Unexpected formation of thiophene-annulated tetrahydro-3-benzazepines by alkylation of thiolactams with ethyl bromoacetate

Article abstract of DOI:10.5560/ZNB.2013-3030

In order to synthesize enantiomerically pure tetrahydro-3-benzazepines with diverse substitution patterns, the lactams 3 were converted into thiolactams 4 upon treatment with Lawesson's reagent. Instead of an Eschenmoser sulfide contraction a thiophene annulation reaction occurred, when the thiolactams 4 were reacted with ethyl bromoacetate. Altogether, enantiomerically pure thiopheneannulated 3-benzazepines 7 were prepared in a very short reaction sequence (five reaction steps) starting from commercially available o-phenylenediacetic acid.

Full text of DOI:10.5560/ZNB.2013-3030

Unexpected Formation of Thiophene-annulated Tetrahydro-3-
benzazepines by Alkylation of Thiolactams with Ethyl Bromoacetate
Soumya Sarkara, Roland Fro¨hlichb and Bernhard Wu¨nscha
a
Institut fu¨r Pharmazeutische und Medizinische Chemie der Westfa¨lischen Wilhelms-Universita¨t
Mu¨nster, Hittorfstraße 58–62, D-48149 Mu¨nster, Germany,
Organisch-Chemisches Institut der Westfa¨lischen Wilhelms-Universita¨t Mu¨nster, Corrensstr.
b
40, D-48149 Mu¨nster, Germany
Reprint requests to Prof. B. Wu¨nsch. Tel.: +49-251-8333311. Fax: +49-251-8332144.
E-mail: wuensch@uni-muenster.de
Z. Naturforsch. 2013, 68b, 223 – 228 / DOI: 10.5560/ZNB.2013-3030
Received January 14, 2013
In order to synthesize enantiomerically pure tetrahydro-3-benzazepines with diverse substitution
patterns, the lactams 3 were converted into thiolactams 4 upon treatment with Lawesson’s reagent.
Instead of an Eschenmoser sulfide contraction a thiophene annulation reaction occurred, when the
thiolactams 4 were reacted with ethyl bromoacetate. Altogether, enantiomerically pure thiophene-
annulated 3-benzazepines 7 were prepared in a very short reaction sequence (five reaction steps)
starting from commercially available o-phenylenediacetic acid.
Key words: Tetrahydro-3-benzazepines, Enantiomerically Pure Compounds, Thiophene Annulation,
Thiolactams, Lawesson’s Reagent, Eschenmoser Sulfide Contraction, X-Ray Crystal
Structure Analysis
Introduction
part of the ring system (positions 1 – 5). Recently
we have published the asymmetric synthesis of 1-
The tetrahydro-3-benzazepine scaffold (Fig. 1) is monosustituted [6, 7], 2-monosubstituted [8, 9], 2,3-
a privileged structure in Medicinal Chemistry [1, 2] disusbstitued [10], 1,4-disubstituted [11, 12], and
because it contains the 2-arylethylamine substruc- 1,3,4-trisubstituted tetrahydro-3-benzazepines of type
ture of several neurotransmitters, e. g. noradrenaline, 1 [13] (Fig. 1). Some of the prepared compounds
dopamine and serotonin. Therefore compounds com- showed promising affinity toward σ1 or NMDA recep-
prising the 3-benzazepine ring can be used for tors [6, 7, 11, 13]. Therefore, it was planned to expand
the activation or inhibition of the corresponding our synthetic strategy to get access to 2,4-disubstituted
neurotransmitter receptors. Prominent examples are and 2,3,4-trisubstituted tetrahydro-3-benzazepines 2.
the prototypical dopamine D1 receptor antagonist
SCH23360 [3, 4], the D1 receptor agonist fenoldopam Results and Discussion
[3, 4], and the 5-HT2C receptor agonist lorcaserin
which is used for the treatment of obesity [5].
