[(3-Cyanopropyl)diisopropylsilyl] acetylene, a more stable analogue of [(3-Cyanopropyl)dimethylsilyl]acetylene

Article abstract of DOI:10.1055/s-2008-1067141

The preparation and application of a new alkyne protecting group is presented. The reactivity and stability of [(3-cyanopropyl)diisopropylsilyl] acetylene is similar to that of the well-known (triisopropylsilyl)acetylene. Its high polarity simplifies chromatographic separation after coupling to aromatics with more than one reactive site. Moreover, compounds with more than one [(3-cyanopropyl)diisopropylsilyl]acetylene group are easily purified after partial deprotection. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067141

SHORT PAPER
2155
[(3-Cyanopropyl)diisopropylsilyl]acetylene, a More Stable Analogue of
[(3-Cyanopropyl)dimethylsilyl]acetylene
[
(3-Cyanopropyl)d
e
iisopropyls
r
ilyl]acet
a
ylene ld Gaefke, Sigurd Höger*
Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
Fax +49(228)735662; E-mail: hoeger@uni-bonn.de
Received 3 May 2008
Dedicated to Prof. R. W. Hoffmann on the occasion of his 75th birthday
It is, however, possible to prepare the same compounds
from diiodo (or dibromo) compounds as starting materi-
als. Then, for example, two acetylenes with protecting
groups of different stability are coupled to the aromatic
Abstract: The preparation and application of a new alkyne protect-
ing group is presented. The reactivity and stability of [(3-cyanopro-
pyl)diisopropylsilyl]acetylene is similar to that of the well-known
(triisopropylsilyl)acetylene. Its high polarity simplifies chromato-
graphic separation after coupling to aromatics with more than one core and one of these protecting groups can be selectively
reactive site. Moreover, compounds with more than one [(3-cyano-
removed, leading to a statistical mixture of bisacetylenes
propyl)diisopropylsilyl]acetylene group are easily purified after
partial deprotection.
protected at both positions, protected at one position, or
deprotected at both sites. The use of a polar protecting
group at the acetylene unit enables easy chromatographic
separation of the desired product from the byproducts of
Key words: alkynes, protecting groups, cross-coupling, oligomers,
phenylene–ethynylenes
this statistical reaction. This method has, for example,
been applied in the iterative synthesis of oligo(phenylene–
Alkynes are important structural elements in complex mo-
lecular structures of natural products and modern materi-
als.1 They are rigid, can be introduced relatively easily and
allow further functionalization. There are several method-
ologies for the preparation of alkynes, among which the
metal-catalyzed coupling reactions of a halide or triflate
compound and a protected acetylene have become more
and more attractive (Sonogashira–Hagihara coupling).2 A
variety of acetylenes with different protecting groups are
commercially available and allow fine tuning of the
deprotection conditions compatible with other functional
groups of the molecule. (Trialkylsilyl)alkynes, such as
(trimethylsilyl)acetylene (TMSA) or (triisopropylsil-
yl)acetylene (TIPSA) are often used because of easy
handling and the mild deprotection conditions.3
ethynylenes) by use of the hydroxymethyl (HOM) pro-
tecting group.7 The hydroxypropan-2-yl (2-HP) protect-
ing group has also been applied successfully to the
synthesis of a series of PPE-based (PPE = p-phenylene
ethynylene) oligomers containing metal-complexing
units.8 Unfortunately, both groups require cleaving condi-
tions that might be incompatible with the rest of the mol-
ecule.
The (3-cyanopropyl)dimethylsilyl (CPDMS) group com-
bines the mild cleaving conditions of the trimethylsilyl
group with the high polarity of hydroxy-containing pro-
tecting groups. By now, the one-pot reaction of TIPSA
and [(3-cyanopropyl)dimethylsilyl]acetylene (CPDMSA)
with diodoarenes and subsequent selective monodesilyla-
tion is a straightforward method towards monoprotected
bisacetylenes as building blocks for linear or cyclic oli-
gophenylene–ethynylenes.9 This protecting group has
also found application in the total synthesis of marine nat-
ural products.10 However, instead of connecting one acet-
ylene carrying a stable nonpolar group and another
acetylene carrying a less stable polar silyl-based protect-
ing group to the molecule, inverse polarity adjustment can
be helpful in some cases. Therefore, we prepared [(3-cy-
anopropyl)diisopropylsilyl]acetylene (1) (CPDIPSA), a
more stable analogue of CPDMSA (Scheme 1).
