A facile route to functionalized cyclopenta[b]thiophenones based on the structure of the selective COX-2 inhibitor Flosulide

Article abstract of DOI:10.1007/PL00013496

The synthesis of three thiophene analogues of Flosulide - a potent and selective inhibitor of cyclooxygenase subtype 2 (COX-2) - is described. Utilizing combined Friedel-Crafts acylation and alkylation of 2-chlorothiophene, simplified procedures were deve

Full text of DOI:10.1007/PL00013496

Monatshefte fuÈr Chemie 129, 887±896 (1998)
A Facile Route to Functionalized
Cyclopenta[b]thiophenones Based on the
Structure of the Selective COX-2 Inhibitor
Flosulide
Ã
Dieter Binder , Michael Pyerin, Roman Steindl, and Martin Weisgram
Institute of Organic Chemistry, Vienna University of Technology, A-1060 Vienna, Austria
Summary. The synthesis of three thiophene analogues of Flosulide ± a potent and selective inhibitor
of cyclooxygenase subtype 2 (COX-2) ± is described. Utilizing combined Friedel-Crafts acylation
and alkylation of 2-chlorothiophene, simpli®ed procedures were developed to obtain cyclopenta[b]-
thiophenones as key products which were further derivatized by nitration, nucleophilic aromatic
substitution, reduction, and mesylation.
Keywords. COX-2 Inhibitor; Cyclopenta[b]thiophene; Aminothiophene.
Ein einfacher Weg zu funktionalisierten Cyclopenta[b]thiophenonen basierend auf der
Struktur des selektiven COX-2-Hemmers Flosulid
Zusammenfassung. Die Synthese dreier Thiophenanaloga von Flosulid ± ein potenter und selektiver
Hemmer der Cyclooxygenase vom Subtyp 2 (COX-2) ± wird beschrieben. Durch Anwendung
kombinierter Friedel-Crafts-Acylierung und -Alkylierung von 2-Chlorthiophen wurden vereinfachte
Verfahren zur Herstellung von Cyclopenta[b]thiophenen als SchluÈsselsubstanzen entwickelt, welche
weiter durch Nitrierung, nucleophile aromatische Substitution, Reduktion und Mesylierung
derivatisiert wurden.
Introduction
Selective COX-2 inhibitors are expected to be potent antiin¯ammatory agents
without ulcerous side effects which are typical for classic nonsteroidal antiin¯am-
matory drugs (NSAIDs) [1, 2]. An important subset of these compounds is
represented by N-arylmethanesulfonamides based on the structures of CPG28237
and CPG28238 (Flosulide) [3].
Whereas substituent positions, sulfonamide acidity, and the 1-oxo group turned
out to be essential [4], the bioisosteric exchange of benzene by thiophene was a
Ã
Corresponding author

888
D. Binder et al.
Fig. 1. Selective COX-2 inhibitors based on N-arylmethanesulfonamides
Fig. 2. Thiophene analogues of Flosulide
hopeful way to improve physiological effects. This method has been demonstrated
in several examples by our group, among them the sedativum Brotizolam (1
Lendormin) [5] derived from valium and the analgesic Tenoxicam (1 Tilcotil) [6]
derived from Piroxicam (1 Felden). From the possible isomers we were especially
interested in the synthesis of compounds 5a±c.
Results and Discussion
Substituents were introduced through o-chloro-nitro-thiophenes by nucleophilic
aromatic substitution with sodium phenolate, reduction of the nitro group, and
mesylation (Scheme 1), similarly demonstrated on the benzene analogue [7].
Scheme 1. Introduction of substituents starting from chlorothiophenes 1

Functionalized Cyclopenta[b]thiophenones
889
Scheme 2. Synthesis of cyclopenta[b]thiophenones by combined Friedel-Crafts acylation and
alkylation
The synthesis of the only known chlorocyclopenta[b]thiophenone 1c involves 5
steps: chloromethylation of 2-chlorothiophene, alkylation with diethyl malonate,
hydrolysis, decarboxylation, and Friedel-Crafts cyclization [8].
