Synthesis and conformational analysis of 1,3-azasilinanes

Article abstract of DOI:10.1016/j.tet.2012.05.106

1-Isopropyl-3-methyl-3-phenyl-1,3-azasilinane 1 and 1-isopropyl-3,3- dimethyl-1,3-azasilinane 2 were synthesized and a detailed analysis of their NMR spectra, conformational equilibria and ring inversion processes is presented. Low temperature ¹

Full text of DOI:10.1016/j.tet.2012.05.106

Tetrahedron 68 (2012) 7494e7501
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and conformational analysis of 1,3-azasilinanes
,
Bagrat A. Shainyan a, Svetlana V. Kirpichenko a, Erich Kleinpeter b
*
a A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Division of the Russian Academy of Sciences, 1 Favorsky Street, 664033 Irkutsk, Russian Federation
b
€
Chemisches Institut der Universitat Potsdam, Karl-Liebknecht-Str. 24-25, D-14476 Potsdam (Golm), Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 April 2012
Received in revised form 21 May 2012
Accepted 24 May 2012
Available online 31 May 2012
1-Isopropyl-3-methyl-3-phenyl-1,3-azasilinane 1 and 1-isopropyl-3,3-dimethyl-1,3-azasilinane 2 were
synthesized and a detailed analysis of their NMR spectra, conformational equilibria and ring inversion
processes is presented. Low temperature 1H/13C NMR spectroscopy, iteration of the 1H NMR spectra and
quantum chemical calculations showed slight predominance of the PheqMeax over the PhaxMeeq con-
former of 1 at low temperature. The barrier for the chair to chair interconversion of both compounds was
measured to be 8.25 kcal/mol.
Keywords:
1,3-Azasilinanes
Ó 2012 Elsevier Ltd. All rights reserved.
Conformational analysis
Dynamic NMR spectroscopy
Quantum chemical calculations
Ring current effect
1. Introduction
conformational effects caused by two heteroatoms (Si and N in
1,3-position) in the saturated six-membered ring. Recently we have
Piperidines are a very important class of compounds generally
found in diverse natural products and drugs.1 The piperidine frag-
ment is a significant structural part of a variety of natural alkaloids
and synthetic compounds with interesting biological and phar-
macological properties. For example, 3-aryl-3-methylpiperidine
derivatives with opioid activity have been described, their stereo-
chemical study reported2 and the significant role of the Ph-axial or
Ph-equatorial conformation in the ligand-receptor interaction was
mentioned in the literature.2
As analogs of known drugs, bioisosteric 4-silapiperidines were
designed by replacement of a carbon atom by silicon.3e5 Pharma-
cological activity and the X-ray molecular structure of their aryl
derivatives was the subject of numerous investigations performed
mainly by Tacke’s group.6e9 On the contrary, limited sets of data are
known for 3-aryl-1,3-azasilinanes, which are of special interest
from different points of view. As other SiePh-substituted com-
pounds, they are useful synthons for the preparation of various
Si-functional heterocycles by electrophilic cleavage of the SiePh
bond.10,11 Recently, stereocontrolled synthesis of 3-aryl-1,3-
azasilinane derivatives as potential Si-containing peptide mimics
was reported.12,13 From the structural point of view these com-
pounds represent an attractive object for investigation of
reported the gas phase electron diffraction molecular structure of
1,3,3-trimethyl-1,3-azasilinane14 and the conformational analysis
of 1,3-dimethyl-3-R-1,3-azasilinanes (R¼Me, Ph).14,15 The former
compound was shown to adopt a slightly distorted chair confor-
mation with the equatorial N-Me group.14 The latter (1,3-dimethyl-
3-phenyl-1,3-azasilinane) exists as an equilibrium mixture of the
PhaxMeeq and PheqMeax chair conformers in the ratio of 1 : 2 with
N-Me in the equatorial position in both conformers as well.15
Our current interest in the stereochemistry of 1,3-silapiperidines
prompted us to examine the effect of the N-alkyl substituent on the
conformational equilibria of 1,3-azasilinanes; up to now only N-Me
analogswerestudied with N-Me anancomericin equatorial position.
To begin with, both 1-isopropyl-3-methyl-3-phenyl-1,3-azasilinane
1 and 1-isopropyl-3,3-dimethyl-1,3-azasilinane 2 were synthesized
and the stereochemistry examined in solution by variable temper-
ature NMR spectroscopy and in the gas phase by theoretical calcu-
lations at the DFT and MP2 level of theory.
