A Tuneable Ge-based Linker that Enables Application-led Solid Phase Synthesis Optimisation - Towards a Robust Iterative Synthesis of Oligothiophenes

Article abstract of DOI:10.1055/s-2003-43363

A convenient synthesis of a new dichlorogermanium-based linker-precursor for solid phase synthesis is described that allows facile introduction of a range of 'spectator' substituents (R) onto germanium. Variation of these R groups allows modulation of the stability of the key germanium-carbon bond between the linker and the aryl library. The tuning process is exemplified by application to the optimisation of a linker for the iterative solid-phase synthesis (SPS) of oligothiophenes.

Full text of DOI:10.1055/s-2003-43363

LETTER
111
A Tuneable Ge-based Linker that Enables Application-led Solid Phase
Synthesis Optimisation – Towards a Robust Iterative Synthesis of
Oligothiophenes
T
uning a Ge-based
l
L
inke
a
for
I
terati
n
S
PS of Oligothio
C
phenes . Spivey,*1 David J. Turner,a Michael L. Turner,a Stephen Yeatesb
a
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
E-mail: a.c.spivey@imperial.ac.uk
b
Avecia Ltd, Hexagon House, Blackley, Manchester M9 8ZS, UK
Received 10 September 2003
nucleophilic ipso-protodemetalation to facilitate ‘double-
coupling’ after each iteration. This double-coupling tactic
was designed to minimise deletion sequences and so aid
the preparation of high purity materials with interesting
Abstract: A convenient synthesis of a new dichlorogermanium-
based linker-precursor for solid phase synthesis is described that al-
lows facile introduction of a range of ‘spectator’ substituents (R)
onto germanium. Variation of these R groups allows modulation of
the stability of the key germanium–carbon bond between the linker electronic properties.7 In order to optimise the efficiency
and the aryl library. The tuning process is exemplified by applica-
of the process and render it sufficiently robust for large-
tion to the optimisation of a linker for the iterative solid-phase syn-
thesis (SPS) of oligothiophenes.
scale automated preparations it was desirable to be able
to tune the two spectator substituents on the germanium
linker (vide infra). The ability to make subtle variations
to the ease of electrophilic and nucleophilic ipso-de-
Key words: solid-phase synthesis, electrophilic aromatic substitu-
tions, heterocycles, cross-coupling, combinatorial chemistry
germylation by such a tuning process was also expected to
accelerate the deployment of this strategy for iterative
synthesis of other conjugated oligomers incorporating
alternative monomers and aid linker selection for other
library applications.
Solid Phase Synthesis (SPS) using parallel or split/mix
techniques constitutes an attractive method for the rapid
preparation of large libraries of molecules for property
screening.2 Central to the success of the method is the
compatibility of the chosen linker with the chemistry re-
quired for library construction and diversification.3 The
time required to achieve this compatibility impacts signif-
icantly on the overall efficiency of the strategy. Indeed,
reservations over potentially long development times
probably constitute the most significant impediment to
more widespread exploitation of SPS.4
The preparation of dimethylgermanium linkers 2a–c re-
lied on the ‘activation’ of trimethylgermanium linker-
precursors 1a–c by chemoselective mono-chlorode-
methylation using excess tin(IV) chloride in nitromethane
as the key step. We have previously reported the use of
this reaction prior to attachment to the resin (1a → 2a), in
a solution phase model system (1b → 2b), and ‘on-resin’
(1c → 2c, Scheme 1).8
As no single linker constitutes a panacea for immobilisa-
tion via a given functional group, linker selection for SPS
usually involves choosing from the growing repertoire of
available linkers then experimentation.5 The process has
close analogy with protecting group (PG) selection for so-
lution synthesis except that the choice is currently more
limited. Moreover, PG selection is greatly aided by the
availability of suites of graded PGs that allow fine-tuning
vis-à-vis compatibility for a given application (such as si-
lyl ethers with varying degrees of acid and fluoride stabil-
ity for alcohol protection e.g. TMS, TES, TBDMS, TIPS,
TBDPS etc.). Clearly, the ready availability of similar
suites of linkers would be highly advantageous for stream-
lining the development of SPS programs.