As a substantial simpli®cation we developed a method employing combined
Friedel-Crafts acylation and alkylation (Scheme 2). Starting from 2-chlorothio-
phene and acrylic acid, we directly obtained isomer 1c by action of polyphosphoric
acid. These ®ndings contrast with the results from the analogous reaction with
methacrylic acid where the corresponding 6-one-derivative was obtained [9].
Instead we detected the formation of large amounts of ketone 6, obviously formed
by intermolecular acylation of the primary alkylation product with a second
equivalent of 2-chlorothiophene, resulting in a yield of only 9% 1c.
To obtain the vinyl ketone 9 we applied selective acylation with acetic acid
anhydride and o-phosphoric acid to 2-chlorothiophene in position 5 [10] with
subsequent Mannich reaction resulting in the dimethylamine hydrochloride 8 [11]
in good yields. Elimination by steam distillation, however, led to a remarkable
degree of polymerization, yielding only 30 to 59% of vinyl ketone 9. Although the
®nal cyclization could be accomplished by polyphosphoric acid as well as by conc.
sulfuric acid, the overall yield was only about 10%.
To shorten this procedure, we again used combined Friedel-Crafts acylation
and alkylation of 2-chlorothiophene with 3-chloropropanoyl chloride, analogously
demonstrated in synthesis of indanone derivatives [12]. The ®rst step, the acylation,
was selectivity achieved in chloroform with aluminum chloride as catalyst in 80%
yield. Subsequent experiments on cyclization with conc. sulfuric acid pointed out
that application of ketone 10 as its complex with aluminum chloride clearly
increased the reactivity with respect to Friedel-Crafts alkylation: When this
complex was produced from the isolated compound 10 and aluminum chloride
in chloroform, the yield of the annelated product 1a rose from 5±10% to 21%

890
D. Binder et al.
Scheme 3. Attempts for subsequent annelation; Ar ˆ 2,4-F2C6H3
compared to cyclization of the free compound. As a consequence, the crude
complex isolated from Friedel-Crafts acylation of 2-chlorothiophene was cyclized
without preceding aqueous workup. Although the overall yield of 13% was
somewhat lower than from the two-step procedure, this ®nally represents the most
ef®cient way. Isomer 1b was derived by chlorination with chlorine and aluminum
chloride as catalyst in position 3 and selective reduction with zinc in acetic acid in
position 2 in high yields.
Subsequently, we aimed at an improvement of the yield of the annelation step,
this time starting from the already substituted thiophene 5d (Scheme 3). However,
at the stage of the Friedel-Crafts acylation with 3-chloropropanoyl chloride, a
maximum yield of only 38% of 12 was obtained using 1.4 equivalents of aluminum
chloride as catalyst. This was explained by competing reactions at the sulfonamide
nitrogen atom. Nevertheless, subsequent cyclization could neither be achieved with
sulfuric acid or polyphosphoric acid nor on the aluminum chloride complex of
compound 12 with sulfuric acid. Even the alternate way via the unstable vinyl ketone
14 produced by elimination of HCl from 12 with potassium acetate led exclusively
to decomposition upon cyclization with polyphosphoric acid. Similar examples are
known from other 2-acryloylthiophenes [9] and acryloylbenzenes [12].
After nitration of chlorothiophenes 1 by usual methods (Scheme 1), nucleo-
philic aromatic substitution with phenol or di¯uorophenol was carried out with
potassium carbonate in acetone and in dimethylformamide for the less reactive
isomer 2d. Substitution of isomer 2b was only satisfactory when applying 3.2
equivalents di¯uorophenol and 3.0 equivalents potassium carbonate in a 1.4:1
mixture of ether and tetrahydrofuran.
The resulting compounds 3 were reduced by hydrogen/Raney nickel (W2) to
the amines 4 in good yields. Due to the low stability of the non-annelated derivative
4d, the reaction time was considerably reduced by raising the reaction temperature
to 50ꢀC, and the crude amine solution was directly applied for the next step.
