Regioselective palladium(0)-catalyzed cross-coupling reactions and metal-halide exchange reactions of tetrabromothiophene: Optimization, scope and limitations

Article abstract of DOI:10.1002/adsc.200900044

The Suzuki reaction of tetrabromothiophene with arylboronic acids provides a regioselective approach to various 5-aryl-2,3,4-tribromothiophenes, symmetrical 2,5-diaryl-3,4-dibromothiophenes, and tetraarylthiophenes. Unsymmetrical 2,5-diaryl-3,4-dibromo thiophenes are prepared by Suzuki reaction of 5-aryl-2,3,4-tribromothiophenes. Tetraarylthiophenes containing two different types of aryl groups are obtained by Suzuki reactions of 2,5-diaryl-3,4- dibromothiophenes. During the optimization of the conditions of each individual reaction, the solvent, the catalyst and the temperature play an important role. In several cases, classical conditions.

Full text of DOI:10.1002/adsc.200900044

FULL PAPERS
DOI: 10.1002/adsc.200900044
Regioselective Palladium(0)-Catalyzed Cross-Coupling Reactions
and Metal-Halide Exchange Reactions of Tetrabromothiophene:
Optimization, Scope and Limitations
a
a
a,c
a
´
ˇ
ˇ
¯
.
Dang Thanh Tꢀng, Dang Thanh Tuꢁn, Nasir Rasool, Alexander Villinger,
¯
.
Helmut Reinke,a Christine Fischer,b and Peter Langera,b,*
Institut fꢂr Chemie, Universitꢃt Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
a
Fax : (+49)-381-498-6412; e-mail: peter.langer@uni-rostock.de
Leibniz-Institut fꢂr Katalyse e. V. an der Universitꢃt Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Department of Chemistry, G. C. University Faisalabad, Faisalabad, Pakistan
b
c
Received: January 21, 2009; Revised: April 14, 2009; Published online: June 12, 2009
Abstract: The Suzuki reaction of tetrabromothio- ceeded sluggishly could be significantly improved by
phene with arylboronic acids provides a regioselec- application of a new biarylmonophosphine ligand de-
tive approach to various 5-aryl-2,3,4-tribromothio- veloped by Buchwald and co-workers. Regioselective
phenes,
symmetrical
2,5-diaryl-3,4-dibromothio- metal-halide exchange reactions of tetrabromothio-
phenes, and tetraarylthiophenes. Unsymmetrical 2,5- phene provide a convenient approach to various 2,5-
diaryl-3,4-dibromothiophenes are prepared by disubstituted 3,4-dibromothiophenes. 5-Alkyl-2-tri-
Suzuki reaction of 5-aryl-2,3,4-tribromothiophenes. methylsilyl-3,4-dibromothiophenes could be pre-
Tetraarylthiophenes containing two different types of pared in one pot by sequential addition of trimethyl-
aryl groups are obtained by Suzuki reactions of 2,5- chlorosilane and alkyl bromides. The reaction of tet-
diaryl-3,4-dibromothiophenes. During the optimiza- rabromothiophene with methyl chloroformate and
tion of the conditions of each individual reaction, the subsequent Suzuki reactions afforded 3,4-diaryl-2,5-
solvent, the catalyst and the temperature play an im- bis(methoxycarbonyl)thiophenes.
portant role. In several cases, classical conditions
[use of tetrakis(triphenylphosphane)palladium(0),
Pd
ACHTUNGTRENNUNG(PPh3)4, as the catalyst] gave excellent yields. The Keywords: cross-coupling reactions; heterocycles;
yields of those transformations which failed or pro- palladium; regioselectivity; thiophenes
Introduction
tionalized thiophenes occur in a number of natural
products.[7]
Regioselective functionalizations of polyhalogenated
2,3-Dibromothiophene has been functionalized by
heterocycles play an increasingly important role in or- regioselective Sonogashira coupling of carbon atom
ganic synthesis.[1] Such reactions rely on the higher re- C-2.[8] A very good C-2 regioselectivity was observed
activity of more electron-deficient carbon atoms while also for the Kumada cross-coupling of 2,3- and 2,4-di-
the other reactive positions remain unattacked. This bromothiophene.[9] 2,5-Disubstituted thiophenes were
concept has been applied to regioselective palladi- prepared by regioselective Sonogashira coupling reac-
um(0)-catalyzed cross-coupling reactions based on dif- tions of tetraiodothiophene[10] and tetrabromothio-
ferent rates of oxidative additions of palladium(0) phene.[11] Recently, we reported the synthesis of sym-
species to different carbon-halide bonds of polyhalo- metrical 2,3,4,5-tetraaryl- and 2,5-diaryl-3,4-dibromo-
genated substrates. Thiophene-containing compounds thiophenes by regioselective Suzuki reactions of tetra-
constitute an important class of materials which show bromothiophene.[12] In our preliminary study, all reac-
intrinsic electronic properties such as luminescence, tions were carried out under ꢄclassicalꢅ conditions [use
redox activity, non-linear optical chromism and elec- of 10–20 mol% of PdACTHUNTRGNE(UNG PPh3)4]. Although these trans-
tron transport.[2] This includes, for example, dibenzo- formations proceeded with excellent yields in a
thiophenes,[3] [2,2’;5’,2’’]terthiophenes,[4] and thienyl- number of cases, several other reactions failed or pro-
diynes.[5] Aryl-substituted thiophenes possess a wide ceeded sluggishly with only moderate or low yields.
range of pharmacological properties and play an im- With respect to our preliminary studies, we herein
portant role in medicinal chemistry.[6] Besides, func- report a significant optimization of the yields by ap-
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FULL PAPERS
.
plication of a new biarylmonophosphine ligand devel-
oped by Buchwald and co-workers. We also report,
for the first time, the selective synthesis of 5-aryl-
2,3,4-tribromothiophenes and their transformation
into unsymmetrical 2,5-diaryl-3,4-dibromothiophenes.
In addition, we report regioselective metal-halide ex- Scheme 2. Synthesis of tetraarylthiophenes 2a–h. Conditions:
i, procedure A:
Pd(PPh3)4 (10 mol%), K3PO4 (8.0 equiv.), solvent/H2O=4:1
(solvent see Table 1); procedure B: (1.0 equiv.),
Ar1B(OH)2 (6.0 equiv.), Pd
(OAc)2 (5 mol%), L (10 mol%,
see Figure 1), K3PO4 (8.0 equiv.), dioxane/toluene, 1008C,
12 h.
1
(1.0 equiv.), Ar1B(OH)2 (5.0 equiv.),
change reactions of tetrabromothiophene. Although a
few isolated examples of such reactions have been re-
ported in the literature,[13] we have studied the prepa-
rative scope and new synthetic applications. In addi-
tion, we have developed a one-pot synthesis of 5-
alkyl-2-trimethylsilyl-3,4-dibromothiophenes by se-
quential addition of trimethylchlorosilane and alkyl
bromides.
AHCTUNGTRENNUNG
1
AHCTUNGTRENNUNG
Table 1. Synthesis of 2,3,4,5-tetraarylthiophenes 2a–h.
2
Ar1
Solvent
% (A)[a]
% (B)[b]
70
Results and Discussion
a
b
c
d
e
f
Ph
Toluene
37[c]
94[d]
38[d]
65[d]
87[c]
89[d]
93[d]
–
4-MeO-C6H4
2-MeO-C6H4
1-Naphthyl
4-Me-C6H4
4-Cl-C6H4
4-F-C6H4
2-Thienyl
1,4-Dioxane
1,4-Dioxane
Toluene
Toluene
Toluene
Suzuki Reactions
65
Tetrabromothiophene (1) was prepared by bromina-
tion of thiophene (following a modified literature pro-
cedure) (Scheme 1).[14] During the optimization, it
g
h
Toluene
Toluene
81
[a]
[b]
[c]
[d]
Isolated yields, procedure A (see Scheme 1).
Isolated yields, procedure B (see legend of Scheme 1).
Reaction time: 12 h.
reaction time: 24 h.
tions were performed based on optimization studies
of Suzuki reactions carried out in our laboratory.[16]
The protocol is defined as ꢄprocedure Aꢅ in the pres-
ent manuscript. Tetrakis(triphenylphosphane)palladi-
um(0) and potassium phosphate were used as catalyst
Scheme 1. Synthesis of tetrabromothiophene (1) Conditions:
i, 1) Br2 (7.0 equiv., slow addition), 08C, CHCl3; 2) reflux,
3 h; 3) NaOH, H2O (2M), reflux, 6 h.
proved to be important to add dropwise an excess of and base, respectively. The stoichiometry of the re-
bromine (dissolved in chloroform) to a chloroform so- agents, the temperature, the solvent, and the presence
lution of thiophene at 08C. A saturated aqueous solu- of water proved to be important parameters. Oxygen-
tion of NaOH was added and the mixture was stirred containing boronic acids showed a better solubility in
under reflux for 6 h. The product was recrystallized 1,4-dioxane than in toluene. On the other hand, the
from a 1:1 solution of chloroform and methanol. The higher boiling point of toluene proved to be advanta-
crude product (red to brownish crystals) was washed geous in many cases. All reactions were carried out in
with cold ethyl acetate for several times to give pure the presence of water (solvent/water=4:1) which
1 as colourless crystals (87%). We have observed that proved to be very important in order to obtain good
it is crucial to isolate 1 in analytically pure form as yields.[17] While products 2b and 2d–g were formed in
colourless crystals. The oily form is generally slightly excellent yields, 2a and 2c could be isolated in only
impure, tends to be considerably less stable and de- moderate yields. The low yield of 2c can be explained
composes within a few days. The presence of impuri- by steric effects. Products 2b, 2e, 2f and 2g, which are
ties results in the failure of Pd(0)-catalyzed cross-cou- derived from boronic acids containing electron-donat-
pling reactions. In contrast, the crystalline solid can ing and electron-withdrawing substituents, were iso-
be stored under an argon atmosphere at ꢀ188C (in lated in excellent yields. This result suggests that the
the dark) for a few weeks. Then, the compound starts electronic nature of the boronic acid does not have a
to slightly darken and it cannot be successfully used major influence on the yield. The relatively low yield
anymore in Pd(0)-catalyzed reactions.
of 2a is surprising, since it cannot be explained by
The tetraarylthiophenes 2a–g, containing four iden- steric or electronic reasons. The low yield of 2a is due
tical aryl groups, were successfully prepared by to practical problems associated with the difficult
Suzuki reaction[15] of 1 (1.0 equiv.) with 5.0 equiv. of chromatographic purification. The synthesis of tetra-
various boronic acids (Scheme 2, Table 1). All reac-
ACHTUNGTREN(NUGN thien-2-yl)thiophene (2h) completely failed. Howev-
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er, products 2a, 2c and 2h could be prepared in good
yields by using PdACHTUNTRGNEUNG(OAc)2 and the new biarylmono-
phosphine ligand L developed by Buchwald and co-
workers (Figure 1).[18]
Scheme 3. Synthesis of symmetrical 2,5-diaryl-3,4-dibromo-
thiophenes 3a–f and tetraarylthiophenes 4a–f. Conditions: i,
Figure 1. Biaryl monophosphine ligand developed by Buch-
wald and co-workers (ref.[18]).
procedure A:
Pd(PPh3)4 (6 mol%), K3PO4 (4.0 equiv.), solvent/H2O=4:1
(solvent see Table 3); procedure B: (1.0 equiv.),
Ar1B(OH)2 (2.2 equiv.), Pd
(OAc)2 (5 mol%), (see
1
(1.0 equiv.), Ar1B(OH)2 (2.2 equiv.),
AHCTUNGTRENNUNG
1
N
L
The reaction of 1 (1.0 equiv.) with 2.2 equiv. of bor-
onic acids allowed the regioselective synthesis of the
2,5-diaryl-3,4-dibromothiophenes 3a–f (Scheme 3,
Figure 1, 10 mol%), K3PO4 (4.0 equiv.), dioxane/toluene,
reflux, 8 h; ii, 3a, b (1.0 equiv.), Ar2B(OH)2 (3.0 equiv.),
Pd
ACHTUGNTERN(NGNU PPh3)4 (10 mol%), K3PO4 (4.0 equiv-), solvent/H2O=4:1
Table 2). The application of procedure A [PdACTHNUTRGNE(UNG PPh3)4]
(solvent see Table 4).
allowed us to prepare the products in moderate yields
(except for 3b which was isolated in good yield). The
yields of 3a and 3c–f were significantly improved by
application of method B [PdACTHNUTRGNEUNG(OAc)2, L]. The reaction oxane again proved to be advantageous in terms of
of 3a, b (1.0 equiv.) with various arylboronic acids yield (vide supra). The structures of all products were
(3.0 equiv.) afforded the tetraarylthiophenes 4a–f, established by spectroscopic methods. The structure
containing two different types of aryl groups, in good of 3b was independently confirmed by an X-ray crys-
yields (Scheme 3, Table 3). For oxygen-containing tal structure analysis.
boronic acids, the use of a mixture of toluene and di-
The Suzuki reaction of 1 with various boronic acids
(1.1 equiv.) afforded the 5-aryl-2,3,4-tribromothio-
phenes 5a–f in good yields and with very good regio-
selectivity (Scheme 4, Table 4). The syntheses of 5a–e
were carried out by application of procedure B
Table 2. Synthesis of symmetrical 2,5-diaryl-3,4-dibromothio-
phenes 3a–f.
3
Ar1
Solvent
% (A)[a]
% (B)[b]
88
[PdACTHNUTRGNE(NUG OAc)2, L]. Thiophene 5f was prepared by appli-
cation of method A. During the optimization, it was
important to suppress the formation of 2,5-diaryl-3,4-
dibromothiophenes, as their separation from the de-
sired products proved to be difficult. The structure of
5f was independently confirmed by an X-ray crystal
structure analysis (Figure 2).[19] The reaction of 5b
with 1.2 equiv. of arylboronic acids, following again
procedure B, resulted in regioselective formation of
the unsymmetrical 2,5-diaryl-3,4-dibromothiophenes
6a–c (Scheme 4).
a
b
c
d
e
f
Ph
Toluene
Toluene
1,4-Dioxane
1,4-Dioxane
Toluene
32[c]
77[c]
43[d]
35[d]
54[d]
54[d]
4-Me-C6H4
4-MeO-C6H4
2-MeO-C6H4
3,5-Me2C6H3
2-Thienyl
85
79
91
71
Toluene
[a]
[b]
[c]
[d]
Isolated yields, procedure A (see Scheme 1).
Isolated yields, procedure B (see Scheme 1).
