Synthesis of 4-silapiperidine building blocks with N-H groups using the Staudinger reaction

Article abstract of DOI:10.1021/om400873w

4-Silapiperidines are important skeletons for drug design. In this context, a novel acid-free method for the synthesis of 4-silapiperidine building blocks with N-H groups has been developed, using the Staudinger reaction as the key step. As a proof of principle, the model compounds 13 and 14 were synthesized, starting from Ph₂SiCl₂ and MeSi(OMe)₃, respectively.

Full text of DOI:10.1021/om400873w

Article
pubs.acs.org/Organometallics
Synthesis of 4‑Silapiperidine Building Blocks with N−H Groups Using
the Staudinger Reaction
Markus Fischer and Reinhold Tacke*
Institut fur Anorganische Chemie, Universitat Wurzburg, Am Hubland, D-97074 Wurzburg, Germany
̈
̈
̈
̈
S
* Supporting Information
ABSTRACT: 4-Silapiperidines are important skeletons for drug design. In this context,
a novel acid-free method for the synthesis of 4-silapiperidine building blocks with N−H
groups has been developed, using the Staudinger reaction as the key step. As a proof of
principle, the model compounds 13 and 14 were synthesized, starting from Ph2SiCl2
and MeSi(OMe)3, respectively.
INTRODUCTION
■
Silicon chemistry has been demonstrated to be a valuable tool
in drug design.1 The carbon/silicon switch strategy (C/Si
exchange, sila substitution) is one of the methods that are
currently used for the development of novel silicon-based
drugs. In this context, a series of silicon compounds with a 4-
silapiperidine skeleton have been synthesized and pharmaco-
logically characterized,2 such as sila-budipine (1),2a,b sila-
haloperidol (2),2d,e,g sila-panamesine (3),2f sila-trifluperidol
(4),2h and σ-receptor ligands of the 1,4′-silaspiro[indane-1,4′-
piperidine] (5−8)2c and 1,2,3,4-tetrahydro-1,4′-silaspiro-
[naphthalene-1,4′-piperidine] type (9−12).2i
Most of the 4-silapiperidines described in the literature are
N-alkyl-substituted compounds, whereas only a few derivatives
with N−H groups (or their hydrochlorides) have been
reported.2,3 4-Silapiperidines of the formula type B can be
synthesized by treatment of silanes A with the corresponding
organylamines H2NR3 (Scheme 1). Suitable Si−R2 moieties
Scheme 1. Synthesis of 4-Silapiperidines B
Compounds 13 and 14 represent building blocks for synthesis
that contain both reactive Si−aryl and N−H groups.
then allow subsequent Si−C cleavage reactions to generate Si-
functional 4-silapiperidines.2d−h,4 In addition, suitable N−R3
groups can be used for subsequent transformations of the type
N−R3 → N−H.3 However, as the latter transformations are
performed under acidic conditions, this synthetic strategy has
some limitations with respect to acid-sensitive Si−R1 and Si−R2
moieties. To overcome this problem, we have developed an
alternative preparative method for the synthesis of 4-
silapiperidines with N−H groups that avoids acid conditions.
As a proof of principle, we have synthesized the 4-
silapiperidines 13 and 14 using the Staudinger reaction.5
RESULTS AND DISCUSSION
■
Syntheses. 4,4-Diphenyl-4-silapiperidine (13) was prepared
according to Scheme 2, starting from dichlorodiphenylsilane
(15), and was isolated as the hydrochloride 13·HCl (7% total
yield). Thus, treatment of 15 with vinylmagnesium bromide in
Received: August 30, 2013
Published: November 12, 2013
© 2013 American Chemical Society
7181
dx.doi.org/10.1021/om400873w | Organometallics 2013, 32, 7181−7185

Organometallics
Article
Scheme 3. Synthesis of Compound 14 (Isolated as 14·HCl)
Scheme 2. Synthesis of Compound 13 (Isolated as 13·HCl)
4-(4-Methoxyphenyl)-4-methyl-4-silapiperidine (14) was
synthesized according to Scheme 3, starting from trimethoxy-
methylsilane (21), and was isolated as the hydrochloride 14·
HCl (5% total yield). Thus, reaction of 21 with (4-
methoxyphenyl)magnesium bromide in tetrahydrofuran af-
forded dimethoxy(4-methoxyphenyl)methylsilane (22; 71%
yield), which upon treatment with vinylmagnesium chloride
in tetrahydrofuran gave (4-methoxyphenyl)methyldivinylsilane
