Scalable and straightforward synthesis of a 2-alkyl-7-arylbenzo-thiophene as a GPR52 agonist via a hemithioindigo derivative

Article abstract of DOI:10.1055/s-0034-1378746

A simple and efficient procedure has been developed for the synthesis of the GPR52 agonist N-(2-amino-2-oxoethyl)-3-{4-fluoro-2-[3-(trifluoromethyl)benzyl]-1-benzothien-7-yl}benzamide. The benzo thiophene unit was directly constructed by reduction of a hemithioindigo derivative prepared by an intramolecular Friedel-Crafts cyclization of (phenylsulfanyl)acetic acid, followed by dehydrative benzylidene formation.

Full text of DOI:10.1055/s-0034-1378746

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3467–3472
paper
3467
N. Fukuda, T. Ikemoto
Paper
Synthesis
Scalable and Straightforward Synthesis of a 2-Alkyl-7-Arylbenzo-
thiophene as a GPR52 Agonist via a Hemithioindigo Derivative
Naohiro Fukuda*
Tomomi Ikemoto
O
NH2
N
Br
HS
CO2Et
H
Br
CF3
O
Chemical Development Laboratories, Takeda Pharmaceutical
Company Limited, Yodogawa-ku, Osaka 532-8686, Japan
naohiro.fukuda@takeda.com
F
S
+
S
CF3
O
F
F
OHC
CF3
F
Received: 01.06.2015
Accepted after revision: 29.06.2015
Published online: 11.08.2015
ceutically active compounds and they are also widespread
in material chemistry.3,4 Several methods are known for the
synthesis of the benzothiophene ring system,5 including
classical Bischler-type cyclizations of aryl thioketones to
give 2-substituted benzothiophenes6 or the annulation of
1-halo-2-ethynylbenzenes with sodium sulfide.7 Also, in-
tramolecular cyclizations of o-alkynyl thioethers by using
iodine8 or transition metals such as palladium, copper,
manganese, or gold have been recently reported.9–12 How-
ever, there are few methods for syntheses of benzothio-
phenes compared with those available for benzofurans and
indoles, probably due to deactivation of the catalysts by the
sulfur atom in the precursor.13,14 Although methods for the
synthesis 2-benzylbenzothiophenes, including arylation of
2-methylbenzothiophenes and direct benzylation of ben-
zothiophenes, have been reported, they are often not suit-
able for scaling up, because they involve cryogenic or harsh
conditions or require laborious workups.15 In its medicinal
chemistry synthesis, GPR52 agonist 1 was constructed by a
strategy involving the Suzuki–Miyaura arylation of the 2-
(bromomethyl)benzothiophene 3 (obtained from carboxyl-
ic acid 2) with the arylboronic acid 5 (Scheme 1).2 Several
steps in this synthesis involved chromatographic purifica-
tions, which decreased its scalability and productivity.16
Therefore, a practical synthesis of 2-benzylbenzothio-
phenes would be attractive, not only to medicinal chemists,
but also to process chemists. Here, we describe the develop-
ment of a scalable synthesis of GPR52 inhibitor 1.
DOI: 10.1055/s-0034-1378746; Art ID: ss-2015-f0349-op
Abstract A simple and efficient procedure has been developed for the
synthesis of the GPR52 agonist N-(2-amino-2-oxoethyl)-3-{4-fluoro-2-
[3-(trifluoromethyl)benzyl]-1-benzothien-7-yl}benzamide. The benzo-
thiophene unit was directly constructed by reduction of a hemithioindi-
go derivative prepared by an intramolecular Friedel–Crafts cyclization of
(phenylsulfanyl)acetic acid, followed by dehydrative benzylidene forma-
tion.
Key words benzothiophenes, Friedel–Crafts reactions, cyclizations,
scalable syntheses, medicinal chemistry
Activation of G protein-coupled receptor 52 (GPR52)
might inhibit D2 receptor signaling as well as activating the
dopamine/N-methyl-D-aspartate
through accumulation of intracellular cyclic adenosine mo-
nophosphate (cAMP).1,2 GPR52 agonist 1 (Figure 1) was dis-
covered by our colleagues,2 and is expected to give rise to a
novel class of antipsychotics.