Scheme 4. Methanesulfonylation via dimesylation; Ar ˆ 2,4-F2C6H3

Functionalized Cyclopenta[b]thiophenones
891
Amines 4a, 4c, and 4d were mono-mesylated in pyridine with methanesulfonyl
chloride, whereas for amine 4b only application of triethylamine in tetrahydrofuran
or, with an even higher overall yield, dimesylation and subsequent mono-cleavage
with sodium methoxide (Scheme 4) was successful.
Experimental
1
Melting points were measured on a Ko¯er apparatus and are uncorrected. H NMR spectra were
recorded on a Bruker 200 FS NMR spectrometer (200.13 MHz) or on a JOEL FX 90Q NMR
spectrometer (88.55 MHz) in CDCl3 (internal standard: TMS, ꢀ ˆ 0.00 ppm) or DMSO-d6 (2.50 ppm
ref. to internal TMS). Abbreviations: DIPE ˆ diisopropyl ether, MTBE ˆ methyl-t-butyl ether,
Ph ˆ phenyl, Th ˆ thiophene, CT ˆ cyclopenta[b]thiophene. Elemental analyses agreed satisfactorily
with the calculated values.
2-Chloro-4,5-dihydro-6H-cyclopenta[b] thiophen-6-one (1a, C7H5ClOS)
320 g (2.40 mol) AlCl3 were added to a mixture of 190 g (1.60 mol) 2-chlorothiophene and 244 g
(1.92 mol) 3-chloropropanoyl chloride in 1.5 l abs. CHCl3 at 0ꢀC within 1 h and stirred for 2 h at
room temperature. The solvent was distilled off and the residue taken up in 2 l conc. H2SO4 and
heated for 2 h at 90ꢀC. The mixture was poured into 6 l ice water, ®ltered over hy¯o, and extracted
with ether. The organic layers were washed with water, 2 N NaOH, and again water, dried over
Na2SO4, ®ltered, and evaporated. Recrystallization of the crude product from DIPE yielded 34.5 g 1a
(12%) as colourless crystals.
1
M.p.: 78±79ꢀC (ether); H NMR (90 MHz, ꢀ, CDCl3): 6.96 (s, 1H, CT-H3), 3.04±2.98 (m, 2H,
CT-H5), 2.90±2.81 (m, 2H, CT-H4) ppm.
3-Chloro-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one (1b, C7H5ClOS)
A mixture of 64.0 g (310 mmol) 11, 41.6 g (620 mmol) zinc, 67 ml acetic acid, and 222 ml water was
heated at re¯ux for 4 h. The mixture was diluted with 300 ml 2 N HCl, extracted with CH2Cl2, and
the organic layer was washed with sat. NaHCO3 solution and dried over Na2SO4, ®ltered, and
evaporated. Recrystallization of the crude product from DIPE yield 48.9 g 1b (92%) as colourless
crystals.
M.p.: 83±85ꢀC (DIPE); 1H NMR (200 MHz, ꢀ, CDCl3): 7.66 (s, 1H, CT-H2), 3.02±2.91 (m, 4H,
CT-H4,5) ppm.
2-Chloro-5,6-dihydro-4H-cyclopenta[b]thiophen-4-one (1c, C7H5ClOS)
A solution of 20.0 g (169 mmol) 2-chlorothiophene and 14.6 g (203 mmol) acrylic acid in 20 ml
dichloromethane was added to 800 g PPA at 60ꢀC within 2 h and stirred for 1 h. The mixture was
poured into 1 l ice water, diluted with 500 ml ether, ®ltered over hy¯o, and the aqueous layer was
extracted with ether. The combined organic layers were washed with water and sat. NaHCO3
solution, dried over Na2SO4, ®ltered, and evaporated. The residue was distilled at 65±80ꢀC/
0.04 mbar and recrystallised from MTBE, yielding 2.54 g 1c (9%) as colourless crystals.
1
M.p.: 100±101ꢀC (MTBE); H NMR (90 MHz, ꢀ, CDCl3): 7.01 (s, 1H, CT-H3), 3.21±3.11 (m,
2H, CT-H5), 2.93±2.81 (m, 2H, CT-H4) ppm.
