Functionalization of the 3-position of thiophene and benzo[b]thiophene moieties by palladium-catalyzed C-C bond forming reactions using diazonium salts

Article abstract of DOI:10.1002/adsc.201100226

The palladium-catalyzed Matsuda-Heck and Suzuki-Miyaura cross-couplings of 2-methoxycarbonylthiophene-3-diazonium tetrafluoroborate 1 were performed to synthesize a series of thiophene derivatives functionalized in the β-position. Good to excellent yields of the cross-coupling products were obtained using palladium acetate [Pd(OAc)₂], a ligandless palladium catalyst, without a base, at room temperature, under aerobic conditions and with short reaction times. A diazotization and cross-coupling sequence can also be performed in a one-pot process avoiding the isolation of the thiophenediazonium salt derivative. In addition, 2-methoxycarbonylbenzo[b]thiophene-3-diazonium tetrafluoroborate 8 was also efficiently arylated by applying the same Suzuki-Miyaura optimized reaction conditions. Copyright

Full text of DOI:10.1002/adsc.201100226

FULL PAPERS
DOI: 10.1002/adsc.201100226
Functionalization of the 3-Position of Thiophene and Benzo[b]-
À
thiophene Moieties by Palladium-Catalyzed C C Bond Forming
Reactions using Diazonium Salts
Mꢀnica Raduꢁn,a Joaquim Padrosa,a Anna Pla-Quintana,a Teodor Parella,b
and Anna Roglansa,*
a
Department of Chemistry, University of Girona, Campus de Montilivi s/n, 17071 Girona, Spain
Fax : (+34)-972-418-150; e-mail: anna.roglans@udg.edu
Servei de RMN, Autonomous University of Barcelona, Cerdanyola, 08193 Barcelona, Spain
b
Received: March 29, 2011; Revised: May 30, 2011; Published online: August 4, 2011
Dedicated to the memory of Professor Rafael Suau.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100226.
Abstract: The palladium-catalyzed Matsuda–Heck pling sequence can also be performed in a one-pot
and Suzuki–Miyaura cross-couplings of 2-methoxy- process avoiding the isolation of the thiophenediazo-
carbonylthiophene-3-diazonium tetrafluoroborate 1 nium salt derivative. In addition, 2-methoxycarbonyl-
were performed to synthesize a series of thiophene benzo[b]thiophene-3-diazonium tetrafluoroborate 8
derivatives functionalized in the b-position. Good to was also efficiently arylated by applying the same
excellent yields of the cross-coupling products were Suzuki–Miyaura optimized reaction conditions.
obtained using palladium acetate [PdACTHNURTGNENG(U OAc)2], a li-
gandless palladium catalyst, without a base, at room Keywords: benzo[b]thiophenes; diazonium salts;
temperature, under aerobic conditions and with Matsuda–Heck reactions; palladium; Suzuki–
short reaction times. A diazotization and cross-cou- Miyaura cross-couplings; thiophenes
Introduction
obtained, has therefore been a major goal in organic
synthesis. Two types of strategy can be employed: (i)
Thiophene moieties[1] can be found both in natural thiophene ring construction and (ii) thiophene ring
products and synthetic chemotherapeutics,[2] where modification. In the latter case, the use of metal-cata-
they are sometimes used as a bioisostere of a benzene lyzed coupling methodologies has been found to be
ring. Especially, significant examples in this field are the most effective strategy.[6] While transition metal-
À
Echinothiophene, a benzothiophene glycoside extract- catalyzed direct arylation of thiophene C H bonds
ed from a natural source, the roots of Echinops grijis- has many advantages,[7] its lack of regioselective con-
sii[3] and Ticlopidine and Clopidogrel, synthetic thio- trol to accomplish the selective functionalization of
phene derivatives used as antithrombotic drugs. Fur- the less activated positions (b position for thiophene
thermore, given the interesting spectroscopic and and its derivatives) makes it necessary to employ
electrochemical properties of thiophene-containing strategies in which a functional group, forcing the
molecules as well as their liquid crystalline character- thiophene moiety to act either as the electrophilic or
istics, thiophene moieties have also been introduced nucleophilic partner, directs the coupling.
in advanced materials such as organic TFTs, light-
If we focus on palladium cross-coupling reactions,
emitting devices and dye-sensitized organic solar cells we find that the efficacy exhibited by coupling simple
with excellent results.[4] The utility of thiophenes as arenes is not always maintained in the coupling of
versatile intermediates in organic synthesis is also heterocycles. For electronic or poisoning reasons, the
noteworthy.[5]
reaction with these substrates is typically much slower
The development of synthetic protocols for thio- than with simple aryl derivatives and generally re-
phenes, allowing a wide variety of derivatives to be quire high catalyst loadings and harsh reaction condi-
Adv. Synth. Catal. 2011, 353, 2003 – 2012
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2003

Mꢀnica Raduꢁn et al.
FULL PAPERS
tions.[8] Despite this, thiophene has been used in palla- excellent stability and can be kept safely at À48C for
dium-catalyzed couplings in recent years, although to unlimited times. After obtaining the diazonium salt,
a much lesser extent than simple arenes.[9]
we proceeded to optimize the conditions for the Mat-
Aryl halides or triflates are the most widely used suda–Heck reaction with ethyl acrylate (Table 1). As
À
electrophilic partners in palladium-catalyzed C C a first attempt, the reaction was run with 10 mol% of
bond forming processes. However, arenediazonium Pd
A
salts were described as far back as the 1970s as effi- the alkenylated thiophene was formed after 24 h of
cient arylating agents[10] and their use, though limited reaction (entry 1, Table 1). We then studied the effect
in comparison with halides and triflates, has become of the addition of a base to the reaction mixture. The
far more common in recent years.[11] The enhanced base we selected, sodium acetate, had a deleterious
leaving properties of nitrogen as a nucleofuge, the effect since the addition of an excess (3 equivalents)
typically mild and base-free reaction conditions, and led to the failure of the reaction. Since the base can
the effectiveness of simple palladium salts as the most sometimes decompose the diazonium salt, we repeat-
efficient catalysts make arenediazonium salts a viable ed the reaction with just 1 equivalent of the base but
À
alternative as a partner in palladium-catalyzed C C a yield of only 9% was obtained (entries 2 and 3,
bond forming reactions. In addition, the use of heter- Table 1). The next parameter to be adjusted was the
oarenediazonium salts as electrophiles in palladium solvent, for which a 1:1 mixture of ethanol-water was
cross-coupling reactions, which has been very limited tested. This proved to be a better reaction media
to date,[12] has great potential as a field of investiga- since a slightly increased 69% yield was obtained
tion.