Reaction time: 12 h.
Reaction time: 24 h.
Table 3. Synthesis of tetraarylthiophenes 4a–f.
4
Ar1
Ar2
Solvent
% (A)[a}
a
b
c
d
e
f
Ph
4-Me-C6H4
Ph
4-MeO-C6H4
4-EtO-C6H4
4-HO-C6H4
4-Cl-C6H4
Toluene
Toluene
Dioxane/Toluene (1:1)
Dioxane/Toluene (1:1)
Dioxane/Toluene (1:1)
Toluene
86[b]
51[b]
76[c]
93[c]
82[c]
91[c]
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
[a]
[b]
[c]
Isolated yields.
Reaction time: 12 h
Reaction time: 24 h
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.
Scheme 5. Synthesis of symmetrical 3,4-dibromothiophenes
7a–h. Conditions: i, 1) n-BuLi (2.5 equiv.), ꢀ788C, 1 h; 2)
RX (3.0 equiv.), ꢀ78!208C, 16 h.
Table 5. Synthesis of symmetrical 3,4-dibromothiophenes
7a–h.
[a]
7
R
X
%
Scheme 4. Synthesis of 5-aryl-2,3,4-tribromothiophenes 5a–f
and unsymmetrical 2,5-diaryl-3,4-dibromothiophenes 6a–c.
a
b
c
d
e
f
Me
n-Bu
Br
I
56
94
77
89
82
55
52
68
Conditions: i,
Pd(OAc)2 (5 mol%), L (see Figure 1, 10 mol%), K3PO4
(4.0 equiv.), dioxane/toluene, reflux, 8 h; ii, 5b (1.0 equiv.),
Ar2B(OH)2 (1.2 equiv.), Pd
(OAc)2 (5 mol%), (see
1
(1.0 equiv.), Ar1B(OH)2 (1.2 equiv.),
iso-Pent
n-Dodec
SiMe3
SMe
CO2Me
COPh
Br
Br
Cl
SMe
Cl
Cl
ACHTUNGTRENNUNG
A
L
Figure 1, 10 mol%), K3PO4 (4.0 equiv.), dioxane/toluene,
reflux, 8 h.
g
h
[a]
Isolated yields
Table 4. Products and yields.
useful, since the Suzuki reaction of tetrabromothio-
phene with alkylboronic acids failed. All attempts to
5
Ar1
% (5)[a]
a
b
c
d
e
f
2-MeO-C6H4
4-MeO-C6H4
3-Ph-C6H4
2-Naphthyl
4-Et-C6H4
Ph
75
80
77
69
87
61
prepare 3,4-dibromo-2,5-dihexylthiophene from
under Suzuki conditions using a variety of different li-
gands [e.g., dppf, P(t-Bu)3, PPh3, BINAP] failed. 3,4-
1
AHCTUNGTRENNUNG
Dibromo-2,5-bis(trimethylsilyl)thiophene (7e) was
prepared in good yield from 1 and trimethylchlorosi-
lane. The reaction of dilithiated 1 with dimethyl disul-
phide afforded thiophene 7f. Thiophenes 7g and 7h
were prepared by reaction of dilithiated 1 with
methyl chloroformate and benzoyl chloride, respec-
tively. During the optimization of the reactions, the
stoichiometry (excess of base and electrophile) played
an important role. The structure of the products was
established by spectroscopic methods. The structure
of 7g was independently confirmed by an X-ray crys-
tal structure analysis (Figure 3).[19]
[a]
Isolated yields (5a–e: procedure B, 5f: procedure A).
Mꢂller and co-workers have recently reported an
interesting one-pot synthesis of 2,5-disubstituted thio-
phenes from 2,5-dibromothiophene.[20] The metal-
halide exchange of 2,5-dibromothiophene, carried out
by means of 2 equiv. of n-BuLi, gave 2,5-dilithiothio-
phene. The sequential addition of two different elec-
trophiles to the latter afforded a number of unsym-
metrical 2,5-disubstituted thiophenes. The best yields
were obtained when the reaction of the electrophile,
which was added first, follows the SN2 mechanism
(e.g., Me3SiCl). The initial use of electrophiles, which
Figure 2. ORTEP plot of 5f (50% probability level).
Metal-Halide Exchange Reactions
The addition of n-butyllithium (2.5 equiv.) to a THF follow an addition-elimination pathway [e.g.,
solution of tetrabromothiophene (1) (1.0 equiv.) and (OMe)3], was less efficient in terms of yield because
BACHTUNGTRENNUNG
subsequent addition of alkyl halides (3.0 equiv.) af- Coulomb interactions of the two anionic sites in the
forded the 2,5-dialkyl-3,4-dibromothiophenes 7a–d intermediate affect the attack of the second electro-
(Scheme 5, Table 5). This approach is preparatively phile. Reactions of primary alkyl halides, which
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AHCTUNGTRENNUNG
The double Suzuki reaction of diester 7g with aryl-
boronic acids afforded the 3,4-diarylthiophenes 9a–d
(Scheme 7, Table 7). Products 9a–c were prepared by
Figure 3. ORTEP plot of 7g.
follow the SN2 mechanism, have not been reported
(either in the first or in the second step).
Scheme 7. Synthesis of 3,4-diarylthiophenes 9a–d. Condi-
tions: i: Procedure A: 7g (1.0 equiv.), ArB(OH)2
We have found that the addition of n-butyllithium
(2.5 equiv.) to a THF solution of tetrabromothiophene
(1) (1.0 equiv.) and subsequent sequential addition of
trimethylchlorosilane (1.0 equiv., slow addition during
3 h) and of an alkyl bromide (1.2 equiv.) directly af-
forded the 5-alkyl-3,4-dibromo-2-(trimethylsilyl)thio-
phenes 8a–f in 51–65% yield (Scheme 6, Table 6). The
(3.0 equiv.), Pd
vent/H2O=4:1 (solvent see Table 5). Procedure B: 7g
(1.0 equiv.), ArB(OH)2 (2.5 equiv.), Pd(OAc)2 (5 mol%), L
ACHTUGNRTEN(NNUG PPh3)4 (5 mol%), K3PO4 (4.0 equiv.), sol-
AHCTUNGTRENNUNG
(see Figure 1, 10 mol%), K3PO4 (4.0 equiv.), dioxane, reflux,
8 h.
Table 7. Synthesis of 3,4-diarylthiophenes 9a–d.
9
Ar
% (A)[a]
% (B)[b]
a
b
c
4-Cl-C6H4
42[c]
45[d]
49[d]
2-MeO-C6H4
2-HO-C6H4
4-HO-C6H4
85[c]
71[d]
Scheme 6. Synthesis of 5-alkyl-2-trimethylsilyl-3,4-dibromo-
thiophenes 8a–f. Conditions: i, 1) 1 (1.0 equiv.), n-BuLi
(2.5 equiv.), TMEDA (2.5 equiv.), ꢀ788C, 30 min; 2)
Me3SiCl (1.0 equiv., addition during 3 h), 30 min, ꢀ788C; 3)
RBr (1.2 equiv.), ꢀ788C, 4 h.
d
[a]
[b]
[c]
[d]
[e]
Isolated yields (procedure A).
Isolated yields (procedure B).
Solvent: toluene.
Solvent: toluene/dioxane=1:1.
Solvent: dioxane.
Table 6. Synthesis of unsymmetrical 3,4-dibromothiophenes
8a–f.
application of procedure A. The best results were ob-
tained, similar to the experiments outlined above,
when dioxane was used for boronic acids containing
oxygen (products 9b, c). The yield of 9b was much im-
proved by application of protocol B. Likewise, prod-
uct 9d was prepared in good yield by application of
protocol B.
Recently, 3,4-bis(4’-hydroxyphenyl)pyrrole-2,5-di-
carboxylic acid was isolated from a new marine Halo-
monas sp. strain.[21] This compound shows potent anti-
tumour-promoting activities. The sulphur analogue 10
[a]
8
R
%
a
b
c
d
e
f
Et
n-Bu
iso-Pent
n-Hex
n-Hept
n-Undec
65
61
60
60
55
51
[a]
Isolated yields.
selective reaction of 1 with one equivalent of Me3SiCl of this natural product was prepared in 96% yield by
in the first step is in line with the results of Mꢂller base-mediated hydrolysis of 9d (Scheme 8). Recently,
et al. and indicates that the reaction of Me3SiCl with the natural product ningaline A, a pyrrole-based bis-
2,5-dilithio-3,4-dibromothiophene
is
significantly lactone, was isolated from marine sources.[22] This
faster than the reaction with 5-lithio-2-trimethylsilyl- compound also exhibits a strong anti-proliferative ac-
3,4-dibromothiophene. However, the application of tivity. The sulphur analogue 11 of ningaline A was
this strategy to the synthesis of unsymmetrical 2,5-di- prepared in 65% yield by treatment of 9b with BBr3
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.
Synthesis of Tetrabromothiophene (1)[14]
To a chloroform solution (10 mL) of thiophene (25 mL) a
chloroform solution (20 mL) of bromine (60 mL) was drop-
wise added within 45 min at 08C. The reaction mixture was
warmed to room temperature and an additional amount of
bromine (10 mL) was added and the reaction mixture was
subsequently stirred under reflux for three hours. A saturat-
ed aqueous solution of NaOH was added and the mixture
was stirred under reflux for 6 h to remove the bromine. The
solvent and the excess of bromine were removed under
vacuum. The product was recrystallized from a 1:1 solution
of chloroform and methanol. The crude product (red to
brownish crystals) was washed with cold ethyl acetate for
several times to give pure 1 as colourless crystals; yield:
87%. 13C NMR (75 MHz, CDCl3): d=110.3, 116.9; MS (EI,
70 eV): m/z (%)=400 (M+, 100), 321 (65), 240 (34), 161
(41).
Scheme 8. Structures of thiophene derivatives 10 and 11.
and subsequent addition of potassium tert-butanolate
(Scheme 8).
Conclusions
In conclusion, we have reported Suzuki reactions of
tetrabromothiophene with arylboronic acids which
provide a regioselective approach to various 5-aryl-
2,3,4-tribromothiophenes, symmetrical 2,5-diaryl-3,4-
dibromothiophenes, and tetraarylthiophenes. Unsym-
metrical 2,5-diaryl-3,4-dibromothiophenes are pre-
pared by Suzuki reaction of 5-aryl-2,3,4-tribromothio-
phenes. Tetraarylthiophenes containing two different
types of aryl groups are obtained by Suzuki reactions
of 2,5-diaryl-3,4-dibromothiophenes. During the opti-
mization of the reaction conditions, the solvent and
the catalyst played an important role. In several cases,
General Procedure A for the Synthesis of 2a–h
To a solution (for the solvents, see the individual procedures
given below) of 1 was added PdACHTUNTRGNEUNG(PPh3)4 (10 mol%) at 208C.
After stirring for 30 min, the arylboronic acid, K3PO4
(8.0 mmol) and water (1.0 mL) were added. The mixture
was stirred for the indicated period of time at the indicated
temperature. After cooling to ambient temperature, the mix-
ture was diluted with EtOAc, dried (Na2SO4), and filtered
through a short Celite pad. The solution was concentrated
under vacuum and the residue was purified by flash column
chromatography (fine flash silica gel, n-heptane). The sol-
vents and the amounts are given in the individual proce-
dures (see below).
classical conditions [PdACHTNUGTRENUNG(PPh3)4] gave excellent yields.
The yields of those transformations which completely
failed or proceeded sluggishly could be significantly
improved by application of a new biarylmonophos-
phine ligand developed by Buchwald and co-workers.
Regioselective metal-halide exchange reactions of tet-
rabromothiophene provide a convenient approach to
2,5-dialkyl-3,4-dibromothiophenes. 2-Trimethylsilyl-5-
General Procedure B for the Synthesis of 2a–h
An oven-dried Schlenk flask was charged with PdACHTUNGTRENNUNG(OAc)2
(5 mol%), ligand L (10 mol%), the starting material 1, the
boronic acid (6.0 equiv.) and powered, anhydrous K3PO4
(8.0 equiv.). The Schlenk flask was filled with argon. The
alkyl-3,4-dibromothiophenes could be prepared in a solvent was added by syringe through a septum. The septum
was replaced by a condenser in an argon stream. The reac-
tion mixture was stirred and refluxed for the indicated
period of time at the indicated temperature. The solution
was allowed to cool to ambient temperature and water
(5 mL) was added. The aqueous and the organic layer were
separated and the latter was dried Na2SO4. The solution was
filtered and the filtrate was concentrated under reduced
pressure. The residue was purified by flash column chroma-
tography (fine flash silica gel, heptanes). The solvents and
the amounts are given in the individual procedures (see
below).
one-pot protocol by sequential addition of trimethyl-
chlorosilane and alkyl bromides. The reaction of tet-
rabromothiophene with methyl chloroformate and
subsequent Suzuki reactions afforded 3,4-diaryl-2,5-
bis(methoxycarbonyl)thiophenes.
Experimental Section
Tetraphenylthiophene (2a): Procedure B: 5 mL of toluene,
reflux 12 h, 1008C. Starting with 1 (0.400 g, 1.0 mmol) and
phenylboronic acid (0.609 g, 5.0 mmol), PdACTHNURGTNEUNG(OAc)2 (11 mg, 5
General Comments
All solvents were dried by standard methods and all reac-
mol%), L (41 mg, 10 mol-%), K3PO4 (1.7 g, 8.0 mmol), 2a
was isolated as a colourless solid; yield: 0.271 g (70%); mp
168–1708C. 1H NMR (300 MHz, CDCl3): d=6.87 (m, 4ꢇ
2H, Ar), 7.03 (m, 4ꢇ2H, Ar), 7.14 (m, 2ꢇ2H, Ar);
13C NMR (75 MHz, CDCl3): d=126.6, 127.2, 127.8, 128.2,
129.1, 130.8 (CH, Ar), 134.2, 136.4, 138.5, 139.4 (C, ArC);
1
tions were carried out under an inert atmosphere. For H
and 13C NMR spectra the deuterated solvents indicated
were used. Mass spectrometric data (MS) were obtained by
electron ionization (EI, 70 eV), chemical ionization (CI,
H2O) or electrospray ionization (ESI). For preparative scale
chromatography, silica gel (60–200 mesh) was used. Melting
points are uncorrected.
