β-Carbonylsilanes with a silacyclohexane skeleton and additional C-functionalized organyl groups at the silicon atom: Synthesis, reactivity, and NMR-spectroscopic characterization

Article abstract of DOI:10.1016/j.jorganchem.2004.08.048

A series of novel β-carbonylsilanes, with a silacyclohexane skeleton and additional C-functionalized organyl groups at the silicon atom, were synthesized, their reactivity was explored, and they were structurally characterized by multinuclear NMR spectros

Full text of DOI:10.1016/j.jorganchem.2004.08.048

Journal of Organometallic Chemistry 690 (2005) 678–684
www.elsevier.com/locate/jorganchem
b-Carbonylsilanes with a silacyclohexane skeleton
and additional C-functionalized organyl groups
at the silicon atom: synthesis, reactivity, and
NMR-spectroscopic characterization
*
Jurgen O. Daiß, Christian Burschka, Reinhold Tacke
¨
Institut fu¨r Anorganische Chemie, Universita¨t Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany
Received 11 June 2004; accepted 12 August 2004
Available online 2 December 2004
Abstract
A series of novel b-carbonylsilanes, with a silacyclohexane skeleton and additional C-functionalized organyl groups at the silicon
atom, were synthesized, their reactivity was explored, and they were structurally characterized by multinuclear NMR spectroscopy.
The aim of these investigations was to provide the basis for the development of novel silicon-based drugs containing a silacyclohex-
ane skeleton, with a CH2C(O)R substituent and an additional C-functionalized organyl group at the silicon atom.
ꢀ 2004 Elsevier B.V. All rights reserved.
Keywords: b-Carbonylsilanes; Silicon; Silicon-based drugs
1. Introduction
lating agent. Thus, the development of convenient syn-
thetic methods for functional group transformations in
the very presence of an Si–CH2C(O)R group represents
a challenging field in organosilicon chemistry to be
explored.
b-Carbonylsilanes, R3SiCH2C(O)R, have attracted
considerable interest for synthetic organic chemistry
because they are useful reagents for the generation of
enolate anions [1]. Their reactivity is mainly based on
the weakness of the Si–CH2C(O)R bond, which is an
intrinsic obstacle when tranformations of C-functional-
ized organyl groups at the silicon atom are intended.
Therefore, most of the publications on the reactivity
of b-carbonylsilanes report on reactions involving
cleavage of the Si–CH2C(O)R bond [2]. A typical
example of this is the use of Me3SiCH2CO2Et as a sily-
In context with our research program dealing with
the development of silicon-based drugs [3], we have
been interested in (i) the synthesis of b-carbonylsilanes,
with a silacyclohexane skeleton and an additional C-
functionalized organyl group at the silicon atom, and
in (ii) reactions of these compounds involving func-
tional group transformations within the C-functional-
ized group without cleavage of the Si–CH2C(O)R
bond. We report here on the synthesis and NMR-
spectroscopic characterization of the b-carbonylsilanes
1–8 that show some structural analogies with sila-gaba-
pentin (9b) [4], a silicon analogue of the antiepileptic
gabapentin (9a).
*
Corresponding author. Tel.: +49 931 888 5250; fax: +49 931 888
4609.
E-mail address: r.tacke@mail.uni-wuerzburg.de (R. Tacke).
0022-328X/$ - see front matter ꢀ 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2004.08.048

J.O. Daiß et al. / Journal of Organometallic Chemistry 690 (2005) 678–684
679
BrMg(CH2)5MgBr
N3
Cl
Cl
Si
Si
Si
Si
Si
CO2CH2Ph
CO2CH2Ph
Cl
Cl3SiCH2Cl
10
1
3
5
2
Cl
N3
Si
t
t
CO2 Bu
CO2 Bu
O
O
4
OCH2Ph
OtBu
Li
Li
Cl
I
Si
Si
[DMPU]
[DMPU]
t
CO2SiMe3
CO2 Bu
6
8
Cl
Cl
Si
Si
Si
Si
O
t
CO2CH2Ph
CO2 Bu
NCO
N
OtBu
H
1
2
3
4
Si
t
t
CO2 Bu
CO2 Bu
NaN3
NaN3
N3
7
NH2
CO2H
N3
El
t
CO2CH2Ph
CO2 Bu
9a: El = C
9b: El = Si
Scheme 1.
Formulas of 1–8, 9a, and 9b
ISiMe3
Cl
Si
Si
CO2SiMe3
Cl
2. Results and discussion
5
Si
t
CO2 Bu
NaI
The b-carbonylsilanes benzyl 2-(1-(chloromethyl)-1-
sila-1-cyclohexyl)acetate (1) and tert-butyl 2-(1-(chlo-
romethyl)-1-sila-1-cyclohexyl)acetate
I
3
t
CO2 Bu
(3)
were
6
synthesized according to Scheme 1 by reaction of 1-
chloro-1-(chloromethyl)-1-silacyclohexane (10) (pre-
pared from trichloro(chloromethyl)silane in 52% yield
by reaction with 1,5-bis(bromomagnesio)pentane [5])
with the lithium reagents LiCH2CO2CH2Ph (! 1, yield
Scheme 2.