(23; 70% yield). Reaction of 23 with 9-borabicyclo[3.3.1]-
nonane in tetrahydrofuran, followed by sequential treatment
with aqueous solutions of sodium hydroxide and hydrogen
peroxide, afforded bis(2-hydroxyethyl)(4-methoxyphenyl)-
methylsilane (24; 74% yield), which upon reaction with
methanesulfonyl chloride in dichloromethane, in the presence
of triethylamine, gave bis(2-((methylsulfonyl)oxy)ethyl)(4-
methoxyphenyl)methylsilane (25; 69% yield). Treatment of
25 with sodium azide in N,N-dimethylformamide provided a
mixture of (2-azidoethyl)(4-methoxyphenyl)methyl(2-
((methylsulfonyl)oxy)ethyl)silane (26) and bis(2-azidoethyl)-
tetrahydrofuran afforded diphenyldivinylsilane (16),6 which
upon reaction with 9-borabicyclo[3.3.1]nonane (9-BBN) in
tetrahydrofuran, followed by sequential treatment with aqueous
solutions of sodium hydroxide and hydrogen peroxide, yielded
bis(2-hydroxyethyl)diphenylsilane (17; 81% yield). Reaction of
17 with methanesulfonyl chloride in dichloromethane, in the
presence of triethylamine, gave bis(2-((methylsulfonyl)oxy)-
ethyl)diphenylsilane (18; 68% yield). Treatment of 18 with
sodium azide in N,N-dimethylformamide provided a mixture of
2-azidoethyl(2-((methylsulfonyl)oxy)ethyl)diphenylsilane (19)
and bis(2-azidoethyl)diphenylsilane (20), which could be
separated by column chromatography. Subsequent treatment
of 19 with triphenylphosphine in dichloromethane afforded
compound 13, which upon reaction with hydrogen chloride in
diethyl ether afforded 13·HCl (16% yield, with respect to 18;
for an alternative synthesis of 13·HCl, see ref 3).
7182
dx.doi.org/10.1021/om400873w | Organometallics 2013, 32, 7181−7185

Organometallics
Article
mixture was then stirred at 20 °C for 16 h. The solvent was removed
under reduced pressure, the residue was dissolved in diethyl ether (15
mL), and the solution was kept undisturbed at −20 °C for 16 h. The
resulting precipitate was removed by centrifugation (16000g, 5 min, 20
°C), and the supernatant was cooled to 0 °C, followed by dropwise
addition of a 1 M solution of hydrogen chloride in diethyl ether (600
μL, 600 μmol of HCl) within 5 min (formation of a precipitate). The
resulting mixture was then kept undisturbed at 0 °C for 16 h, and the
precipitate was isolated by centrifugation (16000g, 5 min, 20 °C),
washed with diethyl ether (3 × 5 mL), and recrystallized from
methanol (slow cooling of a saturated boiling solution to −20 °C).
The product was isolated by filtration and dried in vacuo (0.005 mbar,
20 °C, 5 h) to give 13·HCl in 16% yield as a colorless crystalline solid
(55.2 mg, 190 μmol); mp 223−224 °C. 1H NMR (500.1 MHz,
CDCl3): δ 1.68−1.76 (m, 4 H; SiCH2CH2), 3.37−3.46 (m, 4 H;
SiCH2CH2), 7.35−7.43 (m, 4 H; H-3/H-5, C6H5), 7.36−7.45 (m, 2 H;
H-4, C6H5), 7.51−7.56 (m, 4 H; H-2/H-6, C6H5), 9.6 ppm (br s, 2 H;
NH2). 13C NMR (125.8 MHz, CDCl3): δ 9.0 (SiCH2CH2N), 44.2
(SiCH2CH2N), 128.4 (C-3/C-5, C6H5), 130.4 (C-4, C6H5), 131.9 (C-
1, C6H5), 134.6 ppm (C-2/C-6, C6H5). 29Si NMR (99.4 MHz,
CDCl3): δ −16.9 ppm. Anal. Calcd for C16H20ClNSi: C, 66.30; H,
6.95; N, 4.83. Found: C, 66.54; H, 7.11; N, 4.92.
(4-methoxyphenyl)methylsilane (27), which could be separated
by column chromatography. Subsequent treatment of 28 with
triphenylphosphine in dichloromethane afforded compound 14,
which upon reaction with hydrogen chloride in diethyl ether
afforded 14·HCl (18% yield, with respect to 25).
With the synthesis of compounds 13 and 14 via the
Staudinger reaction, the synthetic potential of this new acid-free
method for the preparation of 4-silapiperidines with N−H
groups has been demonstrated. Although compounds 13 and
14 were isolated as hydrochlorides in this study, their isolation
as free amines by bulb-to-bulb distillation is also possible. This
comes especially into effect when acid-labile groups are present
in the target molecule.
EXPERIMENTAL SECTION
■
General Procedures. All syntheses in organic solvents were
carried out under dry argon. The organic solvents used were dried and
purified according to standard procedures and stored under dry argon.
