Synthesis of a benzo[5,6]cyclohepta[1,2-b]thiophene and thieno[3,2-c]-benzazepine derivatives

Article abstract of DOI:10.1055/s-2002-20033

A new series of 2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[5,6]cyclohepta[1,2-b]thiophene (5) and 2-methyl-4-(4-methylpiperazin-1-yl)thieno[3,2-c][1]benzazepine derivatives 6b - f have been synthesized from 2-methylthiophene and phthalic anhydride. Preparation of the key intermediate 2-methyl-4,5-dihydro-10H-benzo[5,6]cyclohepta[1,2-b]thiophene-4-one (12) and 2-methylthieno[3,2-c][1]benzazepine-4(5H), 10-dione (16) were carried out by intramolecular dehydration of the phenylacetic acid 11 and Lewis acid associated cyclization of the isocyanate 14, respectively.

Full text of DOI:10.1055/s-2002-20033

PAPER
355
Synthesis of a Benzo[5,6]cyclohepta[1,2-b]thiophene and Thieno[3,2-c]-
benzazepine Derivatives
Synthesis of
a
B
o
e
nzo[5,6]cy
s
c
lohepta[1
h
,2-
b
]thiophe
i
ne and
y
T
hieno[3,2-
u
]
benzazepin
k
a
Exploratory Research I (CNS), Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, 7-25 Koyata 3-Chome, Iruma, Sait-
ama 358-0026, Japan
Fax +81(42)9641906; E-mail: Kohara.Toshiyuki@mh.m-pharma.co.jp
b
Department of Functional Polymer Science, Faculty of Textile Science and Technology, Shinshu University, 15-1 Tokida 3-Chome, Ue-
da, Nagano 386-8567, Japan
Received 23 October 2001; revised 3 December 2001
Abstract: A new series of 2-methyl-4-(4-methylpiperazin-1-yl)-
10H-benzo[5,6]cyclohepta[1,2-b]thiophene (5) and 2-methyl-4-(4-
methylpiperazin-1-yl)thieno[3,2-c][1]benzazepine derivatives 6b–f
have been synthesized from 2-methylthiophene and phthalic anhy-
dride. Preparation of the key intermediate 2-methyl-4,5-dihydro-
10H-benzo[5,6]cyclohepta[1,2-b]thiophene-4-one (12) and 2-me-
thylthieno[3,2-c][1]benzazepine-4(5H),10-dione (16) were carried
out by intramolecular dehydration of the phenylacetic acid 11 and
Lewis acid associated cyclization of the isocyanate 14, respectively.
N
N
9
6
X
Y
1
R
4
X
N
Y
R
clozapine (1)
NH 8-Cl
Key words: cyclization, Curtius rearrangement, antipsychotic
agents
clothiapine (2) N
loxapine (3)
S
2-Cl
2-Cl
N
O
Figure 1 The structures of clozapine (1), clothiapine (2) and loxa-
pine (3)
Dibenzodiazepine, dibenzothiazepine and dibenzox-
azepine derivatives have desirable antipsychotic activi-
ties.1–4 Investigations into the synthesis of these novel
compounds and their biological activities have made ex-
citing progress in the medical field. It is known that a
slight modification of this tricycle structure leads to a pro-
found alteration of the activity and toxicity profile. In-
deed, clozapine (1; X = N, Y = NH, R = 8-Cl, Figure 1) is
an atypical neuroleptic agent that very rarely causes ex-
trapyramidal symptoms (EPS) in men, but its therapeutic
use has been hampered because of its toxicity
(agranulocytosis5). On the other hand, clothiapine (2;
X = N, Y = S, R = 2-Cl) and loxapine (3; X = N, Y = O,
R = 2-Cl) are potent antipsychotic agents with a strong
propensity to induce EPS. Most attempts to develop clin-
ically useful heteroazepine (Y = NH, O, S) have been un-
successful for thirty years, because of this unexpected
toxicity or the unacceptable side effects of these com-
pounds. We speculated that the presence of heteroatoms
(X = N, Y = NH, O or S) in these tricyclic compounds
may be the origin of their toxicological problems.
tive structurally related to 4, was also reported.8 As an al-
ternate modification of the olanzapine structure, we
designed
a benzocycloheptathiophene derivative 5
(X = CH, Y = CH2), which is a seven-membered carbocy-
clic analogue of olanzapine, and thienobenzazepine deriv-
atives 6b–f [X = N, Y = C(O), C = CR2 or CHR], which
are structurally similar to azepine 6a. In this paper, we de-
scribe the synthesis of benzo[5,6]cyclohepta[1,2-
b]thiophene derivative 5 and thieno[3,2-c]benzazepine
derivatives 6b–f.