34%), which upon reaction with tert-butanol afforded
tert-butyl 2-(1-(((tert-butoxycarbonyl)amino)methyl)-1-
sila-1-cyclohexyl)acetate (8, yield 44%) (Scheme 3). In
addition, compound 4 was reacted with triphenylphos-
phine according to Scheme 3, followed by treatment
with hydrochloric acid, to give 1,10-oxybis(((1-sila-1-
cyclohexyl)methyl)ammonium) dichloride (11, yield
38%). Thus, the attempted transformation of the
SiCH2N3 group into the SiCH2NH2 moiety and
t
43%) or LiCH2- CO2 Bu (! 3, yield 79%) in the presence
of 1,3-dimethyl-3,4,5,6-tetrahydropyrimidin-2(1H)-one
(DMPU). Treatment of 1 and 3 with sodium azide gave
benzyl 2-(1-(azidomethyl)-1-sila-1-cyclohexyl)acetate (2,
yield 86%) and tert-butyl 2-(1-(azidomethyl)-1-sila-1-
cyclohexyl)acetate (4, yield 89%), respectively (Scheme 1).
Further transformations of 3 (see Scheme 2) include:
(i) the displacement of the tert-butyl group by a trimeth-
ylsilyl moiety by reaction with iodotrimethylsilane to
give trimethylsilyl 2-(1-(chloromethyl)-1-sila-1-cyclo-
hexyl)acetate (5, yield 85%) and (ii) a chlorine/iodine
exchange by reaction with sodium iodide to give tert-
butyl 2-(1-(iodomethyl)-1-sila-1-cyclohexyl)acetate (6, yield
88%).
t
the transformation of the SiCH2CO2 Bu group into
the SiCH2COOH moiety in a one-pot synthesis (! for-
mation of 9b) resulted in an Si–C bond cleavage.
The identities of compounds 1–8, 10, and 11 were
established by elemental analyses and multinuclear
NMR experiments (1H, 13C, 15N (2, 4, 7, and 8 only),
29Si). In addition, compound 11 Æ 2H2O was structurally
characterized by single-crystal X-ray diffraction. The
crystal data and the experimental parameters used for
Reaction of 4 with triphenylphosphine, followed by
treatment with carbon dioxide, gave tert-butyl 2-(1-(iso-
cyanatomethyl)-1-sila-1-cyclohexyl)acetate (7, yield

680
J.O. Daiß et al. / Journal of Organometallic Chemistry 690 (2005) 678–684
NH3
2
+
1. PPh3
Si
Si
2. HCl, H2O
O
2 Cl
NH3
N3
11
Si
t
CO2 Bu
1. PPh3
2. CO2
4
NCO
Si
t
CO2 Bu
7
O
tBuOH
N
OtBu
H
Si
t
CO2 Bu
8
Scheme 3.
this crystal structure analysis are summarized in Table 1.
The structure of the cation of 11 Æ 2H2O is depicted in
Fig. 1; selected bond lengths and angles (which do not
Fig. 1. Structure of the dication in the crystal of 11 Æ 2H2O. Selected
bond distances (A) and angles (ꢁ): Si1–O1 1.6317(9), Si2–O1 1.6360(9),
˚
Si1–C1 1.8826(12), Si1–C2 1.8574(14), Si1–C6 1.8677(12), Si2–C7
1.8859(12), Si2–C8 1.8589(13), Si2–C12 1.8584(13), Si1–O1–Si2
152.05(6), O1–Si1–C1 107.67(5), O1–Si1–C2 110.54(6), O1–Si1–C6
111.88(6), O1–Si2–C7 106.47(5), O1–Si2–C8 112.94(6), O1–Si2–C12
111.04(6), C1–Si1–C2 112.33(6), C1–Si1–C6 109.22(6), C2–Si1–C6
105.25(6), C7–Si2–C8 108.66(6), C7–Si2–C12 111.11(6), C8–Si2–C12
106.67(6).
Table 1
Crystal data and experimental parameters for the crystal structure
analysis of 11 Æ 2H2O
Empirical formula
Formula mass (g molꢀ1
Collection T (K)
C12H34Cl2N2O3Si2
381.49
)
173(2)
0.71073
˚
k (Mo Ka) (A)
Crystal system
Monoclinic
P21/c (14)
16.5887(19)
6.6154(6)
19.072(2)
103.955(14)
2031.2(4)
4
need any further discussion) are given in the figure
legend.
Space group (no.)
