼15.2 Hz, 1H, 1-H), 3.78e3.89 (m, 1H, 4-H), 3.93 (d, J¼15.2 Hz, 1H,
1-H), 5.57 (br s,1H, N-H), 7.02e7.20 (m, 4H, arom). 13C NMR (CDCl3):
(m, 4H, arom). 13C NMR (CDCl3):
d
(ppm)¼14.0 (1C, CH2CH2CH2CH3),
d
(ppm)¼21.9 (1C, CH3), 39.3 (1C, C-5), 41.5 (1C, C-1), 47.7 (1C, C-4),
22.6 (1C, CH2CH2CH2CH3), 27.9 (1C, CH2CH2CH2CH3), 32.9 (1C, CH3),
33.2 (1C, CH2CH2CH2CH3), 36.6 (1C, C-5), 43.2 (1C, C-1), 59.2 (1C, C-
4), 126.9, 127.1, 129.3, 129.4 (4C, PheCH), 134.1, 136.0 (2C, PheC),
171.1 (1C, C]O). Exact mass (ESI): m/z¼calcd for C15H21NOH
232.1701, found 232.1710 Purity (HPLC): 94.8% (tR¼20.19 min).
126.0, 126.3, 128.6, 128.9 (4C, PheCH), 131.5, 135.3 (2C, PheC), 170.7
(1C, C]O). Exact mass (ESI): m/z¼calcd for C11H13NOH 176.1070,
found 176.1083. Purity (HPLC): 99.5% (tR¼14.60 min).
5.3.17. 3,4-Dimethyl-1,3,4,5-tetrahydro-3-benzazepin-2-one
(8b). Following the general procedure D, 2b (40 mg, 0.21 mmol) was
hydrogenated and the crude product was purified by fc (d¼2 cm,
l¼10 cm, V¼10 mL, cyclohexane/EtOAc 80:20, Rf¼0.12 (cyclohexane/
EtOAc 60:40)). Colorless oil, yield 28 mg (70%). C12H15NO (189.3 g/
5.3.21. 3-Benzyl-4-butyl-1,3,4,5-tetrahydro-3-benzazepin-2-one
(8f). Following to the general procedure D, 2f (46 mg, 0.15 mmol)
was hydrogenated and the crude product was purified by fc
(d¼2 cm, l¼10 cm, V¼10 mL, cyclohexane/EtOAc 80:20, Rf¼0.40
(cyclohexane/EtOAc 60:40)). Colorless oil, yield 38 mg (83%).
mol). FT-IR (ATR, film):
n
(cmꢃ1)¼2960 (aliphatic CeH), 1654 (C]O).
1H NMR (CDCl3):
d
(ppm)¼1.18 (d, J¼6.5 Hz, 3H, CH3), 2.81 (s, 3H,
C21H25NO (307.4 g/mol). FT-IR (ATR, film):
n
(cmꢃ1)¼2960 (aliphatic
CH3), 2.90 (dd, J¼15.5/9.7 Hz,1H, 5-H), 3.11 (dd, J¼15.5/3.9 Hz,1H, 5-
H), 3.65 (d, J¼15.4 Hz, 1H, 1-H), 3.78e3.88 (m, 1H, 4-H), 3.94 (d,
J¼15.4 Hz, 1H, 1-H), 6.98e7.26 (m, 4H, arom). 13C NMR (CDCl3):
CeH), 1655 (C]O). 1H NMR (CDCl3):
d
(ppm)¼0.80 (t, J¼6.9 Hz, 3H,
CH2CH2CH2CH3), 1.10e1.31 (m, 4H, CH2CH2CH2CH3), 1.41e1.71 (m,
2H, CH2CH2CH2CH3), 2.84 (dd, J¼15.6/9.3 Hz, 1H, 5-H), 2.97 (dd,
J¼15.6/5.1 Hz, 1H, 5-H), 3.52e3.62 (m, 1H, 4-H), 3.81 (d, J¼15.1 Hz,
1H, 1-H), 3.89 (d, J¼15.1 Hz, 1-H), 4.05 (d, J¼15.4 Hz, 1H, NCH2Ph),
5.02 (d, J¼15.4 Hz,1H, NCH2Ph), 6.81e6.87 (m, 2H, arom), 6.95e7.19
d
(ppm)¼20.2 (1C, CH3), 33.3 (1C, CH3), 39.3 (1C, C-5), 43.3 (1C, C-1),
55.1 (1C, C-4), 126.9, 127.1, 129.2, (4C, PheCH), 134.3, 136.0 (2C,
PheC), 170.2 (1C, C]O). Exact mass (ESI): m/z¼calcd for C12H15NOH
190.1226, found 190.1239. Purity (HPLC): 94.1% (tR¼16.06 min).