SnCl4
GeMe3
R1Me2GeCl
+
MeSnCl3
MeNO2
50 °C
1
2a (99%)
2b (99%)
XO
R1
a X = H
2c (0.8 mmolg-1
)
b X = CH2CH2OEt
c X = QuadragelTM (1.4 mmolg–1
)
Scheme 1
The chemoselectivity of this transformation however pre-
cludes its adaptation to the preparation of analogues hav-
ing spectator substituents other than methyl. Moreover,
the stoichiometric co-formation of toxic methyltintrichlo-
ride and the fact that the on-resin variant of this reaction
fails on tentagel-type resins8c detract from the attractive-
ness of this route.
We recently described solution phase studies directed
towards the development of an iterative SPS of oligo-
thiophenes using a dimethylgermanium-based linker.6
Our approach exploited the orthogonal susceptibility of
a-silyl and a-germyl substituted thiophenes towards
To circumvent these issues a new more flexible route to
dimethylgermanium linker 2a and its analogues was de-
vised. The new synthesis (Scheme 2) began with the se-
lective formation of dichlorogermane 4a from
trichlorogermane 3a.8b This was achieved by arylation
with an excess of 4-anisylmagnesium bromide to provide
SYNLETT 2004, No. 1, pp 0111–0115
0
5.
0
1.
2
0
0
4
Advanced online publication: 26.11.2003
DOI: 10.1055/s-2003-43363; Art ID: D22803ST
© Georg Thieme Verlag Stuttgart · New York

112
A. C. Spivey et al.
LETTER
a crude mixture of di- and triarylgermanes which on It is noteworthy that even for the three linkers having aryl
work-up with concentrated HCl afforded dichloroger- substituents the HCl activation step (5b → 2b) is com-
mane 4a as the exclusive product (84%). The selectivity pletely selective for cleavage of anisole (vs. benzene, tol-
of this process arises from the stepwise attenuation of the uene or fluorobenzene). In all cases this step was complete
rate of cleavage of the anisyl-Ge bonds as successive within 24 hours at ambient temperature except for the
chlorides are introduced onto germanium.9
para-fluorophenyl case for which 48 hours were required.
With the aromatic substituents there is also potential for a
second cleavage event to give a dichloride: this was not
observed.
R1Cl2Ge
GeCl3
d
3
4a (84%)
XO
OMe
OMe
a X = H
b X = CH2CH2OEt
c X = QuadragelTM
The utility of this new suite of sterically and electronically
differentiated solution phase model linkers (2b) for facil-
itating the selection of a linker with an optimal stability
profile for iterative SPS of oligothiophenes employing
double-coupling was investigated next. Initial studies had
employed the dimethylgermanium linker model (2b, R =
Me) in conjunction with a TMS temporary ‘blocking’
group to protect the a-position of the growing oligomer.6
For oligothiophenes greater than the tetramer, the TMS
group proved to be susceptible to partial cleavage by trac-
es of adventitious acid during analysis (e.g. during NMR
spectroscopy in CDCl3).13 This finding indicated that a
new silyl blocking group/germanium linker combination
was needed which retained the orthogonal stability of the
a-silyl vs a-germyl linkages towards CsF but for which
the two partners had enhanced stability towards acid. Spe-
cifically, the following characteristics were required:
R1
a
e
R1R2Ge
R1GeMe3
1a (82%)
1b (90%)
5a R = Me, Et, i-Pr, Ph, p-Tol, p-FC6H4 (see Table 1)
5b R = Me, Et, i-Pr, Ph, p-Tol, p-FC6H4 (see Table 1)
b
b
f
c
MeSnCl3
p-MeOC6H5
R1R2GeCl
2b R = Me, Et, i-Pr, Ph, p-Tol, p-FC6H4 (see Table 1)
R1Me2GeCl
2b (99%)
Previous route8(cf. Scheme 1)
3 steps from 3 (73%)
New route
4 steps from 3 (71%, R = Me)
Scheme 2 (a) MeMgBr, toluene, 110 °C. (b) EtOCH2CH2Cl, n-
Bu4NI, Cs2CO3, MeCN, 85 °C. (c) SnCl4, MeNO2, 50 °C. (d) i) p-
MeOC6H4MgBr, THF, r.t. ii) Concd HCl, CH2Cl2, r.t.10 (e) RMgBr,
THF, 70 °C.11 (f) 1.0 M HCl in Et2O, r.t.
Silyl blocking group: This needed to be significantly
more stable towards acid than TMS (to ensure a robust au-
tomatable process) and sufficiently labile towards fluo-
ride to allow quantitative desilylation in the presence of
the germanium linker (to allow double-coupling).