For the introduction of an additional substituent in
Moreover, the tetrahydro-3-benzazepine ring system 2-position of the 3-benzazepine scaffold, the use of
can be regarded as a homolog of the tetrahydroiso- an Eschenmoser sulfide contraction [14] was planned.
quinoline system, which is also a privileged structure For this purpose the lactams 3 were prepared by re-
and thus found in several pharmacologically active action of o-phenylenediacetic acid with an excess of
compounds.
methyllithium [15] followed by reductive amination
Due to the promising pharmacological potential and ring closure [13]. At first the lactams 3 were con-
of tetrahydro-3-benzazepines, our interest has been verted into thiolactams 4 upon treatment with Lawes-
focused on the development of synthetic methods son’s reagent [16, 17] in refluxing toluene. After 2 h
allowing the stereoselective introduction of differ- the thiolactams 4 were isolated in 81% – 86% yields
ent substituents at all positions of the saturated (Scheme 1).
© 2013 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
Brought to you by | Rutgers University
Authenticated
Download Date | 9/14/15 10:48 PM

224
S. Sarkar et al. · Formation of Thiophene-annulated Tetrahydro-3-benzazepines
R1
R1
Table 1. Synthesis of thiophene-annulated 3-benzazepines 7
from lactams 3.
N R2
N R2
Entry Educt R1
Configu- Product 4 Product 7
ration
rac.
(yield)
(yield)
R3
1
2
3
3a
3b
3c
benzyla
4a (81%) 7a (48%)
4b (86%) 7b (65%)
4c (83%) 7c (68%)
R3
(R)-1-phenylethylb (R,R)
(S)-1-phenylethylc (S,S)
2
1
a
b
Racemic mixture; configuration in 4-position of the 3-benz-
Fig. 1. Tetrahydro-3-benzazepines with different substitution
patterns: Compounds of type 1 with promising affinities to-
wards various receptors in the central nervous system have
already been synthesized; compounds of type 2 are projected
herein.
c
azepine ring is (R); configuration in 4-position of the 3-benzaze-
pine ring is (S).
at 105.5 and 173.1 ppm indicate the presence of two
additional olefinic carbon atoms (C-3a and C-10b) and
In order to perform the Eschenmoser sulfide con- the signal at 195.5 ppm indicates the presence of a ke-
traction [14] the thiolactam 4a was reacted with ethyl tone carbonyl moiety.
bromoacetate and subsequently with PPh3 to obtain the
In order to prove the structure of the thiophene-
enamino ester 6a. However, instead of expected 6a the annulated 3-benzazepines 7 unequivocally, the enan-
thiophene-annulated 3-benzazepine 7a was formed. tiomerically pure compound 7c was recrystallized
Repeating the same reaction in refluxing CHCl3 with- from a CH2Cl2-n-hexane mixture resulting in crystals
out addition of PPh3 provided the tricyclic compound which were suitable for X-ray crystal structure analy-
7a in 48% yield. The same transformation took place sis. The molecular structure of 7c in the crystal is dis-
upon reaction of the phenylethyl-substituted enan- played in Fig. 2. It clearly shows the annulated thio-
tiomerically pure thiolactams 4b and 4c with ethyl bro- phene moiety with the carbonyl group in 1-position.
moacetate. The thieno[3,2-a]-[3]benzazepines 7b and Moreover, the (S)-configuration of both the chiral cen-
7c were isolated in 65% and 68% yield, respectively.
ter in 5-position and in the N-substituent is clearly
1
The H NMR spectrum of the tricyclic compound proved by the structure determination.