2-Chloro-4,5-dihydro-3-nitro-6H-cyclopenta[b]thiophen-6-one (2a, C7H4ClNO3S)
A cold solution of 8.4 g (133 mmol) fuming HNO3 in 150 ml conc. H2SO4 was added to 20.0 g
(116 mmol) 1a in 150 ml conc. H2SO4 at 0ꢀC and stirred for 3 h. The mixture was poured into 1 l ice

892
D. Binder et al.
water, ®ltered, and the residue was triturated with water. Recrystallization from 150 ml ethanol
yielded 20.0 g 2a (80%) as yellow crystals.
M.p.: 127±128ꢀC (ethanol); 1H NMR (90 MHz, ꢀ, CDCl3): 3.43±3.30 (m, 2H, CT-H5), 2.99±2.87
(m, 2H, CT-H4) ppm.
3-Chloro-4,5-dihydro-2-nitro-6H-cyclopenta[b]thiophen-6-one (2b, C7H4ClNO3S)
Applying the same procedure as for 2a and a reaction time of 5 h at ꢁ30ꢀC, 43.0 g (249 mmol) 1b
gave 39.8 g 2b (64%) as yellow crystals.
M.p.: 139ꢀC (ethanol); 1H NMR (200 MHz, ꢀ, CDCl3): 3.10±3.04 (m, 2H, CT-H5), 2.98±2.91 (m,
2H, CT-H4) ppm.
2-Chloro-5,6-dihydro-3-nitro-4H-cyclopenta[b]thiophen-4-one (2c, C7H4ClNO3S)
Applying the same procedure as for 2a and a reaction time of 1 h 2.75 g (16 mmol) 1c gave 3.03 g 2c
(87%) as beige crystals.
M.p.: 125±126ꢀC (ethanol); 1H NMR (90 MHz, ꢀ, CDCl3): 3.28±3.15 (m, 2H, CT-H5), 3.08±2.95
(m, 2H, CT-H6) ppm.
2-(2,4-Di¯uorophenoxy)-4,5-dihydro-3-nitro-6H-cyclopenta[b]thiophen-6-one (3a, C13H7F2NO4S)
To a mixture of 17.8 g (82 mmol) 2a and 22.9 g (176 mmol) 2,4-di¯uorophenol in 700 ml abs.
acetone, 22.6 g (164 mmol) K2CO3 were added at 5ꢀC stirred for 2 h warmed up to 25ꢀC, and stirred
for further 4 h. The mixture was ®ltered over hy¯o, the solvent replaced by dichloromethane, and
washed with 1 N NaOH solution and water. The organic layer was dried over Na2SO4, ®ltered,
evaporated, and the crude product was recrystallized from ethanol yielding 12.8 g 3a (50%) as
colourless crystals.
M.p.: 160±161ꢀC (ethanol); 1H NMR (90 MHz, ꢀ, CDCl3): 7.31±6.99 (m, 3H, Ph-H3,5,6), 3.44±
3.33 (m, 2H, CT-H5), 2.87±2.77 (m, 2H, CT-H4) ppm.
3-(2,4-Di¯uorophenoxy)-4,5-dihydro-2-nitro-6H-cyclopenta[b]thiophen-6-one (3b, C13H7F2NO4S)
A suspension of 11.9 g (54.6 mmol) 2b, 22.7 g (175 mmol) 2,4-di¯uorophenol, and 22.7 g (164 mmol)
dry K2CO3 in 70 ml abs. ether and 50 ml abs. THF was heated at re¯ux for 4 h. The mixture was
®ltered over hy¯o, the ®ltrate evaporated and the residue ®ltered over 100 g silica gel with ethyl
acetate, dried over Na2SO4, ®ltered, and evaporated. The crude product was triturated with 50 ml
ether and recrystallized from ethyl acetate yielding 5.08 g 3b (30%) as yellow crystals.
1
M.p.: 188±189ꢀC (ethyl acetate); H NMR (200 MHz, ꢀ, CDCl3): 7.32±7.19 (m, 1H, Ph-H6),
7.08±6.88 (m, 2H, Ph-H3,5), 2.82±2.74 (m, 2H, CT-H5), 2.50±2.42 (m, 2H, CT-H4) ppm.