Bis-methylation of dichlororgermane 4a with MeMgBr
gave dimethylgermane 5a (R = Me) which, following
Williamson etherification8b to give the ethoxyethyl linker-
precursor 5b (R = Me), underwent activation12 with ex-
cess HCl in Et2O to give dimethylgermane linker 2b (R =
Me). After removal of the volatile anisole by-product and
excess HCl in vacuo, this material was identical to that
prepared by the tin(IV) chloride route (Scheme 2).
Germanium linker: This also needed to be stable to-
wards acid (to ensure a robust automatable process), com-
pletely stable towards CsF (to allow double-coupling) and
yet sufficiently labile to allow for cleavage of the final oli-
gomer from the resin with a range of electrophiles.
This new route proved to be highly efficient for the prep-
aration a series of ethoxyethyl solution phase model link-
ers 2b having a variety of both alkyl and aryl spectator
groups attached to germanium (Table 1).
Three silyl blocking groups were selected for evaluation:
TES, TIPS and TBDMS. To this end, silylthiophenes 7–
10 were prepared from bromothiophene 6 (Scheme 3).
i) n-BuLi, THF,
–78 °C
7 X = Y = Me (TMS)
SiX2Y
S
S
Br
8 X = Y = Et (TES)
Table 1 Preparation of Ethoxyethyl Solution Phase Model Linkers
2b for Stability Studies
9 X = Y = i-Pr (TIPS)
10 X = Me, Y= t-Bu (TBDMS)
ii) X2YSiCl
n-Hex
n-Hex
6
R
Isolated yields (%)
Scheme 3
5a
95
74
53
92
92
92
5b
2b
As the TIPS thiophene 9 readily desilylated during chro-
matography on flash silica, presumably by ipso-protodes-
ilylation promoted by relief of strain with the adjacent
hexyl group,14 only the TES and TBDMS derivatives 8
and 10 were taken forward for screening for their stability
towards acid and fluoride. Screening consisted of moni-
toring the 1H NMR spectrum of ipso-protodesilylation on
exposure to a 1:1 mixture of HOAc in CH2Cl2 or a ca 0.3
M solution of CsF in DMF while the temperature was
stepped up from 25 °C to 60 °C to 110 °C over 72 hours
(Table 2).
Me
90
70
77
80
70
72
99
Et
Not isolated
i-Pr
Not isolated
Ph
98
98
97
p-Tol
p-FC6H4
Synlett 2004, No. 1, 111–115 © Thieme Stuttgart · New York

LETTER
Tuning a Ge-based Linker for Iterative SPS of Oligothiophenes
113
Table 2 Acid and Fluoride Induced ipso-Desilylation of Silyl-
Thiophenes 7, 8 and 10
didates for oligothiophene synthesis. To ensure that ipso-
degermylation with strong electrophiles would still be
possible for final oligomer cleavage from the resin both of
these model systems (11b, R = Ph and p-Tol) were treated
with a 1% solution of TFA in CH2Cl2 and it was found that
they both underwent complete cleavage within ca 20 min.
Substrate
Cleavage conditions
HOAc
CsF
7 (TMS)
8 (TES)
Cleavage at 25 °C
Cleavage at 25 °C
Cleavage at 25 °C
As tolyl methyl groups provide a convenient marker for
NMR reaction monitoring, the di-p-tolyl linker was se-
lected for progression to SPS evaluation in conjunction
with the TBDMS blocking group. Thus, di-p-tolylanisyl
linker precursor 5a was introduced onto QuadragelTM-Br
resin17 by Williamson etherification and the resulting res-
in (5c) activated with HCl in Et2O (→2c). The initial
monomer, a-TBDMS-blocked hexylthiophene 12, was
then efficiently introduced, as its a-lithiated derivative.
As required, TBDMS removal from the resulting resin
bound thiophene proceeded selectively using CsF in DMF
at 110 °C (13c→14c) without detectable cleavage of the
arylgermane. Sequential a-iodination (→15c) and Suzuki
cross-coupling with a-TBDMS-blocked thiophene boron-
ic ester 16 also proceeded smoothly to give the resin
bound bithiophene 17c with high efficiency. The key
double-coupling cycle also proceeded uneventfully
(Scheme 5). HPLC analysis of cleaved (TFA) samples of
bithiophene 1818 before and after double coupling had pu-
rities of 94% and 96% respectively, demonstrating the
utility of this tactic for enhancing iteration efficiency.