after only 1.5 h. This yield was increased to 86% on
Given this situation, our aim was to study the syn- running the reaction for 48 h (compare entry 1 with
thesis of 3-substituted thiophene derivatives by the entries 4 and 5, Table 1). A test was then performed
Matsuda–Heck reaction and Suzuki–Miyaura cross- by decreasing the amount of catalyst to 5 mol% with
coupling using thiophenediazonium salts as electro- the result that a 33% yield was achieved after 20 h of
philic partners. We then also applied the cross-cou- reaction (entry 6, Table 1). Finally, a reaction was run
plings to benzo[b]thiophenediazonium derivatives.
after increasing the temperature to 608C but reducing
the loading of the catalyst to 1 mol%. However, after
46 h of reaction, only an 8% yield of the desired prod-
uct was obtained together with a 16% yield of the
dediazotized product. We therefore concluded that
Results and Discussion
Commercially available methyl 3-aminothiophene-2- 10 mol% and room temperature were the optimum
carboxylate was diazotized using sodium nitrite and reaction conditions for this process due to the moder-
tetrafluoroboric acid to give a 70% yield of the corre- ate thermal stability of the starting material. It should
sponding diazonium salt 1.[13] This compound showed be noted that no transesterification of the methyl
Table 1. Optimization of the reaction conditions in the Matsuda–Heck reaction between 2-methoxycarbonylthiophene-3-di-
azonium tetrafluoroborate (1) and ethyl acrylate (2a).[a]
Entry
Solvent
Base
Time [h]
Yield of 3a [%]
1
2
3
EtOH
EtOH
EtOH
–
24
24
2
61
0
9
NaOAc (3 equiv.)
NaOAc (1 equiv.)
4
EtOH-H2O (1:1)
EtOH-H2O (1:1)
EtOH-H2O (1:1)
EtOH-H2O (1:1)
–
–
–
–
1.5
48
20
46
69
86
33
8[d]
5
6[b]
7[c]
[a]
Reactions were carried out using 1.2 equiv. of diazonium salt 1, 10 mol% of Pd
late 2a at room temperature.
5 mol% of PdACHTUNGTRENNUNG(OAc)2 catalyst was used.
ACHTUNGRTENN(UNG OAc)2 catalyst and 1 equiv. of ethyl acry-
[b]
[c]
[d]
Reaction run with 1 mol% of PdACTHNUTRGNEUNG(OAc)2 at 608C.
Methyl thiophene-2-carboxylate was also isolated with a 16% yield; MS (EI): m/z=142 [M]+, 111 [MÀOMe]+.
2004
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Functionalization of the 3-Position of Thiophene and Benzo[b]thiophene Moieties
Table 2. Matsuda–Heck reactions of 1 and olefins 2b–2h.[a]
Entry
1
Olefin 2
Time [h]
5
Product 3/Yield [%]
2b
2c
3b/86
3c/60
2
3
4
5
2d
24
3d/60
2e
29
3e/85
5[b]
6
2e
2f
19
24
3e/94
3f/0
7
2g
24
3g/40+3g’/60
8[b]
2g
2h
17
2
3g/35+3g’/65
3h/58+3h’/9
9[c]
[a]
Reaction conditions: 10 mol% Pd
The reaction was run at 608C.
Yields of 3h and 3hꢀ were calculated by H NMR integration from an inseparable chromatographed mixture.
ACHTUNGTRENNUNG
[b]
[c]
1
ester of the thiophene derivative occurred when using highly effective giving an 86% yield after 5 h of reac-
EtOH as the solvent. tion (entry 1, Table 2). Furthermore, styrene 2c and
Once the optimum conditions were established, we its derivative 4-acetoxystyrene 2d also participated in
studied the scope of the reaction by testing an array the reaction (entries 2 and 3, Table 2). A reaction be-
of olefins (Table 2). The general applicability of the tween diethyl vinylphosphonate 2e and 1 also fur-
reaction with acrylates was tested by running the re- nished an 85% yield of thiophene derivative 3e after
action with tert-butyl acrylate, which proved to be 29 h of reaction (entry 4, Table 2). However, the reac-
Adv. Synth. Catal. 2011, 353, 2003 – 2012
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Mꢀnica Raduꢁn et al.
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tion time was decreased to 19 h by heating at 608C
and the yield was improved to 94% (entry 5, Table 2).
A different situation was found in the case of acrylo-
nitrile where no reaction took place (entry 6, Table 2).
Other authors have also found a significant decrease
in reactivity when using benzenediazonium salts with
CN groups as substituents and have postulated a pos-
sible complexation of the catalytically active palladi-
um species by the cyano group.[11b] We then turned
our attention to disubstituted olefins. 1,1-Disubstitut-
ed a-methylene-g-butyrolactone 2g was tested and al-
Scheme 1. One-pot synthesis of 3b from 3-aminothiophene
derivative 4.
kenylated product 3g was obtained together with um aryltrifluoroborates[14] as boron counterparts since
product 3g’, which came from an isomerization of the they are less prone to protodeboronation and have
double bond in compound 3g that took place during been shown to be highly effective in combination
the Heck reaction (entry 7, Table 2). The results were with diazonium salts.[15] When we tested the optimized
similar when the reaction mixture was heated at 608C conditions for arenediazonium salts that we had pre-
(entry 8, Table 2). Cyclopentene 2h, a 1,2-disubstitut- viously established,[16] it was found that 2-methoxycar-
ed olefin, was also involved in the reaction giving an bonylthiophene-3-diazonium tetrafluoroborate 1 re-
inseparable mixture of derivative 3h (58% yield) and acted efficiently (Table 3). When the thiophenediazo-
the isomerized compound 3h’ (9% yield) (entry 9, nium salt and potassium phenyltrifluoroborate 5a
Table 2).
were mixed with PdACTHNGUTERN(NUG OAc)2 as a palladium source in
Arylation of olefins 2a–2e only gave products with dioxane, a 77% yield of the arylated product 6a was
the (E)-configuration, as was confirmed by the large obtained after 4 h of reaction at room temperature
coupling constant values (16–18 Hz) observed be-
tween the olefin protons for all compounds 3a–3e.
Table 3. Suzuki–Miyaura cross-coupling of 1 and potassium
Residual proton signals from a tentative (Z)-configu-
trifluoroborates 5.[a]
rated isomer were never observed.
Furthermore, NOESY data indicated that all com-
pounds 3, except 3h, had a conformational restriction
À
due to the hindered rotation of the C C bond be-
tween the thiophene ring and the olefin. Thus, NOE
correlations were observed between the proton in the
a-position with respect to R and the H-4 proton of
the thiophene ring in all compounds. This fact has
been successfully used to determine the double bond
configuration in the case of compound 3g. The only
olefinic proton resonating at d=8.4 ppm represents a
cis position with respect to the carbonyl group of the
lactone as confirmed by the NOE correlation between
the methylene b-protons of the lactone ring and the
H-4 of the thiophene ring. However, this olefinic
proton does not show an NOE with any other proton
(see Supporting Information for 2D NMR experi-
ments).