˚
a (A)
˚
The crystal structure of 11 Æ 2H2O is governed by
hydrogen bonds [6], leading to an infinite two-
dimensional network along the base vectors [010] and
[001]. All six NH groups of the dication and all OH
groups of the two crystallographically independent
water molecules act as proton donors, whereas both
chloride anions and the oxygen atoms of both water
molecules act as proton acceptors.
b (A)
˚
c (A)
b (ꢁ)
3
˚
V (A )
Z
Dcalc (g cmꢀ3
)
1.248
0.447
824
l (mmꢀ1
F(000)
)
Crystal dimensions (mm)
2h range (ꢁ)
Index ranges
0.5 · 0.2 · 0.2
4.52–55.96
ꢀ21 6 h 6 21, ꢀ8
6 k 6 8, ꢀ25 6 l 6 25
17341
3. Conclusions
Number of collected reflections
Number of independent reflections
Rint
4847
0.0379
In this study, a series of b-carbonylsilanes, with a sila-
cyclohexane skeleton and an additional C-functional-
ized organyl group at the silicon atom, were
synthesized and structurally characterized by multinu-
clear NMR spectroscopy. Multistep transformations
were carried out successfully in the C-functionalized
periphery of this type of molecules, without cleavage
(in most cases) of the labile Si–CH2C(O)R bond. These
results may be helpful for the development of silicon-
based drugs of the b-carbonylsilane type containing a
silacyclohexane framework and an additional C-
functionalized organyl group bound to the silicon atom.
Number of reflections used
Number of parameters
Sa
4847
220
0.974
Weight parameters a/bb
0.0537/0.0000
0.0287
0.0757
c
R1 [I > 2r(I)]
wR2 (all data)
d
Maximum/minimum reꢀsi3dual
+0.408/ꢀ0.415
˚
electron density (e A
)
P
2
0:5
a
S ¼ f ½wðF 2o ꢀ F 2c Þ ꢁ=ðn ꢀ pÞg where n is number of reflections
and p is number of parameters.
2
b
wꢀ1 ¼ r2ðF 2oÞ þ ðaPÞ þ bP, with P ¼ ½maxðF o2,0Þ þ 2F 2cꢁ=3.
P
P
c
R1 = iFo| ꢀ |Fci/ |Fo|.
P
P
2
2
0:5
d
wR2 ¼ f ½wðF 2o ꢀ F c2Þ ꢁ= ½wðF 2oÞ ꢁg
.

J.O. Daiß et al. / Journal of Organometallic Chemistry 690 (2005) 678–684
681
4. Experimental
organic phase was separated and washed with a satu-
rated aqueous sodium hydrogen carbonate solution
(300 ml, solution B), the organic phase was separated,
the first aqueous wash solution A was extracted with
diethyl ether (200 ml), the resulting ethereal extract
was used to extract the second aqueous wash solution
B, and the organic extract was separated, followed by
a second extraction of the wash solutions A and B with
a fresh portion of diethyl ether (200 ml), using the same
protocol as described for the first extraction sequence.
The combined organic solutions were dried over anhy-
drous sodium sulfate, the solvent was removed under re-
duced pressure, and the oily residue was purified by
rapid bulb-to-bulb distillation in vacuo (Kugelrohr
apparatus). The distillate (33 g, 140–155 ꢁC/0.001 mbar)
was redistilled in vacuo (Vigreux column, 10 cm) to give
1 in 43% yield as a colorless liquid (14.4 g, 48.5 mmol);
b.p.: 137–138 ꢁC/0.001 mbar. 1H NMR (CDCl3): d 0.65–
0.87 (m, 4H, SiCH2C), 1.32–1.43 (m, 2H,
Si(CH2)2CH2C), 1.56–1.74 (m, 4H, SiCH2CH2C), 2.10
(s, 2H, SiCH2C(O)), 2.86 (s, 2H, SiCH2Cl), 5.07 (s,
2H, OCH2Ph), 7.26–7.38 (m, 5H, C6H5). 13C NMR
(CDCl3): d 9.7 (SiCH2C), 21.7 (SiCH2C(O)), 23.8
(SiCH2CH2C), 27.4 (SiCH2Cl), 29.2 (Si(CH2)2CH2C),
66.2 (OCH2Ph), 128.2 (C-4, Ph), 128.4 (C-2/C-6 or C-
3/C-5, Ph), 128.5 (C-2/C-6 or C-3/C-5, Ph), 136.0 (C-1,
Ph), 171.9 (C@O). 29Si NMR (CDCl3): d ꢀ0.8. Anal.
Found: C, 60.7; H, 7.0. Calc. for C15H21ClO2Si: C,
60.69; H, 7.13%.
4.1. Syntheses
4.1.1. General procedures
All syntheses were carried out under dry nitrogen.
