Copper-catalyzed silylation of cyclopropenes using (trifluoromethyl) trimethylsilane

Article abstract of DOI:10.1039/b717568j

A variety of cyclopropenes undergo direct silylation using (trifluoromethyl)trimethylsilane in the presence of a copper-bisphosphine catalyst; under these conditions, cyclopropenes that might otherwise undergo ring-opening are silylated efficiently. The Royal Society of Chemistry.

Full text of DOI:10.1039/b717568j

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COMMUNICATION
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Copper-catalyzed silylation of cyclopropenes using
(trifluoromethyl)trimethylsilanew
Euan A. F. Fordyce,a Yi Wang,a Thomas Luebbersb and Hon Wai Lam*a
Received (in Cambridge, UK) 13th November 2007, Accepted 10th December 2007
First published as an Advance Article on the web 8th January 2008
DOI: 10.1039/b717568j
A variety of cyclopropenes undergo direct silylation using
(trifluoromethyl)trimethylsilane in the presence of a copper–
bisphosphine catalyst; under these conditions, cyclopropenes
that might otherwise undergo ring-opening are silylated
efficiently.
ð1Þ
ð2Þ
Cyclopropenes have attracted much interest from
synthetic chemists for many years.1 Due to their significant
ring strain, cyclopropenes undergo a range of unique trans-
formations that represent enabling methodologies for organic
synthesis.1 For example, the alkene protons of cyclopropenes
are relatively acidic (pKa B 30),2 allowing deprotonation and
subsequent functionalization using strong bases. By under-
going addition reactions across the double bond,1d they serve
as precursors to functionalized cyclopropanes, which are con-
stituents of many biologically important compounds.3
In addition, conformational constraints imposed by the rigid-
ity of the three-membered ring make cyclopropenes excellent
candidates for the development of new diastereo- and
enantioselective reactions. As a result of these features,
new methods to construct and functionalize cyclopropenes
continue to be of value.
The first method often suffers from low efficiencies, requiring
an excess of alkynylsilane relative to the diazo compound for
acceptable results.8 Although the second method works effi-
ciently in many cases, it is often incompatible with base-
sensitive functionality that is present on the cyclopropene.
For example, anion-stabilizing substituents such as esters may
promote undesired ring-opening (Scheme 1).9a
Scheme 1 Ring-opening of cyclopropenyl lithium species.
While this problem may be overcome in certain cases by
using an inverse addition procedure,9b or by employing free
carboxylic acids in place of esters,10 the development of a
direct silylation process that proceeds under mild reaction
conditions using an operationally simple protocol would be
of utility. In this communication, we demonstrate that
trimethylsilylation of cyclopropenes may be accomplished
using (trifluoromethyl)trimethylsilane in the presence of a
copper–bisphosphine catalyst.
Cyclopropenes that contain a silyl substituent on the
alkene are important synthetic intermediates. For example,
they can serve as precursors to allenylsilanes through
photochemical rearrangement.4 Trimethylsilyl groups can
efficiently control the regioselectivity of transformations such
as cyclopropene carbometalation5 and Pauson–Khand
reactions.6 Gevorgyan and co-workers have recently
described the use of 1-silylcyclopropenes in sila-Morita–
Baylis–Hillman reactions.7 Since silyl groups are readily
removed from the double bond of cyclopropenes with fluoride
or hydroxide/alkoxide ions, they can also serve as protecting
groups for the olefin protons. Common methods used to
construct 1- or 2-silyl-substituted cyclopropenes include cyclo-
propenation of an alkynylsilane eqn (1), and silylation of a
cyclopropenyl lithium species eqn (2).
We surmised that a milder cyclopropene silylation proce-
dure might be realized by identification of conditions to
generate softer, less basic cyclopropenyl metal species, which
we hoped would react with a suitable silylating agent. On the
basis that cyclopropenes often possess ‘‘alkyne-like’’ reactivity,
and that metalation of terminal alkynes may be achieved using
combinations of weak bases and soft Lewis acids,11–13 we
elected to examine reaction conditions based on the use of
copper,11 zinc,12 and silver13 salts. With the hope of simplifying
the experimental procedure, we decided to eschew more con-
ventional silylating reagents such as silyl chlorides or triflates
(where an additional stoichiometric base is required) in favor of
those that contain a functional group that could also function
as the base to effect deprotonation of the cyclopropene.
Our initial experiments began with cyclopropene 1a
(Table 1), which upon attempted silylation using LDA and
TMSCl provided a complex mixture of products. Using
commercially available N,N-dimethyltrimethylsilylamine as
a School of Chemistry, University of Edinburgh, Joseph Black
Building, The King’s Buildings, West Mains Road, Edinburgh, UK
EH9 3JJ. E-mail: h.lam@ed.ac.uk; Fax: +44 (0)131 650 6453;
Tel: +44 (0)131 650 4831
b F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4070 Basel,
Switzerland
w Electronic supplementary information (ESI) available: Experimental
procedures, full spectroscopic data for all new compounds, copies of
NMR spectra, and details of 19F NMR, EPR, and cyclic voltammetry
experiments. See DOI: 10.1039/b717568j
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the silylating agent14 and 5 mol% of CuI in toluene at room
temperature, none of the desired product 2a was observed
(entry 1). Instead, complete conversion into furan 3 took
place, which has precedence in the work of Ma and Zhang.15
The use of Cu(acac)2, AgOAc, or Zn(OTf)2 led only to varying
quantities of furan 3 and aldehyde 416 in low to moderate
