Solvent-free, microwave-assisted synthesis of thiophene oligomers via suzuki coupling

Article abstract of DOI:10.1021/jo026269d

The purpose of this study was to obtain a rapid, efficient, and environmentally friendly methodology for the synthesis of highly pure thiophene oligomers. The solvent-free, microwave-assisted coupling of thienyl boronic acids and esters with thienyl bromides, using aluminum oxide as the solid support, allowed us to rapidly check the reaction trends on changing times, temperature, catalyst, and base and easily optimize the experimental conditions to obtain the targeted product in fair amounts. This procedure offers a novel, general, and very rapid route to the preparation of soluble thiophene oligomers. Thus, for example, quaterthiophene was obtained in 6 min by reaction of 2-bromo-2,2′-bithiophene with bis(pinacolato)diboron (isolated yield 65%), whereas quinquethiophene was obtained in 11 min by reaction of dibremoterthiophene with thienylboronic acid (isolated yield 74%). The synthesis of new chiral 2,2′-bithiophenes is reported. The detailed analysis of the byproducts of some reactions allowed us to elucidate a few aspects of reaction mechanisms. While the use of microwaves proved to be very convenient for the coupling between conventional thienyl moieties, the same was not true for the coupling of thienyl rings to thienyl-S,S-dioxide moieties. Indeed, in this case, the targeted product was obtained in low yields because of the competitive, accelerated, Diels-Alder reaction that affords a variety of condensation products.

Full text of DOI:10.1021/jo026269d

Solven t-F r ee, Micr ow a ve-Assisted Syn th esis of Th iop h en e
Oligom er s via Su zu k i Cou p lin g
Manuela Melucci, Giovanna Barbarella,* and Giovanna Sotgiu
Consiglio Nazionale Ricerche (ISOF), Via Gobetti 101, 40129 Bologna, Italy
barbarella@area.bo.cnr.it
Received J uly 31, 2002
The purpose of this study was to obtain a rapid, efficient, and environmentally friendly methodology
for the synthesis of highly pure thiophene oligomers. The solvent-free, microwave-assisted coupling
of thienyl boronic acids and esters with thienyl bromides, using aluminum oxide as the solid support,
allowed us to rapidly check the reaction trends on changing times, temperature, catalyst, and base
and easily optimize the experimental conditions to obtain the targeted product in fair amounts.
This procedure offers a novel, general, and very rapid route to the preparation of soluble thiophene
oligomers. Thus, for example, quaterthiophene was obtained in 6 min by reaction of 2-bromo-2,2′-
bithiophene with bis(pinacolato)diboron (isolated yield 65%), whereas quinquethiophene was
obtained in 11 min by reaction of dibromoterthiophene with thienylboronic acid (isolated yield 74%).
The synthesis of new chiral 2,2′-bithiophenes is reported. The detailed analysis of the byproducts
of some reactions allowed us to elucidate a few aspects of reaction mechanisms. While the use of
microwaves proved to be very convenient for the coupling between conventional thienyl moieties,
the same was not true for the coupling of thienyl rings to thienyl-S,S-dioxide moieties. Indeed, in
this case, the targeted product was obtained in low yields because of the competitive, accelerated,
Diels-Alder reaction that affords a variety of condensation products.
In tr od u ction
Unfortunately, only very few of these compounds are
commercial, the synthesis of the most appealing of them
is not easy, and the procedures for purification up to the
degree useful for applications in electronics or biomedical
diagnostics are tedious and time-consuming. Moreover,
the two most general procedures used to assemble
functionalized thienyl rings for the regiospecific synthesis
Thiophene oligomers have been proven to be important
multifunctional materials.1 Among their most useful
2
properties are good charge mobility and efficient fluo-
3
rescence. Thiophene oligomers are chemically very stable
and easy to functionalize.4 New dendritic molecular
5
structures have recently been described from which it
is reasonable to expect different self-assembly modalities
and properties. Thiophene oligomers are currently stud-
11
of thiophene oligomerssnamely, the Stille and the
12
Suzuki reactions, based on the coupling of thienyl
metalated reagents with thienyl halogenides or triflates
in the presence of palladium or nickel catalystssare
critically dependent on functionalization types, steric
factors, solvent, temperature, and the catalyst. To the
present state of knowledge of reaction mechanisms, the
best experimental conditions are not easy to predict and
have to be investigated case by case.
6
ied for application in thin film transistors, electrolumi-
7
8
9
nescent diodes, lasers, and photovoltaic cells and as
fluorescent markers for biological molecules.10
(
1) (a) Skotheim, T. A.; Elsenbaumer, R. L.; Reynolds, J . R.
Handbook of Conductive Polymers; Marcel Dekker: New York, 1998.
b) M u¨ llen, K.; Wegner, G. Electronic Materials: The Oligomer Ap-
(
proach; Wiley-VCH: New York, 1998. (c) Fichou D. Handbook of Oligo
and Polythiophenes; Wiley-VCH: New York, 1999.
(7) (a) Suzuki, M.; Fukuyama, M.; Hori, Y.; Hotta, S. J . Appl. Phys.
2002, 91, 5706. (b) Gigli, G.; Inganas, O.; Anni, M.; De Vittorio, M.;
Cingolani, R.; Barbarella, G.; Favaretto, L. Appl. Phys. Lett. 2001, 78,
1493.
(8) Zavelani-Rossi, M.; Lanzani, G.; De Silvestri, S.; Anni, M.; Gigli,
G.; Cingolani, R.; Barbarella, G.; Favaretto, L. Appl. Phys. Lett. 2001,
79, 4082.
(9) (a) Catellani, M.; Boselli, B.; Luzzati, S.; Tripodi, C. Thin Solid
Films 2002, 403-404. (b) Apperloo, J . J .; Martineau, C.; van Hal, P.
A.; Roncali, J .; J anssen, R. A. J . J . Phys. Chem. A 2002, 106, 21. (c)
Vangeneugden, D. L.; Vanderzande, D. J . M.; Salbeck, J .; van Hal, P.
A.; J anssen, R. A. J .; Hummelen, J . C.; Brabec, C. J .; Shaheen, S. E.;
Sariciftci, N. S. J . Phys. Chem. B 2002, 105, 11106.
