Solvent-free microwave synthesis of 3-(4-benzo[b]-thiophene-2-carbonyl)-1-piperazinyl-1-benzo[b]thiophen-2-YL-1-propanones. New hetero bis-ligands with potential 5-HT1A serotonergic activity

Article abstract of DOI:10.3987/COM-08-11326

A novel series of 2-benzothiophenealkylpiperazine derivatives 11 (a-d) with potential affinity at 5-HT_1A serotonin receptors have been synthesized via solvent-free, microwave-promoted Michael addition of benzo[b]thiophene piperazine derivatives 6(a-c) to substituted benzo[b]thiophen-2-yl propenones 10(b,c).

Full text of DOI:10.3987/COM-08-11326

HETEROCYCLES, Vol. 75, No. 8, 2008, pp. 1913 - 1929. © The Japan Institute of Heterocyclic Chemistry
Received, 5th January, 2008, Accepted, 27th March, 2008, Published online, 1st April, 2008. COM-08-11326
SOLVENT-FREE MICROWAVE SYNTHESIS OF 3-(4-BENZO[b]-
THIOPHENE-2-CARBONYL)-1-PIPERAZINYL-1-BENZO[b]THIOPHEN-
2-YL-1-PROPANONES.
NEW
HETERO
BIS-LIGANDS
WITH
POTENTIAL 5-HT1A SEROTONERGIC ACTIVITY
Hernán Pessoa-Mahana,1* Johann Kosche C.,1 Nadia Ron H.,1 Gonzalo
Recabarren-Gajardo,1 Claudio Saitz B.,1 Ramiro Araya- Maturana,1 and C.
David Pessoa-Mahana2
1
Department of Organic and Physical Chemistry, Faculty of Chemical and
Pharmaceuthical Sciences, University of Chile, Casilla 233, Santiago 1, Chile
Corresponding author: e-mail: hpessoa@ciq.uchile.cl
2 Department of Pharmacy, Faculty of Chemistry, Pontificia Universidad Católica
de Chile, Casilla 306, Santiago 22, Chile
Abstract – A novel series of 2-benzothiophenealkylpiperazine derivatives 11(a-d)
with potential affinity at 5-HT1A serotonin receptors have been synthesized via
solvent-free, microwave-promoted Michael addition of benzo[b]thiophene
piperazine derivatives 6(a-c) to substituted benzo[b]thiophen-2-yl propenones
10(b,c).
INTRODUCTION
Serotonin (5-hydroxytryptamine, 5-HT) represents a major target for neurobiological research because of
its involvement in numerous (phato) physiological processes.1,2 The development of drugs that alter 5-HT
neurotransmission is thus an area of intense research because of the potential to find new therapeutic agents.
During last 18 years, seven distinct families of 5-HT receptors (5-HTRs) have been identified
(5-HT1-5-HT7) and at least 15 subpopulations have been described. Among 5-HTRs, the 5-HT1A is
involved in psychiatric disorders such as depression anxiety and memory loss.3 A large number of agonist
and antagonist for 5-HT1A receptors are reported in the literature among these, the long chain
arylpiperazine derivatives represent one of the most important classes of 5-HT1ARs ligands.4-6
In view of the high prevalence of major depression (second leading cause of disease by 2020), and the

inadequacies of current medication (low selectivity with undesirable side effects), there remains an urgent
need to discover novel antidepressants with improved pharmacological profiles. Although most of the
conventional methods are useful for the synthetic goals, the microwave irradiation has been used to
improve many organic syntheses as an efficient and environmentally friendly technique.7-9
Microwave-assisted reactions have become increasingly important in chemical synthesis in the last 20
years due to the advantages they provide over conventional heating methods. Significant reduction in
reaction times, side reactions, increased yields, ease of purification, and minimization of the amount of
solvent used are only a few of these desirable qualities.10-13 Shorter reaction times (usually <15 min)
allow rapid investigation into new methodologies and reaction optimisation. Microwave-assisted reactions
are believed to facilitate polarization of the substrates thereby promoting the reactions.14
Given our interest in the synthesis of bioactive heterocycles at 5-HT1A serotonin receptor, the present study
describes the synthesis of new 3-[4-(benzo[b]thiophene-2-carbonyl)piperazin-1-yl]-1-benzo[b]thiophen-
2-yl-propan-1-one derivatives 11(a-d), by heating functionalised benzothiophene piperazines 6(a-c) and
benzo[b]thiophen-2-yl propenones 10(b,c) under solvent free microwave irradiation. (Figure 1).
O
O
N
N
R1
R2
S
S
Figure 1
11(a): R1 = 5-NO2; R2 = 4’,7’-OMe; 11(b): R1 = 4,7-OMe; R2= 4’,7’-OMe; 11(c): R1 = H; R2= 4’,7’-OMe;
11(d): R1 = 5-NO2; R2= H
RESULTS AND DISCUSSION
As shown in Scheme 1, compounds 11(a-d) were prepared according the retrosynthetic strategy based on
a Michael reaction disconnecting the target molecules in the benzothiophenamides 6(a-c) and the
benzothiophen propenone derivatives 10(b,c).
O
O
O
O
N
N
R1
N
N H
+
R1
R2
R2
S
S
S
S
11(a-d)
6 (a-c)
10 (b-c)
Scheme 1

The required units 6(a-c) and 10 (b-c) were prepared according the synthetic sequences showed in Schemes
2 and 3. The preparation of benzothiophen amide derivatives 6 (a-c) was carried out as follows (Scheme 2).
Treatment of the starting benzaldehydes 1(a-c) with methyl thioglycolate in basic medium at 65-70 °C
provided the corresponding benzo[b]thiophene esters 2(a-c)15,16 in (67%, 70% and 67%) respectively. The
esters were purified and subsequently hydrolyzed at room temperature in a methanolic potassium
hydroxide solution to afford the carboxylic acid derivatives 3(a-c) in good yield: 100% 3(a), 65% 3(b) and
82% 3(c). The aroyl chlorides 4(a-c) were obtained by reaction of the carboxylic acid derivatives 3(a-c)
with thionyl chloride under reflux conditions, and subsequently treated with N-Boc-piperazine under inert
atmosphere to afford the benzothiophene carboxamide derivatives 5(a-c) in good yields 75% 5(a), 83%
5(b) and 73% 5(c). Finally the N-Boc removal was carried out under hydrochloric acidic medium17 to
provide the 1-(1-benzothien-2-ylcarbonyl)piperazines 6(a-c) with yields over 70%.
R1
R1
R2
R2
CHO
R4
a
CO2Me
S
R3
R3
R1
2(a-c)
1(a-c)
b
R1
c
R2
R2
COCl
4(a-c)
CO2H
S
S
d
R3
R3 3(a-c)
R1
R1
O
O
R2
e
R2
N
NH
N
N CO2Bu-t
S
S
5(a-c)
6(a-c)
R3
R3
(a): R1=H; R2=NO2 ; R3=H
(b): R1=OMe; R2=H ; R3=OMe
(c): R1=R2=R3=H
(a): R1=H; R2=NO2 ; R3=H; R4=Cl
1 (b): R1=OMe; R2=H ; R3=OMe; R4=NO2
(c): R1=R2=R3=H ; R4=NO2
2-6
Scheme 2
Reagents and conditions : a) Methyl thioglycolate/K2CO3/DMF, 65-70 °C, 4 h; b) KOH-MeOH, 3 h,
rt, H3O+; c) SOCl2-reflux 3 h; d) N-Boc-piperazine, dry pyridine/anhydrous THF/N2 atmosphere;
e) HCl (concd.)/THF/EtOH, 24 h, rt
Once synthesized the corresponding donor Michael derivatives, our second objective was to prepare the
1-(1-benzothien-2-yl)-2-propenones 10(b-c) (Scheme 3). The esters 2(b,c) were reduced with LiAlH4 to

