A Novel "Double-Coupling" Strategy for Iterative Oligothiophene Synthesis Using Orthogonal Si/Ge Protection

Article abstract of DOI:10.1021/ol025879x

(Matrix Presented) A new iterative synthesis of regioregular oligothiophenes has been developed in which "double-coupling" after each iteration minimizes deletion sequences. The method exploits the susceptibility of α-silyl- but not α-germyl-substituted thiophene derivatives toward nucleophilic ipso-protodemetalation and features an unusual "base-free" Suzuki-type cross-coupling protocol. The strategy has been designed for the solid-phase synthesis of high purity oligothiophenes using a germanium-based linker.

Full text of DOI:10.1021/ol025879x

ORGANIC
LETTERS
2002
Vol. 4, No. 11
1899-1902
A Novel “Double-Coupling” Strategy for
Iterative Oligothiophene Synthesis Using
Orthogonal Si/Ge Protection
,†
Alan C. Spivey,* David J. Turner,† Michael L. Turner,† and Stephen Yeates‡
Department of Chemistry, UniVersity of Sheffield, Brook Hill, Sheffield S3 7HF, U.K.,
and AVecia Ltd., Hexagon House, Blackley, Manchester M9 8ZS, U.K.
a.c.spiVey@sheffield.ac.uk
Received March 15, 2002
ABSTRACT
A new iterative synthesis of regioregular oligothiophenes has been developed in which “double-coupling” after each iteration minimizes
deletion sequences. The method exploits the susceptibility of r-silyl- but not r-germyl-substituted thiophene derivatives toward nucleophilic
ipso-protodemetalation and features an unusual “base-free” Suzuki-type cross-coupling protocol. The strategy has been designed for the
solid-phase synthesis of high purity oligothiophenes using a germanium-based linker.
π-Conjugated heterocylic oligomers such as regioregular
oligo-(â-alkylthiophenes), related block co-oligomers, and
polymers display electronic properties that make them
promising constituents of organic field effect transistors.1
Such devices hold great potential for the development of
simple, low cost, “disposable electronics” items such as
electronic price tags. Suitability for such applications depends
critically on these materials’ displaying reproducibly high
carrier mobilities (>10-2 cm2/Vs) and being amenable to
simple, large area, solution processing technologies (e.g., ink-
jet printing).2 Backbone defects, deletion sequences, and trace
impurities are highly detrimental to achieving high carrier
mobilities, and these imperfections must be minimized during
synthesis and through purification.
similar intermediates following each successive iteration, a
process which is time-consuming and inefficient.3
Recent publications applying solid-phase synthesis (SPS)
to the iterative preparation of oligothiophenes demonstrate
that SPS offers an attractive solution to some of the
purification issues.4 However, the ultimate purity of the
cleaved oligomer is critically dependent on the yields attained
for each individual cross-coupling step. Incomplete cross-
coupling results in deletions and leads to a distribution in
the final oligomer length.
In this communication we describe our development of a
novel strategy by which optimum cross-coupling efficiencies
can be ensured for each iteration (i.e., addition of each
successive thiophene monomer) through double-coupling. By
double-coupling, we mean reactivation and recoupling fol-
lowing an initial coupling to drive each iteration to comple-
tion.5 This is only possible if the R-position of the newly
Traditional approaches toward regioregular oligo-(â-alkyl-
thiophenes) of well-defined length rely on repetitive transition
metal catalyzed cross-coupling of thiophene monomers in
solution with careful purification of chromatographically
(3) Ba¨uerle, P. In Handbook of Oligo-Polythiophenes; Fichou, D., Ed.;
Wiley-VCH: Weinheim, 1999; 89-181.
† University of Sheffield.
‡ Avecia Ltd.
(4) (a) Malenfrant, P. R. L.; Fre´chet, J. M. J. Chem. Commun. 1998,
2657-2658. (b) Huang, H.; Tour, J. M. J. Org. Chem. 1999, 64, 8898-
8906. (c) Briehn, C. A.; Kirschbaum, T.; Ba¨uerle, P. J. Org. Chem. 2000,
65, 352-359. (d) Kirschbaum, T.; Briehn, C. A.; Ba¨uerle, P. J. Chem. Soc.,
Perkin Trans. 1 2000, 1211-1216. (e) Kirschbaum, T.; Ba¨uerle, P. Synth.
Met. 2001, 119, 127-128. (f) Briehn, C. A.; Schiedel, M.-S.; Bonsen, E.
M.; Schuhmann, W.; Ba¨uerle, P. Angew. Chem., Int. Ed. 2001, 40, 4680-
4683.
(1) Reviews: (a) Katz, H. E.; Bao Z.; Gilat, S. L. Acc. Chem. Res. 2001,
34, 359-369. (b) Dimitrakopoulos, C. D.; Mascaro, D. J. IBM J. Res. DeV.
2001, 45, 11-27.
(2) (a) Bao, Z.; Dodabalpur, A.; Lovinger, A. Appl. Phys. Lett. 1996,
69, 4108-4110. (b) Bao, Z.; Lovinger, A. J. Chem. Mater. 1999, 11, 2607-
2612. (c) Sirringhaus, H.; Tessler, N.; Friend, R. H. Science 1998, 280,
1741-1744.
10.1021/ol025879x CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/30/2002

