2,3-Disubstituted benzo[b]thiophenes from diarylalkynes via electrophilic addition-cyclization and palladium-catalyzed cross-coupling

Article abstract of DOI:10.1002/adsc.200700172

Diarylalkynes are readily transformed in 3-chlorobenzo[b]thiophenes in a two-step electrophilic addition-cyclization procedure that runs highly efficiently in solution or in the solid phase. The heteroaromatic carbon-chlorine bond participates in palladium-catalyzed Suzuki-Miyaura or Buchwald-Hartwig cross-couplings to give, in a single step, 2,3-disubstituted derivatives of pharmacological relevance.

Full text of DOI:10.1002/adsc.200700172

UPDATES
DOI: 10.1002/adsc.200700172
2,3-Disubstituted Benzo[b]thiophenes from Diarylalkynes via
Electrophilic Addition-Cyclization and Palladium-Catalyzed
Cross-Coupling
Giuseppe Lamannaa and Stefano Menichettia,*
a
Dipartimento di Chimica Organica e Laboratorio di Progettazione Sintesi e Studio di Eterocicli Biologicamente Attivi
(HeteroBioLab), Università di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax : (+39)-055-457-3531; e-mail: stefano.menichetti@unifi.it
Received: April 4, 2007; Published online: September 11, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Diarylalkynes are readily transformed in
3-chlorobenzo[b]thiophenes in a two-step electro-
philic addition-cyclization procedure that runs
highly efficiently in solution or in the solid phase.
The heteroaromatic carbon-chlorine bond partici-
pates in palladium-catalyzed Suzuki–Miyaura or
Buchwald–Hartwig cross-couplings to give, in a
single step, 2,3-disubstituted derivatives of pharma-
cological relevance .
crowave-assisted or/and solid-phase synthesis[9] and
cross-coupling catalysis.[10]
Several years ago we reported an easy two-step
(one-pot) procedure for the preparation of 3-chloro-
benzo[b]thiophenes.[11] The method is based on the
electrophilic addition of the phthalimidesulfenyl chlo-
ride PhtNSCl (Pht=Phthaloyl) to aryl-alkyl- or sym-
metrical diarylalkynes, to give (E)-b-chlorothiovi-
nylphthalimides with high Markovnikov regioselectiv-
ity. These compounds under Lewis acid catalysis
(AlCl3 and BF3·OEt2 were demonstrated to be the re-
agents of choice) undergo an intramolecular electro-
philic aromatic substitution with closure of the thio-
phene ring and elimination of the phthalimide residue
(Scheme 1).[11]
Keywords: benzo[b]thiophenes; cross-coupling;
electrophilic addition; electrophilic substitution;
phthalimidesulfenyl chloride; solid phase synthesis
In this paper, we describe an update of this meth-
odology for the preparation of 2,3-disubstituted ben-
zo[b]thiophenes of pharmaceutical interest exploiting
the opportunities offered by some of the recent devel-
Introduction
Benzo[b]thiophenes are of interest because of their opments in organic synthesis.
frequent occurrence in nature and their wide range of
biological and physiological effects.[1] Benzo[b]thio-
phene derivatives currently in pharmaceutical use or
development include selective estrogen receptor mod-
ulators (SERM),[2] tubulin-binding agent,[3] modula-
tors of multidrug resistance,[4] angiogenesis inhibi-
tors,[5[ site-directed thrombin inhibitors,[6] and anti-in-
flammatory[7] agents. For example, SERMs raloxifen
1a, arzoxifen 1b and related derivatives 1c–e
(Figure 1) have already found therapeutic use as ef-
fective agents in the prevention of cancer and osteo-
porosis.
Thus, the classical approaches for either the con-
struction of the pentatomic heteroaromatic fused ring
or its functionalization[1] are continuously being com-
plemented by new methods that take advantage of
the more recent acquisitions of synthetic organic
chemistry, including multi-component reactions,[8] mi-
Figure 1. Selected bioactive 2,3-disubstituted benzo[b]thio-
phenes.
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Adv. Synth. Catal. 2007, 349, 2188 – 2194

2,3-Disubstituted Benzo[b]thiophenes from Diarylalkynes
UPDATES
Scheme 1. General procedure for the preparation of 3-chloro-
benzo[b]thiophenes from aryl-alkyl- and symmetrical di-
arylalkynes.