(m, 7H, arom). 13C NMR (CDCl3):
d
(ppm)¼14.0 (1C,
CH2CH2CH2CH3),
22.6
(1C,
CH2CH2CH2CH3), 28.2 (1C,
5.3.18. 3-Benzyl-4-methyl-1,3,4,5-tetrahydro-3-benzazepin-2-one
(8c). Following to the general procedure D, 2c (36 mg, 0.14 mmol)
was hydrogenated and the crude product was purified by fc
(d¼2 cm, l¼10 cm, V¼10 mL, cyclohexane/EtOAc 80:20, Rf¼0.34
(cyclohexane/EtOAc 60:40)). Colorless solid, mp 90 ꢀC, yield 24 mg
CH2CH2CH2CH3), 33.7 (1C, CH2CH2CH2CH3), 37.3 (1C, C-5), 43.6 (1C,
C-1), 48. 9 (1C, NCH2Ph), 57.3 (1C, C-4), 126.9, 127.0, 127.2, 127.3,
128.4, 129.0, 129.3 (9C, PheCH), 134.3, 136.1, 138.0 (3C, PheC), 171.3
(1C, C]O). Exact mass (ESI): m/z¼calcd for C21H25NOH 308.2009,
found 308.2012. Purity (HPLC): 98.3% (tR¼22.44 min).
(67%). C18H19NO (265.3 g/mol). FT-IR (ATR, film):
n
(cmꢃ1)¼2928
(aliphatic CeH), 1635 (C]O). 1H NMR (CDCl3):
d
(ppm)¼1.23 (d,
5.3.22. 4-Phenyl-1,3,4,5-tetrahydro-3-benzazepin-2-one
(8g). Following the general procedure D, 2g (26 mg, 0.11 mmol) was
hydrogenated and the crude product was purified by fc (d¼2 cm,
l¼10 cm, V¼10 mL, cyclohexane/EtOAc 80:20, Rf¼0.12 (cyclohexane/
EtOAc 60:40)). Colorless solid, mp 137 ꢀC, yield 15 mg (58%).
J¼6.6 Hz, 3H, CH3), 2.88 (dd, J¼15.6/9.4 Hz, 1H, 5-H), 3.13 (dd,
J¼15.6/4.4 Hz, 1H, 5-H), 3.83 (d, J¼15.2 Hz, 1H, 1-H), 3.88e3.96 (m,
1H, 4-H), 4.09 (d, J¼15.2 Hz, 1H, 1-H), 4.20 (d, J¼15.6 Hz, 1H,
NCH2Ph), 5.07 (d, J¼15.5 Hz, 1H, NCH2Ph), 6.97e7.28 (m, 9H, arom).
13C NMR (CDCl3):
d
(ppm)¼20.4 (1C, CH3), 39.9 (1C, C-5), 43.5 (1C,
C16H15NO (237.3 g/mol). FT-IR (ATR, film):
n
(cmꢃ1)¼2922 (aliphatic
C-1), 48.1 (1C, C-4), 52.9 (1C, NCH2Ph), 126.9, 127.0, 127.1, 127.2,
128.4, 129.2, 129.3 (9C, PheCH), 134.1, 136.0, 138.2 (3C, PheC), 170.8
(1C, C]O). Exact mass (ESI): m/z¼calcd for C18H19NONa 288.1359,
found 288.1347. Purity (HPLC): 98.4% (tR¼19.27 min).