conversions (entries 2–4). Changing the silylating agent to
(trifluoromethyl)trimethylsilane17 also afforded no product
using Cu(acac)2 (entry 5). However, we were gratified to
observe that the combination of 5 mol% of Cu(acac)2 and
dppe18 provided the desired product 2a in an encouraging
40% yield (entry 6), the remainder of material being unreacted
1a. Switching the solvent to THF increased the yield of 2a to
88% (entry 7). A control experiment performed in the absence
of Cu(acac)2 demonstrated that both copper and dppe are
required for reaction to occur (entry 8).
Table 1 Identification of optimum reaction conditions for silylation
of cyclopropene 1aa
Fig. 1 Direct silylation of assorted cyclopropenes. Unless otherwise
stated, reactions were conducted using 0.20 mmol of cyclopropene,
0.01 mmol of Cu(acac)2 and 0.01 mmol of dppe in THF (0.7 mL).
Cited yields are of isolated material. a Yield in parentheses refers to a
reaction conducted using 2.0 mmol of 1d, 0.10 mmol of Cu(acac)2 and
0.10 mmol of dppe in THF (7 mL).
Metal/ligand
(5 mol% of each)
TMSX
(2 equiv.)
Yield
of 2a (%)b
Entry
Solvent
To gain some insight into these reactions, the silylation of
deuterated cyclopropene 5 (eqn (3)) was followed by 19F NMR
spectroscopy (Fig. 2).w As the reaction proceeded, a new signal
appeared at ꢁ80 ppm (t, JFD = 12.1 Hz), showing that DCF3
was formed. Since substrate 5 was the only source of deuter-
ium in the system, this observation suggests that at some stage
a trifluoromethide species abstracted a deuteron from the
substrate.
1
2
3
4
5
6
7
8
a
CuI
Cu(acac)2
AgOAc
Zn(OTf)2
Cu(acac)2
Cu(acac)2/dppe
Cu(acac)2/dppe
dppe
TMSNMe2
TMSNMe2
TMSNMe2
TMSNMe2
TMSCF3
TMSCF3
TMSCF3
TMSCF3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
0c
0d
0e
0e
0 (SM)
40
88
THF
0 (SM)
Reactions were conducted using 0.20 mmol of 1a in 0.7 mL of
b
c
solvent. Isolated yield. Complete conversion into furan 3 was
d
e
observed. Ca. 72% of 3 and 8% of 4 was observed. Ca. 20% of
was observed. dppe 1,2-bis(diphenylphosphino)ethane.
SM = starting material.
4
=
ð3Þ
Having established satisfactory reaction conditions
with cyclopropene 1a, we proceeded to explore the scope of
the direct silylation process with a range of other 1,3,3-
trisubstituted cyclopropenes (Fig. 1). Analogues of 1a
containing other aromatic or alkyl substituents on the alkene
successfully underwent silylation to provide silylcyclopropenes
2b–2e in 69–99% yield. Replacement of one of the
methyl esters at the 3-position with an aryl substituent, or
both of the methyl esters with ethyl esters was also tolerated,
leading to silylcyclopropenes 2f–2j in 66–84% yield.19
The efficiencies of these reactions are not markedly affected
upon increasing the scale. For example, cyclopropene 2d
was formed in 99% and 93% yields on 0.20 and 2.00 mmol
scales, respectively.
Fig. 2 19F NMR spectrum of the silylation of deuterated cyclo-
propene 5 (eqn (3)).
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The production of DCF3 was also accompanied by the
formation of HCF3 (eqn (3)), which most likely resulted from
reaction of a trifluoromethide species with trace moisture
present in the mixture. EPR and cyclic voltammetry experi-
ments suggest that copper largely retains the +2 oxidation
state in these reactions,w though we cannot exclude the
possibility that the active catalytic species is a Cu(I) complex
that exists as a minor component. With the information
currently available, speculation about the exact nature of the
mechanism of these reactions would be premature. Although
on the basis of our original hypothesis (vide supra) it is
tempting to suggest the involvement of bisphosphine-ligated
copper–trifluoromethyl complexes (that give rise to cyclopro-
penyl copper species that then undergo silylation with
TMSCF3), alternative mechanisms involving electrophilic si-
lylation14 or hypervalent silicon intermediates17a cannot be
excluded. A clearer picture of the mechanism of these reac-
tions therefore awaits further investigations.
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In summary, we have developed a new method for the direct
silylation of cyclopropenes that employs TMSCF3 as the
silylating agent in conjunction with substoichiometric quan-
tities of Cu(acac)2 and dppe. These reactions take place under
operationally more convenient conditions than traditional
silylation procedures, and do not require the use of strong
alkyl lithium or alkali metal amide bases which may affect
base-sensitive functionality. Studies to broaden the scope of
the process,19 and further applications of this methodology
will be the subjects of future reports from this laboratory.
This work was supported by the University of Edinburgh,
EaStCHEM (The Edinburgh and St. Andrews Research
School of Chemistry), F. Hoffmann-La Roche, and the
EPSRC. The EPSRC National Mass Spectrometry Service
Centre at the University of Wales, Swansea, is thanked for
providing high resolution mass spectra. We thank Ross J.
Gordon, Keri L. McCall, and Dr Ganesh Venkatachalam at
the School of Chemistry, University of Edinburgh, for assis-
tance with EPR and cyclic voltammetry experiments. We also
thank Dr Josef Schneider at F. Hoffmann-La Roche for
assistance with 19F NMR experiments.
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with cyclopropene 1a (possibly promoted by metal salt) to form an
intermediate cyclopropyldimethylamine, which then undergoes
ring-opening to provide an iminium ion/enamine that is hydro-
lyzed upon work-up.
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¨
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silylated in lower yields. For a study of the effect of substituents
at the 3-position on the HOMO and LUMO energies of cyclopro-
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1126 | Chem. Commun., 2008, 1124–1126