afford the alcohols 7(b,c) with yields of 65% and 67%. The obtained compounds showed disappearance
of the carbonylic signals in the IR at 1702 and 1725 cm-1, the 1H NMR showed a singulet at δ: 4.87 and a
doublet at δ: 4.92 ppm for the methylenic protons. Subsequent oxidation to the benzothiophene aldehydes
8(b,c) was carried out using pyridinium chlorochromate (PCC) in 92% and 87% yields respectively.
R1
R1
a
CH2OH
CO2Me
S
S
R2
R1
R2
R1
2(b,c)
b
c
7(b,c)
OH
CHO
S
S
R2
d
R2
8(b,c)
9(b,c)
R1
O
S
10(b,c)
R2
b: R1=OMe;R2= OMe
c: R1=H; R2= H.
Scheme 3
Reagents and conditions: a) LiAlH4-anhydrous THF/N2 atmosphere, 50 °C, 3 h; b) PCC/dry CH2Cl2, 3 h;
c) vinylmagnesium bromide, THF, microwave/600W, 4 min; d) MnO2-CH2Cl2, 4 h, 25 °C.
The IR of compounds 8(b,c) exhibited the characteristic carbonylic absorption at 1667 (b) and 1673 (c)
cm-1 and their 1H NMR spectrum showed the expected singlets at downfield δ: 9.98 ppm 8(b) and δ: 9.92
ppm 8(c).
The Grignard reaction of vinylmagnesium bromide on aldehydes 8(b,c) was not successful under
conventional heating, probably due to the low reactivity of the formyl group, bonded to the large aromatic
character of the π-donor benzothiophene moiety. To overcome this problem we decided to carry out the
assay in a microwave-assisted organic synthesizer. The absorption of microwave energy by the polar
reactants, generated enough heat energy to promote the reaction. In general 600 W, 4 min of microwave
irradiation was enough to complete the reaction between aldehydes 8(b,c) and vinyl magnesium bromide.
The obtained alcohols 9(b,c) were purified by column chromatography and subsequently oxidized with
MnO2 to the corresponding 2-propenones 10(b,c) in (58% and 62%) respectively. It should be noted that

an oxidation assay of 9(b,c) with pyridinium chlorochromate (PCC) provided a complex mixture of
products which were not purified.
The crude enones 10(b,c) were purified by column chromatography (CH2Cl2) to afford pure ketones
10(b,c), which displayed typical unsaturated carbonylic signals in the IR at 1665 and 1661 cm-1. In the 1H
NMR spectra we observed the disappearance of signals at δ: 5.45 and δ: 5.46 ppm (methyne protons) and
the appearance of signals in 13C NMR at δ: 184.0 10(b) and 183.9 ppm 10(c).
Finally, a Michael addition assisted by solvent free microwave irradiation,18-20 between piperazine
derivatives 6(a-c) and 1-(1-benzothien-2-yl)-2-propenones 10(b,c) conducted to give the expected
2-benzothiophenealkylpiperazine derivatives 11(a-d) in good yield, 11(a): 73%; 11(b): 65%; 11(c):
75%; and 11(d): 75%. (Scheme 4).
R4
R1
R1
R4
O
O
O
R2
O
R2
a
+
N
NH
N
N
S
S
S
S
R5
R3
6(a-c)
R5
10 (b,c)
R3
11 (a-d)
Scheme 4
11 (a): R1=H; R2=NO2; R3=H; R4=OMe; R5=OMe
11 (b): R1=OMe; R2=H; R3=OMe; R4=OMe; R5=OMe
11 (c): R1=R2=R3= H; R4=OMe; R5=OMe
11 (d): R1=H; R2=NO2; R3=H; R4=H; R5=H
Reagents and conditions: a) microwave irradiation at 600 W for 4 min in an inorganic support of
MnO2/SiO2 (4:1).
1
Formation of series 11(a-d) was mainly supported in H NMR by the presence of two triplets at δ: 2.93
and 3.22 ppm 11(a), δ: 2.93 and 3.24 ppm 11(b), δ: 2.93 and 3.23 ppm 11(c) and δ: 2.96 and 3.24 ppm
11(d), the expected two carbonylic absorptions in the IR: 11(a): 1676(C=O) - 1623(CON) cm-1; 11(b):
1660(C=O) -1620(CON) cm-1; 11(c): 1673(C=O) -1612(CON) cm-1; and 11(d): 1660(C=O) -1612 (CON)
cm.-1 Finally the M+ peaks obtained with HRMS confirmed the proposed structures.
In conclusion we have synthesized new piperazinobenzothiophene derivatives 11(a-d) in good yield using
microwave-assisted Michael addition, to develop potential bioactives ligands in 5-HT1A receptors.
Biological screening is currently under study.
EXPERIMENTAL
Melting points were determined on a hot-stage apparatus and are uncorrected. The IR spectra were

recorded on a FT-IR Bruker IFS 55 spectrophotometer for KBr disc and wave numbers are reported in
1
13
cm-1. The H NMR and C NMR spectra were performed on a Bruker DRX-300 spectrometer (300 and
75 MHz) in deuterochloroform, or DMSO-d6. Chemical shifts were recorded in ppm (δ) relative to TMS
as an internal standard. J values are given in Hz. Microanalyses were carried out on a Fisons EA 1108
analizer. High resolution mass spectrum were recorded on a Thermo Finnigan model MAT 95XP Mass
spectrometer. The microwave-assisted procedures were carried out in a Milestone Mega 240 microwave
oven operating at 600 watts. Manganese (IV) dioxide was prepared by our reported procedure.20 The solid
support was preparing by heating a 4:1 mixture of silica gel (70-230 mesh) and manganese (IV) dioxide at
300 ºC for 2h. Silica gel Merck 60 (70-230 mesh) and DC-alufolien 60 F254 were used for column and
TLC chromatography respectively.
Synthesis of 1-[(5-Nitro-1-benzo[b]thien-2-yl)carbonyl]piperazine 6(a).
5-Nitrobenzo[b]thiophene-2-carboxylic acid methyl ester 2(a).
To a mixture of 2-chloro-5-nitrobenzaldehyde 1(a) (700 mg, 3.8 mmol), and anhydrous K2CO3 (507 mg,
3.8 mmol) in dry DMF (10 mL) was added methyl thioglycolate (0.34 mL, 3.8 mmol) and heated at 70 ºC
for 4 h. The reaction mixture was poured into an ice-water solution and the precipitate was filtered to
provide crude 2(a) (670mg). The crude product was purified by column chromatography (CH2Cl2) to
provide pure ester 2 (a) (603 mg, 67%). mp 199-200 ºC. IR νmax: 1703 (CO2Me), 1529 (NO2), 1346 (NO2).
1H NMR (300 MHz, CDCl3) δ: 3.99 (s, 3H, CO2Me), 8.00 (d, 1H, 7-H, J = 9.0 Hz), 8.19 (s, 1H, 3-H),
8.31 (dd, 1H, 6-H, Jo = 9.0 Hz, Jm = 2.2 Hz), 8.78 (d, 1H, 4-H, Jm =2.1 Hz). 13C NMR (75 MHz, CDCl3):
53.0, 121.0, 121.2, 123.6, 130.7, 137.2, 138.3, 145.9, 147.4, 162.3. HRMS (EI) Calcd for C10H7NO4S
(M+): 237.00958. Found: 237.00841.
5-Nitrobenzo[b]thiophene-2-carboxylic acid 3(a).
A solution of the 5-nitromethyl ester 2(a) (800 mg, 3.38 mmol) in KOH (0.5 N): EtOH (1:1 v/v, 80 mL)
was stirred at rt for 3 h. The mixture was then concentrated in vacuo and acidified with concd. HCl at
0 °C. The solution was extracted with EtOAc (3 x 50 mL) and the organic layers dried over anhydrous
MgSO4. Concentration of the solvent in vacuo afforded a residue (quantitative) which was purified by
silica gel column chromatography (CH2Cl2/MeOH 1:1) to give the benzothiophene carboxylic acid 3(a)
as a yellow pale solid (750 mg, 100%). mp 211-213 °C. IR νmax: 3610-3300 (O-H), 1695 (CO), 1536
1
(NO2), 1350 (NO2). H NMR (300 MHz, DMSO-d6) δ: 4.98(bs, 1H, CO2H), 8.23 (m, 3H, 4-H, 6-H and
7-H), 8.92 (s, 1H, 3-H). 13C NMR (75 MHz, DMSO-d6): 121.0, 121.9, 124.9, 131.3, 138.9, 139.1, 145.8,
147.5, 163.4. HRMS (EI) Calcd for C9H5NO4S (M+): 222.99393. Found: 222.99474.
5-Nitrobenzo[b]thiophene-2-carbonyl chloride 4(a).