Although in azasilinanes, as in the parent piperidines, the NReq
conformers are much more stable and the only observable con-
formers, in other nitrogen-containing diheterocyclohexanes, like
3-alkyl-1-oxa-3-azacyclohexanes, the NRax conformers can
predominate.16,17
Finally, an interesting question is also the effect of the
second heteroatom in silaheterocyclohexanes on the conforma-
tional equilibrium. The so far studied 1-methyl-1-phenyl-
1-silacyclohexane and 3-methyl-3-phenyl-3-silathiane were found
to be conformationally similar18 but strongly different from
* Corresponding author. E-mail addresses: bagrat@irioch.irk.ru (B.A. Shainyan),
ekleinp@uni-potsdam.de, kp@chem.uni-potsdam.de (E. Kleinpeter).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.106

B.A. Shainyan et al. / Tetrahedron 68 (2012) 7494e7501
7495
1-methyl-1-phenylcyclohexane.19,20 How will the relative stability
of the conformers be affected by the nitrogen atom having the lone
For compound 1, the conformational equilibrium in Scheme 3 is
not degenerate. The aliphatic part of the 1H NMR spectrum of 1
differs from that of 2 by the low-field shifts caused by the ring
current effect of the Ph group varying from w0.1 ppm for remote
protons (i-Pr, 6-CH2, 5-CH2) to w0.3 ppm for 2-CH2 and 4-CH2
protons, which are more close to the silicon atom. Besides, due to
the presence of the chiral center at the silicon atom, the protons of
the latter two methylene groups are diastereotopic and appear in
the 1H NMR spectrum as AB pattern (2-CH2) or two multiplets of 8
lines (partly overlapped) each (4-CH2). Upon cooling, the signals
decoalesce. The best resolved 1H NMR spectrum of 1-isopropyl-3-
methyl-3-phenyl-1,3-azasilinane 1 is obtained at 143 K and is
shown in Fig. 1. Two sets of signals were observed and assigned to
the axial or equatorial protons in the two conformers of 1 of
slightly diffent population using the well known general principles
of 1H/13C NMR stereoanalysis: (i) equatorial protons resonate at
electron pair in the
cussed below.
b-position to silicon? All these issues are dis-
2. Results and discussion
2.1. Synthesis
Compounds 1 and 2 were prepared by the sequence of reactions
including the addition of methyl(chloromethyl)phenylsilane 3a or
dimethyl(chloromethyl)silane 3b to the silylated allyl alcohol 4
followed by desilylation of adducts 5a,b to the corresponding al-
cohols 6a,b. Chlorination of the latter and heterocyclization of the
formed dichlorides 7a,b with i-propylamine, proceed all in good
yield (Scheme 1).
H2PtCl6
Me(R)(ClCH2)SiH + CH2=CHCH2OSiMe3
Me(R)(ClCH2)Si(CH2)3OSiMe3
4
3a,b
5a,b
HCl/MeOH
Ph3P/CCl4
Me(R)(ClCH2)SiCH2CH2CH2Cl
Me(R)(ClCH2)SiCH2CH2CH2OH
6a,b
7a,b
R
Me
Si
i-PrNH2
R = Ph (1); Me (2).
N
i-Pr
1, 2
Scheme 1. Synthesis of the studied compounds.
2.2. Variable temperature NMR measurements
R
R
Si
The complete intramolecular flexibility of 1,3-azasilinanes 1
and 2 must include both ring inversion and nitrogen inversion
(Scheme 2).
Si
N
Me
i-Pr
i-Pr
N
Me
1a, 2a
1b, 2b
Scheme 3. Conformational equilibrium of 1,3-azasilinanes 1 and 2.
Me
Si
Me
ring
inversion
Si
R
N
i-Pr
R
N
i-Pr
nitrogen
inversion
nitrogen
inversion
Me
Si
i-Pr
Me
ring
inversion
Si
N
R
i-Pr
N
R
Scheme 2. Conformational equilibria of 1,3-azasilinanes 1 and 2.
However, due to much lower energy of the NReq versus NRax
conformer (vide infra) and similar to the earlier studied Si, N-
containing heterocycles,14,15,21,22 the nitrogen inversion leads to the
conformational equilibrium N-i-Prax%N-i-Preq, which is com-
pletely biased to the N-i-Preq conformer, so, Scheme 2 is simplified
to Scheme 3.
2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0
(ppm)
Fig. 1. 1H NMR spectrum of the frozen conformational equilibrium of compound 1 at
143 K in the solvent mixture of CD2Cl2, CHFCl2, and CHF2Cl in a ratio of 1:1:3 at
600 MHz.

7496
B.A. Shainyan et al. / Tetrahedron 68 (2012) 7494e7501
lower field as compared to the axial protons at the same carbon
atom,16,23 (ii) axial protons split into triplets or quartets due to
2
3
large geminal JHH and vicinal JHH(ax,ax) coupling constants,
whereas the equatorial protons are split only to doublets due to the
3
3
2JHH coupling constants (the much smaller J(ax,eq) and J(eq,eq)
are not resolved due to residual low temperature broadening), and
(iii) axial SieMe carbons (protons) are found at higher (lower)
field than the corresponding equatorial SieMe carbons (pro-
tons).24,25 Adequately, 1H NMR spectra of the two conformers were
assigned (cf. Table 1).