The organic solvents used were dried and purified
according to standard procedures and stored under
dry nitrogen. A Buchi GKR 50 apparatus was used
¨
for the bulb-to-bulb distillations. Melting points were
determined with a Buchi Melting Point B-540 apparatus
¨
1
using open glass capillaries. The H, 13C, 15N, and 29Si
NMR spectra were recorded on a Bruker DRX-300
NMR spectrometer (1H, 300.1 MHz; 13C, 75.5 MHz;
15N, 30.4 MHz; 29Si, 59.6 MHz). CDCl3, CD2Cl2,
[D6]DMSO, or C6D6 were used as the solvent. All spec-
tra were recorded at 22 ꢁC. Chemical shifts (ppm) were
determined relative to internal CHCl3 (1H, d 7.24;
CDCl3), internal CDCl3 (13C, d 77.0; CDCl3), internal
CHDCl2 (1H, d 5.32; CD2Cl2), internal CD2Cl2 (13C, d
53.8; CD2Cl2), internal [D5]DMSO (1H,
[D6]DMSO), internal [D6]DMSO (13C,
d
d
2.49;
39.5;
[D6]DMSO), internal C6HD5 (1H, d 7.28; C6D6), inter-
nal C6D6 (13C, d 128.0; C6D6), external formamide
(15N, d ꢀ268.0; CD2Cl2, C6D6), or external TMS (29Si,
d 0; CDCl3, CD2Cl2, [D6]DMSO, C6D6). Analysis and
assignment of the 1H NMR data was supported by
1H,1H and 13C,1H correlation experiments. Assignment
of the 13C NMR data was supported by DEPT 135
and 13C,1H correlation experiments.
4.1.3. Benzyl 2-(1-(azidomethyl)-1-sila-1-
cyclohexyl)acetate (2)
4.1.2. Benzyl 2-(1-(chloromethyl)-1-sila-1-
cyclohexyl)acetate (1)
A stirred mixture of 1 (10.8 g, 36.4 mmol), sulfolane
(25 ml), and sodium azide (4.94 g, 76.0 mmol) was
heated at 55 ꢁC for 3 days and was then cooled to 20
ꢁC and poured into a stirred two-phase mixture of
diethyl ether (100 ml) and water (200 ml) containing
500 mg of sodium carbonate. The organic layer was sep-
arated, the aqueous phase was extracted with diethyl
ether (2 · 100 ml), all organic extracts were combined
and dried over anhydrous sodium sulfate, and the sol-
vent was removed under reduced pressure. The residue
was purified by column chromatography on silica gel
(column dimensions, 60 · 5.5 cm; silica gel (15–40 lm,
Merck 1.15111), 590 g; eluent, n-hexane/diethyl ether
86:14 (v/v)). The relevant fractions (TLC control) were
combined, and the solvent was completely removed un-
der reduced pressure to give 2 in 86% yield as a colorless
A 2.5 M solution of n-butyllithium in n-hexane (45.6
ml, 114 mmol of n-BuLi) was added dropwise [7] at 0 ꢁC
within 10 min to a stirred (mechanical stirrer) solution
of diisopropylamine (12.5 g, 124 mmol) in tetrahydrofu-
ran (THF) (100 ml), and the mixture was stirred at the
same temperature for another 15 min and then cooled
to ꢀ80 ꢁC, followed by dropwise addition of benzyl ace-
tate (17.2 g, 115 mmol) within 15 min while the reaction
temperature was kept at ꢀ75 ꢁC ( 5 ꢁC). The mixture
was stirred at this temperature for another 15 min, fol-
lowed by dropwise addition of 1,3-dimethyl-3,4,5,6-
tetrahydropyrimidin-2(1H)-one (DMPU) (58.5 g, 456
mmol) at ꢀ75 ꢁC ( 5 ꢁC) within 30 min (formation of
a slurry), and the mixture was then cooled to ꢀ100
ꢁC, followed by dropwise addition of 10 (20.8 g, 114
mmol) within 75 min while the temperature was kept
at ꢀ95 ꢁC ( 5 ꢁC) (formation of a highly viscous slurry).
The mixture was warmed to ꢀ30 ꢁC within 4 h (forma-
tion of a clear solution), and the cold solution was
poured into a stirred two-phase mixture of a saturated
aqueous sodium hydrogen carbonate solution (300 ml,
solution A) and diethyl ether (200 ml) (formation of a
precipitate which remained in the aqueous phase). The
1
oily liquid (9.50 g, 31.3 mmol). H NMR (CD2Cl2): d
0.67–0.85 (m, 4H, SiCH2C), 1.36–1.46 (m, 2H,
Si(CH2)2CH2C), 1.63–1.75 (m, 4H, SiCH2CH2C), 2.07
(s, 2H, SiCH2C(O)), 2.92 (s, 2H, SiCH2N3), 5.08 (s,
2H, OCH2Ph), 7.29–7.40 (m, 5H, C6H5). 13C NMR
(CD2Cl2): d 10.3 (SiCH2C), 22.3 (SiCH2C(O)), 24.2
(SiCH2CH2C), 29.6 (Si(CH2)2CH2C), 39.0 (SiCH2N3),
66.5 (OCH2Ph), 128.5 (C-4, Ph), 128.78 (C-2/C-6 or

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J.O. Daiß et al. / Journal of Organometallic Chemistry 690 (2005) 678–684
C-3/C-5, Ph), 128.81 (C-2/C-6 or C-3/C-5, Ph), 136.8 (C-
1, Ph), 171.9 (C@O). 15N NMR (CD2Cl2): d ꢀ319.8
(CH2NNN), ꢀ172.7 (CH2NNN), ꢀ130.0 (CH2NNN).