(10) Barbarella, G.; Zambianchi, M.; Pudova, O.; Paladini, V.;
Ventola, A.; Cipriani, F.; Gigli, G.; Cingolani, R.; Citro, G. J . Am. Chem.
Soc. 2001, 123, 11600.
(
2) Garnier, F. Acc. Chem. Res. 1999, 32, 209.
(3) (a) Chosrovian, H.; Rentsch, S.; Grebner, D.; Dahom, U.; Birck-
ner, E. Synth. Met. 1993, 60, 23. (b) Kanemitsu, Y.; Suzuki, K.;
Masumoto, Y.; Tomiuchi, Y.; Shiraishi, Y.; Kuroda, M. Phys. Rev. B
1
994, 50, 2301. (c) Oelkrug, D.; Egelhaaf, H. J .; Gierschner, J .;
Tompert, A. Synth. Met. 1996, 249. (d) Barbarella, G.; Favaretto, L.;
Sotgiu, G.; Zambianchi, M.; Bongini, A.; Arbizzani, C.; Mastragostino,
M.; Anni, M.; Gigli, G.; Cingolani, R. J . Am. Chem. Soc. 2000, 122,
1
1971.
4) (a) Blanchard, P.; J ousselme, B.; Fr e` re, P.; Roncali, J . J . Org.
(
Chem. 2002, 67, 3961. (b) Afzali, A.; Breen, T. L.; Kagan, C. R. Chem.
Mater. 2002, 14, 1742. (b) Briehn, C. A.; Schiedel, M. S.; Bonsen, E.
M.; Schuhmann, W.; B a¨ uerle, P. Angew. Chem., Int. Ed. 2001, 40, 4680.
(
2
c) Greve, D. R.; Apperloo, J . J .; J anssen, R. A. J . Eur. J . Org. Chem.
001, 3437. (d) McQuade, D. T.; Pullen, A. E.; Swager, T. M. Chem.
Rev. 2000, 100, 2537.
5) Xia, C.; Fan, X.; Loklin, J .; Advincula, R. C. Org. Lett. 2002, 4,
067.
(11) (a) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Farina, V.; Krishnamurthy, V.; Scott, W. J . The Stille Reaction; J ohn
Wiley & Sons Ltd.: Chichester, 1998.
(
2
(
6) Dimitrakopoulos, C. D.; Mascaro, D. J . IBM J . Res., Dev. 2001,
(12) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b)
Suzuki, A. J . Organomet. Chem. 1999, 576, 147.
4
5, 11.
1
0.1021/jo026269d CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/08/2002
J . Org. Chem. 2002, 67, 8877-8884
8877

Melucci et al.
SCHEME 1. Solven t-F r ee, Micr ow a ve-Assisted
In consequence, there is great need for more expedient
and efficient synthetic methodologies for the preparation
of thiophene oligomers allowing the best experimental
conditions to be rapidly decided for the preparation of
the targeted oligomer, minimize the formation of byprod-
ucts, and simplify the purification procedures, in par-
ticular by reducing the huge amounts of organic solvents
needed to purify the oligomers by silica gel chromatog-
raphy.
Syn th esis of 2,5′:2′,5′′-Ter th iop h en e 3
In the past few years, great effort has been devoted to
the study of the Suzuki reaction for the preparation of a
variety of conjugated molecules, including porphyrins and
phthalocyanines.13 While in the Stille reaction aryl stan-
nanes are employed, in the Suzuki reaction the less toxic
boronic acids or esters are used. Since boronic acids and
esters are not very reactive, the efficiency of the Suzuki
reaction has been improved by means of more efficient
catalysts,14 the presence of bases, the accurate choice
of solvents,16 and microwave activation.17a-c
Resu lts
The importance of alumina in favoring the reaction of
adsorbed organic molecules has been known for a long
time.20 An important factor in obtaining good yields is to
have a nice dispersion of reagents and catalyst on the
solid support. To this purpose, we added to the mixture
15
2 3
of Al O /reagents/catalyst a few drops of methanol, which
However, while there are many papers in the literature
concerning the Suzuki reaction with phenyl boronic
derivatives and phenyl halogenides, much less attention
has been devoted to the Suzuki reaction with thienyl
derivatives, although, as mentioned above, this reaction
was found to be useful in the preparation of thiophene
oligomers and polymers.13
were subsequently evaporated under reduced pressure.
We carried out all reactions in air at constant tempera-
ture using the reactor of our commercial microwave
system (see the Experimental Section). A few attempts
to use Fluorisil instead of alumina as the solid support
were unsuccessful. In some cases the reaction rate was
accelerated by addition of a few drops of aqueous KOH.
The experimental conditions were first optimized for
the preparation of R-conjugated, unsubstituted ter-
thiophene (section I) and then checked in the preparation
of unsubstituted quater- and quinquethiophene (section
II), of a dimethylated sexithiophene (section III), of new
chiral bithiophenes (section IV), and of oligomers con-
taining the thienyl-S,S-dioxide moiety (section V). A few
experiments to elucidate the reaction mechanisms were
also carried out (section VI).
Recently, it has been reported that the use of an
alumina/potassium fluoride mixture without solvent but
with microwave activation is very effective in palladium-
catalyzed reactions, in particular in the Suzuki coupling
1
8
of phenyl iodides with phenylboronic acids. The interest
in this procedure stems from the absence of solvents and
the possibility to recover the reaction products by simple
filtration, while the catalyst and the salts formed in the
course of the reaction remain on the solid support. Thus,
when the products are eluted with poorly polar solvents,
they result to be free of metals.1
(
I) Ca ta lyst a n d Ba se Op tim iza tion . The optimiza-
8b
tion of reaction conditions was carried out using as the
model reaction the Suzuki coupling of 2,5-dibromothio-
phene, 1a , with 2-thiophene boronic acid, 2a , both of
which are commercial products. The target of the reaction
is 2,2′:5′,2′′-terthiophene, 3, whose formation is always
accompanied by variable amounts of byproducts 4 and
We decided to apply this procedure to the synthesis of
thiophene oligomers, some of which are semiconductors
often affected by the presence of what has been named
“unintentional doping”, i.e., the presence of metallic ions
introduced by way of chemical synthesis that alter the
1
9
intrinsic charge transport properties of the material.