N
N
X
Y
S
X
Y
It is known that pharmacological activity is maintained
even though a benzene ring was replaced by the isostere
thiophene ring.6 Indeed, olanzapine (4; X = N, Y = NH,
Figure 2), which is a thienobenzodiazepine derivative
structurally related to 1, is an effective antipsychotic
agent.7 Furthermore, the biological activity of azepine 6a
(X = N, Y = CH2), which is a thienobenzazepine deriva-
olanzapine (4)
N
NH
CH2
5
CH
CH2
C=O
6a
6b
N
N
C=CH2
C=(CH3)2
CH-OH
CH-OMe
6c
N
N
N
N
6d
6e
6f
Synthesis 2002, No. 3, 18 02 2002. Article Identifier:
1437-210X,E;2002,0,03,0355,0360,ftx,en;F07901SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
Figure 2 The structures of olanzapine (4), the benzocycloheptathio-
phene derivative 5 and the thieneobenzazepine derivatives 6a–f

356
T. Kohara et al.
PAPER
N
N
S
O
S
COOH
S
5
12
11
COOH
N
S
O
N
O
H
NCO
N
N
7
Y
S
S
S
O
Y: C(O), C=CR2, CH-R
6b-f
16
14
Scheme 1
The retro synthetic pathway for the target molecules 5 and sponding 2-benzylbenoic acid (17a) in polyphosphoric
6b–f is shown in Scheme 1. In the retro synthetic analysis, acid (PPA) (Scheme 3, eq. 1). However, treatment of 11
5 and 6b–f were considered to be synthesized via the key with PPA resulted in a poor yield of the desired product
cyclization reactions of 11 and 14, respectively. Further- because of the presence of inseparable byproducts. In ad-
more, the intermediates 11 and 14 were planned to be de- dition, an acid chloride prepared from 17b (R = Ph) re-
rived from a common starting material 7. The key sulted in the formation of 18b (yield: 18%) and the
intermediate 11 was synthesized from phthalic anhydride starting material 17b was recovered.12 Therefore, phos-
(Scheme 2). 2-(5-Methyl-2-thenoyl)benzoic acid (7) was phorus pentoxide was chosen as the dehydrating agent in
prepared from 2-methylthiophene and phthalic anhydride this cyclization. Treatment of 11 with phosphorus pentox-
according to the method of MacDowell and Wisowaty.9 ide in refluxing toluene formed the corresponding cyclo-
Although the preparation of thenylbenzoic acid (8) by the heptathiophene 12 in good yield (65%). Finally, 12 was
reduction of 7 in the presence of triethylsilane (3.1 equiv converted to the desired product 5 by the reaction of 1-me-
to 7) was not successful, reduction of 7 was accomplished thylpiperazine in the presence of titanium(IV) chloride.
by zinc dust in ammonia solution (28–30%, as NH3) to
The key intermediate 16 of the thieno[3,2-c]benzox-
give 8 in 67% yield. The carboxylic acid 8 was reduced to
azepine derivatives 6b–f were synthesized from 2-(5-me-
the corresponding benzyl alcohol 9 (2 steps, 95%) with
thyl-2-thenoyl)benzoic acid (7) (Scheme 4). A Curtius
LiAlH4 via the methyl ester derived from 8. Bromination
rearrangement of acyl azide conducted from active mixed
of 9 with hydrobromic acid,10 cyanation of 10 with potas-
anhydride of carboxylic acid 7 afforded the corresponding
sium cyanide in DMF–H2O, and hydrolysis of the cyanide
keto isocyanate 13. Liégeois et al.4 have reported that
using HCl–HOAc led to the carboxylic acid 11. As report-
treatment of 2-[(4-chlorophenyl)thio]nicotinoyl isocyan-
ate, which was prepared from the corresponding acyl
azide, in the presence of aluminum chloride in 1,2-dichlo-
ed previously,11 dihydrodibenzocycloheptene derivative
18a (R = H) was prepared by cyclization of the corre-
O
COOH
COOH
(a)
(b)
(c),(d)
O
S
S
O
O
8
7
OH
Br
COOH
(f),(g)
(e)
S
S
S
9
10
11
Scheme 2 Reagents and conditions: (a) 2-methylthiophene, AlCl3, 1,2-dichloroethane, 40 °C; (b) Zn, CuSO4, ammonia solution (28–30%, as
NH3), 70 °C; (c) SOCl2, MeOH, reflux; (d) LiAlH4, THF, r.t.; (e) 48% HBr, reflux (f) KCN, DMF–H2O, r.t.; (g) concd HCl, HOAc, 55 °C
Synthesis 2002, No. 3, 355–360 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of a Benzo[5,6]cyclohepta[1,2-b]thiophene and Thieno[3,2-c]benzazepine
357
the reaction was judged by the FT-IR spectrum (in neat).
The absorption of the acyl azide (CON3) group and the
isocyanate (N=C=O) group appeared at 2278 and 2133
cm–1, respectively. As a result, the reaction was completed
in 60 minutes at 60 °C. The resulting isocyanate 14 was
used in the next reaction without purification to give the
lactam 15. Furthermore, synthesis of the key intermediate
16 was accomplished by oxidation13 of 15 with potassium
permanganate in acetone in 88% yield.