29Si NMR (CD2Cl2): d ꢀ1.3. Anal. Found: C, 59.7; H,
6.9; N, 13.6. Calc. for C15H21N3O2Si: C, 59.37; H,
6.98; N, 13.85%.
as a colorless liquid; b.p.: 73–74 ꢁC/0.001 mbar. 1H
NMR (CDCl3): d 0.25 (s, 9H, SiCH3), 0.69–0.91 (m,
4H, SiCH2C), 1.35–1.46 (m, 2H, Si(CH2)2CH2C),
1.61–1.76 (m, 4H, SiCH2CH2C), 2.05 (s, 2H, SiCH2-
C(O)), 2.89 (s, 2H, SiCH2Cl). 13C NMR (CDCl3): d
ꢀ0.2 (SiCH3), 9.7 (SiCH2C), 23.8 (SiCH2C(O)), 23.9
(SiCH2CH2C), 27.5 (SiCH2Cl), 29.3 (Si(CH2)2CH2C),
172.6 (C@O). 29Si NMR (CDCl3): d ꢀ1.2 (SiC4), 23.0
(OSiC3). Anal. Found: C, 47.1; H, 8.1. Calc. for
C11H23ClO2Si2: C, 47.37; H, 8.31%.
4.1.4. tert-Butyl 2-(1-(chloromethyl)-1-sila-1-
cyclohexyl)acetate (3)
Compound 3 was prepared analogous to the prepara-
tion of 1 (see above): THF, 100 ml; 2.7 M solution of n-
butyllithium in n-hexane, 41.4 ml (112 mmol of n-BuLi);
diisopropylamine, 12.5 g (124 mmol); tert-butyl acetate,
13.0 g (112 mmol); DMPU, 57.4 g (448 mmol); 10, 20.9
g (114 mmol); distillate after bulb-to-bulb distillation, 28
g (100–130 ꢁC/0.001 mbar). The product was redistilled
in vacuo (Vigreux column, 20 cm) to give 3 in 79% yield
(related to 10) as a colorless liquid (23.8 g, 90.5 mmol);
4.1.7. tert-Butyl 2-(1-(iodomethyl)-1-sila-1-
cyclohexyl)acetate (6)
A stirred mixture of 3 (6.11 g, 23.2 mmol), sodium io-
dide (4.30 g, 28.7 mmol), and acetone (40 ml) was heated
under reflux for 2 h (quantitative conversion (GC con-
trol)). The solids were removed by filtration and washed
with n-heptane (2 · 50 ml), the filtrate and the wash
solutions were combined, and the solvent was removed
under reduced pressure until a residual volume of ca.
100 ml was obtained (postprecipitation), followed by
addition of water (100 ml). The organic phase was sep-
arated, the aqueous layer was extracted with diethyl
ether (2 · 50 ml), all organic extracts were combined
and dried over anhydrous sodium sulfate, the solvent
was removed under reduced pressure, and the residue
was distilled in vacuo (Vigreux column, 5 cm) from cop-
per powder (122 mg, 1.92 mmol) to give 6 in 88% yield
as a colorless liquid (7.24 g, 20.4 mmol); b.p.: 87 ꢁC/
0.002 mbar. 1H NMR (CDCl3): d 0.71–0.90 (m, 4H,
SiCH2C), 1.32–1.46 (m, 2H, Si(CH2)2CH2C), 1.41 (s,
9H, CCH3), 1.61–1.72 (m, 4H, SiCH2CH2C), 1.96 (s,
2H, SiCH2C(O)), 2.11 (s, 2H, SiCH2I). 13C NMR
(CDCl3): d ꢀ17.2 (SiCH2I), 11.4 (SiCH2C), 23.9 (SiCH2-
C(O)), 24.0 (SiCH2CH2C), 28.2 (CCH3), 29.4
(Si(CH2)2CH2C), 80.0 (CCH3), 171.4 (C@O). 29Si
NMR (CDCl3): d 0.3. Anal. Found: C, 40.9; H, 6.3.
Calc. for C12H23IO2Si: C, 40.68; H, 6.54%.
1
b.p.: 70 ꢁC/0.001 mbar. H NMR (CDCl3): d 0.68–0.91
(m, 4H, SiCH2C), 1.34–1.46 (m, 2H, Si(CH2)2CH2C),
1.41 (s, 9H, CCH3), 1.60–1.76 (m, 4H, SiCH2CH2C),
1.94 (s, 2H, SiCH2C(O)), 2.90 (s, 2H, SiCH2Cl). 13C
NMR (CDCl3): d 9.7 (SiCH2C), 23.0 (SiCH2C(O)),
23.9 (SiCH2CH2C), 27.5 (SiCH2Cl), 28.2 (CCH3), 29.3
(Si(CH2)2CH2C), 80.1 (CCH3), 171.4 (C@O). 29Si
NMR (CDCl3): d ꢀ1.2. Anal. Found: C, 54.5; H, 8.5.
Calc. for C12H23ClO2Si: C, 54.83; H, 8.82%.