For the aryl substituted six-membered carbo- and heterocycles
another criterion originally asserted by Eliel was the upfield shift
of the Cipso carboninthe Phax relativetothePheq conformers,2,26,27 the
difference reaching 5.6 ppm in 1-methyl-1-phenylcyclohexane19 and
w2.5 ppm in 3-methyl-3-arylpiperidines.2,27 Thiscriterion is adhered
also to 1-methyl-1-phenyl-1-silacyclohexane and 3-methyl-3-
phenyl-3-silathiane,18 although the difference between the Cipso
signals in the conformers is reduced to w1.5 ppm. In contrast, in the
1,3-azasilinanes studied inthe presentand preceding work,15 theCipso
carbons of the MeeqPhax conformers resonate at a lower field. How-
ever, since the difference of the chemical shifts of Cipso in the two
conformers is as low as 0.15e0.23 ppm, the relative position of the
signals cannot be used as a decisive criterion for the assignmentof the
conformers.
2.8
2.6
2.4
2.2
2.0
1.8
1.6
(ppm)
1.4
1.2
1.0
0.8
0.6
0.4
0.2
Fig. 2. 1H NMR spectrum of the frozen conformational equilibrium of compound 2 at
143 K in the solvent mixture of CD2Cl2, CHFCl2, and CHF2Cl in a ratio of 1:1:3 at
600 MHz.
shifts at 273 K and for the conformers at low temperature [113 K (1)
and 103 K (2), respectively] are collected; carbon atoms were
assigned via HMQC and HMBC 2D correlation spectra (Fig. SI-3 in
Supplementary data).
Table 1
1H and 13C NMR spectra of the 1,3-azasilinanes 1 and 2 at various temperatures in CD2Cl2/CHCl2F/CHClF2
T/K, conformer
(1H)/ppm
273, 1
MeSi
2-CH2
4-CH2
5 ꢁ CH02
6-CH2
2.54
NCH
CCH3
d
0.37
0.43
0.16
2.11
2.24
2.20
1.73
2.55
1.73
0.86
0.99
0.81
0.94
1.15
0.64
0.92
2.87
2.86
2.86
1.04
1.06
0.87
0.89
1.07
1.00
143, 1a
ax
eq
ax
eq
1.73
2.08
1.44
1.94
2.33
2.69
2.33
2.61
MeeqPhax, minor
143, 1b
MeaxPheq, major
13C)/ppm
d
(
273, 1
143, 1a
e4.6
e3.8
37.5
32.9
17.3
20.3
25.9
24.2 br
55.5
56.4
58.8
56.4
12.1
10.4
eq
ax
MeeqPhax, minor
143, 1b
MeaxPheq, major
(1H)/ppm
e7.9
34.2
12.3
24.2
56.4
56.4
10.4
d
273, 2
0.02
0.08
e0.04
1.79 s
1.49 d
2.03 d
0.55 m
0.41 t
0.73 d
1.74 m
1.59 q
1.93 d
2.32 m
2.22 t
2.59 d
2.87
2.83 q
2.83
0.92 d
0.85 d
0.98 d
143, 2a
143, 2b
eq
ax
d (
13C)/ppm
273, 2
143, 2a
143, 2b
e3.6
e3.5
e5.3
38.7
32.3 br
32.3 br
17.4
21.2
10.5
25.7
24.4 br
24.4 br
54.5
56.2 br
56.2 br
57.9
56.5 br
56.5 br
12.9
11.3 br
11.3 br
eq
ax
It is worth mentioning that, as its N-Me analog15 and
unlike 1-methyl-1-phenyl-1-silacyclohexane,18 or 3-methyl-3-
phenyl-3-silathiane,18 the low temperature 13C NMR spec-
trum of compound 1 shows two clearly separated sets of all
aromatic signals (Figs. SI-1, SI-2 in Supplementary data)
with the ratio of intensities practically coinciding with that
determined from the low temperature and iterated 1H NMR
spectra (vide infra).
Both 1H and 13C NMR spectra of the azasilinanes 1 and 2 were
studied not only at the certain temperatures mentioned in Table 1
but between 273 K and 103 K in a freon mixture, which is still liquid
at the lowest temperatures; in Fig. 3 the variable temperature 13C
NMR study of 1-i-propyl-3-methyl-3-phenyl-1,3-azasilinane 1 is
given. Similar dynamic effects were obtained in the 1H NMR
spectrum of 1 and in the temperature variable 1H and 13C NMR
spectra of 2 (see Supplement). Both coalescence temperatures Tc
For compound 2 the equilibrium in Scheme 3 is degenerate:
under the conditions of fast exchange the time-averaged 1H NMR
spectrum is represented by 7 signals. Upon cooling down, the
equilibrium gets frozen and all methylene and methyl protons give
separate signals, the best resolved 1H NMR spectrum of 1-
isopropyl-3,3-dimethyl-1,3-azasilinane 2, again at 143 K, is given
in Fig. 2.