5,6-Dihydro-3-nitro-2-phenoxy-4H-cyclopenta[b]thiophen-4-one (3c, C13H9NO4S)
Applying the same procedure as for 3a and a reaction time of 5 h at re¯ux, 2.00 g (9.20 mmol) 2c and
3.00 g (32.2 mmol) phenol gave 1.05 g 3c (42%) as colourless crystals.
1
M.p.: 179±181ꢀC (ethanol); H NMR (90 MHz, ꢀ, CDCl3): 7.47±7.16 (m, 5H, Ph-H2-6), 3.11±
3.04 (m, 2H, CT-H5), 2.95±2.88 (m, 2H, CT-H6) ppm.
3-(2,4-Di¯uorophenoxy)-2-nitro-thiophene (3d, C10H5F2NO3S)
A mixture of 24.8 (152 mmol) 3-chloro-2-nitro-thiophene, 39.0 g (300 mmol) 2,4-di¯uorophenol,
and 45.6 g (330 mmol) K2CO3 in 250 ml abs. DMF was stirred at 100ꢀC for 1 h. The mixture was

Functionalized Cyclopenta[b]thiophenones
893
poured into water, acidi®ed with 2 N HCl to pH ˆ 5, and extracted with CH2Cl2. The combined
organic layers were washed with 2 N NaOH, dried over Na2SO4, ®ltered, evaporated, and the crude
product was recrystallized from CH2Cl2 yielding 35.0 g 3d (90%) as colourless crystals.
M.p.: 105ꢀC (EtOH); 1H NMR (200 MHz, ꢀ, CDCl3): 7.39 (d, 1H, Th-H5, 3JH;H ˆ 6.0 Hz), 7.18±
3
7.28 (m, 1H, Ph-H3), 6.83±7.04 (m, 2H, Ph-H5,6), 6.48 (d, 1H, Th-H4, JH;H ˆ 6.0 Hz) ppm.
3-Amino-2-(2,4-di¯uorophenoxy)-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one
(4a, C13H9F2NO2S)
11.7 g (38 mmol) 3a in 300 ml abs. methanol were hydrogenated with 11 g Raney nickel(W2) at 70
psi in a Parr apparatus. The suspension was ®ltered over hy¯o, and the solvent was distilled off.
Recrystallization of the crude product (9.7 g) from ethyl acetat gave 7.4 g 4a (70%) as pale green
crystals.
1
M.p.: 177±178ꢀC (ethyl acetate); H NMR (90 MHz, ꢀ, CDCl3): 7.26±6.84 (m, 3H, Ph-H3,5,6),
3.51 (br s, 2H, NH2), 2.96±2.85 (m, 4H, CT-H4, 5) ppm.
2-Amino-3-(2,4-di¯uorophenoxy)-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one
(4b, C13H9F2NO2S)
5.00 g (16.1 mmol) 3b in 150 ml methanol were hydrogenated with 5.0 g Raney nickel (W2) at 70 psi
in a Parr apparatus. The suspension was ®ltered over hy¯o, dried over Na2SO4, and the crude
product was puri®ed by chromatography (KG 60, PE:EE ˆ 1:1) yielding 2.91 g 4b (65%) as colour-
less crystals.
1
M.p.: 153±156ꢀC (SC); H NMR (200 MHz, ꢀ, CDCl3): 6.98±6.72 (m, 3H, Ph-H3,5,6), 4.87 (s,
2H, -NH2), 2.78±2.68 (m, 2H, CT-H5), 2.63±2.55 (m, 2H, CT-H4) ppm.
3-Amino-5,6-dihydro-2-phenoxy-4H-cyclopenta[b]thiophen-4-one (4c, C13H11NO2S)
1.00 g (3.60 mmol) 3c in 40 ml abs. methanol were hydrogenated with 1 g Raney nickel (W2) at 70
psi in a Parr apparatus. The suspension was ®ltered over hy¯o, the solvent distilled off, and the crude
product recrystallized from ethanol yielding 0.38 g 4c (43%) as colourless crystals.