Results and Discussion
We started facing the problem of the regiochemistry
of the addition of PhtNSCl to unsymmetrical diarylal-
kynes bearing those groups (i.e., OMe, OH and F)
found in the more biologically active derivatives. Al-
kynes 2a and 2b, easily prepared by Sonogashira
cross-coupling in up to 90% isolated yield (see Exper-
imental Section), were reacted with PhtNSCl in dry
Scheme 2. Reagents and conditions: a) 1.1 equivs. PhtNSCl,
dichloromethane (DCM) at room temperature to give DCM, room temperature, 3 h; b) 4 equivs. AlCl3, DCM,
room temperature, 4a 4 h, 72%, 4b 2 h, 68% over two steps.
sulfenamides 3a and 3b as single regioisomers but as
1:1 and 5:2 mixtures of E/Z isomers, respectively
(Scheme 2). This peculiar behaviour suggests that the
electrophilic addition to these electron-donating sub- materials and the thiophenes 4a and 4b were isolated
stituted alkynes occurred through a p-methoxy-stabi- in 72% and 68% overall yield, respectively. This can
lized open vinyl cation intermediate, instead of, or to- be rationalized considering that, under the reaction
gether with, the predicted thiirenium ion.[12] The open conditions required for the cyclization, a Z/E isomeri-
intermediate causes the formation of an E/Z mixture zation takes place allowing the complete consumption
of diastereoisomeric sulfenamides 3, but makes cer- of the Z isomer as well.
tain the complete regioselectivity of the reaction for
the favoured attack of the chloride ion to the more carried out in a one-pot procedure, but this caused a
stabilized vinyl cation (Scheme 2). small decrease (5–15%) of the overall yield of benzo-
Sulfenamides 3 can be isolated as mixtures of E/Z thiophenes.
The two steps, addition and cyclization, can also be
diastereoisomers by flash chromatography, however,
The complete regioselectivity and the straightfor-
the successive cyclization to 3-chlorbenzo[b]thiophene wardness of the transformation of alkyne 2a into ben-
can be, more conveniently, carried out on crude 3 as zothiophene 4a prompted us to verify the value of
obtained after a simple aqueous basic work-up. The this methodology in the solid phase. Since the Sono-
intramolecular ring closure to benzothiophene re- gashira reaction has already been applied for the
quires that the sulfenamide sulfur and the aromatic preparation of diarylalkynes in the solid phase[13] and
ring lay cis to each other (see Scheme 1), hence, only recently we demonstrated the fruitful use of PhtNSCl
the E isomer should be consumed in the Lewis acid- in the substitution reaction on solid supported b-keto
catalyzed intramolecular SEAr. In spite of this, react- esters,[14] we envisaged to extend the above described
ing the crude E/Z mixtures of derivatives 3a or 3b methodology (see Scheme 2) using a carboxylic acid-
with 4 equivs. of AlCl3 in DCM at room temperature, modified Merrifield resin as starting material, as de-
we observed complete consumption of the starting scribed in Scheme 3.
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Giuseppe Lamanna and Stefano Menichetti
UPDATES
in 50% overall yield as a pure compound without any
further purification.
Clearly, this demonstrates that the regioselectivity
of the addition as well as the Lewis acid-catalyzed Z/
E equilibration are effective also for solid-supported
reagents, and that the six consecutive steps on the
resin: a) i: formation of the acyl chloride, ii: esterifi-
cation, b) Sonogashira cross-coupling, c), PhtNSCl
electrophilic addition, d) AlCl3-catalyzed intramolecu-
lar SEAr and e) transesterification, occurred with an
average yield close to 90% (Scheme 3).
2-Aryl-3-chlorobenzo[b]thiophenes 4a–c can be
converted into 2,3-disubstituted derivatives of type 1
using literature procedures like, for example, a reduc-
tive dechlorination followed by an SEAr on the very
nucleophilic C-3 position,[1,2a] or an oxidation at sulfur
to facilitate a heteroaromatic nucleophilic substitution
of the chlorine atom.[3c] Our idea was to use these 3-
chlorobenzo[b]thiophenes for a direct functionaliza-
tion via a metal-catalyzed cross-coupling, avoiding
any additional manipulation.