Starting materials and reagents were purchased from ABCR, Acros, or
Aldrich and were used without further purification. Bulb-to-bulb
4-(4-Methoxyphenyl)-4-methyl-4-silapiperidinium Chloride
(14·HCl). Sodium azide (343 mg, 5.28 mmol) was added in a single
portion at 20 °C to a stirred solution of 25 (2.09 g, 5.27 mmol) in
N,N-dimethylformamide (100 mL), and the mixture was then stirred
at 20 °C for 16 h. The solvent was removed under reduced pressure,
and the residue was purified by column chromatography on silica gel
(40−65 μm; eluent n-hexane/ethyl acetate/triethylamine (13/7/1 v/
v/v)). The relevant fractions were combined, and the solvent was
removed under reduced pressure to give the byproduct 27 as a
colorless oil (purity ca. 99%)7 (1H NMR (300.1 MHz, [D6]DMSO): δ
0.31 (s, 3 H; SiCH3), 1.12−1.24 (m, 4 H; SiCH2CH2N), 3.21−3.41
(m, 4 H; SiCH2CH2N), 3.75 (s, 3 H; C6H4OCH3), 6.90−7.00 (m, 2
H; H-3/H-5, C6H4OCH3), 7.39−7.50 ppm (m, 2 H; H-2/H-6,
C6H4OCH3). 13C NMR (75.5 MHz, [D6]DMSO): δ −5.2 (SiCH3),
13.7 (SiCH2CH2N), 47.2 (SiCH2CH2N), 54.8 (C6H4OCH3), 113.8
(C-3/C-5, C6H4OCH3), 125.9 (C-1, C6H4OCH3), 135.1 (C-2/C-6,
C6H4OCH3), 160.4 ppm (C-4, C6H4OCH3). 29Si NMR (59.6 MHz,
[D6]DMSO): δ − 4.8 ppm) and compound 26 as a colorless oil
(purity ca. 96%)7 (1H NMR (500.1 MHz, [D6]DMSO): δ 0.33 (s, 3
H; SiCH3), 1.16−1.24 (m, 2 H; SiCH2CH2N), 1.32−1.42 (m, 2 H;
SiCH2CH2O), 3.10 (s, 3 H; SCH3), 3.24−3.36 (m, 2 H;
SiCH2CH2N), 3.75 (s, 3 H; C6H4OCH3), 4.19−4.31 (m, 2 H;
SiCH2CH2O), 6.90−6.99 (m, 2 H; H-3/H-5, C6H4OCH3), 7.42−7.48
ppm (m, 2 H; H-2/H-6, C6H4OCH3). 13C NMR (125.8 MHz,
[D6]DMSO): δ −5.0 (SiCH3), 13.8 (SiCH2CH2N), 15.6
(SiCH2CH2O), 36.8 (SCH3), 47.1 (SiCH2CH2N), 54.9
(C6H4OCH3), 69.0 (SiCH2CH2O), 113.9 (C-3/C-5, C6H4OCH3),
125.7 (C-1, C6H4OCH3), 135.2 (C-2/C-6, C6H4OCH3), 160.5 ppm
(C-4, C6H4OCH3). 29Si NMR (99.4 MHz, [D6]DMSO): δ −6.5 ppm).
Subsequently, compound 26 was dissolved in tetrahydrofuran (20
mL), triphenylphosphine (840 mg, 3.20 mmol) was added in a single
portion, and the mixture was then stirred at 20 °C for 16 h. The
solvent was removed under reduced pressure, the residue was
dissolved in diethyl ether (20 mL), and the solution was kept
undisturbed at −20 °C for 16 h. The resulting precipitate was removed
by centrifugation (16000g, 5 min, 20 °C), and the supernatant was
cooled to 0 °C, followed by dropwise addition of a 1 M solution of
hydrogen chloride in diethyl ether (1.60 mL, 1.60 mmol of HCl)
within 5 min (formation of a precipitate). The resulting mixture was
then kept undisturbed at 0 °C for 16 h, and the precipitate was isolated
by centrifugation (16000g, 5 min, 20 °C), washed with diethyl ether (3
× 10 mL), and recrystallized from 2-propanol (slow cooling of a
saturated boiling solution to −20 °C). The product was isolated by
filtration and dried in vacuo (0.005 mbar, 20 °C, 5 h) to give 14·HCl
in 18% yield as a colorless crystalline solid (247 mg, 958 μmol); mp
236−237 °C. 1H NMR (500.1 MHz, CDCl3): δ 0.37 (s, 3 H; SiCH3),
1.22−1.32 and 1.42−1.52 (m, 4 H; SiCH2CH2), 3.31−3.42 (m, 4 H;
SiCH2CH2), 3.79 (s, 3 H; C6H4OCH3), 6.89−6.93 (m, 2 H; H-3/H-5,
distillations were performed by using a Buchi GKR-50 glass oven
̈
apparatus. Melting points were determined with a Buchi B-540 melting
̈
1
point apparatus using samples in open glass capillaries. The H, 13C,
and 29Si NMR spectra were recorded at 23 °C on a Bruker DRX-300
(1H, 300.1 MHz; 13C, 75.5 MHz; 29Si, 59.6 MHz) or Bruker Avance
500 NMR spectrometer (1H, 500.1 MHz; 13C, 125.8 MHz; 29Si, 99.4
MHz) using [D6]DMSO, C6D6, CDCl3, or CD2Cl2 as the solvent.