A solution of carboxylic acid 3(a) (600 mg, 2.69 mmol) in thionyl chloride (50 mL) was heated under
reflux for 4 h. Once the reaction proceeded the excess of the thionyl chloride was removed under reduced
pressure, to give 4(a) as an unstable pale yellow solid, which was immediately reacted. mp 159-160 °C.
IR: 1768 (COCl), 1525 (NO2), 1392 (NO2). HRMS (EI) Calcd for C9H4ClNO3S (M+): 240.96004. Found:
240.96102.
4-(5-Nitrobenzo[b]thiophene-2-carbonyl)-1-piperazine-1-carboxylic acid tert-butyl ester 5(a).
Aroyl chloride 4(a) (649 mg, 2.69 mmol) in dry THF (25 mL) was slowly added to a stirred solution at
0 °C of piperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.69 mmol), dry triethylamine (292 mg,
2.89 mmol) in dry THF (25 mL) under nitrogen atmosphere. The mixture was maintained with stirring for
6 h at room temperature and then diluted with water (100 mL). The solution was extracted with EtOAc
(3 x 50 mL) and the organic layers dried over MgSO4. Concentration of the solvent in vacuo afforded a
residue (quantitative yield), which was purified by recristallization (EtOH) to give pure benzothiophene
piperazine carbamate 5(a) (748 mg, 71%). mp 170-171 °C. IR νmax: 1704 (NCO2-tert-Bu), 1612 (NC=O),
1
1532 (NO2), 1347(NO2). H NMR (300 MHz, DMSO-d6) δ: 1.41 (s,9H,(Me)3-), 3.44 (bs, 4H, 2’-H and
6’-H), 3.33 (bs, 4H, 3’-H and 5’-H), 7.98 (s, 1H, 3-H), 8.23 (bd, 1H, 6-H, J = 9.0 Hz), 8.30 (d, 1H, 7-H, J
= 9.0 Hz), 8.84 (s, 1H, 4-H). 13C NMR (75 MHz, DMSO-d6): δ 27.0 (3C), 42.0 (2C), 46.2 (2C), 78.2,
118.7, 119.5, 122.9, 125.3, 137.5, 139.3, 144.2, 144.3, 152.7, 160.8. HRMS (EI) Calcd for C18H21N3O5S
(M+): 391.12019. Found: 391.12002.
1-[(5-Nitro-1-benzo[b]thien-2-yl)carbonyl]piperazine 6(a).
To a solution of carbamate 5(a) (536 mg, 1.37 mmol) in THF-EtOH (1:1, 40 ml), was added HCl (concd.)
(37% w/v, 6 mL, 72 mmol) and the mixture stirred at rt during 12 h. After this time the solution was
basified (NH4OH) to pH 9.0 and extracted with EtOAc (3 x 50 mL), the organic layers dried over
anhydrous MgSO4. Concentration of the solvent in vacuo provided a crude residue (387 mg), which was
purified by silica gel column chromatography (CH2Cl2-MeOH = 1:1) to give 1-[(5-nitro-1- benzo[b]thien-
2-yl)carbonyl]piperazine 6(a) (331 mg, 83%). mp 172-173 ºC. IR νmax: 3300 (N-H), 1626 (NC=O), 1531
(NO2), 1344 (NO2). 1H NMR (300 MHz, DMSO-d6) δ: 2.74 (bs, 4H, 3’-H and 5’-H), 3.31 (bs., 1H, NH),
3.59 (bs, 4H, 2’-H and 6’-H), 7.96 (s, 1H, 3-H), 8.23 (bd, 1H, 6-H, J = 9.0 Hz), 8.31 (d, 1H, 7-H, J = 9.0
Hz), 8.86 (s,1H, 4-H). 13C NMR (75 MHz, DMSO-d6): δ 44.8 (2C), 53.5 (2C), 118.6, 119.5, 122.9, 124.8,
137.6, 139.7, 144.1, 144.2, 160.4. HRMS (EI) Calcd for C13H13N3O3S (M+): 291.06776. Found: 291,
06699.
Synthesis of 1-[(4,7-dimethoxy-1-benzo[b]thien-2-yl)carbonyl]piperazine 6(b).
4,7-Dimethoxy-2-methoxycarbonylbenzo[b]thiophene 2(b).15

