Towards the synthesis of 3-silapiperidines

Article abstract of DOI:10.1002/ejoc.200801197

A straightforward and unprecedented method towards the synthesis of 3-silapiperidines is described. The key step involves a formal double nucleophilic substitution reaction between the (bromomethyl)dimethylsilyl chloride and a N,C- sp²-1,4-dian

Full text of DOI:10.1002/ejoc.200801197

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200801197
Towards the Synthesis of 3-Silapiperidines
Christophe Blaszykowski,[a] Célia Brancour,[a] Anne-Lise Dhimane,*[a] Louis Fensterbank,*[a]
and Max Malacria*[a]
Dedicated to Professor Alain Krief
Keywords: Nucleophilic substitution / Silacycles / Diastereoselectivity / Isomerization / Dianions
A straightforward and unprecedented method towards the
synthesis of 3-silapiperidines is described. The key step in-
volves a formal double nucleophilic substitution reaction be-
tween the (bromomethyl)dimethylsilyl chloride and a N,C-
sp2-1,4-dianionic species generated from N-monoprotected
allylamines. Subsequent functionalizations are also pre-
sented.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Results and Discussion
We first investigated the formation of 3-silapiperidine 1
from allyl–vinylsilane 2 using a ring closing metathesis
(RCM) reaction as the key step (Scheme 2).
Over the last two decades silacycles have received a par-
ticular attention.[1] Their preparation has often provided the
occasion to study the reactivity and to prove the existence,
even transient, of highly reactive and hardly characterizable
species such as silenes (R2Si=CH2, alkene sila analogues)
or silylenes (R2Si, carbene sila analogues). Further motiva-
tion was the desire to obtain sila derivatives possessing
interesting and possibly original chemical,[2] physical[3] or
biological[4] properties, relative to their carbon analogues.[5]
This synthetic effort provided a large variety of silacycles,
but, quite surprisingly, only a limited number of 3-silapiper-
idines I and II (Scheme 1) have been reported in the litera-
ture over the last half-century.[6] Herein, we report a new
first synthesis of a 3-silapiperidine of type II and its subse-
quent functionalization.
Scheme 2.
Allyl–vinylsilane 2 unfortunately did not undergo the ex-
pected RCM to any extent under any attempted conditions
of catalyst, solvent or temperature. In the best case, the only
generated products were diastereomeric enamines (Z)-3 and
(E)-3, along with unreacted precursor 2 (Table 1). The re-
ported relative percentages calculated from the crude 1H
NMR spectra (Entries 1,2 and 4–6) correspond to the con-
version of precursor 2 into enamines (Z)-3 and (E)-3 as well
as to its unreacted form. Gratifyingly, both enamines could
be isolated separately (Entry 3), and their respective config-
urations undoubtedly determined.
The generated enamines (Z)-3 and (E)-3 resulted from
the isomerization of the allyl moiety of precursor 2, its
vinylsilane part remaining apparently untouched during the
process. Interestingly, this isomerization process proved to
be diastereoselective towards enamine (Z)-3, as shown by
Scheme 1.
[a] Université Pierre et Marie Curie - Université Paris 06, Labora-
toire de chimie organique (UMR CNRS 7611), Institut de chi-
mie moléculaire (FR 2769), Tour 44-54, case 229,
4 place Jussieu, C. 229, 75005 Paris, France
Fax: +33-1-44277360
the characteristic double bond coupling constant (Jcis
=
8.3 Hz) obtained for this major diastereomer [a Jtrans coup-
ling constant of 20.2 Hz was measured for the minor dia-
stereomer (E)-3]. In all these reactions, it is believed that a
ruthenium hydride species, generated from the catalyst and
compound 2, triggers the isomerization process with high
E-mail: max.malacria@upmc.fr
louis.fensterbank@upmc.fr
anne.dhimane@upmc.fr
1674
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1674–1678