N
N
S
O
S
(a)
(b)
11
12
5
O
COOH
Syntheses of the azepines 6b–f are depicted in Scheme 5.
Treatment of 16 with phosphorus oxychloride formed the
corresponding imino chloride intermediate, which was
converted to the methylpiperazine derivative 6b (yield:
80%). A Grignard reaction with methylmagnesium bro-
mide on the ketone 6b followed by dehydration with hy-
drochloric acid gave exomethylene derivative 6c in 59%
yield. In a similar manner isopropylidene derivative 6d
was synthesized from 6b (yield: 95%). On the other hand,
6b was reduced with NaBH4 in THF–MeOH to give the
alcohol 6e, and treatment of 6e with MeOH in the pres-
ence of sulfuric acid resulted in the corresponding methyl
ether 6f (2 steps; 54%).
(eq.1)
R
R
17a (R=H)
17b (R=Ph)
18a (R=H)
18b (R=Ph)
Scheme 3 Reagents and conditions: (a) P2O5, toluene, reflux; (b) 1-
methylpiperazine, TiCl4, benzene, 55 °C
robenzene at 160–170 °C afforded 8-chloro-5H-pyri-
do[2,3-b][1,4]benzothiazepine-6-one in 20–30% yield. In
a similar manner, the azepine ring system of 16 could be
constructed from the isocyanate 13. However, treatment
of 13 with aluminum chloride in 1,2-dichlorobenzene was
unsuccessful. As a reason, it seemed likely that the ketone
unit of 13 would reduce the neucleophilicity at the 2-
thiophenyl position. Next, to increase the neucleophilicity
at the 2-thiophenyl position, the cyclization of (2-the-
nyl)phenyl isocyanate derivative 14 was attempted in-
stead of (2-thenoyl)phenyl isocyanate derivative 13.
Fortunately, a Curtius rearrangement of acyl azide ob-
tained from active mixed anhydride of carboxylic acid 8
followed by treatment with aluminum chloride at 100 °C
in 1,2-dichlorobenzene gave azepine 15 in 51% yield.
In conclusion, we have synthesized a new series of 2-me-
thyl-4-(4-methylpiperazin-1-yl)-10H-benzo[5,6]cyclo-
hepta[1,2-b]thiophene (5) and 2-methyl-4-(4-methyl-
piperazin-1-yl)thieno[3,2-c][1]benzazepine derivatives
6b–f from 2-methylthiophene and phthalic anhydride.
Compounds 5 and 6b–f have been tested for their neuro-
leptic activity. The details of the pharmacological proper-
ties will be described elsewhere.
Column chromatography was performed using Merck Kieselgel 60.
Melting points were obtained on a Büchi 535 melting point appara-
1
tus and are uncorrected. H NMR spectra were recorded on a Jeol
400 spectrometer (400 MHz) using TMS as an internal standard.
Both the acyl azide and the isocyanate 14 have a similar Mass spectra were measured on a Jeol-JMS-DX300 instrument. IR
spectra were recorded on a Jasco FT/IR-5300 spectrometer. Ele-
ment analyses were performed on a Yanako CHN coder MT-5, and
Rf value on TLC in the Curtius rearrangement (from the
acyl azide of 8 to the isocyanate 14). Therefore, the end of
NCO
(a),(b),(c)
(d)
X
S
O
O
S
13
H
N
7
O
16
O
S
H
NCO
N
(d)
(e)
(a),(b),(c)
(f)
8
S
14
15
Scheme 4 Reagents and conditions: (a) ClCO2Et, Et3N, acetone, –60 °C; (b) NaN3, 0 °C; (c) 1,2-dichlorobenzene, 60 °C; (d) AlCl3, 1,2-di-
chlorobenzene, 100 °C; (e) Zn, CuSO4, ammonia solution (28–30%, as NH3), 70 °C; (f) KMnO4, acetone, r.t.
Synthesis 2002, No. 3, 355–360 ISSN 0039-7881 © Thieme Stuttgart · New York

358
T. Kohara et al.
PAPER
N
N
N
N
S
N
S
N
S
N
N
N
(a),(b)
(f)
(g)
16
O
HO
6e
MeO
6f
6b
(c),(d)
(e),(d)
N
N
N
S
N
S
N
N
6c
6d
Scheme 5 Reagents and conditions: (a) POCl3, N,N-dimethylaniline, reflux; (b) 1-methylpiperazine, reflux; (c) MeMgBr, THF, 5 °C (d) 4 N
HCl, dioxane, reflux; (e) isopropylmagnesium chloride, THF, 5 °C; (f) NaBH4, THF–MeOH, r.t.; (g) H2SO4, MeOH, reflux
the results indicated by element symbols are within 0.4% of the
calculated values.
H, d, J = 8.3 Hz, ArH), 7.55 (1 H, dd, J = 6.8, 8.3 Hz, ArH), 8.15 (1
H, d, J = 7.8 Hz, ArH).