˜
IR (KBr): n=3058 (w), 3022 (w), 1596 (m), 1495 (m), 1480
(m), 1444 (w), 1073 (w), 1029 (w), 793 (w), 750 (s), 695 (s),
1600
asc.wiley-vch.de
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Regioselective Palladium(0)-Catalyzed Cross-Coupling Reactions
FULL PAPERS
592 (m), 518 cmꢀ1 (w); MS (EI, 70 eV): m/z (%)=388 (M+,
100), 354 (4), 310 (6), 267 (4), 178 (3), 165 (6), 121 (3), 77
(2); HR-MS (EI, 70 eV): m/z=388.1274, calcd. for C28H20S
Tetra
H2O=4:1 (5 mL), reflux 12 h, 1008C. Starting with
(0.400 g, 1.0 mmol) and 4-tolylboronic acid (0.680 g,
5.0 mmol), Pd(PPh3)4 (0.115 g, 10 mol%), K3PO4 (1.7 g,
ACHTUNGTREN(NUNG 4-tolyl)thiophene (2e): Procedure A: toluene:
1
(M+): 388.1280; elemental analysis calcd. (%) for C28H20S
(388.1): C 86.56, H 5.19; found: C 86.73, H 5.29.
ACHTUNGTRENNUNG
8.0 mmol), 2e was isolated as a colourless solid; yield:
1
Tetra(4-methoxyphenyl)thiophene (2b): Procedure A: di-
oxane:H2O=4:1 (5 mL), reflux 24 h, 1008C. Starting with 1
(0.400 g, 1.0 mmol) and (4-methoxyphenyl)boronic acid
0.386 g (87%); mp 151–1528C. H NMR (300 MHz, CDCl3):
3
d=2.29, 2.32 (s, 12H, 2ꢇ2CH3), 6.87, 6.96, 7.03, 7.14 (d, J=
8.2 Hz, 16H, 4ꢇ4CH, Ar); 13C NMR (75 MHz, CDCl3): d=
21.1, 21.2 (C, CH3), 128.5, 128.9, 129.0, 130.7 (CH, Ar),
131.6, 133.6, 135.8, 136.7, 137.7, 138.2 (C, ArC). IR (KBr):
(0.759 g, 5.0 mmol), PdACTHNUTRGNE(UNG PPh3)4 (0.115 g, 10 mol%), K3PO4
(1.7 g, 8.0 mmol), 2b was isolated as a colourless solid; yield:
1
˜
0.477 g (94%); mp 183–1858C. H NMR (300 MHz, CDCl3):
n=3432 (w), 3022 (m), 2918 (w), 1514 (s), 1495 (s), 1456
d=3.65, 3.72 (s, 12H, 2ꢇ2OCH3), 6.59, 6.69, 6.82, 7.09 (d,
4ꢇ4H, CH, Ar); 13C NMR (75 MHz, CDCl3): d=55.00,
56.06 (C, OCH3), 114.8, 116.0, 130.2, 131.9 (CH, Ar), 127. 0,
(m), 1182 (w), 1111 (w), 1109 (w), 834 (m), 818 (s), 807 (m),
733 (m), 556 (w), 527 (w), 507 cmꢀ1 (w); MS (EI, 70 eV):
m/z (%)=444 (M+, 100), 355 (4), 299 (6), 207 (4), 155 (6),
115 (4), 91 (9), 71 (5), 57 (7), 44 (6); HR-MS (EI, 70 eV):
m/z=444.19071, calcd. for C32H28S (M+): 444.19062; elemen-
tal analysis calcd. (%) for C32H28S (444.2): C 86.44, H 6.35;
found: C 86.73, H 6.47.
˜
129.0, 137.1, 138.3, 158.0, 158.6 (C, ArC); IR (KBr): n=3431
(w), 3031 (m), 3003 (m), 2957 (m), 2924 (m), 2840 (m), 1607
(m), 1511 (s), 1495 (s), 1286 (s), 1175 (s), 1031 (s), 834 (s),
799 cmꢀ1 (m); MS (EI, 70 eV): m/z (%)=508 (M+, 100), 255
(31), 178 (15), 172 (29), 160 (26), 96 (10); HR-MS (EI,
70 eV): m/z=508.6277, calcd. for C32H28O4S (M+): 508.6273;
elemental analysis calcd. (%) for C32H28O4S (508.2): C 75.56,
H 5.55, S 6.30; found: C 75.77, H 5.35, S 6.11.
Tetra(4-chlorophenyl)thiophene (2f): Procedure A: tolu-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Tetra(2-methoxyphenyl)thiophene (2c): Procedure B:
5 mL of dioxane, reflux 12 h, 1008C. Starting with 1 (0.400 g,
1.0 mmol) and (2-methoxyphenyl)boronic acid (0.759 g,
8.0 mmol), 2f was isolated as a colourless solid; yield:
1
0.468 g (89%); mp 139–1408C. H NMR (300 MHz, CDCl3):
d=6.75, 7.05, 7.08, 7.09 (d, 8ꢇ2H, Ar); 13C NMR (75 MHz,
CDCl3): d=128.5, 128.7, 130.3, 131.9 (CH, Ar), 130.3, 131.8,
5.0 mmol), PdACHTUNGTRENNUNG(PPh3)4 (0.115 g, 10 mol-%), K3PO4 (1.7 g,
˜
8.0 mmol), 2c was isolated as a colourless solid; yield: 0.33 g
(65%); mp 171–1738C. A doubling of some signals in the H
131.9, 132.4, 137.3, 147.3 (C, Ar); IR (KBr): n=3432 (m),
1
3066 (w), 1492 (s), 1480 (s), 1093 (s), 1086 (s), 834 (s), 806
(s), 769 (m), 526 (m), 520 (w), 501 (w), 487 cmꢀ1 (w); MS
(EI, 70 eV): m/z (%)=530 (M+, [37Cl,37Cl,37Cl,35Cl], 13), 528
(M+, [37Cl,37Cl,35Cl,35Cl], 51), 526 (M+, [37Cl,35Cl,35Cl,35Cl],
100), 524 (M+, [35Cl,35Cl,35Cl,35Cl], 71); HR-MS (EI, 70 eV):
and 13C NMR spectra is observed, due to the presence of
two atropisomers. 1H NMR (300 MHz, CDCl3): d=3.08,
3.15, 3.26, 3.43 (4ꢇs, 12H, 4 OCH3), 6.52 (m, 4H, Ar), 6.69
(m, 4H, Ar), 6.90 (m, 4H, Ar), 7.07 (m, 4H, Ar); 13C NMR
(75 MHz, CDCl3): d=54.6, 54.8, 54.9, 55.1 (OCH3), 110.1,
110.5, 110.8, 110.9, 119.8, 119.7, 120.1, 120.2, 127.4, 127.5,
128.4, 128.5, 131.3, 132.0, 132.1, 132.2 (CH, Ar), 123.7, 123.9,
134.9, 135.1, 136.9, 137.3, 156.5, 156,6, 156.7, 156.8 (C, ArC);
m/z=526.3022,
[37Cl,35Cl,35Cl,35Cl]): 526.3026.
Tetra(4-fluorophenyl)thiophene (2g): Procedure A: tolu-
calcd
for
C28H16Cl4S
(M+,
AHCTUNGTRENNUNG
˜
IR (KBr): n=3432 (w), 3067 (m), 2932 (w), 2830 (w), 1597
(0.400 g, 1.0 mmol) and 4-fluorophenylboronic acid (0.7 g,
(s), 1578 (s), 1493 (s), 1460 (s), 1240 (s), 1117 (s), 1023 (s),
752 (s), 617 cmꢀ1 (w); MS (EI, 70 eV): m/z (%)=508 (M+,
100), 387 (18), 354 (9), 294 (8), 224 (6), 178 (4), 151 (3), 91
(5); HR-MS (EI, 70 eV): m/z=508.1706, calcd. for
C32H28O4S (M+): 508.1703; elemental analysis calcd (%) for
C32H28O4S (508.2): C 75.56, H 5.55, S 6.30; found: C 75.49,
H 5.45, S 6.58.
5.0 mmol), PdACTHNGUTERNNU(G PPh3)4 (0.115 g, 10 mol%), K3PO4 (1.7 g,
8.0 mmol), 2g was isolated as a colourless solid; yield:
1
0.428 g (93%); mp 135–1368C. H NMR (300 MHz, CDCl3):
d=6.82 (m, 6ꢇ2H, CH, Ar), 7.06 (m, 2ꢇ2H, CH, Ar);
3
13C NMR (75 MHz, CDCl3): d=116.9, 117.3 (2ꢇd, JCF, CH,
Ar), 132.1, 133.0 (d, 2J=110 Hz, CF, Ar), 133.1 (d, 2J=
109 Hz, CH, Ar), (CH, Ar) 129.8, 131.9, 137.6, 138.2 (C,
1
1
Tetra(naphtha-1-yl)thiophene (2d): Procedure A: tolu-
ArC), 161.6, (d, J=251 Hz, CF, Ar), 162.1 (d, J=251 Hz,
˜
N
CF, Ar); IR (KBr): n=1536 (s), 1475 (s), 1452 (m), 1178
(w), 1124 (w), 1109 (w), 836 (m), 819 (s), 802 (m), 737 (m),
551 (w), 526 (w), 502 cmꢀ1 (w); MS (EI, 70 eV):
m/z (%)=460 (M+, 100), 366 (43), 321 (6), 262 (10), 201 (8),
149 (9), 97 (7), 83 (9), 69 (13), 57 (14); HR-MS (EI, 70 eV):
m/z=460.0903, calcd. for C28H16F4S (M+): 460.0906; elemen-
tal analysis calcd. (%) for C28H16F4S (460.1): C 73.03, H
3.50, S 6.96; found: C 72.88, H 3.39, S 7.25.
ACHTUNGTRENNUNG
8.0 mmol), 2d was isolated as a colourless solid; yield:
0.382 g (65%); mp 293–2948C. H NMR (300 MHz, CDCl3):
1
d=6.82 (m, 4H, Ar), 7.89 (m, 2H, Ar), 7.06 (m, 8H, Ar),
7.21 (m, 4H, Ar), 7.34 (m, 4H, Ar), 7.49 (m, 2H, Ar), 8.21,
8,29 (d,d, 3J=7.8 Hz, 2H, Ar), 8.58, 8,65 (d,d, 3J=7.8 Hz,
2H, Ar); 13C NMR (75 MHz, CDCl3): d=124.5–129.3 (CH,
Ar), 131.4, 131.6, 133.1, 133.7, 134.2, 134.6, 138.3, 140.6 (C,
Tetra(thien-2-yl)thiophene (2h): Procedure B: 5 mL of
toluene, reflux 8 h, 1008C. Starting with
0.5 mmol) and (thien-2-yl)boronic acid (6.0 equiv., 0.383 g,
0.6 mmol), Pd(OAc)2 (11 mg, 5 mol%), L (41 mg, 10 mol%),
1 (0.200 g,
˜
ArC). IR (KBr): n=3053 (w), 2923 (w), 1592 (w), 1506 (w),
1387 (w), 1261 (w), 1016 (w), 796 (s), 772 (s), 559 (w),
427 cmꢀ1 (w); MS (EI, 70 eV): m/z (%)=388 (M+, 100), 354
(4), 310 (6), 267 (4), 178 (3), 165 (6), 121 (3), 77 (2); HR-
MS (EI, 70 eV): m/z=588.1901, calcd. for C44H28S (M+):
588.1906; elemental analysis calcd. (%) for C44H28S ( 588.2):
C 89.76, H 4.79; found: C 89.39, H 4.58.
ACHTUNGTRENNUNG
K3PO4 (1.7 g, 8.0 mmol), 2h was isolated as a yellow solid;
yield: 0.166 g (81%); mp 110–1128C. 1H NMR (250 MHz,
CDCl3): d=6.90, 7.10, 7.19, 7.30 (d, 2H, 4 CH, thienyl),
6.94, 6.96 (t, 2H, CH, thienyl); 13C NMR (75 MHz, CDCl3):
d=125.4, 126.3, 126.4, 126.8, 127.1, 128.4 (2 CH, thienyl),
Adv. Synth. Catal. 2009, 351, 1595 – 1609
ꢆ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1601

ˇ
Dang Thanh Tꢀng et al.
¯
FULL PAPERS
.
3
˜
132.4, 133.3, 135.3, 135.6 (C); IR (KBr): n=3096 (w), 2959
(w), 2922 (w), 2851 (w), 1259 (w), 1216 (w), 1060 (w), 1036
(w), 1024 (w), 816 (w), 695 cmꢀ1 (m); MS (EI, 70 eV): m/z
(%)=412 (M+, 100), 378 (M+, 8), 367 (M+, 9), 346 (M+, 6),
285 (M+, 4), 283 (M+, 4); HR-MS (EI, 70 eV):
m/z=411.95369, calcd. for C20H12S5 (M+): 411.95371; ele-
mental analysis calcd. (%) for C20H12S5 (411.9): C 58.21, H
2.93; found: C 58.29, H 2.95.
d=2.25 (s, 6H, 2CH3), 7.22 (d, J=8.2 Hz, 4H, Ar), 7.46 (d,
3J=8.2 Hz, 4H, Ar); 13C NMR (75 MHz, CDCl3): d=21.1
(C, CH3), 112.2 (C, CBr), 128.6, 129.1 (CH, Ar), 129.8,
˜
137.2, 137.3 (C, ArC); IR (KBr): n=3432 (br, m), 3021 (m),
2918 (w), 1489 (s), 1266 (w), 864 (m), 809 (m), 798 (s), 755
(m), 490 cmꢀ1 (s); MS (EI, 70 eV): m/z (%)=424 (M+,
[81Br,81Br], 49), 422 (M+, [81Br,79Br], 100), 420 (M+,
[79Br,79Br], 45), 342 (11), 262 (37), 229 (5), 202 (10), 135 (6),
69 (6); HR-MS (EI, 70 eV): m/z=419.91769, calcd. for
C18H14Br2S (M ,CTHNUGTRNENUG
+ A[79Br]): 419.91775; elemental analysis calcd.
General Procedure A for Synthesis of 3,4-Dibromo-
2,5-diarylthiophenes 3a–f
(%) for C18H14Br2S (419.9): C 51.21, H 3.34, S 7.60; found:
C 50.89, H 3.45, S 7.55.
3,4-Dibromo-2,5-di(4-methoxyphenyl)thiophene (3c): Pro-
cedure B: toluene:dioxane=1:1 (4 mL), reflux 8 h, 1008C.