Proton chemical shifts at 273 K (when the ring inversion is fast
on the NMR time scale) and of the frozen conformational equilibria
at 143 K are given in Table 1. In addition, in Table 1 13C chemical
and chemical shift differences Dnc at Tc
trapolation from frozen spectra to Tc) were determined and
(Dnc as obtained by ex-
employed to calculate kc¼pDnc/O2 and via the Eyring equation
D
Gc#
at Tc.27 In case of 1 the population difference of the conformers
deviates from 1:1; the PheqMeax conformer is preferred (58.5%
beside 41.5% of the PhaxMeeq conformer) [K¼1.41;
D
Gꢀ¼ꢁRT
lnK¼0.1 kcal/mol]. Only clearly separated, non overlapping signal
pairs were employed for extraction the kinetic information about
the ring inversion and are given, together with the dynamic NMR
parameters, in Table 2.

B.A. Shainyan et al. / Tetrahedron 68 (2012) 7494e7501
7497
Fig. 3. 13C NMR dynamic NMR study of 1-isopropyl-3-methyl-3-phenyl-1,3-azasilinane 1 at various temperatures in the solvent mixture of CD2Cl2, CHFCl2, and CHF2Cl in a ratio of
1:1:3 at 150 MHz.
Table 2
(freon mixture at low temperature and CD2Cl2 at room temperature)
can be of influence as well but we expect it to contribute only minor.
Unequivocally, however, it can be concluded that within
Dynamic NMR study of the 1,3-azasilinanes 1 and 2
No.
1a
Signal studied
Tc/K
Dnc/Hz
kc
D
G#c /kcal/mol
D
Gꢀ¼
D
HꢀꢁT
D
Sꢀ the temperature dependence of the free energy
SieCH3 (ꢁ4.9 ppm)
C-5 (17.3 ppm)
C-2 (37.5 ppm)
SieCH3 (0.37 ppm)
Mean
SieCH3 (0.02 (ppm)
NeCH(CH3)2 (0.92 ppm)
Mean
188
195
181
180
527.5
1075
162.5
149
1172
2388
361
8.2
8.2
8.8
8.3
8.25
8.3
8.2
8.25
difference of the conformers of 1-isopropyl-3-methyl-3-phenyl-1,3-
azasilinane 1 is only minor and hereby the equilibrium is enthalpi-
cally controlled with minor entropy influence.
331
In order to prove independently the assignment of the con-
formers of 1 the ring current effect of the SiePh substituent in both
conformers on the ring protons was computed. For this purpose our
spatial NICS approach34 was employed. These through-space NMR
shieldings (TSNMRSs) can be visualized34 as iso-chemical-shielding
surfaces (ICSSs) and employed to quantify the anisotropic effects of
functional groups on proton chemical shifts (for determing the
stereochemisty of nuclei proximal to the functional group),35e46 to
separate the anisotropic effect of functional groups from the in-
fluence of steric hindrance on the same proton chemical shifts,47,48
and to visualize and quantify planar,49,50 spherical (anti)
aromaticity51e54 and chelatoaromaticity.55
On basis of the optimized geometries of the two conformers
PhaxMeeq and PheqMeax of 1 the TSNMRS values of the phenyl
substituent were calculated, visualized by ICCS of various size and
direction (cf. Fig. 4) and, finally, the corresponding ring current on
the ring protons at C-2 and C-4eC-6 was computed quantitatively.
2
173
173
60
72
133
160
a
D
Gꢀ¼ꢁRT lnK¼0.1 kcal/mol; 58.5% PheqMeax and 41.5% PhaxMeeq
.
Additionally, the proton NMR spectrum of 1-isopropyl-3-methyl-
3-phenyl-1,3-azasilinane 1 was iterated subject to the present con-
formational equilibrium at room temperature in CD2Cl2 on basis of
computed vicinal H,H coupling constants of the frozen conformers,
given in Table 3. The JH,H values can be successfully employed to
calculate the conformational equilibrium at room temperature in
3
CD2Cl2 [57.25e64.95 % and 35.05e42.75 % (mean values 61%:39%);
K¼1.56;
D
Gꢀ¼e0.3 kcal/mol], which is very similar to the free energy
difference at low temperature in the freon mixture [K¼1.41;
D
Gꢀ¼0.08 kcal/mol]. Unfortunately, the vicinal H,H coupling con-
stants in the two conformers are almost identical (cf. Table 3) and,
therefore, it cannot be decided, which one is the preferred conformer.
It can be suggested, considering our former experiences,18,28,29 the
The corresponding ring current effects (
anddfor deshielding) are given in Table 4 together with experi-
mental chemical shifts /ppm.
s/ppm, þ for shielding
less stable conformer of compound 1 at low temperature, PhaxMeeq
to be the preferred one at room temperature; different solvents
,
d
Critical comparison of the computed and experimental chemical
shift differences prove the correct assignment of the two con-
formers of 1: while proton chemical shifts of H-2 and H-4 are
dominated by other/additional effects and ring current effects on
the H-6 protons are too small, only (as expected) the protons H-5
can be employed. Both ring current effect as computed (Ds) and
chemical shift differences Dd of the protons are completely con-
gruent, and prove independently the correct assignment of the
NMR spectra of compound 2 (Table 4).