7c displays signals for the aliphatic Ph-CH2CHCH3
part of the 3-benzazepine scaffold, i. e. a doublet of
doublets at 2.47 ppm and a doublet at 2.65 ppm (6-
CH2), a multiplet at 3.77 – 3.84 ppm (5-CH) and a dou-
blet at 0.66 ppm (CH3). Signals for the ethoxy group
of the original ester moiety are missing. Two dou-
blets at 3.68 and 3.74 ppm with a coupling constant of
16.9 Hz represent the protons of the methylene moiety
in 2-position. In the 13C NMR spectrum two signals
Fig. 2. Molecular structure of 7c in the crystal (dis-
placement ellipsoids at the 30% probability level). Im-
˚
portant bond lengths (A) and angles (deg): C(1)–S(1)
1.7695(17), C(1)–C(4) 1.394(2), S(1)–C(2) 1.787(2),
C(2)–C(3) 1.509 (3), C(3)–C(4) 1.451(3), N(1)–C(1)
1.346(2), N(1)–C(12) 1.478(2), C(11)–C(12) 1.541(3),
N(1)–C(13) 1.491(2); C(1)–C(4)–C(3) 111.79(16), C(2)–
C(3)–C(4) 113.30(18), S(1)–C(1)–C(4) 114.31(12), C(1)–
S(1)–C(2) 92.41(9), S(1)–C(2)–C(3) 108.19(14), C(5)–
Scheme 1. Reagents and reaction conditions: (a) Lawesson’s C(4)–C(1) 129.07(15), C(4)–C(1)–N(1) 130.35(15), C(1)–
reagent, toluene reflux, 2 h, 81% – 86%; (b) BrCH2CO2Et, N(1)–C(12) 122.76(14), N(1)–C(12)–C(11) 110.48(13),
CHCl3, reflux, 20 h, 48% – 68%.
C(12)–C(11)–C(10) 111.87(15).
Brought to you by | Rutgers University
Authenticated
Download Date | 9/14/15 10:48 PM

S. Sarkar et al. · Formation of Thiophene-annulated Tetrahydro-3-benzazepines
225
It is assumed that the thiophene annulation pro- (reaction with MeLi, reductive amination, cyclization
ceeded via the following reaction pathway (Scheme 1): with CDI), the complete reaction sequence comprises
At first ethyl bromoacetate reacted with the thiolac- only five reaction steps.
tams 4 to produce S-alkylthioiminium salts 5. Instead
of deprotonation in α-position of the ester moiety of Experimental Section
5, which would lead to the desired enamino esters 6,
deprotonation took place at the 1-CH2 moiety of the
Chemistry, general
Unless otherwise mentioned, THF was dried with
sodium/benzophenone and was freshly distilled before use.
Thin layer chromatography (tlc): Silica gel 60 F254 plates
3-benzazepine scaffold adjacent to the positive charge.
An intramolecular attack of the resulting ketene N,S-
acetals on the ester moiety of 5 provided the tricyclic
(Merck). Flash chromatography: Silica gel 60, 40 – 64 µm
ketones 7. This 5-exo-trig cyclization is favored ac-
(Merck); parentheses include: diameter of the column, length
cording to the Baldwin rules [18].
of column, fraction size, eluent, Rf value. Melting point:
Since this unexpected annulation reaction gave ac-
Melting point apparatus SMP 3 (Stuart Scientific), un-
cess to novel thiophene annulated ring systems, the
corrected. IR: IR spectrophotometer 480Plus FT-ATR-IR
(Jasco). 1H NMR (400 MHz), 13C NMR (100 MHz): Mer-
cury plus 400 spectrometer (Varian); δ in ppm relative to
tetramethylsilane; coupling constants are given with 0.5 Hz
resolution. Where necessary, the assignment of the signals
transformations of thiolactams 4 with analogous ethyl
3-bromopropionate and ethyl 2-bromopropionate were
investigated. Unfortunately these reactions failed to
give the desired thiophene-annulated systems. It is as-
sumed that the bromine atom in β-position of ethyl in the 1H NMR and 13C NMR spectra was performed us-
ing 1H-1H and 1H-13C COSY NMR spectra. Optical rota-
3-bromopropionate is less reactive than the bromine
atom in α-position of ethyl 2-bromoacetate. The nu-
cleophilic substitution at the secondary C atom of ethyl
2-bromopropionate is sterically inhibited.