(D1/NMDA)
function
O
N
H
CONH2
7
S
2
In our retrosynthetic analysis, compound 6 appeared to
be an appropriate precursor of the target compound 1,
which could then be obtained by a Suzuki–Miyaura aryla-
tion with [3-(ethoxycarbonyl)phenyl]boronic acid (7), fol-
lowed by hydrolysis and subsequent amide formation with
2-aminoacetamide (Scheme 2). We surmised that the ben-
zothiophene skeleton in 6 might be directly obtainable by
reduction of both the double bond and ketone group of
CF3
F
1
Figure 1
The structure of GPR52 agonist 1 is characterized by a
2-benzyl-7-arylbenzothiophene core. Benzothiophenes ex-
ist in the core structure of many biologically and pharma-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3467–3472

3468
N. Fukuda, T. Ikemoto
Paper
Synthesis
(HO)2B
CO2Et
CO2Et
CF3
Br
F
S
5
CO2H
1
S
2
S
Br
CF3
F
F
2
3
4
Scheme 1 Medicinal chemistry synthesis of GPR52 agonist 1
hemithioindigo 8, followed by dehydration. There had been
little previous investigation17 on such reductions compared
with similar reductions of aurones and hemiindigos into
benzofurans18 and indoles,19 respectively. The reported con-
ditions for reductions of hemithioindigo using triethylsi-
lane and trifluoroacetic acid gave the corresponding ben-
zothiophene in low yield, along with an unexpected rear-
ranged product (a thioflavonol) and other unidentified
byproducts.17 Therefore, alternative effective reaction con-
ditions were required to give the corresponding benzothio-
phene skeleton. The key intermediate 8 was thought to be
obtainable by intramolecular Friedel–Crafts cyclization of
carboxylic acid 9, followed by a Knoevenagel-type conden-
sation with benzaldehyde 10.
In accordance with this strategy, we attempted to con-
vert 2-bromo-5-fluoroaniline into carboxylic acid 9. How-
ever, the reaction of the diazonium salt of 2-bromo-5-fluo-
roaniline with potassium ethylxanthate was sluggish and
gel-like materials were obtained in the reaction mixture.
Next, we attempted the sulfenylation of trihalide 11 with
ethyl sulfanylacetate (15) in the presence of tripotassium
phosphate in N,N-dimethylacetamide. The reaction pro-
ceeded regioselectively at the 2-position (approximately
10:1)20 to give ester 12, which was hydrolyzed to give car-
boxylic acid 9 in 51% yield from 11 after recrystallization
(Scheme 3). To avoid the use of halogenated solvents such
as dichloromethane or chloroform, which cause significant
adverse environmental impacts, we attempted an intramo-
lecular Friedel–Crafts cyclization of the acid chloride ob-
tained from acid 9 with aluminum(III) chloride or zirconi-
reduction and
dehydrative benzothiophene formation
amidation
O
N
CONH2
Br
H
CO2Et
S
+
Suzuki–Miyaura arylation
S
7
CF3
B(OH)2
F
6
CF3
F
1
benzilidene formation
CF3
Br
F
Br
F
S
S
CO2H
CF3
+
10
9
OHC
O
8
intramolecular Friedel–Crafts reaction
Scheme 2 Retrosynthetic analysis of 1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3467–3472

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N. Fukuda, T. Ikemoto
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Synthesis
um(IV) chloride in chlorobenzene, but this gave many by-
products. It was thought that the chlorobenzene solvent
reacted predominantly with the acid chloride of 9 through
an intermolecular Friedel–Crafts acylation rather than by
intramolecular cyclization to produce 13; the presence of
two halogen atoms (F and Br) on the aromatic ring of 9
might retard the desired reaction. Although the reaction in
less reactive 1,2-dichlorobenzene as solvent gave thioin-
doxyl 13 without considerable amounts of byproducts, it
was difficult to distill off the 1,2-dichlorobenzene in a
large-scale preparation. Fortunately, it was found that 13
could be enolized with aqueous sodium hydroxide solution
to afford its sodium salt, which could then be readily ex-
tracted into aqueous solution; 13 was then obtained by re-
extraction into the organic layer after neutralization. In
general, thioindoxyl derivatives are readily oxidized to thio-
indigos under aerobic conditions.21 Therefore, freshly pre-
pared 13 was used in the next step. The hemithioindigo 8
was obtained in 72% yield from 9 by the reaction of thioin-
doxyl 13 with 3-(trifluoromethyl)benzaldehyde (10) in the
presence of a catalytic amount of piperidine.