The barriers to ring inversion in the N-i-Pr-substituted 1,3-
azasilinanes 1, 2 (Table 2) are w0.8 kcal/mol lower than those in
their N-Me-substituted analogs, which were measured to be 9.0 kcal/
mol15 and 9.1 kcal/mol,14 respectively. Probably, this is due to slight
Table 3
Conformational analysis of 1-isopropyl-3-methyl-3-phenyl-1,3-azasilinane
1 at
room temperature employing PERCH30e33
3
3JH,H
Me(eq)/Ph(ax)a
Me(ax)/Ph(eq)a
exp. JH,H
% (1a)
% (1b)
4ax,5ax
4ax,5eq
4eq,5ax
4eq,5eq
5ax,6ax
5eq,6eq
Mean value
12.25
5.42
3.28
3.44
10.07
4.74
3.26
3.38
5.69
12.14
4.39
10.12
8.84
4.74
4.74
8.81
7.69
7.82
62.07
64.95
39.42
38.28
58.10
42.75
60.2
37.93
35.05
60.58
61.72
41.90
57.25
39.8
a
Computed at MP2/6-311G(d,p) level of theory.

7498
B.A. Shainyan et al. / Tetrahedron 68 (2012) 7494e7501
Fig. 4. Ring-current effect of the phenyl ring in the two conformers of 1-isopropyl-3-methyl-3-phenyl-1,3-azasilinane 1 on the ring protons (cf. Table 4) as ICSS of different direction
and size (blue represents 5 ppm shielding, cyan 2 ppm shielding, greenblue 1 ppm shielding, green 0.5 ppm shielding, yellow 0.1 ppm shielding, and orange ꢁ0.5 ppm and red
ꢁ0.1 ppm deshielding).
Table 4
substituents at silicon and that the effect of the presence and the
nature of the second heteroatom is negligible in spite of notable
variations of the CeZ bond length and the degree of the ring folding
for Z¼N, C or S in Scheme 4. Moreover, the effect of the substituent
at the second heteroatom (cf. Z¼NMe and N-i-Pr) may be even
larger than that of this heteroatom itself.
Ring current effect of Si-Phenyl on the ring protons in the two conformers of 1-
isopropylisopropyl-3-methyl-3-phenyl-1,3-azasilinane 1
Proton
Conformer/
d
(exp.)/ppm
Ring current effect/Ds/ppm
Ph(eq),
Me(ax)
Ph(ax),
Me(eq)
Dd/ppm
Ph(eq),
Me(ax)
Ph(ax),
Me(eq)
Ds/ppm
H(2ax)
H(2eq)
H(4ax)
H(4eq)
H(5ax)
H(5eq)
H(6ax)
H(6eq)
2.20
1.73
0.81
0.94
1.73
2.08
2.33
2.69
2.55
1.73
1.15
0.64
1.44
1.94
2.33
2.61
þ0.35
d
ꢁ0.225
ꢁ0.017
ꢁ0.21
ꢁ0.216
ꢁ0.162
ꢁ0.16
0.069
0.057
0.004
þ0.01
ꢁ0.14
þ0.06
þ0.02
þ0.2
X
þ0.34
ꢁ0.3
ꢁ0.29
ꢁ0.12
d
ꢁ0.040
ꢁ0.141
ꢁ0.095
ꢁ0.192
ꢁ0.104
Si
X
Y
Z
Si
Y
þ0.1
Z
ꢁ0.154
þ0.04
ꢁ0.03
ꢁ0.08
ꢁ0.131
Scheme 4.
In view of the aforementioned role of the Ph-axial confor-
mation in the ligand-receptor interaction2 the latter effect might
play a pivotal role in determining the biological activity of Si, N-
heterocycles. Since the experimental value of the equilibrium
constant in Scheme 4 decreases from 2 to 1.4 on going from
Z¼N-Me to N-i-Pr, the fraction of the Phax conformer may in-
crease upon further planarization of the nitrogen atom, thus
providing the synthetic chemists with a guide for the design of
new drugs.
planarization of the nitrogen atom for a branched alkyl group. The
MP2 calculated sum of the bond angles around nitrogen increases
from 330.7ꢀ in the N-Me-substituted 1,3-azasilinanes to 332.8ꢀ in
molecules 1, 2, irrespective of the substituents at silicon (vide infra).
The question that we put in the Introduction on how the relative
stability of the conformers of various silacyclohexanes is affected by
the second heteroatom in b-position to silicon suggests the analysis
of the following conformational equilibria.