5
, as shown in Scheme 1. All catalysts employed were
We are reporting here initial results, showing that
indeed the solvent-free microwave-assisted Suzuki syn-
thesis is a rapid and expedient way for the preparation
of highly pure thiophene oligomers.
commercial and used as received.
The relative amounts of 3, 4, and 5 formed using
different catalysts and bases and estimated by GC/MS
analysis are reported in Table 1.
Table 1 shows how crucial the choice of the catalyst is
in determining the trend of the reaction. Indeed, there
(
13) (a) Hassan, J .; S e´ vignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. Rev. 2002, 102, 1359. (b) Kirschbaum, T.; Azumi, R.; Mena-
Osteriz, E.; Bauerle, P. New J . Chem. 1999, 241.
is no formation at all of terthiophene when Pd
PdCl is used as the catalyst, whereas this compound is
formed in 60% isolated yield when commercial PdCl
2 3
(dba) or
2
(14) Grasa, G. A.; Viciu, M. S.; Huang, J .; Zhang, C.; Trudell, M. L.;
Nolan, S. P. Organometallics 2002, 21, 2866.
2
-
(
(
15) Benbow, J . W.; Martinez, B. L. Tetrahedron Lett. 1996, 37, 8829.
16) (a) Mathews, C. J .; Smith, P. J .; Welton, T. Chem. Commun.
(dppf) is employed (entry 5). On the other hand, the
2
attempt to prepare in situ PdCl (dppf) was unsuccessful,
probably due to the scarce formation of the catalyst itself
in the experimental conditions used.
Also extremely important is the choice of the base, as
shown, for example, by the fact that CsF, one the most
used bases in the Suzuki reaction, is less effective than
KF for the formation of trimer 3 (compare entries 7 and
2
000, 1249. (b) Pei, J .; Ni, J .; Zhou, X. H.; Cao, X. Y.; Lai, Y. H. J .
Org. Chem. 2002, 67, 4924.
17) (a) Caddick, S. Tetrahedron 1995, 38, 10403. (b) Larhed, M.;
(
Hallberg, A. J . Org. Chem. 1996, 61, 9582. (c) Badone, D.; Baroni, M.;
Cardamone, R.; Ielmini, A.; Guzzi, U. J . Org. Chem. 1997, 62, 7170.
(
1
d) Blettner, C. G.; K o¨ nig, W. A.; Stenzel, W.; Schotten, T. J . Org. Chem.
999, 64, 3885. (e) Villemin, D.; G o´ mez-Escalonilla, M. J .; Saint-Clair,
J . F. Tetrahedron Lett. 2001, 42, 635.
18) (a) Villemin, D.; Caillot, F. Tetrahedron Lett. 2001, 42, 639. (b)
Kabalka, G. W.; Pagni, R. M.; Hair, C. M. Org. Lett. 1999, 1, 1423.
19) Hajlaoui, R.; Horowitz, G.; Garnier, F.; Arce-Brouchet, A.;
Laigre, L.; El Kassmi, A.; Demanze, F.; Kouki, F. Adv. Mater. 1997, 9,
89.
(
5
). Apparently, it is the type of base that is important
(
3
(20) Posner, G. H. Angew. Chem., Int. Ed. Engl. 1978, 17, 487.
8
878 J . Org. Chem., Vol. 67, No. 25, 2002

Synthesis of Thiophene Oligomers
TABLE 1. Ca ta lyst a n d Ba se Op tim iza tion for th e
P r ep a r a tion of Ter th iop h en e 3 fr om
in a few minutes high yields and mixtures that are easy
to separate into the different components. Isolated yields
of 60-80% can be obtained by choosing the appropriate
boron and halogen derivatives. These yields are highly
reproducible and competitive with the best yields already
2
2
,5-Dibr om oth iop h en e 1a a n d 2-Th iop h en ebor on ic Acid
a (Sch em e 1)
entrya
catalyst
base/Al2O3
%b
(
1a /3/4/5)
reported for quaterthiophene 7 and quinquethiophene
c
21
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd2(dba)3
PdCl2
Pd(PPh3)2Cl2
PdCl2(dppf)
PdCl2(dppf) in situ
PdCl2(dppf)
PdCl2(dppf)
KF
KF
KF
KF
KF
KF
CsF
KOtBu
(54/-/6.5/3.5)
(100/-/-/-)
(100/-/-/-)
(81/2/11/2.5)
(4/73/1/22)
(61/17/12/10)
(16/50/-/34)
(100/-/-/-)
1
2.
Our data show that in terms of reaction yields, facility
of purification procedures, and solvent saving, it is much
better to grow the oligomer size by adding the thiophene
rings one at a time rather than reacting longer building
blocks. For example, as shown in Table 2, quinquethio-
phene 12 is obtained in high yield (74% isolated yield)
when dibromoterthiophene is reacted with thiophene-
boronic acid (2a ), whereas the yield is drastically reduced
a
1
equiv of 1a , 2.5 equiv of 2a , 5 mol % of catalyst, 5 equiv of
KF, and 150 mg of Al2O3, T ) 100 °C. Conversion estimated by
GC/MS analysis. Byproducts from phosphine reaction.
b
c
(28% isolated yield) when dibromothiophene (1a ) is
reacted with bithiopheneboronic ester (13b). In part, this
is due to the fact that, in the former case, 12 is more
easily purified from the major byproduct of the reaction
TABLE 2. Rea ction Con d ition sa a n d Yield s for th e
Syn th esis of Ter th iop h en e (3), Qu a ter th iop h en e (7), a n d
Qu in qu eth iop h en e (12) Accor d in g to th e P a tter n s of
Sch em e 2
(bithiophene, generated by homocoupling of thiophenebo-
ronic acid). In the latter case, the major byproduct of the
reaction is quaterthiophene, which is less easily sepa-
rated from the desired quinquethiophene.
Table 2 also shows that no formation of 12 was
observed when bithiopheneboronic acid 13a was used
instead of the corresponding ester. We ascribe this result
to the greater stability of boronic esters compared to
boronic acids.
boronic
time
Tmax
isolated
halide derivative (equiv) product (min) (°C)
yield (%)
1
1
6
8
4
1
1
a
2a (2.5)
2a (2.5)
2a (5)
3
3
7
7
10
10
4
2
6
11
10
10
100 60
100 10
80 81
80 40
80 65
70 74
90 no reaction
90 28
b
b
9 (0.5)
10 (0.5)
2a (4.4)
13a (2.0)
7
1c
a
12
12
12
The synthesis of quaterthiophene, pattern 2, is of some
interest. Indeed, the reaction of 5-bromo-2,2′-bithiophene,
4, with bis(pinacolato)diboron, 10, affords quaterthiophene
in a few minutes and in good isolated yield (65%).