1
M.p.: 148±151ꢀC (ethyl acetate); H NMR (90 MHz, ꢀ, CDCl3): 7.34±6.97 (m, 5H, Ph-H2-6),
3.96 (br, s, 2H, NH2), 3.17±3.07 (m, 2H, CT-H5), 2.87±2.76 (m, 2H, CT-H6) ppm.
3-(2,4-Di¯uorophenoxy)-2-thiopheneamine (4d, C10H7F2NOS)
5.00 g (19.4 mmol) 3d in 200 ml methanol were hydrogenated with 5.0 g Raney nickel (W2) at 50ꢀC/
70 psi in a Parr apparatus. The suspension was ®ltered over hy¯o, concentrated to 15 ml, and used
immediately for sulfonylation without further puri®cation.
1H NMR (200 MHz, ꢀ, CDCl3): 6.98±6.69 (m, 5H, Ph-H3,5,6, NH2), 6.56 (d, 1H, Th-H5, 3JH;H
ˆ
3
6.2 Hz), 6.48 (d, 1H, Th-H4, JH;H ˆ 6.2 Hz)
N-(2-(2,4-Di¯uorophenoxy)-5,6-dihydro-6-oxo-4H-cyclopenta[b]thiophen-3-yl)-
methanesulfonamide (5a, C14H11F2NO4S2)
A solution of 7.4 g (26 mmol) 4a in 100 ml abs. pyridine was treated dropwise with 3.9 g (34 mmol)
methanesulfonyl chloride in 10 ml abs. pyridine at ꢁ10ꢀC and stirred for 90 min. The solvent was
distilled off and the residue taken up in water and extracted with ethyl acetate. The organic layer was
washed with 2 N HCl and water, dried over Na2SO4, ®ltered, evaporated, and the crude product was
recrystallized from ethanol yielding 6.0 g 5a (60%) as colourless crystals.

894
D. Binder et al.
1
M.p.: 173±175ꢀC(ethanol); H NMR (90 MHz, ꢀ, CDCl3): 7.32±6.88 (m, 3H, Ph-H3,5,6), 6.33
(s, 1H, NH), 3.20±3.08 (m, 2H, CT-H5), 3.13 (s, 3H, CH3), 2.85±2.73 (m, 2H, CT-H6) ppm.
N-(3-(2,4-Di¯uorophenoxy)-5,6-dihydro-6-oxo-4H-cyclopenta[b]thiophen-2-yl)
methanesulfonamide (5b, C14H11F2NO4S2)
A solution of 550 mg (1.26 mmol) 15 in 6 ml abs. methanol was stirred at 0 ꢀC with 135 mg
(2.52 mmol) sodium methoxide for 20 min. The mixture was poured into 2 N HCl and extracted with
ethyl acetate. The organic layers were dried over Na2SO4, ®ltered, evaporated, and the crude product
was recrystallized from acetonitrile yielding 390 mg 5b (86%) as colourless crystals.
1
M.p.: 160±162ꢀC (acetonitrile); H NMR (200 MHz, ꢀ, DMSO-d6): 7.53±7.40 (m, 1H, Ph-H6),
7.25±7.11 (m, 1H, Ph-H3), 7.10±6.99 (m, 1H, Ph-H5), 3.58±3.27 (br, s, 1H, NH), 3.11 (s, 3H; CH3),
2.75±2.64 (m, 2H, CT-H5), 2.53±2.46 (m, 2H, CT-H4) ppm.
N-(5,6-Dihydro-4-oxo-2-phenoxy-4H-cyclopenta[b]thiophen-3-yl)methanesulfonamide
(5c, C14H13NO4S2)
Applying the same procedure as for 5a using 200 mg (0.80 mmol) 4c and a reaction time of 10 min at
0ꢀC gave 200 mg 5c (77%) as colourless crystals.
M.p.: 170±171ꢀC (ethanol); 1H NMR (90 MHz, ꢀ, CDCl3): 7.49±7.06 (m, 5H, Ph-H2-6), 6.52 (br
s, 1H, NH), 3.23 (s, 3H, CH3), 3.23±3.09 (m, 2H, CT-H5), 2.92±2.79 (m, 2H, CT-H4) ppm.