Chemical shifts (ppm) were determined relative to internal
[D5]DMSO (1H, δ 2.49 ppm; [D6]DMSO), C6HD5 (1H, δ 7.28
ppm; C6D6), CHCl3 (1H, δ 7.24 ppm; CDCl3), CHDCl2 (1H, δ 5.32
ppm; CD2Cl2), [D6]DMSO (13C, δ 39.5 ppm; [D6]DMSO), C6D6
(13C, δ 128.0 ppm; C6D6), CDCl3 (13C, δ 77.0 ppm; CDCl3), CD2Cl2
(13C, δ 53.8 ppm; CD2Cl2), or external TMS (29Si, δ 0 ppm;
[D6]DMSO, C6D6, CDCl3, CD2Cl2). Analysis and assignment of the
1H and 13C NMR spectroscopic data was supported by 1H,1H gradient
selected COSY along with 13C,1H gradient selected HMQC and
HMBC experiments. Assignment of the 13C NMR spectroscopic data
was additionally supported by DEPT 135 experiments. Coupling
constants are given as their absolute values. Elemental analyses were
performed by using a VarioMicro apparatus (Elementar Analysensys-
teme GmbH) or a EURO EA Elemental Analyzer (EuroVector).
4,4-Diphenyl-4-silapiperidinium Chloride (13·HCl). Sodium
azide (75.0 mg, 1.15 mmol) was added in a single portion at 20 °C to a
stirred solution of 18 (500 mg, 1.17 mmol) in N,N-dimethylform-
amide (15 mL), and the mixture was then stirred at 20 °C for 16 h.
The solvent was removed under reduced pressure, and the residue was
purified by column chromatography on silica gel (40−65 μm; eluent n-
hexane/ethyl acetate/triethylamine (13/7/1 v/v/v)). The relevant
fractions were combined, and the solvent was removed under reduced
pressure to give the byproduct 20 as a colorless solid (purity ca. 95%)7
(1H NMR (500.1 MHz, CD2Cl2): δ 1.53−1.59 (m, 4 H;
SiCH2CH2N), 3.31−3.38 (m, 4 H; SiCH2CH2N), 7.38−7.45 (m, 4
H; H-3/H-5, C6H5), 7.40−7.48 (m, 4 H; H-2/H-6, C6H5), 7.49−7.53
ppm (m, 2 H; H-4, C6H5). 13C NMR (125.8 MHz, CD2Cl2): δ 13.4
(SiCH2CH2), 48.0 (SiCH2CH2), 128.6 (C-3/C-5, C6H5), 130.3 (C-4,
C6H5), 133.6 (C-1, C6H5), 135.1 ppm (C-2/C-6, C6H5). 29Si NMR
(99.4 MHz, CD2Cl2): δ −9.4 ppm) and compound 19 as a colorless
solid (purity ca. 97%)7 (1H NMR (500.1 MHz, CD2Cl2): δ 1.56−1.62
(m, 2 H; SiCH2CH2N), 1.77−1.83 (m, 2 H; SiCH2CH2O), 2.88 (s, 3
H; SCH3), 3.34−3.41 (m, 2 H; SiCH2CH2N), 4.30−4.36 (m, 2 H;
SiCH2CH2O), 7.40−7.48 (m, 4 H; H-3/H-5, C6H5), 7.42−7.50 (m, 2
H; H-4, C6H5), 7.51−7.56 ppm (m, 4 H; H-2/H-6, C6H5). 13C NMR
(125.8 MHz, CD2Cl2): δ 13.5 (SiCH2CH2N), 15.3 (SiCH2CH2O),
37.7 (SCH3), 47.9 (SiCH2CH2N), 68.6 (SiCH2CH2O), 128.7 (C-3/C-
5, C6H5), 130.5 (C-4, C6H5), 133.2 (C-1, C6H5), 135.0 ppm (C-2/C-6,
C6H5). 29Si NMR (99.4 MHz, CD2Cl2): δ −10.2 ppm). Subsequently,
compound 19 was dissolved in tetrahydrofuran (10 mL), triphenyl-
phosphine (252 mg, 961 μmol) was added in a single portion, and the
7183
dx.doi.org/10.1021/om400873w | Organometallics 2013, 32, 7181−7185

Organometallics
Article
C6H4OCH3), 7.43−7.47 (m, 2 H; H-2/H-6, C6H4OCH3), 9.4 ppm (br
s, 2 H; NH2). 13C NMR (125.8 MHz, CDCl3): δ −4.7 (SiCH3), 10.2
(SiCH2CH2), 44.2 (SiCH2CH2), 55.1 (C6H4OCH3), 114.1 (C-3/C-5,
C6H4OCH3), 124.6 (C-1, C6H4OCH3), 135.2 (C-2/C-6, C6H4OCH3),
161.2 ppm (C-4, C6H4OCH3). 29Si NMR (99.4 MHz, CDCl3): δ
−12.8 ppm. Anal. Calcd for C12H20ClNOSi: C, 55.90; H, 7.82; N,
5.43. Found: C, 55.77; H, 8.13; N, 5.54.
Dichlorodiphenylsilane (15). This compound was commercially
available.