Partial cleavage at 25 °C,
complete at 60 °C
10 (TBDMS) No cleavage to 110 °C
Cleavage at 60 °C
As expected the TES and TBDMS groups proved to be
more resistant than TMS to ipso-protodesilylation by acid.
The TBDMS group was most promising as it was the most
acid stable. However, as this group also showed notice-
ably greater stability towards fluoride than the TMS or
TES groups it required matching with an appropriately
fluoride stable germanium linker. This was achieved by
preparing hexyl thiophene derivatives of the suite of link-
er models 2b15 and subjecting these compounds to the
above-described screening conditions (Scheme 4 and
Table 3).
S
Li
R = Me (60%)
R1R2Ge
n-Hex
S
R = Et (72%, from 5b)
R = i-Pr (78%, from 5b)
R = Ph (57%)
R1R2GeCl
THF, –40 °C
11b
2b
n-Hex
R = p-Tol (61%)
QuadragelTM-Br
Scheme 4
(0.88 mmolg–1
)
Br
Table 3 Acid and Fluoride Induced ipso-Protodegermylation of
Germyl-Thiophenes 11b
a
p-Tol p-Tol
5c X = p-MeOC6H4 (0.52 mmolg-1
2c X = Cl (0.54 mmolg-1
)
Ge
b
Substrate
Cleavage conditions
HOAc
X
)
CsF
O
S
TBDMS
c
11b (R = Me) Partial cleavage at 25 °C, No cleavage to 110 °C
n-Hex
12
13c Y = TBDMS (0.40 mmolg-1
complete at 60 °C
p-Tol p-Tol
S
Ge
Y
d
)
14c Y = H (0.42 mmolg-1
)
11b (R = Et)
Partial cleavage at 25 °C, No cleavage to 110 °C
complete at 60 °C
e
15c Y = I (0.40 mmolg-1
)
O
n-Hex
n-Hex
11b (R = i-Pr) Partial cleavage at 25 °C, No cleavage to 110 °C
complete at 60 °C
f
O
B
O
TBDMS
S
16
11b (R = Ph)
No cleavage to 110 °C
No cleavage to 110 °C
No cleavage to 110 °C
n-Hex
p-Tol p-Tol
11b (R = p-Tol) No cleavage to 110 °C
S
Ge
TBDMS
S
It can be seen from Table 3 that all the germanium linkers
examined displayed significantly greater stability towards
ipso-protodemetalation by CsF than the TBDMS blocked
thiophene 10 and so in principle were suitable for double-
coupling. Moreover, it is interesting to note that, in con-
trast to the situation with silicon, increasing the steric bulk
around germanium (i.e. R = Me → Et → i-Pr) had no dis-
cernable effect on the rate of cleavage by HOAc (within
the limits of our screen).16 However, the linkers having
aryl spectator substituents (i.e. R = Ph and p-Tol) were
markedly more stable towards acid than those with alkyl
substituents and therefore looked the most promising can-
O
n-Hex
17c
double-coupling
cycle
e,f
17c (0.35 mmolg-1
)
g
g
n-Hex
18
S
S
n-Hex
Scheme 5 (a) 5a, n-Bu4NI, Cs2CO3, MeCN, 85 °C.19 (b) 1.0 M HCl
in Et2O, r.t.20 (c) 12, LDA, THF, –40 °C.21 (d) CsF, DMF, 110 °C.22
(e) (i) LDA, THF, –40 °C, (ii) ICH2CH2I, dark, –40 °C.23 (f) 16,
K3PO4, Pd(PPh3)4, DMF, 60 °C.24 (g) TFA, CH2Cl2, r.t.25
Synlett 2004, No. 1, 111–115 © Thieme Stuttgart · New York