Towards the Synthesis of 3-Sila-Piperidines
Table 1. Attempted RCM reactions.
amines and by the reported reactivity of (bromomethyl)di-
methylsilyl chloride (BMDMSCl) as a 1,2-dielectrophile
(Scheme 4).[15]
Entry Catalyst
Solvent
T, t [h]
Relative% (Z)-3 / (E)-3 / 2
1
2
3
4
5
6
Grubbs I
Grubbs I
Grubbs I
Grubbs I
Grubbs II CH2Cl2
Schrock PhH
CH2Cl2
PhH
PhH
r.t., 22
r.t., 24
reflux, 1
reflux, 18
reflux, 18
r.t., 24
18 / – / 82
3 / – / 97
75 / 10 / –[a]
25 / 75 / –
5 / 25 / 70
Ͻ1 / – / Ͼ99
PhH
[a] Isolated yields.
Scheme 4.
Z diastereoselectivity.[7–9] On the other hand, refluxing con-
ditions and prolonged reactions times would promote the
formation of the E isomer (Entries 3 and 4).
Indeed, under the action of 2 equiv. of a strong base,[16]
N-monoprotected allylamines (N-alkyl, -silyl or -phenyl)
have been shown to form dianionic species of type C.[17]
While the first deprotonation occurs at the nitrogen (most
acidic) site, the second one occurs regioselectively at the ter-
minal position of the double bond.
More importantly, this second deprotonation has been
shown by X-ray analysis[17] to be completely stereoselective
since only the Z-terminal proton is abstracted.[16a,16d,17,18]
Additionally, these dianionic species have proven to ef-
ficiently react with electrophiles to form a large variety of
heterocycles.[16,18,19] BMDMSCl, on the other hand, has
been shown to be an excellent 1,2-dielectrophilic partner for
the formation of sila heterocycles, although reports in the
literature remain sporadic[20,5a,5b] We therefore anticipated
that combination of both the dianionic chemistry of N-
monoprotected allylamines and the 1,2-dielectrophilic prop-
erty of BMDMSCl would constitute a powerful synthetic
tool for the preparation of 3-silapiperidines.
We initially tested our strategy on N-phenylallylamine
(4). Gratifyingly, upon treatment with 2.0 equiv. of nBuLi
at room temperature for 24 h[16] and after trapping of the
generated dianion[21] with BMDMSCl at –78 °C, we were
effectively able to isolate the targeted 3-silapiperidine 5 with
an encouraging yield of 30% (Table 2, Entry 1). We also
recovered 30% of the starting amine 4. Interestingly, when
BMDMSCl was added at 0 °C, the yield increased to 52%,
and the recovery of the starting material was only 18% (En-
try 2). Finally, addition of BMDSMCl at room tempera-
ture, with tBuli as a base, allowed us to even further im-
In order to explain the observed reactivity and to ratio-
nalize why the expected RCM did not or could not occur,
we first hypothesized that the (dimethyl)vinylsilane moiety
was too sterically demanding for the RCM to take place.
Unfortunately, although (methyl)vinylsilanes have indeed
been reported on several occasions to remain inert towards
first generation Grubbs’ catalyst,[10] they have also been
shown to efficiently react through RCM with both second
generation Grubbs’[10c] and Schrock’s[10a,10b] catalysts under
mild conditions.
We then hypothesized that the inability of allyl–vinyl-
silane 2 to undergo RCM simply reflects the physical im-
possibility for the metathesis partners to interact, and we
proposed the existence of intramolecular coordination phe-
nomena occurring within precursor 2 (Scheme 3). These
would be responsible for the formation of rigid conforma-
tions, in which both metathesis partners are too far apart
to react together. As a consequence, the isomerization of
the pendant allyl moiety would then become the beneficiary
process.
Scheme 3.
The proposed intramolecular coordination phenomena prove the yield to 70% (Entry 3).[22] Unfortunately, no other
involves the silicon and the carbonyl oxygen atoms tested N-monoprotected allylamine was as successful; either
(Scheme 3). This type of interaction has already been estab- lower yields (N-p-methoxyphenyl) or side-products [N-
lished by X-ray analyses.[11] This spatial disposition is in- TBDMS, N-(S)-α-methylbenzyl or N-tosyl] were obtained
deed favoured since it simultaneously involves a five-mem- or they did not react (N-Me or N-trityl).
bered chelate, a strong oxygen–silicon interaction[12] and a
pentavalent silicon atom – a situation that is particularly cleophilic substitution reaction (Scheme 5). In a first step
favourable.[13]
(I), the vinylic anion, the most nucleophilic part of dianion
The proposed mechanism relies on a formal double nu-
At this point, we then decided to turn our attention to an C, reacts with the most electrophilic BMDMSCl site (the
alternative strategy. The latter was inspired by the dianionic silicon atom[5]) to give intermediary D. Final intramolecular
chemistry[14] recently developed on N-monoprotected allyl- nucleophilic substitution (II) ultimately gives rise to 5.
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A.-L. Dhimane, M. Malacria et al.
Table 3. Deprotonation/alkylation of 5.
SHORT COMMUNICATION
Table 2. Formation of 3-silapiperidine 5.
Entry Base
T [°C], t [h]
Yield in 5 [%] Recovery of 4 [%]
1
2
3
nBuLi
nBuLi
tBuLi
–78 then r.t., 12 30
30
18
–
0 then r.t., 2
r.t., 0.5
52
70
Scheme 5.
Finally, we turned our attention to the functionalization
of 3-silapiperidine 5. Besides preparing derivatives, we inci-
dentally wanted to develop access to sila analogues of bio-
logical interest. Our strategy consisted of treating 5 with
1 equiv. of base and then intercepting the resulting expected
delocalized anion E[23,24] with an electrophilic species
(Table 3).
Upon treatment with 1 equiv. of tBuLi followed by hy-
drolysis with D2O, 3-silapiperidine 5 regioselectively led to
its 4-deuterated enamine derivative 6 (Entry 1). The same
regioselectivity is observed for compound 7 when 5 is suc-
cessively treated with tBuLi followed by chlorodimethylsil-
ane (Entry 2). Furfuraldehyde and benzaldehyde also ef-
ficiently undergo reaction to provide β-aminoalcohols 8
and 9 in 60 and 75% yields and as 7:3 and 6:4 mixtures of
diastereomers, respectively (Entries 3 and 4). In these cases,
proximal regioselectivity (α to the nitrogen atom) was ob-
served. Unfortunately, methyl chloroformate only afforded
α-aminoester 10 in a low yield of 16% (Entry 5). Neverthe-
less, this compound constitutes an interesting candidate for
the preparation of sila analogues of pipecolic acid, a mole-
cule of biological interest.[26]
[a] Deuterium regioselective incorporation determined by NMR
spectroscopy. [b] NMR yield. [c] Undetermined stereochemistries.
[d] The reverse addition of anion E to ClCO2Me was necessary.[25]
Interestingly, when THF is replaced by ethyl ether for the
anion formation step, tBuLi or nBuLi do not act as bases
but as nucleophiles and give rise to alkylated products 11
and 12 (Scheme 6).
At this stage it is difficult to rationalize the observed re-
gioselectivities, as well as to correlate them with the few
closely reported studies. Indeed, studies on α-silyl anions
suggest that the regioselectivity is dependent on the size of
the silyl substituents, the size of the electrophile or its na-
Scheme 6.
Finally, the saturated 3-silapiperidine 13 was generated
ture.[27] Moreover, the alkylation of 3-silyl enamines gives upon hydrogenation of 3-silapiperidine 5 with palladium on
only α-silyl alkylated products.[28]
charcoal (Scheme 7).
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Towards the Synthesis of 3-Sila-Piperidines
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Scheme 7.
Conclusions
In conclusion, we have reported an interesting and
straightforward method towards the synthesis of unprece-
dented 3-silapiperidines. Our strategy relies on a formal
double nucleophilic substitution reaction involving a N,C-
sp2-1,4-dianionic species generated from N-monoprotected
allylamines and takes advantage of the remarkable but yet
underexploited 1,2-dielectrophilic properties of (bro-
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Acknowledgments
[7]
Financial support from CNRS, UPMC and IUF is gratefully ac-
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1677