Diphenyldivinylsilane (16). This compound was synthesized
according to ref 6.
231 mmol) in diethyl ether (150 mL)) was added dropwise at 20 °C
within 30 min to a stirred solution of 21 (30.0 g, 220 mmol) in diethyl
ether (150 mL), and the reaction mixture was then stirred at 20 °C for
16 h. The resulting precipitate was filtered off, washed with diethyl
ether (3 × 100 mL), and discarded. The filtrate and wash solutions
were combined, and the solvents were removed under reduced
pressure. The residue was purified by fractional distillation in vacuo to
give 22 in 71% yield as a colorless liquid (33.3 g, 157 mmol); bp 61
°C/0.3 mbar. 1H NMR (500.1 MHz, CD2Cl2): δ 0.32 (s, 3 H; SiCH3),
3.54 (s, 6 H; OCH3), 3.82 (s, 3 H; C6H4OCH3), 6.92−6.97 (m, 2 H;
H-3/H-5, C6H4OCH3), 7.52−7.57 ppm (m, 2 H; H-2/H-6,
C6H4OCH3). 13C NMR (125.8 MHz, CD2Cl2): δ −5.0 (SiCH3),
50.6 (OCH3), 55.4 (C6H4OCH3), 113.9 (C-3/C-5, C6H4OCH3),
125.5 (C-1, C6H4OCH3), 136.0 (C-2/C-6, C6H4OCH3), 161.7 ppm
(C-4, C6H4OCH3). 29Si NMR (99.4 MHz, CD2Cl2): δ −14.3 ppm.
Anal. Calcd for C10H16O3Si: C, 56.57; H, 7.60. Found: C, 56.51; H,
7.66.
Bis(2-hydroxyethyl)diphenylsilane (17). 9-Borabicyclo[3.3.1]-
nonane (22.8 g, 93.4 mmol of 9-BBN dimer) was added in a single
portion at 20 °C to a stirred solution of 16 (20.1 g, 85.0 mmol) in
tetrahydrofuran (150 mL), and the resulting mixture was stirred at 20
°C for 16 h. The reaction mixture was then treated sequentially at 20
°C with water (25 mL) and a 3 M aqueous solution of sodium
hydroxide (65 mL, 195 mmol of NaOH). Subsequently, an aqueous
solution of hydrogen peroxide (30 wt %, 71 mL) was added dropwise
at 0 °C within 30 min, and the mixture was then heated under reflux
for 3 h. The reaction mixture was cooled to 20 °C, water (200 mL)
was added, the organic layer was separated, and the aqueous layer was
extracted with dichloromethane (4 × 100 mL). The combined organic
phases were dried over anhydrous sodium sulfate, and the organic
solvents were removed under reduced pressure. The byproduct,
cyclooctane-1,5-diol, was removed from the crude product by bulb-to-
bulb distillation (150 °C at 0.01 mbar), and the residue was
crystallized from n-hexane/ethyl acetate/ethanol (5/2/1 v/v/v; slow
cooling of a saturated boiling solution to 20 °C). The product was
isolated by filtration and dried in vacuo (0.005 mbar, 20 °C, 4 h) to
give 17 in 81% yield as a colorless crystalline solid (18.8 g, 69.0
mmol); mp 83 °C. 1H NMR (500.1 MHz, CD2Cl2): δ 1.52−1.58 (m,
4 H; SiCH2CH2), 2.33 (br s, 2 H; OH), 3.74−3.80 (m, 4 H;
SiCH2CH2), 7.33−7.41 (m, 4 H; H-3/H-5, C6H5), 7.35−7.43 (m, 2 H;
H-4, C6H5), 7.50−7.55 ppm (m, 4 H; H-2/H-6, C6H5). 13C NMR
(125.8 MHz, CD2Cl2): δ 18.3 (SiCH2CH2), 59.5 (SiCH2CH2), 128.3
(C-3/C-5, C6H5), 129.8 (C-4, C6H5), 135.0 (C-2/C-6, C6H5), 135.7
ppm (C-1, C6H5). 29Si NMR (99.4 MHz, CD2Cl2): δ −10.3 ppm.
Anal. Calcd for C16H20O2Si: C, 70.54; H, 7.40. Found: C, 70.56; H,
7.76.