The use of largely diffuse, easy to handle and to
prepare aromatic and heteroaromatic chloro deriva-
tives as efficient partners in cross-coupling reactions
is still an open synthetic problem that has found some
practical but as yet no general solutions.[15] In any
case, examples of chlorothiophenes used as substrates
for cross-coupling reactions are scarce, and almost un-
known for 3-chlorobenzo[b]thiophenes.
Scheme 3. Reagents and conditions: a) i: 5 equivs. SOCl2,
toluene, 608C, 2 h (repeated twice); ii: 2 equivs. 4-iodophe-
nol, 2 equivs. DIPEA, 0.1 equiv. DMAP, DCM, room tem-
perature, 24 h; b) 2 equivs. 4-ethynylanisole,
3 equivs.
Keeping in mind this potential limitation, we start-
ed studying the possibility to transform compounds 4
into derivatives like 1 through a metal-catalyzed
Bu4NOAc, 6% mol Pd(OAc)2 DMF, room temperature,
AHCTREUNG
24 h; c) 1.5 equivs. PhtNSCl, DCM, room temperature, 16 h;
d) 4 equivs. AlCl3, DCM, room temperature, 4 h; e) 5
equivs. NaOMe, THF, room temperature 3 h, 50% overall. cross-coupling that was as general and simple as pos-
sible. Recently PEPPSI (pyridine, enhanced, precata-
lyst, preparation, stabilization and initiation) was in-
The supported carboxylic acid was reacted with troduced as a user-friendly air- and moisture-stable
thionyl chloride followed by esterification with 4-io- catalytic system for a wide-range of cross-coupling re-
dophenol in the presence of DIPEAand a catalytic
actions,[16] thus we decided to study its usefulness on
amount of DMAP. The aryl iodide was cross-coupled 3-chlorobenzo[b]thiophenes 4. Indeed, reacting 4a
under Sonogashira conditions with 4-ethynylanisole, and 4b with 4-methoxyphenylboronic acid catalyzed
and the obtained supported alkyne reacted with by 2% mol of PEPPSI-IPr we observed a clean
PhtNSCl in DCM. Amixture of E/Z supported b- Suzuki–Miyaura coupling affording derivatives 5a and
chlorothiovinylsulfenamide was obtained and cyclized 5b in 85% and 89% isolated yield (Scheme 4). Grati-
with AlCl3 to the benzo[b]thiophene pre-4c. Transes- fyingly, the same catalyst was also effective in the
terification with NaOMe in dry THF allowed the re- Suzuki–Miyaura coupling carried out with 2-phenyle-
lease from the resin and the isolation of thiophene 4c thylboronic acid that, under very similar reaction con-
(Scheme 3). The formation of the solid supported re- ditions, allowed the isolation of 3-ethylphenylben-
agents and the progress of the reactions were moni- zo[b]thiophenes 6a and 6b in very good yields
tored on the resin either by FT-IR, by means of the (Scheme 4). It is noteworthy that the Suzuki–Miyaura
diagnostic stretching bands exhibited by the ester, the couplings on derivative 4a occurred without affecting
alkyne and the N-thiophthalimide functional groups, the acetoxy group on the 4’ position.
1
or by H NMR monitoring mainly the variation of the
These successes in forming new sp2–sp2 and sp2–sp3
chemical shift of the methoxy group in the diverse carbon-carbon bonds prompted us to verify the ability
solid supported intermediates (see Experimental Sec- of PEPPSI-IPr to catalyze the formation of a carbon-
tion). Remarkably, 3-chlorobenzo[b]thiophene 4c was nitrogen bond in a Buckwald–Hartwig process. React-
isolated, by a simple acid work-up of the solution ob- ing thiophene 4a with 4-methoxyaniline and deriva-
tained by washing the resin after transesterification, tive 4b with 3,4,5-trimethoxyaniline, the expected di-
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2,3-Disubstituted Benzo[b]thiophenes from Diarylalkynes
UPDATES
Figure 2. Benzo[b]thiophenes of biological relevance pre-
pared by PEPSSI-IR mediated Buckwald-Hartwig cross-
coupling of 4b and 4c with amine 8.