chlorite in 1,2-dimethoxyethane or by an imide and nitrox-
yl radical dual-catalyzed sodium hypochlorite oxidation
(Scheme 4).22
a or b
CF3
CF3
16
10
HO
OHC
Scheme 4 Reagents and conditions: (a) aq NaOCl, DME, r.t., 81%; (b)
TEMPO (3 mol%), cyanuric acid (10 mol%), aq NaOCl, EtOAc, 98%.
Regarding the formation of the 2-benzylbenzothio-
phene, it was found that the reduction of 8 by triethylsilane
in methanesulfonic acid proceeded smoothly to give 6 in
87% yield. However, the hexaethyldisiloxane byproduct re-
quired removal by chromatographic purification, which is
unsuitable for a scaled-up synthesis. By further investiga-
tion, we found an alternative pathway involving the reduc-
tion of 8 by sodium borohydride and methanol, followed by
dehydration with sulfuric acid; this procedure gave 6 in 89%
yield and in a form that could be used in the next reaction
without further purification. Whereas the Suzuki–Miyaura
arylation of 6 purified by silica gel column chromatography
with boronic acid 7 proceeded smoothly in the presence of
4 mol% of palladium(II) acetate and 16 mol% of triphenyl-
phosphine, the corresponding reaction using crude 6
stalled, with recovery of 6. Attempts to remove the un-
known contaminant that deactivated the catalyst system by
treatment of crude 6 by washing with aqueous sodium bi-
carbonate or by treatment with activated charcoal were in-
effective. On the other hand, the reaction using 16 mol% of
tri(o-tolyl)phosphine was readily completed and, when fol-
lowed by hydrolysis, afforded the penultimate intermediate
14 in 87% yield over three steps. Finally, amidation of 14
with 2-aminoacetamide gave the target compound 1 in 97%
yield.
In conclusion, we have established a scalable and simple
synthesis of the GPR52 agonist, N-(2-amino-2-oxoethyl)-3-
{4-fluoro-2-[3-(trifluoromethyl)benzyl]-1-benzothien-7-
yl}benzamide (1), starting from 1-bromo-2,4-difluoroben-
zene (11). Key features were the development of a regiose-
lective sulfenylation of 11 with ethyl sulfanylacetate (15),
and direct benzothiophene formation from hemithioindigo
8 by reduction with sodium borohydride followed by dehy-
dration with sulfuric acid. The overall yield was dramatical-
ly improved to 33% from the 2% obtained in the previously
reported synthesis. Because this synthesis proceeds in ten
chemical transformations under mild reaction conditions
with effective telescoping of operations and four isolations
of synthetic intermediates, it should be easy to prepare 1 on
a large scale.16a,23 The processes described here might prove
useful for similar organic transformations or for the effi-
cient synthesis of related structures.
Br
Br
Br
S
CO2H
F
S
CO2Et
b, c
a
Br
F
F
9
F
F
12
11
Br
F
CF3
S
f
d, e
S
CF3
O
O
13
10
OHC
8
CO2H
Br
F
S
h, i
CF3
j
g
1
S
6
CF3
F
14
Scheme 3 Reagents and conditions: (a) HSCH2CO2Et (15), K3PO4, N,N-
dimethylacetamide, 25 °C; (b) 2 M aq NaOH, EtOH, 25 °C; (c) recrystalli-
zation from EtOAc–heptane, 51% from 11; (d) SOCl2, DMF (cat.), 1,2-
dichlorobenzene, 60 °C; (e) AlCl3, 1,2-dichlorobenzene, 0–10 °C; (f) 10,
piperidine (5 mol%), toluene, 72% from 9; (g) NaBH4, THF, EtOH, 60 °C,
then H2SO4, 89%; (h) 3-EtO2CC6H4B(OH)2 7, Pd(OAc)2 (4 mol%), (o-Tol)3P
(16 mol%), Na2CO3, DME, reflux; (i) aq NaOH, EtOH, r.t., 87% from 8;
(j) HCl·NH2CH2CONH2, EDC·HCl, HOBt·H2O, DIPEA, N,N-dimethylacet-
amide, 25 °C, then recrystallization from aq EtOH, 97%.