MS: m/z = 325 (M+).
2-Methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[5,6]cyclo-
hepta[1,2-b]thiophene (5)
Anal. Calcd for C18H19N3OS: C, 66.43; H, 5.88; N, 12.91. Found:
C, 66.08; H, 5.86; N, 12.72.
To a solution of 12 (560 mg, 2.45 mmol) and 1-methylpiperazine
(1.13 g, 11.27 mmol) in benzene (18 mL) was added TiCl4 (0.16
mL, 1.47 mmol). The mixture was stirred at 55 °C for 1 h. Aq 2%
NaHCO3 (50 mL) was added and the mixture was extracted with
EtOAc. The extract was washed with brine, dried (Na2SO4), and
evaporated in vacuo. The crude product was purified by column
chromatography (CHCl3–MeOH, 5:1) to give 5 as a yellow oil
(0.39 g, 51%).
2-Methyl-10-methylene-4-(4-methylpiperazin-1-yl)thieno[3,2-
c][1]benzazepine (6c)
To a solution of 6b (160 mg, 0.49 mmol) in THF (5 mL) was added
MeMgBr (3.0 M solution in Et2O, 2.25 mL) at 5 °C. After stirring
at 5 °C for 1.5 h, H2O was added. The solvent was evaporated off in
vacuo and the residue treated with H2O and CHCl3. The organic lay-
er was dried (Na2SO4) and concentrated to give 10-hydroxy-10-me-
thyl-thieno[3,2-c][1]benzazepine (170 mg) as a yellow oil. The
hydroxybenzazepine derivative, 4 M HCl (6 mL) and HCl (37 wt%
in H2O, 3 mL) in dioxane (5 mL) was heated under reflux for 18 h.
The mixture was cooled to r.t. and the mixture was made basic with
aq sat. NaHCO3 solution and extracted with EtOAc. The extract was
washed with brine, dried (Na2SO4), and evaporated. The crude
product was purified by column chromatography (CHCl3–MeOH,
10:1) to give 6c (94 mg, 59%) as a yellow oil. The free base was
converted into the hydrochloride and crystallized from MeOH–
EtOAc–diisopropyl ether (IPE); mp 160–165 °C.
IR (neat): 2939, 1599, 1485, 1448, 1140 cm–1.
1H NMR (400 MHz, CDCl3): = 2.35 (3 H, s, CH3), 2.36 (3 H, s,
CH3), 2.55 (4 H, br s, piperazine H), 3.05 (4 H, br s, piperazine H),
3.64 (2 H, s, CH2), 6.13 (1 H, s, vinyl H), 6.89 (1 H, s, thiophene H),
7.12–7.24 (4 H, m, ArH).
MS: m/z = 310 (M+).
Anal. Calcd for C19H22N2S 1/4H2O: C, 72.45; H, 7.20; N, 8.89.
Found: C, 72.40; H, 7.21; N, 8.52.
2-Methyl-4-(4-methylpiperazin-1-yl)thieno[3,2-c][1]benz-
azepine-10-one (6b)
IR (KBr): 1614, 1506, 1433 cm–1.
2-Methylthieno[3,2-c][1]benzazepine-4(5H),10-dione (16; 430 mg,
1.77 mmol) was suspended in POCl3 (2.7 mL, 29.1 mmol) and N,N-
dimethylaniline (100 mg, 0.80 mmol) was added. The mixture was
stirred under reflux for 1 h. The solvent was completely evaporated
azeotropically with toluene under reduced pressure and 1-meth-
ylpiperazine (10 mL) was added to the residue. The mixture was
stirred under reflux for 2.5 h. The mixture was cooled to r.t. and the
solvent was evaporated under reduced pressure. The crude product
was purified by column chromatography (CHCl3–MeOH, 20:1) to
give 6b (460 mg, 80%) as yellow crystals; mp 166–169 °C (EtOAc–
hexane).
1H NMR (400 MHz, CD3OD): = 2.52 (3 H, s, CH3), 3.03 (3 H, s,
CH3), 3.40–4.60 (8 H, m, piperazine H), 5.76 (1 H, s, vinyl H), 5.80
(1 H, s, vinyl H), 7.14 (1 H, s, thiophene H), 7.50–7.51 (4 H, m,
ArH).
MS: m/z = 323 (M+).
Anal. Calcd for C19H21N3S·2HCl 3H2O: C, 50.66; H, 6.48; N, 9.23.
Found: C, 50.25; H, 6.22; N, 8.92.
2-Methyl-10-(1-methylethylidene)-4-(4-methylpiperazin-1-yl)-
thieno[3,2-c][1]benzazepine (6d)
To a solution of 6b (470 mg, 1.5 mmol) in THF (10 mL) was added
isopropylmagnesium chloride (2.0 M solution in Et2O, 2.25 mL,
4.50 mmol) at 5 °C. After stirring at 5 °C for 2 h, H2O was added to
the mixture. The solvent was evaporated off in vacuo and the resi-
due was treated with H2O and EtOAc. The organic layer was dried
IR (KBr): 1572, 1413, 1253, 1140 cm–1.