Bis(2-((methylsulfonyl)oxy)ethyl)diphenylsilane (18). Meth-
anesulfonyl chloride (4.42 g, 38.6 mmol) was added dropwise over a
period of 45 min at −30 °C to a stirred solution of 17 (5.00 g, 18.4
mmol) and triethylamine (3.92 g, 38.7 mmol) in dichloromethane
(100 mL), and the mixture was then stirred at −30 °C for 30 min. The
reaction mixture was warmed to 20 °C within 30 min and then stirred
at this temperature for 10 min. Subsequently, n-pentane (90 mL) was
added, the precipitate was filtered off, washed with diethyl ether (3 ×
20 mL), and discarded, and the combined organic phases were dried
over anhydrous sodium sulfate. The solvents were removed under
reduced pressure, and the residue was purified by column
chromatography on silica gel (40−65 μm; eluent n-hexane/ethyl
acetate (1/1 v/v)). The relevant fractions were combined, the solvent
was removed under reduced pressure, and the residue was dried in
vacuo (0.001 mbar, 20 °C, 3 h) to give 18 in 68% yield as a colorless
oil, which solidified within 1 day at −20 °C (5.38 g, 12.6 mmol); mp
83 °C. 1H NMR (500.1 MHz, CD2Cl2): δ 1.77−1.84 (m, 4 H;
SiCH2CH2), 2.88 (s, 6 H; SCH3), 4.31−4.37 (m, 4 H; SiCH2CH2),
7.40−7.48 (m, 4 H; H-3/H-5, C6H5), 7.43−7.50 (m, 2 H; H-4, C6H5),
7.51−7.56 ppm (m, 4 H; H-2/H-6, C6H5). 13C NMR (125.8 MHz,
CD2Cl2): δ 15.3 (SiCH2CH2), 37.7 (SCH3), 68.4 (SiCH2CH2), 128.8
(C-3/C-5, C6H5), 130.7 (C-4, C6H5), 132.8 (C-1, C6H5), 135.0 ppm
(C-2/C-6, C6H5). 29Si NMR (99.4 MHz, CD2Cl2): δ −11.0 ppm. Anal.
Calcd for C18H24O6S2Si: C, 50.44; H, 5.64; S, 14.96. Found: C, 50.51;
H, 5.81; S, 15.23.
(4-Methoxyphenyl)methyldivinylsilane (23). A solution of
vinylmagnesium chloride (15 wt %, d = 0.97 g mL−1; 236 mL, 396
mmol of CH2CHMgCl) in tetrahydrofuran was added dropwise at
20 °C within 30 min to a stirred solution of 22 (40.0 g, 188 mmol) in
tetrahydrofuran (100 mL), and the reaction mixture was heated under
reflux for 1 h. The mixture was then cooled to 20 °C, followed by the
addition of n-pentane (50 mL). The resulting precipitate was filtered
off, washed with diethyl ether (3 × 100 mL), and discarded. The
filtrate and wash solutions were combined, and the solvents were
removed under reduced pressure. The residue was purified by
fractional distillation in vacuo to give 23 in 70% yield as a colorless
liquid (26.9 g, 132 mmol); bp 62 °C/0.2 mbar. 1H NMR (500.1 MHz,
CD2Cl2): δ 0.41 (s, 3 H; SiCH3), 3.80 (s, 3 H; C6H4OCH3), 5.78 (δA),
6.12 (δM), and 6.32 (δX) (6 H; CHXCHAHM, 3JAX = 20.3 Hz, 2JAM
=
3
3.8 Hz, JMX = 14.6 Hz), 6.90−6.94 (m, 2 H; H-3/H-5, C6H4OCH3),
7.43−7.48 ppm (m, 2 H; H-2/H-6, C6H4OCH3). 13C NMR (125.8
MHz, CD2Cl2): δ −4.4 (SiCH3), 55.4 (C6H4OCH3), 113.9 (C-3/C-5,
C6H4OCH3), 127.4 (C-1, C6H4OCH3), 134.2 (SiCHCH2), 136.2
(C-2/C-6, C6H4OCH3), 136.7 (SiCHCH2), 161.1 ppm (C-4,
C6H4OCH3). 29Si NMR (99.4 MHz, CD2Cl2): δ −18.1 ppm. Anal.
Calcd for C12H16OSi: C, 70.53; H, 7.89. Found: C, 70.52; H, 7.87.