The aldehyde 10 was readily prepared from 3-(trifluo-
romethyl)benzyl alcohol (16) according to our previously
reported practical oxidation procedure using sodium hypo-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3467–3472

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N. Fukuda, T. Ikemoto
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Synthesis
Procedure B: Oxidation with NaOCl in the presence of catalytic amount
of cyanuric acid and TEMPO
All reactions were performed under N2. All chemicals were obtained
from commercial suppliers and were used without further purifica-
tion. Melting points were determined on a Büchi Melting Point B-540
or a Stanford Research Systems OptiMelt MPA 100 apparatus, and are
uncorrected unless otherwise noted. 1H and 13C NMR spectra were re-
corded on a Bruker Avance 600 (1H: 600 MHz, 13C: 151 MHz) in CDCl3
with TMS as an internal standard. HPLC analysis of the compounds
and reaction monitoring was carried out on a Shimadzu LC-2010CHT
chromatograph. High-resolution mass spectra were recorded on a
Shimadzu Prominence UFLC system with a Thermo Fisher LTQ Or-
bitrap Discovery. Elemental analyses were recorded on an Elementar
vario MICRO cube. IR spectra were recorded on a Thermo Electron FT-
IR Nicolet 4700 spectrophotometer in the ATR mode.
To a mixture of 16 (676 mg, 3.84 mmol), cyanuric acid (50 mg, 0.38
mmol, 0.1 equiv), and K2CO3 (1.06 g, 7.68 mmol, 2.0 equiv) in EtOAc
(10 mL) were added TEMPO (18 mg, 0.12 mmol, 0.03 equiv) and 12%
(w/w) aq NaOCl (2.86 g, 4.61 mmol, 1.2 equiv) at 0–10 °C, and the
mixture was stirred for 5 h at 0–10 °C. The mixture was then extract-
ed with EtOAc (20 mL). The organic layer was washed with 10% aq.
NaCl (10 mL) then concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel, EtOAc–hexane) to
give a colorless oil; yield: 398 mg (98%).
1H NMR (600 MHz, CDCl3): δ = 7.70 (t, J = 7.7 Hz, 1 H), 7.90 (d, J = 7.9
Hz, 1 H), 8.09 (d, J = 7.6 Hz, 1 H), 8.15 (s, 1 H), 10.09 (s, 1 H).
13C NMR (151 MHz, CDCl3): δ = 123.6 (q, J = 272.5 Hz), 126.5 (q, J = 3.8
Hz), 129.8, 130.8 (q, J = 3.3 Hz), 131.9 (q, J = 33.2 Hz), 132.7, 136.9,
190.7.
[(2-Bromo-5-fluorophenyl)sulfanyl]acetic Acid (9)
K3PO4 (88.20 g, 415.73 mmol, 1.2 equiv) was added to a mixture of 1-
bromo-2,4-difluorobenzene (11; 66.90 g, 346.44 mmol) and HSCH2CO2Et
(15; 50.00 g, 415.73 mmol, 1.2 equiv) in N,N-dimethylacetamide (335
mL) at 20–25 °C, and the mixture was stirred for 18 h. 1 M aq NaOH
(693 mL, 693 mmol, 2.0 equiv) was added, and the mixture was
stirred for 1.5 h. The pH of the mixture was adjusted to 2.5–3.0 with 6
M aq HCl (310 mL), and the mixture was extracted with toluene (669
mL). The aqueous layer was then extracted with toluene (2 × 200 mL).
The organic layers were combined and extracted with 1 M aq NaOH
(669 mL). The aqueous layer was adjusted to pH 3.5 with 6 M aq HCl
(110 mL), a seed of 9 (33 mg, 0.05 wt%) was added to the mixture, and
the slurry was stirred for 1 h at r.t. The solids were collected by filtra-
tion to give wet 9. A mixture of the wet 9 and EtOAc (100 mL) was
warmed to 50 °C then cooled to r.t. Heptane (300 mL) was added
dropwise to the mixture, and the resulting slurry was stirred for 1 h.