114
A. C. Spivey et al.
LETTER
residue dissolved in CH2Cl2 (30 mL). HCl (1 N, 5mL) and
then concd HCl (60 mL) were added successively with
stirring and the resultant mixture was stirred vigorously for
40 min. The aq layer was extracted with CH2Cl2 (3 × 50mL),
the combined organic extracts dried (MgSO4) and the
solvent removed in vacuo. The residue was dissolved in
CH2Cl2 (50 mL), extracted with 0.5 M NaOH(aq) (100 mL)
and the aq layer washed with CH2Cl2 (3 × 50 mL). To the aq
layer was added 1 N HCl (15 mL) and then concd HCl
(100mL) with shaking, before extracting with CH2Cl2 (3 ×
100 mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo to give dichlorogermane
4a as an orange oil (1.30 g, 84%). IR (neat): 3019 (broad,
OH), 2935–2835 (CH), 2361, 1591, 1514, 1442, 1403, 1290,
1254 cm–1. 1H NMR (250 MHz, CDCl3): d = 1.96–2.02 (2
H), 2.83–2.90 (2 H), 3.75 (s, 3 H), 4.84 (br s, 1 H), 6.65 (d,
J = 8.5 Hz, 2 H), 6.88 (d, J = 9.0 Hz, 2 H), 6.99 (d, J = 8.5
Hz, 2 H), 7.40 (d, J = 9.0 Hz, 2 H). 13C NMR (63 MHz,
CDCl3): d = 27.8 (t), 28.6 (t), 55.4 (q), 114.6 (2 × d), 115.5
(2 × d), 126.7 (s), 129.4 (2 × d), 133.8 (2 × d, s), 154.1 (s),
162.1 (s). MS (EI+): m/z = 372 [M+]. HRMS: m/z [M+] calcd
for C15H16Cl2Ge74O2: 371.9739; found: 371.9749.
In summary, a convenient route for the preparation of a
new dichlorogermanium linker precursor 4a has been de-
veloped and it has been shown that this compound can
serve as a pivotal intermediate for the preparation of a
range of di-alkyl and di-aryl germanium linkers for SPS.
This new route allows activation of resin-bound linker-
precursors (e.g. 5c) simply by treatment with HCl in Et2O.
The ability to rapidly access a suite of germanium linkers
displaying a range of stabilities towards electrophiles
whilst retaining good stability towards nucleophiles offers
exciting opportunities for tuning a linker to suit a specific
library or other SPS application. This has been illustrated
by the development of an iterative double-coupling
approach to SPS of oligothiophenes wherein the com-
bination of a TBDMS blocking group and a di-p-tolyl-
germanium linker was found to be optimal.
An account of the use of the optimised strategy for the
SPS of high purity oligothiophenes will be disclosed
shortly.
(11) Di-para-tolylgermane 5a (R = p-Tol). To oven dried Mg
turnings (120 mg, 5.00 mmol) in THF (3 mL) was added 4-
bromotoluene (855 mg, 5.00 mmol) dropwise. The resulting
mixture was heated briefly, stirred for 1 h and then added
dropwise to a solution of dichlorogermane 4a (186 mg, 0.50
mmol) in THF (3mL) at r.t. After heating at 110 °C for 16 h
the reaction mixture was quenched with sat. NH4Cl (aq) (100
mL) and extracted with Et2O (3 × 100 mL). The combined
organic extracts were dried (MgSO4), concentrated in vacuo
and the residue purified by flash chromatography (SiO2,
petroleum ether–EtOAc, 3:1) to give ditolylgermane 5a (R =
p-Tol) as a yellow oil (231 mg, 92%); Rf 0.4 (petroleum
ether–EtOAc, 3:1). IR (neat): 3409 (broad), 3012, 2921,
2861, 1593, 1568, 1512, 1442, 1392, 1281, 1247, 1180,
1089, 1031 cm–1. 1H NMR (250 MHz, CDCl3): d = 1.72–
1.80 (2 H), 2.36 (s, 6 H), 2.70–2.77 (2 H), 3.81 (s, 3 H), 4.64
(s, 1 H), 6.71 (d, J = 8.5 Hz, 2 H), 6.92 (d, J = 8.5 Hz, 2 H),
7.04 (d, J = 8.5 Hz, 2 H), 7.19 (d, J = 8.0 Hz, 4 H), 7.38 (d,
J = 8.0 Hz, 4 H), 7.40 (d, J = 8.5 Hz, 2 H). 13C NMR (63
MHz, CDCl3): d = 16.6 (t), 21.6 (2 × q), 30.4 (t), 55.2 (q),
114.2 (2 × d), 115.3 (2 × d), 128.2 (s), 129.0 (2 × d), 129.2
(4 × d), 133.8 (2 × s), 135.0 (4 × d), 136.3 (2 × d), 137.1 (s),
138.8 (2 × s), 153.6 (s), 160.3 (s). MS (EI+): m/z = 484 [M+].