reacting amine 8 (Figure 2), prepared by Mitsunobu
reaction of 4-acetamidophenol with 1-(2-hydroxy-
ethyl)piperidine, with thiophenes 4b and 4c, under the
above reported PEPPSI-IPr catalyzed Buckwald-
Hartwig conditions, compounds 7c and 7d (Figure 2)
were isolated in 86% and 75% yield, respectively. In
fact, BBr3 demethylation of derivative 7d gave dihy-
droxy derivative 1c (see Figure 1) known to be active
in sub-nanomolar concentration as a SERM.[3c] On
the other hand the substitution of the 4’-OH with a
4’-F group, as in 7c, has been indicated as a simple yet
effective way for decreasing the toxicity of dihydroxy
compounds, like 1a–c, caused to their ability to give
glutathione adducts followed by oxidation to unsafe
quinoid species.[18]
Scheme 4. Reagents and conditions: a) 1.5 equivs. 4-methoxy-
phenylboronic acid, 2% mol PEPPSI-IPr, 3 equivs. K2CO3,
toluene, 1008C, 5a, 3 h, 85%, 5b, 6 h, 89%; b) 1.5 equivs. 2-
phenylethylboronic acid, 2% mol PEPPSI-IPr, 3 equivs.
K2CO3, toluene, 1008C, 6a, 7 h 90%, 6b, 3 h 92%; c) for 7a:
1.3 equivs. 4-methoxyaniline, 4% mol PEPPSI-IPr, 3 equivs.
NaO-t-Bu, toluene, 1008C, 5 h, 78%; for 7b: 1.3 equivs.
2,3,4-methoxyaniline, 4% mol PEPPSI-IPr, 3 equivs. NaO-t-
Bu, toluene, 1008C, 4 h, 80%.
Conclusions
arylamines 7a and 7b were isolated in good yield as
reported in Scheme 4. Under these reaction condi- The addition of PhtNSCl to 4,4’-disubstituted unsym-
tions the coupling with acetoxy derivative 4a occurred metrical diarylalkynes occurred with complete regio-
with concomitant deacetylation affording the 4’-hy- selectivity to give b-chloro-N-thiophthalimides as suit-
droxy thiophene 7a (Scheme 4).
able precursors of 3-chlorobenzo[b]thiophenes ob-
Thus the chlorine atom in the 3-position, provided tained by intramolecular electrophilic substitution cat-
by the electrophilic addition of PhtNSCl to the alyzed by AlCl3. The whole procedure, including the
alkyne, becomes the tool for the direct introduction Sonogashira synthesis of the starting alkyne, has been
of substituents by a palladium-catalyzed cross-cou- successfully applied on the solid phase. Eventually,
pling reaction, that is particularly simple using the C-3 carbon-chlorine bond has been cross-coupled
PEPSSI-IPr.[17]
with aryl- or alkyboronic acids and with anilines,
In this light we decided to assess this methodology using PEPPSI-IPr as catalysis, to give 2,3-disubstitut-
for the preparation of benzothiophenes of pharma- ed benzo[b]thiophenes of pharmaceutical relevance
ceutical relevance. We were delighted to find that on with overall yields and number of steps comparable
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Giuseppe Lamanna and Stefano Menichetti
UPDATES
evaporated under reduced pressure to give 3a and 3b as
mixtures of E/Z diastereoisomers in 1:1 (d OMe=3.68 and
to or better than those of the other available synthetic
procedures. The possibility to broaden the cross-cou-
pling reaction of 3-chlorobenzo[b]thiophenes is under
consideration.
3.84 ppm) or 5:2 ratio (d OMemajor =3.68 ppm, OMeminor
=
3.83 ppm), respectively.
Aluminium Trichloride Cyclization to
Benzo[b]thiophenes 4a and 4b
Experimental Section
To a solution of thiophthalimide 3, as a mixture of E/Z dia-
stereoisomers, (1.0 mmol) in dry CH2Cl2 (15 mL), AlCl3
(4.0 mmol) was added under a nitrogen atmosphere. After
stirring at room temperature for 2–4 h, the reaction mixture
was diluted with CH2Cl2 (10 mL), and washed with saturated
NaHCO3 solution (2”30 mL) and water (2”30 mL). The or-
ganic layer was dried over Na2SO4, filtered, concentrated
under reduced pressure, and the crude product was purified
by flash chromatography to provide the desired benzo[b]-
thiophene.