However, complex synthetic problems often require pro-
tecting groups not only with adapted stability but also
with appropriate polarity. For example, the O-protected
[dimethyl(oxy)propyl]silyl (DOPS) group combines po-
larity and orthogonality in its cleaving conditions in con-
trast to the trimethylsilyl and trimethylgermanyl groups.4
Polar acetylene protecting groups have also been used for
the preparation of defined phenylene–ethynylene oligo-
mers.5 Target compounds in those investigations are often
monoprotected bisacetylenes. They are available by palla-
dium-catalyzed stepwise coupling of bromo–iodo com-
pounds with two acetylenes protected with groups of
different stabilities and subsequent specific deprotection
of only one of these groups.6 Problems with this approach
arise when the starting compounds are difficult to access
or when the bromo position is insufficiently reactive.
NC
NC
MgBr
THF, reflux
73%
Si Cl
Si
1
Scheme 1
SYNTHESIS 2008, No. 14, pp 2155–2157
Advanced online publication: 18.06.2008
DOI: 10.1055/s-2008-1067141; Art ID: C01808SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8
As was shown for CPDMSA, the reactivity of CPDIPSA
(1) under Sonogashira–Hagihara conditions is compara-

2156
G. Gaefke, S. Höger
SHORT PAPER
1. CPDIPSA (1)
2. TMSA
THF, piperidine,
Pd(PPh3)2Cl2,
PPh3, CuI
TLC
PE–CH2Cl2 2:1
C6H13O
C6H13O
R1
R2
I
I
OC6H13
OC6H13
3 R1 = R2 = TMS
2
4 R1 = TMS, R2 = CPDIPS
5 R1 = R2 = CPDIPS
3
4
5
4
5
THF, MeOH,
K2CO3
90%
C6H13O
CN
Si
THF, 5 vol.% H2O,
TBAF
OC6H13
55%
6
Scheme 2
ble to that of other (trialkylsilyl)alkynes. A one-pot reac-
tion of diiodobenzene 2 with CPDIPSA (1) and TMSA
provides a statistical mixture of 3, 4, and 5 (Scheme 2).11
Owing to the highly polar cyano group of CPDIPS, the Rf
values of these compounds differ significantly, allowing
easy chromatographic separation of the three products
(see schematic TLC in Scheme 2), and thus 4 was isolated
in 40% yield.
Commercially available chemicals were used as received, unless
otherwise stated. THF was distilled from Na and piperidine from
CaH2. Microanalyses were performed on an Elementar Vario EL
analyzer. 1H and 13C NMR data were recorded on a Bruker AM 250
and a Bruker AM 400 spectrometer, respectively. Chemical shifts
are calibrated against solvent resonances. EI mass spectra were ob-
tained on an A.E.I MS-50 spectrometer. TLC was performed on
Marchery-Nagel Alugram SIL G/UV 254 precoated aluminum
sheets. Merck silica gel 60, 230–400 mesh ASTM was used for col-
umn chromatography. Radial chromatography was performed on a
Chromatotron (Harrison Research Europe); Merck silica gel 60 PF
254 containing gypsum was used.
The unsymmetrical bisacetylene 4 can be selectively
monodeprotected to give monoprotected bisacetylene 6 in
high yield (Scheme 2). Under mild, basic conditions
(K2CO3, MeOH) (trimethylsilyl)acetylenes are cleaved,
whereas [(3-cyanopropyl)diisopropylsilyl]acetylenes re-
main protected, as known from (triisopropylsilyl)acety-
lenes. In addition, we found that [(3-cyano-
propyl)diisopropylsilyl]acetylenes are ideally suited for
partial deprotection. The addition of small amounts of wa-
ter (5–10%) results in slower fluoride-induced desilyla-
tion, which can be monitored by TLC.12 In this way,
monoprotected bisacetylene 6 was obtained in 55% yield
from CPDIPS-diprotected 5 (Scheme 2). Monoprotected
bisacetylene 6 has already found application in the synthe-
sis of macrocycle-cladded molecular wires.13 In this case,
product purification by chromatography on silica gel was
simplified owing to the polarity of the protective groups
on the alkyne. Moreover, ongoing experiments prove that
the iterative synthesis of defined phenylene–butadiy-
[(3-Cyanopropyl)diisopropylsilyl]acetylene (CPDIPSA, 1)
A 0.5 M soln of ethynylmagnesium bromide in THF (162 mL, 81
mmol) was added over 1 h to a soln of CPDIPSCl (16 g, 74 mmol)
in THF (45 mL) at r.t. The mixture was heated to reflux and stirred
overnight. After the mixture had cooled to r.t., Et2O (200 mL), H2O
(100 mL), and a small amount of 1 M aq HCl were carefully added.