A.-L. Dhimane, M. Malacria et al.
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SHORT COMMUNICATION
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a
stirred solution of N-phenylallylamine (4, 2.9 mL, 20 mmol,
1.0 equiv.) in freshly distilled Et2O (50 mL) was added dropwise
freshly titrated tBuLi (1.48 , 27 mL, 40 mmol, 2.0 equiv.) at
–78 °C. After the addition, the reaction mixture was slowly
warmed to 0 °C, after which BMDMSCl (3.4 mL, 24 mmol,
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MgSO4, filtered and evaporated in vacuo. Purification was
achieved by flash column chromatography on silica gel (PE/
Et2O gradient). A pale yellow oil was obtained. Yield: 2.89 g
(70%). 1H NMR (CDCl3, 400 MHz): δ = 7.26 (m, 2 H, m-Ph),
6.97 (m, 2 H, o-Ph), 6.82 (m, 1 H, p-Ph), 6.74 (m, 1 H, CH2–
CH=CH–Si), 5.91 (m, 1 H, CH2–CH=CH–Si), 3.80 (br. s, 2 H,
CH2–CH=CH–Si), 2.80 (s, 2 H, N–CH2–Si), 0.17 (s, 6 H,
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129.1, 125.6, 118.9, 116.6, 53.3, 40.4, –2.4 ppm. IR (neat): ν =
˜
3080, 3060, 3022, 1596, 1245, 1208, 845 cm–1. MS (CI NH3):
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Received: December 1, 2008
Published Online: March 5, 2009
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