Starting with 1 (0.400 g, 1.0 mmol) and (4-methoxyphenyl)-
To a solution of 1 (0.400 g, 1.0 mmol) was added PdACHTNUTRGNE(UNG PPh3)4
(0.070 g, 6 mol%) at 208C. After stirring for 30 min, the ar-
ylboronic acid (2.2 mmol), K3PO4 (4.0 mmol) and water
(1.0 mL) were added. The mixture was stirred at 908C for
12 h. After cooling to ambient temperature, the mixture was
diluted with EtOAc, dried (Na2SO4), and filtered through a
short Celite pad. The solution was concentrated under
vacuum and the residue was purified by flash column chro-
matography (fine flash silica gel, n-heptane).
boronic acid (0.334 g, 2.2 mmol), PdACHTUGNETRN(UNGN OAc)2 (11 mg, 5
mol%), L (41 mg, 10 mol%), K3PO4 (0.848 g, 4.0 mmol), 3c
was isolated as a colourless solid; yield: 0.383 g (85%); mp
171–1738C. 1H NMR (300 MHz, CDCl3): d=3.78 (s, 6H,
2OCH3), 6.93 (d, J=8.2 Hz, 4H, Ar), 7.54 (d, J=8.2 Hz,
4H, Ar); 13C NMR (75 MHz, CDCl3): d=55.6 (C, OCH3),
111.4 (C, CBr), 114.0, 129.9 (CH, Ar), 126.2, 137.3, 159.9 (C,
3
3
General Procedure B for the Synthesis of 3a–f
˜
ArC); IR (KBr): n=3442 (br, w), 2959 (w), 2923 (w), 2835
(w), 1598 (w), 1579 (w), 1482 (s), 1252 (s), 1179 (w), 1117
(m), 1024 (s), 796 (m), 751 cmꢀ1 (s); MS (EI, 70 eV): m/z
(%)=456 (M+, [81Br,81Br], 48), 454 (M+, [81Br,79Br], 100),
452 (M+, [79Br,79Br], 43), 476 (13), 474 (12), 279 (10), 208
(12), 136 (11), 121 (19), 119 (17), 105 (16), 77 (11), 69 (3);
HR-MS (EI, 70 eV): m/z=451.9073, calcd. for C18H14Br2O2S
(M+, [79Br,79Br]): 451.9076; elemental analysis calcd. (%) for
C18H14Br2O2S (451.9): C 47.60, H 3.11, S 7.06; found: C
48.01, H 3.35, S 6.88.
An oven-dried Schlenk flash was charged with PdACTHUNRGTNEUNG(OAc)2 (5
mol%), ligand L (10 mol-%), the starting material, the bor-
onic acid (2.2 equiv.) and powered, anhydrous K3PO4
(4 equiv.). The Schlenk flask was filled with argon. The sol-
vent was added by syringe through a septum. The septum
was replaced by a condenser in an argon stream. The reac-
tion mixture was stirred and refluxed for the indicated
period of time at the indicated temperature. The solution
was allowed to cool to ambient temperature and water
(5 mL) was added. The aqueous and the organic layer were
separated and the latter was dried Na2SO4. The solution was
filtered and the filtrate was concentrated under reduced
pressure. The residue was purified by flash column chroma-
tography (fine flash silica gel, heptanes). The solvents and
the amounts are given in the individual procedures (see
below).
3,4-Dibromo-2,5-di(2-methoxyphenyl)thiophene (3d): Pro-
cedure B: toluene:dioxane=1:1 (4 mL), reflux 8 h, 1008C.
Starting with 1 (0.400 g, 1.0 mmol) and (2-methoxyphenyl)-
boronic acid (0.344 g, 2.2 mmol), PdACHTUGNETRN(UNGN OAc)2 (11 mg, 5
mol%), L (41 mg, 10 mol%), K3PO4 (0.848 g, 4.0 mmol), 3d
was isolated as a colourless solid; yield: 0.365 g (79%); mp
120–1228C. A small amount of impurity could not be re-
moved. 1H NMR (300 MHz, CDCl3): d=3.78 (s, 6H,
2OCH3), 6.93 (m, 2ꢇ2H, Ar), 7.34 (m, 4H, Ar); 13C NMR
(75 MHz, CDCl3): d=55.6 (C, OCH3), 111.2, 120.4, 130.5,
132.2 (CH, Ar), 112.6, 121.7, 134.9, 157.0 (C, ArC); IR
3,4-Dibromo-2,5-diphenylthiophene (3a): Procedure B:
5 mL of toluene, reflux 8 h, 1008C. Starting with 1 (0.400 g,
1.0 mmol) and phenylboronic acid (0.268 g, 2.2 mmol), Pd-
ACHTUNGTRENNUNG(OAc)2 (11 mg, 5 mol%), L (41 mg, 10 mol%), K3PO4
˜
(KBr): n=3432 (br, w), 2995 (w), 2961 (w), 2835 (w), 1608
(0.848 g, 4.0 mmol), 3a was isolated as a colourless solid;
yield: 0.344 g (88%); mp 150–1518C. 1H NMR (300 MHz,
CDCl3): d=7.35 (m, 2ꢇ3H, Ar), 7.61 (m, 2ꢇ2H, Ar);
13C NMR (75 MHz, CDCl3): d=112.2 (C, CBr), 128.4, 128.7,
(s), 1534 (s), 1491 (s), 1299 (w), 1253 (s), 1180 (s), 1040 (s),
828 (s), 805 (m), 754 (w), 578 (w), 514 cmꢀ1 (w); MS (EI,
70 eV): m/z (%)=456 (M+, [81Br,81Br], 47), 454 (M+,
[81Br,79Br], 100), 452 (M+, [79Br,79Br], 43), 376 (56), 374 (53),
279 (22), 264 (37), 237 (16), 208 (9), 149 (7), 147 (7), 131 (5),
104 (6), 71 (16), 57 (25); HR-MS (EI, 70 eV): m/z=
451.9069, calcd. for C18H14Br2O2S (M+, [79Br,79Br]): 451.9070.
3,4-Dibromo-2,5-bis(3,5-dimethylphenyl)thiophene (3e):
Procedure B: 5 mL of toluene, reflux 8 h, 1008C. Starting
with 1 (0.400 g, 1.0 mmol) and (3,5-dimethylphenyl)boronic
˜
128.8 (CH, Ar), 132.8, 138.1 (C, ArC); IR (KBr): n=3051
(w), 2924 (w), 2853 (w), 1477 (m), 1268 (m), 1028 (w), 749
(s), 699 (s), 628 (w), 584 , cmꢀ1 (w); MS (EI, 70 eV): m/z
(%)=396 (M+, [81Br,81Br], 55), 394 (M+, [81Br,79Br], 100),
392 (M+, [79Br,79Br], 53), 314 (3), 234 (48), 202 (8), 197 (7),
189 (22), 117 (12), 95 (6), 77 (5); HR-MS (EI, 70 eV): m/z=
391.8861, calcd. for C16H10Br2S (M+, [79Br,79Br]): 391.8864;
elemental analysis (%) calcd. for C16H10Br2S (391.9): C
48.76, H 2.56, S 8.13; found: C 48.78, H 2.51, S 8.01.
acid (0.385 g, 2.2 mmol), PdACHTNUGTRENUNG(OAc)2 (11 mg, 5 mol%), L
(41 mg, 10 mol%), K3PO4 (0.848 g, 4.0 mmol), 3e was isolat-
ed as a colourless solid; yield: 0.406 g (91%); mp 120–
1218C. A small amount of impurity could not be separated.
1H NMR (300 MHz, CDCl3): d=2.26 (s, 12H, 4CH3), 6.93
(s, 2H, Ar), 7.21 (s, 4H, Ar); 13C NMR (75 MHz, CDCl3):
d=21.6 (C, CH3), 111.8 (C, CBr), 126.2, 129.9 (CH, Ar),
3,4-Dibromo-2,5-di
toluene:H2O=4:1 (5 mL), reflux 12 h, 1008C. Starting with
(0.400 g, 1.0 mmol) and 4-tolylboronic acid (0.299 g,
2.2 mmol), Pd(PPh3)4 (0.070 g, 6 mol%), K3PO4 (0.848 g,
ACHTUNGTRENN(UNG 4-tolyl)thiophene (3b): Procedure A:
1
ACHTUNGTRENNUNG
4.0 mmol), 3b was isolated as a colourless solid; yield:
1
˜
0.323 g (77%); mp 152–1558C. H NMR (300 MHz, CDCl3):
123.3, 138.1, 141.4 (C, ArC); IR (KBr): n=3436 (br, w),
1602
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Regioselective Palladium(0)-Catalyzed Cross-Coupling Reactions
FULL PAPERS
2997 (w), 2917 (m), 1598 (s), 1457 (m), 1298 (w), 1257 (w),
1039 (w), 896 (w), 852 (s), 828 (s), 707 (m), 689 cmꢀ1 (m);
MS (EI, 70 eV): m/z (%)=452 (M+, [81Br,81Br], 50), 450
(M+, [81Br,79Br], 100), 448 (M+, [79Br,79Br], 45), 372 (17), 370
(16), 290 (19), 225 (5), 210 (48), 195 (15), 149 (8), 97 (7), 69
(16); HR-MS (EI, 70 eV): m/z=445.9492, calcd. for
C20H18Br2S (M+, [79Br,79Br]): 447.9491.
3,4-Dibromo-2,5-di(thien-2-yl)thiophene (3f): Procedure
B: 5 mL of toluene, reflux 8 h, 1008C. Starting with 1
(0.400 g, 1.0 mmol) and (thien-2-yl)boronic acid (0.299 g,
6.91 (d, 3J=8.2 Hz, 4H, 2CH, Ar), 7.08 (m, 10H, Ar);
13C NMR (75 MHz, CDCl3): d=21.0 (C, CH3), 126.3, 127.6,
128.8, 128.9, 130.7 (CH, Ar), 131.2, 136.7, 136.8, 138.3, 139.4
˜
(C, ArC); IR (KBr): n=3052 (w), 2918 (w), 1544 (w), 1502
(m), 1439 (m), 1021 (w), 836 (w), 817 (m), 771 (s), 703 (s),
523 (w), 510 cmꢀ1 (w); MS (EI, 70 eV): m/z (%)=416 (M+,
100), 324 (4), 281 (6), 183 (4), 165 (6), 149 (7), 112 (13), 97
(15), 83 (19), 57 (32); HR-MS (EI, 70 eV): m/z=416.1591,
calcd. for C30H24S (M+): 416.1593.
3,4-Di(4-methoxyphenyl)-2,5-di
G
(4c):
2.2 mmol), PdACHTUNGTRENNUNG(OAc)2 (11 mg, 5 mol%), L (41 mg, 10 mol%),
Procedure A: toluene:dioxane:H2O=2:2:1 (5 mL), reflux
K3PO4 (0.848 g, 4.0 mmol), 3f was isolated as a colourless
solid; yield: 0.286 g (71%); mp 89–918C. 1H NMR
(300 MHz, CDCl3): d=7.05 (t, 3J=3.7 Hz, 2ꢇ1H, thio-
24 h, 1008C. Starting with 3b (0.42 g, 1.0 mmol) and (4-me-
thoxyphenyl)boronic acid (0.455 g, 3.0 mmol), PdACHTUNGTRENNUNG(PPh3)4
(0.115 g, 10 mol%), K3PO4 (0.848 g, 4.0 mmol), 4c was iso-
3
phene), 7.28 (d, J=4.1 Hz, 2ꢇ1H, thiophene), 7.41 (m, 2ꢇ
lated as a colourless solid; yield: 0.361 g (76%); mp 230–
1H, thiophene); 13C NMR (75 MHz, CDCl3): d=112.4 (C,
1
2318C. H NMR (300 MHz, CDCl3): d=2.20 (s, 3H, CH3),
CBr), 126.8, 127.1, 127.4 (CH, thiophene), 132.0, 135.1 (C,
3.62 (s, 3H, OCH3), 6.53, 6.75, 6.97, 7.06 (m, 16H, 4ꢇ4CH,
Ar); 13C NMR (75 MHz, CDCl3): d=21.25 (C, CH3), 55.10
(C, OCH3), 113.37, 129.07, 129.09, 132.00 (CH, Ar), 129.00,
131.88, 136.84, 138.44, 139.86, 158.18 (C, ArC). IR (KBr):
˜
ArC); IR (KBr): n=3094 (w), 2960 (w), 2923 (w), 1484 (w),
1418 (w), 1261 (w), 1221 (w), 1060 (w), 844 (m), 815 (m),
699 (m), 686 cmꢀ1 (s); MS (EI, 70 eV): m/z (%)=408 (M+,
[81Br,81Br], 55), 406 (M+, [81Br,79Br], 100), 404 (M+,
[79Br,79Br], 47), 328 (16), 326 (17), 246 (52), 202 (11), 149
(7), 127 (10), 112 (5), 95 (9), 84 (17); HR-MS (EI, 70 eV):
m/z=403.7986, calcd for C12H6Br2S3 (M+, [79Br,79Br]):
403.7993.
˜
n=3446 (m), 2999 (m), 2962 (m), 2835 (m), 1608 (s), 1513
(s), 1290 (s), 1245 (s), 1034 (s), 841 (s), 809 (s), 563 cmꢀ1
(w); MS (EI, 70 eV): m/z (%)=476 (M+, 100), 83 (10), 71
(10), 69 (13), 57 (17), 43 (22), 40 (13); HR-MS (EI, 70 eV):
m/z=476.6255, calcd. for C32H28O2S (M+): 476.6258.
3,4-Di(4-ethoxyphenyl)-2,5-diACTHNUGRTNEUNG(4-tolyl)thiophene (4d): Pro-
cedure A: toluene:dioxane:H2O=2:2:1 (5 mL), reflux 24 h,
1008C. Starting with 3b (0.42 g, 1.0 mmol) and (4-ethoxy-
phenyl)boronic acid (0.497 g, 3.0 mmol), PdACTHNUTRGNE(UNG PPh3)4 (0.115 g,
General Procedure A for the Synthesis of 2,3,4,5-
Tetraarylthiophenes (4a–f)
10 mol%), K3PO4 (0.848 g, 4.0 mmol), 4d was isolated as a
colourless solid; yield: 0.469 g (93%); mp 169–1708C.
1H NMR (300 MHz, CDCl3): d=1.18 (t, 3J=7.3 Hz, 6H,
To a solution of 3,4-dibromothiophene 3 (1.0 mmol) was
added PdACHTUNGTRENNUNG(PPh3)4 (0.116 g, 10 mol%) at 208C. After stirring
for 30 min, the arylboronic acid (3.0 mmol), K3PO4
(4.0 mmol) and water (2.0 mL) were added. The mixture
was stirred at 908C for 24 h. After cooling to ambient tem-
perature, the mixture was diluted with EtOAc, dried
(Na2SO4), and filtered through a short Celite pad. The solu-
tion was concentrated under vacuum and the residue was
purified by flash column chromatography (fine flash silica
gel, n-heptane).