To a solution of dimethoxy nitrobenzaldehyde 1(b) (552 mg, 2.61 mmol) in DMF (10 mL) was added
anhydrous K2CO3 (436 mg, 2.61 mmol) and methyl thioglycolate (0.3 mL, 2.61 mmol). The suspension
was stirred at 70 °C during 4 h and then poured onto crushed ice and vigorously stirred for 15 min. The
resultant precipitate was filtered and washed with water (3 x 25 mL) to afford crude benzothiophene ester
as a pale yellow solid (562 mg), which was purified by column chromatography (CH2Cl2) to afford pure
benzothiophene ester 2(b) (462 mg, 70 %) mp 124-125 ºC. Anal. Calcd for C12H12O4S: C, 57.13; H, 4.80;
1
S, 12.69. Found: C, 56.78; H, 4.90; S, 12.52 %. IR νmax: 3010 (C-H, Ar), 1702 (C=O), 1260 (C-O). H
NMR (300 MHz, CDCl3) δ: 3.91 (s, 3H, OMe), 3.93 (s, 3H, Ar- OMe), 3.94 (s, 3H, Ar- OMe), 6.66 (d,
1H, 5-H, J = 8.5 Hz), 6.76 (d, 1H, 6-H, J = 8.5 Hz), 8.20 (s, 1H, 3-H). 13C- NMR (75 MHz, CDCl3): 52.4,
55.8, 56.0, 104.6, 106.8, 128.0, 131.1, 132.4, 132.9, 148.4, 150.5, 163.2.
4,7-Dimethoxybenzo[b]thiophene-2-carboxylic acid 3(b).
A solution of the methyl ester 2(b) (562 mg, 2.23 mmol) in KOH 0.5 N: EtOH (1:1 v/v, 60 mL) was
stirred at room temperature for 3 h. The mixture was then concentrated in vacuo and acidified with HCl
(concd.) at 0 °C. The resulting precipitate was filtered, washed with small amount of cold water and dried
to provide a pure yellow pale solid 3(b) (345 mg, 65%). mp 129-130 ºC. Anal.Calcd for C11H10O4S: C,
55.45; H, 4.23; S, 13.46. Found: C, 55.45 ; H, 4.50; S, 13.21 %. IR νmax: 3650-2800 (O-H), 1670 (C=O),
1529(ArC=C). 1H NMR (300 MHz, CDCl3) δ: 3.91 (s, 3H, OMe), 3.94 (s, 3H, OMe), 6.86 (d, 1H, 5-H, J
13
= 8.5 Hz), 6.95 (d, 1H, 6-H, J = 8.5 Hz), 8.24 (s, 1H, 3-H), 12.7 (s, 1H, CO2H). C NMR (75 MHz,
CDCl3): 56.2, 56.4, 105.9, 107.3, 122.6, 130.7, 131.4, 135.4, 148.3, 150.0, 171.6.
4,7-Dimethoxy-1-benzo[b]thiophene-2-carbonyl chloride 4(b).
A solution of carboxylic acid 3(b) (1.30 g, 5.50 mmol) in thionyl chloride (50 mL) was heated under
reflux for 4 h. Once the reaction proceeded the excess of the thionyl chloride was removed under reduced
pressure, to give the crude acyl halide 4(b) as a yellow solid. The crude residue was immediately
chromatographed on silica gel column (CH2Cl2) to give pure compound 4(b) (1.30 g, 92%) yield. mp
84-85 ºC. Anal. Calcd for C11H9ClO3S: C, 51.47; H, 3.53; S, 12.49. Found: C, 50.54; H, 3.64; S, 12.45 %.
IR νmax: 1730 (ArCOCl), 1600 (Ar C=C). 1H NMR (300 MHz, CDCl3) δ: 3.93 (s, 3H, OMe), 3.95 (s, 3H,
OMe), 6.68 (d, 1H, 5-H, J = 8.5 Hz), 6.84 (d, 1H, 6-H, J = 8.5 Hz), 8.38 (s, 1H, 3-H). 13C NMR (75 MHz,
CDCl3): 55.8, 56.1, 104.9, 108.6, 130.6, 133.5, 134.8, 135.5, 148.0, 151.1, 161.1.
1-[(4,7-Dimethoxy-1-benzo[b]thiophene-2-carbonyl)-1-piperazine-1-carboxylic acid tert-butyl ester
5(b).
To a solution of aroyl halide 4(b) (1.07 g, 4.17 mmol) in anhydrous THF (60 mL) was added
piperazine-1-carboxylic acid tert-butyl ester (778 mg, 4.17 mmol) and dry pyridine (330 mg, 4.17 mmol)

under nitrogen atmosphere. The mixture was stirred for 4 h, then diluted with water (50 mL) and
extracted with EtOAc (3 x 50 mL), the organic layers were dried over MgSO4 and concentrated in vacuo
to afford crude amide 5(b) (1.54 g, 91%) which was purified by silica gel column chromatography
1
(CH2Cl2/EtOAc 3:1) (1.41 g, 83%). mp 100-101 °C. IR: 1694 (NCO2), 1630(CON), 1484 (ArC=C). H
-NMR (300 MHz, CDCl3) δ: 1.35 (s, 9H, tert-butyl), 3.39 (bs, 4H, Piper. 3”-H and 5”-H ), 3.61 (bs, 4H,
Piper. 2”-H and 6”-H), 3.74 (s, 3H, C-4 or C-7, OMe), 3.77 (s, 3H, C-7 or C-4, OMe), 6.50 (d, 1H, 5-H, J
= 8.5 Hz), 6.56 (d, 1H, 6-H, J = 8.5 Hz), 7.49 (s, 1H, 3-H). 13C NMR (75 MHz, CDCl3): 28.5 (3C), 43.9
(2C), 45.2 (2C) 55.8, 56.0, 80.3, 105.0, 106, 123.0, 130.8, 130.9, 135.7, 148.5, 150.0, 154.6, 164.1.
HRMS (EI) Calcd for C20H26N2O5S, (M+): 406.15624. Found: 406.15643.
1-[(4,7-Dimethoxy- 1-benzo[b]thien-2-yl)carbonyl]piperazine 6(b).
To a solution of carbamate 5(b) (1.37 g, 3.37 mmol) in THF-EtOH (1:1, 50 ml), was added HCl (concd.)
(37% w/v. 6 ml, 72 mmol) and the mixture stirred at rt during 20 h. After this time the solution was
basified (NH4OH) to pH 9.0 and extracted with EtOAc (3 x 50 mL), the organic layers were dried over
MgSO4. Concentration of the solvent in vacuo provided a crude residue (830 mg), which was purified by
silica gel column chromatography (CH2Cl2-MeOH = 1:1) to afford pure 6(b) (763 mg, 74.0%). mp
1
108-108.5 ºC. IR νmax: 3480 (N-H), 1597 (NHCO), 1488 (Ar C=C). H NMR (300 MHz, CDCl3) δ:
1.95-2.15 (bs, 1H, NH), 2.91 (bs, 4H, Piper. 3”-H and 5”-H ), 3.73 (bs, 4H, Piper. 2”-H and 6”-H), 3.89 (s,
3H, Ar-OMe, C-7 or C-4), 3.92 (s, 3H, Ar-OMe, C-4 or C-7), 6.65 (d, 1H, 5-H, J = 8.4 Hz), 6.70 (d, 1H,
6-H, J = 8.4 Hz), 7.59 (s, 1H, 3-H). 13C NMR (75 MHz, CDCl3): 46.2 (2C), 53.0 (2C), 55.7, 56.0, 104.7,
105.6, 122.4, 130.6, 130.8, 135.8, 148.4, 149.8, 163.8. HRMS (EI) Calcd for C15H18N2O3S, (M+):
306.10381. Found : 306.10321.
Synthesis of 1-(1-benzothien-2-ylcarbonyl)piperazine 6(c).
2-Methoxycarbonyl benzo[b]thiophene 2(c).
To a solution of nitrobenzaldehyde 1(c) (700 mg, 4.63 mmol) in DMF (10 mL) was added anhydrous
K2CO3 (639 mg, 4.63 mmol) and methyl thioglycolate (0.42 mL, 4.63 mmol). The suspension was stirred
at 70 °C for 4 h and then poured onto crushed ice and vigorously stirred for 15 min. The resultant
precipitate was filtered and washed with water (3 x 25 mL) to afford crude benzothiophene ester 2(c)
(615 mg) as a pale yellow solid, which was purified by column chromatography (CH2Cl2) to afford pure
benzothiophene ester 2(c) (594 mg, 67%) mp 62-63 ºC. IR νmax: 1725 (CO2Me), 1524 (ArC=C), 1252
1
(C-O). H NMR (300 MHz, CDCl3) δ: 3.98 (s, 3H, CO2Me), 7.46 (m, 2H, 5-H and 6-H), 7.88-7.92 (m,
2H, 4-H and 7-H), 8.10 (s, 1H, 3-H). 13C NMR (75 MHz, DMSO-d6) δ: 52.5, 122.8, 124.9, 125.6, 127.0,
130.7, 133.3, 138.7, 142.2, 163.3. HRMS (IE) Calcd for C10H8O2S, (M+): 192.02450. Found: 192.02343.