Bis(pinacolato)diboron is generally used for borylation
of aryl halides2 and for the one-pot synthesis of biaryls
1
3b (2.0)
a
b
5
mol % of catalyst, 5-10 equiv of KF. 0.2 mL of KOH added.
c0.4 mL of KOH added.
2a
rather than its strength, as indicated by the fact that
when KOtBu is used, only the starting materials are
recovered (entry 8).
Apparently, one never gets rid of byproducts 4 and 5,
whose relative amounts are also dependent on reaction
conditions. Since bithiophene 5 is easier to separate by
silica gel chromatography than its monobrominated
counterpart 4, the conditions of entry 5 lead also to the
mixture from which terthiophene 3 is more easily recov-
ered.
Also very important appears to be the halide chosen
for the reaction. Indeed, when the preparation of ter-
thiophene was carried out using 2,5-diiodothiophene (1b),
instead of the dibromo counterpart (1a ), the yield dropped
to 17% (see below, Table 2).
2
2b
through the in situ formation of aryl boronates.
We
found that this reaction works well with thienyl, bithie-
nyl, and terthienyl monobromides, leading to the rapid
formation of bi-, quater-, and sexithiophene in fair
amounts. Since sexithiophene is insoluble, the methodol-
ogy described here and the reaction workup had to be
modified; then the results concerning this important
semiconductor will be reported in a separate paper.
Since it is known that aryl halides in the presence of
2
3
palladium catalysts may give rise to reductive coupling,
the question arose as to whether and to what extent the
formation of even number oligothiophenes was the result
of the palladium-promoted homocoupling reaction rather
than of the two-step borylation-cross-coupling reaction.
Experiments carried out in the absence of bis(pinaco-
lato)diboron in the same experimental conditions showed
that the palladium-promoted homocoupling of thienyl
halides amounted to a few % at best.
In the subsequent work we then used mainly mono and
dibromo starting materials, PdCl (dppf) as the catalyst
2
and KF as the base, with the aim of fixing the conditions
for a reasonable standardization of the synthetic proce-
dures.
(
III) Syn th esis of 4′′,3′′′-Dim eth yl-2,2′:5′,2′′:5′′,2′′′:
5
′′′,2′′′′:5′′′′,2′′′′′-sexith iop h en e (19). The importance of
(
II) Syn th esis of Un su bstitu ted Qu a ter th iop h en e
a n d Qu in qu eth iop h en e. The different reaction pat-
terns employed for the preparation of R-conjugated
quinque- and sexithiophene are summarized in Scheme
(
21) (a) Van Pham, C.; Burkhardt, A.; Shabana, R.; Cunningham,
D. D.; Mark, H. B., J r.; Zimmer, H. Phosphorus, Sulfur Silicon 1989,
6, 153. (b) Merz, A.; Ellinger, F. Synthesis 1991, 462. (c) Kagan, J .;
4
2
, whereas Table 2 shows the isolated yields for the
Arora, S. K. J . Org. Chem. 1983, 48, 4317. (d) Tasaka, S.; Katz, H. E.;
Hutton, R. S.; Orenstein, J .; Fredrikson, G. H.; Wang, T. T. Synth.
Met. 1986, 16, 17.
different patterns and gives, for comparison, also the
isolated yields of terthiophene prepared according to the
modalities described above.
The results reported in Table 2 show that the careful
optimization of the reaction conditions allows obtaining
(22) (a) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron
Lett. 1997, 38, 3447. (b) Giroux, A.; Han, Y.; Prasit, P. Tetrahedron
Lett. 1997, 38, 3841.
(23) Hassan, J .; Lavenot, L.; Gozzi, C.; Lemaire, M. Tetrahedron Lett.
1999, 40, 857.
J . Org. Chem, Vol. 67, No. 25, 2002 8879

Melucci et al.
SCHEME 2. Solven t-F r ee, Micr ow a ve-Assisted Syn th esis of Qu a ter th iop h en e (7) a n d Qu in qu eth iop h en e
12)
(
SCHEME 3. Solven t-F r ee, Micr ow a ve-Assisted Syn th esis of Sexith iop h en e 19
TABLE 3. Rea ction Con d ition sa a n d Yield s for th e
this compound stems from the fact that it is a soluble
thienyl hexamer, which in the solid state is nearly planar,
self-assembles in parallel layers, and displays good
charge transport properties.24a
Syn th esis of Sexith iop h en e 19 (Sch em e 3)
boronic
time Tmax
isolated
halide
derivative (equiv)
10 (0.5)
2a (R ) H, 3.5)
b (R ) pinacol, 2.2)
product (min) (°C) yield (%)
1
1
4
6a
15
17
17
17
17
19
19
19
6
32
3
7
3
30
10
3
80 70
80 34
80 18
70 85
70 90
80 73
90 no reaction
90 36
We were first able to synthesize this compound in very
2
4a
low yield by means of the Stille coupling; then higher
yields were obtained by means of the Suzuki coupling
and the use of microwaves in solution.2 It was after
having obtained these results that we become aware of
the usefulness of microwaves in the synthesis of thiophene
oligomers.
2
1
6b 2a (4.4)
2b (2.2)
4b
1
1
1
8b
6a
6a
2a (4.4)
13a (R ) H, 2.5)
13b (R ) pinacol, 2.5)
a
mol % of catalyst, 10 equiv of KF. b0.5 mL of KOH added.
5
The present methodology allows hexamer 19 to be
obtained in much higher yields than before, since all
steps afford high yields when one ring is added at a time
and the diiodo derivative 16b is employed instead of the
corresponding dibromo derivative 16a (see Scheme 3 and
Table 3).