HRMS (EI+): m/z [M+] calcd for C29H30Ge74O2: 484.1458;
found: 484.1446.
Acknowledgement
This work was supported by the EPSRC and Avecia Ltd. (Electro-
nic Materials Business) and by the Organic Materials for Electro-
nics Consortium (OMEC, http://www.omec.org.uk/). We thank Jon
Cobb (King’s College London) for help with the MAS-NMR’s, Si-
mon Thorpe and Rob Hanson (Sheffield University) for the HPLC
analysis, and Drs Dom Cupertino, Phil Mackie and Remi Anemain
(Avecia Ltd.) for help with the SPS.
References
(1) Current address: Department of Chemistry, Imperial College
London SW7 2AZ, UK.
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(12) For the analogous ‘activation’ of an arylsilane linker
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Org. Chem. 1997, 62, 6102.
(7) Reviews: (a) Katz, H. E.; Bao, Z.; Gilat, S. L. Acc. Chem.
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(9) Ph2GeBr2 can be prepared similarly by the action of Br2 on
Ph4Ge but the reaction is less selective (57% yield after
distillation): Kraus, C. A.; Brown, C. L. J. Am. Chem. Soc.
1930, 52, 3690.
(10) Dichlorogermane 4a. To oven dried Mg turnings (1.01 g,
42.1 mmol) in THF (25 mL) was added 4-bromoanisole
(5.21 mL, 41.6 mmol) dropwise. The resulting mixture was
heated briefly, stirred for 1 h and then added dropwise to a
solution of germyl trichloride 3a8b (1.25 g, 4.17 mmol) in
THF (10 mL) at r.t. before heating to 70 ºC. After stirring for
16 h the reaction mixture was quenched by dropwise
addition of water, concentrated to dryness in vacuo, and the
(15) Hexylthiophene immobilisation (2b→11b) proceeded
smoothly in all cases except for the para-fluorophenyl case,
which gave a complex mixture of products, tentatively
ascribed to fragmentation pathways following nucleophilic
attack at the carbon ipso to the fluorine substituent.
(16) The insensitivity of Ge cf. Si towards steric shielding has
been noted previously and attributed to longer Ge–C vs Si–
C bond lengths: Eaborn, C. J. Organomet. Chem. 1975, 100,
43.
(17) QuadragelTM-OH (Avecia Ltd.) is a DVB crosslinked PS-
based resin with hydroxyl-terminated PEG grafts containing
4 oxyethyl repeat units.
Synlett 2004, No. 1, 111–115 © Thieme Stuttgart · New York

LETTER
Tuning a Ge-based Linker for Iterative SPS of Oligothiophenes
115
(18) Galvao, D. S.; Dos Santos, D. A.; Laks, B.; Dos Santos, M.
C. Synth. Met. 1991, 43, 3521.
water (1:1, 3 × 75 mL), THF (3 × 75 mL) and MeOH (3 × 75
mL). The resin was then dried in vacuo at 60 °C to give resin
14c as brown granules (560 mg, 100% conversion by 1H
NMR, LL = 0.42 mmol g–1). IR (neat): 3030–2865 (CH),
1601, 1508, 1492, 1451, 1242, 697 (strong) cm–1. 1H MAS–
NMR (400 MHz, CDCl3): d = 0.82 (t, J = 4.5 Hz, CH2CH3),
0.85–2.20 [(CH2)4CH3, ArCH2CH2Ge, CH(Ar)CH2], 2.37 (s,
ArCH3), 2.45–2.50 [CH2(CH2)4CH3], 2.70–2.85 (GeCH2),
3.60–4.15 (OCH2), 6.10–7.30 (ArH), 7.44 (d, J = 4.5 Hz,
ArH), 7.50–7.55 (SCH).