introduced monomer that becomes the terminus of the
growing oligomer is protected toward activation by a
temporary “blocking” group. To achieve this, we employ a
germanium-based linker6 to attach the growing oligothio-
phene to the solid support and use a trimethylsilyl (TMS)
temporary blocking group to protect the R-position of the
introduced thiophene unit. The success of the strategy is
crucially dependent on the fact that the temporary TMS
blocking group can be deprotected (i.e., removed) without
affecting the linkage to the solid support. As such, the method
relies on the orthogonal susceptibility of R-silyl- and
R-germyl-substituted thiophene-derivatives toward nucleo-
philic ipso-protodemetalation (vide infra).7 The germanium-
based linker also allows for final cleavage by electrophilic
ipso-degermylation.5 Cleavage with acid will yield R-H
terminated oligomers, whereas cleavage with halonium ions
will yield R-halo terminated oligomers.5 Such R,ω-differenti-
ated telechelic oligomers are valuable substrates for block
co-oligomer preparation and for oligomer end-capping.8
Readily available chlorogermane 1,9 which we have used
previously as a solution-phase model linker system to
develop methodology for SPS, was reacted with 4- and
3-hexyl-2-lithiothiophenes to give germylthiophenes 2 and
4, respectively. Analogous TMS thiophenes 3 and 5 were
similarly prepared from TMSCl (Scheme 1).
toward nucleophiles than their arylsilane counterparts,10 we
screened a number of nucleophilic conditions to achieve this
goal. Screening comprised H NMR monitoring of ipso-
protodemetalation of R-germylthiophenes 2 and 4 vs R-TMS-
thiophenes 3 and 5 while the temperature was stepped up
from 25 to 60 to 110 °C over 72 h. Both K3PO4 and CsF in
DMF displayed appropriate orthogonality, but CsF was
preferred because of its higher solubility (Table 1).
1
Table 1. Nucleophile Induced Ipso-Demetalation of R-germyl
and R-silyl-â-hexylthiophenes
nucleophile
sub-
strate
K3PO4
CsF
2
4
3
no cleavage to 110 °C
no cleavage to 110 °C
partial cleavage at 25 °C,
complete cleavage at 60 °C
cleavage at 60 °C
no cleavage to 110 °C
no cleavage to 110 °C
cleavage at 60 °C
5
partial cleavage at 25 °C,
complete cleavage at 60 °C
It can be seen from the table that the degree of orthogonal-
ity toward reaction with CsF between Ge and Si is not
significantly affected by the position of the â-hexyl side chain
(cf. 2 vs 3, and 4 vs 5, Table 1). However, Tour has shown
that electrophilic ipso-protodesilylation of R-silyl-â-alkyl-
thiophenes is sensitive to regiochemistry, presumably as a
result of the inductive stabilization imparted to cationic
Wheland-type intermediates by an adjacent alkyl substitu-
ent.11 Furthermore this sensitivity is exacerbated as the
oligothiophene chain-length increases.9 As arylgermanes are
more readily cleaved by electrophiles than arylsilanes (as a
result of the more powerful â-effect of Ge),12 we decided
that it would be prudent to use 2-germyl-4-hexyl-5-TMS
thiophene 6 as our oligomer starter unit to minimize the risk
of unwanted electrophile-induced linker cleavage during
synthesis.
Scheme 1a
Thiophene 6 was prepared by reaction of linker model 1
with lithiated thiophene 3 in 54% yield. Here, the TMS
protecting group ensures that none of the undesired alternate
R-lithiated thiophene is formed and moreover, in the context
of SPS, would allow immobilization to be driven to comple-
tion by repeating the reaction (Scheme 2).
a (a) n-BuLi, THF, -78 °C; 1 (72%). (b) n-BuLi, THF, -78
°C; Me3SiCl (87%). (c) LDA, THF, -50 °C; 1 (60%). (d) LDA,
THF, -50 °C; Me3SiCl (98%).
Scheme 2
Our first objective was to establish conditions under which
an immobilized R-silylthiophene could be deprotected (ipso-
protodesilylated) without affecting the R-germyl linkage. As
arylgermanes are known to be substantially more stable
We were now in a position to investigate the three key
iterative steps envisaged for building up an oligomer and to
check the concept of double-coupling:
(5) The term “double-coupling” is used in the context of solid-phase
peptide synthesis for the process whereby a coupling protocol is repeated
to drive up the yield of a “difficult” peptide coupling step. Our use of the
term is by analogy with this usage. See: Dettin, M.; Pegoraro, S.; Rovero,
P.; Bicciato, S.; Bagno, A.; Di Bello, C. J. Pept. Res. 1997, 49, 103-111.
(6) (a) Spivey, A. C.; Diaper, C. M.; Rudge, A. J. Chem. Commun. 1999,
835-836. (b) Spivey, A. C.; Diaper, C. M.; Adams, H.; Rudge, A. J. Org.
Chem. 2000, 65, 5253-5263.
1900
Org. Lett., Vol. 4, No. 11, 2002