CeH), 1653 (C]O). 1H NMR (CDCl3):
d
(ppm)¼3.18 (dd, J¼15.0/
4.2 Hz,1H, 5-H), 3.26 (dd, J¼15.0/9.7 Hz,1H, 5-H), 3.85 (d, J¼15.6 Hz,
1H, 1-H), 3.92 (d, J¼15.5 Hz, 1H, 1-H), 4.69 (dd, J¼9.7/4.2 Hz, 1H, 4-
H), 5.70 (br s, 1H, NH), 6.91e7.35 (m, 9H, arom). 13C NMR (CDCl3):
d
(ppm)¼40.6 (1C, C-5), 42.5 (1C, C-1), 59.3 (1C, C-4), 126.1, 127.5,
5.3.19. 4-Butyl-1,3,4,5-tetrahydro-3-benzazepin-2-one
(8d). Following to the general procedure D, 2d (34 mg, 0.16 mmol)
was hydrogenated and the crude product was purified by fc
(d¼2 cm, l¼10 cm, V¼10 mL, cyclohexane/EtOAc 80:20, Rf¼0.17
(cyclohexane/EtOAc 60:40)). Colorless solid, mp 110 ꢀC, yield 33 mg
127.6, 128.2, 128.9, 129.1, 129.2 (9C, PheCH), 133.4, 136.2, 142.2 (3C,
PheC), 171.0 (1C, C]O). Exact mass (ESI): m/z¼calcd for C16H15NOH
238.1226, found 238.1238. Purity (HPLC): 98.6% (tR¼18.07 min).
5.3.23. 3-Methyl-4-phenyl-1,3,4,5-tetrahydro-3-benzazepin-2-one
(8h). Following the general procedure D, 2h (25 mg, 0.10 mmol) was
hydrogenated and the crude product was purified by fc (d¼2 cm,
l¼10 cm, V¼10 mL, cyclohexane/EtOAc 80:20, Rf¼0.23 (cyclohexane/
(97%). C14H19NO (217.3 g/mol). FT-IR (ATR, film):
n
(cmꢃ1)¼2975
(aliphatic CeH), 1665 (C]O). 1H NMR (CDCl3):
d
(ppm)¼0.86 (t,
J¼7.0 Hz, 3H, CH2CH2CH2CH3), 1.22e1.52 (m, 6H, CH2CH2CH2CH3),

2694
S. Sarkar et al. / Tetrahedron 68 (2012) 2687e2695
EtOAc 60:40)). Colorless oil, yield 19 mg (76%). C17H17NO (251.3 g/
reduced with BH3$THF complex (1 M in THF, 0.18 mL, 0.18 mmol)
and the crude product was purified by fc (d¼2 cm, l¼10 cm,
V¼10 mL, cyclohexane/EtOAc 90:10, Rf¼0.69 (cyclohexane/EtOAc
60:40)). Colorless oil, yield 15 mg (52%). C23H23N (313.4 g/mol). FT-
mol). FT-IR (ATR, film):
n
(cmꢃ1)¼2953 (aliphatic CeH), 1648 (C]O).
1H NMR (CDCl3):
d
(ppm)¼2.62 (s, 3H, CH3), 3.16 (dd, J¼14.8/9.6 Hz,
1H, 5-H), 3.30 (dd, J¼14.8/4.8 Hz, 1H, 5-H), 3.85 (d, J¼15.4 Hz, 1H, 1-
H), 4.02 (d, J¼15.4 Hz, 1H, 1-H), 4.54 (dd, J¼9.6/4.8 Hz, 1H, 4-H),
IR (ATR, film):
n
(cmꢃ1)¼2968 (aliphatic CeH). 1H NMR (CDCl3):
6.83e7.28 (m, 9H, arom). 13C NMR (CDCl3):
d
(ppm)¼36.5 (1C, CH3),
d
(ppm)¼2.21e2.30 (m, 1H, 4-H), 2.74 (dd, J¼15.0/7.3 Hz, 1H, 5-H),
40.9 (1C, C-5), 43.3 (1C, C-1), 66.8 (1C, C-4), 126.1, 127.4, 127.5, 127.7,
128.3, 128.5, 128.8 (9C, PheCH), 135.4, 135.8, 141.5 (3C, PheC), 169.8
(1C, C]O). Exact mass (ESI): m/z¼calcd for C17H17NOH 252.1383,
found 252.1390. Purity (HPLC): 98.4% (tR¼19.35 min).