Benzo[b]thiophene-2-carboxylic acid 3(c).
A solution of the methyl ester 2(c) (800 mg, 4.17 mmol) in KOH 0.5 N: MeOH (1:1 v/v, 60 mL) was
stirred at rt for 3 h. The mixture was then concentrated in vacuo and acidified with HCl (concd.) at 0 °C.
The resulting precipitate was filtered, washed with small amount of cold water and dried to provide a
yellow pale solid 3(c) (721 mg, 97%) which was purified by column chromatography (CH2Cl2: MeOH
=1:1), to afford (609 mg, 82%). mp 224-225 °C. IR νmax: 3220-2574 (O-H), 1664 (C=O), 1520(ArC=C).
1H NMR (300 MHz, DMSO-d6) δ: 3.50 (s, 1H, CO2H), 7.38-7.46 (m, 2H, 5-H and 6-H), 7.94 (d, 1H, 4-H
or 7-H, J = 7.8 Hz), 7.98 (d, 1H, 7-H or 4-H, J = 7.8 Hz), 8.10 (s, 1H, 3-H). 13C NMR (75 MHz, CDCl3) δ:
123.4, 125.5, 126.2, 127.5, 130.7, 135.2, 139.2, 141.8, 164.0. HRMS (IE) Calcd for C9H6O2S, (M+):
178.00885. Found: 178.00877.
Benzo[b]thiophene-2-carbonyl chloride 4(c).
A solution of carboxylic acid 3(c) (600 mg, 3.37 mmol) in thionyl chloride (50 mL) was heated under
reflux for 4 h. Once the reaction proceeded the excess of the thionyl chloride was removed under reduced
pressure, to give 4(c) as a brown yellow solid (662 mg). mp 76-77 ºC. IR νmax: 1744 (COCl), 1509
(ArC=C), 1497 (ArC=C). 1H NMR (DMSO-d6) δ: 7.39 (t, 1H, 5-H or 6-H, J = 7.6 Hz), 7.44 (t, 1H, 6-H
or 5-H, J = 7.6 Hz), 7.94 (d, 1H, 4-H or 7-H, J = 7.6 Hz), 7.97 (d, 1H, 7-H or 4-H, J = 7.6 Hz), 8.10 (s,
1H, 3-H). 13C NMR (DMSO-d6) δ: 123.4, 125.5, 126.2, 127.4, 130.6, 135.2, 139.2, 141.8, 163.9. HRMS
(IE) Calcd for C9H5ClOS (M+): 195.97496. Found: 195.97458.
tert-Butyl 4-(1-benzothien-2-yl-carbonyl)piperazine-1-carboxylate 5(c).
Aroyl chloride 4(c) (662 mg, 3.37 mmol) in dry THF (25 mL) was slowly added to a stirred solution at
0 °C of piperazine-1-carboxylic acid tert-butyl ester (627 mg, 3.37 mmol), 0.46 mL of dry triethylamine
(340 mg, 3.37 mmol) in dry THF (25 mL) under nitrogen atmosphere. The mixture was stirred for 6 h at
rt and then diluted with water (100 mL). The solution was extracted with EtOAc (3 x 50 mL) and the
organic layers were dried over MgSO4. Concentration of the solvent in vacuo afforded a residue in
quantitative yield, which was purified by recristallization (EtOH) to give (852 mg, 73%) of pure tert-butyl
4-(1-benzothien-2-yl-carbonyl)piperazine-1-carboxylate 5(c). mp 140-141 ºC. IR νmax: 1689 (NCO2R),
1618 (NCO). 1H NMR (DMSO-d6) δ: 1.37 (s,9H,(-CH3)3), 3.38 (broad s., 4H, -CH2-Piper-NCO), 3.62
(broad s., 4H,-CH2-Piper -NCO2), 7.36-7.43 (m, 2H, 4-H, 7-H), 7.70 (s, 1H, 3-H), 7.86 (m, 1H, 5H or
6-H), 7.97 (m, 1H, 6H or 5-H). 13C NMR (DMSO-d6) δ: 28.1(3C), 43.6(2C), 45.8(2C), 80.0, 123.0, 125.4,
126.4, 126.6, 137.1, 138.1, 139.1, 140.1, 154.2, 163.1. HRMS (IE) Calcd for C18H22N2O3S (M+): 346.13511.
Found: 346.13245.
1-(1-Benzothien-2-ylcarbonyl)piperazine 6(c).

To a solution of carbamate 5(c) (400 mg, 1.26 mmol) in THF-EtOH (1:1, 40 ml), was added HCl (concd.)
(37% w/v, 6 mL, 72 mmol) and the mixture stirred at rt for 12 h. After this time the solution was basified
(NH4OH) to pH 9.0, extracted with EtOAc (3 x 50 mL), and the organic layers were dried over MgSO4.
Concentration of the solvent in vacuo provided a crude residue in quantitative yield, which was purified
by silica gel column chromatography (CH2Cl2-MeOH, 1:1) to give 1-(1-benzothien-2-ylcarbonyl)-
1
piperazine 6(c) as viscous liquid (260 mg, 84%). IR νmax: 3475 (N-H), 1620 (NHCO). H NMR:
(DMSO-d6) δ: 1.98 (s, 1H, NH), 2.75 (broad s., 4H, -CH2-Pip), 3.60 (broad s., 4H,-CH2-Pip-CO), 7.44 (m,
13
2H, 4H and 7-H), 7.70 (s, 1H, 3-H), 7.91 (m, 1H, 5-H or 6-H), 8.00 (m, 1H, 6-H or 5-H). C NMR
(DMSO-d6) δ: 44.5 (2C), 48.5 (2C), 122.5, 123.8, 124.9, 125.1, 125.8, 137.0, 138.6, 139.2, 162.4. HRMS
(IE) Calcd for C13H14N2OS (M+): 246.08268. Found: 246.08060.
Synthesis of 1-(benzo[b]thiophen-2-yl)-2-propen-1-one derivative 10(b).
(4,7-Dimethoxy-2-benzothiophen-2yl)methanol 7(b).
To a solution of benzothiophene ester. 2(b) (540 mg, 2.14 mmol) in anhydrous THF (50 mL) was added
LiAlH4 (325 mg, 8.6 mmol) at 0 °C and the mixture stirred under nitrogen atmosphere for 10 min. The
suspension was then heated at 45 °C for 1 h, the reaction mixture was then quenched with AcOEt/H2O
(2:1, 40 mL). The resulting precipitate was filtered and washed with EtOAc (60 mL). The combined
filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude
alcohol 7(b) as a yellow pale solid (413 mg). The residue was purified by column chromatography on
silica gel (CH2Cl2/EtOAc 1:1), to give pure 7(b) (320 mg, 65%). mp 125-126 °C (H2O/EtOH 3:1). IR νmax
:
3356 (O-H), 3017 (C-H Ar),1262 (C-O). Anal. Calcd for C11H12O3S: C, 58.91; H, 5.39; S,14.30. Found:
1
C,58.63; H,5.48; S,14.28 %. H NMR (CDCl3) δ: 1.35(broad t, 1H, OH), 3.92 (s, 3H, Ar-OMe), 3.95 (s,
3H, ArOMe), 4.87 (s, 2H, -CH2-OH), 6.68 (s, 2H, 5-H y 6-H), 7.38 (s, 1H, 3-H). 13C NMR (75 MHz,
CDCl3) δ: 55.8, 55.9, 66.6, 104.3, 104.6, 116.8, 130.3, 131.6, 144.0, 148.7, 149.3.
4,7-Dimethoxybenzo[b]thiophene-2-carbaldehyde 8(b).
A solution of alcohol 7(b) (327 mg, 1.46 mmol) in CH2Cl2 50 (mL) was added pyridinium
chlorochromate (948 mg, 4.4 mol), and the suspension stirred at rt for 3 h. After that TLC showed the
disappearance of the starting material, the solution was concentrated under reduced pressure. The crude
residue was purified by column chromatography on silica gel using CH2Cl2 as the eluent to give 8(b) (298
mg, 92%). Anal. Calcd for C11H10O3S: C, 59.44; H, 4.53; S, 14.43. Found: C, 59.65; H, 4.68; S, 14.43.
mp 109-110 °C (EtOH). IR νmax: 2910 and 2840 (C-H), 1667 (C=O), 1603 and 1526 (ArC=C). 1H NMR
(CDCl3) δ: 3.86 (s, 3H, OMe), 3.88 (s, 3H, OMe), 6.61 (d, 1H, 5-H, J = 8.4 Hz), 6.75 (d, 1H, 6-H, J = 8.4
Hz), 8.10 (s, 1H, 3-H), 9.98 (s, 1H, CHO). 13C NMR (75 MHz, CDCl3) δ: 55.8, 56.0, 104.8, 108.2, 131.1,
132.0, 133.6, 142.5, 148.6, 151.0, 184.6.