(19) Resin 5c. To QuadragelTM-Br (20.0 g, 18.6 mmol, from
QuadragelTM-OH18 0.93 mmol g–1 by treatment with CBr4
and PPh3 in CH2Cl2) swollen in a minimum of MeCN
(200mL) were added germane 5a (R = p-Tol, 19.4 g, 81.2
mmol), tetra-n-butylammonium iodide (740 mg, 2.00 mmol)
and Cs2CO3 (26.2 g, 74.3 mmol) and the resulting mixture
heated at 85 °C for 20 h. The reaction mixture was cooled
and the resin was washed successively with MeCN (3 × 350
mL), DMF (3 × 350 mL), THF–water (1:1, 3 × 350 mL),
THF (3 × 350 mL) and MeOH (3 × 350 mL) and then dried
in vacuo to give resin 5c as light brown granules (13.4 g,
74% conversion by the weight increase of the resin and the
amount of phenol returned, LL = 0.52 mmolg–1). IR (neat):
3030–2865 (CH), 1593, 1510, 1494, 1453, 1281, 1245, 698
(strong) cm–1. 1H MAS–NMR (400 MHz, CDCl3): d = 1.15–
1.65 [CH(Ar)CH2], 1.65–2.10 [ArCH2, CH(Ar)CH2], 2.37
(s, ArCH3), 2.70–2.80 (GeCH2), 3.50–4.15 (OCH3, OCH2),
6.10–6.70 (ArH), 6.70–7.30 (m, ArH), 7.41 (d, J = 4.5 Hz,
ArH). 13C MAS–NMR (100 MHz, CDCl3): d = 17.6, 21.8,
24.9, 25.2, 25.5, 25.7, 26.0, 31.7, 37.4, 41.6, 67.0, 67.3, 67.6,
67.9, 68.2, 71.7, 72.2, 128.9.
(23) Resin 15c. A solution of LDA (315 mL, 2.0 M, 0.63 mmol)
in hexanes–THF–ethylbenzene (6:5:3) was added dropwise
to a suspension of germylthiophene resin 14c (526 mg, LL =
0.42 mmolg–1, 0.22 mmol) in THF (4 mL) at –50 °C. After
stirring for 2 h at –30 °C, a solution of degassed 1,2-
diiodoethane (296 mg, 1.05 mmol) in THF (2 mL) was
added by cannula at –50 °C. The resulting mixture was
stirred in the dark for 2 h at –30 °C, warmed to r.t. and stirred
for a further 1 h. The solvent was then removed by filtration
and the resin washed with Na2S2O3 (aq) (3 × 75 mL), THF–
water (1:1, 3 × 75 mL), THF (3 × 75 mL) and MeOH (3 × 75
mL). The resin was then dried in vacuo at 60 °C to give resin
15c as orange granules (533 mg, 100% conversion by 1H
NMR, LL = 0.40 mmol g–1). IR(neat): 3030–2865 (CH),
1601, 1509, 1493, 1452, 1243, 697(strong) cm–1. 1H MAS–
NMR (400 MHz, CDCl3): d = 0.82 (t, J = 4.5 Hz, CH2CH3),
0.85–2.20 [(CH2)5CH3, ArCH2CH2Ge, CH(Ar)CH2,
ArCH3], 2.70–2.85 (GeCH2), 3.60–4.15 (OCH2), 6.10–7.30
(ArH), 7.42 (d, J = 4.5 Hz, ArH).
(24) Resin 17c. To a degassed solution of boronic ester 16 (242
mg, 0.59 mmol) and iodide resin 15c (493 mg, LL = 0.40
mmolg–1, 0.20 mmol) swelled in DMF (4 mL) was added
Pd(PPh3)4 (11.6 mg, 10.0 mmol) and the resulting mixture
stirred at 60 °C for 48 h. The solvent was then removed by
filtration and the resin washed with DMF (2 × 50mL), THF–
water (1:1, 3 × 50 mL), THF (3 × 50 mL) and MeOH (3 × 50
mL). The resin was then dried in vacuo at 60 °C to give resin
17c as dark brown granules (508 mg, 87% conversion by the
amount of bithiophene 1818 cleaved from the resin, cf.
below, LL = 0.35 mmolg–1). IR (neat): 3030–2865 (CH),
1601, 1509, 1492, 1451, 1244, 697 (strong) cm–1. 1H MAS–
NMR (400 MHz, CDCl3): d = 0.31 [s, Si(CH3)2], 0.75–2.50
[C(CH3)3, (CH2)5CH3, ArCH2CH2Ge, CH(Ar)CH2, ArCH3],
2.70–2.90 (GeCH2), 3.50–4.20 (OCH2), 6.10–7.60 (ArH).