2.84 (d, J¼14.6 Hz, 1H, 1-H), 2.96 (d, J¼13.8 Hz, 1H, NCH2Ph), 3.04
(dd, J¼15.0/10.2 Hz, 1H, 5-H), 3.15 (dd, J¼12.8/7.5 Hz, 1H, 4-H), 3.32
(dd, J¼14.6/9.6 Hz, 1H, 1-H), 3.46 (d, J¼9.3 Hz, 1H, 2-H), 3.66 (d,
J¼13.8 Hz, 1H, NCH2Ph), 6.92e7.45 (m, 14H, arom). 13C NMR
(CDCl3):
d
(ppm)¼35.2 (1C, C-5), 45.0 (1C, C-1), 52.7 (1C, C-4), 59.8
5.3.24. 3-Benzyl-4-phenyl-1,3,4,5-tetrahydro-3-benzazepin-2-one
(8i). Following the general procedure D, 2i (40 mg, 0.12 mmol) was
hydrogenated and the crude product was purified by fc (d¼2 cm,
l¼10 cm, V¼10 mL, cyclohexane/EtOAc 80:20, Rf¼0.42 (cyclohexane/
EtOAc 60:40)). Colorless oil, yield 30 mg (75%). C23H21NO (327.4 g/
(1C, NCH2Ph), 69.1 (1C, C-2), 126.3, 126.7, 126.9, 127.2, 127.5, 128.4,
128.5, 128.7, 128.9, 129.8 (14C, PheCH), 140.1, 140.3, 142.7, 146.4 (4C,
PheC). Exact mass (ESI): m/z¼calcd for C23H23NH 314.1903, found
314.1919. Purity (HPLC): 95.3% (tR¼19.24 min).
mol). FT-IR (ATR, film):
n
(cmꢃ1)¼2930 (aliphatic CeH), 1654 (C]O).
5.4. Receptor binding studies
1H NMR (CDCl3):
d
(ppm)¼3.10 (dd, J¼14.8/8.9 Hz, 1H, 5-H),
3.23e3.37 (m, 2H, 5-H/NCH2Ph), 3.93 (d, J¼15.3 Hz,1H,1-H), 4.06 (d,
J¼15.3 Hz, 1H, 1-H), 4.52 (dd, J¼8.9/5.0 Hz, 1H, 4-H) 5.36 (d,
J¼15.3 Hz,1H, NCH2Ph), 6.72e6.85 (m, 3H, arom), 6.92e7.25 (m,11H,
5.4.1. Determination of s1 receptor affinity. Guinea pig brains were
used as receptor material. The radioligand was [3H]-(þ)-pentazo-
cine. The assay was performed as described in Refs. 11,31.
arom). 13C NMR (CDCl3):
d
(ppm)¼40.4 (1C, C-5), 43.5 (1C, C-1), 49.6
(1C, NCH2Ph), 62.9 (1C, C-4), 126.3, 127.0, 127.3, 127.4, 127.5, 127.7,
128.2, 128.5, 128.7, 128.8 (14C, PheCH), 135.1, 135.6, 137.3, 141.3 (4C,
PheC), 170.1 (1C, C]O). Exact mass (ESI): m/z¼calcd for C23H21NOH
328.1696, found 328.1701. Purity (HPLC): 94.6% (tR¼21.67 min).