tion α (deg) was determined with a Polarimeter 341 (Perkin
Elmer); length 1 dm, wavelength 589 nm (sodium D line);
the unit of the specific rotation [α]Tl (deg mL dm−1 −1) is
g
omitted; concentration of the sample c (g per 100 mL) and
the solvents used are given in brackets. MS: EI = electron
impact, ESI = electrospray ionization: MicroTof (Bruker
Daltronics, Bremen), calibration with sodium formate clus-
ters before measurement. HPLC method for determination
of the product purity: Merck Hitachi Equipment; UV detec-
tor: L-7400; autosampler: L-7200; pump: L-7100; degasser:
L-7614; Method: column: LiChrospher® 60 RP-select B
(5 µm), 250 – 4 mm cartridge; flow rate: 1.00 mLmin−1; in-
jection volume: 5.0 µL; detection at λ = 210 nm; solvents:
A: water with 0.05% (v/v) trifluoroacetic acid; B: acetonitrile
with 0.05% (v/v) trifluoroacetic acid: gradient elution: (A
%): 0 – 4 min: 90%, 4 – 29 min: gradient from 90% to 0%,
29 – 31 min: 0%, 31 – 31.5 min: gradient from 0% to 90%,
31.5 – 40 min: 90%.
A similar thiophene annulation reaction has been
reported by G. Lhommet et al. [19]. Whereas five-,
six-, and seven-membered thiolactams reacted with
ethyl bromoacetate to afford the expected enamino
esters, the transformation of piperidine-2-thiones and
azepane-2-thiones with α-substituted bromoacetates
afforded exclusively thiophene-annulated pyridines
and azepines. It was argued that the ring size of the
thiolactam (6-, 7-membered) and the substituent in α-
position of the bromoacetates were responsible for the
thiophene annulation. The reaction of secondary β-
ketothioamides with ethyl bromoacetate also led to het-
erocyclic systems instead of enamino esters. In this
case the NH moiety of the secondary ketene N,S-acetal
intermediates reacted with the ester moiety leading to
1,3-thiazolidin-4-ones [20]. In the total synthesis of the
natural products (±)-lythrancepine II and III a similar
thiophene annulation was observed, when a thiolactam
reacted with an α-bromoketone [21].
General procedure for the synthesis of thiolactams 4
Lawesson’s reagent (1 equiv) was added to a solution of
lactam 3 (1 equiv) in toluene (10 mL). The mixture was
stirred under reflux for 2 h. The solvent was evaporated in
vacuo to obtain a viscous oil, which was purified by flash
chromatography.
In conclusion, the unexpected formation of
thiophene-annulated 3-benzazepines 7 by alkylation
of thiolactams 4 with ethyl bromoacetate allows a very
facile access to enantiomerically pure tetrasubstituted
3-benzazepines. Together with the three reaction
steps required for the synthesis of lactams 3 starting
3-Benzyl-4-methyl-1,3,4,5-tetrahydro-3-benzazepin-
2-thione (4a)
Following the General Procedure, Lawesson’s reagent
(73 mg, 0.18 mmol) was added to a solution of lactam 3a
from commercially available o-phenylenediacetic acid (49 mg, 0.18 mmol) in toluene (10 mL). The mixture was
Brought to you by | Rutgers University
Authenticated
Download Date | 9/14/15 10:48 PM

226
S. Sarkar et al. · Formation of Thiophene-annulated Tetrahydro-3-benzazepines
stirred under reflux for 2 h. The solvent was evaporated flash chromatography (d = 2 cm, l = 10 cm, V = 10 mL,
in vacuo to obtain a viscous oil, which was purified by cyclohexane-EtOAc 90 : 10, Rf = 0.60 (cyclohexane-EtOAc
flash chromatography (d = 2 cm, l = 10 cm, V = 10 mL, 60 : 40)). – Colorless solid, m. p. 108 – 110 ◦C, yield 44 mg
20
589
cyclohexane-EtOAc 80 : 20, Rf = 0.54 (cyclohexane-EtOAc (83%). – [α] = −7.5 (c = 1.00, CH2Cl2). – Exact mass
60 : 40)). – Colorless viscous oil, yield 42 mg (81%). – (ESI): m/z = 318.1279 (calcd. 318.1287 for C19H21NSNa,
C18H19NS (281.4 gmol−1). – FT-IR (ATR, film): ν (cm−1
)
[MNa]+). – Purity (HPLC): 98.4% (tR = 22.1 min).