As shown in the table, the reaction of 5,5′-diiodo-3,3′-
dimethyl-2,2′-bithiophene, 16b, with thiophene boronic
derivatives affords quaterthiophene 17 in much higher
yields than the corresponding dibromo derivative 16a ,
contrary to what was observed in the preparation of
(24) (a) Barbarella, G.; Zambianchi, M.; Antolini, L.; Ostoja, P.;
Maccagnani, P.; Bongini, A.; Marseglia, E. A.; Tedesco, E.; Gigli, G.;
Cingolani, R. J . Am. Chem. Soc. 1999, 121 (1), 8920. (b) Sotgiu, G.;
Zambianchi, M.; Barbarella, G.; Botta, C. Tetrahedron 2002, 58, 2245.
(
c) Barbarella, G.; Favaretto, L.; Zambianchi, M.; Pudova, O.; Arbizzani,
C.; Bongini, A.; Mastragostino, M. Adv. Mater. 1998, 10, 551. (d)
Barbarella, G.; Favaretto, L.; Zambianchi, M.; Antolini, L.; Pudova,
O.; Bongini, A. J . Org. Chem. 1998, 63, 5497.
8
880 J . Org. Chem., Vol. 67, No. 25, 2002

Synthesis of Thiophene Oligomers
fore and after microwave irradiation (3 min, T ) 80 °C).
Within the limits of experimental error, the two values
(
[R]
found to be the same.
Interestingly, we found that the optical rotatory dis-
persion of bithiophene 23 increased to [R] -536.61° and
+485.52° ([R] +183.63°
D
-133.30° and [R]
D
-127.38°, respectively) were
F IGURE 1.
D
that of bithiophene 24 to [R]
for monomer 22).
D
D
terthiophene, where the dibromo derivative worked much
better than the diiodo one.
(V) Cou p lin g of Th ien yl-S,S-d ioxid e Moieties. The
solvent-free, microwave-assisted methodology was also
tested for the preparation of oligothiophene-S,S-dioxides,
which are compounds characterized by high photolumi-
nescence quantum efficiencies in the solid state, high
The reaction of 5,5′-dibromo-3,3′-dimethyl-2,2′-bithio-
phene, 16a , with thienylboronic acid or ester leads to the
formation of quaterthiophene 17 in low yield. In this case,
the main reaction products are a variety of oligomers
containing repeated dimethylbithiophene subunits (see
Figure 1) and terminating with an unsubstituted thienyl
ring, as already observed when thienylstannane was used
2
4c
7b
electron affinities, and good electroluminescence and
8
lasing properties.
Thus, compounds 25-282 were reacted with thienyl-
boronic derivatives 2a and 2b under microwave irradia-
tion, at T ) 80 °C, 5 mol % of catalyst, 5 equiv of KF for
4d
2
4a
(
Stille coupling). Tetramethylsexithiophene (n ) 2) and
hexamethyloctathiophene (n ) 3) were separated in
sizable amount. This reaction is highly reproducible and
can be viewed as an expedient way to prepare in one pot
regioregular head-to-head methyl-substituted sexi- and
octathiophenes, which are easily separated by chroma-
tography.
(
IV) Syn th esis of Ch ir a l 2,2′-Bith iop h en es. One of
the objectives of our current research work is to inves-
tigate the influence of chirality on the self-assembly
properties of thiophene oligomers. Thus, we have checked
the new methodology presented here for the synthesis
of the two enantiomers of bithiophene bearing R(-) and
S(+) chiral groups at the terminal positions (compounds
1-10 min and PdCl
results in terms of isolated yields in trimer were obtained
using NiCl dppf as the catalyst. However, the coupling
yields never exceeded 30% (15% using palladium cata-
lysts).
2
(dppf) as the catalyst. The best
2
2
3, 24). The synthetic pattern is shown in Scheme 4.
While more detailed studies are currently under way,
on the basis of the NMR spectra, cycloaddition adducts
As shown in the scheme, the monobrominated mono-
2
5
mers 21 and 22 were obtained by condensation of
commercial 5-bromo-2-thiophene aldehyde with R(-) and
S(+) 1-phenylethylamine. Afterward, they were reacted
with bis(pinacolato)diboron using the same experimental
conditions employed for the preparation of quater-
thiophene. After a few minutes of microwave irradiation,
bithiophenes 23 and 24 were recovered in high yield
seem to be in all cases the major reaction products.
Moreover, attempts to obtain the dimer of monobromo
29 by reaction with bis(pinacolato)diboron were unsuc-
cessful.
(VI) Exper im en ts to Elu cidate th e Reaction Mech -
a n ism . To get some insight into the reaction mecha-
nisms, the experiments described in Scheme 5 were
carried out using thiopheneboronic acid 2a as the starting
material, to check the self-coupling reaction of this
compound on changing the reaction conditions.
The yields reported in parentheses are those estimated
by GC/MS analysis. The results show that, while no
homocoupling is observed in the absence of catalyst even
in the presence of microwaves (item 3), the use of
microwaves always leads to the formation of dimer 5,
even in the absence of the base (item 2).
(isolated yield in both compounds: >70%). The NMR
spectrum of the crude product showed the presence of a
second iminic peak at 8.43 ppm, indicating that under
microwave irradiadion partial isomerization of the iminic
1
bond (<10%, from H NMR) takes place.
To exclude the possibility that microwave irradiation
can cause racemization, we first measured the optical
rotatory dispersion value, R, of monomer 21, R(-)-(5-
bromothiophen-2-ylmethylene)(1-phenylethyl)amine, be-
SCHEME 4. Solven t-F r ee, Micr ow a ve-Assisted Syn th esis of R,R(-)- a n d
S,S(+)-5,5′-[Meth ylen e(1-p h en yleth yl)a m in e]-2,2′-bith iop h en es 23 a n d 24
J . Org. Chem, Vol. 67, No. 25, 2002 8881

Melucci et al.
SCHEME 5. Self-Cou p lin g Rea ction of Th iop h en e
Bor on ic Acid 2a in Differ en t Exp er im en ta l
Con d ition s
SCHEME 6. P a lla d iu m -P r om oted Hom ocou p lin g of
Th ien yl Bor on ic Acid or Ester s
When the catalyst and the base are both present, as
well as microwave irradiation (item 1), the percentage
of self-coupling is rather high (item 1).
coupling of thienylboronic derivatives occurs according
to a similar mechanism, consisting of two steps of
oxidative addition of palladium to the “ate” complex of
the thienylboronic derivative, followed by the reductive
elimination of bithiophene, as shown in Scheme 6.