1-(4,7-Dimethoxybenzo[b]thiophen-2-yl)-2-propen-1-ol 9(b).
To a solution of aldehyde 8(b) (356 mg, 1.42 mmol) in anhydrous THF (30 mL) was added vinyl-
magnesium bromide (1 M solution in THF 1.5 mL, 1.5 mmol) and irradiated at 600 W in a microwave
reactor until TLC showed that the starting product had disappeared (5 min). The resulting mixture was
poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined extracts were dried over
anhydrous Na2SO4 and evaporated to dryness. The crude residue was purified by column chromatography
on silica gel (CH2Cl2-AcOEt 1:2) to afford (249 mg, 62%) of 9(b) as a pure yellow oil, which solidified
by petroleum ether addition. mp 105-106 °C IR νmax: 3183 (O-H), 2966 (C-H Aliph.), 1600 (C=C), 1485
(ArC=C). 1H NMR (CDCl3) δ: 2.21 (d, 1H, OH, J = 3.2 Hz), 3.93 (s, 3H, Ar-OMe), 3.95 (s, 3H, Ar-OMe),
5.28 (d, 1H, 3-H, J = 10.3 Hz), 5.45 (d, 2H, 3-H and 1-H, J = 17.2 Hz), 6.16 (m, 1H, 2-H), 6.65 (s, 2H,
13
5’-HBT, and 6’-HBT), 7.35 (s, 1H, 3’-HBT). C NMR (75 MHz, CDCl3) δ: 55.9, 56.0, 71.7, 104.4, 104.7,
118.0, 116.3, 130.1, 131.6, 138.9, 146.6, 148.7, 149.3. HRMS (EI) Calcd for C13H14O3S (M+): 250.06637.
Found: 250.06437.
1-(4,7-Dimethoxy benzo[b]thiophen-2-yl)-2-propen-1-one 10(b).
To a solution of alcohol 9(b) (242 mg, 0.97 mmol) in CH2Cl2 (50 mL) was added MnO2 (252 mg, 2.91
mmol), anhydrous MgSO4 (117 mg, 0.97 mmol), and the mixture stirred at rt for 3 h. The reaction
mixture was filtered off and the solvent removed under reduced pressure to give (151 mg) of crude enone
10(a). The organic residue was purified by column chromatography on silica gel (CH2Cl2) and
recrystallized from (EtOH/cyclohexane 2:1) to afford 10(b) pure (140 mg, 58%) of a yellow-orange solid.
mp 99-100 °C. IR νmax: 3054 (C-H Ar), 2968 (C-H Aliph.), 1665 (C=O), 1556 (C=C). 1H NMR (CDCl3) δ:
3.94 (s, 3H, Ar-OMe), 3.96 (s, 3H, Ar-OMe), 5.92 (dd, 1H, 3-H, J =10.4 Hz and J = 1.6 Hz), 6.55 (dd, 1H,
3-H, J = 17.0 Hz and J = 1.6 Hz), 6.67 (d, 1H, 5’-HBT, J = 8.5 Hz), 6.80 (d, 1H, 6’-HBT, J = 8.5 Hz), 7.22
13
(dd, 1H, 2-H, J = 17.0 Hz and J = 10.4 Hz), 8.16 (s, 1H, 3’-HBT). C NMR (75 MHz, CDCl3) δ: 55.8,
56.0, 104.6, 107.6, 127.0, 129.6, 131.4, 131.6, 133.7, 143.6, 148.6, 150.8, 183.8. HRMS (EI) Calcd for
C13H12O3S (M+): 248.05071. Found: 248.05001.
Synthesis of 1-(benzo[b]thiophen-2-yl)-2-propen-1-one derivative 10(c).
Benzo[b]thiophene-2-carboxylic acid methyl ester 2(c).
To a mixture of 2-nitrobenzaldehyde 1(c) (755 mg, 5.0 mmol), and anhydrous K2CO3 (690 mg, 5.0 mmol)
in dry DMF (9.0 mL) was added methyl thioglycolate (530 mg, 5.0 mmol) and heated at 70 ºC during 4 h.
After this time the reaction mixture was poured into an ice-water solution and the precipitate filtered to
provide 2(c) in (706 mg). The crude was purified by column chromatography (CH2Cl2) providing the pure
1
ester (500 mg, 52%) yield. m.p. 62-63 ºC. IR νmax: 1725 (C=O), 1522 (ArC=C), 1252 (C-O). H NMR
(300 MHz, CDCl3) δ: 3.97 (s, 3H, CO2Me), 7.46 (qt, 2H, 5-H and 6-H, J = 8.9 Hz), 7.91 (d, 1H, 4-H or