The organic layer was separated and extracted with H2O (3 × 50
mL) and brine (1 × 50 mL). After drying (MgSO4) of the organic
layer, the solvent was evaporated to leave a black oil, which was pu-
rified by vacuum distillation; this gave 1.
Yield: 11.13 g (73%); colorless oil; bp 81 °C/0.4 mbar.
1H NMR (250 MHz, CD2Cl2): d = 2.46 (s, 1 H), 2.39 (t, J = 7.0 Hz,
2 H), 1.86–1.73 (m, 2 H), 1.11–0.99 (m, 14 H), 0.81–0.72 (m, 2 H).
13C NMR (400 MHz, CDCl3): d = 119.63, 95.75, 85.24, 21.10,
20.73, 17.96, 17.74, 11.38, 9.34.
Anal. Calcd for C12H21NSi: C, 69.50; H, 10.21; N, 6.75. Found: C,
nylene oligomers can be performed comparatively easily 69.48; H, 9.93; N, 6.77.
when this stable and polar protective group is used.14
These results will be published soon in a different context.
1,4-Bis(hexyloxy)-2,5-bis(2-silylethynyl)benzenes 4 and 5
CPDIPSA (1; 782 mg, 3.77 mmol) was added by syringe to a soln
of [Pd(PPh3)2Cl2] (50 mg, 0.07 mmol), CuI (25 mg, 0.13 mmol),
Ph3P (50 mg, 0.19 mmol), and 1,4-bis(hexyloxy)-2,5-diiodoben-
zene (2; 2 g, 3.77 mmol) in THF (10 mL) and piperidine (5 mL). Af-
ter the mixture had stirred overnight, TMSA (555 mg, 5.66 mmol)
was added, and the mixture was heated to 50 °C and stirred for 2 h.
After cooling to r.t., the mixture was poured into Et2O (150 mL) and
H2O (50 mL). The organic layer was separated, washed with H2O (3
× 50 mL) and brine (1 × 50 mL), and dried (MgSO4). Product isola-
In summary, we have presented the preparation and the
application of a novel polar silylacetylene. Reactivity and
stability are similar to that of the well-known (triisopro-
pylsilyl)acetylene. In particular, the possibility of partial
deprotection under mild conditions should offer a simple
access to new complex molecular structures.
Synthesis 2008, No. 14, 2155–2157 © Thieme Stuttgart · New York

SHORT PAPER
[(3-Cyanopropyl)diisopropylsilyl]acetylene
2157
tion was performed by radial chromatography (PE–CH2Cl2, 3:1,
then 2:1, then 1:1); this gave 4 and 5 separately.
(m, 4 H), 1.38–1.25 (m, 9 H), 1.14–1.05 (m, 14 H), 0.93–0.89 (m, 6
H), 0.85–0.81 (m, 2 H).
13C NMR (400 MHz, CDCl3): d = 153.9, 119.7, 117.1, 113.0, 103.6,
95.3, 82.3, 79.9, 69.2, 31.6, 29.3, 25.7, 22.6, 21.3, 20.7, 18.2, 17.9,
14.0, 11.8.
1-{2-[(3-Cyanopropyl)diisopropylsilyl]ethynyl}-2,5-bis(hexyl-
oxy)-4-[2-(trimethylsilyl)ethynyl]benzene (4)
Yield: 880 mg (40%); pale yellow solid; Rf = 0.25 (PE–CH2Cl2,
2:1).
MS (EI, 70 eV): m/z = 507.3 [M]+.
1H NMR (400 MHz, CDCl3): d = 6.88 (s, 1 H), 6.87 (s, 1 H), 3.97–
3.91 (m, 4 H), 2.42 (t, J = 7.0 Hz, 2 H), 1.91–1.85 (m, 4 H), 1.54–
1.42 (m, 4 H), 1.38–1.29 (m, 8 H), 1.17–1.06 (m, 14 H), 0.92–0.87
(m, 6 H), 0.85–0.80 (m, 2 H).