When the boronic acid or ester of 2,2′-bithiophene is
employed, the self-coupling product is quaterthiophene,
which is more difficult to separate from the targeted
oligomer. In this case, the self-coupling reaction may even
become the predominant one, probably because the cross-
coupling becomes very slow. For example, when the
boronic acid of 2,2′-bithiophene was reacted with 2,5-
dibromothiophene, no formation of quinquethiophene was
observed, whereas when the boronic ester was employed,
the yield in isolated quinquethiophene was only 28% (see
Scheme 2 and Table 2). In both cases, quaterthiophene
was the major product recovered. Once again, the use of
the boronic ester was more convenient for the synthesis
of the targeted product, probably because the self-
coupling of boronic esters is slower than that of boronic
acids and the cross-coupling reaction becomes competi-
tive. Anyway, our results show that by adding one ring
at a time, repeated and easily standardized cycles of
bromination/microwave-assisted Suzuki coupling lead to
Discu ssion
One of the main advantages of the Suzuki reaction is
its versatility and the many tunable parameters that can
be exploited to accelerate the reaction and improve the
yields.
The microwave-assisted methodology described here
allows for the rapid exploitation of the many possibilities
offered by this reaction. The best set of catalyst, base,
and halogen derivative to be used can rapidly be checked
and the experimental conditions optimized. Once the best
synthetic pattern to follow is established, thiophene
oligomers are obtained in high yields and in mixtures
that can easily be purified. Generally, the formation of
the thienyl-thienyl linkage occurs in a few minutes, and
the crude reaction product may be recovered by filtration
free of catalyst and boron salts, from which the desired
oligomers are separated in high isolated yields and very
pure.
One of the most interesting results of the present work
is the fact that in the synthesis of the longer oligomers
it is much more convenient, in terms of purification and
isolated yields, to increase the size by addition of the
thiophene rings one at a time, rather than trying to react
longer building blocks.
One of the reasons for this is that, in the presence of
microwaves, there is always palladium-promoted self-
coupling of the boronic derivatives. When thienylboronic
acid or ester is used, bithiophene is the main byproduct
to be formed, which is easily removed by chromatography.
The self-coupling is more effective with thienylboronic
acid than with the corresponding esters; thus the latter
are more convenient to use than the former.
The data reported in Scheme 5 (items 1-3) unambigu-
ously show that in the presence of microwaves there is
always a sizable amount of self-couplingseven in the
absence of basesif the palladium catalyst is present.
It is known that palladium-promoted self-coupling of
phenylboronic acids occurs when the cross-coupling reac-
tion is slow. Moreno-Manas et al. have carried out a
7
, 12, and 19 in fair amounts (isolated yields up to 80%)
and very rapidly.
The best halogen derivative to employ as the starting
material depends very much on the substrate, and at the
present stage of knowledge, it is rather difficult to make
a choice a priori. For example, terthiophene can be
prepared in good yield (73%) by reaction of 2,5-dibro-
mothiophene, 1a , with thiophene boronic acid, but when
1
a is replaced by the corresponding diiodo derivative 1b,
the yield drops drastically (Table 2).
On the contrary, in the synthesis of sexithiophene 19
(Scheme 3 and Table 3), the use of the diiodo derivative
of the electron-rich 3,3′-dimethyl-2,2′-bithiophene (15)
leads to much better yields in the intermediate quater-
thiophene (17) than the corresponding dibromo derivative
(16a ). Indeed, when the dibromo derivative is used, there
is formation of oligomers up to the octamer and more,
characterized by repeating 3,3′-dimethyl-2,2′-bithiophene
subunits (see Figure 1), which are not formed when the
diiodo derivative is employed.
detailed mechanistic study of the self-coupling reaction
of phenylboronic acids.26 We suggest that the self-
(
25) (a) J ursic, B. S. J . Heterocyclic Chem. 1995, 32, 1445. (b)
(26) Moreno-Manas, M.; Perez, M.; Pleixats, R. J . Org. Chem. 1996,
61, 2346.
Gronowitz, S. Phosphorus, Sulfur Silicon 1993, 74, 113.
8
882 J . Org. Chem., Vol. 67, No. 25, 2002

Synthesis of Thiophene Oligomers
Diels-Alder reactions.25b Our data show that microwave
irradiation accelerates the formation of Diels-Alder
adducts from compounds 25-29, which becomes largely
prevalent over the Suzuki coupling.
SCHEME 7. P ossible Mech a n ism for th e
P a lla d iu m -P r om oted Bor on -Br om in e Exch a n ge of
5
,5′-Dibr om o-3,3′-d im eth yl-2,2′-bith iop h en e
Con clu sion
The solvent-free microwave-assisted synthesis of
thiophene oligomers through the Suzuki reaction pre-
sented in this paper is an environmentally friendly
methodology allowing the rapid optimization of reaction
conditions and the facile preparation of these important
multifunctional materials in very pure form.
There are many intriguing mechanistic and kinetic
aspects of the Suzuki reaction when thiophene-based
building blocks are employed that it is not possible at
the moment to place within a well-defined framework.
We believe that the elucidation of these different aspects
would be of great interest, both from a fundamental point
of view and for further improvements in the synthetic
accessibility of functionalized thiophene oligomers.
The compounds with repeating dimethylated bithio-
phene subunits can be formed only if boron-halogen
exchange takes place. On the basis of the mechanism
proposed by Masuda et al. for the palladium-catalyzed
borylation of aryl halides,27 we suggest that one possible
mechanism for boron-bromine exchange would be that
shown in Scheme 7, consisting in the oxidative addition
of palladium on the C-B bond followed by metathesis of
the borate-palladium complex with the halide.
Our data show that when the dibromo derivative is
employed, the boron-bromine exchange is more rapid
than the cross-coupling and compound 17 is formed in
very low yield. On the contrary, when the diiodo deriva-
tive is used, 17 is formed in much greater yield since
iodine is a better leaving group than bromine, and the
Suzuki coupling is favored because of kinetic factors that
are still to be explored in detail.