= 3026 (aliphaticC−H), 1175 (C = S). – 1H NMR (CDCl3):
δ (ppm) = 1.33 (d, J = 6.7 Hz, 3H, CH3), 2.84 (dd, J =
16.4/10.6 Hz, 1H, 5-H), 2.94 (dd, J = 16.4/5.0 Hz, 1H, 5-
H), 4.33 (d, J = 14.7 Hz, 1H, 1-H), 4.43 – 4.52 (m, 1H, 4-H),
4.64 (d, J = 14.6 Hz, 1H, 1-H), 4.94 (d, J = 15.4 Hz, 1H,
NCH2Ph), 5.64 (d, J = 15.4 Hz, 1H, NCH2Ph), 6.86 – 7.23
(m, 9H, arom). – 13C NMR (CDCl3): δ (ppm) = 20.5 (1C,
CH3), 39.7 (1C, C-5), 51.2 (1C, C-1), 54.6 (1C, C-4), 56.3
(1C, NCH2Ph), 126.8, 127.1, 127.2, 127.6, 128.5, 129.5 (9C,
Ph-CH), 134.0, 134.9, 136.3 (3C, Ph-C), 203.6 (1C, C =S).
– Exact mass (ESI): m/z = 282.1319 (calcd. 282.1311 for
4-Benzyl-5-methyl-5,6-dihydro-2H-thieno[3,2-a][3]benz-
azepin-1(4H)-one (7a)
To a solution of thiolactam 4a (50 mg, 0.18 mmol) in
CHCl3 (10 mL), an excess of ethyl bromoacetate (199 µL,
1.8 mmol) was added. The mixture was stirred under re-
flux for 20 h. The solvent was evaporated in vacuo and
the crude product was purified by flash chromatography
(d = 2 cm, l = 20 cm, V = 10 mL, cyclohexane-EtOAc 80 :
20, Rf = 0.30 (cyclohexane-EtOAc 60 : 40)). – Colorless
solid, m. p. 182 – 184 ◦C, yield 28 mg (48%). – C20H19NOS
(321.4 gmol−1). – FT-IR (ATR, film): ν (cm−1) = 2968
(aliphatic C–H), 1658 (C=O). – 1H NMR (CDCl3): δ (ppm)
= 0.80 (d, J = 6.5 Hz, 3H, CH3), 2.68 (dd, J = 14.6/6.0 Hz,
1H, 6-H), 3.18 (d, J = 14.7 Hz, 1H, 6-H), 3.68 – 3.74 (m, 2H,
2-H), 3.90 – 3.98 (m, 1H, 5-H), 4.60 (d, J = 17.0 Hz, 1H,
C18H19NSH, [M+H]+). – Purity (HPLC): 95.1% (tR
21.3 min).
=
(R)-4-Methyl-3-[(R)-1-phenylethyl]-1,3,4,5-tetrahydro-
3-benzazepin-2-thione (4b)
Following the General Procedure, Lawesson’s reagent NCH2Ph), 4.90 (d, J = 17.0 Hz, 1H, NCH2Ph), 6.89 – 7.41
(87 mg, 0.21 mmol) was added to a solution of lactam 3b (m, 8H, arom), 7.88 – 8.01 (m, 1H, arom). – 13C NMR
(60 mg, 0.21 mmol) in toluene (10 mL). The mixture was (CDCl3): δ (ppm) = 18.5 (1C, CH3), 36.8 (1C, C-6), 40.3
stirred under reflux for 2 h. The solvent was evaporated (1C, C-2), 57.4 (1C, C-5), 60.2 (1C, NCH2Ph), 105.6 (1C,
in vacuo to obtain a viscous oil, which was purified by C-3a), 125.6, 126.6, 126.9, 128.1, 128.5, 129.1, 129.3 (9C,
flash chromatography (d = 2 cm, l = 10 cm, V = 10 mL, Ph-CH), 133.1, 134.5, 135.2 (3C, Ph-C), 174.7 (1C, C-10b),
cyclohexane-EtOAc 90 : 10, Rf = 0.60 (cyclohexane-EtOAc 194.8 (1C, C=O). – Exact mass (ESI): m/z = 322.1274
60 : 40)). – Colorless solid, m. p. 108 – 110 ◦C, yield 54 mg (calcd. 322.1260 for C20H19NOSH, [M+H]+). – Purity
(86%). – C19H21NS (295.4 gmol−1). – FT-IR (ATR, film): (HPLC): 88.5% (tR = 21.0 min).