The solids were collected by filtration and washed with 1:4 EtOAc–
heptane (134 mL). The wet solids were dried at 50 °C under reduced
pressure to give a white solid; yield: 46.7 g (51% over 2 steps from
11); mp 132.6–133.5 °C.
7-Bromo-4-fluoro-1-benzothiophen-3(2H)-one (13)
To a mixture of acid 9 (5.00 g, 18.85 mmol) and DMF (69 mg, 0.94
mmol, 0.05 equiv) in 1,2-dichlorobenzene (15 mL) was added SOCl2
(2.47 g, 20.74 mmol, 1.1 equiv) at r.t. The resulting mixture was
stirred at 60 °C for 1 h then cooled to r.t. The mixture was added
dropwise to a mixture of AlCl3 (5.03 g, 37.70 mmol, 1.5 equiv) and
1,2-dichlorobenzene (10 mL) at 0–10 °C, and the resulting mixture
was stirred at 0–10 °C for 1.5 h then poured into H2O (50 mL) at 0–
30 °C. The mixture was extracted with toluene (65 mL), and the or-
ganic layer was washed successively with 1 M aq HCl (25 mL) contain-
ing NaCl (2.5 g) and with brine (15 mL). The organic layer was extract-
ed with 2 M aq NaOH (25 mL) and 1 M aq NaOH (5 mL). Toluene (25
mL) was added to the aqueous layer and the pH was adjusted to 4.5–
5.0 with 6 M aq HCl (4.5 mL). EtOAc (25 mL) and activated charcoal
(500 mg, Shirasagi A, Wako Pure Chemical Industries, Ltd.) were add-
ed, and the mixture was stirred for 1 h. Insoluble materials were fil-
tered off and washed with EtOAc (15 mL). The organic layer of the fil-
trate was concentrated in vacuo to give crude 13 (4.08 g). An analyti-
cal sample of 13 was isolated by column chromatography (silica gel,
EtOAc–hexane).
IR (ATR): 433, 458, 485, 566, 578, 597, 679, 693, 803, 844, 881, 900,
932, 1021, 1093, 1142, 1213, 1259, 1293, 1388, 1417, 1352, 1571,
1591, 1697 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 3.99 (s, 2 H), 6.98 (td, J = 3.0, 8.5 Hz,
1 H), 7.18 (dd, J = 2.8, 10.0 Hz, 1 H), 7.64 (dd, J = 5.7, 8.7 Hz, 1 H), 13.03
(br s, 1 H).
13C NMR (151 MHz, DMSO-d6): δ = 34.1, 113.5 (d, J = 22.9 Hz), 113.7
(d, J = 26.7 Hz), 115.0, 134.0 (d, J = 8.7 Hz), 140.0 (d, J = 8.7 Hz), 161.7
(d, J = 245.8 Hz), 169.8.
1H NMR (600 MHz, CDCl3): δ = 3.86 (s, 2 H), 6.78 (t, J = 8.8 Hz, 1 H),
7.61–7.69 (m, 1 H).
13C NMR (151 MHz, CDCl3): δ = 40.5, 113.0 (d, J = 4.4 Hz), 113.7 (d, J =
21.3 Hz), 120.9 (d, J = 14.2 Hz), 139.4 (d, J = 8.7 Hz), 157.0 (d, J = 3.4
Hz), 160.2 (d, J = 267.6 Hz), 196.0.
HRMS (ESI): m/z [M – H]– calcd for C8H5BrFO2S: 262.9183; found:
262.9180.
7-Bromo-4-fluoro-2-[3-(trifluoromethyl)benzylidene]-1-benzo-
thiophen-3(2H)-one (8)
To a mixture of crude ketone 13 (4.08 g) and aldehyde 10 (3.18 g,
16.59 mmol) in toluene (8.2 mL) was added piperidine (71 mg, 0.83
mmol, 0.05 equiv). The mixture was stirred at 100 °C for 3 h then
EtOH (29 mL) was added at 80 °C. The mixture was cooled to r.t.,
stirred for 1 h, and then cooled to 0–10 °C for 1 h. The solids were col-
lected by filtration and washed with ice-cold 7:1 EtOH–water (20
mL). The wet solids were dried to give a yellow solid; yield: 5.44 g
(72% over 2 steps from 9); mp 153.9–154.8 °C.