Step 1: cleavage of the TMS blocking group
followed by treatment with excess 1,2-diiodoethane in the
dark was found to be very efficient in this regard. Conversion
of germylthiophene 4 to the corresponding R-iodide 7 under
these conditions was achieved in 97% yield (Scheme 5).
Step 2: conversion to an R-iodide coupling precursor
Step 3: cross-coupling of a TMS blocked monomer
Double-coupling: repeat steps 2 and 3 (Scheme 3).
Scheme 5
Scheme 3
Step 3. Our cross-coupling experiments initially centered
on coupling iodothiophene 7 with the readily prepared
pinnacolato boronic ester 8.14 It became apparent that under
a range of standard Suzuki-type cross-coupling conditions
employing a variety of bases (e.g., NaHCO3, Cs2CO3,
NaOAc, Et3N) and solvents (e.g., THF, toluene, DMF)
substantial ipso-protodesilylation of the TMS group occurred.
To circumvent this problem we developed a “base-free”
protocol involving triethylborate salt 9.15 This salt is obtained
as an easily handled white powder by direct evaporation of
volatiles following lithiation/transmetalation of thiophene 3
with n-BuLi/B(OEt)3 at -50 °C in THF. Using Pd(PPh3)4
(<15 mol %) in DMF at 60 °C in the absence of added
base this salt cross-couples with iodothiophene 7 to give
dithiophene 10 in 81% yield. No ipso-protodesilylation of
the TMS group occurs under these conditions (Scheme 6).
The role of the TMS group is to block the terminal
R-position of the iterated oligomer allowing steps 2 and 3
to be repeated in a double-coupling cycle so as to drive any
unreacted iodide and any uniodinated/deiodinated material
through to iterated product.
Step 1. As expected from our preliminary studies (Table
1) cleavage of the TMS protecting group in thiophene 6 with
CsF was uneventful and gave germylthiophene 4 in 97%
yield with no detectable cleavage of the germyl linker
(Scheme 4).
Scheme 6
Scheme 4
Step 2. R-Iodination of thiophenes is usually accomplished
by electrophilic iodination, sometimes with the assistance
of mercuration.13 For our purposes we required conditions
that would be compatible with the germyl linker, which is
sensitive to electrophilic ipso-degermylation. After consider-
able optimization, the use of excess n-BuLi at -50 °C
With the three crucial iterative steps for oligomer extension
established we were in a position to investigate whether the
TMS group was itself inert to step 2 and therefore sufficiently
robust to enable the envisaged double-coupling.
(7) The term “orthogonal” is used in the context of peptide synthesis to
refer to protecting groups (or families thereof) that can be deprotected in
the presence of each other. Our use of the term is by analogy with this
usage. See: Barany, G.; Merrifield, R. B. J. Am. Chem. Soc. 1977, 99,
7363-7365.
(8) Li; W.; Maddux, T.; Yu, L. Macromolecules 1996, 29, 7329-7334.
(9) The trimethylgermyl precursor to chlorogermane 1 (see Supporting
Information) is commercially available from AFChemPharm Ltd. See:
http://www.afchempharm.co.uk.
(10) Germyl- vs silylalkynes also display orthogonal stability towards
nucleophiles; see: Vasella, A.; Cai, C. HelV. Chim. Acta 1996, 79, 255-
268 and references therein.
(11) Tour, J. M.; Wu, R. Macromolecules 1992, 25, 1901-1907.
(12) Eaborn, C. J. Organomet. Chem. 1975, 100, 43-57.
(13) See, e.g., ref 4c and references therein.
Double-Coupling. Analysis by 1H NMR of the “crude”16
reaction mixture following a cross-coupling between iodo-
(14) Boronic ester 8 was prepared by lithiation/transmetalation of
thiophene 3 with 2,6-(4-isopropyliden-cyclopentadithiophenyl)-4,4,5,5-
tetramethyl-(1,3,2)dioxadiborolane in 52% yield (see Supporting Informa-
tion). The corresponding boronic acid was unstable in our hands.
(15) We have not rigorously characterized salt 9, and its structure must
therefore be regarded as tentative. For an example of the use of a furan-
derived trimethylborate salt in “base-free” cross-coupling, see: Cristofoli,
W. A.; Keay, B. A. Tetrahedron Lett. 1991, 32, 5881-5884.
Org. Lett., Vol. 4, No. 11, 2002
1901