N-(3-(2,4-Di¯uorophenoxy)-2-thienyl)methansulfonamide (5d, C11H9F2NO3S2)
Applying the same procedure as for 5a using the crude solution of amine 4d and a reaction time of
90 min at ꢁ40ꢀC gave 5d (33% overall yield 3d!5d) as colourless crystals.
1
3
M.p.: 68ꢀC (DIPE); H NMR (200 MHz, ꢀ, CDCl3): 7.07 (d, 1H, Th-H5, JH;H ˆ 6.7 Hz), 7.03±
3
6.78 (m, 3H, Ph-H3,5,6), 6.56 (d, 1H,Th-H4, JH;H ˆ 6.7 Hz), 6.43 (s, 1H, NH), 3.12 (s, 3H,
CH3) ppm.
1,3-(Bis-(5-chloro-2-thienyl))-propan-1-one (6, C11H8Cl2OS2)
A solution of 5.00 g (42 mmol) 2-chlorothiophene and 3.65 g (50 mmol) acrylic acid in 5 ml abs.
CH2Cl2 was slowly dropped on 210 g polyphosphoric acid with stirring. The mixture was hydrolyzed
with 100 ml ice water, extracted with ether, and the combined organic layers were washed with sat.
NaHCO3 solution, dried over Na2SO4, ®ltered, and evaporated. The crude product was puri®ed by
chromatography (silica gel KG 60, PE:EE ˆ 7:1) yielding 1.35 g 6 (22%) as colourless crystals.
1
3
M.p.: 55±56ꢀC; H NMR (90 MHz, ꢀ, CDCl3): 7.47 (d, 1H, ThA-H3, JH;H ˆ 3.9 Hz), 6.94 (d,
3
3
1H, ThA-H4, JH;H ˆ 3.9 Hz), 6.69 (d, 1H, ThB-H3, JH;H ˆ 3.9 Hz), 6.59 (d, 1H, ThB-H4,
3JH;H ˆ 4.1 Hz), 3.15 (s, 4H, -CH2-CH2-) ppm.
1-(5-Chloro-2-thienyl)-propen-1-one (9, C7H5ClOS)
A mixture of 4.00 g (15.7 mmol) 1-(5-chloro-2-thienyl)-3-dimethylaminopropan-1-one hydrochlor-
ide [11] and 20 ml water was steam distilled, the product extracted with ethyl acetate, dried over
Na2SO4, and the solvent was distilled off yielding 1.6 g 9 (59%) as an oil.
1
3
20
nD ˆ 1.6255; H NMR (200 MHz, ꢀ, CDCl3): 7.55 (d, 1H, Th-H3, JH;H ˆ 4.1 Hz), 6.98 (d, 1H,
3
Th-H4, JH;H ˆ 4.1 Hz), A2B-System CH=CH2: 7.00, 6.47, 5.89 (2Jgem ˆ 17 Hz, Jtrans ˆ 10 Hz,
3Jcis ˆ 2 Hz); C7H5ClOS Á 0.25 H2O (177.13); calcd.: C 47.5, H 3.1; found: C 47.5, H 3.1.
3

Functionalized Cyclopenta[b]thiophenones
895
3-Chloro-1-(5-chloro-2-thienyl)propan-1-one (10, C7H6Cl2OS)
33.7 g (253 mmol) AlCl3 were added to a solution of 20.0 g (169 mmol) 2-chlorothiophene and 25.7 g
(202 mmol) 3-chloropropanoyl chloride in 200 ml abs. chloroform at 10 ꢀC in small portions, stirred
for 1 h and, after raising the temperature to 25ꢀC, for 4 h. The mixture was poured into 300 ml ice
water containing 5 ml conc. HCl, stirred for 15 min, and extracted with CH2Cl2. The organic layers
were washed with water, dried over Na2SO4, ®ltered, evaporated, and the crude product was
recrystallized from methanol yielding 28.4 g 10 (80%) as colourless crystals.