4.1.5. tert-Butyl 2-(1-(azidomethyl)-1-sila-1-
cyclohexyl)acetate (4)
Compound 4 was prepared analogous to the prepara-
tion of 2 (see above): 3, 11.5 g (43.8 mmol); sulfolane, 25
ml; sodium azide, 5.74 g (88.3 mmol). The product was
isolated in 89% yield as a colorless oily liquid (10.5 g,
1
39.0 mmol). H NMR (CD2Cl2): d 0.70–0.87 (m, 4H,
SiCH2C), 1.35–1.51 (m, 2H, Si(CH2)2CH2C), 1.43 (s,
9H, CCH3), 1.65–1.80 (m, 4H, SiCH2CH2C), 1.92 (s,
2H, SiCH2C(O)), 2.97 (s, 2H, SiCH2N3). 13C NMR
(CD2Cl2): d 10.4 (SiCH2C), 23.6 (SiCH2C(O)), 24.3
(SiCH2CH2C), 28.3 (CCH3), 29.7 (Si(CH2)2CH2C),
39.3 (SiCH2N3), 80.3 (CCH3), 171.4 (C@O). 15N
4.1.8. tert-Butyl 2-(1-(isocyanatomethyl)-1-sila-1-
cyclohexyl)acetate (7)
NMR (CD2Cl2):
d
ꢀ319.5 (CH2NNN), ꢀ172.0
Compound 4 (9.26 g, 34.4 mmol) was added in one
single portion to a solution of triphenylphosphine
(9.30 g, 35.5 mmol) in toluene (300 ml), and the mixture
was stirred at 20 ꢁC for 1 day. Subsequently, a gas
stream of carbon dioxide (ca. 100 g; prepared from
dry ice and dried by passing the gas stream through a
column packed with anhydrous calcium chloride) was
passed through the stirred solution over a period of 3
h. The solvent was removed under reduced pressure,
the residue was purified by bulb-to-bulb distillation in
vacuo (Kugelrohr apparatus), and the distillate (4.4 g,
100–175 ꢁC/0.001 mbar) was redistilled in vacuo (Vig-
reux column, 5 cm) to give 7 in 34% yield as a colorless
liquid (3.16 g, 11.7 mmol); b.p.: 98–99 ꢁC/0.002 mbar.
1H NMR (CD2Cl2): d 0.75–0.85 (m, 4H, SiCH2C),
(CH2NNN), ꢀ129.5 (CH2NNN). 29Si NMR (CD2Cl2):
d ꢀ1.6. Anal. Found: C, 53.6; H, 8.4; N, 15.8. Calc.
for C12H23N3O2Si: C, 53.50; H, 8.60; N, 15.60%.
4.1.6. Trimethylsilyl 2-(1-(chloromethyl)-1-sila-1-
cyclohexyl)acetate (5)
Iodotrimethylsilane (5.15 g, 25.7 mmol) was added in
one portion at 20 ꢁC to a stirred solution of 3 (6.00 g,
22.8 mmol) in dichloromethane (20 ml). The mixture
was heated under reflux for 30 min (quantitative conver-
sion (GC control)), the solvent was removed under re-
duced pressure, and the residue was distilled in vacuo
(Vigreux column, 5 cm) from copper powder (116 mg,
1.83 mmol) to give 5 in 85% yield (5.44 g, 19.5 mmol)

J.O. Daiß et al. / Journal of Organometallic Chemistry 690 (2005) 678–684
683
1.38–1.49 (m, 2H, Si(CH2)2CH2C), 1.43 (s, 9H, CCH3),
1.62–1.82 (m, 4H, SiCH2CH2C), 1.93 (s, 2H, SiCH2-
C(O)), 2.93 (s, 2H, SiCH2N). 13C NMR (CD2Cl2): d
10.0 (SiCH2C), 23.3 (SiCH2C(O)), 24.3 (SiCH2CH2C),
28.3 (CCH3), 29.0 (SiCH2N), 29.7 (Si(CH2)2CH2C),
80.4 (CCH3), 120.5 (NCO), 171.2 (CC(@O)O). 15N
NMR (CD2Cl2): d ꢀ361.3. 29Si NMR (CD2Cl2): d
ꢀ0.8. Anal. Found: C, 57.9; H, 8.5; N, 5.4. Calc. for
C13H23NO3Si: C, 57.96; H, 8.60; N, 5.20%.
was complete, the mixture was stirred at 20 ꢁC for 16
h, the precipitate was separated by filtration and washed
with diethyl ether (2 · 200 ml), the filtrate and the wash
solutions were combined, and the solvent was removed
by distillation under atmospheric pressure, causing a
postprecipitation. The precipitate was separated by
decantation and washed with n-pentane (2 · 50 ml),
and all organic solutions were combined. The solvent
was removed as described above, and the crude product
(79 g) was isolated by distillation in vacuo (Vigreux col-
umn, 30 cm; b.p.: 80–95 ꢁC/18 mbar) and then further
purified by redistillation to afford 10 in 52% yield (re-
lated to 1,5-dibromopentane) as a colorless liquid (67.4
g, 368 mmol); b.p.: 88–90 ꢁC/18 mbar. 1H NMR
(CDCl3): d 0.92–1.12 (m, 4H, SiCH2C), 1.21–1.37,
1.56–1.79, and 1.81–1.95 (m, 6H, SiCH2(CH2)2C), 2.98
(s, 2H, SiCH2Cl). 13C NMR (CDCl3): d 13.4 (SiCH2C),
23.3 (SiCH2CH2C), 28.9 (Si(CH2)2CH2C), 29.0
(SiCH2Cl). 29Si NMR (CDCl3): d 20.8. Anal. Found:
C, 39.0; H, 6.3. Calc. for C6H12Cl2Si: C, 39.35; H,
6.60%.