ν (cm−1) = 2973 (aliphatic C − H), 1173 (C = S). – 1H
(R)-5-Methyl-4-[(R)-1-phenylethyl]-5,6-dihydro
-2H-thieno[3,2-a][3]benzazepin-1(4H)-one (7b)
NMR (CDCl3): δ (ppm) = 1.47 (d, J = 7.1 Hz, 3H, CH3),
1.58 (d, J = 7.1 Hz, 3H, CH3), 2.51 – 2.67 (m, 2H, 5-H),
3.73 – 3.87 (m, 1H, 4-H), 4.37 (d, J = 14.9 Hz, 1H, 1-
H), 4.46 (d, J = 14.9 Hz, 1H, 1-H), 6.75 – 7.25 (m, 10H,
NCH(CH3)Ph/arom). – 13C NMR (CDCl3): δ (ppm) = 15.3
(1C, CH3), 22.6 (1C, CH3), 39.5 (1C, C-5), 51.1 (1C, C-
1), 52.4 (1C, C-4), 60.8 (1C, NCH(CH3)Ph), 127.0, 127.1,
127.2, 127.7, 128.4, 128.7, 129.8 (9C, Ph-CH), 134.5, 135.1,
To a solution of thiolactam 4b (35 mg, 0.12 mmol) in
CHCl3 (10 mL), an excess of ethyl bromoacetate (133 µL,
1.20 mmol) was added. The mixture was stirred under re-
flux for 20 h. The solvent was evaporated in vacuo, and
the crude product was purified by flash chromatography
(d = 2 cm, l = 20 cm, V = 10 mL, cyclohexane-EtOAc 80 :
20, Rf = 0.32 (cyclohexane-EtOAc 60 : 40)). – Colorless
solid, m. p. 143 – 144 ◦C, yield 26 mg (65%). – C21H21NOS
(335.5 gmol−1). – FT-IR (ATR, film): ν (cm−1) = 2966
(aliphatic C–H), 1660 (C=O). – 1H NMR (CDCl3): δ (ppm)
= 0.66 (d, J = 6.7 Hz, 3H, CH3), 1.69 (d, J = 6.9 Hz, 3H,
CH3), 2.47 (dd, J = 14.7/6.7 Hz, 1H, 6-H), 2.65 (d, J =
14.7 Hz, 1H, 6-H), 3.68 (d, J = 16.9 Hz, 1H, 2-H), 3.74 (d,
20
138.8 (3C, Ph-C), 203.2 (1C, C =S). – [α] = +7.0 (c =
589
1.00, CH2Cl2). – Exact mass (ESI): m/z = 318.1288 (calcd.
318.1287 for C19H21NSNa, [MNa]+). – Purity (HPLC):
97.3% (tR = 22.8 min).
(S)-4-Methyl-3-[(S)-1-phenylethyl]-1,3,4,5-tetrahydro-
3-benzazepin-2-thione (4c)
Following the General Procedure, Lawesson’s reagent J = 16.9 Hz, 1H, 2-H), 3.77 – 3.84 (m, 1H, 5-H), 5.61 (q,
(73 mg, 0.18 mmol) was added to a solution of lactam 3c J = 6.9 Hz, 1H, NCH(CH3)Ph), 6.74 – 7.46 (m, 8H, arom),
(50 mg, 0.18 mmol) in toluene (10 mL). The mixture was 8.03 – 8.20 (m, 1H, arom). – 13C NMR (CDCl3): δ (ppm)
stirred under reflux for 2 h. The solvent was evaporated = 18.9 (1C, CH3), 20.7 (1C, CH3), 36.9 (1C, C-6), 41.9 (1C,
in vacuo to obtain a viscous oil, which was purified by C-2), 53.4 (1C, C-5), 61.9 (1C, NCH(CH3)Ph), 105.5 (1C,
Brought to you by | Rutgers University
Authenticated
Download Date | 9/14/15 10:48 PM

S. Sarkar et al. · Formation of Thiophene-annulated Tetrahydro-3-benzazepines
227
C-3a), 125.4, 126.3, 127.4, 128.6, 128.8, 129.1, 129.4 (9C, DENZO [23]; structure solution: SHELXS-97 [24]; structure
Ph-CH), 133.7, 135.3, 138.3 (3C, Ph-C), 173.1 (1C, C-10b), refinement: SHELXL-97 [25]; graphics: XP (Bruker Analyti-
20
195.5 (1C, C=O). – [α]
= +71.2 (c = 0.20, CH2Cl2). cal X-ray Instruments Inc., 2000).