3-(Trifluoromethyl)benzaldehyde (10)24
[CAS Reg. No. 454–89–7]
Procedure A: Oxidation with NaOCl in DME
A mixture of (3-trifluoromethyl)benzyl alcohol (16; 500 mg, 2.84
mmol) in DME (10 mL) was stirred at 20–30 °C, and 12% (w/w) aq
NaOCl (3.52 g, 5.68 mmol, 2.0 equiv) was gradually added to the mix-
ture at 20–25 °C. The reaction was continued for 4 h while the tem-
perature was maintained at 20–25 °C. When the reaction was com-
plete, the mixture was extracted with EtOAc (20 mL). The organic lay-
er was washed with 10% aq NaCl (10 mL) and concentrated under
reduced pressure. The residue was purified by column chromatogra-
phy (silica gel, EtOAc–hexane) to give a colorless oil; yield: 398 mg
(81%).
IR (ATR): 456, 482, 506, 525, 578, 631, 653, 675, 684, 731, 767, 806,
814, 871, 907, 925, 946, 1000, 1056, 1075, 1100, 1165, 1189, 1199,
1232, 1261, 1276, 1288, 1299, 1327, 1427, 1459, 1571, 1597, 1693
cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 7.20 (t, J = 9.06 Hz, 1 H) 7.78–7.90
(m, 2 H) 7.95–8.07 (m, 3 H) 8.11 (s, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3467–3472

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N. Fukuda, T. Ikemoto
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Synthesis
13C NMR (151 MHz, DMSO-d6): δ = 112.2 (d, J = 2.7 Hz), 115.7 (d, J =
21.3 Hz), 119.6 (d, J = 6.1 Hz), 123.8 (q, J = 272.5 Hz), 127.0 (q, J = 3.3
Hz), 127.6 (q, J = 4.4 Hz), 130.1 (q, J = 32.2 Hz), 130.6, 130.8, 132.5,
133.6, 134.3, 140.0 (d, J = 9.3 Hz), 147.6 (d, J = 3.3 Hz), 159.9 (d, J =
264.9 Hz), 184.2.
cessively with 70% aq EtOH (6 mL) and water (7.5 mL, 4.5 mL). The wet
solids were dried at 50 °C to give a white solid; yield: 1.39 g (87% over
3 steps from 8); mp 177.6–178.3 °C.
IR (ATR): 488, 552, 576, 659, 670, 692, 700, 723, 737, 758, 805, 875,
909, 928, 970, 1069, 1097, 1109, 1149, 1166, 1202, 1231, 1254, 1316,
1417, 1449, 1474, 1578, 1674 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C16H8BrF4OS: 402.9415; found:
402.9418.
1H NMR (600 MHz, DMSO-d6): δ = 4.44 (s, 2 H), 7.33 (dd, J = 10.0, 8.1
Hz, 1 H), 7.44 (dd, J = 7.9, 4.9 Hz, 1 H), 7.48 (s, 1 H), 7.56–7.70 (m, 4 H),
7.77 (s, 1 H), 7.88 (d, J = 7.8 Hz, 1 H), 8.04 (d, J = 7.9 Hz, 1 H), 8.23 (t, J =
1.5 Hz, 1 H), 13.20 (br s, 1 H).
7-Bromo-4-fluoro-2-[3-(trifluoromethyl)benzyl]-1-benzothio-
phene (6)
13C NMR (151 MHz, DMSO-d6): δ = 35.2, 110.6 (d, J = 19.6 Hz), 117.2,
123.5 (q, J = 3.8 Hz), 124.1 (q, J = 272.3 Hz), 125.1 (q, J = 3.8 Hz), 125.2,
128.4, 128.7 (d, J = 19.6 Hz), 128.9, 129.4 (q, J = 31.6 Hz), 129.4, 129.6,
131.2 (d, J = 3.8 Hz), 131.6, 132.1, 132.8, 139.2, 140.2 (d, J = 6.5 Hz),
140.8, 145.8, 156.1 (d, J = 250.1 Hz), 166.9.
A mixture of ketone 8 (1.50 g, 3.72 mmol) and THF (7.5 mL) was add-
ed dropwise to a mixture of NaBH4 (211 mg, 5.58 mmol, 1.5 equiv)
and THF (1.5 mL) at 60 °C, and the mixture was stirred for 0.5 h.