1H NMR (400 MHz, CDCl3): = 2.34 (3 H, s, CH3), 2.54 (4 H, m,
piperazine H), 2.55 (3 H, s, CH3), 3.57 (4 H, m, piperazine H), 6.97
(1 H, s, thiophene H), 7.27 (1 H, dd, J = 6.8, 8.3 Hz, ArH), 7.48 (1
Synthesis 2002, No. 3, 355–360 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis of a Benzo[5,6]cyclohepta[1,2-b]thiophene and Thieno[3,2-c]benzazepine
359
(Na2SO4) and the solvent was evaporated under reduced pressure.
The residue was taken in dioxane (18 mL) and HCl (37 wt% in H2O,
24 mL) and refluxed for 4 h. The mixture was made basic with 1 N
NaOH solution and extracted with EtOAc. The extract was washed
with brine, dried (Na2SO4), and evaporated. The crude product was
purified by column chromatography on silica gel (CHCl3–MeOH,
10:1) to give 6d (460 mg, 95%) as a yellow oil. The free base con-
verted into the fumarate and crystallized from MeOH–EtOAc–IPE;
mp 224–225 °C.
with brine, dried (Na2SO4), and evaporated. Recrystallization from
diisopropyl ether gave 7 (120.0 g, 96%) as colorless crystals; mp
124–125 °C (EtOAc–IPE–hexane).
IR (KBr): 2872, 1684, 1630, 1593 cm–1.
1H NMR (400 MHz, CDCl3): = 2.50 (3 H, s, CH3), 6.72 (1 H, d, J
= 3.7 Hz, thiophene H), 7.07 (1 H, d, J = 3.7 Hz, thiophene H), 7.44
(1 H, d, J = 7.3 Hz, ArH), 7.54 (1 H, ddd, J = 1.4, 7.6, 7.8 Hz, ArH),
7.62 (1 H, ddd, J = 1.4, 7.6, 7.6 Hz, ArH), 8.06 (1 H, d, J = 7.8 Hz,
ArH).
IR (KBr): 2854, 1577, 1410, 1371, 1235, 1161 cm–1.
MS: m/z = 325 (M+).
1H NMR (400 MHz, DMSO-d6): = 1.78 (3 H, s, CH3), 1.91 (3 H,
s, CH3), 2.24 [3 H, s, (CH3)2C], 2.38 [3 H, s, (CH3)2C], 3.16–3.60
(10 H, m, piperazine H and CO2H), 6.60 (2 H, s, fumaric acid CH),
6.80 (1 H, s, thiophene H), 6.95–7.02 (4 H, m, ArH).
Anal. Calcd for C13H10O3S 1/5H2O: C, 62.48; H, 4.19. Found: C,
62.67; H, 4.26.
2-(5-Methyl-2-thenyl)benzoic Acid (8)
MS: m/z = 351 (M+).
To a suspension of 7 (40.0 g, 162.4 mmol) and CuSO4 (1.0 g, 6.5
mmol) in NH4OH (28% NH3 in H2O, 1 L) was added zinc powder
(106.0 g, 1624 mmol) at r.t. After stirring at 70 °C for 6 h, HCl
(35 wt% in H2O, 120 mL) was added. The mixture was cooled to r.t.
and partitioned between EtOAc and H2O. The organic layer was
dried (Na2SO4) and evaporated. The obtained residue was recrystal-
lized from EtOAc–hexane to give 8 (15.4 g, 67%) as colorless crys-
tals; mp 130–134 °C (EtOAc–hexane).
Anal. Calcd for C21H25N3S C4H4O4 3/5H2O: C, 62.77; H, 6.36; N,
8.78. Found: C, 62.45; H, 6.36; N, 8.38.
10-Hydroxy-2-methyl-4-(4-methylpiperazin-1-yl)thieno[3,2-c]-
[1]benzazepine (6e)
To a solution of 6b (170 mg, 0.52 mmol) in THF (10 mL) was added
NaBH4 (60 mg, 1.06 mmol) at r.t. After stirring at r.t. for 1 h, MeOH
(30 mL) was added to the mixture. The solvent was evaporated off
in vacuo and the residue treated with H2O and EtOAc. The organic
layer was dried (Na2SO4) and the solvent was evaporated under re-
duced pressure. The crude product was purified by column chroma-
tography (CHCl3–MeOH, 10:1) to give 6e (135 mg, 79%) as
colorless crystals; mp 161–163 °C (EtOAc–hexane).
IR (KBr): 2878, 1687, 1452, 1412, 1288 cm–1.
1H NMR (400 MHz, DMSO-d6): = 2.19 (3 H, s, CH3), 4.37 (2 H,
s, CH2), 6.32 (1 H, s, thiophene H), 6.44 (1 H, s, thiophene H), 7.13–
7.31 (4 H, m, ArH), 7.87 (1 H, s, CO2H).