589
– Exact mass (ESI): m/z = 336.1429 (calcd. 336.1422 for
Crystal structure data: Formula C21H21NOS; Mr =
335.45; colorless crystal, 0.30 × 0.27 × 0.15 mm3; or-
thorhombic; space group P212121 (no. 19), Z = 4; a =
C21H21NOSH, [M+H]+). – Purity (HPLC): 97.2% (tR
22.0 min).
=
˚
8.7257(3), b = 10.2788(3), c = 19.4764(10) A; V =
3
1746.83(12) A ; ρcalcd = 1.28 gcm−3; µ = 1.7 mm−1. Data
(S)-5-Methyl-4-[(S)-1-phenylethyl]-5,6-dihydro-
2H-thieno[3,2-a][3]benzazepin-1(4H)-one (7c)
˚
˚
collection: Radiation: CuKα , λ = 1.54178 A; T = 223 (2) K;
ω- and ϕ-scans, 9028 reflections collected (±h, ±k, ±l),
To a solution of thiolactam (Sa-,4S)-4c (60 mg,
0.20 mmol) in CHCl3 (10 mL), an excess of ethyl bro-
moacetate (221 µL, 2.0 mmol) was added. The mixture
was heated to reflux for 20 h. The solvent was evapo-
rated in vacuo, and the crude product was purified by
flash chromatography (d = 2 cm, l = 20 cm, V = 10 mL,
cyclohexane-EtOAc 80 : 20, Rf = 0.32 (cyclohexane-EtOAc
60 : 40)). – Colorless solid, m. p. 143 – 144 ◦C, yield 46 mg
[(sinθ)/λ] = 0.60 A−1, empirical absorption correction,
˚
Tmin/max = 0.632/0.786, 2873 independent (Rint = 0.032)
and 2805 “observed” reflections [I > 2σ(I)]. Refinement:
219 refined parameters, R1 [I > 2σ(I)] = 0.031, wR2
(all data) = 0.080, Flack parameter x 0.048(17), max. /
min. residual electron density 0.12/−0.16 eA−3. Hydrogen
˚
atoms calculated and refined as riding atoms.
CCDC 913691 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge from Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data request/cif.
20
(68%). – [α] = −70.3 (c = 0.68, CH2Cl2). – Exact mass
589
(ESI): m/z = 336.1420 (calcd. 336.1422 for C21H21NOSH,
[M+H]+). –Purity (HPLC): 96.9% (tR = 21.9 min).
X-Ray crystal structure analysis of 7c
Acknowledgement
For the X-ray crystal structure analysis, a sample of 7c
was recrystallized from CH2Cl2-n-hexane. A data set was
We wish to thank the NRW Graduate School of Chemistry
collected with a Nonius KappaCCD diffractometer. Pro- for a scholarship, which is funded by the Government of the
grams used: data collection: COLLECT (Nonius B. V., 1998); State Nordrhein-Westfalen and the Westfa¨lische Wilhelms-
data reduction: DENZO-SMN [22]; absorption correction: Universita¨t Mu¨nster.
[1] J. Weinstock, J. P. Hieble, J. W. Wilson III, Drug Fut.
1985, 10, 645–696.
[9] S. M. Husain, R. Fro¨hlich, B. Wu¨nsch, J. Org. Chem.