MeOH (1.5 mL) was added dropwise at 60 °C, and the mixture was
stirred for 1 h then cooled to r.t. 1 M aq HCl (15 mL) was added, and
the mixture was extracted with toluene (15 mL). H2SO4 (3 mL) was
added to the organic layer, and the mixture was stirred at 60 °C for 1
h, then cooled to r.t. The mixture was then washed with H2O (15 mL
then 7.5 mL). The organic layer was concentrated in vacuo to give the
crude product. An analytical sample of 6 was isolated by column
chromatography (silica gel, EtOAc–hexane).
1H NMR (600 MHz, CDCl3): δ = 4.29 (s, 2 H), 6.91 (dd, J = 9.4, 8.3 Hz, 1
H), 7.23 (s, 1 H), 7.35 (dd, J = 8.3, 4.2 Hz, 1 H), 7.44–7.51 (m, 2 H),
7.51–7.59 (m, 2 H).
13C NMR (151 MHz, CDCl3): δ = 36.8, 109.7 (d, J = 3.8 Hz), 111.3 (d, J =
20.7 Hz), 118.1, 124.1 (q, J = 272.5 Hz), 124.1 (q, J = 3.6 Hz), 125.5 (q,
J = 3.8 Hz), 127.4 (d, J = 7.6 Hz), 129.3, 129.5 (d, J = 20.2 Hz), 131.3 (q,
J = 32.2 Hz), 132.1, 139.7, 143.6 (d, J = 6.5 Hz), 145.4, 156.5 (d, J =
251.2 Hz).
Anal. Calcd for C23H14F4O2S: C, 64.18; H, 3.28. Found: C, 64.20; H, 3.31.
N-(2-Amino-2-oxoethyl)-3-{4-fluoro-2-[3-(trifluoromethyl)ben-
zyl]-1-benzothien-7-yl}benzamide (1)
DIPEA (310 mg, 2.40 mmol, 1.2 equiv) was added to a solution of acid
14 (860 mg, 2.00 mmol), 2-aminoacetamide hydrochloride (265 mg,
2.40 mmol, 1.2 equiv), HOBt·H2O (306 mg, 2.00 mmol, 1.0 equiv), and
EDC·HCl (460 mg, 2.40 mmol, 1.2 equiv) in N,N-dimethylacetamide
(8.6 mL) at 0–10 °C, and the mixture was stirred at r.t. for 1 h. H2O
(17.2 mL) and sat. aq NaHCO3 (5.2 mL) were added dropwise to the
mixture, and the slurry was stirred for 1 h. The solids were collected
by filtration, and the wet solids were washed successively with H2O
(14.6 mL) and i-Pr2O (10 mL). The wet solids were dried over at 50 °C
to afford crude 1. A mixture of crude 1 in 95% aq EtOH (8 mL) was
warmed up to 60 °C. H2O (3.3 mL) was added to the solution at 60 °C,
and then more H2O (1.2 mL) was added at r.t. The mixture was stirred
for 1 h, and then the solids were collected by filtration and washed
with 60% aq EtOH (2.5 mL). The wet solids were dried at 50 °C to give
a white solid; yield: 480 mg (97%); mp 157.2–157.9 °C.
Ethyl 3-{4-Fluoro-2-[3-(trifluoromethyl)benzyl]-1-benzothien-7-
yl}benzoate (4)
Pd(OAc)2 (33 mg, 0.15 mmol, 0.04 equiv) was added to a mixture of
crude product 6, [3-(ethoxycarbonyl)phenyl]boronic acid (7; 1.08 g,
5.58 mmol, 1.5 equiv), (o-Tol)3P (181 mg, 0.60 mmol, 0.16 equiv), and
2 M aq Na2CO3 (7.4 mL, 14.88 mmol, 4.0 equiv) in DME (15 mL), and
the mixture was stirred at 80 °C for 2 h. H2O (15 mL) was added and
the mixture was extracted with toluene (15 mL). Activated charcoal
(150 mg) was added to the organic layer, and the mixture was stirred
for 0.5 h. Insoluble materials were filtered off, and the filtrate was
concentrated in vacuo to give the crude ester 4. An analytical sample
of 4 was isolated by column chromatography (silica gel, EtOAc–
hexane).