Unfortunately, the available data are very limited and, for the
same substituents at silicon (X¼Ph, Y¼Me) are confined to
Z¼CH2,18 Z¼S,18 Z¼NMe,15 and Z¼N-i-Pr (this work), in all cases the
MeaxPheq conformer being predominant. The content of the con-
former with the equatorial phenyl group is 63% (Z¼CH2),18 68%
(Z¼S),18 67% (Z¼NHMe),15 and 58.5% (Z¼N-i-Pr, this work), which
corresponds to free energy differences close to 0.1 kcal/mol. For
other pairs of the substituents at silicon (Z¼CH2, X¼Me, Y¼F;56,57
Z¼CH2, X¼Me, Y¼CF3;56 Z¼S, X¼Me, Y¼F)57 the free energy dif-
ference is substantially larger. Therefore, the only conclusion to be
made is that the conformational equilibrium in silaheter-
ocyclohexanes is determined, first of all, by the nature of the
2.3. Theoretical calculations
Theoretical calculations proved that compounds 1 and 2 exist as
chair conformers with the equatorial NR group. For compound 1,
the NRax conformers are 3.06 (for 1a) or 3.36 kcal/mol (for 1b)
higher in energy than the corresponding NReq conformers, and for
compound 2 it is 3.62 kcal/mol at the MP2/6-311G(d,p) level of
theory. Therefore, as suggested above, for both compounds the
conformational equilibrium NRax%NReq is completely biased to the
NReq conformers. With this, conformers 2a and 2b in Scheme 2 are

B.A. Shainyan et al. / Tetrahedron 68 (2012) 7494e7501
7499
identical whereas conformers 1a and 1b are different in energy. All
calculations give the total energy of conformer 1a to be lower than
SiO2-60 F254 aluminum plates (visualization with iodine vapors).
Column chromatography was performed using Silica Gel SiO2-60,
230e400 mesh from ICN. Room-temperature 1H, 13C, and 29Si NMR
spectra were recorded on a Brucker DPX 400 spectrometer (1H,
400.1 MHz; 13C, 100.6 MHz; 29Si, 79.5 MHz). Chemical shifts (ppm)
of 1b,
DE being 1.81 (MP2), 0.84 (DFT) and 0.24 kcal/mol (HF).
Apparently, this is due to the intramolecular H-bond of one of the
ortho-protons with the nitrogen atom lying in the plane of the
phenyl ring (Fig. 5). Note, that practically the same structure was
obtained for the N-Me analog of 1a.15
were determined relative to residual CHCl3 (1H,
d
7.27, CDCl3), in-
ternal CDCl3 ( d d 0.00,
13C, 77.0, CDCl3), and external TMS (29Si,
CDCl3). The assignment of the 1H and 13C signals was made from the
j-mod and 2D{1He13C} NMR spectra at 298 K and 143 K.
Low-temperature 1H and 13C NMR spectra were recorded on
a Bruker AV-600 (at 600 and 150 MHz, respectively). Chemical shifts
were determined relative to residual internal CD2Cl2 ( d 53.73)
13C,
and are given in parts per million downfield to TMS. Analysis and
assignment of the 1H NMR data were supported by homonuclear
(COSY) and heteronuclear (HSQC 13Ce1H, HMBC 13Ce1H) 2D corre-
lation experiments. A solvent mixture of CD2Cl2, CHFCl2, and CHF2Cl
in a ratio of 1:1:3 was used for the low temperature measurements.
The probe temperature was calibrated by means of a thermocouple
PT 100 inserted into a dummy tube. The low temperature mea-
surements were estimated to be accurate to ꢂ2 K. The chemical
shifts difference Dnc, Hz was determined by extrapolation to the
lowest temperature available and used to calculate kc and the ring
inversion barriers by the Eyring equation at Tc.
Fig. 5. Orientation of the phenyl ring in the two conformers of 1-isopropyl-3-methyl-
3-phenyl-1,3-azasilinane 1.
However, the ratio of the conformers is determined by the free
Methylphenyl(chloromethyl)silane
(3a)
and
dimethyl(-
energy difference
conformers since the H-bonding lowers the entropy and, thus,
disfavors conformer 1a. As a result, the value of
Go calculated at
D
Gꢀ, which is expected to be different for the two
chloromethyl)silane (3b) were synthesized as described in the
literature.15,58,59
D
the B3LYP/6-311(d,p) level (the corresponding MP2 frequency cal-
culations are computationally too time-consuming) is 0.07 kcal/
mol in favor of conformer 1a, which is in excellent agreement with
the experimental value of 0.08 kcal/mol (vide supra). Taking into
account solvent effects using the PCM, as was shown on the ex-
ample of the N-Me analog of compound 1, cannot reverse the ratio
of the conformer in favor of the MeaxPheq conformer.15 Neither does
taking into account specific solvation by calculation of the solvate
complexes of 1a and 1b with chloroform. Whereas with conformer
4.1.1. (Allyloxy)trimethylsilane (4). (Allyloxy)trimethylsilane (4) was
prepared by silylation of allyl alcohol with 1,1,3,3-
hexamethyldisilazane in 89% yield by the known procedure.59 dH
(400 MHz; CDCl3; Me4Si): 0.15 (9H, s, CH3Si), 4.15 (2H, d t, 3J¼4.9 Hz,
4J¼1.6 Hz, OCH2), 5.11 (1H, d q, 3J¼10.3 Hz, 4J¼1.5 Hz, Hcis), 5.26 (1H,
d q3J¼17.1 Hz, 4J¼1.8 Hz, Htr), 5.94 (d d t, 3J¼17.1 Hz, 3J¼10.3 Hz,
3J¼5.1 Hz, 1Hgem). dC (100 MHz; CDCl3; Me4Si): ꢁ0.47 (CH3Si), 63.65
(OCH2), 114.49 (]CH2), 137.28 (CH]). dSi (79 MHz; CDCl3; Me4Si):
18.80.