Cross-coupling reactions were carried out on flame-dried
flasks under a positive pressure of dry nitrogen. THF was
distilled from sodium in the presence of the blue colour of
benzophenone kethyl, toluene was distilled from sodium,
and DCM was distilled from CaH2. All reactions were moni-
tored by TLC on commercially available precoated plates
(silica gel 60 F254) and the products were visualized with
acid-vanillin solution. Silica gel 60, 230–400 mesh, was used
for column chromatography. Petrol refers to light petrole-
um, bp 40–608C. Melting points were measured on a micro-
scopic apparatus and are uncorrected. 1H and 13C NMR
spectra were recorded at 400 and 100 MHz, respectively, in
CDCl3 solutions. Residual CHCl3 was used as reference at
7.26 and 77.00 ppm, respectively. FT-IR spectra were record-
ed in KBr pellets or CHCl3 solutions. Mass spectra were
measured with a Shimadzu QP5050. Commercially available
reagents, catalysts and ligands were used as obtained from
freshly open containers without further purifications.
PEPPSI-IPr was purchase from Sigma–Aldrich. Phthalimi-
desulfenyl chloride was prepared from the corresponding
commercially available disulfide (purchase from Chemper
snc) as reported elsewhere.[14]
4-(3-Chloro-6-methoxybenzo[b]thiophen-2-yl)phenyl ace-
tate (4a): The product was isolated, after column chroma-
tography (eluent: CH2Cl2/petroleum ether 4:1), as a pale-
brown solid; yield: 72%; mp 121–1238C; IR (KBr): n=
1
2941, 1759 (C=O), 1608, 1474, 1205 cmÀ1; H NMR (CDCl3,
400 MHz): d=2.33 (s, 3H), 3.89 (s, 3H), 7.08 (dd, J=2.4,
8.8 Hz, 1H), 7.17–7.21 (m, 2H), 7.25 (s, 1H), 7.73 (d, J=
8.8 Hz, 1H), 7.75–7.79 (m, 2H); 13C NMR (CDCl3,
100 MHz): d=21.14, 55.68, 104.80, 115.12, 116.39, 121.84,
123.02, 130.18, 131.78, 132.46, 138.08, 150.56, 158.41, 169.28;
MS: m/z (%)=332 (M·+, 44), 290 (100), 275 (72); anal.
calcd. for C17H13ClO3S: C 61.35, H 3.94; found: C 61.25, H
3.81.
3-Chloro-2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene
(4b): The product was isolated, after column chromatogra-
phy (eluent: petroleum ether/CH2Cl2 4:1), as a white solid;
yield: 68%; mp 86–878C; IR (KBr): n=2929, 1608, 1496,
Solid-Phase Synthesis
Carboxylic Merrifield resin was purchased from Novabio-
chem. It is an 1% cross-linked divinylbenzene-styrene copo-
lymer of 100–200 mesh with a loading of 1.4 mmolgÀ1. Solid-
phase reactions were carried in securely sealed vials and the
resin suspensions transferred by plastic pipettes. Solid phase
work-up was carried out by means of the plastic syringe
technique. Flat-bottom PE syringes were equipped with sin-
tered Teflon filters, Teflon tubing and valves which allow
suction to be applied to the syringe from below. The resins
were washed with the solvent used for the reaction and se-
quentially with DCM, MeOH, diethyl ether and again DCM
and the shrunken beads were dried under vacuum over
KOH before further transformations and analyses. Function-
alized resins were analyzed with FT-IR and/or MAS solid-
phase NMR. MAS solid-phase NMR were acquired on a
400 MHz Varian MercuryPlus spectrometer using a PFGID-
Varian Nanoprobe (pulsed field gradient, indirect detec-
tion), at 258C using CDCl3 as solvent with a CPMG modi-
fied sequence to minimize the resin signals.
1233 cmÀ1 1H NMR (CDCl3, 400 MHz): d=3.89 (s, 3H),
;
7.08 (dd, J=2.2, 9.0 Hz, 1H), 7.13–7.18 (m, 2H), 7.25 (s,
1H), 7.70–7.75 (m, 3H); 13C NMR (CDCl3, 100 MHz): d=
55.68, 104.82, 115.13, 115.60, 115.82, 116.29, 123.01, 128.57,
130.86, 130.93, 131.73, 132.30, 137.99, 158.40, 161.40, 163.88;
MS: m/z (%)=292 (M·+, 100), 277 (90), 249 (40); anal.
calcd. for C15H10ClFOS: C 61.54, H 3.44; found: C 61.84, H
3.45.