1H NMR (600 MHz, CDCl3): δ = 1.39 (t, J = 7.0 Hz, 3 H), 4.27 (s, 2 H),
4.40 (q, J = 7.1 Hz, 2 H), 7.10 (dd, J = 8.7 Hz, 1 H), 7.19–7.31 (m, 2 H),
7.38–7.49 (m, 2 H), 7.49–7.58 (m, 3 H), 7.81 (d, J = 7.8 Hz, 1 H), 8.07
(d, J = 8.0 Hz, 1 H), 8.29 (t, J = 1.7 Hz, 1 H).
13C NMR (151 MHz, CDCl3): δ = 14.3, 36.7, 61.2, 110.4 (d, J = 19.6 Hz),
117.6, 123.9 (q, J = 3.8 Hz), 124.1 (q, J = 272.3 Hz), 125.1 (d, J = 7.6 Hz),
125.5 (q, J = 3.8 Hz), 128.9, 129.0, 129.3, 129.3, 129.5, 131.2 (q, J = 32.2
Hz), 131.3, 131.7 (d, J = 3.8 Hz), 132.1, 132.3, 140.0, 140.1, 141.3 (d, J =
6.5 Hz), 144.7, 157.0 (d, J = 251.8 Hz), 166.3.
IR (ATR): 409, 432, 461, 486, 509, 531, 573, 659, 671, 698, 751, 804,
817, 910, 1069, 1111, 1165, 1230, 1257, 1326, 1415, 1471, 1578,
1602, 1620, 1678 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 3.87 (d, J = 4.9 Hz, 2 H), 4.43 (s, 2
H), 7.08 (s, 1 H), 7.34 (t, J = 8.9 Hz, 1 H), 7.39–7.51 (m, 3 H), 7.54–7.71
(m, 4 H), 7.76 (s, 1 H), 7.81 (d, J = 7.2 Hz, 1 H), 7.97 (d, J = 7.2 Hz, 1 H),
8.15 (s, 1 H), 8.83 (s, 1 H).
13C NMR (151 MHz, DMSO-d6): δ = 35.2, 42.5, 110.5 (d, J = 19.1 Hz),
117.2, 123.5 (q, J = 3.8 Hz), 124.2 (q, J = 272.5 Hz), 125.1 (q, J = 3.8 Hz),
125.2, 127.0, 127.0, 128.6 (d, J = 19.6 Hz), 128.9, 129.3 (q, J = 31.6 Hz),
129.7, 130.3, 131.6 (d, J = 3.8 Hz), 132.8, 134.9, 139.0, 140.3 (d, J = 6.5
Hz), 140.9, 145.8, 156.1 (d, J = 250.1 Hz), 166.0, 170.9.
HRMS (ESI): m/z [M + H]+ calcd for C25H19F4N2O2S: 487.1103; found:
487.1094.
Acknowledgment
We thank Dr. David Cork for his help in preparing the manuscript.
3-{4-Fluoro-2-[3-(trifluoromethyl)benzyl]-1-benzothien-7-
yl}benzoic Acid (14)
To a mixture of ester 4 in EtOH (15 mL) was added 2 M aq NaOH (3.7
mL, 7.44 mmol, 2.0 equiv) at r.t. The mixture was stirred at 60 °C for
1.5 h and then 6 M aq HCl (1.3 mL) was added dropwise at 60 °C. Fi-
nally, 6 M aq HCl (0.2 mL) was added at r.t. and the mixture was
stirred for 1 h. The solids were collected by filtration and washed suc-
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378746.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3467–3472

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N. Fukuda, T. Ikemoto
Paper
Synthesis
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Ethyl [(2-Bromo-5-fluorophenyl)sulfanyl]acetate (12)
1H NMR (600 MHz, CDCl3): δ = 1.27 (t, J = 7.2 Hz, 3 H), 3.68 (s, 2
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9.3, 2.8 Hz, 1 H), 7.49 (t, J = 7.5 Hz, 1 H); 13C NMR (151 MHz,
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Ethyl [(4-Bromo-3-fluorophenyl)sulfanyl]acetate (Regioiso-
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3467–3472