Entry
RBF3K
5
R
Time
[h]
Product/
Yield
[%]
1
2
3
4
5a
5b
5c
5d
5d
5d
5d
5d
5e
Ph
4
0.75
1
1.25
0.75
0.5
0.5
5
6a/77
6b/69
6c/82
6d/41
6d/84
6d/85
6d/78
6d/79
6e/68
4-F-C6H4
3-F-C6H4
2,4-F-C6H3
2,4-F-C6H3
2,4-F-C6H3
2,4-F-C6H3
2,4-F-C6H3
2-MeO-
5[b]
6[c]
7[d]
8[e]
9
1.25
C6H4
A tandem diazotization Matsuda–Heck reaction is
a highly attractive option to arylate alkenes as it is
possible to start directly with commercially available
anilines, so generating the corresponding diazonium
salts in-situ and in this way avoiding their prior isola-
tion. Given the importance of this question, we tested
the diazonium salt preparation/Matsuda–Heck reac-
tion sequence in a one-pot process without the isola-
tion of the diazonium salt intermediate (Scheme 1).
The reaction worked effectively affording a 58% yield
of the alkenylated product 3b in two steps.
10
5f
5f
5f
5g
2-Me-C6H4
2-Me-C6H4
2-Me-C6H4
3-thiophene
1.25
0.75
7
6f/44
6f/44
6f/40
6g/78
11[b]
12[f]
13
0.75
[a]
Reaction conditions: 10 mol% PdACTHNUTRGNEUNG(OAc)2, 1 (1 mmol), 5
(1.2 mmol), 1,4-dioxane at room temperature.
EtOH was used as a solvent.
Reaction in EtOH and with a 5 mol% of PdACTHUNGTRENNNUG
Reaction in EtOH, with a 5 mol% of Pd
0.5 equiv. of CaCO3.
Reaction in EtOH and with a 1 mol% of Pd
Reaction in EtOH and with 10 mol% of PdCl2
AHCTUNGRTEG(NNUN CH3CN)2.
[b]
[c]
[d]
ACHTUNGTRENNUNG
[e]
[f]
ACHTUNGERTN(NUNG OAc)2.
We then turned our attention to the Suzuki–
Miyaura cross-coupling. It was decided to test potassi-
a
2006
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Functionalization of the 3-Position of Thiophene and Benzo[b]thiophene Moieties
Table 4. Suzuki–Miyaura cross-coupling of 8 and potassium
trifluoroborates 5.[a]
(entry 1, Table 3). The scope of the reaction was stud-
ied by varying the nature of the organotrifluoroborate
counterpart. Whatever the electronic and steric
nature of the trifluoroborates, the cross-coupling pro-
ceeded extremely fast since the reaction could be per-
formed in about one hour. With F as the substituent,
para-, meta- and ortho, para-derivatives were effi-
ciently coupled (entries 2–4, Table 3). However, since
only a 41% yield of derivative 6d was obtained
(entry 4, Table 3), the process was optimized. The
yield of 6d was improved to 84% by changing the sol-
vent to EtOH (entry 5, Table 2) and we found that it
Entry
RBF3K
5
R
Time
[h]
Product/
Yield
[%]
1
2
5a
5c
5d
5d
5e
Ph
1.5
1
0.75
0.5
1.5
9a/72
9c/72
9d/21
9d/57
9e/57
was possible to reduce the quantity of PdACTHNUGTRENUNG(OAc)2 to
3-F-C6H4
2,4-F-C6H4
2,4-F-C6H4
2-MeO-
C6H3
3
5 mol% in EtOH without hindering the reaction
(entry 6, Table 3). The use of 0.5 equiv. of CaCO3 was
slightly detrimental to the obtained yield (entry 7,
4[b]
5
Table 3). When the amount of PdACTHNUTRGNENUG(OAc)2 was reduced
6
5g
3-thiophene
1
9g/68
to 1 mol%, the cross-coupling was effective although
the reaction time was longer (entry 8, Table 3). ortho-
Substituted derivative 5e with an electron-donating
group was cross-coupled giving a 68% yield of com-
pound 6e (entry 9, Table 3). The case of ortho-methyl-
substituted trifluoroborate 5f was surprising since the
[a]
Reaction conditions: 10 mol% PdACTHNUTRGNEUNG(OAc)2, 8 (1 mmol), 5
(1.2 mmol), 1,4-dioxane at room temperature.
EtOH was used as the solvent.
[b]
maximum yield was 44% and no improvement was stability. The benzo[b]thiophene ring system and its
obtained by running the reaction in EtOH or by using derivatives are present in biologically active com-
PdCl2ACHTUNGTRENNUNG
(CH3CN)2 as a catalytic system (entries 10–12, pounds and functional materials.[18] Therefore, effi-
Table 3). A good yield of the bithiophene product 6g cient methods for the construction of these deriva-
was also achieved when coupling diazonium salt 1 tives is of importance in organic synthesis. Using the
with potassium 3-thienyltrifluoroborate 5g, allowing previously optimized reaction conditions for Suzuki–
the heteroaryl-heteroaryl derivative to be obtained Miyaura cross-coupling, a series of aryltrifluorobo-
(entry 13, Table 3).
rates 5 was coupled with benzo[b]thiophene diazoni-
As in the former Matsuda–Heck reaction, a one- um salt 8 with good results (Table 4). In the specific
pot procedure was also evaluated. It was possible to case of trifluoroborate 5d, the cross-coupled product
perform diazotization and arylation reactions sequen- was obtained but with only a 21% yield (entry 3,
tially giving a 61% yield of compound 6c in a two- Table 4). We then changed the solvent from 1,4-diox-
step process (Scheme 2).
ane to ethanol with the result that the yield increased
In order to extend the methodology to other relat- to 57% (entry 4, Table 4). As in the case of thiophene,
ed substrates, methyl 3-aminobenzo[b]thiophene-2- fluorine atom-containing trifluoroborates 5c and 5d
carboxylate 7, which was easily prepared from com- were chosen because the resulting organofluorine
mercially available 2-nitrobenzonitrile and thioglyco- Suzuki–Miyaura coupling products may have signifi-
late following the method described in the litera- cant industrial and medical applications.[19] Heteroaro-
ture,[17] was diazotized to afford 2-methoxycarbonyl- matic trifluoroborate 5g was also coupled with good
benzo[b]thiophene-3-diazonium tetrafluoroborate 8. results (entry 6, Table 4).