Solid-Phase Synthesis of 4-(3-Chloro-6-
methoxybenzo[b]thiophen-2-yl)phenol (4c)
Commercial Merrifield resin (1.0 mmol) was swelled in dry
toluene (2 mL) under mechanical stirring for 30 min, then
SOCl2 (5.0 mmol) was added and the mixture was heated at
608C for 2 h. The same procedure was repeated to ensure
the complete halogenaÀ1tion: IR (KBr): n=1770 and 1731
À
(C=O), 870 (C Cl) cm .
The solid supported acyl chloride (1.0 mmol) was swelled
in dry CH2Cl2 (4 mL) under mechanical stirring. After
30 min, DMAP (0.1 mmol), 4-iodophenol (2.0 mmol) and
DIPEA(2.0 mmol) were added in sequence and stirring was
continued for 24 h at room temperature to afford the ester-
supported resin: IR (KBr): n=1737 (C=O) cmÀ1.
Addition of PhtNSCl to Alkynes 2a and 2b
To a solution of alkyne (1.0 mmol) in dry CH2Cl2 (10 mL)
was added dropwise, at 08C, a solution of phthalimidesulfen-
yl chloride (1.1 mmol) in dry CH2Cl2 (8 mL) under a nitro-
gen atmosphere. The mixture was stirred at room tempera-
ture for 3 h then diluted with CH2Cl2 (10 mL), and washed
with saturated NaHCO3 solution (2”30 mL) and water (2”
30 mL). The organic layer was dried over Na2SO4 and
An oven-dried Schlenk flask was charged with the ester-
resin (1.0 mmol), Bu4NOAc (3.0 mmol), Pd
ACHTREU(NG OAc)2 (6
mol%) and DMF (5 mL) under a nitrogen atmosphere.
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2,3-Disubstituted Benzo[b]thiophenes from Diarylalkynes
UPDATES
After 10 min of stirring 4-ethynylanisole (2.0 mmol) was
added and stirring was continued at room temperature
under nitrogen for 24 h to give the alkyne-resin: IR (KBr):
169.25; MS: m/z (%)=404 (M·+, 76), 362 (100), 347 (64);
anal. calcd. for C24H20O4S: C 71.27, H 4.98; found: C 71.44,
H 5.07.
n=2207 (CꢀC), 1734 (C=O) cmÀ1
;
1H NMR (CDCl3,
400 MHz): d=3.73 (s, OMe).
General Procedure for the PEPPSI-IPr-Catalyzed
Buchwald–Hartwig Cross-Coupling Reactions
Alkyne-resin (1.0 mmol) was swelled in dry CH2Cl2
(3 mL) under mechanical stirring for 30 min. To the suspen-
sion a solution of phthalimidesulfenyl chloride (1.5 mmol) in
dry CH2Cl2 (1.5 mL) was added dropwise at 08C under a ni-
trogen atmosphere, and stirring was continued for 16 h at
room temperature to obtain a 2:1 mixture of E/Z supported
N-thiophthalimides: IR (KBr): n=1787, 1742 and 1714 (C=
Under nitrogen, 3-chlorobenzo[b]thiophene (1.0 mmol), ani-
line (1.3 mmol), NaO-t-Bu (3.0 mmol), PEPPSI-IPr catalyst
(4 mol%) and dry toluene (6 mL) were added to an oven-
dried Schlenk flask. The resulting mixture was stirred at
1008C for the desired time until complete consumption of
the starting material as judged by TLC, (4–24 h). Upon cool-
ing, the reaction mixture was diluted with diethyl ether
(20 mL), washed with brine (3”30 mL), and dried over
Na2SO4. The crude amine was purified by flash chromatog-
raphy to provide the desired coupling product.
1
O) cmÀ1; H NMR (CDCl3, 400 MHz): d=3.63 (s, OMeminor),
3.81 (s, OMemajor), 7.50–7.80 (m, HaromPht).
The N-thiophthalimide-modified resin (1.0 mmol) was
swelled in dry CH2Cl2 (5 mL) under mechanical stirring.