3
2OCH2CH3), 2.21 (s, 6H, 2CH3), 3.89 (q, J=7.3 Hz, 4H,
2OCH2CH3), 6.51 (d, 3J=8.2 Hz, 4H, 2CH, Ar), 6.74 (d,
3J=8.2 Hz, 4H, 2CH, Ar), 6.92 (d, 3J=8.2 Hz, 4H, 2CH,
3
Ar), 7.03 (d, J=8.2 Hz, 4H, 2CH, Ar); 13C NMR (75 MHz,
CDCl3): d=14.8 (C, OCH2CH3), 21.1 (C, CH3), 63.08 (C,
OCH2CH3), 113.8, 128.9, 128.9, 131.9 (CH, Ar), 131.8, 136.7,
˜
136.8, 137.5, 138.8, 157.4 (C, Ar); IR (KBr): n=3052 (w),
2911 (w), 1546 (w), 1509 (m), 1431 (m), 1027 (w), 838 (w),
815 (m), 771 (s), 707 (s), 522 (w), 517 cmꢀ1 (w); MS (EI,
70 eV): m/z (%)=504 (M+, 100), 475 (5), 384 (15), 242 (4),
149 (7), 112 (5), 97 (9), 83 (10), 69 (12), 57 (16), 44 (26);
HR-MS (EI, 70 eV): m/z=504.2104, calcd. for C34H32O2S
(M+): 504.2107; elemental analysis calcd. (%) for C34H32O2S
(504.2): C 80.92, H 6.39; found: C 80.74, H 6.44.
2,5-Diphenyl-3,4-diACTHNUTRGNE(NUG 4-tolyl)thiophene (4a): Procedure A:
toluene:H2O=4:1 (5 mL), reflux 24 h, 908C. Starting with
3a (0.392 g, 1.0 mmol) and 4-tolylboronic acid (0.407 g,
3.0 mmol), PdACHTUNGTRENNUNG(PPh3)4 (0.115 g, 10 mol-%), K3PO4 (0.848 g,
4.0 mmol), 4a was isolated as a colourless solid; yield:
1
0.358 g (86%); mp 155–1578C. H NMR (300 MHz, CDCl3):
3
d=2.21 (s, 6H, 2CH3), 6.79 (d, J=8.2 Hz, 4H, 2CH, Ar),
6.83 (d, 3J=8.2 Hz, 4H, 2CH, Ar), 7.14 (m, 10H, Ar);
13C NMR (75 MHz, CDCl3): d=21.3 (C, CH3), 127.1, 128.3,
128.6, 129.2, 130.7 (CH, Ar), 134.3, 134.4, 135.9, 137.7, 139.6
3,4-Bis(4-hydroxyphenyl)-2,5-di
G
(4e):
Procedure A: toluene:dioxane:H2O=2:2:1 (5 mL), reflux
24 h, 908C. Starting with 3b (0.42 g, 1.0 mmol) and (4-hy-
droxyphenyl)boronic acid (0.433 g, 3.0 mmol), PdACHTUNGTRENNUNG(PPh3)4
(0.115 g, 10 mol%), K3PO4 (0.848 g, 4.0 mmol), 4e was iso-
˜
(C, ArC); IR (KBr): n=3023 (w), 2918 (w), 1597 (w), 1502
(m), 1482 (m), 1022 (w), 827 (w), 749 (m), 696 (s), 605 (w),
523 cmꢀ1 (w); MS (EI, 70 eV): m/z (%)=416 (M+, 100), 324
(4), 281 (3), 179 (6), 165 (4), 154 (4), 112 (3), 97 (2), 83 (3),
57 (4); HR-MS (EI, 70 eV): m/z=416.1591, calcd. for
C32H24S (M+): 416.1593.
3,4-Diphenyl-2,5-diACTHNUTRGNE(NUG 4-tolyl)thiophene (4b): Procedure A:
toluene:H2O=4:1 (5 mL), reflux 24 h, 908C. Starting with
3b (0.42 g, 1.0 mmol) and phenylboronic acid (0.365 g,
3.0 mmol), PdACHTUNGTRENNUNG(PPh3)4 (0.115 g, 10 mol%), K3PO4 (0.848 g,
lated as a colourless solid; yield: 0.367 g (82%); mp 186–
1
1878C. H NMR (300 MHz, CDCl3): d=2.18 (s, 3H, CH3),
6.49, 6.67, 6.92, 7.06 (d, 16H, 4ꢇ4CH, Ar); 13C NMR
(75 MHz, CDCl3): d=20.2 (C, CH3), 128.7, 128.9, 131.7,
131.8 (CH, Ar), 127.3, 127.9, 136.8, 137.2, 139.6, 156.2 (C,
˜
Ar); IR (KBr): n=3383 (m), 3062 (w), 2921 (m), 1609 (m),
1513 (s), 1263 (s), 1210 (s), 815 (s), 559 cmꢀ1 (w); MS (EI,
70 eV): m/z (%)=449 (M+, 57), 448 (100), 364 (23), 362
(20), 283 (15), 69 (13), 57 (14), 43 (12), 40 (11); HR-MS (EI,
70 eV): m/z=448.5732, calcd. for C30H24O2S (M+): 448.5754;
found: 448.5752, elemental analysis calcd. (%) for
4.0 mmol), 4b was isolated as a colourless solid; yield:
1
0.212 g (51%); mp 154–1558C. H NMR (300 MHz, CDCl3):
3
d=2.22 (s, 3ꢇ2H, CH3), 6.87 (d, J=8.2 Hz, 4H, 2CH, Ar),
Adv. Synth. Catal. 2009, 351, 1595 – 1609
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asc.wiley-vch.de
1603

ˇ
Dang Thanh Tꢀng et al.
¯
FULL PAPERS
.
C30H24O2S (448.1): C 80.33, H 5.39, S 7.15; found: C 79.98,
H 5.19, S 6.88.
3,4-Bis(4-chlorophenyl)-2,5-diACTHNUGRTNEUNG(4-tolyl)thiophene (4f): Pro-
cedure A: toluene:H2O=4:1 (5 mL), reflux 24 h, 1008C.
Starting with 3b (0.42 g, 1.0 mmol) and (4-chlorophenyl)bor-
boronic acid (0.091 g, 0.6 mmol), PdACHTUNRGTNEG(NU OAc)2 (5.6 mg, 5
mol%), L (20.5 mg, 10 mol%), K3PO4 (0.424 g, 4.0 mmol),
5b was isolated as a white solid; yield: 0.17 g (80%); mp
124–1258C. 1H NMR (250 MHz, CDCl3): d=3.84 (s, 3H,
OMe), 6.96, 7.49 (d, 2H, CH, Ar); 13C NMR (75 MHz,
CDCl3): d=55.4 (OMe), 109.3, 109.9, 118.3 (CBr), 114.2,
onic acid (0.469 g, 3.0 mmol), PdACHTNUTRGNEUNG(PPh3)4 (0.115 g, 10 mol%),
K3PO4 (0.848 g, 4.0 mmol), 4f was isolated as a colourless
solid; yield: 0.44 g (91%); mp139–1408C. 1H NMR
(300 MHz, CDCl3): d=2.21 (s, 6H, 2CH3), 6.78 (d, 3J=
8.2 Hz, 4H, 2ꢇ2CH, Ar), 7.02 (m, 12H, 4ꢇ3CH, Ar);
13C NMR (75 MHz, CDCl3): d=20.9 (C, CH3), 127.9, 128.7,
128.9, 131.8 (CH, Ar), 130.7, 132.6, 134.8, 137.3, 137.2, 137.9
˜
130.3 (2 CH, Ar), 124.6, 140.0, 160.3 (C); IR (KBr): n=3028
(w), 3005 (w), 2954 (w), 2895 (w), 2830 (w), 1879 (w), 1603
(w), 1489 (m), 1248 (m), 1177 (m), 1031 (m), 832 cmꢀ1 (m);
MS (EI, 70 eV): m/z (%)=430 (M+, [81Br,81Br,81Br], 35), 428
(M+, [81Br,81Br,79Br], 97), 426 (M+, [81Br,79Br,79Br], 100), 424
(M+, [79Br,79Br,79Br], 33); HRMS (EI, 70 eV): m/z=found:
429.76984, calcd for C11H7Br3S (M+, [81Br,81Br,81Br]):
429.77009; 427.77152, calcd. for (M+, [81Br,81Br,79Br]):
427.77213; 425.77363, calcd. for (M+, [81Br,79Br,79Br]):
425.77418; 423.77564, calcd. for (M+, [79Br,79Br,79Br]):
423.77622; elemental analysis calcd. (%) for C11H7Br3S
(423.8): C 30.94, H 1.65, S 7.51; found: C 30.72, H 1.64, S
7.58.
˜
(C, ArC); IR (KBr): n=3052 (w), 2911 (w), 1546 (w), 1509
(m), 1431 (m), 1027 (w), 838 (w), 815 (m), 771 (s), 707 (s),
522 (w), 517 cmꢀ1 (w); MS (EI, 70 eV): m/z (%)=488 (M+,
[37Cl,37Cl], 14), 486 (M+, [37Cl,35Cl], 70), 484 (M+, [35Cl,35Cl],
100); HR-MS (EI, 70 eV): m/z=484.1581, calcd. for
C30H22Cl2S (M+,[35Cl,35Cl]): 484.1583.
2,3,4-Tribromo-5-(3-biphenyl)thiophene (5c): Procedure
B: 5 mL of toluene, reflux 8 h, 1008C. Starting with 1
(0.200 g, 0.5 mmol) and 3-biphenylboronic acid (0.119 g,
General Procedure B for the Synthesis of 5a–e
An oven-dried Schlenk flash was charged with PdACTHUNRGTNEUNG(OAc)2 (5
0.6 mmol), PdACTHNUTRGNE(UNG OAc)2 (5.6 mg, 5 mol%), L (20.5 mg, 10
mol%), ligand L (10 mol%), the starting material, the bor-
onic acid (1.0 equiv.) and powered, anhydrous K3PO4
(4 equiv.). The Schlenk flask was filled with argon. The sol-
vent was added by syringe through a septum. The septum
was replaced by a condenser in an argon stream. The reac-
tion mixture was stirred and refluxed for the indicated
period of time at the indicated temperature. The solution
was allowed to cool to ambient temperature and water
(5 mL) was added. The aqueous and the organic layer were
separated and the latter was dried Na2SO4. The solution was
filtered and the filtrate was concentrated under reduced
pressure. The residue was purified by flash column chroma-
tography (fine flash silica gel, heptanes). The solvents and
the amounts are given in the individual procedures (see
below).
mol%), K3PO4 (0.424 g, 4.0 mmol), 5c was isolated as a
yellow solid; yield: 0.181 g (77%); mp 116–1178C. H NMR
(250 MHz, CDCl3): d=7.38–7.79 (m, 9H, CH, Ar);
13C NMR (75 MHz, CDCl3): d=110.3, 110.6, 118.6 (CBr),
127.2, 129.9 (2CH, Ar), 127.7, 127.8, 127.9, 129.2 (CH, Ar),
1
˜
132.7, 139.9, 140.2, 141.9 (C); IR (KBr): n=3077 (w), 3056
(w), 3024 (w), 1595 (w), 1567 (w), 1468 (w), 1273 (w), 786
(m), 748 (m), 691 , cmꢀ1 (m); MS (EI, 70 eV): m/z (%)=476
(M+, [81Br,81Br,81Br], 36), 474 (M+, [81Br,81Br,79Br], 97), 472
(M+, [81Br,79Br,79Br], 100), 470 (M+, [79Br,79Br,79Br], 33);
HR-MS (EI, 70 eV): m/z=475.79034, calcd. for C16H9Br3S
(M+, [81Br,81Br,81Br]): 475.79082; 473.79226, calcd. for (M+,
[81Br,81Br,79Br]): 473.79287; 471.79506, calcd. for (M+,
[81Br,79Br,79Br]): 471.79491; found: 469.79689, calcd. for (M+,
[79Br,79Br,79Br]): 469.79696; elemental analysis calcd. (%) for
C16H9Br3S (469.8): C 41.63, H 1.92, S 6.77; found: C 41.27,
H 1.80, S 7.07.
2,3,4-Tribromo-5-(2-methoxyphenyl)thiophene (5a): Pro-
cedure B: toluene:dioxane=1:1 (4 mL), reflux 8 h, 1008C.
Starting with 1 (0.200 g, 0.5 mmol) and (2-methoxyphenyl)-
2,3,4-Tribromo-5-(naphth-2-yl)thiophene (5d): Procedure
B: 5 mL of toluene, reflux 8 h, 1008C. Starting with 1
(0.200 g, 0.5 mmol) and (naphtha-2-yl)boronic acid (0.103 g,
boronic acid (0.091 g, 0.6 mmol), PdACHTUNGETRN(UNNG OAc)2 (5.6 mg, 5
mol%), L (20.5 mg, 10 mol%), K3PO4 (0.424 g, 4.0 mmol),
5a was isolated as a white solid; yield: 0.158 g (75%); mp
72–788C. 1H NMR (250 MHz, CDCl3): d=3.83 (s, 3H,
OMe), 6.98, 7.03 (d, 1H, CH, Ar), 7.34, 7.44 (t, 1H, CH,
Ar); 13C NMR (75 MHz, CDCl3): d=55.6 (OMe), 110.5,
112.6, 117.3 (CBr), 111.3, 120.5, 131.0, 131.9 (CH, Ar),
0.7 mmol), PdACTHNUTRGNE(UNG OAc)2 (5.6 mg, 5 mol%), L (20.5 mg, 10
mol%), K3PO4 (0.424 g, 4.0 mmol), 5d was isolated as an
orange viscous oil; yield: 0.153 g (69%). 1H NMR
(250 MHz, CDCl3): d=7.47–7.97 (m, 7H, CH, Ar);
13C NMR (75 MHz, CDCl3): d=110.9, 113.7, 117.6 (CBr),
125.0, 125.5, 126.4, 127.0, 128.5, 129.4, 130.2 (CH, Ar), 129.5,
˜
120.9, 136.3, 157.0 (C); IR (KBr): n=3077 (w), 3008 (w),
2933 (m), 2831 (m), 2487 (w), 2042 (w), 1903 (w), 1579 (s),
1246 (s), 1022 (s), 744 (s), 723 cmꢀ1 (s); MS (EI, 70 eV): m/z
˜
131.5, 133.5, 138.2 (C); IR (KBr): n=3050 (w), 2962 (w),
(M+,
[81Br,81Br,81Br],
35),
428
(M+,
2848 (w), 1926 (w), 1875 (w), 1814 (w), 1501 (w), 1434 (m),
1386 (m), 1261 (m), 793 (s), 796 (s) 729 cmꢀ1 (m); MS (EI,
70 eV): m/z (%)=450 (M+, [81Br,81Br,81Br], 17), 448 (M+,
[81Br,81Br,79Br], 48), 446 (M+, [81Br,79Br,79Br], 48), 444 (M+,
[79Br,79Br,79Br], 16); HR-MS (EI, 70 eV): m/z=447.77769,
calcd. for C14H7Br3S (M+, [81Br,81Br,79Br]): 447.77777;
445.77989, calcd. for (M+, [81Br,79Br,79Br]): 445.77981; ele-
mental analysis calcd. (%) for C14H7Br3S (443.8): C 37.62, H
1.58, S 7.17; found: C 37.77, H 1.44, S 7.56.