This unreported diazonium salt showed good thermal
Conclusions
We have demonstrated the effectiveness of coupling
thiophenediazonium salts with a range of olefins and
thiophene and benzo[b]thiophene diazonium salts
with potassium organotrifluoroborates using a ligand-
less palladium catalyst without a base at room tem-
perature and with short reaction times. We have also
demonstrated that one-pot processes are efficient for
Matsuda–Heck and Suzuki–Miyaura reactions. These
processes make it possible to obtain a wide range of
thiophene and benzo[b]thiophene derivatives func-
Scheme 2. One-pot synthesis of 6c from 3-aminothiophene
derivative 4.
Adv. Synth. Catal. 2011, 353, 2003 – 2012
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Mꢀnica Raduꢁn et al.
FULL PAPERS
16.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz): d=28.2, 52.3,
80.7, 124.0, 126.7, 130.7, 130.9, 135.6, 141.9, 162.3, 166.0; MS
(EI): m/z=268 [M]+, 212 [MÀt-Bu]+, 195 [MÀO-t-Bu]+, 167
[MÀCO2-t-Bu]+; anal. calcd. for C13H16SO4: C 58.19, H 6.01;
found: C 58.50, H 6.06.
tionalized in their 3-positions. We are currently work-
ing on determining the potential of other heteroaro-
matic diazonium salts in cross-coupling processes.
Methyl 3-(E)-styrylthiophene-2-carboxylate (3c): Purifica-
tion by column chromatography on silica gel (hexanes/ethyl
acetate, 50:1); colourless solid; mp 79–818C (Lit.[21] mp 78–
Experimental Section
798C). IR (neat): n=1700, 1434, 1218 cmÀ1
;
1H NMR
General Remarks
3
(CDCl3, 400 MHz): d=3.90 (s, 3H), 7.11 (d, JH,H =16.6 Hz,
Reaction mixtures were chromatographed through a silica
gel column (230–400 mesh). EI mass spectra were recorded
3
1H), 7.28 (m, 1H), 7.33–7.39 (m, 2H), 7.44 (q, JH,H
=
5.2 Hz, 2H), 7.54–7.59 (m, 2H), 8.13 (d, 3JH,H =16.6 Hz,
1H); 13C NMR (CDCl3, 100 MHz): d=52.0, 121.9, 126.1,
126.5, 126.9, 128.2, 128.7, 130.4, 132.9, 136.9, 145.6, 163.0;
MS (EI): m/z=244 [M]+, 185 [MÀCO2Me]+.
1
at 70 eV. H NMR spectra were measured at 400 MHz and
300 MHz and 13C NMR spectra at 100 MHz and 75 MHz
with Bruker instruments. 1H and 13C chemical shifts (d)
were referenced to internal solvent resonances and reported
relative to SiMe4. Infrared (IR) spectra were recorded as
neat samples in the ATR mode using an FT-IR Mattson-
Galaxy spectrometer.
Methyl
3-[(E)-4-acetoxystyryl]thiophene-2-carboxylate
(3d): Purification by column chromatography on silica gel
(hexanes/ethyl acetate, 50:1); colourless solid; mp 133–
1358C. IR (neat): n=1760, 1707, 1190 cmÀ1
;
1H NMR
Commercially available methyl 3-aminothiophene-2-car-
boxylate (4), olefins 2, and potassium organotrifluoroborates
5 were used without purification. 2-Methoxycarbonylthio-
phene-3-diazonium tetrafluoroborate (1)[13] and methyl 3-
aminobenzo[b]thiophene-2-carboxylate (7)[17] were prepared
as described in the literature. 2-Methoxycarbonylbenzo[b]-
thiophene-3-diazonium tetrafluoroborate (8) was prepared
by diazotization of 7 with sodium nitrite in the presence of
HBF4 following the method for the synthesis of 1.[13]
2-Methoxycarbonylbenzo[b]thiophene-3-diazonium tetra-
fluoroborate (8): Pale yellow solid; mp 206–2078C; IR
(neat): n=2250, 1731 cmÀ1.
(CDCl3, 400 MHz): d=2.30 (s, 3H), 3.90 (s, 3H), 7.08 (m,
1H), 7.09 (d, 3JH,H =8.6 Hz, 2H), 7.43 (s, 2H), 7.55 (d,
3
3JH,H =8.6 Hz, 2H), 8.07 (d, JH,H =16.4 Hz, 1H); 13C NMR
(CDCl3, 100 MHz): d=21.1, 52.0, 121.9, 122.2, 126.0, 126.4,
127.9, 130.5, 131.8, 134.8, 145.4, 150.5, 162.9, 169.4; MS (EI):
m/z=302 [M]+, 260 [MÀ42]+; anal. calcd. for C16H14SO4: C
63.56, H 4.67, S 10.61; found: C 63.65, H 4.63, S 10.17.
(E)-Diethyl 2-[2-(methoxycarbonyl)thiophen-3-yl]vinyl-
phosphonate (3e): Purification by column chromatography
on silica gel (hexanes/ethyl acetate, from 9:1 to 4:6); colour-
1
less oil. IR (neat): n=2982, 1708, 1235, 1020 cmÀ1; H NMR
3
4
(CDCl3, 300 MHz): d=1.37 (dt, JH,H =6.9 Hz, JP, H =0.6 Hz,
6H), 3.91 (s, 3H), 4.16 (dq, 3JH,H =6.9 Hz, 3JP, H =0.9 Hz,
General Procedure for the Matsuda–Heck Reaction
(Table 1 and Table 2)
3
4H), 6.24 (dd, 2JH,P =18.3 Hz, JH,H =17.7 Hz 1H), 7.34 (d,
3JH,H =5.2 Hz, 1H), 7.47 (dd, 3JH,H =5.2 Hz, 4JH,H =0.6 Hz,
3
3
4
1H), 8.27 (dd, JH,P =22.2 Hz, JH,H =17.7 Hz, JH,H =0.6 Hz,
Olefin 2 (1 mmol) and PdACHTNUTRGNENG(U OAc)2 (10 mol%) in EtOH
1H); 13C NMR (CDCl3, 75 MHz): d=16.4 (d, JC,P =6.3 Hz),
3
(1.5 mL) were added to a solution of 2-methoxycarbonylth-
iophene-3-diazonium tetrafluoroborate (1) (1.2 mmol) in
EtOH:H2O (1 mL:2.5 mL) at room temperature. The result-
ing mixture was stirred until the reaction was completed
(TLC monitoring, Table 1 and Table 2). The reaction mix-
ture was filtered through celite, the solvent was evaporated
and the crude was purified by column chromatography on
silica gel to give the desired compound.