13C NMR (400 MHz, CDCl3): d = 120.13, 117.87, 116.96, 114.48,
113.97, 103.99, 101.44, 100.42, 95.70, 69.99, 69.64, 31.99, 31.98,
29.73, 29.70, 26.13, 26.06, 23.03, 23.02, 21.69, 21.05, 18.36, 18.12,
14.22, 12.16, 9.97, –0.04.
Acknowledgment
Financial support from the Volkswagen-Stiftung is gratefully
acknowledged.
References
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MS (EI, 70 eV): m/z = 579.4 [M]+.
1,4-Bis{2-[(3-cyanopropyl)diisopropylsilyl]ethynyl}-2,5-
bis(hexyloxy)benzene (5)
Yield: 675 mg (26%); pale yellow solid; Rf = 0.08 (PE–CH2Cl2,
2:1).
1H NMR (400 MHz, CDCl3): d = 6.86 (s, 2 H), 3.95 (t, J = 6.4 Hz,
4 H), 2.42 (t, J = 7.0 Hz, 4 H), 1.92–1.84 (m, 4 H), 1.81–1.73 (m, 4
H), 1.51–1.44 (m, 4 H), 1.38–1.33 (m, 8 H), 1.13–1.06 (m, 28 H),
0.92–0.89 (m, 6 H), 0.85–0.81 (m, 4 H).
13C NMR (400 MHz, CDCl3): d = 154.01, 119.74, 116.84, 113.71,
103.81, 95.17, 69.24, 31.61, 29.35, 25.75, 22.62, 21.26, 20.73,
18.21, 17.97, 14.05, 11.77, 9.61.
MS (EI, 70 eV): m/z = 688.5 [M]+.
1-{2-[(3-Cyanopropyl)diisopropylsilyl]ethynyl}-4-ethynyl-2,5-
bis(hexyloxy)benzene (6)
Method A (from 4): K2CO3 (812 mg, 5.88 mmol) was added to a soln
of 4 (850 mg, 1.47 mmol) in THF (5 mL) and MeOH (5 mL). The
mixture was stirred for 2 h at r.t. and then poured into Et2O (100
mL) and H2O (100 mL). The organic layer was separated, washed
with H2O (3 × 30 mL) and brine (1 × 30 mL), and dried (MgSO4).
Filtration of the crude product through a short column (silica gel,
PE–CH2Cl2, 2:1; Rf = 0.36) gave 6.
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2802.
Yield: 620 mg (83%); pale yellow solid.
(11) Compound 3 was isolated and characterized. Its NMR
spectra correspond to literature data. See, for example:
(a) Giesa, R.; Schulz, R. C. Makromol. Chem. 1990, 191,
857. (b) Zhou, C.-Z.; Liu, T.; Xu, J.-M.; Chen, Z.-K.
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(13) Becker, K.; Lagoudakis, P. G.; Gaefke, G.; Höger, S.;
Lupton, J. M. Angew. Chem. 2007, 119, 3520.
Method B (from 5): A 1 M soln of TBAF in THF (104 mL, 0.104
mmol) was added to a soln of 5 (80 mg, 0.116 mmol) in THF (3.5
mL) and H2O (175 mL) at 0 °C. The mixture was stirred at r.t., while
conversion was followed by TLC. After 6 h, the reaction was
stopped by the addition of H2O (10 mL) and the mixture was poured
into Et2O (50 mL). The organic layer was separated, washed with
H2O (3 × 20 mL) and brine (1 × 20 mL), and dried (MgSO4). Prod-
uct isolation by column chromatography (silica gel, PE–CH2Cl2,
2:1, then 1:1) gave 6.
Yield: 32 mg (55%); pale yellow solid.
1H NMR (400 MHz, CDCl3): d = 6.91 (s, 1 H), 6.90 (s, 1 H), 3.99
(t, J = 6.6 Hz, 2 H), 3.93 (t, J = 6.5 Hz, 2 H), 3.33 (s, 1 H), 2.42 (t,
J = 7.0 Hz, 2 H), 1.92–1.84 (m, 2 H), 1.81–1.73 (m, 4 H), 1.51–1.43
(14) For a recent approach towards phenylene–butadiynylene
oligomers, see: Li, W.-S.; Jiang, D.-L.; Aida, T. Angew.
Chem. 2004, 116, 3003.
Synthesis 2008, No. 14, 2155–2157 © Thieme Stuttgart · New York