Bis(2-hydroxyethyl)(4-methoxyphenyl)methylsilane (24). 9-
Borabicyclo[3.3.1]nonane (16.1 g, 66.0 mmol of 9-BBN dimer) was
added in a single portion at 20 °C to a stirred solution of 23 (12.8 g,
62.6 mmol) in tetrahydrofuran (90 mL), and the resulting mixture was
stirred at 20 °C for 16 h. The reaction mixture was then treated
sequentially at 20 °C with water (11 mL) and a 3 M aqueous solution
of sodium hydroxide (45.0 mL, 135 mmol of NaOH). Subsequently,
an aqueous solution of hydrogen peroxide (30 wt %, 45.0 mL) was
added dropwise at 0 °C within 20 min, and the mixture was then
heated under reflux for 2 h. The reaction mixture was cooled to 20 °C,
water was added (150 mL), the organic layer was separated, and the
aqueous layer was extracted with dichloromethane (3 × 100 mL). The
combined organic phases were dried over anhydrous sodium sulfate,
and the organic solvents were removed under reduced pressure. The
byproduct, cyclooctane-1,5-diol, was removed from the crude product
by bulb-to-bulb distillation (150 °C at 0.01 mbar), and the residue was
crystallized from n-hexane/ethyl acetate/ethanol (5/2/1 v/v/v; slow
cooling of a saturated boiling solution to 20 °C). The product was
isolated by filtration and dried in vacuo (0.005 mbar, 20 °C, 5 h) to
give 24 in 74% yield as a colorless crystalline solid (11.2 g, 46.6
1
mmol); mp 48 °C. H NMR (500.1 MHz, C6D6): δ 0.39 (s, 3 H;
SiCH3), 1.22−1.37 (m, 4 H; SiCH2CH2), 2.86 (br s, 2 H; OH), 3.47
(s, 3 H; C6H4OCH3), 3.78−3.89 (m, 4 H; SiCH2CH2), 6.97−7.02 (m,
2 H; H-3/H-5, C6H4OCH3), 7.50−7.56 ppm (m, 2 H; H-2/H-6,
C6H4OCH3). 13C NMR (125.8 MHz, C6D6): δ −4.0 (SiCH3), 19.9
(SiCH2CH2), 54.6 (C6H4OCH3), 59.4 (SiCH2CH2), 114.1 (C-3/C-5,
C6H4OCH3), 128.6 (C-1, C6H4OCH3), 135.6 (C-2/C-6, C6H4OCH3),
161.1 ppm (C-4, C6H4OCH3). 29Si NMR (99.4 MHz, C6D6): δ −5.9
ppm. Anal. Calcd for C12H20O3Si: C, 59.96; H, 8.39. Found: C, 60.21;
H, 8.35.
Trimethoxymethylsilane (21). This compound was commercially
available.
Dimethoxy(4-methoxyphenyl)methylsilane (22). A solution of
(4-methoxyphenyl)magnesium bromide (prepared from magnesium
turnings (5.61 g, 231 mmol) and 1-bromo-4-methoxybenzene (43.2 g,
Bis(2-((methylsulfonyl)oxy)ethyl)(4-methoxyphenyl)-
methylsilane (25). Methanesulfonyl chloride (2.00 g, 17.5 mmol)
7184
dx.doi.org/10.1021/om400873w | Organometallics 2013, 32, 7181−7185

Organometallics
Article
was added dropwise over a period of 30 min at −30 °C to a stirred
solution of 24 (2.00 g, 8.32 mmol) and triethylamine (8.42 g, 83.2
mmol) in dichloromethane (80 mL), and the mixture was then stirred
at −30 °C for 30 min. The reaction mixture was warmed to 20 °C
within 30 min and then stirred at this temperature for 10 min.
Subsequently, n-pentane (40 mL) was added, the precipitate was
filtered off, washed with diethyl ether (3 × 20 mL), and discarded, and
the combined organic phases were dried over anhydrous sodium
sulfate. The solvents were removed under reduced pressure, and the
residue was purified by column chromatography on silica gel (40−65
μm; eluent n-hexane/ethyl acetate (1/1 v/v)). The relevant fractions
were combined, the solvent was removed under reduced pressure, and
the residue was dried in vacuo (0.001 mbar, 20 °C, 3 h) to give 25 in
Burschka, C.; Dorrich, S.; Fischer, M.; Muller, B.; Meyerhans, G.;
̈
̈
Schepmann, D.; Wunsch, B.; Arnason, I.; Bjornsson, R. ChemMed-
̈
Chem 2012, 7, 523−532.
(3) Heinrich, T.; Burschka, C.; Penka, M.; Wagner, B.; Tacke, R. J.
Organomet. Chem. 2005, 690, 33−47 and references therein.
(4) Popp, F.; Natscher, J. B.; Daiss, J. O.; Burschka, C.; Tacke, R.
̈
Organometallics 2007, 26, 6014−6028 and references therein.
(5) For reviews dealing with the Staudinger reaction, see:
(a) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron
1981, 37, 437−472. (b) Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron
1992, 48, 1353−1406.
(6) Rosenberg, S. D.; Walburn, J. J.; Stankovich, T. D.; Balint, A. E.;
Ramsden, H. E. J. Org. Chem. 1957, 22, 1200−1202.