(%)=430
[81Br,81Br,79Br], 99), 426 (M+, [81Br,79Br,79Br], 100), 424 (M+,
[79Br,79Br,79Br], 33); HR-MS (EI, 70 eV): m/z=419.77005,
calcd. for C11H7Br3S (M+, [81Br,81Br,81Br]): 429.77009;
427.77182, calcd. for (M+, [81Br,81Br,79Br]): 427.77213;
425.77375, calcd. for (M+, [81Br,79Br,79Br]): 425.77418;
423.77569, calcd. for (M+, [79Br,79Br,79Br]): 423.77622, ele-
mental analysis calcd (%) for C11H7Br3S (423.8): C 30.94, H
1.65, S 7.51; found: C 30.87, H 1.49, S 7.24.
2,3,4-Tribromo-5-(4-ethylphenyl)thiophene (5e): Proce-
dure B: 5 mL of toluene, reflux 8 h, 1008C. Starting with 1
(0.200 g, 0.5 mmol) and (4-ethylphenyl)boronic acid (0.090 g,
2,3,4-Tribromo-5-(4-methoxyphenyl)thiophene (5b): Pro-
cedure B: toluene:dioxane=1:1 (4 mL), reflux 8 h, 1008C.
Starting with 1 (0.200 g, 0.5 mmol) and (4-methoxyphenyl)-
1604
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Regioselective Palladium(0)-Catalyzed Cross-Coupling Reactions
FULL PAPERS
0.6 mmol), Pd
(OAc)2 (5.6 mg, 5 mol%), L (20.5 mg, 10
[79Br,79Br]): 449.92831; elemental analysis calcd. (%) for
C19H16Br2SO (449.9): C 50.46, H 3.57, S 7.09; found: C
50.53, H 3.36, S 6.78.
3,4-Dibromo-2-(4-methoxyphenyl)-5-(3-biphenyl)thio-
phene (6c): Procedure B: toluene:dioxane=1:1 (4 mL),
reflux 8 h, 1008C. Starting with 5b (0.212 g, 0.5 mmol) and
mol%), K3PO4 (0.424 g, 4.0 mmol), 5e was isolated as a light
yellow solid; yield: 0.183 g (87%); mp 58–638C. 1H NMR
(250 MHz, CDCl3): d=1.20 (t, 3H, CH3), 2.62 (q, 2H, CH2),
7.20, 7.40 (d, 2H, CH, Ar); 13C NMR (75 MHz, CDCl3): d=
15.3 (CH3), 28.7 (2H, CH2), 109.7, 110.0, 118.4 (CBr), 128.3,
3-biphenylboronic acid (0.119 g, 0.6 mmol), PdACHTUNGTRENNUNG(OAc)2
˜
128.8 (2 CH, Ar), 129.6, 140.2, 145.6 (C); IR (KBr): n=2965
(5.6 mg, 5 mol%), L (20.5 mg, 10 mol%), K3PO4 (0.424 g,
4.0 mmol), 6c was isolated as an orange solid; yield: 0.171 g
(69%); mp 60–628C. H NMR (250 MHz, CDCl3): d=3.86
(s, 3H, OCH3), 6.99 (d, 2H, CH, Ar), 7.33–7.65 (m, 11H,
CH, Ar); 13C NMR (75 MHz, CDCl3): d=55.4 (O CH3),
111.8, 112.2 (CBr), 114.1, 127.2, 128.9, 130.3 (2 CH, Ar),
127.2, 127.6, 127.7, 127.8, 129.1 (CH, Ar), 125.2, 133.4, 137.3,
(m), 2923 (w), 2874 (w), 2836 (w), 1901 (w), 1888 (w), 1608
(w), 1484 (w), 1433 (w), 1409 (w), 1268 (m), 824 , cmꢀ1 (m);
MS (EI, 70 eV): m/z (%)=428 (M+, [81Br,81Br,81Br], 34), 426
(M+, [81Br,81Br,79Br], 96), 424 (M+, [81Br,79Br,79Br], 97), 422
(M+, [79Br,79Br,79Br], 33); HR-MS (EI, 70 eV): m/z=
427.79059, calcd. for C12H9Br3S (M+, [81Br,81Br,81Br]):
427.79082; 425.79277, calcd. for (M+, [81Br,81Br,79Br]):
425.79287; 423.79458, calcd. for (M+, [81Br,79Br,79Br]):
423.79491; 421.79606, calcd. for (M+, [79Br,79Br,79Br]):
421.79696; elemental analysis calcd. (%) for C12H9Br3S
(421.8): C 33.91, H 2.13, S 7.55; found: C 33.64, H 1.96, S
7.48.
1
˜
138.2, 140.5, 141.7, 160.1 (C); IR (KBr): n=3057 (w), 3029
(w), 3003 (w), 2929 (w), 2833 (w), 1873 (w), 1604 (w), 1474
(m), 1450 (m), 1253 (m), 1179 (m), 1033 (m), 821 (m), 747
(m), 961 cmꢀ1 (m); MS (EI, 70 eV): m/z (%)=502 (M+,
[81Br,81Br], 14), 500 (M+, [81Br,79Br], 30), 498 (M+,
[79Br,79Br], 13), 497 (M+, 66), 486 (M+, 12), 484 (M+, 24);
HR-MS (EI, 70 eV): m/z=501.92450, calcd. for
C23H16Br2SO (M+, [81Br,81Br]): 501.92422; 499.92610, calcd.
for (M+, [81Br,79Br]): 499.92627; 497.92959, calcd. for (M+,
[79Br,79Br]): 497.92831; elemental analysis calcd. (%) for
C23H16Br2SO (497.9): C 55.22, H 3.22, S 6.41; found: C
55.62, H 3.38, S 6.49.
3,4-Dibromo-2-(4-methoxyphenyl)-5-(4-ethylphenyl)thio-
phene (6a): Procedure B: toluene:dioxane=1:1 (4 mL),
reflux 8 h, 1008C. Starting with 5b (0.212 g, 0.5 mmol) and
(4-ethylphenyl)boronic acid (0.090 g, 0.6 mmol), PdACTHNUTRGNEUNG(OAc)2
(5.6 mg, 5 mol%), L (20.5 mg, 10 mol%), K3PO4 (0.424 g,
4.0 mmol), 6b was isolated as an orange solid; yield: 0.163 g
1
(72%); mp 61–768C. H NMR (250 MHz, CDCl3): d=1.33
(t, 3H, CH3), 2.76 (q, 2H, CH2), 3.89 (s, 3H, OMe), 7.02,
7.34, 7.62, 7.65 (d, 2H, CH, Ar); 13C NMR (75 MHz,
CDCl3): d=15.3 (CH3), 28.6 (CH2), 55.3 (OMe), 111.57,
111.63 (CBr), 114.0, 128.1, 128.9, 130.3 (CH, Ar), 125.9,
General Procedure A for the Synthesis of 9a–d
To a solution (for the solvents, see the individual procedures
given below) of starting material was added PdACTHNUTRGNE(UNG PPh3)4 (10
˜
127.6, 137.6, 137.7, 145.0, 159.0 (C); IR (KBr): n=2997 (w),
mol%) at 208C. After stirring for 30 min, the arylboronic
acid, K3PO4 (8.0 mmol) and water (1.0 mL) were added.
The mixture was stirred for the indicated period of time at
the indicated temperature. After cooling to ambient temper-
ature, the mixture was diluted with EtOAc, dried (Na2SO4),
and filtered through a short Celite pad. The solution was
concentrated under vacuum and the residue was purified by
flash column chromatography (fine flash silica gel, n-hep-
tane). The solvents and the amounts are given in the indi-
vidual procedures (see below).
2960 (w), 2929 (w), 2871 (w), 2047 (w), 1905 (w), 1603 (w),
1486 (m), 1248 (m), 1028 (m), 827 (m), 800 cmꢀ1 (m); MS
(EI, 70 eV): m/z (%)=454 (M+, [81Br,81Br], 53), 452 (M+,
[81Br,79Br], 100), 450 (M+, [79Br,79Br], 50), 439 (M+, 22), 437
ACHTUNGTRENNUNG
(M+, 40), 435(M+, 21); HR-MS (EI, 70 eV): m/z=
453.92399, calcd for C19H16Br2SO (M+, [81Br,81Br]):
453.92422; 451.92589, calcd. for (M+, [81Br,79Br]): 451.92627;
449.92798, calcd. for (M+, [79Br,79Br]): 449.92831; elemental
analysis calcd. (%) for C19H16Br2SO (449.9): C 50.46, H 3.57,
S 7.09; found: C 50.30, H 3.81, S 7.40.
3,4-Dibromo-2-(4-methoxyphenyl)-5-(3,5-dimethylphe-
nyl)thiophene (6b): Procedure B: tolulene:dioxane=1:1
(4 mL), reflux 8 h, 1008C. Starting with 5b (0.212 g,
0.5 mmol) and (3,5-dimethylphenyl)boronic acid (0.090 g,
General Procedure B for the Synthesis of 9a–d
An oven-dried Schlenk flash was charged with PdACHTUNGTRENNUNG(OAc)2
(10 mol%), ligand L (20 mol%), the starting material, the
boronic acid and powered, anhydrous K3PO4 (8 equiv.). The
Schlenk flask was filled with argon. The solvent was added
by syringe through a septum. The septum was replaced by a
condenser in an argon stream. The reaction mixture was
stirred and refluxed for the indicated period of time at the
indicated temperature. The solution was allowed to cool to
ambient temperature and water (5 mL) was added. The
aqueous and the organic layer were separated and the latter
was dried Na2SO4. The solution was filtered and the filtrate
was concentrated under reduced pressure. The residue was
purified by flash column chromatography (fine flash silica
gel, heptanes). The solvents and the amounts are given in
the individual procedures (see below).
0.6 mmol), PdACHTUNGTRENNUNG(OAc)2 (5.6 mg, 5 mol%), L (20.5 mg, 10
mol%), K3PO4 (0.424 g, 4.0 mmol), 6b was isolated as an
orange solid; yield: 0.150 g (67%); mp 85–898C. 1H NMR
(250 MHz, CDCl3): d=2.30 (s, 6H, CH3), 3.77 (s, 3H,
OCH3), 6.89, 7.51 (d, 2H, CH, Ar), 6.96 (d, H, CH, Ar),
7.18 (s, 2H, CH, Ar); 13C NMR (75 MHz, CDCl3): d=21.3
(CH3), 55.3 (O CH3), 111.5, 111.7 (CBr), 114.2, 126.8, 131.4
(2 CH, Ar), 131.2 (CH, Ar), 114.3, 125.3, 132.7, 137.7, 138.2,
˜
160.0 (C); IR (KBr): n=2994 (w), 2931 (w), 2912 (w), 2832
(w), 2545 (w), 2077 (w), 1880 (w), 1599 (m), 1530 (m), 1469
(m), 1248 (m), 1033 (m), 824 (m), 796 (m), 739 (m),
689 cmꢀ1 (m); MS (EI, 70 eV): m/z (%)=454 (M+,
[81Br,81Br], 53), 452 (M+, [81Br,79Br], 100), 450 (M+,
ACTHNUTRGNEUNG
[79Br,79Br], 49), 439 (M+, 17), 437 (M+, 32), 435(M+, 16);
Dimethyl 3,4-di(4-chlorophenyl)thiophene-2,5-dicarboxy-
late (9a): Procedure A: toluene:H2O=4:1 (5 mL), reflux
24 h, 1008C. Starting with 7g (0.358 g, 1.0 mmol) and (4-
HR-MS (EI, 70 eV): m/z=453.92398, calcd. for
C19H16Br2SO (M+, [81Br,81Br]): 453.92422; 451.92577, calcd.
for (M+, [81Br,79Br]): 451.92627; 449.92776, calcd. for (M+,
chlorophenyl)boronic acid (0.469 g, 3 mmol), PdACHTUNGTRENNUNG(PPh3)4
Adv. Synth. Catal. 2009, 351, 1595 – 1609
ꢆ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1605

ˇ
Dang Thanh Tꢀng et al.
¯
FULL PAPERS
.
(0.060 g, 5 mol%), K3PO4 (0.848 g, 4.0 mmol), 9a was isolat-
ed as a white solid; yield: 0.176 g (42%): mp 149–1518C.
1H NMR (300 MHz, CDCl3): d=3.64 (s, 6H, 2OCH3), 7.14,
7.51 (d, J=8.2 Hz, 2H, CH, Ar), 7.31 (d, J=8.2 Hz, 4H,
CH, Ar); 13C NMR (75 MHz, CDCl3): d=51.56 (C, OCH3),
127.56, 129.07, 129.85, 132.42 (CH, Ar), 141.30, 159.19
tane) at ꢀ788C. After stirring for 60 min at ꢀ788C, the elec-
trophile (3.0 mmol) was added at ꢀ788C. After warming of
the mixture to 208C within 16 h, a saturated aqueous solu-
tion of NH4Cl (30 mL) was added. The organic and the
aqueous layer were separated and the latter was extracted
with ethyl acetate (2ꢇ30 mL). The combined organic layers
were dried (Na2SO4), filtered and the solvent of the filtrate
was removed under vacuum. The residue was purified by
chromatography (fine silica gel, n-heptane).
3
3
˜
113.73, 141.85 (C, Ar), 160.09 (C, CO); IR (KBr): n=3429
(m), 2950 (m), 1899 (w), 1721 (s), 1593 (w), 1522 (w), 1437
(s), 1095 (m), 1016 (m), 829 (m), 807 (s), 761, cmꢀ1 (m); MS
(EI, 70 eV): m/z (%)=421 (M+, 35), 350 (100), 240 (16), 210
(10), 191 (11), 149 (9), 112 (7), 97 (9), 83 (12), 81 (19), 44
(7); HR-MS (EI, 70 eV): m/z=421.2036, calcd. for
C30H22O4Cl2S (M+): 421.2938.