ꢀ
1b chloroform forms the H-bond of 2.66 A length with the nitrogen
atom, with conformer 1a it forms the H-bond with the p-system of
4.1.2. Methylphenyl(chloromethyl)(3-trimethylsiloxypropyl)silane
(5a). A 0.1 M solution of H2PtCl6$6H2O in isopropyl alcohol
(0.05 mL) was added to a small portion of the mixture of (allyloxy)
trimethylsilane (6.51 g, 0.05 mol) and MePh(ClCH2)SiH (8.52 g,
0.05 mol) that resulted in an exothermic reaction, the temperature
increased to 65 ꢀC. The remaining portion of (allyloxy)trime-
thylsilane was added at 75 ꢀC, the reaction mixture heated at stir-
ring to 110 ꢀC, allowed to cool and the volatiles removed in vacuo.
The crude product (13.07 g, 87%) was used in next stage without
purification. dH (400 MHz; CDCl3; Me4Si): 0.11 (9H, s, Me3SiO), 0.43
(3H, s, MeSiC), 0.93 (2H, m, SiCH2C),1.62 (2H, m, CCH2C), 2.99 (1H, d,
2J¼13.7 Hz, SiCHACl), 3.04 (1H, d, 2J¼13.7 Hz, SiCHBCl), 3.56 (2H, t,
3J¼6.9 Hz CH2O), 7.39 (3H, m, Hm,p), 7.54 (2H, m, Ho). dC (100 MHz;
CDCl3; Me4Si): ꢁ6.35 (SiCH3), 8.31 (MeSiO), 15.23 (SiCH2C), 26.70
(SiCH2Cl), 29.13 (CCH2C), 65.35 (CH2O), 128.04 (Cm), 129.77 (Cp),
133.90 (Co), 135.01 (Ci). dSi (79 MHz; CDCl3; Me4Si): ꢁ2.51.
the axial phenyl ring, the HorthoeN hydrogen bond remains intact
ꢀ
being only somewhat elongated to 2.70 A.
3. Conclusion
1-Isopropyl-3-methyl-3-phenyl-1,3-azasilinane
1
and 1-
isopropyl-3,3-dimethyl-1,3-azasilinane 2 were synthesized and
studied experimentally by low temperature 1H and 13C NMR
spectroscopy down to 103 K, and theoretically at the DFT and MP2
levels of theory. The ratio of the two conformers of 1, PheqMeax
/
PhaxMeeq at low temperature of w60:40 confirms the difference
between silaheterocyclohexanes and their carbon analogs, for
which the PhaxMeeq conformers are more stable. The barrier for the
ring inversion of compounds 1 and 2 is 8.25 kcal/mol, that is,
w0.8 kcal/mol lower as compared to their N-Me-substituted ana-
logs. Such a decrease can be assigned to some planarization of the
nitrogen atom surrounding for a branched alkyl group, as proved by
theoretical calculations.
4.1.3. Dimethyl(chloromethyl)(3-trimethylsiloxypropyl)silane
(5b). Dimethyl(chloromethyl)(3-trimethylsiloxypropyl)silane (5b)
was prepared similar to 5a. dH (400 MHz; CDCl3; Me4Si): 0.11 (6H, s,
Me2Si), 0.12 (9H, s, Me3SiO), 0.62 (m, 2H, SiCH2C), 1.56 (2H, m,
4. Experimental section
3
CCH2C), 2.79 (2H, s, SiCH2Cl), 3.54 (2H, t, J¼6.9 Hz, CH2O).
4.1. Synthesis and NMR study
4.1.4. Methylphenyl(chloromethyl)(3-hydroxypropyl)silane (6a). A
mixture of crude 5a (13.00 g, 43 mmol), MeOH (15 mL), H2O
(2.5 mL) and 2 drops of conc. HCl was heated at reflux for 0.5 h.