2
1
52.3, 62.2 (d, JC,P =5.6 Hz), 118.3 (d, JC,P =189.9 Hz), 126.5,
130.7, 130.8, 139.8 (d, 2JC,P =7.9 Hz), 142.3 (d, JC,P
=
3
27.2 Hz,), 162.2; MS (EI): m/z=304 [M]+, 167
[MÀPO3C4H10]+; HRMS (ESI): m/z=305.0611, calcd. for
[C12H17SO5P+H]+: 305.0607.
Methyl
3-[(E)-(4,5-dihydro-2-oxofuran-3-ylidene)me-
thyl]thiophene-2-carboxylate (3g): Purification by column
chromatography on silica gel (hexanes/ethyl acetate, from
9.5:0.5 to 7:3); colourless solid, mp 149–1508C. IR (neat):
Methyl 3-[(E)-2-(ethoxycarbonyl)vinyl]thiophene-2-car-
boxylate (3a): Purification by column chromatography on
silica gel (hexanes/ethyl acetate, 9.5:0.5); colourless solid;
mp 65–668C (Lit.[12b] mp 65.5–668C). IR (neat): n=1703,
1
n=1738, 1697, 1511, 1435, 1412, 1246, 1186 cmÀ1; H NMR
3
4
(CDCl3, 300 MHz): d=3.18 (dt, JH,H =7.2 Hz, JH,H =3.0 Hz,
3
3
1
1434, 1231, 1184 cmÀ1; H NMR (CDCl3, 400 MHz): d=1.35
2H), 3.93 (s, 3H), 4.46 (t, JH,H =7.2 Hz, 2H), 7.30 (d, JH,H
=
3
4
3
3
5.4 Hz, 1H), 7.56 (dd, JH,H =5.4 Hz, JH,H =0.6 Hz, 1H), 8.40
(t, JH,H =7.2 Hz, 3H), 3.93 (s, 3H), 4.28 (q, JH,H =7.2 Hz,
2H), 6.38 (d, 3JH,H =16.2 Hz, 1H), 7.36 (d, 3JH,H =5.2 Hz,
1H), 7.48 (d, 3JH,H =5.2 Hz, 1H), 8.51 (d, 3JH,H =16.2 Hz,
1H); 13C NMR (CDCl3, 100 MHz): d=14.3, 52.3, 60.7, 122.2,
126.7, 130.8, 131.0, 136.5, 141.9, 162.3, 166.7; MS (EI): m/z=
240 [M]+, 195 [MÀOEt]+, 167 [MÀCO2Et]+, 135
[MÀCO2EtÀOMe]+.
(t, JH,H =3.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=27.5,
4
52.5, 65.2, 125.0, 128.1, 129.2, 130.9, 132.7, 140.8, 162.1,
171.8; MS (EI): m/z=238 [M]+, 207 [MÀOCH3]+, 179
[MÀCO2CH3]+; HR-MS (ESI): m/z=261.0196, calcd. for
[C11H10SO4 +Na]+: 261.0192.
3-[(2-Acetylthiophen-3-yl)methyl]furan-2(5H)-one (3g’):
Purification by column chromatography on silica gel (hex-
anes/ethyl acetate, 9.5:0.5); colourless oil. IR (neat): n=
Methyl 3-[(E)-2-(tert-butoxycarbonyl)vinyl]thiophene-2-
carboxylate (3b): Purification by column chromatography on
silica gel (hexanes/ethyl acetate, 20:1); colourless solid; mp
45–478C (Lit.[20] oil). IR (neat): n=1698, 1438, 1277,
1747, 1703, 1436, 1416, 1264, 1196, 1067, 1044 cmÀ1
;
1H NMR (CDCl3, 300 MHz): d=3.87 (s, 3H), 4.04 (q,
4JH,H =2.1 Hz, 2H), 4.75 (q, 4JH,H =2.0 Hz, 2H), 7.08 (d,
3JH,H =5.1 Hz, 1H), 7.09 (m, 1H), 7.46 (d, 3JH,H =5.1 Hz,
1H); 13C NMR (CDCl3, 75 MHz): d=25.4, 52.0, 70.3, 127.5,
1150 cmÀ1
;
1H NMR (CDCl3, 400 MHz): d=1.54 (s, 9H),
3.91 (s, 3H), 6.30 (d, 3JH,H =16.2 Hz, 1H), 7.33 (d, JH,H
=
=
3
5.4 Hz, 1H), 7.45 (d, 3JH,H =5.4 Hz, 1H), 8.41 (d, JH,H
3
2008
asc.wiley-vch.de
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 2003 – 2012

Functionalization of the 3-Position of Thiophene and Benzo[b]thiophene Moieties
4
130.8, 131.2, 132.5, 145.2, 145.9, 162.7, 173.9; MS (EI) m/z=
207 [MÀOCH3]+, 179 [MÀCO2CH3]+; anal. calcd. for
C11H10SO4: C 55.45, H 4.23; found: C 55.81, H 4.74.
2JC,F =20.8 Hz), 116.3 (d, 2JC,F =22.2 Hz), 125.0 (d, JC,F
=
3
2.8 Hz), 127.4, 129.3 (d, JC,F =8.3 Hz), 130.5, 131.4, 137.7 (d,
1
3JC,F =8.2 Hz), 147.1 (d, 4JC,F =2.2 Hz), 162.2 (d, JC,F
=
243.9 Hz), 162.3; MS (EI): m/z=236 [M]+, 205 [MÀOMe]+,
177 [MÀCO2Me]+, 157 [MÀCO2MeÀF]+; anal. calcd. for
C12H9SO2F: C 61.00, H 3.84, S 13.57; found: C 61.41, H 3.61,
S 13.26.