7-H, J = 4.4 Hz), 7.88 (d, 1H, 7-H or 4-H, J = 4.4 Hz), 8.10 (s, 1H, 3-H). 13C NMR (75 MHz, CDCl3):
52.5, 122.8, 124.9, 125.6, 126.9, 130.7, 133.3, 138.7, 142.2, 163.3. HRMS (EI) Calcd for C10H8O2S (M+):
192.02450. Found: 192.02343.
1-Benzo[b]thiophen-2-yl-2-methanol 7(c).
To a solution of benzothiophene ester 2(c) (500 mg, 2.6 mmol) in anhydrous THF (50 mL) was added
LiAlH4 (706 mg, 18.6 mmoles) at 0 °C and the mixture stirred under nitrogen atmosphere for 10 min.
After this time the reaction mixture was heated at 45 °C for 1 h and then quenched with AcOEt/H2O (2:1,
30 mL). The resulting precipitate was filtered and washed with EtOAc (60 mL). The combined filtrates
were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give alcohol 7(c) (397
mg), which was purified by column chromatography on silica gel (CH2Cl2/EtOAc 1:1) to give pure
1
alcohol 7(c) (286 mg, 67%). mp 97-98 ºC. IR νmax: 3580-3250 (O-H), 1456 (ArC=C), 1034 (C-O). H
NMR (300 MHz, CDCl3) δ: 2.04 (t, 1H, OH, J = 5.8 Hz), 4.92 (d, 2H, -CH2- J = 5.8 Hz), 7.21 (s, 1H,
3-H), 7.26-7.36 (m, 2H, 5-H and 6-H), 7.72 (dd, 1H, 4-H or 7-H, Jo = 6.5 Hz, Jm = 2.1 Hz), 7.82 (dd, 1H,
7-H or 4-H, Jo = 7.6 Hz, Jm = 2.1 Hz). 13C NMR (75 MHz, CDCl3): 60.9, 121.5, 122.5, 123.6, 124.3 (2C),
139.5, 139.9, 144.8. HRMS (EI) Calcd for C9H8OS (M+): 164.02959. Found: 164.02929.
1-Benzo[b]thiophene-2-carbaldehyde 8(c).
To a solution of alcohol 7(c) (794 mg, 4.84 mmol) in CH2Cl2, (50 mL), was added pyridinium
chlorochromate (2.60 g, 12.1 mmol) and the solution stirred for 4 h, the mixture was then concentrated
under vacuum condition and purified by column chromatography using (CH2Cl2) as the eluent to give 8 (c)
1
as a pink liquid (683 mg, 87%). IR νmax: 1673 (CHO), 1589 (ArC=C), 1515 (ArC=C). H NMR (300
MHz, CDCl3) δ: 7.32 (td, 1H, 5-H or 6-H, Jo = 7.3 Hz ; Jm =1.3 Hz), 7.39 (td, 1H, 6-H or 5-H, Jo = 7.3
Hz ; Jm =1.3 Hz), 7.77 (dd, 1H, 7-H or 4-H, Jo =8.1 Hz ; Jm = 0.6 Hz), 7.82 (dd, 1H, 4-H or 7-H, Jo = 8.1;
13
Jm = 0.6 Hz), 7.90 (s, 1H, 3-H), 9.98(s, 1H, CHO). C NMR (75 MHz,CDCl3): 123.3, 125.3, 126.3,
128.2, 134.6, 138.6, 142.7, 143.3, 184.8. HRMS (EI) Calcd for C9H6OS (M+): 162.01394. Found:
162.01468.
1-Benzo[b]thiophene-2-yl-2-propen-1-ol 9(c).
To a solution of aldehyde 8(c) (500 mg, 3.1 mmol) in anhydrous THF (40 mL) was added vinyl-
magnesium bromide (3.1 mL, 3.1 mmol, 1.0 M solution in THF), and irradiated at 600 W in a microwave
equipment until TLC showed that the starting product had disappeared (5 min). The resulting mixture was
poured into water (60 mL) and extracted with EtOAc (3 x 50 mL). The combined extracts were dried over
anhydrous Na2SO4 and evaporated to dryness to afford (537 mg). The crude residue was purified by
column chromatography on silica gel (CH2Cl2) to afford 9(c) (277 mg, 47%). mp 60-61 ºC. IR νmax: 3240

1
(O-H), 2917 (C-H), 1655 (C=C). H NMR (300 MHz, CDCl3) δ: 2.10-2.20 (broad s., 1H, OH), 5.29 (d,
1H, 3’-Hcys, J = 10.0 Hz), 5.42 -5.5 (m, 2H, 3’-H trans and 1’-H), 6.16 (m, 1H, 2’-H), 7.19 (s, 1H, 3-H),
7.26-7.36 (m, 2H, 5-H and 6-H), 7.70 (dd, 1H, 4-H, Jo = 6.6 Hz, Jm = 1.9 Hz), 7.77-7.82 (m, 1H, 7-H).
13C NMR (75 MHz, CDCl3): 72.2, 116.9, 121.3, 123.0, 124.1, 124.8(2C), 139.3, 140.0, 140.2, 147.7.
HRMS (EI) Calcd for C11H10OS (M+): 190.04523. Found: 190.04538.
1-Benzo[b]thiophene-2-yl-propenone 10(c).
To a solution of alcohol 9(c) (430 mg, 2.28 mmol) in CH2Cl2 (50 mL) was added MnO2 (991 mg, 11.4
mmol), anhydrous MgSO4 (275 mg, 2.28 mmol) and the mixture stirred at rt for 6 h. The crude residue
was then filtered off and concentrated in vacuo, to afford (321 mg), which was purified by column
chromatography (CH2Cl2) to provide pure 10(c) (265 mg, 62%). mp 45-46 Cº. IR νmax: 3032 (C-H Arom),
1661 (C=O), 1601 (C=C). 1H NMR (300 MHz, CDCl3) δ: 5.92 (dd, 1H, 3’-Hcys, Jcys = 10.4 Hz ; Jgem = 1.5
Hz), 6.54 (dd, 1H, 3’-Htrans, Jtrans = 17.0 Hz ; Jgem = 1.5 Hz), 7.18 (dd, 1H, 2’-H, Jtrans = 17.0 Hz ; Jcys
=
10.4 Hz), 7.41 (td, 1H, 6-H or 5-H, Jo = 7.5 Hz ; Jm =1.25 Hz), 7.47 (td, 1H, 5-H or 6-H, Jo = 7.5 Hz; Jm
= 1.25 Hz), 7.87 (t, 2H, 4-H and 7-H, Jo =7.1 Hz), 8.0 (s, 1H, 3-H). 13C NMR (75 MHz, CDCl3): 123.0,
125.3, 126.1, 127.6, 128.7, 128.8, 131.4, 139.2, 142.8, 144.2, 183.7. HRMS (EI) Calcd for C11H8OS (M+):
188.02959. Found: 188.02904.
General procedure for the preparation of 3-[4-(benzo[b]thiophene-2-carbonyl)piperazin-1-yl]-1-
benzo[b]thiophen-2-yl-propan-1-one derivatives 11(a-d).
1-(4,7-Dimethoxybenzo[b]thiophen-2-yl)-3-[4-(5-nitrobenzobenzo[b]thiophene-2-carbonyl)-
piperazin-1-yl]-1-propanone 11(a).
To a solution of 1-(4,7-dimethoxybenzo[b]thiophen-2-yl)-2-propen-1-one 10(b) (253 mg, 1.02 mmol) and
5-nitro-2-piperazinocarboxamide 6(a) (300 mg, 1.03 mmol), in dichloromethane (20 mL) was added a
mixture of the inorganic support SiO2- MnO2 (5.0 g, 4:1) and the suspension was vigorously stirred for 15
min at rt. The solvent was removed in vacuo and the solid was irradiated in a microwave equipment at
600 W for 4 min, until TLC showed that the starting product had disappeared. The solid was thoroughly
washed with EtOAc followed by remotion of the solvent, to afford 11(a) as a crude in quantitative yield.
The solid residue was purified by chromatographic column (EtOAc/CH2Cl2 4:1), and recrystallized (THF)
to give (405 mg, 73%). mp 163-164 °C. IR νmax: 3032 (Ar C-H), 1676 (C=O), 1623 (NC=O), 1524 (NO2),
1340 (NO2). 1H NMR (300 MHz, CDCl3) δ: 2.60 (broad s, 4H, Piper. 3”-H and 5”-H ), 2.93 (t, 2H, 3”’-H,
J= 7.0 Hz), 3.22 (t, 2H, 2”’-H, J= 7.0 Hz), 3.77 (broad s, 4H, Piper. 2”-H and 6”-H), 3.92 (s, 3H, Ar-OMe,
C-7 or C-4), 3.93 (s, 3H, Ar-OMe, C-4 or C-7), 6.66 (d, 1H, 5-H, J = 8.5 Hz), 6.77 (d, 1H, 6-H, J = 8.5
Hz), 7.58 (s, 1H, 3-H), 7.98 (d, 1H, 7´-H, J = 8.9 Hz), 8.10 (s, 1H, 3’-H), 8.22 (dd, 1H, 6’-H, Jo = 8.9, Jm
= 2.2 Hz), 8.68 (d, 1H, 4’-H, J = 2.1 Hz). 13C NMR (75 MHz, CDCl3) δ: 36.5, 46.3 (2C), 53.2 (3C), 55.7,