1
3
M.p.: 22±24ꢀC (methanol); H NMR (90 MHz, ꢀ, CDCl3): 7.52 (d, 1H, Th-H3, JH;H ˆ 4.1 Hz),
3
3
6.98 (d, 1H, Th-H4, JH;H ˆ 4.1 Hz), 3.88 (t, 2H, Cl-CH2, JH;H ˆ 7.1 Hz), 3.33 (d, 2H, CO-CH2,
3JH;H ˆ 7.1 Hz) ppm.
2,3-Dichloro-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one (11, C7H4Cl2OS)
To a suspension of 101 g (760 mmol) AlCl3 in 150 ml abs. CHCl3, a solution of 61.0 g (350 mmol) 1a
in 150 ml abs. CHCl3 was slowly added at 0ꢀC, followed by 32.3 g (0.46 mmol) Cl2 in 290 g abs.
CHCl3, and stirred for 1 h at 0ꢀC and for 2 h at room temperature. The mixture was poured on ice
water, the organic layer washed with 2 N HCl and the aqueous solutions were extracted with CHCl3.
The combined organic layers were dried over Na2SO4, ®ltered, evaporated, and the crude product
was recrystallized from DIPE yielding 64.3 g 11 (88%) as pale yellow crystals.
M.p.: 60±61ꢀC (DIPE); 1H NMR (200 MHz, ꢀ, CDCl3) 3.02±2.96 (m, 2H, CT-H5), 2.92±2.86 (m,
2H, CT-H4) ppm.
N-(5-(3-Chloro-1-oxo-propyl)-3-(2,4-di¯uorophenoxy)-2-thienyl)methanesulfonamide
(12, C14H12ClF2NO4S2)
To a suspension of 720 mg (5.39 mmol) AlCl3 in 8 ml abs. CHCl3 at 0ꢀC, 520 mg (4.13 mmol) 3-
chloropropanoyl chlorid were slowly added, followed by 1.20 g (3.93 mmol) 5d in 8 ml abs. CHCl3,
and stirred for 2 h at 60ꢀC. The mixture was poured into 2 N HCl, extracted with ethyl acetate, the
organic layer washed with 2 N HCl, dried over Na2SO4, ®ltered, evaporated, and the crude product
was puri®ed by chromatography (100 g silica gel KG 60, CH2Cl2: EE ˆ 10:1) and subsequent
recrystallization from MTBE yielding 580 mg 12 (37%) as colourless crystals.
1
M.p.: 115±117ꢀC (MTBE); H NMR (200 MHz, ꢀ, CDCl3): 7.16 (s, 1H, Th-H4), 7.11±6.82 (m,
3
3
4H, Ph-H3,5,6, NH), 3.83 (t, 2H, CH2-Cl, JH;CH ˆ 6.8 Hz), 3.21 (t, 2H, CH2-C=O, JH;CH
ˆ
2
2
6.8 Hz, 3.14 (s, 3H, CH3) ppm.
N-(3-(2,4-Di¯uorophenoxy)-5,6-dihydro-6-oxo-4H-cyclopenta[b]thiophene-2-yl)-N-
(methylsulfonyl)methanesulfonamide (15, C15H13F2NO6S3)
A solution of 500 mg (1.78 mmol) amine 5b and 360 mg (3.56 mmol) triethylamine in 5 ml abs. THF
was treated with 410 mg (3.56 mmol) methanesulfonyl chloride at ꢁ30ꢀC and stirred for 2 h. The
mixture was poured into 2 N HCl, extracted with ethyl acetate, the organic layer washed with sat.
NaHCO3 solution, dried over Na2SO4, ®ltered, evaporated, and the crude product was recrystallised
from acetonitrile yielding 590 mg 15 (72%) as colourless crystals.
M.p.: 178ꢀC (acetonitrile); 1H NMR (200 MHz, ꢀ, CDCl3): 7.30±7.17 (m, 1H, Ph-H3), 7.04±6.80
(m, 2H, Ph-H5, 6), 3.49 (s, 6H, CH3), 2.75±2.66 (m, 2H, CT-H5), 2.47±2.39 (m, 2H, CT-H4) ppm.
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È
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Received February 23, 1998. Accepted (revised) May 14, 1998