Methyl 3-(cyclopent-1-enyl)thiophene-2-carboxylate (3h)
and methyl 3-(cyclopent-2-enyl)thiophene-2-carboxylate
(3h’): Purification by column chromatography on silica gel
(hexanes/ethyl acetate, 20:1); pale yellow oil. IR (neat): n=
1
1713, 1434, 1219 cmÀ1; H NMR (CDCl3, 400 MHz) d=1.63–
Methyl
3-(2,4-difluorophenyl)thiophene-2-carboxylate
(6d): Purification by column chromatography on silica gel
3
1.71 (m, 2H, 3h’), 2.01 (q, JH,H =3.6 Hz, 2H, 3h), 2.41–2.50
(m, 2H, 3h’), 2.45–2.55 (m, 2H, 3h), 2.70–2.76 (m, 2H, 3h),
(hexanes/ethyl acetate, 9.5:0.5); colourless solid; mp 149–
1518C. IR (neat): n=1704, 1495, 1282, 1236 cmÀ1; H NMR
1
3.84 (s, 3H, 3h), 3.85 (s, 3H, 3h’), 4.85 (m, 1H, 3h’), 5.75 (m,
3
1H, 3h’), 5.90 (m, 1H, 3h’), 6.15 (m, 1H, 3h), 6.93 (d, JH,H
=
(CDCl3, 300 MHz): d=3.78 (s, 3H), 6.80–6.96 (m, 2H), 7.06
5.1 Hz, 1H, 3h’), 7.00 (d, 3JH,H =5.2 Hz, 1H, 3h), 7.36 (d,
3JH,H =5.1 Hz, 1H, 3h’), 7.38 (d, 3JH,H =5.2 Hz, 1H, 3h);
13C NMR (CDCl3, 75 MHz): d=24.0, 33.5, 35.9, 52.1, 126.0,
129.8, 130.6, 132.3, 138.2, 145.6, 162.7 (3h); 32.4, 44.8, 51.8,
128.1, 128.7, 130.5, 132.2, 133.6, 155.2, 162.7 (3h’); MS (EI):
m/z=208 [M]+, 175, 149 [MÀCO2Me]+; anal. calcd. for
C11H12SO2: C 63.43, H 5.81; found: C 63.72, H 5.89.
3
5
(dd, JH,H =5.1 Hz, JH,F =0.9 Hz 1H), 7.32 (m, 1H), 7.55 (d,
3JH,H =5.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=52.1,
4
103.9 (t, 2JC,F =25.7 Hz), 110.9 (dd, 2JC,F =21.2 Hz, JC,F
=
3.7 Hz), 119.8 (dd, 2JC,F =15.7 Hz, 4JC,F =4.0 Hz), 128.9,
130.4, 131.1, 131.8 (dd, 3JC,F =9.5 Hz, 3JC,F =4.4 Hz), 140.4,
1
3
159.8 (dd, JC,F =249.2 Hz, JC,F =12.5 Hz), 162.1, 162.8 (dd,
1JC,F =236.3 Hz, JC,F =8 Hz); MS (EI): m/z=254 [M]+, 223
3
[MÀOMe]+, 195 [MÀCO2Me]+; HR-MS (ESI): m/z=
255.0279, calcd. for [C12H8SO2F+H]+: 255.0286.
General Procedure for the Suzuki–Miyaura Reaction
(Table 3 and Table 4)
Methyl 3-(2-methoxyphenyl)thiophene-2-carboxylate (6e):
Purification by column chromatography on silica gel (hex-
anes/ethyl acetate, 9.5:0.5); colourless solid; mp 104–1058C.
Potassium aryltrifluoroborate 5 (1.2 mmol) and PdACTHNUTRGNEUNG(OAc)2
IR (neat): n=1704, 1435, 1270, 1228 cmÀ1; H NMR (CDCl3,
1
(10 mol%) in 1,4-dioxane (3 mL) were added to a solution
of thiophene tetrafluoroborate derivatives 1 or 8 (1 mmol)
in 1,4-dioxane (1 mL) at room temperature. The resulting
mixture was stirred until the reaction was completed, as
seen by the ceasing of the release of N2 and TLC monitoring
(Table 3 and Table 4). The reaction mixture was diluted with
CH2Cl2 (10 mL) and then washed with brine (15 mL) and
with H2O (2ꢃ15 mL). The organic phase was dried and
evaporated and the crude material was purified by column
chromatography on silica gel to give the desired compound.
Methyl 3-phenylthiophene-2-carboxylate (6a): Purification
by column chromatography on silica gel (hexanes/ethyl ace-
tate, 9.5:0.5), colourless solid; mp 117–1198C (Lit.[22] 119–
400 MHz): d=3.73 (s, 3H), 3.76 (s, 3H), 6.93–7.03 (m, 2H),
3
3
4
7.07 (d, JH,H =6.8 Hz, 1H), 7.25 (dd, JH,H =10.0 Hz, JH,H
=
2.4 Hz, 1H), 7.35 (ddd, 3JH,H =10.8 Hz, 3JH,H =10.0 Hz,
4JH,H =2.4 Hz, 1H), 7.48 (d, 3JH,H =6.8 Hz, 1H); 13C NMR
(CDCl3, 100 MHz): d=51.8, 55.5, 110.8, 120.2, 125.1, 128.4,
129.4, 129.5, 130.6, 131.7, 144.3, 156.6, 162.6; MS (EI): m/z=
248 [M]+, 217 [MÀOMe]+, 187 [MÀ2OMe]+; anal. calcd. for
C13H12SO3: C 62.88, H 4.87; found: C 63.37, H 5.21.
Methyl 3-(2-methylphenyl)thiophene-2-carboxylate (6f):
Purification by column chromatography on silica gel (hex-
anes/ethyl acetate, 9.5:0.5), colourless solid; mp 102–1048C.
1
IR (neat): n=1702, 1436, 1269, 1231 cmÀ1; H NMR (CDCl3,
3
1
1208C). IR (neat): n=1704, 1437, 1278, 1233 cmÀ1; H NMR
300 MHz): d=2.13 (s, 3H), 3.72 (s, 3H), 6.97 (d, JH,H
=
3
3
5.1 Hz, 1H), 7.12–7.32 (m, 4H), 7.52 (d, JH,H =5.1 Hz, 1H);
13C NMR (CDCl3, 75 MHz): d=20.0, 51.9, 125.3, 127.9,
128.0, 128.9, 129.7, 130.2, 131.3, 136.1, 148.4, 162.2; MS (EI):
m/z=232 [M]+, 201 [MÀOMe]+, 173 [MÀCO2Me]+; HR-MS
(ESI): m/z=233.0624, calcd. for [C13H12SO3 +H]+: 233.0631.
Methyl 3,3’-bithiophene-2-carboxylate (6g): Purification
by column chromatography on silica gel (hexanes/ethyl ace-
tate, 9.5:0.5), yellow solid; mp 71–728C (Lit.[23] 72–738C).
(CDCl3, 300 MHz): d=3.77 (s, 3H), 7.09 (d, JH,H =5.1 Hz,
1H), 7.35–7.48 (m, 5H), 7.50 (d, 3JH,H =5.1 Hz, 1H);
13C NMR (CDCl3, 75 MHz): d=51.9, 126.9, 127.9, 129.2,
130.3, 131.6, 135.7, 148.7, 162.5; MS (EI): m/z=218 [M]+,
187 [MÀOMe]+, 159 [MÀCO2Me]+.
Methyl 3-(4-fluorophenyl)thiophene-2-carboxylate (6b):
Purification by column chromatography on silica gel (hex-
anes/ethyl acetate, 9.5:0.5), colourless solid; mp 111–1138C.