4.1.9. tert-Butyl 2-(1-(((tert-
butoxycarbonyl)amino)methyl)-1-sila-1-
cyclohexyl)acetate (8)
A solution of 7 (802 mg, 2.98 mmol) in tert-butanol (5
ml) was heated under reflux for 1 day. The solvent was
removed under reduced pressure, and the residue was
purified by bulb-to-bulb distillation in vacuo (Kugelrohr
apparatus). The fraction collected at 110–130 ꢁC/0.001
mbar (717 mg) was crystallized from diethyl ether (25
ml) at ꢀ27 ꢁC over a period of 3 days. The product
was isolated by filtration, washed with cold (–27 ꢁC) n-
pentane (5 ml), and dried in vacuo (0.001 mbar, 20 ꢁC,
4 h) to give 8 in 44% yield as a colorless crystalline solid
(450 mg, 1.31 mmol); m.p.: 84–85 ꢁC. 1H NMR (C6D6):
d 0.64–0.74 (m, 4H, SiCH2C), 1.27–1.39 (m, 2H,
Si(CH2)2CH2C), 1.50 (s, 9H, CCH3), 1.59 (s, 9H,
CCH3), 1.61–1.73 (m, 4H, SiCH2CH2C), 1.90 (s, 2H,
4.1.11. 1,10-Oxybis(((1-sila-1-cyclohexyl)methyl)-
ammonium) dichloride (11)
A solution of 4 (720 mg, 2.67 mmol) in toluene (5 ml)
was added at 20 ꢁC in one single portion to a solution of
triphenylphosphine (722 mg, 2.75 mmol) in toluene (5
ml), and the mixture was stirred at 20 ꢁC for 1 day.
The solvent was removed under reduced pressure, 6 M
hydrochloric acid (20 ml) was added to the residue,
and the mixture was then heated under reflux for 2 h
[8], cooled to 20 ꢁC, and washed with dichloromethane
(2 · 10 ml) to remove any triphenylphosphine oxide
formed. The aqueous phase was kept undisturbed at
ꢀ20 ꢁC for 2 days, and the resulting precipitate was iso-
lated by filtration and recrystallized from 6 M hydro-
chloric acid at ꢀ20 ꢁC over a period of 2 days. The
product was isolated by filtration and dried in vacuo
(0.001 mbar, 20 ꢁC, 8 h) to give 11 in 38% yield (includ-
ing workup of the mother liquor) as a colorless crystal-
line solid (177 mg, 512 lmol); m.p.: 256–257 ꢁC (dec.)
1H NMR ([D6]DMSO): d 0.62–0.78 and 0.82–0.96 (m,
8H, SiCH2C), 1.25–1.46 (m, 4H, Si(CH2)2CH2C),
3
SiCH2C(O)), 2.96 (d, JHH = 5.4 Hz, 2H, SiCH2N), 5.1
(br s, 1H, NH). 13C NMR (C6D6): d 10.5 (SiCH2C),
23.7 (SiCH2C(O)), 24.2 (SiCH2CH2C), 27.9 (SiCH2N),
28.2 (CCH3), 28.5 (CCH3), 29.7 (Si(CH2)2CH2C), 78.4
(CCH3), 79.9 (CCH3), 156.8 (NC(@O)O), 171.9
(CC(@O)O). 15N NMR (C6D6): d ꢀ310.4. 29Si NMR
(C6D6): d ꢀ3.0. Anal. Found: C, 59.5; H, 9.5; N, 4.1.
Calc. for C17H33NO4Si: C, 59.44; H, 9.68; N, 4.08%.
4.1.10. 1-Chloro-1-(chloromethyl)-1-silacyclohexane
(10)
50 ml of a solution of 1,5-dibromopentane (161 g, 700
mmol) in diethyl ether (500 ml) were added to a stirred
suspension of magnesium turnings (37.4 g, 1.54 mol) in
diethyl ether (200 ml), and the reaction was started by
gentle heating. Subsequently, the remaining ethereal
1,5-dibromopentane solution was added within 90 min,
causing the mixture to boil under reflux. After the addi-
tion was complete, the mixture was heated under reflux
for a further 90 min and then cooled to 20 ꢁC within 1 h.