56.0, 104.6, 117.4, 119.9, 120.2, 123.1, 125.2, 126.5, 131.3, 133.2, 138.3, 140.5, 142.7, 145.6, 145.7,
148.5, 150.6, 162.4, 193.0. HRMS (EI) Calcd for C26H25N3O6S2 (M+): 539.11848. Found: 539.11513.
3-[4-(4,7-Dimethoxybenzo[b]thiophene-2-carbonyl)piperazin-1-yl]-1-(4,7-dimethoxybenzo[b]-
thiophen2-yl)-1-propanone 11(b).
Prepared from 1-(4,7-dimethoxybenzo[b]thiophen-2-yl)-2-propen-1-one 10(b) (60 mg, 0.24 mmol) and
4,7-dimethoxy-2-piperazinecarboxamide 6(b) (74.0 mg, 0.24 mmol), to afford crude 11(b) (133 mg) yield.
Purified by chromatographic column (EtOAc/CH2Cl2 4:1), (87.0 mg, 65%). mp 193-194 °C .IR νmax
:
1660 (C=O), 1620 (CONH), 1260 (C-O). 1H NMR (300 MHz, CDCl3) δ: 2.61 (bs, 4H, Piper. 3”-H and
5”-H ), 2.93 (t, 2H, 3”’-H, J = 7.0 Hz), 3.24 (t, 2H, 2”’-H, J = 7.0 Hz), 3.80 (bs, 4H, Piper. 2”-H and
6”-H), 3.92 (s, 3H, Ar-OMe), 3.95 (s, 3H, Ar-OMe), 3.96 (s, 6H, 2x Ar-OMe), 6.69 (t, 2H, 5-H and 6-H
or 5’-H and 6`-H, J = 8.0 Hz), 6.79 (t, 2H, 5’-H and 6’-H or 5-H and 6-H, J = 8.4 Hz), 7.72 (s, 1H, 3-H),
8.14 (s, 1H, 3’-H). 13C NMR (75 MHz, CDCl3) δ: 36.6, 45.1 (2C), 53.0 (3C), 55.7 (2C), 56.0 (2C), 104.6,
104.7, 105.6, 107.4, 122.5, 126.5, 130.7, 130.9, 131.4, 133.3, 135.8, 142.8, 148.4, 148.5, 149.9, 150.7,
163.7, 193.1. HRMS (EI) Calcd for C28H30N2O6S2 (M+): 554.15453. Found: 554.15625.
1-Benzo[b]thiophen-2-yl-3-[4-(4,7-dimethoxybenzo[b]thiophene-2-carbonyl)piperazin-1-yl]-1-
propanone 11(c).
Prepared from 1-(4,7-dimethoxybenzo[b]thiophen-2-yl)-2-propen-1-one 10(b) (207 mg, 8.35 mmol) and
benzothiophen-2-piperazinecarboxamide 6(c) (206 mg, 8.35 mmol) to afford crude 11(c) in quantitative
yield. Purified by chromatographic column (EtOAc/CH2Cl2, 4:1) to afford (310 mg). mp 128.0-128.5 °C.
1
IR νmax: 1673 (C=O), 1612 (CO-N), 1260 (C-O). H NMR (300 MHz, CDCl3) δ: 2.60 (bs, 4H, Piper.
3”-H and 5”-H ), 2.93 (t, 2H, 3”’-H, J = 6.5 Hz), 3.23 (t, 2H, 2”’-H, J = 6.5 Hz), 3.79 (bs, 4H, Piper. 2”-H
and 6”-H), 3.95 (s, 3H, Ar-OMe), 3.96 (s, 3H, Ar-OMe), 6.68 (d, 1H, 5’-H, J = 8.5 Hz), 6.80 (d, 1H, 6’-H,
J = 8.5 Hz), 7.39-7.42 (m, 2H, 5-H and 6-H), 7.48 (s, 1H, 3’-H), 7.81 -7.88 (m, 2H, 4-H and 7-H), 8.14 (s,
1H, 3-H). 13C NMR (75 MHz, CDCl3) δ: 36.1, 45.1(2C), 52.6 (3C), 55.3, 55.6, 104.1, 106.9, 121.9, 124.1,
124.3, 124.7, 125.3, 126.0, 130.9, 132.8, 136.0, 138.1, 139.7, 142.4, 148.0, 150.2, 163.3, 192.7. HRMS
(EI) Calcd for C26H26N2O4S2 (M+): 494.13340. Found: 494.13175.
1-Benzo[b]thiophen-2-yl-3-[4-(5-nitrobenzobenzo[b]thiophene-2-carbonyl)piperazin-1-yl]-1-
propanone 11(d).
Prepared from 1-(benzo[b]thiophen-2-yl)-2-propen-1-one 10(c) (60 mg, 0.3mmol) and 5-nitro-2-
piperazinocarboxamide 6(a) (93 mg, 0.32 mmol), to afford crude 11(d) in quantitative yield. Purified by
chromatographic column (EtOAc/CH2Cl2 4:1), (114 mg, 75%). mp 160-161 °C (THF). IR νmax: 3030 (Ar
C-H), 1660 (C=O), 1612 (CO-N),1526 (NO2), 1350 (NO2). 1H NMR (300 MHz, CDCl3) δ: 2.62 (bs, 4H,

Piper. 3”-H and 5”-H ), 2.96 (t, 2H, 3”’-H, J= 7.0 Hz), 3.24 (t, 2H, 2”’-H, J= 7.0 Hz), 3.76 (bs, 4H, Piper.
2”-H and 6”-H), 7.39-7.49 (m, 2H, 4-H and 7-H), 7.59 (s, 1H, 3-H), 7.89 (t, 2H, 5-H and 6-H, J = 7.1 Hz),
7.97 (d, 1H, 7’-H, J = 9.0 Hz), 8.0 (s, 1H, 3’-H), 8.25 (dd, 1H, 6’-H, Jo = 8.9, Jm = 2.1 Hz), 8.71(d, 1H,
4’-H, J =1.9Hz). 13C NMR (75 MHz, CDCl3) δ: 36.7, 46.3 (2C), 53.1(3C), 120.1, 120.3, 123.1, 123.3,
125.3, 125.3, 126.1, 127.8, 129.2, 138.5, 139.2, 140.7, 142.6, 143.6, 145.8, 146, 163.6, 193.2. HRMS (EI)
Calcd for C24H21N3O4S2 (M+): 479.09735 . Found: 479.09803.
ACKNOWLEDGEMENTS
Authors wish to thank to Proyecto FONDECYT 1050289 for their financial support, and Proyecto
MECESUP UCH 0116 de la Red Nacional de Doctorado en Química, for High Resolution Mass Spectra
Analysis.
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