1
IR (neat): n=1702, 1437, 1267, 1235 cmÀ1; H NMR (CDCl3,
1
IR (neat): n=1703, 1494, 1279, 1217 cmÀ1; H NMR (CDCl3,
3
400 MHz): d=3.78 (s, 3H), 7.06 (d, 3JH,H =5.0 Hz, 1H),
400 MHz): d=3.82 (s, 3H), 7.16 (d, JH,H =6.8 Hz, 1H), 7.34
(ddd, 3JH,H =6.8 Hz, 4JH,H =3.6 Hz, 5JH,H =2.0 Hz, 2H), 7.48
3
7.07–7.12 (m, 2H), 7.40–7.46 (m, 2H), 7.50 (d, JH,H =5.0 Hz,
3
4
5
2
1H); 13C NMR (CDCl3, 75 MHz): d=52.0, 114.8 (d, JC,F
=
(d, JH,H =6.8 Hz, 1H), 7.61 (dd, JH,H =3.6 Hz, JH,H =2.0 Hz,
1H); 13C NMR (CDCl3, 75 MHz): d=52.0, 124.5, 124.9,
126.3, 129.1, 130.3, 131.4, 135.4, 142.7, 162.5; MS (EI): m/z=
224 [M]+, 193 [MÀOMe]+, 166 [MÀCO2Me]+.
3
21.3 Hz), 126.9, 130.4, 131.0 (d, JC,F =8.2 Hz), 131.4, 131.5
(d, 4JC,F =3.4 Hz), 147.6, 162.4, 162.5 (d, 1JC,F =245.8 Hz);
MS (EI): m/z=236 [M]+, 205 [MÀOMe]+, 177,
[MÀCO2Me]+; anal. calcd. for C12H9SO2F: C 61.00, H 3.84,
S 13.57; found: C 61.42, H 3.70, S 13.67.
Methyl 3-phenylbenzo[b]thiophene-2-carboxylate (9a):
Purification by column chromatography on silica gel (hex-
anes/ethyl acetate, 9.5:0.5), colourless solid: mp 149–1518C
Methyl 3-(3-fluorophenyl)thiophene-2-carboxylate (6c):
Purification by column chromatography on silica gel (hex-
anes/ethyl acetate, 9.5:0.5), colourless solid; mp 88–908C. IR
(Lit.[24] 154–1558C). IR (neat): n=2947, 1718, 1232 cmÀ1
;
1H NMR (CDCl3, 400 MHz): d=3.78 (s, 3H), 7.35 (ddd,
3JH,H =8.4 Hz, 3JH,H =7.2 Hz, 4JH,H =1.2 Hz, 1H), 7.38–7.42
(m, 2H), 7.45–7.52 (m, 4H), 7.55 (m, 1H), 7.89 (m, 1H);
13C NMR (CDCl3, 75 MHz): d=52.1, 122.5, 124.8, 125.3,
127.2, 127.9, 128.0, 128.1, 129.7, 134.5, 140.1, 140.5, 144.2,
(neat): n=1703, 1436, 1233 cmÀ1
300 MHz): d=3.78 (s, 3H), 7.08 (d, JH,H =5.1 Hz, 1H), 7.09
;
1H NMR (CDCl3,
3
3
(m, 1H), 7.15–7.24 (m, 2H), 7.36 (m, 1H), 7.52 (d, JH,H
=
5.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=52.1, 114.8 (d,
Adv. Synth. Catal. 2011, 353, 2003 – 2012
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2009

Mꢀnica Raduꢁn et al.
FULL PAPERS
162.9; MS (EI): m/z=268 [M]+, 237 [MÀOMe]+, 208
[MÀCO2Me]+.
was then added dropwise and the reaction mixture was
stirred at 0–58C for 20 min. Then a solution of tert-butyl ac-
rylate 2b (0.074 mL, 0.51 mmol) and PdACTHNGURETNNU(G OAc)2 (11.7 mg,
Methyl
3-(3-fluorophenyl)benzo[b]thiophene-2-carbox-
A
0.051 mmol) in EtOH:H2O (1:1) (7 mL) was added and the
reaction mixture was stirred at room temperature for 5 h.
The reaction mixture was filtered through celite, the solvent
was evaporated, and the crude was purified by column chro-
matography on silica gel to give 3b; yield: 78.5 mg (58%).
150–1528C. IR (neat): n=2921, 1714, 1235, 1211 cmÀ1
;
1H NMR (CDCl3, 400 MHz): d=3.80 (s, 3H), 7.10–7.20 (m,
3H), 7.37 (ddd, 3JH,H =8.0 Hz, 3JH,H =7.2 Hz, 4JH,H =0.8 Hz,
1H), 7.44–7.55 (m, 3H), 7.89 (m, 1H); 13C NMR (CDCl3,
2
2
100 MHz): d=52.3, 115 (d, JC,F =20.8 Hz), 116.8 (d, JC,F
=
=
=
General Procedure for the Suzuki–Miyaura Reaction
without Isolation of 1 (Scheme 2)
21.9 Hz), 122.6, 125.0 (d, 4JC,F =2.4 Hz), 125.5 (d, JC,F
4
3
3
2.9 Hz), 127.4, 128.4, 129.6 (d, JC,F =8.4 Hz), 136.6 (d, JC,F
1
A solution of methyl 3-amino-2-thiophenecarboxylate (4)
(50 mg, 0.32 mmol) and 50% aqueous tetrafluoroboric acid
(0.2 mL, 1.6 mmol) in H2O (0.2 mL) was stirred at 0–58C. A
solution of NaNO2 (0.022 g, 0.32 mmol) in H2O (0.05 mL)
was then added dropwise and the reaction mixture was
stirred at 0–58C for 15 min. Then, the supernatant was re-
moved by cannula and a solution of potassium 3-fluorophe-
8.3 Hz), 139.7, 140.4, 142.5, 162.5 (d, JC,F =244.7 Hz), 162.7;
MS (EI): m/z=286 [M]+, 255 [MÀOMe]+; HR-MS (ESI):
m/z=309.0352, calcd. m/z [C16H11SO2F+Na]+: 309.0356.