5.4.2. Determination of s2 receptor affinity. Membrane preparations
of rat liver served as receptor material in the s2 assay. The radio-
ligand [3H]-di-o-tolylguanidine was employed in the presence of
a large excess of (þ)pentazocine to occupy s1 receptors.11,31
5.3.25. 3-Benzyl-2-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(9c). Following the general procedure E, 8c (35 mg, 0.13 mmol) was
reduced with BH3$THF complex (1 M in THF, 0.26 mL, 0.26 mmol)
and the crude product was purified by fc (d¼2 cm, l¼10 cm,
V¼10 mL, cyclohexane/EtOAc 90:10, Rf¼0.56 (cyclohexane/EtOAc
60:40)). Colorless oil, yield 13 mg (40%). C18H21N (251.4 g/mol). FT-
5.4.3. Determination of the affinity to the phencyclidine binding site
of the NMDA receptor. The preparation of the membranes from pig
brain cortex and the performance of the assay with [3H]-MK-801
were done according to the literature.11
Acknowledgements
IR (ATR, film):
n
(cmꢃ1)¼2975 (aliphatic CeH). 1H NMR (CDCl3):
d
(ppm)¼0.76 (d, J¼6.7 Hz, 3H, CH3), 2.50e2.62 (m, 2H, 1-H/5-H),
We wish to thank the NRW Graduate School of Chemistry for
a stipend, which is funded by the Government of the State Nordr-
2.66e2.76 (m, 2H, 4-H/5-H), 3.10e3.17 (m, 2H, 2-H/4-H), 3.30 (d,
J¼14.2 Hz, 1H, 1-H), 3.73 (d, J¼13.8 Hz, 1H, NCH2Ph), 3.79 (d,
J¼13.8 Hz, 1H, NCH2Ph), 6.89e7.37 (m, 9H, arom). 13C NMR (CDCl3):
€
€
hein-Westfalen and the Westfalische Wilhelms-Universitat
€
Munster.
d
(ppm)¼12.7 (1C, CH3), 35.8 (1C, C-5), 41.9 (1C, C-1), 47.5 (1C, C-4),
54.2 (1C, C-2), 59.1 (1C, NCH2Ph), 126.1, 126.3, 127.0, 128.5, 128.8,
130.3 (9C, PheCH), 139.6, 140.3, 142.3 (3C, PheC). Exact mass (ESI):
m/z¼calcd for C18H21NH 252.1747, found 252.1783. Purity (HPLC):
96.6% (tR¼15.41 min).
Supplementary data
In the Supplementary data 1H and 13C NMR spectra of described
compounds, details of the X-ray crystal structure analyses and
discussion of the (Z)-configuration of (S)-4a are given. Supple-
mentary data related to this article can be found online at
doi:10.1016/j.tet.2012.01.052.
5.3.26. 3-Benzyl-2-butyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(9f). Following the general procedure E, 8f (40 mg, 0.13 mmol) was
reduced with BH3$THF complex (1 M in THF, 0.26 mL, 0.26 mmol)
and the crude product was purified by fc (d¼2 cm, l¼10 cm,
V¼10 mL, cyclohexane/EtOAc 90:10, Rf¼0.64 (cyclohexane/EtOAc
60:40)). Colorless oil, yield 24 mg (63%). C21H27N (293.5 g/mol). FT-
References and notes
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IR (ATR, film):
n
(cmꢃ1)¼2960 (aliphatic CeH). 1H NMR (CDCl3):
d
(ppm)¼0.75 (t, J¼7.1 Hz, 3H, CH2CH2CH2CH3), 1.02e1.38 (m, 6H,
CH2CH2CH2CH3), 2.46 (dd, J¼14.7/6.4 Hz, 1H, 1-H), 2.58 (dd, J¼14.6/
5.9 Hz,1H,1-H), 2.71 (dd, J¼13.5/6.0 Hz,1H, 5-H), 2.79e2.83 (m, 2H,
4-H/5-H), 3.08e3.19 (m, 1H, 2-H), 3.32 (d, J¼15.0 Hz, 1H, 4-H), 3.81
(d, J¼13.9 Hz, 1H, NCH2Ph), 3.87 (d, J¼13.8 Hz, 1H, NCH2Ph),
6.91e7.37 (m, 9H, arom). 13C NMR (CDCl3):
d
(ppm)¼14.4 (1C,
CH2CH2CH2CH3),
22.9
(1C,
CH2CH2CH2CH3), 28.9 (1C,
CH2CH2CH2CH3), 29.8 (1C, CH2CH2CH2CH3), 34.0 (1C, C-5), 38.1 (1C,
C-1), 47.3 (1C, C-4), 57.6 (1C, C-2), 59.0 (1C, NCH2Ph), 126.1, 126.7,
127.1, 128.0, 128.4, 128.9, 129.0, 129.2, 130.3 (9C, PheCH), 132.9,
133.4, 142.4 (3C, PheC). Exact mass (ESI): m/z¼calcd for C21H27NH
294.2216, found 294.2209. Purity (HPLC): 96.4% (tR¼19.60 min).
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(9i). Following the general procedure E, 8i (30 mg, 0.09 mmol) was

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