The resulting two-phase Grignard reagent (which was
separated from residual magnesium turnings by decan-
tation, followed by washing of the magnesium with
diethyl ether (2 · 50 ml)) was added dropwise within
90 min to a solution of trichloro(chloromethyl)silane
(129 g, 701 mmol) in diethyl ether (300 ml), causing
the mixture to boil under reflux. During the addition,
the mixture was stirred vigorously with a mechanical
stirrer (formation of a precipitate). After the addition
3
1.49–1.76 (m, 8H, SiCH2CH2C), 2.29 (q, JHH = 5.9
Hz, 4H, SiCH2N), 8.1 (br s, 6H, NH3). 13C NMR
([D6]DMSO): d 13.7 (SiCH2C), 23.7 (SiCH2CH2C),
25.5 (SiCH2N), 28.8 (Si(CH2)2CH2C). 29Si NMR
([D6]DMSO): d 0.7. Anal. Found: C, 41.4; H, 8.3; N,
8.0. Calc. for C12H30Cl2N2OSi2: C, 41.72; H, 8.75; N,
8.11%.
4.2. Crystal structure analysis
A suitable single crystal of 11 Æ 2H2O was obtained di-
rectly from the preparation of this compound (see
above; crystallization from 6 M hydrochloric acid at

684
J.O. Daiß et al. / Journal of Organometallic Chemistry 690 (2005) 678–684
1, vol. 4, Georg Thieme Verlag, Stuttgart, Germany, 2002, p. 757,
and references cited therein.
ꢀ20 ꢁC; no subsequent drying to avoid loss of the water
of crystallization). The crystal was mounted in inert oil
(perfluoroalkyl ether, ABCR) on a glass fiber and then
transferred to the cold nitrogen gas stream of the diffrac-
tometer (Stoe IPDS; graphite-monochromated Mo Ka
[2] (a) E. Nakamura, M. Shimizu, I. Kuwajima, Tetrahedron Lett.
17 (1976) 1699;
(b) E. Nakamura, T. Murofushi, M. Shimizu, I. Kuwajima, J.
Am. Chem. Soc. 98 (1976) 2346;
˚
(c) R. Noyori, K. Yokoyama, J. Sakata, I. Kuwajima, E.
Nakamura, M. Shimizu, J. Am. Chem. Soc. 99 (1977) 1265;
(d) E. Nakamura, K. Hashimoto, I. Kuwajima, Bull. Chem. Soc.
Jpn. 54 (1981) 805;
radiation (k = 0.71073 A)). The structure was solved
by direct methods [9]. All non-hydrogen atoms were re-
fined anisotropically [10]. The NH and OH hydrogen
atoms were localized in difference Fourier syntheses
and refined freely. A riding model was employed in
the refinement of the CH hydrogen atoms. In addition,
crystallographic data (excluding structure factors) for
the structure reported in this paper has been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-247202. Copies
of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: +44 1223 336 033; e-mail: deposit@ccdc.
cam.ac.uk).
(e) A. Gambacorta, S. Turchetta, M. Botta, Synth. Commun. 19
(1989) 2441;
(f) I. Kuwajima, E. Nakamura, K. Hashimoto, in: J.P. Feeman
(Ed.), Organic Syntheses, coll. vol. 7, Wiley, New York, 1990, p.
512.
[3] Review: W. Bains, R. Tacke, Curr. Opin. Drug Discovery Dev. 6
(2003) 526.
[4] R. Tacke, J. Daiss, G.A. Showell, A. Richards (inventors), UK
Patent Application GB2397576 A (28.07.2004).
[5] N.S. Nametkin, V.M. Vdovin, K.S. Pushchevaya, A.N. Egoroch-
kin, Izv. Akad. Nauk SSSR, Ser. Khim. (1967) 2530, Chem.
Abstr. 69 (1968) 59325n.
[6] The hydrogen-bonding system was analyzed by using the program
system PLATON. A.L. Spek, PLATON, University of Utrecht,
Utrecht, The Netherlands, 1998. In this context, see also: G.A.
Jeffrey, W. Saenger, Hydrogen Bonding in Biological Structures,
Springer, Berlin, 1991, pp. 15–24.
Acknowledgement
[7] The same dropping funnel was used for the addition of this and of
all the following reagents and was flushed with THF (10 ml) after
the addition of every reagent, thus diluting the reagent mixture by
a small extent.
Financial support of this work by Amedis Pharma-
ceuticals Ltd., Cambridge, UK, is gratefully
acknowledged.
[8] Under milder reaction conditions (20 ꢁC), the same product was
obtained, but it was formed at a much slower rate.
[9] (a) G.M. Sheldrick, SHELXS-97, University of Go¨ttingen, Go¨ttin-
gen, Germany, 1997;
References
(b) G.M. Sheldrick, Acta Crystallogr., Sect. A 46 (1990) 467.
[1] Review: Y. Landais, in: I. Fleming (Ed.), Science of Synthesis,
Houben-Weyl, Methods of Molecular Transformations, Category
¨ ¨
[10] G.M. Sheldrick, SHELXL-97, University of Gottingen, Gottingen,
Germany, 1997.