MS: m/z = 232 (M+).
IR (KBr): 3061, 1574, 1408, 1248, 1149, 976 cm–1.
Anal. Calcd for C13H12O2S: C, 67.22; H, 5.21. Found: C, 67.19; H,
4.99.
1H NMR (400 MHz, DMSO-d6): = 2.21 (3 H, s, CH3), 2.34 (3 H,
s, CH3), 2.49 (4 H, m, piperazine H), 3.46 (4 H, m, piperazine H),
5.28 (1 H, d, J 4.4 Hz, CHO), 6.61 (1 H, br d, J = 4.4 Hz, OH), 6.64
(1 H, s, thiophene H), 6.92 (1 H, d, J = 7.3 Hz, ArH), 7.03 (1 H, dd,
J = 7.3, 7.4 Hz, ArH), 7.08 (1 H, dd, J = 7.3, 7.4 Hz, ArH), 7.42 (1
H, d, J = 4.4 Hz, ArH).
2-(5-Methyl-2-thenyl)benzyl Alcohol (9)
To a solution of SOCl2 (7.06 mL, 96.85 mmol) in MeOH (140 mL)
was added a solution of 8 (15.0 g, 64.6 mmol) in MeOH (100 mL)
and the mixture was stirred under reflux for 6 h. The mixture was
cooled to r.t., poured into H2O (200 mL), and extracted with EtOAc
(2 ). The EtOAc layer was washed with brine, dried (Na2SO4), and
the solvent was evaporated under reduced pressure. The crude prod-
uct was purified by column chromatography on silica gel (hexane–
EtOAc, 5:1) to give the methyl ester of 9 (12.54 g, 78%) as a yellow
oil. To a solution of the methyl ester (3.62 g, 14.7 mmol) in THF (30
mL) was added LiAlH4 (0.56 g, 14.7 mmol) at r.t. and stirred for 3
h. H2O was added and the mixture was extracted with EtOAc. The
organic extract was washed with brine, dried (Na2SO4), and evapo-
rated. The crude product was purified by column chromatography
on silica gel (hexane–EtOAc, 3:1) to give 9 (2.93 g, 95%) as a yel-
low oil.
MS: m/z = 327 (M+).
Anal. Calcd for C18H21N3OS 1/5H2O: C, 65.31; H, 6.52; N, 12.69.
Found: C, 65.30; H, 6.56; N, 12.95.
2-Methyl-4-(4-methylpiperazin-1-yl)-10-methoxythieno[3,2-c]-
[1]benzazepine (6f)
To a solution of 6e (140 mg, 0.43 mmol) in MeOH (7 mL) was add-
ed H2SO4 (6 drops) at r.t. The mixture was stirred under reflux for 2
h. It was then cooled to r.t., made basic with aq sat. NaHCO3 solu-
tion and extracted with EtOAc. The extract was washed with brine,
dried (Na2SO4), and evaporated. The crude product was purified by
column chromatography on silica gel (CHCl3–MeOH, 10:1) to give
6f (100 mg, 68%) as a yellow oil.
IR (KBr): 3333, 1452, 1039 cm–1.
1H NMR (400 MHz, DMSO-d6): = 2.33 (3 H, s, CH3), 4.06 (2 H,
s, CH2), 4.51 (2 H, d, J = 5.4 Hz, OCH2), 5.11 (1 H, t, J = 5.4 Hz,
OH), 6.57 (2 H, s, thiophene H), 7.15–7.37 (4 H, m, ArH).
IR (KBr): 2934, 1575, 1406, 1290, 1242, 1141 cm–1.
1H NMR (400 MHz, CDCl3): = 2.25 (3 H, s, CH3), 2.30 (3 H, s,
CH3), 2.47 (4 H, m, piperazine H), 3.27 (3 H, s, OCH3), 3.50–3.61
(4 H, m, piperazine H), 4.91 (1 H, s, CHO), 6.45 (1 H, s, thiophene
H), 6.89–7.21 (4 H, m, ArH).
MS: m/z = 218 (M+).
Anal. Calcd for C13H14OS: C, 71.52; H, 6.46. Found: C, 71.22; H,
6.45.
MS: m/z = 341 (M+).
Anal. Calcd for C19
1/2H2O: C, 65.11; H, 6.90; N, 11.99.
2-(5-Methyl-2-thenyl)benzyl Bromide (10)
23
3
Found: C, 65.38; H, 6.84; N, 11.86.
The alcohol 9 (2.93 g, 13.4 mmol) was suspended in 48% HBr
(9 mL). The mixture was stirred under reflux for 2 h. The mixture
was cooled to r.t. and extracted with EtOAc. The organic layer was
dried (Na2SO4) and the solvent was evaporated under reduced pres-
sure. Recrystallization from EtOAc–hexane gave 10 (2.84 g, 75%)
as brown crystals; mp 38–40 °C (EtOAc–hexane).