Dimethyl 3,4-di(2-methoxyphenyl)thiophene-2,5-dicarbox-
ylate (9b): Procedure B: 5 mL of dioxane, reflux 8 h, 1008C.
Starting with 7g (0.358 g, 1.0 mmol) and (2-methoxyphenyl)-
3,4-Dibromo-2,5-dimethylthiophene (7a): Starting with
tetrabromothiophene (0.400 g, 1.0 mmol) and iodomethane
(0.426 g, 3.0 mmol), 7a was isolated as a colourless oil; yield:
1
0.151 g (56%). H NMR (300 MHz, CDCl3): d=2.85 (s, 6H,
2CH3); 13C NMR (75 MHz, CDCl3): d=15.4 (C, CH3),
˜
112.2, 131.7 (C, ArC); IR (KBr): n=2965 (m), 2928 (m),
2879 (w), 1515 (w), 1448 (m), 1445 (w), 1315 cmꢀ1 (w); MS
(EI, 70 eV): m/z (%)=272 (M+, [81Br,81Br], 52), 270 (M+,
[81Br,79Br], 100), 268 (M+, [79Br,79Br], 51), 191 (93), 189 (93),
95 (12), 51 (16); elemental analysis calcd. (%) for C6H6Br2S:
C 26.69, H 2.24, S 11.88; found: C 26.65, H 2.26, S 11.88.
3,4-Dibromo-2,5-dibutylthiophene (7b): Starting with tet-
rabromothiophene (0.400 g, 1.0 mmol) and 1-iodobutane
(0.546 g, 3.0 mmol), 7b was isolated as a colourless oil;
boronic acid (0.299 g, 2.2 mmol), PdACTHNUTRGENUG(N OAc)2 (11.2 mg, 5
mol%), L (41 mg, 10 mol%), K3PO4 (0.848 g, 4.0 mmol), 9b
was isolated as a colourless solid; yield: 0.185 g (45%); mp
205–2078C. A doubling of some signals in the 1H and
13C NMR spectra is observed, due to the presence of two
atropisomers. 1H NMR (300 MHz, CDCl3): d=3.43, 3.51
(2ꢇs, 6H, OCH3), 3.67, 3.68 (2ꢇs, 6H, CO2CH3), 6.61, 6.72
3
3
1
(d, J=8.2 Hz, 2H, CH, Ar), 6.83, 7.18 (t, J=8.2 Hz, 2H,
CH, Ar); 13C NMR (75 MHz, CDCl3): d=52.0 (C, OCH3),
55.0, 55.1 (CH3, OCOCH3), 110.0, 110.1, 119.4, 119.5, 129.0,
129.1, 130.5, 130.8 (CH, Ar), 132.0, 132.1, 145.3, 146.0 (C,
Ar), 123.8, 124.1, 156.6 (C, thiophene), 161.8, 161.9 (C=O);
yield: 0.333 g (94%). H NMR (300 MHz, CDCl3): d=0.82
(t, 3J=7.2 Hz, 6H, 2CH3), 1.22–1.32 (m, 4H, 2CH2,
CH2CH3), 1.40–1.55 (m, 4H, 2CH2, CH2CH2CH3), 2.69 (t,
3J=7.2 Hz, 4H, 2CH2, CH2CH2CH2CH3); 13C NMR
(75 MHz, CDCl3): d=13.9 (C, CH3), 22.4, 29.7, 32.3 (C,
˜
IR (KBr): n=3433 (br, w), 3065 (w), 3029 (w), 3001 (w),
˜
CH2), 118.8, 137.3 (C, ArC); IR (KBr): n=2956 (s), 2926
(m), 2869 (m), 1466 (m), 1384 (w), 1366 (w), 1360 cmꢀ1 (w);
MS (EI, 70 eV): m/z (%)=356 (M+, [81Br,81Br], 14), 354
(M+, [81Br,79Br], 26), 352 (M+, [79Br,79Br], 13), 313 (52), 311
(100), 309 (51), 269 (13), 255 (17), 231 (14), 194 (12); ele-
mental analysis calcd. (%) for C12H18Br2S: C, 40.70, H, 5.12,
S, 9.05; found: C, 40.74, H, 5.12, S, 9.05.
2953 (s), 2833 (s), 1724 (s), 1601 (m), 1583 (s), 1508 (s), 1468
(s), 1289 (s), 1158 (m), 1079 (m), 1048 (m), 762 (s), 750 cmꢀ1
(s); MS (EI, 70 eV): m/z (%)=412 (M+, 98), 382 (25), 381
(100), 322 (10), 321 (46), 307 (16), 305 (9), 287 (19); HR-MS
(EI, 70 eV): m/z=412.0971, calcd. for C22H20O6S (M+):
412.0975; elemental analysis calcd. (%) for C22H20O6S
(412.1): C 64.06, H 4.89, S 7.77; found: C 63.97, H 4.81, S
7.70.
3,4-Dibromo-2,5-di(isopentyl)thiophene (7c): Starting
with tetrabromothiophene (0.400 g, 1.0 mmol) and 1-bromo-
3-methylbutane (0.453 g, 3.0 mmol), 7c was isolated as a col-
ourless oil; yield: 0.294 g (77%). 1H NMR (300 MHz,
CDCl3): d=1.08 (d, 3J=7.2 Hz, 12H, 2ꢇ2CH3), 1.64 [m,
Dimethyl 3,4-di(2-hydroxyphenyl)thiophene-2,5-dicarbox-
ylate (9c): Procedure A: toluene:dioxane:H2O=2:2:1
(5 mL). Starting with 7g (0.358 g, 1.0 mmol) and (2-hydroxy-
phenyl)boronic acid (0.443 g, 3.0 mmol), PdACTHNUTRGNE(UNG PPh3)4 (0.060 g,
4H, 2CH2, CH
2A
5 mol%), K3PO4 (0.848 g, 4.0 mmol), 9c was isolated as a
colourless solid; yield: 0.188 g (49%); mp 159–1608C.
1H NMR (300 MHz, CDCl3): d=3.79 (s, 6H, 2OCH3), 7.31,
2CH2, CH2CH CHTUNGTRENNUNG
2A
23.2 (C, CH3), 27.6, 30.0 (C, CH2), 39.4 (C, CH), 119.8, 137.2
˜
(C, ArC); IR (KBr): n=2956 (s), 2926 (m), 2869 (m), 1466
3
3
9.00 (d, J=8.2 Hz, 2H, CH, Ar), 7.39, 7.51 (t, J=8.2 Hz,
2H, CH, Ar); 13C NMR (75 MHz, CDCl3): d=116.7, 118.0,
123.1, 124.4 (CH, Ar), 112.7, 130.7, 140.6, 155.9 (C, Ar),
(m), 1384 (w), 1366 (w), 1360 cmꢀ1 (w); MS (EI, 70 eV): m/z
(%)=384 (M+, [81Br,81Br], 11), 382 (M+, [81Br,79Br], 21), 380
(M+, [79Br,79Br], 10), 327 (17), 323 (17), 271 (20), 269 (38),
267 (19), 255 (17), 248 (12), 247 (99), 245 (100), 57 (13); ele-
mental analysis calcd. (%) for C14H22Br2S: C, 44.00, H, 5.80,
S, 8.39; found: C, 44.05, H, 5.72, S, 8.33.
˜
160.2 (C, CO); IR (KBr): n=3333 (br, s), 3062 (m), 3023
(m), 2921 (m), 2900 (m), 1688 (m), 1670 (s), 1596 (s), 1523
(s), 1494 (s), 1236 (s), 1142 (m), 1100 (m), 1010 (m), 833 (s),
816 cmꢀ1 (s); MS (EI, 70 eV): m/z (%)=384 (M+, 26), 364
(35), 322 (10), 321 (46), 307 (16), 305 (9), 287 (19), 283
(100); HR-MS (EI, 70 eV): m/z=384.4028, calcd. for
C20H16O6S (M+): 384.4024; elemental analysis calcd. (%) for
C20H16O6S (384.1): C 62.49, H 4.20, S 8.34; found: C 62.41,
H 4.29, S 8.19.
3,4-Dibromo-2,5-diACTHNUTRGNEUNG(dodecyl)thiophene (7d): Starting with
tetrabromothiophene (0.400 g, 1.0 mmol) and 1-bromodode-
cane (0.744 g, 3.0 mmol), 7d was isolated as a colourless oil;
yield: 0.374 g (65%). A small amount of an aliphatic impuri-
1
ty could not be separated. H NMR (300 MHz, CDCl3): d=
3
0.53–0.75 (m, J=7.2 Hz, 12H, 2CH3 +3CH2), 0.93–1.25 (m,
26H, 2ꢇ13CH2), 1.29–1.43 (m, 2H, CH2), 1.55–1.67 (m, 4H,
3
2CH2), 2.44 (m, 2H, CH2), 3.14 (t, J=7.2 Hz, 4H, 2CH2);
General Procedure for the Synthesis of 3,4-
Dibromothiophenes 7a–h
13C NMR (75 MHz, CDCl3): d=14.0 (C, CH3), 22.7, 28.2,
28.8, 28.9, 29.3, 29.5, 29.6, 30.2, 31.9, 32.8, 33.5 (C, CH2),
˜
To
a
THF solution of tetrabromothiophene (0.400 g,
111.8, 137.1 (C, Ar); IR (KBr): n=2956 (s), 2924 (s), 2854
1.0 mmol) was added 1 mL of n-butyllithium (2.5m in hep-
(s), 1465 (m), 1378 (w), 1254 (w), 721 (w), 647 (w), 565 cmꢀ1
1606
asc.wiley-vch.de
ꢆ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1595 – 1609

Regioselective Palladium(0)-Catalyzed Cross-Coupling Reactions
FULL PAPERS
(w); MS (EI, 70 eV): m/z (%)=580 (M+, [81Br,81Br], 28),
578 (M+, [81Br,79Br], 54), 576 (M+, [79Br,79Br], 26), 499 (73),
423 (15), 343 (20), 305 (33), 271 (50), 269 (100), 267 (49),
231 (19), 191 (45), 151 (13), 111 (12), 97 (14), 83 (13), 71
(16), 57 (44); HR-MS (EI, 70 eV): m/z=576.1990, calcd. for
C28H50Br2S (M+, [79Br,79Br]): 576.1994.
General Procedure for the Synthesis of 3,4-
Dibromothiophenes 8a–f
To a THF solution (15 mL) of n-BuLi (2.5M in n-hexane,
1.05 mL, 2.5 mmol) and TMEDA (0.775 mL, 2.5 mmol) was
added tetrabromothiophene (0.200 g, 0.5 mmol) at ꢀ788C
under an argon atmosphere and the mixture was stirred for
30 min. To the stirred solution was dropwise added a THF
solution (5 mL) of TMSCl (0.063 mL, 0.5 mmol) over a
period of 3 h. The reaction mixture was stirred for further
30 min and, subsequently, the 1-bromoalkane (0.75 mmol)
was added. After stirring for 4 h, to the solution was added
a saturated aqueous solution of Na2SO4 (10 mL). The aque-
ous and the organic layer were separated. The organic layer
was dried (Na2SO4), filtered and concentrated under
vacuum. The residue was purified by flash column chroma-
tography (fine flash silica gel, n-heptane).
3,4-Dibromo-2,5-bis(trimethylsilyl)thiophene (7e): Start-
ing with tetrabromothiophene (0.400 g, 1.0 mmol) and
TMSCl (0.324 g, 3.0 mmol), 7e was isolated as a colourless
1
oil; yield: 0.355 g (82%). H NMR (300 MHz, CDCl3): d=
0.20 (s, 18H, 6CH3); 13C NMR (75 MHz, CDCl3): d=0.0 (C,
˜
CH3), 123.1, 141.4 (C, ArC); IR (KBr): n=2956 (m), 2879
(m), 1452 (w), 1409 (w), 1251 (s), 1011 (s), 844 (s), 759 (m),
719 (m), 636 cmꢀ1 (m); MS (EI, 70 eV): m/z (%)=388 (M+,
[81Br,81Br], 18), 386 (M+,[81Br,79Br], 30), 384 (M+, [79Br,79Br],
16), 374 (12), 373 (58), 372 (22), 371 (100), 369 (52), 178
(15), 139 (15), 137 (14), 73 (54); HR-MS (EI, 70 eV): m/z=
385.9011, calcd. for C10H18Br2Si2S (M+, [81Br,79Br]): 385.9014.
3,4-Dibromo-2,5-di(methylthio)thiophene (7f): Starting
with tetrabromothiophene (0.400 g, 1.0 mmol) and dimethyl
disulphide (0.282 g, 3.0 mmol), 7f was isolated as a colour-
3,4-Dibromo-5-ethyl-2-trimethylsilylthiophene (8a): Start-
ing with
1
(0.200 g, 0.5 mmol) and 1-bromoethane
(0.6 mmol, 0.09 mL), 8a was isolated as a colourless oil;
1
yield: 0.112 g (65%). H NMR (250 MHz, CDCl3): d=0.44
1
less oil; yield: 0.226 g (68%). H NMR (300 MHz, CDCl3):
[s, 9H, Si
13C NMR (75 MHz, CDCl3): d=0.7 [CH3, Si
(CH3), 23.4 (CH2), 110.5, 113.7 (CBr), 131.7, 146.7 (C); IR
ACHTUNGTRENNUNG
d=2.42 (s, 6H, SCH3); 13C NMR (75 MHz, CDCl3): d=19.8
AHCTUNGTRENNUNG
˜
(C, SCH3), 117.8, 134.3 (C, ArC); IR (KBr): n=2967 (w),
1456 (w), 1433 (m), 1301 (s), 1245 (s), 1076 (s), 925 (w),
761 cmꢀ1 (m); MS (EI, 70 eV): m/z (%)=336 (M+,
[81Br,81Br], 52), 334 (M+, [81Br,79Br], 88), 332 (M+,
[79Br,79Br], 48), 321 (81), 319 (100), 317 (70), 255 (18), 239
(18), 191 (4), 159 (22), 127 (15), 112 (48), 69 (12), 45 (15).
HR-MS (EI, 70 eV): m/z=333.7975, calcd. for C6H6Br2S3
(M+, [81Br,79Br]): 333.7978.