After 30 min, AlCl3 (4.0 mmol) was added and stirring was
continued for 4 h at room temperature to afford the ben-
zo[b]thiophene resin pre-4c: IR (KBr): n=1734 (C=O)
4-(6-Methoxy-3-{4-[2-(piperidin-1-yl)ethoxy]phenylami-
no}benzo[b]thiophen-2-yl)phenol (7d): The product was iso-
lated by flash chromatography (eluent: CH3OH/EtOAc 1:1)
as a brown solid; yield: 75%; mp 174–1768C; IR (CHCl3):
1
cmÀ1; H NMR (CDCl3, 400 MHz): d=3.70 (s, OMe).
Supported benzothiophene pre-4c (1.0 mmol) was swelled
in dry THF (3.5 mL) under mechanical stirring for 30 min,
then a solution of sodium methoxide 1.35M (5.0 mmol) in
MeOH was added and the mixture was stirred for 3 h at
room temperature. The resin was filtered and washed with
several portions of CH2Cl2 and MeOH. The organic phase
was washed with saturated NH4Cl solution and water, and
then dried over Na2SO4. Evaporation of the solvent under
reduced pressure provided derivative 4c as a pure white
n=3583 (O H), 3393 (N H), 2941, 1606, 1507 cmÀ1
;
À
À
1H NMR (CDCl3, 400 MHz): d=1.42–1.50 (m, 2H), 1.60–
1.67 (m, 4H), 2.51–2.53 (m, 4H), 2.76–2.80 (m, 2H), 3.84 (s,
3H), 4.00–4.04 (m, 2H), 5.32 (s, 1H), 6.57–6.66 (m, 4H),
6.76–6.80 (m, 2H), 6.86 (dd, J=2.4, 8.8 Hz, 1H), 7.24 (d, J=
2.4 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 7.37–7.40 (m, 2H);
13C NMR (CDCl3, 50 MHz): d=23.93, 25.21, 54.71, 55.56,
57.80, 65.33, 105.12, 113.66, 115.30, 116.01, 116.26, 122.84,
124.38, 128.58, 129.47, 130.22, 130.95, 137.73, 140.16, 151.78,
156.79, 157.14; MS: m/z (%)=474 (M·+, 26), 112 (100), 98
(89); anal. calcd. for C28H30N2O3S: C 70.86, H 6.37, N 5.90;
found: C 70.64, H 6.70, N 5.70.
À
solid; yield: 50%; mp 157–1598C; IR (KBr): n=3422 (O
H), 3008, 1608, 1479, 1216 cmÀ1
;
1H NMR [(CD3)2CO,
400 MHz]: d=3.88 (s, 3H), 6.97–7.01 (m, 2H), 7.10 (dd, J=
2.4, 8.8 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.61–7.65 (m, 2H),
7.67 (d, J=8.8 Hz, 1H), 8.76 (s, 1H); 13C NMR [(CD3)2CO,
100 MHz]: d=56.04, 105.92, 115.11, 116.00, 116.57, 123.17,
124.36, 131.16, 132.44, 134.70, 138.57, 158.83, 159.36; MS: m/
z (%)=290 (M·+, 100), 275 (91), 247 (27); anal. calcd. for
C15H11ClO2S: C 61.96, H 3.81; found: C 61.91, H 3.82.
Acknowledgements
Financial support from MIUR (Research project “Stereosele-
zione in Sintesi Organica. Metodologie ed Applicazioni”
contract 2005035330) is gratefully acknowledged. The “Ente
Cassa di Risparmio di Firenze” is acknowledged for the ac-
quisition of a 400 MHzNMR spectrometer.
General Procedure for the PEPPSI-IPr-Catalyzed
Suzuki–Miyuara Cross-Coupling Reactions
An oven-dried Schlenk flask was charged with 3-chloroben-
zo[b]thiophene (1.0 mmol), boronic acid (1.5 mmol), K2CO3
(3.0 mmol), PEPPSI-IPr catalyst (2 mol%) and dry toluene References
(8 mL), under a nitrogen atmosphere. The mixture was
stirred at 1008C under nitrogen until complete consumption
of the starting material as judged by TLC (3–7 h). Upon
cooling, the reaction mixture was diluted with diethyl ether
(20 mL), washed with brine (3”30 mL), and dried over
Na2SO4. Concentration in vacuum afforded the desired cou-
pling product that was chromatographed on silica gel.
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asc.wiley-vch.de
2193

Giuseppe Lamanna and Stefano Menichetti
UPDATES
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2194
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 2188 – 2194