13C MAS–NMR (100 MHz, CDCl3): d = 14.5, 17.3, 18.6,
21.9, 22.9, 23.0, 26.8, 29.6, 29.7, 30.0, 31.1, 31.7, 32.0, 32.2,
40.9, 44.3, 67.9, 70.2, 71.1, 71.2, 114.6, 115.0, 126.1, 128.4,
128.8, 129.1, 129.5, 129.6, 130.5, 133.6, 134.2, 135.0,
135.1, 135.5, 137.4, 138.7, 139.2, 139.5, 140.1, 140.6,
141.6, 145.7, 151.4, 157.3.
(20) Resin 2c. To germylanisole resin 5c (13.1 g, LL = 0.52
mmolg–1, 6.8 mmol) swelled in CH2Cl2 (50 mL) was added
HCl (65 mL, 1.0 M, 65 mmol) in Et2O and the reaction
mixture left to stir for 16 h. The solvent was then removed
by filtration to give resin 2c as brown granules (11.7 g, 100%
conversion by 1H NMR, LL = 0.54 mmol g–1). IR(neat):
3030–2865 (CH), 1601, 1509, 1493, 1452, 1243,
697(strong) cm–1. 1H MAS–NMR (400 MHz, CDCl3): d =
1.00–2.30 [ArCH2, CH(Ar)CH2], 2.47 (s, ArCH3), 2.85–2.95
(GeCH2), 3.60–4.20 (OCH2), 6.10–6.70 (ArH), 6.70–7.30
(ArH), 7.56 (d, J = 4.5 Hz, ArH).
(21) Resin 13c. A solution of LDA (1.11 mL, 2.0 M, 2.21 mmol)
in hexanes–THF–ethylbenzene (6:5:3) was added dropwise
to a degassed solution of silylthiophene 12 (616 mg, 2.18
mmol) in THF (4 mL) at –50 °C. This solution was warmed
to –40 °C, stirred for 40 min at this temperature and recooled
to –50 °C. The solution was then transferred by cannula to a
degassed suspension of germylchloride resin 2c (777 mg,
LL = 0.54 mmolg–1, 0.42 mmol) in THF (10 mL) at –50 °C.
The reaction mixture was stirred for 1 h at –40 °C, warmed
to r.t. and stirred for a further 1 h. After quenching with sat.
NH4Cl (aq) (50 mL), the solvent was removed by filtration
and the resin washed with DMF (3 × 50 mL), THF–water
(1:1, 3 × 50 mL), THF (3 × 50 mL) and MeOH (3 × 50 mL).
The resin was then dried in vacuo at 60 °C to give resin 13c
as yellow/orange granules (876 mg, 83% conversion by
weight increase of resin, LL = 0.40 mmolg–1). IR (neat):
3030–2865 (CH), 1601, 1509, 1492, 1451, 1244, 697
(strong) cm–1. 1H MAS–NMR (400 MHz, CDCl3): d = 0.41
[s, Si(CH3)2], 0.91 (t, J = 4.5 Hz, CH2CH3), 0.95–2.30
[C(CH3)3, (CH2)4CH3, ArCH2CH2Ge, CH(Ar)CH2], 2.47 (s,
ArCH3), 2.54 [t, J = 5.0 Hz, CH2(CH2)4CH3], 2.80–2.95
(GeCH2), 3.60–4.25 (OCH2), 6.10–6.80 (ArH), 6.80–7.30
(ArH), 7.53 (d, J = 4.5 Hz, ArH).
(25) Bithiophene 18.18 To resin 17c (after double-coupling, 40.4
mg, 16.2 mmol) was added a 33% solution of TFA in CH2Cl2
(750 mL) and the mixture left to stir at r.t. for 2 h. The solvent
was then removed by filtration and the resin washed with
CH2Cl2 (3 × 50 mL). These washings were then passed
through a plug of silica and concentrated in vacuo to afford
bithiophene 18 as an orange oil (4.7 mg, 96% pure by HPLC:
Phenomenex Jupiter ODS C-18 column, UV 254 nm
detection, 1 mL/min, 5–100% MeCN in H2O + 0.1% formic
acid, Rt 22.4 min). Spectroscopic data identical to that
previously reported.18
(22) Resin 14c. To germylthiophene resin 13c (642 mg, LL =
0.40 mmolg–1, 0.26 mmol) swelled in DMF (8 mL) was
added CsF (341 mg, 2.24 mmol) and the mixture left to stir
for 72 h at 110 °C. The solvent was then removed by
filtration and the resin washed with DMF (2 × 75 mL), THF–
Synlett 2004, No. 1, 111–115 © Thieme Stuttgart · New York