Exp er im en ta l Section
Gen er a l P r oced u r es. PdCl
2 2 3 2
(dppf), Pd (dba) , PdCl , Pd-
(PPh ) Cl , Pd(PPh ) , 2-bromothiophene, 2,2′-bithiophene, 2,5-
3
2
2
3 4
dibromothiophene, 2,5-diiodothiophene, bis(pinacolato)diboron,
t
5-bromo-2-thiophene aldehyde, 1-phenylethylamine, KO Bu,
CsF, KF, 2-thiopheneboronic acid, and n-butyllithium were
commercially available. All reagents were used without further
purification. Flash chromatographies were carried out using
silica gel (200-300 mesh ASTM) and analytical thin-layer
plates. The visualization in TLC was accomplished by UV
lights (356 and 254 nm).
As shown in Schemes 2 and 4, even number oligo-
thiophenes are formed in good yields in the one-pot
borylation-Suzuki coupling of monobromo derivatives
with bis(pinacolato)diboron, a compound that is used for
the one-pot synthesis of biphenyls through the in situ
Microwave-assisted reactions were carried out in air in a
2
0 mL reactor and were performed using a commercial system
Synthewave 402 manufactured by Prolabo. The typical ex-
perimental procedure was the following: the microwave oven
reactor was charged with 1 equiv of thienyl halide mixed with
2
2b
formation of phenyl boronates.
Currently, we are
experimenting with some modifications of the procedure
described here to apply this reaction also to the prepara-
tion of unsubstituted sexithiophene, which is one of the
best organic semiconductors but is insoluble and difficult
2
-5 equiv of boronic derivative, 5 mol % catalyst, and 10 equiv
of KF and Al (KF/Al , 1:3 w:w). To make the mixture
2
O
3
2 3
O
more homogeneous, 0.1-0.5 mL of methanol was added and
evaporated under reduced pressure. Afterward the mixture
was allowed to undergo the action of microwaves and the
reaction was followed by TLC. In some cases (synthesis of
to prepare in very pure form.2
,28
The one-pot borylation-Suzuki coupling was also
effective in the preparation of chiral 2,2′-bithiophenes
Scheme 4). Since, according to our data, microwave
irradiation does not alter the chirality, the condensation
reaction of commercial thienyl aldehyde with a variety
of chiral amines and the subsequent doubling of the
number of thienylene rings through reaction with bis-
-
1
compounds 7, 12, and 19), 10
M KOH was added to
accelerate the reaction. The detailed procedure is illustrated
(
below by the synthesis of quaterthiophene 7.
Ma ter ia ls. The characteristics of compounds 3-7, 12,21
21
15,2 16a ,
1a
24a,b
16b,
24a,b
and 17-19
24a,b
have already been
described.
4
,4,5,5-T e t r a m e t h y l-2-t h io p h e n e -2-y l[1,3,2]d io x a -
b or ola n e, 2b . A 1.0 g sample of commercial 2-thiophene-
boronic acid (7.81 mmol), 1.2 g of anhydrous pinacol (10 mmol),
(
pinacolato)diboron appears to be a viable way to obtain
chiral thiophene oligomers, whose self-assembly proper-
and 300 mg of anhydrous Na
2 4
SO were added to 25 mL of
ties are a matter of great current interest.29
distilled Et O, and the mixture was stirred for 24 h. Afterward
2
Unfortunately, the methodology presented here cannot
be applied to the preparation of building blocks contain-
ing the thienyl-S,S-dioxide moiety. The aromatic char-
the mixture was filtered through Celite. After evaporation and
crystallization from pentane 1.4 g of a white powder (90%
yield) was obtained. The characteristics of 2b have already
been described.27
2,2′:5′,2′′:5′′,2′′′-Qu a ter th iop h en e, 7. The microwave oven
reactor was charged with 0.1 g (0.31 mmol) of 5,5′-dibromo-
acter of thienyl-S,S-dioxide is much less pronounced than
that of thiophene.25a In consequence, thienyl-S,S-dioxides
are more reactive and capable of behaving as dienes in
2
,2′-bithiophene 6, 0.011 g (0.0155 mmol) of PdCl
2
(dppf), 0.18
g (3.1 mmol) of KF, and 0.54 g of Al . Afterward 0.2 g (1.55
2
O
3
(
27) Murata, M.; Oyama, T; Watanabe, S.; Masuda, Y. J . Org. Chem.
mmol) of 2-thiopheneboronic acid 2a was added (in two
portions). The mixture was homogeneized with methanol and
the solvent evaporated under reduced pressure. The reaction
was followed by TLC, and after 1 min irradiation 200 µL of
2
000, 65, 164.
(
(
28) Dodalabapur, A.; Torsi, L.; Katz, H. E. Nature 1995, 268, 270.
29) Schenning, A. P. H. J .; Kilbinger, A. F. M.; Biscarini, F.;
Cavallini, M.; Cooper, H. J .; Derrick, P. J .; Feast, W. J .; Lazzaroni, R.;
Lecl e` re, Ph.; McDonell, L. A.; Meijer, E. W.; Meskers, S. C. J . J . Am.
Chem. Soc. 2002, 124, 1269.
-
1
1
0
M KOH was added. After 3 min irradiation at T ) 80 °C
the solid mixture was chromatographed on silica gel using
J . Org. Chem, Vol. 67, No. 25, 2002 8883

Melucci et al.
(d, 2H), 2.46 (m, 1 H), 1.54 (d, 3H); 13C NMR (CDCl
, 100 MHz)
petroleum ether f petroleum ether/CH
2
Cl
2
/AcOEt, 80:10:10.
3
A total of 0.083 g (81% yield) of a yellow solid with the
characteristics of R-conjugated quaterthiophene 7 was sepa-
rated.
δ 151.8, 144.8, 144.5, 130.2, 128.5, 126.9, 126.6, 116.9, 69.0,
2
1
24.7; [R] -133.30° (c 0.336, CHCl ).
D
3
S(+)-(5-Br om ot h iop h en -2-ylm et h ylen e)(1-p h en ylet h -
yl)a m in e, 22 was obtained with the same modalities as
compound 21. Mass and NMR spectra were the same as 21:
2
,2′-Bith iop h en e-5-bor on ic Acid , 13a . To a solution of
2
,2′-bithiophene (2.5 g, 15 mmol) in anhydrous THF (20 mL)
n
cooled to -78 °C was added dropwise BuLi (2.5 M, 6.6 mL,
6.5 mmol). The resulting orange mixture was allowed to react
at this temperature for 1 h, then for an additional 2 h at room
temperature. The mixture was cooled to -78 °C, and B(OMe)
2.66 mL, 23 mmol) was added (solution turned blue). The
mixture was stirred for 12 h, then quenched with 2 M HCl
80 mL). After separation of the layers, the aqueous phase was
extracted with Et O. The resulting organic layers were dried
over Na SO . Evaporation of Et O gave 2.1 g (66% yield) of
3a (dark green oil). The product was utilized without further
[R]
D
3
+183.63° (c 0.336, CHCl ).