2009, 74, 2788–2793.
[2] M. Kawase, S. Saito, N. Motohashi, Int. J. Antimicrob [10] S. Sarkar, S. M. Husain, D. Schepmann, R. Fro¨hlich,
Agents 2000, 14, 193–201. B. Wu¨nsch, Tetrahedron 2012, 68, 2687–2695.
[3] D. L. Ladd, J. Weinstock, M. Wiese, G. W. Gessner, [11] S. M. Husain, M. T. Heim, D. Schepman, B. Wu¨nsch,
J. L. Sawyer, K. E. Flaim, J. Med. Chem. 1986, 29,
1904–1912.
[4] W. H. Frishman, J. Clin. Pharmacol. 1998, 38, 2–13.
Tetrahedron: Asymmetry 2009, 20, 1383–1392.
[12] S. Sarkar, D. Schepmann, B. Wu¨nsch, Tetrahedron:
Asymmetry 2011, 22, 1411–1422.
[5] B. M. Smith, J. M. Smith, J. H. Tsai, J. A. Schultz, [13] S. Sarkar, D. Schepmann, J. Ko¨hler, R. Fro¨hlich,
C. A. Gilson, S. A. Estrada, R. R. Chen, D. M. Park, B. Wu¨nsch, Eur. J. Org. Chem. 2012, 5980–5990.
E. B. Prieto, C. S. Gallardo, D. Sengupta, P. I. Dosa, [14] M. Roth, P. Dubs, E. Go¨schi, A. Eschenmoser, Helv.
J. A. Covel, A. Ren, R. R. Webb, N. R. A. Beeley, M. Chim. Acta 1971, 54, 710–714.
Marin, M. Morgan, S. Espitia, H. R. Saldana, C. Bjen- [15] S. M. Husain, B. Wu¨nsch, Synthesis 2008, 2729–2732.
ning, K. T. Whelan, A. J. Grottick, F. Menzaghi, W. J. [16] S. Scheibye, B. S. Pederson, S.-O. Lawesson, Bull. Soc.
Thomsen, J. Med. Chem. 2008, 51, 305–313.
[6] O. Krull, B. Wu¨nsch, Bioorg. Med. Chem. 2004, 12, [17] M. P. Cava, M. I. Levinson, Tetrahedron 1985, 22,
1439–1451. 5061–5087.
[7] U. Wirt, D. Schepmann, B. Wu¨nsch, Eur. J. Org. Chem. [18] J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976,
2007, 462–475. 18, 734–736.
[8] S. M. Husain, R. Fro¨hlich, B. Wu¨nsch, Tetrahedron: [19] P. Marchand, C. Bellec, M.-C. Fargeau-Bellassoued,
Asymmetry 2008, 19, 1613–1616. C. Nezry, G. Lhommet, Heterocycles 1996, 43, 63–70.
Chim. Belg. 1978, 87, 299–304.
Brought to you by | Rutgers University
Authenticated
Download Date | 9/14/15 10:48 PM

228
S. Sarkar et al. · Formation of Thiophene-annulated Tetrahydro-3-benzazepines
[20] T. S. Jagodzinski, A. Wesolowska, J. G. Sosnicki, Pol- [23] Z. Otwinowski, D. Borek, W. Majewski, W. Minor,
ish. J. Chem. 2000, 74, 1101–1114. Acta Crystallogr. 2003, A59, 228–234.
[21] D. J. Hart, W.-P. Hong, L.-Y. Hsu, J. Org. Chem. 1987, [24] G. M. Sheldrick, Acta Crystallogr. 1990, A46, 467–
52, 4665–4673. 473.
[22] Z. Otwinowski, W. Minor in Methods in Enzymology, [25] G. M. Sheldrick, Acta Crystallogr. 2008, A64, 112–
Vol. 276, Macromolecular Crystallography, Part A
(Eds.: C. W. Carter Jr, R. M. Sweet), Academic Press,
New York, 1997, pp. 307–326.
122.
Brought to you by | Rutgers University
Authenticated
Download Date | 9/14/15 10:48 PM