(7) Compounds 19, 20, 26, and 27 turned out to be very unstable,
for which reason the purification by column chromatography on silica
gel had to be performed rapidly in order to minimize decomposition.
This resulted in purities of these products between 95% and 99%.
1
69% yield as a colorless oil (2.29 g, 5.77 mmol). H NMR (500.1
MHz, C6D6): δ 0.19 (s, 3 H; SiCH3), 1.15−1.25 (m, 4 H; SiCH2CH2),
2.33 (s, 6 H; SCH3), 3.43 (s, 3 H; C6H4OCH3), 4.13−4.23 (m, 4 H;
SiCH2CH2), 6.90−6.95 (m, 2 H; H-3/H-5, C6H4OCH3), 7.28−7.33
ppm (m, 2 H; H-2/H-6, C6H4OCH3). 13C NMR (125.8 MHz, C6D6):
δ −4.8 (SiCH3), 16.4 (SiCH2CH2), 36.9 (SCH3), 54.6 (C6H4OCH3),
67.7 (SiCH2CH2), 114.4 (C-3/C-5, C6H4OCH3), 125.2 (C-1,
C6H4OCH3), 135.4 (C-2/C-6, C6H4OCH3), 161.6 ppm (C-4,
C6H4OCH3). 29Si NMR (99.4 MHz, C6D6): δ −6.4 ppm. Anal.
Calcd for C14H24O7S2Si: C, 42.40; H, 6.10; S, 16.17. Found: C, 42.47;
H, 6.02; S, 16.14.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C, and 29Si NMR spectra for compounds 13·HCl, 14·
HCl, 17−20, and 22−27 (Figures S1−S36). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail for R.T.: r.tacke@uni-wuerzburg.de.
■
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) Reviews dealing with silicon-based drugs: (a) Tacke, R.; Linoh,
H. In The Chemistry of Organic Silicon Compounds; Patai, S., Rappaport,
Z., Eds.; Wiley: Chichester, U.K., 1989; Part 2, pp 1143−1206.
(b) Bains, W.; Tacke, R. Curr. Opin. Drug Discovery Dev. 2003, 6, 526−
543. (c) Showell, G. A.; Mills, J. S. Drug Discovery Today 2003, 8, 551−
556. (d) Mills, J. S.; Showell, G. A. Expert Opin. Investig. Drugs 2004,
13, 1149−1157. (e) Pooni, P. K.; Showell, G. A. Mini-Rev. Med. Chem.
2006, 6, 1169−1177. (f) Sieburth, S. McN.; Chen, C.-A. Eur. J. Org.
Chem. 2006, 311−322. (g) Gately, S.; West, R. Drug Dev. Res. 2007,
68, 156−163. (h) Franz, A. K. Curr. Opin. Drug Discovery Dev. 2007,
10, 654−671. (i) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529−2591.
(j) Franz, A. K.; Wilson, S. O. J. Med. Chem. 2013, 56, 388−405.
(2) Publications dealing with silicon-based drugs that contain a 4-
silapiperidine skeleton: (a) Gerlach, M.; Jutzi, P.; Stasch, J.-P.;
Przuntek, H. Z. Naturforsch. 1982, 37b, 657−662. (b) Stasch, J.-P.;
Ruß, H.; Schacht, U.; Witteler, M.; Neuser, D.; Gerlach, M.; Leven,
M.; Kuhn, W.; Jutzi, P.; Przuntek, H. Arzneim.-Forsch./Drug Res. 1988,
38, 1075−1078. (c) Tacke, R.; Handmann, V. I.; Bertermann, R.;
Burschka, C.; Penka, M.; Seyfried, C. Organometallics 2003, 22, 916−
924. (d) Tacke, R.; Heinrich, T.; Bertermann, R.; Burschka, C.;
Hamacher, A.; Kassack, M. U. Organometallics 2004, 23, 4468−4477.
(e) Tacke, R.; Popp, F.; Muller, B.; Theis, B.; Burschka, C.; Hamacher,
̈
A.; Kassack, M. U.; Schepmann, D.; Wunsch, B.; Jurva, U.; Wellner, E.
̈
ChemMedChem 2008, 3, 152−164. (f) Ilg, R.; Burschka, C.;
Schepmann, D.; Wunsch, B.; Tacke, R. Organometallics 2006, 25,
̈
5396−5408. (g) Johansson, T.; Weidolf, L.; Popp, F.; Tacke, R.; Jurva,
U. Drug Metab. Dispos. 2010, 38, 73−83. (h) Tacke, R.; Nguyen, B.;
Burschka, C.; Lippert, W. P.; Hamacher, A.; Urban, C.; Kassack, M. U.
Organometallics 2010, 29, 1652−1660. (i) Tacke, R.; Bertermann, R.;
7185
dx.doi.org/10.1021/om400873w | Organometallics 2013, 32, 7181−7185