Methyl
3-(2,4-difluorophenyl)benzo[b]thiophene-2-car-
boxylate (9d): Purification by column chromatography on
silica gel (hexanes/ethyl acetate, 9.5:0.5); colourless oil. IR
(neat): n=2951, 1721, 1274, 1231 cmÀ1 1H NMR (CDCl3,
;
nyltrifluoroborate (5c) (77 mg, 0.38 mmol) and PdACHTUNGTRENNUNG(OAc)2
400 MHz): d=3.82 (s, 3H), 6.95–7.05 (m, 2H), 7.30–7.42 (m,
2H), 7.48–7.54 (m, 2H), 7.90 (m, 1H); 13C NMR (CDCl3,
100 MHz): d=52.4, 104.2 (t, 2JC,F =25.5 Hz), 111.2 (dd,
2JC,F =21.2 Hz, 4JC,F =3.6 Hz), 118.3 (dd, 2JC,F =16.5 Hz,
4JC,F =6.0 Hz), 122.7, 124.7, 125.1, 127.4, 129.7, 132.2 (dd,
(7.1 mg, 0.031 mmol) in 1,4-dioxane (4 mL) was added. The
resulting mixture was then stirred at room temperature for
55 min (TLC monitoring). Finally, the reaction mixture was
filtered through celite, the solvent was evaporated, and the
crude was purified by column chromatography on silica gel
to give 6c; yield: 46 mg (61%).
3JC,F =9.5 Hz, 3JC,F =4.4 Hz), 136.0, 139.3, 140.4, 160.4 (dd,
1JC,F =283.9 Hz, 3JC,F =12.0 Hz), 162.6, 162.9 (dd, JC,F
=
1
282.4 Hz, 3JC,F =12.1 Hz; MS (EI): m/z=304 [M]+, 273
[MÀOMe]+, 244 [MÀCO2Me]+; HR-MS (ESI): m/z=
327.0253, calcd. for [C16H10SO2F2 +Na]+: 327.0262.
Methyl 3-(2-methoxyphenyl)benzo[b]thiophene-2-carbox-
ylate (9e): Purification by column chromatography on silica
gel (hexanes/ethyl acetate, 9.5:0.5), colourless solid; mp 84–
Acknowledgements
Financial support from MICINN of Spain (CTQ2008-05409-
C02-02 and CTQ2009-08328) and “Generalitat de Catalu-
nya” (2009SGR637) is acknowledged. Spectroscopic data has
been partially funded by the University of Girona under the
project with reference STR-CT00059.
868C. IR (neat): n=2948, 1719, 1232 cmÀ1
;
1H NMR
(CDCl3, 400 MHz): d=3.71 (s, 3H), 3.77 (s, 3H), 7.03 (d,
3JH,H =8.4 Hz, 1H), 7.07 (td, 3JH,H =7.6 Hz, ,4JH,H =1.2 Hz,
1H), 7.24 (dd, 3JH,H =7.6 Hz, 4JH,H =2.0 Hz, 1H), 7.33 (m,
1H), 7.41–7.49 (m, 3H), 7.87 (m, 1H); 13C NMR (CDCl3,
100 MHz): d=52.1, 55.6, 111.1, 120.3, 122.5, 123.6, 124.6,
125.2, 126.9, 128.7, 129.7, 130.9, 139.9, 140.4, 157.2, 162.9;
MS (EI): m/z=298 [M]+, 267 [MÀOMe]+; HR-MS (ESI):
m/z=321.0540, calcd. for [C17H14SO3 +Na]+: 321.0556.
References
[1] a) S. Gronowitz, in: The Chemistry of Heterocyclic
Compounds: Thiophene and Its Derivatives, Vol. 44,
Parts 1–5, (Ed.: S. Gronowitz), Wiley, New York, 1991;
b) T. Eicher, S. Hauptmann, A. Speicher, in: The
Chemistry of Heterocycles, Chapter 5, Section 5.6.,
Wiley-VCH, New York, 2003; c) Heterocyclic Chemis-
try, (Eds.: J. A. Joule, K. Mills), Blackwell Science
Malden, MA, 2000.
[2] For selected recent examples, see: a) C. Wu, E. R.
Decker, N. Blok, H. Bui, T. J. You, J. Wang, A. R.
Bourgoyne, V. Knowles, K. L. Berens, G. W. Holland,
T. A. Brock, R. A. F. Dixon, J. Med. Chem. 2004, 47,
1969–1986; b) K. Dorꢄ, S. Dubus, H.-A. Ho, I. Lꢄv-
esque, M. Brunette, G. Corbeil, M. Boissinot, G.
Boivin, M. G. Bergeron, D. Boudreau, M. Leclerc, J.
Am. Chem. Soc. 2004, 126, 4240–4244; c) R. Scarpelli,
A. Di Marco, F. Ferrigno, R. Laufer, I. Marcucci, E.
Muraglia, J. M. Ontoria, M. Rowley, S. Serafini, C.
Steinkꢅhler, P. Jones, Bioorg. Med. Chem. Lett. 2008,
18, 6078–6082; d) E. Muraglia, S. Altamura, D. Branca,
O. Cecchetti, F. Ferrigno, M. V. Orsale, M. C. Palumbi,
M. Rowley, R. Scarpelli, C. Steinkꢅhler, P. Jones,
Methyl 3-(3-thiophene)benzo[b]thiophene-2-carboxylate
(9g): Purification by column chromatography on silica gel
(hexanes/ethyl acetate, 9.5:0.5); colourless solid; mp 121–
1
1238C. IR (neat): n=2920, 1713, 1233, 1211 cmÀ1; H NMR
4
(CDCl3, 400 MHz): d=3.83 (s, 3H), 7.23 (dd, JH,H =4.8 Hz,
3
3
5JH,H =1.6 Hz, 1H), 7.38 (ddd, , JH,H =8.0 Hz, JH,H =7.2 Hz,
4JH,H =1.2 Hz, 1H), 7.42–7.46 (m, 2H), 7.49 (ddd, JH,H
=
3
3
4
8.0 Hz, JH,H =6.8 Hz, JH,H =1.2 Hz, 1H), 7.70 (m, 1H), 7.87
(m, 1H); 13C NMR (CDCl3, 100 MHz): d=52.3, 122.5, 124.7,
124.9, 125.0, 125.3, 127.3, 128.0, 129.5, 133.8, 138.9, 139.9,
140.3, 162.9; MS (EI): m/z=274 [M]+, 243 [MÀOMe]+; HR-
MS (ESI): m/z=297.0004, calcd. for [C14H10S2O2 +Na]+:
297.0014.
General Procedure for the Matsuda–Heck Reaction
without Isolation of 1 (Scheme 1)
A solution of methyl 3-amino-2-thiophenecarboxylate (4)
(80 mg, 0.51 mmol) and 50% aqueous tetrafluoroboric acid
(0.32 mL, 2.6 mmol) in H2O (0.3 mL) was stirred at 0–58C.
A solution of NaNO2 (0.035 g, 0.51 mmol) in H2O (0.08 mL)
2010
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Adv. Synth. Catal. 2011, 353, 2003 – 2012

Functionalization of the 3-Position of Thiophene and Benzo[b]thiophene Moieties
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