thiophene 7 and an excess of triethyborate salt 9 (Scheme
6) reveals, in addition to >90% cross-coupled product 10,
small amounts of both unreacted iodothiophene 7 and
uniodinated/deiodinated thiophene 4. Therefore, to validate
the concept of double-coupling we subjected this material
to a repeat R-iodination/coupling cycle (steps 2 and 3) and
reexamined the reaction mixture. Following this simulated
double-coupling, byproducts 7 and 8 can no longer be
In summary, we have developed the key iterative steps of
a new strategy for the synthesis of regioregular oligo-(â-
hexylthiophenes) that allows for double-coupling after each
iteration to minimize deletion sequences. The success of the
double-coupling is contingent upon and highlights the
significantly greater stability of (hetero)arylgermanes to
nucleophilic conditions relative to the corresponding (hetero)-
arylsilanes. This enhanced stability constitutes an important
advantage that germanium-based “traceless” linker systems
have for SPS relative to their silicon-based counter-
parts.17
1
detected by H NMR.
A second iteration, including simulated double-coupling,
has been performed on dithiophene 10, yielding trithiophene
13 with analogous results (Scheme 7).
We are currently optimizing the strategy for the SPS of
high purity oligothiophenes and adapting the concept for the
preparation of other oligoheterocycles and derived block co-
oligomers.
Scheme 7a
Acknowledgment. This work was supported by the
EPSRC and Avecia Ltd. (Electronic Materials Business).
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds 1-13. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL025879X
(16) The reaction mixture was worked up and passed through a short
plug of SiO2, eluting with 9:1 petrol (bp 40-60 °C)/EtOAc. This process
removes the “baseline” Pd and excess triethylborate salt 9.
(17) This feature of germanium-based linker systems has not previously
been exploited. Attention has focused on the opportunities that arylgermane-
based linkers provide relative to their arylsilane counterparts for more facile
electrophilic ipso-demetalative cleavage and for employing a wider range
of electrophiles for diversity enhancement. See ref 6 and Plunkett M. J.;
Ellman, J. A. J. Org. Chem. 1997, 62, 2885-2893.
a Step 1: CsF, DMF, 60 °C (99%). Step 2: n-BuLi, -50 °C;
ICH2CH2I (98%). Step 3: 9, Pd(PPh3)4, DMF, 60 °C. Double-
couple: repeat steps 2 and 3 (>90%).
1902
Org. Lett., Vol. 4, No. 11, 2002