Then reaction mixture was taken in H2O (40 mL) and extracted
with diethyl ether (2ꢃ15 mL). The organic extract was dried over
MgSO4 and concetrated in vacuo. The product was purified by
Reagents were purchased from commercial sources and used
without further purification. Solvents were freshly distilled from the
appropriate drying agents immediately before use (diethyl ether,
sodium benzophenone ketyl; benzene, methylene chloride, meth-
anol, CaH2). Thin layer chromatography (TLC) was performed on

7500
B.A. Shainyan et al. / Tetrahedron 68 (2012) 7494e7501
column chromatography using eluents with increasing polarity
from hexane to Et2O to give the title compound as a colorless oil
(6.70 g, 59% yield calculated on the initial hydrosilane). dH
(400 MHz; CDCl3; Me4Si): 0.44 (3H, s, MeSi), 0.98 (2H, m, SiCH2C),
1.65 (3H, m, CCH2CþOH), 3.00 (1H, d, 2J¼13.7 Hz, SiCHACl), 3.05
(1H, d, 2J¼13.7 Hz, SiCHBCl), 3.63 (2H, t, 3J¼6.6 Hz, CH2O), 7.41
(3H, m, Hm,p), 7.55 (2H, m, Ho). dC (100 MHz; CDCl3; Me4Si): ꢁ6.35
(SiCH3), 8.29 (SiCH2C), 26.70 (SiCH2Cl), 29.14 (CCH2C), 65.37
(CH2O), 128.04 (Cm), 129.78 (Cp), 133.90 (Co), 134.99 (Ci). dSi
(79 MHz; CDCl3; Me4Si): 2.51. Found: C, 57.44; H, 7.67; Si, 12.36;
Cl, 15.31%. C11H17SiOCl requires C, 57.74; H, 7.49; Si, 12.28; Cl,
15.50.
(79.5 MHz; CDCl3; Me4Si): ꢁ6.75. Found: C 63.12; H 12.44; Si 16.42;
N 7.97%. C9H21SiN requires C 63.08; H 12.36; Si 16.39; N 8.17%.
4.2. Theoretical calculations
The geometry of the conformers was optimized at the MP2 and
DFT (B3LYP) level of theory with the 6-311G(d,p) basis set. No re-
strictions on the variation of geometric parameters were imposed
during the optimization procedure. Vibrational calculations were
performed at the B3LYP/6-311G(d,p) level, unscaled ZPE corrections
were used. All calculations were performed with the Gaussian 09
computational program.62
4.1.5. Dimethyl(chloromethyl)(3-hydroxypropyl)silane
(6b). Dimethyl(chloromethyl)(3-hydroxypropyl)silane (6b) was
prepared similar to 6a in 54% yield. A crude product was chroma-
tographed on silica gel using eluents with increasing polarity from
hexane to Et2O to afford (6b) as a colorless oil (2.00 g, 54%) dH
(400 MHz; CDCl3; Me4Si): 0.14 (6H, s, Me2Si), 0.67 (2H, m, SiCH2C),
1.61 (2H, m, CCH2C), 1.78 (1H, br s, OH), 2.80 (2H, s, SiCH2Cl), 3.62
(2H, t, 3J¼6.7 Hz, CH2O). dC (100 MHz; CDCl3; Me4Si): ꢁ4.72 (SiCH3),
9.36 (SiCH2C), 26.66 (SiCH2Cl), 30.12 (CCH2C), 65.36 (CH2O). dSi
(79 MHz; CDCl3; Me4Si): 4.23. 1H NMR data are consistent with
reported those reported earlier.59
Acknowledgements
The financial support of this work by the Russian Foundation for
Basic Research and Deutsche Forschungsgemeinschaft (Grant
RFBR-DFG No. 11-03-91334) is greatly acknowledged. We thank Dr.
Alexander Albanov (Irkutsk), Dipl.-Ing (FA) Angela Krtitschka and
Dr. Matthias Heydenreich (University of Potsdam) for recording and
analysis of the NMR spectra.
Supplementary data
Supplementary data containing additional NMR spectra of
compound 1 and 2, and the results of calculation of various con-
formers of 1 and 2 may be found in the online version of this article.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.05.106.
4.1.6. Methylphenyl(chloromethyl)(3-chloropropyl)silane
(7a). Methylphenyl(chloromethyl)(3-chloropropyl)silane (7a) was
prepared by chlorination of the above product 6a using the de-
scribed procedure.60,61 A mixture of 6a (2.4 g, 10.5 mmol), triphe-
nylphosphine (2.59 g, 11.6 mmol) and CCl4 (15 mL) was refluxed for
8 h, then cooled to room temperature and n-pentane (30 mL) was
added. The precipitate formed was filtered off, the filterate con-
centrated in vacuo, the residue purified by column chromatography
on silica gel (63e230 mesh, Gerudan) with n-hexane as an eluent.
The relevant fractions were combined and the solvent removed
under reduced pressure to give the product (1.221 g, 47%) as a col-
orless oil. 1H and 13C NMR spectra coincide with those reported by
us earlier.15
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