Dimethyl 3,4-dibromothiophene-2,5-dicarboxylate (7g):
Starting with tetrabromothiophene (0.400 g, 1.0 mmol) and
methyl chloroformate (0.284 g, 3.0 mmol), 7g was isolated as
a light yellow solid; yield: 0.183 g (52%); mp 140–1428C.
1H NMR (300 MHz, CDCl3): d=3.84 (s, 6H, 2OCH3);
13C NMR (75 MHz, CDCl3): d=52.1 (C, OCH3), 121.0, 130.8
˜
(KBr): n=2955 (w), 2931 (w), 2896 (w), 2872 (w), 1248 (s),
1004 (s), 996 (s), 832 (s), 756 (s), 696 (s), 632 cmꢀ1 (m); MS
(EI, 70 eV): m/z (%)=344 (M+, [81Br,81Br], 17), 342 (M+,
[81Br,79Br], 30), 340 (M+, [79Br,79Br], 15), 329 (M+, 55), 327
(M+, 100), 325 (M+, 50); HR-MS (EI, 70 eV): m/z=
343.89041, calcd for C9H14Br2SSi (M+, [81Br,81Br]):
343.89058; 341.89283, calcd. for (M+, [81Br,79Br]): 341.89263;
339.89459, calcd. for (M+, [79Br,79Br]): 339.89467; elemental
analysis calcd. (%) for C9H14Br2SSi (339.9): C: 31.80, H
4.12; found: C: 31.80, H 4.52.
5-Butyl-3,4-dibromo-2-trimethylsilylthiophene (8b): Start-
ing with
(0.6 mmol, 0.06 mL), 8b was isolated as a colourless oil;
yield: 0.113 g (61%). H NMR (250 MHz, CDCl3): d=0.45
1
(0.200 g, 0.5 mmol) and 1-bromobutane
1
˜
(C, ArC), 158.9 (C, CO); IR (KBr): n=2961 (w), 1735 (s),
1698 (s), 1499 (w), 1432 (m), 1309 (s), 1240 (s), 1098 (s), 927
(w), 764 , cmꢀ1 (m); MS (EI, 70 eV): m/z (%)=360 (M+,
[81Br,81Br], 28), 358 (M+, [81Br,79Br], 54), 356 (M+,
[79Br,79Br], 26), 320 (80), 318 (70), 307 (15), 305 (18), 287
(23); HR-MS (EI, 70 eV): m/z=357.8331, calcd. for
C8H6Br2O4S (M+, [81Br,79Br]): 357.8333.
2,5-Dibenzoyl-3,4-dibromothiophene (7h): Starting with
tetrabromothiophene (0.400 g, 1.0 mmol) and benzoyl chlo-
ride (2.2 mmol), 7h was isolated as a colourless oil; yield:
0.306 g (68%). 1H NMR (300 MHz, CDCl3): d=7.49 (m,
4H, 2CH, Ar), 7.61 (m, 2H, 2CH, Ar), 7.79 (m, 4H, 2CH,
Ar); 13C NMR (75 MHz, CDCl3): d=129.5, 131.4, 135.4
(CH, Ar), 120.5, 140.6, 141.5 (C, ArC), 187.9 (C, CO); IR
[s, 9H, Si
CH2), 2.67 (q, 2H, CH2); 13C NMR (75 MHz, CDCl3): d=
0.4 [CH3, Si(CH3)3], 13.8 (CH3), 22.4, 30.6, 32.7 (CH2),
ACHTNUGRTNE(NUGN CH3)3], 0.98 (t, 3H, CH3), 1.37–1.54 (m, 4H,
AHCTUNGTRENNUNG
˜
110.8, 114.0 (CBr), 138.7, 149.9 (C); IR (KBr): n=2954 (w),
2897 (w), 2859 (w), 1248 (s), 1052 (s), 1005 (s), 913 (w), 831
(s), 756 (s), 695 (m), 638 (m), 538 cmꢀ1 (m); MS (EI, 70 eV):
m/z (%)=372 (M+, [81Br,81Br], 32), 370 (M+, [81Br,79Br], 32),
368 (M+, [79Br,79Br], 16), 357 (M+, 57), 355 (M+, 100), 353
(M+, 49), 327 (M+, 18); HR-MS (EI, 70 eV): m/z=
369.92439, calcd. for C11H18Br2SSi (M+, [81Br,79Br]):
369.92448; 367.92648, calcd. for (M+, [79Br,79Br]): 367.92652.
3,4-Dibromo-5-isopentyl-2-trimethylsilylthiophene
(8c):
Starting with 1 (0.200 g, 0.5 mmol) and 1-bromo-3-methylbu-
tane (0.6 mmol, 0.08 mL), 8c was isolated as a colourless oil;
˜
(KBr): n=3067 (w), 2940 (m), 2917 (m), 2862 (w), 1755 (s),
1644 (s), 1600 (m), 1444 (m), 1440 (m), 1298 (s), 1266 (s),
1076 (m), 772 (s), 689 cmꢀ1 (m); MS (EI, 70 eV): m/z (%)=
452 (M+, [81Br,81Br], 18), 450 (M+, [81Br,79Br], 42), 448 (M+,
[79Br,79Br], 70), 354 (100), 310 (16), 267 (18), 178 (15), 165
(6), 121 (9), 77 (8); HR-MS (EI, 70 eV): m/z=450.1441,
calcd. for C18H10Br2O2S (M+, [81Br,79Br]): 450.1438.
1
yield: 0.115 g (60%). H NMR (250 MHz, CDCl3): d=0.37
[s, 9H, Si
1.51 (q, 2H, CH2), 2.81 (t, 2H, CH2); 13C NMR (75 MHz,
CDCl3): d=0.3 [CH3, Si(CH3)3], 23.2 (CH3), 28.6 (CH), 29.9,
40.3 (CH2), 115.1, 120.6 (CBr), 132.9, 146.4 (C); IR (KBr):
ACHTNUGRTNE(NUGN CH3)3], 0.93, 0.96 (t, 3H, CH3), 1.66 (m, H, CH),
AHCTUNGTRENNUNG
˜
n=2954 (m), 2925 (m), 2869 (w), 1248 (s), 993 (s), 835 (s),
756 (s), 696 (m), 620 (m), 555 cmꢀ1 (m); MS (EI, 70 eV):
m/z (%)=386 (M+, [81Br,81Br], 22), 384 (M+, [81Br,79Br], 40),
382 (M+, [79Br,79Br], 19), 371 (M+, 54), 370 (M+, 18), 369
(M+, 98), 367 (M+, 48), 327 (M+, 29), 249 (M+, 100); HR-
Adv. Synth. Catal. 2009, 351, 1595 – 1609
ꢆ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1607

ˇ
Dang Thanh Tꢀng et al.
¯
FULL PAPERS
.
MS (EI, 70 eV): m/z=385.93628, calcd. for C12H20Br2SSi
(M+, [81Br,81Br]): 385.93753; 383.93849, calcd. for (M+,
[81Br,79Br]): 383.93958; 381.94032, calcd. for (M+,
[79Br,79Br]): 381.94162.
bined organic layers were dried (Na2SO4), filtered and the
filtrate was concentrated under vacuum. The crude product
was washed to give 10 as a brownish solid; yield: 0.111 g
(96%). 1H NMR (250 MHz, CDCl3): d=6.5, 7.4 (d, 2H,
2CH, Ar), 7.25 (s, 2H, OH), 8.14 (b, 2H, COOH, Ar);
13C NMR (75 MHz, CDCl3): d=115.0, 132.3 (CH, Ar),
3,4-Dibromo-5-hexyl-2-trimethylsilylthiophene (8d): Start-
ing with
1
(0.200 g, 0.5 mmol) and 1-bromohexane
˜
(0.6 mmol, 0.09 mL), 8d was isolated as a colourless oil;
yield: 0.119 g (60%). H NMR (250 MHz, CDCl3): d=0.38
128.2, 132.8, 150.0, 157.5, 162.8 (C); IR (KBr): n=3417 (w),
1
3071 (w), 2920 (m), 2850 (m), 2721 (w), 1722 (s), 1601 (s),
1401 (s), 1342 (s), 1187 (s), 1055 (s), 744 cmꢀ1 (s); MS (EI,
70 eV): m/z (%)=356 (M+, 55), 312 (M+, 100), 293 (M+,
15), 268 (M+, 26), 64 (M+, 74), 247 (M+, 13), 220 (M+, 50),
203 (M+, 14), 128 (M+, 23), 44 (M+, 43); HR-MS (EI,
70 eV): m/z=356.03539, calcd. for C18H12O6S (M+):
356.03546.
[s, 9H, Si
CH2), 1.62 (q, 2H, CH2), 2.80 (q, 2H, CH2); 13C NMR
(75 MHz, CDCl3): d=0.3 [CH3, Si(CH3)3], 14.4 (CH3), 23.2,
ACHTUNGTRENNUNG(CH3)3], 0.89 (t, 3H, CH3), 1.33–1.42 (m, 6H,
AHCTUNGTRENNUNG
30.4, 30.5, 30.9, 32.0 (CH2), 115.1, 120.6 (CBr), 132.8, 146.5
˜
(C); IR (KBr): n=2954 (m), 2925 (m), 2855 (w), 1248 (s),
994 (s), 834 (s), 756 (s), 696 (m), 637 (m), 557 cmꢀ1 (m); MS
(EI, 70 eV): m/z (%)=400 (M+, [81Br,81Br], 19), 398 (M+,
[81Br,79Br], 34), 396 (M+, [79Br,79Br], 16), 385 (M+, 56), 384
(M+, 18), 383 (M+, 100), 381 (M+, 49), 327 (M+, 26), 327
(M+, 26); HR-MS (EI, 70 eV): m/z=399.95288, calcd. for
C13H22Br2SSi (M+, [81Br,81Br]): 399.95318; 397.95562, calcd.
for (M+, [81Br,79Br]): 397.95523; 395.95728, calcd. for (M+,
[79Br,79Br]): 395.95727.
Synthesis of the Sulphur Analogue 11 of Ningaline A
To a CH2Cl2 solution (2.5 mL) of 9b (75 mg, 0.2 mmol) was
added BBr3 (1.6 mmol, 0.881 g) at 08C. The solution was al-
lowed to warm to 208C during 4 days. To the solution was
added an aqueous solution of KO-t-Bu (10 mL, 0.1M), and
the solution was stirred for 30 min. The organic layer was
separated, dried (Na2SO4) and filtered, and the filtrate was
concentrated under vacuum. The product was purified by
chromatography (silica gel) and isolated as a yellow solid;
yield: 49 mg (65%). 1H NMR (250 MHz, CDCl3): d=7.58,
8.40 (d, 2H, CH, Ar), 7.41, 7.62 (t, 2H, CH, Ar); 13C NMR
(75 MHz, CDCl3): d=118.4, 124.4, 125.2, 131.2 (CH, Ar),
3,4-Dibromo-5-heptyl-2-trimethylsilylthiophene
(8e):
Starting with 1 (0.200 g, 0.5 mmol) and 1-bromoheptane
(0.6 mmol, 0.09 mL), 8e was isolated as a colourless oil;
1
yield: 0.113 g (55%). H NMR (250 MHz, CDCl3): d=0.39
[s, 9H, Si
CH2), 1.73 (q, 2H, CH2), 3.25 (q, 2H, CH2); 13C NMR
(75 MHz, CDCl3): d=0.4 [CH3, Si(CH3)3], 14.6 (CH3), 22.6,
28.5, 28.6, 31.3, 31.6, 33.0, 33.8 (CH2), 115.0, 120.3 (CBr),
ACHTUNGTRENNUNG(CH3)3], 0.78 (t, 3H, CH3), 1.18–1.39 (m, 8H,
AHCTUNGTRENNUNG
˜
117.1, 133.26, 140.3, 152.7, 156,8 (C); IR (KBr): n=3417
(w), 3071 (w), 2920 (m), 2850 (m), 2721 (w), 1722 (s), 1601
(s), 1401 (s), 1342 (s), 1187 (s), 1055 (s), 744 cmꢀ1 (s); MS
(EI, 70 eV): m/z (%)=321 (M+, 19), 320 (M+, 100), 319
(M+, 17), 263 (M+, 4), 208 (M+, 13), 163 (M+, 13); HR-MS
(EI, 70 eV): m/z=320.01316, calcd. for C18H8O4S (M+):
320.01378.
˜
136.5, 140.5 (C); IR (KBr): n=2954 (m), 2925 (m), 2855
(w), 1248 (s), 994 (s), 834 (s), 756 (s), 696 (m), 637 (m),
557 cmꢀ1 (m); MS (EI, 70 eV): m/z (%)=414 (M+,
[81Br,81Br], 16), 412 (M+, [81Br,79Br], 35), 410 (M+,
[79Br,79Br], 22), 385 (M+, 54), 384 (M+, 19), 383 (M+, 100),
381 (M+, 51), 327 (M+, 31), 327 (M+, 21); HR-MS (EI,
70 eV): m/z=412.29874, calcd. for C14H24Br2SSi (M+,
[81Br,79Br]): 412.29886; 409.97339, calcd. for (M+,
[79Br,79Br]): 409.97347.
Acknowledgements
3,4-Dibromo-2-trimethylsilyl-5-undecylthiophene
(8f):
Starting with 1 (0.200 g, 0.5 mmol) and 1-bromoundecane
(0.6 mmol, 0.27 mL), 8f was isolated as a colourless oil;
Financial support from the Ministry of Education and Train-
ing of Vietnam (scholarships for T. T. D. and T. T. D.) is
gratefully acknowledged.
1
yield: 0.119 g (51%). H NMR (250 MHz, CDCl3): d=0.39
[s, 9H, Si
CH2), 1.73 (q, 2H, CH2), 3.25 (q, 2H, CH2); 13C NMR
(75 MHz, CDCl3): d=0.4 [CH3, Si(CH3)3], 14.6 (CH3), 22.9,
28.7, 28.9, 29.41, 29.46, 29.49, 25.32, 25.39, 32.1, 32.7 (CH2),
ACHTUNGTRENNUNG(CH3)3], 0.78 (t, 3H, CH3), 1.18–1.39 (m, 16H,
AHCTUNGTRENNUNG
References
˜
115.0, 120.3 (CBr), 136.5, 140.5 (C); IR (KBr): n=2954 (m),
2925 (m), 2855 (w), 1248 (s), 994 (s), 834 (s), 756 (s), 696
(m), 637 (m), 557 cmꢀ1 (m); MS (EI, 70 eV): m/z (%)=470
(M+, [81Br,81Br], 21), 468 (M+, [81Br,79Br], 28), 466 (M+,
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1608
asc.wiley-vch.de
ꢆ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1609