2-(5-Methyl-2-thenoyl)benzoic Acid (7)
To a suspension of 2-methylthiophene (49.3 mL, 509.3 mmol) and
phthalic anhydride (90.5 g, 611.2 mmol) in 1,2-dichloroethane (500
mL) was added powdered AlCl3 (135.8 g, 1018.6 mmol) at 5°C. Af-
ter stirring at 40 °C for 2 h, ice water (1 L) was added and the mix-
ture was extracted with EtOAc. The organic extract was washed
IR (KBr): 1491, 1452, 760 cm–1.
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T. Kohara et al.
PAPER
1H NMR (400 MHz, CDCl3): = 2.29 (3 H, s, CH3), 4.21 (2 H, s,
CH2), 4.50 (2 H, s, CH2), 6.51 (1 H, s, thiophene H), 6.52 (1 H, s,
thiophene H), 7.22–7.33 (4 H, m, ArH).
IR (KBr): 3178, 3057, 1668, 1496, 1429 cm–1.
1H NMR (400 MHz, DMSO-d6): = 2.34 (3 H, s, CH3), 3.98 (2 H,
s, CH2), 6.93 (1 H, s, thiophene H), 7.06 (1 H, dd, J = 7.3, 7.3 Hz,
ArH), 7.16 (1 H, d, J = 6.8 Hz, ArH), 7.20 (1 H, dd, J = 7.3, 7.4 Hz,
ArH), 7.27 (1 H, d, J = 7.3 Hz, ArH), 10.11 (1 H, br s, NH).
MS: m/z = 281 (M+).
Anal. Calcd for C13H13BrS: C, 55.52; H, 4.66. Found: C, 55.49; H,
4.99.
MS: m/z = 229 (M+).
Anal. Calcd for C13H11NOS: C, 68.10; H, 4.84; N, 6.11. Found: C,
68.09; H, 4.85; N, 6.06.
2-(5-Methyl-2-thenyl)phenylacetic Acid (11)
To a solution of 10 (12.94 g, 46.0 mmol) in DMF (60 mL) was add-
ed KCN (18 wt% in H2O, 15 mL). The mixture was stirred at r.t. for
3 h. H2O (200 mL) was added and the mixture was extracted with
EtOAc. The organic extract was washed with brine, dried (Na2SO4),
and the solvent was removed in vacuo. To a solution of the residue
in AcOH (80 mL) was added HCl (37 wt% in H2O, 50 mL) at r.t.,
and the mixture was stirred at 95 °C for 4 h. The mixture was stirred
at 55 °C for 1 h, poured into H2O (200 mL) and extracted with
CHCl3. The organic layer was dried (Na2SO4) and the solvent was
evaporated under reduced pressure. The crude product was purified
by column chromatography on silica gel (CHCl3–MeOH, 20:1) to
give 11 (7.84 g, 83%) as yellow crystals; mp 60–63 °C (EtOAc–
hexane).
2-Methylthieno[3,2-c][1]benzazepine-4(5H),10-dione (16)
To a dispersion of 15 (0.84 g, 3.7 mmol) in acetone (30 mL) was
added KMnO4 (1.46 g, 9.25 mmol) at 5 °C. The mixture was stirred
at r.t. for 1 h, diluted with H2O (200 mL), and extracted with EtOAc
(2 ). The organic extract was washed with H2O, and dried
(Na2SO4). The solvent was evaporated under reduced pressure and
the precipitated crystals were collected by filtration and washed
with hexane to give 16 (780 mg, 88%) as yellow crystals; mp 220
°C (EtOAc–IPE).
IR (KBr): 3055, 1662, 1618, 1597, 1483, 1332 cm–1.
1H NMR (400 MHz, DMSO-d6): = 2.57 (3 H, s, CH3), 7.29 (1 H,
dd, J = 6.8, 8.3 Hz, ArH), 7.54 (1 H, s, thiophene H), 7.56 (1 H, d,
J = 8.3 Hz, ArH), 7.69 (1 H, dd, J = 6.8, 7.4 Hz, ArH), 8.21 (1 H, d,
J = 6.8 Hz, ArH), 11.23 (1 H, br s, NH).
IR (KBr): 2916, 1693, 1406, 1238 cm–1.
1H NMR (400 MHz, CDCl3): = 2.37 (3 H, s, CH3), 3.66 (2 H, s,
CH2), 4.10 (2 H, s, CH2), 6.45 (1 H, d, J = 3.4 Hz, thiophene H), 6.49
(1 H, d, J = 3.4 Hz, thiophene H), 7.22–7.24 (4 H, m, ArH).
MS: m/z = 243 (M+).
MS: m/z = 246 (M+).
Anal. Calcd for C13H9NO2S: C, 64.18; H, 3.73; N, 5.76. Found: C,
64.21; H, 4.06; N, 5.52.
Anal. Calcd for C14H14O2S: C, 68.26; H, 5.73. Found: C, 68.43; H,
5.82.