1
R,R(-)-(1-P h en yleth yl)(5′-[1ph en yleth ylim in o)m eth yl]-
[2,2′]bith iop h en yl-5-ylm eth ylen e)a m in e, 23. A 0.3 g (1.02
mmol) sample of 21, 0.129 g (0.51 mmol) of bis(pinacolato)-
3
(
diboron, 0.026 g (0.036 mmol) of PdCl
2
(dppf), 0.296 g (5.1
mmol) of KF, and 0.9 g of Al were introduced in the
2
O
3
(
microwave oven reactor. A 0.5 mL portion of methanol was
added, then the solvent removed under reduced pressure and
the mixture irradiated for 2 min at T ) 70 °C. A 10 mL portion
2
2
4
2
1
2
of Et O was added to the crude product, and the mixture was
•
+
1
purification: MS (m/z) 210 [M ]; H NMR (acetone-d
m, 1H), 7.41 (m, 1H), 7.31 (m, 2H), 7.06 (m, 1H), 5.75 (s, 2H).
-[2,2′]Bit h iop h en yl-5-yl-4,4,5,5-t et r a m et h yl[1,3,2]d i-
oxa bor ola n e, 13b. To a solution of 2,2′-bithiophene (1.4 g,
.57 mmol) in anhydrous THF (20 mL) cooled to -78 °C was
6
) δ 7.60
filtered through Celite. After solvent evaporation, a yellow-
orange oil was obtained. Crystallization from n-Hex afforded
140 mg (65% yield) of a yellow powder, mp 115 °C; MS (m/z)
(
2
•
+
428 [M ]; λmax (CH
2
Cl
(cm ); H NMR (CDCl
14H), 4.55 (m, 2H), 1.61 (d, J ) 7.0 Hz, 6H); C NMR (CDCl
75 MHz) δ 152.32, 144.92, 142.29, 140.10, 130.95, 128.42,
126.85, 126.62, 124.44, 69.02, 24,67; [R] -536.61° (c 0.336,
CHCl ). Anal. Calcd for C26 : C 72.86; H 5.64. Found:
C 72.62; H 5.62.
2
) 377 nm; IR 3435, 2974, 2853, 1633
-
1
1
8
3
, 200 MHz) δ 8.36 (s, 2H), 7.21 (m,
n
3
13
added dropwise BuLi (2.5 M, 3.77 mL, 9.43 mmol). The
resulting orange mixture was allowed to react at this temper-
ature for 2 h, then for an additional 2 h at room temperature.
3
,
D
The mixture was cooled to -78 °C, and B(OMe)
3
(1.3 mL, 11.1
3
24 2 2
H N S
mmol) was added (solution turned blue). The mixture was
stirred for 2 h, then 1.2 g (10.28 mmol) of anhydrous pinacol
was added. After 12 h the mixture was filtered through Celite
and the solvent was evaporated under reduced pressure. The
S,S(+)-(1-P h en yleth yl)(5′-[1p h en yleth ylim in o)m eth yl]-
[2,2′]bith iop h en yl-5-lm eth ylen e)a m in e, 24. The procedure
was the same as for compound 23, and 0.157 g of a yellow
crystalline powder (72% yield) was recovered, mp 120 °C; MS
(m/z) 428, λmax, IR); 1H and C NMR were the same as
crude product was chromatographed on silica gel, using CH
Cl /c-Hex, 80:20, 1.1 g (44% yield) of 13b (dark green oil), and
.35 g of 9 (light green solid). 13b: H NMR (CDCl
2
-
13
2
1
0
3
, 400 MHz)
compound 23; [R]
D
3
+485.52° (c 0.336, CHCl ). Anal. Calcd for
3
13
δ 7.53 (d, J ) 3.60 Hz 1H), 7.23 (m, 3H), 7.01 (m, 1 H);
NMR (CDCl , 100 MHz): δ 143.99, 144.26, 138.07, 137.44,
28.08, 125.15, 125.12, 124.55,0.84.46, 25.20.
,2′-[2,2′]-Bith iop h en yl-5,5′-ylbis(4,4,5,5-tetr a m eth yl)-
C
26 24 2 2
C H N S
: C 72.86; H 5.64. Found: C 72.68; H 5.63.
3
1
Ack n ow led gm en t. Thanks are due to Dr. Olga
2
Pudova (Latvian Institute of Organic Synthesis) for the
preparation of R(-)- and S(+)-5-bromothiophen-2-yl-
methylene)(1-phenylethyl)amine. This work was par-
tially supported by the project “Nuovi emettitori di luce
a semiconduttore organico” (CNR-5% Nanotecnologie).
[
1,3,2]d ioxa bor ola n e, 9: light green solid; mp 155 °C; MS
•
+
1
3
(m/z) 418 [M ]; H NMR (CDCl
3
, 400 MHz) δ 7.51 (d, J )
13
3
.60 Hz 2H), 7.28 (d, 3J ) 3.6 Hz, 2H), 1.35 (s, 24 H);
C
NMR (CDCl , 100 MHz) δ 143.71, 137.82, 125.50, 84.19, 24.88.
3
R(-)-(5-Br om oth iop h en -2-ylm eth ylen e)(1-p h en yleth -
yl)a m in e, 21. This compound was quantitatively obtained by
condensation of 5-bromo-2-thiophene aldehyde with R(-)-
phenylethylamine by mixing an equimolar amount of reagents
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of
boronic esters 9 and 13b and boronic acid 13a . This material
is available free of charge via the Internet at http://pubs.acs.org.
•
+
and stirring for 6 h at room temperature: MS (m/z) 293 [M ];
1
H NMR (CDCl
3
, 200 MHz) δ 8.29 (s, 1H), 7.31 (m, 5H), 6.98
J O026269D
8
884 J . Org. Chem., Vol. 67, No. 25, 2002