Acknowledgements
2-Methyl-4,5-dihydro-10H-benzo[5,6]cyclohepta[1,2-b]thio-
phene-4-one (12)
The authors thank Takeshi Sato and Tamiko Ikke for MS and EA
studies, along with the Discovery Laboratories at Mitsubishi Phar-
ma Corporation.
To a solution of 11 (0.5 g, 2.03 mmol) in toluene (5 mL) was added
P2O5 (1.0 g) and mixture was stirred at 90 °C for 13 h. It was then
cooled to r.t. and washed with 1 N NaOH solution. The organic lay-
er was dried (Na2SO4) and the solvent was evaporated under re-
duced pressure. The crude product was purified by column
chromatography on silica gel (hexane–EtOAc, 5:1) to give 12 (0.30
g, 65%) as yellow crystals; mp 118–110 °C (EtOAc–hexane).
References
(1) Chakrabarti, J. K.; Hotten, T. M.; Pullar, I. A.; Steggles, D.
J. J. Med. Chem. 1989, 32, 2375.
IR (KBr): 1664, 1487, 1238 cm–1.
(2) Press, J. B.; Hofmann, C. M.; Eudy, N. H.; Day, I. P.;
Greenblatt, E. N.; Safir, S. R. J. Med. Chem. 1981, 24, 154.
(3) Lieo, Y.; Venhuis, B. J.; Rodenhuis, N.; Timmerman, W.;
Wikströn, H. J. Med. Chem. 1999, 42, 2235.
(4) Liégeois, J.-F. F.; Rogister, F. A.; Bruhwyler, J.; Damas, J.;
Nguyen, T. P.; Inarejos, M.-O.; Chleide, E. M. G.; Mercier,
M. G. A.; Delarge, J. E. J. Med. Chem. 1994, 37, 519.
(5) Povlen, U. J.; Noring, U.; Fog, R.; Gerlach, J. Acta.
Psychiatr. Scand. 1985, 71, 176.
1H NMR (400 MHz, CDCl3): = 2.33 (3 H, s, CH3), 4.04 (2 H, s,
CH2), 4.35 (2 H, s, CH2), 6.99 (1 H, s, thiophene H), 7.16–7.36 (4
H, m, ArH).
MS: m/z = 228 (M+).
Anal. Calcd for C14H12OS: C, 73.65; H, 5.30. Found: C, 73.68; H,
5.25.
(6) Gronowitz, S. Thiophene and Its Derivatives, Part IV;
Wiley: New York, 1985.
(7) Beasley, C. M.; Tollefson, G.; Tran, P.; Satterlee, W.;
Sanger, T.; Hamilton, S. Neuropsychopharmacology 1996,
14, 111.
(8) Hunziker, F.; Fischer, R.; Kipfer, P.; Schmutz, J.; Bürki, H.
R.; Eichenberger, E.; White, T. G. Eur. J. Chem. 1981, 16,
391.
(9) MacDowell, D. W. H.; Wisowaty, J. C. J. Org. Chem. 1971,
36, 3999.
(10) Leonard, N. J.; Kresge, A. J.; Oki, M. J. Am. Chem. Soc.
1955, 77, 5078.
(11) Paulis, T.; Betts, C. R.; Smith, H. E. J. Med. Chem. 1981, 24,
1021.
(12) Letsinger, R. L.; Jamison, J. D.; Hussey, A. S. J. Org. Chem.
1961, 26, 97.
(13) EI-Abbady, A. M.; Ayoab, S.; Baddor, F. G. J. Chem. Soc.
1960, 2556.
2-Methylthieno[3,2-c][1]benzazepine-4(5H)-one (15)
To a solution of 8 (5.35 g, 23.0 mmol) and Et3N (2.68 g, 26.5 mmol)
in acetone (110 mL) was added ethyl chloroformate (2.75 g, 25.3
mmol) at –60 °C. The mixture was stirred at –60 °C for 1 h and a
solution of NaN3 (10 wt% in H2O, 18 mL) was added. The mixture
was stirred for 2 h at 0 °C, poured into H2O, and extracted with
CHCl3. The organic extract was washed with brine, dried (Na2SO4),
and evaporated. A solution of the residue in 1,2-dichlorobenzene
(100 mL) was heated for 60 min at 60 °C. After cooling, AlCl3 (7.76
g, 58.2 mmol) was added to the mixture and it was heated for
30 min at 100 °C. The mixture was cooled to r.t., poured into H2O
(200 mL), and extracted with CHCl3 (2 ) and washed with H2O.
The organic layer was dried (Na2SO4), and the solvent was evapo-
rated under reduced pressure. The crude product was purified by
column chromatography on silica gel (CHCl3–MeOH, 5:1) to give
15 as yellow crystals (2.2 g, 51%); mp 214–218 °C (EtOAc–hex-
ane).
Synthesis 2002, No. 3, 355–360 ISSN 0039-7881 © Thieme Stuttgart · New York